4-(METHOXYMETHYL)ANILINE

General procedure: A mixture of 2a (243mg, 1mmol) and 1percent Pd/Ni bimetallic catalyst (73mg, 30wtpercent) in MeOH (10mL) was stirred under H5.3a (1.9 g, 9.45 mmoi, 1.0equiv), CuI (0.180 g, 0.94 mmoi, 0.1 equiv), acetyi acetone (0.95 g, 9.45 mmoi, 1.0 equiv) and C52CO3 (6.15 g, 18.9 mmoi, 2.0 equiv) were suspended in N, N-dimethyiformamide (28mL) in sealed tube and ammonium hydroxide (2.18 mL, 5.67 mmol, 6.0 equiv) was added and the reaction mixture was stirred at 100 °C for 5 hours. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a residue. The residue was purified by silica gel column chromatography (0.7 percent MeOH in dichloromethane) to afford product 5.3b (1.1 g, 85 percent yield). LCMS (mlz): 138.2 [M+H]. 1H NMR (400 MHz, DMSO) 6 6.96 (d, J = 8.1 Hz, 2H), 6.52 (d, J 8.1 Hz, 2H), 5.06 (s, 2H), 4.18 (s, 2H), 3.19 (s, 3H).General procedure: To a solution of 1H-pyrrolo[3, 2-H]quinoline-3-sulfonyl chloride (140 mg, 0.52 mmol) in pyridine (1.5 mL) was added 4-chloro-2, 5-difluoroaniline (90 mg, 0.55 mmol). The reaction mixture was stirred at room temperature for 4h and then evaporated to dryness. The residue was triturated in a mixture of water/acetonitrile (8/2) and sonicated. The solid suspension was filtered, rinsed with water, dried under vacuum at 35C, to afford 105 mgof N-(4-chloro-2, 5-difluorophenyl)-1 H-pyrrolo[3, 2-h]quinoline-3-sulfonamide 1-118, as a beige solid.Yield: 50%.Basic LCMS Method 1 (ES): 394 (M+H), 99 % purity.1H NMR (400 MHz, DMSO-d6) 6 13.26 (s, 1H), 10.51 (s, 1H), 8.93 (dd, J = 4.4, 1.6 Hz, 1 H), 8.46 (dd, J = 8.3, 1.6 Hz, 1 H), 8.04 - 7.65 (m, 3H), 7.59 (m, 1 H), 7.51 (dd, J = 9.8, 6.8 Hz, 1H), 7.40 (dd, J = 10.4, 7.0 Hz, 1H).Example 45 Synthesis of 4-amino-7-(1-(fluoromethyl)cyclopropyl)-N-(4-(methoxymethyl)phenyl)-7H-pyrrolo[2, 3-d]pyrimidine-5-carboxamide A solution of 100 mg of 7-(1-(fluoromethyl)cyclopropyl)-5-iodo-7H-pyrrolo[2, 3-d]pyrimidin-4-amine obtained in step 3 of Reference Example 6, 100 mg of 4-(methoxymethyl)aniline, 90 muL of 1, 8-diazabicyclo[5.4.0]undec-7-ene, and 20 mg of 1, 1'-bis(diphenylphosphino) ferrocene-palladium(II) dichloride-dichloromethane complex in 3 mL of NMP was stirred in a carbon monoxide atmosphere at 100 C. for 4 hours. The reaction solution was concentrated and purified by silica gel chromatography (hexane-ethyl acetate-methanol), thereby obtaining 86 mg of the title compound.Step 2: Synthesis of 7-(tert-butyl)-N-(4-(methoxymethyl)phenyl)-4-(methylamino)-7H-pyrrolo[2, 3-d]pyrimidine-5-carboxamide 7-(tert-butyl)-5-iodo-N-methyl-7H-pyrrolo[2, 3-d]pyrimidin-4-amine obtained in step 1, 103 mg of 4-(methoxymethyl)aniline, 90 mul of 1, 8-diazabicyclo[5.4.0]undec-7-ene, and 24 mg of 1, 1'-bis(diphenylphosphino) ferrocene-palladium (II) dichloride-dichloromethane complex were added to 1 mL of DMA, and the mixture was stirred in a carbon monoxide atmosphere at 110 C. for 2 hours. The obtained reaction solution was purified by silica gel chromatography (developing solvent: hexane-ethyl acetate), concentrated, and purified again by basic silica gel chromatography, followed by concentration, thereby obtaining 52 mg of the title compound.Step 2: Synthesis of 4-amino-6-bromo-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)7H-pyrrolo[2, 3-d]pyrimidine-5-carboxamide 10.1 mg of 4-amino-6-bromo-7-(1-methylcyclopropyl)-7H-pyrrolo[2, 3-d]pyrimidine-5-carboxylic acid obtained in step 1 was dissolved in 1 mL of DMF, and 5.3 mg of 4-(methoxymethyl)aniline, 17 muL of DIPEA, and 18.5 mg of HATU were added thereto, followed by stirring at room temperature overnight. The reaction solution was partitioned between ethyl acetate and water, and the organic layer was washed with a 1N NaOH aqueous solution, water, and a saturated aqueous sodium chloride solution, followed by drying over anhydrous sodium sulfate. After filtration, the filtrate was concentrated. The residue was purified by silica gel column (ethyl acetate/methanol=1/0->8/1), thereby obtaining 6.7 mg of the title compound.Synthesis of 4-amino-1-cyclopentyl-N-(4-(methoxymethyl)phenyl)-1H-pyrazolo[3, 4-d]pyrimidine-3-carboxamide 30 mg of 4-amino-1-cyclopentyl-1H-pyrazolo[3, 4-d]pyrimidine-3-carboxylic acid obtained in step 2 of Reference Example 1, 20 mg of 4-(methoxymethyl)aniline, and 55 mg of HATU were dissolved in 1 mL of DMF, and 62 muL of diisopropylethylamine was added thereto. After stirring at room temperature for 18 hours, water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration of the organic solution under reduced pressure. The residue was purified by silica gel chromatography (chloroform->chloroform/methanol=10/1), thereby obtaining 36 mg of the title compound.

Molecular Weight:137.18
XLogP3:0.3
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:2
Exact Mass:137.084063974
Monoisotopic Mass:137.084063974
Topological Polar Surface Area:35.2
Heavy Atom Count:10
Complexity:87.3
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes