A method for synthesizing nifedipine intermediate 2-(3-nitrobenzylidene)-methyl acetoacetate

Abstract

This invention relates to the field of chemical synthesis technology and discloses a method for synthesizing methyl acetoacetate, an intermediate of nifedipine. The method includes: a first pretreatment system preparation step, in which methyl acetoacetate is mixed with a basic catalyst in an aprotic polar solvent, and a free radical scavenger and a complexing stabilizer are added to obtain a pre-activated solution; a second pretreatment system preparation step, in which 3-nitrobenzaldehyde is pre-complexed with a Lewis acid catalyst and a coordination stabilizer is added to obtain a pre-complexed solution; a microchannel rapid mixing reaction step, in which the two pretreatment solutions are rapidly mixed in milliseconds through a microchannel mixer to induce a condensation reaction; and a rapid quenching and product separation step, in which the reaction is immediately quenched at the microchannel outlet and the product is separated. This invention solves the technical problems of low catalytic efficiency, unstable pretreatment solutions, and uneven mixing in traditional methods.

Description

Technical Field

[0001] This invention relates to the field of chemical synthesis technology, and more specifically, to a method for synthesizing methyl 2-(3-nitrobenzylidene)-acetoacetate, an intermediate of nifedipine. Background Technology

[0002] Nifedipine is a widely used calcium channel blocker antihypertensive drug in clinical practice. The quality of the synthesis of its key intermediate, methyl 2-(3-nitrobenzyl)-acetoacetate, directly affects the efficacy and safety of the final drug. In the prior art, the synthesis of this intermediate mainly involves the Knoevenagel condensation reaction of 3-nitrobenzaldehyde and methyl acetoacetate under alkaline conditions.

[0003] However, traditional synthesis methods have significant technical drawbacks: First, a single catalyst system cannot balance reactivity and selectivity; using a base catalyst results in a slow reaction rate and numerous side reactions, while using a Lewis acid catalyst alone leads to insufficient substrate activation; second, conventional reaction systems exhibit low reactant-catalyst contact efficiency, and mass transfer limitations result in long reaction times and high energy consumption; third, the pre-activation strategy suffers from poor stability of the enol anion and aldehyde-catalyst complex, with a shelf life of only 2-4 hours at room temperature, severely impacting production scheduling; fourth, the pretreatment solution undergoes intense exothermic mixing, and traditional stirring methods generate localized overheating and concentration gradients, leading to inconsistent product quality. Summary of the Invention

[0004] To address the aforementioned technical problems, this invention provides a method for synthesizing methyl 2-(3-nitrobenzylidene)-acetoacetate, an intermediate of nifedipine, comprising the following steps:

[0005] Step 1: Preparation of the first pretreatment system:

[0006] Methyl acetoacetate was mixed with a basic catalyst in an aprotic polar solvent to carry out a deprotonation reaction, while a free radical scavenger and a complexing stabilizer were added to obtain a stable first pretreatment solution.

[0007] Step 2: Preparation of the second pretreatment system:

[0008] 3-Nitrobenzaldehyde and Lewis acid catalyst were mixed in an aprotic polar solvent to form a complex, and a coordination stabilizer was added to obtain a stable second pretreatment solution.

[0009] Step 3: Rapid mixing reaction in microchannels:

[0010] The first pretreatment solution and the second pretreatment solution are respectively delivered to a microchannel mixer for rapid mixing, where a condensation reaction occurs within the microchannel to generate the target product.

[0011] Step 4: Rapid quenching and product separation:

[0012] The reaction was terminated by immediately adding a quencher at the microchannel outlet, and methyl 2-(3-nitrobenzylidene)-acetoacetate was obtained by separation and purification.

[0013] Preferably, the aprotic polar solvent is selected from one or more of dimethyl sulfoxide, N,N-dimethylformamide, and N-methylpyrrolidone.

[0014] Preferably, the alkaline catalyst is selected from one or more of sodium methoxide, sodium ethoxide, and potassium tert-butoxide, and the amount used is 0.1-3 times the molar amount of methyl acetoacetate.

[0015] Preferably, the Lewis acid catalyst is selected from one or more of aluminum trichloride, zinc chloride, boron trifluoride diethyl ether complex, and ferric chloride, and the amount used is 0.05-2 times the molar amount of 3-nitrobenzaldehyde.

[0016] Preferably, the free radical scavenger is selected from one or more of hydroquinone, 2,6-di-tert-butyl-4-methylphenol, and butylated hydroxyanisole, and the amount used is 0.01-0.5% of the mass of methyl acetoacetate; the complexing stabilizer is selected from one or more of 18-crown-6 ether, 15-crown-5 ether, and polyethylene glycol 400, and the amount used is 0.1-2 times the molar amount of the alkaline catalyst.

[0017] Preferably, the coordination stabilizer is selected from one or more of triphenylphosphine oxide, dimethyl sulfoxide, and N,N-dimethylformamide, and the amount used is 0.2-3 times the molar amount of Lewis acid catalyst.

[0018] Preferably, the inner diameter of the microchannel mixer is 0.5-2 mm, the flow rate of the two pretreatment liquids is 0.1-2 m / s, the Reynolds number is controlled within the range of 100-2000, and the mixing time is 1-100 milliseconds.

[0019] Preferably, the first and second pretreatment solutions can be stably stored at 0-25°C for 24-48 hours after preparation.

[0020] Preferably, the quenching agent is selected from one or more of the following: acetate buffer solution with pH 4-6, ethyl acetate, and cold water. The amount of quenching agent used is 2-5 times the volume of the reaction liquid, and the quenching temperature is controlled at 0-10℃.

[0021] Preferably, the reaction temperature of the microchannel rapid mixing reaction is controlled at 10-80℃, the reaction completion time is less than 1 second, the product yield is 85-95%, and the purity is 95-99%.

[0022] The beneficial effects of this invention are as follows:

[0023] Revolutionary improvement in reaction efficiency: The combination of dual-catalyst synergistic catalysis and microchannel technology has achieved a significant breakthrough in efficiency. The reaction time has been reduced from 6-8 hours in traditional methods to 30 seconds to 2 minutes, with an efficiency increase of 120-960 times.

[0024] Product quality has been significantly improved: product yield has increased from 68-72% in traditional methods to 91-93%, purity has increased from 84-87% to 97-98%, by-product content has decreased from 8-15% to 1-3%, key impurities such as dimer by-product content have decreased from 3-8% to <0.5%, and oxidation products have decreased from 2-5% to <0.3%.

[0025] Breakthrough in process stability: The shelf life of the pretreatment solution was extended from 2-4 hours to 24-48 hours. After 48 hours, the stabilizer-containing group still maintained 75.3% activity, while the control group only had 6.0% activity. The yield RSD was 1.4% and the purity RSD was 0.8% for 10 consecutive batches, which meets the requirements for industrialization.

[0026] Improved reaction controllability: Microchannel mixing achieves a concentration variation coefficient (CV) of <2% (compared to 15-25% for traditional methods), temperature control accuracy of ±0.5℃ (compared to ±3℃ for traditional methods), and a heat transfer coefficient of 275 W / (m²). 2 ·K) (traditional 50-80 W / (m 2 ·K), the mixing time was reduced from 180 seconds to 45 milliseconds.

[0027] Environmental and economic benefits: Solvent recovery rate reaches 87.96%, wastewater COD is reduced by 70-80%, and unit product energy consumption is reduced by 57-66%; raw material costs are reduced by 21%, solvent costs are reduced by 88%, total production costs are reduced by 34.7%, and the investment payback period is shortened from 3.2 years to 2.1 years. Attached Figure Description

[0028] Figure 1 This is a line graph comparing the storage stability of the pretreatment solution under the protection of the stabilizer of the present invention;

[0029] Figure 2 This is a bar chart comparing the reactivity of the pretreatment solution under different storage times according to the present invention;

[0030] Figure 3 This is a radar chart comparing the overall performance of different hybridization methods of the present invention. Detailed Implementation

[0031] The subject matter described herein will now be discussed with reference to exemplary embodiments. It should be understood that these embodiments are discussed only to enable those skilled in the art to better understand and implement the subject matter described herein, and changes may be made to the function and arrangement of the elements discussed without departing from the scope of this specification. Various processes or components may be omitted, substituted, or added as needed in the examples. Furthermore, some features described in the examples may be combined in other examples.

[0032] Example 1

[0033] This embodiment presents a method for synthesizing methyl 2-(3-nitrobenzylidene)-acetoacetate, an intermediate of nifedipine, comprising the following steps:

[0034] Step 1: Preparation of the first pretreatment system:

[0035] Methyl acetoacetate was mixed with a basic catalyst in an aprotic polar solvent to carry out a deprotonation reaction, while a free radical scavenger and a complexing stabilizer were added to obtain a stable first pretreatment solution.

[0036] Step 2: Preparation of the second pretreatment system:

[0037] 3-Nitrobenzaldehyde and Lewis acid catalyst were mixed in an aprotic polar solvent to form a complex, and a coordination stabilizer was added to obtain a stable second pretreatment solution.

[0038] Step 3: Rapid mixing reaction in microchannels:

[0039] The first pretreatment solution and the second pretreatment solution are respectively delivered to a microchannel mixer for rapid mixing, where a condensation reaction occurs within the microchannel to generate the target product.

[0040] Step 4: Rapid quenching and product separation:

[0041] The reaction was terminated by immediately adding a quencher at the microchannel outlet, and methyl 2-(3-nitrobenzylidene)-acetoacetate was obtained by separation and purification.

[0042] in:

[0043] The nonprotic polar solvent is selected from dimethyl sulfoxide.

[0044] The alkaline catalyst is selected from sodium methoxide, and its amount is 1.5 times the molar amount of methyl acetoacetate.

[0045] Lewis acid catalyst is selected from aluminum trichloride, and its amount is 1.1 times the molar amount of 3-nitrobenzaldehyde.

[0046] The free radical scavenger is selected from hydroquinone, and the amount used is 0.3% of the mass of methyl acetoacetate;

[0047] The complexing stabilizer is selected from 18-crown-6 ether and is used in an amount 1.2 times the molar amount of the basic catalyst.

[0048] The coordination stabilizer is selected from triphenylphosphine oxide and is used in an amount 1.6 times the molar amount of Lewis acid catalyst.

[0049] The microchannel mixer has an inner diameter of 1.2 mm, the flow rate of the two pretreatment liquids is 1.22 m / s, the Reynolds number is controlled at 1100, and the mixing time is 50 milliseconds.

[0050] The first and second pretreatment solutions can be stably stored at 15°C for 36 hours after preparation.

[0051] The quencher was selected from a pH 5 acetate buffer solution, and the amount of quencher was 3 times the volume of the reaction solution. The quenching temperature was controlled at 5℃.

[0052] The reaction temperature of the microchannel rapid mixing reaction was controlled at 45℃, the reaction completion time was less than 1 second, the product yield was 90%, and the purity was 97%.

[0053] Example 2

[0054] The difference between this embodiment and Embodiment 1 is that:

[0055] The aprotic polar solvent is selected from N,N-dimethylformamide.

[0056] The alkaline catalyst is selected from sodium ethoxide, and its amount is 0.1 times the molar amount of methyl acetoacetate.

[0057] Lewis acid catalyst is selected from zinc chloride and is used in an amount 0.05 times the molar amount of 3-nitrobenzaldehyde.

[0058] The free radical scavenger was selected from 2,6-di-tert-butyl-4-methylphenol, and the amount used was 0.01% of the mass of methyl acetoacetate;

[0059] The complexing stabilizer is selected from 15-crown-5 ether and is used in an amount that is 0.1 times the molar amount of the basic catalyst.

[0060] The coordination stabilizer is selected from dimethyl sulfoxide and is used in an amount that is 0.2 times the molar amount of the Lewis acid catalyst.

[0061] The microchannel mixer has an inner diameter of 0.5 mm, the flow rate of the two pretreatment liquids is 0.1 m / s, the Reynolds number is controlled at 100, and the mixing time is 1 ms.

[0062] The first and second pretreatment solutions can be stably stored at 0°C for 24 hours after preparation.

[0063] The quencher was selected from ethyl acetate at pH 4, and the amount of quencher was twice the volume of the reaction liquid. The quenching temperature was controlled at 0℃.

[0064] The reaction temperature of the microchannel rapid mixing reaction was controlled at 10℃, the reaction completion time was less than 1 second, the product yield was 85%, and the purity was 95%.

[0065] Example 3

[0066] The difference between this embodiment and Embodiment 1 is that:

[0067] The aprotic polar solvent is selected from N,N-dimethylformamide and N-methylpyrrolidone.

[0068] The alkaline catalyst is selected from sodium ethoxide and potassium tert-butoxide, and the amount used is 3 times the molar amount of methyl acetoacetate.

[0069] Lewis acid catalysts are selected from boron trifluoride diethyl ether complex and ferric chloride, and the amount used is twice the molar amount of 3-nitrobenzaldehyde.

[0070] The free radical scavenger is selected from 2,6-di-tert-butyl-4-methylphenol and butyl hydroxyanisole, and the amount used is 0.5% of the mass of methyl acetoacetate;

[0071] The complexing stabilizer is selected from 15-crown-5 ether and polyethylene glycol 400, and its amount is twice the molar amount of the alkaline catalyst.

[0072] The coordination stabilizer is selected from dimethyl sulfoxide and N,N-dimethylformamide, and its amount is 3 times the molar amount of Lewis acid catalyst.

[0073] The microchannel mixer has an inner diameter of 2 mm, the flow rate of the two pretreatment liquids is 2 m / s, the Reynolds number is controlled within the range of 2000, and the mixing time is 100 milliseconds.

[0074] The first and second pretreatment solutions can be stably stored at 25°C for 48 hours after preparation.

[0075] The quenching agent is selected from cold water with pH 6. The amount of quenching agent used is 5 times the volume of the reaction liquid, and the quenching temperature is controlled at 10℃.

[0076] The reaction temperature of the microchannel rapid mixing reaction was controlled at 80℃, the reaction completion time was less than 1 second, the product yield was 95%, and the purity was 99%.

[0077] Example 4

[0078] This embodiment presents a method for synthesizing methyl 2-(3-nitrobenzylidene)-acetoacetate, an intermediate of nifedipine, comprising the following steps:

[0079] Step 1: Preparation of the first pretreatment system

[0080] Solvent safety warnings and protective measures:

[0081] When adding an aprotic polar solvent to the reactor, choose one of the following or a mixture thereof, and strictly follow the safety procedures during operation:

[0082] Dimethyl sulfoxide (DMSO): Molecular formula C2H6OS, molecular weight 78.13, boiling point 189℃, purity ≥99%;

[0083] Toxicity: Low acute toxicity, but can promote the transdermal absorption of other substances;

[0084] Protection: Wear nitrile rubber gloves to avoid skin contact; toxicity is low when the operating temperature is <100℃.

[0085] N,N-Dimethylformamide (DMF): Molecular formula C3H7NO, molecular weight 73.09, boiling point 153℃, purity ≥99%;

[0086] Toxicity Warning: Group 2A carcinogen, liver-damaging, and reproductive toxic.

[0087] Protective measures: Must be operated in a fume hood, wear chemical-resistant gloves, and keep workplace concentration <10 ppm;

[0088] Alternatives: DMSO or NMP can be used instead, with slightly different effects but better safety.

[0089] N-Methylpyrrolidone (NMP): Molecular formula C5H9NO, molecular weight 99.13, boiling point 202℃, purity ≥99%;

[0090] Toxicity: Moderately toxic, irritating to the skin, and has reproductive toxicity;

[0091] Protection: Wear solvent-resistant gloves, avoid prolonged exposure, workplace concentration <40 mg / m³ 3 ,

[0092] Methyl acetoacetate is dissolved in a solvent with a molar concentration of 0.1-2.0 mol / L, preferably 0.5-1.5 mol / L.

[0093] An alkaline catalyst, preferably sodium methoxide, sodium ethoxide, or potassium tert-butoxide, is added in an amount of 0.1-3 times, preferably 0.5-1.5 times, the molar amount of methyl acetoacetate. These catalysts exhibit good solubility and chemical stability in aprotic polar solvents. The mixture is stirred at 0-25°C for 30-120 minutes to complete the deprotonation reaction of the methylene group of methyl acetoacetate, generating an enol anion activated species.

[0094] Addition steps: Under an inert atmosphere (nitrogen or argon, purity ≥99.9%), slowly add three types of stabilizers to the above reaction solution in sequence.

[0095] The first type is a free radical scavenger, selected from hydroquinone, 2,6-di-tert-butyl-4-methylphenol, or butylated hydroxyanisole, at a dosage of 0.01-0.5% of the mass of methyl acetoacetate, preferably 0.05-0.2%. The stabilizer is pre-dissolved in a small amount of the same aprotic polar solvent to prepare a stock solution of 10-20 mg / mL, which is then slowly added dropwise at 10-15°C over 5-10 minutes. This allows it to bind with free oxygen free radicals, preventing the oxidative degradation of enol anions.

[0096] The second type is a complexation stabilizer, selected from 18-crown-6 ether, 15-crown-5 ether, or polyethylene glycol 400, at a dosage of 0.1-2 times the molar amount of the alkaline catalyst, preferably 0.3-1 times. It is added slowly at room temperature with a stirring speed of 100-200 rpm over 10-15 minutes to form an inclusion complex with the metal cation, maintaining the stability of the ion pair.

[0097] After the above treatment, a stable first pretreatment solution with a pale yellow to orange transparent appearance was obtained. This solution maintained its activity for 24-48 hours at 0-25℃. The degree of activation was monitored by measuring the characteristic absorption peak of enol anions in the wavelength range of 280-320 nm (the maximum absorption wavelength is usually 295±5 nm) using a UV-Vis spectrophotometer (wavelength accuracy ±1 nm, absorbance accuracy ±0.001) or by measuring the degree of disappearance of the methylene proton signal (δ 3.5-4.0 ppm region) using a 400 MHz nuclear magnetic resonance spectrometer. The concentration of enol anions was maintained above 85% of the initial value.

[0098] Step 2: Preparation of the second pretreatment system

[0099] In a separate, dry reactor (pre-purged with nitrogen for 30 minutes), 3-nitrobenzaldehyde is dissolved in an aprotic polar solvent at a molar concentration of 0.05–1.5 mol / L, preferably 0.2–0.8 mol / L. Safety Warning: Adequate protective measures must be taken before operation, including wearing acid- and alkali-resistant gloves, safety goggles, and a face shield, and the operation must be performed inside a fume hood.

[0100] Add Lewis acid catalyst under dry conditions (ambient humidity <30%RH);

[0101] The amount of Lewis acid catalyst used is 0.05-2 times, preferably 0.1-0.5 times, the molar amount of 3-nitrobenzaldehyde. The mixture is stirred at 150-300 rpm for 15-60 minutes, preferably 30-45 minutes, at 15-25°C to form an aldehyde-Lewis acid coordination complex. The color of the reaction solution changes from colorless and transparent to pale yellow, thus enhancing the electrophilic reactivity of the carbonyl group of 3-nitrobenzaldehyde.

[0102] Addition step: Slowly add a coordination stabilizer to the above complexing reaction solution. Triphenylphosphine oxide, dimethyl sulfoxide (DMSO, when used as a coordination stabilizer), or N,N-dimethylformamide (DMF, when used as a coordination stabilizer) can be selected. The amount added is 0.2-3 times the molar amount of Lewis acid catalyst, preferably 0.5-1.5 times.

[0103] The coordination stabilizer forms a coordination compound with the Lewis acid, occupying some of the coordination sites of the Lewis acid. This prevents polymerization reactions between multiple Lewis acid molecules and self-condensation reactions between multiple aldehyde molecules, while maintaining a moderate activation effect of the Lewis acid on the aldehyde group. The addition process is carried out at a temperature of 5-10℃ for 10-20 minutes to avoid decomposition of the complex due to excessively high temperatures.

[0104] After processing, a stable second pretreatment solution is obtained, which is a transparent solution with a pale yellow to light orange appearance. This solution remains stable when stored at 15-25°C for 24-48 hours.

[0105] Step 3: Rapid mixing reaction in microchannels

[0106] The first pretreatment liquid prepared in step one and the second pretreatment liquid prepared in step two are respectively delivered to the two inlets of the microchannel mixer using a high-precision metering pump (flow accuracy ±1%, flow range 0.1-10 mL / min, pressure range 0-10 bar).

[0107] Microchannel mixer technical specifications: Material selection: 316L stainless steel (recommended, good corrosion resistance) or polytetrafluoroethylene (PTFE, strong chemical inertness); Channel inner diameter: 0.5-2 mm, preferably 0.8-1.2 mm; Channel length: 20-100 mm, preferably 40-60 mm.

[0108] Mixing method: T-type or Y-type merging, feed angle 90° or 60°; Connector specifications: 1 / 16 inch or 1 / 8 inch standard connector; Temperature range: -10℃ to +120℃; Pressure range: 0-50 bar.

[0109] Two pretreatment liquids are sprayed in opposite directions or merged in a T-shape within a microchannel at a flow rate of 0.1-2 m / s. The flow rate is adjusted according to the channel diameter: 0.8-1.5 m / s for an inner diameter of 0.5 mm; 0.4-0.8 m / s for an inner diameter of 1.0 mm; and 0.1-0.4 m / s for an inner diameter of 2.0 mm, ensuring stable mixing under laminar flow conditions with a Reynolds number in the range of 100-2000.

[0110] Rapid mixing and heat transfer processes in microchannels: Microchannels have a diameter of 2000-6000 m. -1 The specific surface area (calculated by formula: 4 / D, where D is the channel diameter) allows the two pretreatment liquids to be uniformly mixed within 1-100 milliseconds, with a mixing efficiency of >95%, avoiding local concentration differences.

[0111] Temperature control system: A constant-temperature circulating bath (temperature control accuracy ±0.5℃) provides external circulating water (10-50℃) or heat transfer oil (50-120℃) to control the microchannel wall temperature. The outer wall of the microchannel is wrapped with a copper tube jacket or embedded with aluminum heat sinks, with an overall heat transfer coefficient of 100-500 W / (m²). 2 ·K), preferably 200-350 W / (m 2 The heat generated by the reaction (approximately 80-120 kJ / mol) is rapidly transferred and removed through the channel wall, with a heat removal efficiency >90%, maintaining the reaction temperature within the range of 10-80℃, preferably 20-50℃.

[0112] Reaction monitoring: An online temperature sensor (accuracy ±0.1℃, response time <2 seconds) and a pressure sensor (accuracy ±0.1%FS) were installed at the microchannel outlet to monitor the reaction status in real time. Under uniform mixing conditions, the enol anion and activated 3-nitrobenzaldehyde immediately undergo a condensation reaction, with the reaction completion time less than 1 second and a conversion rate >95%, producing a pale yellow methyl 2-(3-nitrobenzyl)-acetoacetate product.

[0113] Step 4: Rapid quenching and product separation

[0114] Product pH stability and quencher selection criteria:

[0115] Stability test results of methyl 2-(3-nitrobenzylidene)-acetoacetate under different pH conditions:

[0116] Strong acidity (pH<2): The product undergoes hydrolysis, ester bonds break, and the purity drops to <70% within 30 minutes. Weak acidity (pH 3-6): The product is stable, and the purity remains >95% for 24 hours, with the optimal pH being 4.5.

[0117] Neutral (pH 6-8): The product is relatively stable, but slow Michael addition side reactions may occur;

[0118] Alkaline (pH>9): The product decomposes rapidly, undergoing the reverse Knoevenagel reaction and saponification.

[0119] Quenching procedure: Install a static mixer at the microchannel outlet and immediately add the pre-cooled quenching agent. Quenching agent selection and scientific basis:

[0120] The selection criteria for acetate buffer are: pH 4.5 is the most stable point of the product, it has strong buffering capacity, and it can quickly neutralize residual alkali;

[0121] Mechanism of action: Acetic acid neutralizes the alkaline catalyst, while sodium acetate maintains pH stability and prevents product decomposition.

[0122] Criteria for selecting ethyl acetate: good miscibility with the product, moderate volatility, and ease of subsequent separation;

[0123] Applicable conditions: Use when it is necessary to avoid the introduction of moisture.

[0124] Deionized water selection criteria: economical, environmentally friendly, and suitable for situations where the product precipitates in solid form;

[0125] Limitations: Use only when the product has very low solubility; rapid separation is required.

[0126] Product separation and purification steps:

[0127] Solid-liquid separation: Collect the solid product by Buchner funnel filtration (filter paper: quantitative filter paper, pore size 1-3 μm) or high-speed centrifugation (3000-5000 rpm, temperature 4℃, time 10-15 minutes). If the product is oily, separate it using a separatory funnel or extract it 2-3 times with ethyl acetate (each time the volume of the aqueous phase is 0.5-1 times).

[0128] Washing and purification: Wash the solid product 2-3 times with pre-cooled washing solvent.

[0129] First use: cold ethanol (temperature 0-5℃, volume 2-3 times the product mass).

[0130] Second: Cold isopropanol (temperature 0-5℃, amount is 1-2 times the product mass by volume).

[0131] Third wash: Cold deionized water (temperature 0-5℃, volume equal to the product mass). After each wash, centrifuge or filter. A clear and transparent washing solution indicates that the washing is complete.

[0132] Drying: Transfer the washed wet product to a vacuum drying oven and dry it at 40-60℃ and 0.1-1 kPa reduced pressure for 2-4 hours, preferably at 50℃, 0.5 kPa, and for 3 hours. End-of-drying determination: The product mass changes by <0.1% for 2 consecutive hours.

[0133] Product quality standards: Appearance: pale yellow to yellow crystalline powder; Purity: ≥95% (HPLC area normalization method); Water content: ≤0.5% (Karl Fischer method); Melting point: 117-119℃ (capillary method, uncorrected); Molecular weight: 247.20 (theoretical value).

[0134] The target compound, methyl 2-(3-nitrobenzylidene)-acetoacetate, was finally obtained with a purity of 95-99%, yield of 85-95%, and batch-to-batch quality stability RSD < 2%.

[0135] Experimental verification

[0136] Experiment 1: Comparison of Synergistic Catalytic Efficiency of Two Catalysts

[0137] 1. Experimental Objective

[0138] The significant improvement in reaction rate and product yield achieved by the dual-catalyst synergistic catalysis method compared to the traditional single-catalyst method was verified, demonstrating the catalytic efficiency advantage of the present invention.

[0139] 2. Preparation of experimental samples

[0140] Raw material preparation:

[0141] Methyl acetoacetate: 116.11 g / mol, purity 98%, dosage 1.0 mol;

[0142] 3-Nitrobenzaldehyde: 151.12 g / mol, purity 98%, dosage 1.0 mol;

[0143] Dimethyl sulfoxide (DMSO): as a solvent, 200 mL;

[0144] Sodium methoxide: used as an alkaline catalyst;

[0145] Aluminum trichloride: used as a Lewis acid catalyst.

[0146] Sample group:

[0147] Control group A: Sodium methoxide (1.5 times the molar amount of methyl acetoacetate) was used, and the mixture was stirred in a conventional manner.

[0148] Control group B: Only aluminum trichloride (0.5 times the molar amount of 3-nitrobenzaldehyde) was used, and the mixture was stirred in a conventional manner;

[0149] Control group C: dual catalyst (sodium methoxide 0.5x + AlCl3 0.1x), conventional stirring and mixing;

[0150] Experimental group: dual catalyst (sodium methoxide 0.5x + AlCl3 0.1x), microchannel rapid mixing.

[0151] 3. Experimental conditions

[0152] Reaction temperature: 25±0.5℃ (microchannel precise control) vs 25±3℃ (conventional stirring);

[0153] Mixing method: Microchannel inner diameter 1.0mm, flow rate 0.5m / s vs mechanical stirring 300rpm;

[0154] Reaction environment: Nitrogen protection, humidity <30%RH;

[0155] Monitoring method: Online HPLC analysis of product concentration changes, with sampling intervals adjusted to accommodate rapid reactions.

[0156] 4. Experimental Procedure

[0157] Traditional stirring group experiment procedure:

[0158] (1) Add 200 mL of DMSO solvent to a dry 250 mL three-necked flask and protect it with nitrogen.

[0159] (2) Prepare pretreatment solutions according to the formulas of each group, and add the corresponding catalysts and stabilizers;

[0160] (3) Mix the two pretreatment solutions with stirring and start timing;

[0161] (4) Samples were taken every 5 minutes for the first 30 minutes and every 30 minutes thereafter, and detected by HPLC;

[0162] (5) The reaction is stopped when the conversion rate reaches 95% or after 6 hours.

[0163] Microchannel group experimental steps:

[0164] (1) Prepare the first pretreatment solution and the second pretreatment solution according to the implementation method;

[0165] (2) Use a high-precision metering pump to deliver the two pretreatment liquids to the microchannel mixer;

[0166] (3) Continuous sampling is performed at the microchannel outlet, once every 10 seconds, with high-frequency sampling for the first 5 minutes;

[0167] (4) Monitor the reaction completion time and steady-state conversion rate;

[0168] (5) Run continuously for 30 minutes to test stability and reproducibility.

[0169] 5. Experimental Results

[0170] Table 1: Comparison of reaction kinetic data for different catalyst systems

[0171]

[0172] Table 2: Summary of Catalytic Efficiency Comparison Results

[0173]

[0174] 6. Analysis and Summary

[0175] Experimental results clearly demonstrate the significant advantages of dual-catalyst synergistic catalysis combined with microchannel technology:

[0176] (1) Revolutionary improvement in reaction rate: The conversion rate of the microchannel experimental group reached 92.8% within 30 seconds, while the traditional single catalyst group would take several hours to reach a similar level, and the reaction efficiency was improved by more than 360 times;

[0177] (2) The time to reach 90% conversion rate was shortened from 240-300 minutes in the control group to 25 seconds in the microchannel group, which is 576-720 times more efficient;

[0178] (3) The product yield was significantly improved: from 68.2-72.6% in the control group to 93.2% in the microchannel group, an increase of 20-25%;

[0179] (4) The purity of the product was significantly improved: from 84.8-87.4% in the control group to 97.8% in the microchannel group, and the side reactions were effectively controlled;

[0180] (5) Optimization of catalyst dosage: The microchannel group achieved the best effect with only 0.6 times the amount of catalyst, saving 60% of the catalyst compared with the single catalyst system. The above data fully verify the innovative technical effect of dual catalyst synergistic activation combined with microchannel rapid mixing, and prove the significant synergistic effect among technical elements.

[0181] Experiment 2: Storage stability test of pretreated solution under stabilizer protection

[0182] 1. Experimental Objective

[0183] The effectiveness of the stabilizer protection system in protecting the active components of the pretreatment solution for a long period of time was verified, demonstrating the technological breakthrough of this invention in extending the effective period of the pretreatment solution from 2-4 hours to 24-48 hours.

[0184] 2. Preparation of experimental samples

[0185] Preparation of the first pretreatment solution:

[0186] Methyl acetoacetate: 116.11 g, 1.0 mol;

[0187] Sodium methoxide: 27.0 g, 0.5 mol;

[0188] DMSO: 200 mL;

[0189] Free radical scavenger (BHT): 0.116 g (0.1% of the mass of methyl acetoacetate).

[0190] Complexing stabilizer (18-crown-6 ether): 132.2 g (1.0 times the molar amount of sodium methoxide);

[0191] Preparation of control samples: Pretreatment solutions with the same formulation but without the addition of stabilizers;

[0192] Storage conditions: Temperature: 25±2℃; Atmosphere: Nitrogen protection; Container: Sealed brown bottle.

[0193] 3. Experimental conditions

[0194] Testing time points: 0, 2, 4, 8, 12, 24, 36, 48, 72 hours;

[0195] Activity detection method: UV-Vis measurement of enol anion concentration (295 nm).

[0196] Stability evaluation: 1 H NMR was used to monitor changes in methylene proton signal;

[0197] Reactivity test: The conversion rate was determined by reacting with Lewis acid pretreatment solution.

[0198] 4. Experimental Procedure

[0199] (1) Prepare two sets of pretreatment solutions, one containing stabilizer and the other without stabilizer, each with a capacity of 500 mL, according to the formula;

[0200] (2) Dispense into 20 50 mL sealed bottles, fill with nitrogen, seal and store;

[0201] (3) Samples were taken at specific time points, and UV-Vis and NMR detection were performed immediately;

[0202] (4) Take 1 mL of sample and react it with standard Lewis acid pretreatment solution to determine the activity retention rate;

[0203] (5) Plot the stability decay curve and calculate the half-life and shelf life;

[0204] (6) Analyze the protective mechanism and effect of stabilizers.

[0205] 5. Experimental Results

[0206] Table 3: Stability data of active components in the pretreatment solution

[0207]

[0208] Table 4: Results of Pretreatment Solution Reactivity Retention Test

[0209]

[0210] Figure 1 The comparison of storage stability of pretreatment solutions under stabilizer protection is shown;

[0211] Figure 2 The study demonstrates a comparison of the reactivity of the pretreatment solution under different storage times.

[0212] 6. Analysis and Summary

[0213] The stabilizer protection system demonstrated excellent pretreatment solution protection performance:

[0214] (1) The activity retention time was significantly prolonged: the stabilizer group still maintained 75.3% activity after 48 hours, while the control group only had 6.0% activity, which was more than 12 times longer;

[0215] (2) Excellent reactivity: After 24 hours of storage, the conversion rate of the stabilizer group was 77.3%, while that of the control group was only 18.5%, with the activity increased by more than 3 times;

[0216] (3) Improved decay kinetics: The decay rate constant k of the stabilizer group is 0.0052 h. -1 In the control group, k=0.0487 h -1 Stability is improved by 9.4 times;

[0217] (4) Industrial application value: The 48-hour shelf life fully meets the time scheduling requirements of continuous production, solving the technical bottleneck that traditional pretreatment solutions must be used immediately. Experiments have shown that the stabilizer combination achieves a revolutionary breakthrough in the storage stability of pretreatment solutions through the triple synergistic effect of free radical scavenging, metal complexation and activity protection.

[0218] Experiment 3: Comparison of Microchannel Rapid Mixing and Heat Transfer Effects

[0219] 1. Experimental Objective

[0220] The invention demonstrates the significant advantages of microchannel mixing technology over traditional stirring and mixing in terms of reaction uniformity, heat transfer efficiency, and product quality, proving the technological breakthrough of this invention in reaction controllability.

[0221] 2. Preparation of experimental samples

[0222] Standard pretreatment solution:

[0223] First pretreatment solution: methyl acetoacetate (1.0 M) + sodium methoxide (0.5 M) + stabilizer, DMSO solvent;

[0224] Second pretreatment solution: 3-nitrobenzaldehyde (0.8 M) + AlCl3 (0.4 M) + coordination stabilizer, DMSO solvent.

[0225] Comparison of mixing equipment:

[0226] Microchannel assembly: T-type microchannel mixer, inner diameter 1.0 mm (preferred range 0.8-1.2 mm), length 50 mm (preferred range 40-60 mm).

[0227] Traditional group: 250 mL three-necked flask, mechanical stirrer, 40 mm blade diameter - High-speed group: high-speed disperser, 12000 rpm.

[0228] Tracer experiment:

[0229] Tracer: Rhodamine B dye (concentration 1×10⁻⁶) -4 M);

[0230] Detection method: Laser-induced fluorescence (LIF) imaging technology.

[0231] 3. Experimental conditions

[0232] Reaction temperature: 25±0.5℃ (microchannel) vs 25±3℃ (conventional stirring)

[0233] Flow rate: 0.5 m / s for microchannels, 300 rpm for conventional stirring, and 12,000 rpm for high-speed dispersion.

[0234] Feed ratio: First pretreatment solution : Second pretreatment solution = 1:1 (volume ratio)

[0235] Monitoring parameters: temperature distribution, concentration uniformity, mixing time, heat transfer coefficient

[0236] 4. Experimental Procedure

[0237] (1) Mixing uniformity test: A tracer was added to the first pretreatment solution, and the coefficient of variation of the concentration distribution at the outlet was determined by LIF imaging;

[0238] (2) Heat transfer efficiency test: Measure the temperature response time and heat transfer coefficient of the reaction system and record the local temperature difference;

[0239] (3) Comparison of reaction kinetics: Condensation reaction was carried out under the same conditions, and the conversion rate and by-product formation were monitored;

[0240] (4) Product quality analysis: HPLC was used to analyze the purity and impurity distribution of the product;

[0241] (5) Scale-up effect study: Test the performance changes of each mixing method under different processing volumes;

[0242] (6) Continuous operation stability: After 2 hours of continuous operation, the consistency of product quality was tested.

[0243] 5. Experimental Results

[0244] Table 5: Comparison of heat transfer and mixing performance of different mixing methods

[0245]

[0246] Table 6: Comparison of reaction results with different mixing methods

[0247]

[0248] Table 7: Product quality consistency data after 2 hours of continuous operation

[0249]

[0250] Figure 3 The overall performance comparison of different hybrid methods is shown.

[0251] 6. Analysis and Summary

[0252] Microchannel rapid mixing technology has demonstrated comprehensive technical advantages, enabling precise control of the reaction process:

[0253] (1) Revolutionary improvement in mixing efficiency: The mixing time is reduced from the traditional 180 seconds to 45 milliseconds, an improvement of 4000 times; the concentration variation coefficient is reduced from 18.5% to 1.8%, and the uniformity is improved by 10 times;

[0254] (2) Significantly improved heat transfer performance: the heat transfer coefficient increased from 65 W / (m²) 2 ·K) increased to 275 W / (m 2 (·K), heat transfer efficiency is improved by 4.2 times; temperature control accuracy is improved from ±3.2℃ to ±0.5℃;

[0255] (3) The quality of the reaction was greatly improved: the purity of the product increased from 89.7% to 97.3%, the yield increased from 78.2% to 91.8%, and the reaction completion time was shortened from 120 seconds to 1.2 seconds;

[0256] (4) Excellent continuous stability: During 2 hours of continuous operation, the RSD of the microchannel product yield is only 0.14%, while that of traditional stirring is 2.89%, which improves the stability by 20 times;

[0257] (5) Strong industrial applicability: Microchannel technology eliminates the scale-up effect problem in traditional reactions, providing a reliable technical guarantee for continuous production. Experiments have fully demonstrated that microchannel rapid mixing technology achieves precise control of the reaction process and a significant improvement in product quality through millisecond-level uniform mixing and efficient heat transfer, providing a revolutionary technical solution for the industrial production of nifedipine intermediates.

[0258] The embodiments of the present invention have been described above. However, the embodiments are not limited to the specific implementation methods described above. The specific implementation methods described above are merely illustrative and not restrictive. Those skilled in the art can make more equivalent embodiments under the guidance of the present embodiments, and all of them are within the protection scope of the present embodiments.

Claims

1. A method for synthesizing methyl 2-(3-nitrobenzyl)-acetoacetate, an intermediate of nifedipine, characterized in that, Includes the following steps: Step 1: Preparation of the first pretreatment system: Methyl acetoacetate was mixed with a basic catalyst in an aprotic polar solvent to carry out a deprotonation reaction, while a free radical scavenger and a complexing stabilizer were added to obtain a stable first pretreatment solution. The free radical scavenger is selected from one or more of hydroquinone, 2,6-di-tert-butyl-4-methylphenol, and butylated hydroxyanisole, and is used in an amount of 0.01-0.5% of the mass of methyl acetoacetate; The complexing stabilizer is selected from one or more of 18-crown-6 ether, 15-crown-5 ether, and polyethylene glycol 400, and the amount used is 0.1-2 times the molar amount of the alkaline catalyst; Step 2: Preparation of the second pretreatment system: 3-Nitrobenzaldehyde and Lewis acid catalyst were mixed in an aprotic polar solvent to form a complex, and a coordination stabilizer was added to obtain a stable second pretreatment solution. The coordination stabilizer is selected from one or more of triphenylphosphine oxide, dimethyl sulfoxide, and N,N-dimethylformamide, and its amount is 0.2-3 times the molar amount of Lewis acid catalyst; Step 3: Rapid mixing reaction in microchannels: The first pretreatment solution and the second pretreatment solution are respectively delivered to a microchannel mixer for rapid mixing, where a condensation reaction occurs within the microchannel to generate the target product. Step 4: Rapid quenching and product separation: The reaction was terminated by immediately adding a quencher at the microchannel outlet, and methyl 2-(3-nitrobenzylidene)-acetoacetate was obtained by separation and purification.

2. The synthesis method according to claim 1, characterized in that, The aprotic polar solvent is selected from one or more of dimethyl sulfoxide, N,N-dimethylformamide, and N-methylpyrrolidone.

3. The synthesis method according to claim 1, characterized in that, The alkaline catalyst is selected from one or more of sodium methoxide, sodium ethoxide, and potassium tert-butoxide, and the amount used is 0.1-3 times the molar amount of methyl acetoacetate.

4. The synthesis method according to claim 1, characterized in that, The Lewis acid catalyst is selected from one or more of aluminum trichloride, zinc chloride, boron trifluoride diethyl ether complex, and ferric chloride, and the amount used is 0.05-2 times the molar amount of 3-nitrobenzaldehyde.

5. The synthesis method according to claim 1, characterized in that, The microchannel mixer has an inner diameter of 0.5-2 mm, the flow rate of the two pretreatment liquids is 0.1-2 m / s, the Reynolds number is controlled within the range of 100-2000, and the mixing time is 1-100 milliseconds.

6. The synthesis method according to claim 1, characterized in that, The first and second pretreatment solutions can be stably stored at 0-25°C for 24-48 hours after preparation.

7. The synthesis method according to claim 1, characterized in that, The quenching agent is selected from one or more of the following: acetate buffer solution with pH 4-6, ethyl acetate, and cold water. The amount of quenching agent used is 2-5 times the volume of the reaction liquid, and the quenching temperature is controlled at 0-10℃.

8. The synthesis method according to claim 1, characterized in that, The microchannel rapid mixing reaction is controlled at a reaction temperature of 10-80℃, the reaction completion time is less than 1 second, the product yield is 85-95%, and the purity is 95-99%.

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