1-Methylimidazole → ethyl (2R)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]butan-2-yl (4-{[4-{[6-bromo-2-(methylcarbamoyl)pyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate

HRID 2279907Notes

Reaction equation

HRID 2279907 reaction equation
CN1C=CN=C1.[Br:7][C:8]1[N:13]=[C:12]([C:14](=[O:17])[NH:15][CH3:16])[C:11]([NH:18][C:19]2[C:24]([C:25]([F:28])([F:27])[F:26])=[CH:23][N:22]=[C:21]([NH:29][C:30]3[CH:42]=[CH:41][C:33]([CH2:34][P:35](=[O:40])([OH:39])[O:36][CH2:37][CH3:38])=[CH:32][C:31]=3[O:43][CH3:44])[N:20]=2)=[CH:10][CH:9]=1.[CH3:45][C:46]1([CH3:63])[C:50]([CH3:52])([CH3:51])[O:49][B:48]([C:53]2[CH:54]=[N:55][N:56]([CH2:58][CH2:59][C@H:60](O)[CH3:61])[CH:57]=2)[O:47]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>ClCCCl>[Br:7][C:8]1[N:13]=[C:12]([C:14](=[O:17])[NH:15][CH3:16])[C:11]([NH:18][C:19]2[C:24]([C:25]([F:28])([F:26])[F:27])=[CH:23][N:22]=[C:21]([NH:29][C:30]3[CH:42]=[CH:41][C:33]([CH2:34][P:35](=[O:39])([O:40][C@@H:60]([CH2:59][CH2:58][N:56]4[CH:57]=[C:53]([B:48]5[O:47][C:46]([CH3:63])([CH3:45])[C:50]([CH3:51])([CH3:52])[O:49]5)[CH:54]=[N:55]4)[CH3:61])[O:36][CH2:37][CH3:38])=[CH:32][C:31]=3[O:43][CH3:44])[N:20]=2)=[CH:10][CH:9]=1

Participants

6

Reactant 4

HCID 13901-MethylimidazoleHCID 2724699PyBOPHCID 67817524(2R)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]butan-2-ol2×HCID 86697762Ethyl hydrogen (4-{[4-{[6-bromo-2-(methylcarbamoyl)pyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate2×

Product 1

HCID 86697847ethyl (2R)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]butan-2-yl (4-{[4-{[6-bromo-2-(methylcarbamoyl)pyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonateYield 31.8%

Reagents, catalysts & solvents 1

HCID 111,2-DichloroethaneSolvent

Conditions

Temperature
60 °C

Procedure

1-Methylimidazole (1.91 mL, 24 mmol) was added to a stirring suspension of ethyl hydrogen (4-{[4-{[6-bromo-2-(methylcarbamoyl)pyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (Compound 38C, 1 g, 2 mmol), (2R)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]butan-2-ol (Compound 69B, 430 mg, 1.6 mmol) and (benzotriazol-1-yloxy)tripyrrolidino-phosphonium hexafluorophosphate (5.04 g, 9.69 mmol) in 1,2-dichloroethane (49.5 mL). The reaction was allowed to stir at 60° C. for 24 hrs, after which, it was concentrated in vacuo to a solid and purified using a Teledyne ISCO Combiflash® RF system [0-5% MeOH in 1:1 EtOAc/DCM] to afford 442 mg of the desired product as mixture of diastereomers (32%). MS (ESI): m/z=867.78/869.81 [M+H]+. UPLC: tR=1.69 min (UPLC-TOF: polar—2 min)

Workup

  1. concentrationafter which, it was concentrated in vacuo to a solid
  2. custompurified

Sources & evidence

ORD record
ord-2976556c995344d287437ed68698540c
Source dataset
uspto-grants-2015_09
Patent number
US09133224B2

Reaction notes

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