Hydrochloric Acid → HCID 57415627, compound

HRID 1429103Notes

Reaction equation

HRID 1429103 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[N:23]=[C:24]4[C:29](=[C:30]5[C:35]=3[CH:34]=[CH:33][CH:32]=[CH:31]5)[CH:28]=[CH:27][CH:26]=[CH:25]4)[CH2:20][C@H:14]2[C:13](=[O:36])[NH:12][C@:11]2([C:38]([NH:40][S:41]([CH:44]3[CH2:46][CH2:45]3)(=[O:43])=[O:42])=[O:39])[CH2:37][C@H:10]2[CH2:9][C:8]([F:48])([F:47])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.Cl.[CH3:50][N:51]1[C:55]([CH3:56])=[CH:54][C:53]([C:57](O)=[O:58])=[N:52]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C>ClCCl>[CH:44]1([S:41]([NH:40][C:38]([C@@:11]23[CH2:37][C@H:10]2[CH2:9][C:8]([F:47])([F:48])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]([NH:1][C:57]([C:53]2[CH:54]=[C:55]([CH3:56])[N:51]([CH3:50])[N:52]=2)=[O:58])[C:16](=[O:17])[N:15]2[CH2:18][C@H:19]([O:21][C:22]4[N:23]=[C:24]5[C:29](=[C:30]6[C:35]=4[CH:34]=[CH:33][CH:32]=[CH:31]6)[CH:28]=[CH:27][CH:26]=[CH:25]5)[CH2:20][C@H:14]2[C:13](=[O:36])[NH:12]3)=[O:39])(=[O:43])=[O:42])[CH2:46][CH2:45]1

Participants

7

Reactant 5

HCID 313Hydrochloric Acid2×HCID 81531DiisopropylethylamineHCID 5877571,5-dimethyl-1H-pyrazole-3-carboxylic acidHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 68009051HCID 68009051, compound

Product 1

HCID 57415627HCID 57415627, compoundYield 60%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a mixture of (2R,6S,13aS,14aR,16aS)-6-amino-N-(cyclopropylsulfonyl)-12,12-difluoro-5,16-dioxo-2-(phenanthridin-6-yloxy)octadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide, Hydrochloric Acid (Example 20a, 12 mg, 0.017 mmol), 1,5-dimethyl-1H-pyrazole-3-carboxylic acid (2.57 mg, 0.018 mmol) and 2-(3H-[1,2,3]triazolo [4,5-b]pyridin-3-yl)-1,1,3 ,3-tetramethylisouronium hexafluorophosphate(V) (7.0 mg, 0.018 mmol)in dichloromethane (167 μl) was added N-ethyl-N-isopropylpropan-2-amine (10.18 μl, 0.058 mmol) and the mixture was stirred for 3 h at room temperature. 0.1 N HCl was added and organic layer was separated, dried over anhydrous sodium sulfate, and filtered. The residue after solvent evaporation under reduced pressure was eluted through silica gel with 10% acetone/dichloromethane. The fractions containing the title compound were combined and the resulting crude material was purified by preparative thin layer chromatography on silica gel (20:1 dichloromethane/methanol) to provide the title compound (2R,6S,13aS,14aR,16aS)-N-(cyclopropylsulfonyl)-6-(1,5-dimethyl-1H-pyrazole-3-carboxamido)-12,12-difluoro-5,16-dioxo-2-(phenanthridin-6-yloxy)octadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide (8 mg 60% yield) as a white solid. MS (ESI): m/z=806.1 [M+H]. Example 21 provided a HLM stability value of <50 μl/min/mg; an EC50 of between 2.0 and 5.0 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 1b-con1 background.

Workup

  1. customorganic layer was separated
  2. dry with materialdried over anhydrous sodium sulfate
  3. filtrationfiltered
  4. customThe residue after solvent evaporation under reduced pressure
  5. washwas eluted through silica gel with 10% acetone/dichloromethane
  6. additionThe fractions containing the title compound
  7. customthe resulting crude material was purified by preparative thin layer chromatography on silica gel (20:1 dichloromethane/methanol)

Sources & evidence

ORD record
ord-b924461a84e24015bb23d09824cc0564
Source dataset
uspto-grants-2015_01
Patent number
US08937041B2

Reaction notes

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