JPH01224333A - Production of n,n-di-substituted hydrazine - Google Patents

Abstract

PURPOSE:To obtain the title compound in easy reaction operation without requiring complicate reaction apparatus with high yield, by reacting N,N-di-substituted nitrosoamine in an aqueous medium in the presence of an alkali using thiourea dioxide as a reducing agent so as to reduce the nitrosoamine. CONSTITUTION:A N,N-di-substituted nitrosoamine expressed by formula I [R1 and R2 are (substituted)aliphatic hydrocarbon, (substituted)aromatic hydrocarbon or heterocyclic group or R1 and R2 form heterocyclic ring (containing other hetero atom.) together with binding N] is reacted with thiourea dioxide expressed by formula II of 2.0-4.0mol. and an aqueous solution of alkali such as NaOH of 4.0-10.0mol. based on 1mol. N,N-di-substituted nitrosoamine in an aqueous medium at ambient temperature, as necessary at 0-100 deg.C to provide the aimed compound expressed by formula III such as 1-benzyl-1-phenylhydrazine useful as a synthetic intermediate, etc., of various kind of industrial raw materials, medicine, agricultural chemical, chemical for photograph, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing N,N-disubstituted hydrazines, and more particularly, for producing N,N-disubstituted hydrazines in high yield by reduction of N,N-disubstituted nitrosamines. Regarding the method.

N,N-disubstituted hydrazine is useful as a variety of industrial raw materials or as a synthetic intermediate for pharmaceuticals, agricultural chemicals, photographic agents, etc. Conventionally, N,N-disubstituted nitrosamines have been prepared using zinc powder, acetic acid, sodium Methods have been proposed to produce N,N-disubstituted hydrazines by reduction with reducing agents such as -ethanol, sodium-liquid ammonia, lithium aluminum hydride [e.g.
att,,Org,5ynth,,I[,211(19
43); H, Zimmer, L, F, Aud ri
eth, M., Zimmev, R.A., Rwoe.

J, Am, Chem, Soc,, 77.790 (1'
955); D., M., Lemav, F., Menger, E.
, Coat s, J., Am., Chem, S.;

c,, 86.2395 (19649; W, W, Ha
rtman, L J Roll, Org, 5y
nth, , I [, 418 (1943), etc. 1゜However, these reducing agents are dangerous to handle, are generally expensive, and the treatment of waste liquid after the reaction is complicated.
The above conventional methods are not industrially satisfactory. Furthermore, when the above-mentioned reducing agent is used, the N-N bond is likely to be broken, and N.

The yield of N-disubstituted hydrazine is also not sufficient.

Therefore, the present inventors conducted various studies on industrially advantageous methods for synthesizing N,N-disubstituted hydrazines from N,N-disubstituted nitrosamines, and as a result, we have developed a method using thiourene dioxide as a reducing agent. By using the above conventional method, the absorption rate can be reduced to
It was discovered that -disubstituted hydrazine can be produced, and the present invention was completed.

Thus, according to the invention, in the general formula R1 and R2 each represent a substituted or unsubstituted aliphatic hydrocarbon group, a substituted or unsubstituted aromatic hydrocarbon group or a heterocyclic group, or R1 and R2 together with the nitrogen atom to which they are bonded represent a heterocycle which may further contain another heteroatom. There is provided a method for producing an N,N-disubstituted hydrazine represented by the general formula, wherein R1 and R2 have the above-mentioned meanings, characterized by reacting with an alkali.

Thiourea dioxide used as a reducing agent in the method of the present invention is a compound represented by the following formula, and can be easily produced with good yield from thiourea and hydrogen peroxide [JP-A-50-6
2934 Publication; Japanese Patent Publication No. 49-40451; Japanese Patent Publication No. 45-17665: French Patent No. 20407
No. 97, 22 Jan 1971.5pp].

N in the above formula (1) using this thiourea dioxide.

The reduction of N-disubstituted nitrosamines is carried out in an aqueous medium. The free aqueous medium used includes water or a mixed solvent of water and a water-miscible organic solvent.

Specific examples of the organic solvent include alcohols such as methanol, ethanol, and isopropanol; dioxane,
Ethers such as trioxane and tetrahydrofuran;
etc.

On the other hand, sodium hydroxide is suitable as the alkali used together with thiourea dioxide, but the alkali is not limited thereto, and lithium hydroxide, potassium hydroxide, etc. can also be used.

The amounts of the thio atom dioxide and alkali to be used are not strictly limited and can vary widely depending on the type of di-substituted nitrone amine used as the raw material, reaction conditions, etc.; Thiourea dioxide is in the range of 2.0 to 4.0 moles, preferably 2.1 to 2.5 moles, and the alkali is in the range of 4 to 2.5 moles per mole of di-substituted nitrosamine.
．． It is appropriate to use the amount within the range of 0 to 10 mol, preferably 4.5 to 6.0 mol.

Further, the reaction temperature can usually be set to room temperature, but depending on the case, the reaction may be carried out at a temperature in the range of about 0 to about 100°C.

A more specific description of preferred embodiments of the operation according to the method of the present invention is as follows.

First, an N,N-disubstituted nitrosamine and the N.

For 1 mole of N-disubstituted nitrosamine, 2 to 4 moles of thiourea dioxide and 4 to 10 moles of an alkali, such as sodium hydroxide, and 2 to 10 times the weight of thiourea dioxide and an appropriate amount (for example, 4 to 10 moles of water) are added. Prepare up to twice the weight of organic solvent.

Next, the N,N-disubstituted nitrosamine and the organic solvent were placed in a reaction vessel equipped with a stirrer and a reflux condenser if necessary, and the N,N-disubstituted nitrosamine was dissolved in the organic solvent, and the above amount of water Add the dissolved alkali and maintain the reaction temperature. Thiourea dioxide is then added little by little while stirring.

Once there is substantially no unreacted N,N-disubstituted nitrosamine in the reaction mixture (usually left overnight)
, the reaction is terminated and the resulting N,N-disubstituted hydrazine is separated from the reaction mixture.

Separation and purification of N,N-disubstituted hydrazine can be carried out by methods known per se. For example, in the preferred embodiment described above, the organic solvent is distilled off from the reaction mixture after the completion of the reaction, and the residue is purified by a suitable method. Solvents such as ethers (e.g. diethyl ether, isopropyl ether, n-butyl ether, etc.), aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.), halogenated hydrocarbons (e.g. methylene chloride, carbon tetrachloride, chloroform, (chlorobenzene, etc.), salting out with sodium hydroxide, etc., solvent extraction again, drying the extract, then distilling off the solvent, or precipitating salt formation with an acid such as hydrogen chloride. Accordingly, N,N-disubstituted hydrazine can be obtained. The N,N-disubstituted hydrazine thus obtained may be subjected to precision distillation, chromatography,
It can be further purified by recrystallization or the like.

The N,N-disubstituted nitrosamine of formula (I) used as a starting material in the method of the present invention described above is known per se, or can be produced by a method known per se. For example, it can be easily produced by nitroning the corresponding N,N-disubstituted amine with sodium sulfite and an acid such as hydrochloric acid, sulfuric acid, acetic acid, etc., and the N,N-disubstituted amine produced in this way Nitrosamines can be directly subjected to the method of the present invention without being isolated.

In the formula (I'), the aliphatic hydrocarbon group is linear,
It may be of any type, branched or cyclic, such as methyl, ethyl, propyl, inglevir,
Alkyl groups such as butyl, isobutyl, 5ec-butyl, tert-butyl, pentyl, hexyl, octyl, 2-ethylhexyl, decyl, and cycloalkyl groups such as cyclopentyl and cyclohexyl are included. Particularly preferred are lower alkyl groups. In addition, such aliphatic hydrocarbon groups may be substituted, and examples of the substituents include aryl groups such as phenyl and naphthyl; methoxy,
Examples include alkoxy groups such as ethoxy, halogen atoms such as fluoro and chloro, hydroxyl groups, substituted or unsubstituted amino groups, and heterocyclic groups. Specific examples of substituted aliphatic hydrocarbon groups include aralkyl groups such as benzyl and phenethyl; alkoxyalkyl groups such as methoxymethyl and ethoxymethyl; haloalkyl groups such as chloromethyl and fluoromethyl; hydroxymethyl , hydroxyalkyl groups such as hydroxyethyl; aminoalkyl groups such as aminomethyl and ethylamino; and heterocyclic groups such as fur7lyl and thionyl.

Further, the aromatic hydrocarbon group may be monocyclic or polycyclic, such as phenyl, naphthyl, tolyl,
Includes xylyl and the like. These aromatic hydrocarbon groups may have a substituent, and examples of the substituent include an alkyl group, an aryl group, a halogen atom, a hydroxyl group, an alkoxy group, and an amine group.

Furthermore, examples of the heterocyclic group include pyridyl, furyl, thienyl, piperidyl, quinoyl, and the like.

On the other hand, examples of heterocycles that may contain further heteroatoms (e.g., nitrogen atom, sulfur atom, oxygen atom) that may be formed when R1 and R3 are combined with the nitrogen atom to which they are bonded include, for example. , morpholine ring, N-alkyl-
Examples include a piperazine ring, a virol ring, a piperidine ring, a homopiperidine ring, an indoline ring, a pipecoline ring, a thiomorpholine ring, and the like.

In this specification, the term "lower" means that the number of carbon atoms in the atomic group or compound to which this term is attached is 6 or less, preferably 4 or less.

Thus, specific examples of the N,N-disubstituted nitrosamine of formula (I) that can be used as a starting material in the method of the present invention are as follows.

N,N-dimethyl-N-nitronamine, N,N-diethyl-N-nitronamine, N,N-dipropyl-N-
Nitronamine, N,N-diptyl-N-nitroneamine, N-methyl-N-nitroneethanolamine, N-
Nitron-3-chlorodiphenylamine, N-nitrone-diphenylamine, N-nitrone-2,2'-dipyridylamine, N-nitroso-3-methyldiphenylamine, N-nitrone-N
-Phenyl-2-naphthylamine, N-nitroso-2-
Anilinoethanol, N-nitrone-2-benzylaminopyridine, N-nitrone-4-chloro-N-methylaniline, N-nitrone-N-ditylaniline, N-nitrone-N-ethyltoluidine, N-nitroso-
2-methylaminopyridine, N-nitrone-N-methylaniline, N-nitrone-N-7enylbenzylamine, N-nitrosopyrrolidine, N-nitronepiperidine, N-nitrosohomopiperidine, N-nitrone-2-pipecoline, N-nitrosoindoline, N-nitrosoperhydroindoline, N-nitrosoperhydroquinoline, N-nitrone-4-phenylpiperazine, N-nitrosomorpholine, N-nitrosothiomorpholine, ■-dihytron-4-methylpiperazine t- =Trosseau 4-(β-ethanol)piperazine, l-nitrone-4
-7enylpiperazine, etc.

According to the present invention described above, N in formula (If).

N-disubstituted hydrazines can be produced in good yields. Moreover, according to the present invention, the reaction operation is easy and a complicated reaction apparatus is not required, which is extremely advantageous industrially.

Next, the present invention will be described in more detail with reference to Examples.

In the examples, HPLC stands for high performance liquid chromatography and GC stands for gas chromatography.

Example 1: Synthesis of l-benzyl-1-7enylhydrazine (A) 4 g of N-benzylaniline and 40 g of methanol are placed in a 200 mQ Erlenmeyer flask and stirred with a stir bar. Add 3.3 g of acetic acid.

A solution of 3.0 g of sodium nitrite dissolved in 10 g of water is added dropwise with stirring. After dropping - perform a day and night reaction (HPL
The reaction rate was 98.2% at C).

This reaction solution is used as it is in the next reaction.

The above reaction solution containing N-benzyl-N-nitrosoaniline was neutralized with sodium hydroxide, methanol was distilled off under reduced pressure, extracted with methylene chloride, washed with water, dehydrated with anhydrous sodium sulfate, and extracted with methylene chloride. By distilling off, N-benzyl-N-nitrosoaniline is obtained (
4.4 g of 99.2% HPLC crystals are obtained. The crystallinity is 99.4%. ).

(B) A solution obtained by dissolving 5.7 g of sodium hydroxide in 40 g of water is added to the reaction solution obtained in (A) above while stirring.

After adding 5.6g of thiourea dioxide little by little to this,
- Carry out day and night reactions. The reaction rate was 97.5% by HLPC, and the reaction rate from the Toroso form was 99.2%).

Next, methanol is distilled off under reduced pressure, and the mixture is extracted twice with 50 mQ of methylene chloride and washed with water. The extract was dehydrated over anhydrous sodium sulfate, filtered, and methylene chloride was distilled off under reduced pressure.

The title compound is obtained in a yield of 4.1 g (98.3 HPLC) (yield 93.9%). The yield of the whole process was 93.
It will be 1%.

Example 2: Synthesis of 1-(2-hydroxyethyl)-1-phenylhydrazine Put 4 g of 2-anilinoethanol and 40 g of methanol into a 200 m Erlenmeyer flask and stir with a stir bar. Add acetic acid. A solution of 4.0 g of sodium nitrite dissolved in 10 g of water is added dropwise with stirring. After the addition, the reaction is carried out day and night (reaction rate is 96.5% by HPLC). This reaction solution is Use it as is for the next reaction.

Next, a solution prepared by dissolving 7.6 g of sodium hydroxide in 39 g of water is added dropwise to the reaction solution obtained above while stirring.

Then add 7.6g of thiourea dioxide little by little, and -
Carry out reactions day and night. The reaction rate from the thoron body was 97.5%, which was 94.1% by HPLC).

Methanol is distilled off under reduced pressure, extracted twice with 50 ml of methylene chloride, and washed with water. The extract was dehydrated over anhydrous sodium sulfate, filtered, and methylene chloride was distilled off under reduced pressure. The title compound is obtained in a yield of 3-4 g (93.5% HPLC), giving a total yield of 71.6%.

Example 3: Synthesis of 2-(1-benzylhydrazino)pyridine 4 g of 2-(l-benzylamino)pyridine and 40 g of methanol are placed in a 200 mQ Erlenmeyer flask and stirred with a stir bar. Add 3.4 g of acetic acid. A solution of 3°Og of sodium nitrite dissolved in log water was added dropwise with stirring. After dropping - Reaction is carried out day and night.

The reaction rate is 98.5% by HPLC. This reaction solution is used as it is in the next reaction.

Add 10 g of methanol to this reaction solution. A solution prepared by dissolving 5.9 g of sodium hydroxide in 40 g of water is added dropwise to the above reaction solution while stirring. Thereafter, 5.7 g of thiourea dioxide was added little by little, and the reaction was carried out day and night. 8 by HPLC
The reaction rate from the troso isomer is 88.8%, which is a reaction rate of 7.4%.
7%). Then extract with diethyl ether. After dehydration, diethyl ether was distilled off under reduced pressure and 3.8g (HPL
2-'(1-methylhydrazino)pyridine is obtained with a yield of C93, 5%). The yield of the whole process is 82.1%.

Example 4: Synthesis of 2-C1-methylhydrazino)pyridine 1 g of 2-(1-methyl-1-nitrosamino)pyridine and 5 g of methanol are placed in a 100 m12 Erlenmeyer flask and stirred with a stir bar. A solution prepared by dissolving 1.5 g of sodium hydroxide in 20 g of water was added dropwise to the reaction solution while stirring. After that 2. Add Og of thiourea dioxide little by little and carry out a day and night reaction. The reaction rate was 98.4% by HPLC.

Thereafter, salting out is performed with excess sodium hydroxide, and extraction is performed with diethyl ether. After dehydration, diethyl ether is distilled off under reduced pressure.

2-(1-
Methylhydrazino)pyridine is obtained. Yield is 90.
It is 7%.

Implementation fi5: Synthesis of 4-aminomorpholine 100m
Put Ig's 4-nitrosomorpholine and 15 g of water into a Q Erlenmeyer flask and stir with a stir bar.

A solution of 1.7 g of sodium hydroxide dissolved in log water is added dropwise to the reaction solution while stirring. Thereafter, 2.5 g of thiourea dioxide was added little by little, and the reaction was carried out day and night. The reaction progresses quantitatively. The reaction rate is 99.9% by HPLC. Thereafter, salting out is performed with excess sodium chloride, and extraction is performed with diethyl ether.

After dehydration, diethyl ether is distilled off under reduced pressure. 0°82
4-aminomorpholine is obtained in a yield of g (GC99, 3%). Yield is 92.6%.

Example 6: Synthesis of l-amino-4-methylpiperazine 20g of 1-methylpiperazine, 100g of water and 41.6g of concentrated hydrochloric acid are placed in a 500ml (2) flask and stirred with a stirrer. 20.7g of sodium nitrite
A solution dissolved in 0 g of water is added dropwise while stirring. After 2 hours of reaction, the reaction rate was 97.2% by HPLC. This reaction solution is used as it is in the next reaction.

Add Log of methanol to the above reaction solution. A solution prepared by dissolving 5.9 g of sodium hydroxide in 40 g of water was added dropwise to the reaction solution while stirring. Thereafter, 5.7 g of thiourea dioxide was added little by little to carry out the reaction. After 2 hours of reaction, no nitroso form remained. It was confirmed by the GC internal standard method that 79.4% of the target product was produced.

Salting out is carried out with excess sodium hydroxide, filtered and extracted with diethyl ether. After dehydration, diethyl ether is distilled off under reduced pressure. 18.9g (GC95.

6%) gives ■-amino-4-methylpiperazine. Yield is 70.1%.

Example 7: Synthesis of I,1-dimethylhydrazine 200m
4 g of N-nitrosodimethylamine and 100 g of water were placed in a No. 12 Erlenmeyer flask and stirred with a stirrer. A solution prepared by dissolving 13.0 g of sodium hydroxide in 40 g of water is added dropwise to the stirrer reaction solution. After adding 14.6 g of thiourea dioxide in small portions, the reaction is carried out day and night. 99.2% in GC
is the reaction rate.

Salt out with sodium chloride and extract with diethyl ether. After dehydration, diethyl ether is distilled off under reduced pressure. 3
．． With a yield of 1 g (GC98,9%), l.

■-Dimethylhydrazine was obtained. Yield is 94.5%.

Example 8: Synthesis of 1.1-di-n-butylhydrazine 4 g of di-n-butylamine and 25 g of methanol are placed in a 300 m (2) 4-hole flask equipped with a reflux condenser and stirred with a stirrer.5 Add .8g of acetic acid, 5.3
A solution of g of sodium nitrite dissolved in 25 g of water is added dropwise with stirring. After dropping, the temperature of the reaction solution was raised to 60'C, and 1
Perform a time reaction. The reaction rate was 99.4% by GC. This reaction solution is used as it is in the next reaction.

25 g of methanol is added to the above reaction solution, and a solution prepared by dissolving 12.5 g of sodium hydroxide in 30 g of water is added dropwise to the reaction solution with a stirrer. Thereafter, 12.3 g of thiourea dioxide was added little by little, and the reaction was carried out at 60° C. for 5 hours. G
98.9% reaction rate for C and 99.5% reaction rate from Toroso form).

Extraction is performed with diethyl ether, and after dehydration, diethyl ether is distilled off under reduced pressure to obtain 1.1-di-N-butylhydrazine in a yield of 5.3 g (GC98, 9%). Yield is 93.9%.

Practical Example 9: Synthesis of 1.1-diphenylhydrazine 1
1.98 g of N-nitrosodiphenylamine and 30 g of methanol were placed in a 40 mQ flask and stirred. A solution prepared by dissolving 2.0 g of sodium hydroxide in 33 g of water is added dropwise to the stirrer reaction solution. After adding 3.2 g of thiourea dioxide, the reaction is carried out - day and night. Methanol was distilled off under reduced pressure and extracted with ether. The reaction rate was 89.1% by HPLC.

After dehydration, HCQ gas is blown in to precipitate hydrochloride.

The crystals were collected by filtration and dried under reduced pressure, yielding 1.85 g (HPLC98
, 4%) of 1,1-diphenylhydrazine hydrochloride is obtained. Yield is 82.6%.

Example 1O: Synthesis of 1-methyl-1-phenylhydrazine 5.45 g of N-nitroso-N-methylaniline and 50 g of water are placed in a 200 mQ 40 flask and stirred.

A solution prepared by dissolving 7.68 g of sodium hydroxide in 60 g of water is added dropwise to the stirrer reaction solution. After adding 10.38 g of thiourea dioxide, the temperature of the reaction solution was raised to 50° C. and the reaction was carried out for 2 hours with stirring. The reaction mixture is then extracted with methylene chloride. 92.0% is obtained using the GC internal standard method.

After dehydrating the methylene chloride, the methylene chloride was distilled off under reduced pressure.
．． 3 g (GC97.8%) of 1-methyl-1-phenylhydrazine are obtained. Yield is 86.0%.

Claims (1)

[Claims] General formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (I) In the formula, R_1 and R_2 are each a substituted or unsubstituted aliphatic hydrocarbon group or a substituted or unsubstituted aromatic hydrocarbon group or represents a heterocyclic group, or R_1 and R
_2 together with the nitrogen atom to which they are bonded represents a heterocycle which may further contain another heteroatom. A method for producing N,N-disubstituted hydrazine represented by the general formula ▲Mathematical formula, chemical formula, table, etc.▼ (II) characterized by the reaction, where R_1 and R_2 have the above-mentioned meanings.