Hydrochloric Acid → HCID 57414888, compound

HRID 1429075Notes

Reaction equation

HRID 1429075 reaction equation
[NH2:1][C@@H:2]1[C:16](=[O:17])[N:15]2[CH2:18][C@H:19]([O:21][C:22]3[CH:31]=[N:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=3)[CH2:20][C@H:14]2[C:13](=[O:32])[NH:12][C@:11]2([C:34]([NH:36][S:37]([CH:40]3[CH2:42][CH2:41]3)(=[O:39])=[O:38])=[O:35])[CH2:33][C@H:10]2[CH2:9][C:8]([F:44])([F:43])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.Cl.N1C=CC=CC=1.[CH3:52][C:53]1[O:57][N:56]=[C:55]([C:58](O)=[O:59])[CH:54]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[CH:40]1([S:37]([NH:36][C:34]([C@@:11]23[CH2:33][C@H:10]2[CH2:9][C:8]([F:43])([F:44])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]([NH:1][C:58]([C:55]2[CH:54]=[C:53]([CH3:52])[O:57][N:56]=2)=[O:59])[C:16](=[O:17])[N:15]2[CH2:18][C@H:19]([O:21][C:22]4[CH:31]=[N:30][C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[N:23]=4)[CH2:20][C@H:14]2[C:13](=[O:32])[NH:12]3)=[O:35])(=[O:39])=[O:38])[CH2:42][CH2:41]1

Participants

8

Reactant 5

HCID 313Hydrochloric Acid2×HCID 1049PyridineHCID 769473-Methyl-5-isoxazolecarboxylic acidHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 68008839HCID 68008839, compound

Product 1

HCID 57414888HCID 57414888, compoundYield 86%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of (2R,6S,13aS,14aR,16aS)-6-amino-N-(cyclopropylsulfonyl)-12,12-difluoro-5,16-dioxo-2-(quinoxalin-2-yloxy)octadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide, Hydrochloric Acid (Example 2a, 8.05 mg, 0.012 mmol) in DMF (120 μl) was added pyridine (7 μl, 0.087 mmol) followed by 5-methylisoxazole-3-carboxylic acid (2.28 mg, 0.018 mmol) and then HATU (7.04 mg, 0.019 mmol). The reaction mixture was stirred at room temperature overnight, diluted with ethyl acetate, cooled to 0° C. and neutralized with HCl (4 N in dioxane, 22 μl; diluted with ethyl acetate). The mixture was concentrated and purified by prep-TLC (ethyl acetate) to provide the title compound N-((2R,6S,13aS,14aR,16aS)-14a-(cyclopropylsulfonylcarbamoyl)-12,12-difluoro-5,16-dioxo-2-(quinoxalin-2-yloxy)octadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)-5-methylisoxazole-3-carboxamide (7.65 mg, 10.29 μmol, 86% yield) MS (ESI): m/z=744.3 [M+H]. Example 2 provided an IC50 of >1.0 nM in a 1a enzyme assay; an IC50 of >1.0 nM in a 1b enzyme assay; a HLM stability value of <50 μl/min/mg; an EC50 of >5.0 nM in a replicon cell line assay in a 1a-H77 background, and an EC50 of >5.0 nM in a replicon cell line assay in a 1b-con1 background.

Workup

  1. concentrationThe mixture was concentrated
  2. custompurified by prep-TLC (ethyl acetate)

Sources & evidence

ORD record
ord-7650bae5fd4247a4a2fb56ff15c66a59
Source dataset
uspto-grants-2015_01
Patent number
US08937041B2

Reaction notes

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