阅读说明：本技术 一种微通道反应器合成匹伐他汀钙中间体的方法 (Method for synthesizing pitavastatin calcium intermediate by using microchannel reactor ) 是由 王鹏 吴作伟 唐焕宇 陆沛传 张春 于 2020-06-03 设计创作，主要内容包括：本发明公开一种微通道反应器合成匹伐他汀钙中间体的方法,所述匹伐他汀钙中间体为7-[2-环丙基-4-(4-氟苯基)-3-喹啉-基]-3,5-二羟基-6-庚酸乙酯,所述方法包括以下步骤：将盐酸羟胺溶解于水、醇和丙酮的混合溶液中,再加入6-[[(1E)-2-环丙基-4-(4-氟苯基)-3-喹啉基]-乙烯基]-2,2-二甲基-1,3-二氧六环-4-乙酸叔丁酯并使其溶解,将得到的溶液进行过滤,然后输入微通道反应器预热模块,预热后的反应液进入反应模块中,收集从冷却模块流出的反应液,再经过萃取、纯化得到匹伐他汀叔丁酯。本发明所述方法有机试剂用量少,收率高。(The invention discloses a method for synthesizing a pitavastatin calcium intermediate by using a microchannel reactor, wherein the pitavastatin calcium intermediate is 7- [ 2-cyclopropyl-4- (4-fluorophenyl) -3-quinolyl-3, 5-dihydroxy-6-ethyl heptanoate, and the method comprises the following steps: dissolving hydroxylamine hydrochloride in a mixed solution of water, alcohol and acetone, adding and dissolving tert-butyl 6- [ [ (1E) -2-cyclopropyl-4- (4-fluorophenyl) -3-quinolyl ] -vinyl ] -2, 2-dimethyl-1, 3-dioxane-4-acetate, filtering the obtained solution, inputting the filtered solution into a preheating module of a microchannel reactor, feeding the preheated reaction liquid into a reaction module, collecting the reaction liquid flowing out of a cooling module, and extracting and purifying to obtain pitavastatin tert-butyl ester. The method has the advantages of less organic reagent consumption and high yield.)

1. A method for synthesizing pitavastatin calcium intermediate by a microchannel reactor, wherein the pitavastatin calcium intermediate is 7- [ 2-cyclopropyl-4- (4-fluorophenyl) -3-quinolin-yl ] -3, 5-dihydroxy-6-heptanoic acid ethyl ester, and the method comprises the following steps: dissolving hydroxylamine hydrochloride in a mixed solution of water, alcohol and acetone, adding and dissolving tert-butyl 6- [ [ (1E) -2-cyclopropyl-4- (4-fluorophenyl) -3-quinolyl ] -vinyl ] -2, 2-dimethyl-1, 3-dioxane-4-acetate, filtering the obtained solution, inputting the filtered solution into a preheating module of a microchannel reactor, feeding the preheated reaction liquid into a reaction module, collecting the reaction liquid flowing out of a cooling module, and extracting and purifying to obtain pitavastatin tert-butyl ester.

2. The method for synthesizing the pitavastatin calcium intermediate by using the microchannel reactor as claimed in claim 1, wherein the alcohol is one or more of methanol, ethanol or isopropanol.

3. The method for synthesizing the pitavastatin calcium intermediate by using the microchannel reactor as claimed in claim 1, wherein the concentration of the ethyl 7- [ 2-cyclopropyl-4- (4-fluorophenyl) -3-quinolin-yl ] -3, 5-dihydroxy-6-heptanoate in the mixed solution before the reaction is 50-150 mg/ml; preferably, the concentration is 50-200 mg/ml; more preferably, the concentration is 50-160 mg/ml.

4. The method for synthesizing pitavastatin calcium intermediate by using the microchannel reactor as claimed in claim 1, wherein the molar ratio of hydroxylamine hydrochloride to ethyl 7- [ 2-cyclopropyl-4- (4-fluorophenyl) -3-quinolin-yl ] -3, 5-dihydroxy-6-heptanoate is (1.5-10): 1; preferably, the molar ratio is (1.5-6): 1.

5. the method for synthesizing pitavastatin calcium intermediate by using the microchannel reactor as claimed in claim 1, wherein the ratio of ethyl 7- [ 2-cyclopropyl-4- (4-fluorophenyl) -3-quinolin-yl ] -3, 5-dihydroxy-6-heptanoate to water before the reaction is 1g:

(1-4) ml; preferably, the mass ratio is 1g (1.4-2) ml.

6. The method for synthesizing pitavastatin calcium intermediate by using the microchannel reactor as claimed in claim 1, wherein the ratio of the ethyl 7- [ 2-cyclopropyl-4- (4-fluorophenyl) -3-quinolin-yl ] -3, 5-dihydroxy-6-heptanoate to the alcohol before the reaction is 1g:

(2-10) ml; preferably, the mass ratio is 1g (3-10) ml.

7. The method for synthesizing the pitavastatin calcium intermediate by using the microchannel reactor as claimed in claim 1, wherein the dosage ratio of the ethyl 7- [ 2-cyclopropyl-4- (4-fluorophenyl) -3-quinolin-yl ] -3, 5-dihydroxy-6-heptanoate to acetone before the reaction is 1g (1-8) ml; preferably, the dosage ratio is 1g (1.5-6) ml.

8. The method for synthesizing the pitavastatin calcium intermediate by using the microchannel reactor as claimed in claim 1, wherein the reaction pressure in the reaction module is 1Mpa to 2 Mpa; preferably, the reaction pressure is 1MPa to 1.5 MPa; the reaction temperature in the reaction module is 50-130 ℃; preferably, the reaction temperature is 70-100 ℃; the reaction residence time is 10 s-400 s; preferably, the reaction residence time is from 15s to 100 s.

9. The method for synthesizing the pitavastatin calcium intermediate by the microchannel reactor as claimed in claim 1, wherein the flow rate of the preheated mixed solution entering the reaction module is 0.5ml/min to 100 ml/min; preferably, the flow rate is 15ml/min to 90 ml/min; more preferably, the flow rate is 15ml/min to 50 ml/min.

10. The method for synthesizing the pitavastatin calcium intermediate by using the microchannel reactor as claimed in claim 1, wherein the cooling module cools the reaction liquid to a temperature of 0-30 ℃; preferably 5 ℃ to 20 ℃.

Technical Field

The invention belongs to the technical field of synthesis of statin lipid-lowering drugs in pharmaceutical and chemical industries, and particularly relates to a method for synthesizing a pitavastatin calcium intermediate by using a microchannel reactor.

Background

Pitavastatin calcium is chemically named as + bis { (3R,5S,6E) -7- [ 2-cyclopropyl-4- (fluorophenyl) quinoline-3-phenyl ] -3, 5-dihydroxy-6-heptenoic acid ethyl ester } calcium salt (2:1), and has the following chemical structural formula:

pitavastatin calcium, the first fully synthetic HMG-CoA reductase inhibitor developed by japan chemical and two companies, xinghe and kakko, belongs to the group of statins, and is mainly used for improving elevated blood cholesterol levels by reducing the ability of the liver to produce cholesterol through inhibition of the liver enzyme chemical book, called HMGCo-a reductase, and is mainly used for treating patients with hypercholesterolemia and familial hypercholesterolemia because of its excellent lipid-lowering effect, and is called "super statin", and there are several methods for hydrolyzing t-butyl ester at this time:

(1) a hydrochloric acid hydrolysis method: patent US2013072688 reports a method for removing a protecting group by using concentrated hydrochloric acid, dissolving pitavastatin isopropyl tert-butyl ester in a mixed solution of acetonitrile and water, adding 35% concentrated hydrochloric acid at normal temperature, neutralizing a reaction solution by using sodium bicarbonate after the reaction is finished, extracting by using ethyl acetate, and finally recrystallizing by using n-hexane to obtain pitavastatin tert-butyl ester, wherein the yield is 88.4%, and the purity is 98.5%.

(2) An oxalic acid hydrolysis method: patent US2012016129 reports a method for removing a protecting group by using an oxalic acid aqueous solution, dissolving pitavastatin isopropyl tert-butyl ester in methanol, adding oxalic acid aqueous solution for reaction at 35 ℃, dissolving and neutralizing with sodium bicarbonate after the reaction is finished, filtering to obtain a crude pitavastatin tert-butyl ester, and recrystallizing with toluene and cyclohexane to obtain pitavastatin tert-butyl ester with yield of 75% and purity of 99.6%.

(3) Hydrolysis of levocamphorsulfonic acid: patent WO2012063254 reports a method for removing a protecting group by using levo-camphorsulfonic acid, dissolving pitavastatin isopropyl tert-butyl ester in a mixed solution of acetonitrile and water, adding levo-camphorsulfonic acid, reacting at room temperature, extracting with ethyl acetate after the reaction is finished, separating an organic phase, concentrating to dryness to obtain a pitavastatin tert-butyl ester crude product, and recrystallizing with n-hexane to obtain the pitavastatin tert-butyl ester with the yield of 75% and the purity of 98.8%.

(4) And (3) hydrolysis of hydroxylamine hydrochloride: patent CN103508946A reports a method for removing protective group by hydroxylamine hydrochloride, which comprises dissolving hydroxylamine hydrochloride in a mixed solution of methanol, acetone and water, adding pitavastatin isopropyl tert-butyl ester, reacting at 70 ℃, concentrating, extracting and purifying the reaction solution after the reaction to obtain pitavastatin tert-butyl ester with yield of 65% and purity of 99.9%.

The four methods which are generally adopted for synthesizing the pitavastatin calcium intermediate 7- [ 2-cyclopropyl-4- (4-fluorophenyl) -3-quinoline-yl ] -3, 5-dihydroxy-6-ethyl heptanoate are taken as a kettle type process, and the following defects are mainly existed:

(1) the concentrated hydrochloric acid used in the first method belongs to dangerous chemicals, has strong corrosivity, has high requirements on equipment and high equipment maintenance cost, is difficult to perform daily operation, storage and transportation, and is generally avoided being used as a production reagent as much as possible in industrial production;

(2) toluene used in the post-treatment of the second method belongs to flammable and explosive toxic chemicals, the protection requirement on production operators is high, certain danger exists in the production process, and the yield of the pitavastatin calcium intermediate produced by the method is low;

(3) the levo-camphorsulfonic acid used in the third method has higher cost and belongs to a sulfur-containing compound, the sulfur-containing waste generated in the production process has larger pressure on environmental protection, and the yield of the pitavastatin calcium intermediate produced by the method is lower;

(4) in the fourth method, a large amount of organic reagents are used in the process of synthesizing the pitavastatin calcium intermediate, and the post-treatment step is long and complicated and has low yield.

The traditional kettle type process also has the problems of long reaction time, poor selectivity, low yield, poor purity, large solvent consumption and the like in the production process.

Disclosure of Invention

The invention aims to provide a method for synthesizing a pitavastatin calcium intermediate by using a microchannel reactor, which has the advantages of low organic reagent consumption and high yield.

The purpose of the invention is realized by the following technical scheme:

a method for synthesizing pitavastatin calcium intermediate by a microchannel reactor, wherein the pitavastatin calcium intermediate is 7- [ 2-cyclopropyl-4- (4-fluorophenyl) -3-quinolyl ] -3, 5-dihydroxy-6-heptanoic acid ethyl ester, and the method comprises the following steps: dissolving hydroxylamine hydrochloride in a mixed solution of water, alcohol and acetone, adding and dissolving tert-butyl 6- [ [ (1E) -2-cyclopropyl-4- (4-fluorophenyl) -3-quinolyl ] -vinyl ] -2, 2-dimethyl-1, 3-dioxane-4-acetate, filtering the obtained solution, inputting the filtered solution into a preheating module of a microchannel reactor, feeding the preheated reaction liquid into a reaction module, collecting the reaction liquid flowing out of a cooling module, and extracting and purifying to obtain pitavastatin tert-butyl ester.

In a specific embodiment, the method specifically comprises: preparing methanol, acetone and process water into a mixed solution according to a certain proportion, dissolving hydroxylamine hydrochloride in the mixed solution, adding a reaction precursor 6- [ [ (1E) -2-cyclopropyl-4- (4-fluorophenyl) -3-quinolyl ] -vinyl ] -2, 2-dimethyl-1, 3-dioxane-4-tert-butyl acetate, dissolving the reaction precursor in the mixed solution, filtering the obtained mixed solution to remove mechanical impurities, pumping the mixed solution into a preheating module of a microchannel reactor through a delivery pump for preheating, then entering a reaction module group, reacting at a certain reaction temperature and retention time, cooling the reaction solution in a cooling module, then flowing out, collecting the mixed solution containing a pitavastatin calcium intermediate, extracting, purifying, and purifying, And purifying to obtain the pitavastatin tert-butyl ester.

The synthesis process has the advantages of effectively reducing the emission of organic waste liquid, reducing the cost, accurately controlling reaction conditions, improving the reaction conversion rate and selectivity, shortening the production period, meeting continuous large-scale industrial production and the like. The reaction process is as follows:

in some embodiments, the alcohol is one or more of methanol, ethanol, or isopropanol.

In some embodiments, the concentration of ethyl 7- [ 2-cyclopropyl-4- (4-fluorophenyl) -3-quinolin-yl ] -3, 5-dihydroxy-6-heptanoate in the mixed solution prior to the reaction is 50 to 150 mg/ml; in some embodiments, the concentration is 50-200 mg/ml, and in some more particular embodiments, the concentration is 50-160 mg/ml.

In some embodiments, the molar ratio of hydroxylamine hydrochloride to ethyl 7- [ 2-cyclopropyl-4- (4-fluorophenyl) -3-quinolin-yl ] -3, 5-dihydroxy-6-heptanoate prior to the reaction is (1.5 to 10): 1; in some embodiments, the molar ratio is (1.5-6): 1; in some more specific embodiments, the molar ratio is (1.5-4): 1.

in some embodiments, the amount of ethyl 7- [ 2-cyclopropyl-4- (4-fluorophenyl) -3-quinolin-yl ] -3, 5-dihydroxy-6-heptanoate to water prior to the reaction is 1g (1-4) ml; in some embodiments, the mass ratio is 1g (1.4-2) ml.

In some embodiments, the amount of ethyl 7- [ 2-cyclopropyl-4- (4-fluorophenyl) -3-quinolin-yl ] -3, 5-dihydroxy-6-heptanoate to alcohol prior to reaction is 1g (2-10) ml; in some embodiments, the mass ratio is 1g (3-10) ml.

In some embodiments, the amount of ethyl 7- [ 2-cyclopropyl-4- (4-fluorophenyl) -3-quinolin-yl ] -3, 5-dihydroxy-6-heptanoate to acetone prior to the reaction is 1g (1.5 to 8) ml; in some embodiments, the amount ratio is 1g (1.8-6) ml.

In some embodiments, the reaction pressure in the reaction module is between 1Mpa and 2 Mpa; in some embodiments, the reaction pressure is between 1MPa and 1.5 MPa.

In some embodiments, the reaction temperature in the reaction module is from 50 ℃ to 130 ℃; in some embodiments, the reaction temperature is from 70 ℃ to 100 ℃.

In some embodiments, the reaction residence time in the reaction module is from 10s to 400 s; in some embodiments, the reaction residence time is from 15s to 100 s; in some more specific embodiments, the reaction residence time is from 25s to 100 s.

In some embodiments, the flow rate of the preheated mixed solution entering the reaction module is 0.5ml/min to 100 ml/min; in some embodiments, the flow rate is 15ml/min to 90 ml/min; in some more specific embodiments, the flow rate is 15ml/min to 50 ml/min.

In some embodiments, the cooling module cools the reaction solution to a temperature of 0 ℃ to 30 ℃, and in some embodiments, 5 ℃ to 20 ℃.

Experiments prove that under the preferable conditions, the yield can be greatly improved, the organic reagent dosage can be effectively reduced, and the production cost can be obviously reduced, while under the non-preferable conditions, the problems of poor reaction selectivity, low raw material conversion rate, increased impurities, reduced product yield, reduced quality, increased production cost and the like can occur.

The microchannel reactor in the method is also called a microreactor and mainly comprises a preheating module, a reaction module group, a cooling module, a material delivery pump and other auxiliary supporting facilities; the preheating module is connected in series with the reaction module group, the reaction module group is connected in series with the cooling module, the reaction units of the reaction module group need to select the number of the reaction modules according to the concentration, the feeding speed, the residence time and the like of reaction materials and adopt a series or parallel connection mode for combination, for example, the reaction module group determines the series or parallel connection combination of any number of 1-10 reaction modules according to the concentration, the feeding speed, the residence time and the like of the reaction materials. For example, 5 unit module combinations are taken as an example, the mixed solution is pumped into a preheating module 1 through a delivery pump for preheating, then enters a reaction module 2-4 for reaction, and finally is cooled by a cooling module 5 to flow out, and the flowing out reaction solution is a solution of pitavastatin calcium intermediate 7- [ 2-cyclopropyl-4- (4-fluorophenyl) -3-quinolyl ] -3, 5-dihydroxy-6-ethyl heptanoate, wherein the cooling module is used for cooling the high-temperature reaction solution so as to prevent the reaction solution from continuing to react after flowing out and facilitate the post-treatment of the reaction solution.

The microchannel reactor can adopt a straight structure with one inlet and one outlet or a heart-shaped structure module with two inlets and one outlet, wherein the straight structure with one inlet and one outlet means that the first group of unit modules in the structure module only has one inlet and one outlet, and can be called as a one-inlet and one-outlet structure module; a two-in one-out heart-shaped structural module means that a first group of unit modules in the module has two inlets and one outlet, and can be called a two-in one-out structural module. The mixed liquid before reaction is pumped into the preheating module through the reactor inlet by the material conveying pump, then enters the next unit module through the reaction module group inlet, and finally flows out of the cooling module.

In the flow microchannel reactor described in the method of the present invention, the material of the reaction module includes, but is not limited to, silicon carbide, special glass, ceramic, stainless steel metal or metal alloy (such as titanium alloy) coated with a corrosion-resistant coating, polytetrafluoroethylene, etc. which are conventional in the art, and the microchannel reactor can be assembled by connecting a plurality of reaction modules in series or in parallel. The maximum safe pressure which can be borne by the reactor is different according to different materials of the reactor, and the range of the maximum safe pressure is 1.0-4.0 MPa.

The invention has the beneficial effects that:

the method synthesizes the 7- [ 2-cyclopropyl-4- (4-fluorophenyl) -3-quinoline-yl ] -3, 5-dihydroxy-6-heptanoic acid ethyl ester by using a microchannel reactor for the first time. The synthesis method and the microchannel reactor are different from other synthesis methods and conventional tank reactors, including reaction mechanism, equipment appearance, structure, volume, working mechanism and the like, and overcome the defects of other synthesis methods and tank reactors, and have the following advantages:

(1) the organic reagents used in the method are common reagents, the hydroxylamine hydrochloride used is also an industrial common chemical, and compared with concentrated hydrochloric acid, levo-camphorsulfonic acid and the like used in other methods, the method has the advantages of simpler storage and transportation, more environmental friendliness and the like;

(2) compared with the kettle type process, the continuous flow process omits the step of concentrating the reaction liquid after the reaction is finished, simplifies the production flow, saves the time for mass production, can effectively reduce the usage amount of organic reagents, reduces the production cost, reduces the generation amount of three wastes, and effectively controls the cost and the generation of the three wastes;

(3) compared with a kettle type reactor, the micro-channel reactor has smaller volume, can reduce the occupied area in the actual production, save the space, reduce the working strength of operators, reduce the production cost and the like; when the microchannel reactor works, the liquid holding volume of each unit module is only hundreds of milliliters at most, and each unit module adopts a serial or parallel connection independent working mode, so that the risks of leakage, combustion and explosion in production can be reduced to a great extent;

(4) the unique internal structure of the reaction module can greatly increase the effects of mass transfer and heat transfer in the reaction, thereby effectively shortening the reaction time, improving the reaction conversion rate and selectivity, inhibiting the generation of impurities and improving the quality and yield of products;

(5) the microchannel reactor is made of various materials, such as silicon carbide, special glass, polytetrafluoroethylene, stainless steel, titanium alloy and the like, and suitable materials can be selected for different reaction types in production, so that the production cost can be effectively reduced;

(6) the microchannel reactor adopts a closed mode in the working process, can bear larger pressure, and can work at the reaction temperature higher than the boiling point of a solvent, for example, a mixed solution of methanol, acetone and water is used as the solvent, when the reaction temperature reaches 60 ℃ in a traditional reaction kettle, a reaction system is refluxed and boiled, and the reaction temperature in the microchannel reactor can reach 130 ℃;

(7) the reaction selectivity can be effectively improved through the parameters such as the flow rate, the reaction temperature and the like, the generation of impurities is greatly inhibited, and the purity of the product obtained by the method can reach more than 99.5 percent through the reaction parameters.

Drawings

FIG. 1 is a schematic view of a microchannel reactor according to the present invention.

Detailed Description

In the following embodiments, the method includes a tank process and a continuous flow process for synthesizing pitavastatin calcium intermediate, the microchannel reactor includes a feeding system, a temperature control system, a preheating module, a reaction module group, a cooling module, and the like, wherein the reaction module group includes one or more reaction modules connected in series, and the preheating module, the reaction module, and the cooling module are all heart-shaped structures. The conveying of materials in the invention is metered and controlled by a delivery pump, mixed liquid before reaction is pumped into a reactor preheating module by an infusion pump and then enters a reaction module group, reaction liquid enters a cooling module after the reaction is finished, and solution containing pitavastatin calcium intermediate flows out of the cooling module after the temperature is reduced. The following describes in detail the synthesis of pitavastatin calcium intermediate using a microchannel reactor. A picture of a microchannel reactor used in the following examples can be seen in fig. 1.

Comparative example 1: method for synthesizing pitavastatin calcium by using reaction kettle

Weighing 5g of hydroxylamine hydrochloride (0.07mol) and 10g of 7- [ 2-cyclopropyl-4- (4-fluorophenyl) -3-quinolin-yl ] -3, 5-dihydroxy-6-heptanoic acid ethyl ester (molecular weight: 517.637, 0.0193mol) which are dissolved in a mixed solution of methanol, acetone and purified water, wherein the amount of the methanol is 100ml, the amount of the acetone is 80ml, the amount of the purified water is 18ml, heating the mixed solution to 65 ℃, tracking the reaction process by using an HPLC (high performance liquid chromatography) plate, completely reacting the raw materials after 6 hours of reaction, removing an organic reagent by vacuum concentration, extracting and purifying to obtain 6.0g of pitavastatin calcium intermediate 7- [ 2-cyclopropyl-4- (4-fluorophenyl) -3-quinolin-yl ] -3, 5-dihydroxy-6-heptanoic acid ethyl ester, the yield is 65 percent, and the purity is 90 percent.