Diisopropylethylamine → tert-Butyl ((4aS,5R,7aS)-7a-(2-fluorophenyl)-3,5-dimethyl-4-oxo-3,4,4a,5,7,7a-hexahydrofuro[3,4-d]pyrimidin-2-yl)carbamate

HRID 2281847Notes

Reaction equation

HRID 2281847 reaction equation
[CH3:1][NH:2][C:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=S.[NH2:13][C@@:14]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[F:30])[CH2:18][O:17][C@H:16]([CH3:19])[C@H:15]1[C:20]([O:22]C)=O.C(N(C(C)C)C(C)C)C.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[F:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C@:14]12[CH2:18][O:17][C@H:16]([CH3:19])[C@H:15]1[C:20](=[O:22])[N:2]([CH3:1])[C:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:10])([CH3:9])[CH3:11])=[N:13]2

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 57496573tert-butyl N-(methylcarbamothioyl)carbamateHCID 66869274(2R,3S,4S)-methyl 4-amino-4-(2-fluorophenyl)-2-methyltetrahydrofuran-3-carboxylate

Product 1

HCID 69937526tert-Butyl ((4aS,5R,7aS)-7a-(2-fluorophenyl)-3,5-dimethyl-4-oxo-3,4,4a,5,7,7a-hexahydrofuro[3,4-d]pyrimidin-2-yl)carbamateYield 92.7%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

tert-Butyl (methylcarbamothioyl)carbamate (2.13 g, 11.2 mmol) was added to a stirred mixture of (2R,3S,4S)-methyl 4-amino-4-(2-fluorophenyl)-2-methyltetrahydrofuran-3-carboxylate (2.27 g, 9.0 mmol), N-ethyl-N-(propan-2-yl)propan-2-amine (3.9 mL, 22.4 mmol) and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (1:1) (2.15 g, 11.2 mmol) in dry DMF (18 mL) at RT under nitrogen. The mixture was stirred at RT for 3 days, then partitioned between EtOAc (50 mL) and saturated aqueous NaHCO3 (50 mL) and water (50 mL). The aqueous layer was further extracted with EtOAc (2×50 mL). The combined extracts were dried (Na2SO4), filtered and evaporated. The residue was purified by column chromatography (normal phase, 100 g, Biotage SNAP cartridge KP-Sil, 50 mL per min, gradient 10% to 25% EtOAc in n-hexane) to give the title compound (3.15 g, colourless foam). 1H NMR (400 MHz, CDCl3) δ ppm 1.51 (d, J=6.06 Hz, 3H) 1.54 (s, 9H) 3.28 (s, 3H) 3.40 (dd, J=9.09, 2.02 Hz, 1H) 4.31 (d, J=10.11 Hz, 1H) 4.36-4.45 (m, 2H) 7.10-7.24 (m, 3H) 7.33-7.40 (m, 1H) 10.53 (br. s., 1H).

Workup

  1. custompartitioned between EtOAc (50 mL) and saturated aqueous NaHCO3 (50 mL) and water (50 mL)
  2. extractionThe aqueous layer was further extracted with EtOAc (2×50 mL)
  3. dry with materialThe combined extracts were dried (Na2SO4)
  4. filtrationfiltered
  5. customevaporated
  6. customThe residue was purified by column chromatography (normal phase, 100 g, Biotage SNAP cartridge KP-Sil, 50 mL per min, gradient 10% to 25% EtOAc in n-hexane)

Sources & evidence

ORD record
ord-d123b54d5c0a40ddbe952e8663787730
Source dataset
uspto-grants-2015_09
Patent number
US09139594B2

Reaction notes

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