Convenient synthesis method of phenazosin

Abstract

The invention belongs to the technical field of medicine synthesis, and particularly relates to a convenient synthesis method of phenazosin. According to the preparation method, the 2-cyano-4, 5-dimethoxyaniline is taken as a starting raw material, and the phenazosin is synthesized through four-step reaction, so that the synthesis reaction steps are shortened, compared with the traditional process, 3-4-step reaction is reduced, the synthesis period is greatly shortened, and the yield is increased to 65% or above; the used reagents are more environment-friendly, so that the use of toxic and harmful reagents in the traditional process is avoided, and the pollution to the environment is reduced; meanwhile, as the reaction conditions are mild, the requirements on equipment are reduced, and the production cost is effectively reduced.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and particularly relates to a convenient synthesis method of bunazosin. Background Art

[0002] Bunazosin is a selective postsynaptic α1-adrenergic receptor blocker. In physiological regulation, it selectively acts on α1A-adrenergic receptors, affecting the central nervous system and reducing norepinephrine release, thereby lowering peripheral vascular resistance and achieving a blood pressure-lowering effect. Furthermore, the drug inhibits urate synthase activity, thereby reducing uric acid synthesis and helping to lower uric acid levels in the body. In the urinary system, bunazosin effectively reduces sympathetic nerve excitability, alleviates bladder neck smooth muscle spasm, and significantly improves symptoms such as dysuria. In the reproductive system, this drug can enhance nitric oxide-mediated penile erectile function and promote blood circulation within the corpus cavernosum, thereby alleviating symptoms of impotence. Furthermore, bunazosin can regulate guanylate cyclase, increasing the bioavailability of the endothelial relaxing factor prostacyclin, thereby dilating the pulmonary arteries and reducing pulmonary artery pressure. In addition, relevant literature also describes the effects of bunazosin as an anti-glaucoma drug on ocular circulation and retinal neuron damage.

[0003] The document (Organic Process Research & Development, 2024, 28(1): 101-111) discloses a traditional synthesis method of bunazosin, which uses 3,4-dimethoxybenzoic acid as a raw material and is prepared through seven steps of nitration, carboxylmethylation, reduction reaction, chlorination, and amination. The reaction steps are many and the total yield is low, usually less than 31%. At the same time, some reagents used, such as potassium isocyanate, are highly toxic and environmentally unfriendly. In addition, the reaction conditions are relatively harsh and have high requirements for production equipment, which greatly increases the production cost.

[0004] Given the importance of bunazosin in clinical applications and the shortcomings of traditional synthesis methods, developing a more efficient, environmentally friendly and low-cost convenient synthesis method for bunazosin is of great practical significance. Summary of the Invention

[0005] In view of the above problems, the present invention aims to provide a convenient synthesis method of bunazosin. This method can overcome the shortcomings of traditional synthesis methods and has the advantages of short reaction steps, high yield, environmental protection, and low cost.

[0006] In order to achieve the above effects, the technical solution of the present application discloses a convenient synthesis method of bunazosin, comprising the following steps:

[0007] S1. reacting 2-cyano-4,5-dimethoxyaniline with an excess of carbonic acid diester under strong base catalysis to obtain a quinazoline dione derivative;

[0008] S2. The quinazoline dione derivative is mixed with phosphorus oxychloride and heated to react to obtain 2,4-dichloro-6,7-dimethoxyquinazoline;

[0009] S3. Dissolving 2,4-dichloro-6,7-dimethoxyquinazoline in aqueous ammonia and heating the mixture to obtain 2-chloro-4-amino-6,7-dimethoxyquinazoline;

[0010] S4. Synthesis of bunazosin using 2-chloro-4-amino-6,7-dimethoxyquinazoline.

[0011] Furthermore, the quinazolinedione derivative described in S2 is mixed with phosphorus oxychloride in a molar ratio of 1:3.

[0012] Furthermore, the heating reaction temperature in S2 is 80° C. and the reaction time is 2 h.

[0013] Furthermore, after the heating reaction in S2 is completed, the reaction solution is placed in an ice-water mixture, stirred, filtered, washed with water, and dried to obtain 2,4-dichloro-6,7-dimethoxyquinazoline.

[0014] Furthermore, the ammonia content in the ammonia water in S2 is 20%.

[0015] Furthermore, the heating reaction temperature in S3 is 40° C. and the reaction time is 6 h.

[0016] Furthermore, the synthesis conditions described in S4 are alkaline conditions.

[0017] Furthermore, the two steps S3 and S4 are synthesized in two steps in one pot.

[0018] And, bunazosin is obtained according to the above synthesis method.

[0019] Beneficial effects:

[0020] The present application shortens the synthesis reaction steps, reduces 3-4 reaction steps compared to the traditional process, greatly shortens the synthesis cycle, and improves the yield; the reagents used are more environmentally friendly, avoiding the use of toxic and harmful reagents in traditional processes, and reducing pollution to the environment; at the same time, due to the mild reaction conditions, the equipment requirements are reduced, effectively reducing production costs. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 This is the traditional synthetic process route for bunazosin;

[0022] Figure 2 This is the process route for synthesizing bunazosin in this application. DETAILED DESCRIPTION

[0023] In order to more clearly illustrate the purpose, research methods and advantages of the present invention, the present invention is described in detail through the following examples.

[0024] In order to facilitate comparison and explanation of this application, the prior art bunazosin synthesis method is first published (the method is taken from Organic Process Research & Development, 2024, 28(1): 101-111), such as Figure 1 As shown, specifically: using 3,4-dimethoxybenzoic acid as the raw material, a nitro group is introduced into the benzene ring through a nitration reaction, the carboxyl group is esterified, and then the nitro group is converted into an amino group through a reduction reaction to obtain 2-amino-4,5-dimethoxybenzoic acid methyl ester; 2-amino-4,5-dimethoxybenzoic acid methyl ester is cyclized with potassium isocyanate to form a quinazolinone skeleton structure, and then chlorinated and aminated to obtain the key intermediate 2-chloro-4-amino-6,7-dimethoxyquinazoline 1, which is then condensed with a butyryl homopiperazine derivative 2 to obtain bunazosin 3.

[0025] It can be seen that the above reaction is divided into 7 steps in total, so the total yield of the synthesis reaction is low, usually less than 31%; secondly, some of the reagents used, such as potassium isocyanate, are highly toxic and environmentally unfriendly; thirdly, the reaction conditions are relatively harsh and require high production equipment, which greatly increases the production cost.

[0026] Therefore, the present application proposes a convenient synthesis method of bunazosin, specifically as follows Figure 2 shown.

[0027] Step 1: 2-cyano-4,5-dimethoxyaniline is used as the starting material and reacted with an excess of carbonic acid diester 4 at reflux temperature in the presence of a strong base to obtain a quinazoline dione derivative 5; the strong base can be sodium hydroxide, potassium hydroxide, etc.

[0028] In a specific embodiment, the synthesis method of the quinazoline dione derivative 5 in this step is an improvement on the method disclosed in the prior art CN101747323A, namely, the invention titled "A method for preparing alfuzosin hydrochloride", except that the DMF used is replaced with a carbonic acid diester (preferably dimethyl carbonate (4a: R = Me) or diethyl carbonate (4b: R = Et)). Because the prior art requires the use of a sealed reactor when using DMF, the reaction temperature is high and the conditions are harsh. After switching to a carbonic acid diester, compound 5 can be conveniently prepared under atmospheric reflux conditions, significantly reducing the process conditions. Here, the carbonic acid diester serves as both a reaction reagent and a reaction solvent; the base can be potassium hydroxide or sodium hydroxide.

[0029] Step 2: 5 is mixed with phosphorus oxychloride and heated to react to obtain 2,4-dichloro-6,7-dimethoxyquinazoline 6; in this reaction, 5 and phosphorus oxychloride are mixed in a molar ratio of 1:3, and the mixture is reacted at 80°C for 2 hours. The reaction solution is then poured into an ice-water mixture and stirred for 0.5 hours. After filtration, washing with water, and drying, 2,4-dichloro-6,7-dimethoxyquinazoline solid 6 is obtained.

[0030] Step 3: Dissolve 6 in aqueous ammonia to obtain the key intermediate 2-chloro-4-amino-6,7-dimethoxyquinazoline 1; wherein 6 is dissolved in aqueous ammonia with an ammonia content of 20% and reacted at 40°C for 6 hours.

[0031] Step 4: Intermediate 1 is subjected to a condensation reaction with a butyryl homopiperazine derivative 2 under alkaline conditions to obtain the target product 3.

[0032] In a specific embodiment, the synthesis of step 3 and step 4 can preferably be carried out by a one-step synthesis, wherein the principle and method of the one-step synthesis are referred to the literature (Shi Peijun, Foreign Medicine - Synthetic Drugs, Biochemical Drugs, Preparations, 1990, 11(4): 237-238); but since the conversion of 6 to 1 and 1 to 3 are both completed under alkaline conditions, the conversion of 6 to the target product 3 is designed in this patent by a step-by-step one-pot synthesis, that is, after 6 is synthesized into 1, it is not separated, and after simply removing water, a butyryl homopiperazine derivative 2 is added, and condensation under alkaline conditions can produce the target product 3.

[0033] The specific method is to prepare 1 according to the literature, then filter out the water, add an equimolar amount of a butyryl homopiperazine derivative 2, and conduct a base-catalyzed condensation reaction. The base can be sodium hydroxide, potassium hydroxide, DBU, pyridine, etc.; the reaction solvent can be ethanol, DMF, etc., and the reaction temperature is set at reflux. The final product yield is greater than 65%.

[0034] From the above analysis, it can be seen that the synthesis route of this patent application has fewer reaction steps than the traditional method, and the reagents used are more environmentally friendly and cheaper.

[0035] The preparation method of the present application will be described in detail below through specific examples.

[0036] Example 1

[0037] 1. Synthesis of Key Intermediate 1: In a reaction flask equipped with a stirrer, thermometer, and reflux condenser, add 0.2 mol of 2-cyano-4,5-dimethoxyaniline, an equal amount of potassium hydroxide, and a sufficient amount of carbonic acid diester. Stir and react at reflux for 8 hours. After the reaction is completed, cool to room temperature, pour the reaction solution into water, and extract with ethyl acetate (3 × 100 mL). The purpose of extraction is to utilize the solubility of ethyl acetate in the target product to separate it from the aqueous phase. The organic phases are combined and dried over anhydrous sodium sulfate to remove moisture. After filtration, the solvent is removed by distillation under reduced pressure to obtain 32.3 g of intermediate 2,4-dihydroxy-6,7-dimethoxyquinazoline 5, with a yield of 85%.

[0038] 5 and phosphorus oxychloride were mixed in a ratio of 1:3, and the mixture was reacted at a reaction temperature of 80°C for 2 hours. The reactant was then poured into ice water and stirred for 0.5 hours. The 2,4-dichloro-6,7-dimethoxyquinazoline dichloro derivative 6 was obtained with a yield of 84% by filtration, washing with water, and drying. 6 can be recrystallized from ethanol to further improve its purity.

[0039] 2. Synthesis of Bunazosin 3 (Step-by-Step, One-Pot Method): 2,4-Dichloro-6,7-dimethoxyquinazoline 6 was dissolved in 20% ammonia water and reacted at 40°C for 6 hours. The resulting key intermediate 1 was directly transferred to a reaction flask equipped with a stirrer, thermometer, and reflux condenser. 0.09 mol of seven-membered cyclic amide 2, a slight excess of a base catalyst, and solvent were then added. The mixture was heated under reflux for 6-10 hours. After the reaction was completed, the mixture was cooled to room temperature, poured into water, and extracted with ethyl acetate (3 x 100 mL). The organic phases were combined and washed sequentially with dilute hydrochloric acid to remove alkaline impurities, followed by washing with saturated brine to reduce the solubility of the organic phase in water and further remove residual impurities. The mixture was then dried over anhydrous sodium sulfate, filtered, and the solvent removed by distillation under reduced pressure to obtain the crude product. The crude product was recrystallized from ethanol to obtain the target product, Bunazosin 3, in a 91% yield with a purity of 97% (HPLC analysis).

[0040] Example 2

[0041] 1. Synthesis of dichloro derivative 6 is the same as in Example 1

[0042] 2. Synthesis of key intermediate 1: 2,4-dichloro-6,7-dimethoxyquinazoline solid was dissolved in 20% ammonia water. After reacting at 40°C for 6 hours, 2-chloro-4-amino-6,7-dimethoxyquinazoline 1 was obtained by separation and filtration with a yield of 85%.

[0043] 3. Synthesis of Bunazosin (Stepwise Method): In a reaction flask equipped with a stirrer, thermometer, and reflux condenser, 0.095 mol of key intermediate 1, 0.105 mol of a seven-membered cyclic amide, and 0.11 mol of potassium hydroxide were added. The mixture was heated under reflux in 250 mL of N-methylpyrrolidone for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, poured into water, and extracted with ethyl acetate (3 x 120 mL). The organic phases were combined and washed sequentially with dilute sulfuric acid to remove alkaline impurities and then with saturated brine to reduce the solubility of the organic phase in water and remove residual impurities. The mixture was then dried over anhydrous magnesium sulfate, filtered, and the solvent was removed by distillation under reduced pressure to obtain a crude product. The crude product was recrystallized from acetone to obtain bunazosin 3 with an 82% yield and a purity of 99.2% (HPLC determination).

[0044] Comparative Example 1

[0045] The synthesis of bunazosin was carried out according to a traditional synthesis method.

[0046] 1. Synthesis of key intermediate 1: Using 3,4-dimethoxybenzoic acid as the raw material, 2-amino-4,5-dimethoxybenzoic acid methyl ester was obtained through nitration, esterification, and reduction with a yield of 70%. The key intermediate 1 was then obtained through cyclization with potassium isocyanate, chlorination, and amination with a total yield of 50% (based on 2-amino-4,5-dimethoxybenzoic acid methyl ester).

[0047] 2. Synthesis of Bunazosin: The key intermediate 1 was reacted with a butyryl homopiperazine derivative 2 to produce Bunazosin 3 with a yield of 60% and a purity of 97% (HPLC assay). The total yield was 30% (based on 3,4-dimethoxybenzoic acid).

[0048] By comparing Example 1 and Example 2 with Comparative Example 1, it can be clearly seen that the synthesis method of the present invention has significantly improved yield and purity.

[0049] Finally, it should be noted that the above embodiments are merely preferred embodiments of the present invention, and the scope of protection of the present invention is not limited to the above embodiments. All technical solutions that fall within the scope of protection of the present invention are within the scope of protection of the present invention. It should be noted that improvements and modifications that can be made by persons of ordinary skill in the art without departing from the principles of the present invention are also considered to be within the scope of protection of the present invention.

Claims

1. A convenient synthesis method of bunazosin, characterized in that: The steps include: S1. reacting 2-cyano-4,5-dimethoxyaniline with an excess of carbonic acid diester under strong base catalysis to obtain a quinazoline dione derivative; S2. The quinazoline dione derivative is mixed with phosphorus oxychloride and heated to react to obtain 2,4-dichloro-6,7-dimethoxyquinazoline; S3. Dissolving 2,4-dichloro-6,7-dimethoxyquinazoline in aqueous ammonia and heating the mixture to obtain 2-chloro-4-amino-6,7-dimethoxyquinazoline; S4. Synthesis of bunazosin using 2-chloro-4-amino-6,7-dimethoxyquinazoline.

2. The synthesis method according to claim 1, wherein The quinazolinedione derivative described in S2 is mixed with phosphorus oxychloride in a molar ratio of 1:

3.

3. The synthesis method according to claim 1, wherein The heating reaction temperature in S2 is 80° C. and the reaction time is 2 h.

4. The synthesis method according to claim 1, characterized in that After the heating reaction in S2 is completed, the reaction solution is placed in an ice-water mixture, stirred, filtered, washed with water, and dried to obtain 2,4-dichloro-6,7-dimethoxyquinazoline.

5. The synthesis method according to claim 1, characterized in that The ammonia content in the ammonia water S2 is 20%.

6. The synthesis method according to claim 1, characterized in that The heating reaction temperature in S3 is 40° C. and the reaction time is 6 h.

7. The synthesis method according to claim 1, characterized in that The synthesis conditions described in S4 are alkaline conditions.

8. The synthesis method according to claim 1, characterized in that The two steps S3 and S4 are synthesized in two steps and one pot.

9. Bunazosin synthesized according to any one of the synthesis methods of claims 1 to 7.

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