Diazepam
Diazepam
Diazepam
by Rhodium
Introduction
Benzodiazepines is a large class of compounds, used as sedatives, anxiolytics and/or skeletal
muscle relaxants. They have a good therapeutic window, low toxicity and a wide variety of
pharmacological profiles. The first synthesized benzodiazepine was Librium or Chlordiazepoxide,
and it was discovered serendipiously by L. Sternbach and E. Reeder, when they submitted a sample
of what they thought could be an antibiotic, that they were going to throw out anyway during a
spring cleaning. But they determined the structure of the compound errorneously, it had
rearranged itself to Librium during the synthesis.
One of the benzodiazepines that came shortly after Librium was Diazepam, commonly sold under
the trade name Valium, and it is is your typical benzodiazepine. It can be synthesized relatively
easily in around 50% yield from the commercially available starting material 5-chloro-isatoic
anhydride as can be seen below [1].
Experimental Procedures
All these procedures are presented for informational purposes only. These procedures should not
be carried out without adequate chemical knowledge, or necessary precautions taken. The author
takes no responsibility for any consequences resulting from use or misuse of this information, may
it be legal problems, loss of limbs or euphoria without limits.
Diazepam synthesis I
5-Chloro-N-methyl-isatoic anhydride[1,2]
7-Chloro-1-methyl-3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione[1]
A mixture of finely ground 5-chloro-N-methylisatoic anhydride (5.19 g), 2.25g of glycine, 4.15 ml
of triethylamine. and 30 ml of water was stirred at room temp for 5 hours. All solid material had
disappeared after 3.5-4 h. Voilatile material was removed as completely as possible on a rotavap
and the residue treated with 60 ml glacial acetic acid and heated to reflux for 4.5 hours. After the
mixture cooled, as much acetic acid as possible was removed on the rotary evaporator, and the tan
oily residue was treated with 30 ml of ether. On brief swirling of the mixture, crystallization set in,
and the colorless crystalline materiual was collecting after standing overnight and was washed with
ether (4.60g, mp 176.5-178C). The etheral filtrate (two phases) was diluted with enough ethyl
acetate to render it homogenous, washed twice with dilute sodium carbonate, then with water,
filtered through anhydrous sodium sulfate, and concentrated. Recrystallization of the crystalline
residue (0.53g) gave 0.43 g of product, mp 177-179C. Total yield 5.03g (91.8%).
4-Acetyl-7-chloro-1-methyl-3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione[1]
5-Chloro-2-(glycylmethylamino)-benzophenone[1]
A suspension of 483mg (1.82mmol) finely ground 4-Acetyl-7-chloro-1-methyl-3,4-dihydro-1H-1,4benzodiazepine-2,5- dione (from experiment 3 above) in 12 ml of THF, freshly freshly refluxed with
and distilled from LiAlH4, was treated slowly over 20 min under stirring with 1.00ml (2.18 mmol,
1.2 equiv) of 2.18 N commercial (Fisher) phenylmagnesium chloride at room temp (15-18C).
During the addition the tip of the delivery syringe was kept below the surface of the stirred
solution. During the addition the solution becomes deep red, and the suspended material goes into
solution. Stirring was continued for 1.5h after the addition was complete, during which the color
lightens to a clear bright yellow. The reaction mixture was treated with ammonium chloride solution
and extracted four times with CH2Cl2, the extracts were filtered through anhydrous Na2SO4 and
concentrated, and the residue was pumped out at 100C and reduced pressure to give 684 mg of
yellow glass. This material consists predominantly of the product benzophenone with small
amounts of the starting material, in a ratio 10.8:1 as determined by HPLC; in other runs the ratio
varied between 7:1 and 10:1.
5-Chloro-2-(glycylmethylamino)-benzophenone oxime[1]
Diazepam[1]
378 mg of the crude product obtained in experiment 6 above was refluxed for 12 h with 1.13 g of
NaHSO3 in a mixture of 15ml of alcohol and 7.5 ml of water. Most of the alcohol was removed
under vacuum, and the residue treated with ether and 3% HCl. The ether layer was washed three
more times with 3% HCl, and then the combined acid fractions were extracted five times with
CH2Cl2. The extracts were filtered through anhydrous Na2SO4 and concentrated. The orange-
yellow residue (303mg, 89.3% after thorough drying) crystallized readily on seeding with
diazepam, and had a melting point of 129-131.5C.
Diazepam synthesis II
2-amino-5-chlorobenzophenone[3]
Under Construction!
2-amino-5-chlorobenzophenone alpha/beta-oxime[4]
A mixture of 200g of 2-amino-5-chlorobenzophenone (compound 1 above), 100g of hydroxylamine
hydrochloride and 1 liter of alcohol was stirred under reflux for 22h. The mixture was concentrated
under vacuum to a small volume, diluted with water and neutralized with sodium carbonate.
Benzene was then added, and the stirring was then continued until a considerable amount of
crystalline precipitate had formed. Some petroleum ether was added, and the mixture was filtered.
The crude alpha-oxime (139g, mp 150-160C) remaining in the funnel was washed with benzene
and petroleum ether. After recrystallization from a mixture of ether and petroleum ether, it forms
colorless prisms melting at 164-167C.
The aqueous layer of the filtrate was separated and discarded. The organic solution was dried,
concentrated in vacuum, and the residue taken up in ether. The ether solution was filtered, diluted
with petroleum ether and kept at 0C for 20h. The precipitated crystals, a mixture of the isomers
(42g, mp 119-122C), was filtered off. A third crop of crystals was obtained from the mother
liquors after concentration to a sirup. It consisted of 8g of prisms melting at 127-130C. This
product can be recrystallized from ether/petroleum ether to form pure beta-oxime, mp129-132C.
The total yield of 189g (both alpha- and beta-oximes)corresponds to 89%.
2-Chloroacetamido-5-chlorobenzophenone beta-oxime[5]
7-Chloro-5-phenyl-3H-1,4-benzodiazepin-2(1H)-one 4-oxide[5]
To a solution of 6.4g (20 mmol) of 2-Chloroacetamido-5-chlorobenzophenone beta-oxime
(compound 4 above) in 60cc of dioxane was added 20 cc of 1N NaOH. After 15h, the mixture was
diluted with ice cold 1N NaOH and extracted with ether. The ether extracts was discarded, the
alkaline solution acidified and extracted with methylene chloride. The organic solution was
concentrated to a small volume, and diluted with petroleum ether, yielding 3.1g (54%) of the title
compound.
7-Chloro-1-methyl-5-phenyl-3H-1,4-benzodiazepin-2(1H)-one 4-oxide[5]
To a stirred warm solution of 15 grams of 7-Chloro-5-phenyl-3H-1,4-benzodiazepin-2(1H)-one 4oxide (compound 5 above) in 700 cc of methanol were added 2.78 grams of sodium methoxide,
and after 5 min, 5 cc of dimethyl sulfate. The reaction mixture was refluxed for 1 h, concentrated in
vacuum to a small volume, and dilute with ether and petroleum ether. The formed crystals (11g,
70%) were filtered and washed with water. After recrystallization from acetone, colorless prisms
melting at 188-189C were obtained.
Diazepam[5]
A mixture of 3g of 7-Chloro-1-methyl-5-phenyl-3H-1,4-benzodiazepin-2(1H)-one 4-oxide
(compound 6 above), 30 cc of chloroform and 1 cc of phosphorous trichloride was refluxed for 4
hours. The reaction mixture was then poured on ice and stirred with an excess of 40% NaOH
solution. The chloroform solution was separated, dried with sodium sulfate, filtered and
concentrated under vacuum. The residue was dissolved in methylene chloride and was crystallized
by the addition of petroleum ether yielding 1.8g (63%) of the crystalline reaction product (mp 120122C). after recrystallization from a mixture of petroleum ether and acetone, the product formed
colorless plates melting at 125-126C.
The same compound was also formed in almost quantitative yield by catalytic hydrogenation of
compound 6 in methanol at atmospheric pressure (30-50C) using Raney-Nickel as catalyst.
To a stirred suspension of 10 grams (35 mmol) of 7-chloro-5-phenyl-3H-1,4-benzodiazepin2(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-1,4benzodiazepin-2(1H)one 4-oxide, crystallized in colorless prisms. The product was filtered off and
recrystallized from acetone, MP 188-189C.
A mixture of 3 grams (0.01 mol) of 7-chloro-1-methyl-5-phenyl-3H-1,4-benzodiazepin-2(1H)one 4oxide, 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 125-126C.
2-Methylamino-5-chloro-benzophenone
Dissolve 400 g sodium hydroxide in 4 L ethanol and in a seperate flask, 1.5 moles (175.5 g) benzyl
cyanide (see elsewhere on this site for its synthesis) and 1 mole 1-chloro-4-nitrobenzene and the
min. amoount benzene or toluene or THF to obtain a solid-free solution. Add dropwise this organic
mixture to the NaOH in alcohol at 17-22C (control by cooling), and leave the mix for 4 days. Pour
on 3 kg ice and 12 L water (This mix now contains cyanide and must not be contaminated with
acid!!!). Vacuum-filter (in portions) the resinous mass or decant off the water layer. Dissolve the
water-washed resin in 1 L (or more, but loss) boiling isopropanol and let cool down to 10C, after 1
day, filter the intermediate, 0.9 moles or about 200 g 5-chloro-3-phenyl- benzo(2,1)-isoxazole.
A mix of 200 g benzisoxazole and 500 ml dimethyl sulfate (caution) is stirred 12 h at 80C (4 L
flask), and through the condenser thereafter, 100 mL water and 2 L ethanol is added , then, direct
to the flask, 100 g iron fillings. The flask content is mechanically stirred and over 90 min., 600 mL
conc. hydrochloric acid is added. Then the mix is refluxed 90 min and filtered over Celite hot. The
cake is washed with 1 L hot ethanol and the filtrate concentrated in vacuo to 500 mL. It is poured
in 4 L water and 1 L dichloromethane is added until most is dissolved. The dichloromethane layer is
seperated and reextracted with 1 L more dichloromethane. The combined dichloromethane extracts
are filtered and evaporated to dryness to leave the 2-methylamino- 5-chloro-benzophenone, cryst.
From petrol ether, mp 95-98C. Yield 180 g.
References
[1] M. Gates, New Synthesis of Diazepam J. Org. Chem. 45, 1675-1681 (1980)
[2] G. Palazzo, B. Silvestrini, Substituted anthranilamides and preparation thereof, US Pat.
3,409,668
[3] J. Chem. Soc. 85, 344, (1904) and Chem. Abs 30, 2972 (1936)
[4] L.H. Sternbach, S. Kaiser, E. Reeder, Quinazolidine Compounds, J. Am. Chem. Soc. 82, 475480 (1960)
[5] L.H. Sernbach, E. Reeder, Quinazolidines and 1,4-Benzodiazepines IV, J. Org. Chem. 26,
4936-4941 (1961)
[6] US Pat. 3,136,815
[7] Chem Abstr. 123-339841 p
[8] Russ. J. Org. Chem., Vol. 30, p 1481-1484 (1994) (english)
[9] Coll. Czechoslovak Chem. Commun., Vol. 50, p 1064-1069 (1985