Method of purifying noroxymorphone compounds

FIELD: chemistry.

SUBSTANCE: invention relates to a method of purifying plant extracts which mainly consist of noroxymorphone compounds and contain α,β-unsaturated noroxymorphone compounds as impurities, through (a) conversion of a plant extract or product of the next step in synthesis of the selected noroxymorphone compound as a result of conversion of hydroxyl groups present in the mixture to groups of formula -OR2 which can be split, in which R2 is an introduced radical of the said group which can be split, (b) said groups, if necessary, can be removed once more, after which (c) the obtained mixture is subjected to selective hydrogenation so that a saturated bond forms in the α,β-position of unsaturated noroxymorphone compounds and all the remaining groups which can be split are converted to a hydroxyl group, after which (d) a pure noroxymorphone compound is extracted; processing the purified noroxymorphone to naltrexone or naloxone or a salt of these compounds or a quaternary derivative of these compounds, which are known pharmaceutically active compounds particularly used for reducing psychological dependency and during drug abuse.

EFFECT: improved purification of compounds.

21 cl, 8 ex

 

The present invention relates to a method of cleaning compounds noroxymorphone. This invention relates also to method of obtaining pure compounds noroxymorphone, especially naltrexone and naloxone, especially pure naltrexone.

Noroxymorphone has the chemical name 7,8-dihydro-14-hydroxymorphinan or α,β-dihydro-14-hydroxymorphinan and corresponds to the formula

Connection noroxymorphone and obtaining them are described, for example, in German patent DE 2727805. Selected derivative noroxymorphone is a compound known as naltrexone, which corresponds to the following chemical formula:

Naltrexone, its derivatives and salts, such as naltrexone hydrochloride, N-methylnaltrexone bromide (methylnaltrexone) or naltrexone methobromide are known pharmaceutically active compounds, which are used, in particular, to reduce psychological dependence drug abuse. Naltrexone methobromide used, for example, as an antagonist of mu-receptors for the prevention of side effects of drugs. Naloxone (CAS No. 465-65-5)with allyl radical as a substituent at the nitrogen atom, has a similar pharmaceutical activity. Since these compounds are of proizvodi the mi morphine, they are synthesized from precursors of the class morphine alkaloids wild poppy. Since the total synthesis of complex natural substances of this class is very difficult, starting materials for the synthesis of compounds of noroxymorphone obtained from plants by extraction. However, extraction from plants, in this case from plants of the poppy, it is not possible to obtain individual connection, and gives a mixture of many structurally close compounds. Many of these extracted compounds are toxic or they produce toxic compounds in the course of further chemical reactions, for example for subsequent synthesis with the formation of Oxymorphone, noroxymorphone and naltrexone. Especially problematic impurities were α,β-unsaturated compounds, for example compounds of formulas (Ia), (Ib) and (Ic).

In a mixture, obtained by extraction of plant material, among the impurities may be present also possible precursors of these compounds, for example the corresponding α-substituted and/or β-substituted alcohols, which, in turn, can form an α,β-unsaturated compounds, for example compounds of formulas (Ia), (Ib) and (Ic). In addition, upon receipt of the naltrexone of these plant extracts may form toxic α,β-nen is sisanie connection which may have mutagenic, teratogenic and/or carcinogenic activity. Therefore, limit the levels of these compounds in the naltrexone and derivatives of naltrexone were reduced to 100 parts per million and in some cases up to 10 parts per million, However, these requirements are difficult to fulfill in respect of the products synthesized from a raw material obtained by extraction of plant material by known methods.

It was found that the requirements specified above the threshold level of 10 parts per million can be performed to provide even more low content of the above-mentioned α,β-unsaturated compounds, if a plant extract containing, in addition to connecting noroxymorphone corresponding α,β-unsaturated compound and other impurities, or the product of a later stage of the synthesis of selected compounds of noroxymorphone (a) be subjected to a reaction in which the hydroxyl groups present in the mixture, turn into otsepleniya group, (b) these otsepleniya group, if necessary, you can delete and then (C) subjecting the resulting mixture selective hydrogenation.

Stage (a) and (b), including the possible allocation of the reaction products, preferably carried out in non-aqueous environment, preferably in an environment that does not contain alcohol. Preference is given to removing tseplyaesh groups p is ed by hydrogenation. Hydrogenation, i.e. stage (C)can be carried out in the presence of aprotic solvents and, in mild conditions, in the presence of proton solvents such as water and alcohols. After hydrogenation of all remaining otsepleniya group can be removed by hydrolysis.

As a result of such conversion present in the mixture of hydroxyl groups in otsepleniya group [stage (a)] and, if necessary, subsequent removal of these tseplyaesh groups [stage (b)] all normalized impurities which are present in the source material in a quantity of about 1000 parts per million, are removed during the hydrogenation of [stage (C)] in such an extent that they cannot be detected by analysis by high performance liquid chromatography (HPLC).

Particularly surprising is that in the pre-processing of the raw product, i.e. plant extract, carried out in accordance with the invention, the hydrogenation is valid so selectively that all normalized by-products are removed almost completely, and the desired hydroxyl group are again formed from tseplyaesh groups in the compounds of noroxymorphone, while the existing ketogroup not hereroense, is not removed or converted into a hydroxyl group. Such a high degree of purity cannot be obtained by simple hydrogenation of the initial mixture. Respect to the W what possible precursor compounds noroxymorphone, for example the corresponding α-substituted and/or β-substituted alcohols present as an impurity in the mixture, obtained by extraction from plants, changes in the reactions according to the invention at the stage of (a) or stage (a) and (b) to the extent that they or subsequent products of these reactions (e.g., products of elimination) is converted into a methylene group in the hydrogenation in stage (C). However, this invention is not limited to this explanation.

According to the invention it is also possible, for example, upon receipt of noroxymorphone or further processing in the naltrexone or naloxone and their salts, processed according to the invention the initial mixture or any intermediate or final product, i.e. the naltrexone or naloxone, preferably the original mixture or intermediate product, at the stage of (a) and phase (b) and then subjected to hydrogenation.

The initial mixture consists mainly of Oxymorphone

derived from natural substances thebaine or oripavine extracted from plant materials.

This invention relates to a method of purification of plant extracts, which consist mainly of compounds of noroxymorphone according to the formula (II) include, in the quality of the solid fuel impurities, α,β-unsaturated compounds noroxymorphone and other compounds of noroxymorphone

where R1is hydrogen or optionally substituted by phenyl or by chlorine, alkyl with 1-8 carbon atoms, alkenyl with 2-4 carbon atoms or is in itself known, detachable tsepliaeva group,

characterized in that (a) a plant extract or a product of a later stage of the synthesis of selected compounds of noroxymorphone subjected to reactions, which are present in a mixture of hydroxyl group into otsepleniya group of the formula-OR2where R2- introduced radical tsepliaeva group, (b) these otsepleniya group, if necessary, can then be removed, after which (C) the resulting mixture is subjected to selective hydrogenation, in which is formed a saturated bond in the α,β-position of the impurity compounds noroxymorphone and all remaining otsepleniya group into hydroxyl group, after which it can be (d) allocated net connection noroxymorphone.

The present invention relates also to compounds of Oxymorphone formula (II), purified by the method according to the invention or a mixture of such compounds, and to pharmaceutical compositions containing the compound as such.

R1- preferably hydrogen, alkyl with 1-8 carbon atoms, alkenyl C2-4 carbon atoms or tsepliaeva group, preferably alkyl with 1-6 carbon atoms, allyl or hydrogen, preferably alkyl with 1-6 carbon atoms or hydrogen.

R1as tsepliaeva group is preferably a (C1-C4-allyloxycarbonyl [(C1-C6)-alkyl-O-C(O)-] or vinyloxycarbonyl [phenyl-O-C(O)-], preferably by ethoxycarbonyl, isobutylketone or tert-BUTYLCARBAMATE (Vos), cyclohexyloxycarbonyl, preferably by ethoxycarbonyl or tert-BUTYLCARBAMATE (Boc). The method of introduction of this radical by reaction of compounds of General formula (II) (where R1is hydrogen or substituted radical), for example, anhydride Vos (Vos-Vos) {[(CH3)3C-O-C(O)]2-O} or carbamate Vos [(CH3)3C-O-C(O)-N(C1-4-alkyl)2] itself known. Such radicals and their introduction of nitrogen atoms themselves known.

If the connection according to the formula (II) is the final product, R1it is preferably methylenecyclopropanes (-CH2-C3H5) or allyl (-CH2-CH=CH2). Preference is given to hydrogenation of the compound or mixture of compounds in which R1neither methylenecyclopropanes or allyl, and the preferred end product is obtained from the hydrogenated product.

The definition of "which consist mainly of connected the nd noroxymorphone according to the formula (II) includes, as impurities, α,β-unsaturated compounds noroxymorphone and other compounds, which are impurities of noroxymorphone" means that the plant extracts in the dry state contain at least about 70% by weight, preferably at least about 80% by weight and preferably at least about 90% by weight of compounds noroxymorphone, the connection of noroxymorphone formula (II) to polluting compounds of noroxymorphone is 99,800 to 99,999% by weight of compounds of noroxymorphone formula (II), from about 0.200 to about 0.001% by weight polluting compounds, and all solids present in the extract amounts to 100% by mass.

In tsepliaeva group of the formula-OR2, -OR2preferably represents an ester group, such as formyl ether radical [R2=NS(O)-], acetyl ether radical [R2=CH3C(O)-, methylcarbamyl], trichloroethylene ether radical [R2=CCl3C(O)-], trifluoracetyl ether radical [R2=CF3C(O)-, triptoreline], bentely ether radical [R2=C6H5C(O)-], optionally also substituted benzyl ether group, or the esters of sulfonic acids, in which R2preferably is methylsulfonyl, benzylalkonium or p-toluensulfonyl. Or-OR2may bicostata ester of carbonic acid, in which R2- (C1-C8-allyloxycarbonyl or vinyloxycarbonyl, preferably ethoxycarbonyl, isobutylketone or tert-BUTYLCARBAMATE (Boc), cyclohexyloxycarbonyl, preferably ethoxycarbonyl or tert-BUTYLCARBAMATE (Boc).

The method of formation of an ether residue, for example, in the case of the introduction of the acetyl or tert-BUTYLCARBAMATE (Boc), by reaction of compounds of General formula (II) with acetic anhydride or acetylchloride or anhydride Vos (Vos-Vos) {[(CH3)3C-O-C(O)]2About} itself known. Acetyl and Vos are the representatives of other compounds that react in the same way, i.e. compounds in which a methyl or tert-botilony radical is replaced by another radical with the same reactivity. Otsepleniya groups are usually removed during the reaction, for example, at the stage (b) or by hydrogenation, but if it is necessary in a specific case, you can remove them after hydrogenation method, which is in itself known.

Preference is given to introduction tsepliaeva groups or derivatives via reaction with acid chlorides or anhydrides of the acids, for example acetic anhydride, acetylchloride, triperoxonane anhydride, methanesulfonamido, methanesulfonamido, toluensulfonate and related compounds, which with the mi itself known.

The transformation of R1in tsepliaeva group if R1represents an alkyl group, known from the literature for analogous reactions and does not require more detailed description.

Preference is given to carrying out a further conversion reaction mixture obtained in stage (a), in anhydrous medium, preferably in alcohol-free environment, because in the presence of water can form impurities, in particular alcohols into α - or β-position, the addition of water and possibly alcohol to α,β-unsaturated compounds. This refers to the preparatory phase (a) and remove tseplyaesh groups at the stage (b), including the possible separation of the reaction products. The hydrogenation in stage (C) can be conducted under mild conditions in aqueous and/or alcoholic solvents. For such processing in anhydrous and preferably alcohol-free environments are suitable, in particular, aprotic solvents such as tert-butyl esters.

Tsepliaeva group stage (a) is introduced by treating the reaction mixture alkylating agent as described above, if necessary with heating. Subsequent addition of organic solvents such as MTBE (methyl tert-butyl ether), leads to the precipitation of the product.

Way to remove tseplyaesh groups at the stage (b) is preferably heated product is the reaction stage (a) in nonaqueous solvents, if necessary, more than a few hours, preferably in an aprotic solvent, such as THF (tetrahydrofuran), dioxane, ethyl acetate, MTBE (methyl tert-butyl ether), DMF (dimethylformamide), DMSO (dimethylsulfone) and the like, optionally with addition of a base such as potassium tert-piperonyl or lithium hydroxide, in an aprotic solvents, such as THF, dioxane or ethyl acetate. The product is then preferably deposited by adding an aprotic solvent.

The conditions of hydrogenation in themselves known and are shown, for example, in European patent EP 0158476, international applications WO 99/02529, WO 95/32973 or WO 91/05768. In accordance with the invention, preference is given to hydrogenation conditions in which the hydrogenation in stage (C) use of elemental hydrogen and/or modes or connections leading to the formation of elemental hydrogen in situ. In accordance with the invention, in this case, preference is given to hydrogenation conditions in which the hydrogenation in stage (C) as sources of hydrogen using elemental hydrogen, cyclohexene and/or cyclohexadiene (which reacts with evolution of hydrogen and formation of benzene), and/or ammonium formate (which decomposes with evolution of hydrogen and formation of carbon dioxide and ammonia) or solvent from the class of polar organic the ski solvents, if necessary, add water to solubilize, for example, hydrogenation catalysts. Such hydrogenation catalysts are described below. Of the hydrogenation reaction with hydrogen transport is usually carried out under normal pressure and in themselves known.

Particular preference is given to catalytic hydrogenation using a noble metal as a catalyst in a heterogeneous or homogeneous form. Such catalysts based on noble metal is preferably selected from compounds of the group of transition metals of the periodic table of elements, in particular selected from metals of group VIII of the periodic table and their compounds and complexes, in particular ruthenium (Ru) and osmium (Os), cobalt (Co), rhodium (Rh) and iridium (Ir), Nickel (Ni), palladium (Pd) and platinum (Pt). The preferred rhodium, palladium and platinum, in particular palladium. These metals are used as hydrogenation catalysts in the method, which is in itself known. Thus, it is possible to carry out the hydrogenation in a heterogeneous form, when the catalyst is applied on a substrate, preferably activated carbon or alumina or other substrate, in itself known, preferably activated charcoal.

Compounds of these metals can preferably also be used as homogeneous catalysts, preferably the palladium compounds. Examples of such palladium compounds are compounds of Pd(0), in themselves known, such as tetrakis(triphenylphosphine)palladium, and the corresponding complexes with such ligands as three(2-toluyl)phosphine, three(2-furyl)phosphine, three(tert-butyl)phosphine, or bidentate ligands dppm [1,1-bis(diphenylphosphinomethyl)], dppe [1,2-bis(diphenylphosphino)ethane] and related compounds, and complex Tris(dibenzylideneacetone)dipalladium-chloroform, and compounds of Pd(II), preferably PdCl2Pd(dppe)Cl2Pd(OAc)2Pd(dppe)(OAc)2, π-allyl-Pd complexes, preferably dimer π-allylpalladium chloride. Preference is given to compounds of Pd(0). These compounds, salts and complexes themselves known and described in literature.

These catalysts are used in catalytic amounts, preferably in amounts of 0.0005 to 0.01% by weight of noble metal, preferably of about 0,001-0,005% by weight of noble metal, relative to the total weight of the reagent. However, this upper limit is not critical. So you can also use large amounts of catalysts, for example equimolar amount by weight of the original product. However, this is usually not necessary.

The hydrogenation is preferably carried out with gaseous hydrogen preferably in an inert solvent, such as organic acids, preferably is in glacial acetic acid, formic acid, propionic acid or mixtures of these compounds; alcohols, preferably methanol, ethanol, isopropyl alcohol, n-butanol or a mixture of these compounds; NITRILES, preferably acetonitrile and/or propionitrile; ketones, preferably acetone and/or 2-butanone; esters such as ethyl acetate, in a polar aprotic solvent, preferably in dimethylformamide (DMF) or dimethylacetamide (DMSO), optionally with addition of water. The preferred proton solvents, particularly methanol, ethanol, isopropyl alcohol, n-butanol, or aprotic polar solvents, preferably the acetone, DMF, acetonitrile, optionally in a mixture with 1-99% by weight of water and preferably in the presence of organic acids, for example acetic acid, triperoxonane acid, propionic acid, formic acid, preferably acetic acid, preferably at a concentration of from 0.1% by mass to 99% by weight. The hydrogenation is preferably carried out at a temperature in the range from 0°C to 150°C, preferably in the range from 20°C to 100°C, preferably in the range from normal pressure to 100 bar, preferably in the range from normal pressure to 10 bar.

Instead of hydrogen can also be used compounds that produce hydrogen in situ reaction of i, for example in the reaction of hydrogen transport with ammonium formate, cyclohexene and/or cyclohexadiene. In this case, the hydrogen is removed in the preceding reaction with reagent catalysis.

The present invention relates also to method of obtaining pure noroxymorphone from plant extracts, which consist mainly of noroxymorphone and contain polluting compounds noroxymorphone, wherein the Oxymorphone of the above formula (II)in which R1is methyl, first download in the form of plant extract and (a) plant extract is subjected to the reaction, which are present in a mixture of hydroxyl group into otsepleniya group of the formula-OR2in which R2represents introduced radical tsepliaeva groups, such as those described previously for R1preferably acyl, preferably acetyl;

(A1) N-methyl group [corresponding to the definition of R1for the compounds of formula (II)] remove and replace tsepliaeva group R3in which R3- tsepliaeva group, such as those previously described for R1preferably allyloxycarbonyl, preferably ethoxycarbonyl or Boc, preferably ethoxycarbonyl;

(A2) otsepleniya group R2and R3can be removed from the reaction product obtained is Tudeh (a) and (A1);

(b) at least one of the product obtained in stage (a), (A1) and/or (A2), preferably one of the products obtained in stage (A1) or (A2), preferably in stage (A2), is subjected to the reaction of selective hydrogenation, as described above, and

(c) if necessary, allocate the net connection noroxymorphone.

The product obtained in stage (A2), can be subjected to further processing, preferably with the formation of naltrexone or naloxone, or salts of these compounds or Quaternary derivative of these compounds, preferably hydrochloride, hydrobromide, methochloride or methobromide, preferably the corresponding salts or the Quaternary derivative of naltrexone.

Selective hydrogenation removes otsepleniya group, but, if necessary, this can be done separately on stage (A2) and/or if necessary, in conclusion, after hydrogenation.

At the stage of (a) Oxymorphone preferably atrificial acetic anhydride with the formation of methyl tert-butyl ether (MTBE), is treated in an anhydrous conditions and produce with getting deacetylation (R2=acetyl).

On stage (A1) is preferred transformation using ethylchloride in an aprotic solvent, preferably acetonitrile, demethylation under alkaline conditions, for example with K2With the 3allocating connection Oxymorphone, in which R3- etoxycarbonyl, or the target compound is the corresponding ethoxycarbonyl of deacetylation.

On stage (A2) otsepleniya group R2and R3remove from the reaction product obtained in stage (a) and (A1). To this end, the reaction product of stage (a) or (A1) is heated in a non-aqueous solvents, preferably aprotic solvents, such as THF, dioxane, ethyl acetate, MTBE, DMF, DMSO and the like, if necessary over several hours, if necessary with addition of a base such as potassium tert-piperonyl or lithium hydroxide, in an aprotic solvents such as THF, dioxane, ethyl acetate. This product is then preferably precipitated by adding an aprotic solvent.

At the stage (b) the selected product, such as deacetylation ethoxycarbonyl, preferably dissolved in glacial acetic acid and subjected to hydrogenation by introducing hydrogen gas in the above conditions using palladium on charcoal as catalyst. Subsequently, the remaining otsepleniya group R4and R5removed, adding to the reaction mixture of 40%sulfuric acid with the formation of noroxymorphone sulfate, which can, if necessary, to select. Adding a base, for example, by adding a dissolve is and ammonia in a mixture of ethanol/water, allows you to neutralize and to prepare the reaction mixture for the allocation of free noroxymorphone. Free noroxymorphone insoluble in a mixture of water/ethanol at slightly alkaline pH, preferably a pH of 8-10, and precipitates as a crystalline precipitate when making pH, which allows to separate it by filtration. When analyzing by HPLC α,β-unsaturated compounds not found in the selected noroxymorphone. Thus obtained noroxymorphone can be subjected to further processing, preferably with the formation of high-purity naltrexone or naloxone (CAS No. 465-65-5) or with the formation of salts or Quaternary derivatives. The preferred salts are hydrochloride and hydrobromide. Preferred Quaternary derivatives are compounds naltrexone methobromide (known as methylnaltrexone) or naloxone methobromide [known as mathildelaan (CAS No. 73232-50-5)]. Preference is given naltrexone hydrochloride or hydrobromide and naltrexone to methobromide.

Noroxymorphone received in accordance with the invention, can be subjected to processing, for example, with the formation of high-purity naltrexone or high-purity naloxone, or with the formation of high-purity salts or Quaternary derivative of these compounds.

In this regard, this invention relates to a method for producing a highly the East salts and Quaternary derivative of naltrexone and naloxone, in which the content limit of olefinic impurities below the detection limit, preferably salts, naltrexone, by the reaction of a source material containing noroxymorphone, with an appropriate alkylating agent, i.e. with cyclopropylmethyl-bromide (naltrexone) or allylbromide (naloxone), and the reaction product containing the naltrexone or naloxone, with acid, preferably dilute hydrochloric acid or Hydrobromic acid, with formation of the corresponding salt, in the above case with the formation of the hydrochloride or hydrobromide, or further reaction with an alkylating agent, preferably a bromide, to obtain the naltrexone of methobromide or naloxone of methobromide, characterized in that, at least the source material or product stages (a) or (b)obtained as an intermediate product or final product, preferably a product stages (a) or (b), preferably in stage (b), obtained as an intermediate product is subjected to hydrogenation reactions, as described above. The following examples illustrate the invention.

Example 1 [obtaining deacetylation (DOM), introduction tsepliaeva group to direct removal tsepliaeva group]

20 g of Oxymorphone suspended in a mixture of 10 g of tert-butyl methyl ether and 21 g of acetic anhydride (324 EQ.) at room temperature. The reaction solution is heated under reflux for 5 hours. Then cool and add 70 g of tert-butyl methyl ether. Heat the suspension again to a temperature of phlegmy, then cooled to 0-4°C and stirred until complete precipitation. The product is filtered off with suction, washed with tert-butylmethylamine ether and dried to constant weight at 90°C under reduced pressure. Yield 23 g (91% used Oxymorphone); purity by HPLC 98%. The product contains traces (about 1000 parts per million) of α,β-unsaturated compounds; 3,8,14-triazacyclononane not find.

Example 2 [receive deacetylation (DOM)containing traces of 3,8,14-triazacyclononane; introduction tsepliaeva group]

20 g of Oxymorphone suspended in a mixture of 10 g of tert-butyl methyl ether and 21 g of acetic anhydride (3.24 EQ.) at room temperature. The reaction solution is heated at a temperature not exceeding 30-40°C for 48 hours. Then cool and add 70 g of tert-butyl methyl ether. This mixture is cooled to 0-4°C and stirred until complete precipitation. The product is filtered off with suction, washed with tert-butylmethylamine ether and dried to constant weight at a temperature of 30°C under reduced pressure. The output of 26.8 g (91% used Oxymorphone); purity by HPLC 98%. The product contains traces of 3,8,14-triaza is roximity.

Example 3 [getting deacetylation carbamate] Suspended 30 g deacetylation with 66 g of ethylchloride (8 EQ.) and heterogeneous base (1 EQ. potassium carbonate) in an organic solvent (74 g of acetonitrile and heated at elevated temperature (65-68°C) for several hours (24-28 hours). After the reaction is distilled acetonitrile and ethylchloride under reduced pressure. Add to the precipitate 73 g of acetonitrile. Then filtered heterogeneous base (KHCO3/K2CO3) at room temperature. Distilled acetonitrile under reduced pressure and add 60 g of tert-butyl methyl ether for complete precipitation. After heating to a temperature of phlegmy cool the mixture to 0-5°C and continue to mix, then solid residue is filtered off with suction and washed first with tert-butylmethylamine ether, then with water. Dried colorless product under reduced pressure at 80°C to constant weight. According to HPLC the product contains >1000 parts per million of α,β-unsaturated compounds. Yield 29 g (86% per used deacetylation). Purity according to HPLC >95%.

Example 4 [conversion 3,14-deacetylation (DOM)containing traces of 3,8,14-triazacyclononane, to 3.14-deacetylation (DOM), not containing 3,8,14-triazacyclononane; removing tsepliaeva group]

Su is ponderous 20 g deacetylation with traces 3,8,14-triazacyclononane in a mixture of 20 g of tert-butyl methyl ether and 3-5 g of acetic acid at room temperature. Heat the reaction solution at 70°C for 10-15 hours. Then cool and add 70 g of tert-butyl methyl ether. The mixture is cooled to 0-4°C and stirred until complete precipitation. The product is filtered off with suction, washed with tert-butylmethylamine ether and dried to constant weight at a temperature of 30°C under reduced pressure. Yield 15.7 g (91% per used deacetylation); purity by HPLC 98%, the product contains about 1000 parts per million of α,β-unsaturated compounds, 3,8,14-triazacyclononane not found.

Example 5 [hydrogenation with tsepliaeva group]

Dissolve 20 g of deacetylation with traces 3,8,14-triazacyclononane obtained as in example 2, 60 g of glacial acetic acid at room temperature. Add 0.6 g water-wetted palladium on charcoal (10% Pd on dry matter, water content about 50%). Then injected gaseous hydrogen at a product temperature of 50-60°C and a pressure of 2.7 bar. After hydrogenation the catalyst is filtered off and concentrate the solution to half volume under reduced pressure. Then add MTBE and cooling the mixture to 0-4°C. the Product is filtered off with suction, washed with MTBE and dried at a temperature of 70°C under reduced pressure. Purity 98%; α,β-unsaturated compounds and 3,8,14-triazacyclononane not about arrivalsa, yield 85% (deacetylation per used deacetylation).

Example 6 [hydrogenation with remote atmasamyama groups; obtaining noroxymorphone]

Dissolve 30 g of deacetylation carbamate, obtained as in example 3, 60 g of glacial acetic acid at room temperature. Add 0.6 g water-wetted palladium on charcoal (10% Pd on dry matter, water content about 50%). Then injected gaseous hydrogen at a product temperature of 50-60°C and a pressure of 2.7 bar. After hydrogenation the catalyst is filtered off and concentrate the solution to half volume under reduced pressure. Add triple the amount of 40% sulfuric acid to a concentrated solution in glacial acetic acid. Boil carbamate under reflux for formation of the free amine. During this process, the product is precipitated in the form of a sulfate salt. Filter the formed salt and washed with a small amount of chilled ethanol. Dissolve the resulting solid precipitate in a mixture of water/ethanol and bring the solution pH to 9 with an aqueous solution of ammonia. If the pH falls free noroxymorphone that you want to filter. When analyzing by HPLC α,β-unsaturated by-products do not detect. The yield of 70-75% (calculated on the used diacetylomorphine).

The cleanliness In the LC > 98%, α, β-unsaturated compound and 3,8,14-triazacyclononane not find.

Example 7 [naltrexone hydrochloride]

(A) 100 g of noroxymorphone obtained as in example 6, is suspended in 165 g of N-methylpyrrolidone with 37 g of sodium carbonate, and then added 56 g of bromelicola. The suspension is heated to 70°C for 3 hours and cooled to room temperature. The product is crystallized by using 800 g of water, introducing seed crystals of naltrexone. Adding only the amount of water the pH value was adjusted to 9.5 by adding sodium hydroxide. The product distinguish, washed with water and dried under vacuum. Exit 113 g crude naltrexone, purity more than 95% (purity >95%).

(B) 102 g crude naltrexone obtained as in paragraph (a), is heated in a flask with reflux condenser together with 800 g of ethyl acetate and 7 g of activated charcoal. The mixture is filtered at 75°C. the Filtrate is again mixed with activated carbon and heated in a flask with reflux condenser. After filtration, activated carbon portion of the ethyl acetate is evaporated at atmospheric pressure. In the resulting solution add seed crystals of naltrexone and the product is crystallized by cooling the solution to 0°C. Crystallized naltrexone filtered off, washed with some ethyl acetate and dried under vacuum. Exit 77 g of crystalline naltr is the XON; purity of more than 99% (purity >99%).

(C) 100 g of crystalline naltrexone obtained as in paragraph (B), is heated in 300 g of water and 34 g of concentrated hydrochloric acid to boiling point. A clear solution is slowly cooled to 2°C and add the seed naltrexone · HCl. The product distinguish, washed with water and dried under vacuum. Exit 99 g naltrexone · HCl, purity of more than 99.8 per cent (purity >99.8 per cent).

Example 8 [naloxone hydrochloride]

(A) 80 g of noroxymorphone obtained as in example 6, is suspended in 140 g of dimethylacetamide, and then add 36 g allylbromide and 35 g of diisopropylethylamine. The mixture is stirred for 6 hours at 25°C. Then 128 g of acetone is added and slowly add 300 g of water, and then deposited the basis of naloxone. The suspension is further stirred for 1 hour at 25°C., then cooled to 0°C. and then stirred at this temperature for 4 hours. The product is filtered off, washed with a mixture of 80 g of acetone and 80 g of water and dried under vacuum at 60°C. the Yield of 81.5 g of the base of the naloxone, the purity of more than 99% (purity >99%).

(C) 30 g of the base of the naloxone, obtained as in paragraph (a), is heated together with 2 g of activated carbon and a mixture of 240 g of isopropanol and 25 g of acetonitrile at 45°C. the Mixture was then filtered. Next, add a mixture of 15 g of water and 12 g of concentrated hydrochloric acid. Solution add Aut seed naloxone · HCl and incubated for 60 minutes at 45°C, resulting products are beginning to crystallize. A suspension of the product then slowly cooled to 0°C. Stirring is continued at this temperature for 3 hours. Product naloxone · HCl, filtered, washed with 20 g of isopropanol and dried under vacuum at 40°C for 17 hours. Output 31.0 g; purity of more than 99.8 per cent (purity >99.8 per cent).

1. The method of purification of plant extracts, which consist mainly of compounds of noroxymorphone formula (II) and which contain as impurities of α,β-unsaturated compounds noroxymorphone and other polluting compounds noroxymorphone:

where R1hydrogen, or optionally substituted phenyl or chlorine, alkyl with 1-8 carbon atoms, alkenyl with 2-4 carbon atoms, or itself known detachable tsepliaeva group, preferably a urethane group, wherein (a) a plant extract or a product of a later stage of the synthesis of selected compounds of noroxymorphone convert the reaction of converting the hydroxyl groups present in the mixture in otsepleniya group of the formula-OR2where R2- introduced radical tsepliaeva group, (b) these otsepleniya group, if necessary, again removed, then (C) the resulting mixture is subjected to selective hydrogenation, in which obrazu the Xia saturated bond in the α,β-position of the impurity compounds noroxymorphone and all remaining otsepleniya group into hydroxyl group, then, if necessary, (d) allocate net connection noroxymorphone.

2. The method according to claim 1, characterized in that otsepleniya group is removed prior to hydrogenation.

3. The method according to claim 1, wherein stage (a) and phase (b), including the possible allocation of the reaction products is carried out in anhydrous medium, preferably in an environment that does not contain alcohol.

4. The method according to claim 1, characterized in that the hydrogenation of [stage (C)] is carried out in the presence of aprotic or proton solvents, preferably in water and alcohols.

5. The method according to claim 1, characterized in that otsepleniya group remaining after hydrogenation [stage (C)], is removed by means of hydrolysis.

6. The method according to claim 1, wherein R1represents hydrogen, alkyl with 1-8 carbon atoms, alkenyl with 2-4 carbon atoms or tsepliaeva group; preferably alkyl with 1-6 carbon atoms, allyl or hydrogen, preferably alkyl with 1-6 carbon atoms or hydrogen, and, if the compound of the formula (II) is the final product, R1is preferably methylenecyclopropanes or allyl.

7. The method according to claim 1, characterized in that tsepliaeva group R1is a (C1-C4-allyloxycarbonyl or vinyloxycarbonyl, preferably ethoxycarbonyl, isobutylketone, or tert-BUTYLCARBAMATE (Boc), cyclohexyl-hydroxy shall arbonyl, preferably ethoxycarbonyl or tert-BUTYLCARBAMATE (Boc).

8. The method according to claim 1, characterized in that tsepliaeva group of the formula-OR2is essential residue, preferably formyl ester radical, acetyl ester radical, trichloroethylene ether radical, trifluoracetyl ether radical, benzoline ether radical, possibly substituted benzyl ether groups, i.e. the fact that R2in the radical-OR2is formicaria, methylcarbamyl, trichlorocarbanilide, cryptomaterial, phenylcarbinol, if necessary, replaced by phenylcarbinol, or2is essential balance sulfonic acid, in which R2- methylsulphonyl, benzylmethyl or p-toluensulfonyl.

9. The method according to claim 1, characterized in that-OR2is essential residue of carboxylic acid, in which R2is (C1-C8-allyloxycarbonyl or vinyloxycarbonyl; preferably ethoxycarbonyl, isobutylketone or tert-BUTYLCARBAMATE (Boc), cyclohexyloxycarbonyl, preferably by ethoxycarbonyl or tert-BUTYLCARBAMATE (Boc).

10. The method according to claim 1, characterized in that the plant extract in which R1neither methylenecyclopropanes or allyl, hydronaut and this hydrogenated product get Obedinenie, in which R1is methylenecyclopropanes or allyl.

11. The method according to claim 1, characterized in that the plant extract in dry form contains at least about 70% by weight, preferably at least 80% by weight and preferably at least about 90% by weight of compounds of noroxymorphone, the ratio of the compounds of noroxymorphone formula (II) to polluting compounds of noroxymorphone is in the range from 99,800 to 99,999% by weight of compounds of noroxymorphone formula (II) from about 0.200 to about 0.001% by weight of polluting compounds, and all solids present in the extract, total 100% by mass.

12. The method of claim 1, characterized in that the hydrogenation using elemental hydrogen and/or compounds forming elemental hydrogen in situ.

13. The method according to item 12, characterized in that the hydrogenation using elemental hydrogen, cyclohexene, cyclohexadiene and/or ammonium formate in a solvent selected from the class of polar organic solvents and water, and in the presence of hydrogenation catalysts.

14. The method according to claim 1, characterized in that the hydrogenation is conducted with hydrogen using a noble metal as a catalyst in a heterogeneous or homogeneous form, which is preferably selected from compounds of the group of transition metals of the Periodic table the element is in, preferably from metals of group VIII of the Periodic table and their compounds and complexes, preferably from ruthenium, osmium, cobalt, rhodium, iridium, Nickel, palladium, platinum, preferably from rhodium, palladium and platinum, preferably palladium.

15. The method according to 14, characterized in that the hydrogenation is carried out in heterogeneous form, the catalyst is applied on a substrate, preferably activated carbon or alumina or another, in itself known substrate, preferably activated charcoal.

16. The method according to 14, characterized in that the hydrogenation using homogeneous catalysts, preferably palladium compounds, preferably in themselves known compounds Pd(0).

17. The method according to item 16, characterized in that the catalyst used tetrakis(triphenylphosphine)palladium and the corresponding complexes with such ligands as tri-(2-toluyl)phosphine, tri-(2-furyl)phosphine, tri-(tert-butyl)phosphine, or bidentate ligands dppm [1,1-bis(diphenylphosphinomethyl)], dppe [1,2-bis(diphenylphosphino)ethane] and related compounds, a complex of Tris-(dibenzylideneacetone)dipalladium-chloroform, the compounds of Pd(II), preferably PdCl2Pd(dppe)Cl2Pd(OAc)2Pd(dppe)(OAc)2, π-allyl-Pd complexes, preferably dimer π-allylpalladium chloride.

18. The method according to 14, characterized in that etiketleri used in catalytic quantities, preferably in amounts of 0.0005 to 0.01% by weight of noble metal, preferably of about 0,001-0,005% by weight of noble metal, relative to the weight of the crude reagent.

19. The method according to claim 1, characterized in that the hydrogenation is carried out using gaseous hydrogen in an inert solvent, preferably in an organic proton or aprotic polar solvent, optionally in mixture with water, 1-99% by weight, preferably in the presence of organic acids, in a concentration of preferably from 0.1 to 99% by weight and at a temperature in the range of preferably from 0 to 150°C, preferably in the range from 20 to 100°C., and preferably in the range from normal pressure to 100 bar, preferably in the range from normal pressure to 10 bar.

20. The method according to item 12, characterized in that instead of hydrogen use compounds that emit hydrogen in the reaction in situ, preferably in the form of transfer hydrogenation with hydrogen, ammonium formate, cyclohexene or cyclohexadiene.

21. The method of obtaining pure noroxymorphone from plant extracts, which consist mainly of noroxymorphone and contain polluting compounds noroxymorphone, wherein the Oxymorphone of the formula (II) according to claim 1, where R1is methyl, first download in the form of plant extract and (a) raises the local extract is subjected to the reaction, as a result of which the hydroxyl groups present in the mixture, turn into otsepleniya group of the formula-OR2in which R2represents introduced radical tsepliaeva groups according to claims 1, 8 and 9, preferably acyl, preferably acetyl;
(A1) N-methyl group is removed and replaced with tsepliaeva group R3,in which R3- introduced radical tsepliaeva groups according to claims 1, 8 and 9, preferably allyloxycarbonyl, preferably ethoxycarbonyl or Boc, preferably ethoxycarbonyl;
(A2) otsepleniya group R2and R3if necessary, removed from the reaction product obtained in stage (a) and (A1);
(b) at least one of the product obtained in stage (a), (A1) and/or (A2), preferably one of the products obtained in stage (A1) or (A2), preferably in stage (A2), is subjected to the reaction of selective hydrogenation, as described above, and
(c) if necessary, clean the connection noroxymorphone emit.



 

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