Phosgene → HCID 131721775, compound

HRID 1858851Notes

Reaction equation

HRID 1858851 reaction equation
[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH:24]([O:25][CH2:26][C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)[CH2:23][N:22]([C:37]([O-:39])=[O:38])[CH2:21][CH:20]2[CH2:40][OH:41])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:42](=[O:45])([O-])[O-].[Li+].[Li+].C(Cl)(Cl)=O.[NH2:52][CH2:53][CH2:54][CH2:55][N:56]1[CH2:61][CH2:60][N:59]([CH3:62])[CH2:58][CH2:57]1>O1CCCC1.C1(C)C=CC=CC=1.C(Cl)Cl>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]2[CH:24]([O:25][CH2:26][C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)[CH2:23][N:22]([C:37]([O:39][C:2]([CH3:7])([CH3:3])[CH3:1])=[O:38])[CH2:21][CH:20]2[CH2:40][O:41][C:42](=[O:45])[NH:52][CH2:53][CH2:54][CH2:55][N:56]2[CH2:57][CH2:58][N:59]([CH3:62])[CH2:60][CH2:61]2)=[CH:17][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1

Participants

8

Reactant 4

HCID 6371PhosgeneHCID 11125Lithium CarbonateHCID 783281-(3-Aminopropyl)-4-methylpiperazineHCID 22127100HCID 22127100, compound

Product 1

HCID 131721775HCID 131721775, compoundYield 73%

Reagents, catalysts & solvents 3

HCID 1140TolueneSolventHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent2×

Procedure

A mixture of 90 mg (0.15 mmol) of tert-butyl 3SR,4RS,5RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-hydroxymethyl-5-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate [Example 148(h)] and 60 mg (0.75 mmol) of lithium carbonate in 10 ml of dry tetrahydrofuran was cooled to 0° C. A solution of 0.90 ml (1.6 mmol) of phosgene in toluene (1.93N) was added dropwise thereto while cooling with ice. The mixture was stirred at room temperature overnight in order complete the reaction. The reaction mixture was evaporated under reduced pressure in order to remove the excess phosgene and the crude chloroformate obtained was taken up in 10 ml of tetrahydrofuran. This mixture was treated with 58 mg (0.38 mmol) of 1-(3-aminopropyl)-4-methylpiperizine and stirred at room temperature for 3 hours. For the working-up, the reaction mixture was diluted with 40 ml of methylene chloride and then extracted with 20 ml of water. The organic phase was dried over sodium sulphate and subsequently evaporated under reduced pressure. For purification, the residue was chromatographed on silica gel using a 95:5:0.1 mixture of methylene chloride, methanol and ammonia as the eluent. There were obtained 85 mg (73% of theory) of tert-butyl (3SR,4RS,5RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-[3-(4-methyl-piperazin-1-yl)-propylcarbamoyloxymethyl]-5-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless solid; MS: 795 (M+H)+.

Workup

  1. additionA mixture of 90 mg (0.15 mmol) of tert-butyl
  2. temperaturewhile cooling with ice
  3. customthe reaction
  4. customThe reaction mixture was evaporated under reduced pressure in order
  5. customto remove the excess phosgene
  6. customthe crude chloroformate obtained
  7. stirringstirred at room temperature for 3 hours
  8. extractionextracted with 20 ml of water
  9. dry with materialThe organic phase was dried over sodium sulphate
  10. customsubsequently evaporated under reduced pressure
  11. customFor purification
  12. customthe residue was chromatographed on silica gel using
  13. additiona 95:5:0.1 mixture of methylene chloride, methanol and ammonia as the eluent

Sources & evidence

ORD record
ord-aab8db8a29e043cc91d4bb0e0494a95b
Source dataset
uspto-grants-2000_11
Patent number
US06150526

Reaction notes

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