Process for improved opioid synthesis

a technology of opioid synthesis and process, which is applied in the direction of biocide, drug composition, chemical production, etc., can solve the problems of inability to approve a pharmaceutical composition or dosage form for use and sale, difficulty in separating by-products from final opioids, and inability to reduce the number of by-products, etc., to achieve volume efficient, reduce manufacturing costs, and reduce by-products

Inactive Publication Date: 2015-09-17
NORDBOTICS INC
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  • Abstract
  • Description
  • Claims
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AI Technical Summary

Benefits of technology

[0028]Thus, the formation of a 14-hydroxycodeinone salt (compound of formula V) and the isolation of the precipitated salt appear to prevent or reduce (i) the formation of 8-hydroxyoxycodone during oxidation of thebaine, as compared to processes which do not involve the formation of the compound of formula V, (ii) the presence of 8-hydroxyoxycodone in a composition comprising oxycodone base made via a compound of formula V, and (iii) the presence of 8-hydroxyoxycodone or a salt thereof and 14-hydroxycodeinone or a salt thereof in an oxycodone salt or in a pharmaceutical composition comprising an oxycodone salt. The same applies to other compounds of formula V and the corresponding compounds of formulae I, II, III, and IV.
[0029]Pharmaceutical compositions prepared by processes of the present invention may be quantitatively different from pharmaceutical compositions prepared by conventional processes which do not utilize the compound of formula V, and may offer advantages over the compositions prepared by conventional processes, e.g., in terms of safety, efficiency and reduced manufacturing costs. For example, these compositions may contain less by-products and / or require less or no further processing steps after synthesis of their API.
[0030]Moreover, adding the acid H+nXn− may allow for a more volume efficient oxidation process, as compared to the conventional oxidation reaction which is exemplified in the Background Section for oxidation of thebaine. The volume efficiency of a subsequent reaction utilizing the compound of formula V or solvate thereof as starting material may also be improved, e.g., when the compound of formula V or solvate thereof is used in its precipitated form.

Problems solved by technology

These by-products may be undesired in the final pharmaceutical composition or final dosage form.
Separation of these by-products from the final opioid may often be difficult, time-consuming and not volume efficient (e.g., if a separation by HPLC is required).
Some regulatory authorities do not approve a pharmaceutical composition or dosage form for use and sale to the public if the amount of 14-hydroxycodeinone in the pharmaceutical composition or dosage form exceeds the amount set by these authorities.
These additional processing steps typically increase the production costs of pharmaceutical dosage forms, and have the potential to form new compounds and / or increase amounts of certain compounds above the limits set by the regulatory authorities for these compounds.
The conventional processes for preparing oxycodone or oxycodone salts are also often not very volume and cost efficient in their oxidation step, or they are complicated and require specific equipment.

Method used

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  • Process for improved opioid synthesis
  • Process for improved opioid synthesis
  • Process for improved opioid synthesis

Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparation of 14-hydroxycodeinone sulfate

[0541]

[0542]14-hydroxycodeinone sulfate was prepared as follows:

[0543]1. Into a 100 mL jacketed vessel equipped with a temperature probe, overhead stirrer and an addition funnel, thebaine (12.0 g, 38.6 mmol) was charged as a slurry in deionized water (18 mL).

[0544]2. The jacket temperature for the vessel was set to 20° C. and the slurry was stirred at 300 rpm.

[0545]3. 88% formic acid (6 mL, 140 mmol) was added into the reaction mixture. The solids readily dissolved into solution upon this addition. During the formic acid addition, the temperature of the reaction mixture increased to 29° C.

[0546]4. Sulfuric acid (1.15 mL, 21 mmol) was added to the solution, and the solution was stirred at 300 rpm.

[0547]5. After the solution temperature had cooled below 22° C., 35% hydrogen peroxide (4.00 mL, 46.5 mmol) was added to the reaction over 15 minutes, using the addition funnel.

[0548]6. After the peroxide addition was complete, an additional 3 mL of ...

example 2

Preparation of Oxycodone Base

[0560]

[0561]A composition comprising 99.13% of oxycodone base, 26 ppm 14-hydroxycodeinone, 565 ppm of 8α-hydroxyoxycodone and 298 ppm of 8β-hydroxyoxycodone, based on HPLC area percent, was prepared as follows:

[0562]1. Into a 300 mL hydrogenation vessel equipped with a magnetic stir bar, 14-hydroxycodeinone sulfate obtained in Example 1 (9.01 g, 12.43 mmol (calculated without water of crystallization)), deionized water (90 mL) and methanol (40 mL) were charged. The majority of solids dissolved into solution.

[0563]2. Formic acid (1.20 mL, 28.0 mmol) and 5% palladium on carbon (0.065 g) were added into the reaction mixture.

[0564]3. The vessel was sealed, stirred at 750 rpm and heated to 40° C.

[0565]4. The mixture was then hydrogenated at 60 psia (413.69 kPa) for 5 hours.

[0566]5. The reaction was vented, purged with nitrogen, vented and hydrogenated at 60 psia (413.69 kPa) for an additional 1 hour.

[0567]6. The reaction was vented, purged with nitrogen and c...

example 3

Preparation of Oxycodone Hydrochloride

[0575]

[0576]A composition comprising 99.72% of oxycodone hydrochloride, 9 ppm of 14-hydroxycodeinone hydrochloride, 103 ppm of 8α-hydroxyoxycodone hydrochloride, and 191 ppm of 8β-hydroxyoxycodone hydrochloride, based on HPLC area percent, was prepared as follows:

[0577]1. Into a 300 mL jacketed reaction vessel equipped with a temperature probe, reflux condenser, and overhead stirrer, was charged oxycodone (4.01 g, 12.0 mmol), deionized water (6 mL) and isopropanol (45 mL). The oxycodone comprised 99.13% of oxycodone, 26 ppm of 14-hydroxycodeinone, 565 ppm of 8α-hydroxyoxycodone, and 298 ppm of 8β-hydroxyoxycodone.

[0578]2. The mixture was stirred at 250 rpm and the external jacket of the vessel was heated to 80° C.

[0579]3. When the internal temperature of the mixture had reached 40° C., 37% hydrochloric acid (1.05 mL, 12.8 mmol) was added to the reaction vessel.

[0580]4. When the internal temperature of the mixture had reached 74° C., all visible ...

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Abstract

Compounds and compositions for use as starting materials or intermediate materials in the preparation of opioids including, e.g., oxycodone base and/or an oxycodone salt; processes for preparing these compounds and compositions; uses of these compounds and compositions in the preparation of APIs and pharmaceutical dosage forms; and uses of said APIs and pharmaceutical dosage forms in the treatment of medical conditions.

Description

[0001]The present invention is in the field of pharmaceutical compositions comprising opioids and in the field of pharmaceutical opioid synthesis. It provides compounds and compositions for use as starting materials or intermediate materials in the preparation of opioids including, e.g., oxycodone base and / or an oxycodone salt; processes for preparing these compounds and compositions; uses of these compounds and compositions in the preparation of APIs and pharmaceutical dosage forms; and uses of said APIs and pharmaceutical dosage forms in the treatment of medical conditions.BACKGROUND OF THE INVENTION[0002]Opioids like oxycodone and its hydrochloride salt have long been used as analgesics.[0003]Typically, oxycodone base is prepared by oxidation of thebaine to 14-hydroxycodeinone, and reducing the 14-hydroxycodeinone to oxycodone base. A conventional route for the preparation of oxycodone via oxidation of thebaine to 14-hydroxycodeinone is illustrated in Scheme 1:[0004]Once the oxyc...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D489/08
CPCC07D489/08A61P1/10A61P1/12A61P11/14A61P25/04A61P25/20A61P25/24A61P25/30A61P25/36Y02P20/55
Inventor GEBBIE, STUART JAMESGIGUERE, JOSHUA R.MCCARTHY, KEITHRIDER, LONN S.
Owner NORDBOTICS INC
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