A method for synthesizing milobalin benzylsulfonic acid

Abstract

This invention provides a method for synthesizing milobalin benzylsulfonic acid, comprising the following steps: a chiral enone undergoes a condensation reaction with cyanoacetate in the presence of ammonium acetate to obtain an unsaturated cyano ester; next, the unsaturated cyano ester undergoes a condensation reaction with nitromethane to obtain a nitro ester; the nitro ester is then deesterified at high temperature to obtain a chiral nitro nitrile, which is then reduced to a chiral amino nitrile; subsequently, the chiral amino nitrile is hydrolyzed to obtain the free base of milobalin; finally, the free base of milobalin is salted with benzylsulfonic acid to obtain milobalin benzylsulfonic acid. This invention stereospecifically constructs a chiral cyclobutane quaternary carbon center to obtain a chiral nitro ester with a single stereoconfiguration, avoiding the chiral isomer waste generated by chiral isomer resolution, eliminating the need for chiral column separation or chiral resolution, significantly reducing production costs, and simultaneously avoiding the environmental pollution caused by residual heavy metal titanium in the product and solid waste heavy metal titanium.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, and specifically to a method for synthesizing milobalin benzylsulfonic acid. Background Technology

[0002] In January 2019, Mirogabalinbesilate, developed by Daiichi Sankyo Pharmaceutical Co., Ltd. of Japan, was approved for marketing by the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan for the treatment of peripheral nerve pain (PNP), including diabetic peripheral neuropathy (DPNP) and postherpetic neuralgia (PHN).

[0003]

[0004] Patent CN101878193 discloses a synthetic route (reaction formula two) using racemic ketone 2 as a raw material. First, racemic ketone 2 undergoes a condensation reaction with tert-butyl phosphate to obtain unsaturated tert-butyl ester A. A then undergoes Mac addition with nitromethane to obtain nitro ester B. B is reduced by nitro to obtain racemic amino acid ester C. Subsequently, C is separated by chiral column chromatography to obtain chiral amine D. The chiral amine is hydrolyzed to obtain the free base of milobalin. Finally, the free base of milobalin is salted with benzenesulfonic acid to obtain milobalin benzenesulfonic acid. This route has poor stereoselectivity at the quaternary carbon center during the preparation of compound B from compound A, resulting in stoichiometric chiral isomers and causing unnecessary contamination. These isomers must be chirally separated in subsequent steps. Furthermore, the hydrolysis of tert-butyl ester D requires high-temperature acidic conditions. During this process, positional isomerism of the double bonds occurs, producing difficult-to-remove double bond isomer waste, which is detrimental to obtaining high-purity milobalin benzenesulfonic acid raw material.

[0005]

[0006] Patent CN104755456 discloses a synthetic route (reaction formula 3) using racemic ketone 2 as a raw material. First, racemic ketone 2 undergoes a condensation reaction with diethyl malonate under the catalysis of Lewis acid titanium tetrachloride to obtain an unsaturated ester E. E then undergoes a Mac addition reaction with nitromethane to obtain a nitro ester F. F is degreased at high temperature to obtain a nitro ester G. Subsequently, nitro acid G is hydrolyzed and resolved with s-phenylethylamine to obtain optically pure nitro acid H. The nitro group of nitro acid H is reduced to obtain the free base of milobalin. Finally, the free base of milobalin forms a salt with benzenesulfonic acid to obtain milobalin benzenesulfonic acid. In this route, the preparation of compound F from compound E is problematic because the two ester groups of compound E are chemically equivalent. The stoichiometric diastereomers generated during the reaction require chiral resolution in subsequent steps, resulting in material waste.

[0007]

[0008]

[0009] In addition, the patent also discloses a method for synthesizing chiral nitric acid K, a key intermediate of milobalin, from chiral enone 2. First, chiral enone 2 undergoes a condensation reaction with triethyl acetyl phosphate (EPE) under the action of sodium tert-butoxide to obtain an unsaturated ester J. J then undergoes a Mac addition reaction with nitromethane to obtain nitro ester K. At this point, due to the poor chiral induction effect of the ester group, the ratio of diastereomers generated by the quaternary carbon chiral center is 87:13. The 13% chiral isomers generated must be resolved by chiral amines in subsequent steps to obtain optically pure nitric acid K.

[0010]

[0011] In summary, existing technologies have drawbacks such as the risk of heavy metal residues from the use of titanium tetrachloride as a heavy metal reagent, poor chiral control of the quaternary carbon center of cyclobutane, and the need for chiral column separation or chiral resolution. It is necessary to explore simpler synthetic routes with better chiral control. Summary of the Invention

[0012] This invention provides an improved method for synthesizing milobalin benzylsulfonic acid, which overcomes the shortcomings of existing technologies.

[0013] The core technology of this invention is to use chiral enone compound 2 as a raw material, and to design and synthesize unsaturated cyanoacetate compound 3 with different substituents on both sides of the double bond. This allows for the construction of a stereospecific chiral cyclobutane quaternary carbon center through chiral substrate control when nitromethane undergoes a Mac addition reaction to obtain compound 4. See the following technical solution for details:

[0014] This invention uses chiral enone compound 2 as a starting material. First, chiral enone compound 2 undergoes a condensation reaction with cyanoacetate under the action of ammonium acetate to obtain unsaturated cyano ester compound 3. Second, unsaturated cyano ester compound 3 undergoes a condensation reaction with nitromethane to obtain nitro ester compound 4. Nitro ester compound 4 is deesterified at high temperature to obtain chiral nitro nitrile compound 5. Then, the nitro group is reduced to obtain chiral amino nitrile compound 6. Subsequently, chiral amino nitrile compound 6 is hydrolyzed to obtain milobalin free base. Finally, milobalin free base is salted with benzenesulfonic acid to obtain milobalin benzenesulfonic acid.

[0015]

[0016] Wherein: R is a C1-C4 alkyl or benzyl group.

[0017] Specifically, the method for synthesizing milobalin benzylsulfonic acid according to the present invention includes the following steps:

[0018] Step 1: Chiral enone compound 2 undergoes a condensation reaction with cyanoacetate in the presence of ammonium acetate and acetic acid to obtain unsaturated cyano ester compound 3;

[0019] Step 2: Under alkaline conditions, unsaturated cyano ester compound 3 undergoes a condensation reaction with nitromethane to obtain nitro ester compound 4;

[0020] Step 3: In a high-boiling-point solvent, nitro ester compound 4 is deesterified at high temperature in the presence of inorganic salts to obtain chiral nitro nitrile compound 5;

[0021] Step 4: Chiral nitro nitrile compound 5 is reduced to chiral amino nitrile compound 6 under the action of a reducing agent;

[0022] Step 5: In an alcohol solvent, chiral aminonitrile compound 6 is hydrolyzed under alkaline conditions to obtain milobalin free base compound 7;

[0023] Step 6: Milobalin free base compound 7 is reacted with benzenesulfonic acid to form a salt to obtain milobalin benzenesulfonic acid.

[0024] According to the synthesis method of the present invention, in step 1,

[0025] The molar ratio of the chiral enone compound 2, cyanoacetate, acetic acid, and ammonium acetate is 1:1.0-1.5:0.5-0.8:0.5-0.8, preferably 1:1.4:0.6:0.6;

[0026] The condensation reaction is carried out in toluene, wherein the mass-to-volume ratio (g / mL) of the chiral enone compound 2 to toluene is 1:5-10; preferably 1:6.

[0027] The reaction temperature range is 50–110°C; preferably 65–70°C.

[0028] According to the synthesis method of the present invention, in step 2,

[0029] The base is selected from triethylamine, tripropylamine, tributylamine or diisopropylethylamine, preferably triethylamine;

[0030] The molar ratio of the unsaturated cyano ester compound 3, nitromethane, and base is 1:2.0-4.0:0.3-3; preferably 1:3.0:1.5.

[0031] The condensation reaction is carried out in toluene, wherein the mass-to-volume ratio (g / mL) of the unsaturated cyano ester compound 3 to toluene is 1:5-10; preferably 1:7.

[0032] The reaction temperature range is 0–30°C; preferably 0–5°C.

[0033] According to the synthesis method of the present invention, in step 3,

[0034] The inorganic salt is selected from sodium chloride, potassium chloride, sodium sulfate, potassium sulfate, sodium bromide, or potassium bromide, etc., with potassium chloride being preferred;

[0035] The high-boiling-point solvent is selected from dimethylformamide, dimethylacetamide, dimethyl sulfoxide, toluene or xylene, etc., with dimethyl sulfoxide being preferred;

[0036] The molar ratio of the nitro ester compound 4 to the inorganic salt is 1:0.4 to 2.0, preferably 1:0.7;

[0037] The mass-to-volume ratio of the nitro ester compound 4 to the high-boiling-point solvent is 1:1-10; preferably 1:1.4.

[0038] The reaction temperature range is 80–140°C, preferably 90–100°C.

[0039] According to the synthesis method of the present invention, in step 4,

[0040] The reducing agent can be selected from iron powder / acetic acid, zinc powder / acetic acid, Raney nickel / H2, Pd / C / H2, etc.;

[0041] When the reducing agent is iron powder / acetic acid or zinc powder / acetic acid:

[0042] The molar ratio of the chiral nitronitrile compound 5 to iron powder or zinc powder and acetic acid is 1:5 to 10:5 to 15, preferably 1:6 to 8:8 to 12, and more preferably 1:6:10;

[0043] The organic solvent is selected from methanol, ethanol, isopropanol or tert-butanol, etc., with methanol being preferred;

[0044] The mass-to-volume ratio (g / mL) of the chiral nitronitrile compound 5 to the organic solvent is 1:5 to 12; preferably 1:6 to 10, and more preferably 1:6.8.

[0045] When the reducing agent is Raney nickel / hydrogen or palladium on carbon / hydrogen:

[0046] The mass ratio of the chiral nitronitrile compound 5 to the reducing agent is 1:0.03 to 0.1, preferably 1:0.05;

[0047] The organic solvent is selected from methanol, ethanol, isopropanol or tert-butanol, etc., with methanol being preferred;

[0048] The mass-to-volume ratio (g / mL) of the chiral nitronitrile compound 5 to the organic solvent is 1:5 to 12; preferably 1:6 to 10, and more preferably 1:6.8.

[0049] According to the synthesis method of the present invention, in step 5,

[0050] The alkali may be selected from sodium hydroxide, potassium hydroxide, or lithium hydroxide;

[0051] The molar ratio of chiral aminonitrile compound 6 to the base is 1:2 to 15; preferably 1:5 to 10, more preferably 1:7.5;

[0052] The alcohol solvent is selected from methanol, ethanol, n-propanol, butanol or isopropanol, with ethanol being preferred;

[0053] The mass-to-volume ratio (g / mL) of the chiral aminonitrile compound 6 to the alcohol solvent is 1:2 to 15, preferably 1:2 to 8, and more preferably 1:3;

[0054] The reaction temperature range is 60–100°C; preferably 60–70°C.

[0055] According to the synthesis method of the present invention, in step 6,

[0056] Milobalin free base compound 7 forms a salt with benzenesulfonic acid in water;

[0057] The mass ratio (g / g) of the milobalin free alkali compound 7 to water is 1:6.

[0058] On the other hand, if racemic enone compound 2 is used as a raw material, racemic aminonitrile compound 6 can be obtained according to the above process conditions. Aminonitrile compound 6 is resolved by mandelic acid to obtain optically pure chiral aminonitrile compound 6 (synthetic route is shown below).

[0059]

[0060] Wherein: R is a C1-C4 alkyl or benzyl group.

[0061] Specifically, the method for synthesizing optically pure chiral aminonitrile compound 6 of the present invention includes the following steps:

[0062] Step 1: Racemic enone compound 2 undergoes a condensation reaction with cyanoacetate in the presence of ammonium acetate and acetic acid to obtain racemic unsaturated cyano ester compound 3;

[0063] Step 2: Under alkaline conditions, racemic unsaturated cyano ester compound 3 undergoes a condensation reaction with nitromethane to obtain racemic nitro ester compound 4;

[0064] Step 3: In a high-boiling-point solvent, racemic nitro ester compound 4 is deesterified at high temperature in the presence of inorganic salts to obtain racemic nitro nitrile compound 5.

[0065] Step 4: Racemic nitro nitrile compound 5 is reduced to racemic amino nitrile compound 6 under the action of a reducing agent;

[0066] Step 5: Racemic aminonitrile compound 6 was resolved by mandelic acid to obtain optically pure chiral aminonitrile compound 6.

[0067] According to the method for synthesizing optically pure chiral aminonitrile compound 6 of the present invention, the process conditions of steps 1 to 4 are the same as those of steps 1 to 4 of the method for synthesizing milobalin benzenesulfonic acid as described above.

[0068] According to the method for synthesizing optically pure chiral aminonitrile compound 6 of the present invention, in step 5,

[0069] The mass ratio of racemic aminonitrile compound 6 to mandelic acid is 1:0.8-0.9;

[0070] The mandelic acid used for the separation was D-mandelic acid.

[0071] Beneficial effects

[0072] Compared with the prior art, the advantages of the present invention are:

[0073] (1) The existing technology uses malonic acid ester with symmetrical molecular structure to condense with ketene compound 2. The chirality of the quaternary carbon center is not well controlled during the subsequent condensation of nitromethane. The present invention designs and synthesizes unsaturated cyanoacetic acid ester compound 3 with different substituents on both sides of the double bond. The chirality of the chiral ketene substrate itself is used to induce nitromethane to undergo a Mc addition reaction to stereospecifically construct the chiral cyclobutane quaternary carbon center, thereby obtaining a chiral nitro ester compound 4 with a single stereoconfiguration.

[0074] (2) By using the condensation reagent ethyl cyanoacetate, the present invention introduces a pre-chiral source, thereby realizing the construction of stereospecific chiral quaternary carbons of cyclobutane, avoiding the chiral isomer waste generated by chiral isomer separation, eliminating the need for chiral column separation or chiral separation, and significantly reducing production costs.

[0075] (3) The present invention uses ammonium acetate instead of titanium tetrachloride in the prior art as a condensation catalyst, which has significant cost advantages and avoids the environmental pollution caused by the residue of heavy metal titanium in the product and the heavy metal titanium in solid waste. Detailed Implementation

[0076] The present invention will be described in detail below with reference to specific embodiments and examples, thereby making the advantages and various effects of the present invention more clearly apparent. Those skilled in the art should understand that these specific embodiments and examples are for illustrative purposes only and are not intended to limit the present invention.

[0077] The analytical conditions for the compounds described in this invention are as follows: 1 H NMR, 13C NMR was measured using a Bruker Avance 400 NMR spectrometer; HRMS was measured using a Waters Xevo G2-XS QTof high-resolution mass spectrometer with an ESI source.

[0078] Example 1: Preparation of Compound 3

[0079]

[0080] 50 g of chiral enone compound 2, 50.9 g of methyl cyanoacetate, 17 g of ammonium acetate, 13.2 g of acetic acid, and 300 mL of toluene were added to a reaction vessel. The mixture was heated to 65-70 °C and refluxed at this temperature to separate the water. Liquid chromatography was monitored until the reaction was complete (15-20 hours). The reaction solution was cooled to room temperature, washed twice with 600 mL of water, and the organic layer was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain 75.7 g of compound 3, yield: 95%. HRMS m / z (ESI): C 13 H 16 NO2[M+H + Theoretical value: 218.1176, measured value: 218.1172.

[0081] 1 H-NMR (400MHz, CDCl3) δ: 5.32 (m, 1H), 4.16 (br, 1H), 3.79 (s, 3H), 3.49 (m, 1H), 2.99 ( m, 1H), 2.84-2.70 (m, 2H), 2.29 (m, 1H), 2.08 (q, J=6.4Hz, 2H), 1.03 (t, J=6.4Hz, 3H).

[0082] 13 C-NMR (100MHz, CDCl3) δ: 188.07, 161.65, 149.95, 118.89, 113.83, 99.44, 52.27, 42.41, 40.74, 38.91, 32.70, 24.19, 12.07.

[0083] Compound 3 was prepared by changing the ketone compound 2 and cyanoacetate according to the process parameters and operating steps described in Example 1, as shown in the examples in the table below.

[0084]

[0085]

[0086] NMR data of compound 3 obtained in Example 3:

[0087] 1H-NMR (400MHz, CDCl3) δ: 5.37 (m, 1H), 4.45 (br, 1H), 4.25 (m, 2H), 3.45 (m, 1H), 3.00 (m, 1H), 2.8 8-2.74 (m, 2H), 2.30 (m, 1H), 2.12 (q, J=6.4Hz, 2H), 1.34 (t, J=6.4Hz, 3H), 1.03 (t, J=6.4Hz, 3H).

[0088] 13 C-NMR (100MHz, CDCl3) δ: 187.36, 161.15, 149.83, 118.87, 113.80, 99.85, 61.34, 59.29, 42.36, 38.85, 32.63, 24.15, 14.08, 12.03.

[0089] Example 7: Preparation of Compound 4

[0090]

[0091] 217 g of compound 3, 183 g of nitromethane, and 1500 mL of toluene were added to a reaction vessel. 150 g of triethylamine was slowly added dropwise at 0–5 °C. After the addition was complete, the reaction was maintained at this temperature for 18–24 hours. After the reaction was complete, the temperature was lowered to 0–5 °C, and 10% hydrochloric acid and 500 mL of water were added. The mixture was stirred to separate the layers. The organic layer was washed once with 1000 mL of water, separated, and dried under reduced pressure to obtain 250 g of chiral nitro ester compound 4. Yield: 90%. HRMS m / z (ESI): C 14 H 19 N₂O₄[M+H + Theoretical value: 279.1339, measured value: 279.1332.

[0092] 1 H-NMR (400MHz, CDCl3) δ: 5.35 (m, 1H), 4.82-4.72 (m, 2H), 3.97 (m, 1H), 3.75 (s, 1H), 3.21 (m, 1H), 2.89 (m, 2H), 2.54-2.40 (m, 3H), 2.14 (m, 3H), 1.72 (m, 1H), 1.09 (t, J=6.4Hz, 3H).

[0093] 13 C-NMR (100MHz, CDCl3) δ: 164.51, 153.54, 118.51, 114.16, 79.32, 53.32, 52.59, 45.80, 42.24, 41.48, 34.81, 30.84, 24.40, 12.11.

[0094] Example 8: Racemic compound 4 was prepared by replacing chiral compound 3 with racemic compound 3 according to the process steps described in Example 3, with a yield of 88%.

[0095] Example 9: Preparation of Compound 5

[0096]

[0097] 73 g of compound 4, 100 mL of dimethyl sulfoxide (DMSO), 19.8 g of water, and 26 g of sodium sulfate were added to a reaction flask. The mixture was heated to 95–100 °C and reacted for 18–22 h. After the reaction was completed, the mixture was cooled to room temperature, filtered, and 250 mL of ethyl acetate was added to the filtrate. The filtrate was dried, and the residue was subjected to column chromatography with ethyl acetate:n-hexane = 1:10 as the eluent to give 55 g of compound 5 as an oily liquid, with a yield of 95% and a purity of 95%. HRMS m / z (ESI):C 12 H 17 N2O2[M+H + Theoretical calculated value: 221.1258, measured value: 221.1252.

[0098] [α] 25 D(C=1, ethanol)=-124.8°

[0099] 1 H-NMR (400MHz, CDCl3) δ: 5.35 (br, 1H), 4.73 (s, 2H), 3.19 (m, 1H), 2.91 (m, 1H), 2.64 (s, 2H), 2.54 (m, 1H), 2.29 (m, 1H), 2.16 (m, 3H), 1.61 (m, 1H), 1.10 (t, J=6.4Hz, 3H).

[0100] 13 C-NMR (100MHz, CDCl3) δ: 152.98, 119.27, 117.10, 80.45, 51.67, 43.15, 42.27, 35.39, 30.33, 24.36, 22.59, 12.31.

[0101] Example 10: Racemic compound 5 was prepared by replacing chiral compound 4 with racemic compound 4 according to the process steps described in Example 5, with a yield of 88%.

[0102] Example 11: Preparation of Compound 6

[0103]

[0104] 336 g of iron powder, 220 g of compound 5, 600 g of acetic acid, and 1500 mL of methanol were added to a reaction vessel. The temperature was then raised to 70–75 °C and maintained for 18–22 h. After the reaction was complete, the reaction solution was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure to dryness to obtain 171 g of compound 6 as an oil, yield: 90%. HRMS m / z (ESI): C 12 H 19 N2[M+H + Theoretical value: 191.1543, measured value: 191.1548.

[0105] [α] 25 D(C=1, ethanol)=-131°

[0106] 1 H-NMR (400MHz, CDCl3) δ: 5.35 (br, 1H), 4.79 (br, 2H), 3.69 (m, 2H), 2.96 (m, 1H), 2.69 (m, 2H), 2.42 (m, 2H), 2.08-1.94 (m, 5H), 1.61 (m, 1H), 1.04 (t, J=6.4Hz, 3H).

[0107] 13 C-NMR (100MHz, CDCl3) δ: 165.58, 147.65, 123.01, 69.01, 54.54, 48.34, 42.13, 41.72, 39.01, 30.92, 23.82, 12.33.

[0108] Example 12: Preparation of Compound 6

[0109]

[0110] 11g palladium on carbon (5%), 220g compound 5, and 1500mL methanol were added to a pressure vessel, and then hydrogen was introduced to a pressure of 0.3mPa. The reaction was kept at room temperature for 4h. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain 180g of compound 6 as an oily substance. Yield: 95%.

[0111] [α] 25 D(C=1, ethanol)=-130°

[0112] HRMS m / z(ESI):C 12 H 19 N2[M+H + Theoretical value: 191.1543, measured value: 191.1546.

[0113] Example 13: Racemic compound 6 was prepared by replacing chiral compound 5 with compound 5 according to the process steps described in Example 11, with a yield of 92%.

[0114] Example 14: Chiral resolution of racemic compound 6

[0115]

[0116] 190 g of racemic compound 6, 155 g of D-mandelic acid, and 1000 mL of acetonitrile were added to a reaction vessel. The mixture was heated to 50 °C and stirred until dissolved. Then, the temperature was slowly lowered to 0 °C over 3 hours, resulting in the precipitation of a large amount of white crystals. The crystals were filtered and dried under vacuum to obtain optically pure D-mandelic acid salt of compound 6. The salt was then dissolved in ethanol, and the pH was adjusted to 9 with an aqueous sodium hydroxide solution. The ethanol residue was removed, and the mixture was extracted with 500 mL of ethyl acetate. The organic layer was concentrated under reduced pressure to obtain 76 g of optically pure compound 6, yield: 40%.

[0117] [α] 25 D(C=1, ethanol)=-130°

[0118] Example 15: Preparation of Milobalin Free Base

[0119]

[0120] At -5 to 0°C, 190 g of compound 6, 570 mL of ethanol, and 1500 g of 20% sodium hydroxide aqueous solution were added to a reaction vessel. The temperature was then raised to 60–70°C, and the reaction was monitored by liquid chromatography until complete (24 hours). The pH of the synthesis solution was adjusted to 6–7 using 10% hydrochloric acid, resulting in the precipitation of a large amount of white solid. The solid was filtered, filtered again, and vacuum dried to obtain 199 g of milobalin, yield: 95%. HRMS m / z (ESI): C 12 H 20 NO2[M+H + Theoretical value: 210.1489, measured value: 210.1485.

[0121] 1H-NMR (400MHz, CD3OD) δ: 5.38 (dd, J = 1.7, 3.7 Hz, 1H), 3.18 (d, J = 13.0 Hz, 1H), 3.14 (d, J = 13.0 Hz, 1H), 3.10 (m, 1H), 2.85 (q, J = 7.5 Hz, 1H), 2.51 (d, J = 1 6.2Hz, 1H), 2.46-2.53 (m, 1H), 2.46 (d, J = 16.2Hz, 1H), 2.14 (q, J = 7.4Hz, 2 H), 2.08-2.03 (m, 2H), 1.48 (dd, J=7.5, 12.5Hz, 1H), 1.10 (t, J=7.4Hz, 3H).

[0122] Example 16: Preparation of Milobalin Benzylsulfonic Acid

[0123]

[0124] 200g milobalin, 162g benzenesulfonic acid, and 1200mL purified water were added to a reaction vessel. The mixture was heated to 70-75℃ and stirred until dissolved. Then, the temperature was slowly lowered to 0℃ over 3 hours, resulting in the precipitation of a large amount of white crystals. The crystals were filtered and dried under vacuum to obtain 309g milobalin benzenesulfonic acid (white crystals), yield: 88%.

[0125] The specific embodiments of the present invention have been described in detail above, but they are only preferred embodiments of the present invention. From a technical perspective, optimizations to the reaction conditions in the described implementation steps and method improvements made to obtain the intermediates involved in the present invention, based on the synthetic route of the present invention, should also be considered within the scope of protection of the present invention. Therefore, the present invention is not limited to the specific embodiments described above. For those skilled in the art, any equivalent modifications and substitutions to the present invention are also within the scope of the present invention.

Claims

1. A method for synthesizing milobalin benzyl sulfonate, the reaction formula of which is shown below: Specifically, the following steps are included: Step 1 : The chiral enone compound 2 undergoes condensation with cyanoacetate in the presence of ammonium acetate, acetic acid to give the unsaturated cyanoester 3, wherein, The molar ratio of the chiral enone compound 2, cyanoacetate, acetic acid, and ammonium acetate is 1:1.0-1.5:0.5-0.8:0.5-0.8, and the reaction temperature range is 50-110℃. Step 2: Under alkaline conditions, unsaturated cyano ester compound 3 undergoes a condensation reaction with nitromethane to obtain nitro ester compound 4; Step 3: In a high-boiling-point solvent, nitro ester compound 4 is deesterified at high temperature in the presence of inorganic salt to obtain chiral nitro nitrile compound 5. The high-boiling-point solvent is selected from dimethylformamide, dimethylacetamide, dimethyl sulfoxide, toluene or xylene, and the inorganic salt is selected from sodium chloride, potassium chloride, sodium sulfate, potassium sulfate, sodium bromide or potassium bromide. The reaction temperature range is 80 to 140°C. Step 4: Chiral nitro nitrile compound 5 is reduced to chiral amino nitrile compound 6 under the action of a reducing agent; Step 5: In an alcohol solvent, chiral aminonitrile compound 6 is hydrolyzed under alkaline conditions to obtain milobalin free base compound 7; Step 6: Milobalin free base compound 7 is reacted with benzenesulfonic acid to form a salt to obtain milobalin benzenesulfonic acid.

2. The process for the synthesis of milorin benzenesulfonate according to claim 1, characterized by the fact that: In step 1, the molar ratio of the chiral enone compound 2, cyanoacetate, acetic acid, and ammonium acetate is 1:1.4:0.6:0.

6.

3. The process for the synthesis of milorin benzenesulfonate according to claim 1, characterized by the fact that: In step 1, the reaction temperature range is 65 to 70°C.

4. The process for the synthesis of milorin benzenesulfonate according to claim 1, characterized by the fact that: In step 2, the base used is selected from triethylamine, tripropylamine, tributylamine, or diisopropylethylamine.

5. The method for synthesizing milobalin benzylsulfonic acid according to claim 1, characterized in that: In step 2, the molar ratio of the unsaturated cyano ester compound 3, nitromethane, and base is 1:2.0 to 4.0:1.0 to 1.

5.

6. The method for synthesizing milobalin benzylsulfonic acid according to claim 1, characterized in that: In step 2, the reaction temperature range is 0 to 30°C.

7. The method for synthesizing milobalin benzylsulfonic acid according to claim 6, characterized in that: In step 2, the reaction temperature range is 15 to 20°C.

8. The method for synthesizing milobalin benzylsulfonic acid according to claim 1, characterized in that: In step 4, the reducing agent is selected from iron powder / acetic acid, zinc powder / acetic acid, Raney nickel / hydrogen, or palladium on carbon / hydrogen.

9. The method for synthesizing milobalin benzylsulfonic acid according to claim 1, characterized in that: In step 5, the alkali used is selected from sodium hydroxide, potassium hydroxide, or lithium hydroxide.

10. The method for synthesizing milobalin benzylsulfonic acid according to claim 1, characterized in that: In step 5, the reaction temperature range is 60 to 100°C.

11. The method for synthesizing milobalin benzylsulfonic acid according to claim 1, characterized in that: In step 5, the alcohol solvent is selected from methanol, ethanol, n-propanol, butanol or isopropanol.

12. The method for synthesizing milobalin benzylsulfonic acid according to claim 1, characterized in that: In step 5, the mass-to-volume ratio of chiral aminonitrile compound 6 to alcohol solvent is 1:2 to 15.

13. A method for synthesizing an optically pure chiral aminonitrile 6, comprising using a racemic enone compound 2 as a starting material, obtaining a racemic aminonitrile compound 6 according to the process conditions of steps 1 to 4 of claim 1, and subsequently resolving the racemic aminonitrile compound 6 by mandelic acid to obtain an optically pure chiral aminonitrile compound 6, the synthetic route being shown below:

14. The key ester intermediate for the synthesis of milobalin has the following structure:

15. The key cyano intermediate for the synthesis of milobalin has the following structure: 。

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