CN102432412A - Preparation method of chiral sulphoxide proton pump inhibitor or pharmaceutically-acceptable salt thereof - Google Patents
Preparation method of chiral sulphoxide proton pump inhibitor or pharmaceutically-acceptable salt thereof Download PDFInfo
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- CN102432412A CN102432412A CN2011103332289A CN201110333228A CN102432412A CN 102432412 A CN102432412 A CN 102432412A CN 2011103332289 A CN2011103332289 A CN 2011103332289A CN 201110333228 A CN201110333228 A CN 201110333228A CN 102432412 A CN102432412 A CN 102432412A
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Abstract
The invention relates to a preparation method of a chiral sulphoxide proton pump inhibitor or a pharmaceutically-acceptable salt thereof. The preparation method comprises the following step of: dissolving a chiral (1R)-(-)-(10-camphorsulfonyl)oxaziridine compound shown as a formula I and an imidazole thioether compound shown as a formula II into an appropriate solvent for undergoing an oxidation reaction to obtain the chiral sulphoxide proton pump inhibitor or the pharmaceutically-acceptable salt thereof.
Description
Technical field
The invention belongs to pharmaceutical field, be specifically related to the preparation method of a kind of chiral sulphoxide proton pump inhibitor or its pharmacologically acceptable salt.
Background technology
Contain proton pump inhibitor (like omeprazole, lansoprazole, pantoprazole, the rabeprazole etc.) secretion of gastric acid inhibitory effectively of sulfoxide radicals; Be widely used in treating the digestive tract ulcer property disease that gastroxia causes, comprise stomach ulcer, intestinal ulcer, duodenal ulcer etc.In recent years, the chiral drug that contains the proton pump inhibitor of sulfoxide radicals shows advantages such as excellent drug kinetics, physiologically active, and the research of its enantiomer of drugs is received much concern.US5877192 discloses with its raceme medicine omeprazole and has compared, (
S)-omeprazole has that activity is stronger, advantages such as first pass metabolism is little, bioavailability is high, long action time, and, (
SThe pharmacokinetics of)-omeprazole and three all curative ratios are apparently higher than the raceme omeprazole.Therefore,, how effectively the preparation chiral sulphoxide proton pump inhibitor of highly-solid selectively has become the extremely important research topic of the world of medicine.
Recent two decades comes; The preparation method of chiral sulphoxide proton pump inhibitor mainly comprises Split Method, biological enzyme oxidation style, the catalytic asymmetric oxidation method of chiral catalyst etc.; Wherein, Split Method (like DE4035455, WO9427988, WO2010072759 etc.) is to utilize chemical substance or enzyme to split the raceme of sulfoxide class proton pump inhibitor; Obtain the chiral sulfoxide proton pump inhibitor of optical purity, this method exists the loss of raw material imidazoles thio-ether type compounds and waste very big, defectives such as production cost height; Biological enzyme oxidation style (like WO9617076) is to utilize enzyme that corresponding imidazoles thio-ether type compounds is carried out catalyzed oxidation, and this method can obtain catalyzed oxidation result preferably, but exists production cost higher, is difficult to defectives such as scale operation; The catalytic asymmetric oxidation method of chiral catalyst is used more extensive; Mainly utilize the asymmetric oxidation of chiral ligand and metal coordination catalysis thio-ether type compounds, obtain optically active chiral sulfoxide proton pump inhibitor, like US5714504, CN1995037, CN95194956, WO2004052881, JACS; 1984; 25,1049, Tetrahedron:Asymmetry 2000,11; 3819 grades disclose the aforementioned techniques content, but there are defectives such as heavy-metal residual, heavy metal contamination in this method.
Nineteen eighty-two, Davis is at document JACS, introduced the asymmetric oxidation reaction of camphor sulfonamide epoxy compounds to thioether first in 1982,104,5412, and obtained result preferably; Afterwards, Davis was again respectively at JACS, and 1988; 110,8477, JACS, 1992; 114,1428, JOC, 1992; 57; Put down in writing the improvement optimisation technique achievement of the aspects such as structure, reaction conditions of camphor sulfonamide epoxy compounds (like the mute piperazine of camphor sulphur etc.) in 7274, made that the scope of application of camphor sulfonamide epoxy compounds is more extensive effectively, and also indicated direction for the successful Application of Davis oxygenant (being the camphor sulfonamide epoxy compounds) in the asymmetric oxidation reaction of thioether for its Stereoselective is used to prepare the chiral sulphoxide proton pump inhibitor.
Yet; Find in the research; There is stereoselectivity low (only 12.3%), yield defectives such as low (only 12%) in the method that adopts Davis oxygenant direct oxidation thio-ether type compounds to prepare the chiral sulphoxide proton pump inhibitor; And, when changing reaction solvent the absolute configuration of reaction product is changed, make the application of this method be very limited.Therefore, the preparation method of efficient, the safety of research, Stereoselective chiral sulphoxide proton pump inhibitor is imperative.
Summary of the invention
The object of the present invention is to provide the preparation method of a kind of chiral sulphoxide proton pump inhibitor or its pharmaceutical salts, in temperature of reaction-20
oC-100
oUnder the C condition, structure is dissolved in suc as formula the mixture of the imidazoles thio-ether type compounds shown in the II suc as formula the mute piperazine compounds of the chirality camphor sulphur shown in the I and structure carries out oxidizing reaction in the appropriate solvent, promptly get,
Wherein, the R in the mute piperazine compounds of described chirality camphor sulphur
1, R
2Be selected from any of hydrogen, halogen, aryl, alkyl, alkoxyl group, hetero atom substituents; B in the mixture of described imidazoles thio-ether type compounds (claim again " compd B ") is selected from any or two or more combinations of molecular sieve, silica gel, mineral alkali, organic bases, R, R in the mixture of described imidazoles thio-ether type compounds
3, R
4, R
5Be selected from hydrogen, hydroxyl, halogen, straight chained alkyl, branched-chain alkyl, alkoxyl group, epoxy alkyl, naphthenic base, aryl, fragrant oxygen base respectively, contain any of other heteroatomic alkyl; X is selected from carbon atom or nitrogen-atoms, and said appropriate solvent is selected from any or two or more combinations of water, halogenated hydrocarbon solvent, alcoholic solvent, esters solvent, aromatic hydrocarbon solvent, ketones solvent, ether solvent, nitrile solvents, amide solvent.
In the optimal technical scheme of the present invention, described temperature of reaction is 0
oC-10
OC
In the optimal technical scheme of the present invention, described halogenated hydrocarbon solvent is selected from any or its combination in chloroform, the methylene dichloride.
In the optimal technical scheme of the present invention, described esters solvent is selected from any or its combination in ETHYLE ACETATE, the butylacetate.
In the optimal technical scheme of the present invention, described ketones solvent is selected from any or its combination in acetone, the butanone.
In the optimal technical scheme of the present invention, described ether solvent is selected from isopropyl ether.
In the optimal technical scheme of the present invention, described nitrile solvents is selected from acetonitrile.
In the optimal technical scheme of the present invention, described amide solvent is selected from N.
In the optimal technical scheme of the present invention, described alcoholic solvent is any of methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol etc., more preferably Virahol.
In the optimal technical scheme of the present invention, described aromatic hydrocarbon solvent is any or its combination of toluene, ethylbenzene etc.
In the optimal technical scheme of the present invention, the preparation method of the mixture of described imidazoles thio-ether type compounds comprises the steps ,-20
oC-100
oUnder the C condition, imidazoles thio-ether type compounds and compd B be dissolved in the solvent react, promptly get.Wherein, said solvent is selected from any or two or more combinations of water, halogenated hydrocarbon solvent, alcoholic solvent, esters solvent, aromatic hydrocarbon solvent, ketones solvent, ether solvent, nitrile solvents, amide solvent.Described compd B is selected from any or two or more combinations of molecular sieve, silica gel, mineral alkali, organic bases.
In the optimal technical scheme of the present invention, described mineral alkali is selected from any or its combination of sodium hydride, hydrolith, sodium hydroxide, salt of wormwood.
In the optimal technical scheme of the present invention; Described organic bases is selected from any or its combination of triethylamine, 2-toluquinoline, dicyclohexylamine, pyridine, triethylene diamine, diazabicylo (DBU), tetrabutyl ammonium halide, diisopropylethylamine, is preferably diazabicylo (DBU).
In the optimal technical scheme of the present invention, the consumption mol ratio of the mute piperazine compounds of the mixture of imidazoles thio-ether type compounds and chirality camphor sulphur is 1:0.5-1:5 in the reaction, and preferably the consumption mol ratio of the two is 1:1.
In the optimal technical scheme of the present invention, also comprise the purifying of chiral sulphoxide proton pump inhibitor, said purifying comprises the steps: to add acid-base modifier in the reaction soln after the mixture of the imidazoles thio-ether type compounds shown in mute piperazine compounds of the chirality camphor sulphur shown in the formula I and the formula II is accomplished oxidizing reaction; Regulate its pH value to 7-10, organic solvent extraction is got organic solvent extraction liquid; After the dewatering agent drying; Concentrate, recrystallization promptly gets.
In the optimal technical scheme of the present invention, said acid-base modifier is selected from any or two or more combinations of acid or buffered soln.
In the optimal technical scheme of the present invention, described acid is selected from any or two or more combinations of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid etc.
In the optimal technical scheme of the present invention, described buffered soln is selected from any or two or more combinations of potassium primary phosphate-sodium hydroxide buffer solution, boric acid-Repone K-sodium hydroxide buffer solution, ammonium chloride-ammoniacal liquor buffered soln, boric acid-Repone K-sodium hydroxide buffer solution.
In the optimal technical scheme of the present invention, described organic solvent is selected from any or two or more combinations of halogenated hydrocarbon solvent, esters solvent, aromatic hydrocarbon solvent, ether solvent.
In the optimal technical scheme of the present invention, described dewatering agent is selected from SODIUM SULPHATE ANHYDROUS 99PCT.
In the optimal technical scheme of the present invention, the pharmacologically acceptable salt of described chiral sulphoxide proton pump inhibitor is selected from any or two or more combinations of sodium salt, sylvite, magnesium salts.
The preparation method of chiral sulphoxide proton pump inhibitor of the present invention or its pharmacologically acceptable salt is that oxygenant (Davis oxygenant) carries out asymmetric oxidation to the mixture that draws the azoles thio-ether type compounds with the mute piperazine of the chirality camphor sulphur of cheapness, makes chiral sulphoxide proton pump inhibitor or its pharmacologically acceptable salt.Preparing method of the present invention need not to add chiral ligand and metallic compound; Avoided in reaction, introducing heavy metal; And the camphor sulfonyl imide compounds after the oxidizing reaction is a reusable edible through simple process (comprising recrystallization, oxide treatment etc.), thereby has significantly reduced production cost.And; Preparing method of the present invention has products obtained therefrom (chiral sulphoxide proton pump inhibitor or its pharmacologically acceptable salt) purity high (more than 99.00%), yield high (being not less than 80%), stereoselectivity is special, production cost is low, pollution-free, easy and simple to handle, organic solvent residual is few even organic solvent-free is residual, be suitable for advantage such as industrial mass production; Preparation purifying like the pharmacologically acceptable salt (like sodium salt, sylvite, magnesium salts etc.) of chiral sulphoxide proton pump inhibitor is all made solvent with water, and organic solvent residual is few even organic solvent-free is residual in this purification process.
Except as otherwise noted; When per-cent of the present invention is the per-cent between liquid and the liquid volume per-cent; When per-cent is the per-cent between liquid and the solid volume/weight per-cent; Be weight/volume percent when per-cent is the per-cent between solid and the liquid, all the other are weight/weight percent.
The present invention is through the checking of technical data such as proton nmr spectra: in the imidazoles thio-ether type compounds structure-the NH proton shows in proton nmr spectra obviously, and after it is prepared into the mixture of imidazoles thio-ether type compounds, and its proton blackout then.
For clear statement protection scope of the present invention, the present invention defines term as follows: aryl of the present invention is meant the aryl that organic chemistry filed is generally acknowledged, comprises phenyl, substituted-phenyl etc.
Alkyl of the present invention is meant the alkyl that organic chemistry filed is generally acknowledged, comprises straight chained alkyl, branched-chain alkyl etc.
Alkoxyl group of the present invention is meant the alkoxyl group that organic chemistry filed is generally acknowledged, comprises methoxyl group, oxyethyl group etc.
Hetero atom substituents of the present invention is meant the heteroatoms that organic chemistry filed is generally acknowledged, comprises nitrogen, oxygen etc.
The testing conditions of HPLC of the present invention comprises: 1) chiral column AD, moving phase: normal hexane/Virahol=60 mL/40 mL, λ=254 nm; 2) C
L8The silane group unmodified packed column, moving phase: acetonitrile/buffered soln=130 mL/870 mL; Buffered soln: 3.55 g Sodium phosphate, dibasics are dissolved in the 1 L water, regulate its pH=7.5 with phosphoric acid; λ=302 nm.
Description of drawings
Fig. 1 structure prepares the reaction process of chiral sulphoxide proton pump inhibitor suc as formula the mixture of the imidazoles thio-ether type compounds shown in the II suc as formula mute piperazine compounds of the chirality camphor sulphur shown in the I and structure.
Embodiment
Following embodiment can be made more detailed explanation to content of the present invention, but subject area of the present invention is not limited to following specific embodiment, everyly all belongs to scope of the present invention based on technology, technology that content of the present invention realized.
Embodiment 1The preparation of chiral sulphoxide proton pump inhibitor
1) preparation of omeprazole thioether diazabicylo (DBU) mixture
0.5 g omeprazole thioether is dissolved in the 6 mL Virahols, under the agitation condition, 0.23 mL diazabicylo (DBU) is splashed in the reaction, under the room temperature condition, stirring reaction 30 minutes.Concentrating under reduced pressure gets light yellow oil 0.72 g, and yield is 98%.
1H-NMR?(400?MHz,?
d 6-DMSO):?
δ?=?8.14?(s,?1H),?7.12?(d,?
J?=?8.4?Hz,?1H),?6.82?(d,?
J?=?2.4?Hz,?1H),?6.45?(dd,?
J 1?=?2.4?Hz,?
J 2?=?8.8?Hz,?1H),?5.39?(s,?1H),?4.57?(s,?2H),?3.71?(s,?3H),?3.70?(s,?3H),?3.21-3.17?(m,?4H),?3.09?(t,?
J?=?5.6?Hz,?2H),?2.31-2.29?(m,?2H),?2.26?(s,?3H),?2.19?(s,?3H),?1.71-1.65?(m,?2H),?1.58-1.47?(m,?6H)。
2) (
SThe preparation of)-omeprazole
0.72 g omeprazole thioether diazabicylo (DBU) mixture for preparing is dissolved in the 6 mL Virahols, under the condition of ice bath, 0.35 g (1
R)-(-)-the mute piperazine of camphor sulphur adds in the middle of the reaction solution, under the condition of ice bath, and stirring reaction, TLC detects to reacting completely.Suction filtration is got filter cake (filter cake is the camphor sulfimine compound, and the recovery is 81%) and is washed with Virahol, and filtrating concentrates the back and adds about 3 mL water, and using acetum to transfer its pH is 7-10, ethyl acetate extraction 3 times, it is dry mutually to get ETHYLE ACETATE, concentrate, the spumescence solid (
SAbout 0.43 g of)-omeprazole, yield is 82.7%.
HPLC measures
Ee: 99.09% (HPLC detects: chiral column AD, moving phase: normal hexane/Virahol=60 mL/40 mL, λ=254 nm).
1H-NMR?(400?MHz,?CDCl
3):?
δ?=?8.26?(s,?1H),?7.40?(d,?
J?=?8.8?Hz,?1H),?7.03?(s,?1H),?6.81?(d,?
J?=?8.4?Hz,?1H),?4.82-4.73?(m,?2H),?3.81?(s,?3H),?3.58?(s,?3H),?2.19?(s,?3H),?2.07?(s,?3H)。
MS-ESI?(m/z):?calcd?for?C
17H
19N
3O
3S?+?Na?368.10;?found?367.84。
Embodiment 2The preparation of chiral sulphoxide proton pump inhibitor
1)(
SThe preparation of)-omeprazole
0.18 mL DBU, 0.4 g omeprazole thioether are dissolved in the 5 mL Virahols, and under the room temperature condition, stirring reaction moved to condition of ice bath after 30 minutes, added 0.28 g (1
R)-(-)-the mute piperazine of camphor sulphur, keep condition of ice bath, stirring reaction.TLC detects to reacting completely.Suction filtration, filter cake (filter cake is the camphor sulfimine compound, and the recovery is 82%) is washed with Virahol, filtrating concentrates the back and adds about 2 mL water, using acetum to transfer its pH is 7-10, ethyl acetate extraction 3 times, it is dry mutually to get ETHYLE ACETATE, concentrate, the spumescence solid (
S)-omeprazole 0.35 g, yield: 83.3%.
HPLC measures ee:99.18% (HPLC detects: chiral column AD, moving phase: normal hexane/Virahol=60 mL/40 mL, λ=254 nm).
1H-NMR?(400?MHz,?CDCl
3):?
δ?=?8.26?(s,?1H),?7.40?(d,?
J?=?8.8?Hz,?1H),?7.03?(s,?1H),?6.81?(d,?
J?=?8.4?Hz,?1H),?4.82-4.73?(m,?2H),?3.81?(s,?3H),?3.58?(s,?3H),?2.19?(s,?3H),?2.07?(s,?3H)。
MS-ESI?(m/z):?calcd?for?C
17H
19N
3O
3S?+?Na?368.10;?found?367.84。
2) (
SThe preparation of)-Omeprazole Sodium
With 1g (
SIt is in the sodium hydroxide solution of 0.5 mol/L that)-omeprazole is dissolved in 5 mL concentration, under the room temperature condition, stirs 30 minutes, and dichloromethane extraction twice discards organic layer, and the water intaking solution layer concentrates, the ether washing, obtain the off-white color solid (
S)-Omeprazole Sodium 0.86 g, yield are 90%.
HPLC analytical chemistry purity is 99.0% (HPLC detection: Cl8 silane group unmodified packed column, moving phase: acetonitrile/buffered soln=130 mL/870 mL; Buffered soln: 3.55 g Sodium phosphate, dibasics are dissolved in the 1 L water, regulate its pH=7.5 with phosphoric acid; λ=302 nm).
Embodiment 3The preparation of dextrorotation lansoprazole
Get 2-[3,5-dimethyl--4-(2,2, the 2-trifluoro ethoxy) pyridine-2-methylene sulfenyl]-1H-benzoglyoxaline 10g, be placed in the 250ml there-necked flask, add Virahol 120ml.Under the agitation condition, add DBU (diazabicylo) 3.9g, stirring reaction is after 30 minutes, under the condition of ice bath; In reaction flask, add the inferior piperazine 6.4g of D-camphor sulphur, stirring reaction, TLC detect to reacting completely filtering reacting liquid; The gained solid is used the 20ml washed with isopropyl alcohol, gets light yellow filtrating, after concentrating under reduced pressure is done, adds 50ml water; After stirring, Dropwise 5 0% acetic acid soln in the aqueous solution is regulated pH=8-8.5, ETHYLE ACETATE 50ml * 3 extractions; Combined ethyl acetate layer and with anhydrous sodium sulfate drying filters, and the ethyl acetate layer concentrating under reduced pressure obtains light yellow oily body.Add 20ml acetone to the oily body, after the stirring and dissolving, be added dropwise in the 160ml frozen water, separate out solid, keep 0
oC-5
OC, stir 0.5h, filter, behind the drying under reduced pressure, must about 5g off-white color solid, i.e. (R)-2-[3,5-dimethyl--4-(2,2, the 2-trifluoro ethoxy) pyridine-2-methylene sulfinyl]-1H-benzoglyoxaline], yield is about 48%.
HPLC analytical chemistry purity is 99.5% (HPLC detection: Cl8 silane group unmodified packed column, moving phase: acetonitrile/buffered soln=130 mL/870 mL; Buffered soln: 3.55 g Sodium phosphate, dibasics are dissolved in the 1 L water, regulate its pH=7.5 with phosphoric acid; λ=302 nm).
Claims (10)
1. the preparation method of a chiral sulphoxide proton pump inhibitor or its pharmaceutical salts is characterized in that, in temperature of reaction-20
oC-100
oUnder the C condition, structure is dissolved in suc as formula the mixture of the imidazoles thio-ether type compounds shown in the II suc as formula the mute piperazine compounds of the chirality camphor sulphur shown in the I and structure carries out oxidizing reaction in the solvent, promptly get,
Wherein, the R in the mute piperazine compounds of described chirality camphor sulphur
1, R
2Be selected from any of hydrogen, halogen, aryl, alkyl, alkoxyl group, hetero atom substituents; B in the mixture of described imidazoles thio-ether type compounds (claim again " compd B ") is selected from any or two or more combinations of molecular sieve, silica gel, mineral alkali, organic bases, R, R in the mixture of described imidazoles thio-ether type compounds
3, R
4, R
5Be selected from hydrogen, hydroxyl, halogen, straight chained alkyl, branched-chain alkyl, alkoxyl group, epoxy alkyl, naphthenic base, aryl, fragrant oxygen base respectively, contain any of other heteroatomic alkyl; X is selected from carbon atom or nitrogen-atoms, and described solvent is selected from any or two or more combinations of water, halogenated hydrocarbon solvent, alcoholic solvent, esters solvent, aromatic hydrocarbon solvent, ketones solvent, ether solvent, nitrile solvents, amide solvent.
2. the preparation method of a kind of chiral sulphoxide proton pump inhibitor according to claim 1 or its pharmaceutical salts is characterized in that, described temperature of reaction is 0
oC-10
OC
3. the preparation method of a kind of chiral sulphoxide proton pump inhibitor according to claim 1 or its pharmaceutical salts; It is characterized in that described solvent is selected from any or two or more combinations of water, acetone, butanone, methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, toluene, ethylbenzene.
4. according to the preparation method of each described a kind of chiral sulphoxide proton pump inhibitor of claim 1-3 or its pharmaceutical salts, it is characterized in that the preparation method of the mixture of described imidazoles thio-ether type compounds comprises the steps ,-20
oC-100
oUnder the C condition; Imidazoles thio-ether type compounds and compd B be dissolved in the solvent react; Promptly get; Wherein, said solvent is selected from any or two or more combinations of water, halogenated hydrocarbon solvent, alcoholic solvent, esters solvent, aromatic hydrocarbon solvent, ketones solvent, ether solvent, nitrile solvents, amide solvent, and described compd B is selected from any or two or more combinations of molecular sieve, silica gel, mineral alkali, organic bases.
5. the preparation method of a kind of chiral sulphoxide proton pump inhibitor according to claim 4 or its pharmaceutical salts; It is characterized in that the consumption mol ratio of the mute piperazine compounds of the mixture of imidazoles thio-ether type compounds and chirality camphor sulphur is 1:0.5-1:5 in the reaction.
6. the preparation method of a kind of chiral sulphoxide proton pump inhibitor according to claim 1 or its pharmaceutical salts is characterized in that, also comprises the purifying of chiral sulphoxide proton pump inhibitor; Said purifying comprises the steps: to add acid-base modifier in the reaction soln after the mixture of the imidazoles thio-ether type compounds shown in mute piperazine compounds of the chirality camphor sulphur shown in the formula I and the formula II is accomplished oxidizing reaction; Regulate its pH value to 7-10, organic solvent extraction is got organic solvent extraction liquid; After the dewatering agent drying; Concentrate, recrystallization promptly gets.
7. the preparation method of a kind of chiral sulphoxide proton pump inhibitor according to claim 6 or its pharmaceutical salts is characterized in that, said acid-base modifier is selected from any or its combination of acid or buffered soln.
8. the preparation method of a kind of chiral sulphoxide proton pump inhibitor according to claim 7 or its pharmaceutical salts is characterized in that, described acid is selected from any or two or more combinations of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid etc.
9. the preparation method of a kind of chiral sulphoxide proton pump inhibitor according to claim 7 or its pharmaceutical salts; It is characterized in that described buffered soln is selected from any or two or more combinations of potassium primary phosphate-sodium hydroxide buffer solution, boric acid-Repone K-sodium hydroxide buffer solution, ammonium chloride-ammoniacal liquor buffered soln, boric acid-Repone K-sodium hydroxide buffer solution.
10. the preparation method of a kind of chiral sulphoxide proton pump inhibitor according to claim 1 or its pharmaceutical salts; It is characterized in that the pharmacologically acceptable salt of described chiral sulphoxide proton pump inhibitor is selected from any or two or more combinations of sodium salt, sylvite, magnesium salts.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106188000A (en) * | 2016-07-11 | 2016-12-07 | 成都尚药科技有限公司 | A kind of synthetic method of Dexlansoprazole |
| CN106188101A (en) * | 2016-07-15 | 2016-12-07 | 成都尚药科技有限公司 | A kind of (1S) (+) preparation method of the 10 mute piperazines of Camphora sulphur |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1157614A (en) * | 1994-07-15 | 1997-08-20 | 阿斯特拉公司 | Process for synthesis of substituted sulphoxides |
| CN101323609A (en) * | 2007-06-15 | 2008-12-17 | 成都福瑞生物工程有限公司 | Method for synthesizing high antipode content benzimidazole derivative by unsymmetrical oxidizing thioether into sulphoxide |
| WO2008152462A1 (en) * | 2007-06-15 | 2008-12-18 | Emcure Pharmaceuticals Limited | A process of sulfoxidation of biologically active compounds |
| CN102329302A (en) * | 2011-10-22 | 2012-01-25 | 刘强 | Method for preparing esomeprazole and salts thereof |
-
2011
- 2011-10-28 CN CN2011103332289A patent/CN102432412A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1157614A (en) * | 1994-07-15 | 1997-08-20 | 阿斯特拉公司 | Process for synthesis of substituted sulphoxides |
| CN101323609A (en) * | 2007-06-15 | 2008-12-17 | 成都福瑞生物工程有限公司 | Method for synthesizing high antipode content benzimidazole derivative by unsymmetrical oxidizing thioether into sulphoxide |
| WO2008152462A1 (en) * | 2007-06-15 | 2008-12-18 | Emcure Pharmaceuticals Limited | A process of sulfoxidation of biologically active compounds |
| CN102329302A (en) * | 2011-10-22 | 2012-01-25 | 刘强 | Method for preparing esomeprazole and salts thereof |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106188000A (en) * | 2016-07-11 | 2016-12-07 | 成都尚药科技有限公司 | A kind of synthetic method of Dexlansoprazole |
| CN106188101A (en) * | 2016-07-15 | 2016-12-07 | 成都尚药科技有限公司 | A kind of (1S) (+) preparation method of the 10 mute piperazines of Camphora sulphur |
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Application publication date: 20120502 |