CN115819403A

CN115819403A - Preparation method of pantoprazole sodium

Info

Publication number: CN115819403A
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
Priority date: 2022-09-27
Filing date: 2022-09-27
Publication date: 2023-03-21

Abstract

The invention provides an improved pantoprazole sodium and a preparation process of S-configuration pantoprazole sodium thereof, which comprises the following steps of taking a crude pantoprazole product, adding NaOH aqueous solution, adding sodium ethoxide, stirring for reaction, and keeping the PH value to be 8-11; and adding the reaction solution into a modified molecular sieve, adding a poor solvent into the filtrate to separate out a precipitate, and recrystallizing again to obtain the product, wherein the corresponding products can be obtained by using different molecular sieves according to different requirements, and the crystallization form 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 to obtain an optimized product.

Background

Pantoprazole sodium (Pantoprazole sodium), mesocultural name: 5-difluoromethoxy-2- [ (3,4-dimethoxy-2-pyridyl) methyl ] sulfinyl-1H-benzimidazole sodium salt pantoprazole sodium, which is mainly used for: (1) bleeding from peptic ulcer; (2) acute gastric mucosal injury and ulcer hemorrhage under stress caused by non-steroidal anti-inflammatory drugs; (3) general anesthesia or post-major surgery, as well as debilitating comatose patients prevent acid reflux with aspiration pneumonia.

Pantoprazole is a sulfoxide and a chiral compound in which the sulfur atom is the stereogenic center. Pantoprazole and its salts are therefore usually racemic mixtures of two single enantiomers, the R and S enantiomers, the salts also having the corresponding configuration. Meanwhile, due to the chemical structure of sulfinyl benzimidazole, the stability of sulfinyl benzimidazole is easily affected by various factors such as light, oxidizing and reducing components, heavy metal ions and the like, related substances are unstable, the prepared drug solution is easy to discolor, and a large amount of decomposition products are formed. In order to solve the problem, the prior art generally solves the problem by the combination addition of a plurality of auxiliary materials in the preparation technology. For example, CN201210350519 discloses a freeze-drying agent of pantoprazole sodium, which is added with a freeze-drying agent and an antioxidant adjuvant to improve stability. However, the problem is solved by a preparation process, the requirement on the preparation process is high, the use of the medicine is limited by applying a single preparation variety, and the problems of color change and instability of the raw material medicine exist in the preparation process of the preparation, the raw material medicine turns brown after being stored for one week and cannot be used, and the raw material medicine needs to be strictly stored, so that the process flow is limited.

In addition, compared with racemic pantoprazole sodium and R-configured pantoprazole sodium, S-configured pantoprazole sodium has better curative effect, and R-configured pantoprazole sodium is generally considered to have no curative effect, for example, U.S. Pat. No. 5, 588535 discloses that S-pantoprazole sodium has stronger gastric acid secretion inhibiting effect than racemic pantoprazole sodium and R-pantoprazole sodium, and the literature reports that half dose of S-pantoprazole sodium can be bioequivalent to pantoprazole sodium, so that the problem of optical purity of the medicine is solved, and the prior art researches are more.

ZSM-5 zeolite is used as a selective catalytic material, is mainly used in the main catalytic field of petroleum processing and the like, and is rarely recorded for chiral resolution and compound purification. The skeleton structure is characterized in that five silicon chains parallel to a c axis are formed by 8 five-membered rings through common edges, then mesh layers with ten-membered rings Kong Bozhuang are obtained through the mirror symmetry connection of the five silicon chains, finally, the mesh layers are further connected to form a three-dimensional cross tunnel system, and the molecular network structure is changed through the introduction of polymers.

CN02109182/CN201110340811 discloses a preparation method for preparing various s-pantoprazole salts by chiral oxidation using a sharpless reagent, all of which are chiral oxidation methods, the preparation process is complex, the chiral reagent is high in price and cannot be recycled, and the preparation method is not favorable 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 to be further separated and purified.

CN106496191B discloses a method for hydrolysis and resolution by using soybean hydrolase, and obtaining (-) S-enantiomer after salifying and extracting and separating hydrolysate by adding sodium hydroxide, but the hydrolase is used as a biological medium, so that the requirement on environmental conditions is high, the effect is unstable, and the product quality is difficult to guarantee.

Disclosure of Invention

The inventor finds that the molecular sieve modification can be used for preparing purer pantoprazole sodium with small color difference change under specific conditions in the process of researching chiral compounds prepared by modifying the molecular sieve through a large number of experiments repeatedly in the process of researching the crystallization, the molecular sieve and the high molecular material of the drug bulk drugs for a long time, and the stability of the drug composition prepared by using the molecular sieve modification as the bulk drugs is obviously superior to that of the products sold in the market; under the action of a magnetic field and a gradient sustained-release agent, the molecular sieve can realize certain chiral resolution to obtain S-pantoprazole sodium with higher optical purity.

The method comprises the following specific steps: a method for preparing pantoprazole sodium,

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

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

wherein the weight ratio of NaOH to sodium ethoxide is 1-5:1; preferably 1 to 4:1; 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; the pH of the solution in step 1) is preferably 8.5 to 10.

In another preferred embodiment, the concentration of the aqueous NaOH solution is 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 cross-linking agent. Reaction solution addition methods include, but are not limited to, dropwise addition or batch pouring; further, the filter flask is a suction flask, and the filtration mode is preferably suction filtration; preferably, the modified molecular sieve is placed in a funnel device, more preferably a glass sand core funnel;

the preparation method of the modified molecular sieve comprises the following steps: 1) putting a ZSM-5 molecular sieve into a solution, 2) adding a pore-making agent and a 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 reaction vessel is heated, preferably at a temperature of from 60 to 100 deg.C, more preferably from 70 to 90 deg.C, most preferably 80 deg.C.

Further, the molecular sieve modification process also comprises the following step 4) of adding an aqueous solution of a gradient sustained-release agent into the calcined molecular sieve, standing, and vacuum-drying to obtain the molecular sieve modified by the method, wherein the gradient sustained-release agent is NaCl, and further the aqueous solution of 2% of NaCl

In a preferred technical scheme, the weight ratio of the pore-forming agent to the 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 sustained-release agent solution to the zsm-5 is 1:1-5; the concentration of the gradient sustained-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.

Further the static magnetic field strength is in the range of 10-50MT, preferably 20-30MT, most preferably 25MT.

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

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

Preferably, the modified molecular sieve is placed in a funnel device, more preferably a glass sand core funnel; 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 heating the reaction kettle, wherein the heating temperature is preferably 60-100 ℃, more preferably 70-90 ℃, and most preferably 80 ℃.

More preferably, the weight ratio of the 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 to 25; the weight ratio of the gradient sustained-release agent solution to the zsm-5 is 1:1-5; the concentration of the gradient sustained-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 static magnetic field strength is 10-50MT, preferably 20-30MT, and most preferably 25MT.

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

Preferably, when the solvent is added in the crystallization process, 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 1-100 μm, preferably 5-80 μm, more preferably 10-70 μm, most preferably 10-15 μm;

furthermore, the invention also comprises the recovery of the modified molecular sieve, the molecular sieve is recovered and then added with a small amount of electrolytic water to dissolve, wash, soak overnight, centrifugally precipitate, and then the product is obtained by steam treatment for 1-2h and drying. Further the electrolyzed water may be prepared by a water ionizer or generated by a method of direct current through an aqueous solution. Further, the steam treatment is steam treatment at 100-150 deg.C.

Further, the crude pantoprazole can be obtained by the usual processes described in the prior art, or can be obtained as a commercial product, preferably with a purity of not higher than 90%, preferably with an S configuration of not lower than 50%.

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

further, the drying methods of the present invention include, but are not limited to, vacuum drying, rotary evaporation, oven drying, freeze drying, and the like.

The test compound raw materials and pantoprazole crude products are purchased from sigma company and Guangdong Shuo spectrum biotechnology limited company

ZSM-5 (chemical formula is Na) _n Al _n Si96-nO ₁₉₂ ·16H ₂ O). SiO2/Al2O3 (Si/Al ratio: 90), from Xiancheng 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 purification and crystallization processes of the chiral compound are combined, so that the preparation process is simplified, an expensive chiral resolving agent is saved, and compared with a catalytic resolution method of biological enzyme, the method provided by the invention has the advantages that the controllability of process operation is increased, and the production cost is reduced.

2) In the process of forming the molecular sieve-polymer, the method of combining hole making and crosslinking is adopted, the molecular sieve-polymer composite is placed in a standing magnetic field to form an asymmetric multilayer network structure, the stability of the composite is improved, and Nacl solution is added to delay the release of ionized substances, so that the modified composite 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 uniform particle size distribution, but also can be used for preparing corresponding products according to different purposes (preparation, clinic and purity requirements).

3) Based on the combination of the intelligent material and the compound preparation, the obtained product shows good performance under the conditions of high temperature and high humidity, the crystal physical properties of part of the product are suitable to be used as raw materials, the stability (color change and moisture absorption) is improved, and the possibility is provided 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 micrograph of S-pantoprazole sodium crystals.

Detailed Description

Example 1:

a) A preparation method of pantoprazole crude product;

commercially available 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 90% or less and 50% or more, chemical purity less than 99% as described above) as exemplified below:

1) 2-hydroxymethyl-3,4-dimethoxypyridine (II) is used as a starting material, and under the action of chloride, 2-chloromethyl-3,4-dimethoxypyridine hydrochloride (III) is generated; 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) by using 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-dimethoxypyridine hydrochloride in ethanol, adding sodium iodide, then adding an ethanol solution of 5-difluoromethoxy-2-mercapto-IH-benzimidazole and an aqueous solution of sodium hydroxide, stirring for reaction, distilling under reduced pressure, adding water, continuing stirring, precipitating 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 agents, namely 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 a white-like solid pantoprazole;

pantoprazole has the following structural formula:

b) Modification preparation of the molecular sieve:

putting 500g of a commercial ZSM-5 molecular sieve (with a silicon-aluminum ratio of 90) into a reaction kettle, adding 10L of water, stirring, heating to a temperature of more than 80 ℃, adding 20g of triethylamine and 50g of iron powder after uniformly stirring, adding 50g of N-N methylene bisacrylamide after stirring for 2h, simultaneously placing the reaction kettle in a static magnetic field of 25MT, then using a jacket to heat the reaction kettle to room temperature under a cooling water circulation condition, filtering and precipitating, heating in a muffle furnace to 240 ℃, keeping in a calcining disc for 12h, combining the calcined molecular sieve and a Nacl (2%) aqueous solution, standing and refluxing for 1h, and carrying out vacuum filtration and air drying at room temperature to obtain ZSM-5 modified molecular sieve particles;

c) Preparation of S-pantoprazole sodium

1) Adding 500ml of water and 16g of NaOH into a spherical separating funnel, dissolving, magnetically stirring, taking 100g of pantoprazole crude product (optical purity detection s-pantoprazole content is 54%), adding the pantoprazole crude product into the solution, continuously stirring, keeping the temperature at room temperature, reacting for 2-3h, adding 4g of sodium ethoxide, and keeping the pH of the reaction solution at 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 the glass sand core funnel, placing the reaction bottle on a magnetic stirrer, washing for 2min by using deionized water, then dropwise adding the reaction solution obtained in the step 1) into the sand core funnel at the speed of 1-2ml/min, carrying out suction filtration to enter the reaction bottle, carrying out magnetic stirring at the stirring speed of 30rpm, filtering a small amount of precipitate at the bottom of the bottle, adding diethyl ether into filtrate to separate out precipitate, carrying out centrifugal filtration to precipitate, and adding water/acetone (mass ratio of 1: 1) Stirring the solution until the solution is dissolved, dropwise adding a 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 for crystallization for 2 hours, cooling to 0-5 ℃, keeping the temperature, standing for crystallization for 2 hours, filtering, washing the precipitate with acetone for 2 times, and performing vacuum drying to obtain the s-pantoprazole sodium crystal.

HPLC (high performance liquid chromatography) detection is s-pantoprazole sodium (see attached figure 1), a crystal form electron microscope scanning image is shown in attached figure 3, and the electron microscope detection shows that the crystal grain diameter D90 is about 25-35 mu m; the uniformity is high, and the structure is as follows:

d) Molecular sieve recovery

And (3) recovering the molecular sieve in the sand core funnel, adding a small amount of electrolytic water to dissolve, washing, soaking overnight, centrifuging, precipitating, treating for 1-2h through steam, and drying.

E) And (3) detecting the optical purity: the liquid chromatograph is a high performance liquid chromatograph, and the chromatographic column comprises: 0D-RH (Chiralcel, 150mmX4.6mm, 5ym); detection wavelength: 292nm; flow rate: 0.8ml/min; sample introduction volume: 10 mu 1. The mobile phase is a mixed solvent of water and acetonitrile (3;1), a proper amount of a target object is precisely weighed, the mobile phase is added for dissolution and is prepared into a solution containing about 0.2mg of a compound in each lml, the solution is filtered, and a subsequent filtrate is taken as a test sample solution; precisely measuring pantoprazole sodium racemate, and diluting with a mobile phase to prepare a solution containing 2Pg in lml as a control solution.

F) And (3) detecting chemical purity: HPLC (appendix V D of the second part of the Chinese pharmacopoeia 2005 edition) determination, octadecylsilane chemically bonded silica is used as a filler; phosphate buffer (1.12 g of disodium hydrogen phosphate and 0.18g of sodium dihydrogen phosphate are taken, dissolved in water and diluted to 1000 ml) -acetonitrile (70);

the optical purity of the final product is more than or equal to 99.95 and the chemical purity of the final product is more than or equal to 99.89.

Example 2:

a) The crude pantoprazole product was obtained as in example 1 by the prior art method (optical purity was measured for s-pantoprazole content 67%).

B) Modification preparation of the molecular sieve:

putting 500g of a commercial ZSM-5 molecular sieve (with a silicon-aluminum ratio of 90) into a reaction kettle, adding 12L of water, stirring, heating to a temperature above 80 ℃, adding 30g of triethylamine and 70g of ferroferric oxide powder after uniformly stirring, adding 100g of a mixture of N-N methylene bisacrylamide and ammonium persulfate after stirring for 4h (wherein 80g of N-N methylene bisacrylamide and 20g of ammonium persulfate), standing in a static magnetic field of 25MT after stirring for 3h, slowly adding 5L of Nacl aqueous solution with a mass concentration of 2% in batches, then using a jacket cooling water circulation condition to adjust the temperature of the reaction kettle to room temperature, standing for 3-4h, filtering and precipitating, heating to 140 ℃ by a muffle furnace, and keeping in a calcining disc for 10 h to obtain ZSM-5 modified molecular sieve particles;

c) Preparation of S-pantoprazole sodium

1) Adding 500ml of water and 12g of NaOH into a reaction bottle, dissolving, magnetically stirring, taking 100g of pantoprazole crude product, adding the pantoprazole crude product into the solution, continuously stirring, keeping the temperature at 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 the glass sand core funnel, washing for 2min by using deionized water, then dropwise adding the reaction liquid obtained in the step 1) into the sand core funnel at the speed of 1-2ml/min, carrying out suction filtration, allowing the reaction liquid to enter the reaction bottle, carrying out magnetic stirring at the stirring speed of 30rpm, filtering and removing a small amount of precipitate at the bottom of the bottle, adding diethyl ether into filtrate to separate out precipitate, carrying out centrifugal filtration on the precipitate, and adding water/acetone (mass ratio 1: 1) Stirring the solution until the solution is dissolved, dropwise adding an ether solution which is equal to the volume of the water/acetone solution at the speed of 5-6ml/min until the solution is turbid, introducing cooling water to cool to 5-10 ℃, stirring and crystallizing for 2 hours, cooling to 0-5 ℃, preserving heat, standing and crystallizing for 2 hours, filtering, washing the precipitate with ether for 2 times, and performing vacuum drying to obtain the product. A

D) Molecular sieve recovery and optical purity measurements were performed as in example 1

The HPLC detection spectrum is the same as that of the embodiment 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 crystal grain diameter D90 is about 25-35 μm by microscopic detection; the uniformity is higher.

Example 3:

a) The crude pantoprazole product was obtained as in example 1 by the prior art method (optical purity measured s-pantoprazole content 57%).

C) Modification preparation of the molecular sieve:

putting 500g of a commercial ZSM-5 molecular sieve (with a silicon-aluminum ratio of 90) into a reaction kettle, adding 12L of water, stirring, heating to a temperature above 80 ℃, uniformly stirring, adding 70g of ferric oxide powder, stirring for 4h, adding 100g of a mixture of N-N methylene bisacrylamide and ammonium persulfate (wherein 80g of N-N methylene bisacrylamide and 20g of ammonium persulfate), stirring for 3h, standing in a static magnetic field of 25MT, then using a jacket cooling water circulation condition to adjust the temperature of the reaction kettle to room temperature, standing for 3-4h, filtering and precipitating, heating in a muffle furnace to 140 ℃, and keeping in a calcining disc for 10 h to obtain ZSM-5 modified molecular sieve particles;

c) Preparation of pantoprazole sodium

1) Adding 500ml of water and 20g of NaOH into a reaction bottle, dissolving, magnetically stirring, taking 100g of pantoprazole crude product, adding the pantoprazole crude product into the solution, continuously stirring, keeping the temperature at room temperature, reacting for 2-3h, 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 the glass sand core funnel, washing for 2min by using deionized water, then dropwise adding the reaction liquid obtained in the step 1) into the sand core funnel at the speed of 1-2ml/min, carrying out suction filtration, allowing the reaction liquid to enter the reaction bottle, carrying out magnetic stirring at the stirring speed of 30rpm, filtering and removing a small amount of precipitate at the bottom of the bottle, adding diethyl ether into filtrate to separate out precipitate, carrying out centrifugal filtration on the precipitate, and adding water/acetone (mass ratio 1: 1) Stirring the solution until the solution is dissolved, dropwise adding an ethyl acetate solution which is equal to the volume of the water/acetone solution at the speed of 5-6ml/min until the solution is turbid, introducing cooling water to cool to 5-10 ℃, stirring and crystallizing for 2 hours, cooling to 0-5 ℃, preserving heat, standing and crystallizing for 2 hours, filtering, washing the precipitate with ethyl acetate for 2 times, and performing vacuum drying to obtain the product. A

The pantoprazole sodium crystal is detected by HPLC, the chemical purity is more than or equal to 99.92 percent, the content of s-pantoprazole sodium is 87.76 percent, and the rest is R configuration.

Example 4:

a) The crude pantoprazole product was obtained as in example 1 by the prior art method (optical purity test s-pantoprazole content 57%).

B) Modification preparation of molecular sieve:

putting 500g of a commercial ZSM-5 molecular sieve (with a silicon-aluminum ratio of 90) into a reaction kettle, adding 10L of water, stirring, heating to a temperature of over 100 ℃, adding 20g of triethylamine after stirring uniformly, adding 50g of N-N methylene bisacrylamide after stirring for 2h, then using a jacket cooling water circulation condition to adjust the temperature of the reaction kettle to room temperature, filtering and precipitating, heating to 240 ℃ in a muffle furnace, keeping for 12h in a calcining disc, combining the calcined molecular sieve with a Nacl (2%) aqueous solution, standing and refluxing for 1h, and carrying out vacuum filtration and air drying at room temperature to obtain ZSM-5 modified molecular sieve particles;

c) Preparation of pantoprazole sodium

1) Adding 500ml of water and 15g of NaOH into a spherical separating funnel, dissolving, performing magnetic stirring, taking 100g of pantoprazole crude product (optical purity detection s-pantoprazole content is 57%), adding the solution, continuing stirring, keeping the temperature at room temperature, reacting for 2-3h, adding 5g of sodium ethoxide, and keeping the pH of the reaction solution at 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 the glass sand core funnel, placing the reaction bottle on a magnetic stirrer, washing for 2min by using deionized water, then dropwise adding the reaction solution obtained in the step 1) into the sand core funnel at the speed of 1-2ml/min, carrying out suction filtration to enter the reaction bottle, carrying out magnetic stirring at the stirring speed of 30rpm, filtering a small amount of precipitate at the bottom of the bottle, adding diethyl ether into filtrate to separate out precipitate, carrying out centrifugal filtration to precipitate, and adding water/acetone (mass ratio of 1: 1) Stirring the solution until the solution is dissolved, dropwise adding a 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, introducing cooling water to cool to 5-10 ℃, stirring and crystallizing for 2 hours, cooling to 0-5 ℃, preserving heat, standing and crystallizing for 2 hours, filtering, washing the precipitate with acetone for 2 times, and performing vacuum drying to obtain the product.

The pantoprazole sodium crystal is detected by HPLC, the chemical purity is more than or equal to 98.92 percent, and the s-pantoprazole sodium content is 89.56 percent.

Example 5:

B) Modification preparation of the molecular sieve:

putting 500g of a commercial ZSM-5 molecular sieve (the silica-alumina ratio is 90) into a reaction kettle, adding 12L of water, stirring, heating to above 80 ℃, uniformly stirring, adding 100g of a mixture of N-N methylene bisacrylamide and ammonium persulfate (wherein 80g of N-N methylene bisacrylamide and 20g of ammonium persulfate), then using jacket cooling water circulation condition to adjust the temperature of the reaction kettle to room temperature, standing for 3-4h, filtering and precipitating, heating in a muffle furnace to 140 ℃, and keeping in a calcining tray for 10 h to obtain ZSM-5 modified molecular sieve particles;

c) Preparation of pantoprazole sodium

2) Putting 200g of the modified molecular sieve obtained in the step B) into a glass sand core funnel, connecting a suction filtration reaction bottle below the glass sand core funnel, washing for 2min by using deionized water, then dropwise adding the reaction solution obtained in the step 1) into the sand core funnel at the speed of 1-2ml/min, carrying out suction filtration to enter the reaction bottle, magnetically stirring at the stirring speed of 30rpm, filtering out a small amount of precipitate at the bottom of the bottle, adding diethyl ether into filtrate to separate out precipitate, carrying out centrifugal filtration to precipitate, and adding water/acetone (mass ratio 1: 1) Stirring the solution until the solution is dissolved, dropwise adding an ether solution with the same volume as the water/acetone solution at the speed of 5-6ml/min until the solution is turbid, introducing cooling water, cooling to 5-10 ℃, stirring for crystallization for 2 hours, cooling to 0-5 ℃, keeping the temperature, standing for crystallization for 2 hours, filtering, washing the precipitate with ether for 2 times, and performing vacuum drying to obtain the product. A

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

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

Comparative example 1: commercially available pantoprazole sodium (analytical grade), control example 2: commercially available s-pantoprazole sodium (analytical grade)

Test 1: high temperature high humidity stability test

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

TABLE 1

It can be seen that examples 1-3 exhibit good stability, with example 4 showing a relatively rapid increase in moisture pick-up and a relatively rapid decrease in stability after 10 days, but still being superior to the commercial product.

Test 2: measurement of color difference

SPSS20.0 statistical software is adopted for analysis, differences among groups are compared by adopting t test, the difference with P <0.05 is statistically significant, and the result is shown in a table 2;

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

TABLE 2

According to tables 1 and 2, examples 1 to 4 all exhibited color difference stability, example 5 was significantly different from examples 1 to 4 and the control, and control 1/2 was significantly different from each example. The problem of chromatic aberration is more severe for example 5 over time, and although the chromatic aberration changes are still less for example 5 than for example 4 at 2h, example 4 is better than example 5 for clinical dispensing applications. The crystal of example 3 also shows good stability, from which it can be seen that the S-pantoprazole sodium content (optical purity of the compound) does not affect the change in the degree of chromatic aberration; further factors affecting the color difference may be the stability of the crystal structure or whether impurities affect the oxidation process. Example 5 compared to example 4, the pore-forming agent triethylamine is not used, so that different pores in the molecular sieve polymer structure may cause unfavorable chiral change, the magnetic field may change the network morphology and pore size structure of the molecule, the molecular sieve may not form unidirectional displacement in the absence of the magnetic field to form a pore size structure favorable for chiral formation, the disordered ordering of ions is increased, and the polymer amount is reduced; and no Nacl is used, and gradient adsorption can be formed in a molecular sieve-polymeric layer structure through magnetic field or electrostatic adsorption during the standing process of the Nacl, which can cause ionization to continuously release ions during the passing process of the compound, and can also be the reason for more stable compound crystals. The color difference of the crystal of example 4 is stable but the hygroscopic type is not good, which may be related to the cross-linking agent, and the gradient change of the aperture and the shape is caused by the action of the iron powder and the magnetic field, in the absence of the above conditions, some impurities can only be removed by recrystallization, the crystal performance may be influenced during the recrystallization, and the poor solvent selection during the crystallization may also be the reason of the difference of the crystal performance and the shape.

Test 3: crystal morphology and solubility

1) The particle size and the appearance of the particles were measured for each example and control sample by scanning with an electron microscope;

2) The solubility is that the sample is tabletted by a conventional process, 20 percent of excipient, 10 percent of filler and 5 percent of lubricant are added into the sample respectively, and the mixture is tabletted by a tabletting machine, wherein the excipient is microcrystalline cellulose, the filler is starch, and the lubricant is magnesium stearate. Dissolution of the tablets of the product of the examples in a phosphate buffered solution of sodium lauryl sulfate at room temperature was measured using a Distek dissolution apparatus (DISTEK Corp., 2100A) and had a dissolution surface area of 1cm ² 。

See table 3 for results.

TABLE 3

From the above test results, it can be seen that although the crystal size distribution of example 3 is narrower and the particles are more uniform, the optical purity of examples 1-2 is better. Example 3 is more suitable for preparing preparations with higher requirements on the bulk density or the pharmaceutical substitution of the crystals, such as tablets, granules and the like, and simultaneously contains a certain amount of R configuration; the examples 1-2 are s-pantoprazole sodium with higher optical purity, are more stable in the aspects of chromatic aberration and moisture absorption, and are suitable for the situations of clinical preparation of injections, emergency medication and the like, the tablets of the example 5 and the commercially available raw materials show faster dissolution, and the commercially available raw materials have higher moisture absorption types.

The above-described embodiments are not intended to limit the scope of the invention, which is defined by the claims, and those skilled in the art can make various modifications and applications in light of the above teachings.

Claims

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

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

wherein the weight ratio of NaOH to sodium ethoxide is 1-5:1; the modified molecular sieve is prepared by reacting a ZSM-5 molecular sieve with a cross-linking agent.

2. The process of claim 1, wherein the modified molecular sieve is obtained by the steps of:

1) Placing a ZSM-5 molecular sieve in the solution;

2) Adding a pore-making agent and a cross-linking agent;

3) And (4) calcining.

3. The method of claim 2, wherein 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.

4. The method of claim 2, further comprising the steps of adding an aqueous solution of a gradient sustained release agent into the calcined molecular sieve in the step 4), standing, and drying in vacuum to obtain the gradient sustained release agent, wherein the gradient sustained release agent is NaCl.

5. The method of claim 2, wherein the weight ratio of the 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 to 25; the weight ratio of the water solution of the gradient sustained release agent to the zsm-5 is 1:1-5; the concentration of the gradient sustained-release agent solution is 2g/100ml.

6. The method of claim 2, wherein the reaction device is placed in a static magnetic field after the porogen and cross-linking agent are added in step 2.

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

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

2) Adding a ZSM-5 molecular sieve into water, stirring, heating, adding a pore-forming agent and a cross-linking agent, simultaneously placing in a static magnetic field for reaction, cooling to room temperature, filtering and precipitating, adding a NaCl aqueous solution (the mass volume concentration is 2%) after calcining, standing and refluxing, and drying in vacuum to obtain the modified ZSM-5 molecular sieve;

3) And (2) placing the modified molecular sieve in a funnel device, gradually dropwise adding the reaction liquid obtained in the step (1), adding a poor solvent into the filtrate obtained by suction filtration to separate out a precipitate, recrystallizing again, and drying to obtain the modified molecular sieve.

8. The process according to claim 1 or 2, wherein the poor solvent is selected from the group consisting of diethyl ether, acetone, ethyl acetate and/or methyl isobutyl ketone; the step of recrystallization comprises the steps of adding a precipitate into a solvent 1, and then adding a solvent 2 to separate out crystals, wherein the solvent 1 is selected from water and/or acetone; the solvent 2 is selected from diethyl ether, ethyl acetate and/or methyl isobutyl ketone.