Preparation method of milobalin intermediate

Abstract

The invention belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of a milobalin intermediate. The preparation method comprises the following steps: carrying out hydrogenation reaction on [(1RS, 5SR, 6RS)-6-cyano-3-ethyl bicyclo [3.2. 0] hept-3-ene-6-yl] diethyl malonate serving as a raw material under the action of palladium on carbon or raney nickel to obtain a compound III, and carrying out acid hydrolysis on the compound III to obtain [6-aminomethyl-3-ethyl bicyclo [3.2. 0] hept-3-ene-6-yl] acetic acid (racemization), namely a compound I. The preparation method comprises the following steps: carrying out a reaction on the raw material and the compound I, the method is novel in route, raw materials are easy to obtain, and compared with the prior art, the method has higher yield and is suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and particularly relates to a method for preparing a milobarlin intermediate. Background Art

[0002] Mirogabalin (DS-5565) is a gabapentinoid developed by Daiichi Sankyo Co., Ltd. Similar to drugs such as gabapentin and pregabalin, it acts on the voltage-gated calcium channel subunit α2δ. By binding to α2δ-1, it inhibits calcium-mediated neurotransmitter release in the dorsal fish, blocking neuronal excitation and sensory signaling. On January 8, 2019, mirogabalin besilate, developed by Daiichi Sankyo Co., Ltd., received marketing approval from the Japanese Medical Device Evaluation and Approval Agency (PMDA) under the trade name Tarlige (oral tablets, each containing 2.5mg, 5mg, 10mg, and 15mg of mirogabalin), for the treatment of peripheral neuropathic pain, including diabetic peripheral neuropathy and postherpetic neuralgia. Milobalin benzenesulfonate, chemical name: [(1R,5S,6S)-6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl]acetic acid monobenzenesulfonate. The structural formula is as follows:

[0003]

[0004] CN201480002091.0 discloses the reaction of (1RS, 5SR)-3-ethylbicyclo[3.2.0]hept-3-en-6-one (104.2 mg, 0.765 mmol) with diethyl malonate to produce diethyl [(1RS, 5SR)-3-ethylbicyclo[3.2.0]hept-3-ene-6-ylidene]malonate (racemate). [(1RS, 5SR)-3-ethylbicyclo[3.2.0]hept-3-ene-6-ylidene]malonate (racemate) is reacted with sodium cyanide to produce diethyl [(1RS, 5SR, 6RS)-6-cyano-3-ethylbicyclo[3.2.0]hept-3-en-6-yl]malonate. [(1RS, 5SR, 6RS)-6-cyano-3-ethylbicyclo[3.2.0]hept-3-en-6-yl]diethyl malonate is then subjected to alkaline hydrolysis and acid decarboxylation to obtain [(1RS, 5SR, 6SR)-6-cyano-3-ethylbicyclo[3.2.0]hept-3-en-6-yl]acetic acid; [(1RS, 5SR, 6SR)-6-cyano-3-ethylbicyclo[3.2.0]hept-3-en-6-yl]acetic acid is then resolved with benzylamine to obtain [(1R, 5S, 6S)-6-cyano-3-ethylbicyclo[3.2.0]hept-3-en-6-yl]benzylammonium acetate, which is further acidified and reduced with sponge cobalt to obtain [(1R, 5S, 6S)-6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl]acetic acid.

[0005]

[0006] CN201080015948.4 uses ethyl 3-oxohexanoate as a raw material to react with allyl bromide to obtain ethyl 4-ethyl-3-hydroxyhept-6-enoate through a series of reactions, and then prepares 4-ethyl-3-hydroxyhept-6-enoic acid through alkaline hydrolysis, which is further cyclized to obtain 3-ethylbicyclo[3.2.0]hept-6-en-6-one, and then reacts with tert-butyl dimethoxyphosphonoacetate to obtain tert-butyl 3-ethylbicyclo[3.2.0]hept-3-ene-6-ylideneacetate, and then adds nitromethane to obtain tert-butyl [3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl]acetate. Tert-butyl [3-ethyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl]acetate is reduced in the presence of iron powder and ammonium chloride to give [6-aminomethyl-3-ethylbicyclo[3.2.0]hept-3-en-6-yl]acetic acid, which is then chirally resolved to give milopalline.

[0007]

[0008] CN201911392902.3 reported that 3-ethylbicyclo[3.2.0]hept-3-en-6-one was used as the starting material, which reacted with cyanoacetate and ammonia to form an ammonium salt, which was then heated with sulfuric acid to form a diacid intermediate, which was then reacted with urea to form an imide intermediate, and then a Hofmann degradation reaction occurred in an alkaline solution to form milopalline.

[0009]

[0010] Through analysis of existing technologies, it was found that an intermediate compound in the preparation of milobarlin is relatively important. The structure is as follows:

[0011]

[0012] Therefore, how to prepare [6-aminomethyl-3-ethylbicyclo[3.2.0]hept-3-ene-6-yl]acetic acid in high yield and low cost has become another technical difficulty in the synthesis process of milopaline benzenesulfonate pharmaceutical. Summary of the Invention

[0013] The present invention aims to overcome the deficiencies in the prior art and provide a method for preparing a milopalline intermediate. This method solves the problem of low yield in the prior art. The present invention has a novel route, readily available raw materials, and a higher yield than the prior art, making it suitable for industrial production.

[0014] In order to achieve the above object, the present invention is implemented by the following scheme:

[0015] A method for preparing a milobarlin intermediate comprises the following steps:

[0016] Step 1, compound II is subjected to hydrogenation reaction under the action of hydrogen and a catalyst, and then post-treated to obtain compound III;

[0017] Step 2: Compound III is hydrolyzed under acidic conditions and post-treated to obtain Compound I. The reaction scheme is as follows:

[0018]

[0019] The specific steps are as follows:

[0020] Step 1: Dissolve compound II in an organic solvent at room temperature and add it to a pressure-resistant hydrogenation reactor. Then add a catalyst and perform nitrogen replacement. After nitrogen replacement, replace it with hydrogen. Fill hydrogen to the reaction pressure, control the temperature and stir the reaction. After the reaction is completed, post-process to obtain compound III.

[0021] Step 2: Compound III is added to a reaction vessel, an acid aqueous solution is added at room temperature, the temperature is raised to react, and after the reaction is completed, compound I is obtained by treatment.

[0022] In a preferred embodiment, the mass ratio of compound II to catalyst in step 1 is 1:0.01 to 0.1, preferably 1:0.04 to 0.08.

[0023] Preferably, the catalyst in step 1 is Pd / C or Raney nickel, preferably with a Pd / C content of 10%.

[0024] In a preferred embodiment, the reaction solvent in step 1 is one or more of ethanol, methanol, isopropanol, tetrahydrofuran, ethyl acetate, and 1,4-dioxane; preferably, the reaction solvent is ethanol.

[0025] In a preferred embodiment, the temperature of the hydrogenation reaction in step 1 is 25-50°C; preferably 25-30°C.

[0026] Preferably, the pressure in step 1 is 1 to 6 bar. The flow rate of hydrogen is not limited.

[0027] Preferably, the reaction time in step 1 is 4 to 8 hours.

[0028] In a preferred embodiment, the post-treatment in step 1 is as follows: after the reaction is completed, the catalyst is filtered out, and the filtrate is concentrated under reduced pressure to obtain compound III.

[0029] Preferably, the acid used for the acid hydrolysis in step 2 is sulfuric acid or hydrochloric acid, preferably hydrochloric acid, with a concentration of 6 mol / L.

[0030] In a preferred embodiment, the molar feed ratio of the acid to the compound III in step 2 is 2.0 to 3.0:1.

[0031] Preferably, the reaction temperature of step 2 is 80-100°C, preferably 85-90°C.

[0032] Preferably, the post-processing of step 2 is:

[0033] After the reaction is completed, the temperature is lowered, and the pH of the system is adjusted to pH 5-7 with an aqueous sodium hydroxide solution to allow a white solid to precipitate. The solid is filtered and rinsed with ethanol to obtain Compound I.

[0034] Preferably, the temperature is lowered by 5 to 15°C.

[0035] The concentration of the sodium hydroxide aqueous solution is 5% to 15% by mass.

[0036] Compared with the prior art, the technical effects achieved by the present invention are:

[0037] The present invention provides a method for preparing a milobalin intermediate. Racemic milobalin can be obtained through two-step reactions of hydrogenation and hydrolysis. The route is simple, and the yield of each step reaction is high, thereby ensuring the purity and yield of the final milobalin. DETAILED DESCRIPTION

[0038] The present invention is further illustrated by the following examples. It should be understood that the examples of the present invention are merely for illustrating the present invention, rather than for limiting the present invention. Therefore, simple improvements to the present invention based on the method of the present invention fall within the scope of protection claimed by the present invention.

[0039] The materials used in the present invention can be purchased or synthesized by yourself. For example, compound II can be prepared according to the method provided in CN104755456A. The operations or amounts not detailed in the patent are conventional operations or amounts used in the experiment.

[0040] Example 1

[0041]

[0042] Compound II (10 g), 10% Pd / C (0.5 g), and ethanol (50 mL) were placed in a pressure-resistant autoclave. Nitrogen was first introduced to remove oxygen, followed by hydrogen at a pressure of 5 bar. The autoclave temperature was maintained at 30°C. After 8 hours of reaction, the reaction was terminated. The solids were filtered, and the ethanol was removed under reduced pressure to yield Compound III in a 93.2% yield and 98.5% purity.

[0043] 1 H-NMR: (CDCl3, 300MHz) δ5.0(d,1H),3.78(m,2H),3.3(s,1H),3.2(s,1H),3.1(s,1H),2.0(m,1H),1.9(m,3H),0.9~1.8(m,10H).

[0044]

[0045] Compound III (5.26 g) was placed in a reaction vessel, and 8 mL of 6 mol / L hydrochloric acid solution was added at room temperature. The temperature was raised to 90°C and stirred for a hydrolysis reaction. After the reaction was complete, the reaction was stopped and the reaction mixture was cooled to 10°C. The pH was adjusted to 5 with 10% aqueous sodium hydroxide solution. A white solid precipitated, which was filtered and rinsed with anhydrous ethanol to obtain Compound I with a yield of 84.2% and a purity of 99.5%.

[0046] Example 2

[0047]

[0048] Compound II (10 g), 10% Pd / C (0.8 g), and ethanol (50 mL) were placed in a pressure-resistant autoclave. Nitrogen was first introduced to remove oxygen, followed by hydrogen at a pressure of 6 bar. The autoclave temperature was maintained at 30°C. After 7 hours of reaction, the reaction was terminated. The solids were filtered, and the ethanol was removed under reduced pressure to yield Compound III in a 94.1% yield and 98.0% purity.

[0049]

[0050] Compound III (5.26 g) was placed in a reaction vessel, and 10 mL of a 6 mol / L hydrochloric acid solution was added at room temperature. The temperature was raised to 90°C and stirred for a hydrolysis reaction. After the reaction was complete, the reaction was stopped and the reaction mixture was cooled to 10°C. The pH was adjusted to 5 with a 10% aqueous sodium hydroxide solution. A white solid precipitated, which was filtered and rinsed with anhydrous ethanol to obtain Compound I with a yield of 84.9% and a purity of 99.3%.

[0051] Example 3

[0052]

[0053] Compound II (10 g), 10% Pd / C (0.3 g), and ethanol (50 mL) were placed in a pressure-resistant autoclave. Nitrogen was first introduced to remove oxygen, followed by hydrogen at a pressure of 6 bar. The autoclave temperature was maintained at 30°C. After 8 hours of reaction, the reaction was terminated. The solids were filtered, and the ethanol was removed under reduced pressure to yield Compound III in a 90.2% yield and 97.9% purity.

[0054]

[0055] Compound III (5.26 g) was placed in a reaction vessel, and 6 mL of 6 mol / L hydrochloric acid solution was added at room temperature. The temperature was raised to 80°C and stirred for a hydrolysis reaction. After the reaction was complete, the reaction was stopped and the reaction mixture was cooled to 10°C. The pH was adjusted to 5 with 10% aqueous sodium hydroxide solution. A white solid precipitated, which was filtered and rinsed with anhydrous ethanol to obtain Compound I with a yield of 80.1% and a purity of 99.3%.

[0056] Example 4

[0057]

[0058] Compound II (10 g), Raney nickel (0.8 g), and ethanol (50 mL) were placed in a pressure-resistant autoclave. Nitrogen was first introduced to remove oxygen, followed by hydrogen at a pressure of 5 bar. The autoclave temperature was maintained at 40°C. After 8 hours of reaction, the reaction was stopped. The solids were filtered, and the ethanol was removed under reduced pressure to obtain Compound III with a yield of 90.4% and a purity of 98.1%.

[0059]

[0060] Compound III (5.26 g) was placed in a reaction vessel, and 8 mL of a 3 mol / L sulfuric acid solution was added at room temperature. The temperature was raised to 100°C and stirred for a hydrolysis reaction. After the reaction was complete, the reaction was stopped and the reaction mixture was cooled to 10°C. The pH was adjusted to 5 with a 10% aqueous sodium hydroxide solution. A white solid precipitated, which was filtered and rinsed with anhydrous ethanol to obtain Compound I with a yield of 82.4% and a purity of 99.4%.

Claims

1. A method for preparing a milopalline intermediate, characterized in that: Step 1, compound II is subjected to hydrogenation reaction under the action of hydrogen and a catalyst, and then post-treated to obtain compound III; Step 2: Compound III is hydrolyzed under acidic conditions and post-treated to obtain Compound I. The reaction scheme is as follows:

2. The preparation method according to claim 1, characterized in that The mass ratio of compound II to catalyst in step 1 is 1:0.01-0.1, preferably 1:0.04-0.

08.

3. The preparation method according to claim 1, characterized in that The catalyst in step 1 is Pd / C or Raney nickel, preferably with a content of 10% Pd / C.

4. The preparation method according to claim 1, characterized in that The reaction solvent in step 1 is one or more of ethanol, methanol, isopropanol, tetrahydrofuran, ethyl acetate, and 1,4-dioxane; preferably, the reaction solvent is ethanol.

5. The preparation method according to claim 1, characterized in that The temperature of the hydrogenation reaction in step 1 is 25-50°C, preferably 25-30°C.

6. The preparation method according to claim 1, characterized in that Post-treatment in step 1: After the reaction is completed, filter to remove the catalyst, and concentrate the filtrate under reduced pressure to obtain compound III.

7. The preparation method according to claim 1, characterized in that The acid used for the acid hydrolysis in step 2 is sulfuric acid or hydrochloric acid.

8. The preparation method according to claim 1, characterized in that In the step 2, the molar feed ratio of the acid to the compound III is 2.0-3.0:

1.

9. The preparation method according to claim 1, characterized in that The reaction temperature of step 2 is 80-100°C, preferably 85-90°C.

10. The preparation method according to claim 1, characterized in that Post-treatment of step 2: After the reaction is completed, the temperature is lowered, and the pH of the system is adjusted to 5-7 with an aqueous sodium hydroxide solution to precipitate a white solid, which is filtered and rinsed with ethanol to obtain compound I.

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