Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-01-02
2002-02-05
Higel, Floyd D. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C558S342000
Reexamination Certificate
active
06344569
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a process for producing 6-cyanomethyl-1,3-dioxane-4-acetic acid derivatives by which process an intermediate of medicinal compounds, in particular 1,1-dimethylethyl (4R,6R)-6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate (formula (9)),
which is an important intermediate for the production of the HMG coenzyme A reductase inhibitor atrovastatin (described in International Patent Application 93/07115 pamphlet), and the like, can be produced.
BACKGROUND ART
In the International Patent Application 89/07598 pamphlet, there are disclosed a process starting with isoascorbic acid and a process starting with an optically active epoxide for the production of 1,1-dimethylethyl (4R, 6R)-6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate. For the production thereof from raw materials readily available on the market, however, either process requires an excessively large number of steps and is complicated.
A process is disclosed in the specification of U.S. Pat. No. 5,103,024 which starts with (4R-cis)-1,1-dimethylethyl 6-hydroxymethyl-2,2-dimethyl-1,3-dioxane-4-acetate and derives the desired substance therefrom by two steps, namely conversion to an arylsulfonate and cyanation. However, the starting material disclosed therein is expensive and a multistep synthetic process is required for the preparation of the starting material itself from commercially available materials.
In the specification of U.S. Pat. No. 5,155,251, a process for the production of the desired product is disclosed which comprises cyanating an (S)-4-chloro-3-hydroxybutyric acid ester, reacting with an enolate anion derived from tert-butyl acetate to provide (5R)-1,1-dimethylethyl 6-cyano-5-hydroxy-3-oxohexanoate, and stereoselectively reducing the ketone carbonyl group of the same with a hydride, followed by conversion of the resulting 1,3-diol to the corresponding acetonide.
In the International Patent Application 97/00968 pamphlet, there is disclosed a process for producing the desired product which comprises stereoselectively reducing (5R)-1,1-dimethylethyl 6-cyano-5-hydroxy-3-oxohexanoate with a microorganism, followed by conversion of the resulting 1,3-diol to the corresponding acetonide.
While the compound (5R)-1,1-dimethylethyl 6-cyano-5-hydroxy-3-oxohexanoate, which is commonly used in the processes described in the specification of U.S. Pat. No. 5,155,251 and the Laid-open International Patent Application 97/00968 pamphlet, can be prepared by the process described in the specification of U.S. Pat. No. 5,155,251, investigations by the present inventors revealed that, in the cyanation reaction of the (S)-4-chloro-3-hydroxybutyric acid ester in that process, an unfavorable side reaction, namely a side reaction resulting from epoxide formation under the reaction conditions (J. Org. Chem., 32 (1967), p. 3888) proceeds, resulting in decreases in reaction yield and product purity.
Accordingly, it is an object of the present invention to provide a process for producing a 6-cyanomethyl-1,3-dioxane-4-acetic acid derivative of the general formula (3), which is an important intermediate of medicinal compounds.
wherein R
1
, R
2
and R
3
each independently represents a hydrogen atom, an alkyl group containing 1 to 12 carbon atoms, an aryl group containing 6 to 10 carbon atoms or an aralkyl group containing 7 to 12 carbon atoms, and an optically active isomer thereof from a raw material readily available on the market, at low cost and in high yields.
SUMMARY OF THE INVENTION
The present inventors made intensive investigations in an attempt to solve the above problems and, as a result, succeeded in developing a process which uses, as the starting material, a 3,5-dihydroxy-6-halohexanoic acid derivative of the general formula (1):
wherein R
1
represents a hydrogen atom, an alkyl group containing 1 to 12 carbon atoms, an aryl group containing 6 to 10 carbon atoms or an aralkyl group containing 7 to 12 carbon atoms, and X represents a halogen atom, which can be readily prepared from a 4-chloro-3-hydroxybutyric acid ester readily available on the market in good yields by a per se known two step process, for instance, and by which 6-cyanomethyl-1,3-dioxane-4-acetic acid derivatives of the general formula (3):
wherein
R
1
is as defined above, and R
2
and R
3
each independently represents a hydrogen atom, an alkyl group containing 1 to 12 carbon atoms, an aryl group containing 6 to 10 carbon atoms or an aralkyl group containing 7 to 12 carbon atoms,
can efficiently be produced by a two step process.
The invention thus provides a process for producing a 6-cyanomethyl-1,3-dioxane-4-acetic acid derivative of the above general formula (3)
which comprises cyanation of a 3,5-dihydroxy-6-halohexanoic acid derivative of the above general formula (1) by reaction with a cyanating agent for substitution of a cyano group for the halogen atom
and an acetal formation reaction of the diol moiety with an acetal forming reagent in the presence of an acid catalyst.
The above process is realized by reacting the 3,5-dihydroxy-6-halohexanoic acid derivative of the above general formula (1) with a cyanating agent to provide a 6-cyano-3,5-dihydroxyhexanoic acid derivative of the general formula (2):
wherein
R
1
is as defined above,
followed by an acetal formation reaction of the same with an acetal forming reagent in the presence of an acid catalyst, or by subjecting the 3,5-dihydroxy-6-halohexanoic acid derivative of the above general formula (1) to an acetal formation reaction with an acetal forming reagent in the presence of an acid catalyst to provide a 6-halomethyl-1,3-dioxane-4-acetic acid derivative of the general formula (7):
wherein R
1
, R
2
, R
3
and X are as defined above,
followed by cyanating it with a cyanating agent.
In particular, the present inventors newly found that the substitution reaction of X which proceeds upon reacting a 3,5-dihydroxy-6-halohexanoic acid derivative of the above general formula (1) with a cyanating agent proceeds very effectively owing to the neighboring group effect by the hydroxyl group adjacent to X and, as a result, the corresponding 6-cyano-3,5-dihydroxyhexanoic acid derivative of the above general formula (2) can be produced with great efficiency.
It was further found by the present inventors that when an optically active 3,5-dihydroxy-6-halohexanoic acid derivative is used as the starting material, the corresponding optically active 6-cyano-3,5-dihydroxyhexanoic acid derivative and optically active 6-cyanomethyl-1,3-dioxane-4-acetic acid derivative can be produced, with the configuration of each center of asymmetry being retained.
In the following, the present invention is explained in detail.
DETAILED DISCLOSURE OF THE INVENTION
Two routes were found by the present inventors for the production of a 6-cyanomethyl-1,3-dioxane-4-acetic acid derivative (3) from the corresponding 3,5-dihydroxy-6-halohexanoic acid derivative (1), as shown by the scheme 1 given below.
The first route (hereinafter referred to as “route A”) constitutes a process for producing a 6-cyanomethyl-1,3-dioxane-4-acetic acid derivative (3) which comprises cyanating a 3,5-dihydroxy-6-halohexanoic acid derivative (I) with a cyanating agent (step I) and subjecting the resulting 6-cyano-3,5-dihydroxyhexanoic acid derivative (2) to an acetal formation reaction with an acetal forming reagent in the presence of an acid catalyst (step II).
The second route (hereinafter referred to as “route B”) constitutes a process for producing a 6-cyanomethyl-1,3-dioxane-4-acetic acid derivative (3) which comprises subjecting a 3,5-dihydroxy-6-halohenxanoic acid derivative (1) to an acetal formation reaction with an acetal forming reagent in the presence of an acid catalyst (step III) and cyanating the resulting 6-halomethyl-1,3-dioxane-4-acetic acid derivative (7) with a cyanating agent (step IV).
Referring to the common starting material for route A and route B, namely the 3,5-dihydroxy-6-halohexanoic acid derivative of the general formula (1):
R
1
is a hydrogen atom, an alkyl group containin
Inoue Kenji
Mitsuda Masaru
Miyazaki Makoto
Connolly Bove Lodge & Hutz
D'Souza Andrea M
Higel Floyd D.
Kaneka Corporation
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