Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-03-18
2002-11-12
Morris, Patricia L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06479664
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a process for the preparation of 2-chloro-5-methylpyridine-3-carbaldehyde, a useful intermediate for the variety of pharmaceutical and pesticide products. The present invention particularly relates to a process for the preparation of 2-chloro-5-methylpyridine-3-carbaldehyde of formula 1 given below using diphosgene and triphosgene.
The present invention also relates to a process for the preparation of 2-chloro-5-methyl-pyridine-3-carbaldehyde under suitable conditions of mole ratio, time and temperature with high selectivity.
BACKGROUND OF THE INVENTION
Several pyridine, quinoline and isoquinoline compounds are important intermediates in that they have been reported as potential anti tumor agents (J. Med. Chem, 19, 1209, 1976; CA 85: 116544q). Carbaldehyde based products served as ulcer healing agents (Ger. Offen DE 3324034, 1984; CA 101:54936g), allergy inhibitors (EP 120483, 1984; CA 102:95649e; EP120484, 1984; CA 102:113500f), antiviral agents (CA 113:172015b), and useful as intermediates for pharmaceuticals (Ger. Offen DE 4429465, 1996; CA 124:343116u).
Substituted pyridine carbaldehyde is an important compound to prepare the amlexanox a drug which is useful for treatment of mucosites and in the treatment of aphthous ulcers (Drgs of the future 25(5), 511,200).
Chloropyridinecarbaldehyde is a very useful intermediate to make various compounds like sulfones and vinyl pyridines in organic syntheses (Heterocyclic Commun, 5(3), 257,1999) 1,2,3,4-tetrahydrodibenzo-1,8-naphthyridines are prepared from 2-chloro-3-formyl quinolines (Hetero-cyclic Commun. 6(1),63,2000).
There is only one method appeared in the literature for the preparation of 2-chloro-5-methylpyridine-3-carbaldehyde in 12% yield (J. C. S. Perkin Trans. 1,1173, 1984).
OBJECTS OF THE INVENTION
The main object of the invention is to provide an improved method for the preparation of 2-chloro-5-methylpyridine-3-carbaldehyde in improved yield.
It is another object of the invention to provide an improved method for the preparation of 2-chloro-5-methylpyridine-3-carbaldehyde with shorter reaction times and suitable temperatures.
It is another object of the invention to provide an improved method for the preparation of 2-chloro-5-methylpyridine-3-carbaldehyde wherein product isolation is very easy.
It is another object of the invention to provide an improved method for the preparation of 2-chloro-5-methylpyridine-3-carbaldehyde using easily handled non-toxic diphosgene and triphosgene.
SUMMARY OF THE INVENTION
The present invention describes an improved process for the preparation of 2-chloro-5-methylpyridine-3-carbaldehyde from N-benzyl-N-(1-Propenyl) acetamide using diphosgene and dimethylformamide or triphosgene and dimethylformamide (Vilsmeyer reagent) in 92% yield against reported 12% yield. The present invention has the advantage of using diphosgene and triphosgene instead of toxic phosgene gas and phosphorousoxytrichloride, thereby avoiding the formation of phosphorous salt.
Accordingly the present invention provides a process for the preparation of 2-chloro-5-methylpyridine-3-carbaldehyde of the formula 1 below
comprising reacting N-benzyl-N-(1-Propenyl) acetamide with a reagent selected from dimethylformamide mixed with diphosgene or triphosgene (Vilsmeyer reagent) under dry conditions at a temperature in the range of 75-100° C.
In another embodiment of the invention, the reaction is carried out for a time period in the range of 4-16 hours.
In another embodiment of the invention, the mole ratio of dimethylformamide to diphosgene or triphosgene is in the range of 1:1-2.
In a further embodiment of the invention, the mole ratio of dimethylformamide to diphosgene is in the range of 1:1-2.
In a further embodiment of the invention, the mole ratio of dimethylformamide to triphosgene is 1:1.
In a further embodiment of the invention, N-benzyl-N-(1-Propenyl)acetamide and reagent are mixed before heating in an ice cold bath.
In another embodiment of the invention, the mole ratio of diphosgene and triphosgene with dimethylformamide is critical to the formation of the formylating reagent and subsequent formation of the cyclised product leading to 2-chloro-5-methylpyridine-3-carbaldehyde.
DETAILED DESCRIPTION OF THE INVENTION
The following examples are given by way of illustration of the present invention and there fore should not be construed to the scope of the present invention.
REFERENCES:
patent: 5708180 (1998-01-01), Beck et al.
patent: 0 702 003 (1996-03-01), None
patent: 0 702 003 (1996-03-01), None
Cohn et al., “A Versatile New Synthesis of Quinoline and Related Fused Pyridines. Part 12.1A General Synthesis of 2-Chloropyridines and 2-Pyridones”, J. Chem. Soc. Perkin Trans. 1, 1984, pp. 1173-1182.
Banda Gangadasu
Bhimapaka Chinaraju
Rao Vaidya Jayathirtha
Burns Doane Swecker & Mathis L.L.P.
Council of Scientific and Industrial Research
Morris Patricia L.
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