Hydrochloric Acid → (1r)-Cyclopropanecarboxylic acid {2-[1-(3-ethoxy-4-methoxy-phenyl)-3-hydroxy-3-methyl-butyl]-3-oxo-2,3-dihydro-1h-isoindol-4-yl}-amide

HRID 1797250Notes

Reaction equation

HRID 1797250 reaction equation
C(O[C:6](=[O:25])[NH:7][C@@H:8]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH2:23][CH3:24])[CH:15]=1)[CH2:9][C:10]([OH:13])([CH3:12])[CH3:11])(C)(C)C.Cl.O1CCOCC1.COC(=O)[C:36]1[C:41]([NH:42][C:43]([CH:45]2[CH2:47][CH2:46]2)=[O:44])=[CH:40][CH:39]=[CH:38][C:37]=1[CH2:48]Br.C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[CH2:23]([O:22][C:16]1[CH:15]=[C:14]([C@H:8]([N:7]2[C:6](=[O:25])[C:36]3[C:37](=[CH:38][CH:39]=[CH:40][C:41]=3[NH:42][C:43]([CH:45]3[CH2:47][CH2:46]3)=[O:44])[CH2:48]2)[CH2:9][C:10]([OH:13])([CH3:11])[CH3:12])[CH:19]=[CH:18][C:17]=1[O:20][CH3:21])[CH3:24]

Participants

8

Reactant 5

HCID 313Hydrochloric AcidHCID 8471TriethylamineHCID 312751,4-DioxaneHCID 669203212-Bromomethyl-6-(cyclopropanecarbonyl-amino)-benzoic acid methyl esterHCID 68687518(R)-[1-(3-ethoxy-4-methoxy-phenyl)-3-hydroxy-3-methyl-butyl]-carbamic acid tert-butyl ester

Product 1

HCID 10253337(1r)-Cyclopropanecarboxylic acid {2-[1-(3-ethoxy-4-methoxy-phenyl)-3-hydroxy-3-methyl-butyl]-3-oxo-2,3-dihydro-1h-isoindol-4-yl}-amideYield 52.6%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
80 °C

Procedure

To a solution of (1R)-[1-(3-ethoxy-4-methoxy-phenyl)-3-hydroxy-3-methyl-butyl]-carbamic acid tert-butyl ester (150 mg, 0.42 mmol) in methylene chloride (5 mL) was added a solution of HCl in dioxane (0.5 mL, 4N, 2 mmol). After 2 hrs, the solvent was removed and the crude oil was used in the next step without further purification. A mixture of the resulted oil, 2-bromomethyl-6-(cyclopropanecarbonyl-amino)-benzoic acid methyl ester (130 mg, 0.42 mmol) and triethyl amine (0.12 mL, 0.86 mmol) in DMF (3 mL) was heated at 80° C. for 27 hrs. The solvent was removed in vacuo. The residue was extracted with ethyl acetate (50 mL) and 1N HCl (50 mL). The organic layer was washed with 1N HCl (50 mL), brine (50 mL), and dried over MgSO4. The solvent was removed in vacuo. The residue was purified with Preparative HPLC to give (1R)-cyclopropanecarboxylic acid {2-[1-(3-ethoxy-4-methoxy-phenyl)-3-hydroxy-3-methyl-butyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide (100 mg, 51% yield): mp, 90–92° C.; 1H NMR (CDCl3) δ 0.85–0.93 (m, 2H, CH2), 1.08–1.13 (m, 2H, CH2), 1.25 (s, 3 H, CH3), 1,34 (s, 3H,CH3), 1.45 (t, J=7 Hz, 3H, CH3), 1.67–1.74 (m, 1H, CH), 2.18 (dd, J=4, 14 Hz 1H, CHH), 2.32 (dd, J=9, 14 Hz, 1H, CHH), 2.38 (s, 1H, OH), 3.86 (s, 3H, CH3), 3.94 (d, J=17 Hz, 1H, NCHH), 4.07 (q, J=7 Hz, 2H, CH2), 4.36 (d, J=17 Hz, 1H, NCHH), 5.70 (dd, J=4, 9 Hz, 1H, NCH), 6.82–6.99 (m, 4H, Ar), 7.41 (t, J=8 Hz, 1H, Ar), 8.42 (d, J=8 Hz, 1H, Ar), 10.58 (s, 1H, NH); 13C NMR (CDCl3) δ 8.27, 14.78, 16.19, 29.98, 30.22, 43.95, 46.13, 50.96, 55.98, 64.60, 70.02, 111.43, 112.90, 116.71, 117.51, 117.69, 119.72, 132.48, 133.16, 137.99, 141.50, 148.50, 149.12, 169.63, 172.72; Anal Calcd for C26H32N2O5+1.1 H2O: C, 66.11; H, 7.30; N, 5.93. Found: C, 65.73; H, 6.90; N, 5.82.

Workup

  1. customthe solvent was removed
  2. customthe crude oil was used in the next step without further purification
  3. customThe solvent was removed in vacuo
  4. extractionThe residue was extracted with ethyl acetate (50 mL) and 1N HCl (50 mL)
  5. washThe organic layer was washed with 1N HCl (50 mL), brine (50 mL)
  6. dry with materialdried over MgSO4
  7. customThe solvent was removed in vacuo
  8. customThe residue was purified with Preparative HPLC

Sources & evidence

ORD record
ord-6e1b773f31f146f49b99dbb409f3a6c2
Source dataset
uspto-grants-2006_04
Patent number
US07034052B2

Reaction notes

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