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Preparation method for prostaglandin intermediate

A compound and solution technology, which is applied in the field of preparation of prostaglandin intermediates, can solve the problems of violent reaction, environmental pollution, difficult control and the like

Active Publication Date: 2011-05-11
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

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preparation example Construction

[0034] The preparation method of the compound of formula I provided by the invention comprises the following steps:

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

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

[0037] In the third step, the obtained dichloromethane layer solution is subjected to silica gel chromatography to obtain the compound shown in formula I.

[0038]

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

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] Dess-Martin oxidizer (105.7 g) was stirred and dissolved in dichloromethane (1300 ml) at room temperature, N 2Under protection, cool to 0°C, 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 added dropwise over 20 minutes. Rising to 10°C and stirring for 5h. TLC detects that the reaction is complete.

[0059] A 1.3 L 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 layers, back-extract the water layer with 200 ml of dichloromethane, combine the dichloromethane layers, wash with 1.5 L of water, dry over anhydrous magnesium sulfate, concentrate to dryness to give a light yellow oil, pass through a silica gel column (purchased from Qi...

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

[0064] A 1.3 L 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 layers, back-extract the water layer with 200 ml of dichloromethane, combine the dichloromethane layers, wash with 1.5 L of water, dry over anhydrous magnesium sulfate, concentrate to dryness to give a light yellow oil, pass through a silica gel column...

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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 invention relates to a preparation method of a compound, in particular to a preparation method of 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, thus Facilitates passage of softened stools through the intestinal tract, relieving symptoms of constipation. The U.S. Food and Drug Administration (FDA) has approved lubiprostone (Amitiza) capsules produced by Sucampo Pharmaceuticals of the United States for the treatment of chroni...

Claims

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Application Information

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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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