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Synthesis of oxycodone hydrochloride

Active Publication Date: 2015-06-18
CODY LAB
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Benefits of technology

The patent text describes methods for preparing oxycodone hydrochloride with a reduced amount of impurities. The methods involve converting thebaine to 14-hydroxycodeinone sulfate, reducing it to form oxycodone base, and then dissolving it in an aqueous organic acid to form an oxycodone organic acid salt. The oxycodone organic acid salt can then be converted to oxycodone hydrochloride by adding hydrochloric acid or ammonium chloride. The purified oxycodone hydrochloride has a reduced amount of impurities, particularly 8,14-dihydroxy-7,8-dihydrocodeinone. The methods also involve isolating the 14-hydroxycodeinone sulfate, reducing it to form oxycodone base, and dissolving it in an aqueous organic acid to form an oxycodone organic acid salt. The purified oxycodone hydrochloride can then be crystallized to form a further purified product. Overall, the methods provide a more efficient and effective way to produce high-quality oxycodone hydrochloride.

Problems solved by technology

), or under reflux conditions, can cause acid catalyzed dehydration of residual DHC impurity to form undesirable ABUK in the final product.

Method used

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  • Synthesis of oxycodone hydrochloride
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  • Synthesis of oxycodone hydrochloride

Examples

Experimental program
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example 1

14-Hydroxycodeinone Sulfate Preparation from Thebaine

[0126]14-Hydroxycodeinone sulfate was prepared by oxidation of thebaine as shown in FIG. 2. A 250 mL jacketed reactor was charged with CPS-thebaine (Assay 75.7%; 39.63 g; 96.35 mmol; equivalent to 30.0 g of 100%), NaHSO4 monohydrate (13.57 g, 98.28 mmol), and a solution of DI water (10.25 g) and 97% formic acid (5.26 g, 110.80 mmol).

[0127]The mixture was stirred at 20° C. for 15 minutes to provide a brownish to gray easily stirrable mixture. Hydrogen peroxide (30%, 11.8 mL, 115.62 mmol) was added to the stirred reaction mixture at 20° C. over 7 minutes. After the addition was completed, temperature of the reaction mixture was kept at 20° C. with magnetic stirring for about 15 minutes and then the reaction mixture was heated to 60° C., over a time period of about 30 minutes. Stirring was continued for 5.75 hours until complete conversion from thebaine into 14-hydroxycodeinone was observed by HPLC, as shown in Table 1, HPLC Normaliz...

example 2

Characterization of 14-Hydroxycodeinone Sulfate

[0129]To determine molecular formula, 14-Hydroxycodeinone (ABUK) sulfate (Lot B) and 14-hydroxycodeinone (ABUK) base (Lot A) were analyzed by HPLC. As shown in Scheme 3, ABUK sulfate molecular formula was determined to be ABUK×0.5H2SO4×2H2O (molecular weight 398.42), as shown in Table 2.

[0130]ABUK sulfate and ABUK base samples were analyzed with HPLC. A solution of each sample of ABUK base and ABUK sulfate was analyzed three times (three injections), HPLC responses were corrected according to Karl Fischer water content analysis (10.7% of water in ABUK sulfate sample: 9.04% is water in ABUK sulfate crystals and 1.66% is “absorption” water). HPLC data correlate with ABUK×0.5H2SO4×2H2O (molecular weight 398.42) as a molecular formula.

TABLE 2HPLC Analysis for Determination of Molecular Formula.LotinjectionHPLCHPLCResponse perNumberABUK Formconc., mg / gvolume, μLResponsePurity, %μL and conc.Avg.Lot AABUK Base0.673998.19100.0016.2116.29MW 313....

example 3

Preparation of 14-Hydroxycodeinone Sulfate from Thebaine with Potassium Hydrogen Sulfate

[0136]A 250 mL jacketed reactor was subsequently charged with thebaine (311.37 g / mol, 30.0 g, 96.35 mmol), solution of KHSO4 (14.1 g, 100.44 mmol) in DI water (40 ml) and 97% formic acid (5.2 mL, 133.61 mmol). The mixture was warmed to 30° C. (Julabo thermostat) and stirred for 20 min to give yellow to light brown almost homogeneous pale solution. Hydrogen peroxide (30%, 13.5 mL, 119.12 mmol) was added to the stirred reaction mixture at 30-31° C. over 25 minutes. After the addition was completed, temperature of the reaction mixture was kept at 30° C. for 25 minutes, increased to 50° C. with stirring over 10 minutes and kept 9 hours at 50-51° C. until the thebaine was completely converted into 14-hydroxycodeinone. The precipitation of the yellow solids occurred after 7 hours stirring at 50° C. Water (10 mL) was added to the reaction mixture and the reaction mixture was cooled down to 20° C. and st...

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Abstract

Synthetic methods are provided for preparation of oxycodone and salts thereof with an improved impurity profile. Thebaine is converted to 14-hydroxycodeinone sulfate intermediate to minimize a 7,8-dihydro-8,14-dihydroxycodeinone impurity. Efficient methods for conversion of oxycodone base to oxycodone hydrochloride are provided to minimize 14-hydroxycodeinone impurity in the final product.

Description

FIELD[0001]Synthetic methods are provided for preparation of oxycodone and salts thereof with improved impurity profiles.DESCRIPTION OF THE RELATED ART[0002]Oxycodone hydrochloride is an opioid receptor agonist that is indicated for relief of moderate to severe pain. Preparation of oxycodone hydrochloride from thebaine through intermediate preparation of 14-hydroxycodeinine is a well-known technology that has been employed since 1916.[0003]FIG. 1 shows a prior art conventional synthetic route for preparation of oxycodone hydrochloride by oxidation of thebaine to form 14-hydroxycodeinone (ABUK), reduction of 14-hydroxycodeinone to form oxycodone base, and conversion of the base to oxycodone hydrochloride. A synthetic impurity, 7,8-dihydro-8,14-dihydroxycodeinone, (DHC), interconverts by hydration / dehydration from / to 14-hydroxycodeinone. Conventional conversion methods to form oxycodone HCl from oxycodone base using aqueous HCl at elevated temperatures (40-100° C.), or under reflux co...

Claims

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Application Information

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IPC IPC(8): C07D489/08
CPCC07B2200/13C07D489/08
Inventor ITOV, ZINOVYKUZNETSOV, VLADIMIR F.VOITSEKHOVSKI, IOURI
Owner CODY LAB
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