Trifluoromethanesulfonic anhydride → N-((4aS,5S,7aS)-7a-(2,4-Difluorophenyl)-5-((trityloxy)methyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)benzamide

HRID 68374Notes

Reaction equation

HRID 68374 reaction equation
F[C:2]([F:15])(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[F:16][C:17]1[CH:22]=C(F)[CH:20]=[CH:19][C:18]=1[C@@:24]1([NH:52][C:53]([NH:55][C:56](=[O:63])[C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)=[S:54])[C@H:28]([CH2:29]O)[C@@H:27]([CH2:31][O:32][C:33]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)(C2C=CC=CC=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:26][CH2:25]1>N1C=CC=CC=1>[F:16][C:17]1[CH:22]=[C:2]([F:15])[CH:20]=[CH:19][C:18]=1[C@:24]12[CH2:25][O:26][C@H:27]([CH2:31][O:32][C:33]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C@H:28]1[CH2:29][S:54][C:53]([NH:55][C:56](=[O:63])[C:57]1[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=1)=[N:52]2

Participants

4

Reactant 2

HCID 67749Trifluoromethanesulfonic anhydrideHCID 86707813N-(((3S,4R,5S)-3-(2,4-difluorophenyl)-4-(hydroxymethyl)-5-((trityloxy)methyl)tetrahydrofuran-3-yl)carbamothioyl)benzamide2×

Product 1

HCID 86707814N-((4aS,5S,7aS)-7a-(2,4-Difluorophenyl)-5-((trityloxy)methyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)benzamide

Reagents, catalysts & solvents 1

HCID 1049PyridineSolvent

Conditions

Temperature
-20 °C

Procedure

Trifluoromethanesulphonic acid anhydride (0.40 mL, 2.35 mmol) was added slowly to a stirred solution of N-(((3S,4R,5S)-3-(2,4-difluorophenyl)-4-(hydroxymethyl)-5-((trityloxy)methyl)tetrahydrofuran-3-yl)carbamothioyl)benzamide (1.3 g, 1.96 mmol) in dry pyridine (4 mL) under nitrogen such that the internal temperature remained below −20° C. Upon complete addition, the reaction was stirred at −20° C. for a further 10 minutes and then transferred to an ice bath. After 2 hours at 0° C. the reaction was quenched with saturated aqueous NH4Cl (20 mL) and then the mixture was partitioned between EtOAc (50 mL) and water (25 mL). The layers were separated and the aqueous layer was further extracted with EtOAc (50 mL×1). The combined extracts were washed with half saturated brine (2×50 mL) and brine (50 mL×1), then dried (Na2SO4), filtered and evaporated. The residue was azeotroped with toluene (×2) to give 1.6 g (oil). The reaction was repeated starting with 5.0 g of N-(((3S,4R,5S)-3-(2,4-difluorophenyl)-4-(hydroxymethyl)-5-((trityloxy)methyl)tetrahydrofuran-3-yl)carbamothioyl)benzamide and the crude product from the two experiments was combined for purification by column chromatography (normal phase, 100 g, Biotage SNAP cartridge KP-Sil, 50 mL per min, gradient 5% to 20% to 30% EtOAc in n-hexane) to give the title compound. (3.99 g). 1H NMR (400 MHz, MeOH-d4) δ ppm: 2.71 (dd, J=13.76, 3.97 Hz, 1 H) 3.02-3.17 (m, 1 H) 3.19-3.28 (m, 1 H) 3.31-3.35 (m, 1 H) 3.40 (dd, J=10.27, 4.28 Hz, 1 H) 4.00-4.07 (m, 1 H) 4.38-4.47 (m, 1 H) 4.54 (d, J=9.17 Hz, 1 H) 6.96-7.13 (m, 2 H) 7.17-7.39 (m, 9 H) 7.42-7.58 (m, 10 H) 8.03 (br. s., 2 H).

Workup

  1. customremained below −20° C
  2. additionUpon complete addition
  3. customtransferred to an ice bath
  4. customAfter 2 hours at 0° C. the reaction was quenched with saturated aqueous NH4Cl (20 mL)
  5. customthe mixture was partitioned between EtOAc (50 mL) and water (25 mL)
  6. customThe layers were separated
  7. extractionthe aqueous layer was further extracted with EtOAc (50 mL×1)
  8. washThe combined extracts were washed with half saturated brine (2×50 mL) and brine (50 mL×1)
  9. dry with materialdried (Na2SO4)
  10. filtrationfiltered
  11. customevaporated
  12. customThe residue was azeotroped with toluene (×2)
  13. customto give 1.6 g (oil)
  14. customthe crude product from the two experiments was combined for purification by column chromatography (normal phase, 100 g, Biotage SNAP cartridge KP-Sil, 50 mL per min, gradient 5% to 20% to 30% EtOAc in n-hexane)

Sources & evidence

ORD record
ord-864bfc421c2442efa961e7b8e083b931
Source dataset
uspto-grants-2014_09
Patent number
US08822455B2

Reaction notes

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