CN114524801A - Method for efficiently producing esomeprazole sodium based on mobile phase - Google Patents

Method for efficiently producing esomeprazole sodium based on mobile phase Download PDF

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CN114524801A
CN114524801A CN202210072823.XA CN202210072823A CN114524801A CN 114524801 A CN114524801 A CN 114524801A CN 202210072823 A CN202210072823 A CN 202210072823A CN 114524801 A CN114524801 A CN 114524801A
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ionic liquid
chitosan
esomeprazole sodium
chiral
product
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朱磊
张瑶瑶
李博解
曾艺
杨三明
陈舒晗
张泽浪
赵雪
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HUBEI MERRYCLIN PHARMACEUTICAL CO Ltd
Hubei Engineering University
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HUBEI MERRYCLIN PHARMACEUTICAL CO Ltd
Hubei Engineering University
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Abstract

The invention discloses a method for efficiently producing esomeprazole sodium based on a mobile phase, which mainly comprises the following steps: s1, preparing a chitosan supported chiral ionic liquid titanium catalyst, and filling the catalyst into a microchannel reactor; s2, continuously injecting two raw materials of omeprazole thioether and hydrogen peroxide solution with the mass fraction of 30 wt.% into the microchannel reactor in proportion to continuously carry out oxidation reaction; s3, the product passes through the micro-channel to obtain the chiral (S) -omeprazole medicine with high yield and high enantioselectivity; s4, collecting the product, dissolving the product in an organic solvent, and alkalifying the product by using sodium hydroxide to obtain a crude product of esomeprazole sodium; s5, removing impurities by using activated carbon, and purifying to obtain the refined esomeprazole sodium. The method realizes the preparation of the esomeprazole sodium refined product under the conditions of room temperature, greening and environmental protection, the yield of the esomeprazole sodium can reach 98.5%, the enantioselectivity can reach 99%, and the catalyst can be recycled for multiple times.

Description

Method for efficiently producing esomeprazole sodium based on mobile phase
Technical Field
The invention relates to the technical field of medicinal chemistry, in particular to a method for efficiently producing esomeprazole sodium based on a mobile phase.
Background
Gastric ulcer is a chronic digestive system disease with high clinical morbidity and recurrence rate, and can cause complications such as gastric perforation, gastrorrhagia, canceration and the like. The proton pump inhibitor is the most advanced medicine for treating the peptic gastric ulcer at present, and in the current proton pump inhibitors on the domestic market, the esomeprazole sodium is most widely applied and has the advantages of quick response, strong action, longer duration and the like. Omeprazole is a mixture of two optical isomers 1:1, R and S, and the S optical isomer is esomeprazole.
The existing methods for preparing esomeprazole sodium are mainly divided into an inclusion resolution method (CN-01087739) and an asymmetric oxidation method. The method for resolution of the esomeprazole is mainly to obtain esomeprazole from the prepared omeprazole through resolution of the inclusion or resolution of the esomeprazole through simulated moving bed chromatography, does not generate chemical reaction, is formed only through intermolecular force, and achieves the purpose of separation in modes of easy column passing, solvent exchange and the like. However, the column-passing method limits the yield of the preparation of esomeprazole sodium and limits the industrial production efficiency thereof. The other method is an asymmetric catalytic oxidation method (such as WO9602535, WO03/089408), and the another method is salt-forming preparation with a sodium hydroxide solution, wherein the key point is to prepare the catalyst with low cost and excellent performance, obtain chiral single S-omeprazole through asymmetric catalysis, and determine the configuration and purity of the product by adopting various characterization means. This method also has obvious drawbacks: 1) the chiral ligand is used in too large amount, even reaching the chemical dose; 2) the use of relatively expensive cumene peroxide (CHP); 3) large amounts of special organic bases are required: diisopropylethylamine, which adds cost and operational complexity.
The selective oxidant cumene peroxide (CHP) is replaced by hydrogen peroxide, m-chloroperoxybenzoic acid (m-CPBA), sodium peroxide and the like, the Ee value of the reaction liquid is obviously reduced (Ee is enantioselectivity), and the aim of selectively oxidizing into (S) -type isomer can not be achieved, and currently, more conventional synthetic methods are reported, and the specific route is as follows:
Figure BDA0003482904020000021
if the crude esomeprazole free alkali product prepared after selective oxidation is directly used for preparing esomeprazole sodium, according to the process method, the isomer is about 2% and has only 93% purity, when mixed solvents of methanol and isopropyl ether are selected and refined, the yield is not high, the process is unstable, the isomer is sometimes removed and sometimes cannot be removed, although the route of the conventional method for preparing the esomeprazole sodium salt is short, the actual amplification operation yield is low, the quality stability of the finished product is difficult to guarantee, and the patent CN103044402B selects cumene hydroperoxide for chiral oxidation reaction. The yield of the chiral oxidation reaction is not more than 85%, and a strong oxidant, namely diisopropylamine, is used, so that the chiral oxidation reaction has certain toxicity.
Patent CN1810803B reports the use of a chiral bidentate ligand, titanium tetraisopropoxide (Ti (O)iPr)4) Omeprazole sulfide, an oxidizing agent (TBHP: tert-butyl hydroperoxide and CHP) to obtain the omeprazole. Although this reaction route does not use an organic base, it requires the use of a relatively expensive organic oxidizing agent and a special ligand.
The preparation method of esomeprazole sodium in the existing patent report completes one-time production by one-time feeding, has the problems of discontinuous production, low efficiency and the like, and restricts the production benefits of companies.
Disclosure of Invention
The invention aims to overcome the technical defects, provides a method for efficiently producing esomeprazole sodium based on a mobile phase, and solves the technical problem of the yield of the esomeprazole sodium prepared in the prior art.
In order to achieve the technical purpose, the technical scheme of the invention provides a method for efficiently producing esomeprazole sodium based on a mobile phase, which comprises the following steps:
a method for efficiently producing esomeprazole sodium based on a mobile phase comprises the following steps:
s1, filling the chitosan-supported chiral ionic liquid titanium catalyst into a microchannel reactor;
s2, continuously injecting the raw material omeprazole thioether and hydrogen peroxide solution with the mass fraction of 25-35 wt% into the microchannel reactor simultaneously for oxidation reaction;
s3, completing the reaction in the microchannel reactor to obtain the chiral (S) -omeprazole drug;
s4, collecting the product, dissolving the product in an organic solvent, and alkalifying the product by using sodium hydroxide to obtain a crude product of esomeprazole sodium;
s5, removing impurities by using activated carbon, and purifying to obtain refined esomeprazole sodium;
the general formula of the chitosan supported chiral ionic liquid titanium catalyst is as follows:
Figure BDA0003482904020000031
in formula (1), each independently represents an R configuration or an S configuration, and both are the same;
CS is chitosan;
R1selected from hydrogen, alkyl, aryl substituted alkyl;
R2selected from a hydrogen atom or an alkyl group;
R3is selected from C1～C16Alkyl or substituted aryl of (a);
the structural formula of the raw material omeprazole thioether is as follows:
Figure BDA0003482904020000041
compared with the traditional homogeneous catalyst, the catalytic activity of the heterogeneous catalyst is generally not superior to that of the homogeneous catalyst for the same reaction. The chitosan supported chiral ionic liquid titanium catalyst adopted in the technical scheme contains ionic liquid, and the ionic liquid has good intermiscibility to an oil phase and a water phase, so that the catalyst can be well contacted with an organic reaction substrate and a water system oxidant. The catalyst reduces the mass transfer resistance in the reaction process and accelerates the reaction; and because the catalyst is a heterogeneous catalyst, the concentration of local reaction can be improved, so that the catalytic activity higher than that of the homogeneous catalyst is realized, and the catalyst can be separated and recovered from a liquid phase for recycling. Specifically, in step S1, the preparation method of the chitosan supported chiral ionic liquid titanium catalyst includes:
a) reacting 1-vinyl imidazole with bromopropionic acid to generate a double-bond ionic liquid compound containing carboxylic acid groups: 1-vinyl-3-propionylimidazolium bromide;
b) and reacting the double-bond ionic liquid compound containing carboxylic acid groups with chitosan dissolved in dilute acid solution to obtain chitosan functionalized vinyl ionic liquid II, wherein the general formula of the chitosan functionalized vinyl ionic liquid II is as follows:
Figure BDA0003482904020000042
c) reacting the obtained chitosan functionalized vinyl ionic liquid II with chiral amino acid to obtain the chitosan functionalized chiral amino acid vinyl ionic liquid, wherein the reaction formula is as follows:
Figure BDA0003482904020000051
d) and based on a controlled fragmentation-chain transfer radical polymerization (RAFT) method, taking azobisisobutyronitrile as a chain initiator and carbon thioester as a molecular weight regulator, and controllably polymerizing the chitosan-functionalized chiral amino acid vinyl ionic liquid obtained in the step c) to generate a polymer, wherein the carbon thioester has the following general formula:
Figure BDA0003482904020000052
the reaction formula of the polymer polymerized by the controllable fragmentation-chain transfer free radical polymerization method is as follows:
Figure BDA0003482904020000053
e) complexing the polymer obtained in the step d) with metal titanium salt to obtain the chitosan supported chiral ionic liquid titanium catalyst.
According to the technical scheme, the chitosan with wide sources is used as a carrier, and the high-performance and sustainable catalyst is prepared by utilizing the characteristics of the superior performance of the ionic liquid and the cheap and easily available natural chiral amino acid.
In particular, in step c), the chiral amino acid used is a natural chiral L-amino acid.
Specifically, the method comprises the following steps: the chiral amino acid is selected from L-proline, L-phenylalanine, L-leucine, L-histidine and L-isoleucine.
Specifically, in step (e), the metal titanium salt used is titanium tetraisopropoxide.
Specifically, in step S2, the raw material omeprazole thioether and the hydrogen peroxide solution with the mass fraction of 25-35 wt% are mixed in a ratio of 1: 1.2 continuously injecting into a micro-channel reactor for oxidation reaction. Preferably, a 25-35 wt% hydrogen peroxide solution is used.
Specifically, in step S2, the solvent used in the reaction is water, and the flow rate of the solution is 1-3 mL/min.
Specifically, in step S2, the temperature in the reactor is maintained at room temperature.
Specifically, in step S4, the organic solvent is dichloromethane, absolute ethanol, tetrahydrofuran, toluene, or the like.
Specifically, in step S5, R3Selected from isopropyl, isobutyl, tert-butyl or benzyl.
Compared with the prior art, the invention has the advantages that:
the chitosan supported chiral ionic liquid titanium catalyst is adopted to catalyze, esomeprazole sodium can be efficiently produced in a continuous mobile phase, the yield can reach 98.5 percent under the room temperature condition, the enantioselectivity can reach 99 percent, and the catalyst can be recycled for multiple times. While the yield of the (S) -omeprazole medicine prepared by using the chiral L-proline titanium catalyst of the polyionic liquid without loading chitosan is 46.7 percent, and the enantioselectivity is 84.2 percent.
Drawings
FIG. 1 shows nuclear magnetism of esomeprazole sodium of the present invention1H NMR spectrum;
FIG. 2 shows nuclear magnetism of esomeprazole sodium of the present invention13C NMR spectrum.
Detailed Description
The specific embodiment provides a method for efficiently producing esomeprazole sodium based on a mobile phase, which comprises the following steps:
s1, preparing a high-efficiency chitosan supported chiral ionic liquid titanium catalyst, and filling the catalyst into a microchannel reactor; the preparation route of the catalyst is as follows: reacting vinyl imidazole with bromopropionic acid to generate double-bond ionic liquid containing carboxylic acid groups, then reacting with chitosan to obtain chitosan functionalized vinyl ionic liquid, reacting the obtained chitosan functionalized vinyl ionic liquid with chiral amino acid to obtain chitosan functionalized chiral amino acid vinyl ionic liquid, then carrying out polymerization reaction to generate a polymer, and finally complexing with metal titanium salt to obtain the chitosan functionalized polyionic liquid chiral amino acid titanium catalyst.
S2, continuously introducing two raw materials of omeprazole thioether and a hydrogen peroxide solution with the mass fraction of 30 wt.% into the microchannel reactor at the pressure of 100-120 KPa through a mechanical pump, wherein the ratio is 1: 1.2, continuously injecting the mixture into a microchannel reactor for oxidation reaction;
s3, collecting the product at the sample outlet after the product passes through the micro-channel to obtain the chiral (S) -omeprazole medicine with high yield and high enantioselectivity;
s4, dissolving the collected product in an organic solvent, and alkalifying with sodium hydroxide to obtain a crude esomeprazole sodium product;
and S5, removing impurities by using activated carbon, and purifying to obtain the refined esomeprazole sodium.
For safety reasons, setting the pressure in the microchannel reactor to be more than 120KPa or the temperature to be more than 110 ℃, an alarm is given, the input of gas and liquid is stopped, and the heating is stopped.
The structural formula of the raw material omeprazole thioether is as follows:
Figure BDA0003482904020000071
the structural formula of the product (S) -omeprazole is as follows:
Figure BDA0003482904020000072
the yield of the product prepared by the microchannel reactor is more than 98.5 percent, the enantioselectivity is more than 99 percent, and the product can be directly produced in the next step. The dosage of the raw material compound omeprazole thioether and the oxidant hydrogen peroxide is well controlled, and the reaction can not generate the by-product omeprazole sulfone through peroxidation.
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is described in further detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
Example 1
The specific embodiment provides a method for efficiently producing esomeprazole sodium based on a mobile phase, which comprises the following synthetic route and steps:
wherein, the chitosan ionic liquid type chiral amino acid titanium catalyst has a structure of a general formula (1):
Figure BDA0003482904020000081
in formula (1) of the present embodiment:
CS is chitosan;
R1corresponding L-proline, in particular tetrahydropyrrole; correspondingly, both are in S configuration;
R2and R3Corresponding to the benzyl thiopropionate, the specific structure of the benzyl thiopropionate is as follows:
Figure BDA0003482904020000082
s1, preparing the efficient chitosan supported chiral ionic liquid titanium catalyst: adding 10mmol of redistilled 3-bromopropionic acid and 10ml of acetonitrile as a solvent into a 250ml three-neck flask, slowly dropwise adding 1.1mmol of 1-vinyl imidazole by using a constant-pressure dropping funnel under the condition of heating reflux at 80 ℃, refluxing under magnetic stirring at 60 ℃, reacting for 5h, extracting twice (2X 10ml) by using anhydrous ether after the reaction is finished, taking off the yellow oily substance on the lower layer, and drying in vacuum at 70 ℃ for 24h to obtain yellow thick liquid, namely a double-bond ionic liquid compound containing carboxylic acid groups: 1-vinyl-3-propionylimidazolium bromide, the structure of which is shown below:
Figure BDA0003482904020000091
dissolving the newly prepared 1-vinyl-3-propionic acid imidazole bromide and 1g of chitosan in a dilute acid solution for reacting for 24h to obtain the ionic liquid containing chitosan. The 1-vinyl-3-propionylimidazolium bromide modified chitosan retains hydroxyl and partial unsubstituted amino of chitosan and newly added imidazole group with pH responsiveness to obtain chitosan functionalized vinyl ionic liquid II:
Figure BDA0003482904020000092
slowly dropwise adding the obtained aqueous solution of 10mmol of chitosan functionalized vinyl ionic liquid II and 10mmol of L-proline into a flask, tracking by TLC, and reacting in the following formula 1:
Figure BDA0003482904020000093
obtaining the chitosan functionalized chiral L-proline vinyl ionic liquid, continuously stirring at room temperature for reaction for 15h, then using a rotary evaporator to spin dry the solvent, drying the liquid in vacuum, and then adding methanol: acetonitrile 9: 1, stirring vigorously at room temperature for 2h to separate out unreacted amino acid, filtering, spin-drying the solvent, and vacuum-drying at 80 ℃ for 24h to obtain the pure product.
Dissolving the prepared chitosan functionalized chiral L-proline vinyl ionic liquid (5mmol) in anhydrous methanol, adding benzyl thiopropionate (chain transfer agent, 1/6mmol,0.0330g) and AIBN (chain initiator, 1/30mmol, 0.0052g) into the reaction solution, and adding N2And under protection, placing the reaction solution in a Schlenk tube for reaction at 60 ℃ for 24h, after the reaction is finished, concentrating the reaction solution in vacuum to obtain a light yellow solid product, and drying in vacuum at 30 ℃ to obtain the polymer.
4mmol of the polymer prepared above was dissolved in 30m l anhydrous dichloromethane, and 2mmol of a metal titanium salt (tetraisopropyl titanate) was added thereto, followed by reflux reaction for 3 hours. After the reaction is finished, spin-drying the solvent, and vacuum-drying at 30 ℃ to obtain the chiral L-proline titanium catalyst of the chitosan functionalized ionic liquid:
Figure BDA0003482904020000101
infrared characterization of the product: FT-IR (KBr) < gamma >max/cm-13406 (characteristic peak of-OH in L-proline), 3365 (characteristic peak of-NH-stretching vibration in chitosan), 3152,2961,1645 (characteristic peak of-C ═ O in L-proline), 1623 (characteristic peak of-NH-stretching vibration in L-proline), 1565 (framework vibration of imidazole ring in ionic liquid), 1463 (characteristic peak of-NH-stretching vibration in imidazole ionic liquid)Methylene oscillation characteristic peak), 1377,1335,1163 (imidazole ring skeleton stretching oscillation), 1106,1023,904 (Ti-O characteristic peak in complex), 893 (stretching oscillation peak of chitosan ring), 708 (Ti-O characteristic peak in complex), 646 (imidazole ring characteristic peak) cm-1。
The heterogeneous catalyst structure contains the ionic liquid, and the ionic liquid has good intermiscibility with an oil phase and a water phase, so that an organic reaction substrate and a water system oxidant can be well contacted. Therefore, the catalyst reduces the mass transfer resistance in the reaction process, accelerates the reaction, can use a cheaper and easily obtained water system oxidant, and the heterogeneous catalyst in the application can improve the concentration of the titanium tetraisopropoxide which is locally complexed with the chiral ligand, thereby showing higher catalytic activity than the homogeneous catalyst, and in addition, the heterogeneous catalyst is easy to recover and can be recycled.
S2, filling a chitosan-supported chiral ionic liquid titanium catalyst into a microchannel reactor, and continuously introducing two raw materials, namely omeprazole thioether and a hydrogen peroxide solution with the mass fraction of 30 wt.% into the microchannel reactor at the pressure of 100-120 KPa through a mechanical pump, wherein the ratio is 1: 1.2, continuously injecting the mixture into a microchannel reactor for oxidation reaction;
s3, collecting the product at the sample outlet after the product passes through the micro-channel to obtain the chiral (S) -omeprazole medicine with high yield and high enantioselectivity;
s4, dissolving the collected product in an organic solvent, and alkalifying with sodium hydroxide to obtain a crude esomeprazole sodium product;
and S5, removing impurities by using activated carbon, and purifying to obtain the refined esomeprazole sodium.
The yield of the prepared chiral (S) -omeprazole medicine is 98.5 percent, and the enantioselectivity is 99 percent.
The hydrogen spectrum and carbon spectrum of the (S) -omeprazole drug are shown in figure 1 and figure 2 respectively, and the solvent is deuterated chloroform, which indicates that the (S) -omeprazole drug is successfully prepared.
The preparation method of example 1 was repeated 20 times without replacing the heterogeneous catalyst in the same microchannel reactor, and the yields of the prepared (S) -omeprazole drug were all over 96%.
Example 2
The embodiment provides a second preparation method for efficiently producing esomeprazole sodium, which comprises the following steps:
preparing an efficient chitosan supported chiral ionic liquid titanium catalyst: reacting 5mol of vinylimidazole with 5mol of bromopropionic acid according to step S1 of example 1 to generate a double-bond ionic liquid containing carboxylic acid groups, reacting with 5mol of chitosan to obtain a chitosan-functionalized vinylic ionic liquid, reacting the obtained chitosan-functionalized vinylic ionic liquid with L-phenylalanine to obtain a chitosan-functionalized chiral L-phenylalanine vinylic ionic liquid, then performing reversible addition polymerization reaction, using a chain transfer agent (benzyl thiopropionate, 1/6mmol,0.0330g), a chain initiator (AIBN, 1/30mmol, 0.0052g) to generate a polymer, and finally complexing with a metal titanium salt to obtain a chiral L-phenylalanine titanium catalyst of the chitosan-functionalized polyionic liquid, and performing infrared characterization on the product: FT-IR (KBr) < gamma >max/cm-13407 (characteristic peak of-OH in L-phenylalanine), 3362 (characteristic peak of-NH-stretching vibration in chitosan), 3150,2926 (characteristic peak of-CH in L-phenylalanine)2-characteristic peak), 1647 (characteristic peak of-C ═ O in L-phenylalanine), 1625 (characteristic peak of-NH-stretching vibration in L-phenylalanine), 1563 (vibration of imidazole ring skeleton in ionic liquid), 1460 (characteristic peak of methylene vibration in imidazole ionic liquid), 1375,1334,1165 (stretching vibration of imidazole ring skeleton), 1106,1024,902 (characteristic peak of Ti-O in complex), 895 (characteristic peak of stretching vibration of chitosan ring), 710 (characteristic peak of Ti-O in complex), 645 (characteristic peak of imidazole ring) cm-1. The product is shown as formula 1, R1Is benzyl.
S2, filling a chitosan-supported chiral ionic liquid titanium catalyst into a microchannel reactor, and continuously introducing two raw materials, namely omeprazole thioether and a hydrogen peroxide solution with the mass fraction of 30 wt.% into the microchannel reactor at the pressure of 100-120 KPa through a mechanical pump, wherein the ratio is 1: 1.2, continuously injecting the mixture into a microchannel reactor for oxidation reaction;
s3, collecting the product at the sample outlet after the product passes through the micro-channel to obtain the chiral (S) -omeprazole medicine with high yield and high enantioselectivity;
s4, dissolving the collected product in an organic solvent, and alkalifying with sodium hydroxide to obtain a crude esomeprazole sodium product;
and S5, removing impurities by using activated carbon, and purifying to obtain the refined esomeprazole sodium.
The yield of the prepared chiral (S) -omeprazole medicine is 98 percent, and the enantioselectivity is 99 percent.
The hydrogen spectrum and carbon spectrum of the (S) -omeprazole drug are shown in figure 1 and figure 2 respectively, and the adopted solvent is deuterated chloroform, which indicates that the (S) -omeprazole drug is successfully prepared.
The preparation method of example 1 was repeated 20 times without replacing the heterogeneous catalyst in the same microchannel reactor, and the yields of the prepared (S) -omeprazole pharmaceutical products were all above 95%.
Example 3
The embodiment provides a third preparation method for efficiently producing esomeprazole sodium, which comprises the following steps:
preparing an efficient chitosan supported chiral ionic liquid titanium catalyst: reacting 5mol of vinylimidazole with 5mol of bromopropionic acid according to step S1 of example 1 to generate a double-bond ionic liquid containing carboxylic acid groups, reacting with 5mol of chitosan to obtain a chitosan-functionalized vinylic ionic liquid, reacting the obtained chitosan-functionalized vinylic ionic liquid with L-leucine to obtain a chitosan-functionalized chiral L-leucine vinylic ionic liquid, then performing reversible addition polymerization reaction, using a chain transfer agent (benzyl thiopropionate, 1/6mmol,0.0330g), a chain initiator (AIBN, 1/30mmol, 0.0052g) to generate a polymer, and finally complexing with a metal titanium salt to obtain the chitosan-functionalized polyionic liquid chiral L-leucine titanium catalyst shown in formula 1. Infrared characterization of the product: FT-IR (KBr) < gamma >max/cm-13395 (characteristic peak of-OH in L-leucine), 3368 (characteristic peak of-NH-stretching vibration in chitosan), 3156,2923 (characteristic peak of-CH in L-phenylalanine)2-characteristic peak), 1694 (characteristic peak of-C ═ O in L-leucine), 1620 (characteristic peak of-NH-stretching vibration in L-leucine), 1566 (imidazole ring skeleton vibration in ionic liquid), 1463 (characteristic peak of methylene vibration in imidazole ionic liquid)1374,1337,1163 (imidazole ring skeleton stretching vibration), 1104,1022,904 (Ti-O characteristic peak in complex), 890 (stretching vibration peak of chitosan ring), 709 (Ti-O characteristic peak in complex), 643 (imidazole ring characteristic peak) cm-1. The product is shown as formula 1, R1Is a tert-butyl group.
S2, filling a chitosan-supported chiral ionic liquid titanium catalyst into a microchannel reactor, and continuously introducing two raw materials, namely omeprazole thioether and a hydrogen peroxide solution with the mass fraction of 30 wt.% into the microchannel reactor at the pressure of 100-120 KPa through a mechanical pump, wherein the ratio is 1: 1.2, continuously injecting the mixture into a microchannel reactor for oxidation reaction;
s3, collecting the product at the sample outlet after the product passes through the microchannel to obtain the chiral (S) -omeprazole medicine with high yield and high enantioselectivity;
s4, dissolving the collected product in an organic solvent, and alkalifying with sodium hydroxide to obtain a crude esomeprazole sodium product;
and S5, removing impurities by using activated carbon, and purifying to obtain the refined esomeprazole sodium.
The yield of the prepared chiral (S) -omeprazole medicine is 97 percent, and the enantioselectivity is 99 percent.
The hydrogen spectrum and carbon spectrum of the (S) -omeprazole drug are shown in figure 1 and figure 2 respectively, and the adopted solvent is deuterated chloroform, which indicates that the (S) -omeprazole drug is successfully prepared.
The preparation method of example 1 was repeated 20 times without replacing the heterogeneous catalyst in the same microchannel reactor, and the yields of the prepared (S) -omeprazole drugs were all over 96%.
Example 4
The embodiment provides a fourth preparation method for efficiently producing esomeprazole sodium, which comprises the following steps:
preparing an efficient chitosan supported chiral ionic liquid titanium catalyst: reacting 5mol of vinylimidazole with 5mol of bromopropionic acid according to step S1 of example 1 to generate a carboxylic acid group-containing double-bond ionic liquid, reacting with 5mol of chitosan to obtain a chitosan-functionalized vinylic ionic liquid, and reacting the obtained chitosan-functionalized vinylic ionic liquidReacting the product with L-histidine to obtain a chitosan functionalized chiral L-histidine vinyl ionic liquid, then carrying out reversible addition polymerization reaction, generating a polymer by using a chain transfer agent (benzyl thiopropionate, 1/6mmol,0.0330g) and a chain initiator (AIBN, 1/30mmol, 0.0052g), and finally complexing with a metal titanium salt to obtain a chitosan functionalized polyion liquid chiral L-histidine titanium catalyst, wherein the formula is shown in formula 1. Infrared characterization of the product: FT-IR (KBr) < gamma >max/cm-13392 (characteristic peak of-OH in L-histidine), 3365 (characteristic peak of-NH-stretching vibration in chitosan), 3153,3054 (characteristic peak of-CH in L-histidine)2-characteristic peak), 1696 (characteristic peak of-C ═ O in L-histidine), 1624 (characteristic peak of-NH-stretching vibration in L-histidine), 1560 (vibration of imidazole ring skeleton in ionic liquid), 1461 (characteristic peak of methylene vibration in imidazole ionic liquid), 1372,1335,1161 (stretching vibration of imidazole ring skeleton), 1102,1021,905 (characteristic peak of Ti-O in complex), 892 (stretching vibration peak of chitosan ring), 705 (characteristic peak of Ti-O in complex), 645 (characteristic peak of imidazole ring) cm-1. The product is shown as formula 1, R1Is methyl imidazole.
S2, filling a chitosan-supported chiral ionic liquid titanium catalyst into a microchannel reactor, and continuously introducing two raw materials, namely omeprazole thioether and a hydrogen peroxide solution with the mass fraction of 30 wt.% into the microchannel reactor at the pressure of 100-120 KPa through a mechanical pump, wherein the ratio is 1: 1.2, continuously injecting the mixture into a microchannel reactor for oxidation reaction;
s3, collecting the product at the sample outlet after the product passes through the micro-channel to obtain the chiral (S) -omeprazole medicine with high yield and high enantioselectivity;
s4, dissolving the collected product in an organic solvent, and alkalifying with sodium hydroxide to obtain a crude esomeprazole sodium product;
s5, removing impurities by using activated carbon, and purifying to obtain the refined esomeprazole sodium.
The yield of the prepared chiral (S) -omeprazole medicine is 96 percent, and the enantioselectivity is 98 percent.
The hydrogen spectrum and carbon spectrum of the (S) -omeprazole drug are shown in figure 1 and figure 2 respectively, and the adopted solvent is deuterated chloroform, which indicates that the (S) -omeprazole drug is successfully prepared.
The preparation method of example 1 was repeated 20 times without replacing the heterogeneous catalyst in the same microchannel reactor, and the yields of the prepared (S) -omeprazole pharmaceutical products were all above 95%.
Example 5
The embodiment provides a fifth preparation method for efficiently producing esomeprazole sodium, which comprises the following steps:
preparing an efficient chitosan supported chiral ionic liquid titanium catalyst: reacting 5mol of vinylimidazole with 5mol of bromopropionic acid according to step S1 of example 1 to generate a double-bond ionic liquid containing carboxylic acid groups, reacting with 5mol of chitosan to obtain a chitosan functionalized vinylic ionic liquid, reacting the obtained chitosan functionalized vinylic ionic liquid with L-isoleucine to obtain a chitosan functionalized chiral L-isoleucine vinylic ionic liquid, then performing reversible addition polymerization reaction, using a chain transfer agent (benzyl thiopropionate, 1/6mmol,0.0330g), a chain initiator (AIBN, 1/30mmol, 0.0052g) to generate a polymer, and finally complexing with a metal titanium salt to obtain a chitosan functionalized polyionic liquid chiral L-isoleucine titanium catalyst, wherein the formula is shown in formula 1. Infrared characterization of the product: FT-IR (KBr) < gamma >max/cm-13397 (characteristic peak of-OH in L-isoleucine), 3365 (characteristic peak of-NH-stretching vibration in chitosan), 3154,2922 (characteristic peak of-CH in L-phenylalanine)2-characteristic peak), 1695 (characteristic peak of-C ═ O in L-leucine), 1626 (characteristic peak of-NH-stretching vibration in L-leucine), 1562 (vibration of imidazole ring skeleton in ionic liquid), 1463 (characteristic peak of methylene vibration in imidazole ionic liquid), 1372,1335,1163 (stretching vibration of imidazole ring skeleton), 1104,1022,904 (characteristic peak of Ti-O in complex), 890 (stretching vibration peak of chitosan ring), 709 (characteristic peak of Ti-O in complex), 643 (characteristic peak of imidazole ring) cm-1. The product is shown as formula 1, R1Is sec-butyl.
S2, filling a chitosan-supported chiral ionic liquid titanium catalyst into a microchannel reactor, and continuously introducing two raw materials, namely omeprazole thioether and a hydrogen peroxide solution with the mass fraction of 30 wt.% into the microchannel reactor at the pressure of 100-120 KPa through a mechanical pump, wherein the ratio is 1: 1.2, continuously injecting the mixture into a microchannel reactor for oxidation reaction;
s3, collecting the product at the sample outlet after the product passes through the micro-channel to obtain the chiral (S) -omeprazole medicine with high yield and high enantioselectivity;
s4, dissolving the collected product in an organic solvent, and alkalifying with sodium hydroxide to obtain a crude esomeprazole sodium product;
and S5, removing impurities by using activated carbon, and purifying to obtain the refined esomeprazole sodium.
The yield of the prepared chiral (S) -omeprazole medicine is 96.5 percent, and the enantioselectivity is 98.2 percent.
The hydrogen spectrum and carbon spectrum of the (S) -omeprazole drug are shown in figure 1 and figure 2 respectively, and the adopted solvent is deuterated chloroform, which indicates that the (S) -omeprazole drug is successfully prepared.
The preparation method of example 1 was repeated 20 times without replacing the heterogeneous catalyst in the same microchannel reactor, and the yields of the prepared (S) -omeprazole pharmaceutical products were all above 94%.
Comparative example 1
The comparative example differs from example 1 in that the heterogeneous catalyst does not contain chitosan and the process is otherwise the same.
The chiral ionic liquid titanium catalyst of the comparative example was prepared as follows:
5mol of redistilled bromoethane (0.77kg) and 20ml of ethyl acetate as a solvent are added into a 250ml three-neck flask, an ethyl acetate solution containing 5mol of vinylimidazole (0.47kg) is slowly added dropwise by a constant pressure dropping funnel under the condition of heating reflux at 80 ℃, after white milky turbidity appears, heating reflux is continued to stir for 8 h. After the reaction is finished, the solution is separated into two phases after the stirring is stopped, and the lower layer of colorless viscous liquid is a crude product. And transferring the product into a vacuum drying oven, performing vacuum drying for 24 hours at 50 ℃ to obtain a white solid, performing suction filtration on the product, leaching the product with a small amount of petroleum ether, finally recrystallizing the product with 20mL of acetonitrile and 20mL of ethyl acetate to obtain a white crystal product, and exchanging the white crystal product with 201 x 7 type anion exchange resin to obtain a double-bond ionic liquid compound: 1-vinyl-3-ethylimidazole bromide salt, the structure of which is shown as follows:
Figure BDA0003482904020000171
R1is ethyl;
slowly dropwise adding the obtained aqueous solution of 10mmol of the double-bond ionic liquid compound and 10mmol of L-proline into a flask, tracking by TLC to obtain chiral L-proline vinyl ionic liquid, continuously stirring at room temperature for reaction for 15 hours, then spin-drying water by using a rotary evaporator, vacuum-drying the liquid, and then adding methanol: acetonitrile 9: 1, stirring vigorously at room temperature for 2h to separate out unreacted amino acid, filtering, spin-drying the solvent, and vacuum-drying at 80 ℃ for 24h to obtain the pure product.
Dissolving the prepared chiral L-proline vinyl ionic liquid (5mmol) in anhydrous methanol, adding benzyl thiopropionate (chain transfer agent, 1/6mmol,0.0330g) and AIBN (chain initiator, 1/30mmol, 0.0052g) into the reaction solution, and adding N into the reaction solution2And under protection, placing the reaction solution in a Schlenk tube for reaction at 60 ℃ for 24h, after the reaction is finished, concentrating the reaction solution in vacuum to obtain a light yellow solid product, and drying in vacuum at 30 ℃ to obtain the polymer.
4mmol of the polymer prepared above was dissolved in 30ml of absolute ethanol/ethyl acetate, and 2mmol of a metal titanium salt (titanium tetraisopropoxide) was added thereto, followed by reflux reaction for 2 hours. After the reaction is finished, spin-drying the solvent, and vacuum-drying at 30 ℃ to obtain the polyion liquid chiral L-proline titanium catalyst:
Figure BDA0003482904020000181
infrared characterization of the product: FT-IR (KBr) < gamma >max/cm-13405 (characteristic peak of-OH in L-proline), 3150,1647 (characteristic peak of-C ═ O in L-proline), 1621 (characteristic peak of-NH-stretching vibration in L-proline), 1563 (vibration of imidazole ring skeleton in ionic liquid), 1461 (characteristic peak of methylene vibration in imidazole ionic liquid), 1375,1334,1162 (stretching vibration of imidazole ring skeleton), 1104,1022,905 (characteristic peak of Ti-O in complex), 706 (characteristic peak of Ti-O in complex), 644 (characteristic peak of imidazole ring) cm-1。
The prepared polyion liquid chiral L-proline titanium catalyst is filled into a microchannel reactor, and refined esomeprazole sodium is prepared according to the steps S2-S5 of the example 1.
The yield of the prepared (S) -omeprazole drug was 46.7%, and the enantioselectivity was 84.2%.
Other beneficial effects are as follows:
1. the production pressure is greatly reduced from 5 atm reaction condition to about 1 atm, which can reduce the production risk and prolong the service life of the apparatus.
2. And a heterogeneous catalyst is used for replacing a homogeneous catalyst, so that the catalyst and a product are conveniently separated.
3. The microchannel reaction device can reduce labor, automate all production processes, is intelligent, reduces production risks while reducing labor cost, and can increase yield.
4. Based on the biomass-based catalyst, the source is wide, the cost is low, and the catalyst can be repeatedly used for more than 20 times, so that the product yield is effectively improved.
The above-described embodiments of the present invention should not be construed as limiting the scope of the present invention. Any other corresponding changes and modifications made according to the technical idea of the present invention should be included in the protection scope of the claims of the present invention.

Claims (10)

1. A method for efficiently producing esomeprazole sodium based on a mobile phase is characterized by comprising the following steps:
s1, filling the chitosan supported chiral ionic liquid titanium catalyst into a microchannel reactor;
s2, continuously injecting the raw material omeprazole thioether and hydrogen peroxide solution with the mass fraction of 25-35 wt% into the microchannel reactor simultaneously for oxidation reaction;
s3, completing the reaction in the microchannel reactor to obtain the chiral (S) -omeprazole drug;
s4, collecting the product, dissolving the product in an organic solvent, and alkalifying the product by using sodium hydroxide to obtain a crude product of esomeprazole sodium;
s5, removing impurities by using activated carbon, and purifying to obtain refined esomeprazole sodium;
the general formula of the chitosan supported chiral ionic liquid titanium catalyst is as follows:
Figure FDA0003482904010000011
in formula (1), each independently represents an R configuration or an S configuration, and both are the same;
CS is chitosan;
R1selected from hydrogen, alkyl, aryl substituted alkyl;
R2selected from a hydrogen atom or an alkyl group;
R3is selected from C1～C16Alkyl or substituted aryl of (a);
the structural formula of the raw material omeprazole thioether is as follows:
Figure FDA0003482904010000012
2. the mobile phase-based method for efficiently producing esomeprazole sodium according to claim 1, wherein in the step S1, the preparation step of the chitosan-supported chiral ionic liquid titanium catalyst comprises:
a) reacting 1-vinyl imidazole with bromopropionic acid to generate a double-bond ionic liquid compound containing carboxylic acid groups: 1-vinyl-3-propionylimidazolium bromide;
b) and reacting the double-bond ionic liquid compound containing carboxylic acid groups with chitosan dissolved in dilute acid solution to obtain chitosan functionalized vinyl ionic liquid II, wherein the general formula of the chitosan functionalized vinyl ionic liquid II is as follows:
Figure FDA0003482904010000021
c) reacting the obtained chitosan functionalized vinyl ionic liquid II with chiral amino acid to obtain the chitosan functionalized chiral amino acid vinyl ionic liquid, wherein the reaction formula is as follows:
Figure FDA0003482904010000022
d) and based on a controllable fracture-chain transfer free radical polymerization method, taking azobisisobutyronitrile as a chain initiator and carbon thioester as a molecular weight regulator, and controllably polymerizing the chitosan-functionalized chiral amino acid vinyl ionic liquid obtained in the step c) to generate a polymer, wherein the carbon thioester has the following general formula:
Figure FDA0003482904010000023
the reaction formula of the polymer polymerized by the controllable fragmentation-chain transfer free radical polymerization method is as follows:
Figure FDA0003482904010000031
e) complexing the polymer obtained in the step d) with metal titanium salt to obtain the chitosan supported chiral ionic liquid titanium catalyst.
3. The mobile phase-based method for efficiently producing esomeprazole sodium according to claim 2, wherein in step c), the chiral amino acid used is a natural chiral L-amino acid.
4. The mobile phase-based method for efficiently producing esomeprazole sodium according to claim 3, wherein: the chiral amino acid is selected from L-proline, L-phenylalanine, L-leucine, L-histidine and L-isoleucine.
5. The mobile phase-based method for efficiently producing esomeprazole sodium according to claim 2, wherein in step (e), the metal titanium salt used is titanium tetraisopropoxide.
6. The mobile phase-based method for efficiently producing esomeprazole sodium according to claim 1, wherein in step S2, the raw material omeprazole thioether and hydrogen peroxide solution with a mass fraction of 25-35 wt% are mixed in a ratio of 1: 1.2 continuously injecting into a micro-channel reactor for oxidation reaction.
7. The mobile phase-based method for efficiently producing esomeprazole sodium according to claim 1, wherein the solvent used for the reaction is water, and the flow rate of the solution is 1-3mL/min in step S2.
8. The mobile phase-based method for efficient production of esomeprazole sodium according to claim 1, wherein in step S2, the temperature inside the reactor is maintained at room temperature.
9. The mobile phase-based method for efficiently producing esomeprazole sodium according to claim 1, wherein in step S4, the organic solvent is dichloromethane, absolute ethanol, tetrahydrofuran or toluene.
10. The mobile phase-based method for efficiently producing esomeprazole sodium according to claim 1, wherein: in step S5, R3Selected from isopropyl, isobutyl, tert-butyl or benzyl.
CN202210072823.XA 2022-01-21 2022-01-21 Method for efficiently producing esomeprazole sodium based on mobile phase Pending CN114524801A (en)

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