A process for the preparation of 2-((1R,5S)-3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl)acetic acid

Abstract

The application discloses a method for preparing 2-((1 R ,5 S )‑3‑ethyl‑6‑(nitromethyl)bicyclo[3.2.0]hept‑3‑en‑6‑yl)acetic acid, which comprises the following steps: carrying out a salt reaction of a racemate compound a and a resolving agent b, and then separating to obtain compound I; and treating the compound I with an acid to obtain compound II, i.e. 2-((1 R ,5 S )‑3‑ethyl‑6‑(nitromethyl)bicyclo[3.2.0]hept‑3‑en‑6‑yl)acetic acid. The application innovatively adopts benzylamine as the resolving agent, and the high-efficiency resolution is carried out in one step; the reaction steps are simple; the reaction condition is mild; the resolving agent is low in price and easy to obtain; no special reagent is needed; the operation is simple; and the method is suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a 2-((1) R 5 S Preparation method of 3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl)acetic acid. Background Technology

[0002] Mirogabalin besylate is a GABA analog that acts on the α2-δ1 subunit of the voltage-sensitive calcium channel complex (widely distributed throughout the nervous system mediating pain transmission and processing). Developed by Daiichi Sankyo, it was first approved for marketing in Japan in 2019 for the treatment of peripheral neuropathic pain (PNP). Its structural formula is shown below:

[0003] In the existing technology, the main methods for synthesizing milobalin besylate reported in the literature are as follows: Method 1: Literature WO2015005298A1 reports the following method: After two chiral compound resolutions, the first resolution yielded chiral compound (4a) with a yield of 39%; the second resolution yielded compound (7a). Furthermore, this route uses the highly toxic chemical sodium cyanide.

[0004]

[0005] The disadvantages of this route are: it uses highly toxic NaCN, involves two chiral separations with significant losses, has low 7a separation efficiency, and is relatively expensive.

[0006] Method 2: WO2015005298A1. This route avoids the use of highly toxic NaCN. The disadvantages are: it also involves two chiral separations, resulting in significant losses, low separation efficiency, complex procedures, and high synthesis costs.

[0007]

[0008] Method 3: Reference EP2871176 The drawback of this route is that it uses a chiral preparation and separation method, which has a very high preparation cost and is not conducive to industrial-scale production.

[0009] As can be seen from the methods reported in the literature above, those involving two chiral separations or the use of highly toxic sodium cyanide result in low yields and high costs, all of which have certain drawbacks for industrial production. Therefore, finding a method that is mild, simple to operate, and produces high chemical and optical purity suitable for the industrial production of milogabalin benzylsulfonic acid is a pressing technical problem that needs to be solved in this field. This method is also of great significance for increasing economic and social benefits. Summary of the Invention

[0010] The purpose of this invention is to provide a method for preparing 2-((1) R, 5 S The method of preparing milogabalin by 3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl)acetic acid is proposed to solve the problems of high cost of racemic separation and unsuitability for industrial production in the preparation of milogabalin in the prior art.

[0011] To achieve the above objectives, the present invention adopts the following technical solution: A method for preparing 2-((1) R 5 S The method for 3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl)acetic acid, The synthesis route is as follows:

[0012]

[0013] The synthesis steps are as follows: (1) The racemic compound a was reacted with resolving agent b to form a salt, and compound I was obtained by separation; (2) Treating compound I with acid yields compound II, i.e., 2-((1 R 5 S 3-Ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl)acetic acid.

[0014] Further, in step (1), the molar ratio of compound a to compound b is 1:(0.6~1.4), preferably 1:(0.7~1.3), and more preferably 1:1.1.

[0015] Further, in step (1), the salt-forming reaction is carried out in a single solvent or a mixture of solvents including alcohols, ketones, esters, ethers, and water. Preferably, the salt-forming reaction is carried out in methanol, methyl tert-butyl ether, ethanol, acetonitrile, water, or a mixture thereof. More preferably, the salt-forming reaction is carried out in a single solvent including methyl tert-butyl ether.

[0016] Furthermore, in step (1), the temperature of the salt formation reaction is 0~50℃. Preferably, it is 0~30℃, more preferably 10~20℃.

[0017] Furthermore, in step (1), the reaction time for the salt formation reaction is 1 to 3 hours, preferably 2 hours.

[0018] Furthermore, in step (2), the acid is one or more of hydrochloric acid, sulfuric acid, boric acid, carbonic acid, and phosphoric acid.

[0019] Further, in step (2), the acid treatment step is carried out in water, an organic solvent, or a mixture of water and an organic solvent, wherein the organic solvent is one or more of ethanol, methyl tert-butyl ether, and tetrahydrofuran; when it is a mixture of water and an organic solvent, the volume ratio of water to organic solvent is 1:1.

[0020] Preferably, in step (2), the acid treatment is carried out in hydrochloric acid with a concentration of 5-7 mol / L, and the pH of the system is 2-3 after the addition of hydrochloric acid.

[0021] In step (2), the acid treatment is carried out at 10~35℃ and the acid treatment time is 1~3h, preferably 2h.

[0022] The resolving agent is benzylamine.

[0023] A preparation method based on the present invention for 2-((1) R, 5 S The present invention provides a method for preparing milogabalin benzylsulfonic acid, comprising the following steps: 3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl)acetic acid. (1) Dissolve compound a in methyl tert-butyl ether (the concentration of compound a in methyl tert-butyl ether is 0.1~0.2 g / mL), add benzylamine in methyl tert-butyl ether solution (the concentration of benzylamine in methyl tert-butyl ether is 0.2~0.3 g / mL) at 10~20℃, stir and react at 10~20℃ for 1~3 h, filter, dry to obtain compound I, add compound I to a mixed solvent of methyl tert-butyl ether and water (the concentration of compound I in the mixed solvent is 0.05~0.2 g / mL), add 5~7 mol / L hydrochloric acid under controlled temperature not higher than 35℃, adjust the pH of the system to 2~3, let stand, separate the liquids, wash the aqueous phase once with methyl tert-butyl ether, let stand, separate the liquids, combine the organic phases, concentrate to obtain compound II; (2) Compound II, after hydrogenation, forms a salt with benzenesulfonic acid to give milogabalin benzenesulfonic acid; the reaction formula is as follows: .

[0024] Beneficial effects: The preparation method provided by this invention innovatively performs high-efficiency separation in N-1 steps, with mild reaction conditions, relatively inexpensive resolving agents, simple post-processing, no need for special reagents, and significantly higher yield than existing technologies, making it very suitable for industrial production.

[0025] This invention provides a method for preparing ultra-high e.e.2-((1) R 5 S The method for resolving compound a using 3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl)acetic acid, through extensive screening of resolving agents, revealed that compound b has a significant resolving effect on compound a, achieving an e.e. value of over 99.0% after a single resolving step. This method is simple to operate, uses inexpensive resolving agents, has high yield and high product purity, and is very suitable for industrial production of 2-((1 R 5 S 3-Ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl)acetic acid.

[0026] The advantages of the preparation method of this invention are as follows: This invention innovatively performs high-efficiency separation in one step, with simple reaction steps, mild reaction conditions, and inexpensive and readily available resolving agents. No special reagents are required, the operation is simple, and it is suitable for industrial production. Separating enantiomer mixtures using benzylamine can avoid the use of high-cost and low-efficiency chiral chromatography methods. Moreover, the yield of enantiomer mixtures separated by benzylamine is over 83%, and the content of the final product, milogabarine benzylsulfonic acid, can reach over 99.9%. Attached Figure Description

[0027] Figure 1 The image shows the HPLC chromatogram of the racemic compound a. Figure 2 The HPLC chromatogram of compound I is shown below. Figure 3 The HPLC chromatogram of milogabaline benzyl sulfonate is shown below. Figure 4 HPLC chromatogram of the isomer test solution; Figure 5 This is the HPLC chromatogram of the isomer reference solution; Figure 4 and Figure 5 In the diagram, 405-10A represents impurity A, and 405-10C represents impurity C. Detailed Implementation

[0028] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise stated, the raw materials or reagents used in the embodiments are commercially available or prepared using conventional methods. It should be understood that the specific embodiments detailed herein are merely illustrative of the invention and are not intended to limit the scope of the invention. Example 1

[0029] (1) Preparation of benzylamine diastereomeric salts

[0030] At room temperature (approximately 15°C), add compound a (e.g., ...) to the reaction flask. Figure 1 As shown, the S configuration accounts for 80.4% (100g, 0.42mol). Add 800mL of methyl tert-butyl ether I, and stir at 10-20℃. At this temperature, add a mixture of 49.26g (0.46mol) of benzylamine and 200mL of methyl tert-butyl ether II dropwise. After the addition is complete, heat to an internal temperature of 20℃ and stir for 3 hours. Filter and vacuum dry at 45℃ to obtain 115.0g (molar yield 99.3%) of white crystalline powder. Figure 2 As shown, its purity was determined to be 98.42% by HPLC.

[0031] (2) Preparation of compound II

[0032] At room temperature (approximately 15°C), 100 g (0.29 mol) of compound I, 500 mL of methyl tert-butyl ether, and 500 mL of water were added to a reaction flask. Then, under controlled temperature (not exceeding 35°C), 6 M hydrochloric acid was added, and the pH was adjusted to pH 2.6. The mixture was allowed to stand, and the layers were separated. The aqueous phase was washed once with 300 mL of methyl tert-butyl ether, allowed to stand, and the layers were separated. The organic phases were combined and concentrated until no obvious fraction flowed out, yielding 84.9 g of an oily substance. The residual methyl tert-butyl ether solvent was 0.23%. After removing the residual solvent, 68.5 g of the oily substance, compound II (theoretical purity), was obtained (99.2%). Compound II was hydrogenated to form benzenesulfonate, yielding melogabalin benzenesulfonic acid (the specific process can be found in CN101878193A). The final API content reached 99.92% (e.g., ...). Figure 3 As shown), Figure 4 and Figure 5 As shown, isomer impurity A: 0.03% ( Figure 4 The peak area of ​​405-10A divided by Figure 5 (Peak area of ​​405-10A multiplied by 0.15%); isomer impurity C: not detected.

[0033] The present invention has been described in detail with reference to the above embodiments. It should be noted that the above embodiments are merely illustrative examples of the present invention. Without departing from the spirit and essence of the present invention, those skilled in the art can devise various alternatives and improvements to the present invention, all of which should be understood to be within the scope of protection of the present invention.

Claims

1. A method for preparing 2-((1 R 5 S The method for processing 3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl)acetic acid, characterized in that: The synthesis route is as follows: ， ， The synthesis steps are as follows: (1) The racemic compound a was reacted with resolving agent b to form a salt, and the compounds were separated to obtain compound I. (2) Treating compound I with acid yields compound II, i.e., 2-((1 R 5 S 3-Ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl)acetic acid.

2. The method according to claim 1, characterized in that: In step (1), the molar ratio of compound a to resolving agent b is 1:(0.6~1.4).

3. The method according to claim 1, characterized in that: In step (1), the salt formation reaction is carried out in a single solvent or a mixture of solvents such as alcohols, ketones, esters, ethers and water; the temperature of the salt formation reaction is 0~50℃ and the time is 1~3h.

4. The method according to claim 1, characterized in that: In step (2), the acid is one or more of hydrochloric acid, sulfuric acid, boric acid, carbonic acid, and phosphoric acid; the acid treatment step is carried out in water, an organic solvent, or a mixture of water and an organic solvent, wherein the organic solvent is one or more of ethanol, methyl tert-butyl ether, and tetrahydrofuran; the acid treatment is carried out at 10~35℃; and the acid treatment time is 1~3 h.

5. The method according to claim 1, characterized in that: The resolving agent b is benzylamine.

6. The method according to claim 5, characterized in that: The benzylamine reacts with the racemic compound a in a methyl tert-butyl ether system to give compound I, which is then dissociated with hydrochloric acid in a mixed solvent of methyl tert-butyl ether and water to give compound II.

7. The method according to claim 6, characterized in that: The volume ratio of methyl tert-butyl ether to water is 1:1, the concentration of hydrochloric acid is 5~7 mol / L, and the pH of the system after adding hydrochloric acid is 2~3.

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