Organic Process Research & Development 2000, 4, 613−614
Efficient Molar-Scale Synthesis of 1-Methyl-5-acylimidazole Triflic Acid Salts
Bang-Chi Chen,* Amanda P. Skoumbourdis, Joseph E. Sundeen, George C. Rovnyak, and Sarah C. Traeger
DiscoVery Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543, U.S.A.
Abstract:
for large-scale preparation. We were most attracted to the
third method, because exclusive regioselectivity and a good
yield (75%) were obtained in the methylation of 5-formyl-
A new process for the molar-scale preparation of 1-methyl-5-
acylimidazole triflic acid salts was developed. The new process
consists of: (i) regioselective N-tritylation of 5-acylimidazole
3
14
imidazole with methyl triflate. However, in this report, the
1
to give 3-trityl-5-acylimidazoles, (ii) N-methylation of 3-trityl-
product imidazole was isolated as the free base after column
1
4
5-acylimidazoles, and (iii) hydrolysis of the resulting quaternary
chromatography. We anticipated that the methyl triflate
used for methylation could be utilized as a direct source for
the final triflic acid salt formation. Herein, we describe an
efficient process for the large-scale synthesis of 1-methyl-
5-formylimidazole triflic acid salt from commercially avail-
able 5-formylimidazole. The application of this newly
developed process to the preparation of 1-methyl-5-meth-
oxycarbonylimidazole triflic acid salt is also disclosed.20
The new process begins with the preparation of 1-trityl-
ammonium salts to afford 1-methyl-5-acylimidazole triflic acid
salts. This process is highly efficient, affording 1-methyl-5-
acylimidazole triflic acid salts in 86-88% overall yield in three
steps without chromatographic separation of products.
1-Methyl-5-formylimidazole is an important synthetic
1
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intermediate,
products.
especially in the synthesis of natural
Three methods have been previously reported
7
-14
4
-formylimidazole 1a (Scheme 1). This compound was
for the preparation of 1-methyl-5-formylimidazole. The first
method is the transformation of the 5-formyl group from a
previously prepared in 80% yield by tritylation of 5-formyl-
imidazole with trityl chloride and triethylamine in chloro-
6
-8,15
corresponding 5-hydroxymethyl,
or 5-alkoxycarboxyl
The second method features the installation of
the 5-formyl group via a 5-metalated 1-methylimidazole
2
1
6
,8,15
form. To eliminate the environmentally unfriendly chlo-
roform from the process, tritylation in other solvents was
examined. Thus, treatment of 1a with trityl chloride in
group.
5
,16-18
reactive species.
selective N-methylation of 5-formylimidazole.4 In a pro-
gram of our drug discovery, we required an easy access to
The third method entails a regio-
,14
acetonitrile in the presence of triethylamine gave smoothly
1
2
a which was isolated in 99% yield. H NMR indicated that
the tritylation reaction in acetonitrile was highly regioselec-
tive. The undesired regioisomer was not detected. Reaction
of 2a with methyl triflate in methylene chloride at room
temperature overnight afforded the quaternary ammonium
salt 3a. Product 3a was isolated as a somewhat unstable
crystalline compound in 99% yield after solvent exchange
from methylene chloride to hexane and filtration. It is
important to remove any excess methyl triflate from 3a to
streamline and simplify the product isolation in the subse-
quent step. Treatment of 3a with water in acetone gave
1-methyl-5-formylimidazole triflic acid salt 4a. It was
surprising that the deprotection reaction took place under
such mild conditions. The ease with which the detritylation
occurred is probably due to the resonance between 3a and
a large amount of 1-methyl-5-formylimidazole triflic acid
salt.19
While the first two methods can certainly be adapted to
the preparation of 1-methyl-5-formylimidazole triflic acid
salt, the low overall yields, chromatographic separation, or
high vacuum sublimation of product make them impractical
(1) Lee, J. J.; Huang, L.-F.; Zaw, K.; Bauer, L. J. Heterocycl. Chem. 1998,
3
5, 81.
(
(
2) Jonas, R.; Prucher, H.; Wurziger, H. Eur. J. Med. Chem. 1993, 28, 141.
3) Pfoertner, K.-H.; Montavon, F.; Bernauer, K. HelV. Chim. Acta 1985, 68,
6
00.
(
(
(
4) Sakami, W. J. Biol. Chem. 1944, 154, 215.
5) Walters, M. A.; Lee, M. D. Tetrahedron Lett. 1994, 35, 8307.
6) Aulaskari, P.; Ahlgren, M.; Rouvinen, J.; Vainiotalo, P. J. Heterocycl. Chem.
1
996, 33, 1345.
(7) Jones, R. G.; McLaughlin, K. C. J. Am. Chem. Soc. 1949, 71, 2444.
(8) Dener, J. M.; Zhang, L.-H.; Rapoport, H. J. Org. Chem. 1993, 58, 1159.
(9) Compagnone, R. S.; Rapoport, H. J. Org. Chem. 1986, 51, 1713.
3
′a, with 3′a undergoing facile deprotection in aqueous
acetone. The product 4a from detritylation is highly soluble
in water, whereas the byproduct, trityl alcohol 5, is essentially
insoluble in water after removal of acetone and thus can be
completely removed by simple filtration. Upon concentration,
the final product 4a was obtained in 95% yield. 1-Methyl-
(10) Tchissambou, L.; Benechie, M.; Khung-Huu, F. Tetrahedron Lett. 1978,
1
801.
(11) Tchissambou, L.; Benechie, M.; Khung-Huu, F. Tetrahedron 1982, 38, 2687.
(12) Shapiro, G.; Chengzhi, C. Tetrahedron Lett. 1992, 33, 2447.
(13) Link, H.; Bernauer, K. HelV. Chim. Acta 1972, 55, 1053.
(14) Daninos-Zeghal, S.; Mourabit, A. A.; Ahond, A.; Poupat, C.; Potier, P.
Tetrahedron 1997, 53, 7605.
5
-methoxycarbonylimidazole 4b can be prepared similarly
(15) Kirchlechner, R.; Casutt, M.; Heywang, U.; Schwarz, M. W. Synthesis 1994,
in 90% overall yield following the procedures described
above.
2
47.
(
(
16) Shapiro, G.; Marzi, M. Tetrahedron Lett. 1993, 34, 3401.
17) El Borai, M.; Moustafa, A. H.; Anwar, M.; Ghattas, A. G. Croat. Chem.
Acta 1981, 54, 211.
(20) Methyl-5-methoxycarbonylimidazole is also an important synthetic inter-
mediate, see, Wuonola, M. A.; Woodward, R. B. J. Am. Chem. Soc. 1973,
95, 284. Wuonola, M. A.; Woodward, R. B. Tetrahedron 1976, 32, 1085.
See also refs 6, 8, and 15.
(18) Shapranova, N. I.; Somin, I. N.; Kuznetsov, S. G. Chem. Heterocycl. Compd.
(Engl. Transl.) 1973, 1013.
(19) Compared to its free base, 1-methyl-5-formylimidazole triflic acid salt 4a
shows improved physical properties for better purification and handling.
(21) Bernabe, M.; Burger, A. J. Med. Chem. 1971, 14, 883.
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Vol. 4, No. 6, 2000 / Organic Process Research & Development
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Published on Web 10/27/2000