A kind of Sony Gibb intermediate and the preparation method of Sony Gibb

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...

Examples

Embodiment 1

[0074] Example 1: Preparation of N,N-bis(2S-2-hydroxypropylamino)-5-nitropyridine (Ⅲ1)

[0075] In the 500 milliliter stainless steel autoclave that is connected with stirring and thermometer, add 220 gram tetrahydrofuran, 27.8 gram (0.2 mol) 2-amino-5-nitropyridine (Ⅱ), 0.5 gram zinc chloride, 27.0 gram (0.47 mol) S-propylene oxide, airtight autoclave, nitrogen replacement 3 times, 50 to 55 ℃ stirring reaction for 4 hours, cool to 20-25 ℃, transfer the reaction liquid to the 500 milliliter flask that is connected with stirring, thermometer and distillation device, The solvent was recovered by distillation, and the residue was recrystallized with methyl tert-butyl ether to obtain 47.7 g of N,N-bis(2S-2-hydroxypropylamino)-5-nitropyridine (Ⅲ1). The yield was 93.5%, and the liquid phase purity 99.7%.

Embodiment 2

[0076] Example 2: Preparation of N,N-bis(2R-2-hydroxypropylamino)-5-nitropyridine (Ⅲ2)

[0077] In the 500 milliliter stainless steel autoclave that is connected with stirring and thermometer, add 220 gram tetrahydrofuran, 27.8 gram (0.2 mol) 2-amino-5-nitropyridine (Ⅱ), 0.5 gram zinc chloride, 27.0 gram (0.47 mol) R-propylene oxide, airtight autoclave, nitrogen replacement 3 times, 50 to 55 ℃ stirring reaction 4 hours, cool to 20-25 ℃, transfer the reaction liquid to the 500 milliliter flask that is connected with stirring, thermometer and distillation device, The solvent was recovered by distillation, and the residue was recrystallized with methyl tert-butyl ether to obtain 47.6 g of N,N-bis(2R-2-hydroxypropylamino)-5-nitropyridine (Ⅲ2). The yield was 93.3%, and the liquid phase purity 99.8%.

Embodiment 3

[0078] Example 3: Preparation of (2S,6R)-2,6-dimethyl-4-(5-nitropyridin-2-yl)morpholine (IV)

[0079]In the 500 ml four-neck flask connected with stirring, thermometer, reflux condenser and variable head (connected with two constant pressure dropping funnels A and B), add 150 g of dichloromethane, 30.5 g (0.22 moles) of potassium carbonate, The constant pressure dropping funnel A is equipped with 25.5 grams (0.1 moles) of N, N-two (2S-2-hydroxypropylamino)-5-nitropyridine (Ⅲ1) and 50 grams of dichloromethane solution obtained by the method of embodiment 1, The constant-pressure dropping funnel B is equipped with a solution of 33.0 grams (0.12 moles) of trifluoromethanesulfonic anhydride and 50 grams of dichloromethane, cooled and kept between 15-20 ° C, and drop the two solutions at the same time for 1-2 hours After the addition is complete, thereafter, stir and react at 20 to 25°C for 4 hours, filter, add the resulting filtrate to 100 grams of water, adjust the pH value to 8-...

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...

Examples

Embodiment 1

[0074] Example 1: Preparation of N,N-bis(2S-2-hydroxypropylamino)-5-nitropyridine (Ⅲ1)

[0075] In the 500 milliliter stainless steel autoclave that is connected with stirring and thermometer, add 220 gram tetrahydrofuran, 27.8 gram (0.2 mol) 2-amino-5-nitropyridine (Ⅱ), 0.5 gram zinc chloride, 27.0 gram (0.47 mol) S-propylene oxide, airtight autoclave, nitrogen replacement 3 times, 50 to 55 ℃ stirring reaction for 4 hours, cool to 20-25 ℃, transfer the reaction liquid to the 500 milliliter flask that is connected with stirring, thermometer and distillation device, The solvent was recovered by distillation, and the residue was recrystallized with methyl tert-butyl ether to obtain 47.7 g of N,N-bis(2S-2-hydroxypropylamino)-5-nitropyridine (Ⅲ1). The yield was 93.5%, and the liquid phase purity 99.7%.

Embodiment 2

[0076] Example 2: Preparation of N,N-bis(2R-2-hydroxypropylamino)-5-nitropyridine (Ⅲ2)

[0077] In the 500 milliliter stainless steel autoclave that is connected with stirring and thermometer, add 220 gram tetrahydrofuran, 27.8 gram (0.2 mol) 2-amino-5-nitropyridine (Ⅱ), 0.5 gram zinc chloride, 27.0 gram (0.47 mol) R-propylene oxide, airtight autoclave, nitrogen replacement 3 times, 50 to 55 ℃ stirring reaction 4 hours, cool to 20-25 ℃, transfer the reaction liquid to the 500 milliliter flask that is connected with stirring, thermometer and distillation device, The solvent was recovered by distillation, and the residue was recrystallized with methyl tert-butyl ether to obtain 47.6 g of N,N-bis(2R-2-hydroxypropylamino)-5-nitropyridine (Ⅲ2). The yield was 93.3%, and the liquid phase purity 99.8%.

Embodiment 3

[0078] Example 3: Preparation of (2S,6R)-2,6-dimethyl-4-(5-nitropyridin-2-yl)morpholine (IV)

[0079]In the 500 ml four-neck flask connected with stirring, thermometer, reflux condenser and variable head (connected with two constant pressure dropping funnels A and B), add 150 g of dichloromethane, 30.5 g (0.22 moles) of potassium carbonate, The constant pressure dropping funnel A is equipped with 25.5 grams (0.1 moles) of N, N-two (2S-2-hydroxypropylamino)-5-nitropyridine (Ⅲ1) and 50 grams of dichloromethane solution obtained by the method of embodiment 1, The constant-pressure dropping funnel B is equipped with a solution of 33.0 grams (0.12 moles) of trifluoromethanesulfonic anhydride and 50 grams of dichloromethane, cooled and kept between 15-20 ° C, and drop the two solutions at the same time for 1-2 hours After the addition is complete, thereafter, stir and react at 20 to 25°C for 4 hours, filter, add the resulting filtrate to 100 grams of water, adjust the pH value to 8-...

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