Cesium carbonate → US9777003, Example 69

HRID 628318Notes

Reaction equation

HRID 628318 reaction equation
[CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13](Cl)=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:18]1[S:22][CH:21]=[N:20][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:23]([C:32](OC(C)(C)C)=O)[NH:24]C(OC(C)(C)C)=O.[C:39]([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.NC1C=CC=CC=1C1C=CC=CC=1[Pd]Cl>[CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][C:13]3[N:12]([C:32]([CH3:39])=[N:23][N:24]=3)[C:11]=2[CH:10]=[C:9]1[C:18]1[S:22][CH:21]=[N:20][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

6

Reactant 3

HCID 10796Cesium carbonateHCID 85431Di-tert-butyl bicarbamateHCID 1181597021-benzyl-5-chloro-2-(1,3-thiazol-5-yl)-1H-pyrrolo[3,2-b]pyridine

Product 1

HCID 118159883US9777003, Example 69

Reagents, catalysts & solvents 2

HCID 178439015HCID 178439015, compoundCatalystHCID 1140TolueneSolvent

Conditions

Temperature
110 °C

Procedure

1-Benzyl-5-chloro-2-(1,3-thiazol-5-yl)-1H-pyrrolo[3,2-b]pyridine (67 mg, 0.20 mmol, from Step 1), di-tert-butyl hydrazine-1,2-dicarboxylate (72 mg, 0.31 mmol) and Cs2CO3 (100 mg, 0.31 mmol) were combined in toluene (7.2 mL) and dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium (1:1) (16 mg, 0.020 mmol) was added. The mixture was degassed by a stream of nitrogen through the solution for 10 minutes. The reaction was stirred at 110° C. overnight, then was cooled, diluted with DCM, filtered and concentrated. Flash chromatography, eluting with a gradient from 0-50% EtOAc in hexanes afforded intermediate di-tert-butyl 1-[1-benzyl-2-(1,3-thiazol-5-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl]hydrazine-1,2-dicarboxylate. This intermediate was heated in the microwave as a solution in AcOH (3.0 mL) to 180° C. for 6 minutes. AcOH was removed in vacuo, the residue was reconstituted, and the product was concentrated and purified via preparative HPLC-MS (C18 eluting with a gradient of MeCN and H2O containing 0.15% NH4OH). Yield: (12.5 mg, 18%).

Workup

  1. customThe mixture was degassed by a stream of nitrogen through the solution for 10 minutes
  2. temperaturewas cooled
  3. additiondiluted with DCM
  4. filtrationfiltered
  5. concentrationconcentrated
  6. washFlash chromatography, eluting with a gradient from 0-50% EtOAc in hexanes afforded intermediate di-tert-butyl 1-[1-benzyl-2-(1,3-thiazol-5-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl]hydrazine-1,2-dicarboxylate
  7. temperatureThis intermediate was heated in the microwave as a solution in AcOH (3.0 mL) to 180° C. for 6 minutes
  8. customAcOH was removed in vacuo
  9. concentrationthe product was concentrated
  10. custompurified via preparative HPLC-MS (C18
  11. washeluting with a gradient of MeCN and H2O containing 0.15% NH4OH)

Sources & evidence

ORD record
ord-f0cfdd3c15004bfe9715295da3b8ebb7
Source dataset
uspto-grants-2016_04
Patent number
US09309246B2

Reaction notes

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