7900
J . Org. Chem. 1997, 62, 7900-7901
Communications
Syn th esis of ML-3000, a n In h ibitor of
Cyclooxygen a se a n d 5-Lip oxygen a se
Sch em e 1
J anine Cossy* and Damien Belotti
Laboratoire de Chimie Organique, Associe´ au CNRS,
ESPCI, 10 rue Vauquelin, 75231 Paris Cedex 05, France
Received August 11, 1997
Dual inhibitors of cyclooxygenase and 5-lipoxygenase
of the arachidonic acid cascade have potential as agents
for the treatment of arthritis.1,2 Recently, 2,3-dihydro-
1H-pyrrolizine derivatives such as ML-3000 have been
proven to selectively inhibit the enzymes cyclooxygenase
(IC50 ) 0.2l µM) and 5-lipoxygenase (IC50 ) 0.18 µM).1,2
ML-3000 is the most potent and well-balanced dual
inhibitor of both enzymes. However, the previous syn-
thesis of this nonsteroidal antiinflammatory drug pro-
ceeds with poor overall yield (<5%).1
Sch em e 2. Syn th esis of ML-3000a
Herein, we report a short and efficient synthesis of ML-
3000 that features a thermal acid-promoted bicyclization
of an ω-acetylenic amino ester. In a previous paper, we
described a convenient synthetic method that provided
access to polysubstituted pyrrolidines based on thermal
cyclization of ω-acetylenic amines.3 A smooth thermoly-
sis of ω-acetylenic amines A in the presence of 1 equiv of
acetic acid or pivalic acid without solvent led to cyclic
enamines B, which could be reduced to the corresponding
pyrrolidines C. Furthermore, we have reported an
extension of this method in which the enamine B is
trapped intramolecularly with an appropriate acceptor
such as an ester group to provide an efficient synthesis
of substituted 2,3,5,6-tetrahydro-6-oxo-1H-pyrrolizines
D.4,5 (Scheme 1).
The ω-acetylenic amino ester 3 required for the syn-
thesis of the 2,3-dihydro-1H-pyrrolizine skeleton of ML-
3000 was obtained from 1-chloro-3-phenyl-2-propyne (1)
in two steps. Treatment of chloride 1 with isobutyral-
dehyde under basic phase-transfer catalysis6 in the
presence of a catalytic amount of NaI produced the
aldehyde 2 (90%). This aldehyde was condensed with
methyl glycinate hydrochloride under reductive amina-
tion conditions7 to furnish the ω-acetylenic amino ester
3 (80%). In the key step, the tetrahydro-6-oxo-1H-
pyrrolizine 4 was isolated in good yield (68%) when the
a
Key: (i) isobutyraldehyde, cat. n-Bu4NI, cat. NaI, NaOH/H2O/
toluene, 50 °C; (ii) glycine methyl ester hydrochloride, NaB-
H(OAc)3, Et3N, CH2Cl2 or 1,2-dichloroethane, rt; (iii) ∆, 150 °C, 1
equiv of t-BuCO2H; (iv) (a) EtONa, (EtOCO)2, EtOH, rt, (b) AcOH;
(v) (a) NaH, THF, rt, (b) PhN(SO2CF3)2, rt; (vi) (4-chlorophenyl)-
boronic acid, cat. Pd(PPh3)4, Na2CO3/H2O, THF, reflux; (vii) (a)
p-toluenesulfonyl hydrazide, cat. p-TsOH, EtOH, reflux, (b)
NaBH3CN, EtOH, reflux; (viii) NaOH, H2O, EtOH, 80 °C.
* To whom correspondence should be addressed. Phone: (+33) 1
40 79 44 29. Fax: (+33) 1 40 79 44 25. E-mail: janine.cossy@espci.fr.
(1) Laufer, S. A.; Augustin, J .; Dannhardt, G.; Kiefer, W. J . Med.
Chem. 1994, 37, 1894-1897 and references therein.
(2) Rabasseda, X.; Mealy, N.; Castan˜er, J . Drugs Future 1995, 20,
1007-1009.
(3) Cossy, J .; Belotti, D.; Bellosta, V.; Boggio, C. Tetrahedron Lett.
1997, 38, 2677-2680.
(4) Belotti, D.; Cossy, J . Synlett 1997, in press.
(5) Cossy, J .; Belotti, D. French Patent 9612760, Oct 21, 1996.
(6) Dietl, H. K.; Brannock, K. C. Tetrahedron Lett. 1973, 1273-1275.
(7) Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C.
A.; Shah, R. D. J . Org. Chem. 1996, 61, 3849-3862.
ω-acetylenic amino ester 3 was heated at 150 °C in the
presence of 1 equiv of pivalic acid without solvent.4,5 The
carboxylic acid side chain of ML-3000 was introduced by
acylation of the tetrahydro-6-oxo-1H-pyrrolizine with
diethyl oxalate under basic conditions.8 The resulting
â-diketone 5 (77%) was entirely enolized. The introduc-
S0022-3263(97)01480-1 CCC: $14.00 © 1997 American Chemical Society