1,8-Diazabicyclo(5.4.0)undec-7-ene → HCID 68172046, compound

HRID 1429101Notes

Reaction equation

HRID 1429101 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]([O:28][C:29]3[N:30]=[C:31]4[C:36](=[C:37]5[C:42]=3[CH:41]=[CH:40][CH:39]=[CH:38]5)[CH:35]=[CH:34][CH:33]=[CH:32]4)[CH2:27][C@H:21]2[C:20](=[O:43])[NH:19][C@:18]2([C:45](O)=[O:46])[CH2:44][C@H:17]2[CH2:16][C:15]([F:49])([F:48])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:50]1([S:53]([NH2:56])(=[O:55])=[O:54])[CH2:52][CH2:51]1.N1CCCN2CCCCCC=12>ClC(Cl)C>[CH:50]1([S:53]([NH:56][C:45]([C@@:18]23[CH2:44][C@H:17]2[CH2:16][C:15]([F:49])([F:48])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:23](=[O:24])[N:22]2[CH2:25][C@H:26]([O:28][C:29]4[N:30]=[C:31]5[C:36](=[C:37]6[C:42]=4[CH:41]=[CH:40][CH:39]=[CH:38]6)[CH:35]=[CH:34][CH:33]=[CH:32]5)[CH2:27][C@H:21]2[C:20](=[O:43])[NH:19]3)=[O:46])(=[O:55])=[O:54])[CH2:52][CH2:51]1

Participants

5

Reactant 3

HCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 15765418CyclopropanesulfonamideHCID 68008421HCID 68008421, compound2×

Product 1

HCID 68172046HCID 68172046, compoundYield 79%

Reagents, catalysts & solvents 1

HCID 63651,1-DichloroethaneSolvent

Procedure

A solution of (2R,6S,13aS,14aR,16aS)-6-(tert-butoxycarbonylamino)-12,12-difluoro-5,16-dioxo-2-(phenanthridin-6-yloxy)octadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxylic acid (215 mg, 0.316 mmol) and di(1H-imidazol-1-yl)methanone (Example 19d, 114 mg, 0.701 mmol) in dichloroethane (2 mL) was stirred for 2 h at room temperature. To this mixture was added cyclopropanesulfonamide (115 mg, 0.948 mmol) and 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (0.143 mL, 0.948 mmol, dried with 4 A sieves powder at 42° C. for 2 h prior to usage), and the solution was stirred for 2 h. The reaction mixture was diluted with ethyl acetate (7 mL) and washed with 10 mL of 0.1 N HCl followed by saturated aqueous sodium chloride solution. The organic layer was dried with anhydrous sodium sulfate, filtered, and evaporated under reduced pressure leaving 0.23 g crude solid which was purified via flash chromatography on silica gel (3% methanol/dichloromethane) to provide the title compound tert-butyl (2R,6S ,13aS,14aR,16aS)-14a-(cyclopropylsulfonylcarbamoyl)-12,12-difluoro-5,16-dioxo-2-(phenanthridin-6-yloxy)octadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecin-6-ylcarbamate (195 mg, 0.249 mmol, 79% yield). MS (ESI): m/z=784.1 [M+H]. Example 19 provided an IC50 of <0.1 nM in a 1a enzyme assay; an IC50 of <0.1 0 nM in a 1b enzyme assay; a HLM stability value of >100 μl/min/mg; an EC50 of <1.0 nM in a replicon cell line assay in a 1a-H77 background, and an EC50 of <1.0 nM in a replicon cell line assay in a 1-con1 background.

Workup

  1. customdried with 4 A sieves powder at 42° C. for 2 h
  2. additionThe reaction mixture was diluted with ethyl acetate (7 mL)
  3. washwashed with 10 mL of 0.1 N HCl
  4. dry with materialThe organic layer was dried with anhydrous sodium sulfate
  5. filtrationfiltered
  6. customevaporated under reduced pressure
  7. customleaving 0.23 g crude solid which
  8. customwas purified via flash chromatography on silica gel (3% methanol/dichloromethane)

Sources & evidence

ORD record
ord-6ab1c1cc415646dc87d18c705a70bc56
Source dataset
uspto-grants-2015_01
Patent number
US08937041B2

Reaction notes

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