tert-Butyl (2S)-2-(2-methylpropyl)piperazine-1-carboxylate → tert-butyl (2S)-2-isobutyl-4-[2-(1-tritylpyrazolo[5,4-b]pyridin-3-yl)thiazol-4-yl]piperazine-1-carboxylate

HRID 1044028Notes

Reaction equation

HRID 1044028 reaction equation
Br[C:2]1[N:3]=[C:4]([C:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]([C:16]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:8]=2)[S:5][CH:6]=1.CC(C)([O-])C.[Na+].[CH2:41]([C@H:45]1[CH2:50][NH:49][CH2:48][CH2:47][N:46]1[C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH:42]([CH3:44])[CH3:43]>C1(C)C=CC=CC=1.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C>[CH2:41]([C@H:45]1[CH2:50][N:49]([C:2]2[N:3]=[C:4]([C:7]3[C:15]4[C:10](=[N:11][CH:12]=[CH:13][CH:14]=4)[N:9]([C:16]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:8]=3)[S:5][CH:6]=2)[CH2:48][CH2:47][N:46]1[C:51]([O:53][C:54]([CH3:56])([CH3:55])[CH3:57])=[O:52])[CH:42]([CH3:44])[CH3:43]

Participants

8

Reactant 3

HCID 17750437tert-Butyl (2S)-2-(2-methylpropyl)piperazine-1-carboxylateHCID 23676156Sodium t-butoxideHCID 681079193-(4-Bromothiazol-2-yl)-1-trityl-pyrazolo[5,4-b]pyridine

Product 1

HCID 67212610tert-butyl (2S)-2-isobutyl-4-[2-(1-tritylpyrazolo[5,4-b]pyridin-3-yl)thiazol-4-yl]piperazine-1-carboxylateYield 49%

Reagents, catalysts & solvents 4

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalyst2×HCID 162179852-Dicyclohexylphosphino-2',6'-diisopropoxybiphenylCatalyst2×HCID 1140TolueneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
100 °C

Procedure

3-(4-bromothiazol-2-yl)-1-trityl-pyrazolo[5,4-b]pyridine (234 mg, 0.4470 mmol), sodium tert-butoxide (60.14 mg, 0.6258 mmol), tert-butyl (2S)-2-isobutylpiperazine-1-carboxylate (130.0 mg, 0.5364 mmol), Pd2 dba3 (4.093 mg, 0.004470 mmol) and RUPHOS (8.343 mg, 0.01788 mmol) in toluene (3 mL) were heated in microwave for 2 h at 100° C. Added more Pd2 dba3 (4.093 mg, 0.004470 mmol) and RUPHOS (8.343 mg, 0.01788 mmol) and heated at 100° C. for a further 1 h in microwave. Cooled to room temperature, diluted with EtOAc, washed with water, brine, dried (MgSO4), filtered and concentrated in vacuo. Crude product purified by flash chromatography (12 g SiO2, 0 to 15% EtOAc/petrol) to leave product as a luminous green sticky oil (149 mg, 49%); 1H NMR DMSO-d6 δ 1.01 (dd, 6H), 1.53 (s, 9H), 1.69-1.57 (m, 2H), 1.81-1.76 (m, 1H), 2.80 (td, 1H), 2.94 (dd, 1H), 3.28 (t, 1H), 3.81 (d, 1H), 3.90 (d, 1H), 4.09 (br s, 1H), 4.37 (br s, 1H), 7.15 (dd, 1H), 7.28 (s, 16H), 8.29 (dd, 1H), 8.70 (dd, 1H); ES+ 685.47.

Workup

  1. temperatureCooled to room temperature
  2. washwashed with water, brine
  3. dry with materialdried (MgSO4)
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. customCrude product purified by flash chromatography (12 g SiO2, 0 to 15% EtOAc/petrol)

Sources & evidence

ORD record
ord-0822142c4b0344c88c5240003f3665fd
Source dataset
uspto-grants-2013_10
Patent number
US08563576B2

Reaction notes

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