HOAt → Ethyl 2-(2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)acetamido)acetate

HRID 931926Notes

Reaction equation

HRID 931926 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH2:21][CH:22]3[CH2:24][CH2:23]3)[C:11](=[O:25])[C@@H:10]([CH2:26][C:27](O)=[O:28])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Cl.[NH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].Cl.C(N=C=NCCCN(C)C)C.N1C2C(=NC=CC=2)N(O)N=1.C(=O)([O-])O.[Na+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH2:21][CH:22]3[CH2:23][CH2:24]3)[C:11](=[O:25])[C@@H:10]([CH2:26][C:27]([NH:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:28])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1

Participants

8

Reactant 5

HCID 181649HOAtHCID 516892Sodium BicarbonateHCID 2723640Glycine ethyl ester, hydrochlorideHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 56591370[(3r,5r,6s)-5-(3-Chlorophenyl)-6-(4-Chlorophenyl)-1-(Cyclopropylmethyl)-2-Oxopiperidin-3-Yl]acetic Acid

Product 1

HCID 56591217Ethyl 2-(2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)acetamido)acetate

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
25 °C

Procedure

A solution of 40 mg (93 μmol) of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)acetic acid (Example 35) and ethyl 2-aminoacetate hydrochloride (14 mg, 102 μmol) in DMF (0.31 mL) was treated at 0° C. with N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (27 mg, 139 μmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (19 mg, 139 μmol), and sodium hydrogencarbonate (23 mg, 278 μmol), successively. After being stirred at 25° C. for 12 h, the reaction was diluted with water and extracted with EtOAc. The combined organic layers were successively washed with 10% aq. citric acid solution, sat. aq. NaHCO3 solution and sat. aq. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Purification of the residue by flash chromatography (SiO2, 40% to 60% EtOAc/Hexanes, gradient elution) provided the title compound as a colorless film.

Workup

  1. extractionextracted with EtOAc
  2. washThe combined organic layers were successively washed with 10% aq. citric acid solution, sat. aq. NaHCO3 solution and sat. aq. NaCl solution
  3. dry with materialdried over Na2SO4
  4. filtrationfiltered
  5. concentrationthe filtrate was concentrated under reduced pressure
  6. customPurification of the residue
  7. washby flash chromatography (SiO2, 40% to 60% EtOAc/Hexanes, gradient elution)

Sources & evidence

ORD record
ord-2b2e4ca11549456d95f4dcabf4406867
Source dataset
uspto-grants-2016_03
Patent number
US09296736B2

Reaction notes

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