Pyridine → HCID 25060454, compound

HRID 448507Notes

Reaction equation

HRID 448507 reaction equation
[C:1]([CH2:4][CH2:5][C@H:6]([N:10]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[CH2:20][NH:21][C:22]([CH:24]2[CH2:26][CH2:25]2)=[O:23])[C:11]1=[O:27])[C:7]([OH:9])=O)(=[O:3])[NH2:2].S(Cl)(Cl)=O.N1C=CC=CC=1.C(N(CC)CC)C>C(Cl)Cl>[O:9]=[C:7]1[C@@H:6]([N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[CH2:20][NH:21][C:22]([CH:24]3[CH2:26][CH2:25]3)=[O:23])[C:11]2=[O:27])[CH2:5][CH2:4][C:1](=[O:3])[NH:2]1

Participants

6

Reactant 4

HCID 1049PyridineHCID 8471TriethylamineHCID 24386Thionyl ChlorideHCID 67229349HCID 67229349, compound

Product 1

HCID 25060454HCID 25060454, compoundYield 74.1%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
-40 °C

Procedure

A suspension of (2S)-4-carbamoyl-2-{4-[(cyclopropanecarbonyl-amino)-methyl]-1,3-dioxo-1,3-dihydro-isoindol-2-yl}-butyric acid (1.4 g, 3.8 mmol) in dry CH2Cl2 (87 mL) was cooled to −40° C. with IPA/dry ice bath. Thionyl chloride (0.5 g, 4.1 mmol) was added dropwise, followed by pyridine (0.3 g, 4.1 mmol). The mixture was stirred at −40° C. for 30 minutes. Triethylamine (0.4 g, 4.2 mmol) was added dropwise, and the mixture was stirred at −30 to −40° C. for 3 hours. The mixture was filtered into ice water (150 mL). The aqueous layer was extracted with CH2Cl2 (40 mL), and the combined CH2Cl2 solution was washed with H2O (2×40 mL) and brine (40 mL), and dried (MgSO4). Solvent was removed, and the solid was slurried with ethanol (20 mL) to give cyclopropanecarboxylic acid {2-((3S)-2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-amide (1.0 g, 74%) as a white solid: mp 219-221° C.; Chiral HPLC: Daicel ChiralPak AD, 46×250 mm, 70/30 IPA/hexane, 0.6 mL/min, 19.76 min (98.5% ee); 1H NMR (DMSO-d6) δ 0.69-0.72 (m, 4H), 1.61-1.71 (m, 1H), 2.04-2.08 (m, 1H), 2.50-2.63 (m, 2H), 2.83-2.97 (m, 1H), 4.74 (d, J=5.7 Hz, 2H, CH2), 5.11-5.18 (dd, J=5.2 and 12.4 Hz, 1H, CH), 7.67-7.88 (m, 3H, Ar), 8.69 (t, J=5.6 Hz, 1H, NH), 11.13 (s, 1H, NH); 13C NMR (DMSO-d6) δ 6.41, 13.50, 21.96, 30.91, 37.74, 48.84, 121.84, 127.08, 131.51, 133.31, 134.76, 139.39, 166.92, 167.44, 169.78, 172.72, 173.09; Anal. calcd. for C18H17N3O5: C, 60.84; H, 4.82; N, 11.82. Found: C, 60.49; H, 4.76; N, 11.51.

Workup

  1. stirringthe mixture was stirred at −30 to −40° C. for 3 hours
  2. filtrationThe mixture was filtered into ice water (150 mL)
  3. extractionThe aqueous layer was extracted with CH2Cl2 (40 mL)
  4. washthe combined CH2Cl2 solution was washed with H2O (2×40 mL) and brine (40 mL)
  5. dry with materialdried (MgSO4)
  6. customSolvent was removed

Sources & evidence

ORD record
ord-8a52bf51f9cf4f36a35700b02e577e84
Source dataset
uspto-grants-2013_07
Patent number
US08481568B2

Reaction notes

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