Hydrochloric Acid → HCID 57415125, compound

HRID 1429084Notes

Reaction equation

HRID 1429084 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[C:38]([CH2:39][CH3:40])=[N:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=3)[CH2:27][C@H:21]2[C:20](=[O:41])[NH:19][C@:18]2([C:43]([OH:45])=O)[CH2:42][C@H:17]2[CH2:16][C:15]([F:47])([F:46])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(Cl)C.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:64]1([S:67]([NH2:70])(=[O:69])=[O:68])[CH2:66][CH2:65]1.C1CCN2C(=NCCC2)CC1.Cl>ClCCl>[CH:64]1([S:67]([NH:70][C:43]([C@@:18]23[CH2:42][C@H:17]2[CH2:16][C:15]([F:47])([F:46])[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])([CH3:2])[CH3:3])[C:23](=[O:24])[N:22]2[CH2:25][C@H:26]([O:28][C:29]4[C:38]([CH2:39][CH3:40])=[N:37][C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[N:30]=4)[CH2:27][C@H:21]2[C:20](=[O:41])[NH:19]3)=[O:45])(=[O:69])=[O:68])[CH2:66][CH2:65]1

Participants

8

Reactant 6

HCID 313Hydrochloric AcidHCID 63651,1-DichloroethaneHCID 682631,1'-CarbonyldiimidazoleHCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 15765418CyclopropanesulfonamideHCID 68008851HCID 68008851, compound

Product 1

HCID 57415125HCID 57415125, compoundYield 85%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
40 °C

Procedure

To (2R,6S ,13aS,14aR,16aS)-6-(tert-butoxycarbonylamino)-2-(3-ethylquinoxalin-2-yloxy)-12,12-difluoro-5,16-dioxooctadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxylic acid (Example 7k, 26.2 mg, 0.040 mmol) was added sieves (4 A) and dichloroethane (397 μl). To this mixture was added carbonyldiimidazole (13.5 mg, 0.083 mmol), and the reaction mixture was stirred at 40° C. for 2 hr. The reaction mixture was then cooled to room temperature and cyclopropanesulfonamide (12.4 mg, 0.103 mmol) was added followed by DBU (15 μl, 0.100 mmol). The reaction mixture was stirred at room temperature for 16 h, diluted with dichloromethane and cooled to 0° C. This mixture was neutralized with HCl (4 N in dioxane, 67 μl), and the mixture was filtered to remove sieves. The eluant was concentrated under reduced pressure and the residue was purified by reverse phase HPLC (CH3CN/H2O (0.1% TFA) gradient =45/55-85/15) to provide tert-butyl (2R,6S ,13aS,14aR,16aS)-14a-(cyclopropylsulfonylcarbamoyl)-2-(3-ethylquinoxalin-2-yloxy)-12,12-difluoro-5,16-dioxooctadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecin-6-ylcarbamate (25.8 mg, 85% yield) as a light yellow solid. MS (ESI): m/z=763.0 [M+H], 761.3 [M−H]. Example 7 provided an IC50 of between 0.5 and 1.0 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 >100 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 1b-con1 background.

Workup

  1. temperatureThe reaction mixture was then cooled to room temperature
  2. stirringThe reaction mixture was stirred at room temperature for 16 h
  3. temperaturecooled to 0° C
  4. filtrationthe mixture was filtered
  5. customto remove sieves
  6. concentrationThe eluant was concentrated under reduced pressure
  7. customthe residue was purified by reverse phase HPLC (CH3CN/H2O (0.1% TFA) gradient =45/55-85/15)

Sources & evidence

ORD record
ord-4d39d974f2684c7d82738d89e940ef23
Source dataset
uspto-grants-2015_01
Patent number
US08937041B2

Reaction notes

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