The opiate alkaloids obtained from poppy plants of the family Papaveraceae include some of the most powerfully acting and clinically useful drugs in the depression of the central nervous system. Exemplary opiates include morphine (1), codeine (2), heroin (3), thebaine (4) and oripavine (5).

The fundamental ring system common to each of these compounds is the morphinane skeleton, depicted in formula (A). Compounds containing this skeleton are collectively referred to herein as morphinanes.

Morphine, codeine and heroin are characterised by a double bond at the 7-position (Δ7-morphinanes) while thebaine and oripavine possess a 6,8-diene system (Δ6,Δ8-morphinanes).
Morphine and codeine are principally used as analgesics but also find use as agents for inducing sleep in the presence of pain, easing dyspnea and as an anti-tussive. Despite its valuable clinical properties, morphine has a number of negative aspects as it also depresses respiration and increases the activity and the tone of the smooth muscles of the gastrointestinal, biliary and urinary tracts causing constipation, gallbladder spasm and urinary retention. In addition, if administered to a patient over a period of time, the patient develops a tolerance to the analgesic effect so that the dosage must be increased to obtain the same level of pain relief.
Heroin displays better lipid solubility than either morphine or codeine which allows for easy passage across the blood-brain barrier. It is this effect which is the primary reason heroin is so sought after as a recreational drug. When administered intravenously “users” experience an intense feeling of pleasure and dulling of pain. The problem however with heroin, morphine and related compounds is that in combination with the euphoric effect a physical dependence can develop.
Extensive efforts have been directed towards the semi-synthesis of second generation morphine-like molecules which retain the analgesic properties but avoid the undesirable addictive side effects. For example, replacement of the N-methyl group of morphine with an N-allyl group provides nalorphine which acts as a narcotic antagonist to reverse many of the undesirable side effects of morphine. Substitution of other groups such as methallyl, propyl, isobutyl, propargyl or cyclopropargyl, methylcyclopropyl, and methylcyclobutyl also produce substances that are narcotic antagonists.
Other second generation derivatives of natural opiates include the 14-hydroxy opiate antagonists, such as naltrexone (6), naloxone (7), and 14-hydroxynormorphinone (Nor14-OH) (8).
Naloxone (also known as Narcan) is routinely administered to patients suffering from opiate overdose (for instance, heroin overdose). It counteracts the effects of overdose by competitive inhibition at the opioid receptor sites. In the absence of other opioids, naloxone exhibits essentially no pharmacological activity. Naltrexone (also known as Tecan) is used in the detoxification of opiate addicts. 14-Hydroxynormorphinone is a synthetically valuable intermediate in the production of naloxone and naltrexone.
Accordingly, the 14-hydroxy opiates are pharmacologically important derivatives. The present invention is directed to processes and novel intermediates useful in the manufacture of 14-hydroxy opiates.
                (6) R=cyclopropylmethyl, where  is a single bond        (7) R=allyl, where  is a single bond        (8) R=H, where  is a double bond        
The industrial preparation of these second generation 14-hydroxy compounds presents some common but challenging problems. One problem common to the synthesis of many of these compounds is the removal of the N-methyl substituent present in naturally occurring opiate starting materials such as morphine, codeine, thebaine and oripavine. A second problem common to any synthetic approach to the 14-hydroxy opiates is the introduction of the 14-hydroxy group.
N-Demethylation of tertiary amines was traditionally achieved using cyanogen bromide in the von Braun reaction (von Braun, J. Chem. Ber., 1900, 33, 1438). Limited yields and the toxicity of cyanogen bromide have seen this reaction largely replaced by chloroformate reagents (Cooley, J. H.; Evain, E. J. Synthesis, 1989, 1). Certain chloroformates, such as vinyl chloroformate, generally N-demethylate in high yield and the resultant carbamates are readily cleaved to afford the corresponding secondary amines. Unfortunately this reagent is very expensive, and thus, its applicability to larger scale processes is limited. Some photochemical procedures have been developed for the cleavage of N-methyl amines (Lindner, J. H. E.; Kuhn, H. J.; Gollnick, K. Tetrahedron Lett., 1972, 17, 1705, Santamaria, J.; Ouchabane, R.; Rigaudy, J. Tetrahedron Lett., 1989, 30, 2927, Lopez, D.; Quinoa, E.; Riguera, R., Tetrahedron Lett., 1994, 35, 5727), but these methods have not seen widespread use.
In addition to this WO 02/16367 discloses a multistep complimentary sequence which includes N-demethylation and oxidation of a Δ7-morphinane compound to the Δ6,Δ8-morphinane compound. In the reported procedure, demethylation is achieved by initial oxidation of the N-methyl morphinane to form the N-oxide morphinane which is then treated with a Fe(II) based reducing agent. The oxidation of the Δ7-morphinane to the diene is reported as a separate reaction and is facilitated through the use of γ-MnO2. Both of these procedures are complicated by work-up procedures which are inefficient on large scales. These work-up steps are required in both the N-demethylation and oxidation steps in order to separate the desired morphinanes from the respective Fe or Mn reagents after the respective reactions are completed.
Traditionally, the 14-hydroxy group has been introduced by the oxidation of Δ6,Δ8-morphinanes. For example, GB 939287 describes the oxidation of thebaine (4) in formic acid with 30% hydrogen peroxide at 40-50° C. to give 14-hydroxycodeinone. Interestingly, the commonly used procedures have usually only involved the oxidation of Δ6,Δ8-morphinanes which have a protected 3-hydroxy group. Consequently in the preparation of commercially valuable 14-hydroxy opiates, such as naloxone and naltrexone, an additional step would be required to remove the protective group. Oripavine, which is extracted from the poppy plant in low yields and has an unprotected 3-hydroxy group, has not been widely used as a starting material for the commercial production of 14-hydroxy opiates. Although oripavine is naturally less abundant than either morphine and codeine, its present lack of utility means that there is no real shortage of this naturally occurring opioid. Accordingly, it would be desirable to be able to use oripavine as a starting material for the production of 14-hydroxy opiates.