Dichloromethane → 5-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N,N-dimethylnicotinamide

HRID 1499745Notes

Reaction equation

HRID 1499745 reaction equation
Br[C:2]1[C:3]([O:23][CH3:24])=[C:4]([CH:10]([N:12]2[C:16]3=[N:17][CH:18]=[N:19][C:20]([NH2:21])=[C:15]3[C:14]([CH3:22])=[N:13]2)[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].[CH3:25][N:26]([CH3:44])[C:27](=[O:43])[C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+].ClCCl>C(#N)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[NH2:21][C:20]1[N:19]=[CH:18][N:17]=[C:16]2[N:12]([CH:10]([C:4]3[C:3]([O:23][CH3:24])=[C:2]([C:32]4[CH:31]=[N:30][CH:29]=[C:28]([CH:33]=4)[C:27]([N:26]([CH3:25])[CH3:44])=[O:43])[C:7]([CH3:8])=[C:6]([Cl:9])[CH:5]=3)[CH3:11])[N:13]=[C:14]([CH3:22])[C:15]=12

Participants

8

Reactant 4

HCID 6344DichloromethaneHCID 10340Sodium CarbonateHCID 58412297N,N-dimethyl-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-carboxamideHCID 866776451-[1-(3-Bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Product 1

HCID 866776745-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N,N-dimethylnicotinamide

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolventHCID 6342AcetonitrileSolvent

Conditions

Temperature
95 °C

Procedure

A mixture of 1-[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (25 mg, 0.061 mmol) (chiral pure, first peak from Example 20, Step 2), N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinamide (from PepTech) (25 mg, 0.091 mmol), sodium carbonate (13 mg, 0.12 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II), complex with dichloromethane (1:1) (9.9 mg, 0.012 mmol) in acetonitrile (0.8 mL)/water (0.3 mL) was degassed with N2 and then stirred at 95° C. for 2 h. The mixture was filtered and the filtrate purified by RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. The product was isolated as a single enantiomer. LCMS calculated for C24H27ClN7O2 (M+H)+: m/z=480.2; Found: 480.2. 1H NMR (500 MHz, DMSO-d6) δ 8.64 (1H, s), 8.54 (1H, br s), 8.13 (1H, s), 7.82 (1H, m), 7.53 (1H, s), 7.42 (2H, br s), 6.28 (1H, q, J=6.5 Hz), 3.22 (3H, s), 2.95 (6H, m), 2.58 (3H, s), 2.04 (3H, s), 1.77 (3H, d, J=6.5 Hz) ppm.

Workup

  1. customwas degassed with N2
  2. filtrationThe mixture was filtered
  3. customthe filtrate purified by RP-HPLC (XBridge C18 column
  4. washeluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min)

Sources & evidence

ORD record
ord-01468c415cab4700852c987fba140d65
Source dataset
uspto-grants-2015_12
Patent number
US09199982B2

Reaction notes

Loading…