A process for the preparation of milorine tartrate

Abstract

The application provides a preparation method of milorin benzenesulfonate, and belongs to the technical field of organic synthesis. The synthesis route is shown in the figure, and the specific steps are as follows: compound A is used as a starting material, an amidation reaction is carried out under a nitrogen-containing reagent to generate compound B; compound B is subjected to a hydrolysis reaction under the action of hydantoinase to generate compound C; after Hofmann degradation of compound C in an alkaline solution of a hypohalite, the compound C is subjected to a reaction with benzenesulfonic acid, and milorin benzenesulfonate is obtained. The preparation method uses an enzyme hydrolysis method to construct a chiral center, the chiral purity is higher, the separation treatment process is avoided, the yield is higher, and the purity is higher. In addition, reagents such as sodium cyanide and butyllithium are not involved in the preparation process, and the safety is higher.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology and provides a method for preparing milobalin benzylsulfonic acid. Background Technology

[0002] Currently, the drugs available for treating neuropathic pain on the market are gabapentin and pregabalin, but both of these drugs have serious limitations in clinical treatment. Mirogabalin besylate (trade name Tarlige), a gabapentinoid developed by Daiichi Sankyo Co., Ltd. of Japan, was approved for marketing in Japan in January 2019. It is an α2δ ligand that acts on the α2-δ1 subunit of voltage-sensitive calcium channel complexes (widely distributed throughout the nervous system that mediates pain transmission and processing), thereby treating chronic neuropathic pain. It is used to treat peripheral neuropathic pain, including diabetic peripheral neuropathy (DPNP) and postherpetic neuralgia (PHN), and clinical studies have shown that its efficacy is significantly higher than that of gabapentin and pregabalin.

[0003] Chinese invention patent application CN111116345A (publication date: May 8, 2020) discloses a novel method for preparing racemic Mirogabalin. The method uses 3-ethylbicyclo[3,2,0]hepta-3-en-6-one A as a starting material, reacting it with cyanoacetate and ammonia to generate ammonium salt B. Ammonium salt B is then reacted with sulfuric acid upon heating to generate diacetic acid compound C. Compound C is reacted with urea to generate imide compound D. Compound D is then degraded by Hofmann chromatography to generate racemic Mirogabalin hydrochloride E. Compound E is then resolved to obtain Mirogabalin. The Mirogabalin synthesized by this method has the advantages of relatively mild reaction conditions, simple preparation method, avoidance of the highly toxic NaCN, and suitability for industrial production.

[0004]

[0005] The above synthetic route yielded intermediate E as racemic Mirogabalin hydrochloride. Compound E was esterified with methanol to give methyl mirogabalin ester, which was then resolved with a yield of 35.6%. Subsequently, methyl mirogabalin ester was hydrolyzed to obtain methyl ester with a yield of 76%. The overall yield was less than 30%.

[0006] Therefore, it is necessary to propose a new synthetic route for milobalin benzylsulfonic acid that can directly obtain the pure enantiomeric structure without avoiding the racemic structure. Summary of the Invention

[0007] The purpose of this invention is to provide:

[0008] A method for preparing milobalin benzyl sulfonate is provided to address the technical problems, such as poor safety due to the use of highly hazardous chemical reagents like sodium cyanide and butyllithium in the synthesis of milobalin benzyl sulfonate, the need for separation treatment to obtain pure enantiomers during the preparation process, and the resulting unsatisfactory purity and low yield, or a combination thereof.

[0009] Terminology Explanation: Unless otherwise defined, all technical terms in this document have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter of the claims pertains. Unless otherwise stated, all patents, patent inventions, and disclosures cited in this document are incorporated herein by reference in their entirety. If multiple definitions exist for terms in this document, the definitions in this chapter shall prevail.

[0010] It should be understood that the above brief description and the following detailed description are exemplary and for illustrative purposes only, and do not limit the subject matter of the invention in any way.

[0011] In this invention, unless otherwise specifically stated, the use of the singular includes the plural. It should also be noted that, unless otherwise stated, the use of “or” or “or” means “and / or”. Furthermore, the use of the term “comprising” and other forms such as “including,” “containing,” and “containing” are not limiting.

[0012] The definition of standard chemical terms can be found in the reference "Basic Organic Chemistry (Volumes 1 & 2)" by Xing Qiyi, Higher Education Press, 3rd Edition, 2005-06.

[0013] Unless otherwise stated, conventional methods within the scope of the art, such as stirring, reflux, filtration, washing (rinsing), crystallization, drying, etc., shall be used.

[0014] Unless specifically defined herein, the use of all commercially available products herein employs standard techniques. For example, it may be carried out using the manufacturer's instructions for use with the kit, or in accordance with methods known in the art or the description of this invention. The techniques and methods described herein can generally be implemented according to conventional methods well known in the art, based on the descriptions in the various summary and more specific documents cited and discussed in this specification.

[0015] The term "amidation reaction" in this article refers to the organic chemical reaction in which a carboxylic acid or its derivative reacts with an amine compound to form an amide.

[0016] The term "nitrogen-containing reagent" in this article refers to the amine compound (amine or ammonia) in the amidation reaction, which acts as a nucleophile and reacts with a carboxylic acid or its derivative (compound A in this synthetic route) to form an amide bond (-CO-NH-).

[0017] In this article, "selective hydrolysis" refers to the process in which the amide bond (-CONH-) reacts with water under the action of acids, bases, enzymes, etc., and breaks to generate carboxylic acid (or carboxylate) and ammonia (or amine).

[0018] The term "hydantoinase" in this article refers to a class of amide hydrolases that catalyze the cleavage of cyclic amide bonds in hydantoin and its derivatives. Based on the differences in optical activity between the catalytic substrate and the product, they can be classified into D-type, L-type, and DL-type.

[0019] The “Hofmann degradation” mentioned in this article, also known as the Hofmann rearrangement reaction, refers to the organic chemical reaction in which a primary amide is converted into a primary amine with one less carbon atom under the action of bromine (or chlorine) and a base.

[0020] This invention provides a method for preparing milobalin benzylsulfonic acid, and the synthetic route is as follows:

[0021] Includes the following steps: Step 1: Starting with compound A, an amidation reaction is carried out under a nitrogen-containing reagent to generate compound B; Step 2: Add compound B to solvent A, where it undergoes selective hydrolysis under the action of hydantoin to generate compound C; Step 3: Compound C undergoes Hofmann degradation in an alkaline solution of hypohalite to generate milobalin; Step 4: Milobalin reacts with benzenesulfonic acid in solvent B to obtain the benzenesulfonic acid-milobalin. In step 2, the selective hydrolysis temperature is 40-60℃ and the pH value is 8.0-9.0.

[0022] As some specific embodiments of the present invention, the selective hydrolysis temperature is 40-60°C, including but not limited to 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60°C or any range between two temperatures; preferably 44-56°C; more preferably 48-52°C; in this selective hydrolysis step, lowering the temperature slows down the reaction and the raw material conversion is incomplete; higher temperatures result in poor chiral purity, and the product may hydrolyze into the raw material compound A, reducing the yield.

[0023] As some specific embodiments of the present invention, the pH value of the selective hydrolysis is 8.0-9.0, including but not limited to 8.0, 8.1, 8.2, 8.3, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, or any range between two pH values; preferably 8.0-8.5; more preferably 8.3-8.5. In this selective hydrolysis step, if the reaction pH is too high, the diamide impurities generated by ammonolysis will increase significantly and cannot be completely removed during solid crystallization. At the same time, the raw material compound B will be directly hydrolyzed, further affecting the chiral purity. Moreover, the product compound C will also be partially hydrolyzed into the starting raw material compound A, which enters the mother liquor, resulting in a significant decrease in yield; if the reaction pH is lowered, the reaction slows down, the raw material conversion rate is low, and the yield is also reduced.

[0024] As some specific embodiments of the present invention, in step 1, the nitrogen-containing reagent is selected from any one of ammonia, urea, ammonium salt and thiourea; preferably urea or ammonia; more preferably urea.

[0025] The ammonium salt is selected from any one of ammonium acetate, ammonium carbonate, ammonium bicarbonate, and ammonium sulfide; preferably, it is ammonium acetate.

[0026] As some specific embodiments of the present invention, the molar ratio of compound A to nitrogen-containing reagent is 1:1 to 1:4, including but not limited to: 1:1, 1:1.2, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5 or 1:4; preferably 1:1 to 1:2; more preferably 1:1.

[0027] As some specific embodiments of the present invention, in step 1, the temperature of the amidation reaction is 100-150°C, including but not limited to 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150°C or any two temperature ranges; the specific reaction temperature is determined by the type of nitrogen-containing reagent added, for example, if urea is used as a reactant, the reaction temperature is at or above its melting temperature, specifically 130-150°C; when a solvent is present, the reaction can be carried out at the solvent reflux temperature; when ammonium acetate is used as a reactant, acetic acid will be produced, or when ammonia is used as a reactant, because water is introduced, it should first be evaporated above the boiling point of acetic acid and water to avoid affecting the reaction process, and on this basis, the temperature is further increased to make the reaction more complete.

[0028] As some specific embodiments of the present invention, in step 2, the mass ratio of the hydantoin to compound B is 1:2-1:8, including but not limited to 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5, 1:6, 1:6.5, 1:7, 1:7.5 or 1:8; preferably 1:3-1:6; more preferably 1:5-1:6.

[0029] As some specific embodiments of the present invention, in step 2, the mass ratio of compound B to solvent A is 1:5-1:20, including but not limited to 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19 or 1:20; preferably 1:5-1:15; more preferably 1:9-1:11.

[0030] As some specific embodiments of the present invention, in step 2, solvent A is water or an organic solvent / water mixture; preferably water.

[0031] The organic solvent is selected from one or more of methanol, ethanol, isopropanol, tetrahydrofuran, acetone and cyclohexanone.

[0032] As some specific embodiments of the present invention, in step 3, the molar ratio of compound C, hypohalite, and solute in the alkaline solution is 1:0.96:2.5-1:1.3:4, including but not limited to 1:0.96:2.5, 1:0.96:2.8, 1:0.96:3.2, 1:0.96:4, 1:1.05:2.5, 1:1.05:2.8, and 1:1.05. The ratios are 3.2, 1:1.05:4, 1:1.2:2.5, 1:1.2:2.8, 1:1.2:3.2 or 1:1.2:4, 1:1.3:2.5, 1:1.3:2.8, 1:1.3:3.2 or 1:1.3:4; preferably 1:1.05-1.2:2.8-3.2; more preferably 1:1.05:2.8 or 1:1.2:3.2.

[0033] As some specific embodiments of the present invention, in step 3, the Hofmann degradation temperature is 40-45℃, including but not limited to 40, 41, 42, 43, 44, 45℃ or any range between two temperatures; the time is 1-2h, including but not limited to 1, 1.5 or 2h.

[0034] As some specific embodiments of the present invention, in step 3, the hypohalite includes, but is not limited to, sodium hypochlorite and sodium hypobromite.

[0035] As some specific embodiments of the present invention, in step 3, the alkaline solution includes, but is not limited to, sodium hydroxide solution and potassium hydroxide solution.

[0036] As some specific embodiments of the present invention, in step 4, the molar ratio of milobalin to benzenesulfonic acid is 0.96-1.1:1, including but not limited to 0.96:1, 0.98:1, 1:1, 1.02:1, 1.04:1, 1.06:1, 1.08:1, or 1.1:1.

[0037] As some specific embodiments of the present invention, in step 4, the reaction temperature is 80-85℃, including but not limited to 80, 81, 82, 83, 84, 85℃ or any range between two points; the time is 3-4h, including but not limited to 3, 3.5 or 4h.

[0038] As some specific embodiments of the present invention, in step 4, the solvent B is selected from one or more of water, acetonitrile, isopropanol, tetrahydrofuran, acetone, dichloromethane, methyl tert-butyl ether, and anisole.

[0039] The technical feature "the nitrogen-containing reagent is selected from any one of ammonia, urea, ammonium salts, and thiourea" is summarized from the foregoing explanation and / or the corresponding technical feature "urea, ammonium acetate, and ammonia" in Examples 1.1-1.4. Therefore, those skilled in the art can reasonably infer that the technical feature "the nitrogen-containing reagent is selected from any one of ammonia, urea, ammonium salts, and thiourea," its subordinate concepts, substantially equivalent technical means, and technical means that can replace this technical feature based on existing technology and conventional technical means and common knowledge should all fall within the protection scope of this invention. For example, replacing ammonium acetate with ammonium carbonate while keeping other technical features unchanged still falls within the protection scope of this invention.

[0040] The technical feature “the molar ratio of compound A to the nitrogen-containing reagent is 1:1-1:4” is summarized from the corresponding technical features 1:1.05, 1:1.2, 1:2, and 1:4 in the foregoing explanation and / or Examples 1.1-1.4. Therefore, those skilled in the art can reasonably infer that the molar ratio of compound A to the nitrogen-containing reagent is 1:1-1:4, its subordinate concepts, substantially equivalent technical means, and technical means that can replace this technical feature based on existing technology and conventional technical means and common knowledge should all fall within the protection scope of this invention.

[0041] The technical feature "the amidation reaction temperature is 100-150℃" is summarized from the foregoing explanation and / or the corresponding technical feature reaction temperatures of 135-145℃, 110-115℃, 135-145℃, and 100-110℃ in Examples 1.1-1.5. Therefore, those skilled in the art can reasonably infer that the technical feature of the amidation reaction temperature being 100-150℃, its subordinate concepts, substantially equivalent technical means, and technical means that can replace this technical feature based on existing technology and conventional technical means and common knowledge should all fall within the protection scope of this invention.

[0042] The technical feature "selective hydrolysis temperature of 40-60℃" is summarized from the foregoing explanation and / or the corresponding technical features 50℃, 40-45℃, 55-60℃, and 50℃ in Examples 2.1-2.4. Therefore, those skilled in the art can reasonably infer that the technical feature of selective hydrolysis temperature of 40-60℃, its subordinate concepts, substantially equivalent technical means, and technical means that can replace this technical feature based on existing technology and conventional technical means and common knowledge should all fall within the protection scope of this invention.

[0043] The technical feature “selective hydrolysis pH value of 8.0-9.0” is summarized from the foregoing explanation and / or the corresponding technical features 8.3-8.5 and 8.5-8.7 in Examples 2.1-2.4. Therefore, those skilled in the art can reasonably infer that the technical feature selective hydrolysis pH value of 8.0-9.0, its subordinate concepts, substantially equivalent technical means, and technical means that can replace this technical feature based on existing technology and conventional technical means and common knowledge should all fall within the protection scope of this invention.

[0044] The technical feature “the mass ratio of hydantoin to compound B is 1:2-1:8; and / or the mass ratio of compound B to solvent A is 1:5-1:20” is derived from the feeding mass of compound B, D-hydantoin, and solvent in the foregoing explanation and / or Examples 2.1-2.4. Therefore, those skilled in the art can reasonably infer that the mass ratio of hydantoin to compound B of 1:2-1:8; and / or the mass ratio of compound B to solvent A of 1:5-1:20, its subordinate concepts, substantially equivalent technical means, and technical means that can replace this technical feature based on existing technology and conventional technical means and common knowledge should all fall within the protection scope of this invention.

[0045] The technical feature "solvent A is water or an organic solvent / water mixture" is summarized from the foregoing explanation and / or the corresponding technical features water, methanol / water, and acetone / water in Examples 2.1-2.4. Therefore, those skilled in the art can reasonably infer that the technical feature solvent A is water or an organic solvent / water mixture, its subordinate concepts, substantially equivalent technical means, and technical means that can replace this technical feature based on existing technology and conventional technical means and common knowledge should all fall within the protection scope of this invention.

[0046] The technical feature “the molar ratio of compound C, hypohalate, and solute in the alkaline solution is 1:0.96:2.5-1:1.3:4” is derived from the foregoing explanation and / or the corresponding feed equivalents of compound C, hypohalate (sodium hypochlorite), and solute in the alkaline solution (sodium hydroxide) in Examples 3.1-3.2. Therefore, those skilled in the art can reasonably infer that the molar ratio of compound C, hypohalate, and solute in the alkaline solution of 1:0.96:2.5-1:1.3:4, its subordinate concepts, substantially equivalent technical means, and technical means that can replace this technical feature based on existing technology and conventional technical means and common knowledge should all fall within the protection scope of this invention.

[0047] The technical feature “the molar ratio of milobalin to benzenesulfonic acid is 0.96-1.1:1” is derived from the foregoing explanation and / or the corresponding feed equivalents of milobalin and benzenesulfonic acid in Examples 4.1-4.4. Therefore, those skilled in the art can reasonably infer that the molar ratio of milobalin to benzenesulfonic acid of 0.96-1.1:1, its subordinate concepts, substantially equivalent technical means, and technical means that can replace this technical feature based on existing technology and conventional technical means and common knowledge should all fall within the protection scope of this invention.

[0048] The technical feature "in step 4, the reaction temperature is 80-85℃ and the time is 3-4h" is summarized from the foregoing explanation and / or the corresponding technical features of 80℃, 80-85℃, and 3h in Examples 4.1-4.4. Therefore, those skilled in the art can reasonably infer that the technical feature of 80-85℃ and 3-4h, its subordinate concepts, substantially equivalent technical means, and technical means that can replace this technical feature based on existing technology and conventional technical means and common knowledge should all fall within the protection scope of this invention.

[0049] The technical feature “solvent B is selected from one or more of water, acetonitrile, isopropanol, tetrahydrofuran, acetone, dichloromethane, methyl tert-butyl ether, and anisole” is summarized from the foregoing explanation and / or the corresponding technical features acetonitrile / water, isopropanol / water, and water in Examples 4.1-4.4. Therefore, those skilled in the art can reasonably infer that the technical feature solvent B is selected from one or more of water, acetonitrile, isopropanol, tetrahydrofuran, acetone, dichloromethane, methyl tert-butyl ether, and anisole, its subordinate concepts, substantially equivalent technical means, and technical means that can replace this technical feature based on the existing level of technology and within the scope of conventional technical means and common knowledge should all fall within the protection scope of this invention.

[0050] Compared with the prior art, the present invention has the following beneficial effects: (1) This invention provides a new synthetic route for milobalin benzyl sulfonate, which uses enzymatic hydrolysis to construct chiral centers, resulting in higher chiral purity. It also avoids the separation process, resulting in higher yield and simpler post-processing operation with lower cost.

[0051] (2) The present invention found that the reaction conditions, especially temperature and pH, have a great influence on the hydrolysis efficiency when constructing chiral centers by enzymatic hydrolysis. The present invention further optimizes the hydrolysis conditions of hydantoin, achieving a hydrolysis yield of over 90%, thus ensuring the improvement of the overall synthetic route yield.

[0052] (3) In addition, the synthesis route of the present invention is simple and efficient, and avoids the use of reagents such as sodium cyanide and nitromethane, making it safer and more environmentally friendly. Attached Figure Description

[0053] Figure 1 The image shows a liquid phase detection of compound B produced by the process in Example 1.1. Figure 2 The image shows a liquid phase detection of compound C produced by the process in Example 2.1. Figure 3 This is a chiral detection graph of compound C produced by the process in Example 2.1; Figure 4 The liquid phase detection image of milobalin produced by the process in Example 3.1; Figure 5 The liquid phase analysis image shows the milobalin benzenesulfonate produced by the process in Example 4.1; Figure 6 Chiral detection diagram of milobalin benzenesulfonate produced by the process of Example 4.1. Detailed Implementation

[0054] The following non-limiting embodiments are intended to enable those skilled in the art to gain a more comprehensive understanding of the present invention, but do not limit the invention in any way. The following content is merely an exemplary description of the scope of protection claimed by the present invention, and those skilled in the art can make various changes and modifications to the present invention based on the disclosed content, and such changes should also fall within the scope of protection claimed by the present invention.

[0055] The present invention will be further described below by way of specific embodiments. Unless otherwise specified, all instruments, devices, equipment, reagents, products, etc., used in the embodiments of the present invention are obtained through conventional commercial means.

[0056] Example 1: Synthesis of Compound B

[0057] Example 1.1 50 g (0.2098 mol, 1.0 eq) of compound A and 13.2 g (0.2197 mol, 1.05 eq) of urea were added to a 1 L reaction flask. The mixture was heated to 135℃-145℃ and kept at this temperature for 14 h. After the reaction was completed, the temperature was lowered to 80-90℃, and 200 g of isopropanol and 1.0 g of activated carbon were added. The mixture was kept at this temperature for 1.0 h for decolorization. The mixture was filtered while hot, and 250 g of water was slowly added to the filtrate. A solid precipitated out and was kept at this temperature for 1 h for crystallization. The temperature was then slowly lowered to 0-10℃ and kept at this temperature for 1 h for crystallization. The mixture was filtered, and the filter cake was dried in a 50℃ oven to obtain 42.4 g of off-white compound B, with a yield of 92% and a purity of 100%.

[0058] Example 1.2 The only difference from Example 1.1 is that the reaction was carried out in the solvent toluene. Specifically, 75g (0.3148mol, 1.0eq) of compound A, 22.7g (0.3777mol, 1.2eq) of urea and 300g of toluene were added to a 1L reaction flask, stirred and heated to 110-115℃, refluxed for 18h, and after the reaction was completed, the temperature was slowly lowered to 10℃, stirred and crystallized for 1h, filtered, the filter cake was washed with ice water and dried in a 50℃ oven to obtain 61.5g of brownish-gray compound B, with a yield of 89% and a purity of 100%.

[0059] Example 1.3 The only difference from Example 1.1 is that ammonium acetate is used instead of urea. Specifically, 75g (0.3148mol, 1.0eq) of compound A, 64.3g (0.6295mol, 2.0eq) of acetic anhydride and 36.4g (0.4721mol, 1.5eq) of ammonium acetate are added to a 1L reaction flask. The temperature is raised to 135-145℃ and the reaction is maintained for 10h. After the reaction is completed, the unreacted acetic anhydride and the acetic acid produced in the reaction are evaporated. The temperature inside the reaction flask is controlled at 55-60℃, 400g of methanol is added, and 260g of water is slowly added dropwise. A solid precipitates out. The temperature is maintained for crystallization for 1h. The temperature is slowly lowered to 0-10℃ and maintained for crystallization for 1h. The mixture is filtered, and the filter cake is slurried with 150g of methanol for 1h. After filtration, the filter cake is dried in a 50℃ oven to obtain 62.3g of grayish-white compound B, with a yield of 90% and a purity of 100%.

[0060] Example 1.4 The only difference from Example 1.1 is that ammonia is used instead of urea. Specifically, 120g (0.5036mol, 1.0eq) of compound A and 137g (2.0144mol, 4.0eq) of 25% ammonia are added to a 1L reaction flask. The temperature inside the reaction flask is controlled at 100-110℃. After evaporating the water until no fraction remains, the temperature is maintained for 5 hours. After the reaction is completed, the temperature is lowered to 75-80℃, 600g of ethanol and 2.5g of activated carbon are added, and the mixture is kept warm for 1 hour for decolorization. The mixture is filtered while hot, and 400g of water is slowly added to the filtrate. A solid precipitates out, and the mixture is kept warm for 1 hour for crystallization. The temperature is then slowly lowered to 0-10℃, and the mixture is kept warm for 1 hour for crystallization. The mixture is filtered, and the filter cake is dried in a 50℃ oven to obtain 99.4g of grayish-white solid compound B, with a yield of 90% and a purity of 100%.

[0061] Example 2: Synthesis of Compound C

[0062] Example 2.1 Add 200g of compound B obtained in Example 1.1 of step 1, 36g of D-Hase-101, and 2000g of water to the reaction flask, start stirring, heat to 50℃, control the reaction pH to 8.3-8.5 with 20% ammonia water, and keep the reaction at this temperature for 18h. After the reaction is complete, filter to remove D-Hase, add 4g of activated carbon to the filtrate, keep it at this temperature for 1h for decolorization, filter while hot, cool the filtrate to room temperature, slowly add 36% hydrochloric acid solution to adjust the pH of the system to 1.5-2.5, a large amount of crystals precipitate, keep it at this temperature for 1h for crystallization, then cool to 0-10℃ and keep it at this temperature for 1h, filter, and dry the filter cake in a 50℃ oven to obtain 183.7g of white powdery solid C, with a yield of 90.2% and a purity of 99.97%, of which the 6-S configuration accounts for 99.97%.

[0063] Example 2.2 The only difference from Example 2.1 is that the solvent is methanol / water (3:10 v / v). Specifically, 50g of compound B obtained in Example 1.1 in step 1, 9g of D-Hase-101, 150g of methanol and 500g of water were added to the reaction flask. Stirring was started, and the temperature was raised to 40-45℃. The pH of the reaction was controlled at 8.3-8.5 with 20% ammonia water, and the reaction was maintained at this temperature for 18h. After the reaction was completed, D-Hase was removed by filtration. 1g of activated carbon was added to the filtrate, and the mixture was kept warm for 1h to decolorize. The mixture was filtered while hot, and the filtrate was concentrated to 2 / 3 of its volume. The temperature was lowered to room temperature, and 36% hydrochloric acid solution was slowly added dropwise to adjust the pH of the system to 1.5-2.5. A large number of crystals precipitated. The crystals were kept warm for 1h, and then the temperature was lowered to 0-10℃ and kept warm for 1h. The mixture was filtered, and the filter cake was dried in a 50℃ oven to obtain 44.8g of white powdery solid C, with a yield of 88% and a purity of 99.80%.

[0064] Example 2.3 The only difference from Example 2.1 is that the solvent is acetone / water (1:4 v / v). Specifically, 50g of compound B obtained in Example 1.1 in step 1, 9g of D-Hase-101, 100g of acetone and 400g of water were added to the reaction flask. Stirring was started, and the temperature was raised to 55-60℃. The pH of the reaction was controlled at 8.3-8.5 with 20% ammonia water, and the reaction was maintained at this temperature for 18h. After the reaction was completed, D-Hase was removed by filtration. 1g of activated carbon was added to the filtrate, and the mixture was kept warm for 1h to decolorize. The mixture was filtered while hot, and the filtrate was concentrated to 2 / 3 of its volume. The temperature was lowered to room temperature, and 36% hydrochloric acid solution was slowly added dropwise to adjust the pH of the system to 1.5-2.5. A large number of crystals precipitated. The crystals were kept warm for 1h, and then the temperature was lowered to 0-10℃ and kept warm for 1h. The mixture was filtered, and the filter cake was dried in a 50℃ oven to obtain 45.1g of white powdery solid C, with a yield of 88% and a purity of 99.66%.

[0065] Example 2.4 The only difference from Example 2.1 is that the reaction pH is 8.5-8.7. Specifically, 50g of compound B obtained in Example 1.1 in step 1, 9g of D-Hase-101, and 500g of water were added to the reaction flask. Stirring was started, and the temperature was raised to 50°C. The reaction pH was controlled at 8.5-8.7 with 20% ammonia water, and the reaction was maintained at this temperature for 20h. After the reaction was completed, D-Hase was removed by filtration. 1g of activated carbon was added to the filtrate, and the mixture was kept warm for 1h to decolorize. The mixture was filtered while hot, and the filtrate was cooled to room temperature. 36% hydrochloric acid solution was slowly added dropwise to adjust the pH of the system to 1.5-2.5, resulting in the precipitation of a large number of crystals. The mixture was kept warm for 1h to allow crystallization, and then cooled to 0-10°C and kept warm for 1h. The mixture was filtered, and the filter cake was dried in a 50°C oven to obtain 45.3g of white powdery solid C, with a yield of 89% and a purity of 99.75%.

[0066] Example 2.5 The only difference from Example 2.1 is that the reaction pH is 9.3-9.5. Specifically, 200g of compound B obtained in Example 1.1 of step 1, 36g of D-Hase-101, and 2000g of water were added to the reaction flask. Stirring was started, and the temperature was raised to 50°C. The pH of the reaction was controlled at 9.3-9.5 with 20% ammonia water, and the reaction was maintained at this temperature for 10 hours. After the reaction was completed, the D-Hase was removed by filtration. 4g of activated carbon was added to the filtrate, and the mixture was kept warm for 1 hour for decolorization. The mixture was then filtered while hot, and the filtrate was cooled to room temperature. 36% hydrochloric acid solution was slowly added dropwise to adjust the pH of the system to 1.5-2.5, resulting in the precipitation of a large number of crystals. The crystals were kept warm for 1 hour, then cooled to 0-10°C and kept warm for 1 hour. The mixture was then filtered, and the filter cake was dried in a 50°C oven. 38.7g of powdered solid C was obtained, with a yield of 76% and a purity of 99.44%.

[0067] Example 2.6 The only difference from Example 2.1 is that the reaction temperature is 30-35℃. Specifically, 200.0g of compound B obtained in Example 1.1 in step 1, 36.0g of D-Hase-101, and 2000g of water were added to the reaction flask. Stirring was started, and the temperature was raised to 30℃. The pH of the reaction was controlled at 8.3-8.5 with 20% ammonia water, and the reaction was maintained at this temperature for 20h. After the reaction was completed, D-Hase was removed by filtration. 4g of activated carbon was added to the filtrate, and the mixture was kept warm for 1h to decolorize. The mixture was filtered while hot, and the filtrate was cooled to room temperature. 36% hydrochloric acid solution was slowly added dropwise to adjust the pH of the system to 1.5-2.5, resulting in the precipitation of a large number of crystals. The mixture was kept warm for 1h to allow crystallization, and then cooled to 0-10℃ and kept warm for 1h. The mixture was filtered, and the filter cake was dried in a 50℃ oven to obtain 30.9g of white powdery solid C, with a yield of 61% and a purity of 99.35%.

[0068] Example 2.7 The only difference from Example 2.1 is that the reaction pH is 7.5-8.0. Specifically, 200g of compound B obtained in Example 1.1 of step 1, 36g of D-Hase-101, and 2000g of water were added to the reaction flask. Stirring was started, and the temperature was raised to 50°C. The pH of the reaction was controlled at 7.5-8.0 with 20% ammonia water, and the reaction was maintained at this temperature for 10h. After the reaction was completed, D-Hase was removed by filtration. 4g of activated carbon was added to the filtrate, and the mixture was kept warm for 1h to decolorize. The mixture was filtered while hot, and the filtrate was cooled to room temperature. 36% hydrochloric acid solution was slowly added dropwise to adjust the pH of the system to 1.5-2.5, resulting in the precipitation of a large number of crystals. The mixture was kept warm for 1h to allow crystallization, and then cooled to 0-10°C and kept warm for 1h. The mixture was filtered, and the filter cake was dried in a 50°C oven to obtain 37.0g of powdered solid C, with a yield of 73% and a purity of 99.44%.

[0069] The structural characterization data of the product in Example 2 are as follows: 1H NMR (500 MHz, CD3OD) δ: 5.39-5.38 (m, 1H), 3.16 (s, 1H), 2.87-2.81(m, 1H), 2.65 (q, J=3.5 Hz, 2H), 2.51-2.45 (m, 3H), 2.23-2.13 (m, 3H), 2.04-2.01 (m, 1H), 1.48 (q, J=5.0 Hz, 1H), 1.10 (t, J=7.5 Hz, 3H). 13 C NMR (125 MHz, CD3OD) δ: 177.4, 176.2, 150.7, 56.5, 44.1, 43.1,40.3, 39.5, 32.4, 25.4, 12.9ppm. Example 3: Synthesis of Mirogabalin

[0070] Example 3.1 Add 83.6 g (0.627 mol, 2.8 eq) of 30% sodium hydroxide solution and 50 g of water to a 1 L reaction flask. Cool to 0-5 °C, and add 50 g (0.2239 mol, 1.0 eq) of compound C prepared in Example 2.1 in portions. After the addition is complete, slowly add 159.3 g (0.2352 mol, 1.05 eq) of sodium hypochlorite solution (mass concentration of 11%). After the addition is complete, slowly raise the temperature to 40-45 °C and maintain the reaction for 2 h. After the reaction is complete, control the temperature at 15-30 °C and slowly add 36% hydrochloric acid solution to adjust the pH to 5.8-6.8. A large amount of crystals precipitate out. Raise the temperature to 40-45 °C and slurry for 1 h. Slowly cool to 0-10 °C and maintain the temperature. Filter and dry in a 50 °C hot air oven to obtain 38.9 g of white mirogabalin powder, with a yield of 83% and a purity of 94.63%.

[0071] Example 3.2 The only difference from Example 3.1 is that 95.5g (0.7166mol, 3.2eq) of 30% sodium hydroxide solution and 50.0g of water were added to a 1L reaction flask, the temperature was lowered to 0-5℃, and 50.0g (0.2239mol, 1.0eq) of compound C prepared in Example 2.1 was added in batches. After the addition was complete, 182.1g (0.2688mol, 1.2eq) of sodium hypochlorite solution (mass concentration of 11%) was slowly added dropwise. After the addition was complete, the temperature was slowly raised to 40-45℃ and the reaction was maintained for 2h. After the reaction was completed, the temperature was controlled at 15-30℃, and 36% hydrochloric acid solution was slowly added dropwise to adjust the pH to 5.8-6.8. A large amount of crystals precipitated out. The temperature was raised to 40-45℃ and the mixture was stirred for 1 hour. The temperature was then slowly lowered to 0-10℃ and kept warm. The mixture was filtered and dried in a 50℃ hot air oven to obtain 39.4g of white Mirogabalin powder, with a yield of 84% and a purity of 99.50%.

[0072] The structural characterization data of the product in Example 3 are as follows: 1 H NMR (500 MHz, CD3OD) δ: 5.37-5.35 (m, 1H), 3.15 (q, J=6.0 Hz, 2H), 3.11-3.07(m, 1H), 2.87-2.81 (m, 1H), 2.51-2.43 (m, 3H), 2.16-2.11 (m, 2H), 2.07-2.02 (m, 2H), 1.46 (q, J=7.5 Hz, 1H), 1.09 (t, J=7.5 Hz, 3H). 13 C NMR (125 MHz, CD3OD) δ: 180.3, 151.0, 122.8, 53.7, 46.1, 43.3,43.0, 37.8, 32.3, 25.4, 12.8. Example 4: Synthesis of Milobalin Benzyl Sulfate

[0073] Example 4.1 Add 200 mL of acetonitrile, 28 g of water, and 30.0 g (0.1434 mol, 1.0 eq) of milobalin to a 500 mL reaction flask. Stir at room temperature, and slowly add 25.3 g (1.0 eq) of acetonitrile (80 mL) of benzenesulfonic acid monohydrate solution. After the addition is complete, heat to 80 °C and maintain the temperature for 3 h. Then slowly cool to 0-10 °C and maintain the temperature for 1 h to allow crystals to precipitate. Filter the solution, wash the filter cake with a small amount of ice-cold acetonitrile, and dry it in a 50 °C hot air oven to obtain 48.6 g of white crystals of milobalin benzenesulfonic acid, with a yield of 93% and a purity of 99.99%, of which the 6-S configuration accounted for 99.97%.

[0074] Example 4.2 The only difference from Example 4.1 is the solvent used in the reaction system. Specifically, 200 mL of isopropanol, 15 g of water, and 30.0 g (0.1434 mol, 1.0 eq) of milobalin were added to a 500 mL reaction flask. The mixture was stirred at room temperature, and 25.3 g (1.0 eq) of a solution of benzenesulfonic acid monohydrate in 60 mL of isopropanol was slowly added. After the addition was complete, the mixture was heated to 80-85 °C and refluxed for 3 h. Then, the mixture was slowly cooled to 0-10 °C and kept at this temperature for 1 h to allow crystals to precipitate. The crystals were then filtered and dried in a 50 °C hot air oven to obtain 49.5 g of white crystals of milobalin benzenesulfonic acid, with a yield of 94% and a purity of 99.97%.

[0075] Example 4.3 The only difference from Example 4.1 is the solvent used in the reaction system. Specifically, 120g of water, 30.0g (0.1434mol, 1.0eq) of milobalin and 25.3g (1.0eq) of benzenesulfonic acid monohydrate were added to a 250mL reaction flask. The temperature was raised to 80-85℃ and kept at that temperature for 3h. Then, the temperature was slowly lowered to 0-10℃ and kept at that temperature for 1h to allow crystals to precipitate. The mixture was then filtered and dried in a 50℃ hot air oven to obtain 46.4g of white crystals of milobalin benzenesulfonic acid, with a yield of 88% and a purity of 99.99%.

[0076] Example 4.4 The only difference from Example 4.1 is the amount of sodium benzenesulfonate monohydrate used. Specifically, 200 mL of acetonitrile, 28 g of water, and 30.0 g (0.1434 mol, 1.0 eq) of milobalin were added to a 500 mL reaction flask. The mixture was stirred at room temperature, and 26.5 g (1.1 eq) of acetonitrile (80 mL) of benzenesulfonate monohydrate solution was slowly added. After the addition was complete, the temperature was raised to 80 °C and kept at that temperature for 3 h. Then, the temperature was slowly lowered to 0-10 °C and kept at that temperature for 1 h to allow crystals to precipitate. The mixture was filtered, and the filter cake was washed with a small amount of ice-cold acetonitrile. The mixture was then dried in a 50 °C hot air oven to obtain 49.4 g of white crystals of milobalin benzenesulfonate, with a yield of 93% and a purity of 99.97%.

[0077] The structural characterization data of the product in Example 4 are as follows: 1 H NMR(500 MHz, CD3OD) δ: 7.84-7.82 (m, 2H), 7.45-7.42 (m, 3H), 5.32(s, 1H), 3.32-3.30 (m, 8H), 3.30 (s, 1H), 2.91-2.84 (m, 1H), 2.54-2.48 (m,3H), 2.20-2.07 (m, 4H), 1.52-1.48 (m, 1H), 1.11 (t, J=7.5 Hz, 3H). 13 C NMR(125 MHz, CD3OD) δ: 175.4, 152.1, 146.3, 131.3, 129.3, 126.9,122.0, 53.7,47.6, 43.2, 42.9, 38.5, 37.3, 32.4, 25.3, 12.8. Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, and is not intended to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions made by those skilled in the art to the technical solution of the present invention do not depart from the essence and scope of the technical solution of the present invention.

Claims

1. A method for preparing milobalin benzylsulfonic acid, characterized in that, The synthesis route is as follows: Includes the following steps: Step 1: Starting with compound A, an amidation reaction is carried out under a nitrogen-containing reagent to generate compound B; Step 2: Add compound B to solvent A, where it undergoes selective hydrolysis under the action of hydantoin to generate compound C; Step 3: Compound C undergoes Hofmann degradation in an alkaline solution of hypohalite to generate milobalin; Step 4: Milobalin reacts with benzenesulfonic acid in solvent B to obtain the benzenesulfonic acid-milobalin. In step 2, the selective hydrolysis temperature is 40-60℃ and the pH value is 8.0-9.

0.

2. The preparation method according to claim 1, characterized in that, In step 1, the nitrogen-containing reagent is selected from any one of ammonia, urea, ammonium salt, and thiourea; preferably urea. The ammonium salt is selected from any one of ammonium acetate, ammonium carbonate, ammonium bicarbonate, and ammonium sulfide; More preferably, the molar ratio of compound A to the nitrogen-containing reagent is 1:1 to 1:4; preferably 1:

1.

3. The preparation method according to claim 1, characterized in that, In step 1, the temperature of the amidation reaction is 100-150℃.

4. The preparation method according to claim 1, characterized in that, In step 2, the mass ratio of the hydantoin to compound B is 1:2-1:8; preferably 1:5-1:

6. And / or the mass ratio of compound B to solvent A is 1:5-1:20; preferably 1:9-1:

11.

5. The preparation method according to claim 1, characterized in that, In step 2, solvent A is water or an organic solvent / water mixture; preferably water.

6. The preparation method according to claim 5, characterized in that, The organic solvent is selected from one or more of methanol, ethanol, isopropanol, tetrahydrofuran, acetone, and cyclohexanone.

7. The preparation method according to claim 1, characterized in that, In step 2, the selective hydrolysis temperature is 48-52℃; the pH value is 8.3-8.

5.

8. The preparation method according to claim 1, characterized in that, In step 3, the molar ratio of compound C, hypohalite, and solute in the alkaline solution is 1:0.96:2.5-1:1.3:4; preferably 1:1.05:2.8 or 1:1.2:3.

2. And / or the Hofmann degradation is carried out at a temperature of 40-45°C for 1-2 hours.

9. The preparation method according to claim 1, characterized in that, In step 3, the hypohalite is selected from sodium hypochlorite or sodium hypobromite; and / or the alkaline solution is selected from sodium hydroxide solution or potassium hydroxide solution.

10. The preparation method according to claim 1, characterized in that, In step 4, the molar ratio of milobalin to benzenesulfonic acid is 0.96-1.1:1; And / or the reaction is carried out at a temperature of 80-85°C for 3-4 hours; And / or the solvent B is selected from one or more of water, acetonitrile, isopropanol, tetrahydrofuran, acetone, dichloromethane, methyl tert-butyl ether, and anisole.

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