
Diazepam

7-chloro-1-methyl-5-phenyl-3H-1,4-benzodiazepin-2(1H)-one

CAS#: 439-14-5

Raw Materials:

2-amino-5-chlorbenzophenone-§-oxime, chloroacetyl chloride, phosphorus
trichloride, sodium hydroxide, diazomethane

Manufacturing Process:

Into a stirred, cooled (10'-15'C) solution of 26.2 g (0.1mol) of
2-amino-5-chlorpbenzophenone-§-oxime in 150 ml of dioxane were introduced
in small portions12.4 g (0.11 mol) of chloroacetyl chloride and an
equivalent amount of 3 N NaOH. The chloroacetyl chloride and NaOH were
introduced alternately at such a rate so as to keep the temperature below
15'C ansd the mixture neutral or slightly alkaline. The reaction was
completed after 30 minutes. The mixture was slightly acidified with HCl,
diluted with water and extracted with ether. The ether extract was dried
and concentrated in vacuo. Upon the addition of ether to the oily residue,
the product, 2-chloroactetamido-5-chlorobenzophenone §-oxime crystallized
in colorless prisms melting at 161'-162'C.

20 ml of 1 N NaOH were added to a solution of 6.4 g (20 mmol) of
2-chloroactetamido-5-chlorobenzophenone §-oxime. After 15 hours the mixture
was diluted with ice cold 1 N NaOH and extracted with ether. The ether
extract was discarded. The alkaline solution was acidified with HCl and
extracted with methylene chloride. The methylen chloride solution was
concentrated to a small volume and then diluted with petroleum ether to
obtain 7-chloro-5-phenyl-3H-1,4-benzodiazepin-2(1H)one 4-oxide.

To a stirred suspension of 10 grams (35 mmol) of
7-chloro-5-phenyl-3H-1,4-benzodiazepin-2(1H)one 4-oxide in approximately
150 ml methanol was added in portions an excess of diazomethane in ether.
After about one hour, almost complete solution had occurred and the
reaction mixture was filtered. The filtrate was concentrated in vacuo to a
small volume and diluted with ether and petroleum ether. The reaction
product, 7-chloro-1-methyl-5-phenyl-3H-1,4-benzodiazepin-2(1H)one 4-oxide,
crystallized in colorless prisms. The product was filtered off and
recrystallized from acetone, MP 188'-189'C.

A mixture of 3 grams (0.01 mol) of
7-chloro-1-methyl-5-phenyl-3H-1,4-benzodiazepin-2(1H)one 4-oxide, 30 ml of
chloroform and 1 ml of phosphorus trichloride  was refluxed for 1 hour. The
reaction mixture was then poured on ice and stirred with an excess of 40%
NaOH solution. The chloroform was then separated, dried with sodium
sulfate, filtered and concentrated in vacuo. The residue was dissolved in
methylene chloride and crystallized by the addiction of petroleum ether.
The product, 7-chloro-1-methyl-5-phenyl-3H-1,4-benzodiazepin-2(1H)one, was
recrystallized from a mixture of acetone and petroleum ether forming
colorless plates melting at 125'-126'C.

(From US Pat. 3,136,815) 