1,1'-Carbonyldiimidazole → tert-butyl (2R,6S,13aS,14aR,16aS,Z)-2-(biphenyl-4-yl)-2-(butylthio)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-ylcarbamate

HRID 1666534Notes

Reaction equation

HRID 1666534 reaction equation
[C:1]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:6]=[CH:5][C:4]([C@@:7]2([S:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:38][N:10]3[C:11](=[O:37])[C@@H:12]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH:19][C@@H:20]4[CH2:25][C@@:21]4([C:26](O)=[O:27])[NH:22][C:23](=[O:24])[C@@H:9]3[CH2:8]2)=[CH:3][CH:2]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:62]1([S:65]([NH2:68])(=[O:67])=[O:66])[CH2:64][CH2:63]1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[C:1]1([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:6]=[CH:5][C:4]([C@@:7]2([S:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:38][N:10]3[C:11](=[O:37])[C@@H:12]([NH:29][C:30](=[O:31])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH:19][C@@H:20]4[CH2:25][C@@:21]4([C:26](=[O:27])[NH:68][S:65]([CH:62]4[CH2:64][CH2:63]4)(=[O:67])=[O:66])[NH:22][C:23](=[O:24])[C@@H:9]3[CH2:8]2)=[CH:3][CH:2]=1

Participants

6

Reactant 4

HCID 682631,1'-CarbonyldiimidazoleHCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 15765418CyclopropanesulfonamideHCID 57988333(2R,6S,13aS,14aR,16aS,Z)-2-(biphenyl-4-yl)-6-(tert-butoxycarbonylamino)-2-(butylthio)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylic acid

Product 1

HCID 44511529tert-butyl (2R,6S,13aS,14aR,16aS,Z)-2-(biphenyl-4-yl)-2-(butylthio)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-ylcarbamateYield 63.8%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

A solution of (2R,6S,13aS,14aR,16aS,Z)-2-(biphenyl-4-yl)-6-(tert-butoxycarbonylamino)-2-(butylthio)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylic acid (15 mg, 0.022 mmol) and CDI (7.05 mg, 0.043 mmol) in tetrahydrofuran (1 mL) was heated to gentle reflux for 3 h. Cooled down to rt, cyclopropanesulfonamide (5.27 mg, 0.043 mmol) and DBU (9.83 μL, 0.065 mmol) were added and the reaction continued at r.t. overnight. Removed the solvent in vacuo. The residue was purified by prep-HPLC to afford the desired product tert-butyl (2R,6S,13aS,14aR,16aS,Z)-2-(biphenyl-4-yl)-2-(butylthio)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-ylcarbamate (11 mg, 0.014 mmol, 63.8% yield) as a white solid. 1H NMR (500 MHz, MeOD) δ ppm 0.84 (t, J=7.32 Hz, 3 H) 1.00-1.06 (m, 1 H) 1.09-1.17 (m, 2 H) 1.27-1.38 (m,5 H) 1.38-1.47 (m, 5 H) 1.46-1.63 (m, 14 H) 1.70 (dd, J=8.09, 5.34 Hz, 1 H) 1.86-2.00 (m, 2 H)2.24-2.33 (m, 1 H) 2.39-2.48 (m, 2 H) 2.50-2.58 (m, 1 H) 2.63 (s, 1 H) 2.88-2.97 (m, 2 H) 3.98-4.07 (m,2 H) 4.46 (d, J=9.46 Hz, 1 H) 5.08 (t, J=9.31 Hz, 1 H) 5.28 (d, J=10.38 Hz, 1 H) 5.65-5.75 (m, 1 H) 7.36 (t, J=7.48 Hz, 1 H) 7.46 (t, J=7.63 Hz, 2 H) 7.59 (d, J=8.55 Hz, 4 H) 7.79 (t, J=9.00 Hz, 2 H). LC-MS (retention time: 3.48 min, method C), MS m/z 793(M+H).

Workup

  1. temperatureto gentle reflux for 3 h
  2. customRemoved the solvent in vacuo
  3. customThe residue was purified by prep-HPLC

Sources & evidence

ORD record
ord-764398bd55664c319964cbe9cfd52194
Source dataset
uspto-grants-2011_10
Patent number
US08044023B2

Reaction notes

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