Hydrochloric Acid → HCID 67681922, compound

HRID 1751365Notes

Reaction equation

HRID 1751365 reaction equation
C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:19]=[CH:20][C:21]3[C:30]4[C:25](=[C:26]5[CH:34]=[CH:33][C:32]([C:35]6[NH:39][C:38]([C@@H:40]7[CH2:44][CH2:43][CH2:42][N:41]7[C:45]([O:47][CH2:48][C:49]7[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=7)=[O:46])=[N:37][CH:36]=6)=[CH:31][C:27]5=[CH:28][CH:29]=4)[O:24][CH2:23][C:22]=3[CH:55]=2)=[CH:16][N:17]=1)=O)(C)(C)C.Cl.[CH3:57][O:58][C:59]([NH:61][C@@H:62]([CH:66]([CH3:68])[CH3:67])[C:63]([OH:65])=O)=[O:60].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C)C=O.C(#N)C.CO.[OH-].[Na+].C(OCC)(=O)C.C(O)C>[CH3:57][O:58][C:59]([NH:61][C@@H:62]([CH:66]([CH3:68])[CH3:67])[C:63]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:19]=[CH:20][C:21]3[C:30]4[C:25](=[C:26]5[CH:34]=[CH:33][C:32]([C:35]6[NH:39][C:38]([C@@H:40]7[CH2:44][CH2:43][CH2:42][N:41]7[C:45]([O:47][CH2:48][C:49]7[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=7)=[O:46])=[N:37][CH:36]=6)=[CH:31][C:27]5=[CH:28][CH:29]=4)[O:24][CH2:23][C:22]=3[CH:55]=2)=[CH:16][N:17]=1)=[O:65])=[O:60]

Participants

12

Reactant 5

HCID 313Hydrochloric AcidHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 10942966(2S)-2-((methoxycarbonyl)amino)-3-methylbutanoic acidHCID 89945812(S)-benzyl 2-(5-(8-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-dibenzo[c,h]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

Product 1

HCID 67681922HCID 67681922, compoundYield 80%

Reagents, catalysts & solvents 6

HCID 14798Sodium HydroxideCatalystHCID 702EthanolSolventHCID 887MethanolSolventHCID 6228DimethylformamideSolventHCID 6342AcetonitrileSolventHCID 8857Ethyl AcetateSolvent

Procedure

A solution of (S)-benzyl 2-(5-(8-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-dibenzo[c,h]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (1.2 g, 1.6 mmol), concentrated HCl (1.5 mL) and ethanol (10 mL) was heated to 60° C. for one hour. The reaction was concentrated and redissolved in a minimal amount of methanol. An equal volume of dichloromethane was added and the solution was again concentrated. Dichloromethane was added to the resulting residue and concentrated off three more times, until the crude material was a yellow powder. A portion of the crude amine (0.3 g, ˜0.40 mmol) was dissolved in dimethylformamide (4.7 mL). To this solution was added (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (125 mg, 0.7 mmol), HATU (270 mg, 0.7 mmol) and diisopropylethylamine (0.82 mL, 4.7 mmol). The reaction was stirred at room temperature for one hour, and then diluted with acetonitrile (2 mL) and methanol (2 mL). To this solution was added ten drops of 5M aqueous NaOH solution and stirring was continued for 30 minutes. The reaction was diluted with ethyl acetate and the organic layer was washed with water and brine. The combined aqueous washings were extracted three times with ethyl acetate, and the combined organic layers were dried (MgSO4) and concentrated. The crude material was purified by flash column chromatography to yield (S)-benzyl 2-(5-(8-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-dibenzo[c,h]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (260 mg, ˜80%). LCMS-ESI+: calculated for C46H47N7O6: 793.91; observed [M+1]+: 794.70.

Workup

  1. concentrationThe reaction was concentrated
  2. dissolutionredissolved in a minimal amount of methanol
  3. additionAn equal volume of dichloromethane was added
  4. concentrationthe solution was again concentrated
  5. additionDichloromethane was added to the resulting residue
  6. concentrationconcentrated off three more times
  7. stirringstirring
  8. waitwas continued for 30 minutes
  9. washthe organic layer was washed with water and brine
  10. extractionThe combined aqueous washings were extracted three times with ethyl acetate
  11. dry with materialthe combined organic layers were dried (MgSO4)
  12. concentrationconcentrated
  13. customThe crude material was purified by flash column chromatography

Sources & evidence

ORD record
ord-24c5fc8c3c894c2b94b01bd03fd5cebf
Source dataset
uspto-grants-2015_10
Patent number
US09156823B2

Reaction notes

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