1,1'-Carbonyldiimidazole → (2R,6S,13aS,14aR,16aS,Z)-ethyl 6-(tert-butoxycarbonylamino)-2-(4-fluoroisoindoline-2-carbonyloxy)-5,16-dioxo-2,3,5,6,7,8,10,11,13a,14,14a,15,16,16a-tetradecahydro-1H-cyclopropa(j)pyrrolo[1,2-f][1,6,9]oxadiazacyclopentadecine-14a-carboxylate

HRID 2069174Notes

Reaction equation

HRID 2069174 reaction equation
[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:23](=[O:24])[N:22]2[CH2:25][C@H:26]([OH:28])[CH2:27][C@H:21]2[C:20](=[O:29])[NH:19][C@:18]2([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:30][C@H:17]2[CH:16]=[CH:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1([C:41]([N:43]2[CH:47]=[CH:46]N=[CH:44]2)=[O:42])C=CN=C1.C(N(C(C)C)C(C)C)C.Cl.[F:58][C:59]1[CH:67]=CC=[C:64]2[C:60]=1CN[CH2:63]2>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:23](=[O:24])[N:22]2[CH2:25][C@H:26]([O:28][C:41]([N:43]3[CH2:44][C:67]4[C:46](=[CH:63][CH:64]=[CH:60][C:59]=4[F:58])[CH2:47]3)=[O:42])[CH2:27][C@H:21]2[C:20](=[O:29])[NH:19][C@:18]2([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:30][C@H:17]2[CH:16]=[CH:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]

Participants

6

Reactant 4

HCID 682631,1'-CarbonyldiimidazoleHCID 81531DiisopropylethylamineHCID 426096434-Fluoro-1H-isoindoline hydrochlorideHCID 68789721(2R,6S,13aS,14aR,16aS,Z)-ethyl 6-(tert-butoxycarbonylamino)-2-hydroxy-5,16-dioxo-2,3,5,6,7,8,10,11,13a,14,14a,15,16,16a-tetradecahydro-1H-cyclopropa(j)pyrrolo[1,2-f][1,6,9]oxadiazacyclopentadecine-14a-carboxylate

Product 1

HCID 68787314(2R,6S,13aS,14aR,16aS,Z)-ethyl 6-(tert-butoxycarbonylamino)-2-(4-fluoroisoindoline-2-carbonyloxy)-5,16-dioxo-2,3,5,6,7,8,10,11,13a,14,14a,15,16,16a-tetradecahydro-1H-cyclopropa(j)pyrrolo[1,2-f][1,6,9]oxadiazacyclopentadecine-14a-carboxylateYield 76.7%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Procedure

(2R,6S,13aS,14aR,16aS,Z)-ethyl 6-(tert-butoxycarbonylamino)-2-hydroxy-5,16-dioxo-2,3,5,6,7,8,10,11,13a,14,14a,15,16,16a-tetradecahydro-1H-cyclopropa(j)pyrrolo[1,2-f][1,6,9]oxadiazacyclopentadecine-14a-carboxylate (0.096 g, 0.19 mmol) in toluene (5 mL) was added di(1H-imidazol-1-yl)methanone (0.041 g, 0.25 mmol) in one portion. The reaction was stirred at rt for 3 hrs. To the reaction was then added the N-ethyl-N-isopropylpropan-2-amine (0.17 ml, 0.99 mmol), followed by 4-Fluoroisoindoline hydrochloride (0.11 g, 0.38 mmol). The reaction was stirred at 60° C. for 3 hrs. The solvent was removed. The residue was partitioned between ethyl acetate (20 mL) and saturated sodium bicarbonate solution. The organic layer was separated and dried over sodium sulfate. After removal of solvent, the residue was purified by chromatography (Hexane:Ethyl acetate=1:3) to give (2R,6S,13aS,14aR,16aS,Z)-ethyl 6-(tert-butoxycarbonylamino)-2-(4-fluoroisoindoline-2-carbonyloxy)-5,16-dioxo-2,3,5,6,7,8,10,11,13a,14,14a,15,16,16a-tetradecahydro-1H-cyclopropa(j)pyrrolo[1,2-f][1,6,9]oxadiazacyclopentadecine-14a-carboxylate as white solid (0.096 g, 75%). MS: Calcd.: 658. Found: [M+H]+ 659.

Workup

  1. stirringThe reaction was stirred at 60° C. for 3 hrs
  2. customThe solvent was removed
  3. customThe residue was partitioned between ethyl acetate (20 mL) and saturated sodium bicarbonate solution
  4. customThe organic layer was separated
  5. dry with materialdried over sodium sulfate
  6. customAfter removal of solvent
  7. customthe residue was purified by chromatography (Hexane:Ethyl acetate=1:3)

Sources & evidence

ORD record
ord-af683391c87b46bc90e04c3e3ff22e02
Source dataset
uspto-grants-2012_10
Patent number
US08299021B2

Reaction notes

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