JPH0558955A - Production of beta-fluoro-alpha-keto acid equivalent substance - Google Patents

Abstract

PURPOSE:To easily produce the subject compound at a low cost by using an inexpensive beta, beta, beta-trifluorolactic acid useful as a raw material block for a beta-fluoro-alpha-keto acid block and reacting with an organometallic reagent. CONSTITUTION:The objective beta-fluoro-alpha-keto acid equivalent substance of formula II (R is alkyl) [e.g. 3-fluoro-3-phenyl-2-(p-toluenesulfonyloxy)acrylic acid ethyl ester] is produced by reacting a trifluorolactic acid derivative of formula I (X is OH-protecting group; R' is alkyl for protecting carboxylic acid) [e.g. 3,3,3-trifluoro-2-(p-toluenesulfonyloxy)propionic acid ethyl ester] with an organometallic reagent (especially preferably an organic copper reagent such as a reactional product of copper iodide and a Grignard reagent). The compound is useful as a raw material for physiologically active substance such as pharmaceuticals and agricultural chemicals, functional organic compound such as liquid crystals and surfactants, polymer useful as functional material, etc.

Description

Detailed Description of the Invention

The present invention relates to a β-fluoro-α-keto acid useful as a raw material for physiologically active substances such as pharmaceuticals and agricultural chemicals, functional organic compounds such as liquid crystals and surfactants, and functional material polymers. The present invention relates to a method for producing an equivalent fluorine-containing enol ester compound.

[0002]

2. Description of the Related Art In general, a compound obtained by replacing hydrogen of a known compound having functionality or physiological activity with fluorine has its function or physiological activity enhanced by a specific electronic effect of the fluorine atom, or has a new function or physiological activity. It is known to obtain activity. Therefore, a fluorine-containing building block having a structure similar to the starting material of a known compound has been designed and synthesized [eg, "Fluorine-based physiologically active substances in the 90's, supervised by Nobuo Ishikawa, published by CMC (1991)].

[0003] α-Keto acid is one of the commonly used chemical raw materials, and in particular, it is a raw material of various physiologically active substances and amino acids which are widely used as raw materials for pharmaceuticals. The fluorine-substituted compound β-fluoro-α-keto acid and its equivalent are considered to be useful starting compounds.

As a known method for producing this β-fluoro-α-keto acid, its equivalent, or β-fluoro amino acid, a method of replacing a hydroxyl group, a thiol group, an amino group or the like with fluorine by a fluorinating reagent [eg, J. Kollonitsc
h, S. Marburg, LMPerkins, J. Org. Chem., 40, 3808 (19
75); 40, 771 (1979)], a method of introducing fluorine into the double bond (for example, H.
Gershon, MWMcNeil, EDBergmann, J.Med.Chem.16,1
407 (1973)], aziridine ring, epoxy ring and the like is opened with hydrogen fluoride, then a method of converting to the desired product [eg, AIAyi,
M. Remli, R. Guedj, J. Fluorine Chem. 18, 93 (1981)], a method of reacting the β-position hydrogen of α-keto acid with fluorine (for example, T. Tsusima, K. Kawada, T. Tsuji, J.Org.Che
m., 47, 1107 (1967)], etc. are known.

However, in these methods, in order to prepare various β-fluoro-α-keto acids or their equivalents, it is necessary to prepare fluorine-containing raw materials corresponding thereto, which is not necessarily a simple method. In order to avoid such complications and synthesize various β-fluoro-α-keto acids or their equivalents, various substituents are used with the β-fluoro-α-keto acid moiety as one synthesis raw material block. The method introduced for this is considered optimal.

[0006]

SUMMARY OF THE INVENTION The present invention has been made in view of the above circumstances, and the object of the present invention is to:
By using inexpensive β, β, β-trifluorolactic acid as a raw material block of this β-fluoro-α-keto acid moiety, various β-fluoro-α-keto acids and their equivalents can be easily produced. To provide a method.

[0007]

The present invention provides the following general formula 3

[Chemical 3] (Wherein X represents a hydroxyl-protecting group and R ′ represents an alkyl group for protecting a carboxylic acid), a trifluorolactic acid derivative represented by the following general formula 4

[Chemical 4] (In the formula, R represents an alkyl group derived from an organometallic reagent, X,
R ′ is the same as the above), and a method for producing a β-fluoro-α-keto acid equivalent is particularly preferable, which comprises using an organocopper reagent as the organometallic reagent.

The trifluorolactic acid derivative represented by the above general formula 3, which is the starting material of the present invention, is 3,3,3
Methyl -trifluoro-2- (methanesulfonyloxy) propionate Ethyl 3,3,3-trifluoro-2- (methanesulfonyloxy) propionate 3,3,3-Trifluoro-2- (methanesulfonyloxy) ) Isopropyl propionate, 3,3,3-trifluoro-2- (methanesulfonyloxy) propionate-l-menthyl methyl 3,3,3-trifluoro-2- (p-toluenesulfonyloxy) propionate, Ethyl 3,3,3-trifluoro-2- (p-toluenesulfonyloxy) propionate 3,3,3-trifluoro-
Examples include isopropyl 2- (p-toluenesulfonyloxy) propionate, 3,3,3-trifluoro-2- (p-toluenesulfonyloxy) propionic acid-1-menthyl and the like.

These trifluorolactic acid derivatives are 3,3,3-trifluoropropene oxide obtained by microbial oxidation of trifluoropropene (Japanese Examined Patent Publication No. 61-
14798), the 3,3,3-trifluorolactic acid easily obtained by oxidation (Japanese Patent Application No. 3-06097).
No. 9, Japanese Patent Application No. 3-103630),
After protected by esterification in the presence of an alcohol and a sulfuric acid catalyst or the like, the remaining hydroxyl group is acid-esterified with an acid chloride. Examples of the alcohol used for protecting the carboxyl group in this case include primary alcohols such as methanol, ethanol, propanol, butanol, hexanol, and octanol, secondary alcohols such as isopropanol, s-butanol, and menthyl alcohol, and t-butanol. A tertiary alcohol can be used, and the alcohol is not particularly limited, and it is advisable to select the most suitable alcohol based on the reactivity at the final deprotection or the ease of handling the product. A wide variety of acid chlorides can be used for the protection of hydroxyl groups, but they are not decomposed or modified in the enol ester production step of this reaction, and can be easily deprotected as necessary. Those which are preferable, specifically, sulfonic acid chlorides such as p-toluenesulfonic acid chloride are suitable.

The present invention produces an enol ester represented by the above general formula 4 by reacting such a trifluorolactic acid derivative with an organometallic reagent.

Examples of the organometallic reagent used in the present invention include organolithium reagents, organomagnesium reagents, organoaluminum reagents, organocopper reagents and the like. Considering the reactivity and reaction selectivity, the organocopper reagents are Optimal. There are various types of this organocopper reagent depending on its production method, but it is more preferable to use a highly reactive Norman-type organocopper reagent prepared by reacting a commonly used monovalent copper halide with a Grignard reagent. Good results can be obtained, which is particularly preferable. These organometallic reagents may be used in an amount of 2 to 5 mol per 1 mol of the above-mentioned raw material trifluorolactic acid derivative.

The reaction is carried out in a solvent.
An ether solvent, particularly tetrahydrofuran (THF), is preferable for the stability of the organometallic reagent.

Regarding the reaction temperature, until the time of adding and mixing the organometallic reagent, it is advisable to carry out the reaction at a temperature of room temperature or lower for the stability of the reagent, and when the addition is completed and sufficient mixing is carried out, the reaction is heated. .. The completion of the reaction can be determined by confirming that the raw material has been consumed by an ordinary analytical means. The reaction is fast enough to complete within hours.

The reaction mixture obtained as described above is
After decomposing with acid such as hydrochloric acid, extraction with organic solvent,
It is isolated by a usual post-treatment such as drying and purification.

The thus obtained enol ester compound represented by the above general formula 4 easily undergoes enol = keto tautomerization by removing the protection of the hydroxyl group at the enol position, and the following general formula Conversion 5

[Chemical 5] (Wherein R and R ′ are the same as above), β-fluoro-
It is possible to convert to α-keto acid.

Although the conditions for decomposing the ester bond and the like differ depending on the protective reagent used for protecting the hydroxyl group at the enol position, the optimal method according to various reagents has already been reported [[TW Greene, "Protective Groups in Organic Synth
esis "John Willy & Sons, (1981)].

[0017]

EXAMPLES Example 1 [Production of ethyl 3-fluoro-3-phenyl-2- (p-toluenesulfonyloxy) acrylate] 0.54 g of copper iodide
Phenylmagnesium bromide (3 mmol) was added to a THF suspension solution of (3 mmol), and after stirring for 30 minutes, ethyl 3,3,3-trifluoro-2- (p-toluenesulfonyloxy) propionate 0.33 g ( A THF solution (1 mmol) was added dropwise, and the mixture was heated under reflux for 2 hours.

The reaction solution was poured onto crushed ice, 3% hydrochloric acid was added, and the mixture was extracted with ether. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure, the residue was separated and purified by column chromatography, and further purified by a recrystallization method. The yield was 67%, and 3-fluoro- had the following physical properties.
Ethyl 3-phenyl-2- (p-toluenesulfonyloxy) acrylate was obtained. Melting point: 71-73 ° C ¹ H-NMR (CCl ₄ ) δ: 1.12 (t, 3H), 2.43 (s, 3H), 4.
03 (q, 2H), 7.25 (q, 2H), 7.35 (s, 5H), 7.80
(d, 2H) ppm. ¹⁹ F-NMR (CCl ₄ ) δ: 7.23 (s) ppm. IR (KBr): 1725, 1370, 1600, 1650 cm
^-1 .MS (M + (m / e)): 362

Example 2 [Production of ethyl 3-fluoro-3-methyl-2- (p-toluenesulfonyloxy) acrylate] Methyl magnesium bromide (9 mmol) was added to a THF suspension solution of 1.80 g (9 mmol) of copper iodide. ) Was added and after stirring for 30 minutes, ethyl 3,3,3-trifluoro-2- (p-toluenesulfonyloxy) propionate 0.98 g (3 mmol) of THF was added.
The solution was added dropwise and stirred overnight. The reaction solution was placed on crushed ice and 3% hydrochloric acid was added to perform ether extraction. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was separated and purified by column chromatography to give 3-fluoro-3-methyl-2- (p-toluenesulfonyloxy) acrylic acid having the following physical properties in a yield of 71%. Obtained ethyl. ¹ H-NMR (CCl ₄ ) δ: 1.15 (t, 3H), 2.35 (d, 3H), 2.
40 (s, 3H), 4.02 (q, 2H), 7.21 (d, 2H), 7.67
(d, 2H) ppm. ¹⁹ F-NMR (CCl ₄ ) δ: 2.10 (q) ppm. IR (KBr): 1720, 1670, 1600, 1380,
1450cm ^-1 .MS (M + (m / e)): 302

Example 3 [Production of 3-fluoro-3-methyl-2- (p-toluenesulfonyloxy) acrylic acid-1-menthyl] Methylmagnesium was added to a THF suspension solution of 1.80 g (9 mmol) of copper iodide. Bromide (9 mmol) was added and after stirring for 30 minutes,
1,3,3,3-trifluoro-2- (p-toluenesulfonyloxy) propionic acid-1-menthyl 1.30 g (3 mmol) of TH
The F solution was added dropwise and stirred overnight. The reaction solution was placed on crushed ice and 3% hydrochloric acid was added to perform ether extraction.
After drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography to give a yield of 63.
% 3-fluoro-3-methyl-2- (p-toluenesulfonyloxy) acrylic acid-1-menthyl having the following physical properties was obtained. ¹ H-NMR (CCl ₄ ) δ: 0.40 to 2.13 (m, 18H), 2.38
(d, 3H), 2.42 (s, 3H), 4.29 to 4.99 (br, 1H),
7.21 (d, 2H), 7.71 (d, 2H) ppm. ¹⁹ F-NMR (CCl ₄ ) δ: 1.70 (d) ppm. IR (KBr): 1720, 1670, 1600, 1380,
1450cm ^-1 .MS (M + (m / e)): 412

[0021]

Industrial Applicability According to the present invention, various β-fluoro-α-keto acid equivalents, which are industrially useful fluorine-containing raw material compounds, can be produced simply and inexpensively, and thus can be obtained conventionally. The difficult or impossible β-fluoro-α-keto acid or its equivalent became available at low cost, and this β-fluoro-α-keto acid or its equivalent compound was used as a raw material. It becomes possible to inexpensively produce a physiologically active substance or the like.

Claims (2)

[Claims] 1. The following general formula 1 (Wherein X represents a hydroxyl-protecting group and R ′ represents an alkyl group for protecting a carboxylic acid) and a trifluorolactic acid derivative represented by the following general formula: Chemical 2] (In the formula, R represents an alkyl group, and X and R ′ are the same as above)
A method for producing a β-fluoro-α-keto acid equivalent represented by: 2. A method for producing a β-fluoro-α-keto acid equivalent, wherein the organometallic reagent according to claim 1 is an organocopper reagent. [0001]