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Preparation method of erlotinib base monohydrate crystal form I

A technology for erlotinib base and monohydrate, which is applied in the field of preparation of erlotinib base monohydrate crystal form Form I, can solve the problems of single solvent type, complicated operation, lack of extensiveness and the like, and achieves purity High, simple operation, safe and environmentally friendly process route

Active Publication Date: 2014-12-24
SHANDONG JINCHENG PHARMACEUTICAL GROUP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Above-mentioned two all have more obvious defect, (1) method extraction, liquid separation, drying, the processing route of steaming solvent, industrialization process operation is complicated; Erlotinib base monohydrate crystal form Form I, the type of solvent used is single, not extensive

Method used

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  • Preparation method of erlotinib base monohydrate crystal form I
  • Preparation method of erlotinib base monohydrate crystal form I
  • Preparation method of erlotinib base monohydrate crystal form I

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Add 10.0g of erlotinib hydrochloride, 0.93g of sodium hydroxide, and 60ml of methanol to a clean and dry 250ml reaction bottle, stir at room temperature for 0.5h, take 1.0ml of the reaction solution, add 0.5ml of water, and the reaction solution becomes clear to indicate the reaction After completion, the reaction solution was added dropwise to 120ml of water for 0.5h. After the dropwise addition was completed, under stirring, the temperature was lowered to 0-5°C, filtered with suction, and the filter cake was vacuum-dried at 20°C to obtain a white solid. 8.2 g, yield 89.5%, HPLC purity 99.8%.

Embodiment 2

[0032] Add 10.0g of erlotinib hydrochloride, 1.24g of sodium carbonate, 60ml of methanol to a clean and dry 250ml reaction bottle, stir at room temperature for 1.0h, take 1.0ml of the reaction solution, add 0.5ml of water, the reaction solution becomes clear, indicating that the reaction is complete , add the reaction solution dropwise to 240ml of water, and the dropping time is 0.5h. After the dropwise addition, under stirring, cool down to 0-5°C, filter with suction, and vacuum-dry the filter cake at 20°C to obtain a white solid, 8.3 g, yield 90.6%, HPLC purity 99.7%.

Embodiment 3

[0034] Add 10.0g of erlotinib hydrochloride, 1.4g of sodium hydroxide, and 30ml of dioxane to a clean and dry 250ml reaction bottle, stir at room temperature for 1.0h, take 1.0ml of the reaction solution, add 0.5ml of water, and the reaction solution becomes Clarify that the reaction is complete. Add the reaction solution dropwise to 60ml of water for 0.5h. After the dropwise addition, under stirring, cool down to 0-5°C, filter with suction, and dry the filter cake in vacuum at 50°C to obtain White solid, 8.1 g, yield 88.4%, HPLC purity 99.6%.

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Abstract

The invention belongs to the technical field of pharmaceutical chemicals, and in particular relates to a preparation method of an erlotinib base monohydrate crystal form I. The preparation method comprises the following steps: stirring and mixing erlotinib hydrochloride, base and an organic solvent, or stirring and mixing erlotinib base and an organic solvent; dropwise adding a solution system after an reaction or after being classified to water under a stirring condition; while stirring, decreasing temperature to 0-5 DEG; and filtering and drying in a vacuum environment to obtain erlotinib base monohydrate crystal form I. The erlotinib base monohydrate crystal form I is prepared by crystallization at room temperature through an organic solvent which is cheap, easy to prepare, green and environment-friendly; and the preparation method is safe and environment-friendly in process route, simple to operate, low in cost, good in repeatability, stable, applicable to industrial production and quite high in economic value. The prepared erlotinib base disclosed by the invention has high purity, and can be used for preparing erlotinib hydrochloride high in purity.

Description

technical field [0001] The invention belongs to the technical field of medicine and chemical industry, and in particular relates to a method for preparing erlotinib base monohydrate crystal form Form I. Background technique [0002] Erlotinib base, also known as Erlotinib, chemical name: 4-(3-ethynylphenylamino)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine. Erlotinib base was listed in the United States in the form of hydrochloride in 2004. It is a reversible inhibitor of epidermal growth factor tyrosinase (EGFR) and is suitable for locally advanced and or metastatic non-small cell lung cancer. The structural formula is as follows: [0003] [0004] The patent US5747498 first disclosed the preparation method of erlotinib hydrochloride. The preparation method of erlotinib base mentioned in the patent is separated and purified by silica gel column, and the crystal form of erlotinib base is not mentioned in the patent. . [0005] At present, the disclosed process routes for...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/94
CPCC07D239/94
Inventor 伊茂聪孙滨马庆双南红燕
Owner SHANDONG JINCHENG PHARMACEUTICAL GROUP CO LTD
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