209860-87-7

Basic information

• Product Name: Tafluprost
• Synonyms: 15,15-DIFLUORO-9ALPHA,11ALPHA-DIHYDROXY-16-PHENOXY-17,18,19,20-TETRANOR-PROSTA-5Z,13E-DIEN-1-OIC ACID, ISOPROPYL ESTER;AFP-168;TAFLUPROST;(5Z)-7-[(1R,2R,3R,5S)-2-[(1E)-3,3-Difluoro-4-phenoxy-1-buten-1-yl]-3,5-dihydroxycyclopentyl]-5-heptenoic acid 1-methylethyl ester;Tafluprost5-Heptenoic acid, 7-[(1R,2R,3R,5S)-2-[(1E)-3,3-difluoro-4-phenoxy-1-buten-1-yl]-3,5-dihydroxycyclopentyl]-,1-methylethyl ester, (5Z)-;209860-87-7
• CAS NO: 209860-87-7
• Molecular Formula: C25H34F2O5
• Molecular Weight: 452.53
• Mol File: 209860-87-7.mol

Chemical Properties

• Boiling Point: 552.9ºC at 760mmHg
• Flash Point: 288.2°C
• Appearance: /
• Density: 1.186
• Vapor Pressure: 4.62E-13mmHg at 25°C
• Refractive Index: 1.548
• Storage Temp.: 2-8°C
• PKA: 14.48±0.70(Predicted)
• CAS DataBase Reference: Tafluprost(CAS DataBase Reference)
• NIST Chemistry Reference: Tafluprost(209860-87-7)
• EPA Substance Registry System: Tafluprost(209860-87-7)

Safety Data

• Hazardous Substances Data: 209860-87-7(Hazardous Substances Data)

Usage

Uses

Used in Ophthalmology:
Tafluprost is used as a medication for the treatment of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension. It helps in reducing the risk of blindness caused by glaucoma, which is the second most common cause of blindness after cataracts.
By 2010, it is estimated that approximately 60 million people worldwide will be afflicted by glaucoma, making effective treatments like Tafluprost essential for a large market. Compared to other prostaglandin analogs such as latanoprost, Tafluprost has a 10-fold greater affinity for the prostanoid FP receptor (Ki=0.4 nM), making it a more potent option for glaucoma treatment.
The synthesis of Tafluprost begins with a Wittig condensation of the protected bicyclic lactone carbaldehyde with a dimethyl phosphonate ketone derivative. The bottom appendage is then completed by the fluorination of the ketone with morpholino-sulfur trifluoride. Hydrolysis of the benzoate ester protecting group liberates the hydroxy group, and reduction of the lactone is accomplished with aluminum hydride to generate the lactol. Condensation of this intermediate with the phosphonium salt of the acid side chain generates the free acid, or active ingredient, which is subsequently esterified with 2-iodopropane in the presence of DBU.

Originator

Santen/Asahi Glass (Japan)

Synthesis

The synthesis was initiated from the Corey aldehyde 131. Horner-Emmons condensation of the bicyclic carbaldehyde 131 with the dimethyl phosphonate 132 using NaH in DMF gave enone 133 in 90% yield. Fluorination of the enone 133 was accomplished upon reaction with morpholino-sulfur trifluoride (134) in chloroform to yield the corresponding difluorinated compound 135. Hydrolysis of the benzoate ester group of 135 with K2CO3 in methanol at room temperature afforded alcohol 136 in 71% yield from 133. Reduction of the lactone group of 136 with diisobutyl aluminum hydride (DIBAL) in THF/toluene gave lactol 137 in 83% yield. Lactol 137 was condensed with the phosphonium ylide prepared by deprotonation of phosphonium salt 138 with sodium bis(trimethylsilyl)amide (NaHMDS) in THF/toluene to give the prostaglandin F2-alpha derivative 139 in excellent Z/E selectivity (99:1). The synthesis was completed by esterification of compound 139 with isopropyl iodide and DBU in acetone to provide tafluprost (XVIII) in 72% yield.

InChI:InChI=1/C25H34F2O5/c1-18(2)32-24(30)13-9-4-3-8-12-20-21(23(29)16-22(20)28)14-15-25(26,27)17-31-19-10-6-5-7-11-19/h3,5-8,10-11,14-15,18,20-23,28-29H,4,9,12-13,16-17H2,1-2H3/b8-3+,15-14+

Upstream product

• 75-30-9 2-iodo-propane 
• 209860-88-8 AFP-172 
• 40665-68-7 dimethyl (3-phenoxy-2-oxopropyl)phosphonate 
• 209861-01-8 (3aR,4R,5R,6aS)-4-((E)-3,3-difluoro-4-phenoxybut-1-en-1-yl)-5-hydroxyhexahydro-2H-cyclopenta[b]furan-2-one 
• 209861-02-9 (3aR,4R,5R,6aS)-4-((E)-3,3-difluoro-4-phenoxybut-1-en-1-yl)hexahydro-2H-cyclopenta[b]furan-2,5-diol 
• 51638-91-6 (3aR,4R,5R,6aS)-2-oxo-4-((E)-3-oxo-4-phenoxybut-1-en-1-yl)hexahydro-2H-cyclopenta[b]furan-5-yl benzoate 
• 209861-00-7 (3aR,4R,5R,6aS)-4-((E)-3,3-difluoro-4-phenoxybutan-1-en-1-yl)-hexahydro-2-oxo-2H-cyclopenta[b]furan-5-yl benzoate 
• 1449413-13-1 C₂₂H₂₈F₂O₅*C₁₂H₂₃N 
• 126959-19-1 3-oxo-4-phenoxy-1-butyne 
• 1559057-73-6 propan-2-yl (5Z)-7-[(1R,2R,3R,5S)-3,5-bis(acetyloxy)-2-[(1E)-3,3-difluoro-4-phenoxybut-1-en-1-yl]cyclopentyl]hept-5-enoate 

Relevant articles and documents

Synthesis of the highly potent prostanoid FP receptor agonist, AFP-168: A novel 15-deoxy-15,15-difluoroprostaglandin F2α derivative

A novel 15-deoxy-15,15-difluoro-prostaglandin(PG)F2α derivative 6 (AFP-168) has been synthesized from the Corey aldehyde in six steps. A key aspect of this route is difluorination of an enone and a stereoselective Wittig reaction. The compound shows high affinity to the FP receptor and potent activities for an anti-glaucoma agent.

Method for purifying tafluprost

The purpose of the present invention is to provide a simple and efficient method for purifying tafluprost that can be scaled up in proportion. The present invention relates to the method for purifying tafluprost, which comprises a step for purifying a crude product of tafluprost by silica gel column chromatography and collecting a component containing tafluprost by HPLC analysis. In addition, the present invention also relates to a method for producing tafluprost, which comprises the aforementioned method for purifying tafluprost.

Method for large-scale preparation of tafluprost

The invention discloses a method for industrially preparing tafluprost. The method comprises the following steps: taking Corey lactone as an initial raw material, oxidizing, condensing, fluorinating,deprotecting, reducing, re-condensing, esterifying and r

An Asymmetric Suzuki-Miyaura Approach to Prostaglandins: Synthesis of Tafluprost

We report the catalytic asymmetric synthesis of Tafluprost (1), a prostaglandin analogue. This synthesis demonstrates a new approach to prostaglandins involving symmetrization and desymmetrization of a racemic precursor to control the absolute and relative stereochemistry of the cyclopentyl core. Key steps include a diastereo- and enantioselective Rh-catalyzed Suzuki-Miyaura reaction of a racemic bicyclic allyl chloride and an alkenyl boronic acid and a regio- and diastereoselective Pd-catalyzed Tsuji-Trost reaction with an enolate surrogate.

Crystal form of metallic salt compound of Tafluprost acid and preparation method of crystal form

The invention relates to a crystal form of a metallic salt compound of Tafluprost acid and a preparation method of the crystal form. Specifically, the invention relates to the crystal form of the metallic salt compound of Tafluprost acid, the preparation method of the crystal form and a method for preparing Tafluprost from the metallic salt compound of Tafluprost acid. According to the method, reaction yield is increased, isomer impurities are reduced, and the method is simple and easy to control and facilitates industrial expanded production.

Preparation method of high-purity Tafluprost and analogs thereof and intermediate compound

The invention belongs to the technical field of medicine, and relates to a preparation method of Tafluprost and analogs thereof and a related intermediate compound. The preparation method is characterized in that (4-carboxybutyl)triphenylphosphonium bromide having a structure shown below is used as a witting reaction reagent, wherein R is alkyl or aryl. The method is simple, feasible and convenient for industrial production; and the Tafluprost and analogs thereof which are basically free of omega chain trans-isomers can be prepared.

Preparation method of Tafluprost

The invention discloses a preparation method of Tafluprost. The preparation method comprises the following steps: adopting a compound of formula 1 as a raw material, and carrying out the steps of DIBAL-H reduction, a Wittig reaction and an esterification reaction, wherein alkaline amino acids are adopted for refining after the Wittig reaction. According to the preparation method disclosed by the invention, the total mass yield of the three-step reaction can reach 70%, the technology is stable, a prepared Tafluprost product is colorless or faint yellow thick oily liquid, and the purity reaches up to more than 99%.

A novel convergent synthesis of the potent antiglaucoma agent tafluprost

Tafluprost (AFP-168, 5) is a unique 15-deoxy-15,15-difluoro-16-phenoxy prostaglandin F2α (PGF2α) analog used as an efficacious ocular hypotensive agent in the treatment of glaucoma and ocular hypertension, as monotherapy, or as adjunctive therapy to β-blockers. A novel convergent synthesis of 5 was developed employing Julia-Lythgoe olefination of the structurally advanced prostaglandin phenylsulfone 16, also successfully applied for manufacturing of pharmaceutical grade latanoprost (2), travoprost (3) and bimatoprost (4), with an aldehyde !-chain synthon 17. The use of the same prostaglandin phenylsulfone 16, as a starting material in parallel syntheses of all commercially available antiglaucoma PGF2α analogs 2-5, significantly reduces manufacturing costs resulting from its synthesis on an industrial scale and development of technological documentation. Another key aspect of the route developed is deoxydifluorination of a trans-13,14-en-15-one 30 with Deoxo-Fluor. Subsequent hydrolysis of protecting groups and final esterification of acid 6 yielded tafluprost (5). The main advantages are the preparation of high purity tafluprost (5) and the application of comparatively cheap reagents. The preparation and identification of two other tafluprost acid derivatives, tafluprost methyl ester (32) and tafluprost ethyl amide (33), are also described.

A method for synthesizing his row elementbefore the fluorine,

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 an

METAL-CATALYZED ASYMMETRIC 1,4-CONJUGATE ADDITION OF VINYLBORON COMPOUNDS TO 2-SUBSTITUTED-4-OXY-CYCLOPENT-2-EN-1-ONES YIELDING PROSTAGLANDINS AND PROSTAGLANDIN ANALOGS

This invention provides a novel method for the preparation of 2,3-disubstituted-4-oxy-cyclopentan-1-one compounds that are useful for the synthesis of prostaglandins and prostaglandin analogs of industrial relevance. The method comprises the metal-catalyzed asymmetric 1,4-conjugate addition of vinylboron compounds to 2-substituted-4-oxy-cyclopent-2-en-1-ones. This method relies on the use of less toxic, easily-handled reagents, and can be performed under milder conditions than offered by some conventional methods, affording 2,3-disubstituted-4-oxy-cyclopentan-1-one compounds enantio- and diastereoselectively, which are precursors to the said prostaglandin and prostaglandin analogs, in high yield.