JP2001226316A - Method for producing optically active fluorine- containing lactic acid or derivative thereof, optically active fluorine-containing lactic acid or intermediate for derivative thereof and method for producing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for inexpensively producing an optically active fluorine-containing lactic acid such as 3,3,3-trifluorolactic acid or a derivative thereof useful as a raw material of a functional organic compound such as a liquid crystal, a surfactant or a dye, a physiologically active substance such as medicines or agrochemicals and a functional material polymer in a large amount. SOLUTION: The objective optically active fluorine-containing lactic acid is synthesized by the following reaction [in general formula (I), (II) and (III), Rfs denote each a perfluoroalkyl; R1s and R2s are mutually same or different groups and denote each an alkyl, an aryl, an aralkyl, an alkenyl or an alkynyl independently; Xs denote halogen atoms; and *s denote chiral carbon atoms].

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing an optically active (rotary chiral) fluorinated lactic acid or a derivative thereof, an intermediate of an optically active fluorinated lactic acid or a derivative thereof and a method for producing the same. Things.

[0002]

2. Description of the Related Art In general, a compound obtained by replacing hydrogen in a molecule with fluorine from a known compound having a function or a biological activity has a function or a biological activity due to a specific electronic effect of the fluorine atom. Is known to be enhanced or to obtain new functions and biological activities.

[0003] Therefore, a fluorine-containing building block having a structure similar to that of a known compound raw material has been designed and synthesized ("Fluorine Physiologically Active Substance in the 90's" supervised by Nobuo Ishikawa, published by CMC (1991)). "Latest Trends of Fluorine Materials" Masaaki Yamabe, Jin Matsuo, CMC (199)
4)).

[0004] As such fluorine-containing compounds, functional organic compounds such as liquid crystals, surfactants and dyes, physiologically active substances such as pharmaceuticals and agricultural chemicals, and optically active 3,3 compounds useful as raw materials for functional material polymers and the like. , 3-Trifluorolactic acid are known.

Conventionally, optically active 3,3,3-trifluorolactic acid or an ester thereof has been prepared by a method described in Japanese Patent Application Laid-Open No.
No. 8277, the method described in JP-A-5-78278)
And a synthesis method by diastereoselective reaction (Chemical Society of Japan, 1989,
(9), 1576; J. Org. Chem. 1990, 55, 4216),
Racemic optical resolution method (Chem. Ber. 1992, 125, 2795)
and so on.

[0006]

However, these known methods are not suitable for mass production when using an oxidation reaction, and are expensive for other reactions because the reagents used are expensive. Neither is suitable for mass synthesis.

[0007] An object of the present invention is to solve the above-mentioned problems of the prior art, and to provide functional organic compounds such as liquid crystals, surfactants and dyes, physiologically active substances such as medicines and agricultural chemicals, and functional polymer materials. Optically active 3, useful as a raw material for
An object of the present invention is to provide a method for producing an optically active fluorinated lactic acid such as 3,3-trifluorolactic acid or a derivative thereof or an intermediate thereof in a large amount at low cost, and an intermediate thereof.

[0008]

That is, the present invention provides a compound represented by the general formula (I):

Embedded image (However, in the general formula (I), R _f represents a perfluoroalkyl group, and R ¹ and R ² are the same or different groups, and independently represent an alkyl group, an aryl group, an aralkyl group. , An alkenyl group or an alkynyl group, and * represents a chiral carbon atom.) By reacting an optically active fluorinated thioether compound represented by the formula (III) with a halogenating agent in the presence of a base. :

Embedded image (However, in the general formula (III), R _f , R ¹ , R ² and * are the same as those described above, and X represents a halogen atom.) By obtaining the compound and further hydrolyzing the fluorinated halothioether compound, the compound represented by the general formula (II):

Embedded image (However, in the formula (II), R _f and * are the same as those described above.) A method for producing an optically active fluorinated lactic acid or a derivative thereof, which obtains an optically active fluorinated lactic acid represented by the formula: Or an optically active fluorine-containing halothioether and a method for producing the same.

The production method of the present invention can be represented by the following reaction formula.

Embedded image

According to the production method of the present invention, if the fluorine-containing thioether compound is halogenated with the halogenating agent and a base such as pyridine is added during the halogenation reaction, two halogenation reactions can be performed at once. Progresses, it is possible to synthesize fluorinated lactic acid such as trifluorolactic acid in a short step, and it is possible to produce the target substance in large quantities at low cost.

[0011]

BEST MODE FOR CARRYING OUT THE INVENTION In the production method of the present invention, R _f in the general formula (I) is a perfluoroalkyl group, for example, CF ₃ , C ₂ F ₅ , C ₃ F _{7 and the} like. Particularly, CF ₃ is preferable.

When R ¹ and R ² are alkyl groups,
It is preferably an alkyl group or a cycloalkyl group having 1 to 20 carbon atoms which has a linear, branched or cyclic structure and may have a substituent such as a hetero atom or a halogen atom therein. .

In the case of an aryl group, a phenyl group, a naphthyl group, an anthryl group, a heteroaromatic group having a hetero atom and the like which may have a substituent can be exemplified. In addition, the substituent may have 1 to 10 carbon atoms which may have a branch.
Alkyl group, alkoxy group, amino group, halogen atom and the like.

As the aralkyl group, benzyl group, p-
Methylbensyl group, naphthylmethyl group, furfuryl group,
α-phenethyl group and the like can be exemplified.

Examples of the alkenyl group include vinyl, β-styryl, 1-propenyl, 1-butenyl, 1-hexenyl, 1-decenyl, cyclohexenyl, allyl, cinnamyl and 2-butenyl. , 2-decenyl group and the like.

Examples of the alkynyl group include an ethynyl group, a phenylethynyl group and a 2-propynyl group.

The optically active fluorine-containing thioether represented by the general formula (I), for example, a thioether compound having a trifluoromethyl group at the 2-position, which is a starting material for the reaction according to the present invention, is 3,3,3-tri A method of asymmetric hydrogenation of fluoro-2-acetoxy-1-phenylthiopropene for synthesis (for example, Japanese Patent Application No. 11-281 exemplified below)
No. 044), a method of ring-opening addition of an optically active trifluoropropene oxide (see Japanese Patent Publication No. 61-14798) using a thiol (see Japanese Patent Application Laid-Open No. 4-352766), a reduction method using yeast ( Bull. Chem. Soc.
Jpn. 1997, 70, 2655).

Example of synthesis according to Japanese Patent Application No. 11-281044:

Embedded image

The above-mentioned halogenation reaction in the production method of the present invention is described in JP-A-5-255237 (JP-A-5-186890 as an example of electrolytic oxidation). , Only examples of trifluorolactic acid aldehyde, but no description of the synthesis of trifluorolactic acid. In the halogenation reaction of the present invention, unlike the method disclosed in JP-A-5-255237, by adding a base such as pyridine, two halogenation reactions proceed at once, so that trifluorolactic acid is synthesized in a short step. It became possible. As the base,
Although not particularly limited, pyridine is preferred.

As the halogenating agent to be used, sulfuryl halides such as sulfuryl chloride and N-halocarboxylic imides such as N-halosuccinimide can be used. Sulfuryl halides are preferred.

The solvent used is not particularly limited as long as it does not react with the reagent, and examples thereof include methylene chloride, chloroform and hexane.

The reaction temperature can be appropriately selected from -100 ° C to the boiling point of the solvent, but is preferably in the range of 0 ° C to room temperature.

The hydrolysis reaction may be carried out using an acid such as hydrochloric acid or sulfuric acid, or using a metal salt such as copper chloride or silver trifluoroacetate.

The above-mentioned optically active fluorinated lactic acid may be further esterified with methanol or the like to lead to an ester derivative.

The production method of the present invention can be represented, for example, by the following reaction formula.

Embedded image

[0026]

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

Example 1 (R) -3,3,3-trifluoro-2-acetoxy-
Synthesis of 1,1-dichloro-1-phenylthiopropane:

(R) -3,3,3-trifluoro-2-
Acetoxy-1-phenylthiopropane (83.3 mm
ol, 22.0 g, 87% ee) in dichloromethane (2
50 ml) solution, sulfuryl chloride (333 m
mol, 26.8 ml) and pyridine (333 mmol,
26.9 ml) was added dropwise. Raise the reaction temperature to room temperature, 3
After stirring for an hour, the mixture was poured into ice water, extracted with ether, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and used for the next reaction as it was.

The obtained target substance was 27.6 g (99.7%).
Yield), and the analytical data were as follows. ¹ H-NMR (CDCl ₃ ): σ 2.26 (s, 3H),
5.85 (q, J = 5.9 Hz, 1H), 7.40 −
7.78 (m, 5H). ¹⁹ F-NMR (CDCl ₃ ): σ-68.47 (d, J
= 5.9 Hz, 3F).

Synthesis of (R) -3,3,3-trifluorolactic acid: <Method 1> The above (R) -3,3,3-trifluoro-
Concentrated hydrochloric acid (30 ml) was added to a methanol solution of 2-acetoxy-1,1-dichloro-1-phenylthiopropane (20 g, 60.2 mmol, 87% ee), and the mixture was heated under reflux for 40 hours, returned to room temperature, and saturated. It was made alkaline with aqueous NaHCO ₃ and washed with ether. Further, the aqueous layer was made acidic with concentrated hydrochloric acid and extracted with ether. After drying, the solvent was distilled off under reduced pressure to obtain 6.94 g of crude crystals (80% yield).

By recrystallizing the crude crystals (chloroform / ether), 4.21 g of (R) -3,3,3-trifluorolactic acid was obtained with an optical purity of 99% ee or more.
(45.8% yield). Analytical data for this product was as follows: ¹ H-NMR (CD ₃ OD): σ4.65 (q, J = 7.
6 Hz, 1H). ¹⁹ F-NMR (CD ₃ OD): σ-75.83 (d, J
= 7.6 Hz, 3F). m. p. 74.1-75.1 ° C. [α] _D ²⁵ -21.05 (c 0.95, EtOH).

Example 2 <Method 2> Anhydrous cupric chloride (161 mg, 1.2 mmol)
l) was added to the above (R) -3,3,3-trifluoro-2-acetoxy-1,1-dichloro-1-phenylthiopropane (200 mg, 0.6 mmol, 87% e) at 0 ° C.
A solution of e) in methanol (2 ml) was added, and the mixture was stirred at room temperature for 48 hours, then poured into saturated aqueous NaHCO ₃ and extracted with ether. After drying, the solvent was distilled off and the reaction mixture
After adding N-HCl (2 ml) and heating under reflux for 15 hours, the mixture was poured into saturated aqueous NaHCO ₃ and extracted with ether.
After drying, the solvent was distilled off to obtain 50 mg (58% yield, 85% ee) of the target trifluorolactic acid.

Example 3 Synthesis of S-phenyl (R) -3,3,3-trifluoro-2-acetoxypropanethioate:

(R) -3,3,3-trifluoro-2-
Acetoxy-1,1-dichloro-1-phenylthiopropane (220 mg, 0.66 mmol) in benzene (1
0 ml) solvent to silver trifluoroacetate (293 mg, 1.
33 mmol) was added at 0 ° C., and the mixture was stirred at room temperature for 1 hour. Then, silver trifluoroacetate (293 mg, 1.33) was added.
mmol) at room temperature and stirred for 1 hour. The reaction solution was poured into ice water, extracted with methylene chloride, the solvent was distilled off under reduced pressure, and then dissolved in methanol (3 ml) and water (3 ml).
NaHCO ₃ (167 mg, 1.99 mmol) was added, and the mixture was stirred at room temperature for 15 minutes.

The reaction solution was poured into a 1 / 2N-HCl aqueous solution,
Extracted with ether. After drying, the solvent was distilled off, and the residue was purified by silica gel chromatography to obtain 129 mg of the desired compound (70% yield). Analytical data for this product was as follows: ¹ H-NMR (CDCl ₃ ): σ2.34 (s, 3H),
5.76 (q, J = 7.0 Hz, 1H), 7.35 −
7.55 (m, 5H). ¹⁹ F-NMR (CDCl ₃ ): σ-73.34 (d, J
= 7.0 Hz, 3F).

[0036]

According to the present invention, as described above, the fluorinated thioether compound is halogenated with the halogenating agent in the presence of the base, and the reaction product is hydrolyzed. Fluorinated lactic acid can be synthesized in a short process, so that the cost can be reduced and the target product can be mass-produced.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI theme coat ゛ (Reference) C07C 67/08 C07C 67/08 69/675 69/675 319/20 319/20 323/12 323/12 / / 72 C07M 7:00 C07M 7:00 (72) Inventor Daisuke Asada 3rd Miyukigaoka, Tsukuba City, Ibaraki Prefecture Daikin Industries, Ltd. MEC Research Laboratory (72) Yuko Sakamaki 3rd Miyukigaoka Tsukuba City, Ibaraki Prefecture Daikin Industries F term in MEC Laboratory Co., Ltd. (reference) 4H006 AA01 AA02 AB84 AC46 AC48 AC81 BA92 BE01 BE03 BM10 BN10 BS10 KA06 TA04 TB37

Claims (14)

[Claims] 1. A compound of the general formula (I): (However, in the general formula (I), R _f represents a perfluoroalkyl group, and R ¹ and R ² are the same or different groups, and independently represent an alkyl group, an aryl group, an aralkyl group. , An alkenyl group or an alkynyl group, * represents a chiral carbon atom.) An fluorinated thioether compound is reacted with a halogenating agent in the presence of a base, and the reaction product is hydrolyzed. By doing so, the general formula (II): (However, in the formula (II), R _f and * are the same as those described above.) A method for producing an optically active fluorinated lactic acid or a derivative thereof, which obtains an optically active fluorinated lactic acid represented by the formula: . 2. An optically active 3,3,3-trifluorolactic acid is obtained by using said R _f as a trifluoromethyl group.
A method for producing the optically active fluorinated lactic acid or a derivative thereof according to claim 1. 3. The method for producing an optically active fluorinated lactic acid or a derivative thereof according to claim 1, wherein a sulfuryl halide is used as the halogenating agent. 4. The method for producing an optically active fluorinated lactic acid or a derivative thereof according to claim 1, wherein the hydrolysis is performed with an acid or a metal salt. 5. The method for producing an optically active fluorinated lactic acid or a derivative thereof according to claim 1, wherein the optically active fluorinated lactic acid is further esterified. 6. A compound of the general formula (III): (However, in the general formula (III), R _f represents a perfluoroalkyl group, and R ¹ and R ² are the same or different groups, and independently represent an alkyl group, an aryl group, or an aralkyl group. , An alkenyl group or an alkynyl group, X represents a halogen atom, and * represents a chiral carbon atom.) By hydrolyzing an optically active fluorine-containing halothioether compound represented by the general formula (II): : (However, in the formula (II), R _f and * are the same as those described above.) A method for producing an optically active fluorinated lactic acid or a derivative thereof, which obtains an optically active fluorinated lactic acid represented by the formula: . 7. An optically active 3,3,3-trifluorolactic acid is obtained by using said R _f as a trifluoromethyl group.
A method for producing the optically active fluorinated lactic acid or a derivative thereof according to claim 6. 8. The method for producing an optically active fluorinated lactic acid or a derivative thereof according to claim 6, wherein the hydrolysis is performed with an acid or a metal salt. 9. The method for producing an optically active fluorinated lactic acid or a derivative thereof according to claim 6, wherein the optically active fluorinated lactic acid is further esterified. 10. A compound of the general formula (III): (However, in the general formula (III), R _f represents a perfluoroalkyl group, and R ¹ and R ² are the same or different groups, and independently represent an alkyl group, an aryl group, or an aralkyl group. , An alkenyl group or an alkynyl group, X represents a halogen atom, and * represents a chiral carbon atom). 11. trifluoromethyl group said R _f, X
The optically active fluorine-containing halothioether compound according to claim 10, wherein is a chlorine atom. 12. A compound of the general formula (I): (However, in the general formula (I), R _f represents a perfluoroalkyl group, and R ¹ and R ² are the same or different groups, and independently represent an alkyl group, an aryl group, an aralkyl group. , An alkenyl group or an alkynyl group, and * represents a chiral carbon atom.) By reacting an optically active fluorinated thioether compound with a halogenating agent in the presence of a base. Formula (III): (However, in the above general formula (III), R _f , R ¹ , R ² and * are the same as those described above, and X represents a halogen atom.) For producing an optically active fluorine-containing halothioether compound. 13. trifluoromethyl group said R _f, X
The method for producing an optically active fluorine-containing halothioether compound according to claim 12, wherein is a chlorine atom. 14. The method for producing an optically active fluorine-containing halothioether compound according to claim 12, wherein a sulfuryl halide is used as the halogenating agent.