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

HRID 662089Notes

Reaction equation

HRID 662089 reaction equation
[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[N:28]=[C:27]([C:29](O)=[O:30])[CH:26]=[CH:25][CH:24]=3)=[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:58][C:59]1[CH:60]=[C:61]([CH2:66][NH2:67])[CH:62]=[CH:63][C:64]=1[CH3:65]>ClCCl.CCOC(C)=O>[Br:58][C:59]1[CH:60]=[C:61]([CH2:66][NH:67][C:29]([C:27]2[CH:26]=[CH:25][CH:24]=[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[CH2:32][CH3:33])=[O:22])[N:28]=2)=[O:30])[CH:62]=[CH:63][C:64]=1[CH3:65]

Participants

6

Reactant 3

HCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)3×HCID 53414434(3-Bromo-4-methylphenyl)methanamine3×HCID 578193746-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-2-pyridinecarboxylic acid

Product 1

HCID 57819372N-[(3-bromo-4-methylphenyl)methyl]-N'-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-2,6-pyridinedicarboxamideYield 66.7%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

6-[({[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-2-pyridinecarboxylic acid (2 g, 4.42 mmol) was partially dissolved in dichloromethane (100 mL), and HBTU (1.676 g, 4.42 mmol) was added followed sequentially by [(3-bromo-4-methylphenyl)methyl]amine (0.884 g, 4.42 mmol), and TEA (1.232 mL, 8.84 mmol). The mixture was allowed to stir under argon over night at room temperature. The reaction was not complete so additional HBTU (0.167 g, 0.44 mmol) and [(3-bromo-4-methylphenyl)methyl]amine (0.088 g, 0.44 mmol) was added and the mixture was again stirred overnight. The reaction was still not complete so additional HBTU (0.167 g, 0.44 mmol) and [(3-bromo-4-methylphenyl)methyl]amine (0.088 g, 0.44 mmol) was again added and the mixture was stirred overnight. The reaction mixture was taken up in EtOAc (100 mL) and washed 3× with water (50 mL). Solid was recovered and washed with water and ethyl acetate. Drying the solid under vacuum gave N-[(3-bromo-4-methylphenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-2,6-pyridinedicarboxamide (1.97 g, 2.95 mmol, 66.7% yield). The ethyl acetate layer was washed with brine, dried over anhydrous Na2SO4, filtered and evaporated to give another batch. This batch was taken up in methylene chloride and absorbed on Isolute® Sorbent (Biotage, Uppsala, Sweden; http://www.biotage.com/) and purified with a Combiflash on an 80 g silica column eluted with 0-10% DCM/MeOH. Product fractions were combined and evaporated to give N-[(3-bromo-4-methylphenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-2,6-pyridinedicarboxamide (704 mg, 0.987 mmol, 22.34% yield) as a white solid. LC-MS m/z 435 (M+H)+, 0.94 min (ret time).

Workup

  1. additionwas added
  2. additionwas again added
  3. stirringthe mixture was stirred overnight
  4. washwashed 3× with water (50 mL)
  5. customSolid was recovered
  6. washwashed with water and ethyl acetate
  7. customDrying the solid under vacuum

Sources & evidence

ORD record
ord-b02864e7ed3b413f94c413829d9a4690
Source dataset
uspto-grants-2011_12
Patent number
US08084449B2

Reaction notes

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