Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Patent
1999-04-09
2000-11-07
Killos, Paul J.
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
564317, C07C21300
Patent
active
061439339
DESCRIPTION:
BRIEF SUMMARY
This invention relates to a process for the preparation of optically active methadones and in particular to an enzymatic process for the resolution of 1-dialkyl-amino-2-propanol and conversion of the enantiomers to the optically active methadones in high enantiomeric purity.
Racemic methadone is an analgesic and is used to ease heroin withdrawal. The levo-isomer of methadone has been reported to possess greater physiological activity than the racemic modification (A. A. Larsen, B. F. Tullar, B. Elpern and J. S. Buck, J. Amer. Chem. Soc., 1948, 70, 4194.) Previous methods for preparing optically active methadones involved resolution of racemic methadone itself or its nitrile precursor by preparing diastereomeric salts with d-tartaric acid (A. A. Larsen, B. F. Tullar, B. Elpern and J. S. Buck, J. Amer. Chem. Soc., 1948, 70, 4194.) (W. R. Brode and M. W. Hill, J. Org. Chem., 1948, 13, 191.) or (+)-3-bromocamphor-8-sulphonic acid ammonium salt (E. E. Howe and M. Sletzinger, J. Amer. Chem. Soc., 1949, 71, 2935.) The dextro-isomer of methadone can be synthesised from ethyl L-(-)-lactate involving the intermediates in scheme 2 hereinafter (C. J. Barnett and J. C. Smirz, J. Org. Chem., 1976, 41, 710.).
The present invention seeks to provide an alternative more economical method for preparing optically active methadones.
According to the present invention there is provided a method of preparing optically active methadones comprising the enzymatic resolution of 1-dialkylamino-2-propanol in the presence of ester so as to produce S-1-dialkylamino-2-propanol and R-ester of 1-dialkylamino-2-propanol, the method further comprising the conversion of one or both of the S-1-dialkylamino-2-propanol and/or R-ester of 1-dialkylamino-2-propanol to yield S(+)-methadone and/or R(-)-methadone respectively.
Preferably 1-Dimethylamino-2-propanol is used as the starting material.
The process of the invention involves the enzymatic resolution of racemic 1-dialkyl amino-2-propanol which is a cheap starting material to provide R- and S-enantiomers. These enantiomers can be converted into the optically active methadones in high enantiomeric excess. Advantageously, the resolved alcohol and esters allow conversion, without loss of optical activity, to R(-)- and S(+)-methadones in high enantiomeric purity, as demonstrated by HPLC methods using a chiral stationary phase. (.+-.)-1-dimethylamino-2-propanol may be resolved into its optical isomers by an enzyme, preferably lipase, catalysed transesterification using various esters and enzymes either as crude preparations or purified enzymes immobilised on solid support. The effective enzymes have included the following:
Preferred esters include vinyl acetate and vinyl propionate. The process can be illustrated with the use of a vinyl propionate as the acyl donor and Candida antartica (Novozym.RTM. 435) as the immobilised enzyme. This process gives the R-ester and the S-alcohol. The R-ester can be isolated simply by extraction or alternatively by a distillation process which gives both the ester and the alcohol in good yields. The resolution is illustrated in scheme 1 shown below. ##STR1##
For high enantiomeric excess in formation of the propionate ester 0.5 equivalents of vinyl propionate were used. For high optical purity of the S-alcohol approximately 0.6 equivalents of vinyl propionate were used so that all the R-alcohol would be esterified as well as a small amount of S-alcohol. The remaining S-alcohol has high optical purity.
The alcohol 2 is the first fraction to distil (35.degree. C./-5 mm) followed by a small amount of mixed 1 & 2 and then the propanoate ester 1 (60.degree. C./-5 mm). The resolved S-alcohol ([.alpha]sub.D =23.degree.,lit (C. J. Barnett and J. C. Smirz, J. Org. Chem., 1976, 41, 710.)=24.degree.) was then treated with thionyl chloride to afford the chloro compound 3. This was converted to S-(+)-2,2-diphenyl-4-dimethylaminopentane-nitrile 5a by reaction with diphenylacetonitrile in the presence of strong base (C. J. Barnett and J. C. Smirz, J. org. Chem., 1976, 41, 710.), M
REFERENCES:
Rudaz, S et al. J. Pharm. Biomed Anal (1996) 14 (8-10) 1271-1279.
Berthod, A et al. J. Pharm. Biomed Anal (1990) 8 (2) 123-30.
Hull Jonathan David
Scheinmann Feodor
Turner Nicholas John
Killos Paul J.
Salford Ultrafine Chemicals & Research Ltd.
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