Pyridine → 4-[1-Cyclohexyl-2-(3-fluoro-2-methyl-benzyl)-indolizine-3-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester

HRID 1963047Notes

Reaction equation

[CH:1]1([C:7]2[C:8]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=3[CH3:24])=[CH:9][N:10]3[C:15]=2[CH:14]=[CH:13][CH:12]=[CH:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.Cl[C:32](Cl)([O:34]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[C:50]([O:54][C:55]([N:57]1[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]1)=[O:56])([CH3:53])([CH3:52])[CH3:51]>C(Cl)Cl.Cl>[C:50]([O:54][C:55]([N:57]1[CH2:62][CH2:61][N:60]([C:32]([C:9]2[N:10]3[C:15]([CH:14]=[CH:13][CH:12]=[CH:11]3)=[C:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[C:8]=2[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=2[CH3:24])=[O:34])[CH2:59][CH2:58]1)=[O:56])([CH3:53])([CH3:51])[CH3:52]

Participants

Conditions

Temperature: 0 °C

Procedure

The compound of step 2 (0.488 g, 1.52 mmol) was dissolved in DCM (15.2 ml) under argon and cooled at 0° C. Pyridine (0.12 ml, 1.52 mmol) and triphosgene (0.45 g, 1.52 mmol) were added and the mixture stirred at room temperature for 2 h. The mixture was then cooled to 0° C. and triethylamine (0.85 ml, 6.07 mmol) and 1-tert-butoxycarbonyl-piperazine (1.13 g, 6.07 mmol) were added. The mixture was stirred at room temperature overnight, then diluted with 1 N hydrochloric acid and extracted with DCM. The organic phases were washed with a saturated solution of sodium hydrogencarbonate and twice with a saturated solution of sodium chloride, dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified by silica gel chromatography (cyclohexane/EA, 100:0, then 50:50) to give 0.686 g of 4-[1-cyclohexyl-2-(3-fluoro-2-methyl-benzyl)-indolizine-3-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester as a beige foam. The obtained product was dissolved in 10 ml of DCM, the solution cooled to 0° C. under a nitrogen atmosphere and a solution of TFA (1.91 ml, 25.7 mmol) in 1.91 ml of DCM added. After stirring at room temperature overnight, the mixture was evaporated to dryness under reduced pressure and the residue two times admixed with toluene and evaporated to dryness again. The residue was purified by chromatography on silica gel (DCM/MOH, 9:1, containing 1% of ammonia) to give 0.600 g of [1-cyclohexyl-2-(3-fluoro-2-methyl-benzyl)-indolizin-3-yl]-piperazin-1-yl-methanone. For conversion into the hydrochloride, the obtained product was dissolved in 15 ml of DCM and a 4 N solution of hydrogen chloride in dioxane (0.69 ml, 2.77 mmol) was added. The solution was stirred for 1 h at room temperature and concentrated to dryness under reduced pressure. The solid was triturated three times with diethyl ether, filtered and dried in vacuo at 65° C. to give 0.422 g of the title compound in the form of [1-cyclohexyl-2-(3-fluoro-2-methyl-benzyl)-indolizin-3-yl]-piperazin-1-yl-methanone hydrochloride as an off-white powder with the following characteristics:

Workup

temperatureThe mixture was then cooled to 0° C.
stirringThe mixture was stirred at room temperature overnight
extractionextracted with DCM
washThe organic phases were washed with a saturated solution of sodium hydrogencarbonate and twice with a saturated solution of sodium chloride
dry with materialdried over sodium sulfate
filtrationfiltered
customevaporated to dryness
customThe residue was purified by silica gel chromatography (cyclohexane/EA, 100:0

Sources & evidence

ORD record: ord-f8a0a2765d9142f9be8e96b170e5b73d
Source dataset: uspto-grants-2013_04
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08415336B2

Reaction notes

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