Trifluoroacetic acid → N-{[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N'-[(2-methyl-3'-{[(3S)-3-methyl-1-piperazinyl]methyl}-3-biphenylyl)methyl]-1,3-benzenedicarboxamide

HRID 564629Notes

Reaction equation

HRID 564629 reaction equation
Br[C:2]1[C:3]([CH3:42])=[C:4]([CH2:8][NH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([NH:20][CH2:21][C:22]3[C:23]([NH:35][CH:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)=[C:24]4[CH:32]=[N:31][N:30]([CH2:33][CH3:34])[C:25]4=[N:26][C:27]=3[CH2:28][CH3:29])=[O:19])[CH:13]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1.[CH3:43][C@H:44]1[CH2:49][N:48]([CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[C:53](B3OC(C)(C)C(C)(C)O3)[CH:52]=2)[CH2:47][CH2:46][N:45]1C(OC(C)(C)C)=O.C([O-])([O-])=O.[Na+].[Na+].C(O)(C(F)(F)F)=O>O1CCOCC1.C(Cl)Cl.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.O>[CH2:33]([N:30]1[C:25]2=[N:26][C:27]([CH2:28][CH3:29])=[C:22]([CH2:21][NH:20][C:18]([C:14]3[CH:15]=[CH:16][CH:17]=[C:12]([C:10]([NH:9][CH2:8][C:4]4[C:3]([CH3:42])=[C:2]([C:53]5[CH:54]=[CH:55][CH:56]=[C:51]([CH2:50][N:48]6[CH2:47][CH2:46][NH:45][C@@H:44]([CH3:43])[CH2:49]6)[CH:52]=5)[CH:7]=[CH:6][CH:5]=4)=[O:11])[CH:13]=3)=[O:19])[C:23]([NH:35][CH:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[C:24]2[CH:32]=[N:31]1)[CH3:34]

Participants

9

Reactant 4

HCID 6422Trifluoroacetic acidHCID 10340Sodium CarbonateHCID 578132571,1-dimethylethyl (2S)-2-methyl-4-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}-1-piperazinecarboxylateHCID 57813355N-[(3-Bromo-2-methylphenyl)methyl]-N'-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,3-benzenedicarboxamide

Product 1

HCID 44180194N-{[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N'-[(2-methyl-3'-{[(3S)-3-methyl-1-piperazinyl]methyl}-3-biphenylyl)methyl]-1,3-benzenedicarboxamideYield 59.1%

Reagents, catalysts & solvents 4

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolventHCID 6344DichloromethaneSolventHCID 312751,4-DioxaneSolvent

Procedure

A mixture of N-[(3-bromo-2-methylphenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,3-benzenedicarboxamide (93 mg, 0.00015 mol) in dioxane (4 mL) with 1,1-dimethylethyl (2S)-2-methyl-4-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}-1-piperazinecarboxylate (81.2 mg, 0.000195 mol) was treated with Na2CO3 (48 mg, 0.00045 mol) and 0.75 mL H2O. The mixture was degassed for 15 min with N2, then treated with (PPh3)4Pd (17.3 mg, 0.000015 mol). The mixture was microwaved at 150° C. for 30 min. The reaction was quenched with H2O, then diluted and extracted with EtOAc (2×) combined organic extracts were washed with H2O, sat. aq. NaCl and dried (Na2SO4) and concentrated to give crude t-Boc product. The crude product was taken up in DCM (10 mL) containing 33% TFA and allowed to stand at room temperature for 1.5 h. LC-MS showed the reaction to be complete. Solvent was stripped off. Purification was carried out on a Gilson instrument with acetonitrile-water (0.1% TFA) gradient; C18-RP column. Fractions containing the clean desired product were combined; diluted with EtOAc; washed with sat. aq. NaHCO3; and the aq. phase was back-extracted with EtOAc. Combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. It was taken up in a small amount of DCM and transferred to a vial and pumped down to afford the title compound as an ivory colored glassy solid [65.9 mg (58%)]. LC-MS m/z 743.7 (M+H)+.

Workup

  1. customThe mixture was degassed for 15 min with N2
  2. customThe mixture was microwaved at 150° C. for 30 min
  3. customThe reaction was quenched with H2O
  4. additiondiluted
  5. extractionextracted with EtOAc (2×)
  6. washwere washed with H2O, sat. aq. NaCl
  7. dry with materialdried (Na2SO4)
  8. concentrationconcentrated
  9. customto give crude t-Boc product
  10. customthe reaction
  11. customPurification
  12. additionFractions containing the clean desired product
  13. additiondiluted with EtOAc
  14. washwashed with sat. aq. NaHCO3
  15. extractionand the aq. phase was back-extracted with EtOAc
  16. washCombined organic extracts were washed with sat. aq. NaCl
  17. dry with materialdried (Na2SO4)
  18. concentrationconcentrated to a residue

Sources & evidence

ORD record
ord-1f6464df2b724d2fa14b0b7977c8ff91
Source dataset
uspto-grants-2011_11
Patent number
US08067408B2

Reaction notes

Loading…