Dichloromethane → 1,1-Dimethylethyl N-[1-(2,5-difluorobenzoyl)-3-butyn-1-yl]carbamate

HRID 340751Notes

Reaction equation

HRID 340751 reaction equation
ClCCl.C([Mg]Cl)(C)C.Br[C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[F:17].CON(C)[C:21](=[O:34])[CH:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:23][C:24]#[CH:25]>C1COCC1>[F:17][C:11]1[CH:12]=[CH:13][C:14]([F:16])=[CH:15][C:10]=1[C:21](=[O:34])[CH:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:32])[CH3:31])[CH2:23][C:24]#[CH:25]

Participants

6

Reactant 4

HCID 6344Dichloromethane2×HCID 678622-Bromo-1,4-difluorobenzeneHCID 19364660HCID 19364660, compoundHCID 178418918HCID 178418918, compound2×

Product 1

HCID 577886571,1-Dimethylethyl N-[1-(2,5-difluorobenzoyl)-3-butyn-1-yl]carbamate

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-15 °C

Procedure

An inerted vessel was charged dichloromethane (866 kg) and cooled to −20 to −10° C. Then iso-propylmagnesium chloride solution in THF (2M, 326.1 kg, 669 mol) was slowly added followed by 1-bromo-2,5-difluorobenzene (120.1 kg, 622 mol). After 2 h at this temperature, an additional charge of iso-propylmagnesium chloride in THF solution was slowly added (2M, 58.65 kg, 121 mol) and the reaction aged 1 h. Then, a drop-wise addition of a dichloromethane solution of tert-butyl (1-[methoxy(methyl)amino]-1-oxopent-4-yn-2-yl)carbamate (70.8 kg, 276 mol in 292 kg dichloromethane) was conducted over 2 h at −20 to −20° C. The mixture was then warmed to room temperature and stirred for 10 h. The reaction was then slowly reverse quenched into aqueous ammonium chloride (175.6 kg in 1550 kg of water) at 5-10° C. The solution pH was then adjusted to ˜7 by adding 68 kg of con. HCl. The layers were then separated and the aqueous extracted with dichloromethane (414 kg). The combined organics were then dried with Na2SO4, filtered, treated with activated carbon (10 kg), filtered, and concentrated to 71-141 L. A constant volume (71-141 L) vacuum distillation solvent switch to n-heptane was then performed to crystallize the product. The slurry was then cooled to 0° C. and stirred 2 h. The slurry was filtered and the cake washed with n-heptane, 2-propanol, and then water. The solids were dried under vacuum at 40-50° C. overnight to give tert-butyl [1-(2,5-difluorophenyl)-1-oxopent-4-yn-2-yl]carbamate.

Workup

  1. additionwas slowly added (2M, 58.65 kg, 121 mol)
  2. customthe reaction aged 1 h
  3. waitwas conducted over 2 h at −20 to −20° C
  4. temperatureThe mixture was then warmed to room temperature
  5. customThe reaction was then slowly reverse quenched into aqueous ammonium chloride (175.6 kg in 1550 kg of water) at 5-10° C
  6. additionby adding 68 kg of con
  7. customThe layers were then separated
  8. extractionthe aqueous extracted with dichloromethane (414 kg)
  9. dry with materialThe combined organics were then dried with Na2SO4
  10. filtrationfiltered
  11. additiontreated with activated carbon (10 kg)
  12. filtrationfiltered
  13. concentrationconcentrated to 71-141 L
  14. distillationA constant volume (71-141 L) vacuum distillation solvent switch to n-heptane
  15. customto crystallize the product
  16. temperatureThe slurry was then cooled to 0° C.
  17. stirringstirred 2 h
  18. filtrationThe slurry was filtered
  19. washthe cake washed with n-heptane, 2-propanol
  20. customThe solids were dried under vacuum at 40-50° C. overnight

Sources & evidence

ORD record
ord-00eda4c6226e4e09804d02a8b1aa38b1
Source dataset
uspto-grants-2014_11
Patent number
US08895603B2

Reaction notes

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