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Preparation method for vismodegib

A compound and hydroxyl technology, applied in the field of preparation of 2-chloro-N-phenyl)-4-benzamide and its intermediates, can solve problems such as Hedgehog pathway activation

Active Publication Date: 2014-07-09
LIANYUNGANG RUNZHONG PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the adult body, the Hedgehog signaling channel is mainly in a dormant state, but when tissue growth and self-repair are abnormal, the Hedgehog pathway may be activated

Method used

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  • Preparation method for vismodegib
  • Preparation method for vismodegib
  • Preparation method for vismodegib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0142] Embodiment 1: Preparation of 1-oxo-2-(3-nitrophenyl)pyridine

[0143]

[0144]Add 30mmol 1-oxopyridine, 10mmol 3-bromo-1-nitrobenzene, 12mmol potassium carbonate, 0.05mmol palladium acetate and 0.15mmol tri-tert-butylphosphine tetrafluoroborate, 40ml toluene, argon to a 100ml three-necked flask After three exchanges, reflux for 2 d under argon protection, then pour the reaction solution into 100 ml of ethyl acetate, filter, wash the filtrate with saturated brine, dry, evaporate the solvent under reduced pressure, and perform column chromatography (mobile phase V / V : dichloromethane / methanol=200 / 1), the fractions were collected and the solvent was evaporated under reduced pressure to obtain a light yellow solid with a yield of 70%.

[0145] 1 HNMR (500Hz, DMSO-d6): 8.79(s, 1H), 8.40(t, 1H), 8.32(q, 1H), 8.24(d, 1H), 7.78(q, 2H), 7.48(m, 2H) ;

[0146] MS: 217.2 ([M+H] + ).

Embodiment 2

[0147] Embodiment 2: Preparation of 1-oxo-2-(3-nitrophenyl)pyridine

[0148]

[0149] Add 30mmol of 1-oxopyridine, 10mmol of 3-bromo-1-nitrobenzene, 12mmol of potassium carbonate, 0.1mmol of cuprous iodide and 0.10mmol of 1,10-phenanthroline to a 100ml three-necked flask, 40ml of xylene, argon After three exchanges, reflux for 2 days under the protection of argon, cool down to room temperature, then pour the reaction system into 100ml of dichloromethane, filter, wash the filtrate with saturated brine, dry, filter, evaporate the filtrate to remove the solvent under reduced pressure, and perform column chromatography (Mobile phase V / V: dichloromethane / methanol=200 / 1), a light yellow solid was obtained with a yield of 46%.

Embodiment 3

[0150] Embodiment 3: the preparation of 2-(3-nitrophenyl) pyridine

[0151]

[0152] Add 3.0mmol of 1-oxo-2-(3-nitrophenyl)pyridine, 15mmol of phosphorus trichloride and 30ml of chloroform into a 100ml eggplant-shaped bottle, heat and reflux for 12h, pour the reaction solution into 100ml of water, and add acetic acid Extracted with ethyl ester (50ml×2), combined the organic phases, dried, evaporated the solvent under reduced pressure, and recrystallized from n-hexane to obtain a light yellow solid with a yield of 92%.

[0153] 1 HNMR (500Hz, CDCl 3 ): 8.86(s, 1H), 8.76(d, 1H), 8.40(d, 1H), 8.27(d, 1H), 7.85(q, 2H), 7.66(t, 1H), 7.36(m, 1H) ;

[0154] MS: 201.1 ([M+H] + ).

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Abstract

The invention provides a preparation method for vismodegib, and in other words, a preparation method for 2-chloro-N-(4-chloro-3-(pyridin-2-yl)-phenyl)-4-(methylsulfonyl)benzamide. The method comprises: firstly preparing an intermediate 2-(3-nitrophenyl)pyridine, and then performing chlorination reaction, reduction reaction and acylation reaction to prepare 2-chloro-N-(4-chloro-3-(pyridin-2-yl)-phenyl)-4-(methylsulfonyl)benzamide. The related preparation method has the characteristics of being brief in steps, simple in operation, basically free of waterless requirement on reaction conditions, relatively low in oxygen-free requirement and the like, and is capable of effectively reducing production cost.

Description

technical field [0001] The present invention relates to the fields of organic chemistry and medicinal chemistry, in particular, the present invention relates to 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzene Method for the preparation of formamide (Vismodegib) and its intermediates. Background technique [0002] During embryonic development, the Hedgehog signaling pathway plays an important role in cell differentiation, tissue development and organ formation. In the adult body, the Hedgehog signaling channel is mainly in a dormant state, but when tissue growth and self-repair are abnormal, the Hedgehog pathway may be activated. With the in-depth study of tumors, many evidences show that the occurrence of tumors is closely related to the abnormality of the Hedgehog signaling pathway, such as occasional basal cell carcinoma, medulloblastoma, small cell lung cancer and gastrointestinal cancer and other diseases, so the Hedgehog signaling pathway Target...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/40C07D213/26
CPCC07D213/26C07D213/40
Inventor 李锐顾惠龙赵虎城刘飞王小宁孙键
Owner LIANYUNGANG RUNZHONG PHARMA CO LTD
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