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Triethylamine → methyl (1aRS,7bSR)-5-(2-{[((S)-1-ethylpyrrolidin-3-yl)methylcarbamoyl]methyl}-4-fluoro-benzenesulfonylamino)-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylate

HRID 928003
Notes
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Reaction equation

HRID 928003 reaction equation
C[CH2:2][N:3]=C=NCCCN(C)C.[C:12]([CH2:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[S:23]([NH:26][C:27]1[C:36]([C:37]([O:39][CH3:40])=[O:38])=[C:35]2[C:30]([CH:31]3[CH2:41][CH:32]3[CH2:33][O:34]2)=[CH:29][CH:28]=1)(=[O:25])=[O:24])(O)=[O:13].Cl.Cl.[CH2:44]([N:46]1[CH2:50][CH2:49][C@H:48](NC)[CH2:47]1)[CH3:45].C(N(CC)CC)C>C(Cl)Cl>[CH2:44]([N:46]1[CH2:50][CH2:49][C@@H:48]([CH2:2][NH:3][C:12]([CH2:15][C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[S:23]([NH:26][C:27]2[C:36]([C:37]([O:39][CH3:40])=[O:38])=[C:35]3[C:30]([CH:31]4[CH2:41][CH:32]4[CH2:33][O:34]3)=[CH:29][CH:28]=2)(=[O:24])=[O:25])=[O:13])[CH2:47]1)[CH3:45]
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

6

Reactant 4

HCID 8471TriethylamineHCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 71006995methyl (1aRS,7bSR)-5-(2-carboxymethyl-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate2×HCID 86713333N-((S)-1-ethylpyrrolidin-3-yl)-N-methylamine dihydrochloride2×

Product 1

HCID 86713332
methyl (1aRS,7bSR)-5-(2-{[((S)-1-ethylpyrrolidin-3-yl)methylcarbamoyl]methyl}-4-fluoro-benzenesulfonylamino)-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylate
Yield 351.4%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

EDAC (0.058 g) was added to a stirred solution of methyl (1aRS,7bSR)-5-(2-carboxymethyl-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 83, 0.109 g) in DCM (3 mL) and the mixture was stirred at room temperature for 10 minutes. A solution of N—((S)-1-ethylpyrrolidin-3-yl)-N-methylamine dihydrochloride (Intermediate 127, 0.102 g) and triethylamine (0.151 g) in DCM (3 mL) was added and the mixture stirred for 17 hours. The mixture was evaporated in vacuo and the residue was dissolved in dioxane (4 mL) and the mixture was heated at 75° C. for 20 hours. After cooling, the mixture was diluted with DCM and water and filtered through a phase separator. The filtrate was evaporated in vacuo and the residue was combined with an identical reaction carried out earlier. The material was purified by chromatography on silica, eluting with a mixture of methanol and DCM with a gradient of 0-50% to give methyl (1aRS,7bSR)-5-(2-{[((S)-1-ethylpyrrolidin-3-yl)methylcarbamoyl]methyl}-4-fluoro-benzenesulfonylamino)-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylate (0.48 g) as a light brown foam.

Workup

  1. stirringthe mixture stirred for 17 hours
  2. customThe mixture was evaporated in vacuo
  3. dissolutionthe residue was dissolved in dioxane (4 mL)
  4. temperaturethe mixture was heated at 75° C. for 20 hours
  5. temperatureAfter cooling
  6. additionthe mixture was diluted with DCM and water
  7. filtrationfiltered through a phase separator
  8. customThe filtrate was evaporated in vacuo
  9. customthe residue was combined with an identical reaction
  10. customThe material was purified by chromatography on silica
  11. washeluting with a mixture of methanol and DCM with a gradient of 0-50%

Sources & evidence

ORD record
ord-2fa27e12230e42568951a526c6cfe7d9
Source dataset
uspto-grants-2016_03
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US09290472B2

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes