NL8020319A - INTERMEDIATES FOR PREPARING MORPHINE DERIVATIVES. - Google Patents

Description

802 03 1 9 VO 1759

Subject: Intermediates for the Preparation of Morphine Derivatives.

The invention "relates to new intermediates useful in the preparation of morphine derivatives and a process for their preparation.

The present compounds are intermediates which can be reduced to morphine derivatives which do not exhibit the known undesirable side effects of morphine, e.g. a decrease in respiration and the like. These products are of the type described in U.S. Pat. No. 3,393,197 and correspond to the general formula 1 of the formula sheet wherein R represents an aliphatic group. An--10 with no useful compound from this group is nalbuphine (wherein R in formula 1 is cyclobutyl).

A synthesis of nalbuphine and nalbuphine compounds from oxycodone, a commonly available starting material, hitherto used is shown in Scheme A. In this method, oxycodone is demethylated to oxymorphone, e.g. as described in U.S. Patent Application No. 19531056 of 1978. The oxycodone-oxymorphonom setting, the first stage in reaction A, takes 3 to 18 hours at room temperature and in the presence of a boron demethylating agent, or 1 hour at about 190 ° C in the presence of pyridine hydrochloride. Oxymorphone is then converted to noroxymorphone, which can be acetylated to a cyclobuthylamide intermediate (ester amide III). This acetylation is performed by a reaction between cyclobutanecarboxylic acid and ethyl chloroformate to form a mixed anhydride which then reacts with noroxymorphone to form the esteramide, which can be reduced to nalbuphine or a nalbuphine type compound with lithium aluminum hydride.

While this process has some value, it has certain problems. The oxycodone-oxymorphon conversion takes quite a long time and this is undesirable for a technical process. The addition of the cyclobutylamide intermediate by a reaction between cyelobutane carboxylic acid and ethyl chloroformate to the mixed anhydride which then reacts with noroxymorphone to form the amide is also a rather slow reaction. Thus, it would be particularly desirable to be able to use the cyclobutyryl chloride to form the amide directly in place of the mixed anhydride, resulting in a shorter reaction time 8020319; -2- is reached. Also, due to the complexity and side reactions when working with a noroxymorph fusion intermediate, a change in the order of the reaction stages provides potential benefits in terms of yields as well as conversions.

The invention therefore relates to a R-acyl-dihydro-1-hydroxy-morphorontone intermediate (hereinafter amide II) which is useful in the preparation of nalbuphine and products of the nalbuphine type. The amide II corresponds to the formula 2 of the formula sheet, in which R represents a hydrocarbon group with at most 6 carbon atoms.

According to a preferred embodiment of the invention, the substituent R in formula 2 is saturated and preferably has 3-6 carbon atoms. For example, R alkyl can be with up to 6 carbon atoms, but most preferably cycloalkyl with 3-6 carbon atoms, e.g. cyclopropyl, cyclobutyl or cydopentyl, preferably cyclobutyl.

A new synthetic route shown in Scheme B for preparing nalbuphine and nalbuphine-type compounds from oxy-codon has also been developed. This route involves the preparation of the new amide II compounds. According to this new synthesis, oxycodone is first converted in the presence of CHBr and sulfuric acid to noroxycodone, which is then acylated to a first intermediate amide (amide i). This first amide, which does not need to be isolated, is then demethylated to a second amide (amide II), which can be isolated and reduced to nalbuphine or a nalbuphine-type compound. The demethylation of amide I products to amide II products is the main difference from previous methods of preparing nalbuphine and compounds of the nalbuphine type, while the amide II compounds are new substances. Using this new synthesis route using new intermediates, nalbuphine and nalbuphine-type compounds can be obtained with improved yields, under mild reaction conditions and with shorter reaction times compared to the known synthesis procedure as shown in Scheme A.

According to the new demethylation process, the methyl group is removed from the methoxy substituent of a first amide I of the formula III of the foil sheet, wherein R has the above-mentioned meaning 802031® -3- by an amide I with a demethylating agent under suitable conditions to an amide II to put. This reaction is carried out under mild demineralization conditions, tv. at temperatures between 0 and i + 0 ° C.

Isolation of amide II is simple and can be performed by simple precipitation without the need for further extraction to remove starting material (ethers). This single separation contrasts markedly with the separation of other general type phenolic compounds from their corresponding ethers. The total yield of morphine-type compounds from oxycodone starting material may be 10% or more, which is a marked improvement over the prior art.

In the preparation of amide II compounds, a demethylating amount of an appropriate agent is used, e.g. a boron compound.

This agent can demethylate the methoxy group, but does not generate a large number of by-products. The boron compounds include the boron halide as boron trichloride, boron trichloride or a reaction product of this kind of halides with alcohols, ie with alcohols having 1-10 carbon atoms, most preferably 1-6 carbon atoms, such as methanol, propanol, butanol, hexanol, etc. The preferred demethylating agent is bromotri-brcmide, which is somewhat more active than e.g. brothrichloride as demethylating agent. The demethylating agent can be in an amount of 2.5-8 mol, most preferably 3.5-6.5 mol, e.g. about 6 moles per mole of amide I are used. No advantage is achieved by exceeding 8 moles.

If less than about 2.5 moles are used, the reaction is usually incomplete.

The demethylation conditions include an appropriate reaction time, e.g. from half to H hours at charge reactions and reaction temperatures of e.g. O-Ηθ, preferably 15-25 ° C. In this connection, the temperature of the reaction medium to which the demethylating agent can be added can range from about -25 ° C to + 20 ° C, most preferably from +10 to + 20 ° C.

After amide I and demethylating agent have been combined, the reaction heat can result in an increase in the temperature of the medium, although this temperature can be controlled to avoid undesired temperature increases. Higher temperatures of the reaction medium 8020319 -k- may result in lower yields of amide II. In this connection it may be advantageous to provide the reaction medium with a substantially inert solvent which does not react with the demethylating agent, e.g. chlorobenzene. The demethylating agent can be incorporated in this solvent and this solution can be combined with amide I. The demethylating agent can also be added to the reaction medium separately. E.g. the intermediate amide I can be simply mixed with a demethylating agent.

Recovery of amide II can be carried out by simple precipitation without the need for further extractions to remove starting material. This is a major advantage of the invention over the known methods of preparing nalbuphine and nalbuphine-type compounds. Overall, the invention achieves yields of nalbuphine and nalbuphine derivatives from oxycodone of about 50% or more, compared to 3% or less in known methods.

The following examples further illustrate the invention.

All parts are parts by weight unless otherwise indicated.

Example I;

20 Amide I

3 3

200 cm of anhydrous tetrahydrofuran (THF) and 6.5 g of ethyl chloroformate were added to a 500 cm flask. This mixture was cooled to + 5 ° C. A mixture containing 6 g cyclo-3 g butanecarboxylic acid, 8.5 cm diethylamine and 50 cm THF was slowly added to the flask. The temperature must not rise above 10 ° C. Stirring. The temperature was allowed to warm to 20-25 ° C in 1 to 2 hours. It formed

O

triethylamine salt was filtered and 1 g of noroxycodone and 1.5 cm of triethylamide added to the solution. The mixture was stirred at room temperature for 1-2 hours. The THF was distilled off and the resulting product diluted to 200 cm with chlorobenzene.

Example II:

Cleavage of amide I with boron triacid 3 100cm amide I solution obtained according to example I was added to a 500cm flask and cooled to 10-15 ° C. A mixture 3. 3 35 containing 100 cm chlorobenzene and 6-11 cm BBr 3 was slowly added to the 802 0 3 1 § -5 flask, such that the temperature of the mixture did not exceed 20 ° C. The molar ratio BBr 1 to amide I in the flask can vary from about 2.8 to 5: 1: 1. The mixture was stirred at 20-30 ° C for 30 min 3. .

and quenched by the addition of 300 cm of ice water. The precipitate formed was filtered off, washed with chloroform and air dried. The precipitate was then suspended in methanol, filtered, washed again with methanol and dried. H, U, 9 g corresponding to yields of 51-57% based on noroxycodone.

Example III:

Cleavage of amide I with boron trichloride 3 100 cm @ 3 amide I solution obtained according to Example I} was added to a 500 cm flask and cooled to 10-15 ° C. During this cooling, a solution of boron trichloride prepared by passing brothrichloride gas 3 15 m 100 cm chlorobenzene was added to the cooled solution according to Example I, keeping the temperature below 20 ° C. The mole ratio BCl 2 to amide I in the flask is about 7.7: 1. The reaction mixture was stirred at 20-25 ° C for hours and quenched with 300 ml of ice water. The precipitate formed was filtered off, washed with chlorobenzene and air dried. This precipitate was suspended in methanol, filtered, washed again with methanol and dried. The precipitate recovered weighed 3.6-0.0 g corresponding to a yield of k2-hrJ%. Examples IV-XIX: Temperature, concentration and reaction time variations

Table A lists a number of further experiments, which were performed as methods according to Examples II and III, although variations in temperature upon addition of BBr 1 and BC 1, reaction temperature after addition, duration of reaction and The yields occurred, all in accordance with table A. Some of the results, especially in the first trials, do not agree with results achieved later. The reasons for these differences are not yet clear, although probably lack of experience with this reaction played a role and the fact that an isolated material initially turned out not to be a product material. In later runs, as shown, good product yields were obtained.

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8020319

Claims (10)

1. Compounds useful in preparing nalbuphine and nalbuphine-type compounds of the formula (II), wherein R represents a hydrocarbon group having up to 6 carbon atoms. Compounds according to claim 1, characterized in that R is saturated 5 and has 3 to 6 carbon atoms. Compounds according to claim 2, characterized in that R represents cyclopropyl, cyclopentyl or cyclobutyl. U. Compounds according to claim 3, characterized in that R is cyclobutyl. 5. Process for preparing amide compounds of the formula II of the formula sheet, wherein R represents a hydrocarbon group with up to 6 carbon atoms, characterized in that first an amide of the formula 3, wherein R is a hydrocarbon group with at most 6 ". is carbon atoms with a demethylating amount of a boron demethylating agent in a reaction medium under demethylating conditions. 6. Process according to claim 5, characterized in that the boron demethylating agent is formed by boron tribromide, boron trichloride and the reaction products of this kind of halides with an alcohol and is used in an amount of 2.5-8 mol boron compound per mole of amide compound. A method according to claim 6, characterized in that the boron compound is boron tribromide or boron trichloride. 8. Process according to claim 7, characterized in that the demethylation conditions comprise temperatures between 0 and H0 ° C. 9. Process according to claims 5-8, characterized in that R is saturated and has 3-6 carbon atoms. Process according to claims 6-8, characterized in that R is cyclopropyl, cyclobutyl or cyclopentyl. 11. Process according to claims 5-8, characterized in that R is cyclo butyl. 8020319