Ethanamine, 2-(methylsulfonyl)-, hydrochloride (1:1)

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To a mixture of tert-butyl 2-(methylsulfonyl)ethylcarbamate (1.5 g) and ethyl acetate (10 mL) was added dropwise 4N hydrochloric acid*ethyl acetate solution (3 mL) with stirring under ice-cooling. After stirring at room temperature overnight, the precipitated crystals were collected by filtration and washed with ethyl acetate to give 2-(methylsulfonyl)ethylamine hydrochloride as crystals (1.04 g, yield 97percent). Recrystallization from ethanol gave colorless prism crystal. melting point: 169-170°C3) N - (Boc)-2 - methylsulfonyl ethylamine in soluble in ethanol, under the room temperature condition by adding hydrochloric acid, stir. Stirring overnight, the next day, concentrated under reduced pressure adding anhydrous ethanol then concentrate under reduced pressure to get semi-oil objects, adding isopropyl ether and acetone 5 - 10 °C stirring between 2h, filtering to obtain solid, air-drying the product pulls the handkerchief for the Nepali side chain 2 - (methyl sulfonyl) hydrochloride, Y=88percent, nuclear magnetic Atlas and mass spectrum confirmed that the product is the target product, purity >99percent2M HCl in diethyl ether (50 mL) was added to a solution of (2-methanesulfonylethyl)carbamic acid, tert-butyl ester (10.6 g, 47.5 mmol) in EtOAc (250 mL). A precipitate began forming after about 0.25 hr. The suspension was stirred overnight at room temperature. TLC and LCMS showed the reaction was incomplete. 2M HCl in diethyl ether (120 mL) was added and the mixture was stirred overnight at room temperature. The solids were collected, washed with EtOAc (100 mL) and dried under N2000ml three bottles, Was added 2- (methylthio) ethylamine (91 g, 1 mol) and 500 ml of water, With 37percent concentrated hydrochloric acid to adjust the pH to 3 ~ 4, Keep the temperature 25 ~ 30 , Dropping 30percent hydrogen peroxide solution (240g, 2.1mol), 1 ~ 1.5h drop finished, The reaction was carried out at 25 to 30 ° C for 10 hours, The solvent was distilled off under reduced pressure, The residue was added to 500 ml of ethanol, Precipitation of white solid, filter, Ethanol wash, 60 under reduced pressure to dry 151.2g, Is 2- (methylsulfonyl) ethylamine hydrochloride, Yield 94.8percentThe purity of the product is 99.8percent (GC method).IIIa-1 (0.32 g, 2.0 mmol, 1.0 equivalent weight) and TEA (0.85 mL, 6.0 mmol, 3.0 equivalent weight) weredissolved in DCM (20 mL). In an ice bath, CDI (0.34 g, 2.1 mmol, 1.1 equivalent weight) was added and stirred for 10min, and then the mixture was heated to room temperature and stirring was continued for 30min. Subsequently, at roomtemperature, IIIg-2 (0.32 g, 2.0 mmol, 1.0 equivalent weight) was added dropwise into the above reaction solution, andstirring was continued for 3h. The solvent was concentrated to obtain a sticky liquid. Finally, the sticky liquid was dissolvedin methanol (10mL), and concentrated hydrochloric acid (con. HCl, 2mL) was added dropwise into the reaction mixture, which was then subjected to heating and refluxing for 2h. The solvent was concentrated to obtain 1.00 g colorless andtransparent sticky liquid IIIj. The crude product was directly used for the next reaction without separation (the yield wascalculated based on 100%).LC-MS MS-ESI (m/z) 209.98 [M+H]+, 232.01 [M+Na]+.IIIf-1 (0.20 g, 1.0 mmol, 1.0 equivalent weight) and TEA (0.4 mL, 3.0 mmol, 3.0 equivalent weight) were dissolvedin DCM (40 mL). In an ice bath, CDI (0.17 g, 1.1 mmol, 1.1 equivalent weight) was added and stirred for 10min, andthen the mixture was heated to room temperature and stirring was continued for 30min. Subsequently, at room temperature, IIIg-2 (0.16 g, 1.0 mmol, 1.0 equivalent weight) was added dropwise into the above reaction solution, and stirringwas continued for 3h. The solvent was concentrated to obtain a sticky liquid. Finally, the sticky liquid was dissolved inmethanol (10mL), and concentrated hydrochloric acid (con. HCl, 2mL) was added dropwise into the reaction mixture, which was then subjected to heating and refluxing for 2h. The solvent was concentrated to obtain 0.50g colorless andtransparent sticky liquid IIIg. The crude product was directly used for the next reaction without separation (the yield wascalculated based on 100%).LC-MS MS-ESI (m/z) 254.4 [M+H]+, 276.3 [M+Na]+.In an ice bath, to a solution of compound 5 (1 g, 6.15 mmol) and To a mixture of 4-(5, 6, 7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butanoic acid (20 g, 63.56 mmol) in DCM (400 mL) was added CDI (11.34 g, 69.92 mmol) at 0 C. and the resulting mixture was stirred at rt for 1 h, at which time, 2-(methylsulfonyl)ethanamine hydrochloride (11.16 g, 69.92 mmol) was added and stirred at rt for an additional 2 h. The mixture was diluted with H2O and the layers were separated. The aqueous layer was extracted with DCM and the combine organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was re-dissolved in EtOAc (80 mL) and then heated to reflux, at which time, hexanes (20 mL) was added and the mixture was cooled to rt causing a precipitate to form. The solid was filtered and the filtrate was concentrated in vacuo to give the title compound. LCMS (ESI+): m/z=325.9 (M+H)+At 25 C, Dimethylsulfanylethylamine hydrochloride (0.66 g, 4.1 mmol) was added to a 100 mL two-necked flask, and a mixed solvent of dichloromethane (20 mL) and methanol (10 mL) was added, and the mixture was stirred at 25 C for 5 min.Add triethylamine (0.44 g, 4.3 mmol) and the compound 5-(4-((1-(3-fluorobenzyl)-1H-indazol-5-yl)amino)-5-methylthieno[2] , 3-d]pyrimidinePyridin-6-yl)furan-2-carbaldehyde (0.2 g, 0.41 mmol), Continue to maintain this temperature for 3.0 h, Sodium triacetoxyborohydride (0.26 g, 1.23 mmol) was added.The reaction was stirred at 25 C for 12.0 h. Filter insoluble solids, The filtrate was added to silica gel for dry mixing.Perform column chromatography (eluent:CH2Cl2/MeOH (v/v) = 50/1), 0.05 g of a white solid were obtained in a yield of 20.5%.To a 25 mL round-bottom flask purged and maintained under an inert atmosphere of nitrogen was added a solution of 4-[( 1S, 4S, 5R)-5-[[ 1 -cyclopropyl-4-(2, 6-dichlorophenyl)- 1H-pyrazol-5- yl]methoxy] -2-azabicyclo[2.2. 1 ]heptan-2-yl]-2-fluorobenzoic acid 1-42 (120 mg, 0.23 mmol, 1.00 equiv.) in N, N-dimethylformamide (2.5 mL), A solution of 2-(6-((2S, 5S)-2, 5-dimethylpyrrolidin-1 -yl)pyridin-3-yl)-1 -(2-ethoxyethyl)-1 H- benzo[d]imidazole-5-carboxylic acid (85 mg, 0.208 mmol), N-methylmorpholine (0.080 ml_, 0.728 mmol), and HATU (95 mg, 0.250 mmol) in DMF (1 .5 mL) was stirred at room temperature for 15 minutes. 2-(Methylsulfonyl)ethan-1 -amine hydrochloride (33.2 mg, 0.208 mmol) was then added, and the reaction mixture was stirred at room temperature for 45 minutes. Additional portions of HATU, N-methylmorpholine, and 2- (methylsulfonyl)ethan-l -amine hydrochloride were added and the reaction continued to stir at room temperature for 3 days. The solvent was removed in-vacuo and the remaining residue purified via reverse phase HPLC (15-55% CH3CN/0.1 % formic acid in water). The desired fractions were concentrated and dried under high vacuum, then freeze dried to afford the desired product (45.5 mg) as a white powder. LC-MS (ES) m/z = 514 [M+H]+. 1H NMR (400 MHz, DMSO-d6): delta 8.72 (s, 1 H), 8.56 (d, J = 2.2 Hz, 1 H), 8.16 (d, J = 1 .2 Hz, 1 H), 7.97 (dd, J = 2.5, 8.8 Hz, 1 H), 7.76 (d, J = 1 .7 Hz, 1 H), 7.66-7.74 (m, 1 H), 6.56-6.68 (m, 1 H), 4.46 (t, J = 5.2 Hz, 2H), 3.67-3.81 (m, 4H), 3.42 (t, J = 6.8 Hz, 2H), 3.26-3.33 (m, 4H), 3.06 (s, 3H), 2.25 (t, J = 7.8 Hz, 2H), 1 .66 (d, J = 5.5 Hz, 2H), 1 .15 (d, J = 6.3 Hz, 6H), 0.95 (t, J = 6.9 Hz, 3H).General procedure: To solution of phenyl (3, 5-difluoro-4-{[3-(trifluoromethyl)-1 -{[2-(trimethylsilyl)ethoxy]methyl}-1 H- pyrrolo[2, 3-b]pyridin-4-yl]oxy}phenyl)carbamate (1 .20 g, 2.07 mmol, intermediate 1 ) in DMF (10 mL) was added 3-(morpholin-4-yl)propan-1 -amine (300 muIota_, 2.1 mmol) and this mixture was stirred at 60C for 2 hours. After cooling to room temperature ethyl acetate and water was added. After separation of the organic phase the aqueous phase was extracted two times with ethyl acetate. The combined organic phases were washed 3 times with halfconcentrated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated to dryness. The resulting residue was purified 3 times via a Biotage chromatography system (55g and 2 times 28g snap KP-NH column, hexane / 0 - 100% ethyl acetate, then ethyl acetate / 0 - 100% methanol) to obtain 970 mg (95 % purity, 71 % yield) of the desired title compound. 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: -0.12 - -0.08 (m, 9H), 0.83 (t, 2H), 1 .60 (quin, 2H), 2.27 - 2.36 (m, 6H), 3.13 (q, 2H), 3.53 - 3.62 (m, 6H), 5.68 (s, 2H), 6.42 (t, 1 H), 6.57 (d, 1 H), 7.34 - 7.41 (m, 2H), 8.28 (d, 1 H), 8.36 (s, 1 H), 8.99 (s, 1 H). In analogy to intermediate 2), using phenyl (3, 5-difluoro-4-{[3-(trifluoromethyl)-1 -{[2- (trimethylsilyl)ethoxy]methyl}-1 H-pyrrolo[2, 3-b]pyridin-4-yl]oxy}phenyl)carbamate (100 mg, 173 muetaetaomicronIota), intermediate 1 ) and 2-(methylsulfonyl)ethanamine hydrochloride (1 :1 ) (27.5 mg, 173 muetaiotaomicronIota) together with N, N-diisopropylethylamine (30 muIota_, 170 muetaiotaomicronIota) in DMF (1 .0 ml_, 13 mmol), we obtained after one single purification using a Biotage chromatography system 72.0 mg (100 % purity, 69 % yield) of the desired title compound. 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: -0.1 1 - -0.07 (m, 9H), 0.83 (t, 2H), 3.04 (s, 3H), 3.32 (t, 2H), 3.52 - 3.60 (m, 4H), 5.68 (s, 2H), 6.58 (d, 1 H), 6.61 (t, 1 H), 7.39 (d, 2H), 8.28 (d, 1 H), 8.36 (s, 1 H), 9.33 (s, 1 H).