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Compound LXII (5.1 g, 55 mmol) was dissolved in methanol (250 mL) and the resulting solution was cooled to 0° C. Potassium thiocyanate (5.3 g, 55 mmol) was then added. The resulting solution was stirred for 12 hours at room temperature, concentrated under reduced pressure, diluted with ethyl acetate (200 mL), and filtered under reduced pressure to remove a solid. The filtrate was concentrated under reduced pressure, creating a solid which was filtered under reduced pressure to yield Compound LXIII (2 g (32percent)). The filtrate was further concentrated and applied to column chromatography (SiO2, n-hex:EA=4:1) to yield Compound LXIII (2 g (32percent)).1H NMR (600 MHz, CD3OD) δ 3.27 (s, 3H)
32%
at 0 - 20℃; for 12 h;
Compound LXII (5,1 g, 55 mmol) was dissolved in methanol (250 mL) and the resulting solution was cooled to 0 . Potassium thiocyanate (5.3 g, 55 mmol) was then added. The resulting solution was stirred for 12 hours at room temperature, concentrated under reduced pressure, diluted with ethyl acetate (200 mL), and filtered under reduced pressure to remove a solid. The filtrate was concentrated under reduced pressure, creating a solid which was filtered under reduced pressure to yield Compound LXIII (2 g (32percent)). The filtrate was further concentrated and applied to column chromatography (SiO2, n-hex : EA = 4 : 1) to yield Compound LXIII (2 g (32percent)). 1H NMR (600MHz, CD3OD) δ 3.27(s, 3H)
2 4-hydroxy-2-methyl-5-methoxypyrimidine
Example 2 4-hydroxy-2-methyl-5-methoxypyrimidine A modified form of the Maccoss Malcolm EP 330263 process was used. To a suspension of sodium (4.88 g 0.212 at-gr) in 300 ml of ethyl ether was added dropwise over 1 hour a mixture of 25 g (0.212 mol) of ethylmethoxyacetate and 23.5 g (0.23 mol) of ethyl formate. At the end of the addition, the reaction was refluxed under a N2 atmosphere for 2 hours and thereafter at room temperature overnight. The solvent was removed by decantation and the residue was washed with 3 x 100 ml of ethyl ether. The residue was dissolved in 250 ml of ethanol and 20 g (0.212 mol) acetamidine chloride were added. The mixture was refluxed for 6 hours. It was cooled to room temperature and the salts were filtered. The filter liquors were concentrated to dryness and chromatographed on silica gel, eluding with dichloromethane/ethanol 7/3, yielding 16.7 g of a white solid (56.2%).
3-[(2-aminoethyl)thiomethyl]-5-guanidino-1,2,4-thiadiazole oxalate[ No CAS ]
[ 594-42-3 ]
[ 20846-52-0 ]
[ 21734-85-0 ]
[ 74461-64-6 ]
Yield
Reaction Conditions
Operation in experiment
The 3-[(2-aminoethyl)thiomethyl]-5-guanidino-1,2,4-thiadiazole oxalate used as starting material may be prepared as follows: 5-Chloro-3-chloromethyl-1,2,4-thiadiazole (b.p. 54/2 m.m.) was prepared from chloroacetamidine and trichloromethanesulphenyl chloride by the procedure described by Goerdeler (Chem. Ber., 1957, 90, 182) for the preparation of 5-chloro-3-methyl-1,2,4-thiadiazole. Sodium hydride (4.8 g. of a 50% w/w dispersion in oil) washed free of oil with dried petroleum ether (b.p. 100-120) was stirred and warmed with dry t-butanol (200 ml.) for 30 minutes until gas evolution ceased.
With triethylamine; In methanol; at 0 - 20℃; for 17.33h;Inert atmosphere;
A mixture of crude <strong>[127956-11-0]4-oxo-tetrahydro-pyran-3-carboxylic acid methyl ester</strong> (1780 g, 1 1 mol) and triethylamine (830 g, 8.2 mol) in MeOH (3560 mL) was cooled to 0C under N2. A solution of 2-chloro-acetamidine (567 g, 4.4 mol) in 890 mL of MeOH was added dropwise over 50 minutes. The reaction mixture was stirred at 0C for 30 minutes and then at about 20C for 16 hours. LCMS at 215nm and TLC (DCM:MeOH=10:1) analysis showed that most of <strong>[127956-11-0]4-oxo-tetrahydro-pyran-3-carboxylic acid methyl ester</strong> was consumed. The mixture was then filtered and concentrated to give black oil, which was subsequently purified by flash column chromatography on silica gel and eluted with DCM to give yellow solid/oil mixture, which was further triturated with MTBE (-1200 mL) and H20: CH3CN: EA=1 :1 :2 (-600 mL) to give the title compound as a white solid (318 g). MS m/z 201 .2 (M+H). CHN analysis: calculated (results). C 47.89 (47.95), H 4.52 (4.401), N 13.96 (13.76).
With triethylamine; In methanol; at 0 - 20℃; for 16.5h;Inert atmosphere; Large scale;
A mixture of crude <strong>[127956-11-0]4-oxo-tetrahydro-pyran-3-carboxylic acid methyl ester</strong> (1780 g, 1 1 mol) and NEt3 (830 g, 8.2 mol) in MeOH (3560 mL) was cooled to 0C under N2. A solution of 2-chloro-acetamidine (567 g, 4.4 mol) in 890 mL of MeOH was added dropwise over 50 minutes. The reaction mixture was stirred at 0C for 30 minutes and then at about 20C for 16 hours. LCMS at 215nm and TLC (DCM:MeOH=10:1 ) analysis showed that most of <strong>[127956-11-0]4-oxo-tetrahydro-pyran-3-carboxylic acid methyl ester</strong> was consumed. The mixture was then filtered and concentrated to give black oil, which was subsequently purified by flash column chromatography on silica gel and eluted with DCM to give yellow solid/oil mixture, which was further triturated with MTBE (-1200 mL) and H2O: CH3CN: EA=1 :1 :2 (~600 mL) to give the title compound as a white solid (318 g). MS m/z 201 .2 (M+H). CHN analysis: calculated (results). C 47.89 (47.95), H 4.52 (4.401 ), N 13.96 (13.76).
318 g
Intermediate 10: 2-Chloromethyl-3, 5, 7, 8-tetrahydro-pyrano[4, 3-d]pyrimidin-4-one A mixture of crude <strong>[127956-11-0]4-oxo-tetrahydro-pyran-3-carboxylic acid methyl ester</strong> (1780 g, 1 1 mol) and NEt3 (830 g, 8.2 mol) in MeOH (3560 mL) was cooled to 0C under N2. A solution of 2-chloro-acetamidine (567 g, 4.4 mol) in 890 mL of MeOH was added dropwise over 50 minutes. The reaction mixture was stirred at 0C for 30 minutes and then at about 20C for 16 hours. LCMS at 215nm and TLC (DCM:MeOH=10:1 ) analysis showed that most of <strong>[127956-11-0]4-oxo-tetrahydro-pyran-3-carboxylic acid methyl ester</strong> was consumed. The mixture was then filtered and concentrated to give black oil, which was subsequently purified by flash column chromatography on silica gel and eluted with DCM to give yellow solid/oil mixture, which was further triturated with MTBE (-1200 mL) and H20: CHsCN: EA=1 :1 :2 (-600 mL) to give the title compound as a white solid (318 g). MS m/z 201.2 (M+H). CHN analysis: calculated (results). C 47.89 (47.95), H 4.52 (4.401 ), N 13.96 (13.76).