Acetic Acid → HCID 130473111, compound

HRID 2279955Notes

Reaction equation

HRID 2279955 reaction equation
[CH:1]1([C:18]([O:20][C@@H:21]2[CH:26]3[CH2:27][CH2:28][N:23]([CH2:24][CH2:25]3)[CH2:22]2)=[O:19])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11](OC(C)(C)C)=O.Cl.O1CCOCC1.[Cl:36][C:37]1[CH:38]=[N+:39]([O-:66])[CH:40]=[C:41]([Cl:65])[C:42]=1[CH2:43][C@H:44]([O:55][C:56]([C:58]1[S:59][C:60](C=O)=[CH:61][CH:62]=1)=[O:57])[C:45]1[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[C:47]([O:53][CH3:54])[CH:46]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(OCC)(=O)C.C(#N)C>[N:23]12[CH2:24][CH2:25][CH:26]([CH2:27][CH2:28]1)[C@@H:21]([O:20][C:18]([CH:1]1[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][N:2]1[CH2:11][C:60]1[S:59][C:58]([C:56]([O:55][C@H:44]([C:45]3[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[C:47]([O:53][CH3:54])[CH:46]=3)[CH2:43][C:42]3[C:41]([Cl:65])=[CH:40][N+:39]([O-:66])=[CH:38][C:37]=3[Cl:36])=[O:57])=[CH:62][CH:61]=1)=[O:19])[CH2:22]2

Participants

8

Reactant 5

HCID 176Acetic AcidHCID 5049666Sodium triacetoxyborohydrideHCID 204431481,4-Dioxane hydrochlorideHCID 118117097HCID 118117097, compoundHCID 118142901HCID 118142901, compound

Product 1

HCID 130473111HCID 130473111, compoundYield 18.3%

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

o a solution of O2-tert-butyl O1-[(3R)-quinuclidin-3-yl] 3,4-dihydro-1H-isoquinoline-1,2-dicarboxylate (440 mg, 1.14 mmol) in ethyl acetate (1.42 mL) was added 4N HCl/dioxane (1.42 mL, 5.70 mmol) and the resultant solution was stirred at room temperature for 18 h. The solvent was removed in vacuo to give a white solid. The crude material (200 mg, 0.56 mmol) was dissolved in acetonitrile (5 mL) and [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl]5-formylthiophene-2-carboxylate (270 mg, 0.56 mmol) was added followed by acetic acid (67 μL, 1.12 mmol). The resultant solution was stirred at room temperature for 18 h. The solvent was removed in vacuo and the residue azeotroped with toluene. The residue was rediluted with acetonitrile (5 mL) and sodium triacetoxyborohydride (237 mg, 1.12 mmol) was added and the resultant solution was stirred at room temperature for 18 h. The solvent was removed in vacuo and the residue was taken up in water (20 mL) and ethyl acetate (20 mL). The layers were separated and the aqueous phase was extracted with ethyl acetate (2×20 mL). The combined organic phases were extracted with 0.2 N aqueous hydrochloric acid (40 mL) and water (40 mL). The aqueous extracts were combined and sodium chloride (6 g) was added. The mixture was extracted with chloroform (3×30 mL) and the combined organic extracts were passed through a hydrophobic fit and the solvent was removed in vacuo. Purification of the crude material by preparative HPLC afforded the title compound (77 mg, 18%) as a pale yellow solid.

Workup

  1. customThe solvent was removed in vacuo
  2. customto give a white solid
  3. customThe solvent was removed in vacuo
  4. customthe residue azeotroped with toluene
  5. additionwas added
  6. customThe solvent was removed in vacuo
  7. customThe layers were separated
  8. extractionthe aqueous phase was extracted with ethyl acetate (2×20 mL)
  9. extractionThe combined organic phases were extracted with 0.2 N aqueous hydrochloric acid (40 mL) and water (40 mL)
  10. additionsodium chloride (6 g) was added
  11. extractionThe mixture was extracted with chloroform (3×30 mL)
  12. customthe solvent was removed in vacuo
  13. customPurification of the crude material by preparative HPLC

Sources & evidence

ORD record
ord-47033fb4cb8947149083af9b526d4e1c
Source dataset
uspto-grants-2015_09
Patent number
US09133185B2

Reaction notes

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