High-purity lubiprostone compound and preparation method thereof

Abstract

The invention belongs to the technical field of medicine, and provides a high-purity lubiprostone compound and a preparation method thereof. According to the method, a LB-2 is taken as a raw material, then is subjected to oxidation and hydrogenation reactions, and then is processed to obtain the high-purity lubiprostone compound, wherein the oxidation reaction employs a dess-martin oxidizing agent, and the hydrogenation reaction is one-step hydrogenation. According to the invention, the production process is simplified, overall yield of the reaction is high, and the high-purity lubiprostone compound is prepared.

Description

technical field

[0001] The invention belongs to the technical field of medicine, and relates to a preparation method of a high-purity lubiprostone compound. Background technique

[0002] Lubiprostone is a prostaglandin derivative, which is a selective chloride ion channel activator, which can selectively activate the type 2 chloride ion channel (CIC-2) located on the luminal cell membrane of the apex of the gastrointestinal tract epithelium, and increase the secretion of intestinal fluid. Secretion and motility of the intestine, thereby increasing defecation, reducing symptoms of chronic idiopathic constipation, without changing the concentration of sodium and potassium in plasma. It has a novel mechanism of action and excellent clinical effects.

[0003] Lubiprostone has the following structure:

[0004] It exists in tautomers

[0005] European patent application EP0503887A2 discloses a method for synthesizing lubiprostone. The method uses cree diol as a raw material...

Examples

Embodiment 1

[0029] Example 1: (Z)-7-[(1R,2R,3R)-2-(4,4-difluoro-3-oxooctyl)-5-oxo-3-(benzyl-2- Preparation of benzyl oxo)-cyclopentyl]-5-heptenoate (LB-1)

[0030] Mix Dess-Martin oxidant (80g) with dichloromethane (400mL), cool in an ice-water bath, control the internal temperature at 0-10°C, add (Z)-7-[(1R,2R,3R,5S)-2-( Benzyl 4,4-difluoro-3-hydroxyoctyl)-5-hydroxy-3-(benzyl-2-oxo)-cyclopentyl]-5-heptenoate (LB-2) (50g) . After the addition, the reaction solution was heated to 25°C and stirred for 3-5 hours, and the reaction of the raw materials was complete. Slowly pour the reaction solution into 350g Na 2 S 2 o 3 and 160g NaHCO 3 Aqueous solution (1 L) of the solution, stirred for 15-30 minutes, added 500 mL of dichloromethane for extraction, separated the layers, back-extracted the aqueous layer with dichloromethane (500 mL), combined the dichloromethane layers, washed with water, and washed with brine. The organic phase was filtered with anhydrous sodium sulfate, and concentr...

Embodiment 2

[0031] Example 2: 7-[(2R,4aR,5R,7aR)-2-(1,1-difluoropentyl)-2-hydroxyl-6-oxooctahydrocyclopentadienopyran-5- Base] the preparation of heptanoic acid (lubiprostone)

[0032] (Z)-7-[(1R,2R,3R)-2-(4,4-difluoro-3-oxooctyl)-5-oxo-3-(benzyl-2-oxo) -Cyclopentyl]-5-heptenoic acid benzyl ester (LB-1) (42g) and ethyl acetate (420mL) were charged into a 1L medium-pressure reactor, nitrogen was replaced, and palladium carbon (4.2g) was added to replace hydrogen. 45°C, hydrogenation at 8atm for 6h, the reaction of raw materials was complete. Nitrogen was replaced, suction filtered, and the filtrate was concentrated under reduced pressure. Purified by silica gel column chromatography, eluting with n-hexane / ethyl acetate=3 / 1, collecting the separated liquid, concentrating under reduced pressure, and drying to obtain 7-[(2R,4aR,5R,7aR)-2-(1,1-di Fluoropentyl)-2-hydroxy-6-oxooctahydrocyclopentadienopyran-5-yl]heptanoic acid (lubiprostone) (26 g, yield 96%, HPLC purity 99.76%).

Embodiment 3

[0033] Example 3: (Z)-7-[(1R,2R,3R)-2-(4,4-difluoro-3-oxooctyl)-5-oxo-3-(benzyl-2- Preparation of benzyl oxo)-cyclopentyl]-5-heptenoate (LB-1)

[0034] Mix the Dess-Martin oxidant (100g) with dichloromethane (450mL), cool in an ice-water bath, control the internal temperature at 0-10°C, add (Z)-7-[(1R,2R,3R,5S)-2-( Benzyl 4,4-difluoro-3-hydroxyoctyl)-5-hydroxy-3-(benzyl-2-oxo)-cyclopentyl]-5-heptenoate (LB-2) (50g) . After the addition, the reaction solution was heated to 35°C and stirred for 5 hours, and the reaction of the raw materials was complete. Slowly pour the reaction solution into 350g Na 2 S 2 o 3 and 160g NaHCO 3 Aqueous solution (1 L) of the solution, stirred for 30 minutes, added 500 mL of dichloromethane for extraction, separated the layers, back-extracted the aqueous layer with dichloromethane (500 mL), combined the dichloromethane layers, washed with water, and washed with brine. The organic phase was filtered with anhydrous sodium sulfate, and concentr...

technical field

[0001] The invention belongs to the technical field of medicine, and relates to a preparation method of a high-purity lubiprostone compound. Background technique

[0002] Lubiprostone is a prostaglandin derivative, which is a selective chloride ion channel activator, which can selectively activate the type 2 chloride ion channel (CIC-2) located on the luminal cell membrane of the apex of the gastrointestinal tract epithelium, and increase the secretion of intestinal fluid. Secretion and motility of the intestine, thereby increasing defecation, reducing symptoms of chronic idiopathic constipation, without changing the concentration of sodium and potassium in plasma. It has a novel mechanism of action and excellent clinical effects.

[0003] Lubiprostone has the following structure:

[0004] It exists in tautomers

[0005] European patent application EP0503887A2 discloses a method for synthesizing lubiprostone. The method uses cree diol as a raw material...

Examples

Embodiment 1

[0029] Example 1: (Z)-7-[(1R,2R,3R)-2-(4,4-difluoro-3-oxooctyl)-5-oxo-3-(benzyl-2- Preparation of benzyl oxo)-cyclopentyl]-5-heptenoate (LB-1)

[0030] Mix Dess-Martin oxidant (80g) with dichloromethane (400mL), cool in an ice-water bath, control the internal temperature at 0-10°C, add (Z)-7-[(1R,2R,3R,5S)-2-( Benzyl 4,4-difluoro-3-hydroxyoctyl)-5-hydroxy-3-(benzyl-2-oxo)-cyclopentyl]-5-heptenoate (LB-2) (50g) . After the addition, the reaction solution was heated to 25°C and stirred for 3-5 hours, and the reaction of the raw materials was complete. Slowly pour the reaction solution into 350g Na 2 S 2 o 3 and 160g NaHCO 3 Aqueous solution (1 L) of the solution, stirred for 15-30 minutes, added 500 mL of dichloromethane for extraction, separated the layers, back-extracted the aqueous layer with dichloromethane (500 mL), combined the dichloromethane layers, washed with water, and washed with brine. The organic phase was filtered with anhydrous sodium sulfate, and concentr...

Embodiment 2

[0031] Example 2: 7-[(2R,4aR,5R,7aR)-2-(1,1-difluoropentyl)-2-hydroxyl-6-oxooctahydrocyclopentadienopyran-5- Base] the preparation of heptanoic acid (lubiprostone)

[0032] (Z)-7-[(1R,2R,3R)-2-(4,4-difluoro-3-oxooctyl)-5-oxo-3-(benzyl-2-oxo) -Cyclopentyl]-5-heptenoic acid benzyl ester (LB-1) (42g) and ethyl acetate (420mL) were charged into a 1L medium-pressure reactor, nitrogen was replaced, and palladium carbon (4.2g) was added to replace hydrogen. 45°C, hydrogenation at 8atm for 6h, the reaction of raw materials was complete. Nitrogen was replaced, suction filtered, and the filtrate was concentrated under reduced pressure. Purified by silica gel column chromatography, eluting with n-hexane / ethyl acetate=3 / 1, collecting the separated liquid, concentrating under reduced pressure, and drying to obtain 7-[(2R,4aR,5R,7aR)-2-(1,1-di Fluoropentyl)-2-hydroxy-6-oxooctahydrocyclopentadienopyran-5-yl]heptanoic acid (lubiprostone) (26 g, yield 96%, HPLC purity 99.76%).

Embodiment 3

[0033] Example 3: (Z)-7-[(1R,2R,3R)-2-(4,4-difluoro-3-oxooctyl)-5-oxo-3-(benzyl-2- Preparation of benzyl oxo)-cyclopentyl]-5-heptenoate (LB-1)

[0034] Mix the Dess-Martin oxidant (100g) with dichloromethane (450mL), cool in an ice-water bath, control the internal temperature at 0-10°C, add (Z)-7-[(1R,2R,3R,5S)-2-( Benzyl 4,4-difluoro-3-hydroxyoctyl)-5-hydroxy-3-(benzyl-2-oxo)-cyclopentyl]-5-heptenoate (LB-2) (50g) . After the addition, the reaction solution was heated to 35°C and stirred for 5 hours, and the reaction of the raw materials was complete. Slowly pour the reaction solution into 350g Na 2 S 2 o 3 and 160g NaHCO 3 Aqueous solution (1 L) of the solution, stirred for 30 minutes, added 500 mL of dichloromethane for extraction, separated the layers, back-extracted the aqueous layer with dichloromethane (500 mL), combined the dichloromethane layers, washed with water, and washed with brine. The organic phase was filtered with anhydrous sodium sulfate, and concentr...

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