Diisopropylethylamine → ((R)-1-{4-[(2-Bromo-5-tert-butoxycarbonylamino-thiazole-4-carbonyl)-amino]-2-methyl-2H-pyrazol-3-yl}-perhydro-azepin-4-yl)-carbamic acid benzyl ester

HRID 2089303Notes

Reaction equation

HRID 2089303 reaction equation
[Br:1][C:2]1[S:3][C:4]([NH:10][C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])=[C:5]([C:7]([OH:9])=O)[N:6]=1.[CH2:17]([O:24][C:25](=[O:41])[NH:26][C@@H:27]1[CH2:33][CH2:32][CH2:31][N:30]([C:34]2[N:35]([CH3:40])[N:36]=[CH:37][C:38]=2[NH2:39])[CH2:29][CH2:28]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[CH3:42]N(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)C=O.C(OCC)(=O)C>[CH2:17]([O:24][C:25](=[O:41])[NH:26][C@@H:27]1[CH2:33][CH2:32][CH2:31][N:30]([C:34]2[N:35]([CH3:40])[N:36]=[CH:37][C:38]=2[NH:39][C:7]([C:5]2[N:6]=[C:2]([Br:1])[S:3][C:4]=2[NH:10][C:11]([O:13][C:14]([CH3:16])([CH3:42])[CH3:15])=[O:12])=[O:9])[CH2:29][CH2:28]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=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 58465005(R)-benzyl 1-(4-amino-1-methyl-1H-pyrazol-5-yl)azepan-4-ylcarbamateHCID 674388042-Bromo-5-(isopropoxycarbonylamino)-thiazole-4-carboxylic acid

Product 1

HCID 58464869((R)-1-{4-[(2-Bromo-5-tert-butoxycarbonylamino-thiazole-4-carbonyl)-amino]-2-methyl-2H-pyrazol-3-yl}-perhydro-azepin-4-yl)-carbamic acid benzyl esterYield 99.7%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a stirred solution of 2-bromo-5-(isopropoxycarbonylamino)-thiazole-4-carboxylic acid (650.0 mg, 2.01 mmol) and [(R)-1-(4-amino-2-methyl-2H-pyrazol-3-yl)-azepan-4-yl]-carbamic acid benzyl ester (828.9 mg, 2.41 mmol, 1.2 eq.) in anhydrous N,N-dimethylformamide (22 mL) was added HATU (1.07 g, 2.81 mmol, 1.4 eq.) followed by N,N-diisopropylethylamine (0.88 mL, 5.03 mmol, 2.5 eq.), and the reaction mixture was stirred at RT under N2 for 7 days. The reaction mixture was diluted with ethyl acetate (150 mL). The organic layer was washed with 50% brine/water, water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified via flash column chromatography eluted with 45 to 100% ethyl acetate/heptane to give 1.30 g (79.7%) of ((R)-1-{4-[(2-Bromo-5-tert-butoxycarbonylamino-thiazole-4-carbonyl)-amino]-2-methyl-2H-pyrazol-3-yl}-perhydro-azepin-4-yl)-carbamic acid benzyl ester as a tacky gel. 1H NMR (400 MHz, CDCl3) δ 10.28 (s, 1H), 8.39 (s, 1H), 7.74 (s, 1H), 7.33 (s, 5H), 5.09 (s, 2H), 4.98 (s, 1H), 3.89 (s, 1H), 3.72 (s, 3H), 3.36-3.21 (m, 2H), 3.16-3.03 (m, 2H), 2.19-2.01 (m, 2H), 2.00-1.61 (m, 4H), 1.51 (s, 9H)

Workup

  1. washThe organic layer was washed with 50% brine/water, water and brine
  2. dry with materialdried over Na2SO4
  3. filtrationfiltered
  4. concentrationconcentrated under reduced pressure
  5. customThe crude was purified via flash column chromatography
  6. washeluted with 45 to 100% ethyl acetate/heptane

Sources & evidence

ORD record
ord-b18d0f4949b74a12bab0086264f201d3
Source dataset
uspto-grants-2013_05
Patent number
US08436001B2

Reaction notes

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