Acetic Acid → 3-((3-(1H-pyrazol-5-yl)piperidin-1-yl)methyl)-9-ethyl-6,7,8,9-tetrahydro-5H-carbazole

HRID 659634Notes

Reaction equation

HRID 659634 reaction equation
Cl.Cl.[NH:3]1[C:7]([CH:8]2[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]2)=[CH:6][CH:5]=[N:4]1.CCN(C(C)C)C(C)C.C(O)(=O)C.[CH2:27]([N:29]1[C:41]2[CH:40]=[CH:39][C:38]([CH:42]=O)=[CH:37][C:36]=2[C:35]2[CH2:34][CH2:33][CH2:32][CH2:31][C:30]1=2)[CH3:28].[BH3-]C#N.[Na+].C(=O)(O)[O-].[Na+]>C(O)C.ClCCl.CO>[NH:3]1[C:7]([CH:8]2[CH2:13][CH2:12][CH2:11][N:10]([CH2:42][C:38]3[CH:39]=[CH:40][C:41]4[N:29]([CH2:27][CH3:28])[C:30]5[CH2:31][CH2:32][CH2:33][CH2:34][C:35]=5[C:36]=4[CH:37]=3)[CH2:9]2)=[CH:6][CH:5]=[N:4]1

Participants

10

Reactant 6

HCID 176Acetic AcidHCID 81531DiisopropylethylamineHCID 516892Sodium BicarbonateHCID 5003444Sodium cyanoborohydrideHCID 215175719-ethyl-6,7,8,9-tetrahydro-5H-carbazole-3-carbaldehydeHCID 429613003-(1H-pyrazol-5-yl)piperidine dihydrochloride

Product 1

HCID 679963443-((3-(1H-pyrazol-5-yl)piperidin-1-yl)methyl)-9-ethyl-6,7,8,9-tetrahydro-5H-carbazoleYield 31.3%

Reagents, catalysts & solvents 3

HCID 702EthanolSolventHCID 887MethanolSolventHCID 6344DichloromethaneSolvent2×

Conditions

Temperature
40 °C

Procedure

A 250-mL round-bottomed flask was charged a solution of 3-(1H-pyrazol-5-yl)piperidine dihydrochloride (2.9 g, 13.00 mmol, 1.50 equiv) in ethanol (150 mL) and DIPEA (4.55 g, 35.23 mmol, 4.00 equiv), acetic acid (3.17 g, 52.83 mmol, 6.00 equiv), 9-ethyl-6,7,8,9-tetrahydro-5H-carbazole-3-carbaldehyde (2 g, 8.81 mmol, 1.00 equiv) and NaBH3CN (1.665 g, 26.43 mmol, 3.00 equiv). The resulting mixture was heated to 40° C. in an oil bath for 16 hours. The reaction progress was monitored by TLC (DCM: MeOH=10:1). Upon completion, the mixture was diluted with dichloromethane (200 mL). The pH was adjusted to 9 with aqueous sodium bicarbonate. The mixture was then extracted with dichloromethane (3×100 mL). Combined organic layers were dried over anhydrous sodium sulfate, filtered off and concentrated on a rotary evaporator. The residue was purified by a silica gel column chromatography eluted with dichloromethane/methanol (10/1) affording 3-((3-(1H-pyrazol-5-yl)piperidin-1-yl)methyl)-9-ethyl-6,7,8,9-tetrahydro-5H-carbazole as white solid (1 g, 30%). LCMS: [M+H]+: 363. 1H NMR (CDCl3, 300 MHz) δ 7.45 (d, 1H), 7.43 (s, 1H), 7.26 (d, 1H), 7.19 (d, 1H), 6.06 (d, 1H), 4.05 (m, 2H), 3.92 (m, 2H), 3.36 (br, 1H), 2.73 (m, 4H), 2.65 (br, 2H), 2.11 (s, 2H), 1.86 (m, 5H), 1.75 (br, 1H), 1.55 (m, 1H), 1.47 (m, 1H), 1.31 (t, 3H).

Workup

  1. extractionThe mixture was then extracted with dichloromethane (3×100 mL)
  2. dry with materialCombined organic layers were dried over anhydrous sodium sulfate
  3. filtrationfiltered off
  4. concentrationconcentrated on a rotary evaporator
  5. customThe residue was purified by a silica gel column chromatography
  6. washeluted with dichloromethane/methanol (10/1)

Sources & evidence

ORD record
ord-5db4e4521054486da53a428ca845f2a6
Source dataset
uspto-grants-2011_12
Patent number
US08080566B1

Reaction notes

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