Water → 1,1-dimethylethyl (2S)-4-{[3'-{[({3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]phenyl}carbonyl)amino]methyl}-5'-(methyloxy)-3-biphenylyl]methyl}-2-methyl-1-piperazinecarboxylate

HRID 564604Notes

Reaction equation

Br[C:2]1[CH:3]=[C:4]([CH2:10][NH:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([NH:22][CH2:23][C:24]3[C:25]([NH:37][CH:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)=[C:26]4[CH:34]=[N:33][N:32]([CH2:35][CH3:36])[C:27]4=[N:28][C:29]=3[CH2:30][CH3:31])=[O:21])[CH:15]=2)=[O:13])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[CH3:44][C:45]([O:48][C:49]([N:51]1[CH2:56][CH2:55][N:54]([CH2:57][C:58]2[CH:59]=[C:60](B(O)O)[CH:61]=[CH:62][CH:63]=2)[CH2:53][C@@H:52]1[CH3:67])=[O:50])([CH3:47])[CH3:46].C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:35]([N:32]1[C:27]2=[N:28][C:29]([CH2:30][CH3:31])=[C:24]([CH2:23][NH:22][C:20]([C:16]3[CH:15]=[C:14]([C:12]([NH:11][CH2:10][C:4]4[CH:3]=[C:2]([C:60]5[CH:61]=[CH:62][CH:63]=[C:58]([CH2:57][N:54]6[CH2:55][CH2:56][N:51]([C:49]([O:48][C:45]([CH3:47])([CH3:46])[CH3:44])=[O:50])[C@@H:52]([CH3:67])[CH2:53]6)[CH:59]=5)[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=4)=[O:13])[CH:19]=[CH:18][CH:17]=3)=[O:21])[C:25]([NH:37][CH:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[C:26]2[CH:34]=[N:33]1)[CH3:36]

Participants

Conditions

Temperature: 150 °C

Procedure

237(a) A mixture of N-{[3-bromo-5-(methyloxy)phenyl]methyl}-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,3-benzenedicarboxamide (150 mg, 0.23 mmol), {3-[((3S)-4-{[(1,1-dimethylethyl)oxy]carbonyl}-3-methyl-1-piperazinyl)methyl]phenyl}boronic acid (100 mg, 0.30 mmol), Na2CO3 (74 mg, 0.69 mmol), Pd(PPh3)4 (13.3 mg, 0.01 mmol), water (0.75 mL) in dioxane (2.25 mL) was degassed for 5 min. and then heated in a microwave for 30 min at 150° C. The reaction was quenched with water and then extracted with ethyl acetate twice. The combined organic layers were washed with water and brine. The organic layer was filtered though a 0.45 μM filter and then concentrated to give a crude residue. It was then purified using Combi Flash chromatography, eluting with 0 to 10% MeOH in DCM. The product fractions were combined and concentrated under vacuum to give 1,1-dimethylethyl (2S)-4-{[3′-{[({3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]phenyl}carbonyl)amino]methyl}-5′-(methyloxy)-3-biphenylyl]methyl}-2-methyl-1-piperazinecarboxylate as a solid (130 mg, 65%): LC-MS m/z 859 (M+H)+.

Workup

customwas degassed for 5 min.
customThe reaction was quenched with water
extractionextracted with ethyl acetate twice
washThe combined organic layers were washed with water and brine
filtrationThe organic layer was filtered though a 0.45 μM
filtrationfilter
concentrationconcentrated
customto give a crude residue
customIt was then purified
washeluting with 0 to 10% MeOH in DCM
concentrationconcentrated under vacuum

Sources & evidence

ORD record: ord-266a55c6b0654a68821171b3e8c03a64
Source dataset: uspto-grants-2011_11
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08067408B2

Reaction notes

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