CN101302185B

CN101302185B - Preparation of trandolaprilat

Info

Publication number: CN101302185B
Application number: CN2007100404202A
Authority: CN
Inventors: 李建华; 钟静芬; 时惠麟; 龚欠林; 李小奎; 黄文锋
Original assignee: Shanghai Institute of Pharmaceutical Industry
Current assignee: Shanghai Institute of Pharmaceutical Industry
Priority date: 2007-05-08
Filing date: 2007-05-08
Publication date: 2010-09-01
Anticipated expiration: 2027-05-08
Also published as: CN101302185A

Abstract

The present invention discloses a method for preparing trandolaprilat, which enables trandolapril to be completely reacted in alkali, and then uses acid to adjust the pH value of the reactant liquor to between 2.55 and 3.5. The trandolaprilat is separated out. The product is obtained after filtration and drying. The method is simple and feasible in operation steps, high in yield, reduced in the use of organic solvent, reduced in cost, and environment-friendly.

Description

The preparation method of Trolaprilat

Technical field

The invention belongs to the pharmaceutical chemistry field, specifically, relate to the preparation method of Trolaprilat.

Background technology

In recent years, angiotensin-converting enzyme (ACE) inhibitor is just being brought into play more and more important effect in the control of multiple diseases such as hypertension, myocardial ischemia, heart failure, left ventricular hypertrophy, atherosclerosis, renal insufficiency.

Trolapril (Trandolapril) is by the exploitation of the Roussel Uclaf company of Germany (I), a kind of long lasting angiotensin-convertion enzyme inhibitor (ACEI) that the Sanofi-Aventis company of France produces, went on the market in France in 1993, be used for the treatment of hypertension, congestive heart failure and myocardial infarction.

Trolapril is a prodrug (Prodrug), generate active di-carboxylic acid Trolaprilat (Trandolaprilat) (II) through hydrolysis in vivo after the oral absorption, its chemistry (2S by name, 3aR, 7aS)-1-[(2S)-2-[[(1S)-1-(carboxyl)-3-hydrocinnamyl] amino]-the 1-oxopropyl] octahydro-1H-Indoline-2-carboxylic acid.

Spelling out in the record of European Pharmacopoeia about Trolapril needs control Trolaprilat content to be no more than 0.1%.Therefore need synthetic Trolaprilat to compare medicine, detect the purity of Trolapril.

The preparation method of the Trolaprilat of reporting among the US4933361 is: after Trolapril reacted in potassium hydroxide, transferring pH with hydrochloric acid was 4.0, evaporate to dryness, the residuum ethyl acetate extraction filters insolubles, then the evaporate to dryness ethyl acetate, the isopropyl ether crystallization, filter Trolaprilat.No yield and purity report.This method complex operation.

Summary of the invention

For solving the technical problem that does not prepare the method for Trolaprilat in the prior art easily, the present inventor has carried out a series of research to preparation process.Found that after the complete reaction, only need just has Trolaprilat directly to separate out (seeing Table 1) from reaction solution, thereby simplified the preparation of Trolaprilat widely by regulating pH Trolapril in alkali.

Table 1pH value is to the influence of the Trolaprilat amount of separating out

The pH value	4	3.5	3	2.7	2.4
The pH value	4	3.5	3	2.7	2.4	The amount of separating out of Trolaprilat	Do not have	On a small quantity	Increase	Reduce	Do not have

On this basis, we are that 3.55～2.55 these scopes make further research (seeing Table 2) to pH.

Table 2pH value is to the influence of Trolaprilat yield

The pH value	3.55	3.4	3.2	3.0	2.8	2.6	2.55
The pH value	3.55	3.4	3.2	3.0	2.8	2.6	2.55	Yield (%)	2.7	30.4	63.2	85.6	67.2	13.4	2.7

Therefore, the invention provides a kind of preparation method of Trolaprilat, make Trolapril complete reaction in alkali, transfer to 2.55～3.55 with sour pH then, separate out Trolaprilat, filter, dry promptly reaction solution.

Preferably, described pH is transferred to 2.8～3.2, more preferably, described pH is transferred to 2.9～3.1, most preferably, described pH is transferred to 3.0.

Described alkali is preferably sodium hydroxide, and described acid is preferably hydrochloric acid.

With respect to prior art, the advantage of the inventive method is as follows:

1. operation steps is simple;

2. yield is higher;

3. organic solvent uses and reduces, and reduces cost the protection environment.

Embodiment

Embodiment 1

4.0g (9mmol) add 20ml water and 4mol/L sodium hydroxide 40ml in the Trolapril, molten clear, stirred 2.5 hours, the TLC demonstration reacts completely, and dripping 2mol/L hydrochloric acid accent pH is 3.0, filters out the white solid of separating out, dry white solid 3.2g, yield: 85.6%.Ultimate analysis (C ₂₂H ₃₀N ₂O ₅) measured value (calculated value, %): C65.43 (65.65), H7.65 (7.51), N6.68 (6.96).MS(m/z)：403(M+1) ⁺，425(M+Na) ⁺。

Embodiment 2

4.0g (9mmol) add 20ml water and 4mol/L sodium hydroxide 40ml in the Trolapril, molten clear, stirred 2.5 hours, the TLC demonstration reacts completely, and dripping 2mol/L hydrochloric acid accent pH is 3.2, filters out the white solid of separating out, dry white solid 2.4g, yield: 63.2%.Ultimate analysis (C ₂₂H ₃₀N ₂O ₅) measured value (calculated value, %): C65.53 (65.65), H7.63 (7.51), N6.58 (6.96).MS(m/z)：403(M+1) ⁺，425(M+Na) ⁺。

Embodiment 3

4.0g (9mmol) add 20ml water and 4mol/L sodium hydroxide 40ml in the Trolapril, molten clear, stirred 2.5 hours, the TLC demonstration reacts completely, and dripping 2mol/L hydrochloric acid accent pH is 2.8, filters out the white solid of separating out, dry white solid 2.5g, yield: 67.2%.Ultimate analysis (C ₂₂H ₃₀N ₂O ₅) measured value (calculated value, %): C65.40 (65.65), H7.60 (7.51), N6.69 (6.96).

Embodiment 4

4.0g (9mmol) add 20ml water and 4mol/L sodium hydroxide 40ml in the Trolapril, molten clear, stirred 2.5 hours, the TLC demonstration reacts completely, and dripping 2mol/L hydrochloric acid accent pH is 2.6, filters out the white solid of separating out, dry white solid 0.5g, yield: 13.4%.Ultimate analysis (C ₂₂H ₃₀N ₂O ₅) measured value (calculated value, %): C65.63 (65.65), H7.65 (7.51), N6.78 (6.96).

Embodiment 5

4.0g (9mmol) add 20ml water and 4mol/L sodium hydroxide 40ml in the Trolapril, molten clear, stirred 2.5 hours, the TLC demonstration reacts completely, and dripping 2mol/L hydrochloric acid accent pH is 2.55, filters out the white solid of separating out, dry white solid 0.1g, yield: 2.7%.Ultimate analysis (C ₂₂H ₃₀N ₂O ₅) measured value (calculated value, %): C65.60 (65.65), H7.60 (7.51), N6.68 (6.96).

Embodiment 6

4.0g (9mmol) add 20ml water and 4mol/L sodium hydroxide 40ml in the Trolapril, molten clear, stirred 2.5 hours, the TLC demonstration reacts completely, and dripping 2mol/L hydrochloric acid accent pH is 3.5, filters out the white solid of separating out, dry white solid 0.6g, yield: 15.4%.Ultimate analysis (C ₂₂H ₃₀N ₂O ₅) measured value (calculated value, %): C65.53 (65.65), H7.45 (7.51), N6.78 (6.96).

Embodiment 7

4.0g (9mmol) add 20ml water and 4mol/L sodium hydroxide 40ml in the Trolapril, molten clear, stirred 2.5 hours, the TLC demonstration reacts completely, and dripping 2mol/L hydrochloric acid accent pH is 3.55, filters out the white solid of separating out, dry white solid 0.1g, yield: 2.7%.Ultimate analysis (C ₂₂H ₃₀N ₂O ₅) measured value (calculated value, %): C65.47 (65.65), H7.55 (7.51), N6.69 (6.96).

Claims

1. the preparation method of Trolaprilat makes Trolapril complete reaction in alkali, transfers to 2.8～3.2 with sour pH value with reaction solution then, separates out Trolaprilat, filters, dries promptly.

2. preparation method as claimed in claim 1, wherein said pH value transfers to 2.9～3.1.

3. preparation method as claimed in claim 2, wherein said pH value transfers to 3.0.

4. preparation method as claimed in claim 1, wherein said alkali is sodium hydroxide.

5. preparation method as claimed in claim 1, wherein said acid is hydrochloric acid.