Preparation method of ivabradine hydrochloride crystal form variant DELTA-D

Abstract

The invention relates to a preparation method of an ivabradine hydrochloride crystal form variant DELTA-D, which comprises the following steps: 1) dissolving ivabradine hydrochloride in C2-C4 ketones; 2) heating the material obtained in the step 1) to 30-45 DEG C, and stirring to react for 6-50 hours; and 3) in a nitrogen atmosphere, filtering the reaction system obtained in the step 2), and drying the obtained solid at 40-85 DEG C to a dry state, wherein the water content in the reaction material in the step 1) is 0.1-1%. The control on the water content in the reaction material is used instead of the control on the relative humidity in the reaction process in the prior art, so that the method is convenient to control, does not need any special adjusting facility, and is convenient for implementing industrialization. The C2-C4 ketones are used as the solvent, thereby avoiding the toxic solvent residues in the crystal form. The reaction temperature is controlled at 25-45 DEG C, the reaction time is controlled at 6-50 hours, and the drying is performed to further enhance the purity of the crystal form. The DELTA-D crystal form prepared by the method has favorable storage stability.

Description

technical field [0001] The invention relates to a preparation method of ivabradine hydrochloride crystal form modification DELTA-D. Background technique [0002] Ivabradine hydrochloride, (IVA, )3-{3-[([(7S)-3,4-dimethoxybicyclo[4.2.0]oct-1,3,5-trien-7-yl]-methyl}(methyl) Amino]-propyl}-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-phenylacryrazine-2-one hydrochloride, the structural formula is as follows [0003] [0004] Ivabradine hydrochloride has high pharmacological value and clinical therapeutic effect, and is generally used as an anti-angina drug, especially in slowing down the heart rate and treating heart failure. A variety of ivabradine hydrochloride crystal forms have been disclosed in the prior art, such as viz-α (alpha), β (Beta), β-d (Beta-d), γ (gamma), γ (gamma- d), δ(delta), δ-d(delta-d), Form Z, Form X, Form K, Form ζ (Greekzed), Form I, Form II, Form III, Form IV, Form A, ε (epsilon). [0005] Patent EP1775287 (US2007 / 0082886) discloses anhydrous ivabrad...

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Problems solved by technology

Although the crystal form delta-d was prepared under the premise of avoiding the use of acetonitrile in this process, it needs to be placed in a moisture-proof control box for 72 hours and the relative humidity in the drying box must be strictly controlled, which requires special equipment and is difficult to achieve industrialization; And if it is not equipped with special equipment for controlling relative humidity, it will easily lead to mixed crystals in the product, and the product has low purity.

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