Processes and intermediates for the synthesis of opicapone

Abstract

The present invention relates to a method for preparing an intermediate for the synthesis of opicapone, which comprises the nitration of vanillic acid in an acid anhydride using a nitrating agent. The present invention also relates to an intermediate for the synthesis of opicapone produced by the process. Furthermore, the present invention relates to a solution of the intermediate for the synthesis of opicapone in an acid anhydride.

Description

[Technical Field]

[0001] The present invention relates to a method for preparing opicapone. In particular, the present invention relates to intermediates for preparing opicapone, solutions containing said intermediates, and methods for preparing the same. Furthermore, the present invention allows the opicapone intermediates to be synthesized in a continuous process using flow chemistry in solution. [Background technology]

[0002] Levodopa (L-DOPA) has been used in clinical practice for decades in the symptomatic treatment of various conditions, including Parkinson's disease. L-DOPA can cross the blood-brain barrier and then be converted to dopamine, increasing its levels. However, conversion of L-DOPA to dopamine can also occur in peripheral tissues, potentially causing adverse effects upon L-DOPA administration. Therefore, it has become standard clinical practice to coadminister peripheral amino acid decarboxylase (AADC) inhibitors, such as carbidopa or benserazide, which prevent conversion to dopamine in peripheral tissues. It is also known that the enzyme catechol-O-methyltransferase (COMT) catalyzes the degradation of L-DOPA, and therefore COMT inhibitors can provide clinical improvement in patients with Parkinson's disease receiving L-DOPA treatment.

[0003] As described in International Publication No. WO 2007 / 013830, the nitrocatechol derivative opicapone has been found to be a potent, long-acting COMT inhibitor. This compound is bioactive, bioavailable, and exhibits low toxicity. Therefore, opicapone has potentially valuable pharmaceutical properties in the treatment of several central and peripheral nervous system disorders in which inhibition of catecholamine O-methylation can be therapeutically beneficial, such as mood disorders; movement disorders such as Parkinson's disease, parkinsonian disorders, and restless legs syndrome; gastrointestinal disorders; edema formation states; and hypertension. The development of the opicapone molecule is described in LE Kiss et al., J. Med. Chem., 2010, Vol. 53, pp. 3396-3411, and it was approved for marketing in the EU in June 2016 as adjunctive therapy for the preparation of L-DOPA / AADC in adult patients with Parkinson's disease and motor fluctuations during drug withdrawal.

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

[0005] WO2007 / 013830 employs 3,4-dibenzyloxy-5-nitrobenzoic acid as the starting material, thereby avoiding the problem of nitrating vanillic acid. However, the subsequent steps are less efficient, with condensation, dehydration, oxidation, and deprotection steps affording an opicapone-like compound (compound 42, pp. 50-51) in only 24% overall yield (91%, then 65%, then 54%, then 75%). Summary of the Invention

[0006] Thus, there is a need for an alternative route to synthesize opicapone that avoids the problems associated with the nitration of vanillic acid described in WO 2013 / 089573, but that produces opicapone in higher yields than WO 2007 / 013830. In particular, there is a need for an efficient initial reaction step that is amenable to large-scale production and that allows subsequent coupling, oxidation, and deprotection steps to be carried out in high overall yields. The process should not require high temperatures (e.g., above 60°C) in solution, and ideally should employ inexpensive and readily available starting materials.

[0007] The present inventors have solved this problem by identifying a new process for nitrating vanillic acid in solution, preferably at ambient to moderate temperatures (e.g., 15°C to 60°C). By using an acid anhydride (e.g., acetic anhydride) as a solvent, the inventors have demonstrated that vanillic acid can be dissolved and acylated (preferably at temperatures between 30°C and 60°C) to form an acyl vanillic acid intermediate, which can then be reacted with a nitrating agent (e.g., nitric acid) to form an acyl nitro-vanillic acid intermediate (preferably at ambient to moderate temperatures (15°C to 60°C)). After quenching (e.g., with water), the final product, nitro-vanillic acid, is obtained as a crystalline solid without the need to actively reduce the temperature or thoroughly wash the product. The purity is excellent, thereby avoiding the need for an additional recrystallization step.

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

[0009] [ka] The present invention provides a method for preparing the compound of formula (I), which comprises the nitration of vanillic acid in an acid anhydride using a nitrating agent.

[0010] In a second general embodiment, the invention provides a compound of formula (VI) prepared by the process of the first general embodiment.

[0011] In a third general embodiment, the present invention provides a process for converting a compound of formula (VI) to opicapone.

[0012] In a fourth general embodiment, the invention provides a solution of an acyl vanillic acid or acyl nitro-vanillic acid in an acid anhydride. [Brief explanation of the drawings]

[0013] [Figure 1] FIG. 1 shows a flow diagram of a process for nitrating vanillic acid in acetic anhydride with nitric acid to form nitro-vanillic acid in a continuous process using laboratory-scale flow chemistry. [Figure 2] FIG. 1 shows a flow diagram of a process for nitrating vanillic acid in acetic anhydride with acetyl nitrate to form nitro-vanillic acid in a continuous process using laboratory-scale flow chemistry. [Figure 3] FIG. 1 shows a flow diagram of a scaled-up process for the nitration of vanillic acid in acetic anhydride with 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. [Figure 4]FIG. 1 shows a flow diagram of a scaled-up process for the nitration of vanillic acid in acetic anhydride with nitric acid to form nitro-vanillic acid in a continuous process using flow chemistry with two in-line mixer / reactor flow plates in series. DETAILED DESCRIPTION OF THE INVENTION

[0014] A.Definition The following definitions apply to terms used throughout this specification unless otherwise limited in specific context.

[0015] An "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 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 version thereof) can form acetic anhydride (or a halogenated version thereof). The terms "acetic anhydride," "acetic anhydride," and "AcO" are equivalent. One skilled in the art will recognize that an acid anhydride can contain a proportion of the organic acid produced thereby.

[0016] "Vanillic acid" means 4-hydroxy-3-methoxybenzoic acid.

[0017] "Acylvanillic acid" means 4-acyloxy-3-methoxybenzoic acid. For example, acetylvanillic acid means 4-acetyloxy-3-methoxybenzoic acid.

[0018] "Nitro-vanillic acid" means 4-hydroxy-5-methoxy-3-nitrobenzoic acid.

[0019] "Acylnitro-vanillic acid" means 4-acyloxy-5-methoxy-3-nitrobenzoic acid. For example, acetylnitro-vanillic acid means 4-acetyloxy-5-methoxy-3-nitrobenzoic acid.

[0020] An "acyl" functional group refers to R-(CO)-. Typically, R is an optionally halogenated C1-C3 alkyl group.

[0021] An "acyloxy" functional group refers to R-(CO)-O-. Typically, R is an optionally halogenated C1-C3 alkyl group.

[0022] "C1-C3 alkyl" means a monovalent unsubstituted saturated straight or branched chain hydrocarbon group having 1 to 3 carbon atoms. They can be methyl, ethyl, n-propyl, or isopropyl. For the anhydrides and acyloxy functional groups disclosed herein, methyl (or its halogenated version) is preferred for reasons of cost and compatibility with reagents. Acetic anhydride is the most preferred anhydride, and acetoxy (also called acetyloxy) is the most preferred acyloxy functional group.

[0023] A "nitrating agent" is a chemical compound known in the art for introducing a nitro group into an organic compound. A common nitrating agent is nitric acid (HNO), optionally combined with a catalytic amount of sulfuric acid (HSO) (e.g., 0.1% to 1%).

[0024] A "quench" step refers to the introduction of a material that reacts with any unused reactant, effectively stopping the reaction, for example, the addition of water to hydrolyze the acid anhydride to the free acid.

[0025] "Continuous processing," also known as "flow chemistry" or "flow chemical processing," is a chemical reaction that occurs in a continuous flow rather than in the standard batch production manner. During continuous processing, pumps may move fluids containing reactants, reagents, and / or solvents through a system where the fluids contact each other where tubing connects (e.g., mixers, Tee connectors). This allows chemical or physical reactions to occur as the reagents pass through the system, upon mixing. While continuous processing is suitable for large-scale manufacturing processes, it can be performed at laboratory scale (e.g., up to 10 g), pilot scale (e.g., up to 1 kg), and industrial scale (e.g., greater than 1 kg).

[0026] A "Process Flow Diagram" or "PFD" is a schematic diagram commonly used in chemical and process engineering to show the general arrangement of a flow chemical system.

[0027] The "initial acyl vanillic acid solution" and the "initial nitration solution" are solutions of the two main reagents before mixing. Each solution can be prepared in one or more steps. For example, the initial acyl vanillic acid solution (e.g., the initial acetyl vanillic acid solution) can be prepared by dissolving and acylating vanillic acid in an acid anhydride (e.g., acetic anhydride). For example, the initial nitration solution can be prepared by diluting a nitrating agent (e.g., nitric acid) in a solvent (e.g., water). This solution remains the initial nitration solution until it is mixed with the initial acyl vanillic acid solution to form the "reaction mixture," even if it is further mixed with another solvent (e.g., sulfuric acid and / or acetic anhydride).

[0028] A "mixer" is a vessel, tank, flow reactor (e.g., a capillary reactor or a tube reactor), or junction where reaction solutions are actively or passively mixed. At a laboratory scale, a Vaportec microchip can be used. At a larger scale, one or more mixing plates may be used. For example, one or more A5-size LL-rhombus FlowPlate® can be employed (see A. Macchi et al., Can. J. Chem. Eng., 2019, vol. 97, pp. 2578-2587). The mixer can be temperature controlled or contain sensors to monitor the progress of the reaction. The reaction begins upon mixing and can be carried out in the mixer or transferred to another reactor for continued reaction. If the reaction occurs in the mixer without being transferred to another reactor, the mixer can also be described as a "mixer / reactor."

[0029] A "reactor" is a vessel, tank, flow reactor (e.g., capillary reactor or tube reactor), or junction in which a chemical reaction primarily occurs. A reactor may include active mixing (beyond that achieved by the hydrodynamics of liquid entering and leaving the tank). Such a reactor may also be described as a "mixer / reactor." An example is a "continuously stirred tank reactor." The reaction product may also be collected in the reactor, in which case it may also be known as a "mixer / reactor." Quenching may occur in the reactor or in a separate tank / vessel if the quench results in rapid precipitation of the desired product.

[0030] A "collector" is a vessel, tank, flow cell, or junction where reaction products are collected.

[0031] A "precipitator" is a vessel, tank, flow cell, or junction where precipitation of the reaction product (after quenching) primarily takes place. If precipitation is rapid, it can be initiated in the precipitator. If precipitation is delayed, it can be initiated in a collector and transferred to the precipitator to control the precipitation, especially to improve control of crystallization. Depending on the product, the product can be precipitated and / or collected as an amorphous or crystalline solid.

[0032] A "solution" is a homogeneous liquid mixture in which a minor component (the solute) is uniformly distributed throughout a major component (the solvent). It contains substantially no solute in solid form.

[0033] A "solution of... in an acid anhydride" or a compound "dissolved in an acid anhydride" means that the acid anhydride is the primary solvent in which the compound (e.g., acyl vanillic acid or acyl nitro-vanillic acid) is dissolved. This encompasses situations in which vanillic acid is first dissolved and acylated in an acid anhydride, and then mixed with another solvent (e.g., water) so long as the acyl vanillic acid remains in solution. Preferably, the acid anhydride accounts for at least 50% w / w of the solvent and is therefore the primary solvent. The term "acyl vanillic acid in an acid anhydride" means that the acid anhydride is present in an amount sufficient to solubilize the acyl vanillic acid (e.g., acetyl vanillic acid) and is present in at least a 10 molar excess compared to the acyl vanillic acid (e.g., acetyl vanillic acid). A solution of acetyl vanillic acid in acetic anhydride is preferred.

[0034] A "slurry" or "suspension" is a heterogeneous mixture of solids suspended in a liquid.

[0035] The concentration of a solute in a solvent is defined as "weight percent / weight" or "% w / w." This is equal to grams of solute per 100 grams of solution. For example, an initial acyl vanillic acid solution in acetic anhydride containing 10 g of acyl vanillic acid in 100 g of solution is equal to 10% w / w. As a further example, an initial nitric acid solution in water containing 65 g of nitric acid in 100 g of solution is equal to 65% w / w.

[0036] 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.

[0037] B. Methods for the Synthesis of Nitro-vanillic Acid In a first general embodiment, the present invention provides a compound of formula (VI):

[0038] [ka] The present invention provides a method for preparing the compound of formula (I), which comprises the nitration of vanillic acid in an acid anhydride using a nitrating agent.

[0039] The inventors 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 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 conducted in solution at ambient to moderate temperatures without the need for active cooling enables synthesis in a continuous process using flow chemistry, allowing continuous monitoring of the nitration reaction in small aliquots of the reaction liquid (e.g., during in-process control).

[0040] Vanillic Acid / Anhydride Vanillic acid, acid anhydride, and nitrating agent may be mixed in any order. However, in a preferred embodiment, vanillic acid is dissolved and acylated in acid anhydride to form an initial acyl vanillic acid solution (before mixing with the nitrating agent). This allows the vanillic acid to be completely dissolved and acylated (preferably at a moderate temperature, e.g., 30°C to 60°C, preferably 35°C to 50°C)) before reaction. If needed, the initial acyl vanillic acid solution may be prepared in advance (up to 24 hours before 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 be carried out (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).

[0041] The initial acyl vanillic acid solution may be concentrated or diluted. However, concentrated solutions are generally preferred for larger scale and storage. The inventors have found that the solubility of vanillic acid in acid anhydrides (e.g., acetic anhydride) is generally very high. This is believed to be due to acylation (e.g., acetylation) of the 4-hydroxy group. In particular, vanillic acid was soluble in acetic anhydride at concentrations up to and including 15% w / w at 45°C. However, at this concentration, precipitation / suspension was observed after addition of a nitrating agent (e.g., HNO), making the process less suitable for operation as a continuous process using flow chemistry. Furthermore, upon initiation of the reaction under batch conditions at 15% w / w, the inventors detected the formation of a concentrated solution of acetyl nitrate (from the reaction of nitric acid with acetic anhydride), which is fuming and explosive in moist air. While this does not prevent the reaction from occurring, it is less preferred for safety reasons. Therefore, in another preferred embodiment, the initial acetyl vanillic acid solution is prepared by dissolving 3% w / w to 12% w / w of vanillic acid in acetic anhydride, resulting in 3.75% w / w to 15% w / w of acetyl vanillic acid in acetic anhydride. More preferably, the initial acetyl vanillic acid solution is prepared by dissolving 5% w / w to 10% w / w of vanillic acid in acetic anhydride, resulting in 6.25% w / w to 12.5% ​​w / w of acetyl vanillic acid in acetic anhydride. In contrast, the solubility of vanillic acid in acetic acid is only 2.5% w / w under standard conditions.

[0042] To reduce solvent and optimize reaction scale, a more concentrated initial acyl vanillic acid solution may be employed. To maximize stability, up to 10% w / w vanillic acid may be used to provide an initial acetyl vanillic acid solution of up to 12.5% ​​w / w. Thus, in an even more preferred embodiment, the initial acetyl vanillic acid solution is prepared by dissolving 3% w / w to 10% w / w vanillic acid in acetic anhydride, comprising 3.75% w / w to 12.5% ​​w / w acetyl vanillic acid in acetic anhydride, or further prepared by dissolving 5% w / w to 10% w / w vanillic acid in acetic anhydride, comprising 6.25% w / w to 12.5% ​​w / w acetyl vanillic acid in acetic anhydride.

[0043] In general, the nitration reaction may be carried out in a variety of simple organic acid anhydrides.

[0044] In another preferred embodiment, the reaction occurs in 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, where C1, C2 and C3 represent methyl, ethyl and n-propyl or isopropyl (or halogenated versions thereof), respectively), with the concomitant formation of the corresponding acyl vanillic acid. More preferably, the acid anhydride is acetic anhydride (or a halogenated version thereof) with the concomitant formation of acetyl vanillic acid (or a halogenated version thereof). Even more preferably, the acid anhydride is acetic anhydride or trichloroacetic anhydride with the concomitant formation of acetyl vanillic acid or trichloroacetyl vanillic acid. Acetic anhydride is more preferred, with the concomitant formation of acetyl vanillic acid.

[0045] nitrating agent The preferred embodiments relating to the acid anhydride and vanillic acid may be easily combined with the preferred embodiments relating to the nitrating agent described below.

[0046] Since nitric acid is a liquid, it may be used undiluted. However, in another preferred embodiment, the nitrating agent is provided in the form of an initial nitration solution (before mixing with the initial acyl vanillic acid solution). Preferably, the initial nitration solution comprises a solvent selected from the group consisting of water, acetic acid, AcO, or a water / AcO mixture. More preferably, the initial nitration solution is an aqueous solution (i.e., water is the primary solvent). These solvents are stable and compatible with the initial acyl vanillic acid solution. The initial nitration solution is suitable for use in a continuous process using flow chemistry. Surprisingly, an aqueous solution of nitric acid (e.g., 50% w / w or greater) may be used, even though water is expected to react with acetic anhydride and quench the reactants.

[0047] The initial nitration solution may be concentrated or diluted. However, concentrated solutions are preferred on a larger scale to maximize process efficiency and minimize costs. Therefore, in another preferred embodiment, the initial nitration solution contains 50% w / w to 99.9% w / w of the nitrating agent. More preferably, the initial nitration solution contains 65% w / w to 99.9% w / w of the nitrating agent.

[0048] 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. Since nitric acid is a liquid, it may be directly mixed with the initial acyl vanillic acid solution in pure form. However, in an even more preferred embodiment, the nitric acid is in the form of the initial nitrating solution at the above-mentioned concentrations. Optionally, the initial nitrating solution contains nitric acid (e.g., 50% w / w to 99.9% w / w) together with acetic anhydride to form a "mixed acid" (see F. Bordwell and E. Garbisch, J. Am. Chem. Soc., 1960, vol. 82, pp. 2578-2587). The use of sulfuric acid can play an accelerating role in the nitration reaction. Optionally, the use of nitric acid as a "mixed acid" can improve the yield.

[0049] Reaction conditions In another preferred embodiment, the nitration can be 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. To ensure that the temperature is stable, the vanillic acid and / or acid anhydride and / or nitrating agent are preferably preheated to the reaction temperature prior to the nitration reaction.

[0050] After the nitration reaction, the reaction can be quenched, preferably by directly quenching the nitration reaction product with water. This not only quenches the nitration reaction, but also converts the available acid anhydride (e.g., acetic anhydride) into a free acid (e.g., acetic acid) in which the compound of formula (VI) generally has much lower solubility. Therefore, the compound of formula (VI) only begins to precipitate when the nitration reaction is quenched, for example, with excess water.

[0051] In another preferred embodiment, the quenching is carried out at a temperature of about 4° C. to about 40° C., preferably about 10° C. to about 30° C., and more preferably about 20° C. to about 25° C. This ensures that an adequate amount of reaction product precipitates in an appropriate time frame.

[0052] In another preferred embodiment, some (or all) of the nitration reaction product is quenched with a 1.5- to 20-fold excess of water. Typically, when employing a continuous process using flow chemistry, the nitration reaction is fully quenched on a smaller scale, either semi-batch quenched or quenched in a continuous stirred tank reactor (CSTR). Typically, a larger excess of water (e.g., 5- to 20-fold) is employed in a continuous process using flow chemistry. Larger amounts of water may be used, but are not required.

[0053] Continuous Processing Using Flow Chemistry The embodiments relating to the acid anhydride, vanillic acid and nitrating agent may be easily combined with each other and with the preferred embodiment relating to a continuous process using flow chemistry as described below.

[0054] 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)). Furthermore, the reaction allows the product, 4-hydroxy-5-methoxy-3-nitrobenzoic acid (compound of formula (VI)), to be recovered along with a small amount of the by-product, 6-methoxy-2,4-dinitrophenol. The discovery that the nitration reaction can be carried out in solution enables the synthesis in a continuous process using flow chemistry, allowing continuous monitoring of the reaction in small aliquots of the reaction liquid. The fact that the product can be recovered in high purity without a further recrystallization step makes this particularly suitable for a continuous process using flow chemistry.

[0055] Therefore, in another preferred embodiment, the nitration reaction is carried out as a continuous process in solution. This allows the reaction to be carried out safely, on a large scale, and more efficiently. The prior art process described in WO2013 / 089573 is not suitable for synthesis in a continuous process using flow chemistry because the reaction is carried out as a slurry or suspension and the product requires further recrystallization. The prior art process described in WO2013 / 089573 discloses a yield of about 45%. The use of a continuous process in solution has achieved yields of about 70% or even higher.

[0056] In another preferred embodiment, the process is carried out as a continuous process in solution, where an initial acyl vanillic acid solution is prepared by dissolving 3% w / w to 12% w / w of vanillic acid in acetic anhydride, containing 3.75% w / w to 15% w / w of acetyl vanillic acid in acetic anhydride. More preferably, the initial vanillic acid solution is prepared by dissolving 5% w / w to 10% w / w of vanillic acid in acetic anhydride, containing 6.25% w / w to 12.5% ​​w / w of acetyl vanillic acid in acetic anhydride. In contrast, the solubility of vanillic acid in acetic acid is only 2.5% w / w. The upper limit ensures that there is no precipitation when the initial acetyl vanillic acid solution is mixed with the initial nitration solution.

[0057] Another preferred embodiment is carried out as a continuous process in solution, where the initial nitration solution contains 50% w / w to 99.9% w / w of the nitrating agent, more preferably 65% ​​w / w to 99.9% w / w of the nitrating agent.

[0058] When carried out as a continuous process in solution, the initial acyl vanillic acid solution can be mixed with the initial nitration 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 be carried out 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 is initiated upon contact of the initial acyl vanillic acid solution with the initial nitration solution.

[0059] When the reaction is carried out as a continuous process in solution, in which the initial acyl vanillic acid solution is mixed with the initial nitration solution in one or more mixers (or mixer / reactors) to form a reaction mixture, the initial acyl vanillic acid solution can be introduced into the first mixer (or mixer / reactor) through a first supply pipe, preferably at a flow rate 1 to 30 times higher than the flow rate at which the initial nitration solution is introduced into the first mixer (or mixer / reactor) through a second supply pipe. For example, the initial acyl vanillic acid solution can be introduced into the first mixer (or mixer / reactor) through a first supply pipe at a flow rate of 10 g / min to 600 g / min. For example, the initial nitration solution can be introduced into the first mixer (or mixer / reactor) through a second supply pipe at a flow rate of 1 g / min to 60 g / min. Generally, higher flow rates are used for larger-scale reactions.

[0060] When carried out as a continuous process in solution, where the initial acyl vanillic acid solution is mixed with the initial nitration solution in more than one mixer (or mixer / reactor) to form a reaction mixture, the reaction mixture can flow to a second mixer (or mixer / reactor) after mixing in the first mixer (or mixer / reactor). Preferably, the first and / or second mixer (or mixer / reactor) are heated to a temperature of about 15°C to about 60°C. This allows the nitration reaction to be carried out 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. Although the nitration reaction is initiated upon mixing in the first mixer (or mixer / reactor), yields can be improved by the use of a second mixer (or mixer / reactor) due to improved mixing and allowing for a longer residence time (reaction time).

[0061] When the process is carried out as a continuous process in solution, the initial acyl vanillic acid solution is mixed with the initial nitration solution in one or more mixers (or mixer / reactors) to form a reaction mixture, which can then flow to 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.

[0062] When the reaction mixture is quenched with water in the collector, it forms a quenched reaction mixture. Preferably, water is introduced into the collector through a feed pipe. More preferably, water is introduced into the collector at a flow rate of 50 g / min to 1500 g / min. Generally, higher flow rates are used for larger-scale reactions.

[0063] After quenching, the quenched reaction mixture can flow 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, and even more preferably 70% or more.

[0064] 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 a further recrystallization step.

[0065] C. Downstream Processes for Manufacturing Opicapone The compound of formula (VI) (ie, nitro-vanillic acid) is useful for forming opicapone.

[0066] In a third general embodiment, a compound of formula (VI) may be prepared by the methods in section B above and subjected to one or more further synthetic steps towards the synthesis of opicapone.

[0067] In a further embodiment, the compound of formula (V):

[0068] [ka] is reacted with a compound of formula (VI) to give a compound of formula (III):

[0069] [ka] and the compound of formula (VI) is prepared by the method in section B above. Preferably, the compound of formula (VI) has not undergone a further recrystallization step. The present invention also encompasses the compound of formula (III) when prepared by this process.

[0070] In another further embodiment, the compound of formula (III) prepared by the above method is then oxidized to form the compound of formula (I):

[0071] [ka] to form a compound of the formula:

[0072] The invention also includes compounds of formula (I) when produced by this process.

[0073] In another further embodiment, the compound of formula (I) prepared by the above method is then O-demethylated to give the compound of formula (II):

[0074] [ka] can form a compound of the formula:

[0075] The invention also includes compounds of formula (II) when produced by this process.

[0076] D. Solutions of acylvanillic or acylnitro-vanillic acids in acid anhydrides In a fourth general embodiment, the invention provides a solution of an acyl vanillic acid or an acyl nitro-vanillic acid in an acid anhydride, preferably an acetyl vanillic acid or an acetyl nitro-vanillic acid in acetic anhydride.

[0077] The inventors have discovered that a concentrated acyl vanillic acid solution (e.g., acetyl vanillic acid) may be prepared in an acid anhydride (e.g., acetic anhydride) at a temperature of, for example, about 15°C to about 60°C, and reacted with a nitrating agent (e.g., nitric acid) to form an acyl nitro-vanillic acid (e.g., acetyl nitro-vanillic acid), which upon quenching yields nitro-vanillic acid. In contrast, the solubility of vanillic acid in acetic acid as described in WO2013 / 089573 is only 2.5% w / w.

[0078] In a preferred embodiment, the solution contains 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 contains 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.

[0079] In another preferred embodiment, the compound of formula (VI) is greater than 50% pure with respect to the total vanillic acid and related organic compounds. More preferably, the compound of formula (VI) is greater than 80% pure with respect to the total weight of vanillic acid and related organic compounds, even more preferably greater than 90% pure, and most preferably greater than 95% pure.

[0080] 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 halogenated versions thereof) respectively), and the acyl group of the acyl vanillic acid is acetyl, ethanoyl and n-propanoyl or isopropanoyl (or halogenated versions thereof), respectively. More preferably, the acid anhydride is acetic anhydride (or a halogenated version thereof) and the acyl group of the acyl vanillic acid is acetyl (or a halogenated version thereof). 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.

[0081] Based on the discovery of improved dissolution / acylation and reaction profiles for vanillic acid in acid anhydride, the present invention also extends to acyl vanillic acid solutions in acid anhydride. Vanillic acid was found to dissolve and acetylate in acetic anhydride at concentrations up to and including 15% w / w. The resulting 18.75% w / w acetyl vanillic acid solution is not suitable for use in flow chemistry due to precipitation upon mixing with a nitrating agent, but it can be utilized on a batch scale. Furthermore, because the acetyl vanillic acid solution may be stored for up to 24 hours before reaction, the 18.75% w / w solution is advantageous for storage or transportation, and may be further diluted (e.g., from 3.75% w / w to 15% w / w) for use. In particular, the present invention provides a solution of acetyl vanillic acid in acetic anhydride at 3.75% w / v to 18.75% w / v, preferably a solution of acetyl vanillic acid in acetic anhydride at 3.75% w / w to 15% w / w, more preferably a solution of acetyl vanillic acid at 6.25% w / w to 12.5% ​​w / w.

[0082] To reduce the solvent during storage, a more concentrated initial acyl vanillic acid solution may be employed. A maximum of 18.75% w / w acetyl vanillic acid solution may be used. Thus, in an even more preferred embodiment, the acetyl vanillic acid solution in acetic anhydride contains 3.75% w / w to 18.75% w / w acetyl vanillic acid, or even 6.25% w / w to 18.75% w / w acetyl vanillic acid.

[0083] 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 halogenated versions thereof) respectively), and the acyl group of the acyl vanillic acid is acetyl, ethanoyl and n-propanoyl or isopropanoyl (or halogenated versions thereof), respectively. More preferably, the acid anhydride is acetic anhydride (or a halogenated version thereof) and the acyl group of the acyl vanillic acid is acetyl (or a halogenated version thereof). 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. [Example]

[0084] E. Working Example

[0085] Example 1 - Nitration of vanillic acid in acetic anhydride to form nitro-vanillic acid (compound of formula (VI)) in batch mode

[0086] [ka]

[0087] Scheme 1: Nitration of vanillic acid using acetic anhydride and nitric acid In a round-bottom flask, 4-hydroxy-3-methoxybenzoic acid (vanillic acid; 12.05 g, 71.7 mmol) was dissolved and acetylated in acetic anhydride (115 mL) with heating to a temperature of 50° C. The lower the temperature, the slower the dissolution. Once completely dissolved (10% w / w relative to the vanillic acid starting material), the temperature was reduced to 25° C. and the solution was stirred for 0.5 h. The solution was either used immediately or stored at 0° C. for up to 24 h.

[0088] To a solution of acetylvanillic acid in acetic anhydride at 25°C, nitric acid (65% w / w in water, 8.00 mL, 115 mmol) was added over 30 minutes using a syringe pump at a flow rate of 0.27 mL / min. After the addition, the reaction was left stirring at 25°C for 1 hour and then quenched by the addition of 200 g of water / ice. After 15 minutes, a heavy liquid phase was at the bottom (the "oily" phase), and the mixture was left stirring for 1 hour at room temperature. At this point, precipitation began, and the resulting mixture was filtered using vacuum filtration. The precipitate was washed with 200 mL of water and dried overnight in a vacuum oven at 50°C (m = 3.4 g; purity approximately 95% by LC-MS; yield: 21%). More precipitate formed when the mother liquor was left overnight. The precipitate was filtered and left to dry overnight in a vacuum oven at 50 °C (m = 4.3 g; purity from LC-MS ∼82% purity; yield (overall: 23%)). It is particularly surprising that the reaction proceeded using nitric acid dissolved in water, which hydrolyzed a proportion of the acetic anhydride to acetic acid. Another notable feature is that the intermediates acetylvanillic acid and acetylnitro-vanillic acid remained in solution throughout the course of the reaction, despite the addition of nitric acid in water. This would have been expected to prevent the reaction from occurring efficiently due to precipitation of acetylvanillic acid and / or acetylnitro-vanillic acid. Furthermore, after quenching, the final reaction product (nitro-vanillic acid) reliably precipitated over a period of time and could be collected without the need for a further recrystallization step. Thus, the above reaction is suitable for flow chemistry.

[0089] Example 2 - Nitration of vanillic acid in acetic anhydride to form nitro-vanillic acid (compound of formula (VI)) in a continuous process using flow chemistry on a laboratory scale The process of Example 1 was transferred to a continuous process using flow chemistry on a laboratory scale, and a flow diagram of the process is shown in Figure 1.

[0090] Part 2a - Preparation of 10% w / w acetyl vanillic acid solution in acetic anhydride A 10% w / w solution of acetylvanillic acid (relative to the vanillic acid starting material) in acetic anhydride was prepared in a round-bottom flask by first measuring the mass of vanillic acid and subsequently adding acetic anhydride. The solution was then heated to 40-50°C with stirring to achieve complete dissolution and acetylation. A clear solution (10% w / w acetylvanillic acid (relative to the vanillic acid starting material)) was obtained. Once completely dissolved, the solution was cooled to room temperature. The solution remained clear even after being stored in a 4°C refrigerator for more than a day. The solution is generally prepared on the day of the experiment to minimize degradation of acetylvanillic acid and thereby avoid the presence of impurities. To confirm the quality of the solution, a 200 μL sample was dissolved in 1 mL of THF:MeCN:HO (4:3:3 v / v) and analyzed by LC-MS. The purity remained at 99%. Similar solubility and stability were achieved with trichloroacetic anhydride, albeit as a milky, more viscous solution.

[0091] Thus, acyl vanillic acids are highly soluble and stable in acid anhydrides, especially acetyl vanillic acid in acetic anhydride.

[0092] Part 2b - Nitration of a solution of acetyl vanillic acid in 10% w / w acetic anhydride with nitric acid The flow system consisted of two HPLC pumps (2 × Knauer pumps Vapourtec) for introducing a 10% w / w solution of acetylvanillic acid in acetic anhydride (relative to the vanillic acid starting material) (feed line 1; 0.378–5.149 mL / min) and a 65% w / w aqueous solution of nitric acid (feed line 2; 0.016–0.358 mL / min). The reaction contained 1.6 molar equivalents of HNO per mole of vanillic acid starting material. A flow diagram of the process is shown in Figure 1. Feed lines 1 and 2 were directly pumped using HPLC pumps 1 and 2, respectively. Prior to starting the experiment, the reactor system was flushed by pumping glacial acetic acid through pumps 1 and 2 at a flow rate of 1 mL / min. Subsequently, acetylvanillic acid in 10% w / w acetic anhydride (relative to the vanillic acid starting material) (feed 1) and 65% w / w nitric acid (feed 2) were introduced into the flow system at a flow rate dependent on the residence time and the equivalent amount of HNO (in this case, 1.6 molar equivalents of nitric acid; 40 °C; 5 mL / min of acetylvanillic acid in 10% w / w acetic anhydride (relative to the vanillic acid starting material); 0.358 mL / min of HNO). To start the reaction, pumps 1 and 2 were switched from glacial acetic acid to feed 1 (acetylvanillic acid in 10% w / w acetic anhydride (relative to the vanillic acid starting material)) and feed 2 (65% w / w aqueous nitric acid solution), and these feeds were combined at 20 °C or 40 °C in a Vaportec mixer / reactor microchip (channel width 1.0 mm, residence volume V1 = 1.5 mL). As soon as the system reached thermal steady state, the corresponding fractions were collected. Upon exiting the microchip mixer / reactor, the reaction mixture was diluted to form a reaction mixture:water mixture (2:1 v / v). A sample of the reaction mixture was submitted for analysis by HPLC.

[0093] The product contained up to 91% nitro-vanillic acid (compound of formula (VI)) and only 5.5% of the by-product 6-methoxy-2,4-dinitrophenol.

[0094] Example 3 - Nitration of vanillic acid in acetyl nitrate to form nitro-vanillic acid (compound of formula (VI)) in a continuous process using flow chemistry on a laboratory scale The process of Example 2 was modified on a laboratory scale so that the nitric acid solution was first mixed with acetic anhydride to form acetyl nitrate. A flow diagram of the process is shown in Figure 2.

[0095] Premixing the initial nitric acid solution with acetic anhydride before mixing with the initial acetylvanillic acid solution to form the reaction mixture required an additional mixer / reactor and pump. The flow rates and two temperatures (e.g., Mixer / Reactor 1 and Mixer / Reactor 2) could be varied independently. Increasing the equivalents of HNO3 relative to vanillic acid starting material from 0.68 to 1.6 increased the yield from 46% to 67%. The conditions that produced the best results (0.28 minute residence time, 40°C, and 1.6 equivalents of HNO3 relative to vanillic acid starting material) were carried forward for further testing. For simplicity, both mixer / reactors were operated at the same temperature (40°C). The flow setup consisted of two HPLC pumps (2 × Knauer pumps Vapourtec) and one peristaltic pump (V-3) with chemically resistant tubing (compatible with acetic anhydride and acetic acid) for introducing a 10% w / w solution of acetylvanillic acid in acetic anhydride (relative to the vanillic acid starting material) (feed line 3), nitric acid in 65% w / w water (feed line 2), and acetic anhydride (feed line 1). Feed lines 2 and 1 were directly pumped using HPLC pumps 2 and 1, respectively. Before starting 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 at flow rates that ensured the desired residence time and an equivalence of HNO3 (1.6) relative to the vanillic acid starting material. To start the reaction, pumps 2 and 1 were switched from glacial acetic acid to feed lines 2 and 1, and these feeds were combined in a Vaportec microchip (1.0 mm channel width, residence volume V1 = 0.2 mL) at 40 °C. The microchip mixer / reactor was heated using heated air circulating around the microchip (thermocouples placed directly on the reactor wall with feedback for heater control).After the microchip mixer / reactor, the combined outlet of the initial nitration solution was combined with the initial acetyl vanillic acid solution (feed tube 3; 4.703–4.999 mL / min) in a Vaportec microchip mixer / reactor (1.0 mm channel width, residence volume V = 1.5 mL) at 40 °C to form a reaction mixture. The reaction mixture was flowed through the microchip mixer / reactor and collected in a vial (collector) containing deionized water to quench the nitration reaction (water:reaction mixture 2:1 v / v).

[0096] The product contained up to 67% nitro-vanillic acid (compound of formula (VI)) and only 22% of the by-product 6-methoxy-2,4-dinitrophenol.

[0097] Example 4 - Scaling up of the nitration of vanillic acid in acetic anhydride to form nitro-vanillic acid (compound of formula (VI)) in a continuous process using flow chemistry The process of Example 2 was modified on a larger scale so that the nitric acid solution was mixed with the acetyl vanillic acid solution, and the process flow diagram is shown in Figure 3.

[0098] Part 4a - Process Development Typically, 10% w / w acetylvanillic acid in acetic anhydride (relative to the vanillic acid starting material) was used as the initial acetylvanillic acid solution, and 65% w / w aqueous nitric acid solution was used as the initial nitration solution.

[0099] The addition of catalytic amounts (0.2% w / w) of H2SO4 to a 65% w / w nitric acid solution resulted in an acceleration of the reaction. However, this also resulted in the formation of gas, which resulted in unreliable residence time distribution in flow systems. Therefore, the inclusion of catalytic amounts (e.g., 0.1% w / w to 1% w / w) of H2SO4 is preferred when the reaction rate is to be maximized or when the nitration reaction occurs on a smaller or batch scale. However, the inclusion of H2SO4 is less preferred on a larger scale when employing a continuous process using flow chemistry.

[0100] Increasing the concentration of acetylvanillic acid to 15% w / w (relative to the vanillic acid starting material) in acetic anhydride provided stable solutions that could be stored at low temperatures (0°C to 10°C, preferably 0°C) for up to 24 hours. These solutions are therefore useful for storage. However, at these concentrations, precipitation / suspension was observed after the addition of a nitrating agent (e.g., HNO). 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 in acetic anhydride up to 12% w / w (especially up to 10% w / w) (relative to the vanillic acid starting material) are generally preferred, as they achieve high concentrations without precipitation.

[0101] Part 4b - Sample Production and Use Inspection The development was carried out using an A5 size LL-rhombus FlowPlate® to mix the initial nitration solution and the initial acetyl vanillic acid solution, which were combined using a continuous stirred tank reactor (CSTR) or semi-batch quench technique, providing complete control of the mixing during the nitration reaction.

[0102] Approximately 200 g of nitro-vanillic acid (compound of formula (VI)) was produced using the setup shown in Figure 3 utilizing CSTR quench technology or using a semi-batch quench (not shown). The parameters employed are shown in Table 1:

[0103] [Table 1]

[0104] Nitro-vanillic acid (the compound of formula (VI)) could be isolated almost quantitatively from the reaction solution. The isolated material met HPLC specifications without recrystallization. The purity of the isolated material was >99 area % and assayed >99 wt %. Most importantly, the yield could be increased to approximately 70% (68.1%-71.7%) compared to <45% for the batch manufacturing process of WO2013 / 089573.

[0105] Continuous quenching using a continuous stirred tank reactor (CSTR) has provided excellent results, especially at temperatures at or below 40° C. (e.g., 4° C. to 40° C.). Similar results have been achieved using semi-batch quenching.

[0106] The product could be used without recrystallization in the subsequent coupling, oxidation and deprotection steps to form opicapone as described in WO2013 / 089573.

[0107] Experimental Details: Dissolution / acetylation of vanillic acid was carried out by adding vanillic acid (86.7 g, 503 mmol) to acetic anhydride (763.3 g, 7497 mmol). The mixture was then heated to an internal temperature of 40° C. under stirring until all solids were dissolved.

[0108] Nitration of acetylvanillic acid in acetic anhydride to acetylnitro-vanillic acid in acetic anhydride and quenching to nitro-vanillic acid in acetic acid. The flow system consisted of a piston pump (feed-1) and gear pumps (feeds-2 and 3) for introducing a solution of acetylvanillic acid in acetic anhydride (feed-1), aqueous HNO (65% w / w, feed-2), and water (feed-3). Prior to starting the experiment, the reactor system was flushed by pumping solvent-free acetic acid at a flow rate of 20 g / min using the pump for feed-1. The line for feed-3 was flushed with water at a flow rate of 20 g / min for 5 min. Subsequently, aqueous HNO (feed-2) was introduced into the flow system at a flow rate of 12 g / min for 5 min. After adjusting Feed-2, the flow rate was switched to 10.1 g / min (1.6 equivalents), and the acetyl vanillic acid mixture (Feed-1) was introduced at a flow rate of 109.9 g / min, and water was introduced at a flow rate of 120 g / min (Feed-3). Feeds-1 and 2 were preheated to 40°C in an A5 FlowPlate® (Ehrfeld, 25 mL) before being mixed in a microreactor (Ehrfeld FlowPlate® A5 LL-rhombus, 11 mL) at 40°C. After passing through a temperature sensor and backpressure regulator, the nitration mixture was mixed with water in a CSTR (Continuously Stirred Tank Reactor) at 30°C, and subsequently mixed into a collection tank at 40°C. The FlowPlates®, CSTR, and collection tank were regulated using thermostats.

[0109] To analyze the samples by HPLC, a sample of the suspension after dilution with water was removed and diluted in acetonitrile (2:1 v / v).

[0110] Part 4c - Scale-up execution Two scale-up runs were carried out at double the flow rate of the previous experiment (productivity approximately 33 kg / day).

[0111] Nitro-vanillic acid (compound of formula (VI)) was produced using the scheme shown in Figure 4, which utilizes a batch quench. The parameters employed are shown in Table 2:

[0112] [Table 2]

[0113] At this larger scale, a single FlowPlate® A5 size 200 did not provide sufficient residence time to complete the nitration reaction. Therefore, a second FlowPlate® is preferred to maximize reaction efficiency and yield at the largest scale. This is shown in Figure 4. While the FlowPlates® ideally have the same size (e.g., size 200), the use of a second FlowPlate® of a different size (e.g., size 100) is acceptable when the pressure drop (energy dissipation rate) is held constant. One skilled in the art can modify flow rates and parameters based on the teachings of this disclosure. After steady state was reached (e.g., 5 minutes), the nitration reaction was quenched using a large excess of water. Steady state is achieved, for example, when the energy dissipation rate, flow rate, and conversion, among other factors, are held constant.

[0114] The purity of nitro-vanillic acid (compound of formula (VI)) from both runs was >99 area% and assay >99% by weight. Yields were comparable to previous runs performed on a smaller scale (68.1%-70.2%).

[0115] Longer runs were also performed (5 hours) using smaller FlowPlates® without any clogging issues. In-process control (IPC) of the nitration at 0, 2.5, and 5 hours was comparable to each other and to the previous scale-up run, indicating good process robustness and scalability.

[0116] Experimental Details: Dissolution / acetylation of vanillic acid was carried out by adding vanillic acid (102.0 g, 593 mmol) to acetic anhydride (898.0 g, 8791 mmol). The mixture was then heated to an internal temperature of 40° C. under stirring until all solids were dissolved.

[0117] Nitration of acetyl vanillic acid in acetic anhydride to acetyl nitro-vanillic acid in acetic anhydride and quenching to nitro-vanillic acid in acetic acid. The flow system consisted of a piston pump (feed-1) and a gear pump (feed-2) for introducing a solution of acetyl vanillic acid in acetic anhydride (feed-1) and aqueous HNO (65% w / w, feed-2). Before starting the experiment, the reactor system was flushed by pumping solvent-free acetic acid at a flow rate of 20 g / min using the pump for feed-1. Subsequently, aqueous HNO (feed-2) was introduced into the flow system at a flow rate of 12 g / min for 5 min. 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. Feeds 1 and 2 were preheated to 40°C in an A5 FlowPlate® (Ehrfeld, 30 mL) before being mixed in a microreactor (Ehrfeld FlowPlate® A5 LL-rhombus, 15.5 mL; size 200 and 21.0 mL, size 100) at 40°C. A thermostat was used to regulate all FlowPlates® at 40°C. After the FlowPlate®, the reaction mixture was passed through a temperature sensor and a backpressure regulator set at 3 bar. Dilution / quenching of the discharged solution with a water mixture (e.g., 2:1 w / w water mixture:discharged solution) resulted in hydrolysis of the acetylated version of compound of formula (VI) to give compound of formula (VI). To analyze the sample by HPLC, a sample of the suspension after dilution with water was removed and diluted in acetonitrile (e.g., 2:1 v / v, acetonitrile:suspension).

[0118] Example 5 - Industrial scale nitration of vanillic acid in acetic anhydride to form nitro-vanillic acid (compound of formula (VI)) in a continuous process using flow chemistry The process of Example 4 is modified on a larger scale to mix nitric acid solution with acetyl vanillic acid solution. The flow rate of Feed-1 (acetyl vanillic acid in 10% w / w acetic anhydride (relative to the vanillic acid starting material)) is increased to approximately 500 g / min, the flow rate for Feed-2 (nitric acid in 65% w / w water) is increased to approximately 50 g / min, and the flow rate for Feed-3 (water for quenching) is increased to approximately 1000 g / min. The reaction mixture is passed through one or more (up to six) FlowPlate® A5 (size 200 / 200) or FlowPlate® A4 (size 000). A yield of approximately 70% is expected to be achieved on an industrial scale.

[0119] Other variations to the disclosed embodiments may 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 advantageously used. Any reference signs in the claims should not be construed as limiting their scope.

Claims

1. Formula (VI): 【Chemistry 1】 1. A method for preparing a compound of formula (I), comprising the nitration of vanillic acid in an acid anhydride using a nitrating agent.

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

3. 3. The process according to claim 1 or 2, wherein the acid anhydride is acetic anhydride or a halogenated derivative thereof, preferably acetic anhydride or trichloroacetic anhydride, more preferably acetic anhydride.

4. 3. The method of claim 2, wherein the initial acyl vanillic acid solution is an initial acetyl vanillic acid solution comprising 3.75% w / w to 15% w / w of acetyl vanillic acid in acetic anhydride.

5. 5. The method according to any one of claims 1 to 4, wherein the nitrating agent is in the form of an initial nitrating solution.

6. The initial nitration solution is a mixture of water, H ２ SO ４ , acetic acid, Ac ２ O or water / Ac ２ 6. The process of claim 5, wherein the initial nitration solution comprises a solvent selected from the group consisting of: a mixture of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27,

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

8. The nitrating agent is HNO ３ The method according to any one of claims 1 to 7, wherein

9. 9. The process according to any one of claims 1 to 8, wherein the nitration is carried out at a temperature of from about 15°C to about 60°C, preferably from about 20°C to about 45°C, more preferably from about 25°C to about 40°C, and optionally the vanillic acid and / or acid anhydride and / or nitrating agent are preheated before the nitration reaction.

10. 10. The process of any one of claims 1 to 9, wherein the nitrated reaction product is quenched with water.

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

12. 12. The method of claim 10 or 11, wherein the nitrated reaction product is quenched with a 1.5 to 20-fold excess of water.

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

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

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

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

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

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

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

20. 20. The method of any one of claims 16 to 19, wherein the reaction mixture flows to a second mixer / reactor after being mixed in the first mixer / reactor, the first and / or second mixer / reactor are optionally heated to a temperature of from about 15°C to about 60°C, and the nitration reaction is optionally carried out at a temperature of from 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. 22. The method of claim 21, wherein the reaction mixture is quenched with water in the collector to form a quenched reaction mixture.

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

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

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

26. 26. The method of any one of claims 1 to 25, wherein the compound of formula (VI) is prepared from vanillic acid in an overall yield of 50% or higher.

27. The method of any one of claims 1 to 26, wherein the compound of formula (VI) is precipitated, filtered and dried.

28. 28. The method of claim 27, wherein the compound of formula (VI) is recovered in crystalline form without a further recrystallization step.

29. A compound of formula (VI): produced by the process of any one of claims 1 to 28: 【Chemistry 2】 Compound.

30. The formula (V) 【Transformation 3】 is reacted with the compound of formula (VI) to form a compound of formula (III) 【Chemistry 4】 and wherein said compound of formula (VI) is not subjected to a further recrystallization step.

31. 31. A compound of formula (III) prepared by the process of claim 30 【Transformation 5】 Compound.

32. The compound of formula (III) is oxidized to give the compound of formula (I): 【Transformation 6】 31. The method of claim 30, wherein the compound is formed:

33. 33. A compound of formula (I): 【Transformation 7】 Compound.

34. The compound of formula (I) is converted to the compound of formula (II) by O-demethylation and optional formation of a pharmaceutically acceptable salt. 【Transformation 8】 or a pharmaceutically acceptable salt thereof.

35. 35. A compound of formula (II) prepared by the process of claim 34 【Chemistry 9】 or a pharmaceutically acceptable salt thereof.

36. A solution of acyl nitro-vanillic acid in an acid anhydride, preferably acetyl nitro-vanillic acid in acetic anhydride.

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

38. A solution of acyl vanillic acid in an acid anhydride, preferably acetyl vanillic acid in acetic anhydride.

39. 39. The solution according to 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 said acetylvanillic acid at room temperature and atmospheric pressure.

Images