Preparation of erlotinid hydrochloride

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...

Examples

Embodiment 1

[0040] ①Synthesis of Compound 1

[0041] Add 5L of double-distilled toluene to a 10L four-necked bottle, add 1kg of raw materials 3,4-dihydroxybenzaldehyde, 500g of hydroxylamine hydrochloride, 160g of p-toluenesulfonic acid and 5kg of anhydrous magnesium sulfate under stirring, heat and reflux for 6 hours, cool to room temperature, Filtration, the filter cake was extracted with hot ethyl acetate to TLC to detect no product, combined, washed with water, washed with saturated brine, dried, concentrated until a large amount of product was precipitated, added 2.5L petroleum ether, suction filtered, washed with a small amount of petroleum ether, and dried to obtain The compound is about 1800g.

[0042] ② Synthesis of compound 2

[0043] Add compound 1 (1kg), chloroethyl methyl ether 2kg, potassium carbonate 3kg, tetrabutylammonium iodide 500g and 5 liters of DMSO into a 10-liter four-neck flask, heat to reflux, and after TLC detects that the reaction is complete, cool and pour 10...

Embodiment 2

[0055] ①Synthesis of Compound 1

[0056] Add 5L double-distilled benzene into a 10L four-necked bottle, add 1kg of raw materials 3,4-dihydroxybenzaldehyde, 1kg of hydroxylamine hydrochloride, 100g of p-toluenesulfonic acid and 4kg of anhydrous magnesium sulfate under stirring, heat and reflux for 16 hours, cool to room temperature, Filtration, the filter cake was extracted with hot ethyl acetate to TLC to detect no product, combined, washed with water, washed with saturated brine, dried, concentrated until a large amount of product was precipitated, added 2.5L petroleum ether, suction filtered, washed with a small amount of petroleum ether, and dried to obtain The compound is about 1850g.

[0057] ② Synthesis of compound 2

[0058]Add compound 1 (1kg), chloroethyl methyl ether 2kg, potassium carbonate 3kg, tetrabutylammonium bromide 100g and 5 liters of DMF into a 10-liter four-neck flask, heat to reflux, and after TLC detects that the reaction is complete, cool and pour 10 ...

Embodiment 3

[0070] ①Synthesis of Compound 1

[0071] Add 5L double-distilled toluene to a 10L four-necked bottle, add 1kg of raw materials 3,4-dihydroxybenzaldehyde, 500g of hydroxylamine hydrochloride, 160g of p-toluenesulfonic acid and 5kg of anhydrous sodium sulfate under stirring, heat and reflux for 6 hours, cool to room temperature, Filtration, the filter cake was extracted with hot ethyl acetate to TLC to detect no product, combined, washed with water, washed with saturated brine, dried, concentrated until a large amount of product was precipitated, added 2.5L petroleum ether, suction filtered, washed with a small amount of petroleum ether, and dried to obtain The compound is about 1900g.

[0072] ② Synthesis of Compound 2

[0073] Add compound 1 (1kg), chloroethyl methyl ether 2kg, potassium carbonate 5kg, tetrabutylammonium iodide 300g and 5 liters of THF into a 10 liter four-neck flask, heat to reflux, and after TLC detects that the reaction is complete, cool and pour 10 liter...

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...

Examples

Embodiment 1

[0040] ①Synthesis of Compound 1

[0041] Add 5L of double-distilled toluene to a 10L four-necked bottle, add 1kg of raw materials 3,4-dihydroxybenzaldehyde, 500g of hydroxylamine hydrochloride, 160g of p-toluenesulfonic acid and 5kg of anhydrous magnesium sulfate under stirring, heat and reflux for 6 hours, cool to room temperature, Filtration, the filter cake was extracted with hot ethyl acetate to TLC to detect no product, combined, washed with water, washed with saturated brine, dried, concentrated until a large amount of product was precipitated, added 2.5L petroleum ether, suction filtered, washed with a small amount of petroleum ether, and dried to obtain The compound is about 1800g.

[0042] ② Synthesis of compound 2

[0043] Add compound 1 (1kg), chloroethyl methyl ether 2kg, potassium carbonate 3kg, tetrabutylammonium iodide 500g and 5 liters of DMSO into a 10-liter four-neck flask, heat to reflux, and after TLC detects that the reaction is complete, cool and pour 10...

Embodiment 2

[0055] ①Synthesis of Compound 1

[0056] Add 5L double-distilled benzene into a 10L four-necked bottle, add 1kg of raw materials 3,4-dihydroxybenzaldehyde, 1kg of hydroxylamine hydrochloride, 100g of p-toluenesulfonic acid and 4kg of anhydrous magnesium sulfate under stirring, heat and reflux for 16 hours, cool to room temperature, Filtration, the filter cake was extracted with hot ethyl acetate to TLC to detect no product, combined, washed with water, washed with saturated brine, dried, concentrated until a large amount of product was precipitated, added 2.5L petroleum ether, suction filtered, washed with a small amount of petroleum ether, and dried to obtain The compound is about 1850g.

[0057] ② Synthesis of compound 2

[0058]Add compound 1 (1kg), chloroethyl methyl ether 2kg, potassium carbonate 3kg, tetrabutylammonium bromide 100g and 5 liters of DMF into a 10-liter four-neck flask, heat to reflux, and after TLC detects that the reaction is complete, cool and pour 10 ...

Embodiment 3

[0070] ①Synthesis of Compound 1

[0071] Add 5L double-distilled toluene to a 10L four-necked bottle, add 1kg of raw materials 3,4-dihydroxybenzaldehyde, 500g of hydroxylamine hydrochloride, 160g of p-toluenesulfonic acid and 5kg of anhydrous sodium sulfate under stirring, heat and reflux for 6 hours, cool to room temperature, Filtration, the filter cake was extracted with hot ethyl acetate to TLC to detect no product, combined, washed with water, washed with saturated brine, dried, concentrated until a large amount of product was precipitated, added 2.5L petroleum ether, suction filtered, washed with a small amount of petroleum ether, and dried to obtain The compound is about 1900g.

[0072] ② Synthesis of Compound 2

[0073] Add compound 1 (1kg), chloroethyl methyl ether 2kg, potassium carbonate 5kg, tetrabutylammonium iodide 300g and 5 liters of THF into a 10 liter four-neck flask, heat to reflux, and after TLC detects that the reaction is complete, cool and pour 10 liter...

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