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Hydrochloric Acid → methyl (R)-2-oxo-1-phenyl-2-((S)-2-(5-(4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)ethylcarbamate

HRID 1751406
Notes
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Reaction equation

HRID 1751406 reaction equation
Cl.[CH3:2][C:3]1([CH3:42])[C:7]([CH3:9])([CH3:8])[O:6][B:5]([C:10]2[CH:11]=[CH:12][C:13]3[CH:17]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5[NH:28][C:27]([C@@H:29]6[CH2:33][CH2:32][CH2:31][N:30]6C(OC(C)(C)C)=O)=[N:26][CH:25]=5)=[CH:20][CH:19]=4)[S:15][C:14]=3[CH:41]=2)[O:4]1.CN1CCOCC1.CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.[CH3:77][O:78][C:79]([NH:81][C@H:82]([C:86]1[CH:91]=[CH:90][CH:89]=[CH:88][CH:87]=1)[C:83](O)=[O:84])=[O:80]>O1CCOCC1.ClCCl.C(OCC)(=O)C>[O:84]=[C:83]([N:30]1[CH2:31][CH2:32][CH2:33][C@H:29]1[C:27]1[NH:28][C:24]([C:21]2[CH:20]=[CH:19][C:18]([C:16]3[S:15][C:14]4[CH:41]=[C:10]([B:5]5[O:6][C:7]([CH3:9])([CH3:8])[C:3]([CH3:42])([CH3:2])[O:4]5)[CH:11]=[CH:12][C:13]=4[CH:17]=3)=[CH:23][CH:22]=2)=[CH:25][N:26]=1)[C@H:82]([NH:81][C:79](=[O:80])[O:78][CH3:77])[C:86]1[CH:91]=[CH:90][CH:89]=[CH:88][CH:87]=1
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

9

Reactant 5

HCID 313Hydrochloric AcidHCID 79724-Methylmorpholine2×HCID 10910775(alphaR)-alpha-((Methoxycarbonyl)amino)benzeneacetic acidHCID 69676593(S)-tert-butyl 2-(5-(4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylateHCID 75951468(1-Cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate

Product 1

HCID 86708731methyl (R)-2-oxo-1-phenyl-2-((S)-2-(5-(4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)ethylcarbamateYield 69.6%

Reagents, catalysts & solvents 3

HCID 6344DichloromethaneSolvent2×HCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Procedure

A solution of hydrogen chloride in dioxane (4 N, 5 mL) was added to a solution of (S)-tert-butyl 2-(5-(4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (328 mg, 0.56 mmol) in dichloromethane (5 mL). Gas evolution was observed. After 20 min the solvent was removed under reduced pressure and the residue was placed under high vacuum for 30 min. The solid was taken up in N,N-dimethylformamide (3 mL) and N-methylmorpholine (158 μL, 1.43 mmol) was added to the solution. In a separate vessel, COMU (258 mg, 0.605 mmol), and N-methylmorpholine (158 μL, 1.43 mmol) were added to a solution of (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (126 mg, 0.604 mmol) in dichloromethane (3 mL). This was stirred for 5 minutes and both solutions were combined. After 15 minutes the mixture was diluted with ethyl acetate (20 mL) and washed with water (5 mL) and brine (5 mL). The organic phase was dried over sodium sulfate and filtered. The solvent was removed under reduced pressure and the residue was subjected to flash chromatography with eluant of (10% methanol in ethyl acetate) and hexane. The product containing fractions were combined and the solvent was removed under reduced pressure to provide methyl (R)-2-oxo-1-phenyl-2-((S)-2-(5-(4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)ethylcarbamate (261 mg, 0.39 mmol, 69%).

Workup

  1. customAfter 20 min the solvent was removed under reduced pressure
  2. washwashed with water (5 mL) and brine (5 mL)
  3. dry with materialThe organic phase was dried over sodium sulfate
  4. filtrationfiltered
  5. customThe solvent was removed under reduced pressure
  6. additionThe product containing fractions
  7. customthe solvent was removed under reduced pressure

Sources & evidence

ORD record
ord-58cb4ddbfe8949cd84f48418a6688da1
Source dataset
uspto-grants-2015_10
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US09156823B2

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes