Preparation method and application of minnogabalin besylate intermediate

Abstract

The invention relates to a preparation method and application of a minnogabalin besylate intermediate. The preparation method of the minnogabalin besylate intermediate comprises the following steps: providing an intermediate II; mixing the intermediate III, a KT-02 supported nickel catalyst, ammonium formate and a first solvent for reaction to prepare an intermediate III; according to the method, KT-02 / ammonium formate is taken as a reduction system, the preparation of the amino-containing melogabalin besylate intermediate can be carried out under normal pressure, the safety coefficient is high, the operation is convenient, the cost is low, the post-treatment is simple, few byproducts are produced, the pollution is small, and the prepared product is high in purity and is more suitable for later industrial production.

Description

Technical Field

[0001] The present application relates to the technical field of pharmaceutical chemistry, and in particular to a method for preparing a minoxidil benzenesulfonate intermediate and its application. Background Art

[0002] Mirogabalin besylate is a new drug for the treatment of peripheral neuropathic pain. It exhibits analgesic effects by inhibiting the release of neurotransmitters at nerve endings related to pain. It was approved for marketing by the Japanese Pharmaceutical and Medical Devices Agency (PMDA) on January 8, 2019, and its trade name is Tarlige. Mirogabalin besylate is a selective calcium channel α2δ ligand with unique binding properties and long-lasting effects. It can preferentially and selectively bind to the α2δ-1 subunit of voltage-dependent calcium channels (1 and 2). These calcium channels are widely present in the nervous system that mediates pain transmission and processing in various regions of the body. It helps to treat diabetic peripheral neuropathy, postherpetic neuralgia, and fibromyalgia. Its clinical efficacy is significantly higher than that of pregabalin and gabapentin. It is also reported that Tarlige can be used to treat additional indications related to central neuropathic pain (chronic neuropathic pain, CNP). Melegabalin besylate has the advantages of high safety and good tolerability, and is being developed into a world-class drug for the treatment of neuralgia.

[0003] The process routes for synthesizing melogabalin besylate reported in current literature are mainly as follows:

[0004] Method 1: Patent WO2015005298A1 reports the use of 3-ethyl-bicyclo[3.2.0]heptane-3-ene-6-one and diethyl malonate as starting materials to synthesize melogabalin benzenesulfonate. This route mainly introduces a cyano group by using a highly toxic reagent, sodium cyanide, to participate in the reaction. The cyano group is reduced under the action of cobalt and hydrogen to obtain an amino compound.

[0005]

[0006] Method 2: Patent WO2015005298A1 reports the use of 3-ethyl-bicyclo[3.2.0]heptane-3-ene-6-one and dimethoxyphosphonoethyl acetate as raw materials to synthesize melogabalin benzenesulfonate, mainly using nitromethane to participate in the reaction to introduce a nitro group, and the nitro group is reduced under the action of nickel and hydrogen to obtain an amino compound, which is further split, hydrolyzed, and salified to obtain the melogabalin benzenesulfonate raw material.

[0007]

[0008] Method 3: Patents WO2009041453A1 and JP2010241796A report the use of ethyl butyryl acetate and propylene bromide as raw materials to synthesize melogabalin benzenesulfonate, using nitromethane to participate in the reaction to introduce a nitro group, and iron powder and ammonium chloride are used for reduction to obtain an amino group. After amino protection, ester hydrolysis, and salt formation, melogabalin benzenesulfonate is obtained.

[0009]

[0010] In summary, the current literature reports that there are two main ways to introduce intermediates containing amino groups in the synthesis of melogabalin benzenesulfonate. One is to introduce cyano groups through sodium cyanide reaction, and the other is to introduce nitro groups through nitromethane. Compared with the two methods, nitromethane is safer. The current methods of nitro reduction mainly include palladium carbon and Raney nickel catalytic hydrogen reduction. In addition, there are sodium sulfide, insurance powder, iron powder, stannous chloride and other methods to reduce nitro groups to amino groups. The catalyst palladium carbon is expensive, the production cost is high, and the reaction requires high-pressure reaction, which is not suitable for industrial production; although Raney nickel is cheap, it also requires high-pressure reaction, has high requirements for production equipment, and the production operation is more dangerous; although sodium sulfide, insurance powder, iron powder, stannous chloride and the like are easy to operate, the subsequent treatment is highly polluting to the environment and is not suitable for process production. Therefore, it is of great significance to develop a new reduction system for the preparation of amino-containing melogabalin benzenesulfonate intermediates. Summary of the invention

[0011] Based on this, it is necessary to provide a method for preparing a merogabalin benzenesulfonate intermediate, which adopts a KT-02 / ammonium formate reduction system to synthesize an amino-containing merogabalin benzenesulfonate intermediate III under normal pressure, has simple operation, high safety factor, low production cost, few by-products, and the obtained product has high purity, which is more suitable for industrial production.

[0012] The technical solution of this application is as follows:

[0013] One aspect of the present invention provides a method for preparing a minoxidil benzenesulfonate intermediate, comprising the following steps:

[0014] Providing intermediate II;

[0015] The intermediate III, KT-02 supported nickel catalyst, ammonium formate and the first solvent are mixed and reacted to prepare the intermediate III;

[0016] The structures of the intermediates II and III are shown below:

[0017] , .

[0018] In one embodiment, the mass ratio of the KT-02 supported nickel catalyst to the intermediate II is (0.3-0.5):10.

[0019] In one embodiment, the molar ratio of ammonium formate to intermediate II is (2-3):1.

[0020] In one embodiment, the reaction temperature is 55°C-65°C; and / or

[0021] The reaction pressure is normal pressure.

[0022] In one embodiment, the reaction time is 1 h-3 h.

[0023] In one embodiment, the first solvent is an alcohol solvent;

[0024] Optionally, the first solvent includes one or more of methanol, ethanol, isopropanol, n-butanol or tert-butanol.

[0025] In one embodiment, after the reaction is completed, a post-treatment step is further included, and the post-treatment step includes:

[0026] After the reaction is completed, the reaction solution is filtered and concentrated, tetrahydrofuran is added to dissolve, a second solvent is added, the pH is adjusted to 3-4, the mixture is stirred for crystallization, filtered, and the obtained solid is dried.

[0027] In one embodiment, the second solvent is tetrahydrofuran hydrochloride solution;

[0028] Optionally, in the tetrahydrofuran hydrochloride solution, the concentration of hydrogen chloride is 2 Mol / L-6 Mol / L.

[0029] Another aspect of the present invention provides the use of the method for preparing the minogabalin besylate intermediate as described above in the preparation of melogabalin besylate.

[0030] In one embodiment, the preparation method of minoxidil besylate comprises the following steps:

[0031] The intermediate III prepared by the preparation method of the minogabalin benzenesulfonate intermediate as described above is subjected to chiral resolution, hydrolysis reaction and salt formation reaction to prepare melogabalin benzenesulfonate.

[0032] Compared with the prior art, this application has the following beneficial effects:

[0033] The present application uses KT-02 / ammonium formate as a reduction system to prepare a melogabalin benzenesulfonate intermediate, which has a high safety factor, is easy to operate, and has a low cost, simple post-processing, few by-products, and little pollution. The obtained product has high purity and is more suitable for later industrial production.

[0034] Specifically, the intermediate III obtained by reduction with the KT-02 / ammonium formate system has the following advantages: (1) High safety factor: KT-02 is a supported nickel catalyst, which is more stable than Raney nickel catalysts, and the method is carried out under normal pressure, which is highly safe; (2) Easy to operate: No hydrogen pressurization is required for the reaction, and the post-processing is simple; (3) Low production cost: The price of KT-02 catalyst is much lower than that of Pd / C, and the amount of KT-02 used is only the amount of catalyst; (4) The product obtained has high purity and is more suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] In order to more clearly illustrate the specific implementation methods of the present application or the technical solutions in the prior art, the drawings required for use in the specific implementation methods or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are some implementation methods of the present application. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0036] Figure 1 The HPLC chromatogram of melogabalin besylate intermediate III prepared in one example.

[0037] Figure 2 The mass spectrum of melogabalin besylate intermediate III prepared in one example.

[0038] Figure 3 The figure is the H NMR spectrum of melogabalin besylate intermediate III prepared in one example. DETAILED DESCRIPTION

[0039] The present application will be further described in detail below in conjunction with specific embodiments. The present application can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the disclosure of the present application more thoroughly understood.

[0040] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which this application belongs. The terms used herein in the specification of this application are only for the purpose of describing specific embodiments and are not intended to limit this application.

[0041] Unless otherwise specified or incompatible herewith, the terms and phrases used herein shall have the following meanings:

[0042] As used herein, "one or more" refers to any one, any two, or any two or more of the listed items.

[0043] Herein, the optional scope of "and / or", "or / and", and "and / or" includes any one of two or more relevant listed items, and also includes any and all combinations of the relevant listed items, wherein said any and all combinations include any two relevant listed items, any more relevant listed items, or a combination of all relevant listed items. (It should be noted that when at least three items are connected by at least two conjunctions selected from "and / or", "or / and", and "and / or", it should be understood that in the present application, the technical solution undoubtedly includes technical solutions that are all connected by "logical AND", and also undoubtedly includes technical solutions that are all connected by "logical OR". For example, "A and / or B" includes three parallel solutions of A, B and A+B. For another example, the technical solution of "A, and / or, B, and / or, C, and / or, D" includes any one of A, B, C, and D (that is, technical solutions that are all connected by "logical OR"), and also includes any and all combinations of A, B, C, and D, that is, a combination of any two or any three of A, B, C, and D, and also includes a combination of four items of A, B, C, and D (that is, a technical solution that is all connected by "logical AND").)

[0044] Herein, "further", "further", "particularly" and the like are used for descriptive purposes to indicate differences in content, but should not be construed as limiting the scope of protection of this application.

[0045] Herein, "first aspect", "second aspect", "third aspect", "fourth aspect", etc. are used for descriptive purposes only and cannot be understood as indicating or implying relative importance or quantity, nor can they be understood as implicitly indicating the importance or quantity of the indicated technical features. In addition, "first", "second", "third", "fourth", etc. only serve the purpose of non-exhaustive enumeration and description, and it should be understood that they do not constitute a closed limitation on quantity. Therefore, the features defined as "first" and "second" may explicitly or implicitly include at least one of the features. In the description of the present application, the meaning of "multiple" is at least two, such as two, three, etc., unless otherwise clearly and specifically defined. In the description of the present application, the meaning of "several" is at least one, such as one, two, etc., unless otherwise clearly and specifically defined.

[0046] In this application, when it comes to numerical ranges, unless otherwise specified, the above numerical ranges are deemed to be continuous and include the minimum and maximum values ​​of the range, as well as each value between such minimum and maximum values. Further, when a range refers to an integer, each integer between the minimum and maximum values ​​of the range is included. In addition, when multiple ranges are provided to describe features or characteristics, the ranges can be merged. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all subranges included therein.

[0047] Only some numerical ranges are specifically disclosed herein. However, any lower limit can be combined with any upper limit to form an undefined range; and any lower limit can be combined with other lower limits to form an undefined range, and any upper limit can be combined with any other upper limit to form an undefined range. In addition, each separately disclosed point or single value itself can be combined with any other point or single value as a lower limit or upper limit or with other lower limits or upper limits to form an undefined range. The use of numerical ranges represented by endpoints includes all numbers within the range and any range within the range, for example, 1 to 5 includes 1, 1.1, 1.3, 1.5, 2, 2.75, 3, 3.80, 4 and 5, etc.

[0048] The percentage contents involved in this application, unless otherwise specified, refer to mass percentage for solid-liquid mixing and solid-solid mixing, and refer to volume percentage for liquid-liquid mixing.

[0049] The percentage concentrations mentioned in this application, unless otherwise specified, refer to the final concentration, which refers to the percentage of the added component in the system after the addition of the component.

[0050] The temperature parameters in this application, unless otherwise specified, allow both constant temperature treatment and treatment within a certain temperature range. The constant temperature treatment allows the temperature to fluctuate within the accuracy range controlled by the instrument. Fluctuations within the range of ±5°C, ±2°C, ±1°C, ±0.5°C, ±0.4°C, ±0.3°C, ±0.2°C, and ±0.1°C are allowed. Normal temperature or room temperature in this application refers to no temperature control operation, generally 4°C~35°C, preferably 20±5°C.

[0051] In addition, the terms "first" and "second" are used for descriptive purposes only and should not be understood as indicating or implying relative importance or implicitly indicating the number of the indicated technical features. Therefore, the features defined as "first" and "second" may explicitly or implicitly include at least one of the features. In the description of the present invention, the meaning of "plurality" is at least two, such as two, three, etc., unless otherwise clearly and specifically defined.

[0052] KT-02 is a supported nickel catalyst with diatomaceous earth as carrier. KT-02 series supported nickel catalysts are mainly used in nitro hydrogenation, oils and fats, carbon-carbon double bonds, aldehydes (ketones), other hydrogenation fields. The good performance has been proved by many companies in the hydrogenation process of TDI production, pharmaceutical intermediates, dye intermediates, pesticide intermediates, nitro compounds, etc. In view of the defects of the introduction of amino-containing benzenesulfonic acid merogabalin intermediates in the prior art, the technical personnel of this application unexpectedly discovered a new reduction system KT-02 / ammonium formate after a lot of research. This system can replace Fe powder-NH4Cl and Raney nickel-hydrazine hydrate system to prepare benzenesulfonic acid merogabalin intermediates. It is simple to operate, has no by-products, low cost, less post-processing waste, and is more suitable for later industrial production.

[0053] Specifically, KT-02 belongs to a supported nickel catalyst, which is more stable than Raney nickel catalysts, has a high safety factor, is easy to operate and has low cost, and is suitable for industrial production. Compared with Fe powder-NH4Cl and SnCl2 to reduce nitro groups, the post-processing is simple, it is easier to filter, and it is not easy to produce iron mud that pollutes the environment, which is more suitable for commercial production. KT-02 / ammonium formate is used to prepare melogabalin benzenesulfonate intermediates, and the product purity is high, which is more suitable for commercial production of nitro reduction. In summary, this application introduces KT-02 / ammonium formate to prepare melogabalin benzenesulfonate intermediates, which has a high safety factor, low production cost, convenient post-processing, low pollution, and is more suitable for industrial production of melogabalin benzenesulfonate.

[0054] One aspect of the present invention provides a method for preparing a minoxidil benzenesulfonate intermediate, comprising the following steps:

[0055] Providing intermediate II;

[0056] The intermediate III, KT-02 supported nickel catalyst, ammonium formate and the first solvent are mixed and reacted to prepare the intermediate III;

[0057] The structures of the intermediates II and III are shown below:

[0058] , .

[0059] In some examples, the mass ratio of the KT-02 supported nickel catalyst to the intermediate II is (0.3-0.5): 10. It can be understood that the mass ratio of the KT-02 supported nickel catalyst to the intermediate II includes but is not limited to 0.3:10, 0.32:10, 0.34:10, 0.36:10, 0.38:10, 0.4:10.

[0060] In some examples, the molar ratio of ammonium formate to intermediate II is (2-3): 1. It can be understood that the molar ratio of ammonium formate to intermediate II includes but is not limited to 2: 1, 2.2: 1, 2.4: 1, 2.6: 1, 2.8: 1, 3: 1.

[0061] In some examples, the reaction temperature is 55° C.-65° C. It is understood that the reaction temperature includes but is not limited to 55° C., 57° C., 59° C., 61° C., 63° C., and 65° C.

[0062] In some of these examples, the reaction pressure is atmospheric pressure.

[0063] In some examples, the reaction time is 1 h-3 h. It can be understood that the reaction time includes but is not limited to 1 h, 1.5 h, 2 h, 2.5 h, and 3 h.

[0064] In some examples, the first solvent is an alcohol solvent.

[0065] In some examples, the first solvent includes one or more of methanol, ethanol, isopropanol, n-butanol, or tert-butanol.

[0066] In some examples, after the reaction is completed, a post-processing step is further included, and the post-processing step includes:

[0067] After the reaction is completed, the reaction solution is filtered and concentrated, tetrahydrofuran is added to dissolve, a second solvent is added, the pH is adjusted to 3-4, the mixture is stirred for crystallization, filtered, and the obtained solid is dried.

[0068] In some examples, the second solvent is a tetrahydrofuran hydrochloride solution.

[0069] In some examples, the concentration of hydrogen chloride in the tetrahydrofuran hydrogen chloride solution is 2 Mol / L-6 Mol / L. It can be understood that the concentration of hydrogen chloride in the tetrahydrofuran hydrogen chloride solution includes but is not limited to 2 Mol / L, 3 Mol / L, 4 Mol / L, 5 Mol / L, and 6 Mol / L.

[0070] In some examples, the crystallization time is 0.5h-2h. It can be understood that the crystallization time includes but is not limited to 0.5h, 1h, 1.5h, and 2h.

[0071] In some examples, the concentration temperature is 30° C.-60° C. It can be understood that the concentration temperature includes but is not limited to 30° C., 35° C., 40° C., 45° C., 50° C., 55° C., and 60° C.

[0072] Another aspect of the present invention provides the use of the method for preparing the minogabalin besylate intermediate as described above in the preparation of melogabalin besylate.

[0073] In some examples, the method for preparing minoxidil besylate comprises the following steps:

[0074] The intermediate III prepared by the preparation method of the intermediate of minogabalin benzenesulfonate as described above is subjected to chiral resolution hydrolysis reaction and salt formation reaction to prepare melogabalin benzenesulfonate.

[0075] In one specific example, the preparation method of merogabalin benzenesulfonate includes the following steps: (1R, 5S)-3-ethyl-bicyclo[3.2.0]heptane-3-ene-6-one and dimethoxyphosphonoacetic acid tert-butyl ester are used as starting materials, and compound I is prepared by Homner-Wittig reaction, and compound I is reacted with nitromethane to obtain compound II. Compound II is subjected to nitro reduction reaction under the action of hydrazine hydrate to obtain compound III. Compound III is subjected to chiral resolution reaction with chiral resolution agent D-mandelic acid to obtain compound IV. Compound IV is hydrolyzed under alkaline conditions to remove the tert-butyl protecting group to obtain compound V. Compound V is salified with benzenesulfonic acid to obtain the target compound merogabalin benzenesulfonate.

[0076]

[0077] The following is further described in conjunction with specific embodiments. The raw materials involved in the following specific embodiments, unless otherwise specified, can all be commercially available; the instruments used, unless otherwise specified, can all be commercially available; the processes involved, unless otherwise specified, are all routinely selected by those skilled in the art.

[0078] The synthetic route of melogabalin benzenesulfonate compound III ([(1R,5S,6S)-6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl]acetic acid tert-butyl ester hydrochloride) is as follows:

[0079]

[0080] The following are specific embodiments.

[0081] Example 1

[0082] Preparation of intermediate I: Take 100.00 g of material SM1 ((1R,5S)-3-ethyl-bicyclo[3.2.0]heptane-3-ene-6-one) and add it into a 2L three-necked flask, add 230.46 g of material SM2 (tert-butyl dimethoxyphosphorylacetate), add 4.5L of tetrahydrofuran, stir and disperse, add sodium hydroxide, stir and react at room temperature for 3 hours, add 3000 mL of saturated ammonium chloride aqueous solution to the system, separate the liquids, add 1500 mL of water to the upper layer, wash it, add 250.0 g of anhydrous sodium sulfate after separation, dry it, filter it, and concentrate it to obtain 166.5 g of yellow oil, with a yield of 96.77% and a purity of 97.80%.

[0083] Preparation of intermediate II: Take 15.0 g of the intermediate I oil and add it into a 100 mL three-necked flask, add 45 mL of nitromethane, add 24.0 g of DBU, heat the system to 55 ° C and react for 3 h, cool the system to 30 ° C, add 20 mL of saturated potassium dihydrogen phosphate solution to quench, add methyl tert-butyl ether to extract (3×50 mL), combine the organic phases, wash the organic phases with 50 mL of water, add 30 g of anhydrous sodium sulfate to dry, filter, and concentrate to 18.0 g, with a yield of 95.24% and a purity of 97.15%.

[0084] Preparation of intermediate III: Add 10.00g of intermediate II (purity: 97.15%) to the reaction equipment, add 60mL of ethanol and stir to dissolve, add 0.5g of KT-02 catalyst to the system, add 2eq of 4.26g of ammonium formate, replace with nitrogen three times after the addition is completed, raise the temperature to 65°C, stir the system to react for 2h, stir and cool to 25°C, filter, and concentrate the filtrate at 45°C to obtain 8.9g of yellow oil with a yield of 99.05% and a purity of 98.59%.

[0085] Tetrahydrofuran was added to the oily substance and stirred to dissolve. 4Mol / L tetrahydrofuran hydrochloride solution was added to the system. After adjusting the pH to 3-4, the temperature was controlled and stirred to crystallize for 1 hour. The white solid was filtered and dried to obtain 9.5g of a yield of 93.84% and a purity of 99.78%. The HPLC, mass spectrum and H-NMR spectrum of intermediate III are shown in Figure 1-3 shown.

[0086] Example 2

[0087] According to the method of Example 1, 10 g of intermediate II was prepared, 10.00 g of intermediate II was added to the reaction equipment, 60 mL of ethanol was added and stirred to dissolve, 0.3 g of KT-02 catalyst was added to the system, 2 eq of 4.26 g of ammonium formate was added, and nitrogen was replaced three times after the addition was completed. The temperature was raised to 65°C, the system was stirred to react for 2 h, and the temperature was cooled to 25°C with stirring, filtered, and the filtrate was concentrated at 45°C to obtain 8.78 g of yellow oil with a yield of 97.72% and a purity of 98.56%.

[0088] Tetrahydrofuran was added to the oily substance and stirred to dissolve. 4Mol / L tetrahydrofuran hydrochloride solution was added to the system. After adjusting the pH to 3-4, the mixture was stirred at controlled temperature for crystallization for 1h. The mixture was filtered and dried to obtain 9.61g of a white solid with a yield of 96.22% and a purity of 99.58%.

[0089] Example 3

[0090] According to the method of Example 1, 10 g of intermediate II was prepared, 10.00 g of intermediate II (purity: 97.15%) was added to the reaction equipment, 60 mL of ethanol was added and stirred to dissolve, 0.3 g of KT-02 catalyst was added to the system, 3 eq of 6.40 g of ammonium formate was added, and after the addition was completed, nitrogen was replaced three times, the temperature was raised to 65°C, the system was stirred to react for 2 h, the temperature was cooled to 25°C with stirring, filtered, and the filtrate was concentrated at 45°C to obtain 8.82 g of yellow oil with a yield of 98.16% and a purity of 98.39%.

[0091] Tetrahydrofuran was added to the oily substance and stirred to dissolve. 4Mol / L tetrahydrofuran hydrochloride solution was added to the system. After adjusting the pH to 3-4, the temperature was controlled and stirred for crystallization for 1 hour. The white solid was filtered and dried to obtain 9.58 g of white solid. The yield was 95.51% and the purity was 99.36%.

[0092] Example 4

[0093] According to the method of Example 1, 10 g of intermediate II was prepared, 10.00 g of intermediate II (purity: 97.15%) was added to the reaction equipment, 60 mL of ethanol was added and stirred to dissolve, 0.3 g of KT-02 catalyst was added to the system, 2 eq of 4.26 g of ammonium formate was added, and after the addition was completed, nitrogen was replaced three times, the temperature was raised to 55°C, the system was stirred to react for 2 h, the temperature was cooled to 25°C with stirring, filtered, and the filtrate was concentrated at 45°C to obtain 8.86 g of yellow oil with a yield of 98.61% and a purity of 97.95%.

[0094] Tetrahydrofuran was added to the oily substance and stirred to dissolve. 4Mol / L tetrahydrofuran hydrochloride solution was added to the system. After adjusting the pH to 3-4, the mixture was stirred and crystallized at controlled temperature for 1 hour. The mixture was filtered and dried to obtain 9.65 g of a white solid with a yield of 95.83% and a purity of 99.46%.

[0095] Comparative Example 1

[0096] The preparation method of Comparative Example 1 is substantially the same as that of Example 1, except that a conventional Raney nickel catalyst and hydrogen conditions are used for the reduction reaction, as follows:

[0097] Preparation of intermediate I: Take 20.00 g of material SM1 ((1R,5S)-3-ethyl-bicyclo[3.2.0]heptane-3-ene-6-one) and add it into a 2L three-necked flask, add 46.10 g of material SM2 (tert-butyl dimethoxyphosphorylacetate), add 910 mL of tetrahydrofuran, stir and disperse, add sodium hydroxide, stir and react at room temperature for 3 hours, add 600 mL of saturated ammonium chloride aqueous solution to the system, separate the liquids, add 300 mL of water to the upper layer, wash it, add 50 g of anhydrous sodium sulfate after separation, dry it, filter it, and concentrate it to obtain 33.30 g of yellow oil, with a yield of 96.77% and a purity of 97.10%.

[0098] Preparation of intermediate II: Take 15.0 g of the intermediate I oil and add it into a 100 mL three-necked flask, add 45 mL of nitromethane, add 24.0 g of DBU, heat the system to 55 ° C and react for 3 h, cool the system to 30 ° C, add 20 mL of saturated potassium dihydrogen phosphate solution to quench, add methyl tert-butyl ether to extract (3×50 mL), combine the organic phases, wash the organic phases with 50 mL of water, add 30 g of anhydrous sodium sulfate to dry, filter, and concentrate to 17.0 g, with a yield of 89.94% and a purity of 97.15%.

[0099] Preparation of intermediate III: Add 10.00 g of intermediate II (purity: 97.15%) to the reaction equipment, add 60 mL of methanol and stir to dissolve, add 0.45 g of Raney nickel catalyst to the system, replace with hydrogen three times after the addition is completed, raise the temperature to 35 ° C, maintain the pressure of 0.2 MPa, stir the system to react for 2 h, stir and cool to 25 ° C, filter, and concentrate the filtrate at 45 ° C to obtain 8.4 g of yellow oil with a yield of 93.49% and a purity of 95.89%.

[0100] Tetrahydrofuran was added to the oily substance and stirred to dissolve. 4Mol / L tetrahydrofuran hydrochloride solution was added to the system. After adjusting the pH to 3-4, the temperature was controlled and stirred for crystallization for 1 hour. The white solid (6.5 g) was filtered and dried to obtain a yield of 68.03% and a purity of 97.28%.

[0101] Comparative Example 2

[0102] Preparation of intermediate III: Add 10.00 g of intermediate II (purity: 97.15%) to the reaction equipment, add 60 mL of methanol and stir to dissolve, add 0.5 g of Raney nickel catalyst to the system, replace with hydrogen three times after the addition is completed, increase the temperature to 40 ° C, maintain the pressure of 0.2 MPa, stir the system to react for 2 h, stir and cool to 25 ° C, filter, and concentrate the filtrate at 45 ° C to obtain 8.25 g of yellow oil with a yield of 91.82% and a purity of 96.59%.

[0103] Tetrahydrofuran was added to the oily substance and stirred to dissolve. 4Mol / L tetrahydrofuran hydrochloride solution was added to the system. After adjusting the pH to 3-4, the temperature was controlled and stirred for crystallization for 1 hour. The white solid (6.45 g) was filtered and dried. The yield was 68.73% and the purity was 97.32%.

[0104] Comparative Example 3

[0105] The preparation method of Comparative Example 3 is substantially the same as that of Example 1, except that the reduction reaction is carried out under conventional conditions of ammonium chloride and iron powder, as follows:

[0106] Add 10.00g of intermediate II (purity of 97.15%) to the reaction equipment, add 60mL of ethanol and stir to dissolve, add 5eq of 9.05g of ammonium chloride to the system, add 5eq of 9.45g of iron powder, raise the temperature to 60°C, stir the system to react for 2h, filter, concentrate the filtrate at 45°C to dry out the ethanol, cool to room temperature, add dichloromethane to extract 3×60mL, combine the organic phases, wash the organic phases with 60ml of purified water, dry over anhydrous sodium sulfate, filter and concentrate to obtain 5.8g of yellow oil with a yield of 64.55% and a purity of 81.65%.

[0107] Tetrahydrofuran was added to the oily substance and stirred to dissolve. 4Mol / L tetrahydrofuran hydrochloride solution was added to the system. After adjusting the pH to 3-4, the mixture was stirred at controlled temperature for crystallization for 1 hour. The mixture was filtered and dried to obtain 4.55 g of a white solid with a yield of 68.94% and a purity of 94.65%.

[0108] Comparative Example 4

[0109] Add 10.00g of intermediate II (purity of 97.15%) to the reaction equipment, add 60mL of ethanol and stir to dissolve, add 4.5eq of 8.15g of ammonium chloride to the system, add 4.5eq of 8.50g of iron powder, raise the temperature to 60°C, stir the system to react for 2h, filter, concentrate the filtrate at 45°C to dry out the ethanol, cool to room temperature, add dichloromethane to extract 3×60mL, combine the organic phases, wash the organic phases with 60mL of purified water, dry over anhydrous sodium sulfate, filter and concentrate to obtain 6.0g of yellow oil with a yield of 66.780% and a purity of 78.59%.

[0110] Tetrahydrofuran was added to the oily substance and stirred to dissolve. 4Mol / L tetrahydrofuran hydrochloride solution was added to the system. After adjusting the pH to 3-4, the temperature was controlled and stirred for crystallization for 1 hour. The white solid was filtered and dried to obtain 4.5 g. The yield was 65.93% and the purity was 95.87%.

[0111] The technical features of the above-described embodiments may be arbitrarily combined. To make the description concise, not all possible combinations of the technical features in the above-described embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0112] The above-described embodiments only express several implementation methods of the present application, and the descriptions thereof are relatively specific and detailed, but they cannot be construed as limiting the scope of the patent application. It should be pointed out that, for a person of ordinary skill in the art, several variations and improvements can be made without departing from the concept of the present application, and these all belong to the protection scope of the present application. Therefore, the protection scope of the patent application shall be subject to the attached claims, and the description may be used to interpret the content of the claims.

Claims

1. A method for preparing a minoxidil benzenesulfonate intermediate, characterized in that: The following steps are involved: Providing intermediate II; The intermediate III, KT-02 supported nickel catalyst, ammonium formate and the first solvent are mixed and reacted to prepare the intermediate III; The structures of the intermediates II and III are shown below: 、 。 2. The method for preparing the minoxidil benzenesulfonate intermediate according to claim 1, wherein The mass ratio of the KT-02 supported nickel catalyst to the intermediate II is (0.3-0.5):

10.

3. The preparation method of minoxidil benzenesulfonate intermediate according to claim 1, characterized in that, The molar ratio of the ammonium formate to the intermediate II is (2-3):

1.

4. The method for preparing the minoxidil benzenesulfonate intermediate according to claim 1, wherein: The reaction temperature is 55°C-65°C; and / or The reaction pressure is normal pressure.

5. The method for preparing the minoxidil benzenesulfonate intermediate according to claim 1, characterized in that: The reaction time is 1h-3h.

6. The method for preparing the minoxidil benzenesulfonate intermediate according to claim 1, characterized in that: The first solvent is an alcohol solvent; Optionally, the first solvent includes one or more of methanol, ethanol, isopropanol, n-butanol or tert-butanol.

7. The method for preparing the minoxidil benzenesulfonate intermediate according to any one of claims 1 to 6, characterized in that: After the reaction is completed, a post-processing step is also included, and the post-processing step includes: After the reaction is completed, the reaction solution is filtered and concentrated, tetrahydrofuran is added to dissolve, a second solvent is added, the pH is adjusted to 3-4, the mixture is stirred for crystallization, filtered, and the obtained solid is dried.

8. The method for preparing the minoxidil benzenesulfonate intermediate according to claim 7, characterized in that: The second solvent is tetrahydrofuran hydrochloride solution; Optionally, in the tetrahydrofuran hydrochloride solution, the concentration of hydrogen chloride is 2 Mol / L-6 Mol / L.

9. Use of the method for preparing the minogabalin benzenesulfonate intermediate according to any one of claims 1 to 8 in preparing melogabalin benzenesulfonate.

10. The use according to claim 9, characterized in that: The preparation method of minoxidil benzenesulfonate comprises the following steps: The intermediate III prepared by the preparation method of the minogabalin benzenesulfonate intermediate according to any one of claims 1 to 8 is subjected to chiral resolution, hydrolysis reaction and salt formation reaction to prepare melogabalin benzenesulfonate.

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