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In ethyl acetate; at 5 - 25℃; for 18h;Large scale;
The benzene sulfonic acid 3.3Kg added ethyl acetate 14L clear,Circulating frozen brine bath to 5 ~ 15 ;2-Methanesulfonyl 5-tert-butoxycarbonyl- (2-hydro, 4-hydro, 6-hydro) -pyrrolo [3,4- c] pyrazole2.85Kg added ethyl acetate 14L in a clear,At 5 ~ 15 C was added dropwise to a solution of ethyl benzenesulfonate,Stir for 30 minutes,Go ice-cold bath,Stir at 25 ± 5 C for 16 hours,Centrifuge,Stir the solid with 17 L of ethyl acetate for 1.5 hours;Centrifuge,The solid was rinsed with 4 L of ethyl acetate,Wet products at -0.08MPa ~ -0.1MPa,40 C for 8 hours under vacuum to give a pale yellow solid Compound II 3.16Kg,Yield 92.3%.HPLC: 96.75%
In Isopropyl acetate; at 20 - 40℃; for 18h;
Step D: 2-(Methylsulfonyl )-2.4,5 ,6-tetrahydropyrrolo 3 A-c] pyrazole benzenesulfomc acidsaltTo the product from Step C (87 g, 303 mmol) in isopropyl acetate (1 L) was added benzensulfonic acid (71.8 g, 454 mmol) and the mixture warmed to 40 C and stirred for 2 h. The mixture was cooled to ambient temperature and stirred for 16 h to give an off-white slurry. The solid was filtered, washed with isopropyl acetate, and suction dried to afford the title compound as a white solid. LC/MS: 188.1 (M+l).
In Isopropyl acetate; at 20 - 40℃; for 18h;
To the product from Step C (87 g, 303 mmol) in isopropyl acetate (1 L) was added benzensulfonic acid (71.8 g, 454 mmol) and the mixture warmed to 40 C and stirred for 2 h. The mixture was cooled to ambient temperature and stirred for 16 h to give an off-white slurry. The solid was filtered, washed with isopropyl acetate, and suction dried to afford the title compound as a white solid. LC MS: 188.1 (M+l).
In Isopropyl acetate; at 20 - 40℃; for 18h;
Step D: 2-(Methylsi^fonvn-2,4 ,6-tetrahydropYrrolo 3,4-c1pyrazole benzenesulfonic acid saltTo the product from Step C (87 g, 303 mmol) in isopropyl acetate (1 L) was added benzensulfonic acid (71.8 g, 454 mmol) and the mixture warmed to 40 C and stirred for 2 h. The mixture was cooled to ambient temperature and stirred for 16 h to give an off white slurry. The solid was filtered, washed with isopropyl acetate, and suction dried to afford the title compound as a white solid. LC/MS: 188.1 (M+l).
In Isopropyl acetate; at 0 - 20℃;Large scale;
Step F: 2-(methylsulfonyl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-5-ium benzenesulfonate To a solution of tert-butyl 2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate (32.1 kg, 111 mol) in iso-propylacetate (289 kg) was added benzenesulfonic acid (35.35 kg, 223 mol). The reaction was stirred for 3 days at room temperature and then cooled to 0-10 C. and stirred an additional 1 h. The resulting slurry was filtered and the cake washed with iso-propylacetate. The solids were dried overnight under vacuum at room temperature to give 2-(methylsulfonyl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-5-ium benzenesulfonate.
(2R,3S,5R)-2-(2,5-difiuorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]-1-(1,3-oxazol-4-ylmethyl)piperidin-3-amine tris(trifluoroacetic acid salt)[ No CAS ]
(2R,3S,5R)-2-(2,5-difiuorophenyl)-5-[2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]-1-[(2R)-2-fluoropropyl]piperidin-3-amine tris(trifluoroacetic acid salt)[ No CAS ]
(2R,3S,5R)-2-(2,5-difiuorophenyl)-1-[(2R)-2-fluoropropyl]-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]piperidin-3-amine tris(trifluoroacetic acid salt)[ No CAS ]
tert-butyl {(2R,3S,5R)-2-(2,5-difiuorophenyl)-1-[(2R)-2-fluoropropyl]-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]piperidin-3-yl}carbamate bis(trifluoroacetic acid salt)[ No CAS ]
(2R,3S,5R)-2-(2,5-difiuorophenyl)-1-(2,2-difluoropropyl)-5-(2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)piperidin-3-amine tris(trifluoroacetic acid salt)[ No CAS ]
(2R,3S,5R)-2-(2,5-difiuorophenyl)-1-(2,2-difluoropropyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]piperidin-3-amine tris(trifluoroacetic acid salt)[ No CAS ]
2-{(2R,3S,5R)-3-amino-2-(2,5-difiuorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]piperidin-1-yl}acetamide tris(trifluoroacetic acid salt)[ No CAS ]
{(2R,3S,5R)-3-amino-2-(2,5-difiuorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]piperidin-1-yl}acetic acid tris(trifluoroacetic acid salt)[ No CAS ]
2-{(2R,3S,5R)-3-amino-2-(2,5-difiuorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]piperidin-1-yl}-1-[(3R)-3-fluoropyrrolidin-1-yl]ethanone tris(trifluoroacetic acid salt)[ No CAS ]
tert-butyl {(2R,3S,5R)-2-(2,5-difiuorophenyl)-1-{2-[(3R)-3-fluoropyrrolidin-1-yl]-2-oxoethyl}-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]piperidin-3-yl}carbamate bis(trifluoroacetic acid salt)[ No CAS ]
2-[(2R,3S,5R)-3-amino-2-(2,5-difiuorophenyl)-5-(2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)piperidin-1-yl]-1-[(3R)-3-fluoropyrrolidin-1-yl]ethanone tris(trifluoroacetic acid salt)[ No CAS ]
(2R,3S,5R)-2-(2,5-difiuorophenyl)-1-{2-[(3R)-3-fluoropyrrolidin-1-yl]ethyl}-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]piperidin-3-amine tris(trifluoroacetic acid salt)[ No CAS ]
(2R,3S,5R)-2-(2,5-difiuorophenyl)-5-(2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-1-{2-[(3R)-3-fluoropyrrolidine-1-yl]ethyl}piperidin-3-amine tris(trifluoroacetic acid salt)[ No CAS ]
(2R,3S,5R)-2-(2,5-difiuorophenyl)-5-(2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-1-[2,2,2-trifluoro(2H2)ethyl]piperidin-3-amine tris(trifluoroacetic acid salt)[ No CAS ]
1-{5-[(3R,5S,6R)-5-amino-6-(2,5-difiuorophenyl)piperidin-3-yl]-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl}-2-methylpropan-2-ol tris(trifluoroacetic acid salt)[ No CAS ]
1-{5-[(3R,5S,6R)-5-amino-6-(2,5-difiuorophenyl)piperidin-3-yl]-5,6-dihydropyrrolo[3,4-c]pyrazol-1(4H)-yl}-2-methylpropan-2-ol tris(trifluoroacetic acid salt)[ No CAS ]
(2R,3S,5R)-2-(2,5-difiuorophenyl)-5-[2-(2-fluoro-2-methylpropyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]piperidin-3-amine tris(trifluoroacetic acid salt)[ No CAS ]
(2R,3S,5R)-2-(2,5-difiuorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]piperidin-3-amine tris(trifluoroacetic acid salt)[ No CAS ]