Trimethylsilylacetylene → {4-Fluoro-7-[5-(4-fluoro-benzyl)-[1,2,3]triazol-1-yl]-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl}-acetic acid

HRID 570645Notes

Reaction equation

HRID 570645 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].[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]#[CH:34])=[CH:28][CH:27]=1.C([Si](C)(C)C)#C.C([Mg]Br)C.FC1C=CC(CBr)=CC=1>C1COCC1.[Cu](Br)Br>[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:33]([CH2:32][C:29]4[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=4)=[CH:34][N:3]=[N:2]3)[CH2:5][CH2:6][C:7]1=[C:15]2[CH2:16][C:17]([OH:19])=[O:18]

Participants

8

Reactant 5

HCID 66111TrimethylsilylacetyleneHCID 680214-Fluorobenzyl bromideHCID 105586681-Fluoro-4-prop-2-ynyl-benzeneHCID 86645392Propyl (7-azido-4-fluoro-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)acetateHCID 178418443HCID 178418443, compound

Product 1

HCID 46893928{4-Fluoro-7-[5-(4-fluoro-benzyl)-[1,2,3]triazol-1-yl]-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl}-acetic acid

Reagents, catalysts & solvents 2

HCID 24611Copper bromide (CuBr2)CatalystHCID 8028TetrahydrofuranSolvent2×

Procedure

The title compound was prepared using analogous procedures described in EXAMPLE 3 from propyl (7-azido-4-fluoro-6,7,8,9-tetrahydropyrido[1,2-α]indol-10-yl)acetate (EXAMPLE 7, Step 6) and 1-fluoro-4-prop-2-yn-1-ylbenzene obtained according to the following procedure (Gazz. Chim. Ital. 1990, 120, 783). To a mixture of ethynyltrimethylsilane (1 eq) in THF (0.6M) at room temperature was added ethylmagnesium bromide (1 eq). The mixture was stirred at room temperature for 30 min then copper bromide (I) (0.1 eq) was added. After stirring for 30 min, a 1M solution of 4-fluorobenzyl bromide (1 eq) in THF was added and the mixture was heated to reflux overnight. The reaction mixture was quenched by addition to a cold solution of NH4Cl sat, stirred for 30 min then extracted with Et2O, washed with brine, dried and evaporated. Purification by Combi-flash using a gradient of 0-100% EA/Hex afforded the desired TMS alkyne. The TMS alkyne was directly mixed with potassium fluoride (1.2 eq) in DMF (0.2M containing 1% water). The mixture was stirred at room temperature overnight then quenched by addition of HCl 3N, stirred for 1 h then extracted with pentanes, washed with NaHCO3 sat, brine, dried and evaporated. Crude alkyne compound was used directly for click chemistry described in EXAMPLE 3. The resulting racemic esters were resolved by HPLC using a 4.6×250 mm Chiralpak AS column eluting with 60% EtOH, 39.75% Hexanes and 0.25% Et3N at 0.8 mL/min and 254 nm. The resulting chiral esters (retention times=10.3 and 13.3 min) were hydrolyzed to afford EXAMPLE 8.1 and 8.2 respectively. 11-1 NMR of EXAMPLE 8.1: 1H NMR (400 MHz, DMSO-d6): δ 12.20 (s, 1 H), 7.55 (s, 1 H), 7.33 (dd, 2 H), 7.27 (d, 1 H), 7.17 (t, 2 H), 6.96 (td, 1 H), 6.85 (dd, 1 H), 5.23-5.09 (m, 1 H), 4.58 (dd, 1 H), 4.44 (dd, 1 H), 4.25 (s, 2 H), 3.65-3.52 (m, 2 H), 3.12-3.02 (m, 1 H), 2.89 (ddd, 1 H), 2.32-2.19 (m, 1 H), 2.14-2.02 (m, 1 H). MS (+ESI) m/z: 423.1.

Workup

  1. customobtained
  2. stirringAfter stirring for 30 min
  3. temperaturethe mixture was heated
  4. temperatureto reflux overnight
  5. customThe reaction mixture was quenched by addition to a cold solution of NH4Cl
  6. stirringstirred for 30 min
  7. extractionthen extracted with Et2O
  8. washwashed with brine
  9. customdried
  10. customevaporated
  11. customPurification by Combi-flash

Sources & evidence

ORD record
ord-58a191f3f8bb41a483020128351a3d3e
Source dataset
uspto-grants-2015_05
Patent number
US09023864B2

Reaction notes

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