Preparation method of lapatinib intermediate

A technology for lapatinib and intermediates, applied in the field of preparation of lapatinib intermediate 2-thiamphenicol ethylamine hydrochloride, which can solve unfavorable large-scale production, hidden dangers, and Raney nickel catalytic hydrogenation reaction conditions Harsh and other issues

Inactive Publication Date: 2013-04-10
SHANDONG BOYUAN PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The Raney nickel catalytic hydrogenation reaction conditions used in this method are relatively harsh (hydrogenation pressure reaches 20 kg)

Method used

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  • Preparation method of lapatinib intermediate
  • Preparation method of lapatinib intermediate
  • Preparation method of lapatinib intermediate

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0021] Put 2-methylthioethanol (92 g, 1.0 mol), triethylamine (141 g, 1.4 mol) and dichloromethane (1000 mL) in a 2000 mL three-necked reaction flask, cool down to 0~5 ℃, slowly drip A solution of methylsulfonyl chloride (148 g, 1.3 mol) in dichloromethane (300 mL) was added, and the temperature during the dropwise addition was controlled not to exceed 15 °C. After dripping, the temperature was raised to 30°C, and the reaction was carried out for 6 hours. Water (500 mL) was added, the layers were stirred, and the aqueous layer was added with dichloromethane (200 mL) for extraction. The organic layers were combined, and the solvent was evaporated under reduced pressure. The obtained oil was directly used in the next reaction.

[0022] The preparation method of N-methylthioethyl phthalimide

example 2

[0024] Put phthalimide (85 g, 0.58 mol), the oil obtained in Example 1, potassium carbonate (104 g, 0.75 mol) and N,N-dimethylformamide (800 mL) into 2000 mL three wells The reaction flask was heated to 100°C for 5 hours. Suction filtration while hot under reduced pressure, the filter cake was washed with N,N-dimethylformamide (100 mL), the filtrate was slowly added to ice water (2000 mL), and stirred for 30 minutes. Filter under reduced pressure and dry to obtain a white solid that is N-methylthioethylphthalimide (109 g, yield 85%).

[0025]

[0026] The preparation method of N-methylsulfonyl ethyl phthalimide

example 3

[0028] N-methylthioethylphthalimide (109 g, 0.49 mol) and glacial acetic acid (500 mL) were placed in a 2000 mL three-necked reaction flask, and the temperature was lowered to 5 °C. Slowly add 30% hydrogen peroxide (260 mL) dropwise, and control the reaction temperature not to be higher than 20 °C. After dripping, the reaction was refluxed for 7 hours. The temperature was lowered to 25°C, the reaction solution was slowly poured into ice water (2000 mL), stirred for 30 minutes, suction filtered, and dried to obtain white crystals (89 g, yield 72%).

[0029] The preparation method of 2-methylsulfonylethylamine hydrochloride

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Abstract

The invention provides a preparation method of a lapatinib intermediate 2-methylsulfonylethylamine hydrochloride. The invention is characterized in that 2-methylthioethanol used as an initial raw material is subjected to esterification, SN2 substitution, oxidation and hydrazinolysis to obtain the target product. The method provided by the invention is beneficial to lowering the environmental pollution, is simple to operate, has the advantages of mild reaction conditions, high product purity and cheap and accessible raw material, and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of pharmaceutical synthesis chemistry, in particular to a preparation method of lapatinib intermediate 2-methylsulfonylethylamine hydrochloride. Background technique [0002] Sulfone-containing fatty amines and their salts are important intermediates for the synthesis of some active pharmaceutical ingredients, among which 2-methylsulfonylethylamine hydrochloride is the synthesis of small molecule protein tyrosine kinase inhibitors and antitumor drug lapatib. One of the key intermediates of Lapatinib. [0003] [0004] [0005] The synthetic method of the 2-methylsulfonylethylamine hydrochloride reported in the literature mainly includes the following: [0006] WO2009117080 reported a synthetic route for preparing 2-methylsulfonylethylamine hydrochloride by taking 2-methylsulfonylacetonitrile as a starting material, through a two-step reaction of borane reduction and salt formation (see the formula below). Althou...

Claims

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Application Information

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IPC IPC(8): C07C317/28C07C315/04
Inventor 张立鹏齐英超李斌东长志赵建国
Owner SHANDONG BOYUAN PHARM CO LTD
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