Diisopropylethylamine → (9H-fluoren-9-yl)methyl 4,4,4-trifluoro-1-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethylamino)-1-oxobutan-2-ylcarbamate

HRID 238836Notes

Reaction equation

HRID 238836 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([C@@:15]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)([NH2:23])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:7]=1.N[C:32](=[O:57])[CH:33]([NH:39][C:40](=[O:56])[O:41][CH2:42][CH:43]1[C:55]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[C:49]2[C:44]1=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH2:34][C:35]([F:38])([F:37])[F:36].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:36][C:35]([F:37])([F:38])[CH2:34][CH:33]([NH:39][C:40](=[O:56])[O:41][CH2:42][CH:43]1[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:49]=2[C:50]2[C:55]1=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:32]([NH:23][C@@:15]([C:4]1[CH:5]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:7]=[C:2]([F:1])[CH:3]=1)([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:57]

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 2733179PyBroPHCID 59458485(R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethanamineHCID 59459473(9H-fluoren-9-yl)methyl 1-amino-4,4,4-trifluoro-1-oxobutan-2-ylcarbamate

Product 1

HCID 86613060(9H-fluoren-9-yl)methyl 4,4,4-trifluoro-1-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethylamino)-1-oxobutan-2-ylcarbamateYield 38%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of (R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethanamine (31 mg, 0.07 mmol), prepared as described in Procedure 3, 4, 5 and 6, in DCM (1 mL) was added (9H-fluoren-9-yl)methyl 1-amino-4,4,4-trifluoro-1-oxobutan-2-ylcarbamate (31 mg, 0.08 mmol), followed by PyBrOP and iPr2NEt. The reaction mixture was stirred at rt for 72 h and concentrated. The residue was purified by preparative HPLC (Axia column, 30×100 mm, 60-100% MeOH/H2O with 0.1% TFA over 12 min, flow rate 40 mL/min, monitoring at 220 nm) to yield (9H-fluoren-9-yl)methyl 4,4,4-trifluoro-1-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethylamino)-1-oxobutan-2-ylcarbamate as white solid (20 mg, 38% yield). LCMS: RT=4.5 min [M+H] 787.3 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm). This diastereomer mixture was separated by Chiralpak AD column eluting with 10% MeOH/EtOH (1:1)/90% heptane with flow rate 20 mL/min. (9H-fluoren-9-yl)methyl (S)-4,4,4-trifluoro-1-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethylamino)-1-oxobutan-2-ylcarbamate was eluted at a retention time of 8.26 min and isolated as a white solid (10 mg). (9H-fluoren-9-yl)methyl (R)-4,4,4-trifluoro-1-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethylamino)-1-oxobutan-2-ylcarbamate was eluted at a retention time of 12.97 min and isolated as a white solid (10 mg). The stereochemistry of (9H-fluoren-9-yl)methyl (S)-4,4,4-trifluoro-1-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethylamino)-1-oxobutan-2-ylcarbamate and (9H-fluoren-9-yl)methyl (R)-4,4,4-trifluoro-1-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethylamino)-1-oxobutan-2-ylcarbamate was assigned arbitrarily.

Workup

  1. concentrationconcentrated
  2. customThe residue was purified by preparative HPLC (Axia column, 30×100 mm, 60-100% MeOH/H2O with 0.1% TFA over 12 min, flow rate 40 mL/min, monitoring at 220 nm)

Sources & evidence

ORD record
ord-ab5117a89b2b40b984edd91d878a50f3
Source dataset
uspto-grants-2014_02
Patent number
US08642576B2

Reaction notes

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