Triethylamine → 4-[2-(4-Chlorophenoxy)phenylcarbamoyl]piperidine-1-carboxylic acid tert-butyl ester

HRID 1642227Notes

Reaction equation

HRID 1642227 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[Cl:36][C:37]1[CH:50]=[CH:49][C:40]([O:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[NH2:48])=[CH:39][CH:38]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:16])[NH:48][C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[O:41][C:40]2[CH:49]=[CH:50][C:37]([Cl:36])=[CH:38][CH:39]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]

Participants

7

Reactant 4

HCID 8471TriethylamineHCID 760102-(4-Chlorophenoxy)anilineHCID 3928711-(tert-Butoxycarbonyl)-4-piperidinecarboxylic acidHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochloride

Product 1

HCID 575503174-[2-(4-Chlorophenoxy)phenylcarbamoyl]piperidine-1-carboxylic acid tert-butyl esterYield 55%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6344DichloromethaneSolvent3×

Procedure

A solution of piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (AMR01030, 417 mg, 1.82 mmol) in dry DCM (8 mL) was stirred under nitrogen, and 4-dimethylaminopyridine (DMPA, 40 mg, 0.327 mmol), (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 1.05 g, 5.46 mmol) and triethylamine (0.25 mL) were added. The resulting mixture was stirred for 30 min under nitrogen and 2-(4-chloro-phenoxy)-phenylamine (AMR01029, 400 mg, 1.82 mmol) in dry DCM (4 mL) was added. After stirring at room temperature for 24 h, the mixture was diluted with DCM, washed with HCl 1M (3×25 mL), water, saturated NaHCO3 (2×25 mL) and brine. The organic layer was dried (MgSO4), filtered and evaporated. Flash chromatography on silica gel of the crude product using hexane/EtOAc 8:2 as eluent gave starting material (104 mg). Further elution using hexane/EtOAc 7:3 gave 4-[2-(4-chlorophenoxy)-phenylcarbamoyl]piperidine-1-carboxylic acid tert-butyl ester (430 mg, 55%) as a white solid, mp 97-99° C. Rf: 0.22 (hexane/EtOAc 7:3) LC/MS (APCI) tr=3.83 min, m/z 431.23 (33), 429.21 (M−−H, 100). 1H NMR (270 MHz, CDCl3) δ 1.44 (9H, s, 3CH3), 1.68 (2H, m, CH2), 1.83 (2H, m, CH2), 2.36 (1H, tt, J=11.4, 3.7 Hz), 2.75 (4H, br t, 2CH2), 4.11 (4H, m, 2CH2), 6.81 (1H, dd, J=8.2, 1.5 Hz, ArH), 6.93 (2H, AA′BB′, ArH), 7.01 (1H, td, ArH), 7.12 (1H, td, ArH), 7.31 (2H, AA′BB′, ArH), 7.68 (1H, br s, NH) and 8.40 (1H, dd, J=6.9, 1.5 Hz, ArH).

Workup

  1. stirringAfter stirring at room temperature for 24 h
  2. washwashed with HCl 1M (3×25 mL), water, saturated NaHCO3 (2×25 mL) and brine
  3. dry with materialThe organic layer was dried (MgSO4)
  4. filtrationfiltered
  5. customevaporated
  6. customgave
  7. washFurther elution

Sources & evidence

ORD record
ord-3a300d45d2c042b29bf2a31eae550579
Source dataset
uspto-grants-2012_02
Patent number
US08119627B2

Reaction notes

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