Method for synthesizing mirogabalin besilate

Abstract

A method for synthesizing mirogabalin besilate. The method comprises the following steps: subjecting a chiral ketene and cyanoacetate to a condensation reaction under the action of ammonium acetate to obtain an unsaturated cyano ester, then subjecting the unsaturated cyano ester and nitromethane to a condensation reaction to obtain a nitro ester, subjecting the nitro ester to high-temperature de-esterification to obtain a chiral nitronitrile, then subjecting same to nitroreduction to obtain a chiral aminonitrile, subsequently hydrolyzing the chiral aminonitrile to obtain a mirogabalin free alkali, and finally salifying the mirogabalin free alkali and benzenesulfonic acid to obtain mirogabalin besilate. In the present invention, a chiral cyclobutane quaternary carbon center is stereoscopically and specifically constructed to obtain a chiral nitro ester having a single stereoscopic configuration, thereby preventing chiral isomer waste generated by chiral isomer resolution, such that chiral column separation or chiral resolution is not required, the production cost is significantly reduced, and the residue of heavy-metal titanium in a product and environmental pollution caused by solid waste heavy-metal titanium are also prevented.

Description

A kind of synthetic method of milopalline besylate Technical Field

[0001] The present invention relates to the field of pharmaceutical chemistry, and in particular to a method for synthesizing milopalline besylate. Background Art

[0002] In January 2019, mirogabalin besilate, 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 neuropathic pain (PNP), including diabetic peripheral neuropathy (DPNP) and postherpetic neuralgia (PHN).

[0003] Patent CN101878193 discloses a synthetic route (reaction formula 2) using racemized ketene 2 as a raw material. First, racemized ketene 2 is subjected to a condensation reaction with tert-butyl phosphate to obtain an unsaturated tert-butyl ester A. A then reacts with nitromethane to produce a nitroester B. B is reduced to obtain a racemic amino acid ester C through nitro reduction. Subsequently, C is separated with a chiral column to obtain a chiral amine D. The chiral amine is hydrolyzed to obtain milobarlin free base. Finally, milobarlin free base is salified with benzenesulfonic acid to obtain milobarlin benzenesulfonate. When this route is used to prepare compound B from compound A, the quaternary carbon center stereoselectivity is not very good, and the generation of stoichiometric chiral isomers causes unnecessary pollution. The isomers must be subjected to chiral separation in subsequent steps. In addition, the hydrolysis of compound D tert-butyl ester needs to be carried out under acidic conditions at high temperature. In this process, positional isomerization of double bonds occurs, resulting in waste double bond isomers that are difficult to remove, which is unfavorable for obtaining a high-purity milobarlin benzenesulfonate bulk drug.

[0004] Patent CN104755456 discloses a synthetic route (reaction formula 3) using racemic enone 2 as a raw material. First, racemic enone 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 Michael addition reaction with nitromethane to obtain a nitroester F. F is defatted at high temperature to obtain a nitroester G. Subsequently, nitroacid G is hydrolyzed and split with s-phenylethylamine to obtain an optically pure nitroacid H. Nitroacid H is reduced by the nitro group to obtain milobarlin free base. Finally, milobarlin free base is salified with benzenesulfonic acid to obtain milobarlin benzenesulfonate. When this route prepares compound F from compound E, since the two ester groups of compound E are chemically equivalent, the stoichiometric diastereomeric waste produced in the reaction must be subjected to chiral separation in subsequent steps, resulting in material waste.

[0005] In addition, the patent also discloses a method for synthesizing chiral nitro acid K, a key intermediate of milobarlin, from chiral enone 2. First, chiral enone 2 undergoes a condensation reaction with triethyl phosphate (EPE) under the action of sodium tert-butoxide to obtain unsaturated ester J, and J then undergoes Michael addition reaction with nitromethane to obtain nitroester K. At this time, due to the poor chiral induction effect of the ester group, the diastereoisomer ratio produced by the quaternary carbon chiral center is 87:13. The 13% chiral isomers produced must be split using chiral amines in the subsequent step to obtain optically pure nitro acid K.

[0006] In summary, the existing technology has disadvantages such as the risk of heavy metal residues caused by the use of heavy metal reagent titanium tetrachloride, poor chirality control of the quaternary carbon center of cyclobutane, and the need for chiral column separation or chiral splitting. It is necessary to explore simple synthetic routes with better chirality control.

[0007] Summary of the Invention

[0008] The present invention provides an improved synthesis method of milopalline besylate, which overcomes the shortcomings of the prior art.

[0009] The core technology of the present invention is to use chiral enone compound 2 as raw material, design and synthesize unsaturated cyanoacetate compound 3 with different substituents on both sides of the double bond, so that when nitromethane undergoes Michael addition reaction to obtain compound 4, the chiral substrate is used to control the construction of a stereospecific chiral cyclobutane quaternary carbon center. See the following technical scheme for details:

[0010] The present invention uses a chiral enone compound 2 as a starting material. First, the chiral enone compound 2 undergoes a condensation reaction with cyanoacetic acid ester under the action of ammonium acetate to obtain an unsaturated cyano ester compound 3. Then, the unsaturated cyano ester compound 3 undergoes a condensation reaction with nitromethane to obtain a nitroester compound 4. The nitroester compound 4 is deesterified at high temperature to obtain a chiral nitronitrile compound 5. Then, the nitro group is reduced to obtain a chiral aminonitrile compound 6. Subsequently, the chiral aminonitrile compound 6 is hydrolyzed to obtain milobarlin free base. Finally, the milobarlin free base is salified with benzenesulfonic acid to obtain milobarlin benzenesulfonate.

[0011] Wherein: R is a C1-C4 alkyl group or a benzyl group.

[0012] Specifically, the synthesis method of milopalline besylate of the present invention comprises the following steps:

[0013] Step 1: Chiral enone compound 2 undergoes condensation reaction with cyanoacetate in the presence of ammonium acetate and acetic acid to obtain unsaturated cyanoester compound 3;

[0014] Step 2: Under alkaline conditions, the unsaturated cyano ester compound 3 undergoes a condensation reaction with nitromethane to obtain the nitroester compound 4;

[0015] Step 3: In a high boiling point solvent, the nitroester compound 4 is deesterified at high temperature in the presence of an inorganic salt to obtain the chiral nitronitrile compound 5;

[0016] Step 4: The chiral nitronitrile compound 5 is subjected to nitro reduction in the presence of a reducing agent to obtain the chiral aminonitrile compound 6;

[0017] Step 5: In an alcohol solvent, the chiral aminonitrile compound 6 is hydrolyzed under alkaline conditions to obtain the milobarlin free base compound 7;

[0018] Step 6: Milobalin free base compound 7 is reacted with benzenesulfonic acid to form a salt to obtain milobalin benzenesulfonate.

[0019] According to the synthesis method of the present invention, wherein, in step 1,

[0020] 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;

[0021] The condensation reaction is carried out in toluene, wherein the mass volume ratio (g / mL) of the chiral enone compound 2 to toluene is 1:5-10, preferably 1:6;

[0022] The reaction temperature ranges from 50 to 110°C, preferably from 65 to 70°C.

[0023] According to the synthesis method of the present invention, wherein, in step 2,

[0024] The base is selected from triethylamine, tripropylamine, tributylamine or diisopropylethylamine, preferably triethylamine;

[0025] The molar ratio of the unsaturated cyanoester compound 3, nitromethane and base is 1:2.0-4.0:0.3-3: preferably 1:3.0:1.5;

[0026] The condensation reaction is carried out in toluene, wherein the mass volume ratio (g / mL) of the unsaturated cyano ester compound 3 to toluene is 1:5-10, preferably 1:7;

[0027] The reaction temperature range is 0-30°C, preferably 0-5°C.

[0028] According to the synthesis method of the present invention, wherein, in step 3,

[0029] The inorganic salt is selected from sodium chloride, potassium chloride, sodium sulfate, potassium sulfate, sodium bromide or potassium bromide, etc., preferably potassium chloride;

[0030] The high boiling point solvent is selected from dimethylformamide, dimethylacetamide, dimethyl sulfoxide, toluene or xylene, etc., preferably dimethyl sulfoxide;

[0031] The molar ratio of the nitroester compound 4 to the inorganic salt is 1:0.4 to 2.0, preferably 1:0.7;

[0032] The mass volume ratio of the nitroester compound 4 and the high boiling point solvent is 1:1-10; preferably 1:1.4;

[0033] The reaction temperature ranges from 80 to 140°C, preferably from 90 to 100°C.

[0034] According to the synthesis method of the present invention, wherein, in step 4,

[0035] The reducing agent can be selected from iron powder / acetic acid, zinc powder / acetic acid, Raney nickel / H2, Pd / C / H2, etc.;

[0036] When the reducing agent is iron powder / acetic acid or zinc powder / acetic acid:

[0037] The molar ratio of the chiral nitronitrile compound 5 to iron powder or zinc powder and acetic acid is 1:5-10:5-15, preferably 1:6-8:8-12, and more preferably 1:6:10;

[0038] The organic solvent is selected from methanol, ethanol, isopropanol or tert-butanol, etc., preferably methanol;

[0039] The mass volume ratio (g / mL) of the chiral nitronitrile compound 5 and the organic solvent is 1:5 to 12; preferably 1:6 to 10, and more preferably 1:6.8;

[0040] When the reducing agent is Raney nickel / hydrogen or palladium carbon / hydrogen:

[0041] The mass ratio of the chiral nitronitrile compound 5 to the reducing agent is 1:0.03 to 0.1, preferably 1:0.05;

[0042] The organic solvent is selected from methanol, ethanol, isopropanol or tert-butanol, etc., preferably methanol;

[0043] The mass volume ratio (g / mL) of the chiral nitronitrile compound 5 and the organic solvent is 1:5-12, preferably 1:6-10, and more preferably 1:6.8.

[0044] According to the synthesis method of the present invention, wherein, in step 5,

[0045] The base may be selected from sodium hydroxide, potassium hydroxide or lithium hydroxide;

[0046] The molar ratio of the chiral aminonitrile compound 6 to the base is 1:2 to 15; preferably 1:5 to 10, more preferably 1:7.5;

[0047] The alcohol solvent is selected from methanol, ethanol, n-propanol, butanol or isopropanol, preferably ethanol;

[0048] The mass 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;

[0049] The reaction temperature range is 60-100°C, preferably 60-70°C.

[0050] According to the synthesis method of the present invention, wherein, in step 6,

[0051] Milobalin free base compound 7 is salified with benzenesulfonic acid in water;

[0052] The mass ratio (g / g) of the milobarlin free base compound 7 to water is 1:6.

[0053] On the other hand, if racemic enone compound 2 is used as the 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 (the synthesis route is shown below).

[0054] Wherein: R is C1-C4 alkyl or benzyl

[0055] Specifically, the synthesis method of the optically pure chiral aminonitrile compound 6 of the present invention comprises the following steps:

[0056] Step 1: The racemic enone compound 2 undergoes a condensation reaction with cyanoacetate in the presence of ammonium acetate and acetic acid to obtain the racemic unsaturated cyanoester compound 3;

[0057] Step 2: Under alkaline conditions, the racemic unsaturated cyano ester compound 3 undergoes a condensation reaction with nitromethane to obtain the racemic nitro ester compound 4;

[0058] Step 3: In a high boiling point solvent, the racemic nitroester compound 4 is deesterified at high temperature in the presence of an inorganic salt to obtain the racemic nitronitrile compound 5;

[0059] Step 4: The racemic nitronitrile compound 5 is subjected to nitro reduction in the presence of a reducing agent to obtain the racemic aminonitrile compound 6;

[0060] Step 5: The racemic aminonitrile compound 6 is resolved by mandelic acid to obtain an optically pure chiral aminonitrile compound 6.

[0061] According to the method for synthesizing the optically pure chiral aminonitrile compound 6 of the present invention, the process conditions of steps 1 to 4 are the same as the process conditions of steps 1 to 4 of the method for synthesizing milopalline besylate of the present invention.

[0062] According to the method for synthesizing the optically pure chiral aminonitrile compound 6 of the present invention, in step 5,

[0063] The mass ratio of the racemic aminonitrile compound 6 to mandelic acid is: 1:0.8-0.9;

[0064] The mandelic acid used in the resolution was D-mandelic acid. Beneficial effects

[0065] Compared with the prior art, the advantages of the present invention are:

[0066] (1) The prior art uses a symmetrical molecular structure malonate to condense with an enone compound 2, and the chirality of the quaternary carbon center is poorly controlled during the subsequent nitromethane condensation. The present invention designs and synthesizes an unsaturated cyanoacetate compound 3 with different substituents on both sides of the double bond, and utilizes the chirality of the chiral enone substrate itself to induce the nitromethane to undergo a Michael addition reaction to stereospecifically construct a chiral cyclobutane quaternary carbon center, thereby obtaining a chiral nitroester compound 4 with a single stereoconfiguration.

[0067] (2) The present invention uses a condensation reagent, ethyl cyanoacetate, to introduce a prochiral source, thereby achieving the construction of a stereospecific chiral quaternary carbon of cyclobutane, avoiding the chiral isomer waste generated by chiral isomer resolution, eliminating the need for chiral column separation or chiral resolution, and significantly reducing production costs.

[0068] (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 residual heavy metal titanium in the product and the environmental pollution caused by solid waste heavy metal titanium. DETAILED DESCRIPTION

[0069] The present invention will be described in detail below in conjunction with specific embodiments and examples, and the advantages and various effects of the present invention will be more clearly presented. It should be understood by those skilled in the art that these specific embodiments and examples are for illustrating the present invention, rather than limiting the present invention.

[0070] The analysis conditions of the compounds of the present invention are as follows: 1 H NMR, 13 C NMR was measured using a Bruker Avance 400 nuclear magnetic resonance instrument; HRMS was measured using a Waters Xevo G2-XS QTof high-resolution mass spectrometer, and the ion source was an ESI source.

[0071] Example 1 Preparation of Compound 3

[0072] To a reaction vessel, 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. The temperature was raised to 65-70°C and the reaction was refluxed at this temperature to remove water. The reaction was monitored by liquid chromatography until completion (15-20 hours). The reaction solution was cooled to room temperature and washed twice with 600 mL of water. 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, with a yield of 95%. HRMS m / z (ESI): C 13 H 16 NO2[M+H + ]Theoretical calculated value: 218.1176, measured value: 218.1172.

[0073] 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).

[0074] 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.

[0075] By changing the enone compound 2 and the cyanoacetic acid ester, the compound 3 was prepared according to the process parameters and operation steps described in Example 1, as shown in the following table.

[0076] The NMR data of compound 3 obtained in Example 3 are as follows:

[0077] 1 H-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).

[0078] 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.

[0079] Example 7: Preparation of Compound 4

[0080] To a reaction vessel, 217 g of compound 3, 183 g of nitromethane, and 1500 mL of toluene were added dropwise. 150 g of triethylamine was slowly added dropwise at 0-5°C. The mixture was incubated for 18-24 hours. After the reaction, the temperature was lowered to 0-5°C. 10% hydrochloric acid and 500 mL of water were added, stirred, and the layers separated. The organic layer was washed once with 1000 mL of water. The organic layer was separated and evaporated to dryness under reduced pressure to obtain 250 g of chiral nitroester compound 4, with a yield of 90%. HRMS m / z (ESI): C 14 H 19 N2O4[M+H + ]Theoretical calculated value: 279.1339, measured value: 279.1332.

[0081] 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).

[0082] 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.

[0083] Example 8: Using racemic compound 3 instead of chiral compound 3, racemic compound 4 was prepared according to the process steps described in Example 3 with a yield of 88%.

[0084] Example 9: Preparation of Compound 5

[0085] In a reaction flask, 73 g of compound 4, 100 mL of dimethyl sulfoxide (DMSO), 19.8 g of water, and 26 g of sodium sulfate were added. The temperature was raised to 95-100°C and the reaction was maintained for 18-22 hours. After the reaction, the temperature was lowered to room temperature and filtered. The filtrate was added with 250 mL of ethyl acetate, the material layer was evaporated to dryness, and the residue was purified by column chromatography using ethyl acetate:n-hexane = 1:10 as a developing solvent to obtain 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.

[0086] [α] 25 D(C=1, ethanol)=-124.8°

[0087] 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).

[0088] 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.

[0089] Example 10: Using racemic compound 4 instead of chiral compound 4, racemic compound 5 was prepared according to the process steps described in Example 5 with a yield of 88%.

[0090] Example 11: Preparation of Compound 6

[0091] 336g of iron powder, 220g of compound 5, 600g of acetic acid, and 1500mL of methanol were placed in a reaction vessel. The temperature was then raised to 70-75°C and the reaction was maintained for 18-22 hours. After the reaction was complete, the reaction solution was cooled to room temperature and filtered. The filtrate was concentrated to dryness under reduced pressure to obtain 171g of compound 6 as an oil, with a yield of 90%. HRMS m / z (ESI): C 12 H 19 N2[M+H + ]Theoretical calculated value: 191.1543, measured value: 191.1548.

[0092] [α]25 D(C=1, ethanol)=-131°

[0093] 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).

[0094] 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.

[0095] Example 12: Preparation of Compound 6

[0096] 11 g of palladium carbon (5%), 220 g of compound 5, and 1500 mL of methanol were added to a pressure vessel, and then hydrogen was introduced to a pressure of 0.3 mPa. The reaction was kept at room temperature for 4 h. After the reaction was complete, the reaction liquid was filtered and the filtrate was concentrated to dryness under reduced pressure to obtain 180 g of compound 6 as an oily substance, with a yield of 95%.

[0097] [α] 25 D(C=1, ethanol)=-130°

[0098] HRMS m / z(ESI):C 12 H 19 N2[M+H + ]Theoretical calculated value: 191.1543, measured value: 191.1546.

[0099] Example 13: Compound 5 was used to replace chiral compound 5 and the racemic compound 6 was prepared according to the process steps described in Example 11 with a yield of 92%.

[0100] Example 14: Chiral resolution of racemic compound 6

[0101] In a reaction vessel, 190 g of racemic compound 6, 155 g of D-mandelic acid, and 1000 mL of acetonitrile were added. The temperature was raised to 50° C. and stirred to dissolve the mixture. The temperature was then slowly lowered to 0° C. over 3 hours to precipitate a large amount of white crystals. The resulting crystals were filtered and vacuum-dried to obtain optically pure D-mandelate salt of compound 6, which was then dissolved in ethanol and the pH was adjusted to 9 with aqueous sodium hydroxide solution. The ethanol in the 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, in a yield of 40%.

[0102] [α] 25 D(C=1, ethanol)=-130°

[0103] Example 15: Preparation of Milobalin Free Base

[0104] At -5-0°C, 190 g of compound 6, 570 mL of ethanol, and 1500 g of a 20% aqueous sodium hydroxide 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 the reaction was complete (24 hours). The pH of the resulting solution was adjusted to 6-7 with 10% hydrochloric acid, resulting in the precipitation of a large amount of white solid. The solid was filtered and vacuum dried to obtain 199 g of milopalline, with a yield of 95%. HRMS m / z (ESI): C 12 H 20 NO2[M+H + ]Theoretical calculated value: 210.1489, measured value: 210.1485.

[0105] 1 H-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).

[0106] Example 16: Preparation of Milobalin Besylate

[0107] 200 g of milopalline, 162 g of benzenesulfonic acid, and 1200 mL of purified water were added to a reaction vessel, the temperature was raised to 70-75 ° C, stirred and dissolved, and then slowly lowered to 0 ° C within 3 hours to precipitate a large amount of white crystals. The obtained crystals were filtered and vacuum dried to obtain 309 g of milopalline benzenesulfonate (white crystals), with a yield of 88%.

[0108] The specific embodiments of the present invention are described in detail above, but they are merely preferred examples of the present invention. From a technical perspective, based on the synthetic routes of the present invention, optimization of the reaction conditions in the described steps and improvements in the methods for obtaining the intermediates involved in the present invention are also considered to be 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 of the present invention are also within the scope of the present invention.

Claims

1. A synthetic method of milnacipran benzenesulfonate, and its reaction formula is shown as follows: Specifically, it includes the following steps: Step 1: The chiral enone compound 2 undergoes a condensation reaction with cyanoacetate in the presence of ammonium acetate and acetic acid to obtain the unsaturated cyanoester 3; Step 2: Under basic conditions, the unsaturated cyanoester compound 3 undergoes a condensation reaction with nitromethane to obtain the nitroester compound 4; Step 3: In a high-boiling solvent, the nitroester compound 4 undergoes high-temperature de-esterification in the presence of an inorganic salt to obtain the chiral nitrile compound 5; Step 4: The chiral nitrile compound 5 is reduced by a reducing agent to reduce the nitro group to obtain the chiral aminonitrile compound 6; Step 5: In an alcohol solvent, the chiral aminonitrile compound 6 undergoes hydrolysis under basic conditions to obtain the milnacipran free base compound 7; Step 6: The milnacipran free base compound 7 forms a salt with benzenesulfonic acid to obtain milnacipran besylate.

2. The synthesis method of milnacipran besylate according to claim 1, characterized in that: In step 1, 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.

3. The synthesis method of milnacipran besylate according to claim 2, characterized in 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.

4. The synthesis method of milnacipran besylate according to claim 1, characterized in that: In step 1, the reaction temperature range is 50 - 110 °C.

5. The synthesis method of milnacipran besylate according to claim 4, characterized in that: In step 1, the reaction temperature range is 65 - 70 °C.

6. The synthesis method of milnacipran besylate according to claim 1, characterized in that: In step 2, the base used is selected from triethylamine, tripropylamine, tributylamine, or diisopropylethylamine.

7. The synthesis method of milnacipran besylate according to claim 1, characterized in that: In step 2, the molar ratio of the unsaturated cyanoester compound 3, nitromethane, and the base is 1:2.0 - 4.0:1.0 - 1.

5.

8. The synthesis method of milnacipran besylate according to claim 1, characterized in that: In step 2, the reaction temperature range is 0 - 30 °C.

9. The synthesis method of milnacipran besylate according to claim 8, characterized in that: In step 2, the reaction temperature range is 15 - 20 °C.

10. The synthesis method of milnacipran besylate according to claim 1, characterized in that: In step 3, the high-boiling solvent is selected from dimethylformamide, dimethylacetamide, dimethyl sulfoxide, toluene, or xylene.

11. The synthesis method of milnacipran besylate according to claim 1, characterized in that: In step 3, the reaction temperature range is 80 - 140 °C.

12. The synthesis method of milnacipran besylate according to claim 1, characterized in that: In step 3, the inorganic salt is selected from sodium chloride, potassium chloride, sodium sulfate, potassium sulfate, sodium bromide, or potassium bromide.

13. The synthesis method of milnacipran besylate according to claim 1, It is characterized in that: In step 4, the reducing agent can be selected from iron powder / acetic acid, zinc powder / acetic acid, Raney nickel / hydrogen, or palladium on carbon / hydrogen.

14. The synthesis method of milnacipran besylate according to claim 1, It is characterized in that: In step 5, the base used is selected from sodium hydroxide, potassium hydroxide or lithium hydroxide.

15. The synthesis method of milnacipran besylate according to claim 1, It is characterized in that: In step 5, the reaction temperature range is 60-100 °C.

16. The synthesis method of milnacipran besylate according to claim 1, It is characterized in that: In step 5, the alcohol solvent is selected from methanol, ethanol, n-propanol, butanol or isopropanol.

17. The synthesis method of milnacipran besylate according to claim 1, It is characterized in that: In step 5, the mass-volume ratio of the chiral aminonitrile compound 6 to the alcohol solvent is 1:2-15.

18. A method for synthesizing optically pure chiral aminonitrile 6, which comprises using a racemic enone compound 2 as a raw material, obtaining a racemic aminonitrile compound 6 according to the process conditions of steps 1 to 4 of claim 1, and subsequently, obtaining the optically pure chiral aminonitrile compound 6 by resolving the racemic aminonitrile compound 6 with mandelic acid. The synthetic route is as follows:

19. The key ester intermediate for synthesizing milnacipran has the following structure:

20. The key cyano intermediate for synthesizing milnacipran has the following structure:

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