Preparation methods of Sonidegib intermediate and Sonidegib

Abstract

The invention provides preparation methods of a Sonidegib intermediate and Sonidegib. According to the preparation methods, 2-amino-5-nitropyridine (II) and R-propylene oxide (or S-propylene oxide) are subjected to an epoxy ring-opening substitution reaction, and a condensation reaction is performed to prepare a Sonidegib key intermediate; the nitro of the Sonidegib key intermediate is reduced bya catalytic hydrogenation reaction to obtain (2S,6R)-2,6-dimethyl-4-(5-aminopyridin-2-yl)morpholine; 2-methyl-4'-(trifluoromethoxy)-[1,1'-biphenyl]-3-carboxylic acid and an acyl chlorination reagent are subjected to an acyl chlorination reaction; and the acyl chlorination reaction product and the (2S,6R)-2,6-dimethyl-4-(5-aminopyridin-2-yl)morpholine are subjected to an amidation reaction to prepare the Sonidegib (I). According to the present invention, the method has advantages of inexpensive and easily-available raw materials, low cost, safe, simple and environmentally-friendly preparation steps, low wastewater generation, high product yield and high product purity, and is suitable for industrial production.

Description

technical field [0001] The invention relates to a Sony Gibb intermediate and a preparation method of Sony Jibu, belonging to the technical field of medicinal chemistry. Background technique [0002] Sonidegib, English name Sonidegib, is a SMO receptor antagonist developed by Novartis and approved by the US FDA and EMA on July 24, 2015 and August 14, 2015. Inhibits the Hedgehog pathway, thereby preventing or reducing the development of cancerous changes. Sonijib is used to treat patients with locally advanced basal cell carcinoma who are inoperable for surgery and radiation, or who have relapsed after surgery or radiation. The drug is one of only two drugs currently on the market for the treatment of basal cell carcinoma. [0003] The chemical name of Sony Gibb is N-[6-[(2R,6S)-2,6-dimethyl-4-morpholinyl]-3-pyridyl]-2-methyl-4'-(trifluoro Methoxy)-[1,1'-biphenyl]-3-carboxamide, the CAS number is 956697-53-3, the structural formula is as follows: [0004] [0005] At pr...

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Problems solved by technology

[0013] The above reaction schemes 1 and 2 all use chiral (2S,6R)-2,6-dimethylmorpholine, which is expensive and difficult to obtain; the 2-chloro-5-nitropyridine used needs to be prepared from 2 -Aminopyridine is prepared by nitration reaction, diazotization hydrolysis reaction, and chlorination reaction, the price is high, and the amount of process wastewater is large, which is not conducive to cost reduction and green production

Compound (2S, 6R)-2,6-dimethyl-4-(5-nitropyridin-2-yl) morpholine in routes 1 and 2 is a key intermediate for the preparation of Sony Gibb, but (2S, 6R )-2,6-dimethyl-4-(5-nitropyridin-2-yl)morpholine is synthesized by 2-chloro-5-nitropyridine and cis-2,6-dimethylmorpholine Phenol is raw material, selects DMF or acetonitrile as solvent, and obtains by SN2 reaction under the effect of carbonate (potassium carbonate or sodium carbonate).

[0014] In summary, the synthetic method of Sony Gibb in the prior art has disadvantages such as high raw material price, high cost, large amount of process wastewater, unfavorable environmental protection, unreasonable process route design, etc.

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