Sodium Chloride → Ethyl (9aS)-5-oxo-4-[4-({[(1S)-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 458403Notes

Reaction equation

HRID 458403 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.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[Na+].[Cl-]>CN(C=O)C>[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

6

Reactant 4

HCID 5234Sodium ChlorideHCID 1084921(S)-1-(4-Pyridyl)ethylamineHCID 2724699PyBOPHCID 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 44532691Ethyl (9aS)-5-oxo-4-[4-({[(1S)-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 48%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

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 (0.264 g, 0.491 mmol) was dissolved in 1 mL DMF. (1S)-1-(4-Pyridinyl)ethylamine (0.090 g, 0.736 mmol; prepared identically to its enantiomer, but starting with (R) α-methyl-1(4-pyridyl)methanol) was added followed by PyBOP (0.383 mg, 0.736 mmol). After 14 h, the reaction mixture was added to half-saturated NaCl solution and extracted with EtOAc (3×). The combined organic layers were washed with pH 4.0 phosphate buffer (2×), 5% NaHCO3, and brine and dried over Na2SO4. Purification on SiO2 (hexanes:EtOAc 20:80 to 0:100 to) provided the title compound as a white solid (0.153 g, 0.238 mmol, 48%): mp=158–160° C. 1H NMR (300 MHz, CDCl3) δ 8.62 (d, J=5.7 Hz, 2H), 7.86 (d, J=8.1 Hz, 2H), 7.57 (d, J=8.1 Hz, 2H), 7.49 (d, J=8.1 Hz, 2H), 7.37 (d, J=8.1 Hz, 2H), 7.33 (d, J=5.5 Hz, 2H), 6.52 (d, J=7.5 Hz, 1H), 5.33 (m, 1H), 4.75 (dd, J=10.3, 6.3 Hz, 1H), 4.06 (m, 2H), 3.75 (m, 1H), 3.41 (m, 1H), 3.22 (m, 4H), 2.52 (m, 1H), 2.40 (m, 2H), 1.63 (d, J=7.0 Hz, 3H), 1.40 (m, 1H), 0.97 (t, J=7.1 Hz, 3H) ppm. ESMS m/z 643 (M+H)+. Anal. calcd. for C36H33F3N4O4.½H2O: C, 66.35; H, 5.26; N, 8.60; found: C, 66.35; H, 5.42; N, 8.79.

Workup

  1. customprepared identically to its enantiomer
  2. additionwas added
  3. extractionextracted with EtOAc (3×)
  4. washThe combined organic layers were washed with pH 4.0 phosphate buffer (2×), 5% NaHCO3, and brine
  5. dry with materialdried over Na2SO4
  6. customPurification on SiO2 (hexanes:EtOAc 20:80 to 0:100 to)

Sources & evidence

ORD record
ord-7cd46a19cf2e41fdb66f5035420f74b6
Source dataset
uspto-grants-2007_03
Patent number
US07189851B2

Reaction notes

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