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

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

CN105111141AInactive Publication Date: 2015-12-02苏州摩尔医药有限公司
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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

Examples

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

Patent Timeline
02 Dec 2015
Publication
CN105111141A
IPC
C07D215/22
CPC
C07D215/22
Inventors
张李锋; 蔡建萍