A method of preparation of oxycodone

Technical field

The invention relates to pharmaceutical production, namely the production of Oxycodone (1), which is a strong analgesic used in therapeutic practice in the form of the hydrochloride, or is used as an intermediate in the production of morphine antagonists such as Naloxone or Naltrexone.

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(AND)

State of the art

Oxycodone (I) is produced in two main ways:

a) By transforming thebaine (II), a natural alkaloid isolated from the plant Papaver somniferum L., or its analogs (III) in which R is an alkoxy or aminoalkyl residue. During this procedure (Scheme 1), thebaine (II) reacts in an acidic environment with hydrogen peroxide, peroxyacids or other oxidizing agents to form

14e-hydroxycodeinone (IV), which is subjected to hydrogenation to obtain Oxycodone (I)

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II R = OCH3

R = XCnH2n + 1 X = O or N

IV

AND

Diagram I

Thebaine, dissolved in hot, concentrated acetic acid, is converted to 14e-hydroxycodeinone by reaction with 30% hydrogen peroxide (Freund M., Speyer E .: J. Prakt. Chem. 94, 135 (1916); Lutz RE, Small L : J.Org.Chem. 4, 220-233 (1939); DE 286431) in about 30% yield. Similar performance was also obtained during the oxidation of thebaine (II) with chromic acid (DE 286431; DE 411530) or manganese acetate (Viebock F .: Chem. Ber. 67, 197 (1934)). A much higher yield (about 75%) was recorded when thebaine (II) was reacted with hydrogen peroxide in acetic acid at a temperature not exceeding 40 ° C (Feldmann I.Ch., Liutenberg AI: Zh. Prikl. Khim. 18, 715 ( 1945)), or in a mixture of sulfuric acid and 88% formic acid (Krassnig R., Hederer Ch., Schmidhammer H .: Arch. Phil. 329, 325 (1996)).

Comparable results were obtained when thebaine (II) was reacted with peroxyacids, e.g., m-chloroperbenzoic acid in a mixture of acetic acid and trifluoroacetic acid (Hauser FM, Chen TK., Carroll FI:

1117 (1974)); however, Ijima et al.

this reaction does not provide reproducible yield (about 25%) and many undesirable products are formed (Iijima I., Rice KC, Brossi, A .: Helv. Chim. Acta

J. Med. 17, they found that

60, 2135 (1977)).

In the modified procedure, codeine (V), Scheme 2, which is first oxidized to codeinone (VI) can be used instead of thebaine (II), which, by reaction with any acylating or alkylating agents, provides the enol ether / ester VII (EP 889045, US 5,869,669, US 4,639,520), essentially a thebaine analogue, which then gradually transforms into

14e-hydroxycodeinone (IV) by any of the above methods.

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It is also possible to classify in this group the Sankyo process (GB 1,260,699), which process leads from codeinone (VI), which supplies pyrrolidinylamine amino codeinone (VIII) with pyrrolidine in aprotic solvents, Scheme 3. Next reaction with hydrogen peroxide, chromic acid, organic peroxyacids (peracetic, perbenzoic acid) or permanganate, in the environment of aqueous acetic acid, phosphoric acid, etc., provides 14-hydroxycodeinone (IV).

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VI VIII IV

Diagram 3

b) Oxidation of codeinone (VI) by the action of peroxyacids from a combination of organic acids and hydrogen peroxide, or inorganic oxidizing agents (e.g. Co salts³+), with a maximum yield of 57% 14β-hydroxycodeinone which is hydrogenated to Oxycodone (I) (Coop A., Rice KC: Tetrahedron 55, 11429 (1999)).

The 14e-hydroxycodeinone C-7-C-8 double bond is subjected to catalytic hydrogenation according to CH 75110 (US 1,468,805) on Pt black, colloidal Pd, or in the presence of PdCl2 (US 1,485,673) in dilute acetic acid. Ijima used Pd / BaSO4 as a catalyst in this reaction (J. Med. Chem. 21, 398 (1978)), such as Lutz RE and Small L. (J. Org. Chem. 4, 220 (1939)); the use of 10% Pd / C in concentrated acetic acid was also known (Krassnig R., Hederer Ch., Schmidhammer H .: Arch.Pharm. 329, 325 (1996)) with a yield of about 70%. Feldmann and Liutenberg (Zh. Prikl. Khim. 18, 715 (1945)) hydrogenated 14e-hydroxycodeinone hydrochloride to Ni Raney in hot ethanol with a yield of 74% oxycodone hydrochloride.

All of the mentioned methods for producing oxycodone (I) have the disadvantage that the reaction of the peroxide / peroxyacid with thebaine or its analogs does not give unambiguously reproducible results, a mixture of difficult to separate by-products is created, and the yields are low.

These defects have been corrected by the method of the present invention.

Disclosure of the Invention

The invention provides a process for the preparation of Oxycodone of formula I by the reaction of thebaine (II) or its analogs of formula III in which R is C2 to C5 alkyl, alkylaryl,

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AND

II

III with hydrogen peroxide or peroxyacids such as peracetic acid, perbenzoic acid, m-chloroperbenzoic acid, in the presence of oxalic acid and another organic acid, e.g. formic acid or acetic acid, whereby the crystalline 14-hydroxycodeinone oxalate precipitate is formed. by adding a base, a 14-hydroxycodeinone precipitate of formula IV, which is then hydrogenated with hydrogen in the presence of a catalyst to give Oxycodone (I).

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hydrogen peroxide or peroxyacids in the presence of oxalic acid of another organic acid gives hydroxycodeinone, which with oxalic acid forms a poorly soluble crystalline precipitate of 14-hydroxycodeinone oxalate. In this way, the balance of transformation of thebaine is shifted and further undesirable side reactions are limited, such as oxidation of thebaine to trans-10-hydroxytebaine or addition of water to 14-hydroxycodeinone to form (8S) -hydroxy-oxycodone, etc.

When formic acid is used as the other organic acid, its concentration is preferably 80 to 90%, more preferably 88%. The hydrogen peroxide concentration is preferably 25 to 33%. The molar ratio of thebaine or its analogue: oxalic acid: other organic acid: hydrogen peroxide or peroxyacid is preferably 0.8-2: 1: 2.0-3.0: 2.0-3.0, more preferably 1.5-2 , 0: 1: 2.3-2.7: 2.3-2.7.

The temperature during the reaction of thebaine or its analogs with hydrogen peroxide or peroxyacids is preferably 0 to 35 ° C, more preferably 15 to 25 ° C.

In earlier processes, oxidation of thebaine / thebaine analogues was carried out with hydrogen peroxide / peroxyacids in the presence of an organic or inorganic acid (which is important to promote nitrogen in thebaine molecule to avoid N-oxide formation or to obtain the required solubility of the substrate).

The trial of Krassnig R. et al., Arch.Pharm. 329, 325 (1996) uses a mixture of thebaine, sulfuric acid, formic acid and hydrogen peroxide; the system is homogeneous throughout the entire reaction. After the oxidation, the reaction mixture was poured onto ice and basified by the addition of ammonium hydroxide. The product, 14-hydroxycodeinone, was extracted with dichloromethane.

The advantage of the method of the invention is that the oxidation of thebaine / its analogs with hydrogen peroxide or peroxyacids in the presence of oxalic acid and other organic acids (formic, acetic) produces a product precipitate (14-hydroxycodeinone), creating a heterogeneous system that shifts the balance of oxidation reactions and avoids subsequent reaction of the product (14-hydroxycodeinone) with an oxidizing agent, leading to higher conversion and a cleaner product. After completion of the reaction, the reaction mixture (suspension) was cooled, basified (releasing 14-hydroxycodeinone base from its salts) and the precipitated product (14-hydroxycodeinone) was filtered off, washed and dried. This method offers higher performance and a cleaner product than previous processes.

In known methods (e.g. Arch. Pharm. 329, 325 (1996)) the reaction of thebaine with hydrogen peroxide in the presence of sulfuric acid and formic acid, the yield of 14-hydroxycodeinone was 74.3% and 78.5%, respectively, and the product purity was respectively 88.3% and 90.1% (25 ° C).

In the method of this patent, which used a molar coefficient of thebaine reagents: oxalic acid: formic acid: hydrogen peroxide = 16: 8.6: 22: 21, the yield was 91.3% and the product purity was 93.3% (25 ° C).

The reaction mixture formed by the suspension of 14-hydroxycodeinone oxalate in the reaction medium, after transformation of the introduced thebaine, can be worked up by separating the suspension by centrifugation, decantation or filtration, dissolving 14-hydroxycodeinone oxalate in hot water, and precipitating, by adjusting the pH with the addition of a base, 14 -hydroxycodeinone, which is then separated, washed and dried. Another method of isolating 14-hydroxycodeinone is described in a procedure in which the reaction mixture in which 14-hydroxycodeinone oxalate is suspended is basified by adding a base to adjust the pH to 9-10, preferably 9.2-9.6, 14-hydroxycodeinone is separated by centrifugation or filtration , or optionally extracted from the alkaline medium with an organic solvent.

The 14-hydroxycodeinone obtained by this method is subjected to hydrogenation by a known method in the presence of a rare metal catalyst such as Pt or Pd or Ni in an aqueous solution of an organic acid, for example acetic acid. The resulting oxycodone precipitates from the reaction medium by adjusting the pH with the addition of a base; the precipitate is separated by filtration or centrifugation and the product is dried.

Oxycodone dissolves in dilute hydrochloric acid at 70 to 90 ° C, Oxycodone hydrochloride begins to crystallize during slow cooling. As a result of the process, the product, Oxycodone hydrochloride, is obtained in the form of crystals characterized by X-ray diffraction analysis, the results of which are shown in Table 1.

Oxycodone or Oxycodone hydrochloride obtained according to the invention can be used as the active ingredient in a pharmaceutical preparation, additionally containing at least one pharmaceutically acceptable excipient.

Table 1. Characteristic X-ray diffraction pattern of Oxycodone hydrochloride

<td> 20*</td><td>κι (¾]</td><td></td><td>Ζθ "</td><td>RI [% J</td><td></td><td> 2« "</td><td>R [[% J</td><td></td><td>2β *</td><td>κι [%]</td>

<td>fi, 30</td><td> 85</td><td></td><td> 17.68</td><td> 78</td><td></td><td> 27.64</td><td> 29</td><td></td><td> 35.66</td><td> 21</td>

<td> 10.04</td><td> 37</td><td></td><td> 18.24</td><td> 73</td><td></td><td> 28,10</td><td> 44</td><td></td><td> 36.84</td><td> 18</td>

<td> 10.70</td><td> 79</td><td></td><td> 19.10</td><td> 79</td><td></td><td> 28.92</td><td> 33</td><td></td><td> 38.18</td><td> 20</td>

<td> 1 1.34</td><td> 39</td><td></td><td> 20.26</td><td> 82</td><td></td><td> 29.32</td><td> 26</td><td></td><td> 38.98</td><td> 18</td>

<td> 12.05</td><td> 96</td><td></td><td> 21.54</td><td> 41</td><td></td><td> 29.98</td><td> 44</td><td></td><td> 40.36</td><td> 18</td>

<td> 12.86</td><td> 34</td><td></td><td> 23.48</td><td> 44</td><td></td><td> 31.14</td><td> 21</td><td></td><td> 42.96</td><td> 18</td>

<td> 13.94</td><td> 56</td><td></td><td> 23.98</td><td> 53</td><td></td><td> 33.28</td><td> 29</td><td></td><td> 44.10</td><td> 27</td>

<td> 14.52</td><td> 34</td><td></td><td> 25.14</td><td> 58</td><td></td><td> 33.72</td><td> 26</td><td></td><td> 44.88</td><td> 19</td>

<td> 16.20</td><td> 100</td><td></td><td> 26.00</td><td> 35</td><td></td><td> 34.26</td><td> 25</td><td></td><td> 45.84</td><td> 16</td>

<td> 17 16</td><td> 44</td><td></td><td> 27.10</td><td> 34</td><td></td><td> 35.06</td><td> 36</td><td></td><td> 47.56</td><td> 17</td>

The advantage of the current method is that it allows the product to be obtained with a low impurity content in yields exceeding the data described in the field.

The following examples describe the method of the invention in more detail; however, they do not limit the scope of the invention in any way.

Examples

Example 1

a) 18.66 kg oxalic acid was dissolved in water, 84.8 kg thebaine was added, and after its dissolution 19.50 kg 88% formic acid and 42.4 kg 30% hydrogen peroxide were added. The reaction mixture was stirred at 25 ° C until complete conversion of thebaine (determined by capillary electrophoresis; capillary 50 cm x 0.05 mm, electrolyte 100 mM TRIS / phosphate, pH 2.7, 5 mM dimethoxy-e-cyclodextrin, temperature 25 ° C 30kV; thebaine migration time 5.6 min). The reaction mixture was cooled to 5 ° C, 10% aqueous KOH solution was added with stirring until pH 9.2. Precipitated 14-hydroxycodeinone crystals were centrifuged, washed with water and dried. Approximately 76 kg of 14-hydroxycodeinone (89%) was obtained.

b) 72.50 kg of 14-Hydroxycodeinone was dissolved in 10% aqueous acetic acid, 5% Pd / C catalyst was added, and the mixture was hydrogenated under 104 to 106 kPa electrolytic hydrogen pressure at 30 to 35 ° C. The reaction mixture was diluted with 200 L of water, filtered, the filtrate was cooled to 5 ° C and the oxycodone base was precipitated by adjusting the pH with the addition of an ethanolic ammonia solution to 9.2. The suspension was centrifuged, Oxycodone was washed with water and dried at 70 to 80 ° C. At least 67 kg (92%, purity 98.5%) of Oxycodone was obtained.

c) An aqueous HCl solution (87.0 kg of water and 13.00 kg of HCl) was mixed with 48 kg of Oxycodone base at 80 ° C, activated carbon and diatomaceous earth were added and, after stirring for 15 min, the suspension was filtered, filtrate gradually cooled to a final temperature of 1 to 3 ° C. The precipitated crystals were centrifuged, washed with ethanol, and Oxycodone hydrochloride was dried at a temperature of about 70 to 80 ° C. 51.2 kg (91%) of oxycodone hydrochloride were obtained, m.p. 219 ° C, [a] D²⁰ -145 °, water content 6.0%, purity 99.4% (RP C8 column, 150 x

3.9 mm, 5 μη, with pre-column RP C8, 20 x 3.9 mm, 5 μη, mobile phase 0.005 mol / l sodium hexanesulphonate - methanol - phosphoric acid - triethylamine (vol / vol) (900: 100: 5: 2), pH = 2.5 adjusted with NaOH; flow rate 1.5 ml / min; temperature 50 ° C; UV, λ = 206 nm), content 100.03% (titration).

Example 2

Thebaine (1 kg) was dissolved in an aqueous solution of oxalic acid (0.21 kg in 1 L of water). 0.23 kg 88% formic acid and 0.81 kg peracetic acid (39%) were added. The reaction mixture was stirred at 25 ° C resulting in consumption of thebaine (estimated by CZE). The reaction mixture was cooled to 5 ° C, 10% aqueous sodium hydroxide solution was added with stirring until pH 9.2. Precipitated 14-hydroxycodeinone crystals were centrifuged, washed with water and dried. 0.92 kg of 14-hydroxycodeinone (91.8%) was obtained. A further procedure for the preparation of Oxycodone hydrochloride was carried out according to Examples 1b) and 1c).

Example 3

6-Benzyloxy-4,5a-epoxy-3-methoxy-17-methylmorphine-6.8 (14) -diene (52.5 g) was dissolved in the solution obtained by dissolving 9.8 g of oxalic acid in 35 ml of water, and 10 ml acetic acid and 21.2 ml 30% hydrogen peroxide. The reaction mixture was stirred at 20 ° C until the benzyl analogue of thebaine was completely converted, the reaction mixture was cooled to 20 ° C, and 8% aqueous NaOH solution was added with stirring until pH 9.2. Precipitated 14-hydroxycodeinone crystals were filtered off, washed with water and dried. As a result of the procedure, approx. 37g of 14-hydroxycodeinone (82%) was obtained. The further procedure for preparing Oxycodone HCl is the same as in Examples 1b) and 1c).

Example 4

4,5a-Epoxy-6-ethoxy-3-methoxy-17-methylmorphine-6,8 (14) diene (22.1 g) was dissolved in a solution (10 g oxalic acid in 35 ml water); formic acid (9.8 ml, 88%) and hydrogen peroxide (21.2 ml) were added. The mixture was stirred at 30 ° C for 30 hours, cooled to 10 ° C, the precipitated 14-hydroxycodeinone oxalate was filtered off and washed. The 14-hydroxycodeinone wet oxalate was dissolved in 80 ml water at 65 ° C and 10% potassium hydroxide was added to pH 9.3, the 14-hydroxycodeinone suspension was cooled to 15 ° C, the precipitates were filtered off, washed and dried. Approx.17.6 g 14-hydroxycodeinone (83% yield, 93.2% purity) was obtained.

Industrial use

The preparation of Oxycodone of the formula I and its hydrochloride as described herein brings significant benefits in terms of the factor of economic requirements and environmental responsibility compared to known methods. Oxycodone hydrochloride is used in the manufacture of analgesic pharmaceuticals.