JP2003137835A - Method for producing (r)-3-hydroxy-3-(2-phenyl)hexanoic acid - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing (R)-3-hydroxy-3-(2-phenylethyl) hexanoic acid, by which the (R)-3-hydroxy-3-(2-phenylethyl)hexanoic acid useful as a medicine raw material can efficiently be produced from racemic 3- hydroxy-3-(2-phenylethyl)-hexanoic acid in a high optical purity and in a relative ly high yield. SOLUTION: This method for producing the (R)-3-hydroxy-3-(2-phenylethyl) hexanoic acid is characterized by optically resolving the racemic 3-hydroxy-3-(2- phenylethyl)hexanoic acid with (R)-N-para-hydroxybenzyl-α-phenyl-β-para- tolyethylamine.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to (R) -3-hydroxy-3- (2), which is a useful synthetic intermediate for anti-HIV agents.
-Phenylethyl) hexanoic acid.

[0002]

BACKGROUND OF THE INVENTION The following formula, which is useful as an anti-HIV agent which has been developed in recent years,

[0003]

[Chemical 1]

A useful synthetic intermediate of PNU-140690 represented by

[0005]

[Chemical 2]

3-Hydroxy-3- (2-phenylethyl) hexanoic acid represented by the following formula is known. This 3-hydroxy-3- (2-phenylethyl) hexanoic acid has one asymmetric carbon and has (R) and (S) isomers,
The compound synthesized by the usual method is a racemic body (racemic-3-hydroxy-3- (2-phenylethyl) hexanoic acid). The following formula

[0007]

[Chemical 3]

The (R) -form represented by ((R) -3-hydroxy-3- (2-phenylethyl) hexanoic acid) is preferably used as the synthetic intermediate.

The above racemic-3-hydroxy-3- (2-
As a method for optically resolving (R) -3-hydroxy-3- (2-phenylethyl) hexanoic acid from phenylethyl) hexanoic acid, conventionally, (−)-norephedrine ((1S, 2S) -norephedrine) has been used. Has been reported (J. Org. Chem., Vol. 63, No. 21, 199).
8, 7348-7356). However, with this method, 98%
e. e. (R) -3-hydroxy-3 having the above optical purity
To obtain-(2-phenylethyl) hexanoic acid,
For example, 92% e. e. It is necessary to recrystallize the salt with (-)-norephedrine obtained in step 2 twice, which is industrially inefficient. Further, in the above report, it is described that effective optical resolution could not be achieved even with commonly used amines such as phenylglycinol, ephedrine, sparteine, and α-methylbenzylamine, which is high. Optically pure (R) -3-hydroxy-3
There is a demand for a method capable of efficiently obtaining-(2-phenylethyl) hexanoic acid in a relatively high yield.

[0010]

SUMMARY OF THE INVENTION The present invention has been made to solve the above problems, and its object is to provide (R) -3-hydroxy-3- (2) which is useful as a raw material for pharmaceuticals. -Phenylethyl) hexanoic acid is provided from racemic-3-hydroxy-3- (2-phenylethyl) hexanoic acid with high optical purity and relatively high yield efficiently. .

[0011]

Means for Solving the Problems As a result of intensive studies to solve the above problems, the present inventors have found that the following formula

[0012]

[Chemical 4]

By using (R) -N-parahydroxybenzyl-α-phenyl-β-paratolylethylamine represented by the formula, racemic-3-hydroxy-3- (2-
(R) -3-hydroxy-3- (2-phenylethyl) having higher optical purity than phenylethyl) hexanoic acid
The inventors have found that hexanoic acid can be produced in a much higher efficiency and a relatively higher yield than ever before, and have completed the present invention. That is, the present invention is as follows.

(1) Racemic-3-hydroxy-3- (2
-Phenylethyl) hexanoic acid is optically resolved using (R) -N-parahydroxybenzyl-α-phenyl-β-paratolylethylamine.
(R) -3-hydroxy-3- (2-phenylethyl)
Method for producing hexanoic acid. (2) A salt of (R) -3-hydroxy-3- (2-phenylethyl) hexanoic acid and (R) -N-parahydroxybenzyl-α-phenyl-β-paratolylethylamine was added to ethyl acetate, Methanol, 2-propanol, ethanol, acetonitrile, methyl isobutyl ketone,
Crystallizing in one or more solvents selected from acetone, methyl ethyl ketone, diisopropyl ether, dimethoxyethane and tetrahydrofuran (the solvent may further contain water), characterized by the above ( The method described in 1).

[0015]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in detail below.
The production method of the present invention comprises racemic-3-hydroxy-3-
From (2-phenylethyl) hexanoic acid (hereinafter sometimes referred to as "the racemic-carboxylic acid") to (R) -3.
-Hydroxy-3- (2-phenylethyl) hexanoic acid (hereinafter, may be referred to as "the (R) -carboxylic acid" in some cases) is optically active for optically resolving the following formula.

[0016]

[Chemical 5]

(R) -N-parahydroxybenzyl-α-phenyl-β-paratolylethylamine represented by the formula (hereinafter sometimes referred to as "the optically active amine").
Is used.

According to such a production method of the present invention, by using the above optically active amine, 90% e.
e. Yield of 30% or more (preferably 40% or more) of the salt of the (R) -carboxylic acid having an optical purity of the above (preferably 93% ee or more, more preferably 98% ee or more). Can be obtained at Thus, in the production method of the present invention, (R) -3-hydroxy-3- (2-phenylethyl) using conventional (-)-norephedrine is used.
A salt of (R) -3-hydroxy-3- (2-phenylethyl) hexanoic acid having the same optical purity as that of the optical resolution of hexanoic acid is obtained in a yield of about 1.3 times or more. be able to. Also, as will be described later, 99% e. e. It is possible to obtain a salt of the (R) -carboxylic acid having a remarkably high optical purity as compared with the above-mentioned conventional method in a relatively high yield of 70% or more, preferably 80% or more. According to such a manufacturing method of the present invention,
In the production of the (R) -carboxylic acid, industrial efficiency is remarkably improved as compared with the conventional one.

In the production method of the present invention, specifically, the racemic carboxylic acid and the optically active amine are mixed in a solvent and crystallized (crystallized) to obtain the (R)-
A salt of a carboxylic acid and the optically active amine is obtained.

From the viewpoint of economically obtaining a higher yield and optical purity, the racemic carboxylic acid and the optically active amine are in a ratio of 1: 0.5 to 1: 1.4 (molar ratio). It is preferable to mix them in a ratio of 1: 0.6 to 1:
It is more preferable to mix them so as to be 0.8 (molar ratio). When the amount of the optically active amine used is less than 0.5 mol with respect to 1 mol of the racemic carboxylic acid, the optical purity tends to improve, but the yield tends to decrease, which is not preferable. When the amount of the optically active amine used is more than 1.4 mol per 1 mol of the racemic carboxylic acid, the filterability of the salt tends to be deteriorated, and in addition, in terms of yield and optical purity. There is no particular change and it tends to be economically wasteful, which is not preferable.

Examples of the solvent used in mixing the racemic carboxylic acid and the optically active amine include ethyl acetate, methanol, 2-propanol, ethanol, acetonitrile, methyl isobutyl ketone, acetone, methyl ethyl ketone, One or more solvents selected from diisopropyl ether, dimethoxyethane and tetrahydrofuran may be mentioned. These solvents may further contain water. From the viewpoint of salt yield, optical purity, and safety, among the above,
It is preferable to use one or more solvents selected from ethyl acetate, methanol and 2-propanol, or a solvent obtained by further adding water. The amount of the solvent used is not particularly limited, but in order to obtain a salt with higher yield and higher optical purity, it is preferably 5 L to 15 L with respect to 1 kg of the racemic-carboxylic acid.
More preferably, it is 8L to 11L. When the amount of the solvent used is less than 5 L with respect to 1 kg of the racemic carboxylic acid, the generated salt cannot be dissolved even when heated at the time of producing the salt, and the optical purity tends to decrease, which is preferable. Absent. If the amount of the solvent used exceeds 15 L with respect to 1 kg of the racemic carboxylic acid, the amount of the salt dissolved in the solvent increases, and the yield tends to decrease, which is not preferable. When the above-mentioned solvent is a mixed solvent (including a case where it is a mixture with water), it may be mixed in any conventionally known conventional arbitrary ratio.

The above-mentioned mixing of the racemic-carboxylic acid and the optically active amine is usually carried out by adding the optically active amine to a solution prepared by previously dissolving the racemic-carboxylic acid in a solvent. When the solution is stirred after this addition, the salt precipitates, so the temperature is usually raised to 50 ° C. to 100 ° C. and stirred to dissolve the salt. If the salt is still insufficiently dissolved even by the stirring at elevated temperature, a solvent may be further added until the salt is dissolved. As the solvent to be added here, the same solvents as those mentioned above may be used.

Crystallization of the salt of the (R) -carboxylic acid and the optically active amine is carried out, for example, by stirring after heating at the above temperature.
It is performed by cooling and stirring until the salt crystallizes. After that, it is gradually cooled down to a constant temperature (for example, 2
After further stirring at (5 ° C.), filtration, washing with a solvent and stirring, the amine salt of the (R) -carboxylic acid having a high optical purity can be obtained in a yield as described above.

When gradually cooling and stirring until the salt is sufficiently precipitated, the crystallization temperature is usually 50 ° C. or lower, preferably 0.
℃ ~ 30 ℃, stirring time is usually 0.5 hours to 2
It's 0 hours.

The solvent used for washing after filtration is preferably a solvent having the solvent composition used for crystallization. The amount of the solvent used for washing is not particularly limited as long as it can wash the filtered material sufficiently.

Further, the manufacturing method of the present invention is performed at room temperature (20
(° C) to 50 ° C, the solution of the optically active amine may be gradually added to the solution of the racemic carboxylic acid to gradually perform salt precipitation, and then slowly cooled. When such a method is adopted, it is not necessary to completely dissolve the salt once, as compared with the above method, and there is an advantage that the amount of the solvent used can be reduced.

By recrystallizing after the above optical resolution, the amine salt of the (R) -carboxylic acid can be obtained with a higher optical purity. Specifically, the salt of the (R) -carboxylic acid obtained by the above optical resolution is mixed with a solvent to dissolve the salt, which is gradually cooled, and seed crystals are added at an appropriate temperature, and then gradually. The mixture is further cooled to a constant temperature, further stirred at a constant temperature, filtered, washed with a solvent, and dried to obtain the (R) -carboxylic acid having a higher optical purity than that in the case of performing only the optical resolution. The amine salt of
It can be obtained in a remarkably high yield. According to the manufacturing method of the present invention, only one recrystallization is required after optical resolution,
The amine salt of the (R) -carboxylic acid having a remarkably high optical purity (99% ee or more, preferably 99.5% ee or more) is obtained in a relatively high yield (70% or more, preferably Of 80% or more), and industrial efficiency is significantly improved as compared with the conventional optical resolution using (-)-norephedrine.

In recrystallization, the solvent used for dissolving the (R) -carboxylic acid may be the same solvent used for dissolving the racemic-carboxylic acid in the above optical resolution, and the same applies for the preferred solvent. . The amount of these solvents used in this reaction is not particularly limited, but from the viewpoint that a high yield and high optical purity can be obtained, 8 L to 25 L per 1 kg of the (R) -carboxylic acid salt is obtained.
Is preferable, and 12 L to 25 L is more preferable. When the amount of the solvent used is less than 8 L per 1 kg of the salt of the (R) -carboxylic acid, the salt becomes difficult to dissolve, it becomes difficult to obtain high optical purity, and stirring during cooling becomes difficult. It is not preferable because it tends to occur. If the amount of the solvent used exceeds 25 L with respect to 1 kg of the salt of the (R) -carboxylic acid, the amount of the dissolved salt increases, which tends to cause a decrease in yield, which is not preferable.

After the salt of the (R) -carboxylic acid is mixed with the above solvent, the temperature is usually raised to 50 ° C. to 100 ° C. to dissolve the salt.

After the salt of the (R) -carboxylic acid is dissolved, the solution is gradually cooled to an appropriate temperature (for example, 40 ° C.).
Add seed crystals at ~ 60 ° C) and stir. The stirring time is usually about 10 minutes to 5 hours. In addition, 60
It is gradually cooled to 0 ° C. to 40 ° C., preferably 0 ° C. to 30 ° C., over a period of minutes to 24 hours.

After that, at a constant temperature (for example, 20 ° C.)
After further stirring with, filtering, washing with a solvent, and drying.
As the solvent used for filtration and washing, it is desirable to use the same solvent as that used for crystallization.

The obtained amine salt of the (R) -carboxylic acid can be decomposed into the (R) -carboxylic acid and the optically active amine by a conventional method. For example, the amine salt of the (R) -carboxylic acid is added to an organic solvent (for example, ethyl acetate), for example, a caustic aqueous solution,
Decompose with alkaline carbonate solution or sodium bicarbonate solution,
For example, the (R) -carboxylic acid can be obtained by acidifying the aqueous layer with an inorganic acid such as hydrochloric acid or sulfuric acid and extracting with an organic solvent. In this case, the optically active amine can be obtained from the organic solvent layer. In addition, the amine salt of the (R) -carboxylic acid is treated with an organic solvent (for example, toluene, ethyl acetate, methyl isobutyl ketone,
Alternatively, the (R) -carboxylic acid may be obtained by decomposing it with an acid (for example, an inorganic acid such as hydrochloric acid or sulfuric acid) in a mixed solvent of these and heptane and extracting with the organic solvent. In this case, the optically active amine can be obtained as a salt of the acid used for decomposing the amine salt.

As described above, the (R) -3-hydroxy-3- (2-phenylethyl) hexanoic acid obtained by the production method of the present invention is the anti-HIV agent PNU-14069.
It is considered to be very useful as a synthetic intermediate of 0. The induction of (R) -3-hydroxy-3- (2-phenylethyl) hexanoic acid to PNU-140690 is
For example, the above-mentioned literature (J. Org. Chem., Vol. 63, No. 21, 19
98, 7348-7356).

The racemic carboxylic acid used as a raw material in the method for producing the (R) -carboxylic acid of the present invention is
Known compounds, which have been obtained by various conventionally known methods, can be preferably used, but those obtained by the following novel methods proposed by the present inventors are preferable. That is, first, by activating zinc with chlorotrimethylsilane and a copper compound in an aprotic organic solvent, an activated zinc newly found by the present inventors is obtained, and using the activated zinc, bromo By a Reformacky reaction of ethyl acetate and 1-phenyl-3-hexanone, racemic-3-
Ethyl hydroxy-3- (2-phenylethyl) hexanoate was obtained and this racemic-3-hydroxy-3- (2-
Phenylethyl) ethyl hexanoate is hydrolyzed with caustic alkali or an aqueous solution thereof, and then subjected to acid treatment,
Thus, racemic-3-hydroxy-3- (2
-Phenylethyl) hexanoic acid is produced. Hereinafter, each of the above steps 1 to 3 will be briefly described.

In the first step, chlorotrimethylsilane is added to zinc suspended in an aprotic organic solvent (eg, tetrahydrofuran (THF), toluene, dioxane, dimethoxyethane, benzene, xylene, etc.), and then the mixture is added to the mixture. Copper compounds (for example, copper chloride, copper bromide, copper iodide, copper acetate, acetylacetonato copper (II))
Etc.) or zinc and the copper compound are suspended in the aprotic organic solvent, and chlorotrimethylsilane is added dropwise to the mixture to obtain activated zinc. In the said process, it is preferable to use 3 mL-10 mL of aprotic organic solvents with respect to 1 g of zinc. Chlorotrimethylsilane is preferably used in an amount of 0.01 mol to 0.1 mol with respect to 1 mol of zinc, and the copper compound is used in an amount of 0.005 mol to 0.05 mol with respect to 1 mol of zinc. Is preferred.

The Reformacky reaction in the step (1) is carried out, for example, by a solvent (for example, ethers such as THF, dioxane and dimethoxyethane, aromatic hydrocarbons such as benzene, toluene and xylene, or the above ethers and the above aromatics). A mixed solvent of hydrocarbons, etc.), ethyl bromoacetate is added to a mixture prepared by previously activating the activated zinc and 1-phenyl-3-hexanone obtained in the above-mentioned step, or in advance in the solvent. It is realized by simultaneously adding 1-phenyl-3-hexanone and ethyl bromoacetate to the charged activated zinc. The above Reformacky reaction is usually performed within a temperature range of 25 ° C to 110 ° C. Ethyl racemic-3-hydroxy-3- (2-phenylethyl) hexanoate is obtained through such a Reformacky reaction. In the step, activated zinc is preferably used in an amount of 1 mol to 10 mol per 1 mol of 1-phenyl-3-hexanone, and ethyl bromoacetate is used in an amount of 1 mol per 1 mol of 1-phenyl-3-hexanone. It is preferred to use ~ 5 mol.

In the subsequent step, ethyl racemic-3-hydroxy-3- (2-phenylethyl) hexanoate obtained in the above step is added to, for example, a solvent (ethers such as THF, dioxane and dimethoxyethane, methanol, Alcohols such as ethanol and 2-propanol) in caustic alkali (caustic soda, caustic potassium)
Alternatively, the aqueous solution thereof is allowed to act. This reaction is usually
It is performed within a temperature range of 15 ° C to 100 ° C. Thereafter, the obtained solution of the alkali metal salt of 3-hydroxy-3- (2-phenylethyl) hexanoic acid is acidified to give racemic-3-used as a raw material in the production method of the present invention. Hydroxy-3- (2-phenylethyl) hexanoic acid (the racemic-carboxylic acid) is obtained.

By carrying out the steps 1 to 3, the yield of the racemic-3-hydroxy-3- (2-phenylethyl) hexanoic acid can be improved in a high yield and efficiently as compared with the conventional general method for producing racemic-3-hydroxy-3- (2-phenylethyl) hexanoic acid. Racemic-carboxylic acids can be obtained. Therefore, industrial efficiency is further improved by obtaining the raw material in the production method of the present invention by a method including such steps. The method for synthesizing the racemic carboxylic acid having the steps 1 to 3 will be described later as a reference example.

(R) used in the production method of the present invention
-N-parahydroxybenzyl-α-phenyl-β-paratolylethylamine has already been described, for example, in Patent No. 303.
It can be obtained by the manufacturing method disclosed in No. 1048. The manufacturing example will be described later as a reference example.

[0040]

The present invention will be described in more detail with reference to the following examples, but these are merely examples and do not limit the scope of the present invention. Reference Example 1 : Racemic-3-hydroxy-3- (2-phenylethyl)
) Synthesis of hexanoic acid Preparation of activated zinc 1.05 g (16 mmole) of zinc was suspended in 5 mL of THF, and 0.15 mL (1.2
mmole) was added, the mixture was stirred at room temperature (25 ° C.) for 15 minutes, and further heated to reflux at 67 ° C. for 15 minutes. After cooling to 35 ° C., 50 mg of acetylacetonato copper (II) (0.
19 mmole), and at 10 ° C.-35 ° C.
After stirring for a minute, activated zinc was obtained. Reformacky reaction using activated zinc A mixture of 1-phenyl-3-hexanone (1.76 g, 10 mmole) and ethyl bromoacetate (2.0 g, 12 mmole) was added to the THF suspension of activated zinc obtained above. The mixture was added dropwise at 30 ° C to 40 ° C over 50 minutes. 45 ℃ ~
After stirring at 50 ° C. for 3.5 hours, 10% hydrochloric acid was added to the reaction solution to dissolve excess zinc, and the insoluble material was filtered off. After separating the filtrate, 10 mL of toluene was added to the organic layer, and the organic layer was washed with water, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over sodium sulfate. The solvent was evaporated and the obtained residue was purified by column chromatography (silica gel, ethyl acetate-heptane (ethyl acetate: heptane = 1: 3)). The obtained purified product was analyzed by NMR and confirmed to be ethyl racemic-3-hydroxy-3- (2-phenylethyl) hexanoate. Racemic-3-hydroxy-3- (2-phenylethyl)
1) Synthesis of hexanoic acid Racemic-3-hydroxy-3- (2-
Phenylethyl) ethyl hexanoate 19.71 g (7
4.6 mmole) in 40 mL of methanol and
Add 38 g (95 mmole) of 0% caustic soda water and add 2
The mixture was stirred at 5 ° C for 4.5 hours. 20 mL of water and 20 mL of toluene were added to the reaction solution, and the layers were separated. Water layer again toluene 1
After washing with 0 mL, the aqueous layer was acidified with 10% hydrochloric acid and extracted with toluene (20 mL x 2). After combining the toluene layers that have extracted the acidic aqueous layer, they are dried over sodium sulfate,
When the solvent was distilled off, racemic-3-hydroxy-3- (2
-Phenylethyl) hexanoic acid 15.55 g (88
%) Obtained.

Reference Example 2 : (R) -N-parahydroxybenzyl-α-phenyl
Synthesis of -β -paratolylethylamine 900 mL of methanol and 190.6 g (1.56 mole) of parahydroxybenzaldehyde were charged, and 330 g (1.56 mole) of (R)-(-)-α-phenyl-β-paratolylethylamine. ) Was added. 1
After heating under reflux for a period of time, the mixture was cooled to 0 ° C., and the resulting crystals of benzylidene compound were collected by filtration (weight before drying: 504.8 g). The crystals were suspended in 1.8 L of methanol, and 44.4 g (1.17 mole) of sodium borohydride was added as a solid at 10 ° C or lower. After stirring at 19 ° C to 24 ° C for 2 hours, water 9
00 mL was added, and the generated (R) -N-parahydroxybenzyl-α-phenyl-β-paratolylethylamine crystals were collected by filtration. After further washing with 2 L of water, dry,
(R) -N-parahydroxybenzyl-α-phenyl-
482.7 g of β-paratolylethylamine was obtained. The yield was 97.4% with respect to (R)-(-)-α-phenyl-β-paratolylethylamine.

Example 1 Racemic-3-hydroxy-3- (2-phenylethyl)
Hexanoic acid (5.0 g, purity: 71%, pure amount: 3.55
(R) -N-parahydroxybenzyl-α-phenyl-β-paratolylethylamine (6.7 g, 21.2 g) in a solution of g, 15.0 mmole) in ethyl acetate (50 mL).
mmole) was added and dissolved at 70 ° C. After cooling to 55 ° C., 2 mg of (R) -3-hydroxy-3- (2-phenylethyl) hexanoic acid (R) -N-parahydroxybenzyl-α-phenyl-β-paratolylethylamine salt.
Was added. After stirring at the same temperature for 5 hours and further cooling to 25 ° C., the resulting crystals were collected by filtration to give 93% e. e. An amine salt of (R) -3-hydroxy-3- (2-phenylethyl) hexanoic acid having an optical purity of 3.95 g (4
6.5%) was obtained. The optical purity of the above crystal was determined by the following method. A part of the obtained crystals was suspended in ethyl acetate,
Saturated sodium hydrogen carbonate solution was added and dissolved with stirring. The water layer is separated and collected,
After acidifying with 10% hydrochloric acid, it was extracted with toluene. After adding methanol to the toluene layer, trimethylsilyldiazomethane was added and stirred at room temperature (25 ° C.), and the solution was concentrated. The residue was dissolved in 2-propanol and subjected to HPLC (stationary phase; Daicel Chiralcel OD, mobile phase; 1.5%).
2-propanol / hexane).

Example 2 Racemic-3-hydroxy-3- (2-phenylethyl)
Hexanoic acid (4.84 g, purity: 71%, pure amount: 3.4
4 g, 14.5 mmole) of ethyl acetate (50 mL)
(R) -N-parahydroxybenzyl-α-phenyl-β-paratolylethylamine (3.23 g, 9.
86 mmole) was added and dissolved at 70 ° C. After cooling to 55 ° C., (R) -3-hydroxy-3- (2-phenylethyl) hexanoic acid (R) -N-parahydroxybenzyl-α-phenyl-β-paratolylethylamine salt 2
mg was added. After stirring at the same temperature for 5 hours and further cooling to 25 ° C., the resulting crystals were collected by filtration to give 93% e. e. (R) -3-hydroxy-3- (2- having an optical purity of
3.78 g of amine salt of phenylethyl) hexanoic acid
(46.5%) was obtained.

Example 3 Racemic- 3 -hydroxy-3- (2-phenylethyl)
Hexanoic acid (5.0 g, purity: 71.44%, pure amount:
3.57 g, 15.12 mmole) and (R) -N-parahydroxybenzyl-α-phenyl-β-paratolylethylamine (6.7 g, 21.1 mmole) were added to 2
-Dissolve in propanol (40 mL) at 70 ° C,
After cooling to 0 ° C, 2 mg of (R) -N-parahydroxybenzyl-α-phenyl-β-paratolylethylamine salt of (R) -3-hydroxy-3- (2-phenylethyl) hexanoic acid was added at 25 ° C. Cooled down. After cooling, the precipitated crystals were collected by filtration, and 90.9% e. e. 4.32 g (51.6%) of the amine salt of (R) -3-hydroxy-3- (2-phenylethyl) hexanoic acid having an optical purity of
Obtained.

Example 4 Racemic-3-hydroxy-3- (2-phenylethyl)
Hexanoic acid (5.0 g, purity: 71.44%, pure amount:
3.57 g, 15.12 mmole) and (R) -N-parahydroxybenzyl-α-phenyl-β-paratolylethylamine (2.35 g, 7.4 mmole) were added to 2
-Dissolved in propanol (27 mL) at 50 ° C, and at the same temperature, (R) -3-hydroxy-3- (2-phenylethyl) hexanoic acid (R) -N-parahydroxybenzyl-α-phenyl-β-. Paratolylethylamine salt 2mg
Was added and the mixture was cooled to 25 ° C. After cooling, the precipitated crystals were collected by filtration, and 92.7% e. e. With optical purity of (R)
2.83 g (33.8%) of amine salt of -3-hydroxy-3- (2-phenylethyl) hexanoic acid was obtained.

Example 5 Racemic-3-hydroxy-3- (2-phenylethyl)
Hexanoic acid (5.0 g, purity: 71.44%, pure amount:
3.57 g, 15.12 mmole) and (R) -N-parahydroxybenzyl-α-phenyl-β-paratolylethylamine (2.35 g, 7.4 mmole) were dissolved in ethyl acetate (50 mL) at 70 ° C. , (R) -3-Hydroxy-3- (2-phenylethyl) hexanoic acid (R) -N-parahydroxybenzyl-α-phenyl-β-paratolylethylamine salt 2 m after cooling to 55 ° C.
g and cooled to 25 ° C. After cooling, the precipitated crystals were collected by filtration, and 95.6% e.p. e. (R) -3-hydroxy-3- (2-phenylethyl) having an optical purity of
3.14 g (37.5%) of the amine salt of hexanoic acid was obtained.

Example 6 Racemic-3-hydroxy-3- (2-phenylethyl)
Hexanoic acid (5.0 g, purity: 71%, pure amount: 3.55
g, 15.0 mmole) was dissolved in a mixed solvent (methyl isobutyl ketone-7.7 v / v% methanol) consisting of methyl isobutyl ketone (30 mL) and methanol (2.5 mL), and (R) -N-parahydroxybenzyl- α-phenyl-β-paratolylethylamine (3.2
9 g, 10.4 mmole) was added and dissolved at 70 ° C. After cooling to 60 ° C., (R) -3-hydroxy-3-
2 mg of (R) -N-parahydroxybenzyl-α-phenyl-β-paratolylethylamine salt of (2-phenylethyl) hexanoic acid was added, and the resulting crystals were collected by filtration after cooling to 5 ° C., 97.2 % E. e. 3.83 g (46.0%) of a salt having an optical purity of was obtained.

Example 7 Racemic-3-hydroxy-3- (2-phenylethyl)
Hexanoic acid (5.0 g, purity: 71%, pure amount: 3.55
g, 15.0 mmole) was dissolved in a mixed solvent (methyl isobutyl ketone-16.7 v / v% methanol) consisting of methyl isobutyl ketone (25 mL) and methanol (5 mL), and (R) -N-parahydroxybenzyl-
α-phenyl-β-paratolylethylamine (3.29
g, 10.4 mmole) was added and dissolved at 60 ° C. After cooling to 52 ° C., (R) -3-hydroxy-3-
2 mg of (R) -N-parahydroxybenzyl-α-phenyl-β-paratolylethylamine salt of (2-phenylethyl) hexanoic acid was added, and the resulting crystals were collected by filtration after cooling to 5 ° C. % E. e. 3.31 g (39.8%) of a salt having an optical purity of was obtained.

Example 8 93% e. e. (R) -3-hydroxy-3- (2-phenylethyl) having an optical purity of
Hexanoic acid (R) -N-parahydroxybenzyl-α
-Phenyl-β-paratolylethylamine salt (1.0
g) was dissolved in ethyl acetate (25 mL) at 75 ° C.
After cooling to 55 ° C, (R) -3-hydroxy-3- (2-
2 mg of (R) -N-parahydroxybenzyl-α-phenyl-β-paratolylethylamine salt of phenylethyl) hexanoic acid was added, the solution was cooled to 25 ° C., and the resulting salt was collected by filtration. % E. e. (R) -3
0.71 g (71%) of amine salt of -hydroxy-3- (2-phenylethyl) hexanoic acid was obtained.

Example 9 93% e. e. (R) -3-hydroxy-3- (2-phenylethyl) having an optical purity of
Hexanoic acid (R) -N-parahydroxybenzyl-α
-Phenyl-β-paratolylethylamine salt (2.20
g) was dissolved in a mixed solvent of ethyl acetate (28 mL) and methanol (1.5 mL) (ethyl acetate-5 v / v% methanol) at 75 ° C. The resulting solution was cooled to 60 ° C. and then (R) -3-hydroxy-3- (2-phenylethyl) hexanoic acid (R) -N-parahydroxybenzyl-α-phenyl-β-paratolylethylamine salt. 2 mg
Was added, the mixture was cooled to 5 ° C., and the generated salt was filtered off.
99.7% e. e. 1.65 g (75%) of the salt was obtained.

Example 10 93% e. e. (R) -3-hydroxy-3- (2-phenylethyl) having an optical purity of
Hexanoic acid (R) -N-parahydroxybenzyl-α
-Phenyl-β-paratolylethylamine salt (1.03
g) at 70 ° C., a mixed solvent of ethyl acetate (10.8 mL) and methanol (1.2 mL) (ethyl acetate-10 v / v).
% Methanol). The resulting solution was cooled to 60 ° C. and then (R) -3-hydroxy-3- (2-phenylethyl) hexanoic acid (R) -N-parahydroxybenzyl-α-phenyl-β-paratolylethylamine salt. 2m
g was added, the mixture was cooled to 5 ° C., and the generated salt was collected by filtration to give 99.7% e.p. e. 0.77 g (75%) of salt was obtained.

Boiling point: 145.5 ° C. to 146.0 ° C. IR spectrum (KBr): 3271.4, 2960.
8, 1615.8, 1538.5, 1522.5, 14
54.8, 1389.0, 1277.1, 1214.
^1, 701.7 cm ^-1 . ¹ H-NMR (CDCl ₃ ) δ: 0.95 (3H, t, J
= 7 Hz), 1.35-1.50 (2H, m), 1.6
2-1.65 (2H, m), 1.85-1.89 (2
H, m), 2.26 (3H, s), 2.54 (2H,
s), 2.71 (2H, dd, J = 6, 12Hz),
3.05 (1H, m), 3.21-3.28 (1H,
m), 3.59 (1H, d, J = 13Hz), 3.65
(1H, d, J = 13Hz), 4.03 (1H, t, J
= 7 Hz), 6.55 (2H, d, J = 8 Hz), 6.
86 (4H, t, J = 8Hz), 6.97 (2H, d,
J = 8 Hz), 7.16-7.37 (10H, m).

Example 11 93% e. e. (R) -3-hydroxy-3- (2-phenylethyl) having an optical purity of
Hexanoic acid (R) -N-parahydroxybenzyl-α
-Phenyl-β-paratolylethylamine salt (1.20
g) was dissolved in 2-propanol (18 mL) at 70 ° C. After the obtained solution was cooled to 50 ° C., (R) -3-hydroxy-3- (2-phenylethyl) hexanoic acid (R) -N-parahydroxybenzyl-α-phenyl-
2 mg of β-paratolylethylamine salt was added, the mixture was cooled to 25 ° C., and the resulting salt was collected by filtration.
e. To obtain 0.97 g (80.8%) of salt.

Example 12 (R) -3-Hydroxy-3- (2-) obtained in Example 11
(R) -N-parahydroxybenzyl-α-phenyl-β-paratolylethylamine salt of phenylethyl) hexanoic acid (13.22 g) together with ethyl acetate (80 mL), water (30 mL) and sodium bicarbonate (4.43 g). Stir at 45 ° C. The organic layer was separated and removed, 10% hydrochloric acid (19 mL) was added to the aqueous layer, and the mixture was extracted with toluene (40 mL). The toluene layer was separated, dried over anhydrous sodium sulfate, and the toluene was distilled off. As a result, (R) -3-hydroxy-3- (2-phenylethyl) hexanoic acid was a colorless oil (5.31 g, 94%). ) Was obtained as.

[0055]

[Outer 1]

(C = 0.486, MeOH)

¹ H-NMR (CDCl ₃ ) δ: 0.96
(3H, t, J = 7Hz), 1.35-1.47 (2
H, m), 1.60-1.64 (2H, m), 1.84
-1.89 (2H, m), 2.60 (2H, s), 2.
65-2.70 (2H, m), 7.17-7.20 (3
H, m), 7.26-7.30 (2H, m).

Example 13 (R) -3-Hydroxy-3- (2-) obtained in Example 11
(R) -N-parahydroxybenzyl-α-phenyl-β-paratolylethylamine salt of phenylethyl) hexanoic acid (0.2 g) was suspended in toluene (2 mL),
10% Hydrochloric acid (0.5 mL) was added, and the mixture was stirred at 25 ° C for 20 min. After the reaction solution was filtered, the filtrate was separated and the toluene layer was concentrated to give (R) -3-hydroxy-3- (2-
80.7 mg (95%) of phenylethyl) hexanoic acid was obtained.

[0059]

As is apparent from the above description, according to the present invention, (R) -3-hydroxy-3- (2-phenylethyl) hexanoic acid, which is useful as a raw material for pharmaceuticals, is converted into racemic-3-hydroxy. It is possible to provide a production method capable of efficiently producing -3- (2-phenylethyl) hexanoic acid with high optical purity and relatively high yield.

   ─────────────────────────────────────────────────── ─── Continued front page    (72) Inventor Nobushige Itaya             3-1-2 Utashima, Nishiyodogawa-ku, Osaka             Finechem Co., Ltd. F-term (reference) 4H006 AA02 AB84 AC83 AD15 AD33                       BB14 BB15 BB16 BB17 BB21                       BJ50 BN10 BS10

Claims (2)

[Claims] 1. Optical resolution of racemic-3-hydroxy-3- (2-phenylethyl) hexanoic acid with (R) -N-parahydroxybenzyl-α-phenyl-β-paratolylethylamine. Characteristic, (R)-
A method for producing 3-hydroxy-3- (2-phenylethyl) hexanoic acid. 2. A salt of (R) -3-hydroxy-3- (2-phenylethyl) hexanoic acid and (R) -N-parahydroxybenzyl-α-phenyl-β-paratolylethylamine is converted into acetic acid. One or more solvents selected from ethyl, methanol, 2-propanol, ethanol, acetonitrile, methyl isobutyl ketone, acetone, methyl ethyl ketone, diisopropyl ether, dimethoxyethane and tetrahydrofuran (the solvent may further contain water. The method according to claim 1, characterized in that it is crystallized in