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Method for synthesizing anlotinib and hydrochloride thereof

A synthesis method and technology of cyclopropylamine hydrochloride, applied in the field of pharmaceutical synthesis, can solve problems such as complicated operation, many steps, poor product solubility, etc., and achieve the effects of simple reaction operation, improved reaction efficiency, and simplified technological process.

Active Publication Date: 2018-11-23
SHANGHAI VASTPRO TECH DEV CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The route is relatively long, there are many steps, and the operation is cumbersome
The solubility of the product in the iron powder reduction step is poor, and it is difficult to separate from the by-product iron slime
The cyclopropane fragment raw materials used in the fifth step reaction have poor stability, which is not conducive to the quality control and preservation of raw materials
The palladium catalyzed step is too close to the API step, which is not conducive to the heavy metal residue control of the quality of the final product

Method used

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  • Method for synthesizing anlotinib and hydrochloride thereof
  • Method for synthesizing anlotinib and hydrochloride thereof
  • Method for synthesizing anlotinib and hydrochloride thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Example 1 1-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropylamine Synthesis of hydrochloride:

[0034]

[0035] 1. Preparation of 4-(4-amino-2-fluoro-3-((2-methyl-1,3-dioxolan-2-yl)methyl)phenoxy)-6-methoxyquinoline Lino-7-ol:

[0036] 7-(benzyloxy)-4-(2-fluoro-3-((2-methyl-1,3-dioxolan-2-yl)methyl)-4-nitrophenoxy) -6-Methoxyquinoline (52g, 0.1mol) was placed in a 500mL there-necked flask, 280mL of N-methylpyrrolidone was added, and then wet palladium carbon (5g, ~10wt%) was added, under 0.1 ~ 0.2MPa hydrogen pressure The reaction was carried out at 50-55°C until the reaction was completed as detected by HPLC. The catalyst was removed by filtration, and the resulting toluene was distilled off from the mother liquor under reduced pressure to obtain 4-(4-amino-2-fluoro-3-((2-methyl-1,3-dioxolan-2-yl)methyl) The solution of phenoxy)-6-methoxyquinolin-7-ol in N-methylpyrrolidone was used directly in the next reaction.

[0037] 1...

Embodiment 2

[0047] Example 2 1-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropylamine Synthesis:

[0048]

[0049] 1. Preparation of 4-(4-amino-2-fluoro-3-((2-methyl-1,3-dioxolan-2-yl)methyl)phenoxy)-6-methoxyquinoline Lino-7-ol:

[0050] 7-(benzyloxy)-4-(2-fluoro-3-((2-methyl-1,3-dioxolan-2-yl)methyl)-4-nitrophenoxy) -6-Methoxyquinoline (52g, 0.1mol) was placed in a 500mL three-necked flask, 280mL of N,N-dimethylacetamide was added, and then wet palladium carbon (5g, ~10wt%) was added, at 0.1-0.2 Under the hydrogen pressure of MPa, the reaction was carried out at 50-55 °C until the reaction was completed as detected by HPLC. The catalyst was removed by filtration, and the resulting toluene was distilled off from the mother liquor under reduced pressure to obtain 4-(4-amino-2-fluoro-3-((2-methyl-1,3-dioxolan-2-yl)methyl) Phenoxy)-6-methoxyquinolin-7-ol in N,N-dimethylacetamide was used directly in the next reaction.

[0051] 2. Preparation of 4-...

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Abstract

The invention relates to a method for synthesizing anlotinib and hydrochloride thereof. Specifically, the method comprises steps (1) to (3) and step (4) or (5) in the description. According to the method disclosed by the invention, a technological flow is extremely simplified and the method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and relates to a new method for synthesizing anlotinib and its hydrochloride. Background technique [0002] Anlotinib is a novel small molecule multi-target tyrosine kinase inhibitor, which can effectively inhibit VEGFR, PDGFR, FGFR, c-Kit and other kinases, and has dual effects of anti-angiogenesis and tumor growth inhibition. Anlotinib is currently the only effective single-drug oral preparation among the anti-angiogenesis targeted drugs for advanced non-small cell lung cancer. It has mild adverse reactions and good patient tolerance. standard medication. In addition, Anlotinib has a good therapeutic effect not only on non-small cell lung cancer, but also on soft tissue sarcoma, ovarian cancer and other cancer types. [0003] The chemical name for Anlotinib is 1-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy) Methyl) cyclopropylamine, its chemical structural formula is: [...

Claims

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Application Information

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IPC IPC(8): C07D401/12
CPCC07D401/12Y02P20/55
Inventor 郭朋朱文峰
Owner SHANGHAI VASTPRO TECH DEV CO LTD
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