Method for making naltrexone

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry, particularly a method for making the oxymorphone derivative naltrexone being an opiate antagonist by naltrexone processing by diazomethane in the presence of palladium acetate.

EFFECT: method eliminates using hardly accessible and expensive parent compounds, and it is characterised by ease of implementation.

3 ex

 

The invention relates to a method for producing a medicinal product 17-(cyclopropylmethyl)-4,5A-epoxy-3,14-digidroksimorfinan-6-she-trexone) of the formula (I)

Naltrexone is a drug (Mashkovsky PPM Medicines. ISD / Moscow: New Wave, 2006. - S; Modesto-Lowe V, Van Kirk J. Clinical Uses of naltrexone: A review of the evidence. // Exp. Clin. Psychopharm. - 2002 - v.10. - p.213-227). The pharmacological action of naltrexone differs in that it is a pure opioid antagonist devoid of side effects of morphine.

The main method of receiving naltrexone described in The Organic Chemistry of Drug Synthesis. Vol.1, John Wiley&Sons, New York, 1990. - p.289-291;

Blumberg, H., Pachter I.J. US Pat. 3.332.950 (1967)) and includes a number of successive stages: oxidation of thebaine with getting 14-hydroxycotinine; its hydrogenation to oxycodone; serial dealkylation metal groups in the phenyl ring [Oxymorphone] and the nitrogen atom with getting noroxymorphone (II). Naltrexone get N-alkylation noroxymorphone (II) cyclopropanemethylamine.

In the patent (RF 2236412; SA, 141, 260924, 2005) describes a method for naltrexone (I) of codeine. The method also includes a number of stages: oxidation of codeine to codeinone; transformation of codeinone in girolata of codeinone; oxidation of girolata 14-hydroxycotinine; selective is the W 14-hydroxycotinine to 14-hydroxycodone; similarobama hexamethyldisilazane with getting 14-trimethylsiloxy; dealkylation 14-trimethylsiloxy on the nitrogen atom by the action of bromine cyan obtaining 17-noroxycodone (III). The final stage of the process include N-alkylation (III) chloromethylketones to obtain methyl ester of naltrexone (IV) and O-demethylation of the methyl ether of naltrexone (IV) to obtain (I).

The drawback of both methods of obtaining naltrexone shown in schemes 1 and 2, is the use of remote and expensive compounds - bromelicola or chloromethylstyrene. Get them or using ORGANOMETALLIC compounds (US 3959324), or the recovery of lithium aluminum hydride cyclopropanecarbonyl acid (US 3454575) and subsequent bromirovanii mixture of bromine and triphenyl-phosphine (US 6008420), that is also using inaccessible connections.

Object of the invention is the creation of a technical and economical method of obtaining naltrexone eliminating the use of hard-to-reach cyclopropylmethanol.

The problem is solved by a method of obtaining naltrexone treatment available 17-allyl-4,5A-epoxy-3,14-digidroksimorfinan-6-she (naloxone) with diazomethane in the presence of palladium acetate.

The drug naloxone [hydrochlorid 17-allyl-4,5A-epoxy-3,14-digidroksimorfinan-6-it] (V) produced by the pharmaceutical industry and is a derivative of noroxymorphone, containing allyl group on the nitrogen atom. To obtain it uses readily available allyl bromide, which is a large tonnage on an industrial scale. Consequently, naloxone (V) is relatively affordable medication.

Synthesis of naltrexone (I) carry out the processing of naloxone (V) with diazomethane in the presence of palladium acetate. In the process the reaction is catalyzed by palladium education of the vinylcarbene (CH2:)that is easily attached to the double bond of allyl group with the formation of cyclopropyl-methyl group, that is naltrexone. Palladium, used in the synthesis, acts as a catalyst in the reaction completely extracted from the reaction mass in the form of palladium mobiles. This allows you to re-translate it into acetate and reuse in the synthesis. Conducting the reaction in the absence of a catalyst (palladium acetate) leads to the formation of hardly separated mixture of the desired product and by-products.

Diazomethane used in the proposed method, is widely known and available reagent, which is usually obtained by the action of alkali on nitrozometilmochevinu, nitrosomethylurea, nitrosalicylanilide and the like nitrosopropane of methylamine (Fisher L., Fisher M. Reagents for organic with the NASA / Lane. from English. Vol. 1. - M., 1970. - S-248).

Thus, the application of the developed method allows to avoid the use of difficult and expensive cyclopropylmethyl-halides and significantly reduce the cost of obtaining the target product.

Examples illustrating the invention.

The preparation of the ether solution diazomethane of nitrosomethyl-urea (Becker G., Berger, C., Domske, and other Organikum / Lane. with it. Vol.2. - M., 1979. - S-248).

In the Erlenmeyer flask is placed in 35 ml of cold 40%aqueous solution of potassium hydroxide and 50 ml of ether. Then, constantly shaking the flask in small portions was added 0.5 mol of nitrosodiethylamine at a temperature not exceeding 5°C. After 10 min after adding the last portion is drained yellow ethereal solution diazomethane in flat-bottomed flask, add 50 ml) cooled to 5°With ether, once drained, the operation is repeated with 50 ml of ether. The combined ethereal solutions of diazomethane dried no more than 2 hours over a small amount of sodium hydroxide. The resulting solution was used in the synthesis of naltrexone without any treatment.

Receiving naltrexone

To a solution 0,78 g of naloxone (V) in 50 ml of anhydrous methylene chloride was added 1 g of palladium acetate. Then gradually push the ethereal solution diazomethane. There are intense emission of nitrogen and the formation of stable yellow okra is Ki solution and precipitate palladium mobiles. After addition of the entire solution diazomethane (the nitrogen continues throughout time) in the reaction mixture was added 50 ml of methylene chloride, stirred for further 30 minutes, leave on overnight for complete precipitation palladium mobiles. The reaction mixture is decanted from the precipitate, filtered through a layer of alumina (10 g), the solution evaporated on a rotary evaporator, the residue (0.95 g) was dissolved by heating in tert-butylmethylether ether. Upon cooling is filtered off 0,82 g sediment (TPL 162-168°C). Recrystallization from ethyl acetate to give 0.64 g (78%) naltrexone (I), TPL 167-169°C.

Receiving naltrexone without palladium acetate

To a solution 0,78 g of naloxone (V) in 50 ml of anhydrous methylene chloride gradually pinned ethereal solution diazomethane. Observed evolution of nitrogen and the formation of stable yellow color of the solution. After addition of the entire solution diazomethane (the nitrogen continues throughout time) in the reaction mixture was added 50 ml of methylene chloride, stirred for further 30 min, left overnight to complete the nitrogen excretion. The reaction mixture is evaporated on a rotary evaporator to dryness. The obtained residue according to high performance liquid chromatography contains a mixture of products (mainly original naloxone) containing naltrexone about 10%.

The method of obtaining 17-(Cyclops is epiletic)-4,5α-epoxy-3,14-digidroksimorfinan-6-she formulas (I)
,
wherein the target product is obtained by treatment of 17-allyl-4,5α-epoxy-3,14-digidroksimorfinan-6-it-diazomethane in the presence of palladium acetate.



 

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