阅读说明：本技术 用于从14-羟可待因酮制备盐酸氧可酮的氢化方法 (Hydrogenation process for the preparation of oxycodone hydrochloride from 14-hydroxycodeinone ) 是由 P·戈夫罗 于 2018-06-12 设计创作，主要内容包括：一种制备盐酸氧可酮的方法,所述方法包括在醇类溶剂和盐酸中将14-羟可待因酮氢化以形成盐酸氧可酮,其中(a)氢化在非均相铂族金属(PGM)催化剂和氢气的存在下进行,(b)氢化在氢化催化剂和氢气的存在下,在高于环境温度的一种或多种温度进行,其中将14-羟可待因酮和盐酸的溶液加热至一定温度,然后暴露于氢气,(c)该盐酸氧可酮包含通过HPLC测定<约0.300面积％的量的6α-氧可醇,特征在于(d)14-羟可待因酮和盐酸的溶液的pH在约≥2.5至约≤4.5的范围；(e)该方法一锅进行,和(f)该盐酸氧可酮从该溶液中沉淀出来。(A process for the preparation of oxycodone hydrochloride comprising hydrogenating 14-hydroxycodeinone in an alcoholic solvent and hydrochloric acid to form oxycodone hydrochloride, wherein (a) the hydrogenation is carried out in the presence of a heterogeneous Platinum Group Metal (PGM) catalyst and hydrogen, (b) the hydrogenation is carried out in the presence of a hydrogenation catalyst and hydrogen at one or more temperatures above ambient temperature, wherein a solution of 14-hydroxycodeinone and hydrochloric acid is heated to a temperature and then exposed to hydrogen, (c) the oxycodone hydrochloride comprises 6 α -oxycodone in an amount < about 0.300 area% as determined by HPLC, characterized in that (d) the pH of the solution of 14-hydroxycodeinone and hydrochloric acid is in the range of about 2.5 to about 4.5, (e) the process is carried out in one pot, and (f) the oxycodone hydrochloride precipitates from the solution.)

1. A process for preparing oxycodone hydrochloride comprising hydrogenating 14-hydroxycodeinone in an alcoholic solvent and hydrochloric acid to form oxycodone hydrochloride, wherein

(a) The hydrogenation is carried out in the presence of a heterogeneous Platinum Group Metal (PGM) catalyst and hydrogen,

(b) the hydrogenation is carried out in the presence of a hydrogenation catalyst and hydrogen at one or more temperatures above ambient temperature, wherein 14-hydroxycodeinone in an alcoholic solvent and hydrochloric acid is heated to a temperature and then exposed to hydrogen,

(c) the oxycodone hydrochloride comprises 6 α -oxycodone in an amount of < about 0.300 area percent as determined by HPLC,

is characterized in that

(d) The pH of 14-hydroxycodeinone in an alcoholic solvent and hydrochloric acid is in the range of about 2.5 or more to about 4.5 or less;

(e) the method is carried out in one pot.

2. The process of claim 1, wherein the oxycodone hydrochloride substantially precipitates from solution when the process is conducted at a temperature in the range of about ≥ 30 ° to about ≤ 45 ℃.

3. The process of claim 1, wherein the oxycodone hydrochloride is substantially dissolved when the process is conducted at a temperature in the range of about 45 ℃ or more to about 85 ℃.

4. The process according to any one of the preceding claims, wherein the alcoholic solvent is selected from methanol, ethanol, n-propanol, isopropanol or mixtures thereof, preferably ethanol.

5. The process according to any one of the preceding claims, wherein the heterogeneous Platinum Group Metal (PGM) catalyst is Pd/C.

6. The process of any of the preceding claims, wherein the hydrogen pressure is about 30-55psi, preferably about 40 ± 5 psi.

7. The method according to any of the preceding claims, wherein the temperature or temperatures above ambient temperature is in the range of ≥ about 30 ℃ to ≤ about 85 ℃, preferably in the range of ≥ about 30 ℃ to about ≤ 50 ℃, more preferably about 40 ℃.

8. The method of any one of the preceding claims, wherein the pH is in the range of about ≧ 3.0 to ≦ about 4.0.

9. The method of claim 8, wherein the oxycodone hydrochloride comprises 6 α -oxycodone in an amount of less than or equal to about 0.100 area percent as determined by HPLC.

10. The method according to any one of the preceding claims, wherein the oxycodone hydrochloride comprises α -unsaturated ketone of less than or equal to about 25 ppm.

11. The method according to any one of the preceding claims, wherein the oxycodone hydrochloride comprises α -unsaturated ketone in an amount of less than or equal to about 10 ppm.

Disclosure of Invention

We have developed an improved process which overcomes the disadvantages associated with the prior art processes in the one-pot process of the present invention, oxycodone hydrochloride having a reduced 6 α -oxoalcohol level is precipitated from the alcohol solution, thus allowing for reduced further purification, and in certain embodiments omitted.

Accordingly, in one aspect, the present invention provides a process for the preparation of oxycodone hydrochloride comprising hydrogenating 14-hydroxycodeinone in an alcoholic solvent and hydrochloric acid to form oxycodone hydrochloride, wherein

(a) The hydrogenation is carried out in the presence of a heterogeneous Platinum Group Metal (PGM) catalyst and hydrogen,

(b) the hydrogenation is carried out in the presence of a hydrogenation catalyst and hydrogen at one or more temperatures above ambient temperature, wherein 14-hydroxycodeinone in an alcoholic solvent and hydrochloric acid is heated to a temperature and then exposed to hydrogen,

(c) the oxycodone hydrochloride comprises 6 α -oxycodone in an amount of < about 0.300 area percent as determined by HPLC,

is characterized in that

(d) The pH of the solution of 14-hydroxycodeinone and hydrochloric acid is in the range of about 2.5 or more to about 4.5 or less;

(e) the treatment process is carried out by one pot.

Detailed Description

As described above, in one aspect, the present invention provides a process for preparing oxycodone hydrochloride comprising hydrogenating 14-hydroxycodeinone in an alcoholic solvent and hydrochloric acid to form oxycodone hydrochloride, wherein

(a) The hydrogenation is carried out in the presence of a heterogeneous Platinum Group Metal (PGM) catalyst and hydrogen,

(b) the hydrogenation is carried out in the presence of a hydrogenation catalyst and hydrogen at one or more temperatures above ambient temperature, wherein 14-hydroxycodeinone in an alcoholic solvent and hydrochloric acid is heated to a temperature and then exposed to hydrogen,

(c) the oxycodone hydrochloride comprises 6 α -oxycodone in an amount of < about 0.300 area percent as determined by HPLC,

is characterized in that

(d) The pH of the solution of 14-hydroxycodeinone and hydrochloric acid is in the range of about 2.5 or more to about 4.5 or less;

(e) the treatment process is carried out by one pot.

In addition, the practice of the present invention at a pH range of about 2.5 to about 4.5 produces oxycodone hydrochloride comprising 6 α -oxycodone in an amount of < about 0.300 area percent as determined by HPLC.

The process comprises hydrogenating 14-hydroxycodeinone in an alcoholic solvent and hydrochloric acid. The alcoholic solvent may be a straight or branched C_1-5An alkanol and may be selected from methanol, ethanol, propanol (n-or iso), butanol (n-, iso-or tert), and pentanol. In one embodiment, the alcoholic solvent may be selected from methanol, ethanol, isopropanol, n-propanol or mixtures thereof. In one embodiment, the alcoholic solvent is ethanol. In another embodiment, the alcoholic solvent is SDA-3A, which is 96% ethanol denatured with 4% methanol.

The 14-hydroxycodeinone is substantially dissolved in the alcoholic solvent and the hydrochloric acid. The dissolution of 14-hydroxycodeinone may be enhanced by the use of aids such as stirring and/or ultrasound. The product oxycodone hydrochloride is insoluble and substantially precipitates from solution when the temperature of the reaction mixture after hydrogenation is less than or equal to about 45 ℃. However, oxycodone hydrochloride substantially dissolves when the temperature of the reaction mixture after hydrogenation is ≥ about 45 ℃. When the process is conducted at a temperature in the range of from ≥ about 30 deg.C to ≤ about 45 deg.C, the post-hydrogenation reaction mixture can be heated to ≥ about 45 deg.C after removal of the hydrogen gas, thereby substantially dissolving the oxycodone hydrochloride. Can be further filtered (e.g., by Celite)^TM) To remove the catalyst and may optionally be purified.

The catalyst, hydrochloric acid and/or 14-hydroxycodeinone may be water-wet at the time of use. In this regard, if the alcohol solvent to water ratio is sufficiently large that oxycodone hydrochloride substantially precipitates from the reaction mixture, the amount of water that may be added to the reaction in this manner does not adversely affect the process.

The hydrogenation catalyst may be a heterogeneous Platinum Group Metal (PGM) catalyst. The catalyst is selected such that it preferentially reduces the double bond between C-7 and C-8, rather than reducing the C ═ O bond at C-6 (see fig. 1). In one embodiment, the heterogeneous catalyst is a heterogeneous Platinum Group Metal (PGM) catalyst, such as a heterogeneous palladium or platinum catalyst. In one embodiment, the heterogeneous Platinum Group Metal (PGM) catalyst is a heterogeneous palladium catalyst. Examples of palladium catalysts include, but are not limited to, colloidal palladium, palladium sponge, palladium plate, or palladium wire. Examples of platinum catalysts include, but are not limited to, colloidal platinum, platinum sponge, platinum plate, or platinum wire.

The heterogeneous PGM metal catalyst may be PGM on a solid support the support may be selected from the group consisting of carbon, alumina, calcium carbonate, barium sulfate, titania, silica, zirconia, ceria and combinations thereof when the support is alumina, the alumina may be in the form of α -Al₂O₃、β-Al₂O₃、γ-Al₂O₃、δ-Al₂O₃、θ-Al₂O₃Or a combination thereof. When the support is carbon, the carbon may be in the form of activated carbon (e.g. neutral, basic or acidic activated carbon), carbon black or graphite (e.g. natural or synthetic graphite). An example of a heterogeneous PGM catalyst is palladium on carbon.

The catalyst loading may be up to about 20 mole%. In one embodiment, the catalyst loading may be up to 10 mole percent, and in another embodiment may be in the range of about 0.1 to 10.0 mole percent.

Although it is generally sufficient to add a single batch of hydrogenation catalyst to the reaction mixture, if it has been determined (e.g., by in-process analysis) that the reaction has not been completed and the starting materials remain, a second or additional batch can be added and hydrogenation continued.

Conventionally, the hydrogenation of 14-hydroxycodeinone is carried out at ambient temperature. "ambient temperature" means a temperature of 30 ℃ or less. However, in the present process, the hydrogenation is carried out at one or more temperatures above ambient temperature, i.e. above 30 ℃ and below the boiling point of the reaction mixture. The boiling point of the reaction mixture may vary depending on the pressure at which the hydrogenation reaction is carried out. In one embodiment, the hydrogenation may be carried out at one or more temperatures ranging from ≥ about 30 ℃ to ≤ about 85 ℃. In a preferred embodiment, the hydrogenation is carried out at one or more temperatures in the range of ≥ about 30 ℃ to about ≤ 50 ℃, e.g. about 40 ℃.

The pressure at which the hydrogenation is carried out is not particularly limited. In this regard, the hydrogenation may conveniently be carried out at an initial hydrogen pressure in the range of about 30-55psi, for example about 40. + -.5 psi.

As mentioned above, the hydrogenation is carried out at one or more temperatures above ambient temperature, i.e. above 30 ℃ and below the boiling point of the reaction mixture. Those skilled in the art will understand and consider the pressure of the reaction and its possible effect on the boiling point of the reaction mixture.

In one embodiment, the level of 6 α -oxycodone, which must be controlled to a specific level specified by official monographs such as the U.S. pharmacopoeia (U.S. pharmacopoeia), for example, USP specifies for 33 th reissue of oxycodone hydrochloride that the acceptance criteria for 6 α -oxycodone cannot be greater than 0.25%.

Without wishing to be bound by theory, the 6-oxycodone does not appear to be produced from oxycodone (see FIG. 1). instead, it appears to be produced from 14-hydroxycodeinone which is reduced to 14-hydroxycodeine, and it is this latter compound that results in the formation of 6-oxycodone. thus, the hydrogenation process of the present invention appears to affect the 14-hydroxycodeinone → 14-hydroxycodeine → 6-oxycodone pathway such that the amount of 6 α -oxycodone formed is at a reduced level.

The present invention provides a process wherein the oxycodone hydrochloride comprises 6 α -oxycodone in an amount < about 0.300 area percent as determined by HPLC in the reaction mixture after hydrogenation, hi some embodiments, the oxycodone hydrochloride comprises 6 α -oxycodone in an amount of less than or equal to about 0.100 area percent as determined by HPLC.

The pH of the initial reaction mixture may range from about ≧ 2.5 to about ≦ 4.5, in some embodiments, the pH may be ≧ about 2.6, in some embodiments, the pH may be ≦ about 2.7, in some embodiments, the pH may be ≦ about 2.8, in some embodiments, the pH may be ≦ about 2.9, in some embodiments, the pH may be ≦ about 4.4, in some embodiments, the pH may be ≦ about 4.3, in some embodiments, the pH may be ≦ about 4.2, in some embodiments, the pH may be ≦ about 4.1, in one embodiment, the pH of the initial reaction mixture may range from about ≧ 3.0 to ≦ about 4.0, such as about 3.5 it has been observed that the level of 6 α -oxoalcohol determined by HPLC may be less than 0.100 area% in this pH range.

By one-pot process is meant a process in which a continuous process is carried out in a single reactor, i.e. (a) reduction of 14-hydroxycodeinone to oxycodone, (b) formation of oxycodone hydrochloride, (c) precipitation of oxycodone hydrochloride from solution.

There is also a regulatory other impurity in the official monograph including α -unsaturated ketones (ABUK), such as 14-hydroxycodeinone and codeinone due to the biological activity proposed as genotoxins, ABUK has recently attracted considerable attention, there is therefore a continuing need to develop a process for producing low ABUK oxycodone alkaloids and low ABUK oxycodone salts, such as low ABUK oxycodone hydrochloride, without wishing to be bound by theory, 14-hydroxycodeinone, which may be present as an impurity in oxycodone hydrochloride, appears to be two sources — first residual unreacted 14-hydroxycodeinone starting material, second indirectly from 8, 14-dihydroxy-7, 8-dihydrocodeinone, claims 8, 14-dihydroxy-7, 8-dihydrocodeinone is converted to 14-hydroxycodeinone under acidic conditions, thus even if the reaction conditions can drive the reaction to form oxycodone having <10ppm of 14-hydroxycodeinone, the oxycodone 14 may be present as a salt in the acidic condition, and thus the formation of oxycodone from the oxycodone 14-hydroxycodeinone proceeds as a salt in the formation of 14-hydroxycodeinone, which may be formed by hydrogenation of the starting material, 14-dihydrocodeinone, 14-dihydrocodeinone, and, 8-dihydrocodeinone, which may be formed in the subsequent processes.

Thus, in one embodiment, oxycodone hydrochloride prepared in accordance with the present invention comprises about 50ppm or less of α -unsaturated ketone, for example about 25ppm or less of β 0, β 1-unsaturated ketone, for example about 15ppm or less of α -unsaturated ketone in a preferred embodiment oxycodone hydrochloride comprises about 10ppm or less of α -unsaturated ketone in another embodiment oxycodone hydrochloride is substantially free of α -unsaturated ketone α -unsaturated ketone may be selected from 14-hydroxycodeinone, codeinone and mixtures thereof without wishing to be bound by theory, it is believed that the temperature at which the invention is practiced, i.e., above ambient temperature, is capable of simultaneously dehydrating 8, 14-dihydroxy-7, 8-dihydrocodeinone (to produce 14-hydroxycodeinone), hydrogenating 14-hydroxycodeinone (to form oxycodone), dehydrating 8-hydroxy-7, 8-dihydrocodeinone (if present) (to form hydrocodone), and hydrogenating 14-hydroxycodeinone (if present) to form hydrocodone (hydrogenated).

The reaction vessel may be purged with one or more nitrogen/vacuum cycles (e.g., one, two, three, or four cycles) before the reaction mixture is heated to a temperature. During purging, the reaction mixture may be stirred to facilitate removal of dissolved oxygen. After the final purge cycle, the vessel may be placed under nitrogen and stirred (by stirring or shaking) while heating the vessel. Once the reaction mixture reaches the desired temperature, the hydrogenation reaction can be initiated by exposing the reaction mixture to hydrogen.

Alternatively, the reaction mixture may be heated to and maintained at the desired temperature prior to exposing the reaction mixture to hydrogen. Thus, in one embodiment, the reaction mixture may be maintained at one or more temperatures above ambient for up to about 1 minute or more prior to the addition of hydrogen. In another embodiment, the reaction mixture may be maintained at one or more temperatures above ambient for up to about 15 minutes or more prior to the addition of hydrogen. In yet another embodiment, the reaction mixture may be maintained at one or more temperatures above ambient for up to about 6 hours or more prior to the addition of hydrogen.

The hydrogenation reaction was carried out for a period of time until the reaction was confirmed to be complete. Completion of the reaction can be confirmed by in-process analysis or by confirming that no more hydrogen is absorbed. The reaction mixture may be maintained at a temperature and pressure for up to about 24 hours.

After the reaction is complete, the reaction vessel may be cooled to ambient temperature and purged to remove excess hydrogen (or vice versa). The hydrogenation catalyst may be passed by any suitable method, for example by filtration (for example through Celite)^TM) To be removed and the filtrate (containing oxycodone hydrochloride) may be further treated as required.

The invention will now be described by way of the following non-limiting examples and figures.