DD284028B5 - Process for the preparation of L-alanyl-L-proline derivatives - 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

wherein R is ethyl or hydrogen, and their pharmaceutically acceptable salts, characterized in that Ν, Ο-Bistrimethylsilyl-L-proline of the formula II

(H ₃ C) ₃ Si N

C00Si (CH ₃ ) ₃ with an N- / 1 (S) -ethoxycarbonyl-3-phenylpropyl / L-alanine derivative of the general formula

COOC ₂ H ₅

CH ₂ CH ₂ CH NH CH CO Het CH-

'3

wherein Het an imidazole-1 or 2-thiobenzothiazole radical, in nonpolar organic solvents, such as dioxane, tetrahydrofuran, methylene chloride, preferably tetrahydrofuran, in a temperature range of -10 to +20 ° C condensed and optionally the resulting compound of formula I. in which R is ethyl, hydrolyzed into the compound of formula I wherein R is hydrogen.

Field of application of the invention

The present invention belongs to the field of peptide chemistry and relates to a process for the preparation of L-alanyl-L-proline derivatives of the formula

COOR CH ₀ GH ₀ CH BH CH CO

CH ₃

COOH

wherein R is ethyl or hydrogen, and their pharmaceutically acceptable salts. The compound of general formula I inhibits the conversion of the decapeptide angiotensin I to angiotensin II, which plays a role as a blood pressure regulator. The enzyme renin excreted by renin has an effect on one of the plasma proteins, renin angiotensinogen. The latter is excreted by the liver and decapeptide angiotensin I is cleaved from this substrate. Angiotensin I is converted to angiotensin II by the enzyme angiotensinase. The compound of the general formula I inhibits the enzyme angiotensinase and is suitable for the treatment of cardiovascular diseases, in particular hypertension.

-2-284 Characteristic of the known state of the art

In known processes, L-alanyl-L-proline derivatives of the formula I are obtained by condensation of ethyl 4-phenyl-2-oxobutanoate and L-alanyl-L-proline and hydrogenation (US Pat. No. 4,374,829) or by condensation of N-carboxyanhydride N- / 1 (S) -ethoxycarbonyl-3-phenylpropyl / -L-alanine with an L-proline salt (EP-A 215 335).

Object of the invention

The invention provides a new, technologically and economically improved process for the preparation of L-alanyl-L-proline derivatives which have pharmacologically valuable properties.

Explanation of the essence of the invention

The present invention has for its object to provide a new technologically and economically improved process for the preparation of L-alanyl-L-proline derivatives of the formula I available.

The invention relates to the process for the preparation of L-alanyl-L-proline derivatives of general formula I.

COOR

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CH ₃

COOH

wherein R is ethyl or hydrogen, and their pharmaceutically acceptable salts is carried out by reacting Ν, Ο-Bistrimentylsilyl-L-proline of the formula II

(H ₃ C) ₃ S;

COOSi (CH ₃ ) ₃

with an N- / 1 (S) -ethoxycarbonyl-3-phenylpropyl / -L-alanine derivative of the general formula III

COOC ₂ H ₅

NHCHCOHet ⁱⁿ

wherein Het an imidazole-1 or 2-thiobenzothiazole radical, in nonpolar organic solvents such as dioxane, tetrahydrofuran, methylene chloride, preferably tetrahydrofuran, in a temperature range of -10 to +20 ⁰ C condensed and optionally the resulting compound of formula I. in which R is ethyl, hydrolyzed into the compound of formula I wherein R is hydrogen.

The present process differs from known processes in the use of N, O-bistrimethylsilyl-L-proline of formula II which is condensed with an amide or a thioester of formula III. The method has the following advantages:

The condensation time is shorter, the reaction proceeds quantitatively.

The starting compounds II and III are commercially available or can be prepared in a known manner.

The method is explained in more detail by means of the following examples, but by no means limited thereto.

embodiments example 1

N- / 1 (S) -ethoxycarbonyl-3-phenylpropyl / -L-alanyl-L-proline Maleinsalz

A cooled to -5 ° C solution of 2.8 g of N- / 1 (S) -ethoxycarbonyl-3-phenylpropyl / -L-alanine in 40 ml of methylene chloride is treated with 2.44 g of Ν, Ν'-carbonyldiimidazole and 3 Stirred at a temperature of 0 to -5 ⁰ C hours. Meanwhile, will

Ν, Ο-Bistrimethylsilylyl-L-proline prepared such that admixed with a suspension of 1.72 g of L-proline in 40 ml of methylene chloride with 4.2 ml of triethylamine and 3.8 ml of trimethylchlorosilane and half an hour at 40 ° C and Stirred for 2 hours at room temperature. From such prepared and cooled N, O-Bistrimethylsilylyl-L-proline, the resulting triethylamine. HCI and filtered to N- / 1 (S) -ethoxycarbonyl-3-phenylpropyl / -L-alanyl-imidazole poured. The mixture is stirred at a temperature of 0 to -5 ⁰ C. If it is determined by HPLC that the starting compound is no longer present, methylene chloride is evaporated. The residue is treated with 40 ml of water and 15 ml of ethyl acetate and the pH is adjusted to 8.7 with 2 N NaOH. The aqueous layer is washed once more with 10 ml of ethyl acetate, mixed with NaCl to saturation and with 15 ml of ethyl acetate. pH is adjusted to 4.2 with HCl (1: 1), the layers are separated and the aqueous layer is extracted 7 more times with 8 ml of ethyl acetate. The ethyl acetate layers are dried with Na ₂ SO ₄ and N- / 1 (S) -ethoxycarbonyl-3-phenylpropyl / -L-a-Janyl-L-proline is precipitated with 1.2 g of maleic acid. The precipitate is filtered off and dried in a vacuum dryer at 40 ^° C. There are 4.1 g (83%) of the title product with mp 143 to 147 ⁰ C obtained.

Example 2

To a solution of 1.4 g of N- / 1 (S) -ethoxycarbonyl-3-phenylpropyl / -L-alanine in 40 ml of tetrahydrofuran is added 0.85 g of 2-mercaptobenzothiazole, cooled to 0 ^° C., 1.2 g of N, N'-dicyclohexylcarbodiimide are added and the mixture is stirred for 3 hours at a temperature of -5 to 0 ° C. The precipitated dicyclohexylurea is filtered off and the thus produced ester of 2-mercaptobenzothiazole and N- / KS) -ethoxycarbonyl-3-phenylpropyl / -L-alanine to chilled (on 0 ⁰ C) Ν, Ο-Bistrimethylsilyl-L-proline , which was previously prepared by adding a suspension of 1.1 g of L-proline in 40 ml of tetrahydrofuran with 2.8 ml of triethylamine and 2.6 ml of trimethylchlorosilane and stirring for 3 hours at room temperature, added dropwise. The stirring is continued until after HPLC, the starting compound is no longer present. Tetrahydrofuran is concentrated, the residue is treated with 20 ml of water and 10 ml of methylene chloride, pH adjusted to 8.7 with 2N sodium hydroxide and the layers are separated. The aqueous layer is brought to saturation with sodium chloride, covered with 15 ml of ethyl acetate and pH is adjusted to 4.2 with hydrochloric acid. The layers are separated and the aqueous layer is extracted with 4 χ 8 ml of ethyl acetate. The combined ethyl acetate layers are dried with sodium sulfate and N- / 1 (S) -ethoxycarbonyl-3-phenylpropyl / -L-alanyl-L-proline is precipitated with 0.6 g of maleic acid. The precipitate is filtered off and dried in vacuo at 40 ⁰ C. There are obtained 1.5 g (61%) of the title product.

Example 3

N- / 1 (S) -carboxy-3-phenylpropyl / -L-alanyl-L-proline

1 g of N- / 1 (S) -ethoxycarbonyl-3-phenylpropyl / -L-alanyl-L-proline obtained according to Example 1 is dissolved in 5 ml of ethanol and 5 ml of water,

containing 320 mg of sodium hydroxide, dissolved and stirred until complete hydrolysis. After completion of the hydrolysis, the solvent is concentrated under reduced pressure. The residue is dissolved in 10 ml of water, which is saturated with sodium chloride, covered with 10 ml of ethyl acetate and the pH is adjusted to 4.2 with a solution of hydrogen chloride. The aqueous layer is extracted with ethyl acetate (2 × 10 ml), and the combined ethyl acetate layers are dried and concentrated.

There are obtained 0.71 g (76%) of the title product with mp. About 146 to 152 ⁰ C.

Claims (1)

Claim: Process for the preparation of L-alanyl-L-proline derivatives of the general formula COOR CH ₂ CH ₂ CH NH CH CO N CH ₃ COOH