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

Abstract

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 ...

General Method for the 11C‐Labeling of 2‐Arylpropionic Acids and Their Esters: Construction of a PET Tracer Library for a Study of Biological Events Involved in COXs Expression

“…[17] All precursors and authentic samples were prepared according to conventional synthetic methods or purchased as described in the Experimental Section. [18] Radiochemistry: Scheme 1 illustrates the syntheses of 11 C-labeled 2-arylpropionic acids and their esters; the syntheses were based on rapid C-[ GBq. The addition of ascorbic acid as an antioxidant stabilizer to the reaction mixture before the HPLC purification also effectively prevented the radiolysis.…”

“…After addition of a solution of 10 % formic acid in acetonitrile (300 mL), the mixture was diluted with 50 % acetonitrile in water (300 mL). The given reaction mixture was injected into preparative HPLC (mobile phase: acetonitrile/10 mm sodium phosphate buffer (pH 7.4) 34:66; column: COS-MOSIL, 5C 18 www.chemeurj.org 250 mm, 5 mm; flow rate: 10 mL min À1 ; UV detection: 220 nm; retention time: 16 min). The total synthesis time including HPLC purification and radiopharmaceutical formulation for intravenous administration was 42 min.…”

Chemo-enzymatic fluorination of unactivated organic compounds

“…2a,c). While preparation of α-fluoro derivatives of this compound is straightforward,13 incorporating fluorine atoms in the poorly reactive isobutyl group is not. The general procedure described above enabled us to identify two chemo-enzymatic routes to achieve this goal in a selective (position 1: 75%; position 2: 100%) and efficient manner (yields over two steps for 15 and 16 were 62% and 84%, respectively) and at preparative scales (150–200 mg).…”

A New Method for Production of Chiral 2-Aryl-2-fluoropropanoic Acids Using an Effective Kinetic Resolution of Racemic 2-Aryl-2-fluoropropanoic Acids

“…With this trend, an increasing number of strategies for the syntheses of fluorinated drugs, which include the chiral quaternary carbons bonding with a fluorine atom, has been established [ 2 ]. Among these compounds, the 2-aryl-2-fluoropropanoic acids, such as 2-fluoroibuprofen, a fluorinated analogue of non-steroidal anti-inflammatory drugs (NSAIDs), have been frequently synthesized by several groups [ 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 ], because the substitution of a fluorine atom for a hydrogen atom at the α -positions in the 2-aryl-2-fluoropropanoic acids prohibits the unwanted epimerization of NSAIDs, which converts them from the biologically active chiral forms to less active epimerized forms in vivo [ 14 , 15 , 16 ].…”

“…Schlosser et al kinetically separated a racemic mixture of carboxylic esters by enantioselective hydrolysis using lipase in 1996 [ 4 ]. On the other hand, Takeuchi et al transformed a racemic mixture of carboxylic acids into a diastereomeric mixture of esters by esterification with a chiral alcohol, (–)-carenediol, and then they separated them by column chromatography in 2005 [ 5 ]. However, the former protocol required strict validations of the conditions and substrate tolerance of enzymes, while the latter presented difficulties in the quantitative use of the expensive chiral alcohol.…”