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Process for preparing amlodipine benzenesulphonate

A technology of dipine benzene sulfonate and amino group, applied in the field of preparing amlodipine benzene sulfonate represented by the general formula, can solve the problems such as difficult to realize industrialization, difficult product purification, difficult removal of amino protecting group, etc. Stable, avoid deprotection step, low cost of raw materials

Inactive Publication Date: 2007-03-14
上海开特生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The average yield of this reaction is 54%, which is higher than the general synthetic route yield, but the amino protecting group is difficult to remove in this synthetic route, the purification of the product is difficult, and it is difficult to realize industrialization

Method used

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  • Process for preparing amlodipine benzenesulphonate
  • Process for preparing amlodipine benzenesulphonate
  • Process for preparing amlodipine benzenesulphonate

Examples

Experimental program
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Effect test

Embodiment 1

[0039] Preparation of ethyl 3-amino-4-[2-(tritylamino)ethoxy]crotonate (IX)

[0040] In a 500mL round bottom bottle equipped with an oil-water separator, add ethyl 4-[2-(tritylamino)ethoxy]acetoacetate (VIII) (86.2g, 0.02mol) and 300mL of toluene, The reactant was dissolved under stirring, and then ammonium acetate (7.7 g, 0.1 mol) was added to the reaction system, and the reaction was slowly heated to reflux for dehydration, and the reaction was maintained for 6 hours. Cool the reaction system, add the reactants to 500mL of ice water, extract by layers, and then extract the water layer with 200mL of toluene, combine the organic phases, wash with water, dry and concentrate to obtain a crude product. Yield 75.0%, HPLC: 88%, m.p.116~117℃, 1 H NMR (CDCl 3 , 300MHz) δ: 1.27(t, J=5.4Hz, 3H), 2.26~2.38(m, 2H), 3.56~3.58(m, 2H), 3.99(s, 3H), 4.13(q, J 1 =5.1Hz,J 2 =10.5Hz, 2H), 4, 52(s, 1H), 7.20(t, J=5.1Hz, 3H), 7.28(t, J=5.4Hz, 6H), 7.48(d, J=6.0Hz, 6H ).MS (70eV) m / z (%): 432 (...

Embodiment 2

[0042] Preparation of ethyl 3-amino-4-[2-(tritylamino)ethoxy]crotonate (IX)

[0043] In a 500mL round bottom flask equipped with an oil-water separator, add 4-[2-(tritylamino)ethoxy]ethyl acetoacetate (VIII) (86.2g, 0.02mol) and cyclohexane 350mL, stirred to dissolve the reactant, then added ammonium acetate (7.7g, 0.1mol) to the reaction system, slowly heated the reaction to reflux for dehydration, and maintained the reaction for 6h. Cool the reaction system, add the reactant to 500 mL of ice water, extract by layers, and extract the water layer with 200 mL of cyclohexane, combine the organic phases, wash with water, dry and concentrate to obtain a crude product. Yield 76.0%, HPLC: 88%.

Embodiment 3

[0045] Preparation of ethyl 3-amino-4-[2-(tritylamino)ethoxy]crotonate (IX)

[0046] In a 500mL round bottom bottle, add 4-[2-(tritylamino)ethoxy]ethyl acetoacetate (VIII) (86.2g, 0.02mol) and methanol 300mL, dissolve the reactant under stirring, Ammonium acetate (7.7 g, 0.1 mol) was added to the reaction system, and the reaction was kept stirring at room temperature for 16 h. Concentrate under reduced pressure and recover methanol, add 500 mL of water and 500 mL of dichloromethane to extract the residue, dry and concentrate the organic phase to obtain a crude product with a yield of 78%, HPLC: 91%, and the physical and chemical data of the product are the same as above.

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Abstract

The present invention discloses preparation process of Amlodipine benzene sulfonate. The preparation process includes the following steps: 1. the reaction between 4-[2-(tritylamindo)ethoxy] ethyl acetoacetate and amine compound to produce 3-amino-4-[2-( tritylamindo)ethoxy] ethylcrotonate; 2. the reaction between o-chluoro benzaldehyde and methyl acetoacetate under the catalysis of alkali to produce 2-(2-o-chluorobenzal)-ethyl acetoacetate; 3. the reaction of the products in the foregoing steps to obtain 4-(2-chlorophenyl)-6-methyl-2-((2-(tritylamido) ethoxy) methyl)-1, 4-dihydropyridyl-3-ethyl formate-5-methyl formate; and 4. further direct reaction with benzene sulfonic acid to eliminate protecting group and form Amlodipine benzene sulfonate.

Description

technical field [0001] The invention relates to a method for preparing amlodipine besylate represented by general formula (I). [0002] Background technique [0003] Calcium channel blockers (calcium antagonists) have a good effect in the treatment of heart diseases such as angina pectoris, hypertension and congestive myocardial arrest. Amlodipine is a long-acting calcium channel blocker, which shows good bioavailability and long half-life in vivo, and shows good pharmacological response to heart diseases such as hypertension. Amlodipine is currently the drug of choice for the treatment of hypertension, and its sales rank first in the world of cardiovascular drugs. At present, the commercialized amlodipine product on the market is amlodipine besylate launched by Pfizer, other amlodipine salt products, such as maleate, tartrate, citrate, hydrochloride, Hydrobromide and sulfate are currently under development. [0004] A variety of synthetic methods of amlodipine have be...

Claims

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Application Information

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IPC IPC(8): C07D211/90
CPCY02P20/55
Inventor 潘仙华毛海舫
Owner 上海开特生物科技有限公司
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