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

Abstract

The present invention covers a sequential one-pot synthesis for preparing 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide according to formula (XIII). In particular, the sequential one-pot synthesis uses (4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide according to formula ent-(I) as a starting material to obtain 4-(4-cyano-2-methoxy-phenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide according to formula (XIII) by electrochemical oxidation and electrochemical reduction.

Description

[Technical Field]

[0001] The present invention relates to 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide according to formula (XIII) [ka] This paper covers a sequential one-pot synthesis for the preparation of

[0002] In particular, in a sequential one-pot synthesis, a compound according to formula ent-(I) [ka] as a starting material to obtain compound (XIII) by electrochemical oxidation and electrochemical reduction. Compound (XIII) is obtained by the reaction of the compound (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (I). [ka] It is an intermediate in the synthesis of [Background technology]

[0003] The international nonproprietary name (INN) of the compound of formula (I) is finerenone.It is a nonsteroidal mineralocorticoid receptor antagonist and can be used as a drug for preventing or treating cardiovascular disorders and renal disorders such as heart failure or diabetic nephropathy.Compound (I) and its preparation method are described, for example, in US Patent Application Publication No. 20100136142, US Patent Application Publication No. 20170217957 and US Patent Application Publication No. 15 / 753,406.

[0004] The compound ent-(I) is a by-product or waste product generated in the preparation of finerenone (I). In the commercial synthesis of finerenone, the compound ent-(I) is not further used and must be destroyed / disposed of. Disposal of such waste is a complex and costly process, which implies a high inefficiency in terms of the yield of finerenone. Furthermore, the compound is obtained in significant quantities in one of the final stages of the commercial synthesis, so a potential starting material is discarded here.

[0005] US Patent Application Publication No. 15 / 753,406 describes that in the preparation of compound (I), a compound according to formula ent-(I) is obtained (see Scheme 1).

[0006] Scheme 1: Compound ent-(I) is obtained in the synthesis of finerenone (I) (U.S. Patent Application Publication No. 15 / 753,406). [ka]

[0007] U.S. Patent Application Publication No. 15 / 753,406 further describes a method for recycling compound ent-(I) on a laboratory scale. The method of U.S. Patent Application Publication No. 15 / 753,406 is shown in Scheme 2 below and includes several distinct steps.

[0008] Scheme 2: Method according to U.S. Patent Application Publication No. 15 / 753,406 [ka]

[0009] The process described in U.S. Patent Application Publication No. 15 / 753,406 is characterized by the following steps, each of which is characterized by isolating the corresponding intermediate product as a solid: 1) Oxidation by chemical oxidants to compounds M1a (S) and M1b (R) 2) Isolation of a mixture of compounds M1a (S) and M1b (R) 3) Racemization of compounds M1a(S) and M1b(R) to compound (XVII) 4) Isolation of compound (XVII) 5) Obtaining compound (XIII) by electrochemical reduction of compound (XVII).

[0010] Table 1 provides an overview of the yields after each step and the overall yield (laboratory scale) after all reaction steps described in US Patent Application Publication No. 15 / 753,406.

[0011] [Table 1]

[0012] The method described in U.S. Patent Application Publication No. 15 / 753,406 has several drawbacks, including: -This refers only to process settings that are not suitable for laboratory scale and commercial scale-up. The inadequacy of the procedure described in US Patent Application Publication No. 15 / 753,406 can be seen, for example, in Example 28 of US Patent Application Publication No. 15 / 753,406, where direct electrochemical oxidation failed. Each intermediate must be isolated after each individual step. -Direct electrochemical oxidation does not require these reagents. - Undesirable secondary components may occur. Unwanted secondary components can significantly interfere with further process steps. Undesirable components are oxidizing agents and solvents, which can significantly interfere with further process steps. - Emerging secondary components (e.g. impurities due to low chemoselectivity) should be purged in the crystallization / isolation step. - The secondary component can be the reduced form of a chemical oxidant (oxidation by Fe(3+) leads to Fe(2+), or DDQ takes up an H atom to form H2DDQ), but the component itself (independent of its oxidation state) can be problematic for reaching high selectivity / yield in the next step. The necessary isolation step(s) of one or more intermediates leads to at least two particular drawbacks: Additional process steps such as filtering, washing, drying, and repeated solid handling (e.g., filling of dried solids into containers, intermediate storage, and supply of stock material for the next synthesis step) Yield loss when isolating intermediates, for example, by mother liquor or washing steps The dihydropyridine derivatives of U.S. Patent Application Publication No. 15 / 753,406 are oxidized to their pyridine analogs using indirect electrochemical oxidation with substoichiometric amounts of a mediator (e.g., DDQ, see also U.S. Patent Application Publication No. 15 / 753,406, FIG. 4). Such mediators are also described in Francke and Little, Chem. Soc. Rev. 43(8), 2014, pp. 2492-2521. One or more of these oxidizing agents used in the oxidation step may at least interfere with further process steps or may even limit the electrochemical reduction step. - Solvents used in the oxidation step of US Patent Application Publication No. 15 / 753,406 Many steps proceed at very high dilutions and with large excesses of reagents, resulting in relatively low overall yields, making this synthesis unsuitable for large-scale processing. Furthermore, the synthesis requires numerous intermediate chromatographic purification and / or isolation steps, which are technically generally very laborious, involve high solvent consumption, are expensive, and should be avoided if possible. Some steps cannot be achieved due to safety and process engineering difficulties.

[0013] This list is not exhaustive. [Prior art documents] [Patent documents]

[0014] [Patent Document 1] US Patent Application Publication No. 20100136142 [Patent Document 2] US Patent Application Publication No. 20170217957 [Patent Document 3] U.S. Patent Application Publication No. 15 / 753,406 [Non-patent literature]

[0015] [Non-Patent Document 1] Francke and Little, Chem.Soc.Rev.43(8), 2014, pp. 2492–2521 Summary of the Invention [Problem to be solved by the invention]

[0016] Therefore, there is a need for an industrially viable and / or large-scale synthesis of compounds according to formula (XIII) that reproducibly minimizes reaction steps, minimizes isolation steps, provides high overall yields, low manufacturing costs, and high purity. High demands are placed on the purity of pharmaceuticals and their intermediates. For example, they must meet all regulatory requirements to be suitable for clinical trials, subsequent regulatory submissions, and / or ultimate administration to patients. Examples of such regulations are Good Manufacturing Practice (GMP) and Good Clinical Practice (GCP).

[0017] Surprisingly, a sequential one-pot synthesis has been found that can meet the above requirements. [Means for solving the problem]

[0018] The present invention relates to 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide according to formula (XIII) [ka] 1. A sequential one-pot synthesis for synthesizing 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,6-naphthyridine-3-carboxamide according to formula (XVII) [ka] with (4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide according to formula ent-(I) [ka] a) by electrochemical oxidation of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide according to formula (XIII) [ka] b) by electrochemical reduction of a compound according to formula (XVII), This covers sequential one-pot synthesis, including

[0019] Furthermore, the sequential one-pot synthesis allows for the highly efficient preparation of compounds of formula (XIII). The sequential one-pot synthesis offers significant advantages over the prior art in terms of scalability and technical implementation. The overall yield is significantly higher compared to previously described syntheses.

[0020] In particular, the present invention encompasses a sequential one-pot synthesis as shown in Scheme 3 below.

[0021] Scheme 3: Sequential one-pot synthesis. [ka]

[0022] In contrast to known methods, the synthesis according to the present invention is carried out as a one-pot synthesis, in which electrochemical oxidation (step a)) is carried out first, followed by electrochemical reduction (step b). In sequential one-pot synthesis, isolation of intermediates is not required. The sequential one-pot synthesis can be carried out in one setup / apparatus. For example, the sequential one-pot synthesis can be carried out in one of the setups / apparatuses shown in Figure 1 or Figure 2 below. Thus, electrochemical oxidation and electrochemical reduction can be carried out directly, one after the other, in one device / setup. The sequential one-pot synthesis can be carried out without isolation of intermediates, which is required in known methods. In contrast to this, in known methods, intermediates (compounds M1a(S), M1b(R), and / or XVII)) must be isolated as described above.

[0023] Even though one-pot syntheses are known, the previously known synthesis of U.S. Patent Application Publication No. 15 / 753,406 could not be scaled up and / or implemented as a one-pot synthesis without additional difficulties. The reaction conditions for the single steps described in U.S. Patent Application Publication No. 15 / 753,406 differ significantly from each other. Different steps require different reaction conditions. Reaction conditions for a previous step may not be suitable for a later step. For example, the oxidation step in U.S. Patent Application Publication No. 15 / 753,406 is carried out using nitric acid and acetonitrile. These reaction conditions are not suitable for subsequent thermal racemization on an industrial scale, at least for safety reasons. In U.S. Patent Application Publication No. 15 / 753,406, an excess of oxidizing reagent was used. In the presence of remaining oxidizing reagent, continuous oxidation reactions at high temperatures may occur, leading to the formation of new impurities. This can result in reduced quality and yield.

[0024] Furthermore, the sequential one-pot synthesis allows the recycling of the compound according to formula (XIII) from compound ent-(I) on an industrial scale. Compound (XIII) can then be subjected to enantiomeric resolution again to obtain compound (I). See, for example, Scheme 4.

[0025] Scheme 4: [ka]

[0026] Therefore, the by-products according to formula ent-(I) do not need to be disposed of but can be reused. This is highly sustainable, as less chemical waste needs to be disposed of separately and / or valuable starting materials / intermediates can be recovered in one of the final steps of the process. Because this is a large-scale process, it is not only environmentally friendly, but also saves money, time, and materials. This is highly advantageous for cost reasons, but on the other hand, it is highly advantageous for sustainability reasons, especially since it is a large-scale process.

[0027] The sequential one-pot synthesis described here can be carried out several times in succession, thus offering the possibility of converting compound ent-(I) to compound (XIII). This can be considered a quasi-continuous operation mode, offering significant advantages in terms of cost, time, and / or resources. In this way, the waste product ent-(I), which is repeatedly generated in the preparation of finerenone (I), can be converted back to compound (XIII). Compound (XIII) can then be fed back into the finerenone (I) production process. Thus, after several process cycles of the sequential one-pot synthesis, compound ent-(I) can be almost completely utilized. In the best case scenario, the by-product ent-(I) can be almost completely recycled into the intended product (XIII) or finerenone (I).

[0028] The sequential one-pot synthesis allows for the reproducible, sustainable, and / or economical production of compounds of formula (XIII). After several process cycles of the sequential one-pot synthesis, compound ent-(I) can be almost completely utilized.

[0029] Compound (XIII) can then be used, for example, for the preparation of finerenone, for example, by chiral chromatography, classical resolution by diastereomeric salt formation, crystallization, precipitation, etc. Enantiomeric HPLC is known, for example, from US Patent Application Publication Nos. 20100136142 and 20170217957. Separation of enantiomers by diastereomeric separation is described, for example, in US Patent Application Publication No. 20210163474.

[0030] A further particularly important advantage of the present invention is that the compound of formula (XIII) can be recovered in high chemical purity. As this is an active pharmaceutical ingredient / intermediate, all operations are carried out under GMP and require high purity intermediates.

[0031] It was also surprising that the compound of formula (XIII) could be recovered on a large scale by electrolysis. Commercially, electrolytic cells are used in the electrorefining and electrowinning of several non-ferrous metals. Almost all high-purity aluminum, copper, zinc, and lead are produced industrially in electrolytic cells. However, in the pharmaceutical industry, the use of such electrolytic cells for drug synthesis is uncommon. This also applies to large-scale processes. Industrial production of active ingredients is carried out in so-called "multipurpose plants." Only standard equipment (e.g., including boilers, centrifuges, dryers, etc.) is present. The use of electrolytic cells in such multipurpose plants in the pharmaceutical industry is not a standard setup and is not typically used for commercial pharmaceutical synthesis.

[0032] Unless otherwise defined, the technical terms used herein are used in a manner conventional to those skilled in the art. The nomenclature follows the International Union of Pure and Applied Chemistry (IUPAC). The units used herein follow the International System of Units (SI units).

[0033] 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide is a compound according to formula (XIII) [ka] is.

[0034] The terms "4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide," "compound according to formula (XIII)," and "compound (XIII)" are synonymous. The compound according to formula (XIII) is (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 (I). [ka] Includes.

[0035] (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide is a compound according to formula (I) [ka] is.

[0036] The INN of Compound (I) is "finerenone." The CAS number for finerenone is CAS 1050477-31-0. Compound (I) is the (S)-enantiomer contained in the compound according to 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 synonymous.

[0037] (4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide is a compound according to formula ent-(I) [ka] is.

[0038] Compound ent-(I) is described in U.S. Patent Application Publication No. 15 / 753,406. Compound ent-(I) is the (R)-enantiomer contained in the compound according to formula (XIII). "(4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide," "compound according to formula ent-(I)," and "compound ent-(I)" are synonymous. Compound ent-(I) can be obtained as a waste product or by-product in the synthesis of finerenone (I), as shown in Scheme 1 above.

[0039] Compounds M1a(S) and M1b(R) [ka] are described in U.S. Patent Application Publication No. 15 / 753,406. These compounds are atropisomers contained in compound (XVII). 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,6-naphthyridine-3-carboxamide according to formula (XVII) [ka] .

[0040] Thus, compound (XVII) includes compounds M1a(S) and M1b(R).

[0041] The term "intermediate" can refer to a sequential one-pot synthesis for preparing a compound according to formula (XIII) or an intermediate in a process for preparing a compound according to formula (I). The intermediate can be, for example, a compound according to formula ent-(I), a compound according to formula M1a(S), a compound according to formula M1b(R), a compound according to formula (XVII), a compound according to formula (XIII).

[0042] The term "product" can refer to a compound according to formula (XIII) or a compound according to formula (I). This can depend on which aspect or sub-aspect of the method or step described herein is being referred to. A "conductive salt" or "conductive electrolyte" is a salt that is responsible for charge transport during electrolysis. Conductive salts reduce the ohmic resistance of the solution and allow the depolarizer to be transported to the electrode by diffusion. Conductive salts do not participate in the electrode reaction. Examples of conductive salts are tetrabutylammonium perchlorate BuN4ClO4, Et4NBF4, Bu4NBF4, Bu4NPF6, Bu4NX (where X = I, Br) or the perchlorates NaClO4, LiClO4, Et4NClO4. These conductive salts can be used in the sequential one-pot synthesis according to the present invention.

[0043] The term "solvent" also includes solvent mixtures. Solvents can be recycled and reused as mixtures. In one embodiment, the solvent is recycled. In another embodiment, the solvent is recycled and then the excess produced components can be replenished with fresh solvent to obtain the desired mixture ratio.

[0044] In one embodiment, a suspension or a mixture thereof is used as a solvent. The use of a suspension or a mixture thereof can provide optimal space-time yield. The suspension can be pumped through the system / process configuration used.

[0045] In one embodiment of the present invention, the sequential one-pot synthesis is carried out by electrolysis. Reactive "electrolysis" is also known in the art. Chemical changes caused by passing an electric current through an electrolyte are called electrolysis. Electrical energy is directly converted into chemical energy. Electrolysis processes are electrochemical reactions in which a non-spontaneous material transformation process is forced by applying an external voltage. Electrical energy (current) is converted into chemical energy (substances). Electrolysis is the reversal of a galvanic process by performing electrical work.

[0046] Electrolytic devices or cells are known to those skilled in the art (see, for example, 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), pp. 1313, 1322). Electrolytic devices are also described in U.S. Patent Application Publication No. 15 / 753,406. An industrial-scale electrochemical cell can include one or more electrochemical cells. Such industrial-scale configurations can include one or more electrochemical cells, compartments, containers, and / or tanks. Such industrial-scale systems often consist of or include several electrochemical cells. These can be connected or run in parallel. Such industrial systems can include one or more tanks, reaction vessels, etc. The reaction mixture can be telescoped between the various compartments of such industrial-scale systems. Thus, in such industrial-scale systems, the reaction steps according to the present invention can be carried out sequentially.

[0047] In one embodiment of the present invention, the sequential one-pot synthesis is electrochemical synthesis. In one embodiment of the present invention, the sequential one-pot synthesis is performed in an electrochemical cell. In one embodiment of the present invention, the sequential one-pot synthesis is performed in an electrolytic cell. Electrolytic cells are known in the art. An electrolytic cell is an electrochemical cell that utilizes an external source of electrical energy to drive a chemical reaction that would not otherwise occur. A voltage is applied between two electrodes, an anode (positively charged electrode) and a cathode (negatively charged electrode). This is in contrast to a galvanic cell, which is itself a source of electrical energy. In an electrolytic cell, the external voltage causes a current to pass through the cell, driving a non-spontaneous chemical reaction. An electrolytic cell has three components: an electrolyte and two electrodes (a cathode and an anode). The electrolyte is typically a solution of water or other solvent in which ions are dissolved. When driven by an external voltage applied to the electrodes, ions in the electrolyte are attracted to the electrode with the opposite charge, where a charge transfer (also called a Faradaic or redox) reaction can occur. Only with the correct polarity and sufficient magnitude of external potential (i.e., voltage) can electrolytic cells decompose normally stable or inert compounds in solution. The supplied electrical energy can produce chemical reactions that would not otherwise occur spontaneously (non-spontaneous reactions).

[0048] 1 and 2 show schematic diagrams of electrolysis setups. Such electrolysis setups can be used for large-scale synthesis. The electrolysis setups shown in FIGS. 1 and 2 can also be used for sequential one-pot synthesis according to the invention. Further modifications to such electrolysis setups can be made. For example, several electrolyte 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. Corresponding setups suitable for industrial-scale synthesis are known to those skilled in the art.

[0049] In one embodiment, the sequential one-pot synthesis is carried out in a divided cell. In one embodiment, the sequential one-pot synthesis is carried out in a filter press type cell. Other commercially available cells can be used and are known to those skilled in the art.

[0050] Further modifications can be made to such electrolysis devices. The modifications or adaptations described below can be applied to the schematic standard configurations shown in Figures 1 and / or 2. For example, several electrolyte 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. Corresponding configurations suitable for industrial-scale synthesis are known to those skilled in the art. The process can be carried out continuously and / or discontinuously, in whole and / or in part. A filter unit for solids can be installed. Such filters, for example, allow the isolation or separation of starting materials, intermediates (e.g., ent-(I), M1a(S), M1b(R), (XVII), (XIII)) or products (e.g., (XIII), (I)) from the reaction mixture.

[0051] These filter units could be cooled and the filtrate would then be returned to the process. Additionally, the dwell loop could be thermally heated or cooled. This could result in continuous racemization. A continuous dosing unit could also be installed. A suspension pump could also be installed. The electrolysis cell could contain, comprise, and / or be made (partially) of glass, enamel, or stainless steel, optionally with a Teflon liner or non-"leachable" plastic (GMP approved).

[0052] The electrode geometry can also be adapted to achieve optimal flow. The electrode geometry can also be adapted to achieve optimized flow so that gas formation and discharge can be controlled. Heat dissipation measures can be implemented to match the respective electrode geometry. The fluid distribution in the electrolysis cell or device or process setup can be further adapted. Such adaptation can be achieved, for example, by additional stirring means for better mass transport.

[0053] Different types of electrodes can be used. Examples include electrodes that contain, contain, or consist of precious metals, electrodes coated with precious metals, titanium electrodes, graphite electrodes, and boron-doped diamond electrodes (BDD). Electrodes can include or consist of precious metals, metal or non-metallic supports coated with precious metals, and / or non-metallic electrodes (e.g., graphite).

[0054] Commercially available membranes can be used to realize the divided cell.

[0055] The electrodes can be segmented, with a total electrode area of ​​60-100 cm. 2 In one embodiment, the electrodes are segmented. In one embodiment, the total electrode area is between 60 and 100 cm. 2 In one embodiment, the electrodes are segmented and the total electrode area is between 60 and 100 cm 2 In one embodiment, the electrode area is 80 cm (width) and 25-75 cm (height).

[0056] The electrolysis cell may consist of or include segmented cell units that may be scalable by "numbering up" the stack design.

[0057] Optimization of existing materials and sealing concepts, improvement of electrode structures and cell geometries, and adaptation of system components for, e.g., heat dissipation and control, can be optimally matched by adjusting voltage, current density, temperature and flow rate / flow rate, and / or residence time.

[0058] The process 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 thereof. A mixture of inert and non-inert gases can be used. In one embodiment, the mixture mainly comprises an inert gas.

[0059] The processes described herein can be carried out completely and / or partly in different modes, examples of which are campaign mode or continuous process mode.

[0060] In one embodiment, the process according to the invention is carried out in a continuous mode. In one embodiment, the process according to the invention is carried out in a continuous mode, in which starting materials, intermediates and / or conductive salts are added continuously ... - starting materials, solvents, conductive salts, acids, and / or intermediates are added sequentially; - the product is continuously removed; It is done in continuous mode.

[0061] The cycle time for each of the steps described below is adjustable: one or more of these steps can be performed multiple times, and one or more of the steps can be performed less frequently or only once.

[0062] Long-term stability can also be improved by optimizing the residence time. In one embodiment, the residence time is 20 hours or less. In one embodiment, the residence time is 5-8 hours. In one embodiment, the residence time in an individual unit operation is 6 hours or less. The residence time should be adapted to the geometry and / or flow rate.

[0063] Multiphase flows caused by bubble formation can be suppressed. To this end, heat dissipation strategies and / or the influence of different geometric and / or process parameters on the operating behavior can be optimally designed.

[0064] Step a) The sequential one-pot synthesis comprises step a).

[0065] 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.

[0066] In step a), the temperature can be constant, variable, increasing or decreasing. A specific temperature program can also be performed in step a). In one embodiment, step a) is performed at a temperature between 15 and 150°C, and the temperature is constant, variable, increasing or decreasing, or a specific temperature program is performed.

[0067] In step a), the temperature can be constant, variable, increasing or decreasing. In step a), a specific temperature program can also be carried out.

[0068] In one embodiment, step a) is carried out at a temperature between 15 and 150° C., the temperature being constant, variable, increasing, decreasing or a specific temperature program being carried out.

[0069] In one embodiment, step a) is carried out at a temperature of 15 to 150°C, and the temperature is constant. In one embodiment, step a) is carried out at a temperature of 15 to 120°C, and the temperature is constant. In one embodiment, step a) is carried out at a temperature of 20 to 100°C, and the temperature is constant.

[0070] In one embodiment, step a) is carried out at a temperature of 15 to 150°C, and the temperature is variable. In one embodiment, step a) is carried out at a temperature of 15 to 120°C, and the temperature is variable. In one embodiment, step a) is carried out at a temperature of 20 to 100°C, and the temperature is variable.

[0071] In one embodiment, step a) is carried out at a temperature of 15 to 150°C, with the temperature increasing. In one embodiment, step a) is carried out at a temperature of 15 to 120°C, with the temperature increasing. In one embodiment, step a) is carried out at a temperature of 20 to 100°C, with the temperature increasing.

[0072] In one embodiment, step a) is carried out at a temperature of 15 to 150°C, decreasing temperature. In one embodiment, step a) is carried out at a temperature of 15 to 120°C, decreasing temperature. In one embodiment, step a) is carried out at a temperature of 20 to 100°C, decreasing temperature.

[0073] In one embodiment, step a) is carried out at a temperature of 15 to 150°C and a specific temperature program is implemented. In one embodiment, step a) is carried out at a temperature of 15 to 120°C and a specific temperature program is implemented. In one embodiment, step a) is carried out at a temperature of 20 to 100°C and a specific temperature program is implemented.

[0074] In one embodiment of step a), first the electrochemical oxidation is carried out and then the reaction mixture is heated.

[0075] In one embodiment of step a), electrochemical oxidation is carried out first, and then the reaction mixture is heated to 50 to 150°C. In one embodiment of step a), electrochemical oxidation is carried out first, and then the reaction mixture is heated to 75 to 150°C. In one embodiment of step a), electrochemical oxidation is carried out first, and then the reaction mixture is heated to 80 to 150°C. In one embodiment of step a), electrochemical oxidation is carried out first, and then the reaction mixture is heated to 80 to 140°C. In one embodiment of step a), electrochemical oxidation is carried out first, and then the reaction mixture is heated to 90 to 120°C.

[0076] In one embodiment of step a), first, electrochemical oxidation is carried out, the temperature can be constant, variable, increasing, decreasing or a specific temperature program can be carried out, and then the reaction mixture is heated.

[0077] In one embodiment of step a), first, electrochemical oxidation is carried out, the temperature can be constant, variable, increasing, decreasing, or a specific temperature program can be performed, and then the reaction mixture is heated to 50-150°C.

[0078] In one embodiment of step a), electrochemical oxidation is carried out first, the temperature can be constant, variable, increasing, decreasing, or a specific temperature program can be performed, and then the reaction mixture is heated to 75-150°C.

[0079] In one embodiment of step a), first, electrochemical oxidation is carried out, the temperature can be constant, variable, increasing, decreasing, or a specific temperature program can be performed, and then the reaction mixture is heated to 80-150°C.

[0080] In one embodiment of step a), electrochemical oxidation is carried out first, the temperature can be constant, variable, increasing, decreasing, or a specific temperature program can be performed, and then the reaction mixture is heated to 80-140°C.

[0081] In one embodiment of step a), first, electrochemical oxidation is carried out, the temperature can be constant, variable, increasing, decreasing, or a specific temperature program can be performed, and then the reaction mixture is heated to 90-120°C.

[0082] In one embodiment of step a), first, electrochemical oxidation is 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.

[0083] In one embodiment of step a), 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 can be constant, variable, increasing, decreasing, or can also be a specific temperature program, and then the reaction mixture is heated.

[0084] 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.

[0085] In one embodiment of step a), 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 can be constant, variable, increasing, decreasing, or a specific temperature program can be performed, and then the reaction mixture is heated, where the temperature can be constant, variable, increasing, decreasing, or a specific temperature program can be performed.

[0086] In one embodiment of step a), electrochemical oxidation is carried out first, and then the reaction mixture is heated, where the temperature can be constant, variable, increasing, decreasing, or a specific temperature program is performed, and the reaction mixture is heated to a temperature of 75 to 150°C. In one embodiment of step a), electrochemical oxidation is carried out first, and then the reaction mixture is heated, where the temperature can be constant, variable, increasing, decreasing, or a specific temperature program is performed, and the reaction mixture is heated to a temperature of 80 to 150°C. In one embodiment of step a), electrochemical oxidation is carried out first, and then the reaction mixture is heated, where the temperature can be constant, variable, increasing, decreasing, or a specific temperature program is performed, and the reaction mixture is heated to a temperature of 80 to 140°C. In one embodiment of step a), electrochemical oxidation is carried out first, and then the reaction mixture is heated, where the temperature can be constant, variable, increasing, decreasing, or a specific temperature program is performed, and the reaction mixture is heated to a temperature of 90 to 120°C.

[0087] In one embodiment of step a), first, electrochemical oxidation is carried out, the temperature can be constant, variable, increasing, decreasing, or a specific temperature program can be followed, and then the reaction mixture is heated, the temperature can be constant, variable, increasing, decreasing, or a specific temperature program can be followed.

[0088] In one embodiment of step a), first, electrochemical oxidation is carried out at a temperature of 15-150°C, which can be constant, variable, increasing, decreasing, or a specific temperature program can be followed, and then the reaction mixture is heated to a temperature of 50-150°C, which can be constant, variable, increasing, decreasing, or a specific temperature program can be followed.

[0089] In one embodiment of step a), - first, electrochemical oxidation is carried out at a temperature selected from 15-150°C, 15-120°C, and 20-100°C, the temperature can be constant, variable, increasing, decreasing, or a specific temperature program can be performed; The reaction mixture is then heated to a temperature selected from 50-150°C, 75-150°C, 80-150°C, 80-140°C, 90-120°C, which temperature can be constant, variable, increasing, decreasing or a specific temperature program can be carried out.

[0090] In one embodiment of step a), First, electrochemical oxidation is carried out at a temperature between 15 and 150°C, which can be constant, variable, increasing, decreasing or can be carried out in a specific temperature program; The reaction mixture is then heated to a temperature selected from 50-150°C, 75-150°C, 80-150°C, 80-140°C, 90-120°C, which temperature can be constant, variable, increasing, decreasing or a specific temperature program can be carried out.

[0091] In one embodiment of step a), First, electrochemical oxidation is carried out at a temperature between 15 and 120°C, which temperature can be constant, variable, increasing, decreasing or can be performed under a specific temperature program; The reaction mixture is then heated to a temperature selected from 50-150°C, 75-150°C, 80-150°C, 80-140°C, 90-120°C, which temperature can be constant, variable, increasing, decreasing or a specific temperature program can be carried out.

[0092] In one embodiment of step a), First, electrochemical oxidation is carried out at a temperature between 20 and 100°C, which can be constant, variable, increasing, decreasing or can be carried out in a specific temperature program; The reaction mixture is then heated to a temperature selected from 50-150°C, 75-150°C, 80-150°C, 80-140°C, 90-120°C, which temperature can be constant, variable, increasing, decreasing or a specific temperature program can be carried out.

[0093] In one embodiment of step a), - first, electrochemical oxidation is carried out at a temperature selected from 15-150°C, 15-120°C, and 20-100°C, the temperature can be constant, variable, increasing, decreasing, or a specific temperature program can be performed; The reaction mixture is then heated to a temperature of 50-150°C, which can be constant, variable, increasing, decreasing or a specific temperature program can be carried out.

[0094] In one embodiment of step a), - first, electrochemical oxidation is carried out at a temperature selected from 15-150°C, 15-120°C, and 20-100°C, the temperature can be constant, variable, increasing, decreasing, or a specific temperature program can be performed; The reaction mixture is then heated to a temperature of 75-150°C, which can be constant, variable, increasing, decreasing or a specific temperature program can be carried out.

[0095] In one embodiment of step a), - first, electrochemical oxidation is carried out at a temperature selected from 15-150°C, 15-120°C, and 20-100°C, the temperature can be constant, variable, increasing, decreasing, or a specific temperature program can be performed; The reaction mixture is then heated to a temperature of 80-150°C, which can be constant, variable, increasing, decreasing or a specific temperature program can be carried out.

[0096] In one embodiment of step a), - first, electrochemical oxidation is carried out at a temperature selected from 15-150°C, 15-120°C, and 20-100°C, the temperature can be constant, variable, increasing, decreasing, or a specific temperature program can be performed; The reaction mixture is then heated to a temperature of 80-140°C, which can be constant, variable, increasing, decreasing or a specific temperature program can be carried out.

[0097] In one embodiment of step a), - first, electrochemical oxidation is carried out at a temperature selected from 15-150°C, 15-120°C, and 20-100°C, the temperature can be constant, variable, increasing, decreasing, or a specific temperature program can be performed; The reaction mixture is then heated to a temperature of 90-120°C, which can be constant, variable, increasing, decreasing or a specific temperature program can be carried out.

[0098] In one embodiment of step a), a conductive salt is used. In one embodiment of step a), a conductive salt selected from the group consisting of organic ammonium salts, ionic liquids, tetraalkylammonium fluoroborate, quaternary ammonium salts, and mixtures thereof is used. In one embodiment of step a), a conductive salt selected from the group consisting of tetraethylammonium tetrafluoroborate, tetrabutylammonium hexafluorophosphate, tetrabutylammonium hydrogen sulfate, and mixtures thereof is used.

[0099] In one embodiment of step a), the solvent is used in an amount of 1 to 60 kg / kg based on the (4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula ent-(I). This means that 60 kg of solvent is used per 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 solvent is used in an amount of 5 to 50 kg / kg based on the (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 solvent is used in an amount of 5 to 30 kg / kg relative to the (4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide according to formula ent-(I). In one embodiment of step a), the solvent is used in an amount of 7 to 25 kg / kg. In one embodiment of step a), the solvent is used in an amount of 8 to 20 kg / kg. In one embodiment of step a), the solvent is used in an amount of 9 to 19 kg / kg.

[0100] In one embodiment of step a), the solvent is used in an amount of 80 to 99% by weight, based on the amount of the reaction mixture. In one embodiment of step a), the solvent is used in an amount of 85 to 95% by weight, based on the amount of the reaction mixture. In one embodiment of step a), the solvent is used in an amount of 85 to 92% by weight, based on the amount of the reaction mixture. In one embodiment of step a), the solvent is used in an amount of 90% by weight, based on the amount of the reaction mixture.

[0101] "wt %" is percent by weight. In one example, if the amount of reaction mixture is 100 kg, and an amount of solvent of 80 wt % is used, the amount of solvent is 80 kg.

[0102] 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 list of 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. Further suitable solvents are methoxymethanol, tetramethylurea formamide, DMA (dimethylacetamide), NMP (N-methylpyrrolidone), propionitrile, glycerol, propanol, and 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.

[0103] Further suitable solvents are acids. Examples of suitable acids are propanoic acid, butyric acid, benzoic acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, HBF4, HPF6, ammonium acetate and mixtures of the aforementioned.

[0104] In one embodiment of step a), - a conductive salt selected from the group consisting of organic ammonium salts, ionic liquids, tetraalkylammonium fluoroborates, quaternary ammonium salts and mixtures thereof; and a solvent selected from aprotic solvents, protic solvents, and mixtures thereof is used.

[0105] In one embodiment of step a), - a conductive salt selected from the group consisting of organic ammonium salts, ionic liquids, tetraalkylammonium fluoroborates, quaternary ammonium salts and mixtures thereof; and a solvent selected from polar aprotic solvents is used.

[0106] In one embodiment of step a), a conductive salt selected from the group consisting of tetraethylammonium tetrafluoroborate, tetrabutylammonium hexafluorophosphate, tetrabutylammonium hydrogen sulfate, and mixtures thereof; and a solvent selected from aprotic solvents, protic solvents, and mixtures thereof is used.

[0107] In one embodiment of step a), a conductive salt selected from the group consisting of tetraethylammonium tetrafluoroborate, tetrabutylammonium hexafluorophosphate, tetrabutylammonium hydrogen sulfate, and mixtures thereof; and a solvent selected from polar aprotic solvents is used.

[0108] In one embodiment of step a), - a conductive salt selected from the group consisting of organic ammonium salts, ionic liquids, tetraalkylammonium fluoroborates, quaternary ammonium salts and mixtures thereof; and polar aprotic solvents selected from 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; is used.

[0109] In one embodiment of step a), a conductive salt selected from the group consisting of tetraethylammonium tetrafluoroborate, tetrabutylammonium hexafluorophosphate, tetrabutylammonium hydrogen sulfate, and mixtures thereof; and polar aprotic solvents selected from 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; is used.

[0110] In one embodiment of step a), - a conductive salt selected from the group consisting of organic ammonium salts, ionic liquids, tetraalkylammonium fluoroborates, quaternary ammonium salts and mixtures thereof; and a solvent selected from dimethylformamide (DMF), methanol, acetic acid and mixtures thereof is used.

[0111] In one embodiment of step a), - a conductive salt selected from the group consisting of organic ammonium salts, ionic liquids, tetraalkylammonium fluoroborates, quaternary ammonium salts and mixtures thereof; and a solvent selected from dimethylformamide (DMF), methanol, acetic acid and mixtures thereof is used.

[0112] In one embodiment of step a), a conductive salt selected from the group consisting of tetraethylammonium tetrafluoroborate, tetrabutylammonium hexafluorophosphate, tetrabutylammonium hydrogen sulfate, and mixtures thereof; and a solvent selected from dimethylformamide (DMF), methanol, acetic acid and mixtures thereof is used.

[0113] In one embodiment of step a), - a conductive salt selected from the group consisting of organic ammonium salts, ionic liquids, tetraalkylammonium fluoroborates, quaternary ammonium salts and mixtures thereof; and -methanol is used.

[0114] In one embodiment of step a), - a conductive salt selected from the group consisting of organic ammonium salts, ionic liquids, tetraalkylammonium fluoroborates, quaternary ammonium salts and mixtures thereof; and -methanol is used.

[0115] In one embodiment of step a), a conductive salt selected from the group consisting of tetraethylammonium tetrafluoroborate, tetrabutylammonium hexafluorophosphate, tetrabutylammonium hydrogen sulfate, and mixtures thereof; and -methanol is used.

[0116] In one embodiment of step a), - a conductive salt selected from the group consisting of organic ammonium salts, ionic liquids, tetraalkylammonium fluoroborates, quaternary ammonium salts and mixtures thereof; and -Acetic acid is used.

[0117] In one embodiment of step a), - a conductive salt selected from the group consisting of organic ammonium salts, ionic liquids, tetraalkylammonium fluoroborates, quaternary ammonium salts and mixtures thereof; and -Acetic acid is used.

[0118] In one embodiment of step a), a conductive salt selected from the group consisting of tetraethylammonium tetrafluoroborate, tetrabutylammonium hexafluorophosphate, tetrabutylammonium hydrogen sulfate, and mixtures thereof; and -Acetic acid is used.

[0119] In one embodiment of step a), 0.05 to 1 equivalent of conductive salt is used based on 1 equivalent of compound according to formula ent-(I), meaning that if 0.05 equivalents (0.05 mol) of conductive salt is used, 1 equivalent (1 mol) of compound according to formula ent-(I) is used.

[0120] In one embodiment of step a), 0.1 to 0.5 equivalents of conductive salt are used based on 1 equivalent of compound according to formula ent-(I). In one embodiment of step a), 0.15 to 0.35 equivalents of conductive salt are used based on 1 equivalent of compound according to formula ent-(I). In one embodiment of step a), 0.2 to 0.3 equivalents of conductive salt are used based on 1 equivalent of compound according to formula ent-(I).

[0121] In one embodiment of step a), an acid is used. In one embodiment of step a), an acid selected from organic acids, organic polar acids, and mixtures thereof is used. In one embodiment of step a), an organic acid is used. In one embodiment of step a), an organic acid selected from carboxylic acids and sulfonic acids is used. In one embodiment of step a), an organic polar acid is used. In one embodiment of step a), an acid selected from acetic acid, formic acid, and mixtures thereof is used. In one embodiment of step a), acetic acid is used.

[0122] In one embodiment of step a), the acid is used in an amount of 50 to 500 mmol per liter of reaction mixture. In one embodiment of step a), the acid is used in an amount of 100 to 300 mmol per liter of reaction mixture. In one embodiment of step a), the acid is used in an amount of 150 to 250 mmol per liter of reaction mixture.

[0123] In one embodiment of step a), 0.1 to 10 equivalents of acid are used. In one embodiment of step a), 0.1 to 5 equivalents of acid are used. In one embodiment of step a), 0.5 to 3 equivalents of acid are used. In one embodiment of step a), 1.5 to 2 equivalents of acid are used. In one embodiment of step a), 1.7 equivalents of acid are used. The equivalents are based on the compound according to formula ent-(I). This means that if 1.7 equivalents (1.7 mol) of acid are used, 1 equivalent (1 mol) of the compound according to formula ent-(I) is used.

[0124] 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.

[0125] 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.

[0126] 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.

[0127] 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.

[0128] 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.

[0129] 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 20V, less than 19V, less than 18V, less than 17V, less than 16V, less than 15V, less than 14V, less than 13V, less than 12V, less than 11V, less than 10V, less than 9V, less than 8V, less than 7V, less than 6V, less than 5V, less than 4V, less than 3V, less than 2V, less than 1V, less than 0.5V or less than 0.1V.

[0130] In one embodiment of step a), the electrochemical oxidation is carried out at a current of 1 to 5000 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 In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 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 In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 5000 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 2In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 1000 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 In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 5000 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 In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 100 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 is

[0131] In one embodiment of step a), the current density used is constant, variable, increasing, decreasing or a specific temperature program is performed.

[0132] In one embodiment of step a), the electrochemical oxidation is carried out at a current of 1 to 5000 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 In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 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 The current density may be constant, variable, increasing, decreasing, or following a specific program.

[0133] In one embodiment of step a), the electrochemical oxidation is carried out at a current of 5 to 5000 A / m2 In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 500 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 In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 50 A / m 2 The current density may be constant, variable, increasing, decreasing, or following a specific program.

[0134] In one embodiment of step a), the electrochemical oxidation is carried out at a voltage of 10 to 5000 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 In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 100 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 may be constant, variable, increasing, decreasing, or following a specific program.

[0135] 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 2In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 500 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 In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 50 A / m 2 In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 5000 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 In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 100 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 The current density used is constant.

[0136] In one embodiment of step a), the electrochemical oxidation is carried out at a voltage of 10 to 5000 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 In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 1000 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 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 constant.

[0137] In one embodiment of step a), the current density used is variable.

[0138] In one embodiment of step a), the electrochemical oxidation is carried out at a current of 1 to 5000 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 In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 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 In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 5000 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 In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 100 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 In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 5000 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 In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 100 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 variable.

[0139] In one embodiment of step a), the current density used is increased.

[0140] In one embodiment of step a), the electrochemical oxidation is carried out at a current of 1 to 5000 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 In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 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 In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 5000 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 In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 100 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 In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 5000 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 In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 100 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 and the current density used increases.

[0141] In one embodiment of step a), the current density used is decreased.

[0142] In one embodiment of step a), the current density used is decreased in steps. An example of the use of a stepwise current decrease is exemplarily described in the experimental section below. An example can be found in section C.1.1 below. In one embodiment of step a), the current density used is decreased exponentially. In one embodiment of step a), the current density used is decreased in steps, each step being the same or varying. An example of a decrease in the same steps or stepwise decrease is where the steps are always the same, for example, the same amount of current density is always used. An example of this is where the steps are 10 A / m 2 An example of a reduction in various stages or gradual reduction would be an initial reduction of 10 A / m 2 is used, and in the next stage 1A / m 2 is used, etc.

[0143] Since direct electrochemical oxidation (i.e., without a mediator) had already been described in U.S. Patent Application Publication No. 15 / 753,406 as unsuccessful (see Example 28 of U.S. Patent Application Publication No. 15 / 753,406, yields of less than 50% for XVII), one skilled in the art would not have expected the one-pot synthesis to be successful. This problem is overcome by stepwise current reduction, thus allowing high currents and chemoselectivities to be reached. The oxidation selectivity is surprisingly high, so secondary components that could interfere with the racemization and reduction steps do not increase, and therefore isolation and purging after each step is not required.

[0144] It was surprising that high currents and chemoselectivities could be reached by stepwise current reduction. The oxidation selectivity was surprisingly high, and no secondary products were produced. Such secondary products could interfere with the subsequent racemization and reduction steps, necessitating isolation and purging after each step.

[0145] In one embodiment of step a), the electrochemical oxidation is carried out at a current of 1 to 5000 A / m 2 In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 500 A / m2 In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 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 , and the current density used is reduced.

[0146] In one embodiment of step a), the electrochemical oxidation is carried out at a current of 5 to 5000 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 In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 100 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 reduced.

[0147] In one embodiment of step a), the electrochemical oxidation is carried out at a voltage of 10 to 5000 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 In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 100 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 , and the current density used is reduced.

[0148] In one embodiment of step a), the electrochemical oxidation is carried out at a current of 1 to 5000 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 2In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 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 The current density used is then reduced in steps.

[0149] In one embodiment of step a), the electrochemical oxidation is carried out at a current of 5 to 5000 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 In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 100 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 The current density used is then reduced in steps.

[0150] In one embodiment of step a), the electrochemical oxidation is carried out at a voltage of 10 to 5000 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 In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 100 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 then reduced in steps.

[0151] In one embodiment of step a), the electrochemical oxidation is carried out at a current of 1 to 5000 A / m 2 In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 500 A / m2 In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 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 The current density used decreases exponentially.

[0152] In one embodiment of step a), the electrochemical oxidation is carried out at a current of 5 to 5000 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 In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 100 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 The current density used decreases exponentially.

[0153] In one embodiment of step a), the electrochemical oxidation is carried out at a voltage of 10 to 5000 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 In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 100 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 decreases exponentially.

[0154] In one embodiment of step a), the electrochemical oxidation is carried out at a current of 1 to 5000 A / m 2 The current density used is 0.1 to 100 A / m2 In one embodiment of step a), the electrochemical oxidation is carried out at a rate of 1 to 500 A / m 2 The current density used is 0.1 to 100 A / m 2 In one embodiment of step a), the electrochemical oxidation is carried out at a rate of 1 to 100 A / m 2 The current density used is 0.1 to 100 A / m 2 In one embodiment of step a), the electrochemical oxidation is carried out at a current of 1 to 50 A / m 2 The current density used is 0.1 to 100 A / m 2 The number of patients gradually decreases.

[0155] In one embodiment of step a), the electrochemical oxidation is carried out at a current of 5 to 5000 A / m 2 The current density used is 0.1 to 100 A / m 2 In one embodiment of step a), the electrochemical oxidation is carried out at a current of 5 to 500 A / m 2 The current density used is 0.1 to 100 A / m 2 In one embodiment of step a), the electrochemical oxidation is carried out at a rate of 5 to 100 A / m 2 The current density used is 0.1 to 100 A / m 2 In one embodiment of step a), the electrochemical oxidation is carried out at a current of 5 to 50 A / m 2 The current density used is 0.1 to 100 A / m 2 The number of patients gradually decreases.

[0156] In one embodiment of step a), the electrochemical oxidation is carried out at a voltage of 10 to 5000 A / m 2 The current density used is 0.1 to 100 A / m 2 In one embodiment of step a), the electrochemical oxidation is carried out at a rate of 10 to 500 A / m 2 The current density used is 0.1 to 100 A / m2 In one embodiment of step a), the electrochemical oxidation is carried out at a rate of 10 to 100 A / m 2 The current density used is 0.1 to 100 A / m 2 In one embodiment of step a), the electrochemical oxidation is carried out at a current of 10 to 50 A / m 2 The current density used is 0.1 to 100 A / m 2 The number of patients gradually decreases.

[0157] In one embodiment of step a), the electrochemical oxidation is carried out at a current of 1 to 5000 A / m 2 The current density used is 0.5 to 50 A / m 2 In one embodiment of step a), the electrochemical oxidation is carried out at a rate of 1 to 500 A / m 2 The current density used is 0.5 to 50 A / m 2 In one embodiment of step a), the electrochemical oxidation is carried out at a current of 1 to 50 A / m 2 The current density used is 0.5 to 100 A / m 2 In one embodiment of step a), the electrochemical oxidation is carried out at a current of 1 to 50 A / m 2 The current density used is 0.5 to 50 A / m 2 The number of patients gradually decreases.

[0158] In one embodiment of step a), the electrochemical oxidation is carried out at a current of 5 to 5000 A / m 2 The current density used is 0.5 to 50 A / m 2 In one embodiment of step a), the electrochemical oxidation is carried out at a current of 5 to 500 A / m 2 The current density used is 0.5 to 50 A / m 2 In one embodiment of step a), the electrochemical oxidation is carried out at a rate of 5 to 100 A / m 2 The current density used is 0.5 to 50 A / m 2In one embodiment of step a), the electrochemical oxidation is carried out at a current of 5 to 50 A / m 2 The current density used is 0.5 to 50 A / m 2 The number of patients gradually decreases.

[0159] In one embodiment of step a), the electrochemical oxidation is carried out at a voltage of 10 to 5000 A / m 2 The current density used is 0.5 to 50 A / m 2 In one embodiment of step a), the electrochemical oxidation is carried out at a rate of 10 to 500 A / m 2 The current density used is 0.5 to 50 A / m 2 In one embodiment of step a), the electrochemical oxidation is carried out at a rate of 10 to 100 A / m 2 The current density used is 0.5 to 50 A / m 2 In one embodiment of step a), the electrochemical oxidation is carried out at a current of 10 to 50 A / m 2 The current density used is 0.5 to 50 A / m 2 The number of patients gradually decreases.

[0160] In one embodiment of step a), the electrochemical oxidation is carried out at a current of 1 to 5000 A / m 2 The current density used is 1 to 10 A / m 2 In one embodiment of step a), the electrochemical oxidation is carried out at a rate of 1 to 500 A / m 2 The current density used is 1 to 10 A / m 2 In one embodiment of step a), the electrochemical oxidation is carried out at a rate of 1 to 100 A / m 2 The current density used is 1 to 10 A / m 2 In one embodiment of step a), the electrochemical oxidation is carried out at a current of 1 to 50 A / m 2 The current density used is 1 to 10 A / m 2 The number of patients gradually decreases.

[0161] In one embodiment of step a), the electrochemical oxidation is carried out at a current of 5 to 5000 A / m 2 The current density used is 1 to 10 A / m 2 In one embodiment of step a), the electrochemical oxidation is carried out at a current of 5 to 500 A / m 2 The current density used is 1 to 10 A / m 2 In one embodiment of step a), the electrochemical oxidation is carried out at a rate of 5 to 100 A / m 2 The current density used is 1 to 10 A / m 2 In one embodiment of step a), the electrochemical oxidation is carried out at a current of 5 to 50 A / m 2 The current density used is 1 to 10 A / m 2 The number of patients gradually decreases.

[0162] In one embodiment of step a), the electrochemical oxidation is carried out at a voltage of 10 to 5000 A / m 2 The current density used is 1 to 10 A / m 2 In one embodiment of step a), the electrochemical oxidation is carried out at a rate of 10 to 500 A / m 2 The current density used is 1 to 10 A / m 2 In one embodiment of step a), the electrochemical oxidation is carried out at a rate of 10 to 100 A / m 2 The current density used is 1 to 10 A / m 2 In one embodiment of step a), the electrochemical oxidation is carried out at a current of 10 to 50 A / m 2 The current density used is 1 to 10 A / m 2 The number of patients gradually decreases.

[0163] In one embodiment of step a), the electrochemical oxidation is carried out at a current of 1 to 5000 A / m 2 The current density used is 1 to 5 A / m 2In one embodiment of step a), the electrochemical oxidation is carried out at a rate of 1 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 rate of 1 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 of 1 to 50 A / m 2 The current density used is 1 to 5 A / m 2 The number of patients gradually decreases.

[0164] In one embodiment of step a), the electrochemical oxidation is carried out at a current of 5 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 of 5 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 rate of 5 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 of 5 to 50 A / m 2 The current density used is 1 to 5 A / m 2 The number of patients gradually decreases.

[0165] In one embodiment of step a), the electrochemical oxidation is carried out at a voltage 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 rate of 10 to 500 A / m 2 The current density used is 1 to 5 A / m 2In one embodiment of step a), the electrochemical oxidation is carried out at a rate 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 of 10 to 50 A / m 2 The current density used is 1 to 5 A / m 2 The number of patients gradually decreases.

[0166] In one embodiment of step a), the electrochemical oxidation is carried out at a current of 1 to 5000 A / m 2 The current densities used were 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 one embodiment of step a), the electrochemical oxidation is performed at a voltage of 1 to 500 A / m 2 The current densities used were 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 one embodiment of step a), the electrochemical oxidation is performed at a voltage of 1 to 100 A / m 2 The current densities used were 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 2In one embodiment of step a), the electrochemical oxidation is performed at a voltage of 1 to 50 A / m 2 The current densities used were 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 stepwise decrease is selected from the

[0167] In one embodiment of step a), the electrochemical oxidation is carried out at a current of 5 to 5000 A / m 2 The current densities used were 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 one embodiment of step a), the electrochemical oxidation is performed at a voltage of 5 to 500 A / m 2 The current densities used were 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 one embodiment of step a), the electrochemical oxidation is performed at a voltage of 5 to 100 A / m 2The current densities used were 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 one embodiment of step a), the electrochemical oxidation is performed at a current of 5 to 50 A / m 2 The current densities used were 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 stepwise decrease is selected from the

[0168] In one embodiment of step a), the electrochemical oxidation is carried out at a voltage of 10 to 5000 A / m 2 The current densities used were 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 one embodiment of step a), the electrochemical oxidation is performed at a voltage of 10 to 500 A / m 2 The current densities used were 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 2In one embodiment of step a), the electrochemical oxidation is performed at a voltage of 10 to 100 A / m 2 The current densities used were 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 one embodiment of step a), the electrochemical oxidation is performed at a current of 10 to 50 A / m 2 The current densities used were 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 stepwise decrease is selected from the

[0169] In one embodiment of step a), the electrochemical oxidation is carried out at a current of 1 to 5000 A / m 2 The current densities used were 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 one embodiment of step a), the electrochemical oxidation is performed at a current of 1 to 500 A / m 2The current densities used were 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 one embodiment of step a), the electrochemical oxidation is performed at a current of 1 to 100 A / m 2 The current densities used were 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 one embodiment of step a), the electrochemical oxidation is performed at a current of 1 to 50 A / m 2 The current densities used were 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 steps are selected from the following:

[0170] In one embodiment of step a), the electrochemical oxidation is carried out at a current of 5 to 5000 A / m 2The current densities used were 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 one embodiment of step a), the electrochemical oxidation is performed at a current of 5 to 500 A / m 2 The current densities used were 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 one embodiment of step a), the electrochemical oxidation is performed at a current of 5 to 100 A / m 2 The current densities used were 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 one embodiment of step a), the electrochemical oxidation is performed at a current of 5 to 50 A / m 2 The current densities used were 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 steps are selected from the following:

[0171] In one embodiment of step a), the electrochemical oxidation is carried out at a voltage of 10 to 5000 A / m 2 The current densities used were 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 one embodiment of step a), the electrochemical oxidation is performed at a current of 10 to 500 A / m 2 The current densities used were 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 one embodiment of step a), the electrochemical oxidation is performed at a current of 10 to 100 A / m 2 The current densities used were 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 one embodiment of step a), the electrochemical oxidation is performed at a current of 10 to 50 A / m 2The current densities used were 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 steps are selected from the following:

[0172] In one embodiment of step a), the electrochemical oxidation is carried out at a current of 1 to 5000 A / m 2 The current densities used were 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 one embodiment of step a), the electrochemical oxidation is performed at a current of 1 to 500 A / m 2 The current densities used were 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 one embodiment of step a), the electrochemical oxidation is performed at a current of 1 to 100 A / m 2The current densities used were 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 one embodiment of step a), the electrochemical oxidation is performed at a current of 1 to 50 A / m 2 The current densities used were 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 decreases in stages selected from the range, and the steps vary.

[0173] In one embodiment of step a), the electrochemical oxidation is carried out at a current of 5 to 5000 A / m 2 The current densities used were 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 one embodiment of step a), the electrochemical oxidation is performed at a current of 5 to 500 A / m 2The current densities used were 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 one embodiment of step a), the electrochemical oxidation is performed at a current of 5 to 100 A / m 2 The current densities used were 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 one embodiment of step a), the electrochemical oxidation is performed at a current of 5 to 50 A / m 2 The current densities used were 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 decreases in stages selected from the range, and the steps vary.

[0174] In one embodiment of step a), the electrochemical oxidation is carried out at a voltage of 10 to 5000 A / m 2The current densities used were 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 one embodiment of step a), the electrochemical oxidation is performed at a current of 10 to 500 A / m 2 The current densities used were 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 one embodiment of step a), the electrochemical oxidation is performed at a current of 10 to 100 A / m 2 The current densities used were 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 one embodiment of step a), the electrochemical oxidation is performed at a current of 10 to 50 A / m 2 The current densities used were 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 decreases in stages selected from the range, and the steps vary.

[0175] In one embodiment of step a), the electrochemical oxidation is carried out at a voltage of 10 to 50 A / m 2 The current density used is 50 to 40 A / m 2 , then 40 to 30 A / m 2 , then 30 to 20 A / m 2 , then 20 to 10 A / m 2 It decreases gradually like this.

[0176] In one embodiment of the sequential one-pot synthesis, the current density used in step a) is lower than the current density used in step b). The selectivity with which compound (XVII) was obtained in this embodiment was surprising. The oxidation selectivity was surprisingly high, and no secondary products were produced. The oxidation selectivity was surprisingly high, and no secondary products were produced. Such secondary products may interfere with the subsequent racemization and reduction steps, necessitating isolation and purging after each step.

[0177] In one embodiment of step a), the electrochemical oxidation is carried out at a current of 1 to 5000 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 In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 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 wherein the current density used in step a) is lower than the current density used in step b).

[0178] In one embodiment of step a), the electrochemical oxidation is carried out at a current of 5 to 5000 A / m 2In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 500 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 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).

[0179] In one embodiment of step a), the electrochemical oxidation is carried out at a voltage of 10 to 5000 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 In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 100 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 wherein the current density used in step a) is lower than the current density used in step b).

[0180] In one embodiment, the current density used in the oxidation step a) is lower than that used in the electrochemical reduction step b), and the current density used in step a) is reduced. It was surprising that high current and chemoselectivity could be achieved by reducing the current. The oxidation selectivity was surprisingly high, and no secondary components were produced. Since these components could interfere with the racemization and reduction steps, isolation and purging after each step would not be required.

[0181] In one embodiment of step a), the electrochemical oxidation is carried out at a current of 1 to 5000 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 In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 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 wherein the current density used in step a) is decreased and the current density used in step a) is lower than the current density used in step b).

[0182] In one embodiment of step a), the electrochemical oxidation is carried out at a current of 5 to 5000 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 2In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 100 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 wherein the current density used in step a) is decreased and the current density used in step a) is lower than the current density used in step b).

[0183] In one embodiment of step a), the electrochemical oxidation is carried out at a voltage of 10 to 5000 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 In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 100 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 wherein the current density used in step a) is decreased and the current density used in step a) is lower than the current density used in step b).

[0184] In one embodiment, the current density used in oxidation step a) is lower than that used in electrochemical reduction step b), and the current density used in step a) is gradually decreased. It was surprising that high currents and chemoselectivities were achieved by gradually decreasing the current. The oxidation selectivity was surprisingly high, and no secondary components were produced. Such components would interfere with the racemization and reduction steps, eliminating the need for isolation and purging after each step.

[0185] In one embodiment of step a), the electrochemical oxidation is carried out at a current of 1 to 5000 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, where the current density used in step a) is decreased stepwise, and the current density used in step a) is lower than the current density used in step b). 2 In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 100 A / m, where the current density used in step a) is decreased stepwise, and the current density used in step a) is lower than the current density used in step b). 2 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 in step a) is decreased stepwise, and the current density used in step a) is lower than the current density used in step b).

[0186] In one embodiment of step a), the electrochemical oxidation is carried out at a current of 5 to 5000 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, where the current density used in step a) is decreased stepwise, and the current density used in step a) is lower than the current density used in step b). 2In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 5 to 100 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 wherein the current density used in step a) is decreased stepwise, and the current density used in step a) is lower than the current density used in step b).

[0187] In one embodiment of step a), the electrochemical oxidation is carried out at a voltage of 10 to 5000 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, where the current density used in step a) is decreased stepwise, and the current density used in step a) is lower than the current density used in step b). 2 In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 100 A / m, where the current density used in step a) is decreased stepwise, and the current density used in step a) is lower than the current density used in step b). 2 In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 10 to 50 A / m, where the current density used in step a) is decreased stepwise, and the current density used in step a) is lower than the current density used in step b). 2 wherein the current density used in step a) is decreased stepwise, and the current density used in step a) is lower than the current density used in step b).

[0188] In one embodiment of step a), the electrochemical oxidation is carried out at a current of 1 to 5000 A / m 2 The current density used is 0.1 to 100 A / m 2In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 500 A / m 2 The current density used is 0.1 to 100 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 The current density used is 0.1 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 The current density used is 0.1 to 100 A / m 2 The current density used in step a) is lower than the current density used in step b).

[0189] In one embodiment of step a), the electrochemical oxidation is carried out at a current of 5 to 5000 A / m 2 The current density used is 0.1 to 100 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 The current density used is 0.1 to 100 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 The current density used is 0.1 to 100 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 2The current density used is 0.1 to 100 A / m 2 The current density used in step a) is lower than the current density used in step b).

[0190] In one embodiment of step a), the electrochemical oxidation is carried out at a voltage of 10 to 5000 A / m 2 The current density used is 0.1 to 100 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 0.1 to 100 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 0.1 to 100 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 0.1 to 100 A / m 2 The current density used in step a) is lower than the current density used in step b).

[0191] In one embodiment of step a), the electrochemical oxidation is carried out at a current of 1 to 5000 A / m 2 The current density used is 0.5 to 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 The current density used is 0.5 to 50 A / m 2In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 50 A / m 2 The current density used is 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 The current density used is 0.5 to 50 A / m 2 The current density used in step a) is lower than the current density used in step b).

[0192] In one embodiment of step a), the electrochemical oxidation is carried out at a current of 5 to 5000 A / m 2 The current density used is 0.5 to 50 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 The current density used is 0.5 to 50 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 The current density used is 0.5 to 50 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 The current density used is 0.5 to 50 A / m 2 The current density used in step a) is lower than the current density used in step b).

[0193] In one embodiment of step a), the electrochemical oxidation is carried out at a voltage of 10 to 5000 A / m 2 The current density used is 0.5 to 50 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 0.5 to 50 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 0.5 to 50 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 0.5 to 50 A / m 2 The current density used in step a) is lower than the current density used in step b).

[0194] In one embodiment of step a), the electrochemical oxidation is carried out at a current of 1 to 5000 A / m 2 The current density used is 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 The current density used is 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 The current density used is 1 to 10 A / m 2In one embodiment of step a), the electrochemical oxidation is carried out at a current density of 1 to 50 A / m 2 The current density used is 1 to 10 A / m 2 The current density used in step a) is lower than the current density used in step b).

[0195] In one embodiment of step a), the electrochemical oxidation is carried out at a current of 5 to 5000 A / m 2 The current density used is 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 The current density used is 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 The current density used is 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 The current density used is 1 to 10 A / m 2 The current density used in step a) is lower than the current density used in step b).

[0196] In one embodiment of step a), the electrochemical oxidation is carried out at a voltage of 10 to 5000 A / m 2 The current density used is 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 / m2 The current density used is 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 100 A / m 2 The current density used is 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 50 A / m 2 The current density used is 1 to 10 A / m 2 The current density used in step a) is lower than the current density used in step b).

[0197] In one embodiment of step a), the electrochemical oxidation is carried out at a current of 1 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 1 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 1 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 1 to 50 A / m 2 The current density used is 1 to 5 A / m 2 The current density used in step a) is lower than the current density used in step b).

[0198] In one embodiment of step a), the electrochemical oxidation is carried out at a current of 5 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 5 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 5 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 5 to 50 A / m 2 The current density used is 1 to 5 A / m 2 The current density used in step a) is lower than the current density used in step b).

[0199] In one embodiment of step a), the electrochemical oxidation is carried out at a voltage 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 2In 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 current density used in step a) is lower than the current density used in step b).

[0200] In one embodiment of step a), the electrochemical oxidation is carried out at a current of 1 to 5000 A / m 2 The current densities used were 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) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is performed at a current density of 1 to 500 A / m 2 The current densities used were 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) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is performed at a current density of 1 to 100 A / m 2The current densities used were 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) is lower than the current density used in step b). In one embodiment of step a), the electrochemical oxidation is performed at a current density of 1 to 50 A / m 2 The current densities used were 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 current density used in step a) is lower than the current density used in step b).

[0201] In one embodiment of step a), the electrochemical oxidation is carried out at a current of 5 to 5000 A / m 2 The current densities used were 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 one embodiment of step a), 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 performed at a current density of 5 to 500 A / m 2The current densities used were 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 one embodiment of step a), 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 performed at a current density of 5 to 100 A / m 2 The current densities used were 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 one embodiment of step a), the electrochemical oxidation is performed at a current of 5 to 50 A / m 2 The current densities used were 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 current density used in step a) is lower than the current density used in step b).

[0202] In one embodiment of step a), the electrochemical oxidation is carried out at a voltage of 10 to 5000 A / m 2The current densities used were 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 one embodiment of step a), 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 performed at a current density of 10 to 500 A / m 2 The current densities used were 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 one embodiment of step a), 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 performed at a current density of 10 to 100 A / m 2 The current densities used were 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 one embodiment of step a), 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 performed at a current density of 10 to 50 A / m 2The current densities used were 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 current density used in step a) is lower than the current density used in step b).

[0203] In one embodiment of step a), the electrochemical oxidation is carried out at a current of 1 to 5000 A / m 2 The current densities used were 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 one embodiment of step a), the electrochemical oxidation is performed at a current density of 1 to 500 A / m 2 The current densities used were 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 one embodiment of step a), the electrochemical oxidation is performed at a current density of 1 to 100 A / m 2The current densities used were 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 wherein the steps are identical 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 performed at a current density of 1 to 50 A / m 2 The current densities used were 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 wherein the steps are identical and the current density used in step a) is lower than the current density used in step b).

[0204] In one embodiment of step a), the electrochemical oxidation is carried out at a current of 5 to 5000 A / m 2 The current densities used were 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 one embodiment of step a), the electrochemical oxidation is performed at a current density of 5 to 500 A / m 2The current densities used were 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 one embodiment of step a), the electrochemical oxidation is performed at a current density of 5 to 100 A / m 2 The current densities used were 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 steps are identical 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 performed at a current density of 5 to 50 A / m 2 The current densities used were 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 wherein the steps are identical and the current density used in step a) is lower than the current density used in step b).

[0205] In one embodiment of step a), the electrochemical oxidation is carried out at a voltage of 10 to 5000 A / m 2The current densities used were 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 one embodiment of step a), the electrochemical oxidation is performed at a current density of 10 to 500 A / m 2 The current densities used were 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 one embodiment of step a), the electrochemical oxidation is performed at a current density of 10 to 100 A / m 2 The current densities used were 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 one embodiment of step a), the electrochemical oxidation is performed at a current density of 10 to 50 A / m 2The current densities used were 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 wherein the steps are identical and the current density used in step a) is lower than the current density used in step b).

[0206] In one embodiment of step a), the electrochemical oxidation is carried out at a current of 1 to 5000 A / m 2 The current densities used were 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 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 performed at a current density of 1 to 500 A / m 2 The current densities used were 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 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 performed at a current density of 1 to 100 A / m 2The current densities used were 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 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 performed at a current density of 1 to 50 A / m 2 The current densities used were 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 current density used in step a) is lower than the current density used in step b).

[0207] In one embodiment of step a), the electrochemical oxidation is carried out at a current of 5 to 5000 A / m 2 The current densities used were 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 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 performed at a current density of 5 to 500 A / m 2The current densities used were 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 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 performed at a current density of 5 to 100 A / m 2 The current densities used were 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 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 performed at a current density of 5 to 50 A / m 2 The current densities used were 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 current density used in step a) is lower than the current density used in step b).

[0208] In one embodiment of step a), the electrochemical oxidation is carried out at a voltage of 10 to 5000 A / m 2The current densities used were 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 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 performed at a current density of 10 to 500 A / m 2 The current densities used were 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 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 performed at a current density of 10 to 100 A / m 2 The current densities used were 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 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 performed at a current density of 10 to 50 A / m 2The current densities used were 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 current density used in step a) is lower than the current density used in step b).

[0209] Step b) 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.

[0210] In one embodiment of step b), a solvent is used. In one embodiment of step b), a solvent selected from aprotic solvents, protic solvents, and mixtures thereof is used. In one embodiment of step b), a solvent selected from polar aprotic solvents and mixtures thereof is used. In one embodiment of step b), a solvent selected from polar aprotic solvents selected from dimethylformamide (DMF), dimethyl sulfoxide, acetonitrile, acetone, and mixtures thereof is used. In one embodiment of step b), a solvent selected from protic solvents selected from methanol, acetic acid, ethanol, formic acid, water, and mixtures thereof is used. In one embodiment of step b), a solvent selected from dimethylformamide (DMF), methanol, acetic acid, and mixtures thereof is used. In one embodiment of step b), a solvent selected from methanol, acetic acid, and mixtures thereof is used. In one embodiment of step b), methanol is used. In one embodiment of step b), acetic acid is used.

[0211] In one embodiment of step b), aprotic solvents, protic solvents, and mixtures thereof; or polar aprotic solvents; or a polar aprotic solvent selected from dimethylformamide (DMF), dimethyl sulfoxide, acetonitrile, and acetone; or a protic solvent selected from 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 a mixture of the above A solvent selected from the group consisting of:

[0212] In one embodiment of step b), a conductive salt is used selected from the group consisting of organic ammonium salts, ionic liquids, tetraalkylammonium fluoroborates, quaternary ammonium salts and mixtures thereof.

[0213] In one embodiment of step b), a conductive salt selected from the group consisting of tetraethylammonium tetrafluoroborate, tetrabutylammonium hexafluorophosphate, tetrabutylammonium hydrogen sulfate and mixtures thereof is used.

[0214] In one embodiment of step b), the solvent is used in an amount of 80 to 99% by weight, based on the amount of the reaction mixture. In one embodiment of step b), the solvent is used in an amount of 85 to 95% by weight, based on the amount of the reaction mixture. In one embodiment of step b), the solvent is used in an amount of 85 to 92% by weight, based on the amount of the reaction mixture. In one embodiment of step b), the solvent is used in an amount of 90% by weight, based on the amount of the reaction mixture.

[0215] In one embodiment of step b), - a conductive salt selected from the group consisting of organic ammonium salts, ionic liquids, tetraalkylammonium fluoroborates, quaternary ammonium salts and mixtures thereof; and a solvent selected from dimethylformamide (DMF), methanol, acetic acid and mixtures thereof is used.

[0216] In one embodiment of step b), - a conductive salt selected from the group consisting of organic ammonium salts, ionic liquids, tetraalkylammonium fluoroborates, quaternary ammonium salts and mixtures thereof; and a solvent selected from dimethylformamide (DMF), methanol, acetic acid and mixtures thereof is used.

[0217] In one embodiment of step b), a conductive salt selected from the group consisting of tetraethylammonium tetrafluoroborate, tetrabutylammonium hexafluorophosphate, tetrabutylammonium hydrogen sulfate, and mixtures thereof; and a solvent selected from dimethylformamide (DMF), methanol, acetic acid and mixtures thereof is used.

[0218] In one embodiment of step b), - a conductive salt selected from the group consisting of organic ammonium salts, ionic liquids, tetraalkylammonium fluoroborates, quaternary ammonium salts and mixtures thereof; and -methanol is used.

[0219] In one embodiment of step b), - a conductive salt selected from the group consisting of organic ammonium salts, ionic liquids, tetraalkylammonium fluoroborates, quaternary ammonium salts and mixtures thereof; and -methanol is used.

[0220] In one embodiment of step b), a conductive salt selected from the group consisting of tetraethylammonium tetrafluoroborate, tetrabutylammonium hexafluorophosphate, tetrabutylammonium hydrogen sulfate, and mixtures thereof; and -methanol is used.

[0221] In one embodiment of step b), - a conductive salt selected from the group consisting of organic ammonium salts, ionic liquids, tetraalkylammonium fluoroborates, quaternary ammonium salts and mixtures thereof; and -Acetic acid is used.

[0222] In one embodiment of step b), - a conductive salt selected from the group consisting of organic ammonium salts, ionic liquids, tetraalkylammonium fluoroborates, quaternary ammonium salts and mixtures thereof; and -Acetic acid is used.

[0223] In one embodiment of step b), a conductive salt selected from the group consisting of tetraethylammonium tetrafluoroborate, tetrabutylammonium hexafluorophosphate, tetrabutylammonium hydrogen sulfate, and mixtures thereof; and -Acetic acid is used.

[0224] In one embodiment of step b), 0.05 to 3 equivalents of conductive salt are used based on 1 equivalent of the compound according to formula (XIII). This means that when 0.05 equivalents of conductive salt are used, 1 equivalent of the compound according to formula (XIII) is used. In one embodiment of step b), 0.2 to 2 equivalents of conductive salt are used based on 1 equivalent of the compound according to formula (XIII). In one embodiment of step b), 0.5 to 1.5 equivalents of conductive salt are used based on 1 equivalent of the compound according to formula (XIII). In one embodiment of step b), 0.6 to 1.3 equivalents of conductive salt are used based on 1 equivalent of the compound according to formula ent-(I). The equivalents are based on the compound according to formula (XIII). This means that when 1.3 equivalents (1.3 mol) of acid are used, 1 equivalent (1 mol) of the compound according to formula (XIII) is used.

[0225] 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.

[0226] 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.

[0227] 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.

[0228] 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.

[0229] 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.

[0230] 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.

[0231] In one embodiment of step b), the electrochemical reduction is carried out at a cell voltage of less than 30V, less than 29V, less than 28V, less than 27V, less than 26V, less than 25V, less than 24V, less than 23V, less than 22V, less than 21V, less than 20V, less than 19V, less than 18V, less than 17V, less than 16V, less than 15V, less than 14V, less than 13V, less than 12V, less than 11V, less than 10V, less than 9V, less than 8V, less than 7V, less than 6V, less than 5V, less than 4V, less than 3V, less than 2V, less than 1V, less than 0.5V or less than 0.1V.

[0232] In one embodiment of step b), the electrochemical reduction is performed at a voltage of 1 to 10,000 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 The current density is

[0233] In one embodiment of step b), the electrochemical reduction is performed at a voltage of 5 to 10,000 A / m 2 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 The current density is

[0234] In one embodiment of step b), the electrochemical reduction is performed at a voltage of 10 to 10,000 A / m 2 In one embodiment of step b), the electrochemical reduction is carried out at a current density of 10 to 1000 A / m2 In one embodiment of step b), the electrochemical reduction is carried out at a current density of 10 to 500 A / m 2 In one embodiment of step b), the electrochemical reduction is carried out at a current density of 10 to 400 A / m 2 In one embodiment of step b), the electrochemical reduction is carried out at a current density of 10 to 350 A / m 2 The current density is

[0235] In one embodiment of step b), the electrochemical reduction is performed at a current of 100 to 10,000 A / m 2 In one embodiment of step b), the electrochemical reduction is carried out at a current density of 100 to 1000 A / m 2 In one embodiment of step b), the electrochemical reduction is carried out at a current density of 100 to 500 A / m 2 In one embodiment of step b), the electrochemical reduction is carried out at a current density of 100 to 400 A / m 2 In one embodiment of step b), the electrochemical reduction is carried out at a current density of 100 to 350 A / m 2 The current density is

[0236] In one embodiment of step b), the electrochemical reduction is performed at a voltage of 200 to 400 A / m 2 In one embodiment of step b), the electrochemical reduction is carried out at a constant current density of 200 A / m 2 In one embodiment of step b), the electrochemical reduction is carried out at a constant current density of 250 A / m 2 In one embodiment of step b), the electrochemical reduction is carried out at a constant current density of 300 A / m 2 In one embodiment of step b), the electrochemical reduction is carried out at a constant current density of 350 A / m 2 In one embodiment of step b), the electrochemical reduction is carried out at a constant current density of 400 A / m 2 The current density is constant.

[0237] In one embodiment of step b), the electrochemical reduction is performed at a voltage of 1 to 10,000 A / m 2In 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 The current density may be constant, variable, increasing, decreasing, or may follow a specific program.

[0238] In one embodiment of step b), the electrochemical reduction is performed at a voltage of 5 to 10,000 A / m 2 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. 2In one embodiment of step b), the electrochemical reduction is carried out at a current density of 5 to 350 A / m. 2 The current density may be constant, variable, increasing, decreasing, or may follow a specific program.

[0239] In one embodiment of step b), the electrochemical reduction is performed at a voltage of 10 to 10,000 A / m 2 In one embodiment of step b), the electrochemical reduction is carried out at a current density of 10 to 1000 A / m. 2 In one embodiment of step b), the electrochemical reduction is carried out at a current density of 10 to 500 A / m. 2 In one embodiment of step b), the electrochemical reduction is carried out at a current density of 10 to 400 A / m. 2 In one embodiment of step b), the electrochemical reduction is carried out at a current density of 10 to 350 A / m. 2 The current density may be constant, variable, increasing, decreasing, or may follow a specific program.

[0240] In one embodiment of step b), the electrochemical reduction is performed at a voltage of 1 to 10,000 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 2In 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 The current density may be constant or variable.

[0241] In one embodiment of step b), the electrochemical reduction is performed at a voltage of 5 to 10,000 A / m 2 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 The current density may be constant or variable.

[0242] In one embodiment of step b), the electrochemical reduction is performed at a voltage of 10 to 10,000 A / m 2 In one embodiment of step b), the electrochemical reduction is carried out at a current density of 10 to 1000 A / m 2 In one embodiment of step b), the electrochemical reduction is carried out at a current density of 10 to 500 A / m 2 In one embodiment of step b), the electrochemical reduction is carried out at a current density of 10 to 400 A / m 2 In one embodiment of step b), the electrochemical reduction is carried out at a current density of 10 to 350 A / m 2 The current density may be constant or variable.

[0243] In one embodiment of step b), the electrochemical reduction is performed at a current of 100 to 10,000 A / m 2 In one embodiment of step b), the electrochemical reduction is carried out at a current density of 100 to 1000 A / m 2 In one embodiment of step b), the electrochemical reduction is carried out at a current density of 100 to 500 A / m 2 In one embodiment of step b), the electrochemical reduction is carried out at a current density of 100 to 400 A / m 2 In one embodiment of step b), the electrochemical reduction is carried out at a current density of 100 to 350 A / m 2 The current density may be constant or variable.

[0244] In one embodiment of step b), the electrochemical reduction is performed at a voltage of 200 to 400 A / m 2 In one embodiment of step b), the electrochemical reduction is carried out at a constant current density of 200 A / m 2 In one embodiment of step b), the electrochemical reduction is carried out at a constant current density of 250 A / m 2 In one embodiment of step b), the electrochemical reduction is carried out at a constant current density of 300 A / m 2 In one embodiment of step b), the electrochemical reduction is carried out at a constant current density of 350 A / m 2 In one embodiment of step b), the electrochemical reduction is carried out at a constant current density of 400 A / m 2 The current density may be constant or variable.

[0245] In one embodiment of step b), the electrochemical reduction is performed at a voltage of 1 to 10,000 A / m 2 In one embodiment of step b), the electrochemical reduction is carried out at a current density of 1 to 1000 A / m2 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 The current density is increased or decreased.

[0246] In one embodiment of step b), the electrochemical reduction is performed at a voltage of 5 to 10,000 A / m 2 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 The current density is increased or decreased.

[0247] In one embodiment of step b), the electrochemical reduction is performed at a voltage of 10 to 10,000 A / m 2 In one embodiment of step b), the electrochemical reduction is carried out at a current density of 10 to 1000 A / m 2 In one embodiment of step b), the electrochemical reduction is carried out at a current density of 10 to 500 A / m 2 In one embodiment of step b), the electrochemical reduction is carried out at a current density of 10 to 400 A / m 2 In one embodiment of step b), the electrochemical reduction is carried out at a current density of 10 to 350 A / m2 The current density is increased or decreased.

[0248] In one embodiment of step b), the electrochemical reduction is performed at a current of 100 to 10,000 A / m 2 In one embodiment of step b), the electrochemical reduction is carried out at a current density of 100 to 1000 A / m 2 In one embodiment of step b), the electrochemical reduction is carried out at a current density of 100 to 500 A / m 2 In one embodiment of step b), the electrochemical reduction is carried out at a current density of 100 to 400 A / m 2 In one embodiment of step b), the electrochemical reduction is carried out at a current density of 100 to 350 A / m 2 The current density is increased or decreased.

[0249] In one embodiment of step b), the electrochemical reduction is performed at a voltage of 200 to 400 A / m 2 In one embodiment of step b), the electrochemical reduction is carried out at a constant current density of 200 A / m 2 In one embodiment of step b), the electrochemical reduction is carried out at a constant current density of 250 A / m 2 In one embodiment of step b), the electrochemical reduction is carried out at a constant current density of 300 A / m 2 In one embodiment of step b), the electrochemical reduction is carried out at a constant current density of 350 A / m 2 In one embodiment of step b), the electrochemical reduction is carried out at a constant current density of 400 A / m 2 The current density is increased or decreased.

[0250] Step c) In one embodiment, the sequential one-pot synthesis comprises step c) Step c) Isolation of the compound according to formula (XIII) Further includes:

[0251] In one embodiment of step c), the isolation is selected from filtration and crystallization. In one embodiment of step c), the compound according to formula (XIII) is isolated by filtration. In one embodiment of step c), the compound according to formula (XIII) is isolated by crystallization.

[0252] Step d) In one embodiment, the sequential one-pot synthesis comprises step d) Step d) Crystallization of the compound according to formula (XIII) Further includes:

[0253] In one embodiment of step d), crystallization is carried out in an organic solvent or a mixture of organic solvents. In one embodiment of step c), isolation is selected from chiral chromatography, crystallization, racemic resolution, diastereomeric salt formation and chiral salt formation. For example, isolation by diastereomeric salt formation is described in U.S. Patent Application Publication No. 20100136142, U.S. Patent Application Publication No. 20170217957 or WO2019206909.

[0254] In one embodiment of step d), crystallization is carried out in an organic solvent. In one embodiment of step d), crystallization is carried out in isopropanol, n-propanol, or a mixture thereof. In one embodiment, compound (XIII) is first dissolved and then cooled. In one embodiment, compound (XIII) is first dissolved by heating above 90°C and then cooled to 10°C. In one embodiment, compound (XIII) is first dissolved by heating above 85°C and then cooled to 5°C. In one embodiment, compound (XIII) is first dissolved by heating above 75°C and then cooled to 0°C. These embodiments may result in a highly pure form of the compound according to formula (XIII).

[0255] Further embodiments In one embodiment, the current density used in step a) is lower than that used in step b). The oxidation selectivity is surprisingly high, and no secondary components are produced. Such components may interfere with the racemization and reduction steps, so isolation and purging after each step may not be required.

[0256] In one embodiment, The electrochemical oxidation of step a) is performed at a voltage of 1 to 5000 A / m 2 , 1~500A / m 2 , 1~100A / m 2 , 1~50A / m 2 , 5~5000A / m 2 , 5~500A / m 2 , 5~100A / m 2 , 5~50A / m 2 , 10~5000A / m 2 , 10~500A / m 2 , 10~100A / m 2 , and 10 to 50 A / m 2 at a current density selected from: The electrochemical reduction in step b) is performed at a voltage of 1 to 10,000 A / m 2 , 1A / m 2 ~1000A / m 2 , 1A / m 2 ~500A / m 2 , 5A / m 2 ~10000A / m 2 , 50~1000A / m 2 , 200~500A / m 2 , 10~10000A / m 2 , 10~1000A / m 2 , 10~500A / m 2 , 100~500A / m 2 , 200~400A / m 2 , 200A / m 2 , 250A / m 2 , 300A / m 2 , 350A / m 2 and 400A / m 2 The current density is selected from the following:

[0257] In one embodiment, The electrochemical oxidation of step a) is performed at a voltage of 1 to 5000 A / m 2 at a current density of; The electrochemical reduction in step b) is performed at a voltage of 1 to 10,000 A / m 2 The current density is

[0258] In one embodiment, The electrochemical oxidation of step a) is performed at a voltage of 1 to 500 A / m 2 at a current density of; The electrochemical reduction in step b) is performed at a voltage of 1 to 1000 A / m 2 The current density is

[0259] In one embodiment, The electrochemical oxidation of step a) is performed at a voltage of 1 to 500 A / m 2 at a current density of; The electrochemical reduction in step b) is performed at a voltage of 1 to 500 A / m 2 The current density is selected from the following:

[0260] In one embodiment, The electrochemical oxidation of step a) is performed at a voltage of 1 to 100 A / m 2 at a current density of; The electrochemical reduction of step b) is performed at 1 A / m 2 ~500A / m 2 The current density is

[0261] In one embodiment, The electrochemical oxidation of step a) is performed at a voltage of 1 to 100 A / m 2 at a current density of; The electrochemical reduction in step b) is performed at 10 A / m 2 ~500A / m 2 The current density is

[0262] In one embodiment, The electrochemical oxidation in step a) is performed at a voltage of 1 to 50 A / m 2 at a current density of; The electrochemical reduction in step b) is performed at 10 A / m 2 ~500A / m 2 The current density is

[0263] In one embodiment, The electrochemical oxidation of step a) is performed at a voltage of 1 to 100 A / m 2 at a current density selected from: The electrochemical reduction in step b) is performed at 100-500 A / m 2 The current density is selected from the following:

[0264] In one embodiment, The electrochemical oxidation in step a) is performed at a voltage of 1 to 50 A / m 2 at a current density selected from: The electrochemical reduction in step b) is performed at 100-500 A / m 2 The current density is selected from the following:

[0265] In one embodiment, The electrochemical oxidation of step a) is performed at a voltage of 1 to 100 A / m 2 at a current density selected from: The electrochemical reduction in step b) is performed at 200-400 A / m 2 The current density is selected from the following:

[0266] In one embodiment, The electrochemical oxidation in step a) is performed at a voltage of 1 to 50 A / m 2 at a current density selected from: The electrochemical reduction in step b) is performed at 200-400 A / m 2 The current density is selected from the following:

[0267] In one embodiment, The electrochemical oxidation of step a) is performed at a voltage of 1 to 5000 A / m 2 , 1~500A / m 2 , 1~100A / m 2 , 1~50A / m 2 , 5~5000A / m 2 , 5~500A / m2 , 5~100A / m 2 , 5~50A / m 2 , 10~5000A / m 2 , 10~500A / m 2 , 10~100A / m 2 , and 10 to 50 A / m 2 wherein in step a) the current density used is decreased; The electrochemical reduction in step b) is performed at a voltage of 1 to 10,000 A / m 2 , 1~1000A / m 2 , 1~500A / m 2 , 5~10000A / m 2 , 50~1000A / m 2 , 200~500A / m 2 , 10~10000A / m 2 , 10~1000A / m 2 , 10~500A / m 2 , 100~500A / m 2 , 200~400A / m 2 , 200A / m 2 , 250A / m 2 , 300A / m 2 , 350A / m 2 and 400A / m 2 The current density is selected from the following:

[0268] In one embodiment, The electrochemical oxidation of step a) is performed at a voltage of 1 to 5000 A / m 2 and in step a) the current density used is decreased; The electrochemical reduction in step b) is performed at a voltage of 1 to 10,000 A / m 2 The current density is

[0269] In one embodiment, The electrochemical oxidation of step a) is performed at a voltage of 1 to 500 A / m 2 and in step a) the current density used is decreased; The electrochemical reduction in step b) is performed at a voltage of 1 to 1000 A / m 2 The current density is

[0270] In one embodiment, The electrochemical oxidation of step a) is performed at a voltage of 1 to 500 A / m 2 and in step a) the current density used is decreased; The electrochemical reduction in step b) is performed at a voltage of 1 to 500 A / m 2 The current density is selected from the following:

[0271] In one embodiment, The electrochemical oxidation of step a) is performed at a voltage of 1 to 100 A / m 2 and in step a) the current density used is decreased; The electrochemical reduction of step b) is performed at 1 A / m 2 ~500A / m 2 The current density is

[0272] In one embodiment, The electrochemical oxidation of step a) is performed at a voltage of 1 to 100 A / m 2 and in step a) the current density used is decreased; The electrochemical reduction in step b) is performed at 10 A / m 2 ~500A / m 2 The current density is

[0273] In one embodiment, The electrochemical oxidation in step a) is performed at a voltage of 1 to 50 A / m 2 and in step a) the current density used is decreased; The electrochemical reduction in step b) is performed at 10 A / m 2 ~500A / m 2 The current density is

[0274] In one embodiment, The electrochemical oxidation of step a) is performed at a voltage of 1 to 100 A / m 2 wherein in step a) the current density used is decreased; The electrochemical reduction in step b) is performed at 100-500 A / m 2 The current density is selected from the following:

[0275] In one embodiment, The electrochemical oxidation in step a) is performed at a voltage of 1 to 50 A / m 2 wherein in step a) the current density used is decreased; The electrochemical reduction in step b) is performed at 100-500 A / m 2 The current density is selected from the following:

[0276] In one embodiment, The electrochemical oxidation of step a) is performed at a voltage of 1 to 100 A / m 2 wherein in step a) the current density used is decreased; The electrochemical reduction in step b) is performed at 200-400 A / m 2 The current density is selected from the following:

[0277] In one embodiment, The electrochemical oxidation in step a) is performed at a voltage of 1 to 50 A / m 2 wherein in step a) the current density used is decreased; The electrochemical reduction in step b) is performed at 200-400 A / m 2 The current density is selected from the following:

[0278] In one embodiment, The electrochemical oxidation of step a) is performed at a voltage of 1 to 5000 A / m 2 , 1~500A / m 2 , 1~100A / m 2 , 1~50A / m 2 , 5~5000A / m 2 , 5~500A / m 2 , 5~100A / m 2 , 5~50A / m 2 , 10~5000A / m 2 , 10~500A / m 2 , 10~100A / m2 , and 10 to 50 A / m 2 wherein in step a) the current density used is decreased stepwise; The electrochemical reduction in step b) is performed at a voltage of 1 to 10,000 A / m 2 , 1A / m 2 ~1000A / m 2 , 1A / m 2 ~500A / m 2 , 5A / m 2 ~10000A / m 2 , 50~1000A / m 2 , 200~500A / m 2 , 10~10000A / m 2 , 10~1000A / m 2 , 10~500A / m 2 , 100~500A / m 2 , 200~400A / m 2 , 200A / m 2 , 250A / m 2 , 300A / m 2 , 350A / m 2 and 400A / m 2 The current density is selected from the following:

[0279] In one embodiment, The electrochemical oxidation of step a) is performed at a voltage of 1 to 5000 A / m 2 wherein in step a) the current density used is gradually reduced; The electrochemical reduction in step b) is performed at a voltage of 1 to 10,000 A / m 2 The current density is

[0280] In one embodiment, The electrochemical oxidation of step a) is performed at a voltage of 1 to 500 A / m 2 wherein in step a) the current density used is gradually reduced; The electrochemical reduction in step b) is performed at a voltage of 1 to 1000 A / m 2 The current density is

[0281] In one embodiment, The electrochemical oxidation of step a) is performed at a voltage of 1 to 500 A / m 2 wherein in step a) the current density used is gradually reduced; The electrochemical reduction in step b) is performed at a voltage of 1 to 500 A / m 2 The current density is selected from the following:

[0282] In one embodiment, The electrochemical oxidation of step a) is performed at a voltage of 1 to 100 A / m 2 wherein in step a) the current density used is gradually reduced; The electrochemical reduction of step b) is performed at 1 A / m 2 ~500A / m 2 The current density is

[0283] In one embodiment, The electrochemical oxidation of step a) is performed at a voltage of 1 to 100 A / m 2 wherein in step a) the current density used is gradually reduced; The electrochemical reduction in step b) is performed at 10 A / m 2 ~500A / m 2 The current density is

[0284] In one embodiment, The electrochemical oxidation in step a) is performed at a voltage of 1 to 50 A / m 2 wherein in step a) the current density used is gradually reduced; The electrochemical reduction in step b) is performed at 10 A / m 2 ~500A / m 2 The current density is

[0285] In one embodiment, The electrochemical oxidation of step a) is performed at a voltage of 1 to 100 A / m 2 wherein in step a) the current density used is decreased stepwise; The electrochemical reduction in step b) is performed at 100-500 A / m 2The current density is selected from the following:

[0286] In one embodiment, The electrochemical oxidation in step a) is performed at a voltage of 1 to 50 A / m 2 wherein in step a) the current density used is decreased stepwise; The electrochemical reduction in step b) is performed at 100-500 A / m 2 The current density is selected from the following:

[0287] In one embodiment, The electrochemical oxidation of step a) is performed at a voltage of 1 to 100 A / m 2 wherein in step a) the current density used is decreased stepwise; The electrochemical reduction in step b) is performed at 200-400 A / m 2 The current density is selected from the following:

[0288] In one embodiment, The electrochemical oxidation in step a) is performed at a voltage of 1 to 50 A / m 2 wherein in step a) the current density used is decreased stepwise; The electrochemical reduction in step b) is performed at 200-400 A / m 2 The current density is selected from the following:

[0289] In one embodiment, The electrochemical oxidation of step a) is performed at a voltage of 1 to 5000 A / m 2 , 1~500A / m 2 , 1~100A / m 2 , 1~50A / m 2 , 5~5000A / m 2 , 5~500A / m 2 , 5~100A / m 2 , 5~50A / m 2 , 10~5000A / m 2 , 10~500A / m 2 , 10~100A / m 2 , and 10 to 50 A / m 2wherein in step a) the current density used is decreased; The electrochemical reduction in step b) is performed at a voltage of 1 to 10,000 A / m 2 , 1~1000A / m 2 , 1~500A / m 2 , 5A / m 2 ~10000A / m 2 , 50~1000A / m 2 , 200~500A / m 2 , 10~10000A / m 2 , 10~1000A / m 2 , 10~500A / m 2 , 100~500A / m 2 , 200~400A / m 2 , 200A / m 2 , 250A / m 2 , 300A / m 2 , 350A / m 2 and 400A / m 2 the current density used in step a) is lower than the current density used in step b).

[0290] In one embodiment, The electrochemical oxidation of step a) is performed at a voltage of 1 to 5000 A / m 2 and in step a) the current density used is decreased; The electrochemical reduction in step b) is performed at a voltage of 1 to 10,000 A / m 2 the current density used in step a) is lower than the current density used in step b).

[0291] In one embodiment, The electrochemical oxidation of step a) is performed at a voltage of 1 to 500 A / m 2 and in step a) the current density used is decreased; The electrochemical reduction in step b) is performed at a voltage of 1 to 1000 A / m 2 the current density used in step a) is lower than the current density used in step b).

[0292] In one embodiment, The electrochemical oxidation of step a) is performed at a voltage of 1 to 500 A / m 2 and in step a) the current density used is decreased; The electrochemical reduction in step b) is performed at a voltage of 1 to 500 A / m 2 the current density used in step a) is lower than the current density used in step b).

[0293] In one embodiment, The electrochemical oxidation of step a) is performed at a voltage of 1 to 100 A / m 2 and in step a) the current density used is decreased; The electrochemical reduction of step b) is performed at 1 A / m 2 ~500A / m 2 the current density used in step a) is lower than the current density used in step b).

[0294] In one embodiment, The electrochemical oxidation of step a) is performed at a voltage of 1 to 100 A / m 2 and in step a) the current density used is decreased; The electrochemical reduction in step b) is performed at 10 A / m 2 ~500A / m 2 the current density used in step a) is lower than the current density used in step b).

[0295] In one embodiment, The electrochemical oxidation in step a) is performed at a voltage of 1 to 50 A / m 2 and in step a) the current density used is decreased; The electrochemical reduction in step b) is performed at 10 A / m 2 ~500A / m 2 the current density used in step a) is lower than the current density used in step b).

[0296] In one embodiment, The electrochemical oxidation of step a) is performed at a voltage of 1 to 100 A / m 2 wherein in step a) the current density used is decreased; The electrochemical reduction in step b) is performed at 100-500 A / m 2 the current density used in step a) is lower than the current density used in step b).

[0297] In one embodiment, The electrochemical oxidation in step a) is performed at a voltage of 1 to 50 A / m 2 wherein in step a) the current density used is decreased; The electrochemical reduction in step b) is performed at 100-500 A / m 2 the current density used in step a) is lower than the current density used in step b).

[0298] In one embodiment, The electrochemical oxidation of step a) is performed at a voltage of 1 to 100 A / m 2 wherein in step a) the current density used is decreased; The electrochemical reduction in step b) is performed at 200-400 A / m 2 the current density used in step a) is lower than the current density used in step b).

[0299] In one embodiment, The electrochemical oxidation in step a) is performed at a voltage of 1 to 50 A / m 2 wherein in step a) the current density used is decreased; The electrochemical reduction in step b) is performed at 200-400 A / m 2 the current density used in step a) is lower than the current density used in step b).

[0300] In one embodiment, The electrochemical oxidation of step a) is performed at a voltage of 1 to 5000 A / m 2 , 1~500A / m 2 , 1~100A / m 2 , 1~50A / m 2 , 5~5000A / m 2 , 5~500A / m 2 , 5~100A / m 2 , 5~50A / m 2 , 10~5000A / m 2 , 10~500A / m 2 , 10~100A / m 2 , and 10 to 50 A / m 2 wherein in step a) the current density used is decreased stepwise; The electrochemical reduction in step b) is performed at a voltage of 1 to 10,000 A / m 2 , 1~1000A / m 2 , 1~500A / m 2 , 5A / m 2 ~10000A / m 2 , 50~1000A / m 2 , 200~500A / m 2 , 10~10000A / m 2 , 10~1000A / m 2 , 10~500A / m 2 , 100~500A / m 2 , 200~400A / m 2 , 200A / m 2 , 250A / m 2 , 300A / m 2 , 350A / m 2 and 400A / m 2 the current density used in step a) is lower than the current density used in step b).

[0301] In one embodiment, The electrochemical oxidation of step a) is performed at a voltage of 1 to 5000 A / m 2 wherein in step a) the current density used is gradually reduced; The electrochemical reduction in step b) is performed at a voltage of 1 to 10,000 A / m2 the current density used in step a) is lower than the current density used in step b).

[0302] In one embodiment, The electrochemical oxidation of step a) is performed at a voltage of 1 to 500 A / m 2 wherein in step a) the current density used is gradually reduced; The electrochemical reduction in step b) is performed at a voltage of 1 to 1000 A / m 2 the current density used in step a) is lower than the current density used in step b).

[0303] In one embodiment, The electrochemical oxidation of step a) is performed at a voltage of 1 to 500 A / m 2 wherein in step a) the current density used is gradually reduced; The electrochemical reduction in step b) is performed at a voltage of 1 to 500 A / m 2 the current density used in step a) is lower than the current density used in step b).

[0304] In one embodiment, The electrochemical oxidation of step a) is performed at a voltage of 1 to 100 A / m 2 wherein in step a) the current density used is gradually reduced; The electrochemical reduction of step b) is performed at 1 A / m 2 ~500A / m 2 the current density used in step a) is lower than the current density used in step b).

[0305] In one embodiment, The electrochemical oxidation of step a) is performed at a voltage of 1 to 100 A / m 2 wherein in step a) the current density used is gradually reduced; The electrochemical reduction in step b) is performed at 10 A / m 2 ~500A / m 2the current density used in step a) is lower than the current density used in step b).

[0306] In one embodiment, The electrochemical oxidation in step a) is performed at a voltage of 1 to 50 A / m 2 wherein in step a) the current density used is gradually reduced; The electrochemical reduction in step b) is performed at 10 A / m 2 ~500A / m 2 the current density used in step a) is lower than the current density used in step b).

[0307] In one embodiment, The electrochemical oxidation of step a) is performed at a voltage of 1 to 100 A / m 2 wherein in step a) the current density used is decreased stepwise; The electrochemical reduction in step b) is performed at 100-500 A / m 2 the current density used in step a) is lower than the current density used in step b).

[0308] In one embodiment, The electrochemical oxidation in step a) is performed at a voltage of 1 to 50 A / m 2 wherein in step a) the current density used is decreased stepwise; The electrochemical reduction in step b) is performed at 100-500 A / m 2 the current density used in step a) is lower than the current density used in step b).

[0309] In one embodiment, The electrochemical oxidation of step a) is performed at a voltage of 1 to 100 A / m 2 wherein in step a) the current density used is decreased stepwise; The electrochemical reduction in step b) is performed at 200-400 A / m 2the current density used in step a) is lower than the current density used in step b).

[0310] In one embodiment, The electrochemical oxidation in step a) is performed at a voltage of 1 to 50 A / m 2 wherein in step a) the current density used is decreased stepwise; The electrochemical reduction in step b) is performed at 200-400 A / m 2 the current density used in step a) is lower than the current density used in step b).

[0311] In one embodiment, The electrochemical oxidation of step a) is performed at a voltage of 1 to 5000 A / m 2 , 1~500A / m 2 , 1~100A / m 2 , 1~50A / m 2 , 5~5000A / m 2 , 5~500A / m 2 , 5~100A / m 2 , 5~50A / m 2 , 10~5000A / m 2 , 10~500A / m 2 , 10~100A / m 2 , and 10 to 50 A / m 2 In step a), the current densities used are 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 Decreasing stepwise in steps selected from; The electrochemical reduction in step b) is performed at a voltage of 1 to 10,000 A / m 2 , 1A / m 2 ~1000A / m 2 , 1~500A / m 2, 5~10000A / m 2 , 50~1000A / m 2 , 200~500A / m 2 , 10~10000A / m 2 , 10~1000A / m 2 , 10~500A / m 2 , 100~500A / m 2 , 200~400A / m 2 , 200A / m 2 , 250A / m 2 , 300A / m 2 , 350A / m 2 and 400A / m 2 the current density used in step a) is lower than the current density used in step b).

[0312] In one embodiment, The electrochemical oxidation of step a) is performed at a voltage of 1 to 5000 A / m 2 In step a), the current densities used are 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 Decreasing stepwise in steps selected from; The electrochemical reduction in step b) is performed at a voltage of 1 to 10,000 A / m 2 the current density used in step a) is lower than the current density used in step b).

[0313] In one embodiment, The electrochemical oxidation of step a) is performed at a voltage of 1 to 500 A / m 2In step a), the current densities used are 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 Decreasing stepwise in steps selected from; The electrochemical reduction in step b) is performed at a voltage of 1 to 1000 A / m 2 the current density used in step a) is lower than the current density used in step b).

[0314] In one embodiment, The electrochemical oxidation of step a) is performed at a voltage of 1 to 500 A / m 2 In step a), the current densities used are 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 Decreasing stepwise in steps selected from; The electrochemical reduction in step b) is performed at a voltage of 1 to 500 A / m 2 the current density used in step a) is lower than the current density used in step b).

[0315] In one embodiment, The electrochemical oxidation of step a) is performed at a voltage of 1 to 100 A / m 2In step a), the current densities used are 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 Decreasing stepwise in steps selected from; The electrochemical reduction of step b) is performed at 1 A / m 2 ~500A / m 2 the current density used in step a) is lower than the current density used in step b).

[0316] In one embodiment, The electrochemical oxidation of step a) is performed at a voltage of 1 to 100 A / m 2 In step a), the current densities used are 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 Decreasing stepwise in steps selected from; The electrochemical reduction in step b) is performed at 10 A / m 2 ~500A / m 2 the current density used in step a) is lower than the current density used in step b).

[0317] In one embodiment, The electrochemical oxidation in step a) is performed at a voltage of 1 to 50 A / m 2In step a), the current densities used are 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 Decreasing stepwise in steps selected from; The electrochemical reduction in step b) is performed at 10 A / m 2 ~500A / m 2 the current density used in step a) is lower than the current density used in step b).

[0318] In one embodiment, The electrochemical oxidation of step a) is performed at a voltage of 1 to 100 A / m 2 In step a), the current densities used are 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 Decreasing stepwise in steps selected from; The electrochemical reduction in step b) is performed at 100-500 A / m 2 the current density used in step a) is lower than the current density used in step b).

[0319] In one embodiment, The electrochemical oxidation in step a) is performed at a voltage of 1 to 50 A / m 2In step a), the current densities used are 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 Decreasing stepwise in steps selected from; The electrochemical reduction in step b) is performed at 100-500 A / m 2 the current density used in step a) is lower than the current density used in step b).

[0320] In one embodiment, The electrochemical oxidation of step a) is performed at a voltage of 1 to 100 A / m 2 In step a), the current densities used are 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 Decreasing stepwise in steps selected from; The electrochemical reduction in step b) is performed at 200-400 A / m 2 the current density used in step a) is lower than the current density used in step b).

[0321] In one embodiment, The electrochemical oxidation in step a) is performed at a voltage of 1 to 50 A / m 2In step a), the current densities used are 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 Decreasing stepwise in steps selected from; The electrochemical reduction in step b) is performed at 200-400 A / m 2 the current density used in step a) is lower than the current density used in step b).

[0322] In one embodiment, The electrochemical oxidation of step a) is performed at a voltage of 1 to 5000 A / m 2 , 1~500A / m 2 , 1~100A / m 2 , 1~50A / m 2 , 5~5000A / m 2 , 5~500A / m 2 , 5~100A / m 2 , 5~50A / m 2 , 10~5000A / m 2 , 10~500A / m 2 , 10~100A / m 2 , and 10 to 50 A / m 2 In step a), the current density used is selected from 1 to 100 A / m 2 A gradual decrease in the stages of; The electrochemical reduction in step b) is performed at a voltage of 1 to 10,000 A / m 2 , 1~1000A / m 2 , 1~500A / m 2 , 5A / m 2 ~10000A / m 2 , 50~1000A / m 2 , 200~500A / m 2 , 10~10000A / m 2 , 10~1000A / m 2 , 10~500A / m2 , 100~500A / m 2 , 200~400A / m 2 , 200A / m 2 , 250A / m 2 , 300A / m 2 , 350A / m 2 and 400A / m 2 the current density used in step a) is lower than the current density used in step b).

[0323] In one embodiment, The electrochemical oxidation of step a) is performed at a voltage of 1 to 5000 A / m 2 In step a), the current density used is 1 to 100 A / m 2 A gradual decrease in the stages of; The electrochemical reduction in step b) is performed at a voltage of 1 to 10,000 A / m 2 the current density used in step a) is lower than the current density used in step b).

[0324] In one embodiment, The electrochemical oxidation of step a) is performed at a voltage of 1 to 500 A / m 2 In step a), the current density used is 1 to 100 A / m 2 A gradual decrease in the stages of; The electrochemical reduction in step b) is performed at a voltage of 1 to 1000 A / m 2 the current density used in step a) is lower than the current density used in step b).

[0325] In one embodiment, The electrochemical oxidation of step a) is performed at a voltage of 1 to 500 A / m 2 In step a), the current density used is 1 to 100 A / m 2 A gradual decrease in the stages of; The electrochemical reduction in step b) is performed at a voltage of 1 to 500 A / m 2the current density used in step a) is lower than the current density used in step b).

[0326] In one embodiment, The electrochemical oxidation of step a) is performed at a voltage of 1 to 100 A / m 2 In step a), the current density used is 1 to 100 A / m 2 A gradual decrease in the stages of; The electrochemical reduction of step b) is performed at 1 A / m 2 ~500A / m 2 the current density used in step a) is lower than the current density used in step b).

[0327] In one embodiment, The electrochemical oxidation of step a) is performed at a voltage of 1 to 100 A / m 2 In step a), the current density used is 1 to 100 A / m 2 A gradual decrease in the stages of; The electrochemical reduction in step b) is performed at 10 A / m 2 ~500A / m 2 the current density used in step a) is lower than the current density used in step b).

[0328] In one embodiment, The electrochemical oxidation in step a) is performed at a voltage of 1 to 50 A / m 2 In step a), the current density used is 1 to 100 A / m 2 A gradual decrease in the stages of; The electrochemical reduction in step b) is performed at 10 A / m 2 ~500A / m 2 the current density used in step a) is lower than the current density used in step b).

[0329] In one embodiment, The electrochemical oxidation of step a) is performed at a voltage of 1 to 100 A / m 2In step a), the current density used is selected from 1 to 100 A / m 2 A gradual decrease in the stages of; The electrochemical reduction in step b) is performed at 100-500 A / m 2 the current density used in step a) is lower than the current density used in step b).

[0330] In one embodiment, The electrochemical oxidation in step a) is performed at a voltage of 1 to 50 A / m 2 In step a), the current density used is selected from 1 to 100 A / m 2 A gradual decrease in the stages of; The electrochemical reduction in step b) is performed at 100-500 A / m 2 the current density used in step a) is lower than the current density used in step b).

[0331] In one embodiment, The electrochemical oxidation of step a) is performed at a voltage of 1 to 100 A / m 2 In step a), the current density used is selected from 1 to 100 A / m 2 A gradual decrease in the stages of; The electrochemical reduction in step b) is performed at 200-400 A / m 2 the current density used in step a) is lower than the current density used in step b).

[0332] In one embodiment, The electrochemical oxidation in step a) is performed at a voltage of 1 to 50 A / m 2 In step a), the current density used is selected from 1 to 100 A / m 2 A gradual decrease in the stages of; The electrochemical reduction in step b) is performed at 200-400 A / m 2the current density used in step a) is lower than the current density used in step b).

[0333] In one embodiment, The electrochemical oxidation of step a) is performed at a voltage of 1 to 5000 A / m 2 , 1~500A / m 2 , 1~100A / m 2 , 1~50A / m 2 , 5~5000A / m 2 , 5~500A / m 2 , 5~100A / m 2 , 5~50A / m 2 , 10~5000A / m 2 , 10~500A / m 2 , 10~100A / m 2 , and 10 to 50 A / m 2 In step a), the current density used is selected from 1 to 10 A / m 2 A gradual decrease in the stages of; The electrochemical reduction in step b) is performed at a voltage of 1 to 10,000 A / m 2 , 1~1000A / m 2 , 1~500A / m 2 , 5A / m 2 ~10000A / m 2 , 50~1000A / m 2 , 200~500A / m 2 , 10~10000A / m 2 , 10~1000A / m 2 , 10~500A / m 2 , 100~500A / m 2 , 200~400A / m 2 , 200A / m 2 , 250A / m 2 , 300A / m 2 , 350A / m 2 and 400A / m 2 the current density used in step a) is lower than the current density used in step b).

[0334] In one embodiment, The electrochemical oxidation of step a) is performed at a voltage of 1 to 5000 A / m 2 In step a), the current density used is 1 to 10 A / m 2 A gradual decrease in the stages of; The electrochemical reduction in step b) is performed at a voltage of 1 to 10,000 A / m 2 the current density used in step a) is lower than the current density used in step b).

[0335] In one embodiment, The electrochemical oxidation of step a) is performed at a voltage of 1 to 500 A / m 2 In step a), the current density used is 1 to 10 A / m 2 A gradual decrease in the stages of; The electrochemical reduction in step b) is performed at a voltage of 1 to 1000 A / m 2 the current density used in step a) is lower than the current density used in step b).

[0336] In one embodiment, The electrochemical oxidation of step a) is performed at a voltage of 1 to 500 A / m 2 In step a), the current density used is 1 to 10 A / m 2 A gradual decrease in the stages of; The electrochemical reduction in step b) is performed at a voltage of 1 to 500 A / m 2 the current density used in step a) is lower than the current density used in step b).

[0337] In one embodiment, The electrochemical oxidation of step a) is performed at a voltage of 1 to 100 A / m 2 In step a), the current density used is 1 to 10 A / m 2 A gradual decrease in the stages of; The electrochemical reduction of step b) is performed at 1 A / m 2 ~500A / m 2the current density used in step a) is lower than the current density used in step b).

[0338] In one embodiment, The electrochemical oxidation of step a) is performed at a voltage of 1 to 100 A / m 2 In step a), the current density used is 1 to 10 A / m 2 A gradual decrease in the stages of; The electrochemical reduction in step b) is performed at 10 A / m 2 ~500A / m 2 the current density used in step a) is lower than the current density used in step b).

[0339] In one embodiment, The electrochemical oxidation in step a) is performed at a voltage of 1 to 50 A / m 2 In step a), the current density used is 1 to 10 A / m 2 A gradual decrease in the stages of; The electrochemical reduction in step b) is performed at 10 A / m 2 ~500A / m 2 the current density used in step a) is lower than the current density used in step b).

[0340] In one embodiment, The electrochemical oxidation of step a) is performed at a voltage of 1 to 100 A / m 2 In step a), the current density used is selected from 1 to 10 A / m 2 A gradual decrease in the stages of; The electrochemical reduction in step b) is performed at 100-500 A / m 2 the current density used in step a) is lower than the current density used in step b).

[0341] In one embodiment, The electrochemical oxidation in step a) is performed at a voltage of 1 to 50 A / m 2In step a), the current density used is selected from 1 to 10 A / m 2 A gradual decrease in the stages of; The electrochemical reduction in step b) is performed at 100-500 A / m 2 the current density used in step a) is lower than the current density used in step b).

[0342] In one embodiment, The electrochemical oxidation of step a) is performed at a voltage of 1 to 100 A / m 2 In step a), the current density used is selected from 1 to 10 A / m 2 A gradual decrease in the stages of; The electrochemical reduction in step b) is performed at 200-400 A / m 2 the current density used in step a) is lower than the current density used in step b).

[0343] In one embodiment, The electrochemical oxidation in step a) is performed at a voltage of 1 to 50 A / m 2 In step a), the current density used is selected from 1 to 10 A / m 2 A gradual decrease in the stages of; The electrochemical reduction in step b) is performed at 200-400 A / m 2 the current density used in step a) is lower than the current density used in step b).

[0344] In one embodiment, the current density used in step a) is decreased or stepped down.

[0345] In one embodiment, the current density used in step a) is lower than the current density used in step b).

[0346] 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.

[0347] In one embodiment, in step a), electrochemical oxidation is carried out first, and then the reaction mixture is heated; or electrochemical oxidation is carried out first, 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.

[0348] In one embodiment, in steps a) and / or b), a conductive salt is used, and the conductive salt is selected from the group consisting of organic ammonium salts, ionic liquids, tetraalkylammonium fluoroborates, quaternary ammonium salts, and mixtures thereof; or a conductive salt is used selected from the group consisting of tetraethylammonium tetrafluoroborate, tetrabutylammonium hexafluorophosphate, tetrabutylammonium hydrogen sulfate, and mixtures thereof.

[0349] In one embodiment, in steps a) and / or b), the solvent is aprotic solvents, protic solvents, and mixtures thereof or polar aprotic solvents; or a polar aprotic solvent selected from dimethylformamide (DMF), dimethyl sulfoxide, acetonitrile, and acetone; or a protic solvent selected from 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 a mixture of the above is selected from.

[0350] In one embodiment, in step a), an acid is used or the acid used is - organic acids, sulfonic acids, organic polar acids and their mixtures; - acetic acid, formic acid and their mixtures; -acetic acid; and mixtures thereof is selected from.

[0351] In one embodiment, in step a), the electrochemical oxidation is carried out at a cell voltage of 0.1 to 20V or less than 20V.

[0352] In one embodiment, in step a), the electrochemical oxidation is carried out at a rate of 1 to 5000 A / m 2 , 1~500A / m 2 , 1~100A / m 2 , 1~50A / m 2 , 5~5000A / m 2 , 5~500A / m 2 , 5~100A / m 2 , 5~50A / m 2 , 10~5000A / m 2 , 10~500A / m 2 , 10~100A / m 2 , and 10 to 50 A / m 2 The current density is selected from the following:

[0353] In one embodiment, in step b), the electrochemical reduction is carried out at a cell voltage of 0.1 to 30V or less than 30V.

[0354] In one embodiment, in step b), the electrochemical reduction is carried out at a rate of 1 to 10,000 A / m 2 , 1~1000A / m 2 , 1~500A / m 2 , 5~10000A / m 2 , 50~1000A / m 2 , 200~500A / m 2 , 10~10000A / m 2 , 10~1000A / m 2 , 100~500A / m 2 , 200~400A / m 2 , 200A / m 2 , 250A / m 2 , 300A / m 2 , 350A / m2 and 400A / m 2 The current density is selected from the following:

[0355] In one embodiment, in step b), the electrochemical reduction is carried out at a temperature of 1 to 50° C., 10 to 35° C., 15 to 30° C., or at ambient temperature.

[0356] In one embodiment, the synthesis comprises step c) Step c) Isolation of the compound according to formula (XIII) (In step c), the isolation is optionally selected from filtration and crystallization.) and / or step d) Step d) Crystallization of the compound according to formula (XIII) Further includes:

[0357] In one embodiment, - the current density used in step a) is decreased or gradually decreased; - the current density used in step a) is lower than the current density used in step b); - step a) is carried out at a temperature selected from 20 to 120°C; - in steps a) and / or b) a conductive salt is used, the conductive salt being selected from the group consisting of organic ammonium salts, ionic liquids, tetraalkylammonium fluoroborates, quaternary ammonium salts and mixtures thereof; - in steps a) and / or b), the solvent is selected from aprotic solvents, protic solvents, polar aprotic solvents and mixtures thereof, or selected from polar aprotic solvents; or - in step a) an acid is used or the acid used is selected from organic acids, sulfonic acids, organic polar acids and mixtures thereof; In step a), the electrochemical oxidation is carried out at a voltage of 1 to 50 A / m 2 at a current density selected from: In step b), the electrochemical reduction is carried out at a temperature of 10 to 500 A / m 2The current density is selected from the following:

[0358] In one embodiment, - the current density used in step a) is decreased or gradually decreased; - the current density used in step a) is lower than the current density used in step b); - step a) is carried out at a temperature selected from 20 to 120°C; - in steps a) and / or b) a conductive salt is used, the conductive salt being selected from the group consisting of organic ammonium salts, ionic liquids, tetraalkylammonium fluoroborates, quaternary ammonium salts and mixtures thereof; - in steps a) and / or b), the solvent is selected from aprotic solvents, protic solvents, polar aprotic solvents and mixtures thereof, or selected from polar aprotic solvents; or - in step a) an acid is used or the acid used is selected from organic acids, sulfonic acids, organic polar acids and mixtures thereof; In step a), the electrochemical oxidation is carried out at a voltage of 1 to 100 A / m 2 at a current density selected from: In step b), the electrochemical reduction is carried out at a rate of 10 to 1000 A / m 2 The current density is selected from the following:

[0359] In one embodiment, - the current density used in step a) is decreased or gradually decreased; - the current density used in step a) is lower than the current density used in step b); - step a) is carried out at a temperature selected from 15 to 150°C; - in steps a) and / or b) a conductive salt is used, the conductive salt being selected from the group consisting of organic ammonium salts, ionic liquids, tetraalkylammonium fluoroborates, quaternary ammonium salts and mixtures thereof; - in steps a) and / or b), the solvent is selected from aprotic solvents, protic solvents, polar aprotic solvents and mixtures thereof, or selected from polar aprotic solvents; or - in step a) an acid is used or the acid used is selected from organic acids, sulfonic acids, organic polar acids and mixtures thereof; In step a), the electrochemical oxidation is carried out at a voltage of 1 to 100 A / m 2 at a current density selected from: In step b), the electrochemical reduction is carried out at a rate of 1 to 1000 A / m 2 at a current density selected from: In step b), the electrochemical reduction is carried out at a temperature between 1 and 50°C.

[0360] In one embodiment, - the current density used in step a) is decreased or gradually decreased; - the current density used in step a) is lower than the current density used in step b); - step a) is carried out at a temperature selected from 15 to 150°C, 15 to 120°C, and 20 to 100°C; Optionally, 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; - in steps a) and / or b), a conductive salt is used, the conductive salt being selected from the group consisting of organic ammonium salts, ionic liquids, tetraalkylammonium fluoroborates, quaternary ammonium salts and mixtures thereof; or a conductive salt is used selected from the group consisting of tetraethylammonium tetrafluoroborate, tetrabutylammonium hexafluorophosphate, tetrabutylammonium hydrogen sulfate and mixtures thereof; In steps a) and / or b), the solvent is aprotic solvents, protic solvents, and mixtures thereof or polar aprotic solvents; or a polar aprotic solvent selected from dimethylformamide (DMF), dimethyl sulfoxide, acetonitrile, and acetone; or a protic solvent selected from 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 o Acetic acid; ○ or a mixture of the above Selected from; in step a) an acid is used or the acid used is Organic acids, sulfonic acids, organic polar acids and their mixtures; Acetic acid, formic acid and their mixtures; o Acetic acid; 〇 and mixtures of the above Selected from; In step a), the electrochemical oxidation is carried out at a temperature of 1 to 5000 A / m 2 , 1~500A / m 2 , 1~100A / m 2 , 1~50A / m 2 , 5~5000A / m 2 , 5~500A / m 2 , 5~100A / m 2 , 5~50A / m 2 , 10~5000A / m 2 , 10~500A / m 2 , 10~100A / m 2 , and 10 to 50 A / m 2 at a current density selected from: In step b), the electrochemical reduction is carried out at a rate of 1 to 10,000 A / m 2 , 1~1000A / m 2 , 1~500A / m 2 , 5~10000A / m 2 , 50~1000A / m 2, 200~500A / m 2 , 10~10000A / m 2 , 10~1000A / m 2 , 100~500A / m 2 , 200~400A / m 2 , 200A / m 2 , 250A / m 2 , 300A / m 2 , 350A / m 2 and 400A / m 2 at a current density selected from: In step b), the electrochemical reduction is carried out at a temperature of 1 to 50° C., 10 to 35° C., 15 to 30° C., or at ambient temperature.

[0361] In one embodiment, - the current density used in step a) is decreased or gradually decreased; - the current density used in step a) is lower than the current density used in step b); - step a) is carried out at a temperature selected from 15 to 150°C, 15 to 120°C, and 20 to 100°C; Optionally, 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; - in steps a) and / or b) a conductive salt is used, the conductive salt being selected from the group consisting of organic ammonium salts, ionic liquids, tetraalkylammonium fluoroborates, quaternary ammonium salts and mixtures thereof; or a conductive salt is used selected from the group consisting of tetraethylammonium tetrafluoroborate, tetrabutylammonium hexafluorophosphate, tetrabutylammonium hydrogen sulfate and mixtures thereof, In steps a) and / or b), the solvent is aprotic solvents, protic solvents, and mixtures thereof or polar aprotic solvents; or a polar aprotic solvent selected from dimethylformamide (DMF), dimethyl sulfoxide, acetonitrile, and acetone; or a protic solvent selected from 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 o Acetic acid; ○ or a mixture of the above Selected from; in step a) an acid is used or the acid used is Organic acids, sulfonic acids, organic polar acids and their mixtures; Acetic acid, formic acid and their mixtures; o Acetic acid; 〇 and mixtures of the above Selected from; - in step a), the electrochemical oxidation is carried out at a cell voltage of 0.1 to 20 V or less than 20 V; In step a), the electrochemical oxidation is carried out at a temperature of 1 to 5000 A / m 2 , 1~500A / m 2 , 1~100A / m 2 , 1~50A / m 2 , 5~5000A / m 2 , 5~500A / m 2 , 5~100A / m 2 , 5~50A / m 2 , 10~5000A / m 2 , 10~500A / m 2 , 10~100A / m 2 , and 10 to 50 A / m 2 at a current density selected from: - in step b), the electrochemical reduction is carried out at a cell voltage of 0.1 to 30 V or less than 30 V; In step b), the electrochemical reduction is carried out at a rate of 1 to 10,000 A / m 2 , 1~1000A / m 2, 1~500A / m 2 , 5~10000A / m 2 , 50~1000A / m 2 , 200~500A / m 2 , 10~10000A / m 2 , 10~1000A / m 2 , 100~500A / m 2 , 200~400A / m 2 , 200A / m 2 , 250A / m 2 , 300A / m 2 , 350A / m 2 and 400A / m 2 at a current density selected from: In step b), the electrochemical reduction is carried out at a temperature of 1 to 50° C., 10 to 35° C., 15 to 30° C., or at ambient temperature.

[0362] 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 varied. In one embodiment of step a), the flow rate is between 0.01 mL / min and 10,000 L / min. In one embodiment of step a), the flow rate is between 0.01 mL / min and 1,000 L / min, 0.01 mL / min and 100 L / min, 0.1 mL / min and 1,000 L / min, 0.1 mL / min and 100 L / min, 0.1 mL / min and 10 L / min, 0.1 mL / min and 1,000 mL / min, 0.1 mL / min and 100 mL / min, 0.1 mL / min and 10 mL / min, 0.1 mL / min and 9 mL / min, 0.1 mL / min and 8 mL / min, 0.1 mL L / min~7mL / min, 0.1mL / min~6mL / min, 0.1mL / min~5mL / min, 0.1mL / min~4mL / min, 0.1mL / min~3mL / min, 0.1mL / min~2mL / min, 0.1mL / min~ 1.5mL / min, 0.1mL / min~1mL / min, 0.5mL / min~100L / min, 0.5mL / min~10L / min, 0.5mL / min~1000mL / min, 0.5mL / min~100mL / min, 0.5mL / min~10mL / min, 0.5mL / min~9mL / min, 0.5mL / min~8mL / min, 0.5mL / min~7mL / min, 0.5mL / min~6mL / min, 0.5mL / min~5mL / min, 0.5mL / min~ 4mL / min, 0.5mL / min~3mL / min, 0.5mL / min~2mL / min, 0.5mL / min~1.5mL / min, 0.7mL / min~100L / min, 0.7mL / min~10L / min, 0.7mL / min~10 00mL / min, 0.7mL / min~100mL / min, 0.7mL / min~10mL / min, 0.7mL / min~9mL / min, 0.7mL / min~8mL / min, 0.7mL / min~7mL / min, 0.7mL / min~6 mL / min, 0.7mL / min~5mL / min, 0.7mL / min~4mL / min, 0.7mL / min~3mL / min, 0.7mL / min~2mL / min, 0.7mL / min~1.5mL / min, or 1mL / min.

[0363] In one embodiment of step a), the concentration of the reactants is decreased, increased, continuous and / or varied. The reactants can be added continuously. In one embodiment of step a), the concentration of the conductive salt is decreased, increased, continuous and / or varied. The conductive salt can be added continuously.

[0364] 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 a), the flow rate is varied. In one embodiment of step b), the flow rate is between 0.01 mL / min and 10,000 L / min, 0.01 mL / min and 100 L / min, 0.1 mL / min and 1000 L / min, 0.1 mL / min and 100 L / min, 0.1 mL / min and 10 L / min, 0.1 mL / min and 1000 mL / min, 0.1 mL / min and 100 mL / min, 0.1 mL / min and 10 mL / min, 0.1 mL / min and 9 mL / min, 0.1 mL / min and 8 mL / min, 0.1 mL / min and 7 mL / min, 0.1 mL / min and 6 mL / min, 0.1 mL / min and 5 mL / min, 0.1 mL / min and 4 mL / min. mL / min, 0.1mL / min~3mL / min, 0.1mL / min~2mL / min, 0.1mL / min~1.5mL / min, 0.1mL / min~1mL / min, 0.5mL / min~100L / min, 0.5mL / min~10L / min, 0.5mL / min~1000mL / min, 0.5mL / min~100m L / min, 0.5mL / min~10mL / min, 0.5mL / min~9mL / min, 0.5mL / min~8mL / min, 0.5mL / min~7mL / min, 0.5mL / min~6mL / min, 0.5mL / min~5mL / min, 0.5mL / min~4mL / min, 0.5mL / min~3mL / min, 0.5m L / min~2mL / min, 0.5mL / min~1.5mL / min, 0.7mL / min~100L / min, 0.7mL / min~10L / min, 0.7mL / min~1000mL / min, 0.7mL / min~100mL / min, 0.7mL / min~10mL / min, 0.7mL / min~9mL / min, 0.7m L / min~8mL / min, 0.7mL / min~7mL / min, 0.7mL / min~6mL / min, 0.7mL / min~5mL / min, 0.7mL / min~4mL / min, 0.7mL / min~3mL / min, 0.7mL / min~2mL / min, 0.7mL / min~1.5mL / min, or 1mL / min.

[0365] In one embodiment of step b), the concentration of the reactants is decreased, increased, continuous and / or varied. The reactants can be added continuously. In one embodiment of step b), the concentration of the conductive salt is decreased, increased, continuous and / or varied. The electrolyte can be added continuously.

[0366] The cycle time of each of steps a), b), c) and / or d) can be adjusted individually. One or more of these steps can be performed multiple times, and one or more of the steps are performed less frequently or 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.

[0367] In one embodiment of step a), a pressure of 0.1 to 10 bar is used. In this embodiment, the pressure can be decreasing, increasing, constant or variable. In one embodiment of step a), the pressure can be 0.1 to 9 bar, 0.1 to 8 bar, 0.1 to 7 bar, 0.1 to 6 bar, 0.1 to 5 bar, 0.1 to 4 bar, 0.1 to 2 bar, 0.1 to 1 bar, 0.5 to 9 bar, 0.5 to 8 bar, 0.5 to 7 bar, 0.5 to 6 bar, 0.5 to 5 bar, 0.5 to 4 bar, 0.5 to 2 bar, 0.5 to 1 bar, 0.75 to 9 bar, 0.75 to 8 bar, 0.75 to 7 bar, 0.75 to 8 bar, 0.75 to 7 bar, 0.75 to 9 ... Pressures of 1 bar, 0.75 to 6 bar, 0.75 to 5 bar, 0.75 to 4 bar, 0.75 to 2 bar, 0.75 to 1 bar, 1 to 9 bar, 1 to 8 bar, 1 to 7 bar, 1 to 6 bar, 1 to 5 bar, 1 to 4 bar, 1 to 2 bar, 1 bar, atmospheric pressure to 9 bar, atmospheric pressure to 8 bar, atmospheric pressure to 7 bar, atmospheric pressure to 6 bar, atmospheric pressure to 5 bar, atmospheric pressure to 4 bar, atmospheric pressure to 2 bar, or atmospheric pressure are used. In this embodiment, the pressure can decrease, increase, be constant, or vary. Atmospheric pressure is 1.01325 bar. This pressure can vary as known by those skilled in the art.

[0368] In one embodiment of step b), a pressure of 0.1 to 10 bar is used. In this embodiment, the pressure can be decreasing, increasing, constant, or variable. In one embodiment of step b), the pressure can be 0.1 to 9 bar, 0.1 to 8 bar, 0.1 to 7 bar, 0.1 to 6 bar, 0.1 to 5 bar, 0.1 to 4 bar, 0.1 to 2 bar, 0.1 to 1 bar, 0.5 to 9 bar, 0.5 to 8 bar, 0.5 to 7 bar, 0.5 to 6 bar, 0.5 to 5 bar, 0.5 to 4 bar, 0.5 to 2 bar, 0.5 to 1 bar, 0.75 to 9 bar, 0.75 to 8 bar, 0.75 to 7 bar, 0.75 to 7 bar, 0.75 to 8 bar, 0.75 to 7 bar, 0.75 to 9 ...8 bar, 0.75 to 8 bar, 0.75 to 9 bar, 0.75 to 8 bar, 0.75 to 8 bar, 0.75 to 9 bar, 0.75 to 8 bar, 0.75 to 8 bar, 0.75 to Pressures of 0.75 to 6 bar, 0.75 to 5 bar, 0.75 to 4 bar, 0.75 to 2 bar, 0.75 to 1 bar, 1 to 9 bar, 1 to 8 bar, 1 to 7 bar, 1 to 6 bar, 1 to 5 bar, 1 to 4 bar, 1 to 2 bar, 1 bar to 9 bar, to 8 bar, to 7 bar, to 6 bar, to 5 bar, to 4 bar, to 2 bar, or atmospheric pressure may be used. In this embodiment, the pressure may be decreasing, increasing, constant, or variable.

[0369] The use of pressures higher than 1 bar or ambient pressure in steps a) and / or b) may result in better solubility of the starting materials, solvents, conductive salts, acids, intermediates and / or the resulting products.

[0370] Further Aspects A further aspect of the present invention is (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (I) [ka] 1. A 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) [ka] A sequential one-pot synthesis for synthesizing 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,6-naphthyridine-3-carboxamide according to formula (XVII) [ka] with (4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide according to formula ent-(I) [ka] a) by electrochemical oxidation of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide according to formula (XIII) [ka] b) by electrochemical reduction of a compound according to formula (XVII) Step (1) is a sequential one-pot synthesis comprising: step (2) isolating the compound according to formula (I) from the compound according to formula (XIII); The method includes:

[0371] Embodiments of step a) have already been described above. These embodiments can be used in step (1). Embodiments of step b) have already been described above. These embodiments can be used in step (1).

[0372] In one embodiment of step (1), the synthesis further comprises step c) isolating the compound according to formula (XIII). Embodiments of step c) have already been described above. These embodiments can be used in step (1).

[0373] In one embodiment of step (1), the synthesis further comprises step d) crystallization of the compound according to formula (XIII). Embodiments of step d) have already been described above. These embodiments can be used in step (1).

[0374] In step (2), the compound of formula (I) is isolated from the compound of formula (XIII). In one embodiment of step (2), the isolation is selected from filtration, chiral chromatography, crystallization, racemic resolution, diastereomeric salt formation, and chiral salt formation. For example, isolation by diastereomeric salt formation is described in U.S. Patent Application Publication No. 20100136142, U.S. Patent Application Publication No. 20170217957, or International Publication No. 2019206909.

[0375] In another embodiment, the sequential one-pot synthesis described herein can be carried out several times in succession.

[0376] In one embodiment, the sequential one-pot synthesis is carried out multiple times in succession. In one embodiment, the sequential one-pot synthesis is carried out twice in succession. In one embodiment, the sequential one-pot synthesis is carried out at least twice in succession. In one embodiment, the sequential one-pot synthesis is carried out at least three times in succession. For example, see Scheme 5.

[0377] Scheme 5: [ka]

[0378] This offers the possibility of converting compound ent-(I) to compound (XIII). This can be considered a quasi-continuous operation mode, offering significant advantages in terms of cost, time, and / or resources. In this way, the waste product ent-(I), which is repeatedly generated in the preparation of finerenone (I), can be converted back to compound (XIII). Compound (XIII) can then be fed back into the finerenone (I) production process. Thus, after several process cycles of the sequential one-pot synthesis, compound ent-(I) can be almost completely utilized. In the best case scenario, the by-product ent-(I) can be almost completely recycled into the expected product (XIII) or finerenone (I).

[0379] In one embodiment, the process for preparing (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (I) is carried out in a continuous mode, - starting materials, solvents, conductive salts, acids, and / or intermediates are added sequentially; The compound according to formula (I) is continuously removed.

[0380] In one embodiment, the (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 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.

[0381] 1 and 2 show a schematic representation of the electrolysis setup. [Brief explanation of the drawings]

[0382] [Figure 1]Figure 1 shows an electrolysis setup comprising an electrolysis cell (1), a power supply (2), an electrolyte reservoir (3) and an anolyte reservoir (4). Arrows indicate the flow of electrolyte and / or anolyte. [Figure 2] 1 shows an electrolysis setup comprising an electrolysis cell (1), a power supply (2), an electrolyte reservoir (3), an anolyte reservoir (4), and a pump (5). It may optionally comprise one or more separators (6) and / or one or more heat exchangers (7). Arrows indicate the flow of electrolyte and / or anolyte. DETAILED DESCRIPTION OF THE INVENTION

[0383] 1 and 2, further equipment can be integrated and / or adapted. For example, the electrolysis device can be adapted with respect to electrode geometry, flow rate, residence time, segments, etc. These aspects have been described above. Further equipment can also be added: further pumps can be added, the device can be segmented, further pumps and / or tanks can be added to, for example, supply further starting materials, solvents, conductive salts, acids and / or intermediates to the process, further equipment can be added to remove or add impurities, by-products, starting materials, other reagents, solvents, intermediates and / or products, or to add further starting materials, solvents, conductive salts, acids and / or intermediates and / or products.

[0384] Experimental Department

[0385] [Table 2]

[0386] Table 2 below shows the structures of the compounds found by HPLC. The HPLC retention time assignments are shown below.

[0387] [Table 3A] [Table 3B]

[0388] B. Analysis method Analytical methods for testing organic impurities, content (assay) and enantiomeric purity at the 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)) levels.

[0389] [Table 4]

[0390] [Table 5]

[0391] [Table 6]

[0392] A "main compound" is a compound according to formula (XIII), particularly a mixture of its enantiomers according to formula (I) and / or ent-(I).

[0393] [Table 7]

[0394] [Table 8]

[0395] [Table 9]

[0396] A "main compound" is a compound according to formula (XIII), particularly a mixture of its enantiomers according to formula (I) and / or ent-(I).

[0397] The HPLC analytical data shown in the following examples for 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)) refer only to impurities greater than 0.05% in the product. This is essentially impurity D. All other impurities shown in the table above are typically less than 0.05%. The structures of these impurities were determined by isolation from concentrated mother liquor and structural elucidation.

[0398] [Table 10A] [Table 10B]

[0399] C. Preparation Examples C.1 Preparation of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (XIII) [ka] wherein ent-(I) including step a) and step b) [ka] A sequential one-pot synthesis is described starting from

[0400] C.1.1 Example 1 (XIII), Example 2 (XIII) and Example 3 (XIII) (4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (ent-(I)) was dissolved in a mixture containing DMF, methanol, tetraethylammonium tetrafluoroborate, and acetic acid in a catholyte bath (stirred vessel) at room temperature. This mixture was added to 0.4 ml of the cathode for electrochemical oxidation of (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). 2 (Examples 1 and 2) or 1.2 m 2 The anode and cathode areas of the electrochemical cells (manufactured by Electrocell) of Example 3 were 1.8 m 3 / h (Examples 1 and 2) or 4.5 m 3 / h (Example 3) was pumped from the catholyte reservoir.

[0401] The amounts of ingredients used in Examples 1-3 are summarized in Table 3 below.

[0402] [Table 11]

[0403] The flow was split approximately equally between the anolyte and catholyte half-cells. After exiting the cells, the anolyte and catholyte volumetric flows were recombined and returned to the catholyte reservoir. During pumping, electrolysis was initiated by supplying voltage and current to the cell via a rectifier. To achieve high chemical selectivity and simultaneously high current selectivity, the current density was gradually decreased with increasing conversion. A summary of the current densities used in Examples 1-3 is summarized in Table 4 below:

[0404] [Table 12]

[0405] The reaction solution was then heated to a temperature of approximately 100° C. in the catholyte bath and stirred at this temperature for 16 hours under a reflux condenser.

[0406] The sequential one-pot synthesis was continued by the electrochemical reduction of 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). A second tank (anolyte tank (stirred tank)) filled with a mixture of DMF, tetraethylammonium tetrafluoroborate, acetic acid, and methanol was connected to the electrochemical cell.

[0407] The amounts of ingredients used in Examples 1-3 are summarized in Table 5 below:

[0408] [Table 13]

[0409] This anolyte solution was added to 0.4 ml 2 (Examples 1 and 2) or 1.2 m 2A divided electrochemical cell (Electrocell) with the anode and cathode areas of Example 3 was placed 0.9 m from the cell through the anolyte half-cell. 3 At the same time, the solution obtained by electrochemical oxidation was pumped at the same flow rate (0.9 m 3 The anolyte and catholyte were pumped at a rate of 350 A / m from the catholyte reservoir through the catholyte half-cell of the electrochemical cell. After leaving the cell, the volumetric flows of anolyte and catholyte were returned separately to their respective outlet reservoirs. During pumping, electrolysis was initiated by supplying a voltage and current to the cell via a rectifier. 2 A constant current density of 0.01 was used and the electrolysis was terminated after 20 hours (Example 1), 6 hours (Example 2) or 7 hours (Example 3).

[0410] C.2 Isolation and purification of Examples 1-3 (XIII) [Crude]: In this section, compounds according to formula (XIII) [ka] (see step c)).

[0411] C.2.1 Isolation and purification of Examples 1-3 (XIII) [crude]: The total amount obtained in Examples 1, 2 and 3 after the completion of electrolysis from the catholyte cycle, including the volume from the catholyte reservoir, was further treated as follows to obtain 4-(4-cyano-2-methoxy-phenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (XIII) as an isolated solid:

[0412] The product solution of the electrochemical reduction was concentrated by vacuum distillation at temperatures up to 60 or 70 °C. After the vacuum distillation was completed, (purified) water was added to the solution at 60 °C for 3 or 4 hours to induce crystallization. The suspension was then cooled to room temperature and stirred for a further 2 hours, and the product was filtered and washed with water. The resulting product was then dried at 55 °C in a drying cabinet (under vacuum).

[0413] The yields obtained are summarized in Table 6 below:

[0414] [Table 14]

[0415] C.2.2 Example 1 (XIII) [Pure] This section provides an example of step d).

[0416] Approximately 1000 g of crude Example 1 was suspended at room temperature in a 1:1 v / v mixture of isopropanol and n-propanol (approximately 6% by weight of compound (XIII) [crude, Example 1]). The solid was first heated above 85°C (slight reflux) to completely dissolve, then the solution was cooled (in 3 hours) to 5°C and stirring was continued overnight. During the cooling process, crystallization of compound (XIII) in pure form began. The solid was filtered (using a centrifuge), the reactor was rinsed with 2 L of isopropanol at 5°C, and the wet cake thus obtained was washed with pre-cooled (5°C) isopropanol (2 L). After drying at 55°C in a drying cabinet (under vacuum), more than 890 g of pure compound (XIII) was obtained: Yield: 89% (of theoretical value)

[0417] Analysis results: Assay % Compound (XIII) (HPLC-Method A): 100.3% Area % Main compound [Compound (XIII)] (HPLC-Method A): 99.87% Analysis of the enantiomeric ratio gave the expected value of about 50:50 (49.6:50.4) for the racemate, corresponding to ee%: 0.8% (HPLC-Method C).

[0418] C.3 Example Preparation of 4-(4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (I) An example of this is finerenone (I). [ka] was obtained from recycled 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (XIII).

[0419] The 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (XIII) obtained as described above was separated into its enantiomers (ent-(I) and (I)) either by SMB or by resolution of diastereomeric salt formation (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)), as described, for example, in U.S. Patent Application Publication No. 20100136142, U.S. Patent Application Publication No. 20170217957, or WO 2019206909.

[0420] The (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (I) obtained after separation is then purified by crystallization from ethanol (containing 2% toluene) to give (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (I) in excellent purity.

[0421] C.3.1 (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamido-dibenzoyl-tartrate(II) [ka] 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 in 13.826 kg of a mixture of ethanol (2% toluene) and water (75:25 v / v) [9.719 kg / 4.107 kg] at room temperature (approximately 23 °C). 0.570 kg (1.59 mol) of (+)-O,O-dibenzoyl-D-tartaric acid was added to the solution, followed by the addition of approximately 3 kg of a solvent mixture of ethanol (2% toluene) and water (75:25 v / v) to rinse the equipment. The resulting suspension was heated to an internal temperature of 75 °C within 60 minutes and then stirred at this temperature for 3.0 hours. The mixture was then cooled to 23°C over 5.0 hours using a cooling ramp and stirred at this temperature overnight (approximately 16 hours). The suspension was filtered, washed once with 1.681 kg of a mixture of ethanol (denatured with 2% toluene) / water = 75:25 (v / v), and pressed dry for approximately 45 minutes.

[0422] Wet cake yield: 1.66 kg. The wet product was then dried under reduced pressure (<100 mbar) at 50° C. to constant weight (reached after 17 hours).

[0423] Yield of (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamido-dibenzoyl-tartrate (II): 1.106 kg (103.7% of theory) of a white powder.

[0424] Mother liquor: 14.98 kg of the mother liquor contained a theoretical amount of (4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (ent-(I)) up to 0.548 kg (1.45 mol) which could be used for further recycling.

[0425] C.3.2 (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (I) [crude] 1.104 kg of (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamido-dibenzoyl-tartrate (II) (from Section C.3.1) was suspended in a mixture of ethanol (denatured with 2% toluene) (1.766 kg) and water (8.722 kg) at room temperature (approximately 23 °C). The internal temperature was raised to 50 °C within 1 hour, and 4.416 kg of 9.1% (by weight) aqueous trisodium phosphate solution was added within 30 minutes (pH increased from 5.4 to 7.2). The mixture was stirred at this temperature for an additional 3.0 hours (pH = 7.5). The mixture was then cooled to 23 °C within 2 hours and stirred at this temperature overnight (approximately 14 hours). The white suspension was filtered and then washed once with a solvent mixture of 0.186 kg of ethanol (denatured with 2% toluene) and 0.883 kg of deionized water, followed by two washes with 0.883 kg of deionized water each. Wet cake weight: 0.840 kg. The wet product was resuspended at 23 °C in a mixture of 3.842 kg of ethanol (2% toluene) and 1.280 kg of deionized water. The suspension was heated to 70 °C within 2 hours using a gradient, and the resulting solution was stirred at 70 °C for 15 minutes. The pH was adjusted to 8.5-9.0 (final pH = 8.75) using 0.15% (by weight) aqueous trisodium phosphate solution. 11.04 kg of deionized water was then added to the solution at 70 °C within 30-60 minutes. The white, easily stirrable suspension was cooled to 23 °C within 3 hours using a gradient and stirred for at least 1 hour. After stirring overnight at 23°C, the suspension was filtered, then washed with 1.987 kg of deionized water and pressed dry for approximately 30 minutes. Wet cake weight: 0.571 kg. The wet product was then dried under reduced pressure (<100 mbar) at 50°C until constant mass (reached after 17 hours). Yield: 0.504 kg (88.9% of theoretical) of white crystalline powder

[0426] Analysis results: Duplicate determination: Assay % (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (I), crude: (HPLC-Method B) 99.88% and 100.69% Area % Main compound [Compound (XIII)] (HPLC-Method B): 99.79% Enantiomeric excess ee%: 99.76% (HPLC-Method C)

[0427] C.3.3 (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (I) [pure] 500 g of crude (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 (modified with 2% toluene), and the mixture was then heated to reflux (78 °C). The product dissolved. It was stirred at this temperature for 45 minutes. The solution was filtered through a heated pressure filter, which was then rinsed with 0.5 L of ethanol (modified with 2% toluene). The solvent was then distilled off until a final volume of 2.5 L was reached. The internal temperature was then cooled to 0 °C (gradient: duration approximately 4 hours), and stirring was continued at 0 °C for at least 1 hour (stirring over the weekend was possible, but not necessary). The product was filtered off and washed twice with 0.5 L of ethanol (modified with 2% toluene). Wet cake yield: 0.50 kg. The wet product was then dried under reduced pressure (<100 mbar) at 50° C. until constant weight (reached after 17 hours).

[0428] Analysis results: Yield: 0.440 kg (88.0% of theoretical) of white crystalline powder Identity: The structure confirmed by 1H-NMR corresponds to the published data. Assay % (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% Area % Main compound [Compound (XIII)] (HPLC-Method A): 100.0% Enantiomeric excess ee% = 100.0% (HPLC-Method C) Residual solvent ethanol: 0.05453 wt%

[0429] C.4 Example 5 (XIII) This example describes a sequential one-pot synthesis starting from ent-(I), including recovery of compound ent-(I) from the mother liquor and washes (sections C.3, C3.1), steps a), b) (section C.1) and step c) (section C.2).

[0430] C.4.1 Recovery of (4R)-4-(4-cyano-2-methoxy-phenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (ent-(I)) (from mother liquor and washes) [ka] The mother liquor from section C.3.1, containing 14.98 kg (16.8 L) of mother liquor and washes, was (4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (ent-(I)) (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 this solution was adjusted to pH 7.0-7.5 using aqueous NaPO. The mixture was then concentrated in vacuo (40-85 mbar) to a residual volume of approximately 4.2 L (distillate approximately 12.6 L), yielding a white, easily stirrable suspension. At approximately 23±3°C, 8.4 L of deionized water was added within 15 minutes. After stirring for at least 2 hours (stirring overnight for organizational reasons), the mixture was filtered through a frit, the vessel was rinsed with 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. The wet product was then dried under reduced pressure (<100 mbar) at 50°C until constant mass (reached after 17 hours). Yield: 0.507 kg (92.5% of theory) of a white crystalline powder.

[0431] Analysis results: Assay % (4R)-4-(4-cyano-2-methoxy-phenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (ent-(I)) (HPLC-Method B): 100.1% Area % Main compound [Compound (XIII)] (HPLC-Method B): 99.66% Enantiomeric excess ee% = 97.88% (HPLC-Method C)

[0432] C.4.2 Example 5 (XIII) [Crude] The (4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (ent-(I)) obtained as described above was converted back to racemic (4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (XIII)) and finally crystallized as a solid. The sequential one-pot synthesis was performed on a laboratory scale (starting When performed with 50.4 g of the substance (4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (ent-(I)), a total of 149.0 g of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (XIII) was obtained in four batches. The laboratory approach is described in detail below as an example.

[0433] 50.4 g (0.133 mol) of (4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-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. For the electrochemical oxidation of (4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (ent-(I)) to compound (XVII), this mixture was added to 100 cm 2A total of 50 kg / h was pumped from the vessel (5 L) through an electrochemical laboratory cell (Multipurpose Cell, MPC) manufactured by Electrocell, with an anode and cathode area of ​​1000 kJ / h. The flow was split approximately equally between the anolyte and catholyte half-cells. After leaving the cell, the volumetric flows of anolyte and catholyte were combined and returned to the vessel (thus completing the circulation). During pumping, electrolysis was initiated by supplying voltage and current to the cell via a rectifier. In order to achieve high chemical selectivity and simultaneously high current selectivity, the current density was gradually reduced with increasing conversion: 340 minutes at 0.5A (50A / m 2 ) 210 minutes at 0.4A (40A / m 2 ) 210 minutes at 0.3A (30A / m 2 ) 210 minutes at 0.2A (20A / m 2 ) 510 minutes at 0.1A (10A / m 2 )

[0434] The total charge flow (6.833 Ah) corresponds to approximately 95.6% of the theoretical charge required for 100% conversion (7.147 Ah). The reaction solution was then heated to approximately 100 °C in a 2 L multi-neck flask and stirred at this temperature for a total of 16 hours (2 × 8 hours) using a reflux condenser. A separate vessel (anolyte reservoir, 5 L) was used 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), which was charged with a solution of 2236.9 g DMF, 33.6 g tetraethylammonium tetrafluoroborate, 55.9 g acetic acid, and 559.2 g methanol. The solution prepared in this way was pumped from the vessel through the anolyte half-cell of a divided electrochemical laboratory cell (Multipurpose Cell, MPC) manufactured by Electrocell, with an anode and cathode area of ​​100 cm², at a volumetric flow rate of 25 kg / h. Simultaneously, the solution obtained in step 2 was pumped from the catholyte reservoir (a 5-liter bottle) through the catholyte half-cell of the electrochemical cell at the same delivery volume (25 kg / h). After leaving the cell, the anolyte and catholyte volume flows were returned separately to the starting vessels (two circuits: anolyte circuit and catholyte circuit). During pumping, electrolysis was initiated by supplying voltage and current to the cell via a rectifier. A constant current density of 350 A / m² was used in this partial step, and electrolysis was terminated after 20 h. The total volume obtained from the catholyte cycle after the electrolysis was used for the isolation of the final product: for the crystallization of crude 4-(4-cyano-2-methoxy-phenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (XIII), the product solution of the electrochemical reduction was concentrated by vacuum distillation at temperatures up to 70 °C (4-(4-cyano-2-methoxy-phenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (XIII) increased to 10-14 wt%, and the product remained dissolved at a reactor temperature of 60 °C). After the vacuum was terminated, (purified) water was added to the solution over 4 h at 60 °C to induce crystallization.After all the water was added (approximately 4:1 v / v water:concentrate), the suspension was cooled to room temperature and stirred for another 2 hours, and the product was filtered and washed with water. After drying in a drying cabinet (under vacuum) at 55°C, 39.2 g of crude 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (XIII) was obtained. Yield: 39.2 g (77.8% of theory) of an off-white crystalline powder.

[0435] Analysis results: Assay % 4-(4-cyano-2-methoxy-phenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (XIII) (HPLC-Method B) 98.1% Area % Main compound [Compound (XIII)] (HPLC-Method B): 98.77% Enantiomeric excess ee% = 0.88% (HPLC-Method C)

[0436] C.4.3 Example 4 (XIII) [Pure] 70 g of the racemate thus obtained (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 container at room temperature. 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (XIII) was recrystallized by first completely dissolving the solid by heating above 85°C (slight reflux) and then cooling the solution to 5°C (over 3 hours). This was stirred overnight. The solid was filtered, and the wet cake thus obtained was washed with pre-cooled (5°C) isopropanol (2 x 110 g). After drying in a drying cabinet (under vacuum) at 50°C Yield: 58.1 g (83% of theory) of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (XIII) was obtained as a white crystalline powder.

[0437] Analysis results: 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% Area % Main compound [Compound (XIII)] (HPLC-Method B): 99.31% Enantiomeric excess ee% = 1.04% (HPLC-Method C) D. Summary Results

[0438] Section C.1 described the synthesis of the compound according to formula (XIII) by a sequential one-pot synthesis (step a) and step b). Sections C.2.1 (step c)) and C.2.2 (step d)) respectively describe the further purification of the compound according to formula (XIII).

[0439] Experiments have shown that the sequential one-pot synthesis makes it possible to produce compounds of formula (XIII) very efficiently, in high yield, on a large scale, and with high purity. The sequential one-pot synthesis offers significant advantages over the prior art in terms of scalability and technical implementation. The overall yield is significantly higher compared to previously described syntheses, as summarized in Table 7 below.

[0440] [Table 15]

[0441] From Table 7 above, it is clear that the overall yield of the sequential one-pot synthesis shows a significantly higher overall yield (Example 1: 81.5%; Example 2: 75.3%; Example 3: 80.8%) than the synthesis described in U.S. Patent Application Publication No. 15 / 753,406 (64%). This is also surprising because the sequential one-pot synthesis is a large-scale process. One skilled in the art would not have expected this result.

[0442] Section C.3 describes how finerenone (I) was obtained from recycled 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (XIII). Section C.4 describes the recovery of compound ent-(I) from the mother liquor and washings (Sections C.3, C3.1), and the sequential one-pot synthesis starting from ent-(I), including steps a), b) (Section C.1), and c) (Section C.2).

[0443] We demonstrated that sequential one-pot synthesis can be performed several times in succession, thus offering the possibility of converting compound ent-(I) to compound (XIII). This can be considered a quasi-continuous operation mode, offering significant advantages in terms of cost, time, and / or resources. In this way, the waste product ent-(I), which is repeatedly generated in the preparation of finerenone (I), can be converted back to compound (XIII). Compound (XIII) can then be fed back into the finerenone (I) production process. Thus, after several process cycles of sequential one-pot synthesis, compound ent-(I) can be almost completely utilized. In the best case, the by-product ent-(I) can be almost completely recycled into the expected product (XIII) or finerenone (I). See, for example, Scheme 4 above. Furthermore, finerenone (I) could be obtained in high purity. [Explanation of symbols]

[0444] 1 electrolysis cell 2 Power supply 3 Electrolyte bath 4 Anode liquid tank 5. Pump 6 Separator 7 Heat exchanger

Claims

1. 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide according to formula (XIII) 【Chemistry 1】 1. A sequential one-pot synthesis for synthesizing 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,6-naphthyridine-3-carboxamide according to formula (XVII) 【Chemistry 2】 with (4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide according to formula (I): 【Transformation 3】 a) synthesizing by electrochemical oxidation of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide according to formula (XIII) 【Chemistry 4】 b) by electrochemical reduction of a compound according to formula (XVII) Including, In step a), the current density used is decreased or decreased stepwise, Sequential one-pot synthesis.

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

3. - step a) is carried out at a temperature selected from 15 to 150°C, 15 to 120°C, and 20 to 100°C; and / or - in step a), first the electrochemical oxidation is carried out and then the reaction mixture is heated; and / or - in step a), 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, 3. The sequential one-pot synthesis of claim 1 or 2.

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

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

6. In step a) and / or b), the solvent is aprotic solvents, protic solvents and mixtures thereof, or polar aprotic solvents; or a polar aprotic solvent selected from dimethylformamide (DMF), dimethyl sulfoxide, acetonitrile, acetone; or a protic solvent selected from 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 a mixture of the above 6. The sequential one-pot synthesis of any one of claims 1 to 5, wherein

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

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

9. 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 between 1 and 30,000 A / m 2 , 1 to 20,000 A / m 2 , 1 to 10,000 A / m 2 , and 1 to 500 A / m 2 and / or - the electrochemical oxidation is between 1 and 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 at a current density selected from 9. The sequential one-pot synthesis of any one of claims 1 to 8.

10. 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 between 1 and 30,000 A / m 2 , 1 to 25,000 A / m 2 , 1 to 20,000 A / m 2 , 1 to 15,000 A / m 2 , 1 to 10,000 A / m 2 and 1 to 5000 A / m 2 and / or - the electrochemical reduction is between 1 and 10,000 A / m 2 , 1 to 1000 A / m 2 , 1 to 500 A / m 2 , 5 to 10,000 A / m 2 , 50 to 1000 A / m 2 , 200 to 500 A / m 2 , 10 to 10,000 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 , 200A / m 2 , 250A / m 2 , 300A / m 2 , 350A / m 2 and 400A / m 2 and / or the electrochemical reduction is carried out at a temperature of 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 a temperature of 1 to 50°C, 10 to 35°C, 15 to 30°C, or at ambient temperature; 10. The sequential one-pot synthesis of any one of claims 1 to 9.

11. 11. The sequential one-pot synthesis according to any one of claims 1 to 10, wherein in steps a) and / or b) a pressure of approximately 0.5 bar to 10 bar is used, optionally the pressure used in steps a) and / or b) is decreased, increased, constant or varied.

12. In steps a) and / or b), - the flow rate is decreasing, increasing, constant or changing; and / or - a flow rate between 0.01 mL / min and 10,000 L / min; and / or Pressures of -0.1 to 10 bar are used, 12. The sequential one-pot synthesis of any one of claims 1 to 11.

13. (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (I) 【Transformation 5】 1. A 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) 【Transformation 6】 1. A sequential one-pot synthesis for synthesizing 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,6-naphthyridine-3-carboxamide according to formula (XVII) 【Transformation 7】 with (4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide according to formula (I): 【Transformation 8】 Step a), by electrochemical oxidation of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide according to formula (XIII) 【Chemistry 9】 b) by electrochemical reduction of a compound according to formula (XVII) Step (1) is a sequential one-pot synthesis comprising: (2) isolating the compound according to formula (I) from the compound according to formula (XIII); Including, Optionally, step (1) is characterized by any one of claims 1 to 13, method.

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

15. (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (I) is obtained with an enantiomeric excess e.e. % of less than 1.5%; and / or In step (1) and / or (2), (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 mm / mL based on the total volume of the reaction mixture; 15. The method of claim 13 or 14.

Images