Dimethylformamide → HCID 23120475, compound

HRID 2100420Notes

Reaction equation

HRID 2100420 reaction equation
Br[C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]2[CH:28]=[CH:27][CH:26]=[CH:25][C:11]=2[C:12]([NH:14][C:15]2[CH:16]=[CH:17][C:18]3[C:22]([CH:23]=2)=[N:21][N:20]([CH3:24])[CH:19]=3)=[O:13])[CH:5]=[CH:4][N:3]=1.CN(C=O)C.C(=O)([O-])[O-].[Cs+].[Cs+].[O:40]1[C:44]2([CH2:49][CH2:48][N:47]([C:50]([NH2:52])=[O:51])[CH2:46][CH2:45]2)[O:43][CH2:42][CH2:41]1>O1CCOCC1.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].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH3:24][N:20]1[CH:19]=[C:18]2[C:22]([CH:23]=[C:15]([NH:14][C:12]([C:11]3[CH:25]=[CH:26][CH:27]=[CH:28][C:10]=3[NH:9][CH2:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:52][C:50]([N:47]4[CH2:46][CH2:45][C:44]5([O:40][CH2:41][CH2:42][O:43]5)[CH2:49][CH2:48]4)=[O:51])[CH:7]=3)=[O:13])[CH:16]=[CH:17]2)=[N:21]1

Participants

8

Reactant 4

HCID 6228DimethylformamideHCID 10796Cesium carbonateHCID 231189722-[(2-bromo-pyridin-4-ylmethyl)-amino]-N-(2-methyl-2H-indazol-6-yl)-benzamideHCID 573210241,4-Dioxa-8-azaspiro[4.5]decane-8-carboxamide

Product 1

HCID 23120475HCID 23120475, compoundYield 66.2%

Reagents, catalysts & solvents 3

HCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)CatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
110 °C

Procedure

2-[(2-bromo-pyridin-4-ylmethyl)-amino]-N-(2-methyl-2H-indazol-6-yl)-benzamide (700 mg, 1.6 mmol) was suspended in dioxane (26 mL) and treated consecutively with DMF (7 mL), Pd2dba3 (32 mg, 0.03 mmol), Xantphos (61 mg, 0.1 mmol), cesium carbonate (632 mg, 1.9 mmol) and 1,4-dioxa-8-aza-spiro[4.5]decane-8-carboxylic acid amide (930 mg, 5 mmol). The reaction mixture was placed under a nitrogen atmosphere and heated for 4 hours at 110° C. (bath temperature). On cooling the reaction was partitioned between EtOAc and brine. The organic phase was dried, filtered and concentrated in vacuo. The residue was purified by chromatography on Isolute® Flash silica gel (Separtis) (Gradient elution: 100% CH2Cl2 to CH2Cl2/EtOH 10:1) to give 1,4-dioxa-8-aza-spiro[4.5]decan-8-carboxylic acid(4-{[2-(2-methyl-2H-indazol-6-ylcarbamoyl)-phenylamino]-methyl}-pyridin-2-yl)-amide (574 mg, 66%) as a solid; 1H-NMR (300 MHz, d6-DMSO) 10.20 (1H, s), 9.25 (1H, s), 8.32 (1H, s), 8.21 (1H, d), 8.17 (1H, s), 8.01 (1H, t), 7.87 (1H, s), 7.75-7.80 (1H, m), 7.70 (1H, d), 7.30-7.40 (2H, m), 6.99-7.01 (1H, m), 6.73 (1H, t), 6.60 (1H, d), 4.50 (2H, d), 4.20 (3H, s), 3.97 (4H, s), 3.54-3.59 (4H, m), 1.53-1.58 (4H, m); m/z (ES+) 542 [M+H]+.

Workup

  1. temperatureOn cooling the reaction
  2. customwas partitioned between EtOAc and brine
  3. customThe organic phase was dried
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. customThe residue was purified by chromatography on Isolute® Flash silica gel (Separtis) (Gradient elution: 100% CH2Cl2 to CH2Cl2/EtOH 10:1)

Sources & evidence

ORD record
ord-93447d1516854844b53f692a9266199e
Source dataset
uspto-grants-2009_08
Patent number
US07572794B2

Reaction notes

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