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Synthetic method of erlotinib intermediate

A synthetic method and intermediate technology, applied in the field of drug synthesis, can solve problems such as research, achieve the effects of short reaction time, high reaction yield, and improved drug safety

Inactive Publication Date: 2020-05-01
SHANDONG LUOXIN PARMACEUTICAL GROUP STOCK CO LTD +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] And prior art all adopts triacetylene aniline to participate in reaction, contains above warning structure in triacetylene aniline, but prior art does not carry out research to this kind of impurity, for pharmaceutical engineering, should reduce as far as possible the impurity as reaction by-product content, improve drug safety

Method used

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  • Synthetic method of erlotinib intermediate

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Experimental program
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Effect test

Embodiment 1

[0029] Embodiment 1: the synthesis of compound 3

[0030] in N 2 Under protection, 2-bromo-4,5-dimethoxybenzonitrile (50mmol), formamidine hydrochloride (55mmol), N,N'-dimethylethylenediamine (5mmol), K 2 CO 3 (100mmol) was dissolved in 150mL 1,4-dioxane, stirred for 10min, then CuI (2mmol) was added, heated to reflux for 2.5h, after the reaction was completed, cooled to room temperature, filtered, the filter cake was washed, and the filtrate and washing liquid were combined , The solvent was distilled off under reduced pressure, and the crude product was recrystallized from methanol, filtered and dried to obtain 9.303g of compound 3 with a yield of 90.60% and a purity of 99.92%.

Embodiment 2

[0031] Embodiment 2: the synthesis of compound 3

[0032] in N 2 Under protection, 2-bromo-4,5-dimethoxybenzonitrile (50mmol), formamidine hydrochloride (50mmol), N,N'-dimethylethylenediamine (0.5mmol), K 2 CO 3 (75mmol) was dissolved in 150mL 1,4-dioxane, stirred for 10min, then added CuI (1mmol), heated to reflux for 2.5h, after the reaction was completed, cooled to room temperature, filtered, washed the filter cake, and combined the filtrate and washing liquid , The solvent was distilled off under reduced pressure, and the crude product was recrystallized from methanol, filtered and dried to obtain 8.477g of compound 3 with a yield of 80.49% and a purity of 97.42%.

Embodiment 3

[0033] Embodiment 3: the synthesis of compound 3

[0034]in N 2 Under protection, 2-bromo-4,5-dimethoxybenzonitrile (50mmol), formamidine hydrochloride (60mmol), N,N'-dimethylethylenediamine (10mmol), K 2 CO 3 (125mmol) was dissolved in 150mL 1,4-dioxane, stirred for 10min, then added CuI (5mmol), heated to reflux for 2.5h, after the reaction was completed, cooled to room temperature, filtered, washed the filter cake, and combined the filtrate and washing liquid , the solvent was distilled off under reduced pressure, and the crude product was recrystallized from methanol, filtered and dried to obtain 8.806g of compound 3 with a yield of 84.34% and a purity of 98.27%.

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Abstract

The invention relates to a synthesis method of an erlotinib intermediate, which comprises the following steps: reacting 2-bromo-4,5-dimethoxybenzonitrile with formamidine hydrochloride under the actions of alkali and a catalyst to generate a compound 3; reacting with 1-bromo-triethynylbenzene under the catalysis of alkali to generate a compound 2; carrying out a reaction on the compound 2 with 48%hydrobromic acid under the action of a catalyst to obtain a compound 1. The method is mild in condition, simple in step, safe, environmentally friendly and suitable for industrial production.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a method for synthesizing an erlotinib intermediate. Background technique [0002] Erlotinib, chemical name: N-3-(ethynyl-phenyl)-6,7-bis-(2-methoxyethoxy)-4-quinazolinamine, chemical structural formula: [0003] [0004] Erlotinib is a tyrosine kinase receptor inhibitor, a cancer treatment drug jointly developed by Roche, OSI Biopharmaceutical Company and Genentech Pharmaceutical Company. An innovative drug for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) that has failed at least one chemotherapy regimen. Erlotinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TK), which can selectively block human epidermal growth factor receptor (EGFR) tyrosine kinase and reduce EGFR's own Phosphorylation, which leads to cell growth arrest and apoptosis, is a potent inhibitor of phosphocompounds in EGFR-overexpressing tumor cells...

Claims

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Application Information

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IPC IPC(8): C07D239/94B01J31/04C07D233/58
CPCB01J31/04B01J2231/4283C07D233/58C07D239/94
Inventor 刘振腾梁振刘洪明徐桂超刘磊
Owner SHANDONG LUOXIN PARMACEUTICAL GROUP STOCK CO LTD
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