Methacryloyl chloride → HCID 89629892, compound

HRID 882155Notes

Reaction equation

HRID 882155 reaction equation
[CH3:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.Br[C:12]1[C:20]2[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([NH:27][C:28]([O:30]C(C)(C)C)=O)[CH:22]=3)=[N:18][CH:17]=[N:16][C:15]=2[N:14](C(OC(C)(C)C)=O)[CH:13]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:50][C:51](=C)[C:52](Cl)=O>C1(C)C=CC=CC=1.[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2].CN(C=O)C>[CH3:52][C:51](=[CH2:50])[C:28]([NH:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:19]2[C:20]3[C:12]([C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[CH:7]=4)=[CH:13][NH:14][C:15]=3[N:16]=[CH:17][N:18]=2)[CH:22]=1)=[O:30]

Participants

8

Reactant 4

HCID 13528Methacryloyl chlorideHCID 62657Potassium Phosphate, TribasicHCID 27339503-Tolylboronic acidHCID 117703054HCID 117703054, compound

Product 1

HCID 89629892HCID 89629892, compound

Reagents, catalysts & solvents 3

HCID 178454861HCID 178454861, compoundCatalystHCID 1140TolueneSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
60 °C

Procedure

A mixture of (3-methylphenyl)boronic acid (26.4 mg, 0.194 mmol), tert-butyl 5-bromo-4-{3-[(tert-butoxycarbonyl)amino]phenyl}-7H-pyrrolo[2,3-d]pyrimidine-7-carboxylate (50 mg, 0.10 mmol), potassium phosphate (1 M aqueous solution, 511 μL, 0.511 mmol), and 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (6.66 mg, 10.2 μmol) in degassed toluene (1.02 mL) was heated to 60° C. for 18 hours. The reaction mixture was filtered through Celite and concentrated under reduced pressure. The crude residue was dissolved in 0.5 mL of DCM:TFA:Water (50:48:2) and stirred at room temperature for 2 hours before being concentrated under reduced pressure. To this deprotected intermediate was added DMF (0.50 mL), TEA (57 μl, 0.41 mmol), 3-(diethoxyphosphorylloxy)-1,2,3-benzotriazin-4-(3H)-one (61.1 mg, 0.204 mmol) and 2-methylprop-2-enoyl chloride (17.6 mg, 0.204 mmol). The reaction mixture was stirred at room temperature for 20 hours, filtered, and purified by reverse phase HPLC using an acetonitrile gradient in water with 0.1% TFA modifier to afford 2-methyl-N-{3-[5-(3-methylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]phenyl}prop-2-enamide. LRMS (ESI) calc'd for C23H21N4O [M+H]+: 369, found 369. 1H NMR (600 MHz, DMSO-D6) δ 12.71 (br s, 1H); 9.60 (s, 1H); 8.91 (s, 1H); 7.81 (br s, 1H); 7.74 (s, 1H); 7.65 (d, 1H, J=6.0 Hz), 7.07 (dd, 1H, J=6.5, 6.5 Hz); 6.94 (d, 2H, J=6.0 Hz); 6.88 (d, 1H, J=6.5 Hz); 6.80 (d, 1H, J=5.5 Hz); 6.62 (s, 1H); 5.67 (s, 1H); 5.46 (s, 1H); 1.99 (s, 3H); 1.88 (s, 3H).

Workup

  1. filtrationThe reaction mixture was filtered through Celite
  2. concentrationconcentrated under reduced pressure
  3. dissolutionThe crude residue was dissolved in 0.5 mL of DCM:TFA:Water (50:48:2)
  4. concentrationbefore being concentrated under reduced pressure
  5. stirringThe reaction mixture was stirred at room temperature for 20 hours
  6. filtrationfiltered
  7. custompurified by reverse phase HPLC

Sources & evidence

ORD record
ord-863a66c254da47ceb8c7dd36bb99229f
Source dataset
uspto-grants-2015_03
Patent number
US08993756B2

Reaction notes

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