Acetic Acid → 2-(4-((((R)-2-Hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-2-methylphenoxy)ethyl 4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl) phenoxy)methyl)benzoate

HRID 877315Notes

Reaction equation

HRID 877315 reaction equation
Cl.[NH2:2][CH2:3][C@@H:4]([C:6]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]2[C:7]=1[CH:8]=[CH:9][C:10](=[O:17])[NH:11]2)[OH:5].C(N(CC)CC)C.[C:25]1([C@H:31]([NH:61][C:62]([O:64][C@@H:65]2[CH:70]3[CH2:71][CH2:72][N:67]([CH2:68][CH2:69]3)[CH2:66]2)=[O:63])[C:32]2[CH:33]=[C:34]([CH:58]=[CH:59][CH:60]=2)[O:35][CH2:36][C:37]2[CH:57]=[CH:56][C:40]([C:41]([O:43][CH2:44][CH2:45][O:46][C:47]3[CH:52]=[CH:51][C:50]([CH:53]=O)=[CH:49][C:48]=3[CH3:55])=[O:42])=[CH:39][CH:38]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>CO>[C:25]1([C@H:31]([NH:61][C:62]([O:64][C@@H:65]2[CH:70]3[CH2:71][CH2:72][N:67]([CH2:68][CH2:69]3)[CH2:66]2)=[O:63])[C:32]2[CH:33]=[C:34]([CH:58]=[CH:59][CH:60]=2)[O:35][CH2:36][C:37]2[CH:57]=[CH:56][C:40]([C:41]([O:43][CH2:44][CH2:45][O:46][C:47]3[CH:52]=[CH:51][C:50]([CH2:53][NH:2][CH2:3][C@H:4]([OH:5])[C:6]4[CH:15]=[CH:14][C:13]([OH:16])=[C:12]5[C:7]=4[CH:8]=[CH:9][C:10](=[O:17])[NH:11]5)=[CH:49][C:48]=3[CH3:55])=[O:42])=[CH:39][CH:38]=2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1

Participants

7

Reactant 5

HCID 176Acetic AcidHCID 8471TriethylamineHCID 5049666Sodium triacetoxyborohydrideHCID 71093241(R)-5-(2-Amino-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one hydrochlorideHCID 867208162-(4-formyl-2-methylphenoxy)ethyl 4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoate

Product 1

HCID 747639462-(4-((((R)-2-Hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-2-methylphenoxy)ethyl 4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl) phenoxy)methyl)benzoateYield 11%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent2×

Procedure

To a suspension of (R)-5-(2-amino-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one hydrochloride (0.211 g, 0.83 mmol) in methanol (6 mL) was added triethylamine (0.229 mL, 1.65 mmol). The mixture was stirred for 10 minutes and then a solution of 2-(4-formyl-2-methylphenoxy)ethyl 4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoate (0.445 g, 0.69 mmol) in methanol (2 mL) was added. The mixture was stirred at RT for 1 hour. Sodium triacetoxyborohydride (0.292 g, 1.38 mmol) followed by acetic acid (0.188 mL, 3.28 mmol) added and the reaction continued for a further 18 hours. The reaction mixture was quenched with water and evaporated at reduced pressure. The residue dissolved in iso-butanol and washed with water. The organic phase was evaporated at reduced pressure and the crude material was purified by reverse phase preparative HPLC to afford the title compound (0.065 g, 11%).

Workup

  1. stirringThe mixture was stirred at RT for 1 hour
  2. additionadded
  3. waitthe reaction continued for a further 18 hours
  4. customThe reaction mixture was quenched with water
  5. customevaporated at reduced pressure
  6. dissolutionThe residue dissolved in iso-butanol
  7. washwashed with water
  8. customThe organic phase was evaporated at reduced pressure
  9. customthe crude material was purified by reverse phase preparative HPLC

Sources & evidence

ORD record
ord-926a3a23246440fcaae9c7854b9fb0e6
Source dataset
uspto-grants-2015_03
Patent number
US08987299B2

Reaction notes

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