Process for the preparation of terazosin hydrochloride and intermediates thereof

Abstract

The application discloses a new preparation method of terazosin hydrochloride and belongs to the field of drug synthesis. The method comprises the following steps: firstly, condensing cyanopiperazine and tetrahydrofurfurylic acid; secondly, constructing a quinazoline ring by using 6-amino veratric acid; thirdly, chlorinating, ammoniating and acidifying to obtain terazosin hydrochloride. The method greatly reduces process impurities, reduces the number of refining times, improves the purity and yield of the product, and is more suitable for industrial production.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical chemical industry, and relates to a preparation method of a hypertension and benign prostatic hyperplasia treating drug terazosin hydrochloride and an intermediate thereof. BACKGROUND

[0002] As a new long-acting selective alpha 1-noradrenaline receptor blocker, terazosin hydrochloride can reduce peripheral vascular resistance, and is a new long-acting antihypertensive and benign prostatic hyperplasia treating drug. It has been widely clinically applied in developed countries and regions such as the United States, Europe and Japan, and is also a first-line drug recommended by the International BPH Advisory Committee for treating prostatic hyperplasia. At present, terazosin hydrochloride has been included in the basic drug list of China and the state public medical expense reimbursement variety. In recent years, the market sales of terazosin hydrochloride preparation has rapidly increased, the demand for raw material drugs has continuously increased, and there is a broad market prospect. In order to meet the market demand for terazosin hydrochloride raw material drugs and ensure the supply, the process research on the key intermediate of terazosin hydrochloride has important social and economic value and a broad market prospect.

[0003] The chemical name of terazosin hydrochloride is 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-[(tetrahydrofurfuryl) carbonyl] piperazine hydrochloride dihydrate, and its structural formula is

[0004]

[0005] Patent US6015819 reports a synthesis method of terazosin hydrochloride. The route uses veratraldehyde as a raw material, and 2-amino-4,5-dimethoxybenzoic acid is obtained through nitration, oxidation and reduction, then 2,4-dihydroxy-6,7-dimethoxyquinazoline is obtained through cyclization, then 4-amino-2-chloro-6,7-dimethoxyquinazoline is obtained through chloro substitution and amination, then terazosin is obtained through reaction with anhydrous piperazine and tetrahydrofurfuryl acid, and finally terazosin hydrochloride is obtained through salt formation, and the specific synthesis route is shown as follows.

[0006]

[0007] The route has a long synthesis step, and the total yield is less than 20%. The yield of the synthesis of the quinazoline ring is less than 55%, the reaction temperature is high, sodium cyanate is used as a reagent, and the safety and environmental protection problems such as waste water treatment are prominent. In addition, under the process conditions, 2,4-dichloro-6,7-dimethoxyquinazoline is not stable and is very easy to hydrolyze, which leads to high operation difficulty coefficient and uncontrollable product quality, and limits the industrial application of the process.

[0008] Patent (CN108358828) reports a method for synthesizing terazosin hydrochloride, which is improved on the basis of the route in patent US6015819. The method is to obtain 6-amino veratraldehyde by using trichloroacetaldehyde and hydroxylamine hydrochloride to obtain amino and carboxyl groups. The subsequent reaction steps are completely consistent, and the route is shown below.

[0009]

[0010] This synthesis route only improves the synthesis method of 6-amino veratraldehyde, and has little improvement on the quinazoline ring of terazosin hydrochloride.

[0011] In general, the existing process is to first construct a quinazoline ring, then chlorinate and ammoniate, and then sequentially condense with piperazine and tetrahydrofurfuryl acid to obtain terazosin hydrochloride. There are the following problems:

[0012] 1) The intermediate 2,4-dichloro-6,7-dimethoxyquinazoline of the process method is unstable, and other intermediates are also prone to impurities. These impurities all have quinazoline ring structure, which is very similar to terazosin, and is generated in the later steps of the bulk drug production, and is very difficult to remove. Therefore, the product needs to be refined multiple times to meet the requirements of the pharmacopoeia, resulting in low product yield and low production rate.

[0013] 2) There are two nitrogen atoms that can be acylated in the molecular structure of 4-amino-6,7-dimethyl-2-piperazinyl-4-quinazoline, so the reaction selectivity is not high, resulting in many product impurities, difficult separation, low yield, and difficult quality control.

[0014] 3) The existing process steps are long, the industrial production operation is difficult, the treatment of three wastes is difficult, the yield of the key reaction is low, and the route cost is still high. Therefore, a method for synthesizing terazosin hydrochloride with a simple process route, low cost and suitable for industrial production still needs to be found. SUMMARY

[0015] To solve the above technical problems, the present application provides a preparation method of terazosin hydrochloride with stable intermediates, short steps and high yield.

[0016] To achieve the purpose of the application, one of the purposes of the present application provides an intermediate compound 2 for preparing terazosin hydrochloride and a synthesis method thereof. The structural formula of the compound 2 is as follows:

[0017]

[0018] The synthesis method of the intermediate compound 2 of terazosin hydrochloride is to react the intermediate formula 1 with tetrahydrofurfuryl acid to obtain the compound formula 2.

[0019]

[0020] The second object of the present application is to provide an intermediate compound 4 for preparing terazosin hydrochloride and a synthesis method thereof, and the compound 4 has the following structural formula:

[0021]

[0022] The synthesis method of the intermediate compound 4 of terazosin hydrochloride comprises the following steps: cyclization of the intermediate compound 2 and 6-amino veratric acid, and then chlorination to obtain the compound 4.

[0023]

[0024] The present application relates to the preparation of terazosin hydrochloride, which is prepared by condensation of cyanopiperazine and tetrahydrofurfurylic acid, and then construction of a quinazoline ring, which greatly improves the stability of the quinazoline ring, greatly reduces process impurities, reduces the number of intermediate and product refining, and improves the reaction yield. And by constructing new intermediate compound 2 and compound 4, the experimental conditions are optimized, the yield of each reaction and the separation purity of the intermediate are improved. These improvements greatly improve the efficiency of the route, further reduce the process cost, reduce the generation of by-products and improve the purity of the final product. The process route has the advantages of reduced steps, simple operation, high yield, high purity of the obtained product, and is more suitable for industrial production. The reaction route is as follows:

[0025]

[0026] Step 1: intermediate 1 and tetrahydrofurfurylic acid to form intermediate 2;

[0027] Step 2: cyclization of intermediate 2 and 6-amino veratric acid to obtain intermediate 3;

[0028] Step 3: intermediate 3 is chlorinated to obtain intermediate 4;

[0029] Step 4: ammoniation of intermediate 4 to obtain terazosin, and then acidification with hydrochloric acid to obtain the final product.

[0030] Beneficial effects: the present application provides a preparation method of terazosin hydrochloride, which has the following advantages compared with the prior art: the change of cyclization method improves the stability of the quinazoline ring, and the process impurities are greatly reduced. The intermediate of the preparation method is easy to purify, the reaction conditions are mild, the post-treatment operation is simple, the total yield can reach more than 35%, and it is more suitable for large-scale industrial production. DETAILED DESCRIPTION

[0031] The principles and characteristics of the present application are described below, and the examples are used to further explain the present application, but do not limit the scope of the present application.

[0032] Example 1 4-(Tetrahydrofuran-2-ylcarbonyl)piperazine-1-carbonitrile (Compound 2)

[0033] Cyanopiperazine (55.57 g, 0.50 mol) was added to toluene (277.87 g) and warmed to 40-50 °C. 2-Tetrahydrofurfurylic acid (58.02 g, 0.50 mol) was dissolved in 55.57 g of toluene and added dropwise over 1.0-2.0 h. After the addition was complete, the temperature was raised to reflux (115-120 °C) and the reaction was continued for 5.5 h. After the reaction was complete, the toluene was distilled off under reduced pressure until no distillate was obtained. The product was a light yellow to brown oil. The yield was 83.2% and the purity (GC) was >98.5%.

[0034] Example 2 1-(4-Hydroxy-6,7-dimethoxy-2-quinazolinyl)-4-[(tetrahydrofuryl)carbonyl]piperazine (Compound 3)

[0035] 4-(Tetrahydrofuran-2-ylcarbonyl)piperazine-1-carbonitrile (115.02 g, 0.55 mol), 6- amino veratric acid (98.59 g, 0.50 mol), toluene (266.19 g), drinking water (29.58 g), and NaOH (20.00 g, 0.50 mol) were added to a 1 L autoclave, which was then closed and warmed to 140-160 °C. The reaction was stirred for 6 h. After the reaction was complete, the reaction mixture was transferred to a 1 L flask and cooled to induce crystallization. The crystals were filtered and the filter cake was dried at 80 °C to give a white solid. The yield was 86.9% and the purity (HPLC) was >99.0%.

[0036] Example 3 1-(4-Chloro-6,7-dimethoxy-2-quinazolinyl)-4-[(tetrahydrofuryl)carbonyl]piperazine (Compound 4)

[0037] Compound 3 (194.08 g, 0.50 mol), phosphorus oxychloride (579 ml), and DMF (32.00 g) were added to a 2 L flask and heated to 90-100 °C. The reaction was continued for 10 h. After the reaction was complete, the excess phosphorus oxychloride was distilled off under reduced pressure. Then, ice water (400.00 g) was added dropwise to the residue, which was then extracted twice with dichloromethane (600 ml each time). The dichloromethane phases were combined and the dichloromethane was distilled off under reduced pressure. Toluene (610.29 g) was added to the residue and the mixture was cooled to induce crystallization. The crystals were filtered and the filter cake was dried to give a white powder. The yield was 87.2% and the purity (HPLC) was >99.0%.

[0038] Example 4 Terazosin

[0039] 2-chloro-4-hydroxy-6,7-dimethoxyquinazoline (203.43 g, 0.50 mol), DMF (1017.15 g) were added into a 2 L reaction flask and stirred until the solid was completely dissolved. Ammonia gas was bubbled into the solution for 8 h at room temperature. After the ammonia gas was stopped, the reaction was stirred for another 2 h. The DMF was distilled under reduced pressure until about half of the volume was removed. Ice water (1017.15 g) was added into the flask under ice-bath cooling, and a solid precipitated. The solid was filtered, washed with ice water twice, and air-dried to give a light yellow crystalline solid (183.92 g, 95.1% yield, purity (HPLC) > 99.0%).

[0040] Example 5 Terazosin hydrochloride

[0041] Terazosin (69.71 g, 0.18 mol), anhydrous ethanol (766.70 g), purified water (83.00 g) were added into a reaction flask, stirred and heated to 70-75 °C. 6M hydrochloric acid was added dropwise to adjust the pH to 2.49. After the addition was completed, the solution was stirred for 0.5 h. The temperature was lowered to 40-50 °C and stirred for 1 h. The temperature was further lowered to 0-5 °C and stirred for 2 h. The solution was filtered and air-dried to give a white solid (93.8% yield, purity (HPLC) > 99.5%).

Claims

1. A process for the preparation of terazosin hydrochloride, characterized in that The process comprises the following steps: Step 1: intermediate 1 reacts with tetrahydrofurfurylic acid to form intermediate 2; Step 2: intermediate 2 is cyclized with 6-amino veratric acid to form intermediate 3; Step 3: intermediate 3 is chlorinated to form intermediate 4; Step 4: intermediate 4 is ammoniated to form terazosin, which is then acidified with hydrochloric acid to form the final product 。 2. The method of claim 1, wherein Step 1: a toluene solution of 2-tetrahydrofurfurylic acid is added dropwise to a reaction flask containing intermediate 1 and toluene, and the reaction is carried out under reflux.

3. The method of claim 1, wherein Step 2: intermediate 2, 6-amino veratric acid, toluene, drinking water and sodium hydroxide are added to a reaction kettle, which is heated to 140-160°C for reaction.

4. The method of claim 1, wherein Step 3: intermediate 3, phosphorus oxychloride and DMF are added to a reaction flask, and the reaction is carried out under reflux.

5. The method of claim 1, wherein Step 4: intermediate 4 is dissolved in DMF, and ammonia gas is bubbled into the solution at room temperature to form terazosin. Then, terazosin, ethanol and drinking water are added to a reaction flask, which is heated to 70-75°C with stirring. Hydrochloric acid is added dropwise to adjust the pH to about 2.49, and the reaction is carried out with stirring at 40-50°C, followed by cooling to 0-5°C. The reaction is carried out with stirring at 0-5°C, and then the product is filtered.

6. The method of claim 2, wherein The feeding ratio of intermediate 1 to 2-tetrahydrofurfurylic acid is 1:1, and the reaction is carried out under reflux for 5.5 hours. After the reaction is completed, the product is distilled under reduced pressure.

7. The method of claim 3, wherein The feeding ratio of intermediate 2, 6-amino veratric acid and sodium hydroxide is 1-1.1:1-1.2:1-1.2.

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