Synthesis method of miloabalin or acid salt thereof

Abstract

The invention relates to a synthesis method of milobalin or acid salt thereof, and belongs to the technical field of medicine synthesis. In order to solve the problem that chiral resolution needs to be adopted in the prior art, the invention provides a synthesis method of miloabalin or an acid salt thereof, which comprises the following steps: under the action of an organic strong base, carrying out Michael addition reaction on a compound shown as a formula III and acetonitrile in a non-polar organic solvent at a low temperature of-50 DEG C or below to obtain an intermediate product; under the alkaline condition, the intermediate product is subjected to an oxidation reaction and a hydrolysis reaction under the action of an oxidizing agent, after the reaction is finished, an intermediate product is obtained through acidification, and the intermediate product is subjected to a high-temperature decarboxylation reaction in an aprotic solvent to obtain a compound of a formula VI; and carrying out Hofmann degradation reaction on the compound of formula VI to obtain the compound of formula I miloabalin or miloabalin acid salt. The method has the advantages of high stereoselectivity, no need of chiral resolution operation, avoidance of the problem of large material loss caused by resolution, high chiral purity and high yield.

Description

Technical Field

[0001] This invention relates to a method for synthesizing milobalin or its acid salt, belonging to the field of pharmaceutical synthesis technology. Background Technology

[0002] Mirogabalinbesilate, a gabapentin derivative, is used to treat peripheral neuropathic pain. Developed by Daiichi Sankyo Co., Ltd., it is a novel selective calcium channel α2δ ligand. On January 8, 2019, Mirogabalinbesilate, developed by Daiichi Sankyo, received marketing approval from the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan. It is primarily used to treat diabetic peripheral neuropathy, postherpetic neuralgia, and fibromyalgia. It boasts advantages such as high safety and good tolerability and is developing into a world-class neuropathic pain treatment drug with broad market prospects. The structural formula of mirogabalinbesilate is as follows:

[0003]

[0004] The synthetic routes reported in existing literature, such as those reported by Daiichi Sankyo Pharmaceutical Co., Ltd., use (1R,5S)-3-ethyl-bicyclo[3.2.0]heptane-3-en-6-one as the starting material. The reaction proceeds via HWE, followed by a reaction with nitromethane to form an intermediate. This intermediate is then subjected to nitro reduction, resolution with D-mandelic acid, and detert-butylation, finally yielding milobalin benzylsulfonic acid. However, this route generates double-bond isomers on the five-membered ring during detert-butylation, which are difficult to remove. To avoid this problem, the company optimized the route by first detert-butylating the intermediate formed with nitromethane, then resolving and reducing it, and finally forming a salt to obtain milobalin benzylsulfonic acid. The synthetic routes for the two reactions described above are as follows:

[0005]

[0006] However, both routes require the separation of chiral compounds, which is difficult to operate, results in significant product loss, and is costly.

[0007] For example, existing Chinese patent literature (publication number: CN104755456A) discloses a method using (1R,5S)-3-ethyl-bicyclo[3.2.0]heptane-3-en-6-one as the starting material, first reacting it with diethyl malonate to obtain an intermediate, then reacting it with sodium cyanide, and then resolving, decarboxylating, and reducing it to obtain compound I. The synthetic route is as follows:

[0008]

[0009] As can be seen from the above synthetic route, although this route does not use the more expensive dimethylphosphonoacetate tert-butyl ester, it uses highly toxic sodium cyanide, which is dangerous to operate, and the reaction products still need to be separated, resulting in a low overall yield.

[0010] In summary, existing routes either involve chiral separation, resulting in significant losses, or involve highly toxic substances such as sodium cyanide, which are difficult to operate and environmentally unfriendly. They all have certain drawbacks for industrialization. Therefore, it is necessary to improve upon existing technologies and provide a route that uses readily available raw materials, has a simple process, does not require chiral separation, and has a higher yield. Summary of the Invention

[0011] To address the problems existing in the prior art, this invention provides a method for synthesizing milobalin or its acid salt, solving the problems of avoiding chiral resolution and the use of highly toxic substances, thereby improving operational safety.

[0012] The objective of this invention is achieved through the following technical solution: a method for synthesizing milobalin or its acid salt, the method comprising the following steps:

[0013] A. Under the action of a strong organic base, the compound of formula III is reacted with acetonitrile in a nonpolar organic solvent at a low temperature below -50℃ to obtain the intermediate compound of formula IV.

[0014]

[0015] B. Under alkaline conditions, the compound of formula IV undergoes an oxidation reaction in the presence of an oxidizing agent, converting the cyano group into an amide group, and the ester group undergoes a hydrolysis reaction. After the reaction is completed, it is acidified to obtain the compound of formula V.

[0016]

[0017] C. Compound V is subjected to a high-temperature decarboxylation reaction in an aprotic solvent to obtain compound VI;

[0018]

[0019] D. Compound VI of formula VI is degraded by Hoffmann reaction to obtain compound I, Milobalin;

[0020]

[0021] The synthesis of milobalin acid salts also includes reacting milobalin (compound of formula I) with an acid to form a salt to obtain milobalin acid salts (compound of formula I).

[0022] This invention improves the synthetic route of milobalin by using compound III as a substrate. Under low-temperature conditions below -50°C and the action of a strong organic base, the α-hydrogen of acetonitrile is removed to form a carbanion. This carbanion then undergoes Michael addition with the electron-deficient olefin group in compound III, selectively forming the intermediate compound IV with the desired stereoconfiguration. The reaction between the carbanion formed by acetonitrile and compound III exhibits high stereoselectivity, eliminating the need for chiral resolution and avoiding significant material loss associated with resolution. It offers advantages such as high chiral purity and high yield, effectively avoiding the drawbacks of post-reaction chiral resolving agents and significantly reducing costs. Furthermore, using acetonitrile not only provides high reaction efficiency and good stereoselectivity (chiral ee value exceeding 99%), but also improves safety by replacing the highly hazardous cyanide cyanide reaction, facilitating operator procedures and industrial production. The cyano group is then oxidized by an oxidant to form a stable amide group, followed by high-temperature decarboxylation. This ensures complete removal of the carboxyl group from one molecule, improving conversion rate and selective decarboxylation. Finally, a Hoffmann degradation reaction yields the primary amine, avoiding the need for high-pressure equipment required for reduction and preventing the generation of byproducts such as hydroxylamine and azo compounds. This process further enhances product yield and purity, resulting in strong market competitiveness. The aforementioned milobalin acid salts can be acid salts of inorganic acids, such as milobalin hydrochloride and milobalin sulfate; or acid salts of organic acids, such as milobalin benzenesulfonic acid.

[0023] In the above-mentioned method for synthesizing milobalin or its acid salt, preferably, the Michael addition reaction temperature in step A is -60℃ to -80℃. By combining the low-temperature conditions with the action of a strong organic base, the α-hydrogen of acetonitrile in the raw material can be more effectively removed to form a carbanion, which then selectively undergoes Michael addition with the unsaturated double bond groups of electron-deficient olefins. This results in high stereoselectivity, forming a single-configuration chiral intermediate with superior chiral purity. The obtained intermediate does not require chiral resolution, thus achieving high chiral purity. This avoids the use of resolving agents such as chiral acids for chiral resolution, reduces product loss, and better ensures product yield and quality, achieving an ee value of over 99% and a yield of over 90%. As a further preferred option, the Michael addition reaction temperature is -70℃ to -78℃.

[0024] In the above-described method for synthesizing milobalin or its acid salts, preferably, the strong organic base in step A is selected from one or more of n-butyllithium, tert-butyllithium, isopropyllithium, and tert-butylsodium; the nonpolar organic solvent is selected from one or more of cyclopentyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, and isopropyl ether. The strong organic base promotes the reaction in the forward direction more effectively. The amount of nonpolar organic solvent used can be determined according to the general synthetic reaction methods in the art, but preferably, the amount of nonpolar organic solvent is 6 to 12 times the mass of the compound of formula III.

[0025] In the above-described method for synthesizing milobalin or its acid salts, the amount of raw materials used in step A can be determined according to general molar equivalents used in chemical synthesis. For the strong organic base, a catalytic amount can be added to promote the reaction. To better improve the utilization rate of raw materials and reduce waste, preferably, the molar ratio of compound III: acetonitrile: strong organic base in step A is 1:1-2:1-2. More preferably, the molar ratio of compound III: acetonitrile: strong organic base is 1:1.1-1.3:1.1-1.5.

[0026] In the above-described method for synthesizing milobalin or its acid salts, preferably, the alkaline condition in step B is the presence of an inorganic base, selected from one or more of alkali metal hydroxides, carbonates, and bicarbonates; the oxidant is selected from hydrogen peroxide. By simultaneously presenting alkaline conditions and an oxidant, the oxidation and hydrolysis reactions in this step can be completed in the same reaction system, simplifying the operation. Furthermore, the oxidation reaction forms an amide group, and the ester group is hydrolyzed into a carboxylic acid group under the action of the base. This results in better stability of the amide group, allowing for more efficient removal of a molecule of carboxylic acid group during the subsequent high-temperature decarboxylation reaction, while the amide group remains unaffected. This facilitates better conversion into the desired intermediate and offers the advantage of high intermediate product yield. The aforementioned alkali metal hydroxides are selected from strong alkaline substances such as sodium hydroxide, potassium hydroxide, and lithium hydroxide; carbonates can be sodium carbonate, potassium carbonate, etc.; bicarbonates can be sodium bicarbonate, potassium bicarbonate, etc.; in order to better utilize the raw materials, as a further preferred option, the molar ratio of the compound of formula IV: oxidant: base is 1:5.0~7.0:3.0~8.0.

[0027] In the above-described method for synthesizing milobalin or its acid salts, preferably, the oxidation and hydrolysis reactions in step B are carried out in an alcohol solvent, which is selected from one or more of methanol, ethanol, propanol, butanol, and isopropanol. The amount of alcohol solvent used can be any amount commonly used in chemical synthesis, but preferably the mass of the alcohol solvent is 8 to 12 times the mass of the compound of formula IV.

[0028] In the above-described method for synthesizing milobalin or its acid salt, preferably, the oxidation reaction in step B is carried out at a temperature of 25°C to 35°C, and the hydrolysis reaction is carried out at a temperature of 25°C to 35°C.

[0029] In the above-described method for synthesizing milobalin or its acid salt, preferably, the temperature of the high-temperature decarboxylation reaction in step C is 100℃ to 150℃; the aprotic solvent is selected from one or more of DMSO, DMF, xylene, DMAC, and water. By controlling the reaction temperature within the above range, the removal of one molecule of carboxylic acid group can be effectively achieved, and the carbonization of intermediates due to excessive temperature during the reaction process can be effectively avoided, thus preventing excessive impurities from affecting the purity of the product and better ensuring the yield and purity of the product. Simultaneously, conducting the reaction in the above-described reaction solvent also facilitates a uniform reaction. As a further preferred embodiment, the high-temperature decarboxylation reaction is carried out in the presence of an inorganic salt, selected from one or more of lithium bromide, sodium bromide, lithium chloride, sodium chloride, and magnesium chloride. By activating the carboxyl group in the reaction system under the action of the inorganic salt, the removal of one molecule of carboxylic acid group is better promoted, making decarboxylation easier. Preferably, the molar ratio of the compound of formula IV to the inorganic salt is 1:3.0 to 5.0. As a further preferred option, the temperature of the high-temperature decarboxylation reaction is preferably 120°C to 140°C.

[0030] In the above-described method for synthesizing milobalin or its acid salt, preferably, the acid in step D is benzenesulfonic acid, and the acid salt of the compound of formula I, milobalin, is benzenesulfonic acid milobalin.

[0031] In the above-described method for synthesizing milobalin or its acid salt, preferably, the Hoffmann degradation reaction in step D is carried out under the action of sodium hypochlorite and an alkali metal hydroxide, and the temperature of the Hoffmann degradation reaction is 20°C to 30°C. This effectively ensures the efficient progress of the reaction and promotes the degradation of the amide group to form an amino group. The alkali metal hydroxide can be a strong alkaline substance such as sodium hydroxide or potassium hydroxide, and the sodium hypochlorite can be sodium hypochlorite pentahydrate, etc. To better utilize the raw materials, as a further preferred embodiment, it is preferable that the molar ratio of the compound of formula VI: sodium hypochlorite: alkali metal hydroxide is 1:1.0 to 2.0:2.5 to 3.5. It is also preferable that the molar ratio of the compound of formula VI: sodium hypochlorite: alkali metal hydroxide is 1:1.2 to 1.5:2.6 to 3.0.

[0032] In the above-described method for synthesizing milobalin or its acid salts, it is preferable that both the Hoffmann degradation reaction and the salt formation reaction in step D are carried out in an organic solvent. Further, it is preferable that the organic solvent is selected from one or more of acetonitrile, anisole, acetone, and tert-butyl methyl ether. The molar ratio of the compound of formula I to benzenesulfonic acid may also be 1:1.0 to 1.05.

[0033] In the above-described method for synthesizing milobalin or its acid salts, preferably, the compound of formula III in step A is obtained by the following method:

[0034] Under the catalysis of Lewis acid, compound (1R,5S)-3-ethyl-bicyclo[3.2.0]heptane-3-en-6-one of formula II was reacted with diethyl malonate via an HWE reaction to generate compound III;

[0035]

[0036] The method for synthesizing milobalin or its acid salt according to the present invention can be represented by the following chemical reaction formula:

[0037]

[0038] In summary, compared with the prior art, the present invention has the following advantages:

[0039] 1. Using compound III as a substrate, under low-temperature conditions below -50℃ and the action of a strong organic base, the α-hydrogen of acetonitrile can be removed to form a carbanion. This carbanion can then undergo Michael addition with the electron-deficient olefin group in compound III, selectively forming the intermediate compound IV with the desired stereoconfiguration. This method exhibits high stereoselectivity, eliminates the need for chiral resolution, avoids the problem of large material loss caused by resolution, and has the advantages of high chiral purity and high yield.

[0040] 2. By oxidizing the cyano group with an oxidant to form a stable amide group, followed by high-temperature decarboxylation, the carboxyl group of one molecule can be completely removed, which is beneficial to improving the conversion rate and selective decarboxylation. Finally, the primary amine is obtained by Hoffmann degradation reaction, avoiding the use of high-pressure equipment required for reduction and avoiding the generation of byproducts such as hydroxylamine and azo. This is more conducive to improving the yield and purity of the product and has good market competitiveness. Detailed Implementation

[0041] The technical solution of the present invention will be further described in detail below through specific embodiments, but the present invention is not limited to these embodiments.

[0042] Example 1

[0043] Synthesis of Compound III

[0044]

[0045] 700.00 g of cyclopentyl methyl ether and 83.48 g (0.29 mol) of tetraisopropyl titanate were added to a 2 L clean reaction flask. The mixture was purged with nitrogen three times. Then, under controlled temperature conditions of 5℃~10℃, 153.20 g (0.81 mol) of titanium tetrachloride was added dropwise. After the addition was complete, the mixture was stirred for 30 min, and then 129.37 g (0.81 mol) of diethyl malonate was added. After the addition was complete, the temperature was lowered to 0℃~5℃, and 100 g of (1R,5S)-3-ethyl-bicyclo[3.2.0]heptane-3-en-6-one was added dropwise. 0.00 g (0.73 mol) was added, and the temperature was raised to 25℃~30℃ for 3 h. After the reaction was completed, the temperature was lowered to 0℃~5℃, and 500 g of water was added dropwise for extraction and separation. The organic layer was collected after standing. The organic phase was washed successively with 200 g of 3.5% hydrochloric acid solution, 200 g of 3.0% sodium bicarbonate aqueous solution, and 200 g of water. Finally, the washed organic phase was subjected to vacuum distillation to remove the solvent, and 203.18 g of concentrated compound of formula III was obtained, with a yield of 99% and a purity of 95.03%.

[0046] Example 2

[0047] Synthesis of Formula IV compounds

[0048]

[0049] 700 g of 2-methyltetrahydrofuran and 17.70 g (0.43 mol) of acetonitrile were added to a 3 L reaction flask. The mixture was purged with nitrogen three times, cooled to -78 °C, and 267.44 mL (0.43 mol) of a 1.6 M n-butyllithium cyclohexane solution was added dropwise while maintaining the temperature. After the addition was complete, the mixture was stirred for 30 min. Then, 100 g (0.36 mol) of compound III was added dropwise. After the addition was complete, the mixture was slowly heated to 25 °C and stirred for 1 h. After the reaction was complete, the mixture was opened... The temperature was initially lowered to 5°C, and controlled below 5°C. 500g of a 5% (w / w) ammonium chloride aqueous solution was added dropwise, followed by 700g of dichloromethane. After stirring for 15 minutes, extraction and separation were performed. The organic phase was collected and washed twice with 200g of water each time. The collected organic phase was distilled to remove dichloromethane, yielding 104.57g of a concentrated compound of formula IV. The yield was 91%, the purity was 93.47%, and the chiral ee value was 98.8%-99.5%.

[0050] As can be seen from the chiral purity quality described above, this synthetic route can achieve the advantage of high chiral purity quality without the need for chiral resolving agents.

[0051] Example 3

[0052] Preparation of compound V

[0053]

[0054] 400g of ethanol and 100g (0.31mol) of compound IV were added to a 2L clean reaction flask. At room temperature, 313.09g (1.56mol) of a 20% sodium hydroxide aqueous solution was added dropwise. After the addition was complete, the mixture was stirred and heated to 50℃-70℃ for 3-5 hours. Then, 177.47g (1.56mol) of a 30% hydrogen peroxide solution was added dropwise. After the addition was complete, the mixture was stirred and reacted for 3 hours. After the reaction was complete, 300g of isopropyl acetate was added and the temperature was lowered to 0℃. Acidification was achieved by adding 161.89 g (1.59 mol) of 36% hydrochloric acid solution at 5℃ to adjust the pH of the system to 5-7. The mixture was stirred for 10 min, allowed to stand and separate into layers, and the organic phase was collected. The collected organic phase was washed successively with 100 g of 5% sodium bisulfite aqueous solution and 100 g of water. After confirming the absence of hydrogen peroxide residue by testing with starch-potassium iodide paper, the organic phase was subjected to vacuum distillation to remove the solvent, yielding 78.61 g of concentrated compound V with a yield of 95% and a purity of 92.5%.

[0055] Example 4

[0056] Synthesis of Compound VI

[0057]

[0058] In a 2L clean reaction flask, 360g DMSO, 40g water, 80g of compound V, and 30g sodium chloride were added. The mixture was purged with nitrogen three times, and the temperature was slowly raised to 120℃~125℃ under stirring for a high-temperature decarboxylation reaction for 5h. After the reaction was completed, the temperature was slowly lowered to room temperature, and then 320g water and 320g isopropyl acetate were added for stirring and extraction for 15min. The mixture was allowed to stand and separate into layers, and the organic phase was collected. The organic phase was washed once with 100g water, and then the solvent was removed by vacuum distillation to obtain 62.81g of concentrated compound VI, with a yield of 94% and a purity of 92.3%.

[0059] Example 5

[0060] Preparation of compound I, milobalin

[0061]

[0062] 150g of water and 50g (0.21mol) of compound VI were added to a 1L clean reaction flask. At room temperature, 105.35g (0.53mol) of a 20% sodium hydroxide aqueous solution was added dropwise. After the addition was complete, the temperature was slowly lowered to 0℃~5℃. Then, 38.13g (0.23mol) of sodium hypochlorite pentahydrate was added and the temperature was maintained for 1 hour. The temperature was then raised to 25℃ and maintained at 25℃~30℃ with stirring for another 3 hours. After the reaction was completed... The mixture was cooled to 0℃~5℃, 200g of dichloromethane was added, and 53.41g (0.53mol) of 36% hydrochloric acid was added dropwise to adjust the pH to 6~7. A white solid precipitated out. After stirring at 0℃~5℃ for 1h, the mixture was filtered. The wet product was then vacuum dried at 40℃ for 20h to obtain 31.04g of a white solid product, compound I, milobalin, with a purity of 98.28% and an ee value ≥98.8%. Based on the starting material of formula II, the overall yield of the first 5 steps was 70.38%.

[0063] Example 6

[0064] Preparation of milobalin benzyl sulfonate

[0065]

[0066] 300g of acetonitrile and 30g (0.14mol) of compound I, milobalin, were added to a reaction flask. A mixture of 22.67g (0.14mol) benzenesulfonic acid and 60g of acetonitrile was slowly added dropwise while maintaining the temperature at 20℃~25℃. After the addition was complete, the mixture was kept at this temperature for 1 hour, then cooled to 0℃~5℃ for 2 hours for analytical crystallization. The mixture was filtered and washed with 10ml of acetonitrile to obtain a solid wet product, milobalin benzenesulfonic acid. The wet product was dried under vacuum at 55℃ to obtain 49.67g of dried milobalin benzenesulfonic acid with a purity of 99.69%, an ee value ≥99.5%, and a yield of 94.3%.

[0067] Example 7

[0068] Synthesis of Compound III

[0069]

[0070] 700g of tert-butyl methyl ether and 83.48g (0.29mol) of tetraisopropyl titanate were added to a 2L reaction flask. The mixture was purged with nitrogen three times. Then, under controlled temperature conditions of 5℃~8℃, 153.20g (0.81mol) of titanium tetrachloride was added dropwise. After the addition was complete, the mixture was stirred for 30min, and then 129.37g (0.81mol) of diethyl malonate was added. After the addition was complete, the temperature was lowered to 0℃~5℃, and 1g of (1R,5S)-3-ethyl-bicyclo[3.2.0]heptane-3-en-6-one was added dropwise. 0.00 g (0.73 mol) was added, and the temperature was raised to 25℃~30℃ for 3 h. After the reaction was completed, the temperature was lowered to 0℃~5℃, and 500 g of water was added dropwise for extraction and separation. The collected organic phase was washed successively with 200 g of 3.5% hydrochloric acid solution, 200 g of 3.0% sodium bicarbonate aqueous solution, and 200 g of water. Finally, the washed organic phase was subjected to vacuum distillation to remove the solvent, yielding 201.32 g of concentrated compound III, with a yield of 98.50% and a purity of 94.62%.

[0071] Example 8

[0072] Synthesis of Formula IV compounds

[0073]

[0074] 700 g of tetrahydrofuran and 26.55 g (0.65 mol) of acetonitrile were added to a 3 L reaction flask. The mixture was purged with nitrogen three times, and the temperature was lowered to -70 °C. 404.17 mL (0.65 mol) of a 1.6 M n-butyllithium cyclohexane solution was added dropwise. After the addition was complete, the mixture was stirred for 30 min. Then, 100 g (0.36 mol) of compound III was added dropwise. After the addition was complete, the mixture was slowly heated to 25 °C and stirred for 1 h. After the reaction was completed, the temperature was lowered to... At 5℃, and with the temperature controlled below 5℃, 500g of a 5% ammonium chloride aqueous solution was added dropwise. Then, 700g of dichloromethane was added and stirred for 20 minutes. Extraction and separation were performed, and the organic phase was collected. The organic phase was washed twice with 200g of water each time. The collected organic phase was then subjected to vacuum distillation to remove dichloromethane, yielding 105.98g of a concentrated compound of formula IV. The yield was 92%, the purity was 94.24%, and the chiral ee value was 98.8%.

[0075] Example 9

[0076] Preparation of compound V

[0077]

[0078] 400g of ethanol and 100g (0.31mol) of compound IV were added to a 2L clean reaction flask. At room temperature, 409.90g (2.19mol) of a 30% potassium hydroxide aqueous solution was added dropwise. After the addition was complete, the mixture was stirred and heated to 60℃-70℃ for 4 hours. After the reaction was complete, the reaction solution was cooled to 20-30℃, and 248.45g (2.19mol) of a 30% hydrogen peroxide solution was added dropwise. After the addition was complete, the mixture was stirred and reacted for 3 hours. After the reaction was complete, 300g of isopropyl acetate was added, and... The mixture was cooled to 0℃~5℃ and 226.65g (2.23mol) of 36% hydrochloric acid solution was added dropwise for acidification. The pH of the system was adjusted to 5~7, stirred for 10min, allowed to stand and separate into layers, and the organic phase was collected. The collected organic phase was washed successively with 100g of 5% sodium bisulfite aqueous solution and 100g of water. After confirming the absence of hydrogen peroxide residue by testing with starch-potassium iodide paper, the organic phase was subjected to vacuum distillation to remove the solvent, yielding 79.50g of concentrated compound V, with a yield of 96% and a purity of 91.91%.

[0079] Example 10

[0080] Synthesis of Compound VI

[0081]

[0082] 400g of xylene and 80g of compound V were added to a 2L clean reaction flask. The mixture was purged with nitrogen three times, heated to reflux for high-temperature decarboxylation reaction and held at that temperature for 5 hours. After the reaction was completed, the mixture was slowly cooled to room temperature, and then washed once with 200g of water. The mixture was allowed to stand and separate into layers. The organic phase was collected and the solvent was removed by vacuum distillation to obtain 60.89g of concentrated compound VI, with a yield of 91% and a purity of 90.1%.

[0083] Example 11

[0084] Preparation of compound I, milobalin

[0085]

[0086] 150g of water and 50g (0.21mol) of compound VI were added to a 1L clean reaction flask. 206.8g (0.74mol) of a 20% potassium hydroxide aqueous solution was added dropwise at room temperature. After the addition was complete, the temperature was slowly lowered to 0℃~5℃. 52.00g (0.32mol) of sodium hypochlorite pentahydrate was added and the temperature was maintained for 1 hour. The temperature was then raised to 25℃ and maintained at 25℃~30℃ with stirring for another 3 hours. After the reaction was completed... The mixture was cooled to 0℃~5℃, 200g of dichloromethane was added, and 74.77g (0.74mol) of 36% hydrochloric acid was added dropwise to adjust the pH to 6~7. A white solid precipitated out. After stirring at 0℃~5℃ for 1h, the mixture was filtered. The wet product was then vacuum dried at 40℃ for 20h to obtain 32.43g of a white solid product, compound I, milobalin, with a purity of 98.16% and an ee value ≥99.5%. Based on the starting material of formula II, the overall yield of the first 5 steps was 73.55%.

[0087] Example 12

[0088] Preparation of milobalin benzyl sulfonate

[0089] 300g of anisole and 30g (0.143mol) of compound I, milobalin, were added to a reaction flask. 27g of acetic acid was slowly added at a controlled temperature of 20℃–25℃ until the reaction solution became clear. Then, a mixture of 23.12g (0.146mol) benzenesulfonic acid and 60g of anisole was slowly added dropwise, resulting in the precipitation of a large amount of white solid. After the addition was complete, the mixture was kept at this temperature for 1 hour, then cooled to 0℃–5℃ for 2 hours for analytical crystallization. The mixture was filtered and washed with 15ml of anisole to obtain a solid wet product, milobalin benzenesulfonic acid. The wet product was dried under vacuum at 55℃ to obtain 49.88g of milobalin benzenesulfonic acid with a purity of 99.87%, an ee value ≥99.5%, and a yield of 94.7%.

[0090] Example 13

[0091] Synthesis of Formula IV compounds

[0092]

[0093] 800 g of 2-methyltetrahydrofuran and 22.96 g (0.56 mol) of acetonitrile were added to a 3 L reaction flask. The mixture was purged with nitrogen three times, cooled to -60 °C, and 450 mL (0.72 mol) of a 1.6 M tert-butyllithium cyclohexane solution was added dropwise while maintaining the temperature. After the addition was complete, the mixture was stirred for 40 min. Then, 100 g (0.36 mol) of compound III was added dropwise. After the addition was complete, the mixture was heated slowly to 25 °C and stirred for 1 h. After the reaction was completed, the mixture was allowed to stand. The temperature was lowered to 5°C and controlled below 5°C. 500g of 5% ammonium chloride aqueous solution was added dropwise, followed by 700g of dichloromethane. After stirring for 15 minutes, extraction and separation were performed. The organic phase was collected and washed twice with 200g of water each time. The collected organic phase was distilled to remove dichloromethane, yielding compound IV concentrate 104.20 with a yield of 91%, purity of 92.52%, and chiral ee value of 99.3%.

[0094] Example 14

[0095] Preparation of compound V

[0096]

[0097] 400g of ethanol and 100g (0.31mol) of compound IV were added to a 2L clean reaction flask. At room temperature, 1314g (1.86mol) of a 15% sodium carbonate aqueous solution was added dropwise. After the addition was complete, the mixture was stirred for 5 hours. Then, 182g (1.6mol) of a 30% hydrogen peroxide solution was added dropwise. After the addition was complete, the mixture was stirred for 3 hours. After the reaction was complete, 300g of isopropyl acetate was added, and the mixture was cooled to 0℃~5℃ before being added dropwise. The system was acidified with 170g of 36% hydrochloric acid solution to adjust the pH to 5-7. After stirring for 10 minutes and allowing to stand for separation, the organic phase was collected. The collected organic phase was washed successively with 100g of 5% sodium bisulfite aqueous solution and 100g of water. After confirming the absence of hydrogen peroxide residue by testing with starch-potassium iodide paper, the organic phase was subjected to vacuum distillation to remove the solvent, yielding 80.29g of concentrated compound V, with a yield of 97% and a purity of 92.8%.

[0098] Example 15

[0099] Synthesis of Compound VI

[0100]

[0101] In a 2L clean reaction flask, 300g DMAc, 50g water, 80g of compound V, and 35g sodium chloride were added. The mixture was purged with nitrogen three times, and the temperature was slowly raised to 120℃~122℃ under stirring for a high-temperature decarboxylation reaction for 4 hours. After the reaction was completed, the temperature was slowly lowered to room temperature, and then 320g water and 300g ethyl acetate were added for stirring and extraction for 15 minutes. The mixture was allowed to stand and separate into layers, and the organic phase was collected. The organic phase was washed once with 100g water, and then the solvent was removed by vacuum distillation to obtain 62.25g of concentrated compound VI, with a yield of 93% and a purity of 93.4%.

[0102] Example 16

[0103] Preparation of compound I, milobalin

[0104]

[0105] 150g of water and 50g (0.21mol) of compound VI were added to a 1L clean reaction flask. 126g (0.63mol) of a 20% sodium hydroxide aqueous solution was added dropwise at room temperature. After the addition was complete, the temperature was slowly lowered to 0℃~5℃. 53.05g (0.32mol) of sodium hypochlorite pentahydrate was added and the mixture was kept at this temperature for 1.5h. The temperature was then raised to 25℃ and maintained at 25℃~30℃ with stirring for another 4h. After the reaction was complete, the temperature was lowered to 0℃~5℃, 200g of dichloromethane was added, and 60g of a 36% hydrochloric acid solution was added dropwise to adjust the pH to 6~7. A white solid precipitated. After stirring at 0℃~5℃ for 1h, the mixture was filtered. The wet product was vacuum dried at 40℃ for 20h to obtain 31.87g of a white solid product, compound I milobalin, with a purity of 98.5% and an ee value ≥99.5%.

[0106] The specific embodiments described in this invention are merely illustrative of the spirit of the invention. Those skilled in the art to which this invention pertains can make various modifications or additions to the described specific embodiments or use similar methods to replace them, without departing from the spirit of the invention or exceeding the scope defined by the appended claims.

[0107] Although the present invention has been described in detail and specific embodiments have been cited, it will be apparent to those skilled in the art that various changes or modifications can be made without departing from the spirit and scope of the invention.

Claims

1. A method for synthesizing milobalin or its acid salt, characterized in that, The method includes the following steps: A. Under the action of a strong organic base, the compound of formula III is reacted with acetonitrile in a nonpolar organic solvent at a low temperature below -50℃ to obtain the intermediate compound of formula IV. B. Under alkaline conditions, the compound of formula IV undergoes an oxidation reaction in the presence of an oxidizing agent, converting the cyano group into an amide group, and the ester group undergoes a hydrolysis reaction. After the reaction is completed, it is acidified to obtain the compound of formula V. C. Compound V is subjected to a high-temperature decarboxylation reaction in an aprotic solvent to obtain compound VI; D. Compound VI of formula VI is degraded by Hoffmann reaction to obtain compound I, Milobalin; The synthesis of milobalin acid salts also includes reacting milobalin (compound of formula I) with an acid to form a salt to obtain milobalin acid salts (compound of formula I).

2. The method for synthesizing milobalin or its acid salt according to claim 1, characterized in that, The Michael addition reaction in step A is carried out at a temperature of -60°C to -80°C.

3. The method for synthesizing milobalin or its acid salt according to claim 2, characterized in that, The strong organic base mentioned in step A is selected from one or more of n-butyllithium, tert-butyllithium, isopropyllithium, and tert-butylsodium; the nonpolar organic solvent is selected from one or more of cyclopentyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, and isopropyl ether.

4. The method for synthesizing milobalin or its acid salt according to any one of claims 1-3, characterized in that, The molar ratio of compound III in step A to acetonitrile to strong organic base is 1:1 to 2:1 to 2.

5. The method for synthesizing milobalin or its acid salt according to claim 1, characterized in that, The alkaline condition described in step B is that an inorganic base is present, wherein the inorganic base is selected from one or more of alkali metal hydroxides, carbonates, and bicarbonates; and the oxidant is selected from hydrogen peroxide.

6. The method for synthesizing milobalin or its acid salt according to claim 5, characterized in that, The oxidation and hydrolysis reactions described in step B are carried out in an alcohol solvent, which is selected from one or more of methanol, ethanol, propanol, butanol and isopropanol.

7. The method for synthesizing milobalin or its acid salt according to claim 1, characterized in that, The high-temperature decarboxylation reaction in step C is carried out at a temperature of 100℃ to 150℃; the aprotic solvent is selected from one or more of DMSO, DMF, xylene, DMAC and water.

8. The method for synthesizing milobalin or its acid salt according to any one of claims 1-3 and 5-7, characterized in that, The acid mentioned in step D is benzenesulfonic acid, and the milobalin acid salt of compound I is milobalin benzenesulfonic acid.

9. The method for synthesizing milobalin or its acid salt according to any one of claims 1-3 and 5-7, characterized in that, The Hoffmann degradation reaction described in step D is carried out under the action of sodium hypochlorite and alkali metal hydroxide, and the temperature of the Hoffmann degradation reaction is 20℃~30℃.

10. The method for synthesizing milobalin or its acid salt according to any one of claims 1-3 and 5-7, characterized in that, The compound of formula III described in step A is obtained by the following method: Under the catalysis of Lewis acid, compound (1R,5S)-3-ethyl-bicyclo[3.2.0]heptane-3-en-6-one of formula II was reacted with diethyl malonate via an HWE reaction to generate compound III;

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