Formamidine acetate → HCID 178500110, compound

HRID 625981Notes

Reaction equation

HRID 625981 reaction equation
C[O-].[Na+].C(O)(=O)C.[CH:8]([NH2:10])=[NH:9].[CH3:11][CH:12]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:13]([C:18](OC)=[O:19])[C:14](OC)=[O:15]>CO.C1(C)C=CC=CC=1>[OH:19][C:18]1[C:13]([CH:12]([CH3:11])[CH2:22][C:23]([O:25][CH3:26])=[O:24])=[C:14]([OH:15])[N:10]=[CH:8][N:9]=1

Participants

6

Reactant 3

HCID 160693Formamidine acetateHCID 10942334Sodium MethoxideHCID 13964180HCID 13964180, compound

Product 1

HCID 178500110HCID 178500110, compoundYield 86.9%

Reagents, catalysts & solvents 2

HCID 887MethanolSolvent3×HCID 1140TolueneSolvent

Conditions

Temperature
3.0999999046325684 °C

Procedure

A 12-L, 4-necked reactor, equipped with a mechanical stirrer, was charged with 2.80 L of methanol and sparged with nitrogen. The solvent was treated with NaOMe (1969 mL, 8612 mmol) and transfer washed with 250 mL of methanol. The mixture was left to stir for 1.5 hours before the solution was treated with formamidine acetate (246.6 g, 2368 mmol) in one sum (granular-homogenized). The mixture was allowed to stir for 20 minutes (the solids dissolved within about 10 minutes post addition) to afford a homogeneous solution. Trimethyl 2-methylpropane-1,1,3-tricarboxylate (500 g, 2153 mmol) was added via dropping funnel as a solution in 500 mL of methanol over a five minute period, followed by 200 mL more of methanol to complete transfer. The reaction (clear, bright yellow) was allowed to stir at ambient temperature overnight to completion as measured by NMR analysis (alliquot of 250 uL was removed via pipet and treated with five drops of aq. 3N HCl, reduced under vacuum to dryness, dissolved in d6-DMSO and then filtered) after 16 hours. The reaction was placed in an ice-bath and cooled to about 3.1° C. over a one hour period. A three-pound bottle of HCl (g) was used to quench the reaction (bubbling gas into solution via teflon tubing) over a one hour ten minute period reaching an endpoint of about pH=2.5 (via paper). The temperature was maintained below about 9.6° C. throughout the addition, and the yellow solution changed to an off-white suspension. The suspension was concentrated using vacuum distillation (35-37° C. @ 200 Torr) of the methanol (removed 3.34 L) in vacuo to afford a white/tan paste. The mixture was suspended in 3.75 L of toluene (7.5× volume) and stirred for 30 minutes. The suspension was filtered off (table top filter/polypropylene cloth, pad washed with 2×500 mL portions of toluene). The pad of product was allowed to air-dry under suction overnight on the filter then broken up with a spatula to give 396.8 grams, 86.9% yield.

Workup

  1. customsparged with nitrogen
  2. washtransfer washed with 250 mL of methanol
  3. waitThe mixture was left
  4. stirringto stir for 20 minutes (the solids
  5. dissolutiondissolved within about 10 minutes
  6. additionpost addition)
  7. customto afford a homogeneous solution
  8. customover a five minute
  9. customThe reaction (clear, bright yellow)
  10. stirringto stir at ambient temperature overnight to completion
  11. customwas removed via pipet
  12. additiontreated with five drops of aq. 3N HCl
  13. dissolutiondissolved in d6-DMSO
  14. filtrationfiltered) after 16 hours
  15. customThe reaction was placed in an ice-bath
  16. customto quench
  17. customthe reaction (bubbling gas into solution via teflon tubing) over a one hour ten minute period
  18. temperatureThe temperature was maintained below about 9.6° C. throughout the addition
  19. concentrationThe suspension was concentrated
  20. distillationvacuum distillation (35-37° C. @ 200 Torr) of the methanol (removed 3.34 L) in vacuo
  21. customto afford a white/tan paste
  22. stirringstirred for 30 minutes
  23. filtrationThe suspension was filtered off
  24. filtration(table top filter/polypropylene cloth, pad washed with 2×500 mL portions of toluene)
  25. customto air-dry under suction overnight on the
  26. filtrationfilter
  27. customto give 396.8 grams, 86.9% yield

Sources & evidence

ORD record
ord-f01b9419f45e41f1956ebebdd0fc1fcf
Source dataset
uspto-grants-2016_04
Patent number
US09309204B2

Reaction notes

Loading…