CN103613581A - Preparation method for Dexiansoprazole - Google Patents
Preparation method for Dexiansoprazole Download PDFInfo
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- CN103613581A CN103613581A CN201310386770.XA CN201310386770A CN103613581A CN 103613581 A CN103613581 A CN 103613581A CN 201310386770 A CN201310386770 A CN 201310386770A CN 103613581 A CN103613581 A CN 103613581A
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- lansoprazole
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- 0 CC1=C(CO)*CC1(*)O Chemical compound CC1=C(CO)*CC1(*)O 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
The invention relates to a preparation method for Dexiansoprazole. and especially provides a preparation method for Dexiansoprazole preparation method for Dexiansoprazole obtained through reaction of R-2-[[(4-nitro-3-methyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole and 2,2,2-trifluoroethanol in the alkaline condition. Dexiansoprazole with high optical purity can be obtained through the method. The operation processes are simple, the reaction yield is high, and the method is suitable for industrial production.
Description
Technical field
The present invention relates to prepare the method for R-lansoprazole, especially a kind of method of preparing R-lansoprazole that replaces through trifluoroethanol.
Background technology
R-lansoprazole is a kind of gastroesophageal reflux disease new drug that is better than lansoprazole, its structural formula:
U.S. FDA is ratified esophagitis treatment new drug R-lansoprazole (the general Dexiansoprazole by name) listing of Japanese Wu Tian drugmaker research and development on January 30th, 2009.This medicine is the enantiomorph of proton pump inhibitor lansoprazole, is used for the treatment of the pyrosis sick relevant to Non-erosive gastroesophageal reflux and erosive esophagitis in various degree.
R-lansoprazole is the proton pump inhibitor of dual controlled release (DDR) of 2 releases of first listing.Listing formulation is slow releasing capsule, can make medicine after administration, after 1 ~ 2 hour and 4 ~ 5 hours, occur respectively two Plasma Concentration peak values, and surpass lansoprazole action time, and the administration time unable to take food thing of Kapidex and the impact of meal time.Third stage test shows, this medicine can be in the daytime or accompany night the gastroesophageal reflux disease of pyrosis symptom to provide to reach the Acidinhibitor of 24 hours and lasting remission effect.The specification of preparation is every 30 or 60mg.
R-lansoprazole is got permission listing and is based on the global result of study of more than 20 country to approximately 6000 routine erosives and the evaluation of Non-erosive GERD patient clinical.R-lansoprazole controlled release capsule and lansoprazole have carried out 8 weeks double-blind, randomized controlled clinical study: treatment erosive esophagitis of 2 same design.In the time of 8 weeks, this product (60mg) obtains higher curative ratio (be respectively 87% and 85% in first research, be respectively 85% and 79% in second research) compared with lansoprazole, and patient tolerability is good.
In prior art, disclose the method for splitting of various R-lansoprazoles, these class methods are disclosed in DE4035455 and WO94/27988, and the method need to be through repeatedly splitting and just can obtain the finished product of optical purity, and complicated operation is unfavorable for amplifying and produces.
Prior art discloses methyl-4-(2 with 2-[[[3-, 2,2-trifluoro ethoxy)-2-pyridyl] methyl] sulfo-] benzoglyoxaline is that main raw material is prepared the method for R-lansoprazole by asymmetric oxidation.The method has overcome the deficiency of above-mentioned method for splitting preferably.But, excessive reaction product 2-[[[3-methyl-4-(2,2,2-trifluoro ethoxy) and-2-pyridyl] methyl] alkylsulfonyl] benzoglyoxaline (hereinafter to be referred as sulfone type) also prepares, and conventionally in sulfoxide, exists sulfone to be difficult to remove.
[0008] summary of the invention
The object of the present invention is to provide a kind of method of preparing R-lansoprazole, comprise by formula (1) compound in alkalescence, through trifluoroethanol, replace and make R-lansoprazole.
Formula (1)
Wherein, R is selected from nitro, halogen atom or ester group, more preferably nitro.
Described method is carried out in solvent, and described solvent can be selected inorganic solvent or organic solvent, and wherein organic solvent can be selected from methyl-sulphoxide, toluene, acetone, normal hexane, methyl alcohol, ethanol, glacial acetic acid, esters solvent, ether solvent, halogenated hydrocarbon solvent or its mixture, more preferably methyl-sulphoxide, toluene, acetone, most preferably methyl-sulphoxide;
Described alkali is selected from sodium hydroxide, potassium hydroxide, salt of wormwood, sodium carbonate, sodium tert-butoxide or sodium hydrogen.
Formula (1) compound be by formula (2) compound under toluene, diethyl tartrate, tetraisopropoxy titanium and DIPEA effect, through cumene hydroperoxide oxidation and obtain.
Formula (2)
Preparation method of the present invention, compared with the preparation method in E4035455 and WO94/27988, more easily obtains the R-lansoprazole of high-optical-purity, and simple to operate, is conducive to amplify produce.
embodiment
The preparation of 2,3-Dimethyl-4-nitropyridine-N-oxide, its structural formula is as follows:
By 10.7g(0.1mol) 2,3-lutidine, 20 mL glacial acetic acids, 16 mL(0.15mol) massfraction is 30% hydrogen peroxide adds in 250mL three-necked bottle successively, under magnetic agitation, be heated to 50 ℃, insulation reaction 12h, steam water and acetic acid, drip by 30 mL(0.54mol) vitriol oil and 28 mL(0.4mol) mixed acid liquid that concentrated nitric acid is mixed with, about 30min drips complete, 120 ~ 125 ℃ of reaction 2h, are cooled to room temperature.In impouring 200 mL cold water, with the sodium hydroxide solution of 5mol/L, be neutralized to PH10 ~ 12, with methylene dichloride (60mL * 3) extraction, anhydrous sodium sulfate drying, filter, concentrated, obtain yellow solid, by re-crystallizing in ethyl acetate, obtain 12.5g 2,3-Dimethyl-4-nitropyridine-N-oxide.Yield 78.1%.
The preparation of 2-acetoxy-methyl-4-nitro-3-picoline, its structural formula is as follows:
By 2,3-Dimethyl-4-nitropyridine-N-oxide 16.8g(0.1mol) be dissolved in toluene (100mL), be heated to 100 ℃, slowly drip diacetyl oxide 29.4g(0.3mol), temperature is controlled at 90 ~ 110 ℃.Finish, be incubated 105 ~ 110 ℃ of reaction 2h, thin-layer chromatography detection reaction is complete.Put to room temperature, 60 ℃ of decompressions steam solvent, obtain 2-acetoxy-methyl-4-nitro-3-picoline (yellow oil) 17.6g.Yield 82.3%.
The preparation of 2-methylol-4-nitro-3-picoline, its structural formula is as follows:
By 2-acetoxy-methyl-4-nitro-3-picoline 21.0g(0.1mol) be dissolved in methyl alcohol (50ml), be cooled to 0 ℃, drip the aqueous solution 100mL of 25% potassium hydroxide, control temperature of reaction below 10 ℃, about 30min drips off, and continues insulation reaction 20min, and thin-layer chromatography detection reaction is complete, pressure reducing and steaming methyl alcohol, with methylene dichloride (50mL * 3) extraction, merge organic phase, with anhydrous sodium sulfate drying, filter, filtrate decompression concentrates to obtain 2-methylol-4-nitro-3-picoline 12.8g.Yield 76.2%.
The preparation of 2-chloromethyl-4-nitro-3-picoline, its structural formula is as follows:
By 2-methylol-4-nitro-3-picoline 16.8g(0.1mol) be dissolved in trichloromethane (100mL), be cooled to 0 ~ 5 ℃, stir the lower sulfur oxychloride 14.3g(0.12mol that drips) control temperature of reaction below 10 ℃, about 40min drips off, continue insulation reaction 20min, thin-layer chromatography detection reaction is complete.Concentrating under reduced pressure obtains brown solid, slowly adds frozen water 100ml, with saturated sodium bicarbonate solution (80mL), adjusts PH to 8 ~ 9, with methylene dichloride (100mL * 3), extract, merge organic phase, with saturated nacl aqueous solution washing once, obtain the solution of 2-chloromethyl-4-nitro-3-picoline.
The preparation of [[(4-nitro-3-methyl-2-pyridyl) methyl] sulfydryl] benzoglyoxaline, its structural formula is as follows:
By 16g(0.4mol) sodium hydroxide is dissolved in 150mL water, be cooled to 10 ~ 15 ℃, add 2-mercaptobenzimidazole 15g(0.1mol) and triethyl benzyl ammonia chloride 4.65g(0.02mol), stir 15min, then drip above-mentioned 2-chloromethyl-4-nitro-3-picoline solution, control temperature below 15 ℃.Finish, with 25 ~ 30 ℃ of stir about 2h, thin-layer chromatography detection reaction is complete, reaction solution is concentrated into about 150mL, is cooled to 0 ℃ and stirs 1h, filters, solid washed with dichloromethane, then wash with water, 40 ℃ of vacuum-drying 8h, obtain [[(4-nitro-3-methyl-2-pyridyl) methyl] sulfydryl] benzoglyoxaline (off-white color solid) 22.5g.Yield 76.6%.
R-2-[[(4-nitro-3-methyl-2-pyridyl) methyl] sulfinyl] preparation of-1H-benzoglyoxaline, its structural formula is as follows:
Synthesizing of R-lansoprazole, its structural formula is as follows:
R-2-[[(4-nitro-3-methyl-2-pyridyl that step is made) methyl] sulfinyl]-1H-benzoglyoxaline (15g) joins 2,2,2, in-trifluoroethanol (90mL), adds palladium and potassium tert.-butoxide under stirring, is heated to 80 ℃ of reaction 5h.TLC monitoring reaction is complete, by reaction solution concentrating under reduced pressure, reclaims trifluoroethanol, residuum adds 50mL water, and 30% aqueous solution of sodium bisulfite regulates pH to 9, methylene dichloride (100mL * 2) extraction, anhydrous sodium sulfate drying, filters, concentrated, gained oily matter is dissolved in acetone (30mL), under vigorous stirring, drips purified water (60mL), drip Bi Jixu and stir 1h, filter, dry, obtain white solid.Yield 95.5%.
Claims (4)
1. a method of preparing R-lansoprazole, is characterized in that comprising, by formula (1) compound, under alkaline condition, through trifluoroethanol, is replaced and makes R-lansoprazole, and wherein, R is selected from nitro, halogen atom or nitro,
Formula (1).
2. the method for preparing R-lansoprazole according to claim 1, is characterized in that, described R is nitro.
3. the method for preparing R-lansoprazole according to claim 1, is characterized in that, described alkali is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium tert-butoxide or sodium hydride.
4. the method for preparing R-lansoprazole according to claim 3, is characterized in that, described alkali is sodium hydroxide.
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| CN201310386770.XA CN103613581A (en) | 2013-08-30 | 2013-08-30 | Preparation method for Dexiansoprazole |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105017216A (en) * | 2014-04-16 | 2015-11-04 | 天津药物研究院 | Dexlansoprazole crystal form III and preparation method and application thereof |
| CN106866631A (en) * | 2017-04-06 | 2017-06-20 | 山东裕欣药业有限公司 | A kind of Dexlansoprazole crystal formation and preparation method |
| CN108084158A (en) * | 2016-11-23 | 2018-05-29 | 江苏豪森药业集团有限公司 | The preparation method of R-lansoprazole |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102108077A (en) * | 2009-12-23 | 2011-06-29 | 江苏豪森医药集团有限公司 | Method for preparing dexlansoprazole |
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- 2013-08-30 CN CN201310386770.XA patent/CN103613581A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102108077A (en) * | 2009-12-23 | 2011-06-29 | 江苏豪森医药集团有限公司 | Method for preparing dexlansoprazole |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105017216A (en) * | 2014-04-16 | 2015-11-04 | 天津药物研究院 | Dexlansoprazole crystal form III and preparation method and application thereof |
| CN108084158A (en) * | 2016-11-23 | 2018-05-29 | 江苏豪森药业集团有限公司 | The preparation method of R-lansoprazole |
| CN106866631A (en) * | 2017-04-06 | 2017-06-20 | 山东裕欣药业有限公司 | A kind of Dexlansoprazole crystal formation and preparation method |
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Application publication date: 20140305 |