Triethylamine → Di-tert-butyl 4'-{(3R)-3-methyl-3-(methylsulfonyl)-4-oxo-4-[(tetrahydro-2H-pyran-2-yloxy)amino]butyl}biphenyl-4-yl phosphate

HRID 533540

Reaction equation

HRID 533540 reaction equation
C(N(CC)CC)C.O.ON1C2C=CC=CC=2N=N1.[C:19]([O:23][P:24]([O:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][C:41]([CH2:44][CH2:45][C@@:46]([CH3:54])([S:50]([CH3:53])(=[O:52])=[O:51])[C:47](O)=[O:48])=[CH:40][CH:39]=2)=[CH:34][CH:33]=1)([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])([CH3:22])([CH3:21])[CH3:20].[O:55]1[CH2:60][CH2:59][CH2:58][CH2:57][CH:56]1[O:61][NH2:62].Cl.CN(C)CCCN=C=NCC>ClCCl.O>[P:24]([O:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:39]=[CH:40][C:41]([CH2:44][CH2:45][C@@:46]([CH3:54])([S:50]([CH3:53])(=[O:52])=[O:51])[C:47](=[O:48])[NH:62][O:61][CH:56]3[CH2:57][CH2:58][CH2:59][CH2:60][O:55]3)=[CH:42][CH:43]=2)=[CH:34][CH:33]=1)([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])([O:23][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:25]

Participants

8

Reactant 5

HCID 8471TriethylamineHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 27960291-Hydroxybenzotriazole hydrateHCID 5142091O-(Tetrahydropyran-2-yl)hydroxylamineHCID 66577853(2R)-4-{4'-[(Di-tert-butoxyphosphoryl)oxy]biphenyl-4-yl}-2-methyl-2-(methylsulfonyl)butanoic acid

Product 1

HCID 86668766Di-tert-butyl 4'-{(3R)-3-methyl-3-(methylsulfonyl)-4-oxo-4-[(tetrahydro-2H-pyran-2-yloxy)amino]butyl}biphenyl-4-yl phosphateYield 63%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent2×

Procedure

A solution of triethylamine (2.0 mL, 15 mmol, 1.8 equiv), 1-hydroxyl benzotriazole monohydrate (2.3 g, 15 mmol, 1.8 equiv), (2R)-4-{4′-[(di-tert-butoxyphosphoryl)oxy]biphenyl-4-yl}-2-methyl-2-(methylsulfonyl)butanoic acid (4.4 g, 8.2 mmol, 1.0 equiv), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (1.4 g, 12 mmol, 1.4 equiv), and N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI) (2.2 g, 11 mmol, 1.4 equiv) in dichloromethane (205 mL) was allowed to stir at room temperature for 1 day. The reaction was diluted with water (600 mL) and dichloromethane (600 mL), the aqueous phase was separated and extracted with dichloromethane (2×300 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (60% ethyl acetate in heptane) to provide the title compound (3.29 g, 63%). MS (LCMS) m/z 638.8 (M−1).

Workup

  1. customthe aqueous phase was separated
  2. extractionextracted with dichloromethane (2×300 mL)
  3. dry with materialThe combined organic layers were dried over anhydrous sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated under reduced pressure
  6. customThe crude material was purified by flash chromatography on silica gel (60% ethyl acetate in heptane)

Sources & evidence

ORD record
ord-f5b93785bd3c4a1abbedb9d0fb22be89
Source dataset
uspto-grants-2014_10
Patent number
US08853258B2

Linked notes

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