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A technology of erlotinib hydrochloride and hydroxylamine hydrochloride, which is applied in the field of medicine and chemical industry, can solve the problems of cumbersome synthetic routes, high production costs, and environmental hazards, and achieve the effects of reducing process steps, simplifying operations, and easy separation
Active Publication Date: 2016-06-08
SHANDONG LUOXIN PHARMA GRP HENGXIN PHARMA CO LTD
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[0018] The purpose of this invention is to provide a kind of new synthetic method of Erlotinib hydrochloride, to solve the problems such as too complicated synthetic route, high production cost, harmful to environment in the prior art, this synthetic method technique is relatively simple, raw material is easy to get, Controllable operation, high yield and purity, and environmentally friendly, suitable for industrial production
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Embodiment 1
[0044] Embodiment 1: the synthesis of compound I
[0045] Add 55.2g (0.4mol) of 3,4-dihydroxybenzaldehyde, 54.4g (0.8mol) of sodium formate, and 250mL of formic acid into a three-necked flask, stir and heat up to 80°C, add 80.1g (0.5 mol), TLC tracking reaction complete (about 3h). Cool to room temperature, pour the reaction solution into 300mL cold saturated saline, stir, a large amount of white solid precipitates out, filter to obtain the crude product of compound Ⅰ, recrystallize with ethyl acetate, and obtain 49.2g of refined product after vacuum drying, the HPLC purity is 99.3% , yield 90.5%.
Embodiment 2
[0046] Embodiment 2: the synthesis of compound II
[0047] 40.8g (0.3mol) of compound I prepared in Example 1, 75.6g (0.8mol) of 2-chloroethyl methyl ether, 124.4g (0.9mol) of potassium carbonate, 22.2g (0.06 mol) and 300ml of DMSO were added to a four-neck flask, heated to reflux, and after the reaction was complete as detected by TLC, cooled, DMSO was distilled off under reduced pressure, poured into 600ml of ice water, extracted with dichloromethane, washed with brine, dried, and concentrated to obtain compound II70 .0g, HPLC purity 99.5%, yield 92.3%.
Embodiment 3
[0048] Embodiment 3: the synthesis of compound III
[0049] Compound II (62.8g, 0.25mol) was dissolved in 300ml of acetic acid, added dropwise to nitric acid (300ml) cooled to 0°C, and the temperature was controlled not to exceed 10°C. After stirring for 30 minutes, centrifuged, washed with water, dried, and recrystallized from methanol to obtain 71.0 g of compound III, the HPLC purity was 99.7%, and the yield was 95.3%.
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Abstract
The invention discloses a preparation method of erlotinib hydrochloride. The preparation method comprises the following steps of using 3,4-dihydroxy benzaldehyde (compound I) as a starting raw material; converting an aldehyde group into a cyano group; undergoing six-step reactions of oxyalkylating a side chain, nitrating, hydrolyzing the cyano group, reducing a nitro group, cyclizing and performing salt formation to obtain the erlotinib hydrochloride. According to a synthetic method, the starting material is simple, low in price and easily-obtained; compared with an existing route of first closing ring, then chloridizing and finally ammonifying; the synthetic method disclosed by the invention has the advantages that steps are reduced, the yield is increased, the reaction process is easy in operation and the preparation cycle is shorter; meanwhile, the use of chlorinating agents such as phosphorus trichloride, phosphorus pentachloride, thionyl chloride, phosgene or phosphorus oxychloride with corrosivity is also avoided; the preparation method is suitable for industrial production.
Description
technical field [0001] The invention relates to the technical field of medicine and chemical industry, in particular to a preparation method of 4-(3-ethynylphenylamino)-6,7-dimethoxyquinazoline hydrochloride (ie erlotinib hydrochloride). Background technique [0002] Cancer is the number one killer of human health, and lung cancer is one of the most threatening malignant tumors with the fastest-growing morbidity and mortality. As a branch of lung cancer, non-small cell lung cancer accounts for the 80%, is the most common lung cancer. [0003] Erlotinib hydrochloride (Erlotinib) trade name Tarceva It is a molecular targeted therapy drug, which can achieve anti-tumor effect by inhibiting the activity of tyrosine kinase on epidermal growth factor (EGFR) in human cells, and can effectively improve the survival rate of patients with tumor. The drug was approved by the US Food and Drug Administration (FDA) on November 19, 2004, for the treatment of patients with locally advance...
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Application Information
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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/94
CPCC07D239/94
Inventor 孙松孙运贝陈庆军
Owner SHANDONG LUOXIN PHARMA GRP HENGXIN PHARMA CO LTD
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