CN113024446A - Method for preparing amlodipine besylate intermediate by using micro-reaction device - Google Patents
Method for preparing amlodipine besylate intermediate by using micro-reaction device Download PDFInfo
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Abstract
The invention provides a method for producing an amlodipine besylate intermediate by utilizing a microreactor. The method takes o-chlorobenzaldehyde as a raw material, utilizes a micro-reaction device to rapidly and safely prepare the amlodipine besylate intermediate, has the advantages of high reaction conversion rate, simple post-treatment, small reaction volume, short reaction time, low energy consumption and the like, and has great commercial value.
Description
Technical Field
The invention relates to the field of synthesis of drug intermediates, in particular to a production process for preparing an amlodipine besylate intermediate serving as a hypotensor by using a micro-reaction device.
Technical Field
Amlodipine Besylate (Amlodipine Besylate), chemically known as 3-ethyl-5-methyl-2- (2-aminoethoxymethyl) -4- (2-chlorophenyl) -1, 4-dihydro-6-methyl-3, 5-dipicolinate benzenesulfonate, is a dihydropyridine calcium antagonist developed by the U.S. sponish corporation, and is mainly used for treating hypertension and angina pectoris. The structure is represented by the following formula:
the amlodipine besylate can selectively inhibit calcium ions outside cardiac muscle cells and vascular smooth muscle cells from entering the cells through calcium ion channels of cell membranes, and relax the vascular smooth muscle, thereby achieving the antihypertensive effect. The mechanism for relieving angina pectoris is to reduce myocardial oxygen consumption by dilating peripheral arterioles to reduce peripheral resistance, and to increase myocardial oxygen supply of patients with coronary artery spasm by dilating coronary artery and coronary arterioles in normal and ischemic areas. The amlodipine besylate is sold in the world with the forefront of cardiovascular medicaments as a first choice medicament for treating hypertension.
In the presently disclosed synthesis route of amlodipine besylate, the key intermediate is amlodipine free base. The prior disclosed free base synthesis method is mainly carried out by Hantzsch reaction or Michael reaction, and the synthetic route is as follows:
hantzsch reaction scheme:
michael reaction scheme:
wherein R represents a substituted amine group.
The synthetic route of the Hantzsch reaction is divided into two processes, aldehyde group of o-chlorobenzaldehyde firstly reacts with a beta-dicarbonyl compound, double bonds are generated through dehydration to obtain a condensed intermediate state, then the condensed intermediate state reacts with 3-aminocrotonic acid methyl ester in one pot to complete ring closing, an amlodipine besylate intermediate is obtained, and then amlodipine free base is obtained through corresponding step processing. The synthetic route of the Michael reaction is also divided into two processes, o-chlorobenzaldehyde firstly reacts with methyl acetoacetate to generate an intermediate, the intermediate is subjected to ring closure with a beta-dicarbonyl compound under the condition of ammonium acetate after purification to obtain a product, namely an amlodipine besylate intermediate, and the amlodipine free base is obtained through treatment of corresponding steps.
Korean patent No. (KR87-909) discloses a method for synthesizing an amlodipine besylate intermediate, which employs a Hantzsch reaction route, uses azide as an amino latent functional group, completes a ring-closing reaction, and then generates an amino group by reduction. The method has low yield, and is not suitable for large-scale production due to the explosion risk caused by the instability of the azide.
Korean patent (KR86-1921) taken the Hantzsch reaction route using phthalimide as an amino protecting group, improved the disadvantage of instability of azide compounds, but the overall yield was still low.
The U.S. Pat. No. 5,5389654 (U.S. Pat. No. 5,53) adopts Hantzsch reaction route, uses trityl as amino protecting group, completes the cyclization reaction, uses benzenesulfonic acid to treat, and simultaneously carries out the deprotection step and the salt forming step, thus shortening the reaction flow, but the atom economy is low, and the yield is only 7%.
The U.S. Pat. No. 6,973,337 (US6046337) adopts Hantzsch reaction route, uses halogen to replace amino group to carry out cyclization reaction, and finally uses amino group to replace halogen to synthesize amlodipine. This route has a high yield in the ring closing step, but has a low overall yield due to many side reactions when substituting a halogen with an amino group.
The world patent (WO02072552) took the Hantzsch reaction route, as follows:
the loop closing yield of the route is higher than that of the previous methods and reaches 50 percent, but the price of the starting material 2, 5-hexanedione is higher, and the loop closing product is oily, needs column chromatography for purification and is not suitable for industrial production.
U.S. Pat. No. 4,430,688,327 adopts Michael reaction route, adopts phthalimide as amino protecting group, and acetamide as amination reagent to carry out cyclization reaction, and because the conversion rate is not high, the obtained cyclization product has poor appearance and low yield.
In summary, in the synthesis route embodied in the middle of amlodipine besylate, the cyclization step is taken as a key step, and the problems of low yield, more side reactions and the like still exist, so that a new idea needs to be adopted to improve the step, improve the yield, reduce the side reactions, simplify the post-treatment process and achieve the purpose of further reducing the production cost.
Disclosure of Invention
A microreactor, also known as a microchannel reactor or a microreactor, is a three-dimensional structural element which can be used for carrying out chemical reactions and which is manufactured in a solid matrix by means of special microfabrication techniques. Compared with the traditional kettle type reactor, the micro-reactor has the advantages of extremely high mass and heat transfer efficiency, high reaction safety, accurate material proportioning, good production reproducibility and high automation degree, and is the trend of future chemical production.
The invention provides a method for producing an amlodipine besylate intermediate by using a micro-reaction device. The method is based on a Hantzsch route which can be carried out by a one-pot method, takes o-chlorobenzaldehyde as a raw material, and reacts with a beta-dicarbonyl compound and methyl 3-aminocrotonate in a micro-reaction device to quickly and safely carry out the cyclization step of the amlodipine besylate intermediate, thereby improving the yield, reducing side reactions, simplifying the post-treatment process, reducing the production cost and having good application prospect.
The synthetic route adopted by the invention is as follows:
in order to solve the aforementioned technical problems, the technical solution adopted by the present invention is as follows:
the invention provides a method for producing an amlodipine besylate intermediate by using a micro-reaction device, which comprises the following steps:
(1) dissolving a beta-dicarbonyl compound (a compound shown in a formula II), piperidine and acetic acid in ethanol to obtain a homogeneous solution A;
(2) dissolving 3-aminocrotonic acid methyl ester (III) in ethanol to obtain a homogeneous solution B;
(3) dissolving o-chlorobenzaldehyde (I) in ethanol to obtain a homogeneous solution C;
(4) respectively and simultaneously pumping the homogeneous solution A and the homogeneous solution C into a first micro mixer in a microchannel reaction device, mixing and then introducing into a first microreactor;
(5) respectively pumping the homogeneous phase solution B and the effluent of the first microreactor into a second micromixer in the microchannel reaction device at the same time, mixing and then introducing into the second microreactor;
(6) and collecting effluent liquid of the second microreactor, and treating and purifying to obtain the amlodipine besylate intermediate.
In some embodiments of the present invention, in the method for producing an amlodipine besylate intermediate using a micro-reaction device, in the step (1), the concentration of the β -dicarbonyl compound in the homogeneous solution a is 1.0 to 2.5 mol/L.
In other embodiments of the present invention, in the above method for producing an amlodipine besylate intermediate using a micro-reaction device, in the step (2), the concentration of methyl 3-aminocrotonate in the homogeneous solution B is 1.0 to 2.5 mol/L.
In other embodiments of the present invention, in the method for producing an amlodipine besylate intermediate using a micro-reaction device, in the step (3), the concentration of the o-chlorobenzaldehyde in the homogeneous solution C is 1.0 to 2.5 mol/L.
In some embodiments of the invention, in the method for producing an amlodipine besylate intermediate by using a micro-reaction device, the molar ratio of piperidine to o-chlorobenzaldehyde is 0.05-0.50: 1; the molar ratio of acetic acid to o-chlorobenzaldehyde is 0.05-0.50: 1; the molar ratio of the beta-dicarbonyl compound (formula II) to the o-chlorobenzaldehyde is 1.0-1.2: 1; the molar ratio of the methyl 3-aminocrotonate to the o-chlorobenzaldehyde is 1.0-1.2: 1.
In some embodiments of the invention, in the method for producing an amlodipine besylate intermediate by using a micro-reaction device, in the step (4), the flow rate of the homogeneous solution a pumped into the first micro-mixer in the microchannel reaction device is 0.1-0.5 mL/min; the flow rate of the homogeneous solution C pumped into the first micro mixer in the micro-channel reaction device is 0.1-0.5 mL/min.
In other embodiments of the present invention, in the first microreactor, the reaction temperature is 50 to 90 ℃ and the reaction residence time is 10 to 20 min.
In some embodiments of the invention, in the method for producing an amlodipine besylate intermediate by using a micro-reaction device, in the step (5), the flow rate of pumping the homogeneous solution B into the second micro-mixer of the microchannel reaction device is 0.1-0.5 mL/min.
In other embodiments of the present invention, in the second microreactor, the reaction temperature is 50 to 90 ℃ and the reaction residence time is 10 to 20 min.
The microchannel reaction device for producing amlodipine besylate provided by the invention comprises a first feeding pump, a second feeding pump, a third feeding pump, a first micromixer, a second micromixer, a first microreactor, a second microreactor and a receiver; the volume of the first microreactor is 10-20 mL, and the volume of the second microreactor is 25-35 mL. The first feeding pump and the second feeding pump are connected to a first micro mixer in a parallel mode through pipelines, the first micro mixer is connected with a first micro reactor in series, a discharge port of the first micro reactor and a third feeding pump are connected to a second micro mixer in a parallel mode, the second micro mixer is sequentially connected with a second micro reactor and a receiver in series, the first feeding pump and the second feeding pump are connected through pipelines, and the inner diameter of each pipeline is 0.5-1 mm.
Compared with the prior patent, the method for producing the amlodipine besylate intermediate by utilizing the microchannel reactor has the advantages of high conversion rate, simple post-treatment, small reaction volume, short reaction time and the like, has good product quality and low energy consumption, and is a low-cost, green, environment-friendly and efficient method for synthesizing the amlodipine besylate intermediate.
Drawings
FIG. 1 is a schematic view of a micro-reaction device according to the present invention.
Detailed Description
The invention will be better understood from the following examples. However, those skilled in the art will readily appreciate that the specific material ratios, process conditions and results thereof described in the examples are illustrative only and should not be taken as limiting the invention as detailed in the claims.
Wherein, the model of each part of the microchannel reaction device is as follows:
the first, second and third feed pumps are Raney feed pumps, which are available from Baoding Raney fluid science and technology Co., Ltd, and are of type TYD 01-01-CE;
the first micromixer was a Y-mixer, purchased from Nanjing wetting fluid control devices, Inc.;
the second micromixer was a T-mixer, purchased from Nanjing wetting fluid control devices, Inc.;
the first micro-reactor and the second micro-reactor are both Teflon tubes, which are purchased from Nanjing Ruozi fluid control equipment Limited company, the inner diameter is 0.5-1 mm, and the material of the pipeline is polytetrafluoroethylene. The reagents used in the experiment were all AR, and were purchased from Xiong chemical science, Inc.
Example 1
Preparation of beta-dicarbonyl compounds: dissolving 2-chloroethanol (1.61g,20mmol) and phthalimide potassium salt (4.06g,22.0mmol) in N, N-dimethylformamide (20ml), stirring at 50-60 ℃, after TLC detection reaction is completed, adding water (40ml) and ethyl acetate (40ml) into the reaction solution, stirring, separating, discarding the water phase, washing the organic phase twice with saturated saline (30ml x2), drying with anhydrous sodium sulfate, and concentrating under reduced pressure to dryness to obtain a crude intermediate product of the beta-dicarbonyl compound, which is directly used in the next step. Dissolving the crude product in N, N-dimethylformamide (20ml), adding potassium tert-butoxide (2.46g,22.0mmol), stirring at 20-25 ℃ for about 15min, adding 4-bromoacetoacetic acid ethyl ester (4.18g,20.0mmol), stirring at 20-25 ℃, after TLC detection reaction is completed, adding water (40ml) and ethyl acetate (40ml) into the reaction solution, stirring, separating, discarding an aqueous phase, washing the organic phase twice with saturated saline solution (30ml x2), drying with anhydrous sodium sulfate, and concentrating under reduced pressure to dryness to obtain a beta-dicarbonyl compound which is directly used in the next step.
The β -dicarbonyl compound (3.19g,10.0mmol), piperidine (43mg,0.5mmol) and acetic acid (30mg,0.5mmol) were mixed, dissolved in ethanol (10ml), and stirred uniformly to obtain a homogeneous solution a. O-chlorobenzaldehyde (1.40g,10.0mmol) was dissolved in ethanol (10ml) and stirred well to obtain homogeneous solution C. Pumping the homogeneous solution A and the homogeneous solution C into a Y-shaped mixer at the flow rate of 0.100mL/min respectively, mixing, and introducing into a first microreactor with a coil pipe with the inner diameter of 1mm, wherein the volume of the reactor is 15mL, the reaction temperature is controlled at 90 ℃, and the reaction residence time is 20 min.
Meanwhile, methyl 3-aminocrotonate (1.15g,10.0mmol) was dissolved in ethanol (10ml) and stirred well to obtain a homogeneous solution B. Pumping the homogeneous phase solution B into a T-shaped mixer at the flow rate of 0.100mL/min, mixing, and introducing into a second microreactor with the coil pipe inner diameter of 1mm, wherein the volume of the reactor is 30mL, the reaction temperature is controlled at 90 ℃, and the reaction residence time is 20 min. And (3) collecting an effluent liquid of the second microreactor, adding water (15ml) into the system, stirring for 60-90 min at 25 +/-5 ℃, separating out a light yellow solid, carrying out suction filtration, washing with a mixed solvent of ethanol and water (1:1), and drying in vacuum at 50 ℃ to obtain an cyclization product, namely the amlodipine besylate intermediate. The yield thereof was found to be 82.4%.
Example 2
Preparation of β -dicarbonyl compounds reference is made to example 1.
The β -dicarbonyl compound (3.19g,10.0mmol), piperidine (43mg,0.5mmol) and acetic acid (30mg,0.5mmol) were mixed, dissolved in ethanol (6.6ml), and stirred uniformly to obtain a homogeneous solution a. O-chlorobenzaldehyde (1.40g,10.0mmol) was dissolved in ethanol (6.6ml) and stirred well to obtain homogeneous solution C. Pumping the homogeneous solution A and the homogeneous solution C into a Y-shaped mixer at the flow rate of 0.250mL/min respectively, mixing, and introducing into a first microreactor with a coil pipe with the inner diameter of 1mm, wherein the volume of the reactor is 15mL, the reaction temperature is controlled at 90 ℃, and the reaction residence time is 20 min.
Meanwhile, methyl 3-aminocrotonate (1.15g,10.0mmol) was dissolved in ethanol (6.6ml), and stirred well to obtain a homogeneous solution B. Pumping the homogeneous phase solution B into a T-shaped mixer at the flow rate of 0.250mL/min, mixing, and introducing into a second microreactor with the coil pipe inner diameter of 1mm, wherein the volume of the reactor is 30mL, the reaction temperature is controlled at 90 ℃, and the reaction residence time is 20 min. And (3) collecting an effluent liquid of the second microreactor, adding water (10ml) into the system, stirring for 60-90 min at 25 +/-5 ℃, separating out a light yellow solid, carrying out suction filtration, washing with a mixed solvent of ethanol and water (1:1), and drying in vacuum at 50 ℃ to obtain an cyclization product, namely the amlodipine besylate intermediate. The yield thereof was found to be 74.6%.
Example 3
Preparation of β -dicarbonyl compounds reference is made to example 1.
The β -dicarbonyl compound (3.19g,10.0mmol), piperidine (213mg,2.5mmol) and acetic acid (150mg,2.5mmol) were mixed, dissolved in ethanol (6.6ml), and stirred uniformly to obtain a homogeneous solution a. O-chlorobenzaldehyde (1.40g,10.0mmol) was dissolved in ethanol (6.6ml) and stirred well to obtain homogeneous solution C. Pumping the homogeneous solution A and the homogeneous solution C into a Y-shaped mixer at the flow rate of 0.250mL/min respectively, mixing, and introducing into a first microreactor with a coil pipe with the inner diameter of 1mm, wherein the volume of the reactor is 15mL, the reaction temperature is controlled at 90 ℃, and the reaction residence time is 20 min.
Meanwhile, methyl 3-aminocrotonate (1.15g,10.0mmol) was dissolved in ethanol (6.6ml), and stirred well to obtain a homogeneous solution B. Pumping the homogeneous phase solution B into a T-shaped mixer at the flow rate of 0.250mL/min, mixing, and introducing into a second microreactor with the coil pipe inner diameter of 1mm, wherein the volume of the reactor is 30mL, the reaction temperature is controlled at 90 ℃, and the reaction residence time is 20 min. And (3) collecting an effluent liquid of the second microreactor, adding water (10ml) into the system, stirring for 60-90 min at 25 +/-5 ℃, separating out a light yellow solid, carrying out suction filtration, washing with a mixed solvent of ethanol and water (1:1), and drying in vacuum at 50 ℃ to obtain an cyclization product, namely the amlodipine besylate intermediate. The yield thereof was found to be 76.6%.
Example 4
Preparation of β -dicarbonyl compounds reference is made to example 1.
The β -dicarbonyl compound (3.19g,10.0mmol), piperidine (213mg,2.5mmol) and acetic acid (150mg,2.5mmol) were mixed, dissolved in ethanol (6.6ml), and stirred uniformly to obtain a homogeneous solution a. O-chlorobenzaldehyde (1.40g,10.0mmol) was dissolved in ethanol (6.6ml) and stirred well to obtain homogeneous solution C. Pumping the homogeneous solution A and the homogeneous solution C into a Y-shaped mixer at the flow rate of 0.250mL/min respectively, mixing, and introducing into a first microreactor with a coil pipe with the inner diameter of 1mm, wherein the volume of the reactor is 15mL, the reaction temperature is controlled at 75 ℃, and the reaction residence time is 15 min.
Meanwhile, methyl 3-aminocrotonate (1.15g,10.0mmol) was dissolved in ethanol (6.6ml), and stirred well to obtain a homogeneous solution B. Pumping the homogeneous phase solution B into a T-shaped mixer at the flow rate of 0.250mL/min, mixing, and introducing into a second microreactor with the coil pipe inner diameter of 1mm, wherein the volume of the reactor is 30mL, the reaction temperature is controlled at 75 ℃, and the reaction residence time is 15 min. And (3) collecting an effluent liquid of the second microreactor, adding water (10ml) into the system, stirring for 60-90 min at 25 +/-5 ℃, separating out a light yellow solid, carrying out suction filtration, washing with a mixed solvent of ethanol and water (1:1), and drying in vacuum at 50 ℃ to obtain an cyclization product, namely the amlodipine besylate intermediate. The yield thereof was found to be 68.1%.
Example 5
Preparation of β -dicarbonyl compounds reference is made to example 1.
The β -dicarbonyl compound (3.19g,10.0mmol), piperidine (213mg,2.5mmol) and acetic acid (150mg,2.5mmol) were mixed, dissolved in ethanol (4.0ml), and stirred uniformly to obtain a homogeneous solution a. O-chlorobenzaldehyde (1.40g,10.0mmol) was dissolved in ethanol (4.0ml) and stirred well to obtain homogeneous solution C. Pumping the homogeneous solution A and the homogeneous solution C into a Y-shaped mixer at the flow rate of 0.500mL/min respectively, mixing, and introducing into a first microreactor with a coil pipe with the inner diameter of 1mm, wherein the volume of the reactor is 15mL, the reaction temperature is controlled at 75 ℃, and the reaction residence time is 10 min.
Meanwhile, methyl 3-aminocrotonate (1.15g,10.0mmol) was dissolved in ethanol (4.0ml) and stirred well to obtain a homogeneous solution B. Pumping the homogeneous phase solution B into a T-shaped mixer at the flow rate of 0.500mL/min, mixing, and introducing into a second microreactor with the coil pipe inner diameter of 1mm, wherein the volume of the reactor is 30mL, the reaction temperature is controlled at 75 ℃, and the reaction residence time is 10 min. And (3) collecting an effluent liquid of the second microreactor, adding water (10ml) into the system, stirring for 60-90 min at 25 +/-5 ℃, separating out a light yellow solid, carrying out suction filtration, washing with a mixed solvent of ethanol and water (1:1), and drying in vacuum at 50 ℃ to obtain an cyclization product, namely the amlodipine besylate intermediate. The yield thereof was found to be 69.2%.
Example 6
Preparation of β -dicarbonyl compounds reference is made to example 1.
The β -dicarbonyl compound (3.19g,10.0mmol), piperidine (430mg,5.0mmol) and acetic acid (300mg,5.0mmol) were mixed, dissolved in ethanol (6.6ml), and stirred uniformly to obtain a homogeneous solution a. O-chlorobenzaldehyde (1.40g,10.0mmol) was dissolved in ethanol (6.6ml) and stirred well to obtain homogeneous solution C. Pumping the homogeneous solution A and the homogeneous solution C into a Y-shaped mixer at the flow rate of 0.250mL/min respectively, mixing, and introducing into a first microreactor with a coil pipe with the inner diameter of 1mm, wherein the volume of the reactor is 15mL, the reaction temperature is controlled at 75 ℃, and the reaction residence time is 15 min.
Meanwhile, methyl 3-aminocrotonate (1.15g,10.0mmol) was dissolved in ethanol (6.6ml), and stirred well to obtain a homogeneous solution B. Pumping the homogeneous phase solution B into a T-shaped mixer at the flow rate of 0.250mL/min, mixing, and introducing into a second microreactor with the coil pipe inner diameter of 1mm, wherein the volume of the reactor is 30mL, the reaction temperature is controlled at 75 ℃, and the reaction residence time is 15 min. And (3) collecting an effluent liquid of the second microreactor, adding water (10ml) into the system, stirring for 60-90 min at 25 +/-5 ℃, separating out a light yellow solid, carrying out suction filtration, washing with a mixed solvent of ethanol and water (1:1), and drying in vacuum at 50 ℃ to obtain an cyclization product, namely the amlodipine besylate intermediate. The yield thereof was found to be 71.4%.
Example 7
Preparation of β -dicarbonyl compounds reference is made to example 1.
The β -dicarbonyl compound (3.19g,10.0mmol), piperidine (213mg,2.5mmol) and acetic acid (150mg,2.5mmol) were mixed, dissolved in ethanol (6.6ml), and stirred uniformly to obtain a homogeneous solution a. O-chlorobenzaldehyde (1.40g,10.0mmol) was dissolved in ethanol (6.6ml) and stirred well to obtain homogeneous solution C. Pumping the homogeneous solution A and the homogeneous solution C into a Y-shaped mixer at the flow rate of 0.500mL/min respectively, mixing, and introducing into a first microreactor with a coil pipe with the inner diameter of 1mm, wherein the volume of the reactor is 15mL, the reaction temperature is controlled at 75 ℃, and the reaction residence time is 15 min.
Meanwhile, methyl 3-aminocrotonate (1.15g,10.0mmol) was dissolved in ethanol (6.6ml), and stirred well to obtain a homogeneous solution B. Pumping the homogeneous phase solution B into a T-shaped mixer at the flow rate of 0.500mL/min, mixing, and introducing into a second microreactor with the coil pipe inner diameter of 1mm, wherein the volume of the reactor is 30mL, the reaction temperature is controlled at 75 ℃, and the reaction residence time is 15 min. And (3) collecting an effluent liquid of the second microreactor, adding water (10ml) into the system, stirring for 60-90 min at 25 +/-5 ℃, separating out a light yellow solid, carrying out suction filtration, washing with a mixed solvent of ethanol and water (1:1), and drying in vacuum at 50 ℃ to obtain an cyclization product, namely the amlodipine besylate intermediate. The yield thereof was found to be 71.4%.
Example 8
Preparation of β -dicarbonyl compounds reference is made to example 1.
The β -dicarbonyl compound (3.19g,10.0mmol), piperidine (213mg,2.5mmol) and acetic acid (150mg,2.5mmol) were mixed, dissolved in ethanol (6.6ml), and stirred uniformly to obtain a homogeneous solution a. O-chlorobenzaldehyde (1.40g,10.0mmol) was dissolved in ethanol (6.6ml) and stirred well to obtain homogeneous solution C. Pumping the homogeneous solution A and the homogeneous solution C into a Y-shaped mixer at the flow rate of 0.250mL/min respectively, mixing, and introducing into a first microreactor with a coil pipe with the inner diameter of 1mm, wherein the volume of the reactor is 15mL, the reaction temperature is controlled at 50 ℃, and the reaction residence time is 10 min.
Meanwhile, methyl 3-aminocrotonate (1.15g,10.0mmol) was dissolved in ethanol (6.6ml), and stirred well to obtain a homogeneous solution B. Pumping the homogeneous phase solution B into a T-shaped mixer at the flow rate of 0.250mL/min, mixing, and introducing into a second microreactor with the coil pipe inner diameter of 1mm, wherein the volume of the reactor is 30mL, the reaction temperature is controlled at 50 ℃, and the reaction residence time is 10 min. And (3) collecting an effluent liquid of the second microreactor, adding water (10ml) into the system, stirring for 60-90 min at 25 +/-5 ℃, separating out a light yellow solid, carrying out suction filtration, washing with a mixed solvent of ethanol and water (1:1), and drying in vacuum at 50 ℃ to obtain an cyclization product, namely the amlodipine besylate intermediate. The yield thereof was found to be 60.4%.
Example 9
Preparation of β -dicarbonyl compounds reference is made to example 1.
The β -dicarbonyl compound (3.19g,10.0mmol), piperidine (213mg,2.5mmol) and acetic acid (150mg,2.5mmol) were mixed, dissolved in ethanol (6.6ml), and stirred uniformly to obtain a homogeneous solution a. O-chlorobenzaldehyde (1.16g,83.0mmol) was dissolved in ethanol (6.6ml) and stirred well to obtain homogeneous solution C. Pumping the homogeneous solution A and the homogeneous solution C into a Y-shaped mixer at the flow rate of 0.250mL/min respectively, mixing, and introducing into a first microreactor with a coil pipe with the inner diameter of 1mm, wherein the volume of the reactor is 15mL, the reaction temperature is controlled at 75 ℃, and the reaction residence time is 15 min.
Meanwhile, methyl 3-aminocrotonate (1.15g,10.0mmol) was dissolved in ethanol (6.6ml), and stirred well to obtain a homogeneous solution B. Pumping the homogeneous phase solution B into a T-shaped mixer at the flow rate of 0.250mL/min, mixing, and introducing into a second microreactor with the coil pipe inner diameter of 1mm, wherein the volume of the reactor is 30mL, the reaction temperature is controlled at 75 ℃, and the reaction residence time is 15 min. And (3) collecting an effluent liquid of the second microreactor, adding water (10ml) into the system, stirring for 60-90 min at 25 +/-5 ℃, separating out a light yellow solid, carrying out suction filtration, washing with a mixed solvent of ethanol and water (1:1), and drying in vacuum at 50 ℃ to obtain an cyclization product, namely the amlodipine besylate intermediate. The yield thereof was found to be 66.4%.
The above-mentioned embodiments are merely exemplary embodiments for fully illustrating the present invention, and the scope of the present invention is not limited to the above-mentioned embodiments, but defined by the contents of the claims. All matter disclosed in the specification, including the abstract and drawings, and all methods and steps disclosed, may be combined in any combination, except combinations where any feature and/or step is mutually exclusive. Each feature disclosed in this specification, including the abstract and drawings, may be replaced by alternative features serving the same, equivalent or similar purpose, unless expressly stated otherwise. Thus, unless expressly stated otherwise, each feature disclosed is one example only of a generic series of equivalent or similar features. Those skilled in the art should also realize that such equivalent substitutions and alterations can be made without departing from the spirit and scope of the present invention. Such modifications are also intended to be within the scope of the present invention. Each reference cited in this application is incorporated herein in its entirety.
Claims (10)
1. A method for producing an amlodipine besylate intermediate (formula I) by utilizing a micro-reaction device,
the method comprises the following steps:
(1) dissolving a beta-dicarbonyl compound (formula II), piperidine and acetic acid in ethanol to obtain a homogeneous solution A;
(2) dissolving 3-aminocrotonic acid methyl ester in ethanol to obtain a homogeneous phase solution B;
(3) dissolving o-chlorobenzaldehyde in ethanol to obtain a homogeneous phase solution C;
(4) respectively and simultaneously pumping the homogeneous solution A and the homogeneous solution C into a first micro mixer in a microchannel reaction device, mixing and then introducing into a first microreactor;
(5) respectively pumping the homogeneous phase solution B and the effluent of the first microreactor into a second micromixer in the microchannel reaction device at the same time, mixing and then introducing into the second microreactor;
(6) and collecting effluent liquid of the second microreactor, and carrying out post-treatment to obtain a cyclization product, namely the amlodipine besylate intermediate.
2. The method for producing amlodipine besylate intermediate using a micro-reaction device according to claim 1, wherein the concentration of the β -dicarbonyl compound (formula II) in the homogeneous solution a in the step (1) is 1.0 to 2.5 mol/L.
3. The method for producing amlodipine besylate intermediate using a micro-reaction device according to claim 1, wherein the concentration of methyl 3-aminocrotonate in the homogeneous solution B in the step (2) is 1.0 to 2.5 mol/L.
4. The method for producing amlodipine besylate intermediate using a micro-reaction device according to claim 1, wherein the concentration of methyl 3-aminocrotonate in the homogeneous solution C in the step (3) is 1.0 to 2.5 mol/L.
5. The method for producing amlodipine besylate intermediate using a micro-reaction device according to claim 1, wherein the molar ratio of piperidine to o-chlorobenzaldehyde is 0.05 to 0.50: 1; the molar ratio of acetic acid to o-chlorobenzaldehyde is 0.05-0.50: 1; the molar ratio of the beta-dicarbonyl compound (formula II) to the o-chlorobenzaldehyde is 1.0-1.2: 1; the molar ratio of the methyl 3-aminocrotonate to the o-chlorobenzaldehyde is 1.0-1.2: 1.
6. The method for producing amlodipine besylate intermediate using a micro-reaction device according to claim 1, wherein in the step (4), the flow rate of the homogeneous solution A pumped into the first micro-mixer in the micro-channel reaction device through the first feeding pump is 0.1 to 0.5 mL/min; the flow rate of the homogeneous solution C pumped into the first micro mixer in the microchannel reaction device through the second feeding pump is 0.1-0.5 mL/min.
7. The method for producing the amlodipine besylate intermediate by using the micro-reaction device according to claim 1, wherein the reaction temperature in the first micro-reactor is 50 to 90 ℃ and the reaction residence time is 10 to 20 min.
8. The method for producing amlodipine besylate intermediate using a micro-reaction device according to claim 1, wherein in the step (5), the flow rate at which the homogeneous solution B is pumped into the second micro-mixer of the micro-channel reaction device through the third feeding pump is 0.1 to 0.5 mL/min.
9. The method for producing the amlodipine besylate intermediate by using the micro-reaction device according to claim 1, wherein the reaction temperature in the second micro-reactor is 50 to 90 ℃ and the reaction residence time is 10 to 20 min.
10. The method for producing an amlodipine besylate intermediate using a microreactor means as claimed in claim 1, wherein said microchannel reaction means comprises a first feeding pump, a second feeding pump, a third feeding pump, a first micromixer, a second micromixer, a first microreactor, a second microreactor and a receiver; the volume of the first microreactor is 10-20 mL, and the volume of the second microreactor is 25-35 mL. The first feeding pump and the second feeding pump are connected to a first micro mixer in a parallel mode through pipelines, the first micro mixer is connected with a first micro reactor in series, a discharge port of the first micro reactor and a third feeding pump are connected to a second micro mixer in a parallel mode, the second micro mixer is sequentially connected with a second micro reactor and a receiver in series, the first feeding pump and the second feeding pump are connected through pipelines, and the inner diameter of each pipeline is 0.5-1 mm.
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