N-乙酰-L-谷氨酸

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 10.45 g (34.5 mmol) of N-Boc-L-glutamic acid-α-tertbutyl ester (BACHEM) in 100 mL of methylene chloride under nitrogen is added 3.5 g (17.0 mmol) of solid dicyclohexylcarbodiimide (DCC). The reaction is allowed to stir for 2 h and filtered under nitrogen. The anhydride solution is then added to a solution of 6.42 g (14.9 mmol) of the compound of Example 20 in 75 mL of methylene chloride under nitrogen. The reaction is stirred overnight and is concentrated in vacuo. Purification by silica gel chromatography (Waters Prep-500A) gives pure material by thin-layer chromatography (TLC). This material is redissolved in 100 mL of methylene chloride under nitrogen and cooled to 0° C. prior to the addition of 135 mL of TFA. The stirred reaction is allowed to warm to ambient temperature overnight and is concentrated in vacuo. The crude product is dissolved in 80 mL of acetonitrile/water (1:1) and the pH is adjusted to 9 with 1 M K2CO3. The solution is cooled to 0° C. and 1.1 mL (11 mmol) of acetic anhydride and 11 mL (11 mmol) of 1 M K2CO3 is added every 30 min for 5 h; during the course of this reaction the pH is maintained at 9 and the reaction temperature is kept below 5° C. After the last addition, the reaction is allowed to warm to ambient temperature overnight. The pH was adjusted to 4 with 3 M HCl and the reaction concentrated to 300 mL. Purification by reverse phase chromatography (Waters Delta prep-3000) gives N-acetyl-L-glutamic acid, 5-[5-butyl-1-[[2′-(1H-tetrazol-5-yl) [1,1′-biphenyl]-4-yl]methyl-1H-1,2,4-traizol-3-yl]acetylhydrazide. filtered under nitrogen The reaction is stirred overnight is concentrated in vacuo Purification by silica gel chromatography (Waters Prep-500A) gives pure material by thin-layer chromatography (TLC) The stirred reaction to warm to ambient temperature overnight is concentrated in vacuo The crude product is dissolved in 80 mL of acetonitrile/water (1:1) The solution is cooled to 0° C. during the course of this reaction the pH is maintained at 9 is kept below 5° C After the last addition to warm to ambient temperature overnight the reaction concentrated to 300 mL Purification by reverse phase chromatography (Waters Delta prep-3000)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 4.2 g (0.021 moles) of carnitine hydrochloride are dissolved in 12 mls of trifluoroacetic acid, then at 35° C. and under vigorous stirring 20 cc of a solution of anhydrous chloroform wherein about 4.36 g (0.021 moles) of the acide chloride of the N-acetyl glutamic acid have been dissolved are added dropwise. The reaction is allowed to proceed for about 14 hours at 35° C., and subsequently at 50° C. for two further hours. The reaction mixture is cooled. Upon acetone addition (40 mls) no precipitate forms even though the mixture is cooled below 0° C. 140 mls of ethyl ether are added and after keeping the mixture at 8° C. overnight there are obtained 6.2 g of a solid white product which is crystallized with ethyl ether. After 2 crystallizations 5.4 g (68%) of the desired product having the following characteristics are obtained: have been dissolved are added dropwise subsequently at 50° C. The reaction mixture is cooled is cooled below 0° C at 8° C. overnight

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Equimolar quantities of racemic 3-methyl-1-(2-piperidino-phenyl)-1-butylamine and of N-acetyl-L-glutamic acid were refluxed in aceton, whereby methanol was added in such an amount to yield a clear solution. to yield a clear solution

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 10.45 g (34.5 mmol) of N-Boc-L-glutamic acid-α-tertbutyl ester (BACHEM) in 100 mL of methylene chloride under nitrogen is added 3.5 g (17.0 mmol) of solid dicyclohexylcarbodiimide (DCC). The reaction is allowed to stir for 2 h and filtered under nitrogen. The anhydride solution is then added to a solution of 6.42 g (14.9 mmol) of the compound of Example 20 in 75 mL of methylene chloride under nitrogen. The reaction is stirred overnight and is concentrated in vacuo. Purification by silica gel chromatography (Waters Prep-500A) gives pure material by thin-layer chromatography (TLC). This material is redissolved in 100 mL of methylene chloride under nitrogen and cooled to 0° C. prior to the addition of 135 mL of TFA. The stirred reaction is allowed to warm to ambient temperature overnight and is concentrated in vacuo. The crude product is dissolved in 80 mL of acetonitrile/water (1:1) and the pH is adjusted to 9 with 1M K2CO 3. The solution is cooled to 0° C. and 1.1 mL (11 mmol) of acetic anhydride and 11 mL (11 mmol) of 1M K2CO3 is added every 30 min for 5 h; during the course of this reaction the pH is maintained at 9 and the reaction temperature is kept below 5° C. After the last addition, the reaction is allowed to warm to ambient temperature overnight. The pH was adjusted to 4 with 3M HCl and the reaction concentrated to 300 mL. Purification by reverse phase chromatography (Waters Delta prep-3000) gives N-acetyl-L-glutamic acid, 5-[5-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl-1H-1,2,4-triazol-3-yl]acetylhydrazide. filtered under nitrogen The reaction is stirred overnight is concentrated in vacuo Purification by silica gel chromatography (Waters Prep-500A) gives pure material by thin-layer chromatography (TLC) The stirred reaction to warm to ambient temperature overnight is concentrated in vacuo The crude product is dissolved in 80 mL of acetonitrile/water (1:1) The solution is cooled to 0° C. during the course of this reaction the pH is maintained at 9 is kept below 5° C After the last addition to warm to ambient temperature overnight the reaction concentrated to 300 mL Purification by reverse phase chromatography (Waters Delta prep-3000)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Equimolar quantities of racemic 3-methyl-1-(2-piperidino-phenyl)-1-butylamine and of N-acetyl-L-glutamic acid were refluxed in aceton, whereby methanol was added in such an amount to yield a clear solution. to yield a clear solution

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 10.45 g (34.5 mmol) of N-Boc-L-glutamic acid-α-tertbutyl ester (BACHEM) in 100 mL of methylene chloride under nitrogen is added 3.5 g (17.0 mmol) of solid dicyclohexylcarbodiimide (DCC). The reaction is allowed to stir for 2 h and filtered under nitrogen. The anhydride solution is then added to a solution of 6.42 g (14.9 mmol) of the compound of Example 20 in 75 mL of methylene chloride under nitrogen. The reaction is stirred overnight and is concentrated in vacuo. Purification by silica gel chromatography (Waters Prep-500A) gives pure material by thin-layer chromatography (TLC). This material is redissolved in 100 mL of methylene chloride under nitrogen and cooled to 0° C. prior to the addition of 135 mL of TFA. The stirred reaction is allowed to warm to ambient temperature overnight and is concentrated in vacuo. The crude product is dissolved in 80 mL of acetonitrile/water (1:1) and the pH is adjusted to 9 with 1 M K2CO3. The solution is cooled to 0° C. and 1.1 mL (11 mmol) of acetic anhydride and 11 mL (11 mmol) of 1 M K2CO3 is added every 30 min for 5 h; during the course of this reaction the pH is maintained at 9 and the reaction temperature is kept below 5° C. After the last addition, the reaction is allowed to warm to ambient temperature overnight. The pH was adjusted to 4 with 3 M HCl and the reaction concentrated to 300 mL. Purification by reverse phase chromatography (Waters Delta prep-3000) gives N-acetyl-L-glutamic acid, 5-[5-butyl-1-[[2′-(1H-tetrazol-5-yl) [1,1′-biphenyl]-4-yl]methyl-1H-1,2,4-traizol-3-yl]acetylhydrazide. filtered under nitrogen The reaction is stirred overnight is concentrated in vacuo Purification by silica gel chromatography (Waters Prep-500A) gives pure material by thin-layer chromatography (TLC) The stirred reaction to warm to ambient temperature overnight is concentrated in vacuo The crude product is dissolved in 80 mL of acetonitrile/water (1:1) The solution is cooled to 0° C. during the course of this reaction the pH is maintained at 9 is kept below 5° C After the last addition to warm to ambient temperature overnight the reaction concentrated to 300 mL Purification by reverse phase chromatography (Waters Delta prep-3000)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 4.2 g (0.021 moles) of carnitine hydrochloride are dissolved in 12 mls of trifluoroacetic acid, then at 35° C. and under vigorous stirring 20 cc of a solution of anhydrous chloroform wherein about 4.36 g (0.021 moles) of the acide chloride of the N-acetyl glutamic acid have been dissolved are added dropwise. The reaction is allowed to proceed for about 14 hours at 35° C., and subsequently at 50° C. for two further hours. The reaction mixture is cooled. Upon acetone addition (40 mls) no precipitate forms even though the mixture is cooled below 0° C. 140 mls of ethyl ether are added and after keeping the mixture at 8° C. overnight there are obtained 6.2 g of a solid white product which is crystallized with ethyl ether. After 2 crystallizations 5.4 g (68%) of the desired product having the following characteristics are obtained: have been dissolved are added dropwise subsequently at 50° C. The reaction mixture is cooled is cooled below 0° C at 8° C. overnight