CN103242295B - Esomeprazole sodium crystal-form compound and synthetic method thereof - Google Patents
Esomeprazole sodium crystal-form compound and synthetic method thereof Download PDFInfo
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Abstract
The embodiment of the invention discloses a kind of Esomeprazole sodium crystal-form compound; chemical name is S-5-methoxyl group-2-{ [(4-methoxyl group-3; 5-dimethyl-2-pyridyl) methyl] sulfinyl }-1H-benzoglyoxaline sodium; also disclose a kind of preparation method of Esomeprazole sodium crystal-form compound; comprise; the purifying of the synthesis of omeprazole precursor, the synthesis of Esomeprazole sodium crude product and Esomeprazole sodium crude product, present method technique is simple, cost of manufacture is low, finished product Be very effective.
Description
Technical field
The present invention relates to Esomeprazole sodium field, particularly relate to a kind of Esomeprazole sodium crystal-form compound and synthetic method thereof.
Background technology
Proton pump inhibitor (PPI) is the choice drug of acid related disorder such as treatment peptide ulceration, gastroesophageal reflux disease etc.PPI conventional clinically at present has omeprazole, lansoprazole, rabeprazole, pantoprazole and esomeprazole 5 kinds.Omeprazole is as the first PPI medicine, and the curative effect of its therapic acid relative disease obtains consistent accreditation.Esomeprazole, the resistance to letter of trade(brand)name (Nexium) is the individual isomer of omeprazole, i.e. (S)-isomer.Owing to having metabolic advantage, Esomeprazole sodium has higher bioavailability and more consistent pharmacokinetics compared with omeprazole, and the medicine of arrival proton pump is increased, and acid suppression effect is better than other PPI.
Summary of the invention
Embodiment of the present invention technical problem to be solved is, provide a kind of Esomeprazole sodium crystal-form compound, molecular structure is as follows:
In order to solve the problems of the technologies described above, embodiments provide that a kind of technique is simple, cost of manufacture is low, the synthetic method of the Esomeprazole sodium of finished product Be very effective, comprise the steps:
The synthetic method of described a kind of Esomeprazole sodium, is characterized in that, comprise the steps:
(1) synthesis of omeprazole precursor: add methyl alcohol in retort, raw material 2-sulfydryl-5-methoxyl group-1H-benzoglyoxaline is dropped under whipped state, add 2-chloromethyl-4-methoxyl group-3 more in batches, 5-dimethyl pyrazole thiamine hydrochloride and aqueous sodium hydroxide solution, then 60-65 DEG C is warming up to, timed reflux, TLC detection reaction, add gac return stirring after completion of the reaction, filter, cool to 40-45 DEG C, underpressure distillation, remove most of methyl alcohol, in retort, add methylene dichloride after distillation dissolve, add purified water extracting and demixing, abandon water layer, organic addition saturated sodium-chloride water solution washing layering, abandon water layer, organic phase adds anhydrous sodium sulfate drying, suction filtration, filtrate keeps vacuum tightness-0.08--0.1MPa, is evaporated to dripless and flows out, add acetone solution, be warmed up to 53-55 DEG C, add hexane slowly, be cooled to room temperature, stir growing the grain, centrifugal drying, obtain off-white color solid omeprazole precursor,
(2) synthesis of Esomeprazole sodium crude product: add ethyl acetate in retort, omeprazole precursor is dropped under whipped state, be warming up to 65-70 DEG C, 53-55 DEG C is cooled to after being stirred to dissolving, add D-(-)-diethyl tartrate and titanium tetraisopropylate stirring reaction more successively, N is added successively after reaction cooling, N-diisopropyl ethyl amine, cumyl hydroperoxide stirring reaction, add ethyl acetate again, three times are extracted with ammonia soln, merge aqueous phase, adjust ph is to 7.0-8.0 again, be extracted with ethyl acetate again, merge organic phase, wash with saturated sodium-chloride water solution, organic phase anhydrous sodium sulfate drying, suction filtration, filtrate 28-30 DEG C, concentrating under reduced pressure obtains clear yellow viscous oily thing under vacuum tightness-0.08--0.1MPa, at room temperature, gained oily matter is dissolved in mibk, under stirring, adds aqueous sodium hydroxide solution, acetonitrile successively, stirring reaction, centrifugal blowing, with washing with acetone, after 20 ~ 24 DEG C of vacuum-dryings, obtain white solid Esomeprazole sodium crude product,
(3) purifying of Esomeprazole sodium crude product: in dissolving vessel, adds acetone, Esomeprazole sodium crude product successively, is heated to backflow, stirs, filter, be cooled to 35-38 DEG C, crystallization adds growing the grain, suction filtration, with washing with acetone, vacuum-drying obtains sterling Esomeprazole sodium.
Described step adds methyl alcohol 200-202kg in (1) in retort, raw material 2-sulfydryl-5-methoxyl group-1H-benzoglyoxaline 18-19kg is dropped under whipped state, add 2-chloromethyl-4-methoxyl group-3 in batches, 5-dimethyl pyrazole thiamine hydrochloride 22-23kg, in tank, drip the 4.4mol/L aqueous sodium hydroxide solution 28-32kg prepared, 20 minutes used times added, and were warming up to 60-65 DEG C, timed reflux 4.5h, TLC detection reaction.
1.0-1.4kg gac return stirring is added 30 minutes in solution after completion of the reaction, filter, filtrate is cooled to 40-45 DEG C, underpressure distillation, removes most of methyl alcohol, distill complete, in retort, add 408-410kg methylene dichloride dissolve, add purified water 152-154kg*2 extracting and demixing 2 times, abandon water layer, organic addition saturated sodium-chloride water solution 114.4kg*3 washs layering, abandons water layer; Organic addition anhydrous sodium sulphate 9-10kg is dry, suction filtration; Filtrate 30 DEG C keeps vacuum tightness-0.08--0.1MPa to be evaporated to dripless outflow, add 32-33kg acetone solution, be warming up to 53-55 DEG C, slowly add hexane 42-43kg, slow cooling, to room temperature, stirs growing the grain 1 hour, centrifugal, 36-40 DEG C of dry 2.5h, surveys moisture≤0.5% discharging, obtains off-white color solid.
Described step adds ethyl acetate 132-133kg in (2) in retort, stir lower input omeprazole precursor 29-30kg, be warming up to 65-70 DEG C, after being stirred to dissolving, be cooled to 53-55 DEG C, add after D-(-)-diethyl tartrate 5-6kg stirs 30 minutes, add titanium tetraisopropylate 2-4kg, 55 DEG C of stirring reaction 1.5h, are cooled to 30 DEG C, add N, N-diisopropyl ethyl amine 1-2kg, stirs 20min; Slowly add cumyl hydroperoxide 16-18kg, temperature control 30-34 DEG C of stirring reaction 4.5h after adding.
Ethyl acetate 99-100kg is added in above-mentioned reacted solution, three times are extracted with 12.5% ammonia soln 139.5kg*3, merge aqueous phase, pH to 7.0 ~ 8.0 are regulated with 75% acetic acid 69.8kg, extract three times with ethyl acetate 265.0kg*3 again, merge organic phase, wash three times with saturated sodium-chloride water solution 329.0kg*3, organic phase is dry with anhydrous sodium sulphate 14-15kg, suction filtration; Filtrate 28 ~ 30 DEG C, vacuum tightness-0.08--0.1MPa concentrating under reduced pressure obtains clear yellow viscous oily thing; Under room temperature, gained oily matter is dissolved in 88-89kg mibk, under stirring, adds 40% aqueous sodium hydroxide solution 10-11kg, acetonitrile 172-174kg successively, stirring reaction 2h; Centrifugal blowing, with 2 washings of acetone 57-59kg average mark, obtains white solid after 20 ~ 24 DEG C of vacuum-drying 3h.
To in dissolving vessel in described step (3), add 180-184L acetone, 17-18kg Esomeprazole sodium crude product successively, be heated to backflow, temperature 55-60 DEG C, stir 1h, filter, be cooled to 35-38 DEG C, crystallization adds growing the grain 90 minutes, suction filtration, with 118-122L washing with acetone, 40 DEG C, vacuum is dry obtains sterling Esomeprazole sodium.
Implement the embodiment of the present invention, there is following beneficial effect:
Raw material 2-sulfydryl-5-methoxyl group-1H-benzoglyoxaline is first made into omeprazole precursor by replacement or condensation reaction by the embodiment of the present invention, and then make Esomeprazole sodium crude product by omeprazole precursor, carry out purifying again, present method technique is simple, cost of manufacture is low, makes finished product Be very effective.
Accompanying drawing explanation
Fig. 1 is Esomeprazole sodium crystal-form compound synthetic method embodiment process flow sheet of the present invention.
Embodiment
For making the object, technical solutions and advantages of the present invention clearly, below in conjunction with accompanying drawing, the present invention is described in further detail.
The present embodiment Esomeprazole sodium crystal-form compound, molecular structure is as follows:
The synthetic method of above-mentioned Esomeprazole sodium, comprises the steps:
Technique describes:
The synthesis of omeprazole precursor: the synthesis (replacing or condensation reaction) of 5-methoxyl group-2-[[(4-methoxyl group-3,5-dimethyl-2-pyridyl) methyl] sulfenyl]-1H-benzoglyoxaline
Methyl alcohol 201.7kg is added in retort, raw material 2-sulfydryl-5-methoxyl group-1H-benzoglyoxaline 18.40kg under whipped state, add 2-chloromethyl-4-methoxyl group-3 in batches, 5-dimethyl pyrazole thiamine hydrochloride 22.70kg, the 4.4mol/L aqueous sodium hydroxide solution 30.0kg (4.5kg sodium hydroxide is dissolved in 25.5kg purified water) prepared is dripped in tank, about 20 minutes used times added, be warming up to 60-65 DEG C, timed reflux 4.5h, TLC detection reaction, add 1.20kg gac return stirring after completion of the reaction 30 minutes, filter, filtrate is cooled to 40-45 DEG C, underpressure distillation, remove major part (about 2/3) methyl alcohol, distill complete, in retort, add 408.9kg methylene dichloride dissolve, add purified water 153.2kg*2 extracting and demixing 2 times, abandon water layer, organic addition saturated sodium-chloride water solution 114.4kg*3 washs layering, abandon water layer.Organic addition anhydrous sodium sulphate 9.20kg is dry, suction filtration.Filtrate 30 DEG C keeps vacuum tightness-0.08--0.1MPa to be evaporated to dripless outflow, add 32.3kg acetone solution, be warming up to 53-55 DEG C, add normal hexane 42.4kg slowly, slow cooling is to room temperature, stir growing the grain 1 hour, centrifugal, 36-40 DEG C of drying about 2.5h, surveys moisture≤0.5% discharging, obtain off-white color solid and be about 29.38kg, yield 87.4%.
The synthesis of Esomeprazole sodium crude product
Ethyl acetate 132.5kg is added in retort, stir lower input omeprazole precursor 29.38kg, be warming up to 65-70 DEG C, after being stirred to dissolving, be cooled to 53-55 DEG C, add after D-(-)-diethyl tartrate 5.5kg stirs 30 minutes, add titanium tetraisopropylate 3.0kg, 55 DEG C of stirring reaction 1.5h, are cooled to 30 DEG C, add N, N-diisopropyl ethyl amine 1.5kg, stirs 20min.Slowly add cumyl hydroperoxide 17.0kg, dropwise rear temperature control 30-34 DEG C stirring reaction 4.5h.Add ethyl acetate 99.4kg, three times are extracted with 12.5% ammonia soln 139.5kg*3, merge aqueous phase, pH to 7.0 ~ 8.0 are regulated with 75% acetic acid 69.8kg, extract three times with ethyl acetate 265.0kg*3 again, merge organic phase, wash three times with saturated sodium-chloride water solution 329.0kg*3, organic phase is dry with anhydrous sodium sulphate 14.70kg, suction filtration.Filtrate 28 ~ 30 DEG C, vacuum tightness-0.08--0.1MPa concentrating under reduced pressure obtains clear yellow viscous oily thing.Under room temperature, gained oily matter is dissolved in 88.2kg mibk, under stirring, adds 40% aqueous sodium hydroxide solution 10.5kg, acetonitrile 173.1kg successively, stirring reaction 2h.Centrifugal blowing, with 2 washings of acetone 58.0kg average mark, obtains white solid after 20 ~ 24 DEG C of vacuum-drying 3h and is about 17.70kg, productive rate 54.0%.
The purifying of Esomeprazole sodium crude product
To in dissolving vessel, add 182L acetone, 17.5kg Esomeprazole sodium crude product successively, be heated to reflux (temperature 55-60 DEG C), stir 1h, filter, be cooled to 35-38 DEG C, crystallization adds growing the grain 90 minutes, suction filtration, with 120L washing with acetone, 40 DEG C, vacuum is dry obtains sterling Esomeprazole sodium (about 6 hours of time of drying).Moisture limit value≤0.5%, yield 82-90%.
Pharmacological toxicology and clinical research data summary
Pharmacological action:
This product is the specific inhibitor of proton pump in parietal cell.Esomeprazole is the S-isomer of omeprazole, and reduce gastric acid secretion by specific proton pump restraining effect, the R-isomer of omeprazole has similar pharmacodynamic profiles with S-isomer.
Esomeprazole is a weakly basic drugs, secrete parietal cell in the high acid environment of sour microtubule and concentrate and be converted to activity form, thus suppress the H+/K+-ATP enzyme (proton pump) at this position, all suppression is produced to the gastric acid secretion after basal gastric acid secretion and irriate.
Gastroesophageal reflux disease (GERD) patient every day oral esomeprazole 20mg and 40mg, the mean time maintaining pH > 4 in stomach after 5 days in its 24 hours is respectively 13 hours and 17 hours.Esomeprazole is oral similar with the effect of intravenously administrable.
With the Substitute Indexes of AUC (lower area of blood concentration-time curve) as plasma concentration, the relation between gastric acid secretion suppression and drug exposure after oral administration also can be shown.
In patients with reflux esophagitis oral esomeprazole 40mg4 week, healing rate is about 78%, is 93% after 8 weeks.
At antiacid medicine treatments period, gastric acid secretion minimizing can cause serum gastrin to increase.In the patient of some Long-term Oral Esomeprazole therapy on treatments, observe intestines increasing addicted to chromium sample (ECL) cell, this may be relevant with the rising of level of serum gastrin.
At the antiacid medicine treatments period of life-time service, there is the report that gastric gland tumour incidence to a certain degree increases.These reactions are the physiological reactions significantly suppressed after secreting acid, and it is optimum and reversible.
Toxicological study:
In the single and the clinical front correlation test research such as multiple dosing toxicity research, teratogenesis and mutagenesis of routine, not evidence show that esomeprazole has special harm to the mankind.The carinogenicity research of Oral Administration in Rats racemic mixture (omeprazole) has found that the intestines of stomach are addicted to (ECL) hyperplasia of chromium sample and carcinoid.These effects are secondary to the lasting minimizing of hydrochloric acid in gastric juice generation and significant hypergastrinemia, see the rat after life-time service gastric acid secretion inhibitor.
Clinical application:
Gastroesophageal reflux disease is used for the treatment of reflux esophagitis and (or) has the patient of serious reflux symptom.Intravenous applications esomeprazole can make the curative ratio of erosive esophagitis reach 80%, when gastroesophageal reflux disease has dysphagia, vomiting, the complication such as hemorrhage, vein gives esomeprazole can gastric acid secretion inhibiting quickly and effectively, pH>4 in long-time maintenance stomach, thus reach good therapeutic action.
Upper gastrointestinal hemorrhage is for the process of Non-variceal upper gastrointestinal hemorrhage, and usually first at gastroscope lower hemostasia, rapid drug application successfully of stopping blooding improves more than pH to 6 in stomach, to promote platelet aggregation and to prevent thrombolysis, prevents hemorrhage again.Generally acknowledge at present and can improve more than pH>6 in stomach rapidly, with omeprazole 80mg quiet note at once, continue ideal with the acid suppression effect of 8mg/h maintenance intravenous drip.The Acidinhibitor of esomeprazole be better than omeprazole and the time length longer, beyond any doubt, its be used for the treatment of acute hemorrhage of upper gastrointestinal tract will more effective and facilitate.
In stress ulcer stomach, pH changes with gastric mucosal lesions closely related, if effectively control acidity in gastric acid secretion and gastral cavity, just can control and cure the pathological change of gastric mucosa when stress situation in a way.Now there are some researches show, intravenous injection omeprazole can improve pH in stomach fast, effectively treats stress ulcer.The time maintaining pH>4 in stomach due to esomeprazole is longer, believes that it is used for the treatment of stress ulcer effect more remarkable.
In a word, injection PPI Esomeprazole sodium of new generation because having unique pharmacokinetic characteristics, the more oral esomeprazole of its acid suppression ability and other injection PPI sooner, more effective.Need to use PPI but cannot the patient of oral administration for clinical, as acute hemorrhage of upper gastrointestinal tract and stress ulcer etc., injection esomeprazole can provide potent acid suppression and comprehensively protection.
Above disclosedly be only a kind of preferred embodiment of the present invention, certainly can not limit the interest field of the present invention with this, therefore according to the equivalent variations that the claims in the present invention are done, still belong to the scope that the present invention is contained.
Claims (1)
1. a synthetic method for Esomeprazole sodium, is characterized in that, comprises the steps:
(1) synthesis of omeprazole precursor: add methyl alcohol in retort, raw material 2-sulfydryl-5-methoxyl group-1H-benzoglyoxaline is dropped under whipped state, add 2-chloromethyl-4-methoxyl group-3 more in batches, 5-dimethyl pyrazole thiamine hydrochloride and aqueous sodium hydroxide solution, then 60-65 DEG C is warming up to, timed reflux, TLC detection reaction, add gac return stirring after completion of the reaction, filter, cool to 40-45 DEG C, underpressure distillation, remove most of methyl alcohol, in retort, add methylene dichloride after distillation dissolve, add purified water extracting and demixing, abandon water layer, organic addition saturated sodium-chloride water solution washing layering, abandon water layer, organic phase adds anhydrous sodium sulfate drying, suction filtration, filtrate keeps vacuum tightness-0.08 to-0.1MPa, is evaporated to dripless and flows out, add acetone solution, be warmed up to 53-55 DEG C, add normal hexane slowly, be cooled to room temperature, stir growing the grain, centrifugal drying, obtain off-white color solid omeprazole precursor,
Described step adds methyl alcohol 200-202kg in (1) in retort, raw material 2-sulfydryl-5-methoxyl group-1H-benzoglyoxaline 18-19kg is dropped under whipped state, add 2-chloromethyl-4-methoxyl group-3 in batches, 5-dimethyl pyrazole thiamine hydrochloride 22-23kg, in tank, drip the 4.4mol/L aqueous sodium hydroxide solution 28-32kg prepared, 20 minutes used times added, and were warming up to 60-65 DEG C, timed reflux 4.5h, TLC detection reaction; 1.0-1.4kg gac return stirring is added 30 minutes in solution after completion of the reaction, filter, filtrate is cooled to 40-45 DEG C, underpressure distillation, removes most of methyl alcohol, distill complete, in retort, add 408-410kg methylene dichloride dissolve, add purified water 152-154kg*2 extracting and demixing 2 times, abandon water layer, organic addition saturated sodium-chloride water solution 114.4kg*3 washs layering, abandons water layer; Organic addition anhydrous sodium sulphate 9-10kg is dry, suction filtration; Filtrate 30 DEG C keeps vacuum tightness-0.08 to be evaporated to dripless outflow to-0.1MPa, add 32-33kg acetone solution, be warming up to 53-55 DEG C, slowly add normal hexane 42-43kg, slow cooling, to room temperature, stirs growing the grain 1 hour, centrifugal, 36-40 DEG C of dry 2.5h, surveys moisture≤0.5% discharging, obtains off-white color solid;
(2) synthesis of Esomeprazole sodium crude product: add ethyl acetate in retort, omeprazole precursor is dropped under whipped state, be warming up to 65-70 DEG C, 53-55 DEG C is cooled to after being stirred to dissolving, add D-(-)-diethyl tartrate and titanium tetraisopropylate stirring reaction more successively, N is added successively after reaction cooling, N-diisopropyl ethyl amine, cumyl hydroperoxide stirring reaction, add ethyl acetate again, three times are extracted with ammonia soln, merge aqueous phase, adjust ph is to 7.0-8.0 again, be extracted with ethyl acetate again, merge organic phase, wash with saturated sodium-chloride water solution, organic phase anhydrous sodium sulfate drying, suction filtration, filtrate 28-30 DEG C, concentrating under reduced pressure obtains clear yellow viscous oily thing under vacuum tightness-0.08 to-0.1MPa, at room temperature, gained oily matter is dissolved in mibk, under stirring, adds aqueous sodium hydroxide solution, acetonitrile successively, stirring reaction, centrifugal blowing, with washing with acetone, after 20 ~ 24 DEG C of vacuum-dryings, obtain white solid Esomeprazole sodium crude product,
Described step adds ethyl acetate 132-133kg in (2) in retort, stir lower input omeprazole precursor 29-30kg, be warming up to 65-70 DEG C, after being stirred to dissolving, be cooled to 53-55 DEG C, add after D-(-)-diethyl tartrate 5-6kg stirs 30 minutes, add titanium tetraisopropylate 2-4kg, 55 DEG C of stirring reaction 1.5h, are cooled to 30 DEG C, add N, N-diisopropyl ethyl amine 1-2kg, stirs 20min; Slowly add cumyl hydroperoxide 16-18kg, temperature control 30-34 DEG C of stirring reaction 4.5h after adding; Ethyl acetate 99-100kg is added in above-mentioned reacted solution, three times are extracted with 12.5% ammonia soln 139.5kg*3, merge aqueous phase, pH to 7.0 ~ 8.0 are regulated with 75% acetic acid 69.8kg, extract three times with ethyl acetate 265.0kg*3 again, merge organic phase, wash three times with saturated sodium-chloride water solution 329.0kg*3, organic phase is dry with anhydrous sodium sulphate 14-15kg, suction filtration; Filtrate 28 ~ 30 DEG C, vacuum tightness-0.08 to-0.1MPa concentrating under reduced pressure obtains clear yellow viscous oily thing; Under room temperature, gained oily matter is dissolved in 88-89kg mibk, under stirring, adds 40% aqueous sodium hydroxide solution 10-11kg, acetonitrile 172-174kg successively, stirring reaction 2h; Centrifugal blowing, with 2 washings of acetone 57-59kg average mark, obtains white solid after 20 ~ 24 DEG C of vacuum-drying 3h;
(3) purifying of Esomeprazole sodium crude product: in dissolving vessel, adds acetone, Esomeprazole sodium crude product successively, is heated to backflow, stirs, filter, be cooled to 35-38 DEG C, crystallization adds growing the grain, suction filtration, with washing with acetone, vacuum-drying obtains sterling Esomeprazole sodium;
To in dissolving vessel in described step (3), add 180-184L acetone, 17-18kg Esomeprazole sodium crude product successively, be heated to backflow, temperature 55-60 DEG C, stir 1h, filter, be cooled to 35-38 DEG C, crystallization adds growing the grain 90 minutes, suction filtration, with 118-122L washing with acetone, 40 DEG C, vacuum is dry obtains sterling Esomeprazole sodium.
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| CN104693177A (en) * | 2013-12-09 | 2015-06-10 | 北大方正集团有限公司 | Refining method of esomeprazole sodium |
| CN104693178A (en) * | 2013-12-09 | 2015-06-10 | 北大方正集团有限公司 | Purification method of esomeprazole sodium |
| ES2615637T3 (en) * | 2015-03-06 | 2017-06-07 | F.I.S.- Fabbrica Italiana Sintetici S.P.A. | Improved procedure for optical purification of esomeprazole |
| CN109456306A (en) * | 2018-10-26 | 2019-03-12 | 山西普德药业有限公司 | A kind of esomeprazole sodium and the lyophilized preparation it includes it |
| CN110627771B (en) * | 2019-10-23 | 2022-01-07 | 山东鲁抗医药股份有限公司 | Preparation method of esomeprazole thioether |
| CN113512026A (en) * | 2021-08-26 | 2021-10-19 | 四川子仁制药有限公司 | Synthesis method of esomeprazole sodium |
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| CN102746273A (en) * | 2012-05-29 | 2012-10-24 | 江苏奥赛康药业股份有限公司 | Esomeprazole sodium polymorph and application of esomeprazole sodium polymorph in drugs for injection |
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| CN102746273A (en) * | 2012-05-29 | 2012-10-24 | 江苏奥赛康药业股份有限公司 | Esomeprazole sodium polymorph and application of esomeprazole sodium polymorph in drugs for injection |
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Effective date of registration: 20150914 Address after: Seven of 276017 Shandong province Linyi city Luozhuang District Applicant after: Shandong Luo Xin Pharmaceutical Group Plc Applicant after: Shandong Yu Xin pharmaceutcal corporation, Ltd Applicant after: SHANDONG HENGXIN PHARMACEUTICAL CO., LTD. Address before: Seven of 276017 Shandong province Linyi city Luozhuang District Applicant before: SHANDONG LUOXIN PHARMACY STOCK Co., LTD. |
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Address after: 276017 18 Luo Qi Road, Luozhuang District, Linyi, Shandong Co-patentee after: Shandong Yu Xin pharmaceutcal corporation, Ltd Patentee after: Shandong Luo Xin Pharmaceutical Group Plc Co-patentee after: Shandong Luoxin Pharmaceutical Group Hengxin Pharmacy Co., Ltd. Address before: 276017 Luoqi Road, Luozhuang District, Linyi City, Shandong Province Co-patentee before: Shandong Yu Xin pharmaceutcal corporation, Ltd Patentee before: Shandong Luo Xin Pharmaceutical Group Plc Co-patentee before: SHANDONG HENGXIN PHARMACEUTICAL CO., LTD. |