Cesium carbonate → 4-((4-(Cyclopentyloxy)-5-(4-(methylcarbamoyl)phenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-methoxy-N-methylbenzamide

HRID 529647Notes

Reaction equation

HRID 529647 reaction equation
Cl[C:2]1[N:3]=[C:4]([O:29][CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[C:5]2[C:10]([C:11]3[CH:20]=[CH:19][C:14]([C:15]([NH:17][CH3:18])=[O:16])=[CH:13][CH:12]=3)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:6]=2[N:7]=1.[NH2:35][C:36]1[CH:45]=[CH:44][C:39]([C:40]([NH:42][CH3:43])=[O:41])=[CH:38][C:37]=1[O:46][CH3:47].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[CH:30]1([O:29][C:4]2[C:5]3[C:10]([C:11]4[CH:20]=[CH:19][C:14]([C:15](=[O:16])[NH:17][CH3:18])=[CH:13][CH:12]=4)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:6]=3[N:7]=[C:2]([NH:35][C:36]3[CH:45]=[CH:44][C:39]([C:40]([NH:42][CH3:43])=[O:41])=[CH:38][C:37]=3[O:46][CH3:47])[N:3]=2)[CH2:34][CH2:33][CH2:32][CH2:31]1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 634876Binap, (A+-)-HCID 204444344-Amino-3-methoxy-N-methylbenzamideHCID 867264224-(2-Chloro-4-(cyclopentyloxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N-methylbenzamide

Product 1

HCID 867264244-((4-(Cyclopentyloxy)-5-(4-(methylcarbamoyl)phenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-methoxy-N-methylbenzamideYield 67.1%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
110 °C

Procedure

4-(2-Chloro-4-(cyclopentyloxy)-7-((2-(trimethylsilyl)ethoxy)- methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N-methylbenzamide 1 equiv), 4-amino-3-methoxy-N-methylbenzamide (1.2 equiv), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (binap) (0.2 equiv), cesium carbonate (5 equiv) and palladium(II) acetate (0.1 equiv) were combined in a sealed tube along with 1,4-dioxane (0.14 M). Nitrogen gas was bubbled through the reaction mixture for 2 min, the reaction vessel was sealed and heated in an oil bath at 110° C. for 4 h. The solvent was removed under reduced pressure and the crude material was stirred in DCM. The solids were filtered off and the filtrate was loaded directly onto a silica gel column. The product was purified by silica gel chromatography (Biotage, 20-100% ethyl acetate in hexanes over 400 mL, 100% ethyl acetate for 200 mL, 0-10% methanol in ethyl acetate over 600 mL then held at 10% methanol in ethyl acetate for 500 mL). The fractions containing the desired product were combined and evaporated under reduced pressure to give the title compound (67.1% yield) as a tan solid. MS (ESI) m/z 645.6 [M+1]+.

Workup

  1. customNitrogen gas was bubbled through the reaction mixture for 2 min
  2. customthe reaction vessel was sealed
  3. customThe solvent was removed under reduced pressure
  4. filtrationThe solids were filtered off
  5. customThe product was purified by silica gel chromatography (Biotage, 20-100% ethyl acetate in hexanes over 400 mL, 100% ethyl acetate for 200 mL, 0-10% methanol in ethyl acetate over 600 mL
  6. additionThe fractions containing the desired product
  7. customevaporated under reduced pressure

Sources & evidence

ORD record
ord-bbc0654f060e4a2dbcc4262285d9c6dc
Source dataset
uspto-grants-2016_05
Patent number
US09346812B2

Reaction notes

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