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Preparation method of lubiprostone or midbody thereof

A lubiprostone and intermediate technology, which is applied in the production of bulk chemicals, organic chemistry, etc., can solve the problems of long steps, high cost, expensive upper side chains, etc., and achieves high reproducibility, improved yield, and easy removal effect

Active Publication Date: 2013-04-24
WUHAN QR PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The steps are long and because the upper side chain is more expensive, the cost is higher, and the highly toxic reagent ethanol thallium is used

Method used

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  • Preparation method of lubiprostone or midbody thereof
  • Preparation method of lubiprostone or midbody thereof
  • Preparation method of lubiprostone or midbody thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0064]

[0065]Compound 1 (50g, 0.29mol) was dissolved in DMF (200mL), cooled to 0°C, imidazole (47.5g, 0.70mol) was added, and then a solution of TBSCl (52.3g, 0.35mol) in DMF (200mL) was slowly added to maintain The temperature of the system does not exceed 10°C. After the addition is complete, stir at 0-5°C for 2h, then add saturated ammonium chloride (200mL) to quench the reaction, extract with dichloromethane until TLC shows that the aqueous layer has no compound 2, add citric acid (10 %, 200mL) and washed twice, the organic phase was separated, washed once with saturated NaCl solution (200mL), washed with saturated sodium bicarbonate solution (200mL), washed with saturated brine (200mL), dried over anhydrous sodium sulfate, and concentrated by rotary evaporation The product was obtained by chromatography (80 g, 96.3% yield).

Embodiment 2

[0067]

[0068] Compound 2 (82g, 0.286mol) was dissolved in dichloromethane (820mL), stirred and dissolved, and 2,2,2-trichloroiminoacetate-4-methoxybenzyl ester (192g, 80%, 0.544mol ), then add CSA (6.64g, 0.0286mol), after the addition is complete, add saturated sodium bicarbonate solution (200mL) after fully reacting at room temperature for 24h, after fully stirring, extract with dichloromethane until TLC shows that the water layer has no compound 3 The organic layers were combined, washed with saturated brine (400mL), dried over anhydrous sodium sulfate, concentrated by rotary evaporation and column chromatography to obtain product 3 (100g, yield 86%).

Embodiment 3

[0070]

[0071] Compound 3 (55g, 135mmol) was dissolved in anhydrous toluene (330mL), cooled to -70°C under nitrogen protection, and DIBAL-H (203mL, 1M in toluene, 203mmol) was added dropwise for 1.5h. Stir at -70°C for 2 h, TLC shows that the reaction is complete, add methanol dropwise to quench the reaction, remove the cooling bath, add saturated sodium potassium tartrate solution (400 mL) dropwise, warm to room temperature, and stir well. Dichloromethane was extracted until TLC showed that the aqueous layer was free of compound 4. The organic layers were combined, washed with saturated brine (400 mL), dried over anhydrous sodium sulfate, concentrated by rotary evaporation, and directly used for the next reaction without purification.

[0072] CEPPA (140g, 317mmol) was suspended in anhydrous THF (200mL), stirred in an ice bath, and LiHMDS (102g, 610mmol) in THF (200mL) was slowly added dropwise at 0°C to obtain a brick red solution. yellow solution. After stirring at 0°C...

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PUM

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Abstract

The invention discloses a novel method for preparing a lubiprostone midbody as shown in the formula 7. The method comprises the following steps: (1), a compound as shown in the formula 1 reacts with tert-butyldimethylsilyl chloride to selectively protect a primary hydroxyl group, thereby obtaining a compound shown in the formula 2; (2), a protecting group is applied to the compound 2 under the action of a catalyst, thereby obtaining a compound shown in the formula 3; (3), after the compound 3 is reduced through diisobutylaluminium hydride, a Wittig reaction is carried out on the compound 3, thereby obtaining carboxylic acid shown in the formula 4; (4), the compound 4 is protected in an acetonitrile solvent through a protecting group, thereby obtaining a compound shown in the formula 5; (5), the compound 5 is treated by using the tert-Butyldimethylsilane for removing the protecting group, thereby obtaining a compound shown in the formula 6; and (6), the compound 6 is oxidized by an oxidant and then reacts with a compound shown in the formula (10), thereby obtaining the higher-purity compound shown in the formula 7.

Description

technical field [0001] The invention belongs to the field of biomedicine, and specifically relates to a new method for producing an intermediate of lubiprostone shown in formula 7. Background technique [0002] Lubiprostone is a kind of prostaglandin derivative, which belongs to selective chloride ion channel activator, has a novel mechanism of action, and relieves constipation symptoms by increasing intestinal fluid secretion and enhancing intestinal motility. Its English name: Lubiprostone, chemical name: (-)-7-[(2R, 4aR, 5R, 7aR)-2-(1,1-difluoro-n-pentyl)-2-dihydroxy-6-oxoocta Hydrocyclopentapyran-5-yl] n-heptanoic acid. [0003] The structural formula of lubiprostone is shown in formula 8: [0004] [0005] Experiments have proved that the compound exists in the form of dynamic equilibrium of two structures under normal conditions, as shown below, [0006] [0007] Currently existing patent documents US5886034A, EP0284180A1, US5166174A, US5225439A, US5284858A, U...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C405/00C07D311/94
CPCY02P20/55
Inventor 梅三林刘勇潘新夏有友王朝东
Owner WUHAN QR PHARMA CO LTD
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