New crystal form of conivaptan hydrochloride and preparation method thereof

A conivaptan hydrochloride and crystal form technology, applied in the field of medicinal chemistry, can solve the problems of environmental protection, poor economy, difficult recovery of solvents, and low crystal form purity, and achieve high solubility and bioavailability, low production cost, The effect of meeting the medicinal requirements

Active Publication Date: 2016-01-27
BEIJING COLLAB PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the crystallization and crystal form preparation methods adopted in Japanese patents JP2001002678 and JP2002087962 use mixed solvents, the operation is complicated, the solvent is not easy to recover, the crystal form has low purity, and the preparation process is environmentally friendly and economical.

Method used

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  • New crystal form of conivaptan hydrochloride and preparation method thereof
  • New crystal form of conivaptan hydrochloride and preparation method thereof
  • New crystal form of conivaptan hydrochloride and preparation method thereof

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preparation example Construction

[0036] Preferably, the preparation method of the new crystal form of conivaptan hydrochloride specifically includes

[0037] Step a) dissolving the crude conivaptan hydrochloride in anhydrous methanol and heating to dissolve, decolorizing with activated carbon, filtering, and evaporating the filtrate to dryness;

[0038] Step b) Add acetonitrile, reflux, cool, filter, and dry the filtrate to obtain.

[0039] Wherein, the ratio of the mass of the crude conivaptan hydrochloride to the volume of the anhydrous methanol in step a) is preferably 1 g: 10 mL-15 mL, more preferably 1 g: 10 mL. That is, 10 mL to 15 mL of anhydrous methanol is preferably added to 1 g of crude conivaptan hydrochloride, more preferably 10 mL of anhydrous methanol is added.

[0040]Step a) of the preparation method of the new crystal form of conivaptan hydrochloride according to the present invention: a) the crude conivaptan hydrochloride is dissolved in anhydrous methanol and then heated to dissolve the c...

Embodiment 1

[0052] Embodiment 1: Preparation of new crystal form of conivaptan hydrochloride

[0053] Dissolve 1 g of crude conivaptan hydrochloride in 12 mL of anhydrous methanol, heat it in a water bath to 35-40°C to dissolve it, add 0.06 g of activated carbon into it, heat and stir for 20 minutes to decolorize, filter, and evaporate the filtrate to dryness under reduced pressure at 35-40°C; Add 25mL of acetonitrile, raise the temperature and reflux for 5 hours under rapid stirring, cool to about 15°C, stir for 1 hour and filter, and dry the filter cake at 60°C with an oil pump under reduced pressure to constant weight to obtain 0.694g of white solid powder with a yield of 69.4%. After HPLC analysis, the total amount of related substances in the obtained product was 0.065%, and the maximum single impurity was 0.046% (area normalization method).

[0054] Adopt Japan RigakuD / max-2550 powder X-ray diffractometer, under the test parameter is: copper target, tube flow 150mA, tube pressure 40...

Embodiment 2

[0057] Embodiment 2: Preparation of new crystal form of conivaptan hydrochloride

[0058] Dissolve 20g of crude conivaptan hydrochloride in 200mL of anhydrous methanol, heat it in a water bath to 35-40°C to dissolve, add 1.0g of activated carbon into it, heat and stir for 30min to decolorize, filter, and evaporate the filtrate to dryness under reduced pressure at 35-40°C; Add 400mL of acetonitrile, raise the temperature and reflux for 5 hours under rapid stirring, cool to about 15°C, stir for 1 hour and filter, and dry the filter cake under reduced pressure at 60°C with an oil pump to constant weight to obtain 14.672g of white solid powder with a yield of 73.36%. After HPLC analysis, the total amount of related substances in the obtained product was 0.067%, and the maximum single impurity was 0.042% (area normalization method).

[0059] The product was analyzed by a Japanese Rigaku D / max-2550 powder X-ray diffractometer and a Swiss Mettler DSC1 thermal analyzer. The results sh...

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Abstract

The invention relates to the field of medicinal chemistry, and discloses a conivaptan-hydrochloride novel crystal form and a preparation method of the conivaptan-hydrochloride novel crystal form. The conivaptan-hydrochloride novel crystal form is single in crystal form, high in purity, good in stability, high in solubility and bioavailability, capable of restraining arginine vasopressin V1a and V2 receptors, and capable of being used for preparing medicine for treating hyponatremia. The preparation method of the conivaptan-hydrochloride novel crystal form is simple to operate, avoids complex and fussy crystallization processing conditions, enables solvents to be recycled, is low in production cost, and is suitable for industrial production. Products meet medicinal standards and good in stability.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a new crystal form of conivaptan hydrochloride and a preparation method thereof. Background technique [0002] Conivaptan hydrochloride is a non-peptide dual inhibitor of arginine vasopressin (AVP) V1a and V2 receptors. The FDA approved the listing of conivaptan hydrochloride of AstellasPharmaUS company on December 29, 2005 at the earliest. The product name is Vaprisol, which is an injection of 20mg / 4mL. In patients with syndrome of inappropriate antidiuretic hormone secretion, patients with hypothyroidism, patients with adrenal insufficiency or patients with lung disease) and the treatment of hospitalized patients with hypervolemic hyponatremia. In 2007, the FDA approved conivaptan to increase its indication—hypervolemic hyponatremia, and in 2008, it approved a new dosage form—20mg / 100mL large infusion. [0003] The chemical name of conivaptan hydrochloride is N-{4-[(2-methy...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04A61K31/55A61P3/12
CPCC07D487/04
Inventor 张宪美谈敦潮孟月垒孙志国赵大龙王珂
Owner BEIJING COLLAB PHARMA
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