Diisopropylethylamine → tert-butyl (S)-1-((2S,4R)-4-(biphenyl-4-yl)-4-(butylthio)-2-((1R,2S)-1-(cyclopropylsulfonylcarbamoyl)-2-(2,2-difluoroethyl)cyclopropylcarbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-ylcarbamate

HRID 2425785Notes

Reaction equation

HRID 2425785 reaction equation
[C:1]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:6]=[CH:5][C:4]([C@@:7]2([S:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:11][N:10]([C:12](=[O:26])[C@@H:13]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:14]([CH3:17])([CH3:16])[CH3:15])[C@H:9]([C:27](O)=[O:28])[CH2:8]2)=[CH:3][CH:2]=1.[NH2:41][C@:42]1([C:49]([NH:51][S:52]([CH:55]2[CH2:57][CH2:56]2)(=[O:54])=[O:53])=[O:50])[CH2:44][C@H:43]1[CH2:45][CH:46]([F:48])[F:47].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>CN(C=O)C.CO>[C:1]1([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:6]=[CH:5][C:4]([C@@:7]2([S:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:11][N:10]([C:12](=[O:26])[C@@H:13]([NH:18][C:19](=[O:20])[O:21][C:22]([CH3:25])([CH3:23])[CH3:24])[C:14]([CH3:17])([CH3:15])[CH3:16])[C@H:9]([C:27](=[O:28])[NH:41][C@:42]3([C:49](=[O:50])[NH:51][S:52]([CH:55]4[CH2:57][CH2:56]4)(=[O:53])=[O:54])[CH2:44][C@H:43]3[CH2:45][CH:46]([F:47])[F:48])[CH2:8]2)=[CH:3][CH:2]=1

Participants

7

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 57945187(1R,2S)-1-amino-N-(cyclopropylsulfonyl)-2-(2,2-difluoroethyl)cyclopropanecarboxamideHCID 57998016(2S,4R)-4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoyl)-4-(butylthio)pyrrolidine-2-carboxylic acid

Product 1

HCID 44544499tert-butyl (S)-1-((2S,4R)-4-(biphenyl-4-yl)-4-(butylthio)-2-((1R,2S)-1-(cyclopropylsulfonylcarbamoyl)-2-(2,2-difluoroethyl)cyclopropylcarbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-ylcarbamateYield 58.3%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6228DimethylformamideSolvent

Procedure

To a solution of (2S,4R)-4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoyl)-4-(butylthio)pyrrolidine-2-carboxylic acid (15 mg, 0.026 mmol), (1R,2S)-1-amino-N-(cyclopropylsulfonyl)-2-(2,2-difluoroethyl)cyclopropanecarboxamide (8.84 mg, 0.029 mmol), and HATU (15.03 mg, 0.040 mmol) in DMF (1 mL) was added N,N-Diisopropylethylamine (0.014 mL, 0.079 mmol). The formed light yellow solution was stirred at room temperature for 5 h. Diluted with MeOH, purified by prep-HPLC to yield the desired product tert-butyl (S)-1-((2S,4R)-4-(biphenyl-4-yl)-4-(butylthio)-2-((1R,2S)-1-(cyclopropylsulfonylcarbamoyl)-2-(2,2-difluoroethyl)cyclopropylcarbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-ylcarbamate (14 mg, 0.015 mmol, 58.3% yield) as a white solid. 1H NMR (500 MHz, MeOD) ppm 0.83 (t, J=7.17 Hz, 3H), 1.09-1.12 (m, 10H), 1.22-1.45 (m, 7H) 1.47-1.52 (m, 10H), 1.66 (s, 2H), 2.07-2.38 (m, 4H), 2.37-2.51 (m, 1H), 2.76-2.87 (m, 1H), 2.91-3.04 (m, 11H), 3.85-4.06 (m, 2H), 4.51 (d, J=9.77 Hz, 1H), 5.05 (d, J=11.29 Hz, 1H), 5.73-6.09 (m, 1H), 7.37 (t, J=7.02 Hz, 1H), 7.46 (t, J=7.48 Hz, 2H), 7.54-7.64 (m, 4H), 7.68 (d, J=8.24 Hz, 2H). LC-MS (retention time: 3.48 min, method B), MS m/z 819 (M+H).

Workup

  1. custompurified by prep-HPLC

Sources & evidence

ORD record
ord-4190b15e5db642bd98e083f6ea3af96c
Source dataset
uspto-grants-2011_06
Patent number
US07964560B2

Reaction notes

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