Hydrochloric Acid → HCID 131733537, compound

HRID 2284843Notes

Reaction equation

HRID 2284843 reaction equation
[C:1]1([C@H:7]([NH:32][C:33]([O:35][C@@H:36]2[CH:41]3[CH2:42][CH2:43][N:38]([CH2:39][CH2:40]3)[CH2:37]2)=[O:34])[C:8]2[CH:9]=[C:10]([CH:29]=[CH:30][CH:31]=2)[O:11][CH2:12][C:13]2[CH:28]=[CH:27][C:16]([C:17]([N:19]3[CH2:22][CH:21]([C:23](OC)=[O:24])[CH2:20]3)=[O:18])=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[OH-].Cl.[Cl:47][C:48]1[CH:49]=[N+:50]([O-:68])[CH:51]=[C:52]([Cl:67])[C:53]=1[CH2:54][C@@H:55]([C:57]1[CH:62]=[CH:61][C:60]([O:63][CH3:64])=[C:59]([O:65][CH3:66])[CH:58]=1)[OH:56].Cl.CN(C)CCCN=C=NCC>C1COCC1.CO.CN(C)C1C=CN=CC=1>[Cl:67][C:52]1[CH:51]=[N+:50]([O-:68])[CH:49]=[C:48]([Cl:47])[C:53]=1[CH2:54][C@H:55]([O:56][C:23]([CH:21]1[CH2:22][N:19]([C:17](=[O:18])[C:16]2[CH:15]=[CH:14][C:13]([CH2:12][O:11][C:10]3[CH:29]=[CH:30][CH:31]=[C:8]([C@H:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[NH:32][C:33]([O:35][C@@H:36]4[CH:41]5[CH2:40][CH2:39][N:38]([CH2:43][CH2:42]5)[CH2:37]4)=[O:34])[CH:9]=3)=[CH:28][CH:27]=2)[CH2:20]1)=[O:24])[C:57]1[CH:62]=[CH:61][C:60]([O:63][CH3:64])=[C:59]([O:65][CH3:66])[CH:58]=1

Participants

9

Reactant 5

HCID 313Hydrochloric AcidHCID 3939Lithium HydroxideHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 71092494(S)-3,5-dichloro-4-(2-(3,4-dimethoxyphenyl)-2-hydroxyethyl)pyridine 1-oxideHCID 118114256HCID 118114256, compound

Product 1

HCID 131733537HCID 131733537, compoundYield 3%

Reagents, catalysts & solvents 3

HCID 142844-(Dimethylamino)pyridineCatalystHCID 887MethanolSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

To a solution of methyl 1-(4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoyl)azetidine-3-carboxylate (I23, 350 mg, 0.60 mmol) in THF (3 mL) and MeOH (3 mL) was added an aqueous solution of LiOH (1 N, 1.2 mL, 1.2 mmol) at room temperature. The resulting mixture was stirred for 16 h before being cooled to 0° C. and acidified with 2 N HCl to pH 2. The resulting mixture was then concentrated in vacuo and azeotroped to dryness with toluene. To a solution of the carboxylic acid in DMF (5 mL) was then added (S)-3,5-dichloro-4-(2-(3,4-dimethoxyphenyl)-2-hydroxyethyl)pyridine 1-oxide (248 mg, 0.72 mmol) followed by 4-(dimethylamino)-pyridine (37 mg, 0.30 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (230 mg, 1.20 mmol). The resulting mixture was stirred at room temperature for 16 h and partitioned between EtOAc (50 mL) and water (20 mL). The organic layer was dried over MgSO4, filtered and the solvent was removed in vacuo. The residue was dissolved in DMSO (3.0 mL) and purified by preparative HPLC to provide the title compound (14 mg, 3% over two steps) as white solid.

Workup

  1. concentrationThe resulting mixture was then concentrated in vacuo
  2. customazeotroped to dryness with toluene
  3. stirringThe resulting mixture was stirred at room temperature for 16 h
  4. custompartitioned between EtOAc (50 mL) and water (20 mL)
  5. dry with materialThe organic layer was dried over MgSO4
  6. filtrationfiltered
  7. customthe solvent was removed in vacuo
  8. dissolutionThe residue was dissolved in DMSO (3.0 mL)
  9. custompurified by preparative HPLC

Sources & evidence

ORD record
ord-b8dc2e26a3bb4af0912343e2dfbf386f
Source dataset
uspto-grants-2015_09
Patent number
US09145409B2

Reaction notes

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