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Novel method of synthesizing tafluprost

A technology of tafluprost and compound, applied in the field of intermediate compounds

Active Publication Date: 2014-05-21
TIEN TIANJIN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Because the prostaglandin product containing 15-difluoro in the omega chain is currently only tafluprost, the intermediate of this route after the fluorination step can only be used in the production of tafluprost

Method used

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  • Novel method of synthesizing tafluprost
  • Novel method of synthesizing tafluprost
  • Novel method of synthesizing tafluprost

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] (Z)-7-((1R,2R,3R,5S)-5-Acetoxy-2-((E)-3-oxo-4-phenoxybut-1-en-1-yl)- Isopropyl 3-((tetrahydro-2H-pyran-2-yl)oxy)cyclopentyl)hept-5-enoate 2.

[0049] 2.6 g of dimethyl 2-oxo-3-phenoxypropylphosphonate 7 was dissolved in 30 ml of toluene, and 0.42 g of LiOH.H 2 O, 0.05 g of tetrabutylammonium bromide, stirred at -20°C for 1 hour. Added 5 g of (Z)-7-((1R,2R,3R,5S)-5-acetoxy-2-formyl-3 -((Tetrahydro-2H-pyran-2-yl)oxy)cyclopentyl)hept-5-enoic acid isopropyl ester 1 and 60 ml of toluene mixed solution, continue to stir for 24 hours, TLC detects that raw material 7 remains , the reaction solution was washed twice with brine, dried over anhydrous sodium sulfate, and concentrated to obtain 4.4 g of a light yellow liquid of 2. The yield was 78.5%. It was directly used in subsequent reactions. A small sample was purified by silica gel, ethyl acetate / n-hexane (1:2) was eluted to obtain 2 as a yellow liquid. 1 H-NMR (CDCl 3 ,300MHz)δ(ppm):1.23(d,6H),1.45-2.05(m,13H),2.07(s,3H),...

Embodiment 2

[0051] (Z)-7-((1R,2R,3R,5S)-5-Acetoxy-2-((E)-3-oxo-4-phenoxybut-1-en-1-yl)- Isopropyl 3-((tetrahydro-2H-pyran-2-yl)oxy)cyclopentyl)hept-5-enoate 2.

[0052] Dissolve 3.6 g of dimethyl 2-oxo-3-phenoxypropylphosphonate 7 in 30 ml of dichloromethane, add 0.58 g of butyllithium, 0.05 g of tetrabutylammonium bromide, room temperature (20-30°C ) and stirred for 1 hour. Added 5 g of (Z)-7-((1R,2R,3R,5S)-5-acetoxy-2-formyl-3-((tetrahydro-2H-pyran-2- base)oxy)cyclopentyl)hept-5-enoic acid isopropyl ester 1 and 60 ml of dichloromethane mixed solution, continue to stir at room temperature for 15 hours, TLC detects that there is no residue of raw material 1, and the reaction solution is washed twice with brine , dried over anhydrous sodium sulfate, and concentrated to obtain 5.6 g of a light yellow liquid of 2. The yield was 85.4%. It was directly used in subsequent reactions.

Embodiment 3

[0054] (Z)-7-((1R,2R,3R,5S)-5-Acetoxy-2-((E)-3-oxo-4-phenoxybut-1-en-1-yl)- Isopropyl 3-((tetrahydro-2H-pyran-2-yl)oxy)cyclopentyl)hept-5-enoate 2.

[0055] 6.1 g of 2-oxo-3-phenoxypropyl phosphonic acid dimethyl ester 7 was dissolved in 45 ml of tetrahydrofuran, added 1.0 g of t-BuOK, 0.05 g of tetrabutylammonium bromide, and stirred at 80°C for 1 hour. Added 5 Gram (Z)-7-((1R,2R,3R,5S)-5-acetoxy-2-formyl-3-((tetrahydro-2H-pyran-2-yl)oxy)cyclopentene Base) the mixed solution of isopropyl hept-5-enoate 1 and 60 milliliters of tetrahydrofuran, continue stirring for 1 hour, TLC detects that there is no residue of raw material 1, the reaction solution is poured into 200 milliliters of brine, and extracted with 50ml×4 ethyl acetate, The organic phases were combined, washed twice with brine, dried over anhydrous sodium sulfate, and concentrated to obtain 4.9 g of a light yellow liquid of 2. The yield was 74.9%. It was directly used in subsequent reactions.

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Abstract

The invention relates to a novel method of synthesizing tafluprost. The method comprises the following steps: after suitable protection by Corey Lactone, reducing by DIBAL (Diisobutylaluminium hydride); carrying out Wittig reaction, carboxyl protection and Swern oxidization to obtain a universal intermediate compound 1; and by taking the intermediate 1 as a raw material, carrying out reactions to obtain tafluprost (deprotection step is not taken into consideration, and fluorination is the last step) and a plurality of intermediate products. The intermediate 1 is connected with different omega chains to synthesize other various prost analogues such as misoprost, travoprost and latanoprost. 2-4 prost analogues can be further used for synthesizing other 16-phenoxyl prost.

Description

technical field [0001] The present invention relates to a new method of tafluprost and intermediate compounds involved in the new method. Background technique [0002] Tafluprost, a new prostaglandin derivative launched by Merk, is the first preservative-free prostaglandin analogue eye drops for the treatment of open-angle glaucoma. The mescleral route drains, thereby reducing intraocular pressure. [0003] The synthesis of tafluprost generally adopts Corey Lactone as a raw material, through oxidation, connection of ω chain, fluorination, DIBAL reduction, Wittig reaction connection of α chain, esterification and corresponding protection and deprotection steps to obtain the final product, such as Tetrahedron Letters45( 2004) 1527-1529 [0004] [0005] In this route, the omega chain is first connected, and the 15-position is fluorinated to obtain tafluprost by a conventional method for synthesizing PG. Because the prostaglandin product containing 15-difluoro in the omeg...

Claims

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Application Information

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IPC IPC(8): C07C69/734C07C69/736C07C67/317C07C67/30C07C67/307
CPCC07C67/307C07C67/317C07C69/736C07C405/0025C07C2601/08
Inventor 杨波彭乐
Owner TIEN TIANJIN PHARMA
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