4-Methylmorpholine → HCID 16124590, compound

HRID 2063320Notes

Reaction equation

HRID 2063320 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])[C@@H:13]([C:24](O)=[O:25])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[BH4-].[Na+]>C(COC)OC.O>[OH:25][CH2:24][C@H:13]1[CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:16][CH2:15][N:14]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]

Participants

7

Reactant 4

HCID 79724-MethylmorpholineHCID 62365Isobutyl chloroformateHCID 4311764Sodium borohydrideHCID 7010654(2R)-4-[(Benzyloxy)carbonyl]-1-(tert-butoxycarbonyl)piperazine-2-carboxylic acid

Product 1

HCID 16124590HCID 16124590, compoundYield 87.8%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
0 °C

Procedure

(2R)-4-[(Benzyloxy)carbonyl]-1-(tert-butoxycarbonyl)piperazine-2-carboxylic acid (1.4 g, 3.9 mmol) was dissolved in dimethoxyethane (10 mL) and to the cooled resultant solution was added N-methylmorpholine (0.4 g, 3.9 mmol) followed by isobutyl chloroformate (0.54 g, 3.9 mmol) by means of drops. The mixture was stirred at 0° C. for 20 min and then the mixture was filtered. The filtrate was transferred to a 500 mL flask and then cooled again. Sodium borohydride (0.22 g, 5.9 mmol) dissolved in water (5 mL) was added and the external cooling bath was removed. The reaction mixture was stirred until the temperature of it had reached RT whereupon water (120 mL) was added. The mixture was extracted trice with ethyl acetate and the combined organic solutions were dried and then evaporated. The product was purified by column chromatography on silica gel (ethyl acetate-heptane 10% to 70%). There was obtained 1.2 g (84%) of 4-benzyl 1-tert-butyl (2R)-2-(hydroxymethyl)piperazine-1,4-dicarboxylate as a colorless oil. 1H NMR (500 MHz, CDCl3): 1.4 (s, 9H), 2.7-3.2 (b, 4H), 3.5 (b, 2H), 3.8-4.2 (m, 4H), 5.1 (m, 2H), 7.2-7.4 (m, 5H); LCMS: m/z 349 (M−1)−.

Workup

  1. temperatureto the cooled resultant solution
  2. filtrationthe mixture was filtered
  3. customThe filtrate was transferred to a 500 mL flask
  4. temperaturecooled again
  5. additionwas added
  6. customthe external cooling bath was removed
  7. stirringThe reaction mixture was stirred until the temperature of it
  8. customhad reached RT whereupon water (120 mL)
  9. additionwas added
  10. extractionThe mixture was extracted trice with ethyl acetate
  11. customthe combined organic solutions were dried
  12. customevaporated
  13. customThe product was purified by column chromatography on silica gel (ethyl acetate-heptane 10% to 70%)

Sources & evidence

ORD record
ord-52bf6095f3fe43059d8c9b38ae6cd62f
Source dataset
uspto-grants-2012_10
Patent number
US08288370B2

Reaction notes

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