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Preparation method of lubiprostone or its intermediate

A technology for lubiprostone and intermediates, applied in the production of bulk chemicals, organic chemistry, etc., can solve the problems of long steps, expensive upper and side chains, high cost, etc., achieve high reproducibility, increase yield, and save costs Effect

Active Publication Date: 2016-05-11
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 its intermediate
  • Preparation method of lubiprostone or its intermediate
  • Preparation method of lubiprostone or its intermediate

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 TBSCl (52.3g, 0.35mol) in DMF (200mL) solution was slowly added to maintain The temperature of the system does not exceed 10°C. After the addition, the reaction is quenched by adding saturated ammonium chloride (200mL) after stirring at 0~5°C for 2h. Extracting with dichloromethane until TLC shows no compound 2 in the water layer, adding citric acid (10 %, 200mL) wash twice, separate the organic phase, wash once with saturated NaCl solution (200mL), wash with saturated sodium bicarbonate solution (200mL), wash with saturated brine (200mL), dry with anhydrous sodium sulfate, spin-evaporate and concentrate the column The product was obtained by chromatography (80 g, yield 96.3%).

Embodiment 2

[0067]

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

Embodiment 3

[0070]

[0071] Compound 3 (55g, 135mmol) was dissolved in anhydrous toluene (330mL), the temperature was reduced to -70°C under nitrogen protection, DIBAL-H (203mL, 1Mintoluene, 203mmol) was added dropwise, and the dripping was completed within 1.5 hours. Stir at -70°C for 2 hours, TLC indicated that the reaction was complete, methanol was added dropwise to quench the reaction, the cooling bath was removed, saturated potassium sodium tartrate solution (400 mL) was added dropwise, the temperature was raised to room temperature, and the mixture was stirred thoroughly. Extract with dichloromethane until TLC shows no compound 4 in the water layer. Combine the organic layers, wash with saturated brine (400 mL), dry with anhydrous sodium sulfate, and use rotary evaporation to concentrate directly into the next step without purification.

[0072] CEPPA (140g, 317mmol) was suspended in anhydrous THF (200mL), stirred in an ice bath, and LiHMDS (102g, 610mmol) in THF (200mL) solution was s...

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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 present 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 derivatives and is a selective chloride channel activator. It has a novel mechanism of action. It relieves the symptoms of constipation by increasing the secretion of intestinal juice 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 show that the compound exists in two forms of structural dynamic equilibrium under normal conditions, as shown below, [0006] [0007] The existing patent documents US5886034A, EP0284180A1, US5166174A, US5225439A, US5284858A, US5380709A, US5428062A, US62...

Claims

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Application Information

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Patent Type & Authority Patents(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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