Methylamine → 3-(4-Aminophenyl)-6-fluoro-7-(methylamino)quinazoline-2,4(1H,3H)-dione

HRID 556340Notes

Reaction equation

HRID 556340 reaction equation
Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][C:14](F)=[C:15]([F:20])[CH:16]=3)[NH:11][C:10]2=[O:22])=[CH:5][CH:4]=1.[CH3:23][NH2:24]>CS(C)=O>[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][C:14]([NH:24][CH3:23])=[C:15]([F:20])[CH:16]=3)[NH:11][C:10]2=[O:22])=[CH:5][CH:4]=1

Participants

4

Reactant 2

HCID 6329MethylamineHCID 569243233-(4-Aminophenyl)-6,7-difluoroquinazoline-2,4(1H,3H)-dione--hydrogen chloride (1/1)

Product 1

HCID 247781213-(4-Aminophenyl)-6-fluoro-7-(methylamino)quinazoline-2,4(1H,3H)-dioneYield 76.5%

Reagents, catalysts & solvents 1

HCID 679Dimethyl SulfoxideSolvent

Conditions

Temperature
22 °C

Procedure

The PP1-R2000 (200 L HP reactor) was charged with compound 5b (18 Kg, 1.0 eq.) and pressurized with 100±5 psig of nitrogen. Vent the nitrogen from the reactor through the atmospheric vent line then open the condenser valve and then charged dimethyl sulfoxide into the reactor (>99.7%, 105 Kg) under blanket of argon. The reactor contents were agitated at 22° C. (19-25° C.) for 15 mins. and then pulled maximum achievable vacuum on the 200 L HP reactor and close all the valves. Using the established vacuum charged to the 200 L HP reactor methylamine (33% wt % in absolute ethanol, 37.2 Kg) at a rate that maintains the internal temperature at 25±5° C. and kept a nitrogen blanket on the reagent solution during charging. After rinsing the charging line with dimethyl sulfoxide (5 Kg) closed the 200 L HP reactor condenser valve and heated the reactor contents to 110±5° C. The contents of the reactor were agitated for at least 5 hrs. at 110±5° C. In-process HPLC taken after 5 hr 40 mins. showed compound 5b content of 0.09%, indicating completion of the reaction (in-process specification ≦1%). The contents of 200 L HP reactor were cooled to 25±5° C. While the 200 L reactor is cooling, closed all the valves of the PP1-R1000 reactor (2000 L GL reactor) and charged with process filtered water (550 Kg). The contents of the 200 L HP reactor were transferred to the 2000 L GL reactor over 15 minutes followed by rinsing the charging line with process filtered water (50 Kg). The contents of the 2000 L GL reactor were agitated for 2 hrs at 5±5° C. The filterable solids obtained were filtered onto PPF200 (GL nutsche filter) fitted with Mel-Tuf 1149-12 filter paper under vacuum. The wet filter cake was discharged and transferred into pre-lined vacuum trays with Dupont's fluorocarbon film (Kind 100 A). Clamped down the special oven paper (KAVON 992) over the vacuum trays containing the wet compound 6 and transferred to the vacuum oven tray dryer. The oven temperature was set to 55° C. and compound 6 dried to a constant weight for 12 hrs. The product 5c was discharged (12.70 Kg) in 76.5% yield (expected 85-95%). HPLC shows 98.96% purity and 1H NMR confirmed the structure for compound 5c. 1H NMR (DMSO): δ 11.10 (s, 1H), 7.36 (d, 1H), 6.78 (d, 2H), 6.75 (m, 1H), 6.56 (d, 2H), 6.20 (d, 1H), 5.18 (d, 2H), 2.76 (d, 3H).

Workup

  1. customclose all the valves
  2. customat 25±5° C.
  3. washAfter rinsing the charging line with dimethyl sulfoxide (5 Kg)
  4. customclosed the 200 L HP reactor condenser valve
  5. temperatureheated the reactor contents to 110±5° C
  6. stirringThe contents of the reactor were agitated for at least 5 hrs
  7. customat 110±5° C
  8. waitIn-process HPLC taken after 5 hr 40 mins
  9. customcompletion of the reaction (in-process specification ≦1%)
  10. temperatureThe contents of 200 L HP reactor were cooled to 25±5° C
  11. temperatureWhile the 200 L reactor is cooling
  12. customclosed all the valves of the PP1-R1000 reactor (2000 L GL reactor)
  13. additioncharged with process
  14. filtrationfiltered water (550 Kg)
  15. waitThe contents of the 200 L HP reactor were transferred to the 2000 L GL reactor over 15 minutes
  16. washby rinsing the charging line with process
  17. filtrationfiltered water (50 Kg)
  18. stirringThe contents of the 2000 L GL reactor were agitated for 2 hrs at 5±5° C
  19. customThe filterable solids obtained
  20. filtrationwere filtered onto PPF200 (GL nutsche filter)
  21. customfitted with Mel-Tuf 1149-12
  22. filtrationfilter paper under vacuum
  23. additioncontaining the wet compound 6
  24. customwas set to 55° C.
  25. dry with materialcompound 6 dried to a constant weight for 12 hrs

Sources & evidence

ORD record
ord-9a9cb85f6c824dd799df73b482cf0015
Source dataset
uspto-grants-2011_11
Patent number
US08058284B2

Reaction notes

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