Cesium carbonate → methyl (2S)-5-cyclobutoxy-6-[1-(1,1-dioxo-1lambda6-thian-4-yl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate

HRID 1051717Notes

Reaction equation

HRID 1051717 reaction equation
[CH:1]1([O:5][C:6]2[C:15]([C:16]3[CH:17]=[N:18][NH:19][CH:20]=3)=[CH:14][CH:13]=[C:12]3[C:7]=2[CH2:8][CH2:9][C@H:10]([CH3:25])[N:11]3[C:21]([O:23][CH3:24])=[O:22])[CH2:4][CH2:3][CH2:2]1.CS(O[CH:31]1[CH2:36][CH2:35][S:34](=[O:38])(=[O:37])[CH2:33][CH2:32]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O>[CH:1]1([O:5][C:6]2[C:15]([C:16]3[CH:20]=[N:19][N:18]([CH:31]4[CH2:36][CH2:35][S:34](=[O:38])(=[O:37])[CH2:33][CH2:32]4)[CH:17]=3)=[CH:14][CH:13]=[C:12]3[C:7]=2[CH2:8][CH2:9][C@H:10]([CH3:25])[N:11]3[C:21]([O:23][CH3:24])=[O:22])[CH2:2][CH2:3][CH2:4]1

Participants

6

Reactant 3

HCID 10796Cesium carbonateHCID 898088401,1-dioxidotetrahydro-2H-thiopyran-4-yl methanesulfonateHCID 118075439(S)-methyl 5-cyclobutoxy-2-methyl-6-(1H-pyrazol-4-yl)-3,4-dihydroquinoline-1 (2H)-carboxylate

Product 1

HCID 118086340methyl (2S)-5-cyclobutoxy-6-[1-(1,1-dioxo-1lambda6-thian-4-yl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylateYield 18%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
110 °C

Procedure

A mixture of (S)-methyl 5-cyclobutoxy-2-methyl-6-(1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate (0.160 g, 0.47 mmol), 1,1-dioxidotetrahydro-2H-thiopyran-4-yl methanesulfonate (0.320 g, 1.40 mmol) and cesium carbonate (0.457 g, 1.40 mmol) in N,N-dimethylformamide (5 mL) stirred overnight at 110° C. The reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by preparative thin layer chromatography (eluting with 50% ethyl acetate/petroleum ether). The product was further purified by preparative-HPLC with the following conditions (Waters I): Column, Xbridge RP18 5 um, 19×150 mm; Mobile phase, water (0.05% ammonium bicarbonate) and acetonitrile (40% to 80% acetonitrile in 10 min; flow rate: 20 mL/min); Detector, UV 220&254 nm. This afforded of methyl (2S)-5-cyclobutoxy-6-[1-(1,1-dioxo-1λ6-thian-4-yl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate (0.040 g, 18%) as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm 1.18 (d, J=6.40 Hz, 3H), 1.29-1.31 (m, 1H), 1.47-1.49 (m, 1H), 1.60-1.62 (m, 1H), 2.01-2.08 (m, 4H), 2.11-2.24 (m, 1H), 2.45-2.47 (m, 1H), 2.63-2.68 (m, 4H), 2.90-2.94 (m, 1H), 3.10-3.17 (m, 2H), 3.45-3.47 (m, 2H), 3.78 (s, 3H), 4.06-1.10 (m, 1H), 4.45-4.58 (m, 2H), 7.22 (d, J=8.40 Hz, 1H), 7.31 (d, J=8.40 Hz, 1H), 7.81 (s, 2H). MS (ESI, pos. ion) m/z 474 [M+H]+.

Workup

  1. temperatureThe reaction mixture was cooled to room temperature
  2. extractionextracted with ethyl acetate (3×10 mL)
  3. dry with materialThe combined organic layers were dried over anhydrous sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated under vacuum
  6. customThe residue was purified by preparative thin layer chromatography (eluting with 50% ethyl acetate/petroleum ether)
  7. customThe product was further purified by preparative-HPLC with the following conditions (Waters I)
  8. customMobile phase, water (0.05% ammonium bicarbonate) and acetonitrile (40% to 80% acetonitrile in 10 min; flow rate: 20 mL/min)

Sources & evidence

ORD record
ord-0b309a163fb042669173b515c68e8bb5
Source dataset
uspto-grants-2016_07
Patent number
US09388161B2

Reaction notes

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