Ammonia → Marbofloxacin

HRID 443204Notes

Reaction equation

HRID 443204 reaction equation
[CH:1](O)=O.C=O.N.C.[F:8][C:9]1[CH:10]=[C:11]2[C:16](=[C:17]([OH:26])[C:18]=1[N:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1)[N:15]([NH:27][CH3:28])[CH:14]=[C:13]([C:29]([OH:31])=[O:30])[C:12]2=[O:32]>>[F:8][C:9]1[CH:10]=[C:11]2[C:12](=[O:32])[C:13]([C:29]([OH:31])=[O:30])=[CH:14][N:15]3[C:16]2=[C:17]([C:18]=1[N:19]1[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]1)[O:26][CH2:28][N:27]3[CH3:1]

Participants

6

Reactant 5

HCID 222AmmoniaHCID 284Formic AcidHCID 297MethaneHCID 712FormaldehydeHCID 53722968Marbofloxacin EP Impurity D

Product 1

HCID 60651Marbofloxacin

Conditions

Temperature
70 °C

Procedure

To the dark brown reaction mixture of step 6) containing 12 340 ml of 85% formic acid (ca. 7.5 mol) were added dropwise during 5 minutes without exceeding a temperature of 50° C. In the temperature range of 40°-50° C. 75.0 ml of aqueous 36.5% formaldehyde (ca. 1.0 mol) were added over 5 minutes and the resulting brown suspension was heated to 70° C. for 30 minutes, during which time gas evolution occurred. After cooling to 5°-10° C. 300 ml of 25% aqueous ammonia (ca. 4 mol) were added and the resulting black solution was stirred for 30 minutes. To this solution 9 g of activated charcoal were added and the resulting black suspension was stirred for 15 minutes and filtered through a glass fibre filter. The filtrate was extracted with 5 portions of 1000 ml, in total 5000 ml, of methylene chloride. The combined extracts were filtered through a glass fibre filter to remove small amounts of insoluble by-products, and the dark brown filtrate was evaporated in a rotary evaporator at 50° C./20 torr to dryness to yield 107.6 g of brown crystals. The crystals were taken up in 400 ml of ethanol and the resulting slurry was stirred for 1 hour at 0°-5° C., filtered, and the filter cake was washed with 100 ml of ethanol to yield after drying at 50° C./35 torr overnight 83.7 g of crude 1 as yellow crystals. This crude material was suspended in a mixture of 835 ml of ethanol, 415 ml of toluene and 415 ml of water (deionized) and heated to reflux. From the clear yellow solution formed 835 ml of solvent mixture was distilled off, whereby the temperature rose from 74°-78° C., and a yellow precipitate was formed. The suspension was cooled to room temperature, stirred for 1 hour, filtered, and the filter cake was washed with 3 portions of 60 ml, in total 180 ml, of ethanol to yield after drying at 50° C./35 torr overnight as the product 77.71 g (43% relative, to 6) of 1 as yellow crystals of m.p. 265°-268° C. (dec.).

Workup

  1. additionwere added dropwise during 5 minutes
  2. customa temperature of 50° C
  3. customIn the temperature range of 40°-50° C
  4. temperatureAfter cooling to 5°-10° C
  5. stirringthe resulting black suspension was stirred for 15 minutes
  6. filtrationfiltered through a glass fibre filter
  7. extractionThe filtrate was extracted with 5 portions of 1000 ml, in total 5000 ml, of methylene chloride
  8. filtrationThe combined extracts were filtered through a glass
  9. filtrationfibre filter
  10. customto remove small amounts of insoluble by-products
  11. customthe dark brown filtrate was evaporated in a rotary evaporator at 50° C./20 torr to dryness

Sources & evidence

ORD record
ord-08fd499c02d94894a20985c6e1e48d0b
Source dataset
uspto-grants-1999_04
Patent number
US05892040

Reaction notes

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