CN109456306A - A kind of esomeprazole sodium and the lyophilized preparation it includes it - Google Patents
A kind of esomeprazole sodium and the lyophilized preparation it includes it Download PDFInfo
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Abstract
The present invention provides a kind of esomeprazole sodium and the lyophilized preparation it includes it, and the preparation method of the esomeprazole sodium includes the following steps: the synthesis of 1) intermediate；2) synthesis of esomeprazole sodium；3) esomeprazole sodium is crude；4) purification of esomeprazole sodium.The esomeprazole sodium preparation precision of above method preparation is higher, it is safer to use, simultaneously, esomeprazole sodium is prepared using the above method, its preparation process is easier to manipulate, step is decomposed to be controlled convenient for the quality of intermediate steps, to be conducive to the guarantee of esomeprazole sodium preparation precision, the drug for preparing it is safer.
Description
Technical field
The present invention relates to field of medicaments, specifically, being related to a kind of esomeprazole sodium and the freeze-drying system it includes it
Agent.
Background technique
Esomeprazole is the s- optical isomer of Omeprazole, is the first isomers proton pump inhibitor in the whole world, leads to
Specificity is crossed to inhibit parietal cell proton pump and reduce gastric acid secretion.Confirm through a large amount of clinical trials and drug research: it is maintained
The time of ph > 4 is longer in stomach, and acid suppression is more efficient, and curative effect is better than preceding two generations proton pump inhibitor, and individual difference is small.As new
Generation proton pump inhibitor, existing oneself is widely used in many acid related disorders of clinical treatment.Proton pump inhibitor is treatment digestion
Property escharotic, the stomach food battalion acid related disorders such as reflux disease choice drug.Current clinically common proton pump inhibitor has Aomei
Drawing azoles, Lansoprazole, Rabeprazole, Pantoprazole and 5 kinds of esomeprazole.Omeprazole inhibits as the first proton pump
The curative effect of agent drug, treatment acid related disorder has obtained consistent approval.Esomeprazole is the single isomerism of Omeprazole
Body, i.e. (s)-isomers.For with metabolic advantage, esomeprazole compared with Omeprazole have higher bioavilability and
More consistent pharmacokinetics behavior increases the drug concentration that proton pump is reached in the unit time, and acid suppression effect is better than other
Proton pump inhibitor.Although oral esomeprazole can obtain good clinical effectiveness, in certain patients, such as gulp down tired
Difficult, vomiting, acute hemorrhage of upper gastrointestinal tract and surgery large operation reconvalescent, taking orally becomes a kind of infeasible administration route
When, intravenously administrable approach just becomes inevitable choice.Therefore, injection esomeprazole sodium is applicable to using proton pump
The patient that inhibitor can not but be administered orally.
Develop now with Chinese society, the change of circumstances, the variation of population structure and people life style, mainly because inhaling
Cigarette, drink, be nervous, peptic ulcer rate caused by the factors such as drug irritates gradually increases, become a kind of common disease
And frequently-occurring disease, great pain is brought to patient, patients ' life quality is caused to decline.Based on the above reasons, peptic ulcer
Treatment clinically more and more attention has been paid to and pay attention to, therefore the safe and effective anti-digestibility of development and production burst swing drug oneself by
To concern, and one of emphasis and the hot spot for becoming current drug development research.Proton pump inhibitor is that current treatment digestibility is burst
The state-of-the-art a kind of drug of ulcer, it reaches rapid healing by efficient quickly gastric acid secretion inhibiting and removing helicobacter pylori and bursts
Ulcer.Proton pump inhibitor has blocked the last channel of gastric acid secretion, short of money with the gastric acid inhibitory drug-H2 receptor of previous clinical application
Anti-agent compares, and action site is different and has the characteristics that different, i.e. the Acidinhibitor asked of night is good, rapid-action, and Acidinhibitor is strong
And the time is long, convenient to take, so can inhibit the secretion of basis gastric acid and organize dirty, acetylcholine, gastrin and food to irritate and draw
The acid secretion risen.
When oral therapies are not suitable for, esomeprazole sodium is the choice drug of gastroesophageal reflux disease alternative medicine.By
It is with the obvious advantage in clinical application in it with higher bioavilability.The import at home of injection esomeprazole sodium
Listing in the past few years, has occupied the important market share.Develop now with Chinese society, the change of circumstances, population structure and people
Life style variation, the main peptic ulcer because smoking, drinking, caused by the factors such as nervous, medicine irritation
Rate gradually increases, and becomes a kind of common disease and frequently-occurring disease, brings great pain to patient, therefore development and production are safely, effectively
Medicament for resisting peptic ulcer attracted attention.
Thereby how esomeprazole sodium can be obtained, and pass through the essence for quality by the method for simple possible
Close control guarantees the safety of esomeprazole sodium, is highly important project.
Summary of the invention
The technical problem to be solved by the present invention is in view of the deficiencies of the prior art, provide a kind of esomeprazole sodium and
It includes its lyophilized preparations.
The technical scheme to solve the above technical problems is that
The present invention provides a kind of esomeprazole sodium, and preparation method includes the following steps:
1) 2- chloromethyl -3,5- dimethyl -4-methoxypyridine hydrochloride and 2- the synthesis of intermediate: are added in reaction kettle
Sulfydryl -5- methoxybenzimidazol is using methanol as solvent, and after stirring and dissolving, sodium hydrate aqueous solution is added, after being warming up to reflux,
It is added dropwise sodium hydrate aqueous solution again, after back flow reaction, after being cooled to room temperature, filters, then water and dichloro is added in vacuum distillation
Water layer, is used methylene chloride reextraction by methane extraction, stirring layering again；Merge dichloromethane layer, it is dry that anhydrous sodium sulfate is added
It is dry, filter, methylene chloride washs filter cake, after being evaporated under reduced pressure methylene chloride, then use acetonitrile stirring and dissolving crystallization, rear filtering, vacuum
It is dried to obtain intermediate；
2) synthesis of esomeprazole sodium: intermediate is dissolved with toluene, then D- (-)-tartaric acid two is added in heating
Ethyl ester adds water stirring, tetraisopropyl titanate is then added, and continues insulated and stirred, and n,N-diisopropylethylamine is added in cooling
Cumyl hydroperoxide is added dropwise in stirring, and stirring is added ammonium hydroxide and purified water extracting and demixing, then uses, and ammonium hydroxide extracts reaction solution two
Secondary, merge ammonium hydroxide layer washed once with toluene, purifies and evaporates solvent, obtain esomeprazole sodium semi-finished product；
3) esomeprazole sodium is crude: esomeprazole sodium semi-finished product are dissolved with methanol, and hydroxide is then added
Sodium is stirred at room temperature 2 hours, the decoloration of active carbon stirring and adsorbing；Filtering, takes filtrate to be concentrated by evaporation, and acetone is added and is stirred at reflux 30 points
Clock is down to room temperature filtering, and acetone elution, it is esomeprazole sodium crude product that vacuum drying, which obtains white solid,；
4) purification of esomeprazole sodium: dehydrated alcohol dissolution, room temperature activity charcoal is added in esomeprazole sodium crude product
Filtrate decompression concentration is evaporated, is added by adsorption bleaching, filtering, and acetone is stirred at reflux about 30 minutes, cryogenic liquid circulation temperature lowering
To 10-20 DEG C, crystallization is kept the temperature, filter residue is eluted with acetone, is then dried in vacuo to obtain esomeprazole sodium by filtering.
The beneficial effects of the present invention are the esomeprazole sodium preparation precision of: above method preparation is higher, using rising
It is next safer, meanwhile, esomeprazole sodium is prepared using the above method, preparation process is easier to manipulate, and step is decomposed
It is controlled convenient for the quality of intermediate steps, to be conducive to the guarantee of esomeprazole sodium preparation precision, the drug for preparing it
It is safer.
Further, 2- chloromethyl -3,5- dimethyl -4-methoxypyridine hydrochloride, 2- sulfydryl -5- first in the step 1
The molar ratio of oxygroup benzimidazole and sodium hydroxide is 1:1:2.
Further, in the step 2), intermediate, D- (-)-ethyl tartrate, tetraisopropyl titanate, N, N-bis- is different
Molar ratio between propylethylamine and isopropyl benzene hydroperoxide is 1:0.6:0.3:0.3:0.9.
Further, the molar ratio of esomeprazole sodium semi-finished product and sodium hydroxide is 1:0.61 in the step 3).
Further, the mass ratio of esomeprazole sodium crude product and dehydrated alcohol is 1:10 in the step 4).
Further, 55-65 DEG C is kept after being added dropwise in the step 1 to flow back 2 hours, the temperature of the vacuum distillation is
40 DEG C, the time of the dissolution crystallization is 6 hours, and the vacuum drying temperature is 35 DEG C, and the time is 4 hours.
Further, in the step 2, heating temperature is 50-55 DEG C, and the mixing time after adding water is 30 minutes, and titanium is added
Mixing time after sour tetra-isopropyl is 40 minutes, and the mixing time after n,N-diisopropylethylamine is added is 5 minutes, peroxidating
The time for adding of hydrogen isopropylbenzene is 20 minutes, and the mixing time after dropwise addition is 1 hour.
Further, in the step 3), mixing time is 2 hours, and adsorption time is 30 minutes, is concentrated by evaporation temperature and is
50-55 DEG C, return time is 30 minutes, and vacuum drying temperature is 35 DEG C, and vacuum drying time is 3 hours.
Further, adsorption time is 30 minutes in the step 4), and it is 30 points that evaporation and concentration temperature, which is 50 DEG C of return times,
Clock, crystallization time are 5 hours, and vacuum drying temperature is 35 DEG C, and vacuum drying time is 6 hours.
The present invention also provides a kind of lyophilized preparation comprising esomeprazole sodium, the Ai Siao comprising above method preparation
Beauty draws azoles sodium, and preparation method includes the following steps:
The water for injection after total volume 90% or so cools down 5-1) is added in dense preparing tank, natrium adetate and Ai Si is added
Omeprazole Sodium, stirring make sufficiently to dissolve；
5-2) adjusting pH value with 0.5mol/L sodium hydroxide solution is 11.3 ± 0.1, is stirred evenly, water for injection is used in addition
The active carbon of the 0.05%g/ml of wetting, after stirring and adsorbing 15 minutes, with 0.45 μm of polypropylene filter core decarbonization filtering,
Remaining water for injection 5-3) is added, adjusting pH value with 0.5mol/L sodium hydroxide solution is between 11.3 ± 0.1
Obtain medical fluid；
After 5-4) detection is qualified, by the medical fluid in step 5-3 by dilute preparing tank through 0.22 μm of polyether sulfone filter element filtering to liquid storage
Tank, fluid reservoir medical fluid carry out through 0.22 μm of polyether sulfone filter core refined filtration of twin-stage into the medical fluid receiving tank of bottling department filling；
5-5) it is freeze-dried:
Pre-freeze: being cooled to -40 DEG C for product, keep the temperature 2 hours,
Primary drying: being to slowly warm up to -10 DEG C for 4 hours for sample, and keeps the temperature 12 hours at -10 DEG C, small using 1
When be warming up to 0 DEG C,
Redrying: being to slowly warm up to 30 DEG C (4 hours) for 4 hours for sample, and keep the temperature 4 hours at 30 DEG C, then
30 DEG C of ultimate vacuums are 2 hours dry.
Detailed description of the invention
The preparation flow schematic diagram of esomeprazole Fig. 1 of the invention.
Specific embodiment
Principles and features of the present invention are described with reference to embodiments, the given examples are served only to explain the present invention,
It is not intended to limit the scope of the present invention.
Esomeprazole of the invention can be prepared by chemical equation as follows, and including such as
Lower step:
Step 1: 2- chloromethyl -3,5- dimethyl -4-methoxypyridine hydrochloric acid the synthesis of intermediate: is added in reaction kettle
After stirring and dissolving, hydroxide is added in about 15 minutes in salt 3.76kg, 2- sulfydryl -5- methoxybenzimidazol 3.0kg, 37L methanol
The solution of sodium 0.7kg and water 2.7L, clear solution become muddy.After being warming up to reflux, sodium hydroxide is added dropwise in about 15 minutes
The solution of 0.7kg and water 2.7L.It keeps 55-65 DEG C after being added dropwise to flow back 2 hours, TLC controls (solvent: methylene chloride/first eventually
Alcohol/ammonium hydroxide=30:2:1).Condensed water is down to room temperature after completion of the reaction, filters, and 40 DEG C remove methanol under reduced pressure, and 18L water is then added
It is extracted with 18L methylene chloride, stirring layering, water layer uses 18L methylene chloride reextraction again.Merge dichloromethane layer, is added
1.5kg anhydrous sodium sulfate is 30 minutes dry, filter, methylene chloride washs filter cake.Grease is obtained after removing methylene chloride under reduced pressure.
Grease is dried in vacuo 4 hours at 35 DEG C with filtering after 12L acetonitrile stirring and dissolving crystallization 6 hours and is obtained product 4.70kg, yield
80%-86%.The control parameter being related to are as follows: control return time was at 2 hours.
The chemicals and dosage being related to are as shown in table 1:
A kind of drug being related to of 1 step of table and dosage
| Title | Inventory | Molar ratio | Remarks |
| 2- chloromethyl -3,5- dimethyl -4-methoxypyridine hydrochloride | 3.76kg | 1 | |
| 2- sulfydryl -5- methoxybenzimidazol | 3.00kg | 1 | |
| Methanol | 37L | / | |
| Sodium hydroxide | 1.40kg | 2 | |
| Purified water (1) | 5.40L | / | |
| Methylene chloride | 36L | / | |
| Purified water (2) | 18L | / | |
| Acetonitrile | 12L | / | |
| Anhydrous sodium sulfate | 1.50kg | / |
Wherein, raw material 2- chloromethyl -3,5- dimethyl -4-methoxypyridine hydrochloride is bought from the high moral medical sci-tech in Jinan
Co., Ltd synthesizes equation are as follows:
2- chloromethyl -3,5- dimethyl -4-methoxypyridine hydrochloride, structural formula areFor white
To off-white color crystalline solid.Fusing point is 126~131 DEG C.
Its analysis method mainly includes following several:
Loss on drying: taking this product, is dried in vacuo 2 hours at 70 DEG C, less loss weight must not cross 0.5%.
Residual solvent: methanol, methylene chloride, ethyl acetate take this product, accurately weighed, add n,N-Dimethylformamide quantitative
Solution of every 1ml containing 0.05g is made in dilution, as test solution.Methanol, methylene chloride, appropriate ethyl acetate are taken respectively, essence
It is close weighed, quantitatively diluted with n,N-Dimethylformamide be made in every 1ml containing methanol be about 0.15mg, methylene chloride is about
0.03mg, the solution that ethyl acetate is about 0.25mg, as reference substance solution；According to organic phase residual solvent measuring method (middle traditional Chinese medicines
2015 editions four general rules 0861 of allusion quotation) test.Using -94% dimethyl polysiloxane of 6% cyanogen propyl phenyl as the capillary of fixer
Column is chromatographic column；Using flame ionization ditector (FID), 50 DEG C of column temperature, 3min is maintained, with the heating rate of 40 DEG C/min
It is warming up to 180 DEG C.Detector temperature: 220 DEG C, injector temperature: 200 DEG C.It is accurate respectively to measure test solution and reference substance
Each 1 μ l of solution injects gas chromatograph, records chromatogram, by external standard method with calculated by peak area, contains methanol, methylene chloride, acetic acid
Ethyl ester should all meet regulation.
Related substance: it is measured according to high performance liquid chromatography (2015 editions four general rules 0512 of Chinese Pharmacopoeia).Chromatographic condition is
It is filler with octadecylsilane chemically bonded silica；With methanol -0.1% (V/V) trifluoroacetic acid solution (25:75) for mobile phase,
Detection wavelength is 262nm, 35 DEG C of column temperature, flow velocity 1ml/min.This product is taken, it is accurately weighed, with flowing phased soln and every 1ml is made
Solution containing about 0.5mg (faces with brand-new) as test solution；Precision measures 1ml, sets in 100ml measuring bottle, dilute with mobile phase
It releases to scale, shakes up, as contrast solution.It takes 4- methoxyl group -3,5- dimethyl -2- hydroxymethylpyridine appropriate, adds mobile phase dilute
It releases the solution that every 1ml is made containing about 0.5 μ g and positions solution, precision amount as 4- methoxyl group -3,5- dimethyl -2- hydroxymethylpyridine
Positioning solution, reference substance solution and each 20 μ l of test solution are taken, liquid chromatograph, record chromatogram to principal component are injected separately into
3 times of peak retention time, if any impurity peaks, 4- methoxyl group -3,5- dimethyl -2- hydroxymethylpyridine is in terms of the peak area after correcting
Calculate 0.1 times (0.1%) that contrast solution is not greater than (multiplied by relative correction factor 0.8)；Other single impurity are not greater than pair
According to 0.1 times (0.1%) of solution；Total impurities are not greater than 0.2 times (0.2%) of contrast solution.
Assay: it in the map recorded under in relation to substance-measuring item, is calculated by area normalization method, chloromethane containing 2-
Base -3,5- dimethyl -4-methoxypyridine hydrochloride should be not less than 99.8%.
The raw material 2- sulfydryl -5- methoxybenzimidazol purchase is synthesized from Jinan Gao De Pharmaceutical Technology Co., Ltd
Technique equation are as follows:
2- sulfydryl -5- the methoxybenzimidazol, structural formula areSkeleton symbol is C8H8N2OS,
Molecular weight is 180.23, and for white to off-white powder, fusing point is 255~259 DEG C.
The analysis detection of following aspect is carried out to it:
Residue on ignition: taking this product, checks (2015 editions four general rules 0841 of Chinese Pharmacopoeia) in accordance with the law, remaining residue must not mistake
0.5%.
Residual solvent: taking this product, accurately weighed, adds n,N-Dimethylformamide quantitatively to dilute and every 1ml is made containing 0.1g's
Solution, as test solution.Ethanol control product are taken, it is accurately weighed, it is quantitatively diluted with n,N-Dimethylformamide and every 1ml is made
In be about 0.5mg containing ethyl alcohol solution tried according to residual solvent measuring method (2015 editions four general rules 0861) as reference substance solution
It tests.It is chromatographic column using -94% dimethyl polysiloxane of 6% cyanogen propyl phenyl as the capillary column of fixer；Using hydrogen flame from
Sonization detector (FID), maintains 1min by 60 DEG C of initial temperature, rises to 180 DEG C with the heating rate of 40 DEG C/min, maintains 2min.Vaporization
Room temperature: 200 DEG C, detection room temperature: 220 DEG C.It is accurate respectively to measure test solution and each 1 μ l of reference substance solution, inject gas
Chromatography, regulation should be met containing ethyl alcohol by recording chromatogram by external standard method with calculated by peak area.
Loss on drying: taking this product 1g, is dried under reduced pressure at 105 DEG C 3 hours, less loss weight must not cross 0.5%.Precision weighs sulphur
Sour hydrazine 0.4060g, sets in 1000ml measuring bottle, and the hydrochloric acid solution 10ml of 0.12mol/L is added, dissolution, and is diluted with water to scale,
It shakes up, as hydrazine Standard Stock solutions.It is accurate again to measure 1ml hydrazine Standard Stock solutions, it sets in 100ml measuring bottle, is added
The hydrochloric acid solution 1ml of 0.12mol/L, is diluted with water to scale, shakes up, as hydrazine standard solution.Weigh 2- sulfydryl -5- methoxyl group
Benzimidazole (SM-1) about 667mg, it is accurately weighed, it sets in 25ml color-comparison tube, adds N, N dimethyl acetamide is dissolved and diluted
It to scale, shakes up, as test solution.Precision measures test solution and each 6ml of hydrazine standard solution, sets 25ml tool plug respectively
In colorimetric cylinder, it is diluted to 25ml with the hydrochloric acid solution of 0.12mol/L, 5ml paradime thylaminobenzaldehyde solution is added and (weighs 4.0g
Paradime thylaminobenzaldehyde is dissolved in 95% ethyl alcohol 200ml and 0.12mol/L hydrochloric acid 20ml, is stored in brown bottle, is protected from light guarantor
It deposits.), it mixes, places 20 minutes, absorbance is measured at 458nm wavelength, it is molten that the absorbance of test solution should be less than hydrazine standard
The absorbance (0.00375%) of liquid.
Related substance: it is measured according to high performance liquid chromatography (2015 editions four general rules 0512 of Chinese Pharmacopoeia).
Chromatographic condition: being filler with octadecylsilane chemically bonded silica；It is molten with methanol -0.01mol/L potassium dihydrogen phosphate
Liquid (35:65) be mobile phase, Detection wavelength 253nm, 35 DEG C of column temperature, flow velocity 1ml/min.Take this product, solubilizer [methanol-water
(35:65)] solution of every 1ml containing about 0.25mg is made, as test solution.Take 4- methoxyl group -2- nitroaniline and 4- first
Oxygroup o-phenylenediamine is appropriate, after adding methanol to dissolve in right amount, then solubilizer [methanol-water (35:65)] dilution be made every 1ml containing about
The mixed solution of 0.25 μ g measures reference substance solution and each 20 μ l of test solution, is injected separately into as reference substance solution, precision
Liquid chromatograph, record chromatogram is to 3 times of principal component peak retention time, such as aobvious impurity peaks, 4- methoxyl group -2- nitroaniline and
4- methoxyl group o-phenylenediamine, with calculated by peak area, must not cross 0.1% by external standard method；Other single impurity press area normalization method
It calculates, must not cross 0.1%；Total impurities must not cross 0.3%.
Assay: it in the map recorded under in relation to substance-measuring item, is calculated by area normalization method, sulfydryl containing 2--
5- methoxybenzimidazol should be not less than 99.7%.
The esomeprazole sodium intermediate is white or off-white powder.Its moisture content must not cross 1.0%.And to it
It is detected as follows:
Related substance: it is measured according to high performance liquid chromatography (four general rules 0512 of Chinese Pharmacopoeia version in 2015).
Chromatographic condition: being filler with octadecylsilane chemically bonded silica, with methanol-water (65:35) for mobile phase；Detection
Wavelength 265nm；35 DEG C of column temperature；Flow velocity 1.0ml/min.This product is taken, it is accurately weighed, contained with flowing phased soln and every 1ml being made
The solution of 0.3mg, as test solution；Precision measures 1ml, sets in 100ml measuring bottle, and mobile phase is added to shake up to scale, as
Contrast solution.Take 2- sulfydryl -5- methoxybenzimidazol, 2- chloromethyl -3,5- dimethyl -4-methoxypyridine hydrochloride in
Appropriate mesosome is made in every 1ml with flowing phased soln and dilution containing about 2- sulfydryl -5- methoxybenzimidazol and 2- chloromethyl -
Each 0.3 μ g of 3,5- dimethyl -4-methoxypyridine hydrochloride, solution of the intermediate containing about 3 μ g is as system suitability solution, essence
Close 20 μ l of measurement system suitability solution injects liquid chromatograph, records chromatogram, 2- sulfydryl -5- methoxybenzimidazol, 2-
Chloromethyl -3,5- dimethyl -4-methoxypyridine hydrochloride and intermediate successively appearance, separating degree should conform between each peak
It asks.Precision measures test solution and each 20 μ l of contrast solution injects liquid chromatograph, and record chromatogram to principal component peak retains
3 times of time, if any impurity peaks, 2- sulfydryl -5- methoxybenzimidazol peak area is not greater than multiplied by relative correction factor 0.8
0.1 times (0.1%) of contrast solution peak area, 2- chloromethyl -3,5- dimethyl -4-methoxypyridine hydrochloride peak area multiply
It is not greater than with relative correction factor 1.8 0.1 times (0.1%) of contrast solution peak area, it is molten that single impurity is not greater than control
0.1 times (0.1%) of liquid, total impurities are not greater than 0.3% (other impurities less than 0.02% are not counted in total impurities).
Content: it in the map recorded under in relation to substance-measuring item, is calculated by area normalization method, Ying Bu little containing intermediate
In 99.7%.
Step 2: intermediate 4.65kg is dissolved with 19.0L toluene, is warming up to 50-55 DEG C, and D- (-)-winestone is then added
Diethyl phthalate 1.78kg adds water 30ml and stirs 30 minutes, tetraisopropyl titanate 1.20kg is then added, and heat preservation continues to stir
50 minutes.It is cooled to 15-25 DEG C, n,N-diisopropylethylamine 0.55kg is added, is stirred 5 minutes.Then 80% peroxidating is added dropwise
Hydrogen isopropylbenzene 2.41kg, is added dropwise for about 20 minutes.It is stirred 1 hour at 15-25 DEG C after drop is complete, TLC controls (solvent: acetic acid eventually
Ethyl ester/petroleum ether/triethylamine=2/1/0.1).Ammonium hydroxide 8.88L and purified water is added into reaction solution at room temperature after completion of the reaction
8.8L.It stirs 30 minutes at room temperature, then extracting and demixing.Reaction solution is extracted twice with 4.44L*2 ammonium hydroxide again.Merge ammonium hydroxide layer,
It washed once with toluene 21.0L.It takes ammonium hydroxide to be placed in ice-water bath, is cooled to 5-15 DEG C, methylene chloride 29.6L is then added,
Glacial acetic acid is slowly added dropwise at a temperature of this and adjusts pH=8~9, adjusting in about 1.5 hours finishes.It is warming up to 25-30 DEG C, layering.Dichloro
Methane layer is washed with purified water 14.8L, and 1.5kg anhydrous sodium sulfate is 30 minutes dry.Desiccant is filtered out, 40-50 DEG C removes under reduced pressure
Methylene chloride obtains grease (i.e. esomeprazole sodium semi-finished product).
Step 3: the 29.6L methanol of the grease (i.e. esomeprazole sodium semi-finished product) in step 2 is dissolved, then
Sodium hydroxide 0.345kg is added, is stirred at room temperature 2 hours, active carbon stirring decoloration 30 minutes.Filtering, 50-55 DEG C of concentration of filtrate are steamed
It is dry, 16.0L acetone is added and is stirred at reflux 30 minutes, is down to room temperature filtering, acetone elution, 35 DEG C are dried in vacuo 3 hours white
Solid 2.60kg.Yield: 48%-56%.
Control parameter in above-mentioned steps two and step 3 mainly includes following aspect:
Oxidizing reaction temperature: 15-25 DEG C
Oxidation time: 80min
Dropwise addition glacial acetic acid temperature: 5-15 DEG C
Glacial acetic acid is added dropwise and adjusts pH:8-9
Sodium hydroxide inventory: accurate
Vacuum distillation methanol: it is evaporated
Drug and dosage involved in 2 step 2 of table and step 3
Wherein, esomeprazole sodium crude product should be white or off-white powder.It is detected as follows:
Related substance: it is measured according to high performance liquid chromatography (four general rules 0512 of Chinese Pharmacopoeia version in 2015).
Chromatographic condition: being filler with octadecylsilane chemically bonded silica, with acetonitrile-phosphate buffer [pH7.6, often
The solution of phosphoric acid sodium dihydrogen 0.0052mol and disodium hydrogen phosphate 0.032mol in 1L]-water (10:10:80) be mobile phase A, with
Acetonitrile-phosphate buffer (pH7.6)-water (80:1:19) is Mobile phase B, and according to the form below carries out linear gradient elution.Flow velocity is
1.0ml/min, Detection wavelength 302nm.This product is taken, it is accurately weighed, add mobile phase A to dissolve and quantify dilution and is made in every 1ml about
Solution containing 5mg, as test solution；It measures in right amount, adds mobile phase A dilution to be made in every 1ml containing about the solution of 5 μ g, make
For contrast solution.Precision measures contrast solution and each 20 μ l of test solution, is injected separately into liquid chromatograph, records chromatogram.
Such as aobvious impurity peaks of test solution, the amount of impurity B be not greater than 2 times (0.2%) of contrast solution main peak area, impurity A, C
Amount is not greater than contrast solution main peak area (0.1%), and the amount of other single impurity is not greater than contrast solution main peak area
(0.1%), total impurities are not greater than 5 times (0.5%) of the main peak area of contrast solution.
Step 4 dissolves the esomeprazole sodium crude product 2.55kg dehydrated alcohol that 25.5kg is added, room temperature activity charcoal
Decoloration 30 minutes, filtering, 50 DEG C of reduced pressures are evaporated, and 12.75L acetone is added and is stirred at reflux about 30 minutes.Open cryogenic liquid
Circulating pump about 30 minutes, it is cooled to 10-20 DEG C, keeps the temperature crystallization 5 hours.Filtering, acetone elution, 35 DEG C obtain for vacuum drying 6 hours
Product 2.01kg.Yield: 75%-80%.
Drug and dosage involved in 3 step 4 of table
| Title | Inventory | Feed ratio | Remarks |
| Esomeprazole sodium crude product | 2.55kg | 1 | |
| Dehydrated alcohol | 25.5kg | 10 | |
| Active carbon | 35g | / | |
| Acetone | 12.75L | / |
The present invention also provides a kind of lyophilized preparation comprising esomeprazole sodium, the Ai Siao comprising above method preparation
Beauty draws azoles sodium, and preparation method includes the following steps: that the water for injection after total volume 90% or so cools down is added in dense preparing tank
(25~35 DEG C), are added natrium adetate, the esomeprazole sodium of recipe quantity, and stirring makes sufficiently to dissolve.With 0.5mol/L hydrogen
It is to stir evenly between 11.3 ± 0.1 that sodium hydroxide solution, which adjusts pH value, and the 0.05% (g/ soaked with appropriate water for injection is added
Ml active carbon), after stirring and adsorbing 15 minutes, with 0.45 μm of polypropylene filter core decarbonization filtering, benefit injects water to nearby side
Amount, adjusting pH value with 0.5mol/L sodium hydroxide solution is between 11.3 ± 0.1.Medicinal liquid agitating is sampled after five minutes, workshop
After checking that visible foreign matters are qualified, about 100ml is sampled with triangular pyramidal bottle, Quality Mgmt Dept is sent to carry out intermediate products character, pH value, endogenous toxic material
The detection such as element and content.After intermediate detection is qualified, with air or nitrogen by medical fluid by dilute preparing tank through 0.22 μm of polyether sulfone filter core
To fluid reservoir, fluid reservoir medical fluid is filled through 0.22 μm of polyether sulfone filter core refined filtration of twin-stage into the medical fluid receiving tank of bottling department for filtering
Dress.Freeze-drying: product is cooled to -40 DEG C, keeps the temperature 2 hours by pre-freeze；Primary drying, by sample through slowly heating in 4 hours
To -10 DEG C, and 12 hours are kept the temperature at -10 DEG C, was warming up to 0 DEG C using 1 hour；Redrying, slowly through 4 hours by sample
30 DEG C (4 hours) are warming up to, and keep the temperature 4 hours at 30 DEG C, then is 2 hours dry in 30 DEG C of ultimate vacuums.
Table 4 prepares the formula table of 1000 esomeprazole sodium freeze-dried preparations
Esomeprazole sodium, structural formula areSkeleton symbol is
C17H18N3O3SNa, molecular weight 367.40.Full name is 5- methoxyl group -2- [(S)-[(4- methoxyl group -3,5- dimethyl -2- pyridine
Base) methyl] sulfinyl] -1H- benzimidazole sodium salt.Based on anhydrous and solvent-free object, contain C17H18N3O3SNa should must not be less than
98.0%.For white or off-white powder；Have draw it is moist.It is readily soluble in ethanol.It is as follows that it detects property:
Specific rotation: taking this product, accurately weighed, and being dissolved in water and quantifying dilution is made in every 1ml containing about esomeprazole
The solution of sodium 10mg measures (four general rules 0621 of Chinese Pharmacopoeia version in 2015) in accordance with the law, and specific rotation is+28 ° to+31 °.
Identify: (1) taking this product appropriate, water is added to be made containing about the solution of 15 μ g of esomeprazole sodium in every 1ml, according to purple
Outside-visible spectrophotometry (four general rules 0401 of Chinese Pharmacopoeia version in 2015) measurement, there is maximum suction at the wavelength of 302nm
It receives.(2) in the chromatogram recorded under R- enantiomer check item, the retention time of test solution main peak should be with reference substance solution
The retention time at middle esomeprazole peak is consistent.(3) platinum filament is taken, after being moistened with hydrochloric acid, test sample is dipped, in colourless flame
Burning, the i.e. aobvious foresythia of flame.
Check: impurity absorbance takes this product 2.0g, adds methanol 100ml to make to dissolve, immediately according to UV-VIS spectrophotometry
(four general rules 0401 of Chinese Pharmacopoeia version in 2015), measure at the wavelength of 440nm and 650nm, and absorbance is not greater than
0.05。
Basicity: taking this product 2.0g, after adding water 100ml to dissolve, measures (Chinese Pharmacopoeia four general rules of version in 2015 in accordance with the law
0631), pH value should be 10.3~11.3.
Related substance: it is measured according to high performance liquid chromatography (four general rules 0512 of Chinese Pharmacopoeia version in 2015).
Chromatographic condition and system suitability: with octadecylsilane chemically bonded silica (Microspher C18,4.6 ×
100mm, 3 μm or the comparable chromatographic column of efficiency) it is filler；It is (in every 1000ml phosphorous with water-phosphate buffer (pH7.6)
Acid dihydride sodium 0.0052mol is mobile phase A with disodium hydrogen phosphate 0.032mol)-acetonitrile (80:10:10)；With acetonitrile-phosphate
Buffer (pH7.6)-water (80:1:19) is Mobile phase B, Detection wavelength 302nm, flow velocity 1.0ml/min, according to the form below progress
Linear gradient elution.Impurity A, C, D, H and Omeprazole reference substance about 2mg are weighed respectively, it is accurately weighed, it sets in 50ml measuring bottle,
Add acetonitrile appropriate, ultrasound makes to dissolve, and mobile phase A is added to be diluted to scale, shakes up, as impurity stock solution 1；Weigh respectively impurity E,
K and G reference substance about 2mg, it is accurately weighed, it sets in 50ml measuring bottle, adds mobile phase A dissolution and diluent is to scale, shake up, as miscellaneous
Matter stock solution 2 (impurity K reserve liquor uses after placing 2h).Precision measures above-mentioned each 1ml of impurity stock solution, sets 200ml
In measuring bottle, adds mobile phase A diluent to scale, shake up, as system suitability solution.Precision measures 40 μ l and injects liquid chromatogram
Instrument, records chromatogram, and peak sequence is followed successively by impurity G, K, A, E, D, Omeprazole, H and C, the retention time at Omeprazole peak
It should be 14~19 minutes, the separating degree between each adjacent component peaks should meet regulation.
Measuring method: taking this product, accurately weighed, add mobile phase A to dissolve and quantify dilution be made in every 1ml containing about 0.2mg's
Solution (faces with brand-new), as test solution；It measures in right amount, adds mobile phase A dilution to be made molten containing about 0.2 μ g in every 1ml
Liquid, as contrast solution.It takes 40 μ l of contrast solution to inject liquid chromatograph, adjusts detection sensitivity, make the peak height at principal component peak
About the 10% of full scale, then the accurate 40 μ l of test solution that measures inject liquid chromatograph, record chromatogram.Test solution
In chromatogram (deduct gradient peak) if any with impurity A, the consistent peak of C, D, E, G, H and K retention time, with the peak area after correcting
It calculates (multiplied by relative correction factor), impurity D and E is not greater than 1.5 times (0.15%) of contrast solution main peak area, impurity
A, C, G, H, K and other single impurity peak areas are not greater than contrast solution main peak area (0.10%), each impurity peak area
Sum be not greater than 3 times (0.3%) of contrast solution main peak area.It is any in test solution chromatogram to be less than contrast solution master
(0.02%) can be neglected in the peak that 0.2 times of peak area.
| Impurity code name | Relative correction factor | Limit (%) |
| Impurity G | 0.5 | ≤0.10 |
| Impurity K | 1.5 | ≤0.10 |
| Impurity A | 0.3 | ≤0.10 |
| Impurity E | 1.0 | ≤0.15 |
| Impurity D | 1.0 | ≤0.15 |
| Impurity H | 1.2 | ≤0.10 |
| Impurity C | 0.9 | ≤0.10 |
| Other single unknown impurities | 1.0 | ≤0.10 |
| Total impurities | / | ≤0.3 |
R- enantiomer takes this product appropriate, adds phosphate buffer (pH11.0) (phosphoric acid sodium 0.0028mol in every 1000ml
The solution for diluting and being made in every 1ml containing about 0.32mg is dissolved and quantified with disodium hydrogen phosphate 0.011mol), and precision measures 2ml, sets
In 20ml measuring bottle, it is diluted with water to scale, is shaken up, as test solution；According to high performance liquid chromatography (Chinese Pharmacopoeia 2015
Four general rules 0512 of version) measurement, use α1Acidoglycoprotein (α1- acidglycoprotein) bonded silica gel be filler；With phosphorus
Phthalate buffer (pH6.0) (phosphoric acid sodium dihydrogen 0.0175mol and disodium hydrogen phosphate 0.0025mol in every 1000ml)-acetonitrile
(85:15) is mobile phase, Detection wavelength 302nm.Omeprazole reference substance about 18mg is taken, sets in 100ml measuring bottle, adds methanol
5ml makes to dissolve, and is diluted to scale with above-mentioned phosphate buffer (pH11.0), shakes up, and precision measures 2ml, sets 100ml measuring bottle
In, it is diluted with water to scale, is shaken up, 20 μ l is taken to inject liquid chromatograph, peak sequence is followed successively by R- enantiomer peak and Ai Siao
Beauty draws azoles peak, and the retention time at esomeprazole peak is 4~5 minutes, and the separating degree between two peaks should be greater than 3.Precision measures
20 μ l of test solution injects liquid chromatograph, records chromatogram, calculates by area normalization method, enantiomer containing R- must not mistake
0.5%.
Residual solvent (the residual side sing of methanol/ethanol acetonitrile methylene chloride toluene acetone) takes this product, accurately weighed, adds
Water, which quantitatively dilutes, is made solution of every 1ml containing 0.1g, as test solution.Methanol, ethyl alcohol, acetonitrile, acetone in proper are taken respectively,
It is accurately weighed, quantitatively diluted with water be made in every 1ml containing ethyl alcohol, acetone respectively be about 5mg, methanol is about 3mg, and acetonitrile is about
0.41mg takes toluene, methylene chloride each appropriate as stock solution 1, accurately weighed, adds dimethyl sulfoxide quantitatively to dilute and is made often
Containing toluene in 1ml is about 0.3mg, the solution for being about 0.6mg containing methylene chloride, and as stock solution 2, precision measures stock solution 1 and 2
Each 1ml sets in 10ml measuring bottle, is diluted with water to scale, shake up, as reference substance solution.Precision measures reference substance solution and supplies
Each 3ml of test sample solution, in top set empty bottle, sealing.According to residual solvent measuring method (four general rules 0861 of Chinese Pharmacopoeia version in 2015
Two methods) measurement.It is chromatographic column using -94% methyl polysiloxane of -3% phenyl of 3% cyanogen propyl as the capillary column of fixer；Sample introduction
Mouth temperature is 200 DEG C；Detecting room temperature is 220 DEG C；Initial temperature is 40 DEG C, maintains 3min, then with 40 DEG C per minute of rate liter
Temperature is to 180 DEG C.Ml headspace bottle equilibrium temperature is 80 DEG C, and equilibration time is 30 minutes.Reference substance solution headspace sampling is taken, respectively at swarming
Between separating degree meet the requirements.It takes test solution and reference substance solution to distinguish headspace sampling again, records chromatogram, by outer
Mark method is with calculated by peak area.The residual quantity of toluene must not cross 0.03%, the residual of methanol, ethyl alcohol, acetonitrile, methylene chloride and acetone
Amount should all meet regulation.
The residues detecton of 2- phenyl -2- propyl alcohol: it takes this product to add flowing phased soln and dilute and is made in 1ml containing about 1.0mg's
Solution, as test solution (face with newly match)；Separately take 2- phenyl -2- propyl alcohol reference substance appropriate, it is accurately weighed, add flowing to mix
It solves and dilutes the solution being made in every 1ml containing about 0.1ug, as reference substance solution.According to high performance liquid chromatography (Chinese Pharmacopoeia
Four general rules 0512 of version in 2015) measurement.It is filler (4.6 × 250mm, 5 μm) with octadecylsilane chemically bonded silica, with second
Nitrile-water (50:50) is mobile phase；Detection wavelength is 210nm；Flow velocity 1.0ml/min；35 DEG C of column temperature.Reference substance solution 20ul is taken,
Liquid chromatograph is injected, chromatogram is recorded, theoretical cam curve is calculated by 2- phenyl -2- propyl alcohol peak is not less than 5000.Precision measures
Test solution and each 20 μ l of reference substance solution inject liquid chromatograph, 12 times of record chromatogram to main peak retention time, supply
In test sample solution chromatogram if any with the consistent chromatographic peak of 2- phenyl -2- propyl alcohol retention time, by external standard method with calculated by peak area,
The amount of -2- the propyl alcohol of phenyl containing 2- should must not cross 0.01%.
Atomic absorption spectrophotometry (four general rules 0406 of Chinese Pharmacopoeia version in 2015) 1 are shone in the measurement of sodium sodium content) it is right
According to the preparation of product solution: precision measures sodium standard liquid (Na+1000 μ g/ml) 1ml, sets in 200ml volumetric flask, 1mol/L hydrochloric acid is added
50ml is diluted with water to scale, shakes up；It is accurate respectively again to measure 1.0,2.0,3.0,4.0,5.0ml, 50ml measuring bottle is set respectively
In, it is each that caesium solution 5.0ml is added, be diluted with water to scale, shake up to get.2) preparation of test solution: this product is taken about
160mg, it is accurately weighed, it sets in 10ml measuring bottle, is diluted with water to scale, shake up；It is accurate again to measure 1.0ml, set 200ml measuring bottle
In, 1mol/L hydrochloric acid 50ml is added, is diluted with water to scale, shakes up；It is accurate again to measure 3.0ml, it sets in 50ml measuring bottle, caesium is added
Solution 5.0ml, is diluted with water to scale, shake up to get.3) preparation of blank solution: 1mol/L hydrochloric acid 50ml is taken, 200ml is set
In volumetric flask, it is diluted with water to scale, is shaken up, precision measures 3.0ml, sets in 50ml measuring bottle, and caesium solution 5.0ml is added, uses water
Be diluted to scale, shake up to get.4) measuring method: above-mentioned reference substance solution and test solution are taken, according to atomic absorption spectrphotometry
Method (2015 editions four general rules 0406 of Chinese Pharmacopoeia), at 589.0nm wavelength measure, calculate to get.Based on anhydride, this product
(Na) containing sodium should be 5.6%~6.9%.
Determination of moisture: taking this product, according to aquametry (four general rules of Chinese Pharmacopoeia version in 2015,0,832 first method 1)
Measurement, moisture content must not cross 1.0%.
Content of beary metal measurement: taking this product l.0g to set in crucible, add the dilution heat of sulfuric acid 4ml of 25% magnesium sulfate, mixes,
Slowly blazing to complete charing, it is 1 hour blazing at 700~800 DEG C, it lets cool, residue dilute hydrochloric acid 10ml dissolves, and phenolphthalein is added to indicate
Liquid 1 drips, and liquor ammoniae fortis to solution is added dropwise and shows pink, dropwise addition glacial acetic acid to pink color disappeared, then acetic acid 0.5ml on the rocks, filtration,
It is rinsed with water filter, merging filtrate and washing lotion, is diluted with water to 20ml, examines Check (Chinese Pharmacopoeia four general rules of version in 2015 in accordance with the law
0821 first method), 20/1000000ths must not be crossed containing heavy metal.
Bacteria endotoxin content measurement: taking this product, checks (four general rules 1143 of Chinese Pharmacopoeia version in 2015) in accordance with the law, often
It should be less than 2.0EU containing endotoxic amount in 1mg esomeprazole.
Microbial limit: taking this product, by membrane-filter procedure, according to non-sterile product limit test of microbe (Chinese Pharmacopoeia
Four general rules 1105 of version in 2015), every 1g detection bacterium, yeast and mold sum must not cross 100cfu.
Assay: it is measured according to high performance liquid chromatography (four general rules 0512 of Chinese Pharmacopoeia version in 2015).Chromatographic condition
It with octadecylsilane chemically bonded silica is filler (Microspher C18,4.6 × 100mm, 3 μm with system suitability
Or the comparable chromatographic column of efficiency)；With acetonitrile-phosphate buffer (pH7.4) (phosphoric acid sodium dihydrogen in every 1000ml
0.00123mol [takes hydrogen sulfate tetrabutylammonium 6.8g, adds with disodium hydrogen phosphate 0.00298mol)-hydrogen sulfate tetrabutylammonium solution
1mol/L sodium hydroxide solution 20ml makes to dissolve, and is diluted to 1000ml with above-mentioned phosphate buffer (pH7.4)] (26:69:5)
For mobile phase；Detection wavelength is 280nm；Flow velocity 1.0ml/min.It takes impurity D reference substance and Omeprazole reference substance each appropriate, adds
Phosphate buffer (pH11.0) (phosphoric acid sodium 0.0028mol and disodium hydrogen phosphate in every 1000ml under R- enantiomer item
It 0.011mol) dissolves and dilutes and be made in every 1ml respectively containing about the mixed solution of 0.5 μ g, 20 μ l is taken to inject liquid chromatograph, note
Chromatogram is recorded, the retention time at Omeprazole peak is 6~8 minutes, and theoretical cam curve should be not less than by the calculating of Omeprazole peak
4500, Omeprazole peak and the separating degree of impurity D should be greater than 3.0.Measuring method takes this product appropriate, accurately weighed, adds phosphate slow
Fliud flushing (pH11.0) dissolves and quantifies the solution for diluting and being made in every 1ml containing about 0.1mg, and precision measures 20 μ l and injects liquid chromatogram
Instrument records chromatogram；Separately take Omeprazole reference substance appropriate, be measured in the same method, by external standard method with calculated by peak area to get.
In addition, it includes following several that the esomeprazole in the present invention, which obtains usual impurities type:
(1) impurity A, 2- sulfydryl -5- methoxyl group -1H- benzimidazole, structural formulaStructure letter
Formula: C8H8N2OS, molecular weight 180.23.
(2) impurity C, 5- methoxyl group -2- [[(4- methoxyl group -3,5- dimethyl -2- pyridyl group) methyl] is thio] -1H- benzene
And [d] imidazoles, structural formulaSkeleton symbol C17H19N3O2S, molecular weight 329.42.
(3) impurity D, 5- methoxyl group -2- [[(4- methoxyl group -3,5- dimethyl -2- pyridyl group) methyl] sulfonyl] -1H-
Benzimidazole, structural formula:Skeleton symbol: C17H19N3O4S, molecular weight are
361.42。
(4) impurity E, 4- methoxyl group -2- [[(5- methoxyl group -1-H- benzo [d] imidazoles -2- base) sulfinyl] methyl] -
3,5- lutidines 1- oxides, structural formula:Skeleton symbol: C17H19N3O4S, point
Son amount is 361.42.
(5) impurity H, 5- methoxyl group -2- [[(4- methoxyl group -3,5- dimethyl -2- pyridyl group) methyl] sulfinyl] -1-
Methyl-benzoimidazole and 6- methoxyl group -2- [[(4- methoxyl group -3,5- dimethyl -2- pyridyl group) methyl] sulfinyl] -1- first
Base-benzimidazole, structural formula:Skeleton symbol: C18H21N3O3S, molecular weight are
359.44。
(6) impurity G, Isosorbide-5-Nitrae-dihydro -1- (5- methoxyl group -1H- benzimidazolyl-2 radicals-yl) -3,5- dimethyl -4- oxo -2-
Picolinic acid, structural formula:Skeleton symbol: C16H15N3O4, molecular weight 313.31.
(7) impurity K, 2- [[(5- methoxyl group -1H- benzimidazolyl-2 radicals-yl) sulfinyl] methyl] -3,5- dimethyl -4
(1H) -1- pyridone, structural formula:Skeleton symbol: C16H17N3O3S, molecular weight are
331.39。
The foregoing is merely presently preferred embodiments of the present invention, is not intended to limit the invention, it is all in spirit of the invention and
Within principle, any modification, equivalent replacement, improvement and so on be should all be included in the protection scope of the present invention.
Claims (10)
1. a kind of esomeprazole sodium, which is characterized in that preparation method includes the following steps:
1) 2- chloromethyl -3,5- dimethyl -4-methoxypyridine hydrochloride and 2- mercapto the synthesis of intermediate: are added in reaction kettle
Base -5- methoxybenzimidazol is using methanol as solvent, and after stirring and dissolving, sodium hydrate aqueous solution is added, after being warming up to reflux, then
Secondary dropwise addition sodium hydrate aqueous solution after back flow reaction, after being cooled to room temperature, filters, then water and dichloromethane is added in vacuum distillation
Water layer, is used methylene chloride reextraction by alkane extraction, stirring layering again；Merging dichloromethane layer, the drying of addition anhydrous sodium sulfate,
Filter, methylene chloride washs filter cake, after being evaporated under reduced pressure methylene chloride, then uses acetonitrile stirring and dissolving crystallization, rear to filter, be dried in vacuo
Obtain intermediate；
2) synthesis of esomeprazole sodium: intermediate is dissolved with toluene, then D- (-)-tartaric acid diethyl is added in heating
Ester adds water stirring, tetraisopropyl titanate is then added, and continues insulated and stirred, and cooling is added n,N-diisopropylethylamine and stirs
It mixes, cumyl hydroperoxide is added dropwise, stirring is added ammonium hydroxide and purified water extracting and demixing, then uses, and ammonium hydroxide extracts reaction solution twice,
Merge ammonium hydroxide layer washed once with toluene, purifies and evaporates solvent, obtain esomeprazole sodium semi-finished product；
3) esomeprazole sodium is crude: esomeprazole sodium semi-finished product are dissolved with methanol, and sodium hydroxide, room is then added
Temperature stirring 2 hours, the decoloration of active carbon stirring and adsorbing；Filtering, takes filtrate to be concentrated by evaporation, and acetone is added and is stirred at reflux 30 minutes, drops
It is filtered to room temperature, acetone elution, it is esomeprazole sodium crude product that vacuum drying, which obtains white solid,；
4) purification of esomeprazole sodium: dehydrated alcohol dissolution, the absorption of room temperature activity charcoal is added in esomeprazole sodium crude product
Filtrate decompression concentration is evaporated, is added by decoloration, filtering, and acetone is stirred at reflux about 30 minutes, and cryogenic liquid circulation temperature lowering is extremely
10-20 DEG C, crystallization is kept the temperature, filter residue is eluted with acetone, is then dried in vacuo to obtain esomeprazole sodium by filtering.
2. a kind of esomeprazole sodium according to claim 1, which is characterized in that chloromethyl -3 2- in the step 1,
The molar ratio of 5- dimethyl -4-methoxypyridine hydrochloride, 2- sulfydryl -5- methoxybenzimidazol and sodium hydroxide is 1:1:2.
3. a kind of esomeprazole sodium according to claim 2, which is characterized in that in the step 2), intermediate, D-
(-)-ethyl tartrate, tetraisopropyl titanate, N, molar ratio of the N-between diisopropylethylamine and isopropyl benzene hydroperoxide
For 1:0.6:0.3:0.3:0.9.
4. a kind of esomeprazole sodium according to claim 2, which is characterized in that end Si Aomeila in the step 3)
The molar ratio of azoles sodium semi-finished product and sodium hydroxide is 1:0.61.
5. a kind of esomeprazole sodium according to claim 2, which is characterized in that end Si Aomeila in the step 4)
The mass ratio of azoles sodium crude product and dehydrated alcohol is 1:10.
6. a kind of esomeprazole sodium according to claim 2, which is characterized in that after being added dropwise in the step 1
Kept for 55-65 DEG C flow back 2 hours, the temperature of the vacuum distillation is 40 DEG C, and the time of the dissolution crystallization is 6 hours, described
Vacuum drying temperature is 35 DEG C, and the time is 4 hours.
7. a kind of esomeprazole sodium according to claim 2, which is characterized in that in the step 2, heating temperature is
50-55 DEG C, the mixing time after adding water is 30 minutes, and the mixing time after tetraisopropyl titanate is added is 40 minutes, and N is added,
Mixing time after N- diisopropylethylamine is 5 minutes, and the time for adding of cumyl hydroperoxide is 20 minutes, stirring after dropwise addition
Mixing the time is 1 hour.
8. a kind of esomeprazole sodium according to claim 2, which is characterized in that in the step 3), mixing time
It is 2 hours, adsorption time is 30 minutes, and being concentrated by evaporation temperature is 50-55 DEG C, and return time is 30 minutes, vacuum drying temperature
It is 35 DEG C, vacuum drying time is 3 hours.
9. a kind of esomeprazole sodium according to claim 2, which is characterized in that adsorption time is in the step 4)
30 minutes, it was 30 minutes that evaporation and concentration temperature, which is 50 DEG C of return times, and the crystallization time is 5 hours, and vacuum drying temperature is 35 DEG C,
Vacuum drying time is 6 hours.
10. a kind of lyophilized preparation comprising esomeprazole sodium, which is characterized in that any described comprising claim 1-9
Esomeprazole sodium, preparation method include the following steps:
The water for injection after total volume 90% or so cools down 5-1) is added in dense preparing tank, natrium adetate and Ai Si Aomei is added
Azoles sodium is drawn, stirring makes sufficiently to dissolve；
5-2) adjusting pH value with 0.5mol/L sodium hydroxide solution is 11.3 ± 0.1, is stirred evenly, addition is soaked with water for injection
0.05%g/ml active carbon, after stirring and adsorbing 15 minutes, with 0.45 μm of polypropylene filter core decarbonization filtering,
Remaining water for injection 5-3) is added, adjusting pH value with 0.5mol/L sodium hydroxide solution is to obtain between 11.3 ± 0.1
Medical fluid；
After 5-4) detection is qualified, by the medical fluid in step 5-3 by dilute preparing tank through 0.22 μm of polyether sulfone filter element filtering to fluid reservoir, storage
Flow container medical fluid carries out through 0.22 μm of polyether sulfone filter core refined filtration of twin-stage into the medical fluid receiving tank of bottling department filling；
5-5) it is freeze-dried:
Pre-freeze: being cooled to -40 DEG C for product, keep the temperature 2 hours,
Primary drying: being to slowly warm up to -10 DEG C for 4 hours for sample, and keeps the temperature 12 hours at -10 DEG C, was risen using 1 hour
Temperature to 0 DEG C,
Redrying: sample is to slowly warm up to 30 DEG C (4 hours) for 4 hours, and keeps the temperature 4 hours at 30 DEG C, then at 30 DEG C
Ultimate vacuum is 2 hours dry.
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| CN110946860A (en) * | 2019-12-30 | 2020-04-03 | 丽珠集团丽珠制药厂 | Composition containing omeprazole sodium and preparation method thereof |
| CN111635393A (en) * | 2020-06-28 | 2020-09-08 | 江苏吴中医药集团有限公司 | Preparation method of esomeprazole sodium |
| CN111812253A (en) * | 2020-09-10 | 2020-10-23 | 天津汉一医药科技有限公司 | Method for detecting potential genotoxic impurities in compound containing benzimidazole structure |
| CN112229920A (en) * | 2020-09-17 | 2021-01-15 | 海南中玉药业有限公司 | Method for detecting potential genotoxic impurities of esomeprazole sodium |
| CN112229920B (en) * | 2020-09-17 | 2022-10-21 | 海南中玉药业有限公司 | Method for detecting potential genotoxic impurities of esomeprazole sodium |
| CN112321562A (en) * | 2020-09-29 | 2021-02-05 | 南京海纳医药科技股份有限公司 | Preparation method and detection method of impurities in omeprazole sodium bicarbonate dry suspension |
| CN113512026A (en) * | 2021-08-26 | 2021-10-19 | 四川子仁制药有限公司 | Synthesis method of esomeprazole sodium |
| CN116444487A (en) * | 2022-01-07 | 2023-07-18 | 重庆莱美药业股份有限公司 | Intermediate composition of omeprazole, and preparation method and application thereof |
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