Preparation method of milobalin

Abstract

The invention discloses a preparation method of miloabalin, which is characterized in that the miloabalin is obtained through four-step reaction of Horner-Wittig reaction, Michael addition, nitro reduction and ester hydrolysis, and the reaction yield is higher. Besides, a chiral catalytic synthesis method is adopted, compared with a traditional chiral resolution or chiral separation technology, the atom economy of the reaction is remarkably improved, the method has a good application prospect in industrial production of the miloabalin, and through the efficient synthesis strategy, the production cost is expected to be reduced, and the method is suitable for industrial production of the miloabalin. The purity and the yield of the product are improved, so that the production requirements are met.

Description

Technical Field

[0001] The invention relates to the field of organic chemical synthesis, and in particular to a method for synthesizing mirogabalin. Technical Background

[0002] Mirogabalin besylate, chemical name is {(1R,5S,6S)-6-aminomethyl-3-ethylbicyclo[3.2.0]hept-3-en-6-yl}acetate besylate, molecular formula is C 18 H 25 NO5S. The drug was developed by Daiichi Sankyo Co., Ltd. of Japan and is mainly used to treat peripherally-induced neuropathic pain (PNP). Milobarbital sulfonate exerts analgesic effects by inhibiting the release of neurotransmitters at nerve endings associated with pain. The drug was approved for marketing by the Japanese Pharmaceuticals and Medical Devices Agency (PMDA) on January 8, 2019, with the trade name Tarlige.

[0003] Mirogabalin is the free base of mirogabalin besylate and its main active ingredient. Mirogabalin, whose chemical name is {(1R,5S,6S)-6-aminomethyl-3-ethylbicyclo[3.2.0]hept-3-en-6-yl}acetic acid, is a selective calcium channel α2δ ligand with unique binding properties and long-lasting effects. It preferentially and selectively binds to the α2δ-1 subunit of voltage-dependent calcium channels, which are widely present in various areas of the nervous system and mediate the transmission and processing of pain. Mirogabalin has significantly better clinical effects than pregabalin and gabapentin in the treatment of diabetic peripheral neuropathy, postherpetic neuralgia and fibromyalgia. Mirogabalin and its salts have high safety and good tolerance, and are gradually developing into important drugs in the field of global neuropathic pain treatment.

[0004] The structural formula of milobalin besylate and its free base milobalin is as follows:

[0005] The synthesis of Milobarlin mainly includes the following routes:

[0006] The patent (Method for preparing bicyclic γ-amino acid derivatives, Daiichi Sankyo Co., Ltd., CN102356061B) uses the key intermediate 3-ethylbicyclo[3.2.0]hept-3-en-6-one as the raw material, and obtains milobarline through the steps of Horner-Wittig reaction, Michael addition, chiral preparative separation, nitro reduction, acidic hydrolysis and the like.

[0007]

[0008] The total yield of this route is 5.28%. Its disadvantage is that it uses a chiral preparation and separation method, which has high preparation costs and low yields, and is not conducive to industrial production.

[0009] The patent (optical resolution method of bicyclic compounds using asymmetric catalysts, Daiichi Sankyo Co., Ltd., CN103987687B) uses the key intermediate 3-ethylbicyclo[3.2.0]hept-3-en-6-one as the raw material, and obtains milobarline through Horner-Wittig reaction, Michael addition, alkaline hydrolysis, chiral resolution, nitro reduction and other steps.

[0010]

[0011] The total yield of this route reaches 24.7%. The disadvantage is that the process uses the method of chiral splitting, the process is complicated, and the synthesis cost is high.

[0012] The patent (method for preparing optically active bicyclic γ-amino acid derivatives; Daiichi Sankyo Co., Ltd.; CN104755456B) uses the key intermediate 3-ethylbicyclo[3.2.0]hept-3-en-6-one as the raw material, and obtains milobarline through the steps of Knoevenagel reaction, Michael addition, alkaline hydrolysis, chiral resolution, cyano reduction, etc.

[0013]

[0014] The total yield of this route reaches 24.2%. This process uses highly toxic sodium cyanide and a chiral splitting method, resulting in a high synthesis cost and is not suitable for industrial production. Summary of the invention

[0015] The purpose of the present invention is to overcome the deficiencies of the prior art and provide a method for preparing milopalline.

[0016] The milopalline of the present invention has a structure shown in the following formula I, and its preparation method specifically comprises the following steps:

[0017]

[0018] a) Preparation of 3-ethylbicyclo[3.2.0]hept-3-en-6-ylideneacetic acid methyl ester (III)

[0019]

[0020] Add a base and trimethylphosphonoacetate to the solvent, stir, add compound II, stir, and after the reaction is completed, perform post-treatment to obtain 3-ethylbicyclo[3.2.0]hept-3-ene-6-ylideneacetic acid methyl ester (III);

[0021] b) Preparation of methyl {(1R,5S,6S)-6-nitromethyl-3-ethylbicyclo[3.2.0]hept-3-en-6-yl}acetate (IV)

[0022]

[0023] Add compound III, nitromethane and a catalyst to the solvent, stir, and after the reaction is completed, perform post-treatment to obtain {(1R,5S,6S)-6-nitromethyl-3-ethylbicyclo[3.2.0]hept-3-en-6-yl}acetic acid methyl ester (IV);

[0024] c) Preparation of methyl {(1R,5S,6S)-6-aminomethyl-3-ethylbicyclo[3.2.0]hept-3-en-6-yl}acetate (V)

[0025]

[0026] Add compound IV, a catalyst, and a reducing agent to the solvent, stir, and after the reaction is completed, perform post-treatment to obtain {(1R,5S,6S)-6-aminomethyl-3-ethylbicyclo[3.2.0]hept-3-en-6-yl}acetic acid methyl ester (V);

[0027] d) Preparation of {(1R,5S,6S)-6-aminomethyl-3-ethylbicyclo[3.2.0]hept-3-en-6-yl}acetic acid (I)

[0028]

[0029] Compound V and an aqueous solution of a base are added to the solvent and stirred. After the reaction is completed, {(1R,5S,6S)-6-aminomethyl-3-ethylbicyclo[3.2.0]hept-3-en-6-yl}acetic acid (I) is obtained by post-treatment.

[0030] The preparation method of the above-mentioned Milobalin specifically includes the following route:

[0031]

[0032] In the method for preparing milopaline of the present invention:

[0033] The solvent in step a) is tetrahydrofuran, dichloromethane, N,N-dimethylformamide, N-methyl-2-pyrrolidone, etc., and the base is potassium tert-butoxide, sodium tert-butoxide, potassium hydroxide, sodium hydroxide, cesium hydroxide, etc.

[0034] The solvent in step b) is tetrahydrofuran, cyclohexane, n-hexane, dichloromethane, chloroform, etc., and the catalyst is (R)-1-(3-iminotrimethoxyphenylphosphine-1,1-diphenylpropane-2-yl)-3-(3,5-bis(trifluoromethyl)phenyl)thiourea, and the structural formula of the catalyst is as follows:

[0035] .

[0036] The solvent in step c) is methanol, ethanol, isopropanol, N,N-dimethylformamide, etc., the reducing agent is hydrazine hydrate, hydrogen, and the catalyst is Raney nickel, palladium on carbon, etc.

[0037] The base in step d) is lithium hydroxide and its hydrate, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, etc., and the solvent is tetrahydrofuran, N,N-dimethylformamide, dichloromethane, isopropanol, ethanol, methanol, etc.

[0038] Furthermore, in the method for preparing milopaline of the present invention:

[0039] In step a), the solvent is preferably tetrahydrofuran, and the base is preferably potassium tert-butoxide;

[0040] The solvent in step b) is preferably tetrahydrofuran;

[0041] In step c), the solvent is preferably methanol, the reducing agent is preferably hydrazine hydrate, and the catalyst is preferably Raney nickel;

[0042] In step d), the base is preferably lithium hydroxide monohydrate, and the solvent is preferably tetrahydrofuran.

[0043] The milobalin prepared as described above in the present invention can also be further prepared to obtain milobalin besylate through a simple salt-forming reaction, for example, according to CN104755456B (method for preparing optically active bicyclic γ-amino acid derivatives; Daiichi Sankyo Co., Ltd.).

[0044] In the preparation method of milopalline described in the present invention, the yields of the four-step reactions are all high. In addition, the present invention also adopts a chiral catalytic synthesis method, which significantly improves the atom economy of the reaction compared with the traditional chiral resolution or chiral separation technology, so that the preparation method of the present invention has good application prospects in the industrial production of milopalline.

[0045] The efficient synthesis strategy provided by the present invention is expected to reduce the production cost of milobarlin and improve the purity and yield of the product, thereby meeting production needs. Implementation

[0046] The present invention will be further described below with reference to specific embodiments, but the present invention is not limited thereto. Example

[0047] Preparation of 3-ethylbicyclo[3.2.0]hept-3-en-6-ylideneacetic acid methyl ester (III)

[0048] Potassium tert-butoxide (12.3 g, 0.11 mol) was dissolved in 100 mL of anhydrous tetrahydrofuran, and the temperature was lowered to 0°C. Trimethylphosphonoacetate (20 g, 0.11 mol) was slowly added to the solution, and the mixture was stirred for 1 h. 3-ethylbicyclo[3.2.0]hept-3-en-6-one (13.6 g, 0.1 mol) in 50 mL of tetrahydrofuran was added dropwise to the reaction solution, and the temperature was slowly raised to 50°C, and the mixture was stirred overnight.

[0049] Saturated aqueous ammonium chloride solution (300 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (300 mL×3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 3-ethylbicyclo[3.2.0]hept-3-ene-6-ylideneacetic acid methyl ester (III) (18.1 g, y=94.2%).

[0050] 1 H-NMR (300 MHz, CDCl3): δ 5.45 (m, 1 H), 5.25 (s, 1 H), 3.88 (brs, 1H), 3.62 (s, 3 H), 3.33 (m, 1 H), 2.95 (m, 1 H), 2.65 (m, 2 H), 2.15 (m, 3H), 1.08 (t, J = 7.2 Hz, 3 H).

[0051] Preparation of methyl {(1R,5S,6S)-6-nitromethyl-3-ethylbicyclo[3.2.0]hept-3-en-6-yl}acetate (IV)

[0052] Take 3-ethylbicyclo[3.2.0]hept-3-ene-6-ylideneacetic acid methyl ester (III) (1.92 g, 10 mmol) and nitromethane (1.83 g, 30 mmol) in 5 mL of tetrahydrofuran, add (R)-1-(3-iminotrimethoxyphenylphosphino-1,1-diphenylpropan-2-yl)-3-(3,5-bis(trifluoromethyl)phenyl)thiourea (212 mg, 0.25 mmol) to the solution, and react at room temperature for 48 h under nitrogen protection.

[0053] The solvent was concentrated under reduced pressure, and the residue was separated and purified by rapid silica gel column (PE:EA=10:1) to obtain methyl {(1R,5S,6S)-6-nitromethyl-3-ethylbicyclo[3.2.0]hept-3-en-6-yl} acetate (2.31 g, y=91.3%, ee=86%).

[0054] 1 H NMR (300 MHz, DMSO-d6): δ 5.26 (q, J = 2.0 Hz , 1H), 4.84 (m, 2H), 3.54 (s, 3 H), 3.14 (brs, 1H), 2.86 (m, 1H), 2.43 (m, 1H), 2.39 (m, 2H), 2.21(m, 1H), 2.14 (m, 2H), 2.03 (m, 1H), 1.48 (m, 1H), 1.04 (t, J = 7.5 Hz , 3H).

[0055] Preparation of methyl {(1R,5S,6S)-6-aminomethyl-3-ethylbicyclo[3.2.0]hept-3-en-6-yl}acetate (V)

[0056] Add {(1R,5S,6S)-6-nitromethyl-3-ethylbicyclo[3.2.0]hept-3-en-6-yl}acetic acid methyl ester (2.02 g, 8 mmol) into 20 mL of methanol, add Raney nickel (94 mg, 1.6 mmol) into the solution, add hydrazine hydrate solution (1.92 g, 48 mmol, 80% aqueous solution) dropwise in an ice-water bath, after the addition is complete, raise the temperature to reflux and react for 5 h.

[0057] The mixture was cooled, filtered with activated white clay, and concentrated under reduced pressure to give methyl {(1R,5S,6S)-6-aminomethyl-3-ethylbicyclo[3.2.0]hept-3-en-6-yl}acetate (1.65 g, y=92.1%).

[0058] 1 H NMR (300 MHz, DMSO-d6): δ5.35 (m, 1 H), 3.52 (s, 3 H), 2.90 (brs,1 H), 2.73 (m, 3 H), 2.51(m, 2 H), 2.23 (brs, 2 H), 2.14 (m, 2 H), 1.99 (m, 2H), 1.31(m, 2 H), 1.04 (m, 3 H).

[0059] Preparation of {(1R,5S,6S)-6-aminomethyl-3-ethylbicyclo[3.2.0]hept-3-en-6-yl}acetic acid (I)

[0060] Methyl {(1R,5S,6S)-6-aminomethyl-3-ethylbicyclo[3.2.0]hept-3-en-6-yl}acetate (1.34 g, 6 mmol) was added to 25 mL of tetrahydrofuran, and an aqueous solution (20 mL) containing lithium hydroxide monohydrate (0.38 g, 9 mmol) was added to the solution, and the mixture was stirred at room temperature for 6 h.

[0061] The organic solvent was concentrated under reduced pressure, and 1 M HCl aqueous solution was added dropwise to the remaining aqueous phase until the pH value was 6.6. A white solid precipitated and was filtered to obtain {(1R,5S,6S)-6-aminomethyl-3-ethylbicyclo[3.2.0]hept-3-en-6-yl}acetic acid (1.11 g, y=88.3%, ee=98.4%).

[0062] 1 H NMR (300 MHz, CD3OD): δ 5.38 (m, 1H), 3.33 (d, J = 13.5 Hz , 1H),3.28 (d, J = 13.5 Hz , 1H), 3.13 (m, 1H), 2.88 (m, 1H) , 2.51 (m, 3H) , 2.19(m, 4H) , 1.51 (m, 1H) , 1.10 ( t, J= 7.5 Hz , 3H).

[0063] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several simple adjustments or improvements can be made without departing from the concept of the present invention, which should be regarded as falling within the scope of protection of the present invention.

Claims

1. A method for preparing milopalline, characterized in that The steps include: a) Preparation of 3-ethylbicyclo[3.2.0]hept-3-en-6-ylideneacetic acid methyl ester (III) ； Add a base and trimethylphosphonoacetate to the solvent, stir, add compound II, stir, and after the reaction is completed, perform post-treatment to obtain 3-ethylbicyclo[3.2.0]hept-3-ene-6-ylideneacetic acid methyl ester (III); b) Preparation of methyl {(1R,5S,6S)-6-nitromethyl-3-ethylbicyclo[3.2.0]hept-3-en-6-yl}acetate (IV) ； Add compound III, nitromethane and a catalyst to the solvent, stir, and after the reaction is completed, perform post-treatment to obtain {(1R,5S,6S)-6-nitromethyl-3-ethylbicyclo[3.2.0]hept-3-en-6-yl}acetic acid methyl ester (IV); c) Preparation of methyl {(1R,5S,6S)-6-aminomethyl-3-ethylbicyclo[3.2.0]hept-3-en-6-yl}acetate (V) ； Add compound IV, a catalyst, and a reducing agent to the solvent, stir, and after the reaction is completed, perform post-treatment to obtain {(1R,5S,6S)-6-aminomethyl-3-ethylbicyclo[3.2.0]hept-3-en-6-yl}acetic acid methyl ester (V); d) Preparation of {(1R,5S,6S)-6-aminomethyl-3-ethylbicyclo[3.2.0]hept-3-en-6-yl}acetic acid (I) ； Compound V and an aqueous solution of a base are added to the solvent and stirred. After the reaction is completed, {(1R,5S,6S)-6-aminomethyl-3-ethylbicyclo[3.2.0]hept-3-en-6-yl}acetic acid (I) is obtained by post-treatment.

2. The preparation method according to claim 1, characterized in that The solvent in step a) is tetrahydrofuran, dichloromethane, N,N-dimethylformamide or N-methyl-2-pyrrolidone; the base is potassium tert-butoxide, sodium tert-butoxide, potassium hydroxide, sodium hydroxide or cesium hydroxide.

3. The preparation method according to claim 1, characterized in that The solvent in step b) is tetrahydrofuran, cyclohexane, n-hexane, dichloromethane or chloroform, and the catalyst is (R)-1-(3-iminotrimethoxyphenylphosphine-1,1-diphenylpropan-2-yl)-3-(3,5-bis(trifluoromethyl)phenyl)thiourea.

4. The preparation method according to claim 1, characterized in that The solvent in step c) is methanol, ethanol, isopropanol or N,N-dimethylformamide, the reducing agent is hydrazine hydrate or hydrogen, and the catalyst is Raney nickel or palladium on carbon.

5. The preparation method according to claim 1, characterized in that The base in step d) is lithium hydroxide and its hydrate, sodium hydroxide, potassium hydroxide, potassium carbonate or sodium carbonate, and the solvent is tetrahydrofuran, N,N-dimethylformamide, dichloromethane, isopropanol, ethanol or methanol.

6. The preparation method according to claim 2, characterized in that In step a), the solvent is tetrahydrofuran and the base is potassium tert-butoxide.

7. The preparation method according to claim 3, characterized in that In step b), the solvent is tetrahydrofuran.

8. The preparation method according to claim 4, characterized in that In step c), the solvent is methanol, the reducing agent is hydrazine hydrate, and the catalyst is Raney nickel.

9. The preparation method according to claim 5, characterized in that In step d), the base is lithium hydroxide monohydrate and the solvent is tetrahydrofuran.

10. The preparation method according to claim 1, characterized in that: a) Potassium tert-butoxide is dissolved in tetrahydrofuran, cooled to 0°C, trimethylphosphonoacetate is added to the solution, stirred, tetrahydrofuran containing 3-ethylbicyclo[3.2.0]hept-3-en-6-one is added to the reaction solution, stirred at 50°C; saturated aqueous ammonium chloride solution is added to the reaction solution, extracted with ethyl acetate, the organic layers are combined, dried, filtered, and concentrated under reduced pressure to obtain 3-ethylbicyclo[3.2.0]hept-3-en-6-ylidene acetate methyl ester (III); b) 3-ethylbicyclo[3.2.0]hept-3-en-6-ylidene acetate methyl ester and nitromethane are dissolved in tetrahydrofuran, (R)-1-(3-iminotrimethoxyphenylphosphine-1,1-diphenylpropan-2-yl)-3-(3,5-bis(trifluoromethyl)phenyl)thiourea is added to the solution, and the reaction is carried out at room temperature under nitrogen protection. The solvent is concentrated under reduced pressure and passed through a silica gel column to obtain {(1R,5S,6S)-6-nitromethyl-3-ethylbicyclo[3.2.0]hept-3-en-6-yl} acetate methyl ester (IV); c) Add {(1R,5S,6S)-6-nitromethyl-3-ethylbicyclo[3.2.0]hept-3-en-6-yl}acetic acid methyl ester to methanol, add Raney nickel to the solution, add hydrazine hydrate solution dropwise in an ice-water bath, and after the addition is complete, raise the temperature to reflux for reaction, cool, filter, and concentrate under reduced pressure to obtain {(1R,5S,6S)-6-aminomethyl-3-ethylbicyclo[3.2.0]hept-3-en-6-yl}acetic acid methyl ester (V); d) Methyl {(1R,5S,6S)-6-aminomethyl-3-ethylbicyclo[3.2.0]hept-3-en-6-yl}acetate was added to tetrahydrofuran, and an aqueous solution containing lithium hydroxide monohydrate was added to the solution. The mixture was stirred at room temperature, and the organic solvent was concentrated under reduced pressure. An aqueous solution of HCl was added dropwise to the remaining aqueous phase until the pH value was 6.

6. A white solid was precipitated, and the solid was filtered to obtain {(1R,5S,6S)-6-aminomethyl-3-ethylbicyclo[3.2.0]hept-3-en-6-yl}acetic acid (I).

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