JP3150225B2 - Crystalline modification of mono-p-nitrobenzylmalonate and its preparation - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel crystal modification of mono-p-nitrobenzylmalonate, a production method and a purification method. Mono p-nitrobenzyl malonate is an important intermediate as a pharmaceutical raw material.

[0002]

BACKGROUND OF THE INVENTION There are only a few references in the literature on the industrial production of mono-p-nitrobenzylmalonate. For example, JP-A-57-159762 discloses a method of reacting Meldrum's acid with p-nitrobenzyl alcohol in acetonitrile.
Describes a method of reacting malonic acid with p-nitrobenzyl chloride in dimethylformamide, but this is not an industrial method, such as the use of expensive raw materials and a low yield.

[0003]

In the above manufacturing method,
Since it requires complicated operations and cannot be manufactured industrially at low cost, an inexpensive manufacturing method has been desired.

[0004]

Means for Solving the Problems The present inventors have intensively studied a method for producing mono p-nitrobenzyl malonate by reacting malonic acid with p-nitrobenzyl alcohol. As a result, when a solvent such as benzene, toluene, or xylene is used, malonic acid is hardly soluble in the solvent during the reaction, so that malonic acid is excessively added to reduce the amount of di-p-nitrobenzylmalonate produced. Even when added, they noticed that they precipitated out of the system and were not used for the reaction. p-Nitrobenzyl alcohol and mono-p-nitrobenzyl malonate are also hardly soluble in solvents such as benzene, toluene, and xylene, and form a liquid phase separated from the solvent, so that di-p-nitrobenzyl malonate is easily formed. In addition, when the reaction solution is cooled, malonic acid and mono-p-nitrobenzyl malonate and di-p-nitrobenzyl malonate are precipitated together, so that malonic acid cannot be separated. Was not the target. In short, even though it was found that increasing the ratio of malonic acid to p-nitrobenzyl alcohol suppressed the production of di-p-nitrobenzylmalonate, the ratio of malonic acid could not be recovered. I couldn't make it bigger. In order to avoid such a problem, various solvents were examined. By using a compound having a specific range of dipole moment, the temperature at which malonic acid was dissolved (usually about 50 ° C.) was used.
Above), the reaction system becomes homogenous, and surprisingly, at room temperature, still mono p-nitrobenzyl malonate, di p
It was found that -nitrobenzyl malonate was dissolved, and only malonic acid was precipitated, so that excess malonic acid could be recovered. In addition, it was found that by devising the removal of mono-p-nitrobenzylmalonate from the reaction solution, crystals having high purity and a high filtration rate could be obtained, thus completing the present invention. That is, the present invention provides: (1) a diffraction angle (2θ) [°] 18.39, 19.87, 20.13 in the X-ray diffraction method using Cu-Kα ray.
22.0, 23.8, 24.15, 24.33, 27.
Crystalline modification of mono p-nitrobenzyl malonate characterized by an X-ray diffraction pattern showing a strong peak at 2,27.71. ( 2 ) A mixture of a reaction product containing mono-p-nitrobenzyl malonate and a compound having a dipole moment of 3.0-8.0 Debye or a mixture of the above-mentioned reaction products to obtain mono-p-nitrobenzyl malonate A method for purifying mono-p-nitrobenzyl malonate having the above-mentioned crystal modification, comprising extracting a salt with a basic aqueous solution and subjecting the extracted aqueous solution to acid precipitation with an inorganic acid.

Hereinafter, the present invention will be described in detail. Synthesis of mono p-nitrobenzyl malonate: malonic acid /
The molar ratio of p-nitrobenzyl alcohol is 1.0-1
0.0, more preferably 1.2-5.0, particularly preferably 1.5-3.0. When the ratio exceeds 10.0,
The charging efficiency becomes poor, and if it is less than 1.0, the production amount of di-p-nitrobenzylmalonate increases, and the yield decreases.
The reaction temperature is 30-150 ° C, preferably 40-130 ° C.
° C, more preferably 60-120 ° C, particularly preferably 70-115 ° C. If the temperature exceeds 150 ° C., malonic acid is decomposed to lower the yield, and p-nitrobenzyl acetate as an impurity is produced. If the temperature is lower than 30 ° C., the reaction rate is low and it is not economical.

The reaction medium has a dipole moment of 3.0-8.0 Debye, preferably 3.4-6.
0 Debye, more preferably 3.5-5.0 Debye, particularly preferably 3.6-4.5 Debye, can be used alone, but it can be used by mixing with other organic solvents. it can. In that case, it is necessary to contain the former in an amount of 5% by weight or more, preferably 10% by weight or more, more preferably 20% by weight or more, and particularly preferably 30% by weight or more. Examples of such compounds include o-nitrotoluene (3.66 debye) and m-nitrotoluene (4.
Nitro compounds such as 17 debye), p-nitrotoluene (4.44 debye), and nitrobenzene (4.22 debye). The amount of the compound used is 100-5000% by weight, preferably 200-3% by weight, based on malonic acid.
000% by weight, particularly preferably 300-2000% by weight. Benzene, toluene, xylene, ethylbenzene, as an organic solvent used by mixing with the above compound,
Cumene, mesitylene, durene, tetralin, butylbenzene, p-cymene, cyclohexylbenzene, diethylbenzene, pentylbenzene, dipentylbenzene,
Aromatic compounds such as dodecylbenzene, chlorobenzene and o-dichlorobenzene; alicyclic compounds such as cyclopentane, methylcyclopentane, cyclohexane, methylcyclohexane, ethylcyclohexane, p-menthane, bicyclohexyl and decalin; hexane, 2- Aliphatic such as methylpentane, 2,2-dimethylbutane, 2,3-dimethylbutane, heptane, octane, 2,2,3-trimethylpentane, isooctane, nonane, 2,2,5-trimethylhexane, decane and dodecane Compounds: dichloromethane, chloroform, carbon tetrachloride, 1,1-dichloroethane, 1,2-dichloroethane, 1,1,1-trichloroethane, 1,1,2-trichloroethane, 1,
Halogenated hydrocarbons such as 1,1,2-tetrachloroethane, 1,1,2,2-tetrachloroethane, pentachloroethane and hexachloroethane; dipropyl ether;
Ethers such as diisopropyl ether, dibutyl ether and dihexyl ether are exemplified. Also, a small amount of water, for example, 0-3% by weight based on the reaction medium may be added. The catalyst reacts even without it, but monohydrate of p-toluenesulfonic acid, sulfuric acid and hydrochloric acid are effectively used as the catalyst.
Particularly, a monohydrate of p-toluenesulfonic acid is preferable.

Removal and purification of mono-p-nitrobenzyl malonate: Malonic acid precipitates when cooled after the reaction, and the supernatant of the reaction solution is sucked or the reaction solution is filtered.
The malonic acid is separated. Water is added to the reaction solution from which malonic acid has been separated, and a basic substance is added little by little. For example, an alkali metal salt of mono-p-nitrobenzylmalonate is extracted from the reaction medium system into an aqueous system. The amount of water to be added is from 300 to 2000% by weight, preferably from 400 to 1500% by weight, particularly preferably from 500 to 1300% by weight, based on the produced mono-p-nitrobenzyl malonate. As a reaction medium,
When a compound having a dipole moment of 3.0-8.0 Debye was not used, the reaction solution was cooled to obtain a raw material,
And the reaction product is precipitated. The compound is added to dissolve the raw materials and products other than malonic acid. In that case, the amount of the compound used is 100-50 based on malonic acid.
00% by weight, preferably 200-3000% by weight, particularly preferably 300-2000% by weight.

The basic substance includes, for example, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide and the like. From the viewpoint of solubility, potassium carbonate and potassium hydrogen carbonate are preferred. Particularly preferred. Mono-p-nitrobenzylmalonate alkali metal salt is easily hydrolyzed in water,
In particular, when the pH of the aqueous extraction solution is increased, it is rapidly hydrolyzed at room temperature. Therefore, the basic substance is added little by little, and the pH is 7.5, preferably 7.0, more preferably
6.5, particularly preferably 5.8. The aqueous solution of the mono p-nitrobenzyl malonate alkali metal salt is easily hydrolyzed even at a high temperature, so that it is 5 to 40 ° C, preferably 10 to 30 ° C, particularly preferably 15 to 25 ° C.
Extract with The aqueous solution of the extracted mono-p-nitrobenzyl malonate alkali metal salt may be washed with benzene, toluene, cyclohexane or the like.

To acidify mono-p-nitrobenzyl malonate from its alkali metal salt, for example, an aqueous sulfuric acid solution is used.
A hydrochloric acid aqueous solution was added little by little to adjust the pH to 3.0, and after stirring in that state, the mixture was filtered under reduced pressure, and the cake was washed with a small amount of water.
Dry overnight at 50-60 ° C. The obtained crystal is Cu-K
Diffraction angle (2θ) [°] 1 in X-ray diffraction method using α-ray
8.39, 19.87, 20.13, 22.0, 23.
This is a crystal modification characterized by an X-ray diffraction pattern (see FIG. 1) showing strong peaks at 8, 24.15, 24.33, 27.2, and 27.71, and has a high purity and a good filtration rate. .

[0010]

EXAMPLES The present invention will be described in detail with reference to examples, but the present invention is not limited to these examples. Example 1 In a 200 cc four-necked flask equipped with a stirrer, a thermometer, and a condenser, 15.3 g of p-nitrobenzyl alcohol, 15.6 g of malonic acid, 0.25 g of p-toluenesulfonic acid monohydrate, 100 cc of nitrobenzene, 1g of water
At room temperature, and heated to 107 ° C. over about 2 hours,
It was kept at 107 ° C. for 30 minutes. Then, while maintaining the temperature at 107 ° C., the reaction flask was evacuated to a pressure of 50 ° C. over about 1 hour.
cc of nitrobenzene was distilled off. Final decompression degree is 50
mmHg. The reaction was cooled to room temperature and the contents of the flask were transferred to a 300 cc beaker. The reaction flask was washed with 10 cc of nitrobenzene, and the washing solution was transferred to the beaker. Further, 150 cc of water was added, an electrode for PH measurement was put, and the mixture was sufficiently stirred. The temperature was 25 ° C. P
Potassium carbonate was added over about 1 hour until H was 5.8. The amount used was 12.3 g. Then 30
The mixture was stirred for minutes, and a pH of 5.8 was confirmed. The solution was allowed to stand, and the separated aqueous phase was taken and washed with about 50 cc of toluene.
% Sulfuric acid was added slowly to bring the pH to 3.0. The usage was 17cc. After stirring for about 1 hour, the mixture was filtered under reduced pressure. The filter cake was washed with a small amount of water. The cake is 50-6
It dried under reduced pressure at 0 degreeC. Yield 16.7 g of mono-p-nitrobenzyl malonate, 70% yield vs. p-nitrobenzyl alcohol. 107-110 ° C. Liquid chromatography purity 99.5%. 18. Diffraction angle (2θ) [°] in X-ray diffraction by Cu-Kα ray 18.39, 19.
87, 20.13, 22.0, 23.8, 24.15,
Strong peaks were shown at 24.33, 27.2 and 27.71. (See Fig. 1)

Example 2 In a 200 cc four-necked flask equipped with a stirrer, a thermometer, and a cooler, 15.3 g of p-nitrobenzyl alcohol, 20.8 g of malonic acid, 0.25 g of p-toluenesulfonic acid monohydrate, Nitrobenzene 100cc, water 1g
At room temperature and heated to 105 ° C. over about 2 hours,
It was kept at 105 ° C. for 30 minutes. Thereafter, the reaction flask was evacuated while maintaining the temperature at 105 ° C.
cc of nitrobenzene was distilled off. Final decompression degree is 50
mmHg. When the reaction was cooled to room temperature, malonic acid precipitated. The reaction was blotted and transferred to a 300 cc beaker. The malonic acid remaining in the reaction flask was separated by filtration, washed with nitrobenzene and toluene, and dried at 50-60 ° C to obtain 10 g of malonic acid. The total amount of the filtrate from which the malonic acid was separated and the washing solution of nitrobenzene was about 20.
The cc was transferred to the beaker. Further, 150 cc of water was added, an electrode for PH measurement was put, and the mixture was sufficiently stirred. Temperature is 2
It was 5 ° C. Potassium carbonate was added over about 1 hour until the pH was 5.8. The amount used was 8.5 g.
Thereafter, the mixture was stirred for 30 minutes, and pH 5.8 was confirmed. The solution was allowed to stand, the separated aqueous phase was taken, washed with about 50 cc of toluene, and 20% sulfuric acid was slowly added to adjust the pH to 3.0. The usage was 12cc. After stirring for about 1 hour, the mixture was filtered under reduced pressure. The filter cake was washed with a small amount of water. The cake was dried under reduced pressure at 50-60 ° C. Yield 18.8 g of mono p-nitrobenzyl malonate, 78.7% yield versus p-nitrobenzyl alcohol. 75.8% malonic acid. 107-110 ° C. Liquid chromatography purity 99.5%. Diffraction angle (2θ) [°] in X-ray diffraction by Cu-Kα ray 18.39, 19.87, 2
0.13, 22.0, 23.8, 24.15, 24.3
A strong peak was shown at 3,27.2,27.71.

Example 3 200 cc equipped with a stirrer, thermometer, cooler and water separator
In a 4-neck flask, p-nitrobenzyl alcohol 1
5.3 g, 15.6 g of malonic acid, 0.25 g of p-toluenesulfonic acid monohydrate, and 100 cc of toluene were added at room temperature, and the temperature was raised to 112 ° C. over about 2 hours while separating reaction product water. While maintaining the temperature at 112 ° C. for 30 minutes, about 60 cc of toluene was distilled off. Nitrobenzene
When 60 cc was added to the reaction flask and the reaction product was cooled to room temperature with stirring, malonic acid was precipitated. The reaction was blotted and transferred to a 300 cc beaker. The malonic acid remaining in the reaction flask was separated by filtration, washed with nitrobenzene and toluene, and dried at 50-60 ° C.
was gotten. A total of about 20 cc of the filtrate from which the malonic acid was separated and the washing liquid were transferred to the beaker. Furthermore, 150c of water
c was added, an electrode for PH measurement was added, and the mixture was sufficiently stirred. The temperature was 25 ° C. Potassium carbonate was added over about 1 hour until the pH was 5.8. The amount used was 9.6 g. Thereafter, the mixture was stirred for 30 minutes, and pH 5.8 was confirmed. The solution was allowed to stand, the aqueous phase separated into two phases was taken, and washed with about 50 cc of toluene.
Was set to 3.0. The usage was 14cc. After stirring for about 1 hour, the mixture was filtered under reduced pressure. The filter cake was washed with a small amount of water. The cake was dried under reduced pressure at 50-60 ° C. Amount mono-p-nitrobenzyl malonate 15.1 g, yield 6
3.0% vs. p-nitrobenzyl alcohol. 61.8%
Against malonic acid. 107-110 ° C. Liquid chromatography purity 99.5%. Diffraction angle (2θ) [°] 18.39, 19.8 in X-ray diffraction by Cu-Kα ray
7, 20.13, 22.0, 23.8, 24.15, 2
Strong peaks were observed at 4.33, 27.2 and 27.71.

Example 4 The procedure of Example 1 was repeated, except that 100 cc of o-nitrotoluene was used instead of nitrobenzene of Example 1. Yield Mono p-nitrobenzyl malonate 16.2
g, 67.8% yield versus p-nitrobenzyl alcohol.
107-110 ° C. Liquid chromatography purity 99.5%. Diffraction angle (2θ) [°] in X-ray diffraction by Cu-Kα ray 18.39, 19.87, 20.1
3,22.0,23.8,24.15,24.33,2
A strong peak was shown at 7.2, 27.71.

Example 5 The procedure of Example 1 was repeated, except that 100 cc of m-nitrotoluene was used instead of nitrobenzene of Example 1. Yield Mono p-nitrobenzyl malonate 16.5
g, 69.0% yield vs. p-nitrobenzyl alcohol.
107-110 ° C. Liquid chromatography purity 99.5%. Diffraction angle (2θ) [°] in X-ray diffraction by Cu-Kα ray 18.39, 19.87, 20.1
3,22.0,23.8,24.15,24.33,2
A strong peak was shown at 7.2, 27.71.

[0015]

By using nitrobenzene as the reaction medium, the reaction system becomes uniform, and mono-p-nitrobenzylmalonate can be obtained with high reproducibility and high yield.
In addition, since excess malonic acid can be separated from the reaction solution, the wastewater load is small and economical.

[Brief description of the drawings]

FIG. 1: Mono-p-nitrobenzyl malonate X of the present invention
Line diffraction diagram.

──────────────────────────────────────────────────続 き Continued on the front page (58) Field surveyed (Int. Cl. ⁷ , DB name) C07C 205/42 C07C 201/16 CA (STN) REGISTRY (STN)

Claims (2)

(57) [Claims] 1. Diffraction angle (2θ) [°] in X-ray diffraction by Cu-Kα ray 18.39, 19.87, 20.1
3,22.0,23.8,24.15,24.33,2
Crystal modification of mono p-nitrobenzyl malonate characterized by an X-ray diffraction pattern showing a strong peak at 7.2, 27.71. 2. A mixture of a reaction product containing mono-p-nitrobenzylmalonate and a compound having a dipole moment of 3.0 to 8.0 Debye, or a mixture of the above reaction product and mono-p-nitrobenzyl 2. The method according to claim 1, wherein the benzyl malonate is extracted with a basic aqueous solution, and the extracted aqueous solution is subjected to acid precipitation with an inorganic acid.