1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide → Ethyl (9aS)-4-[4-({[3-(1H-imidazol-1-yl)propyl]amino}carbonyl)phenyl]-5-oxo-2-{2-[4-(trifluoromethyl)phenyl]ethyl}-7,8,9,9a-tetrahydro-5H-pyrido[2,3-a]pyrrolizine-3-carboxylate

HRID 458453Notes

Reaction equation

HRID 458453 reaction equation
[CH2:1]([O:3][C:4]([C:6]1[C:18]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)=[N:17][C:9]2[C@H:10]3[N:14]([C:15](=[O:16])[C:8]=2[C:7]=1[C:31]1[CH:39]=[CH:38][C:34]([C:35]([OH:37])=O)=[CH:33][CH:32]=1)[CH2:13][CH2:12][CH2:11]3)=[O:5])[CH3:2].[CH3:40][CH2:41][N:42]=[C:43]=[N:44][CH2:45][CH2:46][CH2:47][N:48](C)C.NCCCN1C=CN=C1>ClCCl>[N:44]1([CH2:45][CH2:46][CH2:47][NH:48][C:35]([C:34]2[CH:38]=[CH:39][C:31]([C:7]3[C:8]4[C:15](=[O:16])[N:14]5[C@H:10]([C:9]=4[N:17]=[C:18]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=4)[C:6]=3[C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:11][CH2:12][CH2:13]5)=[CH:32][CH:33]=2)=[O:37])[CH:40]=[CH:41][N:42]=[CH:43]1

Participants

5

Reactant 3

HCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 787361H-Imidazole-1-propanamineHCID 695163224-((9aS)-3-(Ethoxycarbonyl)-5-oxo-2-{2-[4-(trifluoromethyl)phenyl]ethyl}-7,8,9,9a-tetrahydro-5H-pyrido[2,3-a]pyrrolizin-4-yl)benzoic acid

Product 1

HCID 86598171Ethyl (9aS)-4-[4-({[3-(1H-imidazol-1-yl)propyl]amino}carbonyl)phenyl]-5-oxo-2-{2-[4-(trifluoromethyl)phenyl]ethyl}-7,8,9,9a-tetrahydro-5H-pyrido[2,3-a]pyrrolizine-3-carboxylateYield 20%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a stirred solution of 4-((9aS)-3-(ethoxycarbonyl)-5-oxo-2-{2-[4 (trifluoromethyl)phenyl]ethyl}-7,8,9,9a-tetrahydro-5H-pyrido[2,3-α]pyrrolizin-4-yl)benzoic acid) Example 4C (0.050 g, 0.102 mmol) in 1 mL of dichloromethane, EDCI (0.023 g, 0.123 mmol) and 1-(3-aminopropyl)imidazole (0.026, 0.205 mmol)were added. The reaction mixture was allowed to stir for ˜3 h. The reaction mixture was concentrated and redissolved in 10 mL ethyl acetate. The organics were then washed with saturated aqueous NaHCO3 (2×) and brine. Filtration and concentration provided a brown oil which was purified by radial chromatography (dichloromethane/methanol (10:1)) to yield 0.013 g (20%) of the desired product as a tan solid: 1H NMR (CDCl3, 400 MHz) δ 7.89 (s, 2H), 7.52–7.50 (d, 2H, J=8.1), 7.39–7.37 (d, 2H, J=7.9), 7.32–7.29 (d, 2H, J=8.1), 7.89–6.89 (m, 2H), 4.73–4.70 (dd, 1H, J=6.4, J=10.3), 4.25 (bs, 2H), 4.04–3.92 (m, 2H), 3.72–3.60 (m, 1H), 3.52 (bs, 2H), 3.40–3.31 (m, 2H), 3.27–3.18(m, 4H), 2.51–2.41(m, 1H), 2.40–2.28 (m, 2H), 2.25–2.11 (m, 2H), 1.43–1.29 (m, 1H), 1.22 (s, 1H), 0.889–0.853 (t, 2H, J=7.2); low resolution MS (ES+) m/e 646 (MH+); TLC (CH2Cl2/MeOH (9:1)): Rf=0.24; RP-HPLC (BDS Hypersil C-18 25 cm×4.6 mm; 10–100% CH3CN in H2O with 0.1% TFA buffer; 30 minutes; 1 mL/min) tr=8.12 min, 96.6% purity.

Workup

  1. concentrationThe reaction mixture was concentrated
  2. dissolutionredissolved in 10 mL ethyl acetate
  3. washThe organics were then washed with saturated aqueous NaHCO3 (2×) and brine
  4. filtrationFiltration and concentration
  5. customprovided a brown oil which
  6. customwas purified by radial chromatography (dichloromethane/methanol (10:1))

Sources & evidence

ORD record
ord-5a84f1faba3149f88e03a3a7ef3ba7da
Source dataset
uspto-grants-2007_03
Patent number
US07189851B2

Reaction notes

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