JPH083126A - Production of n,o-dimethylhydroxylamine - Google Patents

Abstract

PURPOSE:To easily isolate and purify N,O-dimethylhydroxylamine by reaction of hydroxylamine or its salt with methyl chloroformate under specific condition to obtain the intermediate in high yield, and easy methylation of the intermediate in a homogenous system followed by hydrolysis of the methylated product with a base. CONSTITUTION:The reaction of methyl chloroformate with hydroxylamine is carried out at pH of 5-12 at 0-10 deg.C, as methyl chloroformate and a base are simultaneously added to hydroxylamine or its salt to give methyl hydroxycarbamate as an intermediate in high yield. Then, a methylating agent and a base are simultaneously added to the intermediate at pH of 10.5-12.5 at 0-15 deg.C to effect methylation in a homogeneous system to give methyl N,O- dimethylhydroxycarbamate in high yield. The methyl N,O- dimethylhydroxycarbamate is azeotropically distilled off together with water from the reaction mixture to effect isolation and purification of the carbamate in high yield. Finally, a base is used to effect hydrolysis of the carbamate at 50-100 deg.C to give N,O-dimethylhydroxylamine or its salt. The product is useful as a starting material for medicines and agrochemicals.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a process for producing N, O-dimethylhydroxylamine which is useful as a raw material for medicines and agricultural chemicals.

[0002]

2. Description of the Related Art As a method for producing N, O-dialkylhydroxylamine via N, O-dialkylhydroxycarbamate, a hydroxycarbamate is prepared by reacting a chloroformate with a hydroxylamine salt in the presence of a base. There is known a method of producing and then reacting with a dialkyl sulfate in the presence of a base to obtain an N, O-dialkylhydroxycarbamic acid ester, which is further hydrolyzed.

For example, as a production method via ethyl N, O-dimethylhydroxycarbamate, Org. Prep.
The method described in Proced., 19 , 75 (1987) has been reported.
In this method, hydroxylamine hydrochloride and ethyl chloroformate are reacted with 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. To obtain ethyl N, O-dimethylhydroxycarbamate at a rate of 70-73%, and further hydrolyze ethyl N, O-dimethylhydroxycarbamate with concentrated hydrochloric acid to give N, O-dimethylhydroxylamine in a yield of 93- 9
The yield is 5% and the total yield is 65 to 70%.

Further, as a method of passing through butyl N, O-dimethylcarbamate, a method described in DE 3245503 is known. In this method, hydroxylamine sulfate is used as a raw material, and butyl chloroformate and sodium hydroxide are reacted with each other, followed by extraction with dichloromethane, drying and concentration to obtain butyl hydroxycarbamate. A primary amine salt is added as a phase transfer catalyst, and dimethylation is performed using dimethyl sulfate and an aqueous solution of sodium hydroxide to obtain butyl N, O-dimethylhydroxycarbamate with a yield of 65%. Butyl dimethylhydroxycarbamate is hydrolyzed with concentrated hydrochloric acid to obtain N, O-dimethylhydroxylamine with a total yield of 64%.

[0005]

However, the method reported hitherto has a low yield when a hydroxycarbamic acid ester is produced by reacting a hydroxylamine salt with ethyl chloroformate or butyl chloroformate, and , When the hydroxycarbamate ester is butyl hydroxycarbamate, it is water-insoluble, so it is necessary to add a phase transfer catalyst during the methylation reaction, while when the intermediate is ethyl hydroxycarbamate,
Since ethyl N, O-dimethylhydroxycarbamate produced by methylation is highly water-soluble, it is necessary to extract it by using a large amount of an organic solvent such as a halogenated hydrocarbon when isolating it. There were problems in industrially carrying out the production of hydroxylamine.

The present invention has been made to solve the above-mentioned problems, and produces methyl N, O-dimethylhydroxycarbamate, which is an intermediate, in a higher yield than in the conventional method, and further, An object of the present invention is to provide a rational method for producing N, O-dimethylhydroxylamine by purifying the compound by an excellent method.

[0007]

Means for Solving the Problems The inventors of the present invention have conducted extensive studies to solve the above-mentioned problems, and as a result, by reacting hydroxylamine or a salt thereof with methyl chloroformate under specific conditions, an intermediate It was found that methyl hydroxycarbamate, which is ## STR7 ## is obtained in high yield, and that methylation reaction of this product easily proceeds in a homogeneous system to obtain methyl N, O-dimethylhydroxycarbamate in high yield. . Further, they have found that the produced methyl N, O-dimethylhydroxycarbamate can be easily separated and purified with a higher recovery rate than a solvent system containing a salt, and completed the present invention.

That is, according to the present invention, (1) hydroxylamine or a salt thereof is reacted under conditions of pH 5 to 12 and 0 to 10 ° C. while simultaneously adding methyl chloroformate and a base to produce methyl hydroxycarbamate. (2) Then, to the obtained methyl hydroxycarbamate or a reaction mixture or a crude product containing the same, pH 10.5 to 1
The reaction was carried out under the conditions of 2.5 and 0 to 15 ° C. while simultaneously adding a methylating agent and a base to produce methyl N, O-dimethylhydroxycarbamate. (3) Then, N from the obtained reaction mixture was used. , O-dimethylhydroxycarbamate was azeotropically distilled with water to separate and purify (4), and then the N, O-dimethylhydroxycarbamate in the obtained azeotrope was added 0.5 to 4.0 times. A method for producing N, O-dimethylhydroxylamine or a salt thereof, which comprises hydrolyzing at 50 to 100 ° C. with a molar base.

The present invention will be described in detail below. First, the raw materials used in the present invention will be described. Examples of hydroxylamine or a salt thereof to be reacted with methyl chloroformate include hydroxylamine or hydroxylamine salts such as hydroxylamine sulfate and hydroxylamine hydrochloride. From the viewpoint of stability, hydroxylamine sulfate or hydroxylamine hydrochloride is preferable, and the price is low. From the aspect, hydroxylamine sulfate is more preferable. Further, the hydroxylamine salt may be in a state of being dissolved in water or an organic solvent such as methanol.

The base used in the reaction of hydroxylamine or its salt with methyl chloroformate and in the methylation reaction is typified by sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide and barium hydroxide. Alkali metal or alkaline earth metal hydroxides; alkali metal hydrogen carbonates represented by sodium hydrogen carbonate and potassium hydrogen carbonate; alkali metal or alkaline earth metals represented by sodium carbonate, potassium carbonate and barium carbonate Examples thereof include carbonates of metals; and aluminate compounds represented by sodium aluminate and potassium aluminate. These bases may be used alone or in combination of two or more, and in consideration of cost and reactivity,
Preferred are sodium hydroxide, sodium hydrogen carbonate and sodium carbonate, and more preferred is sodium hydroxide. These bases are preferably used in an aqueous solution, but solids may be used as they are or may be used by dissolving them in an organic solvent such as alcohol.

As the methylating agent, dimethyl sulfate, methyl chloride, methyl bromide and methyl iodide can be usually exemplified, but it is particularly preferable to use dimethyl sulfate. Although water is preferably used as the reaction solvent, diethyl ether, ethers typified by tetrahydrofuran, benzene, or an inert organic solvent typified by toluene, such as an aromatic hydrocarbon, is used alone or mixed, or water is used. It may be used in a two-layer system.

One of the features of the present invention is to obtain methyl hydroxycarbamate, which is an intermediate, in a high yield, and the amount of raw materials used, the reaction method and the reaction conditions for producing the same will be described in detail below. The use ratio of each raw material in the method of the present invention is as follows. The amount of methyl chloroformate used is usually 0.9 with respect to hydroxylamine or a salt thereof.
To 2 times mol, preferably 0.9 to 1.5 times mol, more preferably 1.0 to 1.1 times mol.

The amount of the methylating agent used is usually at least 2 times the molar amount of hydroxylamine or a salt thereof, and when dimethyl sulfate is used as the methylating agent, it is preferably 2.0 to 4.0 times the molar amount. , And more preferably 2.0 to 2.2.
It is 5 times the molar amount. The amount of the base used is not particularly limited, but it is necessary to use it in such an amount that the pH of the reaction solution is controlled within the range described below.

In the present invention, in the reaction of hydroxylamine or its salt with methyl chloroformate, hydroxylamine or its salt is first charged, and then methyl chloroformate is supplied simultaneously with the above base,
As a result, the hydrolysis of methyl chloroformate can be suppressed while controlling the reaction temperature and the pH of the reaction solution to be constant, and methyl hydroxycarbamate can be obtained in high yield. When hydroxylamine sulfate or hydrochloride is used as the raw material, it is preferable to add a base to neutralize some or all of these salts before supplying methyl chloroformate.

Similarly, during the methylation reaction, a method of simultaneously supplying the methylating agent and the base while controlling the reaction temperature and the pH of the reaction solution to be constant is particularly preferable. In addition, the intermediate methyl hydroxycarbamate may be isolated before the methylation reaction, but in general, a method in which the two reactions are carried out continuously without isolation is preferable in terms of operation.

The reaction conditions of the reaction of hydroxylamine or a salt thereof with methyl chloroformate and the methylation reaction in the present invention are as follows. The temperature of the reaction between hydroxylamine or a salt thereof and methyl chloroformate is 0 to 10 ° C.
And the pH of the reaction solution at this time is 5 to 12
Range. Among the above conditions, the combination of the reaction temperature within the range of 5 ± 3 ° C. and the pH of the reaction solution within the range of 7 ± 1 has the highest yield, and the reaction temperature and the pH of the reaction solution are easily controlled. Particularly preferred. The reaction time is usually 0.1 to 5 after the completion of the addition of methyl chloroformate while maintaining the above conditions.
Time, preferably 0.2 to 4 hours, more preferably 0.
5 to 2 hours.

The reaction temperature for methylation is in the range of 0 to 15 ° C., and the pH of the reaction solution at this time is 10.5 to 12.
The range is 5. Among the above conditions, a combination of a reaction temperature of 5 ± 3 ° C. and a reaction solution pH of 11.5 ± 1 has the highest yield, and the reaction temperature and the pH of the reaction solution are easily controlled. Is particularly preferred for this. The reaction time is usually 0.1 to 5 hours, preferably 0.2 to 4 hours, more preferably 0.5 after the completion of the addition of the methylating agent while maintaining the above conditions.
~ 3 hours.

The present invention is characterized in that the intermediately formed methyl N, O-dimethylhydroxycarbamate is separated by azeotropic distillation with water without extraction with an organic solvent. It includes a separation step utilizing the superior physical properties of methyl acid, and the conditions of the separation step are as follows. The amount of water required to azeotrope methyl N, O-dimethylhydroxycarbamate with water is usually 1.0 to 1.1 parts by weight of water with respect to 1 part by weight of methyl N, O-dimethylhydroxycarbamate. However, the amount of water may be 1.1 weight times or more in excess. Usually, the required amount of water is added at the time of distillation, but water existing in the already supplied mixture may be used. The mixture is usually a homogeneous system containing an inorganic compound, but it may be a heterogeneous system containing an organic compound such as alcohol and an inorganic salt.

The pressure conditions in the azeotropic distillation are not particularly limited, and usually from normal pressure to reduced pressure conditions are used, preferably in the range of 1 to 760 mmHg, and more preferably in the range of 10 to 250 mmHg. The pressure condition may be used. The distillation temperature is usually a boiling temperature at which azeotropy occurs at a set pressure, and preferably 20 to 160 ° C., more preferably 30 to 80 ° C. It may be.

As the distillation apparatus for the azeotropic composition, it is usually desirable to use an apparatus having a distillation column having a precision distillation function such as an Oldershaw distillation column, that is, an apparatus capable of selectively recovering only the azeotropic composition. It is also possible to use batch and continuous devices having the function of simultaneously recovering other compounds and azeotropic compositions. The process for producing N, O-dimethylhydroxylamine by hydrolysis of methyl N, O-dimethylhydroxycarbamate in the fraction obtained by the azeotropic distillation will be described below.

As the base used for the hydrolysis, hydroxides of alkali metals or alkaline earth metals represented by sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide and barium hydroxide; sodium hydrogen carbonate, Alkali metal hydrogen carbonate represented by potassium hydrogen carbonate; Alkali metal or alkaline earth metal carbonate represented by sodium carbonate, potassium carbonate, barium carbonate;
4-dimethylaminopyridine (4-DMAP), 1,8
-Diazabicyclo [5.4.0] undecene (DBU)
An organic strong base such as Amberlite-93 (registered trademark),
A weak basic ion exchange resin such as Amberlyst-21 (registered trademark) can be exemplified. These bases may be used alone or in combination of two or more, and in view of cost and reactivity, sodium hydroxide, sodium hydrogen carbonate and sodium carbonate are preferable, and sodium hydroxide is more preferable. These bases are preferably used in an aqueous solution, but solids may be used as they are or may be used by dissolving them in an organic solvent such as alcohol.

The amount of base used in the hydrolysis reaction is
It is usually 0.5 to 4 times mol, preferably 0.5 to 4 mol, based on 1 mol of methyl N, O-dimethylhydroxycarbamate.
The molar ratio is 3 times, and more preferably 0.5 to 2 times. As the reaction solvent, water contained in the azeotropic reaction is usually used as it is, but an organic solvent soluble in water such as methanol, alcohols such as ethanol, tetrahydrofuran, cyclic ethers such as dioxane are mixed. You may use it. The amount of water used is usually 1 to 1 with respect to 1 part by weight of methyl N, O-dimethylhydroxycarbamate.
The amount is 00 parts by weight, preferably 2 to 10 parts by weight, more preferably 2 to 4 parts by weight. Further, the amount of the organic solvent mixed with water is usually 0.1 to 10 times by weight with respect to 1 part by weight of water.

The hydrolysis reaction is usually carried out at a temperature of 25 to 120 ° C. for 1 to 20 hours, but preferably 50 to 100 in order to obtain the desired product with a high yield and a high recovery rate.
1 to 10 hours at a temperature of ℃, more preferably 50 to 80 ℃
At a temperature of 1 to 5 hours. As the reaction progresses,
Since the products N, O-dimethylhydroxylamine and methanol are distilled out from the reaction system, they are cooled and recovered. The obtained mixture of N, O-dimethylhydroxylamine and methanol is separated by an ordinary distillation method using a fractionating column, whereby the desired N, O-dimethylhydroxylamine can be easily obtained.

[0024]

EXAMPLES The present invention will be described in more detail 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) 12.6 g (15%) of 95% hydroxylamine sulfate was placed in a 300 ml four-necked flask equipped with a pH electrode, a thermometer and a feed pump feed tube.
0 mmol) and 37.5 ml of water are added, and the internal temperature is 5 while stirring.
Cooled to ° C. Under a nitrogen atmosphere, 50% aqueous sodium hydroxide solution was added dropwise until the pH value of the reaction solution reached 6. While maintaining the internal temperature at 5 ° C. and the pH of the reaction solution at 6, 15.0 g (158 mmol) of methyl chloroformate and a 50% sodium hydroxide aqueous solution were simultaneously supplied over 80 minutes by using a feed pump. Stirring was continued for 2 hours below. Next, while maintaining the reaction temperature at 5 ° C., a 50% aqueous sodium hydroxide solution was supplied to adjust the pH of the reaction solution to 11.5, and under the same conditions, 39.5 g (3% of 99% dimethyl sulfate was added).
10 mmol) and a 50% aqueous sodium hydroxide solution were simultaneously supplied using a feed pump over 1 hour. After the supply, the mixture was further stirred under these conditions for 3 hours, then a saturated aqueous sodium hydrogen carbonate solution was added until the pH of the reaction solution reached 7.5, and the temperature was further raised to 50 ° C. to 0.5. Stir for hours. After cooling to room temperature, the reaction solution was subjected to quantitative analysis using gas chromatography. As a result, 15.9 g of methyl N, O-dimethylhydroxycarbamate (yield 8
9%) had been produced.

(Examples 2 to 9) In Example 1, the reaction was carried out under the condition that only the pH of the reaction solution was changed. The results are shown in Table 1.
Shown in

[0027]

[Table 1]

Comparative Example 1 95% in a 50 ml flask
Hydroxylamine sulfate 1.67 g (20 mmol) and water 5 ml were added, and the internal temperature was cooled to 5 ° C. 2.12 g (22 mmo) of 98% methyl chloroformate under a nitrogen atmosphere.
l) was added and 6.2 ml of 10N aqueous sodium hydroxide solution was added.
1 (62 mmol) while keeping the reaction temperature below 5 ° C.
Dropped over time. Furthermore, stirring was continued for 3 hours while maintaining the internal temperature at 5 ° C. Next, 5.84 g of 95% dimethyl sulfate
After the addition of (44 mmol), 2.4 ml (20 mmol) of 10N aqueous sodium hydroxide solution was added dropwise over 30 minutes, the reaction temperature was further raised to 15 ° C., and stirring was continued for 3 hours. After cooling to room temperature, the reaction solution was quantitatively analyzed using liquid chromatography. As a result, N,
Methyl O-dimethylhydroxycarbamate is 1.15
g (yield 47%) was produced.

Example 10 N, O obtained under the same conditions as in Example 1 (hydroxylamine sulfate 0.95 mol)
-Methyl dimethylhydroxycarbamate 100.5
100 g of fresh water in the reaction mixture containing g (yield: 89%).
And saturated aqueous sodium hydrogen carbonate solution were added until the pH of the reaction solution reached 7.3, and then the reaction solution was heated to 50 ° C. and stirred for 0.5 hour to decompose excess dimethyl sulfate.
Next, attach a 5-stage Oldershaw distillation column, and
Distilled under reduced pressure of mmHg to give an azeotropic fraction with water containing methyl N, O-dimethylhydroxycarbamate 281.4.
g (boiling point 40 to 50 ° C., purity 35%, isolated yield 98%)
I got

Reference Examples 1 to 4 N, which was obtained under the same conditions as in Example 1 (hydroxylamine sulfate 0.95 mol),
99.5 Methyl O-dimethylhydroxycarbamate
The reaction mixture containing g (yield: 88%) was cooled to room temperature, 500 ml of dichloromethane was added, the mixture was stirred for 30 minutes, and then transferred to a separating funnel. After standing for 30 minutes, the oil layer (lower layer) was extracted, extracted again in the same manner with 500 ml of dichloromethane, and then the extracted oil layers were combined,
It was washed with 100 ml of water. Approximately 500 m of washing oil layer was added to a 1 L round bottom flask equipped with a 60 mm Vigreux distillation column.
1, and heated in a water bath (47 to 52 ° C.) to distill off dichloromethane. The remaining wash oil layer was continuously fed using a supply pump, and dichloromethane was similarly distilled off. 300 with a five-stage Oldershaw distillation column
The concentrated liquid was transferred to a round-bottomed flask with a volume of 14 ml and distilled under normal pressure to obtain 98.3 g of a fraction of methyl N, O-dimethylhydroxycarbamate having a boiling point of 142 to 144 ° C (purity: 95.
2%, recovery rate 94.1%) was obtained.

Water having a weight ratio shown in Table 2 was added to 10.0 g of methyl N, O-dimethylhydroxycarbamate obtained by the above-mentioned method, and a 5-stage Oldershaw distillation column was attached to carry out distillation. When was quantitatively analyzed using gas chromatography, the results shown in Table 2 were obtained.

[0032]

[Table 2]

EXAMPLE 11 Methyl N, O-dimethylhydroxycarbamate 11.9 g (0.1 mol) and water 2
12.0 g of 50% aqueous sodium hydroxide solution in an azeotrope consisting of 2.1 g (molar ratio to methyl N, O-dimethylhydroxycarbamate as NaOH of 1.5)
Was added and reacted at 75 ° C. for 5 hours. As the reaction proceeded, N, O-dimethylhydroxylamine and methanol were distilled out from the upper end of the reactor and collected in a receiver cooled to -20 ° C. The distillate contained 6.1 g of N, O-dimethylhydroxylamine and 3.0 g of methanol. As a result, the yield of N, O-dimethylhydroxylamine was 99%. As a result of redistilling a mixture of N, O-dimethylhydroxylamine and methanol at atmospheric pressure using a distillation column, 5.8 g of N, O-dimethylhydroxylamine (purity 99% as a fraction having a boiling point of 42 to 44 ° C) was obtained. , Recovery rate 95%) was obtained.

[0034]

EFFECTS OF THE INVENTION According to the production method of the present invention, N, O-dimethylhydroxycarbamate, which is an intermediate having a low yield in the conventional production method, is highly converted into methyl N, O-dimethylhydroxycarbamate. It is possible to produce the compound in high yield, and as a result, it is possible to produce N, O-in high yield.
It has become possible to produce dimethylhydroxylamine.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Takenori Ishitake No. 6, 1-2 Waki, Waki-cho, Kuga-gun, Yamaguchi Prefecture Mitsui Petrochemical Co., Ltd. (72) Noriaki Kihara Waki, Waki-cho, Kaku-gun, Yamaguchi Prefecture 6-1-2, Mitsui Petrochemical Industry Co., Ltd.

Claims (3)

[Claims] 1. A hydroxylamine or its salt
Under conditions of pH 5 to 12 and 0 to 10 ° C, methyl chloroformate and a base are simultaneously added to react with each other to produce methyl hydroxycarbamate. (2) Then, the obtained methyl hydroxycarbamate or a reaction containing the same PH 1 to mixture or crude product
Under conditions of 0.5 to 12.5 and 0 to 15 ° C., a methylating agent and a base were simultaneously added to react with each other to produce methyl N, O-dimethylhydroxycarbamate. (3) Then, Methyl N, O-dimethylhydroxycarbamate was azeotropically distilled with water from the reaction mixture to separate and purify it. (4) Then, 0.5 to 0.5% of methyl N, O-dimethylhydroxycarbamate in the obtained azeotropic mixture was obtained. A method for producing N, O-dimethylhydroxylamine or a salt thereof, which comprises hydrolyzing at 4.0 to 100 ° C. with a 4.0-fold molar amount of a base. 2. The method according to claim 1, wherein the hydroxylamine or a salt thereof is a sulfate or a hydrochloride. 3. The method according to claim 1, wherein the methylating agent is dimethyl sulfate.