Amantadine → 1-[(1-Acetylpiperidin-4-yl)-3-adamantan-1-yl]urea

HRID 573263Notes

Reaction equation

HRID 573263 reaction equation
[C:1]([N-:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:3])C.[C:11]12([NH2:21])[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2.[C:22](OI(C1C=CC=CC=1)OC(=O)C)(=[O:24])[CH3:23]>C(#N)C>[C:22]([N:8]1[CH2:9][CH2:10][CH:5]([NH:4][C:1]([NH:21][C:11]23[CH2:18][CH:17]4[CH2:16][CH:15]([CH2:14][CH:13]([CH2:19]4)[CH2:12]2)[CH2:20]3)=[O:3])[CH2:6][CH2:7]1)(=[O:24])[CH3:23]

Participants

5

Reactant 3

HCID 2130AmantadineHCID 76724Iodobenzene diacetateHCID 178474325HCID 178474325, compound

Product 1

HCID 120007971-[(1-Acetylpiperidin-4-yl)-3-adamantan-1-yl]ureaYield 72%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Conditions

Temperature
75 °C

Procedure

A reactor was charged with 100 mole-equivalents of N-acetyl piperid-4-yl amide, 0.87 mole-equivalents of 1-adamantyl amine, and 49.7 mole-equivalent of acetonitrile, and the resulting mixture was heated to 75° C. internal under a nitrogen atmosphere. (Diacetoxyiodo)benzene was added, the reaction mixture was cooled to 25° C. internal, and approximately 24 mole-equivalents of solvent was distilled out under vacuum while maintaining internal temperature below 40° C. The reaction mixture was cooled with agitation to 0-5° C. internal and stirred for an additional 2 hours. The technical product was collected by filtration and washed with acetonitrile. The crude product was dried to constant weight in a vacuum oven under a nitrogen bleed maintaining an internal temperature of ≦50° C. The dried, crude product was slurried with water maintaining an internal temperature of 20±5° C. internal for 4 hours and then collected by filtration. The filter cake was washed with heptane under a nitrogen atmosphere then dried to constant weight in a vacuum oven under a nitrogen bleed maintaining an internal temperature of ≦70° C. to afford product as a white solid in 72% yield based on 1-adamantyl amine. 1H NMR(DMSO-d6) δ: 5.65-5.70 (bd, 1H), 5.41 (s, 1H), 4.02-4.10 (m, 1H), 3.61-5.70, (m, 1H), 3.46-3.58 (m, 1H), 3.04-3.23 (m, 1H), 2.70-2.78 (m, 1H), 1.98 (s, 3H), 1.84 (s, 6H), 1.64-1.82 (m, 2H), 1.59 (s, 6H), 1.13-1.25 (m, 1H), 1.00-1.12 (m, 1H); MS: 320 [M+H]+; m.p. 202-204° C.

Workup

  1. temperaturethe reaction mixture was cooled to 25° C. internal
  2. distillationapproximately 24 mole-equivalents of solvent was distilled out under vacuum
  3. temperaturewhile maintaining internal temperature below 40° C
  4. temperatureThe reaction mixture was cooled with agitation to 0-5° C. internal
  5. filtrationThe technical product was collected by filtration
  6. washwashed with acetonitrile
  7. dry with materialThe crude product was dried to constant weight in a vacuum oven under a nitrogen
  8. temperaturebleed maintaining an internal temperature of ≦50° C
  9. customan internal temperature of 20±5° C.
  10. custominternal for 4 hours
  11. filtrationcollected by filtration
  12. washThe filter cake was washed with heptane under a nitrogen atmosphere
  13. customthen dried to constant weight in a vacuum oven under a nitrogen
  14. temperaturebleed maintaining an internal temperature of ≦70° C.
  15. customto afford product as a white solid in 72% yield

Sources & evidence

ORD record
ord-2ae24fce412c4e9ba1c32d593ea34c1f
Source dataset
uspto-grants-2015_05
Patent number
US09029550B2

Reaction notes

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