Diisopropylethylamine → tert-butyl 4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamate

HRID 1915747Notes

Reaction equation

HRID 1915747 reaction equation
[CH2:1]1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)C[CH2:2]1.F[P-](F)(F)(F)(F)F.[Br:34][C:35]1[S:36][C:37]([NH:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[C:38]([C:40]([OH:42])=O)[N:39]=1.[NH2:51][C:52]1[CH:53]=[N:54][N:55]([CH3:72])[C:56]=1[N:57]1[CH2:62][CH2:61][CH:60]([CH2:63][NH:64][C:65](=[O:71])[O:66][C:67]([CH3:70])(C)C)[CH2:59][CH2:58]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:67]([O:66][C:65]([NH:64][CH2:63][CH:60]1[CH2:59][CH2:58][N:57]([C:56]2[N:55]([CH3:72])[N:54]=[CH:53][C:52]=2[NH:51][C:40]([C:38]2[N:39]=[C:35]([Br:34])[S:36][C:37]=2[NH:43][C:44](=[O:45])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:42])[CH2:62][CH2:61]1)=[O:71])[CH2:70][CH2:1][CH3:2]

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 2724699PyBOPHCID 581821562-Bromo-5-((tert-butoxycarbonyl)amino)thiazole-4-carboxylic acidHCID 58464964tert-butyl (1-(4-amino-1-methyl-1H-pyrazol-5-yl)piperidin-4-yl)methylcarbamate

Product 1

HCID 58464898tert-butyl 4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamateYield 96.8%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent3×

Procedure

A solution of PyBOP (2.84 g, 5.46 mmol) and 2-bromo-5-(tert-butoxycarbonylamino)thiazole-4-carboxylic acid (1.39 g, 4.29 mmol) in DCM (10 mL) was stirred at room temperature for 30 min. A solution of tert-butyl (1-(4-amino-1-methyl-1H-pyrazol-5-yl)piperidin-4-yl)methylcarbamate (1.2 g, 3.90 mmol) and DIPEA (1.1 mL, 6.24 mmol) in DCM (20 mL) was added and the mixture stirred at room temperature for 16 hr. The mixture was diluted with DCM and washed with water. The organic layer was separated, passed through a phase separation cartridge and concentrated under reduced pressure. The residue was purified via silica gel column chromatography (0-100% EtOAc/isohexane) to yield tert-butyl 4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamate as a pink solid (2.32 g, 96%). 1H NMR (400 MHz, d6-DMSO) δ 10.62 (s, 1H), 9.64 (s, 1H), 7.23 (s, 1H), 6.86 (t, J=5.8 Hz, 1H), 3.62 (s, 3H), 3.07 (d, J=11.4 Hz, 2H), 2.95 (t, J=11.5 Hz, 2H), 2.87 (t, J=6.3 Hz, 2H), 1.67 (d, J=12.3 Hz, 2H), 1.52 (s, 9H), 1.45 (s, 1H), 1.40 (s, 9H), 1.27-1.16 (m, 2H).

Workup

  1. washwashed with water
  2. customThe organic layer was separated
  3. custompassed through a phase separation cartridge
  4. concentrationconcentrated under reduced pressure
  5. customThe residue was purified via silica gel column chromatography (0-100% EtOAc/isohexane)

Sources & evidence

ORD record
ord-ee87459075c846a0a0cc10c4e6aac0f0
Source dataset
uspto-grants-2013_12
Patent number
US08614206B2

Reaction notes

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