The invention relates to novel intermediate compounds useful in the preparation of morphine derivatives and to a process for preparing these compounds .

The compounds of the present invention are intermediates that may be reduced to form morphine derivative product compounds which do not possess known undesirable side effects of morphine, for example respiratory depression and the like. These product compounds are of the type disclosed in Pachter et al; U. S. Patent 3,393,197; issued July 16, 1968, and such compounds may have the following general structural formula:

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

A presently-used synthesis of nalbuphine and nalbuphine-type compounds from oxycodone, a readily available starting material, is represented in Figure 1. According to the processes, oxycodone is deme hylated to form oxymorphone, for instance, as described in Wilson's

U.S. Patent Application Serial No. 953,056, filed October 19, 1978, now international application No. PCT/US 79/008 The oxycodone-oxymorphone conversion, the first step in Figure 1, takes from about 3 to 18 hours at room temperature in the presence of a boron compound demethylating agent, or about 1 hour at about 190°C. in the presence of pyridine hydrochloride. Oxymorphone is then converted to noroxymorphone which in turn is acetylated to form a eyelobutylamide intermediate (Ester Amide III). Acetylation is accomplished by a reaction between cyclobutane carboxylic acid and ethyl chloroformate to form a mixed anhydride which subsequently reacts with noroxymorphone to form the ester amide which may be reduced with lithium aluminum hydride to form the product nalbuphine or a nalbuphine- type compound.

Although this process has value, certain problems are associated with it. The oxycodone-oxymorphone conversion may be quite time-consuming and this is undesirable in a commercial process. The formation of the eyelobutylamide intermediate utilizing the reaction between cyclobutane carboxylic acid and ethyl chloroformate to form a mixed anhydride which subsequently reacts with noroxymorphone to form the amide, is a rather slow reaction. It would accordingly be highly desirable to use, for instance, cyclobutyryl chloride to form the amide directly, rather than the mixed anhydride, to give faster reaction times. Also, because of the complexity and side reactions of working with a noroxymorphone intermediate, a change in the order of reaction steps offers potential advantages in both yields and throughputs.

Accordingly, the present invention relates to an N- acyl-dihydro-14-hydroxynormorphone intermediate compound (herein Intermediate Amide II) useful in the preparation of nalbuphine and nalbuphine-type product

compounds. Intermediate Amide II has the following general structural formula:

Intermediate Amide II

wherein R is a hydrocarbyl group of up to about 6 carbon atoms. In preferred embodiments of the present invention, the substituent designated R in the structure of Intermediate Amide II is saturated and may have up to about 6 carbon atoms, preferably about 3 to 6 carbon atoms. Thus R may be alkyl of up to about 6 carbon atoms, preferably cycloalkyl of 3 to about 6 carbon atoms, e.g., cyclopropyl, cyclobutyl and cyclopentyl; especially cyclobutyl.

A new synthetic route, represented in Figure 2, for the preparation of nalbuphine and nalbuphine-type compounds from oxycodone has also been developed. This route includes the preparation of the novel 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 in turn acylated, forming a first intermediate amide (Intermediate Amide I in Figure 2). The first intermediate amide, which need not be isolated, is then demethylated to form a second intermediate amide (Intermediate Amide II in Figure 2) which may be isolated and reduced to form the product nalbuphine or nalbuphine-type compounds. The demethylation of the Intermediate Amide I material to

the Intermediate Amide II materials is a major departure from previous schemes for the preparation of nalbuphine and nalbuphine-type compounds, and the Intermediate Amide II materials are novel compounds. By utilizing this new synthesis route involving the novel intermediate amides of the present invention, nalbuphine and nalbuphine-type compounds can be produced in improved yields under milder reaction conditions and with shorter reaction times in comparison with known 0 synthesis procedures such as set forth in Figure 1.

In accordance with this new demethylation process the methyl group is removed from the methoxy substituent of a first intermediate amide compound (Intermediate Amide I) having the following structural formula:

Intermed iate Amide I

5 wherein R is as defined in the Intermediate Amide II structural formula above by reacting Intermediate Amide I with a demethylating agent under suitable conditions whereby the Intermediate Amide II is produced. The reaction is conducted under demethylating conditions which may be mild, and the reaction may, for instance, be run at temperatures of from about 0° to 40°C.

Isolation of the Intermediate Amide II is simple and straightforward, and it may be accomplished by simple precipitation with no further extraction necessary to remove starting material (ethers). This single separation is in marked contrast to the

separation of other phenol-containing compounds of this general type from their corresponding ethers. The overall yield of morphine-type product from the oxycodone starting material may be as much as about 40% or more which is an improvement over the oxycodone- oxymorphone type process described above and in Figure 1.

In preparing the Intermediate Amide II compounds, a demethylating amount of a suitable agent is used, for instance, a boron compound. The agent is capable of demethylating the methoxy group but incapable of forming numerous undesired byproducts. The boron compounds include the boron halides such as boron tribromide, boron trichloride or the reaction product of such halides with alcohols, i.e., those containing 1 to 10 carbon atoms, preferably lower alcohols containing 1 to 6 carbon atoms, e.g., methanol, propanol, butanol, hexanol, etc. The preferred demethylating agent is boron tribromide which is somewhat more active compared, for instance, to boron trichloride demethylating agent. The demethylating agent may be present in an amount from about 2.5 to 8 moles, preferably about 3.5 to 6.5 moles, e.g. about 6 moles, of the demethylating agent per mole of Intermediate Amide I. No significant advantage is achieved by using somewhat more than about 8 moles. Utilizing less than about 2.5 moles may result in incomplete reaction.

The demethylating conditions include suitable reaction times, for example, from about 0.5 to 4 hours in batch procedures, and reaction temperatures, e.g., about 0°C. to 40°C, preferably about 15°C. to 25°C.- In this regard the temperature of the reaction medium to which the demethylating agent may be added may be from about -25°C. to +20°C, preferably about +10°C. to +20°C. After 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 undue temperature increases. Higher temperatures of the reaction medium may result in lower yields of the Intermediate Amide II product. It may be advantageous in this regard to provide in the reaction medium an essentially inert solvent that will not react with the demethylating agent, e.g., chlorobenzene. The demethylating agent can be incorporated in the solvent and the solution combined with the Intermediate Amide I reactant. Alternatively, the demethylating agent and solvent can be added to the reaction medium separately. For example, Intermediate Amide I can simply be mixed with the demethylating agent. Recovery of Intermediate Amide II may be accomplished by simple precipitation with no further extraction being necessary to remove starting materials. This is a distinct advantage of the present invention as compared to other processes for preparing nalbuphine and nalbuphine-type compounds. Overall, yields of

-nalbuphine and nalbuphine-type compounds from oxycodone by the process of .the present invention may be approximately 40% or more versus 34% or less for the presently available processes. The following examples illustrate the invention. All parts are by weight unless otherwise stated.

EXAMPLE I

PREPARATION OF INTERMEDIATE AMIDE I

To a 500 ml flask are added 200 ml of anhydrous tetrahydrofuran (THF) and 6.5 g of ethylchloroformate. The mixture is cooled to 5°C. To this flask, a mixture containing 6 g of cyclobutane carboxylic acid, 8.5 ml of triethyla ine and 50 ml of THF is slowly added. The temperature should not rise above 10°C. during this

- OTM fPoIr

addition. With stirring, the mixture is allowed to rise to 20-25°C. over a 1-2 hr period. The triethylamine salt is filtered off and 14 gms of noroxycodone and 1.5 ml of triethylamine are added to the solution. The mixture is stirred for 1-2 hrs at room temperature. The THF is evaporated and the resulting product is diluted to 200 ml with chlorobenzene.

EXAMPLE II CLEAVAGE OF INTERMEDIATE AMIDE I WITH BORON TRIBROMIDE

One hundred milliliters of the Intermediate Amide I solution as prepared in Example I are 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 such that the temperature of the mixture should not rise above 20°C. The molar ratio of BBr,. to Intermediate Amide I in the flask can range from about 2.8 to 5.1:1. The mixture is stirred at 20- 25°C. for 30 minutes and quenched by adding the mixture to 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 recovered weighs 4.4 to 4.9 grams, representing 51 to 57% yields based on noroxycodone.

EXAMPLE III

CLEAVAGE OF INTERMEDIATE AMIDE I WITH BORON TRICHLORIDE

One hundred milliliters of the Intermediate Amide I solution as prepared in Example I are added to a 500 ml flask and cooled to 10-15°C. While cooling such a solution, a solution of boron trichloride is prepared by introducing boron trichloride gas to 100 ml of

OMPI

- 8 -

chlorobenzene. The boron trichloride solution so formed is added to the Example I cooled solution keeping the temperature below 20°C. The molar ratio of BCl^ to Intermediate Amide A in the flask is about 7.7:1. The reaction mixture is stirred for four hours at 20°-25°C. and quenched in 300 ml of ice water. 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 recovered weighs 3.6 4.0 grams, representing a 42-47% yield based on noroxycodone.

EXAMPLES IV - XIX

TEMPERATURE, CONCENTRATION AND REACTION TIME VARIATION

Table 1 illustrates additional runs which were conducted using procedures similar to those set forth in Examples II and III, although there were variations in temperature of addition of BBr.. and BC1-, temperature of reaction after addition, time of reaction and product yield, all as set forth in Table 1. Some of the results, especially in the earlier runs, are not consistent with results later achieved. The reasons for these discrepancies are not fully understood, although they can be attributed at least in part to a lack of experience in performing the reaction at the outset and to the fact that a material that was being isolated initially was not actually product material. In the later runs, as illustrated, good yields of product were achieved.

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Table 1.

Run Mole Ratio Temperature Temperature Time of Amide II Amide II

Number of BBr ₃ Addition of of Reaction Reaction Product Product (BC1 ₃ if BBr ₃ (BCI3) After Addi¬ After Addi¬ Yield from Yield from . Stated) to to Mixture tion tion of Amide I Noroxycodone ^■ Amide I BBr ₃ (BCI3) i IV 3.6 6 to 20°C 27°C 4 hrs 1% —

V 3.6 15 to 24°C 27°C 3 hrs ca. 1% —

',' VI 3.6 8 to 10°C 5-6°C 1 hr 55% 34%

' VII 4 5 to 9°C 4°C 1 hr 35% 21.7%

VIII 2.6 8 to 12°C 27-30°C 4 hrs 39% 24.2%

IX 2.96 6 to 9°C 4-10°C 11 in 31% ^• 19.2% ! ^' X 3.1 8 to 15°C 7°C 1 hr 10 min 38.5% 23.9%

1, XI 3.8 (BCl ) 6 to 11°C 10-12°C 4 hrs 55 min 1% --

XII 6 0 to -20°C 0-2°C 54 min 52% 32%

1 XIII 6 -16 to -12° C 0°C 64 min 55% 34% σ XIV 6 -24 to -20° C 0°C 34 min 65% 41%

1 XV 8 -18 to -25° C 0°C 15 min not isolated 55%

XVI 8 +15 to +17° C 20°C 30 min not isolated 49%

XVII 4 +15 to +18° C 20°C 30 min not isolated 50%

XVIII 2.6 +15 to +18° C 20°C 30 min not isolated 19%

XIX 7.0 +10 to +16° C 20-25°C 4 hrs not isolated 42%