CN115819403B

CN115819403B - Preparation method of pantoprazole sodium

Info

Publication number: CN115819403B
Application number: CN202211186616.3A
Authority: CN
Inventors: 周胜军; 陈辉; 陆翠军; 聂良邓; 郭卫革; 黄宇萍
Original assignee: Anhui Puli Pharmaceutical Co ltd
Current assignee: Anhui Puli Pharmaceutical Co ltd
Filing date: 2022-09-27
Publication date: 2024-06-25
Anticipated expiration: 2042-09-27

Abstract

The invention provides an improved preparation process of pantoprazole sodium and S-configuration pantoprazole sodium thereof, which comprises the following steps of adding NaOH aqueous solution into a pantoprazole crude product, adding sodium ethoxide, stirring and reacting, and keeping the PH at 8-11; and adding the reaction solution into the modified molecular sieve, adding a poor solvent into filtrate to precipitate, and recrystallizing again to obtain the corresponding product, wherein different molecular sieves can be used according to different requirements, and the crystal morphology is good.

Description

Preparation method of pantoprazole sodium

Technical Field

The invention relates to a preparation process of a compound, in particular to a preparation method of pantoprazole sodium, which comprises a purification process of s-pantoprazole sodium, so as to obtain an optimized product.

Background

Pantoprazole sodium (Pantoprazole sodium), chinese cultural academic name: 5-difluoromethoxy-2- [ (3, 4-dimethoxy-2-pyridyl) methyl ] sulfinyl-1H-benzimidazole sodium salt pantoprazole sodium, which is mainly used for: ① Peptic ulcer bleeding; ② Acute gastric mucosal injury caused by non-steroidal anti-inflammatory drugs and ulcer hemorrhage under stress state; ③ Patients with general anesthesia or major surgery and debilitating coma prevent reflux of gastric acid with aspiration pneumonia.

Pantoprazole is a sulfoxide and chiral compound in which the sulfur atom is the center forming the stereochemistry. Pantoprazole and its salts are therefore usually a racemic mixture of the two individual enantiomers, the R and S enantiomers, which also have the corresponding configuration. Meanwhile, because of the chemical structure of sulfinyl benzimidazole, the stability of the sulfinyl benzimidazole is easily influenced by various factors such as light, oxidative and reductive components, heavy metal ions and the like, related substances are unstable, the prepared medicinal solution is easy to change color, and a large number of decomposition products are formed. In order to solve the problem, the prior art generally adopts the preparation technology and adds a plurality of auxiliary materials to solve the problem. For example, CN201210350519 discloses a freeze-dried preparation of pantoprazole sodium, which improves stability by adding freeze-dried preparation and antioxidant auxiliary materials. However, the preparation process solves the problems that the preparation process has higher requirements, single preparation variety is applied, the use of the medicine is limited, the raw material medicine has the problems of color change and instability in the preparation process, and the raw material medicine turns brown to be unusable after being stored for one week, and the process flow is limited by strict storage.

In addition, compared with the racemic form and the R-configuration pantoprazole sodium, the S-configuration pantoprazole sodium has better curative effect, and the R-configuration pantoprazole sodium is generally considered to have no curative effect, for example, U.S. Pat. No. 3, 588535 discloses that the S-pantoprazole sodium has stronger gastric acid secretion inhibition effect than the racemic pantoprazole sodium and the R-pantoprazole sodium, and the literature reports that half dose of the S-pantoprazole sodium can be bioequivalent with the pantoprazole sodium, so that the problem of optical purity of the medicine is more studied in the prior art.

The ZSM-5 zeolite is used as a selective catalytic material, is mainly used in the main catalytic fields of petroleum processing and the like, and is rarely recorded for chiral resolution and compound purification. The skeleton structure is characterized in that 8 five-membered rings form five-silicon chains parallel to a c-axis through common edges, then the five-silicon chains are connected in a mirror symmetry mode to obtain a net layer with ten-membered ring hole waves, and finally the net layers are further connected to form a three-dimensional cross pore channel system, and the polymer is introduced to change the molecular network structure.

CN02109182/CN201110340811 discloses a preparation method for preparing various s-pantoprazole sodium salt by chiral oxidation using sharpless reagent, which is a chiral oxidation method, the preparation process is complex, the chiral reagent is expensive and cannot be recycled, and the preparation method is unfavorable for environmental protection due to the use of various organic solvents, the optical purity is only about 90%, and if a single s-pantoprazole sodium structural preparation is clinically needed, the compound needs further resolution and purification.

CN106496191B discloses a method for obtaining (-) S-enantiomer by hydrolysis and resolution using soybean hydrolase, adding sodium hydroxide into the hydrolysate to form salt, extracting and separating, but the hydrolase is used as biological medium, the environmental condition requirement is higher, the effect is unstable, and the product quality is difficult to guarantee.

Disclosure of Invention

In the process of researching the crystallization of the drug bulk drug, the molecular sieve and the high polymer material for a long time, the inventor finds that the molecular sieve modification can be used for preparing purer pantoprazole sodium with small chromatic aberration change under specific conditions in the research of preparing chiral compounds by modifying the molecular sieve through repeated fumbling of a large number of experiments, and the stability of the drug composition prepared by taking the molecular sieve as the bulk drug is obviously better than that of a commercial product; under the action of a magnetic field and a gradient slow release agent, the molecular sieve can realize certain chiral resolution to obtain S-pantoprazole sodium with higher optical purity, and the molecular sieve can be recycled and reused and is modified according to different target products, so that the industrial controllability is greatly improved, and the cost of chiral resolution and purification processes is reduced.

The method comprises the following specific steps: a preparation method of pantoprazole sodium,

1) Adding NaOH aqueous solution into the pantoprazole crude product, adding sodium ethoxide, stirring for reaction, and keeping the PH at 8-11;

2) Adding the reaction solution into a modified molecular sieve, adding a poor solvent into filtrate to precipitate a precipitate, and recrystallizing again to obtain the modified molecular sieve;

Wherein the weight ratio of NaOH to sodium ethoxide is 1-5:1, a step of; preferably 1-4:1, a step of; the weight ratio of the pantoprazole crude product to the alkaline reagent (NaOH to sodium ethoxide) is 1:0.5-2, most preferably 1:1, a step of; the pH of the solution in step 1) is preferably from 8.5 to 10.

In another preferred embodiment, the aqueous NaOH solution has a concentration of 2% to 6%, more preferably 3% to 5%.

Further, the modified molecular sieve in the step 2) is prepared by reacting a ZSM-5 molecular sieve with a crosslinking agent. The method of adding the reaction liquid includes, but is not limited to, dropwise addition or batch pouring; further, the filter bottle is a suction filter bottle, and the filtering mode is preferably suction filtration; preferably, the modified molecular sieve is placed in a hopper apparatus, more preferably a glass sand core hopper;

The preparation method of the modified molecular sieve comprises the following steps: 1) putting ZSM-5 molecular sieve into solution, 2) adding pore-forming agent and cross-linking agent, and 3) calcining.

The pore-forming agent is selected from one or more of Fe, fe2O3 and triethylamine, and the cross-linking agent is selected from one or two of N-N methylene bisacrylamide and ammonium persulfate. Preferably, the solution is water and the reaction is carried out in a reaction vessel.

In a further preferred embodiment, the reactor requires heating, preferably at a temperature of 60-100 ℃, more preferably 70-90 ℃, most preferably 80 ℃.

Further, the modification process of the molecular sieve further comprises the following step 4) that the calcined molecular sieve is added with an aqueous solution of a gradient slow release agent, and the mixture is placed still and dried in vacuum, wherein the gradient slow release agent is NaCl, and further is 2% aqueous solution of NaCl

In a preferred technical scheme, the weight ratio of the pore-forming agent to zsm-5 is 1:4-20, preferably 1:4-10, more preferably 1:5-8; the weight ratio of the cross-linking agent to the zsm-5 is 1:2-25, more preferably 1:3-15, most preferably 1:5-10; the weight ratio of the gradient slow-release agent solution to the zsm-5 is 1:1-5; the concentration of the gradient slow-release agent solution is 2g/100ml.

Preferably, after the pore-forming agent and the cross-linking agent are added in the step 2 of preparing the modified molecular sieve, the reaction equipment is placed in a static magnetic field.

Still further the static magnetic field strength is 10-50MT, preferably 20-30MT, most preferably 25MT.

Preferably, the calcination is carried out in a muffle furnace, further preferably at a temperature of 150-350 ℃; further, the poor solvent is selected from one or more of diethyl ether, acetone, ethyl acetate and methyl isobutyl ketone, and the addition amount of the poor solvent is 20% -100% of the volume of the filtrate; more preferably 25% -80%, most preferably 30-60%; the recrystallization step comprises adding solvent 1 into the precipitate, and then adding solvent 2 into the precipitate to separate out crystals, wherein the solvent 1 is selected from water and/or acetone; solvent 2 is selected from diethyl ether, ethyl acetate and/or methyl isobutyl ketone.

The technical scheme of the invention also comprises a preparation method of the s-pantoprazole sodium, which comprises the following steps:

1) Adding NaOH aqueous solution into the pantoprazole crude product, uniformly stirring, adding sodium ethoxide, stirring for reaction, and keeping the pH value at 8-11; 2) Adding ZSM-5 molecular sieve into water, stirring, heating, adding pore-forming agent and cross-linking agent, simultaneously placing in static magnetic field for reaction, cooling to room temperature, filtering for precipitation, calcining, adding NaCl aqueous solution (preferably 2% of mass volume concentration), standing for reflux treatment, and vacuum drying to obtain modified ZSM-molecular sieve; 3) And (3) placing the modified molecular sieve in funnel equipment, gradually dripping the reaction liquid obtained in the step (1), adding a poor solvent into the filtrate obtained by suction filtration to precipitate, recrystallizing again, and drying to obtain the modified molecular sieve.

Preferably, the modified molecular sieve is placed in a hopper apparatus, more preferably a glass sand core hopper; the pore-forming agent is selected from one or more of Fe, fe2O3 and triethylamine, and the cross-linking agent is selected from one or two of N-N methylene bisacrylamide and ammonium persulfate. Preferably, the solution is water and the reaction is carried out in a reaction vessel. Further the reactor is heated, preferably at a temperature of 60-100 ℃, more preferably 70-90 ℃ and most preferably 80 ℃.

More preferably, the weight ratio of pore-forming agent to zsm-5 is 1:4-20, wherein the weight ratio of the cross-linking agent to the zsm-5 is 1:2-25; the weight ratio of the gradient slow-release agent solution to the zsm-5 is 1:1-5; the concentration of the gradient slow-release agent solution is 2g/100ml. The pore-forming agent is selected from one or more of Fe, fe2O3 and triethylamine, and the cross-linking agent is selected from one or two of N-N methylene bisacrylamide and ammonium persulfate. Preferably, the solution is water and the reaction is carried out in a reaction vessel.

The stationary magnetic field strength is 10 to 50MT, preferably 20 to 30MT, most preferably 25MT.

Further, the poor solvent is selected from diethyl ether, acetone, ethyl acetate and/or methyl isobutyl ketone; the addition amount of the poor solvent is 20% -100% of the volume of the filtrate; more preferably 25% -80%, most preferably 30-60%; the recrystallization step comprises adding solvent 1 into the precipitate, and then adding solvent 2 into the precipitate to separate out crystals, wherein the solvent 1 is selected from water and/or acetone; solvent 2 is selected from diethyl ether, ethyl acetate and/or methyl isobutyl ketone.

Preferably, when the solvent is added for crystallization, the reaction solution is stirred, and the dropping speed is 1-10ml/min, preferably 5-6ml/min; in a preferred embodiment, the crystal grain size D ₉₀ is 1-100. Mu.m, preferably 5-80. Mu.m, more preferably 10-70. Mu.m, most preferably 10-15. Mu.m;

The invention further comprises the recovery of the modified molecular sieve, adding a small amount of electrolyzed water after the recovery of the molecular sieve, dissolving, washing and soaking overnight, centrifuging and precipitating, treating for 1-2h by steam, and drying. Still further the electrolyzed water may be prepared by an electrolyzed water machine or generated by direct current through aqueous solution process. Further, the steam treatment is steam treatment at 100-150deg.C.

Further, the pantoprazole crude product can be obtained by a common process described in the prior art, and can also be obtained by a commercial product, preferably the purity is not higher than 90%, and preferably the S configuration accounts for not lower than 50%.

ZSM-5D silica alumina ratio of 40 to 400, preferably 50 to 300, more preferably 90;

Further, the drying method of the present invention includes, but is not limited to, vacuum drying, rotary evaporation, drying, freeze drying, and the like.

The raw materials of the test compound and the pantoprazole crude product are purchased from sigma company, guangdong major Spectrum biotechnology Co., ltd

ZSM-5 (chemical formula: na _nAl_nSi96-nO₁₉₂·16H₂ O). SiO2/Al2O3 (silicon to aluminum ratio: 90) from Nanfeng nanotechnology Co., ltd., specific surface area: 330-400m2/g.

The beneficial effects of the invention include:

1) The modified molecular sieve is used as a catalyst, and the chiral compound purification and crystallization processes are combined, so that the preparation process is simplified, expensive chiral resolving agents are saved, and compared with a catalytic resolving method of biological enzymes, the process operation controllability is improved, and the production cost is reduced.

2) In the process of molecular sieve-polymer formation, the method of combining pore-forming and crosslinking is used for forming an asymmetric multilayer network structure by standing in a magnetic field, so that the stability of a compound is improved, and a NaCl solution is added to delay release of ionized substances, so that the modified compound is easy to control, and the reduction of reaction yield caused by the change of reaction environment is avoided; the product not only has controllable crystallization particles and even particle size distribution, but also can prepare corresponding products according to different purposes (preparation, clinic and purity requirements).

3) The invention is based on the combination of intelligent materials and compound preparation, the obtained product shows good performance under the conditions of high temperature and high humidity, and the crystal physical properties of part of the products are suitable to be used as raw materials, and the stability (color change and moisture absorption) is improved, thus providing possibility for the application research of the responsive intelligent polymer in wider fields.

Drawings

Fig. 1: example 1 detection profile of S-pantoprazole sodium crystals;

fig. 2: example 3 MS identification and purity detection profile of pantoprazole sodium crystals;

fig. 3: example 1 electron microscopy of S-pantoprazole sodium crystals.

Detailed Description

Example 1:

a) A preparation method of a pantoprazole crude product;

Commercial products can be obtained or purchased by known methods including, but not limited to, the methods described in CN102887886a, CN101475561a, CN103232438B, etc. (crude S-pantoprazole content of 90% and 50% above, chemical purity below 99%) are exemplified as follows:

1) 2-hydroxymethyl-3, 4-dimethoxy pyridine (II) is taken as a starting material, and 2-chloromethyl-3, 4-dimethoxy pyridine hydrochloride (III) is generated under the action of chloride; 2) Condensing the obtained compound (III) with 5-difluoromethoxy-2-mercapto-1H-benzimidazole in the presence of inorganic base to generate 5-difluoromethoxy-2- [ (3, 4-dimethoxy-2-pyridyl) methyl ] thio-1H-benzimidazole (IV); 3) Oxidizing the obtained compound (IV) with an oxidizing agent to generate 5-difluoromethoxy-2- [ (3, 4-dimethoxy-2-pyridyl) methyl ] sulfinyl-1H-benzimidazole (pantoprazole);

Or alternatively

(I) Dissolving 2-chloromethyl-3, 4-dimethoxy pyridine hydrochloride in ethanol, adding sodium iodide, then adding an ethanol solution of 5-difluoromethoxy-2-mercapto-IH-benzimidazole and a sodium hydroxide aqueous solution, stirring for reaction, distilling under reduced pressure, adding water, continuously stirring, separating out a solid, filtering, washing with water, and drying to obtain 5- (difluoromethoxy) -2- { [ (3, 4-dimethoxy-2-pyridyl) methyl ] thio } -IH-benzimidazole; (2) Dissolving 5- (difluoromethoxy) -2- { [ (3, 4-dimethoxy-2-pyridyl) methyl ] thio } -1H-benzimidazole in ethyl acetate, cooling, dropwise adding a mixed solution of oxidizing agent m-chloroperoxybenzoic acid and ethyl acetate, reacting, washing, drying an organic phase by using a solid drying agent, filtering, distilling under reduced pressure, adding diisopropyl ether for refining, filtering and drying to obtain an off-white solid pantoprazole;

Pantoprazole has the structural formula:

B) Molecular sieve modification preparation:

500g of a commercial ZSM-5 molecular sieve (silicon-aluminum ratio 90) is placed in a reaction kettle, 10L of water is added for stirring, heating is carried out to more than 80 ℃, 20g of triethylamine and 50g of iron powder are added after stirring uniformly, 50g of N-N methylene bisacrylamide is added after stirring for 2 hours, meanwhile, the mixture is placed in a static magnetic field of 25MT, then the temperature of the reaction kettle is cooled to room temperature by using a jacket cooling water circulation condition, the mixture is filtered and precipitated, a muffle furnace is heated to 240 ℃, the mixture is kept in a calcination disc for 12 hours, the calcined molecular sieve and a water solution of NaCl (2%) are combined, standing and refluxing are carried out for 1 hour, and ZSM-5 modified molecular sieve particles are obtained after vacuum filtration and air drying at room temperature;

C) S-pantoprazole sodium preparation

1) Adding 500ml of water and 16g of NaOH into a spherical separating funnel, magnetically stirring after dissolution, taking 100g of pantoprazole crude product (the optical purity is detected to be 54 percent of the pantoprazole content), adding the solution, continuously stirring, keeping the room temperature, reacting for 2-3 hours, adding 4g of sodium ethoxide, and keeping the pH of the reaction solution to be about 8-11;

2) Placing 200g of the modified molecular sieve obtained in the step B) in a glass sand core funnel, connecting a suction filtration reaction bottle below, placing the reaction bottle on a magnetic stirrer, firstly flushing with deionized water for 2min, then dripping the reaction liquid obtained in the step 1) into the sand core funnel at the speed of 1-2ml/min, suction filtering into the reaction bottle, magnetically stirring, stirring at the speed of 30rpm, filtering a small amount of precipitate at the bottom of the bottle, adding diethyl ether into the filtrate to precipitate, centrifuging, filtering the precipitate, and adding water/acetone (mass ratio 1: 1) Stirring the solution until the solution is dissolved, dripping methyl isobutyl ketone solution with the same volume as the water/acetone solution at the speed of 5-6ml/min until the solution is turbid, cooling to 5-10 ℃ by cooling water, stirring and crystallizing for 2 hours, cooling to 0-5 ℃ and preserving heat and standing for crystallizing for 2 hours, filtering, flushing the precipitate with acetone for 2 times, and vacuum drying to obtain the s-pantoprazole sodium crystal.

The HPLC detection is s-pantoprazole sodium (see figure 1), the crystal form electron microscope scanning chart is shown in figure 3, and the electron microscope detection crystal particle size D90 is about 25-35 mu m; the uniformity is higher, and the structure is as follows:

D) Molecular sieve recovery

And (3) after the molecular sieve in the sand core funnel is recovered, a small amount of electrolyzed water is added for dissolution, washing and soaking overnight, centrifugal precipitation is carried out, and the sand core funnel is treated by steam for 1-2h and dried.

E) Optical purity detection: the liquid chromatograph is a high performance liquid chromatograph, and the chromatographic column is as follows: 0D-RH (Chiralcel, 150mmX4.6mm,5 ym); detection wavelength: 292nm; flow rate: 0.8ml/min; sample injection volume: 10 mu 1. The mobile phase is water and acetonitrile mixed solvent (3; 1), precisely weigh the right amount of target, add mobile phase to dissolve and make about 0.2mg compound solution in every lml, filter, take the subsequent filtrate as the sample solution; precisely weighing pantoprazole sodium racemate, and diluting with a mobile phase to prepare a solution with 2Pg per lml serving as a control solution.

F) Chemical purity detection: HPLC (Chinese pharmacopoeia 2005 edition two appendix V D) measurement, using octadecylsilane chemically bonded silica as filler; phosphate buffer solution (1.12 g of disodium hydrogen phosphate and 0.18g of sodium dihydrogen phosphate are taken, dissolved by adding water and diluted to 1000 ml) -acetonitrile (70:30) is taken as a mobile phase;

the optical purity of the final product is more than or equal to 99.95 and the chemical purity is more than or equal to 99.89 after the detection of the s-pantoprazole sodium.

Example 2:

a) The crude pantoprazole was obtained in the same manner as in the prior art in example 1 (optical purity detection of 67% s-pantoprazole content).

B) Molecular sieve modification preparation:

500g of a commercial ZSM-5 molecular sieve (silicon-aluminum ratio 90) is placed in a reaction kettle, 12L of water is added for stirring, heating is carried out to more than 80 ℃,30 g of triethylamine and 70g of ferroferric oxide powder are added after stirring uniformly, 100g of a mixture of N-N methylene bisacrylamide and ammonium persulfate (wherein, the N-N methylene bisacrylamide is 80g and the ammonium persulfate is 20 g) is added after stirring for 4 hours, the mixture is placed in a static magnetic field of 25MT for standing after stirring for 3 hours, 5L of a Nacl water solution with the mass concentration of 2% is slowly added in batches, then the temperature of the reaction kettle is cooled to room temperature by using a jacket cooling water circulation condition, filtering and precipitating are carried out after standing for 3-4 hours, a muffle furnace is heated to 140 ℃, and ZSM-5 modified molecular sieve particles are obtained after keeping in a calcination tray for 10 hours;

C) S-pantoprazole sodium preparation

1) Adding 500ml of water and 12g of NaOH into a reaction bottle, magnetically stirring after dissolution, taking 100g of pantoprazole crude product, adding the solution, continuously stirring, keeping the room temperature, reacting for 2-3h, adding 8g of sodium ethoxide, and keeping the pH of the reaction solution at about 8-11;

Placing 200g of the modified molecular sieve obtained in the step B) into a glass sand core funnel, connecting a suction filtration reaction bottle below, firstly flushing with deionized water for 2min, then dripping the reaction liquid obtained in the step 1) into the sand core funnel at a speed of 1-2ml/min, suction filtering into the reaction bottle, magnetically stirring, stirring at a speed of 30rpm, filtering out a small amount of sediment at the bottom of the bottle, adding diethyl ether into the filtrate to precipitate, centrifuging, filtering the precipitate, and adding water/acetone (mass ratio 1: 1) Stirring the solution until the solution is dissolved, dripping diethyl ether solution with the same volume as the water/acetone solution at the speed of 5-6ml/min until the solution is turbid, cooling to 5-10 ℃ by cooling water, stirring and crystallizing for 2 hours, cooling to 0-5 ℃ and preserving heat and standing for crystallizing for 2 hours, filtering, flushing the precipitate with diethyl ether for 2 times, and vacuum drying to obtain the nano-crystalline silicon dioxide. A step of

D) Molecular sieve recovery and optical purity detection as in example 1

The HPLC detection spectrum is the same as that of the example 1, the optical purity is more than or equal to 99.99 percent, and the chemical purity is more than or equal to 99.82 percent; the mirror detection crystal grain diameter D90 is about 25-35 mu m; the uniformity is higher.

Example 3:

A) The crude pantoprazole was obtained in the same manner as in the prior art in example 1 (optical purity detection of 57% s-pantoprazole content).

C) Molecular sieve modification preparation:

500g of a commercial ZSM-5 molecular sieve (silicon-aluminum ratio 90) is placed in a reaction kettle, 12L of water is added for stirring, heating is carried out to more than 80 ℃,70 g of ferroferric oxide powder is added after stirring uniformly, 100g of a mixture of N-N methylene bisacrylamide and ammonium persulfate (80 g of N-N methylene bisacrylamide and 20g of ammonium persulfate) is added after stirring for 4 hours, the mixture is placed in a static magnetic field of 25MT for standing after stirring for 3 hours, then the temperature of the reaction kettle is cooled to room temperature by using jacket cooling water circulation, filtering and precipitating are carried out after standing for 3-4 hours, a muffle furnace is heated to 140 ℃, and the mixture is kept in a calcination tray for 10 hours to obtain ZSM-5 modified molecular sieve particles;

C) Pantoprazole sodium preparation

1) Adding 500ml of water and 20g of NaOH into a reaction bottle, magnetically stirring after dissolution, taking 100g of pantoprazole crude product, adding the solution, continuously stirring, keeping the room temperature, reacting for 2-3h, and keeping the pH of the reaction solution to be about 8-11;

placing 200g of the modified molecular sieve obtained in the step B) into a glass sand core funnel, connecting a suction filtration reaction bottle below, firstly flushing with deionized water for 2min, then dripping the reaction liquid obtained in the step 1) into the sand core funnel at a speed of 1-2ml/min, suction filtering into the reaction bottle, magnetically stirring, stirring at a speed of 30rpm, filtering out a small amount of sediment at the bottom of the bottle, adding diethyl ether into the filtrate to precipitate, centrifuging, filtering the precipitate, and adding water/acetone (mass ratio 1: 1) Stirring the solution until the solution is dissolved, dripping ethyl acetate solution with the same volume as the water/acetone solution at the speed of 5-6ml/min until the solution is turbid, cooling to 5-10 ℃ by cooling water, stirring and crystallizing for 2 hours, cooling to 0-5 ℃ and preserving heat and standing for crystallizing for 2 hours, filtering, flushing the precipitate with ethyl acetate for 2 times, and vacuum drying to obtain the nano-crystalline silicon dioxide. A step of

D) Molecular sieve recovery and optical purity detection as in example 1

The HPLC detection shows that the chemical purity of the pantoprazole sodium crystal is more than or equal to 99.92%, wherein the content of the pantoprazole sodium is 87.76%, and the rest is R configuration.

Example 4:

A) The crude pantoprazole was obtained in the same manner as in the prior art in example 1 (optical purity detection s-pantoprazole content 57%).

B) Molecular sieve modification preparation:

500g of a commercial ZSM-5 molecular sieve (silicon-aluminum ratio 90) is placed in a reaction kettle, 10L of water is added for stirring, heating is carried out to more than 100 ℃, 20g of triethylamine is added after stirring is carried out uniformly, 50g of N-N methylene bisacrylamide is added after stirring is carried out for 2 hours, then the temperature of the reaction kettle is cooled to room temperature by using a jacket cooling water circulation condition, the precipitation is filtered, a muffle furnace is heated to 240 ℃, the temperature is kept for 12 hours in a calcination plate, the calcined molecular sieve and a NaCl (2%) aqueous solution are combined, standing and reflux treatment is carried out for 1 hour, and ZSM-5 modified molecular sieve particles are obtained after vacuum filtration and air drying at room temperature;

C) Pantoprazole sodium preparation

1) Adding 500ml of water and 15g of NaOH into a spherical separating funnel, magnetically stirring after dissolution, taking 100g of pantoprazole crude product (the optical purity of which is detected as the content of the S-pantoprazole is 57 percent), adding the solution, continuously stirring, keeping the room temperature, reacting for 2-3h, adding 5g of sodium ethoxide, and keeping the pH of the reaction solution to be about 8-11;

2) Placing 200g of the modified molecular sieve obtained in the step B) in a glass sand core funnel, connecting a suction filtration reaction bottle below, placing the reaction bottle on a magnetic stirrer, firstly flushing with deionized water for 2min, then dripping the reaction liquid obtained in the step 1) into the sand core funnel at the speed of 1-2ml/min, suction filtering into the reaction bottle, magnetically stirring, stirring at the speed of 30rpm, filtering a small amount of precipitate at the bottom of the bottle, adding diethyl ether into the filtrate to precipitate, centrifuging, filtering the precipitate, and adding water/acetone (mass ratio 1: 1) Stirring the solution until the solution is dissolved, dripping methyl isobutyl ketone solution with the same volume as the water/acetone solution at the speed of 5-6ml/min until the solution is turbid, cooling to 5-10 ℃ by cooling water, stirring and crystallizing for 2 hours, cooling to 0-5 ℃, preserving heat, standing and crystallizing for 2 hours, filtering, flushing the precipitate with acetone for 2 times, and vacuum drying to obtain the product.

The HPLC detection shows that the chemical purity of the pantoprazole sodium crystal is more than or equal to 98.92%, wherein the content of the s pantoprazole sodium is 89.56%.

Example 5:

B) Molecular sieve modification preparation:

500g of a commercial ZSM-5 molecular sieve (silicon-aluminum ratio 90) is placed in a reaction kettle, 12L of water is added for stirring, heating is carried out to more than 80 ℃, 100g of a mixture of N-N methylene bisacrylamide and ammonium persulfate (80 g of N-N methylene bisacrylamide and 20g of ammonium persulfate) is added after stirring uniformly, then the temperature of the reaction kettle is cooled to room temperature by using a jacket cooling water circulation condition, the reaction kettle is kept for 3-4 hours, then precipitation is filtered, a muffle furnace is heated to 140 ℃, and the reaction kettle is kept in a calcination disc for 10 hours to obtain ZSM-5 modified molecular sieve particles;

C) Pantoprazole sodium preparation

2) Placing 200g of the modified molecular sieve obtained in the step B) into a glass sand core funnel, connecting a suction filtration reaction bottle below, firstly flushing with deionized water for 2min, then dripping the reaction liquid obtained in the step 1) into the sand core funnel at a speed of 1-2ml/min, suction filtering into the reaction bottle, magnetically stirring, stirring at a speed of 30rpm, filtering out a small amount of sediment at the bottom of the bottle, adding diethyl ether into the filtrate to precipitate, centrifuging, filtering the precipitate, and adding water/acetone (mass ratio 1: 1) Stirring the solution until the solution is dissolved, dripping diethyl ether solution with the same volume as the water/acetone solution at the speed of 5-6ml/min until the solution is turbid, cooling to 5-10 ℃ by cooling water, stirring and crystallizing for 2 hours, cooling to 0-5 ℃, preserving heat, standing and crystallizing for 2 hours, filtering, flushing the precipitate with diethyl ether for 2 times, and vacuum drying to obtain the product. A step of

D) Molecular sieve recovery and optical purity detection were as in example 1.

The chemical purity of the pantoprazole sodium crystal is more than or equal to 98.7, wherein the content of the s-pantoprazole sodium is 72 percent.

Comparative example 1: commercial pantoprazole sodium (analytically pure), control 2: commercial s-pantoprazole sodium (analytically pure)

Test 1: high temperature and high humidity stability test

Samples of the above examples and comparative examples were taken, placed in a glass vessel, and placed at 20 ℃,60 ℃,40% humidity and 80% humidity, and sampled on day 1, 3, and 10, respectively, and the stability results of each index were examined in terms of moisture absorption gain (%), see table 1.

TABLE 1

It can be seen that examples 1-3 exhibited good stability, with example 4 having a faster increase in moisture absorption and a faster decrease in stability after 10 days, but still being better than the commercial product.

Test 2: color difference measurement

Analysis was performed using SPSS20.0 statistical software, the differences between groups were compared using t-test, and P <0.05 was statistically significant, with results shown in table 2;

placing the sample to be tested on a white table top in a darkroom, and under constant temperature and humidity (25 ℃ and 40% humidity) conditions; firstly, detecting by using a corrected color difference meter, immediately detecting the product after drying as a reference standard, detecting again after 2h and 12h respectively under natural light conditions, and calculating an delta E value;

TABLE 2

According to tables 1 and 2, examples 1 to 4 each exhibited color difference stability, and example 5 was significantly different from examples 1 to 4 and the control, and comparative example 1/2 was significantly different from each example. The color difference problem of example 5 is more severe over time, and although example 5 has less color difference change than example 4 at 2h, example 4 is better than example 5 for clinical dispensing applications. The crystals of example 3 also show good stability, thus it can be seen that the sodium S-pantoprazole content (optical purity of the compound) does not affect the colour difference variation; further factors affecting color differences may be crystal structure stability or whether impurities affect the oxidation process. Example 5 compared with example 4, the pore-forming agent triethylamine is not used, so that the pores in the polymer structure of the molecular sieve are different, the chiral change is possibly caused to be unfavorable, the magnetic field can change the network morphology and the pore diameter structure of the molecule, the molecular sieve cannot form unidirectional displacement to form the pore diameter structure favorable for chiral formation under the condition of lack of the magnetic field, the disordered ordering of ions is increased, and the polymer amount is reduced; and by magnetic field or electrostatic adsorption during the rest of the NaCl without using NaCl, gradient adsorption can be formed in the molecular sieve-polymeric layer structure, which can lead to ionization and continuous release of ions during the passing of the compound, which can also be the reason for more stable compound crystals. The crystal of example 4 has stable chromatic aberration but poor hygroscopicity, and may be related to a cross-linking agent, and the action of iron powder and a magnetic field may cause gradient changes in pore diameter and morphology, and in the absence of the above conditions, certain impurities can only be removed by recrystallization, and the crystallization performance may be affected during recrystallization, and poor solvent selection during crystallization may also be the cause of the difference in crystal performance morphology.

Test 3: crystal morphology and solubility

1) Measuring the particle size and observing the appearance of the particles of each example and the control sample by scanning through an electron microscope;

2) Solubility, tabletting by conventional process, adding the above sample, 20% excipient, 10% filler, 5% lubricant, mixing, tabletting by tabletting machine, microcrystalline cellulose as excipient, starch as filler, and magnesium stearate as lubricant. The dissolution rate of the chips of the example product in a phosphate buffer solution of sodium dodecyl sulfate was measured using a Distek dissolution apparatus (DISTEK, 2100A), and the dissolution surface area was 1cm ² at room temperature.

The results are shown in Table 3.

TABLE 3 Table 3

From the above test results, it was found that the optical purity of examples 1-2 was better, although the crystal size distribution was narrower and the particles were more uniform in example 3. Example 3 is more suitable for preparing formulations with higher requirements on bulk density of crystals or drug substitution, such as tablets, granules, etc., and at the same time contains a certain amount of R configuration; examples 1-2 are s-pantoprazole sodium with higher optical purity, are more stable in terms of chromatic aberration and hygroscopicity, are suitable for clinical injection preparation, emergency administration and the like, and both the tablets of example 5 and the tablets of the commercial raw materials show faster dissolution and the commercial raw materials have higher hygroscopicity.

The above embodiments do not limit the scope of the present invention, and those skilled in the art can make various changes and applications of the present invention according to the above description.

Claims

1. A preparation method of s-pantoprazole sodium comprises the following steps:

1) Adding NaOH aqueous solution into the pantoprazole crude product, uniformly stirring, adding sodium ethoxide, stirring for reaction, and keeping the pH value at 8-11;

2) Adding ZSM-5 molecular sieve into water, stirring, heating, adding pore-forming agent and cross-linking agent, simultaneously placing in static magnetic field for reaction, cooling to room temperature, filtering for precipitation, calcining, adding NaCl aqueous solution with mass and volume concentration of 2%, standing for reflux treatment, and vacuum drying to obtain modified ZSM-5 molecular sieve;

3) Placing the modified molecular sieve into funnel equipment, gradually dripping the reaction liquid obtained in the step 1), adding a poor solvent into the filtrate obtained by suction filtration to precipitate, recrystallizing again, and drying to obtain the modified molecular sieve; wherein the poor solvent is selected from diethyl ether, acetone, ethyl acetate and/or methyl isobutyl ketone;

The pore-forming agent is triethylamine and iron powder, triethylamine and ferroferric oxide powder, and the cross-linking agent is selected from 1) N-N methylene bisacrylamide or 2) a combination of N-N methylene bisacrylamide and ammonium persulfate; the weight ratio of pore-forming agent to ZSM-5 is 1:4-20, the weight ratio of the cross-linking agent to ZSM-5 is 1:2-25; the weight ratio of NaCl aqueous solution to ZSM-5 is 1:1-5; the static magnetic field strength is 10-50MT.

2. The method of claim 1, wherein the recrystallization step comprises adding solvent 1 to the precipitate followed by solvent 2 to precipitate crystals, wherein solvent 1 is selected from the group consisting of a mixture of water and acetone; solvent 2 is selected from diethyl ether, ethyl acetate and/or methyl isobutyl ketone.