JP3193136B2 - Method for producing N, O-dialkylhydroxycarbamic acid ester - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a process for producing N, O-dialkylhydroxycarbamic acid esters. N, O-dialkylhydroxycarbamic acid ester is a compound useful as a raw material for N, O-dialkylhydroxylamine such as N, O-dimethylhydroxylamine which is a synthetic intermediate of pharmaceuticals and agricultural chemicals.

[0002]

2. Description of the Related Art Generally, as a method for producing an N, O-dialkylhydroxycarbamate from hydroxylamine or a salt thereof, chloroformate is reacted with a salt of hydroxylamine in the presence of sodium hydroxide, and then sulfated. A method of reacting a dialkyl with sodium hydroxide is known.

For example, as a method for producing ethyl N, O-dimethylhydroxycarbamate, Org. Prep.
d., 19 , 75 (1987). In this method, hydroxylamine hydrochloride and ethyl chloroformate are reacted using an aqueous solution of sodium hydroxide to obtain ethyl hydroxycarbamate, and then dimethylation is performed using dimethyl sulfate and an aqueous solution of sodium hydroxide. ,
Ethyl N, O-dimethylhydroxycarbamate is obtained with a yield of 70 to 73%.

Further, butyl N, O-dimethylcarbamate is disclosed in West German Patent Application No. 32455.
The method described in No. 03 is known. In this method, a hydroxylamine sulfate is used as a raw material, butyl chloroformate is reacted with sodium hydroxide, then extracted with dichloromethane, and then dried and evaporated to obtain butyl hydroxycarbamate. Then, dimethylation is performed using dimethyl sulfate and an aqueous solution of sodium hydroxide,
This is a method of obtaining butyl N, O-dimethylhydroxycarbamate with a total yield of 65%.

[0005]

However, the method reported in the prior art has a problem that the yield of the target N, O-dialkylhydroxycarbamate is low for industrial implementation. . Further, according to the study of the present inventors, when hydroxylamine or a salt thereof is carbamoylated with methyl chloroformate and then dialkylated to produce methyl N, O-dialkylhydroxycarbamate, it is used as a carbamoylating agent. Since the present reaction is carried out using an aqueous solution as a solvent, the methyl chloroformate used is easily hydrolyzed, and, as shown in Reference Example 1 described later, the hydroxyl group of the produced intermediate methyl hydroxycarbamate and chloroformate are used. It has been found that there is a problem that the yield of the target product is further reduced due to the reaction of methyl acid.

The present invention has been made in order to solve the above-mentioned problems in the conventional method, and provides a method for producing N, O-dialkylhydroxycarbamic acid ester in a higher yield than in the conventional method. The purpose is to do.

[0007]

Means for Solving the Problems The present inventors have searched for a carbamoylating agent in order to solve the above-mentioned problems, and found that dihydrocarbyl carbonate hardly undergoes hydrolysis, and that the intermediate hydroxy It was found that when dihydrocarbyl carbonate was used as a carbamoylating agent because it did not react with the hydroxyl group of the carbamic acid ester, the desired N, O-dialkylhydroxycarbamic acid ester could be obtained in high yield. Completed the invention.

Namely, the present invention has the formula: with hydroxylamine or a salt thereof represented by NH ₂ OH, the following equation ^{(1): R 1 OCOOR 1} (1) ( wherein, R ¹ represents a hydrocarbon group ) Is reacted with dihydrocarbyl carbonate represented by the following formula (2): HONHCOOR ¹ (2) (wherein R ¹ has the same meaning as described above). Which is then treated with an alkylating reagent in the presence of a basic compound, characterized by the following formula (3):

[0009]

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(Wherein, R ² represents a lower alkyl group, and R ¹ has the same meaning as described above). Examples of the hydrocarbon group represented by R ¹ in the formulas (1) to (3) include a methyl group, an ethyl group, an n-propyl group,
C1-C3 alkyl group such as isopropyl group; C3-C7 cycloalkyl group such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group; phenyl group, tolyl group, xylyl group, etc. And an aralkyl group such as a benzyl group and a phenethyl group.

In the above formula (3), the lower alkyl group represented by R ² means an alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl and n-butyl. Group, isobutyl group, sec-butyl group, ter
t-butyl group. Examples of the hydroxylamine or a salt thereof used as a raw material include hydroxylamine, hydroxylamine sulfate, and hydroxylamine hydrochloride. Of these, hydroxylamine sulfate and hydroxylamine hydrochloride are preferable in terms of stability and cost. These hydroxylamines or salts thereof may be in the form of an aqueous solution or an organic solution such as methanol.

Examples of the dihydrocarbyl carbonate include dialkyl carbonates such as dimethyl carbonate, diethyl carbonate, di-n-propyl carbonate and diisopropyl carbonate; dicycloalkyl carbonates such as dicyclopentyl carbonate, dicyclohexyl carbonate and dicycloheptyl carbonate; Examples include diaryl carbonate such as diphenyl carbonate, ditolyl carbonate and dixylyl carbonate, and diaralkyl carbonate such as dibenzyl carbonate and diphenethyl carbonate. For example, when producing methyl N, O-dimethylhydroxycarbamate, dimethyl carbonate is used.

The basic compound includes, for example, alkali metal or alkaline earth metal hydroxides represented by sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide and barium hydroxide; sodium hydrogen carbonate, Alkali metal bicarbonate represented by potassium bicarbonate; alkali or alkaline earth metal carbonate represented by sodium carbonate, potassium carbonate, barium carbonate; and aluminate represented by sodium aluminate and potassium aluminate Compounds may be mentioned, and these basic compounds may be used alone or as a mixture of two or more. As the basic compound, sodium hydroxide is particularly preferable in terms of price. These basic compounds are preferably used in an aqueous solution, but may be used as they are, or may be used after being dissolved in an organic solvent such as alcohol.

Examples of the alkylating agent include dialkyl sulfates represented by dimethyl sulfate and diethyl sulfate; alkyl chlorides represented by methyl chloride, ethyl chloride, propyl chloride and butyl chloride; methyl bromide, ethyl bromide; Alkyl bromide represented by propyl bromide and butyl bromide; and alkyl iodide represented by methyl iodide, ethyl iodide, propyl iodide and butyl iodide. Esters are preferred. For example, when producing methyl N, O-dimethylhydroxycarbamate, it is preferable to use dimethyl sulfate.

As a reaction solvent, water is preferably used, but an inert organic solvent such as an ether represented by diethyl ether or tetrahydrofuran or an aromatic compound represented by benzene or toluene is used alone or as a mixture. Or in a two-layer system. The molar ratio of hydroxylamine or a salt thereof to dihydrocarbyl carbonate is usually from 1 / 0.5 to 1/2, preferably from 1/1 to 1/1/2.
1.5, more preferably 1/1 to 1 / 1.3.

The molar ratio between hydroxylamine or a salt thereof and the alkylating agent is usually 1/2 or more. When dimethyl sulfate is used as the alkylating agent, it is preferably from 1/2 to 1/4, more preferably from 1/2 to 1/4.
2.5. The amount of the basic compound used is not particularly limited, but it is preferable to use the basic compound in such an amount that the pH of the reaction solution is controlled within the range described below.

The method of adding the raw materials is not particularly limited, but a method in which hydroxylamine or a salt thereof and a reaction solvent are first charged into a reactor, and then dihydrocarbyl carbonate and a basic compound are simultaneously supplied, is a reaction method. It is preferable because the temperature and the pH of the reaction solution can be constantly controlled. When a hydroxylamine sulfate or hydrochloride is used as a raw material, it is preferable to add a basic compound to neutralize these salts before supplying dihydrocarbyl carbonate.

In the case of the dialkylation reaction, it is preferable to simultaneously supply the alkylating agent and the basic compound in order to keep the reaction temperature and the pH of the reaction solution constant. Further, the intermediate hydroxycarbamic acid ester may be isolated, or two reactions may be carried out successively without isolation in a single reactor. In consideration of the reaction time and the cost of the extraction solvent, it is preferable to carry out the two reactions using a single reactor without isolation in the middle.

The reaction temperature range for the carbamoylation reaction and the dialkylation reaction is usually -20 to 80 ° C, preferably -10 to 40 ° C, more preferably 0 to 25 ° C.
It is. The pH range of the reaction solution at this time is usually 7
To 14, preferably 11 to 14, more preferably 1
2 to 14. In particular, when the combination of the reaction temperature of 5 ± 5 ° C. and the pH of the reaction solution is 12 to 13 is industrially produced, the yield is high, and the control of the reaction temperature and the pH of the reaction solution is easy. Most preferred because of The reaction pressure is
It is usually above normal pressure. When the alkylating reagent becomes a gas under the reaction conditions, it is necessary to carry out the reaction under pressure.

[0020]

EXAMPLES Hereinafter, the present invention will be described more specifically with reference to Examples, Comparative Examples, and Reference Examples, but the scope of the present invention is not limited to the following Examples. (Example 1) A stirrer piece was placed in a 200 ml four-necked flask equipped with a pH meter electrode, a thermometer, a syringe, and a feed pipe of a feed pump, and 8.2 g of 95% hydroxylamine sulfate manufactured by Wako Pure Chemical Industries, Ltd. was placed therein. (95mm
ol) and 25 ml of water, and the mixture was cooled to an internal temperature of 5 ° C. Under a nitrogen atmosphere, a 50% aqueous sodium hydroxide solution was dropped from the syringe until the pH value of the reaction solution reached 13. Internal temperature 5
While maintaining the pH of the reaction solution at 13 ° C., 9
10 g (108 mmol) of 8% dimethyl carbonate was fed simultaneously using a feed pump and a 50% aqueous sodium hydroxide solution using a syringe over 40 minutes. After the supply, stirring was further continued under these conditions for 2 hours. Next, while maintaining the reaction temperature at 5 ° C. and the pH of the reaction solution at 13, using a feed pump, 27.8 g (209 mmol) of 95% dimethyl sulfate manufactured by Wako Pure Chemical Co., Ltd. was injected with a 50% aqueous sodium hydroxide solution using a syringe. And fed simultaneously over 1 hour. After the supply, stirring was further continued for 3 hours under these conditions, and chloroform was added to extract methyl N, O-dimethylhydroxycarbamate. Quantitative analysis of the extract using gas chromatography revealed that 11.0 g of methyl N, O-dimethylhydroxycarbamate (yield 97
%).

(Examples 2 to 6) pH of the reaction solution of Example 1
The reaction was performed under the condition that only was changed. Table 1 shows the experimental results.

[0022]

Table 1 Example pH of carbamoylation reaction Dimethylation reaction PH yield (%) ────────────────────────────────────2 12.5 12.5 98 3 12 12 90 4 12 13 94 5 13 12 94 6 13.5 13.5 92 7 14 13 91 8 14 14 84 (Example 9) After the carbamoylation reaction of Example 1 was completed, the pH of the reaction solution was adjusted to 7, and the reaction solution was evaporated to dryness. 4.55 g (50 mmol) of methyl hydroxycarbamate extracted with ethyl acetate and further isolated by column chromatography and 15 ml of water They were charged into the same reactor as was cooled to an inner temperature of 5 ° C.. Under a nitrogen atmosphere, a 50% aqueous sodium hydroxide solution
After dripping from the syringe until the H value becomes 13, the internal temperature is adjusted to 5
While maintaining the pH of the reaction solution at 13 ° C., 9
13.9 g (105 mmol) of 5% dimethyl sulfate was simultaneously supplied over a period of 1 hour using a feed pump and a 50% aqueous sodium hydroxide solution using a syringe. After the supply, stirring was further continued under these conditions for 5 hours, and chloroform was added to extract methyl N, O-dimethylhydroxycarbamate. When quantitative analysis was performed on the extract using gas chromatography, 5.2 g (87% yield) of methyl N, O-dimethylhydroxycarbamate was obtained.
Had been generated.

Comparative Example 1 A stirrer piece was placed in a 50 ml four-necked flask equipped with a thermometer and a syringe.
Here, 95% hydroxylamine sulfate manufactured by Wako Pure Chemical Industries, Ltd.
67 g (20 mmol) and 5 ml of water were added, and the mixture was cooled to an internal temperature of 2 ° C. Under a nitrogen atmosphere, 2.12 g (22 mmol) of 98% methyl chloroformate manufactured by Wako Pure Chemical Industries, Ltd. was added, and 10N
6.2 ml of an aqueous sodium hydroxide solution was added dropwise from the syringe over 1 hour while maintaining the reaction temperature at 8 ° C or lower. Further, stirring was continued for 3 hours while maintaining the internal temperature at 2 to 5 ° C. Next, 5.84 g (44%) of 95% dimethyl sulfate manufactured by Wako Pure Chemical Industries, Ltd.
mmol), and 2.4 ml of a 10N aqueous sodium hydroxide solution was added dropwise using a syringe over 30 minutes. After the supply, the reaction temperature was raised from 15 to 20 ° C., and stirring was continued at this temperature for 3 hours, and then the reaction solution was subjected to quantitative analysis using liquid chromatography. When the same reaction was performed twice, methyl N, O-dimethylhydroxycarbamate was 0.87 g (yield 37%) and 1.15 g, respectively.
g (yield 47%).

Example 10 The reaction was carried out under exactly the same conditions except that the methyl chloroformate used in Comparative Example 1 was changed to dimethyl carbonate, and the amount of the 10N aqueous sodium hydroxide solution added dropwise after the addition of dimethyl carbonate was changed to 4 ml. After doing
The yield of methyl N, O-dimethylhydroxycarbamate was 72%.

(Reference Example 1) 1.82 g (20 mmol) of methyl hydroxycarbamate and 6 ml of water were charged into a 50 ml four-necked flask equipped with a thermometer and two syringes, and 98% chloroformic acid manufactured by Wako Pure Chemical Industries, Ltd. 0.77 ml of methyl
(10 mmol) and 1m of 10N sodium hydroxide aqueous solution
1 (10 mmol) while maintaining the reaction temperature at 5 ° C.
Minutes and simultaneously dropped from the syringe. Further, stirring was continued for 1 hour while maintaining the internal temperature at 5 ° C. The reaction liquid was subjected to qualitative analysis using liquid chromatography, and as a result, methyl O-methoxycarbonylhydroxycarbamate was formed. The raw materials methyl hydroxycarbamate and O-
The liquid chromatography area ratio of methyl methoxycarbonylhydroxycarbamate was 62:35.

Reference Example 2 The reaction was carried out under exactly the same conditions as in Reference Example 1 except that methyl chloroformate was changed to dimethyl carbonate. As a result, methyl O-methoxycarbonylhydroxycarbamate was not produced at all.

[0027]

According to the production method of the present invention, it has become possible to produce N, O-dialkylhydroxycarbamic acid ester in a high yield, which was low in the yield by the conventional method.

Continuation of the front page (72) Inventor Noriaki Kihara 1-2-1, Waki, Waki-machi, Kuga-gun, Yamaguchi Prefecture Inside Mitsui Petrochemical Industry Co., Ltd. (56) References JP-A-6-41047 (JP, A) (58) ) Field surveyed (Int.Cl. ⁷ , DB name) C07C 291/14 C07C 271/08 C07C 271/12 C07C 269/06 CASREAACT (STN)

Claims (1)

(57) [Claims] 1. A hydroxylamine represented by the following formula: NH ₂ OH or a salt thereof, and the following formula (1): R ¹ OCOOR ¹ (1) (wherein, R ¹ represents a hydrocarbon group). Reaction with dihydrocarbyl carbonate in the presence of a basic compound at a reaction temperature of 5 ±
5 ° C., in pH12~13 conditions of the reaction solution is reacted, the following equation ^{(2): HONHCOOR 1 (2} ) (. In the formula, R ¹ is as defined above) hydroxylamine represented by <br/> After preparing the carbamic acid ester, this is reacted in the presence of a basic compound at a reaction temperature of 5 ± 5 ° C. and a pH of 12 to
Wherein the compound is treated with an alkylating reagent under the condition (13 ): (Wherein, R ² represents a lower alkyl group, and R ¹ has the same meaning as described above.)