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

HRID 570671Notes

Reaction equation

HRID 570671 reaction equation
[N:1]([CH:4]1[CH2:24][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][C:10]=3[F:23])=[N+:2]=[N-:3].[CH3:25][CH:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:27]#[CH:28].BrC(C1C=CC=CC=1)C.C([Si](C)(C)C)#C>>[F:23][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[N:8]1[CH2:24][CH:4]([N:1]3[C:27]([CH:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH3:25])=[CH:28][N:3]=[N:2]3)[CH2:5][CH2:6][C:7]1=[C:15]2[CH2:16][C:17]([OH:19])=[O:18]

Participants

5

Reactant 4

HCID 11454(1-Bromoethyl)benzeneHCID 66111TrimethylsilylacetyleneHCID 575422(1-Methyl-2-propynyl)benzeneHCID 86645392Propyl (7-azido-4-fluoro-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)acetate

Product 1

HCID 46892898{4-Fluoro-7-[5-(1-phenyl-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 procedures described in EXAMPLE 8 from propyl (7-azido-4-fluoro-6,7,8,9-tetrahydropyrido[1,2-α]indol-10-yl)acetate and (1-methylprop-2-yn-1-yl)benzene prepared from (1-bromoethyl)benzene and ethynyltrimethylsilane. Separation of the resulting diastereoisomeric esters by flash chromatography using a gradient of 10-70% EA/Hex afforded 2 enantiomeric mixtures. The less polar enantiomeric mixture was resolved on chiral HPLC using a 4.6×250 mm Chiralpak AD column eluting with 20% iPrOH, 20% EtOH, 59.75% Hexanes and 0.25% Et3N at 1 mL/min and 254 nm. The resulting chiral esters (retention times=7.8 and 11.9 min) were hydrolyzed separately to afford EXAMPLE 32.1 and 32.2 respectively. The more polar enantiomeric mixture was resolved on chiral HPLC using a 4.6×250 mm Chiralcel OD column eluting with 20% MeOH, 20% EtOH, 60% Hexanes at 1 mL/min and 254 nm. The resulting chiral esters (retention times=9.6 and 10.5 min) were hydrolyzed separately to afford EXAMPLE 32.3 and 32.4 respectively. MS (+ESI) m/z: 419.2.

Workup

  1. customSeparation of the resulting diastereoisomeric esters by flash chromatography
  2. customafforded 2 enantiomeric mixtures
  3. washeluting with 20% iPrOH, 20% EtOH, 59.75% Hexanes and 0.25% Et3N at 1 mL/min and 254 nm
  4. customThe resulting chiral esters (retention times=7.8 and 11.9 min)
  5. customto afford EXAMPLE 32.1 and 32.2 respectively
  6. washeluting with 20% MeOH, 20% EtOH, 60% Hexanes at 1 mL/min and 254 nm
  7. customThe resulting chiral esters (retention times=9.6 and 10.5 min)
  8. customto afford EXAMPLE 32.3 and 32.4 respectively

Sources & evidence

ORD record
ord-ef9b969881d7446cb3a47cc98cc6fe01
Source dataset
uspto-grants-2015_05
Patent number
US09023864B2

Reaction notes

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