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

HRID 1963070Notes

Reaction equation

HRID 1963070 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.[C:31](Cl)(Cl)=[O:32].C1(C)C=CC=CC=1.[C:42]([O:46][C:47]([N:49]1[CH2:54][CH2:53][NH:52][CH2:51][C@@H:50]1[CH2:55][C:56]([O:58][CH3:59])=[O:57])=[O:48])([CH3:45])([CH3:44])[CH3:43].C(N(CC)CC)C>C(Cl)Cl>[C:42]([O:46][C:47]([N:49]1[CH2:54][CH2:53][N:52]([C:31]([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:32])[CH2:51][C@@H:50]1[CH2:55][C:56]([O:58][CH3:59])=[O:57])=[O:48])([CH3:45])([CH3:44])[CH3:43]

Participants

8

Reactant 6

HCID 1049PyridineHCID 1140TolueneHCID 6371PhosgeneHCID 8471TriethylamineHCID 29414379tert-Butyl (2S)-2-(2-methoxy-2-oxoethyl)piperazine-1-carboxylateHCID 677730242-(3-Fluoro-2-methyl-benzyl)-1-phenyl-indolizine

Product 1

HCID 67772153(S)-4-[2-(3-Fluoro-2-methyl-benzyl)-1-phenyl-indolizine-3-carbonyl]-2-methoxycarbonylmethyl-piperazine-1-carboxylic acid tert-butyl ester

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent3×

Procedure

To a solution of the compound of example 1, step 3 (1.32 g, 4.19 mmol) in 20 ml of DCM at 0° C. were added pyridine (0.34 ml, 4.19 mmol) and then a 20% solution of phosgene in toluene (2.20 ml, 4.19 mmol). The mixture was stirred at room temperature for 1.5 h and then added dropwise to an ice-cooled (0° C.) solution of the compound of step 3 (1.189 g, 4.60 mmol) and triethylamine (0.58 ml, 4.60 mmol) in 32 ml of DCM. The mixture was stirred at room temperature overnight, then diluted with 30 ml of DCM and washed twice with 1 N hydrochloric acid, twice with a saturated sodium hydrogencarbonate solution and twice with brine. The organic phase was dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure. The residue was purified by chromatography on silica gel (cyclohexane/EA, 80:20, then 70:30) to give 1.44 g of the title compound as a pale yellow-green powder.

Workup

  1. stirringThe mixture was stirred at room temperature overnight
  2. washwashed twice with 1 N hydrochloric acid, twice with a saturated sodium hydrogencarbonate solution and twice with brine
  3. dry with materialThe organic phase was dried over sodium sulfate
  4. filtrationfiltered
  5. customevaporated to dryness under reduced pressure
  6. customThe residue was purified by chromatography on silica gel (cyclohexane/EA, 80:20

Sources & evidence

ORD record
ord-8abc84f792ad4486bad162b0d90f1284
Source dataset
uspto-grants-2013_04
Patent number
US08415336B2

Reaction notes

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