JP2003095991A - Method for producing optically active 3,3,3-trifluoro-2- hydroxy-2-methylpropionic acid - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing optically active 3,3,3-trifluoro-2- hydroxy-2-methylpropionic acid as a raw material of pharmaceuticals, agrochemicals, or the like. SOLUTION: This method for producing the optically active 3,3,3-trifluoro-2- hydroxy-2-methylpropionic acid comprises the steps of mixing 3,3,3-trifluoro-2- hydroxy-2-methylpropionic acid with either one of optically active amines of formulae 1 to 4 (X1 and X4 are each a substituent; X2 , X2 ' and X3 are each H or a substituent; and * denotes an asymmetric carbon atom) to form the corresponding diastereomer salts, and purifying the mixture of the salts by resolution to obtain the objective diastereomer salt.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing optically active 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid useful as a raw material or an intermediate for medicines, agricultural chemicals and the like.

[0002]

BACKGROUND OF THE INVENTION Racemic 3,3,3-trifluoro-2
The synthesis method of -hydroxy-2-methylpropionic acid derivative is widely known [Zh. Org. Khim., 23, 1441-144.
7 (1987), J. Chem. Soc. 2329-2332 (1951), etc.]. On the other hand, as a method for resolving the diastereomer salt of optically active 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid, J. Chem. Soc. 2329-2332 (1951), WO
The method described in 93/23358 is known. J. Chem. Soc. 23
29-2332 (1951) describes a method in which brucine is used as the resolving agent, and WO
The method described in 93/23358 uses α-methylbenzylamine as the resolving agent.

In the prior art, only two kinds of resolving agents are known, and the production of optically active 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid using other optically active amines. No one knew about the law. Therefore, the optically active 3,3,3-trifluoro-2-
A new method for producing hydroxy-2-methylpropionic acid has been desired.

[0004]

The object of the present invention is to provide optically active 3,3,3-trifluoro-2-hydroxy-2-.
It is intended to provide a new method for producing methylpropionic acid.

[0005]

Means for Solving the Problems The present inventors have earnestly conducted research on a new method for producing optically active 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid, and as a result, various optically active substances have been obtained. By forming a salt with an amine, it was found that the diastereomeric salt can be optically resolved, and the present invention has been completed.

That is, the present invention provides (1) 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid represented by the following formulas 1 to 4 (X1 and X4 represent substituents, X
2, X2 'and X3 represent a hydrogen atom or a substituent, and * represents an asymmetric carbon. )

[Chemical 5]

[Chemical 6]

[Chemical 7]

[Chemical 8] An optically active 3,3,3 comprising a step of mixing with any of the optically active amines represented by to produce a diastereomeric salt, and subjecting the mixture to fractional purification to obtain a diastereomeric salt.
-Method for producing trifluoro-2-hydroxy-2-methylpropionic acid, (2) Optically active amine is 3,3,3-
Trifluoro-2-hydroxy-2-methylpropionic acid was added to 3-quinuclidinol, 4-methoxy-α-methylbenzylamine, α- (1-naphthyl) ethylamine, N-
The production method according to (1), which is one of the optically active amines of benzyl-α-methylbenzylamine, (3) 3, 3,
A salt of 3-trifluoro-2-hydroxy-2-methylpropionic acid and an optically active amine represented by any one of formulas 1 to 4, (4) the optically active amine is 3,3,3-trifluoro- 2-hydroxy-2-methylpropionic acid and 3
-Quinuclidinol, 4-methoxy-α-methylbenzylamine, α- (1-naphthyl) ethylamine, N-benzyl-α-methylbenzylamine (3)
The salt described.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in detail below. 3,3,3-trifluoro-2- in the present invention
Hydroxy-2-methylpropionic acid may be racemic or may be biased in either R or S form. Further, the resolving agent, that is, the optically active amine represented by Formulas 1 to 4, may be appropriately determined according to the optically active 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid obtained, It may be either R form or S form. The optical purity is not particularly limited, but it is desirable that the optical purity be high. It is preferably 80% ee or more, more preferably 90% ee or more.

In the present invention, X1, X2 in the formulas 1 to 4,
X2 ′, X3 and X4 are not particularly limited as long as they can be optically resolved by a diastereomeric salt. Formula 1 and Formula 4
X1 and X4 therein represent a substituent, specifically, a halogen atom, a hydroxyl group, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms,
An alkoxy group having 1 to 6 carbon atoms, an alkylthio group having 1 to 6 carbon atoms, an amide group which may have an alkyl group having 1 to 6 carbon atoms, a cyano group, a formyl group, an acyl group having 2 to 7 carbon atoms, Alkoxycarbonyl group having 2 to 7 carbon atoms, 1 carbon atom
Examples of the substituent include an amino group, a nitro group, and a thiol group having an alkyl group of to 6 and a substituent derived from them.

The bonding position of X1 may be any of the o-position, m-position and p-position. Preferred are chlorine atom, bromine atom, hydroxyl group, methyl group, ethyl group, methoxy group, ethoxy group and nitro group. Further, X2, X2 ′ and X3 in Formulas 2 and 3 are each a hydrogen atom or
Represents a substituent, specifically, a halogen atom, a carbon number of 1 to
A C6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C1-6 alkoxy group,
An alkylthio group having 1 to 6 carbon atoms, an amide group which may have an alkyl group having 1 to 6 carbon atoms, a cyano group, a formyl group,
Substituents such as an acyl group having 2 to 7 carbon atoms, an alkoxycarbonyl group having 2 to 7 carbon atoms, an amino group having an alkyl group having 1 to 6 carbon atoms, a hydroxyl group, a nitro group, and a thiol group or the like Examples thereof include derivatized substituents.

The binding position may be any one of them. Further, X2 and X2 'may be the same or different substituents. Further, in these substituents, a hydrogen atom bonded to the carbon atom or the nitrogen atom may be substituted with a substituent such as a halogen or a hydroxyl group. Preferred examples of the optically active amine represented by the formulas 1 to 4 used in the present invention include 3-quinuclidinol, 4-methoxy-α-methylbenzylamine, α
-(1-naphthyl) ethylamine and N-benzyl-α
-S- and R-forms of methylbenzylamine and the like can be mentioned.

The diastereomeric salt formed does not necessarily have to be an optically pure diastereomeric salt. In addition, 3,3,3-trifluoro-2-hydroxy-2-
The salts of methylpropionic acid and the optically active amines represented by any one of formulas 1 to 4 include various diastereomeric salts due to their asymmetric carbons, but all of them are included.

The method for producing the diastereomeric salt is
For example, 3,3,3-trifluoro-2-in a suitable solvent
The racemic hydroxy-2-methylpropionic acid may be dissolved, and the optically active amine represented by Formulas 1 to 4 may be added directly or diluted with a suitable solvent with stirring or without stirring.
In addition, 3,3,3-trifluoro-2 is added to the optically active amine.
A racemic form of -hydroxy-2-methylpropionic acid may be added. The temperature at the time of mixing is selected from the melting point to the boiling point of the solvent used, and is usually 0 to 100 ° C, preferably
10 to 80 ° C.

When mixing, the solvent used is not particularly limited as long as it does not inhibit the formation of the diastereomeric salt. For example, various alcohol solvents such as methanol, ethanol, isopropanol, n-propanol and butanol, ether solvents such as diethyl ether, isopropyl ether, tetrahydrofuran and dioxane, aliphatic hydrocarbon solvents such as pentane, hexane and heptane, benzene , Aromatic hydrocarbon solvents such as toluene and xylene, halogenated hydrocarbon solvents such as methylene chloride, chloroform, carbon tetrachloride and dichloroethane, ester solvents such as ethyl acetate, propyl acetate and butyl acetate, acetone, methyl ethyl ketone, etc. Ketone solvent,
Examples thereof include water, acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide and the like. These solvents can be used alone, but a mixture of two or more kinds can also be used.

During the formation of diastereomeric salts, 3,3,3
-The molar ratio of trifluoro-2-hydroxy-2-methylpropionic acid and the optically active amine is arbitrary, but usually,
It is carried out in the range of 0.5 to 2.

The method for recovering the diastereomeric salt thus produced may be, for example, concentration and recovery as it is. When the diastereomeric salt is insoluble in the solvent used, solid-liquid separation can be carried out by filtration. In addition, the solution in which the diastereomeric salt is formed can be cooled directly or after concentration to precipitate crystals. That is, recrystallization purification can be carried out at the same time.

The obtained diastereomeric salt can be purified by division into a single diastereomeric salt by utilizing its physicochemical properties. The method of fractional purification is arbitrary, but generally, recrystallization operation may be performed using a suitable solvent. For recrystallization, for example, the obtained diastereomeric salt is dissolved in a suitable solvent under heating, and directly or after concentration, cooled to precipitate crystals. Crystals may be precipitated by adding a poor solvent for the diastereomer salt. Furthermore, in order to carry out the precipitation of crystals smoothly and efficiently, seeds of crystals can be seeded. At this time, it is possible to preferentially crystallize a diastereomeric salt having the same optical activity by adding a small amount of a crystal of a diastereomeric salt having a high optical purity as a seed crystal. It is desirable that the optical purity of the seed crystal is high, and the addition amount is 0.01-1% of the dissolved mass.
A degree is preferable. Further, in the case where the diastereomer salt is in a supersaturated state without adding any seed crystal, crystallization of the diastereomeric salt occurs spontaneously, and a diastereomeric salt of the same kind as in the case of adding the seed crystal is precipitated.

The mother liquor after crystal separation is an optically active 3,3,3-trifluoro-2-hydroxy-2 having a different absolute configuration.
-It can be collected as a fraction containing methylpropionic acid. By repeating the above-described divisional purification a plurality of times, a highly pure optically active 3,3,3-trifluoro-2-
It is possible to obtain diastereomeric salts of hydroxy-2-methylpropionic acid.

The crystals of the diastereomeric salt thus obtained are desalted by a known method, for example, treatment with an acid, an alkali or an ion exchange resin, to give an optically active 3,3,3-trifluoro-2- Hydroxy-2-methylpropionic acid can be obtained. Further, the optically active amines represented by Formulas 1 to 4 used as the resolving agent can be recovered after salt removal and reused. Optically active 3,3,3-trifluoro-2
The optical purity of -hydroxy-2-methylpropionic acid is
It can be easily identified by esterification by a conventional method and analysis with a GC capillary column for optical resolution.

[0019]

EXAMPLES The present invention will be described in more detail with reference to typical examples.

<Examples 1 to 4> Racemic 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid
20 g (126.5 mmol) was dissolved in n-butanol under the conditions shown in Table 1, and various amines were slowly added. The diastereomeric salt deposited under each condition was collected by filtration, and the amount thereof and the optical purity of 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid were measured.

The analysis of the optical purity of 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid is as follows.
Similarly, the diastereomeric salt was subjected to methyl esterification with 10% HCl / methanol and measured by gas chromatography (column; CP-Chirasil DEX CB 0.25 mm X 25M, manufactured by Chrompack).

<Table 1>

[0023]

INDUSTRIAL APPLICABILITY The present invention provides a new method for producing optically active 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid, which is an effective intermediate raw material for pharmaceuticals and agricultural chemicals. .

Claims (4)

[Claims] 1. 3,3,3-Trifluoro-2-hydroxy-2-methylpropionic acid represented by the following formulas 1 to 4 (X1
And X4 represent a substituent, X2, X2 'and X3 represent a hydrogen atom or a substituent, and * represents an asymmetric carbon. ) [Chemical 1] [Chemical 2] [Chemical 3] [Chemical 4] An optically active 3,3,3 comprising a step of mixing with any of the optically active amines represented by to produce a diastereomeric salt, and subjecting the mixture to fractional purification to obtain a diastereomeric salt.
-Method for producing trifluoro-2-hydroxy-2-methylpropionic acid. 2. The optically active amine is 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid.
The method according to claim 1, wherein the optically active amine is -quinuclidinol, 4-methoxy-α-methylbenzylamine, α- (1-naphthyl) ethylamine, or N-benzyl-α-methylbenzylamine. 3. A salt of 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid and an optically active amine represented by any one of formulas 1 to 4. 4. The optically active amine is 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid and 3
The salt according to claim 3, which is any one of -quinuclidinol, 4-methoxy-α-methylbenzylamine, α- (1-naphthyl) ethylamine and N-benzyl-α-methylbenzylamine.