1,2-Dichloroethane → Ethyl (9aS)-5-oxo-4-[4-({[(1R)-1-(4-pyridinyl)ethyl]amino}carbonyl)phenyl]-2-{2-[4-(trifluoromethyl)phenyl]ethyl}-7,8,9,9a-tetrahydro-5H-pyrido[2,3-a]pyrrolizine-3-carboxylate

HRID 458402Notes

Reaction equation

HRID 458402 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].[N:40]1[CH:45]=[CH:44][C:43]([C@H:46]([NH2:48])[CH3:47])=[CH:42][CH:41]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl.CCOC(C)=O.CO>[O:16]=[C:15]1[N:14]2[C@@H:10]([CH2:11][CH2:12][CH2:13]2)[C:9]2[N:17]=[C:18]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:7]([C:31]3[CH:39]=[CH:38][C:34]([C:35]([NH:48][C@@H:46]([C:43]4[CH:44]=[CH:45][N:40]=[CH:41][CH:42]=4)[CH3:47])=[O:37])=[CH:33][CH:32]=3)[C:8]1=2

Participants

7

Reactant 4

HCID 111,2-DichloroethaneHCID 757711-HydroxybenzotriazoleHCID 1084922(R)-1-(4-Pyridyl)ethylamineHCID 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 86598163Ethyl (9aS)-5-oxo-4-[4-({[(1R)-1-(4-pyridinyl)ethyl]amino}carbonyl)phenyl]-2-{2-[4-(trifluoromethyl)phenyl]ethyl}-7,8,9,9a-tetrahydro-5H-pyrido[2,3-a]pyrrolizine-3-carboxylateYield 36.3%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 21584119Ethylacetate methanolSolvent

Procedure

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 (0.178 g, 0.331 mmol) was dissolved in 4 mL DCM. (1R)-1-(4-Pyridinyl)ethylamine (0.081 g, 0.661 mmol) was added followed by HOBT (0.054 g, 0.397 mmol) and EDC (0.076 mg, 0.397 mmol). After 3 h, the reaction mixture was washed with pH 4.0 phosphate buffer (2×), 5% NaHCO3, and brine and dried over MgSO4. Purification on SiO2 (EtOAc 100% to EtOAc:MeOH:NH4OH 95:5:0.3) then by TLC (SiO2; EtOAc:MeOH 95:5) provided the title compound as a tan solid (0.077 g, 0.12 mmol, 36%): 1H NMR (400 MHz, CDCl3) δ 8.52 (d, J=6.0 Hz, 2H), 7.80 (d, J=8.0 Hz, 2H), 7.51 (d, J=8.0 Hz, 2H), 7.42 (d, J=8.4 Hz, 2H), 7.30 (d, J=8.4 Hz, 2H), 7.27 (d, J=4.4 Hz, 2H), 6.51 (d, J=7.2 Hz, 1H), 5.27 (m, 1H), 4.69 (dd, J=10.4, 6.4 Hz, 1H), 3.99 (m, 2H), 3.66 (m, 1H), 3.35 (m, 1H), 3.18 (m, 2H), 3.14 (m, 1H), 2.45 (m, 1H), 2.33 (m, 2H), 1.7 (bs, 1NH, 2H2O), 1.56 (d, J=6.8 Hz, 3H), 1.35 (m, 1H), 0.91 (t, J=6.8 Hz, 3H) ppm. ESMS m/z (pos. ion) 643 (M+H)+, (neg. ion) 641 (M−H)+.

Workup

  1. washthe reaction mixture was washed with pH 4.0 phosphate buffer (2×), 5% NaHCO3, and brine
  2. dry with materialdried over MgSO4
  3. customPurification on SiO2 (EtOAc 100% to EtOAc:MeOH:NH4OH 95:5:0.3)

Sources & evidence

ORD record
ord-307bdd02757d46f6bce27a23d41cea59
Source dataset
uspto-grants-2007_03
Patent number
US07189851B2

Reaction notes

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