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Method for preparing L-pantoprazole sodium

A technology of levorotatory pantoprazole sodium and pantoprazole, applied in the field of medicine, can solve the problems of low yield and high oxidation reaction temperature, and achieve the effects of reducing environmental pollution, reducing environmental pollution and improving labor protection

Inactive Publication Date: 2017-04-05
YANGTZE RIVER PHARM GRP CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

This process post-treatment is simple, only needs to filter and wash and can obtain L-pantoprazole crude product, but also has some shortcomings: the one, its yield is on the low side, neglected a large amount of products remaining in the filtrate; High, it is easy to cause a large amount of peroxide impurity sulfone and nitrogen oxides; third, this process also adds tetraisopropyl titanate and water together, and there may be certain risks in mass industrial production

Method used

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  • Method for preparing L-pantoprazole sodium

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Add 1.04 kg of toluene, 200 g of pantoprazole sulfide, 68 g of D-(-)-diethyl tartrate, and 46 g of tetraisopropyl titanate into the reaction bottle, and after the addition, raise the temperature to 65-70°C and stir for 30 minutes to react slowly. 1.5 g of purified water was added dropwise, and the reaction was stirred for 1 h after the drop was completed. The temperature of the reaction solution was lowered to 20-25°C, 20.8 g of N,N-diisopropylethylamine was added, and stirred for 30 minutes. Cool the solution to -5-0°C, add 288 g of dicumyl hydroperoxide dropwise, keep stirring for 13 hours, and stop the reaction. The reaction solution was extracted three times with 1000 g, 400 g, and 400 g of 7.5% by weight sodium hydroxide solution, and all the aqueous layers were combined. The aqueous layer was adjusted to pH 8.5-9.0 with glacial acetic acid, extracted three times with ethyl acetate, each time 720g, combined ethyl acetate layer, concentrated under reduced pressure ...

Embodiment 2

[0046] Add 5.2kg of toluene, 1.0kg of pantoprazole sulfide, 0.34kg of D-(-)-diethyl tartrate, and 0.23kg of tetraisopropyl titanate into a 20L reaction kettle, heat up to 65-70°C and stir after adding After 40 minutes of reaction, 7.4 g of purified water was slowly added dropwise, and after the completion of the dropwise reaction, the reaction was carried out with insulation and stirring for 1 hour. Cool the reaction solution to 20-25°C, add 0.1 kg of N,N-diisopropylethylamine, and stir for 45 minutes. Cool the solution to -5-0°C, add 1.44 kg of dicumyl hydroperoxide dropwise, keep stirring for 14 hours, and stop the reaction. The reaction solution was extracted three times with 5 kg, 2 kg, and 2 kg of 7.5% by weight sodium hydroxide solution, and all aqueous layers were combined. The aqueous layer was adjusted to pH 8.5-9.0 with glacial acetic acid, extracted three times with ethyl acetate, 3.6 kg each time, combined ethyl acetate layer, concentrated under reduced pressure a...

Embodiment 3

[0049] Add 15.6kg of toluene, 3.0kg of pantoprazole sulfide, 1.02kg of D-(-)-diethyl tartrate, and 0.69kg of tetraisopropyl titanate into a 50L reactor, and heat up to 65-70°C and stir after adding After 40 minutes of reaction, 22.2 g of purified water was slowly added dropwise, and the mixture was stirred and reacted for 1 hour. Cool the reaction solution to 15-20°C, add 0.31 kg of N,N-diisopropylethylamine, and stir for 45 minutes. Cool the solution to -5~0°C, add 4.32 kg of dicumyl hydroperoxide dropwise, keep stirring for 14 hours, and stop the reaction. The reaction solution was extracted three times with 15kg, 6kg, and 6kg of 7.5% by weight sodium hydroxide solution respectively, and all the aqueous layers were combined. The aqueous layer was adjusted to pH 8.0-8.5 with glacial acetic acid, extracted three times with ethyl acetate, 10.8 kg each time, combined ethyl acetate layer, concentrated under reduced pressure at 40-45°C until solids precipitated, and separated at ...

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Abstract

The invention discloses a method for preparing L-pantoprazole sodium in an asymmetric oxidation manner. Under the condition that toluene is used as solvent, a chiral coordination compound is generated through pantoprazole thioether under the effect of D-(-)-diethyl tartrate, titanium tetra-isopropoxide and purified water in a brand-new feeding manner; then, the chiral coordination compound is oxidized through an oxidizing agent, namely, p-Dipropylbenzene hydroperoxide, and then L-pantoprazole sodium is prepared; and the high-purity L-pantoprazole sodium can be obtained by conducting one time of refining on the L-pantoprazole sodium and conducting salt formation on the L-pantoprazole sodium and sodium hydroxide. By means of the preparation method, influences of moisture on reaction can be effectively avoided, and therefore the preparation method is suitable for large-batch industrialized production; and by only conducting one time of recrystallization on the L-pantoprazole sodium before and after salt formation, the chromatographic purity and the optical purity of the product can reach 99.5% or above, and the total yield can reach 60% or above. In addition, the preparation method is gentle in reaction condition, small in environment pollution, high in yield and product purity and suitable for industrialized production.

Description

technical field [0001] The invention relates to the technical field of medicines, in particular to a method for preparing L-pantoprazole sodium. Background technique [0002] Levopantoprazole Sodium (Levopantoprazole Sodium), chemical name (-)-(S)-5-difluoromethoxy-2-{[(3,4-dimethoxy-2-pyridyl)-methoxy Base]sulfinyl}-1H-benzimidazole sodium was developed and listed by Emcure Company of India in 2006 under the trade name of PanPure. The drug is the S-type optical isomer of pantoprazole sodium. As a new generation of proton pump inhibitors (Proton Pump Inhibitors, PPI), it accurately acts on the core group of H+-K+-ATPase, and has a special The racemic form of pantoprazole sodium and the R-type isomer have a stronger inhibitory effect on gastric acid secretion. In the treatment of gastric damage in various clinical models, patients take L-pantoprazole at a dose of 50% of the racemic form Sodium would have an equivalent effect. This type of drug has a long half-life, does no...

Claims

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Application Information

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IPC IPC(8): C07D401/12
CPCC07D401/12C07B2200/07
Inventor 刘旭张海波施连勇陈令武
Owner YANGTZE RIVER PHARM GRP CO LTD
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