Hydrochloric Acid → HCID 178502474, compound

HRID 1751617Notes

Reaction equation

HRID 1751617 reaction equation
Cl.[O:2]1[CH2:7][CH2:6]OCC1.[CH3:8][O:9][C:10]([NH:12][C@@H:13]([CH:61]([CH3:63])[CH3:62])[C:14]([N:16]1[C@H:21]([C:22]2[NH:26][C:25]3[C:27]4[C:32]([CH:33]=[CH:34][C:24]=3[N:23]=2)=[CH:31][C:30]([C:35]2[CH:36]=[C:37]3[C:57](=[CH:58][CH:59]=2)[C:41]2[NH:42][C:43]([C@@H:45]5[CH2:49][CH2:48][CH2:47][N:46]5C(OC(C)(C)C)=O)=[N:44][C:40]=2[CH:39]=[CH:38]3)=[CH:29][CH:28]=4)[C@H:20]2[CH2:60][C@@H:17]1[CH2:18][CH2:19]2)=[O:15])=[O:11].COC(N[C@H]([C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1)C(O)=O)=O.CC[N:81](C(C)C)C(C)C.C[CH2:89][O:90][C:91](C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=[O:92].F[P-](F)(F)(F)(F)F>C(Cl)Cl.CN(C=O)C.CO>[CH3:8][O:9][C:10]([NH:12][C@@H:13]([CH:61]([CH3:62])[CH3:63])[C:14]([N:16]1[C@H:21]([C:22]2[NH:26][C:25]3[C:27]4[C:32]([CH:33]=[CH:34][C:24]=3[N:23]=2)=[CH:31][C:30]([C:35]2[CH:36]=[C:37]3[C:57](=[CH:58][CH:59]=2)[C:41]2[NH:42][C:43]([C@@H:45]5[CH2:49][CH2:48][CH2:47][N:46]5[C:7](=[O:2])[C@H:6]([NH:81][C:91](=[O:92])[O:90][CH3:89])[C:76]5[CH:75]=[CH:74][CH:73]=[CH:78][CH:77]=5)=[N:44][C:40]=2[CH:39]=[CH:38]3)=[CH:29][CH:28]=4)[C@H:20]2[CH2:60][C@@H:17]1[CH2:18][CH2:19]2)=[O:15])=[O:11]

Participants

10

Reactant 6

HCID 313Hydrochloric AcidHCID 312751,4-DioxaneHCID 81531DiisopropylethylamineHCID 10910775(alphaR)-alpha-((Methoxycarbonyl)amino)benzeneacetic acidHCID 75951468(1-Cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphateHCID 178502475HCID 178502475, compound

Product 1

HCID 178502474HCID 178502474, compoundYield 53%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent2×

Procedure

Hydrogen chloride in dioxane solution (4N, 1.51 mL, 6.05 mmol) was added to a solution of (S)-tert-butyl 2-(2′-((1S,3S,4R)-2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate (0.305 g, 0.403 mmol) in methylene chloride:methanol (4.0 mL: 0.80 mL). The suspension was allowed to stir at room temperature for two hours. Upon completion by LCMS, the reaction was concentrated to dryness and the crude product (assumed 0.403 mmol) was suspended in methylene chloride (4 mL). (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (0.093 g, 0.484 mmol) and DIPEA (0.282 mL, 1.61 mmol) were added and the slurry was cooled to −40° C. with an external dry ice/acetonitrile bath. COMU (0.259 g, 0.605 mmol) was added at −40° C. and the solution was stirred at reduced temperature for one hour. Upon completion, the crude reaction was diluted with DMF and concentrated in vacuo. The crude product was purified by reverse phase HPLC (Gilson, Gemini, 10-45% acetonitrile/water with 0.1% TFA modifier). Fractions containing product were combined and concentrated until aqueous layer remained. Aqueous sodium bicarbonate was added to aqueous product mixture to obtain a pH of 7-8 (as measured by pH paper) and precipitation was observed. The precipitate was filtered and dried under vacuum for 18 hours to give methyl {(1R)-2-[(2S)-2-{2′-[(1S,3S,4R)-2-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-2-azabicyclo[2.2.1]hept-3-yl]-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl}pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate (0.180 g, 53%) as a while solid. LCMS-ESI+: calc'd for C49H50N8O6: 846.39 (M+); Found: 847.8 (M+H+).

Workup

  1. concentrationUpon completion by LCMS, the reaction was concentrated to dryness
  2. temperaturethe slurry was cooled to −40° C. with an external dry ice/acetonitrile bath
  3. stirringthe solution was stirred at reduced temperature for one hour
  4. customUpon completion, the crude reaction
  5. concentrationconcentrated in vacuo
  6. customThe crude product was purified by reverse phase HPLC (Gilson, Gemini, 10-45% acetonitrile/water with 0.1% TFA modifier)
  7. additionFractions containing product
  8. concentrationconcentrated until aqueous layer
  9. additionAqueous sodium bicarbonate was added to aqueous product mixture
  10. customto obtain
  11. customa pH of 7-8 (as measured by pH paper) and precipitation
  12. filtrationThe precipitate was filtered
  13. customdried under vacuum for 18 hours

Sources & evidence

ORD record
ord-6fc423cd22b34c0a8a2809a180312883
Source dataset
uspto-grants-2015_10
Patent number
US09156823B2

Reaction notes

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