3- fluorophenyl methyl ether

Catalyst 19, which contains the 3-fluorophenyl methyl ether, was found to be the most effective for the epoxidation of (fc)-a,P-unsaturated sulfones (Scheme 5.17). Of note, the (Z)-configured sulfone was converted under the same optimized conditions into the corresponding ds-a,P-cpoxysulfonc, but with a lower enantios-electivity (16% ee). 

Kofler) and dihydrochloride of l-p,p -difluorobenzhydryl piperazine, melting point 178°-180°C (capillary) in anhydrous dimethylformamide are heated under reflux. On completion of this operation the solvent is removed under vacuum and the residue taken up in a mixture of chloroform and of water (1 1). The organic phase is separated, and repeatedly extracted with aqueous N-methanesulphonic acid and the aqueous acidic layers separated. The aforementioned acidic solutions are then combined and rendered alkaline (pH 10) with dilute aqueous sodium hydroxide, the base extracted with ether, the extract dried over anhydrous potassium carbonate, and filtered. The etheral filtrate, upon evaporation yields the 2,4-bis(allylamino)-6-(4-(bis(p-fluorophenyl)methyl)-l-piperazinyl)-s-triazine, melting point 175°-180°C. 

Bromo-l-(4-fluorophenyl)-l-(3-dimethylaminopropyl)-l,3-dihydroisobenzofuran Magnesium Butyl lithium tert-Butyl methyl ether Isopropylmagnesium chloride Thionyl chloride Sulfamide Dry ice... 

To a solution of 5-bromo-l-(4-fluorophenyl)-l-(3-dimethylaminopropyl)-1,3-dihydroisobenzofuran (9 g, 0.024 mole) in tertbutyl methyl ether (150 mL) was added n-BuLi (1.6 M in hexanes, 40 mL) at -78 to -65°C. The temperature of the solution was allowed to raise to -30°C over a period of 2 hours. The reaction mixture was added to dry solid C02 (50 g). After addition, the mixture was left at room temperature for 16 hours. The volatile materials were removed in vacuo and the residue was taken up in water (100 mL). pH was adjusted to 5.5 by adding HCI (aqueous, 4 N). The aqueous phase was extracted with toluene (100 mL). The toluene was removed in vacuo and the 5-carboxy-l-(4-fluorophenyl)-l-(3-dimethylaminopropyl)-l,3-dihydroisobenzofuran was obtained as an oil. Yield 7.5 g. 

A mixture of 5.0 g (0.0357 g/mol) of p-fluorophenylethyl alcohol, 2.0 g (0.007 g/mol) of 5-chloro-2,4-disulphamylaniline, 2.0 g (0.0068 g/mol) of potassium bichromate and 15 ml of concentrated hydrochloric acid (0.176 g/mol) and 25 ml of water is heated under reflux for 1 h. The mixture is allowed to cool, and 15 ml of ether are added to separate the excess of p-fluorophenylethyl alcohol. The aqueous layer is decanted and frozen for 2 h and the precipitate is separated, washed with water and dried in vacuum over phosphoric anhydride. There are collected 1.35 g (yield 47.5%) of the 1,1-dioxide of 3-p-fluorophenyl-methyl-7-sulphamyl-6-chloro-3,4-dihydrobenzo-l,2,4-thiadiazine, which when recrystallised from 30 ml of 50% alcohol on "Norit" active carbon takes the form of a white crystalline substance, melting point is 239°C. 

A suspension of 6-aminopenicillanic acid (36.4 grams) in water was adjusted to pH 7.2 by the addition of N aqueous sodium hydroxide and the resulting solution was treated with a solution of 3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-carbonyl chloride (46.1 grams) in isobutyl methyl ketone. The mixture was stirred vigorously for hours and then filtered through Dicalite. The layers were separated and the isobutyl methyl ketone layer was shaken with saturated brine. Then, precipitation of the sodium salt only took place after dilution of the mixture with ether. In this way there was obtained 60.7 grams of the penicillin sodium salt having a purity of 88% as determined by alkalimetric assay. 

A solution of 60 g of chromic anhydride in 40 ml of water was added dropwise to a suspension of 60 g of 2-aminomethyl-1 -methyl-5-chloro-3-(o-fluorophenyl)-indole hydrochloride in 600 ml of acetic acid. The mixture was stirred at room temperature overnight. To the reaction mixture was added 1.1 liters of ether and 1 liter of water and then 800 ml of 28% ammonium hydroxide, in small portions. The ethereal layer separated, washed with water, dried, and concentrated under reduced pressure. The residue (51.8 g) was dissolved in 100 ml of ethanol, and 100 ml of 20% ethanollc hydrogen chloride was added to the solution and the mixture was cooled. The precipitate was collected by filtration to yield 46.5 g of 1 -methyl-7-chloro-5-(o-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one hydrochloride, melt-... 

Removal of the solvent gave an oil which was taken up In ether and filtered through a pad of Woelm grade I alumina. The eluent was concentrated and the residue was crystallized from methylene chloride/hexane yielding 1-methyl-7-nitro-5-(2-fluorophenyl)-3H-1,4-benzo-diazepin-2(1 H)-one as pale yellow needles melting at 166° to 167°C. 

A mixture of this material with 500 ml of toluene end 30 g of manganese dioxide wes heated to reflux for 1 A hours. The mangenese dioxide wes seperated by filtration over Celite. The filtrate wes evaporated and the residue was crystallized from ether to yield 6-chloro-6-(2-fluorophenyl)-1 -methyl-4H-imidazo[1,5-a] [1, 4] -benzodiazepine, melting point 152°C to 154°C. The analytical sample was racrystallized from methylene chloride/hexane. 

A warm solution of 6.5 g (0.02 mol) of 6-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo-[13-a] [1,4] -benzodiazepine in 30 ml of ethenol wes combined with a warm solution of 2.6 g (0.022 mol) of maleic acid in 20 ml of ethenol. The mixture was diluted with 150 ml of ether and heated on the steam bath for 3 minutes. After cooling, the crystals were collected, washed with ether and dried in vacuo to yield 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazoM, 5-a] [1,4] -benzodiazepine maleete, melting point 148°C to 151°C. 

To a mixture of 4.4 parts of 4-(2-oxo-1 -benzimidazolinyD-piperidine, 3.3 parts sodium carbonate, a few crystals of potassium iodide in 200 parts 4-methyl-2-pentanone are added por-tionwise 6.2 parts 1 -chloro-4,4-di-(4-fluorophenyl)-butane. After the addition is complete, the whole is stirred and refluxed for 65 hours. After cooling the reaction mixture, there are added 70 parts water. The organic layer is separated, dried over potassium carbonate, filtered and evaporated. The solid residue is triturated in diisopropyl-ether, filtered off again and recrystallized from a mixture of 120 parts acetone and 80 parts 4-methyl-2-pentanone, yielding the crude product. After recrystallization of this crop from 80 parts acetone, 1-(4,4-di-(4-fluorophenyD-butyl] -4-(2-oxo-1 -benzimidazolinyD-piperidine is obtained, melting point 217°Cto2l9°C. 

Electrochemical oxidation of alkyl aryl ethers results in oxidative dealkylation and coupling of the intermediate radicals. Electro-oxidation of alkyl (4-fluorophenyl) ethers in the presence of a hydrogen fluoride double salt leads to 4,4-difluorocyclohexa-2,5-dienone in 50% yield (Table 10).182 In the electrochemical oxidation of methyl tetrafluorophenyl ethers with a hydrogen atom at the para position, coupled products 6 arc obtained.183 If the para position in the substrate is occupied by a fluorine substituent, then no reaction occurs. 

The chemistry involved in nucleophilic aromatic substitution is well reflected in the reactions of a variety of nucleophiles with methyl penta-fluorophenyl ether (Ingemann et al 1982a). For most of the nucleophiles such as alkoxide, thiolate, enolate and (un)substituted allyl anions, the dominant reaction channel is the attack upon the fluoro-substituted carbon atoms, as is the case for OH-. The latter ion reacts approximately 75% by attack upon the fluoro-substituted carbon atoms and the remaining 25% by Sn2 (20%) and ipso (5%) substitution as summarized in (41). In the attack upon the fluorinated carbon atoms, the interesting observation is made that a F- ion is displaced via an anionic o-complex to form a F- ion/molecule complex, which is not observed to dissociate into F- as a free ionic product. 

The initial synthesis of aprepitant (1), which relies on a Tebbe olefination and reduction to install a methyl group on the benzyl ether side chain, is shown in Scheme 3.8,19 The initial steps are from a literature-precedented synthesis of p-fluorophenyl glycine based on conversion of chiral oxazolidinone 33 to azide 34. Formation of morpholinone intermediate 36 proceeds via benzylation and reaction with 1,2-dibromoethane. 

Acetic anhydride (10.96 mmol) was added to l-(4-fluorophcnyl-3(//)-(3(.S )-hydroxy-3-(4-fluorophenyl)propyl))-4(5)-(4-hydroxyphenyl)-2-azetidinone (4.98 mmol) containing dimethylaminopyridine (11.96 mmol) dissolved in 15 ml THF and the reaction monitored by TLC using 5% methyl alcohol/toluene. Thereafter, the mixture was then diluted with diethyl ether, washed with 1M HC1 and brine, and dried using Na2S04. The solution was concentrated and the product isolated in 100% yield and used without additional purification. 

Figure 1. Chemical structures of four typical peroxidizing compounds chlorophthalim, N-(4-chlorophenyl)-3,4,5,6-tetrahydrophthalimide oxadiazon, 3-(2,4-dichloro-5-isopropoxyphenyl)-5-tert-butyl-l,3,4-oxadiazol-2(3H)-one oxyfluorfen, 2-chloro-4-(trifluoromethyl)pheny1-3-ethoxy -4-nitroDhenyl ether LS 82-556, (S)3-N-(methylbenzyl)-carbamoyl-5-propionyl-2,6-lutidine. Also 2,4,5-phenylsubstituted pyrimidinediones exhibit peroxidizing activity, e.g. 3-(4-chloro-5-ethoxy-2-fluorophenyl)-l-methyl-6-(trifluoromethyl) -2,4(lll,3H)pyrimidinedione (34).

Figure 4. Degree of polymerization ( ) and polydispersity (O) resulting from cationic polymerizations of (a) 5-[(4 -(4"-cyanophenyl)phenoxy)pentyl]vinyl ether [125, 126] and (b) 8-((4 -(2/f,3S)-2-fluoro-3-methyl-pentyloxycarbonyl)-3 -fluorophenyl-4"-phenoxy)octyl] vinyl ether [ 139] initiated by triflic acid in CH2CI2 at 0 °C in the presence of dimethyl sulfide.

Exactly 0.04 mol / -fluorobenzaldehyde and 1.5 mL 40% aqueous solution of methy-lamine were dissolved in 20 mL methanol, and the mixture was cooled to 0°C. Over a course of 1 h, 0.02 mol dimethyl oxoglutarate was added dropwise to the mixture under stirring at 0°C. The solution was allowed to stand overnight at 5°C. The resulting precipitate was filtered and washed by ether to give 3.84 g dimethyl 2,6-di-(4-fluorophenyl)-Ai-methyl-4-piperidone-3,5-dicarboxylate, in a yield of 46%, m.p. 128-130°C. When no precipitate formed, the solvent was removed in vacuo at 40-50°C, and the remaining residue was dissolved in ethanol or treated with Et20 to obtain the crystal. 

The replacement of a nitrile with a carboxylic acid group is the least detrimental transformation, and is an example of an atypical bioisosteric replacement. Moreover, there are a few others that add polarity to the molecule, such as methyl to methyl amide, addition of a isobutyric acid, 1,2-phenyl to 2,3-pyridine, and 2,3-pyridine to 2,3-pyrazine groups. Interestingly, the substitution of a methyl with an exotic trifluoromethyl ether moiety [34] is bioisosteric, even though there is a considerable increase in lipophilidty. This is also the case for the replacement of the more metabolically labile isopropyl ether with the cydopropyl group. Finally, a little considered bioisosteric transformation is 2-thiophene to para-fluorophenyl, which has been very recently proposed in a large-scale MMP analysis [35]. 

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