JP3242575B2 - Method for converting amino group of primary amine into chloro group and synthesis method utilizing the same - Google Patents

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 using sodium nitrite in hydrochloric acid and then preparing a copper (I) salt. And the Gutterman method of reacting with active metallic copper are known.
Even if the reaction solution in which the diazonium salt is formed is heated as it is, the diazonium base is replaced with a chloro group, but the yield is only over 10%. The Sandmeyer reaction and the Gutterman reaction improve the yield by using a copper salt or metallic copper. However, the method using a copper (I) salt requires a copper (I) salt in an equimolar amount to an amino group, and the operation of separating copper after the reaction is complicated.
Further, since a large amount of copper salt is discarded, sufficient consideration for the environment is required. When active copper metal is used, the same problem as when copper (I) salt is used occurs, and preparation of metallic copper is required, which complicates the process. For this reason, it is not suitable for reactions on an industrial scale. In addition, when a copper salt is used, when an alkali treatment is performed as a post-reaction treatment, a copper salt having poor filtration and separation properties is precipitated and easily adheres to a reactor or the like, so that operability is poor. 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 cuprous salt and left overnight. Later, steam distillation was performed as alkaline (J. Chem. Soc. 1942, p38)
6) The use of copper salts is also complicated. For this reason, a method using a copper salt as a method for converting an amino group of a heterocyclic primary amine into a chloro group is not suitable as an industrial method. On the other hand, as a method for producing 2-chloro-5-chloromethylthiazole useful as a raw material for synthesizing pharmaceuticals and agricultural chemicals, chlorine and allyl isothiocyanate (JP-A-63-83079) and derivatives thereof (JP-A-4-234864). Has been proposed. However, allyl isothiocyanate used as a raw material is expensive and has a pungent odor, so that it is hard to say that it is a method suitable for production on an industrial scale.

[0003]

[0008] The present inventors have found that, of the above-mentioned
In view of the current situation, a method capable of converting an amino group of a heterocyclic primary amine into a chloro group in a high yield without using a copper salt or metallic copper is found, so that it can be produced at low cost.
Considering that it is possible to provide a method for producing 2-chloro-5-chloromethylthiazole suitable for production on an industrial scale from amino-5-methylthiazole, a method for converting an amino group of a heterocyclic primary amine into a chloro group was proposed. Diligently studied. The present invention does not substantially require the presence of copper salts or metallic copper,
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]

DISCLOSURE OF THE INVENTION The present inventors derivatize a heterocyclic primary amine into a diazonium salt in the presence of hydrochloric acid ,
When this reaction solution is heated in the presence of hydrochloric acid in an equimolar amount or more of the diazonium base without the presence of copper salt or metallic copper , unexpectedly, unlike the aromatic diazonium salt,
The inventors have found that a diazonium base is substituted with a chloro group in a high yield, and have completed the present invention. That is, the present invention
After reacting the heterocyclic primary amine with sodium nitrite in the presence of hydrochloric acid , substantially copper
This is a method in which an amino group is converted to a chloro group by heating to 30 to 100 ° C. in the presence of hydrochloric acid in an equimolar amount or more without the presence of salt or metallic copper.
After reacting amino-5-methylthiazole or its hydrochloride with sodium nitrite in the presence of hydrochloric acid, it is at least equimolar, preferably at least 1.
A method for producing 2-chloro-5-methylthiazole by heating to 30 to 100 ° C. in the presence of 0.5 to 3 moles of hydrochloric acid, and further reacting 2-chloro-5-methylthiazole with a chlorinating agent 2 A process for producing -chloro-5-chloromethylthiazole.

[0005]

BEST MODE FOR CARRYING OUT THE INVENTION The term "heterocyclic primary amine" as used herein means an amino group on a heterocyclic ring such as aminothiazole.
Refers to a compound to which (-NH2) is bound, and can be provided for the reaction in the form of a free amine or a hydrochloride. In the present invention, first, the heterocyclic primary amine is converted to a diazonium salt. For the production of the diazonium salt, the heterocyclic primary amine is reacted with sodium nitrite in hydrochloric acid at 10 ° C or lower, preferably at -10 to 10 ° C. Substantially copper salt or metallic copper is present for the diazonium base formed
Without reacting the reaction solution in the presence of equimolar or more hydrochloric acid,
When heated to 100 ° C., a chlorinated heterocyclic compound in which a diazonium base is substituted with a chloro group is produced in a yield of 60% or more. When 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 hydrochloric acid to be present in an equimolar amount or more with respect to the diazonium base generated during the heating reaction, it is preferable that hydrochloric acid be present in the diazotizing reaction at least three times the molar amount of the amino group of the primary amine. By extracting the obtained reaction solution with a suitable solvent, for example, chloroform, a heterocyclic compound in which the desired amino group has been converted to a chloro group can be obtained. When a metal copper or a copper salt is used as the diazonium salt of the heterocyclic primary amine as in the case of the aromatic diazonium salt, the yield is extremely low.

Specifically, 2-amino-5-methylthiazole, which is easily obtained from 2-chloropropionaldehyde and thiourea, is diazotized in hydrochloric acid, and the reaction solution is substantially reacted with the diazonium base formed. Copper salt or gold
Heating to 30-100 ° C. in the presence of at least equimolar hydrochloric acid without the presence of the genus copper gives 2-chloro-5-methylthiazole. Next, when a chlorinating agent is reacted, the methyl group at the 5-position is chlorinated to form 2-chloro-5-.
Chloromethylthiazole is obtained. After the diazotization, chlorination may be carried out by subsequently adding a chlorinating agent. As the chlorinating agent used at this time, N-chlorosuccinimide, chlorine and 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 1 mol of methylthiazole. If N-chlorosuccinimide is used in a large excess, the amount of by-products increases and the purity of the isolation operation is reduced. Although many solvents can be used for the reaction, chloroform, which hardly reacts with the chlorinating agent, is suitable. The reaction is carried out at a temperature of not lower than 20 ° C. and not higher than the reflux temperature of the solvent used. If the temperature is lower than 20 ° C., the reaction rate is low, which 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.

Hereinafter, the present invention will be specifically described with reference to Examples and Comparative Examples.

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

[0008]

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

[0009]

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

[0010]

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

[0011]

Example 2 Synthesis of 2-chloro-5-chloromethylthiazole 200 ml equipped with a stirrer, a dropping funnel and a thermometer
14 g (0.0930 mol) of 2-amino-5-methylthiazole hydrochloride, 36% hydrochloric acid 25
ml and 20 ml of water, and cooled to -5 ° C. 0 ° C
While maintaining at the following temperature, 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 produce a diazonium base. Heat the reaction to 40 ° C
After reaction for 3 hours, the resulting reaction solution was mixed with 30 m of chloroform.
Extraction was performed 1 × 3 times to obtain a chloroform solution containing 2-chloro-5-methylthiazole. After removing chloroform by atmospheric distillation, vacuum distillation was performed to obtain 2-chloro-
10.1 g of 5-methylthiazole (0.0756 mo
l) was isolated. The synthesis yield was 81%.

The obtained 2-chloro-5-methylthiazole was dissolved in 20 ml of chloroform and charged in 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 was added. (0.
0749 mol) and reacted at 50 ° C. for 6 hours under light irradiation. After completion of the reaction, succinimide produced as a by-product was recovered using 30 ml of water, and the chloroform layer was distilled to obtain 9.5 g (0.0565 mol) of 2-chloro-5-chloromethylthiazole. The synthesis yield is 6
1%. In addition, succinimide is chlorinated, and N
-Reused as chlorosuccinimide.

[0013]

Example 3 Synthesis of 2-chloro-5-chloromethylthiazole 300 ml equipped with a stirrer, a dropping funnel and a thermometer
26.2 g (0.175 mol) of 2-amino-5-methylthiazole hydrochloride, 36% hydrochloric acid 8
0 ml (0.931 mol) and 40 ml of water were charged.
Cooled to 5 ° C. While maintaining the temperature below 0 ° C, water 3
14 g of sodium nitrite dissolved in 0 ml (0.203
mol) was gradually added dropwise, and the reaction was further performed at 0 ° C. or lower for 3 hours to produce a diazonium base. This reaction solution was heated, heated to 80 ° C., and reacted at 80 ° C. for 3 hours. Then, the obtained reaction solution was extracted with chloroform (40 ml × 3 times) to obtain 15.1 g of 2-chloro-5-methylthiazole.
(0.113 mol) was obtained.

The obtained 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 was added. (0.120
mol) and 0.4 g of azobisisobutyronitrile, and reacted at 50 ° C. for 10 hours under light irradiation. After completion of the reaction, by-produced succinimide was recovered using 100 ml of water, and the chloroform layer was distilled to obtain 2
-Chloro-5-chloromethylthiazole 13.5 g
(0.080 mol) was obtained. The synthesis 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 a stirrer, a dropping funnel and a thermometer
20 g (0.175 mol) of 2-amino-5-methylthiazole, 80 ml of 36% hydrochloric acid
(0.931 mol) and 40 ml of water were charged and cooled to -5 ° C. While keeping the temperature below 0 ° C, 30 ml of water
14g of sodium nitrite dissolved in water (0.203mo
After l) was gradually added dropwise, the reaction was further carried out at 0 ° C or lower for 3 hours to produce a diazonium base. This reaction solution was heated, heated to 80 ° C., reacted at 80 ° C. for 3 hours, and the obtained reaction solution was extracted three times with 40 ml of chloroform.
17.4 g of 2-chloro-5-methylthiazole (0.1
30 mol) was obtained.

The obtained 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 was added. (0.200
mol) and 0.4 g of azobisisobutyronitrile, and reacted at 50 ° C. for 10 hours under light irradiation. After completion of the reaction, by-product succinimide was recovered using 120 ml of water, and the chloroform layer was distilled to obtain 2
-Chloro-5-chloromethylthiazole 15.5 g
(0.092 mol) was obtained. The synthesis 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 to a chloro group, and a copper salt or metallic copper is used as in the case of an aromatic primary amine. No post-processing is easy. Further, 2-chloro-5-methylthiazole can be synthesized under mild conditions using 2-amino-5-methylthiazole, which is inexpensive and easy to handle, without using an expensive raw material such as allyl isothiocyanate. . Therefore, 2-chloro-5-chloromethylthiazole, which is useful as a raw material for synthesis of medicines, agricultural chemicals, and the like, can be provided at low cost.

──────────────────────────────────────────────────続 き Continuation of the front page (56) References JP-A-5-208977 (JP, A) Translated by Nakanishi et al. 1093-1097 (Tokyo Kagaku Dojin, 1994, 2nd print 1995) HODSON, H .; H. , "THE SANDMEYER REACTION N", Chemical Review w, 40, pp. 251-277 (1947) (58) Fields investigated (Int. Cl. ⁷ , DB name) C07D 277/00-277/593 C07B 39/00 CA (STN) REGISTRY (STN) WPI (DIALOG)

Claims (10)

(57) [Claims] After the reaction of a heterocyclic primary amine with sodium nitrite in the presence of hydrochloric acid , a copper salt or metallic copper is substantially present in the formed diazonium base.
And no method of converting the amino group of the heterocyclic primary amine to a chloro group by heating to 30 to 100 ° C. in the presence of an equimolar or hydrochloric acid. 2. A method according to claim 1, wherein the 2-amino-5-methylthiazole is
After reacting with sodium nitrite in the presence of hydrochloric acid, the resulting diazonium base is substantially copper or gold.
A method for synthesizing 2-chloro-5-methylthiazole, comprising heating to 30 to 100 ° C. in the presence of at least equimolar hydrochloric acid without the presence of copper . 3. The method of claim 2, wherein the 2-amino-5-methylthiazole is
After reacting with sodium nitrite in the presence of hydrochloric acid, the resulting diazonium base is substantially copper or gold.
Heating to 30 to 100 ° C. in the presence of at least equimolar hydrochloric acid without the presence of copper group to induce 2-chloro-5-methylthiazole, which is reacted with a chlorinating agent;
A 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 under light irradiation or /
The method according to claim 3 or 4, wherein the method is carried out in the presence of a radical initiator. 6. A method for producing 2-amino-5-methylthiazole,
After reacting with sodium nitrite in the presence of hydrochloric acid, the resulting diazonium base is substantially copper or gold.
Heating to 30 to 100 ° C. in the presence of at least equimolar hydrochloric acid in the presence of at least an equimolar amount of hydrochloric acid to induce 2-chloro-5-methylthiazole, which is subjected to light irradiation in chloroform or / and radical initiation in the presence of agents, N- chloro after generating the succinimide is reacted 2-chloro-5-chloromethyl-thiazole, succinimide by-product is chlorinated to recover the aqueous layer was added water to the reaction mixture Use cyclically,
A method for synthesizing 2-chloro-5-chloromethylthiazole. 7. A method for synthesizing 2-chloro-5-chloromethylthiazole, wherein 2-chloro-5-methylthiazole is reacted with a chlorinating agent in a solvent under light irradiation and / or in the presence of a radical initiator. . 8. The method according to claim 7, wherein the chlorinating agent is N-chlorosuccinimide. 9. The synthesis method according to claim 7, wherein the chlorinating agent is N-chlorosuccinimide, and the reaction is carried out under light irradiation or / and in the presence of a radical initiator. 10. The method according to claim 7, wherein the solvent is chloroform.