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Novel method for synthetizing prostaglandin analogue

A technology of analogues and prostaglandins, which is applied in the field of synthesizing prostaglandin analogues, can solve problems such as separation difficulties, increased ratio of 5,6-trans isomers, and decreased yield, so as to enhance UV absorption and reduce extraction times , to facilitate the effect of central control monitoring

Inactive Publication Date: 2013-09-11
北京洛斯顿精细化工有限公司
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  • Abstract
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Problems solved by technology

[0009] Because there is a selectivity problem in the reduction of the 9-position carbonyl group involved in route 2, the synthesis of many prostaglandins uses the method of route 1. If the 11 and 15-position hydroxyl groups are not protected, the 5,6-trans isomerization in the Wittig reaction body proportion increase
However, when traditional protecting groups such as THP and other acetal or ketal protecting groups are used, acidic conditions are generally used for deprotection, which may cause dehydration of the 15-position hydroxyl group, resulting in many by-products, resulting in a decrease in yield and separation of products. very difficult
The use of silyl ether protecting groups is a better choice. However, under general silyl ether protecting groups, the reaction site at position 11 may partially migrate to position 9 under Wittig reaction conditions, which increases the complexity of the reaction and produces Many by-products that are difficult to isolate
In addition, the by-product diphenylphosphine valeric acid produced by the Wittig reaction makes its separation from the product very difficult due to its physical properties

Method used

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  • Novel method for synthetizing prostaglandin analogue
  • Novel method for synthetizing prostaglandin analogue
  • Novel method for synthetizing prostaglandin analogue

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] (3aR,4R,5R,6aS)-4-((S,E)-3-(tert-butyldiphenylsilyloxy)-5-phenylpent-1-en-1-yl)-2-oxo Hexahydro-2H-cyclopenta[b]furan-5-ylbenzoate (3a)

[0041] Add 10 grams of compound 2a, 90 milliliters of dichloromethane, 5 grams of imidazole, 0.25 grams of DMAP into a 1L three-necked flask, and cool down to 0-10 degrees under nitrogen protection, and dropwise add a mixture of 10.1 grams of TBDPSCl and 30 milliliters of dichloromethane, about The addition was completed in 10 minutes, and a white insoluble substance was formed. Stir at about 20 degrees for 10 hours, TLC (Rf=0.9, toluene:EtOAc3:2) detected that the reaction was complete, washed twice with brine, dried over anhydrous sodium sulfate, and filtered to obtain compound 3a The solution was used directly for subsequent reactions.

[0042] A small amount was concentrated and then chromatographed on a silica gel column (eluent: dichloromethane:n-hexane 1:1) to obtain the pure product.

[0043] 1 H-NMR (CDCl 3 ,300MHz)δ(ppm)...

Embodiment 2

[0045] (3aR,4R,5R,6aS)-4-((S,E)-3-(tert-butyldiphenylsilyloxy)-5-phenylpent-1-en-1-yl)hexahydro-2H- Cyclopentano[b]furan-2,5-diol (4a)

[0046] Add 140 milliliters of dichloromethane to the solution of Example 1, lower the temperature to -60 degrees under nitrogen protection, add 130 milliliters of 25% DIBAL toluene solution dropwise, and finish adding in about 60 minutes. Keep stirring at -60 degrees for 1.5 hours, slowly Add 70 ml of water to destroy excess DIBAL, filter to remove aluminum hydroxide, and concentrate the filtrate. The residue is subjected to silica gel column chromatography (dichloromethane / methyl tert-butyl ether 1:1) to obtain compound 4a, 15.4 g.

[0047] 1 H-NMR (CDCl 3 ,300MHz)δ(ppm)1.05(s,9H),1.64-2.05(m,6H),2.10-2.29(m,2H),2.58(m,2H),3.60(m,1H),4.19(m, 1H),4.46-4.55(m,1H),5.02(m,1H),5.46-5.62(m,2H),7.09(m,2H),7.16(m,1H),7.22-7.25(m,2H) ,7.34-7.45(m,6H),7.66(m,4H).

Embodiment 3

[0049] (Z)-7-((1R,2R,3R,5S)-2-((S,E)-3-(tert-butyldiphenylsiloxy-5-phenylpent-1-en-1-yl )-3,5-dihydroxycyclopentyl)hept-5-enoic acid (5a)

[0050] Add 50 g of compound 7 (4-carboxybutyl-triphenylphosphine bromide) and 150 ml of anhydrous THF to a 500 ml three-necked flask, add 25.5 g of potassium tert-butoxide in batches under nitrogen protection, stir for 30 minutes, and cool down To 0 to 10 degrees, dropwise add a solution of 14.5 grams of 4a and 25 milliliters of THF, about 20 minutes to complete the addition, maintain 0 to 10 degrees and stir for 1 hour. Naturally rise to room temperature and stir for 10 to 20 hours. Remove most of the solvent under reduced pressure , the residue was dissolved in 300 ml of aqueous solution with 0.6 g of potassium carbonate, the aqueous layer was adjusted to PH=4-5 with 1N hydrochloric acid, 200 ml of MTBE was added, filtered, and the filter cake was rinsed twice with MTBE. The filtrate was separated and the organic phase was combined , an...

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Abstract

The invention relates to a novel method for synthetizing prostaglandin analogues, and an important intermediate compound related to the novel method. The method comprises the steps of (a), just protecting 15-site hydroxyl of the compound of a formula 2 by utilizing a hydroxyl protection group under an alkaline condition; (b) restoring a lactone ketone group from DIBAL (diisobutylaluminium hydride) to obtain the intermediate of a formula 4; (c) carrying out Wittig reaction on the intermediate of the formula 4 by utilizing 4-carboxy butyl-triphenylphosphine bromide, carrying out esterification or amidation after connecting an alpha chain; (d) removing 15-site hydroxyl protection group to obtain the prostaglandin analogue of the formula 1. The method is less in side reaction, easy to monitor, and convenient to separate due to the fact that the difference between a crude product and the polarity of a process material is large.

Description

technical field [0001] The invention relates to a new method for synthesizing prostaglandin analogues and intermediate compounds involved in the new method. Background technique [0002] Prostaglandin (PG) is a group of important active substances widely present in mammals and human body. Its chemical nature is unsaturated fatty acid with 20 carbon atoms. The basic skeleton of PG is prostanoic acid, which has a cyclopentane core and two side chains. Prostaglandins can be divided into types A, B, C, D, E, F, G, H, and I according to the five-membered ring or the entire molecular structure. More studies are E, F, A, B, I type (ie PGE, PGF, PGA, PGB, PGI). The prostaglandin drug PGF2α is currently considered to be the most potential and effective drug for lowering intraocular pressure in the eye, and its effect of lowering intraocular pressure is mainly achieved by improving the drainage of aqueous humor through the uveal sclera pathway rather than the classic trabecular netw...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C405/00C07F7/18
CPCY02P20/55
Inventor 杨波庞智斌崔柏林李延华
Owner 北京洛斯顿精细化工有限公司
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