A method for preparing a chiral intermediate of silodosin

Abstract

The present invention relates to silodosin, and in particular to a method for preparing a silodosin chiral intermediate. The method comprises the steps of obtaining a silodosin key intermediate by subjecting a compound I to a multi-step reaction. The present invention provides a new method for preparing a silodosin key intermediate, which has the advantages of short route, cheap and readily available raw materials, mild conditions, high reaction yield, no chiral separation step, avoiding the use of dangerous and highly toxic drugs, being environmentally friendly, easy to industrialize, and greatly reducing the production cost of the silodosin intermediate.

Description

Technical Field

[0001] The invention relates to silodosin, and in particular to a method for preparing a silodosin chiral intermediate. Background Art

[0002] Silodosin is an α-adrenaline receptor antagonist invented by Kissei Pharmaceutical Company in Japan. It has a very good therapeutic effect on urination disorders related to benign prostatic hyperplasia. The selective effect on the urethra is 12 and 7.5 times higher than that of prazosin and tamsulosin, respectively, and can significantly inhibit the contraction of the human prostate caused by norepinephrine; it has a dose-dependent inhibitory effect on the hyperactive bladder in the rat benign prostatic hypertrophy model and can increase the pressure threshold of bladder contraction. These data suggest that in addition to improving bladder function, silodosin is also effective in relieving symptoms related to benign prostatic hypertrophy. Its chemical name is 2,3-dihydro-1-(3-hydroxypropyl)-5-[(2R)-2-[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethylamino]propyl]-1H-indole-7-carboxamide, CAS registration number 160970-54-7, and the structural formula is as follows:

[0003]

[0004] At present, there are mainly two approaches to the synthesis of silodosin. Representative approaches include the following: intermediates STD-1, STD-2, STD-3, STD-4, STD-5, STD-6, etc. are docked with fragments STD-7 or STD-8 and then hydrolyzed and deprotected, such as patents CN103420893, CN103554003, CN106045895, etc. Most of the key chiral intermediates are obtained by chemical resolution.

[0005]

[0006] Another idea is to directly construct chiral amines, such as patent CN114805170 using Suzuki reaction to construct

[0007] Patent CN114751852 discloses a configuration flipping route to obtain a chiral structure

[0008]

[0009] The above technical routes have the following defects: the chemical splitting route requires the construction of a racemate first and then chiral splitting, which is cumbersome and has a low yield; the chiral construction route has the problem that the source of chiral construction raw materials is not extensive or the construction conditions are too complicated; the synthesis of chiral key intermediates and side chains to obtain silodosin requires 3-4 steps. Therefore, it is particularly important to develop a key chiral intermediate with easy-to-obtain raw materials, simple chiral construction, and as few steps as possible to synthesize silodosin API. Summary of the invention

[0010] In order to overcome the defects of the existing technical route, the present invention provides a new method for preparing a key chiral intermediate of silodosin.

[0011]

[0012] The steps include:

[0013] S1: Synthesis of Compound II

[0014] Dissolve compound I in an organic solvent, add triethylamine, di-tert-butyl dicarbonate and a catalytic amount of 4-dimethylaminopyridine, react at 25°C, monitor by TLC until the raw material disappears, and concentrate the solvent under reduced pressure to obtain compound II;

[0015] S2: Synthesis of Compound III

[0016] Compound II is added to an organic solvent, and a catalytic amount of 10% palladium carbon is added, and the mixture is reacted at 25°C under a hydrogen pressure of 15 psi. The reaction is monitored by TLC until the starting material disappears, and the solvent is filtered and concentrated to obtain compound III;

[0017] S3: Synthesis of Compound IV

[0018] Compound III is dissolved in an organic solvent, N-bromosuccinimide is added at 0-5°C, and the temperature is maintained until the starting material disappears under TLC monitoring, and the solvent is removed by concentration to obtain compound IV;

[0019] S4: Synthesis of Compound V

[0020] Compound IV is dissolved in an organic solvent, an acidic reagent is added, and the reaction is carried out at 25°C. TLC is monitored until the starting material disappears, and the mixture is neutralized with sodium carbonate at 0-5°C to a pH of 8-9. The mixture is extracted with ethyl acetate, separated, dried over anhydrous sodium sulfate, filtered and concentrated, and slurried with petroleum ether / ethyl acetate to obtain compound V;

[0021] S5: Synthesis of Compound VI

[0022] Compound V is dissolved in an organic solvent, 2-(3-chloropropoxy)tetrahydro-2H-pyran is added, an inorganic base is used to cause a nucleophilic substitution reaction, the reaction is heated to 70°C, and TLC is monitored until the starting material disappears, the mixture is filtered, concentrated under reduced pressure, water is added, and the mixture is extracted with ethyl acetate to obtain compound VI;

[0023] S6: Synthesis of Compound VII

[0024] Compound VI was dissolved in an organic solvent, cooled to -70°C in a nitrogen atmosphere, and n-butyl lithium was added dropwise. After the addition, the reaction lasted for 30 minutes. A tetrahydrofuran solution of 2-methyl-2-propyl (4R)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide was added dropwise. After the addition, the reaction was maintained at a certain temperature. TLC was monitored until the raw material disappeared. After the temperature was raised to -50°C, saturated ammonium chloride solution was used for quenching, the reaction was concentrated under reduced pressure, and the compound VII was extracted with ethyl acetate;

[0025] S7: Synthesis of Compound VIII

[0026] Compound VII is dissolved in an organic solvent, sodium hydroxide and hydrogen peroxide are added, and the reaction is maintained at a certain temperature. TLC is monitored until the raw material disappears, and the solution is quenched with a sodium sulfite aqueous solution, extracted with ethyl acetate, washed, and dried to obtain compound VIII;

[0027] S8: Synthesis of key chiral intermediates of silodosin

[0028] Compound VIII is dissolved in an organic solvent, and an ethanolic hydrogen chloride solution (2M-4M) is added, and the reaction is carried out at 25°C. TLC is monitored until the raw material disappears, and the mixture is filtered, dried, and washed with ethanol to obtain a pure product of a key chiral intermediate of silodosin.

[0029] The method is characterized in that the solvent used in the synthesis of step S1 is one or more of dichloromethane, ethyl acetate, tetrahydrofuran, etc.; the molar ratio of compound I to triethylamine di-tert-butyl dicarbonate and 4-dimethylaminopyridine is 1:1.5-2.5:1.05~1.1:0.01~0.05.

[0030] The method is characterized in that the solvent used in the synthesis of step S2 is one or more of ethyl acetate, methanol, ethanol, etc.; the mass ratio of compound II to 10% palladium carbon is 1:0.05-0.2.

[0031] The method is characterized in that the organic solvent used in the synthesis of step S3 is one or more of acetonitrile, N,N-dimethylformamide, ethyl acetate, tetrahydrofuran, etc.; the molar ratio of compound III to N-bromosuccinimide is 1:1.05-1.1.

[0032] The method is characterized in that the organic solvent used in the synthesis of step S4 is one or more of dichloromethane, ethyl acetate, tetrahydrofuran, etc.; the acidic reagent is 2 mol / L to 4 mol / L ethyl acetate solution of hydrogen chloride, trifluoroacetic acid, formic acid, etc.; the molar ratio of compound IV to the acidic reagent is 1:10 to 50.

[0033] The method is characterized in that the organic solvent used in the synthesis of step S5 is one or more of acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, tetrahydrofuran, etc.; the inorganic base used is sodium carbonate, potassium carbonate, cesium carbonate, etc.; the molar ratio of compound V to 2-(3-chloropropoxy)tetrahydro-2H-pyran is 1:1.05~1.3.

[0034] The method is characterized in that the organic solvent used in the synthesis of step S6 is one or more of tetrahydrofuran, 2-methyltetrahydrofuran, toluene, methyl tert-ether, etc.; the reaction temperature is -75-

[0035] -50°C, the molar ratio of compound VI to n-butyl lithium and 2-methyl-2-propyl (4R)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide is: 1:1.1-1.8:1.05~1.5.

[0036] The method is characterized in that in step S7, the molar ratio of compound VII to hydrogen peroxide and inorganic base is 1:2-8:1.1-2; and the reaction temperature is 10-40°C.

[0037] The method is characterized in that the organic solvent used in the synthesis in step S8 is one or more of ethanol, isopropanol, butanone, etc.

[0038] Beneficial effects:

[0039] 1. The present invention avoids the use of chemical splitting routes, the chiral construction raw materials are easily available, and the construction method is brand new, which greatly makes up for the defects of many of the above-mentioned routes. It is particularly emphasized that compound V is synthesized from compound I (7-cyanoindole) through a continuous operation process in four steps, avoiding the boron trichloride reflux and strong base treatment process used by the compound disclosed in CN114751852. When compound VI forms VII, a special reaction reagent (2-methyl-2-propyl (4R)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide) is used. The reaction forms a chiral structure without the need for splitting. Therefore, the chiral intermediate obtained by the preparation method of this patent can be synthesized in one step to obtain the final product (silodosin), that is, the key chiral intermediate for producing silodosin in the present invention can participate in the following reaction to obtain silodosin:

[0040] For example, the two fragments used in patent CN 106083689 were subjected to reductive amination to obtain silodosin in a yield of 85.6%.

[0041]

[0042] JP2016 / 23186 uses the following two fragments to undergo nucleophilic substitution to obtain silodosin with a yield of 60%.

[0043]

[0044] 2. The present invention uses cheap 7-cyanoindole as the starting material and chiral construction reagent 2-methyl-2-propyl

[0045] (4R)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide is a commonly used commercially available reagent. The chiral intermediate was constructed in eight steps with a comprehensive yield of 46%. The synthesis process of compound V is a new process with continuous operation and simple process, and the comprehensive yield is as high as 73%;

[0046] 3. The chiral intermediate obtained by the preparation method of this patent can be synthesized by docking the branched chain in one step to obtain the final product, which greatly reduces the complexity of the synthesis process of the active ingredient of silodosin raw material;

[0047] 4. The preparation process of this patent avoids the use of highly toxic substances such as phosphorus oxychloride, boron trichloride and palladium heavy metal catalysts. The reaction conditions are mild and the reagents used are environmentally friendly, greatly reducing the harm to the human body and the environment. DETAILED DESCRIPTION

[0048] In order to make the purpose, technical scheme and advantages of the present invention clearer, the following specific examples further describe the present invention in detail. The experimental methods in the present invention are conventional methods unless otherwise specified. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.

[0049] The progress of the reaction of the present invention can be monitored by conventional monitoring methods in the art (such as TLC, HPLC or NMR), and the disappearance of the starting material is generally regarded as the reaction endpoint.

[0050] The main raw materials of the present invention were purchased from Shanghai Bid Pharmaceutical Technology Co., Ltd.

[0051] Embodiment 1:

[0052] Example 1 of the present invention provides a method for preparing compound V, and its synthetic route is as follows:

[0053]

[0054] The specific preparation method is as follows:

[0055] Compound I (50 g, 0.35 mol) was dissolved in dichloromethane (0.5 L), triethylamine (71.3 g, 0.70 mol) and 4-dimethylaminopyridine (430 mg, 3.52 mmol) were added, and the mixture was stirred in an ice bath. A solution of di-tert-butyl dicarbonate (80.7 g, 0.37 mol) in dichloromethane (200 ml) was added dropwise, and the mixture was reacted at 25° C. for 3.5 h. After TLC detection, compound I disappeared. After the solvent was removed under reduced pressure, methanol (1.5 L) and 10% palladium carbon (5 g) were added. The atmosphere was replaced with nitrogen three times, and then replaced with hydrogen three times. The reaction was continued at 25° C. at a hydrogen pressure of 15 psi. Overnight, after the reaction is complete, filter and concentrate; after concentration to dryness, add acetonitrile (300 ml), add N-bromosuccinimide (60.4 g, 0.339 mol) in acetonitrile (120 ml) at 0-5°C, and maintain the temperature until the raw material disappears, concentrate and recover the solvent, use ethyl acetate (800 ml) to the residue, add ethyl acetate solution of hydrogen chloride (1.5 L, 2M), after the reaction is complete, neutralize with sodium carbonate at 0-5°C to pH = 8-9, extract with ethyl acetate, separate, dry over anhydrous sodium sulfate, filter and concentrate, and slurry with petroleum ether / ethyl acetate (650 ml:65 ml) to obtain compound V.

[0056] The method was used to prepare 57.2 g of a light yellow solid with a yield of 73% and a purity of 96.3%.

[0057] The intermediate II obtained in this example was identified to obtain the following results:

[0058] ESI-MS (m / z): 221.90;

[0059] 1 H NMR(400MHz,DMSO3)δ7.35(S,1H),7.35(S,1H),7.34(s,1H),6.95(s,1H),3.57(t,3H),3.02(t,2H)

[0060] Embodiment 2:

[0061] Example 2 of the present invention provides a method for preparing compound V, and its synthetic route is as follows:

[0062]

[0063] The specific preparation method is as follows:

[0064] Compound I (50 g, 0.35 mol) was dissolved in dichloromethane (0.5 L), triethylamine (71.3 g, 0.70 mol) and 4-dimethylaminopyridine (430 mg, 3.52 mmol) were added, and the mixture was stirred in an ice bath. A solution of di-tert-butyl dicarbonate (80.7 g, 0.37 mol) in dichloromethane (200 ml) was added dropwise, and the mixture was reacted at 25° C. for 3.5 h. After TLC detection, compound I disappeared, the solvent was removed under reduced pressure, and methanol (1.5 L) and 10% palladium carbon (5 g) were added. The atmosphere was replaced with nitrogen three times, and then with hydrogen three times. The hydrogen pressure was maintained at 15 psi for another 24 h at 25° C. night, after the reaction is completed, filter and concentrate; after concentration to dryness, add acetonitrile (300ml), add N-bromosuccinimide (60.4g, 0.339mol) in acetonitrile (120ml) at 0-5℃, and maintain the temperature until the raw material disappears, concentrate and recover the solvent, dissolve the residue with dichloromethane (100ml), add formic acid (100ml), after the reaction is completed at room temperature, concentrate to remove the solvent, neutralize with sodium carbonate at 0-5℃ to pH=8-9, extract with ethyl acetate, separate the liquids, dry with anhydrous sodium sulfate, filter and concentrate, and slurry with petroleum ether / ethyl acetate (650ml:65ml) to obtain compound V.

[0065] The method was used to prepare 51.7 g of a light yellow solid with a yield of 66% and a purity of 95.2%.

[0066] ESI-MS (m / z): 221.90;

[0067] 1 H NMR(400MHz,DMSO)δ7.35(s,1H),7.34(s,1H),6.95(s,1H),3.57(t,2H),3.02(t,2H)

[0068] Embodiment 3:

[0069] Example 3 of the present invention provides a method for preparing compound V:

[0070]

[0071] Compound V (100 g, 0.448 mol) was dissolved in N,N-dimethylformamide (500 ml), and 2-(3-chloropropoxy)tetrahydro-2H-pyran (96.1 g, 0.538 mol), potassium carbonate (124 g, 0.897 mol), and sodium iodide (6.72 g, 44.8 mmol) were added to react with nucleophilic substitution reaction, and heated to 70°C for reaction. After the reaction was completed, the mixture was filtered, concentrated under reduced pressure, and water was added. The mixture was extracted with ethyl acetate to obtain compound VI;

[0072] The method was used to prepare 146 g of a light yellow oil with a yield of 89% and a purity of 95.4%.

[0073] ESI-MS (m / z): 364.28.

[0074] Embodiment 4:

[0075] Example 4 of the present invention provides a method for preparing compound VII:

[0076]

[0077] Compound VI (365 g, 1 mol) was dissolved in dry tetrahydrofuran (4 L), cooled to -70 °C with nitrogen, and n-butyl lithium (500 ml, 2.5 M) was added dropwise. After the addition was completed, the reaction was maintained at -70 °C for 30 min. A solution of 2-methyl-2-propyl (4R)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (261 g, 1.1 mol) in tetrahydrofuran (300 ml) was added dropwise. After the addition was completed, the reaction was maintained at -70 °C and monitored by TLC until the starting material disappeared. The temperature was raised to -50 °C and quenched with saturated ammonium chloride solution. After stirring to room temperature, the mixture was concentrated under reduced pressure and extracted with ethyl acetate to obtain a light yellow oily compound VII, 438 g, yield: 97% (directly used in the next step).

[0078] Embodiment 5:

[0079] Embodiment 5 of the present invention provides a method for preparing a key chiral intermediate of silodosin:

[0080]

[0081] Compound VII (438g, 0.99mol) was dissolved in dimethyl sulfoxide (4400ml), and an aqueous solution (250ml) of sodium hydroxide (59.2g, 1.48mol) was added. 30% hydrogen peroxide (224g, 1.97mol) was added dropwise at 0-5℃, and the reaction was maintained at 25℃. TLC was monitored until the raw material disappeared, and the starch potassium iodide was neutralized with sodium sulfite aqueous solution until it did not turn blue. 10L of water was added, and the mixture was extracted with ethyl acetate, washed, dried, and concentrated to obtain compound VIII. Compound VIII was dissolved in ethanol (2L), and 10L of ethanolic hydrogen chloride solution (2M) was added. The reaction was carried out at 25℃, and TLC was monitored until the raw material disappeared. The mixture was filtered, washed with ethanol, and dried to obtain 218g of the key chiral intermediate of silodosin as an off-white solid, with a purity of 98.3% and a two-step yield of 71%.

[0082] ESI-MS (m / z): 277.23;

[0083] 1H NMR(400MHz,DMSO)δ8.05-8.01(m,2H),7.75(s,1H),7.35(s,1H),

[0084] 6.92-6.88(m,2H),4.45-4.40(m,1H),3.50-3.16(m,7H),2.91-2.50(m,4H),

[0085] 1.63-1.59(m,2H),1.15-1.10(m,3H)

[0086] Embodiment 6:

[0087] Embodiment 6 of the present invention provides a kind of preparation method of silodosin:

[0088]

[0089] The chiral intermediate (10 g, 36.1 mmol), compound IX (16.2 g, 54.1 mmol), sodium iodide (0.54 g, 3.61 mmol), and tert-butyl alcohol (120 mL) were heated to 80°C and reacted until the raw material disappeared, filtered to remove salt, and concentrated to recover tert-butyl alcohol. The concentrate was added with ethyl acetate for recrystallization to obtain 15.3 g of white solid, with a yield of 84%, a purity of 99.3%, and ee of 99.5%. ESI-MS (m / z): 495.23.

[0090] 1 H NMR (400MHz, CDCl3) δ7.17 (s, 1H) , 7.18-6.80(m,5H),6.75(s,1H),6.34(s,1H),4.45-4.23(m,2H),4.21-4.00(m,2H),3.84-3.65(m,2H),3.56(br,1H) ,3.42-3.34(m,2H),3.30-3.19(m,2H),3.18-2.82(m,5H),2.83-2.40(m,2H),1.95-1.88(m,2H),1.25(d,J=6.4,3H).

Claims

1. A method for preparing a silodosin chiral intermediate, characterized in that: Follow these steps to achieve this: The steps include: S1: Synthesis of Compound II Dissolve compound I in an organic solvent, add triethylamine, di-tert-butyl dicarbonate and a catalytic amount of 4-dimethylaminopyridine, react at 25°C, monitor by TLC until the raw material disappears, and concentrate the solvent under reduced pressure to obtain compound II; S2: Synthesis of Compound III Compound II is added to an organic solvent, and a catalytic amount of 10% palladium on carbon is added, and the mixture is reacted at 25°C under a hydrogen pressure of 15 psi, and monitored by TLC until the starting material disappears, and the mixture is filtered and the solvent is concentrated to obtain compound III; S3: Synthesis of Compound IV Compound III is dissolved in an organic solvent, N-bromosuccinimide is added at 0-5°C, and the temperature is maintained until the starting material disappears under TLC monitoring, and the solvent is concentrated to obtain compound IV; S4: Synthesis of Compound V Compound IV is dissolved in an organic solvent, an acidic reagent is added, and the reaction is carried out at 25°C. TLC is monitored until the starting material disappears, and the mixture is neutralized with sodium carbonate to pH 8-9 at 0-5°C, extracted with ethyl acetate, separated, dried over anhydrous sodium sulfate, filtered, concentrated, and slurried with petroleum ether / ethyl acetate to obtain compound V; S5: Synthesis of Compound VI Compound V is dissolved in an organic solvent, 2-(3-chloropropoxy)tetrahydro-2H-pyran and an inorganic base are added, a nucleophilic substitution reaction occurs, and the reaction is heated to 70°C. TLC is monitored until the starting material disappears, the reaction is filtered, concentrated under reduced pressure, water is added, and the reaction is extracted with ethyl acetate to obtain compound VI; S6: Synthesis of Compound VII Compound VI was dissolved in an organic solvent, cooled to -70°C in a nitrogen atmosphere, and n-butyl lithium was added dropwise. After the addition, the reaction lasted for 30 minutes. A tetrahydrofuran solution of 2-methyl-2-propyl (4R)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide was added dropwise. After the addition, the reaction was carried out and monitored by TLC until the starting material disappeared. After the temperature was raised to -50°C, the reaction was quenched with a saturated ammonium chloride solution, concentrated under reduced pressure, and extracted with ethyl acetate to obtain compound VII; S7: Synthesis of Compound VIII Compound VII is dissolved in an organic solvent, sodium hydroxide and hydrogen peroxide are added, the reaction is maintained, and TLC is monitored until the starting material disappears, the reaction is quenched with a sodium sulfite aqueous solution, extracted with ethyl acetate, washed, and dried to obtain compound VIII; S8: Synthesis of key chiral intermediates of silodosin Compound VIII is dissolved in an organic solvent, and a 2M-4M ethanolic hydrogen chloride solution is added, and the reaction is carried out at 25°C. The reaction is monitored by TLC until the raw material disappears, and the mixture is filtered, dried, and washed with ethanol to obtain a pure product of a key chiral intermediate of silodosin.

2. The method according to claim 1, characterized in that The solvent used in the synthesis of step S1 is one or more of dichloromethane, ethyl acetate, and tetrahydrofuran; the molar ratio of compound I, triethylamine, di-tert-butyl dicarbonate and 4-dimethylaminopyridine is 1:1.5-2.5:1.05~1.1:0.01~0.

05.

3. The method according to claim 1, characterized in that The solvent used in the synthesis of step S2 is one or more of ethyl acetate, methanol, and ethanol; the mass ratio of compound II to 10% palladium carbon is 1:0.05-0.

2.

4. The method according to claim 1, characterized in that: The organic solvent used in the synthesis of step S3 is one or more of acetonitrile, N,N-dimethylformamide, ethyl acetate, and tetrahydrofuran; the molar ratio of compound III to N-bromosuccinimide is 1:1.05-1.

1.

5. The method according to claim 1, characterized in that The organic solvent used in the synthesis of step S4 is one or more of dichloromethane, ethyl acetate, and tetrahydrofuran; the acidic reagent is 2 mol / L to 4 mol / L ethyl acetate solution of hydrogen chloride, trifluoroacetic acid, and formic acid.

6. The method according to claim 1, characterized in that The organic solvent used in the synthesis of step S5 is one or more of acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, and tetrahydrofuran; the inorganic base used is sodium carbonate, potassium carbonate, and cesium carbonate; the molar ratio of compound V to 2-(3-chloropropoxy)tetrahydro-2H-pyran is 1:1.05-1.

3.

7. The method according to claim 1, characterized in that The organic solvent used in the synthesis of step S6 is one or more of tetrahydrofuran, 2-methyltetrahydrofuran, toluene, and tert-methyl ether; the molar ratio of compound VI, n-butyl lithium and 2-methyl-2-propyl (4R)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide is: 1:1.1-1.8:1.05~1.

5.

8. The method according to claim 1, characterized in that In the synthesis of step S7, the molar ratio of compound VII to hydrogen peroxide and sodium hydroxide is 1:2-8:1.1-2; the reaction temperature is 10-40°C.

9. The method according to claim 1, characterized in that: The organic solvent used in the synthesis of step S8 is one or more of ethanol, isopropanol, and butanone.

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