阅读说明：本技术 一种利用连续流管式反应器合成阿托伐他汀钙的方法 (Method for synthesizing atorvastatin calcium by using continuous flow tubular reactor ) 是由 石利平 陈本顺 叶金星 徐春涛 江涛 尹强 万新强 孙伟振 程瑞华 于娜娜 于 2021-09-26 设计创作，主要内容包括：本发明涉及一种利用连续流管式反应器合成阿托伐他汀钙的方法,它包括以下步骤(1)将阿托伐他汀叔丁酯与溶剂混合,得物料A；(2)将氢氧化钠加入至纯化水中,得物料B；(3)将醋酸钙加入至纯化水中,得物料C；(4)将所述物料A和所述物料B分别泵入至第一管式反应器中进行化学反应,反应温度为15～25℃,反应时间为20～50s；然后,将所得反应液和所述物料C继续泵入至第二管式反应器中进行化学反应,反应温度为50～60℃,反应时间为30～90s,得到目标产物,具体合成路线如下。采用本发明的方法,整个反应过程所需时间极短,反应条件温和,目标产物收率高,收率达到96％以上,纯度高,纯度达到99％以上。(The invention relates to a method for synthesizing atorvastatin calcium by using a continuous flow tubular reactor, which comprises the following steps of (1) mixing atorvastatin tert-butyl ester with a solvent to obtain a material A; (2) adding sodium hydroxide into purified water to obtain a material B; (3) adding calcium acetate into purified water to obtain a material C; (4) respectively pumping the material A and the material B into a first tubular reactor for chemical reaction, wherein the reaction temperature is 15-25 ℃, and the reaction time is 20-50 s; and then, continuously pumping the obtained reaction liquid and the material C into a second tubular reactor for chemical reaction at the reaction temperature of 50-60 ℃ for 30-90 s to obtain a target product, wherein the specific synthetic route is as follows. By adopting the method, the time required by the whole reaction process is extremely short, the reaction condition is mild, the yield of the target product is high, the yield reaches over 96 percent, the purity is high, and the purity reaches over 99 percent.)

1. A method for synthesizing atorvastatin calcium by using a continuous flow tubular reactor, which is characterized by comprising the following steps:

(1) mixing atorvastatin tert-butyl ester with a solvent, and stirring until the mixture is clear to obtain a material A;

(2) adding sodium hydroxide into purified water, and stirring until the sodium hydroxide is dissolved clearly to obtain a material B;

(3) adding calcium acetate into purified water, and stirring until the calcium acetate is dissolved clearly to obtain a material C;

(4) respectively pumping the material A and the material B into a first tubular reactor for chemical reaction, wherein the reaction temperature is 15-25 ℃, and the reaction time is 20-50 s; after the reaction is finished, continuously pumping the obtained reaction liquid and the material C into a second tubular reactor for chemical reaction at the reaction temperature of 50-60 ℃ for 30-90 s, and then cooling, centrifuging, pulping and drying the reacted material to obtain a target product, wherein the specific synthetic route is as follows:

wherein in the step (4), the molar ratio of the atorvastatin tert-butyl ester to the sodium hydroxide is 1: 1.2-1.8; the molar ratio of the atorvastatin tert-butyl ester to the calcium acetate is 1: 0.3-1.0.

2. The method for synthesizing atorvastatin calcium by using a continuous flow tube reactor according to claim 1, wherein the molar ratio of atorvastatin tert-butyl ester to sodium hydroxide in the step (4) is 1:1.4 to 1.6, preferably 1: 1.5.

3. The method for synthesizing atorvastatin calcium by using a continuous flow tube reactor according to claim 1, wherein the molar ratio of atorvastatin tert-butyl ester to calcium acetate in step (4) is 1: 0.5-0.7, preferably 1: 0.6.

4. The process for synthesizing atorvastatin calcium using a continuous flow tube reactor of claim 1, wherein in the step (4), the chemical reaction is performed in the first tube reactor at a reaction temperature of 20 ℃; the reaction time was 30 s.

5. The process for synthesizing atorvastatin calcium using a continuous flow tube reactor of claim 1, wherein in the step (4), the chemical reaction is performed in the second tube reactor at a reaction temperature of 55 ℃; the reaction time was 60 s.

6. The method for synthesizing atorvastatin calcium by using a continuous flow tube reactor according to claim 1, wherein in the step (1), the content of atorvastatin tert-butyl ester in the material A is 10-30%, preferably 20%; the solvent is methanol, ethanol or isopropanol, preferably methanol; the percentage content of the sodium hydroxide in the material B is 40-60%, and preferably 50%.

7. The method for synthesizing atorvastatin calcium by using a continuous flow tube reactor according to claim 1, wherein in the step (1), the mixture is stirred to be clear at 35-50 ℃; preferably 42 to 48 ℃.

8. The method for synthesizing atorvastatin calcium by using a continuous flow tube reactor according to claim 1, wherein the continuous flow tube reactor comprises a preheater I, a preheater II and a preheater III, the preheater I and the preheater II are respectively connected with the feeding port of the first tube reactor, and the discharging port of the first tube reactor and the preheater III are respectively connected with the feeding port of the second tube reactor.

9. The method for synthesizing atorvastatin calcium by using a continuous flow tube reactor according to claim 8, wherein the material A is placed in a raw material tank A, and a metering pump I is arranged on a pipeline between the raw material tank A and the preheater I; the material B is placed in a raw material tank B, and a metering pump II is arranged on a pipeline between the raw material tank B and the preheater II; the material C is placed in a raw material tank C, and a metering pump III is arranged on a pipeline between the raw material tank C and the preheater III.

10. The method for synthesizing atorvastatin calcium by using a continuous flow tube reactor according to claim 8, wherein the material of the first tube reactor and the second tube reactor is monocrystalline silicon, ceramic, corrosion-resistant stainless steel, corrosion-resistant alloy or polytetrafluoroethylene.

Technical Field

The invention belongs to the technical field of drug synthesis, and particularly relates to a method for synthesizing atorvastatin calcium by using a continuous flow tubular reactor.

Background

Atorvastatin calcium, having the chemical name [ R- (R ', R') ] -2- (4-fluorophenyl) -beta, alpha-dihydroxy-5- (1-methylethyl) -3-phenyl-4- [ (anilino) carbonyl ] -1-hydro-pyrrole-1-heptanoic acid calcium salt (2:1), CAS number 134523-03-8, is a selective, competitive inhibitor of HMG-CoA reductase and is useful for the treatment of hypercholesterolemia and combined hyperlipidemia, coronary heart disease. The conventional synthesis method comprises the following steps:

for example, chinese patent CN 101560177B discloses a method for preparing atorvastatin calcium, which comprises the following steps: (1) heating an alcohol solvent (such as ethanol) and the compound of the formula II to dissolve, adjusting the pH of a reaction solution to 9-11 by using an aqueous solution of a basic compound (potassium hydroxide), and reacting to obtain the compound of the formula III, wherein the reaction temperature is 30-70 ℃. (2) Adding a 20% calcium salt (such as calcium chloride) water solution into the reaction solution in the formula III, and reacting at a constant temperature of 30-70 ℃. Adding activated carbon, cooling, filtering, and dripping water into filtrate to separate out a solid compound of the formula I, wherein the synthetic route is as follows:

at present, atorvastatin calcium is prepared by a kettle type reaction, and the reaction time is at least several hours, even tens of hours; moreover, in order to prevent the reaction from being too violent or locally overheated, some materials are added in a slow dropwise manner, so that a part of reactants added firstly have too long retention time, and side products are generated.

Disclosure of Invention

The invention aims to provide a method for synthesizing atorvastatin calcium by using a continuous flow tubular reactor on the basis of the prior art, which has the advantages of mild reaction conditions, extremely short time required in the whole reaction process, high yield, high purity, low cost and environmental friendliness, and effectively avoids byproducts generated due to overlong reaction time or overhigh reaction temperature.

The technical scheme of the invention is as follows:

a process for synthesizing atorvastatin calcium using a continuous flow tubular reactor, comprising the steps of:

(1) mixing atorvastatin tert-butyl ester with a solvent, and stirring until the mixture is clear to obtain a material A;

(2) adding sodium hydroxide into purified water, and stirring until the sodium hydroxide is dissolved clearly to obtain a material B;

(3) adding calcium acetate into purified water, and stirring until the calcium acetate is dissolved clearly to obtain a material C;

(4) respectively pumping the material A and the material B into a first tubular reactor for chemical reaction, wherein the reaction temperature is 15-25 ℃, and the reaction time is 20-50 s; after the reaction is finished, continuously pumping the obtained reaction liquid and the material C into a second tubular reactor for chemical reaction at the reaction temperature of 50-60 ℃ for 30-90 s, and then cooling, centrifuging, pulping and drying the reacted material to obtain a target product, wherein the specific synthetic route is as follows:

in the step (4), the molar ratio between the atorvastatin tert-butyl ester and the sodium hydroxide is controlled by strictly controlling the flow rates of the material A and the material B, so that a better yield can be obtained, the generation of byproducts is reduced, and an intermediate product with high purity and high yield is obtained. For the present invention, the molar ratio of atorvastatin tert-butyl ester to sodium hydroxide is 1:1.2 to 1.8, but is not limited to 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7 or 1:1.9, and for better effect, the molar ratio of atorvastatin tert-butyl ester to sodium hydroxide is 1:1.4 to 1.6, and more preferably the molar ratio of atorvastatin tert-butyl ester to sodium hydroxide is 1: 1.5.

In the step (4), the use amount relationship between the intermediate product and the calcium acetate is controlled by controlling the molar ratio of the atorvastatin tert-butyl ester to the calcium acetate, so as to control the yield and the purity of the target product, wherein the molar ratio of the atorvastatin tert-butyl ester to the calcium acetate is 1: 0.3-1.0, and may be, but is not limited to, 1:0.3, 1:0.4, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9 or 1:1.0, and for better effect, the molar ratio of the atorvastatin tert-butyl ester to the calcium acetate is 1: 0.5-0.7, and further preferably, the molar ratio of the atorvastatin tert-butyl ester to the calcium acetate is 1: 0.6.

In the invention, when the atorvastatin calcium is synthesized by adopting the continuous flow tubular reactor, the reaction temperature and the reaction time need to be controlled to improve the yield and the purity of the target product. In the step (4), when the intermediate product is prepared by performing a chemical reaction in the first tubular reactor, the reaction temperature is 15 to 25 ℃, and may be, but is not limited to, 15 ℃, 16 ℃, 17 ℃, 18 ℃, 19 ℃, 20 ℃, 21 ℃, 22 ℃, 23 ℃, 24 ℃ or 25 ℃, and in order to obtain a better effect, the reaction temperature is 20 ℃. The reaction time is 20-50 s, but not limited to 20s, 25s, 30s, 35s, 40s, 45s or 50s, and in order to obtain better effect, the reaction time is 30 s.

In the step (4), when the reaction solution obtained in the first tubular reactor and calcium acetate are subjected to a chemical reaction in the second tubular reactor to prepare the target product, the reaction temperature is 50-60 ℃, and may be, but is not limited to, 50 ℃, 52 ℃, 54 ℃, 55 ℃, 56 ℃, 58 ℃ or 60 ℃, and in order to obtain a better effect, the reaction temperature is 55 ℃. The reaction time is 30-90 s, but not limited to 30s, 40s, 50s, 55s, 60s, 70s, 80s or 90s, and in order to obtain a better effect, the reaction time is 60 s.

In the step (1), the atorvastatin tert-butyl ester is mixed with a solvent, and the mixture is stirred until the mixture is clear, so as to obtain a material A, wherein in the solution of the material A, the percentage content of the atorvastatin tert-butyl ester is 10-30%, and the percentage content can be, but is not limited to, 10%, 15%, 20%, 25% or 30%, and is preferably 20%. The solvent selected is methanol, ethanol or isopropanol, preferably methanol.

In a preferred embodiment, when preparing the solution of material a, the atorvastatin tert-butyl ester and the solvent are stirred at 35 to 50 ℃ until the mixture is clear, and the stirring temperature may be, but is not limited to, 35 ℃, 38 ℃, 40 ℃, 42 ℃, 44 ℃, 45 ℃, 46 ℃, 48 ℃ or 50 ℃, and is further preferably 42 to 48 ℃.

In the step (2), sodium hydroxide is added into the purified water, and stirred until the sodium hydroxide is dissolved to be clear, so as to obtain a material B, wherein in the solution of the material B, the percentage content of the sodium hydroxide is 40-60%, and the sodium hydroxide can be, but is not limited to, 40%, 45%, 50%, 55% or 60%, and is preferably 50%.

In a preferable scheme, in the step (3), calcium acetate is added into purified water, stirred to be clear at 42-48 ℃, filtered by a precision filter with a filter element of 0.45 mu m, and prepared into a calcium salt solution, so as to obtain the material C.

For the invention, the continuous flow tubular reactor comprises a preheater I, a preheater II and a preheater III, wherein the preheater I and the preheater II are respectively connected with a feed inlet of the first tubular reactor, and a discharge outlet of the first tubular reactor and the preheater III are respectively connected with a feed inlet of the second tubular reactor.

In the present invention, the reactants are pumped into the continuous flow tubular reactor by a metering pump. The reactor was precisely adjusted for the temperature required for the reaction by means of an external heat exchanger, while the actual temperature of the reaction was measured by means of a thermocouple. During the reaction process, the feeding molar ratio of the reaction materials is controlled by adjusting the flow rate of the counting pump.

Further, a material A is placed in a raw material tank A, a metering pump I is arranged on a pipeline between the raw material tank A and the preheater I, and the feeding speed of the material A is controlled; the material B is placed in a raw material tank B, a metering pump II is arranged on a pipeline between the raw material tank B and the preheater II, and the feeding speed of the material B is controlled; and the material C is placed in the raw material tank C, and a metering pump III is arranged on a pipeline between the raw material tank C and the preheater III to control the feeding speed of the material C. The feeding speed of the material A is controlled by the metering pump I, the feeding speed of the material B is controlled by the metering pump II, and the materials are respectively pumped into the first tubular reactor for reaction, so that the molar ratio of the atorvastatin tert-butyl ester to the sodium hydroxide in the reaction process is controlled. And (3) controlling the feeding speed of the material C by adopting a metering pump III according to the feeding speed of the material A, thereby controlling the molar ratio of the atorvastatin tert-butyl ester to the calcium acetate.

For the continuous flow tubular reactor of the present invention, the reaction temperature is controlled by an external heat exchanger; the heat exchange medium is heat conducting oil or water. In the invention, the tubular reactor is of a spiral tubular structure, which is beneficial to increasing the contact area between reactants so as to ensure more complete reaction; the length of the tubular reactor is determined by the reaction time.

In a preferred embodiment, the material of the first tubular reactor and the second tubular reactor is monocrystalline silicon, ceramic, corrosion-resistant stainless steel, corrosion-resistant alloy or polytetrafluoroethylene.

By adopting the technical scheme of the invention, the advantages are as follows:

the method utilizes the continuous flow tube reactor to synthesize the target product atorvastatin calcium, strictly controls the consumption of reaction materials and the reaction temperature and time in the reaction process, has extremely short time required in the whole reaction process and mild reaction conditions, effectively avoids byproducts generated by overlong reaction time or overhigh reaction temperature, and has the advantages of high target product yield, high purity (more than 96 percent) and high purity (more than 99 percent), low cost, resource saving, simple product post-treatment and environmental friendliness.

Drawings

FIG. 1 is a schematic diagram of the structure of a continuous flow tubular reactor according to the present invention;

the method comprises the following steps of 1-raw material tank A, 2-raw material tank B, 3-raw material tank C, 4-metering pump I, 5-metering pump II, 6-metering pump III, 7-preheater I, 8-preheater II, 9-preheater III, 10-heat exchange medium, 11-first tubular reactor and 12 second tubular reactor.

Detailed Description

The process for synthesizing atorvastatin calcium using a continuous flow tube reactor according to the present invention is further illustrated by the following examples in conjunction with the accompanying drawings, which are not intended to limit the present invention in any way.

Example 1

The length of the tubular reactor is determined according to the reaction time, the heat exchange medium is heat conduction oil, and the outlet of the first tubular reactor is provided with a precision filter.

Preparation of Material A: adding 200g of atorvastatin tert-butyl ester into 800g of methanol, stirring at 42-48 ℃ until the mixture is clear, obtaining a material A, and placing the material A in a stock tank A;

preparing a material B: adding 200g of sodium hydroxide into 200g of purified water, stirring until the sodium hydroxide is dissolved to obtain a material B, and placing the material B into a raw material tank B;

preparation of Material C: adding 30g of calcium acetate into 3.6kg of purified water, stirring until the calcium acetate is dissolved, filtering by a precision filter with a filter element of 0.45 mu m to obtain a material C, and placing the material C into a raw material tank C;

respectively introducing the material A, B into a preheater I and a preheater II for preheating, wherein the set temperature is 20 ℃; respectively controlling the flow rates of the material A and the material B by a metering pump I and a metering pump II to ensure that the feeding molar ratio of the atorvastatin tert-butyl ester to NaOH is 1: 1.5;

simultaneously conveying the materials A, B to a first tubular reactor, mixing at 20 ℃ and carrying out a first-step reaction for 30s, and filtering through a precision filter at an outlet to obtain a first-step reaction product;

introducing the material C into a preheater III for preheating, and simultaneously preheating the reaction product in the first step at the set temperature of 55 ℃;

controlling the flow rate of the material C by a metering pump III to ensure that the feeding molar ratio of the atorvastatin tert-butyl ester to the calcium acetate is 1: 0.6;

simultaneously conveying the reaction product and the material C in the first step into a continuous flow second tubular reactor, mixing at 55 ℃ and carrying out a second-step reaction for 60s, wherein the material flowing out of the outlet of the second tubular reactor is atorvastatin calcium wet product; and cooling the obtained wet product to 25 ℃, centrifuging, spin-drying, pulping for three times by using purified water, and drying in a hot air circulation oven for 30 hours to obtain the atorvastatin calcium finished product, wherein the yield of the finished product is 99.5%, and the purity of the finished product is 99.6%.

The following examples and comparative examples were carried out with only changes in the charge ratio, reaction temperature and reaction time, and the embodied data are shown in Table 1, wherein the reaction parameters of the blank in each example are the same as those disclosed in example 1.

TABLE 1 reaction parameters and Experimental results in examples and comparative examples

As can be seen from table 1, in the reaction process, the target product with high yield and high purity can be obtained only by strictly controlling the addition ratio of the materials, the reaction temperature and the reaction time in the reaction process, otherwise, the reaction conditions are not well controlled, and the target product with high yield and purity cannot be obtained even by using a continuous flow tubular reactor.

Comparative example 9

Adding 300ml of absolute ethyl alcohol into a 1L three-neck flask under stirring, heating 30g of atorvastatin tert-butyl ester, fully dissolving solid at the temperature of T-50 ℃, dropwise adding 10% of potassium hydroxide at the temperature of T-40 ℃ until the pH value of a reaction solution is 9-11, stopping dropwise adding, reacting at the temperature of T-50-55 ℃ for about 1h, and monitoring by TCL to obtain an intermediate product. Then, controlling the temperature to be between 50 and 55 ℃, dropwise adding 103g of 20 percent calcium nitrate solution into the reaction solution, continuously reacting for 30 minutes after the dropwise adding is finished, adding 1.5g of activated carbon, stirring for 30 minutes at constant temperature, stopping heating, cooling to 38 to 42 ℃, starting suction filtration, dropwise adding 300ml of water into the filtrate under stirring, precipitating a large amount of white solid after about 20 minutes of dropwise adding, standing for crystallization for 2 hours, centrifuging, and washing the filter cake with 1L of water to obtain the white solid. The filter cake was dried in vacuo at 35 ℃ for 20 h to give 27.5g of a white solid with a yield of 95.1% and a purity of 94.8%.

The above examples are only intended to illustrate the technical solution of the present invention, but not to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: modifications of the technical solutions described in the foregoing embodiments are still possible, or some technical features may be equivalently replaced; and the modifications or the substitutions do not make the essence of the corresponding technical solutions depart from the scope of the technical solutions of the embodiments of the present invention.