Phosphorus oxychloride → (trans)-Benzyl 4-(2-chloroquinolin-8-yloxy)-3-fluoropiperidine-1-carboxylate

HRID 1095735Notes

Reaction equation

HRID 1095735 reaction equation
FC1CCCN(C([O-])=O)C1.O=P(Cl)(Cl)[Cl:13].[CH2:16]([O:23][C:24]([N:26]1[CH2:31][CH2:30][C@@H:29]([O:32][C:33]2[CH:34]=[CH:35][CH:36]=[C:37]3[C:42]=2[N+:41]([O-])=[CH:40][CH:39]=[CH:38]3)[C@H:28]([F:44])[CH2:27]1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(OCC)(=O)C.C1(C)C=CC=CC=1.CN(C=O)C>[Cl:13][C:40]1[CH:39]=[CH:38][C:37]2[C:42](=[C:33]([O:32][C@@H:29]3[CH2:30][CH2:31][N:26]([C:24]([O:23][CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[O:25])[CH2:27][C@H:28]3[F:44])[CH:34]=[CH:35][CH:36]=2)[N:41]=1

Participants

7

Reactant 3

HCID 24813Phosphorus oxychlorideHCID 667821658-((trans)-1-(Benzyloxycarbonyl)-3-fluoropiperidin-4-yloxy)quinoline 1-oxideHCID 1317295223-Fluoropiperidine-1-carboxylate

Product 1

HCID 131729521(trans)-Benzyl 4-(2-chloroquinolin-8-yloxy)-3-fluoropiperidine-1-carboxylateYield 51.9%

Reagents, catalysts & solvents 3

HCID 1140TolueneSolvent2×HCID 6228DimethylformamideSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

Preparation of (trans)-benzyl 4-f2-chloroquinolin-8-yloxy)-3-fluoropiperidine-1-carboxylate: To a 0° C. solution of 4 mL 1:1 DMF:toluene was added neat POCl3 (0.360 ml, 3.94 mmol). The reaction mixture was warmed to ambient temperature, stirred 10 minutes, and then cooled to 0° C. A solution of 8-((trans)-1-(benzyloxycarbonyl)-3-fluoropiperidin-4-yloxy)quinoline 1-oxide (1.04 g, 2.62 mmol) in 1.2 mL 1:1 DMF:toluene was added dropwise by syringe to the reaction mixture, and the reaction mixture was heated in a 110° C. sand bath and stirred for 1 hours. The reaction mixture was cooled to ambient temperature and added dropwise to a stirring ice/saturated NaHCO3 mixture. The mixture was stirred 20 minutes, then extracted with DCM, and the combined extracts were dried (Na2SO4), filtered, and concentrated. The crude was purified on silica gel (Biotage 40S, loaded with 12:1hexanes:ethyl acetate, flushed 300 mL, then gradient to 5:1 hexanes:ethyl acetate) to give (trans)-benzyl 4-(2-chloroquinolin-8-yloxy)-3-fluoropiperidine-l-carboxylate (0.563 g, 1.36 mmol, 51.7% yield) as a syrup. MS APCI (+) m/z 415 (M+1) detected.

Workup

  1. temperaturecooled to 0° C
  2. temperaturethe reaction mixture was heated in a 110° C. sand bath
  3. stirringstirred for 1 hours
  4. temperatureThe reaction mixture was cooled to ambient temperature
  5. stirringThe mixture was stirred 20 minutes
  6. extractionextracted with DCM
  7. dry with materialthe combined extracts were dried (Na2SO4)
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customThe crude was purified on silica gel (Biotage 40S
  11. custom1hexanes:ethyl acetate, flushed 300 mL

Sources & evidence

ORD record
ord-983e0bd7166749f28b6978c3f8bc90d3
Source dataset
uspto-grants-2012_03
Patent number
US08138181B2

Reaction notes

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