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Monomethyl auristatin E crystal and preparation method thereof

A crystal form and system technology, which is applied in the crystal of monomethyl auristatin E and its preparation, and the application field of preparation of drug conjugates, can solve the problems affecting the safety and effectiveness of drug conjugates, complicated operations, Poor stability and other issues

Active Publication Date: 2021-07-16
COHERENT BIOPHARMA (SUZHOU) LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] However, currently commercially available monomethyl auristatin E is an amorphous solid, and there is no document or patent reporting the free crystal of monomethyl auristatin E
Because amorphous MMAE is easy to deliquescence and has poor stability, it is not conducive to long-term storage; in addition, amorphous MMAE also has the problem of low purity, which leads to more impurities in drug conjugates prepared by using amorphous MMAE, and subsequent purification is difficult, which affects drug conjugation drug safety and efficacy
[0005] In US2015 / 23989 and CN109200291A, the purification method of reversed-phase liquid phase preparation is used to purify MMAE, which has low yield, complicated operation and high cost

Method used

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  • Monomethyl auristatin E crystal and preparation method thereof
  • Monomethyl auristatin E crystal and preparation method thereof
  • Monomethyl auristatin E crystal and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] Example 1, Preparation of monomethyl auristatin E crystal form A

[0058] Monomethyl auristatin E (0.65g, HPLC: 98.8%) was added to ethyl acetate (2.6mL) and stirred until dissolved, then purified water (28.0mg) was added, stirred evenly, the water content was 1.03% by coulometric titration, and the temperature was lowered to 2.5°C, stirred for 15-20 hours, a large amount of solids precipitated, added dropwise methyl tert-butyl ether (2.6 mL), stirred for 1-2 hours, added dropwise n-heptane (13.0 mL), continued to stir for 2-4 hours, filtered , the solid was rinsed with n-heptane (0.6 mL), and dried under vacuum at 40°C to obtain monomethyl auristatin E crystals.

Embodiment 2

[0059] Example 2, Preparation of monomethyl auristatin E crystal form A

[0060] Monomethyl auristatin E (0.65g, HPLC: 98.8%) was added to ethyl acetate (2.6mL) and stirred until dissolved, then purified water (28.0mg) was added, stirred evenly, and the water content was detected to be 1.03% by coulometric titration, and added Seed crystals (25.0mg), cooled to 2.5°C, stirred for 15-20h, a large amount of solid precipitated, added dropwise methyl tert-butyl ether (2.6mL), stirred for 1-2 hours, added dropwise n-heptane (13.0mL), Stirring was continued for 2-4 hours, filtered, the solid was rinsed with n-heptane (0.6 mL), and dried under vacuum at 40°C to obtain monomethyl auristatin E crystals (0.96 g), HPLC: 99.4%.

Embodiment 3

[0061] Example 3, Preparation of monomethyl auristatin E crystal form A

[0062] Monomethyl auristatin E (1.00g, HPLC: 98.8%) was added with isopropyl acetate (4.0mL) and stirred until dissolved, then purified water (51.1mg) was added, stirred evenly, and the moisture content was detected by coulometric titration to be 1.21%. Add seed crystals (40.0mg), cool down to 2.5°C, stir for 15-20h, a large amount of solid precipitates, add methyl tert-butyl ether (4.0mL) dropwise, stir for 1-2 hours, add n-heptane (20.0mL) dropwise , continue to stir for 2-4 hours, filter, rinse the solid with n-heptane (1.0 mL), and dry under vacuum at 40°C to obtain monomethyl auristatin E crystals (0.95 g), HPLC: 99.5%.

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Abstract

The invention provides a monomethyl auristatin E crystal form A and a preparation method thereof, a pharmaceutical composition containing the crystal form A, and application of the crystal form A in preparation of pharmaceutical conjugates. The crystal form A is high in purity, good in stability, low in hygroscopicity and especially suitable for industrial application, and the defects that in the prior art, amorphous MMAE is low in purity, poor in stability and not suitable for storage, and when the amorphous MMAE is used for preparing conjugates, the requirement for reaction equipment is high, and operation is complex are overcome; and secondly, the preparation method of the MMAE crystal form A provided by the invention is simple to operate, the prepared crystal form is high in purity and uniform in particle size distribution, the production cost is reduced, and the preparation method is suitable for commercial production amplification.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a crystal of monomethyl auristatin E and a preparation method thereof, a pharmaceutical composition containing the crystal, and the application of these crystal forms in the preparation of drug conjugates. Background technique [0002] Monomethyl auristatin E (abbreviated as MMAE, structural formula as shown in formula (I)), is a synthetic dopamine 10 derivative, has a very effective anti-mitotic effect, it blocks the polymerization of tubulin To inhibit cell division and achieve the purpose of anti-tumor. Like vinblastine, it belongs to anti-microtubule drugs, but its toxicity is about 200 times that of vinblastine. Because the toxicity is too high, it cannot be used by direct intravenous infusion, so it can only exert its lethality in drug conjugates (ADC drugs). So far, among the ADC drugs that have been marketed, there are bentuximab developed by Sea...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/027C07K1/02A61K38/07A61P35/00
CPCC07K5/0205A61P35/00A61K38/00
Inventor 毛声飞邵军潘昌明沙飞王贵涛黄保华
Owner COHERENT BIOPHARMA (SUZHOU) LTD
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