JPH09202778A - Conversion of amino group of primary amine to chloro group and chemical synthesis utilizing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a procedure for converting the amino group of a heterocyclic primary amine to a chloro group, a synthetic method of 2-chloro-5- methylthiazole and its derivatives utilizing this conversion. SOLUTION: After a heterocyclic primary amine is allowed to react with sodium nitrite in the presence of hydrochloric acid, sodium nitrite is allowed to react with the formed diazonium base in the presence of an equimolar or more amount of hydrochloric acid based on the diazonium base, then heated at 30-100 deg.C to convert the amino group to the chloro group. In addition, 2- amino-5-methylthiazole is allowed to react with sodium nitrite in the presence of hydrochloric acid, then allowed to react with sodium nitrite in the presence of an equimolar or more amount hydrochloric acid based on the formed diazonium base, and heated at 30-100 deg.C to synthesize 2-chloro-5-methylthiazole. Further, this product is allowed to react with a chlorinating agent to synthesizing 2-chloro-5-chloromethylthiazole.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for converting an amino group of a heterocyclic primary amine into a chloro group and a method for producing a 2-chloro-5-methylthiazole derivative using the same.

[0002]

2. Description of the Related Art As a method for converting an amino group of a primary amine into a chloro group, an aromatic primary amine is prepared by synthesizing a diazonium salt with sodium nitrite in hydrochloric acid and then preparing a copper (I) salt. The Sandmeyer method of reacting with and the Gatterman method of reacting with active metallic copper are known.
Even if the reaction liquid in which the diazonium salt is formed is heated as it is, the diazonium base is replaced with the chloro group, but the yield is only a dozen%. The Sandmeyer reaction and the Gutterman reaction have improved the yield by using a copper salt or metallic copper. However, the method using a copper (I) salt requires a copper (I) salt equimolar to the amino group, and the operation of separating copper after the reaction is complicated.
Furthermore, since a large amount of copper salt is discarded, sufficient consideration for the environment is required. When active metal copper is used, the same problems as in the case of using a copper (I) salt occur, and it is necessary to prepare metal copper, which complicates the process. Therefore, it is not suitable for reaction on an industrial scale. Further, when a copper salt is used, if an alkali treatment is carried out as a post-reaction treatment, a copper salt having poor filterability is deposited and easily adheres to a reactor or the like, resulting in poor operability. Further, as an example of diazotizing a heterocyclic primary amine and substituting an amino group with a chloro group, a solution obtained by diazotizing 2-amino-5-methylthiazole is added to a hydrochloric acid solution of a cuprous salt and left overnight. After that, steam distillation is reported as alkaline (J. Chem. Soc. 1942, p38
6), but using a copper salt and the operation are complicated. For this reason, a method using a copper salt is not suitable as an industrial method for converting an amino group of a heterocyclic primary amine into a chloro group. On the other hand, as a method for producing 2-chloro-5-chloromethylthiazole which is useful as a raw material for synthesizing pharmaceuticals and agricultural chemicals, chlorine and allyl isothiocyanate (JP-A-63-83079) and its derivatives (JP-A-4-234864) Japanese Patent Laid-Open Publication No. 1993-242242 has been proposed. However, since allyl isothiocyanate used as a raw material is expensive and has an irritating odor, it is difficult to say that it is a method suitable for production on an industrial scale.

[0003]

DISCLOSURE OF THE INVENTION The present inventors have found a method capable of inexpensively producing 2-amino-5-methylthiazole by finding a method capable of converting an amino group of a heterocyclic primary amine into a chloro group in good yield. From the above, it was thought that a method for producing 2-chloro-5-chloromethylthiazole suitable for production on an industrial scale can be provided, and a method for converting an amino group of a heterocyclic primary amine into a chloro group was earnestly studied. An object of the present invention is to provide a method for converting an amino group of a heterocyclic primary amine into a chloro group and a method for synthesizing 2-chloro-5-methylthiazole and a derivative thereof using the method.

[0004]

Means for Solving the Problems When the present inventors induce a heterocyclic primary amine into a diazonium salt in the presence of hydrochloric acid and heat the reaction solution in the presence of hydrochloric acid in an equimolar amount or more of the diazonium base, Surprisingly, the inventors have found that, unlike aromatic diazonium salts, the diazonium base substitutes for a chloro group in a high yield, and has completed the present invention. That is, according to the present invention, a heterocyclic primary amine is reacted with sodium nitrite in the presence of hydrochloric acid, and then heated to 30 to 100 ° C. in the presence of hydrochloric acid at an equimolar amount or more to the diazonium base to prepare an amino group. Is converted into a chloro group, and 2-amino-5-methylthiazole or its hydrochloride utilizing this is reacted with sodium nitrite in the presence of hydrochloric acid,
30 to 100 ° C. in the presence of hydrochloric acid in an equimolar amount or more, preferably 1.05 to 3 times the molar amount of the produced diazonium base.
To produce 2-chloro-5-methylthiazole, and further to produce 2-chloro-5-chloromethylthiazole by reacting 2-chloro-5-methylthiazole with a chlorinating agent.

[0005]

BEST MODE FOR CARRYING OUT THE INVENTION The heterocyclic primary amine referred to in the present invention means an amino group in a heterocycle such as aminothiazole.
It refers to a compound having (-NH ₂ ) bound thereto, and can be used in the reaction in the form of a free amine or a hydrochloride.
In the present invention, first, a heterocyclic primary amine is derived into a diazonium salt. The diazonium salt is produced by reacting a heterocyclic primary amine with sodium nitrite in hydrochloric acid at 10 ° C or lower, preferably -10 to 10 ° C. The reaction solution was added in an amount of 30 to 1 in the presence of hydrochloric acid in an equimolar amount or more with respect to the produced diazonium base.
When heated to 00 ° C., a chlorinated compound of a heterocyclic compound in which a diazonium base is replaced with a chloro group is produced in a yield of 60% or more. If the heating temperature is lower than 30 ° C, the substitution reaction of the amino group with the chloro group is not completed. In order to allow equimolar or more hydrochloric acid to be present in the diazonium base generated during the heating reaction, it is preferable that at least 3 times or more molar hydrochloric acid of the amino group of the primary amine be present during the diazotization reaction. The heterocyclic compound in which the desired amino group is converted into a chloro group can be obtained by extracting the obtained reaction solution with a suitable solvent such as chloroform. Incidentally, in the diazonium salt of a heterocyclic primary amine, as in the aromatic diazonium salt,
The yield is significantly lower when metallic copper or copper salts are used.

Specifically, 2-amino-5-methylthiazole, which is easily obtained from 2-chloropropionaldehyde and thiourea, is diazotized in hydrochloric acid, and the reaction solution is added in an equimolar amount or more to the diazonium base. Heating to 30-100 ° C in the presence of hydrochloric acid gives 2-chloro-5-methylthiazole. Then, by reacting with a chlorinating agent, 2-chloro-5 in which the methyl group at the 5-position was chlorinated
-Chloromethylthiazole is obtained. After the diazotization, a chlorinating agent may be subsequently added to carry out the chlorination.
As the chlorinating agent used at this time, N-chlorosuccinimide, chlorine or the like can be used. N-chlorosuccinimide used as a chlorinating agent is 2-chloro-5
-It is preferable to use 0.8 to 2.0 mol per mol of methylthiazole. When N-chlorosuccinimide is used in a large excess, by-products increase and the purity decreases in the isolation operation. Although many solvents can be used in the reaction, chloroform is suitable because it is difficult to react with the chlorinating agent. The reaction temperature is 20 ° C. or higher and the reflux temperature of the solvent used or lower. If the temperature is lower than 20 ° C, the reaction rate is slow and it is not preferable. The reaction is preferably carried out under light irradiation and in the presence of a radical initiator such as azobisisobutyronitrile, but only one of them may be used.

The present invention will be specifically described below with reference to Examples and Comparative Examples.

Example 1 Synthesis of 2-chloro-5-methylthiazole 300 ml equipped with stirrer, dropping funnel, thermometer
2-amino-5-methylthiazole 20 g (0.175 mol), 36% hydrochloric acid 80 ml in a 3-necked flask.
(0.931 mol) and 30 ml of water were charged and cooled to -5 ° C. 30ml water while keeping the temperature below 0 ℃
14g (0.203mo) of sodium nitrite dissolved in
l) was gradually added dropwise, and then the reaction was carried out at 0 ° C. or lower for 3 hours to generate a diazonium base. The reaction solution was heated and reacted at 80 ° C. for 3 hours, and then the obtained reaction solution was extracted with 40 ml of chloroform 3 times to obtain a chloroform solution containing 2-chloro-5-methylthiazole. After removing chloroform by atmospheric distillation, vacuum distillation is performed,
2-Chloro-5-methylthiazole 16.6 g (0.1
24 mol) was isolated. The synthetic yield was 71%.

[0008]

Comparative Example 1 Synthesis of 2-chloro-5-methylthiazole 300 ml equipped with a stirrer, dropping funnel, and thermometer
2-amino-5-methylthiazole 20 g (0.175 mol) and 36% hydrochloric acid 35 ml in a three-necked flask.
(0.407 mol) and 30 ml of water were charged and cooled to -5 ° C. 30ml water while keeping the temperature below 0 ℃
14g (0.203mo) of sodium nitrite dissolved in
l) was gradually added dropwise, and then the reaction was carried out at 0 ° C. or lower for 3 hours to generate a diazonium base. The reaction solution was heated and reacted at 80 ° C. for 3 hours, and then the obtained reaction solution was extracted with 40 ml of chloroform 3 times to obtain a chloroform solution containing 2-chloro-5-methylthiazole. After removing chloroform by atmospheric distillation, vacuum distillation is performed,
2-Chloro-5-methylthiazole 10.3 g (0.0
77 mol) was isolated. The synthetic yield was 44%.

[0009]

Comparative Example 2 Synthesis of 2-chloro-5-methylthiazole 300 ml equipped with a stirrer, dropping funnel and thermometer
2-amino-5-methylthiazole 20 g (0.175 mol), 36% hydrochloric acid 23 ml in a 3-necked flask
(0.267 mol) and 30 ml of water were charged and cooled to -5 ° C. 30ml water while keeping the temperature below 0 ℃
14g (0.203mo) of sodium nitrite dissolved in
l) was gradually added dropwise, and then the reaction was carried out at 0 ° C. or lower for 3 hours to generate a diazonium base. The reaction solution was heated and reacted at 80 ° C. for 3 hours, and then the obtained reaction solution was extracted with 40 ml of chloroform 3 times to obtain a chloroform solution containing 2-chloro-5-methylthiazole. After removing chloroform by atmospheric distillation, vacuum distillation is performed,
5.1 g of 2-chloro-5-methylthiazole (0.03
8 mol) was isolated. The synthetic yield was 22%.

[0010]

Comparative Example 3 Synthesis of 2-chloro-5-methylthiazole 300 ml equipped with a stirrer, dropping funnel and thermometer
2-amino-5-methylthiazole 20 g (0.175 mol), 36% hydrochloric acid 80 ml in a 3-necked flask.
(0.931 mol) and 30 ml of water were charged and cooled to -5 ° C. 30ml water while keeping the temperature below 0 ℃
14g (0.203mo) of sodium nitrite dissolved in
l) was gradually added dropwise, and the reaction was continued at 0 ° C. or lower for 3 hours to prepare a diazonium salt solution. In a 300 ml three-necked flask equipped with a stirrer, a dropping funnel, and a thermometer, 17.3 g (0.175 mol) of cuprous chloride, 3
After charging 80 ml of 6% hydrochloric acid, the mixture was cooled to -5 ° C.
The diazonium salt solution was gradually added dropwise to this aqueous solution while maintaining the temperature at 0 ° C or lower. After further reacting at 0 ° C. or lower for 3 hours, the reaction was performed at 80 ° C. for 3 hours. After the reaction was completed, the solution was made alkaline with a 15% aqueous sodium hydroxide solution, and the precipitated copper salt was filtered off. The obtained filtrate was extracted with 40 ml of chloroform three times to obtain a chloroform solution containing 2-chloro-5-methylthiazole. After removing chloroform by atmospheric distillation, vacuum distillation was performed to remove 2-chloro-5-methylthiazole 8.4.
g (0.063 mol) was isolated. 36% synthetic yield
Met.

[0011]

Example 2 Synthesis of 2-chloro-5-chloromethylthiazole 200 ml equipped with stirrer, dropping funnel, thermometer
2-amino-5-methylthiazole hydrochloride 14 g (0.0930 mol), 36% hydrochloric acid 25
ml and 20 ml of water were charged and cooled to -5 ° C. 0 ° C
While keeping the temperature below, 6.8 g (0.0986 mol) of sodium nitrite dissolved in 10 ml of water was gradually added dropwise, and the reaction was further performed at 0 ° C. or lower for 1 hour to generate a diazonium base. The reaction solution is heated to 40 ° C.
After reacting for 3 hours at room temperature, the reaction solution obtained is chloroform 30m.
It was extracted 1 × 3 times to obtain a chloroform solution containing 2-chloro-5-methylthiazole. After removing chloroform by atmospheric distillation, vacuum distillation was performed to remove 2-chloro-
5-methylthiazole 10.1 g (0.0756 mo
1) was isolated. The synthetic yield was 81%.

The obtained 2-chloro-5-methylthiazole was dissolved in 20 ml of chloroform and charged into a 100 ml three-necked flask equipped with a stirrer, a high pressure mercury lamp and a thermometer, and then 10 g of N-chlorosuccinimide. (0.
(0749 mol) was added and the reaction was carried out at 50 ° C. for 6 hours under light irradiation. After completion of the reaction, succinimide by-produced was recovered using 30 ml of water, and then the chloroform layer was distilled to obtain 9.5 g (0.0565 mol) of 2-chloro-5-chloromethylthiazole. Synthesis yield is 6
1%. In addition, succinimide is chlorinated to give N
-Reused as chlorosuccinimide.

[0013]

Example 3 Synthesis of 2-chloro-5-chloromethylthiazole 300 ml equipped with stirrer, dropping funnel, thermometer
2-amino-5-methylthiazole hydrochloride 26.2 g (0.175 mol), 36% hydrochloric acid 8
Charge 0 ml (0.931 mol) and 40 ml of water,-
Cooled to 5 ° C. While keeping the temperature below 0 ℃, water 3
14 g of sodium nitrite dissolved in 0 ml (0.203
(mol) was gradually added dropwise, and the mixture was reacted at 0 ° C. or lower for 3 hours to generate a diazonium base. The reaction solution was heated, heated to 80 ° C., reacted at 80 ° C. for 3 hours, and the obtained reaction solution was extracted with 40 ml of chloroform 3 times to give 15.1 g of 2-chloro-5-methylthiazole.
A chloroform solution containing (0.113 mol) was obtained.

The resulting chloroform solution of 2-chloro-5-methylthiazole was charged into a 200 ml three-necked flask equipped with a stirrer, a high pressure mercury lamp and a thermometer, and then 16.0 g of N-chlorosuccinimide. (0.120
mol) and 0.4 g of azobisisobutyronitrile were added, and the mixture was reacted under light irradiation at 50 ° C. for 10 hours. After completion of the reaction, 100 ml of water was used to collect the by-produced succinimide, and the chloroform layer was distilled to obtain 2
-Chloro-5-chloromethylthiazole 13.5 g
(0.080 mol) was obtained. The synthetic yield was 46%. The succinimide was chlorinated and reused as N-chlorosuccinimide.

[0015]

Example 4 Synthesis of 2-chloro-5-chloromethylthiazole 300 ml equipped with stirrer, dropping funnel, thermometer
2-amino-5-methylthiazole 20 g (0.175 mol), 36% hydrochloric acid 80 ml in a 3-necked flask.
(0.931 mol) and 40 ml of water were charged and cooled to -5 ° C. 30ml water while keeping the temperature below 0 ℃
14g (0.203mo) of sodium nitrite dissolved in
l) was gradually added dropwise, and then the reaction was carried out at 0 ° C. or lower for 3 hours to generate a diazonium base. This reaction solution is heated, heated to 80 ° C., reacted at 80 ° C. for 3 hours, and then the obtained reaction solution is extracted with 40 ml of chloroform × 3 times,
2-chloro-5-methylthiazole 17.4 g (0.1
A chloroform solution containing 30 mol) was obtained.

The resulting chloroform solution of 2-chloro-5-methylthiazole was charged into a 200 ml three-necked flask equipped with a stirrer, a high pressure mercury lamp and a thermometer, and then 26.7 g of N-chlorosuccinimide. (0.200
mol) and 0.4 g of azobisisobutyronitrile were added, and the mixture was reacted under light irradiation at 50 ° C. for 10 hours. After completion of the reaction, 120 ml of water was used to collect the by-produced succinimide, and then the chloroform layer was distilled to obtain 2
-Chloro-5-chloromethylthiazole 15.5 g
(0.092 mol) was obtained. The synthetic yield was 53%. The succinimide was chlorinated and reused as N-chlorosuccinimide.

[0017]

According to the method of the present invention, the amino group of a heterocyclic primary amine can be easily converted into a chloro group, and a copper salt or metallic copper is used as in the case of an aromatic primary amine. Since it does not exist, post-processing is easy. Further, 2-chloro-5-methylthiazole can be synthesized under mild conditions using 2-amino-5-methylthiazole as a raw material which is inexpensive and easy to handle, without using an expensive raw material such as allyl isothiocyanate. . Therefore, 2-chloro-5-chloromethylthiazole useful as a synthetic raw material for medicines, agricultural chemicals, etc. can be provided at low cost.

Claims (6)

[Claims] 1. A heterocyclic primary amine is reacted with sodium nitrite in the presence of hydrochloric acid and then heated to 30 to 100 ° C. in the presence of hydrochloric acid in an equimolar amount or more to the produced diazonium base. A method of converting an amino group of a primary amine into a chloro group. 2. 2-amino-5-methylthiazole,
A method for synthesizing 2-chloro-5-methylthiazole, which comprises reacting with sodium nitrite in the presence of hydrochloric acid and then heating to 30 to 100 ° C. in the presence of hydrochloric acid in an equimolar amount or more with respect to the produced diazonium base. 3. 2-amino-5-methylthiazole,
After reacting with sodium nitrite in the presence of hydrochloric acid, the resulting diazonium base is heated to 30 to 100 ° C. in the presence of hydrochloric acid in an equimolar amount or more to induce 2-chloro-5-methylthiazole. Reacts with a chlorinating agent, 2
-Method for synthesizing chloro-5-chloromethylthiazole. 4. The method according to claim 3, wherein the reaction with the chlorinating agent is carried out in chloroform. 5. The reaction with a chlorinating agent is performed under light irradiation or /
And 3 or 4 in the presence of a radical initiator.
The method described in. 6. 2-amino-5-methylthiazole,
After reacting with sodium nitrite in the presence of hydrochloric acid, the resulting diazonium base is heated to 30 to 100 ° C. in the presence of hydrochloric acid in an equimolar amount or more to induce 2-chloro-5-methylthiazole. After the reaction with N-chlorosuccinimide in chloroform in the presence of light irradiation and / or in the presence of a radical initiator to form 2-chloro-5-chloromethylthiazole, the by-product succinimide contains water in the reaction solution. In addition, it is recovered in the water layer and chlorinated for recycling.
Method for synthesizing chloro-5-chloromethylthiazole.