Hydrochloric Acid → 5-((1-Methylpiperidin-4-yl)methoxy)-1H-indole-2-carboxylic acid hydrochloride

HRID 1430349Notes

Reaction equation

HRID 1430349 reaction equation
C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]1)=[CH:10][CH:9]=2)=[O:5])C.[OH-].[Na+].[ClH:26]>CO.O>[ClH:26].[CH3:23][N:20]1[CH2:21][CH2:22][CH:17]([CH2:16][O:15][C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:14]3)[CH2:18][CH2:19]1

Participants

6

Reactant 3

HCID 313Hydrochloric AcidHCID 14798Sodium HydroxideHCID 115079545-((1-Methylpiperidin-4-yl)methoxy)-1H-indole-2-carboxylic acid ethyl ester

Product 1

HCID 115081085-((1-Methylpiperidin-4-yl)methoxy)-1H-indole-2-carboxylic acid hydrochlorideYield 69%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 962WaterSolvent

Procedure

A suspension of ester 26 (1.00 g, 3.16 mmol) in MeOH (8 mL) was treated with a solution of NaOH (155 mg, 3.88 mmol) in water (4 mL) and heated at reflux for 3.5 h. After cooling to room temperature, the solution was adjusted to pH 6 with 2 M HCl and the solvent was removed under reduced pressure. The residue was dissolved in MeOH, 2 M HCl was added dropwise, and the formed precipitate was collected by filtration to give 27 (712 mg, 69%) as a brown solid. The residue obtained after evaporation of the mother liquor was purified by column chromatography (CH2Cl2/MeOH, 6:1, 1% cone. HCl) to provide a second batch of 27 (226 mg, 22%). 1H NMR (300 MHz, DMSO-d6): δ=1.56-1.77 (m, 2 H, 3′-Hax, 5′-Hax), 1.89-2.09 (m, 3 H, 3′-Heq, 41-H, 5′-Heq), 2.69 (s, 3 H, NMe), 2.87-3.05 (m, 2 H, 2′-Hax, 6′-Hax) 3.24-3.48 (m, 2 H, 2′-Heq, 6′-Heq), 3.79-3.92 (m, 2 H, ArOCH9), 6.90 (dd, J=9.0, 2.2 Hz, 1 H, 6-H), 6.98 (d, J=1.7 Hz, 1 H, 3-H), 7.12 (d, J=2.2 Hz, 1 H, 4-H), 7.34 (d, J=9.0 Hz, 1 H, 7-H), 10.84 (sbr, 1H, NH+), 11.59 (s, 1H, NH), 12.74 (sbr, 1 H, CO2H) ppm. —13C NMR (75.5 MHz, DMSO-d6): δ=25.8 (C-3′, C-5′), 32.8 (C-4′), 42.5 (NMe), 52.8 (C-2′, C-6′), 71.6 (OCH2), 103.4 (C-4), 106.8 (C-3), 113.3 (C-7), 116.0 (C-6), 127.1 (C-2), 128.7 (C-3a), 132.6 (C-7a), 152.9 (C-5), 162.5 (C═O) ppm. −MS (70 eV, EI): m/z (%)=288 (14) [M−HCl]+, 112 (100) [C7H14N]+. —C16H21ClN2O3 (324.80): calcd. 288.1474 [M−HCl]+; found 288.1474.

Workup

  1. temperatureheated
  2. temperatureat reflux for 3.5 h
  3. customthe solvent was removed under reduced pressure
  4. dissolutionThe residue was dissolved in MeOH
  5. addition2 M HCl was added dropwise
  6. filtrationthe formed precipitate was collected by filtration

Sources & evidence

ORD record
ord-af2422ca63804162b72b44e3f5f5f17e
Source dataset
uspto-grants-2015_01
Patent number
US08940784B2

Reaction notes

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