Tyrosine kinase inhibitor indolinone derivative
A technology of amino and compound, applied in the field of tyrosine kinase inhibitor indolinone derivatives
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[0157] The preparation of step 1 intermediate 1
[0158] Dissolve raw material 1 and organic base in DCM, add raw material 2 dropwise under ice-water bath, raise to room temperature and react for half an hour, add water, extract with DCM, dry, evaporate to dryness, and dry the solid in vacuo to obtain intermediate 1.
[0159] Step 2 Preparation of Intermediate 2
[0160] Dissolve intermediate 1 and organic base in DCM, add raw material 3 dropwise, react at room temperature for 12 h, extract with DCM, dry the organic layer with anhydrous sodium sulfate, and evaporate to dryness to obtain intermediate 2.
[0161] Step 3 Preparation of Intermediate 3
[0162] Dissolve intermediate 2 in DCM, add TFA, after the reaction at room temperature, concentrate to obtain intermediate 3 or dissolve intermediate 2 in methanol, hydrogenate Pd / C overnight, filter, and concentrate to obtain intermediate 3, the product It was directly used in the next reaction without purification.
[0163] Pr...
Embodiment 1
[0223] Example 1 (Z)-3-((4-(N-methyl-2-(6-methyl-2,6-diazaspiro[3.3]heptane-2-yl)acetamido)anilino ) (phenyl) sub Preparation of methyl)-2-oxoindoline-6-carboxylate (compound 1)
[0224]
[0225] (1) 6-(2-(methyl(4-nitrophenyl)amino)-2-oxoethyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert Preparation of butyl ester
[0226]
[0227] Dissolve 2-chloro-Nmethyl-N-(4-nitrophenyl)acetamide (2.28g, 10mmol) and sodium bicarbonate (8.4g, 100mmol) in 60mL THF, add bis(2, 6-diazaspiro[3.3]heptane-2-carboxylate tert-butyl) oxalate (2.43g, 5mmol), the reaction solution was heated to 65°C for 24h. The reaction solution was added with water, extracted with dichloromethane, dried, concentrated and separated by silica gel column (petroleum ether: ethyl acetate = 2:1) to obtain 1.2 g of the product with a yield of 30.7%.
[0228] (2) Preparation of N-methyl-N-(4-nitrophenyl)-2-(2,6-diazaspiro[3.3]heptane-2 base)acetamide
[0229]
[0230] tert-butyl 6-(2-(methyl(4-nitrop...
Embodiment 2
[0242] Example 2 (Z)-3-((4-(N-methyl-2-(3-azabicyclo[3.1.0]hexane-6-yl)acetamido)anilino)(phenyl)phenylene First base)-2-oxoindoline-6-carboxylate methyl ester (compound 2)
[0243]
[0244] (1) Preparation of N-methyl-2-(3-methyl-3-azabicyclo[3.1.0]hexane-6-yl)-N-(4-nitrophenyl)acetamide
[0245]
[0246] Dissolve 2-(3-methyl-3-azabicyclo[3.1.0]hexan-6-ylacetic acid (1.0 g, 6.4 mmol) in 30 mL of DCM, add thionyl chloride (5 mL, 64 mmol), and heat After refluxing for 5h, pull it dry, redissolve it in 40mL of dichloromethane, add triethylamine (5mL, 32mL) and N-methyl-4nitrobenzene (3g, 20mmol).React overnight at room temperature, evaporate the solvent to dryness, The remaining solid was separated by silica gel column (dichloromethane:methanol=30:1) to obtain 1.5g of the product with a yield of 80.6%.
[0247] (2) Preparation of N-(4-aminophenyl)-N-methyl-2-(3-methyl-3-azabicyclo[3.1.0]hexane-6-yl)acetamide
[0248]
[0249] The method is the same as in Example ...
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