JP2002284796A - Method for producing lisinopril dihydrate - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing industrially useful lisinopril dihydrate. SOLUTION: The lisinopril dihydrate is obtained in high yield and in high purity by suspension process of lisinopril anhydride in a hydrous alcohol.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION The present invention relates to a compound represented by the formula

[0002]

Embedded image

Lisinopril (Nα-((S) -1)
-Carboxy-3-phenylpropyl) -L-lysyl-L-
(Proline).

[0004]

2. Description of the Related Art Lisinopril is generally synthesized from each constituent amino acid by a method commonly used in peptide synthesis. This is optionally subjected to a purification step to obtain the target lisinopril dihydrate.

[0005] When refining and refining a crude product of Lisinopril with an organic solvent, the desired Lisinopril is obtained as an anhydride. Therefore, as a means for converting an anhydride to a hydrate, a treatment method for converting the anhydride into a hygroscopic hydrate in a conditioned atmosphere or a method for re-forming from water or a water-containing solvent as disclosed in JP-A-61-36297. Processing methods such as crystal purification and hydration are known.

[0006]

However, the above two methods of hydration have serious industrial disadvantages. In other words, the method of forming a hydrate into an anhydride under a conditioned atmosphere requires a long treatment time, and there is a difference in the rate of hydration between the surface and the inside of the anhydride. The recovery and the time required for processing vary, resulting in quality instability.

In the process of obtaining a hydrate by recrystallization purification from a water-containing solvent, the hydrate is uniformly hydrated. However, since the solubility of lisinopril in water is high, the recovery rate of the obtained hydrate is low. Is not economical.

Further, when hydration is performed directly from a crude form of Lisinopril using a water-containing solvent, the purification effect is lower than in the case of recrystallization purification once with an organic solvent and then hydration with a water-containing solvent. The material is of low purity. Therefore, a new means was required to efficiently obtain high-purity lisinopril hydrate.

[0009]

Means for Solving the Problems The inventors of the present invention have studied for solving the above-mentioned problems, and as a result, have developed a method for obtaining the desired lisinopril dihydrate in a high yield. That is, the present inventors have found that lizinopril dihydrate can be obtained with good yield and stable quality by recrystallizing and purifying a crude product of lizinopril from an organic solvent and then suspending the crude product in a hydroalcoholic solvent. The alcohol used in the present invention includes C1
C4 lower alcohol, preferably ethyl alcohol. The water content of the alcohol is selected from the range of 1 to 20%, preferably 5 to 15%. If the water content is too high, the recovery will be low, and if it is low, the rate of hydration will be slow.
Hereinafter, the present invention will be described in more detail with reference to examples.

[0010]

Example 1 Preparation of Lizinopril Anhydride 2.4 g of Lizinopril crude was mixed with 4.8 ml of ethyl acetate.
And purified by recrystallization from 7.3 ml of methyl alcohol.
1 g of Lizinopril anhydride was obtained (HPLC purity 99.
9%).

[0011]

Example 2 Preparation of Lizinopril dihydrate 1.6 g of Lizinopril anhydride was stirred in 8 ml of 10% aqueous ethyl alcohol at room temperature for 2 days, and the crystals were filtered to obtain 1.4 g of Lizinopril dihydrate. Was. The powder X-ray diffraction spectrum of the obtained lisinopril (FIG. 1) is the same as the powder X-ray diffraction spectrum of lisinopril dihydrate isolated by the preparation method described in JP-A-61-36297 (FIG. 2).
And matched.

[0012]

FIG.

[0013]

FIG. 2

[0014]

Reference Example Preparation of Lizinopril Dihydrate 2.4 g of Lizinopril crude was purified by recrystallization from 16 ml of 10% aqueous ethyl alcohol to obtain 1.4 g of Lizinopril dihydrate 0.52 g. (HPLC purity 98
%)

[0015]

According to the production method of the present invention, lisinopril dihydrate can be obtained with high yield and high purity by a simple operation.

 ──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Yasuhiro Takahashi 26 Kasaya, Ebizawa, Kodaka-cho, Soma-gun, Fukushima F-term in Konica Chemical Co., Ltd. 4H045 AA20 BA11 EA23

Claims (3)

[Claims] 1. Lizinopril (Nα-((S) -1-carboxy-3-phenylpropyl) -L-lysyl-L-proline)
A method for producing lisinopril dihydrate, comprising suspending the anhydride of the above in a hydroalcoholic solvent. 2. The method according to claim 1, wherein the alcohol used is ethyl alcohol. 3. The process according to claim 1, wherein the water content of the alcohol used is between 5 and 15%.