Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Reexamination Certificate
2000-12-21
2001-11-13
Geist, Gary (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
C562S553000
Reexamination Certificate
active
06316667
ABSTRACT:
The invention described herein relates to a chemical process for the stereoselective synthesis of R-(−)-carnitine.
As is known, carnitine contains an asymmetry centre and can therefore exist in the form of two enantiomorphs, designated R-(−)-carnitine and S-(+)-carnitine, respectively. Of these, only R-(−)-carnitine is present in living organisms where it acts as a carrier for the transport of fatty acids across the mitochondrial membranes. Whereas R-(−)-carnitine is the physiologically active enantiomorph, for some years the R,S racemate has been used as a therapeutic agent. It has had to be acknowledged, however, that S-(+)-carnitine is a competitive inhibitor of carnitine acetyltransferases and can lower the levels of R-(−)-carnitine in the myocardium and in skeletal muscle.
It is therefore essential that only R-(−)-carnitine be administered to patients undergoing haemodialysis treatment or those under treatment for cardiac or lipid metabolism disorders.
The same principle applies to the therapeutic use of derivatives of carnitine for the treatment of disorders of cerebral metabolism, peripheral neuropathies, peripheral arteriopathies, etc., for which acetyl R-(−)-carnitine and propionyl R-(−)-carnitine are used, obtained by acylation of R-(−)-carnitine.
Various chemical processes have been proposed for the production of carnitine on an industrial scale. These processes are generally non-stereospecific and therefore lead to racemic mixtures of R and S isomers. Consequently, resolution methods must be used to separate the constituent enantiomorphs of the racemate. Typically, the R,S racemic mixture is reacted with an optically active acid, selected, for example, from d-tartaric acid or d-camphorsulphonic acid, obtaining two diastereoisomers that can be separated from each other. In the classic process described in U.S. Pat. No. 4,254,053, d-camphoric acid is used as the resolvent of a racemic mixture of R,S carnitinamide, obtaining S-(+)-carnitinamide as the waste product, while the R-(−)-carnitinamide is hydrolysed to R-(−)-carnitine.
These resolution processes are therefore complex and expensive and, in any case, lead to the production of both R-(−)-carnitine and an equal amount of S-(+)-carnitine or of a precursor with, however, the opposite configuration to that of R-(−)-carnitine, as a by-product.
In an attempt to use the substantial amounts of S-(+)-carnitine (or of a precursor, such as S-(+)-carnitinamide) which are obtained as a waste product in the industrial production of R-(−)-carnitine, various microbiological processes have recently been proposed based on the stereospeciflc synthesis of R-(−)-carnitine starting from achiral derivatives (crotonobetaine or gamma-butyrobetaine) obtained precisely from this S-(+)-carnitine waste product.
These processes are generally based on the stereospecific hydration of crotonobetaine and differ from one another mainly in the particular micro-organism used to produce the biotransformation. See, for example, the processes described in: EP 0121444 (Hamari), EP 0122794 (Ajinomoto), EP 0148132 (Sigma-Tau), JP 275689/87 (Bioru), JP 61067494 (Seitetsu), JP 61234794 (Seitetsu), JP 61234788 (Seitetsu), JP 61271996 (Seitetsu), JP 61271995 (Seitetsu), EP 0410430 (Lonza), EP 0195944 (Lonza), EP 0158194 (Lonza), EP 0457735 (Sigma-Tau).
JP 62044189 (Seitetsu) describes a process for the stereoselective production of R-(−)-carnitine, starting, instead, from gamma-butyrobetaine, which in turn is obtained from crotonobetaine by an enzymatic method.
All these processes present drawbacks and pose major technical problems.
In the first place, S-(+)-carnitine has to be converted to the achiral compound (crotonobetaine or gamma-butyrobetaine) which constitutes the starting product in all the aforementioned microbiological processes.
The latter present one or more of the following problems in production on an industrial scale:
(i) the R-(−)-carnitine yield is extremely low;
(ii) the micro-organisms must be grown on expensive nutrient media;
(iii) the micro-organisms support only low concentrations of crotonobetaine (up to 2-3% (w/v));
(iv) side reactions occur, such as, in the case of the use of crotonobetaine, for instance, the reduction of the latter to gamma-butyrobetaine, or the oxidation of R-(−)-carnitine to 3-dehydrocarnitine, which diminish the final R-(−)-carnitine yield.
More recently, a chemical process has been described (U.S. Pat. No. 5412113; U.S. Pat. No. 5599978; EP 0609643) based on the conversion to R-(−)-carnitine of a starting compound containing one asymmetric carbon atom with the opposite configuration to that of R-(−)-carnitine, without this compound having first to be converted to the achiral intermediate, crotonobetaine or gamma-butyrobetaine, and this achiral intermediate having to be later converted to R-(−)-carnitine. The starting compound consists in S-(+)-carnitinamide, which, as mentioned above, is obtained as a redundant waste product in the resolution of the R,S-carnitinamide racemic mixture by means of, for instance, d-camphoric acid. According to this process, the S-(+)-carnitinamide is converted to S-(+)-carnitine; the latter is esterified to protect the carboxyl group; the ester is acylated, preferably mesylated; after restoring the carboxyl group, the acyl derivative thus obtained is converted to a chiral lactone presenting the desired R configuration, which, through basic hydrolysis, supplies the R-(−)-carnitine.
It should be noted that both in the microbiological processes that obtain R-(−)-carnitine via an achiral intermediate and in the chemical process that enables R-(−)-carnitine to be obtained via chiral lactone, the starting product is a precursor of carnitine with the opposite configuration to that of the R form normally obtained by resolution of racemic mixtures, e.g. from R,S-carnitinamide.
The advantages to be gained from a process which makes it possible to start from a precursor which is not necessarily related to the prior resolution of racemic mixtures of R,S-carnitine, but which can also be obtained from alternative sources, appear clear.
A process for the preparation of (R)-carnitine starting from (S)-3-hydroxy-4-butyrolactone has now been found and constitutes part of the invention described herein.
(S)-3-hydroxy-4-butyrolactone can be obtained in industrial quantities by conversion of D-hexoses, particularly D-glucose (EP 0513 430), or, alternatively, can be obtained by transforming the S-carnitine isomer, a waste product of the industrial synthesis of R-carnitine, as described in Giannessi F., De Angelis F. RM95A000652; Calvisi G., Catini R., Chiarotti W., Giannessi F., Muck S., Tinti M. O., De Angelis F.
SYNLETT
1997, 71-74.
The process according to the invention is represented by the following reaction diagram:
where X is halogen and R a linear or branched C
1
-C
7
alkyl.
In step a, (S)-3-hydroxy-4-butyrolactone [1] is converted to alkyl (S)-4-halogen-3-hydroxybutyrate [2] by reaction with a linear or branched C
1
-C
7
alcohol; the alcohol shall preferably be selected from the group consisting of methanol, ethanol, isopropanol and isobutanol.
The conversion can be done by means of known techniques, for example, as described in (Larcheveque M., Henrot S.,
Tetrahedron
, 1990, 46, 4277-4282), where the synthesis of the ethyl ester of 4-iodo-3-hydroxybutyric acid is described, and in (Toaka N., Kamiyama N., Inoue K., Takahashi S. (Kanegafuchi) JP 04149151, 1992
; Chem. Abstr
. 1992, 117, 191350p, where the synthesis of the methyl ester of 4-bromo-3-hydroxybutyric acid is reported.
The preferred process is the one described in
Tetrahedron
, 15 1990, 46, 4277-4282, in which isobutanol is used.
In step b, a CN group is substituted for the halogen present in compound [2] to yield the alkyl ester of (R)-4-cyano-3-hydroxybutyric acid [3]. This substitu
De Angelis Francesco
Giannessi Fabio
Tinti Maria Ornella
Geist Gary
Nixon & Vanderhye
Reyes Hector M
Sigma-Tau Industrie Farmaceutiche Riunite S.p.A.
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