Process for the preparation of oxyiminoalkanoic acid...

Details Process for the preparation of oxyiminoalkanoic acid... Process for the preparation of oxyiminoalkanoic acid...

2002-04-25

2003-02-11

Ramsuer, Robert W. (Department: 1626)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C562S440000

Reexamination Certificate

active

06518435

ABSTRACT:

THIS APPLICATION IS A 371 OF PCT/JP00/07481 FILED OCT. 26, 2000.
TECHNICAL FIELD
The present invention relates to a production method of oxyimino-alkanoic acid derivatives having an anti-diabetic activity.
BACKGROUND ART
As a production method of oxyimino-alkanoic acid derivatives involving arylmethylation of the oxime moiety of oxime alkanoic acid, JP-A-10-168071 and JP-A-8-176127 disclose production methods of thiazole acetic acid derivatives used as a side chain of cefem antibiotics. According to the Examples of these publications, potassium carbonate, sodium carbonate or lithium carbonate is used as a base for introducing triphenylmethyl into the oxime moiety by the reaction of an oxime alkanoic acid derivative with triphenylmethyl chloride.
As a production method of oxyimino-alkanoic acid amide derivatives involving arylmethylation of the oxime moiety of oxime alkanoic acid amide, Tetrahedron, vol. 42, p. 6511 (1986) discloses a production method of a synthetic intermediate for &agr;,&bgr;-epoxytryptophan derivatives. According to this method, 1,2-dimethoxyethane is used as a solvent for the reaction of oxime alkanoic acid amide with benzyl bromide.
The present inventors found that, when a weak base, such as alkali metal carbonate and the like disclosed in the aforementioned publications, is used for producing a compound represented by the formula (III)
wherein R
1
is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; X is a bond, —CO—, —CH(OH)— or —NR
6
—(R
6
is a hydrogen atom or an optionally substituted alkyl group); n is an integer of 1 to 3; Y is an oxygen atom, a sulfur atom, —SO—, —SO
2
— or —NR
7
—(R
7
is a hydrogen atom or an optionally substituted alkyl group); ring A is a benzene ring optionally having 1 to 3 additional substituents; p is an integer of 1 to 8; R
2
is a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; q is an integer of 0 to 6; m is 0 or 1; and R
4
and R
5
are the same or different and each is a hydrogen atom or an optionally substituted hydrocarbon group, or R
4
may be bonded to R
2
to form a ring, or a salt thereof, a by-product occurs to lower the yield of the objective oxyimino-alkanoic acid derivative, potentially contaminating the final product as a related substance. It was also clarified that the removal thereof requires further purification by separation using silica gel column chromatography and the like, making operation complicated, and may adversely affect the environment through the disposal of a large amount of waste silica gel and the like.
The present inventors also found that, when a low polar solvent such as 1,2-dimethoxyethane and the like disclosed in the aforementioned papers, is used for producing a compound represented by the formula (V)
wherein R
8
and R
9
are the same or different and each is a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group, or R
8
and R
9
may be bonded to form a ring, and other symbols are as defined above, or a salt thereof, oxime alkanoic acid amide precipitates out in the reaction mixture as a metal salt, which significantly prevents progress of the reaction, lowers the reaction yield and causes residual starting materials. It was also clarified that, for removal of the residual starting materials, further purification by separation using silica gel chromatography and the like is necessary, which in turn makes operation complicated and possibly affects the environment adversely through the disposal of a large amount of waste silica gel and the like.
Under the circumstances, there is a strong demand for the development of an industrially advantageous and environmentally thoughtful production method of oxyimino-alkanoic acid derivatives, which can be put to use for practical production.
DISCLOSURE OF THE INVENTION
In an attempt to solve the above-mentioned problems, the present inventors have conducted intensive studies of an industrially advantageous production method of oxyimino-alkanoic acid derivatives, and found that the use of a metal alkoxide, which is a strong base, for the production of a compound represented by the above-mentioned formula (III) or a salt thereof by arylmethylation of the oxime moiety of oxime alkanoic acid suppresses formation of by-products. They have also found that the use of amides (polar solvents) as a reaction solvent for the production of oxyimino-alkanoic acid amide derivatives represented by the above-mentioned formula (V), by arylmethylation of the oxime moiety of oxime alkanoic acid amide increases reaction rates and decreases remaining starting material.
The present inventors have further developed the studies based on such findings, and, as a result, completed the present invention directed to a production method of oxyimino-alkanoic acid derivatives, which is an industrially advantageous and environmentally thoughtful production method that produces the derivatives having high quality in a high yield without purification by silica gel column chromatography.
Accordingly, the present invention provides
(1) a production method of a compound represented by the formula (III)
 wherein
R
1
is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group;
X is a bond, —CO—, —CH(OH)— or —NR
6
—(R
6
is a hydrogen atom or an optionally substituted alkyl group);
n is an integer of 1 to 3;
Y is an oxygen atom, a sulfur atom, —SO—, —SO
2
— or —NR
7
—(R
7
is a hydrogen atom or an optionally substituted alkyl group);
ring A is a benzene ring optionally having 1 to 3 additional substituents;
p is an integer of 1 to 8;
R
2
is a hydrogen atom or an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group;
q is an integer of 0 to 6;
m is 0 or 1; and
R
4
and R
5
are the same or different and each is a hydrogen atom or an optionally substituted hydrocarbon group, or R may be bonded to R
2
to form a ring,
 or a salt thereof, which comprises reacting a compound represented by the formula (I)
 wherein Z is a halogen atom or OSO
2
R
10
(R
10
is an alkyl group having 1 to 4 carbon atoms or an aryl group having 6 to 10 carbon atoms which is optionally substituted by alkyl group having 1 to 4 carbon atoms), and other symbols in the formula are as defined above, or a salt thereof, with a compound represented by the formula (II)
 wherein the symbols in the formula are as defined above, or a salt thereof, in an amide in the presence of a metal alkoxide,
(2) the production method of the above-mentioned (1), wherein the metal alkoxide is an alkali metal C
1-4
alkoxide,
(3) the production method of the above-mentioned (2), wherein the alkali metal C
1-4
alkoxide is sodium tert-butoxide,
(4) the production method of the above-mentioned (1), wherein the amide is N,N-dimethylacetamide, N,N-dimethylformamide, 1-methyl-2-pyrrolidone or 1,3-dimethyl-2-imidazolidinone,
(5) the production method of the above-mentioned (4), wherein the amide is N,N-dimethylacetamide,
(6) the production method of the above-mentioned (1), wherein the metal alkoxide is sodium tert-butoxide and the amide is N,N-dimethylacetamide,
(7) the production method of the above-mentioned (1), wherein the compound represented by the formula (III) is (E)-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutanoic acid or a salt thereof,
(8) the production method of the above-mentioned (1), wherein the compound represented by the formula (III) is (E)-8-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-8-phenyloctanoic acid or a salt thereof,
(9) a production method of a compound represented by the formula (V)
 wherein R
8
and R
9
are the same or different and each is a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group, or R
8
and R
9
may be bonded to form a ring, and other symbols are as d

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