Methanesulfonyl chloride → 1-Benzyl 4-tert-butyl 2-(aminomethyl)piperazine-1,4-dicarboxylate

HRID 429283Notes

Reaction equation

HRID 429283 reaction equation
[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]1[CH2:24]O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:29](C(C)C)CC)(C)C.CS(Cl)(=O)=O>C(Cl)Cl.CCOC(C)=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]1[CH2:24][NH2:29])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

6

Reactant 3

HCID 31297Methanesulfonyl chlorideHCID 81531DiisopropylethylamineHCID 235310394-(1,1-Dimethylethyl) 1-(phenylmethyl) 2-(hydroxymethyl)-1,4-piperazinedicarboxylate

Product 1

HCID 534139031-Benzyl 4-tert-butyl 2-(aminomethyl)piperazine-1,4-dicarboxylateYield 3.7%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a 0° C. solution of 1.30 g of 1-(benzyloxycarbonyl)-2-hydroxymethyl-4-(tert-butyloxycarbonyl)-piperazine in 20 mL of CH2Cl2 was added 720 mg of diisopropylethylamine, then 510 mg of methanesulfonyl chloride. The mixture was allowed to warm to room temperature over 2 h, then diluted with 50 mL of EtOAc and washed with 25 mL of saturated NaHCO3, 2×25 mL of 1N HCl, 25 mL of saturated NaHCO3, and 25 mL of brine. The organic phase was dried over MgSO4 and concentrated to a yellow oil. This oil was dissolved in 10 mL of DMF and 360 mg of sodium azide was added. The mixture was heated to 100° C. and stirred overnight at this temperature, then cooled, diluted with 25 mL of EtOAc, and washed with 3×10 mL of water and 10 ml of brine. The organic phase was dried over MgSO4 and concentrated to an oily yellow solid. Of this solid, 475 mg was dissolved in 5 mL of 9:1 THF-water and 398 mg of triphenylphosphine was added. The mixture was heated to 50° C. and stirred at this temperature for 16 h, then cooled, poured into 30 mL of 1N HCl, and extracted with 2×10 mL of EtOAc. The aqueous phase was made very basic (pH>12) by addition of 5N NaOH, then extracted with 5×20 mL of EtOAc. The combined organic extracts were dried over MgSO4, and concentrated to yield 48 mg of the title compound. 1H NMR (500 MHz, CDCl3): δ7.28-7.40 (m, 5H), 5.15 (ABq, J=12.4 Hz, 2H), 3.82-4.22 (m, 4H), 2.66-3.30 (m, 5H), 1.45 (br s, 9H).

Workup

  1. washwashed with 25 mL of saturated NaHCO3, 2×25 mL of 1N HCl, 25 mL of saturated NaHCO3, and 25 mL of brine
  2. dry with materialThe organic phase was dried over MgSO4
  3. concentrationconcentrated to a yellow oil
  4. dissolutionThis oil was dissolved in 10 mL of DMF
  5. addition360 mg of sodium azide was added
  6. temperatureThe mixture was heated to 100° C.
  7. temperaturecooled
  8. additiondiluted with 25 mL of EtOAc
  9. washwashed with 3×10 mL of water and 10 ml of brine
  10. dry with materialThe organic phase was dried over MgSO4
  11. concentrationconcentrated to an oily yellow solid
  12. dissolutionOf this solid, 475 mg was dissolved in 5 mL of 9:1 THF-water
  13. addition398 mg of triphenylphosphine was added
  14. temperatureThe mixture was heated to 50° C.
  15. stirringstirred at this temperature for 16 h
  16. temperaturecooled
  17. additionpoured into 30 mL of 1N HCl
  18. extractionextracted with 2×10 mL of EtOAc
  19. additionby addition of 5N NaOH
  20. extractionextracted with 5×20 mL of EtOAc
  21. dry with materialThe combined organic extracts were dried over MgSO4
  22. concentrationconcentrated

Sources & evidence

ORD record
ord-9f248a914be54390852f34e157d062e4
Source dataset
uspto-grants-2001_11
Patent number
US06316444B1

Reaction notes

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