Electrochemical process for the preparation of an ozanimod intermediate

Abstract

The present application relates to the electro-reduction preparation method of ozanimod intermediate (I), 4-cyano-2,3-dihydro-1-indanone oxime (A) is prepared in basic solution, and ozanimod intermediate (I) and hydrochloride thereof are prepared by electro-reduction method: in a divided electrolytic cell, the cathode electrolyte is composed of the basic solution of 4-cyano-2,3-dihydro-1-indanone oxime (A) and an organic solvent, the anode electrolyte is a basic solution, and the cathode electrolytic product of ozanimod intermediate (I) is obtained by electro-reduction reaction.

Description

Technical Field

[0001] This invention relates to a novel method for the electroreduction preparation of ozamod intermediates, specifically a method for preparing ozamod intermediate (I) and its hydrochloride by electroreduction of 4-cyano-2,3-dihydro-1-indanone oxime (A). Background Technology

[0002] Ozanimod (also known as ozanimod, chemical name (S)-5-(3-(1-((2-hydroxyethyl)amino)-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile, English name Ozanimod) is a selective sphingosine monophosphate (S1P) receptor modulator that selectively binds with high affinity to S1P subtypes 1 (S1P 1) and 5 (S1P 5), inducing peripheral blood lymphocyte sequestration and reducing the number of activated lymphocytes circulating to the gastrointestinal tract. It is a potential treatment for multiple sclerosis (MS) and ulcerative colitis (UC) jointly developed by the Scripps Research Institute and Celgene.

[0003] Multiple sclerosis (MS) is a chronic inflammatory, neurodegenerative, central nervous system (CNS) disease associated with the destruction of myelin sheaths in neurons, leading to large focal lesions and ultimately axonal damage. The most common presentation of MS is the relapsing-remitting MS (RRMS) phenotype. Although patients with relapsing MS (RMS) may recover after an acute exacerbation, the deterioration of residual disability can be cumulative over time.

[0004] Ulcerative colitis (UC) is a chronic, nonspecific inflammatory disease of the colon and rectum with ulcerative colitis of unknown etiology. The lesions are confined to the large intestine mucosa and submucosa. The lesions are most commonly located in the sigmoid colon and rectum, but can extend to the descending colon and even the entire colon. The disease has a long course, often with recurrent episodes, and clinical manifestations include diarrhea, abdominal pain, and bloody, mucous stools. It can occur at any age, but is most common between 20 and 30 years of age.

[0005] (S)-1-amino-4-cyano-2,3-dihydroindene (S-Ⅰ) is an important intermediate in the synthesis of ozamod, and is also important for the preparation of pyridine-containing β2-adrenergic receptor agonists—carboxamide drugs, which can be used to treat inflammation, allergies, lung diseases, acute respiratory distress syndrome, and COVID-19.

[0006] Preparation of ozamod: Esther et al. [Selective sphingosine 1 phosphate receptor modulators and methods of chiral synthesis, WO2011060392(A1), 2011.05.19] selected 4-cyano-2,3-dihydro-1-indanone (A) and (S)-tert-butylsulfinamide to react the generated Schiff base (B) with sodium borohydride to give the key intermediate (VI). VI is de-sterilized with (S)-tert-butylsulfinyl group to give the primary amine intermediate (C=S-I) hydrochloride. S-I is protected with tert-butyloxycarbonyl Boc to give (D). Intermediate (D) is N-alkylated with (2-bromoethoxy)-tert-butyldimethylsilane to give (E). Hydroxylamine is introduced onto its cyano group to give (F), which is then converted to a 1,2,4-oxadiazole ring (G) with a benzoic acid derivative. The final portion involves the cleavage and deprotection of tert-butyldimethylsilane to yield ozamod. The preparation reaction is as follows:

[0007]

[0008]

[0009] Chemical reduction preparation of ozamod intermediate (S)-1-amino-4-cyano-2,3-dihydroindene (S-Ⅰ): Loewe et al. [Enantioselective biocatalytic preparation of 4-cyano-substituted 1-aminoindene and ozamod, CN111971398A, 2020.11.20] described the reduction of 4-cyano-2,3-dihydro-1H-indene-1-one oxime in argon and acetic acid with selective zinc powder. 1-Amino-4-cyano-2,3-dihydroindene was prepared by reacting the substrate and zinc powder at a molar ratio of 1:5 at room temperature for 86 h, with a yield of 42%. In 2-methyltetrahydrofuran, ethyl methoxyacetate was selected as the acyl donor, and the reaction was carried out at 60 °C for 20 h under lipase catalysis to prepare (S)-1-amino-4-cyano-2,3-dihydroindene (S-Ⅰ), with a conversion of 58%.

[0010]

[0011] Madhuresh et al. [Stereoselective synthesis of (S)-1-amino-2,3-dihydro-1H-indene-4-carbonitrile using transaminase Enzymes. Asian Journal of Pharmaceutical Analysis and Medicinal Chemistry. 2020, 8(2), 69-76.] described the stereoselective synthesis of 1-amino-4-cyano-2,3-dihydroindene (S-Ⅰ) from 4-cyanoindene via transaminase catalysis. The mass ratio of 4-cyanoindene to transaminase was 1:6.4, the volume ratio of dimethyl sulfoxide to buffer solution was 1:8.9, and the reaction was carried out at 40℃ for 96 h to obtain (S)-1-amino-4-cyano-2,3-dihydroindene (S-Ⅰ). Among them, three enzymes, ATA.EW.127, ATA.EW.135, and CN102-ATA-LP034, can catalyze the formation of 100% (S)-I.

[0012]

[0013] 2019 Florian et al [Chemoenzymatic Synthesis of a Chiral Ozanimod KeyIntermediate Starting from Naphthalene as Cheap Petrochemical Feedstock,TheJournal of Organic [Chemistry. 2019, 84, 4856-4866] describes the synthesis of 4-cyano-2,3-dihydro-1H-indene-1-one oxime using a molar ratio of 4-cyanoindene to hydroxylamine hydrochloride of 1:5 and a volume ratio of ethanol to water of 1:1. The 4-cyano-2,3-dihydro-1H-indene-1-one oxime was then reduced in acetic acid with zinc powder at a substrate-to-zinc powder molar ratio of 1:5 for 70 h at room temperature to obtain 1-amino-4-cyano-2,3-dihydroindene in a yield of 35%. This was followed by CBL-B enzymatic conversion, treatment with hydrochloric acid and sodium hydroxide to obtain (S)-1-amino-4-cyano-2,3-dihydroindene in a total yield of 19%.

[0014]

[0015] In 2015, Martinborough et al. [Selective Sphingosine 1-Phosphate Receptor Modulators and Combination Therapy Therewith, WO 2015066515A1, 2015.05.07] described the condensation of 4-cyanoindanone in N2 and toluene, using a chiral Ellman auxiliary, with a substrate:chiral reagent:Ti(OEt)4 molar ratio of 1:1.11:1.48, at 60 °C for 12 h to form an imine. The imine obtained in the previous step was reacted in N2 and tetrahydrofuran, with an imine:sodium borohydride molar ratio of 1:4, at -78 °C for 1 h. The resulting brown oily crude product was soluble in methanol and salted in HCl-dioxane to prepare (S)-1-amino-4-cyano-2,3-dihydroindene hydrochloride. The overall yield of the three steps was 31%.

[0016]

[0017] Amino compounds are hydrogenated using catalytic methods: zinc powder and sodium borohydride are used as catalysts. The zinc powder catalyst forms a complex with the reduction product—the amino compound intermediate—that is difficult to separate, affecting the purity of the intermediate and leading to excessive heavy metal content in the drug. The large amount of inorganic reducing agent zinc powder used also causes significant environmental pollution. Summary of the Invention

[0018] The technical problem solved by this invention is to provide an electroreduction preparation method for the anti-ozamod intermediate 1-amino-4-cyano-2,3-dihydroindene and its salt (Ⅰ), so as to overcome the problems of classical reduction reactions.

[0019] To solve the technical problem of this invention, the present invention provides the following technical solution:

[0020] The present invention provides an electroreduction method for preparing ozamod intermediate (I), characterized in that ozamod intermediate (I) and its hydrochloride are obtained by electroreduction of 4-cyano-2,3-dihydro-1-indanone oxime (A): the preparation reaction is as follows:

[0021]

[0022] In a partitioned electrolytic cell, an alkaline solution of 4-cyano-2,3-dihydro-1-indanone oxime (A) and an organic solvent are used to form the cathode electrolyte; the anode electrolyte is an alkaline solution; under electrocatalysis, the cathode electrolysis product of ozamado intermediate (I) is obtained through an electroreduction reaction.

[0023] The cathode working electrode voltage is 1.0V to 3.0V relative to the reference electrode; the cathode working electrode current density is 4.0mA / cm². 2~50mA / cm 2 Between 16mA and 200mA, and between 30℃ and 60℃.

[0024] The concentration of 4-cyano-2,3-dihydro-1-indanone oxime should be selected from 5.0 g / L to 15.0 g / L.

[0025] The alkaline solution is selected from: dipotassium hydrogen phosphate solution, disodium hydrogen phosphate solution, sodium hydroxide solution, and sodium acetate solution;

[0026] Alkaline solution concentration selection: 0.3 mol / L, 0.5 mol / L, or 0.7 mol / L;

[0027] Preferably, the reference electrode of the partitioned electrolytic cell is selected from: a saturated potassium chloride calomel electrode.

[0028] The cathode of the partitioned electrolytic cell is selected from zinc sheet, nickel foam, lead sheet or molybdenum sheet electrodes;

[0029] The anode of the partitioned electrolytic cell is selected from: platinum mesh, platinum sheet or graphite electrode;

[0030] The current of the partitioned electrolytic cell is selected from: 16mA, 26mA, 36mA, 50mA, 100mA or 200mA;

[0031] The diaphragm of the partitioned electrolyzer is selected from: N-117 proton exchange membrane or HF-101 strong acid cation exchange membrane;

[0032] The organic solvent in the cathode electrolyte is selected from: acetonitrile, butyronitrile, succinic anhydride, adiponitrile, methanol, ethanol, tetrahydrofuran, or N,N-dimethylformamide;

[0033] The ratio (volume ratio) of organic solvent to alkaline solution in the cathode electrolyte is selected from: organic solvent : alkaline solution = 1 : 1 to 1 : 6.

[0034] Preferably, the alkaline solution in the cathode electrolyte is selected from: dipotassium hydrogen phosphate / sodium.

[0035] Preferably, the cathode electrode of the partitioned electrolytic cell is selected from zinc sheet electrodes.

[0036] Preferably, the anode electrode of the partitioned electrolytic cell is selected from platinum mesh electrodes.

[0037] Preferably, the electrolysis temperature of the partitioned electrolytic cell is selected from 40°C.

[0038] Preferably, the organic solvent in the cathode electrolyte is selected from acetonitrile.

[0039] Preferably, the current of the partitioned electrolytic cell is selected from 26mA.

[0040] Preferably, the ratio of organic solvent to dipotassium hydrogen phosphate / sodium in the cathode electrolyte is selected from: organic solvent : dipotassium hydrogen phosphate / sodium = 1 : 2.2.

[0041] Preferably, the concentration of the alkaline solution in the cathode electrolyte is selected from 0.5 mol / L.

[0042] Beneficial technical effects:

[0043] This invention relates to a method for the electroreduction preparation of ozamod intermediate I. The method for the electroreduction preparation of ozamod intermediate (I) of this invention has the following advantages:

[0044] (1) No toxic or dangerous reducing agents are needed in the reduction reaction. "Electrons" are clean reaction reagents and are an important part of the development of "green pharmaceutical industry".

[0045] (2) No additional catalyst is needed during the electroreduction process; high-purity and high-yield intermediates can be obtained simply in a dipotassium hydrogen phosphate / sodium solution.

[0046] (3) In industrial production, it simplifies the process, reduces production costs, and is safe and environmentally friendly, making it suitable for large-scale promotion and application.

[0047] Electroreduction reactions do not require toxic or hazardous reducing agents, making them an important component of the development of a "green pharmaceutical industry." No additional catalyst is needed; high-purity and high-yield intermediates can be obtained simply in a dipotassium hydrogen phosphate / sodium solution.

[0048] The electroreduction preparation method of the ozamoid intermediate and its hydrochloride (Ⅰ) of the present invention simplifies the process flow and reduces production costs in industrial production, while also causing virtually no environmental pollution, making it suitable for large-scale promotion and application. Attached Figure Description

[0049] Appendix Figure 1 Schematic diagram of a partitioned electrolytic cell Detailed Implementation

[0050] The following examples are intended to illustrate the invention and not to further limit it.

[0051] Example 1

[0052] Electroreduction preparation of 1-amino-4-cyano-2,3-dihydroindene

[0053]

[0054] A partitioned electrolytic cell with an N-117 proton exchange membrane was installed. 0.34 g (1.98 mmol) of 4-cyano-2,3-dihydroindanone oxime was added to the cathode chamber, dissolved in 7 mL of acetonitrile, and 38 mL of 0.5 mol / L Na₂HPO₄ solution was added as the electrolyte. 45 mL of 1.5 mol / L NaOH solution was added to the anode chamber as the electrolyte. The cathode electrode was a 2 × 2 cm lead sheet. 2 The anode electrode is a platinum sheet (1×1cm). 2 The cell voltage was 5.0V, the current was 26mA, the working potential was around 1.6V, the temperature was constant at 40℃, and the electrolysis was carried out for 17h. Acetonitrile was removed by rotary evaporation of the cathode liquid. The remaining alkaline aqueous solution was extracted twice with ethyl acetate, the pH was adjusted to 8-9 with dilute hydrochloric acid solution, and extracted once more. The extracts were combined, dried over Na2SO4, and the solvent was removed to obtain a yellowish-green oily compound. 3mL of tetrahydrofuran was added, and HCl gas was introduced, resulting in a white solid (1-amino-4-cyano-2,3-dihydroindene hydrochloride). The solvent was rotary evaporated to obtain a grayish-white solid. The solid was washed with ethyl acetate, and the filter cake was dried to obtain a white solid powder—0.320g of 1-amino-4-cyano-2,3-dihydroindene hydrochloride, with a yield of 83.1% and mp > 220℃. 1 HNMR (400MHz, DMSO-d6) δ: 8.68 (s, 3H, NH3 + ), 8.04~7.50 (m, 3H, benzene ring), 4.78 (s, 1H, CH), 3.27~3.20 (m, 1H, 3-CH2), 3.08~3.00 (m, 1H, 3-CH2), 2.58~2.53 (m, 1H, 2-CH2), 2.15~2.07 (m, 1H, 2-CH2).

[0055] Example 2

[0056] Electroreduction preparation of 1-amino-4-cyano-2,3-dihydroindene

[0057]

[0058] Install a partitioned electrolytic cell with an N-117 proton exchange membrane. Cathode (zinc sheet, 2×2cm) 2 Add 0.34 g (1.98 mmol) of 4-cyano-2,3-dihydroindanone oxime to the electrolyte chamber, dissolve the substrate in 7 mL of acetonitrile, and add 38 mL of 0.5 mol / L Na₂HPO₄ solution as the electrolyte; anode (platinum mesh, 1 × 1 cm) 245 mL of 1.5 mol / L NaOH solution was added to the electrolyte chamber. The cell voltage was 5.0 V, the current was 26 mA, the working potential was around 1.6 V, and the temperature was kept constant at 40 °C for 17 h. Acetonitrile was removed by rotary evaporation of the cathode liquid. The remaining alkaline aqueous solution was extracted twice with ethyl acetate, and the pH was adjusted to 8-9 with dilute hydrochloric acid solution. The extracts were then extracted once more. The extracts were combined, dried over Na2SO4, and the solvent was removed to obtain a yellow-green oily compound. 3 mL of tetrahydrofuran was added, and HCl gas was introduced. A white solid (1-amino-4-cyano-2,3-dihydroindene hydrochloride) appeared. The solvent was rotary evaporated to obtain a grayish-white solid. The solid was washed with ethyl acetate, and the filter cake was dried to obtain 0.350 g of white solid powder—1-amino-4-cyano-2,3-dihydroindene hydrochloride, with a yield of 90.9%.

[0059] Example 3

[0060] Electroreduction preparation of 1-amino-4-cyano-2,3-dihydroindene

[0061]

[0062] Install a partitioned electrolytic cell with an N-117 proton exchange membrane. Cathode (zinc sheet, 2×2cm) 2 Add 0.34 g (1.98 mmol) of 4-cyano-2,3-dihydroindanone oxime to the electrolyte chamber, dissolve the substrate in 7 mL of acetonitrile, and add 38 mL of 0.5 mol / L Na₂HPO₄ solution as the electrolyte; anode (platinum mesh, 1 × 1 cm) 2 45 mL of 1.5 mol / L NaOH solution was added to the electrolyte chamber. The cell voltage was 5.0 V, the current was 26 mA, the working potential was around 1.6 V, and the temperature was kept constant at 30 °C for 17 h. Acetonitrile was removed by rotary evaporation of the cathode liquid. The remaining alkaline aqueous solution was extracted twice with ethyl acetate, and the pH was adjusted to 8-9 with dilute hydrochloric acid solution. The extracts were then extracted once more. The extracts were combined, dried over Na2SO4, and the solvent was removed to obtain a yellow-green oily compound. 3 mL of tetrahydrofuran was added, and HCl gas was introduced. A white solid (1-amino-4-cyano-2,3-dihydroindene hydrochloride) appeared. The solvent was rotary evaporated to obtain a grayish-white solid. The solid was washed with ethyl acetate, and the filter cake was dried to obtain 0.321 g of white solid powder—1-amino-4-cyano-2,3-dihydroindene hydrochloride, with a yield of 83.4%.

[0063] Example 4

[0064] Electroreduction preparation of 1-amino-4-cyano-2,3-dihydroindene

[0065]

[0066] Install a partitioned electrolytic cell with an N-117 proton exchange membrane. Cathode (zinc sheet, 2×2cm) 2Add 0.34 g (1.98 mmol) of 4-cyano-2,3-dihydroindanone oxime to the electrolyte chamber, dissolve the substrate in 7 mL of acetonitrile, and add 38 mL of 0.5 mol / L Na₂HPO₄ solution as the electrolyte; anode (platinum mesh, 1 × 1 cm) 2 45 mL of 1.5 mol / L NaOH solution was added to the electrolyte chamber. The cell voltage was 5.0 V, the current was 26 mA, the working potential was around 1.6 V, and the temperature was kept constant at 50 °C for 17 h. Acetonitrile was removed by rotary evaporation of the cathode liquid. The remaining alkaline aqueous solution was extracted twice with ethyl acetate, and the pH was adjusted to 8-9 with dilute hydrochloric acid solution. The extracts were then extracted once more. The extracts were combined, dried over Na2SO4, and the solvent was removed to obtain a yellow-green oily compound. 3 mL of tetrahydrofuran was added, and HCl gas was introduced. A white solid (1-amino-4-cyano-2,3-dihydroindene hydrochloride) appeared. The solvent was rotary evaporated to obtain a grayish-white solid. The solid was washed with ethyl acetate, and the filter cake was dried to obtain a white solid powder—0.311 g of 1-amino-4-cyano-2,3-dihydroindene hydrochloride, with a yield of 80.8%.

[0067] Example 5

[0068] Electroreduction preparation of 1-amino-4-cyano-2,3-dihydroindene

[0069]

[0070] Install a partitioned electrolytic cell with an N-117 proton exchange membrane. Cathode (zinc sheet, 2×2cm) 2 Add 0.34 g (1.98 mmol) of 4-cyano-2,3-dihydroindanone oxime to the electrolyte chamber, dissolve the substrate in 7 mL of acetonitrile, and add 38 mL of 0.5 mol / L Na₂HPO₄ solution as the electrolyte; anode (platinum mesh, 1 × 1 cm) 2 45 mL of 1.5 mol / L NaOH solution was added to the electrolyte chamber. The cell voltage was 5.0 V, the current was 36 mA, the working potential was approximately 1.7–1.9 V, the temperature was constant at 40 °C, and electrolysis was carried out for 17 h. Acetonitrile was removed by rotary evaporation of the cathode liquid. The remaining alkaline aqueous solution was extracted twice with ethyl acetate, the pH was adjusted to 8–9 with dilute hydrochloric acid solution, and extracted once more. The extracts were combined, dried over Na₂SO₄, and the solvent was removed to obtain a yellowish-green oily compound. 3 mL of tetrahydrofuran was added, and HCl gas was passed through, resulting in a white solid (1-amino-4-cyano-2,3-dihydroindene hydrochloride). The solvent was rotary evaporated to obtain a grayish-white solid. The solid was washed with ethyl acetate, and the filter cake was dried to obtain 0.320 g of white solid powder—1-amino-4-cyano-2,3-dihydroindene hydrochloride, with a yield of 83.1%.

[0071] Example 6 (Control Experiment 1)

[0072] Metal reduction preparation of 1-amino-4-cyano-2,3-dihydroindene

[0073]

[0074] The following method was used to prepare 1-amino-4-cyano-2,3-dihydro-1H-indene oxime according to Chinese invention patent [Enantioselective biocatalysis for the preparation of 4-cyano-substituted 1-aminoindene and ozanimod, CN111971398A, 2020.11.20]: 4-cyano-2,3-dihydro-1H-indene oxime was prepared by selective reduction with zinc powder in argon and acetic acid, with a substrate:zinc powder molar ratio of 1:5, and the reaction was carried out at room temperature for 86 h, yielding 42% 1-amino-4-cyano-2,3-dihydroindene.

[0075] In this specification, the invention has been described with reference to specific embodiments thereof. However, it will be apparent that various modifications and variations can be made without departing from the spirit and scope of the invention. Therefore, the specification and drawings should be considered illustrative rather than restrictive.

Claims

1. A method for preparing the ozamoid intermediate of Formula I by electroreduction, characterized in that... 4-Cyano-2,3-dihydro-1-indanone (A) was electroreduced to prepare ozamod intermediate (I) and its hydrochloride: the preparation reaction is as follows: In a separate electrolytic cell, an alkaline solution of 4-cyano-2,3-dihydro-1-indanone oxime (A) and an organic solvent are selected to form the cathode electrolyte, and the anode electrolyte is an alkaline solution. The cathode electrolyte product of ozamado intermediate (I) is obtained by electroreduction reaction. The cathode working electrode voltage is 1.0 V to 3.0 V relative to the reference electrode; the cathode working electrode current density is selected from 4.0 mA / cm². 2 ~ 50 mA / cm 2 The current is selected from 16 mA to 200 mA, and the electrolysis temperature is selected from 30℃ to 60℃. The alkaline solution is selected from: dipotassium hydrogen phosphate solution, disodium hydrogen phosphate solution, sodium hydroxide solution, or sodium acetate solution; the reference electrode of the diaphragm electrolytic cell is selected from: saturated potassium chloride calomel electrode.

2. The method for preparing the ozamade intermediate by electroreduction as described in claim 1, characterized in that, The cathode of the partitioned electrolytic cell is selected from zinc sheet, nickel foam, lead sheet or molybdenum sheet electrodes.

3. The method for preparing the ozamoid intermediate by electroreduction as described in claim 1, characterized in that, The anode of the partitioned electrolytic cell is selected from: platinum mesh, platinum sheet or graphite electrode; the diaphragm of the partitioned electrolytic cell is selected from: N-117 proton exchange membrane or HF-101 strong acid cation exchange membrane.

4. The method for preparing the ozamade intermediate by electroreduction as described in claim 1, characterized in that, The organic solvent in the cathode electrolyte is selected from any one or more of the following: acetonitrile, butyronitrile, succinic anhydride, adiponitrile, methanol, ethanol, tetrahydrofuran, or N,N-dimethylformamide.

5. The method for preparing the ozamado intermediate by electroreduction as described in claim 1, characterized in that, The concentration of 4-cyano-2,3-dihydro-1-indanone oxime (A) in the cathode electrolyte is between 5.0 g / L and 25.0 g / L.

6. The method for preparing the ozamade intermediate by electroreduction as described in claim 1, characterized in that, The concentration of the alkaline solution is selected from: 0.3 mol / L, 0.5 mol / L or 0.7 mol / L.

7. The method for preparing the ozamado intermediate by electroreduction as described in claim 1, characterized in that, The volume ratio of organic solvent to alkaline solution in the cathode electrolyte is selected from 1:1 to 1:

6.

8. The method for preparing the ozamod intermediate by electroreduction as described in claim 1, characterized in that, The current of the partitioned electrolytic cell is selected from: 16 mA, 26 mA, 36 mA, 50 mA, 100 mA or 200 mA.

9. The method for preparing the ozamade intermediate by electroreduction as described in claim 1, characterized in that, The alkaline solution in the cathode electrolyte is selected from: dipotassium hydrogen phosphate or disodium hydrogen phosphate.

10. The method for preparing the ozamado intermediate by electroreduction as described in claim 1, characterized in that, The cathode electrode of the partitioned electrolytic cell is selected from zinc sheet electrodes; the anode electrode of the partitioned electrolytic cell is selected from platinum mesh electrodes.

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