阅读说明：本技术 一种米拉贝隆的制备方法 (Preparation method of mirabegron ) 是由 鲁光英 周跃辉 罗盼 毕波 于 2020-04-03 设计创作，主要内容包括：本发明提供了一种米拉贝隆的制备方法,以2-叔丁氧羰基氨基噻唑-4-乙酸为起始原料,经过五步反应得到高收率的米拉贝隆,具有操作方便,反应进程可控,最终产物纯度高、收率高,适宜于工业化生产,从而为制备米拉贝隆提供了更有价值的合成路线,可以带来良好的社会效益和经济效益,经济价值潜力较大。(The invention provides a preparation method of mirabegron, which takes 2-tert-butyloxycarbonylaminothiazole-4-acetic acid as a starting material, obtains the mirabegron with high yield through five steps of reactions, has the advantages of convenient operation, controllable reaction process, high purity and high yield of final products, and is suitable for industrial production, thereby providing a more valuable synthetic route for preparing the mirabegron, bringing good social benefit and economic benefit, and having larger economic value potential.)

1. A preparation method of mirabegron is characterized by comprising the following steps: 2-tert-butyloxycarbonylaminothiazole-4-acetic acid is used as a starting material to generate mirabegron;

the synthesis path is as follows:

the preparation method comprises the following steps:

q1, compound 1 synthesis: carrying out peptide condensation reaction on 2-tert-butoxycarbonylaminothiazole-4-acetic acid and 4-aminobenzaldehyde under the conditions of a reaction solvent and a reaction temperature to obtain a compound 1, wherein the reaction temperature is 20-50 ℃, and the reaction time is 5-9 hours;

q2, compound 2 synthesis: reacting the compound 1 with methyl nitrite in a solvent under the action of alkali to obtain a compound 2;

q3, compound 3 synthesis: carrying out reduction reaction on the compound 2 in an alcohol solvent under the catalysis of palladium carbon in a hydrogen environment to obtain a compound 3;

q4, compound 4 synthesis: carrying out condensation reaction on the compound 3 and phenyl epoxy ethylene in a reaction solvent to obtain a compound 4;

q5, synthesis of mirabegron: and (3) reacting the compound 4 with hydrochloric acid in a reaction solvent to remove Boc groups to obtain a final product mirabegron.

2. The method for preparing mirabegron as claimed in claim 1, wherein the method comprises the following steps: in the Q1, the reaction solvent is one of tetrahydrofuran, N-dimethylformamide, N-hexane and dichloromethane.

3. The method for preparing mirabegron as claimed in claim 2, wherein the method comprises the following steps: in the Q1, the molar ratio of 2-tert-butoxycarbonylaminothiazole-4-acetic acid to 4-aminobenzaldehyde is 1-2: 1; the condensing agent used in the peptide condensation reaction is HATU, and the dosage of the condensing agent is 1.05 equivalent; the catalyst used in the peptide condensation reaction is DMAP, and the dosage of the catalyst DMAP is 0.2 equivalent.

4. The method for preparing mirabegron as claimed in claim 3, wherein the method comprises the following steps: in the Q2, the alkali is selected from sodium hydroxide, and the using amount of the alkali is 2 equivalents; the molar ratio of the compound 1 to the methyl nitrite is 1: 1-2.

5. The method for preparing mirabegron as claimed in claim 4, wherein the method comprises the following steps: in the Q3, the alcohol solvent is one or a mixture of methanol and ethanol; the mass fraction of the palladium carbon is any one of 5%, 10% and 15%.

6. The method for preparing mirabegron as claimed in claim 5, wherein the method comprises the following steps: in the Q3, the mass ratio of the palladium carbon to the compound 2 is 0.005-0.03: 1.

7. The method for preparing mirabegron as claimed in claim 6, wherein the method comprises the following steps: in the Q3, the hydrogen pressure range of the hydrogen environment is 0.5-1.5 MPa.

8. The method for preparing mirabegron as claimed in claim 7, wherein the method comprises the following steps: in Q4, the reaction solvent is any one of ethyl acetate, 1, 4-dioxane, chloroform, 1, 2-dichloroethane, acetone and acetonitrile.

9. The method for preparing mirabegron as claimed in claim 7, wherein the method comprises the following steps: in the Q4, the molar ratio of the compound 3 to the styrene oxide is 1:1 to 3.

10. The method for preparing mirabegron as claimed in claim 9, wherein the method comprises the following steps: in the Q5, the reaction solvent is any one of ethyl acetate, dichloromethane and 1, 4-dioxane.

Technical Field

The invention relates to the technical field of organic matter synthesis pharmacy, in particular to a preparation method of mirabegron.

Background

Mirabegron (mirabegron) is the first β 3 adrenoceptor agonist drug used for treating overactive bladder, mirabegron is a drug developed by Astelai (Astelas) pharmaceutical company in Japan, and it fills the gap of β adrenoceptor agonist in treating overactive bladder greatly, and provides a new treatment scheme for overactive bladder patients.

There are three common synthetic methods of mirabegron:

the synthetic route reported in patent WO9920607a 1:

the synthetic route has the following disadvantages: the method has the advantages of long steps, troublesome post-treatment, time and labor consumption, low yield of the obtained final product, high price of raw materials, high cost and unsuitability for industrial production.

The synthetic route reported in patent WO2015044965a 1:

the synthetic route has the following disadvantages: the borane used in the synthesis has high toxicity and high risk, does not conform to the concept of green chemistry, uses more reagents, has high cost and is not suitable for large-scale industrialization.

Synthetic route of patent CN 103232352A:

the synthetic route has the following disadvantages: the potassium permanganate used in the synthesis has extremely high pollution, can cause great damage to the environment, and the initial raw materials of the reaction are difficult to obtain, so that the industrial production is difficult.

In summary, the synthesis method or steps of mirabegron in the prior art are complicated, the yield is low, or the cost is high, so a simple and efficient synthesis method of mirabegron is needed.

Disclosure of Invention

Aiming at the defects and problems in the prior art, the invention provides a preparation method of mirabegron, which aims to solve the technical problems that: provides a preparation method of mirabegron, which has a better synthetic route and is suitable for large-scale industrialization.

In order to achieve the purpose, the invention provides the following technical scheme:

a preparation method of mirabegron takes 2-tert-butyloxycarbonylaminothiazole-4-acetic acid as a starting material to generate the mirabegron;

the synthesis path is as follows:

the preparation method comprises the following steps:

q1, compound 1 synthesis: performing peptide condensation reaction on 2-tert-butoxycarbonylaminothiazole-4-acetic acid and 4-aminobenzaldehyde in a reaction solvent at a reaction temperature of 20-50 ℃ for 5-9 hours to obtain a compound 1;

q2, compound 2 synthesis: reacting the compound 1 with methyl nitrite in a solvent under the action of alkali to obtain a compound 2;

q3, compound 3 synthesis: carrying out reduction reaction on the compound 2 in an alcohol solvent under the catalysis of palladium carbon in a hydrogen environment to obtain a compound 3;

q4, compound 4 synthesis: carrying out condensation reaction on the compound 3 and phenyl epoxy ethylene in a reaction solvent to obtain a compound 4;

q5, synthesis of mirabegron: and (3) reacting the compound 4 with hydrochloric acid in a reaction solvent to remove the Boc group to obtain a final product mirabegron.

In the above technical scheme, in Q1, the reaction solvent is one of tetrahydrofuran, N-dimethylformamide, N-hexane, and dichloromethane.

In the above technical solution, in Q1, the reaction solvent is dichloromethane.

In the technical scheme, in Q1, the molar ratio of 2-tert-butoxycarbonylaminothiazole-4-acetic acid to 4-aminobenzaldehyde is 1-2: 1; the condensing agent used in the peptide condensation reaction is HATU, and the dosage of the condensing agent is 1.05 equivalent; the catalyst used in the peptide condensation reaction is DMAP, and the dosage of the catalyst DMAP is 0.2 equivalent.

In the above technical solution, in Q2, the solvent is selected from ethanol or diethyl ether, preferably ethanol.

In the above technical solution, in Q2, sodium hydroxide is selected as the alkali, and the amount of the alkali is 2 equivalents; the molar ratio of the compound 1 to the methyl nitrite is 1: 1-2.

In the above technical solution, in Q3, the alcohol solvent is selected from one of methanol and ethanol or a mixture of the two, preferably methanol.

In the above-described embodiment, in Q3, the mass fraction of palladium on carbon is 5%, 10%, or 15%, preferably 10%.

In the above technical solution, in Q3, the mass ratio of palladium on carbon to compound 2 is 0.005-0.03: 1, preferably 0.01-0.03: 1.

In the technical scheme, in the Q3, the hydrogen pressure range of the hydrogen environment is 0.5-1.5 MPa.

In the above technical solution, in Q4, the reaction solvent is any one of ethyl acetate, 1, 4-dioxane, chloroform, 1, 2-dichloroethane, acetone, and acetonitrile, preferably acetonitrile.

In the above technical scheme, in Q4, the molar ratio of compound 3 to styrene oxide is 1:1 to 3.

In the above technical scheme, in Q5, the reaction solvent is any one of ethyl acetate, dichloromethane and 1, 4-dioxane, preferably 1, 4-dioxane.

The method takes 2-tert-butyloxycarbonylaminothiazole-4-acetic acid as a starting material, obtains the mirabegron with high yield through five-step reaction, has the advantages of convenient operation, controllable reaction process, high purity and yield of final products, and suitability for industrial production, thereby providing a more valuable synthetic route for preparing the mirabegron, bringing good social benefit and economic benefit, and having higher economic value potential.

Detailed Description

The technical solutions of the present invention will be described clearly and completely with reference to the following embodiments of the present invention, and it should be understood that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

As an example of the preparation method of mirabegron, 2-tert-butoxycarbonylaminothiazole-4-acetic acid was used as a starting material to produce mirabegron;

the synthesis path is as follows:

the preparation method comprises the following steps:

q1, compound 1 synthesis: performing peptide condensation reaction on 2-tert-butoxycarbonylaminothiazole-4-acetic acid and 4-aminobenzaldehyde in a reaction solvent at a reaction temperature of 20-50 ℃ for 5-9 hours to obtain a compound 1;

q2, compound 2 synthesis: reacting the compound 1 with methyl nitrite in a reaction solvent under the action of alkali to obtain a compound 2;

q3, compound 3 synthesis: carrying out reduction reaction on the compound 2 in an alcohol solvent under the catalysis of palladium carbon in a hydrogen environment to obtain a compound 3;

q4, compound 4 synthesis: carrying out condensation reaction on the compound 3 and phenyl epoxy ethylene in a reaction solvent to obtain a compound 4;

q5, synthesis of mirabegron: and (3) reacting the compound 4 with hydrochloric acid in a reaction solvent to remove the Boc group to obtain a final product mirabegron.

The specific embodiment is as follows:

step one, synthesis of a compound 1:

121g of 4-aminobenzaldehyde, 258g of 2-tert-butoxycarbonylaminothiazole-4-acetic acid, 1200m L150 g of dichloromethane and 10g of DMAP which participate in the reaction are sequentially added into a 3000m L three-mouth reaction flask, the temperature is raised to 40 ℃ under the protection of nitrogen, the mixture is refluxed, the reaction is kept at the temperature for 7 hours, and the reaction is monitored by HP L C.

After the reaction is completed, stirring is continuously carried out, the temperature is reduced to room temperature, filtering is carried out, sodium hydroxide is used for washing, anhydrous sodium sulfate is used for drying, residual solvent is removed under reduced pressure, and 302.7g of compound 1 is obtained after drying, wherein the yield is 83.9%;

step two, synthesis of a compound 2:

122g of methyl nitrite is dissolved in 800ml of ethanol and added into a 2000ml reaction bottle, 361g of compound 1 and 100g of NaOH are added into the reaction bottle, the temperature is raised to 70 ℃, the reaction is continuously stirred, HP L C monitors the reaction process, after the reaction is finished, saturated sodium bicarbonate aqueous solution is used for washing, drying and rectifying the reaction product, 320.1g of compound 2 is obtained, and the yield is 79.2%.

Step three, synthesizing a compound 3:

under the protection of nitrogen, 404g of compound 2, 8g of 10% Pd/C catalyst and 1000ml of methanol are added into a 2000ml three-necked flask, nitrogen is replaced by hydrogen, the mixture is heated to 60 ℃, the pressure is 1Mpa, the mixture reacts for 7 hours under the stirring condition, and the reaction process is monitored by T L C.

After the reaction was completed, the temperature was lowered to room temperature, hydrogen was discharged, the catalyst was filtered, and the mother liquor was concentrated under reduced pressure to dryness to obtain 320.7g of compound 3 with a yield of 85.3%.

Step four, synthesizing a compound 4:

376g of compound 3 and 1200m of L acetonitrile are added into a 2000m L four-neck flask, then 120g of (R) -styrene oxide is slowly dripped, after the dripping is finished, the temperature is raised to 80 ℃ under magnetic stirring, the reaction is kept for 10 hours, and T L C tracks the reaction progress.

After the reaction, the temperature was reduced, the residual solvent was evaporated under reduced pressure, 100m L cyclohexane was added to the residual solution, stirred for crystallization, filtered and dried to obtain 420.9g of compound 4 with a yield of 84.9%.

Step five, synthesizing a compound mirabegron:

adding 1000m L1, 4-dioxane as a reaction solvent into a 2000ml reaction bottle, adding 496g of compound 4 and 72g of hydrochloric acid gas, reacting at room temperature for 10h, monitoring the complete reaction of raw materials by T L C, evaporating residual solvent under reduced pressure, extracting for 3 times by using trichloromethane, combining organic phases, evaporating the trichloromethane to obtain a solid, recrystallizing the obtained solid by using a certain amount of toluene, and drying to obtain 357.7g of mirabegron with the yield of 90.3%.

The above description is only an embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art can easily conceive of changes or substitutions within the technical scope of the present invention, and all such changes or substitutions are included in the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the claims.