2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one (Ketamine) [CAS 6740-88-1; InChIKey YQEZLK by Asch

Query Query

Results

Date

48 reactions in Reaxys

2016-04-08 07h:49m:12s (EST)

1. Query O Cl

Search as: As drawn

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N OH E

HN O

Cl HCl

HCl

Rx-ID: 28008066 View in Reaxys 1/48 Yield

Conditions & References

50%

2.3 :d3-1-[(2-Chlorophenyl)-methylimino-methyl]-cyclopentanol hydrochloride (400 mg, 1.4 mmol) was dissolved in ethyl benzoate (5 mL) and heated at about 170° C. for about 30 minutes. Hexane was then added and the crude product was collected by filtration. Recrystallisation from methanol-ether gave the title product (200 mg, 50percent). 1H NMR (300 MHz, CDCl3) δ 10.57-10.53 (m, 1H), 9.49-9.46 (m, 1H), 8.01 (d, J=7.8 Hz, 1H), 7.55-7.42 (m, 3H), 3.53-3.49 (m, 1H), 2.69-2.46 (m, 3H), 2.00-1.84 (m, 3H), 1.65-1.51 (m, 1H); LC-MS : m/z=241 (MH)+; HPLC: 98percent (Purity). in benzoic acid ethyl ester, Time= 0.5h, T= 170 °C Patent; AUSPEX PHARMACEUTICALS, INC.; US2008/268071; (2008); (A1) English View in Reaxys 2H

2H 2H

O 2H

2H 2 H

2H 2H

Rx-ID: 28008064 View in Reaxys 2/48 Yield

Conditions & References 1.5 :The procedure of Step 5 is carried out as in Hopfgartner et al., J. Mass. Spectrom. 1996, 31, 69-76. At ambient temperature, d11-ketamine is taken up in a 1:1 mixture of deuterium oxide and dioxane, the reaction is maintained at ambient temperature until the disappearance of the exchangeable amide proton, as monitored by 1H-NMR. With water-d2 in 1,4-dioxane, T= 20 °C Patent; AUSPEX PHARMACEUTICALS, INC.; US2008/268071; (2008); (A1) English View in Reaxys

2H 2

N OH E

2H 2H

O 2H

Cl HCl

2H 2H

Cl HCl

2H 2H

2H 2

Rx-ID: 28008070 View in Reaxys 3/48 Yield 20%

Conditions & References 3.4 :d11-1-[(2-Chlorophenyl)-methylimino-methyl]-cyclopentanol hydrochloride (150 mg, 0.5 mmol) was dissolved in ethyl benzoate (5 mL) and heated at about 170° C. for about 30 minutes. Hexane was then added, and the crude product was collected by filtration. Recrystallization with methanol-ether gave the title product (30 mg, 20percent). 1H NMR (300 MHz, CDCl3) δ 10.53 (br.s, 1H), 9.48 (br.s, 1H), 8.01 (d, 1H, J=7.8 Hz), 7.56-7.42 (m, 3H), 2.68-2.53 (m, 2H); LC-MS: m/z=247 (MH)+; HPLC: 90percent (Purity). in benzoic acid ethyl ester, Time= 0.5h, T= 170 °C Patent; AUSPEX PHARMACEUTICALS, INC.; US2008/268071; (2008); (A1) English View in Reaxys

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HN Cl

Rx-ID: 29399735 View in Reaxys 4/48 Yield

Conditions & References

85 %

Stage 1: With hydrogenchloride in water, Inert atmosphere Stage 2: With ozone in methanol, T= -78 °C , Further stages Yokoyama, Takeshi; Yokoyama, Reiko; Nomura, Satoshi; Matsumoto, Satoshi; Fujiyama, Ryoji; Kiyooka, SyunIchi; Bulletin of the Chemical Society of Japan; vol. 82; nb. 12; (2009); p. 1528 - 1532 View in Reaxys

HO Cl O

O Cl

Cl O

O O

Rx-ID: 23566303 View in Reaxys 5/48 Yield

Conditions & References 32 : Preparation of rac-Ketamine Indomethacinate from rac-Ketamine Hydrochloride and Indomethacin rac-Ketamine indomethacinate may be prepared using the following synthetic scheme. Indomethacin (0.3578 g, 1.00 mmol) dissolved in a minimal volume of ethanol is combined with potassium hydroxide (0.05611 g, 1.00 mmol) dissolved in a minimal volume of ethanol and stirred for 1 hour. rac-Ketamine hydrochloride (0.2742 g, 1.00 mmol) is dissolved in a minimal volume of water and combined with the ethanolic indomethacinate solution. The resulting solution is stirred and the total volume reduced to approximately 30 mL. The concentrated solution is transferred to a separatory funnel and the desired product extracted with diethyl ether (4*90 mL). The organic layers are combined and the solvent removed by rotary evaporation. The product is dried under vacuum overnight. With potassium hydroxide in ethanol, water, Time= 1h Patent; Sancilio, Frederick D.; Stowell, Grayson W.; Whittall, Linda B.; White, David; Whittle, Robert R.; US2005/203115; (2005); (A1) English View in Reaxys

Cl O Cl

Rx-ID: 23566305 View in Reaxys 6/48 Yield

Conditions & References 29 : Preparation of rac-Ketamine Ibuprofenate from rac-Ketamine Hydrochloride and Ibuprofen rac-Ketamine ibuprofenate may be prepared using the following synthetic scheme. Ibuprofen (0.2063 g, 1.00 mmol) dissolved in a minimal volume of ethanol is combined with potassium hydroxide (0.05611 g, 1.00 mmol) dissolved in a minimal volume of ethanol and stirred for 1 hour. rac-Ketamine hydrochloride (0.2742 g, 1.00 mmol) is dissolved in a minimal volume of water and combined with the ethanolic ibuprofenate solution. The resulting solution is stirred and the total volume reduced to approximately 30 mL. The concentrated solution is transferred to a separatory funnel and the desired product extracted with diethyl ether (4*90 mL). The organic layers are combined and the solvent removed by rotary evaporation. The product is dried under vacuum overnight.

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With potassium hydroxide in ethanol, water, Time= 1h Patent; Sancilio, Frederick D.; Stowell, Grayson W.; Whittall, Linda B.; White, David; Whittle, Robert R.; US2005/203115; (2005); (A1) English View in Reaxys

O Cl

HO Cl

HO O

Rx-ID: 23566306 View in Reaxys 7/48 Yield

Conditions & References 41 : Preparation of rac-Ketamine Oxaprozinate from rac-Ketamine Hydrochloride and Oxaprozin rac-Ketamine oxaprozinate may be prepared using the following synthetic scheme. Oxaprozin (0.2933 g, 1.00 mmol) dissolved in a minimal volume of ethanol is combined with potassium hydroxide (0.05611 g, 1.00 mmol) dissolved in a minimal volume of ethanol and stirred for 1 hour. rac-Ketamine hydrochloride (0.2742 g, 1.00 mmol) is dissolved in a minimal volume of water and combined with the ethanolic oxaprozinate solution. The resulting solution is stirred and the total volume reduced to approximately 30 mL. The concentrated solution is transferred to a separatory funnel and the desired product extracted with diethyl ether (4*90 mL). The organic layers are combined and the solvent removed by rotary evaporation. The product is dried under vacuum overnight. With potassium hydroxide in ethanol, water, Time= 1h Patent; Sancilio, Frederick D.; Stowell, Grayson W.; Whittall, Linda B.; White, David; Whittle, Robert R.; US2005/203115; (2005); (A1) English View in Reaxys

Rx-ID: 23566307 View in Reaxys 8/48 Yield

Conditions & References 37 : Preparation of rac-Ketamine Suprofenate from rac-Ketamine Hydrochloride and Suprofen rac-Ketamine suprofenate may be prepared using the following synthetic scheme. Suprofen (0.2603 g, 1.00 mmol) dissolved in a minimal volume of ethanol is combined with potassium hydroxide (0.05611 g, 1.00 mmol) dissolved in a minimal volume of ethanol and stirred for 1 hour. rac-Ketamine hydrochloride (0.2742 g, 1.00 mmol) dissolved in a minimal volume of water is combined with the ethanolic suprofenate solution. The resulting solution is stirred and the total volume reduced to approximately 30 mL. The concentrated solution is transferred to a separatory funnel and the desired product extracted with diethyl ether (4*90 mL). The organic layers are combined and the solvent removed by rotary evaporation. The product is dried under vacuum overnight. With potassium hydroxide in ethanol, water, Time= 1h Patent; Sancilio, Frederick D.; Stowell, Grayson W.; Whittall, Linda B.; White, David; Whittle, Robert R.; US2005/203115; (2005); (A1) English View in Reaxys

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Cl O Cl

O O

Rx-ID: 23566309 View in Reaxys 9/48 Yield

Conditions & References 30 : Preparation of rac-Ketamine Acetylsalicylate from rac-Ketamine Hydrochloride and Acetylsalicylic Acid rac-Ketamine acetylsalicylate may be prepared using the following synthetic scheme. Acetylsalicylic acid (0.3003 g, 1.00 mmol) dissolved in a minimal volume of ethanol is combined with potassium hydroxide (0.05611 g, 1.00 mmol) dissolved in a minimal volume of ethanol and stirred for 1 hour. rac-Ketamine hydrochloride (0.2742 g, 1.00 mmol) is dissolved in a minimal volume of water and combined with the ethanolic acetylsalicylate solution. The resulting solution is stirred and the total volume reduced to approximately 30 mL. The solution is transferred to a separatory funnel and the desired product extracted with diethyl ether (4*90 mL). The organic layers are combined and the solvent removed by rotary evaporation. The product is dried under vacuum overnight. With potassium hydroxide in ethanol, water, Time= 1h Patent; Sancilio, Frederick D.; Stowell, Grayson W.; Whittall, Linda B.; White, David; Whittle, Robert R.; US2005/203115; (2005); (A1) English View in Reaxys

HO O F

O Cl

N H O

OH O

Rx-ID: 23566310 View in Reaxys 10/48 Yield

Conditions & References 42 :rac-Ketamine difunisalate may be prepared using the following synthetic scheme. Difunisal (0.2502 g, 1.00 mmol) dissolved in a minimal volume of ethanol is combined with potassium hydroxide (0.05611 g, 1.00 mmol) dissolved in a minimal volume of ethanol and stirred for 1 hour. rac-Ketamine hydrochloride (0.2742 g, 1.00 mmol) is dissolved in a minimal volume of water and combined with the ethanolic difunisalate solution. The resulting solution is stirred and the total volume reduced to approximately 30 mL. The concentrated solution is transferred to a separatory funnel and the desired product extracted with diethyl ether (4.x.90 mL). The organic layers are combined and the solvent removed by rotary evaporation. The product is dried under vacuum overnight. With potassium hydroxide in ethanol, water, Time= 1h Patent; Sancilio, Frederick D.; Stowell, Grayson W.; Whittall, Linda B.; White, David; Whittle, Robert R.; US2005/203115; (2005); (A1) English View in Reaxys

Cl HN

Cl O

H N

O O

Rx-ID: 23566311 View in Reaxys 11/48 Yield

Conditions & References 34 :rac-Ketamine etodolate may be prepared using the following synthetic scheme. Etodolac (0.2874 g, 1.00 mmol) dissolved in a minimal volume of ethanol is combined with potassium hydroxide (0.05611 g, 1.00 mmol) dissolved in a minimal volume of ethanol and stirred for 1 hour. rac-Ketamine hydrochloride (0.2742 g, 1.00 mmol) is dissolved in a minimal volume of water and combined with the ethanolic etodolate solution. The resulting solution is stirred and the total volume reduced to approximately 30 mL. The concentrated solution is transferred to a separatory funnel and the desired product extracted with diethyl ether (4.x.90 mL). The organic layers are combined and the solvent removed by rotary evaporation. The product is dried under vacuum overnight.

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Cl O Cl

O O HO O

Rx-ID: 23566312 View in Reaxys 12/48 Yield

Conditions & References 42 : Preparation of rac-Ketamine Loxoprofenate from rac-Ketamine Hydrochloride and Loxoprofen rac-Ketamine loxoprofenate may be prepared using the following synthetic scheme. Loxoprofen (0.2463 g, 1.00 mmol) dissolved in a minimal volume of ethanol is combined with potassium hydroxide (0.05611 g, 1.00 mmol) dissolved in a minimal volume of ethanol and stirred for 1 hour. rac-Ketamine hydrochloride (0.2742 g, 1.00 mmol) is dissolved in a minimal volume of water and combined with the ethanolic loxoprofenate solution. The resulting solution is stirred and the total volume reduced to approximately 30 mL. The concentrated solution is transferred to a separatory funnel and the desired product extracted with diethyl ether (4*90 mL). The organic layers are combined and the solvent removed by rotary evaporation. The product is dried under vacuum overnight. With potassium hydroxide in ethanol, water, Time= 1h Patent; Sancilio, Frederick D.; Stowell, Grayson W.; Whittall, Linda B.; White, David; Whittle, Robert R.; US2005/203115; (2005); (A1) English View in Reaxys

S Cl

O E

O Cl

S F

Rx-ID: 23566314 View in Reaxys 13/48 Yield

Conditions & References 35 :rac-Ketamine sulindate may be prepared using the following synthetic scheme. Sulindac (0.3564 g, 1.00 mmol) dissolved in a minimal volume of ethanol is combined with potassium hydroxide (0.05611 g, 1.00 mmol) dissolved in a minimal volume of ethanol and stirred for 1 hour. rac-Ketamine hydrochloride (0.2742 g, 1.00 mmol) is dissolved in a minimal volume of water and combined with the ethanolic sulindate solution. The resulting solution is stirred and the total volume reduced to approximately 30 mL. The concentrated solution is transferred to a separatory funnel and the desired product extracted with diethyl ether (4.x.90 mL). The organic layers are combined and the solvent removed by rotary evaporation. The product is dried under vacuum overnight With potassium hydroxide in ethanol, water, Time= 1h Patent; Sancilio, Frederick D.; Stowell, Grayson W.; Whittall, Linda B.; White, David; Whittle, Robert R.; US2005/203115; (2005); (A1) English View in Reaxys

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F O

NH O

OH O

Rx-ID: 23566315 View in Reaxys 14/48 Yield

Conditions & References 38 : Preparation of rac-Ketamine (S)-Flurbiprofenate from rac-Ketamine Hydrochloride and (S)-Flurbiprofen rac-Ketamine (S)-Flurbiprofenate may be prepared using the following synthetic scheme. (S)-Flurbiprofen (0.2443 g, 1.00 mmol) dissolved in a minimal volume of ethanol is combined with potassium hydroxide (0.05611 g, 1.00 mmol) dissolved in a minimal volume of ethanol and stirred for 1 hour. rac-Ketamine hydrochloride (0.2742 g, 1.00 mmol) is dissolved in a minimal volume of water and combined with the ethanolic flurbiprofenate solution. The resulting solution is stirred and the total volume reduced to approximately 30 mL. The solution is transferred to a separatory funnel and the desired product extracted with diethyl ether (4*90 mL). The organic layers are combined and the solvent removed by rotary evaporation. The product is dried under vacuum overnight. With potassium hydroxide in ethanol, water, Time= 1h Patent; Sancilio, Frederick D.; Stowell, Grayson W.; Whittall, Linda B.; White, David; Whittle, Robert R.; US2005/203115; (2005); (A1) English View in Reaxys

OH O

O Cl

O O

NH O

OH O

Rx-ID: 23566316 View in Reaxys 15/48 Yield

Conditions & References 36 : Preparation of rac-Ketamine (S)-Ketoprofenate from rac-Ketamine Hydrochloride and (S)-Ketoprofen rac-Ketamine (S)-ketoprofenate may be prepared using the following synthetic scheme. (S)-Ketoprofen (0.2543 g, 1.00 mmol) dissolved in a minimal volume of ethanol is combined with potassium hydroxide (0.05611 g, 1.00 mmol) dissolved in a minimal volume of ethanol and stirred for 1 hour. rac-Ketamine hydrochloride (0.2742 g, 1.00 mmol) is dissolved in a minimal volume of water and combined with the ethanolic ketoprofenate solution. The resulting solution is stirred and the total volume reduced to approximately 30 mL. The concentrated solution is transferred to a separatory funnel and the desired product extracted with diethyl ether (4*90 mL). The organic layers are combined and the solvent removed by rotary evaporation. The product is dried under vacuum overnight. With potassium hydroxide in ethanol, water, Time= 1h Patent; Sancilio, Frederick D.; Stowell, Grayson W.; Whittall, Linda B.; White, David; Whittle, Robert R.; US2005/203115; (2005); (A1) English View in Reaxys

Cl HN

HO Cl

O Cl

O N H O

Cl O

O O

Rx-ID: 23567999 View in Reaxys 16/48 Yield

Conditions & References 46 : Preparation of (S)-Ketamine Indomethacinate from (S)-Ketamine Hydrochloride and Indomethacin (S)-Ketamine indomethacinate may be prepared using the following synthetic scheme.

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Indomethacin (0.3578 g, 1.00 mmol) dissolved in a minimal volume of ethanol is combined with potassium hydroxide (0.05611 g, 1.00 mmol) dissolved in a minimal volume of ethanol and stirred for 1 hour. (S)-Ketamine hydrochloride (0.2742 g, 1.00 mmol) is dissolved in a minimal volume of water and combined with the ethanolic indomethacinate solution. The resulting solution is stirred and the total volume reduced to approximately 30 mL. The concentrated solution is transferred to a separatory funnel and the desired product extracted with diethyl ether (4*90 mL). The organic layers are combined and the solvent removed by rotary evaporation. The product is dried under vacuum overnight. With potassium hydroxide in ethanol, water, Time= 1h Patent; Sancilio, Frederick D.; Stowell, Grayson W.; Whittall, Linda B.; White, David; Whittle, Robert R.; US2005/203115; (2005); (A1) English View in Reaxys

Cl O Cl

HO O

Rx-ID: 23577062 View in Reaxys 17/48 Yield

Conditions & References 43 : Preparation of (S)-Ketamine Ibuprofenate from (S)-Ketamine Hydrochloride and Ibuprofen (S)-Ketamine ibuprofenate may be prepared using the following synthetic scheme. Ibuprofen (0.2063 g, 1.00 mmol) dissolved in minimal volume of ethanol is combined with potassium hydroxide (0.05611 g, 1.00 mmol) dissolved in a minimal volume of ethanol and stirred for 1 hour. (S)-Ketamine hydrochloride (0.2742 g, 1.00 mmol) is dissolved in a minimal volume of water and combined with the ethanolic ibuprofenate solution. The resulting solution is stirred and the total volume reduced to approximately 30 mL. The concentrated solution is transferred to a separatory funnel and the desired product extracted with diethyl ether (4*90 mL). The organic layers are combined and the solvent removed by rotary evaporation. The product is dried under vacuum overnight. With potassium hydroxide in ethanol, water, Time= 1h Patent; Sancilio, Frederick D.; Stowell, Grayson W.; Whittall, Linda B.; White, David; Whittle, Robert R.; US2005/203115; (2005); (A1) English View in Reaxys

O Cl

O N

Cl O

HO H

N H

N O

HO O

Rx-ID: 23577077 View in Reaxys 18/48 Yield

Conditions & References 55 : Preparation of (S)-Ketamine Oxaprozinate from (S)-Ketamine Hydrochloride and Oxaprozin (S)-Ketamine oxaprozinate may be prepared using the following synthetic scheme. Oxaprozin (0.2933 g, 1.00 mmol) dissolved in a minimal volume of ethanol is combined with potassium hydroxide (0.05611 g, 1.00 mmol) dissolved in a minimal volume of ethanol and stirred for 1 hour. (S)-Ketamine hydrochloride (0.2742 g, 1.00 mmol) is dissolved in a minimal volume of water and combined with the ethanolic oxaprozinate solution. The resulting solution is stirred and the total volume reduced to approximately 30 mL. The concentrated solution is transferred to a separatory funnel and the desired product extracted with diethyl ether (4*90 mL). The organic layers are combined and the solvent removed by rotary evaporation.

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The product is dried under vacuum overnight. With potassium hydroxide in ethanol, water, Time= 1h Patent; Sancilio, Frederick D.; Stowell, Grayson W.; Whittall, Linda B.; White, David; Whittle, Robert R.; US2005/203115; (2005); (A1) English View in Reaxys

OH O

Cl O

N H O

Rx-ID: 23577085 View in Reaxys 19/48 Yield

Conditions & References 51 : Preparation of (S)-Ketamine Suprofenate from (S)-Ketamine Hydrochloride and Suprofen (S)-Ketamine suprofenate may be prepared using the following synthetic scheme. Suprofen (0.2603 g, 1.00 mmol) dissolved in a minimal volume of ethanol is combined with potassium hydroxide (0.05611 g, 1.00 mmol) dissolved in a minimal volume of ethanol and stirred for 1 hour. (S)-Ketamine hydrochloride (0.2742 g, 1.00 mmol) is dissolved in a minimal volume of water and combined with the ethanolic suprofenate solution. The resulting solution is stirred and total volume reduced to approximately 30 mL. The concentrated solution is transferred to a separatory funnel and the desired product extracted with diethyl ether (4*90 mL). The organic layers are combined and the solvent removed by rotary evaporation. The product is dried under vacuum overnight. With potassium hydroxide in ethanol, water, Time= 1h Patent; Sancilio, Frederick D.; Stowell, Grayson W.; Whittall, Linda B.; White, David; Whittle, Robert R.; US2005/203115; (2005); (A1) English View in Reaxys

Cl O Cl

Cl HN

O O

N H O

O O

Rx-ID: 23578916 View in Reaxys 20/48 Yield

Conditions & References 44 : Preparation of (S)-Ketamine Acetylsalicylate from (S)-Ketamine Hydrochloride and Acetylsalicylic Acid (S)-Ketamine acetylsalicylate may be prepared using the following synthetic scheme. Acetylsalicylic acid (0.3003 g, 1.00 mmol) dissolved in a minimal volume of ethanol is combined with potassium hydroxide (0.05611 g, 1.00 mmol) dissolved in a minimal volume of ethanol and stirred for 1 hour. (S)-Ketamine hydrochloride (0.2742 g, 1.00 mmol) is dissolved in a minimal amount of water and combined with the ethanolic acetylsalicylate solution. The resulting solution is stirred and the total volume reduced to approximately 30 mL. The concentrated solution is transferred to a separatory funnel and the desired product extracted with diethyl ether (4*90 mL). The organic layers are combined and the solvent removed by rotary evaporation. The product is dried under vacuum overnight. With potassium hydroxide in ethanol, water, Time= 1h Patent; Sancilio, Frederick D.; Stowell, Grayson W.; Whittall, Linda B.; White, David; Whittle, Robert R.; US2005/203115; (2005); (A1) English View in Reaxys

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O O

N H O

OH O

Rx-ID: 23579987 View in Reaxys 21/48 Yield

Conditions & References 56 :(S)-Ketamine difunisalate may be prepared using the following synthetic scheme. Difunisal (0.2502 g, 1.00 mmol) dissolved in a minimal volume of ethanol is combined with potassium hydroxide (0.05611 g, 1.00 mmol) dissolved in a minimal volume of ethanol and stirred for 1 hour. (S)-Ketamine hydrochloride (0.2742 g, 1.00 mmol) is dissolved in a minimal volume of water and combined with the ethanolic difunisalate solution. The resulting solution is stirred and the total volume reduced to approximately 30 mL. The concentrated solution is transferred to a separatory funnel and the desired product extracted with diethyl ether (4.x.90 mL). The organic layers are combined and the solvent removed by rotary evaporation. With potassium hydroxide in ethanol, water, Time= 1h Patent; Sancilio, Frederick D.; Stowell, Grayson W.; Whittall, Linda B.; White, David; Whittle, Robert R.; US2005/203115; (2005); (A1) English View in Reaxys

OH Cl

O Cl

H N

N H

Rx-ID: 23580085 View in Reaxys 22/48 Yield

Conditions & References 48 :(S)-Ketamine etodolate may be prepared using the following synthetic scheme. Etodolac (0.2874 g, 1.00 mmol) dissolved in a minimal volume of ethanol is combined with potassium hydroxide (0.05611 g, 1.00 mmol) dissolved in a minimal volume of ethanol and stirred for 1 hour. (S)-Ketamine hydrochloride (0.2742 g, 1.00 mmol) is dissolved in a minimal volume of water and combined with the ethanolic etodolate solution. The resulting solution is stirred and the total volume reduced to approximately 30 mL. The concentrated solution is transferred to a separatory funnel and the desired product extracted with diethyl ether (4.x.90 mL). The organic layers are combined and the solvent removed by rotary evaporation. The product is dried under vacuum overnight. With potassium hydroxide in ethanol, water, Time= 1h Patent; Sancilio, Frederick D.; Stowell, Grayson W.; Whittall, Linda B.; White, David; Whittle, Robert R.; US2005/203115; (2005); (A1) English View in Reaxys

O Cl O Cl

N H

O O HO O

Rx-ID: 23580262 View in Reaxys 23/48 Yield

Conditions & References 55 : Preparation of (S)-Ketamine Loxoprofenate from (S)-Ketamine Hydrochloride and Loxoprofen (S)-Ketamine loxoprofenate may be prepared using the following synthetic scheme. Loxoprofen (0.2463 g, 1.00 mmol) dissolved in a minimal volume of ethanol is combined with potassium hydroxide (0.05611 g, 1.00 mmol) dissolved in a minimal volume of ethanol and stirred for 1 hour. (S)-Ketamine hydrochloride (0.2742 g, 1.00 mmol) is dissolved in a minimal volume of water and combined with the ethanolic loxoprofenate solution. The resulting solution is stirred and the total volume reduced to approximately 30 mL. The concentrated solution is transferred to a separatory funnel and the desired product extracted with diethyl ether (4*90 mL). The organic layers are combined and the solvent removed by rotary evaporation.

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S Cl

N H O

S F

Rx-ID: 23580844 View in Reaxys 24/48 Yield

Conditions & References 49 :(S)-Ketamine sulindate may be prepared using the following synthetic scheme. Sulindac (0.3564 g, 1.00 mmol) dissolved in a minimal volume of ethanol is combined with potassium hydroxide (0.05611 g, 1.00 mmol) dissolved in a minimal volume of ethanol and stirred for 1 hour. (S)-Ketamine hydrochloride (0.2742 g, 1.00 mmol) is dissolved in a minimal volume of water and combined with the ethanolic sulindate solution. The resulting solution is stirred and the total volume reduced to approximately 30 mL. The concentrated solution is transferred to a separatory funnel and the desired product extracted with diethyl ether (4.x.90 mL). The organic layers are combined and the solvent removed by rotary evaporation. The product is dried under vacuum overnight. With potassium hydroxide in ethanol, water, Time= 1h Patent; Sancilio, Frederick D.; Stowell, Grayson W.; Whittall, Linda B.; White, David; Whittle, Robert R.; US2005/203115; (2005); (A1) English View in Reaxys

F O

N H

OH O

Rx-ID: 23581892 View in Reaxys 25/48 Yield

Conditions & References 52 : Preparation of (S)-Ketamine (S)-Flurbiprofenate from (S)-Ketamine Hydrochloride and (S)-Flurbiprofen (S)-Ketamine (S)-flurbiprofenate may be prepared using the following synthetic scheme. (S)-Flurbiprofen (0.2443 g, 1.00 mmol) dissolved in a minimal volume of ethanol is combined with potassium hydroxide (0.05611 g, 1.00 mmol) dissolved in a minimal volume of ethanol and stirred for 1 hour. (S)-Ketamine hydrochloride (0.2742 g, 1.00 mmol) is dissolved in a minimal volume of water and combined with the ethanolic flurbiprofenate solution. The resulting solution is stirred and the total volume reduced to approximately 30 mL. The concentrated solution is transferred to a separatory funnel and the desired product extracted with diethyl ether (4*90 mL). The organic layers are combined and the solvent removed by rotary evaporation. The product is dried under vacuum overnight. With potassium hydroxide in ethanol, water, Time= 1h Patent; Sancilio, Frederick D.; Stowell, Grayson W.; Whittall, Linda B.; White, David; Whittle, Robert R.; US2005/203115; (2005); (A1) English View in Reaxys

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O Cl

N H

O O O

OH O

Rx-ID: 23583319 View in Reaxys 26/48 Yield

Conditions & References 50 : Preparation of (S)-Ketamine (S)-Ketoprofenate from (S)-Ketamine Hydrochloride and (S)-Ketoprofen (S)-Ketamine (S)-ketoprofenate may be prepared using the following synthetic scheme. (S)-Ketoprofen (0.2543 g, 1.00 mmol) dissolved in a minimal volume of ethanol is combined with potassium hydroxide (0.05611 g, 1.00 mmol) dissolved in a minimal volume of ethanol and stirred for 1 hour. (S)-Ketamine hydrochloride (0.2742 g, 1.00 mmol) is dissolved in a minimal volume of water and combined with the ethanolic ketoprofenate solution. The resulting solution is stirred and the total volume reduced to approximately 30 mL. The concentrated solution is transferred to a separatory funnel and the desired product extracted with diethyl ether (4*90 mL). The organic layers are combined and the solvent removed by rotary evaporation. The product is dried under vacuum overnight. With potassium hydroxide in ethanol, water, Time= 1h Patent; Sancilio, Frederick D.; Stowell, Grayson W.; Whittall, Linda B.; White, David; Whittle, Robert R.; US2005/203115; (2005); (A1) English View in Reaxys

2H 2H 2H 2

N OH E

2H 2 H

Rx-ID: 28008068 View in Reaxys 27/48 Yield

Conditions & References 1.4 :The procedure of Step 4 is carried out as described in U.S. Pat. No. 3,254,124. d11-1-[(2-chlorophenyl)-methylimino-methyl]-cyclopentanol (2 g) is dissolved in decalin (15 mL) and heated at reflux for about 2.5 hours. The solvent is removed in vacuo and the resulting crude residue is extracted into dilute hydrochloric acid. The solution is treated with decolorizing charcoal and the pH is adjusted to greater than 7 with a solution of sodium hydroxide, to give the title product. in decalin, Time= 2.5h, Heating / reflux Patent; AUSPEX PHARMACEUTICALS, INC.; US2008/268071; (2008); (A1) English View in Reaxys

O Cl

Cl NH

Na +

OH Cl

NH O

H N

Cl –O

Rx-ID: 23566304 View in Reaxys 28/48 Yield

Conditions & References 8 :Aqueous solutions of sodium diclofenac (0.6378 g, 2.005 mmol in 150 mL of water) and (+/-)-2-(2-chlorophenyl)-2(methylamino)cyclohexanone (referred to herein as rac-ketamine) hydrochloride (0.5427 g, 1.979 mmol in 50 mL of water) were combined into a 250 mL Erlenmeyer flask. A white precipitate formed and the solution was stirred for 15 minutes. The solid material was separated by filtration through a 0.45-μm polyvinylidene fluoride (PVDF) filter and the filter cake dissolved in methanol (25 mL). The methanol solution was removed by evaporation under nitrogen and the resulting oily material transferred to a round bottom flask using a small amount of diethyl ether. The diethyl ether was removed by rotary evaporation forming a white solid. The flask placed under vacuum to obtain a white solid product.

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The product was characterized by elemental analysis: Expected: 60.74percent C, 5.10percent H, 5.25percent N, Obtained: 59.88percent C, 4.87percent H, 5.14percent N; DSC: Tg: 40.3° C.; 1H and 13C NMR, FTIR, and FT-Raman Spectroscopy (FT-Raman). Representative bands observed in the FTIR and FT-Raman spectra are listed in the Tables 5a and 5b, respectively. Resonances for the 1H and 13C NMR spectra are listed in Tables 6a and 6b, respectively. in water, Time= 0.25h Patent; Sancilio, Frederick D.; Stowell, Grayson W.; Whittall, Linda B.; White, David; Whittle, Robert R.; US2005/203115; (2005); (A1) English View in Reaxys

Cl O Cl

Ca 2+

O–

Rx-ID: 23566308 View in Reaxys 29/48 Yield

Conditions & References 40 : Preparation of rac-Ketamine Fenoprofenate from rac-Ketamine Hydrochloride and Fenoprofen Calcium Trihydrate rac-Ketamine fenoprofenate may be prepared using the following synthetic scheme. Aqueous solutions of fenoprofen calcium trihydrate (0.2884 g, 0.50 mmol) and of rac-ketamine hydrochloride (0.2742 g, 1.00 mmol) are combined into a suitable flask and stirred for 60 minutes. The resulting solution is transferred to a separatory funnel and the desired product extracted with diethyl ether (4*90 mL). The organic layers are combined and the solvent removed by rotary evaporation. The product is dried under vacuum overnight. in water, Time= 1h Patent; Sancilio, Frederick D.; Stowell, Grayson W.; Whittall, Linda B.; White, David; Whittle, Robert R.; US2005/203115; (2005); (A1) English View in Reaxys

O Cl

Cl HN

O–

Na +

O O

Rx-ID: 23566313 View in Reaxys 30/48 Yield

Conditions & References 33 : Preparation of rac-Ketamine Naproxenate from rac-Ketamine Hydrochloride and Naproxen Sodium rac-Ketamine naproxenate may be prepared using the following synthetic scheme. Aqueous solutions of naproxen sodium (0.2522 g, 1.00 mmol) and of rac-ketamine hydrochloride (0.2742 g, 1.00 mmol) are combined into a suitable flask and stirred for approximately 60 minutes. The resulting solution is transferred to a separatory funnel and the desired product extracted with diethyl ether (4*90 mL). The organic layers are combined and the solvent removed by rotary evaporation. The product is dried under vacuum overnight. in water, Time= 1h Patent; Sancilio, Frederick D.; Stowell, Grayson W.; Whittall, Linda B.; White, David; Whittle, Robert R.; US2005/203115; (2005); (A1) English View in Reaxys

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O Cl

Na +

O HO

O– O

Rx-ID: 23566317 View in Reaxys 31/48 Yield

Conditions & References 39 : Preparation of rac-Ketamine Tolmetinate from rac-Ketamine Hydrochloride and Tolmetin Sodium Dihydrate rac-Ketamine tolmetinate may be prepared using the following synthetic scheme. Aqueous solutions of tolmetin sodium dihydrate (0.3153 g, 1.00 mmol) and of rac-ketamine hydrochloride (0.2742 g, 1.00 mmol) are combined into a suitable flask and stirred for 60 minutes. The resulting solution is transferred to a separatory funnel and the desired product extracted with diethyl ether (4*90 mL). The organic layers are combined and the solvent removed by rotary evaporation. The product is dried under vacuum overnight. in water, Time= 1h Patent; Sancilio, Frederick D.; Stowell, Grayson W.; Whittall, Linda B.; White, David; Whittle, Robert R.; US2005/203115; (2005); (A1) English View in Reaxys

O–

Na +

Rx-ID: 23566318 View in Reaxys 32/48 Yield

Conditions & References 31 : Preparation of rac-Ketamine Salicylate from rac-Ketamine Hydrochloride and Sodium Salicylate rac-Ketamine salicylate may be prepared using the following synthetic scheme. Aqueous solutions of sodium salicylate (0.1601 g, 1.00 mmol) and of rac-ketamine hydrochloride (0.2742 g, 1.00 mmol) are combined into a suitable flask and stirred for 60 minutes. The resulting solution is transferred to a separatory funnel and the desired product extracted with diethyl ether (4*90 mL). The organic layers are combined and the solvent removed by rotary evaporation. The product is dried under vacuum overnight. in water, Time= 1h Patent; Sancilio, Frederick D.; Stowell, Grayson W.; Whittall, Linda B.; White, David; Whittle, Robert R.; US2005/203115; (2005); (A1) English View in Reaxys

O Cl

Cl Cl

Na +

N H

H N

Cl –O

Rx-ID: 23574369 View in Reaxys 33/48 Yield

Conditions & References 56 :(S)-Ketamine diclofenate may be prepared using the following synthetic scheme. Aqueous solutions of sodium diclofenac (0.3181 g, 1.00 mmol) and of (S)-ketamine hydrochloride (0.2742 g, 1.00 mmol) are combined into a suitable flask and stirred for 60 minutes. The resulting solution is transferred to a separatory funnel and the desired product

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extracted with diethyl ether (4.x.90 mL). The organic layers are combined and the solvent removed by rotary evaporation. The product is dried under vacuum overnight. in water, Time= 1h Patent; Sancilio, Frederick D.; Stowell, Grayson W.; Whittall, Linda B.; White, David; Whittle, Robert R.; US2005/203115; (2005); (A1) English View in Reaxys

Cl O

2 Cl

Ca 2+

N H

O–

O OH

Rx-ID: 23578221 View in Reaxys 34/48 Yield

Conditions & References 54 : Preparation of (S)-Ketamine Fenoprofenate from (S)-Ketamine Hydrochloride and Fenoprofen Calcium Trihydrate (S)-Ketamine Fenoprofenate may be prepared using the following synthetic scheme. Aqueous solutions of fenoprofen calcium trihydrate (0.2884 g, 0.50 mmol) and of (S)-ketamine hydrochloride (0.2742 g, 1.00 mmol) are combined into a suitable flask and stirred for 60 minutes. The resulting solution is transferred to a separatory funnel and the desired product extracted with diethyl ether (4*90 mL). The organic layers are combined and the solvent removed by rotary evaporation. The product is dried under vacuum overnight. in water, Time= 1h Patent; Sancilio, Frederick D.; Stowell, Grayson W.; Whittall, Linda B.; White, David; Whittle, Robert R.; US2005/203115; (2005); (A1) English View in Reaxys

Cl O Cl

Cl HN

O–

N H

Na +

OH O

O O

Rx-ID: 23580799 View in Reaxys 35/48 Yield

Conditions & References 47 : Preparation of (S)-Ketamine Naproxenate from (S)-Ketamine Hydrochloride and Naproxen Sodium (S)-Ketamine Naproxenate may be prepared using the following synthetic scheme. Aqueous solutions of naproxen sodium (0.2522 g, 1.00 mmol) and of (S)-ketamine hydrochloride (0.2742 g, 1.00 mmol) are combined into a suitable flask and stirred for 60 minutes. The resulting solution is transferred to a separatory funnel and the desired product extracted with diethyl ether (4*90 mL). The organic layers are combined and the solvent removed by rotary evaporation. The product is dried under vacuum overnight. in water, Time= 1h Patent; Sancilio, Frederick D.; Stowell, Grayson W.; Whittall, Linda B.; White, David; Whittle, Robert R.; US2005/203115; (2005); (A1) English View in Reaxys

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O Cl

N H

Na +

O– O

Rx-ID: 23589632 View in Reaxys 36/48 Yield

Conditions & References 53 : Preparation of (S)-Ketamine Tolmetinate from (S)-Ketamine Hydrochloride and Tolmetin Sodium Dihydrate (S)-Ketamine tolmetinate may be prepared using the following synthetic scheme. Aqueous solutions of tolmetin sodium dihydrate (0.3153 g, 1.00 mmol) and of (S)-ketamine hydrochloride (0.2742 g, 1.00 mmol) are combined into a suitable flask and stirred for 60 minutes. The resulting solution is transferred to a separatory funnel and the desired product extracted with diethyl ether (4*90 mL). The organic layers are combined and the solvent removed by rotary evaporation. The product is dried under vacuum overnight. in water, Time= 1h Patent; Sancilio, Frederick D.; Stowell, Grayson W.; Whittall, Linda B.; White, David; Whittle, Robert R.; US2005/203115; (2005); (A1) English View in Reaxys

O–

Na +

N H O

Rx-ID: 23589633 View in Reaxys 37/48 Yield

Conditions & References 45 : Preparation of (S)-Ketamine Salicylate from (S)-Ketamine Hydrochloride and Sodium Salicylate (S)-Ketamine Salicylate may be prepared using the following synthetic scheme. Aqueous solutions of sodium salicylate (0.1601 g, 1.00 mmol) and of (S)-ketamine hydrochloride (0.2742 g, 1.00 mmol) are combined into a suitable flask and stirred for 60 minutes. The resulting solution is transferred to a separatory funnel and the desired product extracted with diethyl ether (4*90 mL). The organic layers are combined and the solvent removed by rotary evaporation. The product is dried under vacuum overnight. in water, Time= 1h Patent; Sancilio, Frederick D.; Stowell, Grayson W.; Whittall, Linda B.; White, David; Whittle, Robert R.; US2005/203115; (2005); (A1) English View in Reaxys

Cl O

NE Cl HO

Rx-ID: 9690272 View in Reaxys 38/48 Yield

Conditions & References With 2,6-bis[(4S)-isopropyl-2-oxazolin-2-yl]pyridine, nickel dichloride in octanol, Time= 24h, T= 150 °C Brunner, Henri; Kagan, Henri B.; Kreutzer, Georg; Tetrahedron Asymmetry; vol. 14; nb. 15; (2003); p. 2177 - 2187 View in Reaxys

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Cl H N

O Cl

Rx-ID: 28771268 View in Reaxys 39/48 Yield

Conditions & References Stage 1: With hydrogenchloride in water, Inert atmosphere Stage 2: With ozone in methanol, T= -78 °C Stage 3: With dimethylsulfide in methanol, T= -78 °C , Inert atmosphere Yokoyama, Reiko; Matsumoto, Satoshi; Nomura, Satoshi; Higaki, Takafumi; Yokoyama, Takeshi; Kiyooka, Syun-ichi; Tetrahedron; vol. 65; nb. 27; (2009); p. 5181 - 5191 View in Reaxys

O H 11 3 C

Cl H 2N

Cl HN H 11 3 C

Rx-ID: 5050988 View in Reaxys 40/48 Yield

Conditions & References in dimethyl sulfoxide, N,N-dimethyl-formamide, T= 110 °C , Alkylation Hartvig, Per; Valtysson, Johann; Lindner, Karl-Johan; Kristensen, Jens; Karlsten, Rolf; Gustafsson, Lars L.; Persson, Jan; Svensson, Jan O.; ye, Ivar; Antoni, Gunnar; Westerberg, Goran; Langstroem, Bengt; Clinical Pharmacology and Therapeutics; vol. 58; nb. 2; (1995); p. 165 - 173 View in Reaxys

O Cl

Rx-ID: 36532932 View in Reaxys 41/48 Yield

Conditions & References (R)-ketamine hydrochloride was separatedfrom (R,S)-ketamine hydrochloride through a modification of the publishedprocedure for the resolution of (S)-ketamine (Steiner et al., 2000). , Resolution of racemate Li, Yibai; Coller, Janet K.; Hutchinson, Mark R.; Klein, Kathrin; Zanger, Ulrich M.; Stanley, Nathan J.; Abell, Andrew D.; Somogyi, Andrew A.; Drug Metabolism and Disposition; vol. 41; nb. 6; (2013); p. 1264 - 1272 View in Reaxys

O Cl

Cl HN

Rx-ID: 28771277 View in Reaxys 42/48 Yield 68 mg

Conditions & References With sodium hydroxide in water, Inert atmosphere Yokoyama, Reiko; Matsumoto, Satoshi; Nomura, Satoshi; Higaki, Takafumi; Yokoyama, Takeshi; Kiyooka, Syun-ichi; Tetrahedron; vol. 65; nb. 27; (2009); p. 5181 - 5191

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View in Reaxys

O HO

Cl H 2N

Cl HN

Rx-ID: 39583984 View in Reaxys 43/48 Yield

Conditions & References

52 %

With formaldehyd, sodium tris(acetoxy)borohydride, acetic acid Yang, Xiaoyu; Toste, F. Dean; Journal of the American Chemical Society; vol. 137; nb. 9; (2015); p. 3205 - 3208 View in Reaxys

O O O HN

O O

HN O

Rx-ID: 39584022 View in Reaxys 44/48 Yield

Conditions & References Reaction Steps: 2 1.1: trifluoroacetic acid / dichloromethane / 3 h / 20 °C 1.2: |Inert atmosphere 2.1: acetic acid; formaldehyd; sodium tris(acetoxy)borohydride With formaldehyd, sodium tris(acetoxy)borohydride, acetic acid, trifluoroacetic acid in dichloromethane Yang, Xiaoyu; Toste, F. Dean; Journal of the American Chemical Society; vol. 137; nb. 9; (2015); p. 3205 - 3208 View in Reaxys

Cl O Cl HN

Rx-ID: 39584069 View in Reaxys 45/48 Yield

Conditions & References Reaction Steps: 3 1.1: C84H113O4P / neat (no solvent) / 60 h / 45 °C / |Molecular sieve 2.1: trifluoroacetic acid / dichloromethane / 3 h / 20 °C 2.2: |Inert atmosphere 3.1: acetic acid; formaldehyd; sodium tris(acetoxy)borohydride With formaldehyd, C84H113O4P, sodium tris(acetoxy)borohydride, acetic acid, trifluoroacetic acid in dichloromethane Yang, Xiaoyu; Toste, F. Dean; Journal of the American Chemical Society; vol. 137; nb. 9; (2015); p. 3205 - 3208 View in Reaxys

O Cl

Cl N

Rx-ID: 3262360 View in Reaxys 46/48

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Yield

Conditions & References

85 %

in hydrogenchloride, methanol, Time= 8h, electrochemical reduction, -1.2 V; further reductors, Product distribution, Mechanism Oelschlager; El Hossny; Archiv der Pharmazie; vol. 316; nb. 5; (1983); p. 412 - 421 View in Reaxys

O Cl

Rx-ID: 25412732 View in Reaxys 47/48 Yield

Conditions & References The following specific crystallizable substances can be mentioned by way of example. 1. General anesthetics: Ketamine hydrochloride, thiamylal sodium, thiopental sodium, droperidol. Patent; Nippon Shinyaju Co., Ltd.; US5811547; (1998); (A1) English View in Reaxys

O Cl HN

Rx-ID: 7370958 View in Reaxys 48/48 Yield

Conditions & References Imin II, Erhitzen Patent; PARKE; DAVIS and CO.; CH454128; (1963); Chem. Zentralbl. View in Reaxys Imin XVII, Δ Patent; Stevens; BE634208; (1962); ; vol. 61; nb. 5569c; (1964) View in Reaxys 1-OH-Cyclopentyl-o-Cl-Ph-keton-N-methylimin (XI), Δ Patent; Parke; Davis and Co.; US3254124; (1966); ; vol. 65; nb. 5414h; (1966) View in Reaxys 1-Hydroxycyclopentyl-(o-chlorphenyl)-N-methylketimin, Δ Patent; Parke, Davis u. Co.; DE1793315; (1972); ; vol. 77; nb. 61514 View in Reaxys

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