Sequential one-pot synthesis process for preparation of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2, 8-dimethyl-1, 4-dihydro-1, 6-naphthyridine-3-carboxamide

Abstract

The present invention encompasses a sequential one-pot synthesis process for the preparation of 4-(4-cyano-2-methoxy-phenyl)-5-ethoxy-2, 8-dimethyl-1, 4-dihydro-1, 6-naphthyridine-3-carboxamides of the formula (XIII), and a process for the preparation of 4-(4-cyano-2-methoxy-phenyl)-5-ethoxy-2, 8-dimethyl-1, 4-dihydro-1, 6-naphthyridine-3-carboxamides of the formula (XIII). Particularly, in a sequential one-pot synthesis method, (4R)-4-(4-cyano-2-methoxy-phenyl)-5-ethoxy-2, 8-dimethyl-1, 4-dihydro-1, 6-naphthyridine-3-formamide of a formula ent-(I) is used as an initial raw material, and the 4-(4-cyano-2-methoxy-phenyl)-5-ethoxy-2, 8-dimethyl-1, 4-dihydro-1, 6-naphthyridine-3-formamide of a formula (XIII) is obtained through electrochemical oxidation and electrochemical reduction, so that the 4-(4-cyano-2-methoxy-phenyl)-5-ethoxy-2, 8-dimethyl-1, 4-dihydro-1, 6-naphthyridine-3-formamide of a formula (XIII) is obtained. The synthesis method comprises the following steps: adding 2, 8-dimethyl-1, 4-dihydro-1, 6-naphthyridine-3-formamide into a reaction kettle;

Description

[0001] The present invention encompasses a sequential one-pot synthesis method for preparing 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide according to formula (XIII).

[0002]

[0003] In particular, in the sequential one-pot synthesis, the compound according to formula ent-(I)

[0004]

[0005] is used as a starting material and undergoes electrochemical oxidation and electrochemical reduction to obtain compound (XIII). Compound (XIII) is an intermediate for synthesizing the compound of formula (I), (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide.

[0006]

[0007] The International Nonproprietary Name (INN) of the compound of formula (I) is finerenone. It is a non-steroidal antagonist of the mineralocorticoid receptor and can be used as an agent for preventing or treating cardiovascular or kidney diseases, such as heart failure or diabetic nephropathy. The compound (I) and its preparation method are described in, for example, US20100136142 A1, US20170217957 A1, and US15 / 753,406 A1.

[0008] Compound ent-(I) is a by-product or waste generated during the preparation of finerenone (I). In the commercial synthesis of finerenone (I), compound ent-(I) is no longer further utilized and must be destroyed / treated. The treatment of this waste is a complex and cost-intensive process, meaning high inefficiency in terms of the yield of finerenone. In addition, the compound is obtained in large quantities in one of the final stages of the commercial synthesis, so potential starting materials are discarded here.

[0009] US 15 / 753,406 A1 describes that in the preparation of the compound of formula (I), the compound according to formula ent-(I) is obtained (see Scheme 1).

[0010] Scheme 1: Obtaining compound ent-(I) in the synthesis of finerenone (I) (US 15 / 753,406 A1)

[0011]

[0012] US 15 / 753,406 A1 further describes a laboratory-scale process for the recovery of compound ent-(I). The process of US 15 / 753,406 A1 is shown in Scheme 2 below and involves several individual steps.

[0013] Scheme 2: Process according to US 15 / 753,406 A1

[0014]

[0015] The process described in US 15 / 753,406 A1 is characterized by the following steps, each of which is characterized by the isolation of the corresponding intermediate product as a solid:

[0016] 1) Oxidation with a chemical oxidant to form compounds M1a(S) and M1b(R)

[0017] 2) Separation of the mixture of compounds M1a(S) and M1b(R)

[0018] 3) Racemization of compounds M1a(S) and M1b(R) to compound (XVII)

[0019] 4) Separation of compound (XVII)

[0020] 5) Electrochemical reduction of compound (XVII) to obtain compound (XIII).

[0021] An overview of the yields after each step and the overall yield after all reaction steps (laboratory scale) described in US 15 / 753,406 A1 is given in Table 1.

[0022] Table 1 Yields after oxidation (%), yields after racemization (%), yields after reduction (%), and overall yield of the synthesis described in US 15 / 753,406 A1 (US’406)

[0023]

[0024] The process described in US 15 / 753,406 A1 has several disadvantages. For example:

[0025] - It only involves a laboratory-scale process setup that is not suitable for commercial scale-up

[0026] - The method described in US 15 / 753,406 A1 is not suitable, as can also be seen from Example 28 of US 15 / 753,406 A1: Here, direct electrochemical oxidation failed.

[0027] - After each individual step, the corresponding intermediate product must be isolated.

[0028] - The direct electrochemical oxidation reaction does not require those reagents.

[0029] - Unwanted secondary components may be produced.

[0030] - Unwanted secondary components may seriously interfere with subsequent process steps.

[0031] - The unwanted components are oxidants and solvents and may seriously interfere with subsequent process steps. - Any secondary components produced (e.g., impurities due to low chemoselectivity) should be removed in the crystallization / separation step.

[0032] - The secondary component may be the reduced form of a chemical oxidant (oxidation of Fe(3+) to Fe(2+), or absorption of H atoms by DDQ to form H2DDQ), however, the component itself (regardless of its oxidation state) may be a problem for achieving high selectivity / yield in the next step.

[0033] - The separation steps required for intermediates result in at least two specific drawbacks:

[0034] · Additional method steps such as filtration, washing, drying, and repeated solid handling (e.g., filling the dried solid into a container, intermediate storage, and providing the stored material for the next synthesis step)

[0035] · Yield loss during the separation of intermediates, e.g., through mother liquor or washing steps.

[0036] - The dihydropyridine derivatives in US 15 / 753,406 A1 are oxidized to their pyridine analogs (e.g., DDQ, also see US 15 / 753,406 A1, Figure 4) using a substoichiometric amount of a mediator by an indirect electrochemical oxidation method, and these mediators are also described in Francke and Little, Chem. Soc. Rev. 43(8), 2014, pages 2492 - 2521. The oxidants used in the oxidation step cat interfere with further method steps and may even limit the electrochemical reduction step.

[0037] - The solvent used in the oxidation step of US 15 / 753,406 A1

[0038] - This synthesis is not suitable for large-scale processes because many steps are carried out at very high dilution with a very high reagent excess, thus providing a relatively low overall yield. In addition, many intermediate chromatographic purification and / or separation steps are necessary, which are generally very laborious technically and require a large amount of solvent consumption and high cost, so they should be avoided as much as possible. Some stages are not achievable due to safety and process technology difficulties.

[0039] This list is not exhaustive.

[0040] Accordingly, there is a need for an industrially viable and / or large-scale synthetic method that can provide the compound of formula (XIII) in a reproducible manner, with a minimum number of reaction steps, a minimum number of separation steps, a high overall yield, low production costs, and high purity. Medicinal substances and their intermediates have very high requirements for purity. For example, these need to meet all regulatory requirements in order to be suitable for clinical trials, late-stage regulatory submissions, and / or ultimately for use in patients. These regulations are, for example, Good Manufacturing Practice (GMP) and Good Clinical Practice (GCP).

[0041] Surprisingly, a sequential one-pot synthetic method has been found that can meet the above requirements.

[0042] The present invention encompasses a sequential one-pot synthetic method for synthesizing 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide according to formula (XIII)

[0043]

[0044] The said synthesis comprises the following steps:

[0045] Step a) synthesizing 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,6-naphthyridine-3-carboxamide of formula (XVII)

[0046]

[0047] by electrochemically oxidizing (4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula ent-(I)

[0048]

[0049] Step b) synthesizing 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (XIII)

[0050]

[0051] It is carried out by electrochemical reduction of a compound according to formula (XVII).

[0052] Furthermore, the compounds of formula (XIII) can be produced in a very efficient manner by sequential one-pot synthesis. The sequential one-pot synthesis has significant advantages over the prior art in terms of scalability and technical implementation. The overall yield is significantly higher than the aforementioned synthesis.

[0053] In particular, the present invention encompasses the sequential one-pot synthesis as described in Scheme 3 below:

[0054] Scheme 3: Sequential one-pot synthesis

[0055]

[0056] Compared with the known processes, the synthesis of the present invention is a one-pot synthesis, first performing electrochemical oxidation (step a), and then electrochemical reduction (step b). In the sequential one-pot synthesis, it is not necessary to isolate the intermediates. The sequential one-pot synthesis can be run in one apparatus / equipment. For example, the sequential one-pot synthesis can be run in one of the apparatuses / equipments shown as follows Figure 1 or Figure 2 shown. Therefore, the electrochemical oxidation and electrochemical reduction can be directly carried out one after another in one apparatus / equipment. The sequential one-pot synthesis can be run without separating the intermediates required in the known processes. In contrast, in the known methods, the intermediates (compounds M1a(S), M1b(R) and / or (XVII)) must be separated as described above.

[0057] Even though the one-pot synthesis method is known, the synthesis of the known US 15 / 753,406 A1 cannot be directly scaled up and / or carried out as a one-pot synthesis. The reaction conditions of the individual steps described in US 15 / 753,406 A1 are significantly different from each other. Different steps require different reaction conditions. The reaction conditions of the previous step may not be suitable for the next step. For example, the oxidation step in US 15 / 753,406 A1 is carried out using nitric acid and acetonitrile. At least for safety reasons, these reaction conditions are not suitable for subsequent thermal racemization on an industrial scale. In US 15 / 753,406 A1, the oxidant used is in excess. In the presence of residual oxidation reagent, consecutive oxidation reactions may occur at high temperature and lead to the formation of new impurities. This may result in a decrease in quality and yield.

[0058] Furthermore, the sequential one-pot synthesis method can recycle the compound of formula (XIII) from the compound ent-(I) on an industrial scale. Then the compound (XIII) can be subjected to enantiomeric resolution again to obtain the compound (I). See Scheme 4.

[0059] Scheme 4:

[0060]

[0061] Therefore, the by-product of the formula ent-(I) does not need to be destroyed but can be reused. This is very sustainable because there is less chemical waste to be treated separately, and / or valuable raw materials / intermediates can be recovered at one of the final stages of the method. Since this is a large-scale method, this is not only beneficial to the environment but also saves money, time, and materials. For cost reasons, on the other hand, for sustainability reasons, this is very advantageous, especially since this is a large-scale method.

[0062] The sequential one-pot synthesis described here can be carried out continuously multiple times. Therefore, it provides the possibility of converting the compound ent-(I) into the compound (XIII). This can be regarded as a quasi-continuous operation mode, which has great advantages in terms of cost, time, and / or resources. In this way, the waste product ent-(I) that repeatedly appears during the preparation of finerenone (I) can be reconverted into the compound (XIII). Then, the compound (XIII) can in turn be re-introduced into the production process of finerenone (I). Therefore, after several cycles of the sequential one-pot synthesis method, the compound ent-(I) can be almost completely utilized. In the best case, the by-product ent-(I) can be almost completely recovered as the envisaged product (XIII) or finerenone (I).

[0063] The sequential one-pot synthesis can produce the compound of formula (XIII) in a repeatable, sustainable, and / or economical manner. After several cycles of the sequential one-pot synthesis method, the compound ent-(I) can be almost completely utilized.

[0064] The compound (XIII) can subsequently be used for the preparation of finerenone, for example, by chiral chromatography, by forming diastereomeric salts, crystallization, precipitation, and other classical resolution methods. Enantiomeric high-performance liquid chromatography is known from, for example, US20100136142A1 and US20170217957 A1. The method of separating enantiomers by diastereomeric separation is described in US20210163474 A1.

[0065] Another particularly important advantage of the present invention is that the compound of formula (XIII) can be recovered with high chemical purity. Since it is an active pharmaceutical ingredient / intermediate, all operations are carried out under GMP and high purity of the intermediate is required.

[0066] Equally surprisingly, the compound of formula (XIII) can be recovered on a large scale by electrolysis. Commercially, electrolytic cells are used for the electrorefining and electrowinning of several non-ferrous metals. Almost all high-purity aluminum, copper, zinc, and lead are industrially produced in electrolytic cells. However, in the pharmaceutical industry, the use of such electrolytic cells for the synthesis of drugs is not common. This is especially true in large-scale methods. The industrial production of active ingredients is carried out in so-called "multi-purpose production plants". These only include standard equipment (including, for example, boilers, centrifuges, dryers, etc.). The use of electrolytic cells in such multi-purpose production plants in the pharmaceutical industry is neither a standard setting nor commonly used for commercial synthesis in the pharmaceutical industry.

[0067] Unless otherwise defined, technical terms used herein are used in a manner customary to those skilled in the art. Nomenclature follows the nomenclature of the International Union of Pure and Applied Chemistry (IUPAC). The units used here are in accordance with the International System of Units (SI units).

[0068] 4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide is the compound of formula (XIII)

[0069]

[0070] The terms "4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide", "compound of formula (XIII)", and "compound (XIII)" are synonyms. The compound of formula (XIII) includes (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (I) and (4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula ent-(I)

[0071]

[0072] (4S)-4-(4-Cyan-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridin-3-carboxamid ist die Verbindung der Formel (I),

[0073]

[0074] The INN of the compound of formula (I) is "Finerenone". The CAS number of Finerenone is CAS 1050477-31-0. Compound (I) is the (S)-enantiomer included in the compound of formula (XIII). The terms "(4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide", "Finerenone" and "Compound (I)" are synonyms.

[0075] (4R)-4-(4-Cyano-2-methoxy-phenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide is the compound of formula ent-(I)

[0076]

[0077] Compound (I) is described in US 15 / 753,406 A1. Compound ent-(I) is the (R)-enantiomer included in the compound of formula (XIII). The terms "(4R)-4-(4-cyano-2-methoxy-phenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide", "Compound of formula ent-(I)" and "Compound ent-(I)" are synonyms. As described in Scheme 1 above, compound ent-(I) can be obtained as a waste product or by-product in the synthesis of Finerenone (I).

[0078] Compounds M1a(S) and M1b(R)

[0079]

[0080] Are described in US 15 / 753,406 A1. These compounds are atropisomers included in the compound of formula (XVII). 4-(4-Cyano-2-methoxy-phenyl)-5-ethoxy-2,8-dimethyl-1,6-naphthyridine-3-carboxamide is as formula (XVII)

[0081]

[0082] Therefore, compound (XVII) contains compounds M1a(S) and M1b(R)

[0083] The term "intermediate" can refer to an intermediate in the sequential one-pot synthesis of the compound of formula (XIII) or an intermediate in the process for preparing the compound of formula (I). The intermediate can be, for example, a compound of formula ent-(I), a compound of formula M1a(S), a compound of formula M1b(R), a compound of formula (XVII), a compound of formula (XIII).

[0084] The term "product" can refer to the compound of formula (XIII) or the compound of formula (I). It may depend on which aspect or partial aspect of the process or step described herein is being referred to. A "conductive salt" or "conductive electrolyte" is a salt that takes over charge transport during the electrolysis process. The conductive salt reduces the ohmic resistance of the solution and enables the depolarizer to be transported to the electrode by diffusion. It does not participate in the electrode reaction. Examples of conductive salts are tetrabutylammonium perchlorate BuN4ClO4, Et4NBF4, Bu4NBF4, Bu4NPF6, Bu4NX (where X = I, Br) or perchlorates such as NaClO4, LiClO4, Et4NClO4. These conductive salts can be used in the sequential one-pot synthesis of the present invention.

[0085] The term "solvent" also includes solvent mixtures. The solvent can be recovered or reused as a mixture. In one embodiment, the solvent is recovered. In another embodiment, the solvent is recovered and then can be supplemented with fresh solvent to the remaining components of the production to obtain the desired mixing ratio.

[0086] In one embodiment, a suspension or a mixture thereof is used as the solvent. Using a suspension or a mixture thereof can result in an optimal space-time yield. The suspension can be pumped through by the system / method used.

[0087] In one embodiment of the present invention, the sequential one-pot synthesis is carried out by electrolysis. The reaction type "electrolysis" is also known in the art. The chemical change caused by the passage of an electric current through an electrolyte is called electrolysis. Electrical energy is directly converted into chemical energy. The electrolysis process is an electrochemical reaction in which a non-spontaneous substance transformation process is forced by applying an external voltage. Electrical energy (current) is converted into chemical energy (substance). Electrolysis is carried out by applying electrical work and is the reverse process of the galvanic cell process.

[0088] Electrolysis equipment or electrolytic cells are known to those skilled in the art [Encyclopedia of Applied Electrochemistry, G. Kreysa et al. (eds.), Encyclopedia of Applied Electrochemistry, DOI 10.1007 / 978-1-4419-6996-5, Springer Science and Business Media New York 2014, pp. 568 - 578; Electrochmica Acta 161, (2015), pp. 436 - 451; Journal of Applied Electrochemistry 27(1997), p. 1313, p. 1322]. Electrolysis devices are also described in US 15 / 753,406 A1. An industrial-scale electrochemical cell can include one or more electrochemical cells. Such an industrial-scale arrangement can include one or more electrochemical cells, compartments, containers, and / or tanks, etc. Such an industrial-scale system typically consists of or contains several electrochemical cells. These can operate in series or in parallel. Such an industrial system can include one or more tanks, reaction vessels, etc. The reaction mixture can telescope between the various compartments of such an industrial-scale system. Thus, in such an industrial-scale system, the reaction steps according to the present invention can be carried out sequentially.

[0089] In one embodiment of the present invention, the sequential one-pot synthesis is an electrochemical synthesis. In one embodiment of the present invention, the sequential one-pot synthesis is carried out in an electrochemical cell. In one embodiment of the present invention, the sequential one-pot synthesis is carried out in an electrolytic cell. Electrolytic cells are known in the art. An electrolytic cell is an electrochemical cell that uses electrical energy from an external source to drive a chemical reaction that would not otherwise occur. A voltage is applied between two electrodes, namely the anode (the positively charged electrode) and the cathode (the negatively charged electrode). This is the opposite of a galvanic cell, which is itself a source of electrical energy. In an electrolytic cell, an electric current passes through the electrolytic cell by means of an external voltage, causing a non-spontaneous chemical reaction. An electrolytic cell has three components: an electrolyte solution and two electrodes (the cathode and the anode). The electrolyte solution is usually a solution of water or other solvents in which ions are dissolved. When driven by an external voltage applied to the electrodes, the ions in the electrolyte solution are attracted to the electrodes with the opposite charge, where charge transfer (also known as Faraday or redox) reactions occur. Only with an external potential (i.e., voltage) of the correct polarity and sufficient magnitude can the electrolytic cell decompose compounds that are usually stable or inert in the solution. The electrical energy provided can produce chemical reactions that would not otherwise occur spontaneously (non-spontaneous reactions).

[0090] Figure 1 and Figure 2 schematically shows the setup of an electrolysis device. Such an electrolysis device can be used for large-scale synthesis. Figure 1 and Figure 2 The electrolysis device shown can also be used for the sequential one-pot synthesis according to the present invention. Further modifications can be made to such an electrolysis device. For example, multiple electrolyte tanks and / or anolyte tanks can be used. Other devices such as separators (e.g., for gases), heat exchangers, heating devices, cooling devices, etc. can also be used / integrated. The corresponding setups suitable for industrial-scale synthesis are known to those skilled in the art.

[0091] In one embodiment, the sequential one-pot synthesis is carried out in a divided electrolytic cell. In one embodiment, the sequential one-pot synthesis is carried out in a filter press electrolytic cell. Other commercially available electrolytic cells are also available and are known to those skilled in the art.

[0092] Further modifications can be made to such an electrolysis device. The modifications or adjustments described below can be applied to Figure 1 and / or the schematic standard setup described in 2. For example, multiple electrolyte tanks and / or anolyte tanks can be used. Other devices such as separators (e.g., for gases), heat exchangers, heating devices, cooling devices, etc. can also be used / integrated. The corresponding setups suitable for industrial-scale synthesis are known to those skilled in the art. The method can be carried out in whole and / or in part in a continuous and / or discontinuous manner. A filtration unit for solids can be installed. Using such a filter, starting materials, intermediates (e.g., ent-(I), M1a(S), M1b(R), (XVII), (XIII)) or products (e.g., (XIII), (I)) can be isolated or separated from the reaction mixture.

[0093] These filtration devices can be cooled and then the filtrate can be returned to the process. In addition, the residence loop can be heated or cooled. This can cause continuous racemization. A continuous dosing device can also be installed. A suspension pump can also be installed. The electrolytic cell can contain, comprise and / or (partially) be made of glass, enamel or optionally stainless steel with a Teflon lining or a plastic (certified by GMP) having non-“leaching” properties.

[0094] The geometry of the electrodes can also be adjusted to achieve optimal flow rates. The geometry of the electrodes can also be adjusted to achieve optimal flow rates so as to control the formation and emission of gases. Heat dissipation measures can be taken to match the geometry of each electrode. The fluid distribution in the electrolytic cell or device or method setup can be further adjusted. For example, such adjustment can be achieved by additional stirring measures to improve mass transfer.

[0095] Different types of electrodes can be used. For example, electrodes containing or comprising or consisting of noble metals, electrodes coated with noble metals, titanium electrodes, graphite electrodes, boron-doped diamond electrodes (BDD). The electrode can contain noble metals, a metal or non-metal carrier coated with noble metals and / or non-metal electrode materials (such as graphite) or consist thereof.

[0096] Commercially available diaphragms can be used to implement a divided cell.

[0097] The electrode can be segmented. The electrode can be segmented and the total electrode area can be 60 - 100 cm 2 In one embodiment, the electrode is segmented. In one embodiment, the total electrode area is 60 - 100 cm 2 In one embodiment, the electrode is segmented and the total electrode area is 60 - 100 cm 2 In one embodiment, the electrode area is 80 cm (width) and 25 to 75 cm (height).

[0098] The electrolytic cell can be composed of segmented cell units or contain segmented cell units, which can be expanded by "numbering-up" in a stacking design.

[0099] By adjusting the voltage, current density, temperature, flow rate / speed and / or residence time, it is possible to optionally adjust and optimize the existing materials and sealing concepts, improve the electrode structure and cell geometry, and the adaptation of system components (such as components for heat dissipation and control).

[0100] The method can be carried out under an inert gas. Various inert gases are known to those skilled in the art. Examples are CO2, N2, argon (Ar), neon (Ne), radon (Ra), helium (He), krypton (Kr), xenon (Xe), radon (Rn) and / or mixtures thereof. The inert gas used can be a pure gas or a mixture of pure gases. A mixture of an inert gas and a non-inert gas can be used. In one embodiment, the mixture mainly contains an inert gas.

[0101] The methods described herein can be performed in whole and / or in part in different modes. Examples of such modes are the batch method mode (campaign mode), or the continuous method mode.

[0102] In one embodiment, the method according to the invention is carried out in continuous mode. In one embodiment, the method according to the invention is carried out in continuous mode, wherein the raw materials, intermediates and / or conductive salts are continuously added. In one embodiment, the method according to the invention is carried out in continuous mode, wherein

[0103] - Continuously add raw materials, solvents, conductive salts, acids, and / or intermediates, and

[0104] - Continuously remove the product.

[0105] The number of cycles for each of the following steps can be adjusted separately. One or more of the steps can be performed multiple times, while one or more of the steps are performed less frequently, or even only once.

[0106] The improvement of long-term stability can also be optimized. The long-term stability can be enhanced by optimizing the residence time. In one embodiment, the residence time is equal to or less than 20 hours. In one embodiment, the residence time is 5 to 8 hours. In one embodiment, the residence time in a single unit operation is equal to or less than 6 hours. The residence time should be adapted to the geometry and / or flow rate.

[0107] The multiphase flow generated by bubble formation can be suppressed. For this purpose, the heat dissipation strategy and / or the influence of different geometries and / or method parameters on the operating behavior can be optimized.

[0108] Step a)

[0109] The sequential one-pot synthesis method described above includes step a).

[0110] In one embodiment, step a) is carried out at a temperature selected from 15 to 150 °C, 15 to 120 °C, and 20 to 100 °C. In one embodiment, step a) is carried out at a temperature of 15 to 150 °C. In one embodiment, step a) is carried out at a temperature of 15 to 120 °C. In one embodiment, step a) is carried out at a temperature of 20 to 100 °C. In one embodiment, step a) is carried out at a temperature of 15 to 150 °C. In one embodiment, step a) is carried out at a temperature of 15 to 120 °C. In one embodiment, step a) is carried out at a temperature of 20 to 100 °C. In one embodiment, step a) is carried out at ambient temperature.

[0111] In step a), the temperature can be constant, variable, increasing, or decreasing. In step a), a specific temperature program can also be run. In one example, step a) is carried out at a temperature of 15 to 150 °C, where the temperature is constant, variable, increasing, decreasing, or running a specific temperature program.

[0112] In step a), the temperature is constant, variable, increasing, or decreasing. In step a), a specific temperature program can also be run.

[0113] In one embodiment, step a) is carried out at a temperature of 15 to 150 °C, where the temperature is constant, variable, increasing, decreasing, or running a specific temperature program.

[0114] In one embodiment, step a) is carried out at a temperature of 15 to 150 °C, where the temperature is constant. In one embodiment, step a) is carried out at a temperature of 15 to 120 °C, where the temperature is constant. In one embodiment, step a) is carried out at a temperature of 20 to 100 °C, where the temperature is constant.

[0115] In one embodiment, step a) is carried out at a temperature of 15 to 150 °C, where the temperature is variable. In one embodiment, step a) is carried out at a temperature of 15 to 120 °C, where the temperature is variable. In one embodiment, step a) is carried out at a temperature of 20 to 100 °C, where the temperature is variable.

[0116] In one embodiment, step a) is carried out at a temperature of 15 to 150 °C, where the temperature is increasing. In one embodiment, step a) is carried out at a temperature of 15 to 120 °C, where the temperature is increasing. In one embodiment, step a) is carried out at a temperature of 20 to 100 °C, where the temperature is increasing.

[0117] In one embodiment, step a) is carried out at a temperature of 15 to 150 °C, where the temperature is decreasing. In one embodiment, step a) is carried out at a temperature of 15 to 120 °C, where the temperature is decreasing. In one embodiment, step a) is carried out at a temperature of 20 to 100 °C, where the temperature is decreasing.

[0118] In one embodiment, step a) is carried out at a temperature of 15 to 150 °C, where a specific temperature program is run. In one embodiment, step a) is carried out at a temperature of 15 to 120 °C, where a specific temperature program is run. In one embodiment, step a) is carried out at a temperature of 20 to 100 °C, where a specific temperature program is run.

[0119] In one embodiment of step a), electrochemical oxidation is first carried out, and then the reaction mixture is heated.

[0120] In one embodiment of step a), electrochemical oxidation is first carried out, and then the reaction mixture is heated to 50 to 150 °C. In one embodiment of step a), electrochemical oxidation is first carried out, and then the reaction mixture is heated to 75 to 150 °C. In one embodiment of step a), electrochemical oxidation is first carried out, and then the reaction mixture is heated to 80 to 150 °C. In one embodiment of step a), electrochemical oxidation is first carried out, and then the reaction mixture is heated to 80 to 140 °C. In one embodiment of step a), electrochemical oxidation is first carried out, and then the reaction mixture is heated to 90 to 120 °C.

[0121] In one embodiment of step a), electrochemical oxidation is first carried out, where the temperature is constant, variable, rising, falling or a specific temperature program can also be run, and then the reaction mixture is heated.

[0122] In one embodiment of step a), electrochemical oxidation is first carried out, where the temperature is constant, variable, rising, falling or a specific temperature program can also be run, and then the reaction mixture is heated to 50 to 150 °C.

[0123] In one embodiment of step a), electrochemical oxidation is first carried out, where the temperature is constant, variable, rising, falling or a specific temperature program can also be run, and then the reaction mixture is heated to 75 to 150 °C.

[0124] In one embodiment of step a), electrochemical oxidation is first carried out, where the temperature is constant, variable, rising, falling or a specific temperature program can also be run, and then the reaction mixture is heated to 80 to 150 °C.

[0125] In one embodiment of step a), electrochemical oxidation is first carried out, where the temperature is constant, variable, rising, falling or a specific temperature program can also be run, and then the reaction mixture is heated to 80 to 140 °C.

[0126] In one embodiment of step a), electrochemical oxidation is first carried out, where the temperature is constant, variable, rising, falling or a specific temperature program can also be run, and then the reaction mixture is heated to 90 to 120 °C.

[0127] In one embodiment of step a), electrochemical oxidation is first carried out at a temperature selected from 15 to 150 °C, 15 to 120 °C and 20 to 100 °C, and then the reaction mixture is heated.

[0128] In one embodiment of step a), electrochemical oxidation is first carried out at a temperature selected from 15 to 150 °C, 15 to 120 °C and 20 to 100 °C, where the temperature is constant, variable, increasing, decreasing or a specific temperature program can also be run, and then the reaction mixture is heated.

[0129] In one embodiment of step a), electrochemical oxidation is first carried out at a temperature selected from 15 to 50 °C, and then the reaction mixture is heated to 50 to 150 °C. In one embodiment of step a), electrochemical oxidation is first carried out at a temperature selected from 15 to 75 °C, and then the reaction mixture is heated to 75 to 150 °C. In one embodiment of step a), electrochemical oxidation is first carried out at a temperature selected from 15 to 80 °C, and then the reaction mixture is heated to 80 to 150 °C. In one embodiment of step a), electrochemical oxidation is first carried out at a temperature selected from 15 to 80 °C, and then the reaction mixture is heated to 80 to 140 °C. In one embodiment of step a), electrochemical oxidation is first carried out at a temperature selected from 15 to 90 °C, and then the reaction mixture is heated to 90 to 120 °C.

[0130] In one embodiment of step a), electrochemical oxidation is first carried out at a temperature selected from 15 to 150 °C, 15 to 120 °C and 20 to 100 °C, where the temperature is constant, variable, increasing, decreasing or a specific temperature program can also be run, and then the reaction mixture is heated, where the temperature is constant, variable, increasing, decreasing or a specific temperature program can also be run.

[0131] In one embodiment of step a), electrochemical oxidation is first carried out, and then the reaction mixture is heated, where the temperature is constant, variable, increasing, decreasing or a specific temperature program can also be run, and the reaction mixture is heated to 75 to 150 °C. In one embodiment of step a), electrochemical oxidation is first carried out, and then the reaction mixture is heated, where the temperature is constant, variable, increasing, decreasing or a specific temperature program can also be run, and the reaction mixture is heated to 80 to 150 °C. In one embodiment of step a), electrochemical oxidation is first carried out, and then the reaction mixture is heated, where the temperature is constant, variable, increasing, decreasing or a specific temperature program can also be run, and the reaction mixture is heated to 80 to 140 °C. In one embodiment of step a), electrochemical oxidation is first carried out, and then the reaction mixture is heated, where the temperature is constant, variable, increasing, decreasing or a specific temperature program can also be run, and the reaction mixture is heated to 90 to 120 °C.

[0132] In one embodiment of step a), electrochemical oxidation is first carried out, where the temperature is constant, variable, increasing, decreasing or a specific temperature program can also be run, and then the reaction mixture is heated, where the temperature is constant, variable, increasing, decreasing or a specific temperature program can also be run.

[0133] In one embodiment of step a), electrochemical oxidation is first carried out at a temperature of 15 to 150 °C, where the temperature is constant, variable, increasing, decreasing or a specific temperature program can also be run, and then the reaction mixture is heated to a temperature of 50 to 150 °C, where the temperature is constant, variable, increasing, decreasing or a specific temperature program can also be run.

[0134] In one embodiment of step a)

[0135] - First, electrochemical oxidation is carried out at a temperature selected from 15 to 150 °C, 15 to 120 °C and 20 to 100 °C, where the temperature is constant, variable, increasing, decreasing or a specific temperature program can also be run, and

[0136] - Then the reaction mixture is heated to a temperature selected from 50 to 150 °C, 75 to 150 °C, 80 to 150 °C, 80 to 140 °C, 90 to 120 °C, where the temperature is constant, variable, increasing, decreasing or a specific temperature program can also be run.

[0137] In one embodiment of step a)

[0138] - First, electrochemical oxidation is carried out at a temperature of 15 to 150 °C, where the temperature is constant, variable, increasing, decreasing or a specific temperature program can also be run, and

[0139] - Then the reaction mixture is heated to a temperature selected from 50 to 150 °C, 75 to 150 °C, 80 to 150 °C, 80 to 140 °C, 90 to 120 °C, where the temperature is constant, variable, increasing, decreasing or a specific temperature program can also be run.

[0140] In one embodiment of step a)

[0141] - First, electrochemical oxidation is carried out at a temperature of 15 to 120 °C, where the temperature is constant, variable, increasing, decreasing or a specific temperature program can also be run, and

[0142] - Then the reaction mixture is heated to a temperature selected from 50 to 150 °C, 75 to 150 °C, 80 to 150 °C, 80 to 140 °C, 90 to 120 °C, where the temperature is constant, variable, increasing, decreasing or a specific temperature program can also be run.

[0143] In one embodiment of step a)

[0144] - First, electrochemical oxidation is carried out at a temperature of 20 to 100 °C, where the temperature is constant, variable, increasing, decreasing or a specific temperature program can also be run, and

[0145] - Then the reaction mixture is heated to a temperature selected from 50 to 150 °C, 75 to 150 °C, 80 to 150 °C, 80 to 140 °C, 90 to 120 °C, where the temperature is constant, variable, increasing, decreasing or a specific temperature program can also be run.

[0146] In one embodiment of step a)

[0147] - First, electrochemical oxidation is carried out at a temperature selected from 15 to 150 °C, 15 to 120 °C and 20 to 100 °C, where the temperature is constant, variable, increasing, decreasing or a specific temperature program can also be run, and

[0148] - Then the reaction mixture is heated to a temperature of 50 to 150 °C, where the temperature is constant, variable, increasing, decreasing or a specific temperature program can also be run.

[0149] In one embodiment of step a)

[0150] - First, electrochemical oxidation is carried out at a temperature selected from 15 to 150 °C, 15 to 120 °C and 20 to 100 °C, where the temperature is constant, variable, increasing, decreasing or a specific temperature program can also be run, and

[0151] - Then the reaction mixture is heated to a temperature of 75 to 150 °C, where the temperature is constant, variable, increasing, decreasing or a specific temperature program can also be run.

[0152] In one embodiment of step a)

[0153] - First, electrochemical oxidation is carried out at a temperature selected from 15 to 150 °C, 15 to 120 °C and 20 to 100 °C, where the temperature is constant, variable, increasing, decreasing or a specific temperature program can also be run, and

[0154] - Then the reaction mixture is heated to a temperature of 80 to 150 °C, where the temperature is constant, variable, rising, falling or a specific temperature program can also be run.

[0155] In one embodiment of step a)

[0156] - First, electrochemical oxidation is carried out at a temperature selected from 15 to 150 °C, 15 to 120 °C and 20 to 100 °C, where the temperature is constant, variable, rising, falling or a specific temperature program can also be run, and

[0157] - Then the reaction mixture is heated to a temperature of 80 to 140 °C, where the temperature is constant, variable, rising, falling or a specific temperature program can also be run.

[0158] In one embodiment of step a)

[0159] - First, electrochemical oxidation is carried out at a temperature selected from 15 to 150 °C, 15 to 120 °C and 20 to 100 °C, where the temperature is constant, variable, rising, falling or a specific temperature program can also be run, and

[0160] - Then the reaction mixture is heated to a temperature of 90 to 120 °C, where the temperature is constant, variable, rising, falling or a specific temperature program can also be run.

[0161] In one embodiment of step a), a conductive salt is used. In one embodiment of step a), a conductive salt selected from organic ammonium salts, ionic liquids, tetraalkylammonium fluoroborates, quaternary ammonium salts and mixtures thereof is used. In one embodiment of step a), a conductive salt selected from tetraethylammonium tetrafluoroborate, tetrabutylammonium hexafluorophosphate, tetrabutylammonium hydrogen sulfate and mixtures thereof is used.

[0162] In one embodiment of step a), the amount of solvent used for (4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula ent-(I) is 1 to 60 kg / kg. This means that 60 kg of solvent is used for 1 kg of (4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula ent-(I). In one embodiment of step a), the amount of solvent used for (4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula ent-(I) is 5 to 50 kg / kg. In one embodiment of step a), the amount of solvent used for (4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula ent-(I) is 5 to 30 kg / kg. In one embodiment of step a), the amount of solvent is 7 to 25 kg / kg. In one embodiment of step a), the amount of solvent is 8 to 20 kg / kg. In one embodiment of step a), the amount of solvent is 9 to 19 kg / kg.

[0163] In one embodiment of step a), the amount of solvent is 80 to 99 wt%, based on the total amount of the reaction mixture. In one embodiment of step a), the amount of solvent is 85 to 95 wt%, based on the total amount of the reaction mixture. In one embodiment of step a), the amount of solvent is 85 to 92 wt%, based on the total amount of the reaction mixture. In one embodiment of step a), the amount of solvent is 90 wt%, based on the total amount of the reaction mixture.

[0164] "wt%" is weight percentage. In one example, if the amount of the reaction mixture is 100 kg and if the amount of the solvent used is 80 wt%, then the amount of the solvent is 80 kg.

[0165] In one embodiment of step a), a solvent is used. In one embodiment of step a), the solvent is selected from aprotic solvents, protic solvents, and mixtures thereof. In one embodiment of step a), the solvent is selected from polar aprotic solvents. In one embodiment of step a), the solvent is selected from the following polar aprotic solvents: dimethylformamide (DMF), dimethyl sulfoxide, acetonitrile, acetone, dimethylacetamide, N-methylpyrrolidone, sulfolane, or protic solvents such as methanol, acetic acid, ethanol, formic acid, n-butanol, propionic acid, methanesulfonic acid, water, and mixtures thereof. Other suitable solvents are methoxymethanol, tetramethylureaformamide, DMA (dimethylacetamide), NMP (N-methylpyrrolidone), propionitrile, glycerol, propanol, isopropanol. In one embodiment of step a), the solvent is selected from dimethylformamide (DMF), methanol, acetic acid, and mixtures thereof. In one embodiment of step a), the solvent is selected from methanol, acetic acid, and mixtures thereof. In one embodiment of step a), the solvent is methanol. In one embodiment of step a), the solvent is acetic acid.

[0166] Other suitable solvents are acids. Examples of suitable acids are propionic acid, butyric acid, benzoic acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, HBF4, HPF6, ammonium acetate, and mixtures of the above substances.

[0167] In one embodiment of step a),

[0168] - a conductive salt selected from organic ammonium salts, ionic liquids, tetraalkylammonium fluoroborates, quaternary ammonium salts, and mixtures thereof; and

[0169] - a solvent selected from aprotic solvents, protic solvents, and mixtures thereof.

[0170] In one embodiment of step a),

[0171] - a conductive salt selected from organic ammonium salts, ionic liquids, tetraalkylammonium fluoroborates, quaternary ammonium salts, and mixtures thereof; and

[0172] - a solvent selected from polar aprotic solvents.

[0173] In one embodiment of step a),

[0174] - a conductive salt selected from tetraethylammonium tetrafluoroborate, tetrabutylammonium hexafluorophosphate, tetrabutylammonium hydrogen sulfate, and mixtures thereof; and

[0175] - a solvent selected from aprotic solvents, protic solvents, and mixtures thereof.

[0176] In one embodiment of step a),

[0177] - A conductive salt selected from tetraethylammonium tetrafluoroborate, tetrabutylammonium hexafluorophosphate, tetrabutylammonium hydrogen sulfate, and mixtures thereof; and

[0178] - A solvent selected from polar aprotic solvents.

[0179] In one embodiment of step a),

[0180] - A conductive salt selected from organic ammonium salts, ionic liquids, tetraalkylammonium tetrafluoroborates, quaternary ammonium salts, and mixtures thereof; and

[0181] - A polar aprotic solvent selected from dimethylformamide (DMF), dimethyl sulfoxide, acetonitrile, acetone, dimethylacetamide, N-methylpyrrolidone, sulfolane, or a protic solvent such as methanol, acetic acid, ethanol, formic acid, n-butanol, propionic acid, methanesulfonic acid, water, and mixtures thereof

[0182] In one embodiment of step a),

[0183] - A conductive salt selected from tetraethylammonium tetrafluoroborate, tetrabutylammonium hexafluorophosphate, tetrabutylammonium hydrogen sulfate, and mixtures thereof; and

[0184] - A polar aprotic solvent selected from dimethylformamide (DMF), dimethyl sulfoxide, acetonitrile, acetone, dimethylacetamide, N-methylpyrrolidone, sulfolane, or a protic solvent such as methanol, acetic acid, ethanol, formic acid, n-butanol, propionic acid, methanesulfonic acid, water, and mixtures thereof.

[0185] In one embodiment of step a),

[0186] - A conductive salt selected from organic ammonium salts, ionic liquids, tetraalkylammonium tetrafluoroborates, quaternary ammonium salts, and mixtures thereof; and

[0187] - A solvent selected from dimethylformamide (DMF), methanol, acetic acid, and mixtures thereof.

[0188] In one embodiment of step a),

[0189] - A conductive salt selected from organic ammonium salts, ionic liquids, tetraalkylammonium tetrafluoroborates, quaternary ammonium salts, and mixtures thereof; and

[0190] - A solvent selected from dimethylformamide (DMF), methanol, acetic acid, and mixtures thereof. In one embodiment of step a),

[0191] - A conductive salt selected from tetraethylammonium tetrafluoroborate, tetrabutylammonium hexafluorophosphate, tetrabutylammonium hydrogen sulfate, and mixtures thereof; and

[0192] - A solvent selected from dimethylformamide (DMF), methanol, acetic acid, and mixtures thereof.

[0193] In one embodiment of step a), there is used

[0194] - a conductive salt selected from organic ammonium salts, ionic liquids, tetraalkylammonium tetrafluoroborates, quaternary ammonium salts, and mixtures thereof; and

[0195] - methanol.

[0196] In one embodiment of step a), there is used

[0197] - a conductive salt selected from organic ammonium salts, ionic liquids, tetraalkylammonium tetrafluoroborates, quaternary ammonium salts, and mixtures thereof; and

[0198] - methanol.

[0199] In one embodiment of step a), there is used

[0200] - a conductive salt selected from tetraethylammonium tetrafluoroborate, tetrabutylammonium hexafluorophosphate, tetrabutylammonium hydrogen sulfate, and mixtures thereof; and

[0201] - methanol.

[0202] In one embodiment of step a), there is used

[0203] - a conductive salt selected from organic ammonium salts, ionic liquids, tetraalkylammonium tetrafluoroborates, quaternary ammonium salts, and mixtures thereof; and

[0204] - acetic acid.

[0205] In one embodiment of step a), there is used

[0206] - a conductive salt selected from organic ammonium salts, ionic liquids, tetraalkylammonium tetrafluoroborates, quaternary ammonium salts, and mixtures thereof; and

[0207] - acetic acid.

[0208] In one embodiment of step a), there is used

[0209] - a conductive salt selected from tetraethylammonium tetrafluoroborate, tetrabutylammonium hexafluorophosphate, tetrabutylammonium hydrogen sulfate, and mixtures thereof; and

[0210] - acetic acid.

[0211] In one embodiment of step a), based on 1 equivalent of the compound of ent-(I), the amount of the conductive salt used is 0.05 to 1 equivalent. This means that if 0.05 equivalent (0.05 mol) of the conductive salt is used, then 1 equivalent (1 mol) of the compound of formula ent-(I) is used.

[0212] In one embodiment of step a), based on 1 equivalent of the compound of ent-(I), the amount of the conductive salt used is 0.1 to 0.5 equivalents. In one embodiment of step a), based on 1 equivalent of the compound of ent-(I), the amount of the conductive salt used is 0.15 to 0.35 equivalents. In one embodiment of step a), based on 1 equivalent of the compound of ent-(I), the amount of the conductive salt used is 0.2 to 0.3 equivalents.

[0213] In one embodiment of step a), an acid is used. In one embodiment of step a), the acid used is selected from organic acids, organic polar acids, and mixtures thereof. In one embodiment of step a), an organic acid is used. In one embodiment of step a), the organic acid used is selected from carboxylic acids and sulfonic acids. In one embodiment of step a), an organic polar acid is used. In one embodiment of step a), the acid used is selected from acetic acid and formic acid and mixtures thereof. In one embodiment of step a), it is acetic acid.

[0214] In one embodiment of step a), the amount of the acid used is 50 to 500 mmol per liter of the reaction mixture. In one embodiment of step a), the amount of the acid used is 100 to 300 mmol per liter of the reaction mixture. In one embodiment of step a), the amount of the acid used is 150 to 250 mmol per liter of the reaction mixture.

[0215] In one embodiment of step a), 0.1 to 10 equivalents of the acid are used. In one embodiment of step a), 0.1 to 5 equivalents of the acid are used. In one embodiment of step a), 0.5 to 3 equivalents of the acid are used. In one embodiment of step a), 1.5 to 2 equivalents of the acid are used. In one embodiment of step a), 1.7 equivalents of the acid are used. The equivalents are based on the compound of formula ent-(I). This means that if 1.7 equivalents (1.7 mol) of the acid are used, 1 equivalent (1 mol) of the compound of formula ent-(I) is used.

[0216] In one embodiment of step a), the electrochemical oxidation is carried out at a cell voltage of 0.1 to 20 V. In one embodiment of step a), the electrochemical oxidation is carried out at a cell voltage of 0.1 to 15 V. In one embodiment of step a), the electrochemical oxidation is carried out at a cell voltage of 0.1 to 10 V. In one embodiment of step a), the electrochemical oxidation is carried out at a cell voltage of 0.1 to 5 V.

[0217] In one embodiment of step a), the electrochemical oxidation is carried out at a cell voltage of 0.5 to 20 V. In one embodiment of step a), the electrochemical oxidation is carried out at a cell voltage of 0.5 to 15 V. In one embodiment of step a), the electrochemical oxidation is carried out at a cell voltage of 0.5 to 10 V. In one embodiment of step a), the electrochemical oxidation is carried out at a cell voltage of 0.5 to 5 V.

[0218] In one embodiment of step a), the electrochemical oxidation is carried out at a cell voltage of 1 to 20 V. In one embodiment of step a), the electrochemical oxidation is carried out at a cell voltage of 1 to 15 V. In one embodiment of step a), the electrochemical oxidation is carried out at a cell voltage of 1 to 10 V. In one embodiment of step a), the electrochemical oxidation is carried out at a cell voltage of 1 to 5 V.

[0219] In one embodiment of step a), the electrochemical oxidation is carried out at a cell voltage of 2 to 20 V. In one embodiment of step a), the electrochemical oxidation is carried out at a cell voltage of 2 to 15 V. In one embodiment of step a), the electrochemical oxidation is carried out at a cell voltage of 2 to 10 V. In one embodiment of step a), the electrochemical oxidation is carried out at a cell voltage of 2 to 5 V.

[0220] In one embodiment of step a), the electrochemical oxidation is carried out at a cell voltage of 3 to 20 V. In one embodiment of step a), the electrochemical oxidation is carried out at a cell voltage of 3 to 15 V. In one embodiment of step a), the electrochemical oxidation is carried out at a cell voltage of 3 to 10 V. In one embodiment of step a), the electrochemical oxidation is carried out at a cell voltage of 3 to 5 V.

[0221] In one embodiment of step a), the electrochemical oxidation is carried out at a cell voltage of less than 20 V. In one embodiment of step a), the electrochemical oxidation is carried out at a cell voltage of less than 19 V. In one embodiment of step a), the electrochemical oxidation is carried out at a cell voltage of less than 18 V. In one embodiment of step a), the electrochemical oxidation is carried out at a cell voltage of less than 17 V. In one embodiment of step a), the electrochemical oxidation is carried out at a cell voltage of less than 16 V. In one embodiment of step a), the electrochemical oxidation is carried out at a cell voltage of less than 15 V. In one embodiment of step a), the electrochemical oxidation is carried out at a cell voltage of less than 14 V. In one embodiment of step a), the electrochemical oxidation is carried out at a cell voltage of less than 13 V. In one embodiment of step a), the electrochemical oxidation is carried out at a cell voltage of less than 12 V. In one embodiment of step a), the electrochemical oxidation is carried out at a cell voltage of less than 11 V. In one embodiment of step a), the electrochemical oxidation is carried out at a cell voltage of less than 10 V. In one embodiment of step a), the electrochemical oxidation is carried out at a cell voltage of less than 20 V, 19 V, 18 V, 17 V, 16 V, 15 V, 14 V, 13 V, 12 V, 11 V, 10 V, 9 V, 8 V, 7 V, 6 V, 5 V, 4 V, 3 V, 2 V, 1 V, 0.5 V or 0.1 V.

[0222] In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 5000 A / m 2 ². In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 500 A / m 2 ². In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 100 A / m 2 ². In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 50 A / m 2 ². In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 5000 A / m 2 ². In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 500 A / m 2 ². In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 1000 A / m 2 ². In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 50 A / m 2 ². In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 5000 A / m 2 ². In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 500 A / m 2at a current density of 10 to 100 A / m 2 at a current density of 10 to 50 A / m 2 at a current density of

[0223] In one embodiment of step a), the current density used is constant, variable, increasing, decreasing, or runs a specific temperature program.

[0224] In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 5000 A / m 2 at a current density of 1 to 500 A / m, where the current density is constant, variable, increasing, decreasing, or runs a specific program. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 100 A / m 2 at a current density of 1 to 100 A / m, where the current density is constant, variable, increasing, decreasing, or runs a specific program. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 50 A / m 2 at a current density of 1 to 50 A / m, where the current density is constant, variable, increasing, decreasing, or runs a specific program. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 5000 A / m 2 at a current density of 5 to 5000 A / m, where the current density is constant, variable, increasing, decreasing, or runs a specific program.

[0225] In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 5000 A / m 2 at a current density of 5 to 500 A / m, where the current density is constant, variable, increasing, decreasing, or runs a specific program. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 100 A / m 2 at a current density of 5 to 100 A / m, where the current density is constant, variable, increasing, decreasing, or runs a specific program. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 50 A / m 2 at a current density of 5 to 50 A / m, where the current density is constant, variable, increasing, decreasing, or runs a specific program. 2 at a current density of 5 to 50 A / m, where the current density is constant, variable, increasing, decreasing, or runs a specific program.

[0226] In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 5000 A / m 2with a current density, where the current density is constant, variable, increasing, decreasing, or running a specific program. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 500 A / m 2 with a current density, where the current density is constant, variable, increasing, decreasing, or running a specific program. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 100 A / m 2 with a current density, where the current density is constant, variable, increasing, decreasing, or running a specific program. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 50 A / m 2 with a current density, where the current density is constant, variable, increasing, decreasing, or running a specific program.

[0227] In one embodiment of step a), the current density used is constant. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 5000 A / m 2 with a current density, where the current density is constant. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 500 A / m 2 with a current density, where the current density is constant. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 100 A / m 2 with a current density, where the current density is constant. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 50 A / m 2 with a current density, where the current density is constant. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 5000 A / m 2 with a current density, where the current density is constant. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 500 A / m 2 with a current density, where the current density is constant. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 100 A / m 2 with a current density, where the current density is constant. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 50 A / m 2 with a current density, where the current density is constant.

[0228] In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 5000 A / m 2 with a current density, where the current density is constant. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 500 A / m 2 with a current density, where the current density is constant. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 1000 A / m2 is carried out at a current density, where the current density is constant. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 100 A / m 2 is carried out at a current density, where the current density is constant. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 50 A / m 2 is carried out at a current density, where the current density is constant.

[0229] In one embodiment of step a), the current density used is variable.

[0230] In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 5000 A / m 2 is carried out at a current density, where the current density is variable. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 500 A / m 2 is carried out at a current density, where the current density is variable. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 100 A / m 2 is carried out at a current density, where the current density is variable. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 50 A / m 2 is carried out at a current density, where the current density is variable. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 5000 A / m 2 is carried out at a current density, where the current density is variable. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 500 A / m 2 is carried out at a current density, where the current density is variable. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 100 A / m 2 is carried out at a current density, where the current density is variable. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 50 A / m 2 is carried out at a current density, where the current density is variable. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 5000 A / m 2 is carried out at a current density, where the current density is variable. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 500 A / m 2 is carried out at a current density, where the current density is variable. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 100 A / m 2 is carried out at a current density, where the current density is variable. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 50 A / m 2 is carried out at a current density, where the current density is variable.

[0231] In one embodiment of step a), the current density used is increased.

[0232] In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 5000 A / m 2 wherein the current density is increased. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 500 A / m 2 wherein the current density is increased. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 100 A / m 2 wherein the current density is increased. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 50 A / m 2 wherein the current density is increased. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 5000 A / m 2 wherein the current density is increased. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 500 A / m 2 wherein the current density is increased. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 100 A / m 2 wherein the current density is increased. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 50 A / m 2 wherein the current density is increased. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 5000 A / m 2 wherein the current density is increased. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 500 A / m 2 wherein the current density is increased. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 100 A / m 2 wherein the current density is increased. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 50 A / m 2 wherein the current density is increased.

[0233] In one embodiment of step a), the current density used is decreased.

[0234] In one embodiment of step a), the current density used is gradually decreased. Examples of the gradual decrease of the current used are described in detail in the experimental section below. Examples can be found in section C.1.1 below. In one embodiment of step a), the current density used decreases exponentially. In one embodiment of step a), the current density used is gradually decreased, where each step can be the same or different. Examples of decreasing or decreasing in equal steps are that each step is always the same, for example, the current density used always decreases by an equal amount. An example is that the amount decreased in each step is 10 A / m 2 . Examples of decreasing or decreasing in varying steps are that 10 A / m is used in the first step 2 , and 1 A / m is used in the next step 2 and so on.

[0235] Those skilled in the art would not have expected the one-pot synthesis to be successful because the failure of direct electrochemical oxidation (i.e., without a mediator) has been described in US 15 / 753,406 A1 (see Example 28 of US 15 / 753,406 A1, the yield of XVII is <50%). This problem was overcome by gradually reducing the current, thus achieving high current and chemical selectivity. The oxidation selectivity is surprisingly high so that no secondary components (such secondary components may interfere with the racemization and reduction steps) appear, and therefore, separation and purification are not required after each step.

[0236] Surprisingly, high current and chemical selectivity can be achieved by gradually reducing the current. The oxidation selectivity is surprisingly high so that no secondary components appear. Such secondary components may interfere with subsequent racemization and reduction steps, and therefore, separation and purification are required after each step.

[0237] In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 5000 A / m 2 , where the current density used is decreased. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 500 A / m 2 , where the current density used is decreased. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 100 A / m 2 , where the current density used is decreased. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 50 A / m 2 , where the current density used is decreased.

[0238] In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 5000 A / m 2is carried out with a reduced current density being used. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 500 A / m 2 is carried out with a reduced current density being used. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 100 A / m 2 is carried out with a reduced current density being used. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 50 A / m 2 is carried out with a reduced current density being used.

[0239] In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 5000 A / m 2 is carried out with a reduced current density being used. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 500 A / m 2 is carried out with a reduced current density being used. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 100 A / m 2 is carried out with a reduced current density being used. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 50 A / m 2 is carried out with a reduced current density being used.

[0240] In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 5000 A / m 2 is carried out with the current density being gradually reduced. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 500 A / m 2 is carried out with the current density being gradually reduced. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 100 A / m 2 is carried out with the current density being gradually reduced. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 50 A / m 2 is carried out with the current density being gradually reduced.

[0241] In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 5000 A / m 2 is carried out with the current density being gradually reduced. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 500 A / m 2is carried out with the current density used being gradually decreased. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 100 A / m 2 is carried out with the current density used being gradually decreased. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 50 A / m 2 is carried out with the current density used being gradually decreased.

[0242] In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 5000 A / m 2 is carried out with the current density used being gradually decreased. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 500 A / m 2 is carried out with the current density used being gradually decreased. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 100 A / m 2 is carried out with the current density used being gradually decreased. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 50 A / m 2 is carried out with the current density used being gradually decreased.

[0243] In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 5000 A / m 2 is carried out with the current density used being exponentially decreased. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 500 A / m 2 is carried out with the current density used being exponentially decreased. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 100 A / m 2 is carried out with the current density used being exponentially decreased. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 50 A / m 2 is carried out with the current density used being exponentially decreased.

[0244] In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 5000 A / m 2 is carried out with the current density used being exponentially decreased. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 500 A / m 2 is carried out with the current density used being exponentially decreased. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 100 A / m2 is carried out with the current density used decreasing exponentially. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 50 A / m 2 is carried out with the current density used decreasing exponentially.

[0245] In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 5000 A / m 2 is carried out with the current density used decreasing exponentially. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 500 A / m 2 is carried out with the current density used decreasing exponentially. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 100 A / m 2 is carried out with the current density used decreasing exponentially. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 50 A / m 2 is carried out with the current density used decreasing exponentially.

[0246] In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 5000 A / m 2 is carried out with the current density used decreasing step by step at a rate of 0.1 to 100 A / m 2 is carried out with the current density used decreasing step by step at a rate of 0.1 to 100 A / m 2 is carried out with the current density used decreasing step by step at a rate of 0.1 to 100 A / m 2 is carried out with the current density used decreasing step by step at a rate of 0.1 to 100 A / m 2 is carried out with the current density used decreasing step by step at a rate of 0.1 to 100 A / m 2 is carried out with the current density used decreasing step by step at a rate of 0.1 to 100 A / m 2 is carried out with the current density used decreasing step by step at a rate of 0.1 to 100 A / m 2 is carried out with the current density used decreasing step by step at a rate of 0.1 to 100 A / m

[0247] In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 5000 A / m 2 is carried out with the current density used decreasing step by step at a rate of 0.1 to 100 A / m 2The step of the stride is gradually decreased. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 500 A / m 2 in the case where the current density used is gradually decreased at a step of 0.1 to 100 A / m 2 The step of the stride is gradually decreased. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 100 A / m 2 in the case where the current density used is gradually decreased at a step of 0.1 to 100 A / m 2 The step of the stride is gradually decreased. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 50 A / m 2 in the case where the current density used is gradually decreased at a step of 0.1 to 100 A / m 2 The step of the stride is gradually decreased.

[0248] In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 5000 A / m 2 in the case where the current density used is gradually decreased at a step of 0.1 to 100 A / m 2 The step of the stride is gradually decreased. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 500 A / m 2 in the case where the current density used is gradually decreased at a step of 0.1 to 100 A / m 2 The step of the stride is gradually decreased. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 100 A / m 2 in the case where the current density used is gradually decreased at a step of 0.1 to 100 A / m 2 The step of the stride is gradually decreased. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 50 A / m 2 in the case where the current density used is gradually decreased at a step of 0.1 to 100 A / m 2 The step of the stride is gradually decreased.

[0249] In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 5000 A / m 2 in the case where the current density used is gradually decreased at a step of 0.5 to 50 A / m 2 The step of the stride is gradually decreased. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 500 A / m 2 in the case where the current density used is gradually decreased at a step of 0.5 to 50 A / m 2 The step of the stride is gradually decreased. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 50 A / m 2is carried out, wherein the current density used is gradually decreased in steps of 0.5 to 100 A / m 2 In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 50 A / m 2 is carried out, wherein the current density used is gradually decreased in steps of 0.5 to 50 A / m 2 in steps.

[0250] In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 5000 A / m 2 is carried out, wherein the current density used is gradually decreased in steps of 0.5 to 50 A / m 2 in steps. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 500 A / m 2 is carried out, wherein the current density used is gradually decreased in steps of 0.5 to 50 A / m 2 in steps. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 100 A / m 2 is carried out, wherein the current density used is gradually decreased in steps of 0.5 to 50 A / m 2 in steps. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 50 A / m 2 is carried out, wherein the current density used is gradually decreased in steps of 0.5 to 50 A / m 2 in steps.

[0251] In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 5000 A / m 2 is carried out, wherein the current density used is gradually decreased in steps of 0.5 to 50 A / m 2 in steps. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 500 A / m 2 is carried out, wherein the current density used is gradually decreased in steps of 0.5 to 50 A / m 2 in steps. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 100 A / m 2 is carried out, wherein the current density used is gradually decreased in steps of 0.5 to 50 A / m 2 in steps. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 50 A / m 2 is carried out, wherein the current density used is gradually decreased in steps of 0.5 to 50 A / m 2 in steps.

[0252] In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 5000 A / m 2 and the current density used is gradually decreased in steps of 1 to 10 A / m 2 In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 500 A / m 2 and the current density used is gradually decreased in steps of 1 to 10 A / m 2 In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 100 A / m 2 and the current density used is gradually decreased in steps of 1 to 10 A / m 2 In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 50 A / m 2 and the current density used is gradually decreased in steps of 1 to 10 A / m 2 and the current density used is gradually decreased in steps of 1 to 10 A / m

[0253] In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 5000 A / m 2 and the current density used is gradually decreased in steps of 1 to 10 A / m 2 In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 500 A / m 2 and the current density used is gradually decreased in steps of 1 to 10 A / m 2 In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 100 A / m 2 and the current density used is gradually decreased in steps of 1 to 10 A / m 2 In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 50 A / m 2 and the current density used is gradually decreased in steps of 1 to 10 A / m 2 and the current density used is gradually decreased in steps of 1 to 10 A / m

[0254] In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 5000 A / m 2 and the current density used is gradually decreased in steps of 1 to 10 A / m 2 In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 500 A / m 2 and the current density used is gradually decreased in steps of 1 to 10 A / m 2The step size is gradually decreased. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 100 A / m 2 and the current density used is gradually decreased in steps of 1 to 10 A / m 2 The step size is gradually decreased. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 50 A / m 2 and the current density used is gradually decreased in steps of 1 to 10 A / m 2 The step size is gradually decreased.

[0255] In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 5000 A / m 2 and the current density used is gradually decreased in steps of 1 to 5 A / m 2 The step size is gradually decreased. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 500 A / m 2 and the current density used is gradually decreased in steps of 1 to 5 A / m 2 The step size is gradually decreased. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 100 A / m 2 and the current density used is gradually decreased in steps of 1 to 5 A / m 2 The step size is gradually decreased. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 50 A / m 2 and the current density used is gradually decreased in steps of 1 to 5 A / m 2 The step size is gradually decreased.

[0256] In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 5000 A / m 2 and the current density used is gradually decreased in steps of 1 to 5 A / m 2 The step size is gradually decreased. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 500 A / m 2 and the current density used is gradually decreased in steps of 1 to 5 A / m 2 The step size is gradually decreased. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 100 A / m 2 and the current density used is gradually decreased in steps of 1 to 5 A / m 2 The step size is gradually decreased. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 50 A / m 2 and the current density used is gradually decreased in steps of 1 to 5 A / m 2 The step size is gradually decreased.

[0257] In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 5000 A / m 2 The current density used is 1 to 5 A / m 2 In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 500 A / m 2 The current density used is 1 to 5 A / m 2 In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 100 A / m 2 The current density used is 1 to 5 A / m 2 In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 50 A / m 2 The current density used is 1 to 5 A / m 2 The stride gradually decreases.

[0258] In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 5000 A / m 2 45, 46, 47, 48, 49 and 50 A / m 2 In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 500 A / m 2 45, 46, 47, 48, 49 and 50 A / m 2 In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 100 A / m 2is carried out, wherein the current density used is gradually decreased in steps selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2 is carried out at a current density of 1 to 50 A / m in one embodiment of step a) 2 is carried out, wherein the current density used is gradually decreased in steps selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2 in steps

[0259] In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 5000 A / m 2 is carried out, wherein the current density used is gradually decreased in steps selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2 is carried out at a current density of 5 to 500 A / m in one embodiment of step a) 2 is carried out, wherein the current density used is gradually decreased in steps selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2 is carried out at a current density of 5 to 100 A / m in one embodiment of step a) 2It is carried out under the condition that the current density used is selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2 and is gradually decreased in steps selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 50 A / m 2 It is carried out under the condition that the current density used is selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2 and is gradually decreased in steps selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m.

[0260] In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 5000 A / m 2 It is carried out under the condition that the current density used is selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2 and is gradually decreased in steps selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 500 A / m 2 It is carried out under the condition that the current density used is selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2 and is gradually decreased in steps selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 100 A / m2 is carried out at a current density selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2 is gradually decreased in steps. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 50 A / m 2 is carried out at a current density selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2 is gradually decreased in steps.

[0261] In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 5000 A / m 2 is carried out at a current density selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2 is gradually decreased in steps, wherein the steps are the same. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 500 A / m 2 is carried out at a current density selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2The step is gradually decreased, and the steps are the same. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 100 A / m 2 and the current density used is gradually decreased in steps selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2 and the step is gradually decreased, and the steps are the same. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 50 A / m 2 and the current density used is gradually decreased in steps selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2 and the step is gradually decreased, and the steps are the same.

[0262] In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 5000 A / m 2 and the current density used is gradually decreased in steps selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2 and the step is gradually decreased, and the steps are the same. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 500 A / m 2is carried out, wherein the current density used is selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2 and is gradually decreased in steps of, wherein the steps are the same. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 100 A / m 2 is carried out, wherein the current density used is selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2 and is gradually decreased in steps of, wherein the steps are the same. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 50 A / m 2 is carried out, wherein the current density used is selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2 and is gradually decreased in steps of, wherein the steps are the same.

[0263] In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 5000 A / m 2 is carried out, wherein the current density used is selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2with a gradually decreasing step, where the steps are the same. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 500 A / m 2 in the case, where the current density used is selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2 with a gradually decreasing step, where the steps are the same. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 100 A / m 2 in the case, where the current density used is selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2 with a gradually decreasing step, where the steps are the same. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 50 A / m 2 in the case, where the current density used is selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2 with a gradually decreasing step, where the steps are the same.

[0264] In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 5000 A / m 2in a case where the current density used is selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2 and is gradually decreased in steps selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m, where the step is variable. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 500 A / m 2 in a case where the current density used is selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2 and is gradually decreased in steps selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m, where the step is variable. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 100 A / m 2 in a case where the current density used is selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2 and is gradually decreased in steps selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m, where the step is variable. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 50 A / m 2 in a case where the current density used is selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2 and is gradually decreased in steps selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m, where the step is variable.

[0265] In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 5000 A / m 2 and the current density used is gradually decreased in steps selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2 and the step is variable. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 500 A / m 2 and the current density used is gradually decreased in steps selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2 and the step is variable. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 100 A / m 2 and the current density used is gradually decreased in steps selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2 and the step is variable. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 50 A / m 2 and the current density used is gradually decreased in steps selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2with a gradually decreasing step, where the step is variable.

[0266] In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 5000 A / m 2 where the current density used is decreased step by step in a step selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2 where the current density used is decreased step by step in a step selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 500 A / m 2 where the current density used is decreased step by step in a step selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2 where the current density used is decreased step by step in a step selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 100 A / m 2 where the current density used is decreased step by step in a step selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2 where the current density used is decreased step by step in a step selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 50 A / m 2It is carried out under the condition that the current density used is selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2 with a gradually decreasing step, where the step is variable.

[0267] In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 50 A / m 2 under the condition that the current density used is gradually decreased as follows: from 50 to 40 A / m 2 and then from 40 to 30 A / m 2 and then from 30 to 20 A / m 2 and then from 20 to 10 A / m 2 .

[0268] In one embodiment of the sequential one-pot synthesis method, the current density used in step a) is lower than the current density used in step b). The selectivity of obtaining compound (XVII) in this embodiment is surprising. The oxidation selectivity is surprisingly high such that no secondary components appear. The oxidation selectivity is surprisingly high such that no secondary components appear. Such secondary components may interfere with subsequent racemization and reduction steps, and thus need to be separated and purified after each step.

[0269] In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 5000 A / m 2 under the condition that the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 500 A / m 2 under the condition that the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 100 A / m 2 under the condition that the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 50 A / m 2 under the condition that the current density used in step a) is lower than the current density used in step b).

[0270] In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 5000 A / m 2 wherein the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 500 A / m 2 wherein the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 100 A / m 2 wherein the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 50 A / m 2 wherein the current density used in step a) is lower than the current density used in step b).

[0271] In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 5000 A / m 2 wherein the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 500 A / m 2 wherein the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 100 A / m 2 wherein the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 50 A / m 2 wherein the current density used in step a) is lower than the current density used in step b).

[0272] In one embodiment, the current density used for oxidation in step a) is lower than the current density used for electrochemical reduction in step b), and the current density used in step a) is decreased. Surprisingly, high current and chemical selectivity can be achieved by reducing the current. The oxidation selectivity is surprisingly high such that no secondary components appear. Such components may interfere with subsequent racemization and reduction steps, and thus separation and purification are not required after each step.

[0273] In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 5000 A / m 2It is carried out under the condition that the current density used in step a) is reduced, and the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 500 A / m 2 It is carried out under the condition that the current density used in step a) is reduced, and the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 100 A / m 2 It is carried out under the condition that the current density used in step a) is reduced, and the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 50 A / m 2 It is carried out under the condition that the current density used in step a) is reduced, and the current density used in step a) is lower than the current density used in step b).

[0274] In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 5000 A / m 2 It is carried out under the condition that the current density used in step a) is reduced, and the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 500 A / m 2 It is carried out under the condition that the current density used in step a) is reduced, and the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 100 A / m 2 It is carried out under the condition that the current density used in step a) is reduced, and the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 50 A / m 2 It is carried out under the condition that the current density used in step a) is reduced, and the current density used in step a) is lower than the current density used in step b).

[0275] In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 5000 A / m 2 It is carried out under the condition that the current density used in step a) is reduced, and the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 500 A / m 2is carried out, wherein the current density used in step a) is reduced, and wherein the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 100 A / m 2 is carried out, wherein the current density used in step a) is reduced, and wherein the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 50 A / m 2 is carried out, wherein the current density used in step a) is reduced, and wherein the current density used in step a) is lower than the current density used in step b).

[0276] In one embodiment, the current density used for oxidation in step a) is lower than the current density used for electrochemical reduction in step b), and the current density used in step a) is gradually reduced. Surprisingly, high current and chemical selectivity can be achieved by gradually reducing the current. The oxidation selectivity is surprisingly high such that no secondary components appear. Such components would interfere with subsequent racemization and reduction steps, and thus separation and purification are not required after each step.

[0277] In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 5000 A / m 2 is carried out, wherein the current density used in step a) is gradually reduced, and wherein the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 500 A / m 2 is carried out, wherein the current density used in step a) is gradually reduced, and wherein the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 100 A / m 2 is carried out, wherein the current density used in step a) is gradually reduced, and wherein the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 50 A / m 2 is carried out, wherein the current density used in step a) is gradually reduced, and wherein the current density used in step a) is lower than the current density used in step b).

[0278] In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 5000 A / m 2is carried out under the condition that the current density used in step a) is gradually decreased and the current density used in step a) is lower than that used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 500 A / m 2 is carried out under the condition that the current density used in step a) is gradually decreased and the current density used in step a) is lower than that used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 100 A / m 2 is carried out under the condition that the current density used in step a) is gradually decreased and the current density used in step a) is lower than that used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 50 A / m 2 is carried out under the condition that the current density used in step a) is gradually decreased and the current density used in step a) is lower than that used in step b).

[0279] In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 5000 A / m 2 is carried out under the condition that the current density used in step a) is gradually decreased and the current density used in step a) is lower than that used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 500 A / m 2 is carried out under the condition that the current density used in step a) is gradually decreased and the current density used in step a) is lower than that used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 100 A / m 2 is carried out under the condition that the current density used in step a) is gradually decreased and the current density used in step a) is lower than that used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 50 A / m 2 is carried out under the condition that the current density used in step a) is gradually decreased and the current density used in step a) is lower than that used in step b).

[0280] In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 5000 A / m 2 is carried out under the condition that the current density used is from 0.1 to 100 A / m 2The step size is gradually decreased, and the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 500 A / m 2 and the step size of the current density used is gradually decreased by 0.1 to 100 A / m 2 The step size is gradually decreased, and the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 100 A / m 2 and the step size of the current density used is gradually decreased by 0.1 to 100 A / m 2 The step size is gradually decreased, and the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 50 A / m 2 and the step size of the current density used is gradually decreased by 0.1 to 100 A / m 2 The step size is gradually decreased, and the current density used in step a) is lower than the current density used in step b).

[0281] In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 5000 A / m 2 and the step size of the current density used is gradually decreased by 0.1 to 100 A / m 2 The step size is gradually decreased, and the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 500 A / m 2 and the step size of the current density used is gradually decreased by 0.1 to 100 A / m 2 The step size is gradually decreased, and the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 100 A / m 2 and the step size of the current density used is gradually decreased by 0.1 to 100 A / m 2 The step size is gradually decreased, and the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 50 A / m 2 and the step size of the current density used is gradually decreased by 0.1 to 100 A / m 2 The step size is gradually decreased, and the current density used in step a) is lower than the current density used in step b).

[0282] In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 5000 A / m 2 wherein the current density used is gradually decreased in steps of 0.1 to 100 A / m 2 and wherein the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 500 A / m 2 wherein the current density used is gradually decreased in steps of 0.1 to 100 A / m 2 and wherein the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 100 A / m 2 wherein the current density used is gradually decreased in steps of 0.1 to 100 A / m 2 and wherein the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 50 A / m 2 wherein the current density used is gradually decreased in steps of 0.1 to 100 A / m 2 and wherein the current density used in step a) is lower than the current density used in step b).

[0283] In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 5000 A / m 2 wherein the current density used is gradually decreased in steps of 0.5 to 50 A / m 2 and wherein the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 500 A / m 2 wherein the current density used is gradually decreased in steps of 0.5 to 50 A / m 2 and wherein the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 100 A / m 2 wherein the current density used is gradually decreased in steps of 0.5 to 50 A / m 2 and wherein the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 50 A / m 2 wherein the current density used is gradually decreased in steps of 0.5 to 50 A / m2 with a gradually decreasing step size, and the current density used in step a) is lower than the current density used in step b).

[0284] In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 5000 A / m 2 wherein the current density used is gradually decreased in steps of 0.5 to 50 A / m 2 with a gradually decreasing step size, and the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 500 A / m 2 wherein the current density used is gradually decreased in steps of 0.5 to 50 A / m 2 with a gradually decreasing step size, and the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 100 A / m 2 wherein the current density used is gradually decreased in steps of 0.5 to 50 A / m 2 with a gradually decreasing step size, and the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 50 A / m 2 wherein the current density used is gradually decreased in steps of 0.5 to 50 A / m 2 with a gradually decreasing step size, and the current density used in step a) is lower than the current density used in step b).

[0285] In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 5000 A / m 2 wherein the current density used is gradually decreased in steps of 0.5 to 50 A / m 2 with a gradually decreasing step size, and the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 500 A / m 2 wherein the current density used is gradually decreased in steps of 0.5 to 50 A / m 2 with a gradually decreasing step size, and the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 100 A / m 2 wherein the current density used is gradually decreased in steps of 0.5 to 50 A / m 2The step size is gradually decreased, and the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 50 A / m 2 The case where the current density used is gradually decreased in steps of 0.5 to 50 A / m 2 The step size is gradually decreased, and the current density used in step a) is lower than the current density used in step b).

[0286] In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 5000 A / m 2 The case where the current density used is gradually decreased in steps of 1 to 10 A / m 2 The step size is gradually decreased, and the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 500 A / m 2 The case where the current density used is gradually decreased in steps of 1 to 10 A / m 2 The step size is gradually decreased, and the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 100 A / m 2 The case where the current density used is gradually decreased in steps of 1 to 10 A / m 2 The step size is gradually decreased, and the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 50 A / m 2 The case where the current density used is gradually decreased in steps of 1 to 10 A / m 2 The step size is gradually decreased, and the current density used in step a) is lower than the current density used in step b).

[0287] In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 5000 A / m 2 The case where the current density used is gradually decreased in steps of 1 to 10 A / m 2 The step size is gradually decreased, and the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 500 A / m 2 The case where the current density used is gradually decreased in steps of 1 to 10 A / m 2The step size is gradually decreased, and the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 100 A / m 2 and the current density used is decreased step by step at a step size of 1 to 10 A / m 2 The step size is gradually decreased, and the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 50 A / m 2 and the current density used is decreased step by step at a step size of 1 to 10 A / m 2 The step size is gradually decreased, and the current density used in step a) is lower than the current density used in step b).

[0288] In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 5000 A / m 2 and the current density used is decreased step by step at a step size of 1 to 10 A / m 2 The step size is gradually decreased, and the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 500 A / m 2 and the current density used is decreased step by step at a step size of 1 to 10 A / m 2 The step size is gradually decreased, and the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 100 A / m 2 and the current density used is decreased step by step at a step size of 1 to 10 A / m 2 The step size is gradually decreased, and the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 50 A / m 2 and the current density used is decreased step by step at a step size of 1 to 10 A / m 2 The step size is gradually decreased, and the current density used in step a) is lower than the current density used in step b).

[0289] In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 5000 A / m 2 and the current density used is decreased step by step at a step size of 1 to 5 A / m 2The step size is gradually decreased, and the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 500 A / m 2 and the current density used decreases step by step at a rate of 1 to 5 A / m 2 The step size is gradually decreased, and the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 100 A / m 2 and the current density used decreases step by step at a rate of 1 to 5 A / m 2 The step size is gradually decreased, and the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 50 A / m 2 and the current density used decreases step by step at a rate of 1 to 5 A / m 2 The step size is gradually decreased, and the current density used in step a) is lower than the current density used in step b).

[0290] In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 5000 A / m 2 and the current density used decreases step by step at a rate of 1 to 5 A / m 2 The step size is gradually decreased, and the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 500 A / m 2 and the current density used decreases step by step at a rate of 1 to 5 A / m 2 The step size is gradually decreased, and the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 100 A / m 2 and the current density used decreases step by step at a rate of 1 to 5 A / m 2 The step size is gradually decreased, and the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 50 A / m 2 and the current density used decreases step by step at a rate of 1 to 5 A / m 2 The step size is gradually decreased, and the current density used in step a) is lower than the current density used in step b).

[0291] In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 5000 A / m2 is carried out with the current density used being gradually decreased in steps of 1 to 5 A / m 2 and the current density used in step a) being lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 500 A / m 2 is carried out with the current density used being gradually decreased in steps of 1 to 5 A / m 2 and the current density used in step a) being lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 100 A / m 2 is carried out with the current density used being gradually decreased in steps of 1 to 5 A / m 2 and the current density used in step a) being lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 50 A / m 2 is carried out with the current density used being gradually decreased in steps of 1 to 5 A / m 2 and the current density used in step a) being lower than the current density used in step b).

[0292] In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 5000 A / m 2 is carried out with the current density used being gradually decreased in steps selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2 and the current density used in step a) being lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 500 A / m 2 is carried out with the current density used being gradually decreased in steps selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2The step is gradually reduced, and the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 100 A / m 2 The case is carried out, where the current density used is selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2 The step is gradually reduced, and the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 50 A / m 2 The case is carried out, where the current density used is selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2 The step is gradually reduced, and the current density used in step a) is lower than the current density used in step b).

[0293] In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 5000 A / m 2 The case is carried out, where the current density used is selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2 The step is gradually reduced, and the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 500 A / m 2is carried out, wherein the current density used is selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2 and is gradually decreased in steps selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m, and wherein the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 100 A / m 2 is carried out, wherein the current density used is selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2 and is gradually decreased in steps selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m. In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 50 A / m 2 is carried out, wherein the current density used is selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2 and is gradually decreased in steps selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m, and wherein the current density used in step a) is lower than the current density used in step b).

[0294] In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 5000 A / m 2 is carried out, wherein the current density used is selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m2 with a gradually decreasing step size, and the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 500 A / m 2 and the current density used is selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2 with a gradually decreasing step size, and the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 100 A / m 2 and the current density used is selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2 with a gradually decreasing step size, and the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 50 A / m 2 and the current density used is selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2 with a gradually decreasing step size, and the current density used in step a) is lower than the current density used in step b).

[0295] In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 5000 A / m 2is carried out, wherein the current density used is selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2 is gradually decreased in steps, wherein the steps are the same, and wherein the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 500 A / m 2 is carried out, wherein the current density used is selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2 is gradually decreased in steps, wherein the steps are the same, and wherein the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 100 A / m 2 is carried out, wherein the current density used is selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2 is gradually decreased in steps, wherein the steps are the same, and wherein the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 50 A / m 2is carried out, wherein the current density used is selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2 is gradually decreased in steps selected from the above, wherein the steps are the same, and the current density used in step a) is lower than the current density used in step b).

[0296] In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 5000 A / m 2 is carried out, wherein the current density used is selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2 is gradually decreased in steps selected from the above, wherein the steps are the same, and the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 500 A / m 2 is carried out, wherein the current density used is selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2 is gradually decreased in steps selected from the above, wherein the steps are the same, and the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 100 A / m 2is carried out, wherein the current density used is selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2 is gradually decreased in steps selected from the above, wherein the steps are the same, and wherein the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 50 A / m 2 is carried out, wherein the current density used is selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2 is gradually decreased in steps selected from the above, wherein the steps are the same, and wherein the current density used in step a) is lower than the current density used in step b).

[0297] In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 5000 A / m 2 is carried out, wherein the current density used is selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2 is gradually decreased in steps selected from the above, wherein the steps are the same, and wherein the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 500 A / m 2It is carried out under the condition that the current density used is selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2 and is gradually decreased in steps with a step selected from the above, wherein the steps are the same, and the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 100 A / m 2 It is carried out under the condition that the current density used is selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2 and is gradually decreased in steps with a step selected from the above, wherein the steps are the same, and the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 50 A / m 2 It is carried out under the condition that the current density used is selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2 and is gradually decreased in steps with a step selected from the above, wherein the steps are the same, and the current density used in step a) is lower than the current density used in step b).

[0298] In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 5000 A / m 2is carried out, wherein the current density used is selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2 is gradually decreased in steps selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m, wherein the said steps are variable, and wherein the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 500 A / m 2 is carried out, wherein the current density used is selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2 is gradually decreased in steps selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m, wherein the said steps are variable, and wherein the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 100 A / m 2 is carried out, wherein the current density used is selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2 is gradually decreased in steps selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m, wherein the said steps are variable, and wherein the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 50 A / m 2is carried out, wherein the current density used is selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2 and is gradually decreased in steps selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m, wherein the said steps are variable and wherein the current density used in step a) is lower than the current density used in step b).

[0299] In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 5000 A / m 2 and is gradually decreased in steps selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2 and is gradually decreased in steps selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m, wherein the said steps are variable and wherein the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 500 A / m 2 and is gradually decreased in steps selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2 and is gradually decreased in steps selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m, wherein the said steps are variable and wherein the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 100 A / m 2is carried out, wherein the current density used is selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2 in steps that gradually decrease, wherein the steps vary, and wherein the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 50 A / m 2 is carried out, wherein the current density used is selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2 in steps that gradually decrease, wherein the steps vary, and wherein the current density used in step a) is lower than the current density used in step b).

[0300] In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 5000 A / m 2 is carried out, wherein the current density used is selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2 in steps that gradually decrease, wherein the steps vary, and wherein the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 500 A / m 2is carried out, wherein the current density used is selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2 in steps that gradually decrease, wherein the steps vary, and wherein the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 100 A / m 2 is carried out, wherein the current density used is selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2 in steps that gradually decrease, wherein the steps vary, and wherein the current density used in step a) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 50 A / m 2 is carried out, wherein the current density used is selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2 in steps that gradually decrease, wherein the steps vary, and wherein the current density used in step a) is lower than the current density used in step b).

[0301] Step b)

[0302] In one embodiment of step b), the electrochemical reduction is carried out at a temperature of 1 to 50 °C. In one embodiment of step b), the electrochemical reduction is carried out at a temperature of 10 to 35 °C. In one embodiment of step b), the electrochemical reduction is carried out at a temperature of 15 to 30 °C. In one embodiment of step b), the electrochemical reduction is carried out at ambient temperature.

[0303] In one embodiment of step b), a solvent is used. In one embodiment of step b), the solvent used is selected from aprotic solvents, protic solvents, and mixtures thereof. In one embodiment of step b), the solvent used is selected from polar aprotic solvents and mixtures thereof. In one embodiment of step b), the solvent used is selected from polar aprotic solvents, which are selected from the following: dimethylformamide (DMF), dimethyl sulfoxide, acetonitrile, acetone, and mixtures thereof. In one embodiment of step b), the solvent used is selected from protic solvents, which are selected from the following: methanol, acetic acid, ethanol, formic acid, water, and mixtures thereof. In one embodiment of step b), the solvent used is selected from dimethylformamide (DMF), methanol, acetic acid, and mixtures thereof. In one embodiment of step b), the solvent used is methanol, acetic acid, and mixtures thereof. In one embodiment of step b), methanol is used. In one embodiment of step b), acetic acid is used.

[0304] In one embodiment of step b), the solvent is selected from

[0305] - aprotic solvents, protic solvents, and mixtures thereof; or

[0306] - polar aprotic solvents; or

[0307] - polar aprotic solvents, which are selected from the following: dimethylformamide (DMF), dimethyl sulfoxide, acetonitrile, acetone; or

[0308] - protic solvents, which are selected from the following: methanol, acetic acid, ethanol, formic acid, water, and mixtures thereof; or

[0309] - dimethylformamide (DMF), methanol, acetic acid, and mixtures thereof; or

[0310] - methanol, acetic acid, and mixtures thereof; or

[0311] - methanol; or

[0312] - acetic acid;

[0313] or mixtures of the above solvents.

[0314] In one embodiment of step b), a conductive salt is used, selected from organic ammonium salts, ionic liquids, tetraalkylammonium fluoroborates, quaternary ammonium salts, and mixtures thereof.

[0315] In one embodiment of step b), a conductive salt is used, selected from tetraethylammonium tetrafluoroborate, tetrabutylammonium hexafluorophosphate, tetrabutylammonium hydrogen sulfate, and mixtures thereof.

[0316] In one embodiment of step b), the amount of the solvent is 80 to 99% by weight, based on the total amount of the reaction mixture. In one embodiment of step b), the amount of the solvent is 85 to 95% by weight, based on the total amount of the reaction mixture. In one embodiment of step b), the amount of the solvent is 85 to 92% by weight, based on the total amount of the reaction mixture. In one embodiment of step b), the amount of the solvent is 90% by weight, based on the total amount of the reaction mixture.

[0317] In one embodiment of step b),

[0318] - a conductive salt selected from organic ammonium salts, ionic liquids, tetraalkylammonium tetrafluoroborates, quaternary ammonium salts, and mixtures thereof; and

[0319] - a solvent selected from dimethylformamide (DMF), methanol, acetic acid, and mixtures thereof.

[0320] In one embodiment of step b),

[0321] - a conductive salt selected from organic ammonium salts, ionic liquids, tetraalkylammonium tetrafluoroborates, quaternary ammonium salts, and mixtures thereof; and

[0322] - a solvent selected from dimethylformamide (DMF), methanol, acetic acid, and mixtures thereof.

[0323] In one embodiment of step b),

[0324] - a conductive salt selected from tetraethylammonium tetrafluoroborate, tetrabutylammonium hexafluorophosphate, tetrabutylammonium hydrogen sulfate, and mixtures thereof; and

[0325] - a solvent selected from dimethylformamide (DMF), methanol, acetic acid, and mixtures thereof.

[0326] In one embodiment of step b),

[0327] - a conductive salt selected from organic ammonium salts, ionic liquids, tetraalkylammonium tetrafluoroborates, quaternary ammonium salts, and mixtures thereof; and

[0328] - methanol.

[0329] In one embodiment of step b),

[0330] - a conductive salt selected from organic ammonium salts, ionic liquids, tetraalkylammonium tetrafluoroborates, quaternary ammonium salts, and mixtures thereof; and

[0331] - Methanol.

[0332] In one embodiment of step b), use

[0333] - A conductive salt selected from tetraethylammonium tetrafluoroborate, tetrabutylammonium hexafluorophosphate, tetrabutylammonium hydrogen sulfate, and mixtures thereof; and

[0334] - Methanol.

[0335] In one embodiment of step b), use

[0336] - A conductive salt selected from organic ammonium salts, ionic liquids, tetraalkylammonium tetrafluoroborates, quaternary ammonium salts, and mixtures thereof; and

[0337] - Acetic acid.

[0338] In one embodiment of step b), use

[0339] - A conductive salt selected from organic ammonium salts, ionic liquids, tetraalkylammonium tetrafluoroborates, quaternary ammonium salts, and mixtures thereof; and

[0340] - Acetic acid.

[0341] In one embodiment of step b), use

[0342] - A conductive salt selected from tetraethylammonium tetrafluoroborate, tetrabutylammonium hexafluorophosphate, tetrabutylammonium hydrogen sulfate, and mixtures thereof; and

[0343] - Acetic acid.

[0344] In one embodiment of step b), based on 1 equivalent of the compound of formula (XIII), 0.05 to 3 equivalents of the conductive salt are used. This means that if 0.05 equivalents of the conductive salt are used, 1 equivalent of the compound of formula (XIII) is used. In one embodiment of step b), based on 1 equivalent of the compound of formula (XIII), 0.2 to 2 equivalents of the conductive salt are used. In one embodiment of step b), based on 1 equivalent of the compound of formula (XIII), 0.5 to 1.5 equivalents of the conductive salt are used. In one embodiment of step b), based on 1 equivalent of the compound of formula ent-(I), 0.6 to 1.3 equivalents of the conductive salt are used. The equivalents are based on the compound of formula (XIII). This means that if 1.3 equivalents (1.3 mol) of the acid are used, 1 equivalent (1 mol) of the compound of formula (XIII) is used.

[0345] In one embodiment of step b), the electrochemical reduction is carried out at a cell voltage of 0.1 to 30 V. In one embodiment of step b), the electrochemical reduction is carried out at a cell voltage of 0.1 to 20 V. In one embodiment of step b), the electrochemical reduction is carried out at a cell voltage of 0.1 to 15 V. In one embodiment of step b), the electrochemical reduction is carried out at a cell voltage of 0.1 to 10 V. In one embodiment of step b), the electrochemical reduction is carried out at a cell voltage of 0.1 to 5 V.

[0346] In one embodiment of step b), the electrochemical reduction is carried out at a cell voltage of 0.5 to 30 V. In one embodiment of step b), the electrochemical reduction is carried out at a cell voltage of 0.5 to 20 V. In one embodiment of step b), the electrochemical reduction is carried out at a cell voltage of 0.5 to 15 V. In one embodiment of step b), the electrochemical reduction is carried out at a cell voltage of 0.5 to 10 V. In one embodiment of step b), the electrochemical reduction is carried out at a cell voltage of 0.5 to 5 V.

[0347] In one embodiment of step b), the electrochemical reduction is carried out at a cell voltage of 1 to 30 V. In one embodiment of step b), the electrochemical reduction is carried out at a cell voltage of 1 to 20 V. In one embodiment of step b), the electrochemical reduction is carried out at a cell voltage of 1 to 15 V. In one embodiment of step b), the electrochemical reduction is carried out at a cell voltage of 1 to 10 V. In one embodiment of step b), the electrochemical reduction is carried out at a cell voltage of 1 to 5 V.

[0348] In one embodiment of step b), the electrochemical reduction is carried out at a cell voltage of 2 to 30 V. In one embodiment of step b), the electrochemical reduction is carried out at a cell voltage of 2 to 20 V. In one embodiment of step b), the electrochemical reduction is carried out at a cell voltage of 2 to 15 V. In one embodiment of step b), the electrochemical reduction is carried out at a cell voltage of 2 to 10 V. In one embodiment of step b), the electrochemical reduction is carried out at a cell voltage of 2 to 5 V.

[0349] In one embodiment of step b), the electrochemical reduction is carried out at a cell voltage of 3 to 30 V. In one embodiment of step b), the electrochemical reduction is carried out at a cell voltage of 3 to 20 V. In one embodiment of step b), the electrochemical reduction is carried out at a cell voltage of 3 to 15 V. In one embodiment of step b), the electrochemical reduction is carried out at a cell voltage of 3 to 10 V. In one embodiment of step b), the electrochemical reduction is carried out at a cell voltage of 3 to 5 V.

[0350] In one embodiment of step b), the electrochemical reduction is carried out at a cell voltage of less than 30 V. In one embodiment of step b), the electrochemical reduction is carried out at a cell voltage of less than 20 V. In one embodiment of step b), the electrochemical reduction is carried out at a cell voltage of less than 15 V. In one embodiment of step b), the electrochemical reduction is carried out at a cell voltage of less than 10 V. In one embodiment of step b), the electrochemical reduction is carried out at a cell voltage of less than 5 V.

[0351] In one embodiment of step b), the electrochemical reduction is carried out at a cell voltage of less than 30 V, 29 V, 28 V, 27 V, 26 V, 25 V, 24 V, 23 V, 22 V, 21 V, 20 V, 19 V, 18 V, 17 V, 16 V, 15 V, 14 V, 13 V, 12 V, 11 V, 10 V, 9 V, 8 V, 7 V, 6 V, 5 V, 4 V, 3 V, 2 V, 1 V, 0.5 V or 0.1 V.

[0352] In one embodiment of step b), the electrochemical reduction is carried out at a current density of 1 to 10000 A / m 2 In one embodiment of step b), the electrochemical reduction is carried out at a current density of 1 to 1000 A / m 2 In one embodiment of step b), the electrochemical reduction is carried out at a current density of 1 to 500 A / m 2 In one embodiment of step b), the electrochemical reduction is carried out at a current density of 1 to 400 A / m 2 In one embodiment of step b), the electrochemical reduction is carried out at a current density of 1 to 350 A / m 2 In one embodiment of step b), the electrochemical reduction is carried out at a current density of 5 to 10000 A / m

[0353] In one embodiment of step b), the electrochemical reduction is carried out at a current density of 5 to 1000 A / m 2 In one embodiment of step b), the electrochemical reduction is carried out at a current density of 5 to 500 A / m 2 In one embodiment of step b), the electrochemical reduction is carried out at a current density of 5 to 400 A / m 2 In one embodiment of step b), the electrochemical reduction is carried out at a current density of 5 to 350 A / m 2 In one embodiment of step b), the electrochemical reduction is carried out at a current density of 10 to 10000 A / m 2 In one embodiment of step b), the electrochemical reduction is carried out at a current density of 10 to 10000 A / m

[0354] In one embodiment of step b), the electrochemical reduction is carried out at a current density of 10 to 10000 A / m 2The electrochemical reduction is carried out at a current density of 10 to 1000 A / m 2 The electrochemical reduction is carried out at a current density of 10 to 500 A / m 2 The electrochemical reduction is carried out at a current density of 10 to 400 A / m 2 The electrochemical reduction is carried out at a current density of 10 to 350 A / m 2 The electrochemical reduction is carried out at a current density of...

[0355] In one embodiment of step b), the electrochemical reduction is carried out at a current density of 100 to 10000 A / m 2 The electrochemical reduction is carried out at a current density of 100 to 1000 A / m 2 The electrochemical reduction is carried out at a current density of 100 to 500 A / m 2 The electrochemical reduction is carried out at a current density of 100 to 400 A / m 2 The electrochemical reduction is carried out at a current density of 100 to 350 A / m 2 The electrochemical reduction is carried out at a current density of...

[0356] In one embodiment of step b), the electrochemical reduction is carried out at a constant current density of 200 to 400 A / m 2 The electrochemical reduction is carried out at a constant current density of 200 A / m 2 The electrochemical reduction is carried out at a constant current density of 250 A / m 2 The electrochemical reduction is carried out at a constant current density of 300 A / m 2 The electrochemical reduction is carried out at a constant current density of 350 A / m 2 The electrochemical reduction is carried out at a constant current density of 400 A / m 2 The electrochemical reduction is carried out at a constant current density of...

[0357] In one embodiment of step b), the electrochemical reduction is carried out at a current density of 1 to 10000 A / m 2 The electrochemical reduction is carried out at a current density of 1 to 1000 A / m, where the current density is constant, variable, increasing, decreasing, or running a specific program. In one embodiment of step b), the electrochemical reduction is carried out at a current density of 1 to 1000 A / m 2is carried out at a current density, where the current density is constant, variable, increasing, decreasing, or running a specific program. In one embodiment of step b), the electrochemical reduction is carried out at a current density of 1 to 500 A / m 2 is carried out at a current density, where the current density is constant, variable, increasing, decreasing, or running a specific program. In one embodiment of step b), the electrochemical reduction is carried out at a current density of 1 to 400 A / m 2 is carried out at a current density, where the current density is constant, variable, increasing, decreasing, or running a specific program. In one embodiment of step b), the electrochemical reduction is carried out at a current density of 1 to 350 A / m 2 is carried out at a current density, where the current density is constant, variable, increasing, decreasing, or running a specific program.

[0358] In one embodiment of step b), the electrochemical reduction is carried out at a current density of 5 to 10000 A / m 2 is carried out at a current density, where the current density is constant, variable, increasing, decreasing, or running a specific program. In one embodiment of step b), the electrochemical reduction is carried out at a current density of 5 to 1000 A / m 2 is carried out at a current density, where the current density is constant, variable, increasing, decreasing, or running a specific program. In one embodiment of step b), the electrochemical reduction is carried out at a current density of 5 to 500 A / m 2 is carried out at a current density, where the current density is constant, variable, increasing, decreasing, or running a specific program. In one embodiment of step b), the electrochemical reduction is carried out at a current density of 5 to 400 A / m 2 is carried out at a current density, where the current density is constant, variable, increasing, decreasing, or running a specific program. In one embodiment of step b), the electrochemical reduction is carried out at a current density of 5 to 350 A / m 2 is carried out at a current density, where the current density is constant, variable, increasing, decreasing, or running a specific program.

[0359] In one embodiment of step b), the electrochemical reduction is carried out at a current density of 10 to 10000 A / m 2 is carried out at a current density, where the current density is constant, variable, increasing, decreasing, or running a specific program. In one embodiment of step b), the electrochemical reduction is carried out at a current density of 10 to 1000 A / m 2 is carried out at a current density, where the current density is constant, variable, increasing, decreasing, or running a specific program. In one embodiment of step b), the electrochemical reduction is carried out at a current density of 10 to 500 A / m 2is carried out at a current density, where the current density is constant, variable, increasing, decreasing, or running a specific program. In one embodiment of step b), the electrochemical reduction is carried out at a current density of 10 to 400 A / m 2 is carried out at a current density, where the current density is constant, variable, increasing, decreasing, or running a specific program. In one embodiment of step b), the electrochemical reduction is carried out at a current density of 10 to 350 A / m 2 is carried out at a current density, where the current density is constant, variable, increasing, decreasing, or running a specific program.

[0360] In one embodiment of step b), the electrochemical reduction is carried out at a current density of 1 to 10000 A / m 2 is carried out at a current density, where the current density is constant or variable. In one embodiment of step b), the electrochemical reduction is carried out at a current density of 1 to 1000 A / m 2 is carried out at a current density, where the current density is constant or variable. In one embodiment of step b), the electrochemical reduction is carried out at a current density of 1 to 500 A / m 2 is carried out at a current density, where the current density is constant or variable. In one embodiment of step b), the electrochemical reduction is carried out at a current density of 1 to 400 A / m 2 is carried out at a current density, where the current density is constant or variable. In one embodiment of step b), the electrochemical reduction is carried out at a current density of 1 to 350 A / m 2 is carried out at a current density, where the current density is constant or variable.

[0361] In one embodiment of step b), the electrochemical reduction is carried out at a current density of 5 to 10000 A / m 2 is carried out at a current density, where the current density is constant or variable. In one embodiment of step b), the electrochemical reduction is carried out at a current density of 5 to 1000 A / m 2 is carried out at a current density, where the current density is constant or variable. In one embodiment of step b), the electrochemical reduction is carried out at a current density of 5 to 500 A / m 2 is carried out at a current density, where the current density is constant or variable. In one embodiment of step b), the electrochemical reduction is carried out at a current density of 5 to 400 A / m 2 is carried out at a current density, where the current density is constant or variable. In one embodiment of step b), the electrochemical reduction is carried out at a current density of 5 to 350 A / m 2 is carried out at a current density, where the current density is constant or variable.

[0362] In one embodiment of step b), the electrochemical reduction is carried out at a current density of 10 to 10000 A / m 2at a current density, where the current density is constant or variable. In one embodiment of step b), the electrochemical reduction is carried out at a current density of 10 to 1000 A / m 2 at a current density, where the current density is constant or variable. In one embodiment of step b), the electrochemical reduction is carried out at a current density of 10 to 500 A / m 2 at a current density, where the current density is constant or variable. In one embodiment of step b), the electrochemical reduction is carried out at a current density of 10 to 400 A / m 2 at a current density, where the current density is constant or variable. In one embodiment of step b), the electrochemical reduction is carried out at a current density of 10 to 350 A / m 2 at a current density, where the current density is constant or variable.

[0363] In one embodiment of step b), the electrochemical reduction is carried out at a current density of 100 to 10000 A / m 2 at a current density, where the current density is constant or variable. In one embodiment of step b), the electrochemical reduction is carried out at a current density of 100 to 1000 A / m 2 at a current density, where the current density is constant or variable. In one embodiment of step b), the electrochemical reduction is carried out at a current density of 100 to 500 A / m 2 at a current density, where the current density is constant or variable. In one embodiment of step b), the electrochemical reduction is carried out at a current density of 100 to 400 A / m 2 at a current density, where the current density is constant or variable. In one embodiment of step b), the electrochemical reduction is carried out at a current density of 100 to 350 A / m 2 at a current density, where the current density is constant or variable.

[0364] In one embodiment of step b), the electrochemical reduction is carried out at a current density of 200 to 400 A / m 2 at a constant current density, where the current density is constant or variable. In one embodiment of step b), the electrochemical reduction is carried out at a current density of 200 A / m 2 at a constant current density, where the current density is constant or variable. In one embodiment of step b), the electrochemical reduction is carried out at a current density of 250 A / m 2 at a constant current density, where the current density is constant or variable. In one embodiment of step b), the electrochemical reduction is carried out at a current density of 300 A / m 2 at a constant current density, where the current density is constant or variable. In one embodiment of step b), the electrochemical reduction is carried out at a current density of 350 A / m 2is carried out at a constant current density, where the current density is constant or variable. In one embodiment of step b), the electrochemical reduction is carried out at 400 A / m 2 is carried out at a constant current density, where the current density is constant or variable.

[0365] In one embodiment of step b), the electrochemical reduction is carried out at a current density of 1 to 10000 A / m 2 is carried out at a current density, where the current density is increasing or decreasing. In one embodiment of step b), the electrochemical reduction is carried out at a current density of 1 to 1000 A / m 2 is carried out at a current density, where the current density is increasing or decreasing. In one embodiment of step b), the electrochemical reduction is carried out at a current density of 1 to 500 A / m 2 is carried out at a current density, where the current density is increasing or decreasing. In one embodiment of step b), the electrochemical reduction is carried out at a current density of 1 to 400 A / m 2 is carried out at a current density, where the current density is increasing or decreasing. In one embodiment of step b), the electrochemical reduction is carried out at a current density of 1 to 350 A / m 2 is carried out at a current density, where the current density is increasing or decreasing.

[0366] In one embodiment of step b), the electrochemical reduction is carried out at a current density of 5 to 10000 A / m 2 is carried out at a current density, where the current density is increasing or decreasing. In one embodiment of step b), the electrochemical reduction is carried out at a current density of 5 to 1000 A / m 2 is carried out at a current density, where the current density is increasing or decreasing. In one embodiment of step b), the electrochemical reduction is carried out at a current density of 5 to 500 A / m 2 is carried out at a current density, where the current density is increasing or decreasing. In one embodiment of step b), the electrochemical reduction is carried out at a current density of 5 to 400 A / m 2 is carried out at a current density, where the current density is increasing or decreasing. In one embodiment of step b), the electrochemical reduction is carried out at a current density of 5 to 350 A / m 2 is carried out at a current density, where the current density is increasing or decreasing.

[0367] In one embodiment of step b), the electrochemical reduction is carried out at a current density of 10 to 10000 A / m 2 is carried out at a current density, where the current density is increasing or decreasing. In one embodiment of step b), the electrochemical reduction is carried out at a current density of 10 to 1000 A / m 2 is carried out at a current density, where the current density is increasing or decreasing. In one embodiment of step b), the electrochemical reduction is carried out at a current density of 10 to 500 A / m 2with a current density, where the current density is increased or decreased. In one embodiment of step b), the electrochemical reduction is carried out at 10 to 400 A / m 2 with a current density, where the current density is increased or decreased. In one embodiment of step b), the electrochemical reduction is carried out at 10 to 350 A / m 2 with a current density, where the current density is increased or decreased.

[0368] In one embodiment of step b), the electrochemical reduction is carried out at 100 to 10000 A / m 2 with a current density, where the current density is increased or decreased. In one embodiment of step b), the electrochemical reduction is carried out at 100 to 1000 A / m 2 with a current density, where the current density is increased or decreased. In one embodiment of step b), the electrochemical reduction is carried out at 100 to 500 A / m 2 with a current density, where the current density is increased or decreased. In one embodiment of step b), the electrochemical reduction is carried out at 100 to 400 A / m 2 with a current density, where the current density is increased or decreased. In one embodiment of step b), the electrochemical reduction is carried out at 100 to 350 A / m 2 with a current density, where the current density is increased or decreased.

[0369] In one embodiment of step b), the electrochemical reduction is carried out at 200 to 400 A / m 2 with a constant current density, where the current density is increased or decreased. In one embodiment of step b), the electrochemical reduction is at 200 A / m 2 with a constant current density, where the current density is increased or decreased. In one embodiment of step b), the electrochemical reduction is at 250 A / m 2 with a constant current density, where the current density is increased or decreased. In one embodiment of step b), the electrochemical reduction is at 300 A / m 2 with a constant current density, where the current density is increased or decreased. In one embodiment of step b), the electrochemical reduction is at 350 A / m 2 with a constant current density, where the current density is increased or decreased. In one embodiment of step b), the electrochemical reduction is at 400 A / m 2 with a constant current density, where the current density is increased or decreased.

[0370] Step c

[0371] In one embodiment, the sequential one-pot synthesis method further comprises step c)

[0372] Step c) Separation of the compound of formula (XIII)

[0373] In one embodiment of step c), the separation is selected from filtration and crystallization. In one embodiment of step c), the compound of formula (XIII) is separated by filtration. In one embodiment of step c), the compound of formula (XIII) is separated by crystallization.

[0374] Step d

[0375] In one embodiment, the sequential one-pot synthesis method further comprises step d)

[0376] Step d) Crystallization of the compound of formula (XIII)

[0377] In one embodiment of step d), the crystallization is carried out in an organic solvent or a mixture of organic solvents. In one embodiment of step c), the separation is selected from chiral chromatography, crystallization, racemate resolution, diastereomeric salt formation, and chiral salt formation. For example, the separation by forming diastereomeric salts is described in US20100136142 A1, US20170217957 A1, or WO2019206909 A1.

[0378] In one embodiment of step d), the crystallization is carried out in an organic solvent. In one embodiment of step d), the crystallization is carried out in isopropyl alcohol, n-propanol, or a mixture thereof. In one embodiment, the compound (XIII) is first dissolved and then cooled. In one embodiment, the compound (XIII) is first dissolved by heating to above 90 °C and then cooled to 10 °C. In one embodiment, the compound (XIII) is first dissolved by heating to above 85 °C and then cooled to 5 °C. In one embodiment, the compound (XIII) is first dissolved by heating to above 75 °C and then cooled to 0 °C. These embodiments can obtain the compound of formula (XIII) in a very pure form.

[0379] Other embodiments

[0380] In one embodiment, the current density used in step a) is lower than the current density used in step b). The oxidation selectivity is surprisingly high so that no secondary components appear. Such components may interfere with the subsequent racemization and reduction steps, and thus separation and purification are not required after each step.

[0381] In one embodiment,

[0382] - In step a), the electrochemical oxidation is carried out at a current density selected from 1 to 5000 A / m 2 , 1 to 500 A / m 2 , 1 to 100 A / m 2 , 1 to 50 A / m 2 , 5 to 5000 A / m 2 , 5 to 500 A / m 2 , 5 to 100 A / m 2 , 5 to 50 A / m 2 , 10 to 5000 A / m 2 , 10 to 500 A / m 2 , 10 to 100 A / m 2 , 10 to 50 A / m 2 ; and

[0383] - In step b), the electrochemical reduction is carried out at a current density selected from 1 to 10000 A / m 2 , 1 to 1000 A / m 2 , 1 to 500 A / m 2 , 5 to 10000 A / m 2 , 50 to 1000 A / m 2 , 200 to 500 A / m 2 , 10 to 10000 A / m 2 , 10 to 1000 A / m 2 , 10 to 500 A / m 2 , 100 to 500 A / m 2 , 200 to 400 A / m 2 , 200 A / m 2 , 250 A / m 2 , 300 A / m 2 , 350 A / m 2 , 400 A / m 2 .

[0384] In one embodiment,

[0385] - In step a), the electrochemical oxidation is carried out at a current density of 1 to 5000 A / m 2 ; and

[0386] - In step b), the electrochemical reduction is carried out at a current density of 1 to 10000 A / m 2 .

[0387] In one embodiment,

[0388] - In step a), the electrochemical oxidation is carried out at a current density of 1 to 500 A / m 2 ; and

[0389] - In step b), the electrochemical reduction is carried out at a current density of 1 to 1000 A / m 2 .

[0390] In one embodiment,

[0391] - In step a), the electrochemical oxidation is carried out at a current density of 1 to 500 A / m 2 ; and

[0392] - In step b), the electrochemical reduction is carried out at a current density of 1 to 500 A / m 2 .

[0393] In one embodiment,

[0394] - In step a), the electrochemical oxidation is carried out at a current density of 1 to 100 A / m 2 ; and

[0395] - In step b), the electrochemical reduction is carried out at a current density of 1 to 500 A / m 2 .

[0396] In one embodiment,

[0397] - In step a), the electrochemical oxidation is carried out at a current density of 1 to 100 A / m 2 ; and

[0398] - In step b), the electrochemical reduction is carried out at a current density of 10 to 500 A / m 2 .

[0399] In one embodiment,

[0400] - In step a), the electrochemical oxidation is carried out at a current density of 1 to 50 A / m 2 ; and

[0401] - In step b), the electrochemical reduction is carried out at a current density of 10 to 500 A / m 2 .

[0402] In one embodiment,

[0403] - In step a), the electrochemical oxidation is carried out at a current density of 1 to 100 A / m 2 ; and

[0404] - In step b), the electrochemical reduction is carried out at a current density of 100 to 500 A / m 2 .

[0405] In one embodiment,

[0406] - In step a), the electrochemical oxidation is carried out at a current density of 1 to 50 A / m2 is carried out at a current density of; and

[0407] - in step b), the electrochemical reduction is carried out at a current density of 100 to 500 A / m 2 of the current density.

[0408] In one embodiment,

[0409] - in step a), the electrochemical oxidation is carried out at a current density of 1 to 100 A / m 2 of the current density; and

[0410] - in step b), the electrochemical reduction is carried out at a current density of 200 to 400 A / m 2 of the current density.

[0411] In one embodiment,

[0412] - in step a), the electrochemical oxidation is carried out at a current density of 1 to 50 A / m 2 of the current density; and

[0413] - in step b), the electrochemical reduction is carried out at a current density of 200 to 400 A / m 2 of the current density.

[0414] In one embodiment,

[0415] - in step a), the electrochemical oxidation is carried out at a current density selected from 1 to 5000 A / m 2 , 1 to 500 A / m 2 , 1 to 100 A / m 2 , 1 to 50 A / m 2 , 5 to 5000 A / m 2 , 5 to 500 A / m 2 , 5 to 100 A / m 2 , 5 to 50 A / m 2 , 10 to 5000 A / m 2 , 10 to 500 A / m 2 , 10 to 100 A / m 2 , and 10 to 50 A / m 2 of the current density, wherein the current density used in step a) is reduced; and

[0416] - in step b), the electrochemical reduction is carried out at a current density selected from 1 to 10000 A / m 2 , 1 to 1000 A / m 2 , 1 to 500 A / m 2 , 5 to 10000 A / m 2 , 50 to 1000 A / m 2 , 200 to 500 A / m 2, 10 to 10000 A / m 2 , 10 to 1000 A / m 2 , 10 to 500 A / m 2 , 100 to 500 A / m 2 , 200 to 400 A / m 2 , 200 A / m 2 , 250 A / m 2 , 300 A / m 2 , 350 A / m 2 and 400 A / m 2 at the current densities of.

[0417] In one embodiment,

[0418] - the electrochemical oxidation in step a) is carried out at a current density of 1 to 5000 A / m 2 wherein the current density used in step a) is decreased; and

[0419] - the electrochemical reduction in step b) is carried out at a current density of 1 to 10000 A / m 2 at the current densities of.

[0420] In one embodiment,

[0421] - the electrochemical oxidation in step a) is carried out at a current density of 1 to 500 A / m 2 wherein the current density used in step a) is decreased; and

[0422] - the electrochemical reduction in step b) is carried out at a current density of 1 to 1000 A / m 2 at the current densities of.

[0423] In one embodiment,

[0424] - the electrochemical oxidation in step a) is carried out at a current density of 1 to 500 A / m 2 wherein the current density used in step a) is decreased; and

[0425] - the electrochemical reduction in step b) is carried out at a current density of 1 to 500 A / m 2 at the current densities of.

[0426] In one embodiment,

[0427] - the electrochemical oxidation in step a) is carried out at a current density of 1 to 100 A / m 2 wherein the current density used in step a) is decreased; and

[0428] - the electrochemical reduction in step b) is carried out at a current density of 1 to 500 A / m 2 at the current densities of.

[0429] In one embodiment,

[0430] - In step a), the electrochemical oxidation is carried out at a current density of 1 to 100 A / m 2 , where the current density used in step a) is reduced; and

[0431] - In step b), the electrochemical reduction is carried out at a current density of 10 to 500 A / m 2 .

[0432] In one embodiment,

[0433] - In step a), the electrochemical oxidation is carried out at a current density of 1 to 50 A / m 2 , where the current density used in step a) is reduced; and

[0434] - In step b), the electrochemical reduction is carried out at a current density of 10 to 500 A / m 2 .

[0435] In one embodiment,

[0436] - In step a), the electrochemical oxidation is carried out at a current density of 1 to 100 A / m 2 , where the current density used in step a) is reduced; and

[0437] - In step b), the electrochemical reduction is carried out at a current density of 100 to 500 A / m 2 .

[0438] In one embodiment,

[0439] - In step a), the electrochemical oxidation is carried out at a current density of 1 to 50 A / m 2 , where the current density used in step a) is reduced; and

[0440] - In step b), the electrochemical reduction is carried out at a current density of 100 to 500 A / m 2 .

[0441] In one embodiment,

[0442] - In step a), the electrochemical oxidation is carried out at a current density of 1 to 100 A / m 2 , where the current density used in step a) is reduced; and

[0443] - In step b), the electrochemical reduction is carried out at a current density of 200 to 400 A / m 2 .

[0444] In one embodiment,

[0445] - In step a), the electrochemical oxidation is carried out at a current density of 1 to 50 A / m 2 , where the current density used in step a) is decreasing; and

[0446] - In step b), the electrochemical reduction is carried out at a current density of 200 to 400 A / m 2 .

[0447] In one embodiment,

[0448] - In step a), the electrochemical oxidation is carried out at a current density selected from 1 to 5000 A / m 2 , 1 to 500 A / m 2 , 1 to 100 A / m 2 , 1 to 50 A / m 2 , 5 to 5000 A / m 2 , 5 to 500 A / m 2 , 5 to 100 A / m 2 , 5 to 50 A / m 2 , 10 to 5000 A / m 2 , 10 to 500 A / m 2 , 10 to 100 A / m 2 , and 10 to 50 A / m 2 , where the current density used in step a) is gradually decreasing; and

[0449] - In step b), the electrochemical reduction is carried out at a current density selected from 1 to 10000 A / m 2 , 1 to 1000 A / m 2 , 1 to 500 A / m 2 , 5 to 10000 A / m 2 , 50 to 1000 A / m 2 , 200 to 500 A / m 2 , 10 to 10000 A / m 2 , 10 to 1000 A / m 2 , 10 to 500 A / m 2 , 100 to 500 A / m 2 , 200 to 400 A / m 2 , 200 A / m 2 , 250 A / m 2 , 300 A / m 2 , 350 A / m 2 , 400 A / m 2 .

[0450] In one embodiment,

[0451] - In step a), the electrochemical oxidation is carried out at a current density of 1 to 5000 A / m 2 , where the current density used in step a) is gradually decreased; and

[0452] - In step b), the electrochemical reduction is carried out at a current density of 1 to 10000 A / m 2 .

[0453] In one embodiment,

[0454] - In step a), the electrochemical oxidation is carried out at a current density of 1 to 500 A / m 2 , where the current density used in step a) is gradually decreased; and

[0455] - In step b), the electrochemical reduction is carried out at a current density of 1 to 1000 A / m 2 .

[0456] In one embodiment,

[0457] - In step a), the electrochemical oxidation is carried out at a current density of 1 to 500 A / m 2 , where the current density used in step a) is gradually decreased; and

[0458] - In step b), the electrochemical reduction is carried out at a current density of 1 to 500 A / m 2 .

[0459] In one embodiment,

[0460] - In step a), the electrochemical oxidation is carried out at a current density of 1 to 100 A / m 2 , where the current density used in step a) is gradually decreased; and

[0461] - In step b), the electrochemical reduction is carried out at a current density of 1 A / m 2 to 500 A / m 2 .

[0462] In one embodiment,

[0463] - In step a), the electrochemical oxidation is carried out at a current density of 1 to 100 A / m 2 , where the current density used in step a) is gradually decreased; and

[0464] - In step b), the electrochemical reduction is carried out at a current density of 10 A / m 2 to 500 A / m 2 .

[0465] In one embodiment,

[0466] - In step a), the electrochemical oxidation is carried out at a current density of 1 to 50 A / m 2 , where the current density used in step a) is gradually decreased; and

[0467] - In step b), the electrochemical reduction is carried out at a current density of 10 A / m 2 to 500 A / m 2 .

[0468] In one embodiment,

[0469] - In step a), the electrochemical oxidation is carried out at a current density of 1 to 100 A / m 2 , where the current density used in step a) is gradually decreased; and

[0470] - In step b), the electrochemical reduction is carried out at a current density of 100 to 500 A / m 2 .

[0471] In one embodiment,

[0472] - In step a), the electrochemical oxidation is carried out at a current density of 1 to 50 A / m 2 , where the current density used in step a) is gradually decreased; and

[0473] - In step b), the electrochemical reduction is carried out at a current density of 100 to 500 A / m 2 .

[0474] In one embodiment,

[0475] - In step a), the electrochemical oxidation is carried out at a current density of 1 to 100 A / m 2 , where the current density used in step a) is gradually decreased; and

[0476] - In step b), the electrochemical reduction is carried out at a current density of 200 to 400 A / m 2 .

[0477] In one embodiment,

[0478] - In step a), the electrochemical oxidation is carried out at a current density of 1 to 50 A / m 2 , where the current density used in step a) is gradually decreased; and

[0479] - In step b), the electrochemical reduction is carried out at a current density of 200 to 400 A / m 2 .

[0480] In one embodiment,

[0481] - In step a), the electrochemical oxidation is carried out at a current density selected from 1 to 5000 A / m 2 , 1 to 500 A / m 2 , 1 to 100 A / m 2 , 1 to 50 A / m 2 , 5 to 5000 A / m 2 , 5 to 500 A / m 2 , 5 to 100 A / m 2 , 5 to 50 A / m 2 , 10 to 5000 A / m 2 , 10 to 500 A / m 2 , 10 to 100 A / m 2 , and 10 to 50 A / m 2 , where the current density used in step a) is decreasing; and

[0482] - In step b), the electrochemical reduction is carried out at a current density selected from 1 to 10000 A / m 2 , 1 to 1000 A / m 2 , 1 to 500 A / m 2 , 5 to 10000 A / m 2 , 50 to 1000 A / m 2 , 200 to 500 A / m 2 , 10 to 10000 A / m 2 , 10 to 1000 A / m 2 , 10 to 500 A / m 2 , 100 to 500 A / m 2 , 200 to 400 A / m 2 , 200 A / m 2 , 250 A / m 2 , 300 A / m 2 , 350 A / m 2 , 400 A / m 2 , where the current density used in step a) is lower than the current density used in step b).

[0483] In one embodiment,

[0484] - In step a), the electrochemical oxidation is carried out at a current density of 1 to 5000 A / m 2 , where the current density used in step a) is decreasing; and

[0485] - In step b), the electrochemical reduction is carried out at a current density of 1 to 10000 A / m 2 , where the current density used in step a) is lower than the current density used in step b).

[0486] In one embodiment,

[0487] - In step a), the electrochemical oxidation is carried out at a current density of 1 to 500 A / m 2 wherein the current density used in step a) is reduced; and

[0488] - In step b), the electrochemical reduction is carried out at a current density of 1 to 1000 A / m 2 wherein the current density used in step a) is lower than the current density used in step b).

[0489] In one embodiment,

[0490] - In step a), the electrochemical oxidation is carried out at a current density of 1 to 500 A / m 2 wherein the current density used in step a) is reduced; and

[0491] - In step b), the electrochemical reduction is carried out at a current density of 1 to 500 A / m 2 wherein the current density used in step a) is lower than the current density used in step b).

[0492] In one embodiment,

[0493] - In step a), the electrochemical oxidation is carried out at a current density of 1 to 100 A / m 2 wherein the current density used in step a) is reduced; and

[0494] - In step b), the electrochemical reduction is carried out at a current density of 1 A / m 2 to 500 A / m 2 wherein the current density used in step a) is lower than the current density used in step b).

[0495] In one embodiment,

[0496] - In step a), the electrochemical oxidation is carried out at a current density of 1 to 100 A / m 2 wherein the current density used in step a) is reduced; and

[0497] - In step b), the electrochemical reduction is carried out at a current density of 10 A / m 2 to 500 A / m 2 wherein the current density used in step a) is lower than the current density used in step b).

[0498] In one embodiment,

[0499] - In step a), the electrochemical oxidation is carried out at a current density of 1 to 50 A / m 2at a current density, wherein the current density used in step a) is decreased; and

[0500] - in step b), the electrochemical reduction is carried out at a current density of 10 A / m 2 to 500 A / m 2 and the current density used in step a) is lower than the current density used in step b).

[0501] In one embodiment,

[0502] - in step a), the electrochemical oxidation is carried out at a current density of 1 to 100 A / m 2 and the current density used in step a) is decreased; and

[0503] - in step b), the electrochemical reduction is carried out at a current density of 100 to 500 A / m 2 and the current density used in step a) is lower than the current density used in step b).

[0504] In one embodiment,

[0505] - in step a), the electrochemical oxidation is carried out at a current density of 1 to 50 A / m 2 and the current density used in step a) is decreased; and

[0506] - in step b), the electrochemical reduction is carried out at a current density of 100 to 500 A / m 2 and the current density used in step a) is lower than the current density used in step b).

[0507] In one embodiment,

[0508] - in step a), the electrochemical oxidation is carried out at a current density of 1 to 100 A / m 2 and the current density used in step a) is decreased; and

[0509] - in step b), the electrochemical reduction is carried out at a current density of 200 to 400 A / m 2 and the current density used in step a) is lower than the current density used in step b).

[0510] In one embodiment,

[0511] - in step a), the electrochemical oxidation is carried out at a current density of 1 to 50 A / m 2 and the current density used in step a) is decreased; and

[0512] - in step b), the electrochemical reduction is carried out at a current density of 200 to 400 A / m 2with a current density, wherein the current density used in step a) is lower than the current density used in step b).

[0513] In one embodiment,

[0514] - electrochemically oxidizing in step a) at a current density selected from 1 to 5000 A / m 2 、1 to 500 A / m 2 、1 to 100 A / m 2 、1 to 50 A / m 2 、5 to 5000 A / m 2 、5 to 500 A / m 2 、5 to 100 A / m 2 、5 to 50 A / m 2 、10 to 5000 A / m 2 、10 to 500 A / m 2 、10 to 100 A / m 2 、and 10 to 50 A / m 2 with the current density used in step a) being gradually decreased; and

[0515] - electrochemically reducing in step b) at a current density selected from 1 to 10000 A / m 2 、1 to 1000 A / m 2 、1 to 500 A / m 2 、5 to 10000 A / m 2 、50 to 1000 A / m 2 、200 to 500 A / m 2 、10 to 10000 A / m 2 、10 to 1000 A / m 2 、10 to 500 A / m 2 、100 to 500 A / m 2 、200 to 400 A / m 2 、200 A / m 2 、250 A / m 2 、300 A / m 2 、350 A / m 2 、400 A / m 2 with the current density used in step a) being lower than the current density used in step b).

[0516] In one embodiment,

[0517] - electrochemically oxidizing in step a) at a current density of 1 to 5000 A / m 2 with the current density used in step a) being gradually decreased; and

[0518] - In step b), the electrochemical reduction is carried out at a current density of 1 to 10000 A / m 2 and the current density used in step a) is lower than the current density used in step b).

[0519] In one embodiment,

[0520] - In step a), the electrochemical oxidation is carried out at a current density of 1 to 500 A / m 2 and the current density used in step a) is gradually decreased; and

[0521] - In step b), the electrochemical reduction is carried out at a current density of 1 to 1000 A / m 2 and the current density used in step a) is lower than the current density used in step b).

[0522] In one embodiment,

[0523] - In step a), the electrochemical oxidation is carried out at a current density of 1 to 500 A / m 2 and the current density used in step a) is gradually decreased; and

[0524] - In step b), the electrochemical reduction is carried out at a current density of 1 to 500 A / m 2 and the current density used in step a) is lower than the current density used in step b).

[0525] In one embodiment,

[0526] - In step a), the electrochemical oxidation is carried out at a current density of 1 to 100 A / m 2 and the current density used in step a) is gradually decreased; and

[0527] - In step b), the electrochemical reduction is carried out at a current density of 1 A / m 2 to 500 A / m 2 and the current density used in step a) is lower than the current density used in step b).

[0528] In one embodiment,

[0529] - In step a), the electrochemical oxidation is carried out at a current density of 1 to 100 A / m 2 and the current density used in step a) is gradually decreased; and

[0530] - In step b), the electrochemical reduction is carried out at a current density of 10 A / m 2 to 500 A / m 2 and the current density used in step a) is lower than the current density used in step b).

[0531] The current density used in step a) is lower than the current density used in step b).

[0532] In one embodiment,

[0533] - in step a), the electrochemical oxidation is carried out at a current density of 1 to 50 A / m 2 and the current density used in step a) is gradually decreased; and

[0534] - in step b), the electrochemical reduction is carried out at a current density of 10 A / m 2 to 500 A / m 2 and the current density used in step a) is lower than the current density used in step b).

[0535] In one embodiment,

[0536] - in step a), the electrochemical oxidation is carried out at a current density of 1 to 100 A / m 2 and the current density used in step a) is gradually decreased; and

[0537] - in step b), the electrochemical reduction is carried out at a current density of 100 to 500 A / m 2 and the current density used in step a) is lower than the current density used in step b).

[0538] In one embodiment,

[0539] - in step a), the electrochemical oxidation is carried out at a current density of 1 to 50 A / m 2 and the current density used in step a) is gradually decreased; and

[0540] - in step b), the electrochemical reduction is carried out at a current density of 100 to 500 A / m 2 and the current density used in step a) is lower than the current density used in step b).

[0541] In one embodiment,

[0542] - in step a), the electrochemical oxidation is carried out at a current density of 1 to 100 A / m 2 and the current density used in step a) is gradually decreased; and

[0543] - in step b), the electrochemical reduction is carried out at a current density of 200 to 400 A / m 2 and the current density used in step a) is lower than the current density used in step b).

[0544] In one embodiment,

[0545] - In step a), the electrochemical oxidation is carried out at a current density of 1 to 50 A / m 2 and the current density used in step a) is gradually decreased; and

[0546] - In step b), the electrochemical reduction is carried out at a current density of 200 to 400 A / m 2 and the current density used in step a) is lower than the current density used in step b).

[0547] In one embodiment,

[0548] - In step a), the electrochemical oxidation is carried out at a current density selected from 1 to 5000 A / m 2 , 1 to 500 A / m 2 , 1 to 100 A / m 2 , 1 to 50 A / m 2 , 5 to 5000 A / m 2 , 5 to 500 A / m 2 , 5 to 100 A / m 2 , 5 to 50 A / m 2 , 10 to 5000 A / m 2 , 10 to 500 A / m 2 , 10 to 100 A / m 2 , and 10 to 50 A / m 2 and the current density used in step a) is gradually decreased in steps selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2 ; and

[0549] - In step b), the electrochemical reduction is carried out at a current density selected from 1 to 10000 A / m 2 , 1 A / m 2 to 1000 A / m 2 , 1 to 500 A / m 2 , 5 to 10000 A / m 2 , 50 to 1000 A / m 2 , 200 to 500 A / m 2 , 10 to 10000 A / m 2 , 10 to 1000 A / m 2 , 10 to 500 A / m2 、at a current density of 100 to 500 A / m 2 、at a current density of 200 to 400 A / m 2 、at a current density of 200 A / m 2 、at a current density of 250 A / m 2 、at a current density of 300 A / m 2 、at a current density of 350 A / m 2 、at a current density of 400 A / m 2 is carried out, wherein the current density used in step a) is lower than the current density used in step b).

[0550] In one embodiment,

[0551] - the electrochemical oxidation in step a) is carried out at a current density selected from 1 to 5000 A / m 2 wherein the current density used in step a) is gradually decreased in steps selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2 ; and

[0552] - the electrochemical reduction in step b) is carried out at a current density selected from 1 to 10000 A / m 2 wherein the current density used in step a) is lower than the current density used in step b).

[0553] In one embodiment,

[0554] - the electrochemical oxidation in step a) is carried out at a current density of 1 to 500 A / m 2 wherein the current density used in step a) is gradually decreased in steps selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2 ; and

[0555] - the electrochemical reduction in step b) is carried out at a current density of 1 to 1000 A / m 2at a current density such that the current density used in step a) is lower than the current density used in step b).

[0556] In one embodiment,

[0557] - in step a), the electrochemical oxidation is carried out at a current density of 1 to 500 A / m 2 such that the current density used in step a) is decreased stepwise in steps selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2 ; and

[0558] - in step b), the electrochemical reduction is carried out at a current density of 1 to 500 A / m 2 such that the current density used in step a) is lower than the current density used in step b).

[0559] In one embodiment,

[0560] - in step a), the electrochemical oxidation is carried out at a current density of 1 to 100 A / m 2 such that the current density used in step a) is decreased stepwise in steps selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2 ; and

[0561] - in step b), the electrochemical reduction is carried out at a current density of 1 A / m 2 to 500 A / m 2 such that the current density used in step a) is lower than the current density used in step b).

[0562] In one embodiment,

[0563] - in step a), the electrochemical oxidation is carried out at a current density of 1 to 100 A / m 2with a current density, where the current density used in step a) is selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2 and is gradually decreased in steps selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m; and

[0564] - in step b), the electrochemical reduction is carried out at a current density of 10 A / m 2 to 500 A / m 2 where the current density used in step a) is lower than the current density used in step b).

[0565] In one embodiment,

[0566] - in step a), the electrochemical oxidation is carried out at a current density of 1 to 50 A / m 2 with a current density, where the current density used in step a) is selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2 and is gradually decreased in steps selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m; and

[0567] - in step b), the electrochemical reduction is carried out at a current density of 10 A / m 2 to 500 A / m 2 where the current density used in step a) is lower than the current density used in step b).

[0568] In one embodiment,

[0569] - in step a), the electrochemical oxidation is carried out at a current density of 1 to 100 A / m 2at a current density, wherein the current density used in step a) is selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2 and is gradually decreased in steps selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m; and

[0570] - in step b), the electrochemical reduction is carried out at a current density of 100 to 500 A / m 2 wherein the current density used in step a) is lower than the current density used in step b).

[0571] In one embodiment,

[0572] - in step a), the electrochemical oxidation is carried out at a current density of 1 to 50 A / m 2 wherein the current density used in step a) is selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2 and is gradually decreased in steps selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m; and

[0573] - in step b), the electrochemical reduction is carried out at a current density of 100 to 500 A / m 2 wherein the current density used in step a) is lower than the current density used in step b).

[0574] In one embodiment,

[0575] - in step a), the electrochemical oxidation is carried out at a current density of 1 to 100 A / m 2 wherein the current density used in step a) is selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2with a gradually decreasing step size; and

[0576] - in step b), the electrochemical reduction is carried out at a current density of 200 to 400 A / m 2 wherein the current density used in step a) is lower than the current density used in step b).

[0577] In one embodiment,

[0578] - in step a), the electrochemical oxidation is carried out at a current density of 1 to 50 A / m 2 wherein the current density used in step a) is gradually decreased in steps selected from 0.1, 0.2, 0.5, 1, 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 A / m 2 with a gradually decreasing step size; and

[0579] - in step b), the electrochemical reduction is carried out at a current density of 200 to 400 A / m 2 wherein the current density used in step a) is lower than the current density used in step b).

[0580] In one embodiment,

[0581] - in step a), the electrochemical oxidation is carried out at a current density selected from 1 to 5000 A / m 2 、1 to 500 A / m 2 、1 to 100 A / m 2 、1 to 50 A / m 2 、5 to 5000 A / m 2 、5 to 500 A / m 2 、5 to 100 A / m 2 、5 to 50 A / m 2 、10 to 5000 A / m 2 、10 to 500 A / m 2 、10 to 100 A / m 2 、and 10 to 50 A / m 2 wherein the current density used in step a) is gradually decreased in steps of 1 to 100 A / m 2 with a gradually decreasing step size; and

[0582] - in step b), the electrochemical reduction is carried out at a current density selected from 1 to 10000 A / m 2 、1 to 1000 A / m 2, from 1 to 500 A / m 2 , from 5 to 10,000 A / m 2 , from 50 to 1000 A / m 2 , from 200 to 500 A / m 2 , from 10 to 10,000 A / m 2 , from 10 to 1000 A / m 2 , from 10 to 500 A / m 2 , from 100 to 500 A / m 2 , from 200 to 400 A / m 2 , 200 A / m 2 , 250 A / m 2 , 300 A / m 2 , 350 A / m 2 , 400 A / m 2 is carried out at a current density of

[0583] In one embodiment,

[0584] - In step a), the electrochemical oxidation is carried out at a current density of 1 to 5000 A / m 2 wherein the current density used in step a) is gradually decreased in steps of 1 to 100 A / m 2 ; and

[0585] - In step b), the electrochemical reduction is carried out at a current density of 1 to 10,000 A / m 2 wherein the current density used in step a) is lower than the current density used in step b).

[0586] In one embodiment,

[0587] - In step a), the electrochemical oxidation is carried out at a current density of 1 to 500 A / m 2 wherein the current density used in step a) is gradually decreased in steps of 1 to 100 A / m 2 ; and

[0588] - In step b), the electrochemical reduction is carried out at a current density of 1 to 1000 A / m 2 wherein the current density used in step a) is lower than the current density used in step b).

[0589] In one embodiment,

[0590] - In step a), the electrochemical oxidation is carried out at a current density of 1 to 500 A / m 2 wherein the current density used in step a) is gradually decreased in steps of 1 to 100 A / m 2with a gradually decreasing step size; and

[0591] - in step b), the electrochemical reduction is carried out at a current density of 1 to 500 A / m 2 wherein the current density used in step a) is lower than the current density used in step b).

[0592] In one embodiment,

[0593] - in step a), the electrochemical oxidation is carried out at a current density of 1 to 100 A / m 2 wherein the current density used in step a) is gradually decreased in steps of 1 to 100 A / m 2 with a gradually decreasing step size; and

[0594] - in step b), the electrochemical reduction is carried out at a current density of 1 A / m 2 to 500 A / m 2 wherein the current density used in step a) is lower than the current density used in step b).

[0595] In one embodiment,

[0596] - in step a), the electrochemical oxidation is carried out at a current density of 1 to 100 A / m 2 wherein the current density used in step a) is gradually decreased in steps of 1 to 100 A / m 2 with a gradually decreasing step size; and

[0597] - in step b), the electrochemical reduction is carried out at a current density of 10 A / m 2 to 500 A / m 2 wherein the current density used in step a) is lower than the current density used in step b).

[0598] In one embodiment,

[0599] - in step a), the electrochemical oxidation is carried out at a current density of 1 to 50 A / m 2 wherein the current density used in step a) is gradually decreased in steps of 1 to 100 A / m 2 with a gradually decreasing step size; and

[0600] - in step b), the electrochemical reduction is carried out at a current density of 10 A / m 2 to 500 A / m 2 wherein the current density used in step a) is lower than the current density used in step b).

[0601] In one embodiment,

[0602] - in step a), the electrochemical oxidation is carried out at a current density of 1 to 100 A / m 2with a current density, wherein the current density used in step a) is gradually decreased in steps of 1 to 100 A / m 2 ; and

[0603] - in step b), the electrochemical reduction is carried out with a current density of 100 to 500 A / m 2 and the current density used in step a) is lower than the current density used in step b).

[0604] In one embodiment,

[0605] - in step a), the electrochemical oxidation is carried out with a current density of 1 to 50 A / m 2 and the current density used in step a) is gradually decreased in steps of 1 to 100 A / m 2 ; and

[0606] - in step b), the electrochemical reduction is carried out with a current density of 100 to 500 A / m 2 and the current density used in step a) is lower than the current density used in step b).

[0607] In one embodiment,

[0608] - in step a), the electrochemical oxidation is carried out with a current density of 1 to 100 A / m 2 and the current density used in step a) is gradually decreased in steps of 1 to 100 A / m 2 ; and

[0609] - in step b), the electrochemical reduction is carried out with a current density of 200 to 400 A / m 2 and the current density used in step a) is lower than the current density used in step b).

[0610] In one embodiment,

[0611] - in step a), the electrochemical oxidation is carried out with a current density of 1 to 50 A / m 2 and the current density used in step a) is gradually decreased in steps of 1 to 100 A / m 2 ; and

[0612] - in step b), the electrochemical reduction is carried out with a current density of 200 to 400 A / m 2 and the current density used in step a) is lower than the current density used in step b).

[0613] In one embodiment,

[0614] - in step a), the electrochemical oxidation is carried out with a current density selected from 1 to 5000 A / m2 , from 1 to 500 A / m 2 , from 1 to 100 A / m 2 , from 1 to 50 A / m 2 , from 5 to 5000 A / m 2 , from 5 to 500 A / m 2 , from 5 to 100 A / m 2 , from 5 to 50 A / m 2 , from 10 to 5000 A / m 2 , from 10 to 500 A / m 2 , from 10 to 100 A / m 2 , and from 10 to 50 A / m 2 The current density used in step a) is gradually decreased in steps of 1 to 10 A / m; and 2 and

[0615] - In step b), the electrochemical reduction is carried out at a current density selected from 1 to 10000 A / m 2 , 1 to 1000 A / m 2 , 1 to 500 A / m 2 , 5 to 10000 A / m 2 , 50 to 1000 A / m 2 , 200 to 500 A / m 2 , 10 to 10000 A / m 2 , 10 to 1000 A / m 2 , 10 to 500 A / m 2 , 100 to 500 A / m 2 , 200 to 400 A / m 2 , 200 A / m 2 , 250 A / m 2 , 300 A / m 2 , 350 A / m 2 , 400 A / m 2 The current density used in step a) is lower than the current density used in step b).

[0616] In one embodiment,

[0617] - In step a), the electrochemical oxidation is carried out at a current density of 1 to 5000 A / m 2 The current density used in step a) is gradually decreased in steps of 1 to 10 A / m; and 2 and

[0618] - In step b), the electrochemical reduction is carried out at a current density of 1 to 10000 A / m 2is carried out at a current density, wherein the current density used in step a) is lower than the current density used in step b).

[0619] In one embodiment,

[0620] - Electrochemical oxidation in step a) is carried out at a current density of 1 to 500 A / m 2 of the current density, wherein the current density used in step a) is gradually decreased in steps of 1 to 10 A / m 2 ; and

[0621] - Electrochemical reduction in step b) is carried out at a current density of 1 to 1000 A / m 2 of the current density, wherein the current density used in step a) is lower than the current density used in step b).

[0622] In one embodiment,

[0623] - Electrochemical oxidation in step a) is carried out at a current density of 1 to 500 A / m 2 of the current density, wherein the current density used in step a) is gradually decreased in steps of 1 to 10 A / m 2 ; and

[0624] - Electrochemical reduction in step b) is carried out at a current density of 1 to 500 A / m 2 of the current density, wherein the current density used in step a) is lower than the current density used in step b). In one embodiment,

[0625] - Electrochemical oxidation in step a) is carried out at a current density of 1 to 100 A / m 2 of the current density, wherein the current density used in step a) is gradually decreased in steps of 1 to 10 A / m 2 ; and

[0626] - Electrochemical reduction in step b) is carried out at a current density of 1 A / m 2 to 500 A / m 2 of the current density, wherein the current density used in step a) is lower than the current density used in step b).

[0627] In one embodiment,

[0628] - Electrochemical oxidation in step a) is carried out at a current density of 1 to 100 A / m 2 of the current density, wherein the current density used in step a) is gradually decreased in steps of 1 to 10 A / m 2 ; and

[0629] - Electrochemical reduction in step b) is carried out at a current density of 10 A / m 2 to 500 A / m 2is carried out at a current density, wherein the current density used in step a) is lower than the current density used in step b).

[0630] In one embodiment,

[0631] - in step a), the electrochemical oxidation is carried out at a current density of 1 to 50 A / m 2 and the current density used in step a) is gradually decreased in steps of 1 to 10 A / m 2 ; and

[0632] - in step b), the electrochemical reduction is carried out at a current density of 10 A / m 2 to 500 A / m 2 and the current density used in step a) is lower than the current density used in step b).

[0633] In one embodiment,

[0634] - in step a), the electrochemical oxidation is carried out at a current density of 1 to 100 A / m 2 and the current density used in step a) is gradually decreased in steps of 1 to 10 A / m 2 ; and

[0635] - in step b), the electrochemical reduction is carried out at a current density of 100 to 500 A / m 2 and the current density used in step a) is lower than the current density used in step b).

[0636] In one embodiment,

[0637] - in step a), the electrochemical oxidation is carried out at a current density of 1 to 50 A / m 2 and the current density used in step a) is gradually decreased in steps of 1 to 10 A / m 2 ; and

[0638] - in step b), the electrochemical reduction is carried out at a current density of 100 to 500 A / m 2 and the current density used in step a) is lower than the current density used in step b).

[0639] In one embodiment,

[0640] - in step a), the electrochemical oxidation is carried out at a current density of 1 to 100 A / m 2 and the current density used in step a) is gradually decreased in steps of 1 to 10 A / m 2 ; and

[0641] - in step b), the electrochemical reduction is carried out at a current density of 200 to 400 A / m2 at a current density, wherein the current density used in step a) is lower than the current density used in step b).

[0642] In one embodiment,

[0643] - in step a), the electrochemical oxidation is carried out at a current density of 1 to 50 A / m 2 at a current density, wherein the current density used in step a) is gradually decreased in steps of 1 to 10 A / m 2 ; and

[0644] - in step b), the electrochemical reduction is carried out at a current density of 200 to 400 A / m 2 at a current density, wherein the current density used in step a) is lower than the current density used in step b).

[0645] In one embodiment, the current density used in step a) is decreased or gradually decreased.

[0646] In one embodiment, the current density used in step a) is lower than the current density used in step b).

[0647] In one embodiment, step a) is carried out at a temperature selected from 15 to 150 °C, 15 to 120 °C, and 20 to 100 °C.

[0648] In one embodiment, in step a), first the electrochemical oxidation is carried out, and then the reaction mixture is heated; or first the electrochemical oxidation is carried out, and then the reaction mixture is heated to a temperature selected from 50 to 150 °C, 75 to 150 °C, 80 to 150 °C, 80 to 140 °C, and 90 to 120 °C.

[0649] In one embodiment, a conductive salt is used in step a) and / or b), and the conductive salt used is selected from organic ammonium salts, ionic liquids, tetraalkylammonium fluoroborates, quaternary ammonium salts, and mixtures thereof; or selected from tetraethylammonium tetrafluoroborate, tetrabutylammonium hexafluorophosphate, tetrabutylammonium hydrogen sulfate, and mixtures thereof.

[0650] In one embodiment, the solvent in step a) and / or b) is selected from

[0651] - aprotic solvents, protic solvents, and mixtures thereof, or selected from polar aprotic solvents; or

[0652] - polar aprotic solvents selected from: dimethylformamide (DMF), dimethyl sulfoxide, acetonitrile, acetone; or

[0653] - protic solvents selected from methanol, acetic acid, ethanol, formic acid, water, and mixtures thereof; or

[0654] - Dimethylformamide (DMF), methanol, acetic acid, and mixtures thereof; or

[0655] - Methanol, acetic acid, and mixtures thereof; or

[0656] - Methanol; or

[0657] - Acetic acid; or

[0658] - Or mixtures of the aforementioned solvents.

[0659] In one embodiment, an acid is used in step a), or the acid used is selected from the following:

[0660] - Organic acids, sulfonic acids, organic polar acids, and mixtures thereof;

[0661] - Use acetic acid, formic acid, and mixtures thereof;

[0662] - Acetic acid;

[0663] And mixtures thereof.

[0664] In one embodiment, the electrochemical oxidation in step a) is carried out at a cell voltage of 0.1 to 20 V or less than 20 V.

[0665] In one embodiment, the electrochemical oxidation in step a) is carried out at a current density selected from 1 to 5000 A / m 2 、1 to 500 A / m 2 、1 to 100 A / m 2 、1 to 50 A / m 2 、5 to 5000 A / m 2 、5 to 500 A / m 2 、5 to 100 A / m 2 、5 to 50 A / m 2 、10 to 5000 A / m 2 、10 to 500 A / m 2 、10 to 100 A / m 2 、and 10 to 50 A / m 2 The current density is carried out.

[0666] In one embodiment, the electrochemical reduction in step b) is carried out at a cell voltage of 0.1 to 30 V or less than 30 V.

[0667] In one embodiment, the electrochemical reduction in step b) is carried out at a current density selected from 1 to 10000 A / m 2 、1 to 1000 A / m 2 、1 to 500 A / m 2 、5 to 10000 A / m 2 、50 to 1000 A / m 2, 200 to 500 A / m 2 , 10 to 10,000 A / m 2 , 10 to 1,000 A / m 2 , 100 to 500 A / m 2 , 200 to 400 A / m 2 , 200 A / m 2 , 250 A / m 2 , 300 A / m 2 , 350 A / m 2 , 400 A / m 2 at a current density of...

[0668] In one embodiment, the electrochemical reduction in step b) is carried out at 1 to 50 °C, 10 to 35 °C, 15 to 30 °C or at ambient temperature.

[0669] In one embodiment, the synthesis further comprises step c)

[0670] Step c) Separation of the compound of formula (XIII)

[0671] wherein in step c), the separation is optionally selected from filtration and crystallization.

[0672] and / or step d)

[0673] Step d) Crystallization of the compound of formula (XIII)

[0674] In one embodiment,

[0675] - the current density used in step a) is reduced or gradually reduced;

[0676] - the current density used in step a) is lower than the current density used in step b);

[0677] - step a) is carried out at a temperature selected from 20 to 120 °C,

[0678] - a conductive salt is used in step a) and / or b), and the conductive salt used is selected from organic ammonium salts, ionic liquids, tetraalkylammonium fluoroborate, quaternary ammonium salts and mixtures thereof;

[0679] - the solvent in step a) and / or b) is selected from aprotic solvents, protic solvents, polar aprotic solvents and mixtures thereof, or is selected from polar aprotic solvents; or

[0680] - an acid is used in step a) or the acid used is selected from organic acids, sulfonic acids, organic polar acids and mixtures thereof;

[0681] - the electrochemical oxidation in step a) is carried out at a current density selected from 1 to 50 A / m 2 as follows.

[0682] - In step b), the electrochemical reduction is carried out at a current density selected from 10 to 500 A / m 2 of the current density.

[0683] In one embodiment,

[0684] - The current density used in step a) is reduced or gradually reduced;

[0685] - The current density used in step a) is lower than the current density used in step b);

[0686] - Step a) is carried out at a temperature selected from 20 to 120 °C,

[0687] - A conductive salt is used in step a) and / or b), and the conductive salt used is selected from organic ammonium salts, ionic liquids, tetraalkylammonium fluoroborate, quaternary ammonium salts and mixtures thereof;

[0688] - The solvent in step a) and / or b) is selected from aprotic solvents, protic solvents, polar aprotic solvents and mixtures thereof, or is selected from polar aprotic solvents; or

[0689] - An acid is used in step a) or the acid used is selected from organic acids, sulfonic acids, organic polar acids and mixtures thereof;

[0690] - The electrochemical oxidation in step a) is carried out at a current density selected from 1 to 100 A / m 2 of the current density.

[0691] - The electrochemical reduction in step b) is carried out at a current density selected from 10 to 1000 A / m 2 of the current density.

[0692] In one embodiment,

[0693] - The current density used in step a) is reduced or gradually reduced;

[0694] - The current density used in step a) is lower than the current density used in step b);

[0695] - Step a) is carried out at a temperature selected from 15 to 150 °C,

[0696] - A conductive salt is used in step a) and / or b), and the conductive salt used is selected from organic ammonium salts, ionic liquids, tetraalkylammonium fluoroborate, quaternary ammonium salts and mixtures thereof;

[0697] - The solvent in step a) and / or b) is selected from aprotic solvents, protic solvents, polar aprotic solvents and mixtures thereof, or is selected from polar aprotic solvents; or

[0698] - In step a), the acid used or the acid used therein is selected from organic acids, sulfonic acids, organic polar acids, and mixtures thereof;

[0699] - The electrochemical oxidation in step a) is carried out at a current density selected from 1 to 100 A / m 2 of the current density.

[0700] - The electrochemical reduction in step b) is carried out at a current density selected from 1 to 1000 A / m 2 of the current density.

[0701] - The electrochemical reduction in step b) is carried out at a temperature of 1 to 50 °C.

[0702] In one embodiment,

[0703] - The current density used in step a) is decreased or gradually decreased;

[0704] - The current density used in step a) is lower than the current density used in step b);

[0705] - Step a) is carried out at a temperature selected from 15 to 150 °C, 15 to 120 °C, and 20 to 120 °C;

[0706] - Optionally, in step a), electrochemical oxidation is first carried out, and then the reaction mixture is heated; or in which electrochemical oxidation is first carried out, and then the reaction mixture is heated to a temperature selected from 50 to 150 °C, 75 to 150 °C, 80 to 150 °C, 80 to 140 °C, and 90 to 120 °C.

[0707] - A conductive salt is used in step a) and / or b), and the conductive salt used is selected from organic ammonium salts, ionic liquids, tetraalkylammonium fluoroborates, quaternary ammonium salts, and mixtures thereof; or selected from tetraethylammonium tetrafluoroborate, tetrabutylammonium hexafluorophosphate, tetrabutylammonium hydrogen sulfate, and mixtures thereof.

[0708] - The solvent in step a) and / or b) is selected from

[0709] · Aprotic solvents, protic solvents, and mixtures thereof, or selected from polar aprotic solvents; or

[0710] · Polar aprotic solvents, which are selected from the following: dimethylformamide (DMF), dimethyl sulfoxide, acetonitrile, acetone; or

[0711] · Protic solvents, which are selected from the following: methanol, acetic acid, ethanol, formic acid, water, and mixtures thereof; or

[0712] · Dimethylformamide (DMF), methanol, acetic acid, and mixtures thereof; or

[0713] · Methanol, acetic acid, and mixtures thereof; or

[0714] · Methanol; or

[0715] · Acetic acid;

[0716] · Or a mixture of the above solvents.

[0717] - In step a), an acid is used or the acid used is selected from

[0718] · Organic acids, sulfonic acids, organic polar acids, and mixtures thereof;

[0719] · Acetic acid and formic acid, and mixtures thereof;

[0720] · Acetic acid;

[0721] · And mixtures of the above acids.

[0722] - In step a), the electrochemical oxidation is carried out at a current density selected from 1 to 5000 A / m 2 、1 to 500 A / m 2 、1 to 100 A / m 2 、1 to 50 A / m 2 、5 to 5000 A / m 2 、5 to 500 A / m 2 、5 to 100 A / m 2 、5 to 50 A / m 2 、10 to 5000 A / m 2 、10 to 500 A / m 2 、10 to 100 A / m 2 、and 10 to 50 A / m 2 ;

[0723] - In step b), the electrochemical reduction is carried out at a current density selected from 1 to 10000 A / m 2 、1 to 1000 A / m 2 、1 to 500 A / m 2 、5 to 10000 A / m 2 、50 to 1000 A / m 2 、200 to 500 A / m 2 、10 to 10000 A / m 2 、10 to 1000 A / m 2 、100 to 500 A / m 2 、200 to 400 A / m 2 、200 A / m 2 、250 A / m 2 、300 A / m 2 、350 A / m 2 、400 A / m 2 ;

[0724] - The electrochemical reduction in step b) is carried out at 1 to 50 °C, 10 to 35 °C, 15 to 30 °C or at ambient temperature.

[0725] In one embodiment,

[0726] - The current density used in step a) is reduced or gradually reduced;

[0727] - The current density used in step a) is lower than the current density used in step b);

[0728] - Step a) is carried out at a temperature selected from 15 to 150 °C, 15 to 120 °C and 20 to 120 °C;

[0729] - Optionally, electrochemical oxidation is first carried out in step a), and then the reaction mixture is heated; or electrochemical oxidation is first carried out therein, and then the reaction mixture is heated to a temperature selected from 50 to 150 °C, 75 to 150 °C, 80 to 150 °C, 80 to 140 °C and 90 to 120 °C.

[0730] - A conductive salt is used in step a) and / or b), and the conductive salt used is selected from organic ammonium salts, ionic liquids, tetraalkylammonium fluoroborates, quaternary ammonium salts and mixtures thereof; or selected from tetraethylammonium tetrafluoroborate, tetrabutylammonium hexafluorophosphate, tetrabutylammonium hydrogen sulfate and mixtures thereof.

[0731] - The solvent in step a) and / or b) is selected from

[0732] · Aprotic solvents, protic solvents and mixtures thereof, or selected from polar aprotic solvents; or

[0733] · Polar aprotic solvents, which are selected from the following: dimethylformamide (DMF), dimethyl sulfoxide, acetonitrile, acetone; or

[0734] · Protic solvents, which are selected from the following: methanol, acetic acid, ethanol, formic acid, water and mixtures thereof; or

[0735] · Dimethylformamide (DMF), methanol, acetic acid and mixtures thereof; or

[0736] · Methanol, acetic acid and mixtures thereof; or

[0737] · Methanol; or

[0738] · Acetic acid;

[0739] · Or a mixture of the above solvents.

[0740] - An acid is used in step a) or the acid used therein is selected from

[0741] · Organic acids, sulfonic acids, organic polar acids and mixtures thereof;

[0742] · Acetic acid and formic acid and mixtures thereof;

[0743] · Acetic acid;

[0744] · And mixtures of the above acids.

[0745] - In step a), the electrochemical oxidation is carried out at a cell voltage of 0.1 to 20 V or less than 20 V;

[0746] - In step a), the electrochemical oxidation is carried out at a current density selected from 1 to 5000 A / m 2 、1 to 500 A / m 2 、1 to 100 A / m 2 、1 to 50 A / m 2 、5 to 5000 A / m 2 、5 to 500 A / m 2 、5 to 100 A / m 2 、5 to 50 A / m 2 、10 to 5000 A / m 2 、10 to 500 A / m 2 、10 to 100 A / m 2 、and 10 to 50 A / m 2 ;

[0747] - In step b), the electrochemical reduction is carried out at a cell voltage of 0.1 to 30 V or less than 30 V.

[0748] - In step b), the electrochemical reduction is carried out at a current density selected from 1 to 10000 A / m 2 、1 to 1000 A / m 2 、1 to 500 A / m 2 、5 to 10000 A / m 2 、50 to 1000 A / m 2 、200 to 500 A / m 2 、10 to 10000 A / m 2 、10 to 1000 A / m 2 、100 to 500 A / m 2 、200 to 400 A / m 2 、200 A / m 2 、250 A / m 2 、300 A / m 2 、350 A / m 2 、400 A / m 2 ;

[0749] - In step b), the electrochemical reduction is carried out at 1 to 50 °C, 10 to 35 °C, 15 to 30 °C or ambient temperature.

[0750] In one embodiment of step a), the flow rate is decreased. In one embodiment of step a), the flow rate is increased. In one embodiment of step a), the flow rate is continuous. In one embodiment of step a), the flow rate is variable. In one embodiment of step a), the flow rate is from 0.01 mL / min to 10000 L / min.In one embodiment of step a), the flow rate is from 0.01 mL / min to 1000 L / min, from 0.01 mL / min to 100 L / min, from 0.1 mL / min to 1000 L / min, from 0.1 mL / min to 100 L / min, from 0.1 mL / min to 10 L / min, from 0.1 mL / min to 1000 mL / min, from 0.1 mL / min to 100 mL / min, from 0.1 mL / min to 10 mL / min, from 0.1 mL / min to 9 mL / min, from 0.1 mL / min to 8 mL / min, from 0.1 mL / min to 7 mL / min, from 0.1 mL / min to 6 mL / min, from 0.1 mL / min to 5 mL / min, from 0.1 mL / min to 4 mL / min, from 0.1 mL / min to 3 mL / min, from 0.1 mL / min to 2 mL / min, from 0.1 mL / min to 1.5 mL / min, from 0.1 mL / min to 1 mL / min, from 0.5 mL / min to 100 L / min, from 0.5 mL / min to 10 L / min, from 0.5 mL / min to 1000 mL / min, from 0.5 mL / min to 100 mL / min, from 0.5 mL / min to 10 mL / min, from 0.5 mL / min to 9 mL / min, from 0.5 mL / min to 8 mL / min, from 0.5 mL / min to 7 mL / min, from 0.5 mL / min to 6 mL / min, from 0.5 mL / min to 5 mL / min, from 0.5 mL / min to 4 mL / min, from 0.5 mL / min to 3 mL / min, from 0.5 mL / min to 2 mL / min, from 0.5 mL / min to 1.5 mL / min, from 0.7 mL / min to 100 L / min, from 0.7 mL / min to 10 L / min, from 0.7 mL / min to 1000 mL / min, from 0.7 mL / min to 100 mL / min, from 0.7 mL / min to 10 mL / min, from 0.7 mL / min to 9 mL / min, from 0.7 mL / min to 8 mL / min, from 0.7 mL / min to 7 mL / min, from 0.7 mL / min to 6 mL / min, from 0.7 mL / min to 5 mL / min, from 0.7 mL / min to 4 mL / min, from 0.7 mL / min to 3 mL / min, from 0.7 mL / min to 2 mL / min, from 0.7 mL / min to 1.5 mL / min, or 1 mL / min.

[0751] In one embodiment of step a), the concentration of the reactant is decreased, increased, continuous and / or varying. The reactant can be added in a continuous manner. In one embodiment of step a), the concentration of the conductive salt is decreased, increased, continuous and / or varying. The conductive salt can be added in a continuous manner.

[0752] In one embodiment of step b), the flow rate is decreased. In one embodiment of step b), the flow rate is increased. In one embodiment of step b), the flow rate is continuous. In one embodiment of step b), the flow rate is variable. In one embodiment of step b), the flow rate is from 0.01 mL / min to 10000 L / min, from 0.01 mL / min to 100 L / min, from 0.01 mL / min to 1000 L / min, from 0.1 mL / min to 100 L / min, from 0.1 mL / min to 10 L / min, from 0.1 mL / min to 1000 mL / min, from 0.1 mL / min to 100 mL / min, from 0.1 mL / min to 10 mL / min, from 0.1 mL / min to 9 mL / min, from 0.1 mL / min to 8 mL / min, from 0.1 mL / min to 7 mL / min, from 0.1 mL / min to 6 mL / min, from 0.1 mL / min to 5 mL / min, from 0.1 mL / min to 4 mL / min, from 0.1 mL / min to 3 mL / min, from 0.1 mL / min to 2 mL / min, from 0.1 mL / min to 1.5 mL / min, from 0.1 mL / min to 1 mL / min, from 0.5 mL / min to 100 L / min, from 0.5 mL / min to 10 L / min, from 0.5 mL / min to 1000 mL / min, from 0.5 mL / min to 100 mL / min, from 0.5 mL / min to 10 mL / min, from 0.5 mL / min to 9 mL / min, from 0.5 mL / min to 8 mL / min, from 0.5 mL / min to 7 mL / min, from 0.5 mL / min to 6 mL / min, from 0.5 mL / min to 5 mL / min, from 0.5 mL / min to 4 mL / min, from 0.5 mL / min to 3 mL / min, from 0.5 mL / min to 2 mL / min, from 0.5 mL / min to 1.5 mL / min, from 0.7 mL / min to 100 L / min, from 0.7 mL / min to 10 L / min, from 0.7 mL / min to 1000 mL / min, from 0.7 mL / min to 100 mL / min, from 0.7 mL / min to 10 mL / min, from 0.7 mL / min to 9 mL / min, from 0.7 mL / min to 8 mL / min, from 0.7 mL / min to 7 mL / min, from 0.7 mL / min to 6 mL / min, from 0.7 mL / min to 5 mL / min, from 0.7 mL / min to 4 mL / min, from 0.7 mL / min to 3 mL / min, from 0.7 mL / min to 2 mL / min, from 0.7 mL / min to 1.5 mL / min, or 1 mL / min.

[0753] In one embodiment of step b), the concentration of the reactant is decreased, increased, continuous, and / or variable. The reactant can be added in a continuous manner. In one embodiment of step b), the concentration of the conductive salt is decreased, increased, continuous, and / or variable. The conductive salt can be added in a continuous manner.

[0754] The number of cycles of each of steps a), b), c), and / or d) can be adjusted individually. One or more of the steps can be performed multiple times, while one or more of the steps are performed less frequently or even only once. In one embodiment, step a) is performed multiple times. In one embodiment, step b) is performed multiple times. In one embodiment, step c) is performed multiple times. In one embodiment, step d) is performed multiple times.

[0755] In one embodiment of step a), the pressure used is from 0.1 to 10 bar. In this embodiment, the pressure used can be decreased, increased, constant, or variable. In one embodiment of step a), the pressure used is from 0.1 to 9 bar, from 0.1 to 8 bar, from 0.1 to 7 bar, from 0.1 to 6 bar, from 0.1 to 5 bar, from 0.1 to 4 bar, from 0.1 to 2 bar, from 0.1 to 1 bar, from 0.5 to 9 bar, from 0.5 to 8 bar, from 0.5 to 7 bar, from 0.5 to 6 bar, from 0.5 to 5 bar, from 0.5 to 4 bar, from 0.5 to 2 bar, from 0.5 to 1 bar, from 0.75 to 9 bar, from 0.75 to 8 bar, from 0.75 to 7 bar, from 0.75 to 6 bar, from 0.75 to 5 bar, from 0.75 to 4 bar, from 0.75 to 2 bar, from 0.75 to 1 bar, from 1 to 9 bar, from 1 to 8 bar, from 1 to 7 bar, from 1 to 6 bar, from 1 to 5 bar, from 1 to 4 bar, from 1 to 2 bar, 1 bar, from atmospheric pressure to 9 bar, from atmospheric pressure to 8 bar, from atmospheric pressure to 7 bar, from atmospheric pressure to 6 bar, from atmospheric pressure to 5 bar, from atmospheric pressure to 4 bar, from atmospheric pressure to 2 bar, or atmospheric pressure. In this embodiment, the pressure can be decreased, increased, constant, or variable. Atmospheric pressure is 1.01325 bar. As is known to those skilled in the art, the pressure can vary.

[0756] In one embodiment of step b), the pressure used is from 0.1 to 10 bar. In this embodiment, the pressure used can be reduced, increased, constant or variable. In one embodiment of step b), the pressure used is from 0.1 to 9 bar, from 0.1 to 8 bar, from 0.1 to 7 bar, from 0.1 to 6 bar, from 0.1 to 5 bar, from 0.1 to 4 bar, from 0.1 to 2 bar, from 0.1 to 1 bar, from 0.5 to 9 bar, from 0.5 to 8 bar, from 0.5 to 7 bar, from 0.5 to 6 bar, from 0.5 to 5 bar, from 0.5 to 4 bar, from 0.5 to 2 bar, from 0.5 to 1 bar, from 0.75 to 9 bar, from 0.75 to 8 bar, from 0.75 to 7 bar, from 0.75 to 6 bar, from 0.75 to 5 bar, from 0.75 to 4 bar, from 0.75 to 2 bar, from 0.75 to 1 bar, from 1 to 9 bar, from 1 to 8 bar, from 1 to 7 bar, from 1 to 6 bar, from 1 to 5 bar, from 1 to 4 bar, from 1 to 2 bar, 1 bar, from atmospheric pressure to 9 bar, from atmospheric pressure to 8 bar, from atmospheric pressure to 7 bar, from atmospheric pressure to 6 bar, from atmospheric pressure to 5 bar, from atmospheric pressure to 4 bar, from atmospheric pressure to 2 bar, or atmospheric pressure. In this embodiment, the pressure can be reduced, increased, constant or variable.

[0757] Using a pressure above 1 bar or atmospheric pressure in step a) and / or b) can result in better solubility of the starting materials, solvents, conductive salts, acids, intermediates and / or the products obtained.

[0758] Other aspects

[0759] Another aspect of the present invention is a process for synthesizing the compound of formula (I) (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide.

[0760]

[0761] This synthesis comprises the following steps:

[0762] Step (1) Sequential one-pot synthesis for the preparation of 4-(4-cyano-2-methoxy-phenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (XIII)

[0763]

[0764] This synthesis comprises steps a) and b):

[0765] Step a) Synthesis of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,6-naphthyridine-3-carboxamide of formula (XVII)

[0766]

[0767] by electrochemical oxidation of (4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula ent-(I)

[0768]

[0769] Step b) Synthesis of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (XIII)

[0770]

[0771] by electrochemical reduction of the compound of formula (XVII); and

[0772] Step (2) Separation of the compound of formula (I) from the compound of formula (XIII).

[0773] Embodiments of step a) have been described above. These embodiments can be used in step (1). Embodiments of step b) have been described above. These embodiments can be used in step (1).

[0774] In one embodiment of step (1), the synthesis further comprises step c) separation of the compound of formula (XIII). Embodiments of step c) have been described above. These embodiments can be used in step (1).

[0775] In one embodiment of step (1), the synthesis further comprises step d) crystallization of the compound of formula (XIII). Embodiments of step d) have been described above. These embodiments can be used in step (1).

[0776] In step (2), the compound of formula (I) is separated from the compound of formula (XIII). In one embodiment of step (2), the separation is selected from filtration, chiral chromatography, crystallization, racemic resolution, diastereomeric salt formation, and chiral salt formation. For example, separation by formation of diastereomeric salts is described in US20100136142 A1, US20170217957 A1, or WO2019206909 A1.

[0777] On the other hand, the sequential one-pot synthesis described in this application can be carried out continuously multiple times.

[0778] In one embodiment, the sequential one-pot synthesis is carried out multiple times continuously. In one embodiment, the sequential one-pot synthesis is carried out twice continuously. In one embodiment, the sequential one-pot synthesis is carried out at least twice continuously. In one embodiment, the sequential one-pot synthesis is carried out at least three times continuously. See Scheme 5.

[0779] Scheme 5

[0780]

[0781] This provides the possibility of converting the compound ent-(I) into the compound (XIII). This can be regarded as a quasi-continuous operation mode, which has great advantages in terms of cost, time and / or resources. In this way, the waste product ent-(I) that repeatedly appears in the preparation of finerenone (I) can be converted back into the compound (XIII). The compound (XIII) can then be sent back to the production process of finerenone (I). After several process cycles of the sequential one-pot synthesis method, the compound ent-(I) can thus be almost completely utilized. In the best case, the by-product ent-(I) can be almost completely recovered as the desired product (XIII) or finerenone (I).

[0782] In one embodiment, the method for preparing the compound (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (I) operates in a continuous mode, wherein

[0783] - starting materials, solvents, conductive salts, acids and / or intermediates are added continuously and

[0784] - the compound of formula (I) is removed continuously.

[0785] In one embodiment, in step (1) and / or (2), the (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (I) is obtained in an amount of 0.01 to 100 mmol / mL, 0.1 to 50 mmol / L, 0.1 to 20 mmol / L or 0.1 to 10 mmol / L, based on the total volume of the reaction mixture. BRIEF DESCRIPTION OF THE DRAWINGS

[0786] Figure 1 and Figure 2 schematically shows the setup of the electrolysis device.

[0787] Figure 1: Shows the setup of the electrolysis device. The setup includes an electrolytic cell (1), a power supply (2), an electrolyte tank (3), and an anolyte tank (4). The arrows indicate the flow direction of the electrolyte and / or anolyte.

[0788] Figure 2 : Shows the setup of the electrolysis device. The setup includes an electrolytic cell (1), a power supply (2), an electrolyte tank (3), an anolyte tank (4), and a pump (5). Optionally, it may include one or more separators (6) and / or one or more heat exchangers (7). The arrows indicate the flow direction of the electrolyte and / or anolyte.

[0789] In Figure 1 and Figure 2 , other devices can be integrated and / or adapted. For example, the electrolysis device can be adjusted in terms of electrode geometry, flow rate, residence time, segmentation, etc. These aspects are as described above. Other devices can also be further added: more pumps can be added, the setup can be segmented, more pumps and / or tanks to provide, for example, other starting materials, solvents, conductive salts, acids, and / or intermediates for the process, other devices to remove or add impurities, by-products, starting materials, other reagents, solvents, intermediates, and / or products, or to add other starting materials, solvents, conductive salts, acids, and / or intermediates and / or products.

[0790] Embodiment section

[0791] A. Abbreviations and Acronyms

[0792]

[0793]

[0794] Table 2 below gives the structures of the compounds found in HPLC. The HPLC retention time assignments are as follows

[0795] Table 2

[0796]

[0797]

[0798]

[0799] B. Analysis method

[0800] An analytical method for detecting organic impurities, content (assay), and enantiomeric purity at the levels of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (XIII) (crude and pure), (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (I) (crude and pure), and (4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (ent-(I)).

[0801] Method A (detection of and organic impurities)

[0802]

[0803]

[0804]

[0805] The "major compound" is the compound of formula (XIII), in particular a mixture of its enantiomers of formula (I) and / or ent-(I).

[0806] Method B (detection of and organic impurities)

[0807]

[0808]

[0809]

[0810] The "major compound" is the compound of formula (XIII), in particular a mixture of its enantiomers of formula (I) and / or ent-(I).

[0811] The HPLC analysis data on the purity and content of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (XIII) (crude and pure), (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (I) (crude and pure), and (4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (ent-(I)) given in the following examples only relate to the impurities with a content exceeding 0.05% in the product. This is basically impurity D. The contents of all other impurities listed in the above table are generally less than 0.05%. The structures of such impurities were determined by separation from the enriched mother liquor and structure analysis.

[0812] Method C (enantiomeric purity, enantiomeric excess e.e.%)

[0813]

[0814]

[0815] C. Preparation examples

[0816] C.1 4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3- Preparation of formamide (XIII)

[0817]

[0818] Here, the sequential one-pot synthesis starts with ent-(I)

[0819]

[0820] The included steps a) and b) are as described above.

[0821] C.1.1 Example 1 (XIII), Example 2 (XIII) and Example 3 (XIII)

[0822] In the catholyte cell (stirred tank), at room temperature, (4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (ent-(I)) is dissolved in a mixture containing DMF, methanol, tetraethylammonium tetrafluoroborate, and acetic acid. To electrochemically oxidize (4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (ent-(I)) to 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,6-naphthyridine-3-carboxamide (XVII), the mixture is respectively at 1.8 m3 Flow rate of / h (Examples 1 and 2) or 4.5 m 3 / h (Example 3) is pumped out from the catholyte tank and flows through an electrochemical cell (product of Electrocell Company) equipped with an anode and a cathode, and the electrode areas are 0.4 m 2 (Examples 1 and 2) or 1.2 m 2 (Example 3).

[0823] The amounts of each component used in Examples 1 to 3 are summarized in Table 3 below:

[0824] Table 3: Composition of the electrolyte solution (electrochemical oxidation)

[0825]

[0826] The liquid flow is distributed approximately equally to the anolyte half-cell and the catholyte half-cell. After leaving the cell, the anolyte and catholyte volume flows are recombined and transferred back to the catholyte tank. During pumping, voltage and current are supplied to the cell through a rectifier to initiate electrolysis. To achieve high chemical selectivity and simultaneously high current selectivity, the current density gradually decreases with the increase in conversion. The current densities used in Examples 1 to 3 are summarized in Table 4 below:

[0827] Table 4: Current density (gradually decreasing with the increase in conversion) (electrochemical oxidation)

[0828]

[0829] Subsequently, the reaction solution is heated to about 100 °C in the catholyte tank and stirred at this temperature for 16 hours under a reflux condenser.

[0830] The sequential one-pot synthesis is continued by electrochemically reducing 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,6-naphthyridine-3-carboxamide (XVII) to 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (XIII). The second tank (anolyte tank (stirred tank)) is connected to the electrochemical cell and contains a mixture of DMF, tetraethylammonium tetrafluoroborate, acetic acid, and methanol.

[0831] The amounts of each component used in Examples 1 to 3 are summarized in Table 5 below:

[0832] Table 5: Composition of the anolyte (electrochemical reduction)

[0833] Example 1 Example 2 Example 3 DMF 93.0 kg 94.4 kg 200.1 kg Tetraethylammonium tetrafluoroborate 1.43 kg 1.25 kg 2.50 kg Acetic acid 2.32 kg 2.05 kg 3.80 kg Methanol 23.2 kg 16.6 kg 22.2 kg

[0834] The anolyte is at a flow rate of 0.9 m3 The flow rate of / h is pumped out from the tank and flows through the anolyte half-cell of a divided electrochemical cell (product of Electrocell), and the anode and cathode areas of the electrochemical cell are 0.4 m 2 (Examples 1 and 2) or 1.2 m 2 (Example 3). Meanwhile, the solution obtained by electrochemical oxidation is pumped out from the cathode tank at the same volume flow rate (0.9 m 3 / h) and passes through the catholyte half-cell of the electrochemical cell. After leaving the cell, the anolyte and catholyte volume flows return to their outlet tanks independently. During the pumping process, voltage and current are supplied to the cell through a rectifier to initiate electrolysis. The constant current density used is 350 A / m 2 , and the electrolysis is terminated after 20 hours (Example 1), 6 hours (Example 2) or 7 hours (Example 3).

[0835] C.2 Separation and purification of Examples 1 to 3 (XIII) [crude product]

[0836] In this section, the separation of the compound of formula (XIII)

[0837]

[0838] has been described (see step c)).

[0839] C.2.1 Separation and purification of Examples 1 to 3 (XIII) [crude product]

[0840] After the electrolysis is completed, the total amount obtained from the cathode cycles of Example 1, Example 2 and Example 3, including the volume obtained from the catholyte tank, is further processed to obtain 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (XIII) as a separated solid as follows:

[0841] The product solution of electrochemical reduction is concentrated by vacuum distillation at a temperature of 60 °C or 70 °C. After the vacuum distillation is completed, (purified) water is added to the solution, and crystallization is induced at 60 °C for 3 to 4 hours. Subsequently, the suspension is cooled to room temperature and stirred for another 2 hours, and the product is filtered and washed with water. The obtained product is dried in a drying cabinet (under vacuum) at 55 °C.

[0842] The obtained yields are summarized in Table 6 below:

[0843] Table 6: Yield profile of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (XIII) (Examples 1, 2 and 3, crude product)

[0844] Example 1 Example 2 Example 3 % of theoretical yield 81.5％ 75.3％ 80.8％ Purity Greater than 99% 99.9％ 99.8％ Method B B B

[0845] C.2.2 Example 1 (XIII) (pure product)

[0846] One embodiment of step d) in this section is as follows:

[0847] At room temperature, approximately 1000 g of the crude product of Example 1 was suspended in a 1:1 (v / v) mixture of isopropanol and n-propanol (approximately 6 wt% of compound (XIII) [crude product, Example 1]). First, the solid was completely dissolved by heating to above 85 °C (gentle reflux), and then the solution was cooled to 5 °C over 3 hours with continuous stirring overnight. During the cooling process, the pure form of compound (XIII) began to crystallize. The solid was filtered (using a centrifuge), the reactor was rinsed with 2 L of isopropanol at 5 °C, and the wet filter cake thus obtained was washed with pre-cooled (5 °C) isopropanol (2 L). After drying in a drying cabinet at 55 °C (under vacuum), more than 890 g of pure compound (XIII) was obtained:

[0848] Yield: 89% (of the theoretical yield)

[0849] Analysis results:

[0850] Compound (XIII) assay % (HPLC - Method A): 100.3%

[0851] Area % of main compound [compound (XIII)] (HPLC - Method A): 99.87%

[0852] Enantiomeric ratio analysis gave an expected value of the racemate of ~50:50 (49.6:50.4), corresponding to e.e. %: 0.8% (HPLC - Method C)

[0853] C.3 Preparation of Example 4-(4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro- 1,6-naphthyridine-3-formamide (I)

[0854] This example describes finerenone (I)

[0855]

[0856] and how it was obtained from the recovered 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (XIII).

[0857] The 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (XIII) obtained by the above method was separated into enantiomers (ent-(I) and (I)) by SMB or diastereomeric salt resolution method (see Section C.3.1, (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide-dibenzoyl-tartrate (II)), for example, as described in US20100136142 A1, US20170217957 A1 or WO 2019206909A1.

[0858] The (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (I) obtained after separation was then purified by crystallization from ethanol (with 2% toluene) to obtain (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (I) with excellent purity.

[0859] C.3.1 (4S)-4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naph tidine-3-formamide - dibenzoyl - tartrate (II)

[0860]

[0861] 1.095 kg (2.90 mol) of the racemic mixture 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (XIII) was dissolved at room temperature (about 23 °C) in 13.826 kg of a mixture consisting of ethanol (with 2% toluene) / water = 75:25 (v / v) [9.719 kg / 4.107 kg]. To this solution was added 0.570 kg (1.59 mol) of (+)-O,O-dibenzoyl-D-tartaric acid, and then the equipment was rinsed with about 3 kg of a solvent mixture consisting of ethanol (with 2% toluene) / water = 75:25 (v / v). The suspension obtained in this way was heated to an internal temperature of 75 °C within 60 minutes and stirred at this temperature for 3.0 hours. Then the mixture was cooled to 23 °C over 5.0 hours using a cooling ramp and stirred at this temperature overnight (about 16 hours). The suspension was filtered and washed once with 1.681 kg of a mixture consisting of ethanol (denatured with 2% toluene) / water = 75:25 (v / v), and pressed dry for about 45 minutes.

[0862] Wet cake yield: 1.66 kg. The wet product was then dried under reduced pressure (<100 mbar) at 50 °C to a constant mass (reached after 17 hours).

[0863] (4S)-4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide dibenzoyl-tartrate (II) yield: 1.106 kg (103.7% of the theoretical yield), white powder.

[0864] Mother liquor: The mother liquor of 14.98 kg contains at most 0.548 kg (1.45 mol) of the theoretical amount of (4R)-4-(4-cyano-2-methoxy-phenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (ent-(I)), which can be further recovered.

[0865] C.3.2 (4S)-4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naph tidine-3-formamide (I) [Crude product]

[0866] Suspend 1.104 kg of (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide dibenzoyl-tartrate (II) (from Section C.3.1) in a mixture of ethanol (denatured with 2% toluene) (1.766 kg) and water (8.722 kg) at room temperature (about 23 °C). Raise the internal temperature to 50 °C within 1 hour, then add 4.416 kg of a 9.1% (by weight) aqueous sodium phosphate tribasic solution (pH increases from pH 5.4 to 7.2) within 30 minutes. Stir for another 3.0 hours at this temperature (pH = 7.5). Then cool the mixture to 23 °C within 2 hours and stir overnight (about 14 hours) at this temperature. After filtering the white suspension, wash it once with a solvent mixture of 0.186 kg of ethanol (denatured with 2% toluene) and 0.883 kg of deionized water, and then wash it twice with 0.883 kg of deionized water. Wet cake weight: 0.840 kg. The wet product is resuspended at 23 °C in a mixture of 3.842 kg of ethanol (denatured with 2% toluene) and 1.280 kg of deionized water. Heat the suspension rampwise to 70 °C within 2 hours, and stir the resulting solution at 70 °C for 15 minutes. Adjust the pH to pH 8.5 to 9.0 (final pH = 8.75) with a 0.15% (by weight) aqueous sodium phosphate tribasic solution. Then add 11.04 kg of deionized water within 30 - 60 minutes at 70 °C. Cool the white and easily stirrable suspension rampwise to 23 °C within 3 hours and stir for at least 1 hour. After stirring overnight at 23 °C, filter the suspension, wash it with 1.987 kg of deionized water, and press it dry for about 30 minutes. Wet cake weight: 0.571 kg. Then dry the wet product under reduced pressure (<100 mbar) at 50 °C to a constant mass (reached after 17 hours).

[0867] Yield: 0.504 kg (88.9% of the theoretical yield) of white crystalline powder.

[0868] Analysis results:

[0869] Double determination: % of detection of (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (I), crude product (HPLC - method B): 99.88% and 100.69%

[0870] Area % of the main compound [compound (XIII)] (HPLC - method B): 99.79%

[0871] Enantiomeric excess e.e. %: 99.76% (HPLC - method C)

[0872] C.3.3 (4S)-4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naph tidine-3-formamide (I) [Pure product]

[0873] 500 g of the crude product of (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (I) (obtained in section C.3.2) was suspended in 8.5 L of ethanol (denatured with 2% toluene), and then the mixture was heated to reflux (78 °C). The product became a solution. It was stirred at this temperature for 45 minutes. The solution was filtered through a heated pressure filter, and then the pressure filter was rinsed with 0.5 L of ethanol (denatured with 2% toluene). Then the solvent was distilled off until the final volume reached 2.5 L. Then the internal temperature was cooled to 0 °C (ramp: duration approximately 4 hours), and stirring was continued at 0 °C for at least 1 hour (stirring over the weekend, but not necessary). The product was filtered out and then washed twice with 0.5 L of ethanol (2% toluene denatured). Wet cake yield: 0.50 kg. Then the wet product was dried under reduced pressure (<100 mbar) at 50 °C to a constant mass (reached after 17 hours).

[0874] Analysis results:

[0875] Yield: 0.440 kg (88.0% of the theoretical yield) of white crystalline powder

[0876] Identification: By 1 1H-NMR for structural verification, consistent with the published data.

[0877] % of detection of (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (I) (HPLC - method A): 99.91%

[0878] Area % of main compound [compound (XIII)] (HPLC - method A): 100.0%

[0879] Enantiomeric excess e.e. %: 100.0% (HPLC - method C)

[0880] Residual solvent ethanol: 0.05453 wt%

[0881] C.4 Example 5 (XIII)

[0882] In this example, compound ent-(I) (section C.3, C3.1) was recovered from the mother liquor and the wash liquor. A sequential one - pot synthesis starting from ent-(I) was described, which included steps a), b) (section C.1) and step c) (section C.2).

[0883] C.4.1 Recovery of (4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6- naphthyridine-3-formamide (ent-(I)) (from mother liquor and washings)

[0884]

[0885] (4R)-4-(4 - Cyano - 2 - methoxyphenyl)-5 - ethoxy - 2,8 - dimethyl - 1,4 - dihydro - 1,6 - naphthyridine - 3 - carboxamide (ent-(I)) was obtained from the mother liquor of section C3.1, which contained 14.98 kg (16.8 L) of the mother liquor and the wash liquor (corresponding to 0.548 kg of (4R)-4-(4 - cyano - 2 - methoxyphenyl)-5 - ethoxy - 2,8 - dimethyl - 1,4 - dihydro - 1,6 - naphthyridine - 3 - carboxamide (ent-(I))). The pH of the solution was adjusted to 7.0 - 7.5 with an aqueous Na3PO4 solution. Then the mixture was concentrated in vacuo (40 - 85 mbar) to a remaining volume of about 4.2 L (about 12.6 L of distillate) to obtain a white suspension that was easy to stir. At about 23 + / - 3 °C, 8.4 L of deionized water was added within 15 minutes. After stirring for at least 2 hours (stirring overnight due to scheduling reasons), the mixture was filtered through a frit, the container was rinsed with the mother liquor, and the resulting filter cake was washed with 2.3 kg of deionized water and then pressed dry. Wet cake yield: 1.07 kg. Then the wet product was dried under reduced pressure (< 100 mbar) at 50 °C to a constant mass (reached after 17 hours).

[0886] Yield: 0.507 kg (92.5% of the theoretical yield) of white crystalline powder.

[0887] Analysis results:

[0888] Determination of %(4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydronaphthyridine-3-carboxamide (ent-(I)) (HPLC - Method B): 100.1%

[0889] Area % of main compound [compound (XIII)] (HPLC - Method B): 99.66%

[0890] Enantiomeric excess e.e. %: 97.88% (HPLC - Method C)

[0891] C.4.2 Example 5 (XIII) [crude product]

[0892] (4R)-4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydronaphthyridine-3-carboxamide (ent-(I)) obtained by the above method was converted back to racemic 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydronaphthyridine-3-carboxamide (XIII), which was finally crystallized as a solid. The sequential one-pot synthesis was carried out on a laboratory scale (starting material: 50.4 g of (4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydronaphthyridine-3-carboxamide (ent-(I))), and a total of 149.0 g of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydronaphthyridine-3-carboxamide (XIII) was obtained in 4 batches. The following is a detailed description using the laboratory method as an example:

[0893] 50.4 g (0.133 mol) of (4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydronaphthyridine-3-carboxamide (ent-(I)) was dissolved at room temperature in a mixture containing 542.2 g of DMF, 135.6 g of methanol, 8.3 g of tetraethylammonium tetrafluoroborate, and 13.6 g of acetic acid. To electrochemically oxidize (4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydronaphthyridine-3-carboxamide (ent-(I)) to compound (XVII), the mixture was pumped out of a container (5 L) at a total flow rate of 50 kg / h and passed through an electrochemical laboratory cell (multi-purpose cell, MPC) of Electrocell Corporation, the anode and cathode areas of which were 100 cm 2The liquid flow is distributed approximately equally to the anolyte half-cell and the catholyte half-cell. After leaving the cell, the anolyte and catholyte volume flows are combined and transferred back to the said container (circulated in this way). During pumping, voltage and current are supplied to the cell by a rectifier to initiate electrolysis. To achieve high chemical selectivity and, simultaneously, high current selectivity, the current density is gradually decreased as the conversion increases.

[0894] 340 min at 0.5 A (50 A / m 2 )

[0895] 210 min at 0.4 A (40 A / m 2 )

[0896] 210 min at 0.3 A (30 A / m 2 )

[0897] 210 min at 0.2 A (20 A / m 2 )

[0898] 510 min at 0.1 A (10 A / m 2 )

[0899] The total amount of electricity passed (6.833 Ah) is approximately equivalent to 95.6% (7.147 Ah) of the theoretical amount of electricity required to reach 100% conversion. Subsequently, the reaction solution was heated to about 100 °C in a 2 L multi-necked flask and stirred at this temperature under a reflux condenser for a total of 16 h (2×8 h). For the subsequent electrochemical reduction of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (XIII), another container (anolyte storage tank, 5 L) was used, which contained a solution of 2236.9 g of DMF, 33.6 g of tetraethylammonium tetrafluoroborate, 55.9 g of acetic acid and 559.2 g of methanol. The solution prepared in this way was pumped out of the container at a volumetric flow rate of 25 kg / h and passed through the anolyte half-cell of a divided electrochemical laboratory cell (multi-purpose cell, MPC) from Electrocell, the anode and cathode areas of the laboratory cell being 100 cm 2 . At the same time, the solution obtained from step 2 was pumped out of the catholyte storage tank (5 L bottle) at the same delivery rate (25 kg / h) and passed through the catholyte half-cell of the electrochemical cell. After leaving the cell, the anolyte and catholyte volume flows were returned independently to their starting containers (two circuits: anolyte and catholyte circuits). During pumping, voltage and current were supplied to the cell by a rectifier to initiate electrolysis. In this part of the step, a constant current density of 350 A / m 2, the electrolysis was terminated after 20 hours. The total amount obtained from the catholyte circulation after the electrolysis was used for the separation of the final product: For the crystallization of crude 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (XIII), the electrochemically reduced product solution was concentrated by vacuum distillation at a temperature up to 70 °C (the concentration of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (XIII) was increased to 10 - 14 wt%, and the product was still dissolved at a reactor temperature of 60 °C). After the vacuum was ended, (purified) water was added to the solution, and crystallization was induced at 60 °C over 4 hours. After all the water was added (about 4:1 v / v water: concentrate), the suspension was cooled to room temperature and stirred for another 2 hours. The product was filtered and washed with water. It was dried in a drying cabinet (under vacuum) at 55 °C to obtain 39.2 g of crude 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (XIII).

[0900] Yield: 39.2 g (77.8% of the theoretical yield), off-white crystalline powder.

[0901] Analysis results:

[0902] Assay % (4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (XIII) (HPLC - Method B): 98.1%

[0903] Area % of main compound [compound (XIII)] (HPLC - Method B): 98.77%

[0904] Enantiomeric excess e.e. %: 0.88% (HPLC - Method C)

[0905] C.4.3 Example 4 (XIII) [pure product]

[0906] 70 g of the racemate obtained by this method (crude 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (XIII)) was suspended in a 1:1 w / w mixture of isopropanol and n-propanol (591.1 g each) in a 2 L vessel at room temperature. The solid was completely dissolved by heating to over 85 °C (gentle reflux), and then (4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (XIII) was recrystallized by cooling the solution to 5 °C (over 3 h). Stirring was carried out overnight. The solid was filtered and the resulting wet filter cake was washed with pre-cooled (5 °C) isopropanol (2 × 110 g). Drying was carried out in a drying cabinet at 50 °C (under vacuum).

[0907] Yield: 58.1 g (83% of the theoretical yield) of (4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (XIII) in the form of a white crystalline powder was obtained.

[0908] Analysis results:

[0909] Assay % (4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (XIII) (HPLC - Method B): 98.0%

[0910] Area % of main compound [Compound (XIII)] (HPLC - Method B): 99.31%

[0911] Enantiomeric excess e.e. %: 1.04% (HPLC - Method C)

[0912] D. Summary of conclusions

[0913] In Section C.1 a method for the synthesis of compound (XIII) by sequential one - pot method (steps a) and b)) is described. Section C.2.1 (Step c)) and C.2.2( Step d)) respectively describe the further purification of compound (XIII).

[0914] It can be seen from the experiments that by sequential one - pot synthesis, compound (XIII) can be produced in a very efficient manner, with high yield, on a large scale and with high purity. Sequential one - pot synthesis has significant advantages over the prior art in terms of scalability and technical implementation. The overall yield is significantly higher than the previously described synthesis, as shown in Table 7 below.

[0915] Table 7 Yields of US 15 / 753,406 A1 (US’406) and Sequential One-Pot Synthesis

[0916]

[0917] As is clearly shown in Table 7 above, the described sequential one-pot synthesis shows significantly higher overall yields (Example 1: 81.5%; Example 2: 75.3%; Example 3: 80.8%) than the synthesis method described in US 15 / 753,406 A1 (64%). This is also surprising because the sequential one-pot synthesis is a large-scale process. Those skilled in the art could not have foreseen this technical effect.

[0918] In Section C.3 it is described how to obtain finerenone (I) from the recovered 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (XIII). The recovery of compound ent-(I) from the mother liquor and washings (Sections C.3, C.3.1) and the sequential one-pot synthesis method starting from ent-(I), including steps a), b) (Section C.1) and step c) (Section C.2), are described in Section C.4.

[0919] It has now been demonstrated that the sequential one-pot synthesis can be carried out continuously multiple times, thus providing the possibility of converting compound ent-(I) into compound (XIII). This can be regarded as a quasi-continuous operating mode, which has great advantages in terms of cost, time, and / or resources. In this way, the waste product ent-(I) that repeatedly appears during the preparation of finerenone (I) can be re-converted into compound (XIII). Then, compound (XIII) can be re-introduced into the production process of finerenone (I). Therefore, after several cycles of the sequential one-pot synthesis method, compound ent-(I) can be almost completely utilized. In the best case, the by-product ent-(I) can be almost completely recovered as the desired product (XIII) or finerenone (I). See Scheme 4 above. In addition, finerenone (I) of high purity can be obtained.

Claims

1. A sequential one-pot synthesis method for synthesizing 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (XIII) The synthesis comprises the following steps: Step a) Synthesizing 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,6-naphthyridine-3-carboxamide of formula (XVII) By electrochemically oxidizing (4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula ent-(I) Step b) Synthesizing 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (XIII) By electrochemically reducing the compound of formula (XVII), Among them, In step a), the current density used is reduced or gradually reduced.

2. The sequential one-pot synthesis method according to claim 1, wherein the current density used for oxidation in step a) is lower than the current density used in step b).

3. The sequential one-pot synthesis method according to claim 1 or 2, wherein - Step a) is carried out at a temperature selected from 15 to 150 °C, 15 to 120 °C and 20 to 120 °C; and / or - In step a), electrochemical oxidation is first carried out, and then the reaction mixture is heated; and / or - In step a), electrochemical oxidation is first carried out, and then the reaction mixture is heated to a temperature selected from 50 to 150 °C, 75 to 150 °C, 80 to 150 °C, 80 to 140 °C and 90 to 120 °C.

4. The sequential one-pot synthesis method according to any one of claims 1 to 3, wherein a conductive salt is used in step a) and / or b), and the conductive salt is selected from organic ammonium salts, ionic liquids, tetraalkylammonium fluoroborates, quaternary ammonium salts and mixtures thereof; or selected from tetraethylammonium tetrafluoroborate, tetrabutylammonium hexafluorophosphate, tetrabutylammonium hydrogen sulfate and mixtures thereof.

5. The sequential one-pot synthesis method according to any one of claims 1 to 4, wherein - In step a), based on 1 equivalent of the compound of formula ent-(I), 0.05 to 1 equivalent of the conductive salt is used; or - In step b), based on 1 equivalent of the compound of formula (XIII), 0.05 to 3 equivalents of the conductive salt is used.

6. The sequential one-pot synthesis method according to any one of claims 1 to 5, wherein the solvent in step a) and / or b) is selected from - aprotic solvents, protic solvents and mixtures thereof, or selected from polar aprotic solvents; or - polar aprotic solvents, which are selected from the following: dimethylformamide (DMF), dimethyl sulfoxide, acetonitrile, acetone; or - protic solvents, which are selected from the following: methanol, acetic acid, ethanol, formic acid, water and mixtures thereof; or - dimethylformamide (DMF), methanol, acetic acid and mixtures thereof; or - methanol, acetic acid and mixtures thereof; or - methanol; or - acetic acid; - or mixtures of the above solvents.

7. The sequential one-pot synthesis method according to any one of claims 1 to 6, wherein in step a), an acid is used or the acid used is selected from - organic acids, sulfonic acids, organic polar acids, and mixtures thereof; - acetic acid and formic acid and mixtures thereof; - acetic acid; and mixtures of the above acids.

8. The sequential one-pot synthesis method according to any one of claims 1 to 7, wherein in step a) - Use 0.1 to 10 equivalents of acid; or - 0.1 to 5 equivalents of an acid are used; or - 1.5 to 2 equivalents of an acid are used; or - 1.7 equivalents of an acid are used, based on 1 equivalent of the compound of formula (XIII).

9. The sequential one-pot synthesis method according to any one of claims 1 to 8, wherein in step a) - the electrochemical oxidation is carried out at a cell voltage of 0.1 to 50 V or less than 50 V; and / or - the electrochemical oxidation is carried out at a cell voltage of 0.1 to 20 V or less than 20 V; and / or - The electrochemical oxidation is carried out at a current density selected from 1 to 30000 A / m 2 , 1 to 20000 A / m 2 , 1 to 10000 A / m 2 and 1 to 500 A / m 2 ; and / or - Electrochemical oxidation is carried out at a current density selected from 1 to 5000 A / m 2 、1 to 500 A / m 2 、1 to 100 A / m 2 、1 to 50 A / m 2 、5 to 5000 A / m 2 、5 to 500 A / m 2 、5 to 100 A / m 2 、5 to 50 A / m 2 、10 to 5000 A / m 2 、10 to 500 A / m 2 、10 to 100 A / m 2 、and 10 to 50 A / m 2 and is carried out at a current density of 10 to 50 A / m 10. The sequential one-pot synthesis method according to any one of claims 1 to 9, wherein in step b) - the electrochemical reduction is carried out at a cell voltage of 0.1 to 60 V or less than 60 V; and / or - the electrochemical reduction is carried out at a cell voltage of 0.1 to 30 V or less than 30 V; and / or - The electrochemical reduction is carried out at a current density selected from 1 to 30000 A / m 2 、1 to 25000 A / m 2 、1 to 20000 A / m 2 、1 to 15000 A / m 2 、1 to 10000 A / m 2 and 1 to 5000 A / m 2 ; and / or - The electrochemical reduction is carried out at a current density selected from 1 to 10000 A / m 2 、1 to 1000 A / m 2 、1 to 500 A / m 2 、5 to 10000 A / m 2 、50 to 1000 A / m 2 、200 to 500 A / m 2 、10 to 10000 A / m 2 、10 to 1000 A / m 2 、10 to 500 A / m 2 、100 to 500 A / m 2 、200 to 400 A / m 2 、200 A / m 2 、250 A / m 2 、300 A / m 2 、350 A / m 2 and 400 A / m 2 ; and / or - the electrochemical reduction is carried out at 1 to 100 °C, 1 to 50 °C, 10 to 35 °C, 15 to 30 °C, or at ambient temperature; and / or - the electrochemical reduction is carried out at 1 to 50 °C, 10 to 35 °C, 15 to 30 °C, or at ambient temperature.

11. The sequential one-pot synthesis method according to any one of claims 1 to 10, wherein the pressure used in step a) and / or b) is about 0.5 to 10 bar, wherein optionally the pressure used in step a) and / or b) is reduced, increased, constant, or variable, 12. The sequential one-pot synthesis method according to any one of claims 1 to 11, wherein in step a) and / or b) - the flow rate is reduced, increased, constant, or variable; and / or - the flow rate is 0.01 mL / min to 10000 L / min; and / or - the pressure used is 0.1 to 10 bar.

13. A method for synthesizing (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (I). The synthesis comprises the following steps: Step (1) The sequential one-pot synthesis for synthesizing 4-(4-cyano-2-methoxy-phenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (XIII) The synthesis comprises steps a) and b): Step a) Synthesizing 4-(4-cyano-2-methoxy-phenyl)-5-ethoxy-2,8-dimethyl-1,6-naphthyridine-3-carboxamide of formula (XVII) by electrochemical oxidation of (4R)-4-(4-cyano-2-methoxy-phenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula ent-(I) Step b) Synthesis of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (XIII) is carried out by electrochemical reduction of a compound of formula (XVII); and Step (2) isolating the compound of formula (I) from the compound of formula (XIII), Among them, Step (1) optionally has the features described in any one of claims 1 to 13.

14. The method according to claim 13, wherein the enantiomeric excess (e.e.%) of the obtained (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (I) > 99%.

15. The method according to claim 13 or 14, wherein - the enantiomeric excess value (e.e.%) of the obtained (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl - 1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (I) < 1.5%; and / or - based on the total volume of the reaction mixture, the amount of the obtained (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (I) in step (1) and / or (2) is 0.01 to 100 mmol / mL.

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