Preparation method for prostaglandin intermediate

A preparation step, lubiprostone technology, applied in the field of preparation of prostaglandin intermediates, can solve serious, difficult to control, environmental pollution and other problems

Active Publication Date: 2014-03-12
SHANGHAI TECHWELL BIOPHARMACEUTICALS CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the prior art, the oxidant usually uses a reagent containing metallic chromium, which has the disadvantages of serious environmental pollution and severe reaction that is difficult to control

Method used

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  • Preparation method for prostaglandin intermediate
  • Preparation method for prostaglandin intermediate
  • Preparation method for prostaglandin intermediate

Examples

Experimental program
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preparation example Construction

[0034] The method for preparing the compound of formula I provided by the present invention includes the following steps:

[0035] In the first step, the solution 2 containing the compound represented by formula II and the solution 3 containing the compound represented by formula III are mixed at 0-10°C, and then stirred at 0-30°C; the solution 2 or solution 3 contains The solvent is dichloromethane;

[0036] In the second step, after adding the aqueous solution, back-extract with dichloromethane for 1-3 times, and combine the dichloromethane layers; and

[0037] In the third step, the obtained dichloromethane layer solution was subjected to silica gel chromatography to obtain the compound represented by formula I.

[0038]

[0039] Preferably, in the first step, the solution 2 containing the compound represented by formula II can be added dropwise to the solution 3 containing the compound represented by formula III at 0-10°C, and then reacted at 0-30°C; or The solution 3 of the comp...

Embodiment 1

[0056] Preparation of 16,16-difluoro-13,14-dihydro-15-carbonyl-11-[(tetrahydro-2H-pyran-2-yl)oxy]-PGE 2 Methyl ester 1

[0057]

[0058] At room temperature, stir Dess-Martin oxidant (105.7g) and dissolve it in dichloromethane (1300ml), N 2 Under protection, cool to 0℃, add dropwise 16,16-difluoro-13,14-dihydro-15(R,S)-hydroxy-11-[(tetrahydro-2H-pyran-2-yl)oxy ]-PGF 2 A solution of methyl ester (54.3g) in dichloromethane (340ml) was dripped in 20min. Raise to 10°C and stir for 5h. TLC detected that the reaction was complete.

[0059] A 1.3L aqueous solution of 377.6 g of sodium thiosulfate pentahydrate and 139.8 g of sodium bicarbonate was slowly added. Stir for 5 min, separate the layers, extract the water layer with 200ml of dichloromethane, combine the dichloromethane layers, wash with 1.5L of water, dry with anhydrous magnesium sulfate, and concentrate to dry to obtain a light yellow oil, which is passed through a silica gel column (purchased from Qingdao Ocean Chemical, (30...

Embodiment 2

[0061] Preparation of 16,16-difluoro-13,14-dihydro-15-carbonyl-11-[(tetrahydro-2H-pyran-2-yl)oxy]-PGE 2 Benzyl ester 2

[0062]

[0063] At room temperature, add 16,16-difluoro-13,14-dihydro-15(R,S)-hydroxy-11-[(tetrahydro-2H-pyran-2-yl)oxy]-PGF 2a Benzyl ester (54.3g) dissolved in dichloromethane (340ml), N 2 Under protection, cool to 5°C, stir and dissolve Dess-Martin oxidant (157.7g) in dichloromethane (1300ml), drip into the above benzyl ester solution, and finish dripping for 20 minutes. Raise to 20°C and stir for 1h. TLC detected that the reaction was complete.

[0064] A 1.3L aqueous solution of 377.6 g of sodium thiosulfate pentahydrate and 139.8 g of sodium bicarbonate was slowly added. Stir for 5 min, separate the layers, extract the water layer with 200ml of dichloromethane, combine the dichloromethane layers, wash with 1.5L of water, dry with anhydrous magnesium sulfate, and concentrate to dry to obtain a light yellow oil, which is passed through a silica gel column (p...

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Abstract

The invention discloses a preparation method for a prostaglandin intermediate. The method comprises the step of: (1) mixing a compound represented by a formula II and a substitutive o-iodobenzoic acid type compound represented by a formula III to obtain a compound represented by a formula I, wherein R1 is C1-C4 straight chain or alkyl, phenyl or substitutive phenyl which contains branch chains; R2 is tetrahydropregnenolone (THP), silane radical substituted by trialkyl, alkyl acyl, benzoyl or benzoyl of which the benzene ring is provided with a substituent; and R3 is acetoxy.

Description

Technical field [0001] The present invention relates to a method for preparing a compound, in particular to a method for preparing a prostaglandin intermediate. Background technique [0002] Lubiprostone is a prostaglandin compound, namely (-)-7-[(2R, 4aR, 5R, 7aR)-2-(difluoropentyl)-2-hydroxy-6-oxooctahydrocyclopentane Pyran-5-yl]heptanoic acid often exists in the following tautomeric forms: [0003] [0004] As a locally acting chloride channel activator, lubiprostone can specifically act on the type II chloride channel on the epidermal cell membrane of the gastrointestinal tract, stimulate the secretion of intestinal fluid with high chloride ion concentration, and increase intestinal motility. Promote softened stools to pass through the intestines and relieve symptoms of constipation. The U.S. Food and Drug Administration (FDA) has approved lubiprostone (lubiprostone / Amitiza) capsules produced by Sucampo Pharmaceuticals in the United States for the treatment of adult chronic i...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D309/12C07F7/18C07C405/00C07D311/94
Inventor 唐志军何兵明李林舒顺舟卓忠浩郑云满高霄梁季晓铭
Owner SHANGHAI TECHWELL BIOPHARMACEUTICALS CO LTD
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