CN102558151A - Application of trivalent iodine ligand to synthesis of chiral sulfoxide compound - Google Patents
Application of trivalent iodine ligand to synthesis of chiral sulfoxide compound Download PDFInfo
- Publication number
- CN102558151A CN102558151A CN2011104210753A CN201110421075A CN102558151A CN 102558151 A CN102558151 A CN 102558151A CN 2011104210753 A CN2011104210753 A CN 2011104210753A CN 201110421075 A CN201110421075 A CN 201110421075A CN 102558151 A CN102558151 A CN 102558151A
- Authority
- CN
- China
- Prior art keywords
- sulfoxide compound
- iodonium
- chiral sulfoxide
- chiral
- preparing
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Abstract
The invention relates to a method for preparing a chiral sulfoxide compound. A prochiral thioether compound is subjected to asymmetric synthesis in the presence of a trivalent iodine ligand to form a chiral sulfoxide proton pump inhibitor in a single antipode form or an antipode enriched form, namely (R/S)-omeprazole, (R/S)-lansoprazole, (R/S)-pantoprazole, (R/S)-tenatoprazole, (R/S)-rabeprazole, (R/S)-leminoprazole, (R/S)-leminorazole, (R/S)-saviprazole, (R/S)-ilaprazole and (R/S)-RO18-5364 and pharmaceutically acceptable salt thereof. Asymmetric synthesis is performed, so that the method is environment-friendly and easy to operate, enantioselectivity is high, and reaction conditions are mild.
Description
One, technical field
The invention belongs to medical technical field, relate to new preparation process with iodonium part synthesis of chiral sulfoxide compound S-isomer or R-isomer.
Two, background technology
Some sulfoxide compound has inhibition H because of it
+, K
+The activity of-ATP enzyme (being called proton pump again), the effectively secretion of gastric acid inhibitory has been widely used in treating the peptide ulceration diseases associated that gastroxia causes.Listing at home and abroad or the sulfoxide class proton pump inhibitor that is about to go on the market have (R/S)-omeprazole (omeprazole); (R/S)-lansoprazole (lansoprazole); (R/S)-pantoprazole (pantorazole); (R/S)-TU-199 (tenatoprazole); (R/S)-rabeprazole (rabeprazole); (R/S)-leminoprazole (leminoprazole); (R/S)-Lai Minuola azoles (leminorazole); (R/S)-Saviprazole (saviprazole); (R/S)-lY 81149 (Ilaprazole); (R/S)-the RO18-5364 structure is following:
These medicines are two kinds of single enantiomer left-handed (-) bodies and dextrorotation (+) body, the i.e. raceme mixture of S-type and R-type.The chiral proton pump inhibitor of first listing is (S)-5-methoxyl group-2-[[(4-methoxyl group-3; 5-dimethyl--2-pyridyl) methyl] sulfinyl]-1H-benzoglyoxaline (S-omeprazole; Esomprazole), in clinical application, has remarkable advantages than raceme omeprazole; Lansoprazole is after omeprazole, the proton pump inhibitor of second listing.Owing to introduced fluorine, make its character be different from omeprazole, thermodynamics and oxidative stability increase, and have improved biological activity greatly.Lansoprazole in December, 1991 by the exploitation of Japanese Wu Tian company; With its co-market commercial law state Houde company; In France's approval Initial Public Offering, went on the market in the U.S. by TAP drugmaker in Japan's listing in 1992 at present; Be used to treat stomach ulcer, duodenal ulcer and reflux esophagitis, and be used for eliminating pylorus.Some pharmacology researchs show that the lansoprazole drug effect of (R)-configuration obviously is superior to the lansoprazole raceme, and optically active blue rope azoles toxic side effect is lower than raceme.Therefore, the application of synthesizing in medicine of optically pure proton pump inhibitor is an extremely important problem.
The synthetic of racemization imidazoles sulfoxide compound had very sophisticated method, still is a challenging problem at present yet select efficient synthetic individual isomer.The method that obtains this type individual isomer is divided into two types, the asymmetric oxidation method of chemical resolution method and thioether.Patent is most both at home and abroad adopts under (+) or (-) diethyl tartrate or chiral auxiliary(reagent) and titanium isopropylate (IV) or the zirconium existence method of the synthetic sulfoxide class enantiomorph of selectively oxidizing sulfur ether.Yet this method operation and aftertreatment are loaded down with trivial details, and the metal titanium ion or the zirconium ion that produce, and environment is had certain pollution.
Therefore; Press for the associated problem that solve in the above-mentioned technology; The present invention is to be chiral auxiliary(reagent) with the iodonium ligand compound, and asymmetric preparation chiral sulfoxide compounds avoids the use of the metal complexs such as titanium or zirconium of operation and aftertreatment cumbersome approaches and environmental pollution.
Three, summary of the invention
The present invention is that the iodonium ligand compound is chiral auxiliary(reagent) and corresponding sulfide compound synthesis of chiral sulfoxide.
Target compound synthetic route of the present invention is following:
Four, specific embodiment mode
Through following examples with better explanation the present invention.But the present invention does not receive the restriction of following embodiment.
Embodiment 1
Synthesizing of R-lansoprazole
[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridyl] methyl] sulfenyl]-(35.3g 0.1mol) is dissolved in the 150ml trichloromethane 1H-benzoglyoxaline 2-, under the 0-5 ℃ of condition; (50.3g 0.1mol) with the mixed solution of 150ml trichloromethane, drips and finishes, and is warming up to room temperature to drip (+)-MnTIB; Reaction finishes, the aqueous sodium hydroxide solution 100ml of Dropwise 5 %, and stirring at room 3h obtains water layer; Regulate pH7-8 with acetate, use chloroform extraction, combined chloroform layer, washing, drying; Decompression and solvent recovery is used the acetone-water recrystallization, and suction filtration, drying under reduced pressure get white solid 24.3g.Productive rate is 65.8%, mp144-146 ℃;
1H-NMR (400MHz, CDCl
3, ppm) δ: 2.26 (3H, s, CH
3), 4.36 (2H, q, J=7.8Hz, CH
2CF
3), 4.74 (1H, d, J=13.6Hz, SOCH
2), 4.87 (1H, d, J=13.6Hz, SOCH
2), 6.68 (1H, d, J=5.8Hz, Ar-H), 7.26-7.36 (2H, m, Ar-H), 7.45 (1H, m, Ar-H), 7.78 (1H, m, Ar-H), 8.35 (1H, d, J=5.8Hz, Ar-H), 12.63 (1H, s, NH); Content 98.9% (area normalization method), HPLC condition: C
18Chromatographic column (4.6mm * 250mm * 5 μ m); Water-acetonitrile-triethylamine (60: 40: 1) uses phosphorus acid for adjusting pH value to 7.0 to be moving phase; Detect wavelength: 285nm; Flow velocity: 1.0ml/min; Column temperature: 30 ℃.Optical purity ee value >=99%, HPLC condition: chiral column CHIRALCEL OD 4.6 * 250mm; Column temperature: 25 ℃; Moving phase: normal hexane-ethanol (85: 15); Flow velocity: 1.0ml/min; Detect wavelength: 285nm.
Embodiment 2
Synthesizing of esomeprazole
[[(3,5-dimethyl--4-methoxyl group-2-pyridyl) methyl] sulfenyl]-(6.9g 0.02mol) is dissolved in the 50ml methylene dichloride 5-methoxyl group-1H-benzoglyoxaline 2-, under the 0-5 ℃ of condition; (10.6g 0.1mol) with the mixed solution of 50ml methylene dichloride, drips and finishes, and is warming up to room temperature to drip (-)-MnTIB; Reaction finishes, the potassium hydroxide aqueous solution 50ml of Dropwise 5 %, and stirring at room 3h obtains water layer; Regulate pH7.5-8 with acetate, use dichloromethane extraction, combined dichloromethane layer, washing, drying; Decompression and solvent recovery is used the acetone-water recrystallization, and suction filtration, drying under reduced pressure get white solid 4.1g.Productive rate is 56.7%;
1H-NMR (400MHz, CDCl
3, ppm) δ: 2.09～2.20 (s, 6H, CH
3), 3.68～3.81 (s, 6H, OCH
3), 4.63 (2H, q, J=13.7Hz, SOCH
2), 7.05～7.56 (m, 3H, Ar-H), 8.19 (s, 1H, Ar-H), 13.44 (s, 1H, NH); Content detection HPLC condition: C
18Chromatographic column (4.6mm * 250mm * 5 μ m); Water-acetonitrile-triethylamine (60: 40: 1) uses phosphorus acid for adjusting pH value to 7.0 to be moving phase; Detect wavelength: 285nm; Flow velocity: 1.0ml/min; Column temperature: 30 ℃.Optical purity ee value >=99%; Detect the HPLC condition: chiral column CHIRALCEL OD 4.6 * 250mm; Column temperature: 25 ℃; Moving phase: normal hexane-ethanol (90: 10); Flow velocity: 1.0ml/min; Detect wavelength: 285nm.
Embodiment 3
Synthesizing of S-pantoprazole
5-difluoro-methoxy 2-[(3,4-dimethoxy-2-pyridyl] methyl] sulfenyl]-(11g 0.03mol) is dissolved in the 100ml toluene 1H-benzoglyoxaline, under the 0-5 ℃ of condition, drips (-)-MnTIB (16g; 0.03mol) and the mixed solution of 150ml toluene, drip and finish, be warming up to room temperature, reaction finishes; The ammonia soln 90ml of dropping 12%, stirring at room 3h obtains water layer, regulates pH 7-8 with acetate; Use extracted in toluene, combining methylbenzene layer, washing, drying, decompression and solvent recovery; Use the acetone-water recrystallization, suction filtration, drying under reduced pressure gets white solid 5.3g.Productive rate is 47.3%,
1H-NMR (400MHz, CDCl
3, ppm) δ: 3.90 (3H, s, OCH
3), 3.93 (3H, s, OCH
3), 4.48 (2H, q, J=13.0Hz, SOCH
2), 6.51 (1H, d, J=74.6Hz, CH
2CF
3), 6.86 (1H, d, J=6.0Hz, Ar-H), 7.06-7.56 (3H, m, Ar-H), 8.26 (1H, d, J=6.0Hz, Ar-H),, 12.58 (1H, s, NH); Chemical purity 99.1% (area normalization method); HPLC condition: C
18Chromatographic column (4.6mm * 250mm * 5 μ m); Water-acetonitrile-triethylamine (60: 40: 1) uses phosphorus acid for adjusting pH value to 7.0 to be moving phase; Detect wavelength: 285nm; Flow velocity: 1.0ml/min; Column temperature: 30 ℃.Optical purity ee value >=99.1%; HPLC condition: chiral column CHIRALCEL OD 4.6 * 250mm; Column temperature: 30 ℃; Moving phase: normal hexane-ethanol (85: 15); Flow velocity: 1.0ml/min; Detect wavelength: 285nm.
Being merely embodiments of the invention in sum, is not to be used for limiting practical range of the present invention.Be that all equivalences of doing according to the content of claim of the present invention change and modification, all should be technological category of the present invention.
Claims (5)
1. a method for preparing the iodonium part at the chiral sulfoxide compound is characterized in that, comprises step:
A, in organic solvent, under the condition that the iodonium ligand compound exists, make the oxidation of prochirality sulfoxide compound;
B, hydrolysis prepares the chiral sulfoxide compound under alkaline condition.
2. a kind of method for preparing the iodonium part at the chiral sulfoxide compound according to claim 1 is characterised in that: the organic solvent in the steps A is meant acetone, butanone class, methylene dichloride, trichloromethane halo alkanes, toluene, YLENE aromatics, THF, one or more mixed solvents of ether class.
3. a kind of method for preparing the iodonium part at the chiral sulfoxide compound according to claim 1, be characterised in that: the iodonium part in the steps A is to comprise following structure:
4. a kind of method for preparing the iodonium part at the chiral sulfoxide compound according to claim 1, be characterised in that: prochirality sulfoxide compound structure is following in the steps A:
5. a kind of method for preparing the iodonium part at the chiral sulfoxide compound according to claim 1; Be characterised in that: hydrolysis is meant under the alkaline condition in the steps A, hydrolysis in organic and inorganic alkaline solutions such as sodium hydroxide, Pottasium Hydroxide, ammoniacal liquor, hydrated barta.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011104210753A CN102558151A (en) | 2011-12-15 | 2011-12-15 | Application of trivalent iodine ligand to synthesis of chiral sulfoxide compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011104210753A CN102558151A (en) | 2011-12-15 | 2011-12-15 | Application of trivalent iodine ligand to synthesis of chiral sulfoxide compound |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102558151A true CN102558151A (en) | 2012-07-11 |
Family
ID=46404905
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2011104210753A Pending CN102558151A (en) | 2011-12-15 | 2011-12-15 | Application of trivalent iodine ligand to synthesis of chiral sulfoxide compound |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102558151A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107089934A (en) * | 2017-05-19 | 2017-08-25 | 南开大学 | Water-soluble organic trivalent iodine reagent sulfamic acid iodoso benzene-like compounds and synthesis |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101538264A (en) * | 2008-03-19 | 2009-09-23 | 中国科学院成都有机化学有限公司 | Novel method for preparing chiral sulphoxide compound |
-
2011
- 2011-12-15 CN CN2011104210753A patent/CN102558151A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101538264A (en) * | 2008-03-19 | 2009-09-23 | 中国科学院成都有机化学有限公司 | Novel method for preparing chiral sulphoxide compound |
Non-Patent Citations (1)
| Title |
|---|
| DALE G. ET AL.: "Iodinanes with Iodine( 111) -Bound Homochiral Alkoxy Ligands: Preparation and Utility for the Synthesis of Alkoxysulfonium Salts and Chiral Sulfoxides", 《J. AM. CHEM. SOC.》, vol. 112, 31 December 1990 (1990-12-31), pages 5672 - 5673 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107089934A (en) * | 2017-05-19 | 2017-08-25 | 南开大学 | Water-soluble organic trivalent iodine reagent sulfamic acid iodoso benzene-like compounds and synthesis |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU688074B2 (en) | Process for synthesis of substituted sulphoxides | |
| RU2144031C1 (en) | Method of optical purification of enantimer-enriched benzimidazole derivatives | |
| CN101012141B (en) | Method of manufacturing chiral sulfoxide compounds | |
| CN103709143B (en) | The preparation method of esomeprazole and magnesium salts thereof | |
| CA2597632C (en) | Substituted sulfoxide compounds, methods for preparing the same and use thereof | |
| CN102603716B (en) | Method for preparing (S)-pantoprazole in high-enantioselectivity way | |
| CN1810803B (en) | Method for high enantiomer selection preparation of (S)-Omeprazole | |
| CN101343266A (en) | Preparation method for optical pure rebeprazole | |
| US20080319195A1 (en) | Enantioselective Preparation of Benzimidazole Derivatives and Their Salts | |
| ZA200503911B (en) | Process for preparing (s)-pantoprazole | |
| CN102558151A (en) | Application of trivalent iodine ligand to synthesis of chiral sulfoxide compound | |
| CN103113351A (en) | Method for preparing optically pure chiral sulfoxide compound | |
| CN1995037A (en) | Preparation method of chiral proton pump inhibitor | |
| EP2203441A2 (en) | Process for optically active sulfoxide compounds | |
| CN104892575A (en) | Novel synthesis method of chiral imidazole sulfoxide compound | |
| CN104387368A (en) | Method for preparing dexilant | |
| CN104530006A (en) | Lansoprazole preparation method | |
| CN105085487B (en) | A kind of preparation method of esomeprazole magnesium trihydrate | |
| CN102807560B (en) | New method for synthesizing esomeprazole through asymmetrically catalytic oxidation | |
| CN102408412A (en) | (S)-omeprazole preparation method with high antipode selectivity | |
| CN101474544A (en) | Preparation method of trisiloxanes surfactant containing amino group and oxyethyl group | |
| CN102432412A (en) | Preparation method of chiral sulphoxide proton pump inhibitor or pharmaceutically-acceptable salt thereof | |
| CN101372484A (en) | Asymmetric synthesis method of chiral benzimidazole compound | |
| CN103601698A (en) | Benzothiazole compounds and application thereof | |
| CN103880819B (en) | Preparation method of optically pure lansoprazole |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C53 | Correction of patent of invention or patent application | ||
| CB02 | Change of applicant information |
Address after: Science and Technology Industrial Park D-5 No. 168 high tech Zone camphor road in Hefei city of Anhui Province in 230088 Applicant after: Hefei Huafang Pharmaceutical Sciences & Technology Co., Ltd. Address before: Tianda high tech Zone 230088 Hefei Road, Anhui province No. 71 Huayi Science Park G block four building Applicant before: Hefei Huafang Pharmaceutical Sciences & Technology Co., Ltd. |
|
| C12 | Rejection of a patent application after its publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20120711 |