Pyridine → 4-[3-(2-Chloro-4-fluoro-benzoylamino)-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester

HRID 1822021Notes

Reaction equation

HRID 1822021 reaction equation
N1C=CC=CC=1.[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([NH2:27])[CH:22]=2)[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].[Cl:28][C:29]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:30]=1[C:31](Cl)=[O:32]>ClCCl>[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([NH:27][C:31](=[O:32])[C:30]3[CH:34]=[CH:35][C:36]([F:38])=[CH:37][C:29]=3[Cl:28])[CH:22]=2)[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:8])[CH3:9]

Participants

5

Reactant 3

HCID 1049PyridineHCID 27365462-Chloro-4-fluorobenzoyl chlorideHCID 57803194790667-68-4

Product 1

HCID 578936334-[3-(2-Chloro-4-fluoro-benzoylamino)-phenoxy]-piperidine-1-carboxylic acid tert-butyl esterYield 98%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

Add pyridine (0.66 mL, 8.21 mmol) to a solution of 4-(3-amino-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (preparation 30, 2.0 g, 6.84 mmol) in dichloromethane (35 mL) at 0° C. Stir and add 2-chloro-4-fluorobenzoyl chloride dropwise (1.45 g, 7.52 mmol). Stir at 0° C. for 30 min and 1 hr. at room temperature. Dilute with dichloromethane (30 mL) and wash with sodium hydroxide (1N, 2×25 mL). Combine the organic layers, dry over sodium sulfate and concentrate under reduced pressure. Purification by flash chromatography, eluting with ethyl acetate/hexanes [20-40%] to give the title compound (3.0 g, 98%). Mass spectrum (ion spray): m/z=449.0 (M+1); 1H NMR (CDCl3): 7.87 (bs, N—H), 7.80 (dd, J=6.1 Hz, 8.6 Hz, 1H), 7.48 (s, 1H), 7.28-7.24 (m, 1H), 7.21 (dd, J=2.5 Hz, 8.4 Hz, 1H), 7.11 (td, J=2.2 Hz, 8.4 Hz, 1H), 7.03 (d, J=8.4 Hz, 1H), 6.73 (dd, J=2.2 Hz, 8.4 Hz, 1H), 4.52 (septet, J=3.6 Hz, 1H), 3.69 (ddd, J=3.7 Hz, 7.7 Hz, 13.6 Hz, 2H), 3.35 (ddd, J=3.9 Hz, 7.7 Hz, 13.6 Hz, 2H), 1.97-1.89 (m, 2H), 1.81-1.72 (m, 2H), 1.46 (s, 9H).

Workup

  1. stirringStir at 0° C. for 30 min and 1 hr
  2. customat room temperature
  3. washwash with sodium hydroxide (1N, 2×25 mL)
  4. dry with materialCombine the organic layers, dry over sodium sulfate
  5. concentrationconcentrate under reduced pressure
  6. customPurification by flash chromatography
  7. washeluting with ethyl acetate/hexanes [20-40%]

Sources & evidence

ORD record
ord-0448131f7d654a0aa1fedae10b9173d7
Source dataset
uspto-grants-2009_10
Patent number
US07608629B2

Reaction notes

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