CN103232437A - Preparation method of rabeprazole sodium crystal type compound - Google Patents
Preparation method of rabeprazole sodium crystal type compound Download PDFInfo
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- CN103232437A CN103232437A CN2013101669831A CN201310166983A CN103232437A CN 103232437 A CN103232437 A CN 103232437A CN 2013101669831 A CN2013101669831 A CN 2013101669831A CN 201310166983 A CN201310166983 A CN 201310166983A CN 103232437 A CN103232437 A CN 103232437A
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Abstract
The invention relates to the field of medicine production and in particular relates to a preparation method of a rabeprazole sodium crystal type compound. The preparation method of the rabeprazole sodium crystal type compound comprises the following steps of: by taking 2-mercapto benzimidazole and 2-chloromethyl-3-methyl-4-methoxy propoxy pyridine hydrochloride as raw materials and carrying out a condensation reaction to prepare rabeprazole thioether, and subsequently carrying out an oxidation reaction via the rabeprazole thioether and carrying out salt forming reaction via rabeprazole and sodium hydroxide to acquire the rabeprazole sodium. According to the preparation method of the rabeprazole sodium crystal type compound, the raw materials are low in cost and easy to purchase; samples are basically invariant in related substances and contents under the condition with high temperature and high humidity; the articles are stable in property and low in overall manufacturing cost; and the preparation method of the rabeprazole sodium crystal type compound has the advantages of strictly controlling the temperatures in the steps, being less in by-products, high in yield and non-toxic, and also has the advantages of being short in production period and further improving the production efficiency.
Description
Technical field
The present invention relates to medicine field, relate in particular to a kind of preparation method of rabeprazole sodium crystal compound.
Background technology
Peptide ulceration is a kind of common disease and frequently-occurring disease, brings great misery to the patient, causes quality of life to descend.Conditions of Treatment for Peptic Ulcer Drugs becomes one of the emphasis of present research and development and focus.Proton pump inhibitor (the Proton pump inhibitors that come out the eighties in 20th century, PPIS) be to treat the most effective medicine of peptic ulcer disease gastric acid inhibitory secretion at present, be characterized in acting on the gastric mucosa parietal cell, reduce the activity of hydrogen ion-potassium ion-apysase in the cell, thus the gastric acid inhibitory secretion.
First proton pump inhibitor is omeprazole, and this medicine was succeeded in developing by Aktiebolaget Astra in 1988, and at first went on the market in Sweden.After omeprazole, pharmacy industry has been developed proton pump inhibitors such as lansoprazole, pantoprazole, esomeprazole and rabeprazole again in succession.(rabe prazole is proton pump inhibitor of new generation Rab) to rabeprazole, has commodity on Japan and Taiwan and other places at present, and Yang Sen company in Xi'an pushes China market with it.Aspect treatment stomach, duodenal bulbar ulcer, Rab is similar even more effective to omeprazole (Ome) effect; Be better than Ome aspect the symptom improving; Treatment stomach, esophageal reflux disease (GRED), the Rab curative effect is better than Ranitidine HCL (Ran), and is similar to Ran, Ome aspect doing well,improving; Tall and erect Chinese mugwort syndrome (Zollinger-Ellison) Rab is also effective in treatment; Rab has anti-helicobacter pylori (Hp) effect equally, and Rab is as the medication of triple therapy, and (Ear1) is identical with Ome, lansoprazole for the Hp clearance rate, and better tolerance.
There is limitation in first-generation proton pump inhibitor aspect pharmacodynamics and the pharmacokinetics, thereby has influenced result for the treatment of; And proton pump inhibitor of new generation---rabeprazole bioavailability height is rapid-action, can 24h the secretion of comprehensive gastric acid inhibitory, effect is lasting, rabeprazole mainly carries out metabolism by the non-enzyme system of liver and to cytochrome P in addition
450Influence lessly, therefore, the interaction of medicine seldom takes place in rabeprazole.To sum up state, rabeprazole treatment stomach ulcer, duodenal ulcer, erosive stomach-esophageal reflux disease, erosive stomach-esophageal reflux disease keep treatment and ZoUinger-Ellison syndrome and helicobacter pylori infection etc. the time have certain advantage.
In a word, rabeprazole is efficient, quick-acting, a safe proton pump inhibitor, gastric acid inhibitory secretion effectively.Especially relief of symptoms, cure the clinical efficacy aspect of mucosal injury.Has better valency one effect ratio far beyond other proton pump inhibitors and H2 receptor-blocking agent.Rabeprazole is cured high, and is rapid-action, the effect lasting stability, and untoward reaction is few, and usage is convenient, is the ideal medicament for the treatment of peptide ulceration
At present, rabeprazole is mainly derived from Japan, and it is expensive, and the consumer group is restricted.
Summary of the invention
The invention provides a kind of preparation method of rabeprazole sodium crystal compound, its cost of material is low, the preparation method is easy, and cost is low.
The preparation method of rabeprazole sodium crystal compound of the present invention, it may further comprise the steps:
One) first methyl alcohol is dropped into the first clean retort, add 2-chloromethyl-3-methyl-4-methoxy propoxy pyridine hydrochloride, stir and make its dissolving, be prepared into the methanol solution of 2-chloromethyl-3-methyl-4-methoxy propoxy pyridine hydrochloride.
Two) in the second clean retort, add second batch of methyl alcohol, stir and add sodium hydroxide, 20-25 ℃ of temperature of control also drops into 2-mercaptobenzimidazole, be warming up to the methanol solution of the 2-chloromethyl-3-methyl-4-methoxy propoxy pyridine hydrochloride that adds step () after 50-60 ℃ and make, keep thermotonus 3～5h, the reaction terminating after-filtration is also used methanol wash, merge diafiltration liquid, temperature control 40-50 ℃, being evaporated to no methyl alcohol flows out, washing back crystallization, the drying intermediate of winning, wherein the second batch of methanol quality is 2.5～3.5 times of step () quantity of methyl alcohol.
Three) add water and sodium hydroxide in the 3rd clean retort, the dissolving back adds 10% clorox stirs, and gets sodium hydroxide-aqueous sodium hypochlorite solution; In the 4th clean retort, add methylene dichloride, the control temperature is at 20-25 ℃, add step (two) intermediate of winning then, be cooled to jar interior temperature below-5 ℃, add above-mentioned sodium hydroxide-aqueous sodium hypochlorite solution and react, reaction finishes back adding sodium thiosulfate solution also with 50% glacial acetic acid aqueous solution accent pH to 9～10, get organic phase with the methylene dichloride repetitive scrubbing, 25～30 ℃ of temperature controls, crystallization after the underpressure distillation, the washing of cooling back is also dry, gets second intermediate.
Four) in the 5th clean retort, add methyl alcohol, add step (three) gained second intermediate and sodium hydroxide down at 20～25 ℃, adding gac stirs, press filtration was to crystallizer after soup took off charcoal, be warming up to 50～55 ℃, filtrate decompression is distilled to no methyl alcohol and flows out, washing and crystallization, dry Sodium rabeprazole finished product, and wherein methanol quality is 1.5～2 times of step () methyl alcohol add-on.
Wherein, the 2-chloromethyl-3-methyl-4-methoxy propoxy pyridine hydrochloride quality is 0.7～0.9:1 with the ratio of methanol quality in the described step (), and the 2-mercaptobenzimidazole quality is 0.1～0.2:1 with the ratio of methanol quality in the step (two).
Preferably, in the described step (), keep thermotonus 3～5h, Liquid Detection 2-chloromethyl-3-methyl-4-methoxy propoxy pyridine hydrochloride is residual to be not more than 0.5% o'clock reaction terminating.
Preferably, the middle sodium hydroxide of described step (two) is 0.08～0.1:1 with the ratio of methanol quality.
Preferably, in the described step (two), washing back crystallization, drying are specially: add methylene dichloride, add the purified water washing after the stirring and dissolving once, organic phase is standby, water adds washed with dichloromethane once, the water liquid waste disposal merges organic purified water washing that is added to, and organic phase is 25～30 ℃ of temperature, vacuum tightness-0.08～～the 0.1Mpa condition under underpressure distillation to having solid to separate out namely to stop distillation, agitation and dropping sherwood oil crystallization, 0～5 ℃ of growing the grain of temperature control a few hours, centrifugal, washing, the drying intermediate of winning.
Preferably, in the described step (three), the mass ratio of sodium hydroxide and 10% clorox is 1:30～32.
Preferably, in the described step (three), adding the methylene dichloride quality in the 4th clean retort is 52～53:1 with the ratio that adds the sodium hydroxide quality in the 3rd clean retort.
Preferably, in the described step (three), be specially with methylene dichloride repetitive scrubbing process: water adds washed with dichloromethane once after the layering, merge organic purified water that is added to, sodium hydroxide solution with 30% is regulated pH to 13.0～14.0, layering, and organic phase is with the purified water extraction once, merge water, add methylene dichloride, and transfer pH to 9.0-10.0, layering with 50% glacial acetic acid aqueous solution, the water dichloromethane extraction, merge organic phase, added anhydrous sodium sulfate drying 30 minutes, filter, with washed with dichloromethane, merge organic phase.
Preferably, in the described step (four), the sodium hydroxide quality is 1:22～23 with the methanol quality ratio.
Preferably, in the described step (four), the process of washing and crystallization is specially: add toluene, continue 50-55 ℃ of underpressure distillation to solvent-free outflow, after adding ethyl acetate and the toluene dissolving, drip the normal heptane crystallization, be cooled to 20-25 ℃ of growing the grain 1 hour, centrifugal, washing.
The preparation method of the described rabeprazole sodium crystal of embodiment of the invention compound, beneficial effect is:
Select that cost is low, the raw material of easy purchase for use, finally generate rabeprazole sodium crystal compound through condensation, oxidizing reaction, trial-product is related substance and the basic no change of content under high temperature, super-humid conditions, the article stable in properties; Overall low cost of manufacture; Strict control temperature in step, by product is few, yield height, nontoxicity.
Rabeprazole sodium crystal compounds process for production thereof of the present invention has advantage with short production cycle, and then has further improved production efficiency.
Embodiment
For making the purpose, technical solutions and advantages of the present invention clearer, below with the present invention is described in further detail.
Embodiment 1:
Present embodiment provides a kind of preparation method of rabeprazole sodium crystal compound, be to be raw material with 2-mercaptobenzimidazole, 2-chloromethyl-3-methyl-4-methoxy propoxy pyridine hydrochloride, obtain final product through condensation, oxidation and salt-forming reaction, it comprises following preparation process:
Condensation reaction: in the first clean retort, be equipped with the methyl alcohol into 32.6kg, rotating speed with 35Hz stirs, drop into 2-chloromethyl-3-methyl-4-methoxy propoxy pyridine hydrochloride 25.00kg, stirring and dissolving, be prepared into the methanol solution of 2-chloromethyl-3-methyl-4-methoxy propoxy pyridine hydrochloride, standby.
In the second clean retort, be equipped with into methyl alcohol 98.8kg, stir adding sodium hydroxide 8.15kg down with the 40Hz rotating speed, the back temperature control that stirs drops into 2-mercaptobenzimidazole 14.11kg for 20-25 ℃, be warming up to 50-60 ℃, the methanol solution of the temperature control 50-60 ℃ of 2-for preparing more than adding chloromethyl-3-methyl-4-methoxy propoxy pyridine hydrochloride, about 30min adds.Keep this temperature and continue reaction 4h, Liquid Detection 2-chloromethyl-3-methyl-4-methoxy propoxy pyridine hydrochloride is residual is not more than 0.5%, and reaction terminating filters.5.4kg methanol wash, merge diafiltration liquid, temperature control 40-50 ℃, vacuum tightness-0.08～-0.1Mpa is evaporated to no methyl alcohol and flows out, and adds the 66.3kg methylene dichloride, add the washing of 87.5kg purified water after the stirring and dissolving once, organic phase is standby, and water adds the 8.3kg washed with dichloromethane once, the water liquid waste disposal, merge organic 62.4kg purified water washing that is added to, water liquid waste disposal, organic phase be 25～30 ℃ of temperature controls, vacuum tightness-0.08～-the 0.1Mpa underpressure distillation namely stops distillation to there being solid to separate out, stir and drip sherwood oil 33.0kg crystallization down, temperature control 0-5 ℃ growing the grain 3 hours, centrifugal, washing, drying obtains the rabeprazole thioether.Table one is condensation reaction raw material and consumption thereof.
The used supplementary material of table one condensation reaction and consumption
Oxidizing reaction: be equipped with the purified water into 93.3kg in the 3rd clean retort, mixing speed 35Hz drops into 4.67kg sodium hydroxide, after the dissolving, adds 10% chlorine bleach liquor 144.2kg and stirs, and obtains sodium hydroxide-aqueous sodium hypochlorite solution, and is standby.In the 4th clean retort, be equipped with into methylene dichloride 247.3kg, 20～25 ℃ of temperature controls, the rabeprazole thioether that the step makes in the mixing speed 40Hz adding, after the stirring and dissolving, be cooled under-5～5 ℃, sodium hydroxide～the aqueous sodium hypochlorite solution that adds above preparation, about 1 hour of time spent, timing stirring reaction 1 hour, liquid phase monitoring rabeprazole thioether is residual to be not more than 0.5%, reaction finishes, add 27% sodium thiosulfate solution 10.9kg, transfer pH to 9.0～10.0(to use 23.3kg approximately with 50% glacial acetic acid aqueous solution), layering, water adds the 37.1kg washed with dichloromethane once, merge organic 140.0kg purified water that is added to, sodium hydroxide solution with 30% is regulated pH to 13.0～14.0(and is used 25.1kg approximately), layering, organic phase with the extraction of 46.7kg purified water once, merge water, add the 185.7kg methylene dichloride, and transfer pH to 9.0～10.0(to use 23.3kg approximately with 50% glacial acetic acid aqueous solution), layering, water 31.0kg dichloromethane extraction merges organic phase, adds the 28.00kg anhydrous sodium sulfate drying 30 minutes, filter, 61.9kg washed with dichloromethane merges 25～30 ℃ of organic phased temperature, vacuum tightness-0.08～-the 0.1Mpa underpressure distillation flows out to there being methylene dichloride, add 147.5kg acetonitrile stirring and crystallizing, be cooled to 0-5 ℃ of growing the grain 2 hours.Centrifugal, washing, drying obtains rabeprazole.Table two is oxidizing reaction raw material and consumption thereof.
The table titanium dioxide is reacted used supplementary material and consumption
| Name of material | Consumption (kg) |
| The rabeprazole thioether | 28.05 |
| Sodium hydroxide | 4.67 |
| Clorox | 144.2 |
| Methylene dichloride | 563.0 |
| Acetonitrile | 158.5 |
Become the sodium salt reaction: add methyl alcohol 52.5kg in the 5th clean retort, 20～25 ℃ add rabeprazole 20.00kg, add 2.30kg sodium hydroxide, stir after 1 hour, add the 0.90kg gac, stirred 1 hour, temperature remains unchanged, with soup through the press filtration of decarburization strainer to crystallizer, be warming up to 50～55 ℃, filtrate is not flowed out to there being methyl alcohol in the crystallizer underpressure distillation, adds 9.5kg toluene, continues 50-55 ℃ of underpressure distillation to solvent-free outflow, after adding the dissolving of 9.9kg ethyl acetate and 19.2kg toluene, drip normal heptane 136.6kg crystallization, added normal heptane in about 15 minutes, be cooled to 20-25 ℃ of growing the grain 1 hour, centrifugal, washing, drying obtains rabeprazole sodium crystal compound.Table three is into raw material and the consumption thereof of sodium salt reaction.
Table three becomes sodium salt to react used supplementary material and consumption
| Name of material | Consumption (kg) |
| Rabeprazole | 20.00 |
| Sodium hydroxide | 2.30 |
| Methyl alcohol | 52.5 |
| Ethyl acetate | 9.9 |
| Toluene | 28.7 |
| Heptane | 196.6 |
Embodiment 2:
Present embodiment provides a kind of preparation method of rabeprazole sodium crystal compound, be to be raw material with 2-mercaptobenzimidazole, 2-chloromethyl-3-methyl-4-methoxy propoxy pyridine hydrochloride, obtain final product through condensation, oxidation and salt-forming reaction, it comprises following preparation process:
Condensation reaction: in the first clean retort, be equipped with the methyl alcohol into 32.6kg, rotating speed with 35Hz stirs, drop into 2-chloromethyl-3-methyl-4-methoxy propoxy pyridine hydrochloride 22.8kg, stirring and dissolving, be prepared into the methanol solution of 2-chloromethyl-3-methyl-4-methoxy propoxy pyridine hydrochloride, standby.
In the second clean retort, be equipped with into methyl alcohol 81.5kg, stir adding sodium hydroxide 6.52kg down with the 40Hz rotating speed, the back temperature control that stirs drops into 2-mercaptobenzimidazole 8.15kg for 20-25 ℃, be warming up to 50-60 ℃, the methanol solution of the temperature control 50-60 ℃ of 2-for preparing more than adding chloromethyl-3-methyl-4-methoxy propoxy pyridine hydrochloride, about 30min adds.Keep this temperature and continue reaction 4h, Liquid Detection 2-chloromethyl-3-methyl-4-methoxy propoxy pyridine hydrochloride is residual is not more than 0.5%, and reaction terminating filters.5.4kg methanol wash, merge diafiltration liquid, temperature control 40-50 ℃, vacuum tightness-0.08～-0.1Mpa is evaporated to no methyl alcohol and flows out, and adds the 66.3kg methylene dichloride, add the washing of 87.5kg purified water after the stirring and dissolving once, organic phase is standby, and water adds the 8.3kg washed with dichloromethane once, the water liquid waste disposal, merge organic 62.4kg purified water washing that is added to, water liquid waste disposal, organic phase be 25～30 ℃ of temperature controls, vacuum tightness-0.08～-the 0.1Mpa underpressure distillation namely stops distillation to there being solid to separate out, stir and drip sherwood oil 33.0kg crystallization down, temperature control 0-5 ℃ growing the grain 3 hours, centrifugal, washing, drying obtains the rabeprazole thioether.
Oxidizing reaction: be equipped with the purified water into 91kg in the 3rd clean retort, mixing speed 35Hz drops into 4.67kg sodium hydroxide, after the dissolving, adds 10% chlorine bleach liquor 140.1kg and stirs, and obtains sodium hydroxide-aqueous sodium hypochlorite solution, and is standby.In the 4th clean retort, be equipped with into methylene dichloride 242.8kg, 20～25 ℃ of temperature controls, the rabeprazole thioether that the step makes in the mixing speed 40Hz adding, after the stirring and dissolving, be cooled under-5～5 ℃, sodium hydroxide～the aqueous sodium hypochlorite solution that adds above preparation, about 1 hour of time spent, timing stirring reaction 1 hour, liquid phase monitoring rabeprazole thioether is residual to be not more than 0.5%, reaction finishes, add 27% sodium thiosulfate solution 10.9kg, transfer pH to 9.0～10.0(to use 23.3kg approximately with 50% glacial acetic acid aqueous solution), layering, water adds the 37.1kg washed with dichloromethane once, merge organic 140.0kg purified water that is added to, sodium hydroxide solution with 30% is regulated pH to 13.0～14.0(and is used 25.1kg approximately), layering, organic phase with the extraction of 46.7kg purified water once, merge water, add the 185.7kg methylene dichloride, and transfer pH to 9.0～10.0(to use 23.3kg approximately with 50% glacial acetic acid aqueous solution), layering, water 31.0kg dichloromethane extraction merges organic phase, adds the 28.00kg anhydrous sodium sulfate drying 30 minutes, filter, 61.9kg washed with dichloromethane merges 25～30 ℃ of organic phased temperature, vacuum tightness-0.08～-the 0.1Mpa underpressure distillation flows out to there being methylene dichloride, add 147.5kg acetonitrile stirring and crystallizing, be cooled to 0-5 ℃ of growing the grain 2 hours.Centrifugal, washing, drying obtains rabeprazole.
Become the sodium salt reaction: add methyl alcohol 52.5kg in the 5th clean retort, 20～25 ℃ add rabeprazole 20.00kg, add 2.28kg sodium hydroxide, stir after 1 hour, add the 0.90kg gac, stirred 1 hour, temperature remains unchanged, with soup through the press filtration of decarburization strainer to crystallizer, be warming up to 50～55 ℃, filtrate is not flowed out to there being methyl alcohol in the crystallizer underpressure distillation, adds 9.5kg toluene, continues 50-55 ℃ of underpressure distillation to solvent-free outflow, after adding the dissolving of 9.9kg ethyl acetate and 19.2kg toluene, drip normal heptane 136.6kg crystallization, added normal heptane in about 15 minutes, be cooled to 20-25 ℃ of growing the grain 1 hour, centrifugal, washing, drying obtains rabeprazole sodium crystal compound.
Embodiment 3:
Present embodiment provides a kind of preparation method of rabeprazole sodium crystal compound, be to be raw material with 2-mercaptobenzimidazole, 2-chloromethyl-3-methyl-4-methoxy propoxy pyridine hydrochloride, obtain final product through condensation, oxidation and salt-forming reaction, it comprises following preparation process:
Condensation reaction: be equipped with in the first clean retort into 32.6kg first 29.3kg, stirring and dissolving is prepared into the methanol solution of 2-chloromethyl-3-methyl-4-methoxy propoxy pyridine hydrochloride, and is standby.
In the second clean retort, be equipped with into methyl alcohol 98.8kg, stir adding sodium hydroxide 9.88kg down with the 40Hz rotating speed, the back temperature control that stirs drops into 2-mercaptobenzimidazole 19.76kg for 20-25 ℃, be warming up to 50-60 ℃, the methanol solution of the temperature control 50-60 ℃ of 2-for preparing more than adding chloromethyl-3-methyl-4-methoxy propoxy pyridine hydrochloride, about 30min adds.Keep this temperature and continue reaction 4h, Liquid Detection 2-chloromethyl-3-methyl-4-methoxy propoxy pyridine hydrochloride is residual is not more than 0.5%, and reaction terminating filters.5.4kg methanol wash, merge diafiltration liquid, temperature control 40-50 ℃, vacuum tightness-0.08～-0.1Mpa is evaporated to no methyl alcohol and flows out, and adds the 66.3kg methylene dichloride, add the washing of 87.5kg purified water after the stirring and dissolving once, organic phase is standby, and water adds the 8.3kg washed with dichloromethane once, the water liquid waste disposal, merge organic 62.4kg purified water washing that is added to, water liquid waste disposal, organic phase be 25～30 ℃ of temperature controls, vacuum tightness-0.08～-the 0.1Mpa underpressure distillation namely stops distillation to there being solid to separate out, stir and drip sherwood oil 33.0kg crystallization down, temperature control 0-5 ℃ growing the grain 3 hours, centrifugal, washing, drying obtains the rabeprazole thioether.
Oxidizing reaction: be equipped with the purified water into 90.3kg in the 3rd clean retort, mixing speed 35Hz drops into 4.67kg sodium hydroxide, after the dissolving, adds 10% chlorine bleach liquor 149.4kg and stirs, and obtains sodium hydroxide-aqueous sodium hypochlorite solution, and is standby.In the 4th clean retort, be equipped with into methylene dichloride 247.5kg, 20～25 ℃ of temperature controls, the rabeprazole thioether that the step makes in the mixing speed 40Hz adding, after the stirring and dissolving, be cooled under-5～5 ℃, sodium hydroxide～the aqueous sodium hypochlorite solution that adds above preparation, about 1 hour of time spent, timing stirring reaction 1 hour, liquid phase monitoring rabeprazole thioether is residual to be not more than 0.5%, reaction finishes, add 27% sodium thiosulfate solution 10.9kg, transfer pH to 9.0～10.0(to use 23.3kg approximately with 50% glacial acetic acid aqueous solution), layering, water adds the 37.1kg washed with dichloromethane once, merge organic 140.0kg purified water that is added to, sodium hydroxide solution with 30% is regulated pH to 13.0～14.0(and is used 25.1kg approximately), layering, organic phase with the extraction of 46.7kg purified water once, merge water, add the 185.7kg methylene dichloride, and transfer pH to 9.0～10.0(to use 23.3kg approximately with 50% glacial acetic acid aqueous solution), layering, water 31.0kg dichloromethane extraction merges organic phase, adds the 28.00kg anhydrous sodium sulfate drying 30 minutes, filter, 61.9kg washed with dichloromethane merges 25～30 ℃ of organic phased temperature, vacuum tightness-0.08～-the 0.1Mpa underpressure distillation flows out to there being methylene dichloride, add 147.5kg acetonitrile stirring and crystallizing, be cooled to 0-5 ℃ of growing the grain 2 hours.Centrifugal, washing, drying obtains rabeprazole.
Become the sodium salt reaction: add methyl alcohol 52.5kg in the 5th clean retort, 20～25 ℃ add rabeprazole 20.00kg, add 2.38kg sodium hydroxide, stir after 1 hour, add the 0.90kg gac, stirred 1 hour, temperature remains unchanged, with soup through the press filtration of decarburization strainer to crystallizer, be warming up to 50～55 ℃, filtrate is not flowed out to there being methyl alcohol in the crystallizer underpressure distillation, adds 9.5kg toluene, continues 50-55 ℃ of underpressure distillation to solvent-free outflow, after adding the dissolving of 9.9kg ethyl acetate and 19.2kg toluene, drip normal heptane 136.6kg crystallization, added normal heptane in about 15 minutes, be cooled to 20-25 ℃ of growing the grain 1 hour, centrifugal, washing, drying obtains rabeprazole sodium crystal compound.
Below be that embodiment 1 amplifies twice, quadruplication, 40 times of preliminary examination sample result of amplification, as table four and table five.
Table four is raw material usage quantity and the product preparation amount of test agent just
| The lab scale lot number | The 2-mercaptobenzimidazole charging capacity | The pyridine hydrochloride charging capacity | Sodium rabeprazole |
| 110302 | 28.4g | 50.0g | 31.5g |
| 110303 | 56.8g | 100.0g | 62.0g |
| 110401 | 568.0g | 1000.0g | 671.5g |
Table five is the result of test agent just
Physico-chemical property
This product is that white is to little yellow crystal or crystalline powder, odorless, bitter.Easily molten in methyl alcohol, ethanol or chloroform, in water, dissolve, almost insoluble in ether.
Structure elucidation
(1) results of elemental analyses shows that the composition of sample conforms to Sodium rabeprazole, and uncertainty of measurement is in allowed band.
(2) ultra-violet absorption spectrum shows, this product contains the substituted benzene ring structure, conforms to the Sodium rabeprazole structure.
(3) infrared spectra shows, has structures such as secondary ammonium carbamate, methyl in this sample.The infrared spectrogram feature of this sample conforms to the Sodium rabeprazole structure.
(4)
1The H spectrum shows 14 groups of hydrogen, is respectively 1: 1: 1 by low the integration ratio to High-Field hydrogen: 1: 1: 2: 1: 1: 1: 2: 2: 3: 2: 3, conform to the structure of Sodium rabeprazole.
(5) have 15 carbon in the molecular structure of Sodium rabeprazole, and this product
13The C spectrum shows 15 groups of carbon peaks, conforms to the molecular structure of Sodium rabeprazole.
(6) mass spectrum records the molecular ion peak [M-H] of this product
-, its mass-to-charge ratio m/z is 358.2, and is consistent with the molecular ion peak (molecular weight is 359.1) of Sodium rabeprazole.Mass spectrum records the molecular ion peak [M-Na+2H] of this product
+, its mass-to-charge ratio m/z is 360.1, and is consistent with the molecular ion peak (molecular weight is 381.43) of Sodium rabeprazole
(7) the X-ray diffraction spectrogram shows, sample is mainly unformed.
Find out from the DSC curve of rabeprazole sodium sample that (8) exothermic peak of 175 ℃ and 220 ℃ is that it decomposes exothermic peak.
The rabeprazole sodium sample is carried out UV spectrum, infrared spectra, NMR (Nuclear Magnetic Resonance) spectrum, mass spectroscopy, X-ray diffraction analysis and heat simultaneously analyze, the structure of show sample conforms to the Sodium rabeprazole structure as a result.
Impurity analysis
Check possible heavy metal and muriate by chemical process, check that by the GC method possible solvent is residual, check control other possible impurity and degraded products by HPLC method related substance.
Purity testing
Reference substance source: Nat'l Pharmaceutical ﹠ Biological Products Control Institute
The method of the purity of reference substance and check purity: reference substance purity: 99.9%
Check purity method: get this product, accurately claim surely, add mixed solvent [acetonitrile-water-triethylamine (30:70:0.5) is regulated pH to 10.0 with phosphoric acid] and make every 1ml and contain Sodium rabeprazole 0.5mg as need testing solution (facing with newly joining).Precision is measured this solution 10 μ l, injects liquid chromatograph, and the record color atlas is to 4.0 times of principal constituent peak retention time.With area normalization method calculation sample purity.
Check to such an extent that sample purity is 99.7%
Check purity method: get this product, accurately claim surely, add mixed solvent [acetonitrile-water-triethylamine (30:70:0.5) is regulated pH to 10.0 with phosphoric acid] and make every 1ml and contain Sodium rabeprazole 0.5mg as need testing solution (facing with newly joining).Precision is measured this solution 10 μ l, injects liquid chromatograph, and the record color atlas is to 4.0 times of principal constituent peak retention time.With area normalization method calculation sample purity.
Usage and dosage:
Adult every day oral 1 Sodium rabeprazole meter 10mg, but according to oral 1 20mg of the state of an illness also every day.In the ordinary course of things, be that be 6 weeks the course for the treatment of of 8 weeks, duodenal ulcer the course for the treatment of of stomach ulcer, stoma ulcer, reflux esophagitis.
Clinical efficacy:
The opening of carrying out in stomach ulcer, duodenal ulcer, reflux esophagitis and stoma ulcer patient and the clinical study of double blind control show that the Sodium rabeprazole sheet has good curative effect.Concrete outcome such as following table:
| Disease | The endoscopic cure rate |
| Stomach ulcer | 95.2%（401/421） |
| Duodenal ulcer | 98.1%（364/371） |
| Anti-fluidity esophagitis | 90.9%（50/55） |
| Stoma ulcer | 83.3%（10/12） |
Sodium rabeprazole enteric-coated improvement rate to 2 Zhuos-Emhorn syndrome patient is 100%.Clinical pharmacology studies show that pH is better than 10mg in the 20mg Sodium rabeprazole rising stomach, and the treatment intractable ulcer can be with sodium rabeprazole enteric-coated 20mg once a day.In addition, sodium rabeprazole enteric-coated curative effect for the treatment of stomach ulcer and duodenal ulcer determined by double blind trial.
More than be preferred implementation of the present invention, should be pointed out that for those skilled in the art that under the prerequisite that does not break away from the principle of the invention, can also make some improvements and modifications, these improvements and modifications also are considered as protection scope of the present invention.
Claims (9)
1. the preparation method of rabeprazole sodium crystal compound is characterized in that, may further comprise the steps:
(1) first methyl alcohol is dropped into the first clean retort, add 2-chloromethyl-3-methyl-4-methoxy propoxy pyridine hydrochloride, stir and make its dissolving, be prepared into the methanol solution of 2-chloromethyl-3-methyl-4-methoxy propoxy pyridine hydrochloride;
(2) in the second clean retort, add second batch of methyl alcohol, stir and add sodium hydroxide, 20-25 ℃ of temperature of control also drops into 2-mercaptobenzimidazole, be warming up to the methanol solution of the 2-chloromethyl-3-methyl-4-methoxy propoxy pyridine hydrochloride that adds step () after 50-60 ℃ and make, keep thermotonus 3 ~ 5h, the reaction terminating after-filtration is also used methanol wash, merge diafiltration liquid, temperature control 40-50 ℃, being evaporated to no methyl alcohol flows out, washing back crystallization, the drying intermediate of winning, wherein the second batch of methanol quality is 2.5 ~ 3.5 times of step () quantity of methyl alcohol;
(3) add water and sodium hydroxide in the 3rd clean retort, the dissolving back adds 10% clorox stirs, and gets sodium hydroxide-aqueous sodium hypochlorite solution; In the 4th clean retort, add methylene dichloride, the control temperature is at 20-25 ℃, add step (two) intermediate of winning then, be cooled to jar interior temperature below-5 ℃, add above-mentioned sodium hydroxide-aqueous sodium hypochlorite solution and react, reaction finishes back adding sodium thiosulfate solution also with 50% glacial acetic acid aqueous solution accent pH to 9 ~ 10, get organic phase with the methylene dichloride repetitive scrubbing, 25 ~ 30 ℃ of temperature controls, crystallization after the underpressure distillation, the washing of cooling back is also dry, gets second intermediate;
(4) in the 5th clean retort, add methyl alcohol, add step (three) gained second intermediate and sodium hydroxide down at 20 ~ 25 ℃, adding gac stirs, press filtration was to crystallizer after soup took off charcoal, be warming up to 50 ~ 55 ℃, filtrate decompression is distilled to no methyl alcohol and flows out, washing and crystallization, dry Sodium rabeprazole finished product, and wherein methanol quality is 1.5 ~ 2 times of step () methyl alcohol add-on;
Wherein, the 2-chloromethyl-3-methyl-4-methoxy propoxy pyridine hydrochloride quality is 0.7 ~ 0.9:1 with the ratio of methanol quality in the described step (), and the 2-mercaptobenzimidazole quality is 0.1 ~ 0.2:1 with the ratio of methanol quality in the step (two).
2. the preparation method of rabeprazole sodium crystal compound according to claim 1 is characterized in that:
In the described step (), keep thermotonus 3 ~ 5h, Liquid Detection 2-chloromethyl-3-methyl-4-methoxy propoxy pyridine hydrochloride is residual to be not more than 0.5% o'clock reaction terminating.
3. the preparation method of rabeprazole sodium crystal compound according to claim 1 is characterized in that:
Sodium hydroxide is 0.08 ~ 0.1:1 with the ratio of methanol quality in the described step (two).
4. the preparation method of rabeprazole sodium crystal compound according to claim 1 is characterized in that:
In the described step (two), washing back crystallization, drying are specially: add methylene dichloride, add the purified water washing after the stirring and dissolving once, organic phase is standby, water adds washed with dichloromethane once, the water liquid waste disposal, merge organic purified water washing that is added to, organic phase is 25 ~ 30 ℃ of temperature, vacuum tightness-0.08 ~ ~ the 0.1Mpa condition under underpressure distillation namely stop distillation, agitation and dropping sherwood oil crystallization to there being solid to separate out, 0 ~ 5 ℃ of growing the grain of temperature control a few hours, centrifugal, washing, the drying intermediate of winning.
5. the preparation method of rabeprazole sodium crystal compound according to claim 1 is characterized in that:
In the described step (three), the mass ratio of sodium hydroxide and 10% clorox is 1:30 ~ 32.
6. the preparation method of rabeprazole sodium crystal compound according to claim 1 is characterized in that:
In the described step (three), adding the methylene dichloride quality in the 4th clean retort is 52 ~ 53:1 with the ratio that adds the sodium hydroxide quality in the 3rd clean retort.
7. the preparation method of rabeprazole sodium crystal compound according to claim 1 is characterized in that:
In the described step (three), be specially with methylene dichloride repetitive scrubbing process: water adds washed with dichloromethane once after the layering, merge organic purified water that is added to, sodium hydroxide solution with 30% is regulated pH to 13.0 ~ 14.0, layering, organic phase with the purified water extraction once merges water, adds methylene dichloride, and transfer pH to 9.0-10.0 with 50% glacial acetic acid aqueous solution, layering, the water dichloromethane extraction merges organic phase, added anhydrous sodium sulfate drying 30 minutes, filter, with washed with dichloromethane, merge organic phase.
8. the preparation method of rabeprazole sodium crystal compound according to claim 1 is characterized in that:
In the described step (four), the sodium hydroxide quality is 1:22 ~ 23 with the methanol quality ratio.
9. the preparation method of rabeprazole sodium crystal compound according to claim 1 is characterized in that:
In the described step (four), the process of washing and crystallization is specially: add toluene, continue 50-55 ℃ of underpressure distillation to solvent-free outflow, after adding ethyl acetate and the toluene dissolving, drip the normal heptane crystallization, be cooled to 20-25 ℃ of growing the grain 1 hour, and centrifugal, washing.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113336741A (en) * | 2021-05-07 | 2021-09-03 | 湖南德虹制药有限公司 | Rabeprazole sodium anhydrate crystal form and preparation method thereof |
| CN113582973A (en) * | 2021-09-28 | 2021-11-02 | 丽珠医药集团股份有限公司 | Preparation method of thioether |
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| CN1370771A (en) * | 2001-02-27 | 2002-09-25 | 山东新华制药股份有限公司 | Prepn process of 3-methyl-4 [(3-methoxy) propoxy]2-radical-methyl-thio-benzimidazole |
| WO2008045777A2 (en) * | 2006-10-06 | 2008-04-17 | Dr. Reddy's Labortories, Ltd. | A process for the preparation of benzimidazole derivatives and their salts |
| CN101805327A (en) * | 2010-04-29 | 2010-08-18 | 郝志艳 | Rabeprazole sodium compound and novel preparation method thereof |
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| CN1370771A (en) * | 2001-02-27 | 2002-09-25 | 山东新华制药股份有限公司 | Prepn process of 3-methyl-4 [(3-methoxy) propoxy]2-radical-methyl-thio-benzimidazole |
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| CN113336741A (en) * | 2021-05-07 | 2021-09-03 | 湖南德虹制药有限公司 | Rabeprazole sodium anhydrate crystal form and preparation method thereof |
| CN113582973A (en) * | 2021-09-28 | 2021-11-02 | 丽珠医药集团股份有限公司 | Preparation method of thioether |
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