CN104387368A - Method for preparing dexilant - Google Patents
Method for preparing dexilant Download PDFInfo
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- CN104387368A CN104387368A CN201410764574.6A CN201410764574A CN104387368A CN 104387368 A CN104387368 A CN 104387368A CN 201410764574 A CN201410764574 A CN 201410764574A CN 104387368 A CN104387368 A CN 104387368A
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- C07—ORGANIC CHEMISTRY
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- 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 discloses a method for preparing dexilant. The method comprises the steps of enabling 2-[3-mythyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]mythylthio-1H-benzimidazoleand, chiral diol ligand and tetra-isopropyl titanate to have a complex reaction in an organic solvent, adding cumene hydroperoxide into reaction liquid, and obtaining the dexilant in a single enantiomer form or a form with rich enantiomers after an oxidizing reaction. The optical purity of the dexilant prepared with the method is high, the content of impurities is low, and an ee (enantiomeric excess) value of the dexilant in a product reaches 99.0%-99.5%.
Description
Technical field
The present invention relates to technical field prepared by chemicals, be specifically related to a kind of preparation method of R-lansoprazole.
Background technology
Lansoprazole (lansoprazole; Chemical name 2-[3-methyl-4-(2,2,2-trifluoro ethoxy)-2-pyridyl] methylsulfinyl-1H-benzoglyoxaline) be the end of the eighties, the benzimidazoles derivative with gastric acid secretion inhibiting effect developed by Japanese Wu Tian company.Clinical trial proves that this compound has antiulcer activity, can gastric acid secretion inhibiting, protection gastric mucosa, there is hypotoxicity feature.
Structural formula formula I is as follows:
Sulphur atom in lansoprazole structural formula is chiral atom, has two optical isomers.Study confirmation at present, in the medicine of lansoprazole raceme, different enantiomerisms has different drug effects and toxic side effect.Optically pure R-lansoprazole drug effect is obviously better than raceme, and toxic action is lower than racemization lansoprazole (WO99/38512 and WO99/38513).The R-lansoprazole preparation method reported for work is a kind of method [(pyridine methylene) sulfinyl]-1H-benzoglyoxaline being separated into single enantiomer as German patent DE 4035455 and WO94/27988 describe; the method adopts chemical process to introduce chiral radicals in the molecule; former racemize is made to produce stereo disparity; carry out separation and purification again; the chiral radicals of introducing is dissociated, obtains the sulfoxide type chipal compounds of single enantiomer.Application number be 200710010273.4 Chinese patent describe a kind of titan-alkoxide and zirconium alkoxide and chiral amino alcohol ligand of using and generate metal catalyst, prepare S-lansoprazole.Adopt chiral separation method in aforesaid method, raw material availability is low, and cost is higher.Enantioselective oxidation method has obvious advantage, and the method therefore studying enantioselective oxidation is further significant.
Summary of the invention
Technical problem to be solved by this invention is to overcome above-mentioned weak point, and research and design optical purity is high, and technological operation is simple, and reaction conditions is gentle, is applicable to the method for suitability for industrialized production R-lansoprazole.
For reaching above-mentioned purpose, providing a kind of preparation method of R-lansoprazole in one embodiment of the present of invention, comprising the following steps:
(1) in organic solvent, by 2-[3-methyl-4-(2,2,2-trifluoro ethoxy)-2-pyridyl] methylsulfany-1H-benzoglyoxaline and chiral ligand glycol, isopropyl titanate carries out complex reaction;
(2) in reaction solution, add cumyl hydroperoxide, after oxidizing reaction, obtain single enantiomerism or be rich in the R-lansoprazole of enantiomeric forms.
As the embodiment optimized, the reaction solvent of step (1) is tetracol phenixin, chloroform, toluene or methyl-2-pyrrolidone.
As the embodiment optimized, the temperature of reaction of step (1) is 50 DEG C ~ 60 DEG C.
As the embodiment optimized, the chiral diol of step (1) is (S, S)-1,2-diphenylethyleneglycol or 2,2,5,5-tetramethyl--3,4-hexylene glycol.
As the embodiment optimized, 2-[3-methyl-4-(2,2,2-trifluoro ethoxy)-2-pyridyl] methylsulfany-1H-benzoglyoxaline in step (1): the consumption mol ratio of chiral diol is 1:0.4 ~ 0.6.
As the embodiment optimized, 2-[3-methyl-4-(2,2,2-the trifluoro ethoxy)-2-pyridyl] methylsulfany-1H-benzoglyoxaline of step (1): the mol ratio of isopropyl titanate is 1:0.2 ~ 0.3.
As the embodiment optimized, containing water, wherein 2-[3-methyl-4-(2,2,2-trifluoro ethoxy)-2-pyridyl] methylsulfany-1H-benzoglyoxaline in the solution of step (1): the mol ratio of water is 1:1.
As the embodiment optimized, step (2) cumyl hydroperoxide and 2-[3-methyl-4-(2,2,2-trifluoro ethoxy)-2-pyridyl] mol ratio of methylsulfany-1H-benzoglyoxaline is 1.1:1, oxidizing reaction is reacted 12 ~ 16 hours at 0 DEG C ~ 10 DEG C.
In sum, the present invention has the following advantages:
Optical purity is high, and foreign matter content is little, and in product, R-lansoprazole ee value reaches 99.0% ~ 99.5%, and quality product reaches EP standard.Reaction conditions is gentle, and technological operation is simple, is applicable to suitability for industrialized production, has larger using value.
Embodiment
Embodiment 1:
The preparation of (+)-2-[(R) 3-methyl-4-(2,2,2-trifluoro ethoxy)-2-pyridyl] methylsulfinyl-1H-benzoglyoxaline (R-lansoprazole)
By the 2-[3-methyl-4-(2 of 10g (28.3mmol); 2; 2-trifluoro ethoxy)-2-pyridyl] methylsulfany-1H-benzoglyoxaline is dissolved in 100ml toluene; under nitrogen protection; add purified water (total Water 28.3mmol), 3.02g (14.1mmol) (S successively; S)-1,2-diphenylethyleneglycol under nitrogen protection, is uniformly mixed.Be warming up to 50 ~ 60 DEG C, add 2.01g (7.1mmol) isopropyl titanate, keep temperature to continue stirring 2 hours.Cool to 0-10 DEG C, slowly drip cumyl hydroperoxide 4.04g (31.1mmol).Then maintain the temperature within the scope of 0-10 DEG C, stirring reaction 16 hours.Then 30% hypo solution termination reaction is added.After stirring 1h, reaction solution is evaporated to volume 4/5.At keeping temperature 0 ~ 10 DEG C, in concentrated solution, add normal heptane-methyl tertiary butyl ether (volume ratio 1:1,40ml), 140ml normal heptane successively.Filter, filter cake methyl tertiary butyl ether-toluene (4:1) washing.
Upper step being obtained solid crude product is dissolved in 60ml acetone, and under stirring at room temperature, drip 180ml purified water, filter, precipitation separation crystal, filter cake purified water is washed.Then will obtain solid crude product to be dissolved in 60ml acetone, add 1% ammoniacal liquor 180ml, Glacial acetic acid regulator solution PH to 8.0, and have a large amount of off-white color solid to separate out.Filter, obtain off-white color solid crude product.
Upper step being obtained solid crude product is dissolved in during 40ml methylene dichloride adds, and with saturated common salt water washing (40ml x 2), anhydrous sodium sulfate drying, filters.Filtrate activated carbon decolorizing, filter, filtrate is concentrated into dry, adds 20ml acetic acid ethyl dissolution concentrating residues thing, slowly drips 160ml normal heptane, after dropwising, stir 1 hour in filtrate.Filter, filter cake ethyl acetate: normal heptane (1:8) washs, and obtains target compound, collect, drying under reduced pressure at 25 ± 5 DEG C, obtains target compound (4.5g).
Show through efficient liquid phase chromatographic analysis result, containing the sulfide compound of 0.03% in product, the sulfone of 0.07% and the sulfoxide of 99.0%, in sulfoxide, R-lansoprazole ee value is 99.5%.
HPLC detection method:
Chiral column: Daicel CHIRALPAK AD-H
Sample size: 10ul
Flow velocity: 1.0ml/min
Determined wavelength: 285nm
Column temperature: 30 DEG C
Moving phase: normal hexane: Virahol (90:10)
Retention time: 21min
Embodiment 2:
The preparation of (+)-2-[(R) 3-methyl-4-(2,2,2-trifluoro ethoxy)-2-pyridyl] methylsulfinyl-1H-benzoglyoxaline (R-lansoprazole)
By 10g (28.3mmol) 2-[3-methyl-4-(2; 2; 2-trifluoro ethoxy)-2-pyridyl] methylsulfany-1H-benzoglyoxaline is dissolved in 100ml toluene, under nitrogen protection, adds purified water (total Water 28.3mmol), 2.46g (14.1mmol) (S successively; S)-2; 2,5,5-tetramethyl--3; 4-hexylene glycol under nitrogen protection, is uniformly mixed.Be warming up to 50 ~ 60 DEG C, add 2.01g (7.1mmol) isopropyl titanate, keep temperature to continue stirring 2 hours.Cool to 0-10 DEG C, slowly drip cumyl hydroperoxide 4.04g (31.1mmol).Then maintain the temperature within the scope of 0-10 DEG C, stirring reaction 14 hours.Then 30% hypo solution termination reaction is added.After stirring 1h, reaction solution is evaporated to volume 4/5.At keeping temperature 0 ~ 10 DEG C, in concentrated solution, add normal heptane-methyl tertiary butyl ether (volume ratio 1:1,40ml), 140ml normal heptane successively.Filter, filter cake methyl tertiary butyl ether-toluene (4:1) washing.
Upper step being obtained solid crude product is dissolved in 60ml acetone, and under stirring at room temperature, drip 180ml purified water, filter, precipitation separation crystal, filter cake purified water is washed.Then will obtain solid crude product to be dissolved in 60ml acetone, add 1% ammoniacal liquor 180ml, Glacial acetic acid regulator solution PH to 8.0, and have a large amount of off-white color solid to separate out.Filter, obtain off-white color solid crude product.
Upper step being obtained solid crude product is dissolved in during 40ml methylene dichloride adds, and with saturated common salt water washing (40ml x 2), anhydrous sodium sulfate drying, filters.Filtrate activated carbon decolorizing, filter, filtrate is concentrated into dry, adds 20ml acetic acid ethyl dissolution concentrating residues thing, slowly drips 160ml normal heptane, after dropwising, stir 1 hour in filtrate.Filter, filter cake ethyl acetate: normal heptane (1:8) washs, and obtains target compound, collect, drying under reduced pressure at 25 ± 5 DEG C, obtains target compound (4.3g).
Show through efficient liquid phase chromatographic analysis result, containing the sulfide compound of 0.04% in product, the sulfone of 0.05% and the sulfoxide of 99.1%, in sulfoxide, R-lansoprazole ee value is 99.3%.
HPLC detection method:
Chiral column: Daicel CHIRALPAK AD-H
Sample size: 10ul
Flow velocity: 1.0ml/min
Determined wavelength: 285nm
Column temperature: 30 DEG C
Moving phase: normal hexane: Virahol (90:10) retention time: 21min.
Claims (8)
1. a preparation method for R-lansoprazole, comprises the following steps:
(1) in organic solvent, by 2-[3-methyl-4-(2,2,2-trifluoro ethoxy)-2-pyridyl] methylsulfany-1H-benzoglyoxaline and chiral ligand glycol, isopropyl titanate carries out complex reaction;
(2) in reaction solution, add cumyl hydroperoxide, after oxidizing reaction, obtain single enantiomerism or be rich in the R-lansoprazole of enantiomeric forms.
2. the method for claim 1, is characterized in that: the reaction solvent of described step (1) is tetracol phenixin, chloroform, toluene or methyl-2-pyrrolidone.
3. the method for claim 1, is characterized in that: the temperature of reaction of described step (1) is 50 DEG C ~ 60 DEG C.
4. the method for claim 1, is characterized in that: the chiral diol of described step (1) is (S, S)-1,2-diphenylethyleneglycol or 2,2,5,5-tetramethyl--3,4-hexylene glycols.
5. the method for claim 1, it is characterized in that: 2-[3-methyl-4-(2 in described step (1), 2,2-trifluoro ethoxy)-2-pyridyl] methylsulfany-1H-benzoglyoxaline: the consumption mol ratio of chiral diol is 1:0.4 ~ 0.6.
6. the method for claim 1, it is characterized in that: the 2-[3-methyl-4-(2 of described step (1), 2,2-trifluoro ethoxy)-2-pyridyl] methylsulfany-1H-benzoglyoxaline: the mol ratio of isopropyl titanate is 1:0.2 ~ 0.3.
7. the method for claim 1, it is characterized in that, containing water, wherein 2-[3-methyl-4-(2 in the solution of described step (1), 2,2-trifluoro ethoxy)-2-pyridyl] methylsulfany-1H-benzoglyoxaline: the mol ratio of water is 1:1.
8. the method for claim 1, it is characterized in that, described step (2) cumyl hydroperoxide and 2-[3-methyl-4-(2,2,2-trifluoro ethoxy)-2-pyridyl] mol ratio of methylsulfany-1H-benzoglyoxaline is 1.1:1, oxidizing reaction is reacted 12 ~ 16 hours at 0 DEG C ~ 10 DEG C.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107400119A (en) * | 2017-08-29 | 2017-11-28 | 珠海赛隆药业股份有限公司 | A kind of preparation method of Dexlansoprazole |
| CN108440501A (en) * | 2018-04-19 | 2018-08-24 | 湖北省医药工业研究院有限公司 | The preparation method of proton pump inhibitor R-lansoprazole |
| CN113801096A (en) * | 2020-06-12 | 2021-12-17 | 杭州中美华东制药有限公司 | Preparation method of dexlansoprazole |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1810803A (en) * | 2006-02-17 | 2006-08-02 | 中国科学院上海有机化学研究所 | Selective prepn process of (S)-Omeprazole with high antimer |
| CN104177336A (en) * | 2013-05-28 | 2014-12-03 | 上海汇伦生命科技有限公司 | Method for antipodal selective synthesis of (R)-lansoprazole |
-
2014
- 2014-12-11 CN CN201410764574.6A patent/CN104387368A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1810803A (en) * | 2006-02-17 | 2006-08-02 | 中国科学院上海有机化学研究所 | Selective prepn process of (S)-Omeprazole with high antimer |
| CN104177336A (en) * | 2013-05-28 | 2014-12-03 | 上海汇伦生命科技有限公司 | Method for antipodal selective synthesis of (R)-lansoprazole |
Non-Patent Citations (2)
| Title |
|---|
| MARIA IRENE DONNOLI, ET AL.: "Catalytic Asymmetric Oxidation of Aryl Sulfides with a Ti/H2O/(R,R)-Diphenylethane-1,2-diol Complex: a Versatile and Highly Enantioselective Oxidation Protocol", 《J. ORG. CHEM.》, vol. 63, no. 25, 14 November 1998 (1998-11-14), pages 9392 - 9395, XP002269765, DOI: doi:10.1021/jo981346j * |
| YOSHINORI YAMANOI, ET AL.: "Preparation of Enantiopure 2,2,5,5-Tetramethyl-3,4-hexanediol and Its Use in Catalytic Enantioselective Oxidation of Sulfides to Sulfoxides", 《J. ORG. CHEM.》, vol. 62, no. 24, 31 December 1997 (1997-12-31), pages 8560 - 8564 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107400119A (en) * | 2017-08-29 | 2017-11-28 | 珠海赛隆药业股份有限公司 | A kind of preparation method of Dexlansoprazole |
| CN108440501A (en) * | 2018-04-19 | 2018-08-24 | 湖北省医药工业研究院有限公司 | The preparation method of proton pump inhibitor R-lansoprazole |
| CN113801096A (en) * | 2020-06-12 | 2021-12-17 | 杭州中美华东制药有限公司 | Preparation method of dexlansoprazole |
| CN113801096B (en) * | 2020-06-12 | 2023-03-24 | 杭州中美华东制药有限公司 | Preparation method of dexlansoprazole |
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