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Cabozantinib intermediate 4-hydroxy-6,7-dimethoxyquinoline and preparation method thereof

A technology of dimethoxyquinoline and dimethoxyaniline, applied in the field of medicine, can solve the problems of difficult process route, few synthesis methods, large amount of acid, etc., and achieves simple reaction route, cheap and easy-to-obtain raw materials, and easy-to-use raw materials. the effect

Inactive Publication Date: 2015-12-02
苏州摩尔医药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the prior art, there are certain deficiencies in the synthetic method of 4-hydroxyquinoline compounds, for example, in the synthesis of 4-hydroxyquinoline compounds, thermal cyclization reaction (Gould-jacobs reaction or Conrad-Limpach reaction is usually used) ), the reaction is generally carried out under reflux in diphenyl ether or guide oil, the temperature is higher (240-270°C), and the reaction time is longer (4-20h). Such conditions lead to the generation of tar impurities, which are not easy to separate and purify. Cause yield unsatisfactory (<40%), cause product cost to increase significantly, and guide raw oil can bring harm to operator and environment, bring difficulty to suitability for industrialized production; Another kind of synthetic method commonly used is acid-catalyzed cyclization , although adding acid catalysis in the thermal ring closure process can significantly reduce the reaction temperature and improve the yield, the stability of the enamine intermediates generated is not good, and the amount of acid is very large (4-10 times the molar amount of the raw material ), it is very difficult to develop a process route suitable for industrial production
However, there are few reports on the specific synthetic method of cabozantinib intermediate 4-hydroxyl 6,7-dimethoxyquinoline

Method used

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  • Cabozantinib intermediate 4-hydroxy-6,7-dimethoxyquinoline and preparation method thereof
  • Cabozantinib intermediate 4-hydroxy-6,7-dimethoxyquinoline and preparation method thereof
  • Cabozantinib intermediate 4-hydroxy-6,7-dimethoxyquinoline and preparation method thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] In this example, the preparation method of cabozantinib intermediate 4-hydroxyl 6,7-dimethoxyquinoline comprises the following steps:

[0054] (1) Synthesis of 5-(methoxymethenyl)-2,2-dimethyl-1,3-dioxane-4,6-dione

[0055] Add 30.8g (0.29mol) of trimethyl orthoformate and 35g (0.24mol) of isopropylidene malonate into 105g of isopropanol, heat to 90°C, react for 1h, cool down to room temperature, The solvent and excess trimethyl orthoformate were distilled off under reduced pressure at ℃ to obtain 5-(methoxymethylenyl)-2,2-dimethyl-1,3-dioxane-4,6-dione 40.2 g (90% yield), melting point 120.5°C.

[0056] The proton nuclear magnetic resonance spectrum characterization result of step (1) gained product is: 1 HNMR (400MHz, CDCl 3 ): 8.14(1H,s), 4.26(3H,s), 1.71(6H,s).

[0057] (2) Synthesis of 5-(((3,4-dimethoxyphenyl)amino)methyl)-2,2-methyl-1,3-dioxo-4,6-dione

[0058] In turn, 30.6g (0.2mol) 3,4-dimethoxyaniline and 34.6g (0.2mol) 5-(methoxymethenyl)-2,2-dimethyl-1...

Embodiment 2

[0065] In this example, the preparation method of cabozantinib intermediate 4-hydroxyl 6,7-dimethoxyquinoline comprises the following steps:

[0066] (1) Synthesis of 5-(methoxymethenyl)-2,2-dimethyl-1,3-dioxane-4,6-dione

[0067] Add 25.4g (0.24mol) of trimethyl orthoformate and 35g (0.24mol) of isopropylidene malonate into 35g of methanol, heat to 60°C, react for 3 hours, cool down to room temperature, and reduce temperature at 40-50°C. The solvent was distilled off under pressure to obtain 40.4 g of 5-(methoxymethylenyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (90.5% yield). The melting point is 120.5°C.

[0068] The proton nuclear magnetic resonance spectrum characterization result of step (1) gained product is: 1 HNMR (400MHz, CDCl 3 ): 8.14(1H,s), 4.26(3H,s), 1.71(6H,s).

[0069] (2) Synthesis of 5-(((3,4-dimethoxyphenyl)amino)methyl)-2,2-methyl-1,3-dioxo-4,6-dione

[0070] 29.2g (0.19mol) 3,4-dimethoxyaniline and 39g (0.21mol) 5-(methoxymethenyl)-2,2-dimethyl-1,3-dioxan...

Embodiment 3

[0077] In this example, the preparation method of cabozantinib intermediate 4-hydroxyl 6,7-dimethoxyquinoline comprises the following steps:

[0078] (1) Synthesis of 5-(methoxymethenyl)-2,2-dimethyl-1,3-dioxane-4,6-dione

[0079] Add 38.2g (0.36mol) of trimethyl orthoformate and 35g (0.24mol) of isopropylidene malonate into 175g of n-propanol, heat to 100°C, and react for 2 hours. After the reaction is completed, cool down to room temperature. The solvent and excess trimethyl orthoformate were distilled off under reduced pressure at 40-50°C to obtain 5-(methoxymethenyl)-2,2-dimethyl-1,3-dioxane-4, 40.7 g of 6-diketone (91.2% yield), melting point 120.5°C.

[0080] The proton nuclear magnetic resonance spectrum characterization result of step (1) gained product is: 1 HNMR (400MHz, CDCl 3 ): 8.14(1H,s), 4.26(3H,s), 1.71(6H,s).

[0081] (2) Synthesis of 5-(((3,4-dimethoxyphenyl)amino)methyl)-2,2-methyl-1,3-dioxo-4,6-dione

[0082]27.4g (0.179mol) 3,4-dimethoxyaniline and 40...

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Abstract

The invention provides a cabozantinib intermediate 4-hydroxy-6,7-dimethoxyquinoline and a preparation method thereof. According to the method, ortho-formate, isopropylidene malonate and 3,4-dimethoxyaniline used as raw materials are subjected to condensation and cyclization reaction to obtain the 4-hydroxy-6,7-dimethoxyquinoline. The chemical reaction conditions are milder; the yield for each reaction is up to 90% or so; and the total product yield is 71.3-79.3%. The method has the advantages of cheap and accessible raw materials, high safety, low toxicity, environment friendliness and simple preparation technique, and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of medicine, and relates to a cabozantinib intermediate 4-hydroxyl 6,7-dimethoxyquinoline and a preparation method thereof. Background technique [0002] Cabozantinib is an anti-tumor drug that inhibits tumor metastasis and angiogenesis. It uses the protein product (MET) and vascular endothelial growth factor encoded by proto-oncogenes related to the growth and spread of medullary thyroid cancer and prostate cancer. Receptor (VEGFR) and tyrosine kinase as targets, by targeting and inhibiting proto-oncogene encoded protein product (MET), vascular endothelial growth factor receptor (VEGFR) and tyrosine kinase receptor (RET) signaling pathway And play an anti-tumor effect, kill tumor cells, reduce tumor metastasis and inhibit angiogenesis. Cabozantinib can effectively treat prostate cancer, malignant tumors and unresectable malignant locally advanced or metastatic medullary thyroid carcinoma (MTC). In 76% of patients, ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/22
CPCC07D215/22
Inventor 张李锋蔡建萍方瑛陈曾飞
Owner 苏州摩尔医药有限公司
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