Hydrochloric Acid → HCID 91801199, compound

HRID 2284834Notes

Reaction equation

HRID 2284834 reaction equation
C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]([O:15][C@H:16]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH:34]([F:36])[F:35])=[C:29]([O:37][CH2:38][CH:39]2[CH2:41][CH2:40]2)[CH:28]=1)[CH2:17][C:18]1[C:23]([Cl:24])=[CH:22][N+:21]([O-:25])=[CH:20][C:19]=1[Cl:26])=[O:14])=O)(C)(C)C.Cl.O1CCOCC1.Cl[S:50]([C:53]1[CH:54]=[C:55]([CH:59]=[CH:60][CH:61]=1)[C:56]([OH:58])=[O:57])(=[O:52])=[O:51].[OH-].[Na+].O[C:65]1[CH:66]=[C:67]([C@@H:71]([NH:78][C:79](=[O:89])[O:80][C@@H:81]2[CH:86]3[CH2:87][CH2:88][N:83]([CH2:84][CH2:85]3)[CH2:82]2)[C:72]2[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=2)[CH:68]=[CH:69][CH:70]=1.Cl.CN(C)CCCN=C=NCC>CCOC(C)=O.CN(C)C1C=CN=CC=1.CN(C=O)C>[CH:39]1([CH2:38][O:37][C:29]2[CH:28]=[C:27]([C@@H:16]([O:15][C:13]([C@@H:9]3[CH2:10][CH2:11][CH2:12][N:8]3[S:50]([C:53]3[CH:61]=[CH:60][CH:59]=[C:55]([C:56]([O:58][C:69]4[CH:70]=[CH:65][CH:66]=[C:67]([C@H:71]([C:72]5[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=5)[NH:78][C:79]([O:80][C@@H:81]5[CH:86]6[CH2:85][CH2:84][N:83]([CH2:88][CH2:87]6)[CH2:82]5)=[O:89])[CH:68]=4)=[O:57])[CH:54]=3)(=[O:52])=[O:51])=[O:14])[CH2:17][C:18]3[C:19]([Cl:26])=[CH:20][N+:21]([O-:25])=[CH:22][C:23]=3[Cl:24])[CH:32]=[CH:31][C:30]=2[O:33][CH:34]([F:35])[F:36])[CH2:40][CH2:41]1

Participants

11

Reactant 7

HCID 313Hydrochloric Acid2×HCID 14798Sodium HydroxideHCID 312751,4-Dioxane2×HCID 77641Benzoic acid, 3-(chlorosulfonyl)-HCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 71092623HCID 71092623, compoundHCID 118137315HCID 118137315, compound

Product 1

HCID 91801199HCID 91801199, compound

Reagents, catalysts & solvents 3

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of 4-((S)-2-(((S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carbonyl)oxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (I2, 270 mg, 0.44 mmol) dissolved in EtOAc (6 mL) was added a solution of HCl in dioxane (4 N, 7.2 mL, 28.8 mmol) at 0° C. The resulting mixture was stirred at 0° C. for 1 h before addition of HCl in dioxane (4 N, 2 mL, 8.0 mmol). The resulting slurry was stirred for 1 h and then the solvent was removed in vacuo. The residue was redissolved in DCM (50 mL) and washed with saturated aqueous NaHCO3 (20 mL). The organic phase was passed through a hydrophobic fit and the solvent was removed in vacuo to yield an oil that was used immediately without further purification. The residue was then taken up in acetone (4 mL) and THF (4 mL). 3-Chlorosulfonyl benzoic acid (845 mg, 3.86 mmol) and 2 M NaOH (3.86 mL, 7.72 mmol) were added at room temperature and the resulting mixture stirred for 16 h. After concentration in vacuo, the residue was diluted in DCM (50 mL) and the pH adjusted to 2 with an aqueous 1 N HCl saturated with brine. The organic phase was dried over MgSO4 and concentrated in vacuo. The resulting oil (195 mg) was used directly in the next step without further purification. To a solution of the carboxylic acid, (R)-quinuclidin-3-yl ((S)-(3-hydroxyphenyl)(phenyl)methyl)carbamate (197 mg, 0.56 mmol), 4-(dimethylamino)-pyridine (17 mg, 0.14 mmol) in DMF (2.5 mL) was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (107 mg, 0.56 mmol).

Workup

  1. customthe solvent was removed in vacuo
  2. dissolutionThe residue was redissolved in DCM (50 mL)
  3. washwashed with saturated aqueous NaHCO3 (20 mL)
  4. customthe solvent was removed in vacuo
  5. customto yield an oil that
  6. customwas used immediately without further purification
  7. stirringthe resulting mixture stirred for 16 h
  8. concentrationAfter concentration in vacuo
  9. additionthe residue was diluted in DCM (50 mL)
  10. dry with materialThe organic phase was dried over MgSO4
  11. concentrationconcentrated in vacuo
  12. customThe resulting oil (195 mg) was used directly in the next step without further purification

Sources & evidence

ORD record
ord-2842f029cfd74ae882dce0bb4a497e19
Source dataset
uspto-grants-2015_09
Patent number
US09145409B2

Reaction notes

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