Trifluoroacetic acid → Methyl 4-[[1-[4-[n'-(2-chlorophenyl)ureido]-3-methoxylphenylacetyl]-(2s)-pyrrolidinyl]methoxy]cyclohexane carboxylate

HRID 350528Notes

Reaction equation

HRID 350528 reaction equation
C(O[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][O:14][CH:15]1[CH2:20][CH2:19][CH:18]([C:21]([O:23][CH3:24])=[O:22])[CH2:17][CH2:16]1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=[O:26].[CH:32]1[CH:33]=[CH:34][C:35]2N(O)N=[N:38][C:36]=2[CH:37]=1.C([N:44]([CH2:47]C)[CH2:45][CH3:46])C.CCN=C=N[CH2:54][CH2:55][CH2:56]N(C)C.[ClH:60].C1[CH2:65][O:64][CH2:63][CH2:62]1>C(Cl)Cl.CC#N>[Cl:60][C:37]1[CH:32]=[CH:33][CH:34]=[CH:35][C:36]=1[NH:38][C:47](=[O:26])[NH:44][C:45]1[CH:46]=[CH:56][C:55]([CH2:54][C:6]([N:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[CH2:13][O:14][CH:15]2[CH2:16][CH2:17][CH:18]([C:21]([O:23][CH3:24])=[O:22])[CH2:19][CH2:20]2)=[O:7])=[CH:62][C:63]=1[O:64][CH3:65]

Participants

9

Reactant 6

HCID 6422Trifluoroacetic acidHCID 8028TetrahydrofuranHCID 8471TriethylamineHCID 757711-HydroxybenzotriazoleHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 23512198HCID 23512198, compound

Product 1

HCID 20737838Methyl 4-[[1-[4-[n'-(2-chlorophenyl)ureido]-3-methoxylphenylacetyl]-(2s)-pyrrolidinyl]methoxy]cyclohexane carboxylateYield 97%

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolventHCID 6344DichloromethaneSolvent

Procedure

To a stirred solution of methyl 4-[(1-tert-butoxycarbonyl-2-pyrrolidinyl)methoxy]cyclohexane carboxylate (900 mg, 2.6 mmol) in CH2Cl2 (5.0 ml) was added TFA (5.0 ml) at 0° C. The reaction mixture was stirred at room temperature for 0.5 hr. The mixture was concentrated in vacuo. Sat. NaHCO3 was added to the residue, and extracted with CH2Cl2. The extract was washed with brine dried over Na2SO4, and concentrated in vacuo. The crude product was used to the subsequent reaction without further purification. To a stirred solution of the crude product (200 mg, 0.83 mmol), 4-[N′-(2-chlorophenyl)uredio]-3-methoxyphenylacetic acid (277 mg, 0.83 mmol), HOBt (135 mg, 1.0 mmol), and triethylamine (344 ml, 2.48 mmol) in THF (10.0 ml) and MeCN (10.0 ml) was added EDC.HCl (238 mg, 1.24 mmol) at 0° C. The reaction mixture was stirred at room temperature for 16 hr, and concentrated in vacuo. Water was added to the residue, and extracted with EtOAc. The extract was washed with sat. NaHCO3, 2-M citric acid, and sat. NaHCO3, then dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel with n-hexane-EtOAc (1:6, v/v) as eluent to give methyl 4-[[1-[4-[N′-(2-chlorophenyl)ureido]-3-methoxylphenylacetyl]-(2S)-pyrrolidinyl]methoxy]cyclohexane carboxylate (450 mg, 97%) as a colorless oil. 1H-NMR (CDCl3) δ 1.35–2.15 (m, 12H), 2.25–2.40 (m, 1H), 3.40–3.70 (m, 5H), 3.61 (s, 2H), 3.66 (s, 3H), 3.81 (s, 3H), 4.20–4.30 (m, 1H), 6.81–6.99 (m, 3H), 7.17–7.34 (m, 3H), 7.92–7.94 (m, 2H), 8.17–8.19 (m, 2H).

Workup

  1. concentrationThe mixture was concentrated in vacuo
  2. additionSat. NaHCO3 was added to the residue
  3. extractionextracted with CH2Cl2
  4. washThe extract was washed with brine
  5. dry with materialdried over Na2SO4
  6. concentrationconcentrated in vacuo
  7. customThe crude product was used to the subsequent reaction without further purification
  8. stirringThe reaction mixture was stirred at room temperature for 16 hr
  9. concentrationconcentrated in vacuo
  10. additionWater was added to the residue
  11. extractionextracted with EtOAc
  12. washThe extract was washed with sat. NaHCO3, 2-M citric acid, and sat. NaHCO3
  13. dry with materialdried over Na2SO4
  14. concentrationconcentrated in vacuo
  15. customThe residue was purified by column chromatography on silica gel with n-hexane-EtOAc (1:6, v/v) as eluent

Sources & evidence

ORD record
ord-2cf9ded32d8e4be8b2c1ea1b9bdbd818
Source dataset
uspto-grants-2007_02
Patent number
US07179819B2

Reaction notes

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