Heteroaryl fused pyridines, pyrazines and pyrimidines as CRF1 receptor ligands
A heteroaryl group, CR10R11 technology, applied in drug combinations, pharmaceutical formulations, medical preparations containing active ingredients, etc., can solve the problems of anxiolytics and antidepressants that have yet to be fully elucidated, such as the mechanism of action and the position of action
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[0359] Example 1. Dihydroxyboronic acid intermediate preparation method:
[0360] a.2-(dimethylamino)-4-methoxypyridine-5-dihydroxyboronic acid synthesis method
[0361]
[0362] Step A
[0363] Trifluoromethanesulfonic anhydride ( 12.9 g), triethylamine (8.4 g) was added. The reaction mixture was stirred for 20 minutes, then allowed to warm to room temperature. The volatile components were evaporated in vacuo, then the residue was dissolved in EtOAc and washed sequentially with aqueous sodium bicarbonate, water and brine solution. The organic phase was separated, dried and evaporated in vacuo to yield 4-methoxy-pyridin-2-yl triflate. It was used in the next step without further purification.
[0364] Step B
[0365] Dissolve 4-methoxy-pyridin-2-yl trifluoromethanesulfonate (0.5 g) and dimethylamine (2.4 mL of a 2M solution in THF) in DMSO (7 mL) and heat at 40° C. one night. EtOAc was added to the reaction mixture, washed with brine solution. The organic phase was...
example 2
[0452] 5-(1-ethyl-propyl)-2-(2-methoxy-4-trifluoromethoxy-phenyl)-3,7-dimethyl-5H-pyrrolo[2,3- b] pyrazine synthesis method
[0453]
[0454] Step A
[0455] Take the above-mentioned 2-bromo-3-methyl-5-isopentylaminopyrazine (870 mg) and 2-methoxy-4-trifluoromethoxyphenyl dihydroxyboronic acid (796 mg) known from the literature Dissolve in DME (15 mL). After degassing, tetrakis(triphenylphosphine)palladium(0) (390 mg) was added. After a second degassing, 1 N sodium carbonate solution (6.74 mL) was added, at which time the reaction was heated to 80 °C for 6 hours. The yellow mixture was added to water (200 mL), extracted with DCM (3 x 100 mL), and dried over magnesium sulfate. Purification on silica gel yields the coupled product. LCMS: m / z 370.17 (M+H) +
[0456] Step B
[0457] The product of step A (205 mg) was dissolved in chloroform (10 mL), and NBS (99 mg) was added. After stirring for 10 min, the yellow mixture was added to water (100 mL), extracted with DCM ...
example 3
[0463] {5-[3-chloro-5-(1-ethyl-propyl)-7-methyl-5H-pyrrolo[2,3-b]pyrazin-2-yl]-4-ethyl-pyridine -2-yl}-dimethyl-amine
[0464]
[0465] Step A
[0466] The above 2-chloro-6-isoamylaminopyrazine (25.1 g) was dissolved in chloroform (450 mL), and NBS (47.1 g) was added in batches. After stirring for 30 min, the yellow mixture was added to water (400 mL) and saturated sodium bicarbonate (100 mL), extracted with DCM (3 x 200 mL), and dried over magnesium sulfate. The crude product was carried on to Step B without further purification. Rf = 0.57, hexane / ethyl acetate (10 / 1).
[0467] Step B
[0468] The crude product from Step A (28.37 g) and allyl bromide (20.6 mL) were dissolved in DMF (200 mL). Sodium hydride (4.76 g) was added in portions, and the reaction was stirred at room temperature for 5 hours. The mixture was added to water (500 mL), extracted with ethyl acetate / hexane (1 / 20, 3×300 mL). The combined organic layers were dried over magnesium sulfate and purified on...
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