JP2000143581A - Production of hydroxy acid derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To simply and inexpensively obtain a hydroxy acid derivative which is useful as an intermediate for medicines, perfumes, dyes, and so on by treating a specific dialkyl dicyanomethylphosphonate derivative with an acid and so on. SOLUTION: A hydroxy acid derivative shown by formula II (e.g. 2- hydroxycaproic acid) is obtained by treating a dialkyl dicyanomethylphosphonate derivative shown by formula I [R1 is a (substituted) lower alkyl, a (substituted) lower alkenyl or the like; R2 is a (substituted) lower alkyl] (e.g. diethyl 1,1- dicyanopentylphosphonate) with an acid or base (preferably hydrochloric acid or the like) preferably with heating and refluxing for several to 48 h or so. The compound shown by formula I is obtained by reacting a compound shown by the formula: R1-COOH (preferably valeric acid or the like) with a compound shown by the formula: NCP(O)(OR2)2 (e.g. diethyl cyanophosphonate) preferably in the presence of a base such as a trialkylamine (preferably triethylamine or the like).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel industrially excellent method for producing an .alpha.-hydroxy acid which is useful as a pharmaceutical, a fragrance or a dye intermediate.

[0002]

BACKGROUND OF THE INVENTION Glycolic acid, lactic acid, malic acid, tartaric acid,
Α-Hydroxy acids such as citric acid are natural products and can be extracted from natural materials, but conventionally, they have been mainly produced by the following synthetic methods. (1) Oxidation of glycol and the like. (2) Reduction of aldehyde acids, keto acids, dicarboxylic acids, etc. (3) Heat the unsaturated fatty acid and the aqueous alkali solution. (4) Heat the halogenated fatty acid with an aqueous alkali solution or silver hydroxide. (5) Hydrogen cyanide is added to aldehyde or ketone to hydrolyze generated cyanohydrin.

[0003]

[Problems to be solved by the present invention] However, it is difficult to obtain a high-purity product by extraction from natural materials. On the other hand, the above-mentioned synthesis method is not industrially necessary in terms of production cost, work safety and environmental measures. It was not a satisfactory method. In the method of (2) (3) (4) (5), aldehyde,
Ketones, keto acids, halogenated fatty acids, and the like are unstable and need to be prepared as needed, and there is a problem that it is difficult to obtain large quantities for industrial use. As described above, at present, an industrially excellent method for producing an α-hydroxy acid has not yet been established, and a new excellent method has been demanded.

[0004]

Means for Solving the Problems The present inventors have intensively studied to improve the above problems. as a result,
It has been found that the desired α-hydroxy acid can be obtained easily and inexpensively by any of the following methods, and the present invention has been completed. (1) The dialkyl dicyanomethylphosphonate derivative (I) is treated with an acid or a base. (2) The carboxylic acid derivative (III) is reacted with a dialkyl cyanophosphonate derivative (IV) in the presence of a base to obtain a dialkyl dicyanomethylphosphonate derivative (I), which is further treated with an acid or a base. Therefore, the present invention provides an industrially excellent method for producing an α-hydroxy acid.

Next, the present invention will be described in detail. The present invention is a method for producing the α-hydroxy acid (II) represented by the above (1) or (2), and is represented by the following chemical reaction formula.

[0006]

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In the formula, R ¹ and R ² have the same meaning as described above. Here, the dialkyl dicyanomethylphosphonate derivative (I) according to the present invention is a novel compound represented by the following general formula, and is important as a production intermediate in the present invention.

[0008]

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Wherein R ¹ is an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, an optionally substituted lower cycloalkyl group, It means an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted aralkyl group or an optionally substituted heteroarylalkyl group.

Here, R ¹ is more specifically defined as, for example, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a lower cycloalkyl group, a lower halogenated alkyl group, a lower alkoxyalkyl group, a hydroxy lower alkyl group, Lower alkoxycarbonylalkyl group, cyano lower alkyl group, nitro lower alkyl group, lower alkylthioalkyl group, mercapto lower alkyl group, lower acylalkyl group, amino lower alkyl group optionally substituted with a nitrogen atom, ring containing a hetero atom Groups derived from
Aryl group, lower alkylaryl group, lower alkoxyaryl group, halogenated aryl group, cyanoaryl group, nitroaryl group, hydroxyaryl group, mercaptoaryl group, acylaryl group, heteroaryl group, lower alkylheteroaryl group, lower alkoxy Heteroaryl group, halogenated heteroaryl group, cyanoheteroaryl group, nitroheteroaryl group, hydroxyheteroaryl group, mercaptoheteroaryl group, acylheteroaryl group, aralkyl group, lower alkylaralkyl group, lower alkoxyaralkyl group, halogenated Aralkyl groups, cyanoaralkyl groups, nitroaralkyl groups, hydroxyaralkyl groups, mercaptoaralkyl groups, acylaralkyl groups, heteroarylalkyl groups,
Lower alkyl heteroarylalkyl group, lower alkoxyheteroarylalkyl group, halogenated heteroarylalkyl group, cyanoheteroarylalkyl group, nitroheteroarylalkyl group, hydroxyheteroarylalkyl group, mercaptoheteroarylalkyl Group or acylheteroarylalkyl group.

Next, R ² represents a lower alkyl group which may be substituted. The lower alkyl group in the present invention is
A chain or branched alkyl group having 1 to 6 carbon atoms, for example, a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, a t-butyl group , A pentyl group, a hexyl group and the like. In the lower alkyl group for R ² , an ethyl group is more preferable.

Here, specific examples of the dialkyl dicyanomethylphosphonate derivative (I) include, for example, the following compounds, but the present invention is not limited thereto. (1) Diethyl 1,1-dicyanopentylphosphonate (2) Diethyl 1,1-dicyano-2-methylpropylphosphonate (3) Diethyl 1,1-dicyano-2,2-dimethylpropylphosphonate (4) Dicyano Diethyl cyclohexylmethylphosphonate (5) Diethyl 1,1-dicyano-3-methylthiopropylphosphonate (6) Diethyl dicyanophenylmethylphosphonate (7) Diethyl cyano (o-tolyl) methylphosphonate (8) Dicyano (p-tolyl) methylphosphonate Diethyl cyanate (9) Diethyl dicyano (3-methoxyphenyl) methylphosphonate (10) Diethyl dicyano (2-chlorophenyl) methylphosphonate (11) Diethyl dicyano (4-chlorophenyl) methylphosphonate

Next, the α-hydroxy acid (II) of the present invention
Is a target compound of the present invention, and is represented by the following general formula. (In the formula, R ¹ has the same meaning as described above.)

[0014]

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Specific examples of the α-hydroxy acid (II) include, for example, the following compounds, but the present invention is not limited thereto. (1) 2-hydroxycaproic acid (2) 2-hydroxy-3-methylbutyric acid (3) 2-hydroxy-3,3-dimethylbutyric acid (4) hexahydromandelic acid (5) 2-hydroxy-4- (methylthio ) Butyric acid (6) mandelic acid (7) 2-methylmandelic acid (8) 4-methylmandelic acid (9) 3-methoxymandelic acid (10) 2-chloromandelic acid (11) 4-chloromandelic acid

Subsequently, the carboxylic acid derivative according to the present invention (I
II) is represented by the general formula R ¹ -COOH. (In the formula, R ¹ has the same meaning as described above.) Specific examples of the carboxylic acid derivative (III) include, for example, the following compounds, but the present invention is not limited thereto. (1) n-valeric acid (2) isobutyric acid (3) pivalic acid (4) cyclohexanecarboxylic acid (5) 3-methylthiopropionic acid (6) benzoic acid (7) o-toluic acid (8) p-toluic acid (9) m-anisic acid (10) 2-chlorobenzoic acid (11) 4-chlorobenzoic acid The carboxylic acid derivative (III) can be obtained as a pharmaceutical raw material, a reagent, an industrial raw material, and the like.

Finally, the dialkyl cyanophosphonate derivative (IV) according to the present invention is represented by the general formula NCP (O) (OR ² ) ₂ . (Wherein, R ² has the same meaning as described above.) Specific examples of the dialkyl cyanophosphonate derivative (IV) include, for example, the following compounds, but the present invention is not limited thereto. (1) Dimethyl cyanophosphonate (2) Diethyl cyanophosphonate (3) Dipropyl cyanophosphonate
It is available as industrial raw materials, among which diethyl cyanophosphonate (Diethyl phosphorocyanidate, also known as D
iethyl cyanophosphonate, Diethylphosphoryl cyanid
e, [CAS Registry Number: 2942-58-7]) is common and gives favorable results.

Next, the reaction method of the present invention will be described.
In the present invention, first, the carboxylic acid derivative (III) and the dialkyl cyanophosphonate (IV) are reacted in the presence of a base to give a dialkyl dicyanomethylphosphonate.
(I) is obtained (step 1). Here, the order of adding the carboxylic acid derivative (III), the dialkyl cyanophosphonate derivative (IV) or the base is not limited, and may be any order. That is, for example, the following method is possible. (1) The carboxylic acid derivative (III) and the dialkyl cyanophosphonate derivative (IV) are mixed, and then a base is added. (2) The carboxylic acid derivative (III) and the base are mixed, and then the dialkyl cyanophosphonate derivative (IV) is added. (3) A dialkyl cyanophosphonate derivative (IV) is mixed with a base, and then a carboxylic acid derivative (III) is added.

The dialkyl cyanophosphonate derivative (I
Although the use amount of V) is not limited, in order to suppress a side reaction and react in a higher yield, the dialkyl cyanophosphonate derivative (IV) is used in an amount of 2 equivalents or more based on the carboxylic acid derivative (III). Is preferred.

The type of the base is not limited, but usually a monoalkylamine, dialkylamine, trialkylamine, N-monoalkylaniline, N, N-dialkylaniline or pyridine is preferable, and triethylamine is more preferable. The amount of the base to be used is not limited, either, but usually 0.8 to 5 equivalents, preferably 0.9 to 3 equivalents, more preferably 1.0 to 1.5 equivalents, relative to the carboxylic acid derivative (III).

The reaction solvent may be used or not used, but is preferably used to increase the stirring efficiency and facilitate the control of the reaction temperature. The solvent that can be used is not limited as long as it is a solvent inert to the carboxylic acid derivative (III) or the dialkyl cyanophosphonate derivative (IV), but is usually benzene, toluene, xylene, petroleum benzene, pentane, hexane, Petroleum ether, diethyl ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran (hereinafter, THF), dioxane, dioxolan, ethylene glycol dimethyl ether, chloroform, methylene chloride,
1,2-dichloroethane, acetonitrile, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, N, N-dimethylformamide (hereinafter, DMF), 1-methyl-2-pyrrolidone, dimethylsulfoxide (hereinafter, DMSO), hexamethylphosphon Amide (hereinafter, HMPA) etc. can be used, among which THF
Is more preferred.

Although the amount of the solvent used is not limited, it is generally used in an amount of 0 to 100 ml, more preferably 0.5 to 50 ml, and still more preferably 1 to 20 ml, per 1 g of the carboxylic acid derivative (III).

The reaction temperature is not limited, and the reaction can be usually carried out at a temperature not higher than the reflux temperature of the solvent. However, depending on the reactivity of the starting material, -78 to 150 ° C, preferably -50
~ 100 ° C, more preferably -40 ~ 30 ° C, most preferably
It can be selected from the range of -30 to 0 ° C.

The reaction time varies depending on the amount of the solvent used, the reaction temperature and the like, but is usually completed within 24 hours. After completion of the reaction, it can be purified by a conventional method such as recrystallization, various column chromatography, or distillation after washing, drying and concentration as appropriate. However, it can be used without purification in the next step. Furthermore, the reaction solution can be used for the next reaction without post-treatment.

In the present invention, the desired α-hydroxy acid (II) is then obtained by reacting with an acid or a base (step
2). This step is specifically a hydrolysis / decarboxylation reaction of a nitrile, and can be carried out in the presence of an acid or a base according to a conventional method. At this time, the kind of the acid or the base is not limited.
Examples thereof include hydroiodic acid, sulfuric acid, nitric acid, perchloric acid, and phosphoric acid. Examples of the base include sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, barium hydroxide, magnesium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogen carbonate and the like. Among these, hydrochloric acid is more preferred,
Concentrated hydrochloric acid is more preferred.

Here, the amount of the acid or base used is not limited, but in order to shorten the reaction time and to carry out the reaction in a higher yield, an excess amount of the acid or base relative to the dialkyl dicyanomethylphosphonate (I) is used. Is preferred.

The reaction solvent may be used or not used. Although the reaction temperature is not limited, the reaction is usually completed under heating and refluxing in several hours to 48 hours. After completion of the reaction, it can be purified by a conventional method such as recrystallization, various column chromatography, or distillation after washing, drying and concentration as appropriate.

Next, in order to specifically explain the present invention, examples will be given below, but it goes without saying that the present invention is not limited to these examples.

EXAMPLES Example 1 Synthesis of 2-hydroxycaproic acid

[0029]

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218 μl (2.0 mmol) of n-valeric acid was dissolved in 4 ml of THF, and cooled to −20 ° C., and diethyl cyanophosphonate 685 was dissolved.
μl (93%, 4.2 mmol) followed by 293 μl triethylamine (2.
1 mmol) was added. After stirring at −20 ° C. for 3 hours, the reaction solution was diluted with 30 ml of diethyl ether, washed twice with 20 ml of water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Silica gel column chromatography of the residue (hexane / ethyl acetate system)
To give 395 mg of diethyl 1,1-dicyanopentylphosphonate as a slightly yellow syrup. (Yield; 72%) ¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 4.21-4.34 (4H, m), 2.3
1-2.35 (2H, m), 1.64-1.71 (2H, m), 1.47 (2H, ddq, J = 7.6,7.
6,7.6Hz), 1.42 (6H, td, J = 7.2,0.8Hz), 0.99 (3H, t, J = 7.6H)
z). IRν _max (neat); 2965,2250,1284,1028cm ^-1 .

To 395 mg (1.4 mmol) of the above diethyl 1,1-dicyopentylphosphonate was added 5.8 ml of concentrated hydrochloric acid, and the mixture was refluxed for 12 hours. The reaction solution was extracted three times with 20 ml of diethyl ether, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 183 mg of the title compound as colorless crystals. (Yield; 96%) ¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 7.74 (1H, brs), 4.29 (1
H, brdd, J = 6.8,3.6Hz), 1.81-1.98 (1H, m), 1.66-1.75 (1H,
m) 、 1.29-1.51 (4H, m) 、 0.92 (3H, t, J = 7.2Hz). IRν _max (KBr); 3397,2958,1709,1252,1216,1084cm ^-1 . Melting point; 60 ° C

Example 2 2-Hydroxy-3-methylbutyric acid
Synthesis

[0033]

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185 μl (2.0 mmol) of isobutyric acid was dissolved in 4 ml of THF, and cooled to 0 ° C., and 685 μl of diethyl cyanophosphonate was dissolved.
(93%, 4.2 mmol), then 293 μl of triethylamine (2.1 mm
ol). After stirring at 0 ° C. for 3 hours, the reaction solution was diluted with 30 ml of diethyl ether, washed twice with 20 ml of water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate system) to obtain 437 mg of diethyl 1,1-dicyano-2-methylpropylphosphonate as a slightly yellow syrup. (Yield; 84%) ¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 4.22-4.35 (4H, m), 2.5
4 (1H, sept, J = 6.8Hz), 1.42 (6H, td, J = 7.2,1.2Hz), 1.29 (6
H, d, J = 6.8Hz) .IRν _max (neat); 2985,2250,1294,1024cm ^-1 .

To 420 mg (1.6 mmol) of the above diethyl 1,1-dicyano-2-methylpropylphosphonate was added 6.5 ml of concentrated hydrochloric acid, and the mixture was refluxed for 14 hours. The reaction solution is treated with diethyl ether 2
The mixture was extracted three times with 0 ml, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 181 mg of the title compound as colorless crystals. (Yield; 95
%) ¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 6.57 (2H, brs), 4.16 (1
H, d, J = 3.2Hz), 2.16 (1H, ttd, J = 7.2,6.8,3.2Hz), 1.06 (3H,
d, J = 7.2 Hz), 0.93 (3H, 6.8 Hz). IRν _max (KBr); 3434,2973,1712,1275,1129,1029 cm ⁻¹ . Melting point; 86 ° C.

Example 3 2-hydroxy-3,3-dimethylbutyric
Acid synthesis

[0037]

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204 μl (2.0 mmol) of pivalic acid was dissolved in 4 ml of THF, and 685 μl of diethyl cyanophosphonate was cooled to 0 ° C.
(93%, 4.2 mmol), then 293 μl of triethylamine (2.1 mm
ol). After stirring at 20 ° C. for 2 hours, the reaction solution was diluted with 30 ml of diethyl ether, washed twice with 20 ml of water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate system) to obtain 435 mg of diethyl 1,1-dicyano-2,2-dimethylpropylphosphonate as a slightly yellow syrup. (Yield; 7
9%) ¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 4.24-4.34 (4H, m), 1.4
2 (6H, td, J = 7.2,1.2Hz), 1.29 (9H, s) .IRν _max (neat); 2982,2251,1299,1028cm ^-1 .

To 435 mg (1.6 mmol) of the above diethyl 1,1-dicyano-2,2-dimethylpropylphosphonate was added 6.3 ml of concentrated hydrochloric acid, and the mixture was refluxed for 24 hours. The reaction solution is diethyl ether
Extraction was performed three times with 20 ml, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 195 mg of the title compound as colorless crystals. (Yield; 9
3%) ¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 6.81 (2H, brs), 3.91 (1
H, s), 1.03 (9H, s). IRν _max (KBr); 3423,2967,1721,1283,1224,1084cm ^-1 . Melting point; 85 ° C

Example 4 Synthesis of hexahydromandelic acid

[0041]

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248 μl of cyclohexanecarboxylic acid (2.0 mmo
l) was dissolved in 4 ml of THF, and while cooling to 0 ° C., 685 μl (93%, 4.2 mmol) of diethyl cyanophosphonate and then 293 μl (2.1 mmol) of triethylamine were added. After stirring at 0 ° C. for 3 hours, the reaction solution was diluted with 30 ml of diethyl ether, washed twice with 20 ml of water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane /
The residue was purified with ethyl acetate to give 462 mg of diethyl dicyanocyclohexylmethylphosphonate as a slightly yellow syrup. (Yield; 77%) ¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 4.21-4.34 (4H, m), 2.0
5-2.22 (3H, m), 1.88-1.98 (2H, m), 1.73-1.80 (1H, m), 1.42
(6H, td, J = 6.8,1.2Hz), 1.16-1.45 (5H, m) .IRν _max (neat); 2938,2250,1284,1028cm ^-1 .

To 462 mg (1.5 mmol) of the above diethyl dicyanocyclohexylmethylphosphonate was added 6.2 ml of concentrated hydrochloric acid,
The mixture was heated under reflux for 4 hours. The reaction solution was added with 20 ml of diethyl ether.
After extraction three times, drying over anhydrous magnesium sulfate, and concentration under reduced pressure, 195 mg of the title compound was obtained as colorless crystals. (Yield; 96%) ¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 6.17 (2H, brs), 4.12 (1
(H, d, J = 3.6Hz), 1.63-1.87 (5H, m), 1.47-1.58 (1H, m), 1.09-
1.38 (5H, m). IRν _max (KBr); 3439,2932,1716,1280,1232,1103cm ^-1 . Melting point; 134 ° C

Example 5 2-hydroxy-4- (methylthio)
Butyric acid synthesis

[0045]

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207 μl of 3-methylthiopropionic acid (2.0 mmo
l) was dissolved in 4 ml of THF, and while cooling to -40 ° C, 685 µl (93%, 4.2 mmol) of diethyl cyanophosphonate and then 293 µl (2.1 mmol) of triethylamine were added. After stirring at -40 ° C for 6 hours,
The reaction solution was diluted with 30 ml of diethyl ether, and diluted with 20 ml of water.
Washed twice, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate system) to give a slightly yellow syrup of 1,1.
-Dicyano-3-methylthiopropylphosphonic acid diethyl ester 4
24 mg were obtained. (Yield; 73%) ¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 4.16-4.29 (4H, m), 2.7
0-2.74 (2H, m), 2.55-2.59 (2H, m), 2.13 (3H, s), 1.36 (6H, t
d, J = 7.2, 1.2 Hz). IRν _max (neat); 2987, 2920, 2250, 1286, 1032 cm ⁻¹ .

To 424 mg (1.5 mmol) of the above diethyl 1,1-dicyano-3-methylthiopropylphosphonate was added 5.8 ml of concentrated hydrochloric acid, and the mixture was heated under reflux for 5 hours. The reaction solution is diethyl ether
The mixture was extracted five times with 20 ml, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Silica gel column chromatography of the residue
(Ethyl acetate) to give 186 mg of the title compound as colorless crystals. (Yield; 85%) ¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 4.45 (1 H, dd, J = 8.4,4.
0Hz), 2.69 (2H, dd, J = 7.2,7.2Hz), 2.17 (1H, tdd, J = 7.2,6.
8,4.0Hz), 2.12 (3H, s), 2.00 (1H, dtd, J = 8.4,7.2,6.8Hz) .IRν _max (KBr); 3365,2918,1731,1221,1093cm ^-1 .

Example 6 Synthesis of mandelic acid

[0049]

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244 mg (2.0 mmol) of benzoic acid was dissolved in 4 ml of THF, and cooled to −20 ° C., and 685 μl of diethyl cyanophosphonate was dissolved.
(93%, 4.2 mmol), then 293 μl of triethylamine (2.1 mm
ol). After stirring at −20 ° C. for 3 hours, the reaction solution was diluted with 30 ml of diethyl ether, washed twice with 20 ml of water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate system) to obtain 409 mg of pale yellow syrup of diethyl dicyanophenylmethylphosphonate. (Yield; 70%) ¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 7.78-7.81 (2H, m), 7.5
3-7.61 (3H, m), 4.17-4.30 (4H, m), 1.37 (6H, td, J = 7.2,1.2H
z). IRν _max (neat); 2988,2248,1281,1024 cm ^-1 .

To 395 mg (1.3 mmol) of the above diethyl dicyanophenylmethylphosphonate was added 5.4 ml of concentrated hydrochloric acid, and the mixture was refluxed for 12 hours. The reaction solution was extracted three times with 20 ml of diethyl ether, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane / T
HF) to give 128 mg of the title compound as colorless crystals.
(Yield; 63%) ¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 12.6 (1H, brs), 7.26
7.42 (5H, m), 5.83 (1H, brs), 5.01 (1H, s). IRν _max (KBr); 3402,2965,1716,1300,1062cm ^-1 . Melting point; 120 ° C

Example 7 Synthesis of 2-methylmandelic acid

[0053]

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272 mg (2.0 mmol) of o-toluic acid was dissolved in 4 ml of THF, and cooled to -20 ° C. under stirring.
5 μl (93%, 4.2 mmol), then 293 μl triethylamine
(2.1 mmol) was added. After stirring at -20 ° C for 18 hours, the reaction solution was diluted with 30 ml of diethyl ether, washed twice with 20 ml of water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate system) to obtain 420 mg of pale yellow syrup of diethyl dicyano (o-tolyl) methylphosphonate. (Yield; 68
%) ¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 7.83 (1H, dd, J = 7.6, 1.
6Hz), 7.43 (1H, ddd, J = 7.6,7.6,1.2Hz), 7.34-7.38 (2H, m),
4.13-4.29 (4H, m), 2.66 (3H, s), 1.36 (6H, td, J = 7.2,1.2H
z). IRν _max (neat); 2987,2250,1287,1029 cm ^-1 .

To 415 mg (1.4 mmol) of the above diethyl dicyano (o-tolyl) methylphosphonate was added 5.4 ml of concentrated hydrochloric acid, and the mixture was heated under reflux for 4 hours. The reaction solution was extracted three times with 20 ml of diethyl ether, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane / T
HF) to give 56 mg of the title compound as colorless crystals.
(Yield; 25%) ¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 7.32 (1 H, dd, J = 7.6,2.
0Hz), 7.19-7.27 (3H, m), 5.59 (2H, brs), 5.45 (1H, s), 2.44
(3H, s). IRν _max (KBr); 3340,3024,1723,1214,1067cm ^-1 .

Example 8 Synthesis of 4-methylmandelic acid

[0057]

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272 mg (2.0 mmol) of p-toluic acid was dissolved in 4 ml of THF, and cooled to -20 ° C. under stirring.
5 μl (93%, 4.2 mmol), then 293 μl triethylamine
(2.1 mmol) was added. After stirring at −20 ° C. for 5 hours, the reaction solution was diluted with 30 ml of diethyl ether, washed twice with 20 ml of water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate system) to obtain 466 mg of diethyl dicyano (p-tolyl) methylphosphonate as a slightly yellow syrup. (Yield; 76
%) ¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 7.67 (2H, d, J = 8.0 Hz),
7.35 (2H, d, J = 8.0Hz), 4.13-4.28 (4H, m), 2.43 (3H, s), 1.36
(6H, td, J = 7.2,1.2Hz). IRν _max (neat); 2988,2250,1299,1032cm ^-1 .

6.0 ml of concentrated hydrochloric acid was added to 466 mg (1.5 mmol) of the above diethyl dicyano (p-tolyl) methylphosphonate, and the mixture was refluxed for 3 hours. The reaction solution was extracted three times with 20 ml of diethyl ether, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane /
(Ethyl acetate), and purified as colorless crystals of the title compound (225 mg).
I got (Yield; 90%) ¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 7.32 (2H, d, J = 8.0 Hz),
7.19 (2H, d, J = 8.0 Hz), 5.35 (2H, brs), 5.21 (1H, s), 2.35 (3
H, s). IRν _max (KBr); 3408,2922,1712,1299,1060 cm ^-1 . Melting point; 144 ° C

Example 9 Synthesis of 3-methoxymandelic acid

[0061]

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304 mg (2.0 mmol) of m-anisic acid was dissolved in 4 ml of THF, and cooled to -20 ° C. while diethyl cyanophosphonate 685 was dissolved.
μl (93%, 4.2 mmol) followed by 293 μl triethylamine (2.
1 mmol) was added. After stirring at −20 ° C. for 2 hours, the reaction solution was diluted with 30 ml of diethyl ether, washed twice with 20 ml of water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate system) to obtain 445 mg of diethyl dicyano (3-methoxyphenyl) methylphosphonate as a slightly yellow syrup. (Yield: 69%) ¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 7.45 (1 H, dd, J = 8.0,8.
0Hz), 7.33 (1H, ddd, J = 8.0,2.0,0.8Hz), 7.25 (1H, dd, J = 2.
0,2.0Hz), 7.07 (1H, ddd, J = 8.0,2.0,0.8Hz), 4.13-4.28 (4
H, m), 3.84 (3H, s), 1.35 (6H, tm, J = 6.8Hz) .IRν _max (neat); 2987,2252,1296,1026cm ^-1 .

5.5 ml of concentrated hydrochloric acid was added to 445 mg (1.4 mmol) of the above diethyl dicyano (3-methoxyphenyl) methylphosphonate, and the mixture was refluxed for 5 hours. The reaction solution is diethyl ether
The mixture was extracted three times with 20 ml, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Silica gel column chromatography of the residue
(Hexane / ethyl acetate system) to give 102 mg of the title compound as colorless crystals. (Yield; 41%) ¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 7.30 (1 H, dd, J = 8.0, 7.
6Hz), 7.03 (1H, ddd, J = 7.6,1.2,0.8Hz), 6.99 (1H, dd, J = 2.
4,1.2Hz), 6.89 (1H, ddd, J = 8.0,2.4,0.8Hz), 5.23 (1H, s),
3.81 (3H, s). IRν _max (KBr); 3376,2965,1707,1269,1049cm ^-1 . Melting point; 62-63 ° C

Example 10 Synthesis of 2-chloromandelic acid

[0065]

Embedded image

313 mg (2.0 mmol) of 2-chlorobenzoic acid was added to THF 4
Dissolved in 20 ml and cooled to −20 ° C., 685 μl of diethyl cyanophosphonate (93%, 4.2 mmol), then triethylamine 293
μl (2.1 mmol) was added. After stirring at -20 ° C for 12 hours, the reaction solution was diluted with 30 ml of diethyl ether, washed twice with 20 ml of water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane /
(Ethyl acetate), and dicyano in the form of a pale yellow syrup.
399 mg of diethyl (2-chlorophenyl) methylphosphonate were obtained. (Yield; 61%) ¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 7.90 (1 H, dd, J = 7.6,1.
2Hz), 7.59 (1H, dd, J = 8.0,1.6Hz), 7.55 (1H, ddd, J = 7.6,7.
6,1.6Hz), 7.47 (1H, ddd, J = 8.0,7.6,1.2Hz), 4.21-4.36 (4
H, m), 1.34 (6H, td, J = 6.8, 0.8 Hz) .IRν _max (neat); 2988, 2250, 1299, 1024 cm ⁻¹ .

To 789 mg (2.4 mmol) of the above diethyl dicyano (2-chlorophenyl) methylphosphonate was added 9.6 ml of concentrated hydrochloric acid, and the mixture was heated under reflux for 35 hours. The reaction solution is treated with diethyl ether 2
The mixture was extracted three times with 0 ml, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Silica gel column chromatography of the residue
(Hexane / ethyl acetate system) to give 397 mg of the title compound as colorless crystals. (Yield; 89%) ¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 7.36-7.42 (2H, m), 7.2
4-7.31 (2H, m), 6.98 (2H, brs), 5.64 (1H, s). IRν _max (KBr); 3395,3070,1726,1299,1079cm ^-1 . Melting point; 84 ° C

Example 11 Synthesis of 4-chloromandelic acid

[0069]

Embedded image

313 mg (2.0 mmol) of 4-chlorobenzoic acid was added to THF 4
Dissolved in 20 ml and cooled to −20 ° C., 685 μl of diethyl cyanophosphonate (93%, 4.2 mmol), then triethylamine 293
μl (2.1 mmol) was added. After stirring at -20 ° C for 1.5 hours, the reaction solution was diluted with 30 ml of diethyl ether, washed twice with 20 ml of water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane /
(Ethyl acetate), and dicyano in the form of a pale yellow syrup.
424 mg of diethyl (4-chlorophenyl) methylphosphonate were obtained. (Yield; 65%) ¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 7.73 (2 H, dm, J = 8.4 H)
z), 7.54 (2H, dm, J = 8.4 Hz), 4.17-4.31 (4H, m), 1.38 (6H, td,
J = 7.2,1.2Hz) .IRν _max (neat); 2988,2250,1297,1028cm ^-1 .

5.2 ml of concentrated hydrochloric acid was added to 424 mg (1.3 mmol) of the above diethyl dicyano (4-chlorophenyl) methylphosphonate, and the mixture was refluxed for 10 hours. The reaction solution is treated with diethyl ether 2
The mixture was extracted three times with 0 ml, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Silica gel column chromatography of the residue
(Hexane / ethyl acetate system) to give 221 mg of the title compound as colorless crystals. (Yield; 92%) ¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 7.40 (2 H, dm, J = 8.4 H)
z), 7.35 (2H, dm, J = 8.4 Hz), 5.24 (1H, s). IRν _max (KBr); 3409, 2939, 1724, 1260, 1058 cm ^-1 . Melting point; 116-117 ° C

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) C07C 59/56 C07C 59/56 59/64 59/64 319/20 319/20 323/52 323/52 C07F 9/38 C07F 9/38 C

Claims (10)

[Claims] 1. A dialkyl dicyanomethylphosphonate derivative (I) represented by the following general formula: (In the formula, R ¹ is an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, an optionally substituted lower cycloalkyl group, Represents an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted aralkyl group or an optionally substituted heteroarylalkyl group, wherein R ² may be substituted A lower alkyl group) with an acid or a base, wherein α-hydroxy acid (II) is represented by the following general formula. Embedded image (In the formula, R ¹ has the same meaning as described above.) 2. A carboxylic acid derivative (III) represented by the general formula R ¹ —COOH (where R ¹ has the same meaning as described above) and a general formula NCP (O) (OR ² ) ₂ The dialkyl cyanophosphonate derivative (IV) (wherein R ² has the same meaning as described above) is reacted in the presence of a base to give a dialkyl dicyanomethylphosphonate derivative (I), and then an acid or a base. A process for producing α-hydroxy acid (II). 3. Dialkyl cyanophosphonate derivative (IV)
Is used in an amount of 2 equivalents or more based on the carboxylic acid derivative (III).
I) Manufacturing method. 4. R ¹ is a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a lower cycloalkyl group, a lower halogenated alkyl group, a lower alkoxyalkyl group, a hydroxy lower alkyl group, a lower alkoxycarbonylalkyl group, a cyano lower alkyl. Group, nitro lower alkyl group, lower alkyl thioalkyl group, mercapto lower alkyl group, lower acyl alkyl group, amino lower alkyl group optionally substituted with a nitrogen atom, group derived from a ring containing a hetero atom, aryl group, Lower alkylaryl group, lower alkoxyaryl group, halogenated aryl group, cyanoaryl group, nitroaryl group, hydroxyaryl group, mercaptoaryl group, acylaryl group, heteroaryl group, lower alkylheteroaryl group, lower alkoxyheteroaryl Aryl group, halogenated heteroaryl group, cyanoheteroaryl group, nitroheteroaryl group, hydroxyheteroaryl group, mercaptoheteroaryl group, acylheteroaryl group, aralkyl group, lower alkylaralkyl group, lower alkoxyaralkyl group, halogenated Aralkyl, cyanoaralkyl, nitroaralkyl, hydroxyaralkyl, mercaptoaralkyl, acylaralkyl, heteroarylalkyl, lower alkylheteroarylalkyl, lower alkoxyheteroarylalkyl, halogenated heteroaryl Alkyl, cyanoheteroarylalkyl, nitroheteroarylalkyl, hydroxyheteroarylalkyl, mercaptoheteroarylalkyl or acylheteroaryl Process of claims 1 to 3, wherein the α- hydroxy acid (II) is a group selected from the kill group. 5. The method for producing an α-hydroxy acid (II) according to claim 1, wherein R ² is an ethyl group. 6. The method for producing an α-hydroxy acid (II) according to claim 1, wherein the acid for treating the dialkyl dicyanomethylphosphonate derivative (I) is a mineral acid. 7. The α-hydroxy acid (II) according to claim 6, wherein the mineral acid is one selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, perchloric acid and phosphoric acid. Manufacturing method. 8. A base for reacting a carboxylic acid derivative (III) with a dialkyl cyanophosphonate derivative (IV) in the presence of a base, wherein the base is a monoalkylamine, a dialkylamine,
8. The method for producing an α-hydroxy acid (II) according to claim 1, which is one selected from a trialkylamine, N-monoalkylaniline, N, N-dialkylaniline and pyridine. 9. The carboxylic acid derivative (III) comprises propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, pivalic acid,
Lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, cyclopropanecarboxylic acid, cyclobutanecarboxylic acid, cyclopentanecarboxylic acid, cyclohexanecarboxylic acid, cycloheptanecarboxylic acid, cyclooctanecarboxylic acid, 3 -A kind selected from methylthiopropionic acid, benzoic acid, toluic acid, anisic acid, chlorobenzoic acid, naphthalenecarboxylic acid, nicotinic acid, isonicotinic acid, furancarboxylic acid, thiophenecarboxylic acid, phenylacetic acid or cinnamic acid Item 9. The method for producing α-hydroxy acid (II) according to items 2 to 8. 10. A dialkyl dicyanomethylphosphonate derivative (I) represented by the following general formula: (In the formula, R ¹ and R ² have the same meanings as described above.)