Benzoyl isothiocyanate → rel-N-{[(3S,4R,6R)-6-cyclopropyl-3-(2,4-difluorophenyl)-4-(hydroxymethyl)tetrahydro-2H-pyran-3-yl]carbamothioyl}benzamide

HRID 1478716Notes

Reaction equation

HRID 1478716 reaction equation
[C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C@@:13]1([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[F:31])[CH2:18][O:17][C@@H:16]([CH:19]2[CH2:21][CH2:20]2)[CH2:15][C@H:14]1[CH2:22][OH:23]>ClCCl>[CH:19]1([C@@H:16]2[O:17][CH2:18][C@@:13]([NH:12][C:10]([NH:9][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[S:11])([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[F:31])[C@H:14]([CH2:22][OH:23])[CH2:15]2)[CH2:21][CH2:20]1

Participants

4

Reactant 2

HCID 68284Benzoyl isothiocyanateHCID 90253439rel-[(2R,4R,5S)-5-amino-2-cyclopropyl-5-(2,4-difluorophenyl)tetrahydro-2H-pyran-4-yl]methanol

Product 1

HCID 90253442rel-N-{[(3S,4R,6R)-6-cyclopropyl-3-(2,4-difluorophenyl)-4-(hydroxymethyl)tetrahydro-2H-pyran-3-yl]carbamothioyl}benzamide

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

Benzoyl isothiocyanate (0.540 mL, 4.02 mmol) was added drop-wise to a solution of rel-[(2R,4R,5S)-5-amino-2-cyclopropyl-5-(2,4-difluorophenyl)tetrahydro-2H-pyran-4-yl]methanol (C20) (1.20 g, 4.23 mmol) in dichloromethane (45 mL). After the reaction mixture had stirred at room temperature for 15 hours, it was partitioned between aqueous hydrochloric acid (0.1 M, 20 mL) and dichloromethane (35 mL). The organic layer was washed with saturated aqueous sodium bicarbonate solution (25 mL) and with saturated aqueous sodium chloride solution (25 mL), then dried over sodium sulfate, filtered, and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 0% to 45% ethyl acetate in heptane) provided the product as a white solid. Yield: 1.69 g, 3.78 mmol, 89%. LCMS m/z 447.2 [M+H+]. 1H NMR (400 MHz, CD3CN) δ 11.64 (br s, 1H), 9.28 (br s, 1H), 7.89-7.93 (m, 2H), 7.64-7.69 (m, 1H), 7.52-7.58 (m, 2H), 7.44-7.58 (br m, 1H), 6.86-6.99 (m, 2H), 3.48-3.86 (br m, 2H), 3.35-3.47 (m, 1H), 3.01 (ddd, J=11.3, 7.6, 2.7 Hz, 1H), 2.89-3.0 (br m, 1H), 2.3-2.6 (br m, 1H), 1.96-2.03 (m, 1H), 1.7-1.9 (br m, 1H), 0.90-1.00 (m, 1H), 0.44-0.53 (m, 2H), 0.34-0.40 (m, 1H), 0.26-0.31 (m, 1H).

Workup

  1. customit was partitioned between aqueous hydrochloric acid (0.1 M, 20 mL) and dichloromethane (35 mL)
  2. washThe organic layer was washed with saturated aqueous sodium bicarbonate solution (25 mL) and with saturated aqueous sodium chloride solution (25 mL)
  3. dry with materialdried over sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. customPurification via silica gel chromatography (Gradient: 0% to 45% ethyl acetate in heptane)

Sources & evidence

ORD record
ord-57ce9c39ea8f4960b0827177815bf94f
Source dataset
uspto-grants-2016_08
Patent number
US09403846B2

Reaction notes

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