Carboxamide and sulfonamide derivatives useful as tead modulators
A compound and alkyl technology, which is applied in the preparation of carboxylic acid amides, sulfonamides, drug combinations, etc., can solve problems such as protein instability
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example 1
[0424] Preparation of N-(3-(2-cyclohexylcyclopropyl)-4-methoxyphenyl)methanesulfonamide (enantiomer A and enantiomer B)
[0425] The reaction scheme is as follows:
[0426]
[0427] Step 1: N-(3-Bromo-4-methoxyphenyl)methanesulfonamide
[0428] Charge 2-bromo-4-iodoanisole (1.0g, 3.0mmol), methanesulfonamide (1.4g, 15mmol), cuprous iodide (590mg, 3.03mmol), N,N-dimethyl Glycine (319 mg, 3.03 mmol) and tripotassium phosphate (1.3 g, 6.1 mmol), and the flask was purged with nitrogen. N,N-Dimethylglycine (10 mL) was then added, and the reaction was stirred at 100°C for 2 hours. The reaction mixture was diluted with water (10 mL) and 10% aqueous glycine (10 mL), acidified with 1N HCl to pH = 1, extracted with i-PrOAc (3x10 mL), washed with anhydrous MgSO 4 Drying, concentration and purification by silica gel column chromatography (0% to 100% i-PrOAc in heptane) afforded the title compound as a white solid (598 mg, 70% yield). LCMS(ESI+)m / z280(M+H) + .
[0429] Step 2: (E)...
example 2
[0436] (E)-N-(3-(2-(4,4-difluorocyclohexyl)vinyl)-4-methoxyphenyl)methanesulfonamide)
[0437] The reaction scheme is as follows:
[0438]
[0439] Step 1: Diethyl (2-methoxy-5-(methylsulfonamido)benzyl)phosphonate
[0440] 2-(diethoxyphosphorylmethyl)-4-iodo-1-methoxybenzene (5.0g, 13mmol), tert-butyl n-methylsulfonylcarbamate (7.1g, 36mmol), cuprous iodide (2.5g, 13mmol), N,N-dimethylglycine (1.4g, 13mmol) and tripotassium phosphate (11.4g, 52.1mmol), and purged the flask with nitrogen. N,N-Dimethylacetamide (43 mL) was then added and the flask was flushed with nitrogen again and an air balloon was placed on top of the reaction vessel to allow room for gas evolution. The reaction mixture was stirred at 110°C for 16 hours. The resulting mixture was diluted with 10% aqueous glycine and acidified to pH 1 with 1N HCl, extracted with dichloromethane (3x50 mL), washed with anhydrous MgSO 4 Drying, concentration under reduced pressure and purification by silica gel column ch...
example 3
[0444] (E)-N-(3-(2-cyclopentylvinyl)-4-methoxyphenyl)methanesulfonamide
[0445]
[0446] The title compound (14 mg, 38% yield) was prepared according to the procedure of Example 2 using cyclopentanaldehyde. 1 H NMR (400MHz, DMSO-d 6 )δ9.27(s,1H),7.26(d,J=2.6Hz,1H),7.06(dd,J=8.8,2.6Hz,1H),6.95(d,J=8.8Hz,1H),6.57( dd,J=16.0,1.1Hz,1H),6.14(dd,J=16.0,7.9Hz,1H),3.77(s,3H),2.88(s,3H),2.64–2.54(m,1H),1.89 –1.75(m,2H),1.75–1.50(m,4H),1.43–1.27(m,2H); LCMS(ESI+)m / z 296.1(M+H) + .
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