Process for producing butyric ester derivatives

Details Process for producing butyric ester derivatives Process for producing butyric ester derivatives

1999-09-07

2000-10-31

McKane, Joseph K.

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

Organic compounds

Nitriles

558337, 558342, C07C25300

Patent

active

061405272

DESCRIPTION:

BRIEF SUMMARY
FIELD OF THE INVENTION

The present invention relates to a process for producing a butyric acid ester derivative of the following general formula (2) ##STR2## (wherein R represents a straight-chain or branched-chain alkyl group containing 1 to 4 carbon atoms).
The above butyric acid ester derivative of the general formula (2) is an important key intermediate for the production of fine chemicals, for example pharmaceuticals such as the antihyperlipidemic agent atorvastatin of the following formula (4) (Japanese Kohyo Publication Hei-7-500105) and agrochemicals. ##STR3##


BACKGROUND OF THE INVENTION

The known technology for producing a butyric acid ester derivative of the above general formula (2) comprises reacting a compound of the following general formula (3) with a salt of prussic acid ##STR4## (wherein R is as defined above. X represents a group selected from the group consisting of chlorine atom, bromine atom, iodine atom, methanesulfonyloxy group, and substituted or unsubstituted phenylsulfonyloxy group).
More particularly, the typical known technology either comprises reacting ethyl 4-bromo-3-hydroxybutyrate or ethyl 4-toluenesulfonyloxy-3-hydroxybutyrate with sodium cyanide (Japanese Kohyo Publication Hei-7-500105) or comprises reacting ethyl 4-chloro-3-hydroxybutyrate, n-butyl 4-chloro-3-hydroxybutyrate or t-butyl 4-chloro-3-hydroxybutyrate with sodium cyanide (Japanese Kokai Publication Hei-5-331128).
However, the published literature referred to above are quite reticent about the impurity as a contaminant of the product derivative, a method of inhibiting formation of such impurity or a method for removing the impurity.
The inventors of the present invention scrutinized the production processes disclosed in the above published literature and found that in those known processes the by-production of a compound containing an ethylenic bond such as a compound of the following general formula (1) is inevitable and further that some impurities are formed from this byproduct containing an ethylenic bond as a precursor.
Furthermore, the routine purification techniques such as extraction, washing, distillation and crystallization are not efficient enough to remove the above compound containing an ethylenic bond but involve a large purification loss of the butyric ester derivative of the general formula (2), etc. Therefore, as the inventors found that, even if the commercially feasible ordinary isolation and purification procedures described in the above literature are followed, it is difficult to provide the objective butyric acid ester derivative of the general formula (2) in high yield, economically and in a sufficiently high quality grade suitable for use as an intermediate in the production of fine chemicals such as pharmaceuticals and agrochemicals.
Furthermore, the reaction between said compound of the general formula (3) and said salt of prussic acid is a rather violent exothermic reaction and, therefore, although the batch process comprising charging a reactor with the total amounts of both reactants, i.e. said compound of the general formula(3) and salt of prussic acid, in one operation and reacting them at a controlled reaction temperature is feasible on a small laboratory scale because of the ease of heat removal, it is not the case with a commercial production run in which the reaction temperature can hardly be controlled because of the rapid temperature build-up of the reaction system due to the heat of reaction and, moreover, the occasional bumping of the reaction mixture makes it difficult to safely and commercially conduct this reaction involving the use of a salt of prussic acid which is highly toxic. In addition, the semi-batch process which comprises charging a reactor with either the compound of the general formula(3) or the salt of prussic acid in advance of the other, setting the reaction temperature at the necessary level and then feeding the other reactant gradually makes it possible to control the rate of heat evolution and, hence, conduct the reaction with the reaction temperat

REFERENCES:
patent: 5430171 (1995-07-01), Mitsuhashi et al.
patent: 5908953 (1999-06-01), Matsuda et al.

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