CN1810803A - Selective prepn process of (S)-Omeprazole with high antimer - Google Patents
Selective prepn process of (S)-Omeprazole with high antimer Download PDFInfo
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Abstract
The present invention relates to antimer selective catalytic oxidation process for preparing optical active antimer or optically pure antimer (S)-omeprazole. In the presence of the titanium containing catalyst in-situ created with metal titanium reagent and chiral glycol ligand and the oxidant, omeprazole sulfide is catalytically oxidized with antimer. Compared with the process utilizing tetraisopropanol titanium-diethyl tartrate system, the process of the present invention has the advantages of cheap material, high antimer selectivity and high yield. The present invention also relates to the preparation of (S)-omeprazole in neutralized state, partial crystallized state or completely crystallized state.
Description
Technical field
The present invention relates to a kind of method of high antimer selectivity preparation (S)-omeprazole.
Background technology
Compound 5-methoxyl group-2-[[(4-methoxyl group-3,5-dimethyl-2-pyridyl) methyl]-sulfinyl]-1H-benzoglyoxaline (common omeprazole by name) and pharmaceutical salts thereof be described in EP 5129.The special an alkali metal salt of omeprazole is described in EP 124495.Omeprazole is a proton pump inhibitor, gastric acid inhibitory secretion effectively, and as anti ulcer agent.From more general angle, omeprazole can be used to prevent and treat Mammals particularly the people with the hydrochloric acid in gastric juice diseases associated.
In the sulfoxide compound of asymmetric replacement, sulphur atom is a chirality.The chirality of omeprazole just shows on the sulphur atom of sulfoxide.In fact, omeprazole also exists a pair of enantiomer, (S)-(-)-the enantiomorph correspondence be exactly (S)-omeprazole.
The sodium of the single enantiomer of omeprazole, magnesium, lithium, potassium, calcium and quaternary ammonium salt and preparation method thereof are disclosed in WO 9427988; the method that forms the diastereomer ester by chirality acyl group functional group is separated, and hydrolysis obtains the omeprazole of single enantiomer under alkaline condition again.
WO 9602535 discloses in the presence of chirality bitooth ligand diethyl tartrate, titanium metal network and thing and alkali, asymmetry catalysis oxidation prochirality thioether 5-methoxyl group-2-[[(4-methoxyl group-3,5-dimethyl-2-pyridyl) methyl]-sulfo-]-preparation method of the single enantiomer of 1H-benzoglyoxaline (omeprazole thioether) preparation omeprazole and salt thereof.
WO 9617076 discloses the single enantiomer that the method for utilizing microbiological oxidation prochirality thioether prepares omeprazole.
WO 9617077 discloses the single enantiomer that the method for utilizing micro-reduction racemization sulfone prepares omeprazole.
WO 9702261 discloses the method that the omeprazole raceme is separated out easily in the solution of utilizing, and improves the optical activity of omeprazole in the filtrate.
WO 9828294 discloses the crystal habit of the free alkali of S-omeprazole.
WO 9854171 discloses the method for aqueous phase utilization (S)-omeprazole sylvite and magnesium source prepared in reaction (S)-magnesium salt of omeprazole.
WO 00/44744 discloses the new crystalline form of (S)-omeprazole sylvite.
WO 03/008406 discloses the compound for preparing the benzoglyoxaline type by the modification method of oxidizing sulfur ether and control pH removal sulfone impurity.
WO 03/089408 discloses in the presence of chiral monodentate part (S)-(+)-mandelate, titanium or vanadium network and thing and alkali, and the method for stereoselectivity oxidation omeprazole thioether prepares the single enantiomer of omeprazole.
WO 04/002982 discloses omeprazole sodium salt in the presence of D-diethyl tartrate, titanium network and thing, alkali and L-amygdalic acid, obtains L-amygdalic acid-(S)-omeprazole titanium network and thing, and basic solution is handled the single enantiomer that promptly can obtain omeprazole.
EP 1401442 (WO 02/098423) discloses the method for utilizing beta-cyclodextrin inclusion compound (S)-omeprazole.
In the publication of above-mentioned preparation omeprazole single enantiomer, mainly contain following three kinds of methods: the one, adopt the method for chiral selectors that the raceme omeprazole is split, but traditional method for splitting is difficult to effectively the free alkali of omeprazole be split, and this method can be wasted the omeprazole raw material (as WO 9427988, WO 04/002982) of half; The 2nd, adopt biochemical method, use biological enzyme to come the omeprazole thioether is carried out oxidation or the omeprazole sulfone is reduced, obtain the single enantiomer of omeprazole, but this method needs special experimental installation and experimental technique, relatively too loaded down with trivial details and the trouble (as WO 9617076, WO 9617077); The 3rd, adopt the method for asymmetric oxidation, use the prothetic group of chirality or the single enantiomer of Preparation of Catalyst omeprazole, this method relatively the above two convenient and easy (as WO 9602535, WO 03/089408).But present this method also has obvious defects: 1) the chiral ligand usage quantity is too big, even has reached chemical dose; 2) adopt comparatively expensive cumene hydroperoxide CHP; 3) need a large amount of special organic basess: diisopropyl ethyl amine, this has increased the complicacy of cost and operation.
In the above-mentioned relevant publication of the free alkali crystalline forms of (S)-omeprazole (WO 9828294), need a complexity and loaded down with trivial details process: earlier that an alkali metal salt of (S)-omeprazole is soluble in water, pass through the pH value of water soluble acid regulator solution again, with an organic solvent extract the free alkali of (S)-omeprazole then, add poor solvent after the evaporation concentration and obtain the free alkali solid form of (S)-omeprazole.
Rosini has reported the reaction system of a new asymmetry catalysis oxidizing sulfur ether, especially to the phenylbenzyl thioether have very outstanding result (Journal of Organic Chemistry 1998,63,9392-9395).By chirality bitooth ligand and metal titanium complexing, catalyzed oxidation obtains chiral sulfoxide, and wherein chirality phenylbenzyl sulfoxide can reach 99% enantio-selectivity.
The present invention relates to the method that a kind of novel enantio-selectivity catalysed oxidation processes prepares optical activity enantiomorph or optical purity enantiomorph (S)-omeprazole
The present invention relates to a kind of novel preparation (the S)-free alkali solid of omeprazole method, it may be the form of partial crystallization or sufficient crystallising.
Goal of the invention
The purpose of this invention is to provide the method that a kind of novel enantio-selectivity catalysed oxidation processes prepares optical activity enantiomorph or optical purity enantiomorph (S)-omeprazole.
Another object of the present invention provides method preparation (the S)-omeprazole of an easy and cheap enantio-selectivity catalyzed oxidation, under the situation that the bitooth ligand catalyzer exists, do not add any organic bases, use gentle cheap oxygenant direct oxidation omeprazole thioether.
The method of enantio-selectivity catalyzed oxidation has related to different Preparation of Catalyst optical activity enantiomorphs or optical purity enantiomorph (S)-5-methoxyl group-2-[[(4-methoxyl group-3,5-dimethyl-2-pyridyl among the present invention) methyl]-sulfinyl]-1H-benzoglyoxaline ((S)-omeprazole).
Another object of the present invention provides a simple and cheap enantio-selectivity catalysed oxidation processes and prepares optical activity enantiomorph or optical purity enantiomorph (the S)-free alkali solid of omeprazole method, and it may be the form of partial crystallization or sufficient crystallising.
Brief summary of the invention
The invention provides a kind of simple and cheap method and prepare optical activity enantiomorph or optical purity enantiomorph (S)-5-methoxyl group-2-[[(4-methoxyl group-3; 5-dimethyl-2-pyridyl) methyl]-sulfinyl]-method of 1H-benzoglyoxaline ((S)-omeprazole); under the situation that the bitooth ligand catalyzer exists; do not add any organic bases; use gentle cheap oxygenant direct oxidation 5-methoxyl group-2-[[(4-methoxyl group-3,5-dimethyl-2-pyridyl) methyl]-sulfo-]-the 1H-benzoglyoxaline.
The invention provides a simple and cheap enantio-selectivity catalysed oxidation processes and prepare optical activity enantiomorph or optical purity enantiomorph neutrality (the S)-free alkali solid of omeprazole method, it may be the form of partial crystallization or sufficient crystallising.
Summary of the invention
The object of the invention provides a kind of simple and cheap method and prepares optical activity enantiomorph or optical purity enantiomorph (S)-5-methoxyl group-2-[[(4-methoxyl group-3; 5-dimethyl-2-pyridyl) methyl]-sulfinyl]-method of 1H-benzoglyoxaline ((S)-omeprazole); under the situation that the bitooth ligand catalyzer exists; do not add any organic bases; use gentle cheap oxygenant direct oxidation 5-methoxyl group-2-[[(4-methoxyl group-3,5-dimethyl-2-pyridyl) methyl]-sulfo-]-the 1H-benzoglyoxaline.
Among the present invention, except noticing that " alkyl " refers to side chain and the straight chain saturated carbon hydrogen functional group who specifies amount of carbon atom as using herein; If amount of carbon atom is not specified, " alkyl " refers to 1 to 20 carbon atom, preferably the saturated carbon hydrogen functional group who comprises side chain and straight chain of 1 to 4 carbon atom.Halogen refers to fluorine, chlorine, bromine and iodine.
Term " aryl " if unqualified, refers to the carbocyclic ring aromatic group, is exemplified below but is not limited only to following functional group: phenyl, 1-or 2-naphthyl etc." aryl " functional group in the compound of describing among the present invention in carbocyclic ring fragrance skeleton can by but be not limited only to following functional group such as halogen, nitro, alkyl and alkoxyl group independently replace 1 to 3 hydrogen atom.
The compound of the method preparation of passing through the enantio-selectivity catalyzed oxidation that the present invention describes is optical activity enantiomorph or optical purity enantiomorph (S)-5-methoxyl group-2-[[(4-methoxyl group-3,5-dimethyl-2-pyridyl) methyl]-sulfinyl]-1H-benzoglyoxaline ((S)-omeprazole).This reaction formula is as described below:
The method for preparing optical activity enantiomorph or optical purity enantiomorph (S)-omeprazole that the present invention describes may further comprise the steps:
In organic solvent and exist or when not having water, chiral ligand (R, R) or (S, S)-1,2-diaryl-1,2-glycol and metal titanium reagent, 5-methoxyl group-2-[[(4-methoxyl group-3,5-dimethyl-2-pyridyl) methyl]-sulfo-]-1H-benzoglyoxaline and oxygenant be-78 ℃ to 50 ℃ reactions 1～24 hour; The reaction back adds or does not add alkaline aqueous solution cancellation reaction; Purified neutrality (the S)-free alkali of omeprazole that obtains solid form;
Described chiral ligand (R, R) or (S, S)-1,2-diaryl-1,2-glycol, metal titanium reagent, 5-methoxyl group-2-[[(4-methoxyl group-3,5-dimethyl-2-pyridyl) methyl]-sulfo-]-mol ratio of 1H-benzoglyoxaline, oxygenant and water is 0.02～0.4: 0.01～0.2: 1: 0.5～3: 0～2;
Described chirality bitooth ligand is to have following structural formula
(R, R) or (S, S)-1,2-diaryl-1,2-glycols compound, or have following structural formula
Perhaps
(R, R) or (S, S)-1,2-two (2-bromo-phenyl)-1, the 2-glycol:
Wherein, Ar is
Perhaps
R wherein
1, R
2, R
3And R
4Be hydrogen, C independently
1～20Alkyl, C
1～20Alkoxyl group or ester group, halogen, phenyl, trifluoromethyl or nitro;
R
3Be hydrogen, C
1～20Alkyl, C
1～20Alkoxy or halogen;
R
4Be hydrogen or C
1～20Alkyl;
R
5Be hydrogen, C
1～20Alkyl, C
1～20Alkoxyl group or ester group, halogen, phenyl, trifluoromethyl or nitro;
Described metal titanium reagent is four (C
1～4Alkoxyl group) titanium compound;
Described oxygenant is hydrogen peroxide, C
1～4Alkyl peroxide or C
1～4The alkyl phenyl superoxide.
The chirality bitooth ligand that the present invention describes can be (R, R) or (S, S)-1,2-diaryl-1,2-glycols compound, preferably substituted aryl, the more preferably aryl of 2 replacements, most preferably (R, R) or (S, S)-1,2-two (2-bromo-phenyl)-1,2-glycol.The molar ratio of chirality bitooth ligand and omeprazole thioether can be preferably 0.1: 1 for 0.02: 1 to 0.4: 1.
Bitooth ligand titanium network that the present invention describes and thing catalyzer can be by chirality bitooth ligand and the preparations of metal titanium reagent react.Metal titanium reagent is preferably four alkoxy titanium compounds, more preferably the titanium tetraisopropylate compound.The molar ratio of metal titanium reagent and omeprazole thioether can be 0.01: 1 to 0.2: 1, preferably 0.05: 1.
The enantio-selectivity oxidation that the present invention describes can be carried out in the presence of water.The molar ratio of water and omeprazole thioether can be 0.01: 1 to 2: 1, preferably 1: 1.
The oxygenant that the present invention describes can be hydrogen peroxide, alkyl peroxide and alkylaryl superoxide, preferably alkyl peroxide, more preferably tertbutyl peroxide.The molar ratio of oxygenant and omeprazole thioether can be 0.5: 1 to 3: 1, preferably 2: 1.
The enantio-selectivity oxidation system that the present invention describes does not need to add any organic bases.
The organic solvent that the present invention describes can be unsubstituted alkyl, aryl hydrocarbon polymer and ether compound such as methylene dichloride, chloroform, tetracol phenixin, hexane, benzene, toluene, chlorobenzene, oil of mirbane, dimethylbenzene, ether, tertbutyl ether, tetrahydrofuran (THF) and dioxane or their mixture that halogen replaces.Toluene preferably.
Catalyzer can prepare before the omeprazole thioether adds or afterwards in the enantio-selectivity oxidising process that the present invention describes.Preparation preferably.
Temperature can be 20 ℃ to 50 ℃, preferably 20 ℃ to 25 ℃ in the process of the preparation catalyzer that the present invention describes. the time of preparation catalyzer can be 1 to 60 minute, preferably 10 to 15 minutes.
The temperature of reaction of the enantio-selectivity oxidation that the present invention describes can be-78 ℃ to 50 ℃, preferably-20 ℃ to 0 ℃.The time of oxidation can be 2 to 24 hours, preferably 12 to 18 hours.
The purifying of (S)-omeprazole that the present invention describes can be adjusted to alkalescence back, back organic solvent extraction by adding alkaline aqueous solution in the reaction soln, add acidic aqueous solution or organic acid adjustment of acidity in the extraction liquid, and solvent extraction, recrystallization in organic solvent.
Description of drawings
Fig. 1 is the free alkali solid of (S)-omeprazole powder diagram and relevant 2 θ angular datas.
Embodiment
Below the embodiment by the embodiment form is described in further detail foregoing of the present invention again.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following embodiment, all technology that realizes based on foregoing of the present invention all belong to scope of the present invention.
Embodiment 1 general operation
Chirality bitooth ligand (0.16mmol) is dissolved in the 5mL organic solvent, stir and add the four different third oxygen titaniums (0.08mmol) down, add entry (1.6mmol) then, continue to stir, add omeprazole thioether (1.6mmol), reduce to-20 ℃, dropping oxidizing agent (3.2mmol) slowly then, continue reaction 12 hours, aftertreatment promptly can obtain omeprazole.
1H NMR(300MHz，CDCl
3)：2.20(s，3H)，2.22(s，3H)，3.67(s，3H)，3.83(s，3H)，4.77(m，2H)，6.88-6.95(m，2H)，7.62(m，1H)，8.20(s，1H)，12.18(bs，1H)。Chirality HPLC condition is: chirality Chiralpak
The AD analytical column, with ethanol: normal hexane: acetate=50: 50: 5 is moving phase, and flow velocity is 0.7mL/min, and ultraviolet monitoring is at 302nm.Retention time is t
S=10.28, t
R=15.39.
The optimization of embodiment 2 reaction conditionss
Experimental implementation is with embodiment 1, and ingredient proportion is as follows: the omeprazole thioether: (R, R)-1,2-two (2-bromo-phenyl)-1,2-glycol: titanium tetraisopropylate: water: the mol ratio of oxygenant is 1: 0.1: 0.05: 1: 2.The bitooth ligand that uses in this reaction be (R, R)-1,2-two (2-bromo-phenyl)-1,2-glycol, experimental result such as table 1.
Table 1
| Sequence number | Solvent | Part (mole) | Temperature (℃) | Oxygenant (mole) | Productive rate (%) | Ee (％) | Configuration |
| 1 2 | CCl 4/CH 2Cl 2 CCl 4/CH 2Cl 2 | 0.1 0.1 | 0 0 | TBHP(2.0) CHP(2.0) | 90 72 | 68 2 | S S |
| 3 4 5 6 7f 8 9 10 | CCl 4/CH 2Cl 2 CCl 4/CH 2Cl 2 CCl 4/CH 2Cl 2 CCl 4/CH 2Cl 2 CCl 4/CH 2Cl 2 Toluene Toluene Toluene | 0.1 0.1 0.1 0.2 0.1 0.1 0.2 0.1 | 10 0 0 0 0 0 0 -20 | TBHP(2.0) TBHP(3.0) TBHP(1.0) TBHP(2.0) TBHP(2.0) TBHP(2.0) TBHP(2.0) TBHP(2.0) | 88 89 61 90 90 90 89 90 | 35 70 67 60 55 82 80 94 | S S S S S S S S |
Annotate: Ee is an enantio-selectivity.CCl
4It is tetracol phenixin.CH
2Cl
2It is methylene dichloride.Toluene is a toluene.TBHP is a tertbutyl peroxide.CHP is a cumene hydroperoxide.
Embodiment 3 part substituent effects are to the influence of reaction
Experimental implementation is with embodiment 1, and ingredient proportion is as follows: the omeprazole thioether: (R, R)-1,2-two (2-bromo-phenyl)-1,2-diol, derivatives: titanium tetraisopropylate: water: the mol ratio of oxygenant is 1: 0.1: 0.05: 1: 2.The solvent that uses in this reaction is a toluene, and oxygenant is a tertbutyl peroxide, experimental result such as table 2.
Table 2
| Sequence number | Part R 1 | Temperature (℃) | Productive rate (%) | Ee(％) | Configuration |
| 1 2 3 4 5 6 7 | Br Br H H Me Me MeO | 0 -20 0 -20 0 -20 0 | 90 90 80 38 69 82 59 | 68 94 43 68 70 83 8 | S S S S S S S |
| 8 9 | MeO I | -20 -20 | 57 64 | 3 79 | R S |
Annotate: Ee is an enantio-selectivity.
Embodiment 4 water are to the influence of reaction
Experimental implementation is with embodiment 1, and ingredient proportion is as follows: the omeprazole thioether: and the chirality bitooth ligand (R, R)-1,2-two (2-bromo-phenyl)-1,2-glycol: titanium tetraisopropylate: oxygenant=1: 0.1: 0.05: 2.Under the situation of not adding water, investigate the influence of water to reaction.The oxygenant that uses in this reaction is a tertbutyl peroxide, and solvent is a toluene.Productive rate is 55%, and the ee value is 18%.
Embodiment 5 preparation (R)-omeprazoles
Experimental implementation is with embodiment 1, and ingredient proportion is as follows: the omeprazole thioether: chirality bitooth ligand: titanium tetraisopropylate: water: the mol ratio of tertbutyl peroxide is 1: 0.1: 0.05: 1: 2.The part that uses in this reaction be (S, S)-1,2-two (2-bromo-phenyl)-1,2-glycol.Solvent is a toluene.Obtain neutrality (R)-omeprazole, productive rate 90%, the ee value is 94%.
Embodiment 6 adds the influence of organic bases to reaction
Under 54 ℃, (0.6 milligram in water, 0.032 mmole), (S, S)-1,2-two (2-bromo-phenyl)-1, (60 milligrams of 2-glycol, 0.16 mmole) and titanium tetraisopropylate (22.5 milligrams, 0.08 mmole) join (87 milligrams, 0.26 mmole) toluene (2 milliliters) solution of omeprazole thioether successively.System keeps 54 ℃ to stir 50 minutes, reduces the temperature to 30 ℃, adds diisopropyl ethylenediamine (14 microlitres, 0.08 mmole) and cumene hydroperoxide (70%, 52 microlitre, 0.24 mmole).Aftertreatment obtains neutrality (S)-omeprazole.Productive rate 50%, ee value are 2%.
Claims (9)
1. an enantio-selectivity catalyzed oxidation prepares optical activity enantiomorph or optical purity enantiomorph (S)-5-methoxyl group-2-[[(4-methoxyl group-3; 5-dimethyl-2-pyridyl) methyl]-sulfinyl]-method of 1H-benzoglyoxaline ((S)-omeprazole); it is characterized in that in the presence of chirality bitooth ligand metal complex catalyst; do not add any organic bases; use gentle cheap oxygenant direct oxidation 5-methoxyl group-2-[[(4-methoxyl group-3; 5-dimethyl-2-pyridyl) methyl]-sulfo-]-the 1H-benzoglyoxaline; the free alkali solid of the neutrality that obtains (S)-omeprazole, this method may further comprise the steps:
In organic solvent and exist or when not having water, chiral ligand (R, R) or (S, S)-1,2-diaryl-1,2-glycol and metal titanium reagent, 5-methoxyl group-2-[[(4-methoxyl group-3,5-dimethyl-2-pyridyl) methyl]-sulfo-]-1H-benzoglyoxaline and oxygenant be-78 ℃ to 50 ℃ reactions 1～24 hour; The reaction back adds or does not add alkaline aqueous solution cancellation reaction; Purified neutrality (the S)-free alkali of omeprazole that obtains solid form;
Described chiral ligand (R, R) or (S, S)-1,2-diaryl-1,2-glycol, metal titanium reagent, 5-methoxyl group-2-[[(4-methoxyl group-3,5-dimethyl-2-pyridyl) methyl]-sulfo-]-mol ratio of 1H-benzoglyoxaline, oxygenant and water is 0.02～0.4: 0.01～0.2: 1: 0.5～3: 0～2;
Described chirality bitooth ligand is to have following structural formula
(R, R) or (S, S)-1,2-diaryl-1,2-glycols compound, or have following structural formula
Perhaps
(R, R) or (S, S)-1,2-two (2-bromo-phenyl)-1, the 2-glycol:
Wherein, Ar is
R wherein
1, R
2, R
3And R
4Be hydrogen, C independently
1～20Alkyl, C
1～20Alkoxyl group or ester group, halogen, phenyl, trifluoromethyl or nitro;
R
3Be hydrogen, C
1～20Alkyl, C
1～20Alkoxy or halogen;
R
4Be hydrogen or C
1～20Alkyl;
R
5Be hydrogen, C
1～20Alkyl, C
1～20Alkoxyl group or ester group, halogen, phenyl, trifluoromethyl or nitro;
Described metal titanium reagent is four (C
1～4Alkoxyl group) titanium compound;
Described oxygenant is hydrogen peroxide, C
1～4Alkyl peroxide or C
1～4The alkyl phenyl superoxide.
2. the method for claim 1 is characterized in that described catalyzer was prepared by described chirality bitooth ligand of claim 1 and metal titanium reagent real-world effectiveness before the omeprazole thioether adds.
3. the method for claim 1 is characterized in that described four (C
1～4Alkoxyl group) titanium compound is titanium tetraisopropylate.
4. the method for claim 1, the mol ratio that it is characterized in that described water and omeprazole thioether is 0.01～2: 1.
5. the method for claim 1 is characterized in that described oxygenant is a tertbutyl peroxide.
6. the method for claim 1 is characterized in that described organic solvent is methylene dichloride, chloroform, tetracol phenixin, hexane, benzene, toluene, chlorobenzene, oil of mirbane, dimethylbenzene, ether, tertbutyl ether, tetrahydrofuran (THF) and dioxane or their mixture.
7. method as claimed in claim 2, the temperature that it is characterized in that described preparation catalyzer are 20 ℃ to 50 ℃, and preparation time is 1 to 60 minute.
8. the method for claim 1 is characterized in that described oxidizing reaction temperature is 2 to 24 hours for-78 ℃ to 25 ℃ oxidation times.
9. the method for claim 1, it is characterized in that described purifying is to add alkaline aqueous solution in the reaction soln to be adjusted to alkalescence back, back organic solvent extraction, add acidic aqueous solution or organic acid adjustment of acidity in the extraction liquid, and solvent extraction, recrystallization in organic solvent.
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| WO2009114981A1 (en) * | 2008-03-19 | 2009-09-24 | Chengdu Likai Chiral Tech Co., Ltd | Process for preparing sulfoxide compounds |
| CN101914090A (en) * | 2010-08-13 | 2010-12-15 | 埃斯特维华义制药有限公司 | Method for preparing levo-omeprazole |
| EP2264024A1 (en) | 2008-10-14 | 2010-12-22 | LEK Pharmaceuticals d.d. | Process for the preparation of enantiomerically enriched proton pump inhibitors |
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| CA2407208C (en) * | 2000-04-28 | 2010-08-17 | Takeda Chemical Industries, Ltd. | Process for producing optically active sulfoxide derivative |
| WO2004087702A2 (en) * | 2003-03-28 | 2004-10-14 | Sidem Pharma | Method for the enantioselective preparation of sulphoxide derivatives |
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| WO2009114981A1 (en) * | 2008-03-19 | 2009-09-24 | Chengdu Likai Chiral Tech Co., Ltd | Process for preparing sulfoxide compounds |
| EP2264024A1 (en) | 2008-10-14 | 2010-12-22 | LEK Pharmaceuticals d.d. | Process for the preparation of enantiomerically enriched proton pump inhibitors |
| CN101914090A (en) * | 2010-08-13 | 2010-12-15 | 埃斯特维华义制药有限公司 | Method for preparing levo-omeprazole |
| CN101914090B (en) * | 2010-08-13 | 2013-03-20 | 埃斯特维华义制药有限公司 | Method for preparing levo-omeprazole |
| CN102816149B (en) * | 2011-06-10 | 2015-05-13 | 上海汇伦生命科技有限公司 | Preparation method for high-enantioselectivity synthesized (S)-omeprazole and salt thereof |
| CN102816149A (en) * | 2011-06-10 | 2012-12-12 | 上海汇伦生命科技有限公司 | Preparation method for high-enantioselectivity synthesized (S)-omeprazole and salt thereof |
| CN102807560A (en) * | 2011-06-21 | 2012-12-05 | 寿光富康制药有限公司 | New method for synthesizing esomeprazole through asymmetrically catalytic oxidation |
| CN102807560B (en) * | 2011-06-21 | 2014-07-23 | 寿光富康制药有限公司 | New method for synthesizing esomeprazole through asymmetrically catalytic oxidation |
| CN102408412A (en) * | 2011-10-25 | 2012-04-11 | 广东华南药业集团有限公司 | (S)-omeprazole preparation method with high antipode selectivity |
| JP2014181180A (en) * | 2013-03-17 | 2014-09-29 | Japan Polyethylene Corp | Diol compound, olefin polymerization catalyst using the same, and olefin polymer production method |
| CN104387368A (en) * | 2014-12-11 | 2015-03-04 | 扬子江药业集团四川海蓉药业有限公司 | Method for preparing dexilant |
| CN105218392A (en) * | 2015-07-09 | 2016-01-06 | 天津青松华药医药有限公司 | L-TARTARIC ACID monoesters monoamide compounds |
| CN105218392B (en) * | 2015-07-09 | 2017-11-21 | 天津青松华药医药有限公司 | D winestone acid monoester monoamides class compounds |
| CN113845510A (en) * | 2020-06-27 | 2021-12-28 | 鲁南制药集团股份有限公司 | Preparation method of esomeprazole |
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