Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-12-07
2002-06-11
Higel, Floyd D. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C548S232000
Reexamination Certificate
active
06403804
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to a process for preparing an optically active oxazolidinone derivative which is useful as a starting material for pharmaceuticals or optically active amino-alcohols.
BACKGROUND OF THE INVENTION
Optically active oxazolidinone derivatives are known as important intermediates for &bgr;-blockers (see S. Hamaguchi et al.,
Agric. Biol. Chem.,
vol. 48, pp.
2055 & 2331
(1984) and idem, ibid., vol. 49, pp.
1509, 1661 & 1669
(1985)), antidepressants (e.g., JP-A-3-218367), and antibacterials (see.
Drugs Fut
., vol. 21, p. 116 (1996) and EP 0789025A1), and an economical process of preparing them has been demanded.
Conventional processes of preparing an optically active oxazolidinone derivative include (1) a process comprising cyclizing an amino-alcohol obtained from an optically active epoxide with a dialkyl carbonate (see
J. Med. Chem.,
vol. 32, p. 1673 (1989)), (2) a process comprising ring opening of an optically active epoxide with an isocyanate or an acylazide (see
J. Med. Chem.,
vol. 32, p. 1673 (1989)), and (3) a method of synthesis starting with D-mannitol, L-ascorbic acid or (R)- or (S)-malic acid (see
Tetrahedron:Asymmetry
, vol. 6, p. 1181 (1995)).
Processes for synthesizing a racemic oxazolidinone derivative include (4) a process comprising cyclizing a &bgr;-hydroxycarboxylic acid with diphenylphosphorylazide (see
Kor. J. Med. Chem
., vol. 4, p. 52 (1994) and
Bull. Korean Chem. Soc
., vol. 15, p. 525 (1996)), and (5) a process comprising Curtius rearrangement of &bgr;-hydroxypropionohydrazide (see
Heterocycles
, vol. 6, p. 1604 (1977),
Tetrahedron:Asymmetry
, vol. 8, p. 477 (1997), and
Liebigs Ann. Chem
., p. 150 (1979)).
However, these processes (1) to (5) have their several disadvantages as follows.
Process (1) (
J. Med. Chem
., vol. 32, p. 1673 (1989)) comprises optically resolving an amino-alcohol obtained from aniline and an epoxide with optically active mandelic acid, allowing diethyl carbonate to act on the resulting optically active amino-alcohol to obtain an oxazolidinone derivative as shown below. This process has poor economical efficiency because the undesired one of the optically active amino-alcohols obtained by the optical resolution with mandelic acid is to be discarded.
Process (2) (
J. Med. Chem
., vol. 32, p. 1673 (1989)) comprises allowing an optically active epoxide obtained by enzymatic optical resolution to react with an isocyanate to give an optically active oxazolidinone derivative as illustrated below. The optically active epoxide used is prepared by biological resolution of an optically active C
3
chlorohydrin type compound, which requires a large quantity of a solvent and involves by-production of an equal amount of an unnecessary stereoisomer. Therefore, the production efficiency is low.
Process (3) according to
Tetrahedron:Asymmetry
, vol. 6, p. 1181 (1995) involves many steps, no matter which of D-mannitol, L-ascorbic acid, and (R)- or (S)-malic acid is used as a starting material. For example, the synthesis starting with D-mannitol proceeds as follows.
Besides requiring may steps, the process starting from D-(S)-malic acid uses diphenylphosphorylazide that is expensive.
Process (4) according to
Kor. J. Med. Chem
., vol. 4, p. 52 (1994) comprises allowing diphenylphosphorylazide to react on &bgr;-hydroxycarboxylic acid to carry out Curtius rearrangement to obtain a racemic oxazolidinone derivative as illustrated below. As stated above, diphenylphosphorylazide is expensive. Moreover, the reaction is conducted at 80° C. at which there is a danger of explosion, which is unsuited to industrial production.
The process (4) according to
Bull. Korean Chem. Soc.,
vol. 15, p. 525 (1996) also requires expensive diphenylphosphorylazide, and the reaction is conducted at 80° C. at which there is a danger of explosion.
Process (5) (
Tetrahedron:Asymmetry
, vol. 8, p. 477 (1997)) comprises converting a &bgr;-hydroxy ester obtained by optical resolution with lipase into a hydrazide, which is subjected to Curtius rearrangement to give an optically active oxazolidinone derivative as illustrated below. According to this technique, an acylazide is produced at 5° C. or below, and the reaction system is warmed to room temperature, at which it is stirred overnight to produce a desired compound. Since the Curtius rearrangement is performed at room temperature, it needs a long time. The acylazide, being left to stand at room temperature for a long time, involves a danger of explosion, which is not suited to industrial production.
Also, in the process disclosed in
Heterocycles
, vol. 6, p. 1604 (1977) and
Liebigs Ann. Chem
., p. 150 (1979), since a low temperature reaction system having produced an intermediate acylazide is heated to carry out the rearrangement reaction, there will be a danger of explosion where the reaction is performed on an industrial scale.
SUMMARY OF THE INVENTION
An object of the invention is to provide a novel process for obtaining an optically active oxazolidinone derivative having high optical purity in high yield without being accompanied with the above-mentioned various problems of conventional techniques.
In the light of the above circumstances, the present inventors have conducted extensive investigations, seeking for an effective and economical process for preparing an optically active oxazolidinone derivative. As a result, they have found a novel process which can achieve high optical purity and high yield with high production efficiency and no process complexity.
The invention relates to:
(1) A process for preparing an optically active oxazolidinone derivative represented by formula (I):
wherein R
1
represents a lower alkyl group having 1 to 4 carbon atoms, a phenyl group, a methoxymethyl group, a benzyloxymethyl group, a benzyloxycarbonylaminomethyl group which may have a substituent or substituents on the benzene ring thereof, an acylaminomethyl group having 3 to 10 carbon atoms, or an alkyloxycarbonylaminomethyl group having 3 to 6 carbon atoms; R
2
and R
3
, which may be the same or different, each represent a hydrogen atom, a lower alkyl group having 1 to 4 carbon atoms, a phenyl group, an acetylaminomethyl group, a benzoylaminomethyl group, or a benzyl group; and * indicates an asymmetric carbon atom, comprising allowing hydrazine to react with an optically active acid ester having a hydroxyl group at the 3-position which is represented by formula (II):
wherein R
1
, R
2
, R
3
, and * are as defined above; and R
4
represents a lower alkyl group having 1 to 4 carbon atoms, to give an optically active hydrazide having a hydroxyl group at the 3-position which is represented by formula (III):
wherein R
1
, R
2
, R
3
, and * are as defined above, and subjecting the optically active hydrazide to Curtius rearrangement.
(2) A process for preparing an optically active oxazolidinone derivative as set forth above, wherein the optically active hydrazide represented by formula (III) is recrystallized to increase its purity.
(3) A process for preparing an optically active oxazolidinone derivative as set forth above, wherein the optically active acid ester having a hydroxyl group at the 3-position is a compound represented by formula (II) wherein R
1
represents a methyl group, phenyl group, a methoxymethyl group, a benzyloxymethyl group, a benzyloxycarbonylaminomethyl group, an acetylaminomethyl group, a hexanoylaminomethyl group, or a t-butoxycarbonylaminomethyl group; R
2
and R
3
both represent a hydrogen atom, or one of R
2
and R
3
represents a hydrogen atom with the other representing an acetylaminomethyl group, a benzoylaminomethyl group, or a benzyl group; and R
4
represents a lower alkyl group having 1 to 4 carbon atoms.
Further, in the above-described compounds represented by formula (I) or (III), those wherein R
1
is an acylaminomethyl group having 3 to 10 carbon atoms or an alkyloxycarbonylaminomethyl group having 3 to 6 carbon atoms and R
2
and R
3
each represent a hydrogen atom should be novel compounds which haven't so far been known or repo
Imai Takashi
Mitsuhashi Shigeru
Miura Takashi
Nara Hideki
Sumi Kenzo
Higel Floyd D.
Shameem Golam M. M.
Takasago International Corporation
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