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Lubiprostone crystals and methods for preparing the same

A lubiprostone and crystal technology, applied in the field of high-purity lubiprostone crystals and their preparation, can solve problems such as inability to evaluate

Pending Publication Date: 2020-01-21
CHIROGATE INT
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, the advantages for purifying lubiprostone with conventional crystallization methods cannot be assessed on the basis of prior art

Method used

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  • Lubiprostone crystals and methods for preparing the same
  • Lubiprostone crystals and methods for preparing the same
  • Lubiprostone crystals and methods for preparing the same

Examples

Experimental program
Comparison scheme
Effect test

example

[0096] X-Ray Powder Diffraction (XRPD) Analysis: XRPD patterns were collected on a Bruker D2 PHASER diffractometer with fixed divergence slit and ID LYNXEYE detector. The sample (approximately 100 mg) was placed flat on the sample holder. Use CuK α The as-prepared samples were analyzed by radiation at an energy of 10 mA and 30 kV over a 2Θ range of 5° to 50° with a step size of 0.02 degrees and a step time of 1 second. Removal of CuK by Diverging Beam Nickel Filter β radiation.

[0097] Differential Scanning Calorimetry (DSC) Analysis: DSC traces were collected on a TA DISCOVERY DSC25 instrument. Samples (approximately 5 mg) were weighed into aluminum pans with crimped closed aluminum lids. The prepared samples were analyzed from 10°C to 100°C at a scan rate of 10°C / min under nitrogen flow (approximately 50ml / min). The melting point temperature and heat of fusion were calibrated by indium (In) before measurement.

[0098] Fourier transform infrared (FTIR) analysis: FTIR ...

example 1

[0100] preparation of crude biprostone

[0101] 7-[(2R,4aR,5R,7aR)-2-(1,1-difluoro-pentyl)-octahydro-2-hydroxyl-6-oxocyclopentyl[b]pyran-5-yl ) 4-methoxybenzyl heptanoate (60 g, 117.5 mmol, enantiomeric purity > 99%) was dissolved in 600 ml ethyl acetate, and then 5% palladium / activated carbon was added under hydrogen for 3 hours. Subsequently, the reaction mixture was filtered through a pad of celite. The solvent was evaporated under vacuum. The crude product was purified by silica gel chromatography using a mixture of hexane and ethyl acetate as gradient eluent to obtain 40 g of lubiprostone as an oil. HPLC analysis of the product showed that 1.1% impurity A was found.

example 2

[0103] Preparation of lubiprostone crystal VI

[0104] Oily lubiprostone (0.51 g from Example 1) and p-xylene (1.0 ml) were heated at 40°C to dissolve and then cooled to room temperature. n-Pentane solvent (1.0 ml) was slowly added dropwise and the mixture was stirred in an ice-water bath for 1 hour until solid precipitation occurred. The resulting suspension was filtered and rinsed, and then dried under high vacuum at room temperature for 4 hours to yield 0.38 g of lubiprostone crystalline VI. HPLC analysis of the product showed that impurity A was not found. XRPD and DSC results such as Figure 9 and Figure 10 shown in .

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Abstract

This present invention relates to novel Lubiprostone crystals and methods for preparing the same. The preparation methods provided by the invention can effectively reduce or eliminate impurity in theobtained Lubiprostone crystals.

Description

technical field [0001] The present invention relates to a novel lubiprostone crystal and its preparation method, and in particular to high-purity lubiprostone crystal and its preparation method. Background technique [0002] Lubiprostone is a drug used to treat diseases such as chronic idiopathic constipation, mainly female irritable bowel syndrome-related constipation and opioid-induced constipation active pharmaceutical ingredients in. Lubiprostone is classified as a less stable prostaglandin E1 that is easily and rapidly degraded to prostaglandin A1 (hereinafter referred to as impurity A) under acidic or alkaline conditions, or even at room temperature, As shown in Process A below: [0003] Process A [0004] [0005] Therefore, a certain amount of impurity A is produced during the preparation and purification process of lubiprostone, as shown in Scheme A. Impurity A is considered to be the major degradation product or major impurity of lubiprostone. Although imp...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D311/94
CPCC07D311/94C07B2200/13B01D9/0054B01D9/0077B01D9/0022B01D2009/0086B01D9/0004B01D9/0036C07C405/00A61K31/352A61P1/00
Inventor 魏士益郑建邦
Owner CHIROGATE INT