Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-08-16
2002-10-29
Solola, T. A. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C549S375000
Reexamination Certificate
active
06472544
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a process for producing optically active 2-[6-(hydroxymethyl)-1, 3-dioxan-4-yl ]acetic acid derivatives which are of value as intermediates of drugs, particularly intermediates of HMG-CoA reductase inhibitors.
BACKGROUND ART
For the production of a
2-[6
-(hydroxymethyl)-1,3-dioxan-4-yl]acetic acid derivative, the following processes are known.
(1) A process starting with 3-hydroxy-&ggr;-butyrolactone to synthesize a 3,5,6-trihydroxyhexanoic acid ester derivative via a 3,5-dihydroxyhexanoic acid ester derivative (Japanese Kokai Publication Hei-4-173767).
(2) A process starting with 3,4-dihydroxybutyronitrile acetonide to synthesize a 3,5,6-trihydroxyhexanoic acid ester derivative via a 3,5-dihydroxyhexanoic acid ester derivative (Japanese Kokai Publication Hei-2-262537).
(3) A process starting with a 4-chloroacetoacetic acid ester to synthesize a 3,5,6-trihydroxyhexanoic acid ester derivative via conversion to a benzyloxy derivative, reduction and chain extension (Japanese Kokai Publication Hei-6-65226).
(4) A process starting with a 4-chloro-3-hydroxybutyric acid ester to synthesize a 3,5,6-trihydroxyhexanoic acid ester derivative through chain extension, reduction, etc. (USP 5278313).
(5) A process starting with malic acid to synthesize a 3,5,6-trihydroxyhexanoic acid ester via a 2,4-dihydroxyadipic acid derivative (Japanese Kokai Publication Hei-4-69355).
However, those processes involve reactions at a super-low temperature in the neighborhood of −80° C. (1, 2, 4, 5) or a hydrogenation reaction at a high pressure of 100 kg/cm
2
(3), thus requiring the use of special reaction equipment. Moreover, the processes involve the use of costly reagents in some stage or other and, therefore, none of them is an efficient process for commercial-scale production.
The prior art process (4), for instance, comprises reacting a 4-chloro-3-hydroxybutyric acid ester with an enolate of tert-butyl acetate using costly lithium hexamethyl disylazide at a super-low temperature of −78° C. in the first step and performing a stereoselective reduction using costly diethylmethoxyborane and sodium borohydride, again at a super-low temperature of −78° C., in the second step. This process further involves an acetoxylation reaction with costly tetra-n-butylammonium acetate in the costly solvent 1-methyl-2-pyrrolidinone.
SUMMARY OF THE INVENTION
The present invention, developed in the above state of the art, has for its object to provide an expedient process for producing an optically active 2-[6-(hydroxymethyl)-1,3-dioxan-4-yl]acetic acid derivative of the following general formula (I) from inexpensive starting materials without using any special equipment such as that required for super-low temperature reactions.
wherein R
1
represents hydrogen, an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms or an aralkyl group of 7 to 12 carbon atoms, R
4
and R
5
each independently represents hydrogen, an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms or an aralkyl group of 7 to 12 carbon atoms, and R
4
and R
5
may be conjoined each other to form a ring.
As the result of intensive investigations made in light of the above state of the art, the inventors of the present invention have developed an expedient process for producing an optically active 2-[6-(hydroxymethyl)-1,3-dioxan-4-yl]acetic acid derivative of the following general formula (I):
wherein R
1
represents hydrogen, an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms or an aralkyl group of 7 to 12 carbon atoms, R
4
and R
5
each independently represents hydrogen, an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms or an, aralkyl group of 7 to 12 carbon atoms, and R
4
and R
5
may be conjoined each other to form a ring, from inexpensive, readily available starting materials without employing any extraordinary equipment such as that required for low-temperature reactions.
The present invention, thus, is concerned with a process for producing said optically active 2-[6-(hydroxymethyl)-1,3-dioxan-4-yl]acetic acid derivative (I):
wherein R
1
, R
4
and R
5
are respectively as defined below, which comprises
(1) a step comprising reacting an enolate prepared by permitting either a base or a metal having a valency of 0 to act on an acetic ester derivative of the following general formula (II):
wherein R
1
represents hydrogen, an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms or an aralkyl group of 7 to 12 carbon atoms, X
2
represents hydrogen or a halogen atom, with a compound of the following general formula (III):
wherein R
2
represents an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms or an aralkyl group of 7 to 12 carbon atoms, X
1
represents a halogen atom at a temperature of not less than −30° C. to give a compound of the following general formula (IV):
wherein R
1
and X
1
are respectively as defined above,
(2) a step comprising reducing this compound with the aid of a strain of microorganism to give a compound of the following general formula (V):
wherein R
1
and X
1
are respectively as defined above,
(3) a step comprising treating this compound with an acetalizing agent in the presence of an acid catalyst to give a compound of the following general formula (VI):
wherein R
1
and X
1
are respectively as defined above, R
4
and R
5
each independently represents hydrogen, an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms or an aralkyl group of 7 to 12 carbon atoms, and R
4
and R
5
may be conjoined each other to form a ring,
(4) a step comprising acyloxylating this compound with an acyloxylating agent to give a compound of the following general formula (VII):
wherein R
1
, R
4
and R
5
are respectively as defined above, R
3
represents hydrogen, an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms or an aralkyl group of 7 to 12 carbon atoms, and
(5) a step comprising subjecting this compound to solvolysis in the presence of a base.
DISCLOSURE OF THE INVENTION
The present invention is now described in detail.
The present invention is constituted by 5 non-super-low-temperature reaction steps (1) to (5) as illustrated in the following reaction scheme.
The following is a step-by-step description of the present invention. Step (1)
In this step, an enolate prepared by permitting either a base or a metal having a valency of 0 to act upon an acetic ester derivative of the following general formula (II):
is reacted with a (3S) configured hydroxybutyric acid ester derivative of the following general formula (III):
at a temperature of not less than −30° C. to produce a (5S)-configured hydroxyoxohexanoic acid derivative of the following general formula (IV):
Generally when a reaction involving the enolate of an acetic ester or the like is conducted under non-super-low-temperature condition, e.g. at not less than −30° C., the self-condensation of the enolate proceeds predominantly to considerably detract from the conversion rate of the objective reaction. However, by the following procedure developed by the present inventors, the self-condensation of the acetic ester enolate can be minimized so that the objective reaction can be conducted with good yield.
In the hydroxybutyric acid derivative to be used in step (1), namely a compound of the following general formula (III):
the configuration of the 3-position is (S) and R
2
is, for example, an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to12 carbon atoms or an aralkyl group of 7 to 12 carbon atoms, thus as a specific example, there can be mentioned methyl, ethyl, i-propyl, tert-butyl, n-octyl, phenyl, naphthyl, p-methoxyphenyl and p-nitrobenzyl, among others. The preferred is methyl or ethyl, with ethyl being the more preferred.
X
1
represents a halogen atom, e.g. chloro, bromo and iodo, and is
Inoue Kenji
Kizaki Noriyuki
Kondo Takeshi
Mitsuda Masaru
Miyazaki Makoto
Connolly Bove & Lodge & Hutz LLP
Kaneka Corporation
Solola T. A.
LandOfFree
Process for the preparation of optically active... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Process for the preparation of optically active..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process for the preparation of optically active... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2939591