Formaldehyde → HCID 44195124, compound

HRID 1020547Notes

Reaction equation

HRID 1020547 reaction equation
Cl.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][N:13]([C:16]2[CH:17]=[CH:18][C:19]3[C:20]4[CH2:29][N:28]([C:30]([CH:32]5[CH2:36][CH2:35][NH:34][CH2:33]5)=[O:31])[CH2:27][CH2:26][C:21]=4[N:22]([CH3:25])[C:23]=3[CH:24]=2)[C:12](=[O:37])[CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:38]CN(CC)CC.C=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO>[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][N:13]([C:16]2[CH:17]=[CH:18][C:19]3[C:20]4[CH2:29][N:28]([C:30]([CH:32]5[CH2:36][CH2:35][N:34]([CH3:38])[CH2:33]5)=[O:31])[CH2:27][CH2:26][C:21]=4[N:22]([CH3:25])[C:23]=3[CH:24]=2)[C:12](=[O:37])[CH:11]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1

Participants

6

Reactant 4

HCID 712FormaldehydeHCID 8471TriethylamineHCID 5049666Sodium triacetoxyborohydrideHCID 68657528HCID 68657528, compound

Product 1

HCID 44195124HCID 44195124, compoundYield 61.3%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

To a solution of 4-(benzyloxy)-1-(5-methyl-2-(pyrrolidine-3-carbonyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one hydrochloride (105 mg, 0.197 mmol) in CH3OH (3 mL) was added Et3N (40 μL, 0.29 mmol), formaldehyde (23 μL, 0.29 mmol), and NaBH(OAc)3 (86 mg, 0.41 mmol). The reaction mixture was stirred at room temperature until the reaction was complete. Then the mixture was concentrated and the residue was dissolved in CH2Cl2. The organic layer was washed with H2O and 5% LiCl, dried with Na2SO4, filtered and concentrated. Purification by flash column chromatography (silica gel, 10% CH3OH in CH2Cl2) gave 4-(benzyloxy)-1-(5-methyl-2-(1-methylpyrrolidine-3-carbonyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one (60 mg, 60%) as a yellow solid. The free base was converted to the HCl salt to give the title compound (43 mg, 80%) as a yellow solid and as a mixture of rotamers: mp 132-136° C.; 1H NMR (500 MHz, CD3OD) δ 7.61-7.33 (m, 8H), 7.02-6.98 (m, 1H), 6.29-6.27 (m, 1H), 6.12-6.11 (m, 1H), 5.17 (s, 2H), 4.79-4.76 (m, 2H), 4.09-3.97 (m, 2H), 3.81-3.79 (m, 1H), 3.69-3.67 (m, 4H), 3.49-3.42 (m, 1H), 3.22-3.16 (m, 2H), 3.00 (m, 1H), 2.92-2.91 (m, 1H), 2.81-2.78 (2×s, 3H), 2.52-2.36 (m, 1H), 2.18-2.00 (m, 1H); ESI MS m/z 497 [M+H]+; HPLC (Method B) 98.7% (AUC), tR=13.6 min.

Workup

  1. concentrationThen the mixture was concentrated
  2. dissolutionthe residue was dissolved in CH2Cl2
  3. washThe organic layer was washed with H2O and 5% LiCl
  4. dry with materialdried with Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customPurification by flash column chromatography (silica gel, 10% CH3OH in CH2Cl2)

Sources & evidence

ORD record
ord-4ad69de242274b07a9977f453b046316
Source dataset
uspto-grants-2014_05
Patent number
US08716308B2

Reaction notes

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