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

HRID 707697Notes

Reaction equation

HRID 707697 reaction equation
[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:27])=[C:6]([C@:8]23[CH2:16][O:15][C@H:14]([CH2:17][F:18])[C@H:13]2[CH2:12][S:11][C:10]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[N:9]3)[CH:7]=1.[CH3:28][O:29][C:30]1[N:31]=[CH:32][C:33]([C:36](O)=[O:37])=[N:34][CH:35]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.[PH4+]>C(Cl)Cl>[F:27][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:36]([C:33]2[CH:32]=[N:31][C:30]([O:29][CH3:28])=[CH:35][N:34]=2)=[O:37])=[CH:7][C:6]=1[C@:8]12[CH2:16][O:15][C@H:14]([CH2:17][F:18])[C@H:13]1[CH2:12][S:11][C:10]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[N:9]2

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 21584439Phosphonium hexafluorophosphateHCID 457898115-Methoxy-2-pyrazinecarboxylic acidHCID 57827228tert-butyl ((4aS,5S,7aS)-7a-(5-amino-2-fluorophenyl)-5-(fluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)carbamate

Product 1

HCID 68173880tert-butyl ((4aS,5S,7aS)-7a-(2-fluoro-5-(5-methoxypyrazine-2-carboxamido)phenyl)-5-(fluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)carbamateYield 106.5%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a stirred solution of tert-butyl ((4aS,5S,7aS)-7a-(5-amino-2-fluorophenyl)-5-(fluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)carbamate (4.70 g) and 5-methoxypyrazine-2-carboxylic acid (2.65 g), in DCM (60 mL) was added N,N-diisopropylethylamine (8.0 mL) and (1H-benzotriazol-1-yloxy)tripyrrolidin-1-yl)phosphonium hexafluorophosphate (9.0 g, portionwise over 10 min). 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 50% EtOAc in DCM gradient) to afford the title compound (6.71 g, approx. purity 90%) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.54 (m, 9H), 2.71-2.83 (br. s., 1H), 3.03-3.34 (br. s., 1H), 3.81-4.01 (br. s., 1H), 4.09 (m, 3H), 4.48-4.75 (m, 4H), 7.05-7.20 (m, 1H), 7.36-7.58 (m, 1H), 7.93-8.02 (m, 1H), 8.20 (d, J=1.3 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 50% EtOAc in DCM gradient)

Sources & evidence

ORD record
ord-f867807478a44a9583b982a3aa841759
Source dataset
uspto-grants-2015_11
Patent number
US09175013B2

Reaction notes

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