The method of obtaining the n2-(1(s)-carboxy-3-phenylpropyl)-l-lysyl - l - proline

 

The invention relates to a simple, effective method of obtaining the N2-(1(S)-carboxy-3-phenylpropyl)-L-lysyl-L-Proline (2), which includes the first stage of implementation of the alkaline hydrolysis of N2-(1(S)-alkoxycarbonyl-3-phenylpropyl)-N6-TRIFLUOROACETYL-L-lysyl-L-Proline (1) in a mixed solution consisting of water and a hydrophilic organic solvent using an inorganic base n number of molar equivalents (n3) per mole of the above compound (1), the second stage of neutralization of the hydrolysis product with the use of inorganic acid in an amount of (n-1) to n molar equivalents (n3) and remove inorganic salts, obtained at deposition from a solvent system suitable for reducing the solubility of the inorganic salt, and the third stage is crystallization of the compound (2) present in the mixture after removal of inorganic salts from the solvent at its isoelectric point and thereby removing the compound (2) in the form of crystals, salts containing salt of organic acid - derived triperoxonane acid remains dissolved in the mother solution. Before the tetrabutylammonium hydroxide and triperoxonane acid, eliminates the use of column chromatography, makes it possible to crystallization at a temperature of from 40 to 70oWith, this was the resulting product with the release of 85-88%, purity not less than 99%.

Description text in facsimile form (see graphic part).

Claims

1. The method of obtaining the N2-(1(S)-carboxy-3-phenylpropyl)-L-lysyl-L-Proline of the formula (2)

of N2-(1(S)-alkoxycarbonyl-3-phenylpropyl)-N6-TRIFLUOROACETYL-L-lysyl-L-Proline General formula (1)

in which R represents an alkyl group,

including the first stage: implementation alkaline hydrolysis2-(1(S)-alkoxycarbonyl-3-phenylpropyl)-N6-TRIFLUOROACETYL-L-lysyl-L-Proline (1): in a solvent system selected from a mixed solution consisting of water and a hydrophilic organic solvent, and water using inorganic bases in the number n molar equivalents (n3) per mole of the above compound (1), second stage: implementation of the neutralization product of hydrolysis using an inorganic acid in an amount of (n-1) to n, the reaction mixture of the above-mentioned inorganic bases and inorganic acids by precipitation from a solvent system, suitable for reducing the solubility of inorganic salts, with the indicated solvent system selected from hydrophilic organic solvent, a mixed solvent consisting of water and a hydrophilic organic solvent, and water, and the third stage: bicrystalline N2-(1(S)-carboxy-3-phenylpropyl)-L-lysyl-L-Proline (2) present in the mixture after removal of inorganic salts from the solvent at its isoelectric point, with the specified solvent system selected from hydrophilic organic solvent, a mixed solvent consisting of water and a hydrophilic organic solvent, and water, and thus, the selection of2-(1(S)-carboxy-3-phenylpropyl)-L-lysyl-L-Proline (2) in crystalline form while maintaining salts mainly containing salt of an organic acid, triperoxonane acid dissolved in the mother solution.

2. The method according to p. 1, in which the inorganic base used in the first stage, is a hydroxide of an alkali metal, a carbonate of an alkali metal or a hydroxide of alkaline-earth metal.

3. The method according to p. 2, wherein the inorganic base used in the first stage, prom in the second stage, the inorganic acid is used in amount ranging from more than (n-1) to n molar equivalents (n3) and in the third stage, after removal of the inorganic salt mixture is adjusted to the isoelectric point, using the basis of the quantity [(molar equivalents used inorganic acid)]-(n-1)] molar equivalents.

5. The method according to p. 4, in which the second stage of the inorganic acid is used in an amount n molar equivalents (n3) and in the third stage, after removal of the inorganic salt mixture is adjusted to the isoelectric point using one molar equivalent of a base.

6. The method according to p. 4 or 5, in which the third stage is used for tuning to the isoelectric point of the base is an inorganic base selected from the group consisting of hydroxides of alkali metals, carbonates of alkali metals, carbonates of alkali metals, hydroxides of alkaline-earth metals and carbonates of alkaline-earth metals.

7. The method according to p. 6, in which the third stage is used for debugging to the isoelectric point of the base is a primary connection sodium or primary connection potassium.

8. The method according to PP.1-6 or 7, in which the inorganic acid used in the second stage, is a chloride-bodoro the stage and crystallization - the excretion of N2-(1(S)-carboxy-3-phenylpropyl)-L-lysyl-L-Proline (2) the third stage is carried out on a mixed solvent system comprising water and a hydrophilic organic solvent.

10. The method according to p. 9, in which the mass ratio of water and hydrophilic organic solvent in the mixed solvent is from 4:1 to 1:99.

11. The method according to PP.1-9 or 10, in which the hydrophilic organic solvent is a monohydroxy alcohol containing 1-4 carbon atoms.

12. The method according to p. 11 in which the hydrophilic organic solvent is an ethanol.

13. The method according to PP.1-11 or 12, in which in the General formula (1) R is an alkyl group containing 1-4 carbon atoms.

14. The method according to p. 13, in which in the General formula (1) R represents ethyl.

15. The method according to p. 1, in which the second stage formed by the inorganic salt is a potassium sulfate or calcium sulfate and the salt removed by sedimentation from the water.

 

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