Fluorophenyl esters

The major side reaction to the desired acylation product is hydrolysis of the anhydride. In aqueous solutions, anhydrides may breakdown by the addition of one molecule of water to yield two unreactive carboxylate groups. The presence of an excess of the anhydride in the reaction medium usually is used to minimize the effects of competing hydrolysis. 

Since both hydrolysis and acylation result in the release of carboxylic acid functionalities, the medium becomes acidic during the course of the reaction. This requires either the presence of a strongly buffered environment to maintain the pH or periodic monitoring and adjustment of the pH with base as the reaction progresses. 

Fluorophenyl esters react with amine-containing molecules at slightly alkaline pH values to give the same amide bond linkages as NHS esters (Reaction 15). However, in most cases, the fluorophenyl ester compound will display better stability toward hydrolysis in aqueous solution. It has been reported that a TFP ester has over twice the half-life in basic pH buffers (pH 8) than a corresponding NHS ester on the same compound (Molecular Probes). 

Fluorophenyl ester compounds can be coupled to amines at a pH range of 7-9, with 0.1 M sodium bicarbonate, pH 8, a suggested reaction medium. 

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The very first investigations on this topic indicated that racemization can be monitored in micro reactors and that the degree of racemization seems not to be higher than in conventional organic synthesis. For dipeptide formation from the penta-fluorophenyl ester of (Ji)-2-phenylbutyric acid and (S)-a-methylbenzylamine, racemization of 4.2% was found [158]. At higher concentration (0.5 M instead of 0.1 M), a higher degree of racemization was found (7.8%). 

Figure 2.1 Three types of fluorophenyl esters have been used for coupling to amine-containing molecules. The PFP and TFP esters are relatively hydrophobic and typically have better stability toward hydrolysis in aqueous solution than NHS esters. The STP ester is water-soluble due to the negatively charged sulfonate group, and it provides better solubility to associated crosslinkers or bioconjugation reagents similar to that of a sulfo-NHS ester group.

Because O-glycosylation can also be accomplished with active esters (e.g., penta-fluorophenyl esters) [11] of Fmoc serine and threonine, the Fmoc technique provides a general method for the synthesis of glycopeptides. Thomsen-Friedenreich antigen glycopeptides and neoglycoproteins have been obtained by this method in preparative amounts [12], In combination with acid-labile polymeric benzyl ester anchors, this Fmoc technique was applied to solid-phase syntheses of glycopeptides [11,13,14]. 

Hydroxy-3-oxo-2,5-diphenyl-2,3-dihydrothiophene 1,1-dioxide (TDO, 8 see Table 1) es-tersP l have been described which can incorporate the first anoino acid onto hydroxymethyl resins with minimal racemization.P l The use of other active esters, such as penta-fluorophenyl esters, requires the use of DMAP, which carries the risk of racemization. 

Fluorophenyl)-3-fluoro-2-hydroxy-6-oxo-6/7-pyrido[],2-n]pyrimidine-7-carboxylic acid (197, R = 4-FPh, R = H) was obtained from the 2-(4-methyl-]-piperazinyl)-7-ester derivative by the treatment with 1 N NaOH in an 1 1 mixture of H2O and THF at room temperature for 6h (95MIP1, 96JMC3070, 96MIP4, 96USP5580872). 

Chemical Name 7-Chloro-5-(2-fluorophenyl)-2,3-dihydro-2-oxo-1 H-1,4-benzodiazepine-3-carboxylic acid ethyl ester... 

CN [2-amino-6-[[(4-fluorophenyl)methyl]amino]-3-pyridinyl]carbamic acid ethyl ester... 

C,4Hi C1FN02) see Sertindole [[(3-chloro-4-fluorophenyl)amino]methylene]propane-dioic acid diethyl ester... 

C, H7C1FN03 3919-74-2) see Flucloxacillin 3-(2-chloro-6-fluorophenyl)-5-methyI-4-isoxazolecarb-oxylic acid methyl ester (CijHijClFNOj 4415-09-2) see Flucloxacillin... 

C 4H,N 1529-40-4) see Indecainide [3S-[l(cis),3a,4 3]]-l-l4-cyano-4-(4-fluorophenyl)cyclo-hexyl]-3-methyl-4-phenyl-4-piperidinecarboxylic acid phenylmethyl ester (C3iH,5FN202) see Levocabastine... 

C 2HijF,N202 90357-51-0) see Bicalutamide 4 -cyano-3 -trifIuoromethylmethacrylanilide (CijHijFjNjO 90357-53-2) see Bicalutamide Af-[4-cyano-2-(trifluoromethyl)phenyl]acetamide (C (,H7F,N20 175277-96-0) see Mabuterol /V-(4-cyano-3-trifluoromethylphenyl)-3-(fluorophenyl-sulfanyl)-2-hydroxy-2-methylpropionamide (C,hH,4F4N202S 90356-78-8) see Bicalutamide 2-cyano-3-(3,4,5-trimethoxyphenyl)-2-propenoic acid ethyl ester... 

C41H44FN3O4) see Atorvastatin calcium [/t-(/f JJ )]-2-(4-fluorophenyl)-p,6-dibydroxy-S-(l-me-thylethyl)-3-phenyl-4-[(phenylamino)carbonylJ-lff-pyr-role-l-heptanoic acid 1,1-dimethylethyl ester (C37H43FN2O5 134395-00-9) see Atorvastatin calcium... 

The medicinal chemists subsequently discovered an improved route to racemic acid 9 that started with 2-bromo-2-cyclopente-l-one 11 (Scheme 7.2) [5]. Suzuki-Miyaura cross-coupling of 11 with 4-fluorophenyl boronic acid 12 provided 13 in 67% yield. Conjugate addition of cyanide furnished ketone 14 in 71% yield. Reduction of 14 with NaB H4 gave a 2.8 1 mixture of desired 15 and undesired 16 which were separated by silica gel chromatography. The observed diastereoselec-tivity with the cyano group was similar to ester 6. Hydrolysis of 15 with 5 M NaOH in MeOH gave racemic acid 9 in 91% yield, which was resolved as outlined in Scheme 7.1. 

The treatment of 2-fluorophenyl-2-iodophenyl ethers, amines, and thioethers with 3.3 equivalents of f-BuLi and further reaction with selected electrophiles gave rise to functionalized carbazoles, dibenzofurans, and dibenzothiophenes in a direct and regioselective manner. A selected example is illustrated below <06JOC6291>. Benzyl 2-halophenyl ethers was treated with f-BuLi, and then reacted with carboxylic esters to give 2,3-disubstituted benzo[t>]furans <06JOC4024>. 

Gyclocondensation of diazomalonaldehyde 336 with 4-fluoroaniline carried out in methanol-acetic acid provides l-(4-fluorophenyl)-l,2,3-triazole-l-carbaldehyde 337 in 78% yield. Oxidation with MnOz in the presence of sodium cyanide in methanol converts aldehyde 337 into methyl ester 338 with 79% yield. Hydrazide 339 (84% yield) is obtained in a reaction of ester 338 with hydrazine. Product 339 reacts with various aromatic aldehydes to give hydrazones possessing interesting antiplatelet activity (Scheme 53) <2003BMC2051>. 

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