A method for preparing dihydropyridine drug intermediate M2

Abstract

The present application provides a method for preparing a high-purity key intermediate M2 of dicardipine drugs, belonging to the technical field of drug intermediate preparation. A dehydrating agent is added during the preparation of the intermediate M2, and the dehydrating agent is an orthoester dehydrating agent. Using the method provided in the present application, the yield of the intermediate M2 is 84.3%, the HPLC purity is 99.63%, M2Z3: 0.17%; M2Z4: 0.15%; other impurities <0.10%, and the content of impurities P0Z4 (i.e., M2Z3) and P0Z5 in the further prepared nicardipine is determined to be: P0Z5 <0.02%, P0Z4 <0.02%.

Description

Technical Field

[0001] The invention belongs to the technical field of drug intermediate preparation, and in particular relates to a method for preparing a high-purity dihydropyridine drug key intermediate M2. Background Art

[0002] Nicardipine is a dihydropyridine calcium channel antagonist, which is widely used in the clinic to treat hypertension, angina pectoris, arrhythmia, congestive cardiomyopathy and ischemic heart disease. Nicardipine hydrochloride is the first dihydropyridine calcium channel antagonist that can be administered intravenously. It was first launched in Japan in 1981. It has a definite antihypertensive effect, high selectivity for blood vessels, and mild effect on the heart. Its structural formula is as follows:

[0003]

[0004] The preparation methods of various dihydropyridine drugs (such as nicardipine, benidipine, barnidipine, etc.) reported in the existing literature all involve the synthesis of the key intermediate M2, CAS: [75130-24-4], and its structural formula is as follows:

[0005]

[0006] For example, patent CN101643469B discloses a synthesis process of barnidipine hydrochloride, and the key compound III in the reaction route is the intermediate M2 of the present invention:

[0007]

[0008] The literature (Wu Xiaoyun et al. Synthesis and Characterization of 1,4-Dihydro-4-aryl-3,5-pyridinedicarboxylates [J]. Organic Chemistry, 2006, 026(001):93-98.) discloses a series of methods for preparing 1,4-dihydro-4-aryl-3,5-pyridinedicarboxylates, which includes the process of preparing intermediate M2 under ethanol reflux:

[0009] However, this document does not focus on impurities in the reaction, nor does it control related impurities.

[0010] The inventors discovered during the study of the preparation route of the intermediate M2 that the above reaction route would produce two impurities: M2Z3 and M2Z4. This was first discovered because water was produced during the process of generating the intermediate M2 from compounds M1 and SM3, which led to the decomposition of M1 and SM3, and then produced impurities M2Z3 and M2Z4. The principle of impurity generation is shown in the following route:

[0011]

[0012] The European Pharmacopoeia defines the content control limit of impurity M2Z3 (EP impurity C) in nicardipine hydrochloride as 0.15% at most; the content control limit of impurity M2Z3 (EP impurity B) in nitrendipine is not more than 0.4%. The literature (Medina, Ignacio. PREPARATIVE HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY FOR THE PURIFICATION OF NITRENDIPINE AND ITS DIMETHYL ESTER [J]. Journal of Liquid Chromatography & Related Technologies, 1999, 22 (13): 1987-1995.) mentions that dimethyl ester compound b (i.e., M2Z3 of the present invention) is one of the most important impurities in the chemical synthesis of nitrendipine and is an impurity that must be controlled in the industrial production process of nitrendipine.

[0013] Patents CN109734656B and CN1110772553B studied the preparation method for controlling the impurity M2Z3 in nitrendipine, mainly by controlling the reaction conditions such as: the amount of material added, reaction temperature, reaction time, reaction reagents, etc. to reduce the generation of impurities. The operation is complicated, and there is no disclosure of controlling the impurity M2Z4 at the same time.

[0014] In the prior art, the production amount of impurities M2Z3 and M2Z4 in the preparation route of M2 is generally 5-10%, and it is difficult to control and reduce. The prior art has limited control level for the impurities, and it is difficult to reach the limit standard. Therefore, a more convenient preparation method for preparing high-purity intermediate M2 is needed. Summary of the invention

[0015] In view of this, the purpose of the present invention is to provide a method for preparing a high-purity key intermediate M2 of dihydrochloride drugs. The present invention can reduce the production of impurities M2Z3 and M2Z4 by adding a dehydrating agent to the reaction route, and the present invention finds that the dehydrating agent of orthoformate ester has better impurity removal effect and higher yield than other dehydrating agents.

[0016] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0017] On the one hand, the present invention provides a method for preparing a high-purity dihydrochloride drug key intermediate M2, wherein a dehydrating agent is added during the preparation of the intermediate M2, and the dehydrating agent is an orthoester dehydrating agent, and the structural formula of the intermediate M2 is as follows:

[0018]

[0019] In some embodiments, intermediate M2 is obtained by reacting intermediate M1 with compound SM3:

[0020] in:

[0021] An orthoester dehydrating agent is added to the reaction, and the reaction solvent includes anhydrous ethanol and glacial acetic acid.

[0022] In some embodiments, the orthoester dehydrating agent includes orthoformates and orthoacetates, preferably orthoformates, and more preferably trimethyl orthoformate, triethyl orthoformate or triisopropyl orthoformate.

[0023] In some embodiments, the orthoacetate dehydrating agent includes trimethyl orthoacetate and triethyl orthoacetate.

[0024] In some embodiments, the preparation method comprises the following steps:

[0025] 1) mixing the intermediate M1 with anhydrous ethanol to obtain a mixture;

[0026] 2) mixing the mixture obtained in step 1) with glacial acetic acid, a dehydrating agent, and SM3 and reacting the mixture to obtain a reactant;

[0027] 3) The reactant obtained in step 2) is washed with anhydrous ethanol and dried to obtain intermediate M2.

[0028] Preferably, the mass ratio of the intermediate M1 in step 1) to anhydrous ethanol is 1:(4-6.5), preferably 1:5.52.

[0029] Preferably, the mass ratio of the intermediate M1 in step 1) to the glacial acetic acid in step 2) is 1:(0.001-0.04), preferably 1:0.0025.

[0030] Preferably, the mass ratio of the intermediate M1 in step 1) to the dehydrating agent in step 2) is 1:(0.4-1.0), preferably 1:0.595.

[0031] Preferably, the mass ratio of the intermediate M1 in step 1) to the dehydrating agent in step 2) is 1:(0.4-1.0), preferably 1:0.619.

[0032] Preferably, the mass ratio of the intermediate M1 in step 1) to the glacial acetic acid, dehydrating agent and SM3 in step 2) is 1:0.0025:0.595:0.619.

[0033] Preferably, the reaction conditions of step 2) include: temperature of 70-80° C. and reaction time of more than 12 h.

[0034] Preferably, the mass ratio of the intermediate M1 in step 1) to the anhydrous ethanol in step 3) is 1:(0.5-2), preferably 1:1.11.

[0035] Preferably, the reactant obtained in step 2) is stirred at 20-30° C. for 16 h, centrifuged, and the obtained precipitate is rinsed with anhydrous ethanol.

[0036] Preferably, the drying temperature in step 3) is 50°C.

[0037] On the other hand, the present invention also provides a method for preparing high-purity nicardipine hydrochloride, comprising the following synthetic steps: using the intermediate M2 obtained by any of the above-mentioned preparation methods of the present invention, and subjecting the intermediate M2 to the following reaction to obtain high-purity nicardipine hydrochloride:

[0038]

[0039] In some embodiments, the method for preparing high-purity nicardipine hydrochloride comprises the following steps:

[0040] (1): Preparation of intermediate M1,

[0041]

[0042] (2): Preparation of intermediate M2,

[0043]

[0044] (3): Preparation of intermediate M3,

[0045]

[0046] (4): preparing nicardipine hydrochloride,

[0047]

[0048] Wherein: in step (2), a dehydrating agent is added during the preparation of the intermediate M2, and the dehydrating agent is one or more of trimethyl orthoformate, triethyl orthoformate and triisopropyl orthoformate.

[0049] In some embodiments, in the above method for preparing nicardipine hydrochloride, step (2) comprises: adding intermediate M1 and solvent, preferably anhydrous ethanol, adding glacial acetic acid, triethyl orthoformate and SM3 to a reaction kettle, heating to 70-80°C for reaction, reacting for about 10-16 hours, and then controlling by TLC to wait for SM3 to be converted. After the reaction is completed, the solid-liquid separation is performed, and the solid is washed and dried to obtain intermediate M2, impurity M2Z3 and impurity M2Z4, wherein the content of impurity M2Z3 is 0-0.2%, and the content of impurity M2Z4 is 0-0.15%.

[0050]

[0051] In some embodiments, in the above method for preparing nicardipine hydrochloride, step (4) comprises: feeding, reaction and post-treatment; the post-treatment step comprises: adding sodium carbonate aqueous solution and dichloromethane, stirring and then standing, separating the liquids, washing the organic phase with water, collecting the organic layer, cooling to 0-10°C, adding hydrochloric acid dropwise, stirring while keeping warm, standing, separating the liquids, washing the organic phase with water once, and collecting the organic layer;

[0052] The organic phase was concentrated to dryness, acetone and methanol were added, and the mixture was heated to reflux. After the solution was clear, the temperature was lowered to 20-30°C for crystallization for 15±1h, and then the temperature was lowered to 0-10°C, stirred, filtered, and the solid was rinsed with acetone and dried to obtain nicardipine hydrochloride, impurity P0Z5 and impurity P0Z4, wherein the content of impurity P0Z5 was 0-0.02%, and the content of impurity P0Z4 was 0-0.02%.

[0053]

[0054] The beneficial effects of the present invention are:

[0055] 1) It was first discovered that in the preparation route of the intermediate M2, the content of impurities M2Z3 and M2Z4 increased significantly due to the generation of water: the experimental example determined that when 0.1ml-1ml of water was added, the purity of the intermediate product M2 decreased (about 72-85%), the content of impurity M2Z3 increased to 3.83%-8.69%, and the content of impurity M2Z4 increased to 8.28%-16.69%;

[0056] 2) The present invention adds an orthoester dehydrating agent in the preparation route of the intermediate M2, which not only improves the yield but also reduces the generation of impurities M2Z3 and M2Z4;

[0057] 3) The orthoester dehydrating agent selected in the present invention has better impurity removal effect than other dehydrating agents, such as magnesium sulfate, sodium sulfate, etc., and has achieved unexpected technical effects;

[0058] 4) The yield of the intermediate M2 is 84.3%, HPLC purity is 99.63%, M2Z3 is 0.17%, M2Z4 is 0.15%, and other impurities are less than 0.10%. The contents of impurities P0Z4 (i.e., M2Z3) and P0Z5 in nicardipine hydrochloride prepared further are measured as follows: P0Z5 < 0.02%, P0Z4 < 0.02%. (Almost not detected). DETAILED DESCRIPTION

[0059] The present invention provides a method for preparing a high-purity dihydropyridine drug key intermediate M2. A dehydrating agent is added during the preparation of the intermediate M2. The dehydrating agent is preferably one or more of trimethyl orthoformate, triethyl orthoformate and triisopropyl orthoformate. The structural formula of the intermediate M2 is as follows:

[0060]

[0061] In the present invention, the preparation method preferably comprises the following steps:

[0062] 1) mixing the intermediate M1 with anhydrous ethanol to obtain a mixture;

[0063] The structural formula of the intermediate M1 is as follows:

[0064]

[0065] 2) mixing the mixture obtained in step 1) with glacial acetic acid, a dehydrating agent, and SM3 and reacting the mixture to obtain a reactant;

[0066] The structural formula of the SM3 is as follows:

[0067]

[0068] 3) The reactant obtained in step 2) is washed with anhydrous ethanol and dried to obtain intermediate M2.

[0069] The present invention preferably mixes the intermediate M1 with anhydrous ethanol to obtain a mixture. The present invention has no special limitation on the sources of the intermediate M1 and anhydrous ethanol, and commercially available products can be used. In the present invention, the mass ratio of the intermediate M1 to anhydrous ethanol is preferably 1:5.52.

[0070] The present invention preferably reacts the obtained mixture with glacial acetic acid, a dehydrating agent, and SM3 to obtain a reactant. In the present invention, the mass ratio of the intermediate M1 to glacial acetic acid, a dehydrating agent, and SM3 is preferably 1:0.0025:0.595:0.619. The present invention improves the yield and reduces the generation of impurities M2Z3 and M2Z4 by adding a dehydrating agent orthoformate dehydrating agent in the preparation route of the intermediate M2. In the present invention, the reaction conditions preferably include: a temperature of 70 to 80°C and a time of more than 12 hours. The present invention preferably performs TLC control after 12 hours of reaction until SM3 is completely converted. In the present invention, the TLC control conditions preferably include: spotting method: taking the reaction clear solution and directly spotting the plate; developing agent: EA / PE=1:2; color development: ultraviolet 254nm.

[0071] The present invention rinses the obtained reactant with anhydrous ethanol and dries it to obtain an intermediate M2. In the present invention, the mass ratio of the intermediate M1 to anhydrous ethanol is preferably 1:1.11. The present invention preferably stirs the obtained reactant at 20-30°C for 16h and centrifuges, and rinses the obtained precipitate with anhydrous ethanol. The present invention does not specifically limit the conditions for the centrifugation, and those skilled in the art can perform conventional operations. In the present invention, the drying temperature is preferably 50°C.

[0072] The preparation route and impurity conversion route of the high-purity nicardipine hydrochloride prepared by the present invention are as follows: impurities M2Z3 and M2Z4 are further converted into important impurities P0Z4 (i.e., M2Z3) and P0Z5 in the final product content control during the reaction, and the specific conversion route is as follows:

[0073]

[0074]

[0075] Since the production of impurities M2Z3 and M2Z4 was reduced in the preparation of the intermediate M2, the contents of impurities P0Z4 (i.e., M2Z3) and P0Z5 in the final product nicardipine were determined to be: P0Z5 < 0.02%, P0Z4 < 0.02%, (almost not detected).

[0076] The technical solutions provided by the present invention are described in detail below in conjunction with the embodiments, but they should not be construed as limiting the protection scope of the present invention.

[0077] Example 1 Synthesis of Nicardipine Hydrochloride

[0078] 1. Preparation of intermediate M1

[0079]

[0080] 1) Feeding:

[0081] Add 3.96 kg of methanol to a 50 L glass reactor, start stirring, add 1.00 kg of m-nitrobenzaldehyde (SM1), 0.768 kg of methyl acetoacetate (SM2) and 0.225 kg of piperidine, and after the addition is complete, add 0.159 kg of glacial acetic acid, keep warm at 20±5°C for about 8 hours, and monitor the reaction by TLC until the conversion rate of SM1 is greater than 95%.

[0082] 2) TLC control conditions:

[0083] Spotting method: take the reaction clear solution and directly spot it on the plate; developing agent: EA / PE=1:2; color development: ultraviolet 254nm.

[0084] 3) Post-processing:

[0085] After the reaction was completed, the mixture was centrifuged, rinsed with 1.58 akg of methanol, and dried under reduced pressure at 50°C to obtain 4.67 kg of a white solid intermediate M1 with a yield of 94.2%.

[0086] 2. Preparation of intermediate M2

[0087]

[0088] 1) Feeding:

[0089] Add 1.00 kg of intermediate M1 and 5.52 kg of anhydrous ethanol to a 50 L reactor, start stirring, then add 0.0025 kg of glacial acetic acid, 0.595 kg of triethyl orthoformate and 0.619 kg of SM3, heat to 70-80 ° C for reaction, react for about 12 hours, and control by TLC, until SM3 is completely converted.

[0090] 2) Post-processing:

[0091] Stop heating, cool naturally to 25±5℃, stir for 16h, centrifuge, and rinse with 1.11kg of anhydrous ethanol. Dry under reduced pressure at 50℃ to obtain 5.86kg of yellow solid intermediate M2. Yield 84.3%, HPLC purity: 99.63%, M2Z3: 0.17%; M2Z4: 0.15%; other impurities <0.10%.

[0092] 3. Preparation of intermediate M3

[0093]

[0094] 1) Prepare solution:

[0095] Preparation of 1N sodium hydroxide solution: Add 0.109 kg of sodium hydroxide into 2.73 kg of purified water, stir, dissolve and set aside.

[0096] Preparation of 6N hydrochloric acid: Add 0.351 kg of hydrochloric acid to 0.298 kg of purified water and set aside.

[0097] 2) Feeding:

[0098] Add 4.51 kg of tetrahydrofuran (THF) to a 50 L glass reactor, start stirring, then add 1.00 kg of intermediate M2, and dropwise add 1N sodium hydroxide solution. During the dropwise addition, control the system temperature at 25±5°C. After the addition is completed, react for 1 hour and control the reaction by TLC until M2 is completely converted.

[0099] 3) Post-processing:

[0100] Concentrate under reduced pressure to remove THF, add 2.63kg purified water and 1.32kg dichloromethane to the reaction, stir for 20±5min, let stand, separate the liquids, wash the water layer once with 1.32kg dichloromethane, and then wash once with 0.662kg dichloromethane, and collect the water layer. Use 6N hydrochloric acid to adjust pH to 3-4. A large amount of solid precipitates. After adjustment, keep warm and stir for 2h±10min. Centrifuge, rinse with 0.702kg purified water, and blow dry at 70±5℃ for 16h. Obtain 4.52kg of white solid intermediate M3, yield: 92.0%. HPLC: 99.60%, M3Z2: 0.19%. Other impurities <0.10%.

[0101] Note: M3Z2 is the conversion impurity of impurity M2Z4, and its structural formula is as follows:

[0102]

[0103] 4. Preparation of Nicardipine Hydrochloride

[0104]

[0105] 1) Solution preparation:

[0106] Preparation of 5% sodium carbonate aqueous solution: Add 0.100 kg of anhydrous sodium carbonate into 2.00 kg of purified water, stir, dissolve and set aside.

[0107] Preparation of 6N hydrochloric acid: Add 1.50 kg of hydrochloric acid to 1.25 kg of purified water, stir, and set aside.

[0108] 2) Feeding:

[0109] 4.65 kg of dichloromethane was added to the reactor, stirring was started, and then 1.00 kg of intermediate M3, 0.588 kg of DMAP (4-dimethylaminopyridine), 0.865 kg of EDCI (carbodiimide hydrochloride) and 0.746 kg of SM4 were added in sequence, and the temperature was raised to 45° C. After about 6 hours of reaction, the TLC was controlled until M3 was completely reacted.

[0110] 3) Post-processing:

[0111] After the reaction, add the prepared 5% sodium carbonate aqueous solution and 4.65kg dichloromethane, stir for 20±5min, stand, separate, wash the organic phase with 5.00kg water once, collect the organic layer, cool to 0-10°C, add the prepared 6N hydrochloric acid dropwise, keep warm and stir for 1h±10min, stand, separate, wash the organic phase with 5.00dkg water once, collect the organic layer, concentrate the organic phase to dryness under reduced pressure at 40°C to obtain a foamy solid, add 7.90kg acetone and 0.79kg methanol to the residue, heat to reflux, dissolve and then cool to 20-30°C and keep warm for crystallization for 15±1h, cool to 0-10°C, stir for 4h±0.5h, filter, rinse with 0.79kg acetone, and dry under reduced pressure at 50±5°C. 5.12kg of light yellow nicardipine hydrochloride is obtained, with a yield of 82.0%. HPLC: 99.95%, P0Z5<0.02%, P0Z4<0.02%.

[0112] Among them, P0Z4 is M2Z3, and P0Z5 is the conversion impurity of impurity M2Z4, and the structural formula is as follows:

[0113]

[0114] Example 2 Influencing Factors Experiment

[0115] Referring to the method for preparing intermediate M2 in Example 1, water was added to the reaction. After completing step 1), the purity of intermediate M2 in the reaction solution, as well as the contents of impurities M2Z3 and M2Z4 were directly determined:

[0116]

[0117] Table 1 Determination of M2 purity and impurity content in the reaction solution

[0118]

[0119]

[0120] The results showed that when water was added to the reaction, the purity of M2 decreased, and the contents of impurities M2Z3 and M2Z4 increased rapidly. Moreover, as the amount of water increased, the purity of M2 further decreased, and the contents of impurities M2Z3 and M2Z4 further increased, confirming that the presence of water in the reaction was the most important factor affecting the contents of impurities M2Z3 and M2Z4.

[0121] Example 3 Investigation of dehydrating agents

[0122] 1. Referring to the method for preparing intermediate M2 in Example 1, a dehydrating agent is added. After completing step 1) and step 2), the purity of intermediate M2 in the solid, as well as the contents of impurities M2Z3 and M2Z4 are determined:

[0123] Table 2 Purity and impurity content of M2 in solid products

[0124] Serial number Acetic acid (equivalent) Dehydrating agent Yield M2 Purity M2Z3 content M2Z4 content 1 0.01eq ----- 64％ 94.84％ 2.23％ 2.84％ 2 0.01eq Trimethyl orthoformate 78％ 98.88％ 0.16％ 0.78％ 3 0.01eq Triethyl orthoformate 85％ 99.46％ 0.10％ 0.38％

[0125] As shown in the table above, after adding the dehydrating agent trimethyl orthoformate or triethyl orthoformate, the purity of the intermediate M2 is greatly improved, the impurities M2Z3 and M2Z4 are reduced, and the yield of the reaction is also improved.

[0126] 2. Referring to the method for preparing intermediate M2 in Example 1, a dehydrating agent was added. After completing step 1), the purity and impurity content of M2 in the reaction solution were directly determined:

[0127] Table 3 Purity and impurity content of M2 in the reaction solution

[0128]

[0129] As shown in the table above, after adding orthoester dehydrating agents, such as trimethyl orthoformate, triethyl orthoformate and triisopropyl orthoformate, compared with other dehydrating agents, the purity of intermediate M2 is improved, and the contents of impurities M2Z3 and impurity M2Z4 are significantly reduced, achieving unexpected technical effects.

[0130] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A method for preparing a dihydropyridine drug intermediate M2, It is characterized in that In the process of reacting the intermediate M1 with the compound SM3 to obtain the intermediate M2, an orthoester dehydrating agent is added: The orthoester dehydrating agent is an orthoformate dehydrating agent; the orthoformate dehydrating agent is selected from trimethyl orthoformate, triethyl orthoformate or triisopropyl orthoformate; The preparation method comprises the following steps: 1) mixing the intermediate M1 with anhydrous ethanol to obtain a mixture; 2) mixing the mixture obtained in step 1) with glacial acetic acid, a dehydrating agent, and SM3 and reacting the mixture to obtain a reactant; 3) The reactant obtained in step 2) is washed with anhydrous ethanol and dried to obtain intermediate M2.

2. The preparation method according to claim 1, It is characterized in that In the step 1), the mass ratio of the intermediate M1 to anhydrous ethanol is 1:(4-6.5).

3. The preparation method according to claim 1, It is characterized in that The mass ratio of the intermediate M1 to anhydrous ethanol is 1:5.

52.

4. The preparation method according to claim 1, It is characterized in that The mass ratio of the intermediate M1 in step 1) to the glacial acetic acid in step 2) is 1:(0.001-0.04).

5. The preparation method according to claim 3, It is characterized in that The mass ratio of the intermediate M1 to glacial acetic acid is 1:0.0025.

6. The preparation method according to claim 4, It is characterized in that The mass ratio of the intermediate M1 in step 1) to the dehydrating agent in step 2) is 1:(0.4-1.0).

7. The preparation method according to claim 6, It is characterized in that The mass ratio of the intermediate M1 to the dehydrating agent is 1:0.

595.

8. The preparation method according to claim 1, It is characterized in that The reaction conditions of step 2) include: temperature of 70-80° C. and reaction time of more than 12 hours; the mass ratio of the intermediate M1 of step 1) to the anhydrous ethanol of step 3) is 1:(0.5-2).

9. The preparation method according to claim 8, It is characterized in that The mass ratio of the intermediate M1 to anhydrous ethanol is 1:1.11.

Images