Diisopropylethylamine → tert-butyl (S)-1-((2S,4R)-4-(allylthio)-4-(biphenyl-4-yl)-2-((1R,2R)-2-(difluoromethyl)-1-(1-(hept-6-enyl)cyclopropylsulfonylcarbamoyl)cyclopropylcarbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-ylcarbamate

HRID 2061422Notes

Reaction equation

HRID 2061422 reaction equation
[CH2:1]([S:4][C@:5]1([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:30][CH:29]=2)[CH2:9][N:8]([C:10](=[O:24])[C@@H:11]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:12]([CH3:15])([CH3:14])[CH3:13])[C@H:7]([C:25]([OH:27])=O)[CH2:6]1)[CH:2]=[CH2:3].[NH2:40][C@:41]1([C:47]([NH:49][S:50]([C:53]2([CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH:61]=[CH2:62])[CH2:55][CH2:54]2)(=[O:52])=[O:51])=[O:48])[CH2:43][C@H:42]1[CH:44]([F:46])[F:45].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH2:1]([S:4][C@:5]1([C:28]2[CH:29]=[CH:30][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:32][CH:33]=2)[CH2:9][N:8]([C:10](=[O:24])[C@@H:11]([NH:16][C:17](=[O:18])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[C:12]([CH3:15])([CH3:14])[CH3:13])[C@H:7]([C:25](=[O:27])[NH:40][C@:41]2([C:47](=[O:48])[NH:49][S:50]([C:53]3([CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH:61]=[CH2:62])[CH2:54][CH2:55]3)(=[O:52])=[O:51])[CH2:43][C@H:42]2[CH:44]([F:46])[F:45])[CH2:6]1)[CH:2]=[CH2:3]

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 57998012(2S,4R)-4-(allylthio)-4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoyl)pyrrolidine-2-carboxylic acidHCID 59366237(1R,2R)-1-amino-2-(difluoromethyl)-N-(1-(hept-6-enyl)cyclopropylsulfonyl)cyclopropanecarboxamide

Product 1

HCID 59366238tert-butyl (S)-1-((2S,4R)-4-(allylthio)-4-(biphenyl-4-yl)-2-((1R,2R)-2-(difluoromethyl)-1-(1-(hept-6-enyl)cyclopropylsulfonylcarbamoyl)cyclopropylcarbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-ylcarbamateYield 73%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

To a slurry of (2S,4R)-4-(allylthio)-4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoyl)pyrrolidine-2-carboxylic acid (55.3 mg, 0.10 mmol), (1R,2R)-1-amino-2-(difluoromethyl)-N-(1-(hept-6-enyl)cyclopropylsulfonyl)cyclopropanecarboxamide (38.7 mg, 0.10 mmol) and HATU (57.0 mg, 0.150 mmol) in DCM (2 mL) was added N,N-Diisopropylethylamine (0.087 mL, 0.500 mmol). The formed solution was stirred at room temperature overnight. Diluted with DCM, washed with 1M HCl and brine, dried over MgSO4, filtered, and concentrated. The residue was purified by Biotage column, eluted with gradient 5%˜30% Acetone-Hexane to afford the desired product tert-butyl (S)-1-((2S,4R)-4-(allylthio)-4-(biphenyl-4-yl)-2-((1R,2R)-2-(difluoromethyl)-1-(1-(hept-6-enyl)cyclopropylsulfonylcarbamoyl)cyclopropylcarbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-ylcarbamate (65 mg, 0.073 mmol, 73% yield) as a white foam. 1H NMR (400 MHz, MeOD) ppm 0.81-0.88 (m, 2 H) 1.07 (s, 9 H) 1.21-1.61 (m, 17 H) 1.64-1.80 (m, 1 H) 1.81-2.12 (m, 6 H) 2.37 (t, J=11.42 Hz, 1 H) 2.91-3.05 (m, 3 H) 3.91 (dd, J=10.29, 6.53 Hz, 1 H) 3.98 (d, J=11.04 Hz, 1 H) 4.48 (d, J=9.79 Hz, 1 H) 4.86-5.13 (m, 5 H) 5.66-6.14 (m, 3 H) 7.36 (t, J=7.28 Hz, 1 H) 7.45 (t, J=7.53 Hz, 2 H) 7.52-7.76 (m, 6 H). LC-MS (retention time: 3.39 min, Method B), MS m/z 885 (M+H).

Workup

  1. washwashed with 1M HCl and brine
  2. dry with materialdried over MgSO4
  3. filtrationfiltered
  4. concentrationconcentrated
  5. customThe residue was purified by Biotage column
  6. washeluted with gradient 5%˜30% Acetone-Hexane

Sources & evidence

ORD record
ord-5d5a7092e5924db3a69af8686e36c252
Source dataset
uspto-grants-2012_10
Patent number
US08283310B2

Reaction notes

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