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

A crystal form and drug technology, applied in the field of chemical pharmaceuticals, can solve problems such as high viscosity, excessive residual solvents, and poor stability of prostaglandin compounds

Active Publication Date: 2012-12-12
SHANGHAI TECHWELL BIOPHARMACEUTICALS CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The above-mentioned viscous substances are in the form of filaments when sampling or subpackaging, so it is difficult to subpackage and quantify
What's more unfavorable is that due to its high viscosity, it is difficult to concentrate under reduced pressure to remove the residual solvent, resulting in a significant excess of the residual solvent, which is obviously not conducive to the requirements of industrial production
[0005] 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 of prostaglandin analogue, and preparation method and application thereof
  • Crystal form of prostaglandin analogue, and preparation method and application thereof
  • Crystal form of prostaglandin analogue, and preparation method and application thereof

Examples

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preparation example Construction

[0062] The preparation method of compound I crystal form A

[0063] The present invention also provides a preparation method of crystal form A of the compound represented by formula I.

[0064] 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:

[0065] (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 acetone, butanone, methyl acetate, ethyl acetate, isopropyl acetate, or tert-butyl acetate; and

[0066] (2) Cool down and stir the solution 1 to precipitate the crystal form A of the compound of formula I.

[0067] In step (1), the mixing should be performed below the boiling point of solvent 1, preferably at 30-80°C, more preferably at 40-50°C.

[0068] In step (1), the mixing ratio (weight to volume ratio) of the crude compound represented by formula I to solvent 1 is 1:2-50...

Embodiment 1

[0112] Preparation of crude compound I

[0113] Referring to the preparation method reported in similar literature US2005209337A1, using Corey lactone and 2-oxo-3-phenoxypropyl dimethyl phosphate as starting materials, an improved Wittig condensation reaction occurs under the action of sodium hydride to obtain the key intermediate enone compound, and then through chiral reduction, tert-butyldimethylsilane protection, diisobutylaluminum hydride reduction and Wittig condensation to obtain another key intermediate, and then hydrochloric acid hydrolysis, methyl esterification and ethylenediamine aminolysis to obtain the compound I crude.

Embodiment 2

[0115] Preparation of compound I crystal form A

[0116] In a 50ml eggplant-shaped bottle, add the crude compound I obtained in Example 1 (2.0g) and acetone (10ml), heat up to 30°C and dissolve to form a homogeneous solution, then slowly cool down to 5°C and stir for 10h, filter, 5°C Washed 2-3 times with acetone and dried to obtain 1.22 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 99.07%, see Figure 4 . (mass yield: 61%)

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Abstract

The invention discloses a crystal form A of a compound having the structure shown in formula (I), and a preparation method and application thereof. An X-ray powder diffraction (XRPD) chart of the crystal form A has characteristic peaks of 2theta angels including (3.2+ / -0.2) degrees, (5.4+ / -0.2) degrees, (11.3+ / -0.2) degrees, (16.7+ / -0.2) degrees, (19.3+ / -0.2) degrees, (19.8+ / -0.2) degrees, (20.7+ / -0.2) degrees, (22.8+ / -0.2) degrees, (28.3+ / -0.2) degrees.

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] (Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R,E)-3-hydroxy-4-phenoxybutyl-1-enyl) ring Pentyl)-N-ethyl-5-heptaenamine (compound I) is similar in structure to glaucoma drugs latanoprost (Latanorost), bimatoprost (Bimatoprost) and travoprost (Travoprost), and has good application prospects. Among them, US2008269332A1 has reported that compound I can promote the growth of eyelashes and eyebrows. However, there is no research report about the crystal form of this compound. [0003] The inventor prepared the crude product of Compound I with reference to the method reported in similar literature US2005209337A1, and then separated and purified by column chromatography, and then concentrated to dryness under reduced pressure to obtain an extremely viscous substance, and no mat...

Claims

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Application Information

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IPC IPC(8): C07C405/00A61K31/5575A61P17/14A61K8/42A61Q7/00
Inventor 何兵明唐志军郑居上季晓铭
Owner SHANGHAI TECHWELL BIOPHARMACEUTICALS CO LTD
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