Organic Process Research & Development 2009, 13, 581–583
A Simple and Efficient Large-Scale Synthesis of Metal Salts of Medium-Chain Fatty
Acids
Boulos Zacharie,* Abdallah Ezzitouni, Jean-Simon Duceppe, and Christopher Penney
ProMetic BioSciences Inc., 500 BouleVard Cartier Ouest, Bureau 150, LaVal, Que´bec, Canada H7V 5B7
Abstract:
acids.11 This includes the solubility of the acid, lipophilicity,
acid strength as reflected by the dissociation constant of the
carboxyl group, the surfactant aggregation, and the molecular
association of the resulting salt. These characteristics must be
taken into consideration when scaling up the synthesis of MCFA
metal salts. Herein we report a simple, efficient, and high-yield
general one-step procedure for the synthesis of water-soluble
or insoluble MCFA metal salts from water-insoluble MCFAs.
A simple, inexpensive, one-step general procedure was developed
for the preparation of medium-chain fatty acid (MCFA) metal
salts. This approach offers the advantage of a practical route and
is superior to literature methods. Also, it overcomes many of the
limitations previously reported for the preparation of fatty acid
salts. The potential utility of this method is illustrated by the
production of pilot-scale quantities of high-purity (>99.9%)
sodium decanoate.
Results and Discussion
Kilogram quantities of high-purity MCFA salts were required
for our therapeutic program. One approach was the treatment
of the acids with strong base. It was reported12 that sodium
hydroxide (5% in excess) reacted with long-chain fatty acids
such as stearic acid to form the corresponding sodium salt. This
procedure was followed for the preparation of sodium de-
canoate. In our hands, this reaction tended to be problematic
with regard to product yield (43%) and purity (<90%). For
example, the use of water in the workup to remove excess of
sodium hydroxide also solubilized a portion of the sodium
decanoate salt and consequently reduced the yield. However,
this is not the case with sodium stearate which is not soluble13
in water and can be obtained in respectable yield. Solubility in
water is one of many differences that distinguish long-chain
fatty acid salts from MCFA salts. Sodium decanoate obtained
by this procedure was contaminated with a residual amount of
sodium hydroxide which explained the low purity of the MCFA
salt. The next step was to find other bases. For example, the
use of aluminum alkoxides14 was reported in the literature for
the preparation of aluminum salts of long-chain fatty acids. No
examples were reported for the preparation of MCFA salts.
Again, this may be due to the differences in the physical
properties of these fatty acid salts. Accordingly, a variety of
alternative synthetic strategies were evaluated with a view to
scale-up for manufacture.
Introduction
Medium-chain fatty acids (MCFAs), such as hexanoic,
octanoic, decanoic, and dodecanoic acid and their metal salts
are known to be nontoxic compounds with numerous com-
mercial applications.1-7 They are major components of seed
and coconut oil and are used in the food, perfume, and
pharmaceutical industries.
MCFA metal salts are generally produced on a commercial
scale by either the fusion method8 (double decomposition), the
precipitation method,9 or other less common methods.10 How-
ever, they all possess drawbacks and are often fraught with
technical difficulties. This limits the potential for scale-up of
these procedures.
The literature methods do not differentiate between the
preparation of medium- and long-chain fatty acids. In fact,
MCFAs have properties which are different from the usual fatty
* Author for correspondence. E-mail: b.zacharie@prometic.com.
(1) (a) Motlekar, N. A.; Srivenugopal, K. S.; Wachtel, M. S.; Youan, B.-
B. J. Drug Target 2005, 13, 573. (b) Burton, A. F.; McLean, D. U.S.
Patent 5,175,190, 1992; Chem. Abstr. 1993, 118, 132158x.
(2) (a) Donovan, M. D.; Flynn, G. L.; Amidon, G. L. Pharm. Res. 1990,
7, 808. (b) Chao, A. C.; Nguyen, J. V.; Broughall, M.; Griffin, A.;
Fix, J. A.; Daddona, P. E. Int. J. Pharm. 1999, 191, 15. (c) Raoof,
A. A.; Ramtoola, Z.; McKenna, B.; Yu, R. Z.; Hardee, G.; Geary,
R. S. Eur. J. Pharm. Sci. 2002, 17, 131.
(3) Lindmark, T.; So¨derholm, J. D.; Olaison, G.; Alva´n, G.; Ocklind, G.;
Artursson, P. Pharm. Res. 1997, 14, 930.
Development Scale Production, 1 to 500 g. Sodium
decanoate was chosen as a representative example of an MCFA
metal salt. The first step was to select the appropriate base to
react with the acid and a suitable solvent. It was reported that
(4) Klimentova´, J.; Kosa´k, P.; Va´vrova´, K.; Holas, T.; Hraba´lek, Bioorg.
Med. Chem. 2006, 14, 7681, and references cited therein.
(5) Nair, M. K.; Joy, J.; Vasudevan, P.; Hinckley, L.; Hoagland, T. A.;
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(7) MCFAs and especially the salts of decanoic and octanoic acid are
able to induce hematopoiesis; see: (a) Christopher, P.; Gagnon, L.;
Laurin, P.; Zacharie, B. WO 2004/069237, 2004; Chem. Abstr. 2004,
141, 185103. (b) Duceppe, J.-S.; Ezzitouni, A.; Penney, C.; Zacharie,
B. WO 2005/012217 A2, 2005; Chem. Abstr. 2005, 142, 197581.
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1982, 96, 87447e.
(9) Davis, G. M.; Township, C. U.S. Patent 2,945,051, 1960; Chem. Abstr.
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(10) Ohuchida, S.; Kishimoto, K.; Tateishi, N.; Ohno, H. U.S. Patent
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(11) (a) Sneth, G. N.; Subrahmanyam, V. V. R. J. Indian Chem. Soc. 1982,
59, 860. (b) Burton, A. F.; Mclean, D. U.S. Patent 5,175,190,
1992; Chem. Abstr. 1993, 118, 132158x. (c) Vold, M. J.; Macomber,
M.; Vold, R. D. J. Am. Chem. Soc. 1941, 63, 168. (d) Morigati, K.;
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(12) Pan, H.; Lou, A.; Pan, G. CN Patent 1,052,846, 1991; Chem. Abstr.
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(13) McBain, J. W.; Sierichs, W. C. J. Am. Oil Chem. Soc. 1948, 25, 221.
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10.1021/op900038v CCC: $40.75 2009 American Chemical Society
Published on Web 04/08/2009
Vol. 13, No. 3, 2009 / Organic Process Research & Development
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