1-Hydroxybenzotriazole → methyl 4-[1-[4-[N'-(2-chlorophenyl)ureido]-3-methoxy phenylacetyl]-4,4-difluoro-2-pyrrolidinylmethoxy]benzoate

HRID 354438Notes

Reaction equation

HRID 354438 reaction equation
[F:1][C:2]1([F:19])[CH2:6][NH:5][CH:4]([CH2:7][O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)[CH2:3]1.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH:27][C:28](=[O:42])[NH:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37](O)=[O:38])=[CH:32][C:31]=1[O:40][CH3:41].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C1C=CN=CC=1)C.CCOC(C)=O.CN(C=O)C>[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH:27][C:28](=[O:42])[NH:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37]([N:5]2[CH2:6][C:2]([F:1])([F:19])[CH2:3][CH:4]2[CH2:7][O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)=[O:38])=[CH:32][C:31]=1[O:40][CH3:41]

Participants

8

Reactant 4

HCID 757711-HydroxybenzotriazoleHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 235118674-[N'-(2-chlorophenyl)ureido]-3-methoxyphenylacetic acidHCID 23512388Methyl 4-(4,4-difluoro-2-pyrrolidinylmethoxy)benzoate

Product 1

HCID 69333413methyl 4-[1-[4-[N'-(2-chlorophenyl)ureido]-3-methoxy phenylacetyl]-4,4-difluoro-2-pyrrolidinylmethoxy]benzoateYield 97%

Reagents, catalysts & solvents 3

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

A mixture of methyl 4-(4,4-difluoro-2-pyrrolidinylmethoxy)benzoate (229 mg, 0.845 mmol), 4-[N′-(2-chlorophenyl)ureido]-3-methoxyphenylacetic acid (283 mg, 0.845 mmol), EDC.HCl (243 mg, 1.27 mmol), HOBt (cat.), DMAP (cat.), and DMF (10 ml) was stirred overnight. The mixture was diluted with EtOAc (300 ml). The solution was washed with brine (2×100 ml), dried over MgSO4, and concntrated in vacuo. The residue was chromatographed on silica gel with CHCl3-EtOAc (20:1 to 4:1) as eluent to give methyl 4-[1-[4-[N′-(2-chlorophenyl)ureido]-3-methoxyphenylacetyl]-4,4-difluoro-2-pyrrolidinylmethoxy]benzoate (482 mg, 97%) as a colorless viscous solid. 1H-NMR (CDCl3) δ2.50-2.67 (m, 2 H), 3.54-4.71 (series of m, 13 H), 6.69 (d, J=1.5 Hz, 1 H), 6.76 (d, J=8.3 Hz, 1 H), 6.84 (d, J=8.8 Hz, 2 H), 6.98 (dt, J=7.8, 1.5 Hz, 1 H), 7.23-7.27 (m, 1 H), 7.33 (d, J=8.3 Hz, 1 H), 7.39 (m, 2 H), 7.94 (d, J=8.8 Hz, 2 H), 8.00 (d, J=8.3 Hz, 1 H), 8.19 (dd, J=8.3, 1.5 Hz, 1 H).

Workup

  1. washThe solution was washed with brine (2×100 ml)
  2. dry with materialdried over MgSO4
  3. customThe residue was chromatographed on silica gel with CHCl3-EtOAc (20:1 to 4:1) as eluent

Sources & evidence

ORD record
ord-8b4e88936d1041b5bccada2df3fb6a89
Source dataset
uspto-grants-2004_06
Patent number
US06756378B2

Reaction notes

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