Hydrochloric Acid → HCID 57415387, compound

HRID 1429088Notes

Reaction equation

HRID 1429088 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[C:31]([C:32]4[S:33][C:34]5[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=5[N:36]=4)=[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:41])[NH:12][C@:11]2([C:43]([NH:45][S:46]([CH:49]3[CH2:51][CH2:50]3)(=[O:48])=[O:47])=[O:44])[CH2:42][C@H:10]2[CH2:9][C:8]([F:53])([F:52])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.Cl.C(N(C(C)C)CC)(C)C.[CH3:64][C:65]1[O:69][N:68]=[C:67]([C:70](O)=[O:71])[CH:66]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[S:33]1[C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=[C:32]1[C:31]1[C:22]([O:21][C@H:19]2[CH2:18][N:15]3[C:16](=[O:17])[C@@H:2]([NH:1][C:70]([C:67]4[CH:66]=[C:65]([CH3:64])[O:69][N:68]=4)=[O:71])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([F:52])([F:53])[CH2:9][C@@H:10]4[CH2:42][C@@:11]4([C:43](=[O:44])[NH:45][S:46]([CH:49]4[CH2:51][CH2:50]4)(=[O:48])=[O:47])[NH:12][C:13](=[O:41])[C@@H:14]3[CH2:20]2)=[N:23][C:24]2[C:29]([N:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2

Participants

7

Reactant 5

HCID 313Hydrochloric Acid2×HCID 769473-Methyl-5-isoxazolecarboxylic acidHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 68008482HCID 68008482, compound

Product 1

HCID 57415387HCID 57415387, compoundYield 81%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To (2R,6S,13aS,14aR,16aS)-6-amino-2-(3-(benzo [d]thiazol-2-yl)quinoxalin-2-yloxy)-N-(cyclopropylsulfonyl)-12,12-difluoro-5,16-dioxooctadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide, Hydrochloric Acid (Example 14a, 16.1 mg, 0.020 mmol) was added DMF (200 μl) and diisopropylethylamine (25 μl, 0.14 mmol). To the yellow solution was added 5-methylisoxazole-3-carboxylic acid (3.85 mg, 0.030 mmol) followed by HATU (13.89 mg, 0.037 mmol). The reaction mixture was stirred at rt 2 h, cooled to 0° C. and neutralized with HCl (4 N in dioxane, 36 μl, diluted with EA). The solution was concentrated under reduced pressure and purified by prep-TLC (dichloromethane/EA=1/1, 2×) to provide the title compound N-((2R,6S,13aS,14aR,16aS)-2-(3-(benzo [d]thiazol-2-yl)quinoxalin-2- yloxy)-14a-(cyclopropylsulfonylcarbamoy1)-12,12-difluoro-5,16-dioxooctadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)-5-methylisoxazole-3-carboxamide (14.3 mg, 81% yield). MS (ESI): m/z=877.1 [M+H], 875.2 [M−H]. Example 14 provided an IC50 of between 0.1 and 0.5 nM in a 1a enzyme assay; an IC50 of between 0.1 and 0.5 nM in a 1b enzyme assay; 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 between 1.0 and 2.0 nM in a replicon cell line assay in a 1-con1 background.

Workup

  1. concentrationThe solution was concentrated under reduced pressure
  2. custompurified by prep-TLC (dichloromethane/EA=1/1, 2×)

Sources & evidence

ORD record
ord-93e858dd17104a7cabbcc8edced3d314
Source dataset
uspto-grants-2015_01
Patent number
US08937041B2

Reaction notes

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