PL154625B1 - Method of obtaining l-alanyl-l-proline - Google Patents

Abstract

Prodn. of L-alanyl-L-proline derivs. of formula (I), where R is ethyl or hydrogen, or their pharmaceutically acceptable salts, involves reacting derivs. of proline and N(1(S)-ethoxycarbonyl- 3-phenylpropyl)- L-alanine in solvent at (-5) to (20) deg.C. The proline deriv. comprises N-O-bis-trimethylsilyl- L-proline of formula (II). The deriv. of N(1(S)-ethoxycarbonyl- 3-phenyl-propyl)- L-alamine has formula (III), where Het is imidazolyl-1 or benzothiazolyl-2-thio. The condensn. reaction is carried out in non-polar organic solvent, esp. in dioxane, tetrahydrofuran or methylene chloride. When required, the obtd. cpd. of formula (I) in which R is ethyl is hydrolysed to obtain a cpd. of formula (I) in which R is hydrogen. Yield is 76%; m.pt. is 146-152 deg.C. When the maleate is required, a cpd. of formula (I) in which R is ethyl is treated with maleic acid. Yield is 83% and m.pt. is 143-147 deg.C.

Description

RZECZPOSPOLITA PATENT DESCRIPTION 154 625 POLAND

OFFICE

PATENT

RP

Additional patent to patent No. - Filed: 89 07 11 (P. 280 526)

Priority: 88 07 13 Yugoslavia

Application announced: 90 02 05

Patent description published: 1992 04 30

Int. Cl. ^s C07K 5/06

Inventors: Marjo Merslavić, Pavel Zupet, Vesna Flego, Miha Japelj, Branko Stanovnik, Janja Cirnski

The holder of the patent: KRKA tovarna zdravil, n.sol.o.,

Novo Mesto (Yugoslavia)

Method for the production of L-alanyl-L-proline derivatives

The invention relates to a process for the preparation of L-alanyl-L-proline derivatives of the general formula I wherein R is ethyl or hydrogen, as well as their pharmacologically acceptable salts.

The compound of general formula I inhibits the conversion of angiotensin I decapeptide to angiotensin II, which acts as a blood pressure regulator. The enzyme renin, which is secreted by the kidneys, acts on one of the peptides found in blood plasma, i.e. angiotensinogen, the substrate of renin. It is secreted by the liver, and from this substrate the decapeptide angiotensin I is cleaved. Angiotensin I is converted into angiotensin II by the action of the enzyme angiotensin. The compound of general formula I, however, inhibits the enzyme angiotensidase and is suitable for use in the treatment of cardiovascular diseases, in particular hypertension.

According to known methods, the L-alanyl-L-proline derivatives of formula 1 are prepared by condensation of ethyl 4-phenyl-2-ketobutyrate with L-alanyl-L-proline and hydrogenation (US Patent No. 4,374,829). or by condensation of N-carboxyanhydride-N- (1) Setoxycarbonyl-3-phenylpropyl) -L-alanine with an N-proline salt (European Patent Application No. A 215,335).

There was a need to develop a new process for the preparation of L-alanyl-Lproline derivatives of the formula I, which would be technologically and economically more advantageous than the known methods.

The process for the preparation of the L-alanyl-L-proline derivatives of the general formula I, in which R is ethyl or hydrogen, and also their pharmacologically acceptable salts, according to the invention, consists in that N, O-bis (thi'-methylsilyl) -L / proI'in of the formula 2 is condensed with the N- (1SH-e-xycaroyl-o-3-phenylpropyl) -L-alamine derivative of the general formula 3 in which Het is imidazolyl-1 or 2- thiobenzothiazolyl, in non-polar organic solvents such as dioxane, tetrahydrofuran or methyl chloride, preferably tetrahydrofuran, at a temperature of -10 ° C to 20 ° C, and the resulting compound of formula I, where R is ethyl, is optionally hydrolyzed to a compound of Formula 1, wherein R is hydrogen.

154 625

The process according to the invention differs from the known processes in that N, Obis (1) and (N, N-methylsilyl) -L-pyrroline of formula II is used which is condensed with an amide or thioester of formula

3. It is advantageous in that the reaction time is shorter and the reaction is qualitative.

The starting compounds of formulas 2 and 3 are commercially available or can be prepared by known methods.

The process of the invention is illustrated by the following examples.

Example 1 N- (lSS) -ethoxycarbonyl-3-phenylpropyl) -L-alanyl-L-proline maleate.

To a solution of 2.8 g of N- (lSS) -elkxyaroyl-3-fer) ylpropyl) -L-alaioyl in 40 ml of methylene chloride cooled to -5 ° C, 2.44 g of Ν, Ν'-kaabonyldiimidazble are added and it is stirred for 3 hours at a temperature from -5 ° C to 0 ° C. Meanwhile, N, O-bis (trimethylsilyl) -L-proline is prepared by adding 4.2 ml of triethylamine and 3.8 ml of taymethylchlorosilau to a suspension of 1.72 g of L-paolin in 40 ml of methylene chloride, followed by stirring for 0. 5 hours at 40 ° C followed by 2 hours at room temperature. From the thus prepared and cooled N, OriS ( ⁽ 16) [mu] mets1bSililb) -L-prolion, the resulting taitylbaminine hydrochloride is filtered off and the filtrate is poured into N- (lSS) -ethoxskaaroyl-) - 3-phenylpropyl) -L-alanylimidazole. Stirring is continued at -5 ° C to 0 ° C. After high-performance liquid chromatography revealed the absence of starting material, methylene chloride was evaporated off. 40 ml of water and 15 ml of ethyl acetate are added to the residue and the pH is adjusted to 8.7 with 2 ° NaOH. The aqueous layer was washed once more with ethyl acetate (10 ml) then added NaCl until saturation and 15 ml ethyl acetate. The pH was adjusted to 4.2 with HCl (1: 1), the layers were separated and the aqueous layer was extracted with ethyl acetate (7 x 8 ml). The ethyl acetate layers are dried with Na2SO4 and N- (lSS) -ethoxy-carboxonyl-3-phenylpropyl) -L-alanyl-L-proline, 1.2 g of maleic acid are precipitated. The precipitated material is filtered off and dried in a vacuum oven at 40 ° C. The title product (4.1 g, 83%) is obtained with mp 143-147 ° C.

Example II. 0.85 g of 2-mercaptobeozothiazole is added to a solution of N- (lSS) -ethxocarOnyyl-3-phenylpropnlo) -L-alanine (1.4 g) in 40 ml of tetrahydro-uranium, the resulting mixture is cooled to 0 ° C and then By addition of 1.2 g of Ν, dw'-disucnklohexylcarbodiimide, the resulting mixture is stirred at -5 ° C to 0 ° C for 3 hours. The released dicyclbhexylurea is filtered off and the thus obtained ester of 2-mercaptbrenzbthiazole and N- (lSS) -ethkskcarbnyyl-3-pheonlopropnlo) -Lalaoion is added dropwise to the cooled (0 ° C) N, O-bis (trimethyltrsilyl), -L-prissilyl) rope. previously prepared by adding triethylamines (2.8 ml) and triethylchlorosilane (2.6 ml) to a suspension of L-proline (1.1 g) in tetrahydro-uranifium (40 ml) and stirring at room temperature for 3 hours. Stirring is continued until no starting material is detected by high performance liquid chromatography. The tetrahydrbfurao is evaporated off, water (20 ml) and methylene chloride (10 ml) are added to the residue, pH is adjusted to 8.7 with 2N sodium hydroxide and the layers are separated. Sodium chloride is added to the aqueous layer until saturation, the aqueous layer is covered with ethyl acetate (15 ml) and the pH is adjusted to 4.2 by adding hydrochloric acid. The layers are separated and the aqueous layer is extracted with ethyl acetate (4x8 ml). The combined acetate layers were dried with sodium sulfate and N- (lSS) -ethoxyarnyl-3-phenylpropyl) -L-alanyl-L-paoliy was precipitated with maleic acid (0.6 g). The precipitated material is filtered off and dried under vacuum at 40 ° C. There was thus obtained the title product (1.5 g, 61%).

Example III. N— / ΊSS / -aar0c) xy-3-eenylpropyl / -I3-alans <o-L · prr) rope.

N- (lSS) -ethxycarbonyl-3-phenylpropyl) -L-alanyl-L-proline (Ig) prepared according to Example 1 is dissolved in ethanol (5 ml) and water (5 ml) containing sodium hydroxide (320 mg) and stirred until the hydrolysis is complete. After completion of the hydrolysis, the solvent is evaporated off under reduced pressure. The residue is dissolved in water (10 ml) saturated with sodium chloride and the resulting solution is covered with ethyl acetate (10 ml) and the pH is adjusted to pH

4.2 with hydrochloric acid solution. The aqueous layer is extracted with ethyl acetate (2 x 10 ml). The combined acetate layers are then dried and evaporated. There was thus obtained the title product (0.71 g, 76%), mp. about 146-152 ° C.

Claims (1)

Patent claim A process for the preparation of L-alanyl-L-proline derivatives of the general formula I in which R is ethyl or hydrogen, as well as their pharmacologically acceptable salts, characterized in that the N, O-bis (trimethylsilyl) -L-proline of the formula II is condensed with the N- (1 (S) ethoxycarbonyl-3-phenylpropyl) -L-alanine derivative of general formula III, in which Het is imidazolyl-1 or 2-thiobenzothiazolyl, in non-polar organic solvents such as dioxane, tetrahydrofuran or methylene chloride, preferably tetrahydrofuran, at a temperature from -10 ° C to 20 ° C and the resulting compound of formula 1, wherein R is ethyl, is optionally hydrolyzed to a compound where R is hydrogen. coor O> Ol2CH CH ₂ NH CH CO fi J Cl3 and COOH (H ₃ C) ₃ SiN COOSilCHjlj Formula 2 ~ COOC ₂ H ₅ <jC ^Q H ² CH ² CH NH CH CO Het CH3 Formula 3 Department of Publishing of the UP RP. Circulation 100 copies Price: PLN 3,000