JP2614259B2 - Optically active fluorinated alcohol - Google Patents

Description

The present invention relates to an optically active fluorinated alcohol, and more particularly, it can be effectively used as a physiologically active substance, an anticancer agent, an enzyme inhibitor and a ferroelectric liquid crystal. The present invention relates to a novel optically active fluorinated alcohol having high optical purity and diastereomer purity.

[Problems to be solved by conventional technology and invention]

Conventionally, some optically active fluorine-containing alcohols have been reported as optically active compounds applied to liquid crystals and pharmaceuticals. However, there are only a few satisfactory optical purities, and almost no fluorinated alcohols in which adjacent carbon atoms are both optically active.

Accordingly, an object of the present invention is to provide a novel optically active fluorinated alcohol having high optical purity and high isomer (diastereomeric) purity.

[Means for solving the problem]

The present inventors have found that the configuration between two tertiary carbon atoms can be controlled not only relatively but also absolutely by using an asymmetric hydrolysis reaction with oxygen, and the above object has been achieved. The present invention has been completed based on such findings.

That is, the present invention relates to the general formula Wherein R is an alkyl group having 1 to 10 carbon atoms, 6 to 9 carbon atoms.
Or an aralkyl group having 7 to 10 carbon atoms. ] It is intended to provide an optically active fluorine-containing alcohol represented by the formula:

The optically active fluorine-containing alcohol of the present invention is represented by the general formula [I] as described above, wherein R is an alkyl group having 1 to 10 carbon atoms (methyl group, ethyl group, propyl group, Isobutyl group, butyl group, hexyl group, octyl group, decyl group, etc.), aryl group having 6-9 carbon atoms (phenyl group, tolyl group, xylyl group, etc.) or 7-7 carbon atoms.
And 10 aralkyl groups (benzyl group, phenethyl group, etc.).

By the way, various production methods can be considered for this optically active fluorine-containing alcohol derivative, but generally, it involves a very complicated operation of separating diastereomers. However, according to asymmetric hydrolysis using an enzyme, one of them is selectively converted, and an optically active fluoroalcohol derivative having high optical purity and high isomer purity can be efficiently obtained.

First, the case of using a ketone as a starting material in the method for producing the fluorine-containing alcohol derivative represented by the general formula [I] will be considered. Here, the ketone as a starting material has the general formula [Wherein, R is the same as described above. ] Is represented. If this ketone is reduced, the corresponding general formula [Wherein, R is the same as described above. ] The alcohol represented by these is obtained. At this time, it is possible to use sodium borohydride, lithium aluminum hydride, diisobutylaluminum hydride, selecides and the like as a reducing agent. You.

In order to obtain the optically active fluorinated alcohol of the present invention, the alcohol of the general formula [Ia] thus synthesized is once acylated (esterified) using an acylating agent or the like, and formula [Wherein, R is the same as described above, and COR ′ represents an acyl group. And then using an enzyme (eg, lipase P, lipase MY, cellulase) or the like to obtain an ester of the general formula [I] which is not only an enantiomer but also a diastereomer with a high purity. An optically active fluorinated alcohol can be easily obtained. That is, the ketone of the general formula [II] is diastereoselectively reduced to give an alcohol of the general formula [Ia], and this alcohol is further hydrolyzed via the ester of the general formula [III]. Then, only the ester having a specific optical rotation is hydrolyzed, and as a result, the above-mentioned optically active fluorine-containing alcohol of the general formula [I] is produced with high purity.

〔Example〕

Next, the present invention will be described in more detail based on examples.

Example 1 (1) Synthesis of fluorinated ketone 1.46 g (60 mmol) of magnesium and 10 ml of dry ether were placed in a well-dried three-necked flask under a nitrogen stream.
Was added. Thereto, an ether solution (60 ml) of β-phenethyl bromide (60 mmol) was added dropwise at such a rate as to cause gentle reflux, and after completion of the addition, the mixture was stirred at room temperature for 2 hours to obtain a Grignard reagent (PhCH ₂ C
H ₂ MgBr) was prepared.

Meanwhile, 7.03 g (50 mmol) of ethyl chlorofluoroacetate and 50 ml of dry ether were added to another well-dried three-necked flask, and these were cooled to −78 ° C. using a dry ice-acetone bath. The ether solution of the above Grignard reagent was added thereto over 20 minutes, and stirring was continued at this temperature for 3 hours. Next, a saturated aqueous ammonium chloride solution was added to the reaction mixture to terminate the reaction, and the mixture was made almost neutral with 1N hydrochloric acid, followed by ether extraction. Further, after drying over anhydrous magnesium sulfate, ether was distilled off under reduced pressure to obtain a crude product, which was purified by distillation under reduced pressure to obtain a purified product (chlorofluoromethylphenethyl ketone) (85% yield). Was. Its boiling point was 84-85 ° C (2 mmHg).

(2) Synthesis of fluorinated alcohol 1.39 g (6.9 mmol) of ketone prepared in (1) above
Into a three-necked flask containing dry tetrahydrofuran (TH
F, 10 ml) and cooled to -78 ° C. In addition, commercially available L
-Selectride 10.4 ml (1.0 M THF solution, 10.4 mmol)
Was added dropwise over 10 minutes, and stirring was continued for 1.5 hours.
After the completion of the reaction, the reaction mixture was placed in an ice bath, 30 ml of a hydrogen peroxide solution and a 3N aqueous solution of sodium hydroxide were added in 8 ml portions each, and the mixture was stirred for 30 minutes. A crude product was obtained by ether extraction, drying and solvent distillation under reduced pressure according to a conventional method.
Further, by passing this through a short silica gel column, almost pure alcohol (1-chloro-1-fluoro-4) is obtained.
-Phenyl-2-butanol) (77:23 diastereomeric mixture) could be isolated. The yield was 82%.

(3) Synthesis of fluorinated ester The above-mentioned alcohol 1.04 was placed in a dried three-necked flask.
g (5.2 mmol), 0.50 ml (6.2 mmol) of pyridine and 10 ml of dry methylene chloride were added, and the mixture was cooled in an ice bath.
After 0.44 ml (6.2 mmol) of acetyl chloride was added dropwise to this mixture, stirring was continued at room temperature overnight. Water was added to stop the reaction, and the mixture was extracted with 1N hydrochloric acid to make it weakly acidic. After drying over anhydrous magnesium sulfate and evaporating the solvent under reduced pressure, the crude product was passed through a short silica gel column to isolate the acetate. The yield was 88%.

(4) Asymmetric hydrolysis of fluorinated ester A flask containing 20 ml of distilled water and 0.34 g of lipase MY (2000 units, manufactured by Meito Sangyo Co., Candida cylindracea) was placed in a thermostat, and stirred while keeping the temperature at 40 ° C. Was.
Here, 0.49 g (2.0%) of the acetate compound prepared in the above (3) was prepared.
(Mmol) was added dropwise and reacted at room temperature for 1 hour. The acetic acid produced in the reaction solution was titrated with a 1N aqueous solution of sodium hydroxide, and the hydrolysis rate was 39%. The reaction mixture was filtered through celite to remove the enzyme, and extracted with ether and dried in a conventional manner. After the ether was distilled off under reduced pressure, the remaining oily substance was purified by silica gel column chromatography, and 0.17 g of optically active alcohol ((+)-1-chloro-1-fluoro-4-phenyl-2-butanol) was obtained. ) Got. The yield here is 83
%Met. The analysis results of this alcohol are as follows, and its optical purity and the like are shown in Table 1.

Molecular weight 202.66 ¹ H-NMR δ1.51~2.22 _{[m, 2H, CHC H 2 CH} 2 ], Deruta2.48～3.10 [m, 2H, C H ₂ Ph], Deruta2.91 [bs, 1H, OH] δ3 .55～3.96 [m, 1H, C H OH], Deruta5.98 [dd, 1H, J (CHF) = 51.4Hz, J (CHClFC H 2) = 4.7Hz, CHClF ], δ7.06~7.46 (m , 5H, Ph] ¹⁹ F-NMR ^δ63.9 [dd, J (CHF) = 46.4Hz , J (CHCl F C H) = 12.8Hz ] IR 3390 (OH), 3050,1600,1490 ( Ph) cm - ¹ Examples 2 to 15 (1) Synthesis of Fluorinated Ketone In Example 1 (1), a Grignard reagent was prepared using either bromobenzene, benzyl bromide or β-phenethyl bromide instead of β-phenethyl bromide. Then, a fluorinated ketone was synthesized in the same manner as in Example 1 (1).

(2) Synthesis of Fluorinated Alcohol Using the ketone obtained in the above (1), and using L-selectride or sodium borohydride as a reducing agent, a fluorinated alcohol was prepared in the same manner as in Example 1 (2). Alcohol was synthesized.

(3) Synthesis of fluorinated ester Using the fluorinated alcohol obtained in the above (2), and using acetyl chloride or isobutyryl chloride as the acylating agent, the acylated compound ( Acetate or isobutyrate).

(4) Asymmetric hydrolysis of fluorinated ester The acylated product obtained in the above (3) was used, and lipase MY or lipase P (Psuedomonas sp., Manufactured by Amano Pharmaceutical Co., Ltd.) was used as a hydrolase. By the same operation as in (4), the desired optically active alcohol was obtained.
The optical purity and the like are shown in Table 1.

The analysis results of the optically active alcohol obtained in Example 2 are as follows.

Molecular weight 174.60 ¹ H-NMR δ3.25 [bd, IH, OH], Deruta4.75 [dd, 1H, J (CHCl F C H) = 9.0Hz, J (C H ClFC H) = 5.0Hz, CH ], δ6.00 [dd, 1H, J (CHClF) = 51.0Hz, J (C H ClFC H) = 5.0Hz, CHClF ], Deruta7.17～7.42 [m, 5H, Ph] ¹⁹ F-NMR ^δ60.6 [ dd, J (CHF) = 44.4Hz , J (CHCl F C H) = 9.2Hz ] the IR 3430 (OH) cm ^-1, analysis of optically active alcohols obtained in example 4, as follows It is.

Molecular weight 188.63 ¹ H-NMR δ 2.22 [bs, 1 H, OH], δ 2.78 [dd, 1 H, J (CH _a H _b ) = 14.7 Hz, J (CH _a CH) = 7.8 Hz, CH _a ], δ3.03 _{[dd, 1H, J (CH a} H b) = 14.7Hz, J (CH b CH) = 5.4Hz, CH b ], Deruta4.02 [dddd, 1H, J (CHCl F C H) = 10.2 _{Hz, J (CHCH a) =} 7.8Hz, J (C H ClFC H) = 5.4Hz, J (CHCH b) = 5.4Hz, CH ], Deruta6.00 [dd, 1H, J (C H Cl F) = 50.6Hz, J (C H ClFC H ) = 5.4Hz, CHClF ], Deruta7.11～7.50 [m, 5H, Ph] ¹⁹ F-NMR ^δ62.7 [dd, J (CHF) = 50.8Hz , J (CHCl F C H) = 12.0Hz] IR 3420 (OH), as 3050,1500 (Ph) cm ^-1 [effect of the invention on ordination, optically active fluoroalcohol according to the present invention, a significantly high optical purity It is expected to be widely and effectively used as various pharmaceuticals including liquid crystals, or intermediates thereof.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification number Agency reference number FI Technical indication location C09K 19/06 9279-4H C09K 19/06 C12N 9/99 C12N 9/99 C12P 41/00 C12P 41 / 00 Z

Claims (1)

(57) [Claims] (1) General formula Wherein R is an alkyl group having 1 to 10 carbon atoms, 6 to 9 carbon atoms.
Or an aralkyl group having 7 to 10 carbon atoms. ] An optically active fluorine-containing alcohol represented by the formula: