A green synthesis method of lercanidipine hydrochloride

Abstract

The present invention discloses a green synthesis method of lercanidipine hydrochloride, which relates to the technical field of organic synthesis of drugs. First, 1,1,N-trimethyl-N-(3,3-diphenylpropyl)-2-aminoethyl acetoacetate reacts with ammonia water through an ammonolysis reaction to obtain 3-amino-2-butenoic acid-2-[(3,3-diphenylpropyl)methylamino]-1,1-dimethylethyl ester, and then reacts with methyl 2-(3-nitrobenzylidene)-3-oxobutyrate through a cyclization reaction to obtain lercanidipine hydrochloride; while enhancing the environmental protection of the process, the present invention effectively improves the yield and purity of lercanidipine hydrochloride, the product quality is controllable, the reaction conditions are mild, the use of toxic reagents is reduced, the preparation cycle is shortened, the post-treatment operation is simplified, and the separation and purification cost is reduced.

Description

Technical Field:

[0001] The present invention relates to the technical field of pharmaceutical organic synthesis, and particularly relates to a green synthesis method of lercanidipine hydrochloride. Background Art:

[0002] Lercanidipine hydrochloride belongs to the third-generation dihydropyridine calcium channel antagonists. Its chemical name is methyl 2-[(3,3-diphenylpropyl)methylamino]-1,1-dimethylethyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate hydrochloride, and its chemical formula is C 36 H 42 ClN 3 O 6 。The mechanism of action of lercanidipine hydrochloride is similar to that of other drugs of the same kind. It reversibly blocks the influx of calcium ions through the L-type calcium channels in the vascular smooth muscle cell membrane, dilates peripheral blood vessels, and reduces blood pressure. The chemical structural formula of lercanidipine hydrochloride is shown as follows:

[0003]

[0004] Compared with other drugs of the same kind, lercanidipine hydrochloride has the following characteristics: (1) It has a unique double benzene ring side chain and a relatively large three-dimensional molecular structure, with strong lipophilicity, and can bind to the vascular smooth muscle cell membrane persistently. Therefore, it has a short plasma half-life and a long-lasting effect; (2) It has less impact on the myocardial function indexes during the blood pressure reduction process and has more significant vascular selectivity; (3) It has an anti-atherosclerotic effect that has nothing to do with blood pressure reduction and lipid-lowering effects, and at the same time has a protective effect on target organs such as the kidneys, heart, retina, and brain; (4) The incidence of adverse reactions is low, and it has good tolerance and safety.

[0005] The synthesis of lercanidipine hydrochloride mainly adopts the following two routes:

[0006]

[0007] In Route 1, the reactant diketene is toxic, not easy to transport, and the preparation equipment is complex; moreover, in the last step of the cyclization reaction, there are many by-products, the yield of lercanidipine hydrochloride is low, and the removal of by-products requires purification technologies such as column chromatography that are difficult to industrialize. In Route 2, 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-methylcarbonyl-3-pyridinecarboxylic acid (DHPCOOH) has a relatively mature production process in China. After DHPCOOH is chlorinated and reacted with the side chain alcohol, lercanidipine hydrochloride is obtained, and the yield is about 70%. Summary of the Invention:

[0008] The technical problem to be solved by the present invention is to provide a synthetic method of lercanidipine hydrochloride, which can enhance the environmental protection of the process while improving the yield of lercanidipine hydrochloride, reduce the use of toxic reagents, simplify the post-treatment operation, reduce the separation and purification cost, and is suitable for industrial production.

[0009] The technical problem to be solved by the present invention is achieved by the following technical solutions:

[0010] The first object of the present invention is to provide a green synthetic method of lercanidipine hydrochloride, comprising the following steps:

[0011] (1) 1,1,N-Trimethyl-N-(3,3-diphenylpropyl)-2-aminoethyl acetoacetate (Compound 1) reacts with ammonia water through an ammonolysis reaction to obtain 3-amino-2-butenoic acid-2-[(3,3-diphenylpropyl)methylamino]-1,1-dimethylethyl ester (Compound 2);

[0012] (2) 3-Amino-2-butenoic acid-2-[(3,3-diphenylpropyl)methylamino]-1,1-dimethylethyl ester (Compound 2) reacts with methyl 2-(3-nitrobenzylidene)-3-oxobutyrate (Compound 3) through a cyclization reaction to obtain lercanidipine hydrochloride.

[0013] The synthetic route is as follows:

[0014]

[0015] Preferably, the molar ratio of 1,1,N-trimethyl-N-(3,3-diphenylpropyl)-2-aminoethyl acetoacetate to ammonia in ammonia water is 1:(10 - 30). Ammonia water serves as both a reactant and a reaction solvent, and after the reaction is completed, the excess ammonia water is removed by vacuum distillation.

[0016] Preferably, the reaction temperature of the ammonolysis reaction is 30 - 50 °C.

[0017] Preferably, the molar ratio of 3-amino-2-butenoic acid-2-[(3,3-diphenylpropyl)methylamino]-1,1-dimethylethyl ester to methyl 2-(3-nitrobenzylidene)-3-oxobutyrate is 1:(1.05 - 1.1).

[0018] Preferably, at least one of methanol, ethanol, and isopropanol is used as the reaction solvent for the cyclization reaction. Further preferably, isopropanol is used as the reaction solvent for the cyclization reaction.

[0019] Preferably, the cyclization reaction is carried out under reflux conditions.

[0020] Preferably, the cyclization reaction uses cyclopentadienyl nickel carbonyl dimer as the catalyst. The catalyst in the cyclization reaction has a great influence on the yield of the product lercanidipine hydrochloride. Only by using a catalyst with high catalytic activity can the yield of the product lercanidipine hydrochloride be substantially increased. The inventor finally screened cyclopentadienyl nickel carbonyl dimer as the catalyst for this step of cyclization reaction from nearly a hundred different types of catalysts, so that the yield of lercanidipine hydrochloride reached more than 90%, and the purity ≥ 99.98%.

[0021] The second object of the present invention is to provide a method for synthesizing 1,1,N-trimethyl-N-(3,3-diphenylpropyl)-2-aminoethyl acetoacetate, which is prepared by a substitution reaction of 2,N-dimethyl-N-(3,3-diphenylpropyl)-1-amino-2-propanol and 3-oxobutyryl chloride.

[0022] The synthesis route is as follows:

[0023]

[0024] Preferably, the molar ratio of 2,N-dimethyl-N-(3,3-diphenylpropyl)-1-amino-2-propanol to 3-oxobutyryl chloride is 1:(2-4).

[0025] Preferably, the substitution reaction uses at least one of triethylamine, N,N-diisopropylethylamine, pyridine, and potassium carbonate as the catalyst. Further preferably, the substitution reaction uses triethylamine as the catalyst.

[0026] The present invention uses freshly prepared 3-oxobutyryl chloride as the reactant to synthesize 1,1,N-trimethyl-N-(3,3-diphenylpropyl)-2-aminoethyl acetoacetate by substitution reaction with 2,N-dimethyl-N-(3,3-diphenylpropyl)-1-amino-2-propanol. Compared with diketene, 3-oxobutyryl chloride has low toxicity, high reaction activity, and can be quenched by adding water after the reaction ends. The post-treatment is simple, and the conversion rate of 2,N-dimethyl-N-(3,3-diphenylpropyl)-1-amino-2-propanol is high, thereby increasing the yield and purity of 1,1,N-trimethyl-N-(3,3-diphenylpropyl)-2-aminoethyl acetoacetate.

[0027] The third object of the present invention is to provide a method for synthesizing methyl 2-(3-nitrobenzylidene)-3-oxobutyrate, which is prepared by the Knoevenagel reaction of m-nitrobenzaldehyde and methyl acetoacetate.

[0028] The synthesis route is as follows:

[0029]

[0030] Preferably, the molar ratio of m-nitrobenzaldehyde to methyl acetoacetate is 1:(1.1 - 1.2).

[0031] In the art, piperidine, pyridine, and amine are usually used as catalysts for the Knoevenagel reaction. However, when these catalysts are applied to the synthesis of methyl 2-(3-nitrobenzylidene)-3-oxobutyrate, the conversion rate of m-nitrobenzaldehyde is not high, and these catalysts have the disadvantage of being difficult to separate from the reaction system.

[0032] Preferably, the Knoevenagel reaction uses a nitrogen-doped porous carbon-silicon composite material as a catalyst.

[0033] Specifically, the nitrogen-doped porous carbon-silicon composite material is prepared by pyrolysis reaction of silane coupling agent KH550 and polyvinylpyrrolidone K30 in an inert gas.

[0034] Preferably, the mass ratio of silane coupling agent KH550 to polyvinylpyrrolidone K30 is 1:(1 - 5). Further preferably, the mass ratio of silane coupling agent KH550 to polyvinylpyrrolidone K30 is 1:3.

[0035] Preferably, the temperature of the pyrolysis reaction is 300 - 600 °C. It can adopt a one-time heating method or a stepwise heating method, and the heating rate is 1 - 10 °C / min.

[0036] Using the nitrogen-doped porous carbon-silicon composite material prepared by the present invention as the catalyst for the above Knoevenagel reaction can enable the catalyst to fully contact with the reaction raw materials, improve the reaction activity and the conversion rate of raw materials; and during post-treatment, the catalyst can be removed by filtration and reused after washing and drying, with good stability.

[0037] The beneficial effects of the present invention are as follows: The present invention provides a synthesis method of lercanidipine hydrochloride, which effectively improves the yield and purity of lercanidipine hydrochloride while enhancing the environmental protection of the process. The product quality is controllable, the reaction conditions are mild, the use of toxic reagents is reduced, the preparation cycle is shortened, the post-treatment operation is simplified, and the separation and purification cost is reduced, thus being applicable to industrial production. Specific embodiments:

[0038] In order to make the technical means, creative features, achieved purposes, and effects of the present invention easy to understand, the present invention will be further described below in conjunction with specific embodiments.

[0039] Example 1

[0040] (1) To compound 1 (3.8 g, 10 mmol), 25% ammonia water (13.6 g, 200 mmol, calculated based on the molar amount of ammonia in ammonia water) was added, and then it was heated to 40 °C and stirred at a constant temperature for 12 h; after the reaction, ammonia water was removed by distillation under reduced pressure, and the residue was extracted with 50 mL of ethyl acetate. The organic layer was taken, and ethyl acetate was recovered by distillation under reduced pressure to obtain compound 2.

[0041] (2) To 50 mL of isopropanol, compound 2 (3.8 g, 10 mmol), compound 3 (2.6 g, 10.5 mmol), and cyclopentadienylcarbonyl nickel dimer (0.12 g, 0.5 mmol) were added in sequence, and it was heated to reflux and stirred for 3 h; after the reaction, it was naturally cooled to room temperature, concentrated hydrochloric acid was added dropwise to adjust the pH to 3 - 4, isopropanol was recovered by distillation under reduced pressure, 30 mL of ethyl acetate was added to the residue, stirred for 15 min and then left standing for 12 h, filtered, the filter cake was vacuum dried at 45 °C and then stirred and dissolved in absolute ethanol (absolute ethanol was added dropwise, and the amount used was just enough to completely dissolve the filter cake at 70 °C), left standing for 24 h, filtered, and vacuum dried at 45 °C to obtain lercanidipine hydrochloride. ESI-MS: m / z = 612.3 [M + 1] + . The yield of lercanidipine hydrochloride was 91.7%, and the HPLC purity was 99.99%.

[0042] Example 2

[0043] (1) To compound 1 (3.8 g, 10 mmol), 25% ammonia water (20.4 g, 300 mmol, calculated based on the molar amount of ammonia in ammonia water) was added, and then it was heated to 30 °C and stirred at a constant temperature for 12 h; after the reaction, ammonia water was removed by distillation under reduced pressure, and the residue was extracted with 50 mL of ethyl acetate. The organic layer was taken, and ethyl acetate was recovered by distillation under reduced pressure to obtain compound 2.

[0044] (2) To 50 mL of isopropanol, compound 2 (3.8 g, 10 mmol), compound 3 (2.7 g, 11 mmol), and cyclopentadienylcarbonyl nickel dimer (0.36 g, 1.5 mmol) were added in sequence, and it was heated to reflux and stirred for 5 h; after the reaction, it was naturally cooled to room temperature, concentrated hydrochloric acid was added dropwise to adjust the pH to 3 - 4, isopropanol was recovered by distillation under reduced pressure, 30 mL of ethyl acetate was added to the residue, stirred for 15 min and then left standing for 12 h, filtered, the filter cake was vacuum dried at 45 °C and then stirred and dissolved in absolute ethanol (absolute ethanol was added dropwise, and the amount used was just enough to completely dissolve the filter cake at 70 °C), left standing for 24 h, filtered, and vacuum dried at 45 °C to obtain lercanidipine hydrochloride. The yield of lercanidipine hydrochloride was 93.6%, and the HPLC purity was 99.98%.

[0045] Example 3

[0046] (1) 25% aqueous ammonia (6.8 g, 100 mmol calculated as the molar amount of ammonia in the aqueous ammonia) was added to Compound 1 (3.8 g, 10 mmol), and then the mixture was heated to 50 °C and stirred for 12 h; after the reaction was completed, the aqueous ammonia was removed by distillation under reduced pressure, and the residue was extracted with 50 mL of ethyl acetate. The organic layer was taken, and the ethyl acetate was recovered by distillation under reduced pressure to obtain Compound 2.

[0047] (2) Compound 2 (3.8 g, 10 mmol), Compound 3 (2.7 g, 11 mmol) and cyclopentadienylcarbonyl nickel dimer (0.24 g, 1 mmol) were successively added to 50 mL of isopropanol, and the mixture was heated to reflux and stirred for 3 h; after the reaction was completed, it was naturally cooled to room temperature, concentrated hydrochloric acid was added dropwise to adjust the pH to 3 - 4, and the isopropanol was recovered by distillation under reduced pressure. 30 mL of ethyl acetate was added to the residue, and after stirring for 15 min, it was allowed to stand for 12 h, filtered, and the filter cake was vacuum dried at 45 °C and then stirred and dissolved in absolute ethanol (absolute ethanol was added dropwise, and the amount used was just enough to completely dissolve the filter cake at 70 °C), allowed to stand for 24 h, filtered, and vacuum dried at 45 °C to obtain Lercanidipine hydrochloride. The yield of Lercanidipine hydrochloride was 92.8%, and the HPLC purity was 99.98%.

[0048] Example 4

[0049] 2,N - Dimethyl - N - (3,3 - diphenylpropyl) - 1 - amino - 2 - propanol (5.9 g, 20 mmol) and triethylamine (2.0 g, 20 mmol) were added to 100 mL of toluene, and freshly prepared 3 - oxobutyryl chloride (9.6 g, 80 mmol) was added dropwise at 10 °C. After the addition was completed, the mixture was stirred for 1 h and then heated to reflux for 3 h; after the reaction was completed, it was naturally cooled to room temperature, 50 mL of water was added and stirred for 10 min, and after standing for 30 min, the organic layer was taken, and the toluene was recovered by distillation under reduced pressure to obtain Compound 1. ESI - MS: m / z = 382.2 [M + 1] + . The yield of Compound 1 was 98.6%, and the HPLC purity was 98.85%.

[0050] Example 5

[0051] To 100 mL of toluene, 2,N-dimethyl-N-(3,3-diphenylpropyl)-1-amino-2-propanol (5.9 g, 20 mmol) and triethylamine (2.0 g, 20 mmol) were added. Freshly prepared 3-oxobutyryl chloride (4.8 g, 40 mmol) was added dropwise at 10 °C. After the addition was complete, stirring was continued for 1 h, and then the reaction was heated to reflux for 3 h. After the reaction was completed, it was naturally cooled to room temperature. 50 mL of water was added and stirred for 10 min. After standing for 30 min, the organic layer was taken, and toluene was recovered by distillation under reduced pressure to obtain Compound 1. The yield of Compound 1 was 97.2%, and the HPLC purity was 98.74%.

[0052] Example 6

[0053] To the silane coupling agent KH550, polyvinylpyrrolidone K30 was added. The mass ratio of the silane coupling agent KH550 to polyvinylpyrrolidone K30 was 1:5. They were ground and mixed evenly, and pyrolyzed in an argon atmosphere at a heating rate of 5 °C / min. The heating program was as follows: first heated from room temperature to 300 °C and held for 0.5 h, then continued to heat to 400 °C and held for 1 h, and then heated to 550 °C and held for 3 h, and then naturally cooled to room temperature to obtain a nitrogen-doped porous carbon-silicon composite material.

[0054] To 100 mL of isopropanol, m-nitrobenzaldehyde (15.1 g, 0.1 mol), methyl acetoacetate (12.8 g, 0.11 mol) and 0.5 g of the nitrogen-doped porous carbon-silicon composite material were added. The mixture was heated to reflux and stirred for 3 h. After the reaction was completed, the nitrogen-doped porous carbon-silicon composite material was removed by hot filtration. It was naturally cooled to room temperature and filtered again. The filter cake was vacuum dried at 45 °C and then stirred and dissolved in absolute ethanol (absolute ethanol was added dropwise, and the amount used was just enough to completely dissolve the filter cake at 70 °C). It was left standing for 24 h, filtered, and vacuum dried at 45 °C to obtain Compound 3. ESI-MS: m / z = 250.1 [M+1] + . The yield of Compound 3 was 98.2%, and the HPLC purity was 99.97%.

[0055] Example 7

[0056] To the silane coupling agent KH550, polyvinylpyrrolidone K30 was added. The mass ratio of the silane coupling agent KH550 to polyvinylpyrrolidone K30 was 1:3. They were ground and mixed evenly, and pyrolyzed in an argon atmosphere at a heating rate of 5 °C / min. The heating program was as follows: first heated from room temperature to 350 °C and held for 0.5 h, then continued to heat to 450 °C and held for 1 h, and then heated to 550 °C and held for 3 h, and then naturally cooled to room temperature to obtain a nitrogen-doped porous carbon-silicon composite material.

[0057] 15.1 g (0.1 mol) of m-nitrobenzaldehyde, 13.9 g (0.12 mol) of methyl acetoacetate and 0.8 g of nitrogen-doped porous carbon-silicon composite were added to 100 mL of isopropanol, and the mixture was heated to reflux and stirred for 3 h; after the reaction, the nitrogen-doped porous carbon-silicon composite was removed by hot filtration while it was hot, and the mixture was naturally cooled to room temperature and filtered again. The filter cake was vacuum dried at 45 °C and then stirred and dissolved in absolute ethanol (absolute ethanol was added dropwise, and the amount used was just enough to completely dissolve the filter cake at 70 °C), and the mixture was allowed to stand for 24 h, filtered, and vacuum dried at 45 °C to obtain Compound 3. The yield of Compound 3 was 99.0%, and the HPLC purity was 99.96%.

[0058] Comparative Example 1

[0059] The only difference between Comparative Example 1 and Example 1 was that cyclopentadienylcarbonyl nickel dimer was replaced with ammonium acetate in the same molar amount, and the remaining steps were the same as those in Example 1. The yield of lercanidipine hydrochloride was 86.2%, and the HPLC purity was 99.96%.

[0060] Comparative Example 2

[0061] The only difference between Comparative Example 2 and Example 7 was that silane coupling agent KH550 was not added, and only polyvinylpyrrolidone K30 was used to prepare the nitrogen-doped porous carbon composite and used as the catalyst for the Knoevenagel reaction, and the remaining steps were the same as those in Example 1. The yield of Compound 3 was 93.8%, and the HPLC purity was 99.94%.

[0062] Comparative Example 3

[0063] The only difference between Comparative Example 3 and Example 7 was that the nitrogen-doped porous carbon-silicon composite was replaced with piperidine in the same mass, and the remaining steps were the same as those in Example 1. The yield of Compound 3 was 92.4%, and the HPLC purity was 99.95%.

[0064] The foregoing has shown and described the basic principles, main features and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited by the above embodiments, and what is described in the above embodiments and the specification is only to illustrate the principle of the present invention. Without departing from the spirit and scope of the present invention, the present invention will have various changes and improvements, and these changes and improvements fall within the scope of the present invention claimed. The scope of protection claimed by the present invention is defined by the appended claims and their equivalents.

Claims

1. A green synthesis method of lercanidipine hydrochloride, characterized in that, it comprises the following steps: (1) 1,1,N-Trimethyl-N-(3,3-diphenylpropyl)-2-aminoethyl acetoacetate reacts with ammonia water through an ammonolysis reaction to obtain 2-[(3,3-diphenylpropyl)methylamino]-1,1-dimethylethyl 3-aminocrotonate; (2) 2-[(3,3-diphenylpropyl)methylamino]-1,1-dimethylethyl 3-aminocrotonate reacts with methyl 2-(3-nitrobenzylidene)-3-oxobutyrate through a cyclization reaction to obtain lercanidipine hydrochloride; The cyclization reaction uses cyclopentadienylcarbonyl nickel dimer as a catalyst.

2. The green synthesis method according to claim 1, characterized in that: The molar ratio of 1,1,N-Trimethyl-N-(3,3-diphenylpropyl)-2-aminoethyl acetoacetate to ammonia in the ammonia water is 1:(10 - 30).

3. The green synthesis method according to claim 1, characterized in that: The reaction temperature of the ammonolysis reaction is 30 - 50 °C.

4. The green synthesis method according to claim 1, characterized in that: The molar ratio of 2-[(3,3-diphenylpropyl)methylamino]-1,1-dimethylethyl 3-aminocrotonate to methyl 2-(3-nitrobenzylidene)-3-oxobutyrate is 1:(1.05 - 1.1).

5. The green synthesis method according to claim 1, characterized in that: The cyclization reaction uses at least one of methanol, ethanol, and isopropanol as a reaction solvent.

6. The green synthesis method according to claim 5, characterized in that: The cyclization reaction is carried out under reflux conditions.

7. The green synthesis method according to any one of claims 1 - 6, characterized in that: The 1,1,N-Trimethyl-N-(3,3-diphenylpropyl)-2-aminoethyl acetoacetate is prepared by a substitution reaction of 2,N-Dimethyl-N-(3,3-diphenylpropyl)-1-amino-2-propanol and 3-oxobutyryl chloride.

8. The green synthesis method according to claim 7, characterized in that: The molar ratio of 2,N-Dimethyl-N-(3,3-diphenylpropyl)-1-amino-2-propanol to 3-oxobutyryl chloride is 1:(1.1 - 1.2).

9. The green synthesis method according to claim 7, characterized in that: The substitution reaction uses at least one of triethylamine, N,N-diisopropylethylamine, pyridine, and potassium carbonate as a catalyst.

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