Hydrochloric Acid → [(1S)-1-[3-(Cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl](2S)-3-[3-[[3-[(N-[(3R)-quinuclidin-3-yl]oxycarbonylanilino)methyl]phenoxy]methyl]benzoyl]thiazolidine-2-carboxylate

HRID 520338Notes

Reaction equation

HRID 520338 reaction equation
[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10]([N:12]([CH2:19][C:20]1[CH:21]=[C:22]([CH:35]=[CH:36][CH:37]=1)[O:23][CH2:24]C1C=CC(C(OC)=O)=CC=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11])[CH2:2]2.[OH-].[Li+].Cl.Cl.[CH:42]1([CH2:45][O:46][C:47]2[CH:48]=[C:49]([C@@H:57]([O:68][C:69]([C@H:71]3[NH:75][CH2:74][CH2:73][S:72]3)=[O:70])[CH2:58][C:59]3[C:64]([Cl:65])=[CH:63][N+:62]([O-:66])=[CH:61][C:60]=3[Cl:67])[CH:50]=[CH:51][C:52]=2[O:53][CH:54]([F:56])[F:55])[CH2:44][CH2:43]1.Cl.CN(C)[CH2:79][CH2:80][CH2:81]N=C=NCC.[CH2:88]1[CH2:92][O:91][CH2:90][CH2:89]1>CO.CN(C)C1C=CN=CC=1>[CH:42]1([CH2:45][O:46][C:47]2[CH:48]=[C:49]([C@@H:57]([O:68][C:69]([C@H:71]3[N:75]([C:90](=[O:91])[C:89]4[CH:88]=[CH:92][CH:81]=[C:80]([CH2:24][O:23][C:22]5[CH:35]=[CH:36][CH:37]=[C:20]([CH2:19][N:12]([C:10]([O:9][C@@H:3]6[CH:4]7[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]7)[CH2:2]6)=[O:11])[C:13]6[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=6)[CH:21]=5)[CH:79]=4)[CH2:74][CH2:73][S:72]3)=[O:70])[CH2:58][C:59]3[C:64]([Cl:65])=[CH:63][N+:62]([O-:66])=[CH:61][C:60]=3[Cl:67])[CH:50]=[CH:51][C:52]=2[O:53][CH:54]([F:56])[F:55])[CH2:44][CH2:43]1

Participants

9

Reactant 6

HCID 313Hydrochloric AcidHCID 3939Lithium HydroxideHCID 8028TetrahydrofuranHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochloride2×HCID 710925203,5-dichloro-4-((S)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((S)-thiazolidine-2-carbonyloxy)ethyl)pyridine 1-oxide hydrochloride3×HCID 118558468Methyl 4-[[3-[(N-[(3R)-quinuclidin-3-yl]oxycarbonylanilino)methyl]-phenoxy]methyl]benzoate2×

Product 1

HCID 118558499[(1S)-1-[3-(Cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl](2S)-3-[3-[[3-[(N-[(3R)-quinuclidin-3-yl]oxycarbonylanilino)methyl]phenoxy]methyl]benzoyl]thiazolidine-2-carboxylateYield 8%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalyst2×HCID 887MethanolSolvent

Procedure

A solution of methyl 4-[[3-[(N-[(3R)-quinuclidin-3-yl]oxycarbonylanilino)-methyl]phenoxy]methyl]benzoate (Intermediate 5 above described) (419 mg, 0.84 mmol) in THF (2 mL) and methanol (2 mL) was added with an aqueous solution of 1N lithium hydroxide (1.7 mL, 1.68 mmol). The reaction was stirred at room temperature for 18 hours. The mixture was cooled to 0° C. and acidified by addition of 2 N hydrochloric acid dropwise to pH≈2-3. The mixture was allowed to warm to room temperature and the solvent removed in vacuo and azeotroped with toluene to dryness. This crude material was dissolved in DMF (5 mL) and ⅓ of the solution was used in the next step. [(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl](2S)-thiazolidine-2-carboxylate hydrochloride (Intermediate 9 above described) (142 mg, 0.25 mmol), 4-(dimethylamino)pyridine (13 mg, 0.11 mmol) followed by N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (81 mg, 0.42 mmol) were added and the reaction mixture was stirred at room temperature for 18 hours. Additional amounts of [(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)-phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl](2S)-thiazolidine-2-carboxylate hydrochloride (140 mg, 0.25 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (81 mg, 0.42 mmol) and 4-(dimethylamino)pyridine (13 mg, 0.11 mmol) were added to the reaction mixture and was stirred at room temperature for a further 18 hours. The solvent was removed in vacuo and the residue was partitioned between EtOAc (50 mL) and water. The organic phase was dried over MgSO4, filtered and the solvent was removed in vacuo. The residue was purified by preparative HPLC to yield the title compound as white solid (16 mg, 8% yield over two steps).

Workup

  1. temperatureThe mixture was cooled to 0° C.
  2. temperatureto warm to room temperature
  3. customthe solvent removed in vacuo
  4. customazeotroped with toluene to dryness
  5. dissolutionThis crude material was dissolved in DMF (5 mL)
  6. additionwere added
  7. stirringthe reaction mixture was stirred at room temperature for 18 hours
  8. stirringwas stirred at room temperature for a further 18 hours
  9. customThe solvent was removed in vacuo
  10. customthe residue was partitioned between EtOAc (50 mL) and water
  11. dry with materialThe organic phase was dried over MgSO4
  12. filtrationfiltered
  13. customthe solvent was removed in vacuo
  14. customThe residue was purified by preparative HPLC

Sources & evidence

ORD record
ord-6723735d0e5641c0a09ea7270cb43e79
Source dataset
uspto-grants-2016_05
Patent number
US09326976B2

Reaction notes

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