CN1995037A - Preparation method of chiral proton pump inhibitor - Google Patents
Preparation method of chiral proton pump inhibitor Download PDFInfo
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- CN1995037A CN1995037A CN 200610172184 CN200610172184A CN1995037A CN 1995037 A CN1995037 A CN 1995037A CN 200610172184 CN200610172184 CN 200610172184 CN 200610172184 A CN200610172184 A CN 200610172184A CN 1995037 A CN1995037 A CN 1995037A
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Abstract
The invention discloses a making method of chiral proton pump inhibitor, which is S-omeprazole, S-lansoprazole, S-pantoprazole, S-rabeprazole and S-tenatoprazole under chiral tartaric derivant and alkoxy vanadium compound.
Description
Invention field:
The invention belongs to medical technical field, relate to new preparation process with the active chiral proton pump inhibitor of anti-peptic ulcer.
Background technology:
Proton pump inhibitor has inhibition H because of it
+, K
+The activity of-ATP enzyme, effectively gastric acid inhibitory secretion has been widely used in treating the peptide ulceration diseases associated that gastroxia causes.At home and abroad Shang Shi proton pump inhibitor has 5-methoxyl group-2-[[(4-methoxyl group-3; 5-dimethyl-2-pyridyl) methyl] sulfinyl]-1H-benzoglyoxaline (omeprazole; omeprazole); 2-[[[3-methyl-4-(2; 2; the 2-trifluoro ethoxy)-and the 2-pyridyl] methyl] sulfinyl]-1H-benzoglyoxaline (lansoprazole; lansoprazole); 5-difluoro-methoxy-2-[[(3; 4-dimethoxy-2-pyridyl) methyl] sulfinyl]-1H-benzoglyoxaline (pantoprazole; pantoprazole); 2-[[[3-methyl-4-(3-methoxyl group-1-propoxy-)-2-pyridyl] methyl] sulfinyl]-1H-benzoglyoxaline rabeprazole (rabeprazole); being in has a 2-[[[2-(4-methoxyl group-3 in the clinical study; the 5-dimethyl) pyridyl] methyl] sulfinyl]-5-methoxyl group imidazoles [4; 5-b] and pyridine (tenatoprazole, tanetoprazole).Such drug molecule has the 2-[[(2-pyridyl) methyl] sulfinyl]-the sulfoxide class formation of 1H-benzimidazole structure or structurally associated; sulphur atom is a stereogenic centres; therefore, these medicines are that two kinds of single enantiomer left-handed (-) bodies and dextrorotation (+) body are the 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.
Above-mentioned proton pump inhibitor adopts the corresponding sulfide compound of oxidation to prepare usually, and what obtain is racemic mixture, adopts special method for oxidation (as adding chiral reagent), can obtain single enantiomer or be rich in the product of enantiomeric form.
Because the single enantiomer of this type of medicine has significant advantage than racemic modification, the preparation method's of its single enantiomer research has also caused extensive concern.
German patent DE 4035455 (WO92/08716) has been described first and a kind of [(pyridyl-methyl) sulfinyl]-1H-benzoglyoxaline has been separated into the method for single enantiomer; this method adopts chemical process to introduce a chirality group in molecule; make former export trade revolve body and produce stereo disparity; the purifying of classifying again; then the chirality group that introduces is dissociated; obtain the sulfoxide class chiral proton pump inhibitor of single enantiomer; in an embodiment; provided compound (+)-and (-)-5-methoxyl group-2-[[(4-methoxyl group-3; 5-dimethyl-2-pyridyl) methyl] sulfinyl]-the 1H-benzoglyoxaline [(+)-and (-)-or R-and S-omeprazole); (+)-and (-)-5-difluoro-methoxy-2-[[(3; 4-dimethoxy-2-pyridyl) methyl] sulfinyl]-the 1H-benzoglyoxaline [[(+)-and (-)-or R-and S-pantoprazole], and mention the treatment that these single enantiomer compounds can be used for the peptic ulcer disease relevant with gastroxia.
WO91/12221 and WO94/27988 have described the method that directly sulfoxide compound of racemic modification is split into single enantiomer, mention especially omeprazole is split into single enantiomer.
WO96/17076 and WO96/17077 have described the use microorganism and have carried out selectively oxidizing sulfur ether or selective reduction sulfone compound, obtain the method for the sulfoxide compound of single enantiomer.
The inclusion that CN98124029.1 has described optical purity benzimidazoles medicines resisting peptic ulcer splits the preparation method; CN00113036.6 has described and has adopted the inclusion Split Method to prepare the method for optical purity lansoprazole; CN03135164 has described the pure neutral S-of acquisition Solid (-)-and the preparation method of R-(+)-omeprazole, and CN200510049387 provided a kind of simulated moving bed chromatographic separation process of omeprazole enantiomer.
CN95194956.X (WO96/02535, US5948789) described a kind of (+)-or (-)-diethyl tartrate and titanium isopropylate (IV) in the presence of, the method of the synthetic sulfoxide class enantiomorph of selectively oxidizing sulfur ether, especially provided (+)-and (-)-or R-and S-omeprazole, (+)-and (-)-or R-and S-lansoprazole, (+)-and (-)-or R-and S-pantoprazole, (+)-and (-)-or the synthetic method of R-and S-rabeprazole.
CN200380104409.8 (WO2004/052881) has described and has used chirality zirconium complex or chirality hafnium complex to prepare the method for S-pantoprazole.This method be (+)-or (-)-tartaric acid derivatives and zirconium alkoxide (IV) or alkoxyl group hafnium (IV) in the presence of, selectively oxidizing sulfur ether synthesizes the S-pantoprazole.
CN200610023955 has described a kind of use metal titanium and chiral diol part original position generates titanium-containing catalyst, prepares the method for S-omeprazole;
The Split Method raw material availability is low, and method for selective synthesis has the remarkable economical advantage than Split Method.
Summary of the invention:
The invention provides preparation chiral proton pump inhibitor (-) or-S-omeprazole, (-) or-S-lansoprazole, (-) or-S-pantoprazole, (-) or-S-rabeprazole and (-) or-a kind of novel method of S-tenatoprazole, above-claimed cpd can be prepared into its pharmaceutically acceptable basic salt with ordinary method.Described method is: in the presence of chirality tartaric acid derivatives and vanadium alkoxy (IV) compound, the corresponding sulfide compound of selective oxidation obtains the chiral sulphoxide proton pump inhibitor of single enantiomer or enantiomorph enriched form.
Above-mentioned reaction is to carry out in the organic solvent of commercially available quality, as methylene dichloride, chloroform, ethyl acetate, acetone, tetrahydrofuran (THF), toluene, acetonitrile, can add the water of suitable proportion.
Described chirality tartaric acid derivatives be (-)-D-diethyl tartrate and (-)-D-tartrate two-(N, N-diformamide), its consumption is 0.1 to 2.0 equivalent, preferred 0.5 to 1.5 equivalent.
Described oxygenant is the hydrop thing, preferred tertbutanol peroxide and cumyl hydroperoxide, and the consumption of oxygenant is 0.8 to 1.2 equivalent, wherein preferred 0.9 to 1.0 equivalent.
Described vanadium (IV) compound is vanadium acetylacetonate (IV), tetraethoxy vanadium (IV), four propoxy-vanadium (IV), four butoxy vanadium (IV), tetraisopropoxide vanadium (IV), four isobutoxy vanadium (IV), four tert.-butoxy vanadium (IV), preferred tetraisopropoxide vanadium (IV), four isobutoxy vanadium (IV), four tert.-butoxy vanadium (IV), its consumption is 0.01 to 1.5 equivalent, preferred 0.1 to 1.0 equivalent.
Described oxidizing reaction preferably 0 ℃ under 50 ℃, carry out under the preferred especially room temperature, suitable organic bases is a tertiary amine, preferred triethylamine and N, N-diisopropyl ethyl amine.
Use described method, can obtain optical purity, optical purity is reached more than 97% through crystallization purifying greater than 90% (-)-or the product of S configuration.
Advantage of the present invention is: the raw material availability height, and selectivity chiral oxidization yield reaches 50%, and optical purity is more than 97%, and preparation technology is simple, and no loaded down with trivial details repeatedly extraction separation process is suitable for suitability for industrialized production.
Embodiment:
Embodiment 1
(-)-5-methoxyl group-2-[[(4-methoxyl group-3,5-dimethyl-2-pyridyl) methyl] sulfinyl]-preparation of 1H-benzoglyoxaline sodium salt [(-)-or S-Omeprazole Sodium]
With 32.9g 5-methoxyl group-2-[[(4-methoxyl group-3,5-dimethyl-2-pyridyl) methyl] sulfenyl]-the 1H-benzoglyoxaline, 20.4g D-(-)-tartrate is two-(N, the N-dimethyl) acid amides, 14.4g tetraisopropoxide vanadium (IV), 0.1mL it is molten entirely that water and 100mL methylene dichloride mix to, reflux 2 hours, in-10 ℃, add 9mL N, the N-diisopropyl ethyl amine, 20.5mL cumyl hydroperoxide (70%) ,-10 ℃～0 ℃ was stirred 6 hours down, and the sodium hydroxide solution that adds 100mL 20% stirred 2 hours, isolated water, handle with 2 * 50mL methylene dichloride, transfer to pH8～9, separate out solid with acetate, through crystallization purifying, get S-omeprazole 17.4g, again with sodium hydroxide salify, crystallization, obtain the S-Omeprazole Sodium 18.2g of enantiomeric excess 96%, total recovery 49.6%.
Embodiment 2
(-)-2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-2-pyridyl] methyl] sulfinyl]-the 1H-benzoglyoxaline ((-)-or the S-lansoprazole)
With 17.6g 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-and the 2-pyridyl] methyl] sulfenyl]-the 1H-benzoglyoxaline, 18.6g D-(-)-diethyl tartrate, 14.4g tetraisopropoxide vanadium (IV), 0.05mL water and 150mL ethyl acetate mixture, 40 ℃ were stirred 2 hours, in room temperature, add 5mLN, the N-diisopropyl ethyl amine, 18.0mL cumyl hydroperoxide (70%), stirring reaction 16 hours, the sodium hydroxide solution that adds 150mL 20% stirred 2 hours, isolated water, handle with 2 * 50mL methylene dichloride, transfer to pH8～9 with acetate, the solid of separating out is again through crystallization purifying, obtain the S-lansoprazole 8.4g of enantiomeric excess 94%, yield 47%.
Embodiment 3
(-)-5-difluoro-methoxy-2-[[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl]-the 1H-benzoglyoxaline [(-)-or the S-pantoprazole]
With 36.7g5-difluoro-methoxy-[[(3,4-dimethoxy-2-pyridyl) methyl] sulfenyl]-the 1H-benzoglyoxaline is dissolved in the 400mL chloroform, add 0.1mL water, 5.2g (-)-D-diethyl tartrate, 6.8g tetraisopropoxide vanadium (IV), 50 ℃ were stirred 3 hours, add 3mL triethylamine, 24g cumyl hydroperoxide (70%) under the room temperature, stirred 5 hours, concentrating under reduced pressure reclaims chloroform, it is fine to add 250mL second in residuum, separate out solid after the cooling, through crystallization purifying, get the S-pantoprazole 16.5g of enantiomeric excess 98%, yield 43% again.
Embodiment 4
(-)-2-[[[3-methyl-4-(3-methoxyl group-1-propoxy-)-2-pyridyl] methyl] sulfinyl]-the 1H-benzoglyoxaline [(-)-or the S-rabeprazole]
With 6.7g 2-[[[3-methyl-4-(3-methoxyl group-1-propoxy-)-2-pyridyl] methyl] sulfenyl]-the 1H-benzoglyoxaline, 7.5g D-(-)-diethyl tartrate, 5.8g tetraisopropoxide vanadium (IV), 0.02mL water and 150mL ethyl acetate mixture, 40 ℃ were stirred 2 hours, in room temperature, add 2mLN, the N-diisopropyl ethyl amine, 7mL cumyl hydroperoxide (70%), stirring reaction 24 hours, the sodium hydroxide solution that adds 150mL 20% stirred 2 hours, isolated water, handle with 2 * 50mL methylene dichloride, transfer to pH8～9 with acetate, the solid of separating out is again through crystallization purifying, obtain the S-rabeprazole 2.7g of enantiomeric excess 94%, yield 38%.
Embodiment 5
2-[[[2-(4-methoxyl group-3,5-dimethyl) pyridyl] methyl] sulfinyl]-5-methoxyl group imidazoles [4,5-b] and pyridine [(-)-or the S-tenatoprazole]
With 3.3g 2-[[[2-(4-methoxyl group-3, the 5-dimethyl) pyridyl] methyl] sulfenyl]-5-methoxyl group imidazoles [4, ' 5-b] and pyridine, 2.1 g D-(-)-diethyl tartrate, 2.9g tetraisopropoxide vanadium (IV), the 50mL toluene mixture, 40 ℃ were stirred 1 hour, in room temperature, add 0.5mL N, the N-diisopropyl ethyl amine, 2.2mL cumyl hydroperoxide (70%), stirring reaction 24 hours, ammoniacal liquor (20%) extraction with 3 * 60mL transfers to pH8～9 with acetate, and the solid of separating out is again through crystallization purifying, obtain (-)-S-tenatoprazole 1.8g of enantiomeric excess 95%, yield 52%.
Claims (10)
1, a kind of preparation method of chiral proton pump inhibitor, it is characterized in that: adopt method for selective synthesis, in organic solvent, in the presence of chirality tartaric acid derivatives and vanadium alkoxy compound, obtain single enantiomer or be rich in the S type proton pump inhibitor of enantiomeric form with the corresponding prochirality thioether of oxygenant oxidation.
2, the preparation method of a kind of chiral proton pump inhibitor according to claim 1 is characterized in that: the S type proton pump inhibitor of gained can be transformed into pharmaceutically acceptable basic salt.
3, the preparation method of a kind of chiral proton pump inhibitor according to claim 1 is characterized in that: described chiral proton pump inhibitor is S-omeprazole, S-lansoprazole, S-pantoprazole, S-rabeprazole, S-tenatoprazole and they are at pharmaceutically acceptable basic salt.
4, the preparation method of a kind of chiral proton pump inhibitor according to claim 1 and 2, it is characterized in that: the optical purity of the chiral proton pump inhibitor that is obtained is greater than 90%.
5, the preparation method of a kind of chiral proton pump inhibitor according to claim 1, it is characterized in that: described prochirality thioether is 5-methoxyl group-2-[[(4-methoxyl group-3,5-dimethyl-2-pyridyl) methyl] sulfenyl]-the 1H-benzoglyoxaline, 2-[[[3-methyl-4-(2,2, the 2-trifluoro ethoxy)-and the 2-pyridyl] methyl] sulfenyl]-the 1H-benzoglyoxaline, 5-difluoro-methoxy-2-[[(3,4-dimethoxy-2-pyridyl) methyl] sulfenyl]-the 1H-benzoglyoxaline, 2-[[[3-methyl-4-(3-methoxyl group-1-propoxy-)-2-pyridyl] methyl] sulfenyl]-the 1H-benzoglyoxaline, 2-[[[2-(4-methoxyl group-3, the 5-dimethyl) pyridyl] methyl] sulfenyl]-5-methoxyl group imidazoles [4,5-b] and pyridine.
6, the preparation method of a kind of chiral proton pump inhibitor according to claim 1 is characterized in that: described oxygenant is a cumyl hydroperoxide; Vanadium alkoxy is the alkanol vanadium.
7, the preparation method of a kind of chiral proton pump inhibitor according to claim 4 is characterized in that: described chain alkoxy vanadium is a vanadium acetylacetonate, the tetraethoxy vanadium, four propoxy-vanadium, four butoxy vanadium, tetraisopropoxide vanadium, four isobutoxy vanadium, four tert.-butoxy vanadium.
8, the preparation method of a kind of chiral proton pump inhibitor according to claim 1, it is characterized in that: described chirality tartaric acid derivatives is (-)-D-diethyl tartrate, (-)-D-tartrate diisopropyl ester, (-)-D-tartrate tert-butyl ester, (-)-D-tartrate is two-(N, N-dimethyl) acid amides.
9, according to the preparation method of claim 1 or 6 or 7 described a kind of chiral proton pump inhibitors, it is characterized in that: the amount of described vanadium alkoxy compound is 0.01～1.5 equivalent.
10, the preparation method of a kind of chiral proton pump inhibitor according to claim 1 is characterized in that: described oxidizing reaction temperature is under 0～50 ℃ temperature.
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| CN 200610172184 CN1995037A (en) | 2006-12-31 | 2006-12-31 | Preparation method of chiral proton pump inhibitor |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN103224489A (en) * | 2013-05-20 | 2013-07-31 | 青岛正大海尔制药有限公司 | Method for enhancing production yield and rate of esomeprazole |
| CN104138357A (en) * | 2014-05-22 | 2014-11-12 | 浙江磐谷药源有限公司 | Specific L-pantoprazole sodium superfine powder lyophilized preparation and preparation method thereof |
| CN110746428A (en) * | 2019-10-29 | 2020-02-04 | 株洲千金药业股份有限公司 | Preparation method of R-type chiral sulfoxide compound |
-
2006
- 2006-12-31 CN CN 200610172184 patent/CN1995037A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN103224489A (en) * | 2013-05-20 | 2013-07-31 | 青岛正大海尔制药有限公司 | Method for enhancing production yield and rate of esomeprazole |
| CN103224489B (en) * | 2013-05-20 | 2015-03-04 | 青岛正大海尔制药有限公司 | Method for enhancing production yield and rate of esomeprazole |
| CN104138357A (en) * | 2014-05-22 | 2014-11-12 | 浙江磐谷药源有限公司 | Specific L-pantoprazole sodium superfine powder lyophilized preparation and preparation method thereof |
| CN110746428A (en) * | 2019-10-29 | 2020-02-04 | 株洲千金药业股份有限公司 | Preparation method of R-type chiral sulfoxide compound |
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Open date: 20070711 |