Toluene → tert-Butyl N-(7-methyl-5-azaspiro-[2.4]heptan-7-yl)carbamate

HRID 389255Notes

Reaction equation

HRID 389255 reaction equation
[C:1]([OH:11])(=[O:10])[C@@H](C1C=CC=CC=1)O.[NH2:12][C:13]1([CH3:27])[C:17]2([CH2:19][CH2:18]2)[CH2:16][N:15](CC2C=CC=CC=2)[CH2:14]1.[OH-].[Na+].[C:30]1([CH3:36])[CH:35]=CC=C[CH:31]=1>>[C:30]([O:11][C:1]([NH:12][C:13]1([CH3:27])[C:17]2([CH2:18][CH2:19]2)[CH2:16][NH:15][CH2:14]1)=[O:10])([CH3:36])([CH3:35])[CH3:31]

Participants

4

Reactant 3

HCID 1140TolueneHCID 14798Sodium HydroxideHCID 131728788(-)-7-Amino-5-benzyl-7-methyl-5-azaspiro[2.4]heptane d-mandelate

Product 1

HCID 57758641tert-Butyl N-(7-methyl-5-azaspiro-[2.4]heptan-7-yl)carbamateYield 97%

Procedure

(−)-7-Amino-5-benzyl-7-methyl-5-azaspiro[2.4]heptane D-mandelate (5.99 g) was dissolved in toluene (60 mL). To the solution, 5N Aqueous sodium hydroxide (60 mL) was added, and the mixture was stirred at room temperature, followed by separation of the toluene layer. Toluene was also added to the remaining aqueous layer for extraction. All the toluene layers were combined, and t-butyl dicarbonate (19.0 mL) was added to the combined toluene layer, followed by stirring at room temperature for 2 hours. After completion of reaction, 10% aqueous citric acid was added to the reaction mixture, to thereby extract the aqueous citric acid layer. Separately, 10% aqueous citric acid was added to the remaining toluene layer, to thereby separate another aqueous citric acid layer. Thereafter, all the aqueous layers were combined, and the combined aqueous layer was alkalified with 5N aqueous sodium hydroxide (30 mL). Subsequently, toluene was added to the alkalified aqueous layer so as to extract the organic layer, and the solvent of the organic layer obtained through extraction was evaporated under reduced pressure. Methanol (60.0 mL) was added to the residue, and 5% palladium carbon (0.59 g, water content: 50%) was added to the mixture, followed by stirring at room temperature in a hydrogen atmosphere. After 14 hours, 5% palladium carbon was removed through filtration. The filtrate was concentrated under reduced pressure, to thereby yield the title product (3.576 g, yield: 97%). This product can be purified through recrystallization from a solvent such as hexane, heptane, or acetonitrile, or formation of a crystalline salt with, for example, oxalic acid.

Workup

  1. customfollowed by separation of the toluene layer
  2. additionToluene was also added to the remaining aqueous layer for extraction
  3. additiont-butyl dicarbonate (19.0 mL) was added to the combined toluene layer
  4. stirringby stirring at room temperature for 2 hours
  5. customAfter completion of reaction, 10% aqueous citric acid
  6. additionwas added to the reaction mixture
  7. extractionto thereby extract the aqueous citric acid layer
  8. additionSeparately, 10% aqueous citric acid was added to the remaining toluene layer
  9. customto thereby separate another aqueous citric acid layer
  10. additionSubsequently, toluene was added to the alkalified aqueous layer so as
  11. extractionto extract the organic layer
  12. customthe solvent of the organic layer obtained through extraction
  13. customwas evaporated under reduced pressure
  14. additionMethanol (60.0 mL) was added to the residue, and 5% palladium carbon (0.59 g, water content: 50%)
  15. additionwas added to the mixture
  16. stirringby stirring at room temperature in a hydrogen atmosphere
  17. custom5% palladium carbon was removed through filtration
  18. concentrationThe filtrate was concentrated under reduced pressure

Sources & evidence

ORD record
ord-3cb627425424469792b0ffc9f3fa978d
Source dataset
uspto-grants-2013_02
Patent number
US08378119B2

Reaction notes

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