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Preparation method for azelnidipine

A kind of technology of azelaine and compound, which is applied in the field of preparation of azeldipine, can solve the problems of increased cost, difficult handling, difficult industrialized production, etc., and achieves the effect of reducing the requirement of anhydrous degree and being easy to operate.

Active Publication Date: 2013-07-03
迪嘉药业集团股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] In the process of preparing amidinate 4 in the traditional reaction route, hydrogen chloride gas and ammonia gas need to be fed successively, so the reaction requires anhydrous reagents. According to literature reports, the reaction yield is about 70%. From the perspective of industrial synthesis, anhydrous reagents The application of gas will undoubtedly increase the cost. At the same time, the use of gas will increase the difficulty of operation and require the use of high-pressure equipment. At the same time, the post-reaction treatment is difficult and it is difficult to industrialize production. Therefore, there is a reality that this step reaction needs to be further improved.

Method used

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  • Preparation method for azelnidipine
  • Preparation method for azelnidipine
  • Preparation method for azelnidipine

Examples

Experimental program
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Effect test

Embodiment 1

[0028] Embodiment 1: Preparation of Azeldipine

[0029] Add 50g of compound 3, 1500mL of dichloromethane, and 16.64mL of absolute ethanol into a 5L three-neck flask. Under mechanical stirring, pass HCl gas below -5°C to saturation. After saturation, keep the reaction at -5°C for 24h. Protected from light and protected by nitrogen, slowly add the above reaction system to 1665ml of ammonia water with a concentration of 2.5-3.0% under the control of 0-5°C. After the addition is complete, stir for 0.5h, let stand for 0.5h, and separate the liquids. The dichloromethane layer was washed once with 2000mL saturated brine, left to stand for 1.0h, separated, and the dichloromethane layer was drained under reduced pressure to obtain a white solid, which was not dried. It was directly added to 2000mL acetonitrile, slowly heated to dissolve, and added 11.7g of ammonium acetate, temperature controlled at 55°C-60°C, reacted for 2h under mechanical stirring. The temperature was lowered, the ...

Embodiment 2

[0031] Embodiment 2; Preparation of Azeldipine

[0032] Add 50g of compound 3, 1500mL of dichloromethane, and 16.64mL of absolute ethanol into a 5L three-necked flask. Under mechanical stirring, pass HCl gas below -5°C to saturation. After saturation, keep it at -6°C to -8°C for 24 hours. Under the condition of controlling 0-5°C, slowly add the above reaction system into ammonia water with a concentration of 2.5-3.0%, adjust the pH to 7.8-8.5, after the addition is completed, stir for 0.5h, stand still for 0.5h, and separate the liquids. The dichloromethane layer was washed once with 2000mL saturated brine, left to stand for 1.0h, separated, and the dichloromethane layer was drained under reduced pressure to obtain a white solid, which was not dried. It was directly added to 2000mL acetonitrile, slowly heated to dissolve, and added 11.7g of ammonium acetate, temperature controlled at 55°C-60°C, reacted for 2h under mechanical stirring. After cooling down, the solid was precip...

Embodiment 3

[0034] Embodiment 3: the preparation of amidinate 4

[0035] Add 50g of compound 3, 1500mL of dichloromethane, and 16.64mL of absolute ethanol into a 5L three-neck flask. Under mechanical stirring, pass HCl gas below -5°C to saturation. After saturation, keep it at -7°C to -9°C for 24 hours. Slowly add the above reaction system to ammonia water with a concentration of 2.5-3.0% under controlled conditions of 0-5°C, adjust the pH to 8.5-9.5, after the addition is complete, stir for 0.5h, let stand for 0.5h, and separate the liquids. The dichloromethane layer was washed once with 2000mL saturated brine, left to stand for 1.0h, separated, and the dichloromethane layer was drained under reduced pressure to obtain a white solid, which was not dried. It was directly added to 2000mL acetonitrile, slowly heated to dissolve, and added 11.7g of ammonium acetate, temperature controlled at 55°C-60°C, reacted for 2h under mechanical stirring. After cooling down, the solid was precipitated,...

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Abstract

The invention relates to a preparation method for an antihypertensive drug, azelnidipine, which belongs to the field of medicine. The synthesis condition of amidine 4 in traditional synthetic route is improved by the method; and the original anhydrous reaction condition is changed into the reaction in water, so that the operation is convenient; and the requirement for the anhydrous degree of the reaction solvent is reduced. Therefore, the preparation method is very suitable for industrial production.

Description

Technical field: [0001] The invention relates to a preparation method of azelnidipine, which belongs to the field of medicine. Background of the invention: [0002] Azelnidipine (Azelnidipine) is a new type of dihydropyridine calcium channel blocker jointly developed by Japan Sankyo Co., Ltd. and Ube Industries Co., Ltd. It inhibits the entry of calcium ions into excitable tissues, causing peripheral blood vessels and coronary arteries Vasodilation to lower blood pressure. Clinically, it is widely used in patients with mild or moderate symptoms of essential hypertension, hypertension with renal dysfunction and severe hypertension. Compared with similar antihypertensive drugs, azedipine has a slow and long-lasting antihypertensive effect. [0003] Azedipine chemical structure is similar to nifedipine: [0004] [0005] Chinese patent CN87107150.9 reported this compound earlier, and introduced its synthesis in detail; since then, most of the synthesis of azelnidipine has...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12C07D205/04
Inventor 王兆杰闵庆祥张新涛
Owner 迪嘉药业集团股份有限公司
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