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

HRID 350500Notes

Reaction equation

HRID 350500 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.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH2:39][C:40](O)=[O:41])[CH:25]=[CH:26][C:27]=1[NH:28][C:29]([NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH3:38])=[O:30].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C1C=CN=CC=1)C.CN(C=O)C.CCOC(C)=O>[F:19][C:2]1([F:1])[CH2:6][N:5]([C:40](=[O:41])[CH2:39][C:24]2[CH:25]=[CH:26][C:27]([NH:28][C:29]([NH:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[CH3:38])=[O:30])=[C:22]([O:21][CH3:20])[CH:23]=2)[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

Participants

8

Reactant 4

HCID 757711-HydroxybenzotriazoleHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 114498403-Methoxy-4-o-tolylureidophenylacetic acidHCID 23512388Methyl 4-(4,4-difluoro-2-pyrrolidinylmethoxy)benzoate

Product 1

HCID 69332941methyl 4-[4,4-difluoro-1-[3-methoxy-4-[N'-(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinylmethoxy]benzoateYield 89%

Reagents, catalysts & solvents 3

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

Procedure

A mixture of methyl 4-(4,4 difluoro-2-pyrrolidinylmethoxy)benzoate (540 mg, 1.99 mmol), 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetic acid (626 mg, 1.99 mmol), EDC.HCl (572 mg, 2.99 mmol), HOBt (cat.), and DMAP (cat.) in DMF (10 ml) was stirred overnight. The mixture was diluted with EtOAc (300 ml), washed with brine (2×100 ml), dried over MgSO4, and concntrated in vacuo. The residue was chromatographed on silica gel with CHCl3-MeOH (20:1) as eluent to give methyl 4-[4,4-difluoro-1-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinylmethoxy]benzoate (1.00 g, 89%) as a colorless foam. 1H-NMR (CDCl3) δ 2.31 (s, 3 H), 2.47–2.63 (m, 2 H), 3.52–3.97 (series of s and m, total 10 H), 4.07–4.30 (mi 2 H), 4.67–4.69 (m, 1 H), 6.45 (s, 1 H), 6.65 (d, J=1.7 Hz, 1 H), 6.74–6.76 (m, 1 H), 6.84 (d, J=8.8 Hz, 2 H), 7.14 (m, 2 H), 7.24 (m, 2 H), 7.52–7.54 (m, 1 H), 7.94 (d, J=8.8 Hz, 2 H), 8.09 (d, J=8.1 Hz, 1H).

Workup

  1. washwashed with brine (2×100 ml)
  2. dry with materialdried over MgSO4
  3. customThe residue was chromatographed on silica gel with CHCl3-MeOH (20:1) as eluent

Sources & evidence

ORD record
ord-ed05b4cc4090449588451e8366e4ee9a
Source dataset
uspto-grants-2007_02
Patent number
US07179819B2

Reaction notes

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