Complete Synthesis of Methadone

[Rhodium]

I wrote the document

https://www.thevespiary.org/rhodium/Rhodium/chemistry/methadone.html

today. Now I'm tired, seeya.

I would really like to get some input on this document, with questions, suggestions and corrections now.

[muriatic_asshole]

My chemistry isn't good enough to find flaws, but I must congratulate you on the beautiful and organized layout.  It
almost resembles a PDF document.

...


  [it's now 2 hours later - Rhodium's site is available as an 811 page PDF book for anyone interested.]

   "Asocial Smut Heir"

[Ritter]

You did a damn good job on that writeup Rhodium!  You managed to dig up all of the papers which report significant improvements in the synthesis of this compound from its inception in WWII!!!!  The only bone I have to pick is the diphenylacetonitrile synthesis.  SWIM has wasted countless hours and pounds of good precursor chemicals on this reaction.  The bromination of phenylacetonitrile is a very difficult reaction for several reasons.  The reaction tends to suddenly overheat and once the temperature goes above 115'C polymerization immediately sets in.  Stirring is difficult because the bromine eats teflon and steel stirrer paddles.   The variation I recommend using is to replace bromophenylacetonitrile with benzaldehyde cyanohydrin for the Friedel Crafts reaction.  This process is simple and high yielding.  Let me know if you want me to dig out the ref.  Another pet project of mine was synthesis of diphenylacetonitrile from benzhydrol.  The benzyl alcohol was heated w/ conc. HCl and CaCl2 to make benzhydryl chloride which was reacted with KCN in DMF for 8 hours at 50'C.  The reaction produced over 50% diphenylacetonitrile however it was all destroyed in an attempted vacuum distillation.

[Rhodium]

Yes, please give me the references I am missing. Let this document get as good as it can.

[Ritter]

Rhodium,

Here is another ref to add concerning synthesis of Diphenylacetonitrile:   US Patent 2,443,246

A superior alternative to the method they use to make the mandelonitrile follows:  To a 40 degree C solution of 40 g NaHSO3 and 250 mL water 34 g benzaldehyde (0.324 mol) is added with vigorous stirring.  After 20 minutes cool the reaction mixture down to 0 degrees, add 200 mL Ether and drip in a solution of 17 g NaCN in 70 mL water.  Agitate for 30 minutes at 0 degrees, then seperate the organic phase and extract the aqueous phase twice with 50 mL portions of ether(or toluene).  The combined ether extracts are washed with 2 x 100ml conc. NaHSO3 solution to remove traces of unreacted benzaldehyde(dont skip this step), washed 1 x 50ml brine then dried over anhydrous calcium chloride.  After rotovaping the solvent under a vacuum, the remaining oil is allowed to solidify upon cooling then placed in the vacuum dessicator to remove last traces of water.  Yield is very high and mandelonitrile produced using this method is ideal for use in the Friedel-Crafts reaction described in the patent.

I dont have a ref for this procedure, it is based on a ref someone posted for synth of p-methoxymandelonitrile.  It has been run 3 times and works as described.