2-[(Diphenylmethyl)sulfinyl]acetamide (Modafinil) by Asch

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Rx-ID: 9650601 Find similar reactions

98%

With 1-methyl-3,5-dinitropyridinium trifluoromethanesulfonate; dihydrogen peroxide in methanol; water

T=25°C; 21.5 h; Reagent/catalyst;

Šturala, Jiří; Boháčová, Soňa; Chudoba, Josef; Metelková, Radka; Cibulka, Radek

Journal of Organic Chemistry, 2015 , vol. 80, # 5 p. 2676 - 2699 Title/Abstract Full Text View citing articles Show Details

98%

With 1-octyl-3,5-dinitropyridinium triflate; dihydrogen peroxide in aq. phosphate buffer; chloroform

T=25°C; pH=2; 4 h; Green chemistry; Reagent/catalyst; chemoselective reaction;

Hartman, Tomáš; Šturala, Jiří; Cibulka, Radek

Advanced Synthesis and Catalysis, 2015 , vol. 357, # 16-17 p. 3573 - 3586 Title/Abstract Full Text View citing articles Show Details

93%

With formic acid; dihydrogen peroxide in water

T=10°C; 1 h;

Bicherov; Akopova; Spiglazov; Morkovnik

Russian Chemical Bulletin, 2010 , vol. 59, # 1 p. 91 - 101 Title/Abstract Full Text View citing articles Show Details

92%

With 3-cyano-1-ethylpyrazinium tetrafluoroborate; dihydrogen peroxide in methanol; water

T=25°C; 24 h; chemoselective reaction;

Menova, Petra; Kafka, Frantisek; Dvorakova, Hana; Gunnoo, Smita; Sanda, Miloslav; Cibulka, Radek

Advanced Synthesis and Catalysis, 2011 , vol. 353, # 6 p. 865 - 870 Title/Abstract Full Text View citing articles Show Details

90%

With oxygen in water; acetonitrile

T=23 - 27°C; 1 h; IrradiationGreen chemistry; chemoselective reaction;

Neveselý, Tomáš; Svobodová, Eva; Chudoba, Josef; Sikorski, Marek; Cibulka, Radek

Advanced Synthesis and Catalysis, 2016 , vol. 358, # 10 p. 1654 - 1663 Title/Abstract Full Text View citing articles Show Details

85%

With dihydrogen peroxide; acetic acid in water

T=11 - 44°C; Product distribution / selectivity; Hide Experimental Procedure

MALLINCKRODT INC.?

Patent: WO2005/42479 A1, 2005 ; Location in patent: Page/Page column 10-11; 13 ; Title/Abstract Full Text Show Details

3; 4.3:

EXAMPLE 3 Preparation of benzhydrylsulphinylacetamide To a 500ml three-necked round bottom flask was charged 50 grams of benzhydrylthioacetamide and 100 ml of acetic acid. The mixture was stirred until all solids were dissolved and then the reaction mixture was cooled to 15°C. Subsequently, 25 ml of hydrogen peroxide solution (30percent) were added to the reaction mixture in step-wise fashion (5- 10ml portions) while maintaining the temperature of the reaction mixture below 20°C. The reaction mixture was then stirred at room temperature (20°C) or until the amide disappeared. There was then added 500 ml of water to the reaction mixture thereby precipitating the product. The reaction mixture was cooled to 15°C and filtered. The crude solid product was then rinsed with 50 ml of water. The product was then purified by first combining it with nheptane (3. 5ml/lg crude) and then chloroform (7ml/lg of crude). The combined slurry was refluxed for 30 min. at a temperature of 70-75°C. The solution was slowly cooled to 10°C with stirring and the solid precipitate then filtered and oven dried. The yield was 85percent (molar) and the purity was 99.8percent.; Thioacetamide 5 and acetic acid were charged to a 12 L 3NRB reaction flask. The mixture was stirred until all solids were dissolved. The reaction temperature dropped to 11°C (endotherm). Hydrogen peroxide solution (30percent) was slowly charged to the flask while maintaining the temperature of the mixture less than 20°C. Although the temperature of the mixture dropped immediately after the peroxide was charged it rose several degrees and once at 17°C, exotherms became much more dramatic as reaction temperature rose to 41°C in the first hour After the reaction mixture was cooled to 20°C, the remaining 40percent of the peroxide was charged. The reaction mixture was stirred overnight at room temperature (20°C). Then, 8 L of water was slowly charged to the flask to precipitate the product benzhydrylsulphinylacetamide 6. The solids were recovered by filtration and then washed with 3 L of water. 80%

With ε-phthalimido-peroxy-hexanoic acid in dichloromethane

T=20°C; 6 h; Hide Experimental Procedure

Dipharma S.p.A.

Patent: EP1466897 A1, 2004 ; Location in patent: Page 5 ; Title/Abstract Full Text Show Details

4:EXAMPLE 4; Preparation of modafinil

EXAMPLE 4 Preparation of modafinil 10 g (38.9 mmoles) of 2-[(diphenylmethyl)thio]acetamide are dissolved in 100 ml of dichloromethane.. The solution is added with 15.7 g of 68percent w/w ε-phthalimidoperhexanoic acid, keeping the temperature at about 20°C, and after 6 h is diluted with water, adjusting the PH to 8-9 with aqueous ammonia.. The resulting phases are separated and the organic one is evaporated to dryness, to obtain 8.5 g of 2-[(diphenylmethyl)sulfinyl]acetamide (modafinil).. Molar yield: 80percent. 1H NMR (CDCl3): 3.22-3.27 ppm, d, 1H, (S(O)CH2); 3.63-3.68 ppm, d, 1H(J=12.5 Hz), (S(O)CH2); 5.32 ppm, s, 1H, (S(O)CHPh2); 7.38 - 7.5 ppm, m, 10H, (Aromatic). 80%

With ε-phthalimido-peroxy-hexanoic acid in dichloromethane

T=20°C; 6 h; Hide Experimental Procedure

DINAMITE DIPHARMA S.P.A. abbreviated DIPHARMA S.P.A.

Patent: US2004/192929 A1, 2004 ; Location in patent: Page 4 ; Title/Abstract Full Text Show Details

4:Example4; Preparation of 2-[(diphenylmethyl)sulfinyl]acetamide

10 g (38.9 mmoles) of 2-[(diphenylmethyl)thio]acetamide are dissolved in 100 ml of dichloromethane. The solution is added with 15.7 g of 68percent epsilon-phthalimidoperhexanoic acid, keeping the temperature at about 20 C., and after 6 h is diluted with water, adjusting the pH to 8-9 with aqueous ammonia. The resulting phases are separated and the organic one is evaporated to dryness, to obtain 8.5 g of 2[(diphenylmethyl)sulfinyl]acetamide (modafinil). Molar yield: 80percent. [0068] 1H NMR (CDCl3): [TABLE-US-00001] 3.22 - 3.27 ppm d 1H S(O)CH2 3.63 - 3.68 ppm d 1H (J = 12.5 Hz) S(O)CH2 5.32 ppm s 1H S(O)CHPh2 7.38 - 7.5 ppm m 10H Aromatic 67%

With dihydrogen peroxide; acetic acid

T=40°C;

Prisinzano, Thomas; Podobinski, John; Tidgewell, Kevin; Luo, Min; Swenson, Dale

Tetrahedron Asymmetry, 2004 , vol. 15, # 6 p. 1053 - 1058 Title/Abstract Full Text View citing articles Show Details

67%

With dihydrogen peroxide in water; acetic acid

T=40 - 45°C; 4.5 h;

CHEMAGIS LTD.

Patent: EP1260501 A1, 2002 ; Location in patent: Referential example 2 ; Title/Abstract Full Text Show Details

67%

With dihydrogen peroxide in acetic acid

T=40°C;

Jung, Jae-Chul; Lee, Yeonju; Son, Jee-Young; Lim, Eunyoung; Jung, Mankil; Oh, Seikwan

Molecules, 2012 , vol. 17, # 9 p. 10446 - 10458 Title/Abstract Full Text View citing articles Show Details

43%

With dihydrogen peroxide in water; acetic acid

KANDULA, Mahesh

Patent: WO2013/179153 A1, 2013 ;

4 h; Cooling; Hide Experimental Procedure

Location in patent: Paragraph 0095; 00100-00101 ; Title/Abstract Full Text Show Details

1.3:[00100] Step-3: Synthesis of compound 5:

[00100] Step-3: Synthesis of compound 5: [00101] Diphenylmethylthioacetamide 4 (3.46 g, 0.013 mole) was taken in glacial acetic acid (14 ml) with stirring; to this was added 1.34 ml of 30percent H202 with chilling in ice water. The mixture was left in the refrigerator for 4 h and thereafter worked up by treating it with 70 ml of ice-cold water. The precipitated material was filtered under suction and washed with ice-cold water to give 1.5 g of white crystals 5 (43percent), mp 159— 160°C. Rf 0.6. Recrystallization from hot MeOH gave mp 161-162°C. 43%

With dihydrogen peroxide; acetic acid

T=0°C; 4 h; Hide Experimental Procedure

Kandula, Mahesh

Patent: US2015/141513 A1, 2015 ; Location in patent: Paragraph 0106; 0111; 0112 ; Title/Abstract Full Text Show Details

3:Step-3: Synthesis of Compound 5

Step-3: Synthesis of Compound 5: [0112] Diphenylmethylthioacetamide 4 (3.46 g, 0.013 mole) was taken in glacial acetic acid (14 ml) with stirring; to this was added 1.34 ml of 30percent H2O2 with chilling in ice water. The mixture was left in the refrigerator for 4 h and thereafter worked up by treating it with 70 ml of ice-cold water. The precipitated material was filtered under suction and washed with ice-cold water to give 1.5 g of white crystals 5 (43percent), mp 159-160° C. Rf 0.6. Recrystallization from hot MeOH gave mp 161-162° C. With dihydrogen peroxide; acetic acid in water; chlorobenzene

T=55°C; 2.16667 h; Hide Experimental Procedure

CEPHALON, INC.

Patent: WO2003/99774 A1, 2003 ; Location in patent: Page 12 ; Title/Abstract Full Text Show Details

2:Example 2:

Example 2: A suspension of benzhydrol (200.00 g, 1.075 mol, 1 equivalent) and thiourea (99.4 g, 1.293 mol, 1.20 equivalents) in monochlorobenzene/water (477 ml/300.5 ml) was heated at [70C.] An aqueous [48percent] HBr solution (145 ml, 1.29 mol, 1.2 equivalents) was then added over a 5 min period. After 3 h stirring at [70C,] the uronium intermediate was hydrolyzed by addition of an aqueous 9.3N potassium hydroxide solution (321.7 ml, 2.825 mol, 2.63 equivalents) over a 50 min period. After 1.5 h stirring at [70C,] chloroacetamide (152.3 g, 1.612 mol, 1.5 equivalents) in powder form was added for over a 15 min period. After 30 min stirring at [70C,] the reaction mixture was cooled down to [55C] and the stirring was stopped. The lower aqueous phase was removed, and water (600 ml) was added to the reactor. The reaction mixture was again stirred for 45 min. The lower aqueous phase was then removed. Acetic acid (173.3 ml, 3.000 mol, 2.79 equivalents) was added. Hydrogen peroxide 30percent (175.4 ml, 1.718 mol, 1.6 equivalents) was slowly added for 80 min. After 50 minutes of stirring at [55C,] the reaction mixture was quenched with an aqueous sodium bisulfite solution (275 g). The lower aqueous phase was removed and the reaction mixture was cooled 0- [5C.] Monochlorobenzene [(386] g) was added to dilute the reaction mixture. The resultant suspension was then filtered, and the solid was washed with water and monochlorobenzene, and dried to yield modafinil (216.7 g, global yield 69. 3percent, strength 93.9 wt. [percent).] The crude modafinil was purified by recrystallization in methanol With dihydrogen peroxide; acetic acid in tetrahydrofuran; water

T=55°C; 1.5 h; Hide Experimental Procedure

CEPHALON, INC.

Patent: WO2003/99774 A1, 2003 ; Location in patent: Page 12 ; Title/Abstract Full Text Show Details

1:Example 1:

Example 1: To a suspension of benzhydrol (35.00 g, 0.188 mol, 1 equivalent) and thiourea (17.40 g, 0.226 mol, 1.20 equivalents) in tetrahydrofuran/water (35.5 ml/52.5 ml), was added an aqueous [48percent] HBr solution (25.3 ml, 0.226 mol, 1.2 equivalents) over a 10 min period. During the addition, the reaction mixture is heated to [70C.] After 3 h stirring at [70C,] the uronium intermediate was hydrolyzed by addition of an aqueous 9.3N potassium hydroxide solution (58 ml, 0.542 mol, 2. 88 equivalents) over a 55 min period. After 1.5 h stirring at [70C,] chloroacetamide (26.6 g, 0.282 mol, 1.5 equivalents) in a tetrahydrofuran/water [(80] ml/79 [ML)] solution was added over 15 min. After 1 h stirring at [70C,] the reaction mixture was cooled down to [55C] and the stirring was stopped. The lower aqueous phase was removed, and the reaction mixture was again stirred. Acetic acid (34.7 ml, 0.601 mol, 3.2 equivalents) was added. Hydrogen peroxide 30percent (38.4 ml, 0.376 mol, 2 equivalents) was slowly added over 30 min. After 1 h stirring, the reaction mixture was cooled to [20C] and water (263 ml) was added. The resultant suspension was stirred at [0C] overnight. The suspension was then filtered and the solid was washed with water, and dried to yield modafinil (47.9 g, 80.4percent). The crude modafinil was purified by recrystallization in methanol. With dihydrogen peroxide; acetic acid in methanol; water

T=40 - 65°C; 1 - 7.5 h; Product distribution / selectivity; Hide Experimental Procedure

MALLINCKRODT INC.

Patent: WO2007/70238 A2, 2007 ; Location in patent: Page/Page column 38-41 ; Title/Abstract Full Text Show Details

EXAMPLE 1; [0289 ] In this Example, the modafinil intermediate compound benzhydrylthioacetamide was oxidized to produce modafinil according to the processes described herein using various ratios of alcohol to organic acid and various reaction mixture temperatures.[0290] First, benzhydrylthioacetamide (10 g; MW = 257.35; 1.0 eq.), methanol, and acetic acid were charged to a 250 ml_ flask. Hydrogen peroxide (4.3 ml 1.05 eq.) was then charged to the resulting mixture over the course of about 5 minutes. The reaction was allowed to proceed for about 24 hours, with samples periodically taken for HLPC analysis. Several different trials using <n="40"/>particular ratios of methanol and acetic acid at particular temperatures were performed. Results are illustrated in Tables 1-7, below.Table 1 : 20 ml_ methanol/20 mL acetic acid; 400CTable 2: 30 mL methaπol/10 mL acetic acid; 400CTable 3: 35 mL methanol/5 mL acetic acid; 400C <n="41"/>Table 4: 39 mL methanol/1 mL acetic acid; 400C <n="42"/>[0291] As illustrated in Tables 1-7 above, the processes of the present invention are effective in producing modafinil at high yield and with relatively low sulfone impurity content. Specifically, as illustrated in Table 2, a reaction mixture comprising 30 mL of methanol and 10 mL acetic acid (i.e., methanol and acetic acid are present in the reaction mixture at a ratio of about 3:1 ) with the oxidation reaction proceeding at 400C is particularly effective, producing modafinil at about 96percent yield with a sulfone impurity content of about 0.22percent. Stage #1: With acetic acid in methanol

T=30 - 40°C; 0.25 h; Stage #2: With dihydrogen peroxide in methanol; water

T=38 - 43°C; 24 h; Product distribution /

MALLINCKRODT INC.

Patent: WO2007/70238 A2, 2007 ; Location in patent: Page/Page column 41-42 ; Title/Abstract Full Text Show Details

selectivity; Hide Experimental Procedure

EXAMPLE 2; [0292] In this Example, the modafinil intermediate benzhydrylthioacetamide was oxidized on a commercial scale to produce modafinil according to the processes described herein.[0293] First, benzhydrylthioacetamide (100 g; MW = 257.35, 1.0 eq.) was charged to a reaction chamber. The reaction chamber was purged with about 5 psig N2 and vented through chemical scrubber. Approximately 155 kg of methanol (1.50-1.67 kg/kg benzhydrylthioacetamide) was then charged to the reaction chamber. The temperature of the reaction chamber was adjusted to about 30°C-40°C and the resulting mixture was agitated at about 70-90 RPM.[ 0294 ] Next, approximately 0.70 kg of acetic acid (0.68-0.72 kg/kg benzhydrylthioacetamide) was charged to the reaction chamber. The resulting mixture was then stirred for about 15 minutes, and the temperature was maintained at about 30°C-40°C.[ 0295 ] To the benzhydrylthioacetamide/methanol/acetic acid mixture was then added approximately 0.472 kg of 30percent hydrogen peroxide (0.448-0.496 kg/kg benzhydrylthioacetamide) at a rate of about 1-2 kg/min. The resulting mixture was then heated to and maintained at about 38°C- 43°C and stirred for about 24 hours.[ 0296 ] After about 24 hours, the reaction mixture was cooled to about 20°C-30°C and the reaction chamber was pressurized to about 3-7 psig with N2 and vented through a chemical scrubber. The reaction mixture was further cooled to about 0"C-5°C and stirred for about 2 hours. The reaction mixture was then charged to an N2-purged centrifuge (<7percent O2 content). The centrifuge was cycled on low speed until the centrifuge basket was less than 3/4 full with the crude modafinil product (-15 minutes). The centrifuge load was washed with about 113 liters of cool methanol, and the crude modafinil cake was deliquored at high speed centrifugation for about 15-30 minutes.[0297] The white- to offwhite crude modafinil product (-85.2 kg) was then loaded onto a TeflonO-lined tray and dried at about 60°C-70°C for at least about 6 hours (6-24 hours). After drying, a 5-10 gram sample was analyzed by HPLC. The results are illustrated in Table 8, below: <n="43"/>Table 8 With dihydrogen peroxide; acetic acid in methanol; water

T=40°C; 24 h;

Cao, Jianjing; Prisinzano, Thomas E.; Okunola, Oluyomi M.; Kopajtic, Theresa; Shook, Matthew; Katz, Jonathan L.; Newman, Amy Hauck

ACS Medicinal Chemistry Letters, 2011 , vol. 2, # 1 p. 48 - 52 Title/Abstract Full Text View citing articles Show Details

123 mg

With dihydrogen peroxide; acetic acid in methanol; water

T=40°C; 4 h; Sonication;

Bogolubsky, Andrey V.; Moroz, Yurii S.; Mykhailiuk, Pavel K.; Ostapchuk, Eugeniy N.; Rudnichenko, Alexander V.; Dmytriv, Yurii V.; Bondar, Anna N.; Zaporozhets, Olga A.; Pipko, Sergey E.; Doroschuk, Roman A.; Babichenko, Liudmyla N.; Konovets, Anzhelika I.; Tolmachev, Andrey

ACS Combinatorial Science, 2015 , vol. 17, # 6 p. 348 - 354 Title/Abstract Full Text View citing articles Show Details

93 %Chromat.

With dihydrogen peroxide in 1,2-dichloroethane

T=20°C; 1.5 h; Hide Experimental Procedure

Taghizadeh, Mohammad Javad; Karimi, Homman; Abandansari, Hamid Sadeghi

Research on Chemical Intermediates, 2016 , vol. 42, # 12 p. 8201 - 8215 Title/Abstract Full Text View citing articles Show Details

Catalytic experiments

General procedure: To examine the catalytic activity of the heterogeneous catalyst, 1 mmol of sulde,1.5 ml of hydrogen peroxide 30 percent as oxidant and 5 percent mol of catalyst weredissolved in 3 ml solvent and reacted at room temperature for different times(Scheme 4; Table 1; Fig. 7). The monitoring of the sulfoxide formation was carried out by TLC (n-hexanes:EtOAc, 1:1 or CHCl3:MeOH, 9:1 as eluent). Aftercompletion of the reaction, the solvent was evaporated and the crude product waspuried by a recrystallization method (using EtOAC/n-hexane) (Table 2). Thecatalyst was recovered and reused for further runs.

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Rx-ID: 13517346 Find similar reactions

Multi-step reaction with 3 steps 1: thionyl chloride / benzene / 1.5 h / Heating 2: 17.0 g / aq. NH4OH / CH2Cl2 / 2 h 3: 67 percent / aq. H2O2; acetic acid / 40 °C View Scheme

Prisinzano, Thomas; Podobinski, John; Tidgewell, Kevin; Luo, Min; Swenson, Dale

Tetrahedron Asymmetry, 2004 , vol. 15, # 6 p. 1053 - 1058 Title/Abstract Full Text View citing articles Show Details

Multi-step reaction with 3 steps 1: potassium carbonate / acetone / 4 h / Reflux 2: ammonium hydroxide; ammonium chloride / methanol / 72 h / 50 °C 3: dihydrogen peroxide; acetic acid / methanol; water / 24 h / 40 °C View Scheme

Cao, Jianjing; Prisinzano, Thomas E.; Okunola, Oluyomi M.; Kopajtic, Theresa; Shook, Matthew; Katz, Jonathan L.; Newman, Amy Hauck

ACS Medicinal Chemistry Letters, 2011 , vol. 2, # 1 p. 48 - 52 Title/Abstract Full Text View citing articles Show Details

Multi-step reaction with 3 steps 1: thionyl chloride / benzene / 2 h / |Reflux

Jung, Jae-Chul; Lee, Yeonju; Son, Jee-Young; Lim, Eunyoung; Jung, Mankil; Oh, Seikwan

Molecules, 2012 , vol. 17, # 9 p. 10446 - 10458

2: ammonium hydroxide / dichloromethane / 20 h / 2 °C 3: dihydrogen peroxide / acetic acid / 40 °C View Scheme

Title/Abstract Full Text View citing articles Show Details

Multi-step reaction with 4 steps 1: sulfuric acid / 16 h / |Reflux 2: sulfuric acid; dihydrogen peroxide / methanol; isopropyl alcohol / 2 h / 20 °C 3: sodium hydroxide / ethanol; water / 2 h / 20 °C 4: ammonium hydroxide / dichloromethane / 2 h / 20 °C View Scheme

Jung, Jae-Chul; Lee, Yeonju; Son, Jee-Young; Lim, Eunyoung; Jung, Mankil; Oh, Seikwan

Molecules, 2012 , vol. 17, # 9 p. 10446 - 10458 Title/Abstract Full Text View citing articles Show Details

Multi-step reaction with 3 steps 1: thionyl chloride / benzene / 1 h / |Inert atmosphere; |Reflux 2: ammonium hydroxide / water; dichloromethane / 1 h / 0 °C 3: dihydrogen peroxide / water; acetic acid / 4 h / |Cooling View Scheme

KANDULA, Mahesh

Patent: WO2013/179153 A1, 2013 ;

Multi-step reaction with 2 steps 1.1: thionyl chloride / benzene / 1 h / 20 °C / |Inert atmosphere; |Reflux 1.2: 1 h / 0 °C 2.1: dihydrogen peroxide; acetic acid / 4 h / 0 °C View Scheme

Kandula, Mahesh

Patent: US2015/141513 A1, 2015 ;

Title/Abstract Full Text Show Details

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Multi-step reaction with 4 steps 1: water; acetone / 3 h / 20 - 70 °C / |Inert atmosphere 2: thionyl chloride / benzene / 1 h / |Inert atmosphere; |Reflux 3: ammonium hydroxide / water; dichloromethane / 1 h / 0 °C 4: dihydrogen peroxide / water; acetic acid / 4 h / |Cooling View Scheme

KANDULA, Mahesh

Patent: WO2013/179153 A1, 2013 ;

Multi-step reaction with 3 steps 1.1: water; acetone / 3 h / 20 - 70 °C / |Inert atmosphere 2.1: thionyl chloride / benzene / 1 h / 20 °C / |Inert atmosphere; |Reflux 2.2: 1 h / 0 °C 3.1: dihydrogen peroxide; acetic acid / 4 h / 0 °C View Scheme

Kandula, Mahesh

Patent: US2015/141513 A1, 2015 ;

Title/Abstract Full Text Show Details

Rx-ID: 37114182 Find similar reactions

Synthesize Find similar Multi-step reaction with 2 steps 1.1: thiourea / isopropyl alcohol / 2 h / 100 °C / |Sealed tube 1.2: 2 h / 60 °C / |Sonication 2.1: acetic acid; dihydrogen peroxide / methanol; water / 4 h / 40 °C / |Sonication View Scheme

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Rx-ID: 40471604 Find similar reactions

ACS Combinatorial Science, 2015 , vol. 17, # 6 p. 348 - 354 Title/Abstract Full Text View citing articles Show Details

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Rx-ID: 13527854 Find similar reactions

Multi-step reaction with 2 steps 1: 17.0 g / aq. NH4OH / CH2Cl2 / 2 h 2: 67 percent / aq. H2O2; acetic acid / 40 °C View Scheme

Prisinzano, Thomas; Podobinski, John; Tidgewell, Kevin; Luo, Min; Swenson, Dale

Tetrahedron Asymmetry, 2004 , vol. 15, # 6 p. 1053 - 1058 Title/Abstract Full Text View citing articles Show Details

Multi-step reaction with 2 steps 1: ammonium hydroxide / dichloromethane / 20 h / 2 °C 2: dihydrogen peroxide / acetic acid / 40 °C View Scheme

Jung, Jae-Chul; Lee, Yeonju; Son, Jee-Young; Lim, Eunyoung; Jung, Mankil; Oh, Seikwan

Molecules, 2012 , vol. 17, # 9 p. 10446 - 10458 Title/Abstract Full Text View citing articles Show Details

Multi-step reaction with 2 steps 1: ammonium hydroxide / water; dichloromethane / 1 h / 0 °C 2: dihydrogen peroxide / water; acetic acid / 4 h / |Cooling View Scheme

KANDULA, Mahesh

Patent: WO2013/179153 A1, 2013 ; Title/Abstract Full Text Show Details

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Rx-ID: 9978935 Find similar reactions

81%

With Bacillus subtilis var. niger IFO-3180 in N,N-dimethyl-formamide

T=28°C; 168 h;

Olivo, Horacio F.; Osorio-Lozada, Antonio; Peeples, Tonya L.

Tetrahedron Asymmetry, 2005 , vol. 16, # 21 p. 3507 - 3511 Title/Abstract Full Text View citing articles Show Details

72.2%

Stage #1: With 1,1'-carbonyldiimidazole in dichloromethane

T=15°C; Stage #2: With ammonia in water

T=0 - 25°C; 0.5 h; Hide Experimental Procedure

DINAMITE DIPHARMA S.P.A., in abbreviated form DIPHARMA S.P.A.

Patent: WO2003/95423 A1, 2003 ; Location in patent: Page/Page column 8-9 ; Title/Abstract Full Text Show Details

3.2:preparation of 2-[(diphenylmethyl)sulfinyl]acetamide (modafinil)

Method 2 A solution of 20 g (0.073 mols) of 2-[(diphenylmethyl) sulfinyl] acetic acid (9) in 132 g of dichloromethane cooled at 15°C is added with 13.6 g (0.084 mols) of N, N'-carbonyldiimidazole in 5 portions of 2.7 g each. After completion of the addition, the mass is cooled to 0-5°C and added with 120 ml (1.06 mols) of a 15percent aqueous ammonia solution. After that, the inner temperature is brought to 20. 25°C keeping these conditions for about 30', then the mixture is diluted with 100 ml of water. The phases are separated, the lower organic phase is added with 80 ml of water and dichloromethane is distilled off at atmospheric pressure. The mass is cooled to 20-25°C and added with 40 ml of ethyl acetate, keeping stirring for about 1 hour; the precipitate is filtered and washed with water to obtain 14.4 g of 2-[(diphenylmethyl) sulfinyl] acetamide (modafinil) (yield: 72.2percent, HPLC purity > 99.5percent). 70%

Stage #1: With 1,1'-carbonyldiimidazole in dichloromethane

T=15°C; Stage #2: With ammonia in dichloromethane

T=0 - 25°C; 0.5 h; Hide Experimental Procedure

DINAMITE DIPHARMA S.P.A., in abbreviated form DIPHARMA S.P.A.

Patent: WO2003/95423 A1, 2003 ; Location in patent: Page/Page column 8 ; Title/Abstract Full Text Show Details

2.1:preparation of 2-[(diphenylmethyl)sulfinyl]acetamide (modafinil)

Method 1 A solution of 10 g (0.036 mols) of 2-[(diphenylmethyl) sulfinyl] acetic acid (9) in 66 g of dichloromethane cooled at 15°C is added with 6.8 g (0.042 mols) of N, N'-carbonyldiimidazole in 5 portions of 1.3 g each. After completion of the addition, the mass is cooled to 0-5°C and gas ammonia is bubbled therein. After that, the inner temperature is brought to 20-25°C keeping these conditions for about 30', then the mixture is diluted with 50 ml of water. The phases are separated, the organic phase is added with 40 ml of water and dichloromethane is distilled off at atmospheric pressure. The mass is cooled to 20=25°C and added with 20 ml of ethyl acetate, keeping stirring for about 1 hour; the precipitate is filtered, washed with water to obtain 6.9 g (0.025 mols) of 2-[(diphenylmethyl) sulfinyl] acetamide (modafinil) (yield: 70percent, HPLC purity >99.5percent).

With ammonium hydroxide in dichloromethane

T=20°C; 2 h;

Jung, Jae-Chul; Lee, Yeonju; Son, Jee-Young; Lim, Eunyoung; Jung, Mankil; Oh, Seikwan

Molecules, 2012 , vol. 17, # 9 p. 10446 - 10458 Title/Abstract Full Text View citing articles Show Details

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Multi-step reaction with 4 steps 1: trifluoroacetic acid / 20 °C 2: potassium carbonate / acetone / 4 h / Reflux 3: ammonium hydroxide; ammonium chloride / methanol / 72 h / 50 °C 4: dihydrogen peroxide; acetic acid / methanol; water / 24 h / 40 °C View Scheme

Cao, Jianjing; Prisinzano, Thomas E.; Okunola, Oluyomi M.; Kopajtic, Theresa; Shook, Matthew; Katz, Jonathan L.; Newman, Amy Hauck

ACS Medicinal Chemistry Letters, 2011 , vol. 2, # 1 p. 48 - 52 Title/Abstract Full Text View citing articles Show Details

Multi-step reaction with 3 steps 1: trifluoroacetic acid / 3 h 2: sulfuric acid; dihydrogen peroxide / methanol / 16 h / 20 °C 3: ammonium hydroxide / dichloromethane / 2 h / 20 °C View Scheme

Jung, Jae-Chul; Lee, Yeonju; Son, Jee-Young; Lim, Eunyoung; Jung, Mankil; Oh, Seikwan

Molecules, 2012 , vol. 17, # 9 p. 10446 - 10458 Title/Abstract Full Text View citing articles Show Details

Multi-step reaction with 4 steps 1: Lawesson's reagent / toluene / 3 h / |Reflux; |Inert atmosphere 2: potassium carbonate / acetone / 6 h 3: potassium hydroxide / ethanol / 6 h / |Reflux 4: dihydrogen peroxide / acetic acid / 40 °C View Scheme

Jung, Jae-Chul; Lee, Yeonju; Son, Jee-Young; Lim, Eunyoung; Jung, Mankil; Oh, Seikwan

Molecules, 2012 , vol. 17, # 9 p. 10446 - 10458 Title/Abstract Full Text View citing articles Show Details

Multi-step reaction with 4 steps 1: trifluoroacetic acid / 3 h 2: thionyl chloride / benzene / 2 h / |Reflux 3: ammonium hydroxide / dichloromethane / 20 h / 2 °C 4: dihydrogen peroxide / acetic acid / 40 °C View Scheme

Jung, Jae-Chul; Lee, Yeonju; Son, Jee-Young; Lim, Eunyoung; Jung, Mankil; Oh, Seikwan

Molecules, 2012 , vol. 17, # 9 p. 10446 - 10458 Title/Abstract Full Text View citing articles Show Details

Multi-step reaction with 5 steps 1: trifluoroacetic acid / 3 h 2: sulfuric acid / 16 h / |Reflux 3: sulfuric acid; dihydrogen peroxide / methanol; isopropyl alcohol / 2 h / 20 °C 4: sodium hydroxide / ethanol; water / 2 h / 20 °C 5: ammonium hydroxide / dichloromethane / 2 h / 20 °C View Scheme

Jung, Jae-Chul; Lee, Yeonju; Son, Jee-Young; Lim, Eunyoung; Jung, Mankil; Oh, Seikwan

Molecules, 2012 , vol. 17, # 9 p. 10446 - 10458 Title/Abstract Full Text View citing articles Show Details

Synthesize Find similar Multi-step reaction with 3 steps 1: potassium carbonate / acetone / 6 h 2: potassium hydroxide / ethanol / 6 h / |Reflux 3: dihydrogen peroxide / acetic acid / 40 °C View Scheme

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Rx-ID: 34133527 Find similar reactions

Jung, Jae-Chul; Lee, Yeonju; Son, Jee-Young; Lim, Eunyoung; Jung, Mankil; Oh, Seikwan

Molecules, 2012 , vol. 17, # 9 p. 10446 - 10458 Title/Abstract Full Text View citing articles Show Details

Synthesize Find similar Multi-step reaction with 2 steps 1: potassium hydroxide / ethanol / 6 h / |Reflux 2: dihydrogen peroxide / acetic acid / 40 °C View Scheme

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Rx-ID: 34133534 Find similar reactions

Jung, Jae-Chul; Lee, Yeonju; Son, Jee-Young; Lim, Eunyoung; Jung, Mankil; Oh, Seikwan

Molecules, 2012 , vol. 17, # 9 p. 10446 - 10458 Title/Abstract Full Text View citing articles Show Details

Synthesize Find similar Multi-step reaction with 3 steps 1: sulfuric acid; dihydrogen peroxide / methanol; isopropyl alcohol / 2 h / 20 °C 2: sodium hydroxide / ethanol; water / 2 h / 20 °C 3: ammonium hydroxide / dichloromethane / 2 h / 20 °C View Scheme

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Rx-ID: 34133560 Find similar reactions

Jung, Jae-Chul; Lee, Yeonju; Son, Jee-Young; Lim, Eunyoung; Jung, Mankil; Oh, Seikwan

Molecules, 2012 , vol. 17, # 9 p. 10446 - 10458 Title/Abstract Full Text View citing articles Show Details

Synthesize Find similar Multi-step reaction with 2 steps 1: sodium hydroxide / ethanol; water / 2 h / 20 °C 2: ammonium hydroxide / dichloromethane / 2 h / 20 °C View Scheme

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Rx-ID: 34133583 Find similar reactions

Jung, Jae-Chul; Lee, Yeonju; Son, Jee-Young; Lim, Eunyoung; Jung, Mankil; Oh, Seikwan

Molecules, 2012 , vol. 17, # 9 p. 10446 - 10458 Title/Abstract Full Text View citing articles Show Details

Synthesize Find similar Multi-step reaction with 2 steps 1: ammonium hydroxide; ammonium chloride / methanol / 72 h / 50 °C 2: dihydrogen peroxide; acetic acid / methanol; water / 24 h / 40 °C View Scheme

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Rx-ID: 30449853 Find similar reactions

Cao, Jianjing; Prisinzano, Thomas E.; Okunola, Oluyomi M.; Kopajtic, Theresa; Shook, Matthew; Katz, Jonathan L.; Newman, Amy Hauck

ACS Medicinal Chemistry Letters, 2011 , vol. 2, # 1 p. 48 - 52 Title/Abstract Full Text View citing articles Show Details

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Synthesize Find similar Rx-ID: 22963878 Find similar reactions

A: 95.73% B: 0.083%

With dihydrogen peroxide in acetic acid

T=40°C; 6 h; Hide Experimental Procedure

PROCOS S.P.A.

Patent: US2004/106829 A1, 2004 ; Location in patent: Page 4 ; Title/Abstract Full Text Show Details

7:EXAMPLE 7. Synthesis of Modafinil

2-(Benzhydrylthio)acetamide obtained according to Example 4 (30 g-HPLC 97.9percent) and acetic acid (120 ml) are loaded into a 1000 ml round-bottom flask. The mixture is heated to 40° C., slowly added with 35percent hydrogen peroxide (11.7 g) and reacted at 40° C. for about 6 hours. The mixture is then cooled to 30° C., added with water (900 ml) and further cooled to 15° C. The product is filtered and washed with water. The wet product (49.4 g) thus obtained (HPLC: 95.73percent, 0.083percent (sulfone)) is dried at 50° C. under reduced pressure. Yield: 29.7 g. Crude modafinil is recrystallized from methanol (193 ml), by heating under reflux and cooling then to 15° C. The precipitate is filtered, washed with cold methanol and dried at 50° C. under reduced pressure. Yield: 23.4 g (HPLC: 99.9percent, 0.01percent (sulfone)). With dihydrogen peroxide; acetic acid in methanol; water

T=40 - 65°C; 1 - 28.75 h; Product distribution / selectivity; Hide Experimental Procedure

MALLINCKRODT INC.

Patent: WO2007/70238 A2, 2007 ; Location in patent: Page/Page column 38-41 ; Title/Abstract Full Text Show Details

sulfone impurity content of about 0.22percent.

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With ammonia in methanol

T=25°C; 13.1667 h; Industry scale; Conversion of starting material; Hide Experimental Procedure

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Rx-ID: 23251270 Find similar reactions

Orsymonde (Organisation de synthese Mondiale)

Patent: EP1477476 A1, 2004 ; Location in patent: Page 14 ; Title/Abstract Full Text Show Details

II.C.15:C. 2500-litre scale; Example 15; 2500-litre scale procedure; A reactor of type BE 2500 (De Dietrich) with a capacity of 2500 litres, equipped with an impeller stirrer and a gas introduction pipe, was charged with 500 kg of DMSAM and 1500 litres of methanol. The suspension was stirred at 100 rpm and 20°C for 10 min and then heated to 35°C to dissolve the solids. The solution was subsequently stirred at 100 rpm for 35 min, then cooled to 25°C and stirred at 100 rpm at this temperature for 30 min. 106 kg of ammonia were then introduced over 3 h 10 min at 25°C. The reaction medium was left in contact for 10 h at 25°C with stirring at 100 rpm before finally being cooled to -10°C, and then was drained and clarified with 80 litres of ice-cold methanol. The moist product was then dried under vacuum at 45°C. Yield = 91 percent, median = 23 m. 91.6%

With ammonia in methanol

T=25°C; 13.1667 h; Conversion of starting material; Hide Experimental Procedure

Orsymonde (Organisation de synthese Mondiale)

Patent: EP1477476 A1, 2004 ; Location in patent: Page 13 ; Title/Abstract Full Text Show Details

II.A.12:II. Modafinil synthesis process without water; A. 1-litre scale; Example 12: 1-litre scale procedure A 1-litre automated reactor of type SIMULAR (Hazard Evaluation Laboratory, HEL) equipped with an impeller stirrer and a gas introduction tube was charged with 240 g of DMSAM and 720 ml of methanol. The suspension was stirred at 200 rpm and 20°C for 10 min and then heated to 35°C to dissolve the solids. The solution was subsequently stirred at 200 rpm for 15 min, then cooled to 25°C and stirred at 350 rpm and at this temperature for 30 min. 50.9 g of ammonia were then introduced over 3 h 10 min at 25°C. The reaction medium was left in contact for 10 h at 25°C with stirring at 350 rpm before finally being cooled to -10°C and then filtered over a frit of porosity 3. The moist product was then dried under vacuum at 45°C. Yield = 94.9percent, median = 33.9 m. Advantageously it was possible to work with only 3.6 equivalents (and not 4.0) of NH3, added at the same flow rate, while retaining a granulometric median and a granulometric profile which were in accordance with specification.A reactor of type AE 100 (De Dietrich) with a capacity of 100 litres, equipped with an impeller stirrer (De Dietrich) and a gas introduction pipe, was charged with 24 kg of DMSAM and 72 litres of methanol. The suspension was stirred at 150 rpm and 20°C for 10 min and then heated to 35°C to dissolve the solids. The solution was subsequently stirred at 150 rpm for 15 min, then cooled to 25°C and stirred at 150 rpm at this temperature for 30 min. 5.1 kg of ammonia were then introduced over 3 h 10 min at 25°C. The reaction medium was left in contact for 10 h at 25°C with stirring at 150 rpm before finally being cooled to -10°C, and then was drained and clarified with 20 litres of ice-cold methanol. The moist product was then dried under vacuum at 45°C. Yield = 91.6percent, median = 34.4 m. 89.5%

With ammonia in methanol; water

T=25°C; 14.5 h; Industry scale; Conversion of starting material; Hide Experimental Procedure

Orsymonde (Organisation de synthese Mondiale)

Patent: EP1477476 A1, 2004 ; Location in patent: Page 12 ; Title/Abstract Full Text Show Details

I.C.11; II.A.13; II.A.14:C. 2500-LITRE SCALE; Example 11: 2500-litre scale A reactor of type BE 2500 (De Dietrich) with a capacity of 2500 litres, equipped with an impeller stirrer and a gas introduction pipe, was charged with 250 kg of DMSAM, 750 litres of methanol and 55 litres of water. The suspension was stirred at 100 rpm and 20°C for 10 min and then heated to 35°C to dissolve the solids. The solution was subsequently stirred at 100 rpm for 35 min, then cooled to 25°C and stirred at 100 rpm at this temperature for 30 min. 78 kg of ammonia were then introduced over 4.5 h at 25°C. The reaction medium was left in contact for 10 h at 25°C with stirring at 100 rpm before finally being cooled to -10°C, and then was drained and clarified with 40 litres of ice-cold methanol. The moist product was then dried under vacuum at 45°C. Yield = 89.5percent, median = 27 m

87%

With ammonia in methanol; water

T=23 - 27°C; 14.5 h; Conversion of starting material; Hide Experimental Procedure

Orsymonde (Organisation de synthese Mondiale)

Patent: EP1477476 A1, 2004 ; Location in patent: Page 7 ; Title/Abstract Full Text Show Details

I.A.1;I.A.2;I.A.3;I.A.4;I.A.5;I.A.6;I.A.7;I.A.8;I.A.9;I.A.10:I. MODAFINIL SYNTHESIS PROCESS WITH WATER; A. 1-LITRE SCALE; Example 1: 1-litre scale procedure A 1-litre reactor of type SIMULAR (Hazard Evaluation Laboratory, HEL) equipped with an impeller stirrer and a gas introduction tube was charged with 150 g of DMSAM, 450 ml of methanol and 33 ml of water. The suspension was stirred at 100 rpm and 20°C for 10 min and then heated to 35°C to dissolve the solids. The solution was subsequently stirred at 200 rpm for 10 min, then cooled to 25°C and stirred at 350 rpm and at this temperature for 20 min. 46.8g of ammonia were then introduced over 4.5 h at 25°C. The reaction medium was left in contact for 10 h at 25°C with stirring at 350 rpm before finally being cooled to -10°C and then filtered

over a frit of porosity 3. The moist product was then dried under vacuum at 45°C. Yield = 89percent, median = 34.1 m. With ammonia in methanol; water

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Laboratoire L. Lafon

Patent: US4177290 A1, 1979 ; Title/Abstract Full Text Show Details

1.a.d:(d) (d) CRL 40476 1 kg of methyl benzhydrylsulphinylacetate is dissolved in 3.5 liters of anhydrous methanol in a 10-liter balloon flask. NH3 is bubbled in at a high rate of flow for 1 hour, and then left in contact for 4 hours. Filtration, drying without heat and washing with water are then carried out. By recrystallisation from a mixture of water and methanol (4:1 v/v) and then from a mixture of water and methanol (9:1 v/v) and drying under reduced pressure, CRL 40476 is obtained in the form of a white crystalline powder. M.p.inst (Kofler): 164°-166° C. Total yield (calculated from the benzhydrol): 41percent. With ammonia

Product distribution / selectivity; Hide Experimental Procedure

TEVA PHARMACEUTICAL INDUSTRIES LTD.; TEVA PHARMACEUTICALS USA, INC.

Patent: WO2007/103221 A2, 2007 ; Location in patent: Page/Page column 22-23 ; Title/Abstract Full Text Show Details

10:

Example 10: Preparation of Modafinil with thionyl chloride; <n="24"/>A 100 ml flask was charged with modafmic acid (3.0 g) and methanol (50 ml) and cooled to 00C. Thionyl chloride (1.63g, 1.7 eq.) was added drop wise. The reaction mixture was heated at 400C for three hours and then cooled to room temperature. The solvent was evaporated from the reaction mixture and the methyl ester of modafmic acid was isolated. The methyl ester of modafinic acid was converted into modafinil by reaction with bubbling ammonia. (RMDF-DS: about 2.5percent by HPLC) A

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Synthesize Find similar Rx-ID: 25760212 Find similar reactions

Stage #1: With acetic acid in methanol

T=30 - 40°C; 0.25 h; Stage #2: With dihydrogen peroxide in methanol; water

T=38 - 43°C; 24 h; Product distribution / selectivity; Hide Experimental Procedure

MALLINCKRODT INC.

Patent: WO2007/70238 A2, 2007 ; Location in patent: Page/Page column 41-42 ; Title/Abstract Full Text Show Details

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Stage #1: With acetic acid in methanol

T=30 - 40°C; 0.25 h; Stage #2: With dihydrogen peroxide in methanol; water

T=38 - 43°C; 24 h; Product distribution / selectivity; Hide Experimental Procedure

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MALLINCKRODT INC.

Patent: WO2007/70238 A2, 2007 ; Location in patent: Page/Page column 41-42 ; Title/Abstract Full Text Show Details

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Synthesize Find similar Rx-ID: 25914212 Find similar reactions

With ammonia; ammonium chloride in water

T=20°C; 17 h; Product distribution / selectivity; Hide Experimental Procedure

TEVA PHARMACEUTICAL INDUSTRIES LTD.; TEVA PHARMACEUTICALS USA, INC.

Patent: WO2007/103221 A2, 2007 ; Location in patent: Page/Page column 22 ; Title/Abstract Full Text Show Details

7; 8:

Example 7: Preparation of Modafinil with HCl as reagent; A 50 ml flask was charged with modafinic acid (1.0 g), methanol (10 ml) and HCl32percent (0.1 ml, 0.25 eq.) to form a suspension. The suspension was stirred at reflux temperature for 1 hour, then cooled to room temperature to obtain a clear solution. NH4Cl (0.23 g, 1.2 eq.) and NH4OH 25percent (18 ml) were added to the solution and the solution was stirred at room temperature for 17 hours. Crystals precipitated from the solution. The crystals were collected by filtration and washed with water to obtain white crystals of racemic modafinil (0.5 g, 52.9percent). (RMDF-DS: about 2.5percent by HPLC).; Example 8: Preparation of Modafinil with HCl as reagent; A 50 ml flask was charged with modafinic acid (1.0 g), methanol (5 ml) and HCl 32percent (0.1 ml) to form a suspension. The suspension was stirred at room temperature for 19 hours to obtain a clear solution. NH4Cl (0.23 g, 1.2 eq.) and NH4OH 25percent (18 ml) were added to the solution and the solution was stirred at room temperature for 24 hours. Crystals precipitated from the solution. The crystals were filtered and washed with water to obtain white crystals of racemic modafinil (0.66 g, 69.9percent). (RMDF-DS: about 2.5percent by HPLC).

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Rx-ID: 7203814 Find similar reactions

Benzhydrylthioacetylchlorid, H2O2;

Lab. L. Lafon S.A.

Patent: DE2809625 , 1978 ; Chem.Abstr., vol. 90, # 22644 Full Text Show Details

Methylbenzhydrylsulfinylacetat, NH3;

Lab. L. Lafon S.A.

Patent: DE2809625 , 1978 ; Chem.Abstr., vol. 90, # 22644 Full Text Show Details

Entspr. Sulfid, H2O2;

Lab. Lafon

Patent: DE2809625US4177290 , 19781979 ; Chem.Abstr., vol. 93, # 7872 Full Text Show Details

Entspr. Methylester, NH3;

Lab. Lafon

Patent: DE2809625US4177290 , 19781979 ; Chem.Abstr., vol. 93, # 7872 Full Text Show Details

Dipharma S.p.A.

Patent: EP1466897 A1, 2004 ; Location in patent: Page 5 ; Title/Abstract Full Text Show Details

DINAMITE DIPHARMA S.P.A. abbreviated DIPHARMA S.P.A.

Patent: US2004/192929 A1, 2004 ; Location in patent: Page 4 ; Title/Abstract Full Text Show Details

Hide Experimental Procedure

CHEMAGIS LTD.

Patent: US2002/183552 A1, 2002 ; Title/Abstract Full Text Show Details

R.2:REFERENCE EXAMPLE 2 REFERENCE EXAMPLE 2 A 1.0 L reactor was charged with diphenylmethylthioacetamide crude wet (220 gr.) obtained from example 1a and glacial acetic acid (610 ml). The mixture was heated to 40° C. and stirred until full dissolution is achieved. 5.8percent H2O2 solution (500 g, 1.2 eq.) was added dropwise during 0.5 hours at 40-450 C. The reaction mixture was stirred at 40-45° C. for 4 hours. Then sodium metabisulfite (18.3 gr.) in 610 ml. water was added in order to quench the unreacted H2O2 and the suspension was stirred for 0.5 hours. Then the reaction mixture was cooled to 15° C. and filtered. The cake was washed with water (610 ml.) and dried on air to obtain crude wet Modafinil (205 g).

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Jacobs, Martin J.; Patel, Piyush R.

Patent: US2002/160982 A1, 2002 ;

Title/Abstract Full Text Show Details

1:Preparation of Modafinil in Aqueous 50percent Hydroxypropyl-β-Cyclodextrin Solution

Example 1 Preparation of Modafinil in Aqueous 50percent Hydroxypropyl-β-Cyclodextrin Solution A solution of hydroxypropyl-β-cyclodextrin (3.53 grams) in 3.54 grams of water was stirred with warming at 60-70° C. to give a clear, slightly viscous solution. To this solution modafinil(micronized)(0.1815 grams) was added in one portion and stirred until no particulate matter remained. Cooling to room temperature gave a volume of near 6 mL with no precipitate formation and a modafinil concentration of approximately 30 mg/mL.

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Multi-step reaction with 4 steps 1: 99 percent / trifluoroacetic acid / 3 h / 20 °C 2: thionyl chloride / benzene / 1.5 h / Heating 3: 17.0 g / aq. NH4OH / CH2Cl2 / 2 h 4: 67 percent / aq. H2O2; acetic acid / 40 °C View Scheme

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Rx-ID: 13513708 Find similar reactions

Prisinzano, Thomas; Podobinski, John; Tidgewell, Kevin; Luo, Min; Swenson, Dale

Tetrahedron Asymmetry, 2004 , vol. 15, # 6 p. 1053 - 1058 Title/Abstract Full Text View citing articles Show Details

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Rx-ID: 25835101 Find similar reactions

80.4%

With potassium hydroxide; hydrogen bromide; dihydrogen peroxide; acetic acid; thiourea in tetrahydrofuran; water

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Largeau, Denis; Oddon, Gilles

Patent: US2004/2547 A1, 2004 ; Title/Abstract Full Text Show Details

1:Example 1

Example 1 To a suspension of benzhydrol (35.00 g, 0.188 mol, 1 equivalent) and thiourea (17.40 g, 0.226 mol, 1.20 equivalents) in tetrahydrofuran/water (35.5 ml/52.5 ml), was added an aqueous 48percent HBr solution (25.3 ml, 0.226 mol, 1.2 equivalents) over a 10 min period. During the addition, the reaction mixture is heated to 70° C. After 3 h stirring at 70° C., the uronium intermediate was hydrolyzed by addition of an aqueous 9.3N potassium hydroxide solution (58 ml, 0.542 mol, 2.88 equivalents) over a 55 min period. After 1.5 h stirring at 70° C., chloroacetamide (26.6 g, 0.282 mol, 1.5 equivalents) in a tetrahydrofuran/water (80 ml/79 ml) solution was added over 15 min. After 1 h stirring at 70° C., the reaction mixture was cooled down to 55° C. and the stirring was stopped. The lower aqueous phase was removed, and the reaction mixture was again stirred. Acetic acid (34.7 ml, 0.601 mol, 3.2 equivalents) was added. Hydrogen peroxide 30percent (38.4 ml, 0.376 mol, 2 equivalents) was slowly added over 30 min. After 1 h stirring, the reaction mixture was cooled to 20° C. and water (263 ml) was added. The resultant suspension was stirred at 0° C. overnight. The suspension was then filtered and the solid was washed with water, and dried to yield modafinil (47.9 g, 80.4percent).

The crude modafinil was purified by recrystallization in methanol.