JPH02174735A - Production of trifluoromethyl derivative - Google Patents

Abstract

PURPOSE:To simply obtain the title compound useful as a raw material for medicine, especially optically active substance thereof from an inexpensive raw material in good yield by reacting 1,2-epoxy-3,3,3-trifluoropropane with a specific organometallic compound. CONSTITUTION:1,2-Epoxy-3,3,3-trifluoropropane, especially optically active sub stance thereof is reacted with an organometallic compound expressed by the formula RM (R is alkyl, alkenyl, alkynyl or aryl; M is alkali metal or magne sium halide), preferably of 1-5 equivalent based on the above-mentioned com pound, preferably in the presence of a reaction solvent, further preferably together with a monovalent copper salt such as CuC1 or CuI of 0.005-0.5 equiva lent based on the above-mentioned raw material at-80-50 deg.C, preferably-20-30 deg.C to advantageously provide the aimed compound expressed by the formula useful also as a raw material for agricultural chemical, functional material, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION Industrial 1. The present invention relates to a method for obtaining trifluoromethyl derivatives, particularly optically active derivatives thereof, which are useful as raw materials for medicines, agricultural chemicals, functional materials, etc.

In general, many fluorine-containing compounds have unique physical properties and physiological activities, and many studies have been conducted on their synthesis methods [for example, Chemistry Review, "New Fluorine Chemistry" 1 edited by the Chemical Society of Japan] , published by Gakkai Publishing Center (1980)).

On the other hand, as a method for producing fluorine-containing carbinol, a method has been proposed in which a fluorine-containing aliphatic iodide is reacted with a carbonyl compound using zinc powder, etc., and then hydrolyzed [Japanese Patent Publication No. 60-55046 A method of obtaining an optically active form of this type of compound by kinetic optical resolution using an enzyme has also been proposed [Journal of Organic Chemistry (J.

Org, Che+s,), 52.3211 (198
7)) - This method requires expensive trifluoroiodomethane as a starting material and the optical resolution operation is complicated, so a simpler method for synthesis with high yield has been desired.

The present invention was made in view of the above-mentioned current situation, and an object of the present invention is to produce trifluoromethyl derivatives useful as raw materials for medicines, agricultural chemicals, functional materials, etc., particularly optically active forms thereof, at low cost. It is an object of the present invention to provide a method for producing the product more easily and with good yield using raw materials.

The present invention provides a method for converting 1,2-epoxy-3,3,3-trifluoropropane into RM Representing magnesium halide], the following formula (
1) A method for producing a trifluoromethyl derivative represented by the formula % [wherein R represents an alkyl group, an alkenyl group, an alkynyl group, or an aryl group] and an optically active substance thereof.

1,2-epoxy-3,3 which is the starting material of the present invention
, 3-trifluoropropane can be obtained by microbial oxidation [see Japanese Patent Publication No. 61-14798], and the compound obtained by this method is an optically active compound.

The RM of the organometallic compound includes methyllithium, ethyllithium, propyllithium, butyllithium, pentyllithium, hexyllithium, heptyllithium, octyllithium, ethynyllithium, propenyllithium, butenyllithium, pentenyllithium, hexenyllithium. , heptenyl lithium, octenyl lithium, ethynyl lithium, propynyl lithium, butynyl lithium, pentynyl lithium, hexynyl lithium, hebutynyl lithium, octynyl lithium,
Phenyllithium, alkylphenyllithium, alkylphenyllithium, biphenyllithium, alkylbiphenyllithium, alkoxybiphenyllithium, methylmagnesium halide, ethylmagnesium halide, propylmagnesium halide, butylmagnesium halide, pentylmagnesium halide, hexyl halide Magnesium, heptylmagnesium halide, octylmagnesium halide, ethynylmagnesium halide, propenylmagnesium halide, butenylmagnesium halide, hexynylmagnesium halide, octynylmagnesium halide, phenylmagnesium halide, alkylphenyl halide Magnesium, halogenated alkoxyphenylmagnesium, halogenated biphenylmagnesium, halogenated alkylbiphenylmagnesium, halogenated alkoxybiphenylmagnesium, etc. can be used. It is preferable to use 1 to 5 equivalents of these organometallic compounds based on the raw material.

In this reaction, a monovalent copper salt such as CuC1 or CuI is added to the above organometallic compound.

The coexistence of 0.005 to 0.5 equivalents is particularly preferred since the reaction rate can be increased.

In addition, this reaction is preferably carried out in the presence of a reaction solvent, and in this case, the reaction solvent is an aprotic polar solvent such as diethyl ether, tetrahydrofuran, dimethoxyethane, dimethyl sulfoxide, hexamethylphosphoramide, etc. If the organometallic compound is a solution of a non-polar hydrocarbon solvent (for example, a hexane solution), the above-mentioned non-polar hydrocarbon solvent may be selected. Even if the reaction is carried out in a mixed solvent system of this and a polar solvent without removing the
There are no problems.

The reaction temperature in this reaction is preferably -80 to 50°C, preferably -20 to 30°C.

Completion of the reaction can be confirmed by gas chromatography, thin layer chromatography, etc. The reaction mixture is poured into an aqueous ammonium chloride solution, diluted hydrochloric acid, etc., and the trifluoromethyl derivative represented by the above formula can be obtained by ordinary post-treatment operations such as extraction and distillation.

Father-in-law in the cold (reference example) Preparation of art suspension: Nocardia cora
lli-na) B-276 (FERN-P-4094
) were placed in NBG medium (10 g of Labrenco Powder manufactured by Oxoid, Bacteriological Peptone Log,
Add tap water to glucose Log and 5 g of sodium chloride to obtain IQ, and adjust the pH to 7.5 with 1N caustic soda aqueous solution.
500+ containing 100 mQ of liquid culture medium) prepared in
Inoculate each of 40 Sakalo flasks with sR volume and incubate at 30°C.
The cells were cultured with shaking for 16 hours.

This culture solution was inoculated into a 30,012 volume jar fermentor containing the same liquid medium 200Q as above, and
4 at a ventilation rate of 10012/min and stirring rotation speed of 450 rpm.
Cultured for 8 hours.

The bacterial bodies produced by these cultures were 0. By washing with OIM-phosphate buffer (PH8), then washing with the reaction medium shown below, and resuspending in the same reaction medium,
An art suspension was prepared.

In addition, the bacterial concentration of the art suspension is 36.6g as a dry matter concentration.
I made it to be IQ.

reaction medium; In, I(PO.

MgSO4.7H,0 FeSO4.7I]20 Glyose water Epoxidation of olefins: Pour 2.5Q of the image suspension prepared according to the above procedure into two 5Q jar fermenters, and apply 5V/ν.
2% of air containing 3.3.3-trifluoropropene
, 5 D/win, the first fur 1.74 g 1.50 g 0.05 g 32 g
The off-gas was cooled to -70°C, and the product was liquefied and recovered. Four of these reaction systems were arranged in parallel, and a 40% glycose aqueous solution was added to each fermenter at a temperature of 12.5°C.
Q/h) at 35°C and stirring speed of 80 or
pm and pH 7.2 (adjusted with 1N sodium hydroxide and 1N sulfuric acid!1) for 48 hours. The recovered products of each reaction system were distilled to give 5-(-)-1,2-epoxy-3,
280 g of 3,3-trifluoropropane were isolated.

(cz) Knee 9.2° (c 5,3.CllCl,)”
HNMR (CDCI, ): 2.8-3.0 (211
, m), 3.2-3.6 (IH9■, JHF ~4
．． 8H2) (Example 1) A heptylmagnesium bromide solution was prepared using 0.29 g (12 m+5 ol) of magnesium, 15 g (12 mmol) of 1-bromoheptane 2, and 20 s2 of tetrahydrofuran. This solution was cooled with water and copper iodide (1)
Add 95 mg (0.5 mmol) and add 5-(-)
-1,2-epoxy-3,3,3-trifluoropropane 1,12 g (10 + mol) was added to ether 10IIIQ
was added dropwise. After stirring at 0°C for 30 minutes and at room temperature for 2 hours, it was poured into 1 N hydrochloric acid, extracted with ether,
Dry (MgSOJ, concentrated. The crude product was purified by silica gel column chromatography, and then distilled under reduced pressure to obtain 5-(-)-1,1,1- with the following physicochemical properties.
1.24 g of trifluoro-2-decanol (yield 58%)
) was obtained.

Boiling point (kugelol): 120-b ”HNMR (CDCI, ): 0.8g (311,b
t), 1.30 (12+1.m), 1.5-1.8 (2
t(,m), 2.60(Off, bs), 3.6~4
゜2 (IH, Seal) "CNMR (CDC1z-67,9MHz): 14
．． 1 (CIO), 22-8 (C9) 25.1.29.
4 (2C), 29.6.32.0170.5 (C2゜q
, J cF=31.5)1z), 125.4(CI,
(1.
), the optical purity of the above compound was 74%e.
It was e.

(Example 2) 2.28 g (12 mmol) of copper iodide (1) was suspended in Ether 10OQ, and 1.5 mol of butyllithium-hexane solution 16u+I2 (24 mmol) was added dropwise under ice cooling. To this reaction solution was added 1.12 g (10
A solution of +smol) dissolved in ether 5IIQ was added dropwise. After stirring at 0°C for 30 minutes and then at room temperature for 2 hours,
It was poured into an aqueous ammonium chloride solution, extracted with ether, dried (MgSO4), and distilled under reduced pressure to obtain 1.31 g of 5-(-)-1,1,1-trifluoro-2-heptatool, which has first-order physical and chemical properties. A yield of 77% was obtained.

Boiling point (kugelol) near 0-b 1H TomoR (CDCI3): 0.8g (3H, bt)
, 1.1-1.8 (8H, am) 2.30 (OH, b
), 3.5 to 4.2 (III, +i) When the above product was converted into MTPA ester and analyzed by gas chromatography (PE020M, 25Otori), the optical purity of the above product was 75% ee. (Example 3) 0.24 g (10 mmol) of magnesium and 1.81 g (5 mmol) of 4-bromo-4'-octyloxybiphenyl
ol), 1,2-dibromoethane 0.94 g (5 mmo
Bromide 4 using L) and tetrahydrofuran 20IIQ
A solution of '-octyloxy-4-biphenylmagnesilla 11 was prepared. Add 19+++ g of copper iodide (1) to this solution.
(0.1 mmol) was added to the first 5-(-)-1,2-
Epoxy-3,3,3-trifluoropropane 0.56
A solution prepared by dissolving g (5 mmol) in tetrahydrofuran 5IIQ was added dropwise at room temperature. After stirring this at room temperature for 1.5 hours, it was poured into an aqueous ammonium chloride solution.

Extracted with ether, dried over magnesium sulfate, and concentrated. The crude product was purified by silica gel column chromatography to obtain 2S-1,1,1- with the following physical and chemical properties.
Trifluoro-3-(4'-octyloxy-4-biphenyl)-2-propatol 1.30 g (yield 66%)
I got it.

'HNMR (CDCI, ): 0.88 (3B, bt),
1.1-2.0 (12H, meal) 2.29 (OH, d,
5.6Hz), 2.57-3.30 (2+1.m), 3
．． 7-4.4 (LH, m), 3.97 (2H, t, 6
,0tlz), 6°80-7.60(811,m) It has the special effect of being able to be produced simply and with good yield using raw materials.

Claims (2)

[Claims] (1) 1,2-epoxy-3,3,3-trifluoropropane RM [wherein R is an alkyl group, an alkenyl group,
represents an alkynyl group or an aryl group, and M represents an alkali metal or magnesium halide].
I) ▲Mathematical formulas, chemical formulas, tables, etc. are available▼(I) A method for producing a trifluoromethyl derivative represented by [In the formula, R represents an alkyl group, an alkenyl group, an alkynyl group, or an aryl group]. (2) The method for producing an optically active trifluoromethyl derivative according to claim (1), wherein optically active 1,2-epoxy-3,3,3-trifluoropropane is used as a starting material.