Diisopropylethylamine → N-(3-((4aS,5S,7aS)-2-amino-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-fluorophenyl)-5-methoxypyrazine-2-carboxamide

HRID 1429636Notes

Reaction equation

HRID 1429636 reaction equation
C(OC(=O)[NH:7][C:8]1[S:9][CH2:10][C@@H:11]2[C@@H:16]([C:17]([F:20])([F:19])[F:18])[O:15][CH2:14][C@:12]2([C:21]2[CH:26]=[C:25]([NH2:27])[CH:24]=[CH:23][C:22]=2[F:28])[N:13]=1)(C)(C)C.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>[NH2:7][C:8]1[S:9][CH2:10][C@@H:11]2[C@@H:16]([C:17]([F:20])([F:19])[F:18])[O:15][CH2:14][C@:12]2([C:21]2[CH:26]=[C:25]([NH:27][C:60]([C:57]3[CH:56]=[N:55][C:54]([O:53][CH3:52])=[CH:59][N:58]=3)=[O:61])[CH:24]=[CH:23][C:22]=2[F:28])[N:13]=1

Participants

7

Reactant 5

HCID 81531DiisopropylethylamineHCID 516892Sodium BicarbonateHCID 21584439Phosphonium hexafluorophosphateHCID 457898115-Methoxy-2-pyrazinecarboxylic acidHCID 68171522tert-butyl[(4aS,5S,7aS)-7a-(5-amino-2-fluorophenyl)-5-trifluoromethyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl]carbamate

Product 1

HCID 57525003N-(3-((4aS,5S,7aS)-2-amino-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-fluorophenyl)-5-methoxypyrazine-2-carboxamideYield 66%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

tert-Butyl((4aS,5S,7aS)-7a-(5-amino-2-fluorophenyl)-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)carbamate (Preparation Example 1, 56 mg) was dissolved in DCM (2 mL) and 5-methoxypyrazine-2-carboxylic acid (40 mg), N,N-diisopropylethylamine (80 mg) and (1H-benzotriazol-1-yloxy)tripyrrolidin-1-yl)phosphonium hexafluorophosphate (135 mg) were added. The reaction mixture was stirred at RT for 18 h, 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 amide (40 mg) as a white solid. The amide was dissolved in DCM (2 mL) and TFA (1 mL) was added. After stirring at RT for 2 h, the reaction mixture was evaporated and sodium bicarbonate (sat., aq., 25 mL) was added. The mixture was extracted with EtOAc (2×25 mL), and the combined organic portions dried over MgSO4 and evaporated to afford the title compound as a white solid (34 mg). 1H NMR (400 MHz, CDCl3) δ ppm 2.78-2.87 (m, 1 H), 3.11-3.21 (m, 1 H), 3.38-3.48 (m, 1 H), 3.82-4.06 (m, 4 H), 4.48-4.72 (m, 2 H), 6.96-7.10 (m, 1 H), 7.52 (d, J=4.8 Hz, 1 H), 7.87 (d, J=8.8 Hz, 1 H), 8.09 (s, 1 H), 8.95 (s, 1 H), 9.46 (br. 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-31ef89b9069644c6a56f8da29a5cf85f
Source dataset
uspto-grants-2015_01
Patent number
US08940734B2

Reaction notes

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