2-cyclopentyl-2-hydroxy-2-phenylacetic acid (alpha-Cyclopentylmandelic acid) [CAS 427-49-6; I by Asch

Query Query

Results

Date

46 reactions in Reaxys

2016-04-25 15h:05m:56s (EST)

46 reactions in Reaxys

2016-04-25 15h:07m:15s (EST)

OH O

1. Query

Search as: As drawn 2. Query

(1. Query) AND NOT itemno in (4)

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OH O

OH OH

Rx-ID: 28271510 View in Reaxys 1/46 Yield

Conditions & References 1 :Intermediate (1d) (280 mg, 1.3 mmol) was dissolved in MeOH (2.50 mL, 61.7 mmol) and the reaction flask was flushed with nitrogen before 28 mg of 10percent Pd/C was added to the mixture. The mixture was stirred at room temperature under 1 atm hydrogen and the reaction was monitored by HPLC until the starting material was consumed (~24 hours). The reaction vessel was flushed with nitrogen, then the mixture was filtered through celite and rinsed with MeOH. The filtrate was concentrated under vacuum to obtain the title compound as a slightly yellow solid (284 mg). With hydrogen, palladium 10 on activated carbon in methanol, Time= 24h, T= 20 °C , p= 760.051Torr Patent; Theravance, Inc.; US2009/69335; (2009); (A1) English View in Reaxys 1 :Intermediate (1d) (280 mg, 1.3 mmol) was dissolved in MeOH (2.50 mL, 61.7 mmol) and the reaction flask was flushed with nitrogen before 28 mg of 10percent Pd/C was added to the mixture. The mixture was stirred at room temperature under 1 atm hydrogen and the reaction was monitored by HPLC until the starting material was consumed (24 hours). The reaction vessel was flushed with nitrogen, then the mixture was filtered through celite and rinsed with MeOH. The filtrate was concentrated under vacuum to obtain the title compound as a slightly yellow solid (284 mg). With hydrogen, palladium 10 on activated carbon in methanol, Time= 24h, T= 20 °C , p= 760.051Torr Patent; Ji, YuHua; Husfeld, Craig; Lee, Rick; Mu, YongQi; Smith, Cameron; US2009/170870; (2009); (A1) English View in Reaxys

Rx-ID: 28008498 View in Reaxys 2/46 Yield

OH O O

Rx-ID: 10350237 View in Reaxys 3/46

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Yield

Conditions & References

62%

To a solution of cis-(2S,5S)-2-(tert-butyl)-5-cyclopentyl-5-phenyl-1,3-dioxolan-4-one (14.35 g, 50 mmol) in 100 ml methanol and 50 ml water, 15 g of KOH was added slowly. The mixture was stirred and heated (65° C.) to reflux for 3-4 hr, then cooled down to the room temperature, and methanol was removed. To the aqueous solution, 100 ml of ethyl acetate was added, then acidified to pH 1 with 3N HCl. The mixture was poured into a separation funnel, and the organic layer was separated. The aqueous layer was extracted two times with ethyl acetate (50 ml). The combined organic layers were dried over Na2SO4, filtered, and the solvent was removed to provide 13.44 g of yellowish crude product, which was re-crystallized to give a pure product of S(+)-cyclopentylmandelic acid, 12 (6.89 g, yield 62percent, white crystal). 1H NMR (CDCl3, 300 MHz): 1.28-1.75 (m, 8H), 2.94 (m, 1H), 7.24-7.34 (m, 3H), 7.62-7.68 (m, 2H). 13C NMR (CDCl3, 300 MHz): 25.9, 26.3, 26.4, 26.9, 47.1, 79.2, 125.8, 127.7, 128.2, 140.8, 180.9. Stage 1: With potassium hydroxide, water in methanol, Time= 3 - 4h, T= 65 °C , Heating / reflux Stage 2: With hydrogenchloride in water, ethyl acetate, pH= 1 Patent; Bodor, Nicholas S.; US2007/123557; (2007); (A1) English View in Reaxys With potassium hydroxide in methanol, water, Time= 3h, Heating Liu, Yu-Min; Liu, He; Zhong, Bo-Hua; Liu, Ke-Liang; Synthetic Communications; vol. 36; nb. 13; (2006); p. 1815 1822 View in Reaxys

Rx-ID: 8713870 View in Reaxys 4/46 Yield

Conditions & References

93 %

With hydrogen, 10percent Pd/C in methanol, Time= 18h, p= 760.051Torr , Hydrogenation Grover, Paul T.; Bhongle, Nandkumar N.; Wald, Stephen A.; Senanayake, Chris H.; Journal of Organic Chemistry; vol. 65; nb. 19; (2000); p. 6283 - 6287 View in Reaxys

OH O HO

Rx-ID: 25759957 View in Reaxys 5/46 Yield 33.3 - 37.6 %

Conditions & References (-)-Strychnine (6.10 g) in 50 ml of methanol (suspension) was added to racemic cyclopentylmandelic acid 1, (3.96 g) in methanol (20 ml) at room temperature. The reaction solution was let to stand for overnight. The crystals were removed by filtration and crystallized again with hot methanol. The second crop of crystals was collected by filtration and treated with sodium hydroxide solution. The basic solution was extracted with methylene chloride twice (methylene chloride solution discarded), and then acidified with hydrochloric acid to recover the resolved cyclopentylmandelic acid. To this resolved acid (20.6 mg in 0.1 ml of ethyl acetate), 13 μL of (+)-α-phenylethylamine was added. The precipitate which formed was washed with hexane three times and dried under vacuum. The precipitate was identified by NMR as optically pure cyclopentylmandelic acid, R(-)1, (1.49 g, 37.6percent). M.p.: 121-122° C. [α]25° 1 D=-22.5° (c=1 g/100 ml, CHCl3). H NMR(CDCl3, 500 MHz): 1.28-1.39, 1.42-1.50, 1.51-1.61, 1.64-1.73 [8H, m, (CH2)4], 2.93 [1H, p, CHC(OH)], 7.25-7.28, 7.32-7.35, 7.64-7.65(5H, m, Ph) ppm. ; (-)-Strychnine (11.4 g) in 100 ml of methanol (suspension) was added to racemic cyclopentylmandelic acid 1 (7.5 g) in methanol (20 ml) at room temperature. The reaction solution was allowed to stand overnight. The crystals were filtered and crystallized again with hot methanol. The second crop of crystals was collected by filtration and treated with sodium hydroxide solution. The basic solution was extracted with methylene chloride twice (methylene chloride solution discarded), and then acidified with hydrochloric acid to recover the resolved cyclopentylmandelic acid. To this resolved acid (20.6 mg in 0.1 ml

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of ethyl acetate), 13 μL of (+)-α-phenylethylamine was added. The precipitate which formed was washed with hexane three times and dried under vacuum. The precipitate was identified by NMR as optically pure cyclopentylmandelic acid, R(-)1, (2.5 g, 33.3percent). M.p.: 121-122° C. [α]25° D=-22.5° (c=1 g/100 ml, CHCl3). 1H NMR(CDCl3, 300 MHz): 1.28-1.39, 1.42-1.50, 1.51-1.61, 1.64-1.73 [8H, m, (CH2)4], 2.93 [1H, p, CHC(OH)], 7.25-7.28, 7.32-7.35, 7.64-7.65(5H, m, Ph) ppm. Stage 1: With (-)-strychnine in methanol, T= 20 °C Stage 2: With d-(+)-α-methylbenzylamine in ethyl acetate Patent; Bodor, Nicholas S.; US2007/123557; (2007); (A1) English View in Reaxys

OH O HO

HO O

Rx-ID: 728427 View in Reaxys 6/46 Yield

Conditions & References

36.4 %

Cyclopentylmagnesium bromide ether solution (100 ml, 2M; 0.2 mol) was added drop-wise to benzoylformic acid (15 g, 0.1 mol) in 330 ml of anhydrous ethyl ether at 0° C. The mixture was stirred at 0° C. for 30 min and at room temperature for 24 h. The reaction mixture was treated with 1 N HCl, and the aqueous solution was extracted with ether. The combined ether solution was treated with K2CO3 solution. The potassium carbonate solution was acidified with HCl and extracted with ether twice. The ether solution was dried with anhydrous sodium sulfate and evaporated to give a crude product. The crude product was washed with water to get pure racemic cyclopentylmandelic acid 1 (8.0 g, 36.4percent). Needle-like crystal, m.p.: 153-154° C. 1H NMR (CDCl3,300 MHz): 1.28-1.39, 1.42-1.50, 1.51-1.61, 1.63-1.72 [8H, m, (CH2)4], 2.93 [1H, p, CHC(OH)], 7.26-7.30, 7.33-7.36, 7.65-7.67(5H, m, Ph) ppm.; Cyclopentylmagnesium bromide ether solution (100 ml, 2M; 0.2 mol) was added drop-wise to benzoylformic acid (15 g, 0.1 mol) in 330 ml of anhydrous ethyl ether at 0° C. The mixture was stirred at 0° C. for 30 min and at room temperature for 24 h. The reaction mixture was treated with 1 N HCl, and the aqueous solution was extracted with ether. The combined ether solution was treated with K2CO3 solution. The potassium carbonate solution was acidified with HCl and extracted with ether twice. The ether solution was dried with anhydrous sodium sulfate and evaporated to give a crude product. The crude product was washed with water to get pure racemic cyclopentylmandelic acid 1 (8.0 g, 36.4percent). Needle-like crystals, m.p.: 153-154° C. 1H NMR (CDCl3, 500 MHz): 1.28-1.39, 1.42-1.50, 1.51-1.61, 1.63-1.72 [8H, m, (CH2)4], 2.93 [1H, p, CHC(OH)], 7.26-7.30, 7.33-7.36, 7.65-7.67(5H, m, Ph) ppm. in diethyl ether, Time= 24.5h, T= 0 - 20 °C Patent; Bodor, Nicholas S.; US2007/123557; (2007); (A1) English View in Reaxys

36.4 %

Stage 1: in diethyl ether, Time= 24.5h, T= 0 - 20 °C Stage 2: With hydrogenchloride in diethyl ether, water Wu; Mori; Buchwald; Bodor, Nicholas; Pharmazie; vol. 63; nb. 3; (2008); p. 200 - 209 View in Reaxys Faust et al.; Journal of the American Chemical Society; vol. 81; (1959); p. 2214,2218 View in Reaxys

O O F

S O

F N OO

S O

O O

HO O

Rx-ID: 24721489 View in Reaxys 7/46 Yield

Conditions & References 28.1.2 : Step 1-2. Step 1-2.

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Asymmetric synthesis of (2R)-2-cyclopentyl-2-hydroxy-2-phenylacetic acid 1 ml of a solution of 1.5M lithium diisopropylamide in hexane was added dropwise to a solution of 293 mg of (2S, 5S)-2-(t-butyl)-5-phenyl-1,3-dioxolan-4-one in 10 ml of tetrahydrofuran at -78° C., and this solution was stirred for 30 minutes. After the addition of 0.15 ml of cyclopentenone, the solution was stirred for an additional hour. A solution of 510 mg of N-phenyltrifluoromethanesulfonimide in 5 ml of tetrahydrofuran was added to the reaction mixture, and the resulting mixture was stirred at room temperature overnight. The reaction mixture was poured into a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the resulting residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=40/1) to obtain 360 mg of a yellow oily substance. This was dissolved in 4 ml of methanol, and 45 mg of sodium acetate and 15 mg of 10percent palladium-carbon were added thereto. This mixture was stirred at room temperature under atmospheric pressure in an atmosphere of hydrogen for 6 hours. After the reaction mixture was filtered through celite, the solvent was distilled off under reduced pressure. The organic layer was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the resulting residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=19/1) to obtain 63 mg of a colorless oily material. This was dissolved in 1 ml of methanol, and 1 ml of a 1N aqueous solution of sodium hydroxide was added thereto. This mixture was stirred at 60° C. for 3 hours. After the methanol was distilled off under reduced pressure, the resulting residue was washed with diethyl ether, made acidic with 1N hydrochloric acid, and then extracted with chloroform. The organic layer was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. Thereafter, the solvent was distilled off under reduced pressure to obtain 46 mg of the title compound. It was confirmed by high-performance liquid chromatography using a chiral column column: DAICEL CHIRALCEL OJ, 0.46 cm (inner diameter)*250 cm! that the compounds obtained in Steps 1-1 and 1-2 were identical. From the viewpoint of synthetic chemistry, the steric configuration at the 2-position of the compound obtained in Step 1-2 was presumed to be R. With sodium hydroxide, sodium chloride, ammonium chloride, sodium acetate, lithium diisopropyl amide, palladium monocarbide in tetrahydrofuran, methanol, hexane Patent; Banyu Pharmaceutical Co., Ltd.; US5750540; (1998); (A1) English View in Reaxys

OH H

OH O HO

Rx-ID: 12144380 View in Reaxys 8/46 Yield

Conditions & References Reaction Steps: 5 1.1: trifluoromethanesulfonic acid / pentane / 6 h / Heating 2.1: lithium bis(trimethylsilyl) amide / tetrahydrofuran; hexane / 1 h / cooling 2.2: tetrahydrofuran; hexane / 3 h 3.1: thionyl chloride; pyridine / tetrahydrofuran / 3 h / 0 °C 4.1: hydrogen / Pd/C / methanol / 10 h / 760 Torr 5.1: KOH / methanol; H2O / 3 h / Heating With pyridine, potassium hydroxide, thionyl chloride, trifluorormethanesulfonic acid, hydrogen, lithium hexamethyldisilazane, palladium on activated charcoal in tetrahydrofuran, methanol, hexane, water, pentane Liu, Yu-Min; Liu, He; Zhong, Bo-Hua; Liu, Ke-Liang; Synthetic Communications; vol. 36; nb. 13; (2006); p. 1815 1822 View in Reaxys

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Reaction Steps: 2 1.1: 80 percent / trifluoromethanesulfonic acid / pentane / 24 h / Heating 2.1: lithium diisopropylamide / hexane; diethyl ether / 0.5 h / -60 °C 2.2: 2 h / -60 °C 2.3: KOH / H2O; methanol / 3 h / Heating With trifluorormethanesulfonic acid, lithium diisopropyl amide in diethyl ether, hexane, pentane Liu, Yan-Qing; Liu, He; Zhong, Bo-Hua; Deng, Yu-Lin; Liu, Ke-Liang; Synthetic Communications; vol. 35; nb. 10; (2005); p. 1403 - 1412 View in Reaxys Reaction Steps: 3 1.1: 60 percent / p-TsOH; H2SO4 / pentane / 24 h / Heating 2.1: lithium diisopropylamine / hexane; diethyl ether / 0.5 h / -78 °C 2.2: hexane; diethyl ether / -78 °C 3.1: aq. KOH / methanol / Heating With potassium hydroxide, sulfuric acid, toluene-4-sulfonic acid, lithium diisopropyl amide in methanol, diethyl ether, hexane, pentane Han, Xiang-Yu; Liu, He; Liu, Chun-He; Wu, Bo; Zhong, Bo-Hua; Liu, Ke-Liang; Journal of Chemical Research; nb. 12; (2004); p. 816 - 817 View in Reaxys Reaction Steps: 5 1: 96 percent / TfOH / pentane / 5.5 h / Heating 2: 74 percent / LiHMDS / hexane; tetrahydrofuran / 2.5 h / -78 °C 3: 1.6 g / SOCl2 / tetrahydrofuran; pyridine / 1 h / 0 °C 4: 92 percent / KOH / methanol; H2O / 3 h / Heating 5: 93 percent / H2 / 10percent Pd/C / methanol / 18 h / 760.05 Torr With potassium hydroxide, thionyl chloride, trifluorormethanesulfonic acid, hydrogen, lithium hexamethyldisilazane, 10percent Pd/C in tetrahydrofuran, pyridine, methanol, hexane, water, pentane, 1: acetalization / 2: Condensation / 3: Dehydration / 4: Hydrolysis / 5: Hydrogenation Grover, Paul T.; Bhongle, Nandkumar N.; Wald, Stephen A.; Senanayake, Chris H.; Journal of Organic Chemistry; vol. 65; nb. 19; (2000); p. 6283 - 6287 View in Reaxys

O N

OH O HO

Rx-ID: 24426369 View in Reaxys 9/46 Yield

Conditions & References 1.4 : (4) (4) Synthesis of (2R)-N-[1-(6-methyl-2-pyridylmethyl)-piperidin-4-yl]-2-cyclopentyl-2-hydroxy-2-phenylacetamide To a solution of 110 mg of (2R)-2-cyclopentyl-2-hydroxy-2-phenylacetic acid, which had been obtained in Step (1A), in 8 ml of N,N-dimethylformamide, 95 mg of 1,1-carbonyldiimidazole was added at room temperature, and stirred for an hour at the same temperature. To the reaction mixture, further 180 mg of 4-amino-1-(6-methyl-2-pyridylmethyl)piperidine trihydrochloride as obtained in Step (3), 0.75 ml of triethylamine and 7.5 mg of 4-dimethylaminopyridine were added and stirred for 16 hours. The reaction mixture was poured into saturated aqueous solution of sodium hydrogencarbonate and extracted with diethyl ether. The extract was sequentially washed with water and saturated saline solution, dried over anhydrous magnesium sulfate and removed of the solvent by reduced pressure distillation. With 4-(N,N-dimethlyamino)pyridine, sodium hydrogencarbonate, triethylamine in 4-amino-1-(6-methyl-pyridin-2-ylmethyl)-piperidine trihydrochloride, N,N-dimethyl-formamide

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Patent; Banyu Pharmaceutical Coaltd; US6130232; (2000); (A1) English View in Reaxys

O O HO

Rx-ID: 28608152 View in Reaxys 10/46 Yield

Conditions & References

77 %

With sodium chlorite, 2,2,6,6-tetramethyl-1-piperidinyloxy, free radical in acetonitrile, Time= 48h, T= 55 °C , pH= 6.5, aq. phosphate buffer Roy, Siddharth; Sharma, Anubha; Mula, Soumyaditya; Chattopadhyay, Subrata; Chemistry - A European Journal; vol. 15; nb. 7; (2009); p. 1713 - 1722 View in Reaxys

OH O O

Rx-ID: 28196225 View in Reaxys 11/46 Yield

Conditions & References

62 %

Stage 1: With potassium hydroxide in methanol, water, Time= 3 - 4h, T= 65 °C Stage 2: With hydrogenchloride in water, ethyl acetate, pH= 1 Wu; Mori; Buchwald; Bodor, Nicholas; Pharmazie; vol. 63; nb. 3; (2008); p. 200 - 209 View in Reaxys

OH O O O

HO O

Rx-ID: 12147798 View in Reaxys 12/46 Yield

Conditions & References Reaction Steps: 4 1.1: lithium bis(trimethylsilyl) amide / tetrahydrofuran; hexane / 1 h / cooling 1.2: tetrahydrofuran; hexane / 3 h 2.1: thionyl chloride; pyridine / tetrahydrofuran / 3 h / 0 °C 3.1: hydrogen / Pd/C / methanol / 10 h / 760 Torr 4.1: KOH / methanol; H2O / 3 h / Heating With pyridine, potassium hydroxide, thionyl chloride, hydrogen, lithium hexamethyldisilazane, palladium on activated charcoal in tetrahydrofuran, methanol, hexane, water Liu, Yu-Min; Liu, He; Zhong, Bo-Hua; Liu, Ke-Liang; Synthetic Communications; vol. 36; nb. 13; (2006); p. 1815 1822 View in Reaxys Reaction Steps: 4 1: 74 percent / LiHMDS / hexane; tetrahydrofuran / 2.5 h / -78 °C 2: 1.6 g / SOCl2 / tetrahydrofuran; pyridine / 1 h / 0 °C 3: 92 percent / KOH / methanol; H2O / 3 h / Heating 4: 93 percent / H2 / 10percent Pd/C / methanol / 18 h / 760.05 Torr

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With potassium hydroxide, thionyl chloride, hydrogen, lithium hexamethyldisilazane, 10percent Pd/C in tetrahydrofuran, pyridine, methanol, hexane, water, 1: Condensation / 2: Dehydration / 3: Hydrolysis / 4: Hydrogenation Grover, Paul T.; Bhongle, Nandkumar N.; Wald, Stephen A.; Senanayake, Chris H.; Journal of Organic Chemistry; vol. 65; nb. 19; (2000); p. 6283 - 6287 View in Reaxys

OH O

O O

Rx-ID: 12157008 View in Reaxys 13/46 Yield

Conditions & References Reaction Steps: 2 1: hydrogen / Pd/C / methanol / 10 h / 760 Torr 2: KOH / methanol; H2O / 3 h / Heating With potassium hydroxide, hydrogen, palladium on activated charcoal in methanol, water Liu, Yu-Min; Liu, He; Zhong, Bo-Hua; Liu, Ke-Liang; Synthetic Communications; vol. 36; nb. 13; (2006); p. 1815 1822 View in Reaxys Reaction Steps: 2 1: 92 percent / KOH / methanol; H2O / 3 h / Heating 2: 93 percent / H2 / 10percent Pd/C / methanol / 18 h / 760.05 Torr With potassium hydroxide, hydrogen, 10percent Pd/C in methanol, water, 1: Hydrolysis / 2: Hydrogenation Grover, Paul T.; Bhongle, Nandkumar N.; Wald, Stephen A.; Senanayake, Chris H.; Journal of Organic Chemistry; vol. 65; nb. 19; (2000); p. 6283 - 6287 View in Reaxys

OH O

O O

Rx-ID: 12157062 View in Reaxys 14/46 Yield

Conditions & References Reaction Steps: 3 1: thionyl chloride; pyridine / tetrahydrofuran / 3 h / 0 °C 2: hydrogen / Pd/C / methanol / 10 h / 760 Torr 3: KOH / methanol; H2O / 3 h / Heating With pyridine, potassium hydroxide, thionyl chloride, hydrogen, palladium on activated charcoal in tetrahydrofuran, methanol, water Liu, Yu-Min; Liu, He; Zhong, Bo-Hua; Liu, Ke-Liang; Synthetic Communications; vol. 36; nb. 13; (2006); p. 1815 1822 View in Reaxys Reaction Steps: 3 1: 1.6 g / SOCl2 / tetrahydrofuran; pyridine / 1 h / 0 °C 2: 92 percent / KOH / methanol; H2O / 3 h / Heating 3: 93 percent / H2 / 10percent Pd/C / methanol / 18 h / 760.05 Torr With potassium hydroxide, thionyl chloride, hydrogen, 10percent Pd/C in tetrahydrofuran, pyridine, methanol, water, 1: Dehydration / 2: Hydrolysis / 3: Hydrogenation

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Grover, Paul T.; Bhongle, Nandkumar N.; Wald, Stephen A.; Senanayake, Chris H.; Journal of Organic Chemistry; vol. 65; nb. 19; (2000); p. 6283 - 6287 View in Reaxys

Rx-ID: 28196235 View in Reaxys 15/46 Yield

Conditions & References

33.3 %

Stage 1: With [3H]-Strychnine in methanol, T= 20 °C , Resolution of racemate Stage 2: With sodium hydroxide in water Stage 3: With hydrogenchloride in water Wu; Mori; Buchwald; Bodor, Nicholas; Pharmazie; vol. 63; nb. 3; (2008); p. 200 - 209 View in Reaxys

OH O O O

HO O

Rx-ID: 12155050 View in Reaxys 16/46 Yield

Conditions & References Reaction Steps: 4 1.1: lithium bis(trimethylsilyl) amide / tetrahydrofuran; hexane / 1 h / cooling 1.2: 67 percent / tetrahydrofuran; hexane / 3 h 2.1: thionyl chloride; pyridine / tetrahydrofuran / 3 h / 0 °C 3.1: 87 percent / hydrogen / Pd/C / methanol / 10 h / 760 Torr 4.1: KOH / methanol; H2O / 3 h / Heating With pyridine, potassium hydroxide, thionyl chloride, hydrogen, lithium hexamethyldisilazane, palladium on activated charcoal in tetrahydrofuran, methanol, hexane, water Liu, Yu-Min; Liu, He; Zhong, Bo-Hua; Liu, Ke-Liang; Synthetic Communications; vol. 36; nb. 13; (2006); p. 1815 1822 View in Reaxys Reaction Steps: 3 1: 1.) LDA 2: 60 percent / H2 / 10 percent Pd/C, AcONa / methanol 3: aq. NaOH / methanol With sodium hydroxide, hydrogen, lithium diisopropyl amide, palladium on activated charcoal, sodium acetate in methanol Mitsuya, Morihiro; Kawakami, Kumiko; Ogino, Yoshio; Miura, Keiko; Mase, Toshiaki; Bioorganic and Medicinal Chemistry Letters; vol. 9; nb. 14; (1999); p. 2037 - 2038 View in Reaxys

Rx-ID: 34556393 View in Reaxys 17/46 Yield 25 %

Conditions & References With sodium hydroxide in methanol, water, T= 20 °C , Inert atmosphere

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Allmendinger, Thomas; Bixel, Dominique; Clarke, Adrian; Di Geronimo, Laura; Fredy, Jean-Wilfried; Manz, Marco; Gavioli, Elena; Wicky, Regine; Schneider, Martin; Stauffert, Fabien J.; Tibi, Markus; Valentekovic, Darko; Organic Process Research and Development; vol. 16; nb. 11; (2012); p. 1754 - 1769 View in Reaxys

Rx-ID: 11156513 View in Reaxys 18/46 Yield

Conditions & References With potassium hydroxide in methanol, T= 20 °C Kumar, Naresh; Kaur, Kirandeep; Aeron, Shelly; Dharmarajan, Sankaranarayanan; Silamkoti, Arun D.V.; Mehta, Anita; Gupta, Suman; Chugh, Anita; Gupta, Jang B.; Salman, Mohammad; Palle, Venkata P.; Cliffe, Ian A.; Bioorganic and Medicinal Chemistry Letters; vol. 17; nb. 18; (2007); p. 5256 - 5260 View in Reaxys

OH O HO

Rx-ID: 12145583 View in Reaxys 19/46 Yield

Conditions & References Reaction Steps: 5 1.1: 91 percent / trifluoromethanesulfonic acid / pentane / 6 h / Heating 2.1: lithium bis(trimethylsilyl) amide / tetrahydrofuran; hexane / 1 h / cooling 2.2: 67 percent / tetrahydrofuran; hexane / 3 h 3.1: thionyl chloride; pyridine / tetrahydrofuran / 3 h / 0 °C 4.1: 87 percent / hydrogen / Pd/C / methanol / 10 h / 760 Torr 5.1: KOH / methanol; H2O / 3 h / Heating With pyridine, potassium hydroxide, thionyl chloride, trifluorormethanesulfonic acid, hydrogen, lithium hexamethyldisilazane, palladium on activated charcoal in tetrahydrofuran, methanol, hexane, water, pentane Liu, Yu-Min; Liu, He; Zhong, Bo-Hua; Liu, Ke-Liang; Synthetic Communications; vol. 36; nb. 13; (2006); p. 1815 1822 View in Reaxys Reaction Steps: 2 1.1: trifluoromethanesulfonic acid / pentane / 24 h / Heating 2.1: lithium diisopropylamide / hexane; diethyl ether / 0.5 h / -60 °C 2.2: hexane; diethyl ether / 2 h / -60 °C 2.3: KOH / methanol; H2O / 3 h / Heating With trifluorormethanesulfonic acid, lithium diisopropyl amide in diethyl ether, hexane, pentane Liu, Yan-Qing; Liu, He; Zhong, Bo-Hua; Deng, Yu-Lin; Liu, Ke-Liang; Synthetic Communications; vol. 35; nb. 10; (2005); p. 1403 - 1412 View in Reaxys

O O

(CO)5Cr=C(OEt)Ph

Rx-ID: 16343048 View in Reaxys 20/46

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Yield

Conditions & References Reaction Steps: 3 1: 1.) LDA 2: 60 percent / H2 / 10 percent Pd/C, AcONa / methanol 3: aq. NaOH / methanol With sodium hydroxide, hydrogen, lithium diisopropyl amide, palladium on activated charcoal, sodium acetate in methanol Mitsuya, Morihiro; Kawakami, Kumiko; Ogino, Yoshio; Miura, Keiko; Mase, Toshiaki; Bioorganic and Medicinal Chemistry Letters; vol. 9; nb. 14; (1999); p. 2037 - 2038 View in Reaxys

F F

O S

O HO O

O O

Rx-ID: 16376561 View in Reaxys 21/46 Yield

Conditions & References Reaction Steps: 2 1: 60 percent / H2 / 10 percent Pd/C, AcONa / methanol 2: aq. NaOH / methanol With sodium hydroxide, hydrogen, palladium on activated charcoal, sodium acetate in methanol Mitsuya, Morihiro; Kawakami, Kumiko; Ogino, Yoshio; Miura, Keiko; Mase, Toshiaki; Bioorganic and Medicinal Chemistry Letters; vol. 9; nb. 14; (1999); p. 2037 - 2038 View in Reaxys

OH O

O O

Rx-ID: 12118585 View in Reaxys 22/46 Yield

Conditions & References Reaction Steps: 2 1: 87 percent / hydrogen / Pd/C / methanol / 10 h / 760 Torr 2: KOH / methanol; H2O / 3 h / Heating With potassium hydroxide, hydrogen, palladium on activated charcoal in methanol, water Liu, Yu-Min; Liu, He; Zhong, Bo-Hua; Liu, Ke-Liang; Synthetic Communications; vol. 36; nb. 13; (2006); p. 1815 1822 View in Reaxys

OH O

O O

Rx-ID: 12118626 View in Reaxys 23/46 Yield

Conditions & References Reaction Steps: 3 1: thionyl chloride; pyridine / tetrahydrofuran / 3 h / 0 °C

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2: 87 percent / hydrogen / Pd/C / methanol / 10 h / 760 Torr 3: KOH / methanol; H2O / 3 h / Heating With pyridine, potassium hydroxide, thionyl chloride, hydrogen, palladium on activated charcoal in tetrahydrofuran, methanol, water Liu, Yu-Min; Liu, He; Zhong, Bo-Hua; Liu, Ke-Liang; Synthetic Communications; vol. 36; nb. 13; (2006); p. 1815 1822 View in Reaxys O OH

O O O

Rx-ID: 11051120 View in Reaxys 24/46 Yield

Conditions & References Stage 1: With immobilized Pseudomonas cepacia lipase in phosphate buffer, acetonitrile, Time= 24h, T= 30 °C , pH= 7.0 Stage 2: With hydrogenchloride, Heating, Further stages. Title compound not separated from byproducts. Recuero, Veronica; Ferrero, Miguel; Gotor-Fernandez, Vicente; Brieva, Rosario; Gotor, Vicente; Tetrahedron Asymmetry; vol. 18; nb. 8; (2007); p. 994 - 1002 View in Reaxys

Br O O

Rx-ID: 9938995 View in Reaxys 25/46 Yield

Conditions & References Stage 1: With lithium diisopropyl amide in diethyl ether, hexane, Time= 0.5h, T= -60 °C Stage 2: in diethyl ether, hexane, Time= 2h, T= -60 °C Stage 3: With potassium hydroxide in methanol, water, Time= 3h, Heating, Title compound not separated from byproducts Liu, Yan-Qing; Liu, He; Zhong, Bo-Hua; Deng, Yu-Lin; Liu, Ke-Liang; Synthetic Communications; vol. 35; nb. 10; (2005); p. 1403 - 1412 View in Reaxys

Br O O

Rx-ID: 9938998 View in Reaxys 26/46 Yield

Conditions & References Stage 1: With lithium diisopropyl amide in diethyl ether, hexane, Time= 0.5h, T= -60 °C Stage 2:Time= 2h, T= -60 °C Stage 3: With potassium hydroxide in methanol, water, Time= 3h, Heating, Title compound not separated from byproducts Liu, Yan-Qing; Liu, He; Zhong, Bo-Hua; Deng, Yu-Lin; Liu, Ke-Liang; Synthetic Communications; vol. 35; nb. 10; (2005); p. 1403 - 1412 View in Reaxys

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OH O O

O O

Rx-ID: 5168285 View in Reaxys 27/46 Yield

Conditions & References With sodium hydroxide in methanol Mitsuya, Morihiro; Kawakami, Kumiko; Ogino, Yoshio; Miura, Keiko; Mase, Toshiaki; Bioorganic and Medicinal Chemistry Letters; vol. 9; nb. 14; (1999); p. 2037 - 2038 View in Reaxys

OH O

Rx-ID: 11348212 View in Reaxys 28/46 Yield

Conditions & References Reaction Steps: 2 1: tetrahydrofuran / 0 - 20 °C 2: KOH / methanol / 20 °C With potassium hydroxide in tetrahydrofuran, methanol Kumar, Naresh; Kaur, Kirandeep; Aeron, Shelly; Dharmarajan, Sankaranarayanan; Silamkoti, Arun D.V.; Mehta, Anita; Gupta, Suman; Chugh, Anita; Gupta, Jang B.; Salman, Mohammad; Palle, Venkata P.; Cliffe, Ian A.; Bioorganic and Medicinal Chemistry Letters; vol. 17; nb. 18; (2007); p. 5256 - 5260 View in Reaxys

OH O

Rx-ID: 11389504 View in Reaxys 29/46 Yield

OH H

OH O HO

Rx-ID: 13005530 View in Reaxys 30/46 Yield

Conditions & References Reaction Steps: 2 1.1: 80 percent / trifluoromethanesulfonic acid / pentane / 24 h / Heating

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2.1: lithium diisopropylamide / hexane; diethyl ether / 0.5 h / -60 °C 2.2: 2 h / -60 °C 2.3: KOH / H2O; methanol / 3 h / Heating With trifluorormethanesulfonic acid, lithium diisopropyl amide in diethyl ether, hexane, pentane Liu, Yan-Qing; Liu, He; Zhong, Bo-Hua; Deng, Yu-Lin; Liu, Ke-Liang; Synthetic Communications; vol. 35; nb. 10; (2005); p. 1403 - 1412 View in Reaxys Reaction Steps: 3 1.1: 60 percent / p-TsOH; H2SO4 / pentane / 24 h / Heating 2.1: lithium diisopropylamine / hexane; diethyl ether / 0.5 h / -78 °C 2.2: hexane; diethyl ether / -78 °C 3.1: aq. KOH / methanol / Heating With potassium hydroxide, sulfuric acid, toluene-4-sulfonic acid, lithium diisopropyl amide in methanol, diethyl ether, hexane, pentane Han, Xiang-Yu; Liu, He; Liu, Chun-He; Wu, Bo; Zhong, Bo-Hua; Liu, Ke-Liang; Journal of Chemical Research; nb. 12; (2004); p. 816 - 817 View in Reaxys

OH O O

O O

Rx-ID: 10350238 View in Reaxys 31/46 Yield

Conditions & References With potassium hydroxide in methanol, water, Time= 3h, Heating Liu, Yu-Min; Liu, He; Zhong, Bo-Hua; Liu, Ke-Liang; Synthetic Communications; vol. 36; nb. 13; (2006); p. 1815 1822 View in Reaxys

OH O

OH N

Rx-ID: 11584561 View in Reaxys 32/46 Yield

Conditions & References Reaction Steps: 2 1.1: pyridine / CH2Cl2 / 24 h / 60 °C 2.1: immobilized Pseudomonas cepacia lipase / acetonitrile; aq. phosphate buffer / 24 h / 30 °C / pH 7.0 2.2: aq. HCl / Heating With pyridine, immobilized Pseudomonas cepacia lipase in phosphate buffer, dichloromethane, acetonitrile Recuero, Veronica; Ferrero, Miguel; Gotor-Fernandez, Vicente; Brieva, Rosario; Gotor, Vicente; Tetrahedron Asymmetry; vol. 18; nb. 8; (2007); p. 994 - 1002 View in Reaxys

OH O

OH N

Rx-ID: 11584562 View in Reaxys 33/46

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Yield

OH O

Rx-ID: 11604184 View in Reaxys 34/46 Yield

Conditions & References Reaction Steps: 3 1.1: ZnI2 / CH2Cl2 / 24 h / 20 °C 2.1: pyridine / CH2Cl2 / 24 h / 60 °C 3.1: immobilized Pseudomonas cepacia lipase / acetonitrile; aq. phosphate buffer / 24 h / 30 °C / pH 7.0 3.2: aq. HCl / Heating With pyridine, immobilized Pseudomonas cepacia lipase, zinc(II) iodide in phosphate buffer, dichloromethane, acetonitrile Recuero, Veronica; Ferrero, Miguel; Gotor-Fernandez, Vicente; Brieva, Rosario; Gotor, Vicente; Tetrahedron Asymmetry; vol. 18; nb. 8; (2007); p. 994 - 1002 View in Reaxys

OH O

Rx-ID: 11604185 View in Reaxys 35/46 Yield

O H

OH OH

OH O HO

Rx-ID: 13006605 View in Reaxys 36/46

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Yield

Conditions & References Reaction Steps: 2 1.1: trifluoromethanesulfonic acid / pentane / 24 h / Heating 2.1: lithium diisopropylamide / hexane; diethyl ether / 0.5 h / -60 °C 2.2: hexane; diethyl ether / 2 h / -60 °C 2.3: KOH / methanol; H2O / 3 h / Heating With trifluorormethanesulfonic acid, lithium diisopropyl amide in diethyl ether, hexane, pentane Liu, Yan-Qing; Liu, He; Zhong, Bo-Hua; Deng, Yu-Lin; Liu, Ke-Liang; Synthetic Communications; vol. 35; nb. 10; (2005); p. 1403 - 1412 View in Reaxys

OH O

O O

Rx-ID: 13211901 View in Reaxys 37/46 Yield

Conditions & References Reaction Steps: 2 1.1: lithium diisopropylamine / hexane; diethyl ether / 0.5 h / -78 °C 1.2: hexane; diethyl ether / -78 °C 2.1: aq. KOH / methanol / Heating With potassium hydroxide, lithium diisopropyl amide in methanol, diethyl ether, hexane Han, Xiang-Yu; Liu, He; Liu, Chun-He; Wu, Bo; Zhong, Bo-Hua; Liu, Ke-Liang; Journal of Chemical Research; nb. 12; (2004); p. 816 - 817 View in Reaxys

OH O

O O

Rx-ID: 13211902 View in Reaxys 38/46 Yield

OH O

O O

Rx-ID: 34556370 View in Reaxys 39/46 Yield

Conditions & References Reaction Steps: 2 1.1: iodine; magnesium / tetrahydrofuran / 0 °C / |Reflux; |Inert atmosphere 1.2: 10 - 20 °C / |Inert atmosphere 2.1: sodium hydroxide / water; methanol / 20 °C / |Inert atmosphere

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With iodine, magnesium, sodium hydroxide in tetrahydrofuran, methanol, water Allmendinger, Thomas; Bixel, Dominique; Clarke, Adrian; Di Geronimo, Laura; Fredy, Jean-Wilfried; Manz, Marco; Gavioli, Elena; Wicky, Regine; Schneider, Martin; Stauffert, Fabien J.; Tibi, Markus; Valentekovic, Darko; Organic Process Research and Development; vol. 16; nb. 11; (2012); p. 1754 - 1769 View in Reaxys

OH O

O O

Rx-ID: 9827662 View in Reaxys 40/46 Yield

Conditions & References With potassium hydroxide in methanol, Heating, Title compound not separated from byproducts Han, Xiang-Yu; Liu, He; Liu, Chun-He; Wu, Bo; Zhong, Bo-Hua; Liu, Ke-Liang; Journal of Chemical Research; nb. 12; (2004); p. 816 - 817 View in Reaxys

OH O O

OH O HO

Rx-ID: 11051130 View in Reaxys 41/46 Yield

Conditions & References With hydrogenchloride, Heating Recuero, Veronica; Ferrero, Miguel; Gotor-Fernandez, Vicente; Brieva, Rosario; Gotor, Vicente; Tetrahedron Asymmetry; vol. 18; nb. 8; (2007); p. 994 - 1002 View in Reaxys

N+ Cl –

O O HO

Rx-ID: 3022226 View in Reaxys 42/46 Yield

Conditions & References With potassium chloride in methanol, T= 24.9 °C , different pH values from 298-323 K, different ion strength of KCl solution, Rate constant, Kinetics, Mechanism Chigareva, S. M.; Kuznetsov, S. G.; Vinogradova, N. D.; Pharmaceutical Chemistry Journal; vol. 17; nb. 12; (1983); p. 876 - 881; Khimiko-Farmatsevticheskii Zhurnal; vol. 17; nb. 12; (1983); p. 1458 - 1462 View in Reaxys

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OH O HO

Rx-ID: 5966354 View in Reaxys 43/46 Yield

Conditions & References 7, KMnO4 (Oxid.) Blumbergs et al.; Journal of Organic Chemistry; vol. 37; (1972); p. 1248,1249, 1251 View in Reaxys Cyclopentylmagnesiumchlorid, Aethylbenzoylformat Bobysheva et al.; Journal of Organic Chemistry USSR (English Translation); vol. 8; (1972); p. 2109; Zhurnal Organicheskoi Khimii; vol. 8; (1972); p. 2062 View in Reaxys /BRN= 124474/, /BRN= 72921/ Bobysheva et al.; Journal of Organic Chemistry USSR (English Translation); vol. 8; (1972); p. 2109; Zhurnal Organicheskoi Khimii; vol. 8; (1972); p. 2062 View in Reaxys α-Cyclopentyl-mandelsaeure-ethylester, Hydrol. Pelz; Protiva; Collection of Czechoslovak Chemical Communications; vol. 32; nb. 8; (1967); p. 2840 View in Reaxys (yield)70percent Pelz; Protiva; Collection of Czechoslovak Chemical Communications; vol. 32; nb. 8; (1967); p. 2840 View in Reaxys Cyclopentyl-glyoxylsaeure, Phenyl-MgBr Dobrina; Joffe; Pharmaceutical Chemistry Journal; vol. 11; nb. 6; (1977); p. 817; Khimiko-Farmatsevticheskii Zhurnal; vol. 11; nb. 6; (1977); p. 90,92 View in Reaxys 3.b Patent; RANBAXY LABORATORIES LIMITED; WO2004/14853; (2004); (A1) English View in Reaxys R.9 : 2-cyclopentyl-2-hydroxy-2-phenylacetic acid To the solution 20 ml of 4N aqueous sodium hydroxide solution was added at room temperature, followed by stirring for 2 hours at the same temperature and further for 1 hour at 50° C. Distilling the methanol off under reduced pressure, the aqueous layer was made weakly acidic with 4N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and then brine and dried over anhydrous magnesium sulfate. Distilling the solvent off under reduced pressure, the residue was washed with 1:1 mixture of diethyl ether and hexane. Thus, 8.7 g of the title compound was obtained. Patent; Banyu Pharmaceutical Co., Ltd.; US5948792; (1999); (A1) English View in Reaxys 27.1 : Step 1. This was dissolved in 40 ml of methanol, and 20 ml of a 4N aqueous solution of sodium hydroxide was added thereto at room temperature. This mixture was stirred at the same temperature for 2 hours and then at 50° C. for an hour. After the methanol was distilled off under reduced pressure, the aqueous layer was made weakly acidic with 4N hydrochloric acid and then extracted with ethyl acetate.

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The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the resulting solid was washed with diethyl ether/hexane (=1/1) to obtain 8.7 g of the title compound. Patent; Banyu Pharmaceutical Co., Ltd.; US5750540; (1998); (A1) English View in Reaxys a Patent; RANBAXY LABORATORIES LIMITED; WO2006/35282; (2006); (A2) English View in Reaxys

OH O HO

Rx-ID: 22986521 View in Reaxys 44/46 Yield

Conditions & References 19.a Patent; RANBAXY LABORATORIES LIMITED; WO2004/14853; (2004); (A1) English View in Reaxys 1.A : (1A) The salt was dissolved in a mixture of diethyl ether and 1N hydrochloric acid, and the organic layer was washed with water and then with saturated saline solution, and dried over anhydrous magnesium sulfate. Distilling the solvent off under reduced pressure, 3.0 g of the title compound was obtained as a white solid Patent; Banyu Pharmaceutical Coaltd; US6130232; (2000); (A1) English View in Reaxys 1.B : (1B) To the solution 45 mg of sodium acetate and 15 mg of 10percent palladium-on-carbon were added and stirred for 6 hours in a hydrogen atmosphere at normal pressure and room temperature. The reaction mixture was filtered through celite pad and removed of the solvent by reduced pressure distillation. To the residue ethyl acetate and saturated aqueous sodium hydrogencarbonate solution were added. The organic layer was separated, washed with saturated saline solution, dried over anhydrous magnesium sulfate and removed of the solvent by reduced pressure distillation. The residue was purified by preparative thin layer chromatography (Kieselgel.(TM). 60F254, Art 5744: Merck, hexane/ ethyl acetate=19/1) to give 63 mg of a colorless oily substance. This product was dissolved in 1 ml of methanol, added with 1 ml of 1N sodium hydroxide solution and stirred for 3 hours at 60° C. Distilling the methanol off under reduced pressure, the remaining reaction mixture was washed with diethyl ether, made acidic with 1N hydrochloric acid and extracted with chloroform. The organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate and removed of the solvent by reduced pressure distillation, to give 46 mg of the title compound as a white solid. Patent; Banyu Pharmaceutical Coaltd; US6130232; (2000); (A1) English View in Reaxys T.Tii Patent; NOVARTIS AG; NOVARTIS PHARMA GMBH; WO2006/48225; (2006); (A1) English View in Reaxys

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HO HO

rel-configuration

Rx-ID: 23024588 View in Reaxys 45/46 Yield

Conditions & References 3.3a : Eexample 3 step 3a Patent; RANBAXY LABORATORIES LIMITED; WO2004/67510; (2004); (A1) English View in Reaxys

OH O HO

Rx-ID: 23041186 View in Reaxys 46/46 Yield

Conditions & References 20.a Patent; RANBAXY LABORATORIES LIMITED; WO2004/14853; (2004); (A1) English View in Reaxys

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