CN108623564B - Preparation method of rabeprazole analogue - Google Patents
Preparation method of rabeprazole analogue Download PDFInfo
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- CN108623564B CN108623564B CN201710159805.4A CN201710159805A CN108623564B CN 108623564 B CN108623564 B CN 108623564B CN 201710159805 A CN201710159805 A CN 201710159805A CN 108623564 B CN108623564 B CN 108623564B
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Abstract
The invention discloses a preparation method of rabeprazole analogues, and particularly relates to a preparation method of dextro-rabeprazole. In the method, under the combined action of vanadium metal and a tetradentate organic ligand, an oxidant is used for oxidizing a prochiral thioether compound to generate the dextro-rabeprazole. The method has the advantages of high enantioselectivity, high purity and high yield, and is suitable for industrial production.
Description
Technical Field
The invention belongs to the field of medicine synthesis, and particularly relates to a method for synthesizing dextro-rabeprazole.
Background
Imidazole sulfoxide compounds are proton pump inhibitors, reduce gastric acid secretion by specifically inhibiting proton pumps of gastric parietal cells, and are widely used for treating diseases related to gastric acid secretion disorder, such as gastric ulcer, duodenal ulcer, peptic ulcer recurrence, reflux esophagitis, zollinger's syndrome and the like. In the asymmetrically substituted imidazole sulfoxides, the sulfur atom is chiral. In fact, these compounds exist in two single enantiomers, the levo- (-) -and the dextro- (+) -forms, i.e. the S-and R-configurations. Early studies showed that S- (-) -omeprazole has a better clinical efficacy, so the first marketed chiral proton pump inhibitor was S- (-) -omeprazole.
Rabeprazole sodium is a novel PPI novel drug developed by Wei material of Japan, and is approved to be marketed in Japan in 1997. The product is used as a second generation proton pump inhibitor, and is a partially reversible proton pump inhibitor; can inhibit gastric acid secretion, and can be widely used for treating peptic ulcer related diseases caused by gastric acid hypersecretion.
The sulfoxide drugs have two stereo structures with different chiralities due to structural factors; the compound with single configuration also has different effects clinically. Compared with racemic rabeprazole sodium, the dextro-rabeprazole sodium has obviously stronger pharmacological action, has the advantages of smaller minimum effective dose, long metabolic half-life period and the like, and can obviously improve the curative effect and reduce the occurrence of toxic and side reactions. At present, the D-rabeprazole sodium is developed by the first pharmaceutical company of India EMCURE, and is on the market in Europe and America, and no product is on the market in China. There are two main methods for obtaining chiral sulfoxides: chiral resolution and asymmetric oxidation. However, the chiral resolution process is complex, the operability is poor, the yield is generally low, and the possibility of application to the industrialized production is low.
German patent DE4035455 (WO 92/08716) and WO94/27988 describe a method for separating [ (pyridylmethylene) sulfinyl ] -1H-benzimidazole into single enantiomers, which comprises introducing chiral groups into molecules by a chemical method to generate stereo difference of original racemes, then carrying out separation and purification, and then dissociating the introduced chiral groups to obtain the sulfoxide chiral proton pump inhibitor of single enantiomer. WO91/12221 describes the direct resolution of racemic omeprazole into single enantiomers by immobilizing a cellulase on a silica support.
WO96/17076 and WO96/17077 describe methods for obtaining single enantiomeric sulfoxides by selective oxidation of thioethers or selective reduction of sulfones, respectively, using microorganisms.
Chinese patent ZL98124029.1 describes a preparation method for inclusion resolution of an optically pure benzimidazole anti-peptic ulcer medicament; chinese patent ZL00113036.6 describes a method for preparing optically pure lansoprazole by adopting an inclusion resolution method; chinese patent ZL03135164.6 describes a process for the preparation of solid optically pure neutral S- (-) -and R- (+) -omeprazole; chinese patent with application number 200510049387 provides a simulated moving bed chromatographic separation method of omeprazole enantiomer.
Chinese patent ZL95194956.X (WO 96/02535,US5948789) describes a process for enantioselective oxidation of thioethers to sulfoxides in the presence of (+) -or (-) -diethyl tartrate and titanium (IV) isopropoxide; and the method synthesizes (-) -and (+) -omeprazole, (-) -and (+) -lansoprazole, (-) -and (+) -pantoprazole and (-) -and (+) -rabeprazole. Chinese patent application No. 200380104409.8 (WO 2004/052881) describes a process for the synthesis of S-pantoprazole by selective oxidation of thioethers in the presence of (+) -or (-) -tartaric acid derivatives and zirconium (IV) or hafnium (IV) alkoxides.
Chinese patent application No. 200610023955 (DE 102005061720) describes a process for the preparation of S- (-) -omeprazole by in situ generation of a titanium-containing catalyst using titanium metal and a chiral diol ligand; chinese patent application No. 200710010273.4 describes a process for the preparation of S-omeprazole, S-lansoprazole, S-pantoprazole, S-rabeprazole and S-tenatoprazole using titanium (IV) or zirconium (IV) alkoxide and a chiral aminoalcohol ligand to generate a metal catalyst in situ.
Asymmetric oxidation of thioethers originally proposed simultaneously by Kagan and Modena to improve Sharpless oxidation for asymmetric synthesis of thioethers, and subsequent studies on asymmetric oxidation of thioethers catalyzed by transition metals for the preparation of chiral sulfoxides have also been extensively conducted. Which comprises the following steps: having a structure of C 2 And C 3 Symmetric chiral alcohols and metal complexes, salen (salan) -metal complexes, porphyrin metal complexes, chiral Schiff base-metal complexes, and the like. The above methods allow the preparation of chiral sulfoxide drugs, but generally suffer from several disadvantages: 1) The catalyst is used in a large amount; 2) The peroxide impurities are easy to appear and are difficult to remove; 3) A large amount of special base is required as an additive, increasing the cost and operability of the reaction. These disadvantages have all greatly limited the industrial production of chiral drugs.
Disclosure of Invention
The rabeprazole analogue is dextro-rabeprazole. The preparation method of the dextro-rabeprazole comprises the following steps:
(1) Dissolving vanadium acetylacetonate and chiral tetradentate ligand in an organic solvent;
(2) Keeping the temperature at 20-30 ℃ for reaction for 0.5-1 hour;
(3) Adding 2- [4- (3-methoxy propoxy-3-methyl-2-pyridyl) methylthio ] -1H-benzimidazole (prochiral thioether intermediate) and diisopropylethylamine, and cooling to-10-0 ℃ for reaction;
(4) Slowly adding 80% cumene hydroperoxide, keeping the temperature at-10-0 ℃ for reaction for 3-8 hours, and reacting for 4-5 hours;
(5) And (4) carrying out post-treatment to obtain the dextro-rabeprazole.
The organic solvent is selected from toluene, dichloromethane, tetrahydrofuran, acetonitrile or chloroform, and can also be toluene.
The chiral tetradentate organic ligand is a compound of formula (I),
the invention relates to a qualitative and quantitative analysis method of chiral imidazole sulfoxide compounds, which comprises the following steps:
LC-20AD type high performance liquid chromatograph; SPD-M20A type ultraviolet and visible light detector; SIL-20 autosampler; a CTO-20A column incubator; an LC Solution chromatography workstation;
stationary phase: chiralpak AD-H (250 mm. Times.4.6, 5um, LTD, japan);
mobile phase: n-hexane: isopropanol: dihexylamine (75;
sample introduction amount: 20 mu L of the solution;
detection wavelength: 302nm
Flow rate: 1.0mL/min
Column temperature: 30 deg.C
And (4) qualitatively determining by an area normalization method, and quantitatively detecting by an external standard method.
In the analysis method, unreacted rabeprazole prochiral thioether is referred to as thioether for short, dextro-rabeprazole is referred to as sulfoxide for short, and a product of rabeprazole peroxidation as shown in the following formula is referred to as sulfone for short.
Rabeprazole peroxide impurity sulfone
Aiming at the problems commonly existing in the prior art for preparing the dextro-rabeprazole, vanadium in the same family with titanium is adopted as metal, and a complex compound formed by the vanadium and a tetradentate ligand with good chiral coordination capacity is used as a chiral catalyst.
Detailed Description
In order to embody the technical solutions of the present invention and the effects achieved thereby, the present invention will be further described with reference to specific embodiments, but the scope of the present invention is not limited to the specific embodiments.
Example one
30mL of methanol and 30mmol of salicylaldehyde are added into a reaction bottle, chiral dinaphthalene diamine (30 mmol) is added into a three-necked bottle, and the mixture is heated to 60 ℃ to react for 3 hours. Cool to room temperature and filter to collect a yellow solid. The yellow solid was added to 30mL of methanol, 31mmol of sodium borohydride were added portionwise and slowly to the reaction mixture, stirring was continued for 3h, the solvent was removed under vacuum 30mL of distilled water was added, 31mmol of glacial acetic acid were dissolved in 15mL of distilled water, slowly added dropwise, to pH =7, and extracted 3 times with 40mL of dichloromethane. The lower layer was collected, dried over anhydrous sodium sulfate, filtered, and the solvent was removed in vacuo to give an off-white solid in 95% yield.
1 H NMR(250MHz):4.38(s，4H)；6.72(d，J＝7.8，2H)；6.75–6.81(m，2H)； 6.98–7.08(m，6H)；7.18–7.28(m，4H)；7.35(d，J＝8.8，2H)；7.76–7.80(m，2H)； 7.84(d，J＝9.1，2H)。 13 CNMR:67.91(t)，115.09(s)，115.62(d)，116.46(d)，120.08(d)， 123.30(d)，123.67(s)，123.91(d)，127.13(d)，128.22(d)，128.48(d)，128.67(d)，128.92(s)， 130.15(d)，133.33(s)，143.88(s)，155.93(s)。MS(ESI):497.2[M+H] + 。
Example two
Vanadium acetylacetonate (26mg, 0.1mmol), chiral tetradentate organic ligand (74.5mg0.15mmol) of the formula (I) and 300ml toluene are mixed, the mixture is reacted for 0.5 to 1H at the temperature of 20 to 30 ℃, 2- [4- (3-methoxy propoxy-3-methyl-2-pyridyl) methylthio ] -1H-benzimidazole (34.3g, 10mmol) is added, diisopropylethylamine (50 ml) is added, and the temperature is reduced to-10 to 0 ℃. Slowly adding 80% cumene hydroperoxide (50 ml), and reacting for 4h at-10-0 ℃. HPLC detection shows that the content of the unreacted thioether in the reaction solution is 0.13%, the content of the peroxidation impurity sulfone is 0.07%, the content of the sulfoxide is 99.5%, and the enantiomeric excess is 99.6%.
Adding 30% sodium thiosulfate solution, stirring for 10min, adding 1000ml of n-hexane, and separating out white solid. And (3) filtering, dissolving the solid in acetone, filtering, adding water into the filtrate to separate out the solid, filtering and drying to obtain the dextro-rabeprazole (32.1 g), wherein the yield is 89.8 percent and the enantiomeric excess is 99.6 percent.
EXAMPLE III
Vanadium acetylacetonate (26mg, 0.1mmol), chiral tetradentate organic ligand (74.5mg0.15mmol) of the formula (I) and 300ml toluene are mixed, the mixture is reacted for 0.5 to 1H at the temperature of 20 to 30 ℃, 2- [4- (3-methoxy propoxy-3-methyl-2-pyridyl) methylthio ] -1H-benzimidazole (34.3g, 10mmol) is added, diisopropylethylamine (50 ml) is added, and the temperature is reduced to-10 to 0 ℃. Slowly adding 80% cumene hydroperoxide (50 ml), and keeping the temperature at minus 10-0 ℃ for reaction for 6h. HPLC detection shows that the content of the unreacted thioether in the reaction solution is 0.14%, the content of the peroxidation impurity sulfone is 0.10%, the content of the sulfoxide is 99.3%, and the enantiomeric excess is 99.5%.
Example four
Mixing vanadium acetylacetonate (26mg, 0.1mmol), chiral tetradentate organic ligand (74.5mg0.15mmol) of the formula (I) and 300ml of toluene, keeping the temperature at 20-30 ℃, reacting for 0.5-1H, adding 2- [4- (3-methoxy propoxy-3-methyl-2-pyridyl) methylthio ] -1H-benzimidazole (34.3g, 10mmol), adding diisopropylethylamine (50 ml), and cooling to-10-0 ℃. Slowly adding 80% cumene hydroperoxide (50 ml), and reacting for 8h at-10-0 ℃. HPLC detection shows that the content of the unreacted thioether in the reaction solution is 0.17%, the content of the peroxidation impurity sulfone is 0.20%, the content of the sulfoxide is 99.1%, and the enantiomeric excess is 99.1%.
EXAMPLE five
Mixing vanadium acetylacetonate (26mg, 0.1mmol), chiral tetradentate organic ligand (74.5mg0.15mmol) of the formula (I) and 300ml of toluene, keeping the temperature at 20-30 ℃, reacting for 0.5-1H, adding 2- [4- (3-methoxy propoxy-3-methyl-2-pyridyl) methylthio ] -1H-benzimidazole (34.3g, 10mmol), adding diisopropylethylamine (50 ml), and cooling to-10-0 ℃. Slowly adding 80% cumene hydroperoxide (50 ml), and reacting for 2h at-10-0 ℃. HPLC detection shows that the content of the unreacted thioether in the reaction solution is 0.47%, the content of the peroxidation impurity sulfone is 0.09%, the content of the sulfoxide is 97.9%, and the enantiomeric excess is 99.0%.
Example six
Mixing vanadium acetylacetonate (26mg, 0.1mmol), chiral tetradentate organic ligand (74.5mg0.15mmol) of the formula (I) and 300ml of dichloromethane, keeping the temperature at 20-30 ℃ for reacting for 0.5-1H, adding 2- [4- (3-methoxypropoxy-3-methyl-2-pyridyl) methylthio ] -1H-benzimidazole (34.3g, 10mmol), adding diisopropylethylamine (50 ml), and cooling to-10-0 ℃. Slowly adding 80% cumene hydroperoxide (50 ml), and keeping the temperature between minus 10 ℃ and 0 ℃ for reaction for 4h. HPLC detection shows that the content of the unreacted thioether in the reaction solution is 0.27%, the content of the peroxidation impurity sulfone is 0.19%, the content of the sulfoxide is 88.9%, and the enantiomeric excess is 98.2%.
EXAMPLE seven
Mixing vanadium acetylacetonate (26mg, 0.1mmol), chiral tetradentate organic ligand (74.5mg0.15mmol) of the formula (I) and 300ml tetrahydrofuran, keeping the temperature at 20-30 ℃, reacting for 0.5-1H, adding 2- [4- (3-methoxy propoxy-3-methyl-2-pyridyl) methylthio ] -1H-benzimidazole (34.3g, 10mmol), adding diisopropylethylamine (50 ml), and cooling to-10-0 ℃. Slowly adding 80% cumene hydroperoxide (50 ml), and keeping the temperature between minus 10 ℃ and 0 ℃ for reaction for 4h. HPLC detection shows that the content of the unreacted thioether in the reaction solution is 0.37 percent, the content of the peroxidation impurity sulfone is 0.29 percent, the content of the sulfoxide is 88.2 percent, and the enantiomeric excess is 98.0 percent.
Example eight
Mixing vanadium acetylacetonate (26mg, 0.1mmol), chiral tetradentate organic ligand (49.6mg0.1mmol) of formula (I) and 300ml of toluene, keeping the temperature at 20-30 ℃ for reaction for 0.5-1H, adding 2- [4- (3-methoxy propoxy-3-methyl-2-pyridyl) methylthio ] -1H-benzimidazole (34.3g, 10mmol), adding diisopropylethylamine (50 ml), and cooling to-10-0 ℃. Slowly adding 80% cumene hydroperoxide (50 ml), and keeping the temperature between minus 10 ℃ and 0 ℃ for reaction for 4h. HPLC detection shows that the content of the unreacted thioether in the reaction solution is 0.17%, the content of the peroxidation impurity sulfone is 0.09%, the content of the sulfoxide is 98.2%, and the enantiomeric excess is 96.0%.
Claims (2)
1. A preparation method of dextro-rabeprazole is characterized in that in an organic solvent, a complex formed by a chiral tetradentate organic ligand and vanadium acetylacetonate is used as a catalyst, an oxidant is used for oxidizing a rabeprazole prochiral thioether compound into the dextro-rabeprazole,
wherein the chiral tetradentate organic ligand is a compound of formula (I),
the organic solvent is toluene; the oxidizing agent is cumene hydroperoxide; the reaction time is 4 hours; the molar ratio of the chiral tetradentate organic ligand to the vanadium acetylacetonate is 1.5.
2. The method of claim 1, wherein the reaction temperature is selected from-10 to 0 ℃.
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| CN101172973A (en) * | 2006-10-30 | 2008-05-07 | 迪法玛弗朗西斯有限公司 | A process for the preparation of pyridine-methylsulfinyl compounds |
| WO2009027533A1 (en) * | 2007-08-31 | 2009-03-05 | Krka, Tovarna Zdravil, D.D., Novo Mesto | Process for preparing 2-sulfinyl-1h-benzimidazoles |
| CN105859685A (en) * | 2016-05-12 | 2016-08-17 | 山东裕欣药业有限公司 | Method for preparing dexrabeprazole sodium |
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| JP2004524303A (en) * | 2001-02-02 | 2004-08-12 | テバ ファーマシューティカル インダストリーズ リミティド | Method for producing substituted 2- (2-pyridylmethyl) sulfinyl-1H-benzimidazoles |
| JP2006523201A (en) * | 2003-03-28 | 2006-10-12 | シデム ファーマ | Process for the enantioselective preparation of sulfoxide derivatives |
| PL1802584T3 (en) * | 2004-10-11 | 2010-03-31 | Ranbaxy Laboratories Ltd | Processes for the preparation of substituted sulfoxides |
| CA2660112A1 (en) * | 2006-08-08 | 2008-02-14 | Jubilant Organosys Limited | Process for producing sulphoxide compounds |
| 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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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101172973A (en) * | 2006-10-30 | 2008-05-07 | 迪法玛弗朗西斯有限公司 | A process for the preparation of pyridine-methylsulfinyl compounds |
| WO2009027533A1 (en) * | 2007-08-31 | 2009-03-05 | Krka, Tovarna Zdravil, D.D., Novo Mesto | Process for preparing 2-sulfinyl-1h-benzimidazoles |
| CN105859685A (en) * | 2016-05-12 | 2016-08-17 | 山东裕欣药业有限公司 | Method for preparing dexrabeprazole sodium |
Non-Patent Citations (1)
| Title |
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| Efficient Asymmetric Oxidation of Sulfides and Kinetic Resolution of Sulfoxides Catalyzed by a Vanadium-Salan System;Jiangtao Sun等;《J. Org. Chem.》;20041028(第69期);第8501页图1、表1 * |
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