Method for preparing alfuzosin

An alfuzosin and quinazoline-based technology, which is applied in the field of preparation of alfuzosin, can solve the problems of many by-products, harsh conditions, long reaction steps, etc., and achieves improved product yield and quality, and mild reaction conditions. , the effect of simplifying the preparation method

Inactive Publication Date: 2007-03-28
浙江华纳药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

When the cyano group is reduced in the preparation process, high temperature and high pressure and metal (such as rhodium, platinum, nickel, etc.) catalysts are required, the conditions are harsh, the cost is high, the equipment requirements are high, and it is difficult to realize large-scale industrial production; the preparation method disclosed in US 6313293B1 and CN1616438A Carry out according to route 3, compared with route 1 and route 2, got rid of this step of cyano group reduction reaction, and reaction condition is gentle, and reaction process simplifies, but reaction raw material N-methyl propanediamine is difficult to buy on the market, needs self-preparation, N -Methylpropylenediamine synthesis reaction step is long, difficult, and yield is low, and the condensation reaction of N-methylpropylenediamine and 2-tetrahydrofuran formic acid, two amino groups of N-methylpropylenediamine can produce amide chemical reaction, which makes the reaction complicated and has many by-products, which also limits its industrial production

Method used

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  • Method for preparing alfuzosin
  • Method for preparing alfuzosin
  • Method for preparing alfuzosin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] a. Preparation of N-3-chloropropyl-2-tetrahydrofuran carboxamide (II)

[0027] In a 500mL three-necked flask, add the compound 2-tetrahydrofuroyl chloride (26.9g, 0.2mol), triethylamine (30.3g, 0.3mol), and 180mL of dichloromethane, stir and mix, and cool the mixture to 0°C to 5°C. Keeping the reaction temperature below 10°C, a solution of 3-chloropropylamine (21.11 g, 0.2 mol) and 50 mL of dichloromethane was added dropwise with stirring. After the addition was complete, the reaction was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, and the resulting residue was extracted three times with 300 mL of chloroform. The chloroform extract was washed twice with 200 mL of water, twice with 200 mL of saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 4-(4-chlorobutyl)-1-(2,3-dichlorophenyl)piperazine (II). Yield: 79.8%.

[0028] b. Preparation of N-3-methylami...

Embodiment 2

[0033] a. Preparation of N-3-chloropropyl-2-tetrahydrofuran carboxamide (II)

[0034] In a 500mL three-necked flask, add the compound 2-tetrahydrofuroyl chloride (26.9g, 0.2mol), pyridine (23.7g, 0.3mol), and 180mL of chloroform, stir and mix, and cool the mixture to 0°C to 5°C to keep the reaction With the temperature below 15°C, a solution of 3-chloropropylamine (21.11 g, 0.2 mol) and 50 mL of chloroform was added dropwise with stirring. After the addition was complete, the reaction was stirred overnight at room temperature. The solvent was distilled off under reduced pressure, and the resulting residue was extracted three times with 300 mL of chloroform. The chloroform extract was washed twice with 200 mL of water, twice with 200 mL of saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 4-(4-chlorobutyl)-1-(2,3-dichlorophenyl)piperazine (II). Yield: 75.3%, mp.

[0035] b. Preparation of N-3-methylaminop...

Embodiment 3

[0040] a. Preparation of N-3-chloropropyl-2-tetrahydrofuran carboxamide (II)

[0041] In a 500mL three-necked flask, add compound 2-tetrahydrofuroyl chloride (26.9g, 0.2mol), pyridine (23.7g, 0.3mol), N,N-dimethylformamide (DMF) 150mL, stir and mix, and cool the mixture To 0 ℃ ~ 5 ℃, keep the reaction temperature below 15 ℃, dropwise add a solution of 3-chloropropylamine (21.11g, 0.2mol) and N,N-dimethylformamide (DMF) 50mL under stirring, the dropwise addition is complete , 50 ℃ ~ 55 ℃ stirring reaction for 14 hours. The solvent was distilled off under reduced pressure, and the resulting residue was extracted three times with 300 mL of chloroform. The chloroform extract was washed twice with 200 mL of water, twice with 200 mL of saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 4-(4-chlorobutyl)-1-(2,3-dichlorophenyl)piperazine (II). Yield: 82.5%, mp.

[0042] b. Preparation of N-3-methylaminopropyl-2-...

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Abstract

The invention discloses an Alfuzosin preparing method, adopting 3- halogenated propylamine as raw material, making condensation reaction with 2-tetrahydrofurioic acid or 2-tetrahydro furoyl chloride and obtaining intermediate N-3-halogenated propyl-2-tetrahydro furoyl amine, which then condenses with methylamine to obtain intermediate N-3-methylamino propyl-2-tetrahydro furoyl amine, which then condenses with 2-chloro-4-amino-6, 7-dimethoxy-quinazoline to obtain Alfuzosin. And the mentioned synthesis method is simple, low-cost, and has reacting conditions easy to control, high product yield and relatively improved quality of product, suitable for industrialized production.

Description

technical field [0001] The present invention relates to a kind of alfuzosin (Alfuzosin), namely N-[(3-(4-amino-6,7-dimethylamino-2-quinazolinyl)methylamino)propyl]tetrahydro-2- A new method for the chemical synthesis of furocarboxamides. Background technique [0002] Alfuzosin (Alfuzosin) is a generic compound of N-[(3-(4-amino-6,7-dimethylamino-2-quinazolinyl)methylamino)propyl]tetrahydro-2-furancarboxamide name, its structure is as follows: [0003] [0004] Alfuzosin was developed by the Beiezsdozf company in Germany and first launched in France in 1988 for the treatment of clinical symptoms of benign prostatic hyperplasia. Alfuzosin is a quinazoline derivative that can selectively bind to alpha 1 -Receptor competitive binding, antagonizes α 1 - Receptor-mediated smooth muscle contraction. Alfuzosin can significantly reduce voiding disorder in clinical patients with benign prostatic hyperplasia, increase urine flow, and effectively improve the quality of life of p...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/12
Inventor 胡高云相红琳徐利明
Owner 浙江华纳药业有限公司
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