Carbon Dioxide → HCID 9899706, compound

HRID 278284Notes

Reaction equation

HRID 278284 reaction equation
[C:1]1([CH3:7])C=CC=CC=1.[F:8][C:9]1[CH:10]=[C:11]([C@H:15]([CH:20]=[CH2:21])[CH2:16][C:17]([OH:19])=O)[CH:12]=[CH:13][CH:14]=1.[C:22](=O)=[O:23].Cl.[OH2:26]>C(Cl)Cl>[F:8][C:9]1[CH:10]=[C:11]([C@H:15]([CH:20]=[CH2:21])[CH2:16][C:17](=[O:19])[CH2:7][C:1]([O:23][CH3:22])=[O:26])[CH:12]=[CH:13][CH:14]=1

Participants

7

Reactant 5

HCID 280Carbon Dioxide3×HCID 313Hydrochloric AcidHCID 962WaterHCID 1140TolueneHCID 9942382HCID 9942382, compound

Product 1

HCID 9899706HCID 9899706, compoundYield 95%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
2.5 °C

Procedure

The toluene solution of (3S)-3-(3-fluorophenyl)pent-4-enoic acid from Step E (11,230 g of a solution containing 1158 g of acid and 1043 g of a second solution containing 102 g of acid) was concentrated to an oil using a Buchi rotary evaporator. The oil was dissolved in methylene chloride (0.5 L). The KF was 36 μg/mL. A 50 L, 4-necked round bottom flask, equipped with mechanical stirrer, thermocouple, reflux condenser with nitrogen inlet, addition funnel, and steam pot, was charged sequentially with methylene chloride (5.5 L), monomethylmalonate potassium salt (7, 1.52 kg), and magnesium chloride (618 g). The mixture was cooled to 0-5° C. Triethylamine (2.71 L) was charged to the addition funnel and added to the mixture over 2-5 min. The addition was slightly exothermic; the temperature rose 2° C. The mixture was aged for 30 min at 0-5° C., then warmed to 20° C. and aged for 30 min. A 22 L, 4-necked round bottom flask, equipped with mechanical stirrer, thermocouple, nitrogen inlet, dry ice condenser, and addition funnel, was charged with methylene chloride (4 L) and 1,1′-carbonyldiimidazole (1.10 kg). The monoacid solution from above was charged to the addition funnel and added to the 22 L flask over 30-40 min to give a solution. Gas (CO2) vigorously evolved, which entrained methylene chloride, hence the need for the dry ice condenser. The resulting solution of activated monoacid was pumped into the 50 L flask. The dry ice condenser was moved from the 22 L flask to the top of the water condenser on the 50 L flask. The reaction mixture was heated to 41° C. During the addition of activated monoacid, the temperature rose from 20.1° C. to 20.7° C. The temperature continued to slowly rise to 28° C., at which point steam was intermittently applied to the 50 L flask. The progress of the reaction was followed by HPLC. When the reaction was complete (about 1.5 h), the mixture was cooled to 0-5° C. To the cold mixture was added cold 2 N HCl (19 L). The pH of the aqueous phase was 2.9. The addition was exothermic; the temperature increased to 20° C. The two phase mixture was transferred to a 50 L extractor, and the layers were separated. The aqueous phase was extracted with methylene chloride (3 L). The methylene chloride extracts were combined and dried with anhydrous sodium sulfate (1 kg). The mixture was filtered and the cake was washed with methylene chloride (1 L). The filtrate and washes were combined. Final yield was >95%.

Workup

  1. concentrationwas concentrated to an oil
  2. customa Buchi rotary evaporator
  3. dissolutionThe oil was dissolved in methylene chloride (0.5 L)
  4. customA 50 L, 4-necked round bottom flask, equipped with mechanical stirrer
  5. temperaturethermocouple, reflux condenser
  6. additionwith nitrogen inlet, addition funnel
  7. additionsteam pot, was charged sequentially with methylene chloride (5.5 L), monomethylmalonate potassium salt (7, 1.52 kg), and magnesium chloride (618 g)
  8. additionTriethylamine (2.71 L) was charged to the addition funnel
  9. additionadded to the mixture over 2-5 min
  10. additionThe addition
  11. customrose 2° C
  12. temperaturewarmed to 20° C. and aged for 30 min
  13. customA 22 L, 4-necked round bottom flask, equipped with mechanical stirrer
  14. additionthermocouple, nitrogen inlet, dry ice condenser, and addition funnel
  15. additionwas charged with methylene chloride (4 L) and 1,1′-carbonyldiimidazole (1.10 kg)
  16. additionThe monoacid solution from above was charged to the addition funnel
  17. additionadded to the 22 L flask over 30-40 min
  18. customto give a solution
  19. temperatureThe reaction mixture was heated to 41° C
  20. additionDuring the addition of activated monoacid
  21. customrose from 20.1° C. to 20.7° C
  22. customto slowly rise to 28° C., at which point steam
  23. custom(about 1.5 h)
  24. temperaturethe mixture was cooled to 0-5° C
  25. additionThe addition
  26. temperaturethe temperature increased to 20° C
  27. customthe layers were separated
  28. extractionThe aqueous phase was extracted with methylene chloride (3 L)
  29. dry with materialdried with anhydrous sodium sulfate (1 kg)
  30. filtrationThe mixture was filtered
  31. washthe cake was washed with methylene chloride (1 L)

Sources & evidence

ORD record
ord-ffafe5ed04344d06b7ca5fdb66b1230e
Source dataset
uspto-grants-2002_03
Patent number
US06358979B1

Reaction notes

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