Processes and intermediates for the preparation of 2-substituted

Details Processes and intermediates for the preparation of 2-substituted Processes and intermediates for the preparation of 2-substituted

1994-12-07

1997-08-19

Burn, Brian M.

Organic compounds -- part of the class 532-570 series

Organic compounds

Amino nitrogen containing

564409, 564414, 568426, 568436, C07C20942

Patent

active

056590849

DESCRIPTION:

BRIEF SUMMARY
This application is a 35 USC 371 of PCT/US93/02803, filed Mar. 25, 1993.


FIELD OF THE INVENTION

This invention relates to novel intermediates and processes for preparing useful intermediates in the synthesis of pharmaceutically active agents.


BACKGROUND

2-Substituted benzaldehydes are useful intermediates for preparing pharmaceutically active compounds. For example, certain compounds which are leukotriene antagonists and useful in the treatment of asthma may be prepared from 2-substituted benzaldehydes of the general formula(Ia): ##STR2## wherein:
R.sub.x is (L).sub.a --(CH.sub.2).sub.b --(T).sub.c --M;
a is 0or 1;
b is 3 to 14;
c is 0 or 1;
L and T are independently sulfur, oxygen, or CH.sub.2 ; and
M is C.sub.1-4 alkyl, ethynyl, trifluoromethyl, isopropenyl, furanyl, thienyl, cyclohexyl or phenyl optionally mono substituted with Br, Cl, CF.sub.3, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, methylthio, or trifluoromethylthio;
R.sub.2 and A are independently selected from H, CF.sub.3, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, F, Cl, Br, I, OH, NO.sub.2 or NH.sub.2 ;
or R.sub.1 and A are H and R.sub.2 is (L).sub.a --(CH.sub.2).sub.b --(T).sub.c --M wherein a, b, c, L, T, and M are as defined above.
Such compounds are disclosed, for instance in U.S. Pat. No. 4,820,719, U.S. Pat. No. 4,874,792 and EP-A 0 296 732, the disclosures of which are incorporated herein by reference. Accordingly, two general methods for preparing the 2-substituted benzaldehydes are reported therein: 1) palladium catalyzed addition of a substituted 1-alkynyl compound to a 2-halo benzaldehyde effects a coupling to provide a 2-(1-alkynyl)benzaldehyde directly, and 2) a 2-methoxy-benzoic acid may be converted to 2-(2-methoxy-phenyl)-4,4-dimethyl-oxazoline and treated with an alkyl or aralkyl Grignard reagent to prepare the corresponding 2-(2-alkyl phenyl)-4,4-dimethyl-oxazoline or 2-(2-aralkyl phenyl)4,4-dimethyl-oxazoline (subsequent treatment of the 2-substituted oxazoline with methyl iodide, reduction with sodium borohydride and subsequent acid hydrolysis produces the corresponding 2-substituted benzaldehyde). The latter method is based upon methods disclosed by Meyers et at., J. Org. Chem., 43, 1372(1978). Similar methods for preparing 2-substituted benzaldehydes are disclosed by Perchonock et al., J. Med. Chem., 28, 1145 (1985). In general, these methods employ reagents which functionally displace substituents upon the aryl ring.
Methods for adding an ortho substituent to an aryl ring by rendering the aryl ring nucleophilic are also known. Org. Reactions, 26, 43-61 (1979) discloses that certain functional groups which contain nitrogen heteroatoms and are attached to phenyl rings can stabilize a phenyl ring toward lithiation, preferably in the ortho position. The lithiated site may then be treated with a suitable electrophilic reagent to effect substitution. Functional groups which are reported therein to be particularly effective for this purpose are mono- or di-alkyl amides, amines, N,N-dialkyl hydrazones, imidazolines and oxazolines. De Silva et at., Tetrahedron Lett., 5107 (1978), report an ortho-lithiation of a benzamide using sec-butyllithium and a diisopropyl amine, and Trecourt et al., J. Org. Chem., 53, 1367 (1988), report ortho-lithiation of 2-methoxy-pyridine with methyllithium and a catalytic mount of diisopropylamine. Arylcarbimines, however, are reported to have limited synthetic utility due to their tendency to suffer from reaction at the azomethine linkage and alpha-deprotonation. See Org. Reactions, 26, 57-58 (1979). Zeigler et at., J. Org. Chem., 41, 1564 (1976) report that arylcarbimines may be induced to undergo ortho-lithiation if an adjacent ether substituent is present.
In addition, it has been reported that methyl groups can be lithiated if located in the ortho position of benzamides, 2-phenyl imidazolines and 2-phenyl oxazolines. Thus, Watanabe et al., J. Org. Chem., 49, 742 (1984) report chain extension via an ortho-toluamide in the synthesis of isocoumarins; Gschwend, et al., J. Org. Chem., 40, 2008 (1975), report ben

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