NO802139L - OUTPUT CONNECTIONS FOR PREPARING MORPHINE DERIVATIVES, AND PROCEDURE FOR PREPARING OUTPUT - Google Patents

Description

The present invention relates to new intermediate products suitable for use in the production of morphine derivatives,

as well as the method for producing the intermediate products.

The compounds present are intermediates such as

can be reduced to form morphine derivatives that do not have the unwanted side effects of morphine, e.g. reduction of breathing and the like. These intermediates are of the type described in US Patent No. 3,393,197, and such compounds have the following general formula:

where R is an aliphatic group. A particularly useful compound from the above group is known as nalbuphine (where R in the formula is cyclobutyl).

A useful synthesis for nalbuphine and nalbuphine-like compounds from oxycodone, an easily available starting material, can be represented as follows:

According to the processes, oxycodone is demethylated to form oxymorphone, e.g. as described in US Application No. 953056 (International Application No. PCT/US 79/00862. The oxycodone-oxymorphone conversion, the first step in the above reaction scheme takes from about 3 to 18 hours at room temperature in the presence of a boron -demethylating agent, or about 1 hour at about 190°C in the presence of pyridine hydrochloride. Oxymorphone is then converted to noroxymorphone which is again acetylated to form a cyclobutylamide intermediate (esteramide III). Acetylation is achieved by reaction between cyclobutanecarboxylic acid and ethyl chloroformate for forming a mixed anhydride which then reacts with noroxymorphone to form the ester amide which can be reduced with lithium aluminum hydride to form the product nalbuphine or a nalbuphine-type compound.

Although this process is of value, it is associated with certain problems. The oxycodone-oxymorphone conversion can be quite time consuming and this is undesirable in a commercial process ^ The formation of the cyclobutylamide intermediate using the reaction between cyclobutadienecarboxylic acid and ethyl chloroformate to form a mixed anhydride which then reacts with noroxymorphone to form the amide , is a rather slow reaction. It would therefore be highly desirable e.g. to use cyclobutyryl chloride for direct formation of the amide instead of the mixed anhydride, so that faster reaction times are obtained. Furthermore, due to the complex conditions and side reactions when working with a noroxymorphone intermediate, a change in the sequence of reaction steps offers potential advantages in both yields and turnover.

The present invention relates to an N-acyl-dihydro-14-hydroxynormorphone intermediate (hereinafter referred to as intermediate amide II) which is useful in the production of nalbuphine and products of the nalbuphine type. Intermediate amide II has the following general formula.

where R is a hydrocarbyl group with up to approx. 6 carbon atoms.

In preferred embodiments of the invention, the group R in intermediate amide II is saturated and can have up to approx. 6 carbon atoms, preferably approx. 3-6 carbon atoms. R can thus be alkyl with up to approx. 6 carbon atoms, preferably cycloalkyl with from 3 to approx. 6 carbon atoms, e.g. cyclopropyl, cyclobutyl and cyclopentyl, especially cyclobuty 1.

For the production of nalbuphine and compounds of the nalbuphine type from oxycodone, a new synthetic pathway has also been developed which can be represented by the following reaction core:

This reaction pathway includes the preparation of the new intermediate amide II compounds. According to this new synthesis, oxycodone is first converted in the presence of CNBr and sulfuric acid to noroxycodone which is then acylated to form a first intermediate amide (intermediate amide I in the above reaction scheme). The first intermediate amide/which does not need to be isolated becomes then demethylated to form another intermediate amide (intermediate amide II in the reaction scheme) which can be isolated and reduced to form nalbuphine or compounds of the nalbuphine type. The demethylation of intermediate amide I compounds to intermediate amide II compounds represents a major departure from previous synthesis routes for the production of nalbuphine and compounds of the nalbuphine type, and the intermediate amide II compounds are new compounds. By using this new synthesis route, the new intermediate product amides according to the present invention comprise. can nalbuphine and compounds of the nalbuphine type. are produced in improved yields under milder reaction conditions and with shorter reaction times compared to known synthesis methods as indicated in the first reaction scheme indicated above.

According to this new demethylation process, the methyl group is removed from the methoxy substituent in a first intermediate amide compound (intermediate amide I) which has the following formula:

where R has the meaning given in connection with the formula for intermediate product amide II, by reacting intermediate product amide I with a demethylating agent under suitable conditions whereby intermediate product amide II is produced. The reaction is carried out under demethylation conditions which can be mild, and the reaction can e.g. carried out at temperatures from approx. 0 to 40°C.

Isolation of intermediate amide II is simple and straightforward, and can be achieved by simple precipitation without the need for any further extraction to remove the starting material (ethers). This easy separation is in marked contrast to the separation of other phenolic compounds of this general type from their corresponding ethers. The total yield of the morphine-type product from the oxycodone starting material can be as much as approx. 40% or more which is an improvement over the oxycodone-oxymorphone process as described above and illustrated in the first indicated reaction core.

When preparing the intermediate amide II compounds, a demethylating amount of a suitable agent is used, e.g. a boron compound. The agent can demethylate the methoxy group, but cannot form more unwanted by-products. The boron compounds include the boron halides such as boron tribromide, boron trichloride and the reaction product of such halides with alcohols, i.e. those containing 1-10 carbon atoms, preferably lower alcohols containing 1-6 carbon atoms, e.g. methanol, propanol, butanol, hexanol, etc. The preferred demethylating agent is boron tribromide which is somewhat more active compared to the demethylating agent boron trichloride. The demethylating agent can be present in an amount of from approx. 2.5 to 8 mol, preferably approx. 3.5 to 6.5 moles, e.g. about. 6 mol, of the demethylating agent per mol of intermediate amide I. No particular advantage is obtained by using anything more than about 8 mol. Application of less than approx. 2.5 mol may result in incomplete reaction.

The demethylation conditions include suitable reaction times, e.g. from approx. 0.5 to 4 hours in batch methods, and reaction temperatures, e.g. from approx. 0 to 40°C, . preferably from approx. 15 to 25°C. In this connection, it should be mentioned that the temperature of the reaction medium to which the demethylating agent can be added can be from approx. -25 to +20°C, preferably from approx. +10 to +20°C. After the intermediate amide I and the demethylating agent are combined, the heat of reaction may result in an increase in the temperature of the reaction medium, although the temperature may be controlled to avoid inappropriate temperature increases. High temperatures in the reaction medium can result in lower yields of intermediate amide II. In this connection, it can be advantageous to use a substantially inert solvent in the reaction medium which will not react with the demethylating agent, e.g. the chlorloene. The demethylating agent can be incorporated into the solvent and the solution combined with the intermediate amide I reactant. Alternatively, the demethylating agent and the solvent can be added to the reaction medium separately. Intermediate amide I can e.g. simply mixed with the demethylating agent; •Recovery of intermediate amide II can be achieved by simple precipitation without at. additional extraction is required to remove starting materials. This is a significant advantage of the present invention compared to other processes for the production of nalbuphine and compounds of the nalbuphine type. In total, yields of nalbuphine and compounds of the nalbuphine type from oxycodone by the present method can be about 40% or more in relation to 34% or less for the previously known processes.

The following examples illustrate the invention, and all part statements are calculated by weight unless otherwise stated.

Example I

Preparation of intermediate amide I

200 ml of anhydrous tetrahydrofuran (THF) and 6.5 g of ethyl chloroformate are added to a 500 ml flask. The mixture is cooled to 5°C. A mixture containing 6 g of cyclobutanecarboxylic acid, 8.5 ml of triethylamine and 50 ml of THF is slowly added to this flask. The temperature should not rise above 10°C during this addition. During stirring, the temperature of the mixture is allowed to rise to 20-25°C over a period of 1-2 hours. The triethylamine salt is filtered off and 14 g of noroxycodone and 1.5 ml of triethylamine are added to the solution. The mixture is stirred for 1-2 hours at room temperature. The THF material is evaporated and the resulting product is diluted with 200 ml of chlorobenzene.

Example II

Cleavage of intermediate amide I with boron tribromide

100 ml of intermediate amide I solution as prepared in Example I is added to a 500 ml flask and cooled to 10-15°C. A mixture containing 100 ml of chlorobenzene and 6-11 ml of BBr^ is slowly added to the flask so that the temperature in the mixture does not rise above 20°C The molar ratio between BBr^ and intermediate amide I in the flask

can vary from approx. 2.8 to 5.1:1. The mixture is stirred at 20-25°C for 30 min. and quench by adding the mixture to 300 ml of ice water. The solid substance is filtered off, washed with chlorobenzene and air-dried. The solid is then slurried in methanol, filtered, washed again with methanol and dried. The recovered solid weighs 4.4-4.9 g, representing yields of 51-57% based on noroxycodone.

Example III

Cleavage of intermediate amide I with boron trichloride

100 ml of intermediate amide I solution as prepared in example I is added to a 500 ml flask and cooled to 10-15°. While this solution is cooling, a solution of boron trichloride is prepared by introducing boron trichloride gas into 100 ml of chlorobenzene. The boron trichloride solution thus formed is added to the cooled solution from example I while the temperature is kept below 20°C. The molar ratio between BCl^ and -intermediate amide A in the flask is approx. 7.7:1. The reaction mixture is stirred for 4 hours at 20-25°C and quenched in 300 ml of ice water. The solid is filtered off, washed with chlorobenzene and air-dried. The solid is then slurried in methanol, filtered, washed again with methanol and dried. The solid obtained weighs 3.6-4.0 g, which represents a yield of 42-47% based on noroxycodone.

Examples IV - XIX

Variation of temperature, concentration and reaction time

Table 1 illustrates further experiments which were carried out using methods similar to those set out in Examples II and III, although there were variations in addition temperature for BBr 2 and BCl 2 , reaction temperature after addition, reaction time and pro - duct yield, all indicated in table 1. Some of the results, especially in the first attempts, are not in accordance with the results that were later obtained. The reason for

.these differences are not fully understood, although they may be attributed, at least in part, to a lack of experience in performing the reaction at the outset and the fact that a material initially isolated does not actually

was product material. In the later experiments, as illustrated, good yields of the product were obtained.

Claims (10)

1.. Compounds for use in the production of nalbuphine and compounds of the nalbuphine type, characterized in that they have the general formula: where R is hydrocarbyl with up to approx. 6 carbon atoms. 2. Compounds according to claim 1, characterized in that R is saturated and contains from approx. 3 ■to 6 carbon atoms. 3. Compounds according to claim 2, characterized in that R is selected from cyclopropyl, cyclopene tyl and cyclobutyl. 4. Compound according to claim 3, characterized in that R is cyclobutyl. 5. Process for the production of amide compounds with the general formula: where R is hydrocarbyl with up to approx. 6 carbon atoms, characterized by converting a first amide with the general formula: where R is hydrocarbyl with up to approx. 6 carbon atoms, with a demethylating amount of a boron demethylating agent in a reaction medium under demethylating conditions. 6. Method according to claim 5, characterized in that the boron demethylation compound is selected from the group consisting of boron tribromide, boron trichloride and. the reaction products of such halides with a lower alcohol, and is used in an amount to provide from approx. 2.5 to approx. 8 mol of the boron compound per moles of said amide compound. 7. Process according to claim 6, characterized in that the boron compound is boron tribromide or boron trichloride. 8. Method according to claim 7, characterized in that the demethylation conditions include temperatures of from approx. 0 to approx. 40°C. 9. Method according to claim 5, 6, 7 or .8, . characterized ' in that R is saturated and contains from approx. 3 to 6 carbon atoms. 10. Method according to claim 5, 6, 7 or 8, characterized in that R is selected from the group consisting of cyclopropyl, cyclobutyl and cyclopentyl, preferably cyclobutyl.