3-(substituted xylylenimine-2-yl)-2,6-piperidine diketone polymorph and medical composition

A polymorph, isoindole technology, applied in the field of 3-(substituted dihydroisoindol-2-yl)-2,6-piperidinedione polymorph and pharmaceutical composition, capable of Solve problems such as unfavorable industrial scale preparation and no consideration

Active Publication Date: 2013-05-08
NANJING CAVENDISH BIO ENG TECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Since 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione is almost insoluble in water or hexane, toluene, acetone , acetonitrile, methyl alcohol, ethyl acetate and other organic solvents, even under the heating situation, a large amount of (more than 100 times) solvents need to be used, which is not conducive to industrial scale preparation; in addition, this method of application document CN 1871003A cannot make the appearance color of the product It has been improved from the original light yellow to white or off-white; and it has not been considered that the use of (such as toluene, acetonitrile, etc.) harmful to the human body (such as toluene, acetonitrile, etc.) should be avoided as much as possible when the final product is synthesized. There will be residual organic solvents in the product, which will cause adverse effects on the human body

Method used

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  • 3-(substituted xylylenimine-2-yl)-2,6-piperidine diketone polymorph and medical composition
  • 3-(substituted xylylenimine-2-yl)-2,6-piperidine diketone polymorph and medical composition
  • 3-(substituted xylylenimine-2-yl)-2,6-piperidine diketone polymorph and medical composition

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0199] Preparation of polymorph I:

[0200] Add 100 g of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione to 400 ml of DMF (or 300 ml of DMSO) In the solution, stir and heat to make it dissolve, add dropwise 1600 milliliters of pure water (or a mixed solvent system of 1000 milliliters of pure water and 600 milliliters of organic solvent (such as water and acetone, acetonitrile, ethyl acetate, dichloromethane, isopropanol, methanol , ethanol and other 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione insoluble organic solvents or binary or binary or more mixed system), slowly lower the temperature under stirring to precipitate the solid, recover the solid, and dry it under reduced pressure to obtain 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindoline Indol-2-yl)piperidine-2,6-dione polymorph I.

[0201] DMF / water system: the product weighs 78 grams, and the yield is 78%;

[0202] DMSO / water system: the product weighed 90 grams, and the yield was 90...

Embodiment 2

[0205] Preparation of polymorph II:

[0206] Add 100 g of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione to 400 ml of anhydrous DMF, stir and heat to It dissolves; add 1800 milliliters of anhydrous ethanol (or 1600-2000 milliliters of single or mixed solvents such as methanol, acetone, ethyl acetate, acetonitrile, dichloromethane, acetonitrile) dropwise, slowly cool down under stirring to precipitate solids, and recover solids , dried in vacuo under reduced pressure to obtain 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione polymorph II.

[0207] The product weighed 72 grams, and the yield was 72%.

[0208]

Embodiment 3

[0210] Preparation of polymorph III:

[0211] Add 100 g of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione into 300 ml of anhydrous DMSO, stir slowly Slowly heat to make it dissolve, add dropwise 2000 ml of anhydrous ethanol (other optional organic solvents such as: methanol, acetone, ethyl acetate, acetonitrile, dichloromethane, etc. 3-(4-amino-1-oxo- 1,3-dihydro-2H-isoindol-2-yl) piperidine-2,6-dione insoluble single or mixed solvents), slowly cool down under stirring to precipitate solids, reclaim the solids, depressurize and vacuum Drying affords 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione polymorph III.

[0212] Product weight: 86 grams, yield 86%.

[0213]

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PUM

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Abstract

The invention discloses a polymorph of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidine-2,6-diketone. In addition, the invention discloses a preparation method and a medical composition of the polymorph.

Description

[0001] This application is submitted on November 2, 2009. The application number is 200910210392.3, and the invention name is "3-(substituted dihydroisoindol-2-yl)-2,6-piperidinedione polymorph and medicinal A divisional application of the "composition" application. technical field [0002] The present invention relates to polymorphic forms of pharmaceutical compounds, more particularly to 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2, The polymorphic form of 6-diketone, in addition, the present invention also relates to the preparation method of the polymorphic form and its pharmaceutical composition. Background technique [0003] Muller et al. described in "Amino-substituted thalidomide analogs: Potent inhibitors of TNF-αproduction" (Bioorganic & Medicinal Chemistry Letters, Vol.9, Issue 11, June 7, 1999, pp1625-1630) and Chinese patent ZL97180299.8 A 3-(substituted dihydroisoindolin-2-yl)-2,6-piperidinedione, especially 3-(4-amino-1-oxo-1,3-dihydro-2H- isoi...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/04A61K31/454A61P35/00A61P29/00A61P27/02A61P7/06A61P25/00A61P25/20A61P9/12A61P11/00A61P17/00A61P37/00A61P25/28A61P43/00
Inventor 杨浩严荣许永翔
Owner NANJING CAVENDISH BIO ENG TECH
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