JPH0558954A - Production of trifluorolactic acid derivative - Google Patents

Abstract

PURPOSE:To obtain a compound having specific protected functional group by hydrolyzing a trifluorolactic acid ester compound with an acidic compound such as aluminum chloride, thereby easily performing the mutual conversion of trifluorolactic acid derivatives. CONSTITUTION:The trifluorolactic acid derivative of formula II or formula III (e.g. 3,3,3-trifluoro-2-hydroxypropionic acid ethyl ester) is produced by hydrolyzing a trifluorolactic acid ester of formula I (R is straight, branched or cyclic alkyl; X is alkylsulfonyl or arylsulfonyl) [e.g. 3,3,3-trifluoro-2-(p-toluenesulfonyloxy)propionic acid ethyl ester] with an acidic compound (especially preferably aluminum chloride). The trifluorolactic acid derivative can easily be produced in high efficiency at a low cost. The compound is useful as a raw material for physiologically active substance such as pharmaceuticals and agricultural chemicals or for functional organic compound such as liquid crystals and surfactants.

Description

Detailed Description of the Invention

FIELD OF THE INVENTION The present invention relates to a trifluorolactic acid derivative 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 particularly a method for producing an optically active substance thereof. Regarding

[0002]

2. Description of the Related Art In general, a compound having functional or physiological activity in which hydrogen is replaced by fluorine has its function or physiological activity enhanced by the specific electronic effect of the fluorine atom, or has a new function or physiological activity. Is known to get. Therefore, many fluorine-containing building blocks having a structure similar to the starting materials of known compounds have been designed and synthesized [eg, “Fluorine-based physiologically active substances in the 90's”, supervised by Nobuo Ishikawa, CMC (1991), or “Flu
orine in Bioorganic Chemistry '' JT Welch, S. Eswarakr
ishnan, John Wiley & Sons (1991)].

Trifluorolactic acid has been attracting attention as a compound having high value and potential which satisfies these conditions. The applicant has previously proposed a method for producing this compound relatively easily and inexpensively (Japanese Patent Application No. 3-0609).
No. 79 and Japanese Patent Application No. 3-103630), this compound is difficult to use for organic chemical reaction due to its high hydrophilicity as it is, and for its complete enantiomeric separation, it is not compatible with an optically active alcohol or the like. Diastereomerization by ester formation is required. For this reason, the carboxyl group and the hydroxyl group, which are the hydrophilic source of trifluorolactic acid, are protected by appropriate ester, but it is difficult to remove only one protecting group of this compound. In order to change the state in which two functional groups are esterified to the state in which only one is protected by a protective group, it is necessary to decompose the two esters once and esterify only one side again, which is troublesome and complicated. It was inconvenient because it reduced the yield.

[0004]

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:
An object of the present invention is to provide a simple method for interconversion between trifluorolactic acid derivatives, that is, a method for producing a trifluorolactic acid derivative in which a specific functional group is protected.

[0005]

The present invention provides the following general formula 4

[Chemical 4] (Wherein R represents an alkyl group having a linear, branched, or cyclic structure, and X represents an alkylsulfonyl group or an arylsulfonyl group), and a trifluorolactic acid ester represented by The following general formula 5 or 6 is characterized in that it is hydrolyzed using

[Chemical 5]

[Chemical 6] In the method for producing a trifluorolactic acid derivative represented by the formula (X and R are the same as those in Chemical formula 4,) particularly preferably, aluminum chloride is used as the acidic compound, and the compound represented by the general formula 4 is used. The trifluorolactic acid ester represented by the above general formula 5 is used as the trifluorolactic acid ester having an alkyl group having a primary linear, branched or cyclic structure as the R of the ester group. The trifluorolactic acid ester produced or represented by the above general formula 4 has R of the ester group.
Is a method of producing a trifluorolactic acid derivative represented by the above general formula 6 by using a compound having an alkyl group having a secondary linear, branched or cyclic structure.

Examples of the trifluorolactic acid ester represented by the above general formula 4 which is the starting material of the present invention include the following compounds.

Methyl 3,3,3-trifluoro-2- (p-toluenesulfonyloxy) propionate Ethyl 3,3,3-trifluoro-2- (p-toluenesulfonyloxy) propionate 3,3 Isopropyl 3-, 3-trifluoro-2- (p-toluenesulfonyloxy) propionate 3,3,
Cyclohexyl 3-trifluoro-2- (p-toluenesulfonyloxy) propionate 3,3,3-trifluoro-2
L-menthyl- (p-toluenesulfonyloxy) propionate Methyl 3,3,3-trifluoro-2- (o-nitrobenzenesulfonyloxy) propionate 3,3,3-trifluoro-2- (o- Nitrobenzenesulfonyloxy) ethyl propionate, 3,3,3-trifluoro-2- (o-nitrobenzenesulfonyloxy) isopropyl propionate,
Cyclohexyl 3,3,3-trifluoro-2- (o-nitrobenzenesulfonyloxy) propionate l-menthyl 3,3,3-trifluoro-2- (o-nitrobenzenesulfonyloxy) propionate 3,3,3 Methyl 3-trifluoro-2- (methanesulfonyloxy) propionate 3,3,3-
Ethyl trifluoro-2- (methanesulfonyloxy) propionate Isopropyl 3,3,3-trifluoro-2- (methanesulfonyloxy) propionate 3,3,3-Trifluoro-2- (methanesulfonyloxy) Cyclohexyl propionate, l-menthyl 3,3,3-trifluoro-2- (methanesulfonyloxy) propionate.

The above-mentioned trifluorolactic acid ester is obtained by esterifying the carboxylic acid moiety of trifluorolactic acid with an alcohol using a dehydration catalyst.
It can be obtained by esterifying the remaining hydroxyl portion with a sulfonic acid halide.

As the primary alcohol among the alcohols in this case, any kind of alcohol can be used without any particular problem, and examples thereof include methanol, ethanol, 1-propanol, 1-butanol and 1-hexanol. .. Also, as a secondary alcohol, regardless of type,
It can be used without particular trouble, and examples thereof include isopropanol, menthyl alcohol, cyclohexanol, cyclopentanol, sec-butanol and the like. It should be noted that the use of an optically active menthyl alcohol as the secondary alcohol allows the derivative to be diastereomerically resolved, which is extremely convenient.

Further, as the sulfonic acid halide,
Examples thereof include alkyl or aryl sulfonic acid halides such as methanesulfonic acid chloride, p-toluenesulfonic acid chloride and o-nitrobenzenesulfonic acid chloride.

In the present invention, the sulfonic acid ester is treated by reacting an acidic substance with the trifluorolactic acid ester represented by the general formula 4 which is ester-protected with the above alkyl or aryl sulfonic acid and a primary alcohol. Only part is selectively hydrolyzed.

On the other hand, in the present invention, the trifluorolactic acid ester represented by the above-mentioned general formula 4 which is ester-protected with an alkyl or aryl sulfonic acid and a secondary alcohol is reacted with an acidic substance. Only the acid ester moiety is selectively hydrolyzed.

Examples of acidic substances used in these reactions include protic acids such as hydrochloric acid, sulfuric acid and hydrobromic acid, and Lewis acids such as aluminum chloride and titanium tetrachloride. A protonic acid is preferable, and a Lewis acid is preferable in the decomposition of carboxylic acid ester. In particular, aluminum chloride is suitable as the Lewis acid in the latter decomposition reaction. These acidic substances are preferably used in an amount of 1.5 to 4 molar equivalents based on 1 mole of trifluorolactic acid ester.

This reaction is carried out in a reaction solvent, and this solvent is appropriately selected depending on the acidic substance to be used. When the acidic substance is a protic acid, water or alcohol is preferable, and when it is a Lewis acid, methylene chloride or benzene. An aprotic solvent such as is preferable because it prevents the decomposition of the acidic substance. In addition, when a Lewis acid is used, the reaction is easily affected by moisture, so it is desirable that the solvent used be sufficiently dried.

The reaction temperature is determined by the reactivity of the acidic substance used, but when aluminum chloride is used, for example, the reaction proceeds at room temperature. Generally, it is appropriately selected within the range of 0 to 100 ° C.

The completion of the reaction can be determined by using ordinary analytical means such as NMR and gas chromatography, but the reaction is usually sufficiently fast and completed within several hours.

The post-treatment of the reaction is carried out as it is when a protic acid is used in a water solvent, and in other cases, a weakly alkaline aqueous solution is added to hydrolyze and decompose the compound in the form of a metal complex. The target compound can be isolated by a suitable purification means after extraction with tell, drying and evaporation of the solvent.

[0018]

【Example】Example 1  [3,3,3-trifluoro-2-hydroxypropionic acid
Synthesis of ethyl] 3,3,3-trifluoro-synthesized from trifluorolactic acid
Ethyl 2- (p-toluenesulfonyloxy) propionate
Was a compound having the following physical properties.¹ H-NMR (CCl_Four) δ: 1.17 (t, 3H), 2.40 (s, 3H), 4.
14 (q, 2H), 5.27 (q, 1H), 7.29 (d, 2H), 7.45
(d, 2H) ppm.¹⁹ F-NMR (CCl_Four) δ: -4.60 (d) ppm. IR (neat): 1765cm_- ¹.MS (m / e): 326.

Ethyl 3,3,3-trifluoro-2- (p-toluenesulfonyloxy) propionate 2.5 g (10 mmo
l) was dissolved in 20 ml of benzene, 2.0 g of aluminum chloride (15 mmol) was added, and the mixture was stirred for 2 hours. afterwards,
The reaction solution was slowly added to a thin aqueous solution of sodium carbonate, the aqueous phase was separated, hydrochloric acid was added to this, and the mixture was extracted with methylene chloride and concentrated under reduced pressure to obtain 3,3,3-trifluoro-2- (p- The toluene portion of ethyl (toluenesulfonyloxy) propionate was hydrolyzed, and ethyl 3,3,3-trifluoro-2-hydroxypropionate having the following physical properties had a yield of 90% or more as the only product. Obtained in. ¹ H-NMR (CCl ₄ ) δ: 1.33 (t, 3H), 4.31 (q, 2H), 4.
42 (s, 1H), 4.50 (q, 1H) ppm 19 F-NMR (CDCl 3) δ: -2.50 (d) ppm IR (neat):.. 3480,1750cm - 1.

[0020]Example 2  [3,3,3-trifluoro-2- (p-toluenesulfonyl
Synthesis of (oxy) propionic acid] 3,3,3-trifluoro-synthesized from trifluorolactic acid
2- (p-toluenesulfonyloxy) propionic acid 1-me
Nethyl was a compound having the following physical properties.¹ H-NMR (CDCl₃) δ: 0.40 to 2.20 (m, 18H), 2.45
(s, 3H), 4.40 to 4.90 (m, 1H), 5.10 (q, 2H), 7.
25 (d, 2H), 7.75 (d, 2H) ppm.¹⁹ F-NMR (CDCl3) δ: -5.00 (d) ppm. IR (neat): 1750cm_- ¹.

2.2 g of 1-menthyl 3,3,3-trifluoro-2- (p-toluenesulfonyloxy) propionate
(5 mmol) was dissolved in 10 ml of benzene, 1.0 g (7.25 mmol) of aluminum chloride was added, and the mixture was stirred for 2 hours. Then, the reaction solution was slowly added to a dilute aqueous solution of sodium carbonate, the aqueous phase was separated, hydrochloric acid was added thereto, and the mixture was extracted with methylene chloride and concentrated under reduced pressure to obtain 3,3,3-trifluoro-2- ( p-Toluenesulfonyloxy) propionate l-menthyl carboxylate moiety of which is hydrolyzed to give 3,3,3-trifluoro-2- (p
-Toluenesulfonyloxy) propionic acid was obtained as the only product in a yield of around 60%. Melting point: 101 to 104 ° C. ¹ H-NMR (CDCl ₃ ) δ: 2.43 (s, 3H), 5.21 (q, 2H), 7.
27 (d, 2H), 7.77 (d, 2H) ppm 19 F-NMR (CDCl 3) δ: 0.55 (d) ppm IR (neat):.. 3400,1740cm - 1.

[0022]Example 3  [3,3,3-trifluoro-2- (p-toluenesulfonyl
Synthesis of (oxy) propionic acid] 3,3,3-trifluoro-synthesized from trifluorolactic acid
2- (p-toluenesulfonyloxy) propionic acid cyclo
Hexyl was a compound having the following physical properties.¹ H-NMR (CDCl₃) δ: 0.89 to 2.07 (m, 10H), 2.44
(s, 3H), 4.78 (br, 1H) 5.09 (q, 1H), 7.09 to 7.
99 (m, 4H) ppm.¹⁹ F-NMR (CDCl₃) δ: -6.60 (d) ppm.

Cyclohexyl 3,3,3-trifluoro-2- (p-toluenesulfonyloxy) propionate 2.
After dissolving 0 g (5 mmol) in 10 ml of benzene, 1.0 g (7.25 mmol) of aluminum chloride was added and the mixture was stirred for 2 hours. Then, the reaction solution was slowly added to a dilute aqueous solution of sodium carbonate, the aqueous phase was separated, hydrochloric acid was added to this, and the mixture was extracted with methylene chloride and concentrated under reduced pressure to obtain 3,3,
Only 3,3,3-trifluoro-2- (p-toluenesulfonyloxy) propionic acid is obtained by hydrolyzing the carboxylate moiety of cyclohexyl 3-trifluoro-2- (p-toluenesulfonyloxy) propionate. Was obtained in 63% yield.

[0024]Example 4  3,3,3-Trifluoro-2- (o-nitrobenzenesulfoni
Synthesis of (roxy) propionic acid)

3,3,3-synthesized from trifluorolactic acid
Trifluoro-2- (o-nitrobenzenesulfonyloxy)
L-menthyl propionate was a compound having the following physical properties. ¹ H-NMR (CDCl ₃ ) δ: 0.47 to 3.30 (m, 18H), 4.77
(br, 1H), 5.43 (q, 1H) 7.50-8.38 (m, 4H) ppm. ¹⁹ F-NMR (CDCl ₃ ) δ: −5.63 (d) ppm.

2.4 g (5 mmol) of 1-menthyl 3,3,3-trifluoro-2- (o-nitrobenzenesulfonyloxy) propionate was dissolved in 10 ml of benzene, and then 1.0 g (7.25 mmol) of aluminum chloride was added. ) Was added and stirred for 2 hours. Then, the reaction solution was slowly added to a dilute aqueous solution of sodium carbonate, the aqueous phase was separated, hydrochloric acid was added to this, and the mixture was extracted with methylene chloride and concentrated under reduced pressure to obtain 3,3,
3-Trifluoro-2- (o-nitrobenzenesulfonyloxy) propionate l-menthyl carboxylate, which is hydrolyzed at the carboxylate moiety, has the following physical properties: 3,3,3-trifluoro-2- (o-nitrobenzenesulfonyloxy) ) Propionic acid was obtained as the only product in a yield of 64%. ¹ H-NMR (CDCl ₃ ) δ: 5.48 (s, 1H), 7.58 to 8.30
.. (m, 4H), 11.88 (q, 1H) ppm 19 F-NMR (CDCl 3) δ: -4.33 (d) ppm IR (neat): 3550,1760cm - 1.

[0027]Example 5  [3,3,3-trifluoro-2- (o-nitrobenzenesulfon
Synthesis of (nyloxy) propionic acid]

3,3,3-synthesized from trifluorolactic acid
Trifluoro-2- (o-nitrobenzenesulfonyloxy)
Cyclohexyl propionate was a compound having the following physical properties. ¹ H-NMR (CDCl ₃ ) δ: 1.00 to 2.11 (m, 10H), 4.86
(br, 1H), 5.39 (q, 1H) 7.59-8.26 (m, 4H) ppm. ¹⁹ F-NMR (CDCl ₃ ) δ: −5.33 (d) ppm.

After dissolving 2.1 g (5 mmol) of cyclohexyl 3,3,3-trifluoro-2- (o-nitrobenzenesulfonyloxy) propionate in 10 ml of benzene, 1.0 g (7.25 mmol) of aluminum chloride was added. Addition and stirring for 2 hours. After that, the reaction solution was slowly added to a dilute aqueous solution of sodium carbonate, the aqueous phase was separated, hydrochloric acid was added to this, extraction was performed with methylene chloride, and the mixture was concentrated under reduced pressure.
3,3-Trifluoro-2- (o-nitrobenzenesulfonyloxy) cyclohexyl propionate carboxylate moiety of 3,3,3-trifluoro-2- (o-
Nitrobenzenesulfonyloxy) propionic acid was obtained as the only product in a yield of 74%.

[0030]Example 6  [3,3,3-trifluoro-2- (methanesulfonyloxy
Si) Synthesis of propionic acid] 3,3,3-trifluoro-synthesized from trifluorolactic acid
2- (Methanesulfonyloxy) propionate l-menthyl
Was a compound having the following physical properties.¹ H-NMR (CDCl₃) δ: 0.53 to 2.33 (m, 20H), 3.21
(s, 3H), 5.26 (q, 1H) ppm.¹⁹ F-NMR (CDCl₃) δ: −5.57 (d) ppm.

1.9 g (5 mmo of 1-menthyl 3,3,3-trifluoro-2- (methanesulfonyloxy) propionate)
l) was dissolved in 10 ml of benzene, 1.0 g (7.25 mmol) of aluminum chloride was added, and the mixture was stirred for 2 hours. Then, the reaction solution was slowly added to a dilute aqueous solution of sodium carbonate, the aqueous phase was separated, hydrochloric acid was added thereto, and the mixture was extracted with methylene chloride and concentrated under reduced pressure to obtain 3,3,3-trifluoro-2- ( Methanesulfonyloxy) propionic acid
-The hydrolyzed carboxylate part of menthyl has the following physical properties 3,3,3-trifluoro-2- (methanesulfonyloxy) propionic acid as the only product 60%
It was obtained with a yield of. ¹ H-NMR (CDCl ₃ ) δ: 3.32 (s, 1H), 5.45 (q, 1H), 8.
. 17 (s, 3H) ppm 19 F-NMR (CDCl 3) δ: -5.57 (d) ppm IR (neat):. 3560,1750cm - 1.

[0032]Example 7  [3,3,3-trifluoro-2- (methanesulfonyloxy
Si) Synthesis of propionic acid] 3,3,3-trifluoro-synthesized from trifluorolactic acid
2- (Methanesulfonyloxy) propionic acid cyclohexyl
Sil was a compound having the following physical properties.¹H-N
MR (CDCl₃) δ: 3.17 (s, 3H), 4.96 (br, 1H), 5.2
7 (q, 1H) ppm.

1.6 g (5 parts) of this cyclohexyl 3,3,3-trifluoro-2- (methanesulfonyloxy) propionate
(mmol) was dissolved in 10 ml of benzene, 1.0 g (7.25 mmol) of aluminum chloride was added, and the mixture was stirred for 2 hours. Then, the reaction solution was slowly added to a dilute aqueous solution of sodium carbonate, the aqueous phase was separated, hydrochloric acid was added thereto, and the mixture was extracted with methylene chloride and concentrated under reduced pressure to obtain 3,3,3-trifluoro-2- ( Methanesulfonyloxy) 3,3,3-trifluoro-2- (methanesulfonyloxy) in which the carboxylate moiety of cyclohexyl propionate is hydrolyzed
Propionic acid was obtained as the only product in a yield of 47%.

[0034]

INDUSTRIAL APPLICABILITY According to the present invention, trifluorolactic acid derivatives, which are industrially useful fluorine-containing raw material compounds, can be produced simply and efficiently, that is, at low cost, and various optically active trifluorolactic acid derivatives can be easily obtained. As a result, it becomes extremely easy to produce an organic compound such as a physiologically active substance using this trifluorolactic acid derivative as a raw material.

Claims (4)

[Claims] 1. The following general formula 1 (Wherein R represents an alkyl group having a linear, branched, or cyclic structure, and X represents an alkylsulfonyl group or an arylsulfonyl group), and a trifluorolactic acid ester represented by The following general formula (2) or (3) is characterized by being used for hydrolysis. [Chemical 3] A method for producing a trifluorolactic acid derivative represented by the formula (X and R in the formula are the same as those in Chemical formula 1). 2. A method for producing a trifluorolactic acid derivative, wherein the acidic compound according to claim 1 is aluminum chloride. 3. R in the trifluorolactic acid ester represented by the general formula 1 according to claim 1 is an alkyl group having a primary linear, branched or cyclic structure. The method for producing the trifluorolactic acid derivative represented by the general formula 2 according to claim 1. 4. The R in the trifluorolactic acid ester represented by the general formula 1 according to claim 1 is an alkyl group having a secondary linear, branched or cyclic structure. The method for producing the trifluorolactic acid derivative represented by the general formula 3 according to claim 1. [0001]