Salts of HMG-CoA reductase inhibitors

Details Salts of HMG-CoA reductase inhibitors Salts of HMG-CoA reductase inhibitors

2001-04-25

2003-06-24

Davis, Brian J. (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S494000, C549S292000, C560S248000, C560S256000

Reexamination Certificate

active

06583295

ABSTRACT:

TECHNICAL FIELD
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, Amycolat psis, 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 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 (microbiological) processes, or from the reaction mixture in case the substances are produced by semisynthetic or total chemical synthesis. The step of forming salts with amine may be one of the steps in the process for isolation and/or purification of HMG-CoA reductase inhibitors or precursor substances thereof. The amines described in the present specification are very useful for the formation of salts in the composition of media in processes for biotechnological modification of HMG-CoA reductase inhibitors or precursors thereof. The salts thus formed may be used as the starting substances or intermediates for the preparation of semisynthetic derivatives and analogs thereof, or by employing simple techniques known from the literature, if required, to be converted into the pharmaceutically acceptable salts and lactones, respectively.
The processes for the isolation and purification of antihypercholesterolemic agents known from patent and technical literature include different combinations of extraction, chromatography, lactonization and crystallization methods. Some of them additionally include the isolation and purification via different salts. In U.S. Pat. Nos. 9,342,767 and 4,319,039, the ammonium salt of lovastatin (in the carboxylate form) is isolated directly from the organic phase which has been extracted from the fermentation medium. In the same patent the preparation of ethylenediamine, tetramethylammonium, potassium and N-methylglucamine salts as well as the salts of different amino acids such as L-lysine, L-arginine and L-ornithine is also described. The aforementioned salts are prepared from the already purified substance and the option for their use in the process of isolation or purification is not mentioned. GB 2055100A also describes the formation of the sodium and calcium salts of lovastatin, which comprises the extraction in methanol, two steps of preparative liquid reverse-phase chromatography, crystallization from methanol and recrystallization from ethanol, and the conversion into the salt using an aqueous solution of sodium or calcium hydroxide. However, without including various chromatography methods, the methods described do not yield a product of the purity comparable to the product obtained by using the present invention. 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. EP 65,835 discloses the preparation of the L-ornithine and t-octylamine salts of tetrahydro-M4 or tetrahydro-IsoM-4 (wherein M4 denotes a specific HMG-CoA reductase inhibitor, M4 and IsoM-4 representing the isomers hydroxylated at 6- and 3-biphenyl ring position, respectively, and “tetrahydro” means that the condensed biphenyl ring system is fully hydrogenated) as final products, that is from the respectively purified sodium salts thereof, but not as intermediates via which the isolation would be carried out. Other salts of tetrahydro-M-4 or IsoM:4 with ammonia, an amino acid or an organic amine are also contemplated as final products, including octylamine, 2-ethylhexylamine, benzylamine, a-methyl-benzylamine, phenethylamine, dibenzylamine, N-methylbenzylamine, N,N-dimethylbenzylamine, N,N-diethylbenzylamine, N-ethyl-N-methylbenzylamine, tribenzylamine, cyclopentylamine, cyclohexylamine cycloheptylamine, N-methylcyclopentylamine, N-ethylcyclohexylamine, N-ethylcycloheptylamine, dicyclohexylamine, N,N-dimethylcyclopentylamine, N,N-dimethylcyclohexylamine, N,N-diethylcycloheptylamine, pyrrolidine, N-methylpyrrolidine, piperidine, N-methylpiperidine and morpholine. GB 2073199A also discloses the preparation of different salts of HMG-CoA reductase inhibitors from the already isolated substance in the lactone form. U.S. Pat. Nos. 5,763,653 and 5,763,646 disclose the preparation of the cyclopropylamine and n-butylamine amides of lovastatin and their use in a process of chemical semisynthesis of simvastatin. U.S. Pat. No.5,403,860 discloses, as final products, amine salts of octahydronaphthalene oxime derivatives of HMG-CoA inhibitors, the derivatives deriving from ML-236A, ML-236B, MB-530A and MB-530B. As final amine salts, t-octylamine, dibenzylamine, dicyclohexylamine, morpholine, D-phenylglycine alkylester and D-glucosamine salts are mentioned.
In industry there exists a constant need for rationalization of the production and shortening of the production processes as well as for the use of least expensive starting raw materials or intermediate substances. To date the isolation of the final products in the case of HMG-CoA reductase inhibitors has been a multi-stage process wherein each step adds its share to the losses resulting in the final yield rarely greater than 60%. In addition, a product in the lactone form or lactone converted into the sodium salt is used as the starting substance in the process of semisynthesis (erg. in a process for preparing simvastatin) or biochemical conversion (e.g. in a process for preparing pravastatin). 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%. Therefore, there is a constant need for the starting substances and/or the intermediate substances which would be sufficiently pure, with small losses during their conversion, low costs, and the preparation per se should be technologically simple.
In our developmental and research work we have surprisingly found that HMG-CoA reductase inhibitors form the salts with certain amines which crystallize from mother liquor once they are formed. It has surprisingly been found that crystals of the amine salt of the desired HMG-CoA reductase inhibitor of high purity may be obtained from the liquors containing a large number of impurities and undesired HMG-CoA reductase inhibitor analogs. Contrary to the statements from U.S. Pat. No. 5,403,860 that lower yields are obtained when using the salts of HMG-CoA reductase inhibitor as starting or intermediate substances in a process for preparing the substances (Ia) mentioned below, we have surprisingly found that, when using the amine salts of HMG-CoA reductase inhibitors according to the present invention, the yields and the purity of the prepared HMG-CoA reductase inhibitors are equal to or greater than when using the HMG-CoA reductasel inhibitors in the lactone form.
Exemplified Formula Ia
R
1
: CH
3
, CH
2
OH, OH
a and b: both may be double bonds, one of them may be a single bond, both may be single bonds
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 purifi

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