WO2023180283A2

WO2023180283A2 - Electrochemical reactor and processes using the electrochemical reactor

Info

Publication number: WO2023180283A2
Application number: PCT/EP2023/057142
Authority: WO
Inventors: Oliver KAPPE; Florian Sommer; David CANTILLO
Original assignee: Karl-Franzens-Universität Graz; Research Center Pharmaceutical Engineering Gmbh
Priority date: 2022-03-24
Filing date: 2023-03-21
Publication date: 2023-09-28
Also published as: WO2023180283A3

Abstract

The present invention relates to an electrochemical reactor capable of processing an organic mixture comprising a suspension of a solid and a liquid, wherein the electrochemical reactor comprises an inner electrode, an outer electrode, wherein the inner electrode and the outer electrode are arranged concentrically forming a first cavity therebetween, a first inlet configured for introducing the liquid into the first cavity of the electrochemical reactor, a second inlet configured for introducing the solid into the first cavity of the electrochemical reactor, wherein the first inlet and the second inlet are arranged such that the liquid and the solid are introduced separately, wherein the inner electrode is configured to be rotatable around its longitudinal axis, wherein the inner electrode comprises one or more mixing elements. The present invention further relates to processes for the electrochemical N- demethylation and N- and O-demethylation, respectively, of an opioid precursor by means of the electrochemical reactor. The present invention further relates to a one-pot process for the N- and O-demethylation of an opioid precursor.

Description

Electrochemical reactor and processes using the electrochemical reactor

FIELD OF THE INVENTION

The present invention relates to an electrochemical reactor capable of processing an organic mixture comprising a suspension (slurry) of a solid and a liquid and to processes for the electrochemical N-demethylation and N- and O-demethylation, respectively, of an opioid precursor by means of the electrochemical reactor in which the solid opioid precursor and the liquid electrolyte are introduced separately into an electrochemical cell. The present invention further relates to a one-pot process for the N- and O-demethylation of an opioid precursor.

BACKGROUND

Synthetic chemistry is at the core of drug discovery and development in the pharmaceutical industry. The development of new synthetic methods can have major impacts on the pharmaceutical industry, not only by increasing overall efficiency but also can result in new chemical routes. Electrochemistry is an underutilized synthetic technology in the pharmaceutical industry. While electricity is a versatile, non-toxic and inexpensive redox agent, its use in the pharmaceutical industry is limited to homogeneous reaction mixtures.

Scale-up technology for the commercial-scale implementation of electrochemical processes is based on the utilization of narrow-gap parallel plate flow electrolysis cells, in which the electrodes are separated small distance (< 1 mm) and the reaction mixture is flown through the reactor using suitable pumping systems (D. Pletcher, F. C. Walsh, Industrial Electrochemistry, Second Edition, Springer, Dordrecht, Netherlands, 1993).

AD:MS:ko The shape of the electrodes can be rectangular planar, disk, or cylindrical - as concentrical electrodes (D. Pletcher, R. A. Green, R. C. D. Brown, Flow Electrolysis Cells for the Synthetic Organic Chemistry Laboratory. Chem. Rev. 2018, 118, 4573-4591). In all cases, the efficiency of the electrolysis is ensured by the small interelectrode gap and the high electrode surface area- to-reactor volume ratio. However, the small channels and gaps that characterize flow electrolysis cells have the drawback that only homogeneous solutions can be processed, as the presence of solids in the reaction mixture often cause clogging issues (Y. Chen, J. C. Sabio, R. L. Hartman, J. Flow Chem. 2015, 5, 166-171). In the case of organic materials that are poorly soluble in suitable organic solvents, very high dilutions are needed to ensure that the reaction mixture is homogeneous and can therefore be processed in a flow cell. This issue significantly increases the amount of solvents required for the reaction, which negatively affects the process-mass intensity of the reaction as well as its cost and environmental impact. Electrolysis of oxycodone, for example, had to be carried out at concentrations below 0.05 M to ensure homogeneous solutions processable in conventional flow cells (G. Glotz, C. 0. Kappe, D. Cantillo, Org. Lett. 2020, 22, 6891-6896;

WO2021249708A1).

Apart from parallel plate reactors, other type of electrochemical devices that may support continuous processing but resemble batch vessels have been disclosed. This type of device and operation has been called continuous stirred electrochemical reactor, and has mainly been used for water waste treatment (A. M. Polcaro, A. Vacca, M. Mascia, S. Palmas, R. Pompei, S. Laconi, Electrochim. Acta 2007, 52, 2595-2602) and metal recovery (J. R. Hernandez- Tapia, J. Vazquez-Arenas, I. Gonzalez, J. Haz. Mat. 2013, 262, 709-716; J. L. Nava-M. de Oca, E. Sosa, C. Ponce de Leon, M. T. Oropeza, Chem. Eng. Sci. 2001, 56, 2695-2702). All these examples deal with homogeneous solutions and have never been applied to electrochemical organic synthesis. An electrochemical reactor with a rotary disk electrode, which may be used for organic synthesis, has also been disclosed (JP 2005-290416 A). However, in this system the reagent (typically a gas) is introduced through the surface of the electrode and therefore it is incompatible with the use of solid reagents.

N- and/or O-Demethylation is an important transformation for the semisynthesis of various opioid antagonists (e.g., naltrexone, naloxone, and nalbuphine. The synthesis involves N-demethylation of an opioid precursor (e.g., oxycodone, 14-hydroxymorphinone) and subsequent N-alkylation of the ensuing nor-derivative (U. Rinner, T. Hudlicky, Synthesis of Morphine Alkaloids and Derivatives. In: Alkaloid Synthesis (Ed. : H. J. Knolker). Topics in Current Chemistry, vol 309. Springer, Berlin, Heidelberg, 2011, pp 33-66; S. Thavaneswaran, K. McCamley, P. J. Scammells, Nat. Prod. Commun. 2006, 1, 885-897). If the opioid precursor also contains a O-methyl group in the aromatic ring (e.g., oxycodone), demethylation of both the N- and O- methyl groups is required. Currently N- and/or O-demethylation of an opioid precursor is a lengthy process and is carried out on a large scale using stoichiometric amounts of hazardous chemicals like cyanogen bromide or chloroformates. Recently, it was shown that the intermediate N-cyanodihydro- 14-acetoxynorcodeinone was able to undergo conversion to 14-hydroxy-7,8- dihydronormorphinone in a single step reaction via demethoxylation and subsequent hydrolysis in the presence of simple hydrobromic acid (CN101033228 B). In WO2021249708 Al, a more environmentally friendly single step N-demethylation of an opioid precursor was described using flow cell electrolysis. The hydrolysis of the resulting oxazolidine electrolysis product was carried out in the presence of hydrochloric acid after it was transferred to the solution reservoir. It should be noted that the flow cell technology described in WO2021249708 Al is limited to homogenous systems and the presence of solid materials in the reaction mixture is not possible. Moreover, gases formed during the electrochemical reaction (i.e., hydrogen) may cover the surface of the electrode as there is little to no headspace within the flow cell, thus decreasing the cell efficiency. As aforementioned, selective N- demethylation of morphinan alkaloids has been carried out by anodic oxidation in an electrochemical cell, with concurrent hydrogen generation at the cathode as sole byproduct (G. Glotz, C. 0. Kappe, D. Cantillo, Org. Lett. 2020, 22, 6891-6896; WO2021249708A1), however its use is limited to homogeneous highly diluted mixtures and small scale.

Thus, the issue of providing a scalable electrochemical reactor for organic synthesis that can handle solid/liquid slurries and, in particular, that is capable of directly receiving solid reagents as input in a continuous manner and keeping the suspension or slurry stable by vigorous mixing, remain unsolved.

OBJECTS OF THE INVENTION

An object of the present invention is to provide an electrochemical reactor for organic synthesis capable of processing suspensions or slurries, i.e., heterogeneous mixtures of solids and liquids. Another object of the present invention is to provide a process for the electrochemical N-demethylation and N- and O-demethylation of opioid alkaloids in concentrated slurries of the solid opioid precursor in a suitable solvent using the reactor above. Another object of the present invention is to provide a one-pot process for the N- and O- demethylation of opioid alkaloids.

SUMMARY OF THE INVENTION

The present inventors have made diligent studies and have found that by designing the electrochemical reactor such that the solid and liquid materials can be introduced separately in the reactor and by providing a rotating electrode with one or more mixing elements, a stable suspension of the solids (for instance a solid opioid precursor) in the liquid (for instance an electrolyte in a solvent) without settling may be achieved, thereby allowing an electrochemical reaction (for instance an N-demethylation of the opioid precursor) in a high concentration as well as in a continuous manner. Accordingly, the present invention relates to an electrochemical reactor (herein also referred to as "slurry electrochemical reactor" or simply as "slurry cell") capable of processing an organic mixture comprising a suspension (slurry) of a solid and a liquid, wherein the electrochemical reactor comprises an inner electrode, an outer electrode, wherein the inner electrode and the outer electrode are arranged concentrically forming a first cavity therebetween (herein also referred to as "electrode cavity"), a first inlet configured for introducing the liquid into the first cavity of the electrochemical reactor, a second inlet configured for introducing the solid into the first cavity of the electrochemical reactor, wherein the first inlet and the second inlet are arranged such that the liquid and the solid are introduced separately, wherein the inner electrode is configured to be rotatable around its longitudinal axis, wherein the inner electrode comprises one or more mixing elements (configured to produce turbulence upon rotation, thereby keeping the suspension stable).

The electrochemical reactor can be used in a variety of syntheses of organic compounds, such as an electrochemical N-demethylation or an electrochemical N- and O-demethylation of an opioid precursor. The electrochemical reactor is in particular suitable for processing suspensions or slurries, i.e., heterogeneous mixtures of solids and liquids.

Accordingly, the present invention further relates to a process for preparing a compound of Formula (I) (herein also referred to as "nor-opioid compound" or simply as "nor-opioid") by means of an electrochemical reactor as described herein, in particular having the above features, the process comprising the steps of providing a compound of Formula (II) (herein also referred to as "opioid precursor") in the electrochemical reactor, (separately) providing a liquid containing an electrolyte (which may also be referred to as "supporting electrolyte") and a solvent in the electrochemical reactor, forming (and maintaining) a suspension (slurry) of the solid and the liquid by rotating the inner electrode having one or more mixing elements, electrolyzing the suspension in the electrochemical reactor, and subsequently treating the reaction mixture with an acid, wherein the acid is selected from the group consisting of hydrochloric acid, acetic acid and sulfuric acid, wherein the compound of Formula (I) has the following structure:

wherein each represents a single or double bond, provided that two double bonds are not adjacent to each other;

R¹ is selected from the group consisting of H, Ci-io alkyl, Ce-io aryl, C3-10 cycloalkyl, C1-10 alkylene-Ce-io aryl, C1-10 alkylene-Cs-io cycloalkyl and a protecting group;

R³ is selected from the group consisting of C1-10 alkyl, Ce-io aryl, C3-10 cycloalkyl, C1-10 alkylene-Ce-io aryl, C1-10 alkylene-Cs-io cycloalkyl and a protecting group or is absent; wherein one or more hydrogen atoms on the R¹ and R³ groups may be replaced with F and/or Cl; wherein the compound of Formula (II) has the following structure:

wherein

R¹, R³ and — — ,z are as defined above; and R² is selected from the group consisting of H, C(O)R⁶, S(O)R⁶,SO2 ⁶, P(O)R⁶R⁷, P(O)(OR⁶)R⁷, and P(O)(OR⁶)(OR⁷), and

R⁶ and R⁷ are each independently selected from the group consisting of C3-10 cycloalkyl, C3-10 heterocycloalkyl, C3-10 cycloalkenyl, C1-10 alkyl, C2-10 alkenyl, Ce-io aryl and C5-10 heteroaryl, each of the groups being unsubstituted or substituted with one or more substituents independently selected from C1-4 alkyl, O-C1-4 alkyl, halogen, CN, NO2, Ce-io aryl and O-Ce-io aryl.

In addition, the present invention relates to a process for preparing a compound of Formula (III) by means of an electrochemical reactor as described herein, in particular having the above features, the process comprising the steps of providing a compound of Formula (II) in the electrochemical reactor, (separately) providing a liquid containing an electrolyte and a solvent in the electrochemical reactor, forming (and maintaining) a suspension (slurry) of the solid and the liquid by rotating the inner electrode having one or more mixing elements, electrolyzing the suspension in the electrochemical reactor, and subsequently treating the reaction mixture with hydrogen bromide (HBr), wherein the compound of Formula (III) has the following structure:

wherein each

represents a single or double bond, provided that two double bonds are not adjacent to each other; R³ is selected from the group consisting of C1-10 alkyl, Ce-io aryl, C3-10 cycloalkyl, C1-10 alkylene-Ce-io aryl, C1-10 alkylene-Cs-io cycloalkyl and a protecting group or is absent; wherein one or more hydrogen atoms on the R³ group may be replaced with F and/or Cl; wherein the compound of Formula (II) has the following structure:

wherein

R³ and are as defined above; and

R.¹ is selected from the group consisting of H, Ci-io alkyl, Ce-io aryl, C3-10 cycloalkyl, C1-10 alkylene-Ce-io aryl, C1-10 alkylene-Cs-io cycloalkyl and a protecting group, wherein one or more hydrogen atoms on the R¹ group may be replaced with F and/or Cl;

R² is selected from the group consisting of H, C(O)R.⁶, S(O)R.⁶,SO2R.⁶, P(O)R.⁶R.⁷, P(O)(OR.⁶)R.⁷, and P(O)(OR⁶)(OR⁷), and

The present inventors have further found that a one-pot process for the preparation of a compound of Formula (III) may also be achieved by an initial oxidation of the tertiary amine of a compound of Formula (II) with stoichiometric amounts of a chemical oxidizing reagent (oxidant), followed by treatment with an aqueous solution of HBr.

Thus, the present invention further relates to a process for preparing a compound of Formula (III), the process comprising the steps of: reacting a compound of Formula (II) with a chemical oxidant, and subsequently treating the reaction mixture with hydrogen bromide (HBr); wherein the compound of Formula (III) has the following structure:

wherein each

represents a single or double bond, provided that two double bonds are not adjacent to each other;

R³ is selected from the group consisting of Ci-io alkyl, Ce-io aryl, C3-10 cycloalkyl, C1-10 alkylene-Ce-io aryl, C1-10 alkylene-Cs-io cycloalkyl and a protecting group or is absent; wherein one or more hydrogen atoms on the R³ group may be replaced with F and/or Cl; wherein the compound of Formula (II) has the following structure:

wherein

are as defined above; and

Other objects and many of the attendant advantages of embodiments of the present invention will be readily appreciated and become better understood by reference to the following detailed description of embodiments and examples and the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows a cross-sectional view of a slurry electrochemical reactor in accordance with the embodiments of the present invention. Figure 2 shows exploded views of the embodiment of Figure 1, in which some parts have been omitted for clarity.

Figure 3 shows an exemplary embodiment of the schematic view of a setup for the operation of the slurry cell as a continuous stirred electrochemical reactor.

Figure 4 shows an exemplary embodiment of the schematic view of series of slurry electrochemical reactors connected in series for continuous stirred tank electrochemical reactor cascade operation mode.

Figure 5 shows an exemplary embodiment of a reaction scheme of a process for the electrochemical N- and O-demethylation of an opioid precursor.

DETAILED DESCRIPTION OF THE INVENTION

Hereinafter, details of the present invention and other features and advantages thereof will be described. However, the present invention is not limited to the following specific descriptions, but they are rather for illustrative purposes only.

It should be noted that features described in connection with one exemplary embodiment or exemplary aspect may be combined with any other exemplary embodiment or exemplary aspect, in particular features described with any exemplary embodiment of the slurry electrochemical reactor and its operation may be combined with any further exemplary embodiment of an electrochemical reaction and vice versa, unless specifically stated otherwise.

Where an indefinite or definite article is used when referring to a singular term, such as "a", "an" or "the", a plural of that term is also included and vice versa, unless specifically stated otherwise, whereas the word "one" or the number "1", as used herein, typically means "just one" or "exactly one". The expression "comprising", as used herein, includes not only the meaning of "comprising", "including" or "containing", but also encompasses "consisting essentially of" and "consisting of".

In an embodiment, a slurry electrochemical reactor and a description of its typical operation is provided. In particular, an electrochemical reactor capable of processing an organic mixture comprising a suspension (slurry) of a solid and a liquid is provided, wherein the electrochemical reactor comprises an inner electrode (having a cylindrical shape, in particular a filled cylindrical shape), an outer electrode (having a cylindrical shape, in particular a hollow cylindrical shape), wherein the inner electrode and the outer electrode are arranged concentrically forming a first cavity therebetween, a first inlet configured for introducing the liquid into the first cavity of the electrochemical reactor, a second inlet configured for introducing the solid into the first cavity of the electrochemical reactor, wherein the first inlet and the second inlet are arranged such that the liquid and the solid are introduced separately, wherein the inner electrode is configured to be rotatable around its longitudinal axis, wherein the inner electrode comprises one or more mixing elements (configured to produce turbulence upon rotation, thereby keeping the suspension stable).

The terms "suspension" and "slurry" are used substantially interchangeable herein. These terms may particularly denote a heterogeneous mixture of solids and liquids, such as a liquid containing solid particles, as commonly understood by a person skilled in the art.

The electrochemical reactor comprises a first inlet configured for introducing a liquid into the first cavity (i.e. the cavity between the inner and the outer electrodes, herein also referred to as "electrode cavity") of the electrochemical reactor and a second inlet configured for introducing a solid into the first cavity of the electrochemical reactor, wherein the first inlet and the second inlet are arranged such that the liquid and the solid are introduced separately (independently from each other). Thus, there is no need to mix the liquid and the solid in advance prior to the introduction into the electrochemical reactor, thereby avoiding an additional process step of premixing. Rather, the liquid and the solid may be introduced separately from each other into the electrochemical reactor, which additionally allows an independent dosage of the liquid and the solid from each other. The liquid and the solid may be introduced in a batchwise manner, but also in a continuous manner.

The electrochemical reactor comprises an inner electrode and an outer electrode, wherein the inner electrode and the outer electrode are arranged concentrically forming a first cavity therebetween. The terms "inner electrode" and "outer electrode" therefore denote two separate, concentrically arranged electrodes (spaced apart by the electrode cavity, wherein the distance between the inner electrode and the outer electrode may also be referred to as "interelectrode distance" or "interelectrode gap" herein), wherein the outer electrode is arranged more remote (distant) from the center than the inner electrode. The inner electrode may have a cylindrical shape, in particular formed as a filled cylinder. The outer electrode may have a hollow cylindrical or tubular shape. In an embodiment, the outer electrode may be non-rotatable or stationary.

In an embodiment, the inner electrode may act as an anode in an electrochemical reaction and the outer electrode may act as a cathode. In another embodiment, the inner electrode may act as a cathode in an electrochemical reaction and the outer electrode may act as an anode.

In an embodiment, the inner electrode and/or the outer electrode comprise at least one of the group consisting of stainless steel, nickel, lead, bronze, platinum, tin, copper, titanium, chromium, zinc, magnesium aluminum, or any metal alloy thereof, or other materials coated or plated with another metal, or carbon-containing materials, such as graphite, impervious graphite, reticulated vitreous carbon, glassy carbon, boron doped diamond or composite materials made thereof.

In an embodiment, a diameter of the inner electrode and a diameter of the outer electrode are selected such that a desired distance between the inner electrode and the outer electrode ("target interelectrode gap") is achieved in accordance with the following formula: outer electrode diameter = inner electrode diameter + 2 x interelectrode gap.

In an embodiment, a distance between the inner electrode and the outer electrode (i.e. the interelectrode gap or interelectrode distance) is (kept) constant for a given process independent of a size of the electrochemical reactor. By taking this measure, the electrode surface area-to-volume ratio may be increased with the reactor size (for instance during scale up). The interelectrode distance may be set to values between 0.1 mm and 100 mm. Preferably, the interelectrode distance is set to values between 5 mm and 10 mm.

The inner electrode is configured to be rotatable around its longitudinal axis (i.e. around its center). To this end, the inner electrode may be coupled with driving means configured for rotating the inner electrode, for instance via a shaft and a shaft coupling. By rotating the inner electrode, electrochemical reactions which are to take place in the electrochemical reactor may be promoted. However, a mere rotating electrode may not be sufficient to enable an electrochemical reaction if the reaction mixture is a slurry, in particular to maintain a stable suspension of solids in the liquid without settling during the electrochemical reaction to take place.

Therefore, the inner electrode comprises one or more mixing elements, such as grooves, recesses or depressions in the surface of the inner electrode and/or protrusions at the surface of the inner electrode and/or separate (i.e. non-integral) mixing elements attached to the inner electrode. The one or more mixing elements are integral of the inner electrode and/or coupled to the inner electrode such that they rotate together with the inner electrode upon its rotation. In other words, the one or more mixing elements are adapted such that they rotate together with the inner electrode upon its rotation. In particular, the one or more mixing elements are configured to produce turbulence upon rotation, thereby keeping the suspension stable (without settling). The one or more mixing elements may be arranged at any position along the length of the inner electrode. It may however be advantageous if one or more mixing elements are arranged at or near the bottom of the inner electrode, which may be particularly efficient for mixing and maintaining a stable suspension.

In an embodiment, the electrochemical reactor further comprises a (containment) vessel enclosing the inner electrode and the outer electrode, wherein a second cavity (herein also referred to as "vessel cavity") is formed between the outer electrode and the vessel, wherein the second cavity is configured to be filled with a thermostated fluid, in particular such that the outer electrode is in direct contact with the thermostated fluid. By taking this measure, an efficient temperature control of the outer electrode as well as of the entire electrochemical reactor, in particular within the first cavity where the electrochemical reactions take place, may be achieved.

In an embodiment, the electrochemical reactor further comprises an outlet, such as an output valve, configured for allowing a removal (in particular a continuous removal) of electrolyzed reaction mixture from the electrochemical reactor.

In an embodiment, the outlet is configured to be connected to an inlet of another reactor (thereby linking two or more electrolytic cells in a cascade). Such a continuous stirred electrochemical reactor cascade (CSTER.C) will be explained in further detail below referring to Figure 4. In a nutshell, an electrochemical reactor according to an exemplary embodiment comprises a jacketed cylindrical vessel, with the vessel wall acting as an outer electrode and the jacket as containment for passing a thermostated fluid, a (second) inner electrode placed inside of the cylindrical vessel; a solid input device (i.e. the second inlet) to introduce continuously solid materials into the reactor; a liquid pump to continuously introduce liquid materials into the reactor via the first inlet; an output valve (i.e. the outlet) to empty the reactor or continuously remove reaction mixture from the reactor; a power supply as a source of electrical current and a motor that spins the inner electrode.

In another embodiment, the inner electrode contains mixing elements and it is rotated. Rotation of the inner electrode containing mixing elements produces a high turbulence capable of maintaining solid suspensions stable and avoids settling of solid particles.

In another embodiment, electrochemical processes are carried out in the electrochemical reactor by introducing solid starting materials and liquid starting materials separately in a continuous manner. If the solid materials are not fully soluble in the liquid, a stable slurry or suspension is formed within the reactor due to the high mixing produced by the rotating inner electrode comprising one or more mixing elements.

In another embodiment, the distance between the two concentrical electrodes in the electrochemical reactor is kept constant and independent of the size of the reactor. The constant interelectrode distance and cylindrical shape result in an increase of the electrode a rea-to- reactor volume ratio as the size of the reactor increases during scale up.

The electrochemical reactor as described herein may in particular be used in processes for the electrochemical N-demethylation and N- and 0- demethylation, respectively, of an opioid precursor, as will be explained in further detail below. However, the electrochemical reactor as described herein may of course also be advantageously used for other electrochemical reactions, in particular where the reaction mixture is a suspension or slurry.

In an embodiment, the present invention relates to a process for preparing a compound of Formula (I) by means of an electrochemical reactor as described herein, the process comprising the steps of: providing a compound of Formula (II) (in solid form) in the electrochemical reactor,

(separately) providing a liquid containing an (supporting) electrolyte and a (suitable) solvent in the electrochemical reactor, forming (and maintaining) a suspension (slurry) of the solid and the liquid by rotating the inner electrode having one or more mixing elements; electrolyzing the suspension in the electrochemical reactor (thereby electrochemically demethylating the compound of Formula (II)); and subsequently (removing the reaction mixture from the electrochemical reactor and) treating the reaction mixture with an acid (in particular an aqueous solution of the acid in water) (after having removed the reaction mixture from the electrochemical reactor), wherein the acid is selected from the group consisting of hydrochloric acid, acetic acid and sulfuric acid; wherein the compound of Formula (I) has the following structure:

wherein each represents a single or double bond, provided that two double bonds are not adjacent to each other; R¹ is selected from the group consisting of H, Ci-io alkyl, Ce-io aryl, C3-10 cycloalkyl, C1-10 alkylene-Ce-io aryl, C1-10 alkylene-Cs-io cycloalkyl and a protecting group;

wherein

are as defined above; and

R² is selected from the group consisting of H, C(O)R⁶, S(O)R⁶,SO2 ⁶, P(O)R⁶R⁷, P(O)(OR⁶)R⁷, and P(O)(OR⁶)(OR⁷), and

In an embodiment, the step of providing a compound of Formula (II) in the electrochemical reactor comprises introducing the compound of Formula (II) in solid form into the electrochemical reactor via the second inlet, and the step of providing a liquid containing an electrolyte and a solvent in the electrochemical reactor comprises introducing the liquid into the electrochemical reactor via the first inlet. The term "alkyl", as used herein, refers to, whether it is used alone or as part of another group, straight- or branched-chain, saturated alkyl groups. The term "Ci-io alkyl" means an alkyl group having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. In some embodiments, one or more, including all of the available hydrogen atoms in the alkyl groups may be replaced with a halogen, such as F and/or Cl.

The term "aryl", as used herein, refers to cyclic groups that contain at least one aromatic ring. The aryl group may contain 6, 9 or 10 atoms, such as phenyl, naphthyl or indanyl. In some embodiments, one or more, including all of the available hydrogen atoms in the aryl groups may be replaced with a halogen, such as F and/or Cl.

The term "cycloalkyl", as used herein, refers to, whether it is used alone or as part of another group, cyclic, saturated alkyl groups. The term "C3-10 cycloalkyl" means a cycloalkyl group having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. In some embodiments, one or more of the hydrogen atoms in the cycloalkyl groups may be replaced with a halogen, such as F and/or Cl.

The term "alkylene", as used herein, refers to, whether alone or as part of another group, an alkyl group that is bivalent; i.e., that is substituted on two ends with another group. The term "C1-10 alkylene" means an alkylene group having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. In some embodiments, one or more, including all of the available hydrogen atoms in the alkylene groups may be replaced with a halogen, such as F and/or Cl.

The term "protecting group", as used herein, refers to a chemical moiety which protects or masks a reactive portion of a molecule to prevent side reactions in those reactive portions of the molecule, while reacting a different portion of the molecule. Thus, a protecting group may be introduced into a molecule by chemical modification of a functional group so as to achieve chemoselectivity in a subsequent chemical reaction. After the reaction is completed, the protecting group can be removed under conditions that do not degrade or decompose the remaining portions of the molecule. The selection of a suitable protecting group can be appropriately made by a person skilled in the art. Examples of suitable protecting groups include, but are not limited to acetyl, benzoyl and silyl ethers, such as t-butyl-dimethylsilyl (TBDMS) or trimethylsilyl (TMS).

The term "heterocycloalkyl", as used herein, refers to, whether it is used alone or as part of another group, cyclic, saturated alkyl groups containing at least one heteroatom, such as N, 0 and/or S. The term "C3-10 heterocycloalkyl" means a heterocycloalkyl group having 3, 4, 5, 6, 7, 8, 9 or 10 atoms including carbon atoms, in which at least one atom is a heteroatom, such as N, 0 and/or S. In some embodiments, one or more, including all of the available hydrogen atoms in the heterocycloalkyl groups may be replaced with a halogen, such as F and/or Cl.

The term "cycloalkenyl", as used herein, refers to, whether it is used alone or as part of another group, cyclic, unsaturated alkyl groups. The term "C3-10 cycloalkenyl" means a cycloalkenyl group having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms and at least one double bond. In some embodiments, one or more, including all of the available hydrogen atoms in the cycloalkenyl groups may be replaced with a halogen, such as F and/or Cl.

The term "alkenyl", as used herein, refers to, whether it is used alone or as part of another group, straight- or branched-chain, unsaturated alkenyl groups. The term "C2-10 alkenyl" means an alkenyl group having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms and at least one double bond. In some embodiments, one or more, including all of the available hydrogen atoms in the alkenyl groups may be replaced with a halogen, such as F and/or Cl. The term "heteroaryl", as used herein, refers to cyclic groups that contain at least one aromatic ring and at least one heteroatom, such as N, 0 and/or S. The term "C5-10 heteroaryl" means an aryl group having 5, 6, 7, 8, 9 or 10 atoms including carbon atoms, in which at least one atom is a heteroatom, such as N, 0 and/or S. In some embodiments, one or more, including all of the available hydrogen atoms in the heteroaryl groups may be replaced with a halogen, such as F and/or Cl.

In an embodiment, R² is at least one of H or an acyl group, such as C1-10 acyl. The term "acyl", as used herein, refers to, whether it is used alone or as part of another group, a straight or branched, saturated alkyl chain bound at a carbonyl (-C(O)-) group. The term C1-10 acyl means an acyl group having 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 carbon atoms (i.e. -C(0)-Ci-io alkyl). In some embodiments, one or more, including all of the available hydrogen atoms in the acyl groups may be replaced with a halogen, such as F and/or Cl, and thus may include, for example trifluoroacetyl.

In an embodiment, the nor-opioid compound is a compound of Formula (la) depicted below and the opioid precursor compound is a compound of Formula (Ila) depicted below. In this embodiment, R³ in the compounds of Formulas (I) and (II) is absent.

wherein represents a single or double bond;

R¹ is selected from the group consisting of H, Ci-io alkyl, Ce-io aryl, C3-10 cycloalkyl, C1-10 alkylene-Ce-io aryl, C1-10 alkylene-Cs-io cycloalkyl and a protecting group, wherein one or more hydrogen atoms on the R¹ groups may be replaced with F and/or Cl.

wherein

R.¹ and are as defined above; and

In another embodiment, the present invention relates to a process for preparing a compound of Formula (III) by means of an electrochemical reactor as described herein, the process comprising the steps of: providing a compound of Formula (II) (in solid form) in the electrochemical reactor,

(separately) providing a liquid containing an electrolyte and a (suitable) solvent in the electrochemical reactor, forming (and maintaining) a suspension (slurry) of the solid and the liquid by rotating the inner electrode having one or more mixing elements; electrolyzing the suspension in the electrochemical reactor (thereby electrochemically demethylating the compound of Formula (II)); and subsequently (removing the reaction mixture from the electrochemical reactor and) treating the reaction mixture with hydrogen bromide (HBr) (in particular an aqueous solution of the acid in water) (after having removed the reaction mixture from the electrochemical reactor); wherein the compound of Formula (III) has the following structure:

wherein each — — ,z represents a single or double bond, provided that two double bonds are not adjacent to each other;

wherein

are as defined above; and R¹ is selected from the group consisting of H, Ci-io alkyl, Ce-io aryl, C3-10 cycloalkyl, C1-10 alkylene-Ce-io aryl, C1-10 alkylene-Cs-io cycloalkyl and a protecting group, wherein one or more hydrogen atoms on the R¹ group may be replaced with F and/or Cl;

R² is selected from the group consisting of H, C(O)R⁶, S(O) ⁶,SO2 ⁶, P(O)R⁶R⁷, P(O)(OR⁶)R⁷, and P(O)(OR⁶)(OR⁷), and

The above process for the preparation of a compound of formula (III) from a compound of formula (II) by a sequential N- and O-defunctionalization comprising electrolysis in the slurry electrochemical reactor followed by hydrolysis in an aqueous HBr solution is particularly advantageous, as removal of both the nitrogen and oxygen groups is needed for the synthesis of opioid antagonists such as naloxone.

In an embodiment, the step of providing a compound of Formula (II) in the electrochemical reactor comprises introducing the compound of Formula (II) in solid form into the electrochemical reactor via the second inlet, and the step of providing a liquid containing an electrolyte and a solvent in the electrochemical reactor comprises introducing the liquid into the electrochemical reactor via the first inlet.

In an embodiment, the hydrolysis step (i.e. treating the reaction mixture with hydrogen bromide (HBr)) is carried out with an aqueous solution of HBr with a HBr concentration between 5% and 99%. HBr concentrations between 25% and 45% have shown particularly suitable in terms of reaction yield and (minimum) side products. In an embodiment, the hydrolysis step with a solution of HBr is carried out at temperatures ranging between 10 °C and 200 °C. Temperatures ranging between 80 °C and 120 °C have shown particularly suitable in terms of reaction yield.

In an embodiment, the hydrolysis step with a solution of HBr is carried out for periods of time ranging between 10 min and 12 h. Reaction times ranging between 2 h and 4 h have shown particularly suitable in terms of reaction yield.

In an embodiment, the electrolyte is selected from the group consisting of a quaternary ammonium salt, a lithium salt, a sodium salt, a potassium salt and mixtures or combinations thereof. Suitable examples of the quaternary ammonium salt include tetraalkylammonium (such as tetraethylammonium or tetrabutylammonium) salts having tetrafluoroborate or hexafluorophosphate anions, such as tetraethylammonium tetrafluoroborate (Et4NBF4), tetrabutylammonium tetrafluoroborate (nBu4NBF4) and tetrabutylammonium hexafluorophosphate (nBu4NPF₆). Suitable examples of potassium salts include potassium acetate (KOAc). Suitable examples of lithium salts include lithium perchlorate (LiCICU), lithium tetrafluoroborate (UBF4) and lithium hexafluorophosphate (LiPF₆) and suitable examples of sodium salts include sodium perchlorate (NaCICU), sodium tetrafluoroborate (NaBF₄) and sodium hexafluorophosphate (NaPFe). In particular, quaternary ammonium and potassium salts have proven particularly suitable for solving the object of the present invention. Potassium acetate (KOAc) has shown particularly suitable in terms of an improved efficiency (yield and selectivity) of the N-demethylation process.

In an embodiment, the electrolytic unit further comprises a solvent. For instance, the vessel cavity may be at least partially filled with a solvent. While not excluded, it is not required for the N-demethylation process according to the invention that the solvent is anhydrous, which contributes to a convenient and cost-effective process.

In an embodiment, the solvent is selected from the group consisting of acetonitrile, dimethylformamide, dimethylacetamide, methanol, ethanol, n- propanol, isopropanol, hexafluoroisopropanol (HFIP), trichloromethane (chloroform), dichloromethane, tetra hydrofuran, methyltetrahydrofuran, acetone and mixtures or combinations thereof. It may be advantageous to use mixtures or combinations of these solvents. In particular a combination of acetonitrile (MeCN) and methanol (MeOH), for instance in a volume ratio MeCN/MeOH of from 1 : 10 to 10: 1, such as 4: 1, has proven particularly suitable for solving the object of the present invention. Combination of ethanol as the solvent and potassium acetate (KOAc) as the electrolyte has shown particularly suitable in terms of an improved efficiency (yield and selectivity) of the N-demethylation process.

In an embodiment, the step of electrolyzing the suspension (e.g. electrochemically demethylating the compound of Formula (II)) may be carried out at room temperature, but may also be carried out in a temperature range of from 5 to 50 °C, such as from 10 to 40 °C.

The duration of the step of electrolyzing the suspension (e.g. electrochemically demethylating the compound of Formula (II)) in the slurry electrochemical reactor is not particularly limited and may be appropriately adjusted by a person skilled in the art, for instance by monitoring the reaction and thereby determining the completion of the conversion.

In an embodiment, the step of electrolyzing the suspension (e.g. electrochemically demethylating the compound of Formula (II)) in the slurry electrochemical reactor comprises an electrolytic oxidation of the tertiary N- methylamine functional group of the compound of Formula (II) under constant current (galvanostatic) conditions, but may also be carried out under constant potential (potentiostatic) conditions. Current densities from 1 mA/cm² to 300 mA/cm² may be utilized under constant current. Current densities in the range of 2 mA/cm² to 20 mA/cm² have proven particularly suitable for solving the object of the present invention. Cell voltages from 1 V to 30 V may be utilized. Cell voltages in the range of 2 to 5 V have proven particularly suitable for solving the object of the present invention.

In an embodiment, the present invention relates to a (one-pot) process for preparing a compound of Formula (III), the process comprising the steps of: reacting a compound of Formula (II) with a chemical oxidant, and subsequently treating the reaction mixture with hydrogen bromide

(HBr); wherein the compound of Formula (III) has the following structure:

wherein each

wherein

R³ and ~s~z.z are as defined above; and

In an embodiment, the step reacting a compound of Formula (II) with a chemical oxidant, and the subsequent step of treating the reaction mixture with hydrogen bromide (HBr) may be carried in the same reaction vessel. Therefore, this process may also be designated as a "one-pot process".

In an embodiment, the chemical oxidant is selected from the group consisting of hydrogen peroxide, manganese(IV) oxide, meta-chloroperbenzoic acid, hypervalent iodine compounds, 2,3-dichloro-5,6-dicyanobenzoquinone, hypochlorites, oxygen (O2) or air. In an embodiment, the step of reacting a compound of Formula (II) with a chemical oxidant is carried out in a solvent, such as acetonitrile, dimethylformamide, dimethylacetamide, methanol, ethanol, n-propanol, isopropanol, hexafluoroisopropanol (HFIP), trichloromethane (chloroform), dichloromethane, tetra hydrofuran, methyltetrahydrofuran, acetone and mixtures or combinations thereof.

In an embodiment, the step of reacting a compound of Formula (II) with a chemical oxidant is carried out at a temperature of from 0 °C to 150 °C and/or for 10 min to 12 h.

In an embodiment, the step of treating the reaction mixture with hydrogen bromide (HBr) is carried out with an aqueous solution of HBr with a HBr concentration between 5% and 95%. HBr concentrations between 25% and 45% have shown particularly suitable in terms of reaction yield and (minimum) side products.

In an embodiment, the step of treating the reaction mixture with hydrogen bromide (HBr) is carried out at temperatures ranging between 10 °C and 200 °C. Temperatures ranging between 80 °C and 120 °C have shown particularly suitable in terms of reaction yield.

In an embodiment, the step of treating the reaction mixture with hydrogen bromide (HBr) is carried out for 10 min to 12 h.

The present invention is further described by reference to the accompanying figures and by the following examples, which are solely for the purpose of illustrating specific embodiments and shall not be construed as limiting the scope of the invention in any way.

Figure 1 shows an electrochemical reactor 1 according to an exemplary embodiment. An outer electrode 2 having a tubular shape is contained inside a (containment) vessel 3 which acts a jacket for the passage of a thermostated fluid. The outer electrode 2 can be made of any impervious electrode material. Impervious electrode materials include but are not limited to any solid metal material such as stainless steel, nickel, lead, bronze, platinum, tin, copper, titanium, chromium, zinc, magnesium or aluminium, or any metal alloys or other materials coated or plated with another metal, or carbon materials including but not limited to graphite, glassy carbon, boron doped diamond or composite materials made thereof.

The containment vessel 3 is made of an electrically insulating material. The containment vessel 3 comprises an input 4 and an output 5 for a circulating thermostated fluid, which is used to control the temperature of the reactor. The thermostated fluid is in direct contact with the outer electrode 2, which improves the heat transfer properties.

A cylindrical base 6 is used to assemble the outer electrode 2 to the containment vessel 3. The cylindrical base 6 comprises an outlet 7, for instance an output valve that serves as an outlet for the electrochemical cell. The cylindrical base 6 also comprises a circular groove 8 (recess) in which a first bearing 9 can be inserted. The first bearing 9 connects an inner electrode 10 to the cylindrical base 6 through a connector 11 while permitting free rotation of the inner electrode 10. The inner electrode 10 can have cylindrical shape. Optionally, the inner electrode 10 can have grooves in the surface to improve turbulence of a mixture contained between the outer and the inner electrodes 2 and 10 upon rotation. The electrolysis takes place in the space between the outer and the inner electrodes 2 and 10, i.e. in a first cavity 15. The inner electrode 10 can be made of any electrode material, including but are not limited to any metal material such as stainless steel, nickel, lead, bronze, platinum, tin, copper, titanium, chromium, zinc, magnesium or aluminium, or any metal alloys or other materials coated or plated with another metal, or carbon materials including but not limited to graphite, glassy carbon, boron doped diamond or composite materials made thereof. A mixing element 12 is attached to inner electrode 10. The mixing element 12 rotates with inner electrode 10 during operation of the electrolytic cell. Motion of mixing element 12 produces efficient mixing of the reaction mixture contained in the electrolytic cell. If the reaction mixture comprises a suspension or slurry of a solid in a liquid, motion of mixing element 12 maintains the slurry or suspension stable and avoids solid settling at the bottom of the electrochemical reactor. The mixing element 12 can be placed anywhere along the length of the inner electrode 10. Optimal mixing is achieved when the mixing element 12 is placed at the bottom of the inner electrode 10.

A reactor lid 13 is attached to the top of the containment vessel 3, the outer electrode 2 and the inner electrode 10. The reactor lid 13 closes the top part of the second cavity 14 ("vessel cavity") formed between the containment vessel 3 and the outer electrode 2, and serving for thermostated fluid circulation The reactor lid 13 also closes the first cavity 15 ("electrode cavity") between the outer electrode 2 and the inner electrode 10, in which the reaction takes place. The reactor lid 13 has a circular groove in the center, in which a second bearing 16 can be attached. Additionally, the reactor lid 13 comprises two or more through holes and typically four through holes 17, 18, 19 and 20 which pass through the lid from top to bottom. The through hole 17 is located in the center of the reactor lid 13 and is aligned with the second bearing 16. The through hole 17 is provided for allowing a shaft 21, which is attached to the second bearing 16 and the inner electrode 10, to pass though the reactor lid 13 and may therefore also be denoted "through hole for shaft" 17. The shaft 21 is used to transmit a rotational motion to the inner electrode 10. The through hole 18 serves for a liquid input into the electrochemical reactor 1 and therefore represents the first inlet 18 configured for introducing the liquid into the first cavity 15 of the electrochemical reactor 1. Liquids are inputted into the reactor using a pump 22. The pump 22 and the first inlet 18 are connected with a conduit 23, such as a tube. The through hole 19 serves for a solid input for the electrochemical reactor 1 and therefore represents the second inlet 19 configured for introducing the solid into the first cavity 15 of the electrochemical reactor 1. The second inlet 19 comprises a solid conveyor 24. The solid conveyor 24 introduces solid material from a solid container 25 into the reactor. The solid conveyor 24 is actuated by a motor 26.

The through hole 20 is provided for allowing an electrical connector 27, which connects the inner electrode 2 to an electrical power supply 28, to pass though the reactor lid 13 and may therefore also be denoted "through hole for electrical connector" 20. An electrical connection between the inner electrode 10 and the electrical power supply 28 is established through the shaft 21, which is made of a conductive material, and a spinning electrical connector 29.

Furthermore, the shaft 21 is driven by an overhead stirrer 30 or a similar driving means configured for rotating inner electrode. Transmission of the rotational motion between the overhead stirrer 30 and the shaft 21 is established using a shaft coupling 31.

Figure 2 shows exploded views of the embodiment of Figure 1, in which some parts have been omitted for clarity.

In another embodiment, the dimensions of the electrodes 2 and 10 are selected in a way that the distance between the inner wall of the outer electrode 2 and the outer wall of the inner electrode 10 is a given value called "interelectrode distance". The interelectrode distance can be set to values between 0.1 mm and 100 mm. Ideally, the interelectrode distance is set to values between 5 mm and 10 mm. The interelectrode distance remains constant independently of the size of the reactor. For example, if the target interelectrode distance is 5 mm, the outer diameter of the inner electrode 10 equals the inner diameter of the outer electrode 2 minus 10 mm. This formula is utilized independent of the overall dimensions of the slurry electrochemical reactor. Thus, due to the cylindrical geometry of the slurry reactor, the electrode area-to-reactor volume ratio of the system increases with the reactor size. These properties facilitate the scale up of electrochemical processes developed in this electrolytic cell.

In a typical reactor operation, a solid substrate is loaded in the solid container 25. Introduction of the solid into the reactor is initiated by starting the motor 26 and the solid conveyor 24. Simultaneously, the liquid component of the electrochemical reaction, which may comprise a solvent and a supporting electrolyte, is introduced into the reactor by initiating the pump 22. Activation of the overhead stirrer 30 rotates the inner electrode 10 and the mixing element 12. If the reaction mixture is homogeneous, excellent mass transfer is provided by the rotation of the inner electrode 10 and the turbulence provoked by the mixing element 12. If the solid component of the reaction is not fully soluble in the liquid, a slurry or suspension if formed. In this case, rotation of the inner electrode 10 and the mixing element 12 keeps the suspension stable and avoids settling of the solid at the bottom of the electrolytic cell. Once the electrolytic reactor is filled with the desired amount of liquid and solid material, electrolysis is started by activating the electrical power supply 28. Rotation of the inner anode 10 and the mixing element 12 is continued during the electrolysis process. The slurry reactor does not require homogenous solutions to operate. Thus, the use of large amounts of organic solvents is avoided for the processing of starting materials that are poorly soluble in suitable solvents.

In an embodiment, the slurry electrochemical reactor operation described above can be carried out in batch mode. In batch mode, the desired amounts of the solid and the liquid materials are introduced in the reactor under the stirring of the rotating inner electrode 10 and the mixing element 12. Once the desired amount of material has been introduced into the slurry reactor, addition of material stops and the electrolysis is started by activating the electrical power supply 28. When the electrolysis is finalized, the reaction mixture can be removed from the electrolytic cell by opening the outlet 7.

In another embodiment as shown in Figure 3, the slurry electrochemical reactor can be operated as a continuous stirred electrochemical reactor (CSTER). In CSTER operation mode, the solid and liquid starting materials are continuously introduced into the reactor while stirring by the rotation of the inner electrode 10 and the mixing element 12. Then, the electrolytic cell has reached the desired filling level, the mixture is simultaneously removed via the outlet 7. Electrolysis is initiated by activating power supply 28. In this operation mode, a continuous stream of electrolyzed reaction mixture is obtained from the reactor outlet.

In another embodiment as shown in Figure 4, the slurry electrochemical reactor can be operated as a continuous stirred electrochemical reactor cascade (CSTERC). In CSTERC operation mode, two or more slurry reactors are connected in series. This is achieved by connecting the outlet 7 of a slurry reactor to the first inlet 18 for liquid input of the second reactor. Transfer of material from a slurry reactor to the next in a CSTERC can be aided by pumps or promoted by gravity. In this operation mode, a continuous stream of electrolyzed reaction mixture is obtained from the reactor output from the last electrolytic cell in the CSTERC. In CSTERC operation mode, higher reaction conversions can be achieved compared to CSTER mode.

The slurry reactor object of this invention present significant advantages with respect to parallel plate flow electrolysis cells. While parallel plate flow electrolysis cells require the use of homogeneous solutions and thus occasionally high dilutions with large amounts of solvent, the slurry reactor can process solid suspensions. Moreover, as the slurry reactor possesses a headspace, generation of gases during the electrolytic process (e.g., hydrogen evolution at the cathode during an anodic oxidation) is not problematic. The gas generated can move to the head space, from where it can be conveniently removed. This is not possible in a standard parallel plate reactor, in which the gas generated is typically trapped between the electrodes. Gas generation displaces the liquid from the electrode surface and make it difficult to achieve high conversions in a single-pass processing.

Further details on the electrolytic cell operation, including the different modes of operation and experimental procedures for the electrolysis will be given in the context of the Examples below.

Examples

I) Batch processing of homogeneous solutions with the electrolytic reactor

In order to illustrate batch processing of homogeneous solutions with the electrolytic reactor, the anodic decarboxylative oxidation of diphenylacetic acid in methanol to benzhydryl methyl ether was used as a model electrochemical reaction.

in MeOH diphenylacetic acid benzhydryl methyl ether

The slurry electrochemical reactor was assembled using stainless steel and graphite as electrodes, with graphite as the anode and rotating inner electrode. Under stirring (300 rpm), 345 mL of a solution of sodium methoxide (0.05 M) in methanol was introduced into the cell via the first inlet using a peristaltic pump. Simultaneously, diphenylacetic acid (73 g) was introduced in the reactor as a solid via the second inlet by activating the solid conveyor. When the reactor was fully loaded, the mixture was electrolyzed under a constant current of 5 A. After 2.5 F/mol of charge had been passed through the mixture, electrolysis was stopped and the crude solution removed from the reactor via the output valve. HPLC analysis of the reaction mixture showed that 94% yield of benzydryl methyl ether had been obtained. II) Processing of homogeneous solutions with the electrolytic reactor in continuous stirred tank electrochemical reactor (CSTER.) mode

CSTER mode processing of homogeneous solutions with the electrolytic reactor is also illustrated with the anodic decarboxylative oxidation of diphenylacetic acid. The slurry electrochemical reactor was assembled using stainless steel and graphite as electrodes, with graphite as the anode and rotating inner electrode. Under stirring (300 rpm), a solution of sodium methoxide (0.05 M) in methanol was introduced into the cell via the first inlet using a peristaltic pump with a flow rate of 12 mb/min. Simultaneously, diphenylacetic acid was introduced in the reactor as a solid via the second inlet by activating the solid conveyor. The solid conveyor was adjusted for a solid input rate of 264 mg/min. When the reactor was fully loaded, and while maintaining the input of materials, the reactor output valve was opened to keep constant the liquid level within the reactor. Then, electrolysis was started under a constant current of 5 A. This setting produced a constant stream of benzydryl methyl ether solution from the reactor output (80% HPLC yield).

Ill) Processing of homogeneous solutions with the electrolytic reactor in continuous stirred tank electrochemical reactor cascade (CSTERC) mode

CSTERC mode processing of homogeneous solutions with the electrolytic reactor is also illustrated with the anodic decarboxylative oxidation of diphenylacetic acid. In this case, three slurry electrochemical reactors were assembled and connected in series. In all three electrolytic cells, stainless steel and graphite were used as electrodes, with graphite as the anode and rotating inner electrode. All three electrolytic cells were stirred at 300 rpm. A solution of sodium methoxide (0.05 M) in methanol was introduced into the first cell via the first inlet using a peristaltic pump with a flow rate of 28 mL/min. Simultaneously, diphenylacetic acid was introduced in the reactor as a solid via the second inlet by activating the solid conveyor. The solid conveyor was adjusted for a solid input rate of 616 mg/min. When the first reactor was fully loaded, and while maintaining the input of materials, the reaction mixture was pumped from the output valve of the first reactor to the first inlet (liquid input) of the second reactor. When the second reactor was fully loaded, the reaction mixture was pumped using a peristaltic pump from the output valve of the second reactor to the liquid input of the third reactor. When the three reactors were full and while maintaining all flows of material constant, electrolysis was initiated under a constant current of 6 A, 6.4 A and 6.4 A for the first, second and third reactor, respectively. Under steady state conditions, a constant stream of benzydryl methyl ether solution was collected from the reactor output (94% HPLC yield). Constant operation was demonstrated for more than 3 h, which corresponds to processing ca. 5 L of reaction solution and more than 100 g of solid material.

IV) Batch processing of heterogeneous solid/liquid mixtures (slurries) with the electrolytic reactor

In order to illustrate batch processing of a heterogeneous solid/liquid mixture (slurry) with the electrolytic reactor, the anodic oxidation of cortisone to adrenosterone was used as a model electrochemical reaction. Cortisone is poorly soluble in the solvent system MeCN/HzO. Thus, thick slurries are formed upon mixing of the solid cortisone and the solvent.

The slurry electrochemical reactor was assembled using stainless steel and graphite as electrodes, with graphite as the anode and rotating inner electrode. Under stirring (300 rpm), 345 mL of a solution of potassium tetrafluoroborate (0.1 M) in acetonitrile/water 40: 1 was introduced into the cell via the first inlet using a peristaltic pump. Simultaneously, cortisone (12 g) was introduced in the reactor as a solid via the second inlet by activating the solid conveyor. When the reactor was fully loaded, the mixture was electrolyzed under a constant current of 1.09 A. After 3 F/mol of charge had been passed through the mixture, electrolysis was stopped and the crude solution removed from the reactor via the output valve. HPLC analysis of the reaction mixture showed that 99% conversion of cortisone to adrenosterone had been obtained.

V) Processing of heterogeneous solid/liquid mixtures (slurries) with the electrolytic reactor in continuous stirred tank electrochemical reactor cascade (CSTER.C) mode

CSTERC-mode processing of heterogeneous solid/liquid mixtures (slurries) with the electrolytic reactor was also exemplified with the anodic oxidation of cortisone to adrenosterone. Three slurry electrochemical reactors were assembled and connected in series. In all three electrolytic cells, stainless steel and graphite were used as electrodes, with graphite as the anode and rotating inner electrode. All three electrolytic cells were stirred at 300 rpm. A solution of potassium tetrafluoroborate (0.1 M) in acetonitrile/water 40: 1 was introduced into the cell via the first inlet using a peristaltic pump with a flow rate of 9 mb/min. Simultaneously, cortisone was introduced in the reactor as a solid via the second inlet by activating the solid conveyor. The solid conveyor was adjusted for a solid input rate of 321 mg/min. When the first reactor was fully loaded, and while maintaining the input of materials, the reaction mixture was pumped from the output valve of the first reactor to the first inlet (liquid input) of the second reactor. When the second reactor was fully loaded, the reaction mixture was pumped using a peristaltic pump from the output valve of the second reactor to the liquid input of the third reactor. When the three reactors were full and while maintaining all flows of material constant, electrolysis was initiated under a total constant current of 4.3 A. Under steady state conditions, a constant stream of adrenosterone solution was collected from the reactor output. A fraction of the reaction mixture after 1 h collection (ca. 0.5 L) was evaporated under reduced pressure, and the residue extracted with dichloromethane/water. The organic phase was dried with magnesium sulfate and evaporated, yielding 16 g (90%) of adrenosterone.

VI) Electrochemical N-demethylation of oxycodone in a slurry electrochemical reactor

The slurry electrochemical reactor was assembled using stainless steel and graphite as electrodes, with graphite as the anode and rotating inner electrode. Under stirring (300 rpm), 345 mL of a solution of potassium acetate (0.1 M) in ethanol was introduced into the cell via the first inlet using a peristaltic pump. Simultaneously, oxycodone (10.9 g) was introduced in the reactor as a solid via the second inlet by activating the solid conveyor. When the reactor was fully loaded, the resulting solid/liquid slurry was electrolyzed under a constant current of 0.7 A. After 4 F/mol of charge had been passed through the mixture, electrolysis was stopped and the crude solution removed from the reactor via the output valve.

The crude electrolysis reaction mixture was evaporated under reduced pressure. The residue was treated with 2 M HCI and heated under reflux for 20 min. Evaporation of the solvent yielded noroxycodone hydrochloride (94%) as a white powder.

VII) Electrochemical N- and O-demethylation of oxycodone in a procedure according to the reaction scheme as shown in Figure 5

A slurry of 10.9 g of oxycodone in 345 mL of ethanol containing 0.1 M potassium acetate was electrolyzed following the procedure from Example 6.

The crude electrolysis reaction mixture was evaporated under reduced pressure to ca. 10% of the initial volume. The residue was treated with 350 mL of an aqueous solution of HBr (35 wt%) and heated at 120 °C for 2 h or under reflux for 5 h. Evaporation of the solvent yielded noroxymorphone (98% assay yield).

While the present invention has been described in detail by way of specific embodiments and examples, the invention is not limited thereto and various alterations and modifications are possible, without departing from the scope of the invention.

List of reference signs

1 electrochemical reactor

2 outer electrode

3 vessel

4 input for a circulated thermostated fluid

5 output for a circulated thermostated fluid

6 cylindrical base

7 outlet

8 circular groove

9 first bearing

10 inner electrode

11 connector

12 mixing element

13 reactor lid

14 second cavity

15 first cavity

16 second bearing

17 through hole for shaft

18 first inlet

19 second inlet

20 through hole for electrical connector

21 shaft

22 pump

23 conduit

24 solid conveyor

25 solid container

26 motor

27 electrical connector

28 electrical power supply

29 spinning electrical connector

30 overhead stirrer 31 shaft coupling

Claims

1. An electrochemical reactor (1) capable of processing an organic mixture comprising a suspension of a solid and a liquid, wherein the electrochemical reactor comprises: an inner electrode (10); an outer electrode (2), wherein the inner electrode (10) and the outer electrode (2) are arranged concentrically forming a first cavity (15) therebetween; a first inlet (18) configured for introducing the liquid into the first cavity (15) of the electrochemical reactor (1); a second inlet (19) configured for introducing the solid into the first cavity (15) of the electrochemical reactor (1), wherein the first inlet (18) and the second inlet (19) are arranged such that the liquid and the solid are introduced separately, wherein the inner electrode (10) is configured to be rotatable around its longitudinal axis, wherein the inner electrode (10) comprises one or more mixing elements (12).

2. The electrochemical reactor according to claim 1, wherein the electrochemical reactor (1) further comprises a vessel (3) enclosing the inner electrode (10) and the outer electrode (2), wherein a second cavity (14) is formed between the outer electrode (2) and the vessel (3), wherein the second cavity (14) is configured to be filled with a thermostated fluid.

3. The electrochemical reactor (1) according to claims 1 and 2, wherein the inner electrode (10) and/or the outer electrode (2) comprise at least one of the group consisting of stainless steel, nickel, lead, bronze, platinum, tin, copper, titanium, chromium, zinc, magnesium aluminum, or any metal alloy thereof, or carbon materials, such as graphite, glassy carbon, boron doped diamond or composite materials made thereof.

4. The electrochemical reactor (1) according to claims 1 to 3, wherein the electrochemical reactor (1) further comprises an outlet (7), such as an output valve, configured for allowing a removal of electrolyzed reaction mixture from the electrochemical reactor (1).

5. The electrochemical reactor (1) according to claim 4, wherein the outlet (7) is configured to be connected to an inlet of another reactor.

6. The electrochemical reactor (1) according to claims 1 to 5, wherein a diameter of the inner electrode (10) and a diameter of the outer electrode (2) are selected such that a desired distance between the inner electrode (10) and the outer electrode (2) is achieved in accordance with the following formula: outer electrode diameter = inner electrode diameter + 2 x interelectrode gap

7. The electrochemical reactor according to claims 1 to 6, wherein a distance between the inner electrode (10) and the outer electrode (2) is constant for a given process independent of a size of the electrochemical reactor (1).

8. A process for preparing a compound of Formula (I) by means of an electrochemical reactor (1) according to any one of claims 1 to 7, the process comprising the steps of: providing a compound of Formula (II) in the electrochemical reactor (1), providing a liquid containing an electrolyte and a solvent in the electrochemical reactor (1), forming a suspension of the solid and the liquid by rotating the inner electrode (10) having one or more mixing elements (12); electrolyzing the suspension in the electrochemical reactor (1); and subsequently treating the reaction mixture with an acid, wherein the acid is selected from the group consisting of hydrochloric acid, acetic acid and sulfuric acid; wherein the compound of Formula (I) has the following structure:

wherein

R¹, R³ and — — ,z are as defined above; and

9. The process according to claim 8, wherein the step of providing a compound of Formula (II) in the electrochemical reactor (1) comprises introducing the compound of Formula (II) in solid form into the electrochemical reactor (1) via the second inlet (19); and wherein the step of providing a liquid containing an electrolyte and a solvent in the electrochemical reactor (1) comprises introducing the liquid into the electrochemical reactor (1) via the first inlet (18).

10. A process for preparing a compound of Formula (III) by means of an electrochemical reactor according to any one of claims 1 to 7, the process comprising the steps of: providing a compound of Formula (II) in the electrochemical reactor (1), providing a liquid containing an electrolyte and a solvent in the electrochemical reactor (1), forming a suspension of the solid and the liquid by rotating the inner electrode (10) having one or more mixing elements (12); electrolyzing the suspension in the electrochemical reactor (1); and subsequently treating the reaction mixture with hydrogen bromide (HBr); wherein the compound of Formula (III) has the following structure:

wherein each

wherein

R³ and ~s~z.z are as defined above; and