Dichloromethane → methyl 1-[3-(benzyloxy)propyl]-4-[5-({2-[(4-{[ethoxy(hydroxy)phosphoryl]methyl}-2-methoxyphenyl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}amino)-6-(methylcarbamoyl)pyridin-2-yl]-1H-pyrrole-2-carboxylate

HRID 2279822Notes

Reaction equation

HRID 2279822 reaction equation
ClCCl.C(=O)([O-])[O-].[K+].[K+].Br[C:11]1[N:16]=[C:15]([C:17](=[O:20])[NH:18][CH3:19])[C:14]([NH:21][C:22]2[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]3[CH:45]=[CH:44][C:36]([CH2:37][P:38](=[O:43])([OH:42])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=3[O:46][CH3:47])[N:23]=2)=[CH:13][CH:12]=1.[CH2:48]([O:55][CH2:56][CH2:57][CH2:58][N:59]1[CH:63]=[C:62](B2OC(C)(C)C(C)(C)O2)[CH:61]=[C:60]1[C:73]([O:75][CH3:76])=[O:74])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>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].O1CCOCC1>[CH2:48]([O:55][CH2:56][CH2:57][CH2:58][N:59]1[CH:63]=[C:62]([C:11]2[CH:12]=[CH:13][C:14]([NH:21][C:22]3[C:27]([C:28]([F:31])([F:29])[F:30])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:45]=[CH:44][C:36]([CH2:37][P:38]([O:39][CH2:40][CH3:41])([OH:42])=[O:43])=[CH:35][C:34]=4[O:46][CH3:47])[N:23]=3)=[C:15]([C:17](=[O:20])[NH:18][CH3:19])[N:16]=2)[CH:61]=[C:60]1[C:73]([O:75][CH3:76])=[O:74])[C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1

Participants

7

Reactant 4

HCID 6344DichloromethaneHCID 11430Potassium CarbonateHCID 86697762Ethyl hydrogen (4-{[4-{[6-bromo-2-(methylcarbamoyl)pyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate2×HCID 86697763methyl 1-[3-(benzyloxy)propyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carboxylate2×

Product 1

HCID 86697761methyl 1-[3-(benzyloxy)propyl]-4-[5-({2-[(4-{[ethoxy(hydroxy)phosphoryl]methyl}-2-methoxyphenyl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}amino)-6-(methylcarbamoyl)pyridin-2-yl]-1H-pyrrole-2-carboxylateYield 82.3%

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 312751,4-DioxaneSolvent

Procedure

A mixture of [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (77.9 mg, 0.095 mmol), potassium carbonate (366 mg, 2.65 mmol), ethyl hydrogen (4-{[4-{[6-bromo-2-(methylcarbamoyl)pyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (Compound 38C, 543 mg, 0.877 mmol) and methyl 1-[3-(benzyloxy)propyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carboxylate (Compound 38E, 385 mg, 0.964 mmol) in 4:1 dioxane:H2O (3.8 mL) was degassed with Argon and irradiated for 30 min at 100° C. in a CEM microwave reactor. The reaction was then concentrated in vacuo and purified using a Teledyne ISCO Combiflash® Rf system [5→100% MeOH in Water] to afford 586 mg of the title compound (82%). MS (ESI): m/z 812.60 [M+H]+. UPLC: tR=1.57 min (UPLC-TOF: polar—2 min).

Workup

  1. customH2O (3.8 mL) was degassed with Argon
  2. customirradiated for 30 min at 100° C. in a CEM microwave reactor
  3. concentrationThe reaction was then concentrated in vacuo
  4. custompurified

Sources & evidence

ORD record
ord-2ebb5f8c34904bfe9e3fc1d83af97071
Source dataset
uspto-grants-2015_09
Patent number
US09133224B2

Reaction notes

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