ethanimidamide;hydrochloride

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

Procedure: The first intermediate, 4,6-dihydroxy-2-10 methylpyrimidinamine, is synthesized by preparing sodium ethoxide in situ from sodium and an hydrous ethanol under a nitrogen blanket. Acetamidine hydrochloride and diethyl malonate are added and the reaction mixture heated to boiling for 2 to 5 hours to afford 4,6-dihydroxy-2-methylpyrimidine. the reaction mixture heated

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

Procedure: Acetamidine hydrochloride (37.16 g, 0.39 mole) was stirred in sodium ethoxide in ethanol (73 mL of a 21% solution, 0.20 mole) for 5 minutes. Diethyl ethoxymethylenemalonate (31.5 mL, 0.15 mole) was added, and the reaction mixture was refluxed for 5 h. The reaction mixture was allowed to cool to room temperature overnight, and diluted with dichloromethane (100 mL). The solution was filtered, washing the solid cake with dichloromethane. The filtrate was concentrated at reduced pressure. The residue was dissolved in dichloromethane (150 mL) and 2.0N HCl (30 mL). The pH of the aqueous layer was 1. The organic layer was washed with water, saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was dissolved in hot dichloromethane (50 mL). Ethyl acetate was added (50 mL). The product precipitated. The solution was boiled for 5 minutes, cooled to room temperature, and hexanes were added (50 mL). The resulting crystals were filtered, then washed with ethyl acetate (20 mL) followed by hexanes (50 mL) to yield the title compound (7.22 g, 27%) as off-white crystals. Rf=0.27 (silica gel, 10% isopropanol in dichloromethane). the reaction mixture was refluxed for 5 h The solution was filtered washing the solid cake with dichloromethane The filtrate was concentrated at reduced pressure The residue was dissolved in dichloromethane (150 mL) The organic layer was washed with water, saturated sodium bicarbonate and brine dried over anhydrous magnesium sulfate the solvent was removed under reduced pressure The residue was dissolved in hot dichloromethane (50 mL) Ethyl acetate was added (50 mL) The product precipitated cooled to room temperature hexanes were added (50 mL) The resulting crystals were filtered washed with ethyl acetate (20 mL)

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of acetamidine hydrochloride (6.0 g) in ethanol (20 mL) was added sodium ethoxide (20 mL of a 21% solution in ethanol) and the reaction mixture was heated at 50° C. and mucobromic acid (6.82 g) in ethanol (10 mL) was added. After stirring at 50° C. for 1 h, a further portion of sodium ethoxide (10 mL of a 21% solution in ethanol) was added and the mixture was stirred at room temperature for 16 h. The mixture was then filtered and the filtrate reduced in vacuo. The residue was then treated with 2 M aqueous hydrochloric acid (30 mL) and stirred vigorously for 30 minutes. The resulting solid was filtered, washed with water and air dried to give 5-bromo-2-methyl-pyrimidine-4-carboxylic acid (1.46 g). This was then heated at 175° C. for 16 h. After cooling to room temperature the mixture was purified by Kugelrohr distillation to give 5-bromo-2-methyl-pyrimidine as a white solid (746 mg). the mixture was stirred at room temperature for 16 h The mixture was then filtered The residue was then treated with 2 M aqueous hydrochloric acid (30 mL) stirred vigorously for 30 minutes The resulting solid was filtered washed with water and air dried

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of acetamidine hydrochloride (6.0 g) in ethanol (20 mL) was added sodium ethoxide (20 mL of a 21% solution in ethanol) and the reaction mixture was heated at 50° C. and mucobromic acid (6.82 g) in ethanol (10 mL) was added. After stirring at 50° C. for 1 h, a further portion of sodium ethoxide (10 mL of a 21% solution in ethanol) was added and the mixture was stirred at room temperature for 16 h. The mixture was then filtered and the filtrate reduced in vacuo. The residue was then treated with 2 M aqueous hydrochloric acid (30 mL) and stirred vigorously for 30 minutes. The resulting solid was filtered, washed with water and air dried to give 5-bromo-2-methyl-pyrimidine-4-carboxylic acid (1.46 g). This was then heated at 175° C. for 16 h. After cooling to room temperature the mixture was purified by Kugelrohr distillation to give 5-bromo-2-methyl-pyrimidine as a white solid (746 mg). the mixture was stirred at room temperature for 16 h The mixture was then filtered The residue was then treated with 2 M aqueous hydrochloric acid (30 mL) stirred vigorously for 30 minutes The resulting solid was filtered washed with water and air dried

Conditions: temp:72.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To the solution of 4-[4-(7-Methoxy-6-methyl-indan-4-ylmethyl)-3,5-dimethyl-pyrazol-1-yl]-3-oxo-butyric acid ethyl ester (1.0 gm, 0.0025 mole) in Ethanol (60 ml), Acetamidine hydrochloride (0.71 gm, 0.0075 mole) was added. Further to this, Sodium ethoxide (0.51 gm, 0.0075 mole) was added at 5-10° C. and then stirred at 70-75° C. for 2 hours. The Ethanol was distilled under vacuum and residue was partitioned between Ethyl acetate (100 ml) and water (100 ml). Further aqueous layer was extracted with Ethyl acetate (2×100 ml). The combined volume of Ethyl acetate layer was reduced to 20 ml and then filtered to give 800 mg of desired product. The Ethanol was distilled under vacuum and residue was partitioned between Ethyl acetate (100 ml) and water (100 ml) Further aqueous layer was extracted with Ethyl acetate (2×100 ml) filtered

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Sodium (356 mg, 15.5 mmol) was carefully added to ethanol (5.9 mL) to prepare sodium ethoxide solution in ethanol. The above freshly prepared sodium ethoxide in ethanol solution (3.5 mL) was added to a stirred suspension of acetamidine hydrochloride (0.91 g, 9.69 mmol). The mixture was warmed to 50° C., then the heating bath was removed and a solution of mucobromic acid (1 g, 3.87 mmol) in ethanol was added dropwise at a rate which maintained a constant temperature, followed by a further sodium ethoxide in ethanol solution (2 mL). After cooling, the mixture was filtered and evaporated to a residue which was shaken vigorously with hydrochloric acid (2 M×2.4 mL). The brown precipitate was filtered and washed with cold water, then freeze-dried to give 5-bromo-2-methylpyrimidine-4-carboxylic acid (350 mg, 42%) as a brown solid. LCMS: 218 [M+1]+, 1H NMR (400 MHz, DMSO-d6): δ 2.62 (s, 3H), 9.03 (s, 1H). the heating bath was removed maintained a constant temperature After cooling the mixture was filtered evaporated to a residue which The brown precipitate was filtered washed with cold water freeze-dried

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

Procedure: Ethyl 4-amino-3-methylthiazoline-2-thione-5-carboxylate (1.4 g, 6.4 mmoles), prepared according to the procedure of Gewald, J. Prakt. Chem., 32, 26-30 (1966), was suspended in approximately 40 ml of ethanol. Acetamidine hydrochloride (0.6 g, 6.4 mmole) and 2.77 g (12.8 mmole) of a 25% solution of sodium methoxide in methanol were added to the suspension and the resultant mixture refluxed for approximately 20 hours. The ethanol was removed in vacuo and the residue was suspended in water and neutralized with concentrated hydrochloric acid. The resultant precipitate was filtered and dried to provide 1 g of 3,5-dimethyl-6H-thiazolo[4,5-d]pyrimidin-7-one-2-thione. The structural assignment was confirmed by nuclear magnetic resonance spectral analysis. The ethanol was removed in vacuo The resultant precipitate was filtered dried

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

Procedure: A solution of 2.46 g (6.33 mmol) ethyl 2-[(4-iodophenyl)methyl]-3-oxoheptanoate, 6.0 g (63.3 mmol) acetamidine hydrochloride, 5.2 g (63.3 mmol) sodium acetate, and 84 mg (0.381 mmol) 2,6-di-tert-butyl-4-methylphenol in 30 mL DMF was heated to 153° C. for 12 hours. The cooled reaction mixture was poured into brine and extracted 3 times with ether. The combined organic material was washed with brine, dried over MgSO4, stripped of solvent in vacuo, then was medium pressure chromatographed on silica gel using 1/65/34 AcOH/EtOAc/hexane to give 485 mg of the title compound, 20% yield. Unreacted ethyl 2-[(4-iodophenyl)methyl]-3-oxoheptanoate was recycled. Rf 0.25 in 1/65/34 AcOH/EtOAc/hexane, visualized by UV and ninhydrin stain; The cooled reaction mixture extracted 3 times with ether The combined organic material was washed with brine dried over MgSO4 chromatographed on silica gel using 1/65/34 AcOH/EtOAc/hexane

Conditions: temp:190.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solid mix of 4-amino-5-imidazolecarboxamide hydrochloride (30.75 mmol, 5 g) and acetamidine hydrochloride (2 eq, 61.5 mmol, 5.8 g) and sodium acetate (3 eq, 92.25 mmol, 7.6 g) were heated at 190° C. for 1 h. To the resultant off-white solid, at RT, NaOH (100 ml) was added and a white ppt was filtered away. The filtrate was acidified to pH 6.0 with AcOH (5 ml) and the resultant ppt filtered away. Both precipitates were dried separately in a vacuum oven at 80° C. for 24 h. The combined weight of pure product was (4.16 g, 90%). The first precipitate (2.11 g) analyzed as follows: mp.>300° C. DCI/MS (M+1)=151. (300 MHz) 1H-nmr (DMSO-d6)δ: 8.0 (s, 1H), 2.3 (s, 3H). a white ppt was filtered away the resultant ppt filtered away Both precipitates were dried separately in a vacuum oven at 80° C. for 24 h

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

Procedure: To a stirred solution of 0.233 g of acetamidine hydrochloride in 36 ml of methyl alcohol under argon is added 0.133 g of NaOCH3. After 5 minutes, 0.600 g of 4-[(dimethylamino)methylene]-1,2,3,4-tetrahydro-1-(4-nitrobenzoyl)-5H-1-benzazepin-5-one is added and stirring continued for 18 hours. The volatiles are evaporated to a residue which is dissolved in ethyl acetate and passed through a pad of silica gel. The filtrate is evaporated in vacuo to give 590 mg of the desired product as tan crystals, m.p. 211°-212° C. HR FABMS: Exact mass (M+H):361.1295. continued for 18 hours The volatiles are evaporated to a residue which is dissolved in ethyl acetate The filtrate is evaporated in vacuo

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

Procedure: To a stirred solution of 0.233 g of acetamidine hydrochloride in 36 ml of methyl alcohol under argon is added 0.133 g of NaOCH3. After 5 minutes, 0.600 g of 4-[(dimethylamino)methylene]-1,2,3,4-tetrahydro-1-(4-nitrobenzoyl)-5H-1-benzazepin-5-one is added and stirring continued for 18 hours. The volatiles are evaporated to a residue which is dissolved in ethyl acetate and passed through a pad of silica gel. The filtrate is evaporated in vacuo to is give 590 mg of the desired product as tan crystals, m.p. 211°-212° C. HR FABMS: Exact mass (M+H):361.1295. continued for 18 hours The volatiles are evaporated to a residue which is dissolved in ethyl acetate The filtrate is evaporated in vacuo

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

Procedure: 2-Amino-5-chlorobenzoic acid (3.58 g, 20.9 mmol, 1 eq.), acetamidine hydrochloride (2.36 g, 25.1 mmol, 1.2 eq.) and 2-ethoxyethanol (70 mL) were mixed and refluxed for 48 h. The resultant solids were filtered and dried to yield 1.57 g of yellow solid product. MS (ES+)=195/197 (M+H)++. refluxed for 48 h The resultant solids were filtered dried