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Environment-friendly method for preparing high-yield erlotinib hydrochloride

An erlotinib hydrochloride, high-yield technology, applied in the field of drug synthesis, can solve the problems of low reaction yield, difficult conversion into cyano groups, etc., and achieve the effects of simple post-processing, reduced emissions, and reduced dosage

Inactive Publication Date: 2015-06-24
SHANDONG UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

When 3,4-dihydroxybenzaldehyde reacts with hydroxylamine hydrochloride, it will produce oxime isomers, its E configuration is relatively stable, it is not easy to convert into cyano groups, and the reaction yield is low

Method used

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  • Environment-friendly method for preparing high-yield erlotinib hydrochloride
  • Environment-friendly method for preparing high-yield erlotinib hydrochloride
  • Environment-friendly method for preparing high-yield erlotinib hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065] Embodiment 1: Preparation of 3,4-dihydroxybenzoic acid ethyl ester

[0066] Put 3,4-dihydroxybenzoic acid (5.0 g, 32.0 mmol) into a reaction flask, add 40 mL of ethanol, heat up to 40° C., and then add 5 mL of concentrated sulfuric acid dropwise. After the dropwise addition, the temperature was raised to 80° C. for reflux reaction for 10 h. After cooling to room temperature, 10M potassium hydroxide solution was added to adjust the pH to neutral. The solvent was distilled off under reduced pressure to precipitate a solid, which was washed with a small amount of water to obtain ethyl 3,4-dihydroxybenzoate.

[0067] Ethyl 3,4-dihydroxybenzoate: white solid; yield 89%; mp: 127~128℃; MS(ESI,calcd / found)[M+H] + : 183.2 / 183.3; 1 H-NMR (DMSO-d 6 )δ:9.52(s,2H),7.35(d,J=2.0Hz,1H),7.31(dd,J 1 =8.0Hz,J 2 =8.0Hz, 1H), 6.80(d, J=8.0Hz, 1H), 4.22(q, J=7.2Hz, 2H), 1.28(t, J=7.2Hz, 3H).

Embodiment 2

[0068] Embodiment 2: the preparation of 3,4-two (2-methoxyethoxy) ethyl benzoate

[0069] Take ethyl 3,4-dihydroxybenzoate (1.7g, 9.3mmol) in a reaction flask, add DMF 8mL to make it completely dissolved, add potassium tert-butoxide (2.0g, 17.8mmol) and potassium iodide (1.0g, 6.0 mmol), after heating up to 100°C, 2-chloroethyl methyl ether (3.52 g, 37.2 mmol) was added dropwise, and the reaction was continued for 12 h after the addition was completed. Cool to room temperature, add ice water (200 mL), and extract three times with ethyl acetate (3×200 mL). The organic phases were combined, washed three times with distilled water, washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure to obtain an oil, which was subjected to column chromatography (elution system: petroleum ether / ethyl acetate=6: 1) Obtain ethyl 3,4-bis(2-methoxyethoxy)benzoate.

[0070] Ethyl 3,4-bis(2-methoxyeth...

Embodiment 3

[0071] Embodiment 3: Preparation of 2-nitro-4,5-two (2-methoxyethoxy) ethyl benzoate

[0072] Take ethyl 3,4-bis(2-methoxyethoxy)benzoate (0.4 g, 1.3 mmol) into a reaction flask, add 5 mL of concentrated sulfuric acid, and stir at room temperature to dissolve it. A mixture of fuming nitric acid (0.1 g, 1.3 mmol) and concentrated sulfuric acid (1 mL) was slowly added dropwise in the dark, and stirring was continued for 1 h after the addition was complete. Add ice water (100 mL), extract three times with ethyl acetate (60 ml×3), combine the organic phases, wash three times with saturated sodium bicarbonate and three times with saturated sodium chloride, dry over anhydrous magnesium sulfate overnight, and filter. The filtrate was evaporated to remove the solvent under reduced pressure, and the resulting oil was subjected to column chromatography (elution system: petroleum ether / ethyl acetate = 6:1) to obtain 2-nitro-4,5-bis(2-methoxyethoxy base) ethyl benzoate.

[0073] Ethyl 2...

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Abstract

The invention discloses an environment-friendly method for preparing high-yield erlotinib hydrochloride. The method comprises the following steps: directly performing cyclic condensation by taking 2-amino-4,5-di(2-methoxy ethyoxyl) ethyl benzoate hydrochloride as a key intermediate, reacting with aminophenylacetylene to generate erlotinib hydrochloride after performing chlorination, and refining to obtain the high-purity erlotinib hydrochloride. The process route provided by the invention is mild in reaction condition and high in yield; the first-class reagent and other reagents harmful to the environment and the operators are not used, the byproduct is few, the aftertreatment is simple and the commercial process can be easily processed.

Description

technical field [0001] The present invention relates to the preparation method of N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine hydrochloride (erlotinib hydrochloride), which belongs to the field of drug synthesis. Background technique [0002] Erlotinib Hydrochloride (Erlotinib Hydrochloride), jointly developed by Genetech, OSI and Roche, and produced by Roche (Roche), is used for the treatment of locally advanced or metastatic non-small cell lung cancer after at least one chemotherapy regimen failure innovative medicines. In November 2004, it was approved for marketing by the FDA, in September 2005, it was approved for marketing by the European Union, and in April 2006 it was launched in China. FDA also approved the combination of erlotinib hydrochloride and gemcitabine for the treatment of advanced pancreatic cancer in 2005, becoming the first approved drug for the treatment of advanced pancreatic cancer in the past 10 years. [0003] Erlotinib hydroch...

Claims

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Application Information

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IPC IPC(8): C07D239/94
CPCC07D239/94
Inventor 赵桂森李鹏战史永强尹燕振王永涛
Owner SHANDONG UNIV
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