Pyridine → 4-[2-(3-Fluoro-2-methyl-benzyl)-1-phenyl-indolizin-3-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester

HRID 1963044Notes

Reaction equation

HRID 1963044 reaction equation
[F:1][C:2]1[C:3]([CH3:24])=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH2:5][C:6]1[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:8]2[N:13]([CH:14]=1)[CH:12]=[CH:11][CH:10]=[CH:9]2.N1C=CC=CC=1.Cl[C:32](Cl)([O:34]C(=O)OC(Cl)(Cl)Cl)Cl.[C:43]([O:47][C:48]([N:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1)=[O:49])([CH3:46])([CH3:45])[CH3:44].C(N(CC)CC)C>C(Cl)Cl.Cl>[C:43]([O:47][C:48]([N:50]1[CH2:55][CH2:54][N:53]([C:32]([C:14]2[N:13]3[C:8]([CH:9]=[CH:10][CH:11]=[CH:12]3)=[C:7]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:6]=2[CH2:5][C:4]2[CH:21]=[CH:22][CH:23]=[C:2]([F:1])[C:3]=2[CH3:24])=[O:34])[CH2:52][CH2:51]1)=[O:49])([CH3:46])([CH3:44])[CH3:45]

Participants

8

Reactant 5

HCID 1049PyridineHCID 8471TriethylamineHCID 94429TriphosgeneHCID 143452tert-Butyl piperazine-1-carboxylateHCID 677730242-(3-Fluoro-2-methyl-benzyl)-1-phenyl-indolizine

Product 1

HCID 677735834-[2-(3-Fluoro-2-methyl-benzyl)-1-phenyl-indolizin-3-carbonyl]-piperazine-1-carboxylic acid tert-butyl esterYield 76.8%

Reagents, catalysts & solvents 2

HCID 313Hydrochloric AcidSolventHCID 6344DichloromethaneSolvent2×

Conditions

Temperature
0 °C

Procedure

The compound of step 3 (0.635 g, 2.01 mmol) was dissolved in DCM (5 ml) under argon and cooled at 0° C. Pyridine (0.16 ml, 2.01 mmol) and triphosgene (0.598 g, 2.01 mmol) were added, and the mixture was stirred at room temperature for 80 min. The mixture was then added dropwise to a solution of 1-tert-butoxycarbonyl-piperazine (1.50 g, 8.05 mmol) and triethylamine (1.12 ml, 8.05 mmol) in DCM (15 ml) cooled to 0° C. After stirring at room temperature overnight, the mixture was diluted with 1 N hydrochloric acid and extracted with DCM. The extracts were washed with a saturated solution of sodium hydrogencarbonate and twice washed with saturated solution of sodium chloride. The organic phase was dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified by silica gel chromatography with DCM/MOH (from 100:0 to 98:2) and subsequent silica gel chromatography with cyclohexane/EA (from 100:0 to 70:30) to give 0.815 g of 4-[2-(3-fluoro-2-methyl-benzyl)-1-phenyl-indolizin-3-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester as a light pink powder. For removal of the tert-butoxycarbonyl group and conversion into the hydrochloride, 0.689 g of the obtained product were dissolved in DCM (10 ml), the solution cooled to 0° C. and saturated with gaseous hydrogen chloride. After stirring for 1 h at 0° C., the mixture was evaporated to dryness. The residue was triturated with diethyl ether, filtered, washed with diethyl ether and dried under reduced pressure to give 0.53 g of the title compound in the form of [2-(3-fluoro-2-methyl-benzyl)-1-phenyl-indolizin-3-yl]-piperazin-1-yl-methanone hydrochloride as an off-white powder with the following characteristics:

Workup

  1. temperaturecooled to 0° C
  2. stirringAfter stirring at room temperature overnight
  3. extractionextracted with DCM
  4. washThe extracts were washed with a saturated solution of sodium hydrogencarbonate
  5. washtwice washed with saturated solution of sodium chloride
  6. dry with materialThe organic phase was dried over sodium sulfate
  7. filtrationfiltered
  8. customevaporated to dryness
  9. customThe residue was purified by silica gel chromatography with DCM/MOH (from 100:0 to 98:2) and subsequent silica gel chromatography with cyclohexane/EA (from 100:0 to 70:30)

Sources & evidence

ORD record
ord-fbd8949dce79487ead001a53ba69a50a
Source dataset
uspto-grants-2013_04
Patent number
US08415336B2

Reaction notes

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