1,2-Dimethoxyethane → tert-butyl 4-(8-carbamoyl-6-(1-methyl-1H-indazol-5-yl)-9H-carbazol-2-yl)piperazine-1-carboxylate

HRID 2410890Notes

Reaction equation

HRID 2410890 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([C:15](=[O:17])[NH2:16])[CH:14]=1)[NH:11][C:10]1[CH:9]=[C:8]([N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[CH:7]=[CH:6][C:5]2=1.[CH3:31][N:32]1[C:40]2[C:35](=[CH:36][C:37](B(O)O)=[CH:38][CH:39]=2)[CH:34]=[N:33]1.COCCOC.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O>[C:15]([C:13]1[CH:14]=[C:2]([C:37]2[CH:36]=[C:35]3[C:40](=[CH:39][CH:38]=2)[N:32]([CH3:31])[N:33]=[CH:34]3)[CH:3]=[C:4]2[C:12]=1[NH:11][C:10]1[CH:9]=[C:8]([N:18]3[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:22][CH2:23]3)[CH:7]=[CH:6][C:5]2=1)(=[O:17])[NH2:16]

Participants

7

Reactant 4

HCID 80711,2-DimethoxyethaneHCID 10340Sodium Carbonate2×HCID 225589101-Methyl-1H-indazole-5-boronic acid2×HCID 66605155tert-butyl 4-(6-bromo-8-carbamoyl-9H-carbazol-2-yl)piperazine-1-carboxylate

Product 1

HCID 66605037tert-butyl 4-(8-carbamoyl-6-(1-methyl-1H-indazol-5-yl)-9H-carbazol-2-yl)piperazine-1-carboxylateYield 61.8%

Reagents, catalysts & solvents 2

HCID 178418807HCID 178418807, compoundCatalyst2×HCID 962WaterSolvent

Conditions

Temperature
100 °C

Procedure

A 20 ml microwave vial was loaded with tert-butyl 4-(6-bromo-8-carbamoyl-9H-carbazol-2-yl)piperazine-1-carboxylate (0.49 g, 0.518 mmol), 1-methyl-1H-indazol-5-ylboronic acid (0.255 g, 1.377 mmol), DME (15 mL), PdCl2(dppf)-CH2Cl2 adduct (40 mg, 0.049 mmol) and Na2CO3 (2M) (1.55 mL, 3.10 mmol). The vial was sealed, flushed with nitrogen for 15 minutes, then heated to 100° C. for 2 hours. LCMS showed partial conversion of bromide starting material. 1-Methyl-1H-indazol-5-ylboronic acid (0.115 g, 0.621 mmol), PdCl2(dppf)-CH2Cl2 adduct (30 mg, 0.037 mmol) and Na2CO3 (2M) (1.0 mL, 2.0 mmol) were added and heating continued for 4 hours at 100° C. The reaction mixture was poured into a separating funnel that is loaded with 100 ml water+25 ml sat. aq. NH4Cl solution and extracted with EtOAc (2×). The organic layers were washed once with dilute NaHCO3 solution, then brine, then dried over MgSO4+3 g SILICYCLE® thiol resin [to capture Pd and ferrocene] overnight. Filtration and evaporation to dryness gave the crude product, which was purified by chromatography on silica. (Gradient from 100% dichloromethane to 50% DCM+50% EtOAc (85 fractions a 12 ml, fractions A), then gradient from 50% DCM+50% EtOAc to 40% DCM+40% EtOAc+20% MeOH (85 fractions a 12 ml, fractions B). Product containing fractions (B20-B27) were combined and evaporated to dryness to give 168 mg tert-butyl 4-(8-carbamoyl-6-(1-methyl-1H-indazol-5-yl)-9H-carbazol-2-yl)piperazine-1-carboxylate. Estimated purity ˜50% (contains significant amount of 1-methyl-1H-indazol-5-ylboronic acid). MS (ESI) m/e+=525.

Workup

  1. customThe vial was sealed
  2. customflushed with nitrogen for 15 minutes
  3. temperatureheating
  4. additionThe reaction mixture was poured into a separating funnel that
  5. extractionextracted with EtOAc (2×)
  6. washThe organic layers were washed once with dilute NaHCO3 solution
  7. dry with materialbrine, then dried over MgSO4+3 g SILICYCLE® thiol resin [to capture Pd and ferrocene] overnight
  8. filtrationFiltration and evaporation to dryness
  9. customgave the crude product, which
  10. customwas purified by chromatography on silica
  11. additionProduct containing fractions (B20-B27)
  12. customevaporated to dryness

Sources & evidence

ORD record
ord-3127431c1ae54b8c9d5d64edccb55ffd
Source dataset
uspto-grants-2014_08
Patent number
US08815840B2

Reaction notes

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