JPH0460461B2 - - Google Patents

Description

Detailed Description of the Invention (Industrial Field of Application) The present invention is based on the general formula ()NH ₂ OR ² (in the formula, R ² represents an alkyl group, an alkenyl group, or a haloalkenyl group), which is important as an agricultural and pharmaceutical intermediate. This relates to a method for producing a hydroxylamine derivative represented by:

(Prior Art) The following is known as a general method for producing a hydroxylamine derivative represented by the general formula ().

NaNO ₂ +NaOH+2SO ₂ →HON (SO ₃ Na) ₂ (R ² O) ₂ SO ₂ or R ² X, NaOH ――――――――――――――――――――――→ R ₂ ON (SO ₃ Na) ₂ HCl, H ₂ O ――――――――→ R ₂ ONH ₂・HCl However, this method has a low yield, and the 50% hydroxylamine produced by this method The derivative aqueous solution contains nitrosamines represented by the general formula (R ² ) ₂ NNO, which poses a carcinogenic problem, at a concentration of 1.0%.
It contained ~10 ppm.

(Means for Solving the Problems) The present inventors have invented an industrially excellent method for producing hydroxylamine derivatives as shown below.

R ¹ COOR ³ +NH ₂ OH + 1/nM (OH) _o → R ¹ CONHC・1/nM (R ² O) ₂ SO ₂ or R ² X ――――――――――――――――→ Process R ¹ CONHOR ² Mineral acid・R ³ OH−H ₂ O ――――――――――――→ −1 Process NH ₂ OR ²・Mineral acid + R ¹ COOR ³ Neutralization―――― --→ -2 step NH ₂・OR ² That is, the present invention uses the general formula R ¹ CONHO ・1/nM
(In the formula, R ¹ represents a lower alkyl group, M represents an alkali metal or alkaline earth metal, and n represents the valence of M.) and the general formula (R ² O) ₂ SO ₂ or ^a compound represented ^{by R 2} , R ¹ and R ² have ^the same meanings as above.
(In the formula, R ³ represents a lower alkyl group.) After reacting with a mineral acid in an aqueous solution, the alcohol represented by the formula NH ₂ OR ² (in the formula, R ² is the same as above) is neutralized. A general formula characterized by comprising the above two steps:
NH ₂ OR ² (In the formula, R ² has the same meaning as above.)
This is a method for producing a hydroxylamine derivative represented by

The production method of the present invention has a good yield, and utilizes the ester represented by R ¹ COOR ³ produced as a by-product in step -1.
This is an industrially excellent manufacturing method because it can produce hydroxamic salts expressed as R ¹ CONHO・1/nM;
The content of nitrosamines in the % hydroxylamine aqueous solution was also reduced to 2-4 ppm.

The present inventors have further conducted extensive research on a method for producing hydroxylamine derivatives with a low content of nitrosamines, and by allowing an oxidizing agent or aldehydes to be present in the reaction system, a hydroxylamine derivative containing almost no nitrosamines can be obtained. I discovered that.

When carrying out the production method of the first step using a halide represented by R ² (Excluding low boiling point compounds such as methyl.) React for 2 to 7 hours while stirring at 20 to 50°C. The molar ratio used is 1 to 2 moles of halide to 1 mole of hydroxamate. The halides used include ethyl bromide, n-propyl bromide,
Alkyl halides such as iso-propyl, n-butyl bromide, iso-butyl bromide, tert-butyl bromide, allyl chloride, allyl bromide, 1-propenyl chloride, 1-propenyl bromide, crotyl chloride, 3-chloride Alkenyl halides such as putenyl and 1,3-dichloropropene are used.

In addition, when a low boiling point halide such as methyl bromide or methyl chloride is reacted, the desired product is obtained by reacting at 40 to 70°C for 4 to 10 hours under pressure conditions of 10 kg/cm ² or less. In addition, when reacting a low boiling point halide, a lower alcohol solution or a lower alcohol-aqueous solution is used as the solvent,
The reaction is preferably carried out using 1.5 to 3 mol of halide per mol of hydroxamate.
During this reaction, if an alkali metal hydroxide or an alkaline earth metal hydroxide is added in moles of 0.05 to 0.5 times, preferably 0.1 to 0.2 times the mole of the hydroxamate, the yield of the target product can be increased. It is possible to further improve this by several percentage points. When the target product is isolated, the pH of the reaction product solution is adjusted to 3 to 5, and if the target product is a crystal, it is removed by filtration, but in other cases, the reaction product solution is concentrated to dryness, and then Extraction may be performed using lower alcohol, ether, chloroform, or the like. Furthermore, when a lower alcohol solvent is used, methanol or ethanol is usually used as the alcohol. Also, lower alcohol-
When an aqueous solution is used, the yield of the product is slightly higher than when a simple water solvent or lower alcohol solvent is used.

When using a sulfuric ester represented by (R ² O) ₂ SO ₂ , add the sulfuric ester to a water or lower alcohol solution of hydroxamate and react for 2 to 6 hours with stirring at 20 to 30°C. . The molar ratio used is 1 to 1.1 mol of sulfuric ester per 1 mol of hydroxamate. In this reaction, as in the case of using a halide, 0.1 to 0.5 mol of alkali metal hydroxide or alkaline earth metal hydroxide, preferably 0.1 mol, per 1 mol of hydroxamate.
By adding ~0.2 mol before or during the reaction, the yield of the target product can be further improved by several percent. In order to isolate the desired product, the reaction product may be extracted with ether, chloroform, etc. after adjusting the pH of the reaction product to 3 to 5.

The types of oxidizing agents added after the first step include potassium permanganate, sodium hypochlorite, copper sulfate, cuprous chloride, cupric chloride, etc.
Continue stirring at 30°C for 1 to several hours. However, when using a monovalent or divalent copper compound as an oxidizing agent, it is better to add the copper compound before the reaction in the first step, that is, before adding the sulfuric ester, because the amount used is smaller and it takes less time. This is advantageous because it can be shortened. Furthermore, when aldehydes such as benzaldehyde are used, it is necessary to add them before the reaction in the first step and then stir the mixture at 20 to 30°C for 10 to 60 minutes.

The molar ratio used is 1 mole of hydroxamate,
In the case of divalent copper compounds, 0.000005 to 0.0001 mol,
In the case of other oxidizing agents, 0.0001 to 0.05 mol is sufficient, and in the case of aldehydes, 0.001 to 0.01 mol is sufficient.

To carry out the first step, add R ¹ CONHOR ² to R ¹ CONHOR ² in a lower alcohol aqueous solution.
Add concentrated mineral acid containing 1.0 to 2.5 times the molar amount of mineral acid,
The mixture may be stirred under reflux for 0.5 to 3 hours. After the reaction is completed, an alcohol aqueous solution of carboxylic acid lower alcohol ester is recovered by distillation.

Thereafter, the reaction solution containing NH ₂ OR and hydrochloride is made alkaline with caustic soda or the like, and then distilled to obtain NH ₂ OR ² as an aqueous solution.

The monovalent or divalent copper compound is preferably added after the mineral acid is added and an alcohol aqueous solution of carboxylic acid lower alcohol ester is recovered by distillation, or after subsequent neutralization with caustic soda or the like. In this case, it is preferable to stir the mixture at 20 to 70° C. for one to several hours after neutralization, and at that time, blow air or the like to further enhance the effect of the oxidizing agent.

However, if a monovalent or divalent copper compound is used as the oxidizing agent in the first step and the second step is carried out without isolation, the addition of the divalent copper compound in this step is not necessary.

In this step, the required amount of the divalent copper compound to be added is 0.000005 to 0.0001 mol per 1 mol of the hydroxamate, as in the first step.

The present inventors have conducted extensive research aimed at reducing the content of nitrosamine compounds contained in hydroxylamine derivatives, and as a result, the nitrosamine compounds are mainly shown below. It was discovered that it is generated by two routes.

(a) NH ₂ OH＋(R ² O) ₂ SO ₂ (or R ² X) →
(R ² ) ₂ NOH→(R ² ) ₂ NNO (b) (R ² ) ₂ NH+NH ₂ OH Fe ³⁺ ---→(R ² ) ₂ NNO Therefore, the inventors have determined (a), ( b) Studies were conducted to suppress the production of nitrosamines from both routes.

As a result, (a) root suppression method is to add aldehydes before the first step.
It has been found that a method of converting NH ₂ OH into oxime and removing it or a method of decomposing (R ² ) ₂ NOH produced after the first step with an oxidizing agent is effective.

On the other hand, as a method for suppressing route (b), Fe ³⁺ ,
It was thought that either (R ² ) ₂ NH or NH ₂ OH should be removed.

First, in the case of small-scale laboratory synthesis, Fe ³⁺ can be prevented from entering the system by taking measures such as using distilled water as the water used; (b) The production of nitrosamines from the route can be suppressed. However, in the case of industrial large-scale synthesis, it is difficult to prevent Fe ³⁺ contamination, and especially in the case of large-scale synthesis, when continuous distillation is adopted as the preferred distillation method, Fe ions may accumulate. .

Next, regarding (R ² ) ₂ NH, ammonia (ammonium sulfate in _the case of hydroxylamine sulfate, ammonium sulfate in the case of hydroxylamine hydrochloride, In the case of ammonium chloride or hydroxylamine aqueous solution, it indicates ammonium hydroxide.)
is produced by reacting with (R ² O _{) 2} SO ₂ or R ² However, it is not always easy to generate NH ₂ OH with a low ammonia content, and when NH ₂ OH with a high ammonia content is used, it is not easy to remove (R ² ) ₂ NH.

As mentioned above, in the Fe ³⁺ and (R ² ) ₂ NH removal method, suppression of nitrosamines via route (b) is possible in some cases, but not possible in other cases. We conducted an investigation to find a method that could also be applied to water, and found that the method of decomposing NH ₂ OH was good. The method is shown below.

When the hydroxamate remaining unreacted in the first step is treated with mineral acid in the second step, NH ₂ OH is converted to NH ₂ OH (approximately 3 mol% to hydroxamate).
Since it will be generated again as
The method of removing NH ₂ OH is insufficient, and it is necessary to generate it again and then decompose it. We have studied this method in detail and found that it is effective to apply an oxidizing agent to decompose the material after neutralization in the second step.

However, if an oxidizing agent such as potassium permanganate is used as an oxidizing agent after this neutralization, it will also decompose the hydroxylamine derivative represented by the general formula (), which is the product, so the oxidizing agent used here is is preferably a monovalent or divalent copper compound. Therefore, when carrying out a continuous reaction, the oxidizing agent used in the first step is usually a monovalent or divalent copper compound. The function of this copper compound is that it acts as an oxidizing agent in the form of a divalent copper compound, and after becoming a monovalent copper compound, it becomes a divalent copper compound again with air (oxygen) and acts as an oxidizing agent. A small amount is sufficient, and the decomposition of (R ² ) ₂ NOH in the first step and the decomposition of NH ₂ OH after neutralization in the second step proceed almost completely, and the yield of the hydroxylamine derivative produced is reduced. There is no effect on the rate.

Of these, (b) is produced during distillation and mixed into the distilled ethoxyamine aqueous solution in the form of (R ² ) ₂ NHO.

On the other hand, the main route for (a) is that it is mixed into the distilled ethoxyamine aqueous solution after distillation in the form of (R ² ) ₂ NOH produced in the first step, and converted to (R ² ) ₂ NNO during storage. It is. In addition, even when using a distilled ethoxyamine aqueous solution as a raw material immediately after distillation,
During subsequent reactions, (R ² ) ₂ NOH is often converted to (R ² ) ₂ NNO.

Therefore, as a simple method to determine the (R ² ) ₂ NNO content, a distilled ethoxyamine aqueous solution was heated at 50°C.
A better method is to measure (R ² ) ₂ NNO after completely converting (R ² ) ₂ NOH to ⁽ R ² ) ₂ NNO by subjecting it to abuse for ×1 week. ) ₂ The value after the above treatment is used as the NNO content.

(Example) The present invention will be described in more detail below by taking the synthesis of ethoxyamine as an example.

Note that the content of nitrosamines was measured using GC-TEA543 manufactured by Shimadzu Corporation.

Example 1 105.7 g of ethyl acetate, 922 g of ethanol and 50 g of water
83.8 g of hydroxylamine sulfate (purity 98%) was added to this mixture with stirring. While stirring, 659.0 g of a 28% caustic soda aqueous solution was added dropwise to the resulting slurry solution over 4 hours while maintaining the temperature at 20 to 30°C. Thereafter, the mixture was further stirred at the same temperature for 1 hour. When the resulting aqueous solution was quantitatively determined using a titration curve, the yield of acetohydroxamic acid sodium salt was 98% (based on hydroxylamine sulfate charged).

Next, 1.2 g of a 1% CuSO ₄ aqueous solution [0.0075 mol% (based on hydroxylamine sulfate)] was added to this acetohydroxamic acid sodium salt aqueous solution, and then 165.0 g of diethyl sulfate was added to the acetohydroxamic acid sodium salt aqueous solution for 2 hours while maintaining the temperature at 20 to 30°C. dripped. After the dropwise addition, stirring was performed at 30°C for 2 hours. The yield of ethylacetohydroxamate in the resulting aqueous solution was 93% (based on hydroxylamine sulfate charged).

Next, 230 g of hydrochloric acid was added to this ethylacetohydroxamate aqueous solution and refluxed for 1 hour, and then ethyl acetate was distilled off over 4 hours to a distillation temperature of 83°C. The distilled amount was 226 g. As a result of gas chromatographic analysis of the recovered ethyl acetate/alcohol aqueous solution, 95 g of ethyl acetate and 86 g of ethanol were found.
g and 45 g of water, and the recovery rate of ethyl acetate was 90% (to ethyl acetate charged). Furthermore, the can liquid was heated to a distillation temperature of 106° C. over 2 hours to distill off residual ethanol and the like.

Next, the can liquid was cooled to 40° C. or lower and the pH was adjusted to 10 with a 28% caustic soda aqueous solution, followed by patch distillation to obtain 110 g of an ethoxyamine aqueous solution. temperature is 50%
The yield was 90% (based on hydroxylamine sulfate charged).

The content of diethylnitrosamine in the distilled ethoxyamine aqueous solution was 0.03 ppm or less.

Example 2 165.0 g of diethyl sulfate was added to an aqueous solution of acetohydroxamic acid sodium salt obtained in the same manner as in Example 1.
g was added dropwise over 2 hours while maintaining the temperature at 20 to 30°C. After stirring at 30°C for 2 hours after the dropwise addition, 3.2 g of a 1% potassium permanganate aqueous solution [0.02 mol% (based on hydroxylamine sulfate)] was added, and the mixture was further stirred at the same temperature for 2 hours.
Stir for hours. Thereafter, it was treated in the same manner as in Example 1,
110 g of an aqueous ethoxyamine solution was obtained. Humidity is 49%
The yield was 88% (based on hydroxylamine sulfate charged).

The content of diethylnitrosamine in the distilled ethoxyamine aqueous solution was 0.03 ppm or less.

Example 3 Benzaldehyde was added to an acetohydroxamic acid sodium salt aqueous solution obtained in the same manner as in Example 1.
0.53 g (0.5 mol% [based on hydroxylamine sulfate]) was added and stirred at 20 to 30°C for 30 minutes.

Next, 165.0 g of diethyl sulfate was added dropwise over 2 hours while maintaining the temperature at 20 to 30°C. Thereafter, it was treated in the same manner as in Example 1 to obtain 110 g of an aqueous ethoxyamine solution.

In this case, the ethoxyamine humidity is 50% [yield 90%]
(to hydroxylamine sulfate)], and the diethylnitrosamine content was 0.08 ppm.

Example 4 Ethyl acetate 1723Kg, ethanol 1387Kg, hydroxylamine sulfate 1260Kg (purity 98%) and water 752Kg
Kg was charged into an 11 m ³ reaction tank, and 5015 kg of a 28% caustic soda aqueous solution was added dropwise over 4 hours at 20 to 40°C.
Thereafter, the mixture was further stirred at the same temperature for 30 minutes.

Next, 17 kg of a 1% aqueous copper sulfate solution was added to this acetohydroxamic acid sodium salt aqueous solution, and then 2482 kg of diethyl sulfate was added dropwise over 2 hours while maintaining the temperature at 20 to 30°C. After the addition, the mixture was stirred at the same temperature for 4 hours.

Next, this ethylacetohydroxamate aqueous solution was transferred to a 15 m ³ reaction tank, 3372 kg of 35% hydrochloric acid was added thereto, and the mixture was refluxed for 1 hour.

Thereafter, a mixture of ethyl acetate, ethanol, water, etc. was distilled over 4 hours until the distillation temperature reached 88°C.
After adjusting the pH of this distillate, it was used again to produce acetohydroxamic acid sodium salt as a raw material.

Furthermore, the can liquid was heated to an internal temperature of 114° C. over 8 hours to distill off the ethanol and the like present.

Next, the canned liquid was cooled to 50℃ and placed in a ^4m3 neutralization tank at 28℃.
% caustic soda aqueous solution to pH 10 to 10.5, air was blown in to oxidize and decompose hydroxylamine, etc. (average residence time: 4 hours), and then continuous distillation was performed to obtain 1592 kg of an ethoxyamine aqueous solution. In this case, the ethoxyamine humidity was 53% [yield 92% (based on hydroxylamine sulfate charged)], and the diethylnitrosamine content was 0.03 ppm.

Example 5 The diethylnitrosamine content in a 50% ethoxyamine aqueous solution obtained by the same procedure as in Example 1 except that the 1% copper sulfate aqueous solution was not added was
It was 2.0ppm.

(Effects of the Invention) The present invention is an industrially excellent method for producing hydroxylamine derivatives.

In addition, by allowing an oxidizing agent or aldehydes to be present in the reaction system, a hydroxylamine derivative with an extremely low content of nitrosamines can be obtained.

Claims (1)

[Claims] 1 General formula R ¹ CONHO・1/nM (wherein R ¹
represents a lower alkyl group, M represents an alkali metal or alkaline earth metal, and n represents the valence of M. )
Hydroxamate represented by the general formula (R ² O) ₂ SO ₂ or R ² X (wherein R ² is an alkyl group,
It represents an alkenyl group or a haloalkenyl group, and X represents a halogen atom. ) with a compound represented by the general formula R ¹ CONHOR ² (wherein R ¹ and R ²
has the same meaning as above. ) Process of producing a hydroxamic acid ester represented by the above hydroxamic acid ester and the general formula R ³ OH
(In the formula, R ³ represents a lower alkyl group.) After reacting with a mineral acid in an aqueous solution, the alcohol represented by the formula NH ₂ OR ² (in the formula, R ² is the same as above) is neutralized. A general formula characterized by comprising the above two steps:
NH ₂ OR ² (In the formula, R ² has the same meaning as above.)
A method for producing a hydroxylamine derivative represented by 2 General formula characterized by the presence of an oxidizing agent or aldehyde in the reaction system in the above production method
NH ₂ OR ² (In the formula, R ² has the same meaning as above.)
A method for producing a hydroxylamine derivative represented by 3. The manufacturing method according to claim 2, wherein after the first step, an oxidizing agent such as a monovalent or divalent copper compound, potassium permanganate, or sodium hypochlorite is added. 4 Claim 2 in which monovalent or divalent copper compounds or aldehydes are added before the first step reaction
Manufacturing method described in section. 5. The manufacturing method according to claim 2, wherein a monovalent or divalent copper compound is added after the neutralization in the second step.