HUE034668T2 - Eljárás morfinán-származékok szintézisére és azok intermedierjei - Google Patents

Description

(12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07D 498110 <200e 01> C07D 489108 <200601> 15.03.2017 Bulletin 2017/11 A61K 31I485<2006 01> (21) Application number: 04761332.8 (86) International application number: PCT/AU2004/001297 (22) Date of filing: 22.09.2004 (87) International publication number: WO 2005/028483 (31.03.2005 Gazette 2005/13)

(54) PROCESS FOR THE SYNTHESIS OF MORPHINANE COMPOUNDS AND INTERMEDIATES THEREOF

VERFAHREN ZUR SYNTHESE VON MORPHINANVERBINDUNGEN UND ZWISCHENPRODUKTEN DAVON

PROCEDE DE SYNTHESE DE COMPOSES DE MORPHINANE ET LEURS INTERMEDIATES (84) Designated Contracting States: · WILSON,George, Scott AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Edinburgh EH6 6DY (GB)

HU IE IT LI LU MC NL PL PT RO SE SI SK TR

(74) Representative: Whitcombe, Nicole Jane et al (30) Priority: 22.09.2003 AU 2003905153 Johnson Matthey PLC

Gate 20 (43) Date of publication of application: Orchard Road 07.06.2006 Bulletin 2006/23 Royston

Hertfordshire SG8 5HE (GB) (73) Proprietors: • GlaxoSmithKline Australia Pty Ltd (56) References cited:

Boronia VIC 3155 (AU) WO-A-02/16367 WO-A1 -02/16367 • Johnson Matthey Public Limited Company GB-A- 939 287

London EC4A 4AB (GB) · KRASSNIG R ET AL: "Optimization of the

Synthesis of Oxycodone and (72) Inventors: 5-Methyloxycodone" ARCHIV DER PHARMAZIE, • SMITH, Craig VERLAG CHEMIE. WEINHEIM, DE, vol. 329, 1

Warrnambool, Victoria 3280 (AU) January 1996 (1996-01-01), pages 325-326, • PURCELL, Stuart XP008055004

Port Fairy, VIC 3284 (AU) · PROKSA ET AL: "10-Hydroxythebaine" ARCHIV

• WADDELL, Lucy DER PHARMAZIE, VCH

Launceston, VERLAGSGESELLSCHAFT MBH, WEINHEIM,

Tasmania 7250 (AU) DE, vol. 332, no. 10,1 January 1999 (1999-01-01), • HAYES, Nicholas pages 369-370, XP009096606 ISSN: 0365-6233

Port Fairy, VIC 3284 (AU) · IIJIMA I ET AL: "Studies in the (+) morphinan • RITCHIE, Jarrod series. V. Synthesis and biological properties of

Launceston, (+) naloxone" JOURNAL OF MEDICINAL

Tasmania 7250 (AU) CHEMISTRY, AMERICAN CHEMICAL SOCIETY, • HALLIDAY, Scott, Brian WASHINGTON, US, vol. 21, no. 4,1 January 1978

Meadowbank, Edingburgh EH7 5TN (GB) (1978-01-01), pages 398-400,XP002428747 ISSN: • MITCHELL, Melville 0022-2623

Edinburgh EH10 3EG (GB)

Description [0001] This invention relates to intermediates useful in the preparation of opiate alkaloids, particularly morphinane compounds. The invention also relates to processes for preparing such intermediates and to processes which utilise such intermediates in the synthesis of morphinane compounds.

[0002] KraBnig et al (Archiv der Pharmazie, 1996, 329, 325-326) describes an optimization of the synthesis of oxycodone and 5-methyloxycodone.

[0003] 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).

(1) R1 = R2=H (4) R1 = R2 = CH3 (2) R1 = Me, R2 = H (5) R1 = H, R2 = Me. (3) R1 = R2 = MeC(0) [0004] 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.

(A) [0005] Morphine, codeine and heroin are characterised by a double bond at the 7-position (A7-morphinanes) while thebaine and oripavine possess a 6,8-diene system (A6,A8-morphinanes).

[0006] 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.

[0007] 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.

[0008] 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.

[0009] 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).

[0010] 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.

[0011] 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 [0012] 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.

[0013] 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.

[0014] In addition to this WO 02/16367 discloses a multistep complimentary sequence which includes N-demethylation and oxidation of a A7-morphinane compound to the Δ6, A8-morphinane compound. In the reported procedure, demeth-ylation is achieved by initial oxidation of the N-methyl morphinane to form the N-oxide morphinane which is then treated with a Fe(ll) based reducing agent. The oxidation of the A7-morphinane to the diene is reported as a separate reaction and is facilitated through the use of γ-Μη02. 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.

[0015] Traditionally, the 14-hydroxy group has been introduced by the oxidation of A6,A8-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-γπογ-phinanes 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.

[0016] In one aspect the present invention provides a method for preparing a 6-oxo-14-hydroxy A7-morphinane comprising oxidising a 6-methoxy-N-methyl-A6,A8-morphinane for a time and under conditions sufficient to form a 6-oxo-14-hydroxy-N-methyl-A7-morphinane-N-oxide and converting the formed N-oxide to the 6-oxo-14-hydroxy-A7-morphinane as defined in claim 1 [0017] The present invention also describes a method for converting a 6-oxo-14-hydroxy-N-methyl-A7-morphinane-N-oxide to a 6-oxo-14-hydroxy-A7-morphinane comprising subjecting the N-oxide to reducing conditions to ring close the N-methyl group with the 14-hydroxy group forming an oxazolidine ring, and hydrolysing the ring closed oxazolidine product to form the 6-oxo-14-hydroxy-A7-morph inane.

[0018] The invention describes a compound having the following modified morphinane skeleton:

(B) [0019] The invention describes a method of preparing a morphinane compound having a modified morphinane skeleton (B) comprising treating a 6-oxo-N-methyl-14-hydroxy-A7-morphinane-N-oxide with an Fe(ll) reducing agent for a time and under conditions sufficient to ring close the N-methyl group with the 14-hydroxy group.

[0020] In another aspect of the invention there is provided a method as defined in claim 20 for preparing N-alkyl or N-alkenyl 6-oxo-14-hydroxy morphinanes comprising: oxidising a 6-methoxy-N-methyl-A6,A8-morphinane for a time and under conditions sufficient to form a 6-oxo-14-hydroxy-N-methyl-A7-morphinane-N-oxide, converting the formed N-oxide to a 6-oxo-14-hydroxy-A7-morphinane, reducing the Δ7 double bond to form a 6-oxo-14-hydroxy morphinane, and subjecting the 6-oxo-14-hydroxy-morphinane to N-alkylation to introduce the N-alkyl or N-alkenyl substituent.

[0021] The processes according to the present invention are capable of being performed using naturally isolatable A6,A8-morphinanes like oripavine (4) and thebaine (3) as starting materials. Preferably the 6-methoxy-N-methyl-A6,A8-morphinane is a compound of formula I:

I where R is H, C^Cg alkyl, benzyl or acyl.

[0022] The term "C^Cg alkyl" as used herein refers to a straight chain or branched alkyl group having from 1 to 6 carbon atoms. Examples of suitable alkyl groups include methyl, ethyl, propyl, isopropyl and n-butyl.

[0023] The term "acyl" as used herein refers to a group of formula RNC(=0)-, where RN is generally an C.j-C6 alkyl group. An example of acyl group is an acetyl group.

[0024] It is also possible for R to represent an hydroxy protecting group, although protection of the hydroxy group is not necessary in the process of the present invention.

[0025] There are also many reported synthetic approaches to 6-methoxy-N-methyl-A6,A8-morphinanes and both synthetic and naturally derived compounds can be incorporated into the processes of the present invention. The preferred A6,A8-morphinanes to be used in the process of the present invention are oripavine and thebaine. Oripavine, however, is the most preferred starting material.

[0026] The process according to the present invention allows for the conversion of 6-methoxy-N-methyl-A6,A8-mor-phinanes to 6-oxo-14-hydroxy-N-methyl-A7-morphinane-N-oxides in a single step. That is, in a single step, the 14-hydroxy group is introduced, the N-methyl group is oxidized to the corresponding N-methyl oxide, the 6-methoxy is converted to 6-oxo group and the Δ6,Δ8 conjugated diene is converted to Δ7 double bond. The 6-oxo-14-hydroxy-N-methyl-A7-mor-phinane-N-oxide may be a compound of formula II:

II where R is H, CrC6 alkyl, benzyl or acyl.

[0027] This oxidation is carried out by treating the 6-methoxy-N-methyl-A6,A8-morphinane with hydrogen peroxide (H202) in the presence of formic acid or other suitable carboxylic acids such as, for instance, acetic acid. The preferred concentration of hydrogen peroxide used in the oxidation is between 30-50% by weight in water. More preferably, the hydrogen peroxide is at a concentration of 50% by weight in water. Preferably the 6-methoxy-N-methyl-\6,A8-morphinane is treated with the hydrogen peroxide in molar excess, for example with 2-5 equivalents, more preferably at least 3 equivalents.

[0028] The oxidation process is preferably carried out in the presence of formic acid. Preferably the formic acid concentration is between 30-96% by weight in water. More preferably the concentration is between 35-55% and even more preferably 40-50%. Most preferably the formic acid is at a concentration of 45%.

[0029] It is preferred that the reaction temperature of the oxidation is carried out at below 50°C. Preferably the reaction is carried out at a temperature from 20-40°C, however a constant reaction temperature of ~20°C is particularly preferred.

[0030] In a preferred embodiment oxidation of the 6-methoxy-N-methyl-A6,A8-morphinane to the 6-oxo-14-hydroxy-N-methyl-A7-morphinane-N-oxide is performed in the presence of a solvent. Preferably the solvents are polar solvents, which may be protic or aprotic. Preferably the solvent is an alcohol, for example methanol, ethanol, propanol, isopropanol, etc. Most preferably the solvent is ethanol.

[0031] In another preferred embodiment of the oxidation process the 6-methoxy-N-methyl-A6,A8-morphinane is dissolved in a mixture of formic acid and the solvent prior to the addition of the hydrogen peroxide.

[0032] The reaction should be carried out for a time which allows for the formation of the desired N-oxide. This time may depend on the amount of material being treated, the amount, nature and concentration of the oxidizing agent present and the temperature at which the reaction is carried out. Monitoring the reaction by chromotographic means, such as thin layer chromatography (TLC) will allow the skilled practitioner to determine the completeness of the reaction. Suitably, the oxidation reaction is carried out for at least 30 minutes, although more usually it will be for at least 1 or 2 hours.

[0033] The oxidation of the 6-methoxy-N-methyl-A6,A8-morphinane to the 6-oxo-14-hydroxy-N-methyl-A7-morphinane-N-oxide may be followed by an isolation step before conversion to the 6-oxo-14-hydroxy-A7-morphinane. The isolation of the 6-oxo-14-hydroxy-N-methyl-A7-morphinane-N-oxide may be achieved by any suitable means. For example, upon completion, the crude reaction mixture may be neutralized to a pH of about 7. This can be efFected by the addition of a suitable base, for example, sodium or potassium hydroxide, potassium carbonate, etc. In a preferred embodiment, the oxidation reaction mixture is neutralized with a sodium hydroxide solution at a rate which ensures that the reaction temperature reaches 55°C. This is preferably done over a period of time (for example 2hrs) at which time the reaction is allowed to continue for a further 1 -2hr period before being cooled. After this time the crude N-oxide product (compound of formula II) can be collected as a solid. This crude solid may be subject to further purification steps (eg. washing with water and/or ethanol) or it may be reduced in crude form.

[0034] The 6-oxo-14-hydroxy-N-methyl-A7-morphinane-N-oxide is then converted to 6-oxo-14-hydroxy-A7-morphina-ne by performing an N-demethylation. This is generally done by treating it with a reducing agent. Suitable reducing conditions are outlined in WO02/16367. Exemplary reducing agents include Fe (II) based agents such as FeS04, FeCI2 or Fe-porphrin complexes. Preferably when the reduction is to be carried out on a plant scale the reaction is preformed at a temperature of around 10°C. The reaction can be monitored by TLC to determine the completeness of the reduction (N-demethylation). In order to remove any excess Fe(ll) species the reaction mixture may be subjected to work-up step(s) which may, for instance, involve addition of ammonium hydroxide and subsequent filtering. The 6-oxo-14-hydroxy-A7-morphinane will generally be a compound of formula III:

in where R is H, CrC6 alkyl, benzyl or acyl.

[0035] It has now been surprisingly found thatwhen the 6-oxo-14-hydroxy-N-methyl-A7-morphinane-N-oxide is treated with a Fe(ll) based reducing agent and formic acid, a novel product having a morphinane skeleton

(B) is formed in good yield. Such oxazolidines may be easily separable from the crude reaction mixture as an insoluble precipitate and can be readily hydrolyzed to prepare a 6-oxo-14-hydroxy-A7-morphinane. The oxazolidine compound will generally be of formula IV:

IV where R is H, C.|-C6 alkyl, benzyl or acyl.

[0036] Structural elucidation studies, including 2-D NMR (1H COSY, HMQC and HMBC), have indicated that the intermediate has this structure.

[0037] In a preferred embodiment of this process the 6-oxo-14-hydroxy-N-methyl-A7-morphinane-N-oxide is treated as a slurry in methanol with FeS04, whereby formic acid is then added which forms the oxazolidine compound of formula IV as an acid insoluble precipitate.

[0038] One particular advantage in the formation of the oxazolidine compound is that its acid insolubility makes it easy to separate from the iron reducing agent and the crude reaction mixture. This is generally achieved by a simple filtration step. The crude oxazolidine intermediate can then be immediately hydrolyzed or subjected to a further washing step (for example with methanol). This process is extremely beneficial in the production of kilogram scales of 14-hydroxy opiates as the tedious work-up steps generally required to remove the iron reducing agent are avoided.

[0039] Conversion of the oxazolidine compound to the 6-oxo-14-hydroxy-A7-morphinane by hydrolysis can be achieved by treating the oxazolidine compound with a strong acid. Preferred strong acids include, hydrochloric acid, sulphuric acid, hydrobromic acid, phosphoric acid, etc. Preferably the compound of formula IV is hydrolyzed with hydrochloric acid. More preferably the hydrolysis is preformed at elevated temperatures. In a preferred embodiment hydrolysis is conducted with a strong acid followed by ammonia at an elevated temperature.

[0040] As stated earlier, the 6-oxo-14-hydroxy-A7-morphinane is an important intermediate for the preparation of 14-hydroxy opiates, especially those which have a non-methyl N-substituent, for example naltrexone (6) and naloxone (7). Processes for converting 6-oxo-14-hydroxy-A7-morphinanes into other useful morphinane compounds are described in the literature.

[0041] The compound of formula III where R = H is of particular importance in the preparation of compounds (6) and (7) as its use alleviates the need for a further deprotection step.

[0042] The production of these compounds can be achieved in two steps from a compound of formula III. Such a synthesis would include an initial reduction step, for example using catalytic hydrogenation, to afford the dihydro derivative (6-oxo-14-hydroxy-morphinane), followed by N-alkylation with a suitable alkylating agent, such as L-RN where L is a leaving group and RN is an alkyl or alkylene group. Such a process is illustrated in Scheme 1 below.

Scheme 1

[0043] As indicated above an example of a treatment to reduce the double bond at the 7-position involves catalytic hydrogenation. GB 939,287 describes such a process in which platinum chloride is used as a catalyst in 10% acetic acid. US 5,112,975, US 5,927,876 and US 5,922,876 also disclose suitable methods for reducing the A7-double bond of compounds of formula III

[0044] An example of an alkylation treatment would be the reaction of the N-demethylated compound with R’-Brand a base, such as K2C03. Suitable N-alkylation conditions are disclosed in US 3,254,088, US 3,332,950 and US 5,922,876.

[0045] Exemplary R’ groups include C2_6 alkyl, such as straight chain, branched and cyclic isomers of ethyl, propylbutyl, isobutyl pentyl (all isomers), hexyl (all isomers), cyclopropylmethyl, (as found in naltrexone (5)) and cyclobutylmethyl (as found in nalbuphine and butorphanol), C2_6 alkenyl residues such as alkyl (as found in nalorphine and naloxone (6)), and C2_6 alkynyl, such as propargyl.

[0046] Examples of leaving groups include halogen, such as Br, Cl and I, mesylate, tosylate and triflate.

[0047] In an alternate preferred embodiment a 6-oxo-14-hydroxy-N-methyl-A7-morphinane can be first hydrogenated and subsequently oxidised to form the corresponding N-oxide. Hydrogenation to reduce the A7-double bond may be carried out in the presence of platinum or palladium catalysts under the standard hydrogenation conditions as discussed above. The N-oxide from this procedure may be reduced as mentioned previously to form an oxazolidine compound. The oxazolidine compound will generally be of formula V:

¥ where R is H, C^Cgalkyl, benzyl or acyl.

[0048] Hydrolysis of the oxazolidine and alkylation to form, for instance, naltrexone (6) and naloxone (7), may follow the synthetic route previously discussed.

[0049] Following the preparation of the N-alkyl or N-alkenyl 6-oxo-14-hydroxymorphinane it is possible to further modify the compound using known techniques to prepare further morphinane derivatives. For example, if the Δ7 double bond is not reduced, further chemistry can be performed on the α, β unsaturated keto moiety. The oxygen atom in the 3-position can be subjected to esterification, transesterification and etherification reactions using known techniques.

[0050] The reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that that prior art forms part of the common general knowledge in Australia.

[0051] The invention will now be described with reference to the following examples which are intended only for the purpose of illustrating certain embodiments of the invention and are not to be taken as limiting the generality of the invention previously described.

EXAMPLES

Example 1 a) Oripavine oxidation to 14-hydroxymorphinone-N-oxide (14-NO) [0052] Formic acid 45% (100L) is added to ethanol (100L). Oripavine is dissolved in the acidic ethanol (100kg/200L). 50% hydrogen peroxide (70L) is added and the temperature is maintained at 20°C by cooling. After 2 hrs the reaction mixture is neutralised to pH 7 with the addition of 23% NaOH at a rate which ensures that the temperature of the reaction reaches 55°C. This is performed over2hrs. When this temperature is reached the mixture is allowed to react for a further 1-2 hrs. After this time the reaction mixture is cooled to 15°C and solid material filtered. The filtered cake is washed with water (100L/100kg) and then with ethanol (80% yield);. LC-MS mlz 316 (M+H) b) Reduction of (14-NO) to oxazolidine (compound of formula IV, where R = H) [0053] 14-Hydroxymorphinone-N-oxide (14-NO) (4kg) is added to 100 L of methanol (>98%). The resultant slurry is stirred for 5 minutes. To the slurry is added 0.8kg FeSO4.7H20 and the resultant mixture is vigorously stirred for about 5 minutes. After 2 minutes 15L of 85% Formic acid is added and the resultant precipitate is immediately filtered after mixing complete. The precipitated oxazolidine is washed with methanol (55% yield); 13C NMR (DC02D) δ 25.4 (C10), 29.5 (C15), 45.8 (C16), 48.1 (C13), 65.7 (C9), 78.8 (C14), 84.0 (C17), 86.1 (C5), 120.4 (C1), 121.3 (C11), 122.0 (C2), 128.5(012), 136.6(09), 139.5(03), 142.6(08), 143.4 (C4), 196.6(06) ppm; 1HNMR (D0O2D) δ 2.8 (m, 1H, H15), 3.5 (m, 1H, H15), 4.2 (m, 2H, H10, H16), 4.4 (m, 2H, H10, H16), 5.4 (d, 1 Η, H9), 5.7 (s, 1 Η, H5), 6.1 (dd, 2H, H17), 7.1 (d, 1 Η, H7), 7.45 (d, 1H, H1), 7.51 (d, 1H, H2), 7.60 (d, 1H, H8) ppm. c) Hydrolysis of oxazolidine to 6-oxo-14-hydroxy-A7-morphinane (compound of formula III, where R is H) [0054] The oxazolidine (1 kg) is added to a solution of 25% ammonium hydroxide (0.96 L) in H20 (7.2L). 30% Hydrochloric acid (1.65 L) is then added and the mixture is heated to 50°C followed by the addition of activated carbon (0.025kg). After 30 min the activated carbon is removed by filtration and the filtrate is stirred for a further 30 min. The pH is then adjusted to pH 9.0 with 25% ammonia and stirred for a further 15 hours at 50°C. After this time the mixture is cooled below 20°C and the precipitate is filtered and washed with H20 (5L) (85% yield); 13C NMR (D20/DCI) δ 25.2 (C15), 26.7 (C10), 37.3 (C16), 46.3 (C13), 56.6 (C9), 66.6 (C14), 86.1 (C5), 118.9 (C1), 121.3 (C2), 122.4 (C11), 128.9 (C12), 133.0 (C7), 138.8 (C4), 142.7 (C3), 147.9 (C8), 196.9 (C6) ppm.

Example 2 a) 14-hydroxycodeinone oxidation to 14-hydroxycodeinone-N-oxide tartrate [0055] 14-Hydroxycodeinone (20.0 g) was added to methanol (100 mL) followed by mCPBA (21.9 g, 50% wet). After stirring for 40 min, L(+)-Tartaric acid was added to pH 3.5 to precipitate 14-hydroxycodeinone-N-oxide tartrate which was collected by filtration (83% yield). LC-MS mlz 330 [M+H], b) Reduction of 14-hydroxycodeinone-N-oxide tartrate to oxazolidine (compound of formula IV, where R = CH3) [0056] 14-Hydroxycodeinone-N-oxide tartrate (14.8 g) was slurried in methanol (200 mL). FeS04.7H20 (2.0 g) was then added and the solution was stirred for 40 min. The product was collected by filtration and the solid was washed with methanol (40 mL) to yield the oxazolidine (-10% yield, ESI-MS mlz 312 [M+H]) as a mixture with 14-hydroxycodei-none.

Example 3 a) Benzylation of 14-hydroxymorphinane-N-oxide [0057] 14-Hydroxymorphinone-N-oxide (100 g) was slurried in ethanol (500 mL). K2C03 (52.5 g) was then added followed by benzyl bromide (95.0 g). The resulting mixture was stirred at RT for 16 h then at 50°C for 4h. The solution was cooled to RT then filtered and the solid was washed with ethanol (200 mL). The solid was slurried in water (500 mL) for 30 min then was collected by filtration to yield 3-benzyl-14-hydroxymorphinone-N-oxide (78% yield). ESI-MS m/z 406 [M+H], b) Reduction of 3-benzyl-14-hydroxymorphinone-N-oxide to oxazolidine (compound of formula IV, where R = benzyl) [0058] 3-Benzyl-14-Hydroxymorphinone-N-oxide (5.0 g) was slurried in methanol (100 mL). FeS04.7H20 (0.5 g) was then added and the solution was stirred for 15 min. The product was collected by filtration and the solid was washed with methanol (20 mL) to yield the oxazolidine (-15% yield, ESI-MS mlz 388 [M+H]) as a mixture with 3-benzyl-14-hydroxymorphinone.

Example 4 a) Oxymorphone oxidation to Oxymorphone-N-oxide [0059] Oxymorphone (4.0 g) was added to methanol (40 mL) followed by mCPBA (5.50 g, 50% wet). After stirring for 5 min oxymorphone-N-oxide was collected by filtration (75% yield). ESI-MS mlz 318 [M+H], b) Reduction of Oxymorphone-N-oxide to oxazolidine (compound of formula V, where R = H).

[0060] Oxymorphone-N-oxide (2.0 g) was slurried in methanol (40 mL). FeS04.7H20 (0.4 g) was then added and the solution was stirred for 15 min. The product was collected by filtration and the solid was washed with methanol (15 mL) to yield the oxazolidine (-50% yield, ESI-MS mlz 300 [M+H]) as a mixture with oxymorphone.

[0061] Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

Claims 1. A method for preparing a compound of formula III comprising oxidising a compound of formula I for a time and under conditions sufficient to form a compound of formula II and converting the formed compound of formula II to the compound of formula III; wherein: the oxidation is carried out by treating the compound of formula I with hydrogen peroxide in molar excess in the presence of a carboxylic acid; the formed compound of formula II is converted to the compound of formula III by N-demethylating the compound of formula II; and the compounds of formulae I, II and III are:

r

where R is H, C^Cg alkyl, benzyl or acyl. 2. A method according to claim 1 wherein the oxidation is carried out by treating the compound of formula I with 2-5 equivalents of hydrogen peroxide in the presence of a carboxylic acid. 3. A method according to claim 2 wherein the carboxylic acid is formic acid or acetic acid. 4. A method according to claim 3 wherein the carboxylic acid is formic acid. 5. A method according to claim 4 wherein the concentration of formic acid is 45% by weight formic acid in water. 6. A method according to any one of claims 2 to 5 wherein the compound of formula I is treated with a molar excess of hydrogen peroxide at a concentration of 50% by weight in water. 7. A method according to any one of claims 2 to 6 wherein the compound of formula I is dissolved in a mixture of the carboxylic acid and a solvent prior to the addition of the hydrogen peroxide. 8. A method according to claim 7 wherein the solvent is ethanol. 9. A method according to any one of claims 1 to 8 wherein the oxidation is conducted at a temperature below 50°C. 10. A method according to claim 9 wherein the temperature is about 20°C. 11. A method according to any one of claims 1 to 10 including the additional step of isolating the compound of formula II before the conversion to the compound of formula III. 12. A method according to claim 11 wherein the isolation step comprises neutralising the oxidation reaction mixture to a pH of about 7 by adding a base and collecting the compound of formula II as a solid. 13. A method according to claim 12 wherein the base is selected from sodium or potassium hydroxide or potassium carbonate. 14. A method according to claim 13 wherein the base is sodium hydroxide. 15. A method according to claim 14 wherein sodium hydroxide is added to the oxidation mixture at a rate which ensures that the reaction temperature reaches 55°C. 16. A method according to any one of claims 1 to 15 wherein the formed compound of formula II is converted to the compound of formula III by treating the compound of formula II with a reducing agent. 17. A method according to claim 16 wherein the reducing agent is a Fe(ll) based reducing agent. 18. A method according to claim 17, wherein the Fe(ll) based reducing agent is selected from the group consisting of FeS04, FeCI2 and Fe-porphrin complexes. 19. A method according to anyone of claims 16 to 18 including the additional step of adding ammonium hydroxide and subsequently filtering. 20. A method for preparing N-alkyl or N-alkenyl 6-oxo-14-hydroxy-morphinanes comprising: oxidising a compound of formula I for a time and under conditions sufficient to form a compound of formula II, wherein the oxidation is carried out by treating the compound of formula I with hydrogen peroxide in molar excess in the presence of a carboxylic acid, converting the formed compound of formula II to a compound of formula III by N-demethylating the compound of formula II, reducing the Δ7 double bond to form a compound of formula III’, and subjecting the compound of formula III’ to N-alkylation to introduce the N-alkyl or N-alkenyl substituent; wherein: the compounds of formulae I, II, III and III’ are:

Hí

where R is H, C^Cg alkyl, benzyl or acyl. 21. A method according to claim 20 wherein a reducing agent converts compound of formula II to compound of formula III. 22. A method according to claim 21 wherein the reducing agent is a Fe(ll) based reducing agent. 23. A method according to claim 22, wherein the Fe(ll) based reducing agent is selected from the group consisting of FeS04, FeCI2 and Fe-porphrin complexes. 24. A method according to any one of claims 22 to 24 including the additional step of adding ammonium hydroxide and subsequently filtering. 25. A method according to any one of claims 1 to 24 wherein R of the compound of formula I is FI or Chi3. 26. A method according to claim 25 wherein R of the compound of formula I is FI. 27. A method according to any one of claims 1 to 24 wherein R of the compound of formula II is FI or CFi3. 28. A method according to claim 27 wherein R of the compound of formula II is FI. 29. A method according to any one of claims 1 to 24 wherein R of the compound of formula III is FI or CFI3. 30. A method according to claim 29 wherein R of the compound of formula III is FI.

Patentansprüche 1. Verfahren zur Fierstellung einer Verbindung der Formel III, welches das Oxidieren einer Verbindung der Formel I über eine Zeitdauer und unter Bedingungen umfasst, die ausreichen, um eine Verbindung der Formel II zu bilden, wobei die Verbindung der Formel II nach ihrer Bildung in die Verbindung der Formel III umgewandelt wird; wobei: die Oxidation erfolgt, indem die Verbindung der Formel I in Gegenwart einer Carbonsäure mit einem molarem Überschuss an Wasserstoffperoxid behandelt wird; die Verbindung der Formel II nach ihrer Bildung in die Verbindung der Formel III umgewandelt wird, indem die

Verbindung der Formel II eine N-Demethylierung erfährt; und die Verbindungen der Formeln I, II und III folgendermaßen beschaffen sind:

wobei R gleich H, C1-C6-Alkyl, Benzyl oder Acyl ist. 2. Verfahren nach Anspruch 1, wobei die Oxidation erfolgt, indem die Verbindung der Formel I in Gegenwart einer Carbonsäure mit 2 bis 5 Äquivalenten an Wasserstoffperoxid behandelt wird. 3. Verfahren nach Anspruch 2, wobei es sich bei der Carbonsäure um Ameisensäure oder Essigsäure handelt. 4. Verfahren nach Anspruch 3, wobei es sich bei der Carbonsäure um Ameisensäure handelt. 5. Verfahren nach Anspruch 4, wobei die Konzentration der Ameisensäure 45 Gewichts-% an Ameisensäure in Wasser beträgt. 6. Verfahren nach einem beliebigen der Ansprüche 2 bis 5, wobei die Verbindung der Formel I mit einem molaren Überschuss an Wasserstoffperoxid in einer Konzentration von 50 Gewichts-% in Wasser behandelt wird. 7. Verfahren nach einem beliebigen der Ansprüche 2 bis 6, wobei die Verbindung der Formel I in einer Mischung aus der Carbonsäure und einem Lösungsmittel aufgelöst wird, bevor das Wasserstoffperoxid zugesetzt wird. 8. Verfahren nach Anspruch 7, wobei es sich bei dem Lösungsmittel um Ethanol handelt. 9. Verfahren nach einem beliebigen der Ansprüche 1 bis 8, wobei die Oxidation bei einer Temperatur von weniger als 50 °C durchgeführt wird. 10. Verfahren nach Anspruch 9, wobei die Temperatur ungefähr 20 °C beträgt. 11. Verfahren nach einem beliebigen der Ansprüche 1 bis 10, wobei es zusätzlich den Schritt des Isolierens der Verbindung der Formel II umfasst, bevor die Umwandlung zur Verbindung der Formel III erfolgt. 12. Verfahren nach Anspruch 11, wobei der Isolierungsschritt das Neutralisieren der Oxidationsreaktionsmischung auf einen pH-Wert von ungefähr 7 durch Zusatz einer Base und das Gewinnen der Verbindung der Formel II in Form eines Feststoffs umfasst. 13. Verfahren nach Anspruch 12, wobei die Base aus Natrium-oder Kaliumhydroxid oder Kaliumcarbonat ausgewählt ist. 14. Verfahren nach Anspruch 13, wobei es sich bei der Base um Natriumhydroxid handelt. 15. Verfahren nach Anspruch 14, wobei das Natriumhydroxid der Oxidationsmischung mit einer Geschwindigkeit zugesetzt wird, die gewährleistet, dass die Temperatur des Reaktionsansatzes 55 °C erreicht. 16. Verfahren nach einem beliebigen der Ansprüche 1 bis 15, wobei die Verbindung der Formel II nach ihrer Bildung indie Verbindung der Formel III umgewandelt wird, indem die Verbindung der Formel II mit einem Reduktionsmittel behandelt wird. 17. Verfahren nach Anspruch 16, wobei es sich bei dem Reduktionsmittel um ein Reduktionsmittel auf Basis von Fe(ll) handelt. 18. Verfahren nach Anspruch 17, wobei das Reduktionsmittel auf Basis von Fe(ll) aus der Gruppe ausgewählt ist, die aus FeS04, FeCI2 und Fe-Porphrinkomplexen besteht. 19. Verfahren nach einem beliebigen der Ansprüche 16 bis 18, wobei es zusätzlich den Schritt des Zusetzens von Ammoniumhydroxid und des anschließenden Filtrierens umfasst. 20. Verfahren zur Herstellung von N-Alkyl- oder N-Alkenyl-6-oxo-14-hydroxymorphinanen, wobei es Folgendes umfasst:

Oxidieren einer Verbindung der Formel I über eine Zeitdauer und unter Bedingungen, die ausreichen, um eine Verbindung der Formel II zu bilden, wobei die Oxidation erfolgt, indem die Verbindung der Formel I in Gegenwart einer Carbonsäure mit einem molarem Überschuss an Wasserstoffperoxid behandelt wird,

Umwandeln der Verbindung der Formel II, nach der Bildung derselben, in eine Verbindung der Formel III, indem die Verbindung der Formel II eine N-Demethylierung erfährt,

Reduzieren der Ä7-Doppelbindung, um eine Verbindung der Formel III’ zu bilden, und

Einwirkenlassen einer N-Alkylierung auf die Verbindung der Formel III’, um den N-Alkyl- oder N-Alkenylsubs- tituenten einzuführen; wobei: die Verbindungen der Formeln I, II, III und III’ folgendermaßen beschaffen sind:

ill

wobei R gleich H, C^Cg-Alkyl, Benzyl oder Acyl ist. 21. Verfahren nach Anspruch 20, wobei ein Reduktionsmittel die Verbindung der Formel II in die Verbindung der Formel III umwandelt. 22. Verfahren nach Anspruch 21, wobei es sich bei dem Reduktionsmittel um ein Reduktionsmittel auf Basis von Fe(ll) handelt. 23. Verfahren nach Anspruch 22, wobei das Reduktionsmittel auf Basis von Fe(ll) aus der Gruppe ausgewählt ist, die aus FeS04, FeCI2 und Fe-Porphrinkomplexen besteht. 24. Verfahren nach einem beliebigen der Ansprüche 22 bis 24, wobei es zusätzlich den Schritt des Zusetzens von Ammoniumhydroxid und des anschließenden Filtrierens umfasst. 25. Verfahren einer nach einem beliebigen der Ansprüche 1 bis 24, wobei R in der Verbindung der Formel I für H oder CH3 steht. 26. Verfahren nach Anspruch 25, wobei R in der Verbindung der Formel I gleich H ist. 27. Verfahren einer nach einem beliebigen der Ansprüche 1 bis 24, wobei R in der Verbindung der Formel II für H oder CH3 steht. 28. Verfahren nach Anspruch 27, wobei R in der Verbindung der Formel II gleich H ist. 29. Verfahren einer nach einem beliebigen der Ansprüche 1 bis 24, wobei R in der Verbindung der Formel III für H oder CH3 steht. 30. Verfahren nach Anspruch 29, wobei R in der Verbindung der Formel III gleich H ist.

Revendications 1. Procédé pour préparer un composé répondant à la formule III comprenant l’oxydation d’un composé répondant à la formule I pendant un laps de temps et dans des conditions qui sont suffisantes pour obtenir un composé répondant à la formule II et la transformation du composé obtenu répondant à la formule II en un composé répondant à la formule III, dans lequel l’oxydation est mise en oeuvre en traitant le composé répondant à la formule I avec du peroxyde d’hydrogène en un excès molaire en présence d’un acide carboxylique ; le composé obtenu répondant à la formule II est transformé pour obtenir le composé répondant à la formule III via une N-déméthylation du composé répondant à la formule II ; et les composés répondant aux formules I, Il et III sont :

c

dans lesquels R représente un atome d’hydrogène, un groupe alkyle en CrC6, un groupe benzyleou un groupe acyle. 2. Procédé selon la revendication 1, dans lequel l’oxydation est mise en oeuvre en traitant le composé répondant à la formule I avec de 2 à 5 équivalents de peroxyde d’hydrogène en présence d’un acide carboxylique. 3. Procédé selon la revendication 2, dans lequel l’acide carboxylique est l’acide formique ou l’acide acétique. 4. Procédé selon la revendication 3, dans lequel l’acide carboxylique est l’acide formique. 5. Procédé selon la revendication 4, dans lequel la concentration de l’acide formique représente 45 % en poids d’acide formique dans de l’eau. 6. Procédé selon l’une quelconque des revendications 2 à 5, dans lequel on traite le composé répondant à la formule I avec un excès molaire de peroxyde d’hydrogène à une concentration de 50 % poids dans de l’eau. 7. Procédé selon l’une quelconque des revendications 2 à 6, dans lequel on dissout le composé répondant à la formule I dans un mélange de l’acide carboxylique et d’un solvant, avant l’addition du peroxyde d’hydrogène. 8. Procédé selon la revendication 7, dans lequel le solvant est l’éthanol. 9. Procédé selon l’une quelconque des revendications 1 à 8, dans lequel on met en oeuvre l’oxydation à une température inférieure à 50 °C. 10. Procédé selon la revendication 9, dans lequel la température s’élève à environ 20 °C. 11. Procédé selon l’une quelconque des revendications 1 à 10, englobant l’étape supplémentaire dans laquelle on isole le composé répondant à la formule II avant la transformation pour obtenir le composé répondant à la formule III. 12. Procédé selon la revendication 11, dans lequel l’étape d’isolation comprend la neutralisation du mélange réactionnel d’oxydation jusqu’à un pH d’environ 7 par addition d’une base et la récolte du composé répondant à la formule II sous la forme d’un produit solide. 13. Procédé selon la revendication 12, dans lequel la base est choisie parmi l’hydroxyde de sodium ou de potassium ou le carbonate de potassium. 14. Procédé selon la revendication 13, dans lequel la base est l’hydroxyde de sodium. 15. Procédé selon la revendication 14, dans lequel on ajoute de l’hydroxyde de sodium au mélange d’oxydation à un débit qui garantit le fait que la température réactionnelle atteigne 55 °C. 16. Procédé selon l’une quelconque des revendications 1 à 15, dans lequel on transforme le composé obtenu répondant à la formule II en composé répondant à la formule III en traitant le composé répondant à la formule II avec un agent de réduction. 17. Procédé selon la revendication 16, dans lequel l’agent de réduction est un agent de réduction à base de Fe(ll). 18. Procédé selon la revendication 17, dans lequel l’agent de réduction à base de Fe(ll) est choisi parmi le groupe constitué par du FeS04, du FeCI2 et des complexes de Fe-porphrine. 19. Procédé selon l’une quelconque des revendications 16 à 18, englobant l’étape supplémentaire dans laquelle on ajoute de l’hydroxyde d’ammonium et ensuite on filtre. 20. Procédé pour préparer des N-alkyl- ou des N-alcényl-6-oxo-14-hydroxymorphinanes comprenant ; l’oxydation d’un composé répondant à la formule I pendant un laps de temps et dans des conditions qui sont suffisantes pour obtenir un composé répondant à la formule II, l’oxydation étant mise en oeuvre en traitant le composé répondant à la formule I avec du peroxyde d’hydrogène en un excès molaire en présence d’un acide carboxylique ; la transformation du composé obtenu répondant à la formule II en un composé répondant à la formule III par N-déméthylation du composé répondant à la formule II ; la réduction de la liaison double Δ7 pour obtenir un composé répondant à la formule ΙΙΓ ; et le fait de soumettre le composé répondant à la formule III’ à une N-alkylation afin d’introduire le substituant N-alkyle ou N-alcényle ; dans lequel les composés répondant aux formules I, II, III et ΙΙΓ sont :

dans lesquels R représente un atome d’hydrogène, un groupe alkyle en C1-C6, un groupe benzyle ou un groupe acyle. 21. Procédé selon la revendication 20, dans lequel un agent de réduction transforme le composé répondant à la formule Il pour obtenir un composé répondant à la formule III. 22. Procédé selon la revendication 21, dans lequel l’agent de réduction est un agent de réduction à base de Fe(ll). 23. Procédé selon la revendication 22, dans lequel l’agent de réduction à base de Fe(ll) est choisi parmi le groupe constitué par du FeS04, du FeCI2 et des complexes de Fe-porphrine. 24. Procédé selon l’une quelconque des revendications 22 à 24, englobant l’étape supplémentaire dans laquelle on ajoute de l’hydroxyde d’ammonium et on filtre ensuite. 25. Procédé selon l’une quelconque des revendications 1 à 24, dans lequel R du composé répondant à la formule I représente un atome d’hydrogène ou un groupe CH3. 26. Procédé selon la revendication 25, dans lequel R du composé répondant à la formule I représente un atome d’hydrogène. 27. Procédé selon l’une quelconque des revendications 1 à 24, dans lequel R du composé répondant à la formule II représente un atome d’hydrogène ou un groupe CH3. 28. Procédé selon la revendication 27, dans lequel R du composé répondant à la formule II représente un atome d’hydrogène. 29. Procédé selon l’une quelconque des revendications 1 à 24, dans lequel R du composé répondant à la formule III représente un atome d’hydrogène ou un groupe CH3. 30. Procédé selon la revendication 29, dans lequel R du composé répondant à la formule III représente un atome d’hydrogène.

REFERENCES CITED IN THE DESCRIPTION

This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

Patent documents cited in the description • WO 0216367 A [0014] [0034] · US 5922876 A [0043] [0044] • GB 939287 A [0015] [0043] · US 3254088 A [0044] • US 5112975 A [0043] · US 3332950 A [0044] • US 5927876 A [0043]

Non-patent literature cited in the description • KRASNIG et al. Archiv der Pharmazie, 1996, vol. · LINDNER, J.H.E.; KUHN, H.J.; GOLLNICK, K. Tet- 329, 325-326 [0002] rahedron Lett., 1972, vol. 17, 1705 [0013] • BRAUN. J. Chem. Ber., 1900, vol. 33, 1438 [0013] · SANTAMARIA, J.; OUCHABANE, R.; RIGAUDY, • COOLEY, J.H.; EVAIN, E.J. Synthesis, 1989, 1 J. Tetrahedron Lett., 1989, vol. 30, 2927 [0013] [0013] · LOPEZ, D.; QUINOA, E.; RIGUERA, R. Tetrahe dron Lett., 1994, vol. 35, 5727 [0013]

Claims (9)

1. Eljárás szintézisére és azok imeraiedíerieí Szabad aha i igén ypo-t n >k ]. Eljárás a ílí.l^l^-^gyto«iMí{tásÉ^».iöé^kí0íMegy l képiéit! letá yegyirleilk^ ideig és körülmények között oxídálarifc ésa kapott Ili képiéül veg> illetet íll képien! vegyüknté alakítjuk: ahol: az oxidációt az 1 képlett vegyidéinek móifeieskgben léve hidrogénpejhíddal történő keze-' 'Hsáéi* egy karbonsav jelenlétében; végezzük; a keletkezén. II képlétű:éegyüi«tbé'lk-dgíáetlléáéssél' álaki|;uk^:b Hl képiért; végytletté; és az k II la Hl vegyüleíek az;

   képletnek telelnek Meg, abol R jelentése i, 14 s^naiomos aikilöbenzi vagy adlesgpert,
2. 2. Λζ I. igénypont szerinti eljárás, által az oxidációi az I képletü vegyidéinek 2-5 iooiegsenéneknyí hidosgéoperoxiddak egy karbonsav jelenlétében történd kezdésével végezzük. 3, A 2. Igénypontszerinti éBirás, Mio! a karbonsav hangyasas vagy eceísav. C A 3. igénypont szerinti eljárás, ahol a karbonsav hangyasav. 5. A4. igénypont szerinti eljárás, ahol a hangyasav koncentrációja 45 tőrneg%-os vizeaMíP gyasav. ö. A 2Ά, igénypontok bármelyike szened eljárás, áhoinz IképletS vágyöletet ® iÖnaégA-oS:: vizes hidrogépgerox jel mólícies Icggel kezelj ük. 7. A 2-6* igénypontok bármelyike szerinti eljárás, áltol az 1 képiéül vegyületet a htdrogénperoxki hozzáadása elölt égy karbonsav és égy oldószer elegyében oldjuk. &amp; A 2. igénypont szerinti eljárás, abölm-oidöáz:«^»l.
3. 9. Az: 1A, igénypontok; bármélyíkeíaanrlnlí eljánls, ahol; az oxidációt ' ten végezzük. 10. A 9. igénypont szerinti eljárás, ahol aMmérséktó iörölbelÖl llFC. 1 i. Az 1 -10, igénypontok bármelyike szerinti eljárás, melynek során továbbá a II képietü ve-gynktel izoláljuk a III képlett! vegyületté történd átalakítás előtt, 12. A 11. Igénypont szeri ni eljárás, ahol az izolálást lépés során az oxidációs reakcióelegyet körülbelül 7 pK-ertehre semlegesníük eg> bázis hozzaadasásal, es a II képiéin ug\ öletet szilárd anyagként választjuk el. 13. A 12. igénypont szerinti eljárás, ahol a bázis nátrium- vagy káhnrahidroxid vagy káliumkarbonát közül választott. .14. Λ 13. igénypont szerinti eljárás, ahol a bázis nátriurnhidroxid. 15. A 13. igénypont szerinti eljárás, ahol nátriumhidroxidot adunk az oxidációs elegyhez olyan mértékben, mely biztosítja, hogy a reakció hőmérséklete eiétp az SS^C-i
4. 16. Az 1' 15. igénypontok bánit eh ike szerinti eljárás, ahol a keletkezett II képiéin vegyiddel égy tedükáiószarrd kezelve alakítjuk át Hl képlett* vegyűieHé.
5. 17, A lő. Igénypont, szerinti eljárna, ahol a rednkálőszer egy Fe(It>alapó rediskálószer. 10. A 17. igénypont szerinti eljárás, ahol a Pét lli-alapú redukáloszer FeSCtt FeCl? és Fe·· portéin komplexek közül választott
6. 19, A lő-18. igénypontok bármelyike szerinti eljárás, melynek során további lépésként ant-mónlumhidroxiucH adagolunk, majd szűrést végzünk.
7. 20. Bprás N-atfcil- vágy IkiálkéíiEő-oxo-P-itidzöxl^niorEnánok elbállltásáraj metptek során; egy í képlett! vegyoletel a 11 képletü vegyülei képződéséhez megléiefd Ideig és körülményéi között oxidálunk* ahol az oxidációt az I képIt^égyilto^.:üiÉI&amp;‘teiogbeö.léy# hidrogénperoxiddal történő kezdéssel, egy a keletkezeit II képletü vegyületet N-demetílezéssei alakijuk a Ifi képletü vegyüíeUé; a á’-iéildskölést rediikáfjuk egy Itt képletü vegyülei előállítására, és a Itt vagy Nmlketnl szubsztilnens beviteiére; ahol; az j, II. 01 és ΠΓ vegyüíetek az:

   képletnek feleinek nteg, ΛI R 11, alk&amp;;í5v^ Sa^ <mikMpct., 21. A 20. igénypont szerinti eljárás, ahol s rednkilószer a ii képA^* v^yülwiet 111 kvp^íi vegyületíé alakítja. 22, A 21, Igénypont szerinti eljárás, ábol a rédukátoszer FeCiH^^ *.^ukábt»*u. 22. A 22, igénypont szerinti elírás, ahol a Íe(HAa!aph vvCdz as 1-é» porirtü kóaiglézek közül választóik 24, A 22*24, Igénypöthok bármelyike szerinti eljárás, melynek sot'Sh toyápfeá ntnnionlamikdí·' oxidot adagolunk, majd szűrést végzünk. Iái Az 1*24, igénypontok bármelyike szerinti eljlíly, tétoii m'1 1.jefetHfc* se H vagy CH». 26. A 25, igénypont szerinti eljárás, ahol az I képiem vegyületben E jelentése M.
8. 27. Az 1-24, igénypontok bármelyike szerinti eljárás, ahol a 11 képiem vegyületben R jelentése H vagy Cl! 3. 28. A 27. igénypont szerinti eyáras, ahol a 1:1 képlete vegyületben E jelentése H,
9. 22. Az 1 -24. igénypontok bármelyike szerinti eljárás:, ahol a Hl képiem vegyületben E jelenté, se 11 vagy 0-1$. 3A A 22. Igénypont szerinti eljárás, ahol a Ili klpkti yégyülétbepl, pteáésn: M.