6-AMINO-2-N-BOC-1,2,3,4-TETRAHYDRO-ISOQUINOLINE

To a stirred solution of 2 (2.2 g, 5.75 mmol) in EtOH (25 mL) was added ammonium formate (3.68 g, 57.5 mmol) and the reaction mixture was refluxed for 6 h. It was cooled, filtered though a celiteEXAMPLE 3. Synthesis of N-[2-(4-chloroρhenyl)ethyl]-7-[(methylsulfonyl)amino]-3, 4- dihydroisoquinoline-2(lH)-carbothioamide (Res-10-73) and N-[2-(4-chlorophenyl)ethyl]- 6- [(methylsulfonyl)amino] -3 , 4-dihydroisoquinoline-2(l H)-carbothioamide (Res-12-31).; The title compounds were synthesized according to Scheme 2. Scheme 2. Synthesis ofN-[2-(4-chlorophenyl)ethyl]-7-[(methylsulfonyl)amino]-3, 4- dihydroisoquinoline-2(lH)-carbothioamide (Res-10-73) and N-[2-(4-chlorophenyl)ethyl] - 6-[(methylsulfonyl)amino] -3 , 4-dihydroisoquinoline-2(lH)-carbothioamide (Res-12-31).1, 2, 3, 4-Tetrahydroisoquinoline (1) (1 eq.) was cooled on ice and acetic anhydride (1.5 eq.) was added dropwise. The mixture was stirred for 2 hours and then diluted with EtOAc. The organic phase was washed with NaHCOIntermediate 11 , 1 -Dimethvlethyl 6-r(N-{r(Dhenvlmethvl)oxvlcarbonvl}-L-methionvl)aminol-3, 4-dihvdro-2(1 HVisoalphauinolinecarboxvlate; 1 , 1-Dimethylethyl 6-amino-3, 4-dihydro-2(1 H)-isoquinolinecarboxylate (2.03g), N- {[(phenylmethyl)oxy]carbonyl}-L-methionine (2.55g), HATU (3.42g) and DIPEA (1.71 ml) were stirred together in DCM (20ml) at ambient temperature. After 64h the volatiles were removed and the residue partitioned between water and chloroform. The chloroform layer was washed with 0.5N aqueous HCI (x2), saturated aqueous sodium bicarbonate (x2) and brine and then passed through a hydrophobic frit. This solution was loaded directly onto 2 x 9Og Biotage silica columns and eluted with 1 :1 ethyl acetate:cyclohexane, furnishing the title compound as a yellow oil (4.3g). Mass spectrum: Found: MH+ 514 H.p.l.c. R, 3.52minTert-butyl 6-amino-3, 4-dihydroisoquinoline-2(1H)-carboxylate (248mg, 1mmol), 4-nitrobenzoic acid (167mg, 1mmol), EDCI (212mg, 1.1mmol), and catalytic quantity of 4-DAMP are added into DCM (10mL) and the mixture were stirred for 8h. The reaction mixture was diluted with DCM and filtered using Celite, then evaporated. Starting with the residue which was not purified, Tert-butyl 6-(4-(vinylsulfonamido)benzamido)-3, 4-dihydroisoquinoline-2(1H)-carboxylate (DC-TEADin07-1) was obtained as a white solid by using general synthesis procedure 1b and 2b (yield 45%). 1H NMR (400MHz, Methanol-d4) delta 7.87 (d, J=8.9Hz, 2H), 7.55-7.41 (m, 2H), 7.28 (d, J=8.9Hz, 2H), 7.11 (d, J=8.5Hz, 1H), 6.71 (dd, J=16.5, 10.0Hz, 1H), 6.24 (d, J=16.5Hz, 1H), 6.01 (d, J=9.9Hz, 1H), 5.48 (s, 2H), 4.53 (s, 2H), 3.63 (t, J=5.9Hz, 2H), 2.83 (t, J=5.9Hz, 2H), 1.49 (s, 9H).General procedure: 4-(naphthalen-2-ylmethyl)aniline (DC-TEADin02-2, 80mg, 0.34mmol) was stirred with pyridine (0.5mL) in DCM (10mL) at 0C, then 2-Chloroethanesulfonyl chloride (56mg, 0.343mmol) which was diluted with DCM (2mL) was slowly added into the mixture. The reaction mixture was stirred for 2h then evaporated. The residue was diluted and extracted with EtOAc then washed with water for 3 times. The organic layers were dried over Na2SO4 and evaporated. The residue was chromatographed (silicagel, Petroleum ether/EtOAc=5:1) to give N-(4-(naphthalen-2-ylmethyl)phenyl)ethenesulfonamide (DC-TEADin02) (93mg, 85%) as a white solid.Step-4: Synthesis of tert-butyl 6-((2-isopropyl-1-(2-(N-methylmethylsulfonamido)pyridin-4-yl)-3-oxo-2, 3-dihydro-1H-pyrazolo[3, 4-d]pyrimidin-6-yl)amino)-3, 4-dihydroisoquinoline-2(1H)-carboxylate To a stirred solution of N-(4-(2-isopropyl-6-(methylthio)-3-oxo-2, 3-dihydro-1H-pyrazolo [3, 4-d] pyrimidin-1-yl) pyridin-2-yl)-N-methylmethanesulfonamide (120 mg, 0.294 mmol, 1.0 eq) in (3.0 mL) of toluene was added m-CPBA (102 mg, 0.5882 mmol, 2.0 eq) and allowed to stir at rt for 1 h. Step-1: Synthesis of tert-butyl tert-butyl 6-((2-allyl-1-(2-(tert-butyl)pyridin-4-yl)-3-oxo-2, 3-dihydro-1H-pyrazolo[3, 4-d]pyrimidin-6-yl)amino)-3, 4-dihydroisoquinoline-2(1H)-carboxylate To a stirred solution of 2-allyl-1-(2-(tert-butyl)pyridin-4-yl)-6-(methylthio)-1, 2-dihydro-3H-pyrazolo[3, 4-d]pyrimidin-3-one (170 mg, 0.5 mmol, 1.0 eq) in (2.0 mL) of toluene was added m-CPBA (247 mg, 1.0 mmol, 2 eq) and allowed to stir at rt for 1 h. Step-5: Synthesis of tert-butyl 6-((1-(2-(tert-butyl)pyridin-4-yl)-2-isopropyl-3-oxo-2, 3-dihydro-1H-pyrazolo[4, 3-c]pyridin-6-yl)amino)-3, 4-dihydroisoquinoline-2(1H)-carboxylate To a stirring solution of 1-(2-(tert-butyl)pyridin-4-yl)-6-chloro-2-isopropyl-1, 2-dihydro-3H-pyrazolo[4, 3-c]pyridin-3-one (200 mg, 0.579 mmol, 1 eq) in dioxane (20 mL),

Molecular Weight:248.32
XLogP3:2
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:2
Exact Mass:248.152477885
Monoisotopic Mass:248.152477885
Topological Polar Surface Area:55.6
Heavy Atom Count:18
Complexity:311
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes