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Crystal form of bortezomib key intermediate, and preparation method and application of crystal form

A technology of bortezomib and crystal form, which is applied in the field of high-purity bortezomib API products, can solve the problems of no research, no study of crystallization conditions, no provision of crystal form and crystal preparation method, etc., to achieve stable properties, Ease of storage and transport

Inactive Publication Date: 2014-07-02
朱继东
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] This compound is described in patents WO2010114982 and WO2011087822. The patent only pointed out a method for preparing compound II, but only listed the NMR data of the structural study of the compound, and did not provide a stable crystal form and crystal preparation method, and did not The study of the process of the key intermediate from the solvation state in a certain spatial order to form a solid (that is, the crystallization process) did not study the conditions of crystallization, the type of crystallization, and its stability characteristics, and did not point out that the compound is in The important role of bortezomib in the purification of raw materials

Method used

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  • Crystal form of bortezomib key intermediate, and preparation method and application of crystal form
  • Crystal form of bortezomib key intermediate, and preparation method and application of crystal form
  • Crystal form of bortezomib key intermediate, and preparation method and application of crystal form

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050]

[0051] Dissolve 4.6 grams of compound Ia (prepared according to the document J.Am.Chem.Soc.2008, 130, 6910-6911) in ethyl acetate, add 2.6 grams of diethanolamine, and stir at room temperature for 12 hours, that is, a large amount of solids precipitate out , filtered to obtain the crude product of Compound II, and washed the filter cake with ethyl acetate to obtain 4.0 g of α-form crystal product of Compound II (yield 88.4%).

Embodiment 2

[0053]

[0054] Dissolve 5.2 grams of compound Ib (prepared according to patent CN200580017645) in methanol, add 2.6 grams of diethanolamine, stir at room temperature for 24 hours, a large amount of solids precipitate out, filter to obtain the crude compound II, wash the filter cake with methanol to obtain 4.4 grams The α-form crystal product of compound II (yield 97.3%).

Embodiment 3

[0056]

[0057] Dissolve 4.5 g of compound Ic (prepared according to patent CN201210147057) in tert-butyl methyl ether, add 2.6 g of diethanolamine, stir at room temperature for 24 hours, a large amount of solids precipitate out, filter to obtain the crude compound II, and wash the filter cake with tert-butyl methyl ether That is, 4.2 g of α-form crystal product of compound II was obtained (yield 92.9%).

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Abstract

The invention discloses a novel crystal form of a bortezomib key intermediate II for the first time, provides a novel crystal form of a bortezomib key intermediate, namely (2S)-N-[(1R)-1-(1,2,6,2-dioxo-aza-boron-octane-2-yl)-3-methyl butyl]-3-phenyl-2-pyrazine-2-yl-formamido) propanamide (compound II), namely an alpha crystal form, and discloses a preparation of the compound II, a preparation method of the alpha crystal form, and a method for preparing high-purity bortezomib by using the alpha crystal form intermediate II. The alpha crystal form of the compound II is stable in property, and is conductive to purification of the bortezomib, long-term storage under conventional storage and transportation conditions and especially, development of industrial purification of the bortezomib.

Description

Technical field: [0001] The present invention specifically relates to a new crystal form of the key intermediate II of bortezomib and a preparation method thereof, and a high-purity bortezomib bulk drug product obtained by purifying the new crystal form of the key intermediate II of bortezomib. Background technique: [0002] Bortezomib (Bortezomib), trade name ( Ten thousand ) is a new type of anti-tumor drug developed by the American Millennium Pharmaceutical Company. It is a synthetic dipeptide boronic acid derivative. The drug is a 26S protease inhibitor. , leading to tumor cell death. A large number of studies have found that bortezomib has strong anti-tumor activity against various tumors, especially multiple myeloma, mantle cell lymphoma, other B-cell lymphoma, and Hodgkin's lymphoma in hematological tumors. In addition, bortezomib is used in combination with chemotherapy drugs to treat acute myeloid leukemia, acute lymphoblastic leukemia, and adult T lymphocytic ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/078C07K1/107C07K1/14
Inventor 朱继东
Owner 朱继东
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