JPS61176546A - Fluorine-containing carbonyl compound and method for producing the same - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION A. Field of Industrial Application The present invention relates to a fluorine-containing carbonyl compound and a method for producing the same.

BACKGROUND OF THE INVENTION Recently, there has been interest in the microbiological behavior of halogen-containing compounds that are hardly degraded by microorganisms in biological systems.

The present inventor has already reported in Japanese Patent Application No. 57-151010 that a fluorine-containing carbonyl compound was asymmetrically reduced using active baker's yeast as shown in the following formula, and a fluorine-containing alcohol was converted into microorganisms under the control of the steric structure. We proposed a method to obtain it scientifically.

(However, Rf is a perfluoroalkyl group, R is an alkyl group, or CHz Cot Et, etc.) Furthermore, according to recent literature on fluorine chemistry, chiral synthetic means useful for asymmetric synthesis of fluorine-containing bioactive molecules is attracting attention (
G.B.

Quistad, D.C., Cerf, D.A.
5chooley.

and G, B, 5taal, Nature,
289. 176 (1981] etc.).

The present inventor investigated the microbiological conversion of fluorine-containing compounds and found that, for example, an enantiotoxic stepwise reaction using 2,2.2-) refluoroethanol resulted in microbiological carbon-carbon The present invention has been achieved based on the discovery that it is possible to generate inter-bonds.

Among the trifluoromethylating agents known so far, 2,2,2-trifluoroethanol is the suicide substance of alcohol dehydrogenase.
known as (D, C, Ande vator)
rson and F, W, Dahlquist,
Biochemistry, 2 Sat.

3569 (1982)).

Object of the Invention An object of the present invention is to provide a novel fluorine-containing carbonyl compound having fluorine at a predetermined position in the molecule and having excellent optical activity and physiological activity.

Another object of the present invention is to provide a manufacturing method that allows the above-mentioned fluorine-containing carbonyl compound to be obtained easily in high yield.

20 Structure of the invention and its effects, that is, the present invention has the general formula: atom or an aliphatic or aromatic group; R4 is a hydrogen atom, an aliphatic or aromatic group, or an -OR' group (wherein R5 is a hydrogen atom or an aliphatic or aromatic group), and R2 is a lower fluoro group; If it is not an aliphatic group or a fluorine atom, it may be combined with R4 to form a ring (if R4 is -O
When it is an R' group, an ether bond may be formed by removal of R'OH between the hydroxyl group (-OH) at the γ-position.

] This relates to a fluorine-containing carbonyl compound represented by the following.

This fluorine-containing carbonyl compound is located at a predetermined position within the molecule (β
It has a lower fluoroaliphatic group at the 1-position), and the carbon atom at the γ-position is chiral, so it exhibits excellent physiological activity, such as efficacy as a semi-synthetic intermediate for anti-inflammatory agents and antibiotics. It is something that can be done. This is particularly noticeable when a lactone ring is formed by an ether bond due to the above-mentioned R'OH removal.

The present invention also provides a method for effectively obtaining the above-mentioned fluorine-containing carbonyl compound by combining an alcohol represented by the general formula: % formula % and an α,β-unsaturated carbonyl compound represented by the general formula in the presence of yeast. % [However, in the above, one of R1, R2, and R3 is a lower fluoroaliphatic group or a fluorine atom, and the others are a hydrogen atom, a halogen atom, or a fluorine atom. Aliphatic or aromatic group; R
4 is a hydrogen atom, an aliphatic or aromatic group, or an -OR' group (however, R% is a hydrogen atom or an aliphatic or aromatic group), and when R2 is not a lower fluoroaliphatic group or a fluorine atom may be combined with R4 to form a ring, and when R4 is -OR' group, the hydroxyl group at the γ position (-O
An ether bond may be formed by removal of R'OH between H). ] The present invention also provides a method for producing a fluorine-containing carbonyl compound for obtaining a fluorine-containing carbonyl compound represented by the following.

According to this method, the fluorine-containing carbonyl compound of the present invention can be easily obtained in high yield by allowing microorganisms (especially baker's yeast) to act upon the reaction between the alcohol and the α,β-unsaturated carbonyl compound. be able to.

In the fluorine-containing carbonyl compound and the method for producing the same of the present invention, one of R1, R2 and R3 is preferably a lower fluoroaliphatic group, particularly a lower fluoroalkyl group (Rf) having 10 or less carbon atoms. , such Rf (particularly perfluoroalkyl groups) has the general formula: CF!
(CFz)n- or (CF3)zcF (CFz
), 1-, for example CF:l-1
CFzCFz-1CFs(CFz)z-1CFz(CF
z)2-1CF! (CF z)a-1CFa(CF
z)s-1CF3(CFtub-1(CF,
)! CF-1(CFzh CFCFz-1(CF
s)z CF(CFz)z −1(CFs)z CF(
CFz)s -, etc. In addition to these, Rf is a fluorine-containing alkenyl group, such as CFt=CFCFt-1
CF3CF=CF- etc. are also applicable.

Further, among R', R'' and R3, the group other than Rf is a lower aliphatic group having 10 or less carbon atoms, and CR3 (CHz
), 1- or (CHs)z CH(cHt)+%-, or CH! = CHCHHz−1
Alkenyl groups such as CH, CH=CH-, etc. are applicable. Furthermore, aromatic groups such as phenyl groups are also applicable.

Furthermore, R4 and R8 above may also be the lower aliphatic groups exemplified above, similar to RI SR1 and R:1.

The production method of the present invention is particularly suitable for use under weakly acidic conditions of pH 4 to 7.5 (
It is desirable to carry out the reaction at a pH of 5.5 to 6.2) in order to avoid causing other unnecessary reactions. In addition, the reaction temperature is 25 to 40°C, which is necessary for efficient yeast action.
The temperature is preferably 35 to 37°C.

As for other reaction conditions, the solvent may be water, and the reaction time is preferably about several days to one week.

Next, the present invention will be explained in more detail according to the reaction formula.

First, a microbiological transformation is carried out using α,β-unsaturated ketone 1 according to the following formula.

The results obtained when various ketones were used are shown in Table 1 below. From 1, considerable amounts of other alcohols 3 and 4 were produced, and at the same time, the desired optically active fluorine-containing carbinol 2 was produced. Ru. This reaction proceeds more slowly than without 2.2.2-trifluoroethanol.

Carbinol 2 was identified by various analytical data, but in particular, according to the I9F NMR spectrum, the CF group appears in a doublet at 61.3 ppm (external standard CFs Cot H) (C) (sprinted with OH hydrogen). .

Optical purity was determined by FNMR after converting the alcohol to a diastereomeric ester with an optically active perfluorocarboxylic acid.

The above reaction proceeds similarly when β-substituted α,β-unsaturated ketone 5 is used.

On the other hand, when various α,β-unsaturated esters were reacted in the presence of baker's yeast, lactone U was produced through the intermediate product ring as shown below.

In this case, for example after fermentation for 7 days, the carbon-carbon double bond is reduced and a new intermediate product is first formed. The reaction conditions are the same as described above.

(2) Among the products, lactone 1 in particular has a physiologically active action as an anti-inflammatory agent, and if the R8 group in the molecule is relatively long chain, it can be expected to be effective as an antibiotic.

(The following margins are continued on the next page.) Next, unlike the reaction described above, fluorine-containing α,β-unsaturated ketones and ethanol were used as starting materials, and these were mixed in the presence of baker's yeast in the same manner as above. Compound 1 of the present invention can also be obtained by reacting with

Even if the 13th compound or a fluorine-containing α,β-unsaturated carboxylic acid ester is used, the lactone of the present invention can be obtained through intermediate product 1 as follows.

Now Pier The mulberry fruits are summarized in Table 2 below.

Margin below c, continued on next page. ) As described above, according to the present invention, it has become possible to microbiologically introduce carbon-carbon bonds into fluorine-containing compounds by a new synthetic route, and it has become possible to transform difficult-to-degradable fluorine-containing materials into flexible molecules. can be microbiologically converted into

E. Examples Hereinafter, the present invention will be explained in more detail with reference to specific examples, but the following examples do not limit the present invention, and various changes can be made based on the technical idea thereof.

A 1/15 mol NazHPOm aqueous solution (60 mJ) and 1
/15 mol of KH2PO, in a buffer solution (600 ml, pH 5,9) prepared from an aqueous solution (540 nl),
Active baker's yeast (manufactured by Oriental Yeast) (50g)
) and soluble starch (Wako Daiichi Grade 1) (75 g) were suspended. Transfer this suspension to a jar fermenter (
The mixture was stirred at 35 to 36° C. for 60 minutes in a tube (manufactured by Tokyo Rikakikai Co., Ltd.) for 60 minutes. Add methyl vinyl ketone (2.1 g,
30 mmol and 2.2.2-) refluoroethanol (10 g, IQOmmo1) were added and the whole mixture was then stirred at 35-36<0>C. After stirring for 3 days, baker's yeast (50g) and soluble starch (75g)
g) was further added and stirring was continued for 4 days. Then, in this stirring mixture, P-713 (manufactured by Daiichi Kogyo Seiyaku Co., Ltd.)
A 200 ppm flocculant solution (100 nl) prepared from
was added over several minutes. After standing for 1 hour, mix the mixture with 3
% HCI and the precipitate was separated by filtration. The oil layer was extracted with diethyl ether, and the ether extract was dried over anhydrous magnesium sulfate, and then the solvent was distilled off.

As a result, the corresponding 6,6. Lotrifluoro-5-hydroxy-2-hexanone was obtained with a yield of 26%, its boiling point was bp 92-94°C 15 mmHg, [αo
) (neat) was -12.1, and the optical purity was 93%ee.

In Example 1, cyclohexanone (2.9 g, 30 mmol) was used instead of methyl vinyl ketone as the starting material.
l) was used and reacted in the same manner as above.

After distillation, 2-(β,β,β-trifluoroα-hydroxy)ethylcyclohexanone was obtained with a yield of 38%, and its diastereomixing ratio was 9228 from the 19F NMR signal intensity, and M” (m /e) was 196. Other peaks were also observed in the mass spectrum.

In Daiarashi Medical Example 1, ethyl acrylate (3 g, 30 mmol) was used instead of methyl vinyl ketone,
The reaction was carried out in the same manner as above. By distillation, 5-trifluoromethyl-γ-butyrolactone was obtained with a yield of 47%, its optical purity was 79%ee, and (αD)
(neat) was +13.6. Other peaks were also observed in the mass spectrum.

1/15 mol N az HP O4 aqueous solution (60n
+j Rito 1/15MoRv (D K Ht P O4
Buffer solution prepared from aqueous solution (540+*j)
Active baker's yeast (manufactured by Oriental Yeast Co., Ltd.) (75 g) and soluble starch (Wako Daiichi Grade 1) (115 g) were suspended in 0 ml Sp H5,9).

This suspension was stirred at 35-36° C. for 60 minutes in a jar fermenter (manufactured by Tokyo Rikakikai ■). To this mixture were added 5.5.5-)lifluoro-3-penten-2-one (4.1 g, 30 mmol) and ethanol (15
g) was added and the whole mixture was then stirred at 35-36°C.

After stirring for 3 days, additional baker's yeast (75 g) and soluble starch (115 g) were added and stirring continued for 4 days. In this stirred mixture, a 200 ppm flocculant solution prepared from P-713 (manufactured by Daiichi Kogyo Seiyaku Co., Ltd.) <2
00tail) was added over several minutes. After standing for 1 hour, the mixture was acidified with 3% HC2 and the precipitate was separated by filtration. Extract the oil layer with diethyl ether,
After drying the ether extract with anhydrous magnesium sulfate,
The solvent was distilled off. As a result, the corresponding 5-hydroxy-
4-Trifluoromethyl-2-hexanone was obtained in 62% yield and its mass spectrum was M” (m/e
) It was 184.

Other peaks were observed in the same spectrum.

In back coating Example 4, ethyl(
β-trifluoromethyl)acrylate (5g, 30
mmoj was used and the reaction was carried out in the same manner as above. After distillation, 4-trifluoromethyl-5-methyl-T-butyrolactone was obtained with a yield of 56% and its M
e) was 168 and other peaks were observed in the mass spectrum.

Claims (1)

[Claims] 1. General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [However, one of R^1, R^2 and R^3 is a lower fluoroaliphatic group or a fluorine atom. Yes, others are hydrogen atoms,
A halogen atom or an aliphatic or aromatic group; R^4 is a hydrogen atom, an aliphatic or aromatic group, or an -OR^5 group (wherein R^5 is a hydrogen atom or an aliphatic or aromatic group); If R^2 is not a lower fluoroaliphatic group or a fluorine atom, it may be combined with R^4 to form a ring, and if R^4 is -OR^5 group, the γ-position An ether bond may be formed by removing R^5OH between the hydroxyl group (-OH). ] A fluorine-containing carbonyl compound represented by: 2. The claim that one of R^1, R^2 and R^3 is a lower fluoroalkyl group having 10 or less carbon atoms, and the other is a lower aliphatic group having 10 or less carbon atoms. The compound described in item 1. 3. The compound described in claim 1, wherein R^4 is a lower aliphatic group having 10 or less carbon atoms. 4. The compound described in claim 1, wherein R^5 is a lower aliphatic group having 10 or less carbon atoms. 5. An alcohol represented by the general formula: R^1CH_2OH and an α,β-unsaturated carbonyl compound represented by the general formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ are reacted in the presence of yeast, thereby , general formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [However, in the above, one of R^1, R^2 and R^3 is a lower fluoroaliphatic group or a fluorine atom,
Others are hydrogen atoms, halogen atoms, or aliphatic or aromatic groups; R^4 is hydrogen atoms, aliphatic or aromatic groups, or -
OR^5 group (however, R^5 is a hydrogen atom or an aliphatic or aromatic group), and if R^2 is not a lower fluoroaliphatic group or a fluorine atom, it is bonded to R^4. A ring may be formed, and when R^4 is an -OR^5 group, an ether bond may be formed by removal of R^5OH between the hydroxyl group (-OH) at the γ position. ] A method for producing a fluorine-containing carbonyl compound to obtain a fluorine-containing carbonyl compound represented by the following. 6. The method according to claim 5, wherein the reaction is carried out at a pH of 4 to 7.5 and a temperature of 25 to 40°C. 7. Claims in which one of R^1, R^2 and R^3 is a lower fluoroalkyl group having 10 or less carbon atoms, and the others are lower aliphatic groups having 10 or less carbon atoms. The method described in Section 5. 8. The method according to claim 5, wherein R^4 is a lower aliphatic group having 10 or less carbon atoms. 9. The method according to claim 5, wherein R^5 is a lower aliphatic group having 10 or less carbon atoms.