4-(2-methoxyethoxymethoxy)aniline

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-chloro-5-fluoro-N-(3-nitrophenyl)pyrimidin-4-amine (0.400 g) and 4-[(2-methoxyethoxy)methoxy]aniline (0.458 g), in ethanol (20 mL), was added acetic acid (4.65 mg). The reaction mixture was heated to reflux for 24 hr. Completion of reaction was monitored by TLC using hexane:ethyl acetate (8:2) as mobile phase. After completion of the reaction, ethanol was removed under reduced pressure at 40° C. To the residue water (25 mL) was added and mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and distilled under reduced pressure to give 0.4 g of 5-fluoro-N2-(4-((2-methoxyethoxy)methoxy)phenyl)-N4-(3-nitrophenyl)pyrimidine-2,4-diamine as a solid. The reaction mixture was heated to reflux for 24 hr Completion of reaction was removed under reduced pressure at 40° C To the residue water (25 mL) was added mixture was extracted with ethyl acetate The organic layer was dried over sodium sulfate distilled under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of Pd/C (0.5 g) in methanol (25 mL), 1-[(2-methoxyethoxy)methoxy]-4-nitrobenzene (2.35 g) was added to a 50 mL 3-neck RBF at room temperature under nitrogen atmosphere. Hydrogen gas was bubbled through the reaction mixture for 1-2 hr at room temperature and the reaction was monitored on TLC using chloroform:methanol (9.8:0.2) as mobile phase. After completion, the reaction mixture was filtered using Celite and washed with methanol. The combined filtrate was concentrated under reduced pressure at 40° C. to give 2.0 g of 4-[(2-methoxyethoxy)methoxy]aniline as a dark brown liquid. was added to a 50 mL 3-neck RBF at room temperature under nitrogen atmosphere Hydrogen gas was bubbled through the reaction mixture for 1-2 hr at room temperature After completion, the reaction mixture was filtered washed with methanol The combined filtrate was concentrated under reduced pressure at 40° C.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 510 mg (2.58 mmol) of 4-[(2-methoxyethoxy) methoxy]benzenamine (22) in 8 mL of dichloromethane and 2 mL of anhydrous pyridine (Aldrich) was added 380 mg (3.8 mmol) of succinic anhydride portionwise. The mixture was stirred at room temperature for 18 hours. To the reaction mixture was added 20 mL of methanol and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated and purified by preparative thin layer chromatography using 8:2 chloroform:methanol as an eluent to yield 420 mg (1.41 mmol, 55%) of 4-[[4-[(2-methoxyethoxy)methoxy]phenyl]amino]-4-oxobutanoic acid (23). NMR, IR and MS data confirmed the compound identity. the mixture was stirred at room temperature for 2 hours The mixture was concentrated purified by preparative thin layer chromatography

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 200 mg (0.88 mmol) of 1-[(2-methoxyethoxy) methoxy]-4-nitrobenzene (21), 100 mg of 10% Pd/C and 550 mg (8.7 mmol) of ammonium formate in 10 mL of absolute ethanol was stirred at room temperature for 18 hours. The reaction mixture was diluted with 100 mL of absolute ethanol and passed through a small pad of celite. The filtrate was concentrated and purified by silica gel column chromatography using 8:2 ethyl acetate:hexane as the eluent to yield 130 mg (0.65 mmol, 75%) of 4-[(2-methoxyethoxy)methoxy]benzenamine (22). NMR, IR and MS data confirmed compound identity. The filtrate was concentrated purified by silica gel column chromatography

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: For the synthesis of an acetaminophen FP tracer having an acyclic linker, p-Nitrophenol was protected as a methoxyethoxy methyl ether (FIG. 6). The nitro group was reduced to an amino in the presence of ammonium formate and 10% Pd--C in ethanol to yield 4-[(2-methoxyethoxy)methoxy]benzenamine (22). The amino group was succinylated and the acid derivative produced was coupled to 4'-aminomethylfluorescein. Deprotection of the methoxyethoxy ether (27) in the presence of trifluoroacetic acid yielded rac-4-[[[3',6'-dihydroxy-3-oxospiro-[isobenzofuran-1(3H),9'-[9H] xanthen]-4'-yl)methyl]amino]-N-(4-hydroxyphenyl)-4-oxobutamide (28) .

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-chloro-5-fluoro-N-(3-nitrophenyl)pyrimidin-4-amine (0.400 g) and 4-[(2-methoxyethoxy)methoxy]aniline (0.458 g), in ethanol (20 mL), was added acetic acid (4.65 mg). The reaction mixture was heated to reflux for 24 hr. Completion of reaction was monitored by TLC using hexane:ethyl acetate (8:2) as mobile phase. After completion of the reaction, ethanol was removed under reduced pressure at 40° C. To the residue water (25 mL) was added and mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and distilled under reduced pressure to give 0.4 g of 5-fluoro-N2-(4-((2-methoxyethoxy)methoxy)phenyl)-N4-(3-nitrophenyl)pyrimidine-2,4-diamine as a solid. The reaction mixture was heated to reflux for 24 hr Completion of reaction was removed under reduced pressure at 40° C To the residue water (25 mL) was added mixture was extracted with ethyl acetate The organic layer was dried over sodium sulfate distilled under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of Pd/C (0.5 g) in methanol (25 mL), 1-[(2-methoxyethoxy)methoxy]-4-nitrobenzene (2.35 g) was added to a 50 mL 3-neck RBF at room temperature under nitrogen atmosphere. Hydrogen gas was bubbled through the reaction mixture for 1-2 hr at room temperature and the reaction was monitored on TLC using chloroform:methanol (9.8:0.2) as mobile phase. After completion, the reaction mixture was filtered using Celite and washed with methanol. The combined filtrate was concentrated under reduced pressure at 40° C. to give 2.0 g of 4-[(2-methoxyethoxy)methoxy]aniline as a dark brown liquid. was added to a 50 mL 3-neck RBF at room temperature under nitrogen atmosphere Hydrogen gas was bubbled through the reaction mixture for 1-2 hr at room temperature After completion, the reaction mixture was filtered washed with methanol The combined filtrate was concentrated under reduced pressure at 40° C.