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Hydrochloric Acid → Di-tert-butyl (1R,2R,3 S,4S,5R,6R)-2-[(tert-butoxycarbonyl)amino]-3-[(3,4-dichlorobenzyl)oxy]-4-[(1-methyl-1,2,4-triazol-3-yl)sulfanyl]bicyclo[3.1.0]hexane-2,6-dicarboxylate

HRID 2172993
Notes
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Reaction equation

HRID 2172993 reaction equation
[C:1]([O:5][C:6]([NH:8][C@@:9]1([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[C@@H:13]([S:25][C:26]2[N:30]=[CH:29][NH:28][N:27]=2)[C@@H:12]2[C@H:10]1[C@H:11]2[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:45]C(C)([O-])C.[K+].CI.Cl>O1CCCC1.O>[C:1]([O:5][C:6]([NH:8][C@@:9]1([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[C@@H:13]([S:25][C:26]2[N:30]=[CH:29][N:28]([CH3:45])[N:27]=2)[C@@H:12]2[C@H:10]1[C@H:11]2[C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])=[O:7])([CH3:4])([CH3:2])[CH3:3]
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 6328Methyl iodideHCID 23665647Potassium tert-butoxideHCID 178452941HCID 178452941, compound

Product 1

HCID 86695977Di-tert-butyl (1R,2R,3 S,4S,5R,6R)-2-[(tert-butoxycarbonyl)amino]-3-[(3,4-dichlorobenzyl)oxy]-4-[(1-methyl-1,2,4-triazol-3-yl)sulfanyl]bicyclo[3.1.0]hexane-2,6-dicarboxylate
Yield 26%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-78 °C

Procedure

Dissolve di-tert-butyl (1R,2R,3S,4S,5R,6R)-2-[(tert-butoxycarbonyl)amino]-3-[(3,4-dichlorobenzyl)oxy]-4-(1H-1,2,4-triazol-3-ylsulfanyl)bicyclo[3.1.0]hexane-2,6-dicarboxylate (0.60 g, 0.893 mmol) in anhydrous tetrahydrofuran (3.6 mL) in a flame-dried flask and cool to −78° C. Add potassium t-butoxide (0.80 g, 0.893 mmol) and stir for 15 minutes. Add methyl iodide (0.127 g, 0.893 mmol, pretreated by filtration through basic alumina) and allow to stir at −78° C. for 15 minutes. Allow the mixture to warm to room temperature and then stir for 30 minutes at room temperature. Pour crude reaction mixture into water and adjust pH to 6 with 1N aqueous HCl and extract into ethyl acetate. Dry the organic layer over magnesium sulfate, filter and concentrate under reduced pressure. Purify by reverse phase flash chromatography (100 g C18 column eluting with 45-95% Acetonitrile/Water (with 0.1% trifluoroacetic acid in both), compound elutes at 89% Acetonitrile). Combine the desired fractions and neutralize with aqueous bicarbonate. Extract with ethyl acetate, dry the organic layer over magnesium sulfate, filter and concentrate under reduced pressure to yield the title compound as a white foam (0.16 g, 0.23 mmol, 26%): MS (m/z): 473/475/477 (M+1).

Workup

  1. temperatureAllow the mixture to warm to room temperature
  2. stirringstir for 30 minutes at room temperature
  3. additionPour crude
  4. extractionextract into ethyl acetate
  5. dry with materialDry the organic layer over magnesium sulfate
  6. filtrationfilter
  7. concentrationconcentrate under reduced pressure
  8. customPurify by reverse phase flash chromatography (100 g C18 column
  9. washeluting with 45-95% Acetonitrile/Water (with 0.1% trifluoroacetic acid in both), compound elutes at 89% Acetonitrile)
  10. extractionExtract with ethyl acetate
  11. dry with materialdry the organic layer over magnesium sulfate
  12. filtrationfilter
  13. concentrationconcentrate under reduced pressure

Sources & evidence

ORD record
ord-7ede3b166b994bf3afe5c479954525f9
Source dataset
uspto-grants-2015_06
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US09056844B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes