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Ethyl Acetate → N-(((3S,4R,5S)-3-(2-fluorophenyl)-4-(hydroxymethyl)-5-(trifluoromethyl)tetrahydrofuran-3-yl)carbamothioyl)benzamide

HRID 2195792
Notes
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Reaction equation

HRID 2195792 reaction equation
C(O[C@@H]([C@H](OC(=O)C1C=CC=CC=1)C(O)=O)C(O)=O)(=O)C1C=CC=CC=1.[NH2:27][C@@:28]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[F:45])[CH2:32][O:31][C@H:30]([C:33]([F:36])([F:35])[F:34])[C@H:29]1[CH2:37][OH:38].CCOC(C)=O.[OH-].[Na+].[C:54]([N:62]=[C:63]=[S:64])(=[O:61])[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1>C(Cl)Cl>[F:45][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=1[C@@:28]1([NH:27][C:63]([NH:62][C:54](=[O:61])[C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)=[S:64])[C@H:29]([CH2:37][OH:38])[C@@H:30]([C:33]([F:36])([F:34])[F:35])[O:31][CH2:32]1
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

6

Reactant 4

HCID 8857Ethyl Acetate2×HCID 14798Sodium HydroxideHCID 68284Benzoyl isothiocyanateHCID 86668368((2S,3R,45)-4-Amino-4-(2-fluorophenyl)-2-(trifluoromethyl)tetrahydrofuran-3-yl)methanol (2S,3S)-2,3-bis(benzoyloxy)succinate

Product 1

HCID 60169627
N-(((3S,4R,5S)-3-(2-fluorophenyl)-4-(hydroxymethyl)-5-(trifluoromethyl)tetrahydrofuran-3-yl)carbamothioyl)benzamide
Yield 106.1%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
-3 °C

Procedure

To chiral salt ((2S,3R,4S)-4-Amino-4-(2-fluorophenyl)-2-(trifluoromethyl)tetrahydrofuran-3-yl)methanol (2S,3S)-2,3-bis(benzoyloxy)succinate (0.361 kg, 0.556 mol) was added EtOAc (1.08 L) and the suspension was cooled to −3° C. 1.0 N aq. NaOH (1.30 L) was added over 20 mins while maintaining T<5° C. After 5 mins, benzoyl isothiocyanate (80.0 mL, 594 mmol) was added over 8 mins while maintaining T<5° C. After 1 h, EtOAc (722 mL) was charged. The aq. layer was removed, and the organics were washed with sat. aq. NaHCO3 (361 mL) and sat. aq. NaCl (361 mL). The organics were filtered over celite (90 g) and rinsed with EtOAc (360 mL). The organics were concentrated under vacuum to afford a residue which was re-dissolved into CH2Cl2 (1.1 L) and concentrated to afford the title compound as yellow foam (261 g, 99% yield accounting for residual solvents) which was used in the following step. 1H NMR (500 MHz, DMSO) δ ppm 12.04 (s, 2H), 11.20 (s, 2H), 7.95 (d, J=7.4 Hz, 2H), 7.69-7.60 (m, 1H), 7.56-7.42 (m, 2H), 7.37-7.28 (m, 1H), 7.24-7.12 (m, 2H). 5.59 (t, J=4.5 Hz, 1H), 5.03 (d, J=9.7 Hz, 1H), 4.92 (d, J=9.7 Hz, 1H), 4.75-4.63 (m, 1H), 3.92-3.74 (m, 2H), 2.77-2.66 (m, 1H); 13C NMR (125 MHz, DMSO) δ ppm 179.98, 167.85, 159.75 (d, JCF=245.0 Hz), 133.44, 132.58, 129.88, 129.81, 129.04, 128.85, 126.31 (d, JCF=9.8 Hz), 124.36, 116.83 (d, JCF=23.4 Hz), 76.11 (q, JCF=31.0 Hz). 74.37 (d, JCF=6.1 Hz), 68.77 (d, JCF=3.4 Hz), 57.03, 52.23.

Workup

  1. temperaturewhile maintaining T<5° C
  2. temperaturewhile maintaining T<5° C
  3. waitAfter 1 h
  4. customThe aq. layer was removed
  5. washthe organics were washed with sat. aq. NaHCO3 (361 mL) and sat. aq. NaCl (361 mL)
  6. filtrationThe organics were filtered over celite (90 g)
  7. washrinsed with EtOAc (360 mL)
  8. concentrationThe organics were concentrated under vacuum
  9. customto afford a residue which
  10. concentrationconcentrated

Sources & evidence

ORD record
ord-d4b33f051a004dc6b64d6a12c8fdef55
Source dataset
uspto-grants-2012_12
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08338407B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes