New salts of HMG-CoA reductase inhibitors

Abstract

Lovastatin, pravastatin, simvastatin, mevastatin, atorvastatin, and derivatives and analogs thereof are known as HMG-CoA reductase inhibitors and are used as antihypercholesterolemic agents. The majority of them are produced by fermentation using microorganisms of different species identified as species belonging to Aspergillus, Monascus, Nocardia, Amycolatopsis, Mucor or Penicillium genus, some are obtained by treating the fermentation products using the methods of chemical synthesis or they are the products of total chemical synthesis. The present invention relates to the new amine salts of HMG-CoA reductase inhibitors, the preparation thereof, the preparation of pure HMG-CoA reductase inhibitors via amine salts thereof, use of the amine salts of HMG-CoA reductase inhibitors in the process for semisynthetic preparation of HMG-CoA reductase inhibitors, use of the amine salts of HMG-CoA reductase inhibitors in the process for biotechnological modification of HMG-CoA reductase inhibitors as well as the conversion of the amine salts of HMG-CoA reductase inhibitors into the pharmaceutically acceptable salts of the HMG-CoA reductase inhibitors and the conversion of the amine salts of HMG-CoA reductase inhibitors into the HMG-CoA reductase inhibitors in the lactone form.

Description

TECHNICAL FIELD AND BACKGROUND ART Lovastatin, pravastatin, simvastatin, mevastatin, atorvastatin and derivatives and analogs thereof are examples of known as HMG-CoA reductase inhibitors which are used as antihypercholesterolemic agents. The majority of them are produced biotechnologically by fermentation using microorganisms of different species identified as species belonging to Aspergillus, Monascus, Nocardia, Amycolatopsis, Mucor or Penicillium genus, some are obtained by treating the fermentation products using the methods of chemical synthesis, thus leading to semi-synthetic substances, or they are the products of total chemical synthesis. The present invention relates to a new industrial process for isolation and / or purification of HMG-CoA reductase inhibitors via salts thereof with specific amines. The invention enables a user to obtain the pure amine salts of HMG-CoA reductase inhibitors from the fermentation broth in case the substances are produced by biotechnological ...

AI Technical Summary

Benefits of technology

Furthermore, we surprisingly discovered that in processes for the biotechnological modification of HMG-CoA reductase inhibitors the formation of amine salts of HMG-CoA reductase inhibitors in the medium which derives from the fermentation liquor provides, in comparison with the mere metal salts as described in publicly accessible literature, an efficient means for the isolation and / or purification of HMG-CoA reductase inhibitors by means of simple crystallization. The amines which are described in the present specification and which readily form salts with HMG-CoA reductase inhibitors are thus particularly suitable as auxiliary materials or processing aids for the isolation and / or purification of HMG-CoA reductase inhibitors. Furthermore, they can be excellently used as starting materials or intermediates of semisynthetic preparation or biotechnological modification of HMG-CoA reductase inhibitors and, furthermore, for the conversion into pharmaceutically acceptable salts or into the lactone form of the respective HMG-CoA reductase inhibitors. Accordingly, the novel amine salts of HMG-CoA reductase inhibitors of the present invention are also highly valuable as such.

Advantageous examples of amines which form the salt with HMG-CoA reductase inhibitors are: (±)-1,2-dimethylpropylamine, 3-(2-aminoethylamino)-propylamine, n-butylamine, secondary butylamine, tertiary butylamine (TBA), dibutylamine, tertiary amylamine, cyclopentylamine, cyclohexylamine, cycloheptylamine, dicyclohexylamine (DCHA), N-methylcyclohexylamine, N,N′-diisopropylethylenediamine (DIPEDA), N,N′-diethylenediamine, N-methyl-1,3-propanediamine, N-methylethylenediamine, N,N,N′,N′-tetramethyl-1,2-diaminoethane, N,N,N′,N′-tetramethyl-1,4-diaminobutane, N,N,N′,N′-tetramethyl-1,6-diaminohexane, 1,2-dipiperidinethane, dipiperidinemethane, 2-amino-3,3-dimethylbutane, N,N-dimethylcyclohexylamine, neopentylamine, adamantylamine, N,N-diethylcyclohexylamine, N-isopropylcyclohexylamine, N-methyl-cyclohexylamine, cyclobutylamine and norborylamine. Preferably in terms of crystallization efficiency, combined with low toxicity and low costs, the amine is selected from the group consisting of n-butylamine, secondary butylamine, TBA, dibutylamine, tertiary amylamine, cyclohexylamine, DCHA, N-methylcyclohexylamine and DIPEDA. The amine may particularly be selected from the group consisting of TBA, DIPEDA, DCHA and N-methylcyclohexylamine.

Problems solved by technology

U.S. Pat. No. 4,346,227 discloses a process for the preparation of the sodium salt of pravastatin, wherein chromatographic techniques are also used but the final product is obtained only after lyophilization which is not an economical process in a large scale production operations.

The preparation of lactone is one of the least economical steps in the production of HMG-CoA reductase inhibitors since losses in the course of the conversion from the acid into the lactone form and optionally further into the salts are greater than 20%.

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