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Demethylivabradine salt as well as preparation method and application thereof

A technology of sulfate and phosphate, which is applied in the field of medicine, can solve the problems affecting the production, quality, absorption and curative effect of medicines, and achieve the effect of favorable preparation and preservation, low requirements for storage environment and production equipment, and strong heart rate inhibition

Active Publication Date: 2014-04-16
SHANDONG CHENGCHUANG PHARMA R&D
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] However, the applicant found through preliminary research that there are large differences in the stability, hygroscopicity, and solubility of the salts of norivabradine, and these differences may affect the production, quality, absorption, and efficacy of the drug

Method used

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  • Demethylivabradine salt as well as preparation method and application thereof
  • Demethylivabradine salt as well as preparation method and application thereof
  • Demethylivabradine salt as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Example 1 Preparation of norivabradine citrate

[0047] Prepare nor-ivabradine citrate by nor-ivabradine, the chemical reaction formula is as follows:

[0048]

[0049] 45.4 g (100 mmol) of norivabradine was dissolved in 1000 mL of acetone at 30° C., and 21.1 g (110 mmol) of citric acid were added. The mixture was stirred and reacted at room temperature for 2 hours, and the precipitated crystals were suction-filtered, rinsed with 200 mL of acetone, and vacuum-dried to obtain 52.4 g of norivabradine citrate, with a yield of 81%, HPLC: 99.734%.

[0050] The physicochemical properties and identification data of the prepared norivabradine citrate are as follows:

[0051] M.p.141-143℃:

[0052] DSC curve (closed pan 10°C / min): starting at 143.6°C.

[0053] IR spectrum (KBr, in cm -1 calculation): 417, 432, 460, 491, 516, 543, 570, 613, 639, 657, 677, 696, 723, 758, 789, 827, 860, 871, 885, 917, 937, 962, 980, 1005 . , 2644, 2833, 2921, 2935, 2969, 3384.

[0054] 1 H...

Embodiment 2

[0056] Example 2 Preparation of Norivabradine Citrate

[0057] Dissolve 4.54 g (10 mmol) of norivabradine in 100 mL of ethyl acetate at 30° C., and add 2.11 g (11 mmol) of citric acid. The mixture was stirred and reacted at room temperature for 2 hours, and the precipitated crystals were suction filtered, rinsed with 20 mL of ethyl acetate, and dried in vacuo to obtain 5.56 g of norivabradine citrate, with a yield of 86%, HPLC: 99.644% .

Embodiment 3

[0058] Example 3 Preparation of norivabradine citrate

[0059] 4.54 g (10 mmol) of norivabradine was dissolved in 100 mL of ethanol at 40° C., and 2.11 g (11 mmol) of citric acid were added. The mixture was stirred and reacted at room temperature for 2 hours, the temperature was raised to 55° C., 0.3 g of activated carbon was added for decolorization for 10 minutes, and filtered while hot. Place it at 20-25°C for crystallization for 3 hours. The precipitated crystals were suction-filtered, rinsed with 20 mL of ethanol, and vacuum-dried to obtain 5.36 g of norivabradine citrate, with a yield of 83%, HPLC: 99.840%.

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Abstract

The invention belongs to the technical field of the medicine, and specifically relates to a demethylivabradine salt as well as a preparation method and an application thereof. The demethylivabradine salt is a pharmaceutically acceptable salt, wherein the pharmaceutically acceptable salt includes citrate, hydrobromide, sulfate, phosphate, acetate, trifluoroacetate, lactate, acetonate, malonate, succinate, glutarate, fumarate, maleate, ascorbate, oxalate, mesylate, benzene sulfonate and camphorate, and has excellent stability and solubility, and also has low hygroscopicity and remarkable advantages.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to nor-ivabradine salt and its preparation method and application. Background technique [0002] Ivabradine (ivabradine) disclosed in the patent EP 0534859 was approved by the European Union EMA in 2005. It is a tablet with a specification of 5 mg. It is used for the treatment of chronic stable angina pectoris with normal sinus rhythm that is contraindicated or intolerant to β-blockers Treatment of patients; treatment of patients with chronic stable angina pectoris whose symptoms are not well controlled on beta-blockers; and treatment of chronic heart failure (heart failure) with abnormal systolic function. The structure of ivabradine is as follows: [0003] [0004] Nor-ivabradine is the main active metabolite of ivabradine, its chemical name is: 3-[3-[[(8S)-3,4-dimethoxy-8-bicyclo[4.2.0] Octa-1,3,5-triene]-methylamino]propyl]-7,8-dimethoxy-2,5-dihydro-1H-3-benzaz...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D223/16C07C51/41C07C59/265C07C57/15C07C57/145C07C59/255A61K31/55A61K9/48A61K9/20A61P9/10A61P9/06
CPCC07D223/16A61K9/2018A61K9/2054A61K9/4858A61K9/4866A61K31/55A61P9/06A61P9/10C07C57/145C07C57/15C07C59/255C07C59/265
Inventor 王志刚娄红祥李文保马恩龙
Owner SHANDONG CHENGCHUANG PHARMA R&D
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