Triphenylphosphine → N-[(4R,4aR,6R,8aS)-6-[(benzyloxy)methyl]-8a-(2,4-difluorophenyl)-4-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide

HRID 590610Notes

Reaction equation

HRID 590610 reaction equation
N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:32]([O:39][CH2:40][C@@H:41]1[O:46][CH2:45][C@@:44]([NH:55][C:56]([NH:58][C:59](=[O:66])[C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)=[S:57])([C:47]2[CH:52]=[CH:51][C:50]([F:53])=[CH:49][C:48]=2[F:54])[C@H:43]([C@@H:67](O)[CH3:68])[CH2:42]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>O1CCCC1>[CH2:32]([O:39][CH2:40][C@@H:41]1[O:46][CH2:45][C@:44]2([C:47]3[CH:52]=[CH:51][C:50]([F:53])=[CH:49][C:48]=3[F:54])[N:55]=[C:56]([NH:58][C:59](=[O:66])[C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)[S:57][C@H:67]([CH3:68])[C@@H:43]2[CH2:42]1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1

Participants

5

Reactant 3

HCID 11776TriphenylphosphineHCID 220568ethyl N-ethoxycarbonyliminocarbamateHCID 86701087N-{[(3S,4R,6R)-6-[(benzyloxy)methyl]-3-(2,4-difluorophenyl)-4-[(1S)-1-hydroxyethyl]tetrahydro-2H-pyran-3-yl]carbamothioyl}benzamide

Product 1

HCID 89889266N-[(4R,4aR,6R,8aS)-6-[(benzyloxy)methyl]-8a-(2,4-difluorophenyl)-4-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

Diethyl azodicarboxylate (21.3 mL, 136 mmol) was added drop-wise to a solution of triphenylphosphine (35.7 g, 136 mmol) in tetrahydrofuran (850 mL), and the mixture was stirred for 30 minutes before being cooled in an ice bath. A solution of N-{[(3S,4R,6R)-6-[(benzyloxy)methyl]-3-(2,4-difluorophenyl)-4-[(1S)-1-hydroxyethyl]tetrahydro-2H-pyran-3-yl]carbamothioyl}benzamide (C20) (24.5 g, 45.3 mmol) in tetrahydrofuran (115 mL) was added drop-wise to the reaction mixture, which was then stirred for 1 hour under ice cooling. After concentration in vacuo, the residue was loaded onto a silica gel column that had been equilibrated with dichloromethane, and the column was eluted with 1:1 ethyl acetate/heptane. Fractions containing product were combined and concentrated under reduced pressure; the resulting material was triturated with 15% ethyl acetate in heptane, and the solid was removed via filtration. The filtrate was concentrated in vacuo and chromatographed on silica gel (Gradient: 20% to 40% ethyl acetate in heptane), affording the product as a white solid. Yield: 17.23 g, 32.97 mmol, 73%. LCMS m/z 523.2 [M+H+]. 1H NMR (400 MHz, CDCl3) δ 8.23 (br d, J=6.5 Hz, 2H), 7.49-7.55 (m, 1H), 7.36-7.48 (m, 3H), 7.24-7.36 (m, 5H), 6.84-6.96 (m, 2H), 4.58 (AB quartet, JAB=12.0 Hz, ΔνAB=25.0 Hz, 2H), 4.18 (dd, J=12.2, 1.7 Hz, 1H), 3.87-3.94 (m, 1H), 3.84 (d, J=12.2 Hz, 1H), 3.63 (dd, half of ABX pattern, J=10.2, 6.4 Hz, 1H), 3.50 (dd, half of ABX pattern, J=10.2, 4.4 Hz, 1H), 3.23-3.31 (m, 1H), 2.88-2.96 (m, 1H), 1.61-1.79 (m, 2H), 1.25 (d, J=6.9 Hz, 3H).

Workup

  1. temperaturebefore being cooled in an ice bath
  2. stirringwas then stirred for 1 hour under ice cooling
  3. concentrationAfter concentration in vacuo
  4. washthe column was eluted with 1:1 ethyl acetate/heptane
  5. additionFractions containing product
  6. concentrationconcentrated under reduced pressure
  7. customthe resulting material was triturated with 15% ethyl acetate in heptane
  8. customthe solid was removed via filtration
  9. concentrationThe filtrate was concentrated in vacuo
  10. customchromatographed on silica gel (Gradient: 20% to 40% ethyl acetate in heptane)

Sources & evidence

ORD record
ord-eabfeea657cb4ab8b935e1491bf2adcd
Source dataset
uspto-grants-2016_01
Patent number
US09233981B1

Reaction notes

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