Gimeracil

1. Description Off-White Solid https://www.echemi.com/ https://www.echemi.com/ Basic Attributes CAS No：103766-25-2 Molecular Formula ：C5H4ClNO2 Molecular Mass ：145.54400 Exact Mass ：144.99300 PSA ：53.09000 LogP ：-0.1 InChIKeys ：ZPLQIPFOCGIIHV-UHFFFAOYSA-N H-bond Acceptor ：2 H-bond Donor ：2 SP3 ：0.00 RBN ：0 Characteristics Density ：1.56 g/cm3 Melting Point ：274ºC Bolling Point ：281.9ºC at 760 mmHg Flash Point ：124.3ºC Refractive Index ：1.617 Vapor Pressure ：0.000408mmHg at 25°C Safety Information Packing Group ：II

2. Hazard Class ：3 HS Code ：2942000000 UN No. ：UN 2985 3/PG 2 WGK_Germany ：1 Risk Code ：R11; R14; R34 Safety Instructions ：S16; S26; S33; S36/37/39 Dangerous Mark ：F; C Product Usage 1. Gimeracil is an inhibitor of dihydropyrimidine dehydrogenase, which inhibits the early step in homologous recombination for double strand breaks repair. 2. Gimeracil is an antitumor agent. Gimeracil is a potent inhibitor of dihydropyrimidine dehydrogenase (DPD). 3. Antitumor agent. A potent inhibitor of dihydropyrimidine dehydrogenase (DPD) Production Methods A mixture of compound 6 (8.0 g, 44 mmol), acetonitrile (100 mL), acetic acid (3 mL)and sodium iodide (13.2 g, 88 mmol) was heated for 8 h at 60 °C. Then the mixture was cooled to room temperature and poured into 10percent sodium thiosulfate solution (200 mL) to precipitate a colourless solid, which was recrystallised from water to give pure compound 2: Yield 5.6 g (86percent); m.p.272–273 °C (lit.7 273–274 °C); 1H NMR (400 MHz, DMSO-d6): δ 5.70(s, 1H), 7.51 (s, 1H), 11.29 (br, 2H) ; 13C NMR (100 MHz, DMSO-d6): δ163.5, 163.2, 134.6, 105.6,

3. 98.7; LRMS (ESI) m/z (percent): 146 (100) [M (35Cl+ 1]+, 148 (30) [M (37Cl) + 1]+; HRMS (ESI) m/z calcd for C5H535ClNO2:[M + H]+: 146.0003; found: 146.0012; calcd for C5H537ClNO2: [M + H]+:147.9975; found: 147.9975.Xylene (40 mL) was added to 2, 2-cyclohexyl-5-chloro-1, 3-dioxin-4-one (4.25 g, 0.021 mol), produced in Referential Example 2, and ketene diethyl ether (2.91 g, 0.025 mol), and the mixture was stirred under heating at 128 to 130 ° C (internal temperature) for 40 minutes. The reaction mixture was cooled to room temperature, and concentrated. The residue was dissolved in ethanol (60 mL), and at room temperature, acetyl chloride (0.17 g, 0.0022 mol) was added to the solution, followed by stirring for one hour. To the reaction mixture, concentrated ammonia (28percent) (4.2 mL) was added, followed by stirring at room temperature for four hours. A 30percent aqueous solution of sodium hydroxide (3 g, 0.0225 mol) was added to the reaction mixture, followed by stirring at room temperature for 12 hours. The precipitated crystals were collected through filtration, washed with ethanol (10 mL, two times), and dried under reduced pressure at room temperature for five hours, to thereby yield 3.04 g of a product as crystals. The thus-obtained crystals were dissolved in water (30 mL) under heating, and the solution was cooled to room temperature. 6N Aqueous hydrochloric acid (4.5 g) was added to the solution, followed by stirring at room temperature for five hours. The precipitated crystals were collected through filtration, washed with water, and dried under reduced pressure at 40 to 45°C for 18 hours, to thereby yield 2.21 g of the title compound (yield with respect to 2, 2-cyclohexyl-5-chloro-1, 3-dioxin-4-one: 72.4percent).The compound (0.23 g, 0.001 mol) was dissolved in ethanol (5 mL), and acetyl chloride (0.1 mL) was added to the solution at room temperature, followed by stirring for one hour. The reaction mixture was concentrated, and the residue was dissolved in ethanol (5 mL). Concentrated aqueous ammonia (28percent) (1 mL) was added to the solution, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated, and water (1.4 mL) and acetic acid (0.14 mL) were added to the residue, followed by stirring at room temperature for two hours. The precipitated crystals were collected through filtration, washed with water, and dried under reduced pressure at 40 to 45°C for 18 hours, to thereby yield 0.05 g of the title compound (yield with respect to 5-chloro-2, 2-diethoxy-2, 3-dihydropyran-4-one: 33.0percent, yield with respect to 5-chloro-2, 2-dimethyl-1, 3-dioxin-4-one: 29.4percent).Reference Example 8 Alternative synthesis 3-{3-[4-hydroxy-5-chloro-2-pyridyloxycarbonyl]benzoyl}-1-ethoxymethyl-5-fluorouracil (Compound 8a) 1-Ethoxymethyl-3-m-hydroxycarbonylbenzoyl-5-fluorouracil dissolved in methylene chloride (50 mL). Thionyl chloride (0.9 mL) and dimethylformamide (0.04 mL) were then added thereto. The resulting reaction product was refluxed for 2.5 hours, and the solvents were then evaporated. The residue was dissolved in dimethylacetamide (12 mL) to obtain a dimethylacetamide solution of acid chloride. The dimethylacetamide solution of acid chloride was added dropwise under ice cooling to a solution of 2, 4-dihydroxy-5-chloropyridine (1.5 g), triethylamine (1.57 mL), and dimethylacetamide (15 mL). The resulting reaction product was stirred at room temperature for 8 hours. Water was added thereto, and the mixture was separated by a mixed solvent of ethyl acetate and n-hexane (1:1). The organic layer was dried with sodium sulfate, and the solvent was then evaporated. The residue was purified by silica gel column chromatography (eluted with ethyl acetate/n-hexane (1:1)) to obtain Compound 8a (668 mg). Yield: 14percentReference Example 6-dibenzyloxyisonicotinoyloxy}-5-chloro-2-hydroxypyridine of (3.46 g) was 4 Synthesis of 4-{2, 2-{2, (Compound 5a),

4. 6-dibenzyloxyisonicotinoyloxy}-5-chloro-4-hydroxypyridine 6-dibenzyloxyisonicotinoyloxy}-5-chloropyridine (Compound 5c). Thionyl chloride (98.5 mL) and dimethylformamide (1.7 mL) were added dropwise to a solution of 2, 6-dibenzyloxyisonicotinic acid (Compound 2a) (75.45 g) obtained in Reference and toluene (800 mL), and the mixture was stirred at 80 ° C for 4.5 hours. After being cooled, the solvents were evaporated. Without purification, the residual acid chloride was dissolved in dimethylacetamide (100 mL) to obtain a dimethylacetamide solution of acid chloride to be used in the following reaction. The dimethylacetamide solution of acid chloride was added dropwise under ice cooling to a solution of 2, 4-dihydroxy-5-chloropyridine (31.9 g), triethylamine (31.19 mL) and dimethylacetamide (1.6 L). The resulting mixture was stirred at room temperature for 1 hour, and water (1.7 L) was then added thereto. The mixture was separated by a mixed solvent (1 L) of ethyl acetate and n-hexane (3:1). After the solution was dried with sodium sulfate, the solvent was evaporated. The precipitate was filtered and dried to obtain Compound 5a. Yield: 44.8g (45percent) Meanwhile, the filtrate was concentrated and the resulting residue was purified by silica gel column chromatography (eluted with ethyl acetate/n-hexane (1:1)) to obtain Compound 5b (18.94 g) and Compound 5c (4.74 g). Compound 5a 1H-NMR (DMSOd6, deltaPPM): 12.09 (1H, brs), 7.91 (1H, s), 7.50-7.30 (10H, m), 6.99 (2H, s), 6.58 (1H, s), 5.42 (4H, s)Melting point: 149-150°C12.09 (1H, brs), 7.91 (1H, s), 7.50-7.30 (10H, m), 6.99 (2H, s), 6.58 (1H, s), 5.42 (4H, s)Compound 5b1H-NMR (DMSOd6, deltaPPM): 12.26 (1H, brs), 8.27 (1H, s), 7.50-7.30 (10H, m), 6.98 (2H, s), 6.86 (1H, s), 5.42 (4H, s)Melting point: 136-138°C (decomposition temperature)12.26 (1H, brs), 8.27 (1H, s), 7.50-7.30 (10H, m), 6.98 (2H, s), 6.86 (1H, s), 5.42 (4H, s)Compound 5c1H-NMR (DMSOd6, deltaPPM): 8.75 (1H, s), 7.79 (1H, s), 7.50-7.30 (20H, m), 7.05 (2H, s), 7.02 (2H, s), 5.42 (8H, s)8.75 (1H, s), 7.79 (1H, s), 7.50-7.30 (20H, m), 7.05 (2H, s), 7.02 (2H, s), 5.42 (8H, s) (Compound 5b), and 2, 4-di{2,