A process for the preparation of arolool hydrochloride

Abstract

The application relates to a preparation method of arolool hydrochloride, which uses 5-acetylthiophene-2-carboxamide as raw material and only uses a catalytic amount of copper bromide to prepare a key intermediate 5-(2-sulfhydryl-4-thiazolyl)-2-thiophene carboxamide through one-pot bromination and cyclization.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to a method for preparing apronolol hydrochloride. Background Technology

[0002] Arotinolol Hydrochloride has the chemical name 5-[2-[2RS]-3-(1,1-dimethylethyl)amino-2-(hydroxypropyl)thio-4-thiazolyl]thiophene-2-carboxamide hydrochloride, and its structural formula is shown in I.

[0003]

[0004] Arprolol hydrochloride was developed by Sumitomo Pharmaceutical Co., Ltd. of Japan and first launched in Japan in 1985. It is mainly used clinically for essential hypertension (mild to moderate), angina pectoris, tachycardia-induced arrhythmias, essential tremor, etc. Arprolol hydrochloride is a selective β1-adrenergic receptor antagonist, and also has a mild α1-adrenergic receptor blocking effect. It can inhibit α-adrenergic receptor excitation while lowering blood pressure, reducing sympathetic nerve tone, resulting in a more ideal antihypertensive effect. It has advantages such as low dosage, few side effects, excellent efficacy, and long-lasting effect.

[0005] There are three main synthetic routes for aprrolol hydrochloride:

[0006] Patent EP 0021840 discloses a method for preparing apronolol hydrochloride, as shown below:

[0007]

[0008] This route uses 5-acetylthiophene-2-carboxamide as a starting material, which is brominated and then cyclized with ammonium dithiocarbamate to form the intermediate 5-(2-mercapto-4-thiazolyl)-2-thiophenecarboxamide. This intermediate is then condensed with 1-tert-butylamino-3-chloro-2-propanol to form a salt, yielding arolol hydrochloride. This route uses toxic and harmful bromine, and the intermediate purification is very complex. Furthermore, 1-tert-butylamino-3-chloro-2-propanol has poor stability. Routes two and three require two substitution steps to obtain the product, and the required starting material, 5-acetylthiophene-2-carboxylic acid, is very expensive, making them uneconomical.

[0009] Chinese patent CN104370900A discloses a method for preparing alorol hydrochloride, comprising: (1) preparing 2-[2,3-epoxypropyl-4-(5-carbamoyl-2-thienyl)]thiazole; (2) dissolving the above 2-[2,3-epoxypropyl-4-(5-carbamoyl-2-thienyl)]thiazole in anhydrous ethanol, adding tert-butylamine, and refluxing to obtain alorol; (3) dissolving the above alorol in dimethyl sulfoxide and adding concentrated hydrochloric acid to form a salt to generate alorol hydrochloride. The starting material of this method, 5-(2-mercapto-4-thiazolyl)-2-thiophenecarboxamide, is also prepared from 5-acetylthiophene-2-carboxamide via bromination and cyclization. This method is environmentally unfriendly and expensive. The final step of this route uses the high-boiling-point solvent DMSO, posing a significant risk of excessive residual solvent.

[0010]

[0011] Patent CN112300149 discloses another method for preparing apronolol hydrochloride, which involves constructing the core and side chains separately, and then linking them in a one-pot process, as shown below:

[0012]

[0013] This method has an excessively long route and low yield. The constructed side chains require additional deprotection, and the use of precious metal catalysts results in poor atom economy. Summary of the Invention:

[0014] To overcome the shortcomings of existing technologies, this invention provides a novel method for preparing alorol hydrochloride. Using 5-acetylthiophene-2-carboxamide as a starting material, the key intermediate 5-(2-mercapto-4-thiazolyl)-2-thiophenecarboxamide is prepared via a one-pot bromination cyclization process using only a catalytic amount of copper bromide. This route shortens the process by one step, replaces the brominating reagent with a catalytic amount of copper bromide, is more inexpensive, simpler to operate, and environmentally friendly. Furthermore, it eliminates the need for high-boiling-point solvents, results in high-purity products, and is easily industrialized. The synthetic route is as follows:

[0015]

[0016] To achieve the above-mentioned technical effects, the present invention adopts the following technical solution:

[0017] A method for preparing apronolol hydrochloride as shown in structural formula I.

[0018]

[0019] The steps include the following:

[0020] Step 1: Preparation of compounds with structural formula IV

[0021]

[0022] Starting with a compound of structural formula V, a one-pot method was used to bromine and cyclize copper sulfide to obtain a compound of structural formula IV.

[0023]

[0024] Step 2, Preparation of Structure III

[0025]

[0026] Tert-butylamine, epichlorohydrin, and hydrochloric acid react in methanol, and the mixture is concentrated and crystallized to obtain III.

[0027] Step 3, Preparation of Structure II

[0028]

[0029] The compound of structural formula IV reacts with the compound of structural formula III to give the compound of structural formula II, namely, free arolol.

[0030] Step 4: Preparation of compound with structure I

[0031] The compound of structure II reacts with hydrochloric acid to give the compound of structure I, namely arolol hydrochloride.

[0032] The above synthetic route is shown below:

[0033]

[0034] Preferably, in reaction step 1, the molar ratio of the compound of structural formula V to copper bromide is 1:0.1-1:0.5; more preferably, it is 1:0.3.

[0035] Preferably, in reaction step 1, the reaction solvent is DMSO.

[0036] Preferably, in reaction step 1, the mass-to-volume ratio of the compound of structural formula V to DMSO is 1:4-1:12, more preferably 1:6-1:10.

[0037] Preferably, in reaction step 1, the reaction temperature is 70-110℃, more preferably 80-100℃.

[0038] Preferably, in reaction step 1, the molar ratio of the compound of structural formula V to ammonium dithiocarbamate is 1:1.0-1:2.0; more preferably, it is 1:1.5.

[0039] Preferably, the reaction temperature in step 2 is 20-60°C, more preferably 25-45°C.

[0040] Preferably, in step 2, the solvent for the crystallization reaction is either ethanol or isopropanol, more preferably ethanol.

[0041] Preferably, in reaction step 2, the molar ratio of tert-butylamine to epichlorohydrin is 1:1.0-1:2.0; more preferably, it is 1:1.1.

[0042] Preferably, in step 3, the molar ratio of the compound of structural formula IV to the compound of structural formula III is 1:1.0-1:2.0; more preferably, it is 1:1.2.

[0043] Preferably, in step 3, the molar ratio of the compound of structural formula IV to sodium hydroxide is 1:2.0-1:4.0; more preferably, it is 1:2.5.

[0044] Preferably, in step 3, the reaction temperature is 20-60℃, more preferably 25-45℃. Preferably, in reaction step 4, the mass-to-volume ratio of the compound of structural formula II to methanol is 5:1-15:1, more preferably 8:1-12:1.

[0045] Preferably, in reaction step 4, the molar ratio of the compound of structural formula II to hydrochloric acid is 1:1.0-1:2.0, more preferably 1:1.5.

[0046] The method for preparing aprololol hydrochloride provided by this invention uses 5-acyl-thiophene-2-amide as a raw material and employs a one-pot bromination cyclization process with a catalytic amount of copper bromide. Compared to liquid bromine, this method produces less pollution, is more environmentally friendly, has higher specificity, and a shorter route. The parent core is then prepared by cyclization with ammonium dithiocarbamate. A side chain is prepared from tert-butylamine and epichlorohydrin, which requires no protection or deprotection. Finally, the parent core and side chain are condensed to form a salt to obtain aprololol hydrochloride. This invention features a short production cycle, cheaper raw materials, and lower synthesis costs. The post-processing is simple, requiring no alkali adjustment or crystallization purification of free aprolol, avoiding the cumbersome post-processing and use of high-boiling-point solvents in previous patents and literature, making the process more gentle, reliable, and safe.

[0047] In summary, the method for preparing apronolol hydrochloride provided by this invention is environmentally friendly, easy to operate, and produces products with high purity and yield. It is suitable for industrialization and can provide high-quality raw materials for pharmaceutical production. Detailed Implementation

[0048] The present invention will be described below with reference to specific embodiments. Those skilled in the art will understand that these embodiments are for illustrative purposes only and do not limit the scope of the invention in any way.

[0049] Examples 1-8: Preparation of 5-(2-mercapto-4-thiazolyl)thiophene-2-carboxamide (compound of structural formula IV)

[0050] Weigh the compound of structural formula V, CuBr2, and DMSO into a 500 mL three-necked flask. Heat to the reaction temperature and stir hot for 1 h, then cool to 0-10 °C. Weigh ammonium dithiocarbamate, dissolve it in 100 mL of methanol, and add it dropwise to the above reaction solution. After the addition is complete, heat to the reaction temperature and continue the reaction. After the reaction is complete, cool to 0-10 °C, add 200 mL of distilled water, cool to 0-10 °C, stir to precipitate crystals, filter, and wash the filter cake twice with 50 mL of distilled water and 50 mL of methanol, respectively. Dry in a vacuum drying oven at 60 °C for 6 h to obtain the compound of structural formula IV. Weigh and calculate the yield, and determine the purity.

[0051] The amount of compound of structural formula V was 16.92 g. The controlled variables were the molar ratio of compound of formula V to CuBr2, the mass-volume ratio of compound of formula V to DMSO, the molar ratio of compound of formula V to ammonium dithiocarbamate, and the reaction temperature. The reaction conditions, yields, and purities of each example are shown in Tables 1-1 and 1-2.

[0052] Table 1-1: Reaction conditions for Examples 1-13

[0053]

[0054] Table 1-2: Yields and Purities of Examples 1-13

[0055]

[0056]

[0057] Examples 9-14: Preparation of 1-chloro-3-[(2-methyl-2-propyl)amino]-2-propanol hydrochloride (compound of structural formula III)

[0058] Weigh 700 mL of tert-butylamine, epichlorohydrin, and methanol into a 2 L three-necked flask and stir at room temperature for 4 h. Add 111.52 g of HCl dropwise while controlling the temperature. Continue the reaction after the addition is complete. After the reaction is complete, remove the solvent by rotation to obtain a viscous liquid. Dissolve the liquid in 300.0 mL of ethanol or isopropanol, then cool to 0-10 °C and allow to crystallize overnight. Filter the mixture, wash the filter cake twice with 50 mL of ice-cold ethanol, and dry under vacuum at 50.0 °C to obtain the compound of structural formula III. Weigh the mixture, calculate the yield, and determine the purity.

[0059] The amount of tert-butylamine used was 73.14 g, and the controlled variables were the molar ratio of tert-butylamine to epichlorohydrin, the reaction temperature, and the solvent.

[0060] Table 2: Reaction conditions, yields, and purity of Examples 14-20

[0061]

[0062] Examples 15-21: Preparation of aprolol (a compound of structural formula II)

[0063] Under nitrogen protection, weigh compound of structural formula IV into a 500 ml three-necked flask, add 5% (w / w) NaOH solution, and stir at 25 °C. Weigh compound of structural formula III, dissolve it in 60 ml of methanol, and then slowly add it dropwise, controlling the temperature not to exceed 30.0 °C. After the addition is complete, raise the temperature to the reaction temperature and continue the reaction. After the reaction is complete, cool to 0-10 °C and add 120 ml of distilled water, stirring at 0-10 °C to induce crystallization. Filter, wash the filter cake twice with 20 ml of water, and dry under vacuum at 50-60 °C for 6 h to obtain the target compound. Weigh and calculate the yield, and determine the purity.

[0064] The amount of compound IV was 12.12 g, and the controlled variables were the molar ratio of compound IV to sodium hydroxide, the molar ratio of compound IV to compound III, and the reaction temperature.

[0065] Table 3: Reaction conditions, yields, and purity of Examples 21-28

[0066]

[0067] Examples 22-25: Preparation of apronolol hydrochloride (compound of structural formula I)

[0068] Weigh 0.62 g of compound of structural formula II and activated carbon into a 200 ml three-necked flask, add methanol and heat to dissolve, then reflux and stir for 1 h. Cool to 40-50 °C and filter. Maintain 40-50 °C and add concentrated hydrochloric acid dropwise. After the addition is complete, a large amount of solid is formed. Cool to 0-10 °C to crystallize and stir for 1 h, then filter. Wash the filter cake twice with 20 ml of ethanol and dry under vacuum at 40-50 °C for 6 h to obtain 12.16 g of white solid, yield 89.5%, purity 99.9%. Weigh and calculate the yield, and determine the purity.

[0069] The amount of compound II was 12.38 g. The controlled variables were the mass-to-volume ratio of compound II to methanol and the molar ratio of compound II to hydrochloric acid. The concentration of concentrated hydrochloric acid was 36.5%.

[0070] Table 4: Reaction conditions, yields, and purity of Examples 29-34

[0071]

[0072]

[0073] This invention presents a novel synthetic method for arololol hydrochloride. Starting with 5-acetylthiophene-2-carboxamide, a one-pot bromination cyclization with a catalytic amount of copper bromide is used to prepare the key intermediate 5-(2-mercapto-4-thiazolyl)-2-thiophenecarboxamide, which is then condensed into a salt to prepare arololol hydrochloride. Compared to other synthetic routes, this route avoids the use of highly polluting bromine and expensive NBS, and shortens the synthetic route through a one-step cyclization. Overall, this route is greener, more environmentally friendly, simpler to operate, and more economical.

Claims

1. A method for preparing 5-(2-mercapto-4-thiazolyl)-2-thiophenecarboxamide, a key intermediate in aprololol hydrochloride, characterized in that... It is prepared by one-pot bromination cyclization using 5-acetylthiophene-2-carboxamide and ammonium dithiocarbamate as raw materials and with catalytic copper bromide. The molar ratio of 5-acetylthiophene-2-carboxamide to copper bromide is 1:0.1-1:0.5, the reaction solvent is DMSO, the mass-volume ratio of 5-acetylthiophene-2-carboxamide to DMSO is 1:4-1:12 (g / ml), and the reaction temperature is 70-110℃.

2. The preparation method according to claim 1, characterized in that... The molar ratio of 5-acetylthiophene-2-carboxamide to copper bromide is 1:0.3; the molar ratio of 5-acetylthiophene-2-carboxamide to ammonium dithiocarbamate is 1:1.0-1:2.

0.

3. The preparation method according to claim 1, characterized in that... The mass-to-volume ratio of 5-acetylthiophene-2-carboxamide to DMSO (g / ml) is 1:6-1:

10.

4. The preparation method according to claim 1, characterized in that... The reaction temperature is 80-100℃.

5. A method for preparing apronolol hydrochloride, characterized in that... Includes the following steps: Step 1: Prepare intermediate 5-(2-mercapto-4-thiazolyl)-2-thiophenecarboxamide using any of the methods in claims 1-4; Step 2: React tert-butylamine, epichlorohydrin and hydrochloric acid in methanol, and then concentrate and crystallize to obtain 1-chloro-3-[(2-methyl-2-propyl)amino]-2-propanol hydrochloride; Step 3: 5-(2-mercapto-4-thiazolyl)-2-thiophene carboxamide and 1-chloro-3-[(2-methyl-2-propyl)amino]-2-propanol hydrochloride were reacted to give free aprolol; Step 4: Free aprolol reacts with hydrochloric acid to obtain aprolol hydrochloride.

6. The method for preparing apronolol hydrochloride according to claim 5, characterized in that... In step 2, the crystallization solvent is either ethanol or isopropanol; the reaction temperature is 20-60℃.

7. The method for preparing apronolol hydrochloride according to claim 6, characterized in that... In step 2, the crystallization solvent is ethanol, and the reaction temperature is 25-45℃.

8. The method for preparing apronolol hydrochloride according to claim 5, characterized in that... In step 2, the molar ratio of tert-butylamine to epichlorohydrin is 1:1.0-1:2.

0.

9. The method for preparing apronolol hydrochloride according to claim 8, characterized in that... In step 2, the molar ratio of tert-butylamine to epichlorohydrin is 1:1.

1.

10. The method for preparing apronolol hydrochloride according to claim 5, characterized in that... In step 3, the reaction solvent is a 5% w / w sodium hydroxide solution, and the molar ratio of 5-(2-mercapto-4-thiazolyl)-2-thiophene carboxamide to sodium hydroxide is 1:2.0-1:4.0; the molar ratio of 5-(2-mercapto-4-thiazolyl)-2-thiophene carboxamide to 1-chloro-3-[(2-methyl-2-propyl)amino]-2-propanol hydrochloride is 1:1.0-1:2.

0.

11. The method for preparing apronolol hydrochloride according to claim 10, characterized in that... In step 3, the molar ratio of 5-(2-mercapto-4-thiazolyl)-2-thiophene carboxamide to sodium hydroxide is 1:2.5; the molar ratio of 5-(2-mercapto-4-thiazolyl)-2-thiophene carboxamide to 1-chloro-3-[(2-methyl-2-propyl)amino]-2-propanol hydrochloride is 1:1.

2.

12. The method for preparing apronolol hydrochloride according to claim 5, characterized in that... In step 3, the reaction temperature is 20-60℃.

13. The method for preparing allolol hydrochloride according to claim 12, characterized in that... In step 3, the reaction temperature is 25-45℃.

14. The method for preparing apronolol hydrochloride according to claim 5, characterized in that... In step 4, the molar ratio of free apronolol to hydrochloric acid is 1:1.0-1:

2.

15. The method for preparing apronolol hydrochloride according to claim 14, characterized in that... In step 4, the molar ratio of free apronolol to hydrochloric acid is 1:1.5.

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