Manufacturing Process
50.0 g of maleic anhydride and 180 ml of methanol are heated for 1 h under
reflux while stirring. The reaction mixture is cooled to room temperature and
the excess methanol is evaporated under reduced pressure. 67.0 g of
monomethyl maleate are obtained. The monomethyl maleate is then cooled to
0°C after which 90 ml of triethylamine and then 34.0 g of isobutylamine are
introduced over a period of 1 h. The reaction mixture is heated under reflux
for 1 h, then cooled to 50°C and 200 ml of acetone added; as a result of
filtering off the crystals which separate there are obtained 73.7 g of methyl Nisobutyl-
β-aspartate, melting point 250°C.
Over a period of 10 min 860 ml of concentrated hydrochloric acid are added to
a suspension of 340.0 g of methyl N-isobutyl-β-aspartate in 860 ml of water
whilst stirring. The solution is cooled to 0°C and 128.0 g of sodium nitrite
dissolved in 280 ml of water are introduced over a period of 1 h 20 min. The
reaction mixture is stirred for 2 h at 0°C and extraction is then carried out
thrice with a total of 3000 ml of diethyl ether. The organic phase is thrice
washed with a total of 1500 ml of water, dried over magnesium sulfate and
the ether evaporated under reduced pressure. The residue, when dissolved in
a mixture of 1400 ml of petroleum ether and 230 ml of ether, gives, after
cooling to 3°C, 325.0 g of methyl N-isobutyl-N-nitroso-β-aspartate, melting
point 95°C.
Over a period of 15 min and whilst stirring 158.0 g of methyl N-isobutyl-Nnitroso-
β-aspartate are added to 340 ml of acetic anhydride and then, drop by
drop, 0.95 ml of 70% perchloric acid. The reaction mixture is then stirred for
2 h at room temperature. The acetic anhydride is evaporated under reduced
pressure, and the residue is then successively dissolved once in 100 ml of
chloroform, thrice in 100 ml of benzene each time and twice in 100 ml of
diethyl ether each time, the solvent being evaporated each time under
reduced pressure. 155.0 g of red oil are obtained which are dissolved in 2
volumes of hot di-isopropyl ether and cooled. After 1 min at 3°C the crystals
which separate are filtered and there are thus obtained 78.0 g of methyl 3-
isobutyl-4-sydnonyl acetate, melting point 39°C.
120.0 g of methyl 3-isobutyl-4-sydnonylacetate and 110.0 g of diphenylacetylene
dissolved in 600 ml of xylene are heated under reflux whilst being
stirred for 70 h. The solution is cooled to room temperature and the xylene is
evaporated under reduced pressure. The residue is dissolved in a mixture of
800 ml of 1 N sodium carbonate and 800 ml of acetone. The resulting solution
is heated under reflux for 4 h whilst stirring and is then cooled to room
temperature and separated. The aqueous phase has 1000 ml of water added
thereto and is then extracted thrice with a total of 900 ml of benzene. The
aqueous phase is then made acid by the addition of 68 ml of concentrated
hydrochloric acid. The oil which separates from the acidified mixture is
extracted using a total of 1000 ml of chloroform in five extractions. The
combined chloroform extracts are dried over magnesium sulfate and the
chloroform is evaporated under reduced pressure. 78.0 g of a brown oil are
obtained which are submitted to chromatography upon silica gel using a
mixture of chloroform-methanol 99:1 parts. So the 1-isobutyl-3,4-
diphenylpyrazolyl-5-acetic acid, melting point 181°C (recrystallisation from
acetonitrile) is obtained.
