Cathepsin k inhibitors and uses thereof
A compound, an independent technology, applied in anti-inflammatory agents, drug combinations, non-central analgesics, etc.
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Embodiment 1
[0217] Example 1N-(1-((1-cyanocyclopropyl)carbamoyl)cyclohexyl)-5-(4-(methylsulfonyl)phenyl)-benzofuran-2-carboxamide
[0218]
[0219] Step 1: Ethyl 5-bromobenzofuran-2-carboxylate
[0220] Add 5-bromo-2-hydroxybenzaldehyde (15g, 74.63mmol), ethyl bromoacetate (18.7g, 111.9mmol), potassium carbonate (31g, 223.9mmol) and anhydrous DMF (80mL) into a 250mL two-necked flask , the reaction mixture was heated to 130° C. for 5 hours to complete the reaction. After filtration, the filtrate was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (100 mL), washed with saturated brine (50 mL×3), and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the crude product was subjected to silica gel column chromatography (ethyl acetate:petroleum ether=1:20, V / V) to obtain 16.6 g of light yellow solid with a yield of 83%.
[0221] MS(ESI,pos.ion)m / z:269.9(M+2);
[0222] Step 2: 5-Bromobenzofuran-2...
Embodiment 2
[0235] Example 2N-(1-((1-cyanocyclopropyl)carbamoyl)cyclohexyl)-6-fluoro-5-(4-(methylsulfonyl)phenyl)-benzofuran-2-methyl Amide
[0236]
[0237] Step 1: Ethyl 5-bromo-4-fluorobenzofuran-2-carboxylate
[0238] Add 5-bromo-4-fluoro-2-hydroxybenzaldehyde (16.3g, 74.63mmol), ethyl bromoacetate (18.7g, 111.9mmol), potassium carbonate (31g, 223.9mmol) and no Water DMF (80mL), prepared according to the synthetic method of Example 1 Step 1, the crude product was subjected to silica gel column chromatography (ethyl acetate:petroleum ether=1:20, V / V) to obtain 16.1g of a light yellow solid, the yield 75%.
[0239] MS(ESI,pos.ion)m / z:287.9(M+2);
[0240] Step 2: 5-Bromo-4-fluorobenzofuran-2-carboxylic acid
[0241] Add ethyl 5-bromo-4-fluorobenzofuran-2-carboxylate (4.26g, 14.86mmol), methanol (50mL) and NaOH solution (22.3mL, 44.6mmol) into a 100mL two-necked flask, according to Example 1. Prepared by the synthetic method of step 2. After vacuum drying, 3.46 g of white solid wa...
Embodiment 3
[0250] Example 3 N-(1-((1-cyanocyclopropyl)carbamoyl)cyclohexyl)-5-(2-oxopyrrolidin-1-yl)benzofuran-2-carboxamide
[0251]
[0252] Step 1: Ethyl 5-bromobenzofuran-2-carboxylate
[0253] Add 5-bromo-2-hydroxybenzaldehyde (15g, 74.63mmol), ethyl bromoacetate (18.7g, 111.9mmol), potassium carbonate (31g, 223.9mmol) and anhydrous DMF (80mL) into a 250mL two-necked flask , was prepared according to the synthesis method in Step 1 of Example 1, and the crude product was subjected to silica gel column chromatography (ethyl acetate:petroleum ether=1:20, V / V) to obtain 16.6 g of a light yellow solid with a yield of 83%.
[0254] MS(ESI,pos.ion)m / z:269.9(M+2);
[0255] Step 2: 5-Bromobenzofuran-2-carboxylic acid
[0256] Add ethyl 5-bromobenzofuran-2-carboxylate (4g, 14.86mmol) and methanol (50mL) into a 100mL two-necked flask, then add NaOH solution (22.3mL, 44.6mmol), according to step 2 of Example 1 Prepared by the synthetic method, obtained white solid 3.30g after vacuum dryin...
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