Diisopropylethylamine → tert-butyl ((4aS,5S,7aS)-5-(difluoromethyl)-7a-(2-fluoro-5-(5-methoxypyrazine-2-carboxamido)phenyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)carbamate

HRID 707699Notes

Reaction equation

HRID 707699 reaction equation
[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:28])=[C:6]([C@:8]23[CH2:16][O:15][C@H:14]([CH:17]([F:19])[F:18])[C@H:13]2[CH2:12][S:11][C:10]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[N:9]3)[CH:7]=1.[CH3:29][O:30][C:31]1[N:32]=[CH:33][C:34]([C:37](O)=[O:38])=[N:35][CH:36]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.[PH4+]>C(Cl)Cl>[F:18][CH:17]([F:19])[C@@H:14]1[C@@H:13]2[C@@:8]([C:6]3[CH:7]=[C:2]([NH:1][C:37]([C:34]4[CH:33]=[N:32][C:31]([O:30][CH3:29])=[CH:36][N:35]=4)=[O:38])[CH:3]=[CH:4][C:5]=3[F:28])([N:9]=[C:10]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[S:11][CH2:12]2)[CH2:16][O:15]1

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 21584439Phosphonium hexafluorophosphateHCID 457898115-Methoxy-2-pyrazinecarboxylic acidHCID 57827488tert-butyl ((4aS,5S,7aS)-7a-(5-amino-2-fluorophenyl)-5-(difluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)carbamate

Product 1

HCID 86724404tert-butyl ((4aS,5S,7aS)-5-(difluoromethyl)-7a-(2-fluoro-5-(5-methoxypyrazine-2-carboxamido)phenyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)carbamateYield 48.6%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a stirred solution of tert-butyl ((4aS,5S,7aS)-7a-(5-amino-2-fluorophenyl)-5-(difluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)carbamate (2.70 g) and 5-methoxypyrazine-2-carboxylic acid (1.25 g, described in WO2009/091016), in DCM (30 mL) was added N,N-diisopropylethylamine (3.5 mL) and (1H-benzotriazol-1-yloxy)tripyrrolidin-1-yl)phosphonium hexafluorophosphate (4.2 g). The reaction mixture was stirred at RT for 18 h, concentrated under vacuum to circa 20 mL, and sodium bicarbonate (sat., aq., 100 mL) was added. The mixture was extracted with EtOAc (2×150 mL), the combined organic portions were dried over MgSO4, evaporated and purified by silica gel chromatography (0% to 25% EtOAc in DCM gradient) to afford the title compound (1.74 g) as a white solid. NMR (400 MHz, CDCl3) δ ppm 1.54 (s, 9H), 2.76-2.88 (m, 1H), 2.95-3.28 (m, 1H), 3.34-3.53 (m, 1H), 3.83-3.93 (m, 1H), 4.10 (s, 3H), 4.46-4.68 (m, 2H), 5.98 (dt, J=3.6, 56.8 Hz, 1H), 7.07-7.20 (m, 1H), 7.36-7.48 (m, 1H), 7.96-8.04 (d, J=7.8 Hz, 1H), 8.20 (d, J=1.0 Hz, 1H), 9.04 (d, J=1.3 Hz, 1H), 9.53 (br. s., 1H)

Workup

  1. concentrationconcentrated under vacuum to circa 20 mL, and sodium bicarbonate (sat., aq., 100 mL)
  2. additionwas added
  3. extractionThe mixture was extracted with EtOAc (2×150 mL)
  4. dry with materialthe combined organic portions were dried over MgSO4
  5. customevaporated
  6. custompurified by silica gel chromatography (0% to 25% EtOAc in DCM gradient)

Sources & evidence

ORD record
ord-7bbf952a837b4377a79ebf090f5ae712
Source dataset
uspto-grants-2015_11
Patent number
US09175013B2

Reaction notes

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