Hydrochloric Acid → Ethyl(9aS)-4-(5-{[(1R)-2,3-dihydro-1H-inden-1-ylamino]carbonyl}-2-thienyl)-2-[2-(4-fluorophenyl)ethyl]-5-oxo-7,8,9,9a-tetrahydro-5H-pyrido[2,3-a]pyrrolizine-3-carboxylate

HRID 458421Notes

Reaction equation

HRID 458421 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]([F:27])=[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:28]1[S:32][C:31]([C:33]([OH:35])=O)=[CH:30][CH:29]=1)[CH2:13][CH2:12][CH2:11]3)=[O:5])[CH3:2].CCN=C=[N:40][CH2:41][CH2:42][CH2:43]N(C)C.[CH:47]1[CH:48]=[CH:49][C:50]2N(O)N=N[C:51]=2[CH:52]=1.Cl>C(Cl)Cl>[C@H:41]1([NH:40][C:33]([C:31]2[S:32][C:28]([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]([F:27])=[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:29][CH:30]=2)=[O:35])[C:51]2[C:50](=[CH:49][CH:48]=[CH:47][CH:52]=2)[CH2:43][CH2:42]1

Participants

6

Reactant 4

HCID 313Hydrochloric AcidHCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 695166925-{(9aS)-3-(ethoxycarbonyl)-2-[2-(4-fluorophenyl)ethyl]-5-oxo-7,8,9,9a-tetrahydro-5H-pyrido[2,3-a]pyrrolizin-4-yl}-2-thiophenecarboxylic acid

Product 1

HCID 10240118Ethyl(9aS)-4-(5-{[(1R)-2,3-dihydro-1H-inden-1-ylamino]carbonyl}-2-thienyl)-2-[2-(4-fluorophenyl)ethyl]-5-oxo-7,8,9,9a-tetrahydro-5H-pyrido[2,3-a]pyrrolizine-3-carboxylate

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

5-{(9aS)-3-(ethoxycarbonyl)-2-[2-(4-fluorophenyl)ethyl]-5-oxo-7,8,9,9a-tetrahydro-5H-pyrido[2,3-a]pyrrolizin-4-yl}-2-thiophenecarboxylic acid (0.100 g, 0.202 mmol) was dissolved in CH2Cl2 (2 mL). R-(−)-1-aminoindane (0.026 mL, 0.303 mmol) was added followed by EDCI (0.047 g, 0.243 mmol) and HOBt (0.033 g, 0.243 mmol). After 14 h of stirring at ambient temperature the reaction mixture was poured onto 5% HCl solution and extracted with CH2Cl2. The organics were washed with sat'd NaHCO3, brine and then dried (Na2SO4), filtered and concentrated to a brown residue. Chromatography on silica gel using 4:1 EtOAc:Hexanes eluted the product to provide the title compound upon concentration as a white solid (0.066 g, 0.108 mmol, 54% yield): 1H NMR (CDCl3, 400 MHz) δ 7.48 (d, J=3.7 Hz, 1H), 7.36 (d, J=6.7 Hz, 1H), 7.28–7.20 (m, 2H), 7.19–15 (m, 3H), 6.97 (t, J=8.6 Hz, 2H), 6.24–6.20 (m, 1H), 5.67 (dd, J=15.3, 7.6 Hz, 1H), 4.69 (dd, J=10.3, 6.4 Hz, 1H), 4.19 (dd, J=14.3, 7.1), 3.76–3.66 (m, 1H), 3.42–3.36 (m, 1H), 3.18–3.01 (m, 5H), 2.96–2.87 (m, 1H), 2.71–2.66 (m, 1H), 2.48–2.40 (m, 1H), 2.37–2.25 (m, 2H), 1.96–1.86 (m, 1H), 1.42–1.35 (m, 1H), 1.13 (t, J=7.1 Hz, 3H); ESMS m/z 610 (M+H)+, 608 (M−H)+; Anal. Calcd. For C35H32F1N3O4S.½H2O: C 67.94 H, 5.38; N, 6.79; found C, 68.09 H 5.31 N 6.80.

Workup

  1. extractionextracted with CH2Cl2
  2. washThe organics were washed with sat'd NaHCO3, brine
  3. dry with materialdried (Na2SO4)
  4. filtrationfiltered
  5. concentrationconcentrated to a brown residue
  6. washChromatography on silica gel using 4:1 EtOAc:Hexanes eluted the product

Sources & evidence

ORD record
ord-26a774427cc042da9e960d73065d47bf
Source dataset
uspto-grants-2007_03
Patent number
US07189851B2

Reaction notes

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