Convenient routes to 2-aryl-2-fluoropropionic acids: Synthesis of monofluorinated analogues of (±)-ibuprofen, (±)-naproxen and related compounds

Goj, O.; Kotila, Sirpa; Haufe, Günter

doi:10.1016/0040-4020(96)00758-2

Cited by 48 publications

(20 citation statements)

References 28 publications

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“…Its formation results from the presence of water in the substrate, which is a highly hygroscopic compound. In some cases, the reaction performed at room temperature (entries 6,11,12) or over a longer period of time (entry 7) gave comparable or better results compared to the standard conditions.…”

Section: Resultsmentioning

confidence: 80%

“…[5] Schlosser obtained a 2-fluorinated analogue of ibuprofen by treating the corresponding hydroxyl derivative with diethylaminosulfur trifluoride (DAST). [3] A route via 2-aryl-2-fluoropropanols prepared from 2-arylpropene oxides by BF 3 -catalysed ring-opening was described by Haufe et al [6] 2-Aryl-substituted perfluoropropionic acids have been rarely investigated. Their potentially interesting properties were first pointed out by Ricci and Ruzziconi, who elaborated a general approach to the synthesis of 2-phenanthryl-2-fluoropropionic and 2-phenanthrylperfluoropropionic esters and acids.…”

Section: Introductionmentioning

confidence: 99%

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New Synthesis of 2‐Heteroarylperfluoropropionic Acids Derivatives by Reaction of Azine N‐Oxides with Hexafluoropropene

Loska

Mąkosza

2008

Chemistry A European J

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Hexafluoropropene reacts with aromatic azine N-oxides under mild conditions to produce fluorides of 2-heteroarylperfluoropropionic acids. The reaction proceeds as 1,3-dipolar cycloaddition followed by spontaneous scission of the N--O bond in the isoxazolidine ring and elimination of HF. When the reaction is carried out in the presence of alcohols or N-alkyl anilines, the in situ formed acyl fluorides give the corresponding esters and amides. They can be also treated separately with nucleophiles to produce the respective acylation products, whereas their hydrolysis leads to unstable carboxylic acids that undergo spontaneous decarboxylation to 1-aryl-1,2,2,2-tetrafluoroethanes. This new reaction provides a simple and general method of synthesizing 2-heteroarylperfluoropropionic acid derivatives that were previously unknown and unavailable.

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Section: Resultsmentioning

confidence: 80%

Section: Introductionmentioning

confidence: 99%

New Synthesis of 2‐Heteroarylperfluoropropionic Acids Derivatives by Reaction of Azine N‐Oxides with Hexafluoropropene

Loska

Mąkosza

2008

Chemistry A European J

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“…First enantiopure amine-HF-reagents, such as (S)-N,N-dimethyl-phenylethylamineÁ3HF have been applied, but the ee never exceeded 2% [146]. Almost 10 years ago we realized that epoxide ring opening with neat Et 3 NÁ3HF, which needs elevated temperature, can be catalyzed with BF 3 ÁOEt 2 without loss of regio-and diastereoselectivity and then occurred at room temperature [147,148]. Thus, it was obvious to apply chiral Lewis acids in combination with hydrofluorinating reagents for asymmetric ring opening of meso-and racemic epoxides.…”

Section: Synthesis By Nucleophilic Ring Opening Of Epoxidesmentioning

confidence: 99%

Regio- and stereoselective synthesis of vicinal fluorohydrins

Haufe

2004

Journal of Fluorine Chemistry

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“…1, 2), 5,6) or electrophilic fluorination of the enol silyl ether of 3a with acetyl hypofluorite (Eq. 3).…”

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confidence: 99%

“…6 A solution of methyl esters 3 or 5 (4.0 mmol) in dry THF (5 ml) was added to a stirred solution of lithium diisopropylamide [1.5 eq, prepared at 0°C from diisopropylamine and butyllithium (1.5 M in hexane) in dry THF (15 ml)] cooled at Ϫ40°C. The stirred solution was maintained at Ϫ40°C for 10 min and diluted FClO 3 gas in nitrogen [9][10][11] was introduced for 1 h. Hexane (10 ml) was added and the resulting mixture was filtered through a short column chromatography on silica gel to remove polar substances.…”

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confidence: 99%

Synthesis and Optical Resolution of 2-Aryl-2-fluoropropionic Acids, Fluorinated Analogues of Non-steroidal Anti-inflammatory Drugs (NSAIDs)

Fujisawa

Fujiwara

Takéuchi

et al. 2005

CHEMICAL & PHARMACEUTICAL BULLETIN

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2-Arylpropionic acids 1 are used clinically as nonsteroidal anti-inflammatory drugs (NSAIDs) (Fig. 1). The (S)-enantiomers have been considered to be pharmacologically more active than the (R)-enantiomers of these acids. 1)Nonetheless, these agents are normally marketed as racemates. This is possible because it has been shown [1][2][3][4] that an in vivo inversion at the stereogenic center converts the pharmacologically less active (R)-enantiomers into the more active (S )-enantiomers, thereby obviating a prior separation of enantiomers.Owing to this in vivo epimerization, it is difficult to examine and clarify the medicinal actions or metabolism of each enantiomer closely. The replacement of hydrogen with fluorine can produce isosteric analogues (pseudologues) that often mimic the parent with respect to biological behavior. Therefore, to provide tools to study the in vivo behavior of the individual enantiomers of these NSAIDs, we have prepared a series of chiral non-epimerizable 2-fluorinated 2-arylpropionic acids 2 (Fig. 2).Some other groups have reported the synthesis of 2-aryl-2-fluoropropionic acid derivatives 2a, b, and 4a (RϭMe) by nucleophilic fluorination of the corresponding 2-hydroxy acids or 2-aryl epoxides with (diethylamino)sulfur trifluoride (DAST) or Et 3 N · 3HF, respectively (Eqs. 1, 2), 5,6) or electrophilic fluorination of the enol silyl ether of 3a with acetyl hypofluorite (Eq. 3).7) Laurent et al. reported the synthesis of 2-fluorinated ester 4a (RϭEt) by electrochemical oxidation in fluorinating media (Eq. 4).8) However, all of these methods require rather delicate conditions and/or many steps, and therefore, they lack synthetic generality (Chart 1).In this paper, we report an efficient and practical synthesis of 2-aryl-2-fluoropropionic acids 2 by direct fluorination of readily available 2-arylpropionic acid methyl esters 3 with diluted perchloryl fluoride (FClO 3 ), according to the convenient procedure we have reported previously.9-11) A simple and general procedure for optical resolution of the 2-fluoro acids 2 is also described. Results and DiscussionWe first attempted direct fluorination of carbanions derived from methyl ester 3a using selectfluor 12) and N-fluorobenzenesulfonimide.13) However, the yields seemed sensitive to the amount and kind of bases employed for the reaction and the results were found not to be reproducible. We then focused on fluorination using diluted FClO 3 , 9-11) considering the successful results obtained in the preparation of the structurally similar 2-cyano-2-fluoro-p-tolylacetic acid ethyl ester. 14,15) We first examined bases and temperatures for the fluorination of ibuprofen methyl ester 3a with FClO 3 in order to optimize reaction conditions (Table 1). The best result was obtained when a solution of the lithium enolate of 3a in tetrahydrofuran (THF), formed by treatment with lithium diisopropylamide (LDA) by usual procedure, was subjected to slow introduction of diluted FClO 3 , at Ϫ40°C for 1 h, to give a-fluoroibuprofen methyl ester 4a in 93% yield ...

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Convenient routes to 2-aryl-2-fluoropropionic acids: Synthesis of monofluorinated analogues of (±)-ibuprofen, (±)-naproxen and related compounds

Cited by 48 publications

References 28 publications

New Synthesis of 2‐Heteroarylperfluoropropionic Acids Derivatives by Reaction of Azine N‐Oxides with Hexafluoropropene

New Synthesis of 2‐Heteroarylperfluoropropionic Acids Derivatives by Reaction of Azine N‐Oxides with Hexafluoropropene

Regio- and stereoselective synthesis of vicinal fluorohydrins

Synthesis and Optical Resolution of 2-Aryl-2-fluoropropionic Acids, Fluorinated Analogues of Non-steroidal Anti-inflammatory Drugs (NSAIDs)

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