A process for the preparation of milorine tartrate

Abstract

The application provides a preparation method of milorin benzenesulfonate, and the preparation method comprises the following steps: performing a hydrolysis reaction on a compound 6 to obtain a compound 7; and performing a reaction on the compound 7 and benzenesulfonic acid to obtain a compound 8, i.e. milorin benzenesulfonate. The preparation method does not produce carbon-carbon double bond isomer impurities, does not use the toxic substance NaCN in the preparation method, raw materials are easy to obtain, the method is simple, the synthesis cost is low, and the product has a high yield.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology and relates to a method for preparing milobalin besylate. Background Technology

[0002] Mirogabalin besylate is a novel drug developed by Daiichi Sankyo in Japan for the treatment of peripheral neuropathic pain (PNP). PNP is caused by damage or dysfunction of the peripheral nerves due to various reasons. Typical PNP includes diabetic PNP (DPNP) and postherpetic neuralgia (PNN). Diabetic PNP is one of the most common long-term complications in diabetic patients, with symptoms including acute pain or hypersensitivity, numbness, loss of balance and coordination, tingling, and burning sensations, which worsen at night. Shingles is caused by a weakened immune system against the varicella-zoster virus, which forms a latent infection in the ganglia. In PNN, even after shingles has healed, burning pain or electric shock-like pain persists; the disease is considered intractable and can lead to muscle weakness and, in rare cases, paralysis.

[0003] Mirogabalin besylate is an α2δ ligand that, when administered orally, preferentially and selectively binds to the α2δ-1 subunit of voltage-dependent calcium channels (1 and 2). These calcium channels are widely distributed throughout the nervous system, mediating pain transmission and processing in various regions of the body. Mirogabalin besylate exhibits unique binding properties and a long-lasting effect with these calcium channels. Clinical studies have shown that its potency is significantly higher than that of gabapentin and pregabalin. The structural formula of mirogabalin besylate is as follows:

[0004]

[0005] There are three main synthetic routes:

[0006] The first method is the route disclosed in WO2015005298A1, as follows:

[0007]

[0008] Sodium cyanide, a highly toxic substance, is used in its synthesis process.

[0009] The second route is the one reported in WO2015005298A1, as follows:

[0010]

[0011] This route avoids the use of the highly toxic substance NaCN, but its disadvantage is that it uses triethyl phosphonoacetate, which has a high synthesis cost.

[0012] The third type is the following route disclosed in WO2009041453A1 and JP2010241796A:

[0013]

[0014] The inventors discovered through testing that the milobalin benzylsulfonic acid synthesized via this route contained impurity A (which has two isomers with overlapping HPLC peaks) and impurity B, which were difficult to remove.

[0015] Summary of the Invention

[0016] In view of the shortcomings of existing technologies, such as the use of highly toxic substance NaCN, high synthesis cost, and the presence of impurities A and B in the product, the purpose of this invention is to provide a method for preparing milobalin benzylsulfonic acid that avoids the use of highly toxic substance NaCN, uses inexpensive and readily available raw materials, and produces a product free of impurities A and B with a high yield.

[0017] To achieve this objective, the present invention adopts the following technical solution:

[0018] On one hand, the present invention provides a method for preparing milobalin benzylsulfonic acid, the method comprising the following steps:

[0019] Compound 6 undergoes a hydrolysis reaction with a hydrolysis reagent, which is zinc bromide or cerium trichloride, in the presence of a solvent. After the hydrolysis reaction is completed, the pH of the reaction solution is adjusted to be alkaline to obtain compound 7.

[0020] Compound 7 reacts with benzenesulfonic acid to give compound 8, namely milobalin benzenesulfonic acid;

[0021] The structures of each compound are as follows:

[0022]

[0023] In this invention, compound 6 is directly hydrolyzed to obtain compound 7, and then compound 7 is reacted with benzenesulfonic acid to obtain milobalin benzenesulfonic acid. This method can effectively control the generation of carbon-carbon double bond isomers, resulting in high yield and high purity of the product.

[0024] Preferably, the solvent for the hydrolysis reaction is any one or a combination of at least two of acetonitrile, dichloromethane, methanol, ethanol, or tetrahydrofuran.

[0025] Preferably, the hydrolysis reaction is carried out at a temperature of 40–60°C (e.g., 50°C, 53°C, 55°C, 58°C or 60°C) and for a reaction time of 1–8 h (e.g., 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h or 8 h).

[0026] After the hydrolysis reaction is completed, the pH of the reaction solution is adjusted to alkaline using an organic base, preferably between 8 and 14, such as 8, 8.5, 9, 9.5, 10, 10.5, 11, or 12. The inventors have experimentally demonstrated that when the pH of the reaction solution is acidic, impurities A and B in the product will increase.

[0027] Preferably, the organic base is any one of triethylamine, diisopropylethylamine, or ammonia.

[0028] Preferably, the molar ratio of compound 7 to benzenesulfonic acid is 1:0.95-1.2, for example 1:0.95, 1:0.98, 1:1, 1:1.05, 1:1.1, 1:1.15 or 1:1.2.

[0029] Preferably, the reaction of compound 7 with benzenesulfonic acid is carried out in a solvent, namely water.

[0030] In this invention, water is used as a solvent, which can dissolve the impurities at a temperature of 40-60°C. If an organic solvent is used, it is difficult to dissolve the impurities at this temperature or a higher temperature is required. The system is acidic, and at higher temperatures, there is a risk of increased impurities A and B.

[0031] Preferably, the reaction of compound 7 with benzenesulfonic acid is carried out as follows: benzenesulfonic acid is added dropwise to a reaction system containing compound 7 at 50-60°C (e.g., 50°C, 53°C, 55°C, 58°C or 60°C), and the reaction is carried out for 0-6 hours (e.g., 0 hours, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours or 6 hours), followed by cooling and crystallization to obtain compound 8.

[0032] Preferably, the cooling crystallization involves cooling to 30–40°C (30°C, 35°C, 38°C, or 40°C), and then reducing the temperature to 0–10°C (e.g., 0°C, 2°C, 4°C, 5°C, or 10°C) at a rate of 5–15°C / h (e.g., 5°C / h, 7°C / h, 9°C / h, 10°C / h, 12°C / h, or 15°C / h), while stirring for 1–6 h (e.g., 1 h, 2 h, 3 h, 4 h, 5 h, or 6 h).

[0033] Preferably, the benzenesulfonic acid is added dropwise to a reaction system containing compound 7 at 50-60°C, reacted for 0-6 hours, and then filtered while hot (filtration is an added step for scale-up production and can be omitted in small-scale tests). The filtrate is cooled to 30-40°C, and then cooled to 0-10°C at a rate of 5-15°C / h, and stirred for 1-6 hours.

[0034] Preferably, compound 6 is prepared by the following method:

[0035] (1) Compound 1 reacts with tert-butyl dimethoxyphosphonoacetate to give compound 2:

[0036] (2) Compound 2 reacts with nitromethane to give compound 3;

[0037] (3) Compound 3 undergoes a nitro reduction reaction to yield compound 4;

[0038] (4) Compound 4 was resolved by a resolving agent to obtain compound 5;

[0039] (5) Compound 5 reacts in the presence of an alkaline substance to give compound 6;

[0040] The structures of each compound are as follows:

[0041]

[0042] Preferably, the molar ratio of compound 1 to tert-butyl dimethoxyphosphonoacetate in step (1) is 1:1.1 to 1.3, for example, 1:1.1, 1:1.15, 1:1.18, 1:1.2, 1:1.25, 1:1.28 or 1:1.3. When the molar ratio of compound 1 to tert-butyl dimethoxyphosphonoacetate exceeds 1:1.3, for example, 1:1.5, there are more impurities.

[0043] Preferably, the reaction in step (1) is carried out in the presence of an alkaline substance.

[0044] Preferably, the alkaline substance is an organic base.

[0045] Preferably, the organic base is selected from any one or a combination of at least two of sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, or DBU.

[0046] Preferably, the reaction in step (1) is carried out in a solvent selected from any one or a combination of at least two of toluene, methyl cyclopentyl ether or methyl tert-butyl ether.

[0047] Preferably, in step (1), compound 1 is added dropwise to the reaction system containing tert-butyl dimethoxyphosphonoacetate.

[0048] Preferably, the temperature of the reaction system containing dimethoxyphosphonoacetic acid tert-butyl ester is controlled at 0–10°C (e.g., 0°C, 3°C, 5°C, 8°C, or 10°C) and compound 1 is added dropwise.

[0049] Preferably, the reaction temperature in step (1) is -5 to 15°C, for example -5°C, -3°C, 0°C, 3°C, 5°C, 8°C, 10°C, 12°C, or 15°C, and the reaction time is 2 to 10 hours, for example 2 hours, 3 hours, 4 hours, 5 hours, or 6 hours. If the reaction temperature in step (1) is too high, exceeding 15°C, the purity of the product will deteriorate, and the reaction time should not be too long, otherwise the purity of the product will also decrease.

[0050] Preferably, the molar ratio of compound 2 to nitromethane in step (2) is 1:3.5 to 5, for example, 1:3.5, 1:3.8, 1:4, 1:4.3, 1:4.5, 1:4.8 or 1:5.

[0051] Preferably, the reaction in step (2) is carried out in the presence of an alkaline substance.

[0052] Preferably, the alkaline substance is selected from any one or a combination of at least two of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), sodium tert-butoxide, or potassium tert-butoxide.

[0053] Preferably, the reaction temperature in step (2) is 20-30°C (e.g., 20°C, 22°C, 25°C, 28°C or 30°C), and the reaction time is 15-20h (e.g., 15h, 17h, 19h or 20h).

[0054] Preferably, the reducing agent used in the nitro reduction reaction in step (3) is Raney nickel and hydrazine hydrate, ammonium chloride and iron powder, or palladium on carbon and hydrogen.

[0055] Preferably, the nitro reduction reaction in step (3) is carried out in a solvent, which is selected from any one of methanol, ethanol, a mixture of methanol and water, or a mixture of ethanol and water.

[0056] Preferably, the volume percentage of methanol or ethanol in the mixture of methanol and water or the mixture of ethanol and water is not less than 80%.

[0057] Preferably, the temperature of the nitro reduction reaction in step (3) is 20-30°C (e.g., 20°C, 22°C, 25°C, 28°C or 30°C), and the reaction time is 15-20h (e.g., 15h, 17h, 19h or 20h).

[0058] Preferably, the resolving agent in step (4) is D-mandelic acid, L-mandelic acid, D-tartaric acid, or D-dibenzoyl tartaric acid, with D-mandelic acid or D-tartaric acid being preferred. In this invention, selecting D-mandelic acid and D-tartaric acid as resolving agents can reduce the generation of impurities. Selecting L-mandelic acid results in a relatively large amount of impurities in the mother liquor. While D-dibenzoyl tartaric acid can also be used as a resolving agent, its large molecular weight requires more solvent for dissolution.

[0059] Preferably, the separation in step (4) is carried out in a solvent selected from any one or a combination of at least two of acetonitrile, methyl tert-butyl ether, or methyl cyclopentyl ether. In this invention, if methanol, ethanol, ethyl acetate, or acetone are chosen as the solvent for separation, the losses will be relatively large.

[0060] Preferably, the separation in step (4) is carried out at a temperature of 40–50°C (e.g., 40°C, 43°C, 45°C, 48°C, or 50°C), and the reaction time for the separation is 1–24 h, for example, 1 h, 3 h, 5 h, 8 h, 10 h, 12 h, 15 h, 18 h, 20 h, 22 h, or 24 h. The salt formation reaction of the separation is very fast. Under the condition of excess resolving agent, there is no significant change in purity after 10 h, but the purity will deteriorate if the holding time exceeds 24 h.

[0061] The alkaline substance mentioned in step (5) is a weak base, preferably any one or a combination of at least two of sodium carbonate, potassium carbonate, ammonia, or triethylamine. The inventors have experimentally demonstrated that using a strong alkaline substance (such as sodium hydroxide) in step (5) will produce a large amount of impurities.

[0062] Preferably, the reaction in step (5) is carried out at room temperature (15-30°C) for a time of 5 min to 5 h, such as 5 min, 8 min, 10 min, 30 min, 50 min, 1 h, 2 h, 3 h, 4 h, or 5 h, until the system is completely dissolved and the reaction is complete. If the reaction time in step (5) exceeds 5 h, the amount of lactam impurities produced will increase significantly.

[0063] Preferably, the reaction in step (5) is carried out in a solvent selected from any one or a combination of at least two of toluene, methyl tert-butyl ether (MTBE) or dichloromethane.

[0064] As a preferred technical solution, the preparation method of the milobalin benzylsulfonic acid includes the following steps:

[0065] (1) The temperature of the reaction system containing dimethoxyphosphonoacetate tert-butyl ester is controlled at 0-10℃. Compound 1 is added dropwise. Compound 1 and dimethoxyphosphonoacetate tert-butyl ester are reacted at a molar ratio of 1:1.1-1.3 in the presence of an alkaline substance at -5-15℃ for 2-10 h to obtain compound 2. The alkaline substance is an organic base. The organic base is selected from any one or a combination of at least two of sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, or DBU.

[0066] (2) Compound 2 and nitromethane react in a molar ratio of 1:3.5 to 5 at 20 to 30 °C for 15 to 20 h in the presence of an alkaline substance to obtain compound 3; the alkaline substance is selected from any one or a combination of at least two of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), sodium tert-butoxide or potassium tert-butoxide;

[0067] (3) Compound 3 is subjected to a nitro reduction reaction in a solvent at 20-30°C for 15-20 h under the action of a reducing agent to obtain compound 4; wherein the reducing agent is Raney nickel and hydrazine hydrate, ammonium chloride and iron powder, or palladium on carbon and hydrogen, and the solvent is selected from any one of methanol, ethanol, a mixture of methanol and water, or a mixture of ethanol and water;

[0068] (4) Compound 4 was subjected to a resolving reaction at 40-50℃ for 1-24 h under the action of a resolving agent to obtain compound 5, wherein the resolving agent was D-mandelic acid, L-mandelic acid, D-tartaric acid or D-dibenzoyl tartaric acid.

[0069] (5) Compound 5 is reacted in a solvent at room temperature (15-30°C) for 5 min-5 h in the presence of an alkaline substance to obtain compound 6, wherein the alkaline substance is any one or a combination of at least two of sodium carbonate, potassium carbonate, ammonia or triethylamine, and the solvent is selected from any one or a combination of at least two of toluene, methyl tert-butyl ether or dichloromethane.

[0070] (6) Compound 6 is hydrolyzed at 40-60°C for 1-8 hours under the action of a hydrolysis reagent. After the hydrolysis reaction is completed, the pH of the reaction solution is adjusted to 8-14 to obtain compound 7. The hydrolysis reagent is zinc bromide or cerium trichloride, and the solvent is any one or a combination of at least two of acetonitrile, dichloromethane, methanol, ethanol or tetrahydrofuran.

[0071] (7) Add benzenesulfonic acid dropwise to a reaction system containing compound 7 at 50-60℃, react for 0-6 hours, cool down to crystallize, and obtain compound 8, namely benzenesulfonic acid milobalin, wherein the molar ratio of compound 7 to benzenesulfonic acid is 1:0.95-1.2, and the solvent of the reaction is water.

[0072] Compared with the prior art, the present invention has the following beneficial effects:

[0073] 1) In the hydrolysis reaction of compound 6 of the present invention, zinc bromide and cerium trichloride are selected as hydrolysis reagents and zinc bromide and cerium trichloride are used as salts. After the hydrolysis reaction is completed, the pH is close to neutral, which avoids the carbon-carbon double bond isomerism of compound 6 caused by the use of strong acid as hydrolysis reagent, thereby avoiding the generation of carbon-carbon double bond isomer impurities A and B.

[0074] 2) All chemical reactions involved in this invention do not use the highly toxic substance NaCN, the raw materials are readily available, the methods are simple, the synthesis cost is low, and the products have a high yield. Detailed Implementation

[0075] The technical solution of the present invention will be further illustrated below through specific embodiments. Those skilled in the art should understand that the embodiments described are merely illustrative of the present invention and should not be construed as limiting the invention.

[0076] The overall process for preparing the compounds involved in the examples is as follows:

[0077]

[0078] Example 1

[0079] Synthesis of Compound 2

[0080] Sodium tert-butoxide (104.2 g, 1.08 mol, 1.2 eq.) and toluene (1230 mL) were added sequentially to a reaction flask. The mixture was cooled to 5 °C, and tert-butyl dimethoxyphosphonoacetate (232.8 g, 1.04 mol, 1.15 eq.) was added dropwise. The mixture was kept at this temperature for 0.5 h. A solution of compound 1 (123.0 g, 0.903 mol, 1.0 eq.) and toluene (1230 mL) was added dropwise. The mixture was kept at this temperature for 2 h, and the reaction was monitored by GC (Agilent 8890+7697A). A saturated ammonium chloride solution (1000 g) was added dropwise, and the mixture was separated. The organic phase was washed with water (1000 g), concentrated, and dried to obtain 215 g of an oily substance with a purity of 97.0%, a crude yield of 102%, and 3.2% toluene residue.

[0081] Example 2-1

[0082] Synthesis of Compound 3

[0083] Intermediate 2 (210.0 g, 0.896 mol, 1.0 eq.), DBU (273.0 g, 1.793 mol, 2.0 eq.), and nitromethane (218.8 g, 3.585 mol, 4.0 eq.) were added sequentially to a reaction flask and incubated at 25 °C for 20 h. The reaction was monitored by GC (Agilent 8890+7697A). Toluene (1000 mL) was added, followed by water (1000 g), and the mixture was separated. The pH of the organic phase was adjusted to 4 with 1 M hydrochloric acid. The organic phase was washed with water (1000 g) and concentrated to dryness to obtain 264 g of an oily substance with a purity of 96.2%, a crude yield of 100%, and 2.5% toluene residue.

[0084] Example 2-2

[0085] Intermediate 2 (10.0 g, 42.7 mmol, 1.0 eq.), potassium tert-butoxide (9.6 g, 85.6 mmol, 2.0 eq.), and nitromethane (10.4 g, 170.4 mol, 4.0 eq.) were added sequentially to a reaction flask and incubated at 25 °C for 20 h. The reaction was monitored by GC (Agilent 8890+7697A). Toluene (50 mL) was added, followed by water (50 g), and the mixture was separated. The pH of the organic phase was adjusted to 4 with 1 M hydrochloric acid. The organic phase was washed with water (50 g) and concentrated to dryness to obtain 11.7 g of an oily substance with a purity of 92.7%, a crude yield of 93%, and a toluene residue of 2.0%.

[0086] Example 3

[0087] Synthesis of Compound 4

[0088] Intermediate 3 (200.0 g, 0.677 mol, 1.0 eq.), ethanol (1600 mL), and Raney nickel (100.0 g) were added sequentially to a reaction flask. 50% hydrazine hydrate (150.0 g) was added dropwise, and the mixture was kept at 25 °C for 18 h. The reaction was monitored by GC (Agilent 8890+7697A). Diatomaceous earth (100.0 g) was added, the mixture was filtered, washed with an appropriate amount of ethanol, and concentrated to dry ethanol to obtain 160.0 g of oil with a purity of 95.0% and a yield of 89%.

[0089] Example 4-1

[0090] Synthesis of Compound 5

[0091] Intermediate 4 (150.0 g, 0.565 mol, 1.0 eq.) and acetonitrile (1500 mL) were added sequentially to a reaction flask. The mixture was heated to 45 °C, and a solution of D-mandelic acid (73.1 g, 0.480 mol, 0.85 eq.) and acetonitrile (1500 mL) was added dropwise. A solid precipitated during the later stages of addition. The mixture was kept at this temperature for 1 h, cooled to 5 °C, filtered, and dried at 50 °C to obtain 165.5 g of solid. The yield was 70%, the purity was 95.2%, and the chiral purity was 99.0%.

[0092] Example 4-2

[0093] Intermediate 4 (30.0 g, 0.113 mol, 1.0 eq.) and acetonitrile (300 mL) were added sequentially to a reaction flask. The mixture was heated to 45 °C, and a solution of L-mandelic acid (5.2 g, 0.034 mol, 0.30 eq.) and acetonitrile (300 mL) was added dropwise. A solid precipitated during the later stages of addition. The mixture was kept at this temperature for 1 h, cooled to 5 °C, filtered, and the filtrate was concentrated to dryness to obtain 24.1 g of solid, with a yield of 80%, a purity of 93.2%, and a chiral purity of 98.3%.

[0094] Example 5

[0095] Synthesis of Compound 6

[0096] Intermediate 5 (160.0 g, 0.384 mol, 1.0 eq.), MTBE (500 mL), and 20% potassium carbonate solution (500 g) were added sequentially to the reaction flask. The mixture was stirred at room temperature for 0.5 h. The mixture was separated, and the organic phase was washed twice with water (500 mL). The mixture was concentrated to dryness to obtain 100.1 g of the oily substance of compound (6), with a yield of 98%, a purity of 96.6%, and a chiral purity of 99.5%.

[0097] Comparative Example 1

[0098] Intermediate 5 (20.0 g, 0.048 mol, 1.0 eq.), MTBE (60 mL), sodium hydroxide (3.0 g, 0.075 mol, 1.6 eq.) and water (60.0 mL, 3 V) were prepared into a solution and added sequentially to the reaction flask. The mixture was stirred at room temperature for 0.5 h, separated, and the organic phase was washed twice with water (500 mL). The solution was concentrated to dryness to obtain 12.3 g of the oily substance of compound (6), with a yield of 97%, a purity of 55%, and a lactam (impurity) purity of 40%.

[0099] Example 6-1

[0100] Synthesis of Compound 7

[0101] Intermediate 6 (10 g, 37.7 mmol, 1.0 eq.), acetonitrile (50 mL), and zinc bromide (42.4 g, 188.3 mmol, 5 eq.) were added sequentially to a reaction flask, and the mixture was heated to 55 °C and reacted for 5 h, monitored by HPLC. The mixture was filtered, and water (50 mL), EDTA (10 g), and n-butanol (50 mL) were added. The mixture was separated, and the aqueous phase was extracted again with n-butanol (50 mL). The combined organic phases were washed once with water (50 mL), the organic phase was separated, and the mixture was evaporated to dryness under reduced pressure. Water (50 mL) and dichloromethane (50 mL) were added, and the pH was adjusted to 12 with triethylamine. A white solid precipitated, which was filtered. The wet product was slurried with dichloromethane (30 mL) for 1 h, and then filtered. The solid was dried at 50 °C to give 6.7 g, with a yield of 85%. HPLC analysis (Agilent 1260) showed that impurities A and B were not detected.

[0102] Example 6-2

[0103] Synthesis of Compound 7

[0104] Intermediate 6 (10 g, 37.7 mmol, 1.0 eq.), dichloromethane (50 mL), and zinc bromide (42.4 g, 188.3 mmol, 5 eq.) were added sequentially to a reaction flask, and the mixture was heated to reflux for 2 h, monitored by HPLC. The mixture was filtered, and 50 mL of water, 10 g of EDTA, and 50 mL of n-butanol were added. The aqueous phase was separated, and 50 mL of n-butanol was added for extraction. The combined organic phases were washed once with 50 mL of water, and the organic phase was separated and evaporated to dryness under reduced pressure. 50 mL of water and 50 mL of dichloromethane were added, and the pH was adjusted to 10 with triethylamine. A white solid precipitated, which was dried at 40 °C to give 6.8 g of solid, with a yield of 86%. Impurities A and B were not detected.

[0105] Example 6-3

[0106] Synthesis of Compound 7

[0107] Intermediate 6 (10 g, 37.7 mmol, 1.0 eq.), methanol (50 mL), and zinc bromide (42.4 g, 188.3 mmol, 5 eq.) were added sequentially to a reaction flask, and the mixture was heated to 55 °C and reacted for 7 h, monitored by HPLC. The mixture was filtered, and water (50 mL), EDTA (10 g), and n-butanol (50 mL) were added. The mixture was separated, and the aqueous phase was extracted again with n-butanol (50 mL). The combined organic phases were washed once with water (50 mL), the organic phase was separated, and the mixture was evaporated to dryness under reduced pressure. Water (50 mL) and dichloromethane (50 mL) were added, and the pH was adjusted to 11 with triethylamine. A white solid precipitated, which was filtered. The wet product was slurried with dichloromethane (30 mL) for 1 h, and then filtered. The solid was dried at 45 °C to give 6.7 g, with a yield of 85%. Impurities A and B were not detected by HPLC (Agilent 1260).

[0108] Example 6-4

[0109] Synthesis of Compound 7

[0110] Intermediate 6 (10 g, 37.7 mmol, 1.0 eq.), ethanol (50 mL), and zinc bromide (42.4 g, 188.3 mmol, 5 eq.) were added sequentially to a reaction flask, and the mixture was heated to 50 °C and reacted for 8 h, monitored by HPLC. The mixture was filtered, and water (50 mL), EDTA (10 g), and n-butanol (50 mL) were added. The mixture was separated, and the aqueous phase was extracted again with n-butanol (50 mL). The combined organic phases were washed once with water (50 mL), the organic phase was separated, and the mixture was evaporated to dryness under reduced pressure. Water (50 mL) and dichloromethane (50 mL) were added, and the pH was adjusted to 10 with triethylamine. A white solid precipitated, which was filtered. The wet product was slurried with dichloromethane (30 mL) for 1 h, and then filtered. The solid was dried at 50 °C to give 6.5 g, with a yield of 82%. HPLC analysis (Agilent 1260) showed that impurities A and B were not detected.

[0111] Example 6-5

[0112] Synthesis of Compound 7

[0113] Intermediate 6 (10 g, 37.7 mmol, 1.0 eq.), tetrahydrofuran (50 mL), and zinc bromide (42.4 g, 188.3 mmol, 5 eq.) were added sequentially to a reaction flask, and the mixture was heated to 60 °C and reacted for 5 h, monitored by HPLC. The mixture was filtered, and water (50 mL), EDTA (10 g), and n-butanol (50 mL) were added. The mixture was separated, and the aqueous phase was extracted again with n-butanol (50 mL). The combined organic phases were washed once with water (50 mL), the organic phase was separated, and the mixture was evaporated to dryness under reduced pressure. Water (50 mL) and dichloromethane (50 mL) were added, and the pH was adjusted to 10 with triethylamine. A white solid precipitated, which was filtered. The wet product was slurried with dichloromethane (30 mL) for 1 h, filtered, and dried at 50 °C to obtain 6.2 g of solid, with a yield of 78%. HPLC analysis (Agilent 1260) showed that impurities A and B were not detected.

[0114] Example 6-6

[0115] Synthesis of Compound 7

[0116] Intermediate 6 (20 g, 75.4 mmol, 1.0 eq.), acetonitrile (100 mL), sodium iodide (16.9 g, 112.7 mmol, 1.5 eq.), cerium trichloride (37.1 g, 150.5 mmol, 2 eq.), and water (10 mL) were added sequentially to a reaction flask, and the mixture was heated to reflux for 3 h, monitored by HPLC. The acetonitrile was concentrated, and water (100 mL), EDTA (20 g), and n-butanol (100 mL) were added. The mixture was separated, and the aqueous phase was extracted again with n-butanol (100 mL). The combined organic phases were washed once with water (100 mL), the organic phase was separated, evaporated to dryness under reduced pressure, and water (100 mL) and dichloromethane (100 mL) were added. The pH was adjusted to 10 with triethylamine, and a white solid precipitated. The solid was filtered, and the wet product was slurried with dichloromethane (60 mL) for 1 h, and then filtered. 13.4 g of solid was obtained by drying at 40 °C, with a yield of 85%. Impurities A and B were not detected by high performance liquid chromatography (Agilent 1260).

[0117] Examples 6-7

[0118] Synthesis of Compound 7

[0119] Intermediate 6 (10 g, 37.7 mmol, 1.0 eq.), dichloromethane (50 mL), and zinc bromide (42.4 g, 188.3 mmol, 5 eq.) were added sequentially to a reaction flask, and the mixture was heated to reflux for 2 h, monitored by HPLC. The mixture was filtered, and 50 mL of water, 10 g of EDTA, and 50 mL of n-butanol were added. The aqueous phase was separated, and 50 mL of n-butanol was added for extraction. The combined organic phases were washed once with 50 mL of water, and the organic phase was separated and evaporated to dryness under reduced pressure. 50 mL of water and 50 mL of dichloromethane were added, and the pH was adjusted to 8 with triethylamine. A white solid precipitated, which was dried at 40 °C to give 5.7 g of solid, with a yield of 72%. Impurities A and B were not detected.

[0120] Comparative Example 2

[0121] Synthesis of Compound 7

[0122] Compound 6 (10 g, 37.7 mmol, 1.0 eq.) and ethyl acetate (50 mL) were added sequentially to a reaction flask, cooled to 5 °C, and a solution of 4 M HCl in ethyl acetate (94.3 mL, 0.377 mmol, 10 eq.) was added dropwise. The mixture was kept at this temperature for 5 h, and the reaction was monitored by HPLC. Triethylamine was added dropwise to adjust the pH to 10, and the temperature was maintained at 5 °C. A solid precipitated, which was filtered, washed with ethyl acetate (30 mL), and slurried with dichloromethane (30 mL) for 1 h. The solid was dried to obtain 5.8 g of solid, with a yield of 73%. HPLC analysis (Agilent 1260) revealed 0.52% impurity A and 1.23% impurity B.

[0123] Comparative Example 3

[0124] Compound 6 (10 g, 37.7 mmol, 1.0 eq.) and dichloromethane (50 mL) were added sequentially to a reaction flask, cooled to 5 °C, and 36% hydrochloric acid (38.2 g, 0.377 mmol, 10 eq.) was added dropwise. The mixture was kept at this temperature for 5 h, and the reaction was monitored by HPLC. Triethylamine was added dropwise to adjust the pH to 10, and the temperature was controlled to not exceed 25 °C. A solid precipitated, which was filtered, washed with dichloromethane (30 mL), and slurried with DCM (30 mL) for 1 h. The solid was dried to obtain 5.8 g, with a yield of 73%. HPLC analysis (Agilent 1260) showed that impurity A was 0.62% and impurity B was 1.37%.

[0125] Comparative Example 4

[0126] Compound 6 (10 g, 37.7 mmol, 1.0 eq.) and dichloromethane (50 mL) were added sequentially to a reaction flask, cooled to 5 °C, and trifluoroacetic acid (43.0 g, 0.377 mmol, 10 eq.) was added dropwise. The mixture was kept at this temperature for 5 h, and the reaction was monitored by HPLC. Triethylamine was added dropwise to adjust the pH to 10, and the temperature was controlled to not exceed 25 °C. A solid precipitated, which was filtered, washed with dichloromethane (30 mL), and slurried with DCM (30 mL) for 1 h. The solid was dried to obtain 6.0 g of solid, with a yield of 76%. HPLC analysis (Agilent 1260) showed that impurity A was 0.41% and impurity B was 0.78%.

[0127] Comparative Example 5

[0128] Compound 6 (10 g, 37.7 mmol, 1.0 eq.) and formic acid (55.5 g, 1.21 mol, 32 eq.) were added sequentially to a reaction flask. The mixture was heated to 55 °C and maintained at this temperature for 5 h, monitored by HPLC. Formic acid was distilled off at 40–45 °C, leaving 19.8 g. Triethylamine was added dropwise to adjust the pH to 10, and the temperature was controlled to not exceed 25 °C, resulting in the precipitation of a solid. The solid was filtered, washed with dichloromethane (30 mL), and slurried with DCM (30 mL) for 1 h. After drying, 6.8 g of solid was obtained, with a yield of 86%. HPLC analysis (Agilent 1260) revealed 0.08% impurity A and 0.09% impurity B.

[0129] Example 7

[0130] Synthesis of milobalin benzyl sulfonate

[0131] Water (50 mL) and compound 7 (10 g, 47.8 mmol, 1.0 eq) were added to a reaction flask and heated to 55 °C. A solution of BsOH (7.6 g, 48.0 mmol, 1.0 eq) in water (50 mL) was then added dropwise. The mixture was filtered while hot, and the filtrate was gradually cooled, precipitating at approximately 35 °C. The mixture was stirred at room temperature for 1–2 hours, then slowly cooled to 5 °C and stirred for 1 hour. The crystals were filtered, washed with MTBE, and dried under vacuum at 45 °C to constant weight to obtain 16.2 g of compound 8, with a yield of 92% and a purity of 99.8%.

[0132] The 1H NMR data for the product, milobalin benzyl sulfonate, are as follows: 1 H-NMR (400MHz, DMSO): δppm: 1.06(3H,t),1.31-1.33(1H,dd),1.98-2.02(1H,d),2.10(3H,m),2.33(3H,m),2.74(1H ,m), 3.07(1H,d),3.13-3.21(2H,d),5.22(1H,d),7.33-7.44(3H,m),7.62-7.63(2H,m),7.78(3H,m),12.23(1H,m).

[0133] Comparative Example 6

[0134] Add 50 mL of ethanol and compound 7 (10 g, 47.8 mmol, 1.0 eq) to a reaction flask, heat to 55 °C, and then add dropwise a solution of BsOH (7.6 g, 48.0 mmol, 1.0 eq) in ethanol (50 mL). If the solution does not dissolve completely, gradually lower the temperature. Stir the mixture at room temperature for 1–2 hours, then slowly cool to 5 °C and stir for 1 hour. Filter to obtain crystals, wash with MTBE, and dry under vacuum at 45 °C to constant weight to obtain 15.2 g of compound 8, with a yield of 86% and a purity of 99.6%. Using ethanol as a solvent is suitable for laboratory use but not for large-scale production.

[0135] The applicant declares that the present invention illustrates the preparation method of milobalin besylate through the above embodiments, but the present invention is not limited to the above embodiments, that is, it does not mean that the present invention must rely on the above embodiments to be implemented. Those skilled in the art should understand that any improvements to the present invention, equivalent substitutions of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

Claims

1. A method for preparing milobalin benzylsulfonic acid, characterized in that, The preparation method includes the following steps: Compound 6 undergoes a hydrolysis reaction with a hydrolysis reagent, which is zinc bromide or cerium trichloride, in the presence of a solvent. After the hydrolysis reaction is completed, the pH of the reaction solution is adjusted to be alkaline to obtain compound 7. Compound 7 reacts with benzenesulfonic acid to give compound 8, namely milobalin benzenesulfonic acid; The structures of each compound are as follows:

2. The preparation method according to claim 1, characterized in that, The solvent for the hydrolysis reaction is any one or a combination of at least two of acetonitrile, dichloromethane, methanol, ethanol, or tetrahydrofuran; Preferably, the hydrolysis reaction is carried out at a temperature of 40–60°C for 1–8 hours. Preferably, after the hydrolysis reaction is completed, the pH of the reaction solution is adjusted to alkaline using an organic base, preferably pH 8 to 14; Preferably, the organic base is any one of triethylamine, diisopropylethylamine, or ammonia.

3. The preparation method according to claim 1 or 2, characterized in that, The molar ratio of compound 7 to benzenesulfonic acid is 1:0.95-1.2; Preferably, the reaction of compound 7 with benzenesulfonic acid is carried out in a solvent, wherein the solvent is water; Preferably, the specific operation of the reaction between compound 7 and benzenesulfonic acid is as follows: benzenesulfonic acid is added dropwise to a reaction system containing compound 7 at 50-60°C, the reaction is carried out for 0-6 hours, and the mixture is cooled to crystallize, thereby obtaining compound 8; Preferably, the cooling crystallization involves cooling to 30-40°C, then reducing the temperature to 0-10°C at a rate of 5-15°C / h, and stirring for 1-6 hours. Preferably, the specific operation of the reaction between compound 7 and benzenesulfonic acid is as follows: benzenesulfonic acid is added dropwise to a reaction system containing compound 7 at 50-60°C, the reaction is carried out for 0-6 hours, filtered while hot, and then the filtrate is cooled to 30-40°C, and then cooled to 0-10°C at a rate of 5-15°C / h, and stirred for 1-6 hours.

4. The preparation method according to any one of claims 1-3, characterized in that, Compound 6 was prepared by the following method: (1) Compound 1 reacts with tert-butyl dimethoxyphosphonoacetate to give compound 2: (2) Compound 2 reacts with nitromethane to give compound 3; (3) Compound 3 undergoes a nitro reduction reaction to yield compound 4; (4) Compound 4 was resolved by a resolving agent to obtain compound 5; (5) Compound 5 reacts in the presence of an alkaline substance to give compound 6; The structures of each compound are as follows:

5. The preparation method according to claim 4, characterized in that, The molar ratio of compound 1 to tert-butyl dimethoxyphosphonoacetate in step (1) is 1:1.1 to 1.3; Preferably, the reaction in step (1) is carried out in the presence of an alkaline substance; Preferably, the alkaline substance is an organic base; Preferably, the organic base is selected from any one or a combination of at least two of sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, or DBU.

6. The preparation method according to claim 4 or 5, characterized in that, The reaction in step (1) is carried out in a solvent selected from any one or a combination of at least two of toluene, methyl cyclopentyl ether or methyl tert-butyl ether; Preferably, in step (1), compound 1 is added dropwise to the reaction system containing tert-butyl dimethoxyphosphonoacetate; Preferably, the temperature of the reaction system containing dimethoxyphosphonoacetic acid tert-butyl ester is controlled at 0–10 °C, and compound 1 is added dropwise; Preferably, the temperature of the reaction in step (1) is -5 to 15°C and the reaction time is 2 to 10 hours.

7. The preparation method according to any one of claims 4-6, characterized in that, The molar ratio of compound 2 to nitromethane in step (2) is 1:3.5 to 5; Preferably, the reaction in step (2) is carried out in the presence of an alkaline substance; Preferably, the alkaline substance is selected from any one or a combination of at least two of 1,8-diazabicyclo[5.4.0]undec-7-ene, sodium tert-butoxide, or potassium tert-butoxide; Preferably, the reaction temperature in step (2) is 20-30°C and the reaction time is 15-20h.

8. The preparation method according to any one of claims 4-7, characterized in that, The reducing agent used in the nitro reduction reaction in step (3) is Raney nickel and hydrazine hydrate, ammonium chloride and iron powder, or palladium on carbon and hydrogen. Preferably, the nitro reduction reaction in step (3) is carried out in a solvent, wherein the solvent is selected from any one of methanol, ethanol, a mixture of methanol and water, or a mixture of ethanol and water; Preferably, the volume percentage of methanol or ethanol in the mixture of methanol and water or the mixture of ethanol and water is not less than 80%. Preferably, the temperature of the nitro reduction reaction in step (3) is 20-30°C and the reaction time is 15-20h.

9. The preparation method according to any one of claims 4-8, characterized in that, The resolving reagent in step (4) is D-mandelic acid, L-mandelic acid, D-tartaric acid or D-dibenzoyl tartaric acid, preferably D-mandelic acid or D-tartaric acid; Preferably, the separation in step (4) is carried out in a solvent, which is selected from any one or a combination of at least two of acetonitrile, methyl tert-butyl ether or methyl cyclopentyl ether; Preferably, the splitting in step (4) is carried out at a temperature of 40-50°C, and the splitting time is 1-24 hours; Preferably, the alkaline substance in step (5) is a weak base; Preferably, the alkaline substance is any one or a combination of at least two of sodium carbonate, potassium carbonate, ammonia, or triethylamine; Preferably, the reaction in step (5) is carried out at room temperature (15-30°C) for 5 min-5 h. Preferably, the reaction in step (5) is carried out in a solvent selected from any one or a combination of at least two of toluene, methyl tert-butyl ether, or dichloromethane.

10. A method for preparing milobalin benzylsulfonic acid, characterized in that, The preparation method includes the following steps: (1) The temperature of the reaction system containing dimethoxyphosphonoacetate tert-butyl ester is controlled at 0-10℃. Compound 1 is added dropwise. Compound 1 and dimethoxyphosphonoacetate tert-butyl ester are reacted at a molar ratio of 1:1.1-1.3 in the presence of an alkaline substance at -5-15℃ for 2-10 h to obtain compound 2. The alkaline substance is an organic base. The organic base is selected from any one or a combination of at least two of sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, or DBU. (2) Compound 2 and nitromethane react in a molar ratio of 1:3.5 to 5 at 20 to 30 °C for 15 to 20 h in the presence of an alkaline substance to obtain compound 3; the alkaline substance is selected from any one or a combination of at least two of 1,8-diazabicyclo[5.4.0]undec-7-ene, sodium tert-butoxide or potassium tert-butoxide; (3) Compound 3 is subjected to a nitro reduction reaction in a solvent at 20-30°C for 15-20 h under the action of a reducing agent to obtain compound 4; wherein the reducing agent is Raney nickel and hydrazine hydrate, ammonium chloride and iron powder, or palladium on carbon and hydrogen, and the solvent is selected from any one of methanol, ethanol, a mixture of methanol and water, or a mixture of ethanol and water; (4) Compound 4 was subjected to a resolving reaction at 40-50℃ for 1-24 h under the action of a resolving agent to obtain compound 5, wherein the resolving agent was D-mandelic acid, L-mandelic acid, D-tartaric acid or D-dibenzoyl tartaric acid. (5) Compound 5 is reacted in a solvent at room temperature (15-30°C) for 5 min-5 h in the presence of an alkaline substance to obtain compound 6, wherein the alkaline substance is any one or a combination of at least two of sodium carbonate, potassium carbonate, ammonia or triethylamine, and the solvent is selected from any one or a combination of at least two of toluene, methyl tert-butyl ether or dichloromethane. (6) Compound 6 is hydrolyzed at 40-60°C for 1-8 hours under the action of a hydrolysis reagent. After the hydrolysis reaction is completed, the pH of the reaction solution is adjusted to 8-14 to obtain compound 7. The hydrolysis reagent is zinc bromide or cerium trichloride, and the solvent is any one or a combination of at least two of acetonitrile, dichloromethane, methanol, ethanol or tetrahydrofuran. (7) Add benzenesulfonic acid dropwise to a reaction system containing compound 7 at 50-60℃, react for 0-6 hours, cool down to crystallize, and obtain compound 8, namely benzenesulfonic acid milobalin, wherein the molar ratio of compound 7 to benzenesulfonic acid is 1:0.95-1.2, and the solvent of the reaction is water.

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