Benzyl Isothiocyanate → N-(((3S,4R,5S)-3-(2,3-difluorophenyl)-4-(hydroxymethyl)-5-((trityloxy)methyl)tetrahydrofuran-3-yl)carbamothioyl)benzamide

HRID 707704Notes

Reaction equation

HRID 707704 reaction equation
[C:1]([C@@](C(O)=O)(O)[C@@](C(=O)C1C=CC=CC=1)(O)C(O)=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:27][C@@:28]1([C:56]2[CH:61]=[CH:60][CH:59]=[C:58]([F:62])[C:57]=2[F:63])[CH2:32][O:31][C@H:30]([CH2:33][O:34][C:35]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C@H:29]1[CH2:54][OH:55].[OH-].[Na+].C([N:73]=[C:74]=[S:75])C1C=CC=CC=1>CCOC(C)=O>[F:63][C:57]1[C:58]([F:62])=[CH:59][CH:60]=[CH:61][C:56]=1[C@@:28]1([NH:27][C:74]([NH:73][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[S:75])[C@H:29]([CH2:54][OH:55])[C@@H:30]([CH2:33][O:34][C:35]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)([C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[O:31][CH2:32]1

Participants

5

Reactant 3

HCID 2346Benzyl IsothiocyanateHCID 14798Sodium HydroxideHCID 131733709((2S,3R,4S)-4-amino-4-(2,3-difluorophenyl)-2-((trityloxy)methyl)tetrahydrofuran-3-yl)methanol (-)dibenzoyl-L-tartaric acid

Product 1

HCID 60169626N-(((3S,4R,5S)-3-(2,3-difluorophenyl)-4-(hydroxymethyl)-5-((trityloxy)methyl)tetrahydrofuran-3-yl)carbamothioyl)benzamideYield 100.9%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent2×

Conditions

Temperature
1.7000000476837158 °C

Procedure

A suspension of ((2S,3R,4S)-4-amino-4-(2,3-difluorophenyl)-2-((trityloxy)methyl)tetrahydrofuran-3-yl)methanol (−)dibenzoyl-L-tartaric acid (44.21 g, 0.051 mol, 1.0 equiv.) in EtOAc (133 mL) was cooled down to 1.7° C. Aq. NaOH (1.0 M, 121 mL, 0.12 mol, 2.4 equiv.) was added while maintaining temperature below 5° C. The reaction was stirred for 5 min then benzyl isothiocyanate (9.43 g, 0.058 mol, 1.12 equiv.) was added over 5 min. After 1.5 h, EtOAc (133 mL) was added. The organic phase was isolated and successively washed with saturated aq. NaHCO3 (130 mL) and 18% aq.NaCl (44 mL). The combined aqueous phases were extracted with EtOAc (66 mL) and CH2Cl2 (30 mL). All the organic phase were combined, filtered and concentrated under reduced pressure. The title compound (34.2 g) was isolated as a foam after chasing the residual solvent with CH2Cl2 (88 mL). 1H NMR (500 MHz, DMSO) δ ppm 11.97 (br s, 1H), 11.20 (br s, 1H), 7.94 (d, J=7.4 Hz, 2H), 7.63 (t, J=7.4 Hz, 1H), 7.51 (t, J=7.8 Hz, 2H), 7.38-7.21 (m, 17H), 7.13 (dd, J=13.4, 7.9 Hz, 1H), 5.13 (t, J=4.4 Hz, 1H), 5.07 (d, J=9.7 Hz, 1H), 4.47 (d, J=9.8 Hz, 1H), 4.24-4.16 (m, 1H), 3.68 (t, J=4.6 Hz, 2H), 3.19 (dd, J=10.1, 2.9 Hz, 1H), 3.01 (dd, J=10.1, 4.8 Hz, 1H), 2.63-2.52 (m, 1H); 13C NMR (125 MHz, DMSO) δ ppm 180.06, 168.14, 150.75 (dd, JCF=244.6, 13.2 Hz), 147.93 (dd, JCF=247.5, 13.5 Hz), 144.15, 133.46, 132.55, 131.90 (d, JCF=6.4 Hz), 129.04, 128.86, 128.67, 128.28, 127.43, 124.41, 124.25, 116.12 (d, JCF=17.0 Hz), 86.27, 79.75, 75.03, 68.04, 64.63, 58.16, 53.35.

Workup

  1. temperaturewhile maintaining temperature below 5° C
  2. waitAfter 1.5 h
  3. customThe organic phase was isolated
  4. washsuccessively washed with saturated aq. NaHCO3 (130 mL) and 18% aq
  5. extractionThe combined aqueous phases were extracted with EtOAc (66 mL) and CH2Cl2 (30 mL)
  6. filtrationfiltered
  7. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-6c2cbf61fc6a4394bffa87b144fe06eb
Source dataset
uspto-grants-2015_11
Patent number
US09175013B2

Reaction notes

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