1,2-Dichloroethane → (R)-Quinuclidin-3-yl((S)-(3-((4-((2-(1,3-dioxolan-2-yl)ethyl)(benzyl)-carbamoyl)benzyl)oxy)phenyl)(phenyl)methyl)carbamate

HRID 874830Notes

Reaction equation

HRID 874830 reaction equation
C(N(CC)CC)C.[C:8]1([C@H:14]([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:15]2[CH:16]=[C:17]([CH:29]=[CH:30][CH:31]=2)[O:18][CH2:19][C:20]2[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][CH:21]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.OC1C=CC=C[N+]=1[O-].C(Cl)CCl.[CH2:56]([NH:63][CH2:64][CH2:65][CH:66]1[O:70][CH2:69][CH2:68][O:67]1)[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1>CN(C=O)C.C(OCC)(=O)C>[N:38]12[CH2:43][CH2:42][CH:41]([CH2:40][CH2:39]1)[C@@H:36]([O:35][C:33](=[O:34])[NH:32][C@H:14]([C:15]1[CH:31]=[CH:30][CH:29]=[C:17]([O:18][CH2:19][C:20]3[CH:28]=[CH:27][C:23]([C:24](=[O:26])[N:63]([CH2:64][CH2:65][CH:66]4[O:67][CH2:68][CH2:69][O:70]4)[CH2:56][C:57]4[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=4)=[CH:22][CH:21]=3)[CH:16]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:37]2

Participants

8

Reactant 5

HCID 111,2-DichloroethaneHCID 8471TriethylamineHCID 11769681N-benzyl-2-(1,3-dioxolan-2-yl)ethanamineHCID 867208154-((3-((S)-Phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)-phenoxy)methyl)benzoic acidHCID 178526252HCID 178526252, compound

Product 1

HCID 90209997(R)-Quinuclidin-3-yl((S)-(3-((4-((2-(1,3-dioxolan-2-yl)ethyl)(benzyl)-carbamoyl)benzyl)oxy)phenyl)(phenyl)methyl)carbamateYield 87.1%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

Triethylamine (0.278 mL, 2.00 mmol) was added to a solution of 4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoic acid (0.418 g, 0.80 mmol) in DMF (2 mL). This mixture was stirred at room temperature for 5 minutes and then 2-hydroxypyridine-N-oxide (0.107 g, 0.96 mmol) and EDC (0.184 g, 0.96 mmol) and the mixture stirred for a further 10 minutes. A solution of N-benzyl-2-(1,3-dioxolan-2-yl)ethanamine (0.331 g, 1.6 mmol) in DMF (2 mL) was added. The reaction mixture was heated at 40° C. for 4 hours followed by stirring at room temperature for 48 hours. The reaction mixture was diluted with ethyl acetate and washed with 10% aqueous potassium carbonate and twice with brine. The organic phase was dried (magnesium sulfate), filtered and the solvent evaporated at reduced pressure. The residue was purified by flash column chromatography eluting with 100% ethyl acetate to 8% methanolic ammonia/ethyl acetate to afford the title compound (0.471 g, 87%). The material was used in the next step with no further characterisation.

Workup

  1. temperatureThe reaction mixture was heated at 40° C. for 4 hours
  2. stirringby stirring at room temperature for 48 hours
  3. washwashed with 10% aqueous potassium carbonate and twice with brine
  4. dry with materialThe organic phase was dried (magnesium sulfate)
  5. filtrationfiltered
  6. customthe solvent evaporated at reduced pressure
  7. customThe residue was purified by flash column chromatography
  8. washeluting with 100% ethyl acetate to 8% methanolic ammonia/ethyl acetate

Sources & evidence

ORD record
ord-ffede51b5f044293a6cdb0e75d33447c
Source dataset
uspto-grants-2015_03
Patent number
US08980913B2

Reaction notes

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