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Method for preparing lisinopril intermediate

An intermediate, lysine technology, applied in the field of preparation of lisinopril intermediates, can solve the problems of high safety protection cost, easy spontaneous combustion, low product yield, etc., to avoid toxic by-products, increase content, reduce cost effect

Inactive Publication Date: 2012-08-01
JIANGXI DIRUI SYNTHETIC CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The reductive amination reaction in routes 1 and 2 has also been reported using Raney nickel (Raney Ni) or palladium carbon (Pd / C) to catalyze hydrogenation (see J.Org.Chem., 1988,53,837-844, and CN1140708A) , although the method of catalytic hydrogenation is environmentally friendly, but hydrogenation needs to be pressurized, the cost of equipment safety protection is high, the catalyst is easy to spontaneously ignite during the post-treatment process, and the product yield is not high (≤50%)

Method used

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  • Method for preparing lisinopril intermediate

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] This embodiment adopts the following steps:

[0023] 32.4g (0.095mol) N e -(trifluoroacetyl)-L-lysine-L-proline with 23.05g (0.109mol) NaBH(OAc) 3 , 5.1ml (0.088mol) glacial acetic acid, 200ml 1,2-dichloroethane mixed, stirred well; cooled to 5 oC , then dropwise add a mixture of 19.6g (0.096mol) ethyl α-oxophenylbutyrate dissolved in 25ml 1,2-dichloroethane, drop it for about 30min, and then in 10 oC React at room temperature for 1 h, then react at room temperature for 4 h, TLC (thin layer chromatography) to detect the reaction end point; add 100 ml of water, separate the liquids, and extract the aqueous phase with dichloroethane (100ml×2), each time with dichloroethane 100 ml of alkanes, extracted twice, combined the organic phases, dried with anhydrous sodium sulfate, removed the solvent, and recrystallized the residue with methyl tert-butyl ether / n-hexane to obtain 35.8 g of white crystals, yield 71.2%, m.p.75.3 -77.4 oC , [a] 25 405 -53.8 o [a] 25 D ...

Embodiment 2

[0029] N e -(tert-butoxycarbonyl)-N a -Synthesis of [(S)-1-(ethoxycarbonyl)-3-phenylpropyl]-L-lysine-L-proline (Ⅰb)

[0030] This embodiment includes the following steps:

[0031] 16.29g (47.5mmol) N e -(tert-butoxycarbonyl)-L-lysine-L-proline with 21.57g (54.5mmol) NaBH(OAc) 3 , 2.6ml (44.7mmol) glacial acetic acid, 100ml 1,2-dichloroethane mixed, stirred evenly; cooled to 5 oC , and then dropwise added a mixture of 9.8g (48mmol) ethyl α-oxobenzenebutyrate dissolved in 15ml 1,2 dichloroethane, and dropped it in about 20 minutes. oCReact at room temperature for 30 minutes, then react at room temperature for 4 hours, TLC to detect the end point, add 50ml of water, separate the liquids, extract the aqueous phase with dichloroethane (50ml×2), combine the organic phases, dry over anhydrous sodium sulfate, and remove the solvent. The residue was recrystallized from ethyl acetate / n-hexane to obtain 17.4g, yield 68.5%, white crystal, m.p. 81.3-83.1 oC .

[0032] The N prepa...

Embodiment 3

[0034] N e -(Trifluoroacetyl)-N a -Synthesis of [(S)-1-(ethoxycarbonyl)-3-phenylpropyl]-L-lysine-L-proline (Ⅰa)

[0035] This embodiment adopts the following steps:

[0036] 16.2g (47.5mmol) N e -(trifluoroacetyl)-L-lysine-L-proline, 9.9g (47.9mmol) ethyl a-oxophenylbutyrate, 2.6ml glacial acetic acid (44.7mmol) and 150ml dichloromethane were mixed , stir well; cool to 5 oC , then dropwise added 11.6g (55mmol) NaBH(OAc) 3 Dissolve the mixed solution in 75ml of dichloromethane solution, drop it in about 30min, in 10 oC React at low temperature for 30 minutes, then warm up to room temperature and react for 2.5 hours, and detect the end point by TLC; after the reaction is completed, add 50ml of water, separate the liquids, extract the aqueous phase with dichloromethane (50×2ml), combine the organic phases, and dry them with anhydrous sodium sulfate. The solvent was removed, and the residue was recrystallized from methyl tert-butyl ether / n-hexane to obtain 17.6 g of white ...

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Abstract

The invention relates to a method for preparing a lisinopril intermediate. The method comprises the following steps of: mixing and stirring N-protecting group-L-lysine or N-protecting group-L-lysine-L-proline, sodium triacetoxyborohydride, glacial acetic acid and a reaction solvent uniformly; cooling, dripping a mixed solution of alpha-oxo-phenylbutyrate and the reaction solvent, and continuing to react; reacting at room temperature for 2 to 6 hours; and adding water, extracting, recrystallizing, filtering and drying to obtain the lisinopril intermediate, wherein the sequence of dripping raw materials and the sequence of reaction can be adjusted. According to the method, NaBH3CN is replaced by NaBH(OAc), so that the generation of toxic side products is avoided; and the method is environment-friendly, and the reaction is performed under normal pressure, so that the efficiency and safety are improved, the content of an S isomer in the obtained product is improved, and the cost is reduced.

Description

technical field [0001] The present invention relates to a kind of preparation method of lisinopril intermediate, relate in particular to a kind of N e -Protecting group-N a - a preparation method of [(S)-1-(ethoxycarbonyl)-3-phenylpropyl]-L-lysine-L-proline compound. Background technique [0002] N e -Protecting group-N a -[(S)-1-(ethoxycarbonyl)-3-phenylpropyl]-L-lysine-L-proline (N e -Trifluoroacetyl-N a -[(S)-1-(ethoxycarbonyl)-3-phenylpropyl]-L-lysine-L-proline Ia, N e -tert-butoxycarbonyl-N a -[(S)-1-(ethoxycarbonyl)-3-phenylpropyl]-L-lysine-L-proline Ib,) is a new type of angiotensin-converting enzyme inhibitor lisinopril (lisinopril) an important intermediate. In the prior art, b-ethyl benzoyl acrylate and ethyl a-oxobenzenebutyrate are used as starting materials to synthesize respectively, and the synthetic route of using ethyl a-oxobenzenebutyrate as raw materials is as follows: [0003] [0004] In Route 1, the reductive amination of ethyl α-oxophenylbu...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/068C07K1/107C07C233/47C07C231/12
CPCY02P20/55
Inventor 吴健龙姚峰
Owner JIANGXI DIRUI SYNTHETIC CHEM
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