Organic Process Research & Development 2009, 13, 429–433
Mechanism and Processing Parameters Affecting the Formation of Methyl
Methanesulfonate from Methanol and Methanesulfonic Acid: An Illustrative Example
for Sulfonate Ester Impurity Formation
Andrew Teasdale,*,† Stephen C. Eyley,*,† Ed Delaney,‡ Karine Jacq,§ Karen Taylor-Worth,⊥ Andrew Lipczynski,⊥ Van Reif,¶
David P. Elder,0 Kevin L. Facchine,b Simon Golec,4 Rolf Schulte Oestrich,1 Pat Sandra,§ and Frank David§
AstraZeneca, R&D Charnwood, Bakewell Road, Loughborough, Leicestershire LE11 5RH, United Kingdom,
Reaction Science Consulting, LLC, Suite 202/11 Deer Park DriVe, Monmouth Junction, New Jersey 08852, U.S.A.,
Research Institute for Chromatography, Pres. Kennedypark 26, B-8500, Kortrijk, Belgium, Pfizer Global Research
and DeVelopment, Analytical R&D, Ramsgate Road, Sandwich, Kent CT13 9NJ, United Kingdom, Schering-Plough,
556 Morris AVenue, Summit, New Jersey 07901-1330, U.S.A., GlaxoSmithKline, Park Road, Ware, Hertfordshire
SG12 0DP, United Kingdom, GlaxoSmithKline, FiVe Moore DriVe, Research Triangle Park, North Carolina
27709-3398, U.S.A., Wyeth Research, 500 Arcola Road, CollegeVille, PennsylVania 19426, U.S.A., and F.
Hoffmann-La Roche Ltd., Grenzacher Strasse, 4070 Basel, Switzerland
Abstract:
Introduction
Sulfonic acids are widely used for salt formation during the
Sulfonate salts offer useful modification of physicochemical
properties of active pharmaceutical ingredients (APIs) con-
taining basic groups, but there are regulatory concerns over
the presence of sulfonate esters as potential genotoxic
impurities (PGIs). Whilst sulfonate esters could theoretically
result from interaction between sulfonic acids and alcohols,
literature on their formation is sparse. GC-MS analysis of
reactions of methanesulfonic acid (MSA) and isotopically
labeled methanol (18O-label) confirm methanol C-O
bond cleavage in the formation of the methyl meth-
anesulfonate (MMS), consistent with reversal of well-
established mechanisms for solvolysis of sulfonate
esters. Studies of reaction profiles quantify methyl
methanesulfonate formation under a range of condi-
tions relevant to API processing. Maximum conversion
to MMS in reaction mixtures was 0.35%, determined
by analytical methods developed specifically for reac-
tion mixture analysis. Sulfonate ester formation is
dramatically reduced at lower temperatures, in the
presence of small amounts of water, or when acid is
partially neutralized by substoichiometric amounts of
the weak base, 2,6-lutidine, used to mimic conversion
of a basic API to a salt in pharmaceutical manufacture.
In the presence of a slight excess of base, ester
formation was not detected. These findings, particu-
larly those involving an excess of base, are compelling
and provide a scientific understanding to allow for the
design of processing conditions to minimize and control
sulfonate ester formation.
synthesis and production of drug substances. Sulfonic acids can
react with low molecular weight alcohols such as methanol,
ethanol, or isopropanol to form the corresponding sulfonate
esters. These sulfonate esters have a demonstrated potential for
genotoxicity, and therefore their potential presence in trace levels
in active pharmaceutical ingredients (APIs) has recently raised
concerns.1,2 Such alcohols are commonly used as solvents during
salt formation and in earlier steps of drug synthesis.
Whilst there is much literature on the solvolytic instability
of sulfonate esters,3-7 there is little information in the literature
on the extent of their formation from these alcohols and sulfonic
acids or potentially from sulfonate salts.8 Synthetically useful
yields of sulfonate esters from the relevant sulfonic acids have
been reported under forcing conditions employing ortho-
formates9 or orthoacetates,10 but such sulfonate esters are
normally prepared using strategies involving alternative sul-
fonate precursors, e.g. sulfonyl chlorides.
Given the paucity of literature on the formation of sulfonate
esters from these alcohol/sulfonic acid systems, and the
importance of the quantities formed from a product safety
perspective, we endeavored to elucidate and understand the
extent to which these substances may be formed under condi-
tions that mimic the preparation of salts of APIs. To facilitate
(1) Mesylate Ester Type Impurities Contained in Medicinal Products,
Swissmedic Department for Control of the Medicinal Products Market,
October 23, 2007.
(2) Coordination Group for Mutual Recognition-Human committee (CMDh),
Request to Assess the Risk of Occurrence of Contamination with
Mesilate Esters and Other Related Compounds in Pharmaceutical,
EMEA/CMDh/ 98694/2008, London, February 27, 2008.
(3) Winstein, S.; Grunwald, E.; Jones, H. W. J. Am. Chem. Soc. 1951,
73, 2700.
* Authors for corresondence. E-mail: andrew.teasdale@astrazeneca.com;
(4) Robertson, R. E. Can. J. Chem. 1953, 31, 589.
(5) Smith, M. B.; March, J. March’s AdVanced Organic Chemistry; Wiley:
New York, 2001; p 464.
(6) Isaacs, N. Physical Organic Chemistry; Prentice Hall: Harlow, 1995;
p 418.
† AstraZeneca, R&D.
‡ Reaction Science Consulting, LLC.
§ Research Institute for Chromatography.
⊥ Pfizer Global Research and Development, Analytical R&D.
¶ Schering-Plough.
(7) Bentley, T. W.; Bowen, C. T.; Brown, H. C.; Chloupek, F. J. J. Org.
Chem. 1981, 46, 38.
0 GlaxoSmithKline, U.K.
(8) Snodin, D. J. Regul. Toxicol. Pharmacol. 2006, 45, 79.
(9) Padmapriya, A. A.; Just, G.; Lewis, N. G. Synth. Commun. 1985, 15,
1057.
b GlaxoSmithKline, U.S.A.
4 Wyeth Research.
1 F. Hoffmann-La Roche Ltd.
(10) Golborn, P. Synth. Commun. 1973, 3, 273.
10.1021/op800192a CCC: $40.75 2009 American Chemical Society
Published on Web 01/14/2009
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