Sodium Chloride → (1-{[(2-chloro-4-pyrimidinyl)oxy]methyl}cyclobutyl)methyl (1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate

HRID 1180774Notes

Reaction equation

HRID 1180774 reaction equation
[Cl:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]2([CH2:14][OH:15])[CH2:13][CH2:12][CH2:11]2)[CH:5]=[CH:4][N:3]=1.[C:16](Cl)(Cl)=[O:17].[NH2:20][C@@H:21]([CH2:35][CH2:36][CH2:37][CH3:38])[CH:22]([OH:34])[C:23]([NH:25][C@@H:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH3:27])=[O:24].C(N(CC)C(C)C)(C)C.[Cl-].[Na+]>ClCCl.C1(C)C=CC=CC=1.O1CCCC1.C(OCC)(=O)C>[OH:34][CH:22]([C@@H:21]([NH:20][C:16](=[O:17])[O:15][CH2:14][C:10]1([CH2:9][O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH2:13][CH2:12][CH2:11]1)[CH2:35][CH2:36][CH2:37][CH3:38])[C:23](=[O:24])[NH:25][C@@H:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH3:27]

Participants

10

Reactant 5

HCID 5234Sodium ChlorideHCID 6371PhosgeneHCID 81531DiisopropylethylamineHCID 11265560(3S)-3-amino-2-hydroxy-N-[(1R)-1-phenylethyl]heptanamideHCID 11413552(1-{[(2-Chloro-4-pyrimidinyl)oxy]methyl}cyclobutyl)methanol

Product 1

HCID 11489253(1-{[(2-chloro-4-pyrimidinyl)oxy]methyl}cyclobutyl)methyl (1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamateYield 828.5%

Reagents, catalysts & solvents 4

HCID 1140TolueneSolventHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of 0.106 g (0.05 mmol) of (1-{[(2-chloro-4-pyrimidinyl)oxy]methyl}cyclobutyl)methanol in 2 mL of dichloromethane cooled to 0° C. was added a 1.0 M solution of 0.937 mL (0.75 mmol) of phosgene in toluene and the contents stirred for 16 h. The reaction mixture was concentrated and the residue was dissolved in 4 mL of tetrahydrofuran and added to a 0° C. solution of 0.132 g (0.50 mmol) of (3S)-3-amino-2-hydroxy-N-[(1R)-1-phenylethyl]heptanamide and 0.259 mL (1.5 mmol) of N,N-diisopropylethylamine in 2 mL of tetrahydrofuran. After stirring for 5 h, ethyl acetate and saturated sodium chloride were added. The organic phase was isolated, dried using magnesium sulfate, concentrated under vacuum, and the residue was purified by silica gel chromatography eluting with ethyl acetate:hexane (7:3) to afford 0.215 g (89%) of (1-{[(2-chloro-4-pyrimidinyl)oxy]methyl}cyclobutyl)methyl (1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 8.29 (d, J=6 Hz, 1H), 7.32-7.10 (m, 6H), 6.67 (d, J=6 Hz, 1H), 5.61-5.53 (m, 1H), 5.13-5.08 (m, 1H), 4.79, 4.89 (2d, J=5, 6 Hz, 1H), 4.36, 4.39 (2s, 2H), 4.38-4.18 (m, 3H), 3.84 (m, 1H), 2.07-1.50 (m, 10 H), 1.47-1.26 (m, 5H), 0.88 (m, 3H). LC-MS m/z 519 (M+H).

Workup

  1. concentrationThe reaction mixture was concentrated
  2. dissolutionthe residue was dissolved in 4 mL of tetrahydrofuran
  3. stirringAfter stirring for 5 h
  4. customThe organic phase was isolated
  5. customdried
  6. concentrationconcentrated under vacuum
  7. customthe residue was purified by silica gel chromatography
  8. washeluting with ethyl acetate:hexane (7:3)

Sources & evidence

ORD record
ord-a7ca0f1c4b104f2aa1806a97b1e03648
Source dataset
uspto-grants-2007_10
Patent number
US07282512B2

Reaction notes

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