Preparation method for synthesizing homopiperony lamine through continuous flow reaction

Abstract

The invention belongs to the technical field of medicines, and discloses a preparation method for synthesizing homopiperony lamine by adopting a continuous flow reaction, and the synthesis route is as follows: # imgabs0. According to the method, benzodioxole is taken as an initial raw material, and chloromethylation reaction, cyanidation substitution reaction and hydrogenation reduction reaction are performed through a continuous flow reactor to prepare the homopiperony lamine. The method is characterized in that a reaction solution is conveyed into a continuous flow module or a fixed bed through a metering pump for mixed reaction, the process is stable, the reaction rate is high, the selectivity is good, the overall yield of a route is high, the product purity is high, operation is easy and convenient, safety and environment friendliness are achieved, and the safety risk when reagents such as phosphorus trichloride, hydrochloric acid, sodium hydride and a Raney nickel catalyst are used is greatly reduced; and the method has a good enlarged production prospect, and also has a good industrial application value in the aspect of improving the production efficiency.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical synthesis, and particularly relates to a preparation method for synthesizing pepperethylamine through continuous flow reaction. Background Art

[0002] As an important starting material for the synthesis of berberine hydrochloride, the synthesis method of piperine ethylamine plays a decisive role in the cost control of berberine hydrochloride. Berberine hydrochloride, commonly known as berberine, is a major alkaloid contained in the rhizome of Coptis chinensis, a plant of the Ranunculaceae family. It can be extracted from Coptis chinensis, Phellodendron amurense or Tripterygium wilfordii, or it can be synthesized artificially. It has the characteristics of a broad antibacterial spectrum, low toxicity and side effects. It is often used clinically as a drug against intestinal bacterial infections. It can also be used to treat hyperlipidemia, heart failure, etc. Therefore, the preparation of berberine hydrochloride has important application value.

[0003] At present, the synthesis of berberine is mainly carried out using piperonyl ethylamine and 2,3-dimethoxybenzaldehyde as raw materials, among which the synthesis of piperonyl ethylamine is the most critical.

[0004] The existing synthetic process route of piperidine is as follows:

[0005]

[0006] The continuous flow equipment process of steps (1) and (2) is as follows: Figure 1 As shown:

[0007] Step (3) Continuous flow hydrogenation equipment process as follows Figure 2 As shown:

[0008] Patent CN 116715652 A also reports a route for preparing piperonyl ethylamine, which has the lowest cost. In step (1), the current method for preparing 3,4-methylenedioxybenzyl chloride at a relatively low cost is to use hydrochloric acid, Lewis acid, phosphorus trichloride, etc. with paraformaldehyde to chloromethylate the piperonyl ring, but conventional autoclave reactions will inevitably generate dichloromethylated byproducts and bimolecular substitution byproducts.

[0009]

[0010] As the scale of the reaction increases, the reaction time increases, and the material ratio is inaccurate, the by-products will increase dramatically, and the yield will be greatly reduced. The yield is mostly between 51% and 65%, the conversion rate is low, and the selectivity is also poor.

[0011] In step (2), due to the use of highly toxic reagents such as sodium cyanide, it is extremely dangerous. In step (3), a fixed bed is used to load a nickel-based catalyst, and a traditional intermittent reaction is used. The intermittent reaction reported in this step has a disubstituted impurity ratio of about 10-15%, a yield of about 70-80%, and a long reaction time of generally 6-8h. As the batch size increases, the amount of Raney nickel catalyst used increases. On the one hand, the safety hazard during use increases (it is easy to spontaneously combust when exposed to air). On the other hand, the recovery and reuse of Raney nickel catalyst is also an important problem. At present, most of the methods of outsourcing to catalyst companies for recovery are adopted, and the cost ratio is relatively high. In addition, this process is a heterogeneous hydrogenation process, which is closely related to the stirring condition, usually resulting in a relatively unstable process, a large fluctuation in the proportion of by-products, and an unstable product purity.

[0012]

[0013] Due to the current technological deficiencies, in order to meet the needs of industrial production, it is urgently necessary to optimize and improve the process. Summary of the invention

[0014] The invention aims to provide a preparation method for synthesizing pepperethylamine by continuous flow reaction with high yield, good purity, safe reaction process, short time and suitable for industrialized scale-up production.

[0015] To achieve the purpose of the present invention, the synthetic route is as follows:

[0016]

[0017] The specific steps include:

[0018] (1) S1: Compound SM1 is mixed with a chlorinating agent and a solvent to form solution 1, and an aldehyde agent, hydrochloric acid and a Lewis acid are mixed with a solution 2. Solutions 1 and 2 are respectively pumped into a continuous flow preheater through respective metering pumps for preheating and then introduced into a tubular reactor for chloromethylation to obtain compound I;

[0019] (2) S2: Compound I is solution 3, and inorganic cyanide, phase transfer catalyst and base are configured into solution 4. Solutions 3 and 4 are respectively pumped into a continuous flow preheater through respective metering pumps for preheating and then introduced into a tubular reactor for reaction to obtain compound II;

[0020] (3) S3: Compound II and an ammonia source solvent are prepared into solution 5, which is pumped into a continuous flow preheater by a metering pump for preheating and then introduced into a tubular reactor containing a nickel-based catalyst supported on γ-Al2O3, and hydrogenated and reduced in a hydrogen environment to obtain compound III;

[0021] Furthermore, the reaction solvent described in S1 is one of 1,2-dichloroethane, dichloromethane, and chloroform; the chlorination reagent is one of phosphorus trichloride, phosphorus oxychloride, and thionyl chloride, and the preferred chlorination reagent is phosphorus trichloride; the aldehyde reagent is one of formaldehyde solution, paraformaldehyde, and triformaldehyde, and the preferred aldehyde reagent is paraformaldehyde; the flow rate of metering pump 1 is 1 to 100 ml / min, and the flow rate of metering pump 2 is 1 to 100 ml / min; the flow rate ratio of metering pump 1 to metering pump 2 is 1:(0.5 to 2); the molar ratio of piperonyl ring, aldehyde reagent, and chlorination reagent in the reaction is 1:(1.0 to 1.5):(0.2 to 0.5), and the preferred molar ratio is 1:1.2:0.3.

[0022] Further, the inorganic cyanide described in S2 is one of sodium cyanide, potassium cyanide, and cuprous cyanide, and the preferred cyaniding agent is sodium cyanide; the base is one of sodium hydroxide, potassium hydroxide, and zirconium hydroxide, and preferably sodium hydroxide; the phase transfer catalyst is one of tetrabutylammonium bromide, dodecyltrimethylammonium bromide, and hexadecyltrimethylammonium bromide, and preferably tetrabutylammonium bromide; the flow rate of the metering pump 3 is 1-50 ml / min, the flow rate of the metering pump 4 is 1-50 ml / min, and the flow rate ratio of the metering pump 3 to the metering pump 4 is 1:(0.8-1.5). The molar ratio of piperonyl chloride, cyanide, base, and phase transfer catalyst in the reaction is 1:(1.0-1.5):(0.01-0.2):(0.01-0.1), and the preferred molar ratio is 1:1.05:0.03:0.026.

[0023] Furthermore, the catalyst described in S3 is a nickel-based catalyst supported on γ-Al2O3, the ammonia source is one of ammonia water and ammonia methanol, preferably ammonia methanol, the concentration of ammonia methanol is 4-7M, the hydrogen pressure is 1-4MPa, the reaction temperature is 80-110°C, the pump liquid flow rate is 0.2-1ml / min, and the hydrogen flow rate is 15-40ml / min, preferably the ammonia methanol concentration is 4.5M, the hydrogen pressure is 2MPa, the reaction temperature is 100°C, the metering pump liquid flow rate is 0.5ml / min, and the hydrogen flow rate is 15ml / min.

[0024] The present invention adopts a tubular reactor device for continuous flow production, and the reaction raw materials are prepared into an aqueous solution before being carried out, which is highly safe, avoids the risk of human contact, greatly reduces the risk of exposure, and has the following advantages:

[0025] 1. The reaction time is short, generally the reaction time is completed within a few minutes, and the reaction efficiency is high.

[0026] 2. Good selectivity, which can effectively avoid the formation of bimolecular substitution by-products. The by-products in the effluent account for only 3-4%, and the products account for 96-97%.

[0027] 3. High yield, the yield is more than 94%, good repeatability, and the purity is as high as 96-98%.

[0028] 4. The post-treatment is simple, and the effluent can be directly concentrated under reduced pressure to obtain the target product;

[0029] 5. Catalyst recycling: Compared with traditional Raney nickel catalysts, nickel-based catalysts loaded on γ-Al2O3 have no risk of spontaneous combustion and can be reused 6 to 8 times, which meets the requirements of green production and greatly reduces the cost of catalyst use.

[0030] The experimental results show that the continuous flow reaction process for synthesizing piperidine is stable and feasible, can accurately control the conditions, has a high yield, a fast reaction rate, good selectivity, is easy and safe to operate, is environmentally friendly, can be stably and continuously produced, has the prospect of scaled-up production, and has great application value in improving production efficiency and controlling cost and energy consumption. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 A flow chart of a continuous flow device for preparing piperidine by an existing process;

[0032] Figure 2 A flow chart of a continuous flow hydrogenation device for preparing piperidine by an existing process;

[0033] Figure 3 Compound Ⅰ of Example 1 1 H NMR result diagram;

[0034] Figure 4 For Example 1 Compound II 1 H NMR result diagram;

[0035] Figure 5 is the compound III of Example 1 1 H NMR results. DETAILED DESCRIPTION

[0036] The present invention is described in more detail below through examples, but the protection scope of the present invention is not limited thereto.

[0037] The preparation method of synthesizing pepperethylamine by continuous flow reaction, the specific preparation steps are as follows:

[0038] Embodiment 1:

[0039] (1) Preparation of piperonyl chloride

[0040] 30 g (246 mmol) of piperonyl cyclopentane, 8.7 g (63 mmol) of phosphorus trichloride and 39 ml of 1,2-dichloroethane were mixed to form solution 1, and connected to metering pump 1; 8.85 g (295 mmmol) of paraformaldehyde, 1.68 g (12.3 mmol) of anhydrous zinc chloride and 60 ml of concentrated hydrochloric acid were mixed to form solution 2, and connected to metering pump 2.

[0041] Set the continuous flow preheater 1, the circulation temperature is 40℃, and it reaches stability; set the continuous flow preheater 2, the circulation temperature is 40℃, and it reaches stability; set the continuous flow tubular reactor 1, the circulation temperature is 40℃, and it reaches stability; set the flow rate of metering pump 1 to 7.4mL / min, set the flow rate of metering pump 2 to 7.0ml / min; start metering pump 1 and metering pump 2 at the same time, run for 120s and collect in the storage tank. After the operation is completed, separate the liquid, collect the organic phase, P = 5mmHg, T = 85 ~ 105℃ vacuum distillation, and obtain 39.39g of product. The obtained product is a colorless liquid with a GC purity of 98.71% and a yield of 94.46%.

[0042] (2) Preparation of piperonitrile

[0043] 40.3 g (236 mmol) of piperonyl chloride is prepared as solution 1, which is connected to metering pump 1; 11.48 g (240 mmol) of sodium cyanide, 0.294 g (7.4 mmol) of sodium hydroxide, 1.98 g (6.1 mmol) of tetrabutylammonium bromide and 20 ml of water are mixed to form solution 2, which is connected to metering pump 2.

[0044] Set the continuous flow preheater 1, the circulation temperature is 80℃, and it reaches stability; set the continuous flow preheater 2, the circulation temperature is 80℃, and it reaches stability; set the continuous flow tubular reactor 1, the circulation temperature is 80℃, and it reaches stability; set the flow rate of metering pump 1 to 5mL / min, set the flow rate of metering pump 2 to 4.2ml / min; start metering pump 1 and metering pump 2 at the same time, run for 120s and collect in the storage tank. After the operation is completed, separate the liquid, collect the organic phase, and distill under reduced pressure to obtain 36.17g of the product. The obtained product is an off-white solid with a GC purity of 97.55% and a yield of 95.26%.

[0045] (3) Preparation of piperidine

[0046] Weigh 20g (124mmol) of pepper acetonitrile, add 80ml of 4.5M ammonia methanol to prepare solution 1, connect metering pump 1, load nickel-γAl2O3 catalyst into the fixed bed of tubular reactor, set the hydrogen back pressure valve pressure to 2MPa, the flow rate of metering pump 1 to 0.5ml / min, and the hydrogen flow rate to 15ml / min. After the pressure stabilizes, set the preheater temperature to 100℃, the reactor temperature to 100℃, open the pump liquid valve, and start collecting in the storage tank after running for 20min. After the operation is completed, collect the effluent, distill under reduced pressure, and obtain 19.36g of product, which is a light yellow liquid with a purity of 97.85% and a yield of 94.45%.

[0047] Embodiment 2:

[0048] (1) Preparation of piperonyl chloride

[0049] 30 g (246 mmol) of piperonyl cyclopentane, 9.66 g (63 mmol) of phosphorus oxychloride and 39 ml of chloroform were mixed to form solution 1, and metering pump 1 was connected; 8.85 g (295 mmmol) of paraformaldehyde, 1.68 g (12.3 mmol) of anhydrous zinc chloride and 60 ml of concentrated hydrochloric acid were mixed to form solution 2, and metering pump 2 was connected.

[0050] Set the continuous flow preheater 1, the circulation temperature is 40℃, and it reaches stability; set the continuous flow preheater 2, the circulation temperature is 40℃, and it reaches stability; set the continuous flow tubular reactor 1, the circulation temperature is 40℃, and it reaches stability; set the flow rate of metering pump 1 to 7.8mL / min, set the flow rate of metering pump 2 to 7.0ml / min; start metering pump 1 and metering pump 2 at the same time, run for 120s and collect in the storage tank. After the operation is completed, separate the liquid, collect the organic phase, P = 5mmHg, T = 85 ~ 105℃ vacuum distillation, and obtain 39.34g of product. The obtained product is a colorless liquid with a GC purity of 97.65% and a yield of 93.88%.

[0051] (2) Preparation of piperonitrile

[0052] 20.2 g (118 mmol) of piperonyl chloride is prepared as solution 1, which is connected to metering pump 1; 7.81 g (120 mmol) of potassium cyanide, 0.147 g (3.7 mmol) of sodium hydroxide, 0.99 g (3.1 mmol) of tetrabutylammonium bromide and 10 ml of water are mixed to form solution 2, which is connected to metering pump 2.

[0053] Set the continuous flow preheater 1, the circulation temperature is 80℃, and it reaches stability; set the continuous flow preheater 2, the circulation temperature is 80℃, and it reaches stability; set the continuous flow tubular reactor 1, the circulation temperature is 80℃, and it reaches stability; set the flow rate of metering pump 1 to 5mL / min, set the flow rate of metering pump 2 to 4.3ml / min; start metering pump 1 and metering pump 2 at the same time, run for 60s and collect in the storage tank. After the operation is completed, separate the liquid, collect the organic phase, and distill under reduced pressure to obtain 18.13g of the product. The obtained product is an off-white solid with a GC purity of 97.23% and a yield of 95.01%.

[0054] (3) Preparation of piperidine

[0055] Weigh 18g (112mmol) of pepper acetonitrile, add 72ml of 4.5M ammonia methanol to prepare solution 1, connect metering pump 1, load nickel-γAl2O3 catalyst into the fixed bed of tubular reactor, set the hydrogen back pressure valve pressure to 2MPa, the flow rate of metering pump 1 to 0.5ml / min, and the hydrogen flow rate to 15ml / min. After the pressure stabilizes, set the preheater temperature to 100℃, the reactor temperature to 100℃, open the pump liquid valve, and start collecting in the storage tank after running for 15min. After the operation is completed, collect the effluent, distill under reduced pressure, and obtain 17.46g of product, which is a light yellow liquid with a purity of 96.42% and a yield of 94.66%.

[0056] Embodiment 3:

[0057] (1) Preparation of piperonyl chloride

[0058] 50 g (410 mmol) of piperonyl cyclopentane, 14.5 g (105 mmol) of phosphorus trichloride and 65 ml of chloroform were mixed to form solution 1, and metering pump 1 was connected; 14.77 g (164 mmmol) of trioxymethylene, 2.79 g (20.5 mmol) of anhydrous zinc chloride and 100 ml of concentrated hydrochloric acid were mixed to form solution 2, and metering pump 2 was connected.

[0059] Set the continuous flow preheater 1, the circulation temperature is 40℃, and it reaches stability; set the continuous flow preheater 2, the circulation temperature is 40℃, and it reaches stability; set the continuous flow tubular reactor 1, the circulation temperature is 40℃, and it reaches stability; set the flow rate of metering pump 1 to 7.7mL / min, set the flow rate of metering pump 2 to 7.0ml / min; start metering pump 1 and metering pump 2 at the same time, run for 120s and collect in the storage tank. After the operation is completed, separate the liquid, collect the organic phase, P = 5mmHg, T = 85 ~ 105℃ vacuum distillation, and obtain 65.95g of product. The obtained product is a colorless liquid with a GC purity of 97.18% and a yield of 94.42%.

[0060] (2) Preparation of piperonitrile

[0061] 60 g (352 mmol) of piperonyl chloride is prepared as solution 1, which is connected to metering pump 1; 17.53 g (359 mmol) of sodium cyanide, 0.438 g (10.55 mmol) of sodium hydroxide, 3.48 g (9.15 mmol) of dodecyltrimethylammonium bromide and 30 ml of water are mixed to form solution 2, which is connected to metering pump 2.

[0062] Set the continuous flow preheater 1, the circulation temperature is 80℃, and it reaches stability; set the continuous flow preheater 2, the circulation temperature is 80℃, and it reaches stability; set the continuous flow tubular reactor 1, the circulation temperature is 80℃, and it reaches stability; set the flow rate of metering pump 1 to 5mL / min, set the flow rate of metering pump 2 to 4.5ml / min; start metering pump 1 and metering pump 2 at the same time, run for 120s and collect in the storage tank. After the operation is completed, separate the liquid, collect the organic phase, and distill under reduced pressure to obtain 53.18g of the product. The obtained product is an off-white solid with a GC purity of 97.55% and a yield of 93.82%.

[0063] (3) Preparation of piperidine

[0064] Weigh 10g (62mmol) of pepper acetonitrile, add 40ml of 4.5M ammonia methanol to prepare solution 1, connect metering pump 1, load nickel-γAl2O3 catalyst into the fixed bed of tubular reactor, set the hydrogen back pressure valve pressure to 2MPa, the flow rate of metering pump 1 to 0.5ml / min, and the hydrogen flow rate to 15ml / min. After the pressure stabilizes, set the preheater temperature to 100℃, the reactor temperature to 100℃, open the pump liquid valve, and start collecting in the storage tank after running for 10min. After the operation is completed, collect the effluent, distill under reduced pressure, and obtain 9.67g of product, which is a light yellow liquid with a purity of 96.82% and a yield of 94.33%.

[0065] The above description is only a preferred embodiment of the present invention and does not limit the present invention in any form. 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, and these improvements and modifications should also be regarded as the protection scope of the present invention.

Claims

1. A method for preparing pepperethylamine by continuous flow reaction, characterized in that: This is accomplished by the following steps: (1) S1: Compound SM1, chlorination reagent, and solvent are prepared into solution 1, and aldehyde reagent, hydrochloric acid, and Lewis acid are prepared into solution 2. Solutions 1 and 2 are respectively pumped into a continuous flow preheater through respective metering pumps for preheating and then introduced into a tubular reactor for chloromethylation reaction to obtain compound I; (2) S2: Compound I is solution 3, and inorganic cyanide, phase transfer catalyst and base are configured into solution 4. Solutions 3 and 4 are respectively pumped into a continuous flow preheater through respective metering pumps for preheating and then introduced into a tubular reactor for reaction to obtain compound II; (3) S3: Compound II and an ammonia source are prepared into solution 5, which is pumped into a continuous flow preheater through a metering pump for preheating and then introduced into a tubular reactor containing a fixed bed of a nickel-based silica catalyst, and hydrogenated and reduced in a hydrogen environment to obtain compound III; Wherein in step (1): the reaction solvent is one of 1,2-dichloroethane, dichloromethane and chloroform; the chlorination reagent is one of phosphorus trichloride, phosphorus oxychloride and thionyl chloride; the aldehyde reagent is one of formaldehyde solution, paraformaldehyde and trioxymethylene; the Lewis acid is one of anhydrous zinc chloride, anhydrous ferric chloride and anhydrous aluminum chloride; In step (2), the inorganic cyanide is one of sodium cyanide, potassium cyanide and cuprous cyanide; the phase transfer catalyst is one of tetrabutylammonium bromide, dodecyltrimethylammonium bromide and hexadecyltrimethylammonium bromide; In step (3): the catalyst is a nickel-based catalyst supported on γ-Al2O3, and the ammonia source is one of ammonia water and ammonia methanol.

2. The method for preparing pepperethylamine by continuous flow reaction according to claim 1, characterized in that: In step (1), the flow rate of the solution 1 metering pump is 1-100 ml / min, and the flow rate of the solution 2 metering pump is 1-100 ml / min; the flow rate ratio of the solution 1 metering pump to the solution 2 metering pump is 1:(0.5-2); In step (2), the flow rate of the solution 3 metering pump is 1-50 ml / min, and the flow rate of the solution 4 metering pump is 1-50 ml / min; the flow rate ratio of the solution 3 metering pump to the solution 4 metering pump is 1:(0.8-1.5); In step (3), the pump liquid flow rate is 0.2-1 ml / min, and the hydrogen flow rate is 15-40 ml / min.

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