JP3041444B2 - Method for producing carbazic acid derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel method for producing a carbazic acid derivative.

[0002]

2. Description of the Related Art Carbazic acid derivatives such as alkyl carbazates and alkyl carbazides include, for example,
These compounds are useful as pharmaceutical intermediates, agricultural chemical raw materials, oxygen absorber raw materials, etc., but as described in detail below, an industrially advantageous production method capable of producing them at low cost and high yield is still being developed. It has not been.

Conventionally, alkyl carbazates have been produced by reacting dialkyl carbonate (or alkyl chlorocarbonate) with hydrazine. In this method, the dialkyl carbonate and hydrazine are separately synthesized and isolated from the reaction system. After purification, these two compounds must be reacted further. That is, methyl carbazate cannot be produced from a raw material in a one-step reaction, which complicates the production process and raises production costs. In addition, hydrazine is expensive, which contributes to an increase in manufacturing cost.

Further, dialkyl carbonate (or alkyl chlorocarbonate), which is one of the starting compounds in the above reaction, is produced, for example, by reacting methanol with carbon dioxide gas or reacting phosgene with methanol in the presence of a copper catalyst. However, the former requires strict control of the reaction, and the latter is not preferred because phosgene has strong toxicity.

Alkyl carbazide is mainly composed of, for example, hydrazine and (1) alkyl urea,
It is produced by reacting (2) an alkyl isocyanate or (3) phosgene with an alkylamine. However, in the case of (1), the alkylcarbazide obtained is extremely expensive because both starting compounds are expensive,
In the case of (2), in addition to the fact that both starting compounds are expensive, the toxicity of alkyl isocyanate is strong, and (3)
In the above case, as described above, phosgene has extremely high toxicity, and in any case, it cannot be said that the production method is industrially advantageous.

[0006]

The present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, have found that an industrially advantageous novel production method capable of obtaining a carbazic acid derivative at low cost and high yield. And completed the present invention here.

That is, the present invention provides a compound represented by the general formula

[0008]

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The monochlorourea sodium salt represented by the general formula (1) has the following general formula: R ¹ OH wherein R ¹ represents an alkyl group. An alcohol represented by the general formula R ¹
R ² NH wherein R ¹ is as defined above. R ² represents a hydrogen atom or an alkyl group. Or (3) a cyclic amine which may have at least one selected from an oxygen atom, a nitrogen atom and a sulfur atom as a hetero atom.

[0010]

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[In the formula, R 'represents an alcoholate group, an alkylamino group, a dialkylamino group or a cyclic amino group. And a method for producing a carbazic acid derivative represented by the formula:

In each of the above formulas, the alkyl groups represented by R ¹ and R ² are not particularly limited, and include known aliphatic hydrocarbon groups and alicyclic hydrocarbon groups. Group, ethyl group, n-propyl group,
1-4 carbon atoms such as n-butyl group and tert-butyl group
Straight or branched chain alkyl groups. Examples of the cyclic amino group represented by R ′ include, for example, at least one selected from an oxygen atom, a nitrogen atom, and a sulfur atom as a heteroatom such as a piperidino group, a pyrrolidyl group, a pyrazolidyl group, and a morpholino group. A cyclic amino group, preferably a 5- or 6-membered cyclic amino group, may be mentioned.

In the present invention, monochlorourea sodium salt represented by the above general formula (1) is used as a starting compound. The compound is, for example, a hydrazine
And its application ", by Toshio Yokota, Jinjinshokan, published on March 9, 1968, page 9. The compound is considered to have the following resonance, and can be represented by the formula (1) ′.

[0014]

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The monochlorourea sodium salt represented by the general formula (1) is, for example, represented by the following reaction formula-1 to reaction formula-
It can be produced according to a known method such as No. 3.

[0016]

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In the reaction shown in Reaction Formula 1, specifically,
For example, first, chlorine gas is allowed to react with an aqueous sodium hydroxide solution to obtain sodium hypochlorite. At this time, it is preferable to use sodium hydroxide in an excessive amount. Then, a reaction mixture containing sodium hypochlorite is mixed and reacted with an aqueous urea solution to obtain monochlorourea sodium salt of the general formula (1). The reaction temperature is preferably about 5 to 10C. The use ratio of sodium hypochlorite and urea may usually be about 1: 1 (molar ratio), but preferably an excess amount of urea (for example, about 1 to 2 mol) may be used. In this reaction, chlorine may be passed through an aqueous solution containing urea and sodium hydroxide.

[0018]

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In the reaction shown in Reaction formula-2, specifically,
For example, an aqueous sodium hydroxide solution and monochlorourea or an aqueous solution thereof may be mixed. At this time, the reaction temperature is 5
Preferably, the temperature is about 10 ° C. The amount of sodium hydroxide used is usually about 1 mol (theoretical value) per mol of monochlorourea, preferably an excess (about 1 to 1.5 mol).
It is good to do. Monochlorourea is a known compound, for example, Journal of American Chemical Society [Journal of Ameri]
can Chemical Society, 76,
2572 (1954)]. Specifically, for example, tert-butyl hypochloride may be added to a methanol solution of urea.

[0020]

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In the reaction shown in Reaction formula-3, the reaction temperature is 5
The temperature is preferably set to about 20 ° C.

In the present invention, the other raw material is represented by the general formula R ¹ OH wherein R ¹ represents an alkyl group. An alcohol represented by the general formula R ¹ R ² NH
Wherein R ¹ is as defined above. R ² represents a hydrogen atom or an alkyl group. Or a cyclic amine which may have at least one selected from an oxygen atom, a nitrogen atom and a sulfur atom as a hetero atom.

Preferred examples of the alcohol include, for example, methanol, ethanol, propanol,
Examples thereof include n-butanol and tert-butanol. Preferred specific examples of the amine include, for example, methylamine, ethylamine, diethylamine,
Propylamine, n-butylamine, tert-butylamine and the like can be mentioned. Further, preferred specific examples of the cyclic amine include, for example, piperidine, pyrrolidine, pyrazolidine, morpholine and the like.

The reaction of the monochlorourea sodium salt represented by the general formula (1) with an alcohol, an amine or a cyclic amine is usually carried out in a suitable solvent with stirring as required. The amount of the alcohol, amine or cyclic amine used is not particularly limited, but is usually about 1 to 1000 mol, preferably 1 to 1 mol per mol of monochlorourea sodium salt.
What is necessary is just to be about 0-500 mol. There is no particular limitation as long as the solvent does not affect the reaction,
Water, lower alcohols such as methanol and ethanol can be preferably used. When a lower alcohol is used as a reaction substrate, it can be used also as a solvent. This reaction is generally carried out at about 5 to 150 ° C., preferably 50 to 150 ° C.
The reaction is carried out at a temperature of about 150 ° C., usually about 0.5 to 3 hours, preferably about 0.5 to 1 hour. This reaction can be carried out in any of an open system and a closed system.

This reaction can be carried out in the presence of a catalyst. As such a catalyst, for example, at least one selected from a zinc compound and a cadmium compound can be used. Specific examples of the zinc compound include, for example, zinc chloride, zinc sulfate, zinc carbonate, zinc acetate, zinc salicylate,
Examples thereof include zinc hydroxide, an ammine complex of zinc, and an ethylenediamine complex. As the cadmium compound, for example, cadmium chloride, cadmium sulfate,
Examples thereof include cadmium carbonate, cadmium acetate, cadmium salicylate, cadmium hydroxide, an ammine complex of cadmium and an ethylenediamine complex. The amount of the catalyst used is not particularly limited, but may be generally about 0.01 to 1 mol, preferably about 0.1 to 0.5 mol, per 1 mol of monochlorourea sodium salt.

Further, in the present reaction, a known alkaline agent such as ammonia or sodium hydroxide may be added to the reaction system in order to make the reaction proceed more advantageously.

The carbazic acid derivative of the above general formula (2) obtained by this reaction can be easily isolated and purified from the reaction system by ordinary separation means such as concentration, recrystallization and chromatography.

[0028]

According to the present invention, a target carbazic acid derivative can be produced at a high yield and at low cost by a one-step reaction from a raw material.

[0029]

The present invention will be further clarified with reference to the following reference examples and examples.

Reference Example 1 Synthesis Example of Chlorurea Sodium Salt 90 g of a methanol solution of sodium methylate having a content of 7.5% by weight was placed in a 300 ml four-necked flask equipped with a thermometer and a stirrer, and stirred at 5 ° C. And cooled.
To this, 10.05 g (0.1 mol) of chlorurea crystals having an effective chlorine content of 70.65% by weight were added little by little. After completion of the dropwise addition, redox titration and high performance liquid chromatography confirmed formation of chlorurea sodium salt having an effective chlorine content of 7.03% by weight. This corresponded to a yield of 99 mol%.

Reference Example 2 Synthesis Example of Chlorurea Sodium Salt 9 g (0.15 mol) of urea and 30 g of methanol were placed in a 200 ml four-necked flask equipped with a thermometer and a stirrer, and cooled to 5 ° C. with stirring. . To this, an aqueous sodium hypochlorite solution 2 having an effective chlorine content of 29.95% by weight was added.
3.71 g (0.1 mol) of 30
Dropped over minutes. After completion of the dropwise addition, the available chlorine content was determined to be 11.2 by redox titration and high performance liquid chromatography.
The formation of 1% by weight of chlorurea sodium salt was confirmed. This corresponded to a yield of 99 mol%.

Example 1 In a 500 ml glass four-necked flask equipped with a thermometer, a stirrer and a cooler, 50.53 g (0.05 mol) of a chlorurea sodium salt solution having an effective chlorine content of 7.03% by weight was placed. I put it. To this, add methyl alcohol 11 under stirring.
8.08 g (3.69 mol) and zinc chloride 2.04 g
(0.015 mol) was added in sequence and heated. After 30 minutes of reflux, the reaction vessel was cooled and the reaction mixture was removed. Oxidation-reduction titration confirmed the formation of a reducing substance (95 mol% yield).

The reaction mixture was concentrated and recrystallized with a mixed solvent of benzene / ethanol (70/30) to obtain white crystals. About this crystal, IR spectrum, NMR
As a result of measuring the spectrum and mass spectrum,
This was consistent with the methyl carbazate standard. Incidentally, by high performance liquid chromatography, methyl carbazate 4.05 was obtained.
g (94 mol%) was confirmed.

Example 2 The procedure of Example 1 was repeated, except that the catalyst was changed to that shown in Table 1 below, to obtain methyl carbazate. No. 4 and No. 4. 5 used 0.0075 mol of each of the two catalysts. Table 1 also shows the yields of methylcarbazate (MC) and reducing substances.

[0035]

[Table 1]

Example 3 The same operation as in Example 1 was carried out except that the amount of methyl alcohol used was changed to the amount shown in Table 2, to obtain methyl carbazate. In addition, No. 5 and No. 5 No. 6 reacted without using a catalyst. Table 2 also shows the yields of methylcarbazate (MC) and reducing substances.

[0037]

[Table 2]

Example 4 The same operation as in Example 1 was carried out except that the reaction temperature and the reaction time were changed, to obtain methyl carbazate. No. 3 to N
o. 5 is 500 m equipped with a stirrer, thermometer and pressure gauge
The reaction was performed using a 1-volume stainless steel sealed container. Table 3 shows the yields of methylcarbazate (MC) and reducing substances.
It is described together.

[0039]

[Table 3]

Example 5 The same operation as in Example 1 was carried out except that 31.67 g (0.05 mol) of a chlorurea sodium salt solution having an effective chlorine content of 11.21% by weight synthesized in Reference Example 2 was used. A reducing substance (yield: 93 mol%) and methyl carbazate (yield: 85 mol%) were obtained.

Example 6 The procedure of Example 5 was repeated, except that no catalyst was used, to obtain a reducing substance (yield: 78 mol%) and methylcarbazate (yield: 70 mol%).

Example 7 Ethyl alcohol was used instead of methyl alcohol.
In the same manner as in Example 1 except that ethyl alcoholate is used instead of methyl alcoholate, a reducing substance (yield: 90 mol%) and ethyl carbazate (yield:
89 mol%).

Example 8 In a 1000 ml stainless steel autoclave equipped with a stirrer, a thermometer and a cooler, 50.53 g (0.03 g of chlorurea sodium salt solution having an effective chlorine content of 7.03% by weight) was added.
51.4 mol), 321.4 g (5 mol) of a 70% aqueous solution of ethylamine and 2.04 g of zinc chloride were added thereto with stirring.
(0.015 mol) was added successively and sealed, and the reaction was carried out at 100 ° C. for 30 minutes.
5 mol%) and 4.84 g of 4-ethylcarbazate (yield: 94 mol%).

Example 9 The same operation as in Example 8 was carried out except that no catalyst was used, and a reducing substance (yield: 80 mol%) and 4.02 g of 4-ethylcarbazate (yield: 78 mol%) ) Got.

Example 10 A carbazineamide derivative was obtained in the same manner as in Example 8, except that the other amines shown in Table 4 were used instead of ethylamine. Table 4 also shows the yields of the carbazine amide derivative and the reducing substance.

[0046]

[Table 4]

Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI // C07B 61/00 300 C07B 61/00 300 (56) References WO 92/12124 (WO, A1) (58) Fields investigated (Int. .Cl. ⁷ , DB name) CA (STN) REGISTRY (STN)

Claims (2)

(57) [Claims] 1. A compound of the general formula In the monochlorourea sodium salt represented by the general formula (1), R ¹ OH [where R ¹ represents an alkyl group. And (2) a general formula R ¹ R ² NH wherein R ¹ is as defined above. R ² represents a hydrogen atom or an alkyl group. Or a cyclic amine which may have at least one kind selected from an oxygen atom, a nitrogen atom and a sulfur atom as a hetero atom (3). [In the formula, R ′ represents an alcoholate group, an alkylamino group, a dialkylamino group or a cyclic amino group. ] The method for producing a carbazic acid derivative represented by the formula: 2. The method for producing a carbazic acid derivative according to claim 1, wherein the reaction is performed in the presence of at least one compound selected from a zinc compound and a cadmium compound.