Preparation method of levosimendan

Abstract

The invention discloses a preparation method of a levosimendan intermediate, propionyl chloride is used as an initial raw material, a chiral induction reagent reacts with halogenated ethyl acetate, hydrolysis is performed under an alkaline condition, and (S)-4-ethoxy-2-methyl-4-oxobutyric acid is prepared, the method reduces the production cost, the reaction condition is mild, and the method is suitable for industrial production. The invention further provides a preparation method of levosimendan, (S)-4-ethoxy-2-methyl-4-oxobutyric acid is used as a chiral raw material, a complicated traditional chiral resolution process is avoided, and the product yield is greatly improved.

Description

Technical Field

[0001] The invention relates to a preparation method of levosimendan, and belongs to the technical field of drug intermediate synthesis. Background Art

[0002] Levosimendan is a calcium ion sensitizer that works by changing the calcium binding information transmission. Levosimendan directly binds to troponin, stabilizing the spatial configuration of myocardial fibrin necessary for calcium ion-induced myocardial contraction, thereby increasing myocardial contractility, while heart rate and myocardial oxygen consumption do not change significantly. At the same time, levosimendan has a strong vasodilator effect, which dilates blood vessels by activating potassium channels sensitive to adenosine triphosphate (ATP). This product mainly dilates peripheral veins and reduces cardiac preload, which is beneficial for the treatment of heart failure. When levosimendan is used in large doses, it has a certain phosphodiesterase inhibitory effect, which can increase the concentration of cAMP in myocardial cells and exert an additional positive inotropic effect. The drug was developed by Orion, a Finnish company, and was first launched in Sweden in October 2000 for the short-term treatment of acute decompensated heart failure (ADHF) that requires increased myocardial contractility.

[0003] The main route for synthesizing levosimendan is to use the starting material 4-(4-aminophenyl)-3-methyl-4-oxobutyric acid as a raw material, and then undergo hydrazine hydrate ring closure, chiral resolving agent resolving, freeing, diazotization and malononitrile reaction to prepare levosimendan. Therefore, the chiral intermediate ((R)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone) is an important intermediate in the synthesis of levosimendan. There are currently two publicly disclosed methods for preparing levosimendan by constructing a chiral center:

[0004] 1. Literature reports use tartaric acid (L-tartaric acid [US5569657], D-tartaric acid [US6180789] or D-(+)-di-p-methoxybenzoyltartaric acid [WO2011007123A1]) as a chiral resolving agent to resolve 6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone to obtain an optically active intermediate. The synthetic route is as follows:

[0005]

[0006] The chiral intermediates are prepared by the chiral resolution method, but the resolution yield is low, the ee value is about 70% at most, and the amount of resolution agent used is large, which is costly. In order to further remove the isomeric impurities, the highly toxic solvent dioxane is required. In addition, the starting material 4-(4-aminophenyl)-3-methyl-4-oxobutanoic acid is expensive, and the utilization rate of the chiral intermediates generated by the reaction is not high, resulting in high product costs, which limits its application in drug synthesis.

[0007] 2. Franklin et al. (Franklin FO; Margaret F.; Conrad JK, et al. An Enantioselective Synthesis of SK&F93505, a Key Intermediate for Preparing Cardiotonic Agents [J]. J. Org. Chem (1991) 56: 1963-1966.) reported a method of introducing a chiral center in the initial stage of the reaction, and synthesized an important optically active intermediate through Friedel-Crafs acylation, hydrolysis, alkylation, Pd / C-catalyzed hydrogenolysis, decarboxylation, cyclization and other reactions.

[0008]

[0009] Compared with the traditional splitting method, the chiral synthesis method not only saves raw materials and avoids waste, but also greatly saves time and energy. However, this method uses (R)-(-)-chloropropionyl chloride, which is expensive, has complicated steps, and requires hydrogenation to remove the benzyl protecting group, which is not suitable for industrial production.

[0010] Therefore, designing a new preparation method for constructing the chiral center of levosimendan is the key to reducing the cost of levosimendan, simplifying the process, improving the safety of the process, and constructing a synthetic route that is more suitable for industrial production. Summary of the invention

[0011] The present invention aims at the deficiencies in the prior art and provides a new preparation method of levosimendan. Levosimendan is synthesized by using (S)-4-methoxy-2-methyl-4-oxobutyric acid as a chiral raw material, avoiding the complicated traditional chiral separation process, simplifying the process, greatly improving the product yield, and reducing the cost. The present invention also develops a preparation method of (S)-4-methoxy-2-methyl-4-oxobutyric acid, using propionyl chloride as a starting material, reacting a chiral inducing reagent with a haloacetic acid alkyl ester, and further hydrolyzing under alkaline conditions to obtain (S)-4-methoxy-2-methyl-4-oxobutyric acid. The method reduces production costs, has mild reaction conditions, and is suitable for industrial production.

[0012] The technical solution of the present invention is specifically as follows:

[0013] A method for preparing a levosimendan intermediate comprises the following steps:

[0014] (1) Propionyl chloride and chiral inducing reagent Acylation reaction was carried out under DMAP catalysis to obtain compound 1

[0015] Preferably, the chiral inducing agent is selected from (R)-4-benzyl-2-oxazolidinone, (R)-(+)-5,5-diphenyl-4-benzyl-2-oxazolidinone (R)-(+)-4-(Diphenylmethyl)-2-oxazolidinone (R)-(-)-4-(4-Hydroxybenzyl)-2-oxazolidinone One or more of

[0016]

[0017] (2) Compound 1 reacts with an alkyl halide acetate XCH2COOR3, R3 represents a C1-C6 alkyl group, and X represents F, Cl, Br or I (the alkyl halide acetate is preferably methyl chloroacetate, ethyl bromoacetate, methyl bromoacetate) under alkaline conditions to obtain compound 2.

[0018]

[0019] (3) Compound 2 undergoes hydrolysis under alkaline conditions to obtain compound 3;

[0020]

[0021] In the above preparation method, the reaction solvents in step (1) or (2) are the same or different and are selected from one or more of tetrahydrofuran, N-methylpyrrolidone, dimethylformamide, and dimethyl sulfoxide. The reaction solvent in step (3) is selected from one or more of C1-C6 fatty alcohols, preferably methanol, ethanol, and isopropanol.

[0022] In the above preparation method, preferably, the reaction temperature in step (1) is -20 to 30°C, and the reaction time is 1 to 10 h. The reaction temperature in step (2) is -10 to 40°C, and the reaction time is 0.5 to 10 h.

[0023] In the above preparation method, the base used in step (2) is selected from one or more of potassium bis(trimethylsilyl)amide, lithium bis(trimethylsilyl)amide, lithium diisopropylamide, and sodium bis(trimethylsilyl)amide, preferably sodium bis(trimethylsilyl)amide.

[0024] In the above preparation method, the base in step (3) is selected from one of lithium hydroxide, sodium methoxide, sodium ethoxide and potassium tert-butoxide, the reaction temperature is -10 to 20° C., and the reaction time is 1 to 10 hours.

[0025] A method for preparing levosimendan comprises the following steps:

[0026] (4) (S)-4-Methoxy-2-methyl-4-oxobutanoic acid is activated by a chlorination reagent (preferably thionyl chloride, phosphorus oxychloride, phosphorus pentachloride) to an acyl chloride, which reacts with acetanilide to obtain compound 4.

[0027]

[0028] (5) Compound 4 is cyclized with hydrazine and hydrolyzed under alkaline conditions to obtain compound 5.

[0029]

[0030] (6) Compound 5 undergoes diazotization and addition reaction with sodium nitrite and malononitrile to obtain levosimendan.

[0031]

[0032] In the preparation method of the present invention, the reaction solvent in step (4) is selected from one or more of dichloromethane, toluene, dimethylformamide, and dimethyl sulfoxide, the chlorination reagent is selected from one of thionyl chloride, phosphorus oxychloride, or phosphorus pentachloride, the reaction temperature is 0 to 100° C., and the reaction time is 0.5 to 6 hours.

[0033] In the preparation method of the present invention, the reaction solvent in step (5) is selected from C1-C6 fatty alcohols, preferably ethanol or methanol; the reaction temperature is 60-90° C., the reaction time is 1-7 hours, and the base used for hydrolysis is selected from one or more of sodium hydroxide, potassium hydroxide, and lithium hydroxide.

[0034] Technical effects:

[0035] The present invention uses propionyl chloride and a chiral inducing agent as starting materials, obtains (S)-4-methoxy-2-methyl-4-oxobutyric acid through condensation and hydrolysis, and then obtains levosimendan through substitution, Friedel-Crafts acylation, ring closure, diazotization, and addition. Compared with the traditional chiral resolution method (WO2011007123A1), the total yield of the route of the present invention can reach 46.0%, which is nearly 34% higher than WO2011007123A1 (total yield 12.6%). The ee value of levosimendan obtained by the method of the present invention is 99.7%, while the method in the traditional chiral resolution method (WO2011007123A1) cannot effectively control isomeric impurities, and the ee value is only 93.6%. The present invention solves the problem of excessive isomeric impurities of levosimendan. Compared with the existing chiral synthesis method, the present invention uses propionyl chloride and a chiral inducing reagent as starting materials, which not only significantly reduces the cost of production raw materials, but also has mild process reaction conditions, high yield, and is suitable for industrial production. At the same time, the method of the present invention avoids the use of a large amount of chiral resolving agents, meets the reaction atom economy, reduces process safety risks, reduces the generation of waste liquid, and has higher practical application value. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figure 1 This is the chiral HPLC test result of levosimendan prepared by the method of the present invention.

[0037] Figure 2 This is the chiral HPLC test result of levosimendan prepared by the method described in Comparative Example 1.

[0038] Figure 3 This is the chiral HPLC test result of levosimendan prepared by the method described in Comparative Example 2. DETAILED DESCRIPTION

[0039] The specific steps of the present invention are described below by way of examples, but are not limited to the examples.

[0040] The terms used in the present invention, unless otherwise specified, generally have the meanings commonly understood by those of ordinary skill in the art.

[0041] The present invention will be further described in detail below in conjunction with specific examples and with reference to data. It should be understood that these examples are only intended to illustrate the present invention and are not intended to limit the scope of the present invention in any way.

[0042] In the following examples, various processes and methods not exhaustively described are conventional methods well known in the art.

[0043] Example 1 Preparation method of levosimendan

[0044]

[0045]

[0046] Step 1: Preparation of compound 1

[0047] Example 1: Under nitrogen protection, add (R)-4-benzyl-2-oxazolidinone (56g), DMAP (1.12g) and anhydrous tetrahydrofuran (1.3L) to the reaction bottle, cool the reaction bottle to 0°C, slowly add propionyl chloride (67.2g), stir and react for 2.5 hours, and detect the reaction by TLC. After the reaction is completed, quench the reaction with saturated ammonium chloride solution (1.3L), add ethyl acetate (2L) to dilute, separate the liquids, extract the aqueous phase with ethyl acetate (2L×2), wash the mixed organic phase with saturated brine, dry with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain white solid compound 1-A (67.9g), with a reaction yield of 92%.

[0048]

[0049] Example 2: Under nitrogen protection, (R)-(+)-5,5-diphenyl-4-benzyl-2-oxazolidinone (56 g), DMAP (1.12 g) and anhydrous tetrahydrofuran (1.3 L) were added to the reaction bottle, the reaction bottle was cooled to 0°C, propionyl chloride (67.2 g) was slowly added, the reaction was stirred for 2.5 hours, and the reaction was detected by TLC. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution (1.3 L), ethyl acetate (2 L) was added to dilute, the liquid was separated, the aqueous phase was extracted with ethyl acetate (2 L × 2), the mixed organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a white solid compound 1-B (52.6 g), and the reaction yield was 80%.

[0050]

[0051] Example 3: Under nitrogen protection, (R)-(+)-4-(diphenylmethyl)-2-oxazolidinone (56 g), DMAP (1.12 g) and anhydrous tetrahydrofuran (1.3 L) were added to the reaction bottle, the reaction bottle was cooled to 0°C, propionyl chloride (67.2 g) was slowly added, the reaction was stirred for 2.5 hours, and the reaction was detected by TLC. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution (1.3 L), ethyl acetate (2 L) was added to dilute, the liquid was separated, the aqueous phase was extracted with ethyl acetate (2 L × 2), the mixed organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain white solid compound 1-C (58.1 g), and the reaction yield was 85%.

[0052]

[0053] Step 2: Preparation of compound 2

[0054] Example 1: Under nitrogen protection, add sodium bis(trimethylsilyl)amide (59.6g) tetrahydrofuran solution (500ml) to the reaction bottle, cool the system to -5~0℃, add compound 1-A (73g) tetrahydrofuran (500mL) solution to the system, stir and react for 2 hours, then slowly add bromoacetate (78.4g) to the reaction solution, warm the reaction solution to room temperature, and detect the reaction by TLC. After the reaction is completed, add saturated ammonium chloride solution (500mL) to quench the reaction, and extract with ethyl acetate (1L×3). The combined organic phase is washed with saturated brine (750mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain white solid compound 2 (86.5g), with a reaction yield of 87%.

[0055] Example 2: Under nitrogen protection, add sodium bis(trimethylsilyl)amide (20.5g) tetrahydrofuran solution (200ml) to the reaction bottle, cool the system to -5~0℃, add compound 1-A (25.1g) tetrahydrofuran (200mL) solution to the system, keep warm and stir for 2 hours, then slowly add methyl chloroacetate (15.8g) to the reaction solution, warm the reaction solution to room temperature, and detect the reaction by TLC. After the reaction is completed, add saturated ammonium chloride solution (200mL) to quench the reaction, and extract with ethyl acetate (200L×3). The combined organic phase is washed with saturated brine (400mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain white solid compound 2 (28.8g), with a reaction yield of 84%.

[0056] Step 3: Preparation of compound 3

[0057] Example 1: Add compound 2 (80 g) and EtOH (500 mL) to a reaction bottle, stir and dissolve, add lithium hydroxide (12 g) at 0°C, react for 4 h, detect the reaction by TLC, and concentrate the reaction solution under reduced pressure after the reaction is completed. Add 500 ml of water to the residual solution, adjust the pH to 6-7 with 6N hydrochloric acid, extract the aqueous phase with ethyl acetate (1.5 L × 2), dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a light yellow oily liquid compound 3 (33.0 g), with a reaction yield of 83%. HNMR (600 MHz, DMSO) δ = 12.25 (s, 1H), 3.59-3.58 (d, 3H), 2.74-2.67 (m, 1H), 2.60-2.55 (m, 1H), 2.43-2.39 (m, 1H), 1.11-1.10 (d, 3H). Chiral HPLC: (2S)-4-methyl methylsuccinate was eluted with n-heptane-isopropanol-trifluoroacetic acid: ee value 97.2%, t=21.98 min.

[0058] Isomer detection method of compound 3:

[0059] Chiral HPLC is determined in accordance with high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Rules 0512).

[0060] Chromatographic conditions: use amylose-tris[3,5-dimethylphenylcarbamate] bonded silica gel as filler (ChiralpakIA-3, 4.6mmx250mm, 3um or chromatographic column with equivalent performance); use n-heptane-isopropanol-trifluoroacetic acid (95:5:0.2) as mobile phase; flow rate is 0.5ml per minute; detection wavelength is 210nm; column temperature is 15℃; injection volume is 10μl; running time is 40min. Example 2: Add compound 2 (40g) and MeOH (200mL) to the reaction bottle, stir and dissolve, then add sodium methoxide (6g) at 0℃, react for 8h and detect the reaction by TLC. After the reaction is completed, the reaction solution is concentrated under reduced pressure. 300 ml of water was added to the residual solution, and the pH was adjusted to 6-7 with 6N hydrochloric acid. The aqueous phase was extracted with ethyl acetate (600 ml×2), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a light yellow oily liquid compound 3 (15.6 g) with a yield of 78% and an ee value of 96.5%.

[0061] Using step 1 product compounds 1-B and 1-C, respectively, referring to the methods of step 2 example 1 and step 3 example 1, oily liquid compound 3 was prepared, with reaction yields of 71% and 74%, respectively, and ee values ​​of 95.5% and 95.1%, respectively.

[0062] Step 4: Preparation of compound 4

[0063] Under nitrogen protection, dichloromethane (300ml) and compound 3 (29.97g) were added to the reaction bottle, and then DMF (10ml) and thionyl chloride (44.52g) were added, the temperature was raised to 50°C, and the reaction was stirred for 1.5h. After the reaction was completed, the system was concentrated until no liquid dripped out, the concentrate was dissolved in dichloromethane (300ml), and acetanilide (25.29g) and anhydrous aluminum chloride (76.0g) were added in sequence, the temperature was raised to 40-50°C, and the reaction was stirred for 3h. The temperature was lowered to 0°C, and 1N hydrochloric acid (200ml) solution was added dropwise to quench the reaction. The mother liquor was filtered, the organic phase was taken, and it was concentrated under reduced pressure to obtain an off-white powder compound 4 (41.1g, yield 79.2%).

[0064] Step 5: Preparation of compound 5

[0065] Add anhydrous ethanol (240 ml), compound 4 (40 g) and hydrazine hydrate (17.8 g) to the reaction bottle, raise the temperature to reflux, and stir to react for 3 hours. Cool down to 50-60°C, add 10% sodium hydroxide solution (60 g), and continue to stir to react for 2 hours. Cool down to 0°C, keep warm for crystallization for 2 hours. Filter and vacuum dry to obtain off-white crystalline powder compound 5 (38.5 g, yield 95.1%).

[0066] Step 6: Preparation of Levosimendan

[0067] Purified water (600 ml), concentrated hydrochloric acid (75 ml) and compound 5 (30 g) were added to the reaction flask, stirred to dissolve, cooled to 0°C, and sodium nitrite (10.7 g) aqueous solution (100 ml) was added dropwise. After the addition was completed, the mixture was stirred and reacted for 1 hour. Malononitrile (9.75 g) aqueous solution (100 ml) was added dropwise, and the mixture was reacted for 2 hours. After the reaction was completed, 25% sodium acetate solution was used to adjust the pH of the system to 5-6, and solids precipitated. Filtered and vacuum dried to obtain levosimendan (25.8 g, yield 92.0%, ee value 99.7% (see Figure 1 ), chiral HPLC was determined according to high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition Part IV General Rules 0512), the same as the chiral HPLC detection of compound 3). LC-ESI (m / z) C 14 H 12 Calculated value for N6O: 280.29; Found: 281.05 [M+H] + . HNMR (600MHz, DMSO) δ = 13.11 (brs, 1H), 11.00 (s, 1H), 7.85-7.84 (d, 2H), 7.53-7.51 ( d,2H), 3.41-3.36(m,1H), 2.72-2.68(dd,1H), 2.27-2.24(d,1H), 1.09-1.08(d,3H).

[0068] Comparative Example 1

[0069] Levosimendan was prepared according to the method in WO2011007123A1.

[0070] The reaction route is as follows:

[0071]

[0072] (1) Add 30 g of 4-(4-aminophenyl)-3-methyl-4-oxobutanoic acid to 95% ethanol (300 ml), control the internal temperature to ≤40°C, slowly add hydrazine hydrate (14.7 g) dropwise, raise the temperature to reflux after the addition is complete, stir and react for 3 h, cool and crystallize, filter and dry to obtain 6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone (25.5 g, yield 86.6%) as an off-white crystalline powder.

[0073] (2) Add 25 g of 6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone to ethanol (250 ml), heat to 65°C, stir and react for 0.5 h, then add D-(+)-di-p-methoxybenzoyltartaric acid (56 g) and purified water (250 ml), keep warm and stir for 1 h. The system is cooled to 15°C, crystallized for 0.5 h, filtered, the filter cake is added to purified water (250 ml), the pH is adjusted to 8-9 with ammonia water, stirred for 0.5 h, filtered and dried to obtain (R)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone (4.1 g, 16.3%).

[0074] (3) 4 g of (R)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone was added to purified water (160 ml) and concentrated hydrochloric acid (10 ml), cooled to 0-5°C, and sodium nitrite (1.6 g) aqueous solution (16 ml) was added dropwise. After stirring for 10 min, malononitrile (1.3 g) aqueous solution (16 ml) was added dropwise. The reaction was stirred at room temperature for 1 h. The pH was adjusted to 6 using saturated sodium acetate solution. After the solid precipitated, it was filtered and dried to obtain levosimendan (5.5 g, yield 89.0%, ee value 93.1% (see Figure 2 )).

[0075] Comparative Example 2

[0076] (1) Under nitrogen protection, add dichloromethane (100 ml) and (R)-(-)-2-chloropropionyl chloride (23 g) to the reaction bottle, cool to 0-10°C, add acetanilide (20 g) and anhydrous aluminum chloride (60 g) in sequence while stirring, raise the temperature to 45°C, stir and react for 2.5 hours, cool to 0°C, add 1N hydrochloric acid (200 ml) solution dropwise to quench the reaction. Filter by suction, let the mother liquor stand for stratification, take the organic phase, and concentrate under reduced pressure to obtain an oily substance;

[0077] (2) Add dilute sulfuric acid to the above concentrate, heat to 50°C, stir and react for 3 hours, neutralize the reaction with alkali solution, and then add ethyl acetate for extraction; after separation, the organic phase is washed with purified water and saturated sodium chloride solution and dried, and then concentrated under reduced pressure to obtain a light yellow oil, which is directly used in the next step;

[0078] (3) Add N,N-dimethylformamide to the concentrate obtained in (2), stir to dissolve, then add benzylethylmalonic acid (32.9 g) and potassium carbonate (81.8 g) in sequence, and stir to react at room temperature for 3 h. After the reaction is completed, add purified water to the system, filter the precipitated solid, and dry the filter cake to obtain 26.2 g of dark solid, with a total yield of 48% for the three steps.

[0079] (4) Add ethyl acetate (300 ml) to the concentrated solid obtained in (3), stir to dissolve, add 10% palladium on carbon, react the system at room temperature for 2.5 hours under 1 atm hydrogen pressure, filter, and concentrate the filtrate under reduced pressure. Add 6N hydrochloric acid solution to the concentrate, raise the temperature to 80°C, stir to react for 4 hours, and after the reaction is complete, cool to room temperature, adjust the pH to 8-9 with 2N sodium hydroxide solution, add ethyl acetate, stir and extract; after separation, wash the organic phase with purified water and saturated sodium chloride solution and dry, and then concentrate under reduced pressure to obtain a light yellow oily substance, which is directly used in the next step;

[0080] (5) Add anhydrous ethanol, the oil obtained in step 4 and hydrazine hydrate to the reaction flask, raise the temperature to reflux, and stir to react for 3 hours. Cool to 0°C and keep warm for 2 hours to crystallize. Filter and vacuum dry to obtain an off-white crystalline powder compound 5. Referring to the process of step 6 in Example 1, 13.9 g of levosimendan was finally obtained with a total yield of 33.5% and an ee value of 95.2% (see Figure 3 ).

[0081] Comparative Example 3

[0082] (S)-4-ethoxy-2-methyl-4-oxobutanoic acid was prepared by referring to the prior art (J.Am.Chem.Soc.2001,123,11302-11303).

[0083] Add methyl succinic anhydride (5g), trifluoroethanol (1ml) and ether (50ml) to the reaction flask, stir and cool to -15°C, add 10% hydroquinidine (anthraquinone-1,4-diyl) diether dropwise, and stir and react for 20h. Wash the reaction mixture twice with 1N HCl aqueous solution, and then add ether to the system for extraction. Combine the organic phases, dry with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain an oily substance with a yield of 54.5% and an ee value of 76.5%.

Claims

1. A method for preparing a levosimendan intermediate, characterized in that The steps include: (1) Propionyl chloride and chiral inducing reagent Acylation reaction was carried out under DMAP catalysis to obtain compound 1 The chiral inducing agent is selected from one or more of (R)-4-benzyl-2-oxazolidinone, (R)-(+)-5,5-diphenyl-4-benzyl-2-oxazolidinone, (R)-(+)-4-(diphenylmethyl)-2-oxazolidinone, and (R)-(-)-4-(4-hydroxybenzyl)-2-oxazolidinone. (2) Compound 1 reacts with an alkyl haloacetate XCH2COOR3 under alkaline conditions to obtain Compound 2, wherein R3 represents a C1-C6 alkyl group, and X represents F, Cl, Br or I. (3) Compound 2 undergoes hydrolysis under alkaline conditions to obtain compound 3; 2. The preparation method according to claim 1, characterized in that The reaction solvent in step (1) is selected from one or more of tetrahydrofuran, N-methylpyrrolidone, dimethylformamide, and dimethyl sulfoxide, the reaction temperature is -20 to 30° C., and the reaction time is 1 to 10 hours.

3. The preparation method according to claim 1, characterized in that The reaction solvent of step (2) is selected from one or more of tetrahydrofuran, N-methylpyrrolidone, dimethylformamide, and dimethyl sulfoxide; the base is selected from one or more of bistrimethylsilyl potassium amide, bistrimethylsilyl lithium amide, diisopropyl lithium amide, and sodium bis(trimethylsilyl)amide; the reaction temperature is -10 to 40° C.; and the reaction time is 0.5 to 10 h.

4. The preparation method according to claim 1, characterized in that The reaction solvent of step (3) is selected from one or more of C1-C6 fatty alcohols, the base is selected from one of lithium hydroxide, sodium methoxide, sodium ethoxide, and potassium tert-butoxide, the reaction temperature is -10 to 20° C., and the reaction time is 1 to 10 hours.

5. A method for preparing levosimendan, comprising the following steps: (4) (S)-4-methoxy-2-methyl-4-oxobutyric acid is activated by a chlorination reagent to an acyl chloride, which reacts with acetanilide to obtain compound 4. (5) Compound 4 is cyclized with hydrazine and hydrolyzed under alkaline conditions to obtain compound 5. (6) Compound 5 undergoes diazotization and addition reaction with sodium nitrite and malononitrile to obtain levosimendan.

6. The preparation method according to claim 5, characterized in that The reaction solvent in step (4) is selected from one or more of dichloromethane, toluene, dimethylformamide, and dimethyl sulfoxide, the chlorination reagent is selected from one of thionyl chloride, phosphorus oxychloride, or phosphorus pentachloride, the reaction temperature is 0 to 100° C., and the reaction time is 0.5 to 6 h.

7. The preparation method according to claim 5, characterized in that The reaction solvent in step (5) is selected from C1-C6 fatty alcohols, the reaction temperature is 60-90° C., the reaction time is 1-7 hours, and the base used for hydrolysis is selected from one or more of sodium hydroxide, potassium hydroxide, and lithium hydroxide.

8. The preparation method according to claim 7, characterized in that The reaction solvent in step (5) is ethanol or methanol.

9. The preparation method according to claim 5, characterized in that The compound 3 in step (4) is prepared by the method according to any one of claims 1 to 4.

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