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

HRID 564437Notes

Reaction equation

HRID 564437 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[CH:24]=[C:25]([CH:29]=[CH:30][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].[NH2:34][CH2:35][C:36]1[CH:37]=[CH:38][C:39]([F:50])=[C:40]([C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([CH2:48][OH:49])[CH:43]=2)[CH:41]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[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[CH:31]=[CH:30][CH:29]=[C:25]([C:26]([NH:34][CH2:35][C:36]4[CH:41]=[C:40]([C:42]5[CH:47]=[CH:46][CH:45]=[C:44]([CH2:48][OH:49])[CH:43]=5)[C:39]([F:50])=[CH:38][CH:37]=4)=[O:27])[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]

Participants

6

Reactant 4

HCID 81531Diisopropylethylamine2×HCID 2724699PyBOP2×HCID 578132773-[({[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]benzoic AcidHCID 57813296[5'-(Aminomethyl)-2'-fluoro-3-biphenylyl]methanol

Product 1

HCID 57813265N-{[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N'-{[6-fluoro-3'-(hydroxymethyl)-3-biphenylyl]methyl}-1,3-benzenedicarboxamideYield 97.8%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of 3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]benzoic acid (446 mg, 1 mmol) in DMF (70 mL) was added [5′-(aminomethyl)-2′-fluoro-3-biphenylyl]methanol (230 mg, 1 mmol), PyBOP (570 mg, 1.1 mmol) and diisopropylethylamine (0.69 mL, 4 mmol) and the mixture was stirred at ambient temperature for 16 h. Additional PyBOP (518 mg, 1 mmol) and diisopropylethylamine (0.69 mL, 4 mmol) were added and the mixture stirred for an additional 2 h. The mixture was then concentrated to dryness and the residue was treated with water (400 mL) and extracted with dichloromethane (2×200 mL). The combined organics were dried (hydrophobic frit) and concentrated in vacuo and the resulting yellow oil was subjected to purification by flash chromatography (100 g silica cartridge, gradient elution from 0-100% ethyl acetate/cyclohexane) to afford 650 mg of the title compound. LC-MS m/z 665 (M+H)+, 0.98 min (ret time).

Workup

  1. stirringthe mixture stirred for an additional 2 h
  2. concentrationThe mixture was then concentrated to dryness
  3. additionthe residue was treated with water (400 mL)
  4. extractionextracted with dichloromethane (2×200 mL)
  5. customThe combined organics were dried (hydrophobic frit)
  6. concentrationconcentrated in vacuo
  7. customthe resulting yellow oil was subjected to purification by flash chromatography (100 g silica cartridge, gradient elution from 0-100% ethyl acetate/cyclohexane)

Sources & evidence

ORD record
ord-9ac8a57306f74bdb814745e2e257ef31
Source dataset
uspto-grants-2011_11
Patent number
US08067408B2

Reaction notes

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