Process for preparing halogenopyridine derivatives

Details Process for preparing halogenopyridine derivatives Process for preparing halogenopyridine derivatives

1998-05-06

2000-09-12

Rotman, Alan L.

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

546294, C07D21361, C07D21362, C07D21371

Patent

active

06118005&

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

The present invention relates to a process for preparing halogenopyridine derivatives. The halogenopyridine derivatives produced in accordance with the present invention are useful as intermediates for the synthesis of medicinal and agrochemical compounds, for example as intermediates for the synthesis of lazabemide, which is under clinical development as an antiparkinsonian agent.


BACKGROUND ART

The so-far known processes for preparing halogenopyridine derivatives, for example 2,5-dichloropyridine, typically comprise reacting 3-chloropyridine-N-oxide with phosphorus oxychloride [cf. Chem. Pharm. Bull., Vol. 36, page 2244 (1988)], or chlorinating 2-chloropyridine (cf. Japanese Patent Application Laid-Open No. Sho 58-206564), or chlorinating 2-amino-5-chloropyridine (cf. Laid-open British Patent Specification 1,215,387).
However, the above-mentioned processes for preparing halogenopyridine derivatives cannot be said to be good processes for preparing halogenopyridine derivatives, since they have problems, for instance, the selectivity in the chlorination step is low, isomers which are difficult to separate are formed, and/or the raw materials are expensive.
On the other hand, a process for preparing pyridine derivatives by using a cyclization reaction is known. It comprises reacting a methyl-substituted butadienyl ester with a sulfonyl cyanide and then reacting the resulting methyl-substituted 2-sulfonylpyridine derivative with a halogenating agent to give the corresponding halogenomethyl-2-halogenopyridine (cf. Laid-open International Patent Application 96/26188). However, the cyclization reaction between a halogeno-1,3-butadienyl ester and a sulfonyl cyanide remains unknown and the halogenation of halogeno-2-sulfonylpyridine derivatives is also unknown.
It is known that when comparison is made between a methyl-substituted 1,3-butadiene (typically isoprene) and a halogen-substituted 1,3-butadiene (typically chloroprene), which are similar in structure and for which several cyclization reactions are known, the reactivity of chloroprene in the cyclization reactions is very low, namely 1/22 to 1/1100 of that of isoprene and chloroprene reacts slowly in spite of the fact that the difference in chemical structure therebetween is slight, namely the only difference is that the substituent is methyl or chlorine [cf. Kobunshi Jikkengaku (Experiments in Polymer Science), Vol. 2, Monomers I, page 171 (1971); The Chemistry of Alkenes (Interscience Publishers), page 921 (1964); J. Org. Chem., Vol. 47, page 1453 (1982); Ind. Eng. Chem., Fundam., Vol. 13, page 174 (1974)]. Furthermore, as regards the polymerization reaction predictable as a side reaction, it is known that chloroprene polymerizes more readily than isoprene [cf. Kobunshi Jikkengaku, Vol. 2, Monomers I, page 171 (1971)].
In spite of the above comparisons between isoprene and chloroprene, which make it very doubtful whether the use of a halogeno-1,3-butadienyl ester, instead of the corresponding methyl-substituted butadienyl ester, in the cyclization reaction known for the methyl-substituted butadienyl ester would allow the desired cyclization addition reaction to proceed with good efficiency, without leading to polymerization, the present inventors found that when a halogeno-1,3-butadienyl ester is reacted with a sulfonyl cyanide, the desired cyclization reaction proceeds with good efficiency. This finding has led to completion of the present invention.
The cyclization reaction between a methyl-substituted butadienyl ester and a sulfonyl cyanide is carried out batchwise, as described in the above-cited laid-open International Patent Application. The present inventors found that when the reaction is operated on a large scale, it becomes very difficult to control the reaction temperature, because such reaction involves marked heat generation while heating is required for initiating the reaction. While the same applies to the reaction between a halogeno-1,3-butadienyl ester and a sulfonyl cyanide, the present inventors found that it is poss

REFERENCES:
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