Formic Acid → Ademetionine

HRID 2201595Notes

Reaction equation

HRID 2201595 reaction equation
[CH2:1]([OH:21])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH3:20].Br[CH:23]([CH2:27][CH3:28])[C:24]([OH:26])=[O:25].CC([O-])(C)C.[Na+].C(O)=O.Cl>CC(OC)(C)C.O.C1(C)C=CC=CC=1.C1COCC1>[CH2:1]([O:21][CH:23]([CH2:27][CH3:28])[C:24]([OH:26])=[O:25])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH3:20]

Participants

10

Reactant 5

HCID 284Formic AcidHCID 313Hydrochloric AcidHCID 66552-Bromobutanoic acid2×HCID 23676156Sodium t-butoxide4×HCID 59539494HCID 59539494, compound

Product 1

HCID 78210211Ademetionine

Reagents, catalysts & solvents 4

HCID 962WaterSolvent2×HCID 1140TolueneSolventHCID 8028TetrahydrofuranSolventHCID 15413tert-Butyl methyl etherSolvent4×

Conditions

Temperature
7.5 °C

Procedure

(5Z,8Z,11Z,14Z,17Z)-Icosa-5,8,11,14,17-pentaen-1-ol (2) (25 kg, 1.0 eq.), THF (235 kg), toluene (7 kg) and 2-bromobutyric acid (21.5 kg. 1.5 eq.) were charged into a reactor at ambient temperature. The BHT level was adjusted to 3000 ppm. The reaction mixture was cooled to 5-10° C. Over a period of 30-60 minutes, 117.6 kg of a 17% solution of NaOtBu (20 kg active content, 2.4 eq.) in MTBE was added. After the addition was complete, the reaction was stirred for 30 minutes at 5-10° C. Over a period of 30 minutes, 19.4 kg of a 17% solution of NaOtBu (0.4 eq.) in MTBE was added. After the addition was complete, the reaction was stirred for 60 minutes at 5-10° C. Over a period of 30 minutes, 2-bromobutyric acid (14.5 kg, 1.0 eq.) was added. After the addition was complete, the reaction was stirred for 60 minutes at 5-10° C. Over a period of 30 minutes, 40 kg of a 17% solution of NaOtBu (0.8 eq.) in MTBE was added. After the addition was complete, the reaction was stirred for 60 minutes at 5-10° C. Over a period of 30 minutes, 19.4 kg of a 17% solution of NaOtBu (0.4 eq.) in MTBE was added. After the addition was complete, the reaction was stirred for 60 minutes at 5-10° C. The reaction temperature was maintained between 5-10° C., and formic acid (2 kg, 0.5 eq.) and water (66 kg) were added. The reaction was stirred at 15-25° C., and the pH was adjusted to 2-2.5 using 1:1 concentrated HCl and DI water. The organic and aqueous phases were separated, and the aqueous phase was extracted with MTBE (2×44 kg). The combined organic phases were washed three times with DI water (66 kg). If necessary the organic phase can be washed a fourth time with DI water. The organic phase was dried over Na2SO4 (20.0 kg) and Celite (5.0 kg) and the solids were filtered and washed with MTBE (15 kg). The organic phase was evaporated using a thin film evaporator. The crude product mixture (Crude A) was dissolved in 2-methyltetrahydrofuran (2-MeTHF) (140 kg), and washed three times with a saturated aqueous NaHCO3 solution (70 kg) and then with a saturated aq. NaCl solution (70 kg). Optionally, the washing procedure is repeated to remove remaining 2-bromobutyric acid and/or crotonic acid. 2-MeTHF (710 kg) and DI water (710 kg) were added to the crude product (Crude B), and the pH was adjusted to 12-13 with a 50% aq. NaOH solution to transfer the product to the aqueous phase. The mixture was stirred for 30 minutes, and then the phases were allowed to separate. The phases were separated and 2-MeTHF (700 kg) was added to the aqueous phase and the mixture was stirred for 30 minutes. The phases were again allowed to separate and the phases were separated. The aqueous phase was clarified with charcoal (2.5 kg) and Celite (5.5 kg), and the solids were filtered and washed with 30 kg of 20% aqueous NaOH. The combined aqueous phase was clarified with Celite (5.5 kg), and the solids were filtered and washed with 30 kg of 20% aqueous NaOH. The pH was adjusted to 2-2.5 with conc. HCl(aq.), and the resulting mixture was extracted with MTBE (3×55 kg). The combined organic phases were washed with DI water (74 kg). The organic phase was concentrated by passing through a thin film evaporator twice. The residue was dissolved in pentane (135 kg), and clarified using silica (2 kg) twice, filtering each time and washing with pentane (17.5 kg). BHA stabilizer (0.03%) was added. The mixture was filtered on 0.5 □m filter, and the solvent was evaporated in vacuo to obtain 2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenyloxy)butanoic acid (3). The total yield starting from EPA ethyl ester (1) was about 65%. The purity was determined to be 96% by HPLC.

Workup

  1. additionAfter the addition
  2. waitOver a period of 30 minutes
  3. additionAfter the addition
  4. stirringthe reaction was stirred for 60 minutes at 5-10° C
  5. waitOver a period of 30 minutes
  6. additionAfter the addition
  7. stirringthe reaction was stirred for 60 minutes at 5-10° C
  8. waitOver a period of 30 minutes
  9. additionAfter the addition
  10. stirringthe reaction was stirred for 60 minutes at 5-10° C
  11. waitOver a period of 30 minutes
  12. additionAfter the addition
  13. stirringthe reaction was stirred for 60 minutes at 5-10° C
  14. temperatureThe reaction temperature was maintained between 5-10° C.
  15. stirringThe reaction was stirred at 15-25° C.
  16. customThe organic and aqueous phases were separated
  17. extractionthe aqueous phase was extracted with MTBE (2×44 kg)
  18. washThe combined organic phases were washed three times with DI water (66 kg)
  19. washIf necessary the organic phase can be washed a fourth time with DI water
  20. dry with materialThe organic phase was dried over Na2SO4 (20.0 kg) and Celite (5.0 kg)
  21. filtrationthe solids were filtered
  22. washwashed with MTBE (15 kg)
  23. customThe organic phase was evaporated
  24. customa thin film evaporator
  25. dissolutionThe crude product mixture (Crude A) was dissolved in 2-methyltetrahydrofuran (2-MeTHF) (140 kg)
  26. washwashed three times with a saturated aqueous NaHCO3 solution (70 kg)
  27. customto remove
  28. addition2-MeTHF (710 kg) and DI water (710 kg) were added to the crude product (Crude B), and the pH
  29. stirringThe mixture was stirred for 30 minutes
  30. customto separate
  31. customThe phases were separated
  32. addition2-MeTHF (700 kg) was added to the aqueous phase
  33. stirringthe mixture was stirred for 30 minutes
  34. customto separate
  35. customthe phases were separated
  36. filtrationthe solids were filtered
  37. washwashed with 30 kg of 20% aqueous NaOH
  38. filtrationthe solids were filtered
  39. washwashed with 30 kg of 20% aqueous NaOH
  40. extractionthe resulting mixture was extracted with MTBE (3×55 kg)
  41. washThe combined organic phases were washed with DI water (74 kg)
  42. concentrationThe organic phase was concentrated
  43. customby passing through a thin film evaporator twice
  44. dissolutionThe residue was dissolved in pentane (135 kg)
  45. filtrationfiltering each time
  46. washwashing with pentane (17.5 kg)
  47. additionBHA stabilizer (0.03%) was added
  48. filtrationThe mixture was filtered on 0.5 □m
  49. filtrationfilter
  50. customthe solvent was evaporated in vacuo

Sources & evidence

ORD record
ord-f073b4a4ecf84b19b940385341bb040a
Source dataset
uspto-grants-2016_06
Patent number
US09365482B2

Reaction notes

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