Cesium carbonate → US9611269, Example 37

HRID 2363345Notes

Reaction equation

HRID 2363345 reaction equation
Cl[C:2]1[C:14]([F:15])=[CH:13][C:5]([C:6]([NH:8][CH2:9][CH:10]([F:12])[F:11])=[O:7])=[C:4]([F:16])[CH:3]=1.Cl.C[Si](C)(C)CCOC[N:24]1[C:28]2[N:29]=[CH:30][N:31]=[C:32]([C:33]3[CH:34]=[N:35][N:36]([C:38]4([CH2:42][C:43]#[N:44])[CH2:41][NH:40][CH2:39]4)[CH:37]=3)[C:27]=2[CH:26]=[CH:25]1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:43]([CH2:42][C:38]1([N:36]2[CH:37]=[C:33]([C:32]3[C:27]4[CH:26]=[CH:25][NH:24][C:28]=4[N:29]=[CH:30][N:31]=3)[CH:34]=[N:35]2)[CH2:41][N:40]([C:2]2[C:14]([F:15])=[CH:13][C:5]([C:6]([NH:8][CH2:9][CH:10]([F:12])[F:11])=[O:7])=[C:4]([F:16])[CH:3]=2)[CH2:39]1)#[N:44]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 71143531{3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile hydrochlorideHCID 86675758HCID 86675758, compound

Product 1

HCID 71499233US9611269, Example 37Yield 45%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 1140TolueneSolvent

Conditions

Temperature
105 °C

Procedure

A solution of 4-chloro-N-(2,2-difluoroethyl)-2,5-difluorobenzamide (0.907 g, 3.55 mmol), {3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile HCl salt (1.57 g, 3.52 mmol), palladium acetate (55 mg, 0.24 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (285 mg, 0.493 mmol) and cesium carbonate (2.16 g, 6.63 mmol) in toluene (25 mL) was de-gassed and purged with N2 (g) several times prior to heating to 105° C. and stirring for 3 d. LCMS data indicated that ˜50% of the starting material was converted to the desired product. In an effort to drive the reaction to completion a second aliquot of 4-chloro-N-(2,2-difluoroethyl)-2,5-difluorobenzamide (353 mg), palladium acetate (58 mg), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (274 mg), and cesium carbonate (550 mg) was added and stirring was continued overnight at 105° C. LCMS data indicated that there was no significant improvement. The crude reaction mixture was filtered through a pad of celite and the inorganics were washed thoroughly with ethyl acetate. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography on a silica gel column with methanol in dichloromethane (0-15%) to afford the desired product (0.789 g).

Workup

  1. custompurged with N2 (g) several times
  2. customthe reaction to completion a second aliquot of 4-chloro-N-(2,2-difluoroethyl)-2,5-difluorobenzamide (353 mg), palladium acetate (58 mg), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (274 mg), and cesium carbonate (550 mg)
  3. additionwas added
  4. stirringstirring
  5. waitwas continued overnight at 105° C
  6. customThe crude reaction mixture
  7. filtrationwas filtered through a pad of celite
  8. washthe inorganics were washed thoroughly with ethyl acetate
  9. concentrationThe filtrate was concentrated under reduced pressure
  10. customthe residue was purified by flash chromatography on a silica gel column with methanol in dichloromethane (0-15%)

Sources & evidence

ORD record
ord-a24085a7f38143b995d5486cae7f0fd4
Source dataset
uspto-grants-2014_04
Patent number
US08691807B2

Reaction notes

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