Photocatalytic preparation method of milobalin intermediate

Abstract

The invention belongs to the technical field of medicinal chemistry, and particularly relates to a photocatalytic preparation method of a milobalin intermediate. Comprising the following steps: dissolving (1S, 5R)-3-ethyl-bicyclo [3.2. 0] hept-3-en-6-one in a solvent, adding a photosensitizer, carrying out a reaction under light with a specific wavelength and at a temperature, and after the reaction is finished, carrying out post-treatment to obtain the 3-ethyl-bicyclo [3.2. 0] hept-3-en-6-one racemate, namely (1S, 5R)-3-ethyl-bicyclo [3.2. 0] hept-3-en-6-one racemate, namely (1S, 5R)-3-ethyl-bicyclo [3.2. 0] hept-3-en-6-one racemate and (1S, 5R)-3-ethyl-bicyclo [3.2. 0] hept-3-en-6-one racemate. The yield is good and the purity is high. And the recycling of the waste compound (1S, 5R)-3-ethyl bicyclo [3.2. 0] hept-3-ene-6-ketone is realized.

Description

Technical Field

[0001] This invention belongs to the technical field of medicinal chemistry, specifically relating to a photocatalytic preparation method for a milobalin intermediate. Background Technology

[0002] On January 8, 2019, Mirogabalin besilate, developed by Daiichi Sankyo Co., Ltd. of Japan, was approved for marketing by the Japan Medical Device Evaluation and Approval Agency (PMDA) under the brand name Tarlige (oral tablets containing 2.5mg, 5mg, 10mg, and 15mg of Mirogabalin per tablet), for the treatment of peripheral neuropathic pain, including diabetic peripheral neuropathy and postherpetic neuralgia. In June 2024, Mirogabalin besilate was approved for marketing by the National Medical Products Administration (NMPA) of China.

[0003] Mirogabalin (DS-5565) is a gabapentin-like drug, similar to gabapentin and pregabalin, acting on the voltage-gated calcium channel subunit α2δ. By binding to α2δ-1, it inhibits the release of calcium ions-mediated neurotransmitters in the nervous system, interrupting neuronal excitation and sensory signal transduction. Mirogabalin is a novel selective α2δ-1 ligand with high potency and selectivity for the α2δ-1 subunit of voltage-sensitive calcium channel complexes in the central nervous system. Mirogabalin can bind to α2δ calcium channels (1 and 2), with significantly higher potency than pregabalin. It has shown good efficacy in clinical trials for the treatment of diabetic peripheral neuropathic pain. Its structural formula is as follows:

[0004] EP2192109, US2010249229, US2010110361, and CN101878193A report the synthesis of a key intermediate for milobalin. This route begins with ethyl 3-oxohexanoate, which reacts with allyl bromide to yield ethyl 4-ethyl-3-hydroxyhept-6-enoate, followed by reduction and hydrolysis to obtain 4-ethyl-3-hydroxyhept-6-enoic acid. Subsequently, 4-ethyl-3-hydroxyhept-6-enoic acid is dissolved in acetic anhydride, potassium acetate is added, and the mixture is heated under reflux to yield the racemic 3-ethylbicyclo[3.2.0]hept-3-en-6-one. Finally, milobalin is synthesized.

[0005]

[0006] CN103562170B reports the formation of a key intermediate, 3-ethylbicyclo[3.2.0]hept-3-en-6-one racemic mixture, using n-butyraldehyde and allyl alcohol as starting materials, through acetal protection, Claisen rearrangement, Knoevenagel condensation reaction, and intramolecular [2+2] reaction.

[0007]

[0008] WO2013089189A1 reports the preparation of (1) using chemical resolution technology. R 5 S The method for preparing 3-ethylbicyclo[3.2.0]hept-3-en-6-one (compound A) involves reacting sulfur dioxide, water, and the racemic mixture of 3-ethylbicyclo[3.2.0]hept-3-en-6-one, followed by salt formation with a chiral amine to form an epimer. The target compound is prepared by taking advantage of the difference in solubility of this epimer in the solvent system. However, this preparation method has a low yield and generates waste (1... S 5 R The use of 3-ethylbicyclo[3.2.0]hept-3-en-6-one results in poor atom economy, which is detrimental to the cost control of milobalin.

[0009]

[0010] No solution has yet been found in the existing technology for waste (1 S 5 R A method for preparing the racemic form of 3-ethylbicyclo[3.2.0]hept-3-en-6-one. Therefore, how to greenly and efficiently convert (1)-3-ethylbicyclo[3.2.0]hept-3-en-6-one into its racemic form is needed. S 5 R The conversion of 3-ethylbicyclo[3.2.0]hept-3-en-6-one into the racemic form of 3-ethylbicyclo[3.2.0]hept-3-en-6-one, turning waste into treasure, has become a technical challenge in the synthesis process of milobalin. Summary of the Invention

[0011] The purpose of this invention is to solve the problems in the prior art and provide a photocatalytic preparation method for milobalin intermediates, which uses waste (1 S 5 R The method for preparing the racemic form of 3-ethylbicyclo[3.2.0]hept-3-en-6-one by converting it into a simple reaction under mild conditions allows for the resource-based reuse of waste materials and can be industrialized.

[0012] To achieve the above objectives, the present invention is implemented through the following technical approach, as follows:

[0013] This invention provides a method for preparing the racemic form of 3-ethylbicyclo[3.2.0]hept-3-en-6-one, specifically comprising the following steps: (1 S 5 R 3-Ethylbicyclo[3.2.0]hepta-3-en-6-one was dissolved in a solvent and a photosensitizer was added. The reaction was carried out under light and temperature of a specific wavelength. After the reaction was completed, the racemic mixture of 3-ethylbicyclo[3.2.0]hepta-3-en-6-one was obtained after post-treatment.

[0014] Preferably, the reaction solvent is one or more of methanol, diethyl ether, tetrahydrofuran, toluene, ethyl acetate, and isopropyl acetate, with tetrahydrofuran and isopropyl acetate being more preferred.

[0015] Preferably, the photosensitizer is one of 4-[4,5-bis[4-(dimethylamino)phenyl]-1H-imidazol-2-yl]-2,6-dimethoxyphenol, 3-hydroxypyridine, 1,2,3,4-dibenzothracene, and p-isophthalonitrile, more preferably one of 4-[4,5-bis[4-(dimethylamino)phenyl]-1H-imidazol-2-yl]-2,6-dimethoxyphenol and 3-hydroxypyridine.

[0016] The photosensitizer has the following structure:

[0017] Preferably, the (1) S 5 R The molar ratio of 3-ethylbicyclo[3.2.0]hepta-3-en-6-one to photosensitizer is 1:0.001 to 0.08. Preferably, it is 1:0.02 to 0.05.

[0018] Preferably, the reaction temperature is 0℃~60℃, more preferably 0℃~40℃, and even more preferably 20℃~30℃.

[0019] Preferably, the wavelength of the light is 200–500 nm, and more preferably 260–420 nm.

[0020] Preferably, the reaction time is 0.1 to 5 hours, and more preferably 0.5 to 1.5 hours.

[0021] Preferably, the post-treatment involves: evaporating the reaction solution under reduced pressure to dryness, dissolving it in methanol, adding an aqueous solution of sodium bisulfite, stirring until no more white solid is formed, filtering and washing with methanol, collecting the filter cake and transferring it to a reaction flask, then adding an aqueous solution of sodium carbonate, stirring until the solid disappears, then using dichloromethane as an extractant, stirring and allowing to stand before separating the liquid, collecting the organic phase, then washing once with dilute hydrochloric acid, once with water, washing with saturated brine, drying with anhydrous sodium sulfate, and then removing the organic solvent by rotary evaporation under reduced pressure to obtain the racemic mixture of 3-ethylbicyclo[3.2.0]hept-3-en-6-one.

[0022] Compared with the prior art, the technical effects achieved by the present invention are as follows:

[0023] This invention provides a method for (1) S 5 R A method for the direct and efficient synthesis of the racemic form of 3-ethylbicyclo[3.2.0]hep-3-en-6-one from 3-ethylbicyclo[3.2.0]hep-3-en-6-one, and its scale-up preparation, is also described. This invention enables the resource utilization of waste materials. The racemic form of 3-ethylbicyclo[3.2.0]hep-3-en-6-one can be further processed using existing resolution techniques to prepare the key intermediate of milobalin (1). R 5 S )-3-ethylbicyclo[3.2.0]hepta-3-en-6-one provides a basic raw material for the subsequent synthesis of milobalin, which is conducive to the industrial production of milobalin. Attached Figure Description

[0024] Figure 1 In the example (1) S , 5 R Optical isomer liquid phase spectra of 3-ethylbicyclo[3.2.0]hept-3-en-6-one.

[0025] Figure 2 In the example (1) S , 5 R Liquid phase spectra of related substances of 3-ethylbicyclo[3.2.0]hept-3-en-6-one.

[0026] Figure 3 The liquid phase spectrum of the racemic optical isomer of 3-ethylbicyclo[3.2.0]hept-3-en-6-one obtained in Example 1.

[0027] Figure 4 For (1) R , 5 S Liquid phase localization spectrum of the 3-ethylbicyclo[3.2.0]hept-3-en-6-one isomer.

[0028] Figure 5Liquid phase spectra of the racemic mixture of 3-ethylbicyclo[3.2.0]hept-3-en-6-one obtained in Example 1. Detailed Implementation

[0029] The present invention will be further illustrated by the following embodiments. It should be understood that the embodiments of the present invention are merely for illustrating the present invention and are not intended to limit the present invention. Therefore, any simple improvements to the present invention under the premise of the method of the present invention are within the scope of protection claimed by the present invention.

[0030] Example 1

[0031] (1) S 5 R 13.6 g (0.1 mol) of 3-ethylbicyclo[3.2.0]hepta-3-en-6-one and 1.8 g (0.004 mol) of photosensitizer 4-[4,5-bis[4-(dimethylamino)phenyl]-1H-imidazol-2-yl]-2,6-dimethoxyphenol were dissolved in tetrahydrofuran. The reaction was carried out at 280 nm and the reaction temperature was controlled at 25 °C. After 50 minutes, the reaction was detected as complete and the reaction was stopped. The reaction solution was evaporated to dryness under reduced pressure, dissolved in methanol, and then an aqueous solution of sodium bisulfite was added. The mixture was stirred until no more white solid was formed. The solution was filtered and washed with methanol. The filter cake was collected and transferred to a reaction flask. An aqueous solution of sodium carbonate was then added, and the mixture was stirred until the solid disappeared. Dichloromethane was then used as an extractant. The mixture was stirred, allowed to stand, and separated. The organic phase was collected and washed once with dilute hydrochloric acid, once with water, and once with saturated brine. The solution was dried over anhydrous sodium sulfate, and the organic solvent was removed by rotary evaporation under reduced pressure to obtain the racemic 3-ethylbicyclo[3.2.0]hept-3-en-6-one in 90.6% yield. The purity was 99.39% according to HPLC.

[0032] Example 2

[0033] (1) S 5 R13.6 g (0.1 mol) of 3-ethylbicyclo[3.2.0]hepta-3-en-6-one and 0.9 g (0.002 mol) of photosensitizer 4-[4,5-bis[4-(dimethylamino)phenyl]-1H-imidazol-2-yl]-2,6-dimethoxyphenol were dissolved in tetrahydrofuran. The reaction was carried out at 280 nm and the reaction temperature was controlled at 25 °C. After 50 minutes, the reaction was detected as complete and the reaction was stopped. The reaction solution was evaporated to dryness under reduced pressure, dissolved in methanol, and then an aqueous solution of sodium bisulfite was added. The mixture was stirred until no more white solid was formed. The solution was filtered and washed with methanol. The filter cake was collected and transferred to a reaction flask. An aqueous solution of sodium carbonate was then added, and the mixture was stirred until the solid disappeared. Dichloromethane was then used as an extractant. The mixture was stirred, allowed to stand, and separated. The organic phase was collected and washed once with dilute hydrochloric acid, once with water, and once with saturated brine. The solution was dried over anhydrous sodium sulfate, and the organic solvent was removed by rotary evaporation under reduced pressure to obtain the racemic 3-ethylbicyclo[3.2.0]hept-3-en-6-one in 86.5% yield. The purity was 99.32% according to HPLC.

[0034] Example 3

[0035] (1) S 5 R 3-Ethylbicyclo[3.2.0]hepta-3-en-6-one (13.6 g, 0.1 mol) and photosensitizer 4-[4,5-bis[4-(dimethylamino)phenyl]-1H-imidazol-2-yl]-2,6-dimethoxyphenol (2.7 g, 0.006 mol) were dissolved in tetrahydrofuran and heated at 280 °C. Under nm conditions, the reaction temperature was controlled at 25℃. After 50 minutes, the reaction was detected as complete, and the reaction was stopped. Methanol was added to dissolve the solid, followed by an aqueous solution of sodium bisulfite. The mixture was stirred until no more white solid was formed. The mixture was filtered and washed with methanol. The filter cake was collected and transferred to a reaction flask. An aqueous solution of sodium carbonate was then added, and the mixture was stirred until the solid disappeared. Dichloromethane was then used as an extractant. The mixture was stirred, allowed to stand, and separated. The organic phase was collected and washed once with dilute hydrochloric acid, once with water, and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, and the organic solvent was removed by rotary evaporation under reduced pressure to obtain the racemic mixture of 3-ethylbicyclo[3.2.0]hepta-3-en-6-one with a yield of 89.3%. The purity was 99.29% according to HPLC.

[0036] Example 4

[0037] (1) S 5 R13.6 g (0.1 mol) of 3-ethylbicyclo[3.2.0]hepta-3-en-6-one and 1.8 g (0.004 mol) of photosensitizer 4-[4,5-bis[4-(dimethylamino)phenyl]-1H-imidazol-2-yl]-2,6-dimethoxyphenol were dissolved in methanol. The reaction was carried out at 260 nm and the reaction temperature was controlled at 25 °C. After 60 minutes, the reaction was detected as complete and the reaction was stopped. The reaction solution was evaporated to dryness under reduced pressure, dissolved in methanol, and then an aqueous solution of sodium bisulfite was added. The mixture was stirred until no more white solid was formed. The solution was filtered and washed with methanol. The filter cake was collected and transferred to a reaction flask. An aqueous solution of sodium carbonate was then added, and the mixture was stirred until the solid disappeared. Dichloromethane was then used as an extractant. The mixture was stirred, allowed to stand, and separated. The organic phase was collected and washed once with dilute hydrochloric acid, once with water, and once with saturated brine. The solution was dried over anhydrous sodium sulfate, and the organic solvent was removed by rotary evaporation under reduced pressure to obtain the racemic mixture of 3-ethylbicyclo[3.2.0]hepta-3-en-6-one in 86.4% yield. The purity was 99.37% according to HPLC.

[0038] Example 5

[0039] (1) S 5 R 13.6 g (0.1 mol) of 3-ethylbicyclo[3.2.0]hepta-3-en-6-one and 0.38 g (0.004 mol) of photosensitizer 3-hydroxypyridine were dissolved in diethyl ether. The reaction was carried out at 420 nm and controlled at 25 °C for 50 minutes. The reaction was then stopped after confirming completion. The reaction solution was evaporated to dryness under reduced pressure, dissolved in methanol, and then an aqueous solution of sodium bisulfite was added. The mixture was stirred until no more white solid was formed, filtered, and washed with methanol. The filter cake was collected and transferred to a reaction flask, and an aqueous solution of sodium carbonate was added. The mixture was stirred until the solid disappeared, and then extracted with dichloromethane. After stirring and allowing to stand, the organic phase was collected, washed once with dilute hydrochloric acid, once with water, and washed with saturated brine. The mixture was dried over anhydrous sodium sulfate, and the organic solvent was removed by rotary evaporation under reduced pressure to obtain the racemic mixture of 3-ethylbicyclo[3.2.0]hepta-3-en-6-one in 88.4% yield. The purity was 99.33% according to HPLC.

[0040] Example 6

[0041] (1) S 5 R13.6 g (0.1 mol) of 3-ethylbicyclo[3.2.0]hepta-3-en-6-one and 0.5 g (0.004 mol) of photosensitizer terephthalonitrile were dissolved in isopropyl acetate. The reaction was carried out at 280 nm and 40 °C for 50 minutes. The reaction was then stopped after confirming completion. The reaction solution was evaporated to dryness under reduced pressure, dissolved in methanol, and then an aqueous solution of sodium bisulfite was added. The mixture was stirred until no more white solid was formed, filtered, and washed with methanol. The filter cake was collected and transferred to a reaction flask, and an aqueous solution of sodium carbonate was added. The mixture was stirred until the solid disappeared, then extracted with dichloromethane. After stirring and allowing to stand, the organic phase was collected, washed once with dilute hydrochloric acid, once with water, and washed with saturated brine. The mixture was dried over anhydrous sodium sulfate, and the organic solvent was removed by rotary evaporation under reduced pressure to obtain the racemic mixture of 3-ethylbicyclo[3.2.0]hepta-3-en-6-one in 91.1% yield. The purity was 99.19% according to HPLC.

[0042] Example 7

[0043] (1) S 5 R 13.6 g (0.1 mol) of 3-ethylbicyclo[3.2.0]hepta-3-en-6-one and photosensitizer 1,2,3,4-dibenzanthracene (1.1 g (0.004 mol)) were dissolved in toluene. The reaction was carried out at 280 nm and the reaction temperature was controlled at 0 °C. After 65 minutes, the reaction was considered complete and the reaction was stopped. The reaction solution was evaporated to dryness under reduced pressure, dissolved in methanol, and then an aqueous solution of sodium bisulfite was added. The mixture was stirred until no more white solid was formed, filtered, and washed with methanol. The filter cake was collected and transferred to a reaction flask, and an aqueous solution of sodium carbonate was added. The mixture was stirred until the solid disappeared, and then extracted with dichloromethane. After stirring and allowing to stand, the organic phase was collected, washed once with dilute hydrochloric acid, once with water, and washed with saturated brine. The mixture was dried over anhydrous sodium sulfate, and the organic solvent was removed by rotary evaporation under reduced pressure to obtain the racemic 3-ethylbicyclo[3.2.0]hepta-3-en-6-one in 84.6% yield. The purity was 99.30% according to HPLC.

Claims

1. A method for preparing a racemic mixture of 3-ethylbicyclo[3.2.0]hept-3-en-6-one, characterized in that, Specifically, the steps include the following: (1) S 5 R 3-Ethylbicyclo[3.2.0]hepta-3-en-6-one was dissolved in a solvent, and a photosensitizer was added. The reaction was carried out under specific wavelength light and temperature. After the reaction was completed, the racemic mixture of 3-ethylbicyclo[3.2.0]hepta-3-en-6-one was obtained after post-treatment. The route is as follows: 。 2. The method according to claim 1, characterized in that, The reaction solvent is one or more of methanol, diethyl ether, tetrahydrofuran, toluene, ethyl acetate, and isopropyl acetate, preferably tetrahydrofuran or isopropyl acetate.

3. The method according to claim 1, characterized in that, The photosensitizer is one of 4-[4,5-bis[4-(dimethylamino)phenyl]-1H-imidazol-2-yl]-2,6-dimethoxyphenol, 3-hydroxypyridine, 1,2,3,4-dibenzanthracene, and p-isophthalonitrile, preferably one of 4-[4,5-bis[4-(dimethylamino)phenyl]-1H-imidazol-2-yl]-2,6-dimethoxyphenol and 3-hydroxypyridine.

4. The method according to claim 1, characterized in that, The (1) S 5 R The molar ratio of 3-ethylbicyclo[3.2.0]hepta-3-en-6-one to photosensitizer is 1:0.001 to 0.08, preferably 1:0.02 to 0.

05.

5. The method according to claim 1, characterized in that... The reaction temperature is 0℃~60℃, preferably 0℃~40℃.

6. The method according to claim 1, characterized in that, The wavelength of the light is 200–500 nm, preferably 260–420 nm.

7. The method according to claim 1, characterized in that, The post-treatment was as follows: the reaction solution was evaporated to dryness under reduced pressure, dissolved in methanol, and then an aqueous solution of sodium bisulfite was added. The mixture was stirred until no more white solid was formed. The mixture was filtered and washed with methanol. The filter cake was collected and transferred to a reaction flask. An aqueous solution of sodium carbonate was added and stirred until the solid disappeared. Then, dichloromethane was used as an extractant. The mixture was stirred, allowed to stand, and separated. The organic phase was collected and then washed once with dilute hydrochloric acid, once with water, and once with saturated brine. The mixture was dried with anhydrous sodium sulfate and then the organic solvent was removed by rotary evaporation under reduced pressure to obtain the racemic mixture of 3-ethylbicyclo[3.2.0]hept-3-en-6-one.

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