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Anlotinib hydrochloride intermediate and preparation method of anlotinib hydrochloride

A technology of anlotinib hydrochloride and intermediates, applied in the field of medicinal chemistry, can solve the problems of cumbersome operation, unfavorable green industrial production, high price, etc., and achieve the effect of short process flow

Active Publication Date: 2019-10-22
XINFA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] The above route 1 and route 2 have long steps, cumbersome operation, and are not suitable for industrial production
The operation process of route three is relatively simple, but the raw materials 7-benzyloxy-6-methoxy-4-hydroxyquinoline and 4-fluoro-5-hydroxyl-2-methyl-1H-indole are expensive, and route three The chlorination reaction step uses a large amount of phosphorus oxychloride, and the post-treatment produces a large amount of acidic wastewater, which is not conducive to green industrial production

Method used

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  • Anlotinib hydrochloride intermediate and preparation method of anlotinib hydrochloride
  • Anlotinib hydrochloride intermediate and preparation method of anlotinib hydrochloride
  • Anlotinib hydrochloride intermediate and preparation method of anlotinib hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065] Example 1: Preparation of 4-(2-fluoro-3-methyl-4-nitrophenyl)oxy-6-methoxy-7-benzyloxyquinoline (Ⅳ1)

[0066] To a 500 ml four-neck flask connected with stirring, a thermometer, and a reflux condenser, add 200 g of N,N-dimethylformamide, 28.0 g (0.1 mole) of 4-hydroxy-6-methoxy-7-benzyl Oxyquinoline (II1), 25.5 g (0.11 mol) 2-fluoro-3-bromo-6-nitrotoluene (III1), 19.5 g (0.14 mol) potassium carbonate, stirred at 95 to 100°C for 3 hours. Cool to 20 to 25°C, filter to remove potassium salt, wash the filter cake with 30 grams of solvent, combine the filtrates, distill under reduced pressure to recover the solvent, then add 0.5 grams of activated carbon and 160 grams of 80% ethanol to the residue, react and stir at 80°C for decolorization For 1 hour, filter while hot, cool and recrystallize, filter and dry to obtain 39.6 grams of 4-(2-fluoro-3-methyl-4-nitrophenyl)oxy-6-methoxy-7-benzyloxy Quinoline, the yield is 91.2%, and the liquid phase purity is 99.7%.

Embodiment 2

[0067] Example 2: Preparation of 4-(2-fluoro-3-methyl-4-nitrophenyl)oxy-6-methoxy-7-benzyloxyquinoline (Ⅳ1)

[0068] In the 500 milliliter four-necked flask that is connected with stirring, thermometer, reflux condenser, add 200 gram tetrahydrofuran, 28.0 gram (0.1 mol) 4-hydroxyl-6-methoxy-7-benzyloxyquinoline (II1), 29.0 g (0.1 mole) of 2-fluoro-3-iodo-6-nitrotoluene (Ⅲ2), 20.7 g (0.15 mole) of potassium carbonate, and stirred at 65 to 70° C. for 6 hours. Cool to 20 to 25°C, filter to remove potassium salt, wash the filter cake with 30 grams of solvent, combine the filtrates, distill under reduced pressure to recover the solvent, then add 0.5 grams of activated carbon and 160 grams of 80% ethanol to the residue, react and stir at 80°C for decolorization For 1 hour, filter while hot, cool and recrystallize, filter, and dry to obtain 39.2 grams of 4-(2-fluoro-3-methyl-4-nitrophenyl)oxy-6-methoxy-7-benzyloxy Quinoline, the yield is 90.3%, and the liquid phase purity is 99.3%. ...

Embodiment 3

[0069] Example 3: 4-(2-fluoro-3-methyl-4-nitrophenyl)oxy-6-methoxy-7-(1-acetylaminocyclopropanyl-1-yl)methyloxy Preparation of Quinoline (Ⅳ2)

[0070] In a 500 ml four-neck flask connected with stirring, a thermometer, and a reflux condenser, add 200 g of N,N-dimethylformamide, 30.2 g (0.1 mole) of 4-hydroxyl-6-methoxyl-7-( 1-Acetamidocyclopropanyl-1-yl)methyloxyquinoline (Ⅱ2), 25.7 grams (0.11 moles) 2-fluoro-3-bromo-6-nitrotoluene (Ⅲ1), 20.7 grams (0.15 moles ) Potassium carbonate, stirred and reacted at 95 to 100° C. for 3 hours. Cool to 20 to 25°C, filter to remove potassium salt, wash the filter cake with 30 grams of solvent, combine the filtrates, distill under reduced pressure to recover the solvent, then add 0.5 grams of activated carbon and 220 grams of 80% ethanol to the residue, react and stir at 80°C for decolorization 1 hour, filtered while hot, cooled and recrystallized, filtered and dried to obtain 40.9 grams of 4-(2-fluoro-3-methyl-4-nitrophenyl)oxy-6-methoxy...

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Abstract

The invention provides an anlotinib hydrochloride intermediate and a preparation method of anlotinib hydrochloride. 4-hydroxy-6-methoxyl-7-GO substituted quinolone and 2-fluorine-3-halogenate-6-bitrotoluene are used for generating 4-(2-fluorine-3-methyl-4- nitrobenzophenone)epoxide-6-methoxyl-7-GO substituted quinolone under action of an acid-binding agent through substitution reaction, and then condensation reaction is conducted with triglyceride orthoacetate to obtain 4-[2-fluorine-3-(2-alkyloxyethyl-propylene-1-base)-4-nitrobenzophenone]epoxide-6-methoxyl-7-GO substituted quinolone, and then under existing of a catalyst, reduction-cyclization reaction is conducted to obtain the anlotinib hydrochloride intermediate. The obtained anlotinib hydrochloride intermediate can be used for preparing the anlotinib hydrochloride according to the prior art or the preparation method of the anlotinib hydrochloride. According to the anlotinib hydrochloride intermediate and the preparation method ofthe anlotinib hydrochloride, raw materials are cheap and easy to obtain, the technology process is simple and short, operation is easy and convenient, safety and environmental protection are achieved, the cost is low, and selectivity, the yield coefficient and the purity are high.

Description

technical field [0001] The invention relates to an anlotinib hydrochloride intermediate and a preparation method of anlotinib hydrochloride, belonging to the technical field of medicinal chemistry. Background technique [0002] Anlotinib Hydrochloride (Ⅰ), the English name is Anlotinib Hydrochloride, is a new type of multi-target tyrosine kinase inhibitor independently developed by my country, which can effectively inhibit VEGFR, PDGFR, FGFR, c-Kit and other kinases, and has anti- Tumor angiogenesis and inhibition of tumor growth. Anlotinib hydrochloride was granted orphan drug qualification by the US FDA for the treatment of ovarian cancer in 2015. It is currently used in a phase III study (ALTER-0303) for the third-line treatment of advanced NSCLC and has successfully reached the treatment endpoint, and has entered China's CFDA rapid review Channel, is expected to become the third-line treatment standard for advanced NSCLC in China. In addition, China Chia Tai Tianqing Ph...

Claims

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Application Information

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IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 戚聿新刘月盛王保林鞠立柱吕强三
Owner XINFA PHARMA
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