From: [d--e] at [unislc.slc.unisys.com] (Dale Clark)
Subject: METHADONE
Date: Mon, 14 Jun 1993 14:56:14 -0600 (MDT)


		     ----------------------------------
                                METHADONE 
                     ----------------------------------


GENERAL INFO
------------
6-dimethylamino-4,4-diphenyl-3-heptanone HCl;  1,1-diphenyl-1-(2-
dimethylaminopropyl)-2-butanone HCl; 4,4-diphenyl-6-dimethylamino-3-
heptanone HCl.  C21 H28 CINO.  US pat. 2,644,010 (1953 to Merck & Co.); 
US pat. 2,983,757 (1961 to Abbott).  First developed in Nazi Germany 1943.  
Platelets from alcohol + ether.  Melting point 235F. pH of 1% aqueous 
solution: 4.5-5.6.  Free base (melting point 78F) is precipitated from
solutions with a pH > 6.  Aqueous solutions can be autoclaved at 120F 
for one hour without loss of potency.


STRUCTURE
---------

			C6H5   N(CH3)2
	 	          |    |
	          CH3CH2COC----CH2CHCH3  .  HCl
	                  |
		          C6H5


                         CH2 CH3
                         |
	     -----       CO       CH3
            //   \\      |         |
           ||     ||---- C -- CH2 CHN(CH3)2   .   HCl
            \\   //      |
             -----       |
	               -----
                      //   \\
                     ||     ||
                      \\   //
                       -----


COMMERCIAL DRUG NAMES
---------------------
Adanon, Algidon, Algolysin, Amidon, AN-148, Butalgin, Depridol, Diaminon, 
Dolophine, Fenadone, Heptadon, Hoechst 10820, Ketalgin, Mecodin, Mephenon,
Miadone, Moheptan, Phenadone, Physeptone, Tussal. 


LD-50
----
Orally in rats: 95 mg/kg.


ACTIONS
-------
Methadone is a synthetic opioid-agonist that acts primarily at the
mu-opioid receptor sites.  Its analgesic potency and duration is equal
to that of morphine.  When taken IV, the portal circulation is
bypassed and, being highly lipophilic, it readily crosses the blood-
brain barrier and is twice as potent as when taken orally.

Absorption from the gastrointestinal tract is essentially complete.
There is extensive initial hepatic uptake of approximately 90%.
The drug is then gradually released from hepatic binding sites in 
unchanged form into the effluent blood.  The result is a flat curve
of blood plasma levels over a 24 to 36 hour period, with peak levels
at 2 to 6 hours less than two times the nadir or trough level.

Large doses given daily can result in the constant availability of
methadone to receptor sites, a prevention of opioid withdrawl symptoms,
and an apparent block of the euphoric effects of heroin.  Optimal
dosing which maintains blood levels of 150 to 600ng/mL are the goal
of most methadone treatment centers.


DRUG INTERACTIONS
-----------------
Other drugs which interact with methadone include: phenytoin
(which can accelerate methadone metabolism), rifampin (a potent
inducer of the hepatic microsomal system), desipramine (which may
degrade slower), phenobarbital (indefinite interactions) and
monoamine oxidase inhibitors (which can precipitate severe
untoward reactions).	


CREATION PROCESS
----------------
When completed, methadone is a white, crystalline powder with a
bitter taste that is water soluble.  It is insoluble in ether and
glycerol.  Methadone is relatively inexpensive and easy to prepare, 
the entire process requiring approximately 10 hours. 

First, diphenylacetonitrile and dimethylamino-2-chloropropane are
combined with alkali.  The mixture is then vacuum distilled.  Next, a series
of organometallic reagents (Grignard reagents) are made using
ethylmagnesium bromide, phosphorus tribromide, propylene oxide, and
sodamide.  The last two reactions of the Grignard process are in two steps,
the second of which requires water.  The process requires caution in
handling and preparation because of the high flammability.

Finally, the compound is adjusted for pH by adding hydrochloric
acid and/or sodium hydroxide.  Chlorobutanol can be added as a
preservative to slow decomposition (0.5% per 20-mL).

The original method of synthesis of methadone is similar in nature.
Diphenylacetonitrile and dimethylamino-2-chloropropane are condensed 
with sodamide (NaNH2) as base (better results can be obtained with 
potassium t-butoxide).  The mixed nitriles (which can be easily separated 
if desired) are collected and reacted with ethylmagnesium bromide.  
This is quenched in dilute HCl to form the final product.


CHEMICAL			COMMERCIAL USE / HAZARDS
--------			------------------------
chlorobutanol			Chloroform derivative, preservative.
				TOXIC / IRRITANT.

diphenylacetonitrile		Herbicide, organic preparations, synthetic
				pharmaceuticals.
				TOXIC: AVOID CONTACT.

dimethylamino-2-chloropropane	Organic preparations.

ethylmagnesium bromide		Organic preparations. (Grignard reagent).
				FLAMMABLE.

phosphorus tribromide		Organic preparations.
				CORROSIVE: AVOID CONTACT.

propylene oxide			Detergents, lubricant, fumigant, 
				urethane-form production. 
				TOXIC / FLAMMABLE.

hydrochloric acid		Wide uses.  
				CORROSIVE / TOXIC.

sodium hydroxide		Wide uses. 
				CORROSIVE / TOXIC.