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With hydrogenchloride; sodium methylate; In methanol;
(i) 6-Ethylpyrimidin-4(3H)-one To a solution of sodium methoxide (4.19 kg, 77.6 mol) and formamidine acetate (3.0 kg, 28.8 mol) in methanol (45 L) at 5-10 C. was added slowly a solution of methyl propionylacetate (2.5 kg, 19.2 mol) in methanol (10 L) maintaining the temperature below 20 C. throughout the addition. The resulting mixture was stirred at room temperature overnight after which time the pH was adjusted to 7 by the addition of concentrated hydrochloric acid. The reaction mixture was concentrated under reduced pressure to ca.10 L in volume, diluted with water (10 L) and was extracted with 2-butanone (2*30 L). The combined organic extracts were concentrated under reduced pressure to ca. 2 L in volume and diluted with ethyl acetate (4 L). The desired product crystallized from the solution (2.4 kg, 70%) and was recrystallized from isopropanol to yield a product of m.p. 132-134 C. Found: C,58.45; H,6.37; N,22.41; C6 H8 N2 O requires: C,58.05; H,6.50; N,22.57%.
With sodium methylate; acetic acid; In methanol; at 20 - 40℃;Large scale;
Add methanol (15L) to the 20L reactor, start mechanical stirring, add sodium methoxide (2409 g, 44.6 mol, 4 eq), cooled to below 40 C. Add formamidine acetate(1740 g, 16.73 mol, 1.5 eq), then ethyl 3-oxopentanoate (1450 g, 10.06 mol, 1 eq). After the dropwise addition, the reaction was carried out at room temperature overnight. TLC (PE: EA = 1:1) shows that the raw materials have been reacted all. The HCl gas was passed to the system pH = 5, and allowed to stand overnight after completion. The solid in the bottle was filtered, and the filter cake was washed twice with acetone: methanol = 1:1, and the washing liquid was combined. The mixture was concentrated to obtain a crude product, which was then beaten with MTBE, filtered, and dried to obtain 1501 g of a product. Yield greater than 100%, containing inorganic salts
With dihydrogen peroxide; In hydrogenchloride; water; toluene; trichlorophosphate;
(ii) 4,5-Dichloro-6-ethylpyrimidine To a solution of <strong>[124703-78-2]6-ethylpyrimidin-4(3H)-one</strong> (the product of part (i)) (18.6 g, 150 mmol) in concentrated hydrochloric acid (120 ml) at 30-40 C. was added dropwise a 30 wt. % solution of hydrogen peroxide in water (18 ml) over a period of 30 minutes (slight exotherm resulted) and the resulting mixture was stirred overnight at 40 C. The mixture was concentrated under reduced pressure and the residue was suspended/dissolved in toluene and the toluene removed under reduced pressure. The residue was dissolved in phosphorus oxychloride (150 ml) and heated under reflux for 3 hours after which time the excess phosphorus oxychloride was removed under reduced pressure. The residue was poured into ice/water, extracted with methylene chloride (3*50 ml) and the combined organic extracts were washed with water (30 ml) and dried over magnesium sulphate. The solvent was removed under reduced pressure and the resulting oil was distilled under reduced pressure to yield the title compound (5.4 g, 20%), b.p. 104 C. at 22 mm Hg, which was characterised by 1 H-NMR spectroscopy. 1 H-NMR (CDCl3): delta=1.3 (t, 3H, J=10Hz), 3.04 (q, 2H, J=10Hz), 8.75 (s, 1H), ppm.
A-2a) 6-Ethyl-3H-pyrimidin-4-one 90 g (0.58 mol) 4-Hydroxy-2-mercapto-6-ethyl pyrimidine and 270 g Raney-Nickel are suspended in water (1000 mL). The suspension is heated and stirred under reflux over night. Full conversion is detected by TLC (10% MeOH in DCM). The catalyst is filtered off over celite and the filtrate is evaporated to give crude product as a pale green solid (70.0 g; 98%). The product is used without further purification for the next step.
With N-iodo-succinimide; acetic acid; at 20℃; for 30.0h;
To 70 g (0.56 mol) A-4 in acetic acid is added 127 g (0.56 mol) NIS portion wise at RT within 15 min. The reaction is stirred at RT until all starting material is consumed (30 h). The reaction mixture is diluted with water and the solid product is filtered off, washed with an aqueous sodium thiosulfate solution to remove excess iodine and dried in vacuo. Yield: 90 g (64 %).
With N-iodo-succinimide; acetic acid; at 20℃; for 30.0h;
To 70 g (0.56 mol) A-4 in acetic acid is added 127 g (0.56 mol) NIS portion wise at RT within 15 min. The reaction is stirred at RT until all starting material is consumed (30 h). The reaction mixture is diluted with water and the solid product is filtered off, washed with an aqueous sodium thiosulfate solution to remove excess iodine and dried in vacuo. Yield: 90 g (64 %).
90 g
With N-iodo-succinimide; acetic acid; In acetic acid; at 20℃; for 30.0h;
To 70 g (0.56 mol) A-4 in acetic acid is added 127 g (0.56 mol) NIS portion wise at RT within 15 min. The reaction is stirred at RT until all starting material is consumed (30 h). The reaction mixture is diluted with water and the solid product is filtered off, washed with an aqueous sodium thiosulfate solution to remove excess iodine and dried in vacuo. Yield: 90 g (64 %).
90 g
With N-iodo-succinimide; In acetic acid; at 20℃; for 30.25h;
To 70 g (0.56 mol) A-4 in acetic acid is added 127 g (0.56 mol) NIS portion wise at RT within 15 min. The reaction is stirred at RT until all starting material is consumed (30 h). The reaction mixture is diluted with water and the solid product is filtered off, washed with an aqueous sodium thiosulfate solution to remove excess iodine and dried in vacuo. Yield: 90 g (64%).
90 g (0.58 mol) 4-Hydroxy-2-mercapto-6-ethylpyrimidine and 270 g Raney-Nickel are suspended in water (1000 mL) and the suspension is heated and stirred under reflux over night. The reaction mixture is filtered over celite and the filtrate is concentrated under reduced pressure to give crude product. Yield: 70.0 g (98 %).
With hydrogen;Raney-Nickel; In water;Reflux;
90 g (0.58 mol) 4-Hydroxy-2-mercapto-6-ethylpyrimidine and 270 g Raney-Nickel are suspended in water (1000 mL) and the suspension is heated and stirred under reflux over night. The reaction mixture is filtered over celite and the filtrate is concentrated under reduced pressure to give crude product. Yield: 70.0 g (98 %).
With Raney-Nickel; In water;Reflux;
90 g (0.58 mol) 4-Hydroxy-2-mercapto-6-ethylpyrimidine and 270 g Raney-Nickel are suspended in water (1000 mL) and the suspension is heated and stirred under reflux over night. The reaction mixture is filtered over celite and the filtrate is concentrated under reduced pressure to give crude product. Yield: 70.0 g (98 %).
With water;Reflux;
90 g (0.58 mol) 4-Hydroxy-2-mercapto-6-ethylpyrimidine and 270 g Raney-Nickel are suspended in water (1000 mL) and the suspension is heated and stirred under reflux over night. The reaction mixture is filtered over celite and the filtrate is concentrated under reduced pressure to give crude product. Yield: 70.0 g (98%).
6.01.15.01 4- 6-ethyl-pyrimidin-4-yl)-piperazine-l-carboxylic acid tert-butyl ester 4 mL DIPEA and 3 g PYBOP was added to 2.9 g <strong>[124703-78-2]6-ethyl-3H-pyrimidin-4-one</strong> in 10 mL DMF. The reaction was stirred 5 min at ambient temperature and 1.1 g piperazine-l-carboxylic acid tert-butyl ester was added. The reaction was stirred overnight at RT. The solvent was removed and the residue was purified by HPLC to give 1 g of the desired compound. Rt: 1.82 min (method L), (M+H)+: 293
1 g
6.01.15.01 4-(6-ethyl-pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester 4 mL DIPEA and 3 g PYBOP was added to 2.9 g <strong>[124703-78-2]6-ethyl-3H-pyrimidin-4-one</strong> in 10 mL DMF. The reaction was stirred 5 min at ambient temperature and 1.1 g piperazine-1-carboxylic acid tert-butyl ester was added. The reaction was stirred overnight at RT. The solvent was removed and the residue was purified by HPLC to give 1 g of the desired compound. Rt: 1.82 min (method L), (M+H)+: 293
The compound <strong>[124703-78-2]6-ethyl-4-pyrimidinone</strong> (426.5 g, 3.437 mol, 1 eq), Acetic acid (2.5L) was added to the 5L reaction bottle together. Bromine (550g, 3.437mol, 1 eq) was added dropwise at room temperature, and there was a temperature rise. The temperature control is less than 40 C, and after the addition, return to room temperature and stir for 0.5 h. The TLC (PE: EA = 1:1) starting material was completely reacted. Concentrate acetic acid, beat MTBE, Drying gave 780 g of 5-bromo-<strong>[124703-78-2]6-ethyl-4-pyrimidinone</strong> hydrobromide. To dissolve 5-bromo-<strong>[124703-78-2]6-ethyl-4-pyrimidinone</strong> hydrobromide in ice water, The pH was adjusted to 5-6 with sodium acetate, extracted with ethyl acetate and dried over sodium sulfate. Filtration and spin-drying gave the product 5-bromo-<strong>[124703-78-2]6-ethyl-4-pyrimidinone</strong>. Yield: 80%.
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