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Formaldehyde → 4-(1-(4-Cyclobutyl-2-methyl-5-(5-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile

HRID 541439
Notes
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Reaction equation

HRID 541439 reaction equation
[CH:1]1([C:5]2[C:26]([C:27]3[NH:35][C:30]4[CH2:31][NH:32][CH2:33][CH2:34][C:29]=4[N:28]=3)=[CH:25][C:8]([C:9]([N:11]3[CH2:16][CH2:15][CH:14]([C:17]4[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=4)[CH2:13][CH2:12]3)=[O:10])=[C:7]([CH3:36])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[BH-](OC(C)=O)(OC(C)=O)O[C:39](C)=O.[Na+].C=O>O1CCCC1>[CH:1]1([C:5]2[C:26]([C:27]3[NH:35][C:30]4[CH2:31][N:32]([CH3:39])[CH2:33][CH2:34][C:29]=4[N:28]=3)=[CH:25][C:8]([C:9]([N:11]3[CH2:12][CH2:13][CH:14]([C:17]4[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=4)[CH2:15][CH2:16]3)=[O:10])=[C:7]([CH3:36])[CH:6]=2)[CH2:2][CH2:3][CH2:4]1
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

5

Reactant 3

HCID 712FormaldehydeHCID 5049666Sodium triacetoxyborohydrideHCID 682890604-(1-(4-Cyclobutyl-2-methyl-5-(4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile

Product 1

HCID 665485004-(1-(4-Cyclobutyl-2-methyl-5-(5-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrileYield 16%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of 4-(1-(4-cyclobutyl-2-methyl-5-(4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile (406.3, 190 mg, 0.30 mmol, 1.00 equiv, 75%) in tetrahydrofuran (10 mL) were added NaBH(OAc)3 (252 mg, 1.13 mmol, 3.00 equiv, 95%) and HCHO (37%) (2.2 mL, 2.00 equiv). The resulting mixture was stiffed for 2 h at 40° C. in an oil bath and then concentrated under reduced pressure. The residue was diluted with dichloromethane and washed with aqueous saturated sodium bicarbonate and brine. The organic layer was dried (Na2SO4) and concentrated. The crude product (˜80 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, Xbridge Prep C18, 5 um, 19*150 mm; mobile phase, water with 0.03% NH3H2O and CH3CN (36% CH3CN up to 48% in 8 min, up to 100% in 1 min, down to 36% in 1.5 min); Detector, Waters 2489 254&220 nm. The fractions containing pure compound were combined and lyophilized to yield 23.4 mg (16%) of the title compound as a white solid. m/z (ES+) 494 (M+H)+. 1H NMR (300 MHz, CD3OD): δ 7.69 (d, J=6.0 Hz, 2H), 7.48 (d, J=6.0 Hz, 2H), 7.37-7.31 (m, 1H), 7.26 & 7.15 (2 singlets, amide rotamers, Ar—H, 1H), ˜4.9 (1H partially obscured by water peak), 4.02-3.90 (m, 1H), 3.73-3.57 (m, 1H), 3.57 (s, 2H), 3.34-3.21 (m, 1H), 3.06-2.94 (m, 2H), 2.90-2.77 (m, 4H), 2.54 (s, 3H), 2.45 & 2.34 (2 singlets, amide rotamers, ArCH3, 3H), 2.11-1.86 (m, 6H), 1.86-1.54 (m, 4H).

Workup

  1. concentrationconcentrated under reduced pressure
  2. additionThe residue was diluted with dichloromethane
  3. washwashed with aqueous saturated sodium bicarbonate and brine
  4. dry with materialThe organic layer was dried (Na2SO4)
  5. concentrationconcentrated
  6. customThe crude product (˜80 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU))
  7. waitmobile phase, water with 0.03% NH3H2O and CH3CN (36% CH3CN up to 48% in 8 min
  8. waitup to 100% in 1 min
  9. waitdown to 36% in 1.5 min)
  10. additionThe fractions containing pure compound

Sources & evidence

ORD record
ord-cc948f41c4ee49628f1f8625b907be96
Source dataset
uspto-grants-2014_10
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08871790B2

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes