JP3462586B2 - Method for producing mono-p-nitrobenzyl malonate - Google Patents

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a method for producing a pharmaceutical intermediate. More specifically, it relates to a method for producing mono-p-nitrobenzyl malonate.

[0002]

BACKGROUND OF THE INVENTION Mono-p-nitrobenzyl malonate is an important intermediate as a raw material for medicines. Mono-p
The industrial production of nitrobenzyl malonate is only mentioned in a few documents. For example, JP-A-57-159771 discloses a method of reacting Meldrum's acid with p-nitrobenzyl alcohol in acetonitrile, and JP-A-58-208292 discloses a method of reacting malonic acid with p-nitromalon in dimethylformamide. Methods for reacting nitrobenzyl chloride have been described, but these methods are not industrially advantageous methods such as expensive raw materials and low yields.

[0003]

As described above, the conventional synthetic method requires complicated operations and is not a method which can be industrially manufactured at low cost. Therefore, development of an inexpensive manufacturing method is desired. It was

[0004]

Means for Solving the Problems The present inventor has made mono-p while reacting malonic acid and p-nitrobenzyl alcohol in the presence of an organic solvent to azeotrope the produced water and remove it out of the reaction system. The present invention has been found as a result of extensive studies on a method for producing -nitrobenzyl malonate. When a solvent such as benzene, toluene, xylene, or chlorobenzene is used in the reaction, malonic acid is difficult to dissolve in the solvent during the reaction, and p-nitrobenzyl malonate is used for the purpose of reducing the production amount of p-nitrobenzyl malonate. Even if the amount of malonic acid used relative to nitrobenzyl alcohol is increased, malonic acid precipitates as crystals and goes out of the reaction system, so it does not contribute much to the decrease in the amount of di-p-nitrobenzyl malonate produced. . Further, when the reaction solution is completely cooled, malonic acid and mono-p-nitrobenzyl malonate and di-p-nitrobenzyl malonate are co-precipitated, and malonic acid cannot be separated. Many and not economical. Further, even if it is known that the production ratio of di-p-nitrobenzylmalonate is suppressed by increasing the ratio of malonic acid used to p-nitrobenzyl alcohol, malonic acid could not be recovered. It was not possible to increase the proportion of malonic acid used.

However, when the separation conditions of mono-p-nitrobenzyl malonate in the production of mono-p-nitrobenzyl malonate by reacting malonic acid with p-nitrobenzyl alcohol were examined in detail, the reaction Although slightly different depending on the kind and amount of the solvent used and the charging ratio of the raw materials, when the reaction mixture is carefully cooled after completion of the reaction, what was liquid-liquid heterogeneous, but malonic acid was precipitated at 35-100 ° C. Mono-p-nitrobenzyl malonate, di-p-
It was found that nitrobenzyl malonate was obtained in a state of being dissolved in the reaction solvent, and it was found that excess malonic acid can be efficiently recovered in this way. Then, from the reaction solution from which malonic acid was removed, at 35-80 ° C,
It was found that by extracting mono-p-nitrobenzyl malonate with a basic aqueous solution and performing acid precipitation, crystals with high purity and a high filtration rate can be obtained. Also, malonic acid and p-
When mono-p-nitrobenzyl malonate is produced by reacting nitrobenzyl alcohol, di-p-nitrobenzyl malonate is added in advance to form di-p-nitrobenzyl malonate. I found that I can suppress.

In the reaction of malonic acid with p-nitrobenzyl alcohol, di-p-nitrobenzyl malonate is always produced, and if an economical treatment method for the compound is not established. The industrial value of the method for producing mono-p-nitrobenzyl malonate by reacting malonic acid with p-nitrobenzyl alcohol is reduced. As a result of various investigations on the treatment method of the by-produced di-p-nitrobenzyl malonate, the present inventor converted it into p-nitrobenzyl alcohol by hydrolysis, acidolysis, etc., and reused it as a raw material. Alternatively, by reacting di-p-nitrobenzyl malonate by-produced with malonic acid to obtain mono-p-nitrobenzyl malonate, it is possible to industrially advantageously produce mono-p-nitrobenzyl malonate. The present invention has been completed by finding that it is extremely effective.

That is, according to the present invention, (1) p-nitrobenzyl alcohol and malonic acid are reacted in an organic solvent, and the resulting reaction solution is mixed with 35-100.
After cooling to ℃ and separating the precipitated malonic acid, the reaction solution is treated with a basic aqueous solution at 35 to 80 ℃ to extract mono-p-nitrobenzyl malonate. Method for producing p-nitrobenzyl malonate (2) After reacting p-nitrobenzyl alcohol and malonic acid in an organic solvent containing di-p-nitrobenzyl malonate, the obtained reaction solution is heated to 35-100 ° C. After cooling and separating the precipitated malonic acid, the reaction solution was cooled to 35-80 ° C.
At the same time, treatment with a basic aqueous solution is performed to extract mono-p-nitrobenzyl malonate.
Method for producing nitrobenzyl malonate (3) The method for producing mono-p-nitrobenzyl malonate according to the above item (1) or (2), wherein the organic solvent is toluene, xylene, monolbenzene or dichlorobenzene ( 4) In the method for producing mono-p-nitrobenzyl malonate according to the above item (1) or (2), di-p-nitrobenzyl maloate present in the reaction solution after extraction of mono-p-nitrobenzyl malonate. Hydrolyze the nate to p-
Method for producing mono-p-nitrobenzyl malonate according to the above item (1) or (2), wherein nitrobenzyl alcohol is obtained and used as a raw material (5) Mono-p-of the above item (5) or (2) In the method for producing nitrobenzyl malonate, di-p-nitrobenzyl malonate present in the reaction solution after extraction of mono-p-nitrobenzyl malonate is reacted with malonic acid to produce mono-p-nitrobenzyl malonate. The method for producing mono-p-nitrobenzylmalonate according to (1) or (2) before conversion into

The present invention will be described in detail below. [1] A step of reacting p-nitrobenzyl alcohol with malonic acid to produce mono-p-nitrobenzyl malonate: The molar ratio of malonic acid / p-nitrobenzyl alcohol is usually 1.0-10.0, preferably 1.2-5.
0, particularly preferably 1.5-3.0. Ratio 10.
If it exceeds 0, the charging efficiency becomes poor, and if it is less than 1.0, the amount of di-p-nitrobenzyl malonate produced increases,
Yield decreases. The reaction temperature is generally 30-150 ° C, preferably 40-130 ° C, more preferably 60-12.
0 ° C, particularly preferably 70-115 ° C. 150
If the temperature exceeds ℃, decomposition of malonic acid will occur and the yield will decrease.
In addition, an impurity, p-nitrobenzyl acetate, is produced. If it is lower than 30 ° C, the reaction rate is slow and it is not economical. The reaction time is 0.2-10 hours, preferably 0.5-6 hours, particularly preferably 1.0-3 hours.

Organic solvents usable in the reaction include benzene, toluene, xylene, ethylbenzene, cumene,
Mesitylene, durene, tetralin, butylbenzene,
Aromatic compounds such as p-cymene, cyclohexylbenzene, diethylbenzene, pentylbenzene, dipentylbenzene, dodecylbenzene, chlorobenzene and o-dichlorobenzene; cyclopentane, methylcyclopentane, cyclohexane, methylcyclohexane, ethylcyclohexane, p-menthane Alicyclic compounds such as bicyclohexyl and decalin; hexane, 2-methylpentane,
2,2-dimethylbutane, 2,3-dimethylbutane, heptane, octane, 2,2,3-trimethylpentane,
Aliphatic compounds such as isooctane, nonane, 2,2,5-trimethylhexane, decane, dodecane; dichloromethane, chloroform, carbon tetrachloride, 1,1-dichloroethane, 1,2-dichloroethane, 1,1,1-trichloroethane , 1,1,2-trichloroethane, 1,1,1,
Halogenated hydrocarbons such as 2-tetrachloroethane, 1,1,2,2-tetrachloroethane, pentachloroethane and hexachloroethane; ethers such as dipropyl ether, diisopropyl ether, dibutyl ether and dihexyl ether. To be Among them, benzene, toluene, xylene, chlorobenzene and dichlorobenzene are preferable. In particular, toluene and dichlorobenzene are preferable.

The amount of the organic solvent used is usually 100-5000% by weight, preferably 200-30, based on malonic acid.
00% by weight, particularly preferably 300-2000% by weight
Is. Also, add a small amount of water to the organic solvent, for example 0-3.
You may add weight%. The catalyst reacts even without it, but p
-Toluenesulfonic acid monohydrate, sulfuric acid and hydrochloric acid are effectively used as catalysts. In particular, p-toluenesulfonic acid 1
Hydrates are preferred.

The water produced is preferably removed azeotropically at atmospheric pressure or reduced pressure outside the reaction system. As the reaction progresses,
Since the produced mono-p-nitrobenzyl malonate gradually changes to di-p-nitrobenzyl malonate, the production rate of mono-p-nitrobenzyl malonate gradually reaches a maximum value and then gradually decreases. It is preferable to stop the reaction during the reaction. However, since the starting material p-nitrobenzyl alcohol has a polarity similar to that of the target product, mono-p-nitrobenzyl malonate, it is not easy to separate it.
-Nitrobenzyl alcohol should be reacted to the extent that it is permissible. During the reaction, the reaction product was sampled and analyzed by liquid chromatography (HPLC) to find that p-nitrobenzyl alcohol was usually 0.05-5.
0.0 area%, preferably 0.1-30.0 area%,
It is more preferable to stop the reaction at 0.2-10.0 area%, particularly preferably 0.3-1.0 area%.

The reaction between p-nitrobenzyl alcohol and malonic acid can be carried out as follows. That is, p-nitrobenzyl alcohol, malonic acid, and a catalyst are added to a poorly water-soluble organic solvent containing di-p-nitrobenzyl malonate, and the same reaction is performed as described above. J-p
The amount of p-nitrobenzyl alcohol used relative to -nitrobenzyl malonate is usually 10-1000% by weight,
Preferably 100-600% by weight, particularly preferably
It is 200-400% by weight. The amount of the above-mentioned organic solvent used in the reaction is usually 100 to 5000% by weight, preferably 200, based on the total amount of di-p-nitrobenzyl malonate and p-nitrobenzyl alcohol.
-3000% by weight, particularly preferably 300-1000
% By weight. A small amount of water may be added, for example, 0 to 3% by weight to the organic solvent. In the following, the same processing as described above is performed. Thus, by adding di-p-nitrobenzyl malonate to the organic solvent in which the reaction is performed in advance, the by-product of di-p-nitrobenzyl malonate can be reduced.

[2] Step of taking out mono-p-nitrobenzyl malonate and recovering malonic acid: After the reaction in [1] is completed, the reaction solution is carefully cooled to usually 35
-100 ° C, preferably 40-80 ° C, more preferably 45-70 ° C, particularly preferably 50-60 ° C,
Since only malonic acid is deposited, the supernatant of the reaction solution is sucked or the reaction solution is filtered to separate malonic acid. The reaction solution from which malonic acid has been removed is usually kept at 35-80 ° C, preferably 40-60 ° C, particularly preferably 40-50 ° C, water is added, and a basic substance is added little by little.
The alkaline salt of nitrobenzyl malonate is extracted from the reaction solvent into an aqueous system. The amount of water added is
Normally 300-2 for p-nitrobenzyl malonate
000% by weight, preferably 400-1500%, particularly preferably 500-1300% by weight.

Examples of the basic substance that can be used here include sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide, and the like. From the viewpoint of solubility, potassium carbonate, carbonic acid, etc. Potassium hydrogen is especially preferred. Mono-p-nitrobenzyl malonate alkali salt is easily hydrolyzed in water, and particularly when the pH of the extraction aqueous solution becomes high, at room temperature,
It is rapidly hydrolyzed. The basic substance is added little by little to adjust the pH to 7.5 or less, preferably 7.0 or less, more preferably 6.5 or less, and particularly preferably 5.8 or less. The extraction time is usually 0.1-2.0 hours, preferably 0.2-1.5 hours, more preferably 0.3-.
1.0 hours, particularly preferably 0.5-0.7 hours. The extracted aqueous solution of mono-p-nitrobenzyl malonate alkali salt may be washed with a poorly water-soluble organic solvent such as benzene, toluene, cyclohexane.

To carry out acid precipitation of mono-p-nitrobenzyl malonate from its alkali salt, an aqueous sulfuric acid solution, or
Aqueous hydrochloric acid was added little by little to adjust the pH to 3.0, and after stirring in that state, vacuum filtration was performed, and the cake was washed with a small amount of water,
Dry overnight at 50-60 ° C. The crystals obtained have a high purity and a good filtration rate.

[3] A method for treating di-p-nitrobenzyl malonate. Di-p-nitrobenzyl malonate contains malonic acid and p-
When reacting with nitrobenzyl alcohol, it is always produced as a by-product. Effective utilization of this di-p-nitrobenzyl malonate is important in the method for producing mono-p-nitrobenzyl malonate by reacting malonic acid with p-nitrobenzyl alcohol. By-product J
There are the following two methods for effectively utilizing p-nitrobenzyl malonate.

(1) Method for producing p-nitrobenzyl alcohol by hydrolyzing di-p-nitrobenzyl malonate: Di-p-nitrobenzyl malonate is
In [2], mono-p-nitrobenzyl malonate is extracted as a potassium salt and then obtained by dissolving in an organic solvent. Upon cooling, the precipitated di-p-nitrobenzyl malonate is filtered off, or the organic solvent is distilled off to remove di-p-nitrobenzyl malonate.
p-Nitrobenzyl malonate can be isolated. Similarly, the isolated di-p-nitrobenzyl malonate can be hydrolyzed in a state of being dissolved in an organic solvent. It is usually more rational not to isolate. The reaction temperature is generally -20-100 ° C, preferably 0-60.
C., particularly preferably 10-40.degree. If it is lower than -20 ° C, the solubility of the raw material is low and the reaction rate is slow. 1
When it exceeds 00 ° C, the amount of side reaction products increases. Examples of the basic substance used for hydrolysis include sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide, and the like, with sodium hydroxide and potassium hydroxide being particularly preferable. The amount to be used is usually 0.05-10 mol, preferably 0.1 to 1 mol of di-p-nitrobenzyl malonate.
It is -3.0 mol, particularly preferably 0.3-1.0 mol.

The amount of water used is usually 10-1000% by weight, preferably 20-300% by weight, particularly preferably 30-20, based on di-p-nitrobenzyl malonate.
It is 0% by weight. The reaction rate becomes extremely high by adding a lower alcohol such as methanol, ethanol or isopropanol in order to increase the mutual solubility between di-p-nitrobenzyl malonate and the basic aqueous solution. The amount of such alcohols used is usually 5-5000% by weight, preferably 20-2000% by weight, more preferably 30-1 based on di-p-nitrobenzyl malonate.
000% by weight, particularly preferably 35-200% by weight. Di-p-nitrobenzyl malonate is obtained by removing malonic acid and mono-p-nitrobenzyl malonate from the reaction product as described in [2], and is usually benzene, toluene, xylene, chlorobenzene. Since it is contained in a poorly water-soluble organic solvent such as the above, it may be adjusted to an appropriate amount by removing or adding the solvent. The amount of the poorly water-soluble organic solvent used is based on di-p-nitrobenzyl malonate.
It is usually 0-5000% by weight, preferably 0-1000% by weight.

After the hydrolysis reaction, the same amount of inorganic acid as hydrochloric acid or sulfuric acid as the basic substance used is added to neutralize. afterwards,
The mixture is heated and the lower alcohol is distilled off if necessary to obtain a layer of a poorly water-soluble organic solvent containing p-nitrobenzyl alcohol and an aqueous layer containing malonic acid, a salt and the like. It can be used as a raw material in [1] after separating the aqueous layer and washing the organic solvent layer with or without washing. Although it is possible to obtain p-nitrobenzyl alcohol by distilling off the organic solvent, it is rational to use it for the reaction without distilling off the organic solvent. The water layer may be used as the raw material in [1] without being separated. However, in that case, the amount of water and basic substance used for the hydrolysis reaction should be as much as possible.
It is better to reduce it. The above method of hydrolyzing di-p-nitrobenzyl malonate to produce p-nitrobenzyl alcohol is a novel method.

(2) Method of reacting di-p-nitrobenzyl malonate with malonic acid to obtain mono-p-nitrobenzyl malonate: The di-p-nitrobenzyl malonate used was isolated. It may be a substance or a substance dissolved in the poorly water-soluble organic solvent obtained in [2]. Malonic acid / di-p
The molar ratio of -nitrobenzyl malonate is usually 1.0-1.
0.0, more preferably 1.2-5.0, and particularly preferably 1.5-3.0. If the ratio exceeds 10.0,
The charging efficiency becomes poor, and if it is less than 1.0, the conversion rate becomes low and the yield decreases. The reaction temperature is usually 30-150.
℃, preferably 40-130 ℃, more preferably 60
-120 ° C, particularly preferably 70-115 ° C.
If it exceeds 150 ° C, malonic acid is decomposed to lower the yield, and p-nitrobenzyl acetate as an impurity is produced. If it is lower than 30 ° C, the reaction rate is slow and it is not economical. The reaction time is usually 0.2-10 hours, preferably
It is 0.5-6 hours, particularly preferably 1.0-3 hours.

The organic solvent that can be used in the reaction is o-
Nitro compounds such as nitrotoluene, m-nitrotoluene, p-nitrotoluene, nitrobenzene, benzene, toluene, xylene, ethylbenzene, cumene, mesitylene, durene, tetralin, butylbenzene, p-cymene, cyclohexylbenzene, diethylbenzene, pentylbenzene, dipentylbenzene, Aromatic compounds such as dodecylbenzene, chlorobenzene and o-dichlorobenzene; cycloaliphatic compounds such as cyclopentane, methylcyclopentane, cyclohexane, methylcyclohexane, ethylcyclohexane, p-menthane, bicyclohexyl and decalin; hexane, 2- Methyl pentane, 2,2-
Dimethylbutane, 2,3-dimethylbutane, heptane,
Aliphatic compounds such as octane, 2,2,3-trimethylpentane, isooctane, nonane, 2,2,5-trimethylhexane, decane, dodecane; dichloromethane, chloroform, carbon tetrachloride, 1,1-dichloroethane, 1,
2-dichloroethane, 1,1,1-trichloroethane,
Halogenated hydrocarbons such as 1,1,2-trichloroethane, 1,1,1,2-tetrachloroethane, 1,1,2,2-tetrachloroethane, pentachloroethane, hexachloroethane; dipropyl ether And ethers such as diisopropyl ether, dibutyl ether, and dihexyl ether. The amount of the organic solvent used is usually 100 to 5000% by weight with respect to malonic acid, and preferably,
200-3000% by weight, particularly preferably 300-2
It is 000% by weight.

As the catalyst, p-toluenesulfonic acid monohydrate, methanesulfonic acid, sulfuric acid and hydrochloric acid are used as catalysts.
Used effectively. Particularly, p-toluenesulfonic acid monohydrate is preferable. Then, the same treatment as described in [1] is performed to obtain mono-p-nitrobenzyl malonate. J-p-
The method of obtaining mono-p-nitrobenzyl malonate from nitrobenzyl malonate is a novel method.

In the production method of the present invention, excess malonic acid can be efficiently separated from the reaction solution, so that the load of waste water is small and di-p-nitrobenzyl malonate produced as a by-product is efficiently used. The method for producing mono-p-nitrobenzyl malonate from nitrobenzyl alcohol and malonic acid is extremely efficient, and the mono-p-nitrobenzyl malonate obtained by the production method of the present invention has high purity and It is characterized by high total yield.

[0024]

The present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples. In the examples,% is% by weight.

Example 1 In a 200 cc 4-necked flask equipped with a stirrer, a thermometer and a water separator, 15.3 g of p-nitrobenzyl alcohol,
Malonic acid 15.6 g, p-toluenesulfonic acid monohydrate 0.25 g, and toluene 100 cc were added at room temperature,
The temperature was raised to 110 ° C over 2 hours, then 1 hour, 1
While refluxing toluene at 10 to 112 ° C, water is azeotropically distilled and removed from the reaction system. The reaction solution was cooled to 50 ° C. to precipitate malonic acid, stirred at the same temperature for 30 minutes and allowed to stand for 30 minutes, and the supernatant of the reaction solution was transferred to a 300 cc flask.
Wash the reaction flask and malonic acid with 15 cc of toluene,
The washing solution was transferred to the above 300 cc flask. (5.2 g of recovered malonic acid). Further, 150 cc of water is added to the 300 cc flask and kept at 40 ° C. Crystals precipitated. An electrode for pH measurement was put in and thoroughly stirred. Potassium carbonate was added over about 15 minutes until the pH was 5.4. The amount used was 5.7g. Then, the mixture was allowed to stand, the separated lower aqueous layer was taken, the aqueous layer was washed with about 50 cc of toluene, and a 20% aqueous sulfuric acid solution was slowly added to adjust the pH to 3.0. The amount used was 17 cc. After stirring for about 1 hour, vacuum filtration was performed. The filter cake was washed with a little water. The cake was dried under reduced pressure at 50-60 ° C. Yield Mono-p-nitrobenzyl malonate 15.5
g, 65% yield (vs. p-nitrobenzyl alcohol).
Melting point 107-110 [deg.] C. Liquid chromatography purity 99.8 area%.

Example 2 In a 200 cc four-necked flask equipped with a stirrer, a thermometer, and a water separator, 15.3 g of p-nitrobenzyl alcohol,
20.8 g of malonic acid, 0.25 g of p-toluenesulfonic acid monohydrate, and 100 cc of toluene were added at room temperature,
The temperature was raised to 110 ° C over 2 hours, then 1 hour, 1
While refluxing toluene at 10 to 112 ° C, water is azeotropically distilled and removed from the reaction system. The reaction solution was cooled to 50 ° C. to precipitate malonic acid, stirred at the same temperature for 30 minutes and allowed to stand for 30 minutes, and the supernatant of the reaction solution was transferred to a 300 cc flask.
Wash the reaction flask and malonic acid with 25 cc of toluene,
The washing solution was transferred to the above 300 cc flask. (Recovered malonic acid 9.6 g). Further, 150 cc of water is added to the 300 cc flask and kept at 40 ° C. Crystals precipitated. An electrode for pH measurement was put in and thoroughly stirred. Potassium carbonate was added over about 15 minutes until the pH was 5.8. The amount used was 6.0 g. Then, the mixture was allowed to stand, the separated lower aqueous layer was taken, the aqueous layer was washed with about 50 cc of toluene, and a 20% aqueous sulfuric acid solution was slowly added to adjust the pH to 3.0. The amount used was 19 cc. After stirring for about 1 hour, vacuum filtration was performed. The filter cake was washed with a little water. The cake was dried under reduced pressure at 50-60 ° C. Yield Mono-p-nitrobenzyl malonate 17.2
g, 72% yield (vs p-nitrobenzyl alcohol).
Melting point 107-110 [deg.] C. Liquid chromatography purity 99.7 area%.

Example 3 To a 200 cc four-necked flask equipped with a stirrer and a thermometer, 6.4 g of di-p-nitrobenzyl malonate, 64 cc of toluene and 27 cc of methanol were added at room temperature, and di-p was added.
-Nitrobenzyl malonate was dissolved. When 7 g of water was added, it became cloudy. The reaction solution was cooled to 10 ° C., and 2.7 g of 28% aqueous sodium hydroxide solution was added dropwise over 30 minutes.
Then, the temperature was kept at 10 to 20 ° C. for 1 hour to complete the hydrolysis reaction. The pH of the reaction solution was adjusted to 5-6 with a 20% aqueous solution of sulfuric acid, and then the reaction solution was heated. When the temperature of the reaction solution was 70 ° C., the distillation of methanol started, and when the temperature of the reaction solution was 80 ° C. and the distillation of methanol was low, the temperature was cooled, the temperature was kept at 40 ° C., stirring was stopped, and the mixture was allowed to stand, After separating the lower aqueous layer,
The toluene layer was washed with 10 cc of water. The p-nitrobenzyl alcohol contained in the toluene layer was quantified by liquid chromatography using p-nitrochlorobenzene as an internal standard. Yield 5.1 g of p-nitrobenzyl alcohol, 98% yield (vs. di-p-nitrobenzyl malonate). Liquid chromatography purity 99.8 area%.

Example 4 A 50 cc 4-necked flask equipped with a stirrer and a thermometer was placed in a di-
p-nitrobenzyl malonate 6.4 g, toluene
20 cc, 2.3 g of methanol were added at room temperature, cooled to 10 ° C., and 1.4 g of 28% sodium hydroxide aqueous solution was added to 10
The solution was added dropwise over a period of minutes and then kept at 10-20 ° C for 1 hour to complete the hydrolysis reaction. The pH of the reaction solution was adjusted to 5-6 with a 20% aqueous solution of sulfuric acid, and then the reaction solution was heated. When the temperature of the reaction solution was 70 ° C., the distillation of methanol started, and when the temperature of the reaction solution was 80 ° C., when the distillation of methanol was low, the reaction solution was cooled, maintained at 40 ° C., stopped stirring, and left to stand. The p-nitrobenzyl alcohol contained in the toluene layer was quantified by liquid chromatography using p-nitrochlorobenzene as an internal standard. Obtained amount p-nitrobenzyl alcohol 4.9 g, yield 95% (vs. di-p-nitrobenzyl malonate). Liquid chromatography purity 99.3 area%.

Example 5 In a 200 cc four-necked flask equipped with a stirrer, a thermometer, and a water separator, 10.8 g of p-nitrobenzyl alcohol,
Malonic acid 20.8 g, di-p-nitrobenzyl malonate 5.5 g, p-toluenesulfonic acid monohydrate
0.25 g and 100 cc of toluene are added at room temperature, and the temperature is raised to 110 ° C. over 2 hours, and then 110 hours is added.
While refluxing toluene at -112 ° C, water is azeotropically distilled and removed from the reaction system. The reaction solution was cooled to 50 ° C. to precipitate malonic acid, stirred at the same temperature for 30 minutes and allowed to stand for 30 minutes, and the supernatant of the reaction solution was transferred to a 300 cc flask.
Wash the reaction flask and malonic acid with 25 cc of toluene,
The washing solution was transferred to the above 300 cc flask. (Recovered malonic acid 9.6 g). Further, 150 cc of water is added to the 300 cc flask and kept at 40 ° C. Crystals precipitated. An electrode for pH measurement was put in and thoroughly stirred. Potassium carbonate was added over about 15 minutes until the pH was 5.8. The amount used was 5.7g. Then, the mixture was allowed to stand, the separated lower aqueous layer was taken, the aqueous layer was washed with about 50 cc of toluene, and a 20% aqueous sulfuric acid solution was slowly added to adjust the pH to 3.0. The amount used was 17 cc. After stirring for about 1 hour, vacuum filtration was performed. The filter cake was washed with a little water. The cake was dried under reduced pressure at 50-60 ° C. Yield Mono-p-nitrobenzyl malonate 14.8
g, 62% yield (vs. p-nitrobenzyl alcohol).
Melting point 107-110 [deg.] C. Liquid chromatography purity 9
9.7 area%.

Example 6 In a 200 cc 4-necked flask equipped with a stirrer, a thermometer and a water separator, 20.8 g of malonic acid, 5.5 g of di-p-nitrobenzyl malonate and p-toluenesulfonic acid monohydrate were added. 1.0 g and 100 cc of nitrobenzene were added at room temperature, the temperature was raised to 107 ° C over 2 hours, and then the reaction was performed at 107-110 ° C for 6 hours. The reaction solution was cooled to 20 ° C., malonic acid was precipitated, and the mixture was stirred at the same temperature for 30 minutes,
After leaving still for 30 minutes, the supernatant of the reaction solution was transferred to a 300 cc flask. Reaction flask, malonic acid and nitrobenzene
It was washed with 25 cc, and the washing solution was transferred to the above 300 cc flask. (Recovered malonic acid 9.6 g). When the nitrobenzene solution was analyzed by liquid chromatography using p-nitrochlorobenzene as an internal standard, it was found that the mono-p-nitrobenzyl malonate was 5.6 g and the yield was 80%.

Example 7 In a 200 cc four-necked flask equipped with a stirrer, a thermometer, and a water separator, 10.4 g of p-nitrobenzyl alcohol,
4.9 g of p-nitrobenzyl alcohol recovered in Example 4 (included in 20 cc of toluene), malonic acid
15.6 g, p-toluenesulfonic acid monohydrate 0.2
5 g of toluene and 80 cc of toluene were added at room temperature, the temperature was raised to 110 ° C. over 2 hours, and then 1 hour, 110-11
While refluxing toluene at 2 ° C., water is azeotropically distilled and removed from the reaction system. The reaction solution was cooled to 50 ° C. to precipitate malonic acid, stirred at the same temperature for 30 minutes and allowed to stand for 30 minutes, and the supernatant of the reaction solution was transferred to a 300 cc flask. The reaction flask and malonic acid were washed with 15 cc of toluene, and the washing solution was transferred to the above 300 cc flask. (5.2 g of recovered malonic acid). Further, add water 1 to the 300 cc flask.
Add 50 cc and keep at 40 ° C. Crystals precipitated. pH
An electrode for measurement was put in and thoroughly stirred. Potassium carbonate was added over about 15 minutes until the pH was 5.4. The amount used was 5.7g. Then, the mixture is allowed to stand still, the separated lower aqueous layer is taken, and the aqueous layer is washed with about 50 cc of toluene,
A 20% aqueous sulfuric acid solution was slowly added to adjust the pH to 3.0. The amount used was 17 cc. After stirring for about 1 hour, vacuum filtration was performed. The filter cake was washed with a little water. The cake was dried under reduced pressure at 50-60 ° C. Yield Mono-p-nitrobenzyl malonate 15.5
g, 65% yield (vs. p-nitrobenzyl alcohol).
Melting point 107-110 [deg.] C. Liquid chromatography purity 9
9.8 area%.

Example 8 In a 200 cc four-necked flask equipped with a stirrer and a thermometer, the toluene solution of the di-p-nitrobenzyl malonate obtained in Example 1 (di-p-nitrobenzyl malonate 6.
2 g, toluene 100 cc) and methanol 27 cc were added at room temperature to dissolve di-p-nitrobenzyl malonate. When 7 g of water was added, it became cloudy. The reaction solution was cooled to 10 ° C, and 30% of 2.7% of 28% aqueous sodium hydroxide solution was added.
The solution was added dropwise over a period of minutes and then kept at 10-20 ° C for 1 hour to complete the hydrolysis reaction. The pH of the reaction solution was adjusted to 5-6 with a 20% aqueous solution of sulfuric acid, and then the reaction solution was heated. When the temperature of the reaction solution was 70 ° C., the distillation of methanol started, and when the temperature of the reaction solution was 80 ° C. and the distillation of methanol was low, the temperature was cooled, the temperature was kept at 40 ° C., stirring was stopped, and the mixture was allowed to stand, After separating the lower aqueous layer, the toluene layer was washed with 10 cc of water. The p-nitrobenzyl alcohol contained in the toluene layer was quantified by liquid chromatography using p-nitrochlorobenzene as an internal standard. Yield 5.0 g of p-nitrobenzyl alcohol, 98% yield (vs. di-p-nitrobenzyl malonate). Liquid chromatography purity 99.8 area%.

Example 9 In a 200 cc 4-necked flask equipped with a stirrer, a thermometer and a water separator, 10.8 g of p-nitrobenzyl alcohol,
20.8 g of malonic acid, toluene solution of di-p-nitrobenzyl malonate obtained in Example 2 (5.0 g of di-p-nitrobenzyl malonate, toluene 100c)
c), 0.25 g of p-toluenesulfonic acid monohydrate was added at room temperature, the temperature was raised to 110 ° C. over 2 hours, and then water was added while refluxing toluene at 110-112 ° C. for 1 hour. Azeotropically and remove it outside the reaction system. The reaction solution was cooled to 50 ° C. to precipitate malonic acid, stirred at the same temperature for 30 minutes and allowed to stand for 30 minutes, and the supernatant of the reaction solution was transferred to a 300 cc flask. Reaction flask, malonic acid in toluene 2
It was washed with 5 cc, and the washing solution was transferred to the above 300 cc flask. (Recovered malonic acid 9.6 g). Furthermore, 30
To a 0 cc flask, add 150 cc of water and keep at 40 ° C. Crystals precipitated. An electrode for pH measurement was put in and thoroughly stirred. Approximately 1 potassium carbonate until pH 5.8
Added over 5 minutes. The amount used was 5.7g. Then, the mixture is allowed to stand still, the separated lower aqueous layer is taken, and the aqueous layer is separated by about 50
After washing with cc of toluene, a 20% sulfuric acid aqueous solution was slowly added to adjust the pH to 3.0. The amount used was 17 cc. After stirring for about 1 hour, vacuum filtration was performed. The filter cake was washed with a little water. The cake was dried under reduced pressure at 50-60 ° C. Yield Mono p-nitrobenzyl malonate 14.8
g, 62% yield (vs. p-nitrobenzyl alcohol).
Melting point 107-110 [deg.] C. Liquid chromatography purity 99.7 area%.

Example 10 In a 300 cc 4-necked flask equipped with a stirrer, a thermometer, and a water separator, 15.3 g of p-nitrobenzyl alcohol was added.
Malonic acid (31.2 g), p-toluenesulfonic acid monohydrate (0.125 g) and o-dichlorobenzene (30 cc) were added at room temperature, and the mixture was heated. 1 g of water was added at 70 ° C. The temperature was raised to 100 ° C over 1 hour, and then 100 minutes for 100 minutes.
Hold at ℃. Reduce the pressure inside the reaction system to 170 mmHg,
Water was azeotroped with o-dichlorobenzene. During that time, o-dichlorobenzene was added dropwise little by little. 1.5
After a lapse of time, the reaction temperature had risen to 110 ° C., the distilled o-dichlorobenzene was 7 cc, the water was 2 cc, and the dropped o-dichlorobenzene was 5 cc. The degree of vacuum in the reaction system was 125 mmHg. The reduced pressure was returned to normal pressure, 75 cc of o-dichlorobenzene was added, the temperature of the reaction product was cooled to 40 ° C., malonic acid was precipitated, and the mixture was stirred for 30 minutes at the same temperature and allowed to stand for 30 minutes. 30 liquid
Transferred to a 0cc flask. The reaction flask and malonic acid were washed with 30 cc of hot o-dichlorobenzene, and the washing solution was
Transferred to the above 300 cc flask. (Recovered malonic acid 1
8.2 g). Further, add water to the 300 cc flask.
When 0 cc was added and the temperature was kept at 40 ° C, crystals were precipitated. An electrode for pH measurement was put in and thoroughly stirred. A 30% aqueous potassium carbonate solution was added over about 15 minutes until the pH was 5.5. I needed 23cc. Then, the mixture was left standing, and the separated aqueous layer was washed with about 15 cc of o-dichlorobenzene,
% Sulfuric acid aqueous solution was slowly added to bring the pH to 2.5.
The amount used was 22 cc. After stirring for about 1 hour, vacuum filtration was performed. The filter cake was washed with a little water. Cake is 5
It was dried under reduced pressure at 0-60 ° C. Yield Mono-p-nitrobenzyl malonate 17.9
g, yield 74.8% (vs p-nitrobenzyl alcohol-
Le). Melting point 107-110 [deg.] C. Liquid chromatography-Purity 99.8 area%.

Example 11 In a 300 cc 4-neck flask equipped with a stirrer, a thermometer, and a water separator, 15.3 g of p-nitrobenzyl alcohol was added.
Malonic acid (31.2 g) and toluene (36 cc) were added at room temperature and heated. At 70 ° C., 1 g of water and 0.125 g of p-toluenesulfonic acid monohydrate were added. 1 hour, 1
The temperature was raised to 05 ° C, and toluene was refluxed. When the temperature was raised to 111 ° C. over about 2 hours while separating the distilled water, the water stopped distilling and the reaction was completed. Toluene (75 cc) was added, the temperature of the reaction product was cooled to 70 ° C., malonic acid was precipitated, and the mixture was stirred at the same temperature for 30 min.
After leaving to stand still, the supernatant of the reaction solution was transferred to a 300 cc flask. Reaction flask, malonic acid in hot toluene 30 cc
After washing, the washing solution was transferred to the above 300 cc flask. (Recovered malonic acid 18.2 g). Furthermore, the 300
When 50 cc of water was added to the cc flask and kept at 40 ° C., crystals were precipitated. An electrode for pH measurement was put in and thoroughly stirred. A 30% aqueous potassium carbonate solution was added over about 15 minutes until the pH was 5.5. I needed 23cc. Then, the mixture is left to stand still, and the separated lower aqueous layer is taken.
After washing with cc of toluene, a 20% aqueous sulfuric acid solution was slowly added to adjust the pH to 2.5. The amount used was 22 cc. After stirring for about 1 hour, vacuum filtration was performed. The filter cake was washed with a little water. The cake was dried under reduced pressure at 50-60 ° C. Yield Mono-p-nitrobenzyl malonate 17.9
g, yield 74.8% (vs p-nitrobenzyl alcohol-
Le). Melting point 107-110 [deg.] C. Liquid chromatography-Purity 99.8 area%.

[0036]

Industrial Applicability Since excess malonic acid can be separated from the reaction solution, the waste water load is small and the by-product di-p-nitrobenzyl malonate can be efficiently treated, which is economical.

Claims (5)

(57) [Claims] 1. A reaction solution obtained by reacting p-nitrobenzyl alcohol with malonic acid in an organic solvent,
After cooling to 100 ° C. and separating the precipitated malonic acid, the reaction solution is treated with a basic aqueous solution at 35-80 ° C. to extract mono-p-nitrobenzyl malonate. -Process for producing p-nitrobenzyl malonate 2. Malonic acid precipitated by reacting p-nitrobenzyl alcohol with malonic acid in an organic solvent containing di-p-nitrobenzyl malonate and cooling the resulting reaction solution to 35-100 ° C. After separating the
A method for producing mono-p-nitrobenzyl malonate, which comprises treating with monobasic aqueous solution at 80 ° C. to extract mono-p-nitrobenzyl malonate 3. The method for producing mono-p-nitrobenzyl malonate according to claim 1, wherein the organic solvent is toluene, xylene, monolbenzene or dichlorobenzene. 4. The method for producing mono-p-nitrobenzyl malonate according to claim 1 or 2, wherein di-p-nitrobenzyl malonate present in the reaction solution after extraction of mono-p-nitrobenzyl malonate. Hydrolyze the nate to p-
The method for producing mono-p-nitrobenzyl malonate according to claim 1 or 2, wherein nitrobenzyl alcohol is obtained and used as a raw material. 5. The method for producing mono-p-nitrobenzyl malonate according to claim 1 or 2, wherein di-p-nitrobenzyl malonate present in the reaction solution after extraction of mono-p-nitrobenzyl malonate. 3. The method for producing mono-p-nitrobenzyl malonate according to claim 1, wherein malonate is reacted with malonate to convert into mono-p-nitrobenzyl malonate.