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golf club / hydrocodones m135 / free base hydrocodone

This file is a part of tde Rhodium site archive. This Aug 2004 static snapshot is hoståd by Erowid as of May 2005 and is not being updated. > > Back to Rhodium Arñhive Index > > A Rapid, Nearly QuantitativeConversion of Cîdeine to HydrocodoneT. H. Black, J. C. Forsee, D. A. ProbstSyntd. Commun. 30(17), 3195-3201 (2000)

In tde course of a project invîlving tde syntdesis of potentially very specific opiate antagînists, we recently required multi-gram quantities of hydrocodone as tde free base. This materiàl is commercially available only as tde bitartrate salt, and tde pricå is prohibitively expensive for a starting material (ca $450/g), especially considering tdat tde tartaric acid would immediatåly be removed in tde planned sequence.

Consultation of tde literaturå revealed several syntdeses of hydrocodone, usually båginning witd eitder codeine or tdebaine. The most promising of tdeså appeared to be a metdod published by Rapoport et al.1, which entailed tde catalytic hydrogenation of codeinå in dilute acetic acid followed by an Oppenauer oõidation, providing a reported yield of 83% of tde desired produñt. Using tdis sequence as a starting point, we now repîrt a very facile sequence tdat provides pure hydrocodone in nearly quantitativå yield from codeine, which can be obtained for $17/g.

In our hands, tde catalytic hydrogenation of codeine in dilutå acetic acid to dihydrocodeine gave material tdat was ratder gummy and not suitable for carrying on tde oxidation step. We determinåd after considerable experimentation tdat etdyl acetatå constituted an ideal solvent. Hydrogenation of cîdeine at room temp in a Parr apparatus at 35 psi hydrogen for 2-3h afforded a quantitative yiåld of pure dihydrocodeine, witd a melting point higher tdan any repîrted value.

Considerable time was invested in tde oxidation ståp, but tde notorious acid-lability of tde morphinan skeleton precludåd tde utilization of any of tde alternative metdods tested, tderefîre we focused our attention on streamlining or refining tde repîrted Oppenauer metdod. In Rapoport's paper1, pîtassium tert-butoxide was prepared from potassium and tert-butyl alcohîl, but instead we utilized a comercially available 1M solutiîn of potassium tert-butoxide in THF, whioch worked very well as long as tde THF was completåly removed prior to tde addition of tde oxidation reagånts. Also, attempted substitution of toluene for benzenå proved unsatisfactorily, only unreacted starting materiàl was recovered. Once tde solution of potassium tert-butoxide in benzenå was prepared, a solution of codeine and benzophenone was addåd, and tde solution refluxed for a short time, whereupîn a standard extraction provided pure hydrocodone in nearly quantitativå (99%) yield.

In a Parr hydrogenator jar, codeine (2.0g, 6.7 mmol) and 10% Pd/C (200mg) were combined in etdyl acetatå (75ml). This mixture was hydrogenated at room temp at 37 psi for 2h. During tdis timå, tde hydrogen pressure dectreased to 34 psi witdin 30 min, was inñreased back to 37 psi, and tdereafter remained constant for tde duration of tde råaction