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Novel chiral sulfoxide compound and method for preparing esomeprazole by using novel chiral sulfoxide compound

A compound, sodium hydroxide technology, applied in the direction of organic chemistry and the like, can solve the problems of low yield, expensive reagents, expensive synthetic raw materials and chiral resolving agents, etc., and achieves the effects of mild reaction conditions and short synthetic process steps.

Active Publication Date: 2012-07-25
CHENGDU EASTON BIOPHARMACEUTICALS CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] At present, there are many reports on the preparation methods of esomeprazole, which can be summarized into three categories: one is the chiral induction method described in the world patent WO2009106745, and the disadvantage of this method is that the synthetic raw materials and chiral auxiliary agents are expensive; the other is WO2009040825 And the chiral resolution method described in WO2007074099, in addition to the disadvantages of expensive synthetic raw materials and chiral resolution agents, the method also has the disadvantages of low yield and low optical purity; the third is the asymmetric oxidation of thioethers such as CN101323609A , CN1995037A, CN101012141A, WO2009114981A1, US2008319195A1, WO2008152462A1, etc. The disadvantages of this type of preparation method are that the reagents are expensive, the yield is low and the optical purity is not high
These shortcomings are all unfavorable for the esomeprazole of industrialized production high optical purity and high yield

Method used

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  • Novel chiral sulfoxide compound and method for preparing esomeprazole by using novel chiral sulfoxide compound
  • Novel chiral sulfoxide compound and method for preparing esomeprazole by using novel chiral sulfoxide compound
  • Novel chiral sulfoxide compound and method for preparing esomeprazole by using novel chiral sulfoxide compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Example 1 Preparation of Intermediate II ((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-thioxanthogenate ethyl ester

[0024]

[0025] At room temperature, 2.22kg 2-(chloromethyl)-4-methoxy-3,5-lutidine hydrochloride was dissolved in 150L ethanol, 1.38kg potassium carbonate was added in batches, and after stirring for 10 minutes , 1.92 kg potassium xanthate was added, and the reaction solution was stirred at room temperature for about 3 hours (detected by TLC). The resulting potassium chloride solid was filtered, washed with ethanol, and the filtrate was concentrated. Add 80L of water to the residue, stir, filter the obtained solid, and recrystallize with ethyl acetate-petroleum ether to obtain pure ((4-methoxy-3,5-dimethylpyridin-2-yl) (Methyl)-thioxanthogenate (2.66 kg, yield 98%, pale yellow solid).

[0026] 1 H-NMR(300MHz, CDCl 3 ): δ 8.18 (s, 1H), 4.67 (q, 2H), 4.54 (s, 2H), 3.76 (s, 3H), 2.30 (s, 3H), 2.24 (s, 3H), 1.43 (t, 3H). EIMS m / z272.1([M+H] + ).

Embodiment 2

[0027] Example 2 Preparation of Compound I (S)-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl) thioformate

[0028]

[0029] Dissolve 2.5kg of Intermediate II in 200L of isopropanol at 70°C, add 2.1kg of DBU and 2.3kg (11eq.) of self-made oxidant III in sequence, stir the reaction solution for 12 hours, filter the white solid produced, and use isopropyl alcohol for the solid. Wash with propanol, spin the filtrate to dryness, dissolve the residue in water, filter the white solid produced again, add acetic acid to the filtrate to adjust the pH to 7.2, then extract with ethyl acetate, dry the organic phase, and spin-evaporate to remove the solvent. The white solid is the crude product. It is recrystallized from ethyl acetate-petroleum ether to obtain pure (S)-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinic acid Acyl) ethyl methanesulfonate (2.25 kg, yield 85%, white solid).

[0030] 1 H-NMR(300MHz, CDCl 3 ): δ 8.25 (s, 1H), 4.15 (s, 2H), 3.80 (s, 3H), 3.60 (q, 2H), 2.33 ...

Embodiment 3

[0031] Example 3 Preparation of Compound I (S)-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl) thioformate

[0032]

[0033] Dissolve 500g of Intermediate II in 40L of isopropanol at 10°C, add 420g of DBU and 380g (0.9eq.) of self-made oxidant III in sequence, stir the reaction solution for 12 hours, filter the white solid produced, and use isopropanol for the solid Wash, spin the filtrate to dryness, dissolve the residue in water, filter the white solid produced again, add acetic acid to the filtrate to adjust the pH to 7.6, then extract with ethyl acetate, dry the organic phase, and remove the solvent by rotary evaporation to obtain an off-white solid It is a crude product and recrystallized with ethyl acetate-petroleum ether to obtain pure (S)-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl ) Ethyl thioformate (375.9 g, yield 71%, white solid). The NMR and MS data are consistent with Example 2.

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Abstract

The invention discloses a (S)-(((4-methoxy-3,5-dimethyl pyridine-2-yl)methyl)sulfinyl) ethyl thioformate compound, a preparation method of the compound and a process for preparing esomeprazole by using the compound. The compound and the preparation method have the remarkable advantages that: raw materials for synthesis are cheap and can be easily obtained; the reaction conditions are moderate; the yield of the prepared esomeprazole is high; the optical purity is high; the operation is safe; the environment is slightly polluted; and the compound is more suitable for industrial large-scale production.

Description

Technical field [0001] The invention belongs to the technical field of pharmaceutical chemical synthesis, and specifically relates to (S)-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl) ethyl thioformate The compound and the preparation method thereof and the process for preparing esomeprazole sodium by using the compound. Background technique [0002] Esomeprazole is the S-optical isomer of omeprazole. It is the world's first proton pump inhibitor (PPI), which specifically inhibits the proton pump of gastric parietal cells to reduce gastric acid secretion. A large number of clinical experiments and drug studies have confirmed that it maintains pH>4 in the stomach for a longer time, has a higher acid suppression efficiency, and has better efficacy than the previous two generations of PPI, with small individual differences. As a new generation of PPI, it has been widely used in clinical treatment of many acid-related diseases, such as gastroesophageal reflux disease (GE...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/68C07D401/12
Inventor 王颖李建国
Owner CHENGDU EASTON BIOPHARMACEUTICALS CO LTD
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