Dimenoxadol

[Paregoric Kid]

anyone have any info on this?

[bi11i]

other than it being a schedule i?

[Paregoric Kid]

if possible, yes

[bi11i]

sorry, no. that's a rare one. gotta wonder what it's all about. let me know what you find out....

[bwitiacumen]

From: Dianna
Newsgroups: alt.drugs.chemistry
Subject: dimenoxadol synthesis repost
Date: Thu, 2 May 1996

(Original post 27 Apr 1996 - check DejaNews)

Dimenoxadol: A Hypothetic synthetic route from easily available chemicals.
The information contained herein is not quite complete for safety
purposes. The transition from benzoin to benzilic acid is omitted. This
discussion of hypothetical synthesis is for informational purposes only.


The Ingredients and Preparation Tips I Gathered:
Benzoin can be had at many pharmacies in the united states quite cheap.
Ask for it, I believe it is used as a disinfectent or something.

O
Ph------Ph BENZOIN
/
HO

Benzoin is easily rearranged to Benzilic Acid, also called
a-hydroxy-a-phenylbenzeneacetic acid, diphenylglycolic acid

OH
/
O==< OH Benzilic Acid
\/
/\
Ph Ph

This would need to be reacted with something (ethanol and sulfuric acid?)
to give both the ethyl ester and ether, which would then be hydrolysed to
give diphenylethoxyacid, one major ingredient which would need to be
purified, distilled, or something. Distillation would likely be easier
performed on the ethyl ester rather than the acid form. Purification
might involve crystalization with sodium (from NaOH - good drain opener)
and washing with some solvent?

The next major ingredient, dimethylchloroethylamine, might be prepared
with ZnCl2, HCl, and DMAE, available OTC as DMAE bitartarate from many
health food joints in the USA. HCl is drain cleaner, and ZnHCl might be
made from Zinc and HCl with some really vigourous drying technique and
venting of excess acid (i.e. dont ruin yer metal stove drying it)

DMAE, if unobtainable, could also be produced by the reduction of glycine
followed with methylation. Probably too difficult for underequipped home
chemists. Reduction of DMG (dimethylglycine) is an option, but if you
cant get weird supplements like DMAE you probably cant get weird
supplements like DMG either :)

DMAE HCl should probably be the form disolved into the reaction to give
dimethylchloroethylamine. That means ya need to remove the tartaric acid
from your DMAE bitartarate. Probably the best way to do this is some form
of acid base extraction: DMAE base is miscible in alcohol, water, and
ether, so repeatad extractions are probably a good thing to do.

Furthermore, a tip:
DMAE bitartarate is disolved in a minimum of water, then isopropanol is
added, 70% will do but 100% should be given some extra water so this
trick will work good. Sodium hydroxide is added to this mixture until
there are layers formed upon standing: the isopropanol + DMAE base
mixture should have "salted out", while damn near all of the NaOH and
NaTartarate stay in the water! Addition of HCl and removal of solvent can
then give DMAE HCl in a probably acceptable form.


Lastly;


_____
/ \
H3C--N O dimenoxadol
| /
H3C O==< O--CH2--CH3
\ /
X
/ \
Ph Ph


Prepared by the reaction of diphenylethoxyacid with
dimethylchloroethylamine in the presence of isopropanol.
(which sounds easy... anyone got the details this is all merck gives but
it makes good sense)

--Whatcha think--

This is a C1 opiate in the United States.
Was it just never marketed, or is there something _wrong_ with it, like
prolonged use does something hideous to you (besides making you a fiend!)

* * * * * * * * * * * * * * * * * * * * *

For those of the elite few with good access to reference libraries, the
merck provides this reference for the above reaction:

Klosa, Arch. Pharm. 288,42 (1955)

as well as a reference to an imporved method:

C. N. Yakhontov et al Pharm. Chem. J. 8,189 (1974)

The compound is insoluable in ether, ethyl acetate, benzene, but IS
soluable in water an alcohols (only slightly soluable in acetone and
chloroform)

--------------------------------------------------------------------------------

A New Series of Potent Analgesics
J. Am. Chem. Soc. 78, 3862 (1956)
Paul A. J. Janssen

Continuing our research program on substituted phenylpropylamines (1), we
have synthesized and screened for pharmacological activity, a series of
over 100 new basic amides of structure I (CONRR' = secondary or tertiary
amide group; alpha and beta = H or CH3; NAA' = tertiary amine group).

Some of these compounds are highly active analgesics in mice, rats,
cats, guinea pigs, dogs and man. The relation between chemical structure
and analgesic activity within this series can be described as follows:

(1) NRR': highest activity was found among N-pyrrolidine- and
N,N'-dimethylamides.
(2) alpha and beta: branching the side chain with a methyl-group in
alpha-position, considerably increases analgesic activity; the
beta-CH3 isomers are much less active.
(3) NAA': the most active compounds are N-substituted morpholines.
Some piperidines, pyrrolidines and dimethylamines were also
found to cause marked analgesia.
(4) Quaternary amines are devoid of analgesic activity.
(5) In the alpha-CH3 series, one of the optical isomers of each
enantiomorphic pair is twice as active as the racemic mixture;
the other optical isomer is devoid of significant analgesic
activity. The spatial configuration of the analgesically active
optical isomers is probably identical and related to that of
D-(-)alanine (2).
(6) Reduction or complete loss in activity occurs when one or both
phenyl groups are substituted or replaced, or when the ethyl side
chain is lengthened or shortened.

These basic amides (I) are formed when a secondary or tertiary
amine is allowed to react in suitable conditions with the corresponding
acid chloride (1d, 1f, 3, 4).
The tertiary amides of type I may also be prepared by condensation
of an N,N'-disubstituted diphenylacetamide with a tertiary aminoalkyl
chloride, using a condensing agent such as sodamide (1d, 1f, 4, 5).
Mixtures of alpha-CH3 and beta-CH3 isomers of type I are formed when
tertiary aminoisopropylchlorides are used in this reaction.
Serial number R 610 (II: dl-2,2-diphenyl-3-methyl-4-morpholino-
butyryl-pyrrolidine) appears to be one of the promising candidates for
further study (m.p. 170-172_).
The d-isomer of II, serial number R 875, is twice as active as the
racemic mixture (m.p. 180-184_; [a]20D + 25.5 ~ 0.5_ in benzene; c = 5.0).
As an analgesic, R 875 is 60 to 100 times more active than meperidine, 10
to 40 times more active than morphine, 5 to 20 times more active than
methadon and about four times more active than diacetylmorphine (heroin) in
various experimental conditions.
In animals R 875 has a higher oral activity and a better therapeutic
ratio than any other analgesic compound tested. Preliminary double-blind
experiments with the racemic modification of II in patients indicate an
analgesic potency of about three times that of morphine; no side effects
were observed after subcutaneous injections of up to 12 mg R 610. The
physicochemical and pharmacological properties of these compounds will be
published elsewhere.

(1) (a) P. Janssen, Arch. int. Pharmacodyn., 103, 82 (1955);
(b) P. Janssen, Arch. int. Pharmacodyn., 103, 100 (1955)
(c) P. Janssen, Arch. int. Pharmacodyn., 103, 120 (1955);
(d) P. Janssen, This Journal, 77, 4423 (1955);
(e) P. Janssen, Arch. int. Pharmacodyn., 106, 199 (1956);
(f) P. Janssen, "Over de pharmacologie van een reeks propylaminen",
University Ghent, 1956;
(g) P. Janssen, Arch. int. Pharmacodyn., in press.
(2) A. Beckett, J. Chem. Soc., 900 (1955).
(3) R. Clarke, This Journal, 71, 2821 (1949).
(4) M. Bockm_hl, German patent 731,560 (1943), Chem. Abstr., 38, 551 (1944),
(5) L. C. Cheney, J. Org. Chem. 17, 770 (1952).

--------------------------------------------------------------------------------

Epikur

Dimenoxadol

On Rhodium's page there is some information on this substance, but most of it is
guesswork, so I contribute this short dossier on dimenoxadol and hope it will
find it's way to supplement the information on Rhodium's page.

The Merck Index lists dimenoxadol as 'analgesic' with the remark 'abuse leads to
habituation or addiction', which is an strong indication that it's a opiate type
substance. Additionally it's a controlled substance (schedule I). Dimenoxadol
looks like this:

Ph
|
CH3CH2-O-C-COO-CH2-CH2-N(CH3)2 Ph = Phenyl
|
Ph

Unlike in many other opiates, minor structural changes completely abolish the
opiate activity. Substituents other than ethoxy or dimethylamine are not active,
with one exception that will be mentioned latter.

Methods for the preparation can be found in GB pat 716,700, as well as brief
information on the pharmacology. The preparation from benzilic acid is not as
easy as one might think and involves rather unpleasant chemicals like sodium
metal. It would most probably be better to acquire 2-dimethylaminoethyl
benzilate, a spasmolytic, mydriatic, antirhinitic which is commercially
available:

Ph
|
HO-C-COO-CH2-CH2-N(CH3)2 Ph = Phenyl
|
Ph

The two steps to dimenoxadol are 1) replacing the OH with a Cl, using thionyl
chloride and 2) forming ethyl ether by refluxing for 24h in absolute ethanol
with CaCO3 added.

The LD50 in mice is 200 mg/kg sc and 650 mg/kg po, while the LD50 of morphine is
470-500 mg/kg sc and that of meperidine 195 mg/kg. Unlike the common opiates it
supposedly does not suppress respiration, but has an atropine- and
papaverinelike spasmolytic action. Even the hydrochloride is sparsely soluble in
water (5-10%), making injections difficult. The potency is about 25% of
morphine, i.e. the dosage is about 4 times higher. The recommended dosage is 1 -
3 mg/kg iv and 3 - 5 mg/kg im and sc. Alltogether, the pharmacological profile
seems to resemble that of meperidine (pethidine).

An alternative compound is disclosed in GB pat 1,050,467:

Ph
|
Cl-CH2HC2CH3CH2-O-C-COO-CH2-CH2-N(CH3)2 Ph = Phenyl
|
Ph

The preparation is similar to the one of dimenoxadol, but insted of ethanol
there is 4-chlorobutanol (available commercially) used in the etherifying step.

This compound has an activity slightly higher than morphine (+10%), with a LD50
of 220 mg/kg, therefore it's about 4 times safer and more potent than
dimenoxadol. It also is a very powerful spasmolytic and anticonvulsant. Unlike
morphine, it does not suppress, but rather increase respiration.

For the clandestine manufacturer (CM), this substance would have the advantage
that it's not a controlled substance. One could also argue that it's not an
analog of a controlled substance (dimenoxadol) but rather a derivative of a
non-controlled substance (2-dimethylaminoethyl benzilate). This is an important
point in countries with Controlled Substance Analogs laws. But better consult
someone who knows more about CsA laws that me. One advantage for the CM is that
none of the precursors are watched or suspicious chemicals.

However, the spasmolytic/anticholinergic activity could possibly spoil the fun
with this substance, and it is not known if it produces a good high. There are
other substances which can be made with similarely little effort and which are
most likely much more rewarding.

------------------------------------------------------------------------------
Benzilic Acid from Benzoin (from Mann & Saunders, Practical Organic Chemistry)
------------------------------------------------------------------------------

Benzoin is oxidised to benzil by nitric acid:

Place 10g of powdered benzoin and 25ml of concentrated nitric acid in a 150ml
flask fitted with a reflux water condensor, and heat the flask on a boiling
water bath. A flask having a ground-glass neck fitting directly to the condensor
is best for this purpose. If not available, fit the flask to the condensor by
means of a cork (not a rubber stopper) and clamp both flask to the condensor
securely in position during heating on the water bath: the nitrous fumes rot
cork during the heating, and ifonly one clamp is used, the flask may possibly
slip away from the condensor, or alternatively the latter may fall sideways
under its own weight. Continue the heating for 1.5 hrs, when the crystalline
benzoin will have been completely replaced by the oily benzil. Then pour the
mixture into a beaker of cold water, when on vigorous stirring the oil will
crystallise into a yellow solid. Filter off the later at the pump and wash
thoroughly with water to ensure complete elimination of acid. Recrystallise from
methlated or rectified spirit. Benzil spearates as clear yellow crystals, m.p.
95 degrees; yield 9g.

Benzilic acid from Benzil

Dissolve 5g of benzil in 15ml of boiling ethanol in a conical flask fitted with
a reflux water-condensor. Then add a solution of 5g of KOH in 10ml water, and
heat the mixture (which rapidly develops a purple colour) on a boiling
water-bath for about 15mins. Cool and stir the solution, from which the
potassium benzilate separates in fine crystals. Filter the product at the pump,
using an alkali-resisting filter-paper, or a sintered glass filter funnel. Wash
the crystals on the filter with a small quantity of ethanol to remove the purple
colour, and then drain thoroughly.

To obtain the free acid, dissolve the potassium salt in 50ml of cold water,
filter the solution if a small undissolved residue remains; and boil the clear
solution gently whilst dilute h2so4 is added until the separation of the acid is
complete. Cool the solution and filter off the pale orange-coloured crystals of
the benzilic acid; wash the crystaks on the filter with some hot dH2O, drain
well, and then dry in a dessicator. Yield of crude acid, 4g.

Recrystallise from much hot water. The benzilic acid is obtained as colourless
crystals, m.p. 150 degrees.