Process for producing dikegulac, its salts and derivatives

Details Process for producing dikegulac, its salts and derivatives Process for producing dikegulac, its salts and derivatives

2000-02-23

2001-05-29

Trinh, Ba K. (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06239293

ABSTRACT:

TECHNICAL FIELD
The present invention relates generally to a process for the preparation of di-O-isopropylidene-2-Keto-L-gulonic acid (dikegulac) as well as its salts and related derivatives (e.g., esters).
BACKGROUND OF THE INVENTION
Dikegulac, its salts, and related derivatives are well known in the art to be useful as plant growth regulators and/or herbicides. Methods for the preparation of dikegulac, its salts, and related derivatives are described in, for example, U.S. Pat. No. 3,832,355 to Jaffe et al; U.S. Pat. No. 4,007,206 to Szkrybalo, U.S. Pat. No. 4,337,080 to Szkrybalo, and U.S. Pat. No. 5,688,971 to Kwiatkowski et al.
The present invention relates to a novel method for the preparation of dikegulac, its salts and related derivatives, from 2-Keto-L-gulonic acid. 2-Keto-L-gulonic acid is an important, well known and readily available intermediate in the manufacture and production of vitamin C. It is derived from sorbitol which is first oxidized to L-sorbose by bacteria. The L-sorbose is then subjected to condensation with acetone in the presence of sulfuric acid followed by oxidation with permanganate and hydrolysis of the diisopropylidene derivative (dikegulac) by boiling in the presence of an acid. This procedure is described in, for example, U.S. Pat. No. 2,301,811 to Reichstein. Also, much more efficient and cost effective processes to directly produce 2-Keto-L-gulonic acid are known. They do not involve its diisopropylidene derivative (dikegulac) as an intermediate. Biochemical oxidation using Pseudomonas is described in U.S. Pat. No. 3,043,749 to Huang while biochemical oxidation using Pseudomonas and Acetobacter is described in U.S. Pat. No. 3,234,105 to Motizuki, et al.
In the prior art, it has also been known to prepare dikegulac, its salts, and related derivatives by the treatment of 2-Keto-L-gulonic acid with 2,2-dimethoxypropane, (see U.S. Pat. No. 5,688,971 to Kwiatkowski et al.). However, the process uses a number of filtration, trituration, and drying steps which increase the time and cost needed to prepare the final product. In addition, the process of the prior art Kwiatkowski et al. patent uses large volumes of solvents. Although the prior art Kwiatkowski et al. process provided an improved approach for the preparation of dikegulac, the process described is still not as cost effective as it could be.
SUMMARY OF THE INVENTION
It is, accordingly, one object of the present invention to provide a new process for producing dikegulac, its salts, and related derivatives using readily available starting materials including 2-Keto-L-gulonic acid, an important and readily available intermediate from the production or manufacture of vitamin C.
A further object of the present invention is to provide a safe and effective process for the efficient and economical production of dikegulac, its salts, and related derivatives, well known to be useful as plant growth regulators and/or herbicides.
It is another object of the present invention to provide a process for the production of dikegulac, its salts, and related derivatives that is less time consuming and more cost efficient than the processes previously known.
Other objects and advantages of the present invention will become apparent as the description thereof proceeds.
In satisfaction of the forgoing objects and advantages there is provided by this invention a process for producing dikegulac. The process comprises reacting 2-Keto-L-gulonic acid
with a reagent selected from a group consisting of 2,2-dimethoxypropane and a mixture of 2,2-dimethoxypropane and acetone in the presence of a catalytic amount of a strong acid (e.g. sulfuric acid, an alkylsulphonic acid, an arylsulphonic acid) at an elevated temperature between 30°-50° C. and still more specifically between 35-45° C. (e.g. approximately 40° C.) to produce a reaction intermediate identified by structural formula (1).
This is followed by the step of reacting the reaction intermediate of formula (1) with a base to complete hydrolysis and produce an acid salt having a chemical formula (2)
wherein M
+
=sodium, potassium, ammonium, calcium, magnesium, copper, as well as other members of the alkali and alkaline earth metal groups of the periodic table. The process may further include reacting the acid salt with an acid to produce dikegulac. Preferably, from a stand point of efficiency and cost of production the base utilized in the process is sodium hydroxide and the acid utilized is sulfuric acid.


REFERENCES:
patent: 2301811 (1942-11-01), Reichstein
patent: 3043749 (1962-07-01), Huang
patent: 3234105 (1966-02-01), Motizuki
patent: 3832355 (1974-08-01), Jaffe
patent: 4007206 (1977-02-01), Szkrybalo
patent: 4337080 (1982-06-01), Szkrybalo
patent: 5688971 (1997-11-01), Kwiatkotski

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