Ethyl Acetate → Benzyl piperazine-1-carboxylate

HRID 260899Notes

Reaction equation

HRID 260899 reaction equation
C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[OH-].[Na+].C(OCC)(=O)C>Cl.O1CCOCC1>[CH2:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)=[O:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1

Participants

5

Reactant 3

HCID 8857Ethyl AcetateHCID 14798Sodium HydroxideHCID 15016698Benzyl tert-butyl piperazine-1,4-dicarboxylate

Product 1

HCID 643495Benzyl piperazine-1-carboxylateYield 159.6%

Reagents, catalysts & solvents 1

HCID 204431481,4-Dioxane hydrochlorideSolvent

Procedure

Commercially available N-tert-butyloxycarbonyl-piperazine (0.5 g, 2.68 mmol) was dissolved in 5 mL of THF:water (1:1) and cooled in an ice bath. Triethylamine (0.748 mL, 5.4 mmol), followed by benzyloxycarbonyl chloride (0.575 mL, 3.21 mmol) in diethyl ether was slowly added to the reaction mixture. It was stirred at 0° C. for 1.5 hours. Solvents were removed and 50 mL of ethyl acetate was added to the residue. The ethyl acetate layer was washed with saturated NaHCO3 (20 mL×3), brine (20 mL×3), and dried over anhydrous sodium sulfate. N-tert-butyloxycarbonyl-N;benzyloxycarbonyl-piperazine (1.0 g) was obtained after evaporated to dryness in quantitative yield. MS: M+NH4 =338. M+H+ =321. N-tert-butyloxycarbonyl-N'-benzyloxycarbonyl-piperazine (1.8 g, 3.13 mmol) was dissolved in 10 mL of 4N-HCl/dioxane. It was stirred at room temperature for 30 minutes. The reaction mixture was cooled in an ice bath, 1N-NaOH solution was carefully added to the mixture to adjust pH above 10. Ethyl acetate (50 mL×3) was used to extract the compound. The combined ethyl acetate layers were washed with brine, dried over anhydrous sodium sulfate. After removal of the solvent, 1.1 g of N-benzyloxycarbonyl-piperazine was obtained in quantitative yield. Following the procedure of Example 6, but replacing 1-benzylpiperazine with N-benzyloxycarbonyl-piperazine, provided the desired compound. The product of Example 3 (1.1 g, 1.06 mmol), N-benzyloxycarbonyl-piperazine (700 mg, 3.18 mmol), and triethylamine (0.44 mL, 3.15 mmol) in 5 mL of methylene chloride were used. 339 mg of pure compound (C-32-N-benzyloxycarbonyl-piperazinyl-C-24-TBDMS-Ascomycin) was isolated in 29% yield. MS (FAB) m/z: M+H=1108. M+K-1146. The above obtained product (329 mg, 0.297 mmol) was treated with 48%-HF (0.55 mL) in 10 mL of acetonitrile in the procedure described in Example 5. 316 mg of semi pure compound (C-32-N-benzyloxycarbonyl-piperazinyl-Ascomycin) was isolated. This was directly used for the next reaction without further purification. The obtained product (317 mg, 0.32 mmol) was carefully hydrogenated in 40 mL of methanol in the presence of 10%-palladium on charcoal until theoretical ammount of hydrogen gas was consumed. 290 mg of crude product was purified by reverse phase-HPLC. 117 mg of the pure title compound was obtained in 47% yield. MS (FAB) m/z: M+H=860. M+K=898. mp=132° C. (dec).

Workup

  1. customafter evaporated to dryness in quantitative yield
  2. temperatureThe reaction mixture was cooled in an ice bath
  3. extractionto extract the compound
  4. washThe combined ethyl acetate layers were washed with brine
  5. dry with materialdried over anhydrous sodium sulfate
  6. customAfter removal of the solvent

Sources & evidence

ORD record
ord-7814e8d080f74fc7971e6b6ab4ce59b7
Source dataset
uspto-grants-1996_06
Patent number
US05530119

Reaction notes

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