Industrialized production method for erlotinib hydrochloride B type crystal

A technology of erlotinib hydrochloride and erlotinib, which is applied in the field of producing erlotinib hydrochloride B-type crystal, can solve the problems of expensive acetonitrile, environmental pollution, and affecting the total yield, and achieves simple method and high yield , The effect of the method is simple and easy

Active Publication Date: 2013-12-04
CHONGQING HUAPONT PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] This method can only obtain a mixture of type A crystal and type B crystal. If pure type B crystal is to be obtained, special crystal transformation is also required; in addition, toxic solvents such as chloroform and ether are used, which will cause environmental pollution. Not suitable for industrial production
[0010] In the prior art, there are also people who first prepare the crude product of erlotinib hydrochloride, and then recrystallize with acetone or acetone and water, erlotinib hydrochloride type B crystal, which needs to carry out two steps, instead of using erlotinib to form The salt method obtains erlotinib hydrochloride type B crystal in one step, and it will affect the total yield
[0011] Others generate Erlotinib Hydrochloride B-type crystal with HCl gas in acetonitrile. For industrialized large-scale production, acetonitrile is relatively expensive and not environmentally friendly.

Method used

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  • Industrialized production method for erlotinib hydrochloride B type crystal
  • Industrialized production method for erlotinib hydrochloride B type crystal

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Experimental program
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Effect test

preparation example Construction

[0036] 1. The preparation method of raw material Erlotinib is:

[0037] Type I crystal, type II crystal and type III crystal of erlotinib are prepared according to the method of CN101547910A; type G1 crystal, type G2 crystal, type G3 crystal and amorphous type of erlotinib are prepared according to the method of US2009012295.

[0038] 2. HPLC detection conditions are:

[0039] Chromatographic column: Agilent Eclipse XDB C8 (4.6×150mm×5μm), mobile phase: acetonitrile: 0.05mol / L potassium dihydrogen phosphate (42:58), injection volume: 20μl, column temperature: 30°C, detection wavelength: 247nm.

[0040] 3. X-powder diffraction conditions are:

[0041] Scanning instrument: German BRUKER D8 DISCOVER X-ray diffractometer, scanning conditions: CuKα radiation, tube voltage 40KV, tube current 40mA, scanning range 5~60 degrees. The scanning step is 0.02 degrees, and the scanning speed is 2.4 degrees / minute.

[0042] 4. The concentration of hydrochloric acid is the mass concentratio...

Embodiment 1

[0043] Example 1 Preparation of Erlotinib Hydrochloride Type B Crystal 393.17 with Erlotinib Mixed Crystal

[0044] Add 3500g of erlotinib mixed crystals (obtained according to the method of CN1066142C Example 20) and 35L of acetone into the reaction kettle at room temperature, start stirring, and heat in a water bath to completely dissolve erlotinib. Add 9.8 mol of hydrogen chloride gas to the solution.

[0045] After passing through, the reaction system was left to cool down slowly, and a large amount of solids were precipitated. After the reaction system no longer precipitates solids, centrifuge and dry under reduced pressure to obtain 3523g of finished product, the yield is 92.2%, the HPLC content is 99.1%, and the 2θ values ​​measured by X-powder diffraction are: 6.259, 12.527, 13.402, 16.997, 20.224, 21.127 , 22.990, 24.493, 25.168, 26.923 (type B crystal).

Embodiment 2

[0046] Example 2 Preparation of Erlotinib Hydrochloride Type B Crystal with Erlotinib Type II Crystal

[0047] Add 3500g of erlotinib type II crystal, 77L of acetone, and 77L of purified water into the reaction kettle at room temperature, start stirring, and heat in a water bath to completely dissolve erlotinib. Add 4.4 L of 37% hydrochloric acid and continue stirring for 40 minutes.

[0048] The temperature of the reaction system was slowly lowered with a cold water bath. After a large amount of solids were precipitated, the temperature was then lowered with an ice water bath until no solids were precipitated in the reaction system. After centrifugation and drying under reduced pressure, 3638g of the finished product was obtained, the yield was 95.2%, the HPLC content was 99.8%, and the 2θ values ​​measured by X-powder diffraction were: 6.250, 12.516, 13.381, 16.987, 20.223, 21.187, 22.972, 24.482, 25.226, 26.915 ( B-type crystal).

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Abstract

An industrialized production method for erlotinib hydrochloride B type crystal comprises: reacting a raw material erlotinib with hydrogen chloride, and after the reaction cooling and precipitating a crystal to obtain the finished product erlotinib hydrochloride B type crystal, wherein the reaction solvent is acetone or a mixture of acetone and water. The usable raw materials of the method comprise erlotinib amorphous solid or crystal, wherein the crystal form of the crystal is unlimited and can be a singular crystal form or a mixed crystal form. The method is simple, has no crystal form conversion step, is applicable to industrialized production, and has no toxic and harmful solvents needed and no pollution to environment; and product purity reaches 99% or more and product yield reaches 95% or more.

Description

technical field [0001] The invention relates to a method suitable for large-scale industrial production of erlotinib hydrochloride type B crystal. Background technique [0002] Erlotinib hydrochloride is an anti-tumor drug developed by OSI. [0003] [0004] Erlotinib hydrochloride has a variety of crystal forms, known as A-type, B-type, E-type, M-type, N-type, P-type, L-type, etc., wherein the B-type crystal is relatively stable, and CN100351241C records erlotinib hydrochloride The X-powder diffraction 2θ values ​​of Tini B crystal are: 6.26, 12.48, 13.39, 16.96, 20.20, 21.10, 22.98, 24.46, 25.14, 26.91. [0005] Regarding the preparation method of type B crystal, the following methods are recorded in the prior art: [0006] CN100351241C discloses a method for preparing erlotinib hydrochloride type B crystal: 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline and 3-ethynylaniline are reacted in acetonitrile to generate Erlotinib hydrochloride was crystallized, and then the ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/94
Inventor 李伟高太平
Owner CHONGQING HUAPONT PHARMA
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