JP2002114749A - Method for producing optically active 2-hydroxy-3- phenylpropionitrile derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for catalytically synthesizing an optically active 2-hydroxy-3-phenylpropionitrile derivative using an asymmetric point-free compound as the starting material. SOLUTION: This method for producing the objective optically active 2- hydroxy-3-phenylpropionitrile derivative of formula (II) (* indicates R- or S- configuration) is characterized by comprising reaction of a compound of formula (I) (R1 is H or an OH-protective group) with a cyanating agent in the presence of an optically active catalyst.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an optically active 2-hydroxy-, which is an important intermediate of a compound useful as a medicine.
The present invention relates to a method for producing 3- (4-hydroxyphenyl) propionitrile. After converting the cyano group of the optically active 2-hydroxy-3- (4-hydroxyphenyl) propionitrile produced by the method of the present invention into a carboxyl group or a compound in which the carboxyl group is protected under acidic conditions, phenyl is optionally added. Optically active 3- (4-hydroxyphenyl) lactic acid can be produced by removing the protecting group for the hydroxyl group at position 4 and / or the protecting group for the carboxyl group. The optically active 3- (4-hydroxyphenyl) lactic acid can be converted into an optically active compound having a strong hypoglycemic effect described in, for example, JP-A-11-193272.

[0002]

2. Description of the Related Art As a method for producing optically active 3- (4-hydroxyphenyl) lactic acid, a method derived from a natural product such as an amino acid (Tetrahedron Letters. 1971, 25, 2283-2286, etc.) is used. To obtain a diastereomer salt and perform optical resolution by crystallization (WO2000
/ 026200), a method using an enzyme (Bioorg. Med. Chem. 199).
9,7,821-830), asymmetric reduction of α-keto acids using stoichiometric amounts of asymmetric reagents (Tetrahedron Lett)
ers. 1998, 39, 5501-5504).

[0003]

However, a method for catalytically synthesizing a compound having no asymmetric point as a starting material has not yet been known.

Optically active 3- (4-hydroxyphenyl)
In the case of synthesizing lactic acid from an amino acid derivative, it is difficult to obtain a non-natural type raw material, and the method of resolving a racemic form also produces unnecessary enantiomers at the same time. The present invention uses an easily available starting material having no asymmetry point, and provides an excellent optical activity to obtain only a necessary enantiomer.
The present invention relates to a method for producing (4-hydroxyphenyl) lactic acid. Since the present invention is a catalytic reaction, only a small amount of asymmetric reagent is used, and the method is more efficient than the method of performing asymmetric reduction on α-keto acid using a stoichiometric amount of asymmetric reagent. is there.

[0005]

The present invention provides a compound represented by the following general formula (I):

[0006]

Embedded image Wherein R ₁ represents a hydrogen atom or a hydroxyl-protecting group. A compound represented by the following general formula (II), which is reacted with a cyanating agent in the presence of an optically active catalyst.

[0007]

Embedded image (In the formula, R ₁ has the same meaning as described above, and * indicates the R or S configuration.) This is a method for producing an optically active 2-hydroxy-3-phenylpropionitrile derivative represented by the formula:

In the present invention, the term "protecting group for hydroxyl group" means a "protecting group in a reaction" which can be cleaved by a chemical method such as hydrogenolysis, hydrolysis, electrolysis or photolysis. Examples of such “hydroxyl protecting group” include, for example, methyl, t-butyl, methoxymethyl, 2-methoxyethoxymethyl, methylthiomethyl, allyl, cyclohexyl, benzyl, o-nitrobenzyl, 4-picolyl, t -Butyldimethylsilyl, acetyl and pivaloyl groups, and preferably a benzyl group.

In the present invention, “optically active catalyst” refers to
The following general formula (V)

[0010]

Embedded image (Wherein * represents R or S configuration, n represents an integer of 0 to 5, R ₃ is the same or different and is a hydrogen atom, an alkyl group, an alkoxy group, an alkylamino group, a nitro group or a halogen atom. Has axial asymmetry represented by
It is an aluminum compound coordinated with a 1,1′-bi-2-naphthol (BINOL) derivative.

Among the compounds represented by the general formula (V), those wherein n is 0 to 2 are preferred. R ₃
Is most preferably a hydrogen atom. The substitution position of R _{3 on} the benzene ring is not particularly limited.

Here, the "alkyl group" is a linear or branched hydrocarbon group having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n
-Butyl, isobutyl, s-butyl, t-butyl, n-
Pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2, Examples thereof include 2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, and 2-ethylbutyl.

The "alkoxy group" is a group in which the above "alkyl group" is bonded to an oxygen atom.

An "alkylamino group" is a group in which the above "alkyl group" is bonded to one or two amino groups.

"Halogen atom" is a fluorine, chlorine, bromine or iodine atom.

The compound represented by the general formula (V) is a compound represented by JA
m. Chem. Soc. 1999, 121, 2641-2642.

In the present invention, the “cyanating agent” is a reagent used when a cyano group is introduced by forming a carbon-carbon bond. Such "cyanating agent"
Examples thereof include trimethylsilyl cyanide, triethylsilyl cyanide and t-butyldimethylsilyl cyanide, and most preferably trimethylsilyl cyanide.

[0018]

BEST MODE FOR CARRYING OUT THE INVENTION The process of the present invention (step A in the following formula) and the general formula (I) produced by the process of the present invention
Method for producing optically active 3- (4-hydroxyphenyl) lactic acid from the compound represented by I) (Step B in the following formula)
And step C) is as follows.

[0019]

Embedded image (In the formula, R ₁ and * have the same meanings as described above, and R ₂ represents a hydrogen atom or a carboxyl-protecting group.) Step A is the reaction of the present invention.

The solvent used in the present reaction is not particularly limited as long as it does not inhibit the present reaction, and examples thereof include hydrocarbons such as benzene, toluene and hexane, and halogenated hydrocarbons such as dichloromethane and chloroform. Can be mentioned.

This reaction is carried out at a reaction temperature of -80 ° C to 0 ° C, and the reaction time is 30 minutes to 1 week.

The optical yield is improved by carrying out the reaction in the presence of a phosphine oxide such as a trialkylphosphine oxide, a diarylalkylphosphine oxide, a dialkylarylphosphine oxide, and a triarylphosphine oxide. Most preferably, such phosphine oxide is tributyl phosphine oxide. The amount of the phosphine oxide to be added is 1 to 10 times, preferably 4 to 8 times, by mole ratio to the catalyst (V).

After completion of the reaction according to a conventional method, hydrochloric acid is added to the reaction mixture, the mixture is stirred, and an organic solvent such as ethyl acetate or dichloromethane is added.
The organic solvent layer can be obtained by washing with water, drying and evaporating the solvent, and can be purified by recrystallization, column chromatography or the like, if desired.

In step B, the cyano group of the optically active 2-hydroxy-3- (4-hydroxyphenyl) propionitrile produced by the method of the present invention or a compound in which the hydroxyl group is protected is converted to a carboxyl group under acidic conditions. Or a step of converting the carboxyl group into a protected compound.

In R ₂ , “protecting group for carboxyl group”
Is a "protecting group in a reaction" that can be cleaved by chemical methods such as hydrogenolysis, hydrolysis, electrolysis, and photolysis.
It is. Examples of such a “protecting group for a carboxyl group” include an alkyl group (the alkyl group may be substituted with a trialkylsilyl group or an alkoxy group), a benzyl group, or an allyl group. .

Here, "alkyl group" and "alkoxy group" have the same meaning as described above.

Examples of the alkyl group as the “protecting group for carboxyl group” include methyl, ethyl, t-butyl 2,2,2-trimethylsilylethyl, methoxymethyl,
Ethoxymethyl can be mentioned.

This reaction is carried out by adding an inorganic acid in a solvent.
Examples of such an inorganic acid include hydrochloric acid, sulfuric acid, hydrobromic acid, nitric acid, and phosphoric acid.

Examples of the solvent for this reaction include hydrocarbons such as benzene, toluene and hexane; halogenated hydrocarbons such as dichloromethane and chloroform;
Dioxane, tetrahydrofuran, ethers such as ether, methanol, ethanol, propanol, isopropanol, n-butanol, t-butanol, alcohols such as benzyl alcohol, allyl alcohol, water, preferably alcohols, ethers, water Alternatively, there may be mentioned a mixture thereof, but there is no particular limitation as long as the solvent does not inhibit the reaction.

This reaction is carried out at room temperature or under reflux if necessary.

The reaction time is between one hour and one week.

After completion of the reaction, the target compound of this reaction is obtained by distilling off the solvent, adding an organic solvent such as ethyl acetate or dichloromethane, washing the organic solvent layer with water, drying and evaporating the solvent. It can be purified by recrystallization, column chromatography or the like, if necessary.

Step C is a step of removing the protecting group for the hydroxyl group at the 4-position of the phenyl group and / or the protecting group for the carboxyl group in the compound represented by the general formula (III) produced in the above step B.

In the step C, a hydroxyl-protecting group R ₁
Examples of the elimination reaction include: an elimination reaction with an acid (for example, removal of a methyl group and a benzyl group with hydrogen bromide), and a reaction using palladium (0) as a catalyst (for example, conversion of an allyl group with palladium tetrakistriphenylphosphine). Removal), a hydrogenation reaction using a hydrogenation reduction catalyst (for example, removal of a benzyl group using a palladium carbon catalyst), and a hydrolysis reaction using a base in an alcohol solvent (for example, removal of an acetyl group using potassium carbonate). it can.

Similarly, the elimination reaction of R ₂ , which is a carboxyl-protecting group, is also carried out, for example, by a hydrolysis reaction with an alkali metal (for example, removal of a methyl or ethyl group with lithium hydroxide, sodium hydroxide or potassium hydroxide). Elimination reaction with acid (for example, removal of benzyl group with hydrogen bromide, removal of t-butyl and methoxymethyl group with hydrogen chloride), reaction catalyzed by palladium (0) (for example, allyl reaction with palladium tetrakistriphenylphosphine) Group removal), hydrogenation reaction using a palladium catalyst (for example, removal of a benzyl group using a palladium carbon catalyst), hydrolysis reaction using a base in an alcohol solvent (for example, removal of an acetyl group using potassium carbonate), fluoride ion (Eg, trimethylsilyl with tetrabutylammonium fluoride) Removal of the methyl group) can be exemplified.

[0036]

The present invention will be described in more detail with reference to examples and reference examples, but the scope of the present invention is not limited to these examples.

[0037]

Example 1 (R) -3- (4-benzyloxyphenyl) -2-
Hydroxypropionitrile tributyl phosphine oxide 41 mg was dissolved in anhydrous dichloromethane 0.25 ml, diethyl aluminum chloride 0.95mo
49 μl of a l / l hexane solution was added, and the mixture was stirred at room temperature for 1 hour.
To the reaction solution was added a solution of (S) -3,3'-bis (diphenylphosphinoyl) -1,1'-binaphthol (35 mg, 1.0 ml in dichloromethane), and the mixture was stirred for 1 hour. At -40 ° C, 4-benzyloxyphenylacetaldehyde (117 mg) was added. Of 0.50 ml of dichloromethane was added. After stirring at −40 ° C. for another 30 minutes, 124 μl of trimethylsilyl cyanide was added dropwise over 6.5 hours.
Stir for 3.5 hours. After completion of the reaction, 2.0 ml of 1 N hydrochloric acid and 2.0 ml of tetrahydrofuran were added, and the mixture was stirred at room temperature for 30 minutes, and then extracted three times from the aqueous layer using ethyl acetate.
The combined organic layer was washed twice with water and once with saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel with hexane: ethyl acetate = 4: 1 to give the target compound as colorless crystals.
116 mg were obtained. Optical isomer excess is obtained by treating the dichloromethane solution of the obtained target compound with 2,6-lutidine and t-butyldimethylsilyl triflate, converting the hydroxyl group to t-butyldimethylsilyl ether, and then using HPLC. Were determined. Melting point: 127-128 ° C. [α] ²⁵ _D + 3.1 ° (c 1.12, CHCl ₃ ) ¹ H-NMR (CDCl ₃ , δ ppm): 2.43 (1H, d, J = 7.0 Hz), 3.07
(2H, d, J = 6.0Hz), 4.60-4.65 (1H, m), 5.06 (2H, s),
6.98 (2H, d, J = 8.5Hz), 7.22 (2H, d, J = 8.5Hz), 7.30-
7.44 (5H, m) HPLC (Daicel Chiralpack OD, hexane: isopropanol = 99: 1, 1 ml / min, λ = 254 nm): t _R = 20.2 min and 24.0 min (optical isomer excess 97% ee)

[0038]

[Reference example]

[0039]

Reference Example 1 (R) -3- (4-hydroxyphenyl) lactic acid 507 mg of (R) -3- (4-benzyloxyphenyl) -2-hydroxypropionitrile obtained in Example 1 was degassed. It was dissolved in 8.0 ml of ethanol, 4.0 ml of 12N hydrochloric acid was added, and the mixture was heated under reflux for 64 hours. After completion of the reaction, the reaction solution was concentrated, ethyl acetate was added, and the organic layer was washed with water. The aqueous layer was further extracted twice with ethyl acetate. The organic layers were combined, washed twice with water, washed once with a saturated saline solution, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained crude (R)-
432 mg of ethyl 3- (4-hydroxyphenyl) lactate was dissolved in 8.0 ml of ethanol, 4.0 ml of a 1 N aqueous sodium hydroxide solution was added under ice cooling, and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction solution was concentrated, ethyl acetate was added, and the mixture was washed with water. The extraction operation was performed twice more from the aqueous layer with ethyl acetate.
The organic layers were combined, washed twice with water, and then washed with a saturated saline solution.
After washing twice, it was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained crystals were collected by filtration using isopropyl ether and hexane to obtain 176 mg of the desired compound as colorless crystals. Melting point: 169-170 ° C. [α] ²⁵ _D + 17.5 ° (c 1.04, H ₂ O) ¹ H-NMR (DMSOd ₆ , δ ppm): 2.66 (1H, dd, J = 4.0, 8.0H)
z), 2.82 (1H, dd, J = 4.5,13.5Hz), 4.04-4.07 (1H, m),
6.64 (2H, d, J = 8.5Hz), 7.00 (2H, d, J = 8.5Hz).

[0040]

According to the production method of the present invention, optically active 2-hydroxy-3- (4-hydroxyphenyl) propionitrile and optically active 3- (4- (Hydroxyphenyl) lactic acid can be produced catalytically with good optical purity using a readily available compound having no asymmetric point as a starting material.

Claims (1)

[Claims] 1. A compound represented by the following general formula (I): Wherein R ₁ represents a hydrogen atom or a protecting group for a hydroxyl group, wherein the compound is reacted with a cyanating agent in the presence of an optically active catalyst. Formula 2 (Wherein, R ₁ has the same meaning as described above, and * indicates R or S configuration.) A method for producing an optically active 2-hydroxy-3-phenylpropionitrile derivative represented by the formula: