Triethylamine → Gabapentin

HRID 2398119Notes

Reaction equation

HRID 2398119 reaction equation
C([N:3](CC)CC)C.[C:8]1([CH2:19][C:20]([O-:22])=[O:21])([CH2:14]C(OC)=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.ClC(OCC)=O.[N-]=[N+]=[N-].[Na+]>O.CC(C)=O>[NH2:3][CH2:14][C:8]1([CH2:19][C:20]([OH:22])=[O:21])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1

Participants

7

Reactant 4

HCID 8471TriethylamineHCID 10928Ethyl chloroformateHCID 33557Sodium AzideHCID 85865712HCID 85865712, compound

Product 1

HCID 3446Gabapentin

Reagents, catalysts & solvents 2

HCID 180AcetoneSolvent2×HCID 962WaterSolvent

Conditions

Temperature
0 °C

Procedure

5.6 ml. Triethylamine in 16 ml. anhydrous acetone are added dropwise, with stirring and cooling to 0° C., to a solution of 7.28 g. monomethyl 1,1-cyclohexane-diacetate, whereafter a solution of 3.6 ml. ethyl chloroformate in 16 ml. anhydrous acetone is added thereto. The reaction mixture is further stirred for 30 minutes at 0° C. and and then a solution of 3.4 g. sodium azide in 12 ml. water added dropwise thereto. The reaction mixture is stirred for 1 hour at 0° C., then poured into ice water and extracted three times with 50 ml. amounts of ice-cold toluene. The combined extracts are dried over anhydrous sodium sulphate at 0° C. and subsequently introduced drop-wise into a flask pre-heated to 100° C. The mixture is then heated for a further hour under reflux and thereafter evaporated in a vacuum. The crude methyl 1-isocyanatomethyl-1-cyclohexane-acetate which remains behind is heated under reflux for 3 hours with 50 ml. 20% hydrochloric acid. After cooling the solution, it is extracted three times with 100 ml. amounts of chloroform to remove the 1-amino-methyl-1-cyclohexane-acetic acid lactam formed as a by-product product and the aqueous hydrochloric acid solution evaporated in a vacuum, whereby 1-aminomethyl-1-cyclohexane-acetic acid crystallises as the hydrochloride; m.p. 117°-118° C., after recrystallisation from acetone/methanol/ether. After recrystallization from methanol/ether the melting point of the product is 129°-133° C.

Workup

  1. stirringThe reaction mixture is further stirred for 30 minutes at 0° C.
  2. stirringThe reaction mixture is stirred for 1 hour at 0° C.
  3. extractionextracted three times with 50 ml
  4. dry with materialThe combined extracts are dried over anhydrous sodium sulphate at 0° C.
  5. temperaturesubsequently introduced drop-wise into a flask pre-heated to 100° C
  6. temperatureThe mixture is then heated for a further hour
  7. temperatureunder reflux
  8. customevaporated in a vacuum
  9. temperatureThe crude methyl 1-isocyanatomethyl-1-cyclohexane-acetate which remains behind is heated
  10. temperatureunder reflux for 3 hours with 50 ml
  11. temperatureAfter cooling the solution, it
  12. extractionis extracted three times with 100 ml
  13. customamounts of chloroform to remove the 1-amino-methyl-1-cyclohexane-acetic acid lactam
  14. customformed as a by-product product
  15. customthe aqueous hydrochloric acid solution evaporated in a vacuum, whereby 1-aminomethyl-1-cyclohexane-acetic acid
  16. customcrystallises as the hydrochloride
  17. customm.p. 117°-118° C., after recrystallisation from acetone/methanol/ether
  18. customAfter recrystallization from methanol/ether the melting point of the product
  19. customis 129°-133° C.

Sources & evidence

ORD record
ord-d5dfb76c07a2455da7434732e196e2e9
Source dataset
uspto-grants-1977_05
Patent number
US04024175

Reaction notes

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