Cesium carbonate → 4-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-isopropylbenzamide

HRID 2363299Notes

Reaction equation

HRID 2363299 reaction equation
Br[C:2]1[CH:13]=[CH:12][C:5]([C:6]([NH:8][CH:9]([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=1.Cl.[CH3:15][Si:16]([CH3:43])([CH3:42])[CH2:17][CH2:18][O:19][CH2:20][N:21]1[C:25]2[N:26]=[CH:27][N:28]=[C:29]([C:30]3[CH:31]=[N:32][N:33]([C:35]4([CH2:39][C:40]#[N:41])[CH2:38][NH:37][CH2:36]4)[CH:34]=3)[C:24]=2[CH:23]=[CH:22]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:40]([CH2:39][C:35]1([N:33]2[CH:34]=[C:30]([C:29]3[C:24]4[CH:23]=[CH:22][N:21]([CH2:20][O:19][CH2:18][CH2:17][Si:16]([CH3:15])([CH3:43])[CH3:42])[C:25]=4[N:26]=[CH:27][N:28]=3)[CH:31]=[N:32]2)[CH2:36][N:37]([C:2]2[CH:13]=[CH:12][C:5]([C:6]([NH:8][CH:9]([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=2)[CH2:38]1)#[N:41]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 36586214-Bromo-N-isopropylbenzamideHCID 71143531{3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile hydrochloride

Product 1

HCID 711435494-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-isopropylbenzamideYield 61%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 1140TolueneSolvent

Conditions

Temperature
105 °C

Procedure

A mixture of 4-bromo-N-isopropylbenzamide (1.82 g, 7.52 mmol), {3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile hydrogen chloride (2.23 g, 5.00 mmol), palladium acetate (78 mg, 0.35 mmol, Aldrich [3375-31-3]), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (405 mg, 0.700 mmol, Aldrich [161265-03-8]), and cesium carbonate (3.03 g, 9.30 mmol) in toluene (22 mL) was de-gassed and purged several times with N2 (g) prior to heating at 105° C. in a sealed vial for 2 days. Upon cooling to room temperature the reaction mixture was filtered through a pad of celite, concentrated in-vacuo and purified by flash chromatography on a silica gel column eluting with MeOH in methylene chloride (0-5%) to afford the desired product (1.74 g, 61% yield). LCMS (M+H)+: m/z=571.3.

Workup

  1. customwas de-gassed
  2. custompurged several times with N2 (g)
  3. temperatureUpon cooling to room temperature the reaction mixture
  4. filtrationwas filtered through a pad of celite
  5. concentrationconcentrated in-vacuo
  6. custompurified by flash chromatography on a silica gel column
  7. washeluting with MeOH in methylene chloride (0-5%)

Sources & evidence

ORD record
ord-82cc0130f1374c60bcd89da226d08db0
Source dataset
uspto-grants-2014_04
Patent number
US08691807B2

Reaction notes

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