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Subject:      Benzodiazepine Synthesis
From:	      Mike Hamilton <mdh@freenet.calgary.ab.ca>
Date:	      1995/07/04

	I did a little researching and came up with some interesting
and possibly useful info on bdz synthesis.  The synthesis doesn't
seem to difficult or require any watched chemicals.

	To start with you need p-chloro aniline and benzoyl chloride.
These two are reacted along with ZnCl2 to form a dimer which can
then be hydrolyzed to form o-benzoyl p-chloro aniline.	This
compound is them aminated with hydroxyamine to form the oxime of
o-benzoyl p-chloro aniline.  This compound can them be acetylated
with chloro acetyl chloride and sodium hydroxide in a complex
rearrangement reaction to form the N-oxide of diazepam. One could
reduce this to form diazepam.  One could also react it with acetic
acid and apply a little heat (I think) to cause another neat little
rearrangement which results in the acetyl ester of oxazepam, which
of course could be hydrolyzed to form oxazepam.

	There are other, but more complicated, synthesis' for other
bdzs but I think the above would be most easily done, as it requires
both easily obtained chemicals and no pressure bombs.

	Given the high potentcy of the bdzs, Valium ~10mg and
oxazepam a little more potent (I think!) this synthesis may
be quite valuble!!

	I'm going to look up the references to see what is really
required and post any neat stuff I find.

	Mike

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Subj: Synthesis of benzodiazepines?
From: hamiltmd@acs.ucalgary.ca (NigNog)

>> I can provide references of some very good articles
>> straight from the Hoffman-Roche laboratories.

There are four papers on this in J Am Chem Soc and J Org Chem

Paper I:   JACS 82, p475 (1960) - deals with ring rearrangements etc
Paper II:  JOC 26, p1111 (1961) - as above
Paper III: JOC 26, 4448 (1961) - best of the four, deals from
	    beginning to end with synthesis
Paper IV:  JOC 26, 4936 (1961) - deals mainly with rearrangements and
	    related derivative, some on oxazepam, chlordiazepoxide

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Subj: Re: Benzodiazapines ?
From: dmurphy3@aol.com (DMurphy3)

Several derivatives of valium, chemically
7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-Benzodiazepin-2-one, are
possible starting with the reaction of hydroxylamine or its salts with a
2-aminobenzophenone in ethanol to give the oxime.  Here are a couple;
(1). In a 500 mL round bottom flask set up for reflux (i.e., with a
condenser column set up straight in the neck so vapors condense and fall
back into the flask; refer to a standard lab text) combine 16.8 g
2-aminobenzophenone and 11.9 g of glycine ethyl ester hydrochloride with
200 mL pryidine. [Note: benzophenone (diphenyl ketone) may be prepared by
the Freidel-Crafts rxn of benzene and benzoyl chloride with aluminum
chloride; by the rxn of benzene and carbon tetrachloride and subsequent
hydrolysis of the product, a,a-dichlorodiphenylmethane; by air oxidaion of
diphenylmethane; etc (Ullmanns Encyklopadie der technischen Chemie, 4th
ed, Verlag Chemie, Weinheim, Vol 14, 224, 1977). Glycine ethyl ester HCl
can be made by the esterifiction of the amino acid glycine (Yamazaki and
Higashi, Tett. Lett.; 5047, 1972 reviews several amino acid
esterifications).] Reflux 1 h, set up for distillation and distill off 20
mL pyridien. Reflux an additional 15 h, add 11.9 g more of the glycine
ester salt, and reflux 4 additional h. Strip off solvents under vacuum
(i.e., evaporate the solvents by using a vacuum pump or aspirator or, if
you have access, a rotovap). Dilute the residue with water and ether and
allow to slowly evaporate to  recover crystals of the product
5-phenyl-3H-1,4-benzodiaxepin-2-(IH)-one. Recrystallize from acetone.
Crystals are colorless, rhombic prisms melting at 182-183 C. Useable as
is, or proceed to next synthesis.

(2). Suspend 4.4 g of the product drom synth 1 in 75 mL MeOH. Add 1.1 g
sodium methylate. Stir the solution 10 minutes (it should be clear at this
point) at room temp. Dry by vacuum, add 95 mL dimethylformamide to the
brown residue. forming an initially clear solution which will develop a
grey precipitate.  Add 3.8 mL (8.52 g) methyl iodide, dropwise. This
should have been previouly chilled thoroughly in a salt water ice bath or
freezer as it is quite volatile. The best way to add it is with a syringe,
otherwise it will quickly evaporate and it is very irritating to the eyes
and mucous membranes. The temperature will rise to 30 C during this time.
Stir 1 h at room temp, then pour into 1 L of ice water (distilled,
please). Stir an additional 1 h then add 2 g sodium thiosulfate (available
at photography suppliers). Extract the cold mixture with 4x300 mL of
methylene chloride.  Combine the organic extracts and wash with ice cold
water, dry with anhydrous sodium sulfate, and concentrate under vacuum
(careful, it might bump and you could lose all your product). Cool in the
top of the refrigerator overnight and recover the white prism-like
crystals of the product, 1-methyl-5-phenyl-3H-1,4-benzodiazepin-(2H)-one.

Disclaimer: For information purposes only. This is not intended to be used
for any unlawful purpose including, but not limited to, attempting to
synthesize these compounds, attempting to purchase any controlled
sbstances, or sending free samples to the poster.

Cheers,
Dex

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Comments to the above text:

Other benzophenone ref: Vogel, Pract Org Chem, 5ed, p1009 & p1049.

One note is that the product of part 1 could be reacted with acetyl
chloride followed by hydrazine (bonding to those ketone groups) to form the
ultra-powerful Triazolo derivatives. I think prosom is about 20X stronger
than nordiazepam. I recommend 'Controlled Substances' by everyones dream
grand-dad Alexander (Sasha) Shulgin. It goves a really good
structure-relationship chart. Its a MUST BUY item.

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Subject:      Re: Synthesis of benzodiazepines?
From:         jkenner@cello.gina.calstate.edu (Jason Kennerly)
Date:         1996/03/18

        I did a little researching and came up with some interesting
and possibly useful info on bdz synthesis.  The synthesis doesn't 
seem to difficult or require any watched chemicals.
 
        To start with you need p-chloro aniline and benzoyl chloride.
These two are reacted along with ZnCl2 to form a dimer which can
then be hydrolyzed to form o-benzoyl p-chloro aniline.  This 
compound is them aminated with hydroxyamine to form the oxime of
o-benzoyl p-chloro aniline.  This compound can them be acetylated
with chloro acetyl chloride and sodium hydroxide in a complex
rearrangement reaction to form the N-oxide of diazepam. One could
reduce this to form diazepam.  One could also react it with acetic
acid and apply a little heat (I think) to cause another neat little
rearrangement which results in the acetyl ester of oxazepam, which
of course could be hydrolyzed to form oxazepam.
 
        There are other, but more complicated, synthesis' for other
bdzs but I think the above would be most easily done, as it requires
both easily obtained chemicals and no pressure bombs.
 
        Given the high potentcy of the bdzs, Valium ~10mg and 
oxazepam a little more potent (I think!) this synthesis may
be quite valuble!!

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Subject:      Re: Synthesis of benzodiazepines?
From:         hamiltmd@acs.ucalgary.ca (NigNog)
Date:         1996/03/20

> Does anyone know the synthesis of any of the benzodiazepines? 

        You betcha, you start by synthesizing the substituted benzophenone
(usually p-chloro) in a Friedel-Crafts acylation. You then used to
hydroxylamine to form the oxime, reacting it with chloro-acetyl
chloride to give the 6 membered ring system, which when reacted with
methylamine gives the rearranged product of the benzodiazepine system,
chlordiazepoxide.  Variations of this can produce all the
benzodiazepines.  I can provide references of some very good articles
straight from the Hoffman-Roche laboratories.

        Mike
