JPH08283222A - Production of substituted amine - Google Patents

Abstract

PURPOSE: To obtain an N,O-dialkylhydroxylamine or an O-alkylhydroxylamine useful as a raw material for medicines or agrochemicals by reacting an N,O- bisalkoxycarbonylhydroxylamine with a hydroxyl group-having amine as starting raw materials. CONSTITUTION: This method for producing a substituted amine comprises reacting a compound of formula I (R<1> is an alkyl) with a hydroxylamine (salt) in the coexistence of a base, reacting the obtained compound of formula II with an alkylating agent (e.g. a dialkyl sulfate) in the coexistence of a base, and further hydrolyzing the obtained compound of formula III (R<2> is R<1> ; R<3> is H, R<1> ) thus obtaining a compound of the formula: R<2> O-NHR<3> . The compound of formula I is obtained e.g. by reacting hydroxylamine or its salt with two or more times moles of a haloformic acid alkyl ester in the presence of a base.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a process for producing N, O-dialkylhydroxylamine or O-alkylhydroxylamine 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. Pr
ep. 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 carried out using dimethyl sulfate and an aqueous solution of sodium hydroxide to obtain ethyl acetate. Ethyl N, O-dimethylhydroxycarbamate is obtained at a rate of 70 to 73%. Further, ethyl N, O-dimethylhydroxycarbamate is hydrolyzed with concentrated hydrochloric acid to obtain N, O-dimethylhydroxylamine in a yield of 93 to 95% and a total yield of 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 is reacted with sodium hydroxide, followed by extraction with dichloromethane, drying and concentration to obtain butyl hydroxycarbamate. Then, a quaternary amine salt is added as a phase transfer catalyst, and dimethylation is performed using dimethyl sulfate and an aqueous sodium hydroxide solution to obtain butyl N, O-dimethylhydroxycarbamate with a yield of 65%. Furthermore, N, O
-Butyl dimethylhydroxycarbamate is hydrolyzed with concentrated hydrochloric acid to give N, O-dimethylhydroxylamine in a total yield of 64%.

[0005]

However, the method reported hitherto is such that when a hydroxycarbamic acid ester is produced by reacting a hydroxylamine salt with ethyl chloroformate or butyl chloroformate, the general formula (V) is used.
Indicated by

[Chemical 4] (R represents an ethyl group or a butyl group.) As a by-product of N, O-bisalkoxycarbonylhydroxylamine, the yield of hydroxycarbamic acid ester becomes low, and the target N, There is a problem that the yield of O-dimethylhydroxylamine decreases. Further, in these reports, no attempt was made to positively utilize N, O-bisalkoxycarbonylhydroxylamine represented by the general formula (V) for the production of N, O-dimethylhydroxylamine. The present invention has been made to solve the above problems,
By producing a hydroxycarbamic acid ester which is an intermediate in a higher yield than ever before, the target N, O-
It is an object to provide a method for producing dialkylhydroxylamine or O-alkylhydroxylamine in high yield.

[0006]

Means for Solving the Problems That is, the present invention provides (a)
The following general formula (I)

Embedded image (R ¹ represents an alkyl group), N, O-bisalkoxycarbonylhydroxylamine and hydroxylamine or a salt thereof are reacted in the presence of a base to give the following general formula (II).

[Chemical 6] (R ¹ represents an alkyl group), and an alkyl hydroxycarbamate represented by the following general formula (III)

[Chemical 7] (R ¹ and R ² represent an alkyl group, and R 3 represents a hydrogen atom or an alkyl group.),
(C) Next, the compound represented by the general formula (III) is hydrolyzed in the presence of a base, the general formula (IV) R ² O—NHR ³ ... (IV) (R ² and R ³ are as described above. The same as the above).

[0007]

DETAILED DESCRIPTION OF THE INVENTION The present invention will be specifically described below, but the scope of the present invention is not limited to the following conditions. The alkyl group in R ¹ , R ² and R ³ of the general formulas (I) to (IV) is an alkyl group having 1 to 6 carbon atoms,
Specifically, methyl group, ethyl group, n-propyl group, i-
Examples thereof include propyl group, n-butyl group, i-butyl group, sec-butyl group, t-butyl group and the like, n-pentyl group, n-hexyl group and the like. Preferred examples of the compound represented by the general formula (I) include N, O-bismethoxycarbonylhydroxylamine. Preferred examples of the compound represented by the general formula (II) include methyl hydroxycarbamate. General formula (II
Preferable examples of the compound represented by I) include methyl N, O-dimethylhydroxycarbamate and methyl O-methylhydroxycarbamate. The compound represented by the general formula (IV) is preferably N, O-
Examples are dimethylhydroxylamine or O-methylhydroxylamine.

The compound of the general formula (I) is usually obtained by reacting hydroxylamine or a salt thereof with an alkyl haloformate in the presence of a base. Examples of hydroxylamine or a salt thereof 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 from the viewpoint of price, hydroxylamine sulfate is preferable. More preferable. Further, the hydroxylamine salt may be used in a state of being dissolved in an organic solvent such as water or methanol. Examples of the alkyl haloformate include methyl chloroformate, ethyl chloroformate, butyl chloroformate, methyl bromoformate, ethyl bromoformate, and butyl bromoformate, with methyl chloroformate being preferred.

The bases used for producing the compounds of the general formulas (I), (II) and (III) are 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 view of cost and reactivity, sodium hydroxide, sodium hydrogen carbonate or sodium carbonate is 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.

Water is preferably used as a reaction solvent used in producing the compounds of the general formulas (I), (II) and (III), but alcohols represented by methanol and ethanol, diethyl ether, Organic solvents such as ethers typified by tetrahydrofuran and aromatic compounds typified by benzene and toluene may be used alone or as a mixture or in a two-layer system with water.

Examples of the alkylating agent used in the production of the compound of the general formula (III) include dialkyl sulfate such as dimethyl sulfate and haloalkyl such as methyl chloride, methyl bromide and methyl iodide. I can, but
It is particularly preferable to use dimethyl sulfate when producing methyl N, O-dimethylhydroxycarbamate or methyl O-methylhydroxycarbamate as the compound of the general formula (III).

Next, the amounts of raw materials used, the reaction method and the reaction conditions for producing the compounds of the general formulas (I), (II) and (III) will be described in detail below.

<Amount of Raw Material Used> The compound of the general formula (I) is
Alkyl haloformate with respect to hydroxylamine or a salt thereof (in the case of a hydroxylamine salt, it is calculated not by the number of moles as a salt but by the number of moles of hydroxylamine of the salt. The same applies hereinafter). It can be selectively produced by using usually 2 times or more moles, preferably 2.0 to 3.0 times moles, and more preferably 2.0 to 2.1 times moles.

In the production of the compound of the general formula (II), the amount of hydroxylamine used is usually at least 1 time mol, preferably the molar amount of the hydroxylamine charged in the production of the compound of the general formula (I). It is 1.0 to 2.0 times mol, and more preferably 1.0 to 1.05 times mol.

In the preparation of the compound of the general formula (III), an alkylating agent is added to the total hydroxylamine or the salt thereof used in the preparation of the compound of the general formula (I) or (II).
Usually 2 times or more, preferably 2.0 to 4.0 times,
More preferably, when 2.0 to 2.25 moles are used, N,
Alkyl O-dialkylhydroxycarbamate is the main component. Further, the alkylating agent is represented by the general formula (I) or (I
Usually 0.5 to 1.5 times mol, preferably 0.9 to 1.2 times mol, more preferably 1.0 to 1.0 mol, based on the total hydroxylamine or salt thereof used in the production of the compound of I).
When used in a 1.1-fold molar amount, alkyl O-alkylhydroxycarbamate becomes the main component.

The amount of the base used in each reaction is not particularly limited, but it is preferably used in such an amount that the pH of the reaction solution is controlled within the range described below.

<Reaction Method> In the reaction of hydroxylamine and alkyl haloformate, the method of adding the raw materials is not particularly limited, but usually hydroxylamine or a salt thereof is charged first, and then the alkyl haloformate is added as described above. Particularly preferred is a method of supplying simultaneously with a base, and as a result, the hydrolysis of alkylhaloformate is suppressed while controlling the reaction temperature and the pH of the reaction solution at a constant level, and the N represented by the compound (I) can be obtained in high yield. An O-bisalkoxycarbonylhydroxylamine compound can be obtained. Also,
When hydroxylamine sulfate and hydrochloride are used as raw materials, it is preferable to add a base to completely neutralize these salts before supplying alkyl haloformate.

In addition, in the reaction of the hydroxylamine aqueous solution with the compound (I), the method of adding the raw materials is not particularly limited, but usually, an aqueous solution of hydroxylamine or a salt thereof is added to the compound (I) with the above-mentioned base. A method of simultaneously supplying is particularly preferable, and as a result, alkyl hydroxycarbamate can be obtained in high yield while controlling the reaction temperature and the pH of the reaction solution to be constant.

Similarly, in the alkylation reaction, it is preferable to simultaneously supply the alkylating agent and the base while keeping the reaction temperature and the pH of the reaction solution constant. In addition, it is preferable in terms of operation to carry out the next reaction continuously without isolation of alkyl hydroxycarbamate which is usually an intermediate, but it may be isolated before the alkylation reaction.

<Reaction conditions> The reaction temperature of hydroxylamine or a salt thereof with an alkyl haloformate is usually -20 to 20.
50 ° C, preferably -10 to 25 ° C, more preferably 0
It is in the range of -10 ° C, and the pH of the reaction solution at this time
Is usually 4 to 14, preferably 5 to 13, and more preferably 5 to 9. Under the above conditions, the reaction temperature is 5 ± 5
The combination of the range of ° C and the pH of the reaction solution within the range of 7 ± 2 is particularly preferable because the yield is highest and the reaction temperature and the pH of the reaction solution can be easily controlled. After completion of the addition of the alkyl haloformate, the reaction time is usually 0.
It is 1 to 5 hours, preferably 0.2 to 4 hours, more preferably 0.5 to 2 hours, and it is desirable that the excess amount of alkyl haloformate is completely hydrolyzed after the completion of the reaction.

After completion of the reaction, the compound (I) is separated from the aqueous layer, and oil / water separation is usually carried out at 0 to 50 ° C, preferably 5 to 40 ° C, more preferably 10 to 25 ° C. The pH of the aqueous layer at this time is usually 4 to 14, preferably 5 to 13, and more preferably 6 to 8. After the oil / water separation operation, the lower aqueous layer can be further extracted with an organic solvent such as a halogenated hydrocarbon, but normally, the compound (I) is almost quantitatively isolated only by separating the upper oil layer. it can.

The reaction temperature of the compound (I) with the hydroxylamine aqueous solution is usually from -20 to 50 ° C, preferably -1.
0 to 25 ° C, more preferably 0 to 10 ° C,
The pH of the reaction solution at this time is usually 4 to 14, preferably 5 to 13, and more preferably 5 to 9. Among the above conditions, the combination of the reaction temperature within the range of 5 ± 5 ° C. and the pH of the reaction solution within the range of 7 ± 2 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 hours, preferably 0.2 to 4 hours, more preferably 0.5 to 2 hours after the addition of hydroxylamine while maintaining the above conditions.

When an alkyl N, O-dialkylhydroxycarbamate is produced as the compound of the general formula (III), the reaction temperature for the alkylation is usually -20 to 50 ° C, preferably -10 to 25 ° C, particularly preferably It is in the range of 0 to 15 ° C., and the pH of the reaction solution at this time is usually 7 to
It is 14, preferably 9 to 13, and particularly preferably 10.5 to 12.5. Under the above conditions, the reaction temperature is in the range of 10 ± 5 ° C, and the pH of the reaction solution is 11.5 ±.
The combination in the range of 1.0 is particularly preferable because the yield is highest and the control of the reaction temperature and the pH of the reaction solution is easy. The reaction time is usually 0.1 to 5 hours after the addition of the alkylating agent, while maintaining the above conditions, preferably 0.
It is 2 to 4 hours, more preferably 0.5 to 3 hours.

When producing an alkyl O-alkylhydroxycarbamate as the compound of the general formula (III), the reaction temperature for the alkylation is usually -20 to 50 ° C, preferably -10 to 25 ° C, particularly preferably 0 to The temperature is in the range of 20 ° C., and the pH of the reaction solution at this time is usually 7 to 14, preferably 8 to 13, and particularly preferably 9 to 9.
The range is 12. Under the above conditions, the reaction temperature is 10 ± 5 ℃
, The pH of the reaction solution is 10.5 ± 1.5, the highest yield is obtained, and the reaction temperature and the p of the reaction solution are
It is particularly preferable because H can be easily controlled. The reaction time is usually 0.1 to 5 hours, preferably 0.2 to 4 hours, more preferably 0.5 to 3 hours after the addition of the alkylating agent while maintaining the above conditions.

As a method for separating the compound of the general formula (III) from the mixture containing the product obtained by the alkylation reaction, a method of extracting with an organic solvent may be used, but the following method is preferable. . That is, this is a method in which the mixture is azeotropically distilled with water and the alkyl N, O-dialkylhydroxycarbamate is separated from the mixture as an azeotropic fraction with water.

The amount of water required to azeotrope an N, O-dialkylhydroxycarbamate with water is N, O.
-For alkyl dialkyl hydroxycarbamate,
Water is usually 1.0 times by weight or more, preferably 1.0 to 1.1
It is twice the weight. Usually, the required amount of water is added during distillation,
It is also possible to use the water present in the mixture already provided. 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 above-mentioned azeotropic distillation are not particularly limited, such as normal pressure, reduced pressure, and increased pressure, but usually from normal pressure to reduced pressure conditions are used, preferably 1 to 760 mmHg.
The range is more preferably 10 to 250 mmHg. Although the distillation temperature is not particularly limited, it is usually carried out at a boiling point temperature at which azeotropy occurs at a set pressure, and preferably 20 to
The temperature may be 160 ° C, more preferably 30 to 80 ° C.

As the distillation apparatus for the azeotropic composition, it is usually desirable to use an apparatus having a distillation having a precision distillation function such as an Oldershaw distillation column, that is, an apparatus capable of selectively recovering only the azeotropic composition. , Batch and continuous devices having the function of simultaneously recovering other compounds and azeotropic compositions can also be used.

When N, O-dialkylhydroxylamine is prepared as the compound of the general formula (IV), the alkyl N, O-dialkylhydroxycarbamate in the fraction obtained by the azeotropic distillation is hydrolyzed. Can be manufactured by. Further, when O-alkylhydroxylamine is produced as the compound of the general formula (IV), O- contained in the mixture after removing the azeotropic fraction is
It can be produced by hydrolyzing an alkyl alkyl hydroxycarbamate.

The method for producing the compound of the general formula (IV) will be described below. Hydrolysis is carried out in the presence of bases or acids. Examples of the base used for hydrolysis include hydroxides of alkali metals and alkaline earth metals represented by sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, and barium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate. Alkali metal hydrogen carbonate represented by, sodium carbonate, potassium carbonate, alkali and alkaline earth metal carbonate represented by barium carbonate,
N, N-dimethylaminopyridine (4-DAMP),
1,8-diazabicyclo [5.4.0] undecene (D
Examples thereof include strong organic bases such as BU) and weak basic ion exchange resins such as Amberlite-93 and Amberlyst-21. 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. Examples of the acid used for the hydrolysis include mineral acids such as hydrochloric acid, sulfuric acid and phosphoric acid, and preferably hydrochloric acid or sulfuric acid.

The amount of the base or acid used in the hydrolysis reaction is usually 0.1 to 10 times mol, preferably 0.5 to 5 times mol, and more preferably 0.1 to 10 times the mol of the compound of the general formula (III).
It is in the range of 5 to 2 times by mole.

As the reaction solvent, water or a mixed solvent of water and an organic solvent which is soluble in water, such as alcohols such as methanol and ethanol, cyclic ethers such as tetrahydrofuran and dioxane, and water may be used. Usually, the amount of water used is 1 to 1 with respect to the compound of the general formula (III).
It is 100 times by weight, preferably 2 to 10 times by weight, and more preferably 2 to 4 times by weight. The amount of the organic solvent mixed with water is usually 0.1 to 10 parts by weight with respect to 1 part by weight of water. When the compound of the general formula (III) is separated by the azeotropic distillation, the water contained in the azeotropic distillation is used as it is.

Usually, the hydrolysis reaction is carried out at a temperature of 25 to 120 ° C. for 1 to 20 hours, but preferably 50 to 50 in order to obtain the desired product with a high yield and a high recovery rate.
1 to 10 hours at a temperature of 100 ° C., more preferably 50
The reaction is carried out at a temperature of ~ 80 ° C for 1-5 hours. When a base is used, as the reaction proceeds, the product represented by the general formula (I
Since the compound of V) and alcohol are distilled out from the reaction system, they are cooled and recovered. The obtained mixture of general formula (IV) and alcohol is separated by a usual distillation method using a fractionating column, and the desired compound of general formula (IV) can be easily obtained. In the case of acid hydrolysis, after completion of the reaction, the reaction solution is adjusted to pH 7 or higher and the compound of the general formula (IV) is distilled and isolated.

[0034]

As described above in detail, it has become possible to produce N, O-dialkylhydroxylamine or O-alkylhydroxylamine in high yield, which was low in yield by the conventional production method.

[0035]

The present invention will be described in more detail with reference to Examples and Comparative Examples, but the scope of the present invention is not limited to the following Examples.

Example 1 In a 300 ml four-necked flask equipped with a pH electrode, a thermometer and a feed pump feed tube, 6.3 g (7%) of 95% hydroxylamine sulfate was added.
5 mmol) and 19 ml of water were added, and the mixture was cooled to an inner temperature of 5 ° C. with stirring. Under a nitrogen atmosphere, 50% aqueous sodium hydroxide solution was added dropwise until the pH value of the reaction solution reached 7. While maintaining the internal temperature at 5 ° C. and the pH of the reaction solution at 7, 15.0 g (158 mmol) of methyl chloroformate and 50% aqueous sodium hydroxide solution were simultaneously supplied using a feed pump over 80 minutes. Stirring was continued for 2 hours below. After the temperature of the aqueous layer of the reaction solution was raised to room temperature while maintaining the pH at 8, the stirring was stopped and the mixture was allowed to stand for 30 minutes to separate the lower aqueous layer. Here, N, O-bismethoxycarbonylhydroxylamine (Compound I) was 11.07 g (149 mmo).
l) produced. Next, an aqueous solution prepared by dissolving 6.3 g (75 mmol) of 95% hydroxylamine sulfate in 19 ml of water and a 50% aqueous solution of sodium hydroxide were used at a reaction temperature of 5 ° C.
While being kept at the same temperature, they were simultaneously fed using a feed pump over 80 minutes, and stirring was further continued for 2 hours under these conditions.
Here, 13.45 g of methyl hydroxylcarbamate
(148 mmol) was produced.

Then, after cooling to 5 ° C., the pH of the reaction solution was adjusted to 11.5, and under the same conditions, 39.5 g (310 mmol) of 99% dimethyl sulfate and a 50% sodium hydroxide aqueous solution were fed through a feed pump. Used for 1 hour and fed simultaneously. After feeding, the mixture was further stirred under these conditions for 3 hours, and saturated N 2 was added until the pH of the reaction solution reached 7.5.
An aHCO3 aqueous solution was added, the temperature was further raised to 50 ° C, and the mixture was stirred for 0.5 hours. After cooling to room temperature, the reaction solution was subjected to quantitative analysis using gas chromatography,
Methyl N, O-dimethylhydroxycarbamate is 1
7.2 g was produced. Then the reaction mixture is replenished with fresh water.
0 g was added, and a 5-stage Oldershaw distillation column was attached.
Distilled under reduced pressure of 0 to 80 mmHg. 48.1 g of an azeotropic fraction with water containing methyl N, O-dimethylhydroxycarbamate (boiling point 40-50 ° C., purity 35%) was obtained.
Subsequently, the azeotrope mixture was added with 50% aqueous sodium hydroxide solution 1
7.0 g was added and reacted at 75 ° C. for 5 hours. As the reaction proceeded, N, O-dimethylhydroxylamine and methanol were distilled from the upper end of the reactor and collected in a receiver cooled to -20 ° C. The distillate contained 8.5 g of N, O-dimethylhydroxylamine and 4.1 g of methanol.
Was included. As a result, the yield of N, O-dimethylhydroxylamine was 98% (based on the charged hydroxylamine). As a result of redistilling a mixture of N, O-dimethylhydroxylamine and methanol under atmospheric pressure using a distillation column, 8.2 g of N,
O-dimethylhydroxylamine (purity 99%, recovery 95%, total yield 90%) was obtained.

(Examples 2 to 9) In Example 1, hydroxylamine, methyl chloroformate and compound (I) were used.
Of N, O- after the N, O-dimethylation reaction is carried out under the condition that only the pH of the reaction between OH and hydroxylamine is changed.
The yield of methyl dimethylhydroxycarbamate was investigated. The results are shown in Table 1.

[Table 1]

Comparative Example 1 In a 300 ml four-necked flask equipped with a pH electrode, a thermometer, and a feed pump feed tube, 12.6 g of 95% hydroxylamine sulfate was added.
(150 mmol) and 37.5 ml of water were added, and the mixture was stirred.
The internal temperature was cooled to 5 ° 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 50
8% aqueous sodium hydroxide solution using a feed pump
They were fed simultaneously over 0 minutes, and stirring was continued for 2 hours under these conditions. Next, while maintaining the reaction temperature at 5 ° C, 50
% Aqueous solution of sodium hydroxide to adjust the pH of the reaction solution to 1
Adjusted to 1.5, and under the same conditions, 99% dimethyl sulfate 39.
5 g (310 mmol) and 50% sodium hydroxide aqueous solution were simultaneously supplied using a feed pump over 1 hour. After feeding, the mixture was further stirred under these conditions for 3 hours, and then saturated NaHCO 3 was added until the pH of the reaction solution reached 7.5.
3 aqueous solution was added, the temperature was further raised to 50 ° C., and the mixture was stirred for 0.5 hours. After cooling to room temperature, the reaction solution was subjected to quantitative analysis using gas chromatography. As a result, 15.9 g (yield 89%) of methyl N, O-dimethylhydroxycarbamate was produced, and N, 0.6 g of O-bismethoxycarbonylhydroxylamine (Compound I)
(Yield 3%, based on charged hydroxylamine) It was a by-product.

Comparative Examples 2 to 9 In Comparative Example 1, the reaction was carried out under the condition that only the pH of the reaction solution was changed. Table 2 shows the results
Shown in

[Table 2]

Example 10 The same operation as in Example 1 was carried out until the step of producing methyl hydroxycarbamate in Example 1. 5 equipped with pH electrode connected to pH controller, feed tube of feed pump controlled by pH controller, thermometer, and dropping funnel 5
The rotor was placed in a 00 ml four-necked flask, and 105.4 g of methyl hydroxycarbamate (70
0 mmol, purity 99%) and 100 ml of water were added, and while keeping the reaction temperature at 5 to 10 ° C. and the pH of the reaction solution at 9.5 to 9.7, 95% dimethyl sulfate 97.6 g (735 mm).
ol) and 50% aqueous sodium hydroxide solution were simultaneously supplied over 1.5 hours. After feeding, stirring was continued for 3 hours under these conditions. When this reaction solution was quantified by high performance liquid chromatography, methyl O-methylhydroxamate was produced in a yield of 92% and methyl N, O-dimethylhydroxamate was produced in a yield of 5.6%. By-products N, O-
Methyl dimethylhydroxamate and low boiling impurities were removed azeotropically with water under reduced pressure (100-120 mmHg). 59.5 g (595 mmol) of 98% sulfuric acid in the aqueous phase
Was added and stirred at 80 ° C. for 3 hours. Then, the pH of the reaction solution was adjusted to 13.5 with a 50% sodium hydroxide aqueous solution.
And distilled under reduced pressure (80-120 mmHg) to obtain a liquid containing methoxyamine. When this was quantitatively analyzed using gas chromatography, methoxyamine was formed in a total yield of 85%. After adding 29.2 g (298 mmol) of concentrated sulfuric acid to this distillation product, methanol and ethanol were distilled off under reduced pressure to obtain a sulfuric acid aqueous solution of methoxyamine.

Claims (6)

[Claims] (A) The following general formula (I): (R ¹ represents an alkyl group), N, O-bisalkoxycarbonylhydroxylamine and hydroxylamine or a salt thereof are reacted in the presence of a base to give a compound represented by the following general formula (II): (R ¹ represents an alkyl group), an alkyl hydroxycarbamate represented by the formula (b) is then reacted with an alkylating agent in the presence of a base, and the following general formula (III) Chemical 3] (R ¹ and R ² represent an alkyl group, and R ³ represents a hydrogen atom or an alkyl group.),
(C) Next, the compound represented by the general formula (III) is hydrolyzed, and the compound is represented by the following general formula (IV) R ² O—NHR ³ (IV) (R ² and R ³ are the same as above). Method of making the indicated substituted amines. 2. A compound represented by the general formula (I), which is produced by reacting hydroxylamine or a salt thereof with 2 times or more moles of an alkyl haloformate in the presence of a base. The method of claim 1, wherein the method is: 3. The method according to claim 1, wherein R ¹ is a methyl group. 4. The method according to claim 1, wherein R ² is a methyl group and R ³ is a hydrogen atom or a methyl group. 5. The method according to claim 1, wherein the hydroxylamine salt is sulfate or hydrochloride. 6. The method according to claim 1, wherein the alkylating agent is dialkyl sulfate.