FR2465735A1 - INTERMEDIATE COMPOUNDS FOR THE PREPARATION OF MORPHINE DERIVATIVES, AND PROCESS FOR THEIR PREPARATION - Google Patents

Abstract

THE INTERMEDIARIES ARE N-ACYL-DIHYDRO-14-HYDROXYNORMORPHONES SUCH AS N- (CYCLOALKYLCARBONYL) -DIHYDRO-14-HYDROXYNORMORPHONES, AND A PROCESS FOR PREPARING THEM IS ALSO DESCRIBED. THE MORPHINE DERIVATIVES OBTAINED, WHICH ARE ANTAGONISTS OF NARCOTICS AND ANALGESICS, INCLUDE IN PARTICULAR NALBUPHINE AND NALBUPHINE-TYPE COMPOUNDS.

Description

Intermediate compounds for the preparation of morphine derivatives,

  The present invention relates to novel intermediates useful for the preparation of morphine derivatives, as well as to a process for preparing such compounds. The compounds according to the present invention are intermediates which can be reduced to form compounds derived from morphine which do not possess known undesirable side effects of morphine, for example respiratory failure and similar effects. These compounds are of the type described in U.S. Patent No. 3,393,197 and may have the following general structural formula:

UV

  Ho oR wherein R is an aliphatic group. A particularly useful compound selected from the above group is known as "nalbuphine" (R is then the cyclobutyl radical). A currently used synthesis method of nalbuphine and nalbuphine compounds from oxycodone, a readily available starting material, is shown in Figure 1 attached. According to this process, oxycodone is demethylated to form oxymorphone, as described, for example, in U.S. Patent Application No. 953,056 filed October 19, 1978, now International Application No. PCT / US 79/00862. The conversion of oxycodone to oxymorphone, the first step of Figure 1, takes about 3 to 18 hours at room temperature in the presence of a demethylating agent which is a boron compound, or about 1 hour at 190 ° C. approximately, in the presence of pyridine hydrochloride. The oxymorphone is then converted into noroxymorphone which is then acetylated to form

  an intermediate cyclobutylamide (amide ester III). The acetylation

  The reaction is carried out by reaction between cyclobutane carboxylic acid and ethyl chloroformate with the formation of a mixed anhydride which then reacts with noroxymorphone to form the amide ester which can be reduced by hydride. of lithium and aluminum, to form the product, the nalbuphine

or a compound of the nalbuphine type.

  This process is interesting, but it poses certain problems.

  my. It may take a long time to convert oxycodone to oxymorphone, and this is undesirable in a

  industrial process. The formation of cyclobutylamide

  mediated by the reaction between cyclic acid

  butane-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 therefore be extremely desirable to use, for example, cyclobutyryl chloride to directly form amide instead of mixed anhydride to have higher reaction rates. On the other hand, because of the complexity and side reactions involved in the use of an intermediate noroxymorphone, a change in the order of the reaction steps offers potential advantages both from the point of view of the yields.

that abilities.

  Accordingly, the present invention relates to an intermediate Nacyl-dihydro-14-hydroxynormorphone compound (herein referred to as "intermediate amide II") usable for the

  Preparation of nalbuphine and nalbuphine compounds

  Intermediate amide II has the following general structural formula: HO

O

N-C-R Intermediate Amide II

  wherein R is a "hydrocarbyl" group (hydro-

  carbon) having up to about 6 carbon atoms.

  In the preferred embodiments of the invention the substituent designated R in the expanded formula of intermediate amide II is saturated and may have up to about 6 carbon atoms, preferably about 3 to 6 carbon atoms. carbon. This is how R can be a radical

  alkyl having up to about 6 carbon atoms, preferably

  cycloalkyl radical of 3 to about 6 carbon atoms, for example cyclopropyl, cyclobutyl,

  or cyclopentyl, and in particular the cyclobutyl radical.

  A new synthetic route, shown in Figure 2 attached, for the preparation of nalbuphine and nalbuphine-type compounds from oxycodone

  has also been developed. This path includes the preparation

  ration of the new compounds called intermediate amides II. According to this new synthetic route, oxycodone is first converted, in the presence of CNBr cyanogen bromide and sulfuric acid, to noroxycodone which is in turn acylated to form a first intermediate amide (intermediate amide I on Figure 2). This first intermediate amide, which does not need to be isolated, is then demethylated to form a second intermediate amide (intermediate amide II in FIG. 2) which can be isolated and reduced to form the product, nalbuphine or a compound of the nalbuphine type. The demethylation of intermediate amides I to intermediate amides II is a major innovation over previous schemes for the preparation of nalbuphine and nalbuphine compounds, and intermediate amides II are novel compounds. Using this new synthetic route using the novel intermediate amides according to the present invention, it is possible to obtain nalbuphine and nalbuphine compounds in higher yields under milder reaction conditions and longer reaction times. brief, compared to known synthetic processes such as

  than the one shown in Figure 1.

  According to this new demethylation process, the methyl group of the methoxy substituent of a first intermediate amide (intermediate amide I) having the following structural formula is removed

C C3 | "HIO

10. \ l

t <t LN-C-R -

  Intermediate Amide I in which R has the same definition as in the above structural formula of intermediate amide II by reacting amide intermediate I with a demethylating agent under appropriate conditions to obtain the intermediate amide II. This reaction is carried out in demethylation conditions which may be mild, and the reaction may for example be carried out

  temperatures from about 0 to 40 ° C.

  The isolation of the intermediate amide II is simple and straightforward, and can be done by simple precipitation, without any further extraction being necessary to remove the starting material (ethers). This unique separation represents a marked contrast with the separation of the other phenol-containing compounds of this general type from their corresponding ethers. The overall yield of the morphine product from the starting oxycodone can be up to about 40% or more, which is an improvement over the oxycodone-oxymorphone type process described above and

Figure 1.

  To prepare intermediate amides II, a demethylating amount of a suitable agent, a boron compound for example, is used. This agent is capable of demethylating the

  methoxy group but unable to form many sub-

  undesirable products. The boron compounds include boron halides such as boron tribromide, boron trichloride or the product of the reaction thereof.

  halides with alcohols, that is to say those containing

  from 1 to 10 carbon atoms, preferably lower alcohols containing from 1 to 6 carbon atoms, for example

  methanol, propanol, butanol, hexanol, etc.

  The preferred demethylating agent is boron tribromide which is slightly more active as a demethylating agent than boron trichloride, for example. The demethylating agent may be present

  in an amount of from about 2.5 to about 8 moles, preferably

  from about 3.5 to about 6.5 moles, for example about 6 moles, per mole of intermediate amide I.

  significant advantage when using more than 8 moles.

  Use of less than about 2.5 moles may result

by an incomplete reaction.

  The demethylation conditions include appropriate reaction times, for example about 0.5 to 4 hours in the batch procedures, and suitable reaction temperatures, for example, about 0 ° C to 40 ° C, preferably about 150 ° C to about 40 ° C. 250C. In this respect, the temperature

  of the reaction medium to which the demethylating agent can be added

  lant can be from about -250C to + 20C, preferably from about +100C to +200C. After the intermediate amide I and the demethylating agent have combined, the heat of

  reaction can result in an increase in the temperature

  ture of the reaction medium, but this temperature can be regulated

  erature in order to avoid temperature increases

  excessive. Higher temperatures of the reaction medium

  These can result in a decrease in the yield of intermediate amide II. It can be advantageous to this

  to provide in the reaction medium a solvent practically

  inert which does not react with the demethylating agent, chlorobenzene for example. The demethylating agent can be incorporated into the solvent and the solution can be combined with the amide

  intermediate I that reacts. Or, we can add separately

  the demethylating agent and the solvent to the reaction medium.

  For example, you can simply mix the amide inter-

  I with the demethylating agent.

  The recovery of the intermediate amide II can be done by simple precipitation, without any further extraction being necessary to remove the starting materials. This represents a clear advantage of the present invention over other processes for preparing nalbuphine and

  compounds of the nalbuphine type. The overall yield in Nalbu-

  phine and nalbuphine-type compounds compared to oxy-

  The codon, by the method according to the present invention, may be about 40% or more, compared to 34% or less for

  processes currently available.

  The following examples serve to illustrate the invention.

  All parts are by weight unless otherwise indicated.

EXAMPLE I

  Preparation of the intermediate amide I

  In a 500 ml flask, 200 ml of

  anhydrous hydrofuran (THF) and 6.5 g of ethyl chloroformate.

  Cool the mixture to 5 C. In this balloon, we add

  a mixture containing 6 g of cyclobutane

  carboxylic acid, 8.5 ml of triethylamine and 50 ml of THF. The temperature must not rise above 10 C during this addition. With stirring, the temperature of the mixture is allowed to rise to 20-25 C in one to two hours. The triethylamine salt is separated by filtration and added to the

  solution 14 g of noroxycodone and 1.5 ml of triethylamine.

  The mixture is stirred for one to two hours at room temperature.

  ambient temperature. The THF is evaporated and the

  resulting product to 200 ml with chlorobenzene.

EXAMPLE II

  Cleavage (cleavage) of the intermediate amide I with boron tribromide 100 ml of the intermediate amide solution I are added

  prepared in Example I to a 500 ml flask, and cooled

  10-15 ° C. A mixture containing 100 ml of chlorobenzene and 6 to 11 ml of boron tribromide is slowly added to the flask, so that the temperature of the mixture does not rise.

  does not rise above 20 C. The molar ratio of

  boron mildew to the intermediate amide I in the flask can i

P465735

  be between about 2.8 and 5.1 / 1. The mixture is stirred at 20 ° C. for 30 minutes and cooled rapidly by adding it to 300 ml of ice water. The solid is filtered off, washed with chlorobenzene and dried in air. The solid is then stirred into methanol, filtered, washed again with methanol and

  dried. The recovered solid weighs 4.4 to 4.9 g, which represents

  It has a yield of 51 to 57% relative to noroxycodone.

EXAMPLE III

  Cleavage of intermediate amide I with boron trichloride 100 ml of the intermediate amide solution I prepared in Example I are added to a 500 ml flask and cooled to 10-150 ° C. While cooling this solution,

  a solution of boron trichloride is prepared by introducing

  boron trichloride gas in 100 ml chlorine

  benzene. The boron trichloride solution thus formed is added to the cooled solution of Example I, keeping the temperature below 200C. The molar ratio of boron trichloride to intermediate amide I in the flask is about 7.7 / 1. The reaction mixture is stirred for 4 hours at 20.degree.-25.degree. C. and cooled rapidly in 300 ml of ice water. The solid is separated by filtration,

  it is washed with chlorobenzene and air dried.

  The solid is then stirred into methanol, filtered, washed again with methanol and dried. The recovered solid weighs 3.6 to 4.0 g, which represents a

  yield of 42 to 47% compared to noroxycodone.

EXAMPLES IV A XIX

  Variations in temperature, concentration and reaction time

  Table I below illustrates the additional tests

  which were carried out using operational modes

  similar to those shown in Examples II and III, but by varying the addition temperature of boron tribromide and boron trichloride, the reaction temperature after addition, the reaction time and the product yield, the whole. being shown in Table I. Some of the results, especially in the first tests, do not agree with the results obtained later. The reasons for these discrepancies are not fully understood, but can be attributed at least in part to a lack of experience in the initial implementation of the reaction, and to the fact that a product that had initially been isolated was not really the desired product. In the latest tests, as shown in

  Table I, good product yields were obtained.

TABLE I

  N of the test Molar ratio of BBr (or BC13) to amide I IV VI VI VIII VIII IX XI XII XIII xviii xviii X XV XV XVII XVIII XIX 3,6 3,6 3,6 2,6 2.96 3.1

3.8 (BC13)

  2.6 7.0 Temperature Addition temperature of reaction after BBr3 (BC13) to mixture addition

6 to 20 C

at 24 C

8 to 10 C

at 9 C

8 to 12 C

6 to 9 C

8 to 15 C

6 to 11 C

0 to -20 C

-16 to -12 C

-24 to -20 C

-18 to -25 C

+15 to +17 C

+15 to +18 C

+15 to +18 C

+ 10 to +16 C

27 C 270C -60C 4 C

27-30 C

4-10 C

  7 C -12 C 0-2 C 0 C 00 C 00 CC QC C -25 C Reaction time after addition of BBr3 (BC13) 4h 3h 1 h 1 h 4h 11 min 1 h 10 min 4 h 55 min 54 min 64 min. 34 min. min. mn. min. 4 h. Amide II yield relative to amide I 1% approx. 1%%% 39% 31%

38.5%

  1% 52%%% not isolated not isolated not isolated not isolated not isolated Yield of amide II relative to noroxycodone 34% 21.7 24.2 19.2 23.9 32% 34% 41%% 49%% 19 % 42%%%%%% 0t, '- "I vn

Claims (11)

  1. Compounds usable for the preparation of nalbuphine and nalbuphine compounds, characterized by the following structural formula: OH 0   in which R is a hydrocarbon radical having up to About 6 carbon atoms.   2. Compounds according to claim 1, characterized in that R is saturated and contains from about 3 to 6 atoms of carbon.   3. Compounds according to claim 2, characterized in that R is a cyclopropyl, cyclopentyl or cyclobutyl radical. 4. Compound according to claim 3, characterized   in that R is the cyclobutyl radical.   5. A process for the preparation of amides having the following structural formula: HO DE-N-C-R J-; in which R is a hydro carbon radical having up to about 6 carbon atoms, characterized in that a first amide having the following structural formula is reacted: CH 3 OH O i N-C-R   wherein R is a hydrocarbon radical having up to about 156 carbon atoms, with a suitable amount of a demethylating agent which is a boron compound, in which   a reaction medium, under demethylation conditions.   6. Process according to claim 5, characterized in that the boron compound used as demethylating agent is boron tribromide, boron trichloride or the product of the reaction of boron tribromide or boron trichloride with a lower alcohol, and in that it is used in an amount such that there is from about 2.5 to about 8   moles of the boron compound per mole of said first amide.   7. Process according to claim 6, characterized in that said boron compound is boron tribromide or boron trichloride.   8. Process according to claim 7, characterized in that the demethylation conditions comprise   temperatures from about 0 C to about 40 C.   9. Process according to claim 5, 6, 7 or 8, characterized in that R is saturated and contains about 3 to 6 carbon atoms.   10. Process according to claim 5, 6, 7 or 8, characterized in that R is a cyclopropyl radical, cyclobutyl, or cyclopentyl.   11. The method of claim 5, 6, 7 or 8,   characterized in that R is the cyclobutyl radical.