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

HRID 1642228Notes

Reaction equation

HRID 1642228 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]=[C:49]([Cl:51])[CH:48]=[CH:47][C:38]=1[O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[NH2:46]>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:46][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[O:39][C:38]2[CH:47]=[CH:48][C:49]([Cl:51])=[CH:50][C:37]=2[Cl:36])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]

Participants

7

Reactant 4

HCID 8471TriethylamineHCID 968292-(2,4-Dichlorophenoxy)anilineHCID 3928711-(tert-Butoxycarbonyl)-4-piperidinecarboxylic acidHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochloride

Product 1

HCID 159518694-[2-(2,4-Dichlorophenoxy)-phenylcarbamoyl]piperidine-1-carboxylic acid tert-butyl esterYield 84%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6344DichloromethaneSolvent3×

Procedure

A solution of piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (489 mg, 2.13 mmol) in dry DCM (10 mL) was stirred under nitrogen, and 4-dimethylaminopyridine (DMPA, 40 mg, 0.327 mmol), (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 1.116 g, 5.82 mmol) and triethylamine (0.3 mL) were added. The resulting mixture was stirred for 30 min under nitrogen and 2-(2,4-dichlorophenoxy)phenylamine (AMR01026, 491 mg, 1.93 mmol) in dry DCM (5 mL) was added. After stirring at room temperature for 72 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 to give 4-[2-(2,4-Dichlorophenoxy)phenylcarbamoyl]piperidine-1-carboxylic acid tert-butyl ester (754 mg, 84%) as a white solid (mp 120-121° C. from hexane), which was used in the next step without further purification. Rf: 0.31 (Hexane/EtOAc 7:3) LC/MS (APCI) tr=1.39 min, m/z 464.96 (21), 462.94 (M−−H, 32), 253.90 (66), 251.89 (100). 1H NMR (270 MHz, CDCl3) δ 1.44 (9H, s, 3CH3), 1.70 (2H, m, CH2), 1.86 (2H, br d, CH2), 2.40 (1H, tt, J=11.3, 3.7 Hz, CH), 2.77 (2H, br t, CH2), 4.14 (2H, m, CH2), 6.71 (1H, dd, J=8.2, 1.7 Hz, ArH), 6.94 (1H, d, J=8.9 Hz, ArH), 7.01 (1H, td, J=8.2, 1.5, ArH), 7.12 (1H, td, J=8.2, 1.5 Hz, ArH), 7.21 (1H, dd, J=8.9, 2.5 Hz, ArH), 7.48 (1H, d, J=2.5 Hz, ArH), 7.76 (1H, br s, NH) and 8.40 (1H, dd, J=7.9, 1.5 Hz, ArH).

Workup

  1. stirringAfter stirring at room temperature for 72 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

Sources & evidence

ORD record
ord-2b1d91f02dc243fe8409e3a94ce29360
Source dataset
uspto-grants-2012_02
Patent number
US08119627B2

Reaction notes

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