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Diazepam (Valium) Synthesis

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]

To a solution of 13 grams of 5-chloro-isatoic anhydride in 120ml of dimethylformamide, 7 grams of


anhydrous sodium carbonate and 18 grams of methyl iodide was added. The reaction mixture was
stirred for 20h at room temperature, and then poured into 700 ml of water to give crude N-methyl5-chloro-isatoic anhydride. Recrystallization from acetic acid gave 85% yield of product melting at
201-203C.

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]

A mixture of 1.0 gram of 7-Chloro-1-methyl-3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione


(compound 2 above), and 3 ml of acetic anhydride was heated to reflux in a craig tube for 2.5 h.
The original suspension went into solution more or less rapidly, and after about 1h crystalline
material began to separate, and was cooled, allowed to stand overnight, and collected. 1.12g
(94%) of colorless prismatic blades, mp 207-208.5C.

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]

Crude 5-Chloro-2-(glycylmethylamino)-benzophenone from experiment 4 above (568 mg) and


485mg hydroxylamine hydrochloride were heated in 10ml of pyridine under N2 in a bath
maintained at 70C for 45 hours. The pyridine was removed as completely as possible on a
rotovap, and the residue taken up in an etheral solution of 3% HCl, the layers were separated, and
the ether layer was extracted three more times with 3% HCl. The combined acid extracts was
washed four times with CH2Cl2, the CH2Cl2 backwashed once with 3% HCl, and the combined 3%
HCl extracts made basic with excess ammonia. The liberated basic material was taken into CH2Cl2
(four extractions), filtered through anhydrous Na2SO4, concentrated and pumped out to yield 259
mg of nearly colorless glass, which spontaneously crystallized; mp 202-204C. The original ether
raffinate and the CH2Cl2 washes of the 3% acid solution was combined, filtered and concentrated
to yield 248mg of a yellow glass whose TLC showed it to contain quite a bit of unchanged ketone.
It was heated under N2 with 210 mg of hydroxylamine hydrochloride in 7 ml of pyridine at 70C for
43.5 hours as above. A similar workup yielded 106 mg more oxime, mp 201-203.5C and 122 mg
of acid-insoluble material. The oxime, when crystalline is very sparingly soluble in most organic
solvents. After several recrystallizations from methanol, colorless crystals with a mp of 212-213C
was obtained.

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 (alternative route from compound 4)[1]


502 mg of crude 5-Chloro-2-(aceturoylmethylamino)-benzophenone (product from experiment 4)
was dissolved in 25 ml of methanol and treated with 100% H2SO4 under reflux for 3.25h. Most of
the methanol was removed under vacuum, and the residue was taken up in a mixture of 25 ml
water and 25ml of ether. The layers were separated, and the ether layer was washed three times
with a 3% HCl solution, and the combined aqueous layers was made basic with ammonia and
extracted four times with methylene chloride. The extracts were washed with a small amount of
water, filtered through anhydrous Na2SO4, and concentrated to give 264 mg of a pale yellow glass.
This residue was taken into about 2-3 ml of alcohol and treated with 60% perchloric acid until acid
to congo red. Crystallization of the sparingly soluble Diazepam Perchlorate begins almost at once.
It is filtered and wased with a little alcohol. Yield 255mg (52.5%). The perchlorate was converted
to the freebase by distributing between methylene chloride and dilute ammonia (three extractions
with CH2Cl2). The washed, filtered and concentrated organic extracts yielded 191mg of very pale
yellow glass which crystallized readily; mp 130-131.5C.

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-Amino-5-chlorobenzophenone beta-oxime (from the alpha oxime)[5]


A solution of 20 grams of 2-Amino-5-chlorobenzophenone alpha-oxime (compound 2 above) in 150
cc of formic acid (98-100%) was refluxed for 3h, concentrated under vacuum to a small volume
and neutralized with cooling with 3N NaOH. The precipitated quinazolide 3-oxide was filtered off
and dissolved in 100ml of alcohol, and after the addition of 40 ml 3N NaOH the solution was
refluxed for 15min. The solution was then partly concentrated in vacuum, and the beta-oxime
precipitated by the addition of dry ice (solid CO2). It was extracted with ether and crystallized by
partial concentration. It formed prisms (7.7g) melting at 129-132C.

2-Chloroacetamido-5-chlorobenzophenone beta-oxime[5]

Into a stirred, cooled (10-15C) solution of 26.2g (0.1 mole) of 2-Amino-5-chlorobenzophenone


beta-oxime (compound 3 above) in 150 cc of dioxane were introduced in small portions 12.4g
(0.11 mole) of chloroacetyl chloride and an equivalent of 3N sodium hydroxide. The chloroacetyl
chloride and sodium hydroxide solution were introduced alternately at such a rate as to keep the
temperature below 15C and the mixture neutral or slightly alkaline. The reaction was completed
after 30 min. The mixture was then acidified with HCl, diluted with water and extracted with ether.
The ether extract was dried and concentrated under vacuum. Upon the addition of ether to the oily
residue, the product crystallized in colorless prisms melting at 166-167C. The yield was about
50%.

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.

Diazepam synthesis III [6]


Into a stirred, cooled (10'-15'C) solution of 26.2 g (0.1mol) of 2-amino-5-chlorobenzophenone-oxime in 150 ml of dioxane were introduced in small portions 12.4 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 15C and 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, 2chloroactetamido-5-chlorobenzophenone -oxime crystallized in colorless prisms melting at 161162C.
20 ml of 1 N NaOH were added to a solution of 6.4 g (20 mmol) of 2-chloroactetamido-5chlorobenzophenone -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-benzodiazepin2(1H)one 4-oxide.

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.

Diazepam synthesis IV (By Psycho Chemist)[7,8,9]

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.

Diazepam (personal experience)


Dissolve 180 g 2-methylamino-5-chlorobenzophenone in 1 l dry dichloromethane, add 100 g
chloroacetyl chloride over 1 h and reflux 10 h. Rotovap off the dichloromethane (dryness in the
flask, end (60 C, 20 torr).
Dissolve 400 g hexamethylene tetramine (urotropine) in 3 l ethanol, and add to the
chloroacetylated residue. Reflux and stirr 24 h (all organic material is dissolved) and then
evapotate to dryness. Add 100 mL toluene, and 1 g toluenesulphonic acid, and reflux with a DeanStark water-trap until no more water separates. Add 1 L water, heat to 70C and let cool down to
15C. Filter off your diazepam, and wash with 50 mL ice-cold toluene. Dry in vacuo. Almost pure
150 g Diazepam will result.

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