Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1) → N-[(3-bromo-4-chlorophenyl)methyl]-N'-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-5-methyl-1,3-benzenedicarboxamide

HRID 564422Notes

Reaction equation

HRID 564422 reaction equation
[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:33][CH3:34])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([CH:29]=[C:30]([CH3:32])[CH:31]=3)[C:26](O)=[O:27])=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:59][C:60]1[CH:61]=[C:62]([CH2:67][NH2:68])[CH:63]=[CH:64][C:65]=1[Cl:66]>ClCCl>[Br:59][C:60]1[CH:61]=[C:62]([CH2:67][NH:68][C:26]([C:25]2[CH:29]=[C:30]([CH3:32])[CH:31]=[C:23]([C:21]([NH:20][CH2:19][C:10]3[C:11]([NH:12][CH:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[C:6]4[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]4=[N:8][C:9]=3[CH2:33][CH3:34])=[O:22])[CH:24]=2)=[O:27])[CH:63]=[CH:64][C:65]=1[Cl:66]

Participants

5

Reactant 3

HCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 578133503-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-5-methylbenzoic acidHCID 578133923-Bromo-4-chlorobenzylamine

Product 1

HCID 57813318N-[(3-bromo-4-chlorophenyl)methyl]-N'-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-5-methyl-1,3-benzenedicarboxamideYield 16.2%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

The 3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-5-methylbenzoic acid (931 mg, 2 mmol) was partially dissolved in the dichloromethane (50 mL), and HBTU (758 mg, 2.000 mmol) was added followed sequentially by [(3-bromo-4-chlorophenyl)methyl]amine (441 mg, 2.000 mmol), and TEA (0.558 mL, 4.00 mmol). The mixture was allowed to stir under argon overnight at room temperature. The solvent was removed on a rotavap. The residue was taken up in EtOAc (100 mL) and washed 3× with water (50 mL) (emulsion, a few drops of 1N NaOH helps break emulsion), 1× with brine. A substantial amount of solid would not dissolve in either the EtOAc or aqueous phases. This was filtered off and set aside. The organic phase was dried over anhydrous Na2SO4, filtered and evaporated to give N-[(3-bromo-4-chlorophenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-5-methyl-1,3-benzenedicarboxamide (349 mg, 0.324 mmol, 16.20% yield). The solid that had been set aside was washed with water and ethyl acetate and dried under vacuum to give another batch of N-[(3-bromo-4-chlorophenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-5-methyl-1,3-benzenedicarboxamide (993.7 mg, 1.488 mmol, 74.4% yield) as a white solid. LC-MS m/z 667.2 (M+H)+, 1.02 min (ret time); mp 212-214° C.

Workup

  1. additionwas added
  2. customThe solvent was removed on a rotavap
  3. washwashed 3× with water (50 mL) (emulsion, a few drops of 1N NaOH helps break emulsion), 1× with brine
  4. dissolutionA substantial amount of solid would not dissolve in either the EtOAc or aqueous phases
  5. filtrationThis was filtered off
  6. dry with materialThe organic phase was dried over anhydrous Na2SO4
  7. filtrationfiltered
  8. customevaporated

Sources & evidence

ORD record
ord-f79daec8baef4aa29f0aa4d7ae7aa5bb
Source dataset
uspto-grants-2011_11
Patent number
US08067408B2

Reaction notes

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