JPH08253497A - Peptide-type compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain in a highly diastereomerically selective way a new peptide- type compound useful as e.g. an intermediate for producing angiotensinase- inhibitory lisinopril, by reaction of proline benzyl ester with an N²-substituted- N⁶-acyllysine.

SOLUTION: This new compound is N²-(1S)-(1-ethoxycarbonyl-3-phenylpropyl)- N⁶-trifluoroacetyl-(L)-lysyl-(L)-proline benzyl ester (salt) of formula I, being useful as e.g. an intermediate for producing lisinopril which inhibits angiotensinase. This compound is obtained by the following procedure: (L)- proline benzyl ester hydrochloride of formula II is suspended in anhydrous dichloromethane followed by chilling to 0-5°C and then addition of dicyclohexylcarbodiimide followed by addition of N²-(1S)-(1-ethoxycarbonyl-3- phenylpropyl)-N⁶-trifluoroacetyl-(L)-lysine of formula III to carry out a reaction.

COPYRIGHT: (C)1996,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to the formula (II)

[Chemical 7] And a salt thereof and a method for producing the same.

Another object of the present invention is to provide a compound of formula (I
a)

Embedded image Formula (I) via an intermediate represented by

[Chemical 9] Is used in the production of lisinopril.

[0003]

BACKGROUND OF THE INVENTION Lisinopril and other related compounds that inhibit angiotensin converting enzyme were first described in EP Patent No. 12,401. In all the methods described therein, the final product is produced as a mixture of diastereoisomers, from which the desired S, S, S-diastereomer is isolated by chromatography.

One direction of further research is to achieve high diastereomeric selectivity. An example of this kind is E
No. 168,769. here,
Reacting ethyl 4-phenyl-2-oxobutyrate with N ⁶ -trifluoroacetyl-L-lysyl-L-proline,
Some N ^2- (1R) -diastereomer is formed with the main product N ^2- (1S) -diastereomer of formula (Ia). However, the separation of the individual diastereomers is a low yield of 51%.

Another direction of research is the combination of high diastereomeric selectivity with early diastereomeric separations in the synthesis. That is, according to the method described in HU Patent No. 207,837, formula (III)

[Chemical 10] The compound represented by is obtained in good yield in S, S-configuration. This compound is further described in HU Patent No. 207,736.
React with proline ethyl ester according to the No. However, although this step is easy to do in the laboratory, it has drawbacks on a factory scale due to the instability of proline ethyl ester.

[0006]

[Means for Solving the Problem] Surprisingly, the formula (II
A compound represented by the formula (IV)

[Chemical 11] When reacted with a proline benzyl ester of the compound represented by or its acid addition salt, S, represented by the formula (II),
It has been found that new compounds with S, S-configuration can be obtained without stability problems, even on a factory scale. If desired, the salts of the novel compounds may be, for example, hydrochloric acid, maleic acid,
It can be formed with succinic acid, oxalic acid, dibenzoyl tartaric acid and the like.

The reaction between the compound represented by the formula (III) and the compound represented by the formula (IV) can be carried out by a method known in peptide chemistry (for example, M. Bodanski: Principles of the Peptide Syn.
Thesis, Springer Verlag, Berlin, 1984).

According to a preferred embodiment of the reaction, the acid addition salt of the proline benzyl ester of formula (IV) is used as starting material, from which the base is released, in the presence of dicyclohexylcarbodiimide and an inert solvent, III)
To react with the compound shown by. Reaction is at room temperature or 0
It is performed in the range of 25 ° C to 25 ° C.

Alternatively, the compound of formula (III) is reacted with phosgene to form a suitable N-carboxylic acid anhydride, which is preferably reacted as such with the compound of formula (IV). This reaction is carried out in an inert organic solvent such as chlorinated hydrocarbon, ether or ester type solvent.

The novel compound of formula (II) obtained in 80-85% yield is then subjected to catalytic hydrogenation to give the compound of formula (Ia) in substantially quantitative yield. obtain. Subsequent hydrolysis of the compound of formula (Ia) by known methods provides formula (I), for example according to the method described in the abandoned EP patent 168,769. The present invention
Further, the present invention will be explained by the following examples, but the present invention is not limited to this.

[0011]

【Example】

Example ^{1 N 2 - (1S) -} (1- ethoxycarbonyl-3-phenylpropyl) -N ⁶ - trifluoroacetyl - (L) - lysyl - (L) - proline benzyl ester maleate salt [Formula (I
Compound represented by I)] N ^2- (1S)-(1-ethoxycarbonyl-3-phenylpropyl) -N ⁶ -trifluoroacetyl- (L) -lysine
[Compound represented by the formula (III)] 34.56 g (80 mmol) and (L) -proline benzyl hydrochloride [compound represented by the formula (IV)] 19.34 g (80 mmol) are added to dry dichloromethane 2
Suspend in 00 ml. The suspension is cooled to 0 ° C to 5 ° C and N-
8.8 ml (8.8 mmol) methylmorpholine, then dicyclohexylcarbodiimide 1 in 50 ml dry dichloromethane.
8 g (88 mmol) are added. The reaction mixture is maintained at 0 ° C. for 6 hours with stirring. The precipitate is filtered off and washed with dry dichloromethane. The mother liquor is extracted successively with water, 5% aqueous sodium carbonate solution, 1% aqueous acetic acid solution and water.
Then, it is dried over anhydrous magnesium sulfate and the solvent is distilled off. The oily residue is dissolved in 200 ml of methyl tert-butyl ether and 9.28 g (80 mmol) of maleic acid are added to the solution. After stirring for 3 hours at 0 ° C., the crystalline product is filtered off and washed with methyl-t-butyl ether at 0 ° C. to give 4.82 g (82%) of the title compound; mp 106-107 ° C.
^{_{[α] D 25 = -36 °}} (c = 1, methanol).

Example 2 [N ^2- (1S)-(1-ethoxycarbonyl-3-phenylpropyl) -N ⁶ -trifluoroacetyl- (L) -lysyl- (L) -proline] benzyl hydrochloride [formula] Compound represented by (II)] To a suspension of 21.6 g (50 mmol) of the compound represented by the formula (III) in 250 ml of dry dichloromethane, 20 g of phosgene is added.
(0.2 mol) is added at a temperature in the range of -10 ° C to -20 ° C. The reaction mixture is refluxed for 4 hours, then the solvent and excess phosgene are removed by evaporation and the residue (the corresponding N-carboxylic acid anhydride) is dissolved in 100 ml of dry dichloromethane. The solution is cooled to 0 ° C., 12.2 g (50 mmol) of (L) -proline benzyl ester hydrochloride, 11 ml (50 mmol) of N-methylmorpholine and 100 ml of dry dichloromethane.
Add to suspension consisting of ml. The temperature is maintained at 0 ° C. during the addition and then the reaction mixture is kept at 20 ° C. for 8 hours under stirring.
The reaction mixture is successively extracted with water, 5% aqueous potassium carbonate solution, 2% aqueous acetic acid solution and water. The organic layer is dried over anhydrous magnesium sulfate and the solvent is distilled off. The residue is dissolved in 150 ml of diethyl ether and 16.6 ml of 3N hydrochloric acid in ether are added to the solution to give a precipitate of the title compound.
Yield: 23.5 g (76%); mp 55-58 ° C; [α] _D ²⁵
= -35.3 [deg.] (C = 1, methanol).

In the above process, the maleate salt of the compound of formula (II) having the same physical properties as that obtained in Example 1 can also be prepared. The dibenzoyl tartrate salt of the compound represented by the formula (II) can also be produced by the above method; mp 59-64 ° C, [α] _D ²⁵ = -76 ° (c = 1, methanol).

Example 3 N ^2- (1S)-(1-ethoxycarbonyl-3-phenylpropyl) -N ⁶ -trifluoroacetyl- (L) -lysyl- (L) -prolinedibenzoyl tartrate [formula ( Compound of formula (II)] Compound 1 of formula (II) in 100 ml of dichloromethane
A solution of 4.71 g (20 mmol) is extracted with 80 ml of 5% aqueous potassium carbonate solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off. The residue is dissolved in 100 ml of ethanol and 10
Hydrogenate in the presence of 1 g of% palladium on carbon. When 1 equivalent of hydrogen has been taken up (about 15 minutes), the catalyst is filtered off and the filtrate is distilled off, yielding 10.5 g (about 100%) of product in the form of a base as a colorless oil. It can be converted to lisinopril dihydrate (see Example 4) or its dibenzoyltartaric acid without further purification as follows: 2.1 g (4 mmol) of product 10 ml of diethyl ether
dissolves in l. To this solution is added 1.5 g (4 mmol) of dibenzoyl- (L) -tartaric acid and the salt is precipitated by addition of n-hexane. The crystalline salt is filtered off and washed with n-hexane to give 3.45 g (96%) of the title compound: mp95-
^{_{97 ℃, [α] D 25}} = -64.5 ° (c = 1, methanol).

Example 4 Lisinopril dihydrate [Compound of formula (I)] Compound 1 of formula (II) in 100 ml of dichloromethane
A solution of 4.71 g (20 mmol) is extracted with 80 ml of 5% aqueous potassium carbonate solution, dried over anhydrous magnesium sulfate and the solvent is distilled off. Dissolve the residue in 100 ml of ethanol and
Hydrogenate in the presence of 1 g of 0% palladium on carbon. When 1 molar equivalent of hydrogen has been taken up, the catalyst is filtered off. The filtrate is concentrated to half volume, cooled to 0 ° C. and 23.4 ml (66 mmol) of 25% aqueous tetramethylammonium hydroxide solution are added to the concentrate. The mixture is kept under stirring at 20-25 ° C. for 8 hours, then 50 ml of ethanol are added and the pH is adjusted to 6.5 by adding 50% trifluoroacetic acid. The crystalline product is cooled to 0 ° C., filtered off and washed with a mixture of 85% ethanol and water to give 7.85 g of lisinopril dihydrate (89%). mp169-172 ° C,
^{_{[α] D 25 = -41.2 °}} (0.25M zinc acetate).

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Larslaw Dubai Hungary, Har-1073 Budapest, Kertess U 42-44 (72) Inventor Bella Stefko Hungary, Har-1117 Budapest, Orlai U 2 / Beh (72) Inventor Lajosh Kovac Chu Hungary, Har-1196 Budapest, Garbol Andoru 72 No. (72) Inventor Geza Ivagne Hungary, Har-2335 Takushoku, Arkotomagne No. 7 (72) ) Inventor Tamarsh Jüberhard Hungary, Har-1101 Budapest, Pratan Shor 13

Claims (7)

[Claims] 1. Formula (II): And a salt thereof. 2. A method for producing a compound represented by the formula (II) and a salt thereof, which comprises the formula (IV): A compound represented by the formula: A reaction with a compound represented by the formula (1) and, if desired, converting the obtained product into a salt by a method known per se. 3. The method according to claim 2, wherein the reaction is carried out in the presence of carbodiimide. 4. The compound of formula (III) is used in the form of its N-carboxylic acid anhydride.
The described method. 5. The method according to claim 2, wherein the reaction is carried out in an inert organic solvent. 6. A compound of formula (I): A process for producing lisinopril represented by the formula (II): A compound represented by the formula
a) embedded image A compound represented by the formula (1) and subjecting the compound to hydrolysis. 7. The method of claim 6, wherein the hydrolysis product is one that separates at its isoelectric point.