Ammonium 3,5,6-trihydroxyhexanoate derivatives and...

Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

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C549S369000, C549S373000, C549S374000, C549S357000

Reexamination Certificate

active

06365755

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to an ammonium (3R,5S)-3,5,6-trihydroxyhexanoate derivative which is a novel useful compound as an intermediate for the synthesis of pharmaceuticals.
This ammonium (3R,5S)-3,5,6-trihydroxyhexanoate derivative is a useful compound as an intermediate commonly used for the synthesis of various HMG-CoA (3-hydroxyglutaryl coenzyme A) reductase inhibitors whose action as an anti-hyperlipemia has attracted attentions.
BACKGROUND OF THE INVENTION
As a process for preparing a (3R,5S)-3,5,6-trihydroxyhexanoic acid derivative, already reported are (1) a process for diastereoseletively reducing an (S)-5,6-dihydroxy-3-oxohexanoic acid derivative with a reducing agent such as sodium borohydride and, trialkylborane or alkoxydialkylborane (JP-A-1-199945 (the term “JP-A” as used herein means an “unexamined published Japanese patent application”), JP-A-2-262537); and (2) a process for subjecting an (S)-5,6-dihydroxy-3-oxohexanoic acid derivative to asymmetric hydrogenation in the presence of a ruthenium-optically active phosphine complex as a catalyst (JP-A-6-65226).
Many of the (3R,5S)-3,5,6-trihydroxyhexanoic acid derivatives so far reported are obtained as oily matter. It is the present situation that such crude products tend to be provided for a subsequent step without being improved into a high-purity syn-isomer.
According to the report by G. Beck, et al. (Synthesis, 1014(1995)), the below-described compound (a) is oily matter, from which a crude product (b) is obtained as oily matter by isolating and purifying the oily matter (a) by chromatography on a silica gel column, followed by reductive debenzylation. Chromatography on a silica gel column, however, is not suited for production on an industrial scale.
wherein Bn means a benzyl group and
t
Bu means a tert-butyl group.
For preparation of various HMG-CoA reductase inhibitors, tert-butyl (3R,5S)-3,5-O-isopropylidene-3,5,6-trihydroxyhexanoate (b) having the 6-hydroxyl group deprotected is a particularly important compound, because the 6-position of the (3R,5S)-3,5,6-trihydroxyhexanoic acid derivative is a bonding site to another compound.
In consideration of the preparation on an industrial scale, it is preferred to isolate and purify the compound formed in each step as highly pure and stable crystals which can be handled easily.
Although reports on the isolation of a (3R,5S)-3,5,6-trihydroxyhexanoic acid derivative in the form of crystals are not so many, examples include: 1) U.S. Pat. No. 5,278,313 describes preparation of compounds (c) and (e), which will be described below, in the form of crystals at −20 to −5° C. It does not include a description on diastereoselectivity. Moreover, no attempt is made to improve the diastereoselectivity by recrystallization. 2) JP-A-2-262537 describes preparation of the below-described compounds (c) and (d) in the form of crystals by isolation and purification through chromatography on a silica gel column. As described above, however, separation by chromatography on a silica gel column is not suited for industrial production. 3) JP-T-6-502162 (the term “JP-T” as used herein means an “unexamined published Japanese patent application based on International application”) describes isolation of the below-described compound (f) (X=Cl, Br or NO
2
) as a solid. No attempt, however, is made in order to improve the diastereoselectivity by crystallization.
wherein Bz represents a benzoyl group,
t
Bu means a tert-butyl group, Ac means an acetyl group and X represents a chlorine atom, a bromine atom or a nitro group.
Although it is essential to improve the diastereoselectivity of a (3R,5S)-3,5,6-trihydroxyhexanoic acid derivative for production on an industrial scale, it is the present state that no attempt has been made to improve the diastereoselectivity by crystallization.
SUMMARY OF THE INVENTION
An object of the present invention is therefore to prepare, safely in a high yield in a simple manner, a (3R,5S)-3,5,6-trihydroxyhexanoic acid derivative which can satisfy the above-described demands, is in the form of crystals permitting easy handling and has high chemical purity.
Under such situations, the present inventors have carried out an extensive investigation with a view to attaining the above-described object. As a result, it has been found that a novel ammonium (3R,5S)-3,5,6-trihydroxyhexanoate derivative in the form of crystals can be prepared in a high yield by causing a specific amine to act on a (3R,5S)-3,5,6-trihydroxyhexanoic acid derivative. It has also been found that isolation and purification of an ammonium derivative in the form of crystals permitting easy handling make it possible to improve the chemical purity of the derivative and that the chemical purity thus attained is markedly high, leading to the completion of the present invention.
The present invention therefore embraces the following aspects.
1) An ammonium (3R,5S)-3,5,6-trihydroxyhexanoate derivative represented by the following formula (I):
wherein R
1
represents a benzyl group which may have a substituent, a triphenylmethyl group which may have a substituent, an organosilyl group or a C
1-5
acyl group; and A represents at least one amine selected from the group consisting of a primary amine represented by the following formula (IIIa):
R
2
—NH
2
  (IIIa)
(in which R
2
represents a C
1-7
alkyl group or a C
5-7
alicyclic group), a primary benzylamine represented by the following formula (IIIb):
(in which R
3
represents a hydrogen atom, a methyl group or a hydroxymethyl group and Ar represents a phenyl group which may have a substituent), a secondary amine represented by the following formula (IIIc):
(in which R
4
and R
5
are the same or different and each independently represents a C
5-7
alicyclic group), cinchamidine, cinchotine, cinchonamine, cinchonidine and cinchonine.
2) An ammonium (3R,5S)-3,5,6-trihydroxyhexanoate as described above in 1), wherein a ratio of the syn-isomer to the anti-isomer falls within a range of 99.0/1.0 to 100/0.
3) A process for producing an ammonium (3R,5S)-3,5,6-trihydroxyhexanoate in the form of crystals, which comprises causing the amine (A) as described above in 1) to act on a (3R,5S)-3,5,6-trihydroxyhexanoic acid represented by the following formula (II):
wherein R
1
has the same meaning as described above.
4) A process for producing a high-purity ammonium (3R,5S)-3,5,6-trihydroxyhexanoate in the form of crystals, which comprises causing the amine (A) as described above in 1) to act on the (3R,5S)-3,5,6-trihydroxyhexanoic acid represented by the formula (II) and crystallizing the resulting ammonium (3R,5S)-3,5,6-trihydroxyhexanoate derivative precursor to improve the chemical purity thereof.
DETAILED DESCRIPTION OF THE INVENTION
The present invention will next be described more specifically.
In the ammonium (3R,5S)-3,5,6-trihydroxyhexanoate derivative of the invention, R
1
represents a benzyl group which may have a substituent, a triphenylmethyl group which may have a substituent, an organosilyl group or a C
1-5
acyl group.
Specific examples of R
1
include a benzyl group which may have a substituent, for example, a lower C
1-4
alkyl group such as methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, isobutyl or sec-butyl, a lower C
1-4
alkoxy group such as methoxy, ethoxy, propoxy or butoxy, or a halogen atom such as fluorine, chlorine, bromine or iodine; a triphenylmethyl group which may have a substituent, for example, a lower C
1-4
alkyl group such as methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, isobutyl or sec-butyl, a lower C
1-4
alkoxy group such as methoxy, ethoxy, propoxy or butoxy, or a halogen atom such as fluorine, chlorine, bromine or iodine; organosilyl groups such as tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triethylsilyl, dimethylcumylsilyl, triisopropylsilyl, dimethylthexylsilyl, trimethylsilyl, and dimethylhexylsilyl; C
1-5
acyl groups such as formyl, acetyl, propionyl, butyloyl, valeloyl, isovaleloyl and pivaloyl.
Preferred specific examples of R
1
include

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