JPH0873400A - Process for producing optically active cyclopropanecarboxylic acid derivative - Google Patents

Abstract

(57) [Summary] [Structure] General formula (2) The cyclopropenecarboxylic acid derivative represented by the general formula (3) The asymmetric hydrogen reduction in the presence of a metal catalyst modified with an optically active metallocenylphosphine derivative represented by the general formula (1) A method for producing an optically active cyclopropanecarboxylic acid derivative represented by: [Effect] The optically active cyclopropanecarboxylic acid derivative represented by the general formula (1), particularly the cis form thereof, can be easily produced with good conversion and good yield.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a method for producing an optically active cyclopropanecarboxylic acid derivative.

[0002]

2. Description of the Related Art General formula (1) (In the formula, R ¹ represents a lower alkyl group, a cycloalkyl group having 5 to 8 carbon atoms, an aryl group or a heterocyclic ring having 5 to 6 carbon atoms, and R ² represents a lower alkyl group or an aryl group.) The optically active cyclopropanecarboxylic acid derivative is capable of easily converting the carboxylic acid group into an amine, an alcohol, etc., and particularly, in the above general formula, the cis-form in which the substituent R ¹ and the carboxyl group have a cis configuration is It is well known as an important optically active intermediate for the production of medicines and the like.

As a conventional method for producing such an optically active cyclopropanecarboxylic acid derivative, a method for producing a carboxylic acid ester by asymmetric cyclopropanation with an olefin and a diazoacetic acid ester using an asymmetric copper catalyst is well known. Has been. However, the product obtained by this method is a cis / trans mixture, and there is a problem that the optical purity is generally not high unless the ester site of the diazoacetic acid ester is increased. Further, the reactivity of asymmetric cyclopropanation varies greatly depending on the type of olefin, and in general, a trisubstituted olefin has a low cis / trans isomer ratio and a low optical purity, so that the target optically active cyclopropanecarboxylic acid derivative is obtained. Therefore, operations such as separation of cis- and trans-forms and optical resolution are required, which is very complicated.

[0004]

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention
The present inventor has investigated a method for efficiently and easily producing an optically active cyclopropanecarboxylic acid derivative represented by the general formula (1), particularly a cis isomer thereof, at an optical purity,
The present invention has been completed.

[0005]

The present invention is based on the general formula (2) (In the formula, R ¹ and R ² have the same meanings as described above.)
The cyclopropenecarboxylic acid derivative represented by the general formula (3) (In the formula, R ³ and R ⁴ represent a lower alkyl group, and R ⁵ and R ⁶ represent a hydrogen atom or a lower alkyl group. Further, R ⁵ and R ⁶ are bonded to each other to form a heterocycle with a nitrogen atom. The hetero ring may further contain an oxygen atom or a nitrogen atom, Ph represents a phenyl group, M represents Fe or Ru, and n is an integer of 1 to 3.) Asymmetric hydrogen reduction in the presence of a metal catalyst modified with an active metallocenylphosphine derivative, a method for producing an optically active cyclopropanecarboxylic acid derivative represented by the above general formula (1), particularly a cis isomer thereof. Is provided.

The cyclopropenecarboxylic acid derivative which is the starting compound in the method of the present invention is represented by the above general formula (2), and the lower alkyl group of the substituent R ¹ in the formula is methyl, ethyl, isopropyl or n-. Propyl,
n-butyl, t-butyl, etc. are cyclopentyl, cyclohexyl, cycloalkyl groups having 5 to 8 carbon atoms,
Cyclooctyl and the like, phenyl as the aryl group,
Examples of the phenyl group which may be substituted with lower alkyl or lower alkoxyl such as tolyl, xylyl, isopropylphenyl, methoxyphenyl and propoxyphenyl, and the heterocyclic ring having 5 to 6 carbon atoms include furyl, pyridyl and piperidyl. To be done. Further, the lower alkyl group and the aryl group of the substituent R ² are also exemplified in the same manner as above.

Specific examples of the cyclopropenecarboxylic acid derivative represented by the general formula (2) include 3,3-
Dimethyl-2-methyl-cyclopropenecarboxylic acid,
3,3-dimethyl-2- (n-propyl) -cyclopropenecarboxylic acid, 3,3-dimethyl-2-phenyl-cyclopropenecarboxylic acid, 3,3-dimethyl-2- (p
-Tolyl) -cyclopropenecarboxylic acid, 3,3-diethyl-2- (p-methoxyphenyl) -cyclopropenecarboxylic acid, 3,3-dimethyl-2-cyclohexyl-
Cyclopropenecarboxylic acid, 3,3-diphenyl-2-
Methyl-cyclopropenecarboxylic acid, 3,3-dimethyl-2-pyridyl-cyclopropenecarboxylic acid and the like are exemplified, and these are described in, for example, J. Am. Chem. Soc., Vol. 85, 99 (1
963), J. Chem. Soc. Perkin Trans. I, 1845 (1986) and the like.

The present invention uses a metal catalyst modified with an optically active metallocenylphosphine derivative. The optically active metallocenylphosphine derivative is represented by the above-mentioned general formula (3), Examples of the lower alkyl group of the substituents R ^{3 to} R ^{6 in} the formula include methyl, ethyl, isopropyl, n-propyl, n-butyl, t-butyl and the like, and R ⁵ and R ⁶ are bonded to each other to form a nitrogen atom. Examples of the hetero ring to be formed include a piperidyl group, a pyrrolidyl group, an imidazolyl group, an oxazolyl group and the like. In such a compound, the substituent R ³ is a methyl group or an ethyl group, R ⁴ is a methyl group, R ⁵ and R ⁶ are both lower alkyl groups, or R ⁵ and R ⁶ are combined to form a piperidyl group together with a nitrogen atom. A compound which forms a heterocycle such as a pyrrolidyl group and n is 2 is preferably used.

Examples of such optically active metallocenylphosphine derivatives include (R) -N-methyl- [2- (diethylamino) ethyl] -1-[(S) -1 ', 2-bis (diphenylphosphine). Phino) ferrocenyl] ethylamine (R) -N-methyl- [2- (diethylamino) ethyl] -1-[(S) -1 ′, 2-bis (diphenylphosphino) ruthenocenyl] propylamine (R) -N- Methyl- [2- (piperidyl) ethyl]-
1-[(S) -1 ', 2-bis (diphenylphosphino)
Specific examples include ferrocenyl] ethylamine, which are available from Bull.Chem.Soc.Jp.
n., Vol. 53, 1138 (1980), J. Organomet. Chem., No. 382, 19
(1990), Tetrahedron: Asymmetry, Vol. 4, 1763 (1993) and the like.

The present invention uses a metal catalyst modified with such an optically active metallocenylphosphine derivative. For example, a metal component such as Rh (COD) ₂ BF ₄ and [RuCl ₂ (COD)] n. It can be produced by ligand exchange of the above-mentioned optically active metallocenylphosphine derivative with a cation complex containing a metal complex such as Rh ₂ (COD) ₂ Cl ₂ and AgBF ₄ It can also be prepared by mixing a silver salt and an optically active metallocenylphosphine derivative in a reaction system. In the metal catalyst modified with such an optically active metallocenylphosphine derivative, a transition metal, particularly rhodium, iridium or ruthenium is preferably used as the metal component. As a metal catalyst modified with such an optically active metallocenylphosphine derivative, specifically,
Rh [(R)-(S) -BPPF-NMeCH ₂ CH ₂ NEt ₂ ] (COD) BF ₄ , Rh [(R)-(S)
-Et-BPPR-NMeCH ₂ CH ₂ NEt ₂ ] (NBD) BF ₄ , Ru ₂ Cl ₂ [(R)-(S) -B
_{PPF-NMeCH 2 CH 2 NEt 2} ] 2 , etc. can be exemplified. In the above, (R)-(S) -BPPF-NMeCH ₂ CH ₂ NEt ₂ is (R) -N
-Methyl- [2- (diethylamino) ethyl] -1-
[(S) -1 ′, 2-bis (diphenylphosphino) ferrocenyl] ethylamine was converted into (R)-(S) -Et-BPPR-NMeCH ₂
CH ₂ NEt ₂ is (R) -N-methyl- [2- (diethylamino) ethyl] -1-[(S) -1 ′, 2-bis (diphenylphosphino) luterosenyl] propylamine, C
OD is 1,5-cyclooctadiene, NBD is 2,5
-Represents norbornadiene respectively.

In the method of the present invention, the amount of the metal catalyst modified with such an optically active metallocenylphosphine derivative is 0.001 to 10 with respect to the cyclopropenecarboxylic acid derivative represented by the general formula (2) as a raw material. It is in the range of mol%, preferably 0.01 to 1 mol%.

The reaction is usually carried out in a solvent, and the solvent can be used without particular limitation as long as it is inert to the reaction. For example, methanol, ethanol, isopropanol, butanol, benzene, toluene, tetrahydrofuran, dichloromethane, etc. Various organic solvents or water or a mixture thereof, such as methanol,
Ethanol is preferably used. The amount of the solvent used is usually 1 to 5 with respect to the raw material cyclopropenecarboxylic acid derivative.
The amount is 00 times by weight, preferably 10 to 200 times by weight.

The hydrogen pressure during the reduction reaction is generally in the range of atmospheric pressure to 500 kg / cm ² , preferably 10 to 150 kg / cm ² . The reaction temperature is in the range of 0 to 150 ° C, preferably 20 to 100 ° C. In this reaction, adding a tertiary amine such as triethylamine or tri-n-propylamine to the reaction system is effective for improving the reactivity. When a tertiary amine is used, the amount used for exhibiting its effect is 0.1 to 100 mol times, preferably 1 to 20 mol times, of the metal catalyst.

[0014]

According to the method of the present invention, the optically active cyclopropanecarboxylic acid derivative represented by the general formula (1), particularly the cis form thereof, can be easily produced with a good conversion and a good yield. Further, by using a metal catalyst modified with an optically active metallocenylphosphine derivative having a changed configuration, it is possible to control the configuration of the optically active cyclopropanecarboxylic acid derivative to be produced.

[0015]

EXAMPLES The present invention will be described below with reference to examples, but it goes without saying that the present invention is not limited thereto.

Example 1 Rh ₂ (COD) ₂ Cl ₂ 1.2 mg (0.0025 mmol),
AgBF ₄ 1.0 mg (0.005 mmol), (R)-(S) -Et
-BPPR-NMeCH ₂ CH ₂ NEt ₂ (4.8 mg, 0.00625 mmol), triethylamine (5.1 mg, 0.05 mmol) and methanol (7.5 ml) were charged and dissolved in a 35 ml autoclave. To this, 3,3-dimethyl-2-phenylcyclopropenecarboxylic acid 188.2
mg (1 mmol) was added and dissolved. After replacing the inside of the autoclave with hydrogen gas, the pressure of hydrogen was increased to 50 kg / cm ² , and the mixture was stirred at room temperature for 66 hours. After the reaction was completed, hydrogen was depressurized and methanol was distilled off, followed by alkali extraction, acid precipitation,
Ether extraction and concentration were carried out to obtain cis (+)-3,
188.2 mg of 3-dimethyl-2-phenylcyclopropanecarboxylic acid was obtained. Conversion 100% Selectivity> 98% Optical yield 94.2% ee cis (+) Optical rotation [α] _D ²⁵ = + 8.6 ° (c = 1.0)
3, CHCl ₃ ) The conversion and selectivity were calculated by NMR, and the optical yield was calculated by liquid chromatogram using an optically active column and optical rotation. The structure of (R)-(S) -Et-BPPR-NMeCH ₂ CH ₂ NEt ₂ is as follows.

Example 2 (R)-(S) -Et-BPPR-NMeCH ₂ CH ₂ NEt ₂ Instead of (R)-(S) -BPPF
The reaction and post-treatment were carried out in the same manner as in Example 1 except that -NMeCH ₂ CH ₂ NEt ₂ was used to obtain 186 mg of cis (+)-3,3-dimethyl-2-phenylcyclopropanecarboxylic acid. Conversion 100% Selectivity> 98% Optical yield 90.7% ee cis (+) The structure of (R)-(S) -BPPF-NMeCH ₂ CH ₂ NEt ₂ is as follows.

Claims (3)

[Claims] 1. General formula (2) (In the formula, R ¹ represents a lower alkyl group, a cycloalkyl group having 5 to 8 carbon atoms, an aryl group or a heterocyclic ring having 5 to 6 carbon atoms, and R ² represents a hydrogen atom, a lower alkyl group or an aryl group. ) A cyclopropenecarboxylic acid derivative represented by the general formula (3) (In the formula, R ³ and R ⁴ represent a lower alkyl group, and R ⁵ and R ⁶ represent a hydrogen atom or a lower alkyl group. Further, R ⁵ and R ⁶ are bonded to each other to form a heterocycle with a nitrogen atom. The hetero ring may further contain an oxygen atom or a nitrogen atom, Ph represents a phenyl group, M represents Fe or Ru, and n is an integer of 1 to 3.) General formula (1) characterized by asymmetric hydrogen reduction in the presence of a metal catalyst modified with an active metallocenylphosphine derivative (In the formula, R ¹ and R ² have the same meanings as described above.)
A method for producing an optically active cyclopropanecarboxylic acid derivative represented by: 2. The method for producing an optically active cyclopropanecarboxylic acid derivative according to claim 1, wherein the metal component of the metal catalyst is a transition element. 3. The method for producing an optically active cyclopropanecarboxylic acid derivative according to claim 2, wherein the transition element is rhodium, iridium or ruthenium.