3-(Aminomethyl)pyrazole

Colorless Liquid

General procedure: To a solutionof the corresponding aldehyde (1.2 eq.; unless stated otherwise) in DMF (2 inL per 0.3 mmol of aldehyde; unless stated otherwise) was added the corresponding amine (2.5 eq.; unless stated otherwise) and the resulting solution was stirred at 25 C to form the corresponding inline. Then, the corresponding isocyano(tosyl)methyl)arene reagent (1 eq.; unless stated otherwise) and K2CO3 (1.5 eq.; unless stated otherwise*) were added and the reaction mixture was stirred at 25 C (unless stated otherwise). The reaction was stopped after the time indicated for each particular reaction. The reaction progress was monitored by TLC. (0083) A saturated aqueous solution of NH4CI (10 mL per 1 mmol of aldehyde) was added to the reaction mixture, which was then extracted with EtOAc (2 x 30 mL per 1 mmol of aldehyde). The combined organic extracts were washed with H2O (2 x 25 mL per 1 mmol of aldehyde), dried over MgSCC, filtered, and the solvent was evaporated in vacuo to provide the crude product. The residue obtained after the workup was purified using column chromatography or preparative TLC (unless stated otherwise). (0084) * note: in cases when the amine was used as HC1 salt, 4 eq. of K2CO3 were usedTo a solution of 4-chloro-7-(l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-5- yl)quinolin-2-amine (20 mg, 0.061 mmol) and (lH-pyrazol-3-yl)methanamine (59.1 mg, 0.608 mmol) in DMSO (0.5 mL) was added Hunig's Base (0.032 mL, 0.182 mmol). The reaction was heated to 120 C overnight. The reaction was cooled, diluted with water, and extracted three times with EtOAc. The organic layers were concentrated, then dissolved in 0.4 mL DCM and 0.4 mL TFA. After 1 hour, the reaction was complete by LCMS. The reaction was concentrated and azeotroped with DCM. The residue was dissolved in DMF, filtered through a syringe filter, and the crude material was purified via preparative LC/MS with the following conditions: Column: XBridge CI 8, 200 mm x 19 mm, 5-muiotatauiota particles; Mobile Phase A: 5:95 acetonitrile: water with 0.1%trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile: water with 0.1% trifluoroacetic acid; Gradient: a 0-minute hold at 0% B, 0-40% B over 20 minutes, then a 4-minute hold at 100% B; Flow Rate: 20 mL/min; Column Temperature: 25 C. Fraction collection was triggered by MS signals. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparative LC/MS with the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5-mupiiota particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: a 3- minute hold at 0% B, 0-32% B over 25 minutes, then a 5-minute hold at 100% B; Flow Rate: 20 mL/min; Column Temperature: 25 C. Fraction collection was triggered by MS signals. Fractions containing the desired product were combined and dried via centrifugal evaporation to give N4-((lH-pyrazol-3-yl)methyl)-7-(lH-pyrazol-5-yl)quinoline-2, 4- diamine (4.6 mg, 24.7%). NMR (500 MHz, DMSO-de) delta 8.00 (br d, J=8.2 Hz, 1H), 7.75 (s, 1H), 7.72 (br s, 1H), 7.58 (br s, 1H), 7.54 (br d, J=7.9 Hz, 1H), 7.43 (br s, 1H), 6.76 (s, 1H), 6.62 - 6.41 (m, 1H), 6.20 (s, 1H), 5.76 (s, 1H), 4.42 (br d, J=5.2 Hz, 2H). LC RT: 0.99 min. M/Z= 306.18. (1550)To a solution of C-(1H-pyrazol-3 -yl)-methylamine (81.5 mg, 0.84 mmol) in dioxane (30 mL) was added 4-phenoxycarbonylamino-benzoic acid ethyl ester (200 mg, 0.7 mmol) and DIPEA (181 mg, 1.4 mmol). After stirred at 90 C overnight, the reaction mixture was concentrated in vacuum. The residue was purified by pre-HPLC to afford ethyl 4-(3-((1H-pyrazol-3- yl)methyl)ureido)benzoate (25 mg, 12%) as a white solid. 'H NIVIR (400 IVIHz, CD3OD): oe = 7.91 (d, J= 8.8 Hz, 2H), 7.57 (s, 1H), 7.49 (d, J= 8.4 Hz, 2H), 6.29 (s, 1H), 4.43 (s, 2H), 4.32 (q, J 7.2 Hz, 2H), 1.37 (t, J= 7.2 Hz, 3H). MS: m/z 289.0 (M+H).To a solution of [4-(1-methyl-1H-pyrazolo[4, 3-c]pyridin-3-yl)-phenyl]-carbamic acid phenyl ester (120 mg, 0.35 mmol) in ACN (10 mL) was added To a solution of [4-(2-pyridin-4-yl-benzenesulfonyl)-phenyl]-carbamic acid phenyl ester (100 mg, 0.23 mmol) in ACN (10 mL) was added A 5 mL microwave reaction vial equipped with a stirbar was charged with 4-fluoro-2- hydroxy-5-(N-(4-isopropoxyphenyl)sulfamoyl)benzamide (Example 107, 0.250 gl) and (1 H-pyrazol-3-yl)methanamine (0.198 g). The solids were taken up in 1 -butanol (3.4 mL) and the resulting reaction mixture was subjected to microwave irradiation at 1 10 C with stirring on high absorption setting for 2 sessions of 2 h each for a total of 4 h reaction time. The reaction mixture was resubjected to microwave irradiation at 140 C with stirring for an additional 2 sessions of 2 h and 8 h (14 h total microwave reaction time). The mixture was then cooled to room temperature, diluted with ethanol to ~20 mL total volume, filtered, and concentrated to a residue. The residue was taken up in a minimum amount of DMSO for purification by reverse phase silica gel using a 30 gram RediSep Gold C18 reverse phase silica cartridge (0-90% acetonitrile in 0.2M aq ammonium acetate). Fractions containing the desired material were pooled and then concentrated to remove the acetonitrile. The aqueous layer was acidified to ~pH 4.5 by addition of 1 N aq hydrochloric acid. The mixture was extracted twice with ethyl acetate and the organic layers were pooled, dried over sodium sulfate, filtered, and concentrated to dryness. The solid mass was triturated with diethyl ether to afford the title compound as an off-white solid (52 mg. LCMS m/z 446.3 (M+H)+. 1H NMR (400 MHz, DMSO-c/6) delta ppm 1 .13 - 1 .23 (m, 6 H) 4.38 (d, J=5.58 Hz, 2 H) 4.47 (spt, J=6.04 Hz, 1 H) 6.13 (s, 1 H) 6.16 (d, J=2.03 Hz, 1 H) 6.63 - 6.81 (m, 3 H) 6.89 - 7.01 (m, 2 H) 7.62 (br. s., 2 H) 8.06 (s, 1 H) 8.27 (br. s., 1 H) 9.81 (br. s., 1 H) 12.52 (br. s., 1 H) 13.74 (br. s., 1 H).

Molecular Weight:97.12
XLogP3:-0.9
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:1
Exact Mass:97.063997236
Monoisotopic Mass:97.063997236
Topological Polar Surface Area:54.7
Heavy Atom Count:7
Complexity:54.9
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes