1,1'-Carbonyldiimidazole → HCID 57988373, compound

HRID 2081121Notes

Reaction equation

HRID 2081121 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH2:12][N:11]([C:16](=[O:30])[C@@H:17]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[C:18]([CH3:21])([CH3:20])[CH3:19])[CH:10]([C:31]([NH:33][C@:34]1([C:39](O)=[O:40])[CH2:36][C@H:35]1[CH:37]=[CH2:38])=[O:32])[CH2:9]2.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:57]1([S:60]([NH2:63])(=[O:62])=[O:61])[CH2:59][CH2:58]1.N12CCCN=C1CCCCC2>ClCCCl.CO.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH2:12][N:11]([C:16](=[O:30])[C@@H:17]([NH:22][C:23]1[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=1)[C:18]([CH3:19])([CH3:21])[CH3:20])[CH:10]([C:31]([NH:33][C@:34]1([C:39](=[O:40])[NH:63][S:60]([CH:57]3[CH2:59][CH2:58]3)(=[O:62])=[O:61])[CH2:36][C@H:35]1[CH:37]=[CH2:38])=[O:32])[CH2:9]2

Participants

7

Reactant 4

HCID 682631,1'-CarbonyldiimidazoleHCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 15765418CyclopropanesulfonamideHCID 57988391HCID 57988391, compound

Product 1

HCID 57988373HCID 57988373, compound

Reagents, catalysts & solvents 2

HCID 111,2-DichloroethaneSolventHCID 21584188Chloroform methanolSolvent

Conditions

Temperature
40 °C

Procedure

The crude (1R,2S)-1-(6-(3-chlorophenoxy)-2-((S)-2-(4-fluorophenylamino)-3,3-dimethylbutanoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamido)-2-vinylcyclopropanecarboxylic acid (112 mg, 0.180 mmol) was dissolved in 1.0 mL of 1,2-dichloroethane (DCE) and 1,1′-carbonyldiimidazole (CDI, 88 mg, 0.54 mmol) was added. The reaction was heated to 40° C. for 4 h. TLC run in 10% MeOH/CHCl3 showed conversion to a higher Rf spot. Cyclopropyl sulfonamide (65 mg, 0.54 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 81 μL, 0.54 mmol) were added and the reaction heated to 50° C. and stirred overnight. The reaction was concentrated to 400 μL volume and loaded on a Biotage size 12, C-18 samplet for purification using the Horizon LC (12 m, C-18 column) eluting with a gradient from 0% acetonitrile/water to 100% acetonitrile/water over 40-6 mL fractions. Upon concentration product is a white solid. Compound 10 (26 mg, 20%) 1H NMR (CDCl3, 500 MHz): δ 9.72 (br s, 1H), 7.32-7.22 (m, 1H), 7.20-7.07 (m, 2H), 7.02-6.68 (m, 7H), 6.58 (br s, 1H), 5.85-5.49 (m, 2H), 5.31-5.03 (m, 2H), 4.83-4.67 (m, 2H), 4.54-4.42 (m, 1H), 4.32 (br s, 1H), 4.18 (br s, 1H), 3.24-2.76 (m, 3H), 1.94 (br s, 1H), 1.86-1.18 (m, 5H), 1.17-0.95 (m, 10H); MS m/e 722 (M−−H).

Workup

  1. temperaturethe reaction heated to 50° C.
  2. concentrationThe reaction was concentrated to 400 μL volume
  3. customloaded on a Biotage size 12, C-18 samplet for purification
  4. washeluting with a gradient from 0% acetonitrile/water to 100% acetonitrile/water over 40-6 mL fractions
  5. concentrationUpon concentration product

Sources & evidence

ORD record
ord-a2012f2965de4bf7bb95b2cbf25bd9aa
Source dataset
uspto-grants-2011_04
Patent number
US07932277B2

Reaction notes

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