New crystal form of pemetrexed diacid and preparation method thereof

A crystal form, dihydrogen technology, applied in the field of medicinal chemistry, can solve the problems of long preparation time, difficult separation, and difficult removal, etc., and achieves the effect of simple preparation method, small electrostatic effect, and improved quality.

Active Publication Date: 2017-03-08
JIANGSU HANSOH PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The pemetrexed diacids FromC, FromD and FromE disclosed in the patent US20080045711 have a higher boiling point, which is difficult to remove in the process of preparing pemetrexed disodium, which is not conducive to the quality of the product; although FromA and FromB overcome The shortcomings of the previous crystal forms are overcome, but the preparation yield of FromA is low and has no practicability; the preparation time of FromB is long, and only crystallization will take 18 hours, which is not conducive to production economy; the pemetrexed reported in patent CN101684121A The preparation yield of FormH in the diacid crystal form is low (about 60%), and the water content is as high as 75%, which is not conducive to filtration and difficult to dry; the crystals in the preparation process of FormI and FormJ are viscous and difficult to separate, which is not suitable for industrial production.

Method used

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  • New crystal form of pemetrexed diacid and preparation method thereof
  • New crystal form of pemetrexed diacid and preparation method thereof
  • New crystal form of pemetrexed diacid and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036]N-{4-[2-(2-Amino-4,7-dihydro-4-oxo-1H-pyrrole[2,3-d]pyrimidin-5-yl)ethyl]benzoyl}-L - Add 10.0 g of dibenzyl glutamate to 200 ml of NaOH aqueous solution (2 mol / L), heat to 50° C., stir for 4 hours, and filter. Add 250ml of absolute ethanol to the filtrate, adjust the pH to 2-3 with dilute hydrochloric acid, and precipitate a large amount of solids. The crystallization system was heated to 55-65° C., stirred for 1 hour, cooled, filtered, and dried to obtain 6.9 g of crystal form X with a molar yield of 96%.

[0037] After testing and verification, its X-ray powder diffraction pattern is as follows: figure 1 As shown, its DSC spectrum, TGA spectrum and figure 2 and image 3 Matched, proving that the obtained crystal form is crystal form X.

[0038] During the process of filtering the crystals obtained in this example after being precipitated from the crystallization system, the filtrate flowed down in lines, and there was no clogging phenomenon in the whole process, ...

Embodiment 2

[0041] N-{4-[2-(2-Amino-4,7-dihydro-4-oxo-1H-pyrrole[2,3-d]pyrimidin-5-yl)ethyl]benzoyl}-L - Add 10.0 g of dibenzyl glutamate to 200 ml of NaOH aqueous solution (2 mol / L), heat to 50° C., stir for 4 hours, and filter. Add 250ml of acetone to the filtrate, adjust the pH to 2-3 with dilute sulfuric acid, and precipitate a large amount of solids. The crystallization system was heated to 55-65° C., stirred for 1 hour, cooled, filtered, and dried to obtain 6.7 g of crystal form X with a molar yield of 93%.

[0042] After testing and verification, its X-ray powder diffraction pattern is as follows: figure 1 As shown, its DSC spectrum, TGA spectrum and figure 2 and image 3 Matched, proving that the obtained crystal form is crystal form X.

Embodiment 3

[0044] N-{4-[2-(2-Amino-4,7-dihydro-4-oxo-1H-pyrrole[2,3-d]pyrimidin-5-yl)ethyl]benzoyl}-L - Add 10.0 g of dibenzyl glutamate to 200 ml of NaOH aqueous solution (2 mol / L), heat to 50° C., stir for 4 hours, and filter. Add 250ml of anhydrous methanol to the filtrate, adjust the pH to 2-3 with acetic acid, and precipitate a large amount of solids. The crystallization system was heated to 55-65° C., stirred for 1 hour, cooled, filtered, and dried to obtain 6.7 g of crystal form X with a molar yield of 93%.

[0045] After testing and verification, its X-ray powder diffraction pattern is as follows: figure 1 As shown, its DSC spectrum, TGA spectrum and figure 2 and image 3 Matched, proving that the obtained crystal form is crystal form X.

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Abstract

The invention discloses a new crystal form of pemetrexed diacid and a preparation method thereof. Specifically, the invention relates to a new crystal form of N-{4-[2-(2-amino-4, 7-dihydro-4-oxy-1 H-pyrrole [2, 3-d] pyrimidine-5-yl) ethyl] benzoyl}-L-glutamate dehydrate and a preparation method thereof, wherein an XRPD (X-ray powder diffraction) spectrum of the new crystal form at least contains diffraction peaks of 2theta + / -0.20 degree of 5.7, 11.5, 12.3, 18.4, 20.3, 27.6 and 28.1. The new crystal form has the advantages of good stability, high purity, simple preparation and easy operation, and is suitable for industrial production.

Description

technical field [0001] The present invention relates to the field of medicinal chemistry, in particular to N-{4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrole[2,3-d]pyrimidin-5-yl)ethyl Base]benzoyl}-L-glutamic acid dihydrate new crystal form and its preparation method and pharmaceutical use. Background technique [0002] N-{4-[2-(2-Amino-4,7-dihydro-4-oxo-1H-pyrrole[2,3-d]pyrimidin-5-yl)ethyl]benzoyl}-L- Glutamic acid dihydrate (formula I, pemetrexed diacid) has the following structure: [0003] [0004] N-{4-[2-(2-Amino-4,7-dihydro-4-oxo-1H-pyrrole[2,3-d]pyrimidin-5-yl)ethyl]benzoyl}-L- Glutamic acid dihydrate (I) is an antifolate metabolite, which enters cells through reduced folic acid carrier, α-folate receptor and diprotic folic acid carrier, and rapidly generates polyglutamine in vivo catalyzed by folic acid polyglutamic acid synthase Pemetrexed acid; more stable and better affinity for target enzymes than monomer, N-{4-[2-(2-amino-4,7-dihydro-4-oxo-1H -pyrrole[2,3-d...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/519A61K9/08A61P35/00
CPCA61K9/0019C07B2200/13C07D487/04
Inventor 徐进王艳军张小兵赵军军
Owner JIANGSU HANSOH PHARMA CO LTD
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