Formic Acid → N-((4aS,5S,7aS)-7a-(2,3-difluorophenyl)-5-(hydroxymethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)benzamide

HRID 707706Notes

Reaction equation

HRID 707706 reaction equation
C(O)=O.[F:4][C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[C@:12]12[CH2:20][O:19][C@H:18]([CH2:21][O:22]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C@H:17]1[CH2:16][S:15][C:14]([NH:42][C:43](=[O:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[N:13]2.C(N(CC)CC)C>O>[F:4][C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[C@:12]12[CH2:20][O:19][C@H:18]([CH2:21][OH:22])[C@H:17]1[CH2:16][S:15][C:14]([NH:42][C:43](=[O:50])[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)=[N:13]2

Participants

5

Reactant 3

HCID 284Formic AcidHCID 8471TriethylamineHCID 60168235N-((4aS,5S,7aS)-7a-(2,3-difluorophenyl)-5-((trityloxy)methyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)benzamide

Product 1

HCID 68173766N-((4aS,5S,7aS)-7a-(2,3-difluorophenyl)-5-(hydroxymethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)benzamideYield 101.8%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Procedure

Formic acid (116 mL) was added to N-((4aS,5S,7aS)-7a-(2,3-difluorophenyl)-5-((trityloxy)methyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)benzamide (33.30 g, 0.051 mol, 1.0 equiv.), the mixture was stirred at r.t for 25 min. Water (17 mL) was added dropwise then the reaction was stirred for another 30 min. The resulting suspension was filtered; the filtrate was dried by azeotropic distillation under vacuum with toluene (360 mL). Methanol (110 mL) was added followed by triethylamine (22 mL, 0.15 mol, 3.0 equiv.) and the solution was stirred for 2 h. The solvent was removed under vacuum and chased with toluene (66 mL). The residual oil was dissolved in CH2Cl2 (250 ml) and washed successively with aq.HCl (1M, 100 mL), sat aq.NaHCO3 (67 mL) and 18% aq.NaCl (67 mL). The organic phase was concentrated under reduce pressure. Toluene (66 mL) and THF (67 mL) were added to the residue then the solution was filtered through celite and concentrated under reduced pressure to yield the title compound (21 g). 1H NMR (500 MHz, DMSO) ppm 8.11 (dd, J=16.4, 4.2 Hz, 2H), 7.70-7.58 (m, 1H), 7.57-7.44 (m, 3H), 7.43-7.34 (m, 1H), 7.34-7.26 (m, 1H), 4.43 (d, J=9.5 Hz, 1H), 4.25-4.16 (m, 1H), 4.10 (d, J=9.2 Hz, 1H), 3.59 (d, J=4.5 Hz, 2H), 3.30-3.21 (m, 1H), 3.20-3.08 (m, 2H); 13C NMR (125 MHz, DMSO) δ ppm 169.08, 150.95 (dd, JCF=245.8, 13.1 Hz), 148.22, 148.09 (dd, JCF=248.7, 13.2 Hz), 133.46, 129.11, 128.99, 128.62, 125.43, 124.70, 118.16 (d, JCF=16.9 Hz), 81.36, 75.29, 66.76, 62.39, 40.77, 24.25.

Workup

  1. stirringthe reaction was stirred for another 30 min
  2. filtrationThe resulting suspension was filtered
  3. dry with materialthe filtrate was dried by azeotropic distillation under vacuum with toluene (360 mL)
  4. additionMethanol (110 mL) was added
  5. stirringthe solution was stirred for 2 h
  6. customThe solvent was removed under vacuum and chased with toluene (66 mL)
  7. dissolutionThe residual oil was dissolved in CH2Cl2 (250 ml)
  8. washwashed successively with aq
  9. concentrationThe organic phase was concentrated
  10. additionToluene (66 mL) and THF (67 mL) were added to the residue
  11. filtrationthe solution was filtered through celite and
  12. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-53a13ee1d0834086982e671d40e5b2b9
Source dataset
uspto-grants-2015_11
Patent number
US09175013B2

Reaction notes

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