Dicyclohexylcarbodiimide → N-homocysteine thiolactonyl retinamide

HRID 1595136Notes

Reaction equation

HRID 1595136 reaction equation
[CH2:1]1[C@H:6]([NH2:7])[C:4](=[O:5])[S:3][CH2:2]1.[CH3:8][C:9]1[CH2:14][CH2:13][CH2:12][C:11]([CH3:16])([CH3:15])[C:10]=1/[CH:17]=[CH:18]/[C:19](/[CH3:29])=[CH:20]/[CH:21]=[CH:22]/[C:23](/[CH3:28])=[CH:24]/[C:25](O)=[O:26].C1(N=C=NC2CCCCC2)CCCCC1.[OH-].[Na+]>O.C(Cl)Cl>[CH3:8][C:9]1[CH2:14][CH2:13][CH2:12][C:11]([CH3:15])([CH3:16])[C:10]=1/[CH:17]=[CH:18]/[C:19](/[CH3:29])=[CH:20]/[CH:21]=[CH:22]/[C:23](/[CH3:28])=[CH:24]/[C:25]([NH:7][CH:6]1[C:4](=[O:5])[S:3][CH2:2][CH2:1]1)=[O:26]

Participants

7

Reactant 4

HCID 10868DicyclohexylcarbodiimideHCID 14798Sodium HydroxideHCID 134505Homocysteine thiolactone4×HCID 444795Retinoic Acid2×

Product 1

HCID 6505314N-homocysteine thiolactonyl retinamide

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
20 °C

Procedure

McCully (U.S. Pat. No. 4,618,685; “the '685 patent”, incorporated herein by reference) attempted to synthesize thioretinamide, the precursor to the compound of the invention, from homocysteine thiolactone free base and retinoic acid. McCully's synthesis of thioretinamide involves the conjugation of homocysteine thiolactone to retinoic acid using dicyclohexylcarbodimide as a coupling agent. The process in that patent starts with the preparation of the free base of homocysteine thiolactone. This is done by dissolving sodium hydroxide (NaOH) in water, adding methylene chloride and rapidly mixing. Homocysteine thiolactone hydrochloride is then slowly added to the mixture. After 15 minutes of mixing, the methylene chloride layer is separated, dried over anhydrous sodium sulfate and the solvent is evaporated under reduced pressure at 37° C. The resulting clear liquid (homocysteine thiolactone free base) is immediately added to tetrahydrofuran (or any other non-polar solvent) containing all-trans-retinoic acid. Then, dicyclohexylcarbodiimide is added, and the reaction mixture is stirred 16 hours at 20° C., protected from light. The tetrahydrofuran is removed at 37° C. under reduced pressure, and the yellow-white residue is added to 500 ml of water and 500 ml of ethyl acetate. The mixture is stirred vigorously for one hour, and the ethyl acetate layer is separated and dried over anhydrous sodium sulfate. The ethyl acetate is concentrated to about 20 ml at 50° C. under reduced pressure and cooled. The resulting N-homocysteine thiolactonyl retinamide, (a yellow powder) was produced with a 69% theoretical yield and a melting point of 172° C.

Workup

  1. customto synthesize thioretinamide
  2. customMcCully's synthesis of thioretinamide
  3. additionrapidly mixing
  4. additionAfter 15 minutes of mixing
  5. customthe methylene chloride layer is separated
  6. dry with materialdried over anhydrous sodium sulfate
  7. customthe solvent is evaporated under reduced pressure at 37° C
  8. additionThe resulting clear liquid (homocysteine thiolactone free base) is immediately added to tetrahydrofuran (or any other non-polar solvent)
  9. additioncontaining all-trans-retinoic acid
  10. additionThen, dicyclohexylcarbodiimide is added
  11. customThe tetrahydrofuran is removed at 37° C. under reduced pressure
  12. additionthe yellow-white residue is added to 500 ml of water and 500 ml of ethyl acetate
  13. stirringThe mixture is stirred vigorously for one hour
  14. customthe ethyl acetate layer is separated
  15. dry with materialdried over anhydrous sodium sulfate
  16. concentrationThe ethyl acetate is concentrated to about 20 ml at 50° C. under reduced pressure
  17. temperaturecooled

Sources & evidence

ORD record
ord-4a83a898bc1141dd9ca16785b39c7c70
Source dataset
uspto-grants-2001_09
Patent number
US06287818B1

Reaction notes

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