thc

Query 1. Query

Query

Results

Date

RX.PXRN=4354308

101 reactions in Reaxys

2018-07-07 10h:47m:43s (UTC)

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O

O H

N H OH

H

H

O

H

O

Rx-ID: 24898064 View in Reaxys 1/101 Yield

Conditions & References A sample of the purified benzyl carbamate derivative (0.20 g, 0.447 mmol) was combined with K2CO3 (0.33 g, 2.4 mmol), 3 mL of water and ethanol (added until a homogeneous solution was obtained). The reaction mixture was stirred at ambient temperature for 16 h until deemed complete as indicated by TLC (9:1 hexane:EtOAc). The reaction mixture was adjusted to pH7 with saturated ammonium chloride. The solution was concentrated and purified by column chromatography (using 95:5 hexane:EtOAc as the eluent) to give 0.134 g (95percent yield) of dronabinol (98.6percent a/a HPLC purity).

With water, potassium carbonate in ethanol, Time= 16h, T= 20 °C Patent; Field, Jason Edward; Oudenes, Jan; Gorin, Boris Ivanovich; Orprecio, Ricardo; Souza, Fabio Eduardo Silva e; Ramjit, Navindra Jainarine; Moore, Emma-Louise; US2006/264647; (2006); (A1) English View in Reaxys

O

O

OH

O

H

Mg

I H

O

O

Rx-ID: 39259639 View in Reaxys 2/101 Yield

Conditions & References Stage 1: in diethyl ether, T= 0 °C , Inert atmosphere Stage 2:Time= 0.833333h, T= 160 °C , p= 112.511Torr , Inert atmosphere Stage 3: With magnesium sulfate, zinc dibromide in dichloromethane, Time= 4h, T= 20 °C , Inert atmosphere Schafroth, Michael A.; Zuccarello, Giuseppe; Krautwald, Simon; Sarlah, David; Carreira, Erick M.; Angewandte Chemie - International Edition; vol. 53; nb. 50; (2014); p. 13898 - 13901; Angew. Chem.; vol. 126; nb. 50; (2014); p. 14118 - 14121,4 View in Reaxys Stage 1: in diethyl ether, Time= 0.5h, T= 0 - 20 °C , Inert atmosphere Stage 2:Time= 2h, T= 160 °C , p= 112.511Torr Stage 3: With magnesium sulfate, zinc dibromide in dichloromethane, Time= 8h, T= 20 °C Shultz, Zachary P.; Lawrence, Grant A.; Jacobson, Jeffrey M.; Cruz, Emmanuel J.; Leahy, James W.; Organic Letters; vol. 20; nb. 2; (2018); p. 381 - 384 View in Reaxys

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OH

OH H

H

OH

O

Rx-ID: 338559 View in Reaxys 3/101 Yield

Conditions & References 5.8.8 :A solution of 15.0 g (47.8 mmol) of the crystallized (-)-CBD (3a) in anhydrous dichloromethane (45 mL) was added dropwise over 1 hour to a stirred solution of BF3-Et2O (8.4 g, 59.2 mmol) in anhydrous dichloromethane (180 mL) at -1O0C under an Ar atmosphere. The mixture was stirred for 2 hours at -100C and poured into ice water (100 g). The resultant biphasic mixture was further stirred for 20 minutes at 00C. The resultant organic phase was collected, washed with cold water (50 mL), 7 percent aqueous sodium bicarbonate (50 mL), and water (50 mL). The organic phase was dried with Na2SO4 and filtered. The resultant filtrate was concentrated under reduced pressure at 40°C to provide trans-(-)-Δ9-THC (Ia) as a yellow oil. Yield: 14.9 g, 99percent. Analysis (CG) of the product indicated that it contained 81.9percent of trans-(-)-Δ9-THC (Ia).

With boron trifluoride diethyl etherate in dichloromethane, Time= 3h, T= -10 - 0 °C , Product distribution / selectivity Patent; EURO-CELTIQUE S.A.; WO2006/53766; (2006); (A1) English View in Reaxys 4 : Step 4: Cyclization, Synthesis of Delta-9-THC Step 4: Cyclization, Synthesis of Delta-9-THC: (0212) 50 g of pure cannabidiol are dissolved in 250 g methyl-tert-butylether and 40 g of boron trifluoride*acetic acid complex are added under stirring within 10 min at ca. 22° C. It is stirred for 3 h at said temperature and then 200 g of ice water are added, the organic phase is washed with sodium bicarbonate solution and the solvent is removed using a rotary evaporator. The remaining raw material of ca. 50 g contains 74percent Δ-9-tetrahydrocannabinol (delta-9-THC), 25percent of side products as well as <1percent cannabidiol. After purification by column chromatography, 30 g of pure delta-9-THC are obtained, which corresponds to a theoretical yield of 60percent.

With borontrifluoride acetic acid in tert-butyl methyl ether, Time= 3.16667h, T= 22 °C Patent; SYMRISE AG; Koch, Oskar; Götz, Marcus Rudolf; Looft, Jan; Vössing, Tobias; US2015/336874; (2015); (A1) English View in Reaxys 5.8.8 :A solution of (+)-p-mentha-2,8-dien-l-ol(84.5 g, 0.56 mol) in dichloromethane (325 mL) was added drop-wise over 1 hour to a stirred mixture of olivetol (100.0 g, 0.56 mol), zinc chloride (100.3 g, 0.72 mol), water (10.0 mL, 0.56 mol) and dichloromethane (1 L) at 40°C. The mixture was stirred for an additional 30 minutes at 40°C. The mixture was cooled to 25 °C, poured into ice water (500 g), and the resultant biphasic mixture stirred for 20 minutes at O0C. The resultant organic phase was collected and washed with cold water (2 x 250 mL). The organic phase was collected and concentrated under reduced pressure to provide a first residue (185.5 g). Analysis (GC) of the first residue indicated that it contained (-)-CBD (51.8percent), abn-CBO (13.2percent), olivetol (8.0percent) and dialkylated olivetol (13.4percent).The first residue (185.5 g ) was dissolved inn-heptane (1.1 L), and the resultant solution was admixed with a solution of 10percent sodium hydroxide (1.3 L). The resultant organic phase was collected, washed with water (250 mL), and concentrated under reduced pressure to provide an oily-brown second residue (124.3 g). Analysis (GC) of the second residue indicated that it contained (-)-CBD (66.0percent), abn-CBO (0.0percent), olivetol (0.0percent) and dialkylated olivetol (16.8percent).The second residue (124.3 g) was fractionally distilled (171°-178°C; 0.1 mm Hg) to provide a 87.0 g of a distillate. Analysis (GC) of the distillated indicated that it contained 74.3percent of (-)-CBD. The distillate (87.0 g) was dissolved in heptane (425 mL) at 57°C and filtered. The resultant filtrate was cooled to 0° to 5°C and seeded with -0.02 mg of powdered crystalline (-)-CBD (3a). The seeded solution was stirred at 0° to 5°C for 5 hours then at -15° to -2O0C for 48 hours. The resultant mixture was filtered, and the resultant solids were washed with cold heptane. The solids were then dried under EPO <DP n="47"/>reduced pressure at 40°C to provide (-)-CBD (3a). Yield: 39.2 g; 22percent. Analysis (GC) of the product indicated that it contained (-)-CBD (3a) (97.1 percent) and trans-(-)- Δ9-THC (Ia) (1.44percent). The structure of 3a was confirmed by 1H NMR spectroscopy. An analytical sample was prepared by recrystallizing a portion of the crude 3a from heptane as described above.Melting point: 64°-65°C.Optical rotation: [α]D 20 -132° (c = 0.12, 95percent EtOH). in n-heptane, Time= 53h, T= -20 - 5 °C , Purification / work up Patent; EURO-CELTIQUE S.A.; WO2006/53766; (2006); (A1) English View in Reaxys

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With hydrogenchloride, ethanol Adams et al.; Journal of the American Chemical Society; vol. 62; (1940); p. 2402,2405; Journal of the American Chemical Society; vol. 63; (1941); p. 2209,2212 View in Reaxys Gaoni; Mechoulam; Journal of the American Chemical Society; vol. 86; (1964); p. 1646 View in Reaxys 3 :A solution of crystallized (-)-CBD (3a) in anhydrous dichloromethane can be added drop-wise over 1 hour to a stirred solution Of BF3-Et2O in anhydrous dichloromethane at -100C under an Ar atmosphere. The mixture can then be stirred for 2 hours at -1O0C and poured into ice water. The resultant biphasic mixture is then further stirred for 20 minutes at 00C. The resultant organic phase can be collected, washed sequentially with cold water, 7 percent aqueous sodium bicarbonate, and water. The organic phase can then be dried with Na2SO4 EPO <DP n="83"/>and filtered. The resultant filtrate can be concentrated under reduced pressure at 400C and is expected to provide trans-(-)-Δ9-THC (Ia) as a yellow oil having a purity of about 80percent.

With boron trifluoride diethyl etherate in dichloromethane, water, Time= 3.33333h, T= -10 - 0 °C , Product distribution / selectivity Patent; EURO-CELTIQUE S.A.; WO2006/133941; (2006); (A2) English View in Reaxys 1.4 : Step 4: Cvclization, synthesis of delta-9-THC: 50 g of pure cannabidiol are dissolved in 250 g methyl-iert-butylether and 40 g of boron trifluoride*acetic acid complex are added under stirring within 10 min at ca. 22 C. It is stirred for 3 h at said temperature and then 200 g of ice water are added, the organic phase is washed with sodium bicarbonate solution and the solvent is removed using a rotary evaporator. The remaining raw material of ca. 50 g contains 74percent trans-(-)-delta-9-tetrahydrocannabinol (delta-9-THC), 25percent of side products as well as < 1 percent cannabidiol.

With boron trifluoride diacetate in tert-butyl methyl ether, Time= 3.16667h, T= 22 °C Patent; SYMRISE AG; ERFURT, Harry; WEBER, Maria; NIEMEYER, Hans-Jürgen; GÖTZ, Marcus Rudolf; WINKLER, Matthias; (44 pag.); WO2017/194173; (2017); (A1) English View in Reaxys

O

S

O

OH H

O H

H O

O H

Rx-ID: 22983786 View in Reaxys 4/101 Yield

Conditions & References 13 : Example 13. Hydrolysis of Δ 9-tetrahydrocannabinol tosylate to free Delta 9-tetrahydrocannabinol With potassium n-butoxide in water, tert-butyl alcohol, Time= 5h, T= 65 - 70.1 °C Patent; MALLINCKRODT INC.; WO2004/43946; (2004); (A1) English View in Reaxys 2 :EXAMPLE 2[0071] In this example, the 9α -THC tosylate prepared in Example 1 was hydrolyzed to obtain α9-THC.[0072] 0.28 g of the 9α -THC tosylate prepared in Example 1 was placed in a flask along with 1.64 mL t-butanol and 0.043 mL water. 0.02 g of potassium butoxide was then added, and the resulting slurry was stirred and heated at 65°C for 5 hours. 5 mL of water was then charged into the reactor, and the resulting solution was cooled to 25°C. 5 mL of hexane was then added, and the resulting bipha-

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sic solution was stirred for 10 minutes. The organic phase was then separated and washed twice with 5 mL of water and once with 5 mL of brine. The organic phase was then dried over magnesium sulfate and filtered through Whatman 541 filter paper.

The solvent was evaporated to give 56 mg of pure 9α - <n="29"/>THC as a light yellow oil. The resulting 9α -THC was 95percent pure 9α -THC, and contained only 0.44percent α8- THC. With potassium tert-butylate, water in tert-butyl alcohol, Time= 5h, T= 65 °C Patent; MALLINCKRODT INC.; WO2009/99868; (2009); (A1) English View in Reaxys

HO OH H

H

HO O

Rx-ID: 23762931 View in Reaxys 5/101 Yield

Conditions & References 8 : Step 8: Step 8: Synthesis of Dronabinol (I) A 1000 mL round-bottom flask equipped with a magnetic stir bar, reflux condenser and nitrogen inlet was charged with dichloromethane (200 mL), zinc chloride (5.30 g, 39 mmol) and magnesium sulfate (28.30 g, 235 mmol).

The solvent was brought to reflux, and a solution of intermediate II (13.00 g, 39 mmol) in dichloromethane (200 mL) was added in one portion.

The resulting suspension was refluxed for 50 minutes, after which the reaction mixture was quickly cooled in an ice-water bath and then quenched by pouring into 400 mL of saturated sodium bicarbonate.

The layers were separated and the aqueous phase was extracted with 2*200 mL of dichloromethane.

The combined organic layers were washed once with brine, then dried over magnesium sulfate, filtered and concentrated under vacuum to give a yellow oil.

Purification by column chromatography (1:100 ethyl acetate:hexane) gave 6.00 g (49percent) of dronabinol as a colorless oil.

With magnesium sulfate, zinc(II) chloride in dichloromethane, Time= 0.833333h, Heating / reflux Patent; Souza, Fabio E.S.; Field, Jason E.; Pan, Ming; Ramjit, Navindra J.; Tharmanathan, Tharsika; Jende-Tindall, Tracey; US2006/74252; (2006); (A1) English View in Reaxys

OH H

H

OH

O

Rx-ID: 25608828 View in Reaxys 6/101 Yield

Conditions & References 19 :A 250-mL reactor was charged with dichloromethane (240 g) and boron trifluoride diethyletherate (8.4 g) and filled with argon. The resulting solution was cooled to -10 0C and the solution of n-cannabidiol (15.0 g) in dichloromethane (60 g) was added dropwise to the mixture over a one-hour period at -10 0C. The reaction mixture was stirred for an additional two hours at the same temperature ( -10 0C). A sample taken after 1.5 hours was analyzed (gas chromatography) and found to contain (-)-Δ9tetrahydrocannabinol ((-)-Δ9-THC) (80.8percent), rc-cannabidiol (CBD) (4.46percent) and Δ8-iso-THC (12.3percent). EPO <DP n="100"/>The reaction mixture was poured into ice- water (100 g) and the mixture was stirred for 20 minutes at 0 0C. The dichloromethane layer was washed successively with cold water (50 g), dilute sodium hydrogen carbonate solution (50 g) and water (50 g). The dichloromethane solution was dried over anhydrous sodium sulfate (15 g), and solvent was evaporated under

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reduced pressure at 40 0C (i.e. temperature of the water bath) to provide 14.9 g of a yellow oil (yield 99percent) containing 81.8percent of (-)-Δ9-THC, according to HPLC analysis.

With boron trifluoride diethyl etherate in dichloromethane, Time= 3h, T= -10 °C , Product distribution / selectivity Patent; EURO-CELTIQUE S.A.; WO2006/133941; (2006); (A2) English View in Reaxys

HO

H

OH

OH H

H

H

O

O

Rx-ID: 35091849 View in Reaxys 7/101 Yield

Conditions & References Stage 1: With hydrogenchloride, acetic acid, zinc(II) chloride in water, Time= 3h, T= 20 °C , Inert atmosphere Stage 2: With potassium tert-butylate in benzene, Time= 0.25h, T= -5 - 65 °C , Inert atmosphere Cheng, Li-Jie; Xie, Jian-Hua; Chen, Yong; Wang, Li-Xin; Zhou, Qi-Lin; Organic Letters; vol. 15; nb. 4; (2013); p. 764 - 767 View in Reaxys

OH

O

H

H

H

H

O

O

Rx-ID: 9199679 View in Reaxys 8/101 Yield

Conditions & References With sodium thioethylate in N,N-dimethyl-formamide, Time= 8h, T= 120 °C William, Anthony D.; Kobayashi, Yuichi; Journal of Organic Chemistry; vol. 67; nb. 25; (2002); p. 8771 - 8782 View in Reaxys With sodium thioethylate in N,N-dimethyl-formamide, Time= 10h, T= 140 °C Trost, Barry M.; Dogra, Kalindi; Organic Letters; vol. 9; nb. 5; (2007); p. 861 - 863 View in Reaxys

OH OH H

OH

H

HO

OH O

Rx-ID: 28747565 View in Reaxys 9/101 Yield

Conditions & References 1 :EXAMPLE 1[0066] In this example, 9α -THC tosylate was synthesized.[0067] To begin, 0.53 g olivetol and 0.50 g of p-mentha-2-en-1 ,8-diol were dissolved in 35 mL dichloromethane in a flask. 2.12 g magnesium sulfate was added to the flask. The resulting suspension was chilled to less than 5°C. A solution of 37 μL boron trifluoride etherate in 5 mL <n="28"/>dichloromethane was added dropwise to the suspension over a period of five minutes. The temperature of the reaction mixture was increased to 12°C, and maintained at that temperature for 6 hours to allow the reaction to occur.[0068] 0.82 mL triethylamine and

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1.12 g p-toluenesuifonyl chloride were added to the reaction mixture. The temperature of the reaction mixture was raised to room temperature, and the reaction was stirred overnight.[0069] The resulting reaction mixture was filtered using vacuum filtration through Whatman 541 filter paper to remove the magnesium sulfate. Evaporation of the solvent produced an oily residue containing crude 9α -THC tosylate. The crude tosylate was purified using a single pass through of a reverse-phase preparative chromatography column under the following conditions: Column: 250 x 10 mm, packed with Develosil RP-Aqueous Phase; Eiuaαt: 3/3/2/2 acetonitrile/methanol/THF/water isocratic; Flow Rate 4.7 mL/min.[0070] The fractions of 9α -THC tosylate isolated using chromatography that contained less than 2percent 8α -THC tosylate were identified using reverse-phase liquid chromatography with UV detection (255 nm), and were combined and recrystallized. Specifically, 0.48 grams of the isolated fractions of α9THC tosylate was dissolved in 7 mL of refiuxing methanol. Upon cooling to room temperature, the 9α -THC tosylate began to precipitate. The crystals were collected by vacuum filtration and dried under high vacuum overnight. The purity of the resulting crystalline 9α -THC tosylate was determined using reverse-phase liquid chromatography with UV detection (255 nm). The crystalline 9α -THC tosylate was found to be 99.6percent pure, and contained only 0.34percent α8-THC tosylate.

With boron trifluoride diethyl etherate, magnesium sulfate in dichloromethane, T= 5 - 12 °C Patent; MALLINCKRODT INC.; WO2009/99868; (2009); (A1) English View in Reaxys

OH OH H

H

HO

OH O

Rx-ID: 39376209 View in Reaxys 10/101 Yield

Conditions & References With boron trifluoride diethyl etherate in dichloromethane, Time= 0.333333h, T= 20 °C , Inert atmosphere, diastereoselective reaction Dethe, Dattatraya H.; Erande, Rohan D.; Mahapatra, Samarpita; Das, Saikat; Kumar B., Vijay; Chemical Communications; vol. 51; nb. 14; (2015); p. 2871 - 2873 View in Reaxys

OH

HO

OH

H H

H O

H

HO

OH

O O

H

O

HO

O

HO

HO

OH

H

OH

O

HO

H

OH O

O H OH

HO

OH

OH

HO

OH

OH

H

O

O

O HO

H

O H

O OH H

O H

H OH

HO OH

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HO OH

H

H

H

O O

H

Rx-ID: 23326199 View in Reaxys 11/101 Yield

Conditions & References 3 : Example 3 Preparation of (-)-TRANS-A9-TETRAHYDROCANNABINOL : The freshly prepared olivetol/cyclodextrin complex of Example 1 and 9 g of MGS04 were mixed together in 500 ml of tetrahydrofuran. The reaction mixture was COOLED IN AN ICE WATER BATH TO KEEP THE TEMPERATURE AT ABOUT 5° C. 4.4 G OF (+) -2, 8- MENTHADIENE-1-OL was placed in an addition funnel and BF3ET2O acid was placed into a SYRINGE. THE (+) -2, 8-MENTHADIENE-L-OL AND THE ACID CATALYST WERE ADDED TO THE REACTION mixture drop wise over 15 minutes. The reaction progress was monitored by HPLC and, upon completion of the reaction, an excess OF NAHCO3 was added to quench the reaction. Salts were filtered out from the reaction mixture and the organic solvent was evaporated to give an oil. Approximately 7.0 g of the oil was obtained as a mixture of (-)-trans-A9- tetrahydrocannabinol and some minor amount of (-)-TRANS-A8-TETRAHYDROCANNABINOL. The oil was dissolved into 100 ml of petroleum ether and was washed with 300 ml of water twice and brine solution once. The product mixture was purified via chromatography on a silica gel column and (-)-TRANS-A9-TETRAHYDROCANNABINOL eluted with heptane/acetonitrile (98: 2) as mobile phase. A fraction containing the (-)-TRANS-A9-TETRAHYDROCANNABINOL, with purity over 98percent, was concentrated to give a light yellow oil.

With boron trifluoride diethyl etherate, magnesium sulfate in tetrahydrofuran, Time= 0.25h, T= 5 °C Patent; MALLINCKRODT INC.; WO2004/92101; (2004); (A2) English View in Reaxys

Br

OH H

HO H

O

O

Rx-ID: 10090184 View in Reaxys 12/101 Yield

Conditions & References With lithium aluminium tetrahydride in tetrahydrofuran, Time= 1h, T= 20 °C Qi, Longwu; Yamamoto, Noboru; Meijler, Michael M.; Altobell III, Laurence J.; Koob, George F.; Wirsching, Peter; Janda, Kim D.; Journal of Medicinal Chemistry; vol. 48; nb. 23; (2005); p. 7389 - 7399 View in Reaxys

OH O

O

O

OH

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HO OH

H

H

H

O H

O

Rx-ID: 23670173 View in Reaxys 13/101 Yield

Conditions & References 1; 7 :The reaction of the carbonate 6 shown in Figures 6 7 with olivetol in the presence of various Lewis acids was examined using scheme shown in Figure 7. The results are shown in Table 1 below. [0042] Use of BF3-Et20 initially gave a moderate yield of THC by HPLC with an approximately 2/1 ratio of No.9-THC/No.8-THC (entry 1). The addition of the inorganic K2C03 led to an enhanced ratio (entry 2), while use of the organic base pyridine led to a reversal in the selectivity (entry 3). The presence of molecular sieves did not improve the ratio significantly (entry 4). [0043] The use of BF3-THF gave a higher ratio than BF3-Et20 (entry 5). The addition of K2C03 to the reaction gave a synthetically useful ratio of No.9-THC/No.8- THC (entry 6). The promising results with BF3-THF led us to further examine this complex. Running the reaction at ambient temperature or using two equivalents of BF3-THF (versus one equivalent) did not improve the overall yield (entries 7 and 8). Use of organic soluble hindered amine bases in combination with BF3- THF gave no reaction by TLC analysis (entries 9 and 10). A brief solvent screen revealed that when the reaction is run in the coordinating solvents CH3CN and THF no reaction occurs (entries 11 and 12), while use of toluene as the solvent gave the best ratio to date (entry 13). Use of other BF3 complexes led to inferior results (entries 14-16). [0044] Other Lewis acids were examined. Zinc bromide in the presence of molecular sieves gave a 3.9/1 ratio of No.9-THC/No.8-THC while ZnC12 led to a reversal of selectivity (entries 17 and 18). The weaker Lewis acids LiBr, MgC12, and Ti(O-iPr)4 gave no No.9-THC or No.8-THC by HPLC (entries 19-21). It should be understood that the Lewis acids and conditions are not limited to those summarized in Figure 7. In particular, other conditions using Lewis and Bronsted acids can potentially be used either by themselves or in the presence of other organic or inorganic bases.

With boron trifluoride diethyl etherate in dichloromethane, T= 0 - 10 °C , Product distribution / selectivity Patent; CEDARBURG PHARMACEUTICALS, INC.; WO2005/100333; (2005); (A1) English View in Reaxys 1; 7 :The reaction of the carbonate 6 shown in Figures 6 7 with olivetol in the presence of various Lewis acids was examined using scheme shown in Figure 7. The results are shown in Table 1 below. [0042] Use of BF3-Et20 initially gave a moderate yield of THC by HPLC with an approximately 2/1 ratio of No.9-THC/No.8-THC (entry 1). The addition of the inorganic K2C03 led to an enhanced ratio (entry 2), while use of the organic base pyridine led to a reversal in the selectivity (entry 3). The presence of molecular sieves did not improve the ratio significantly (entry 4). [0043] The use of BF3-THF gave a higher ratio than BF3-Et20 (entry 5). The addition of K2C03 to the reaction gave a synthetically useful ratio of No.9-THC/No.8- THC (entry 6). The promising results with BF3-THF led us to further examine this complex. Running the reaction at ambient temperature or using two equivalents of BF3-THF (versus one equivalent) did not improve the overall yield (entries 7 and 8). Use of organic soluble hindered amine bases in combination with BF3- THF gave no reaction by TLC analysis (entries 9 and 10). A brief solvent screen revealed that when the reaction is run in the coordinating solvents CH3CN and THF no reaction occurs (entries 11 and 12), while use of toluene as the solvent gave the best ratio to date (entry 13). Use of other BF3 complexes led to inferior results (entries 14-16). [0044] Other Lewis acids were examined. Zinc bromide in the presence of molecular sieves gave a 3.9/1 ratio of No.9-THC/No.8-THC while ZnC12 led to a reversal of selectivity (entries 17 and 18). The weaker Lewis acids LiBr, MgC12, and Ti(O-iPr)4 gave no No.9-THC or No.8-THC by HPLC (entries 19-21). It should be understood that the Lewis acids and conditions are not limited to those summarized in Figure 7. In particular, other conditions using Lewis and Bronsted acids can potentially be used either by themselves or in the presence of other organic or inorganic bases.

With borontrifluoride-dimethyl sulfide complex in dichloromethane, T= 0 - 10 °C , Product distribution / selectivity Patent; CEDARBURG PHARMACEUTICALS, INC.; WO2005/100333; (2005); (A1) English View in Reaxys 1; 7 :The reaction of the carbonate 6 shown in Figures 6 7 with olivetol in the presence of various Lewis acids was examined using scheme shown in Figure 7. The results are shown in Table 1 below. [0042] Use of BF3-Et20 initially gave a moderate yield of THC by HPLC with an approximately 2/1 ratio of No.9-THC/No.8-THC (entry 1). The addition of the inorganic K2C03 led to an enhanced ratio (entry 2), while use of the organic base pyridine led to a reversal in the selectivity (entry 3). The presence of molecular sieves did not improve the ratio significantly (entry 4). [0043] The use of BF3-THF gave a higher ratio than BF3-Et20 (entry 5). The addition of K2C03 to the reaction gave a synthetically useful ratio of No.9-THC/No.8- THC (entry 6). The promising results with BF3-THF led us to further examine this complex. Running the reaction at ambient temperature or using two equivalents of BF3-THF (versus one equivalent) did not improve the overall yield (entries 7 and 8). Use of organic soluble hin-

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dered amine bases in combination with BF3- THF gave no reaction by TLC analysis (entries 9 and 10). A brief solvent screen revealed that when the reaction is run in the coordinating solvents CH3CN and THF no reaction occurs (entries 11 and 12), while use of toluene as the solvent gave the best ratio to date (entry 13). Use of other BF3 complexes led to inferior results (entries 14-16). [0044] Other Lewis acids were examined. Zinc bromide in the presence of molecular sieves gave a 3.9/1 ratio of No.9-THC/No.8-THC while ZnC12 led to a reversal of selectivity (entries 17 and 18). The weaker Lewis acids LiBr, MgC12, and Ti(O-iPr)4 gave no No.9-THC or No.8-THC by HPLC (entries 19-21). It should be understood that the Lewis acids and conditions are not limited to those summarized in Figure 7. In particular, other conditions using Lewis and Bronsted acids can potentially be used either by themselves or in the presence of other organic or inorganic bases.

With zinc dibromide in dichloromethane, T= 0 - 10 °C , Molecular sieve, Product distribution / selectivity Patent; CEDARBURG PHARMACEUTICALS, INC.; WO2005/100333; (2005); (A1) English View in Reaxys 1; 7 :The reaction of the carbonate 6 shown in Figures 6 7 with olivetol in the presence of various Lewis acids was examined using scheme shown in Figure 7. The results are shown in Table 1 below. [0042] Use of BF3-Et20 initially gave a moderate yield of THC by HPLC with an approximately 2/1 ratio of No.9-THC/No.8-THC (entry 1). The addition of the inorganic K2C03 led to an enhanced ratio (entry 2), while use of the organic base pyridine led to a reversal in the selectivity (entry 3). The presence of molecular sieves did not improve the ratio significantly (entry 4). [0043] The use of BF3-THF gave a higher ratio than BF3-Et20 (entry 5). The addition of K2C03 to the reaction gave a synthetically useful ratio of No.9-THC/No.8- THC (entry 6). The promising results with BF3-THF led us to further examine this complex. Running the reaction at ambient temperature or using two equivalents of BF3-THF (versus one equivalent) did not improve the overall yield (entries 7 and 8). Use of organic soluble hindered amine bases in combination with BF3- THF gave no reaction by TLC analysis (entries 9 and 10). A brief solvent screen revealed that when the reaction is run in the coordinating solvents CH3CN and THF no reaction occurs (entries 11 and 12), while use of toluene as the solvent gave the best ratio to date (entry 13). Use of other BF3 complexes led to inferior results (entries 14-16). [0044] Other Lewis acids were examined. Zinc bromide in the presence of molecular sieves gave a 3.9/1 ratio of No.9-THC/No.8-THC while ZnC12 led to a reversal of selectivity (entries 17 and 18). The weaker Lewis acids LiBr, MgC12, and Ti(O-iPr)4 gave no No.9-THC or No.8-THC by HPLC (entries 19-21). It should be understood that the Lewis acids and conditions are not limited to those summarized in Figure 7. In particular, other conditions using Lewis and Bronsted acids can potentially be used either by themselves or in the presence of other organic or inorganic bases.

With zinc(II) chloride in dichloromethane, T= 0 - 10 °C , Molecular sieve, Product distribution / selectivity Patent; CEDARBURG PHARMACEUTICALS, INC.; WO2005/100333; (2005); (A1) English View in Reaxys 1; 7 :The reaction of the carbonate 6 shown in Figures 6 7 with olivetol in the presence of various Lewis acids was examined using scheme shown in Figure 7. The results are shown in Table 1 below. [0042] Use of BF3-Et20 initially gave a moderate yield of THC by HPLC with an approximately 2/1 ratio of No.9-THC/No.8-THC (entry 1). The addition of the inorganic K2C03 led to an enhanced ratio (entry 2), while use of the organic base pyridine led to a reversal in the selectivity (entry 3). The presence of molecular sieves did not improve the ratio significantly (entry 4). [0043] The use of BF3-THF gave a higher ratio than BF3-Et20 (entry 5). The addition of K2C03 to the reaction gave a synthetically useful ratio of No.9-THC/No.8- THC (entry 6). The promising results with BF3-THF led us to further examine this complex. Running the reaction at ambient temperature or using two equivalents of BF3-THF (versus one equivalent) did not improve the overall yield (entries 7 and 8). Use of organic soluble hindered amine bases in combination with BF3- THF gave no reaction by TLC analysis (entries 9 and 10). A brief solvent screen revealed that when the reaction is run in the coordinating solvents CH3CN and THF no reaction occurs (entries 11 and 12), while use of toluene as the solvent gave the best ratio to date (entry 13). Use of other BF3 complexes led to inferior results (entries 14-16). [0044] Other Lewis acids were examined. Zinc bromide in the presence of molecular sieves gave a 3.9/1 ratio of No.9-THC/No.8-THC while ZnC12 led to a reversal of selectivity (entries 17 and 18). The weaker Lewis acids LiBr, MgC12, and Ti(O-iPr)4 gave no No.9-THC or No.8-THC by HPLC (entries 19-21). It should be understood that the Lewis acids and conditions are not limited to those summarized in Figure 7. In particular, other conditions using Lewis and Bronsted acids can potentially be used either by themselves or in the presence of other organic or inorganic bases.

With THF·BF3 in dichloromethane, T= 0 - 20 °C , Product distribution / selectivity Patent; CEDARBURG PHARMACEUTICALS, INC.; WO2005/100333; (2005); (A1) English View in Reaxys 1; 7 :The reaction of the carbonate 6 shown in Figures 6 7 with olivetol in the presence of various Lewis acids was examined using scheme shown in Figure 7. The results are shown in Table 1 below. [0042] Use of BF3-Et20 initially gave a moderate yield of THC by HPLC with an approximately 2/1 ratio of No.9-THC/No.8-THC (entry 1). The addition of the inorganic K2C03 led to an enhanced ratio (entry 2), while use of the organic base pyridine led to a reversal in the selectivity (entry 3). The presence of molecular sieves did not improve the ratio significantly (entry 4). [0043] The use of BF3-THF gave a higher ratio than BF3-Et20

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(entry 5). The addition of K2C03 to the reaction gave a synthetically useful ratio of No.9-THC/No.8- THC (entry 6). The promising results with BF3-THF led us to further examine this complex. Running the reaction at ambient temperature or using two equivalents of BF3-THF (versus one equivalent) did not improve the overall yield (entries 7 and 8). Use of organic soluble hindered amine bases in combination with BF3- THF gave no reaction by TLC analysis (entries 9 and 10). A brief solvent screen revealed that when the reaction is run in the coordinating solvents CH3CN and THF no reaction occurs (entries 11 and 12), while use of toluene as the solvent gave the best ratio to date (entry 13). Use of other BF3 complexes led to inferior results (entries 14-16). [0044] Other Lewis acids were examined. Zinc bromide in the presence of molecular sieves gave a 3.9/1 ratio of No.9-THC/No.8-THC while ZnC12 led to a reversal of selectivity (entries 17 and 18). The weaker Lewis acids LiBr, MgC12, and Ti(O-iPr)4 gave no No.9-THC or No.8-THC by HPLC (entries 19-21). It should be understood that the Lewis acids and conditions are not limited to those summarized in Figure 7. In particular, other conditions using Lewis and Bronsted acids can potentially be used either by themselves or in the presence of other organic or inorganic bases.

With BF3-tert-butyl methyl etherate in dichloromethane, T= 0 - 20 °C , Product distribution / selectivity Patent; CEDARBURG PHARMACEUTICALS, INC.; WO2005/100333; (2005); (A1) English View in Reaxys 1; 3; 7 :The reaction of the carbonate 6 shown in Figures 6 7 with olivetol in the presence of various Lewis acids was examined using scheme shown in Figure 7. The results are shown in Table 1 below. [0042] Use of BF3-Et20 initially gave a moderate yield of THC by HPLC with an approximately 2/1 ratio of No.9-THC/No.8-THC (entry 1). The addition of the inorganic K2C03 led to an enhanced ratio (entry 2), while use of the organic base pyridine led to a reversal in the selectivity (entry 3). The presence of molecular sieves did not improve the ratio significantly (entry 4). [0043] The use of BF3-THF gave a higher ratio than BF3-Et20 (entry 5). The addition of K2C03 to the reaction gave a synthetically useful ratio of No.9-THC/No.8- THC (entry 6). The promising results with BF3-THF led us to further examine this complex. Running the reaction at ambient temperature or using two equivalents of BF3-THF (versus one equivalent) did not improve the overall yield (entries 7 and 8). Use of organic soluble hindered amine bases in combination with BF3- THF gave no reaction by TLC analysis (entries 9 and 10). A brief solvent screen revealed that when the reaction is run in the coordinating solvents CH3CN and THF no reaction occurs (entries 11 and 12), while use of toluene as the solvent gave the best ratio to date (entry 13). Use of other BF3 complexes led to inferior results (entries 14-16). [0044] Other Lewis acids were examined. Zinc bromide in the presence of molecular sieves gave a 3.9/1 ratio of No.9-THC/No.8-THC while ZnC12 led to a reversal of selectivity (entries 17 and 18). The weaker Lewis acids LiBr, MgC12, and Ti(O-iPr)4 gave no No.9-THC or No.8-THC by HPLC (entries 19-21). It should be understood that the Lewis acids and conditions are not limited to those summarized in Figure 7. In particular, other conditions using Lewis and Bronsted acids can potentially be used either by themselves or in the presence of other organic or inorganic bases.To a 25 mL round bottom flask equipped with a magnetic stir bar and septa was added 35 mg (0.18 mmol) of 6,35 mg (0.19 mmol) of olivetol, and 0.12 g (0.87 mmol) of K2C03. The flask was then placed under a nitrogen atmosphere and 5 mL of CH2C12 was added. The suspension was then cooled to an external temperature of 0-10°C. BF3-Et20 (23 microliters, 0.18 mmol) was then added via microsyringe. The suspension gradually turned light brown. After 2 hours, 5 mL of 5percent aqueous Na2C03 was added to the reaction. The reaction was stirred for 15 minutes, the layers were separated and the organic layer was dried over Na2S04. The dried organic layer was then purged with nitrogen to remove the majority of the solvent. Area percent HPLC analysis of the resulting oil indicated a 6.3/1 ratio of No.9-THC/No.8-THC. With potassium carbonate, boron trifluoride diethyl etherate in dichloromethane, Time= 2h, T= 0 - 10 °C , Product distribution / selectivity Patent; CEDARBURG PHARMACEUTICALS, INC.; WO2005/100333; (2005); (A1) English View in Reaxys 1; 4; 7 :The reaction of the carbonate 6 shown in Figures 6 7 with olivetol in the presence of various Lewis acids was examined using scheme shown in Figure 7. The results are shown in Table 1 below. [0042] Use of BF3-Et20 initially gave a moderate yield of THC by HPLC with an approximately 2/1 ratio of No.9-THC/No.8-THC (entry 1). The addition of the inorganic K2C03 led to an enhanced ratio (entry 2), while use of the organic base pyridine led to a reversal in the selectivity (entry 3). The presence of molecular sieves did not improve the ratio significantly (entry 4). [0043] The use of BF3-THF gave a higher ratio than BF3-Et20 (entry 5). The addition of K2C03 to the reaction gave a synthetically useful ratio of No.9-THC/No.8- THC (entry 6). The promising results with BF3-THF led us to further examine this complex. Running the reaction at ambient temperature or using two equivalents of BF3-THF (versus one equivalent) did not improve the overall yield (entries 7 and 8). Use of organic soluble hindered amine bases in combination with BF3- THF gave no reaction by TLC analysis (entries 9 and 10). A brief solvent screen revealed that when the reaction is run in the coordinating solvents CH3CN and THF no reaction occurs (entries 11 and 12), while use of toluene as the solvent gave the best ratio to date (entry 13). Use of other BF3 complexes led to inferior results (entries 14-16). [0044] Other Lewis acids were examined. Zinc bromide in the presence of molecular sieves gave a 3.9/1 ratio of No.9-THC/No.8-THC while ZnC12 led to a reversal of selectivity (entries 17 and 18). The weaker Lewis acids LiBr, MgC12, and Ti(O-iPr)4 gave no No.9-THC or No.8-THC by HPLC (entries 19-21). It should be understood that the Lewis acids and conditions are not limited to those summarized in Figure 7. In particular, other conditions using Lewis and Bronsted acids can potentially be used either by themselves or in the presence of other organic or inorganic bases.To a 25 mL round bottom flask

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equipped with a magnetic stir bar and septa was added 50 mg (0.25mmol) of carbonate 6,51 mg (0.28 mmol) of olivetol, and 0.14 g (1.0 mmol) of K2C03. The flask was then placed under a nitrogen atmosphere and 5 mL of CH2CI2 was added. The suspension was then cooled to an external temperature of 0-10°C. BF3-THF (29 microliters, 0.26 mmol) was then added via microsyringe. The slurry turned light yellow during the addition. After 3.25 hours, 5 mL of 5percent aqueous Na2C03 was added to the reaction. The layers were separated and the organic layer was dried over Na2S04. The dried organic layer was then purged with nitrogen to remove the majority of the solvent. Area percent HPLC analysis of the resulting oil indicated a 12/1 ratio of No.9-THC/No.8- THC. With potassium carbonate, THF·BF3 in dichloromethane, Time= 3.25h, T= 0 - 20 °C , Product distribution / selectivity Patent; CEDARBURG PHARMACEUTICALS, INC.; WO2005/100333; (2005); (A1) English View in Reaxys 1; 5; 7 :The reaction of the carbonate 6 shown in Figures 6 7 with olivetol in the presence of various Lewis acids was examined using scheme shown in Figure 7. The results are shown in Table 1 below. [0042] Use of BF3-Et20 initially gave a moderate yield of THC by HPLC with an approximately 2/1 ratio of No.9-THC/No.8-THC (entry 1). The addition of the inorganic K2C03 led to an enhanced ratio (entry 2), while use of the organic base pyridine led to a reversal in the selectivity (entry 3). The presence of molecular sieves did not improve the ratio significantly (entry 4). [0043] The use of BF3-THF gave a higher ratio than BF3-Et20 (entry 5). The addition of K2C03 to the reaction gave a synthetically useful ratio of No.9-THC/No.8- THC (entry 6). The promising results with BF3-THF led us to further examine this complex. Running the reaction at ambient temperature or using two equivalents of BF3-THF (versus one equivalent) did not improve the overall yield (entries 7 and 8). Use of organic soluble hindered amine bases in combination with BF3- THF gave no reaction by TLC analysis (entries 9 and 10). A brief solvent screen revealed that when the reaction is run in the coordinating solvents CH3CN and THF no reaction occurs (entries 11 and 12), while use of toluene as the solvent gave the best ratio to date (entry 13). Use of other BF3 complexes led to inferior results (entries 14-16). [0044] Other Lewis acids were examined. Zinc bromide in the presence of molecular sieves gave a 3.9/1 ratio of No.9-THC/No.8-THC while ZnC12 led to a reversal of selectivity (entries 17 and 18). The weaker Lewis acids LiBr, MgC12, and Ti(O-iPr)4 gave no No.9-THC or No.8-THC by HPLC (entries 19-21). It should be understood that the Lewis acids and conditions are not limited to those summarized in Figure 7. In particular, other conditions using Lewis and Bronsted acids can potentially be used either by themselves or in the presence of other organic or inorganic bases.To a 25 mL round bottom flask equipped with a magnetic stir bar and septa was added 50 mg (0.25mmol) of carbonate 6, 52 mg (0.29 mmol) of olivetol, and 0.14 g (1.0 mmol) of K2C03. The flask was then placed under a nitrogen atmosphere and 5 mL of PhCH3 was added. The suspension was then cooled to an external temperature of 0-10°C. BF3-THF (29 microliters, 0:26 mmol) was then added via microsyringe. The slurry turned light yellow during the addition. After 2 hours, 5 mL of 5percent aqueous Na2C03 was added to the reaction. The layers were separated and the organic layer was dried over Na2S04. Area percent HPLC analysis of the resulting solution indicated a 34/1 ratio of No.9-THC/No.8-THC. With potassium carbonate, THF·BF3 in toluene, Time= 2h, T= 0 - 10 °C , Product distribution / selectivity Patent; CEDARBURG PHARMACEUTICALS, INC.; WO2005/100333; (2005); (A1) English View in Reaxys 1; 7 :The reaction of the carbonate 6 shown in Figures 6 7 with olivetol in the presence of various Lewis acids was examined using scheme shown in Figure 7. The results are shown in Table 1 below. [0042] Use of BF3-Et20 initially gave a moderate yield of THC by HPLC with an approximately 2/1 ratio of No.9-THC/No.8-THC (entry 1). The addition of the inorganic K2C03 led to an enhanced ratio (entry 2), while use of the organic base pyridine led to a reversal in the selectivity (entry 3). The presence of molecular sieves did not improve the ratio significantly (entry 4). [0043] The use of BF3-THF gave a higher ratio than BF3-Et20 (entry 5). The addition of K2C03 to the reaction gave a synthetically useful ratio of No.9-THC/No.8- THC (entry 6). The promising results with BF3-THF led us to further examine this complex. Running the reaction at ambient temperature or using two equivalents of BF3-THF (versus one equivalent) did not improve the overall yield (entries 7 and 8). Use of organic soluble hindered amine bases in combination with BF3- THF gave no reaction by TLC analysis (entries 9 and 10). A brief solvent screen revealed that when the reaction is run in the coordinating solvents CH3CN and THF no reaction occurs (entries 11 and 12), while use of toluene as the solvent gave the best ratio to date (entry 13). Use of other BF3 complexes led to inferior results (entries 14-16). [0044] Other Lewis acids were examined. Zinc bromide in the presence of molecular sieves gave a 3.9/1 ratio of No.9-THC/No.8-THC while ZnC12 led to a reversal of selectivity (entries 17 and 18). The weaker Lewis acids LiBr, MgC12, and Ti(O-iPr)4 gave no No.9-THC or No.8-THC by HPLC (entries 19-21). It should be understood that the Lewis acids and conditions are not limited to those summarized in Figure 7. In particular, other conditions using Lewis and Bronsted acids can potentially be used either by themselves or in the presence of other organic or inorganic bases.

With pyridine, boron trifluoride diethyl etherate, T= 20 °C , Product distribution / selectivity Patent; CEDARBURG PHARMACEUTICALS, INC.; WO2005/100333; (2005); (A1) English View in Reaxys

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1; 7 :The reaction of the carbonate 6 shown in Figures 6 7 with olivetol in the presence of various Lewis acids was examined using scheme shown in Figure 7. The results are shown in Table 1 below. [0042] Use of BF3-Et20 initially gave a moderate yield of THC by HPLC with an approximately 2/1 ratio of No.9-THC/No.8-THC (entry 1). The addition of the inorganic K2C03 led to an enhanced ratio (entry 2), while use of the organic base pyridine led to a reversal in the selectivity (entry 3). The presence of molecular sieves did not improve the ratio significantly (entry 4). [0043] The use of BF3-THF gave a higher ratio than BF3-Et20 (entry 5). The addition of K2C03 to the reaction gave a synthetically useful ratio of No.9-THC/No.8- THC (entry 6). The promising results with BF3-THF led us to further examine this complex. Running the reaction at ambient temperature or using two equivalents of BF3-THF (versus one equivalent) did not improve the overall yield (entries 7 and 8). Use of organic soluble hindered amine bases in combination with BF3- THF gave no reaction by TLC analysis (entries 9 and 10). A brief solvent screen revealed that when the reaction is run in the coordinating solvents CH3CN and THF no reaction occurs (entries 11 and 12), while use of toluene as the solvent gave the best ratio to date (entry 13). Use of other BF3 complexes led to inferior results (entries 14-16). [0044] Other Lewis acids were examined. Zinc bromide in the presence of molecular sieves gave a 3.9/1 ratio of No.9-THC/No.8-THC while ZnC12 led to a reversal of selectivity (entries 17 and 18). The weaker Lewis acids LiBr, MgC12, and Ti(O-iPr)4 gave no No.9-THC or No.8-THC by HPLC (entries 19-21). It should be understood that the Lewis acids and conditions are not limited to those summarized in Figure 7. In particular, other conditions using Lewis and Bronsted acids can potentially be used either by themselves or in the presence of other organic or inorganic bases.

With boron trifluoride diethyl etherate in dichloromethane, T= 0 - 10 °C , Molecular sieve, Product distribution / selectivity Patent; CEDARBURG PHARMACEUTICALS, INC.; WO2005/100333; (2005); (A1) English View in Reaxys

O

OH

HO OH H

H

O O

Rx-ID: 28046313 View in Reaxys 14/101 Yield

Conditions & References 9 :Example 9 9α -THC-2-Carboxylic Acid (THCA) Vaporization and Aerosol GenerationAerosols were generated using a benchtop screening device operated by discharging a capacitor in circuit with the drug-coated foil. Electrical resistance rapidly (within < 500 msec) heats the drug-coated foil to a selectable vaporization temperature. Thermophoresis draws the drug vapor away from the foil, while air drawn across the foil from an in-house vacuum facilitates the recondensation of the vapor to form drug aerosol particles.The aerosol was collected with either a Teflon filter for quality analysis or using an Anderson-type Cascade Impactor (ACI) for particle sizing. The aerosol was <n="17"/>extracted from the collection apparatus using organic solvent and was analyzed using HPLC.Initial vaporization tests of THCA coated onto stainless steel foils indicated that prodrug conversion is proportional to drug loading (linear fit R2 = 85 percent), with an asymptote appearing around 92 percent (drug loading ~ 1.6 mg/cm2). Figure 13 is a plot 1300 showing THC formed (mole percent) 1302 as a function of coated film thickness 1304.As shown in Figure 13, films with higher drug loadings (i.e., film thicknesses) had higher prodrug conversion rates than films with lower drug loadings. This was attributed to the fact that heat transfer mechanisms in thicker films increase the temporal duration that the drug is exposed to decarboxylation conditions, relative to that of thinner films. In essence, the thicker the drug film, the longer the drug is heated. The decarboxylation kinetics were optimized for our bench-top vaporization apparatus using drug loadings in the 1 mg/cm2 range and a vaporization temperature in the range of 35O0C to 375 0C.Table Two, below, summarizes the results from a conversion optimized vaporization experiment of THCA test articles heated to 3680C using the electrical bench-top apparatus.Table 2 Summary of the Results of an Optimized Vaporization Study of THCA (n = 5)As shown in Table 2, above, both the coating and vaporization processes were highly reproducible, with relative standard deviations (RSD) of less than 5 percent. In addition, the aerosol comprised over 90 percent THC, indicating a relatively efficient conversion process. Efforts to improve the conversion efficiency (device modifications allowing slower heating, step-wise heating, and/or improving coating height uniformity) increased the conversion efficiency to about 94 percent. <n="18"/>The aerodynamic diameter of an aerosol particle is one of the key defining properties that dictate pulmonary deposition and absorption. Particles with aerodynamic diameters larger than 5 μm risk deposition in the throat or upper airway, while particles with aerodynamic diameters smaller than 1 μm may be exhaled before having a chance to settle in the deep lung. These guidelines are strongly dependent on individual breathing habits such as breath-hold; nevertheless, the particle size distribution is currently used in the pharmaceutical industry as a predictor of the efficacy of deep lung drug delivery.Particle size distribution is characterized by the mass median aerodynamic diameter (MMAD) and the geometric standard deviation (GSD). For thermal condensation aerosols, such as those disclosed herein and in our previous patent applications, particle size is governed by the competing mechanisms of condensation

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and Brownian aggregation. The density of drug vapor in the airflow, and hence air flow rate and drug mass, governs the condensation / aggregation kinetics. All particle size experiments were conducted by vaporizing drug films into an8-stage Anderson Cascade Impactor (ACI) fitted with a glass fiber filter. The ACI consists of several stages, with each successive stage having a smaller size cutoff. By extracting and determining the mass of drug deposited at each stage, it is possible to estimate the particle size distribution of the aerosol. An air flow of 28.3 L/min was used to generate the aerosol and distribute it through the ACI. Each stage and filter was extracted with organic solvent and analyzed using HPLC. The MMAD and GSD were calculated from the quantity of aerosol on each stage. The MMAD for the THC aerosol (generated from THCA film, drug loading = 1 mg/cm2; aerosol mass = 1 mg) was 2.2 μm and the GSD [84/16] was 2.2. In addition, the fine particle fraction (FPF, MMAD < 5 μm) was over 95 percent. These values are well within the range normally accepted for effective pulmonary deposition. , T= 325 - 420 °C , p= 760.051Torr , Reactivity Patent; ALEXZA PHARMACEUTICALS, INC.; WO2008/134668; (2008); (A2) English View in Reaxys T= 139.84 °C , Kinetics Perrotin-Brunel, Helene; Buijs, Wim; Spronsen, Jaap Van; Roosmalen, Maaike J.E. Van; Peters, Cor J.; Verpoorte, Rob; Witkamp, Geert-Jan; Journal of Molecular Structure; vol. 987; nb. 1-3; (2011); p. 67 - 73 View in Reaxys 1 : Decarboxylation [0070] In a vessel, THC-A (11.8 g) is dissolved in ethanol (food grade, 99percent, 175mL) and stirred. In another heated vessel, water (990 mL) is boiled and bubbling under nitrogen. The ethanol/THC-A solution is added to boiling water and the temperature is maintained at 90-91 °C for 30-40 minutes to reflux, then allowed to cool down to room temperature.

With water in ethanol, T= 90 - 91 °C Patent; AXIM BIOTECHNOLOGIES, INC.; CHANGOER, Lekhram; VAN DER LOO, Cornelis Herman Michel; KELLER, Erik; (23 pag.); WO2016/179247; (2016); (A1) English View in Reaxys T= 105 °C Patent; PASENTURE, INC.; HEIMARK, Jacob Foster; GWIN, Justin Thomas; MCFARLAND, William Royden; (46 pag.); WO2017/53731; (2017); (A1) English View in Reaxys

OH

OH

OH H

H

OH O

Rx-ID: 48051780 View in Reaxys 15/101 Yield

Conditions & References With tetrafluoroboric acid diethyl ether in dichloromethane, Time= 3h, T= -78 - 20 °C Hoffmann, Grete; Studer, Armido; Organic Letters; vol. 20; nb. 10; (2018); p. 2964 - 2966 View in Reaxys

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OH

HO

H

H

O

O

Rx-ID: 24801895 View in Reaxys 16/101 Yield

Conditions & References 5.21.21 :(+/-)-Δ9-THC (2.00 g, 97.7percent pure) was eluted by flash chromatography on a Merck column (210 x 50 mm) using Chiralpak.(R). AD.(TM). 20 μm chiral (Daicel, Tokyo, Japan) as the stationary phase (loading capacity 500 mg per injection, UV at 228 nm) and n-heptane:2-propanol (95:5 (v:v)) as the mobile phase at a flow rate of 200 mL/min at 20° to 25°C. The fractions in which only trans-(-)-Δ9-THC was observed were combined, and the volatiles removed using a rotary evaporator at 35° to 40°C to provide trans-(-)-Δ9-THC (Ia). Yield: 0.89 g; 89percent. Analysis of the product (HPLC) indicated that it was at least 99.9percent pure, i.e., no other cannabinoids were detected. in n-heptane, isopropyl alcohol, T= 20 - 25 °C , Resolution of racemate, Product distribution / selectivity Patent; EURO-CELTIQUE S.A.; WO2006/53766; (2006); (A1) English View in Reaxys OH

OH

OH

HO OH

H

H

H

O H

O

Rx-ID: 24814723 View in Reaxys 17/101 Yield 0.71 %, 5.06 %

Conditions & References 5.9.9 :A mixture of olivetol (50.0 g, 0.28 mol), zinc chloride (50.0 g, 0.36 mol) and anhydrous dichloromethane (510 mL) was stirred at 40°C for 1 hour under an Ar atmosphere. A solution of (+)-/>-mentha-2,8-dien-l-ol (42.2 g, 0.28 mol) and dichloromethane (155 mL) was added drop- wise over 1 hour to the stirred olivetol- containing mixture, and the resultant mixture was stirred for an additional 40 minutes at 40°C. The mixture was cooled to -10°C, and a solution OfBF3Et2O (23.6 g, 166 mmol) in anhydrous dichloromethane (37 mL) was added dropwise over one hour. The resultant mixture was stirred for 1.5 hours at -10°C. Cold water (250 mL) was added, and the resultant organic phase was collected and washed with cold water EPO <DP n="48"/>(120 mL), 7percent aqueous sodium bicarbonate (120 mL), and water (120 niL). The organic phase was dried with Na2SO4 (30 g) and filtered. The resultant filtrate was concentrated under reduced pressure to provide trans-(-)-Δ9-THC (Ia) as a brown oil. Yield: 89.14 g, 46percent based on the trans-(-)-Δ9-THC content in the oil. Analysis (GC) of the product indicated that it contained trans-(-)-Δ9-THC (Ia) (45.1percent), (-)-Δ8-THC (5.06percent) (2a), (-)-Δ8-iso-THC (17.6percent), CBD (3a) (0.71percent), olivetol (7.95percent) and dialkylated olivetol (10.8 wt.percent); no trans-(+)-Δ9-THC (Ib) was detected.A solution of the trans-(-)-Δ9-THC oil (20.0 g) in heptane (120 mL) was thoroughly washed with 10percent NaOH (150 mL) and water (50 mL), dried over Na2SO4, and filtered. The resultant filtrate was then concentrated under reduced pressure to provide a first crude residue (16.6 g) containing 38.5 wt. percent of trans-(-)- Δ9-THC (Ia) using HPLC; and trans-(-)-Δ9-THC (Ia) (47.4percent), Δ8-THC (2a) (8.6percent), Δ8-iso-THC (19.6percent), CBD (0.5percent), olivetol (0.0percent) and dialkylated olivetol (10.9percent) using GC. A solution of the first crude residue (16.5 g) in heptane (240 mL) was extracted with an aliquot of 9percent NaOH in 80percent methanol (3 x 180 mL). The combined basic methanolic extracts were acidified to approximately pH 7

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with 20percent citric acid and extracted with heptane (3 x 90 mL). The combined organic fractions were washed with water (50 mL), dried over Na2SO4, and filtered. The resultant filtrate was then concentrated under reduced pressure to provide 13.7 g of crude residue which contained 44.0 wt. percent of trans-(-)-Δ9-THC using HPLC; and trans-(-)-Δ9-THC (Ia) (51.8percent), Δ8THC (2a) (10.0percent), Δ8-iso-THC (22.3percent), CBD (0.0percent), olivetol (0.0percent) and dialkylated olivetol (1.3percent) using GC. Stage 1: With zinc(II) chloride in dichloromethane, Time= 1h, T= 40 °C Stage 2: in dichloromethane, Time= 1.66667h, T= 40 °C Stage 3: With boron trifluoride diethyl etherate in dichloromethane, Time= 2.5h, T= -10 °C , Product distribution / selectivity Patent; EURO-CELTIQUE S.A.; WO2006/53766; (2006); (A1) English View in Reaxys

OH S

OH

OH

HO OH

H

H

H

O O

H

Rx-ID: 23670174 View in Reaxys 18/101 Yield

Conditions & References 10 :To a 25 mL round bottom flask equipped with a magnetic stir bar and septa was added 260 mg (1.00 mmol) 8, 193 mg (1.07 mmol) of olivetol, and about 150 mg Na2C03, under a nitrogen atmosphere with 10 mL of CH2CI2. The suspension was then cooled to an external temperature of-20°C. BF3-Et20 (3 X 40 uL: 0.95 mmol) was then added via syringe. The suspension showed an immediate light yellow color. After 20 minutes, the temperature was -11 °C. There was No.9-THC present, along with starting material and thiophenol, but no No.8-THC was detected. After warming to zero, the area percent by HPLC analysis of the resulting reaction mixture was 93 to 7, No.9-THC to No.8-THC. With sodium carbonate, boron trifluoride diethyl etherate in dichloromethane, T= -20 - 0 °C , Product distribution / selectivity Patent; CEDARBURG PHARMACEUTICALS, INC.; WO2005/100333; (2005); (A1) English View in Reaxys

O

O

OH H

H O

O

Rx-ID: 12603870 View in Reaxys 19/101 Yield

Conditions & References Reaction Steps: 5 1.1: Mg / tetrahydrofuran / 1 h / Heating

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1.2: 93 percent / tetrahydrofuran / -78 - 20 °C 2.1: TMSCl; NaI / acetonitrile; hexane; diethyl ether / 24 h / 20 °C 3.1: 1.236 g / BBr3 / CH2Cl2 / 36 h / 20 °C 4.1: 37.5 percent / MgSO4; BF3*Et2O / CH2Cl2 / 2.5 h / 0 °C 5.1: 47 percent / LiAlH4 / tetrahydrofuran / 1 h / 20 °C With lithium aluminium tetrahydride, chloro-trimethyl-silane, boron trifluoride diethyl etherate, boron tribromide, magnesium sulfate, magnesium, sodium iodide in tetrahydrofuran, diethyl ether, hexane, dichloromethane, acetonitrile, 1.2: Grignard reaction Qi, Longwu; Yamamoto, Noboru; Meijler, Michael M.; Altobell III, Laurence J.; Koob, George F.; Wirsching, Peter; Janda, Kim D.; Journal of Medicinal Chemistry; vol. 48; nb. 23; (2005); p. 7389 - 7399 View in Reaxys Reaction Steps: 7 1.1: NaH / tetrahydrofuran / 15 h 1.2: 50 percent / tetrahydrofuran / 12 h / 20 °C 2.1: 85 percent / H2 / Pd/C; Pd(OH)2 / methanol / 16.5 h 3.1: 99 percent / LiAlH4 / tetrahydrofuran / 2.67 h 4.1: 86 percent / PPh3; CBr4 / CH2Cl2 / 14 h / 20 °C 5.1: 98 percent / BBr3 / CH2Cl2 / 6.75 h / -78 - 20 °C 6.1: 37.5 percent / MgSO4; BF3*Et2O / CH2Cl2 / 2.5 h / 0 °C 7.1: 47 percent / LiAlH4 / tetrahydrofuran / 1 h / 20 °C With lithium aluminium tetrahydride, carbon tetrabromide, boron trifluoride diethyl etherate, hydrogen, boron tribromide, sodium hydride, magnesium sulfate, triphenylphosphine, palladium dihydroxide, 10 wt. % palladium on activated carbon in tetrahydrofuran, methanol, dichloromethane Qi, Longwu; Yamamoto, Noboru; Meijler, Michael M.; Altobell III, Laurence J.; Koob, George F.; Wirsching, Peter; Janda, Kim D.; Journal of Medicinal Chemistry; vol. 48; nb. 23; (2005); p. 7389 - 7399 View in Reaxys

OH OH H

OH

H

OH O

Rx-ID: 11005461 View in Reaxys 20/101 Yield

Conditions & References With boron trifluoride diethyl etherate, sodium hydrogencarbonate, magnesium sulfate Brogan, Andrew P.; Eubanks, Lisa M.; Koob, George F.; Dickerson, Tobin J.; Janda, Kirn D.; Journal of the American Chemical Society; vol. 129; nb. 12; (2007); p. 3698 - 3702 View in Reaxys 4 :A mixture of olivetol, zinc chloride, and anhydrous dichloromethane is stirred at 40°C for 1 hour under an Ar atmosphere. A solution of (+)-p-mentha-2,8-dien-l-ol and dichloromethane is added drop-wise over 1 hour to the stirred olivetol-containing mixture, and the resultant mixture is then stirred for an additional 40 minutes at 40°C. The mixture can then be cooled to - 10°C, and a solution of BF3Et2O in anhydrous dichloromethane is then added dropwise over one hour. The resulting mixture can then be stirred for 1.5 hours at -10°C. Cold water is then added, and the resulting organic phase can then be collected and washed with cold water, 7percent aqueous sodium bicarbonate, and water. The organic phase can then be dried with Na2SO4 and filtered.

The resulting filtrate can then be concentrated under reduced pressure to provide crude trans-(-)-Δ -THC (Ia) as a brown oil.The crude trans-(-)-Δ9-THC oil can be dissolved in heptane and the resulting mixture can then be thoroughly washed with 10percent NaOH and water, dried over Na2SO4, and then filtered. The resulting filtrate can then be concentrated under reduced pressure to provide a first crude residue that contains trans-(-)-Δ9-THC (Ia). The crude residue is also expected to contain Δ -THC (2a), and Δ -iso-THC.This first crude residue can be dissolved in heptane to provide a solution that can then be extracted three times with 9percent NaOH in 80percent methanol. The combined basic methanolic extracts are then acidified to approximately pH 7 with 20percent citric acid and then extracted three times with heptane. The combined organic fractions can EPO <DP n="84"/>then

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be washed with water, dried over Na2SO4, and then filtered. The resulting filtrate can then be concentrated under reduced pressure to provide a crude residue containing about 40 wt. percent (HPLC) of trans-(-)-Δ9-THC. Stage 1: With zinc(II) chloride in dichloromethane, Time= 1h, T= 40 °C Stage 2: in dichloromethane, Time= 1.66667h, T= -10 - 40 °C Stage 3: With boron trifluoride diethyl etherate in dichloromethane, Time= 2.5h, T= -10 °C , Product distribution / selectivity Patent; EURO-CELTIQUE S.A.; WO2006/133941; (2006); (A2) English View in Reaxys

O O O

OH H

H

O O

Rx-ID: 12618270 View in Reaxys 21/101 Yield

Conditions & References Reaction Steps: 6 1: 85 percent / H2 / Pd/C; Pd(OH)2 / methanol / 16.5 h 2: 99 percent / LiAlH4 / tetrahydrofuran / 2.67 h 3: 86 percent / PPh3; CBr4 / CH2Cl2 / 14 h / 20 °C 4: 98 percent / BBr3 / CH2Cl2 / 6.75 h / -78 - 20 °C 5: 37.5 percent / MgSO4; BF3*Et2O / CH2Cl2 / 2.5 h / 0 °C 6: 47 percent / LiAlH4 / tetrahydrofuran / 1 h / 20 °C With lithium aluminium tetrahydride, carbon tetrabromide, boron trifluoride diethyl etherate, hydrogen, boron tribromide, magnesium sulfate, triphenylphosphine, palladium dihydroxide, 10 wt. % palladium on activated carbon in tetrahydrofuran, methanol, dichloromethane Qi, Longwu; Yamamoto, Noboru; Meijler, Michael M.; Altobell III, Laurence J.; Koob, George F.; Wirsching, Peter; Janda, Kim D.; Journal of Medicinal Chemistry; vol. 48; nb. 23; (2005); p. 7389 - 7399 View in Reaxys

HO OH

OH H

H H

H

O

O

Rx-ID: 35091774 View in Reaxys 22/101 Yield

Conditions & References Stage 1: With hydrogenchloride, acetic acid, zinc(II) chloride in water, Time= 3h, T= 20 °C , Inert atmosphere Stage 2: With potassium tert-butylate in benzene, Time= 0.25h, T= -5 - 65 °C , Inert atmosphere Cheng, Li-Jie; Xie, Jian-Hua; Chen, Yong; Wang, Li-Xin; Zhou, Qi-Lin; Organic Letters; vol. 15; nb. 4; (2013); p. 764 - 767 View in Reaxys

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OH OH

OH H

H H

H

O

O

Rx-ID: 35091844 View in Reaxys 23/101 Yield

Conditions & References Stage 1: With hydrogenchloride, acetic acid, zinc(II) chloride in water, Time= 3h, T= 20 °C , Inert atmosphere Stage 2: With potassium tert-butylate in benzene, Time= 0.25h, T= -5 - 65 °C , Inert atmosphere Cheng, Li-Jie; Xie, Jian-Hua; Chen, Yong; Wang, Li-Xin; Zhou, Qi-Lin; Organic Letters; vol. 15; nb. 4; (2013); p. 764 - 767 View in Reaxys

OH H

OH

H

O

Rx-ID: 12616732 View in Reaxys 24/101 Yield

Conditions & References Reaction Steps: 2 1: 37.5 percent / MgSO4; BF3*Et2O / CH2Cl2 / 2.5 h / 0 °C 2: 47 percent / LiAlH4 / tetrahydrofuran / 1 h / 20 °C With lithium aluminium tetrahydride, boron trifluoride diethyl etherate, magnesium sulfate in tetrahydrofuran, dichloromethane Qi, Longwu; Yamamoto, Noboru; Meijler, Michael M.; Altobell III, Laurence J.; Koob, George F.; Wirsching, Peter; Janda, Kim D.; Journal of Medicinal Chemistry; vol. 48; nb. 23; (2005); p. 7389 - 7399 View in Reaxys Reaction Steps: 4 1.1: boron trifluoride diethyl etherate / chlorobenzene / 22 °C 1.2: 0.33 h / 20 °C 2.1: potassium hydroxide / 2 h / 120 °C / 375.04 Torr 3.1: 2 h / 150 °C / 375.04 Torr 4.1: borontrifluoride acetic acid / tert-butyl methyl ether / 3.17 h / 22 °C With boron trifluoride diethyl etherate, borontrifluoride acetic acid, potassium hydroxide in tert-butyl methyl ether, chlorobenzene Patent; SYMRISE AG; Koch, Oskar; Götz, Marcus Rudolf; Looft, Jan; Vössing, Tobias; US2015/336874; (2015); (A1) English View in Reaxys Reaction Steps: 4 1.1: boron trifluoride diethyl etherate / chlorobenzene / 22 °C / Flow reactor 1.2: 0.33 h / 22 °C 2.1: potassium hydroxide / 2 h / 120 °C / 375.04 Torr 3.1: 2 h / 150 °C / 375.04 Torr 4.1: boron trifluoride diacetate / tert-butyl methyl ether / 3.17 h / 22 °C With boron trifluoride diethyl etherate, boron trifluoride diacetate, potassium hydroxide in tert-butyl methyl ether, chlorobenzene Patent; SYMRISE AG; ERFURT, Harry; WEBER, Maria; NIEMEYER, Hans-Jürgen; GÖTZ, Marcus Rudolf; WINKLER, Matthias; (44 pag.); WO2017/194173; (2017); (A1) English View in Reaxys

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O OH H

H

O O

Rx-ID: 21199259 View in Reaxys 25/101 Yield

Conditions & References Reaction Steps: 5 1: 1.) Li, 2.) cuprous bromide, 3.) boron trifluoride etherate 2: HBr / CH2Cl2 / -20 °C 3: CH2Cl2 / 5 h / Ambient temperature 4: 58 percent / boron tribromide / CH2Cl2 / 1.) -76 deg C, 2.) room temp., 7 h 5: KOBu-t / benzene / 1.) 5 deg C, 1 h, 2.) 65 deg C, 10 min With boron trifluoride diethyl etherate, potassium tert-butylate, hydrogen bromide, boron tribromide, lithium, copper(I) bromide in dichloromethane, benzene Rickards; Ronneberg; Journal of Organic Chemistry; vol. 49; nb. 3; (1984); p. 572 - 573 View in Reaxys Reaction Steps: 10 1.1: N,N,N,N,-tetramethylethylenediamine / tetrahydrofuran / -78 °C / Inert atmosphere 1.2: 1.67 h / -78 - 0 °C / Inert atmosphere 1.3: 1.53 h / 0 - 20 °C / Inert atmosphere 2.1: sodium hydroxide / water / 12 h / 60 °C 3.1: sodium tetrahydroborate / ethanol / 10.5 h / 0 - 20 °C 4.1: Savinase 12T; triethylamine / tetrahydrofuran / 72 h / 20 °C / Inert atmosphere; Enzymatic reaction 5.1: sodium hydroxide / ethanol; water / 3 h / Reflux 6.1: dicyclohexyl-carbodiimide; dmap / dichloromethane / 0 - 20 °C 7.1: potassium hexamethylsilazane / toluene / 1.16 h / -78 °C 7.2: 4.25 h / -78 - 20 °C 8.1: toluene; hexane; methanol / 0.5 h / 0 - 20 °C 9.1: Ru(=CHPh)Cl2(N,N'-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene)(Pcyclohexyl3)2 / dichloromethane / 15 h / 40 °C / Inert atmosphere 10.1: diethyl ether / 0.5 h / 0 - 20 °C / Inert atmosphere 10.2: 2 h / 160 °C / 112.51 Torr 10.3: 8 h / 20 °C With Ru(=CHPh)Cl2(N,N'-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene)(Pcyclohexyl3)2, dmap, sodium tetrahydroborate, N,N,N,N,-tetramethylethylenediamine, Savinase 12T, potassium hexamethylsilazane, triethylamine, dicyclohexyl-carbodiimide, sodium hydroxide in tetrahydrofuran, methanol, diethyl ether, ethanol, hexane, dichloromethane, water, toluene, 6.1: | Claisen-Ireland Rearrangement Shultz, Zachary P.; Lawrence, Grant A.; Jacobson, Jeffrey M.; Cruz, Emmanuel J.; Leahy, James W.; Organic Letters; vol. 20; nb. 2; (2018); p. 381 - 384 View in Reaxys Reaction Steps: 8 1.1: N,N,N,N,-tetramethylethylenediamine / tetrahydrofuran / -78 °C / Inert atmosphere 1.2: 1.67 h / -78 - 0 °C / Inert atmosphere 1.3: 1.53 h / 0 - 20 °C / Inert atmosphere 2.1: sodium hydroxide / water / 12 h / 60 °C 3.1: (3aR)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole / toluene / 0.25 h / -78 °C / Inert atmosphere 3.2: 0.58 h / -78 °C / Inert atmosphere 4.1: dicyclohexyl-carbodiimide; dmap / dichloromethane / 0 - 20 °C 5.1: potassium hexamethylsilazane / toluene / 1.16 h / -78 °C 5.2: 4.25 h / -78 - 20 °C 6.1: toluene; hexane; methanol / 0.5 h / 0 - 20 °C 7.1: Ru(=CHPh)Cl2(N,N'-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene)(Pcyclohexyl3)2 / dichloromethane / 15 h / 40 °C / Inert atmosphere

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8.1: diethyl ether / 0.5 h / 0 - 20 °C / Inert atmosphere 8.2: 2 h / 160 °C / 112.51 Torr 8.3: 8 h / 20 °C With Ru(=CHPh)Cl2(N,N'-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene)(Pcyclohexyl3)2, dmap, N,N,N,N,-tetramethylethylenediamine, potassium hexamethylsilazane, dicyclohexyl-carbodiimide, sodium hydroxide, (3aR)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole in tetrahydrofuran, methanol, diethyl ether, hexane, dichloromethane, water, toluene, 4.1: |Claisen-Ireland Rearrangement Shultz, Zachary P.; Lawrence, Grant A.; Jacobson, Jeffrey M.; Cruz, Emmanuel J.; Leahy, James W.; Organic Letters; vol. 20; nb. 2; (2018); p. 381 - 384 View in Reaxys Reaction Steps: 8 1.1: N,N,N,N,-tetramethylethylenediamine / tetrahydrofuran / -78 °C / Inert atmosphere 1.2: 1.67 h / -78 - 0 °C / Inert atmosphere 1.3: 1.53 h / 0 - 20 °C / Inert atmosphere 2.1: sodium hydroxide / water / 12 h / 60 °C 3.1: sodium tetrahydroborate / ethanol / 10.5 h / 0 - 20 °C 4.1: Savinase 12T; triethylamine / tetrahydrofuran / 120 h / 20 °C / Inert atmosphere 5.1: potassium hexamethylsilazane / toluene / 1.16 h / -78 °C 5.2: 4.25 h / -78 - 20 °C 6.1: toluene; hexane; methanol / 0.5 h / 0 - 20 °C 7.1: Ru(=CHPh)Cl2(N,N'-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene)(Pcyclohexyl3)2 / dichloromethane / 15 h / 40 °C / Inert atmosphere 8.1: diethyl ether / 0.5 h / 0 - 20 °C / Inert atmosphere 8.2: 2 h / 160 °C / 112.51 Torr 8.3: 8 h / 20 °C With Ru(=CHPh)Cl2(N,N'-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene)(Pcyclohexyl3)2, sodium tetrahydroborate, N,N,N,N,-tetramethylethylenediamine, Savinase 12T, potassium hexamethylsilazane, triethylamine, sodium hydroxide in tetrahydrofuran, methanol, diethyl ether, ethanol, hexane, dichloromethane, water, toluene Shultz, Zachary P.; Lawrence, Grant A.; Jacobson, Jeffrey M.; Cruz, Emmanuel J.; Leahy, James W.; Organic Letters; vol. 20; nb. 2; (2018); p. 381 - 384 View in Reaxys

O

OH

OH H

H O

O

Rx-ID: 39259621 View in Reaxys 26/101 Yield

Conditions & References Reaction Steps: 5 1.1: bis(1,5-cyclooctadiene)diiridium(I) dichloride; zinc trifluoromethanesulfonate; (S)-(+)-N-(3,5-dioxa-4-phosphacyclohepta-[2,1-a;3,4-aα]dinaphthalen-4-yl)dibenz[b,f]azepine; (S)-2-{bis[3,5-bis(trifluoromethyl)phenyl][(trimethylsilanyl)oxy]methyl}pyrrolidine / 1,2-dichloro-ethane / 20 h / 25 °C / Inert atmosphere 2.1: Ru(=CHPh)Cl2(N,N'-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene)(Pcyclohexyl3)2 / dichloromethane / 18 h / 25 °C / Inert atmosphere 3.1: sodium chlorite; sodium dihydrogenphosphate; 2-methyl-but-2-ene / tert-butyl alcohol; water / 3 h / 25 °C 4.1: diazomethyl-trimethyl-silane / benzene; diethyl ether / 0.75 h / 0 °C / Inert atmosphere 5.1: diethyl ether / 0 °C / Inert atmosphere 5.2: 0.83 h / 160 °C / 112.51 Torr / Inert atmosphere 5.3: 4 h / 20 °C / Inert atmosphere With (S)-2-{bis[3,5-bis(trifluoromethyl)phenyl][(trimethylsilanyl)oxy]methyl}pyrrolidine, Ru(=CHPh)Cl2(N,N'-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene)(Pcyclohexyl3)2, (S)-(+)-N-(3,5-dioxa-4-phosphacyclohepta-[2,1-a;3,4-aα]dinaphthalen-4-yl)dibenz[b,f]azepine, sodium chlorite, sodium dihydrogenphosphate, bis(1,5-cyclooctadiene)diiridium(I) dichloride, 2-

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methyl-but-2-ene, zinc trifluoromethanesulfonate, diazomethyl-trimethyl-silane in diethyl ether, dichloromethane, water, 1,2-dichloro-ethane, tert-butyl alcohol, benzene Schafroth, Michael A.; Zuccarello, Giuseppe; Krautwald, Simon; Sarlah, David; Carreira, Erick M.; Angewandte Chemie - International Edition; vol. 53; nb. 50; (2014); p. 13898 - 13901; Angew. Chem.; vol. 126; nb. 50; (2014); p. 14118 - 14121,4 View in Reaxys

O OH H

O

H

O

O

Rx-ID: 39259633 View in Reaxys 27/101 Yield

Conditions & References Reaction Steps: 4 1.1: Ru(=CHPh)Cl2(N,N'-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene)(Pcyclohexyl3)2 / dichloromethane / 18 h / 25 °C / Inert atmosphere 2.1: sodium chlorite; sodium dihydrogenphosphate; 2-methyl-but-2-ene / tert-butyl alcohol; water / 3 h / 25 °C 3.1: diazomethyl-trimethyl-silane / benzene; diethyl ether / 0.75 h / 0 °C / Inert atmosphere 4.1: diethyl ether / 0 °C / Inert atmosphere 4.2: 0.83 h / 160 °C / 112.51 Torr / Inert atmosphere 4.3: 4 h / 20 °C / Inert atmosphere With Ru(=CHPh)Cl2(N,N'-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene)(Pcyclohexyl3)2, sodium chlorite, sodium dihydrogenphosphate, 2-methyl-but-2-ene, diazomethyl-trimethyl-silane in diethyl ether, dichloromethane, water, tert-butyl alcohol, benzene Schafroth, Michael A.; Zuccarello, Giuseppe; Krautwald, Simon; Sarlah, David; Carreira, Erick M.; Angewandte Chemie - International Edition; vol. 53; nb. 50; (2014); p. 13898 - 13901; Angew. Chem.; vol. 126; nb. 50; (2014); p. 14118 - 14121,4 View in Reaxys

O

OH H

H

O

O

O

Rx-ID: 39259636 View in Reaxys 28/101 Yield

Conditions & References Reaction Steps: 3 1.1: sodium chlorite; sodium dihydrogenphosphate; 2-methyl-but-2-ene / tert-butyl alcohol; water / 3 h / 25 °C 2.1: diazomethyl-trimethyl-silane / benzene; diethyl ether / 0.75 h / 0 °C / Inert atmosphere 3.1: diethyl ether / 0 °C / Inert atmosphere 3.2: 0.83 h / 160 °C / 112.51 Torr / Inert atmosphere 3.3: 4 h / 20 °C / Inert atmosphere With sodium chlorite, sodium dihydrogenphosphate, 2-methyl-but-2-ene, diazomethyl-trimethyl-silane in diethyl ether, water, tert-butyl alcohol, benzene Schafroth, Michael A.; Zuccarello, Giuseppe; Krautwald, Simon; Sarlah, David; Carreira, Erick M.; Angewandte Chemie - International Edition; vol. 53; nb. 50; (2014); p. 13898 - 13901; Angew. Chem.; vol. 126; nb. 50; (2014); p. 14118 - 14121,4 View in Reaxys

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O

OH H

H

O

O

OH O

Rx-ID: 39259637 View in Reaxys 29/101 Yield

Conditions & References Reaction Steps: 2 1.1: diazomethyl-trimethyl-silane / benzene; diethyl ether / 0.75 h / 0 °C / Inert atmosphere 2.1: diethyl ether / 0 °C / Inert atmosphere 2.2: 0.83 h / 160 °C / 112.51 Torr / Inert atmosphere 2.3: 4 h / 20 °C / Inert atmosphere With diazomethyl-trimethyl-silane in diethyl ether, benzene Schafroth, Michael A.; Zuccarello, Giuseppe; Krautwald, Simon; Sarlah, David; Carreira, Erick M.; Angewandte Chemie - International Edition; vol. 53; nb. 50; (2014); p. 13898 - 13901; Angew. Chem.; vol. 126; nb. 50; (2014); p. 14118 - 14121,4 View in Reaxys

OH

O O

OH

OH

OH

H

H

H

O

O

Rx-ID: 8925224 View in Reaxys 30/101 Yield 23 %

Conditions & References With [Mo(CO)4Br]2Br2 in dichloromethane, Time= 4h, T= 20 °C , Title compound not separated from byproducts Malkov, Andrei V.; Kocovsky, Pavel; Collection of Czechoslovak Chemical Communications; vol. 66; nb. 8; (2001); p. 1257 1268 View in Reaxys

OH

O

H

H

O

Rx-ID: 14561258 View in Reaxys 31/101 Yield

Conditions & References Reaction Steps: 12 1.1: 72 percent / BF3*OEt2 / acetic anhydride / 3 h / 0 °C 2.1: 85 percent / allyl methyl carbonate; DPPE; Bu3SnOMe / Pd(OAc)2 / acetonitrile / 5 h / 80 °C 3.1: 94 percent / DIBAL / tetrahydrofuran; hexane / 1.5 h / -78 °C

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4.1: 76 percent / PCC; Celite / CH2Cl2 / 2 h 5.1: 85 percent / imidazole / dimethylformamide 6.1: 73 percent / I2; pyridine / CCl4 7.1: n-BuLi / diethyl ether; hexane 7.2: CuCN / diethyl ether; hexane 7.3: 62 percent / BF3*Et2O / diethyl ether; hexane / -78 °C 8.1: EtMgBr / tetrahydrofuran / 0.17 h / 0 °C 8.2: 66 percent / tetrahydrofuran / 2 h / 0 °C 9.1: Ni(acac)2 / tetrahydrofuran / 0.17 h / 0 °C 9.2: 93 percent / tetrahydrofuran 10.1: 73 percent / NaSEt / dimethylformamide / 12 h / 140 °C 11.1: 84 percent / ZnBr2; MgSO4 / CH2Cl2 / 12 h 12.1: 68 percent / NaSEt / dimethylformamide / 8 h / 120 °C With pyridine, 1H-imidazole, bis(acetylacetonate)nickel(II), n-butyllithium, allyl methyl carbonate, Celite, boron trifluoride diethyl etherate, ethylmagnesium bromide, iodine, tributyltin methoxide, diisobutylaluminium hydride, magnesium sulfate, pyridinium chlorochromate, 1,2-bis-(diphenylphosphino)ethane, zinc dibromide, sodium thioethylate, palladium diacetate in tetrahydrofuran, tetrachloromethane, diethyl ether, hexane, dichloromethane, acetic anhydride, N,N-dimethyl-formamide, acetonitrile William, Anthony D.; Kobayashi, Yuichi; Journal of Organic Chemistry; vol. 67; nb. 25; (2002); p. 8771 - 8782 View in Reaxys

OH H

H

O

Rx-ID: 14563283 View in Reaxys 32/101 Yield

Conditions & References Reaction Steps: 13 1.1: 78 percent / O3 / methanol / 2.5 h / -78 °C 2.1: 72 percent / BF3*OEt2 / acetic anhydride / 3 h / 0 °C 3.1: 85 percent / allyl methyl carbonate; DPPE; Bu3SnOMe / Pd(OAc)2 / acetonitrile / 5 h / 80 °C 4.1: 94 percent / DIBAL / tetrahydrofuran; hexane / 1.5 h / -78 °C 5.1: 76 percent / PCC; Celite / CH2Cl2 / 2 h 6.1: 85 percent / imidazole / dimethylformamide 7.1: 73 percent / I2; pyridine / CCl4 8.1: n-BuLi / diethyl ether; hexane 8.2: CuCN / diethyl ether; hexane 8.3: 62 percent / BF3*Et2O / diethyl ether; hexane / -78 °C 9.1: EtMgBr / tetrahydrofuran / 0.17 h / 0 °C 9.2: 66 percent / tetrahydrofuran / 2 h / 0 °C 10.1: Ni(acac)2 / tetrahydrofuran / 0.17 h / 0 °C 10.2: 93 percent / tetrahydrofuran 11.1: 73 percent / NaSEt / dimethylformamide / 12 h / 140 °C 12.1: 84 percent / ZnBr2; MgSO4 / CH2Cl2 / 12 h 13.1: 68 percent / NaSEt / dimethylformamide / 8 h / 120 °C With pyridine, 1H-imidazole, bis(acetylacetonate)nickel(II), n-butyllithium, allyl methyl carbonate, Celite, boron trifluoride diethyl etherate, ethylmagnesium bromide, iodine, tributyltin methoxide, diisobutylaluminium hydride, magnesium sulfate, ozone, pyridinium chlorochromate, 1,2-bis-(diphenylphosphino)ethane, zinc dibromide, sodium thioethylate, palladium diacetate in tetrahydrofuran, methanol, tetrachloromethane, diethyl ether, hexane, dichloromethane, acetic anhydride, N,N-dimethyl-formamide, acetonitrile William, Anthony D.; Kobayashi, Yuichi; Journal of Organic Chemistry; vol. 67; nb. 25; (2002); p. 8771 - 8782 View in Reaxys

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OH

O

H

O

O

H

O O

Rx-ID: 14566604 View in Reaxys 33/101 Yield

Conditions & References Reaction Steps: 11 1.1: 85 percent / allyl methyl carbonate; DPPE; Bu3SnOMe / Pd(OAc)2 / acetonitrile / 5 h / 80 °C 2.1: 94 percent / DIBAL / tetrahydrofuran; hexane / 1.5 h / -78 °C 3.1: 76 percent / PCC; Celite / CH2Cl2 / 2 h 4.1: 85 percent / imidazole / dimethylformamide 5.1: 73 percent / I2; pyridine / CCl4 6.1: n-BuLi / diethyl ether; hexane 6.2: CuCN / diethyl ether; hexane 6.3: 62 percent / BF3*Et2O / diethyl ether; hexane / -78 °C 7.1: EtMgBr / tetrahydrofuran / 0.17 h / 0 °C 7.2: 66 percent / tetrahydrofuran / 2 h / 0 °C 8.1: Ni(acac)2 / tetrahydrofuran / 0.17 h / 0 °C 8.2: 93 percent / tetrahydrofuran 9.1: 73 percent / NaSEt / dimethylformamide / 12 h / 140 °C 10.1: 84 percent / ZnBr2; MgSO4 / CH2Cl2 / 12 h 11.1: 68 percent / NaSEt / dimethylformamide / 8 h / 120 °C With pyridine, 1H-imidazole, bis(acetylacetonate)nickel(II), n-butyllithium, allyl methyl carbonate, Celite, ethylmagnesium bromide, iodine, tributyltin methoxide, diisobutylaluminium hydride, magnesium sulfate, pyridinium chlorochromate, 1,2-bis-(diphenylphosphino)ethane, zinc dibromide, sodium thioethylate, palladium diacetate in tetrahydrofuran, tetrachloromethane, diethyl ether, hexane, dichloromethane, N,N-dimethyl-formamide, acetonitrile William, Anthony D.; Kobayashi, Yuichi; Journal of Organic Chemistry; vol. 67; nb. 25; (2002); p. 8771 - 8782 View in Reaxys

H

H

OH H O

H

O

Rx-ID: 11673229 View in Reaxys 34/101 Yield

Conditions & References Reaction Steps: 2 1.1: (PhSe)2; NaBH4 / 0 °C 1.2: 28 percent / H2O2 / 0 °C 2.1: 20 percent / BF3*Et2O; MgSO4; NaHCO3 With sodium tetrahydroborate, diphenyl diselenide, boron trifluoride diethyl etherate, sodium hydrogencarbonate, magnesium sulfate Brogan, Andrew P.; Eubanks, Lisa M.; Koob, George F.; Dickerson, Tobin J.; Janda, Kirn D.; Journal of the American Chemical Society; vol. 129; nb. 12; (2007); p. 3698 - 3702 View in Reaxys Reaction Steps: 3 1.1: PhSeSePh; NaBH4 / ethanol / 2 h / Heating 1.2: 52 percent / aq. H2O2 / tetrahydrofuran / 2 h / Heating 2.1: 37.5 percent / MgSO4; BF3*Et2O / CH2Cl2 / 2.5 h / 0 °C

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3.1: 47 percent / LiAlH4 / tetrahydrofuran / 1 h / 20 °C With sodium tetrahydroborate, lithium aluminium tetrahydride, diphenyl diselenide, boron trifluoride diethyl etherate, magnesium sulfate in tetrahydrofuran, ethanol, dichloromethane Qi, Longwu; Yamamoto, Noboru; Meijler, Michael M.; Altobell III, Laurence J.; Koob, George F.; Wirsching, Peter; Janda, Kim D.; Journal of Medicinal Chemistry; vol. 48; nb. 23; (2005); p. 7389 - 7399 View in Reaxys

OH OH OH H

H

O O

Rx-ID: 11928367 View in Reaxys 35/101 Yield

Conditions & References Reaction Steps: 2 1: ZnBr2; MgSO4 / CH2Cl2 / 20 °C 2: 45.5 mg / NaSEt / dimethylformamide / 10 h / 140 °C With magnesium sulfate, zinc dibromide, sodium thioethylate in dichloromethane, N,N-dimethyl-formamide Trost, Barry M.; Dogra, Kalindi; Organic Letters; vol. 9; nb. 5; (2007); p. 861 - 863 View in Reaxys Reaction Steps: 2 1: 84 percent / ZnBr2; MgSO4 / CH2Cl2 / 12 h 2: 68 percent / NaSEt / dimethylformamide / 8 h / 120 °C With magnesium sulfate, zinc dibromide, sodium thioethylate in dichloromethane, N,N-dimethyl-formamide William, Anthony D.; Kobayashi, Yuichi; Journal of Organic Chemistry; vol. 67; nb. 25; (2002); p. 8771 - 8782 View in Reaxys

OH

OH H

H OH

O

Rx-ID: 47350231 View in Reaxys 36/101 Yield

Conditions & References Reaction Steps: 11 1.1: potassium carbonate / acetone / 12.08 h / 80 °C / Inert atmosphere 2.1: N,N,N,N,-tetramethylethylenediamine / tetrahydrofuran / -78 °C / Inert atmosphere 2.2: 1.67 h / -78 - 0 °C / Inert atmosphere 2.3: 1.53 h / 0 - 20 °C / Inert atmosphere 3.1: sodium hydroxide / water / 12 h / 60 °C 4.1: sodium tetrahydroborate / ethanol / 10.5 h / 0 - 20 °C 5.1: Savinase 12T; triethylamine / tetrahydrofuran / 72 h / 20 °C / Inert atmosphere; Enzymatic reaction 6.1: sodium hydroxide / ethanol; water / 3 h / Reflux 7.1: dicyclohexyl-carbodiimide; dmap / dichloromethane / 0 - 20 °C 8.1: potassium hexamethylsilazane / toluene / 1.16 h / -78 °C 8.2: 4.25 h / -78 - 20 °C 9.1: toluene; hexane; methanol / 0.5 h / 0 - 20 °C 10.1: Ru(=CHPh)Cl2(N,N'-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene)(Pcyclohexyl3)2 / dichloromethane / 15 h / 40 °C / Inert atmosphere

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11.1: diethyl ether / 0.5 h / 0 - 20 °C / Inert atmosphere 11.2: 2 h / 160 °C / 112.51 Torr 11.3: 8 h / 20 °C With Ru(=CHPh)Cl2(N,N'-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene)(Pcyclohexyl3)2, dmap, sodium tetrahydroborate, N,N,N,N,-tetramethylethylenediamine, Savinase 12T, potassium hexamethylsilazane, potassium carbonate, triethylamine, dicyclohexyl-carbodiimide, sodium hydroxide in tetrahydrofuran, methanol, diethyl ether, ethanol, hexane, dichloromethane, water, acetone, toluene, 7.1: |Claisen-Ireland Rearrangement Shultz, Zachary P.; Lawrence, Grant A.; Jacobson, Jeffrey M.; Cruz, Emmanuel J.; Leahy, James W.; Organic Letters; vol. 20; nb. 2; (2018); p. 381 - 384 View in Reaxys Reaction Steps: 9 1.1: potassium carbonate / acetone / 12.08 h / 80 °C / Inert atmosphere 2.1: N,N,N,N,-tetramethylethylenediamine / tetrahydrofuran / -78 °C / Inert atmosphere 2.2: 1.67 h / -78 - 0 °C / Inert atmosphere 2.3: 1.53 h / 0 - 20 °C / Inert atmosphere 3.1: sodium hydroxide / water / 12 h / 60 °C 4.1: (3aR)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole / toluene / 0.25 h / -78 °C / Inert atmosphere 4.2: 0.58 h / -78 °C / Inert atmosphere 5.1: dicyclohexyl-carbodiimide; dmap / dichloromethane / 0 - 20 °C 6.1: potassium hexamethylsilazane / toluene / 1.16 h / -78 °C 6.2: 4.25 h / -78 - 20 °C 7.1: toluene; hexane; methanol / 0.5 h / 0 - 20 °C 8.1: Ru(=CHPh)Cl2(N,N'-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene)(Pcyclohexyl3)2 / dichloromethane / 15 h / 40 °C / Inert atmosphere 9.1: diethyl ether / 0.5 h / 0 - 20 °C / Inert atmosphere 9.2: 2 h / 160 °C / 112.51 Torr 9.3: 8 h / 20 °C With Ru(=CHPh)Cl2(N,N'-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene)(Pcyclohexyl3)2, dmap, N,N,N,N,-tetramethylethylenediamine, potassium hexamethylsilazane, potassium carbonate, dicyclohexyl-carbodiimide, sodium hydroxide, (3aR)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole in tetrahydrofuran, methanol, diethyl ether, hexane, dichloromethane, water, acetone, toluene, 5.1: |Claisen-Ireland Rearrangement Shultz, Zachary P.; Lawrence, Grant A.; Jacobson, Jeffrey M.; Cruz, Emmanuel J.; Leahy, James W.; Organic Letters; vol. 20; nb. 2; (2018); p. 381 - 384 View in Reaxys Reaction Steps: 9 1.1: potassium carbonate / acetone / 12.08 h / 80 °C / Inert atmosphere 2.1: N,N,N,N,-tetramethylethylenediamine / tetrahydrofuran / -78 °C / Inert atmosphere 2.2: 1.67 h / -78 - 0 °C / Inert atmosphere 2.3: 1.53 h / 0 - 20 °C / Inert atmosphere 3.1: sodium hydroxide / water / 12 h / 60 °C 4.1: sodium tetrahydroborate / ethanol / 10.5 h / 0 - 20 °C 5.1: Savinase 12T; triethylamine / tetrahydrofuran / 120 h / 20 °C / Inert atmosphere 6.1: potassium hexamethylsilazane / toluene / 1.16 h / -78 °C 6.2: 4.25 h / -78 - 20 °C 7.1: toluene; hexane; methanol / 0.5 h / 0 - 20 °C 8.1: Ru(=CHPh)Cl2(N,N'-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene)(Pcyclohexyl3)2 / dichloromethane / 15 h / 40 °C / Inert atmosphere 9.1: diethyl ether / 0.5 h / 0 - 20 °C / Inert atmosphere 9.2: 2 h / 160 °C / 112.51 Torr 9.3: 8 h / 20 °C With Ru(=CHPh)Cl2(N,N'-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene)(Pcyclohexyl3)2, sodium tetrahydroborate, N,N,N,N,-tetramethylethylenediamine, Savinase 12T, potassium hexamethylsilazane, potassium carbonate, triethylamine, sodium hydroxide in tetrahydrofuran, methanol, diethyl ether, ethanol, hexane, dichloromethane, water, acetone, toluene Shultz, Zachary P.; Lawrence, Grant A.; Jacobson, Jeffrey M.; Cruz, Emmanuel J.; Leahy, James W.; Organic Letters; vol. 20; nb. 2; (2018); p. 381 - 384 View in Reaxys

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O OH H

H

O

O O

Rx-ID: 47350258 View in Reaxys 37/101 Yield

Conditions & References Reaction Steps: 7 1.1: sodium hydroxide / water / 12 h / 60 °C 2.1: (3aR)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole / toluene / 0.25 h / -78 °C / Inert atmosphere 2.2: 0.58 h / -78 °C / Inert atmosphere 3.1: dicyclohexyl-carbodiimide; dmap / dichloromethane / 0 - 20 °C 4.1: potassium hexamethylsilazane / toluene / 1.16 h / -78 °C 4.2: 4.25 h / -78 - 20 °C 5.1: toluene; hexane; methanol / 0.5 h / 0 - 20 °C 6.1: Ru(=CHPh)Cl2(N,N'-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene)(Pcyclohexyl3)2 / dichloromethane / 15 h / 40 °C / Inert atmosphere 7.1: diethyl ether / 0.5 h / 0 - 20 °C / Inert atmosphere 7.2: 2 h / 160 °C / 112.51 Torr 7.3: 8 h / 20 °C With Ru(=CHPh)Cl2(N,N'-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene)(Pcyclohexyl3)2, dmap, potassium hexamethylsilazane, dicyclohexyl-carbodiimide, sodium hydroxide, (3aR)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole in methanol, diethyl ether, hexane, dichloromethane, water, toluene, 3.1: |Claisen-Ireland Rearrangement Shultz, Zachary P.; Lawrence, Grant A.; Jacobson, Jeffrey M.; Cruz, Emmanuel J.; Leahy, James W.; Organic Letters; vol. 20; nb. 2; (2018); p. 381 - 384 View in Reaxys Reaction Steps: 7 1.1: sodium hydroxide / water / 12 h / 60 °C 2.1: sodium tetrahydroborate / ethanol / 10.5 h / 0 - 20 °C 3.1: Savinase 12T; triethylamine / tetrahydrofuran / 120 h / 20 °C / Inert atmosphere 4.1: potassium hexamethylsilazane / toluene / 1.16 h / -78 °C 4.2: 4.25 h / -78 - 20 °C 5.1: toluene; hexane; methanol / 0.5 h / 0 - 20 °C 6.1: Ru(=CHPh)Cl2(N,N'-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene)(Pcyclohexyl3)2 / dichloromethane / 15 h / 40 °C / Inert atmosphere 7.1: diethyl ether / 0.5 h / 0 - 20 °C / Inert atmosphere 7.2: 2 h / 160 °C / 112.51 Torr 7.3: 8 h / 20 °C With Ru(=CHPh)Cl2(N,N'-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene)(Pcyclohexyl3)2, sodium tetrahydroborate, Savinase 12T, potassium hexamethylsilazane, triethylamine, sodium hydroxide in tetrahydrofuran, methanol, diethyl ether, ethanol, hexane, dichloromethane, water, toluene Shultz, Zachary P.; Lawrence, Grant A.; Jacobson, Jeffrey M.; Cruz, Emmanuel J.; Leahy, James W.; Organic Letters; vol. 20; nb. 2; (2018); p. 381 - 384 View in Reaxys Reaction Steps: 9 1.1: sodium hydroxide / water / 12 h / 60 °C 2.1: sodium tetrahydroborate / ethanol / 10.5 h / 0 - 20 °C 3.1: Savinase 12T; triethylamine / tetrahydrofuran / 72 h / 20 °C / Inert atmosphere; Enzymatic reaction 4.1: sodium hydroxide / ethanol; water / 3 h / Reflux 5.1: dicyclohexyl-carbodiimide; dmap / dichloromethane / 0 - 20 °C 6.1: potassium hexamethylsilazane / toluene / 1.16 h / -78 °C 6.2: 4.25 h / -78 - 20 °C 7.1: toluene; hexane; methanol / 0.5 h / 0 - 20 °C

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8.1: Ru(=CHPh)Cl2(N,N'-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene)(Pcyclohexyl3)2 / dichloromethane / 15 h / 40 °C / Inert atmosphere 9.1: diethyl ether / 0.5 h / 0 - 20 °C / Inert atmosphere 9.2: 2 h / 160 °C / 112.51 Torr 9.3: 8 h / 20 °C With Ru(=CHPh)Cl2(N,N'-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene)(Pcyclohexyl3)2, dmap, sodium tetrahydroborate, Savinase 12T, potassium hexamethylsilazane, triethylamine, dicyclohexyl-carbodiimide, sodium hydroxide in tetrahydrofuran, methanol, diethyl ether, ethanol, hexane, dichloromethane, water, toluene, 5.1: |Claisen-Ireland Rearrangement Shultz, Zachary P.; Lawrence, Grant A.; Jacobson, Jeffrey M.; Cruz, Emmanuel J.; Leahy, James W.; Organic Letters; vol. 20; nb. 2; (2018); p. 381 - 384 View in Reaxys

O OH H

H

O

O O

Rx-ID: 47350270 View in Reaxys 38/101 Yield

Conditions & References Reaction Steps: 6 1.1: sodium tetrahydroborate / ethanol / 10.5 h / 0 - 20 °C 2.1: Savinase 12T; triethylamine / tetrahydrofuran / 120 h / 20 °C / Inert atmosphere 3.1: potassium hexamethylsilazane / toluene / 1.16 h / -78 °C 3.2: 4.25 h / -78 - 20 °C 4.1: toluene; hexane; methanol / 0.5 h / 0 - 20 °C 5.1: Ru(=CHPh)Cl2(N,N'-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene)(Pcyclohexyl3)2 / dichloromethane / 15 h / 40 °C / Inert atmosphere 6.1: diethyl ether / 0.5 h / 0 - 20 °C / Inert atmosphere 6.2: 2 h / 160 °C / 112.51 Torr 6.3: 8 h / 20 °C With Ru(=CHPh)Cl2(N,N'-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene)(Pcyclohexyl3)2, sodium tetrahydroborate, Savinase 12T, potassium hexamethylsilazane, triethylamine in tetrahydrofuran, methanol, diethyl ether, ethanol, hexane, dichloromethane, toluene Shultz, Zachary P.; Lawrence, Grant A.; Jacobson, Jeffrey M.; Cruz, Emmanuel J.; Leahy, James W.; Organic Letters; vol. 20; nb. 2; (2018); p. 381 - 384 View in Reaxys Reaction Steps: 6 1.1: (3aR)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole / toluene / 0.25 h / -78 °C / Inert atmosphere 1.2: 0.58 h / -78 °C / Inert atmosphere 2.1: dicyclohexyl-carbodiimide; dmap / dichloromethane / 0 - 20 °C 3.1: potassium hexamethylsilazane / toluene / 1.16 h / -78 °C 3.2: 4.25 h / -78 - 20 °C 4.1: toluene; hexane; methanol / 0.5 h / 0 - 20 °C 5.1: Ru(=CHPh)Cl2(N,N'-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene)(Pcyclohexyl3)2 / dichloromethane / 15 h / 40 °C / Inert atmosphere 6.1: diethyl ether / 0.5 h / 0 - 20 °C / Inert atmosphere 6.2: 2 h / 160 °C / 112.51 Torr 6.3: 8 h / 20 °C With Ru(=CHPh)Cl2(N,N'-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene)(Pcyclohexyl3)2, dmap, potassium hexamethylsilazane, dicyclohexyl-carbodiimide, (3aR)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole in methanol, diethyl ether, hexane, dichloromethane, toluene, 2.1: |Claisen-Ireland Rearrangement Shultz, Zachary P.; Lawrence, Grant A.; Jacobson, Jeffrey M.; Cruz, Emmanuel J.; Leahy, James W.; Organic Letters; vol. 20; nb. 2; (2018); p. 381 - 384

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View in Reaxys Reaction Steps: 8 1.1: sodium tetrahydroborate / ethanol / 10.5 h / 0 - 20 °C 2.1: Savinase 12T; triethylamine / tetrahydrofuran / 72 h / 20 °C / Inert atmosphere; Enzymatic reaction 3.1: sodium hydroxide / ethanol; water / 3 h / Reflux 4.1: dicyclohexyl-carbodiimide; dmap / dichloromethane / 0 - 20 °C 5.1: potassium hexamethylsilazane / toluene / 1.16 h / -78 °C 5.2: 4.25 h / -78 - 20 °C 6.1: toluene; hexane; methanol / 0.5 h / 0 - 20 °C 7.1: Ru(=CHPh)Cl2(N,N'-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene)(Pcyclohexyl3)2 / dichloromethane / 15 h / 40 °C / Inert atmosphere 8.1: diethyl ether / 0.5 h / 0 - 20 °C / Inert atmosphere 8.2: 2 h / 160 °C / 112.51 Torr 8.3: 8 h / 20 °C With Ru(=CHPh)Cl2(N,N'-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene)(Pcyclohexyl3)2, dmap, sodium tetrahydroborate, Savinase 12T, potassium hexamethylsilazane, triethylamine, dicyclohexyl-carbodiimide, sodium hydroxide in tetrahydrofuran, methanol, diethyl ether, ethanol, hexane, dichloromethane, water, toluene, 4.1: |Claisen-Ireland Rearrangement Shultz, Zachary P.; Lawrence, Grant A.; Jacobson, Jeffrey M.; Cruz, Emmanuel J.; Leahy, James W.; Organic Letters; vol. 20; nb. 2; (2018); p. 381 - 384 View in Reaxys

O

OH

O

O

H

H

O

O

Rx-ID: 11895239 View in Reaxys 39/101 Yield

Conditions & References Reaction Steps: 7 1: 50 percent / LiHMDS / tetrahydrofuran / -40 °C 2: Grubb's II catalyst / CH2Cl2 / 20 °C 3: 91.6 percent / MeONa / methanol / 72 h / 65 °C 4: 93 percent / diethyl ether / -78 - 20 °C 5: 97 percent / NaSEt / dimethylformamide / 3 h / 140 °C 6: ZnBr2; MgSO4 / CH2Cl2 / 20 °C 7: 45.5 mg / NaSEt / dimethylformamide / 10 h / 140 °C With Ru(=CHPh)Cl2(N,N'-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene)(Pcyclohexyl3)2, sodium methylate, magnesium sulfate, zinc dibromide, lithium hexamethyldisilazane, sodium thioethylate in tetrahydrofuran, methanol, diethyl ether, dichloromethane, N,N-dimethyl-formamide Trost, Barry M.; Dogra, Kalindi; Organic Letters; vol. 9; nb. 5; (2007); p. 861 - 863 View in Reaxys Reaction Steps: 6 1: 50 percent / LiHMDS / tetrahydrofuran / -40 °C 2: 92.9 percent / Grubb's II catalyst / CH2Cl2 / 20 °C 3: 93 percent / diethyl ether / -78 - 20 °C 4: 97 percent / NaSEt / dimethylformamide / 3 h / 140 °C 5: ZnBr2; MgSO4 / CH2Cl2 / 20 °C 6: 45.5 mg / NaSEt / dimethylformamide / 10 h / 140 °C With Ru(=CHPh)Cl2(N,N'-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene)(Pcyclohexyl3)2, magnesium sulfate, zinc dibromide, lithium hexamethyldisilazane, sodium thioethylate in tetrahydrofuran, diethyl ether, dichloromethane, N,N-dimethylformamide Trost, Barry M.; Dogra, Kalindi; Organic Letters; vol. 9; nb. 5; (2007); p. 861 - 863

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View in Reaxys

O O OH

O H

O O H

O

O

Rx-ID: 11897664 View in Reaxys 40/101 Yield

Conditions & References Reaction Steps: 8 1: 83 percent / aq. NaCl / dimethylsulfoxide / 160 °C 2: 50 percent / LiHMDS / tetrahydrofuran / -40 °C 3: Grubb's II catalyst / CH2Cl2 / 20 °C 4: 91.6 percent / MeONa / methanol / 72 h / 65 °C 5: 93 percent / diethyl ether / -78 - 20 °C 6: 97 percent / NaSEt / dimethylformamide / 3 h / 140 °C 7: ZnBr2; MgSO4 / CH2Cl2 / 20 °C 8: 45.5 mg / NaSEt / dimethylformamide / 10 h / 140 °C With Ru(=CHPh)Cl2(N,N'-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene)(Pcyclohexyl3)2, sodium methylate, magnesium sulfate, sodium chloride, zinc dibromide, lithium hexamethyldisilazane, sodium thioethylate in tetrahydrofuran, methanol, diethyl ether, dichloromethane, dimethyl sulfoxide, N,N-dimethyl-formamide, 1: Krapcho decarboxylation Trost, Barry M.; Dogra, Kalindi; Organic Letters; vol. 9; nb. 5; (2007); p. 861 - 863 View in Reaxys Reaction Steps: 7 1: 83 percent / aq. NaCl / dimethylsulfoxide / 160 °C 2: 50 percent / LiHMDS / tetrahydrofuran / -40 °C 3: 92.9 percent / Grubb's II catalyst / CH2Cl2 / 20 °C 4: 93 percent / diethyl ether / -78 - 20 °C 5: 97 percent / NaSEt / dimethylformamide / 3 h / 140 °C 6: ZnBr2; MgSO4 / CH2Cl2 / 20 °C 7: 45.5 mg / NaSEt / dimethylformamide / 10 h / 140 °C With Ru(=CHPh)Cl2(N,N'-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene)(Pcyclohexyl3)2, magnesium sulfate, sodium chloride, zinc dibromide, lithium hexamethyldisilazane, sodium thioethylate in tetrahydrofuran, diethyl ether, dichloromethane, dimethyl sulfoxide, N,N-dimethyl-formamide, 1: Krapcho decarboxylation Trost, Barry M.; Dogra, Kalindi; Organic Letters; vol. 9; nb. 5; (2007); p. 861 - 863 View in Reaxys

O

OH H O

O

H

O O

Rx-ID: 11899289 View in Reaxys 41/101 Yield

Conditions & References Reaction Steps: 6 1: Grubb's II catalyst / CH2Cl2 / 20 °C 2: 91.6 percent / MeONa / methanol / 72 h / 65 °C 3: 93 percent / diethyl ether / -78 - 20 °C

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4: 97 percent / NaSEt / dimethylformamide / 3 h / 140 °C 5: ZnBr2; MgSO4 / CH2Cl2 / 20 °C 6: 45.5 mg / NaSEt / dimethylformamide / 10 h / 140 °C With Ru(=CHPh)Cl2(N,N'-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene)(Pcyclohexyl3)2, sodium methylate, magnesium sulfate, zinc dibromide, sodium thioethylate in methanol, diethyl ether, dichloromethane, N,N-dimethyl-formamide Trost, Barry M.; Dogra, Kalindi; Organic Letters; vol. 9; nb. 5; (2007); p. 861 - 863 View in Reaxys Reaction Steps: 5 1: 92.9 percent / Grubb's II catalyst / CH2Cl2 / 20 °C 2: 93 percent / diethyl ether / -78 - 20 °C 3: 97 percent / NaSEt / dimethylformamide / 3 h / 140 °C 4: ZnBr2; MgSO4 / CH2Cl2 / 20 °C 5: 45.5 mg / NaSEt / dimethylformamide / 10 h / 140 °C With Ru(=CHPh)Cl2(N,N'-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene)(Pcyclohexyl3)2, magnesium sulfate, zinc dibromide, sodium thioethylate in diethyl ether, dichloromethane, N,N-dimethyl-formamide Trost, Barry M.; Dogra, Kalindi; Organic Letters; vol. 9; nb. 5; (2007); p. 861 - 863 View in Reaxys

OH

OH H O

O

H

O O

Rx-ID: 11899323 View in Reaxys 42/101 Yield

Conditions & References Reaction Steps: 7 1: K2CO3 / acetone / 3 h / Heating 2: Grubb's II catalyst / CH2Cl2 / 20 °C 3: 91.6 percent / MeONa / methanol / 72 h / 65 °C 4: 93 percent / diethyl ether / -78 - 20 °C 5: 97 percent / NaSEt / dimethylformamide / 3 h / 140 °C 6: ZnBr2; MgSO4 / CH2Cl2 / 20 °C 7: 45.5 mg / NaSEt / dimethylformamide / 10 h / 140 °C With Ru(=CHPh)Cl2(N,N'-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene)(Pcyclohexyl3)2, sodium methylate, magnesium sulfate, potassium carbonate, zinc dibromide, sodium thioethylate in methanol, diethyl ether, dichloromethane, N,N-dimethyl-formamide, acetone Trost, Barry M.; Dogra, Kalindi; Organic Letters; vol. 9; nb. 5; (2007); p. 861 - 863 View in Reaxys Reaction Steps: 6 1: K2CO3 / acetone / 3 h / Heating 2: 92.9 percent / Grubb's II catalyst / CH2Cl2 / 20 °C 3: 93 percent / diethyl ether / -78 - 20 °C 4: 97 percent / NaSEt / dimethylformamide / 3 h / 140 °C 5: ZnBr2; MgSO4 / CH2Cl2 / 20 °C 6: 45.5 mg / NaSEt / dimethylformamide / 10 h / 140 °C With Ru(=CHPh)Cl2(N,N'-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene)(Pcyclohexyl3)2, magnesium sulfate, potassium carbonate, zinc dibromide, sodium thioethylate in diethyl ether, dichloromethane, N,N-dimethyl-formamide, acetone Trost, Barry M.; Dogra, Kalindi; Organic Letters; vol. 9; nb. 5; (2007); p. 861 - 863

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View in Reaxys Rx-ID: 28046312 View in Reaxys 43/101 Yield

Conditions & References 8 :Example 8α9-THC-2-Carboxylic Acid (THCA) Coated FilmsCoated substrates were generated by spray depositing prodrug, 9α THC-2- carboxylic acid, solution (about 50 mg/mL prodrug in organic solvent) onto a small section of a laser-cut stainless steel (SS) foil coupon (SAE 304, 1 = 6 cm, w = 1.25 cm, t = 0.01 cm). The spray coating system consisted of an ultrasonic nozzle spray nozzle (Sono-Tek Corp, Milton, NY) mounted on a Cartesian robot and fed by a calibrated syringe pump. The prodrug loading (coated mass normalized over coated surface area [mg/cm2]) was accurately controlled by varying the coating surface area and the syringe pump delivery rate. The coat content and prodrug loading were verified by recovering the coated prodrug from the foil in organic solvent and analyzing the solution using high performance liquid chromatography (HPLC). The solvent was evaporated, leaving behind a prodrug film.A 6-month comprehensive stability study of α9-THC-2-carboxylic acid (THCA; shown in Figure 3; obtained from Aphios Corporation, Woburn, MA) coated onto vaporization substrates (1 mg/cm2) was conducted using three temperature and relative humidity (RH) conditions:1) 25°C + 60 percent RH (normal room conditions);2) 400C + 75 percent RH (FDA accelerated stability conditions); and 3) 400C + anhydrous.By the end of 6 months, the samples stored at normal room conditions experienced an inconsequential loss in purity, whereas the samples stored at 4O0C and 75 percent RH experienced a nearly 60percent loss in chemical purity.The major degradant identified in the accelerated stability condition was the therapeutic α9-THC. This is an acceptable degradant. When stored at normal room temperature and humidity, the chemical integrity of THCA coated on stainless steel foil is preserved for at least 6 months.Previous studies indicated that dronabinol (THC) remains only 60 percent pure after 4 weeks dark storage at room temperature and humidity, and roughly 30 percent pure after <n="16"/>14 weeks in the same conditions. Hence, in comparison with pure THC, THCA presents a viable formulation strategy for addressing this shelf-life issue. The major known degradation products comprised > 0.5percent total peak area (confirmed with internal standards). The corresponding fraction of total peak area for 1.0 mg/cm2 THCA coatings stored at 4O0C and 75 percent relative humidity (worst case scenario) are set forth in Table One, below.Table 1Major Degradation Products Identified After a 6-Month Stability Study of THCA Coated onto SS Foils and Stored at 4O0C and 75 percent RH* RRT = Relative retention time to THCA (RT = 34.1 min); 60 min gradient with acidic mobile phase; detection at 215 nm.An advantage of THCA is that it is a solid that forms a physically stable film, as opposed to α9-THC, which is a viscous oil whose coated films are subject to flow. Physical stability drop tests indicated that THCA coatings (maximum loading tested was 1.0 mg/cm2) on stainless steel substrates are physically robust, even after 6 months storage at various environmental conditions.

With water, Time= 4383h, T= 40 °C , p= 760.051Torr , Reactivity Patent; ALEXZA PHARMACEUTICALS, INC.; WO2008/134668; (2008); (A2) English View in Reaxys

O

O OH H

H

F O

O

O

Rx-ID: 35091762 View in Reaxys 44/101 Yield

Conditions & References Reaction Steps: 4 1.1: tetrahydrofuran; diethyl ether / 3 h / 0 °C / Reflux; Inert atmosphere 2.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 1 h / 130 - 140 °C / Inert atmosphere 3.1: sodium hydride; 2-(diethylamine)ethanethiol / N,N-dimethyl-formamide; mineral oil / 6 h / 130 - 140 °C / Inert atmosphere 4.1: acetic acid; zinc(II) chloride; hydrogenchloride / water / 3 h / 20 °C / Inert atmosphere 4.2: 0.25 h / -5 - 65 °C / Inert atmosphere With hydrogenchloride, sodium hydride, acetic acid, 2-(diethylamine)ethanethiol, zinc(II) chloride in tetrahydrofuran, diethyl ether, water, N,N-dimethyl-formamide, mineral oil Cheng, Li-Jie; Xie, Jian-Hua; Chen, Yong; Wang, Li-Xin; Zhou, Qi-Lin; Organic Letters; vol. 15; nb. 4; (2013); p. 764 - 767 View in Reaxys Reaction Steps: 4 1.1: tetrahydrofuran; diethyl ether / 3 h / 0 °C / Reflux; Inert atmosphere

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2.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 1 h / 130 - 140 °C / Inert atmosphere 3.1: sodium hydride; 2-(diethylamine)ethanethiol / N,N-dimethyl-formamide; mineral oil / 6 h / 130 - 140 °C / Inert atmosphere 4.1: acetic acid; zinc(II) chloride; hydrogenchloride / water / 3 h / 20 °C / Inert atmosphere 4.2: 0.25 h / -5 - 65 °C / Inert atmosphere With hydrogenchloride, sodium hydride, acetic acid, 2-(diethylamine)ethanethiol, zinc(II) chloride in tetrahydrofuran, diethyl ether, water, N,N-dimethyl-formamide, mineral oil Cheng, Li-Jie; Xie, Jian-Hua; Chen, Yong; Wang, Li-Xin; Zhou, Qi-Lin; Organic Letters; vol. 15; nb. 4; (2013); p. 764 - 767 View in Reaxys

O

O O

OH H

H

O

F

O

Rx-ID: 35091802 View in Reaxys 45/101 Yield

Conditions & References Reaction Steps: 7 1.1: acetic acid / water / 2 h / 100 °C / Reflux; Inert atmosphere 2.1: Jones reagent / water; acetone / 2 h / 20 °C / Cooling with ice; Inert atmosphere 3.1: potassium carbonate / N,N-dimethyl-formamide / 12 h / 20 °C / Inert atmosphere 3.2: 24 h / 20 °C / Inert atmosphere 4.1: tetrahydrofuran; diethyl ether / 3 h / 0 °C / Reflux; Inert atmosphere 5.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 1 h / 130 - 140 °C / Inert atmosphere 6.1: sodium hydride; 2-(diethylamine)ethanethiol / N,N-dimethyl-formamide; mineral oil / 6 h / 130 - 140 °C / Inert atmosphere 7.1: acetic acid; zinc(II) chloride; hydrogenchloride / water / 3 h / 20 °C / Inert atmosphere 7.2: 0.25 h / -5 - 65 °C / Inert atmosphere With hydrogenchloride, Jones reagent, sodium hydride, potassium carbonate, acetic acid, 2-(diethylamine)ethanethiol, zinc(II) chloride in tetrahydrofuran, diethyl ether, water, N,N-dimethyl-formamide, acetone, mineral oil Cheng, Li-Jie; Xie, Jian-Hua; Chen, Yong; Wang, Li-Xin; Zhou, Qi-Lin; Organic Letters; vol. 15; nb. 4; (2013); p. 764 - 767 View in Reaxys Reaction Steps: 7 1.1: acetic acid / water / 2 h / 100 °C / Reflux; Inert atmosphere 2.1: Jones reagent / water; acetone / 2 h / 20 °C / Cooling with ice; Inert atmosphere 3.1: potassium carbonate / N,N-dimethyl-formamide / 12 h / 20 °C / Inert atmosphere 3.2: 24 h / 20 °C / Inert atmosphere 4.1: tetrahydrofuran; diethyl ether / 3 h / 0 °C / Reflux; Inert atmosphere 5.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 1 h / 130 - 140 °C / Inert atmosphere 6.1: sodium hydride; 2-(diethylamine)ethanethiol / N,N-dimethyl-formamide; mineral oil / 6 h / 130 - 140 °C / Inert atmosphere 7.1: acetic acid; zinc(II) chloride; hydrogenchloride / water / 3 h / 20 °C / Inert atmosphere 7.2: 0.25 h / -5 - 65 °C / Inert atmosphere With hydrogenchloride, Jones reagent, sodium hydride, potassium carbonate, acetic acid, 2-(diethylamine)ethanethiol, zinc(II) chloride in tetrahydrofuran, diethyl ether, water, N,N-dimethyl-formamide, acetone, mineral oil Cheng, Li-Jie; Xie, Jian-Hua; Chen, Yong; Wang, Li-Xin; Zhou, Qi-Lin; Organic Letters; vol. 15; nb. 4; (2013); p. 764 - 767 View in Reaxys

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O

O OH

O

H

H

O

O

F

Rx-ID: 35091813 View in Reaxys 46/101 Yield

Conditions & References Reaction Steps: 6 1.1: Jones reagent / water; acetone / 2 h / 20 °C / Cooling with ice; Inert atmosphere 2.1: potassium carbonate / N,N-dimethyl-formamide / 12 h / 20 °C / Inert atmosphere 2.2: 24 h / 20 °C / Inert atmosphere 3.1: tetrahydrofuran; diethyl ether / 3 h / 0 °C / Reflux; Inert atmosphere 4.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 1 h / 130 - 140 °C / Inert atmosphere 5.1: sodium hydride; 2-(diethylamine)ethanethiol / N,N-dimethyl-formamide; mineral oil / 6 h / 130 - 140 °C / Inert atmosphere 6.1: acetic acid; zinc(II) chloride; hydrogenchloride / water / 3 h / 20 °C / Inert atmosphere 6.2: 0.25 h / -5 - 65 °C / Inert atmosphere With hydrogenchloride, Jones reagent, sodium hydride, potassium carbonate, acetic acid, 2-(diethylamine)ethanethiol, zinc(II) chloride in tetrahydrofuran, diethyl ether, water, N,N-dimethyl-formamide, acetone, mineral oil Cheng, Li-Jie; Xie, Jian-Hua; Chen, Yong; Wang, Li-Xin; Zhou, Qi-Lin; Organic Letters; vol. 15; nb. 4; (2013); p. 764 - 767 View in Reaxys Reaction Steps: 6 1.1: Jones reagent / water; acetone / 2 h / 20 °C / Cooling with ice; Inert atmosphere 2.1: potassium carbonate / N,N-dimethyl-formamide / 12 h / 20 °C / Inert atmosphere 2.2: 24 h / 20 °C / Inert atmosphere 3.1: tetrahydrofuran; diethyl ether / 3 h / 0 °C / Reflux; Inert atmosphere 4.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 1 h / 130 - 140 °C / Inert atmosphere 5.1: sodium hydride; 2-(diethylamine)ethanethiol / N,N-dimethyl-formamide; mineral oil / 6 h / 130 - 140 °C / Inert atmosphere 6.1: acetic acid; zinc(II) chloride; hydrogenchloride / water / 3 h / 20 °C / Inert atmosphere 6.2: 0.25 h / -5 - 65 °C / Inert atmosphere With hydrogenchloride, Jones reagent, sodium hydride, potassium carbonate, acetic acid, 2-(diethylamine)ethanethiol, zinc(II) chloride in tetrahydrofuran, diethyl ether, water, N,N-dimethyl-formamide, acetone, mineral oil Cheng, Li-Jie; Xie, Jian-Hua; Chen, Yong; Wang, Li-Xin; Zhou, Qi-Lin; Organic Letters; vol. 15; nb. 4; (2013); p. 764 - 767 View in Reaxys

O

O OH

O H

H

O

F O

OH

Rx-ID: 35091825 View in Reaxys 47/101 Yield

Conditions & References Reaction Steps: 5 1.1: potassium carbonate / N,N-dimethyl-formamide / 12 h / 20 °C / Inert atmosphere 1.2: 24 h / 20 °C / Inert atmosphere 2.1: tetrahydrofuran; diethyl ether / 3 h / 0 °C / Reflux; Inert atmosphere 3.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 1 h / 130 - 140 °C / Inert atmosphere 4.1: sodium hydride; 2-(diethylamine)ethanethiol / N,N-dimethyl-formamide; mineral oil / 6 h / 130 - 140 °C / Inert atmosphere 5.1: acetic acid; zinc(II) chloride; hydrogenchloride / water / 3 h / 20 °C / Inert atmosphere 5.2: 0.25 h / -5 - 65 °C / Inert atmosphere

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With hydrogenchloride, sodium hydride, potassium carbonate, acetic acid, 2-(diethylamine)ethanethiol, zinc(II) chloride in tetrahydrofuran, diethyl ether, water, N,N-dimethyl-formamide, mineral oil Cheng, Li-Jie; Xie, Jian-Hua; Chen, Yong; Wang, Li-Xin; Zhou, Qi-Lin; Organic Letters; vol. 15; nb. 4; (2013); p. 764 - 767 View in Reaxys Reaction Steps: 5 1.1: potassium carbonate / N,N-dimethyl-formamide / 12 h / 20 °C / Inert atmosphere 1.2: 24 h / 20 °C / Inert atmosphere 2.1: tetrahydrofuran; diethyl ether / 3 h / 0 °C / Reflux; Inert atmosphere 3.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 1 h / 130 - 140 °C / Inert atmosphere 4.1: sodium hydride; 2-(diethylamine)ethanethiol / N,N-dimethyl-formamide; mineral oil / 6 h / 130 - 140 °C / Inert atmosphere 5.1: acetic acid; zinc(II) chloride; hydrogenchloride / water / 3 h / 20 °C / Inert atmosphere 5.2: 0.25 h / -5 - 65 °C / Inert atmosphere With hydrogenchloride, sodium hydride, potassium carbonate, acetic acid, 2-(diethylamine)ethanethiol, zinc(II) chloride in tetrahydrofuran, diethyl ether, water, N,N-dimethyl-formamide, mineral oil Cheng, Li-Jie; Xie, Jian-Hua; Chen, Yong; Wang, Li-Xin; Zhou, Qi-Lin; Organic Letters; vol. 15; nb. 4; (2013); p. 764 - 767 View in Reaxys

HO O OH H

H

F O

OH

Rx-ID: 35091847 View in Reaxys 48/101 Yield

Conditions & References Reaction Steps: 2 1.1: sodium hydride; 2-(diethylamine)ethanethiol / N,N-dimethyl-formamide; mineral oil / 6 h / 130 - 140 °C / Inert atmosphere 2.1: acetic acid; zinc(II) chloride; hydrogenchloride / water / 3 h / 20 °C / Inert atmosphere 2.2: 0.25 h / -5 - 65 °C / Inert atmosphere With hydrogenchloride, sodium hydride, acetic acid, 2-(diethylamine)ethanethiol, zinc(II) chloride in water, N,N-dimethyl-formamide, mineral oil Cheng, Li-Jie; Xie, Jian-Hua; Chen, Yong; Wang, Li-Xin; Zhou, Qi-Lin; Organic Letters; vol. 15; nb. 4; (2013); p. 764 - 767 View in Reaxys Reaction Steps: 2 1.1: sodium hydride; 2-(diethylamine)ethanethiol / N,N-dimethyl-formamide; mineral oil / 6 h / 130 - 140 °C / Inert atmosphere 2.1: acetic acid; zinc(II) chloride; hydrogenchloride / water / 3 h / 20 °C / Inert atmosphere 2.2: 0.25 h / -5 - 65 °C / Inert atmosphere With hydrogenchloride, sodium hydride, acetic acid, 2-(diethylamine)ethanethiol, zinc(II) chloride in water, N,N-dimethyl-formamide, mineral oil Cheng, Li-Jie; Xie, Jian-Hua; Chen, Yong; Wang, Li-Xin; Zhou, Qi-Lin; Organic Letters; vol. 15; nb. 4; (2013); p. 764 - 767 View in Reaxys

OH

O OH H

H

O O

Rx-ID: 47350280 View in Reaxys 49/101

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Yield

Conditions & References Reaction Steps: 5 1.1: Savinase 12T; triethylamine / tetrahydrofuran / 120 h / 20 °C / Inert atmosphere 2.1: potassium hexamethylsilazane / toluene / 1.16 h / -78 °C 2.2: 4.25 h / -78 - 20 °C 3.1: toluene; hexane; methanol / 0.5 h / 0 - 20 °C 4.1: Ru(=CHPh)Cl2(N,N'-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene)(Pcyclohexyl3)2 / dichloromethane / 15 h / 40 °C / Inert atmosphere 5.1: diethyl ether / 0.5 h / 0 - 20 °C / Inert atmosphere 5.2: 2 h / 160 °C / 112.51 Torr 5.3: 8 h / 20 °C With Ru(=CHPh)Cl2(N,N'-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene)(Pcyclohexyl3)2, Savinase 12T, potassium hexamethylsilazane, triethylamine in tetrahydrofuran, methanol, diethyl ether, hexane, dichloromethane, toluene Shultz, Zachary P.; Lawrence, Grant A.; Jacobson, Jeffrey M.; Cruz, Emmanuel J.; Leahy, James W.; Organic Letters; vol. 20; nb. 2; (2018); p. 381 - 384 View in Reaxys Reaction Steps: 7 1.1: Savinase 12T; triethylamine / tetrahydrofuran / 72 h / 20 °C / Inert atmosphere; Enzymatic reaction 2.1: sodium hydroxide / ethanol; water / 3 h / Reflux 3.1: dicyclohexyl-carbodiimide; dmap / dichloromethane / 0 - 20 °C 4.1: potassium hexamethylsilazane / toluene / 1.16 h / -78 °C 4.2: 4.25 h / -78 - 20 °C 5.1: toluene; hexane; methanol / 0.5 h / 0 - 20 °C 6.1: Ru(=CHPh)Cl2(N,N'-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene)(Pcyclohexyl3)2 / dichloromethane / 15 h / 40 °C / Inert atmosphere 7.1: diethyl ether / 0.5 h / 0 - 20 °C / Inert atmosphere 7.2: 2 h / 160 °C / 112.51 Torr 7.3: 8 h / 20 °C With Ru(=CHPh)Cl2(N,N'-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene)(Pcyclohexyl3)2, dmap, Savinase 12T, potassium hexamethylsilazane, triethylamine, dicyclohexyl-carbodiimide, sodium hydroxide in tetrahydrofuran, methanol, diethyl ether, ethanol, hexane, dichloromethane, water, toluene, 3.1: |Claisen-Ireland Rearrangement Shultz, Zachary P.; Lawrence, Grant A.; Jacobson, Jeffrey M.; Cruz, Emmanuel J.; Leahy, James W.; Organic Letters; vol. 20; nb. 2; (2018); p. 381 - 384 View in Reaxys

HO

OH

O

H

H

O

O

Rx-ID: 11898117 View in Reaxys 50/101 Yield

Conditions & References Reaction Steps: 3 1: 97 percent / NaSEt / dimethylformamide / 3 h / 140 °C 2: ZnBr2; MgSO4 / CH2Cl2 / 20 °C 3: 45.5 mg / NaSEt / dimethylformamide / 10 h / 140 °C With magnesium sulfate, zinc dibromide, sodium thioethylate in dichloromethane, N,N-dimethyl-formamide Trost, Barry M.; Dogra, Kalindi; Organic Letters; vol. 9; nb. 5; (2007); p. 861 - 863 View in Reaxys

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O

O

OH

O

H

H

O

O

Rx-ID: 11898138 View in Reaxys 51/101 Yield

Conditions & References Reaction Steps: 5 1: 91.6 percent / MeONa / methanol / 72 h / 65 °C 2: 93 percent / diethyl ether / -78 - 20 °C 3: 97 percent / NaSEt / dimethylformamide / 3 h / 140 °C 4: ZnBr2; MgSO4 / CH2Cl2 / 20 °C 5: 45.5 mg / NaSEt / dimethylformamide / 10 h / 140 °C With sodium methylate, magnesium sulfate, zinc dibromide, sodium thioethylate in methanol, diethyl ether, dichloromethane, N,N-dimethyl-formamide Trost, Barry M.; Dogra, Kalindi; Organic Letters; vol. 9; nb. 5; (2007); p. 861 - 863 View in Reaxys

O

O

OH

O

H

H

O

O

Rx-ID: 11898141 View in Reaxys 52/101 Yield

Conditions & References Reaction Steps: 4 1: 93 percent / diethyl ether / -78 - 20 °C 2: 97 percent / NaSEt / dimethylformamide / 3 h / 140 °C 3: ZnBr2; MgSO4 / CH2Cl2 / 20 °C 4: 45.5 mg / NaSEt / dimethylformamide / 10 h / 140 °C With magnesium sulfate, zinc dibromide, sodium thioethylate in diethyl ether, dichloromethane, N,N-dimethyl-formamide Trost, Barry M.; Dogra, Kalindi; Organic Letters; vol. 9; nb. 5; (2007); p. 861 - 863 View in Reaxys

OH O

OH

O

H

H

O

O

Rx-ID: 12584188 View in Reaxys 53/101 Yield

Conditions & References Reaction Steps: 4 1: TMSCl; NaI / acetonitrile; hexane; diethyl ether / 24 h / 20 °C 2: 1.236 g / BBr3 / CH2Cl2 / 36 h / 20 °C 3: 37.5 percent / MgSO4; BF3*Et2O / CH2Cl2 / 2.5 h / 0 °C 4: 47 percent / LiAlH4 / tetrahydrofuran / 1 h / 20 °C

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With lithium aluminium tetrahydride, chloro-trimethyl-silane, boron trifluoride diethyl etherate, boron tribromide, magnesium sulfate, sodium iodide in tetrahydrofuran, diethyl ether, hexane, dichloromethane, acetonitrile Qi, Longwu; Yamamoto, Noboru; Meijler, Michael M.; Altobell III, Laurence J.; Koob, George F.; Wirsching, Peter; Janda, Kim D.; Journal of Medicinal Chemistry; vol. 48; nb. 23; (2005); p. 7389 - 7399 View in Reaxys

OH Br

OH H

H OH

O

Rx-ID: 12603400 View in Reaxys 54/101 Yield

Conditions & References Reaction Steps: 2 1: 37.5 percent / MgSO4; BF3*Et2O / CH2Cl2 / 2.5 h / 0 °C 2: 47 percent / LiAlH4 / tetrahydrofuran / 1 h / 20 °C With lithium aluminium tetrahydride, boron trifluoride diethyl etherate, magnesium sulfate in tetrahydrofuran, dichloromethane Qi, Longwu; Yamamoto, Noboru; Meijler, Michael M.; Altobell III, Laurence J.; Koob, George F.; Wirsching, Peter; Janda, Kim D.; Journal of Medicinal Chemistry; vol. 48; nb. 23; (2005); p. 7389 - 7399 View in Reaxys

O

OH

O

H

H

O

O

Rx-ID: 12603626 View in Reaxys 55/101 Yield

Conditions & References Reaction Steps: 3 1: 1.236 g / BBr3 / CH2Cl2 / 36 h / 20 °C 2: 37.5 percent / MgSO4; BF3*Et2O / CH2Cl2 / 2.5 h / 0 °C 3: 47 percent / LiAlH4 / tetrahydrofuran / 1 h / 20 °C With lithium aluminium tetrahydride, boron trifluoride diethyl etherate, boron tribromide, magnesium sulfate in tetrahydrofuran, dichloromethane Qi, Longwu; Yamamoto, Noboru; Meijler, Michael M.; Altobell III, Laurence J.; Koob, George F.; Wirsching, Peter; Janda, Kim D.; Journal of Medicinal Chemistry; vol. 48; nb. 23; (2005); p. 7389 - 7399 View in Reaxys

O HO OH H

H

O O

Rx-ID: 12604722 View in Reaxys 56/101 Yield

Conditions & References Reaction Steps: 4

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1: 86 percent / PPh3; CBr4 / CH2Cl2 / 14 h / 20 °C 2: 98 percent / BBr3 / CH2Cl2 / 6.75 h / -78 - 20 °C 3: 37.5 percent / MgSO4; BF3*Et2O / CH2Cl2 / 2.5 h / 0 °C 4: 47 percent / LiAlH4 / tetrahydrofuran / 1 h / 20 °C With lithium aluminium tetrahydride, carbon tetrabromide, boron trifluoride diethyl etherate, boron tribromide, magnesium sulfate, triphenylphosphine in tetrahydrofuran, dichloromethane Qi, Longwu; Yamamoto, Noboru; Meijler, Michael M.; Altobell III, Laurence J.; Koob, George F.; Wirsching, Peter; Janda, Kim D.; Journal of Medicinal Chemistry; vol. 48; nb. 23; (2005); p. 7389 - 7399 View in Reaxys

O Br OH H

H O O

Rx-ID: 12604728 View in Reaxys 57/101 Yield

Conditions & References Reaction Steps: 3 1: 98 percent / BBr3 / CH2Cl2 / 6.75 h / -78 - 20 °C 2: 37.5 percent / MgSO4; BF3*Et2O / CH2Cl2 / 2.5 h / 0 °C 3: 47 percent / LiAlH4 / tetrahydrofuran / 1 h / 20 °C With lithium aluminium tetrahydride, boron trifluoride diethyl etherate, boron tribromide, magnesium sulfate in tetrahydrofuran, dichloromethane Qi, Longwu; Yamamoto, Noboru; Meijler, Michael M.; Altobell III, Laurence J.; Koob, George F.; Wirsching, Peter; Janda, Kim D.; Journal of Medicinal Chemistry; vol. 48; nb. 23; (2005); p. 7389 - 7399 View in Reaxys

O O O

OH H

H

O O

Rx-ID: 12618275 View in Reaxys 58/101 Yield

Conditions & References Reaction Steps: 5 1: 99 percent / LiAlH4 / tetrahydrofuran / 2.67 h 2: 86 percent / PPh3; CBr4 / CH2Cl2 / 14 h / 20 °C 3: 98 percent / BBr3 / CH2Cl2 / 6.75 h / -78 - 20 °C 4: 37.5 percent / MgSO4; BF3*Et2O / CH2Cl2 / 2.5 h / 0 °C 5: 47 percent / LiAlH4 / tetrahydrofuran / 1 h / 20 °C With lithium aluminium tetrahydride, carbon tetrabromide, boron trifluoride diethyl etherate, boron tribromide, magnesium sulfate, triphenylphosphine in tetrahydrofuran, dichloromethane Qi, Longwu; Yamamoto, Noboru; Meijler, Michael M.; Altobell III, Laurence J.; Koob, George F.; Wirsching, Peter; Janda, Kim D.; Journal of Medicinal Chemistry; vol. 48; nb. 23; (2005); p. 7389 - 7399 View in Reaxys

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HO

O

OH

OH

H

H

H

H O

O

Rx-ID: 24801896 View in Reaxys 59/101 Yield

Conditions & References 5.22.22; 5.23.23 :5.22. Example 22: Resolution of trans-(-VΔ9-THC and trans-(+VΔ9-THC from (+/-VΔ9-THCCrystalline (+/-)Δ9-THC from Example 15 (3.8 g) was dissolved in 8 ml of heptane :2-propanol (95:5 (v:v)) mixture. The resultant solution was injected into a 2 inch stainless steel "Load and Lock" column (Varian) packed with Chiralpak.(R). AD chiral derivatized silica (Chiral Technologies, Inc. Exton, PA). Elution was carried out under isocratic conditions with a solution of heptane :isopropanol (95:5 (v:v)) at a temperature of about 25°C and at a flow rate of EPO <DP n="60"/>250 mL of eluent/min. Detection of compounds in the eluent was carried out by UV absorption at 235 nm.Trans-(+)-Δ9-THC eluted first, and the combined trans-(+)-Δ9THC eluents were concentrated under reduced pressure to provide 1.5 g of trans-(+)-Δ9- THC (Ib) as a reddish-yellow oil.Trans(-)-Δ9-THC eluted after the trans-(+)-Δ9-THC, and the combined trans-(-)-Δ9-THC eluents were concentrated under reduced pressure to provide trans- (-)-Δ9-THC (Ia) as a thick viscous reddish-yellow oil. Yield: 1.4 g. Analysis (HPLC) of the trans-(-)Δ9-THC product indicated that it had a purity of 99.4percent.; 5.23. Example 23: Resolution of trans-(-VΔ9-THC and trans(+VΔ9-THC from (db>Δ9-THCCrystalline (+/-)-Δ9-THC from Example 13 (about 2.0 g) was dissolved in a about 26 ml of 95:5 heptane:IPA (v:v) mixture to provide a 10 wt.percent solution. A portion of the 10percent solution (about 5g) was injected into 220 x 50 mm stainless steel column (Merck) packed with Chiralpak.(R). AD 20 μm chiral derivatized silica (Daicel, Tokyo, Japan). Elution was carried out under isocratic conditions with a solution of heptane :2-propanol (95:5 (v:v)) solvent at about 25°C and at a flow rate of 200 mL of eluent/min. Detection of products in the eluent was carried out by UV absorption at 228 nm. The elution of the remaining portions of the 10percent solution was carried on about 3 x 5 g samples as described above.The fractions containing (+)-Δ9-THC were combined and concentrated under reduced pressure to provide (+)-Δ9-THC as reddish-yellow oil. Yield: 1.0 g. Analysis (HPLC) of the oil indicated that it had a purity of 97.0percent.The fractions containing trans-(-)-Δ9THC were combined and concentrated under reduced pressure to provide trans-(-)-Δ -THC (Ia) as a thick EPO <DP n="61"/ >viscous reddish-yellow oil. Yield: 1.0 g. Analysis (HPLC) of the product indicated that it had a purity of 99.9percent.The product was stored in a freezer and protected from light and oxygen. in n-heptane, isopropyl alcohol, T= 25 °C , Resolution of racemate, Product distribution / selectivity Patent; EURO-CELTIQUE S.A.; WO2006/53766; (2006); (A1) English View in Reaxys 16; 17; 18 :(+/-)-Δ9-THC prepared according to any of the above procedures can be separated by flash chromatography on a Merck column using Chiralpak.(R). AD.(TM). 20 μm chiral (Daicel, Tokyo, Japan) as the stationary phase (loading capacity 500 mg per injection, UV at 228 nm) and n-heptane:2-propanol (95:5 (v:v)) as the mobile phase. Fractions containing only the trans(-)-Δ9-THC isomer can be combined and the volatiles removed using a rotary evaporator at 35° to 400C to provide trans-(-)-Δ9THC (Ia). In this manner, up to 99.9percent pure trans-(-)-Δ9-THC can be isolated.; 6.17 Example 17: Resolution of trans-MA9-THC and trans- (+)-A9-THC from (+/-VA9-THCCrystalline (+/-)-Δ -THC, prepared according to any of the above procedures, can be dissolved in heptane:2-propanol (95:5 (v:v)) mixture. The resultant solution is then EPO <DP n="98"/>injected into a 2 inch stainless steel "Load and Lock" column (Varian) packed with Chiralpak AD chiral derivatized silica (Chiral Technologies, Inc. Exton, PA). Elution can be carried out under isocratic conditions with a solution of heptane :isopropanol (95:5 (v:v)) at a temperature of about 25°C and at a flow rate of 250 mL of eluent/min. Detection of compounds in the eluent can be carried out by UV absorption at 235 nm.Trans-(+)- Δ9-THC will elute first, and the combined trans-(+)- Δ9-THC eluents can be concentrated under reduced pressure to provide trans-(+)-Δ9-THC (Ib) as a reddish- yellow oil.Trans-(-)-Δ9-THC will elute after

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the trans-(+)-Δ9-THC, and the combined trans-(-)- Δ -THC eluents can be concentrated under reduced pressure to provide trans(-)-Δ9-THC (Ia) as a thick viscous reddish-yellow oil. Trans-(-)-Δ9- THC product prepared in this manner can have a purity of over 99percent.; 6.18 Example 18: Resolution of trans-M-Δ9-THC and trans-(+)-A9-THC from (+/-VA9-THCCrystalline (+/-)Δ9-THC, e.g. prepared according to any of the above procedures, can be dissolved in a 95:5 heptane:IPA (v:v) mixture to provide a 10 wt.percent solution. A portion of the 10percent solution is injected into a 220 x 50 mm stainless steel column (Merck) packed with Chiralpak.(R). AD 20 mm chiral derivatized silica (Daicel, Tokyo, Japan). Elution can be carried out under isocratic conditions with a solution of heptane:2-propanol (95:5 (v:v)) solvent at about 25°C and at a flow rate of 200 mL of eluent/min.

Detection of products in the eluent can be carried out by UV absorption at 228 nm. EPO <DP n="99"/>The fractions containing (+)-Δ9-THC can be combined and concentrated under reduced pressure to provide (+)-Δ9-THC as reddish- yellow oil having a purity of about 97.0percent.The fractions containing trans-(-)-Δ9-THC can be combined and concentrated under reduced pressure to provide trans-(-)-Δ9-THC (Ia) as a thick viscous reddish-yellow oil having a purity of 99.9percent. This product is stored in a freezer and protected from light and oxygen. , Resolution of racemate, Product distribution / selectivity Patent; EURO-CELTIQUE S.A.; WO2006/133941; (2006); (A2) English View in Reaxys

HO O OH H

H

F O

OH

Rx-ID: 35091769 View in Reaxys 60/101 Yield

Conditions & References Reaction Steps: 3 1.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 1 h / 130 - 140 °C / Inert atmosphere 2.1: sodium hydride; 2-(diethylamine)ethanethiol / N,N-dimethyl-formamide; mineral oil / 6 h / 130 - 140 °C / Inert atmosphere 3.1: acetic acid; zinc(II) chloride; hydrogenchloride / water / 3 h / 20 °C / Inert atmosphere 3.2: 0.25 h / -5 - 65 °C / Inert atmosphere With hydrogenchloride, sodium hydride, acetic acid, 2-(diethylamine)ethanethiol, zinc(II) chloride in water, N,N-dimethyl-formamide, mineral oil Cheng, Li-Jie; Xie, Jian-Hua; Chen, Yong; Wang, Li-Xin; Zhou, Qi-Lin; Organic Letters; vol. 15; nb. 4; (2013); p. 764 - 767 View in Reaxys

OH

O

OH H

H H H

O

O

Rx-ID: 35091772 View in Reaxys 61/101 Yield

Conditions & References Reaction Steps: 2 1.1: sodium hydride; 2-(diethylamine)ethanethiol / N,N-dimethyl-formamide; mineral oil / 6 h / 130 - 140 °C / Inert atmosphere 2.1: acetic acid; zinc(II) chloride; hydrogenchloride / water / 3 h / 20 °C / Inert atmosphere 2.2: 0.25 h / -5 - 65 °C / Inert atmosphere With hydrogenchloride, sodium hydride, acetic acid, 2-(diethylamine)ethanethiol, zinc(II) chloride in water, N,N-dimethyl-formamide, mineral oil Cheng, Li-Jie; Xie, Jian-Hua; Chen, Yong; Wang, Li-Xin; Zhou, Qi-Lin; Organic Letters; vol. 15; nb. 4; (2013); p. 764 - 767 View in Reaxys

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HO O OH H

H

F O

OH

Rx-ID: 35091837 View in Reaxys 62/101 Yield

Conditions & References Reaction Steps: 3 1.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 1 h / 130 - 140 °C / Inert atmosphere 2.1: sodium hydride; 2-(diethylamine)ethanethiol / N,N-dimethyl-formamide; mineral oil / 6 h / 130 - 140 °C / Inert atmosphere 3.1: acetic acid; zinc(II) chloride; hydrogenchloride / water / 3 h / 20 °C / Inert atmosphere 3.2: 0.25 h / -5 - 65 °C / Inert atmosphere With hydrogenchloride, sodium hydride, acetic acid, 2-(diethylamine)ethanethiol, zinc(II) chloride in water, N,N-dimethyl-formamide, mineral oil Cheng, Li-Jie; Xie, Jian-Hua; Chen, Yong; Wang, Li-Xin; Zhou, Qi-Lin; Organic Letters; vol. 15; nb. 4; (2013); p. 764 - 767 View in Reaxys

HO

O

OH H

H H H

O

O

Rx-ID: 35091841 View in Reaxys 63/101 Yield

Conditions & References Reaction Steps: 2 1.1: sodium hydride; 2-(diethylamine)ethanethiol / N,N-dimethyl-formamide; mineral oil / 6 h / 130 - 140 °C / Inert atmosphere 2.1: acetic acid; zinc(II) chloride; hydrogenchloride / water / 3 h / 20 °C / Inert atmosphere 2.2: 0.25 h / -5 - 65 °C / Inert atmosphere With hydrogenchloride, sodium hydride, acetic acid, 2-(diethylamine)ethanethiol, zinc(II) chloride in water, N,N-dimethyl-formamide, mineral oil Cheng, Li-Jie; Xie, Jian-Hua; Chen, Yong; Wang, Li-Xin; Zhou, Qi-Lin; Organic Letters; vol. 15; nb. 4; (2013); p. 764 - 767 View in Reaxys

OH H

H

O

Rx-ID: 39376199 View in Reaxys 64/101 Yield

Conditions & References Reaction Steps: 3 1.1: chromium(VI) oxide / tetrachloromethane; tert-butyl alcohol / 2 h / Reflux; Inert atmosphere 2.1: cerium(III) chloride heptahydrate / methanol / 0.17 h / 20 °C / Inert atmosphere 2.2: 0.5 h / 0 - 20 °C 3.1: boron trifluoride diethyl etherate / dichloromethane / 0.33 h / 20 °C / Inert atmosphere With chromium(VI) oxide, cerium(III) chloride heptahydrate, boron trifluoride diethyl etherate in methanol, tetrachloromethane, dichloromethane, tert-butyl alcohol

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Dethe, Dattatraya H.; Erande, Rohan D.; Mahapatra, Samarpita; Das, Saikat; Kumar B., Vijay; Chemical Communications; vol. 51; nb. 14; (2015); p. 2871 - 2873 View in Reaxys

O

OH H

H

O

Rx-ID: 39376223 View in Reaxys 65/101 Yield

Conditions & References Reaction Steps: 2 1.1: cerium(III) chloride heptahydrate / methanol / 0.17 h / 20 °C / Inert atmosphere 1.2: 0.5 h / 0 - 20 °C 2.1: boron trifluoride diethyl etherate / dichloromethane / 0.33 h / 20 °C / Inert atmosphere With cerium(III) chloride heptahydrate, boron trifluoride diethyl etherate in methanol, dichloromethane Dethe, Dattatraya H.; Erande, Rohan D.; Mahapatra, Samarpita; Das, Saikat; Kumar B., Vijay; Chemical Communications; vol. 51; nb. 14; (2015); p. 2871 - 2873 View in Reaxys

OH

O OH H

H

O O

Rx-ID: 47350290 View in Reaxys 66/101 Yield

Conditions & References Reaction Steps: 5 1.1: dicyclohexyl-carbodiimide; dmap / dichloromethane / 0 - 20 °C 2.1: potassium hexamethylsilazane / toluene / 1.16 h / -78 °C 2.2: 4.25 h / -78 - 20 °C 3.1: toluene; hexane; methanol / 0.5 h / 0 - 20 °C 4.1: Ru(=CHPh)Cl2(N,N'-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene)(Pcyclohexyl3)2 / dichloromethane / 15 h / 40 °C / Inert atmosphere 5.1: diethyl ether / 0.5 h / 0 - 20 °C / Inert atmosphere 5.2: 2 h / 160 °C / 112.51 Torr 5.3: 8 h / 20 °C With Ru(=CHPh)Cl2(N,N'-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene)(Pcyclohexyl3)2, dmap, potassium hexamethylsilazane, dicyclohexyl-carbodiimide in methanol, diethyl ether, hexane, dichloromethane, toluene, 1.1: |Claisen-Ireland Rearrangement Shultz, Zachary P.; Lawrence, Grant A.; Jacobson, Jeffrey M.; Cruz, Emmanuel J.; Leahy, James W.; Organic Letters; vol. 20; nb. 2; (2018); p. 381 - 384 View in Reaxys

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O

O

OH

O H

H

O

O

Rx-ID: 47350309 View in Reaxys 67/101 Yield

Conditions & References Reaction Steps: 6 1.1: sodium hydroxide / ethanol; water / 3 h / Reflux 2.1: dicyclohexyl-carbodiimide; dmap / dichloromethane / 0 - 20 °C 3.1: potassium hexamethylsilazane / toluene / 1.16 h / -78 °C 3.2: 4.25 h / -78 - 20 °C 4.1: toluene; hexane; methanol / 0.5 h / 0 - 20 °C 5.1: Ru(=CHPh)Cl2(N,N'-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene)(Pcyclohexyl3)2 / dichloromethane / 15 h / 40 °C / Inert atmosphere 6.1: diethyl ether / 0.5 h / 0 - 20 °C / Inert atmosphere 6.2: 2 h / 160 °C / 112.51 Torr 6.3: 8 h / 20 °C With Ru(=CHPh)Cl2(N,N'-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene)(Pcyclohexyl3)2, dmap, potassium hexamethylsilazane, dicyclohexyl-carbodiimide, sodium hydroxide in methanol, diethyl ether, ethanol, hexane, dichloromethane, water, toluene, 2.1: |Claisen-Ireland Rearrangement Shultz, Zachary P.; Lawrence, Grant A.; Jacobson, Jeffrey M.; Cruz, Emmanuel J.; Leahy, James W.; Organic Letters; vol. 20; nb. 2; (2018); p. 381 - 384 View in Reaxys

O OH H

O

O H

O

O

Rx-ID: 47350317 View in Reaxys 68/101 Yield

Conditions & References Reaction Steps: 4 1.1: potassium hexamethylsilazane / toluene / 1.16 h / -78 °C 1.2: 4.25 h / -78 - 20 °C 2.1: toluene; hexane; methanol / 0.5 h / 0 - 20 °C 3.1: Ru(=CHPh)Cl2(N,N'-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene)(Pcyclohexyl3)2 / dichloromethane / 15 h / 40 °C / Inert atmosphere 4.1: diethyl ether / 0.5 h / 0 - 20 °C / Inert atmosphere 4.2: 2 h / 160 °C / 112.51 Torr 4.3: 8 h / 20 °C With Ru(=CHPh)Cl2(N,N'-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene)(Pcyclohexyl3)2, potassium hexamethylsilazane in methanol, diethyl ether, hexane, dichloromethane, toluene Shultz, Zachary P.; Lawrence, Grant A.; Jacobson, Jeffrey M.; Cruz, Emmanuel J.; Leahy, James W.; Organic Letters; vol. 20; nb. 2; (2018); p. 381 - 384 View in Reaxys

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O OH H

HO

O H

O

O

Rx-ID: 47350326 View in Reaxys 69/101 Yield

Conditions & References Reaction Steps: 3 1.1: toluene; hexane; methanol / 0.5 h / 0 - 20 °C 2.1: Ru(=CHPh)Cl2(N,N'-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene)(Pcyclohexyl3)2 / dichloromethane / 15 h / 40 °C / Inert atmosphere 3.1: diethyl ether / 0.5 h / 0 - 20 °C / Inert atmosphere 3.2: 2 h / 160 °C / 112.51 Torr 3.3: 8 h / 20 °C With Ru(=CHPh)Cl2(N,N'-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene)(Pcyclohexyl3)2 in methanol, diethyl ether, hexane, dichloromethane, toluene Shultz, Zachary P.; Lawrence, Grant A.; Jacobson, Jeffrey M.; Cruz, Emmanuel J.; Leahy, James W.; Organic Letters; vol. 20; nb. 2; (2018); p. 381 - 384 View in Reaxys

O OH H

O

O H

O

O

Rx-ID: 47350333 View in Reaxys 70/101 Yield

Conditions & References Reaction Steps: 2 1.1: Ru(=CHPh)Cl2(N,N'-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene)(Pcyclohexyl3)2 / dichloromethane / 15 h / 40 °C / Inert atmosphere 2.1: diethyl ether / 0.5 h / 0 - 20 °C / Inert atmosphere 2.2: 2 h / 160 °C / 112.51 Torr 2.3: 8 h / 20 °C With Ru(=CHPh)Cl2(N,N'-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene)(Pcyclohexyl3)2 in diethyl ether, dichloromethane Shultz, Zachary P.; Lawrence, Grant A.; Jacobson, Jeffrey M.; Cruz, Emmanuel J.; Leahy, James W.; Organic Letters; vol. 20; nb. 2; (2018); p. 381 - 384 View in Reaxys

OH

O

OH

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HO OH

H

H

H

O O

H

Rx-ID: 3865486 View in Reaxys 71/101 Yield

Conditions & References With toluene-4-sulfonic acid in benzene, Time= 24h, T= 20 °C Crombie; Palmer; Jamieson; Tetrahedron Letters; vol. 24; nb. 30; (1983); p. 3129 - 3132 View in Reaxys

OH H OH

H

O

Rx-ID: 15147313 View in Reaxys 72/101 Yield

Conditions & References Reaction Steps: 2 1: 85 percent / Et3N; DMAP / diethyl ether / 4 h / 20 °C 2: 51 percent / [Mo(CO)4Br]2Br2 / CH2Cl2 / 4 h / 20 °C With dmap, triethylamine, [Mo(CO)4Br]2Br2 in diethyl ether, dichloromethane Malkov, Andrei V.; Kocovsky, Pavel; Collection of Czechoslovak Chemical Communications; vol. 66; nb. 8; (2001); p. 1257 1268 View in Reaxys

O

OH H

H O

O O

Rx-ID: 14566595 View in Reaxys 73/101 Yield

Conditions & References Reaction Steps: 10 1.1: 94 percent / DIBAL / tetrahydrofuran; hexane / 1.5 h / -78 °C 2.1: 76 percent / PCC; Celite / CH2Cl2 / 2 h 3.1: 85 percent / imidazole / dimethylformamide 4.1: 73 percent / I2; pyridine / CCl4 5.1: n-BuLi / diethyl ether; hexane 5.2: CuCN / diethyl ether; hexane 5.3: 62 percent / BF3*Et2O / diethyl ether; hexane / -78 °C 6.1: EtMgBr / tetrahydrofuran / 0.17 h / 0 °C 6.2: 66 percent / tetrahydrofuran / 2 h / 0 °C 7.1: Ni(acac)2 / tetrahydrofuran / 0.17 h / 0 °C 7.2: 93 percent / tetrahydrofuran 8.1: 73 percent / NaSEt / dimethylformamide / 12 h / 140 °C

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9.1: 84 percent / ZnBr2; MgSO4 / CH2Cl2 / 12 h 10.1: 68 percent / NaSEt / dimethylformamide / 8 h / 120 °C With pyridine, 1H-imidazole, bis(acetylacetonate)nickel(II), n-butyllithium, Celite, ethylmagnesium bromide, iodine, diisobutylaluminium hydride, magnesium sulfate, pyridinium chlorochromate, zinc dibromide, sodium thioethylate in tetrahydrofuran, tetrachloromethane, diethyl ether, hexane, dichloromethane, N,N-dimethyl-formamide William, Anthony D.; Kobayashi, Yuichi; Journal of Organic Chemistry; vol. 67; nb. 25; (2002); p. 8771 - 8782 View in Reaxys

O

OH H

H OH

O

Rx-ID: 14579872 View in Reaxys 74/101 Yield

Conditions & References Reaction Steps: 8 1.1: 85 percent / imidazole / dimethylformamide 2.1: 73 percent / I2; pyridine / CCl4 3.1: n-BuLi / diethyl ether; hexane 3.2: CuCN / diethyl ether; hexane 3.3: 62 percent / BF3*Et2O / diethyl ether; hexane / -78 °C 4.1: EtMgBr / tetrahydrofuran / 0.17 h / 0 °C 4.2: 66 percent / tetrahydrofuran / 2 h / 0 °C 5.1: Ni(acac)2 / tetrahydrofuran / 0.17 h / 0 °C 5.2: 93 percent / tetrahydrofuran 6.1: 73 percent / NaSEt / dimethylformamide / 12 h / 140 °C 7.1: 84 percent / ZnBr2; MgSO4 / CH2Cl2 / 12 h 8.1: 68 percent / NaSEt / dimethylformamide / 8 h / 120 °C With pyridine, 1H-imidazole, bis(acetylacetonate)nickel(II), n-butyllithium, ethylmagnesium bromide, iodine, magnesium sulfate, zinc dibromide, sodium thioethylate in tetrahydrofuran, tetrachloromethane, diethyl ether, hexane, dichloromethane, N,Ndimethyl-formamide William, Anthony D.; Kobayashi, Yuichi; Journal of Organic Chemistry; vol. 67; nb. 25; (2002); p. 8771 - 8782 View in Reaxys

OH H OH

H

HO

O

Rx-ID: 14579879 View in Reaxys 75/101 Yield

Conditions & References Reaction Steps: 9 1.1: 76 percent / PCC; Celite / CH2Cl2 / 2 h 2.1: 85 percent / imidazole / dimethylformamide 3.1: 73 percent / I2; pyridine / CCl4 4.1: n-BuLi / diethyl ether; hexane 4.2: CuCN / diethyl ether; hexane 4.3: 62 percent / BF3*Et2O / diethyl ether; hexane / -78 °C 5.1: EtMgBr / tetrahydrofuran / 0.17 h / 0 °C 5.2: 66 percent / tetrahydrofuran / 2 h / 0 °C

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6.1: Ni(acac)2 / tetrahydrofuran / 0.17 h / 0 °C 6.2: 93 percent / tetrahydrofuran 7.1: 73 percent / NaSEt / dimethylformamide / 12 h / 140 °C 8.1: 84 percent / ZnBr2; MgSO4 / CH2Cl2 / 12 h 9.1: 68 percent / NaSEt / dimethylformamide / 8 h / 120 °C With pyridine, 1H-imidazole, bis(acetylacetonate)nickel(II), n-butyllithium, Celite, ethylmagnesium bromide, iodine, magnesium sulfate, pyridinium chlorochromate, zinc dibromide, sodium thioethylate in tetrahydrofuran, tetrachloromethane, diethyl ether, hexane, dichloromethane, N,N-dimethyl-formamide William, Anthony D.; Kobayashi, Yuichi; Journal of Organic Chemistry; vol. 67; nb. 25; (2002); p. 8771 - 8782 View in Reaxys

O

OH H

H

O Si

O

Rx-ID: 14582404 View in Reaxys 76/101 Yield

Conditions & References Reaction Steps: 7 1.1: 73 percent / I2; pyridine / CCl4 2.1: n-BuLi / diethyl ether; hexane 2.2: CuCN / diethyl ether; hexane 2.3: 62 percent / BF3*Et2O / diethyl ether; hexane / -78 °C 3.1: EtMgBr / tetrahydrofuran / 0.17 h / 0 °C 3.2: 66 percent / tetrahydrofuran / 2 h / 0 °C 4.1: Ni(acac)2 / tetrahydrofuran / 0.17 h / 0 °C 4.2: 93 percent / tetrahydrofuran 5.1: 73 percent / NaSEt / dimethylformamide / 12 h / 140 °C 6.1: 84 percent / ZnBr2; MgSO4 / CH2Cl2 / 12 h 7.1: 68 percent / NaSEt / dimethylformamide / 8 h / 120 °C With pyridine, bis(acetylacetonate)nickel(II), n-butyllithium, ethylmagnesium bromide, iodine, magnesium sulfate, zinc dibromide, sodium thioethylate in tetrahydrofuran, tetrachloromethane, diethyl ether, hexane, dichloromethane, N,N-dimethyl-formamide William, Anthony D.; Kobayashi, Yuichi; Journal of Organic Chemistry; vol. 67; nb. 25; (2002); p. 8771 - 8782 View in Reaxys

O I

OH H

H

O Si

O

Rx-ID: 14585187 View in Reaxys 77/101 Yield

Conditions & References Reaction Steps: 6 1.1: n-BuLi / diethyl ether; hexane 1.2: CuCN / diethyl ether; hexane 1.3: 62 percent / BF3*Et2O / diethyl ether; hexane / -78 °C

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2.1: EtMgBr / tetrahydrofuran / 0.17 h / 0 °C 2.2: 66 percent / tetrahydrofuran / 2 h / 0 °C 3.1: Ni(acac)2 / tetrahydrofuran / 0.17 h / 0 °C 3.2: 93 percent / tetrahydrofuran 4.1: 73 percent / NaSEt / dimethylformamide / 12 h / 140 °C 5.1: 84 percent / ZnBr2; MgSO4 / CH2Cl2 / 12 h 6.1: 68 percent / NaSEt / dimethylformamide / 8 h / 120 °C With bis(acetylacetonate)nickel(II), n-butyllithium, ethylmagnesium bromide, magnesium sulfate, zinc dibromide, sodium thioethylate in tetrahydrofuran, diethyl ether, hexane, dichloromethane, N,N-dimethyl-formamide William, Anthony D.; Kobayashi, Yuichi; Journal of Organic Chemistry; vol. 67; nb. 25; (2002); p. 8771 - 8782 View in Reaxys

Si

OH

O

H

O H

O

O

Rx-ID: 14591919 View in Reaxys 78/101 Yield

Conditions & References Reaction Steps: 3 1: 73 percent / NaSEt / dimethylformamide / 12 h / 140 °C 2: 84 percent / ZnBr2; MgSO4 / CH2Cl2 / 12 h 3: 68 percent / NaSEt / dimethylformamide / 8 h / 120 °C With magnesium sulfate, zinc dibromide, sodium thioethylate in dichloromethane, N,N-dimethyl-formamide William, Anthony D.; Kobayashi, Yuichi; Journal of Organic Chemistry; vol. 67; nb. 25; (2002); p. 8771 - 8782 View in Reaxys

O I O OH H

H

O O Si

O

Rx-ID: 14592592 View in Reaxys 79/101 Yield

Conditions & References Reaction Steps: 5 1.1: EtMgBr / tetrahydrofuran / 0.17 h / 0 °C 1.2: 66 percent / tetrahydrofuran / 2 h / 0 °C 2.1: Ni(acac)2 / tetrahydrofuran / 0.17 h / 0 °C 2.2: 93 percent / tetrahydrofuran 3.1: 73 percent / NaSEt / dimethylformamide / 12 h / 140 °C 4.1: 84 percent / ZnBr2; MgSO4 / CH2Cl2 / 12 h 5.1: 68 percent / NaSEt / dimethylformamide / 8 h / 120 °C With bis(acetylacetonate)nickel(II), ethylmagnesium bromide, magnesium sulfate, zinc dibromide, sodium thioethylate in tetrahydrofuran, dichloromethane, N,N-dimethyl-formamide William, Anthony D.; Kobayashi, Yuichi; Journal of Organic Chemistry; vol. 67; nb. 25; (2002); p. 8771 - 8782

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View in Reaxys

Si O OH H

O

O

O P O

H

O O

O

Rx-ID: 14593992 View in Reaxys 80/101 Yield

Conditions & References Reaction Steps: 4 1.1: Ni(acac)2 / tetrahydrofuran / 0.17 h / 0 °C 1.2: 93 percent / tetrahydrofuran 2.1: 73 percent / NaSEt / dimethylformamide / 12 h / 140 °C 3.1: 84 percent / ZnBr2; MgSO4 / CH2Cl2 / 12 h 4.1: 68 percent / NaSEt / dimethylformamide / 8 h / 120 °C With bis(acetylacetonate)nickel(II), magnesium sulfate, zinc dibromide, sodium thioethylate in tetrahydrofuran, dichloromethane, N,N-dimethyl-formamide William, Anthony D.; Kobayashi, Yuichi; Journal of Organic Chemistry; vol. 67; nb. 25; (2002); p. 8771 - 8782 View in Reaxys

O

OH H

H O

O

Rx-ID: 21206578 View in Reaxys 81/101 Yield

Conditions & References Reaction Steps: 4 1: HBr / CH2Cl2 / -20 °C 2: CH2Cl2 / 5 h / Ambient temperature 3: 58 percent / boron tribromide / CH2Cl2 / 1.) -76 deg C, 2.) room temp., 7 h 4: KOBu-t / benzene / 1.) 5 deg C, 1 h, 2.) 65 deg C, 10 min With potassium tert-butylate, hydrogen bromide, boron tribromide in dichloromethane, benzene Rickards; Ronneberg; Journal of Organic Chemistry; vol. 49; nb. 3; (1984); p. 572 - 573 View in Reaxys

OH O

H

O

H

O

Rx-ID: 21210727 View in Reaxys 82/101

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Yield

Conditions & References Reaction Steps: 5 1: 1.) Li, 2.) cuprous bromide, 3.) boron trifluoride etherate 2: HBr / CH2Cl2 / -20 °C 3: CH2Cl2 / 5 h / Ambient temperature 4: 58 percent / boron tribromide / CH2Cl2 / 1.) -76 deg C, 2.) room temp., 7 h 5: KOBu-t / benzene / 1.) 5 deg C, 1 h, 2.) 65 deg C, 10 min With boron trifluoride diethyl etherate, potassium tert-butylate, hydrogen bromide, boron tribromide, lithium, copper(I) bromide in dichloromethane, benzene Rickards; Ronneberg; Journal of Organic Chemistry; vol. 49; nb. 3; (1984); p. 572 - 573 View in Reaxys

OH

O

H

Br H

O

O

Rx-ID: 21216906 View in Reaxys 83/101 Yield

Conditions & References Reaction Steps: 2 1: 58 percent / boron tribromide / CH2Cl2 / 1.) -76 deg C, 2.) room temp., 7 h 2: KOBu-t / benzene / 1.) 5 deg C, 1 h, 2.) 65 deg C, 10 min With potassium tert-butylate, boron tribromide in dichloromethane, benzene Rickards; Ronneberg; Journal of Organic Chemistry; vol. 49; nb. 3; (1984); p. 572 - 573 View in Reaxys

Br O OH H

H

O Br

O

Rx-ID: 21218772 View in Reaxys 84/101 Yield

Conditions & References Reaction Steps: 3 1: CH2Cl2 / 5 h / Ambient temperature 2: 58 percent / boron tribromide / CH2Cl2 / 1.) -76 deg C, 2.) room temp., 7 h 3: KOBu-t / benzene / 1.) 5 deg C, 1 h, 2.) 65 deg C, 10 min With potassium tert-butylate, boron tribromide in dichloromethane, benzene Rickards; Ronneberg; Journal of Organic Chemistry; vol. 49; nb. 3; (1984); p. 572 - 573 View in Reaxys

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HO

HO Br

O

O

HO OH

H

H

H

O O

H

Rx-ID: 2584705 View in Reaxys 85/101 Yield

Conditions & References With potassium tert-butylate in benzene, 1.) 5 deg C, 1 h, 2.) 65 deg C, 10 min, Title compound not separated from byproducts Rickards; Ronneberg; Journal of Organic Chemistry; vol. 49; nb. 3; (1984); p. 572 - 573 View in Reaxys

O

O OH H

OH

H

O

OH

Rx-ID: 41631374 View in Reaxys 86/101 Yield

Conditions & References Reaction Steps: 4 1.1: boron trifluoride diethyl etherate / chlorobenzene / 22 °C 1.2: 0.33 h / 20 °C 2.1: potassium hydroxide / 2 h / 120 °C / 375.04 Torr 3.1: 2 h / 150 °C / 375.04 Torr 4.1: borontrifluoride acetic acid / tert-butyl methyl ether / 3.17 h / 22 °C With boron trifluoride diethyl etherate, borontrifluoride acetic acid, potassium hydroxide in tert-butyl methyl ether, chlorobenzene Patent; SYMRISE AG; Koch, Oskar; Götz, Marcus Rudolf; Looft, Jan; Vössing, Tobias; US2015/336874; (2015); (A1) English View in Reaxys Reaction Steps: 4 1.1: boron trifluoride diethyl etherate / chlorobenzene / 22 °C / Flow reactor 1.2: 0.33 h / 22 °C 2.1: potassium hydroxide / 2 h / 120 °C / 375.04 Torr 3.1: 2 h / 150 °C / 375.04 Torr 4.1: boron trifluoride diacetate / tert-butyl methyl ether / 3.17 h / 22 °C With boron trifluoride diethyl etherate, boron trifluoride diacetate, potassium hydroxide in tert-butyl methyl ether, chlorobenzene

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Patent; SYMRISE AG; ERFURT, Harry; WEBER, Maria; NIEMEYER, Hans-Jürgen; GÖTZ, Marcus Rudolf; WINKLER, Matthias; (44 pag.); WO2017/194173; (2017); (A1) English View in Reaxys

O HO

O

OH H

H HO

O

Rx-ID: 41631375 View in Reaxys 87/101 Yield

Conditions & References Reaction Steps: 3 1: potassium hydroxide / 2 h / 120 °C / 375.04 Torr 2: 2 h / 150 °C / 375.04 Torr 3: borontrifluoride acetic acid / tert-butyl methyl ether / 3.17 h / 22 °C With borontrifluoride acetic acid, potassium hydroxide in tert-butyl methyl ether Patent; SYMRISE AG; Koch, Oskar; Götz, Marcus Rudolf; Looft, Jan; Vössing, Tobias; US2015/336874; (2015); (A1) English View in Reaxys Reaction Steps: 3 1: potassium hydroxide / 2 h / 120 °C / 375.04 Torr 2: 2 h / 150 °C / 375.04 Torr 3: boron trifluoride diacetate / tert-butyl methyl ether / 3.17 h / 22 °C With boron trifluoride diacetate, potassium hydroxide in tert-butyl methyl ether Patent; SYMRISE AG; ERFURT, Harry; WEBER, Maria; NIEMEYER, Hans-Jürgen; GÖTZ, Marcus Rudolf; WINKLER, Matthias; (44 pag.); WO2017/194173; (2017); (A1) English View in Reaxys

OH

HO

H

H

O

O

Rx-ID: 16952896 View in Reaxys 88/101 Yield

Conditions & References Reaction Steps: 2 1: HCl, ZnCl2 / CH2Cl2 / 0 °C 2: potassium tert-amylate / benzene / 0.5 h / other reactants: 9α-chlorohexahydrocannabinol, deuterated analogues With hydrogenchloride, potassium 2-methylbutan-2-olate, zinc(II) chloride in dichloromethane, benzene Banijamali, Ali R.; Van Der Schyf, Cornelis J.; Makriyannis, Alexandros; Journal of Labelled Compounds and Radiopharmaceuticals; vol. 41; nb. 2; (1998); p. 121 - 130 View in Reaxys

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HO OH

H

H

H

O O

H

Rx-ID: 16956976 View in Reaxys 89/101 Yield

Conditions & References Reaction Steps: 2 1: HCl, ZnCl2 / CH2Cl2 / 0 °C 2: potassium tert-amylate / benzene / 0.5 h / other reactants: 9α-chlorohexahydrocannabinol, deuterated analogues With hydrogenchloride, potassium 2-methylbutan-2-olate, zinc(II) chloride in dichloromethane, benzene Banijamali, Ali R.; Van Der Schyf, Cornelis J.; Makriyannis, Alexandros; Journal of Labelled Compounds and Radiopharmaceuticals; vol. 41; nb. 2; (1998); p. 121 - 130 View in Reaxys

Cl

OH

OH H

H

H

H O

O

Rx-ID: 16986018 View in Reaxys 90/101 Yield

Conditions & References Reaction Steps: 3 1: potassium tert-amylate / benzene / 0.5 h / other reactants: 9α-chlorohexahydrocannabinol, deuterated analogues 2: HCl, ZnCl2 / CH2Cl2 / 0 °C 3: potassium tert-amylate / benzene / 0.5 h / other reactants: 9α-chlorohexahydrocannabinol, deuterated analogues With hydrogenchloride, potassium 2-methylbutan-2-olate, zinc(II) chloride in dichloromethane, benzene Banijamali, Ali R.; Van Der Schyf, Cornelis J.; Makriyannis, Alexandros; Journal of Labelled Compounds and Radiopharmaceuticals; vol. 41; nb. 2; (1998); p. 121 - 130 View in Reaxys

HO

OH H

O

H

OH OH

O

O

Rx-ID: 46738976 View in Reaxys 91/101 Yield

Conditions & References Reaction Steps: 2 1: 2 h / 150 °C / 375.04 Torr 2: boron trifluoride diacetate / tert-butyl methyl ether / 3.17 h / 22 °C With boron trifluoride diacetate in tert-butyl methyl ether

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Patent; SYMRISE AG; ERFURT, Harry; WEBER, Maria; NIEMEYER, Hans-Jürgen; GÖTZ, Marcus Rudolf; WINKLER, Matthias; (44 pag.); WO2017/194173; (2017); (A1) English View in Reaxys

O

OH OH

HO

O

HO

OH O

OH

OH H

H

OH

O

Rx-ID: 23335356 View in Reaxys 92/101 Yield

Conditions & References Portions of milled dried plant material were subjected to heat (approximately 0.25 g with particle size 1-2 mm). A pilot scale experimental system was set up, with the objective of determining parameters for the optimal conversion of THCA or CBDA into THC and CBD respectively, with concomitant minimal loss of these ensuing compounds into their thermal degradation products, in the case of THC the formation of CBN. [0172] Brief Description of Materials and Methods: [0173] Portions (0.25 g) of milled (approximately 1-2 mm particle size) of both THCA and CBDA herbal materials were placed in 20-ml glass headspace vials and the vials sealed tightly with crimp capped Teflon-faced butyl rubber seals. Sealed vials were heated at one of three temperatures, for periods of up to 4 hrs as follows: 105° C., 120° C., 140° C. for 0.5, 1.0, 2.0 and 4.0 hours. [0174] The heating was performed in an oven with forced air circulation. Oven conditions were shown to be accurate to within 0.5-1.0 degree at the three temperatures used. [0175] After the heating process was complete representative samples of the decarboxylated herb were assayed using HPLC, GC and TLC techniques. Standards of THC, CBD and CBN were include in the HPLC and GC sequences. [0176] Results and Discussions: [0177] HPLC analysis of the solvent extracts was able to demonstrate the disappearance of either CBDA or THCA as a function of time at the two lower temperatures. At 140° C., the earliest time point samples at 0.5 hour contained only very modest levels of a peak eluting at the retention times of CBDA or THCA. [0178] Tables 3 and 4 present HPLC data quantifying the conversion of CBDA or THCA into the free compounds; also presented is data showing the content of CBD or THC and the ratio of CBD/CBDA+CBD or THC/THCA+THC. The conversion of the carboxylic acid forms to the corresponding decarboxylated form can be monitored by comparing the decarboxylated/decarboxylated plus un-decarboxylated ratio with the absolute content of the decarboxylated compounds. Thus, when the ratio reaches a maximum value (>0.95), the earliest time/temperature point at which the content of THC or CBD is also maximal, should be optimal for the conversion process. [0179] Thus, for CBD containing herb, 1 hour at 120° C. or 0.5 hour at 140° C., was appropriate. [0180] This is confirmed by examination of the TLC chromatogram for the solvent extracts, CBDA is absent after 1 hour at 120° C. or at any time point at 140° C. [0181] For THC there is a third criterion, formation of CBN, where it is desirable to minimise the formation of this compound during the thermal decarboxylation process. Table 5 provides Gas Chromatography (GC) data where a CBN/THC ratio can be derived. Taken into consideration, alongside the THC/THCA+THC ratio and the maximum THC content, minimal CBN formation occurs after 0.5 or 1.0 hour at 120° C. At 140° C., even 0.5 hour gives a higher content of CBN than either of the two lower time/temperature points. [0182] Therefore laboratory studies demonstrate the optimum conditions for the decarboxylation of: [0183] Chemovar producing primarily CBD is 1 hour at 120° C. or 0.5 hour at 140° C. [0184] Chemovar producing primarily THC to minimise CBN formation, is 1 to 2 hours at 105° C. or 1 hour at 120° C. [0185] Thin layer chromatography reveals that virtually all of the THCA has disappeared after 4 hours at 105° C. and after 1 hour at 120° C. No THCA is visible at any time point when the herb is heated at 140° C. A small amount of residual staining at this retention value on TLC and the presence at low levels of a peak coincident with THCA on HPLC analysis may indicate the presence of a minor cannabinoid rather than residual THCA. The decarboxylation conditions for a batch scale of about 4 kg of botanical raw material (BRM) are as follows: [0189] Approximately 4 kg of milled BRM (either THCA or CBDA) to be decarboxylated was initially heated to 105° C. and held at this temperature for about 15 minutes to evaporate off any retained water and to allow uniform heating of the BRM. The batch was then further heated to 145° C. and held at this temperature for 45 minutes to allow decarboxylation to be completed to greater than 95percent efficiency. [0190] The heating time for CBDA BRM was extended to 55 minutes at 145° C. as it became apparent from results that CBDA was slightly more resistant to decarboxylation than THCA. This

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difference between CBD and THC would be even more pronounced at commercial scale batches. The THC BRM heating time was retained at 145° C. for 45 minutes. [0191] The conditions used in pilot scale closely reflect those conditions determined as optimal from the laboratory studies. The differences can be explained by slower and less efficient heat transfer via the containers and through the BRM at the increased batch size for the pilot scale. [0192] Tables 6 and 7 provide data to demonstrate the efficiency of decarboxylation measured in terms of content of the biologically active cannabinoid, THC or CBD. Increase in batch size of CBD BRM from approximately 4 kg to 6 kg resulted in a need to increase decarboxylation time. The decarboxylation time at 145° C. was increased from 55 minutes to 90 minutes. , Time= 0.5 - 4h, T= 105 - 140 °C , Product distribution / selectivity Patent; Whittle, Brian A.; US2004/33280; (2004); (A1) English View in Reaxys

OH

HO

H

Cl H

O

O

Rx-ID: 1750980 View in Reaxys 93/101 Yield

Conditions & References With potassium 2-methylbutan-2-olate, Yield given Mechoulam, Raphael; Lander,N.; Tamir, I.; Ben-Zvi, Z.; Kimmel,Y.; Angewandte Chemie; vol. 92; nb. 7; (1980); p. 577 578 View in Reaxys 3B With potassium 2-methylbutan-2-olate in tert-butyl methyl ether, toluene, Time= 0.333333 - 0.416667h, T= 20 °C , Heating / reflux, Product distribution / selectivity Patent; CILAG LTD.; WO2006/7734; (2006); (A1) German View in Reaxys

OH

O

OH

OH OH

HO OH

H

H

/PBERB265-1120/ O H

H

O

Rx-ID: 6218022 View in Reaxys 94/101 Yield

Conditions & References With toluene-4-sulfonic acid in benzene, T= 20 °C , investigation with (+)-p-menthadienol, Product distribution, Mechanism Crombie; Palmer; Jamieson; Tetrahedron Letters; vol. 24; nb. 30; (1983); p. 3129 - 3132

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View in Reaxys

OH

OH

HO

OH OH

HO OH

H

H

H

O H

O

Rx-ID: 3865498 View in Reaxys 95/101 Yield

Conditions & References With toluene-4-sulfonic acid in benzene, Time= 1.58333h, T= 25 °C , Product distribution Crombie, Leslie; Crombie, W. Mary L.; Jamieson, Sally V.; Palmer, Christopher J.; Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999); (1988); p. 1243 - 1250 View in Reaxys

Cl

OH

OH H

H

H

H O

O

Rx-ID: 4916317 View in Reaxys 96/101 Yield

Conditions & References With potassium 2-methylbutan-2-olate in benzene, Time= 0.5h, Yield given Banijamali, Ali R.; Van Der Schyf, Cornelis J.; Makriyannis, Alexandros; Journal of Labelled Compounds and Radiopharmaceuticals; vol. 41; nb. 2; (1998); p. 121 - 130 View in Reaxys With potassium 2-methylbutan-2-olate in benzene, Time= 0.5h, other reactants: 9α-chlorohexahydrocannabinol, deuterated analogues, Mechanism Banijamali, Ali R.; Van Der Schyf, Cornelis J.; Makriyannis, Alexandros; Journal of Labelled Compounds and Radiopharmaceuticals; vol. 41; nb. 2; (1998); p. 121 - 130 View in Reaxys

OH

O

OH

OH OH

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HO OH

H

H

H

H

O HO

OH

O

H

Rx-ID: 3865516 View in Reaxys 97/101 Yield

Conditions & References

24 % Chro- With toluene-4-sulfonic acid in benzene, Time= 0.75h, T= 40 °C , various temperatures, Product distribution, Mechanism mat., 32 % Chromat., 6 Crombie, Leslie; Crombie, W. Mary L.; Jamieson, Sally V.; Palmer, Christopher J.; Journal of the Chemical Society, Perkin % Chromat. Transactions 1: Organic and Bio-Organic Chemistry (1972-1999); (1988); p. 1243 - 1250 View in Reaxys

H

OH

H

OH

O

H

OH OH

HO OH

H

H

H

H

O HO

OH

O

H

Rx-ID: 3865517 View in Reaxys 98/101 Yield

Conditions & References With toluene-4-sulfonic acid in benzene, Time= 0.5h, T= 60 °C , Mechanism, Product distribution Crombie, Leslie; Crombie, W. Mary L.; Jamieson, Sally V.; Palmer, Christopher J.; Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999); (1988); p. 1243 - 1250 View in Reaxys

OH

OH

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HO OH

H

H

H

O O

H

Rx-ID: 25586164 View in Reaxys 99/101 Yield

Conditions & References 1 in n-heptane, Heating / reflux, Molecular sieve, Product distribution / selectivity Patent; BIONORICA AG; WO2006/136273; (2006); (A1) German View in Reaxys 3; 4; 5 With zinc dibromide in n-heptane, Heating / reflux, Molecular sieve, Product distribution / selectivity Patent; BIONORICA AG; WO2006/136273; (2006); (A1) German View in Reaxys 2 With zinc dibromide in n-heptane, Heating / reflux, Product distribution / selectivity Patent; BIONORICA AG; WO2006/136273; (2006); (A1) German View in Reaxys

O OH

O

H

H H

O

O H

Rx-ID: 23844751 View in Reaxys 100/101 Yield

Conditions & References 5 With methanol, sodium hydroxide, water in tetrahydrofuran, Time= 9h, Product distribution / selectivity Patent; CILAG LTD.; WO2006/7734; (2006); (A1) German View in Reaxys

OH H

H

O

Rx-ID: 5507690 View in Reaxys 101/101

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Yield

Conditions & References 2 : EXAMPLE 2 EXAMPLE 2 A mixture of methyl Δ9 -tetrahydrocannabinolate-B (1 part) in methanol (30 parts), water (15 parts), and sodium hydroxide (10 parts) was heated at reflux under a nitrogen atmosphere for 8 hours, cooled, diluted with water, neutralized to pH 7.5 with carbon dioxide, and extracted exhaustively with hexane.

The combined extracts were purified by flash chromatography on silica gel using 5percent ethyl acetate in hexane to afford dronabinol in 66percent yield having a purity of 97.2percent (HPLC and GC).

Patent; The Australian National University; US5342971; (1994); (A) English View in Reaxys 1 : Preparation of the Compound of the Present Invention 7 mg of p-toluenesulfonic acid was added to the solution of resorcinol 4 (63.3 mg, 0.25 mmol) and 43.6 mg of cis/trans-p-menthedienol (0.28 mmol) in 2.5 mL of chloroform, and the mixture was refluxed for 45 min.

The solution was cooled to room temperature, washed with 10percent sodium bicarbonate, dried, and evaporated.

The residue was chromatographed on silica gel (7percent ethyl ether-petroleum ether) to afford 35 mg of tetrahydrocannabinol 5 and 7 mg of tetrahydrocannabinol 6 (combined yield 63percent).

Patent; The University of Connecticut; US6166066; (2000); (A) English View in Reaxys 5.15.15 Patent; EURO-CELTIQUE S.A.; WO2006/53766; (2006); (A1) English View in Reaxys Gaoni; Mechoulam; Journal of the American Chemical Society; vol. 93; (1971); p. 217,223 View in Reaxys Gaoni; Mechoulam; Israel Journal of Chemistry; vol. 6; (1968); p. 679,684,688 View in Reaxys 1 : Preparation of the Compound of the Present Invention Starting from 61.6 mg (0.26 mmol) of the resorcinol 8, 59.2 mg (62percent) of tetrahydrocannabinol 9 was obtained.

Patent; The University of Connecticut; US6166066; (2000); (A) English View in Reaxys 1 : EXAMPLE 1 EXAMPLE 1 A quantity of Δ-9-Tetrahydrocannabinol (Mol. Wt. 314.45) in ethanol was concentrated to a constant weight in vacuo leaving 0.200 grams of a gummy residue.

It was immediately dissolved in 6.0 ml of freshly distilled (from KOH) pyridine and stirred under nitrogen with cooling (in an ice bath).

0.225 grams of N-chloroformyl bis(2-chloroethylamine) (Mol. Wt. 190.48), at refrigerating temperature, was added dropwise via syringe over a six minute period using 1 ml of pyridine to ensure complete transfer.

The reaction mixture was stirred at room temperature under nitrogen for a total of 72 hours; ice was added, about 25 grams, and the solution stirred and transferred to a separatory funnel.

Ethyl acetate (40, 30, 30 ml) was used to extract the yellow solution three times.

Aqueous layer 13-A. The combined ethyl acetate layers were: washed with a saturated salt solution, and then dried over anhydrous magnesium sulfate (5 hours).

The aqueous layers, 13-A, 13-B, and 13-C were back extracted with chloroform to give a second solution.

The ethyl acetate sample was evaporated to dryness to give 0.2759 grams (91percent yield) of a pale yellow oil.

To remove trace amounts of ethyl acetate, the sample was redissolved in chloroform, filtered, and evaporated to give 0.2746 g of product.

The identity of the compound was established by means of an EM-390 90 MHz NMR Spectrometer, as shown in FIG. 1.

The N Formyl chloride used in the foregoing reaction with Δ-9-Tetrahydrocannabinol was prepared as follows: Patent; Calcol, Inc.; US4327028; (1982); (A) English View in Reaxys

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