Heptane → Ureidovaline

HRID 1275357Notes

Reaction equation

HRID 1275357 reaction equation
[CH3:1][NH:2][CH2:3][C:4]1[N:5]=[C:6]([CH:9]([CH3:11])[CH3:10])[S:7][CH:8]=1.[O:12]([C:19]([NH:21][C@H:22]([C:26]([OH:28])=[O:27])[CH:23]([CH3:25])[CH3:24])=O)C1C=CC=CC=1.CCCCCCC>C1COCC1.C1(C)C=CC=CC=1>[CH3:1][N:2]([C:19]([NH:21][C@H:22]([C:26]([OH:28])=[O:27])[CH:23]([CH3:25])[CH3:24])=[O:12])[CH2:3][C:4]1[N:5]=[C:6]([CH:9]([CH3:11])[CH3:10])[S:7][CH:8]=1

Participants

6

Reactant 3

HCID 8900HeptaneHCID 9816135N-Phenoxycarbonyl-L-valineHCID 107496872-Isopropyl-4-(N-methyl)amino-methyl thiazole

Product 1

HCID 9818282UreidovalineYield 83.8%

Reagents, catalysts & solvents 2

HCID 1140TolueneSolvent2×HCID 8028TetrahydrofuranSolvent4×

Conditions

Temperature
20 °C

Procedure

To a suspension of LiOH monohydrate (3.2 kg, 76.54 mol) in THF (66 kg) at 0° C. to 6° C. was added 11.3 kg (66.4 mol) of N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amine, followed by a 15 kg THF rinse. To this solution was added a cooled (0° C. to 6° C.) solution of N-phenoxycarbonyl-L-Valine (15 kg, 63.22 mol) dissolved in 41 kg of THF. Following a 25 kg THF rinse, 3.5 kg of water was added, and the reaction mixture was allowed to warm to 20° C. After 3 hours, the reaction was cooled to 10° C. and quenched with water (180 kg). The THF was removed under reduced pressure, MTBE (111 kg) was added, and the biphasic solution was adjusted to pH 9.0 with 4 N HCl. The layers were separated and the aqueous layer was washed with an additional 111 kg of MTBE. The aqueous layer was stirred with 130 kg of toluene and adjusted to pH 3 with 4 N HCl, and the phases were separated. The aqueous layer was back-extracted once more with 130 kg of toluene. The combined organic extracts were filtered and the material removed by filtration washed with toluene (50 kg). The combined filtrates were concentrated in vacuo. The residue obtained was redissolved in 100 kg of toluene and re-concentrated in vacuo. The residue obtained was cystallized using toluene and heptane to afford 16.6 kg (83.8%) of the title compound.

Workup

  1. washrinse
  2. additionTo this solution was added
  3. washrinse
  4. addition3.5 kg of water was added
  5. temperaturethe reaction was cooled to 10° C.
  6. customquenched with water (180 kg)
  7. customThe THF was removed under reduced pressure, MTBE (111 kg)
  8. additionwas added
  9. customThe layers were separated
  10. washthe aqueous layer was washed with an additional 111 kg of MTBE
  11. customthe phases were separated
  12. extractionThe aqueous layer was back-extracted once more with 130 kg of toluene
  13. filtrationThe combined organic extracts were filtered
  14. customthe material removed by filtration
  15. washwashed with toluene (50 kg)
  16. concentrationThe combined filtrates were concentrated in vacuo
  17. customThe residue obtained
  18. concentrationre-concentrated in vacuo
  19. customThe residue obtained

Sources & evidence

ORD record
ord-13ec0793a8994815b7791e1dcb3eec3b
Source dataset
uspto-grants-2000_12
Patent number
US06160122

Reaction notes

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