Formic Acid → Arofylline

HRID 1588478Notes

Reaction equation

HRID 1588478 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:15]([NH2:16])=[CH:14][C:12](=[O:13])[N:11]([CH2:17][CH2:18][CH3:19])[C:9]2=[O:10])=[CH:4][CH:3]=1.C(O)=O.N([O-])=O.[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+].[CH:35]([NH2:37])=O>>[CH2:17]([N:11]1[C:12](=[O:13])[C:14]2[NH:37][CH:35]=[N:16][C:15]=2[N:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:9]1=[O:10])[CH2:18][CH3:19]

Participants

6

Reactant 5

HCID 284Formic AcidHCID 713FormamideHCID 24489Sodium DithioniteHCID 2822728HCID 2822728, compoundHCID 23668193Sodium Nitrite

Product 1

HCID 166553ArofyllineYield 64.3%

Conditions

Temperature
60 °C

Procedure

A mixture of 1-(4-chlorophenyl)-3-n-propyl-6-aminouracil (28.0 g; 0.1 mole), formic acid (15.1 ml; 0.4 moles) and sodium nitrite (7 g; 0.1 mole) in formamide (600 ml) was heated to 60° C. for 10 minutes. The temperature was then increased to 100° C. and sodium dithionite (2.3 g; 0.013 moles) was added over a period of 10 minutes. After addition, the temperature was increased to 190° C., mantained for 30 minutes and the reaction mixture was cooled and extracted with chloroform. The organic solution was extracted with 2N sodium hydroxide aqueous solution, washed with diethyl ether, acidified with 2N hydrochloric acid aqueous solution and extracted with chloroform. The organic extracts were washed with water, dried (Na2SO4) and the solvent was removed in vacuo to give 1-n-propyl-3-(4-chlorophenyl)-xanthine (19.5 g; yield 64.3%). After recrystallization from 90% ethanol, the melting point is 233°-234° C.

Workup

  1. temperatureThe temperature was then increased to 100° C.
  2. additionAfter addition
  3. temperaturethe temperature was increased to 190° C.
  4. temperaturethe reaction mixture was cooled
  5. extractionextracted with chloroform
  6. extractionThe organic solution was extracted with 2N sodium hydroxide aqueous solution
  7. washwashed with diethyl ether
  8. extractionextracted with chloroform
  9. washThe organic extracts were washed with water
  10. dry with materialdried (Na2SO4)
  11. customthe solvent was removed in vacuo

Sources & evidence

ORD record
ord-9080cb378ed143da8d9745e882f63d79
Source dataset
uspto-grants-1993_06
Patent number
US05223504

Reaction notes

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