A method for recycling benidipine hydrochloride by-products

Abstract

The present invention relates to a method for recycling benidipine hydrochloride byproducts, comprising mixing the byproducts, a racemization solvent, and a weakly acidic catalyst, reacting the mixture at 70 to 100° C., and then recrystallizing and crystallizing the reaction product to produce benidipine hydrochloride enantiomers. The present invention racemizes the pharmacologically inactive benidipine hydrochloride byproducts, and then crystallizes and crystallizes the resulting benidipine hydrochloride enantiomers to produce pharmacologically active benidipine hydrochloride. This method allows for the recycling of the byproducts. The method is simple to operate, has mild reaction conditions, and produces high-purity products, making it suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of medicine, and in particular relates to a method for recycling benidipine hydrochloride by-products. Background Art

[0002] Benidipine hydrochloride's chemical name is 3-[(3RS)-1-benzylpiperidin-3-yl]5-methyl(4RS)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid monohydrochloride. Benidipine hydrochloride is a dihydropyridine calcium antagonist with advantages such as stable blood pressure reduction, long-lasting efficacy, and good safety and compliance. It is indicated for essential hypertension and angina pectoris. EP0063365A1, EP0161877A2, JP57-171968A, EP0106275A2, etc. disclose one or more synthetic routes for benidipine hydrochloride and its analogs. EP0106275A2 also summarizes the synthetic route of benidipine hydrochloride. In the above documents, it is suggested that the synthesized benidipine hydrochloride should be separated into α-isomer and β-isomer by column chromatography to obtain the pharmacologically active (±)-α-isomer, which has the following structural formula:

[0003]

[0004] However, in the reaction of preparing the pharmaceutically acceptable (±)-α-isomer, the pharmacologically inactive (±)-β-isomer is inevitably produced at a ratio of approximately 1:1, with the following structural formula:

[0005]

[0006] The (±)-β-isomer has no pharmacological activity and causes huge waste after being produced in large quantities. However, there is no report in the prior art on the recycling of the (±)-β-benidipine hydrochloride by-product. Summary of the Invention

[0007] The purpose of the present invention is to provide a method for recycling benidipine hydrochloride by-products.

[0008] Another object of the present invention is to provide a method for cultivating benidipine hydrochloride single crystals.

[0009] In order to achieve the above object, the technical solution adopted by the present invention is:

[0010] A method for recycling benidipine hydrochloride byproducts comprises mixing the byproducts, a racemization solvent and a weakly acidic catalyst and reacting them at 70-100° C., and then recrystallizing and crystallizing the reaction products to prepare benidipine hydrochloride, wherein the byproducts are benidipine hydrochloride enantiomers.

[0011] If otherwise specified, the benidipine hydrochloride described in this application is (±)-α-benidipine hydrochloride with pharmacological effects, and the specific structure can be referred to the above background technology.

[0012] Preferably, the catalyst is a weakly acidic cation exchange resin.

[0013] More preferably, the weakly acidic cation exchange resin is a weakly acidic methacrylic resin.

[0014] In some embodiments, the weakly acidic cation exchange resin is Purolite C115E.

[0015] Preferably, the feed mass ratio of the by-product to the catalyst is 1:(0.2-0.8), more preferably 1:(0.4-0.6), for example 1:0.4, 1:0.45, 1:0.5, 1:0.55 or 1:0.6.

[0016] Preferably, the racemization solvent is dimethyl carbonate.

[0017] Preferably, the mass volume ratio of the by-product to the racemization solvent is 1 g: (5-20) mL, more preferably 1 g: (5-15) mL, and even more preferably 1 g: (8-12) mL.

[0018] Preferably, the reaction temperature is controlled to be 80-90°C, more preferably 83-88°C.

[0019] Preferably, the reaction time is controlled to be 18 to 30 hours, more preferably 20 to 26 hours, and even more preferably 22 to 25 hours.

[0020] Preferably, the recrystallization comprises mixing the reaction product with a recrystallization solvent, heating to dissolve the mixture, then performing hot filtration, and cooling the filtrate to crystallize the mixture.

[0021] Further preferably, the recrystallization solvent is methanol.

[0022] In some embodiments, the mass volume ratio of the reaction product to the recrystallization solvent is 1 g: (5-15) mL, preferably 1 g: (8-12) mL.

[0023] Preferably, the reaction product and the recrystallization solvent are heated to 50-65° C. for dissolution.

[0024] Preferably, the crystallization comprises mixing the product obtained by recrystallization with a crystallization solvent.

[0025] More preferably, the crystallization solvent is ethyl acetate.

[0026] In some embodiments, the mass volume ratio of the reaction product to the crystallization solvent is 1 g: (15-25) mL, preferably 1 g: (18-22) mL.

[0027] Preferably, the temperature of the crystallization is controlled to be 20-30° C. and the time is controlled to be 18-30 h.

[0028] Preferably, the method further comprises filtering and collecting the solid after the crystallization is completed, washing and drying the solid to obtain the benidipine hydrochloride.

[0029] Preferably, after the reaction is completed, the reaction system is cooled to 20-30° C., filtered, and the filtrate is selectively concentrated under reduced pressure using acetone once or multiple times. Acetone is added to the concentrated product, and finally the reaction product is crystallized by cooling, filtered, slurried, drained, and vacuum dried to obtain the reaction product.

[0030] Preferably, the benidipine hydrochloride enantiomer is pharmacologically inactive (±)-β-benidipine hydrochloride, and its specific structure can be referred to the above background technology.

[0031] In some embodiments, (Z)-methyl 2-(3-nitrobenzylidene)-3-oxobutanoate is subjected to a cyclization reaction with (1-benzyl-3-piperidinyl) acetoacetate and ammonium acetate, and the reaction product is post-treated to obtain the by-product. The cyclization reaction can be specifically described in CN 114907256 B.

[0032] Preferably, the by-product is recrystallized using acetone and n-heptane, and then the obtained crystalline product is reacted with the racemization solvent and the catalyst.

[0033] More preferably, the volume ratio of acetone to n-heptane used for the recrystallization is 1:(3-8), and even more preferably 1:(4-6).

[0034] Preferably, the method further comprises culturing single crystals of the benidipine hydrochloride obtained by the crystallization, and then confirming its structure, wherein the solvent used for the single crystal cultivation is a mixed solvent of isopropanol and acetone.

[0035] Further preferably, in the mixed solvent, the volume ratio of isopropyl alcohol to acetone is 1:(1-10), and further preferably 1:(3-8), for example 1:3, 1:4, 1:5, 1:6, 1:7 or 1:8.

[0036] Preferably, the mass volume ratio of the benidi hydrochloride to the solvent used for single crystal cultivation is 1 g: (20-40) mL, more preferably 1 g: (25-35) mL, and even more preferably 1 g: (28-32) mL.

[0037] Preferably, the single crystal cultivation is carried out under light-proof conditions.

[0038] Preferably, the temperature of the single crystal culture is 0-30° C. and the time is 20-40 days.

[0039] The present invention also provides a method for culturing a benidipine hydrochloride single crystal. The culturing method is similar to the above-mentioned single crystal culturing method and will not be described in detail here.

[0040] Due to the application of the above technical solution, the present invention has the following advantages compared with the prior art:

[0041] The present invention racemizes a pharmacologically inactive benidipine hydrochloride by-product and then prepares pharmacologically active benidipine hydrochloride through recrystallization and crystal transformation, thereby achieving the reuse of the by-product. The method has simple operation, mild reaction conditions, high product purity, and is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] Figure 1 is an ellipsoidal diagram of the crystal molecular structure of Example 4;

[0043] Figure 2 This is the cell stacking diagram of Example 4. DETAILED DESCRIPTION

[0044] When preparing pharmaceutically usable benidipine hydrochloride (i.e., the α isomer), it is inevitable to produce a benidipine hydrochloride by-product (i.e., the β isomer) with a pharmacologically inactive ratio of about 1:1, resulting in huge waste. For the recycling of benidipine hydrochloride by-products, there are no relevant research reports in the prior art. After a lot of research and experimental verification, the applicant has explored a method for recycling benidipine hydrochloride by-products. By collecting benidipine hydrochloride by-products, and then racemizing, recrystallizing, and transcrystallizing the benidipine hydrochloride by-products, benidipine hydrochloride can be prepared. This method realizes the reuse of benidipine hydrochloride by-products, and the obtained product has high purity, which is of great significance for improving the yield of benidipine hydrochloride and reducing costs.

[0045] The present invention is further described below with reference to the following examples. However, the present invention is not limited to the following examples. The implementation conditions used in the examples may be further adjusted according to the specific requirements of the application. Unspecified implementation conditions are conventional conditions in the industry. The technical features involved in the various embodiments of the present invention may be combined with each other as long as they do not conflict with each other.

[0046] In the following examples and comparative examples, the raw materials and instruments used were all commercially available. The reaction flask may optionally contain a reflux condenser.

[0047] Example 1 Recovery of by-product (±)-β-isomer

[0048] Referring to CN 114907256 B Example 3, a method for preparing a crude benidipine hydrochloride product is provided, wherein an acetone mother liquor containing a (±)-β-isomer by-product is obtained, specifically comprising: adding 80.0 g of methanol to a reaction flask, starting stirring, and then adding 41.6 g of intermediate P1 (2 equivalents), 12.9 g of ammonium acetate (2 equivalents) and 23.0 g of intermediate P2 (1 equivalent), respectively; stirring and reacting at 50-60° C. for 6 hours, cooling to 25° C., filtering, washing the filter cake with 24.0 g of methanol, and sampling the filtrate; concentrating under reduced pressure to remove methanol (T≤70° C., vacuum pressure of -0.09 to -0.07 MPa) until no fraction flows out; adding to the reaction flask; 90.0g dichloromethane and 45.0g purified water, stirred for 5 minutes, allowed to stand for 30 minutes, separated, and the lower organic phase was collected; 45.0g dichloromethane was added to the aqueous phase, stirred for 5 minutes, allowed to stand for 30 minutes, separated, and the lower organic phase was collected; the lower organic phase was combined with the organic phase of the previous step; a mixed solution of 12.0g sodium bicarbonate and 45.0g purified water was slowly added to the combined organic phase, stirred for 5 minutes, allowed to stand for 30 minutes, separated, and the lower organic phase was collected; 30.0g purified water and 15.0g concentrated hydrochloric acid were added to the lower organic phase, stirred at 20-30°C for 30 minutes, and allowed to stand. 30 minutes, layered, and the lower organic phase was collected; 5.0g of ammonium chloride and 45.0g of purified water were added to the lower organic phase, stirred for 5 minutes, and allowed to stand for 30 minutes; layered, and the lower organic phase was collected; stirring was turned on, 8.0g of anhydrous sodium sulfate was added to the organic phase, and stirred for 30 minutes; filtered to remove anhydrous sodium sulfate, and the filter cake was washed once with 23.0g of dichloromethane; the obtained filtrate was concentrated under reduced pressure (T = ≤ 45 ° C, vacuum pressure of ≤ -0.05MPa) until no distillate flowed out, 23.0g of acetone was added to the reaction flask, stirred evenly, and continued to be concentrated under reduced pressure (T = 15 ~ 45 ° C, vacuum pressure of ≤ -0.05MPa) The reaction flask was added with 23.0 g of acetone, stirred evenly, and then concentrated under reduced pressure (T = 15-45 ° C, vacuum pressure ≤ -0.05 MPa) until no distillate flowed out; 230.0 g of acetone was added to the reaction flask, and stirred at 30-50 ° C for 30 minutes to fully dissolve the material; the material was cooled to 20-30 ° C, and stirred until a small amount of solid precipitated; when a small amount of solid appeared, stirring was continued at 25 ° C for 24 hours; filtered, the filter cake was slurried with 23.0 g of acetone, and dried to obtain an acetone mother liquor containing the by-product (±)-β-isomer.

[0049] The acetone mother liquor containing the by-product (±)-β-isomer was concentrated under reduced pressure at 20-30°C to 75 mL, 375 mL of n-heptane was slowly added dropwise, and stirring was continued for 24 hours. The solid was collected by filtration, washed with 40 mL of n-heptane, and dried. The wet product was placed in a vacuum drying oven (T = 55-60°C) and dried to constant weight to obtain 12.8 g of the by-product (±)-β-isomer with HPLC purity of 98.2%.

[0050] Example 2 Racemization of by-product (±)-β-isomer

[0051] 100 mL of dimethyl carbonate was added to the reaction flask, stirring was started, 10.0 g of the by-product (±)-β-isomer (from Example 1) and 5.0 g of weakly acidic cation exchange resin ProLite C115E were added, the reaction solution was heated to 85 ° C, and the stirring reaction was continued for 24 hours. The temperature of the feed solution in the crystallization flask was reduced to 20-30 ° C, and the solid (weakly acidic cation exchange resin) was collected by filtration. The solid was washed with 10 mL of dimethyl carbonate and dried. The filtrate was concentrated under reduced pressure (T≤45 ° C, vacuum pressure ≤-0.05 MPa) until no obvious distillate flowed out. 10 mL of acetone was added to the reaction flask, stirred evenly, and then concentrated under reduced pressure (T = 15-45 ° C, vacuum pressure ≤-0.05 MPa) until no distillate flowed out; ... , continue to concentrate under reduced pressure (T = 15 ~ 45 ° C, vacuum pressure ≤ -0.05 MPa) until no distillate flows out; add 100 mL of acetone to the reaction flask and stir at 30 ~ 50 ° C for 30 minutes to fully dissolve the material; cool the material to 20 ~ 30 ° C, stir until a small amount of solid precipitates; when a small amount of solid appears, continue stirring at 25 ° C for 24 hours; filter, beat the filter cake with 10 mL of acetone, drain and discharge; vacuum dry (T = 55 ~ 65 ° C, vacuum pressure ≤ 0.05 MPa) to constant weight, discharge to obtain 4.5 g of crude benidipine hydrochloride with HPLC purity of 99.85%.

[0052] Example 3 Preparation of Benidipine Hydrochloride

[0053] 40 mL of methanol was added to the reaction flask, stirring was started, and 4.0 g of crude benidipine hydrochloride (from Example 2) was added; the reaction solution was heated to 55-60° C. to dissolve all the solids; the reaction solution was then hot filtered through a filter membrane, the reaction flask and filter membrane were washed with 4 mL of methanol, and the filtrate was transferred to a crystallization flask; the temperature of the feed solution in the crystallization flask was lowered to 20-30° C.; the temperature of the feed solution in the crystallization flask was controlled at 20-30° C. and stirred at this temperature for 3 hours; the solid was collected by filtration and discharged to obtain a methanol wet product; the methanol wet product was placed in a crystallization flask, 80 mL of ethyl acetate was added, and stirred at 20-30° C. until the system turned bright yellow, which took about 24 hours; the solid was collected by filtration, the solid was washed with 8 mL of ethyl acetate, and the material was discharged to obtain an ethyl acetate wet product; the wet product was placed in a vacuum drying oven and dried (T=55-60° C.) to a loss on drying of ≤0.5%, to obtain 3.7 g of benidipine hydrochloride finished product with an HPLC purity of 99.96%.

[0054] Example 4 Single Crystal Cultivation of Benidipine Hydrochloride

[0055] Add 1 mL of isopropanol and 5 mL of acetone and 0.2 g of benidipine hydrochloride (from Example 3) to the reaction flask, stir at 45°C for 1 hour, filter into a vial, place the vial in a stable, light-proof laboratory cabinet, and place at 0-30°C for 31 days to grow single crystals, which are then sent for single crystal X-ray diffraction.

[0056] The results of single crystal structure analysis are consistent with the absolute configuration of benidipine hydrochloride.

[0057] The crystal formula is C 28 H 32 CLN3O6·H2O, belongs to the monoclinic system, P21 / c space group, unit cell parameters α=γ=90°, β=111.717°, Z=4,μ(Cu Kα)=1.615mm -1 ,ρ caLc =1.314g / cm 3 25445 measured diffraction points (7.134°≤2θ≤

[0058] 130.152°), 4823 independent diffraction points (R int =0.0998,R sigma =0.0654). For the observable diffraction point R1=0.0666, wR2=0.1708, GOF=1.118, completeness: 99.94%.

[0059] See the attached ellipsoid diagram of the crystal molecular structure Figure 1 , see the attached cell stacking diagram Figure 2 .

[0060] Comparative Example 1 Racemization of the by-product (±)-β-isomer

[0061] 100 mL of methanol was added to the reaction flask, stirring was started, 10.0 g of the (±)-β-isomer by-product and 5.0 g of the weakly acidic cation exchange resin ProLite C115E were added, the reaction solution was heated to 60°C, and the stirring reaction was continued for 24 hours. The solid was collected by filtration, washed with 10 mL of dimethyl carbonate, and dried. The filtrate was concentrated under reduced pressure (T≤45°C, vacuum pressure ≤-0.05MPa) until no fraction flowed out, 10mL of acetone was added to the reaction flask, stirred evenly, and then concentrated under reduced pressure (T=15-45°C, vacuum pressure ≤-0.05MPa) until no fraction flowed out; 10mL of acetone was added to the reaction flask, stirred evenly, and then concentrated under reduced pressure (T=15-45°C, vacuum pressure ≤-0.05MPa) until no fraction flowed out; 100mL of acetone was added to the reaction flask, stirred evenly, and then concentrated under reduced pressure (T=15-45°C, vacuum pressure ≤-0.05MPa) until no fraction flowed out; 100mL of acetone was added to the reaction flask, stirred at 30-50°C for 30 minutes to fully dissolve the material; the material was cooled to 20-30°C, stirred for 24h, filtered, and the filter cake was slurried with 10mL of acetone, drained, and discharged; vacuum dried (T=55-65°C, vacuum pressure ≤0.05Mpa) to constant weight, and discharged to obtain 1.5g of crude benidipine hydrochloride.

[0062] The quality of the crude benidipine hydrochloride obtained in this comparative example was reduced. The applicant speculated that the racemization reaction was incomplete due to the low boiling point of methanol.

[0063] Comparative Example 2 Racemization of by-product (±)-β-isomer

[0064] Add 100 mL of dimethyl carbonate to the reaction flask, start stirring, add 10.0 g of the by-product (±)-β-isomer and 0.5 g of formic acid, heat the reaction solution to 85°C, and continue stirring for 24 hours. Concentrate the reaction mixture under reduced pressure (T≤45°C, vacuum pressure≤-0.05 MPa) until no fraction flows out. Add 10 mL of acetone to the reaction flask, stir evenly, and continue to concentrate under reduced pressure (T=15-45°C, vacuum pressure≤-0.05 MPa) until no fraction flows out. Add another 10 mL of acetone to the reaction flask, stir evenly, and continue to concentrate under reduced pressure (T=15-45°C, vacuum pressure≤-0.05 MPa) until no fraction flows out. Add 100 mL of acetone to the reaction flask and stir at 30-50°C for 30 minutes to fully dissolve the material. Cool the material to 20-30°C and continue stirring for 24 hours. No solid precipitation occurs. The applicant speculates that since formic acid is highly acidic, the ester bond of the (±)-β-isomer decomposes, and therefore no product precipitates.

[0065] Comparative Example 3 Racemization of by-product (±)-β-isomer

[0066] Add 200 mL of dimethyl carbonate to the reaction flask, start stirring, add 10.0 g of the (±)-β-isomer byproduct and 0.5 g of sodium methoxide, heat the reaction solution to 85°C, and continue stirring for 24 hours. Concentrate the reaction mixture under reduced pressure on a rotary evaporator (T≤60°C, vacuum pressure≤-0.09 MPa) until no fraction flows out. Add 10 mL of acetone to the reaction flask, stir evenly, and continue concentrating under reduced pressure (T=15-45°C, vacuum pressure≤-0.05 MPa) until no fraction flows out. Add another 10 mL of acetone to the reaction flask, stir evenly, and continue concentrating under reduced pressure (T=15-45°C, vacuum pressure≤-0.05 MPa) until no fraction flows out. Add 100 mL of acetone to the reaction flask and stir at 30-50°C for 30 minutes to fully dissolve the material. Cool the material to 20-30°C and continue stirring for 24 hours. No solid precipitation occurs. The applicant speculates that sodium methoxide has a strong alkalinity, which leads to the decomposition of the ester bond of the (±)-β-isomer, so no product is precipitated.

[0067] Comparative Example 4 Racemization of by-product (±)-β-isomer

[0068] Add 100 mL of dimethyl carbonate to the reaction flask, start stirring, add 10.0 g of the by-product (±)-β-isomer, heat the reaction solution to 85°C, and continue stirring for 24 hours. Concentrate the reaction mixture under reduced pressure (T≤45°C, vacuum pressure≤-0.05 MPa) until no fraction flows out. Add 10 mL of acetone to the reaction flask, stir evenly, and continue to concentrate under reduced pressure (T=15-45°C, vacuum pressure≤-0.05 MPa) until no fraction flows out. Add another 10 mL of acetone to the reaction flask, stir evenly, and continue to concentrate under reduced pressure (T=15-45°C, vacuum pressure≤-0.05 MPa) until no fraction flows out. Add 100 mL of acetone to the reaction flask and stir at 30-50°C for 30 minutes to fully dissolve the material. Cool the material to 20-30°C and continue stirring for 24 hours. No solid precipitation occurs. The applicant speculates that the (±)-β-isomer cannot be racemized without the addition of a weakly acidic cation exchange resin catalyst and therefore no product is precipitated.

[0069] Comparative Example 5 Single Crystal Cultivation of Benidipine Hydrochloride

[0070] Add 10 mL of water and 0.2 g of benidipine hydrochloride to the reaction flask, stir at 45° C. for 1 hour, filter into a vial, place the vial in a stable, light-proof laboratory cabinet at 0-30° C., and precipitate small crystals, but no single crystals grow.

[0071] No single crystals were grown using anhydrous ethanol, methanol, isopropanol, acetone or acetonitrile.

[0072] No single crystals were grown using mixed solvents of water and any of anhydrous ethanol, methanol, isopropanol, acetone, and acetonitrile.

[0073] No single crystal was grown using any of the mixed solvents of anhydrous ethanol, methanol, acetonitrile and acetone.

[0074] The above detailed description of the present invention is intended to enable persons familiar with the art to understand the contents of the present invention and implement them. It does not limit the scope of protection of the present invention. Any equivalent changes or modifications made based on the spirit of the present invention should be included in the scope of protection of the present invention.

Claims

1. A method for recycling benidipine hydrochloride by-products, characterized in that: The method comprises mixing a by-product, a racemization solvent and a weakly acidic catalyst and reacting them at 70-100° C., and then recrystallizing and crystallizing the reaction product to prepare benidipine hydrochloride, wherein the by-product is benidipine hydrochloride (±)-β-isomer, the weakly acidic catalyst is a weakly acidic cation exchange resin, and the racemization solvent is dimethyl carbonate. The recrystallization comprises mixing the reaction product with a recrystallization solvent, heating the mixture to 50-65° C. for dissolution, then hot filtering the mixture, and cooling the filtrate for crystallization, wherein the recrystallization solvent is methanol; The crystallization comprises mixing the product obtained by the recrystallization with a crystallization solvent, wherein the crystallization solvent is ethyl acetate, and the crystallization temperature is controlled to be 20-30°C.

2. The method for recycling benidipine hydrochloride by-products according to claim 1, wherein: The feed mass ratio of the by-product to the catalyst is 1:(0.2~0.8).

3. The method for recycling benidipine hydrochloride by-products according to claim 1, wherein: The feed mass volume ratio of the by-product to the racemization solvent is 1 g: (5-20) mL.

4. The method for recycling benidipine hydrochloride by-products according to claim 1, wherein: The mass volume ratio of the reaction product to the recrystallization solvent is 1 g: (5-15) mL.

5. The method for recycling benidipine hydrochloride by-products according to claim 1, wherein: The mass volume ratio of the reaction product to the crystallization solvent is 1 g: (15-25) mL; and / or, The crystallization time is controlled to be 18 to 30 hours.

6. The method for recycling benidipine hydrochloride by-products according to claim 1, wherein: After the reaction is completed, the reaction system is cooled to 20-30° C., filtered, and the filtrate is selectively concentrated under reduced pressure using acetone once or multiple times, acetone is added to the concentrated product, and finally the reaction product is crystallized by cooling, filtered, slurried, drained, and vacuum dried to obtain the reaction product; and / or, The method further comprises culturing a single crystal of the benidipine hydrochloride prepared by the crystal transformation, and then confirming its structure. The solvent used for the single crystal cultivation is a mixed solvent of isopropyl alcohol and acetone.

7. The method for recycling benidipine hydrochloride by-products according to claim 1, wherein: (Z)-methyl 2-(3-nitrobenzylidene)-3-oxobutyrate is subjected to a cyclization reaction with (1-benzyl-3-piperidinyl) acetoacetate and ammonium acetate, and the cyclization reaction product is post-treated to obtain the by-product.

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