Morpholine → HCID 178433643, compound

HRID 2271109Notes

Reaction equation

HRID 2271109 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:10]([C:15](=[O:25])[N:16]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=4)[N:17]=3)=[CH:11][NH:12][C:13]=2[CH3:14])=[CH:4][CH:3]=1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.CC(C)([O-])C.[Na+].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CN(C=O)C.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]>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([N:16]2[C:15](=[O:25])[C:10]3=[CH:11][NH:12][C:13]([CH3:14])=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)=[CH:3][CH:4]=4)[C:9]3=[N:17]2)=[CH:19][CH:20]=1

Participants

7

Reactant 4

HCID 8083MorpholineHCID 634876Binap, (A+-)-2×HCID 23676156Sodium t-butoxideHCID 178433629HCID 178433629, compound

Product 1

HCID 178433643HCID 178433643, compoundYield 26%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalyst2×HCID 6228DimethylformamideSolvent

Conditions

Temperature
80 °C

Procedure

A mixture of 7-(4-bromophenyl)-2-(4-chlorophenyl)-2,5-dihydro-6-methylpyrazolo[4,3-c]pyridin-3-one (69.1 mg, 0.167 mmol), morpholine (34.9 ml, 0.400 mmol) and sodium tert-butoxide (61.1 mg, 0.636 mmol) in Ianhydrous DMF (3 ml) was degassed by evaporating the flask under vacuum and refilling with nitrogen several times. Solid (S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl [(S)-BINAP] (10.5 mg, 0.0169 mmol) and tris(dibenzylideneacetone)dipalladium(0) (7.6 mg, 0.0083 mmol) were added and the mixture was stirred at 80° C. under nitrogen for 47 h, adding more (S)-BINAP (10.7 mg, 0.172 mmol) and tris(dibenzylideneacetone)dipalladium(0) (7.9 mg, 0.0086 mmol) after 23 h. The solvent was removed in vacuo and the residue was purified by flash chromatography (silica gel, 3-5% MoOH/CH2Cl2) and preparative HPLC (YMCSIL D column, 7% MeOH/1-chlorobutane) to give 17.9 mg (26%) of the title compound; mp 306-315° C. (CH2Cl2-MeOH-EtOAc); 1H NMR (360 MHz, DMSO-d6) δ2.27 (3H, s), 3.20 (4H, m), 3.77 (4H, m), 7.05 (2H, d, J8.8 Hz), 7.40 (2H, d), 7.42 (2H, d, J8.9 Hz), 8.15 (2H, d, J9.0 Hz), 8.51 (1H, s), 12.35 (1H, br s); MS (ES+) m/z 421/423[MH]+. Anal. found: C, 65.57; H, 4.84; N, 13.22. C23H21CIN4O2 requires: C, 65.63; H, 5.03; N, 13.31%.

Workup

  1. customwas degassed
  2. customby evaporating the flask under vacuum
  3. customThe solvent was removed in vacuo
  4. customthe residue was purified by flash chromatography (silica gel, 3-5% MoOH/CH2Cl2) and preparative HPLC (YMCSIL D column, 7% MeOH/1-chlorobutane)

Sources & evidence

ORD record
ord-1c3c518d450d4fe8adcc1b50bbcf5c7b
Source dataset
uspto-grants-2001_12
Patent number
US06333336B1

Reaction notes

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