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Bortezomib crystal form J and preparation method thereof

A bortezomib and crystal form technology, applied in the field of bortezomib crystal form J and its preparation, can solve problems affecting drug quality, safety, effectiveness and its application, affecting drug stability, solubility and bioavailability, Appearance, physical and chemical properties and differences in biological activity, etc., to achieve the effect of low changes in pH and impurity content, simple preparation method, and stable labeled content

Active Publication Date: 2014-03-05
CHONGQING SINTAHO PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] Different crystal forms of the same compound have the same chemical composition but different microscopic crystal structures, which lead to differences in their appearance, physicochemical properties and biological activities
These characteristics directly affect the preparation performance of the drug, and will affect the stability, solubility and bioavailability of the drug, which in turn will affect the quality, safety, effectiveness and application of the drug

Method used

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  • Bortezomib crystal form J and preparation method thereof
  • Bortezomib crystal form J and preparation method thereof
  • Bortezomib crystal form J and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] Embodiment 1: Preparation of bortezomib crystal form J

[0056] Add 300 mL of a mixed solution of ethyl acetate and toluene (the volume fraction of ethyl acetate is 10%) to 35 g of crude bortezomib, stir at room temperature for 3 hours, filter, and use a mixed solution of ethyl acetate and toluene (with acetic acid The volume fraction of ethyl ester is 5%), and then washed twice with methyl tert-butyl ether, suction filtered, and the filter cake was dried to obtain the finished product of bortezomib. The refined product was added to 150ml of ethyl acetate, spin-dried under reduced pressure at 40°C, and dried under reduced pressure at 40°C for 20 hours to obtain 19.5g of the new crystal J of bortezomib. The purity detected by HPLC is ≥99.85%, and the residue of ethyl acetate detected by GC is 2200ppm.

Embodiment 2

[0057] Embodiment 2: Preparation of bortezomib crystal form J

[0058] Add 80 mL of a mixed solution of ethyl formate and toluene (the volume fraction of ethyl formate is 12%) to 13 g of bortezomib crystals of amorphous form J, stir at room temperature for 3 h, filter, and filter the cake with a mixture of ethyl formate and toluene The mixed solution (wherein the volume fraction of ethyl formate is 12%) was washed, suction filtered, and the filter cake was dried under reduced pressure for 24 hours to obtain 11.8 g of the new crystal form J of bortezomib. HPLC detection purity ≥ 99.81%.

Embodiment 3

[0059] Embodiment 3: Preparation of bortezomib crystal form J

[0060] Add 350 mL of 5% methyl formate / toluene mixed solution to 27 g of bortezomib mixed crystals, stir at room temperature for 5 hours, filter, wash the filter cake with 5% methyl formate / toluene mixed solution, and then wash with methyl tert-butyl ether Wash twice, filter with suction, and dry the filter cake to obtain the finished product of bortezomib. The refined product was added to 200ml of methyl formate, spin-dried under reduced pressure at 40°C, and dried under reduced pressure at 40°C for 12 hours to obtain 25.4g of the new crystal J of bortezomib. The purity detected by HPLC is ≥99.83%, and the residual methyl formate is 2100ppm detected by GC. Embodiment 4: Preparation of bortezomib crystal form J

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Abstract

The invention relates to the field of medicinal chemistry, and relates to a bortezomib crystal form J and a preparation method thereof. On, X-ray powder diffraction diagram of the bortezomib crystal form J provided by the invention has peaks when 2-theta is at 3.12, 4.66, 6.18, 8.58, 9.44, 10.33, 11.95, 12.29, 14.68, 16.28, 17.84, 20.25, 21.33, 22.57, 23.38, 24.71, 26.85, 28.05, 28.01 and 37.45+ / - 0.2 degrees. Meanwhile, the invention provides a preparation method of the crystal form. The bortezomib crystal form J provided by the invention has the characteristics of high stability, high purity, and simple and convenient preparation method.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to bortezomib crystal form J and a preparation method thereof. Background technique [0002] Bortezomib, trade name Velcade, chemical name: [(1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyridine Azicarboxyl) amino] propyl] amino] butyl] - boronic acid, the molecular formula is C 19 h 25 BN 4 o 4 , which has a structure as shown in formula I: [0003] [0004] Bortezomib is a new anti-tumor drug developed by Millennium Pharmaceutical Company of the United States. It is a synthetic, highly selective, reversible inhibitor of chymotrypsin-like activity of the 26S proteasome, which can induce apoptosis in a variety of tumor cell lines and cancerous cells. , can significantly enhance the efficacy of certain chemotherapeutic drugs and ionizing radiotherapy inducing tumor cell apoptosis, while the toxic effect on normal cells is relatively small. Studies have confirmed that at 1.3mg...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/078C07K1/30
Inventor 吴进朱小峰姚全兴李靖
Owner CHONGQING SINTAHO PHARM CO LTD