1,2-Dichloroethane → methyl (2S)-5-(4-fluorophenoxy)-2-methyl-6-(1-(2-methylazetidin-3-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate

HRID 1051682Notes

Reaction equation

HRID 1051682 reaction equation
C([N:14]1[CH2:17][CH:16]([N:18]2[CH:22]=[C:21]([C:23]3[C:24]([O:38][C:39]4[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=4)=[C:25]4[C:30](=[CH:31][CH:32]=3)[N:29]([C:33]([O:35][CH3:36])=[O:34])[C@@H:28]([CH3:37])[CH2:27][CH2:26]4)[CH:20]=[N:19]2)[CH:15]1[CH3:46])(C1C=CC=CC=1)C1C=CC=CC=1.ClCCCl.ClC(OC(Cl)C)=O>C(OCC)(=O)C>[F:45][C:42]1[CH:41]=[CH:40][C:39]([O:38][C:24]2[C:23]([C:21]3[CH:20]=[N:19][N:18]([CH:16]4[CH2:17][NH:14][CH:15]4[CH3:46])[CH:22]=3)=[CH:32][CH:31]=[C:30]3[C:25]=2[CH2:26][CH2:27][C@H:28]([CH3:37])[N:29]3[C:33]([O:35][CH3:36])=[O:34])=[CH:44][CH:43]=1

Participants

5

Reactant 3

HCID 111,2-DichloroethaneHCID 5213051-Chloroethyl chloroformateHCID 118075635(2S)-methyl 6-(1-(1-benzhydryl-2-methylazetidin-3-yl)-1H-pyrazol-4-yl)-5-(4-fluorophenoxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate

Product 1

HCID 118086277methyl (2S)-5-(4-fluorophenoxy)-2-methyl-6-(1-(2-methylazetidin-3-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
80 °C

Procedure

A 50-mL round-bottom flask was charged with (2S)-methyl 6-(1-(1-benzhydryl-2-methylazetidin-3-yl)-1H-pyrazol-4-yl)-5-(4-fluorophenoxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (0.020 g, 0.03 mmol), 1,2-dichloroethane (5 mL) and 1-chloroethyl chloroformate (1 mL), and the resulting solution stirred for 3 h at 80° C. The reaction mixture was cooled to room temperature and then diluted with ethyl acetate (20 mL). The organic phase was separated and washed with water (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting 25% ethyl acetate-petroleum ether). The product was further purified by preparative-HPLC with the following conditions (Waters I): Column, Xbridge RP C18, 19×150 mm, 5 um; mobile phase, water (0.05% ammonium bicarbonate) and acetonitrile (20% to 80% acetonitrile in 10 min; flow rate: 20 mL/min); Detector, UV254&220. This afforded methyl (2S)-5-(4-fluorophenoxy)-2-methyl-6-(1-(2-methylazetidin-3-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate (0.0021 g, 14%) as a white solid. 1H NMR (300 MHz, CD3OD) δ ppm 0.75 (d, J=6.40 Hz, 3H), 0.85-0.97 (m, 1H), 1.10-1.18 (m, 3H), 1.29-1.39 (m, 3H), 1.52-1.65 (m, 1H), 1.99-2.25 (m, 2H), 2.41-2.75 (m, 2H), 3.82 (s, 3H), 4.05-4.17 (m, 2H), 4.26-4.35 (m, 1H), 4.62-4.73 (m, 1H), 5.16-5.23 (m, 1H), 6.73-6.81 (m, 2H), 6.93-6.99 (m, 2H), 7.51-7.62 (m, 2H), 7.85 (s, 1H), 8.05 (s, 1H). MS (ESI, pos. ion) m/z 451 [M+H]+.

Workup

  1. temperatureThe reaction mixture was cooled to room temperature
  2. customThe organic phase was separated
  3. washwashed with water (10 mL)
  4. dry with materialdried over anhydrous sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated under vacuum
  7. customThe residue was purified via column chromatography on silica gel (eluting 25% ethyl acetate-petroleum ether)
  8. customThe product was further purified by preparative-HPLC with the following conditions (Waters I)
  9. custommobile phase, water (0.05% ammonium bicarbonate) and acetonitrile (20% to 80% acetonitrile in 10 min; flow rate: 20 mL/min)

Sources & evidence

ORD record
ord-d70c3d5c2d994c3a8f3287e261b47641
Source dataset
uspto-grants-2016_07
Patent number
US09388161B2

Reaction notes

Loading…