Acetic Acid → HCID 131733494, compound

HRID 2279931Notes

Reaction equation

HRID 2279931 reaction equation
[CH3:1][Si:2]([CH3:12])([CH3:11])[O:3][C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7].[Cl:13][C:14]1[CH:15]=[N+:16]([O-:43])[CH:17]=[C:18]([Cl:42])[C:19]=1[CH2:20][C@H:21]([O:32][C:33]([C:35]1[S:36][C:37]([CH:40]=O)=[CH:38][CH:39]=1)=[O:34])[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>C(Cl)Cl>[Cl:42][C:18]1[CH:17]=[N+:16]([O-:43])[CH:15]=[C:14]([Cl:13])[C:19]=1[CH2:20][C@H:21]([O:32][C:33]([C:35]1[S:36][C:37]([CH2:40][NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:4]([O:3][Si:2]([CH3:12])([CH3:11])[CH3:1])[CH:5]=2)=[CH:38][CH:39]=1)=[O:34])[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=1

Participants

6

Reactant 4

HCID 176Acetic AcidHCID 5972763-TrimethylsilyloxyanilineHCID 5049666Sodium triacetoxyborohydrideHCID 118142901HCID 118142901, compound

Product 1

HCID 131733494HCID 131733494, compound

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

A mixture of 3-((trimethylsilyl)oxy)aniline (0.14 g, 0.77 mmol) and [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl]5-formylthiophene-2-carboxylate (0.186 g, 0.39 mmol) in DCM (5 mL) was stirred at room temperature for 18 h. NaBH(OAc)3 (0.206 g, 0.97 mmol) and acetic acid (0.043 mL, 0.75 mmol) was added and the reaction mixture was stirred at room temperature for a further 3 h. The reaction mixture was diluted with DCM (10 mL) and washed with saturated aqueous NaHCO3 solution (25 mL). The aqueous phase was further extracted with DCM (10 mL), and the combined organic phases were washed with brine (20 mL), filtered through a phase separator cartridge and the solvent was removed in vacuo, co-evaporated with MeCN to give [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl]5-[(3-trimethylsilyloxyanilino)methyl]thiophene-2-carboxylate as a light brown gum. A mixture of this material (0.185 g, 0.29 mmol) and (R)-quinuclidin-3-yl carbonochloridate (0.162 g, 0.72 mmol) in MeCN (5 mL) was heated in a microwave at 80° C. for 6 min. Additional (R)-quinuclidin-3-yl carbonochloridate (0.08 g, 0.35 mmol) was added and heated in the microwave at 80° C. for a further 6 min. The solvent was removed in vacuo and the residue was partitioned between EtOAc (20 mL) and water (20 mL). The separated aqueous phase was basified by the addition of saturated aqueous NaHCO3 solution and extracted with EtOAc (2×20 mL). The organic extracts were combined and filtered through a phase separator and the solvent was removed in vacuo. Purification by preparative HPLC gave the title compound as a white solid (0.02 g, 9.6%).

Workup

  1. stirringthe reaction mixture was stirred at room temperature for a further 3 h
  2. washwashed with saturated aqueous NaHCO3 solution (25 mL)
  3. extractionThe aqueous phase was further extracted with DCM (10 mL)
  4. washthe combined organic phases were washed with brine (20 mL)
  5. filtrationfiltered through a phase separator cartridge
  6. customthe solvent was removed in vacuo, co-evaporated with MeCN

Sources & evidence

ORD record
ord-0f2d67d5fe84478fb233e303f3cb6700
Source dataset
uspto-grants-2015_09
Patent number
US09133185B2

Reaction notes

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