Processes and intermediates for synthesis of olpinapone

Abstract

The invention relates to a method for preparing an intermediate for synthesis of olpinapone. The method comprises the step of nitrating vanillic acid in anhydride by using a nitrating agent. The present invention also relates to an intermediate for the synthesis of olpiapone produced by this process. In addition, the present invention relates to a solution of an intermediate for the synthesis of olpiapone in an anhydride.

Description

Technical Field

[0001] The present invention relates to a method for preparing opicapone. In particular, the present invention relates to an intermediate for preparing opicapone, a solution containing the intermediate, and a method for preparing the same. Furthermore, the present invention allows the synthesis of the intermediate of opicapone in a continuous process in solution using flow chemistry. Background Art

[0002] Levodopa (L-DOPA) has been used in clinical practice for the symptomatic treatment of various diseases including Parkinson's disease for decades. L-DOPA can cross the blood-brain barrier and is then converted into dopamine and increases its level in the blood-brain barrier. However, the conversion of L-DOPA to dopamine may also occur in peripheral tissues, which may cause adverse effects when levodopa is administered. Therefore, co-administration of peripheral amino acid decarboxylase (AADC) inhibitors (such as carbidopa or benserazide) has become standard clinical practice, which prevents conversion to dopamine in peripheral tissues. Inhibitors of the enzyme catechol-O-methyltransferase (COMT) are also known to provide clinical improvement in patients with Parkinson's disease who have been treated with L-DOPA, because COMT catalyzes the degradation of L-DOPA.

[0003] As described in International Publication No. WO 2007 / 013830, the nitrocatechol derivative opicapone has been found to be an effective and long-acting COMT inhibitor. The compound is bioactive, bioavailable, and exhibits low toxicity. Therefore, opicapone has potentially valuable pharmaceutical properties in the treatment of some central and peripheral nervous system diseases (where inhibition of O-methylation of catecholamines may have therapeutic benefits), such as mood disorders; movement disorders, such as Parkinson's disease, Parkinson's disease, and restless legs syndrome; gastrointestinal disorders; edema-forming states; and hypertension. The development of the opicapone molecule is described in LEKiss et al., J. Med. Chem., 2010, 53, 3396-3411, and it was approved for marketing in the European Union in June 2016 as an adjunct therapy to L-DOPA / AADC formulations in adult patients with Parkinson's disease and post-dose motor fluctuations.

[0004] WO 2009 / 116882 describes various polymorphs of opicapone, of which polymorph A is kinetically and thermodynamically stable. WO 2013 / 089573 describes an optimized process for producing opicapone in good yields using simple starting materials. The process of WO 2013 / 089573 utilizes the inexpensive and readily available starting material, vanillic acid (Example 1), and the subsequent steps of the process (coupling, oxidation, and deprotection steps; Examples 4 to 7) achieve high yields exceeding 80%. However, the initial nitration step is performed as a slurry in acetic acid and nitric acid, which must be heated to 90°C to 105°C to form a solution and then cooled to recrystallize the crude product. The product is washed with a series of solutions or with large amounts of water to recover the final product. Yields of 45% to 55% are moderate to poor. The required additional recrystallization severely impacts the efficiency of scale-up.

[0005] WO 2007 / 013830 uses 3,4-dibenzyloxy-5-nitrobenzoic acid as a starting material, thus avoiding the problem of nitration of vanillic acid. However, the subsequent steps are less efficient, and the condensation, dehydration, oxidation, and deprotection steps produce an opicapone-like compound (compound 42, pages 50-51) with an overall yield of only 24% (91%, then 65%, then 54%, then 75%).

[0006] Therefore, there is a need for an alternative synthetic route to opicapone that avoids the problems associated with vanillic acid nitration described in WO 2013 / 089573, but produces opicapone in higher yields than in WO 2007 / 013830. In particular, there is a need for an efficient initial reaction step that is amenable to large-scale production but allows subsequent coupling, oxidation, and deprotection steps to proceed in high overall yields. The method should be carried out in solution without requiring high temperatures (e.g., above 60°C) and ideally utilize inexpensive and readily available starting materials. Summary of the Invention

[0007] The present inventors have now solved this problem by identifying a new method for the nitration of vanillic acid in solution, preferably at ambient to moderate temperatures (e.g., 15°C to 60°C). The present inventors have found that by using an anhydride (e.g., acetic anhydride) as a solvent, vanillic acid can be dissolved and acylated (preferably at temperatures of 30°C to 60°C) to form an acylvanillic acid intermediate, which can then react with a nitrating agent (e.g., nitric acid) to form an acylnitro-vanillic acid intermediate (preferably at ambient to moderate temperatures (15°C to 60°C)), which, after quenching (e.g., with water), yields the final product, nitro-vanillic acid, as a crystalline solid, without the need to actively lower the temperature or extensively wash the product. The purity is excellent, thereby avoiding the need to undergo an additional recrystallization step.

[0008] Thus, in a first general embodiment, the present invention provides a process for preparing a compound of formula (VI) (also referred to herein as nitro-vanillic acid):

[0009]

[0010] It involves nitrating the vanillic acid in the anhydride using a nitrating agent.

[0011] In a second general embodiment, the invention provides a compound of formula (VI) prepared by the process of the first general embodiment.

[0012] In a third general embodiment, the present invention provides a process for converting a compound of formula (VI) to opicapone.

[0013] In a fourth general embodiment, the invention provides a solution of acylvanillic acid or acylnitro-vanillic acid in anhydride. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 Shown is a process flow diagram for the nitration of vanillic acid in acetic anhydride by nitric acid to form nitro-vanillic acid in a continuous process using flow chemistry at laboratory scale.

[0015] Figure 2 Shown is a process flow diagram for the nitration of vanillic acid in acetic anhydride by acetyl nitrate to form nitro-vanillic acid in a continuous process using flow chemistry at laboratory scale.

[0016] Figure 3 Shown is a scale-up process flow diagram for the nitration of vanillic acid in acetic anhydride by nitric acid to form nitro-vanillic acid in a continuous process using flow chemistry with a continuous stirred tank reactor (CSTR) to quench the reaction product.

[0017] Figure 4 Shown is a scale-up process flow diagram for the nitration of vanillic acid in acetic anhydride by nitric acid to form nitro-vanillic acid in a continuous process using flow chemistry with two in-line mixer / reactor flow plates. DETAILED DESCRIPTION

[0018] A. Definition

[0019] Unless otherwise limited in specific cases, the following definitions apply to the terms used throughout the specification.

[0020] "Acid anhydride" contains the functional group R-(CO)-O-(CO)-R' and can be formed when one equivalent of water is removed from two equivalents of an organic acid, R-COOH and R'-COOH, in a dehydration reaction. Typically, R and R' are each independently an optionally halogenated C1-C3 alkyl group. For example, two equivalents of acetic acid (or a halogenated form thereof) can form acetic anhydride (or a halogenated form thereof). The terms "acetic acid anhydride," "acetic anhydride," and "Ac2O" are equivalent. Those skilled in the art will appreciate that anhydrides can contain a certain proportion of the organic acid from which they are prepared.

[0021] "Vanillic acid" means 4-hydroxy-3-methoxybenzoic acid.

[0022] "Acylvanillic acid" means 4-acyloxy-3-methoxybenzoic acid. For example, acetylvanillic acid means 4-acetyloxy-3-methoxybenzoic acid.

[0023] "Nitro-vanillic acid" means 4-hydroxy-5-methoxy-3-nitrobenzoic acid.

[0024] "Acylnitro-vanillic acid" means 4-acyloxy-5-methoxy-3-nitrobenzoic acid. For example, acetylnitro-vanillic acid means 4-acetyloxy-5-methoxy-3-nitrobenzoic acid.

[0025] An "acyl" functional group refers to R-(CO)-. Typically, R is an optionally halogenated C1-C3 alkyl group.

[0026] An "acyloxy" functional group refers to R-(CO)-O-. Typically, R is an optionally halogenated C1-C3 alkyl group.

[0027] "C1-C3 alkyl" means a monovalent unsubstituted saturated straight or branched hydrocarbon radical having 1 to 3 carbon atoms. These can be methyl, ethyl, n-propyl, or isopropyl. In the case of the anhydride and acyloxy functional groups disclosed herein, methyl (or its halogenated form) is preferred for reasons of cost and compatibility with reagents. Acetic anhydride is the most preferred anhydride, and acetoxy (also known as acetyloxy) is the most preferred acyloxy functional group.

[0028] A "nitrating agent" is a compound known in the art to introduce a nitro group into an organic compound. A commonly used nitrating agent is nitric acid (HNO3), optionally combined with a catalytic amount of sulfuric acid (H2SO4) (e.g., 0.1% to 1%).

[0029] The "quenching" step describes the introduction of a material that reacts with any unused reactants and effectively stops the reaction, for example, adding water to hydrolyze the anhydride to the free acid.

[0030] "Continuous process", also known as "flow chemistry" or "flow chemistry method", is a chemical reaction that is run in a continuous flow stream, rather than by a standard batch production method. In a continuous process, a pump can move a fluid containing reactants, reagents and / or solvents through a system in which the fluids are in contact with each other at a pipe connection (e.g., a mixer, a three-way connector). This allows a chemical or physical reaction to occur when mixing, and the reagents continue to pass through the system simultaneously. Although a continuous process is suitable for large-scale manufacturing methods, it can be carried out on a laboratory scale (e.g., up to 10 g), a pilot scale (e.g., up to 1 kg), and an industrial scale (e.g., more than 1 kg).

[0031] A "process flow diagram" or "PFD" is a schematic diagram commonly used in chemistry and process engineering to indicate the general arrangement of a flow chemistry system.

[0032] The "initial acylvanillic acid solution" and the "initial nitrating solution" are solutions obtained by mixing the first two main reagents. Each solution can be prepared in one or more steps. For example, an initial acylvanillic acid solution (e.g., an initial acetylvvanillic acid solution) can be prepared by dissolving and acylating vanillic acid in an anhydride (e.g., acetic anhydride). For example, an initial nitrating solution can be prepared by diluting a nitrating agent (e.g., nitric acid) in a solvent (e.g., water). Even if this solution is further mixed with other solvents (e.g., sulfuric acid and / or acetic anhydride), it remains an initial nitrating solution until it is mixed with the initial acylvanillic acid solution to form the "reaction mixture."

[0033] A "mixer" is a container, tank, flow reactor (e.g., capillary reactor or tubular reactor) or connector in which the reaction solutions are actively or passively mixed. On a laboratory scale, a Vapourtec microchip can be used. On a larger scale, one or more mixing plates can be used. For example, one or more A5-sized LL-rhombus (See A. Macchi et al., Can. J. Chem. Eng., 2019, 97, 2578-2587). The mixer can be temperature controlled or contain sensors to monitor the progress of the reaction. The reaction will start when mixing and can be carried out in the mixer or transferred to a separate reactor to continue the reaction. When the reaction occurs in the mixer and is not transferred to a separate reactor, the mixer can also be described as a "mixer / reactor".

[0034] A "reactor" is a container, tank, flow reactor (e.g., capillary reactor or tubular reactor), or joint where the primary chemical reaction occurs. The reactor may include active mixing (beyond mixing achieved by the fluid dynamics of the liquids entering and leaving the tank). Such a reactor may also be described as a "mixer / reactor." An example is a "continuous stirred tank reactor." The reaction products may also be collected in the reactor, in which case it may be referred to as a "reactor / collector." If quenching results in rapid precipitation of the desired product, the quenching may be performed in the reactor or in a separate tank / container.

[0035] A "collector" is a container, tank, flow cell, or junction that collects reaction products.

[0036] "Precipitator" is a container, tank, flow cell or joint where precipitation of the reaction product primarily occurs (after quenching). If precipitation is rapid, precipitation can be initiated in the precipitator. If precipitation is delayed, precipitation can be initiated in a collector and transferred to the precipitator to control precipitation, particularly to improve control of crystallization. Depending on the product, it can be precipitated and / or collected as an amorphous solid or a crystalline solid.

[0037] A "solution" is a homogeneous liquid mixture in which a minor component (the solute) is uniformly distributed throughout a major component (the solvent). It is substantially free of the solute in solid form.

[0038] By "a solution ... in an anhydride" or a compound "dissolved in an anhydride" is meant that the anhydride is the primary solvent in which the compound (e.g., acylvanillic acid or acylnitro-vanillic acid) is dissolved. It covers situations where the vanillic acid is initially dissolved in the anhydride and acylated and then mixed with another solvent (e.g., water), as long as the acylvanillic acid remains in solution. Preferably, the anhydride comprises at least 50% w / w of the solvent and is therefore the primary solvent. The term "acylvanillic acid in anhydride" means that the anhydride is present in an amount sufficient to dissolve the acylvanillic acid (e.g., acetylvanillic acid) and is present in at least a 10 molar excess compared to the acylvanillic acid (e.g., acetylvanillic acid). Solutions of acetylvanillic acid in acetic anhydride are preferred.

[0039] A "slurry" or "suspension" is a heterogeneous mixture of solids suspended in a liquid.

[0040] The concentration of a solute in a solvent is defined as "weight / weight percent" or "% w / w." This is equal to the grams of solute per 100 grams of solution. For example, an initial acetylvianillic acid acetic anhydride solution containing 10 grams of acetylvianillic acid in 100 grams of solution is equivalent to 10% w / w. As another example, an initial nitric acid aqueous solution containing 65 grams of nitric acid in 100 grams of solution is equivalent to 65% w / w.

[0041] In the claims, the word "comprising" does not exclude other elements or steps, and the indefinite article "a" or "an" does not exclude a plurality.

[0042] B. Methods for Synthesizing Nitro-Vanillic Acid

[0043] In a first general embodiment, the present invention provides a process for preparing a compound of formula (VI):

[0044]

[0045] It involves nitrating the vanillic acid in the anhydride using a nitrating agent.

[0046] The present inventors have surprisingly discovered that the use of an anhydride solvent system allows the inexpensive and readily available vanillic acid starting material to be dissolved and acylated (preferably at moderate temperatures (e.g., 30°C to 60°C, preferably 35°C to 50°C)) and then nitrated (preferably at ambient to moderate temperatures (e.g., 15°C to 60°C, preferably 20°C to 45°C, more preferably 25°C to 40°C)). Furthermore, conducting the nitration reaction in this manner allows the product nitro-vanillic acid (compound of formula (VI)) to be recovered in high yield and high purity upon quenching, along with a small amount of the by-product 6-methoxy-2,4-dinitrophenol, without the need for an additional recrystallization step. Furthermore, the discovery that the nitration reaction can be carried out in solution at ambient to moderate temperatures without the need for active cooling makes it suitable for synthesis in a continuous process using flow chemistry and allows the nitration reaction to be continuously monitored in small aliquots of the reaction liquid (e.g., during in-process control).

[0047] Vanillic acid / anhydride

[0048] Vanillic acid, anhydride, and nitrating agent can be mixed in any order. However, in a preferred embodiment, vanillic acid is dissolved in the anhydride and acylated to form an initial acylvanillic acid solution (before mixing with the nitrating agent). This allows the vanillic acid to be completely dissolved and acylated prior to the reaction (preferably at a moderate temperature (e.g., 30°C to 60°C, preferably 35°C to 50°C)). If desired, the initial acylvanillic acid solution can be prepared in advance (up to 24 hours before the reaction) and then stored at a low temperature (0°C to 10°C, preferably 0°C) to prevent side reactions. The reaction with the nitrating agent can then occur (preferably at ambient to moderate temperatures (e.g., 15°C to 60°C, preferably 20°C to 45°C, more preferably 25°C to 40°C)).

[0049] The initial acylvanillic acid solution can be concentrated or diluted. However, concentrated solutions are generally preferred for larger scales and for storage. The present inventors have found that the solubility of vanillic acid in anhydrides (e.g., acetic anhydride) is generally very high. This is believed to be due to acylation (e.g., acetylation) of the 4-hydroxyl group. In particular, vanillic acid is soluble in acetic anhydride at 45°C at concentrations up to and including 15% w / w. However, at this concentration, precipitation / suspension is observed after addition of a nitrating agent (e.g., HNO3), making this method less suitable for continuous operation using flow chemistry. In addition, when starting the reaction at 15% w / w under batch conditions, the present inventors detected the formation of a concentrated solution of acetyl nitrate (from the reaction of nitric acid and acetic anhydride), which fumes and is explosive in humid air. Although this does not prevent the reaction from occurring, it is less preferred for safety reasons. Thus, in another preferred embodiment, the initial acetylvanillic acid solution is prepared by dissolving 3% w / w to 12% w / w vanillic acid in acetic anhydride and comprises 3.75% w / w to 15% w / w acetylvanillic acid in the acetic anhydride. More preferably, the initial acetylvanillic acid solution is prepared by dissolving 5% w / w to 10% w / w vanillic acid in acetic anhydride and comprises 6.25% w / w to 12.5% w / w acetylvanillic acid in the acetic anhydride. In comparison, the solubility of vanillic acid in acetic acid under standard conditions is only 2.5% w / w.

[0050] To reduce solvent and optimize reaction scale, a more concentrated initial acylvanillic acid solution can be used. To maximize stability, up to 10% w / w vanillic acid can be used to provide an initial acetylvanillic acid solution of up to 12.5% w / w. Thus, in an even more preferred embodiment, the initial acetylvanillic acid solution is prepared by dissolving 3% w / w to 10% w / w vanillic acid in acetic anhydride and contains 3.75% w / w to 12.5% w / w acetylvanillic acid in the acetic anhydride, or even by dissolving 5% w / w to 10% w / w vanillic acid in acetic anhydride and containing 6.25% w / w to 12.5% w / w acetylvanillic acid in the acetic anhydride.

[0051] Generally, nitration reactions can be carried out in the presence of various simple organic acid anhydrides.

[0052] In another preferred embodiment, the reaction is carried out in a linear or branched short-chain organic anhydride (C1-(CO)-O-(CO)-C1, C2-(CO)-O-(CO)-C2 or C3-(CO)-O-(CO)-C3, wherein C1, C2 and C3 represent methyl, ethyl and n-propyl or isopropyl (or their halogenated forms) respectively), with the formation of the corresponding acylvanillic acid. More preferably, the anhydride is acetic anhydride (or its halogenated form), with the formation of acetylvanillic acid (or its halogenated form). Even more preferably, the anhydride is acetic anhydride or trichloroacetic anhydride, with the formation of acetylvanillic acid or trichloroacetylvanillic acid. Acetic anhydride is most preferred, with the formation of acetylvanillic acid.

[0053] Nitrating agent

[0054] The preferred embodiments concerning the anhydride and vanillic acid can be readily combined with the preferred embodiments concerning the nitrating agent, as described below.

[0055] Nitric acid is a liquid and can therefore be used undiluted. However, in another preferred embodiment, the nitrating agent is provided in the form of an initial nitrating solution (before mixing with the initial acylvanillic acid solution). Preferably, the initial nitrating solution comprises a solvent selected from the group consisting of water, acetic acid, Ac2O, or a water / Ac2O mixture. More preferably, the initial nitrating solution is an aqueous solution (i.e., water is the primary solvent). These solvents are stable and compatible with the initial acylvanillic acid solution. The initial nitrating solution is suitable for use in a continuous process using flow chemistry. Surprisingly, aqueous solutions of nitric acid (e.g., 50% w / w or higher) can be used, even though water is expected to react with acetic anhydride and quench the reaction.

[0056] The initial nitrating solution can be concentrated or diluted. However, concentrated solutions are preferred on a larger scale to maximize process efficiency and minimize costs. Thus, in another preferred embodiment, the initial nitrating solution comprises from 50% w / w to 99.9% w / w of nitrating agent. More preferably, the initial nitrating solution comprises from 65% w / w to 99.9% w / w of nitrating agent.

[0057] In another preferred embodiment, the nitrating agent is nitric acid or a derivative thereof, such as acetyl nitrate (which can be formed when nitric acid contacts acetic anhydride). More preferably, the nitrating agent is nitric acid. Nitric acid is a liquid and can therefore be directly mixed with the initial acylvanillic acid solution in pure form. However, in an even more preferred embodiment, nitric acid is in the form of the above-mentioned initial nitrating solution at the above-mentioned concentration. Optionally, the initial nitrating solution comprises nitric acid (e.g., 50% w / w to 99.9% w / w) and acetic anhydride to form a "mixed acid" (see F. Bordwell and E Garbisch, J. Am. Chem. Soc., 1960, 82, 2578-2587). The use of sulfuric acid can have an accelerating effect in the nitration reaction. Using nitric acid (optionally as a "mixed acid") can improve yield.

[0058] Reaction conditions

[0059] In another preferred embodiment, the nitration is carried out at a temperature of about 15° C. to about 60° C., more preferably at a temperature of about 20° C. to about 45° C., and even more preferably at a temperature of 25° C. to 40° C. In order to ensure that the temperature is stable, the vanillic acid and / or anhydride and / or the nitrating agent are preferably preheated to the reaction temperature before the nitration reaction.

[0060] After the nitration reaction, the reaction can be quenched, preferably wherein the nitration reaction product is directly quenched with water. This not only quenches the nitration reaction, but also converts the available anhydride (e.g., acetic anhydride) into a free acid (e.g., acetic acid), wherein the compound of formula (VI) generally has a much lower solubility. Therefore, the compound of formula (VI) only begins to precipitate after the nitration reaction, for example, is quenched by excess water.

[0061] In another preferred embodiment, quenching is performed at a temperature of about 4° C. to about 40° C., preferably about 10° C. to about 30° C., more preferably about 20° C. to about 25° C. This ensures precipitation of an optimal amount of reaction product within a suitable time frame.

[0062] In another preferred embodiment, some (or all) of the nitration reaction products are quenched with 1.5 to 20 times excess water. Typically, the nitration reaction is completely quenched on a smaller scale, and when a continuous process using flow chemistry is employed, semi-batch quenching or quenching in a continuous stirred tank reactor (CSTR). Typically, a larger excess of water (e.g., 5 to 20 times) is employed in continuous processes using flow chemistry. Larger amounts of water may be used, but this is unnecessary.

[0063] Continuous methods using flow chemistry

[0064] The embodiments involving anhydride, vanillic acid, and a nitrating agent can be readily combined with each other and with the preferred embodiment involving a continuous process using flow chemistry, as described below.

[0065] As described above, the use of an anhydride solvent system allows the inexpensive and readily available vanillic acid starting material to be dissolved and acylated (preferably at moderate temperatures (e.g., 30°C to 60°C, preferably 35°C to 50°C)) and then nitrated (preferably at ambient to moderate temperatures (e.g., 15°C to 60°C, preferably 20°C to 45°C, more preferably 25°C to 40°C)). In addition, the reaction allows for recovery of the product 4-hydroxy-5-methoxy-3-nitrobenzoic acid (compound of Formula (VI)) and a small amount of the by-product 6-methoxy-2,4-dinitrophenol. The discovery that the nitration reaction can occur in solution makes it suitable for synthesis in a continuous process using flow chemistry and allows for continuous monitoring of the reaction on small aliquots of the reaction liquid. The fact that the product can be recovered in high purity without the need for an additional recrystallization step makes it particularly suitable for continuous processes using flow chemistry.

[0066] Therefore, in another preferred embodiment, the nitration reaction is carried out in solution as a continuous process. This allows the reaction to be carried out safely, on a large scale, and more efficiently. The prior art method described in WO 2013 / 089573 is not suitable for synthesis in a continuous process using flow chemistry because the reaction occurs as a slurry or suspension, and the product requires additional recrystallization. The prior art method described in WO 2013 / 089573 discloses a yield of approximately 45%. Yields of approximately 70% or even higher can be achieved using a continuous process in solution.

[0067] In another preferred embodiment, carried out as a continuous process in solution, the initial acylvanillic acid solution is prepared by dissolving 3% w / w to 12% w / w vanillic acid in acetic anhydride and contains 3.75% w / w to 15% w / w acetylvantic acid in the acetic anhydride. More preferably, the initial vanillic acid solution is prepared by dissolving 5% w / w to 10% w / w vanillic acid in acetic anhydride and contains 6.25% w / w to 12.5% w / w acetylvantic acid in the acetic anhydride. In comparison, the solubility of vanillic acid in acetic acid is only 2.5% w / w. This upper limit ensures that no precipitation occurs when the initial acetylvantic acid solution is mixed with the initial nitrating solution.

[0068] In another preferred embodiment carried out as a continuous process in solution, the initial nitrating solution comprises from 50% w / w to 99.9% w / w of nitrating agent. More preferably, the initial nitrating solution comprises from 65% w / w to 99.9% w / w of nitrating agent.

[0069] When conducted as a continuous process in solution, the initial acylvanillic acid solution can be mixed with the initial nitrating solution in one or more mixers to form a reaction mixture. Preferably, the initial solution is preheated to a temperature of about 15°C to about 60°C. This allows the nitration reaction to occur at a preferred temperature of about 15°C to about 60°C, more preferably 20°C to 45°C, and even more preferably 25°C to 40°C. The nitration reaction begins when the initial acylvanillic acid solution contacts the initial nitrating solution.

[0070] When carried out as a continuous process in solution, wherein the initial acylvanillic acid solution is mixed with the initial nitrating solution in one or more mixers (or mixers / reactors) to form a reaction mixture, the initial acylvanillic acid solution can be introduced into the first mixer (or mixer / reactor) via a first feed line, preferably at a flow rate of 1 to 30 times the flow rate of the initial nitrating solution introduced into the first mixer (or mixer / reactor) via a second feed line. For example, the initial acylvanillic acid solution can be introduced into the first mixer (or mixer / reactor) via the first feed line at a flow rate of 10 g / min to 600 g / min. For example, the initial nitrating solution can be introduced into the first mixer (or mixer / reactor) via the second feed line at a flow rate of 1 g / min to 60 g / min. Typically, higher flow rates are used for larger-scale reactions.

[0071] When carried out as a continuous process in solution, wherein the initial acylvanillic acid solution is mixed with the initial nitrating solution in more than one mixer (or mixer / reactor) to form the reaction mixture, the reaction mixture can flow to the second mixer (or mixer / reactor) after mixing in the first mixer (or mixer / reactor). Preferably, the first mixer and / or the second mixer (or mixer / reactor) are heated to a temperature of about 15°C to about 60°C. This allows the nitration reaction to occur at a preferred temperature of about 15°C to about 60°C, more preferably about 20°C to about 45°C, and even more preferably 25°C to 40°C. The nitration reaction begins upon mixing by the first mixer (or mixer / reactor), but the yield can be improved by using a second mixer (or mixer / reactor) because it improves mixing and allows for a longer residence time (reaction time).

[0072] When carried out as a continuous process in solution, the initial acylvanillic acid solution is mixed with the initial nitrating solution in one or more mixers (or mixer / reactors) to form a reaction mixture, which can then flow into a collector. The nitration reaction can continue in the collector until the nitration reaction is complete or quenched. The nitration reaction is preferably quenched with water.

[0073] When the reaction mixture is quenched with water in the collector, it forms a quenched reaction mixture. Preferably, water is introduced into the collector via a feed pipe. More preferably, water is introduced into the collector at a flow rate of 50 g / min to 1500 g / min. Typically, higher flow rates are used for larger-scale reactions.

[0074] After quenching, the quenched reaction mixture can be passed to a precipitator. The compound of formula (VI) can then be collected, preferably as a crystalline solid. Preferably, the compound of formula (VI) is produced from vanillic acid in an overall yield of 50% or more, more preferably 60% or more, even more preferably 70% or more.

[0075] The compound of formula (VI) may be precipitated, filtered and subsequently dried. Preferably, the compound of formula (VI) is recovered in dry crystalline form without the need for an additional recrystallization step.

[0076] C. Downstream Methods for Producing Opicapone

[0077] The compound of formula (VI) (ie, nitro-vanillic acid) can be used to form opicapone.

[0078] In a third general embodiment, the compound of formula (VI) produced by the method in Section B above can be subjected to one or more additional synthetic steps to synthesize opicapone.

[0079] In another embodiment, the compound of formula (V):

[0080]

[0081] React with a compound of formula (VI) to form a compound of formula (III):

[0082]

[0083] wherein the compound of formula (VI) is produced by the method in Section B above. Preferably, the compound of formula (VI) is not subjected to an additional recrystallization step. The present invention also includes the compound of formula (III) produced by this method.

[0084] In another further embodiment, the compound of formula (III) produced by the above process may then be oxidized to form a compound of formula (I):

[0085]

[0086] The present invention also includes compounds of formula (I) produced by this process.

[0087] In another further embodiment, the compound of formula (I) produced by the above process may then be O-demethylated to form a compound of formula (II):

[0088]

[0089] The present invention also includes compounds of formula (II) produced by this method.

[0090] D. Solutions of acylvanillic acid or acylnitrovanillic acid in anhydride

[0091] In a fourth general embodiment, the present invention provides a solution of acylvanillic acid or acylnitro-vanillic acid in an acid anhydride, preferably a solution of acetylvanillic acid or acetylnitro-vanillic acid in acetic anhydride.

[0092] The present inventors have discovered that concentrated acylvanillic acid solutions (e.g., acetylvanthryl) can be prepared in an anhydride (e.g., acetic anhydride) at a temperature of about 15°C to about 60°C and reacted with a nitrating agent (e.g., nitric acid) to form acylnitrovanillic acids (e.g., acetylnitrovanillic acid), which upon quenching yield nitrovanillic acid. In contrast, the solubility of vanillic acid in acetic acid, as described in WO2013 / 089573, is only 2.5% w / w.

[0093] In a preferred embodiment, the solution comprises 4.6% w / w to 18.2% w / w, preferably 7.6% w / w to 15.2% w / w of acetylnitro-vanillic acid at room temperature and pressure. In another preferred embodiment, the solution comprises 6.4% w / w to 25.6% w / w, preferably 10.7% w / w to 21.3% w / w of trichloroacetylnitro-vanillic acid at room temperature and pressure.

[0094] In another preferred embodiment, the purity of the compound of formula (VI) relative to the total weight of vanillic acid and related organic compounds is greater than 50%. More preferably, the purity of the compound of formula (VI) relative to the total weight of vanillic acid and related organic compounds is greater than 80%, even more preferably greater than 90%, and most preferably greater than 95%.

[0095] In another preferred embodiment, the acid anhydride is a linear or branched short-chain organic acid anhydride (C1-(CO)-O-(CO)-C1, C2-(CO)-O-(CO)-C2 or C3-(CO)-O-(CO)-C3, wherein C1, C2 and C3 represent methyl, ethyl and n-propyl or isopropyl (or their halogenated forms) respectively), and the acyl group of the acyl vanillic acid is acetyl, ethanoyl and n-propionyl or isopropionyl (or their halogenated forms) respectively. More preferably, the acid anhydride is acetic anhydride (or its halogenated form), and the acyl group of the acyl vanillic acid is acetyl (or its halogenated form). Even more preferably, the acid anhydride is acetic anhydride or trichloroacetic anhydride, and the acyl group of the acyl vanillic acid is acetyl or trichloroacetyl. Acetic anhydride is most preferred, and the acyl group of the acyl vanillic acid is most preferably acetyl.

[0096] Based on the discovery of improved dissolution / acylation and reaction profiles of vanillic acid in anhydrides, the present invention also extends to anhydride solutions of acylvanillic acid. It was found that vanillic acid dissolves and acetylates in acetic anhydride to a concentration of up to and including 15% w / w. Although the resulting 18.75% w / w acetylvanillic acid solution is not suitable for use in flow chemistry due to precipitation upon mixing with a nitrating agent, it can be used on a batch scale. In addition, since acetylvanillic acid solutions can be stored for up to 24 hours before reaction, 18.75% w / w solutions are advantageous for storage or transportation and can be further diluted for use (e.g., 3.75% w / w to 15% w / w). In particular, the present invention provides solutions of acetylvanillic acid in acetic anhydride ranging from 3.75% w / v to 18.75% w / v, preferably solutions of acetylvanillic acid in acetic anhydride ranging from 3.75% w / w to 15% w / w, and more preferably 6.25% w / w to 12.5% w / w of acetylvanillic acid.

[0097] To reduce the amount of solvent present during storage, a more concentrated initial acylvanillic acid solution may be used. Acetylvanillic acid solutions of up to 18.75% w / w may be used. Thus, in an even more preferred embodiment, the acetylvanillic acid solution in acetic anhydride comprises from 3.75% w / w to 18.75% w / w acetylvanillic acid or even from 6.25% w / w to 18.75% w / w acetylvanillic acid.

[0098] In a preferred embodiment, the acid anhydride is a linear or branched short-chain organic acid anhydride (C1-(CO)-O-(CO)-C1, C2-(CO)-O-(CO)-C2 or C3-(CO)-O-(CO)-C3, wherein C1, C2 and C3 represent methyl, ethyl and n-propyl or isopropyl (or their halogenated forms) respectively), and the acyl group of the acyl vanillic acid is acetyl, ethanoyl and n-propionyl or isopropionyl (or their halogenated forms) respectively. More preferably, the acid anhydride is acetic anhydride (or its halogenated form), and the acyl group of the acyl vanillic acid is acetyl (or its halogenated form). Even more preferably, the acid anhydride is acetic anhydride or trichloroacetic anhydride, and the acyl group of the acyl vanillic acid is acetyl or trichloroacetyl. Acetic anhydride is most preferred, and the acyl group of the acyl vanillic acid is most preferably acetyl.

[0099] E. Examples

[0100] Example 1 - Nitration of Vanillic Acid in Acetic Anhydride in Batch Mode to Form Nitro-Vanillic Acid (Compound of Formula (VI))

[0101]

[0102] Scheme 1: Nitration of Vanillic Acid Using Acetic Anhydride and Nitric Acid

[0103] 4-Hydroxy-3-methoxybenzoic acid (vanillic acid; 12.05 g, 71.7 mmol) was dissolved and acetylated in acetic anhydride (115 mL) in a round-bottom flask while heating to a temperature of 50°C. Dissolution was slower at lower temperatures. Once completely dissolved (10% w / w based on the vanillic acid starting material), the temperature was lowered to 25°C and the solution was stirred for 0.5 h. The solution was used immediately or stored at 0°C for up to 24 h.

[0104] At 25 ° C, nitric acid (65% w / w in water, 8.00 mL, 115 mmol) was added to a solution of acetyl vanillic acid in acetic anhydride using a syringe pump at a flow rate of 0.27 mL / min over 30 minutes. After the addition, the reaction was stirred at 25 ° C for 1 hour and then quenched by adding 200 g of water / ice. After 15 minutes, the heavy liquid phase was at the bottom ("oil" phase) and the mixture was stirred for 1 hour to reach room temperature. At this point, precipitation began to occur and vacuum filtration was used to filter the resulting mixture. The precipitate was washed with 200 mL of water and dried in a vacuum oven at 50 ° C overnight (m = 3.4 g; purity from LC-MS was about 95%; yield: 21%). The mother liquor was left overnight and more precipitate formed. The precipitate was filtered and dried in a vacuum oven at 50 ° C overnight (m = 4.3 g; purity from LC-MS was about 82% pure; yield (total yield: 23%)). Particularly surprising is that the reaction is carried out using nitric acid dissolved in water, which hydrolyzes a portion of the diacetic anhydride to acetic acid. Another noteworthy feature is that the intermediates acetylvanillic acid and acetylnitro-vanillic acid remain in solution throughout the reaction, despite the addition of nitric acid-containing water. Due to the precipitation of acetylvanillic acid and / or acetylnitro-vanillic acid, this may be expected to prevent the reaction from effectively occurring. In addition, after cancellation, the final reaction product (nitro-vanillic acid) reliably precipitates over a period of time and can be collected without the need for an additional recrystallization step. Therefore, the above reaction is suitable for flow chemistry.

[0105] Example 2 - Nitration of Vanillic Acid in Acetic Anhydride in a Continuous Process Using Flow Chemistry on a Laboratory Scale To form nitro-vanillic acid (compound of formula (VI))

[0106] The method of Example 1 was transferred to a continuous process using flow chemistry on a laboratory scale. The process flow diagram is shown in Figure 1 middle.

[0107] Part 2a - Preparation of a 10% w / w solution of acetylvanoic acid in acetic anhydride

[0108] By first measuring the quality of vanillic acid, then adding acetic anhydride, in a round-bottom flask, prepare a solution of 10% w / w acetyl vanillic acid in acetic anhydride (based on the vanillic acid starting material). After this, the solution is heated to 40 ℃ to 50 ℃, stirred to achieve complete dissolution and acetylation. Obtain a clear solution (acetyl vanillic acid 10% w / w (based on the vanillic acid starting material)). Once completely dissolved, the solution is cooled to room temperature. Even if placed in a refrigerator at 4 ℃ for more than one day, the solution still remains a clear solution. Usually, the solution is prepared on the same day of the experiment to minimize the degradation of acetyl vanillic acid and therefore avoid the presence of impurities. In order to confirm the quality of the solution, 200 μ L samples are dissolved in 1 mL THF: MeCN: H o (4: 3: 3 v / v) and analyzed by LC-MS. The purity remains on 99%. Similar solubility and stability are achieved with trichloroacetic anhydride, although it is a milky, more viscous solution.

[0109] Therefore, acylvanillic acid is highly soluble and stable in acid anhydrides, especially acetylvanillic acid in acetic anhydride.

[0110] Part 2b - Nitration of a 10% w / w acetylvanillic acid solution in acetic anhydride by nitric acid

[0111] The flow apparatus consisted of two HPLC pumps (2x Knauer pumps Vapourtec) to introduce a 10% w / w solution of acetylvanoic acid in acetic anhydride (based on the vanillic acid starting material) (feed line 1; 0.378 mL / min to 5.149 mL / min) and a 65% w / w aqueous nitric acid solution (feed line 2; 0.016 mL / min to 0.358 mL / min). The reaction involved 1.6 molar equivalents of HNO3 per mole of vanillic acid starting material. The process flow diagram is shown in FIG. Figure 1HPLC pump 1 and HPLC pump 2 were used to directly pump feed line 1 and feed line 2, respectively. Before the start of the experiment, the reactor apparatus was flushed by pumping glacial acetic acid at a flow rate of 1 mL / min through pump 1 and pump 2. Subsequently, 10% w / w acetyl vanillic acid (based on the vanillic acid starting material) in acetic anhydride (feed line 1) and 65% w / w nitric acid (feed line 2) were introduced into the flow system at a flow rate that depended on the residence time and HNO3 equivalents (in this case 1.6 molar equivalents nitric acid; 40°C; 5 mL / min 10% w / w acetyl vanillic acid (based on the vanillic acid starting material) in acetic anhydride; 0.358 mL / min HNO3). To start the reaction, pumps 1 and 2 were switched from glacial acetic acid to feed line 1 (10% w / w acetyl vanillic acid (based on vanillic acid starting material) in acetic anhydride) and feed line 2 (65% w / w aqueous nitric acid), and these feeds were combined at 20° C. or 40° C. in a Vapourtec mixer / reactor microchip (1.0 mm channel width, residence volume V1 = 1.5 mL). Once the system reached thermal stability, the corresponding fractions were collected. Upon leaving the microchip mixer / reactor, the reaction mixture was diluted to form a reaction mixture:water mixture (2:1 v / v). Samples of the reaction mixture were submitted for analysis by HPLC.

[0112] The product contained up to 91% of nitro-vanillic acid (compound of formula (VI)) and as little as 5.5% of the by-product 6-methoxy-2,4-dinitrophenol.

[0113] Example 3 - Nitration of vanilla in acetyl nitrate in a continuous process using flow chemistry at laboratory scale Acid to form nitro-vanillic acid (compound of formula (VI))

[0114] The process of Example 2 was modified so that the nitric acid solution was initially mixed with acetic anhydride to form acetyl nitrate on a laboratory scale. The process flow diagram is shown in FIG. Figure 2 middle.

[0115] Premixing the initial nitric acid solution with acetic anhydride prior to mixing with the initial acetylvantimony acid solution to form the reaction mixture requires an additional mixer / reactor and pump. The flow rate and both temperatures (for mixer / reactor 1 and mixer / reactor 2) can be varied independently. Increasing the equivalents of HNO3 to vanillic acid starting material from 0.68 to 1.6 increased the yield from 46% to 67%. The conditions that yielded the best results (0.28 min residence time, 40°C, and 1.6 equivalents of HNO3 to vanillic acid starting material) were used for further testing. For simplicity, both mixer / reactors were operated at the same temperature (40°C). The flow set-up consisted of two HPLC pumps (2 x Knauer pumps Vapourtec) and one peristaltic pump (V-3) with chemically resistant tubing (compatible with acetic anhydride and acetic acid) to introduce a 10% w / w solution of acetylvanoic acid in acetic anhydride (based on the vanillic acid starting material) (feed line 3), water containing 65% w / w nitric acid (feed line 2), and acetic anhydride (feed line 1). Feed lines 2 and 1 were pumped directly using HPLC pump 2 and HPLC pump 1. Prior to the start of the experiment, the flow system was flushed by pumping glacial acetic acid at a flow rate of 1 mL / min using pumps 1, 2, and 3. Subsequently, nitric acid (feed line 2; 0.337 mL / min) and acetic anhydride (feed line 1; 0.457 mL / min) were introduced into the flow system to ensure the desired residence time and a flow rate of 1.6 equivalents of HNO3 to the vanillic acid starting material. To start the experiment, pump 2 and pump 1 are switched to feed tube 2 and feed tube 1 from glacial acetic acid, and these feeds are mixed at 40 ℃ in a Vapourtec microchip (1.0 mm channel width, residence volume V1 = 0.2 mL). The hot air circulating around the microchip is used to heat the microchip mixer / reactor (a thermocouple is directly located on the reactor wall and is fed back to the heater control). After the microchip mixer / reactor, the outlet of the combined initial nitrifying solution is merged with the initial acetyl vanillic acid solution (feed tube 3; 4.703 mL / min to 4.999 mL / min) in a Vapourtec microchip mixer / reactor (1.0 mm channel width, residence volume V2 = 1.5 mL) at 40 ℃, to form a reaction mixture. The reaction mixture flows through the microchip mixer / reactor and is collected in a vial (collector) containing deionized water to quench the nitration reaction (water: reaction mixture 2: 1 v / v).

[0116] The product contained up to 67% of nitro-vanillic acid (compound of formula (VI)) and as little as 22% of the by-product 6-methoxy-2,4-dinitrophenol.

[0117] Example 4 - Scale-up of the nitration of vanillic acid in acetic anhydride to form Nitro-vanillic acid (compound of formula (VI))

[0118] The method of Example 2 was modified so that the nitric acid solution was mixed with the acetylvanillic acid solution on a larger scale. The process flow diagram is shown in FIG. Figure 3 middle.

[0119] Section 4a - Method Development

[0120] Typically, 10% w / w acetylvanillic acid (based on the vanillic acid starting material) in acetic anhydride was used as the initial acetylvanillic acid solution, and 65% w / w aqueous nitric acid was used as the initial nitrating solution.

[0121] Adding catalytic amounts (0.2% w / w) of H2SO4 to a 65% w / w nitric acid solution results in an acceleration of the reaction. However, it also results in gas formation, which can lead to less reliable residence time distributions in flow systems. Therefore, when the reaction rate is to be maximized or when the nitration reaction is to occur on a smaller or batch scale, it is preferred to include catalytic amounts of H2SO4 (e.g., 0.1% w / w to 1% w / w). However, when a continuous process using flow chemistry is employed, the inclusion of H2SO4 is less preferred on a large scale.

[0122] Increasing the concentration of acetylvanillic acid in acetic anhydride to 15% w / w (based on the vanillic acid starting material) provides stable solutions that can be stored at low temperatures (0°C to 10°C, preferably 0°C) for up to 24 hours. Therefore, these solutions are useful for storage. However, at these concentrations, precipitation / suspension is observed after addition of a nitrating agent (e.g., HNO3). While this is not a problem on a small scale, it is less suitable for synthesis in a continuous process using flow chemistry. Therefore, concentrations of acetylvanillic acid (based on the vanillic acid starting material) in acetic anhydride of up to 12% w / w (especially up to 10% w / w) are generally preferred because they achieve high concentrations without precipitation.

[0123] Section 4b - Sample Generation and Use Testing

[0124] Use A5 size LL-rhombus The initial nitration solution and the initial acetylvanillic acid solution are mixed for development. This is combined with a continuous stirred tank reactor (CSTR) or semi-batch quenching technology. The nitration reaction is well-mixed and controlled.

[0125] use Figure 3 Approximately 200 g of nitro-vanillic acid (compound of formula (VI)) was produced using the apparatus shown in FIG (which utilizes a CSTR quench technique) or using a semi-batch quench (not shown). The parameters employed are shown in Table 1:

[0126]

[0127]

[0128] Nitro-vanillic acid (compound of Formula (VI)) can be isolated almost quantitatively from the reaction solution. The isolated material meets HPLC specifications without recrystallization. The purity of the isolated material is >99 area % and assays >99 weight %. Most importantly, the yield can be increased to approximately 70% (68.1% to 71.7%), compared to <45% in the batch production process of WO 2013 / 089573.

[0129] Continuous quenching using a continuous stirred tank reactor (CSTR) produced excellent results, particularly at temperatures of 40° C. and below (eg, 4° C. to 40° C.) Similar results were obtained using semi-batch quenching.

[0130] As described in WO 2013 / 089573, the product can be used without recrystallization in subsequent coupling, oxidation and deprotection steps to form opicapone.

[0131] Experimental details:

[0132] Dissolution / acetylation of vanillic acid was performed by adding vanillic acid (86.7 g, 503 mmol) to acetic anhydride (763.3 g, 7497 mmol).The mixture was then heated to 40°C internal temperature with stirring until all solids were dissolved.

[0133] The acetyl vanillic acid in the diacetic anhydride is nitrated into the acetyl nitro-vanillic acid in the diacetic anhydride and quenched into the nitro-vanillic acid in acetic acid. The flow apparatus is composed of a piston pump (feed-1), a gear pump (feed-2 and feed-3), to introduce a solution of acetyl vanillic acid in diacetic anhydride (feed-1), an HNO aqueous solution (65% w / w, feed-2) and water (feed-3). Before the experiment began, the reactor apparatus was flushed with pure acetic acid at a flow rate of 20 g / min by using the pump used for feed-1. The pipeline of feed-3 was flushed with water at a flow rate of 20 g / min for 5 minutes. Subsequently, the HNO aqueous solution (feed-2) was introduced into the flow system at a flow rate of 12 g / min for 5 minutes. After adjusting feed-2, the flow rate was switched to 10.1 g / min (1.6 equivalents), the acetyl vanillic acid mixture (feed-1) was introduced at a flow rate of 109.9 g / min, and water (feed-3) was introduced at a flow rate of 120 g / min. Feed-1 and feed-2 were mixed at A5. (Ehrfeld, 25 mL) was preheated to 40°C and then A5 LL-rhombus, 11 mL) was mixed at 40 ° C, and after passing through a temperature sensor and a back pressure regulator, the nitration mixture was mixed with water at 30 ° C in a CSTR (continuous stirred tank reactor) and then entered a collection tank at 40 ° C. The temperature was adjusted using a thermostat. CSTR and collection tank.

[0134] For analysis of the samples by HPLC, a sample of the suspension after dilution with water was removed and diluted in acetonitrile (2:1 v / v).

[0135] Section 4c - Scaling Up Operations

[0136] Two scale-up runs were performed at twice the flow rate of the previous experiment (productivity approximately 33 kg / day).

[0137] Nitro-vanillic acid (compound of formula (VI)) is used Figure 4 The apparatus shown in was used to produce the quenched product using batch quenching. The parameters used are shown in Table 2:

[0138]

[0139]

[0140] On this larger scale, a single A5 size 200 does not produce enough residence time to complete the nitration reaction. Therefore, the second Maximize reaction efficiency and yield on the largest scale. This is depicted in Figure 4 In. Although Ideally, they would be of the same size (e.g., size 200), but when the pressure drop (energy dissipation rate) is kept constant, a second size (e.g., size 100) would be used. is acceptable. The skilled person can modify the flow rate and parameters based on the teachings of the present disclosure. After reaching a steady state (e.g., 5 minutes), the nitration reaction is quenched with a large excess of water. For example, a steady state is achieved when the energy dissipation rate, flow rate, and conversion rate remain constant, as well as other factors.

[0141] The purity of nitro-vanillic acid (compound of formula (VI)) from both runs was >99 area % and assayed to >99 wt %. The yields were comparable to previous runs performed on a smaller scale (68.1% to 70.2%).

[0142] Also use smaller Long-term experiments (5 h) were performed without any clogging issues. Nitrification in-process controls (IPCs) were performed at 0 h, 2.5 h, and 5 h and were comparable to each other and previous scale-up runs, demonstrating good process robustness and scalability.

[0143] Experimental details:

[0144] Dissolution / acetylation of vanillic acid was performed by adding vanillic acid (102.0 g, 593 mmol) to acetic anhydride (898.0 g, 8791 mmol).The mixture was then heated to 40°C internal temperature with stirring until all solids were dissolved.

[0145] The acetyl vanillic acid in acetic anhydride is nitrated into acetyl nitro-vanillic acid in acetic anhydride and quenched into nitro-vanillic acid in acetic acid. The flow apparatus consists of a piston pump (feed-1) and a gear pump (feed-2) to introduce a solution of acetyl vanillic acid in acetic anhydride (feed-1) and an HNO3 aqueous solution (65% w / w, feed-2). Before the experiment began, the reactor apparatus was flushed by pumping pure acetic acid at a flow rate of 20 g / min using the pump for feed-1. Subsequently, the HNO3 aqueous solution (feed-2) was introduced into the flow system at a flow rate of 12 g / min for 5 minutes. After adjusting feed-2, the flow rate was switched to 18.6 g / min (1.6 equivalents) and the acetyl vanillic acid mixture (feed-1) was introduced at a flow rate of 201.4 g / min. Feed-1 and feed-2 were heated at 40 ° C in a microreactor (Ehrfeld A5LL-rhombus, 15.5mL; size 200 and 21.0mL, size 100) before mixing in A5 (Ehrfeld, 30 mL) was preheated to 40°C. All Adjust to 40℃. Afterwards, the reaction mixture is passed through a temperature sensor and a back pressure regulator set to 3 bar. The output solution is diluted / quenched with a water mixture (e.g., 2:1 w / w water mixture: output solution) to hydrolyze the acetylated form of the compound of formula (VI) to obtain the compound of formula (VI). In order to analyze the sample by HPLC, a sample of the suspension diluted with water is removed and diluted in acetonitrile (e.g., 2:1 v / v, acetonitrile: suspension).

[0146] Example 5 - Industrial scale nitration of vanillic acid in acetic anhydride to form Nitro-vanillic acid (compound of formula (VI))

[0147] The process of Example 4 was modified so that the nitric acid solution was mixed with the acetylvanillic acid solution on a larger scale. The flow rate of feed-1 (10% w / w acetylvanillic acid (based on the vanillic acid starting material) in acetic anhydride) was increased to about 500 g / min; the flow rate of feed-2 (65% w / w nitric acid in water) was increased to about 50 g / min; and the flow rate of feed-3 (water for quenching) was increased to about 1000 g / min. The reaction mixture was passed through one or more (up to 6) A5 (size 200 / 200) or A4 (size 000). It is predicted that a yield of about 70% should be achieved on an industrial scale.

[0148] Other variations to the disclosed embodiments can be understood and effected by those skilled in the art in practicing the claimed invention, from a study of the drawings, the disclosure, and the appended claims. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage. Any reference signs in the claims should not be construed as limiting the scope.

Claims

1. A method for preparing a compound of formula (VI): It involves nitrating the vanillic acid in the anhydride using a nitrating agent.

2. The method of claim 1, wherein the vanillic acid is dissolved and acylated in the anhydride to form an initial acylvanillic acid solution prior to nitration.

3. A process according to any preceding claim, wherein the anhydride is acetic anhydride or a halogenated derivative thereof, preferably acetic anhydride or trichloroacetic anhydride, more preferably acetic anhydride.

4. The process of claim 2, wherein the initial acylvanillic acid solution is an initial acetylvvanillic acid solution comprising 3.75% w / w to 15% w / w acetylvvanillic acid in acetic anhydride.

5. A process as claimed in any preceding claim, wherein the nitrating agent is in the form of an initial nitrating solution.

6. The method of claim 5, wherein the initial nitrating solution comprises a solvent selected from the group consisting of water, H2SO4, acetic acid, Ac2O or a water / Ac2O mixture, preferably the initial nitrating solution is an aqueous solution.

7. A method according to claim 5 or 6, wherein the initial nitrating solution comprises 50% w / w to 99.9% w / w of nitrating agent.

8. A method as claimed in any preceding claim, wherein the nitrating agent is HNO3.

9. The process according to any preceding claim, wherein the nitration is carried out at a temperature of about 15°C to about 60°C, preferably at a temperature of about 20°C to about 45°C, more preferably at a temperature of about 25°C to about 40°C, and optionally, wherein the vanillic acid and / or anhydride and / or nitrating agent are preheated prior to the nitration reaction.

10. A process as claimed in any preceding claim wherein the nitration reaction product is quenched with water.

11. The method of claim 10, wherein quenching is performed at about 4°C to about 40°C.

12. The method of claim 10 or 11, wherein the nitration reaction product is quenched with 1.5 to 20 times excess water.

13. The process of any one of claims 1 to 12, wherein the nitration reaction is carried out in solution as a continuous process.

14. The method of claim 13, wherein the initial acylvanillic acid solution comprises 3.75% w / w to 15% w / w acylvanillic acid.

15. The method of claim 13 or 14, wherein the initial nitrating solution comprises 50% w / w to 99.9% w / w nitrating agent.

16. The process of any one of claims 5 to 15, wherein the initial acylvanillic acid solution is mixed with the initial nitrating solution in one or more mixers / reactors to form a reaction mixture, optionally after preheating the initial acylvanillic acid solution and the initial nitrating solution to a temperature of about 15°C to about 60°C, and wherein the nitration reaction is optionally carried out at a temperature of about 15°C to about 60°C.

17. The method of claim 16, wherein the initial acylvanillic acid solution is introduced into the first mixer / reactor at a flow rate that is 1 to 30 times the flow rate at which the initial nitrating solution is introduced into the first mixer / reactor.

18. The process of claim 16 or 17, wherein the initial acylvanillic acid solution is introduced into the first mixer / reactor at a flow rate of 0.1 g / min to 600 g / min.

19. The process of any one of claims 16 to 18, wherein the initial nitrating solution is introduced into the first mixer / reactor at a flow rate of 0.1 g / min to 60 g / min.

20. The process of any one of claims 16 to 19, wherein the reaction mixture flows to a second mixer / reactor after mixing in the first mixer / reactor, wherein the first mixer / reactor and / or the second mixer / reactor are optionally heated to a temperature of about 15°C to about 60°C, and wherein the nitration reaction is optionally carried out at a temperature of about 15°C to about 60°C.

21. The method of any one of claims 16 to 20, wherein the reaction mixture subsequently flows to a collector.

22. The method of claim 21, wherein the reaction mixture is quenched with water in the collector to form a quenched reaction mixture.

23. The method of claim 22, wherein the water is introduced into the collector at a flow rate that is 1 to 2 times the flow rate at which the reaction mixture is introduced into the collector.

24. The method of claim 22 or 23, wherein the water is introduced into the collector at a flow rate of 50 g / min to 1500 g / min.

25. The method of any one of claims 22 to 24, wherein the quenched reaction mixture flows to a precipitator.

26. A process as claimed in any preceding claim, wherein the compound of formula (VI) is produced from vanillic acid in an overall yield of 50% or greater.

27. A process as claimed in any preceding claim wherein the compound of formula (VI) is precipitated, filtered and dried.

28. The process of claim 27, wherein the compound of formula (VI) is recovered in crystalline form without the need for an additional recrystallization step.

29. A compound of formula (VI): It is produced by the method according to any one of claims 1 to 28.

30. The method according to any one of claims 1 to 28, wherein the compound of formula (V) reacting with the compound of formula (VI) to form a compound of formula (III) wherein the compound of formula (VI) is not subjected to an additional recrystallization step.

31. A compound of formula (III) It is prepared by the method according to claim 30.

32. The method of claim 30, wherein the compound of formula (III) is oxidized to form a compound of formula (I):

33. A compound of formula (I): It is prepared by the method according to claim 32.

34. The method of claim 32, wherein the compound of formula (I) undergoes O-demethylation and optional pharmaceutically acceptable salt formation to form a compound of formula (II) or a pharmaceutically acceptable salt thereof:

35. A compound of formula (II) or a pharmaceutically acceptable salt thereof: It is prepared by the method according to claim 34.

36. A solution of acylnitro-vanillic acid in anhydride, preferably a solution of acetylnitro-vanillic acid in acetic anhydride.

37. The solution of claim 36, wherein the solution comprises 4.6% w / w to 18.2% w / w, preferably 7.6% w / w to 15.2% w / w of the acetylnitro-vanillic acid at room temperature and pressure.

38. A solution of acylvanillic acid in anhydride, preferably a solution of acetylvanillic acid in acetic anhydride.

39. The solution of claim 38, wherein the solution comprises 3.75% w / w to 18.75% w / w, preferably 3.75% w / w to 15% w / w, more preferably 6.25% w / w to 12.5% w / w of the acetylvavanillic acid at room temperature and pressure.

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