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Method for preparing N-[1-(S)-carbethoxy-3-hydrocinnamyl] -L-alanine-N-carboxy acid anhydride

A technology of aminopropionic acid and ethyl carboxyl group, which is applied in the field of manufacturing of N-[1-(S)-ethyl carboxyl-3-phenylpropyl]-L-alanine-N-carboxy anhydride, can solve the problem of Steam toxicity, difficult manufacturing engineering, expensive and other issues, to achieve the effect of low toxicity, low risk, and easy operation

Inactive Publication Date: 2005-02-02
EVERLIGHT USA INC
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the yield of phosgene process is high, phosgene is a highly toxic gas. Based on industrial safety considerations, a special design must be used to avoid the leakage of phosgene. Although diphosgene and triphosgene are liquid or Solid, but the vapor produced when heated is extremely poisonous, special care must be taken in handling
In addition, the treatment process of waste gas and waste generated in the manufacturing process is also quite difficult, and it is easy to cause harm to the environment, so it is a difficult manufacturing project in industrial applications.
Other preparation methods that replace the direct use of phosgene have also been developed one after another. As described in U.S. Pat. No. 5,359,086, N, N'-carbonyldiimidazole (N, N'-carbonyldiimidazole) is used to replace phosgene; but N, N'-carbonyldiimidazole is expensive, and if it is to be recycled, it still needs to be regenerated with phosgene, which is not suitable for industrial use

Method used

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  • Method for preparing N-[1-(S)-carbethoxy-3-hydrocinnamyl] -L-alanine-N-carboxy acid anhydride
  • Method for preparing N-[1-(S)-carbethoxy-3-hydrocinnamyl] -L-alanine-N-carboxy acid anhydride
  • Method for preparing N-[1-(S)-carbethoxy-3-hydrocinnamyl] -L-alanine-N-carboxy acid anhydride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] 27.9 g of NEPA and 90 ml of dichloroethane were added into the reactor, followed by 13.1 g of ethyl chloroformate and 10.0 g of triethylamine, and stirred at room temperature until the reaction was complete. After the organic layer was washed twice with 50 ml of water, the pH was adjusted to 3 to 4 with hydrochloric acid, the organic layer was dried with magnesium sulfate, filtered, and the filtrate was preserved.

[0041] Add 13.1 g of sulfinyl chloride to the reactor, and slowly drop the previous filtrate into the reactor at 5-10°C, then stir at room temperature until the reaction is complete, wash the organic layer twice with 50 ml of water, and then wash it with sulfuric acid Magnesium was dried and filtered, and the crude product was obtained after concentration under reduced pressure. Finally, recrystallization was carried out to obtain white crystals of N-[1-(S)-carboethoxy-3-phenylpropyl]-L-alanine-N-carboxy anhydride with a total yield of 70%.

[0042] Product...

Embodiment 2

[0044] 27.9 g of NEPA and 60 ml of dichloroethane were added to the reactor, and then 13.1 g of ethyl chloroformate and 9.6 g of polyvinylpyridine were added, and stirred at room temperature until the reaction was complete. After the organic layer was washed twice with 50 ml of water, the pH was adjusted to 3-4 with hydrochloric acid. The organic layer was dried with magnesium sulfate, filtered, and the filtrate was preserved.

[0045] Add 10.2 g of acetyl chloride into the reactor, and slowly drop the previous filtrate into the reactor at 5-10°C, then stir at room temperature until the reaction is complete, wash the organic layer twice with 50 ml of water, then dry and filter with magnesium sulfate , the crude product can be obtained after concentration under reduced pressure. Finally, recrystallization was carried out to obtain white crystals of N-[1-(S)-carboethoxy-3-phenylpropyl]-L-alanine-N-carboxy anhydride with a total yield of 91%.

[0046]Product melting point: 68°C...

Embodiment 3

[0048] 1.2 liters of dichloroethane and 560 grams of NEPA were added to the reactor, followed by 237.6 grams of ethyl chloroformate. After stirring for half an hour, 230 ml of 10M aqueous sodium hydroxide solution was added to the reactor and stirred for another hour.

[0049] After the reaction is completed, add 188.4 g of acetyl chloride, react at 85-95°C for 2 hours, then add 800 ml of water, keep the temperature at 70-80°C, stir until the reaction is complete, extract the organic layer, and concentrate under reduced pressure The crude product can be obtained afterwards. Finally, recrystallization was carried out to obtain white crystals of N-[1-(S)-carboethoxy-3-phenylpropyl]-L-alanine-N-carboxy anhydride with a total yield of 82%.

[0050] Product melting point: 68°C; 1H-NMR (CDCl3): δ1.26(t, 3H), δ1.53(d, 3H), δ2.22~2.48(m, 2H), δ2.66~2.84(m, 2H), δ3.39(q, 1H), δ4.20(d, 2H), δ4.33(d, 1H) and δ7.15~7.34(m, 5H).

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Abstract

A process for preparing N-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanine N-carboxyanhydride of the following formula (I), is to react N-[1 -(S)-ethyoxy carbonyl-3-phenylpropyl]-L-alanine with XCOOR, wherein X is halogen atom, R is C1-C6 alkyl, to obtain a N-alkoxycarbonyl compound, then reacting with an acyl group activation reagent, finally contact with water. The compound of formula (I) is a key intermediate of ACE inhibitors. The preparation process has the advantages such as low toxicity, low hazard and easy operation etc.

Description

field of invention [0001] The present invention relates to a method for producing a derivative having the effect of inhibiting vascular boosting converting enzyme (AngiotensinConverting Enzyme, hereinafter referred to as ACE); more specifically, the present invention relates to a N- [1-(S)-Ethyoxycarbonyl-3-phenylpropyl]-L-alanine N-carboxy anhydride (N-[1-(S)-ethyoxycarbonyl-3-phenylpropyl]-L-alanine N- Carboxy-anhydride, hereinafter referred to as NEPA-NCA) manufacturing method. [0002] Background of the invention [0003] Hypertension is the most common cardiovascular disease. In order to treat hypertension, the demand for antihypertensive drugs is increasing. Therefore, a relatively simple and convenient manufacturing method is required to produce compounds with ACE inhibitory effects. As antihypertensive agent (antihypertensive agent), wherein enalapril maleate (Enalapril Maleate) is as follows formula (II): [0004] [0005] It is a known and commonly used ant...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C269/04C07C271/22C07D263/44
CPCC07D263/44A61P43/00
Inventor 陈聪明刘育良赵雅洁吴建煌
Owner EVERLIGHT USA INC
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