CN111187255A - Preparation method of dextro-ilaprazole potassium salt and preparation method of dextro-ilaprazole - Google Patents

Abstract

The invention discloses a preparation method of dexilaprazole potassium salt and a preparation method of dexilaprazole, and relates to the technical field of medicines. The preparation method of the dextro-ilaprazole potassium salt comprises the following steps: mixing the crude product of the dextro-ilaprazole, an alcohol solvent, a first organic solvent and KOH to perform a potassium salt reaction, and then precipitating dextro-ilaprazole potassium salt solid. In the application, a crude product of the dextrorotation ilaprazole is used as an initial raw material, the crude product is mixed with an alcohol solvent, a first organic solvent and KOH, the mixture is stirred, a sylvite reaction is performed to generate sylvite, the obtained dextrorotation ilaprazole sylvite crystal form can be kept consistent, the solubility is basically consistent, and the dextrorotation ilaprazole obtained by subsequent preparation can be improved, and the content of the dextrorotation ilaprazole sulfone and ilaprazole thioether impurities is lower than 0.2%. The preparation method is suitable for industrial production, and the difference of each batch is small.

Description

Preparation method of dextro-ilaprazole potassium salt and preparation method of dextro-ilaprazole

Technical Field

The invention relates to the technical field of medicines, and particularly relates to a preparation method of dexilaprazole potassium salt and a preparation method of dexilaprazole.

Background

Ilaprazole is a novel proton pump inhibitor and is used for treating duodenal ulcer, gastric ulcer and erosive esophagitis. Ilaprazole contains one chiral center and is a racemic mixture of two single enantiomers, the R and S enantiomers. CN101098867A discloses a method for preparing a single enantiomer of ilaprazole, and animal experiments show that the optically pure isomer of ilaprazole, i.e. dextrorotatory or levorotatory ilaprazole, has more excellent therapeutic effect in treating diseases associated with hyperacidity compared with its racemate.

Currently, there is an asymmetric chemical synthesis method for obtaining an optically pure ilaprazole isomer, for example, patent CN108689995A discloses that 5- (1H-pyrrol-1-yl) -2-mercaptobenzimidazole is used as an initial raw material to prepare optically active ilaprazole through a series of chemical reactions. And the patent does not mention how to obtain dexilaprazole with a high e.e value from ilaprazole racemate or crude dexilaprazole. In addition, a method for selectively extracting a certain enantiomer by using an organic solvent is disclosed in patent CN101098867B, for example, a method for purifying a crude product of dextrorotatory ilaprazole is disclosed, the crude product of (+) -ilaprazole is dissolved in the organic solvent to obtain a clear solution, and activated carbon is used for decoloring at room temperature, filtering and evaporating. The residue was dissolved in a mixture of dichloromethane and butanone, stirred at room temperature for one or two days, left overnight in a refrigerator, and filtered to give (+) -ilaprazole as a white solid. The method has long time consumption and harsh experimental conditions, needs to be placed overnight at low temperature, and is not suitable for industrial production.

Other single enantiomer purification methods of prazole medicines, such as mixed organic solvent purification, patent CN1197861C discloses reacting omeprazole with NaOH solution, converting into omeprazole sodium salt, adding omeprazole sodium salt into mixed solvent of methanol and inorganic acid salt or methyl formate for dissolving, cooling for crystallization, and vacuum drying to obtain powder solid.

However, the e.e value of the dexilaprazole obtained by the existing preparation method is not good, and more impurities are remained.

In view of this, the invention is particularly proposed.

Disclosure of Invention

The invention aims to provide a preparation method of a dextrorotatory ilaprazole potassium salt, wherein the e.e value of the obtained dextrorotatory ilaprazole potassium salt is more than 98.0%, and the contents of impurity ilaprazole thioether and ilaprazole sulfone are both less than 0.2%.

The invention aims to provide a preparation method of dexilaprazole, which can obtain dexilaprazole with a high e.e value and has little impurity residue.

The invention is realized by the following steps:

in a first aspect, embodiments provide a method for preparing a potassium salt of dexilaprazole, comprising:

mixing the crude product of the dextro-ilaprazole, an alcohol solvent, a first organic solvent and KOH to perform a potassium salt reaction, and then precipitating dextro-ilaprazole potassium salt solid.

In an alternative embodiment, the potassium salt forming reaction is carried out at 15-30 ℃ for 2-3 h;

preferably, carrying out crystallization for 2-3h at 15-30 ℃, and then carrying out solid-liquid separation to obtain the dextro-ilaprazole potassium salt solid;

preferably, the e.e value of the dextro-ilaprazole potassium salt is > 98.0%.

In alternative embodiments, the first organic solvent comprises a mixture of any one or more of dichloromethane, ethyl acetate, and acetonitrile;

preferably, the first organic solvent is dichloromethane or ethyl acetate;

preferably, the alcoholic solvent comprises a mixture of one or more of methanol, ethanol and ethylene glycol;

preferably, the alcohol solvent is methanol.

In an alternative embodiment, the amount of the alcohol solvent added per gram of the crude dexilaprazole is 3.0 to 3.5 mL.

In an alternative embodiment, the amount of the first organic solvent added per gram of the crude dexilaprazole is 8 to 12mL, preferably 10 to 12 mL.

In an alternative embodiment, the molar ratio of KOH to the crude dexilaprazole is 1: 1-1.5; preferably, the molar ratio is 1: 1.1-1.3.

In a second aspect, embodiments provide a method for preparing dexilaprazole, wherein dexilaprazole is prepared by using a dexilaprazole potassium salt obtained by the method for preparing dexilaprazole potassium salt according to any one of the preceding embodiments as a raw material;

preferably, the dexilaprazole potassium salt, water, a second organic solvent and a reaction acid are mixed, an extraction solvent is added for extraction, and the organic phase obtained by extraction is mixed with a third organic solvent to precipitate the dexilaprazole;

preferably, a drying agent is added to the organic phase obtained by extraction before mixing the organic phase with the third organic solvent, then filtering is carried out, and the filtrate is dried;

preferably, the drying agent is anhydrous magnesium sulfate and triethylamine;

preferably, the organic phase is mixed with the third organic solvent by stirring at a temperature of 20-30 ℃ to precipitate the dexilaprazole.

In an alternative embodiment, in the step of mixing the potassium salt of dexilaprazole with the reaction acid for reaction, the pH of the reaction mixture solution is 8 to 9;

preferably, the acid for the reaction is a weak acid; more preferably, the acid for reaction is selected from any one of dilute acetic acid, phosphoric acid, potassium dihydrogen phosphate and ammonium chloride; further preferably dilute acetic acid;

preferably, the mass concentration of the acid for reaction is 25.0-50.0%.

In alternative embodiments, the second organic solvent is selected from any one or more of methanol, ethanol, and isopropanol; preferably methanol;

preferably, the extraction solvent used in the extraction process is dichloromethane;

preferably, the amount of the extraction solvent added per gram of the crude product of dexilaprazole is 3-5 mL.

In alternative embodiments, the third organic solvent is selected from isopropanol and/or acetonitrile, preferably isopropanol;

preferably, the amount of the third organic solvent added per gram of the crude dexilaprazole is 4-6 mL.

The invention has the following beneficial effects:

in the application, a (+) -ilaprazole crude product is used as a starting raw material, is mixed with an alcohol solvent, a first organic solvent and KOH, is stirred, and is reacted to generate a potassium salt through a potassium salt forming reaction, so that the finally obtained crystal form of the dextrorotatory ilaprazole potassium salt can be kept consistent, the solubility is basically consistent, and the dextrorotatory ilaprazole obtained by subsequent preparation is favorably improved, has a high e.e value and high purity, and the contents of impurities ilaprazole sulfone and ilaprazole thioether are all lower than 0.2%. The preparation method of the dextro-ilaprazole potassium salt and the preparation method of the dextro-ilaprazole are suitable for industrial production, and the difference of each batch is small.

Detailed Description

In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.

The application provides a preparation method of a dextro-ilaprazole potassium salt, which comprises the following steps:

mixing a crude product of the dextro-ilaprazole (namely: (+) -ilaprazole), an alcohol solvent, a first organic solvent and KOH to perform a potassium salt forming reaction, and crystallizing a dextro-ilaprazole potassium salt solid.

Specifically, in the application, (+) -ilaprazole is added into a mixed solvent of an alcohol solvent and a first organic solvent, KOH is added, a potassium salt forming reaction is performed for 2-3 hours at 15-30 ℃, then the reaction mixed solution is crystallized for 2-3 hours at 15-30 ℃, and solid-liquid separation is performed to obtain a dextrorotatory ilaprazole potassium salt solid. Among them, there are various solid-liquid separation methods, including but not limited to: filtration, centrifugation, and the like.

In this embodiment, the value of (+) -ilaprazole may be any e.e value, that is, the e.e value of (+) -ilaprazole crude product is more than 1% and can be used as the raw material of the present application, specifically, in this embodiment, the e.e value of (+) -ilaprazole is 70% to 80%.

The alcohol solvent comprises one or more of methanol, ethanol and glycol; preferably, the alcohol solvent is methanol, and the dosage of the alcohol solvent added in each gram of (+) -ilaprazole is 3.0-3.5 mL;

the first organic solvent comprises a mixture of any one or more of dichloromethane, ethyl acetate and acetonitrile; preferably, the first organic solvent is dichloromethane or ethyl acetate; the dosage of the first organic solvent added into each gram of (+) -ilaprazole is 8-12mL, and preferably 10-12 mL.

The molar ratio of KOH to (+) -ilaprazole is 1: 1-1.5; preferably, the molar ratio is 1: 1.1-1.3.

In the application, a (+) -ilaprazole crude product is used as an initial raw material, is mixed with an alcohol solvent, a first organic solvent and KOH, is stirred, and is reacted to generate a potassium salt through a potassium salt forming reaction, so that the finally obtained crystal form of the dextrorotatory ilaprazole potassium salt is kept consistent, the solubility is basically consistent, the e.e value of the dextrorotatory ilaprazole prepared subsequently is favorably improved, and the small difference of each batch is ensured.

In addition, the reaction condition of the potassium salt forming reaction is mild, the reaction can be carried out at 20-30 ℃, the reaction time is short, and the reaction can be completed only in 2-3 h.

It is noted that the selection of the alcohol solvent and the first organic solvent as the mixed solvent, especially the selection of methanol and dichloromethane as the mixed solvent, can allow the selective precipitation of the ilaprazole potassium salt in the mixed solvent. Compared with the method of adding a single alcohol solvent or a single first organic solvent, the target product (the dextro-ilazole potassium salt) can be well deposited in a solid phase instead of a liquid phase by compounding the alcohol solvent and the first organic solvent, so that the residues of impurities (ilaprazole sulfone and ilaprazole thioether) can be effectively reduced. And then, solid and liquid can be separated through filtration, and the target product in the application is deposited in a solid phase, so that the filter cake obtained after solid and liquid separation in the application is the dextro-ilaprazole potassium salt.

The e.e value of the dextro-ilazole potassium salt obtained by the preparation method of the dextro-ilazole potassium salt is more than 98.0%, the residues of impurities of ilazole thioether and ilazole sulfone are few, the contents of the ilazole thioether and the ilazole sulfone are both less than 0.2%, and the dextro-ilazole potassium salt is stable.

In a second aspect, the present application further provides a method for preparing dexilaprazole using the dexilaprazole potassium salt prepared by the above method for preparing dexilaprazole potassium salt as a raw material, which comprises the following steps:

s1, mixing the dextro-ilaprazole potassium salt, water, a second organic solvent and the reaction acid.

In the application, the dextro-ilazole potassium salt is prepared by the method, the stability is good, the e.e value is high, the residues of impurity ilazole sulfide and ilazole sulfone are few, wherein the e.e value is about more than 98.0%, and the residues of impurity ilazole sulfide and ilazole sulfone are both less than 0.2%.

In the present application, water includes, but is not limited to, a mixture of one or more of deionized water, distilled water, pure water, and ultrapure water.

Preferably, the second organic solvent is selected from any one or more of methanol, ethanol and isopropanol; methanol is preferred.

Preferably, the reacting acid is a weak acid; more preferably, the acid for reaction is selected from any one of dilute acetic acid, phosphoric acid, potassium dihydrogen phosphate and ammonium chloride; further preferably dilute acetic acid, and preferably, the mass concentration of the acid for reaction is 25.0-50.0%. In this application, the pH of the reaction mixture solution is adjusted to 8 to 9 by using an acid for the reaction.

S2, extracting to obtain an organic phase.

Specifically, an extraction solvent is added to the mixed reaction solution of step S1 for extraction, the extraction solvent used in the present application is dichloromethane, the addition amount of the extraction solvent is calculated by the amount of the crude product of dexilaprazole, specifically, the amount of the extraction solvent added per gram of the crude product of dexilaprazole is 3 to 5mL (the amount of the extraction solvent may be, for example, any one of 3, 4 and 5mL or a range value therebetween), and then the organic phase is taken.

Before the organic phase is obtained and step S3 is performed, a drying agent may also be added to the organic phase, and then filtered again, and the filtrate is dried, preferably in a rotary drying manner in this application. Preferably, the drying agents used in this application are anhydrous magnesium sulfate and triethylamine.

S3, mixing the organic phase and the third organic solvent to precipitate the dexilaprazole.

Specifically, adding a third organic solvent into the dried filtrate, stirring at the temperature of 15-30 ℃ to separate out a solid, and filtering to obtain the dexilaprazole with the improved e.e value.

In the present application, the third organic solvent is selected from isopropanol and/or acetonitrile, preferably isopropanol. The addition amount of the third organic solvent is calculated by the amount of the crude product of the dexilaprazole, and specifically, the amount of the third organic solvent added in each gram of the crude product of the dexilaprazole is 4-6 mL.

The preparation method of dexilaprazole provided by the application mainly uses the dexilaprazole potassium salt prepared by the preparation method of the dexilaprazole potassium salt as a raw material, the crystal forms of the dexilaprazole potassium salt prepared by the same method are basically consistent, the difference of each batch is small, and then the stability of the e.e value of the final product of the dexilaprazole is improved, so that the difference of the final product is small.

The features and properties of the present invention are described in further detail below with reference to examples.

The raw material (+) -ilaprazole crude product is prepared by the following method: 10g of thioether, 6.53g of DBU, 50mL of isopropanol, and 50mL of toluene were sequentially added to a 100mL three-necked flask at room temperature. Then adding 7.22g of (S-) camphorsulfodumene, reacting for 2h at 10 ℃, stopping the reaction, filtering to obtain mother liquor (the e.e value is 70-80%), spinning to dry the solvent, adding 50mL of water and 10mL of isopropanol into the oily matter, adding 25% by mass of acetic acid aqueous solution while stirring, and adjusting the pH value to 8.0-9.0. The aqueous phase was extracted twice with 50 mL/dichloromethane, the organic phases were combined and the aqueous phase was discarded. And (3) spin-drying the organic phase, adding 100mL of isopropanol into the oily matter, stirring for 2h at normal temperature, and filtering to obtain a dexilaprazole solid with an e.e value of 70-80%.

Example 1

Adding 10g of (+) -ilaprazole into a mixed solvent of 120mL of dichloromethane and 30mL of methanol, adding 1.84g of KOH (equivalent to the molar ratio of the (+) -ilaprazole being 1.2), carrying out potassium salt forming reaction at 15-30 ℃, crystallizing after about 2.5h, crystallizing at 20-30 ℃ for 2.5h, filtering, and taking a filter cake. Adding a proper amount of water and methanol into the filter cake, and then adding dilute acetic acid to adjust the pH value of the filtrate to 8-9; adding 50mL of dichloromethane for extraction, taking an organic phase, adding anhydrous magnesium sulfate and triethylamine for drying, filtering out a drying agent, and spin-drying; and adding 50mL of isopropanol into the rotary dried substance, stirring at 15-30 ℃ for 1.5h, separating out a solid, and filtering to obtain 5.3g of dexilaprazole. The e.e value of the filter cake is more than 98.0 percent, and the contents of impurities ilaprazole thioether and ilaprazole sulfone are both less than 0.2 percent; the e.e value of the final product was 99.0%, the yield was 53%, the content of ilaprazole sulfide as an impurity was 0.12%, and the content of ilaprazole sulfone was 0.04%.

Example 2

Adding 20g of (+) -ilaprazole into a mixed solvent of 240mL of dichloromethane and 64mL of methanol, adding 3.67g of KOH (equivalent to the molar ratio of the (+) -ilaprazole being 1.2), carrying out a potassium salt forming reaction at 15-30 ℃, crystallizing after about 2.5h, crystallizing at 15-30 ℃ for 2.5h, filtering, and taking a filter cake. Adding a proper amount of water and methanol into the filter cake, and then adding dilute acetic acid to adjust the pH value of the filtrate to 8-9; adding 100mL of dichloromethane for extraction, taking an organic phase, adding anhydrous magnesium sulfate and triethylamine for drying, filtering out a drying agent, and spin-drying; and adding 110mL of acetonitrile into the rotary dried substance, stirring at 15-30 ℃ for 1.5h, separating out a solid, and filtering to obtain 11g of dexilaprazole. The e.e value of the filter cake is more than 98.0 percent, and the contents of impurities ilaprazole thioether and ilaprazole sulfone are both less than 0.2 percent; the e.e value of the final product was 98.9%, the yield was 55%, the content of ilaprazole sulfide as an impurity was 0.09%, and ilaprazole sulfone was not detected.

Example 3

Adding 20g of (+) -ilaprazole into a mixed solvent of 200mL of ethyl acetate and 64mL of ethanol, adding 3.67g of KOH (equivalent to the molar ratio of the (+) -ilaprazole being 1.2), carrying out potassium salt forming reaction at 15-30 ℃, crystallizing after about 2.5h, crystallizing at 15-30 ℃ for 2.5h, filtering, and taking a filter cake. Adding a proper amount of water and methanol into the filter cake, and adding phosphoric acid to adjust the pH value of the filtrate to 8-9; adding 100mL of dichloromethane for extraction, taking an organic phase, adding anhydrous magnesium sulfate and triethylamine for drying, filtering out a drying agent, and spin-drying; and adding 50mL of isopropanol and 55mL of acetonitrile into the rotary dried substance, stirring at 15-30 ℃ for 1.5h, separating out a solid, and filtering to obtain 10.5g of dexilaprazole. The e.e value of the filter cake is more than 98.0 percent, and the contents of impurities ilaprazole thioether and ilaprazole sulfone are both less than 0.2 percent; the e.e value of the final product was 99.1%, the yield was 52.5%, the content of ilaprazole sulfide as an impurity was 0.07%, and the content of ilaprazole sulfone was 0.02%.

Note that the yields in examples 1-3 above were calculated as follows:

(amount of final product/molecular weight of ilaprazole)/(charge of ilaprazole/molecular weight of ilaprazole) 100%), wherein the molecular weight of ilaprazole is 366.44.

Experimental example I screening of organic solvent

(a) Taking 3g of 4 parts of (+) -ilaprazole crude product, respectively adding the 3g of (+) -ilaprazole crude product into methanol solvents with the volumes of 12mL, 18 mL, 24mL and 30mL, adding 0.55g of KOH (equivalent to the molar ratio of the (+) -ilaprazole to 1.2), carrying out potassium salt forming reaction at 15-30 ℃, carrying out crystallization after about 1-2h, carrying out crystallization at 15-30 ℃ for 2-3h, filtering, and taking a filter cake. The e.e value of the filter cake and the contents of ilaprazole sulfide and ilaprazole sulfone as impurities were measured after vacuum drying for 16h, and the results are shown in table 1.

Table 1 results of selective precipitation of ilaprazole potassium salt in methanol solvent

Volume of methanol	Sulfone content (%)	Thioether content (%)	e.e value (%)
				12mL	0.03	0.11	87.9
18mL	N.D	0.08	87.5
				24mL	0.02	0.13	88.9
30mL	0.03	0.11	88.2

(b) Taking 3g of 4 parts of (+) -ilaprazole crude product, respectively adding the 3g of (+) -ilaprazole crude product into acetone solvents with the volumes of 12mL, 18 mL, 24mL and 30mL, adding 0.55g of KOH (equivalent to the molar ratio of the (+) -ilaprazole to 1.2), carrying out a potassium salt forming reaction at 15-30 ℃, reacting for about 5h, and not precipitating solids.

(c) Taking 3g of 4 parts of (+) -ilaprazole crude product, and adding 18, 24, 30, 36 and 42mLCH in volume respectively₂Cl₂0.55g of KOH (corresponding to a molar ratio of (+) -ilaprazole of 1.2) is added into the solvent, a potassium salt forming reaction is carried out at 15-30 ℃, crystallization is started after about 2 hours of reaction, mother liquor is obtained after 3 hours of crystallization, the e.e value of ilaprazole potassium salt and the contents of ilaprazole thioether and ilaprazole sulfone impurities in the mother liquor are measured, and the results are shown in Table 2. The e.e value of the ilaprazole potassium salt in the mother liquor is more than or equal to 98.0 percent, but the impurity growth is serious due to the enrichment of the mother liquor, the ilaprazole sulfone content is about 1.0 percent, and the ilaprazole thioether content is about 2.0 percent.

Table 2: results of selective precipitation of ilaprazole potassium salt in dichloromethane solvent

Description of experiment example one: respectively adding ilaprazole into 3 single solvents of methanol, acetone and dichloromethane, and adding KOH to form potassium salt, so that the dextro-ilaprazole potassium salt cannot be selectively precipitated well, wherein the obtained ilaprazole potassium salt in the methanol solvent has a low e.e value; no precipitate could be obtained in acetone solution; in a dichloromethane solvent, the dextro-ilaprazole potassium salt is enriched in the mother liquor, and the impurity content is high. Further comparing each group of data of example 1 and experimental example one, it can be seen that, in the present application, methanol and dichloromethane are selected as the mixed solvent, which can selectively precipitate the dextro-ilazole potassium salt well, and the dextro-ilazole potassium salt is deposited into the solid phase, thereby obtaining a high e.e value of dextro-ilazole with little impurity residue.

Second example, ilaprazole was selectively precipitated (not to form a potassium salt) directly in a mixed solvent

Taking 4 parts of (+) -ilaprazole 3g (the e.e values are all 74.7%), respectively adding 30mL of dichloromethane solvent, respectively adding 3 mL, 6mL, 9 mL and 12mL of methanol solvent, stirring and pulping for 5-6h at normal temperature, filtering, taking a filter cake, drying in vacuum for 16h, and then measuring the e.e value of the filter cake, wherein the results are shown in Table 3.

Table 3: results of beating ilaprazole in a mixed solvent of methanol and dichloromethane

Volume of methanol	Mother liquor e.e value (%)	Solid e.e value (%)
			3mL	74.4	75.1
6mL	74.5	74.9
			9mL	74.7	74.8
12mL	74.4	75.0

The results show that: the e.e value of the mother liquor is only 70-80%, and the e.e value of the filter cake (i.e. ilaprazole) is only 70-80%. It is shown that the selective precipitation of ilaprazole directly in a mixed solvent of dichloromethane and methanol does not improve the e.e value of dexilaprazole in the solid phase well.

Experiment example III selective precipitation of ilaprazole Potassium in Mixed solvent

Taking 5g of (+) -ilaprazole potassium in 3 batches, respectively adding the (+) -ilaprazole potassium into a mixed solvent with the volume of 50mL of dichloromethane and 15mL of methanol, stirring and pulping for 5-6h at normal temperature, and filtering to obtain a filter cake. The e.e value of the filter cake after vacuum drying for 16h was measured, and the contents of impurities ilaprazole sulfide and ilaprazole sulfone in the filter cake were measured, and the results are shown in table 4.

The method for synthesizing the D-ilaprazole potassium Salt can be obtained by referring to the method for synthesizing the prazole drugs (Davis Oxazidine-media asymmetry Synthesis of protopurp Inhibitors Using DBU Salt of Prochial Sulfide organic Process Research & Development 2010,14, 1264-1268).

Specifically, the method for synthesizing 3 batches of the potassium dexilaprazole in the experimental example comprises the following steps:

10g of thioether, 6.53g of DBU, 50mL of isopropanol and 50mL of toluene were sequentially added to a 100mL three-necked flask at room temperature. Then adding 7.22g of (S-) camphorsulfodumene, reacting for 2 hours at 10 ℃, stopping the reaction, filtering to obtain mother liquor (the e.e value is 70-80%), spin-drying the solvent, adding 50ml of water, opening the stirring, dropwise adding 25% glacial acetic acid aqueous solution by mass fraction into the mixed phase system, adjusting the pH to be approximately equal to 8.0, adding 50 ml/time dichloromethane, and extracting twice. Separating an organic layer, carrying out spin drying, adding 1.2mL of KOH and 2mL of methanol relative to the mass of the ilaprazole per gram into the oily substance, stirring for a certain time, then beginning to separate out potassium salt, slowly adding 10mL of isopropyl ether relative to the mass of the ilaprazole per gram, promoting the separation of potassium salt, and filtering to obtain dextro-ilaprazole potassium salt solid, wherein the e.e value is 70-80%. The above process was repeated 3 times to obtain 3 batches of the potassium salt of dexilaprazole.

Due to the influence of the crystal form of the ilaprazole potassium salt on the adding time and the dropping speed of the solvent, the obtained 3 batches of the crystal forms of the dextro-ilaprazole potassium salt have different differences, and due to the influence of the crystal form of the dextro-ilaprazole potassium salt, the solubility of the ilaprazole potassium salt in a mixed solvent of dichloromethane and methanol is different each time, so that the yield of the ilaprazole potassium salt in the obtained precipitate (namely a filter cake) is different, the yield of the ilaprazole potassium salt in 3 batches is respectively 11.5%, 53.1% and 28.1%, and the difference between the batches is large.

Table 4: results of precipitation of ilaprazole potassium salt in a mixed solvent of dichloromethane and methanol

Experimental example four screening of the amount of methanol used

(1) Sequentially adding the following components into a 250mL three-necked bottle: 10g of crude dextro-ilaprazole (e.e value is 70-80%), 120mL of dichloromethane, 17mL of methanol and 1.83g of KOH, and the mixture is stirred and reacts for about 2 hours at the temperature of 15-30 ℃. And after crystallization is started, timing for 2-3h, and filtering to obtain solid ilaprazole potassium (e.e value is 93.5%) with a lower e.e value.

(2) The e.e values of solid ilaprazole potassium measured according to the experimental method of (1) with varying volumes of methanol of 20mL, 25mL, 30mL, 35mL and 40mL are shown in table 5.

TABLE 5 e.e values of solid ilaprazole potassium at different methanol volumes

Volume of methanol (mL)	17	20	25	30	35	40
							e.e(％)	93.5	95.2	97.4	98.5	98.5	96.9

The mixed solvent of methanol and dichloromethane is selected in the step (1), so that the target product of the dextro-ilazole potassium can be enriched in a solid phase, when the addition amount of methanol is 1.7 mL, 2.0 mL, 2.5 mL and 4.0mL relative to each g of raw material of the dextro-ilazole, the dextro-ilazole potassium is enriched in the solid phase, but the e.e value is lower than 97%, and when the addition amount of methanol is 3.0-3.5mL relative to each g of raw material of the dextro-ilazole, the e.e of the product is more than 98.5%.

Fifth example of experiment, scale-up experiment

(1) In a 250mL flask were added: 10g of crude dextro-ilaprazole (e.e value 76.4%), 120mL of dichloromethane, 30mL of methanol and 1.83g of KOH, and stirring and reacting for 2 hours at room temperature. And after crystallization is started, timing for 2-3h, and filtering to obtain solid ilaprazole potassium. Vacuum drying to obtain 6.1g of D-ilaprazole potassium (e.e value 98.3%, ilaprazole sulfone ND, ilaprazole thioether content 0.02%)

(2) In a 1L flask were charged: 50g of crude dexilaprazole (e.e value 75.4%), 600mL of dichloromethane, 160mL of methanol and 9.18g of KOH, and the reaction is stirred at room temperature for about 3 hours. And after crystallization is started, timing for 2-3h, and filtering to obtain solid ilaprazole potassium. Vacuum drying to obtain 31g of D-ilaprazole potassium (e.e value 99.3%, ilaprazole sulfone ND, ilaprazole thioether content 0.13%)

(3) In a 2L flask were added: 70g of crude levo-ilaprazole (e.e value 73.6%), 840mL of dichloromethane, 224mL of methanol and 12.87g of KOH12.87g, and the reaction is stirred at room temperature for about 3 hours. And after crystallization is started, timing for about 3 hours, and filtering to obtain solid ilaprazole potassium. Vacuum drying to obtain 43.5g of L-ilaprazole potassium (e.e. 98.9%, ilaprazole sulfone ND, ilaprazole thioether ND)

(4) In a 3L flask were added: 140g of crude dextro-ilaprazole (e.e value is 73.1%), 1700mL of dichloromethane, 450mL of methanol and 25.72g of KOH, and the reaction is stirred at room temperature for about 3 hours. And after crystallization is started, timing for about 3.5 hours, and filtering to obtain solid ilaprazole potassium. Vacuum drying to obtain 113g of D-ilaprazole potassium (e.e value 99.0%, ilaprazole sulfone content 0.03%, ilaprazole thioether content 0.02%)

Experiments in experimental example five show that the preparation method of the dextro-ilazole potassium salt and the method for preparing the dextro-ilazole by using the dextro-ilazole potassium salt as the raw material can be amplified to industrial production, and the dextro-ilazole with a high e.e value and little impurity residue can be prepared.

In summary, in the application, a (+) -ilaprazole crude product is used as a starting raw material, mixed with an alcohol solvent, a first organic solvent and KOH, stirred, and reacted to form a potassium salt, so that the finally obtained crystal form of the dextrorotatory ilaprazole potassium salt is kept consistent, the solubility is basically consistent, and the dextrorotatory ilaprazole obtained by subsequent preparation is further improved to have a high e.e value and high purity, and the contents of impurities ilaprazole sulfone and ilaprazole thioether are all lower than 0.2%. The preparation method of the dextro-ilaprazole potassium salt and the preparation method of the dextro-ilaprazole are suitable for industrial production, and the difference of each batch is small.

The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (10)

1. A preparation method of a dextro-ilaprazole potassium salt is characterized by comprising the following steps:

mixing the crude product of the dextro-ilaprazole, an alcohol solvent, a first organic solvent and KOH to perform a potassium salt reaction, and then precipitating dextro-ilaprazole potassium salt solid.

2. The process for the preparation of the potassium salt of dexilaprazole of claim 1, wherein the potassium salt forming reaction is carried out at 15-30 ℃ for 2-3 h;

preferably, carrying out crystallization for 2-3h at 15-30 ℃, and then carrying out solid-liquid separation to obtain the dextro-ilaprazole potassium salt solid;

preferably, the e.e value of the dextro-ilaprazole potassium salt is > 98.0%.

3. The method for preparing a potassium salt of dexilaprazole of claim 1, wherein the first organic solvent comprises a mixture of any one or more of dichloromethane, ethyl acetate, and acetonitrile;

preferably, the first organic solvent is dichloromethane or ethyl acetate;

preferably, the alcoholic solvent comprises a mixture of one or more of methanol, ethanol and ethylene glycol;

preferably, the alcohol solvent is methanol.

4. The method for preparing dexilaprazole potassium salt of claim 1, wherein the amount of the alcohol solvent added per gram of the crude product of dexilaprazole is 3.0-3.5 mL.

5. The method for preparing dexilaprazole potassium salt according to claim 1, wherein the amount of the first organic solvent added per gram of the crude product of dexilaprazole is 8-12mL, preferably 10-12 mL.

6. The method of preparing a potassium salt of dexilaprazole of claim 1, wherein the molar ratio of KOH to the crude product of dexilaprazole is 1: 1-1.5; preferably, the molar ratio is 1: 1.1-1.3.

7. A method for preparing dexilaprazole, characterized by preparing dexilaprazole by using the dexilaprazole potassium salt prepared by the method for preparing dexilaprazole potassium salt according to any one of claims 1 to 6 as a raw material;

preferably, the dexilaprazole potassium salt, water, a second organic solvent and a reaction acid are mixed, an extraction solvent is added for extraction, and the organic phase obtained by extraction is mixed with a third organic solvent to precipitate the dexilaprazole;

preferably, a drying agent is added to the organic phase obtained by extraction before mixing the organic phase with the third organic solvent, then filtering is carried out, and the filtrate is dried;

preferably, the drying agent is anhydrous magnesium sulfate and triethylamine;

preferably, the organic phase is mixed with the third organic solvent by stirring at a temperature of 15-30 ℃ to precipitate the dexilaprazole.

8. The process for producing dexilaprazole according to claim 7, wherein in the step of mixing the potassium salt of dexilaprazole with the reaction acid, the reaction mixture solution has a pH of 8 to 9;

preferably, the acid for the reaction is a weak acid; more preferably, the acid for reaction is selected from any one of dilute acetic acid, phosphoric acid, potassium dihydrogen phosphate and ammonium chloride; further preferably dilute acetic acid;

preferably, the mass concentration of the acid for reaction is 25.0-50.0%.

9. The process for preparing dexilaprazole of claim 7, wherein the second organic solvent is selected from any one or more of methanol, ethanol and isopropanol; preferably methanol;

preferably, the extraction solvent used in the extraction process is dichloromethane;

preferably, the amount of the extraction solvent added per gram of the crude product of dexilaprazole is 3-5 mL.

10. The process for the preparation of dexilaprazole according to claim 7, wherein the third organic solvent is selected from isopropanol and/or acetonitrile, preferably isopropanol;

preferably, the amount of the third organic solvent added per gram of the crude dexilaprazole is 4-6 mL.