SI8811355A - Process for preparing of L-alanine-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

(57) A process for the preparation of L-ala derivatives is described and condensed with the N- [1 (S) -ethoxycarbonyl-3nyl-L-proline derivative of formula I of phenipropyl / -L-alanine of general formula III

COOH

Fig. 8811355 A in which R is ethyl or hydrogen, and their pharmaceutically acceptable salts, wherein the N, O-bistrosylsilyl-L-proline of formula II in which Het is a residue of imidazole-1 or 2-thiobenzothiazole, in non-polar organic solvents, as dioxane, tetrahydrofuran, methylene chloride, preferably tetrahydrofuran, in the temperature range from -10 to +20 degrees Celsius, and optionally the compound of formula I in which R is ethyl is hydrolyzed to a compound of formula I wherein R is hydrogen.

(HjCJjSiN

C00S1 (CH ₃ ) j

KRKA, drug factory, n.sol.o.

A process for the preparation of L-alanyl-L-proline derivatives

FIELD OF THE INVENTION

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

COOH in which R is ethyl or hydrogen, and pharmaceutically acceptable salts thereof.

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

A technical problem

There was a need to find a new process for the preparation of an L-alanyl-L-proline derivative of Formula I that would be more technologically advantageous and more economical than the known methods.

The state of the art

For known methods, the preparation of L-alanyl-L-proline of formula I is prepared by condensation of ethyl-4-phenyl-2-oxobutanoate and L-alanyl-L-proline and by hydrogenation (US-PS 4 374 829) or by condensation of N-carboxyanhydride-N - / 1 (S) -ethoxycarbonyl-3-phenylpropyl / -L-alanine with L-proline salt (EP 215 335).

Description of a solution to a technical problem with an implementation example

A process for the preparation of L-alanyl-L-proline derivatives of general formula I

COOH

I in which R is ethyl or hydrogen, and their pharmaceutically acceptable salts are carried out such that N, O-bistrimethylsilyl-L-proline of formula II

C00Si (CH ₃ ) _{3 is} condensed with the N- / 1 (S) -ethoxycarbonyl-3-phenylpropyl / L-alanine derivative of the general formula III C00C ₂ H ₅

C'rLCH „CH NH CH COHet

III in which Het represents a residue of imidazole-1 or 2-thiobenzothiazole, in non-polar organic solvents such as dioxane, tetrahydrofuran, methylene chloride, preferably tetrahydrofuran, in a temperature range of -10 to +20 ° C, and optionally a compound of formula I, wherein R is ethyl is hydrolyzed to a compound of formula I wherein R is hydrogen.

The present process differs from the known methods in that N, O-bistrimethylsilyl-L-proline of the formula is used

II which is condensed with an amide or thioester of formula

III. It has the following advantages: the condensation time is shorter and the reaction proceeds quantitatively.

The starting compounds II and III are commercially available, respectively.

they can be prepared in a familiar way.

The procedure is explained in more detail by the following embodiments, but is not limited in any way.

EXAMPLE 1

N- / 1 (S) -ethoxycarbonyl-3-phenylpropyl / -L-alanylL-proline maleic salt

To a solution of 2.8 g of N- / 1 (S) -ethoxycarbonyl-3-phenylpropyl / L-alanine in 40 ml of methylene chloride cooled to -5 ° C was added 2.44 g of N, N'-carbonyldiimidazole and allowed to stir 3 hours at 0 to -5 ° C. Meanwhile, N, O-bistrimethylsilylyl-L-proline is prepared by adding 4.2 ml of triethylamine and 3.8 ml of trimethylchlorosilane to a suspension of 1.72 g of L-proline in 40 ml of methylene chloride and allowing to stir for half an hour at 40 ° C and 2 hours at room temperature. From the thus prepared and cooled N, O-bistrimethylsilylyl-L-proline, the resulting triethylamine.HCl was filtered off and poured into N- (S) -ethoxycarbonyl-3-phenylpropyl / -L-alanyl-imidazole. It is stirred further at a temperature of 0 to -5 ° C. When the starting compound is no longer present by HPLC, the methylene chloride is evaporated. 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 N NaOH. The aqueous layer was washed again with 10 m ethyl acetate, NaCl was added to saturation and 15 ml ethyl acetate. The pH was adjusted to 4.2 with HC1 (1: 1), the layers were separated and the aqueous layer was further separated

It is extracted 7 times with 8 ml of ethyl acetate each. The ethyl acetate layers were dried over Na2SO ₄ and N / l (S) -ethoxycarbonyl-3-phenylpropyl / -L-alanyl-L-proline is precipitated with 1.2 g of maleic acid. The precipitate was filtered off and dried in a vacuum oven at 40 ° C. 4.1 g (83%) of the title product are obtained from the soil. 143 to 147 ° C.

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

N, N′-dicyclohexylcarbodiimide and allowed to stir for 3 hours at -5 to 0 ° C. The separated dicyclohexylurea is filtered off and the 2-mercaptobenzothiazole and N- (S) -ethoxycarbonyl-3-phenylpropyl / -L-alanine ester thus prepared is added dropwise to the cooled (at C) N, O-bistrimethylsilyl-L-proline, which was prepared by suspending 1.1 g of L-proline in 40 ml of tetrahydrofuran with 2.8 ml of triethylamine and 2.6 ml of trimethylchlorosilane and allowed to stir at room temperature for three hours. Continue stirring until the starting compound is no longer present after HPLC. The tetrahydrofuran was evaporated, 20 ml of water and 10 ml of methylene chloride were added to the residue, the pH was adjusted to 8.7 with 2 n sodium hydroxide and the layers were separated. Sodium chloride was added to the aqueous layer to saturation, covered with 15 ml of ethyl acetate and adjusted to pH 4.2 with hydrochloric acid. Separate the layers and extract the aqueous layer with 4x8 ml of ethyl acetate. The combined ethyl acetate layers were dried with sodium sulfate and N- [1 (S) -ethoxycarbonyl-3-phenylpropyl] ·

L-alanyl-L-proline was precipitated with 0.6 g of maleic acid. The precipitate was filtered off and dried in vacuo at 40 ° C. 1.5 g (61%) of the title product are obtained.

EXAMPLE 3

N- [1 (S) -carboxy-3-phenylpropyl] -L-alanyl-L-proline g N- [1 (S) -ethoxycarbonyl-3-phenylpropyl] -L-alanyl L-proline A of Example 1, dissolved in 5 ml of ethanol and 5 ml of water containing 320 mg of sodium hydroxy, and allowed to stir until complete hydrolysis takes place. After complete hydrolysis, the solvent is evaporated off under reduced pressure. Dissolve the residue in 10 ml of water, saturated with sodium chloride, cover with 10 ml of ethyl acetate and adjust the pH to 4.2 with a solution of hydrogen chloride. The aqueous layer was extracted with ethyl acetate (2x10 ml), and the combined ethyl acetate layers were dried and evaporated.

0.71 g (76%) of the title product is obtained from the soil. about 146 to 152 ° C.

Claims (2)

A process for the preparation of L-alanyl-L-proline derivatives of formula I in which R is ethyl or hydrogen, and their pharmaceutically acceptable salts, characterized in that N, O-bistrimethylsilyl-L-proline of formula II cooskch ₃ ) _{3 is} condensed with the N- / 1 (S) -ethoxycarbonyl-3-phenylpropyl / L-alanine derivative of the general formula III cooc ₂ H ₅ CH ₂ CH ₂ CH NH CH CO Het III H. in which Het represents a residue of imidazole-1 or 2-thiobenzothiazole, in non-polar organic solvents such as dioxane, tetrahydrofuran methylene chloride, preferably tetrahydrofuran, in a temperature range of -10 to +20 ° C, and optionally a compound of formula I wherein R ethyl is hydrolyzed to a compound of formula I wherein R is hydrogen. For KRKA, Medicines Factory, n.sol.o .: 2O44O-VII-88 / LZ P O VZ E T E K A process for the preparation of L-alanylL-proline derivatives of formula I is described COOH in which R is ethyl or. hydrogen, and pharmaceutically acceptable salts thereof, wherein N, O-bistrimethylsilyl-L-proline of formula II C00Si (CH ₃ ) _{3 is} condensed with the N- / 1 (S) -ethoxycarbonyl-3-phenylpropyl / L-alanine derivative of general formula III C ° 0C ₂ ^h 5 CH ₀ CH ₀ CH NH CH COHet m ² 1 CH. in which Het represents a residue of imidazole-.1 or 2-thiobenzothiazole, in non-polar organic solvents such as dioxane, tetrahydrofuran methylene chloride, preferably tetrahydrofuran, in a temperature range of -10 to +20 ° C, and optionally a compound of formula I in which is R ethyl, hydrolyzed to a compound of formula I wherein R is hydrogen.