JPH0597735A - Production of optically active secondary alcohol - Google Patents

Abstract

PURPOSE:To obtain the subject alcohol useful as a raw material for pharmaceuticals, liquid crystals, etc., in high optical yield by using a 2- pyrrolidine methanol derivative as an asymmetric catalyst. CONSTITUTION:The objective optically active secondary alcohol can be produced in high optical yield by the alkylation reaction of an aldehyde or the reduction of a ketone by using a 2-pyrrolidine methanol derivative of formula I [R<1> and R<2> are H or phenyl which may have 1-5 substituents (halogen or NO2); Z is H, Li, Na, K, MgC2H5 or (substituted)1-6C alkyl; * mark represents asymmetric carbon] as a catalyst. The compound of formula I can easily be produced by reacting a compound of formula II with dichloromethane.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing an optically active secondary alcohol using a pyrrolidine methanol derivative.

[0002]

2. Description of the Related Art Optically active secondary alcohols are useful as raw materials for pharmaceuticals, liquid crystals, etc., but are difficult to obtain because their production method requires optical resolution, and those available are expensive. ..

Conventionally, a pyrrolidine methanol derivative has been known as a compound used as an asymmetric catalyst when an optically active secondary alcohol is produced from an aldehyde or a ketone, but the simplest (S) -2- Pyrrolidine methanol generally does not give high asymmetric yields, so conversion to more complex derivatives was necessary (eg K. Soaiet
al., J. Am. Chem. Soc., 109, 7111 (1987)). In addition, there are few compounds containing two pyrrolidine methanol structures in the molecule, and an example of producing an optically active secondary alcohol using the same was not well known (for example, L. Colombo et.
al., Tetrahedron 38,2725 (1982)).

[0004]

The object of the present invention is to provide 2-pyrrolidinemethano- which is easy to produce and useful as an asymmetric catalyst.
To provide an optically active secondary alcohol.
Is to manufacture

[0005]

Means for Solving the Problems The present inventors have made extensive studies to solve the above problems
The present invention was completed by discovering that pyrrolidine methanol derivatives are excellent as asymmetric catalysts. That is, the present invention has the general formula

[Chemical 6] (In the formula, R 1 and R 2 may be the same or different and each is a hydrogen atom or a phenyl group which may be substituted with 1 to 5 halogen atoms or nitro groups, Z is a hydrogen atom, Li,
Na, K, -MgC2H5 or an alkyl group having 1 to 6 carbon atoms which may have a substituent, and * represents an asymmetric carbon. The present invention relates to a method for producing an optically active secondary alcohol, which comprises using a 2-pyrrolidinemethanol derivative represented by the formula (4) as a catalyst for an aldehyde alkylation reaction or a ketone reduction reaction.

The 2-pyrrolidine methanol represented by the formula 1 used in the present invention can be obtained by reacting the compound represented by the formula 4 with dichloromethane. In the formula of the general formula 1, R1 and R2 may be the same or different and each is a hydrogen atom or a phenyl group which may be substituted with 1 to 5 halogen atoms or nitro groups, Z is a hydrogen atom, L
i, Na, K, -MgC2H5 or an alkyl group which may have a substituent having 1 to 6 carbon atoms such as a methyl group or an ethyl group, and * represents an asymmetric carbon.

This reaction is preferably carried out in the presence of an inorganic or organic base, for example by heating a dichloromethane solution of Chemical formula 4 under reflux with an aqueous sodium hydroxide solution overnight to obtain the compound of Chemical formula 1 in high yield. it can. Examples of the inorganic base include sodium hydroxide and potassium hydroxide, and examples of the organic base include sodium methoxide and triethylamine. The amount of base is
Usually, 5 equivalents or less are used with respect to the starting material shown in.

The amount of dichloromethane used is usually in a large excess.

The reaction temperature is 25 to 50 ° C., and the reaction time is several hours to several days. The obtained 2-pyrrolidinemethanol derivative represented by Chemical formula 1 can be easily isolated by recrystallization.

The 2-pyrrolidine methanol represented by Chemical formula 1 used in the present invention can be used as an asymmetric reaction catalyst in an asymmetric synthesis reaction. More specifically, it can be used as an asymmetric catalyst in the production of, for example, an optically active secondary alcohol. Examples of the method for producing the optically active second alcohol include a method of alkylating an aldehyde, a method of reducing a ketone, a method of oxidizing an alkene, and the like.
These reactions can be carried out stereoselectively by adding the compounds of the present invention during the reaction.

Aldehydes used for the alkylation of aldehydes have the general formula

[Chemical 7] (In the formula, R3 represents an alkyl group having 1 to 12 carbon atoms or a functional group represented by the general formula 8). Specific examples thereof include acetaldehyde and benzaldehyde.

[0012]

[Chemical 8] (In the formula, X and Y may be the same or different and each is a hydrogen atom, a halogen atom, a nitro group or a cyano group, m and n are 0, 1 or 2, and α and β are alkylene, ester or ether. R4 represents an alkyl group having 1 to 16 carbon atoms.

In the alkylation reaction, a commonly used alkylating agent can be used, and examples thereof include dialkyl zinc and alkyl lithium. The ketone used in the reduction reaction of the ketone has the general formula

[Chemical 9] (In the formula, R5 represents an alkyl group having 1 to 12 carbon atoms or a functional group represented by the general formula 8; R6 represents an alkyl group, an alkenyl group, an aryl group or an aralkyl group which may have a substituent. And R5 and R6 may together form a ring). Specific examples include acetophenone and propiophenone.

As the reducing agent, a commonly used reducing agent can be used. For example, lithium aluminum hydride, sodium borohydride, borane and the like are used. The amount of catalyst used varies depending on the substrate, but is usually 0.1 to 1 equivalent in the alkylation reaction and 1 to 4 equivalents in the reduction reaction with respect to the substrate.

[0015]

【Example】

Example 1 Synthesis of N, N'-bis ((S) -2-hydroxymethylpyrrolidinyl) methane (s) -prolinol 1.0 g (9.9 mmol) and sodium hydroxide 2.1 g were added to dichloromethane 20 ml.
Was dissolved in a two-phase system of 4 ml of water and heated under reflux for 24 hours. After the completion, anhydrous sodium sulfate was added to a dichloromethane solution obtained by extracting 3 times with 30 ml of dichloromethane and drying, and then the solvent was distilled off to obtain 0.99 g of the title compound (yield 93.3%). It was recrystallized from ether-hexane for purification. Melting point 65.0-66.0 ° C IR (KBr): 3600-2400, 1460, 12
40-1000,950,800,750 cm-1 1H-NMR (CDCl3) δ: 1.42-1.55
(M, 2H), 1.68-1.78 (m, 4H), 1.
94-2.08 (m, 4H), 2.53 (ABq, J =
9.0 Hz, 2H), 2.60-2.70 (m, 2
H), 3.10-3.18 (m, 2H), 3.37.
(S, 2H), 3.58 (d, J = 6Hz, 4H) pp
m FDMS: 215 (M + H), 429 (2M + H) [α] 20 = + 76.5 (c = 1, toluene)

Example 2 N, N'-bis ((S) -2-
Synthesis of benzyloxymethylpyrrolidinyl) methane Under an argon atmosphere, 460 mg of 60% sodium hydride (60% oil suspension) was suspended in 5 ml of anhydrous dimethylformamide, and cooled with ice. 1.07 g of the compound of Example 1 was dissolved in 1 ml of anhydrous dimethylformamide and added, and the mixture was stirred at 0 ° C. for 30 minutes and at room temperature for 1 hour. The mixture was ice-cooled again to 0 ° C., 1.37 ml of benzyl bromide was added, and the mixture was stirred at 0 ° C. for 1 hour and at room temperature for 21 hours. After the completion, 2 ml of methanol and 50 ml of water were added to the reaction solution, and the mixture was extracted 3 times with 30 ml of diethyl ether. The organic layers were combined, washed twice with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel chromatography using a 1: 1 mixed solution of ether-hexane as an eluent to obtain 692.0 mg of the title compound (yield 35.1%).

Example 3 1-by asymmetric alkylation reaction
Synthesis of Phenyl-1-pentanol 321 mg of the compound of Example 1 was treated with anhydrous dimethoxymethane 2
It was dissolved in 0 ml and stirred at 0 ° C. 5.63 ml of n-butyllithium (1.6 M / l hexane solution) was added,
The mixture was stirred at 0 ° C for 30 minutes. After cooling to −65 ° C., 305 μl of benzaldehyde was added dropwise. After stirring at the same temperature for 1.5 hours, 10 ml of 3N hydrochloric acid was added and the mixture was extracted 3 times with 10 ml of ether. The extract was washed with saturated saline and dried over anhydrous magnesium sulfate. Preparative silica gel TLC fractionation gave 453 mg of the title compound (yield 92%). When analyzed by an optically active column (Daicel Chiralcel OB), the optical purity was 5.6% ee (R form).

Example 4 1-by asymmetric alkylation reaction
Synthesis of Phenyl-1-propanol 64.3 mg of the compound of Example 1 was dissolved in 3 ml of toluene and stirred at 25 ° C. After adding 6 ml of diethyl zinc (1.0 M / l hexane solution) and stirring at 25 ° C. for 15 minutes, 318.4 mg of benzaldehyde was added under ice cooling. After stirring at 5 ° C. for 21 hours, 10 ml of 3N hydrochloric acid was added, 10 ml of ether was added, and the insoluble matter was removed by filtration.
The filtrate was separated into layers, and the aqueous layer was extracted 3 times with 10 ml of ether. The organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel chromatography to give the title compound (173.4 mg) (yield 42.5%). Optically active column (Daicel Ch
Optical purity is 29.0% when analyzed by iralcel OB)
It was ee (R form).

Example 5 Synthesis of 1-phenyl-1-propanol by asymmetric reduction reaction To 400 mg of lithium aluminum hydride, 6 ml of tetrahydrofuran (THF) was added under an argon atmosphere,
5.0 ml of a THF solution of ethanol (2 M / l) was added dropwise. 2.14 g of the compound of Example 1 was dissolved in 17 ml of THF and added dropwise. After stirring at room temperature for 30 minutes, -78 ° C
After cooling, the THF solution (3 ml) of 402 mg of propiophenone was added dropwise over 8 minutes. After stirring at the same temperature for 5 hours, 1.2 ml of methanol was added. The temperature was raised to room temperature, 24 ml of 2N hydrochloric acid was added, and the mixture was extracted 3 times with 20 ml of ether. After combining the organic layers and washing with saturated saline,
It was dried over anhydrous magnesium sulfate. The solvent was distilled off, and the title compound 30 was purified by silica gel chromatography.
0.0 mg was obtained (yield 73.4%). When analyzed by an optically active column (Daicel Chiralcel OB), the optical purity was 67.8% ee (R form).

[0020]

By using the pyrrolidinemethanol derivative of the present invention as a catalyst, an optically active secondary alcohol can be produced with a high optical yield.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor, Osamu Ikemura 1-1, Suzuki-cho, Kawasaki-ku, Kanagawa Prefecture Central Research Institute of Ajinomoto Co., Inc. 1 Central Research Laboratory, Ajinomoto Co., Inc.

Claims (4)

[Claims] 1. A general formula: (In the formula, R 1 and R 2 may be the same or different and each is a hydrogen atom or a phenyl group which may be substituted with 1 to 5 halogen atoms or nitro groups, Z is a hydrogen atom, Li,
Na, K, -MgC2H5 or an alkyl group having 1 to 6 carbon atoms which may have a substituent, and * represents an asymmetric carbon. 2. A method for producing an optically active secondary alcohol by an alkylation reaction of an aldehyde, which comprises using a 2-pyrrolidinemethanol derivative represented by the formula) as a catalyst. 2. A general formula: (In the formula, R 1 and R 2 may be the same or different and each is a hydrogen atom or a phenyl group which may be substituted with 1 to 5 halogen atoms or nitro groups, Z is a hydrogen atom, Li,
Na, K, -MgC2H5 or an alkyl group having 1 to 6 carbon atoms which may have a substituent, and * represents an asymmetric carbon. 2. A method for producing an optically active secondary alcohol by a reduction reaction of a ketone, which comprises using a 2-pyrrolidinemethanol derivative as a catalyst. 3. A general formula: (In the formula, R 1 and R 2 may be the same or different and each is a hydrogen atom or a phenyl group which may be substituted with 1 to 5 halogen atoms or nitro groups, Z is a hydrogen atom, Li,
Na, K, -MgC2H5 or an alkyl group having 1 to 6 carbon atoms which may have a substituent, and * represents an asymmetric carbon. ) 2-pyrrolidine methanol derivative represented by 4. A general formula: (In the formula, R 1 and R 2 may be the same or different and each is a hydrogen atom or a phenyl group which may be substituted with 1 to 5 halogen atoms or nitro groups, Z is a hydrogen atom, Li,
Na, K, -MgC2H5 or an alkyl group having 1 to 6 carbon atoms which may have a substituent, and * represents an asymmetric carbon. ) A compound represented by the general formula: (In the formula, R 1 and R 2 may be the same or different and each is a hydrogen atom or a phenyl group which may be substituted with 1 to 5 halogen atoms or nitro groups, Z is a hydrogen atom, Li,
Na, K, -MgC2H5 or an alkyl group having 1 to 6 carbon atoms which may have a substituent, and * represents an asymmetric carbon. ) The manufacturing method of the 2-pyrrolidine methanol derivative represented by these.