Preparation of erlotinid hydrochloride

A technology of erlotinib hydrochloride and mixed acid, which is applied in the field of hydrochloric acid 4-6, can solve the problems of increasing steps and reducing the yield, and achieves the effects of avoiding excessive hydrolysis, shortening the synthesis route, and mild reaction conditions

Active Publication Date: 2009-06-24
FUJIAN SOUTH PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This route requires first demethylation and then protection, followed by dep

Method used

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  • Preparation of erlotinid hydrochloride
  • Preparation of erlotinid hydrochloride
  • Preparation of erlotinid hydrochloride

Examples

Experimental program
Comparison scheme
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Example Embodiment

[0038] Example 1

[0039] ① Synthesis of compound 1

[0040] Add 5L of re-distilled toluene into a 10L four-neck flask, add 1kg of 3,4-dihydroxybenzaldehyde, 500g of hydroxylamine hydrochloride, 160g of p-toluenesulfonic acid and 5kg of anhydrous magnesium sulfate while stirring, heat to reflux for 6 hours, and cool to room temperature. Filter, extract the filter cake with hot ethyl acetate until TLC detects no product, combine, wash with water, wash with saturated brine, dry, concentrate until a large amount of product precipitates, add 2.5L of petroleum ether, filter with suction, wash with a small amount of petroleum ether, and dry to obtain The compound is about 1800g.

[0041] ② Synthesis of compound 2

[0042] Compound 1 (1kg), 2kg of chloroethyl methyl ether, 3kg of potassium carbonate, 500g of tetrabutylammonium iodide and 5 liters of DMSO were added to a 10-liter four-necked flask, heated to reflux, TLC detected the reaction was complete, cooled, and poured into 10 Liter ...

Example Embodiment

[0053] Example 2

[0054] ① Synthesis of compound 1

[0055] Add 5L of redistilled benzene to a 10L four-necked flask, add 1kg of raw materials 3,4-dihydroxybenzaldehyde, 1kg of hydroxylamine hydrochloride, 100g of p-toluenesulfonic acid and 4kg of anhydrous magnesium sulfate with stirring, heat to reflux for 16 hours, and cool to room temperature. Filter, extract the filter cake with hot ethyl acetate until TLC detects no product, combine, wash with water, wash with saturated brine, dry, concentrate until a large amount of product precipitates, add 2.5L of petroleum ether, filter with suction, wash with a small amount of petroleum ether, and dry to obtain The compound is about 1850g.

[0056] ② Synthesis of compound 2

[0057]Compound 1 (1 kg), 2 kg of chloroethyl methyl ether, 3 kg of potassium carbonate, 100 g of tetrabutyl ammonium bromide and 5 liters of DMF were added to a 10-liter four-neck flask, heated to reflux, and TLC detected that the reaction was complete, cooled, an...

Example Embodiment

[0068] Example 3

[0069] ① Synthesis of compound 1

[0070] Add 5L of re-distilled toluene into a 10L four-neck flask, add 1kg of raw material 3,4-dihydroxybenzaldehyde, 500g hydroxylamine hydrochloride, 160g p-toluenesulfonic acid and 5kg anhydrous sodium sulfate with stirring, heat to reflux for 6 hours, and cool to room temperature. Filter, extract the filter cake with hot ethyl acetate until TLC detects no product, combine, wash with water, wash with saturated brine, dry, and concentrate until a large amount of product precipitates, add 2.5L petroleum ether, filter with suction, wash with a small amount of petroleum ether, and dry to obtain The compound is about 1900g.

[0071] ② Synthesis of compound 2

[0072] Compound 1 (1kg), 2kg of chloroethyl methyl ether, 5kg of potassium carbonate, 300g of tetrabutylammonium iodide and 5 liters of THF were added to a 10-liter four-necked flask, heated to reflux, TLC detected the reaction was complete, cooled, and poured into 10 Liter ...

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Abstract

The invention discloses a preparation method of erlotinib hydrochloride. The method is characterized by taking 3,4-dihydroxybenzaldehyde as a raw material, synthesizing to obtain 6,7-dimethoxyquinazoline-4-one, directly chloridizing to obtain a product, allowing the product to react with meta-ethynylaniline to obtain the erlotinib hydrochloride. The method has mild reaction condition and is applicable to industrialized production.

Description

Technical field: [0001] The invention relates to the field of synthesis of pharmaceutical compounds, in particular to a preparation method of 4-(3-ethynylphenylamino)-6,7-dimethoxyquinazoline hydrochloride (erlotinib hydrochloride). Background technique: [0002] 4-(3-ethynylphenylamino)-6,7-dimethoxyquinazoline hydrochloride (erlotinib hydrochloride, Erlotinib Hydrochloride, trade name: Tarceva, Tarceva) is an epidermal growth factor (EGFR) Selective inhibitors of tyrosine kinases are currently clinically used for the treatment of non-small cell lung cancer. [0003] [0004] Erlotinib hydrochloride molecular structure [0005] The synthetic route of erlotinib hydrochloride is mainly Schnur of U.S. Pfizer Inc.N.Y., Rodney.C. etc. report (US5747498), and its synthetic route is as follows: [0006] [0007] This route uses ethyl 3,4-dihydroxybenzoate as a raw material, first reacts with bromoethyl methyl ether, then nitrates, reduces nitro to amino, cyclizes, chlorate...

Claims

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Application Information

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IPC IPC(8): C07D239/94
Inventor 沈鑫廖立新林复兴何晓杨继东詹华杏
Owner FUJIAN SOUTH PHARMA CO LTD
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