Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-02-21
2004-09-07
Trinh, Ba K. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C549S548000, C549S549000
Reexamination Certificate
active
06787657
ABSTRACT:
The present invention relates to an optically active epoxypropionate derivative, an intermediate thereof and processes for their production. The optically active propionate derivative of the present invention is useful as an intermediate for the preparation of pharmaceuticals or agricultural chemicals.
As an optically active propionate derivative, one having a methoxy group introduced at the 4-position (the p-position) of a phenyl ring, is known as an intermediate for the preparation of a known diltiazem (see, for example, JP-A-60-13776 and JP-A-6-287183). However, an optical active epoxypropionate derivative of the following Formula (1):
wherein symbol * represents optically active carbon, or the following Formula (2):
wherein symbol * represents optically active carbon, has not been known.
Further, as a process for producing an optically active epoxypropionate derivative, a process for separating an optically active substance from a racemic modification by optical resolution is known, but a process for producing such a compound by an asymmetric synthesis has not been known.
Under these circumstances, the present invention has been made, and it is an object of the present invention to provide a novel optically active epoxypropionate derivative expected to be an intermediate for the preparation of pharmaceuticals or agricultural chemicals, an intermediate for its preparation and a process for their production.
The present inventors have conducted an extensive study to prepare a novel optically active epoxypropionate derivative expected to be an intermediate for the preparation of pharmaceuticals or agricultural chemicals and as a result, have found the optically active epoxypropionate derivative of the above Formula (1) or (2) and an optically active epoxyenone derivative of the following Formula (3):
wherein symbol * represents optically active carbon, which is an intermediate for the preparation of the compound of the above formula (1). And, they have found processes for their production by asymmetric syntheses. The present invention has been accomplished on the basis of these discoveries.
Namely, the present invention provides the optically active epoxypropionate derivative of the above Formula (1) or (2), the optically active epoxyenone derivative of the above Formula (3) and processes for their production.
Now, the present invention will be described in detail with reference to the preferred embodiments.
The optically active epoxypropionate derivative of the above Formula (1) of the present invention is specifically t-butyl(2S, 3R)-trans-2,3-epoxy-3-(4′-fluorophenyl) propionate, t-butyl(2S, 3R)-trans-2,3-epoxy-3-(3′-fluorophenyl) propionate, t-butyl(2S, 3R)-trans-2,3-epoxy-3-(2′-fluorophenyl) propionate, t-butyl(2R, 3S)-trans-2,3-epoxy-3-(4′-fluorophenyl) propionate, t-butyl(2R, 3S)-trans-2,3-epoxy-3-(3′-fluorophenyl) propionate, or t-butyl(2R, 3S)-trans-2,3-epoxy-3-(2′-fluorophenyl) propionate.
The optically active epoxypropionate derivative of the above Formula (2) of the present invention is specifically phenyl trans-3-(2-chlorophenyl)-(2S, 3R)-epoxypropionate, phenyl trans-3-(3-chorophenyl)-(2S, 3R)-epoxypropionate, phenyl trans-3-(4-chlorophenyl)- (2S, 3R)-epoxypropionate, phenyl trans-3-(2-chlorophenyl)-(2R, 3S)-epoxypropionate, phenyl trans-3-(3-chlorophenyl)-(2R, 3S)-epoxypropionate, or phenyl trans-3-(4-chlorophenyl)-(2R, 3S)-epoxypropionate.
The optically active epoxyenone derivative of the above Formula (3) of the present invention is specifically (1R, 2S)-trans-1,2-epoxy-1-(4′-fluorophenyl)-4,4-dimethyl-pentan-3-one, (1R, 2S)-trans-1,2-epoxy-1-(3′-fluorophenyl)-4,4-dimethyl-pentan-3-one, (1R, 2S)-trans-1,2-epoxy-1-(2′-fluorophenyl)-4,4-dimethyl-pentan-3-one, (1S, 2R)-trans-1,2-epoxy-1-(4′-fluorophenyl)-4,4-dimethyl-pentan-3-one, (1S, 2R)-trans-1,2-epoxy-1-(3′-fluorophenyl)-4,4-dimethyl-pentan-3-one, or (1S, 2R)-trans-1,2-epoxy-1-(2′-fluorophenyl)-4,4-dimethyl-pentan-3-one.
The compound of the above Formula (1) of the present invention can be prepared by the following synthetic route using a known enone as the staring material, although the preparation is not particularly limited.
In the above formulae, symbol * represents optically active carbon.
Namely, the optically active epoxyenone derivative of the above Formula (3) is prepared by asymmetric epoxidation of an enone, and further, the derivative is oxidized with an oxidizing agent, whereby the optically active epoxypropionate derivative of the above Formula (1) is prepared.
Further, the compound of the above Formula (2) of the present invention can be prepared by the following route by asymmetric epoxidation of an enone using a known enone as the starting material, although the preparation is not particularly limited.
In the formulae, symbol * represents optically active carbon.
As a catalyst to be used for the asymmetric epoxidation reaction of the present invention, any asymmetric epoxidation catalyst for enones can be used. However, it is preferred to employ a catalyst comprising:
(A) an optically active binaphthol,
(B) lanthanum triisopropoxide,
(C) triphenylphosphine oxide, and
(D) cumene hydroperoxide (hereinafter referred to as CMHP) or tert-butyl hydroperoxide (hereinafter referred to as TBHP), since the substrate selectivity is low, and it provides good yield and a high optical purity. Here, in the present invention, the optically active binaphthol is specifically (R)-(+)-1,1′-bi-2-naphthol (hereinafter referred to as (R)-binaphthol) or (S)-(−)-1,1′-bi-2-naphthol (hereinafter referred to as (S)-binaphthol).
With respect to the constituting proportions of the above-mentioned catalyst components, theoretically, the respective constituting components may be present in equivalent amounts. However, in order to let the catalyst form stably in the reaction system, (A) the binaphthol is usually from 1 to 3 mols, preferably from 1 to 1.5 mols, (C) the triphenylphosphine oxide is usually from 0.1 to 10 mols, preferably from 1 to 10 mols, and (D) CMHP or TBHP is usually from 1 to 20 mols, preferably from 1 to 10 mols, per mol of (B) the lanthanum triisopropoxide.
In the asymmetric epoxidation reaction of the present invention, it is preferred that the above catalyst components are preliminarily formulated into a catalyst solution in the reaction system and then used for the epoxidation reaction of an enone.
Further, in the asymmetric epoxidation reaction of the present invention, if (R)-binaphthol is employed, the steric configuration at the 2-position (&agr;-position of carbonyl group) and 3-position (&bgr;-position of carbonyl group) of the epoxyenone of the present invention will be (2S, 3R), and if (S)-binaphthol is employed, it will be (2R, 3S).
In the asymmetric epoxidation reaction of the present invention, the amount of the catalyst is not particularly limited, but it is usually within a range of from 0.01 to 50 mol %, more preferably within a range of from 0.1 to 25 mol %, based on the molar amount of the lanthanum isopropoxide, relative to the substrate subjected to the reaction.
The solvent useful for the asymmetric epoxidation reaction of the present invention may be any solvent so long as it is a solvent inert to the catalyst and to the epoxidation reaction. However, from the viewpoint of the stability of the catalyst and the reaction efficiency of the epoxidation reaction, an ether type solvent such as dimethyl ether, diisopropyl ether, 1,2-dimethoxyethane or tetrahydrofuran (hereinafter referred to as THF), is preferred, and among them, it is THF that gives the highest results. Such a solvent can be used also as a solvent for the preparation of the above catalyst solution.
The amount of the solvent is usually from 2 to 200 times, preferably from 5 to 100 times, by weight, to the enone to be subjected to the reaction.
In the asymmetric epoxidation reaction of the present invention, a complex catalyst comprising:
(A) an optically active binaphthol,
(B) lanthanum triisopropoxide,
(C) triphenylphosp
Kagawa Takumi
Tanaka Akinori
Tosoh Corporation
Trinh Ba K.
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