JP2002371028A - Method for producing 3,3,3-trifluoro-2-hydroxypropionic acid derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a producing method capable of efficiently obtaining a 3,3,3-trifluoro-2-hydroxypropionic acid derivative which is an important intermediate for medicines and agrochemicals. SOLUTION: 1,1,1-Trichloro-3,3,3-trifluoro-2-propanol derivative is reacted with a base in methanol to produce a 3,3,3-trifluoro-2-methoxypropionic acid derivative, which is further demethylated to efficiently produce a 3,3,3- trifluoro-2-hydroxypropionic acid derivative.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing a 3,3,3-trifluoro-2-hydroxypropionic acid derivative, which is an important intermediate of medicines and agricultural chemicals.

[0002]

2. Description of the Related Art 3,3,3-Trifluoro-2-hydroxypropionic acid derivatives are important intermediates for pharmaceuticals and agricultural chemicals. As a method for producing the hydroxypropionic acid derivative, trifluoroacetone or 2,2,2-
Method for hydrolyzing cyanohydrin of trifluoroacetophenone (J. Chem. Soc., 2329 (1951), J. Org. Ch.
em., 34, 2543 (1969)), a method of reacting methyl trifluoropyruvate with dimethylcadmium or diphenylcadmium (Zh. Org. Khim., 23, 1441 (198
7)), a method of reacting CF ₃ CPh (OH) CF ₂ Cl with potassium hydroxide in water (Tetrahedron, 30, 3539)
(1974)). These conventional techniques have problems as production methods, such as the necessity of a highly toxic cyanide compound or cadmium compound (), and the burden of the by-produced fluorine ions on the glass material of the reaction vessel ().

[0003] As a related technique, Zh. Org. Khim., 1
By reacting CF ₃ CR (OH) CF ₂ Cl with potassium hydroxide in methanol on 1,961 (1975), 3,3,3-trifluoro-2- represented by the general formula [2] is obtained.
Although a reaction example for producing a methoxypropionic acid derivative has been reported, also in this reaction example, there are restrictions on the materials that can be used because fluorine ions are by-produced.

The 1,1,1-trichloro-3,3,3-trifluoro-2-propanol derivative represented by the general formula [1], which is the object of the present invention, is reacted with a base in methanol to give a general compound. 3,3,3 represented by the formula [2]
A method for producing a trifluoro-2-methoxypropionic acid derivative has not been reported. Further, by demethylating the 3,3,3-trifluoro-2-methoxypropionic acid derivative represented by the general formula [2], the 3,3,3-trifluoro-derivative represented by the general formula [3] is demethylated. A method for producing a 2-hydroxypropionic acid derivative has not been reported.

[0005]

SUMMARY OF THE INVENTION The present invention provides a novel method for producing a 3,3,3-trifluoro-2-hydroxypropionic acid derivative which solves the problems of the prior art.

[0006]

The present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, have found that 1,1,1-trichloro-3,3,3-trifluoro-2-propanol derivative. Is reacted with a base in methanol to produce a 3,3,3-trifluoro-2-methoxypropionic acid derivative. Further, by demethylating the methoxypropionic acid derivative, 3,3,3 -Trifluoro-2-hydroxypropionic acid derivative can be produced.

In the present invention, since the trichloromethyl group is decomposed and converted into a carboxyl group or a methoxycarbonyl group, the load or restriction on the material of the reaction vessel is reduced.

That is, the present invention provides (1) a general formula [1]

[0009]

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[Wherein R represents an alkyl group or an aryl group], 1,1,1-trichloro-3,3
By reacting a 3-trifluoro-2-propanol derivative with a base in methanol, the general formula [2]

[0011]

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Wherein R represents an alkyl group or an aryl group and R ¹ represents a hydrogen atom or a methyl group, and a method for producing a 3,3,3-trifluoro-2-methoxypropionic acid derivative represented by the formula: It is.

Further, the present invention provides (2) a general formula [2]

[0014]

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Wherein R represents an alkyl group or an aryl group, and R ¹ represents a hydrogen atom or a methyl group. The 3,3,3-trifluoro-2-methoxypropionic acid derivative represented by the formula By doing, the general formula [3]

[0016]

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This is a method for producing a 3,3,3-trifluoro-2-hydroxypropionic acid derivative represented by the formula: wherein R represents an alkyl group or an aryl group.

Further, the present invention is (3) the above-mentioned production method wherein demethylation is performed using hydrobromic acid.

The present invention also provides (4) a compound represented by the general formula [1]:
[2] or [3], wherein the substituent R is a methyl group.

The present invention also provides (5) a compound represented by the general formula [1]:
In the above production method, wherein the substituent R is a phenyl group in [2] or [3].

[0021]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, a method for producing a 3,3,3-trifluoro-2-hydroxypropionic acid derivative of the present invention will be described in detail.

The production method of the present invention comprises reacting a 1,1,1-trichloro-3,3,3-trifluoro-2-propanol derivative with a base in methanol,
A first step of producing a 3,3,3-trifluoro-2-methoxypropionic acid derivative and demethylation of the methoxypropionic acid derivative to obtain 3,3,3-trifluoro-2-hydroxypropionic acid It comprises a second step of producing the derivative.

In the first step of the present invention, the general formula [2]
The 3,3,3-trifluoro-2-methoxypropionic acid derivative represented by can be efficiently produced by the following method.

The alkyl substituent of the 1,1,1-trichloro-3,3,3-trifluoro-2-propanol derivative represented by the general formula [1] includes a methyl group, an ethyl group, an n-propyl group, i-propyl group, n-butyl group,
Examples thereof include an i-butyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, an n-hexyl group, an n-heptyl group, and an n-octyl group. Examples of the aryl substituent include a phenyl group, a lower alkyl group-substituted phenyl group, a lower alkoxy group-substituted phenyl group, and a halogen atom-substituted phenyl group. The lower alkyl group or the lower alkoxy group represents a linear or branched alkyl group or an alkoxy group having 1 to 6 carbon atoms, and the halogen atom represents fluorine, chlorine, bromine or iodine.

The 1,1,1-trichloro-3,3,3-trifluoro-2-propanol derivative represented by the general formula [1] is 1,1,1-trichloro-1 ′, 1 ′, 1 ′
Reaction with a Grignard reagent (RMgX / X = Cl, Br or I) corresponding to trifluoroacetone, or 1,1,1-trichloro-1 ′, 1 ′, 1′-triamine in the presence of a Lewis acid It can be easily produced by a Friedel-Crafts reaction between fluoroacetone and a corresponding aromatic compound (JP-A-11-228470).

Examples of the base include sodium hydroxide, potassium hydroxide, sodium methoxide, potassium methoxide and the like.

The amount of the base used is 1,1,1-trichloro-3,3,3-trifluoro-formula represented by the general formula [1].
It is sufficient to use at least 3 molar equivalents per 1 mol of the 2-propanol derivative, preferably 3 to 50 molar equivalents, particularly preferably 3 to 20 molar equivalents.

The amount of methanol used should be at least 1 volume per 1 volume of the 1,1,1-trichloro-3,3,3-trifluoro-2-propanol derivative represented by the general formula [1]. Good, preferably 1 to 50 volumes, especially 1
-20 volumes are more preferred.

The reaction can be carried out at a temperature in the range of 0 ° C. to around the boiling point of methanol, preferably 30 to 65 ° C.

This reaction is carried out by adding methanol, a base and 1,1,1-trichloro-3,3,3 represented by the general formula [1].
A method of dissolving a trifluoro-2-propanol derivative and gradually raising the temperature; adding 1,1,1-trichloro-3,3,3-trifluoro-2-propanol derivative represented by the general formula [1] to methanol Dissolving and successively dropping a base, Dissolving the base in methanol and successively dropping a 1,1,1-trichloro-3,3,3-trifluoro-2-propanol derivative represented by the general formula [1] It can be performed by any of them, and may be used properly as appropriate.

In the post-treatment, a crude product can be obtained by performing a usual post-treatment operation after the completion of the reaction. The crude product may be subjected to purification operations such as activated carbon, distillation, recrystallization, and column chromatography, if necessary, to obtain a product of high chemical purity.

In the second step of the present invention, the general formula [3]
The 3,3,3-trifluoro-2-hydroxypropionic acid derivative represented by the following formula can be efficiently produced by the following method.

As demethylating agents, trimethylsilyl iodide (Me ₃ SiI), boron tribromide (BB)
r ₃ ), hydrobromic acid and the like. Among them, hydrobromic acid is more preferred.

The amount of the demethylating agent to be used may be 1 mole equivalent or more based on 1 mole of the 3,3,3-trifluoro-2-methoxypropionic acid derivative represented by the general formula [2]. 1 to 50 molar equivalents are preferred, especially 1 to 20
Molar equivalents are more preferred.

Examples of the reaction solvent include aliphatic hydrocarbons such as n-pentane, n-hexane, c-hexane and n-heptane, aromatic hydrocarbons such as benzene, toluene, xylene and mesitylene, methylene chloride, chloroform. , 1,
Halogenated hydrocarbons such as 2-dichloroethane, ethers such as diethyl ether and dioxane, ethyl acetate,
Esters such as n-butyl acetate; nitriles such as acetonitrile and propionitrile; alcohols such as methanol, ethanol, n-propanol and i-propanol; and water. These reaction solvents can be used alone or in combination. This reaction can also be performed without using a reaction solvent.

When the reaction solvent is used, the amount of the solvent used may be at least 1 volume per 1 volume of the 3,3,3-trifluoro-2-methoxypropionic acid derivative represented by the general formula [2]. , 1 to 50 volumes, preferably 1 to 2 volumes
Zero volume is more preferred.

The reaction can be carried out at a temperature in the range of 0 ° C. to 200 ° C., preferably 50 to 150 ° C.

In the post-treatment, a crude product can be obtained by performing ordinary post-treatment operations after the completion of the reaction. The crude product may be subjected to purification operations such as activated carbon, distillation, recrystallization, and column chromatography, if necessary, to obtain a product of high chemical purity.

[0039]

EXAMPLES Hereinafter, the embodiments of the present invention will be described specifically with reference to examples, but the present invention is not limited to these examples.

[Reference Example 1, Examples 1 and 2]
-Trifluoro-2-hydroxy-2-methylpropionic acid [Reference Example 1] 1,1,1-trichloro-3,3,3-
Under a nitrogen atmosphere, trifluoro-2-methyl-2-propanol was added to 1425 ml of tetrahydrofuran.
1,382 g (6.41 mol, 1 eq) of 1,1,1-trichloro-1 ′, 1 ′, 1′-trifluoroacetone
While controlling the internal temperature at -7 to -14 ° C, 3112 ml (6.41 mol, 1e) of a tetrahydrofuran solution of methylmagnesium chloride (2.06M).
q) was added, and the mixture was further stirred at -10 ° C for 30 minutes. At the same temperature, 3000 ml of 2.14N hydrochloric acid was added, and the organic layer was dried over anhydrous sodium sulfate and distilled under reduced pressure (60-66 ° C /
40 mmHg) to obtain 1,
1,1-trichloro-3,3,3-trifluoro-2-
1,589 g of methyl-2-propanol was obtained (containing 25 wt% of THF). ^The yield calculated from ¹ H-NMR was 8
0% and GC purity was 98.5%.

[0041]

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¹ H-NMR (TMS, CDCl ₃ ):
82 (s, 3H), 3.81 (br, 1H).

Example 1 3,3,3-trifluoro-2-methoxy-2-methylpropionic acid (first step) The reaction and post-treatment were carried out using a glassy reaction vessel.

Under ice cooling, 1885 g (33.60 mol, 7e) of potassium hydroxide was added to 6720 ml of methanol.
q) while dissolving and controlling the internal temperature to 55 to 60 ° C.
The 1,1,1-trichloro-3, produced in Reference Example 1
3,481 g of 3,3-trifluoro-2-methyl-2-propanol (containing 25 wt% of THF, 4.80 mol
l, 1 eq) over 7 hours and then at 50-60 ° C
For 5 hours. After cooling to room temperature, the precipitated inorganic salt was filtered, the filtrate was concentrated under reduced pressure, the residue was dissolved in 2,000 ml of water, washed with 1000 ml of toluene, and concentrated hydrochloric acid was added until the pH of the collected aqueous layer became 1; More water 15
Then, the organic layer was washed with 2,000 ml of saturated saline, dried over anhydrous sodium sulfate, concentrated under reduced pressure, the residue was filtered through celite, washed with 50 ml of ethyl acetate, and the filtrate was added. Was concentrated under reduced pressure to give 3,3,3-trifluoro-2-
750 g of methoxy-2-methylpropionic acid was obtained. ¹⁹
The yield calculated from F-NMR was 54%, and the GC purity was 8
0.5%.

[0045]

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¹ H-NMR (TMS, CDCl ₃ ):
65 (s, 3H), 3.51 (s, 3H), 9.90
(Br, 1H).

Example 2 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid (second step) 3102 g of hydrobromic acid (18.02 mol, 7 eq)
750 g of 3,3,3-trifluoro-2-methoxy-2-methylpropionic acid produced in [Example 1]
(2.57 mol, 1 eq) was added and the internal temperature was set to 11
It was set at 0 ° C. and stirred for 21 hours. Under ice-cooling, sodium hydroxide was added until the pH of the reaction-terminated liquid reached 1, and the mixture was extracted twice with 1,000 ml of ethyl acetate.
The extract was washed with 2,000 ml of a saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 475 g of 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid represented by the following formula. ^The yield calculated from ¹⁹ F-NMR was quantitative.

[0048]

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¹ H-NMR (TMS, CDCl ₃ ):
67 (s, 3H), 5.65 (br, 2H).

Examples 3 and 4 3,3,3-trifluoro-2-hydroxy-2-phenylpropionic acid

Example 3 3,3,3-Trifluoro-2-methoxy-2-phenylpropionic acid (first step) The reaction and post-treatment were carried out using a glassy reaction vessel.

In 10 ml of methanol, 1,1,1-trichloro-3,3,3-trifluoro-2-phenyl-
1.06 g of 2-propanol (3.60 mmol, 1
eq) and 2.52 g (36.00) of potassium methoxide
mmol, 10 eq), the temperature was gradually raised to 60 ° C., and the mixture was stirred at the same temperature for 6.5 hours. The mixture was cooled to room temperature, 5 ml of water was added, and the mixture was stirred at room temperature for 1 hour. The reaction-terminated liquid was poured into 50 ml of water, concentrated hydrochloric acid was added until the pH of the aqueous layer became 1, extracted twice with 30 ml of ethyl acetate, and the organic layer was washed with 20 ml of saturated saline and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure, and 3,3,3-trifluoro-2-methoxy-2-phenylpropionic acid represented by the following formula was added to 7
50 mg were obtained. ^The yield calculated from ¹⁹ F-NMR was 77%.
Met.

[0053]

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Example 4 3,3,3-trifluoro-2-hydroxy-2-phenylpropionic acid (second step) 2.39 g of hydrobromic acid (13.86 mmol, 5e)
q) is 750 of 3,3,3-trifluoro-2-methoxy-2-phenylpropionic acid produced in [Example 3].
mg (1 eq to 2.77 mmol) was added, the internal temperature was set to 110 ° C., and the mixture was stirred for 18 hours. Under ice cooling, sodium hydroxide was added until the pH of the reaction-terminated liquid reached 1,
Extract twice with 5 ml of ethyl acetate to reduce the organic layer to 10 wt%.
The extract was washed with 5 ml of brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and 3,3,3-trifluoro-2-hydroxy-2-phenylpropionic acid represented by the following formula was added to 6
50 mg were obtained. ^The yield calculated from ¹⁹ F-NMR was quantitative.

[0055]

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[0056]

Industrial Applicability The important intermediates of pharmaceuticals and pesticides, 3,
A 3,3-trifluoro-2-hydroxypropionic acid derivative can be obtained efficiently.

 ──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Manabu Yasumoto 2805 Imafukunakadai, Kawagoe-shi, Saitama Prefecture Central Research Laboratory of Glass Co., Ltd. (72) Inventor Katsura Kuriyama 2805 Imafukunakadai, Kawagoe-shi, Saitama Central Inside Glass Chemical Company (72) Inventor Takashi Hayami 2805 Imafukunakadai, Kawagoe City, Saitama Prefecture Central Glass Glass Company Chemical Research Laboratory (72) Koji Kume 2805 Imafuku Nakadai, Kawagoe City, Saitama Central Glass Stock (72) Inventor Hideaki Imura 2805 Imafukunakadai, Kawagoe-shi, Saitama F-term (reference) in Chemical Laboratory, Central Glass Co., Ltd. 4H006 AA02 AC41 AC46 AC48 BA66 BB14 BC10 BC35 BE10 BM10 BM71 BN10 BP10 BS10 4H039 CA60 CA61 CA65 CA66 CE10 CE20

Claims (5)

[Claims] 1. A compound of the general formula [1] By reacting the 1,1,1-trichloro-3,3,3-trifluoro-2-propanol derivative represented by the formula [wherein R represents an alkyl group or an aryl group] with a base in methanol, Formula [2] [Wherein, R represents an alkyl group or an aryl group, R ¹
Represents a hydrogen atom or a methyl group].
A method for producing a 3-trifluoro-2-methoxypropionic acid derivative. 2. A compound of the general formula [2] [Wherein, R represents an alkyl group or an aryl group, R ¹
Represents a hydrogen atom or a methyl group].
By demethylating the 3-trifluoro-2-methoxypropionic acid derivative, a compound of the general formula [3] [Wherein, R represents an alkyl group or an aryl group], a method for producing a 3,3,3-trifluoro-2-hydroxypropionic acid derivative represented by the following formula: 3. The method according to claim 2, wherein the demethylation is performed using hydrobromic acid. 4. The method according to claim 1, wherein in the general formula [1], [2] or [3], the substituent R is a methyl group. 5. The production method according to claim 1, wherein in the general formula [1], [2] or [3], the substituent R is a phenyl group.