Definition
ChEBI: A member of the class of triazolobenzodiazepines that is 4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine carrying methyl, phenyl and chloro substituents at positions 1, 6 and 8 respectively. Alprazolam is only found in individu
ls that have taken this drug.
Manufacturing Process
6-Chloro-2-hydrazino-4-phenylquinoline: A stirred mixture of 2,6-dichloro-4-
phenylquinoline (2.7 g, 0.01 mol) and hydrazine hydrate (6.8 g) was refluxed
under nitrogen for 1 hour and concentrated in vacuum. The residue was
suspended in warm water, and the solid was collected by filtration, dried and
recrystallized from ethyl acetate-Skelly B hexanes to give 1.81 g (67% yield)
of 6-chloro-2-hydrazino-4-phenylquinoline of melting point 156.5-157°C.
7-Chloro-1-methyl-5-phenyl-s-trizolo[4,3-a]quinoline: A stirred mixture of 6-
chloro-2-hydrazino-4-phenylquinoline (1.4 g, 0.0052 mol), triethylorthoacetate
(0.925 g, 0.0057 mol) and xylene (100 ml) was refluxed, under
nitrogen, for 2 hours 40 minutes. During this period the ethanol formed in the
reaction was removed by distillation through a short, glass helix-packed
column. The mixture was concentrated to dryness in vacuum and the residue
was crystallized from methanol-ethyl acetate to give: 1.28 g of 7-chloro-1-
methyl-5-phenyl-s-triazolo[4,3-a]quinoline (83.9% yield). The analytical
sample was crystallized from methylene chloride:methanol and had a melting
point 252.5-253.5°C.
5-Chloro-2-(3-methyl-4H-1,2,4-triazol-4-yl)benzophenone (Oxidation of 7-
chloro-1-methyl-5-phenyl-s-trizolo[4,3-a]quinoline): A stirred suspension of 7-
chloro-1-methyl-5-phenyl-s-triazolo[4,3-a] quinoline (2,94 g, 0.01 mol) in
acetone (110 ml) was cooled in an ice-bath and treated slowly with a solution
prepared by adding sodium periodate (2 g) to a stirred suspension of
ruthenium dioxide (200 mg) in water (35 ml). The mixture became dark.
Additional sodium periodate (8 g) was added during the next 15 minutes. The
ice-bath was removed and the mixture was stirred for 45 minutes. Additional
sodium periodate (4 g) was added and the mixture was stirred at ambient
temperature for 18 hours and filtered. The solid was washed with acetone and
the combined filtrate was concentrated in vacuum. The residue was suspended
in water and extracted with methylene chloride. The extract was dried over
anhydrous potassium carbonate and concentrated. The residue was
chromatographed on silica gel (100 g) with 10% methanol and 90% ethyl
acetate; 50 ml fractions were collected. The product was eluted in fractions
10-20 and was crystallized from ethyl acetate to give: 0.405 g of melting point 168-169.5°C and 0.291 g of melting point 167.5-169°C (23.4% yield) of
5-chloro-2-(3-methyl-4H-1,2,4-triazol-4-yl)benzophenone. The analytical
sample had a melting point of 168°C.
5-Chloro-2-[3-(hydroxymethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone:
A stirred mixture of 5-chloro-2-(3-methyl-4H-1,2,4-triazolo-4-
yl)benzophenone, (2.98 g, 0.01 mol) paraformaldehyde (3 g) and xylene (100
ml) was warmed under nitrogen, in a bath maintained at 125°C for 7 hours.
The mixture was then concentrated in vacuum. The residue was
chromatographed on silica gel (150 g) with 3% methanol-97% chloroform.
Fifty ml fractions were collected. The product was eluted in fractions 20-44.
The fractions were concentrated and the residue was crystallized from
ethanol-ethyl acetate to give: 1.64 g of melting point 138-142°C; 0.316 g of
melting point 138.5-141°C; 0.431 g of melting point 139-141°C (72.8% yield)
of 5-chloro-2-[3-(hydroxymethyl)-5-methyl-4H-1,2,4-triazol-4-
yl]benzophenone. The analytical sample had a melting point of 138-139°C.
5-Chloro-2-[3-(bromomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]-benzophenone:
A solution of 5-chloro-2-[3-(hydroxymethyl)-5-methyl-4H-1,2,4-triazol-4-yl]-
benzophenone (328 mg, 0.001 mol) in dry, hydrocarbon-stabilized chloroform
(5 ml) was cooled in an ice-bath and treated with phosphorus tribromide (0.1
ml). The colorless solution was kept in the ice-bath for 55 minutes, at ambient
temperature (22-24°C), for 5 hours. The resulting yellow solution was poured
into a mixture of ice and dilute sodium bicarbonate. This mixture was
extracted with chloroform. The extract was washed with brine, dried over
anhydrous magnesium sulfate and concentrated. The residue was crystallized
from methylene chloride-ethyl acetate to give: 0.285 g of melting point 200-
240°C (decomposition) and 0.030 g of melting point 200-220°C
(decomposition) of 5-chloro-2-[3-(bromomethyl)-5-methyl-4H-1,2,4-triazol-4-
yl]benzophenone. The analytical sample had a melting point of 200-240°C.
8-Chloro-1-methyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine: A
stirred suspension of 5-chloro-2-[3-(bromomethyl)-5-methyl-4H-1,2,4-triazol-
4-yl]-benzophenone (391 mg, 0.001 mol) in tetrahydrofuran (15 ml) was
cooled in an ice-bath and treated with a saturated solution of ammonia in
methanol (12.5 ml). The resulting solution was allowed to warm to ambient
temperature and stand for 24 hours. It was then concentrated in vacuum. The
residue was suspended in water, treated with a little sodium bicarbonate and
extracted with methylene chloride. The extract was washed with brine, dried
with anhydrous potassium carbonate and concentrated. The residue was
crystallized from methylene chloride-ethyl acetate to give 0.220 g of crude
product of melting point 227-228.5°C. Recrystallization of this material from
ethyl acetate gave 0.142 g of melting point 228-229.5°C of 8-chloro-1-
methyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
General Description
Alprazolam, 8-chloro-1-methyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine (Xanax), israpidly absorbed from the GI tract. Protein binding is lower(～70%) than with most benzodiazepines because of itslower lipophilicity.α-Hydroxylation of the methyl group tothe methyl alcohol (a reaction analogous to benzylic hydroxylation)followed by conjugation is rapid; consequently,the duration of action is short. The drug is a highlypotent anxiolytic on a milligram basis.
