Organic Process Research & Development 2004, 8, 408−410
Practical One-Pot Synthesis of N-(tert-Butoxycarbonyl)sulfamide from
Chlorosulfonyl Isocyanate via N-(tert-Butoxycarbonyl)aminosulfonylpyridinium
Salt
Toshiaki Masui,† Mikio Kabaki, Hideaki Watanabe, Tatsuya Kobayashi, and Yoshiyuki Masui*
Bulk Chemicals Process R&D Department, Manufacturing Technology R&D Laboratories, Shionogi & Co., Ltd.,
1-3, Kuise Terajima 2-chome, Amagasaki, Hyogo 660-0813, Japan
Scheme 1
Abstract:
An efficient and practical process for the one-pot synthesis of
N-(tert-butoxycarbonyl)sulfamide (4), a raw material for the
aminosulfamoyl-containing side chain 3 of a novel carbapenem
antibiotic doripenem hydrate (S-4661: 1), is described. In the
previous process, chlorosulfonyl isocyanate was converted to
N-(tert-butoxycarbonyl)aminosulfonyl chloride (7), an extremely
unstable intermediate against moisture, which afforded the
target compound 4 using liquid ammonia at cryogenic temper-
atures in 90% isolated yield. The use of liquid ammonia
required cryogenic reaction temperatures because of heat
generated from the highly exothermic reaction and the low
boiling point of ammonia. In the improved process, the
deactivation of the sulfonyl chloride 7 with pyridine at 0 °C
afforded water-resistant N-(tert-butoxycarbonyl)aminosul-
fonylpyridinium salt (8) which was converted in situ to the
target compound 4 in the presence of water at 0 °C in 90-
96% isolated yields. Aqueous ammonia can be used, and no
cryogenic temperatures are necessary for this new one-pot
process.
the synthesis of ertapenem as a starting material.6 Both the
enolphophate 2 and the side chain 3 are now commercially
available. Both N-(tert-butoxycarbonyl)sulfamide (4)2,4 and
trans-4-hydroxy-L-proline (5) are raw materials for the side
chain 3.
Alcohols or phenols react with chlorosulfonyl isocyanate
(CSI: 6) to form alkyl or aryl N-(chlorosulfonyl)carbam-
ates,7,8 which react with amines containing a reactive
Introduction
Doripenem hydrate (S-4661: 1),1 which was discovered
by Shionogi Research Laboratories, Shionogi & Co., Ltd.,
Osaka, Japan, is a novel parenteral 1â-methylcarbapenem
antibiotic. In our previous reports,1,2 its synthesis, biology,
and structure-activity relationships (SAR) have been re-
ported. Compound 1 exhibited potent, broad, and well-
balanced antibacterial activity against a wide range of both
Gram-positiveandGram-negativebacteriaincludingPseudomo-
nas aeruginosa. Following conventional carbapenem ret-
rosynthetic analysis of a carbapenem (Scheme 1), doripenem
can be assembled from 4-nitrobenzyl-protected 1â-methyl-
carbapenem enolphosphate 23 and the aminosulfamoyl-
containing side chain 3.4,5 Enolphosphate 2 is also used for
(4) (a) A portion of this study was patented. Nishino, Y.; Yuasa, T.;
Komurasaki, T.; Kakinuma, M.; Masui, T.; Kobayashi, M. Patent Applica-
tion No. JP 2001-140782. (b) Nishino, Y.; Komurasaki, T.; Yuasa, T.;
Kakinuma, M.; Izumi, K.; Kobayashi, M.; Fujiie, S.; Gotoh, T.; Masui,
Y.; Hajima, M.; Takahira, M.; Okuyama, A.; Kataoka, T. Org. Process
Res. DeV. 2003, 7, 649-654.
(5) Nishino, Y.; Kobayashi, M.; Shinno, T.; Izumi, K.; Yonezawa, H.; Masui,
Y.; Takahira, M. Org. Process Res. DeV. 2003, 7, 846-850.
(6) Brands, K. M. J.; Jobson, R. B.; Conrad, K. M.; Williams, J. M.; Pipik,
B.; Cameron, M.; Davies, A. J.; Houghton, P. G.; Ashwood, M. S.; Cottrell,
I. F.; Reamer, R. A.; Kennedy, D. J.; Dolling, U.-H.; Reider, P. J. J. Org.
Chem. 2002, 67, 4771-4776.
† Current Address: Clinical Trial Drugs Producing Unit, Manufacturing
Technology R&D Laboratories, Shionogi & Co., Ltd., 1-3, Kuise Terajima
2-chome, Amagasaki, Hyogo 660-0813, Japan.
(7) (a) Graf, R. German Pat. 931467, Farbwerke Hoechst AG 1952. (b) Chem.
Zbl. 1955, 11094.
(1) Iso, Y.; Irie, T.; Nishino, Y.; Motokawa, K.; Nishitani, Y. J. Antibiotics
1996, 49, 199-209.
(2) Iso, Y.; Irie, T.; Iwaki, T.; Kii, M.; Sendo, Y.; Motokawa, K.; Nishitani,
Y. J. Antibiotics 1996, 49, 478-484.
(3) (a) Shih, D. H.; Baker, F.; Cama, L.; Christensen, B. G. Heterocycles 1984,
21, 29-40. (b) There are many efficient approaches to this compound 2:
Berks, A. H. Tetrahedron 1996, 52, 331-375. (c) This is commercially
available from Takasago, Kaneka, and Nisso companies.
(8) (a) Graf, R. Chem. Ber. 1963, 96, 56-67. (b) Picard, J. A.; O’Brien, P.
M.; Sliskovic, D. R.; Anderson, M. K.; Bousley, R. F.; Hamelehle, K. L.;
Krause B. R.; Stanfield, R. L. J. Med. Chem. 1996, 39, 1243-1252. (c)
Abdaoui, M.; Dewynter, G.; Aouf, N.; Favre, G.; Morere, A.; Montero,
J.-L. Bioorg. Med. Chem. 1996, 4, 1227-1235. (d) Abdaoui, M.; Dewynter,
G.; Montero, J.-L. Tetrahedron Lett. 1996, 37, 5695-5698. (e) Regainia,
Z.; Abdaoui, M.; Aouf, N.-E.; Dewynter, G.; Montero, J.-L. Tetrahedron
2000, 56, 381-387.
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Vol. 8, No. 3, 2004 / Organic Process Research & Development
10.1021/op0499728 CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/09/2004