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

HRID 707688Notes

Reaction equation

HRID 707688 reaction equation
[NH2:1][C:2]1[CH:3]=[C:4]([F:29])[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.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.[PH4+].C(=O)(O)[O-].[Na+].[CH3:52][O:53][C:54]1[N:55]=[CH:56][C:57]([C:60](O)=[O:61])=[N:58][CH:59]=1>C(Cl)Cl>[F:28][C:5]1[C:4]([F:29])=[CH:3][C:2]([NH:1][C:60]([C:57]2[CH:56]=[N:55][C:54]([O:53][CH3:52])=[CH:59][N:58]=2)=[O:61])=[CH:7][C:6]=1[C@:8]12[CH2:16][O:15][C@H:14]([CH:17]([F:19])[F:18])[C@H:13]1[CH2:12][S:11][C:10]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[N:9]2

Participants

7

Reactant 5

HCID 81531DiisopropylethylamineHCID 516892Sodium BicarbonateHCID 21584439Phosphonium hexafluorophosphateHCID 457898115-Methoxy-2-pyrazinecarboxylic acidHCID 68173772tert-butyl ((4aS,5S,7aS)-7a-(5-amino-2,3-difluorophenyl)-5-(difluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)carbamate

Product 1

HCID 86724399tert-butyl ((4aS,5S,7aS)-7a-(2,3-difluoro-5-(5-methoxypyrazine-2-carboxamido)phenyl)-5-(difluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)carbamate

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

tert-butyl ((4aS,5S,7aS)-7a-(5-amino-2,3-difluorophenyl)-5-(difluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)carbamate, synthesized in preparation example 1-(13), (100 mg) was dissolved in DCM (2 mL) and 5-methoxypyrazine-2-carboxylic acid (50 mg), N,N-diisopropylethylamine (100 mg) and (1H-benzotriazol-1-yloxy)tripyrrolidin-1-yl)phosphonium hexafluorophosphate (175 mg) were added. The reaction mixture was stirred at RT for 3 days, and sodium bicarbonate (sat., aq., 25 mL) was added. The mixture was extracted with EtOAc (2×40 mL), the combined organic portions were dried over MgSO4, evaporated and purified by silica gel chromatography (EtOAc/hexanes gradient) to afford the title compound (108 mg) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.54 (s, 9H), 2.82 (dd, J=13.5, 3.4 Hz, 1H), 3.08 (d, J=12.9 Hz, 1H), 3.33-3.45 (m, 1H), 3.84-3.93 (m, 1H), 4.10 (s, 3H), 4.46-4.65 (m, 2H), 5.97 (dt, J=3.8, 56.6 Hz, 1H), 7.08 (br. s., 1H), 7.27-7.36 (m, 1H), 8.14 (ddd, J=11.6, 7.0, 2.7 Hz, 1H), 8.20 (d, J=1.3 Hz, 1H), 9.04 (d, J=1.3 Hz, 1H), 9.55 (s, 1H)

Workup

  1. extractionThe mixture was extracted with EtOAc (2×40 mL)
  2. dry with materialthe combined organic portions were dried over MgSO4
  3. customevaporated
  4. custompurified by silica gel chromatography (EtOAc/hexanes gradient)

Sources & evidence

ORD record
ord-f939ab42f79f46759f825e0539df32ca
Source dataset
uspto-grants-2015_11
Patent number
US09175013B2

Reaction notes

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