Triethylamine → 3-Chloro-4'-((R)-1-{[3-(9H-fluoren-9-ylmethoxycarbonylamino)-oxetane-3-carbonyl]-amino}-ethyl)-3'-fluoro-biphenyl-2-carboxylic acid methyl ester

HRID 1404545Notes

Reaction equation

HRID 1404545 reaction equation
[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:19]3([C:23](O)=[O:24])[CH2:22][O:21][CH2:20]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.Cl.[CH3:50][O:51][C:52]([C:54]1[C:55]([C:61]2[CH:66]=[CH:65][C:64]([C@H:67]([NH2:69])[CH3:68])=[C:63]([F:70])[CH:62]=2)=[CH:56][CH:57]=[CH:58][C:59]=1[Cl:60])=[O:53].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>CN(C=O)C.O>[CH3:50][O:51][C:52]([C:54]1[C:55]([C:61]2[CH:66]=[CH:65][C:64]([C@H:67]([NH:69][C:23]([C:19]3([NH:18][C:16]([O:15][CH2:14][CH:12]4[C:11]5[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=5[C:5]5[C:13]4=[CH:1][CH:2]=[CH:3][CH:4]=5)=[O:17])[CH2:22][O:21][CH2:20]3)=[O:24])[CH3:68])=[C:63]([F:70])[CH:62]=2)=[CH:56][CH:57]=[CH:58][C:59]=1[Cl:60])=[O:53]

Participants

9

Reactant 6

HCID 8471TriethylamineHCID 516892Sodium BicarbonateHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 27960291-Hydroxybenzotriazole hydrateHCID 161029164'-((R)-1-Amino-ethyl)-3-chloro-3'-fluoro-biphenyl-2-carboxylic acid methyl ester hydrochlorideHCID 679511683-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)oxetane-3-carboxylic acid2×

Product 1

HCID 679793093-Chloro-4'-((R)-1-{[3-(9H-fluoren-9-ylmethoxycarbonylamino)-oxetane-3-carbonyl]-amino}-ethyl)-3'-fluoro-biphenyl-2-carboxylic acid methyl ester

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent2×

Procedure

To a solution of 3-(9H-fluoren-9-ylmethoxycarbonylamino)-oxetane-3-carboxylic acid (207 mg, 610 μmol, intermediate 8) in dry DMF (2.11 ml) were added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (129 mg, 671 μmol) and 1-hydroxybenzotriazole hydrate (103 mg, 671 μmol) at room temperature. The colorless solution was stirred for 10 min before a solution of 4′-((R)-1-amino-ethyl)-3-chloro-3′-fluoro-biphenyl-2-carboxylic acid methyl ester hydrochloride (210 mg, 610 μmol) and triethylamine (61.7 mg, 85.0 μl, 610 μmol) in dry DMF (2.11 ml) was added. After addition, the brown solution was stirred at room temperature over night. Then water was added and the pH of the mixture was adjusted to 7 by addition of sat. NaHCO3 solution. The mixture was extracted three times with EtOAc and the combined organic layers were washed with water and brine, dried with Na2SO4 and evaporated. The remaining residue was purified by chromatography (silica gel; DCM/MeOH 99:1-95:5) and the title compound was obtained as white solid (312 mg, 81%). MS: 629.3 [M+H]+.

Workup

  1. additionwas added
  2. additionAfter addition
  3. extractionThe mixture was extracted three times with EtOAc
  4. washthe combined organic layers were washed with water and brine
  5. dry with materialdried with Na2SO4
  6. customevaporated
  7. customThe remaining residue was purified by chromatography (silica gel; DCM/MeOH 99:1-95:5)

Sources & evidence

ORD record
ord-45091853a4ab46aa9c927953bbcc6f21
Source dataset
uspto-grants-2014_12
Patent number
US08912221B2

Reaction notes

Loading…