JP2001354665A - Optically active epoxy propionate derivatives and methods for their production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an optically active epoxypropionic acid ester derivative useful as a synthetic intermediate for pharmaceuticals and agricultural chemicals, and a method for producing the same. SOLUTION: The following formula (3): Is epoxidized in the presence of an asymmetric catalyst to give the following formula (2): (In the formula, an asterisk indicates an optically active carbon.) An optically active epoxy enone derivative represented by the following formula is obtained and oxidized to obtain the following formula (1). To obtain an optically active epoxy propionate derivative represented by the formula:

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an optically active epoxy propionate derivative and a method for producing the same. The optically active propionate derivative of the present invention is useful as a synthetic intermediate for pharmaceuticals and agricultural chemicals.

[0002]

2. Description of the Related Art As an optically active propionate derivative, a derivative in which a methoxy group is introduced at the 4-position (p-position) of a phenyl ring is known as a known diltiazem synthesis intermediate (Japanese Patent Application Laid-Open No. 60-1985). No. 13776, Japanese Unexamined Patent Publication No. 6-287183) is obtained by the following formula (1).

[0003]

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[0004] An optically active epoxy propionic acid ester derivative represented by the formula (* represents an optically active carbon) is not known.

As a method for producing an optically active epoxypropionate derivative, a method for separating an optically active form from a racemic form by an optical resolution method is known, but a method for producing a similar compound by an asymmetric synthesis method is known. Is not known.

[0006]

SUMMARY OF THE INVENTION The present invention has been made in view of the above-mentioned problems, and has as its object to provide a novel optically active epoxypropionate derivative which is expected as a synthetic intermediate for pharmaceuticals and agricultural chemicals; And a method for producing the same.

[0007]

The present inventors have conducted intensive studies on the creation of a novel optically active epoxypropionate derivative which is expected to be an intermediate for the synthesis of pharmaceuticals and agricultural chemicals. The present inventors have found an optically active epoxy propionate derivative which has been completed, and have completed the present invention.

That is, the present invention is an optically active epoxy propionate derivative represented by the above formula (1), and a method for producing the same.

The present invention will be described in detail below.

The optically active epoxy propionate derivative of the present invention is specifically exemplified by phenyl trans-
3- (2-chlorophenyl)-(2S, 3R) -epoxypropionate, phenyl trans-3- (3-
Chlorophenyl)-(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, 3
S) -epoxypropionate, phenyl trans
-3- (4-Chlorophenyl)-(2R, 3S) -epoxypropionate.

The synthesis route of the compound of the present invention is not particularly limited, but the following route can be obtained by using known enones as raw materials and asymmetric epoxidation reaction of enones.

[0012]

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(In the formula, an asterisk indicates an optically active carbon.)

As the catalyst used in the asymmetric epoxidation reaction of the present invention, any asymmetric epoxidation catalyst for enones can be used, but preferably, the substrate has low selectivity, high yield and high optical purity. (A) optically active binaphthol, (B) lanthanum triisopropoxide,
It is preferable to use a catalyst containing (C) triphenylphosphine oxide and (D) cumene hydroperoxide (hereinafter abbreviated as CMHP) or tertiary butyl hydroperoxide (hereinafter abbreviated as TBHP).

As for the composition ratio of the above catalyst components, it is theoretically sufficient that each component is present in an equivalent amount. However, in order to actually form a catalyst stably in the reaction system, (B) lanthanum triisopropoxide is required. (A) binaphthol is usually 1 to 3 mol, preferably 1 to 1.5 mol, per 1 mol of the side,
(C) Triphenylphosphine oxide is usually 0.1%.
1 to 10 mol, preferably 1 to 10 mol, (D) CMH
P or TBHP is 1 to 20 mol, preferably 1 to 10 mol.

In the asymmetric epoxidation reaction of the present invention,
It is preferable that the above catalyst is prepared in advance as a catalyst solution in a reaction system and then used for the epoxidation reaction of enones.

In the asymmetric epoxidation reaction of the present invention,
When (R) -binaphthol is used, the configuration at the 2- and 3-positions of the epoxy enones of the present invention gives (2S, 3R), and when (S) -binaphthol is used, (2R,
3S).

In the asymmetric epoxidation reaction of the present invention, the amount of the catalyst to be used is not particularly limited, but lanthanum isopropoxide may be used in an amount of 0.01 mol based on the number of moles of the substrate used in the reaction. To 50 mol%, more preferably 0.1 to 25 mol%.

As the solvent applicable to the asymmetric epoxidation reaction of the present invention, any solvent can be used as long as it is a catalyst and a solvent inert to the epoxidation reaction. In terms of performance, ether solvents such as dimethyl ether, diisopropyl ether, 1,2-dimethoxyethane, and tetrahydrofuran (hereinafter abbreviated as THF) are preferable, and THF gives the highest result.

The amount of the solvent used is in the range of 2 to 200 times, more preferably 5 to 100 times the weight of the enone used in the reaction in terms of weight.

In the asymmetric epoxidation reaction of the present invention,
A complex catalyst comprising (A) optically active binaphthol, (B) lanthanum triisopropoxide, (C) triphenylphosphine oxide, and (D) cumene hydroperoxide or tertiary butyl hydroperoxide is further added to the product. Gives high optical activity.

The preparation of the complex catalyst comprises the following steps:
The formation time of the catalyst varies depending on the selection of the oxidizing agent, the type of the solvent, and the catalyst concentration, but is usually within a range of -50 ° C to 100 ° C.
It can be prepared by holding for 5 hours to 4 hours, and the color tone of the solution after complex formation exhibits yellowish green to dark green.

As the TBHP used as an oxidizing agent in the asymmetric epoxidation reaction of the present invention, a commercially available solution of decane or the like may be used as it is, or a solution of 70% or 90% aqueous solution extracted with toluene and dried with magnesium sulfate or the like. Later, it may be used in the present invention. CMHP is a commercially available 80% by weight.
The product may be used after purification, or may be used as it is without purification, but is preferably purified or commercially available CM
By using HP, a pure optically active substance can be obtained.

The asymmetric epoxidation reaction of the present invention is carried out by adding the above enones to a catalyst solution prepared in advance and then adding CMHP or THP.
The reaction is performed by supplying BHP. The supply rate of the oxidizing agent is set so that the oxidizing agent does not become excessively large in the system. Specifically, the reaction rate in the actual system is measured, and the supply rate is determined. When the feed rate is higher than the reaction rate, the yield may decrease, and when the feed rate is lower, the optical purity may decrease.

In the asymmetric epoxidation reaction of the present invention, the amount of the oxidizing agent used is theoretically equal to the amount of the enone used in the reaction, including the amount used for forming the catalyst and the amount added during the reaction. The amount is sufficient, but in order to complete the reaction, it is preferably used in an amount of 1.1 mole times or more.

The reaction temperature in the asymmetric epoxidation reaction of the present invention varies depending on the difference in the substrates of the enones.
In the range of 50 ° C to 100 ° C, the reaction time is usually 4
The reaction is completed within 8 hours.

In the asymmetric epoxidation reaction of the present invention, a zeolite is used as necessary for the purpose of dehydrating the inside of the system at the time of preparing and reacting the catalyst and accelerating the catalyst formation reaction and the epoxidation reaction. Zeolite can be used in any quantitative ratio with respect to the enones.
Use about 10 mg to 2 g per 1. As the types of zeolites, A-type zeolites represented by molecular sieves 3A, 4A, and 5A, molecular sieves 13X, Y
Various zeolites such as a type and an L type can be applied, and among these, molecular sieve 4A is preferable.

After completion of the epoxidation reaction of the present invention, post-treatment,
By performing purification by column chromatography, etc.,
The optically active epoxy enone represented by the above formula (2) can be obtained with high yield and high optical purity.

In order to obtain the optically active epoxy propionate of the present invention, the optically active epoxy enones obtained by the above-mentioned method are derived to the desired product by carrying out an oxidative transfer reaction by a Baeyer-Villiger reaction.

The Baeyer-Villiger of the present invention
As the oxidizing agent used for the reaction, any peracids and peroxides can be applied, and specifically, potassium persulfate, hydrogen peroxide, perbenzoic acid, m-chloroperbenzoic acid, CMH
P, TBHP and the like, and the reaction is usually performed at a temperature in the range of 0 ° C. to 150 ° C. for 1 to 48 hours to induce the desired product. In addition, depending on the type of the peracid and the peroxide, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, and lithium hydroxide may be used in combination in a water-alcohol solvent.

The Baeyer-Villiger of the present invention
The amount of the oxidizing agent to be used in the reaction is usually 1 to 10 times, more preferably 2 to 5 times, the molar amount of the epoxy enone used in the reaction.

The Baeyer-Villiger of the present invention
After completion of the reaction, the peracid or peroxide is deactivated, followed by extraction with an organic solvent, drying, concentration, and purification by column chromatography to obtain the desired optically active epoxypropionate derivative.

[0033]

Industrial Applicability The optically active epoxy propionate derivative of the present invention has a high optical purity and can be used for various pharmaceuticals,
Expected as an important intermediate of pesticides.

[0034]

The present invention will be described in detail with reference to the following examples, but the present invention is not limited to the examples. The analysis of the product was performed using the following equipment.

(Measurement of optical rotation) SEPA manufactured by HORIBA
Use -300.

(Measurement of melting point) MP-500 manufactured by Yanaco Co., Ltd.
Use D.

(Measurement of ¹ H-NMR and 13 C-NMR)
Use Varian Gemini-200 (200M
Hz).

(Mass measurement) M-80B manufactured by Hitachi was used.

(IR measurement) A 2000FT-IR manufactured by Perkin Elmer was used.

(Assay for optical purity) High-performance liquid chromatography equipped with a chiral column AD of Daicel Co., Ltd., elution solvent: Hexane / i-PrOH = 9
The measurement was performed at 5/5 (vol / vol) at a flow rate of 1 ml / min.

Example 1 trans-3- (4-chlorophenyl)-(2S, 3
Synthesis of R) -Epoxy-1-phenylpropan-1-one

[0042]

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A molecular sieve 4A (827) was placed in a 100 mL eggplant-shaped flask containing a magnetic stirrer.
mg, and dried at 180 ° C. for 4 hours under reduced pressure), and dried by heating with a heat gun for 3 minutes under reduced pressure using a vacuum pump. After cooling to room temperature, triphenylphosphine oxide (345 mg, 1.24 mmol) and (R) -binaphthol (119 mg, 0.41 mmol) were added, and the reaction system was replaced with nitrogen gas. Then, THF (20m
L) was added and dissolved by stirring for 5 minutes.
Lanthanum isopropoxide (La (OiPr) 3,1
31 mg, 0.41 mmol) in a THF solution (20 m
L), stirred for 1 hour, and further added CMHP (80
%, 153 μL, 0.83 mmol) and stirred for 2 hours to prepare a catalyst solution.

After confirming that the catalyst solution turned yellow-green, trans-4-chlorochalcone (2.01) was added thereto.
g, 8.27 mmol) and CMHP (80%, 3.1).
(7 mL, 17.2 mmol) in THF (25 mL) was added dropwise over 2 hours and then stirred for 1 hour.

After completion of the reaction, 2.0 g of silica gel and 20 mL of methanol were added and stirred for 1 hour, followed by filtration, concentration, and silica gel column (hexane / ethyl acetate = 6/9).
By purifying in 1), trans-3- (4-chlorophenyl)-(2S, 3R) -epoxy-1-phenylpropan-1-one was obtained as white crystals (yield 93%, optical purity 99). .6ee%).

Melting point: 76-79 ° C. ¹ H-NMR (CDCl ₃ ) δ 7.26-7.8.03
(M, 9H), 4.25 (d, 1H, J = 1.8H
z), 4.06 (d, 1H, J = 1.8 Hz) ¹³ C-NMR (CDCl ₃ ) δ 192.7, 135.
4,134.9,134.1,129.0,128.
9, 128.3, 127.1, 125.4 IR (KBr; ν cm ^-1 ) 3069, 1683, 15
97, 1495, 1446, 1339, 1237, 10
90,1006,887,843,806,705,5
35,476 EI-MS (m / z) 258 (M ⁺ ) Elemental analysis C: 69.4%, H: 4.4%, Cl: 1
3.5% (calc. C: 69.6%, H: 4.3%, Cl:
13.7%) specific rotation (c = 1.035, CHCl ₃ )
[Α] ²⁸ _D = + 246 ° Example 2 Synthesis of phenyl trans-3- (4-chlorophenyl)-(2S, 3R) -epoxypropionate

[0047]

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In a 100 ml eggplant-shaped flask equipped with a magnet stirrer, the trans-3- obtained in Example 1 was placed.
(4-chlorophenyl)-(2S, 3R) -epoxy-
1-phenylpropan-1-one (203 mg, 0.7
73 mmol), m-chloroperbenzoic acid (80% mCP
BA, 333 mg, 1.55 mmol) and sodium hydrogen carbonate (195 mg, 2.32 mmol) were dissolved in 10 mL of dichloromethane, and the mixture was refluxed and stirred for 6 hours to carry out a reaction. After the reaction solution was cooled to room temperature, 20 mL of water and 20 mL of dichloromethane were added thereto, and the organic layer was separated.
Washed three times with 0 mL. After drying over magnesium sulfate,
Precipitates and adsorbates were removed by a silica gel short column, and then washed with 100 mL of dichloromethane. The residue obtained by concentrating and drying the eluate under reduced pressure is then purified by a silica gel column (hexane / ethyl acetate = 6/1) to give phenyl trans-3- (4-chlorophenyl)-(2S, 3R)-. Epoxy propionate was obtained as white crystals (yield 46%, optical purity 99ee).
%that's all).

Melting point: 107-110 ° C. ¹ H-NMR (CDCl ₃ ) δ 7.14-7.45 (m,
9H), 4.24 (d, 1H, J = 1.8 Hz), 3.
69 (d, 1H, J = 1.8 Hz) ¹³ C-NMR (CDCl ₃ ) δ 166.4, 150.
2, 135.2, 134.5, 133.2, 130.
3, 129.8, 129.6, 129.0, 127.
9, 127.3, 126.4, 121.1, 57.7,
56.7 IR (KBr; ν cm ^-1 ) 3068, 1752, 15
98, 1591, 1487, 1430, 1397, 12
67, 1201, 1164, 1090, 1013, 89
4,831,810,751,730,688,54
6,479 EI-MS (m / z) 274 (M ⁺ ) Elemental analysis C: 65.4%, H: 4.0%, Cl: 1
3.2% (calc. C: 65.6%, H: 4.0%, Cl:
12.9%) Specific rotation (c = 0.760, CHCl ₃ ) [α] ²⁸ _D =
+ 170 °

Claims (4)

[Claims] [Claim 1] The following formula (1) An optically active epoxy propionate derivative represented by the formula: (In the formula, * indicates optically active carbon.) 2. The following formula (2): The method for producing an optically active epoxy propionate derivative according to claim 1, wherein the optically active epoxy enone derivative represented by the formula (* is an optically active carbon) is oxidized. 3. The following formula (3): 3. The method for producing an optically active epoxy enone derivative according to claim 2, wherein the enone derivative represented by the formula (1) is epoxidized in the presence of an asymmetric catalyst. 4. An asymmetric catalyst comprising (A) an optically active binaphthol, (B) lanthanum triisopropoxide, (C) triphenylphosphine oxide and (D) cumene hydroperoxide or tertiary butyl hydroperoxide. 4. The composition according to claim 3, wherein
The method for producing an optically active epoxy enone derivative represented by the general formula (3) described in (1).