Hydrochloric Acid → HCID 118114152, compound

HRID 2284849Notes

Reaction equation

HRID 2284849 reaction equation
[C:1]1([C@H:7]([NH:34][C:35]([O:37][C@@H:38]2[CH:43]3[CH2:44][CH2:45][N:40]([CH2:41][CH2:42]3)[CH2:39]2)=[O:36])[C:8]2[CH:9]=[C:10]([CH:31]=[CH:32][CH:33]=2)[O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([N:22]3[CH2:26][CH2:25][CH2:24][C@H:23]3[C:27]([O:29]C)=[O:28])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[OH-].Cl.CN(C=O)C.[Cl:54][C:55]1[CH:56]=[N+:57]([O-:80])[CH:58]=[C:59]([Cl:79])[C:60]=1[CH2:61][C@@H:62]([C:64]1[CH:69]=[CH:68][C:67]([O:70][CH:71]([F:73])[F:72])=[C:66]([O:74][CH2:75][CH:76]2[CH2:78][CH2:77]2)[CH:65]=1)[OH:63].Cl.CN(C)CCCN=C=NCC>C1COCC1.CO.CN(C)C1C=CN=CC=1>[CH:27]([OH:29])=[O:28].[CH:76]1([CH2:75][O:74][C:66]2[CH:65]=[C:64]([C@@H:62]([O:63][C:27]([C@@H:23]3[CH2:24][CH2:25][CH2:26][N:22]3[S:19]([C:16]3[CH:17]=[CH:18][C:13]([CH2:12][O:11][C:10]4[CH:31]=[CH:32][CH:33]=[C:8]([C@H:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[NH:34][C:35]([O:37][C@@H:38]5[CH:43]6[CH2:42][CH2:41][N:40]([CH2:45][CH2:44]6)[CH2:39]5)=[O:36])[CH:9]=4)=[CH:14][CH:15]=3)(=[O:20])=[O:21])=[O:28])[CH2:61][C:60]3[C:59]([Cl:79])=[CH:58][N+:57]([O-:80])=[CH:56][C:55]=3[Cl:54])[CH:69]=[CH:68][C:67]=2[O:70][CH:71]([F:73])[F:72])[CH2:78][CH2:77]1

Participants

10

Reactant 6

HCID 313Hydrochloric AcidHCID 3939Lithium HydroxideHCID 6228DimethylformamideHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 71092687HCID 71092687, compoundHCID 118114112HCID 118114112, compound

Product 1

HCID 118114152HCID 118114152, compoundYield 29%

Reagents, catalysts & solvents 3

HCID 142844-(Dimethylamino)pyridineCatalystHCID 887MethanolSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

To a solution of (S)-methyl 1-((4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)phenyl)sulfonyl)pyrrolidine-2-carboxylate (I35, 576 mg, 0.91 mmol) in THF (4 mL) and MeOH (4 mL) was added an aqueous solution of LiOH (1 N, 1.8 mL, 1.8 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. The resulting carboxylic acid was redissolved in DMF (9.0 mL). To a solution of the acid in DMF (3 mL, 0.30 mmol) was then added (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (151 mg, 0.36 mmol) followed by 4-(dimethylamino)-pyridine (18 mg, 0.15 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (151 mg, 0.60 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 (1.5 mL) and purified by preparative HPLC to provide the title compound (90 mg, 29% over two steps) as white solid.

Workup

  1. concentrationThe resulting mixture was then concentrated in vacuo
  2. customazeotroped to dryness with toluene
  3. dissolutionThe resulting carboxylic acid was redissolved in DMF (9.0 mL)
  4. stirringThe resulting mixture was stirred at room temperature for 16 h
  5. custompartitioned between EtOAc (50 mL) and water (20 mL)
  6. dry with materialThe organic layer was dried over MgSO4
  7. filtrationfiltered
  8. customthe solvent was removed in vacuo
  9. dissolutionThe residue was dissolved in DMSO (1.5 mL)
  10. custompurified by preparative HPLC

Sources & evidence

ORD record
ord-8044638b1ca14ebd9b2977849111ea51
Source dataset
uspto-grants-2015_09
Patent number
US09145409B2

Reaction notes

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