Organic Process Research & Development 2009, 13, 812–814
An Efficient Process of Racemization of 3-(Carbamoylmethyl)-5-methylhexanoic
acid: A Pregabalin Intermediate
Anil B. Chavan,* Golak C. Maikap,* and Mukund K. Gurjar
Emcure Pharmaceuticals Ltd, R & D Centre, Plot No.12/2, F-II Block, M.I.D.C., Pimpri, Pune - 411018, India
Scheme 1
Abstract:
A simple and cost-effective process for racemization of undesired
(S)-3-(carbamoylmethyl)-5-methylhexanoic acid (9), produced dur-
ing the resolution step, is described. The literature procedure is
fraught with many difficulties including number of steps and
hazardous reagents. We have developed a one pot process for the
above-mentioned racemization of S-enantiomer. The basic objec-
tive is to convert S-enantiomer into the symmetrical glutarimide
derivative followed by hydrolysis with an alkali. The transforma-
tion of 9 into glutarimide derivative (10) has been achieved with
piperidine in refluxing toluene.
Scheme 2
Introduction
(S)-3-Aminomethyl-5-methylhexanoic acid (pregabalin, 1)
Scheme 3
was designed as a more potent substitute of gabapentin, an
anticonvulsant drug used for naturopathic pain treatment.1 The
first synthesis of pregabalin (1) was evaluated by Hoekstra et
al.2,3 and later reviewed by Ordonez and Cativiela.4 One of the
preferred processes of pregabalin manufacturing (Scheme 1)
comprises aminolysis of 3-isobutylglutaric anhydride (3) ob-
tained from 3-isobutylglutaric acid (2) followed by resolution
of the intermediary amide 4 with (R)-(+)-1-phenylethylamine
in chloroform. The R-enantiomer of 3-(carbamoylmethyl)-5-
methylhexanoic acid (5) preferentially crystallizes out which
is then transformed into pregabalin (1).
Very recently Martinez and co-workers reported5 a chemoen-
zymatic process for pregabalin (1) in which commercially
available lipase was employed to resolve racemic-2-carboxy-
ethyl-3-cyano-5-methylhexanoic acid ethyl ester (6) to give (S)-
2-carboxyethyl-3-cyano-5-methylhexanoic acid (8). Subse-
quently 8 was subjected to decarboxylation and reduction to
provide 1. This new route (Scheme 2) undoubtedly improved
the efficiency and ensured smooth racemization of unwanted
(R)-enantiomer 7.
In our laboratory Scheme 1 of pregabalin 1 was successfully
accomplished. The filtrate, after the resolution step, was
subsequently decomposed with an acid and analysed for
percentages of both enantiomers. It contained typically around
85% of the undesired S-enantiomer 9 along with 15% of the
R-enantiomer 5. In order to make this process economically
viable, the racemization of 9 from the mother liquor was a
necessity. The reported procedure (Scheme 3) of racemization
of 9 involved an extraction of the chloroform filtrate with
aqueous sodium hydroxide solution followed by acidification
of aqueous layer with concentrated hydrochloric acid. The acidic
solution was heated under reflux for 24 h, extracted with methyl
* Author for correspondence. E-mail: golak.maikap@emcure.co.in.
(1) Belliotti, T. R.; Capiris, T.; Ekhato, V.; Kinsora, J. J.; Field, M. J.;
Heffner, T. G.; Meltzor, L. T.; Schwazz, J. B.; Tayler, C. P.; Thorpe,
A. J.; Vartanian, M. G.; Wise, L. D.; Zhi, S. V.; Weber, M. L.;
Wustrow, D. J. J. Med. Chem. 2005, 48, 2294–2307.
(2) Marvin, S.; Hoekstra, D. M.; Sobieray, M. A.; Schwindt, T. S.;
Mulhern, T. M.; Grote, B. K.; Huckabee, V. S.; Hendrikson, L. C.;
Franklin, E. J.; Granger, G. L. Org. Process Res. DeV. 1997, 1, 26–
38.
(3) Huckabee, B.; Keith, S.; Denis, M. World Patent, WO96/38405, 1996.
(4) Ordrienz, M.; Cativiela, C. Tetrahedron: Asymmetry 2007, 18, 3–99.
(5) Martinez, C. A.; Hu, S.; Dumond, Y.; Tao, J.; Kelleher, P.; Tully, L.
Org. Process Res. DeV. 2008, 12, 392–398.
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Vol. 13, No. 4, 2009 / Organic Process Research & Development
10.1021/op900064x CCC: $40.75 2009 American Chemical Society
Published on Web 05/18/2009