A preparation method of nicardipine hydrochloride

Abstract

The invention discloses a kind of preparation method of nicardipine hydrochloride, the preparation method is with 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl) pyridine-3,5-dicarboxylic acid monomethyl ester and 2-chloroethanol as starting materials, obtains compound 3;Then react esterification with 2-naphthalenesulfonyl chloride, obtain compound 5;Replace with N-methylbenzylamine effect, then add hydrochloric acid to form salt, obtain crude compound 7;Finally, refine, obtain nicardipine hydrochloride. The present invention avoids using expensive condensing agents such as EDCI in preparation process for condensation, reduces production cost;And adopt specific mixed solvent acetone, tetrahydrofuran and acetonitrile in refining process, without using anhydrous magnesium sulfate drying, simplify preparation process, be beneficial to industrialized production. The content of prepared nicardipine hydrochloride is 99.98-100.10%, and benzene solvent is not detected, and does not contain potential genotoxic impurities, meets pharmacopoeia requirements.

Description

Technical Field

[0001] The invention belongs to the technical field of medicine, and particularly relates to a preparation method of nicardipine hydrochloride. Background Art

[0002] Nicardipine hydrochloride is a potent dihydropyridine calcium antagonist that inhibits calcium influx and selectively inhibits phosphodiesterase in the brain and coronary arteries, raising intracellular cyclic adenosine monophosphate (CAMP) levels. This relaxes vascular smooth muscle and significantly dilates blood vessels, rapidly lowering blood pressure and significantly increasing cerebral blood flow. It is highly effective in treating hypertension, cerebrovascular disease, cerebral thrombosis, sequelae of cerebral hemorrhage, and arteriosclerosis. It also has some efficacy in treating coronary heart disease and angina pectoris. Nicardipine hydrochloride boasts high efficacy, a wide range of indications, and minimal side effects.

[0003] Nicardipine hydrochloride, whose chemical name is 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid, 3-[β-(N-benzyl-N-methyl)amino]ethyl ester-5-methyl ester hydrochloride, has a molecular formula of C 26 H 29 N3O6·HCl, the chemical structure is as follows:

[0004]

[0005] Currently, the synthesis process for nicardipine hydrochloride generally uses N-methylbenzylamine as the starting material. Industrial production of N-methylbenzylamine involves the reaction of benzyl chloride with monomethylamine in benzene. Benzene, a Class 1 solvent, has a PDE value (PDE refers to the maximum daily dose of an organic solvent that can be ingested without toxicity) of 0.0002%, resulting in a high risk of pharmaceutical residues. Furthermore, residual monomethylamine often introduces non-UV-absorbing impurities, making the nicardipine hydrochloride content difficult to control and failing to meet the pharmacopoeial requirements (99.0-101.0%). Therefore, obtaining high-content nicardipine hydrochloride is a major challenge in research and development. Furthermore, the existing synthesis process for the side chain of nicardipine hydrochloride also utilizes condensation reagents such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) or uses anhydrous magnesium sulfate for drying during dewatering. This cumbersome operation, equipment-unfriendly, and unsuitable for industrialization, resulting in high production costs.

[0006] For example, Chinese invention patent, publication number CN115850158A, discloses a method for preparing nicardipine hydrochloride, the synthetic route of which is as follows:

[0007]

[0008] The disadvantages of this preparation method are that the content of nicardipine hydrochloride is difficult to control and can only be 96-98%, which cannot meet the requirements of the pharmacopoeia, and the expensive EDCI chemical reagent is used.

[0009] The preparation method of nicardipine hydrochloride reported in the document Synthesis of asymmetric 4-aryl-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylates with vasodilating and antihypertensive activities, Chemical and Pharmaceutical Bulletin; 1986.34(4).1589-1606, has the following synthetic route:

[0010]

[0011] This preparation method uses anhydrous magnesium sulfate for drying during the post-processing process, which is cumbersome and not conducive to industrialization. In addition, the benzene residue is far higher than the PDE value, and the content is difficult to meet the requirements of the pharmacopoeia. Summary of the Invention

[0012] The present invention aims to address at least one of the technical problems existing in the above-mentioned prior art. To this end, the present invention provides a method for preparing nicardipine hydrochloride. The nicardipine hydrochloride produced by this method has a content of 99.9-101.0%, meeting pharmacopoeial requirements, and contains no detectable benzene solvent and no potentially genotoxic impurities.

[0013] To solve the above technical problems, the first aspect of the present invention provides a method for preparing nicardipine hydrochloride, which comprises the step of refining a crude nicardipine hydrochloride product, wherein the mixed solvent used for the refining comprises acetone, tetrahydrofuran and acetonitrile.

[0014] The study found that the nicardipine hydrochloride obtained by refining with a specific mixed solvent including acetone, tetrahydrofuran and acetonitrile can effectively increase the content of nicardipine hydrochloride in the product.

[0015] Preferably, the volume ratio of acetone, tetrahydrofuran and acetonitrile is 2:1:0.2.

[0016] As a further improvement of the above solution, the raw material for preparing nicardipine hydrochloride includes 2-naphthalenesulfonyl chloride.

[0017] The study found that the reaction activity of 2-naphthalenesulfonyl chloride is higher than that of traditional toluenesulfonyl chloride, the intermediate obtained is easy to purify, and it does not introduce hydroxychlorinated impurities with potential genotoxicity, which are difficult to control.

[0018] The chemical structure of the potential genotoxic impurity is as follows:

[0019]

[0020] At the same time, the present invention uses 2-naphthalenesulfonyl chloride instead of traditional methylsulfonyl chloride and p-toluenesulfonyl chloride, which can avoid the use of expensive condensing agents such as EDCI for condensation during the preparation process, not only reducing the production cost, but also eliminating the need for anhydrous magnesium sulfate drying during post-treatment, simplifying the preparation process, and the prepared nicardipine hydrochloride has a high content, no benzene solvent is detected, and meets the requirements of the pharmacopoeia.

[0021] As a further improvement of the above scheme, the preparation method of nicardipine hydrochloride comprises the following steps:

[0022] (1) Compound 1,1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylic acid monomethyl ester and chemical 2,2-chloroethanol are used as starting materials, heated, and reacted in a first inert solvent to obtain compound 3;

[0023] (2) Compound 3 and compound 4, 2-naphthalenesulfonyl chloride are mixed and subjected to esterification reaction in a second inert solvent to obtain compound 5;

[0024] (3) Compound 5 and Compound 6 are mixed, heated, and subjected to a substitution reaction; hydrochloric acid is then added to form a salt to obtain Compound 7, i.e., crude nicardipine hydrochloride;

[0025] (4) Adding a mixed solvent to compound 7 for purification, dissolving it, cooling it for crystallization, and obtaining compound 8, i.e., nicardipine hydrochloride;

[0026] The synthetic route of described nicardipine hydrochloride is as follows:

[0027]

[0028] Specifically, the present invention uses 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylic acid monomethyl ester (Compound 1) and 2-chloroethanol (Compound 2) as starting materials to obtain Compound 3; then, the compound is reacted with 2-naphthalenesulfonyl chloride (Compound 4) for esterification to obtain Compound 5; then, the compound is reacted with N-methylbenzylamine (Compound 6) for substitution, and salted with hydrochloric acid to obtain a crude product of nicardipine hydrochloride (Compound 7); finally, the compound is purified in a mixed solvent to obtain a finished product of nicardipine hydrochloride (Compound 8).

[0029] Preferably, in step (1), the mass ratio of compound 1 to compound 2 is 3:(2-3).

[0030] Preferably, in step (1), the heating temperature is 35-60°C; further preferably, the heating temperature is 40-60°C.

[0031] Preferably, in step (1), the first inert solvent comprises acetone.

[0032] Preferably, in step (1), the reaction step of compound 3 is as follows: first, compound 1 is mixed with a first inert solvent, refluxed and stirred, and then compound 2 is slowly added dropwise thereto, and the reaction is carried out for 4-6 hours after the addition is completed, and the reaction is controlled by TLC until the reaction is completed.

[0033] Preferably, in step (2), the mass ratio of compound 3 to compound 4 is 1:(1-3).

[0034] Preferably, in step (2), the temperature of the esterification reaction is -5°C to 35°C.

[0035] Preferably, in step (2), the second inert solvent comprises acetonitrile.

[0036] Preferably, in step (2), the reaction step of compound 5 is as follows: first, compound 3 is mixed with a second inert solvent, and stirred at 30±5°C to obtain a solution of compound 3; another compound 4 is mixed with a second inert solvent, and stirred to dissolve to obtain a solution of compound 4; then, the solution of compound 3 is slowly added dropwise to the solution of compound 4 at 0±5°C, and the reaction is carried out for 4-6 hours after the addition is completed, and the reaction is controlled by TLC until the end.

[0037] Preferably, in step (3), the heating temperature is 65-85° C.; more preferably, the heating temperature is 70-85° C. In step (3), compound 6 is used as the solvent, and no additional solvent is required.

[0038] Preferably, in step (3), the hydrochloric acid is dilute hydrochloric acid; further preferably, the concentration of the hydrochloric acid is 1-5 mol / L; further preferably, the concentration of the hydrochloric acid is 1-2 mol / L.

[0039] Preferably, in step (3), the reaction step of compound 7 is as follows: first, compound 5 and compound 6 are mixed, the temperature is raised to 65-85°C, and the reaction is carried out for 10-15 hours. No obvious material is observed by TLC during the reaction; then the temperature is lowered to 0±5°C, dilute hydrochloric acid is added to wash the layers, and the organic layer is retained; and dilute hydrochloric acid is continued to be added and stirred to form a salt.

[0040] Preferably, in step (4), the temperature is lowered to 0-10°C.

[0041] Preferably, in step (4), the purification step of compound 8 is as follows: adding a mixed solvent to compound 7, heating to 40±5°C to dissolve; then cooling to 0-10°C, stirring and crystallizing for 2-4 hours to obtain compound 8.

[0042] Preferably, step (1), step (2), step (3) and step (4) are all carried out under the protection of an inert gas.

[0043] Preferably, the inert gas is nitrogen.

[0044] Compared with the prior art, the above technical solution of the present invention has at least the following technical effects or advantages:

[0045] The present invention utilizes a specific mixed solvent of acetone, tetrahydrofuran, and acetonitrile during the refining process of crude nicardipine hydrochloride, effectively increasing the nicardipine hydrochloride content in the product. Furthermore, the present invention utilizes 2-naphthalenesulfonyl chloride instead of conventional methylsulfonyl chloride and p-toluenesulfonyl chloride to prepare nicardipine hydrochloride, further increasing the nicardipine hydrochloride content in the product. Furthermore, the present invention avoids the use of expensive condensing agents such as EDCI during the preparation process, thereby reducing production costs. Furthermore, the present invention eliminates the need for drying with anhydrous magnesium sulfate, simplifying the preparation process and facilitating industrial production.

[0046] The content of the nicardipine hydrochloride prepared by the invention is 99.98-100.10 percent, no benzene solvent is detected, and no potential genotoxic impurities are contained, thus meeting the requirements of the pharmacopoeia. BRIEF DESCRIPTION OF THE DRAWINGS

[0047] Figure 1 HPLC chromatogram of nicardipine hydrochloride prepared in Example 1;

[0048] Figure 2 This is the mass spectrum of nicardipine hydrochloride prepared in Example 1;

[0049] Figure 3 This is the NMR image of nicardipine hydrochloride prepared in Example 1;

[0050] Figure 4 HPLC chromatogram of nicardipine hydrochloride prepared in Example 2;

[0051] Figure 5 This is a high performance liquid chromatogram of nicardipine hydrochloride prepared in Example 3;

[0052] Figure 6 This is the mass spectrum of the potential genotoxic impurities in Comparative Example 3;

[0053] Figure 7 This is the NMR image of the potential genotoxic impurities in Comparative Example 3. DETAILED DESCRIPTION

[0054] The present invention is described in detail below with reference to the examples to facilitate understanding of the present invention by those skilled in the art. It is necessary to point out that the examples are only used to further illustrate the present invention and are not to be construed as limiting the scope of protection of the present invention. Non-essential improvements and adjustments made to the present invention by those skilled in the art based on the above-mentioned invention should still fall within the scope of protection of the present invention. At the same time, the raw materials mentioned below that are not described in detail are all commercially available products; the process steps or preparation methods that are not mentioned in detail are all process steps or preparation methods known to those skilled in the art.

[0055] The preparation process of 1.2 mol / L dilute hydrochloric acid in the following examples and comparative examples is as follows: 100 mL of 12 mol / L concentrated hydrochloric acid is measured, 900 mL of water is added, and the mixture is stirred and diluted at 30±5°C to obtain the product.

[0056] Example 1

[0057] A method for preparing nicardipine hydrochloride comprises the following steps:

[0058] (1) Synthesis of compound 3, the synthetic route is as follows:

[0059]

[0060] In a 500mL three-necked flask, 30.00g of compound 1, 14.97g of sodium hydroxide and 150mL of acetone were added, nitrogen protection, reflux stirring (internal temperature 56°C), and 20.89g of 2-chloroethanol was slowly added dropwise; the reaction was allowed to proceed for 5 hours after the addition, and the reaction was controlled by TLC until the reaction was complete and returned to room temperature; 300mL of ethyl acetate (EA) was added, and the mixture was extracted and washed with water twice, with 300mL of water used each time; the organic layer was retained and concentrated under reduced pressure (50±5°C, ≤-0.09Mpa); vortexed until no obvious droplets appeared to obtain a brown viscous liquid; 30mL of isopropanol was added and stirred to disperse; 60mL of n-heptane was slowly added dropwise at 30±5°C; stirring was maintained for 1 hour after the addition was completed; the temperature was lowered to -10±5°C and stirred for 1 hour; filtered to obtain a yellow solid compound 3 weighing 27.12g with a molar yield of 79.82%.

[0061] (2) Synthesis of compound 5, the synthetic route is as follows:

[0062]

[0063] In a 250mL three-necked flask, add 18.00g of compound 3, 33.88g of sodium hydroxide, and 45mL of acetonitrile, under nitrogen protection, and stir at 30±5℃; take 38.24g of 2-naphthalenesulfonyl chloride, add 45mL of acetonitrile, stir to dissolve, and transfer to a dropping funnel for later use; slowly add 20.0g of 2-naphthalenesulfonyl chloride in acetonitrile; after the addition, react at room temperature for 5 hours; control the reaction by TLC until the reaction is complete; after the reaction is complete, stop heating and cool to 50±5°C; add all the above 5% sodium carbonate aqueous solution and stir for 0.5 hour; transfer the reaction solution to a dropping funnel and slowly add 20 mL of glacial acetic acid; after the addition, add 200 mL of ethyl acetate to extract and separate the layers, retain the organic layer, and wash it with 200 mL of water; retain the organic layer and concentrate under reduced pressure (50±5°C, ≤-0.09Mpa); swirl until no droplets appear, add 36 mL of methanol to dissolve; slowly add 144 mL of n-heptane at 0±5°C; crystallize for 2 hours after the addition; filter to obtain a yellow solid, which is dried at 30±5°C to obtain compound 4, weighing 23.03 g, with a yield of 84.99%, and the content of potential genotoxic impurities is not detected.

[0064] (3) Synthesis of compound 8, nicardipine hydrochloride, the synthetic route is as follows:

[0065]

[0066] In a 500 mL three-necked flask, 15.00 g of compound 5 and 84.40 g of compound 6 were added, nitrogen protection was applied, and the temperature was raised to 85° C. for reaction; the reaction was carried out for 12.5 hours; no obvious raw material was observed by TLC during the reaction; after the reaction was completed, the temperature was lowered to 0±5° C., 250 mL of 1.2 mol / L dilute hydrochloric acid was added, the layers were washed, and the organic layer was retained. 250 mL of 1.2 mol / L dilute hydrochloric acid was added at 0±5° C. and stirred for 0.5 hours to form a salt; the layers were separated, the organic layer was retained, and the salified layer was concentrated under reduced pressure (50±5° C., ≤-0.09 MPa); the mixture was vortexed until a yellow viscous solid appeared to obtain compound 7; 100 mL of acetone, 50 mL of tetrahydrofuran, and 10 mL of acetonitrile were added, and the mixture was heated at 40±5° C. to dissolve; the temperature was lowered to -10° C. and stirred for crystallization for 3 hours to obtain the finished product nicardipine hydrochloride compound 8, weighing 13.21 g, with a yield of 96.70%, and no benzene residue was detected.

[0067] The material cost of preparing nicardipine hydrochloride in Example 1 is 2327 yuan / kg, and the total yield of nicardipine hydrochloride is 65.60%.

[0068] Figure 1-3 The HPLC chromatogram, mass spectrum and NMR spectrum of nicardipine hydrochloride prepared in Example 1 are shown in FIG. Figure 2 The molecular ion peak [MH] can be found in - =478. Since the substance is a hydrochloride salt, its free state is shown on the mass spectrum, proving that its free molecular weight is 479. Figure 3 The characterization results of NMR are as follows:

[0069]

[0070] 1 H NMR(600MHz,DMSO-d6)δ10.36(s,1H),9.24(s,1H),8.03-7.90(m,2H),7.63-7.42(m,7H),4.99(s,1 H),4.48-4.13(m,4H),3.64-3.49(m,3H),2.62(d,J=5.1Hz,4H),2.31(d,J=2.1Hz,3H),2.28(s,3H).

[0071] Example 2

[0072] A method for preparing nicardipine hydrochloride comprises the following steps:

[0073] (1) Synthesis of compound 3, the synthetic route is as follows:

[0074]

[0075] In a 500mL three-necked flask, 300.0g of compound 1, 149.7g of sodium hydroxide and 150mL of acetone were added, and under nitrogen protection, reflux stirring was performed, and 208.9g of 2-chloroethanol was slowly added dropwise; the reaction was allowed to proceed for 5 hours after the addition, and the reaction was controlled by TLC until the reaction was complete and the temperature was restored to room temperature; 3000mL of EA was added, and the mixture was extracted and washed with water twice, with 3000mL of water used each time; the organic layer was retained and concentrated under reduced pressure (50±5℃, ≤-0.09Mpa); vortexed until no obvious droplets appeared to obtain a brown viscous liquid; 300mL of isopropanol was added and stirred to disperse; 600mL of n-heptane was slowly added dropwise at 30±5℃; stirring was maintained for 1 hour after the addition was completed; the temperature was lowered to -10±5℃ and stirred for 1 hour; and filtered to obtain a yellow solid compound 3 weighing 275.2g with a molar yield of 81.00%.

[0076] (2) Synthesis of compound 5, the synthetic route is as follows:

[0077]

[0078] In a 250mL three-necked flask, add 180.0g of compound 3, 338.8g of sodium hydroxide, and 450mL of acetonitrile, under nitrogen protection, stir at 30±5℃; take 382.4g of 2-naphthalenesulfonyl chloride, add 450mL of acetonitrile, stir to dissolve, transfer to a dropping funnel for later use; slowly add 200.0g of 2-naphthalenesulfonyl chloride in acetonitrile; after the addition, react at room temperature for 5 hours; control the reaction by TLC; after the reaction is completed, stop heating and cool to 50±5°C; add all the above 5% sodium carbonate aqueous solution and stir for 0.5 hour; transfer the reaction solution to a dropping funnel and slowly add 200mL of glacial acetic acid; after the addition, add 2000mL of ethyl acetate to extract and separate the layers, retain the organic layer, and wash it with 2000mL of water; retain the organic layer and concentrate under reduced pressure (50±5°C, ≤-0.09Mpa); swirl until no droplets appear, add 360mL of methanol to dissolve; slowly add 1440mL of n-heptane at 0±5°C; crystallize for 2 hours after the addition; filter to obtain a yellow solid, which is dried at 30±5°C to obtain compound 4, weighing 240.3g, with a yield of 88.68%, and no potential genotoxic impurities were detected.

[0079] (3) Synthesis of compound 8, nicardipine hydrochloride, the synthetic route is as follows:

[0080]

[0081] In a 500mL three-necked flask, 150.0g of compound 5 and 844.0g of compound 6 were added, nitrogen protection was applied, and the temperature was raised to 85°C for reaction; the reaction was carried out for 12.5 hours; no obvious raw material was observed by TLC during the reaction; after the reaction was completed, the temperature was lowered to 0±5°C, 2500mL of 1.2mol / L dilute hydrochloric acid was added to wash the layers, the organic layer was retained, and 2500mL of 1.2mol / L dilute hydrochloric acid was added at 0±5°C and stirred for 0.5 hours to form a salt; the layers were separated, the organic layer was retained, and the mixture was concentrated under reduced pressure (50±5°C, ≤-0.09Mpa); the mixture was vortexed until a yellow viscous solid appeared to obtain compound 7; 1000mL of acetone, 500mL of tetrahydrofuran, and 100mL of acetonitrile were added, and the mixture was heated at 40±5°C to dissolve; the temperature was lowered to -10°C and stirred for crystallization for 3 hours to obtain the finished product nicardipine hydrochloride compound 8, weighing 132.1g, with a yield of 96.70%, and no benzene residue was detected. The liquid chromatogram is shown as follows Figure 4 shown.

[0082] The material cost of preparing nicardipine hydrochloride in Example 2 is 2216 yuan / kg, and the total yield of nicardipine hydrochloride is 69.46%.

[0083] Example 3

[0084] A method for preparing nicardipine hydrochloride comprises the following steps:

[0085] (1) Synthesis of compound 3, the synthetic route is as follows:

[0086]

[0087] In a 500mL three-necked flask, 300.0g of compound 1, 149.7g of sodium hydroxide and 150mL of acetone were added, nitrogen protection was applied, stirring was carried out at 40°C, and 300.0g of 2-chloroethanol was slowly added dropwise; the reaction was allowed to proceed for 5 hours after the addition, and the reaction was controlled by TLC until the reaction was complete and the temperature was restored to room temperature; 3000mL of EA was added, and the mixture was extracted and washed with water twice, with 3000mL of water used each time; the organic layer was retained and concentrated under reduced pressure (50±5°C, ≤-0.09Mpa); vortexed until no obvious droplets appeared to obtain a brown viscous liquid; 300mL of isopropanol was added and stirred to disperse; 600mL of n-heptane was slowly added dropwise at 30±5°C; stirring was maintained for 1 hour after the addition was completed; the temperature was lowered to -10±5°C and stirred for 1 hour; filtered to obtain a yellow solid compound 3 weighing 270.2g with a molar yield of 79.53%.

[0088] (2) Synthesis of compound 5, the synthetic route is as follows:

[0089]

[0090] In a 250mL three-necked flask, add 180.0g of compound 3, 338.8g of sodium hydroxide, and 450mL of acetonitrile, under nitrogen protection, and stir at 30±5℃; take another 180.0g of 2-naphthalenesulfonyl chloride, add 450mL of acetonitrile, stir to dissolve, and transfer to a dropping funnel for later use; slowly add 200.0g of 2-naphthalenesulfonyl chloride in acetonitrile; after the addition, react at 0±5°C for 5 hours; control by TLC until the reaction is complete; after the reaction is complete, stop heating and cool to 50±5°C; add all the above 5% sodium carbonate aqueous solution and stir for 0.5 hour; transfer the reaction solution to a dropping funnel and slowly add 200mL of glacial acetic acid; after the addition, add 2000mL of ethyl acetate to extract and separate the layers, retain the organic layer, and wash it with 2000mL of water; retain the organic layer and concentrate under reduced pressure (50±5°C, ≤-0.09Mpa); swirl until no droplets appear, add 360mL of methanol to dissolve; slowly add 1440mL of n-heptane at 0±5°C; crystallize for 2 hours after the addition; filter to obtain a yellow solid, which is dried at 30±5°C to obtain compound 4, weighing 238.3g, with a yield of 87.95%, and no potential genotoxic impurities were detected.

[0091] (3) Synthesis of compound 8, nicardipine hydrochloride, the synthetic route is as follows:

[0092]

[0093] In a 500mL three-necked flask, 150.0g of compound 5 and 844.0g of compound 6 were added, nitrogen protection was applied, and the temperature was raised to 70°C for reaction; the reaction was carried out for 12.5 hours; no obvious raw material was observed by TLC during the reaction; after the reaction was completed, the temperature was lowered to 0±5°C, 2500mL of 1.2mol / L dilute hydrochloric acid was added to wash the layers, the organic layer was retained, and 2500mL of 1.2mol / L dilute hydrochloric acid was added at 0±5°C and stirred for 0.5 hours to form a salt; the layers were separated, the organic layer was retained, and the solution was concentrated under reduced pressure (50±5°C, ≤-0.09Mpa); the mixture was vortexed until a yellow viscous solid appeared to obtain compound 7; 1000mL of acetone, 500mL of tetrahydrofuran, and 100mL of acetonitrile were added, and the mixture was heated at 40±5°C to dissolve; the temperature was lowered to 0°C and stirred for crystallization for 3 hours to obtain the finished product nicardipine hydrochloride compound 8, weighing 135.1g, with a yield of 98.89%, and no benzene residue was detected. The HPLC chromatogram is shown as follows Figure 5 shown.

[0094] The material cost of preparing nicardipine hydrochloride in Example 3 is 2207 yuan / kg, and the total yield of nicardipine hydrochloride is 69.17%.

[0095] Comparative Example 1

[0096] Nicardipine hydrochloride was prepared according to the preparation method disclosed in Example 1 of the Chinese invention patent (publication number CN115850158A), comprising the following steps:

[0097] 4.65 g of dichloromethane was added to a 100 mL single-necked bottle, stirring was started, and then 1.00 g of intermediate M3, 0.588 g of DMAP (4-dimethylaminopyridine), 0.865 kg of EDCI (carbodiimide hydrochloride) and 0.746 g of SM4, heated to 45 ° C for reaction, TLC control after about 6 hours, after the reaction is complete, add the configured 5% sodium carbonate aqueous solution and 4.65g dichloromethane, stir for 20±5min, let stand, separate, wash the organic phase with 5.00g water once, collect the organic layer, and cool to 5 ° C, add the configured 6N hydrochloric acid dropwise, keep stirring for 1 hour, let stand, separate, wash the organic phase with 5.00g water once, collect the organic layer, and concentrate the organic phase at 40 ° C under reduced pressure to dryness to obtain a foamy solid. 7.90g acetone and 0.79g methanol were added to the residue, heated to reflux, dissolved and then cooled to 25 ° C for crystallization for 15 hours, then cooled to 5 ° C, stirred for 4 hours, filtered, rinsed with 0.79g acetone, and dried under reduced pressure at 50±5 ° C to obtain light yellow nicardipine hydrochloride.

[0098] Comparative Example 2

[0099] Nicardipine hydrochloride is prepared according to the preparation method disclosed in the document (Synthesis of asymmetric 4-aryl-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylates with vasodilating and antihypertensive activities, Chemical and Pharmaceutical Bulletin), comprising the following steps:

[0100] To a 100-mL single-necked flask, add 6.0 g of compound 16b and 20 mL of nitrogen-methylbenzylamine. React at 95°C for 8 hours to terminate the reaction. Cool and dissolve in 10 mL of dichloromethane. Wash twice with 10 mL of 2N dilute hydrochloric acid and once with 10 mL of water. Dry over 5 g of anhydrous magnesium sulfate for 30 minutes. Filter and concentrate the filtrate to obtain a sample. Add 10 mL of ethyl acetate and crystallize overnight at 5°C. Filter to obtain the crude product. Crystallize from acetone to obtain compound 17 (nicardipine hydrochloride), a finished product with a melting point of 168-170°C and a benzene residue of 0.06%. Drying with anhydrous magnesium sulfate was incomplete, and the stirring process severely impacted the glass wall, resulting in significant impact on the equipment during the scale-up process.

[0101] Comparative Example 3

[0102] The only difference between Comparative Example 3 and Example 1 is that in step (3) of Comparative Example 3, the volume ratio of acetone, tetrahydrofuran and acetonitrile is 2:1:1 / 30.

[0103] In Comparative Example 3, the synthesis steps of Compound 8, Nicardipine Hydrochloride, are as follows:

[0104] In a 500 mL three-necked flask, 30.00 g of compound 5 and 168.81 g of compound 6 were added, and the mixture was heated to 85° C. under nitrogen protection and reacted for 12.5 hours. No obvious raw material was observed by TLC during the reaction. After the reaction was completed, the temperature was lowered to 0±5° C., 500 mL of 1.2 mol / L dilute hydrochloric acid was added to wash the layers, and the organic layer was retained. 500 mL of 1.2 mol / L dilute hydrochloric acid was added at 0±5° C. and stirred for 0.5 hours to form a salt. The layers were separated, the organic layer was retained, and the mixture was concentrated under reduced pressure (50±5° C., ≤-0.09 MPa). The mixture was vortexed until a yellow viscous solid appeared to obtain compound 7. A mixed solvent of 300 mL of acetone, 150 mL of tetrahydrofuran, and 10 mL of acetonitrile was added, and the mixture was heated to 40±5° C. to dissolve the mixture. The temperature was lowered to -10° C. and stirred for crystallization for 3 hours to obtain the finished product, nicardipine hydrochloride compound 8, with a yield of 78.5%.

[0105] During the preparation process of Comparative Example 3, a potential genotoxic impurity was detected with a content of 5.6%. The mass spectrum and NMR spectrum of the impurity are shown in FIG. Figure 6-7 As shown. Figure 6 The molecular ion peak [MH] can be found in - =393, proving its molecular weight is 394. Figure 7 The characterization results of NMR are as follows:

[0106] 1 H NMR (600MHz, DMSO-d6) δ9.13(s,1H),8.11-7.90(m,2H),7.64(d,J=7.8Hz,1H),7.54(t,J=7.9Hz,1H),4.99(s,1 H),4.22(qdd,J=12.3,6.3,3.9Hz,2H),3.78(qdd,J=11.8,6.4,3.9Hz,2H),3.55(s,3H),2.30(d,J=7.2Hz,6H).

[0107] Comparative Example 4

[0108] The only difference between Comparative Example 4 and Comparative Example 3 is that in step (3) of Comparative Example 4, the volume ratio of acetone, tetrahydrofuran and acetonitrile is 4:1:1 / 80.

[0109] In Comparative Example 4, the synthesis steps of Compound 8, Nicardipine Hydrochloride, are as follows:

[0110] In a 500 mL three-necked flask, 30.00 g of compound 5 and 168.81 g of compound 6 were added, and the mixture was protected by nitrogen and heated to 85° C. for reaction; the reaction was carried out for 12.5 hours; no obvious raw material was observed by TLC during the reaction; after the reaction was completed, the temperature was lowered to 0±5° C., 500 mL of 1.2 mol / L dilute hydrochloric acid was added to wash the layers, the organic layer was retained, and 500 mL of 1.2 mol / L dilute hydrochloric acid was added at 0±5° C. and stirred for 0.5 hours to form a salt; the layers were separated, the organic layer was retained, and the mixture was concentrated under reduced pressure (50±5° C., ≤-0.09 MPa); the mixture was vortexed until a yellow viscous solid appeared to obtain compound 7; a mixed solvent of 400 mL of acetone, 100 mL of tetrahydrofuran, and 5 mL of acetonitrile was added, and the mixture was heated at 40±5° C. to dissolve; the temperature was lowered to -10° C. and stirred for crystallization for 3 hours to obtain the finished product, nicardipine hydrochloride compound 8, with a yield of 78.5%.

[0111] Comparative Example 5

[0112] The only difference between Comparative Example 5 and Comparative Example 3 is that in step (3) of Comparative Example 5, acetonitrile is not added, and the volume ratio of acetone to tetrahydrofuran is 4:1.

[0113] In Comparative Example 5, the synthesis steps of Compound 8, Nicardipine Hydrochloride, are as follows:

[0114] In a 500 mL three-necked flask, 30.00 g of compound 5 and 168.81 g of compound 6 were added, and the mixture was protected by nitrogen and heated to 85° C. for reaction; the reaction was carried out for 12.5 hours; no obvious raw material was observed by TLC during the reaction; after the reaction was completed, the temperature was lowered to 0±5° C., 500 mL of 1.2 mol / L dilute hydrochloric acid was added to wash the layers, the organic layer was retained, and 500 mL of 1.2 mol / L dilute hydrochloric acid was added at 0±5° C. and stirred for 0.5 hours to form a salt; the layers were separated, the organic layer was retained, and the mixture was concentrated under reduced pressure (50±5° C., ≤-0.09 MPa); the mixture was vortexed until a yellow viscous solid appeared to obtain compound 7; a mixed solvent of 400 mL of acetone and 100 mL of tetrahydrofuran was added, and the mixture was heated at 40±5° C. to dissolve the mixture; the temperature was lowered to -10° C. and stirred for crystallization for 3 hours to obtain the finished product nicardipine hydrochloride compound 8 with a yield of 70.5%.

[0115] Comparative Example 6

[0116] The only difference between Comparative Example 6 and Comparative Example 3 is that in step (3) of Comparative Example 6, acetone is not added, and the volume ratio of tetrahydrofuran to acetonitrile is 10:1.

[0117] In Comparative Example 6, the synthesis steps of Compound 8, Nicardipine Hydrochloride, are as follows:

[0118] In a 500 mL three-necked flask, 30.00 g of compound 5 and 168.81 g of compound 6 were added, and the mixture was heated to 85° C. under nitrogen protection and reacted for 12.5 hours. No obvious raw material was observed by TLC during the reaction. After the reaction was completed, the temperature was lowered to 0±5° C., 500 mL of 1.2 mol / L dilute hydrochloric acid was added to wash the layers, and the organic layer was retained. 500 mL of 1.2 mol / L dilute hydrochloric acid was added at 0±5° C. and stirred for 0.5 hours to form a salt. The layers were separated, the organic layer was retained, and the mixture was concentrated under reduced pressure (50±5° C., ≤-0.09 MPa). The mixture was vortexed until a yellow viscous solid appeared to obtain compound 7. A mixed solvent of 1000 mL of tetrahydrofuran and 100 mL of acetonitrile was added, and the mixture was heated to 40±5° C. to dissolve the mixture. The temperature was lowered to -10° C. and stirred for crystallization for 3 hours to obtain the finished product, nicardipine hydrochloride compound 8, with a yield of 68.5%.

[0119] Comparative Example 7

[0120] The only difference between Comparative Example 7 and Comparative Example 3 is that in step (3) of Comparative Example 7, acetone and tetrahydrofuran are not added, and only acetonitrile is added.

[0121] In Comparative Example 7, the synthesis steps of Compound 8, Nicardipine Hydrochloride, are as follows:

[0122] In a 500 mL three-necked flask, 30.00 g of compound 5 and 168.81 g of compound 6 were added, and the mixture was protected by nitrogen and heated to 85° C. for reaction; the reaction was carried out for 12.5 hours; no obvious raw material was observed by TLC during the reaction; after the reaction was completed, the temperature was lowered to 0±5° C., 500 mL of 1.2 mol / L dilute hydrochloric acid was added to wash the layers, the organic layer was retained, and 500 mL of 1.2 mol / L dilute hydrochloric acid was added at 0±5° C. and stirred for 0.5 hours to form a salt; the layers were separated, the organic layer was retained, and the mixture was concentrated under reduced pressure (50±5° C., ≤-0.09 MPa); vortexed until a yellow viscous solid appeared to obtain compound 7; 400 mL of acetonitrile was added, and the mixture was heated at 40±5° C. to dissolve; the temperature was lowered to -10° C. and stirred for crystallization for 3 hours to obtain the finished product nicardipine hydrochloride compound 8 with a yield of 71.3%.

[0123] Performance Testing

[0124] 1. Related substance testing methods

[0125] Liquid chromatography conditions are as follows:

[0126] Chromatographic column: Use octadecyl bonded silica gel as filler (Waters XTERRARP184.6×150mm, 3.5μm or equivalent performance column);

[0127] Mobile phase A: acetonitrile: methanol = 82:18 (V / V);

[0128] Mobile phase B: phosphate buffer (3.4 g / L potassium dihydrogen phosphate aqueous solution, pH adjusted to 4.8 with 0.1 mol / L potassium hydroxide aqueous solution);

[0129] Flow rate: 1.0 ml / min;

[0130] Detection wavelength: 237nm;

[0131] Injection volume: 50 μl;

[0132] Column temperature: 35°C;

[0133] The gradient elution program is shown in 1.

[0134] Table 1:

[0135] Time (minutes) Mobile phase A (%) Mobile phase B (%) 0 20 80 5 20 80 40 60 40 45 60 40 50 20 80 60 20 80

[0136] 2. Content test method

[0137] (1) Instruments: Electronic analytical balance, moisture-potential integrated titrator

[0138] (2) Reagents: acetic anhydride, glacial acetic acid, perchloric acid titrant

[0139] (3) Solution preparation:

[0140] 1) Diluent (blank solution): Take 700 ml of acetic anhydride and 300 ml of glacial acetic acid and mix them evenly.

[0141] 2) Test solution: Take about 0.9 g of nicardipine hydrochloride, accurately weigh it, place it in a 250 ml beaker, add 100 ml of diluent, and dissolve it by ultrasonication.

[0142] (4) Determination method

[0143] Titrate with 0.1 mol / L perchloric acid (potentiometric titration). The equivalence point is determined by consuming 25 ml of titrant or reaching 5 equivalence points. Titrate the blank solution first, then the test solution. Each ml of 0.1 mol / L perchloric acid is equivalent to 51.60 mg of nicardipine hydrochloride.

[0144] (5) Calculation formula

[0145]

[0146] Where: cactual: actual concentration of titrant, mol / L;

[0147] ctheoretical: theoretical concentration of the titrant, 0.1 mol / L;

[0148] △V: The difference between the volume of the titrant consumed by the sample when it reaches the equivalence point and the volume of the blank solution consumed, mL;

[0149] 51.6: Each 1ml of titrant (0.1mol / L) consumed is equivalent to 51.6mg of nicardipine hydrochloride, mg

[0150] M: the weight of the test sample, g

[0151] D: Loss on drying of sample, %

[0152] (6) Acceptable standards

[0153] EP Pharmacopoeia requirements:

[0154] Content: Calculated on the basis of dry product, contains nicardipine hydrochloride (C 26 H 29 N3O6·HCl) is between 99.0% and 101.0%.

[0155] The present invention uses the above test method to detect the related substances (purity) and content of nicardipine hydrochloride prepared in each embodiment and comparative example. The results are shown in Table 2.

[0156] Table 2:

[0157]

[0158]

[0159] As shown in Table 2, the nicardipine hydrochloride prepared in Examples 1-3 of the present invention has a content of 99.98-100.10%, which meets the requirements of the pharmacopoeia. However, in Comparative Examples 1-2 and Comparative Examples 3-7, the nicardipine hydrochloride prepared in each case has a lower content and does not meet the requirements of the pharmacopoeia, because they respectively adopt the existing preparation method of nicardipine hydrochloride or use a mixed solvent different from that in the examples (acetone, tetrahydrofuran, and acetonitrile in a volume ratio of 2:1:0.2) during the purification process.

[0160] For those skilled in the art to which the present invention belongs, a number of simple deductions or substitutions can be made without departing from the concept of the present invention, without having to resort to creative work. Therefore, based on the disclosure of the present invention, simple improvements made by those skilled in the art to the present invention should be within the scope of protection of the present invention. The above embodiments are preferred embodiments of the present invention, and all processes similar to the present invention and equivalent changes made should fall within the scope of protection of the present invention.

Claims

1. A method for preparing nicardipine hydrochloride, characterized in that: The following steps are involved: (1) Compound 1, i.e., 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylic acid monomethyl ester and chemical 2, i.e., 2-chloroethanol, are used as starting materials, heated, and reacted in a first inert solvent to obtain compound 3; (2) Compound 3 and compound 4, i.e., 2-naphthalenesulfonyl chloride, are mixed and subjected to an esterification reaction in a second inert solvent to obtain compound 5; (3) Compound 5 and Compound 6 are mixed, heated, and subjected to a substitution reaction; hydrochloric acid is then added to form a salt to obtain Compound 7, i.e., crude nicardipine hydrochloride; (4) adding a mixed solvent to compound 7 for purification, dissolving it, cooling it for crystallization, and obtaining compound 8, namely, nicardipine hydrochloride; the mixed solvent used in the purification is acetone, tetrahydrofuran, and acetonitrile, and the volume ratio of acetone, tetrahydrofuran, and acetonitrile is 2:1:0.2; The synthetic route of described nicardipine hydrochloride is as follows:

2. The method for preparing nicardipine hydrochloride according to claim 1, wherein In step (1), the mass ratio of compound 1 to compound 2 is 3:(2-3).

3. The method for preparing nicardipine hydrochloride according to claim 1, wherein In step (1), the heating temperature is 35-60° C.; and / or the first inert solvent is acetone.

4. The method for preparing nicardipine hydrochloride according to claim 1, wherein In step (2), the mass ratio of compound 3 to compound 4 is 1:(1-3).

5. The method for preparing nicardipine hydrochloride according to claim 1, wherein In step (2), the temperature of the esterification reaction is -5°C to 35°C; and / or the second inert solvent is acetonitrile.

6. The method for preparing nicardipine hydrochloride according to claim 1, wherein In step (3), the heating temperature is 65-85°C; and / or, in step (4), the cooling temperature is 0-10°C.

7. The method for preparing nicardipine hydrochloride according to claim 1, wherein Step (1), step (2), step (3) and step (4) are all carried out under the protection of inert gas.

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