Hydrochloric Acid → [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxylphenyl)ethyl]3-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]-5-methyl-benzoate

HRID 1497987Notes

Reaction equation

HRID 1497987 reaction equation
[CH:1](O)=O.[Cl:4][C:5]1[CH:6]=[N+:7]([O-:54])[CH:8]=[C:9]([Cl:53])[C:10]=1[CH2:11][C@H:12]([O:23][C:24](=[O:52])[C:25]1[CH:30]=[C:29]([CH2:31][N:32]([C:40]([O:42][C@@H:43]2[CH:48]3[CH2:49][CH2:50][N:45]([CH2:46][CH2:47]3)[CH2:44]2)=[O:41])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[F:39])[CH:28]=[C:27](Br)[CH:26]=1)[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=1.CB1OBOBO1.Cl.ClC1C=[N+]([O-])C=C(Cl)C=1C[C@@H](C1C=CC(OC)=C(OC)C=1)O.Cl.CN(C)CCCN=C=NCC>O1CCOCC1.O.CN(C=O)C.CN(C)C1C=CN=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:4][C:5]1[CH:6]=[N+:7]([O-:54])[CH:8]=[C:9]([Cl:53])[C:10]=1[CH2:11][C@H:12]([O:23][C:24](=[O:52])[C:25]1[CH:26]=[C:27]([CH3:1])[CH:28]=[C:29]([CH2:31][N:32]([C:40]([O:42][C@@H:43]2[CH:48]3[CH2:49][CH2:50][N:45]([CH2:46][CH2:47]3)[CH2:44]2)=[O:41])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[F:39])[CH:30]=1)[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=1

Participants

11

Reactant 5

HCID 313Hydrochloric AcidHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 71092494(S)-3,5-dichloro-4-(2-(3,4-dimethoxyphenyl)-2-hydroxyethyl)pyridine 1-oxideHCID 86720710[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxylphenyl)ethyl]3-bromo-5-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate formateHCID 177697481CID 177697481

Product 1

HCID 86720709[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxylphenyl)ethyl]3-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]-5-methyl-benzoateYield 12.9%

Reagents, catalysts & solvents 5

HCID 142844-(Dimethylamino)pyridineCatalystHCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
160 °C

Procedure

A mixture of [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxylphenyl)ethyl]3-bromo-5-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate formate salt (98 mg, 0.20 mmol), methylboroxine (0.03 mL, 0.20 mmol) and Pd(PPh3)4 (23 mg, 0.02 mmol) in 10% dioxane in water (2.5 mL) was heated to 160° C. under microwave irradiation for 5 minutes. After cooling to room temperature, the reaction mixture was neutralized with 0.30 mL of 2 N HCl and filtered through celite, washed with EtOAc (50 mL) The solvent was removed in vacuo and the residue was azeotroped with toluene to yield a white foam that was redissolved in DMF (2 mL). (S)-3,5-dichloro-4-(2-(3,4-dimethoxylphenyl)-2-hydroxyethyl)pyridine 1-oxide (76 mg, 0.22 mmol) followed by 4-(dimethylamino)-pyridine (12 mg, 0.10 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (77 mg, 0.40 mmol) were then added, and the resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was washed with brine, dried over Na2SO4, filtered and the solvent was removed in vacuo. The residue was purified by preparative HPLC to provide [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxylphenyl)ethyl]3-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]-5-methyl-benzoate (19 mg) as white solid.

Workup

  1. temperatureAfter cooling to room temperature
  2. filtrationfiltered through celite
  3. washwashed with EtOAc (50 mL) The solvent
  4. customwas removed in vacuo
  5. customthe residue was azeotroped with toluene
  6. customto yield a white foam that
  7. additionwere then added
  8. customThe reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution
  9. washThe organic layer was washed with brine
  10. dry with materialdried over Na2SO4
  11. filtrationfiltered
  12. customthe solvent was removed in vacuo
  13. customThe residue was purified by preparative HPLC

Sources & evidence

ORD record
ord-44a009c9ddbf4398820e15e25b061521
Source dataset
uspto-grants-2015_12
Patent number
US09199980B2

Reaction notes

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