Preparation Method and Application of Minogabalin Benzene Sulfonate Intermediate

Abstract

The present invention relates to a method for preparing a minogabalin besylate intermediate and its application. The method for preparing the minogabalin besylate intermediate comprises the following steps: providing intermediate II; mixing intermediate III, a KT-02 supported nickel catalyst, ammonium formate and a first solvent for reaction to prepare intermediate III. This method uses KT-02 / ammonium formate as a reduction system, and can prepare the intermediate of meloxicam besylate containing an amino group under normal pressure. It has a high safety factor, is easy to operate, has low cost, simple post-treatment, few by-products, little pollution, and the prepared product has high purity, and is more suitable for later industrial production.

Description

Technical Field

[0001] This application relates to the technical field of pharmaceutical chemistry, and particularly to a method for preparing an intermediate of mirogabalin benzenesulfonate and its application. Background Art

[0002] Mirogabalin benzenesulfonate is a new drug for treating peripheral neuropathic pain. It exhibits analgesic effects by inhibiting the release of neurotransmitters at nerve endings related to pain, and was approved for marketing by the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan on January 8, 2019, under the trade name Tarlige. Mirogabalin benzenesulfonate is a selective calcium channel α2δ ligand with unique binding characteristics and a long-acting effect. It can preferentially and selectively bind to the α2δ-1 subunit of voltage-dependent calcium channels (1 and 2), which are widely present in the nervous systems of various regions of the body that mediate pain transmission and processing, and is helpful for treating diabetic peripheral neuropathy, postherpetic neuralgia, and fibromyalgia. Its clinical efficacy is significantly higher than that of pregabalin and gabapentin. Another report shows that Tarlige can be used to treat additional indications related to central neuropathic pain (chronic neuropathic pain, CNP). Mirogabalin benzenesulfonate has advantages such as high safety and good tolerance, and is developing into a world-class drug for treating neuralgia.

[0003] The currently reported synthetic process routes for mirogabalin benzenesulfonate are mainly as follows:

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

[0005]

[0006] Method 2: Patent WO2015005298A1 reports using 3-ethyl-bicyclo[3.2.0]hept-3-ene-6-one and ethyl dimethoxyphosphorylacetate as raw materials to synthesize mirogabalin benzenesulfonate. It mainly uses 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 resolved, hydrolyzed, and salt-formed to obtain the mirogabalin benzenesulfonate raw material drug.

[0007]

[0008] Method 3: Patent WO2009041453A1 and JP2010241796A reported that ethyl butyrylacetate and 3-bromo-1-propene were used as raw materials to synthesize megalol gabapentin benzenesulfonate. Nitromethane was involved in the reaction to introduce a nitro group, and the nitro group was reduced to an amino group with iron powder and ammonium chloride. After amino protection, ester hydrolysis, and salt formation, megalol gabapentin benzenesulfonate was obtained.

[0009]

[0010] In summary, as reported in the current literature, there are mainly two ways to introduce the intermediate containing an amino group in the synthesis of megalol gabapentin benzenesulfonate. One is to introduce a cyano group through a reaction with sodium cyanide, and the other is to introduce a nitro group through nitromethane. Comparing the two methods, nitromethane is safer. Currently, the main methods for reducing nitro groups are catalytic hydrogenation with palladium-carbon or Raney nickel. In addition, there are also methods using sodium sulfide, sodium dithionite, iron powder, stannous chloride, etc. to reduce the nitro group to an amino group. The catalyst palladium-carbon is expensive, resulting in high production costs, and the reaction requires high pressure, which is not suitable for industrial production; although Raney nickel is inexpensive, it also requires high pressure reaction, has high requirements for production equipment, and the production operation is relatively dangerous; although sodium sulfide, sodium dithionite, iron powder, stannous chloride, etc. are easy to operate, their post-treatment causes great environmental pollution and is not suitable for industrial production. Therefore, it is of great significance to develop a new reduction system for the preparation of the intermediate of megalol gabapentin benzenesulfonate containing an amino group. Summary of the Invention

[0011] Based on this, it is necessary to provide a method for preparing the intermediate of minogabapentin benzenesulfonate, which uses the KT-02 / ammonium formate reduction system to synthesize the intermediate III of megalol gabapentin benzenesulfonate containing an amino group under atmospheric pressure. The operation is simple, the safety factor is high, the production cost is low, the by-products are few, the purity of the obtained product is high, and it 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 the intermediate of minogabapentin benzenesulfonate, comprising the following steps:

[0014] Provide intermediate II;

[0015] Mix intermediate III, KT-02 supported nickel catalyst, ammonium formate and a first solvent for reaction to prepare intermediate III;

[0016] The structures of the intermediate II and III are as follows:

[0017] , .

[0018] In one embodiment, the mass ratio of the KT-02 supported nickel catalyst to 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 atmospheric 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, it further includes a post-treatment step, and the post-treatment step includes:

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

[0027] In one embodiment, the second solvent is a tetrahydrofuran hydrogen chloride solution;

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

[0029] Another aspect of the present invention provides the application of the preparation method of the minogabalin benzenesulfonate intermediate as described above in the preparation of melegabalin benzenesulfonate.

[0030] In one embodiment, the preparation method of minogabalin benzenesulfonate includes 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 melegabalin benzenesulfonate.

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

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

[0034] Specifically, the reduction of intermediate III by the KT-02 / ammonium formate system has the following advantages: (1) High safety factor: KT-02 belongs to a supported nickel catalyst, which is more stable than Raney nickel catalysts, and this method is carried out under atmospheric pressure reaction, with high safety; (2) Easy to operate; There is no need for hydrogen pressurization for the reaction, and the post-treatment is simple; (3) Low production cost: The price of the KT-02 catalyst is much lower than that of Pd / C, and the dosage of KT-02 is only the catalytic amount; (4) High purity of the obtained product, which is more suitable for industrial production. Description of the Drawings

[0035] In order to more clearly illustrate the specific embodiments of the present application or the technical solutions in the prior art, the following will briefly introduce the drawings required for the description of the specific embodiments or the prior art. Obviously, the following drawings are some embodiments of the present application. For those of ordinary skill in the art, without creative efforts, other drawings can also be obtained based on these drawings.

[0036] Figure 1 It is the high performance liquid chromatography of the meloxicam balin intermediate III prepared in an embodiment.

[0037] Figure 2 It is the mass spectrum of the meloxicam balin intermediate III prepared in an embodiment.

[0038] Figure 3 It is the nuclear magnetic resonance hydrogen spectrum of the meloxicam balin intermediate III prepared in an embodiment. Specific Embodiments

[0039] The following further details the present application 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, these embodiments are provided to make the understanding of the disclosed content of the present application more thorough and comprehensive.

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

[0041] Unless otherwise stated or there is a contradiction, the terms or phrases used herein 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] In this text, the optional scope of "and / or", "or / and", and "and / or" includes any one of two or more related listed items, and also includes any and all combinations of the related listed items. The said any and all combinations include any two related listed items, any more related listed items, or the combination of all related listed items. (It should be noted that when at least three items are connected by at least two conjunctive combinations selected from "and / or", "or / and", and "and / or", it should be understood that in this application, this technical solution undoubtedly includes the technical solution connected by "logical AND", and also undoubtedly includes the technical solution connected by "logical OR". For example, "A and / or B" includes three parallel solutions: A, B, and A + B. 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, the technical solution connected by "logical OR"), and also includes any and all combinations of A, B, C, and D, that is, it includes the combination of any two or any three of A, B, C, and D, and also includes the combination of the four items A, B, C, and D (that is, the technical solution connected by "logical AND").)

[0044] In this text, words such as "further", "even further", and "especially" are used for descriptive purposes, indicating differences in content, but should not be construed as limiting the scope of protection of this application.

[0045] In this text, "first aspect", "second aspect", "third aspect", "fourth aspect", etc. are only used for descriptive purposes, and should not be construed as indicating or implying relative importance or quantity, nor should it be construed 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 enumerative description, and it should be understood that they do not constitute a closed limitation on quantity. Thus, the features defined with "first" and "second" may explicitly or implicitly include at least one such feature. In the description of this application, the meaning of "a plurality of" is at least two, such as two, three, etc., unless otherwise clearly and specifically defined. In the description of this 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 considered continuous and include the minimum value and the maximum value of the range, as well as each value between such minimum value and maximum value. Further, when the range refers to integers, it includes each integer between the minimum value and the maximum value of the range. In addition, when multiple ranges are provided to describe features or characteristics, these ranges can be combined. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all sub-ranges subsumed therein.

[0047] This document specifically discloses only some numerical ranges. However, any lower limit can be combined with any upper limit to form a range not explicitly recited; and any lower limit can be combined with other lower limits to form a range not explicitly recited, and similarly any upper limit can be combined with any other upper limit to form a range not explicitly recited. In addition, each individually disclosed point or single numerical value itself can be used as a lower limit or an upper limit and combined with any other point or single numerical value or with other lower limits or upper limits to form a range not explicitly recited. The use of a numerical range represented by endpoints includes all numbers within that range and any range within that range. For example, the range from 1 to 5 includes 1, 1.1, 1.3, 1.5, 2, 2.75, 3, 3.80, 4, and 5, etc.

[0048] In this application, the percentage content involved, unless otherwise specified, refers to the mass percentage for solid-liquid mixing and solid-solid mixing, and refers to the volume percentage for liquid-liquid mixing.

[0049] In this application, the percentage concentration involved, unless otherwise specified, refers to the final concentration. The final concentration refers to the proportion of the added component in the system after adding this component.

[0050] The temperature parameters in this application, unless otherwise specifically defined, 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. Fluctuation within ranges such as ±5°C, ±2°C, ±1°C, ±0.5°C, ±0.4°C, ±0.3°C, ±0.2°C, ±0.1°C is allowed. Normal temperature or room temperature in this application refers to no temperature control operation, generally referring to 4°C to 35°C, preferably 20 ± 5°C.

[0051] In addition, the terms "first" and "second" are used only for descriptive purposes and cannot be construed as indicating or implying relative importance or implicitly specifying the quantity of the indicated technical features. Thus, features defined with "first" and "second" may explicitly or implicitly include at least one such feature. In the description of the present invention, "a plurality" means at least two, such as two, three, etc., unless otherwise specifically defined.

[0052] KT-02 is a supported nickel catalyst with diatomite as the carrier. The KT-02 series of supported nickel catalysts are mainly applied in the fields of nitro hydrogenation, oils and fats, carbon-carbon double bonds, aldehydes (ketones), and other hydrogenation. It has been proven to have good performance through the hydrogenation use by many enterprises in the production processes of TDI, pharmaceutical intermediates, dye intermediates, pesticide intermediates, nitro compounds, etc. In view of the defects existing in the introduction of the minogabalin intermediate of benzenesulfonic acid containing amino in the prior art, the technical personnel of this application unexpectedly found a new reduction system, KT-02 / ammonium formate, through a large number of studies. This system can replace the Fe powder-NH4Cl and Raney nickel-hydrazine hydrate systems to prepare the melogabalin intermediate of benzenesulfonic acid, with simple operation, few by-products, low cost, and less post-treatment waste, and is more suitable for later industrial production.

[0053] Specifically, KT-02 belongs to the supported nickel-based catalyst. Compared with the Raney nickel-based catalyst, it has stable properties, high safety factor, is easy to operate and has low cost, and is suitable for industrial production. Compared with the post-treatment of Fe powder-NH4Cl and SnCl2 for reducing nitro groups, it is simpler, easier to filter, and not easy to produce iron mud that pollutes the environment, and is more suitable for commercial production. Using KT-02 / ammonium formate to prepare the melogabalin intermediate of benzenesulfonic acid, the product has high purity and is more suitable for the commercial production of nitro reduction. In summary, the introduction of KT-02 / ammonium formate in this application to prepare the melogabalin intermediate of benzenesulfonic acid has a high safety factor, low production cost, convenient post-treatment, and small pollution, and is more suitable for the industrial production of melogabalin of benzenesulfonic acid.

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

[0055] Provide intermediate II;

[0056] Mix intermediate III, the KT-02 supported nickel catalyst, ammonium formate, and a first solvent and react to prepare intermediate III;

[0057] The structures of the above-mentioned intermediate II and III are shown as follows:

[0058] 、 。

[0059] In some examples, the mass ratio of the KT-02 supported nickel catalyst to intermediate II is (0.3-0.5):10. It can be understood that the mass ratio of the KT-02 supported nickel catalyst to 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 of these examples, the molar ratio of ammonium formate to Intermediate II is (2 - 3):1. It is understandable 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 of these examples, the temperature of the reaction is 55°C - 65°C. It is understandable that the temperature of the reaction includes but is not limited to 55°C, 57°C, 59°C, 61°C, 63°C, 65°C.

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

[0063] In some of these examples, the time of the reaction is 1 h - 3 h. It is understandable that the time of the reaction includes but is not limited to 1 h, 1.5 h, 2 h, 2.5 h, 3 h.

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

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

[0066] In some of these examples, after the reaction is completed, it further includes a post-treatment step, and the post-treatment step includes:

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

[0068] In some of these examples, the second solvent is a tetrahydrofuran hydrogen chloride solution.

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

[0070] In some of these examples, the time for crystallization is 0.5 h - 2 h. It is understandable that the time for crystallization includes but is not limited to 0.5 h, 1 h, 1.5 h, 2 h.

[0071] In some of these examples, the temperature for concentration is 30°C - 60°C. It is understandable that it includes but is not limited to 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C.

[0072] Another aspect of the present invention provides the use of the preparation method of the minogabapin benzenesulfonate intermediate as described above in the preparation of melegabalin benzenesulfonate.

[0073] In some of these examples, the preparation method of the minogabapin benzenesulfonate comprises the following steps:

[0074] The intermediate III prepared by the preparation method of the minogabapin benzenesulfonate intermediate as described above is subjected to chiral resolution hydrolysis reaction and salification reaction to prepare melegabalin benzenesulfonate.

[0075] In one specific example, the preparation method of the minogabapin benzenesulfonate comprises the following steps: Using (1R,5S)-3-ethyl-bicyclo[3.2.0]hept-3-ene-6-one and tert-butyl dimethoxyphosphorylacetate as starting materials, compound I is prepared through the Homner-Wittig reaction, and compound II is prepared by the addition reaction of compound I with nitromethane. Compound II undergoes nitro reduction reaction under the action of hydrazine hydrate to prepare compound III. Compound III undergoes chiral resolution reaction with the chiral resolving agent D-mandelic acid to prepare compound IV. Compound IV undergoes hydrolysis reaction under alkaline conditions to remove the tert-butyl protecting group to prepare compound V. Compound V and benzenesulfonic acid are salified to obtain the target compound melegabalin benzenesulfonate.

[0076]

[0077] The following is further illustrated with specific examples. For the raw materials involved in the following specific examples, unless otherwise specified, they can all be obtained commercially; for the instruments used, unless otherwise specified, they can all be obtained commercially; for the processes involved, unless otherwise specified, they are all conventional selections of those skilled in the art.

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

[0079]

[0080] The following are specific examples.

[0081] Example 1

[0082] Preparation of Intermediate Ⅰ: 100.00 g of material SM1 ((1R,5S)-3-ethyl-bicyclo[3.2.0]hept-3-ene-6-one) was taken and added to a 2 L three-necked flask. 230.46 g of material SM2 (tert-butyl dimethoxyphosphorylacetate) was added, 4.5 L of tetrahydrofuran was added, and the mixture was stirred and dispersed. Sodium hydroxide was added, and the reaction was stirred at room temperature for 3 h. 3000 mL of saturated ammonium chloride aqueous solution was added to the system, and liquid separation was performed. The upper layer was washed with 1500 mL of water. After liquid separation, 250.0 g of anhydrous sodium sulfate was added for drying, filtration was carried out, and concentration gave 166.5 g of a yellow oil. Yield: 96.77%, Purity: 97.80%.

[0083] Preparation of Intermediate Ⅱ: 15.0 g of the Intermediate Ⅰ oil was taken and added to a 100 mL three-necked flask. 45 mL of nitromethane was added, 24.0 g of DBU was added, the temperature of the system was raised to 55 °C and the reaction was carried out for 3 h. The temperature of the system was lowered to 30 °C, 20 mL of saturated potassium dihydrogen phosphate solution was added for quenching, and extraction was carried out with methyl tert-butyl ether (3×50 mL). The organic phases were combined, the organic phase was washed with 50 mL of water, 30 g of anhydrous sodium sulfate was added for drying, filtration was carried out, and concentration gave 18.0 g. Yield: 95.24%, Purity: 97.15%.

[0084] Preparation of Intermediate Ⅲ: 10.00 g of Intermediate Ⅱ (purity 97.15%) was added to the reaction equipment, 60 mL of ethanol was added and stirred until dissolved. 0.5 g of KT-02 catalyst was added to the system, 2 eq of 4.26 g of ammonium formate was added. After feeding, nitrogen replacement was carried out three times, the temperature was raised to 65 °C, and the system was stirred and reacted for 2 h. Stirring was carried out to cool down to 25 °C, filtration was carried out, and the filtrate was concentrated to dryness at 45 °C to obtain 8.9 g of a yellow oil. Yield: 99.05%, Purity: 98.59%.

[0085] Tetrahydrofuran was added to the oil and stirred until dissolved. 4 Mol / L of tetrahydrofuran hydrogen chloride solution was added to the system. After adjusting the pH to 3 - 4, crystallization was carried out with temperature control and stirring for 1 h. Filtration and drying gave 9.5 g of a white solid. Yield: 93.84%, Purity: 99.78%. The high performance liquid chromatography chart, mass spectrometry chart and 1H NMR chart of Intermediate III are as Figures 1-3 shown.

[0086] Example 2

[0087] 10 g of Intermediate Ⅱ was prepared according to the method of Example 1. 10.00 g of Intermediate Ⅱ was added to the reaction equipment, 60 mL of ethanol was added and stirred until dissolved. 0.3 g of KT-02 catalyst was added to the system, 2 eq of 4.26 g of ammonium formate was added. After feeding, nitrogen replacement was carried out three times, the temperature was raised to 65 °C, and the system was stirred and reacted for 2 h. Stirring was carried out to cool down to 25 °C, filtration was carried out, and the filtrate was concentrated to dryness at 45 °C to obtain 8.78 g of a yellow oil. Yield: 97.72%, Purity: 98.56%.

[0088] Add tetrahydrofuran to the oily substance and stir to dissolve it. Add a 4 Mol / L tetrahydrofuran hydrogen chloride solution to the system. After adjusting the pH to 3 - 4, control the temperature and stir to crystallize for 1 h. Filter and dry to obtain 9.61 g of white solid, yield: 96.22%, purity 99.58%.

[0089] Example 3

[0090] Prepare 10 g of intermediate II according to the method of Example 1. Add 10.00 g of intermediate II (purity 97.15%) to the reaction equipment, add 60 mL of ethanol and stir to dissolve it. Add 0.3 g of KT - 02 catalyst to the system, add 3 eq of 6.40 g of ammonium formate. After feeding, replace with nitrogen three times. Raise the temperature to 65 °C, stir the system to react for 2 h, stir and cool to 25 °C, filter, and concentrate the filtrate to dryness at 45 °C to obtain 8.82 g of yellow oily substance, yield: 98.16%, purity: 98.39%.

[0091] Add tetrahydrofuran to the oily substance and stir to dissolve it. Add a 4 Mol / L tetrahydrofuran hydrogen chloride solution to the system. After adjusting the pH to 3 - 4, control the temperature and stir to crystallize for 1 h. Filter and dry to obtain 9.58 g of white solid, yield: 95.51%, purity 99.36%.

[0092] Example 4

[0093] Prepare 10 g of intermediate II according to the method of Example 1. Add 10.00 g of intermediate II (purity 97.15%) to the reaction equipment, add 60 mL of ethanol and stir to dissolve it. Add 0.3 g of KT - 02 catalyst to the system, add 2 eq of 4.26 g of ammonium formate. After feeding, replace with nitrogen three times. Raise the temperature to 55 °C, stir the system to react for 2 h, stir and cool to 25 °C, filter, and concentrate the filtrate to dryness at 45 °C to obtain 8.86 g of yellow oily substance, yield: 98.61%, purity: 97.95%.

[0094] Add tetrahydrofuran to the oily substance and stir to dissolve it. Add a 4 Mol / L tetrahydrofuran hydrogen chloride solution to the system. After adjusting the pH to 3 - 4, control the temperature and stir to crystallize for 1 h. Filter and dry to obtain 9.65 g of white solid, yield: 95.83%, purity 99.46%.

[0095] Comparative Example 1

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

[0097] Preparation of Intermediate Ⅰ: Take 20.00 g of material SM1 ((1R,5S)-3-ethyl-bicyclo[3.2.0]hept-3-ene-6-one) and add it to a 2 L three-necked flask. Add 46.10 g of material SM2 (tert-butyl dimethoxyphosphorylacetate), add 910 mL of tetrahydrofuran, stir and disperse. Add sodium hydroxide, and stir the reaction at room temperature for 3 h. Add 600 mL of saturated ammonium chloride aqueous solution to the system, separate the layers. Wash the upper layer with 300 mL of water, separate the layers, add 50 g of anhydrous sodium sulfate for drying, filter, and concentrate to obtain 33.30 g of a yellow oil. Yield: 96.77%, Purity: 97.10%.

[0098] Preparation of Intermediate Ⅱ: Take 15.0 g of the Intermediate Ⅰ oil and add it to 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 for extraction (3×50 mL), combine the organic phases. Wash the organic phase with 50 mL of water, add 30 g of anhydrous sodium sulfate for drying, filter, and concentrate to obtain 17.0 g. Yield: 89.94%, Purity: 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. After feeding, replace with hydrogen three times. Raise the temperature to 35 °C, maintain a pressure of 0.2 Mpa, stir the system to react for 2 h. Stir and cool to 25 °C, filter, and concentrate the filtrate to dryness at 45 °C to obtain 8.4 g of a yellow oil. Yield: 93.49%, Purity: 95.89%.

[0100] Add tetrahydrofuran to the oil and stir to dissolve. Add a 4 Mol / L tetrahydrofuran hydrogen chloride solution to the system. After adjusting the pH to 3 - 4, control the temperature and stir to crystallize for 1 h. Filter and dry to obtain 6.5 g of a white solid. Yield: 68.03%, Purity: 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. After feeding, replace with hydrogen three times. Raise the temperature to 40 °C, maintain a pressure of 0.2 Mpa, stir the system to react for 2 h. Stir and cool to 25 °C, filter, and concentrate the filtrate to dryness at 45 °C to obtain 8.25 g of a yellow oil. Yield: 91.82%, Purity: 96.59%.

[0103] Add tetrahydrofuran to the oily substance and stir to dissolve it. Add a 4 Mol / L tetrahydrofuran-hydrochloric acid solution to the system. After adjusting the pH to 3 - 4, control the temperature and stir to crystallize for 1 h. Filter and dry to obtain 6.45 g of white solid, yield: 68.73%, purity: 97.32%.

[0104] Comparative Example 3

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

[0106] Add 10.00 g of Intermediate II (purity 97.15%) to the reaction equipment, add 60 mL of ethanol and stir to dissolve it. Add 5 eq of 9.05 g of ammonium chloride and 5 eq of 9.45 g of iron powder to the system. Raise the temperature to 60 °C, and stir the system to react for 2 h. Filter, and concentrate the filtrate at 45 °C to distill off ethanol. Cool to room temperature, add dichloromethane for extraction 3×60 mL, combine the organic phases, wash the organic phase with 60 ml of purified water, dry with anhydrous sodium sulfate, filter and concentrate to obtain 5.8 g of yellow oily substance, yield: 64.55%, purity: 81.65%.

[0107] Add tetrahydrofuran to the oily substance and stir to dissolve it. Add a 4 Mol / L tetrahydrofuran-hydrochloric acid solution to the system. After adjusting the pH to 3 - 4, control the temperature and stir to crystallize for 1 h. Filter and dry to obtain 4.55 g of white solid, yield: 68.94%, purity 94.65%.

[0108] Comparative Example 4

[0109] Add 10.00 g of Intermediate II (purity 97.15%) to the reaction equipment, add 60 mL of ethanol and stir to dissolve it. Add 4.5 eq of 8.15 g of ammonium chloride and 4.5 eq of 8.50 g of iron powder to the system. Raise the temperature to 60 °C, and stir the system to react for 2 h. Filter, and concentrate the filtrate at 45 °C to distill off ethanol. Cool to room temperature, add dichloromethane for extraction 3×60 mL, combine the organic phases, wash the organic phase with 60 mL of purified water, dry with anhydrous sodium sulfate, filter and concentrate to obtain 6.0 g of yellow oily substance, yield: 66.780%, purity: 78.59%.

[0110] Add tetrahydrofuran to the oily substance and stir to dissolve it. Add a 4 Mol / L tetrahydrofuran-hydrochloric acid solution to the system. After adjusting the pH to 3 - 4, control the temperature and stir to crystallize for 1 h. Filter and dry to obtain 4.5 g of white solid, yield: 65.93%, purity 95.87%.

[0111] The technical features of the above-described embodiments can be combined arbitrarily. For the sake of brevity of description, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, it should be considered as the scope described in this specification.

[0112] The above-described embodiments only express several implementation manners of the present application. The description is relatively specific and detailed, but it should not be construed as a limitation on the scope of the patent application. It should be noted that for those of ordinary skill in the art, without departing from the concept of the present application, several modifications and improvements can still be made, and these all belong to the protection scope of the present application. Therefore, the protection scope of the patent of the present application shall be subject to the appended claims, and the specification can be used to explain 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.

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

8. The method for preparing the minoxidil benzenesulfonate intermediate according to any one of claims 1 to 7, 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.

9. The method for preparing the minoxidil benzenesulfonate intermediate according to claim 8, characterized in that: The second solvent is tetrahydrofuran hydrogen chloride solution.

10. The method for preparing the minoxidil benzenesulfonate intermediate according to claim 9, characterized in that: In the tetrahydrofuran hydrogen chloride solution, the concentration of hydrogen chloride is 2Mol / L-6Mol / L.

11. Use of the method for preparing the minogabalin besylate intermediate according to any one of claims 1 to 10 in preparing melogabalin besylate.

12. The use according to claim 11, 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 10 is subjected to chiral resolution, hydrolysis reaction and salt formation reaction to prepare melogabalin benzenesulfonate.

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