Preparation method of breprazol

Abstract

The invention discloses a method for preparing brepazine, comprising the following steps: (1) using 4-bromobenzothiophene as a raw material, reacting with anhydrous piperazine under the catalysis of a complex formed by cuprous iodide and a nitrogen ligand to obtain 4-(1-piperazinyl)benzo[b]thiophene; (2) subjecting 4-(1-piperazinyl)benzo[b]thiophene to substitution and cyclization with 1,4-dihalobutane to obtain 8-(benzo[b]thiophene-4-yl)-5,8-diazaspiro[4,5]-decane halide; and (3) reacting 8-(benzo[b]thiophene-4-yl)-5,8-diazaspiro[4,5]-decane halide with 7-hydroxy-2(1H)-quinolinone in an alkaline environment to obtain brepazine. The starting materials, reagents and solvents used in the present invention are all relatively cheap and environmentally friendly; the selected process conditions are mild, the safety risk is low, the quality of intermediates and products is more controllable, and the process is suitable for industrial production.

Description

Technical Field

[0001] The present invention relates to the technical field of drug synthesis, and in particular to a method for preparing brepazole. Background Art

[0002] Brexpiprazole, chemical name: 7-(4-(4-(benzo[b]thiophene-4-yl-piperazine-1-yl)butoxy)-1H-quinolin-2-one; is the first dopamine D2, 5-HT1A receptor partial agonist, and 5-HT2A receptor antagonist compound jointly developed by Lundbeck Pharmaceuticals of Denmark and Otsuka Corporation of Japan. It is an atypical antipsychotic drug. Brexpiprazole is a partial agonist of serotonin receptor 5-HT1A and dopamine receptors D2 and D3, and is also a serotonin It is a partial antagonist of the receptors 5-HT2A and 5-HT2B, as well as the adrenergic receptors α-1 and α-2, and has a broad binding affinity for other central monoamine receptor subtypes. On July 10, 2015, the US FDA approved the marketing of brepirazole, with the trade name Rexulti, for the treatment of major depressive disorder (MDD) and schizophrenia. It was subsequently approved in Japan and the European Union in January and July 2018, respectively. Currently, brepirazole is considered to be the drug with the most market prospects after the best-selling antipsychotic drug aripiprazole.

[0003]

[0004] The currently disclosed synthetic routes of brepazine are mainly the following:

[0005] 1. The original research enterprise, Japan Otsuka Pharmaceutical Co., Ltd., disclosed the following synthetic route 1 in the patent application with publication number WO2006112464A2 (Chinese patent family number CN101155804B):

[0006]

[0007] This route uses 4-bromobenzothiophene as a raw material, and reacts with piperazine under palladium catalysis to produce 4-(1-piperazinyl)benzo[b]thiophene through a coupling reaction. After column separation and purification, it is salified with concentrated hydrochloric acid to obtain 4-(1-piperazinyl)benzo[b]thiophene dihydrochloride; then it is further separated and purified by column and 7-(4-chlorobutoxy)-1H-quinolin-2-one to obtain breprazol. This process for synthesizing 4-(1-piperazinyl)benzo[b]thiophene requires expensive metal palladium and phosphorus ligand complex catalysis, and each step requires column separation and purification, resulting in a long production cycle and high manufacturing cost. At the same time, the literature (Organic Process Research & Development 2018, 22 (11), 1471-1480: Identification, Synthesis, and Control of Process-Related Impurities in the Antipsychotic Drug Substance Brexpiprazole; Rahul Tyagi, Harnam Singh, Jagat Singh, Himanshu Arora, Vijayalaxmi Yelmeli, Sathyanarayana Girigani, Pramod Kumar) disclosed that multiple impurities with genotoxic warning structures may be produced during the synthesis of 7-(4-chlorobutoxy)-1H-quinoline-2-one. The impurity structures are shown below:

[0008]

[0009] Most of these impurities contain genotoxic warning structures, and most of them may be transmitted and exist in brepazine. Since the structures of these impurities are very similar to the molecular structure of the final product and have similar solubility properties to brepazine, purification is difficult. At the same time, analytical methods for these impurities also need to be established, which is a huge workload.

[0010] Prior art CN109970705B discloses a method for preparing an epipiprazole intermediate and epipiprazole using cheap copper metal, wherein 4-halogenated benzo[b]thiophene and piperazine are dissolved in a solvent under nitrogen protection, a base, a ligand, and a copper-based catalyst are added to react to obtain a 4-piperazineylbenzothiophene hydrochloride intermediate, and then a 7-(4-chlorobutoxy)-1H-quinoline-2-one intermediate is prepared, and finally 4-piperazineylbenzothiophene hydrochloride is reacted with 7-(4-chlorobutoxy)-1H-quinoline-2-one to generate epipiprazole. The 7-(4-chlorobutoxy)-1H-quinoline-2-one intermediate prepared in the process of producing epipiprazole in this patent may also contain impurities with genotoxic warning structures.

[0011] In addition, Japan's Otsuka Pharmaceutical Co., Ltd. also disclosed in its patent application with publication number CN103717587A that during the synthesis of 4-(1-piperazinyl)benzo[b]thiophene, 2,3-addition impurity 1 and 1,4-disubstituted piperazine impurity 2 are produced. The structures of impurity 1 and impurity 2 are shown below:

[0012]

[0013] 2. Patent application and literature of Otsuka Pharmaceutical Co., Ltd. with publication number WO2013015456A (Organic Process Research & Development 2015, 19(4), 555-558: An Improved Synthesis of 4-

[0014] (1-Piperazinyl)benzo[b]thiophene Dihydrochloride, Chunhui Wu, Weiming Chen, Dehui Jiang, Xiangrui Jiang, Jingshan Shen) discloses the following synthesis route 2:

[0015]

[0016] Based on route 1, this process uses 1-tert-butyloxycarbonyl-piperazine as a raw material to prepare 4-(1-piperazinyl)benzo[b]thiophene dihydrochloride; then it is reacted with 7-(4-chlorobutoxy)-1H-quinoline-2-one to prepare brepirazole through a substitution reaction. This process has good selectivity and does not require column separation and purification; however, a large amount of process impurities will be generated when synthesizing 7-(4-chlorobutoxy)-1H-quinoline-2-one, and palladium catalysts and phosphine ligand complexes are still required in the process. In addition, the price of 1-tert-butyloxycarbonylpiperazine is relatively high, resulting in high production costs, unfriendly to the environment, and not suitable for industrial production.

[0017] 3. The following synthesis route 3 is disclosed in the patent application with publication number CN106938982A:

[0018]

[0019] This route uses 1-tert-butyloxycarbonyl-piperazine as a raw material, first reacts with 1,4-dihalobutane (X, X' in the above formula are chloro-, bromo-) to obtain 8-tert-butyloxycarbonyl-5,8-diazaspiro[4,5]-quinoline halide, and then reacts with 7-hydroxy-2(1H)-quinolinone to obtain 7-[4-(1-piperazinyl)-butoxy]-1H-quinoline-2-one after substitution reaction and deprotection reaction, and finally couples with 4-chlorobenzothiophene to obtain brepirazole, with a total process yield of 57.9%. Compared with route 2, this scheme uses cheaper starting materials, improves the selectivity of the reaction, and shortens the process cycle. However, the last step still requires the preparation of brepirazole through a palladium-catalyzed coupling reaction, which not only fails to effectively reduce the process cost, but may also cause elemental impurities in the finished product to exceed the standard and thus affect the product quality.

[0020] From the synthesis methods of breprazol disclosed in existing patents and literature, it can be seen that these schemes will inevitably have the following problems: (1) expensive metal palladium catalysis is required; (2) impurities containing genotoxic impurity warning structures will be generated during the synthesis of intermediates; (3) the process controllability is poor, and a large number of process impurities are easily generated, resulting in uncontrollable quality of intermediates or finished products; (4) the process yield is low, the reagents used are not environmentally friendly, the production cost is high, and the process cycle is long. Therefore, it is urgent to develop a better process scheme to achieve the goals of stable process, controllable product quality, low production cost, and low safety risk. Summary of the invention

[0021] The present invention provides a method for preparing brepirazoline, so as to solve the technical problems of difficult product quality control and high production cost in the method for synthesizing brepirazoline in the prior art.

[0022] According to one aspect of the present invention, there is provided a method for preparing brepazole, comprising the following steps:

[0023] (1) Using 4-bromobenzothiophene as a raw material, reacting with anhydrous piperazine under the catalysis of a complex formed by cuprous iodide and a nitrogen ligand to obtain 4-(1-piperazinyl)benzo[b]thiophene; reacting 4-(1-piperazinyl)benzo[b]thiophene with hydrochloric acid or oxalic acid to form a salt, separating and purifying to obtain 4-(1-piperazinyl)benzo[b]thiophene hydrochloride / oxalate;

[0024] (2) 4-(1-piperazinyl)benzo[b]thiophene hydrochloride / oxalate is reacted with 1,4-dihalobutane to undergo substitution and cyclization to obtain 8-(benzo[b]thiophen-4-yl)-5,8-diazaspiro[4,5]-decane halide;

[0025] (3) reacting 8-(benzo[b]thiophene-4-yl)-5,8-diazaspiro[4,5]-decane halide with 7-hydroxy-2(1H)-quinolinone in an alkaline environment to obtain brepazole;

[0026] The nitrogen ligand is any one of N,N'-bis(2,6-dimethoxy-4-hydroxyphenyl)oxalamide, N,N'-bis(2,4,6-trimethoxyphenyl)oxalamide, N,N'-bis(2-methyl-4-methoxy-6-phenyl)oxalamide, N,N'-bis(furan-2-ylmethyl)oxalamide, N,N'-dibenzyloxalyl diamide, and [(2,6-xylyl)amino](oxy)acetic acid;

[0027] Or the nitrogen ligand is any one of N-((2,4,6-tri-tert-butylphenyl)amino)-2-oxoacetic acid, N-((2,6-diisopropylphenyl)amino)-2-oxoacetic acid, N-((4-methoxy)amino)-2-oxoacetic acid, N-(2,6-dimethylphenyl)-N-methylamino-2-oxoacetic acid, N-((4-nitrophenyl)amino)-2-oxoacetic acid, and N-((2-tert-butylphenyl)amino)-2-oxoacetic acid.

[0028] Furthermore, the reaction in step (1) is carried out in an alkaline environment, the added alkaline compound is one of potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, and potassium phosphate, and the reaction solvent is one of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and dimethyl sulfoxide.

[0029] Furthermore, the molar ratio of cuprous iodide to 4-bromobenzothiophene is 0.03-0.05, the molar ratio of nitrogen ligand to 4-bromobenzothiophene is 0.05-0.10, the molar ratio of basic compound to 4-bromobenzothiophene is 0.8-2.5, and the molar ratio of anhydrous piperazine to 4-bromobenzothiophene is 2.5-4.0.

[0030] Furthermore, in step (1), the reaction temperature is 80-140° C. and the reaction time is 6-12 h;

[0031] The solvent for the salt-forming reaction is one or more of methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile, ethyl acetate, methyl tert-butyl ether, and isopropyl ether.

[0032] Furthermore, in step (2), the molar ratio of 1,4-dihalobutane to 4-(1-piperazinyl)benzo[b]thiophene hydrochloride / oxalate is 1.0-1.1;

[0033] The 1,4-dihalobutane includes one of 1,4-dibromobutane, 1,4-dichlorobutane, 4-bromo-1-chlorobutane and 4-iodo-1-chlorobutane.

[0034] Furthermore, the reaction in step (2) is carried out in an alkaline environment, and the added alkaline compound is one of potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, and potassium phosphate; and the solvent used in the reaction is one of methanol, ethanol, isopropanol, acetonitrile or tetrahydrofuran.

[0035] Furthermore, in the step (2), the reaction temperature is 40-80° C. and the reaction time is 4-8 hours. After the reaction is complete, the by-product inorganic salt is removed by filtration, and then crystallization is performed using a polar solvent.

[0036] Furthermore, the reaction in step (3) is carried out in an alkaline environment, and the added alkaline compound is one of potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, and potassium phosphate; the solvent used in the reaction is one of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and dimethyl sulfoxide.

[0037] Furthermore, in step (3), the molar ratio of 7-hydroxy-2(1H)-quinolinone to 8-(benzo[b]thiophene-4-yl)-5,8-diazaspiro[4,5]-decane bromide is 1-1.2; and the molar ratio of the alkaline compound used in the reaction to 8-(benzo[b]thiophene-4-yl)-5,8-diazaspiro[4,5]-decane halide is 1.2-2.0.

[0038] Furthermore, in the step (3), the reaction temperature is 100-150° C., and the reaction time is 8-12 h. After the reaction is complete, water is added dropwise to crystallize, filter, and dry to obtain a crude product of brepazole.

[0039] The present invention has the following beneficial effects:

[0040] (1) The present invention does not use 7-(4-chlorobutoxy)-1H-quinolin-2-one intermediates in the process of preparing brepirazole, thereby avoiding the generation of impurities containing genotoxic warning structures in the process of producing brepirazole; instead, 4-bromobenzothiophene is used as a starting material, catalyzed by cuprous iodide and a nitrogen ligand complex, and reacted with piperazine to obtain 4-piperazine-benzothiophene; the obtained 4-piperazine-benzothiophene is reacted with 1,4-dihaloalkane to obtain a spirocyclic quaternary ammonium salt; the spirocyclic quaternary ammonium salt is then used as a raw material to react with 7-hydroxy-2(1H)-quinolinone to synthesize brepirazole; the impurities, especially impurities containing genotoxic warning structures, are less in the entire reaction process, and the purity and yield are high, and the cost of the raw materials used is also lower.

[0041] (2) The method for synthesizing brepazole provided by the present invention has the advantages of easy-to-obtain reaction raw materials, mild reaction conditions, and good total yield; the selected process conditions are mild, highly controllable, low safety risks, short preparation cycle, less "three wastes", and more controllable quality of intermediates and products; and fewer impurities are generated in the process route, and the quality of intermediates and products is more controllable, which greatly reduces the analytical research work and is more suitable for industrial scale-up production.

[0042] (3) The present invention uses 4-bromobenzothiophene as a raw material, reacts with a small amount of inexpensive cuprous iodide, a nitrogen ligand, and an alkaline compound in a solvent, and then purifies the reactant by salt formation to obtain 4-(1-piperazinyl)benzo[b]thiophene hydrochloride or oxalate with a purity of more than 92%; 4-(1-piperazinyl)benzo[b]thiophene hydrochloride / oxalate is substituted with 1,4-dihalobutane, and reacted in an alkaline environment to obtain 8-(benzo[b]thiophene-4-yl) -5,8-diazaspiro[4,5]-decane bromide, the product purity is more than 99%; finally, 8-(benzo[b]thiophen-4-yl)-5,8-diazaspiro[4,5]-decane bromide is reacted with 7-hydroxy-2(1H)-quinolinone to prepare brepirazole, and after the reaction is complete, water is directly added for crystallization to obtain a crude brepirazole with a yield of 68.3-84.4% and a purity of more than 96%, and the purity of the fine brepirazole reaches 99.9% or more. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] The drawings constituting a part of this application are used to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute an improper limitation of the present invention. In the drawings:

[0044] Attached Figure 1 is the HPLC chromatogram of 4-(1-piperazinyl)benzo[b]thiophene dihydrochloride prepared in Example 2;

[0045] Attached Figure 2 This is the H NMR spectrum of 4-(1-piperazinyl)benzo[b]thiophene dihydrochloride prepared in Example 2;

[0046] Attached Figure 3 The carbon NMR spectrum of 4-(1-piperazinyl)benzo[b]thiophene dihydrochloride prepared in Example 2;

[0047] Attached Figure 4 is the mass spectrum of 4-(1-piperazinyl)benzo[b]thiophene dihydrochloride prepared in Example 2;

[0048] Attached Figure 5 This is the infrared spectrum of 4-(1-piperazinyl)benzo[b]thiophene dihydrochloride prepared in Example 2;

[0049] Attached Figure 6 The H NMR spectrum of the 4-(1-piperazinyl)benzo[b]thiophene free base prepared in Example 2;

[0050] Attached Figure 7 This is the HPLC chromatogram of 8-(Benzo[b]thiophen-4-yl)-5,8-diazaspiro[4,5]-decane bromide prepared in Example 1;

[0051] Attached Figure 8 This is the H NMR spectrum of 8-(Benzo[b]thiophene-4-yl)-5,8-diazaspiro[4,5]-decane bromide prepared in Example 1;

[0052] Attached Fig. 9 The carbon NMR spectrum of 8-(benzo[b]thiophen-4-yl)-5,8-diazaspiro[4,5]-decane bromide prepared in Example 1;

[0053] Figure 10 is a mass spectrum of 8-(benzo[b]thiophene-4-yl)-5,8-diazaspiro[4,5]-decane bromide prepared in Example 1;

[0054] Attached Fig.11 The infrared spectrum of 8-(benzo[b]thiophene-4-yl)-5,8-diazaspiro[4,5]-decane bromide prepared in Example 1;

[0055] Attached Fig.12 This is a high performance liquid chromatogram of the fine product of breprazol prepared in Example 5;

[0056] Attached Fig.13 is the hydrogen nuclear magnetic resonance spectrum of the crude brepazole prepared in Example 1;

[0057] Attached Fig.14 The carbon NMR spectrum of the crude breprazol prepared in Example 1;

[0058] Attached Fig.15 is the mass spectrum of the crude breprazol prepared in Example 1;

[0059] Attached Fig.16 is the infrared spectrum of the crude brepirazoline prepared in Example 1;

[0060] Attached Fig.17 This is the X-ray powder diffraction spectrum of the fine anhydrous brepizole prepared in Example 5;

[0061] Attached Fig.18 is the hydrogen nuclear magnetic resonance spectrum of N-((2,6-diisopropylphenyl)amino)-2-oxoacetic acid;

[0062] Attached Fig.19is the carbon NMR spectrum of N-((2,6-diisopropylphenyl)amino)-2-oxoacetic acid;

[0063] Attached Fig. 20 is the mass spectrum of N-((2,6-diisopropylphenyl)amino)-2-oxoacetic acid;

[0064] Attached Fig.21 is the hydrogen nuclear magnetic resonance spectrum of N-((2-tert-butylphenyl)amino)-2-oxoacetic acid;

[0065] Attached Fig. 22 is the carbon nuclear magnetic resonance spectrum of N-((2-tert-butylphenyl)amino)-2-oxoacetic acid;

[0066] Attached Fig.23 is the mass spectrum of N-((2-tert-butylphenyl)amino)-2-oxoacetic acid;

[0067] Attached Fig.24 is the hydrogen nuclear magnetic resonance spectrum of N-((2,4,6-tri-tert-butylphenyl)amino)-2-oxoacetic acid;

[0068] Attached Fig.25 is the carbon nuclear magnetic resonance spectrum of N-((2,4,6-tri-tert-butylphenyl)amino)-2-oxoacetic acid;

[0069] Attached Fig.26 This is the mass spectrum of N-((2,4,6-tri-tert-butylphenyl)amino)-2-oxoacetic acid. DETAILED DESCRIPTION

[0070] The embodiments of the present invention are described in detail below with reference to the accompanying drawings. However, the present invention can be implemented in many different ways as defined and covered below.

[0071] An embodiment of the first aspect of the present invention provides a method for preparing brepazole according to one aspect of the present invention, comprising the following steps:

[0072] (1) Using 4-bromobenzothiophene as a raw material, reacting with anhydrous piperazine under the catalysis of a complex formed by cuprous iodide and a nitrogen ligand to obtain 4-(1-piperazinyl)benzo[b]thiophene; reacting 4-(1-piperazinyl)benzo[b]thiophene with hydrochloric acid or oxalic acid to form a salt, separating and purifying to obtain 4-(1-piperazinyl)benzo[b]thiophene hydrochloride / oxalate;

[0073] (2) 4-(1-piperazinyl)benzo[b]thiophene hydrochloride / oxalate is reacted with 1,4-dihalobutane to undergo substitution and cyclization to obtain 8-(benzo[b]thiophen-4-yl)-5,8-diazaspiro[4,5]-decane halide;

[0074] (3) reacting 8-(benzo[b]thiophene-4-yl)-5,8-diazaspiro[4,5]-decane halide with 7-hydroxy-2(1H)-quinolinone in an alkaline environment to obtain brepazole;

[0075] The nitrogen ligand is any one of N,N'-bis(2,6-dimethoxy-4-hydroxyphenyl)oxalamide, N,N'-bis(2,4,6-trimethoxyphenyl)oxalamide, N,N'-bis(2-methyl-4-methoxy-6-phenyl)oxalamide, N,N'-bis(furan-2-ylmethyl)oxalamide, N,N'-dibenzyloxalyl diamide, and [(2,6-xylyl)amino](oxy)acetic acid; or

[0076] The nitrogen ligand is any one of N-((2,4,6-tri-tert-butylphenyl)amino)-2-oxoacetic acid, N-((2,6-diisopropylphenyl)amino)-2-oxoacetic acid, N-((4-methoxy)amino)-2-oxoacetic acid, N-(2,6-dimethylphenyl)-N-methylamino-2-oxoacetic acid, N-((4-nitrophenyl)amino)-2-oxoacetic acid, and N-((2-tert-butylphenyl)amino)-2-oxoacetic acid.

[0077] The present invention uses a complex formed by a new nitrogen ligand and cuprous iodide as a catalyst to achieve the construction of a CN bond, thereby efficiently, quickly and low-cost synthesizing the intermediate 4-(1-piperazinyl)benzo[b]thiophene, which is then reacted with a cheaper dihalide to generate a spiro intermediate, which is reacted with 7-hydroxy-2(1H)-quinolinone to generate brepirazole. This novel method for synthesizing brepirazole effectively avoids the problems of many impurities, low yield, difficult separation and purification, and high production cost in the existing synthesis process.

[0078] The invention uses 4-bromobenzothiophene as a raw material, reacts a small amount of cheap cuprous iodide, a nitrogen ligand and an alkaline compound in a solvent, and then purifies the reactant by salt formation to obtain 4-(1-piperazinyl)benzo[b]thiophene hydrochloride or oxalate with a purity of more than 92%; and reacts 4-(1-piperazinyl)benzo[b]thiophene hydrochloride / oxalate with 1,4-dihalobutane in an alkaline environment to obtain 8-(benzo[b] The method comprises the following steps: preparing brepazole by reacting 8-(benzo[b]thiophene-4-yl)-5,8-diazaspiro[4,5]-decane bromide with 7-hydroxy-2(1H)-quinolinone, and directly adding water for crystallization to obtain a crude brepazole with a yield of 68.3-84.4% and a purity of 95.5-98.5%.

[0079] The nitrogen ligand used in the present invention can be a substituted oxalamide derivative or one of the oxoacetic acid structures.

[0080] The substituted oxalamide derivative has the following structure:

[0081]

[0082] In the above structure:

[0083] The Chinese name of BHMPO is: N,N'-bis(2,6-dimethoxy-4-hydroxyphenyl)oxalamide

[0084] The Chinese name of BTMPO is: N,N'-bis(2,4,6-trimethoxyphenyl)oxalamide

[0085] The Chinese name of BPMPO is: N,N'-bis(2-methyl-4-methoxy-6-phenyl)oxalamide

[0086] The Chinese name of BFMO is: N,N'-bis(furan-2-ylmethyl)oxalamide

[0087] The Chinese name of DBO is: N,N'-dibenzyl oxalyl diamide

[0088] The Chinese name of DMPAO is: [(2,6-dimethylphenyl)amino](oxy)acetic acid

[0089] The nitrogen ligands shown above are all commercially available products.

[0090] The present invention also provides another nitrogen ligand of oxoacetic acid structure, the structural formula of which is shown below:

[0091]

[0092] Among them, the preparation method of N-((2,4,6-tri-tert-butylphenyl)amino)-2-oxoacetic acid is as follows: add 2,4,6-tri-tert-butylaniline (2.63g, 0.01mol), dichloromethane (30ml), and triethylamine (1.52g, 0.015mol) into a reaction bottle, cool to 0-5°C after dissolution, add ethyl oxalyl chloride (1.40g, 0.01mol), and react for 1h; add water to quench the reaction, stand for 5min and separate the liquids, extract the aqueous phase once with dichloromethane (15ml), combine the organic phases, wash once with water (15ml), and concentrate the organic phase to obtain a yellow solid;

[0093] The solid was dissolved in methanol (20 ml), and a 20% aqueous sodium hydroxide solution was added dropwise until the pH of the reaction solution reached 12-13, and the mixture was kept at 20-25° C. for 3 h. The mixture was neutralized with 6 mol / L hydrochloric acid until the pH of the reaction solution reached 2-3, and the reaction solution was concentrated to dryness. Dichloromethane (30 ml) and water (15 ml) were added to the residual liquid, and the liquids were separated. The aqueous phase was extracted once with dichloromethane (15 ml), and the organic phases were combined and washed once with water (15 ml). The dichloromethane phase was concentrated to dryness to obtain a paste, which was washed with a mixed solution of n-hexane (20 ml) and ethyl acetate (2 ml). The mixture was kept at 20-25° C. for crystallization for 1 h, and the solid was filtered, and the solid was collected and placed in a forced air drying oven and dried at 45-50° C. for 12 h to obtain 3.0 g of N-((2,4,6-tri-tert-butylphenyl)amino)-2-oxoacetic acid, with a yield of 90.9% and a purity of 99.31%. See the test diagram Figure 24-26 .

[0094] The characterization data of N-((2,4,6-tri-tert-butylphenyl)amino)-2-oxoacetic acid are: melting point: 257.5°C-260.1°C. 1H-NMR (400MHz, DMSO-d 6 )δppm: 10.76 (s, 1H), 7.37 (s, 2H), 1.32 (d, J=10.4Hz, 27H). 13C-NMR (100MHz, DMSO-d 6 )δppm: 163.38, 160.25, 148.92, 148.05, 130.64, 123.13, 36.53, 35.03, 32.57, 31.66; mass spectrum (ESI) C 20 H 31 NO 3 , [MH] - Theoretical calculated value: 332.22, measured [MH] - =332.2.

[0095] The preparation method of the above-mentioned N-((2,6-diisopropylphenyl)amino)-2-oxoacetic acid is as follows: add 2,6-diisopropylaniline (1.80 g, 0.01 mol), dichloromethane (30 ml), and triethylamine (1.54 g, 0.015 mol) into a reaction bottle, cool to 0-5°C after dissolution, add ethyl oxalyl chloride (1.39 g, 0.01 mol), and react for 1 hour; add water to quench the reaction, stand for 5 minutes and separate the liquids, extract the aqueous phase once with dichloromethane (15 ml), combine the organic phases, wash once with water (15 ml), and concentrate the organic phase to dryness to obtain a yellow solid;

[0096] Dissolve the above solid with methanol (20ml), add 20% sodium hydroxide aqueous solution to pH 12-13, keep warm at 20-25℃ for 3h; neutralize with 4mol / L hydrochloric acid to pH 2-3, and then concentrate the reaction solution; add dichloromethane (30ml) and water (15ml) to the residual liquid, separate the liquid, extract the aqueous phase with dichloromethane (15ml) once, combine the organic phases, and wash once with water (15ml); concentrate the dichloromethane phase to obtain a paste, and wash it with a mixture of n-hexane (20ml) and ethyl acetate (2ml); keep warm at 20-25℃, crystallize for 1h, filter, collect the filtered solid, place it in a forced drying oven, and dry it at 45-50℃ for 12h; obtain 2.3g of N-((2,6-diisopropylphenyl)amino)-2-oxoacetic acid, with a yield of 92.4% and a purity of 99.26%. See the detection diagram Figure 18-20 .

[0097] The characterization data of N-((2,6-diisopropylphenyl)amino)-2-oxoacetic acid are: melting point: 145.4°C-147.8°C; 1 H-NMR (400 MHz, DMSO-d 6 )δppm: 10.18 (s, 1H), 7.30 (t, J=8.0Hz, 1H), 7.19 (d, J=8.0Hz, 2H), 2.99 (m, 2H), 1.13 (d, J=8.0Hz, 12H); 13 C-NMR (100 MHz, DMSO-d 6 )δppm: 162.96, 159.48, 146.13, 131.88, 128.39, 123.48, 28.53, 23.88; mass spectrum (ESI) C 14 H 19 NO 3 , [MH] - Theoretical calculated value: 248.13, measured [MH] - =248.2.

[0098] The preparation method of N-((2-tert-butylphenyl)amino)-2-oxoacetic acid described above is as follows: 2-tert-butylaniline (1.50 g, 0.01 mol), dichloromethane (30 ml), and triethylamine (1.52 g, 0.015 mol) are added to a reaction bottle, and the mixture is cooled to 0-5°C after dissolution, and ethyl oxalyl chloride (1.38 g, 0.01 mol) is added, and the mixture is reacted for 1 hour; water is added to quench the reaction, and the mixture is allowed to stand for 5 minutes to separate the liquids, and the aqueous phase is extracted once with dichloromethane (15 ml), the organic phases are combined, and the mixture is washed once with water (15 ml), and the organic phase is concentrated to dryness to obtain a yellow oil;

[0099] Dissolve the above oily substance with methanol (20ml), add 20% sodium hydroxide aqueous solution dropwise to pH 12-13, keep warm at 20-25℃ for 3h; neutralize with 4mol / L hydrochloric acid to pH 2-3, and then concentrate the reaction solution; add dichloromethane (30ml) and water (15ml) to the residual liquid, separate the liquid, extract the aqueous phase with dichloromethane (15ml) once, combine the organic phases, and wash once with water (15ml); concentrate the dichloromethane phase to obtain a paste, and wash it with a mixture of n-hexane (20ml) and ethyl acetate (2ml); keep warm at 20-25℃, crystallize for 1h, filter, collect the filtered solid, place it in a forced air drying oven, and dry it at 45-50℃ for 12h; obtain 2.0g of N-((2-tert-butylphenyl)amino)-2-oxoacetic acid, with a yield of 90.6% and a purity of 99.44%. See the detection diagram Figure 21-23 .

[0100] The characterization data of N-((2-tert-butylphenyl)amino)-2-oxoacetic acid are: melting point: 111.5°C-113.1°C; 1 H-NMR (400 MHz, DMSO-d 6 )δppm: 10.06 (s, 1H), 7.45 (dd, J=4.0Hz, 2.4Hz, 1H), 7.27 (t, J=4.0Hz, 3H), 1.35 (s, 9H); 13 C-NMR (100 MHz, DMSO-d 6 )δppm: 163.04, 158.24, 145.55, 135.05, 129.58, 127.55, 127.28, 127.08, 35.11, 31.12; mass spectrum (ESI) C 12 H 15 NO 3 , [MH] - Theoretical calculated value: 220.10, measured [MH] - =220.1.

[0101] The preparation methods of the other three nitrogen ligands of oxoacetic acid structure can be prepared by referring to the above method.

[0102] The nitrogen ligand of the present invention is preferably DMPAO, N-((2-tert-butylphenyl)amino)-2-oxoacetic acid, or N-((2,6-diisopropylphenyl)amino)-2-oxoacetic acid.

[0103] The design route of breprazol of the present invention is:

[0104] The present invention selects an excellent and cheap catalyst system, that is, a catalyst formed by a smaller amount of cuprous iodide and a nitrogen ligand, and smoothly causes 4-bromobenzothiophene to undergo an Ullmann coupling reaction with piperazine to obtain 4-(1-piperazinyl)benzo[b]thiophene; however, the substitution reaction of 4-(1-piperazinyl)benzo[b]thiophene with 1,4-dibromobutane does not smoothly obtain 1-benzo[b]thiophene-yl-4-(4-bromobutyl)piperazine, but obtains 8-(benzo[b]thiophene-4-yl)-5,8-diazaspiro[4,5]-decane bromide with high purity and high yield; we speculate that 1-benzo[b]thiophene-yl-4-(4-bromobutyl)piperazine is first obtained in the reaction process, but the structure is unstable and can rapidly undergo an intramolecular cyclization reaction to obtain a spiro compound, which contains fewer impurities, especially does not contain impurities with a genotoxic warning structure, as described in the following reaction process:

[0105]

[0106] Finally, 8-(benzo[b]thiophene-4-yl)-5,8-diazaspiro[4,5]-decane halide reacted with 7-hydroxy-2(1H)-quinolinone to obtain breprazol. The general synthesis route is as follows:

[0107]

[0108] The present invention does not use 7-(4-chlorobutoxy)-1H-quinoline-2-one intermediates in the process of preparing brepirazole, thereby avoiding the generation of impurities containing genotoxic warning structures in the process of producing brepirazole; instead, 4-bromobenzothiophene is used as a starting material, catalyzed by cuprous iodide and a nitrogen ligand complex, and reacted with piperazine to obtain 4-piperazine-benzothiophene; the prepared 4-piperazine-benzothiophene is reacted with 1,4-dihaloalkane to obtain a spirocyclic quaternary ammonium salt; the spirocyclic quaternary ammonium salt is then used as a raw material to react with 7-hydroxy-2(1H)-quinolinone to synthesize brepirazole; the impurities, especially the impurities containing warning structures, are less in the whole reaction process, the purity is high, the yield is high, and the cost of the raw materials used is also lower.

[0109] In an embodiment of the present invention, the reaction in step (1) is carried out in an alkaline environment, and the added alkaline compound is one of potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, and potassium phosphate, preferably potassium phosphate;

[0110] The reaction solvent is one of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone and dimethyl sulfoxide; preferably N,N-dimethylformamide.

[0111] In the embodiment of the present invention, the molar ratio of cuprous iodide to 4-bromobenzothiophene is 0.03-0.05, the molar ratio of nitrogen ligand to 4-bromobenzothiophene is 0.05-0.10, the molar ratio of basic compound to 4-bromobenzothiophene is 0.8-2.5, preferably 1.2, the molar ratio of anhydrous piperazine to 4-bromobenzothiophene is 2.5-4.0, and the more preferred molar ratio is 3.0. 3-15 ml of reaction solvent is required based on 1 g of 4-bromobenzothiophene.

[0112] In an embodiment of the present invention, the reaction temperature in step (1) is 80-140° C., preferably 125-135° C.; the reaction time is 6-12 h, preferably 8-10 h; in the salt-forming reaction, the acidic compound used can be one of methanesulfonic acid, p-toluenesulfonic acid, tartaric acid, fumaric acid, and maleic acid in addition to hydrochloric acid and oxalic acid; the solvent for the salt-forming reaction is one or more of methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile, ethyl acetate, methyl tert-butyl ether, and isopropyl ether.

[0113] The step (1) further comprises cooling the mixture to 25-35° C. after the reaction is complete, adding 5 volumes of water and 10 volumes of dichloromethane, extracting the aqueous phase with 5 volumes of dichloromethane after separation, combining the dichloromethane phases, and washing the organic phase with 5 parts of 15% sodium chloride solution for three times; concentrating the organic phase to dryness to obtain 4-(1-piperazinyl)benzo[b]thiophene free base; dissolving the 4-(1-piperazinyl)benzo[b]thiophene free base in 5 volumes of methanol, salifying the mixture with hydrochloric acid in a molar ratio of 3.75 to 4-bromobenzothiophene, or oxalic acid in a molar ratio of 1.2, filtering, and drying to obtain 4-(1-piperazinyl)benzo[b]thiophene hydrochloride or oxalate with a purity of 99.0-99.8% and a yield of 70.8-84.3%.

[0114] In an embodiment of the present invention, the molar ratio of 1,4-dihalobutane to 4-(1-piperazinyl)benzo[b]thiophene hydrochloride / oxalate in step (2) is 1.0-1.1, preferably 1.04-1.05; the 1,4-dihalobutane includes one of 1,4-dibromobutane, 1,4-dichlorobutane, 4-bromo-1-chlorobutane and 4-iodo-1-chlorobutane.

[0115] In an embodiment of the present invention, the reaction in step (2) is carried out in an alkaline environment, and the added alkaline compound is one of potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, and potassium phosphate, preferably potassium carbonate; the solvent used in the reaction is one of methanol, ethanol, isopropanol, acetonitrile or tetrahydrofuran, preferably acetonitrile.

[0116] In an embodiment of the present invention, the reaction temperature in step (2) is 40-80°C, preferably 60-70°C, and the reaction time is 4-8h, preferably 5-6h; after the reaction is complete, the temperature is lowered to 25-35°C, and the by-product inorganic salts such as potassium bromide, potassium chloride, potassium carbonate, potassium bicarbonate, etc. are filtered to remove the by-product inorganic salts, and the filtrate is concentrated to a paste under reduced pressure, and then 2.5-4 volumes of polar solvent are added and the temperature is further lowered to 0-10°C for crystallization, and 8-(benzo[b]thiophene-4-yl)-5,8-diazaspiro[4,5]-decane bromide is obtained by filtration. Then, a polar solvent such as isopropanol, ethyl acetate, or isopropyl acetate is used for crystallization, and the amount of the crystallization solvent used is 3-5 volumes of the raw material 4-(1-piperazinyl)benzo[b]thiophene.

[0117] In an embodiment of the present invention, the reaction in step (3) is carried out in an alkaline environment, the alkaline compound added is one of potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, potassium phosphate, preferably potassium carbonate; the solvent used in the reaction is one of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, preferably N-methylpyrrolidone. The amount of the solvent used is 1g / 3-10ml calculated based on the raw material.

[0118] In an embodiment of the present invention, in the step (3), the molar ratio of 7-hydroxy-2(1H)-quinolinone to 8-(benzo[b]thiophene-4-yl)-5,8-diazaspiro[4,5]-decane bromide is 1-1.2, preferably 1.0-1.12; the molar ratio of the basic compound to 8-(benzo[b]thiophene-4-yl)-5,8-diazaspiro[4,5]-decane halide is 1.2-2.0.

[0119] In an embodiment of the present invention, the reaction temperature in step (3) is 100-150°C, preferably 130-140°C, and the reaction time is 8-12h, preferably 7-8h; after the reaction is complete, 10-15V volume of water is added dropwise for crystallization, the temperature is lowered to 10-30°C, filtered, and the filtered product is dried in a forced air drying oven at 50-60°C to obtain a crude product of brepazole.

[0120] Further studies have shown that in the process of synthesizing brepirazole by the reaction of 8-(benzo[b]thiophene-4-yl)-5,8-diazaspiro[4,5]-decane halide and 7-hydroxy-2(1H)-quinolinone, the spirocyclic compound may be in a dynamic equilibrium of ring-opening reaction and intramolecular ring closure to form the raw material. As the reaction proceeds, the product brepirazole is obtained, as shown below:

[0121]

[0122] The crude brepazole is further purified by forming a hydrochloride and dissociating in ethanol and water solvents to obtain a fine brepazole with a purity of 99.9% or more.

[0123] The preferred synthetic route of the present invention is as follows:

[0124]

[0125] The reagents and solvents used in the brepazole synthesis method of the present invention are simple, easy to obtain, cheap and environmentally friendly; the selected process conditions are mild and highly controllable; the process impurities in each step of the scheme are small, which is conducive to quality research and quality control; more importantly, no expensive metal catalytic reagents are used, and the total process yield is good, which greatly reduces the production cost.

[0126] The following examples describe the present disclosure in more detail, and these examples are intended for illustrative purposes only.

[0127] Example 1

[0128] This embodiment provides a method for synthesizing crude brepazole, comprising the following steps:

[0129] (1) Synthesis of 4-(1-piperazinyl)benzo[b]thiophene oxalate: 4-bromobenzothiophene (21.3 g, 0.1 mol), anhydrous piperazine (25.9 g, 0.3 mol), potassium phosphate (25.5 g, 0.12 mol), cuprous iodide (0.58 g, 3 mmol), DMPAO (0.97 g, 5 mmol) and N,N-dimethylformamide (106 ml) were added to a reaction flask in sequence; the temperature was raised under a nitrogen atmosphere and kept at 125-130° C. for 8 h. After the reaction was completed, the temperature was lowered and dichloromethane (215 ml) and water (105 ml) were added at 25-35° C. The layers were separated and the aqueous layer was extracted once with dichloromethane (105 ml); the organic phases were combined and washed three times with 15% sodium chloride solution, each time with 105 ml;

[0130] The dichloromethane phase was concentrated to dryness under reduced pressure, and then methanol (106 ml) was added, and the mixture was kept warm at 25-30°C and stirred to dissolve. Then, a solution of oxalic acid (9.5 g, 0.105 mol) in methanol (53 ml) was slowly added dropwise over 0.5 h to precipitate a light yellow solid. After the addition was completed, crystallization was continued for 1 h. The precipitated solid was filtered and placed in a forced air drying oven at 55-60°C for 12 h to obtain 25.8 g of the product 4-(1-piperazinyl)benzo[b]thiophene oxalate with a yield of 84.3% and a purity of 99.45% as determined by HPLC.

[0131] (2) Synthesis of 8-(Benzo[b]thiophene-4-yl)-5,8-diazaspiro[4,5]-decane bromide: 4-(1-piperazinyl)benzo[b]thiophene oxalate (15.5 g, 0.05 mol), acetonitrile (77 ml), potassium carbonate (13.8 g, 0.1 mol), and 1,4-dibromobutane (11.2 g, 0.052 mol) were added to a reaction flask. The temperature was raised under a nitrogen atmosphere and kept at 70-75°C for reaction. After 5 h, the temperature was lowered to 25-3 0℃, filter to remove inorganic salts, concentrate the filtrate to dryness under reduced pressure, add ethyl acetate (60ml), keep warm at 20-25℃ and stir for 1h; then cool to 0-5℃, continue crystallization for 1h, filter, collect the filtered solid, place the solid in a forced air drying oven, dry at 55-60℃ for 12h, and obtain 14.8g of off-white solid 8-(benzo[b]thiophene-4-yl)-5,8-diazaspiro[4,5]-quercetin bromide, with a yield of 83.8% and a purity of 99.17% as determined by HPLC. See the detection diagram Figure 7-11 .

[0132] The characterization data of 8-(Benzo[b]thiophene-4-yl)-5,8-diazaspiro[4,5]-decane bromide are: melting point: 220.5℃-223.7℃; 1H-NMR (400MHz, DMSO-d6) δppm: 7.78 (d, J=5.6Hz, 1H), 7.72 (d, J=8.0Hz, 1H), 7.52 (d, J=5.6Hz, 1H), 7.34 (t, J=8.0Hz, 1H), 7.02 (d, J=7.6Hz, 1H), 3.73-3.68 (m, 8H), 3.43-3.40 (m, 4H), 2.15-2.12 (m, 4H). 13C-NMR (100MHz, DMSO-d6) δppm: 146.74, 141.05, 133.89, 127.16, 122.21, 118.34, 113.47, 59.31, 47.26, 21.39. Infrared (KBr, cm-1): 2836.65, 1628.74, 1559.80, 1452.08, 1410.42, 1383.13, 1355.85, 1239.51, 1206.47, 1167.69, 1151.89, 1138.97, 1067.15, 1045.61, 1025.50, 966.61, 920.65, 863.20, 810.06, 772.72, 726.76, 690.85, 565.46; Mass spectrum (ESI) C16H23N+2SBr-, theoretical calculated value of [M-Br]+: 273.14, measured: [M-Br]+=273.4.

[0133] (3) Synthesis of crude brexpiprazole: 8-(benzo[b]thiophen-4-yl)-5,8-diazaspiro[4,5]-decane bromide (17.8 g, 0.05 mol), potassium carbonate (10.4 g, 0.075 mol), N-methylpyrrolidone (70 ml) and 7-hydroxy-2(1H)-quinolinone (8.5 g, 0.052 mol, 1.05 eq) were added to a reaction flask, the temperature was raised to 130-135° C., and the reaction was kept at this temperature for 10 h. The reaction solution was cooled to 60-65°C, and water (70ml) was slowly added dropwise. After 1 hour, a light yellow solid was precipitated in the reaction solution. After the addition was completed, the mixture was stirred for 0.5 hours, and water (70ml) was added dropwise again. After 15 minutes, the mixture was cooled to 15-20°C, and crystallization was continued for 1 hour. The solid was filtered and collected. The wet product was placed in a forced air drying oven and dried at 55-60°C for 12 hours. 15.6g of crude breprazol was obtained, with a yield of 72.1% and a purity of 97.65% as determined by HPLC. See the detection diagram for details. Figure 13-16 .

[0134] The characterization data of crude breprazol are as follows: melting point: 175.5°C-178.2°C; 1 H-NMR (400 MHz, DMSO-d 6 )δppm: 11.55 (s, 1H), 7.79 (d, J=8.0Hz, 1H), 7.68 (d, J=4.0Hz, 1H), 7.60 (d, J=8.0Hz, 1H ), 7.54 (d, J=8.0Hz, 1H), 7.39 (d, J=8.0Hz, 1H), 7.26 (t, J=8.0Hz, 1H), 6.87 (d, J=8.0Hz , 1H), 6.78-6.81 (m, 2H), 6.29 (d, J=8.0Hz, 1H) 4.05 (t, J=4.0Hz, 2H), 3.06 (t, J=8.0Hz, 4H), 2.61 (t, J=4.0Hz, 4H), 2.44 (t, J=8.0Hz, 2H), 1.82-1.78 (m, 2H), 1.62-1.65 (m, 2H); 13 C-NMR (100 MHz, DMSO-d 6 )δppm: 162.16, 160.41, 148.22, 140.63, 140.35, 139.90, 133.34, 129.16, 125.70, 125.02, 121.82, 118.43, 116.54, 113.22, 111.97, 110.77, 98.62, 67.60, 57.32, 52.94, 51.69, 26.52, 22.67; infrared (KBr, cm -1): 3144.01, 3067.89, 2950.11, 2817.97, 1653.15, 1624.43, 1556.92, 1509.53, 1466.44, 1447.77, 1414.73, 1373.08, 1317.07, 1265.36, 1239.51, 1220.84, 1197.85, 1134.6 6, 1098.75, 1067.15, 1039.86, 998.21, 966.61, 927.83, 864.64, 833.04, 814.37, 797.13, 771.28, 719.57, 696.59, 636.27, 624.78, 552.97, 531.42, 484.03, 459.61; mass spectrum (ESI) C 25 H 27 N 3 O 2 S, [M+H] + Theoretical calculated value: 434.19, measured [M+H] + =434.4.

[0135] Example 2

[0136] A method for preparing a crude breprazol comprises the following steps:

[0137] (1) Synthesis of 4-(1-piperazinyl)benzo[b]thiophene dihydrochloride: 4-bromobenzothiophene (43.1 g, 0.2 mol), anhydrous piperazine (51.9 g, 0.6 mol), potassium phosphate (51.2 g, 0.24 mol), cuprous iodide (1.15 g, 6 mmol), DMPAO (1.94 g, 10 mmol) and N,N-dimethylformamide (210 ml) were added to a reaction flask in sequence, and the temperature was raised under a nitrogen atmosphere, and the temperature was kept at 125-130° C. for 8 h. After the reaction was completed, the temperature was lowered, and when the internal temperature was 25-30° C., dichloromethane (435 ml) and water (210 ml) were added, and the liquids were separated. The aqueous layer was extracted once with dichloromethane (210 ml); the organic phases were combined and washed three times with 15% sodium chloride solution, each time with 210 ml;

[0138] The dichloromethane phase was concentrated to dryness under reduced pressure, methanol (210 ml) was added, and the mixture was kept at 25-30°C, stirred to dissolve, and then a mixed solution of methanol (105 ml) and concentrated hydrochloric acid (63 ml, 0.75 mol) was slowly added dropwise over 0.5 h to precipitate a light yellow solid. After the addition was completed, crystallization was continued for 1 h, filtered, and the filtered solid was collected. The solid was placed in a forced air drying oven and dried at 55-60°C for 12 h to obtain 47.0 g of off-white solid 4-(1-piperazinyl)benzo[b]thiophene dihydrochloride, with a yield of 80.8% and a purity of 99.65% as determined by HPLC; the melting point was 303.2°C-305.4°C. See the detection diagram for Figure 1-5 .

[0139] The characterization data of the prepared 4-(1-piperazinyl)benzo[b]thiophene dihydrochloride are: 1 H-NMR (400 MHz, CDCl 3 )δppm: 11.39 (1H, s), 9.63 (2H, s), 7.75 (1H, d, J = 5.2Hz), 7.69 (1H, d, J = 8.0Hz), 7.53 (1H, d, J = 5.6Hz), 7.31 (1H, t, J = 8.0Hz), 6.97 (1H, d, J = 7.6Hz), 3.31 (8H, s). 13 C-NMR (100 MHz, DMSO-d 6 )δppm: 147.48, 141.08, 133.89, 126.94, 125.54, 122.38, 118.15, 113.00, 49.01, 43.53. Infrared (KBr, cm -1 ): 3092.30, 3004.69, 2911.33, 2707.38, 2642.75, 2506.30, 1594.27, 1558.36, 1475.06, 1450.64, 1431.97, 1414.73, 1397.50, 1361.59, 1321.37, 1291.21, 1179.18, 114 7.59, 1082.95, 1047.05, 1009.70, 947.94, 923.53, 912.04, 897.67, 867.51, 854.58, 810.06, 801.44, 788.52, 774.15, 723.88, 705.21, 676.49, 573.07, 537.17; mass spectrum (ESI) C 12 H 16 N 2 SCl 2 , [M-2HCl+H] + Theoretical calculation value: 219.10, measured [M-2HCl+H]+ =219.4.

[0140] (2) Synthesis of 8-(Benzo[b]thiophene-4-yl)-5,8-diazaspiro[4,5]-decane bromide: 4-(1-piperazinyl)benzo[b]thiophene dihydrochloride (46.6 g, 0.16 mol), dichloromethane (235 ml), and 200 g of a 10% aqueous sodium hydroxide solution were added to a reaction flask, and the mixture was stirred at 25-30° C. for 2 h. After the solid was completely dissolved, the mixture was allowed to stand, and the aqueous phase was extracted once with dichloromethane (115 ml). The organic phases were combined, washed once with water (115 ml), and concentrated to dryness under reduced pressure to obtain 4-(1-piperazinyl)benzo[b]thiophene free base.

[0141] 4-(1-piperazinyl)benzo[b]thiophene free base was dissolved in acetonitrile (235 ml), and potassium carbonate (22.1 g, 0.16 mol) and 1,4-dibromobutane (36.4 g, 0.17 mol) were added in sequence. The temperature was raised under a nitrogen atmosphere and kept at 70-75° C. for 5 h. After the reaction was complete, the temperature was lowered to 25-30° C. and the inorganic salt was removed by filtration. The filtrate was concentrated to dryness under reduced pressure, and ethyl acetate (120 ml) was added and stirred at 20-25° C. for 1 h. The temperature was then further lowered to 0-5° C. for crystallization for 1 h, and the filtered solid was collected. The solid was placed in a forced air drying oven and dried at 55-60° C. for 12 h to obtain 48.6 g of off-white solid 8-(benzo[b]thiophene-4-yl)-5,8-diazaspiro[4,5]-conitane bromide, with a yield of 86.0% and a purity of 99.69% as determined by HPLC.

[0142] The characterization data of 4-(1-piperazinyl)benzo[b]thiophene free base are: 1 H-NMR (400 MHz, CDCl 3 )δppm: 7.54 (d, J = 8.0 Hz, 1H), 7.42 (d, J = 5.6 Hz, 1H), 7.37 (d, J = 5.2 Hz, 1H), 7.27 (t, J = 7.2 Hz, 1H), 6.89 (d, J = 7.6 Hz, 1H), 3.12 (s, 8H). See Figure 6 .

[0143] (3) Synthesis of crude brexpiprazole: 8-(Benzo[b]thiophene-4-yl)-5,8-diazaspiro[4,5]-decane bromide (17.6 g, 0.05 mol), potassium carbonate (10.4 g, 0.075 mol), N-methylpyrrolidone (90 ml) and 7-hydroxy-2(1H)-quinolinone (9.3 g, 0.055 mol) were added to a reaction flask, and the mixture was heated to 130-135° C. with stirring and reacted for 10 h. The reaction solution was cooled to 60-65°C, and water (90 ml) was slowly added dropwise over 1 hour, and a yellow solid was precipitated in the reaction solution; after the addition, the mixture was stirred for 0.5 hour, and water (90 ml) was added dropwise again over 15 minutes. After the addition of water, the mixture was slowly cooled and kept at 5-10°C. Crystallization was performed for 1 hour, and the solid was filtered and collected. The solid was placed in a forced air drying oven and dried at 55-60°C for 12 hours. 16.1 g of crude brepirazole was obtained with a yield of 74.4% and a purity of 97.48%.

[0144] Example 3

[0145] A method for preparing a crude breprazol comprises the following steps:

[0146] (1) Synthesis of 4-(1-piperazinyl)benzo[b]thiophene dihydrochloride: 4-bromobenzothiophene (10.68 g, 0.05 mol), anhydrous piperazine (12.97 g, 0.15 mol), potassium phosphate (12.80 g, 0.06 mol), cuprous iodide (0.29 g, 1.5 mmol), N-((2-tert-butylphenyl)amino)-2-oxoacetic acid (0.57 g, 2.5 mmol) and N,N-dimethylformamide (55 ml) were added to a reaction flask in sequence, and the temperature was raised under a nitrogen atmosphere and kept at 125-130° C. for 8 h. After the reaction was completed, the temperature was lowered and dichloromethane (105 ml) and water (50 ml) were added at an internal temperature of 25-30° C. to separate the layers; the aqueous layer was extracted once with dichloromethane (50 ml), the organic phases were combined, and washed three times with 15% sodium chloride solution, 50 ml each time;

[0147] The dichloromethane phase was concentrated to dryness under reduced pressure, methanol (50 ml) was added, and the mixture was kept at 25-30°C, stirred to dissolve, and then a mixed solution of methanol (25 ml) and concentrated hydrochloric acid (15 ml, 0.18 mol) was added dropwise. The addition was completed within 0.5 h, and an off-white solid was precipitated. After the addition was completed, crystallization was continued for 1 h, and the filtered solid was collected and placed in a forced air drying oven at 55-60°C for 12 h to obtain 10.9 g of an off-white solid with a yield of 74.9% and a purity of 98.13% as determined by HPLC.

[0148] (2) Synthesis of 8-(Benzo[b]thiophene-4-yl)-5,8-diazaspiro[4,5]-decane bromide: Referring to the method for preparing 8-(Benzo[b]thiophene-4-yl)-5,8-diazaspiro[4,5]-decane bromide according to step (2) in Example 2, 10.4 g of off-white solid was obtained with a yield of 85.6% and a purity of 99.54%.

[0149] (3) Synthesis of crude brexpiprazole: 8-(Benzo[b]thiophen-4-yl)-5,8-diazaspiro[4,5]-decane bromide (8.9 g, 0.025 mol) synthesized in step (2) of Example 3, potassium carbonate (5.2 g, 0.037 mol), N,N-dimethylacetamide (45 ml) and 7-hydroxy-2(1H)-quinolinone (4.5 g, 0.028 mol) were added to a reaction flask, and the mixture was heated with stirring for 135-240 ℃. The reaction mixture was reacted at 140°C for 10 h; the reaction mixture was then cooled to 60-65°C, and water (45 ml) was slowly added dropwise over 1 h to precipitate a yellow solid; the mixture was stirred for 0.5 h after the addition was completed, and water (45 ml) was added dropwise again over 15 min to complete the addition, and the mixture was cooled after the addition of water, kept at 5-10°C, and crystallized for 1 h; the solid was filtered, collected, placed in a forced air drying oven, and dried at 55-60°C for 12 h to obtain 7.4 g of crude brepazole with a yield of 68.3% and a purity of 96.58%.

[0150] Example 4

[0151] A method for preparing a crude breprazol comprises the following steps:

[0152] (1) Synthesis of 4-(1-piperazinyl)benzo[b]thiophene dihydrochloride: 4-bromobenzothiophene (10.71 g, 0.05 mol), anhydrous piperazine (12.94 g, 0.15 mol), potassium phosphate (12.85 g, 0.06 mol), cuprous iodide (0.28 g, 1.5 mmol), N-((2,6-diisopropylphenyl)amino)-2-oxoacetic acid (0.63 g, 2.5 mmol) and N,N-dimethylformamide (55 ml) were added to a reaction flask in sequence, and the temperature was raised under a nitrogen atmosphere and kept at 125-130° C. for 8 h. After the reaction was completed, dichloromethane (105 ml) and water (50 ml) were added, and the layers were separated. The aqueous layer was extracted once with dichloromethane (50 ml). The organic phases were combined and washed three times with 15% sodium chloride solution, 50 ml each time.

[0153] The dichloromethane phase was concentrated to dryness under reduced pressure, methanol (50 ml) was added, and the mixture was kept at 25-30°C, stirred to dissolve, and then a mixed solution of methanol (25 ml) and concentrated hydrochloric acid (15 ml, 0.18 mol) was added dropwise over 0.5 h to complete the addition, and a light yellow solid was precipitated. After the addition was completed, the mixture was cooled and kept at 5-10°C to crystallize for 1 h; the filtered solid was collected and placed in a forced air drying oven at 55-60°C for 12 h to obtain 10.3 g of a light yellow solid with a yield of 70.8% and a purity of 98.02% as determined by HPLC.

[0154] (2) Synthesis of 8-(Benzo[b]thiophene-4-yl)-5,8-diazaspiro[4,5]-decane bromide: Referring to the method for preparing 8-(Benzo[b]thiophene-4-yl)-5,8-diazaspiro[4,5]-decane bromide in step (2) of Example 2, 10.1 g of off-white solid was obtained with a yield of 83.6% and a purity of 99.38%.

[0155] (3) Synthesis of crude brexpiprazole: Add 8-(benzo[b]thiophen-4-yl)-5,8-diazaspiro[4,5]-decane bromide (8.9 g, 0.025 mol) prepared in step (2), potassium carbonate (5.2 g, 0.0375 mol), N,N-dimethylformamide (45 ml) and 7-hydroxy-2(1H)-quinolinone (4.4 g, 0.027 mol) into a reaction flask, raise the temperature to 130-135° C., and keep the temperature for 10 h; then cool the reaction solution to To 60-65°C, then slowly add a mixed solution of water (45ml) and methanol (25ml) dropwise, add it within 1 hour, and a yellow solid will precipitate in the reaction solution; after stirring for 0.5h, add a mixed solution of water (45ml) and methanol (25ml) dropwise again, add it within 15min, cool to 5-10°C after adding, keep warm for 1h to crystallize, filter, collect the filtered product, place it in a forced air drying oven, and dry it at 55-60°C for 12h; 7.9g of crude brepazole is obtained, with a yield of 72.8% and a purity of 96.52%.

[0156] Example 5

[0157] A method for preparing a fine product of breprazol comprises the following steps:

[0158] The crude product of brepazole (10.1 g, purity 97.48%) prepared in Example 1 was added to the reaction flask, and then ethanol (75.5 g), water (60 ml) and acetic acid (8 g) were added in sequence, and the temperature was raised to 80-85° C. until the solid was dissolved; then a mixed solution of concentrated hydrochloric acid (3.0 g) and ethanol (6 ml) was slowly added dropwise for 5 min to precipitate a white solid; after the addition was completed, the temperature was lowered, kept at 0-10° C., crystallized for 1 h, filtered, the filtered solid was collected, placed in a forced air drying oven, and dried at 50-55° C. for 10 h to obtain 10.2 g of brepazole hydrochloride, with a yield of 92.8% and a purity of 99.50%;

[0159] Add brepazine hydrochloride (10.0g), ethanol (150g), and water (90g) to the reaction bottle, raise the temperature to 75-80°C, and brepazine hydrochloride gradually dissolves; then dissolve sodium hydroxide (2g) in a mixture of (30g) ethanol and (60g) water, and then slowly drop the prepared alkali solution into the reaction bottle, control the internal temperature at 70-75°C, and add it in 0.5h; after adding, cool down, keep warm at 10-15°C, and crystallize for 1h. Filter, collect the filtered solid, place it in a forced air drying oven, and dry it at 55-60°C for 12h to obtain 7.82g of brepazine fine product; the total yield of the two steps is about 77.4%, and the purity is 99.97%. See the detection diagram Fig.12 and Fig.17 .

[0160] Example 6

[0161] A method for preparing 8-(benzo[b]thiophene-4-yl)-5,8-diazaspiro[4,5]-decane bromide comprises the following steps:

[0162] To the reaction flask, add 4-(1-piperazinyl)benzo[b]thiophene dihydrochloride (5.85 g, 0.02 mol) prepared in step (1) of Example 2, acetonitrile (23.5 ml), potassium carbonate (8.56 g, 0.04 mol), 4-bromo-1-chlorobutane (3.62 g, 0.021 mol) and potassium bromide (1.21 g, 0.01 mol), and heat at 70-75° C. under nitrogen atmosphere for 6 h. , then cool the reaction solution to 25-30°C, filter and remove inorganic salts; concentrate the filtrate to dryness under reduced pressure, add ethyl acetate (20.5 ml), stir at room temperature for 0.5-1h, then cool to 0-5°C, keep warm for crystallization for 1h, filter, collect the filtered solid, place the solid in a forced air drying oven, dry at 55-60°C for 10h, and obtain 5.14g of off-white solid, with a yield of 72.9% and a purity of 98.61% detected by HPLC.

[0163] Example 7

[0164] Synthesis of 4-(1-piperazinyl)benzo[b]thiophene oxalate:

[0165] 4-Bromobenzothiophene (4.21 g, 0.02 mol), piperazine (5.17 g, 0.06 mol), potassium phosphate (5.12 g, 0.024 mol), cuprous iodide (0.12 g, 0.6 mmol), N-((2,4,6-tri-tert-butylphenyl)amino)-2-oxoacetic acid (0.34 g, 1.0 mmol) and N,N-dimethylformamide (21.5 ml) were added to the reaction flask in sequence, and the temperature was raised under a nitrogen atmosphere, and the temperature was kept at 125-130°C for 10 hours. After the reaction was completed, the temperature was lowered to room temperature, and dichloromethane (45 ml) and water (21 ml) were added, and the liquid was separated. The aqueous layer was extracted once with dichloromethane (45 ml), and the organic phases were combined and washed three times with 15% sodium chloride solution, each time with 21 ml;

[0166] The dichloromethane phase was concentrated to dryness under reduced pressure, methanol (20 ml) was added, stirred at room temperature to dissolve, and then a solution of oxalic acid (1.8 g, 0.025 mol) in methanol (11 ml) was slowly added dropwise over 0.5 h to precipitate a yellow solid; the mixture was kept at 20-25°C and crystallized for 1 h. The filtered solid was collected and placed in a forced air drying oven at 55-60°C for 12 h to obtain 2.78 g of a light yellow solid, with a yield of 45.1% and a purity of 93.35% as determined by HPLC.

[0167] Example 8

[0168] Synthesis of 4-(1-piperazinyl)benzo[b]thiophene oxalate:

[0169] 4-Bromobenzothiophene (4.22 g, 0.02 mol), piperazine (5.16 g, 0.06 mol), potassium phosphate (5.13 g, 0.024 mol), cuprous iodide (0.12 g, 0.6 mmol), BHMPO (0.33 g, 1.0 mmol) and N,N-dimethylformamide (21.6 ml) were added to the reaction flask in sequence, and the temperature was raised under a nitrogen atmosphere, and the temperature was kept at 125-130°C for 10 hours. After the reaction was completed, the temperature was lowered to room temperature, and dichloromethane (45 ml) and water (21 ml) were added, and the liquid was separated. The aqueous layer was extracted once with dichloromethane (45 ml), and the organic phases were combined and washed three times with 15% sodium chloride solution, each time with 21 ml;

[0170] The dichloromethane phase was concentrated to dryness under reduced pressure, methanol (20 ml) was added, stirred at room temperature to dissolve, and then a solution of oxalic acid (1.8 g, 0.025 mol) in methanol (11 ml) was slowly added dropwise over 0.5 h to precipitate a yellow solid; the mixture was kept at 20-25°C and crystallized for 1 h. The filtered solid was collected and placed in a forced air drying oven at 55-60°C for 12 h to obtain 3.94 g of a light yellow solid, with a yield of 64.0% and a purity of 94.89% as determined by HPLC.

[0171] Example 9

[0172] Synthesis of 4-(1-piperazinyl)benzo[b]thiophene oxalate:

[0173] 4-Bromobenzothiophene (4.20 g, 0.02 mol), piperazine (5.13 g, 0.06 mol), potassium phosphate (5.12 g, 0.024 mol), cuprous iodide (0.12 g, 0.6 mmol), BTMPO (0.43 g, 1.0 mmol) and N,N-dimethylformamide (21.6 ml) were added to the reaction flask in sequence, and the temperature was raised under a nitrogen atmosphere, and the temperature was kept at 125-130°C for 10 hours. After the reaction was completed, the temperature was lowered to room temperature, and dichloromethane (45 ml) and water (21 ml) were added, and the liquid was separated. The aqueous layer was extracted once with dichloromethane (45 ml), and the organic phases were combined and washed three times with 15% sodium chloride solution, each time with 21 ml;

[0174] The dichloromethane phase was concentrated to dryness under reduced pressure, methanol (20 ml) was added, stirred at room temperature to dissolve, and then a solution of oxalic acid (1.8 g, 0.025 mol) in methanol (11 ml) was slowly added dropwise over 0.5 h to precipitate a yellow solid; the mixture was kept at 20-25°C and crystallized for 1 h. The solid was filtered and collected, and the solid was placed in a forced air drying oven and dried at 55-60°C for 12 h to obtain 3.28 g of a light yellow solid, with a yield of 53.2% and a purity of 94.11% as determined by HPLC.

[0175] Example 10

[0176] Synthesis of 4-(1-piperazinyl)benzo[b]thiophene oxalate:

[0177] 4-Bromobenzothiophene (4.20 g, 0.02 mol), piperazine (5.13 g, 0.06 mol), potassium phosphate (5.12 g, 0.024 mol), cuprous iodide (0.12 g, 0.6 mmol), BPMPO (0.42 g, 1.0 mmol) and N,N-dimethylformamide (21 ml) were added to the reaction flask in sequence, and the temperature was raised under a nitrogen atmosphere, and the temperature was kept at 125-130°C for 10 hours. After the reaction was completed, the temperature was lowered to room temperature, and dichloromethane (45 ml) and water (21 ml) were added, and the liquid was separated. The aqueous layer was extracted once with dichloromethane (45 ml), and the organic phases were combined and washed three times with 15% sodium chloride solution, each time with 21 ml;

[0178] The dichloromethane phase was concentrated to dryness under reduced pressure, methanol (20 ml) was added, stirred at room temperature to dissolve, and then a solution of oxalic acid (1.8 g, 0.025 mol) in methanol (11 ml) was slowly added dropwise over 0.5 h to precipitate a yellow solid; the mixture was kept at 20-25°C and crystallized for 1 h. The filtered solid was collected and placed in a forced air drying oven at 55-60°C for 12 h to obtain 3.37 g of a light yellow solid, with a yield of 54.7% and a purity of 92.68% as determined by HPLC.

[0179] Embodiment 11

[0180] Synthesis of 4-(1-piperazinyl)benzo[b]thiophene oxalate:

[0181] 4-Bromobenzothiophene (4.20 g, 0.02 mol), piperazine (5.13 g, 0.06 mol), potassium phosphate (5.12 g, 0.024 mol), cuprous iodide (0.12 g, 0.6 mmol), DBO (0.27 g, 1.0 mmol) and N,N-dimethylformamide (21 ml) were added to the reaction flask in sequence, and the temperature was raised under a nitrogen atmosphere, and the temperature was kept at 125-130°C for 10 h; after the reaction was completed, the temperature was lowered to room temperature, and dichloromethane (45 ml) and water (21 ml) were added, and the liquids were separated, and the aqueous layer was extracted once with dichloromethane (45 ml), and the organic phases were combined and washed three times with 15% sodium chloride solution, each time with 21 ml;

[0182] The dichloromethane phase was concentrated to dryness under reduced pressure, methanol (20 ml) was added, stirred at room temperature to dissolve, and then a solution of oxalic acid (1.8 g, 0.025 mol) in methanol (11 ml) was slowly added dropwise over 0.5 h to precipitate a yellow solid; the mixture was kept at 20-25°C and crystallized for 1 h. The filtered solid was collected and placed in a forced air drying oven at 55-60°C for 12 h to obtain 3.37 g of a light yellow solid, with a yield of 54.7% and a purity of 92.68% as determined by HPLC.

[0183] Example 12

[0184] Synthesis of 4-(1-piperazinyl)benzo[b]thiophene oxalate:

[0185] 4-Bromobenzothiophene (4.21 g, 0.02 mol), piperazine (5.17 g, 0.06 mol), potassium phosphate (5.12 g, 0.024 mol), cuprous iodide (0.12 g, 0.6 mmol), BFMO (0.26 g, 1.0 mmol) and N,N-dimethylformamide (21.5 ml) were added to the reaction flask in sequence, and the temperature was raised under a nitrogen atmosphere, and the temperature was kept at 125-130°C for 10 hours. After the reaction was completed, the temperature was lowered to room temperature, and dichloromethane (45 ml) and water (21 ml) were added, and the liquid was separated. The water layer was extracted once with dichloromethane (45 ml); the organic phases were combined and washed three times with 15% sodium chloride solution, each time with 21 ml;

[0186] The dichloromethane phase was concentrated to dryness under reduced pressure, methanol (20 ml) was added, stirred at room temperature to dissolve, and then a solution of oxalic acid (1.8 g, 0.025 mol) in methanol (11 ml) was slowly added dropwise over 0.5 h to precipitate a yellow solid, which was kept at 20-25 ° C and crystallized for 1 h. The filtered solid was collected and placed in a forced air drying oven at 55-60 ° C for 12 h to obtain 3.31 g of a light yellow solid, with a yield of 55.4% and a purity of 93.35% as determined by HPLC.

[0187] Example 13

[0188] Synthesis of 4-(1-piperazinyl)benzo[b]thiophene oxalate:

[0189] 4-bromobenzothiophene (4.23g, 0.02mol), piperazine (5.17g, 0.06mol), potassium phosphate (5.12g, 0.024mol), cuprous iodide (0.12g, 0.6mmol), N-(2,6-dimethylphenyl)-N-methylamino-2-oxoacetic acid (0.21g, 1.0mmol) and N,N-dimethylformamide (20ml) were added to the reaction bottle in sequence, and the temperature was raised under a nitrogen atmosphere, and the temperature was kept at 125-130℃ for 10h. After the reaction was completed, the temperature was lowered to room temperature, and dichloromethane (45ml) and water (21ml) were added, and the liquid was separated. The water layer was extracted once with dichloromethane (45ml); the organic phases were combined and washed three times with 15% sodium chloride solution, each time with 21ml;

[0190] The dichloromethane phase was concentrated to dryness under reduced pressure, methanol (20 ml) was added, stirred at room temperature to dissolve, and then a solution of oxalic acid (1.8 g, 0.025 mol) in methanol (11 ml) was slowly added dropwise over 0.5 h to precipitate a yellow solid, which was kept at 20-25°C for crystallization for 1 h. The filtered solid was collected and placed in a forced air drying oven at 55-60°C for 12 h to obtain 2.98 g of a light yellow solid, with a yield of 48.4% and a purity of 92.61% as determined by HPLC.

[0191] Embodiment 14

[0192] Synthesis of 4-(1-piperazinyl)benzo[b]thiophene oxalate: 4-bromobenzothiophene (4.24 g, 0.02 mol), piperazine (5.17 g, 0.06 mol), potassium phosphate (5.10 g, 0.024 mol), cuprous iodide (0.12 g, 0.6 mmol), N-((4-methoxy)amino)-2-oxoacetic acid (0.20 g, 1.0 mmol) and N,N-dimethylformamide (20 ml) were added to a reaction flask in sequence, and the temperature was raised under a nitrogen atmosphere, and the temperature was kept at 125-130° C. for 10 h; after the reaction was completed, the temperature was lowered to room temperature, and dichloromethane (45 ml) and water (21 ml) were added, and the liquids were separated, and the aqueous layer was extracted once with dichloromethane (45 ml); the organic phases were combined and washed three times with 15% sodium chloride solution, each time with 21 ml;

[0193] The dichloromethane phase was concentrated to dryness under reduced pressure, methanol (20 ml) was added, stirred at room temperature to dissolve, and then a solution of oxalic acid (1.8 g, 0.025 mol) in methanol (11 ml) was slowly added dropwise over 0.5 h to precipitate a yellow solid, which was kept at 20-25°C for crystallization for 1 h. The filtered solid was collected and placed in a forced air drying oven at 55-60°C for 12 h to obtain 3.57 g of a light yellow solid, with a yield of 57.9% and a purity of 95.33% as determined by HPLC.

[0194] Embodiment 15

[0195] Synthesis of 4-(1-piperazinyl)benzo[b]thiophene oxalate:

[0196] 4-Bromobenzothiophene (4.22 g, 0.02 mol), piperazine (5.18 g, 0.06 mol), potassium phosphate (5.15 g, 0.024 mol), cuprous iodide (0.12 g, 0.6 mmol), N-((4-methoxy)amino)-2-oxoacetic acid (0.23 g, 1.0 mmol) and N,N-dimethylformamide (21 ml) were added to the reaction flask in sequence, and the temperature was raised under a nitrogen atmosphere, and the temperature was kept at 125-130°C for 10 h; after the reaction was completed, the temperature was lowered to room temperature, and dichloromethane (45 ml) and water (21 ml) were added, and the liquids were separated, and the aqueous layer was extracted once with dichloromethane (45 ml); the organic phases were combined and washed three times with 15% sodium chloride solution, each time with 21 ml;

[0197] The dichloromethane phase was concentrated to dryness under reduced pressure, methanol (20 ml) was added, stirred at room temperature to dissolve, and then a solution of oxalic acid (1.8 g, 0.025 mol) in methanol (11 ml) was slowly added dropwise over 0.5 h to precipitate a yellow solid, which was kept at 20-25°C for crystallization for 1 h. The filtered solid was collected and placed in a forced air drying oven at 55-60°C for 12 h to obtain 2.83 g of a light yellow solid, with a yield of 45.9% and a purity of 91.87% as determined by HPLC.

[0198] Comparative Example 1

[0199] 4-Bromobenzothiophene (2.10 g, 0.01 mol), anhydrous piperazine (2.61 g, 0.03 mol), potassium phosphate (2.60 g, 0.012 mol), cuprous iodide (39 mg, 0.2 mmol), DMPAO (58 mg, 0.3 mmol) and N,N-dimethylformamide (10.5 ml) were added to the reaction flask in sequence; the temperature was raised under a nitrogen atmosphere, and the temperature was kept at 125-130°C for 8 h. After the reaction was completed, the temperature was lowered, and dichloromethane (22 ml) and water (11 ml) were added at 25-35°C, and the liquids were separated. The aqueous layer was extracted once with dichloromethane (11 ml); the organic phases were combined. , wash three times with 15% sodium chloride solution, each time using 11 ml; concentrate the dichloromethane phase to dryness under reduced pressure, add methanol (20 ml), keep warm at 25-30°C, stir to dissolve, then slowly add a mixed solution of methanol (10 ml) and concentrated hydrochloric acid (6 ml, 0.07 mol) dropwise, add it over 0.5 h, precipitate a little light yellow solid, continue crystallization for 1 h after addition, filter, collect the filtered solid, place the solid in a forced air drying oven, dry it at 55-60°C for 12 h, and obtain 1.7 g of off-white solid 4-(1-piperazinyl)benzo[b]thiophene dihydrochloride, with a yield of 58.4% and a purity of 95.43% detected by HPLC.

[0200] Comparative Example 2

[0201] 4-Bromobenzothiophene (2.15 g, 0.01 mol), anhydrous piperazine (2.59 g, 0.03 mol), potassium phosphate (2.57 g, 0.012 mol), cuprous iodide (0.14 g, 0.75 mmol), DMPAO (0.23 g, 1.2 mmol) and N,N-dimethylformamide (10.5 ml) were added to the reaction flask in sequence; the temperature was raised under a nitrogen atmosphere and kept at 125-130°C for 8 h. After the reaction was completed, the temperature was lowered and dichloromethane (22 ml) and water (11 ml) were added at 25-35°C. The liquids were separated and the aqueous layer was extracted once with dichloromethane (11 ml); the organic layer was combined and the mixture was stirred for 2 h. The phase was washed three times with 15% sodium chloride solution, each time with 11 ml; the dichloromethane phase was concentrated to dryness under reduced pressure, methanol (20 ml) was added, and the mixture was kept at 25-30°C, stirred to dissolve, and then a mixed solution of methanol (10 ml) and concentrated hydrochloric acid (6 ml, 0.07 mol) was slowly added dropwise over 0.5 h to precipitate a small amount of light yellow solid. After the addition was completed, crystallization was continued for 1 h, filtered, and the filtered solid was collected. The solid was placed in a forced air drying oven and dried at 55-60°C for 12 h to obtain 2.4 g of off-white solid 4-(1-piperazinyl)benzo[b]thiophene dihydrochloride, with a yield of 82.4% and a purity of 99.05% detected by HPLC.

[0202] From the above comparative example 1, it can be seen that when the molar ratio of the nitrogen ligand to 4-bromobenzothiophene is lower than 0.05, the reaction of 4-(1-piperazinyl)benzo[b]thiophene dihydrochloride is significantly worse, resulting in a significant decrease in the product yield; from comparative example 2, it can be seen that when the amount of nitrogen ligand is increased, the reaction does not improve significantly, and the yield does not change much. Therefore, increasing the amount of nitrogen ligand does not lead to better results in the reaction. Considering the cost factor, the preferred amount of nitrogen ligand is 0.05-0.10eq.

[0203] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for preparing breprazol, characterized in that: The following steps are involved: (1) 4-bromobenzothiophene is used as a raw material, and reacts with anhydrous piperazine under the catalysis of a complex formed by cuprous iodide and a nitrogen ligand to obtain 4-(1-piperazinyl)benzo[b]thiophene; 4-(1-piperazinyl)benzo[b]thiophene is reacted with hydrochloric acid or oxalic acid to form a salt, and then separated and purified to obtain 4-(1-piperazinyl)benzo[b]thiophene dihydrochloride or oxalate; The reaction with anhydrous piperazine in step (1) is carried out in an alkaline environment, and the added alkaline compound is one of potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, and potassium phosphate; the reaction solvent is one of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and dimethyl sulfoxide; The molar ratio of cuprous iodide to 4-bromobenzothiophene is 0.03-0.05, the molar ratio of the nitrogen ligand to 4-bromobenzothiophene is 0.05-0.10, the molar ratio of the basic compound to 4-bromobenzothiophene is 0.8-2.5, and the molar ratio of anhydrous piperazine to 4-bromobenzothiophene is 2.5-4.0; (2) Substitution and cyclization of 4-(1-piperazinyl)benzo[b]thiophene dihydrochloride or oxalate with 1,4-dihalobutane to obtain 8-(benzo[b]thiophen-4-yl)-5,8-diazaspiro[4,5]-decane halide; (3) reacting 8-(benzo[b]thiophen-4-yl)-5,8-diazaspiro[4,5]-decane halide with 7-hydroxy-2(1H)-quinolinone in an alkaline environment to obtain brepazole; The nitrogen ligand is any one of [(2,6-xylyl)amino](oxy)acetic acid, N-((2,6-diisopropylphenyl)amino)-2-oxoacetic acid, and N-((2-tert-butylphenyl)amino)-2-oxoacetic acid.

2. The method for preparing breprazol according to claim 1, characterized in that: The temperature of the reaction with anhydrous piperazine in step (1) is 80-140° C., and the reaction time is 6-12 h; The solvent for the salt-forming reaction is one or more of methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile, ethyl acetate, methyl tert-butyl ether, and isopropyl ether.

3. The method for preparing breprazol according to claim 1, characterized in that: In step (2), the molar ratio of 1,4-dihalobutane to 4-(1-piperazinyl)benzo[b]thiophene dihydrochloride or oxalate is 1.0-1.1; The 1,4-dihalobutane is one of 1,4-dibromobutane, 1,4-dichlorobutane, 4-bromo-1-chlorobutane and 4-iodo-1-chlorobutane.

4. The method for preparing breprazol according to claim 1, characterized in that: The reaction in step (2) is carried out in an alkaline environment, and the added alkaline compound is one of potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, and potassium phosphate; the solvent used in the reaction is one of methanol, ethanol, isopropanol, acetonitrile or tetrahydrofuran.

5. The method for preparing breprazol according to claim 1, characterized in that: In the step (2), the reaction temperature is 40-80° C. and the reaction time is 4-8 hours. After the reaction is complete, the by-product inorganic salt is removed by filtration and then crystallized using a polar solvent.

6. The method for preparing breprazol according to claim 1, characterized in that: The reaction in step (3) is carried out in an alkaline environment, and the added alkaline compound is one of potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, and potassium phosphate; the solvent used in the reaction is one of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and dimethyl sulfoxide.

7. The method for preparing breprazol according to claim 6, characterized in that: In the step (3), the molar ratio of 7-hydroxy-2(1H)-quinolinone to 8-(benzo[b]thiophene-4-yl)-5,8-diazaspiro[4,5]-decane halide is 1-1.2; and the molar ratio of the basic compound used in the reaction to 8-(benzo[b]thiophene-4-yl)-5,8-diazaspiro[4,5]-decane halide is 1.2-2.

0.

8. The method for preparing breprazol according to claim 1, characterized in that: In the step (3), the reaction temperature is 100-150° C. and the reaction time is 8-12 h. After the reaction is complete, water is added dropwise to crystallize, filter, and dry to obtain a crude product of brepazole.

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