Compounds for inhibiting insulin secretion and methods related thereto
a technology of compound and insulin, applied in the field of compound, can solve the problems of hyperglycemia and/or excessive weight gain, none of the current pharmacological therapies correct the underlying biochemical defect, and all currently available treatments improve. , to achieve the effect of enhancing insulin secretion
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example 1
[0103]
Synthesis of 4-chloro-1′,1′,1′-trimethylacetanilide (2a)
[0104] To a solution of 4-chloroaniline (1a) (20 g, 0.157 mole) in DCM (400 ml) at 0° C. was added DIEA (54.7 ml, 0.314 mol) and pivaloyl chloride (23.2 ml, 0.188 mol). The mixture was stirred for 2 hours and washed with water (500 ml×2), 10% NaHCO3 (aq.) (500 ml×2), water (500 ml×2) and dried over Na2SO4. The crude product was recrystalized from ethyl acetate to give the title compound 2a as a white solid (23 g, 69% yield).
Synthesis of 3a (W1=5-Cl, R1=4-pyridyl)
[0105] To a solution of the 4-chloro-1′,1′,1′-trimethylacetanilide (a (509 mg, 2.4 mmol) in THF (10 ml) under an atmosphere of nitrogen cooled to −78° C. was added n-butyllithium (2.5 ml, 2.4 M solution in diethyl ether, 6 mmol) over 5 min. The reaction was left to warm up to 0° C. and kept at this temperature for 2 hrs. Pyridine-4-carboxaldehyde (515 mg, 4.8 mmol) dissolved in THF (2 ml) was added and the reaction was left to slowly warm to room temperature ov...
example 2
[0110]
Synthesis of 5a (W1=5-Cl, R2=NH2)
[0111] To a solution of N,O-dimethylhydroxylamine hydrochloride (2.0 g, 20 mmol) dissolved in 90% ethanol (40 ml) was added triethylamine (2.5 ml, 20 mmol). The reaction was left stirring for 10 min and 5-chloroisatoic anhydride (3 g, 15.2 mmol) was added to the above solution in small portions. The reaction was heated to reflux for 1 h, after which time it was poured into a 1:1 ice / saturated sodium bicarbonate solution (50 ml). The ethanol was removed under reduced pressure and the resulting aqueous solution was extracted with ethyl acetate (3×50 ml). The combined organic phase was dried over magnesium sulfate, filtered and the solvent removed in vacuum to yield a colorless oil. This material was further purified by flash chromatography on silica gel (150 g) using petroleum ether:ethyl acetate 2:1 then 1:1 as eluent, to provide the desired compound 5a as a slightly off white solid (2.61 g, 70% yield)); Rf (petroleum ether:ethyl acetate (2:1)=...
example 3
[0138]
Synthesis of 8a (W1=5-methyl)
[0139] A mixture of 2-amino-5-methylbenzoic acid (La) (2.0 g, 0.013 mol) and AR grade THF (21 ml) was cooled to 0° C. With vigorous stirring, anhydrous sodium carbonate (2.2 g, 0.021 mol, 1.6 eq.) was added followed by benzoyl chloride (3.02 ml, 0.026 mol, 2 eq.) dropwise. The mixture was left to stand at 0° C. for an additional 30 min, after which the cold bath was removed and the mixture stirred at rt overnight. Water (15 ml) was added. The reaction mixture was evaporated under reduced pressure (to remove the THF), extracted with CH2Cl2 (×2). The combined CH2Cl2 fractions were dried (Na2SO4) and evaporated under reduced pressure to give 8a as a cream colored solid (2.55 g, 82% yield). LC / MS tR=8.16 (256.1, acyclic amide), 9.47 (237.9 [M+H]+) min. The crude material was used in the next step.
Synthesis of 9a (W1=5-methyl, R1=2-methylphenyl)
[0140] A solution of the crude material 8a from the previous step (0.5 g, 2 mmol) in CH2Cl2 (15 ml) was coo...
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