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Crystal form, preparation method and application of prostaglandin analogue

一种晶型、药物的技术，应用在化学制药领域，能够解决前列腺素类化合物稳定性差等问题

Inactive Publication Date: 2013-07-10
SHANGHAI TECHWELL BIOPHARMACEUTICALS CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Generally, prostaglandin compounds have poor stability and need to be stored below -20°C. From the perspective of compound stability and purity, there is an urgent need in this field to obtain a stable crystal form of compound I

Method used

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  • Crystal form, preparation method and application of prostaglandin analogue
  • Crystal form, preparation method and application of prostaglandin analogue
  • Crystal form, preparation method and application of prostaglandin analogue

Examples

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preparation example Construction

[0050] The preparation method of compound I crystal form A

[0051] The present invention also provides a preparation method of crystal form A of the compound represented by formula I.

[0052] In one embodiment provided by the invention, the preparation method of the crystal form A of the compound of formula I comprises the following steps:

[0053] (1) Mix the crude product of the compound shown in formula I with solvent 1 to obtain solution 1; the solvent 1 is selected from the group consisting of methanol, acetonitrile, ethyl acetate, methyl acetate, isopropyl acetate, and / or or tert-butyl acetate;

[0054] (2) Cool down the temperature of solution 1 or add solvent 2 and stir to precipitate crystal form A of the compound of formula I.

[0055] In step (1), the mixing should be performed below the boiling point of solvent 1, preferably at 0-80°C; preferably at 20-50°C; more preferably at 30-50°C.

[0056] In step (1), the mixing ratio (weight to volume ratio) of the crud...

Embodiment 1

[0082] Preparation of crude compound I

[0083] With reference to the preparation method reported in the document J.Org.Chern.2004, 69, 1890-1902, (1R, 2R, 3aS, 9aS)-2,3,3a,4,9,9a-hexahydro-1-[( 3S)-3-Hydroxyoctyl]-1H-phenyl[f]indene-2,5-diol was used as the starting material, and 41 g of crude compound I was obtained without purification.

Embodiment 4

[0089] Preparation of compound I crystal form A

[0090] In a 25ml eggplant-shaped bottle, add the compound I crude product (1.0g) and methanol (1.0ml) obtained in Example 1, warm up to 30°C and dissolve to form a homogeneous solution, then slowly add pure water (0.6ml), and cool down to Stir at 5°C for 10 h, filter, wash with 10% aqueous methanol at 5°C for 2-3 times, and dry to obtain 0.91 g of crystalline solid. X-ray powder diffraction pattern see figure 1 , differential scanning calorimetry (DSC) chart see figure 2 , see the infrared spectrum image 3 , HPLC purity 99.90%. Organic residue: methanol 0.04% (mass yield: 91%)

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Abstract

The invention discloses a crystal form A, a preparation method and application of a compound with a structural formula shown as a formula I. An X-ray powder diffraction graph (XRPD) of the crystal form A shows characteristic peaks at the following 2theta angles: 2.9 + / - 0.2 DEG, 13.6 + / - 0.2 DEG, 17.3 + / - 0.2 DEG and 18.6 + / - 0.2 DEG.

Description

technical field [0001] The invention relates to the field of chemical pharmacy, in particular to a crystal form of a prostaglandin analogue and a preparation method and use thereof. Background technique [0002] Treprostinil (UT15, Treprostinil) is a new class of drugs for the treatment of pulmonary arterial hypertension. Its structure is as shown in formula I: [0003] [0004] Pulmonary arterial hypertension (PAH) is a disease characterized by vasospasm, intimal hyperplasia and remodeling of pulmonary arterioles. Vascular proliferation and remodeling of pulmonary arterioles lead to a progressive increase in pulmonary vascular resistance, eventually leading to right ventricular failure and death. [0005] Epoprostenol (Flolan) is the first prostacyclin drug approved by the US Food and Drug Administration (FDA) for the treatment of PAH. The half-life of epoprostenol in the circulation is about 3 to 5 minutes, and continuous intravenous administration is required, and i...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C59/72C07C51/43A61K31/5575A61K31/192A61P9/12A61P9/00
CPCC07C51/43C07C2603/14C07C59/72A61P9/00A61P9/12
Inventor 唐志军刘毓彬何兵明杨君季晓铭
Owner SHANGHAI TECHWELL BIOPHARMACEUTICALS CO LTD
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