Acetonitrile → (R/S) tert-butyl 5-(4-(((2-(tert-butoxycarbonylamino)ethyl)amino)methyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-indazole-1-carboxylate

HRID 2278712Notes

Reaction equation

HRID 2278712 reaction equation
I[C:2]1[C:6]([CH2:7][N:8](C)[CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:5][N:4]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[N:3]=1.[C:26]([O:30][C:31]([N:33]1[C:41]2[C:36](=[CH:37][C:38](B(O)O)=[CH:39][CH:40]=2)[CH:35]=[N:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].C(Cl)Cl.CC#N>COCCOC.O.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:14]([O:13][C:12]([NH:11][CH2:10][CH2:9][NH:8][CH2:7][C:6]1[C:2]([C:38]2[CH:37]=[C:36]3[C:41](=[CH:40][CH:39]=2)[N:33]([C:31]([O:30][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:32])[N:34]=[CH:35]3)=[N:3][N:4]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[CH:5]=1)=[O:18])([CH3:15])([CH3:16])[CH3:17]

Participants

8

Reactant 4

HCID 6342Acetonitrile2×HCID 6344DichloromethaneHCID 674250521-BOC-Indazole-5-boronic acidHCID 90433946tert-butyl(2-(((3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)methyl)(methyl)amino)ethyl)carbamate

Product 1

HCID 131733470(R/S) tert-butyl 5-(4-(((2-(tert-butoxycarbonylamino)ethyl)amino)methyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-indazole-1-carboxylateYield 21.5%

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolvent2×HCID 80711,2-DimethoxyethaneSolvent

Procedure

A mixture of (R/S) tert-butyl N-[2-([[3-iodo-1-(oxan-2-yl)-1H-pyrazol-4-yl]methyl](methyl)amino)ethyl]carbamate (200 mg, 0.43 mmol, 1.00 equiv), K3PO4.3H2O (439 mg, 1.65 mmol, 3.83 equiv), 1-(tert-butoxycarbonyl)-1H-indazol-5-ylboronic acid (300 mg, 1.14 mmol, 2.66 equiv) and Pd(dppf)Cl2.CH2Cl2 (135 mg) in ethylene glycol dimethyl ether (20 mL) and water (1 mL) was stirred under nitrogen at 85° C. for 3 h. The resulting mixture was cooled to room temperature and concentrated under vacuum. The residue was dissolved in 5 mL of methanol and 5 mL of DMSO and then purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-005 (Waters)): Column, XBridge Shield RP18 OBD Column, 5 μm, 19×150 mm; mobile phase, water with 10 mmol NH4HCO3 and CH3CN (18% CH3CN up to 58% in 10 min, up to 95% in 1 min, down to 18% in 2 min); Detector, UV 254/220 nm to give 50 mg (21%) of (R/S) tert-butyl 5-(4-(((2-(tert-butoxycarbonylamino)ethyl)amino)methyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-indazole-1-carboxylate as a colorless oil. LCMS (method A, ESI): RT=1.34 min, m/z=555.1 [M+H].

Workup

  1. concentrationconcentrated under vacuum
  2. dissolutionThe residue was dissolved in 5 mL of methanol
  3. custom5 mL of DMSO and then purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-005 (Waters))
  4. waitdown to 18% in 2 min)

Sources & evidence

ORD record
ord-70dca9af2618467da16083efab38c853
Source dataset
uspto-grants-2015_09
Patent number
US09133189B2

Reaction notes

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