Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1996-05-23
1998-03-10
Rotman, Alan L.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
546296, 546298, 546300, 546301, 546302, C07D21369, C07D21370, C07D21378
Patent
active
057263159
DESCRIPTION:
BRIEF SUMMARY
CROSS-REFERENCE
This application is a 371 of PCT/EP94/02028 filed Jun. 20, 1994.
The present invention relates to an improved process for the preparation of substituted pyridine derivatives. Substituted pyridine derivatives are disclosed in WO93/06085 as medicaments being useful for the treatment of various diseases such as psoriasis.
Various processes for the preparation of these medicaments are also disclosed in WO93/06085. In particular, methyl pyridine, that is to say, the compound of the following structure: ##STR3## is disclosed as an important intermediate compound. However, the known procedure for the preparation of this type of compound is not ideally suited to large scale application. The object of the present invention is to provide an alternative process, using organometallic chemistry, for the preparation of such intermediates which is suitable for large scale commercial use. Palladium catalysed coupling reactions of halopyridines are known in the art, e.g. Chem. Pharm. Bull. vol. 33, 1985, pages 4764-4768.
The present invention therefore provides, in a first aspect, a process for the preparation of a compound of formula (I) or a salt or N-oxide thereof: ##STR4## in which R.sup.1 is hydrogen, benzyl or a group of formula (A): ##STR5## in which n is 1 to 20; and R.sup.5 is hydrogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy or trifluoromethyl; alkyl; and ##STR6## in which R.sup.1 is as defined in formula (I) and R.sup.7 is a leaving group, with a compound of formula (III) or a salt thereof: ##STR7## in which R.sup.2, R.sup.3 and R.sup.4 are as defined in formula (I) in the presence of an organometallic catalyst, and optionally thereafter: formula (I)
Suitable organometallic catalysts include, for example, palladium catalysts. Those skilled in the art will appreciate that palladium catalysts can, if desired, be formed in situ. The processes of the invention can be carded out using pre-prepared catalysts or catalysts formed in situ. Preferred catalysts are palladium (II) catalysts such as Pd(OAc).sub.2, Pd(OAc).sub.2 /(o-tol).sub.3 P, Pd(OAc).sub.2 /Ph.sub.3 P, Pd(OAc).sub.2 /tri(2-furyl)phosphine, (Ph.sub.3 P).sub.2 PdCl.sub.2 and PdCl.sub.2 /Ph.sub.3 P.
Preferably R.sup.1 is a group of formula (A) where R.sup.5 is C.sub.1-6 alkoxy, for example methoxy. When R.sup.1 is a group of formula (A), n is suitably 1 to 20, preferably n is 2 to 8.
Suitably R.sup.2 and R.sup.3 are hydrogen or C.sub.1-6 alkyl, preferably R.sup.2 and R.sup.3 are both hydrogen.
Suitably R.sup.4 is cyano or CO.sub.2 R.sup.6 where R.sup.6 is hydrogen or C.sub.1-6 alkyl, preferably R.sup.4 is CO.sub.2 R.sup.6 where R.sup.6 is C.sub.1-6 alkyl such as methyl or butyl.
Suitably R.sup.7 is a leaving group such as halogen, OTf or (Triflate, e.g. OSO.sub.2 CF.sub.3) and OSO.sub.2 Ar where Ar is an optionally substituted aryl group. Suitable substituents include C.sub.1-6 alkyl, for example methyl. Preferably R.sup.7 is halogen, in particular bromo or iodo.
Preferred compounds of formula (I) which can be prepared using the above process include: propenoate, propenoate, propenoate, acid,
The coupling reaction is carried out in a suitable solvent, preferably at elevated temperature. Preferably the coupling reaction is carried out in DMF, in particular aqueous DMF, at a temperature of about 80.degree. to about 160.degree. C., preferably at about 120.degree. C.
The term `salts` in relation to compounds of formula (III) refers to carboxylate salts of compounds of formula (III), in which R.sup.4 is CO.sub.2.sup..crclbar. M.sup..sym. where M is a metal ion such as sodium or potassium. Examples of such compounds include potassium acrylate.
Salts of compounds of formula (I) can be prepared by treatment with an inorganic or organic acid, or when R.sup.4 is CO.sub.2 H, by treatment with an inorganic or organic base. N-oxides of the pyridyl nitrogen can be prepared using standard techniques.
Compounds of formulae (II) and (III) are commercially available or can be prepared using standard procedures well known to those skilled in the art.
For example, co
REFERENCES:
patent: 3952101 (1976-04-01), Jen et al.
Chemical & Pharmaceutical Bulletin; Sakamoto, et al.; vol. 33, No. 11; pp. 4764-4768.
M.G. Dauben `Organiz Reactions vol. 27, Chapter 1`; 1982, Wiley, NY; pp. 354-356.
Journal of Organic Chemistry; Taylor & Wong; vol. 54, No. 15; 1989; pp. 3618-3624.
Journal of Organic Chemistry; Frank, et al.; vol. 43, No. 15; 1978; pp. 2947-2949.
Chemical & Pharmaceutical Bulletin; Sakamoto, et al.; vol. 30, No. 10; 1982; pp. 3647-3656.
Chemical & Pharmaceutical Bulletin; Edo et al.; vol. 27, No. 1; 1979; pp. 193-197.
Chem.Abstracts,vol.116,No.23, abst.No.116:235,440w,Jun. 8, 1992.
Chem.Abstracts,vol. 119,No.13,abst.No.119:139,113h,Sep. 27, 1993.
Bickle Peter William
Powling Laurence Charles
Sheldrake Peter William
Kanagy James M.
Lentz Edward T.
Rotman Alan L.
SmithKline Beecham Plc
Venetianer Stephen
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