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Hydrochloric Acid → (R)-1-(1-(3-(Dimethylamino)-2-hydroxypropyl)-1H-indazol-5-yl)-4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-one hydrochloride

HRID 2390449
Notes
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Reaction equation

HRID 2390449 reaction equation
[O:1]1[CH2:3][C@@H:2]1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([N:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=4)=[CH:16][C:15]3=[O:30])=[CH:11][CH:12]=2)[CH:7]=[N:6]1.[CH3:31][NH:32][CH3:33].[ClH:34]>O1CCCC1.ClCCl>[ClH:34].[CH3:31][N:32]([CH3:33])[CH2:3][C@@H:2]([OH:1])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([N:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:29])[F:28])=[CH:22][CH:21]=4)=[CH:16][C:15]3=[O:30])=[CH:11][CH:12]=2)[CH:7]=[N:6]1
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

6

Reactant 3

HCID 313Hydrochloric AcidHCID 674DimethylamineHCID 57625522(S)-1-(1-(oxiran-2-ylmethyl)-1H-indazol-5-yl)-4-(4-(trifluoromethyl)phenyl)-pyridin-2(1H)-one

Product 1

HCID 66719376(R)-1-(1-(3-(Dimethylamino)-2-hydroxypropyl)-1H-indazol-5-yl)-4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-one hydrochlorideYield 80%

Reagents, catalysts & solvents 2

HCID 6344
Dichloromethane
Solvent
2×
HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
45 °C

Procedure

To (S)-1-(1-(oxiran-2-ylmethyl)-1H-indazol-5-yl)-4-(4-(trifluoromethyl)phenyl)-pyridin-2(1H)-one (200 mg, 0.48 mmol) in tetrahydrofuran (5 mL) was added LiClO4 (775 mg, 7.3 mmol) followed by dimethylamine (2.4 ml of a 2 M solution in tetrahydrofuran, 4.9 mmol). The reaction mixture was heated in a 45° C. oil bath for 4.5 h. The reaction mixture was cooled to ambient temperature, diluted with dichloromethane (50 ml), washed with water (25 mL) and brine (25 mL), dried (Na2SO4), and concentrated under reduced pressure. The material was purified by column chromatography (silica gel, 9:1 CH2Cl2/MeOH to 90:9:1 CH2Cl2/MeOH/conc. NH4OH). The dried residue (160 mg, 0.35 mmol) was dissolved in dichloromethane (10 mL) and HCl (1.25 M solution in methanol, 0.31 mL, 0.43 mmol) was added. The mixture was concentrated under reduced pressure and dried to afford the title compound (190 mg, 80%) as a yellow solid: mp 210-213° C.; 1H NMR (500 MHz, DMSO-d6) δ 9.50 (br s, 1H), 8.22 (s, 1H), 8.02-8.00 (m, 2H), 7.89-7.84 (m, 5H), 7.48 (dd, J=9.0, 2.0 Hz, 1H), 6.89 (d, J=2.0 Hz, 1H), 6.74 (dd, J=7.0 Hz, 2.0 Hz, 1H), 6.01 (br s, 1H), 4.58-4.49 (m, 2H), 4.40 (br s, 1H), 3.28-3.24 (m, 1H), 3.15-3.10 (m, 1H), 2.81 (d, J=4.5 Hz, 3H), 2.78 (d, J=4.5 Hz, 3H); ESI MS m/z 457 [M+H]+; HPLC (Method B) 96.5% (AUC), tR=14.4 min; [α]23D +10.4° (c 0.11, Methanol).

Workup

  1. temperatureThe reaction mixture was cooled to ambient temperature
  2. washwashed with water (25 mL) and brine (25 mL)
  3. dry with materialdried (Na2SO4)
  4. concentrationconcentrated under reduced pressure
  5. customThe material was purified by column chromatography (silica gel, 9:1 CH2Cl2/MeOH to 90:9:1 CH2Cl2/MeOH/conc. NH4OH)
  6. concentrationThe mixture was concentrated under reduced pressure
  7. customdried

Sources & evidence

ORD record
ord-fcaf2b6e163a46509c768117be787d8e
Source dataset
uspto-grants-2012_09
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08273770B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes