Sodium Hydroxide → (7-{5-[1-(4-Fluoro-phenyl)-1-hydroxy-ethyl]-[1,2,3]triazol-1-yl}-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)-acetic acid

HRID 570641Notes

Reaction equation

HRID 570641 reaction equation
[N:1]([CH:4]1[CH2:23][N:8]2[C:9]3[C:14]([C:15]([CH2:16][C:17]([O:19]CCC)=[O:18])=[C:7]2[CH2:6][CH2:5]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N+:2]=[N-:3].[F:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([OH:35])([C:33]#[CH:34])[CH3:32])=[CH:27][CH:26]=1.[OH-].[Na+]>>[F:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]([C:33]2[N:1]([CH:4]3[CH2:23][N:8]4[C:9]5[C:14]([C:15]([CH2:16][C:17]([OH:19])=[O:18])=[C:7]4[CH2:6][CH2:5]3)=[CH:13][CH:12]=[CH:11][CH:10]=5)[N:2]=[N:3][CH:34]=2)([OH:35])[CH3:32])=[CH:29][CH:30]=1

Participants

4

Reactant 3

HCID 14798Sodium HydroxideHCID 162178622-(4-Fluorophenyl)-3-butyn-2-olHCID 59487226Propyl (7-azido-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)acetate

Product 1

HCID 46893925(7-{5-[1-(4-Fluoro-phenyl)-1-hydroxy-ethyl]-[1,2,3]triazol-1-yl}-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)-acetic acid

Procedure

The title compound was prepared using analogous procedures described in EXAMPLE 3 from propyl (7-azido-6,7,8,9-tetrahydropyrido[1,2-α]indol-10-yl)acetate and 2-(4-fluorophenyl)but-3-yn-2-ol. Separation of the resulting diastereoisomers was performed at the ester stage by flash chromatography using a gradient of 10-70% EA/Hex afforded two enantiomeric mixtures. The faster eluting enantiomeric mixture was resolved on chiral HPLC using a 50×400 mm Chiralcel OD column eluting with 8% iPrOH, 8% EtOH, 83.75% Hexanes and 0.25% Et3N at 60 mL/min and 254 nm. The resulting esters (retention times=18.4 and 22.1 min) were hydrolyzed separately in THF/MeOH (2:1, 0.1M) at room temperature using 1M solution of sodium hydroxide (10 eq). The reaction mixture was stirred at room temperature for 2 h then quenched by adding HCl 10% until acidic pH and diluted with DCM. Filtration through a phase separator followed by evaporation afforded the desired EXAMPLE 5.1 and 5.2 respectively. The slower eluting enantiomeric mixture was resolved on chiral HPLC using a 50×400 mm Chiralcel OD eluting with 30% iPrOH, 70% Hexanes at 60 mL/min and 254 nm. The resulting esters (retention times=18.3 and 34 min) were hydrolyzed in a similar fashion as described above to afford EXAMPLE 5.3 and 5.4 respectively. 1H NMR data is for EXAMPLE 5.1: 1H NMR (400 MHz, DMSO-d6): δ 12.13 (s, 1 H), 7.97 (s, 1 H), 7.45 (d, 1 H), 7.36 (dd, 2 H), 7.31 (d, 1 H), 7.20 (t, 2 H), 7.11-7.00 (m, 2 H), 6.68 (s, 1 H), 5.03 (s, 1 H), 4.54 (dd, 1 H), 4.24 (t, 1 H), 3.60-3.48 (m, 2 H), 3.01-2.91 (m, 1 H), 2.37-2.26 (m, 1 H), 2.02-1.93 (m, 1 H), 1.90 (s, 3 H), 1.36-1.24 (m, 1 H). MS (+ESI) m/z: 435.1.

Workup

  1. customSeparation of the resulting diastereoisomers
  2. customafforded two enantiomeric mixtures
  3. washThe faster eluting enantiomeric mixture
  4. washeluting with 8% iPrOH, 8% EtOH, 83.75% Hexanes and 0.25% Et3N at 60 mL/min and 254 nm
  5. customThe resulting esters (retention times=18.4 and 22.1 min)
  6. customwere hydrolyzed separately in THF/MeOH (2:1, 0.1M) at room temperature
  7. customthen quenched
  8. additionby adding HCl 10% until acidic pH
  9. additiondiluted with DCM
  10. filtrationFiltration through a phase separator
  11. customfollowed by evaporation
  12. customafforded the desired EXAMPLE 5.1 and 5.2 respectively
  13. washThe slower eluting enantiomeric mixture
  14. washeluting with 30% iPrOH, 70% Hexanes at 60 mL/min and 254 nm
  15. customThe resulting esters (retention times=18.3 and 34 min)
  16. customto afford EXAMPLE 5.3 and 5.4 respectively

Sources & evidence

ORD record
ord-1b909727b1aa4d3fac3319a2589e9c2f
Source dataset
uspto-grants-2015_05
Patent number
US09023864B2

Reaction notes

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