Preparation method of milobalin

Abstract

The invention belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of miloabalin. According to the preparation method, (1R, 5S)-3-ethyl bicyclo [3.2. 0] hept-3-ene-6 ketone is taken as an initial raw material, and is sequentially subjected to three steps of chemical reactions (a Horner-Witting reaction, a Mecanum addition reaction and a Hofmann degradation-hydrolysis reaction), so that the miloabalin can be obtained. The preparation method provided by the invention is short in synthetic route, the use of highly toxic sodium hydride and flammable and explosive nitromethane and Raney nickel catalytic hydrogenation process are avoided, and the safety is greatly improved. Moreover, the miloabalin prepared by the preparation method provided by the invention is high in total yield and high in purity, and is suitable for industrial batch production.

Description

Technical Field

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

[0002] Milobalin (structural formula shown in Formula I) is a new type of preferentially selective α2δ-1 ligand, and its unique pharmacodynamic properties are that it can efficiently and selectively act on the α2δ-1 subunit of the voltage-sensitive calcium channel complex in the central nervous system (CNS). This mechanism of action has a significant effect on the treatment of diseases related to neuropathic pain. In 2019, Japan approved Milobalin for the treatment of neuropathic pain, which has broad market prospects.

[0003]

[0004] PCT patent WO2010110361A1 discloses that racemic 3-ethylbicyclo[3.2.0]hept-3-en-6-one is used as the starting material, and milobarlin is obtained by four-step chemical reaction and one-step chiral separation (reaction flow chart as shown in FIG. Figure 1 This route has a long process and uses flammable and explosive nitromethane as a reaction reagent. In addition, flammable and explosive Raney nickel and hydrogen are used to catalyze the reduction of nitro groups, which poses a high safety risk and is not conducive to industrial production.

[0005] PCT patent WO2015005298A1 discloses that (1R,5S)-3-ethylbicyclo[3.2.0]hept-3-en-6-one is used as the starting material, and milobarlin is obtained by four-step chemical reaction and one-step chiral separation (reaction flow chart as shown in FIG. Figure 2 This route uses highly toxic sodium cyanide as a reaction reagent, and uses flammable and explosive Raney nickel and hydrogen to catalyze the reduction of nitro groups. It also has the problem of high safety risks and long reaction steps that are not conducive to industrial production. Summary of the invention

[0006] The object of the present invention is to provide a method for preparing milobalin. The method for preparing milobalin provided by the present invention has a short synthesis route, a simple process, and extremely high safety, and is suitable for industrial production.

[0007] In order to achieve the above object, the present invention provides the following technical solutions:

[0008] The present invention provides a method for preparing milopalline, comprising the following steps:

[0009] Mixing (1R,5S)-3-ethylbicyclo[3.2.0]hept-3-en-6-one, tert-butyl dimethoxyphosphoryl acetate, a first basic compound and a first organic solvent to carry out a Horner-Witting reaction to obtain tert-butyl (1R,5S)-3-ethylbicyclo[3.2.0]hept-3-en-6-ylidene acetate;

[0010] The (1R, 5S)-3-ethylbicyclo[3.2.0]hept-3-ene-6-ylidene acetate tert-butyl ester, acetamide, a second basic compound and a second organic solvent are mixed to carry out a Michael addition reaction to obtain (1R, 5S)[3-ethyl-6-(2-amino-2-oxoethyl)bicyclo[3.2.0]hept-3-ene-6-yl] acetate tert-butyl ester;

[0011] The (1R, 5S) [3-ethyl-6- (2-amino-2-oxoethyl) bicyclo [3.2.0] hept-3-en-6-yl] acetate tert-butyl ester, hypochlorite, alkali metal hydroxide and polar solvent are mixed to carry out Hofmann degradation and hydrolysis reaction to obtain the milopalline.

[0012] Preferably, the first alkaline compound comprises one or more of sodium hydroxide, potassium tert-butoxide and sodium tert-butoxide;

[0013] The first organic solvent includes one or more of tetrahydrofuran, isopropyl ether and methyl tert-butyl ether.

[0014] Preferably, the molar ratio of the (1R, 5S)-3-ethylbicyclo[3.2.0]hept-3-en-6-one to the dimethoxyphosphorylacetic acid tert-butyl ester is (0.3-0.4): (0.4-0.5);

[0015] The molar ratio of the dimethoxyphosphoryl acetate to the first basic compound is 1:1.

[0016] Preferably, after the Horner-Witting reaction is completed, a Horner-Witting reaction solution is obtained;

[0017] After obtaining the Horner-Witting reaction liquid, the method further comprises mixing the Horner-Witting reaction liquid and an extractant to perform extraction and separation to obtain an organic phase product; removing the solvent from the organic phase product to obtain the (1R, 5S)-3-ethylbicyclo[3.2.0]hept-3-ene-6-ylideneacetic acid tert-butyl ester;

[0018] The extractant is water or a mixture of toluene and water, and the volume ratio of toluene to water is (2-3):1.

[0019] Preferably, the second basic compound comprises one or more of 1,8-diazabicyclo[5.4.0]undec-7-ene, triethylamine and diisopropylethylamine;

[0020] The second organic solvent includes tetrahydrofuran and / or N,N-dimethylformamide.

[0021] Preferably, the mass ratio of the (1R, 5S)-3-ethylbicyclo[3.2.0]hept-3-ene-6-ylideneacetic acid tert-butyl ester to the acetamide is (80-90): (40-45);

[0022] The molar ratio of the acetamide to the second basic compound is (0.7-0.8):(0.3-0.8).

[0023] Preferably, the temperature of the Michael addition reaction is 60-70°C and the time is 5-8h;

[0024] After the Michael addition reaction is completed, a Michael addition reaction liquid is obtained;

[0025] After obtaining the Michael addition reaction liquid, the method further includes mixing the Michael addition reaction liquid and an extractant to perform extraction and separation to obtain an organic phase product; removing the solvent from the organic phase product to obtain the (1R, 5S) [3-ethyl-6-(2-amino-2-oxoethyl) bicyclo [3.2.0] hept-3-en-6-yl] acetate tert-butyl ester;

[0026] The extractant includes ethyl acetate and water, and the volume ratio of ethyl acetate to water is 1 to 2:1.

[0027] Preferably, the hypochlorite is an alkali metal hypochlorite; the alkali metal hydroxide is sodium hydroxide; the polar solvent includes water and / or tetrahydrofuran;

[0028] The molar ratio of the hypochlorite to the alkali metal hydroxide is (2-3):1.

[0029] Preferably, the temperature of the Hofmann degradation and hydrolysis reaction is 60-70° C. and the time is 6-8 hours.

[0030] Preferably, after the Hofmann degradation and hydrolysis reaction is completed, a Hofmann degradation and hydrolysis reaction liquid is obtained;

[0031] After obtaining the Hofmann degradation and hydrolysis reaction liquid, the method further includes mixing the Hofmann degradation and hydrolysis reaction liquid and an extractant to perform extraction and liquid separation to obtain an aqueous phase product; adjusting the pH value of the aqueous phase product to 6 to 7.5 and then performing solid-liquid separation to obtain a solid phase product; drying the solid phase product to obtain the milopalline; the extractant is ethyl acetate, and the drying is vacuum drying.

[0032] The invention provides a method for preparing milopalline, comprising the following steps: mixing (1R, 5S)-3-ethylbicyclo[3.2.0]hept-3-ene-6-one, dimethoxyphosphoryl acetate tert-butyl ester, a first alkaline compound and a first organic solvent to carry out Horner-Witting reaction to obtain (1R, 5S)-3-ethylbicyclo[3.2.0]hept-3-ene-6-ylidene acetate tert-butyl ester; , acetamide, a second alkaline compound and a second organic solvent are mixed to carry out a Michael addition reaction to obtain (1R, 5S) [3-ethyl-6- (2-amino-2-oxoethyl) bicyclo [3.2.0] hept-3-ene-6-yl] acetate tert-butyl ester; the (1R, 5S) [3-ethyl-6- (2-amino-2-oxoethyl) bicyclo [3.2.0] hept-3-ene-6-yl] acetate tert-butyl ester, hypochlorite, alkali metal hydroxide and polar solvent are mixed to carry out Hofmann degradation and hydrolysis reaction to obtain the milobalin. The present invention uses (1R, 5S) -3-ethylbicyclo [3.2.0] hept-3-ene-6-one as a starting material, and sequentially undergoes three chemical reactions (Horner-Witting reaction, Michael addition reaction, Hofmann degradation and hydrolysis reaction) to obtain milobalin. The preparation method provided by the present invention has a short synthetic route, avoids the use of highly toxic sodium hydride and the catalytic hydrogenation process of nitromethane and Raney nickel which is flammable and explosive, and greatly improves the safety. Moreover, the total yield of milopaline obtained by the preparation method provided by the present invention is high, the purity is high, and it is suitable for industrialized batch production. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 The synthesis route of Milobarlin disclosed in the prior art PCT patent WO2010110361A1;

[0034] Figure 2 The synthetic route of Milobarlin disclosed in the prior art PCT patent WO2015005298A1;

[0035] Figure 3 The present invention provides a synthetic route diagram of Milobarlin. DETAILED DESCRIPTION

[0036] The present invention provides a method for preparing milopalline, comprising the following steps:

[0037] Mixing (1R,5S)-3-ethylbicyclo[3.2.0]hept-3-en-6-one, tert-butyl dimethoxyphosphoryl acetate, a first basic compound and a first organic solvent to carry out a Horner-Witting reaction to obtain tert-butyl (1R,5S)-3-ethylbicyclo[3.2.0]hept-3-en-6-ylidene acetate;

[0038] The (1R, 5S)-3-ethylbicyclo[3.2.0]hept-3-ene-6-ylidene acetate tert-butyl ester, acetamide, a second basic compound and a second organic solvent are mixed to carry out a Michael addition reaction to obtain (1R, 5S)[3-ethyl-6-(2-amino-2-oxoethyl)bicyclo[3.2.0]hept-3-ene-6-yl] acetate tert-butyl ester;

[0039] The (1R, 5S) [3-ethyl-6- (2-amino-2-oxoethyl) bicyclo [3.2.0] hept-3-en-6-yl] acetate tert-butyl ester, hypochlorite, alkali metal hydroxide and polar solvent are mixed to carry out Hofmann degradation and hydrolysis reaction to obtain the milopalline.

[0040] In the present invention, unless otherwise specified, all preparation raw materials / components are commercially available products well known to those skilled in the art or are prepared by methods well known to those skilled in the art.

[0041] The present invention is to mix (1R, 5S)-3-ethylbicyclo [3.2.0] hept-3-ene-6-one, dimethoxyphosphoryl acetate tert-butyl ester, a first basic compound and a first organic solvent (hereinafter referred to as the first mixture) to perform Horner-Witting reaction to obtain (1R, 5S)-3-ethylbicyclo [3.2.0] hept-3-ene-6-ylidene acetate tert-butyl ester. In the present invention, the first basic compound preferably includes one or more of sodium hydroxide, potassium tert-butoxide and sodium tert-butoxide, and in the embodiment, it is specifically potassium tert-butoxide or sodium hydroxide. The first organic solvent preferably includes one or more of tetrahydrofuran, isopropyl ether and methyl tert-butyl ether, and in the embodiment, it is specifically methyl tert-butyl ether, isopropyl ether or tetrahydrofuran. The molar ratio of the (1R, 5S)-3-ethylbicyclo[3.2.0]hept-3-en-6-one to the dimethoxyphosphoryl acetate tert-butyl ester is preferably (0.3-0.4): (0.4-0.5), and specifically 0.367:0.441 in the embodiment. The molar ratio of the dimethoxyphosphoryl acetate to the first alkaline compound is preferably 1:1. The present invention has no special requirements for the amount of the first organic solvent, as long as the above raw materials are mixed evenly and the Horner-Witting reaction can be carried out smoothly. The first mixing preferably includes the following steps: dissolving the first alkaline compound in part of the first organic solvent to obtain a first alkaline compound solution; stirring and mixing the first alkaline compound solution with the dimethoxyphosphoryl acetic acid tert-butyl ester at ≤10°C, and then dripping (1R, 5S)-3-ethylbicyclo[3.2.0]hept-3-ene-6-one solution, wherein the (1R, 5S)-3-ethylbicyclo[3.2.0]hept-3-ene-6-one solution includes (1R, 5S)-3-ethylbicyclo[3.2.0]hept-3-ene-6-one and the remaining first organic solvent. The temperature of the first alkaline compound solution during the stirring and mixing is preferably 3 to 5°C. The temperature condition of the stirring and mixing is preferably ≤10°C, more preferably ≤5°C. The stirring and mixing time is preferably 1 to 2h. After the dropwise addition is completed, a mixed solution is obtained, and the present invention preferably subjects the mixed solution to the Horner-Witting reaction. The temperature of the Horner-Witting reaction is preferably 40 to 65° C., specifically 60° C. or 65° C. in the embodiment. The time of the Horner-Witting reaction is preferably 2 to 3 hours. The Horner-Witting reaction is preferably carried out under stirring.

[0042] In the present invention, after the Horner-Witting reaction is completed, a Horner-Witting reaction liquid is obtained; after obtaining the Horner-Witting reaction liquid, the present invention preferably further comprises mixing the Horner-Witting reaction liquid and an extractant (hereinafter referred to as the first extractant) for extraction and separation to obtain an organic phase product; removing the solvent from the organic phase product to obtain the (1R, 5S)-3-ethylbicyclo[3.2.0]hept-3-ene-6-ylidene acetate tert-butyl ester. In the present invention, the first extractant is preferably a mixture of toluene and water or water. When the first extractant is specifically a mixture of toluene and water, the volume ratio of toluene and water in the toluene and water mixture is preferably (2 to 3): 1. In the present invention, the specific embodiment of the solvent removal is preferably reduced pressure concentration. The (1R, 5S)-3-ethylbicyclo[3.2.0]hept-3-ene-6-ylidene acetate tert-butyl ester obtained by the present invention is a light yellow oil. In the present invention, the light yellow oily product obtained by removing the solvent from the organic phase product obtained by the Horner-Witting reaction is directly used for the subsequent Michael addition reaction.

[0043] After obtaining (1R, 5S)-3-ethylbicyclo[3.2.0]hept-3-ene-6-ylidene acetate tert-butyl ester, the present invention mixes the (1R, 5S)-3-ethylbicyclo[3.2.0]hept-3-ene-6-ylidene acetate tert-butyl ester, acetamide, a second basic compound and a second organic solvent (hereinafter referred to as the second mixture) to carry out a Michael addition reaction to obtain (1R, 5S) [3-ethyl-6-(2-amino-2-oxoethyl)bicyclo[3.2.0]hept-3-ene-6-yl] acetate tert-butyl ester. In the present invention, the second basic compound preferably includes one or more of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), triethylamine and diisopropylethylamine, and specifically DBU, triethylamine or diisopropylethylamine in the embodiment. The second organic solvent preferably includes tetrahydrofuran and / or N,N-dimethylformamide, and in the embodiment, it is specifically N,N-dimethylformamide or tetrahydrofuran. The mass ratio of the (1R,5S)-3-ethylbicyclo[3.2.0]hept-3-ene-6-ylidene acetate to the acetamide is preferably (80-90):(40-45), and in the embodiment, it is specifically 85.8:43.3, 83.2:43.3 or 84.3:43.3. The molar ratio of the acetamide and the second alkaline compound is preferably (0.7-0.8):(0.3-0.8), and in the embodiment, it is specifically 0.734:0.367 or 0.734:0.734. The present invention has no special requirements for the amount of the second organic solvent, and it is sufficient to ensure that the above-mentioned reaction raw materials are mixed evenly and the Michael addition reaction is carried out smoothly. The second mixing preferably includes the following steps: dissolving (1R, 5S)-3-ethylbicyclo[3.2.0]hept-3-ene-6-ylidene acetate tert-butyl ester in a second organic solvent to obtain a (1R, 5S)-3-ethylbicyclo[3.2.0]hept-3-ene-6-ylidene acetate tert-butyl ester solution; then stirring and mixing the (1R, 5S)-3-ethylbicyclo[3.2.0]hept-3-ene-6-ylidene acetate tert-butyl ester solution, acetamide and a second alkaline compound. In the present invention, the temperature of the Michael addition reaction is preferably 60 to 70°C, and specifically 65°C or 70°C in the embodiment. The time of the Michael addition reaction is preferably 5 to 8 hours, and specifically 5 hours or 6 hours in the embodiment;

[0044] In the present invention, after the Michael addition reaction is completed, a Michael addition reaction liquid is obtained; after obtaining the Michael addition reaction liquid, the present invention preferably further comprises mixing the Michael addition reaction liquid and an extractant (hereinafter referred to as a second extractant) for extraction and separation to obtain an organic phase product; the organic phase product is desolventized to obtain the (1R, 5S) [3-ethyl-6-(2-amino-2-oxoethyl) bicyclo [3.2.0] hept-3-en-6-yl] acetate tert-butyl ester. In the present invention, the second extractant preferably comprises ethyl acetate and water, and the volume ratio of ethyl acetate to water is 1:1. The specific implementation of the desolventization is preferably reduced pressure concentration. The (1R, 5S) [3-ethyl-6-(2-amino-2-oxoethyl) bicyclo [3.2.0] hept-3-en-6-yl] acetate tert-butyl ester obtained by the present invention is a light brown oily substance. The light brown oily product obtained by desolventizing the organic phase product obtained by the Michael addition reaction is directly used for the subsequent Hofmann degradation and hydrolysis reaction.

[0045] After obtaining (1R, 5S) [3-ethyl-6-(2-amino-2-oxoethyl) bicyclo [3.2.0] hept-3-en-6-yl] acetate tert-butyl ester, the present invention mixes the (1R, 5S) [3-ethyl-6-(2-amino-2-oxoethyl) bicyclo [3.2.0] hept-3-en-6-yl] acetate tert-butyl ester, hypochlorite, alkali metal hydroxide and polar solvent (hereinafter referred to as the third mixture) to perform Hofmann degradation and hydrolysis reaction to obtain the milopalline.

[0046] In the present invention, the Hofmann degradation and hydrolysis reaction includes a Hofmann degradation reaction and a hydrolysis reaction. In the present invention, the Hofmann degradation reaction and the hydrolysis reaction are carried out simultaneously in the above reaction.

[0047] The hypochlorite is preferably an alkali metal hypochlorite, and in the embodiment, it is specifically sodium hypochlorite. The alkali metal hydroxide is specifically sodium hydroxide. The polar solvent preferably includes water and / or tetrahydrofuran, and in the embodiment, it is specifically water or water and tetrahydrofuran. The molar ratio of the hypochlorite to the alkali metal hydroxide is preferably (2-3):1, and in the embodiment, it is specifically 2.5:1. The mass ratio of the (1R, 5S) [3-ethyl-6-(2-amino-2-oxoethyl) bicyclo [3.2.0] hept-3-en-6-yl] acetate to the alkali metal hydroxide is preferably (100-110):30, and in the embodiment, it is specifically 105.5:30, 102.3:30 or 104.4:30. In the present invention, when the polar solvent is water, the third mixing preferably includes the following steps: dissolving hypochlorite in part of the water to obtain an aqueous hypochlorite solution; dissolving an alkali metal hydroxide in the remaining water to obtain an aqueous alkali metal hydroxide solution; and stirring and mixing the 1R, 5S) [3-ethyl-6-(2-amino-2-oxoethyl) bicyclo [3.2.0] hept-3-en-6-yl] acetate, the aqueous hypochlorite solution and the aqueous metal hydroxide solution. In the present invention, when the polar solvent is tetrahydrofuran and water, the third mixing preferably comprises the following steps: dissolving (1R, 5S) [3-ethyl-6-(2-amino-2-oxoethyl) bicyclo [3.2.0] hept-3-ene-6-yl] acetate tert-butyl ester in tetrahydrofuran to obtain (1R, 5S) [3-ethyl-6-(2-amino-2-oxoethyl) bicyclo [3.2.0] hept-3-ene-6-yl] acetate tert-butyl ester solution; dissolving hypochlorite in part of the water to obtain a hypochlorite aqueous solution; dissolving an alkali metal hydroxide in the remaining water to obtain an alkali metal hydroxide aqueous solution; stirring and mixing the 1R, 5S) [3-ethyl-6-(2-amino-2-oxoethyl) bicyclo [3.2.0] hept-3-ene-6-yl] acetate tert-butyl ester solution, the hypochlorite aqueous solution and the metal hydroxide aqueous solution. In the present invention, the stirring and mixing temperature is preferably room temperature, and the time is preferably 20 to 30 minutes. In the present invention, the temperature of the Hofmann degradation and hydrolysis reaction is preferably 60-70°C, specifically 70°C or 60°C in the embodiments, and the time of the Hofmann degradation and hydrolysis reaction is preferably 6-8h, specifically 6h in the embodiments.

[0048] In the present invention, after the Hofmann degradation and hydrolysis reaction is completed, a Hofmann degradation and hydrolysis reaction liquid is obtained; after obtaining the Hofmann degradation and hydrolysis reaction liquid, the present invention preferably further comprises mixing the Hofmann degradation and hydrolysis reaction liquid and an extractant (hereinafter referred to as a third extractant) for extraction and liquid separation to obtain an aqueous phase product; adjusting the pH value of the aqueous phase product to 6 to 7.5 and then performing solid-liquid separation to obtain a solid phase product; drying the solid phase product to obtain the milobarlin. In the present invention, the third extractant is preferably ethyl acetate. The number of extraction and liquid separation is preferably 2 times. The reagent used to adjust the pH value of the aqueous phase product is preferably hydrochloric acid, and the mass percentage of the hydrochloric acid is preferably 10%. The present invention preferably adjusts the pH value of the aqueous phase product to 6.5 to 7.5, specifically 6.5, 7 or 7.5 in the embodiment. The present invention preferably adjusts the pH value of the aqueous phase product to 6 to 7.5, and a large amount of white solid is precipitated in the aqueous phase product. The solid-liquid separation is preferably filtration. The drying is preferably vacuum drying.

[0049] In summary, the preparation method of milopalline provided by the present invention has a short synthetic route, a simple process, and extremely high safety, and is suitable for industrial production.

[0050] In order to further illustrate the present invention, the technical solutions provided by the present invention are described in detail below in conjunction with embodiments, but they should not be construed as limiting the protection scope of the present invention.

[0051] The following examples are based on Figure 3 The flow chart shown is for the preparation of milobarlin.

[0052] Example 1

[0053] (1) Preparation of (1R,5S)-3-ethylbicyclo[3.2.0]hept-3-ene-6-ylideneacetic acid tert-butyl ester:

[0054] Add potassium tert-butoxide (49.4g, 0.441mol) and tetrahydrofuran 250mL to a 2000mL three-necked flask, stir and dissolve, then cool to 3°C, and slowly add dimethoxyphosphoryl acetate tert-butyl ester (98.8g, 0.441mol) at a temperature below 5°C. Continue stirring for 1h, and drop a mixed solution of (1R, 5S)-3-ethylbicyclo[3.2.0]hept-3-ene-6-one (50.0g, 0.367mol) and tetrahydrofuran (125mL). After the addition is complete, continue stirring for 2h, add 500mL of toluene and 250mL of water to extract the liquid. The organic phase is concentrated to dryness under reduced pressure to obtain 85.8g (yield 100%) of light yellow oil, which is directly used in the next step.

[0055] (2) Preparation of tert-butyl (1R, 5S) [3-ethyl-6-(2-amino-2-oxoethyl) bicyclo [3.2.0] hept-3-en-6-yl] acetate:

[0056] Dissolve the oil obtained in step (1) above in 430 mL of N,N-dimethylformamide and transfer to a 2000 mL three-necked flask. Add acetamide (43.3 g, 0.734 mol) and DBU (55.8 g, 0.367 mol) and stir to dissolve. Heat to 65°C for 5 h and cool to room temperature. Add 500 mL of ethyl acetate and 500 mL of water to extract. Concentrate the organic phase under reduced pressure to dryness to obtain 105.5 g of light brown oil with a yield of 98%. 1 H-NMR(400Hz, CDCl3)δ:5.36-5.33(1H,m),3.02-2.98(1H,m),2.71-2.61(3H,m),2.51-2.36(m,2H),2.18-2 .16(2H,m),2.14-2.06(m,2H),1.99-1.90(m,2H),1.44-1.40(m,9H),1.31-1.25(m,2H),1.01-0.98(m,3H).

[0057] (3) Preparation of Milobarlin:

[0058] To the oil obtained in step (2), add 20% sodium hydroxide aqueous solution (water 120mL, sodium hydroxide 30g, 0.75mol) and 10% sodium hypochlorite aqueous solution 1.36kg (sodium hypochlorite 1.84mol), stir at room temperature for 30min, heat to 60°C and react for 6h. Cool to room temperature, extract twice with 500mL of ethyl acetate, adjust the pH of the aqueous phase to 6.5 with 10% hydrochloric acid, precipitate a large amount of white solid, and filter. Collect the filter cake and vacuum dry (45-50°C) to obtain 67.7g of off-white milopaline, with a yield of 90% and a HPLC purity of 99.3%. 1 H-NMR(400Hz, CDCl3)δ:5.42(1H,d),3.17(2H,d),3.06(1H,d),2.75-2.69(1H,m),2.3 3-2.51(3H,m),2.07-2.15(3H,m),1.98-2.02(1H,d),1.51-1.48(1H,d),1.02(3H,t).

[0059] Example 2

[0060] (1) Preparation of (1R,5S)-3-ethylbicyclo[3.2.0]hept-3-ene-6-ylideneacetic acid tert-butyl ester:

[0061] Add sodium hydroxide (17.6g, 0.441mol) and isopropyl ether 250mL to a 2000mL three-necked flask, stir and dissolve, cool to 5℃, and slowly add dimethoxyphosphoryl acetate tert-butyl ester (98.8g, 0.441mol) at a temperature below 10℃. Continue stirring for 1h, and drop a mixed solution of (1R,5S)-3-ethylbicyclo[3.2.0]hept-3-ene-6-one (50.0g, 0.367mol) and isopropyl ether (125mL). After the addition is complete, heat to 60℃ and continue stirring for 3h. Cool to room temperature, add 250mL of water to extract and separate. The organic phase is concentrated to dryness under reduced pressure to obtain 83.2g (yield 96.7%) of light yellow oil, which is directly used in the next step.

[0062] (2) Preparation of tert-butyl (1R, 5S) [3-ethyl-6-(2-amino-2-oxoethyl) bicyclo [3.2.0] hept-3-en-6-yl] acetate:

[0063] Dissolve the oil obtained in step (1) above with 415 mL of N,N-dimethylformamide and transfer to a 2000 mL three-necked flask. Add acetamide (43.3 g, 0.734 mol) and triethylamine (74.8 g, 0.734 mol) and stir to dissolve. Heat to 70°C for 6 h and cool to room temperature. Add 500 mL of ethyl acetate and 500 mL of water to extract. Concentrate the organic phase under reduced pressure to dryness to obtain 102.3 g of light brown oil, with a yield of 95%.

[0064] (3) Preparation of Milobarlin:

[0065] To the oil obtained in step (2), add 20% aqueous sodium hydroxide solution (120 mL of water, 30 g of sodium hydroxide, 0.75 mol) and 1.36 kg (1.84 mol) of 10% aqueous sodium hypochlorite solution, stir at room temperature for 30 min, and heat to 70°C for 6 h. Cool to room temperature, extract twice with 500 mL of ethyl acetate, adjust the pH of the aqueous phase to 7 with 10% hydrochloric acid, precipitate a large amount of white solid, and filter. Collect the filter cake and vacuum dry (45-50°C) to obtain 65.4 g of off-white milopalline, with a yield of 87% and an HPLC purity of 98.8%.

[0066] Example 3

[0067] (1) Preparation of (1R,5S)-3-ethylbicyclo[3.2.0]hept-3-ene-6-ylideneacetic acid tert-butyl ester:

[0068] Add sodium hydroxide (17.6g, 0.441mol) and 250mL of methyl tert-butyl ether to a 2000mL three-necked flask, stir and dissolve, then cool to 5°C, and slowly add tert-butyl dimethoxyphosphoryl acetate (98.8g, 0.441mol) at a temperature below 10°C. Continue stirring for 1h, and drop a mixed solution of (1R, 5S)-3-ethylbicyclo[3.2.0]hept-3-ene-6-one (50.0g, 0.367mol) and methyl tert-butyl ether (125mL). After the addition is complete, heat to 65°C and continue stirring for 3h. Cool to room temperature, add 250mL of water to extract and separate. The organic phase is concentrated to dryness under reduced pressure to obtain 84.3g (yield 98.0%) of light yellow oil, which is directly used in the next step.

[0069] (2) Preparation of tert-butyl (1R,5S)[3-ethyl-6-(2-amino-2-oxoethyl)bicyclo[3.2.0]hept-3-en-6-yl]acetate.

[0070] Dissolve the oil obtained in step (1) above in 420 mL of tetrahydrofuran and transfer to a 2000 mL three-necked flask. Add acetamide (43.3 g, 0.734 mol) and diisopropylethylamine (94.8 g, 0.734 mol) and stir to dissolve. Heat to 70°C for 6 h and cool to room temperature. Add 500 mL of ethyl acetate and 500 mL of water to extract. Concentrate the organic phase under reduced pressure to dryness to obtain 104.4 g of light brown oil, with a yield of 97%.

[0071] (3) Preparation of Milobarlin

[0072] To the oil obtained in step (2), add 400 mL of tetrahydrofuran, 50% aqueous sodium hydroxide solution (30 mL of water, 30 g of sodium hydroxide, 0.75 mol) and 1.36 kg (1.84 mol) of 10% aqueous sodium hypochlorite solution, stir at room temperature for 30 min, and heat to 70°C for 6 h. Cool to room temperature, extract twice with 500 mL of ethyl acetate, adjust the pH of the aqueous phase to 7.5 with 10% hydrochloric acid, precipitate a large amount of white solid, and filter. Collect the filter cake and vacuum dry (45-50°C) to obtain 69.2 g of off-white milopalline, with a yield of 92% and an HPLC purity of 99.1%.

[0073] Comparative Example 1

[0074] (1) Prepare (1R,5S)-3-ethylbicyclo[3.2.0]hept-3-ene-6-ylideneacetic acid tert-butyl ester according to step (1) in Example 3;

[0075] (2) Preparation of tert-butyl (1R,5S)[3-ethyl-6-(2-amino-2-oxoethyl)bicyclo[3.2.0]hept-3-en-6-yl]acetate.

[0076] Dissolve the oil obtained in step (1) above in 420 mL of tetrahydrofuran and transfer to a 2000 mL three-necked flask. Add acetamide (43.3 g, 0.734 mol) and pyridine (58.1 g, 0.734 mol) and stir to dissolve. Heat to 70°C for 6 h and cool to room temperature. Add 500 mL of ethyl acetate and 500 mL of water to extract the liquid. Concentrate the organic phase under reduced pressure to dryness to obtain 78.6 g of light brown oil, with a yield of 73%.

[0077] Comparative Example 1 is compared with Example 3. In Comparative Example 1, the basic compound used in the preparation of (1R, 5S) [3-ethyl-6- (2-amino-2-oxoethyl) bicyclo [3.2.0] hept-3-en-6-yl] acetate tert-butyl ester is pyridine. Under the same molar amount of the basic compound, the basic compound used in Example 3 is diisopropylethylamine. When pyridine is used in Comparative Example 1, the yield of the target product (1R, 5S) [3-ethyl-6- (2-amino-2-oxoethyl) bicyclo [3.2.0] hept-3-en-6-yl] acetate tert-butyl ester obtained in step (2) is reduced from 97% in Example 3 to 73%. This indicates that in Example 3 of the present invention, by selecting an appropriate alkaline compound in step (2), the yield of (1R, 5S)[3-ethyl-6-(2-amino-2-oxoethyl)bicyclo[3.2.0]hept-3-ene-6-yl]acetic acid tert-butyl ester in step (2) can be effectively improved.

[0078] Comparative Example 2

[0079] (1) Prepare (1R,5S)-3-ethylbicyclo[3.2.0]hept-3-ene-6-ylideneacetic acid tert-butyl ester according to step (1) in Example 1;

[0080] (2) Preparation of tert-butyl (1R,5S)[3-ethyl-6-(2-amino-2-oxoethyl)bicyclo[3.2.0]hept-3-en-6-yl]acetate.

[0081] Dissolve the oil obtained in step (1) above in 430 mL of N,N-dimethylformamide and transfer to a 2000 mL three-necked flask. Add acetamide (43.3 g, 0.734 mol) and DBU (55.8 g, 0.367 mol) and stir to dissolve. Heat to 45°C for 5 h and cool to room temperature. Add 500 mL of ethyl acetate and 500 mL of water to extract. Concentrate the organic phase under reduced pressure to dryness to obtain 84.0 g of light brown oil, with a yield of 78%.

[0082] Comparative Example 2 is compared with Example 1. When preparing (1R, 5S)[3-ethyl-6-(2-amino-2-oxoethyl)bicyclo[3.2.0]hept-3-en-6-yl]acetate tert-butyl ester in Comparative Example 2, the temperature of the Michael addition reaction is 45°C. Under the conditions that the types and amounts of the raw materials are the same, the temperature of the Michael addition reaction in Example 1 is 65°C, while when the Michael addition reaction temperature of Comparative Example 2 is 45°C, the yield of the target product (1R, 5S)[3-ethyl-6-(2-amino-2-oxoethyl)bicyclo[3.2.0]hept-3-en-6-yl]acetate obtained in step (2) is reduced from 98% in Example 1 to 78%. This indicates that Example 1 of the present invention can effectively improve the yield of tert-butyl (1R, 5S)[3-ethyl-6-(2-amino-2-oxoethyl)bicyclo[3.2.0]hept-3-en-6-yl]acetate in step (2) by controlling the temperature of the Michael addition reaction in step (2).

[0083] Comparative Example 3

[0084] (1) Prepare (1R,5S)-3-ethylbicyclo[3.2.0]hept-3-ene-6-ylideneacetic acid tert-butyl ester according to step (1) in Example 1;

[0085] (2) According to Example 1, tert-butyl 1R, 5S) [3-ethyl-6-(2-amino-2-oxoethyl) bicyclo [3.2.0] hept-3-en-6-yl] acetate was prepared.

[0086] (3) Preparation of Milobarlin:

[0087] To the oil obtained in step (2), add 20% aqueous sodium hydroxide solution (120 mL of water, 30 g of sodium hydroxide) and 1.36 kg of 10% aqueous sodium hypochlorite solution (1.84 mol of sodium hypochlorite), stir at room temperature for 30 min, and heat to 40°C for 6 h. Cool to room temperature, extract twice with 500 mL of ethyl acetate, adjust the pH of the aqueous phase to 6.5 with 10% hydrochloric acid, precipitate a large amount of white solid, and filter. Collect the filter cake and vacuum dry (45-50°C) to obtain 56.4 g of off-white milopalline, with a yield of 75% and an HPLC purity of 90.6%.

[0088] Comparative Example 3 is compared with Example 1. When preparing milobalin in Comparative Example 3, the temperature of Hofmann degradation and hydrolysis reaction is 40°C. Under the same conditions of the type and amount of raw materials, the temperature of Hofmann degradation and hydrolysis reaction in Example 1 is 60°C, while when the temperature of Hofmann degradation and hydrolysis reaction in Comparative Example 3 is 40°C, the yield of the target product milobalin obtained in step (3) is reduced from 90% in Example 1 to 75%, and the purity of milobalin is reduced from 99.3% in Example 1 to 90.6%. It shows that Example 1 of the present invention can effectively improve the yield and purity of milobalin in step (3) by controlling the temperature of Hofmann degradation and hydrolysis reaction.

[0089] Comparative Example 4

[0090] (1) Prepare (1R,5S)-3-ethylbicyclo[3.2.0]hept-3-ene-6-ylideneacetic acid tert-butyl ester according to step (1) in Example 1;

[0091] (2) According to Example 1, tert-butyl 1R, 5S) [3-ethyl-6-(2-amino-2-oxoethyl) bicyclo [3.2.0] hept-3-en-6-yl] acetate was prepared.

[0092] (3) Preparation of Milobarlin:

[0093] To the oil obtained in step (2), add 20% aqueous sodium hydroxide solution (120 mL of water, 30 g of sodium hydroxide, 0.75 mol) and 0.68 kg of 10% aqueous sodium hypochlorite solution (0.92 mol of sodium hypochlorite), stir at room temperature for 30 min, and heat to 60°C for 6 h. Cool to room temperature, extract twice with 500 mL of ethyl acetate, adjust the pH of the aqueous phase to 6.5 with 10% hydrochloric acid, precipitate a large amount of white solid, and filter. Collect the filter cake and vacuum dry to obtain 39.9 g of off-white milopalline, with a yield of 53% and an HPLC purity of 78.6%.

[0094] Comparative Example 4 is compared with Example 1. When preparing milobalin in Comparative Example 4, the molar ratio of sodium hypochlorite to sodium hydroxide is 1.2:1. Under the same other reaction conditions, the molar ratio of sodium hypochlorite to sodium hydroxide in Example 1 is 2.5:1, and when the molar ratio of sodium hypochlorite to sodium hydroxide in Comparative Example 4 is 1.2:1, the yield of the target product milobalin obtained in step (3) is reduced from 90% in Example 1 to 53%, and the purity of milobalin is reduced from 99.3% in Example 1 to 75.6%. It shows that Example 1 of the present invention can effectively improve the yield and purity of milobalin in step (3) by controlling the molar ratio of sodium hypochlorite to sodium hydroxide.

[0095] From the above examples, it can be seen that the present invention uses (1R, 5S)-3-ethylbicyclo[3.2.0]hept-3-ene-6-one as the starting material, and sequentially undergoes three chemical reactions (Horner-Witting reaction, Michael addition reaction, Hofmann degradation and hydrolysis reaction) to obtain milobalin. The preparation method provided by the present invention has a short synthetic route, avoids the use of highly toxic sodium hydride and the flammable and explosive nitromethane and Raney nickel catalytic hydrogenation process, and the safety is greatly improved. Moreover, the total yield of milobalin obtained by the preparation method provided by the present invention is high, the purity is high, and it is suitable for industrial batch production.

[0096] Although the above embodiment describes the present invention in detail, it is only a part of the embodiments of the present invention, not all of the embodiments. Other embodiments can be obtained based on this embodiment without creativity, and these embodiments all fall within the protection scope of the present invention.

Claims

1. A method for preparing milopalline, characterized in that: The following steps are involved: Mixing (1R,5S)-3-ethylbicyclo[3.2.0]hept-3-en-6-one, tert-butyl dimethoxyphosphoryl acetate, a first basic compound and a first organic solvent to carry out a Horner-Witting reaction to obtain tert-butyl (1R,5S)-3-ethylbicyclo[3.2.0]hept-3-en-6-ylidene acetate; The (1R, 5S)-3-ethylbicyclo[3.2.0]hept-3-ene-6-ylidene acetate tert-butyl ester, acetamide, a second basic compound and a second organic solvent are mixed to carry out a Michael addition reaction to obtain (1R, 5S)[3-ethyl-6-(2-amino-2-oxoethyl)bicyclo[3.2.0]hept-3-ene-6-yl] acetate tert-butyl ester; The (1R, 5S) [3-ethyl-6- (2-amino-2-oxoethyl) bicyclo [3.2.0] hept-3-en-6-yl] acetate tert-butyl ester, hypochlorite, alkali metal hydroxide and polar solvent are mixed to carry out Hofmann degradation and hydrolysis reaction to obtain the milopalline.

2. The preparation method according to claim 1, characterized in that: The first alkaline compound includes one or more of sodium hydroxide, potassium tert-butoxide and sodium tert-butoxide; The first organic solvent includes one or more of tetrahydrofuran, isopropyl ether and methyl tert-butyl ether.

3. The preparation method according to claim 1 or 2, characterized in that: The molar ratio of the (1R,5S)-3-ethylbicyclo[3.2.0]hept-3-en-6-one to the dimethoxyphosphorylacetic acid tert-butyl ester is (0.3-0.4):(0.4-0.5); The molar ratio of the dimethoxyphosphoryl acetate to the first basic compound is 1:

1.

4. The preparation method according to claim 1, characterized in that: After the Horner-Witting reaction is completed, a Horner-Witting reaction solution is obtained; After obtaining the Horner-Witting reaction liquid, the method further comprises mixing the Horner-Witting reaction liquid and an extractant to perform extraction and separation to obtain an organic phase product; removing the solvent from the organic phase product to obtain the (1R, 5S)-3-ethylbicyclo[3.2.0]hept-3-ene-6-ylideneacetic acid tert-butyl ester; The extractant is water or a mixture of toluene and water, and the volume ratio of toluene to water in the mixture of toluene and water is (2-3):

1.

5. The preparation method according to claim 1, characterized in that: The second basic compound includes one or more of 1,8-diazabicyclo[5.4.0]undec-7-ene, triethylamine and diisopropylethylamine; The second organic solvent includes tetrahydrofuran and / or N,N-dimethylformamide.

6. The preparation method according to claim 1 or 5, characterized in that: The mass ratio of the (1R,5S)-3-ethylbicyclo[3.2.0]hept-3-ene-6-ylideneacetic acid tert-butyl ester to the acetamide is (80-90):(40-45); The molar ratio of the acetamide to the second basic compound is (0.7-0.8):(0.3-0.8).

7. The preparation method according to claim 1, characterized in that: The temperature of the Michael addition reaction is 60-70°C and the time is 5-8h; After the Michael addition reaction is completed, a Michael addition reaction liquid is obtained; After obtaining the Michael addition reaction liquid, the method further includes mixing the Michael addition reaction liquid and an extractant to perform extraction and separation to obtain an organic phase product; removing the solvent from the organic phase product to obtain the (1R, 5S) [3-ethyl-6-(2-amino-2-oxoethyl) bicyclo [3.2.0] hept-3-en-6-yl] acetate tert-butyl ester; The extractant includes ethyl acetate and water, and the volume ratio of ethyl acetate to water is 1 to 2:

1.

8. The preparation method according to claim 1, characterized in that: The hypochlorite is an alkali metal hypochlorite; the alkali metal hydroxide is sodium hydroxide; the polar solvent includes water and / or tetrahydrofuran; The molar ratio of the hypochlorite to the alkali metal hydroxide is (2-3):

1.

9. The preparation method according to claim 1 or 8, characterized in that: The temperature of the Hofmann degradation and hydrolysis reaction is 60-70° C. and the time is 6-8 hours.

10. The preparation method according to claim 1, characterized in that: After the Hofmann degradation and hydrolysis reaction is completed, a Hofmann degradation and hydrolysis reaction liquid is obtained; After obtaining the Hofmann degradation and hydrolysis reaction liquid, the method further includes mixing the Hofmann degradation and hydrolysis reaction liquid and an extractant to perform extraction and liquid separation to obtain an aqueous phase product; adjusting the pH value of the aqueous phase product to 6 to 7.5 and then performing solid-liquid separation to obtain a solid phase product; drying the solid phase product to obtain the milopalline; the extractant is ethyl acetate, and the drying is vacuum drying.

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