Nicardipine hydrochloride intermediate as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of medicinal chemistry, and particularly relates to a nicardipine hydrochloride intermediate as well as a preparation method and application thereof. The nicardipine hydrochloride intermediate compound E provided by the invention is oxalate, is in a solid form, is stable in property and can be used for preparing nicardipine hydrochloride. The invention also relates to a preparation method of the compound E and application of the compound E, namely the compound E can be used for preparing nicardipine hydrochloride. The intermediate compound E is prepared by adopting a one-pot method, the post-treatment process is greatly simplified, the operation is simple, the cost is low, the purity is good, the yield is high, and the method is more suitable for industrial production. The method for preparing nicardipine hydrochloride by using the intermediate E is low in cost, the total yield is greater than 60%, the purity is greater than or equal to 99.9%, and the method is more suitable for industrial production.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to an intermediate compound E of nicardipine hydrochloride. The present invention also relates to a preparation method of compound E, and the use of compound E, that is, compound E can be used to prepare nicardipine hydrochloride. Background Art

[0002] Nicardipine hydrochloride, with the English name Nicardipine Hydrochloride, has the chemical name: 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. Nicardipine hydrochloride belongs to the second-generation dihydropyridine calcium antagonists. Injectable nicardipine hydrochloride is mainly used for the emergency treatment of abnormal hypertension during surgery and hypertensive emergencies. It has the advantages of rapid onset, long duration, wide indications and few side effects.

[0003] Several main preparation methods of nicardipine hydrochloride are described in the patent document US4769465A:

[0004] Method 1:

[0005]

[0006] This route uses 2-(benzylmethylamino)ethyl acetoacetate, 3-nitrobenzaldehyde and methyl β-aminocrotonate as starting materials to react to obtain nicardipine hydrochloride. We prepared nicardipine hydrochloride according to this preparation method, and its yield was lower than 19.3%, and the product needed to be purified by column chromatography, which was not conducive to large-scale production.

[0007] Method 2:

[0008]

[0009] This route uses 2-(benzyl(methyl)amino)ethyl-2-(3-nitrobenzylidene)-3-oxobutanoic acid and methyl β-aminocrotonate as starting materials, and obtains nicardipine free base through a cyclization reaction. In the post-treatment process, it is acidified into salt by extraction and then further refined to obtain nicardipine hydrochloride, with a yield of 48.5%. This route has few by-products and controllable quality. The difficulty of this preparation method is that the starting material 2-(benzyl(methyl)amino)ethyl-2-(3-nitrobenzylidene)-3-oxobutanoate is difficult to obtain, and this compound is an oil, resulting in the overall difficulty of large-scale production of this method; the preparation yield of nicardipine hydrochloride also needs to be further improved.

[0010] Method 3:

[0011]

[0012] In this preparation method, the raw material 2-chloroethyl 3-oxobutyrate required is difficult to obtain, and the yield of the intermediate preparation is only 23.2%, which is not suitable for large-scale production; the post-treatment in the second step is cumbersome, requiring repeated extraction, washing, and purification, and the total yield is less than 14.2%.

[0013] Method 4:

[0014]

[0015]

[0016] In the second step of this preparation method, the hydrolysis yield under alkaline conditions is 66%. The post-treatment in the third step requires repeated extraction, washing, and purification, which increases the difficulty of large-scale production, and the total yield is only 46%.

[0017] The above-mentioned preparation methods of nicardipine hydrochloride all have the situations of cumbersome post-treatment, high purification difficulty, or low yield. Summary of the Invention

[0018] In view of the above problems existing in the prior art, the present invention provides an intermediate compound E of nicardipine hydrochloride, and a method for preparing nicardipine hydrochloride using compound E. This preparation method is simple to operate, has a high product yield, good purity, controllable quality, and is suitable for large-scale production.

[0019] The free base of compound E It is an oil, which is not conducive to purification and scale-up production. We conducted research experiments on its salt formation, including: salt formation experiments with hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, succinic acid, tartaric acid, oxalic acid, etc. Finally, it was found that only the oxalate compound, that is, compound E, is in solid form, has stable properties, a melting point of 119 °C, and the rest of the salts are all oils.

[0020] The overall preparation process from the preparation of compound E to the preparation of nicardipine hydrochloride using compound E is as follows:

[0021]

[0022]

[0023] In the above preparation route, compound E is an oxalate and is prepared by a one-pot method. By forming a salt to obtain a solid, while greatly simplifying the post-treatment process, the purity of the target product nicardipine hydrochloride is also improved.

[0024] The first aspect of the present invention provides a new compound E, which has the following structure:

[0025]

[0026] The second aspect of the present invention provides a method for preparing the compound E as described above, comprising the following steps:

[0027] (1) Reacting compound A with compound B to obtain a solution of compound C,

[0028] (2) Reacting compound D with the solution of compound C obtained in step (1) to obtain compound E:

[0029]

[0030] The present invention provides a method for preparing the compound E as described above. In some preferred embodiments, it comprises the following steps:

[0031] (1) Adding compound A to a reaction solvent, adding compound B, and stirring until the reaction is complete to obtain a solution of compound C,

[0032] (2) Adding an organic base and an organic acid to the reaction solvent for mixing, adding a drying agent, compound D, and the solution of compound C obtained in step (1), stirring until the reaction is complete, filtering to obtain a filtrate,

[0033] (3) Adding oxalic acid or its organic solution to the filtrate obtained in step (2), cooling for crystallization, filtering, washing, and drying to obtain compound E:

[0034]

[0035] In the method for preparing the compound E of the present invention, in some preferred embodiments, the reaction solvent described in step (1) and step (2) is selected from one or more of tetrahydrofuran, dioxane, acetonitrile, dichloromethane, chloroform, ethyl acetate, isopropyl acetate, methyl tert-butyl ether, and n-heptane solvents; preferably one or more of dichloromethane, chloroform, ethyl acetate, and isopropyl acetate; most preferably dichloromethane and / or ethyl acetate.

[0036] In some preferred embodiments, the organic base described in step (2) is selected from one or more of piperidine, pyridine, triethylamine, and diethylamine; preferably piperidine and / or diethylamine; most preferably piperidine.

[0037] In some preferred embodiments, the organic acid described in step (2) is selected from one or more of glacial acetic acid, formic acid, trifluoroacetic acid, and methanesulfonic acid; preferably glacial acetic acid and / or formic acid; most preferably glacial acetic acid.

[0038] In some preferred embodiments, the drying agent described in step (2) is selected from one or more of anhydrous magnesium sulfate, anhydrous sodium sulfate, and molecular sieves.

[0039] In some preferred embodiments, the organic solvent for dissolving oxalic acid in step (3) is selected from one or more of dichloromethane, chloroform, ethyl acetate, isopropanol, and ethanol solvents; preferably one or more of ethyl acetate, isopropanol, and ethanol; most preferably isopropanol.

[0040] The third aspect of the present invention provides a method for preparing nicardipine hydrochloride using compound E as described above, comprising the following steps:

[0041] (1) Reacting compound E with compound F to obtain a solvate of 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, i.e., compound J,

[0042] (2) Refining the compound J obtained in step (1) in acetone to obtain nicardipine hydrochloride:

[0043]

[0044] The present invention provides a method for preparing nicardipine hydrochloride using compound E as described above. In some preferred embodiments, it comprises the following steps:

[0045] (1) Adding an organic solvent to compound E, mixing evenly, then adding compound F and trimethylchlorosilane, heating up, and maintaining the temperature until the reaction ends,

[0046] (2) Cooling to crystallize, filtering by suction to obtain solid 1,

[0047] (3) Adding solid 1 to ethyl acetate, adding an alkaline aqueous solution, stirring until there are no obvious particles in the system, standing for liquid separation, and separating to obtain the organic phase,

[0048] (4) Adding a hydrogen chloride solution to the organic phase, stirring until a solid precipitates, then cooling to crystallize, and filtering by suction to obtain solid 2,

[0049] (5) Pulping solid 2 with a solvent and drying to obtain compound J,

[0050] (6) Refining the compound J obtained in step (5) in acetone to obtain nicardipine hydrochloride:

[0051]

[0052]

[0053] In some preferred embodiments, the temperature after heating in step (1) is 30°C to 80°C; the temperature after cooling in step (2) is 0 to 30°C; the temperature after cooling in step (4) is -10°C to 20°C.

[0054] The method for preparing nicardipine hydrochloride using compound E according to the present invention, in some preferred embodiments, the organic solvent in step (1) is selected from a mixed solvent of a benign solvent and a non-benign solvent. The benign solvent is selected from one or more of DMF, DMA, and DMSO; preferably DMF and / or DMA; most preferably DMF. The non-benign solvent is selected from one or more of ethyl acetate, isopropyl acetate, isopropanol, ethanol, tetrahydrofuran, and acetonitrile; preferably ethyl acetate and / or isopropyl acetate; most preferably isopropyl acetate.

[0055] The base in the alkaline aqueous solution in step (3) can be any inorganic base. In some preferred embodiments, the base in the alkaline aqueous solution in step (3) is selected from one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, and potassium carbonate.

[0056] The method for preparing nicardipine hydrochloride using compound E according to the present invention, in some preferred embodiments, the slurrying solvent used for solid 2 in step (5) is selected from acetonitrile or ethyl acetate:

[0057] When the slurrying solvent used for solid 2 is acetonitrile, the compound J is an acetonitrile complex of 3-[β-(N-benzyl-N-methyl)amino]ethyl 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate hydrochloride.

[0058] When the slurrying solvent used for solid 2 is ethyl acetate, the compound J is a 1 / 2 ethyl acetate complex of 3-[β-(N-benzyl-N-methyl)amino]ethyl 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate hydrochloride.

[0059] The method for preparing nicardipine hydrochloride using compound E according to the present invention, in some preferred embodiments, the refining in acetone in step (6) includes the following steps:

[0060] (1) Add acetone to compound J, heat to 35°C - 60°C, stir until completely dissolved, filter to obtain a filtrate.

[0061] (2) Add nicardipine hydrochloride seeds to the filtrate obtained in step (1), cool to 0 - 30°C, keep warm and stir for 1h - 20h, filter by suction to obtain a filter cake.

[0062] (3) Wash the filter cake obtained in step (2) with acetone and dry to obtain the target product nicardipine hydrochloride.

[0063] Among them, in some preferred embodiments, the mass ratio of acetone to compound J in step (1) is (5 - 15):1; preferably (6 - 9):1; more preferably 7:1. In some preferred embodiments, the drying temperature in step (3) is 20°C - 80°C; preferably 50°C - 70°C.

[0064] In another some preferred embodiments of the method for preparing nicardipine hydrochloride using compound E of the present invention, the refining in acetone in step (6) includes the following steps:

[0065] (1) Add acetone to compound J, heat up to 40°C - 55°C, stir until completely dissolved, filter to obtain a filtrate.

[0066] (2) Add nicardipine hydrochloride seed crystals to the filtrate obtained in step (1), cool down to 5°C - 20°C, keep warm and stir for 9h - 15h, then perform suction filtration to obtain a filter cake.

[0067] (3) Wash the filter cake obtained in step (2) with acetone, dry it to obtain the target product nicardipine hydrochloride.

[0068] Among them, in some preferred embodiments, the mass ratio of acetone to compound J in step (1) is (5 - 15):1; preferably (6 - 9):1; more preferably 7:1. In some preferred embodiments, the drying temperature in step (3) is 20°C - 80°C; preferably 50°C - 70°C.

[0069] Advantageous technical effects of the present invention:

[0070] 1. The free base of intermediate compound E in the prior art is an oily substance, which is not conducive to purification and production scale-up. The compound E provided by the present invention is an oxalate, which is in solid form, has stable properties, and can be used to prepare nicardipine hydrochloride.

[0071] 2. The intermediate compound E is prepared by a one-pot method, which greatly simplifies the post-treatment process, has simple operation, low cost, good purity and high yield, and is more suitable for industrial production.

[0072] 3. Compared with the prior art, the method for preparing nicardipine hydrochloride using intermediate E of the present invention has low cost, and greatly improves the purity and yield of nicardipine hydrochloride, and is more suitable for industrial production. The total yield of nicardipine hydrochloride > 60%, and the product purity ≥ 99.9%. BRIEF DESCRIPTION OF THE DRAWINGS

[0073] Figure 1It is the related substance chromatogram of 3-[β-(N-benzyl-N-methyl)amino]ethyl 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate hydrochloride (nicardipine hydrochloride).

[0074] Figure 2 It is the TGA-DSC thermogram of 2-[benzyl(methyl)amino]ethyl 2-(3-nitrobenzylidene)-3-oxobutyrate oxalate (Compound E). Detailed implementation manners

[0075] The above content of the present invention will be further described in detail through specific implementation manners below, but this should not be construed as any limitation to the protected subject matter of the present invention. Any technical solution implemented based on the above content of the present invention falls within the scope of the present invention.

[0076] In the following text, if not specifically stated otherwise, the operations carried out in the present invention are carried out at room temperature, and the room temperature refers to 20 - 35°C, preferably 20 - 30°C, and more preferably 25 - 30°C.

[0077] Example 1 Preparation of 2-[benzyl(methyl)amino]ethyl 2-(3-nitrobenzylidene)-3-oxobutyrate oxalate (Compound E)

[0078] 6L of ethyl acetate and 3 kg of N-benzyl-N-methylethanolamine were added to a reaction kettle, stirring was started, and a solution of 1.8 kg of diketene dissolved in 3L of ethyl acetate was added. The temperature was raised to 45°C, and after holding the reaction for 1.5 h, the temperature was lowered to 25 ± 5°C to obtain a reaction solution of 2-(benzylmethylamino)ethyl acetoacetate for standby.

[0079] 21L of ethyl acetate was added to the reaction kettle, 462 g of piperidine and 227 g of glacial acetic acid were added, stirring was started, 9 kg of molecular sieve, 3.12 kg of m-nitrobenzaldehyde and the above-mentioned reaction solution of 2-(benzylmethylamino)ethyl acetoacetate were added. The temperature was controlled at 25 ± 5°C, the reaction was held for 2 h, filtered, and a solution of 3.0 kg of oxalic acid dissolved in 23.7 kg of isopropanol was added to the organic phase. Crystallization was carried out at room temperature for 2 h, suction filtration was carried out, and drying was carried out at 50°C for 2.5 h to obtain 7.3 kg of 2-[benzyl(methyl)amino]ethyl 2-(3-nitrobenzylidene)-3-oxobutyrate oxalate, with a yield of 85.1% and a purity of 98%.

[0080] Example 2 Preparation of 2-[benzyl(methyl)amino]ethyl 2-(3-nitrobenzylidene)-3-oxobutyrate oxalate (Compound E)

[0081] 2 L of ethyl acetate and 1 kg of N-benzyl-N-methylethanolamine were added to a reaction kettle. Stirring was started, and a solution of 0.6 kg of diketene dissolved in 3 L of ethyl acetate was added. The temperature was raised to 40 °C, and after maintaining the reaction for 1.5 h, the temperature was lowered to 25 ± 5 °C to obtain a reaction solution of 2-(benzylmethylamino)ethyl acetoacetate for standby.

[0082] 7 L of ethyl acetate was added to the reaction kettle, 154 g of piperidine and 89 g of glacial acetic acid were added. Stirring was started, and 3 kg of anhydrous magnesium sulfate, 1.04 kg of m-nitrobenzaldehyde and the above-mentioned reaction solution of 2-(benzylmethylamino)ethyl acetoacetate were added. The temperature was controlled at 25 ± 5 °C, and the reaction was maintained for 2 h. Filtration was carried out, 990 g of oxalic acid was added to the organic phase, and crystallization was carried out at room temperature for 2 h. Suction filtration was carried out, and drying was carried out at 55 °C for 2.5 h to obtain 2.5 kg of 2-[benzyl(methyl)amino]ethyl-2-(3-nitrobenzylidene)-3-oxobutyrate oxalate, with a yield of 87.5% and a purity of 98%.

[0083] Example 3 Preparation of 3-[β-(N-benzyl-N-methyl)amino]ethyl 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate hydrochloride

[0084] (1) Preparation of acetonitrile complex of 3-[β-(N-benzyl-N-methyl)amino]ethyl 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate hydrochloride

[0085] 6.87 kg of 2-[benzyl(methyl)amino]ethyl-2-(3-nitrobenzylidene)-3-oxobutyrate oxalate (Compound E) was added to a reaction kettle, 26.2 L of N,N-dimethylformamide and 44 L of isopropyl acetate were added. Stirring was started. 2.18 kg of methyl β-aminocrotonate and 2.26 kg of trimethylchlorosilane were added. The temperature was raised to 55 ± 5 °C, and the reaction was maintained for 4 h. The temperature was lowered to 10 ± 5 °C, and crystallization was carried out for 2.5 h. Suction filtration was carried out, and the wet product was added to 61.8 kg of ethyl acetate. Stirring was started, and a solution of 4.88 kg of sodium bicarbonate dissolved in 55 kg of purified water was added. Stirring was carried out for 1 h, and layering was carried out. The organic phase was washed with 55 kg of purified water again. 2.08 kg of 28% hydrochloric acid isopropyl alcohol solution was added to the organic phase at room temperature, and stirring was carried out for 1 h. The temperature was lowered to 15 ± 5 °C, and crystallization was carried out for 2 h. Suction filtration was carried out, and the wet product was added to 40.5 kg of acetonitrile. Stirring was carried out for 2.5 h. Suction filtration was carried out, and drying was carried out at 40 °C for 3.5 h to obtain 6.2 kg of acetonitrile complex of 3-[β-(N-benzyl-N-methyl)amino]ethyl 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate hydrochloride, with a yield of 76.5%.

[0086] (2) Preparation of 3-[β-(N-benzyl-N-methyl)amino]ethyl 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate hydrochloride

[0087] 5.67 kg of the acetonitrile complex of 3-[β-(N-benzyl-N-methyl)amino]ethyl 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate hydrochloride and 40.3 kg of acetone were added to a reaction kettle. The temperature was controlled at 45 ± 5 °C, and the mixture was stirred until dissolved. After filtration, seeds of nicardipine hydrochloride were added, and the temperature was lowered to 15 ± 5 °C. The mixture was kept warm and stirred for 12 h, then filtered by suction, washed with acetone, and dried at 55 °C for 5.5 h to obtain 5.0 kg of 3-[β-(N-benzyl-N-methyl)amino]ethyl 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate hydrochloride, with a yield of 95.2% and a purity of 99.9%. The total yield was 62.0%.

[0088] Example 4 Preparation of 3-[β-(N-benzyl-N-methyl)amino]ethyl 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate hydrochloride

[0089] (1) Preparation of the 1 / 2 ethyl acetate complex of 3-[β-(N-benzyl-N-methyl)amino]ethyl 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate hydrochloride

[0090] 2.34 kg of 2-[benzyl(methyl)amino]ethyl 2-(3-nitrobenzylidene)-3-oxobutyrate oxalate (Compound E) was added to a reaction kettle. 8 L of N,N-dimethylformamide and 16 L of ethyl acetate were added, and stirring was started. 0.74 kg of methyl β-aminocrotonate and 770 g of trimethylchlorosilane were added, and the temperature was raised to 55 ± 5 °C. The reaction was carried out at this temperature for 4 h, then the temperature was lowered to 10 ± 5 °C, and crystallization was carried out at this temperature for 2.5 h. After filtration by suction, the wet product was added to 21 kg of ethyl acetate, and stirring was started. A solution of 1.66 kg of sodium bicarbonate dissolved in 19 kg of purified water was added, and the mixture was stirred for 45 min. After liquid separation, the organic phase was washed again with 18.7 kg of purified water. At room temperature, 2.5 kg of an 8% hydrogen chloride ethyl acetate solution was added to the organic phase, and the mixture was stirred at a constant temperature for 1 h. The temperature was lowered to 15 ± 5 °C, and crystallization was carried out at this temperature for 2 h. After filtration by suction, the wet product was added to 13.8 kg of ethyl acetate, and the mixture was stirred at a constant temperature for 2 h. After filtration by suction, the product was dried at 45 °C for 4 h to obtain 2.05 kg of the 1 / 2 ethyl acetate complex of 3-[β-(N-benzyl-N-methyl)amino]ethyl 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate hydrochloride, with a yield of 73.9%.

[0091] (2) Preparation of 3-[β-(N-benzyl-N-methyl)amino]ethyl 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate hydrochloride

[0092] 1.56 kg of the 1 / 2 ethyl acetate complex of 3-[β-(N-benzyl-N-methyl)amino]ethyl 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate hydrochloride and 11.1 kg of acetone were added to a reaction kettle. The temperature was controlled at 45 ± 5 °C and stirred until dissolved. Then, it was filtered by suction. The filtrate was added with the seed crystal of nicardipine hydrochloride and slowly cooled to 15 ± 5 °C, and kept warm and stirred for 12 h. Then, it was filtered by suction and washed with acetone, and dried at 65 °C for 6 h to obtain 1.35 kg of 3-[β-(N-benzyl-N-methyl)amino]ethyl 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate hydrochloride, with a yield of 93.9% and a purity of 99.9%. The total yield was 60.7%.

[0093] Nicardipine hydrochloride was prepared according to Method 4 described in US4769465 in Comparative Example 1

[0094] (1) Preparation of dimethyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate

[0095] 20 g of m-nitrobenzaldehyde, 30.7 g of methyl acetoacetate, 21 g of ammonium bicarbonate, 40 ml of absolute ethanol, and 80 ml of purified water were added to a reaction flask. It was stirred and heated to 60 °C. After reacting for 1 h, it was heated to reflux. After the TLC detection was completed, it was cooled to room temperature, filtered, and dried to obtain 32 g of dimethyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate, with a yield of 70%.

[0096] (2) Preparation of 5-(methoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid 30 g of dimethyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate was added to 500 ml of methanol. 42 g of sodium hydroxide dissolved in 150 ml of aqueous solution was added. Stirring was started and heated to 70 °C. Stir until there was no obvious change in the reaction detected by TLC. Then, it was cooled. 400 ml of 1N hydrochloric acid aqueous solution was added, and 1500 ml of purified water was added. It was filtered, and the filtrate was reserved. The pH of the filtrate was adjusted to 2 with 1N hydrochloric acid aqueous solution, filtered by suction, washed with water, and dried to obtain 15 g of 5-(methoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid, with a yield of 52% and a purity of 89%.

[0097] (3) Preparation of nicardipine hydrochloride

[0098] 12 g of 5-(methoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid, 18 g of N-benzyl-N-methylethanolamine, and 7.4 g of 1,3-dicyclohexylcarbodiimide were added to 20 ml of DMF solution. The mixture was stirred and heated to 70 °C, and the reaction was maintained until the TLC detection was completed. Then, 70 ml of chloroform was added, and the mixture was washed three times with 200 ml of water. The organic phase was further washed with 65 ml of 10% hydrochloric acid aqueous solution, and then washed three times with 40 ml of water. The organic phase was dried over anhydrous sodium sulfate, evaporated to dryness under reduced pressure to obtain an oily substance, which was purified by ethyl acetate and then by acetone to obtain 14 g of nicardipine hydrochloride, with a yield of 81%, a total yield of 29.5%, and a purity of 99.2%.

[0099] It can be seen from Comparative Example 1 that the purity of the product obtained by Method 4 described in US4769465 is relatively low, and the total yield is even lower than 30%. Among them, the volume-mass ratio of the maximum volume of the post-treatment in step (2) to the feeding amount is 80 ml / g, which is not suitable for large-scale production. The post-treatment in step (3) is too cumbersome, and the frequent extraction and washing will seriously extend the production cycle in production.

[0100] In Comparative Example 2, in the preparation route we currently determined, when Compound E is a free base, the preparation of nicardipine hydrochloride

[0101] (1) Preparation of 2-(benzylmethylamino)ethyl acetoacetate

[0102] 60 ml of ethyl acetate and 30 g of N-benzyl-N-methylethanolamine were added to a reaction flask, and stirring was started. A solution of 18 g of diketene dissolved in 30 ml of ethyl acetate was added. The temperature was raised to 45 °C, and the reaction was maintained for 1.5 h. Then, the temperature was lowered to 25 ± 5 °C, and 20 ml of 1N hydrochloric acid aqueous solution was added for washing. The aqueous phase was retained, 50 ml of dichloromethane was added, and the pH of the aqueous phase was adjusted to alkaline with 20% sodium carbonate aqueous solution during stirring. The aqueous phase was extracted once more with 20 ml of dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure to obtain 38.5 g of 2-(benzylmethylamino)ethyl acetoacetate as an oily substance, with a yield of 85%.

[0103] (2) Preparation of 2-[benzyl(methyl)amino]ethyl-2-(3-nitrobenzylidene)-3-oxobutyrate (Compound E free base)

[0104] Add 140 ml of dichloromethane into a reaction flask, add 3.1 g of piperidine and 1.5 g of glacial acetic acid. Start stirring, and add 60 g of molecular sieve, 20.7 g of m-nitrobenzaldehyde and 30 g of 2-(benzylmethylamino)ethyl acetoacetate. Control the temperature at 25 ± 5 °C, keep the temperature for reaction for 2 h, filter, concentrate the organic phase to dryness to obtain an oily substance, add 80 ml of toluene and 160 ml of 1N hydrochloric acid aqueous solution, stir for 1 h and then separate the layers. Wash the aqueous phase with toluene once again, and then extract the aqueous phase with 60 ml of dichloromethane for 3 times. Dry the organic phase with anhydrous sodium sulfate, filter, and distill under reduced pressure to obtain 27.6 g of 2-[benzyl(methyl)amino]ethyl-2-(3-nitrobenzylidene)-3-oxobutyrate as an oily substance, with a yield of 60% and a purity of 75%.

[0105] (3) Preparation of nicardipine hydrochloride

[0106] Add 20 g of 2-[benzyl(methyl)amino]ethyl-2-(3-nitrobenzylidene)-3-oxobutyrate into 70 ml of DMF solution, add 9 g of methyl β-aminocrotonate, start stirring, heat up to 95 °C, stir until the reaction ends detected by TLC, cool down, add 80 ml of chloroform, and wash with 200 ml of water for three times. Wash the organic phase with 65 ml of 10% hydrochloric acid aqueous solution, and then wash the organic phase with 40 ml of water for three times. Dry the organic phase with anhydrous sodium sulfate, distill under reduced pressure to dryness to obtain an oily substance, and purify it with ethyl acetate and then with acetone to obtain 13.9 g of nicardipine hydrochloride, with a yield of 52%, an overall yield of 33.2%, and a purity of 99.1%.

[0107] It can be seen from Comparative Example 2 that the purity of the product nicardipine hydrochloride obtained by this preparation method is relatively low, and the overall yield is lower than 35%. Compared with Example 1 and Example 2, in this preparation method, the key lies in the free base of compound E obtained in step (2), which is in the form of an oily substance. This oily substance cannot be purified by crystallization, resulting in only limited purification by extraction and washing in the post-treatment of step (2), leading to a relatively low yield in step (2) and a too low purity of the obtained intermediate oily substance. The post-treatments of both step (2) and step (3) are relatively complex and cumbersome, resulting in an overly long production cycle.

Claims

1. A compound having the structure shown below:

2. A method for preparing the compound E according to claim 1, comprising the following steps: (1) Reacting compound A with compound B to obtain a solution of compound C, (2) Reacting compound D with the solution of compound C obtained in step (1) to obtain compound E:

3. A method for preparing the compound E according to claim 1, comprising the following steps: (1) Adding compound A to a reaction solvent, adding compound B, and stirring until the reaction is complete to obtain a solution of compound C, (2) Adding an organic base and an organic acid to the reaction solvent for mixing, adding a drying agent, compound D, and the solution of compound C obtained in step (1), stirring until the reaction is complete, filtering to obtain a filtrate, (3) Adding oxalic acid or its organic solution to the filtrate obtained in step (2), cooling for crystallization, suction filtering and washing, and drying to obtain compound E:

4. The method for preparing compound E according to claim 3, wherein The reaction solvent described in step (1) and step (2) is selected from one or more of tetrahydrofuran, dioxane, acetonitrile, dichloromethane, chloroform, ethyl acetate, isopropyl acetate, methyl tert-butyl ether, and n-heptane solvents; preferably one or more of dichloromethane, chloroform, ethyl acetate, and isopropyl acetate; most preferably dichloromethane and / or ethyl acetate, The organic base described in step (2) is selected from one or more of piperidine, pyridine, triethylamine, and diethylamine; preferably piperidine and / or diethylamine; most preferably piperidine, The organic acid described in step (2) is selected from one or more of glacial acetic acid, formic acid, trifluoroacetic acid, and methanesulfonic acid; preferably glacial acetic acid and / or formic acid; most preferably glacial acetic acid, The drying agent described in step (2) is selected from one or more of anhydrous magnesium sulfate, anhydrous sodium sulfate, and molecular sieves, The organic solution for dissolving oxalic acid in step (3) is selected from one or more of dichloromethane, chloroform, ethyl acetate, isopropanol, and ethanol solvents; preferably one or more of ethyl acetate, isopropanol, and ethanol; most preferably isopropanol.

5. A method for preparing nicardipine hydrochloride using the compound E according to claim 1, comprising the following steps: (1) Reacting compound E with compound F to obtain a solvate of 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, i.e., compound J, (2) Refining the compound J obtained in step (1) in acetone to obtain nicardipine hydrochloride:

6. A method for preparing nicardipine hydrochloride using the compound E according to claim 1, comprising the following steps: (1) Adding an organic solvent to compound E, mixing evenly, adding compound F and trimethylchlorosilane, heating, and maintaining the temperature until the reaction is complete, (2) Cooling for crystallization, suction filtering to obtain solid 1, (3) Adding solid 1 to ethyl acetate, adding an alkaline aqueous solution, stirring until there are no obvious particles in the system, standing for liquid separation, and separating to obtain an organic phase, (4) Adding a hydrogen chloride solution to the organic phase, stirring until a solid precipitates, then cooling for crystallization, suction filtering to obtain solid 2, (5) Pulping solid 2 with a solvent and drying to obtain compound J, (6) The compound J obtained in step (5) is refined in acetone to obtain nicardipine hydrochloride:

7. According to the preparation method described in claim 6, the organic solvent in step (1) is selected from a mixed solvent of a benign solvent and a non-benign solvent, the benign solvent is selected from one or more of DMF, DMA, and DMSO; preferably DMF and / or DMA; most preferably DMF, the non-benign solvent is selected from one or more of ethyl acetate, isopropyl acetate, isopropanol, ethanol, tetrahydrofuran, and acetonitrile; preferably ethyl acetate and / or isopropyl acetate; most preferably isopropyl acetate, Preferably, the base in the alkaline aqueous solution in step (3) is selected from one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, and potassium carbonate.

8. According to the preparation method described in claim 6, the slurrying solvent used for solid 2 in step (5) is selected from acetonitrile or ethyl acetate, When the slurrying solvent used for solid 2 is acetonitrile, the compound J is an acetonitrile complex of 3-[β-(N-benzyl-N-methyl)amino]ethyl 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate hydrochloride; When the slurrying solvent used for solid 2 is ethyl acetate, the compound J is a 1 / 2 ethyl acetate complex of 3-[β-(N-benzyl-N-methyl)amino]ethyl 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate hydrochloride.

9. According to the preparation method described in claim 6, the refining in acetone in step (6) includes the following steps: (1) Acetone is added to compound J, heated to 35°C - 60°C, stirred until completely dissolved, filtered to obtain a filtrate, (2) Nicardipine hydrochloride seeds are added to the filtrate obtained in step (1), cooled to 0 - 30°C, kept warm and stirred for 1 h - 20 h, and suction filtered to obtain a filter cake, (3) The filter cake obtained in step (2) is washed with acetone and dried to obtain the target product nicardipine hydrochloride, Preferably, the mass ratio of acetone to compound J in step (1) is (5 - 15):1; preferably (6 - 9):1; more preferably 7:1, Preferably, the drying temperature in step (3) is 20°C - 80°C; preferably 50°C - 70°C.

10. According to the preparation method described in claim 6, the refining in acetone in step (6) includes the following steps: (1) Acetone is added to compound J, heated to 40°C - 55°C, stirred until completely dissolved, filtered to obtain a filtrate, (2) Nicardipine hydrochloride seeds are added to the filtrate obtained in step (1), cooled to 5°C - 20°C, kept warm and stirred for 9 h - 15 h, and suction filtered to obtain a filter cake, (3) The filter cake obtained in step (2) is washed with acetone and dried to obtain the target product nicardipine hydrochloride, Preferably, the mass ratio of acetone to compound J in step (1) is (5 - 15):1; preferably (6 - 9):1; more preferably 7:1, Preferably, the temperature of the drying in step (3) is 20°C - 80°C; preferably 50°C - 70°C.

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