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2D
Structure of 102-52-3*Storage: {[proInfo.prStorage]}
EXAMPLE 4 2(1 H)-Pyrimidinethione, 1-methyl To a stirred mixture of 1-methyl-2-thiourea (76.6 g, 0.85 mol) and malonaldehyde bis(dimethyl acetal) (126.8 g, 0.77 mol) in EtOH (1.5 L) was added 10 M HCI (76.6 mL, 0.77 mol) in one portion. The resulting mixture was stirred at 25° C. for 18 h, then spin-evaporated in vacuo. The residue was dissolved in H2O (1.25 L). The solution was made alkaline by the portionwise addition of K2CO3 and extracted with CH2Cl2 (4*500 mL). The combined extracts were dried over MgSO4 and spin-evaporated in vacuo to a solid. The crude product was recrystallized from EtOH (600 mL) then dried to constant weight in vacuo at room temperature to give 22.9 g (23percent) of product; mp 186-188° C. (uncorrected). An additional reaction was performed to give a total of 40.7 g.
23%
With potassium carbonate In ethanol; water
EXAMPLE 4 2(1H)-Pyrimidinethione, 1-methyl To a stirred mixture of 1-methyl-2-thiourea (76.6 g, 0.85 mol) and malonaldehyde bis(dimethyl acetal) (126.8 g, 0.77 mol) in EtOH (1.5 L) was added 10 M HCI (76.6 mL, 0.77 mol) in one portion. The resulting mixture was stirred at 25° C. for 18 h, then spin-evaporated in vacuo. The residue was dissolved in H2O (1.25 L). The solution was made alkaline by the portionwise addition of K2CO3 and extracted with CH2Cl2 (4*500 mL). The combined extracts were dried over MgSO4 and spin-evaporated in vacuo to a solid. The crude product was recrystallized from EtOH (600 mL) then dried to constant weight in vacuo at room temperature to give 22.9 g (23percent) of product; mp 186-188° C. (uncorrected). An additional reaction was performed to give a total of 40.7 g.
a) 1-(2-Methoxyphenyl)-1H-pyrazol 200 mg of 2-methoxyphenyl hydrazine hydrochloride was dissolved in 5 ml of ethanol, and 189 μl of malonaldehyde bisdimethylacetal was added and heated at reflux for 2 hours. To the reaction mixture was added 50 ml of water, neutralized with a saturated aqueous solution of sodium carbonate, and extracted with 60 ml of ethyl acetate. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to yield 179.4 mg of the title compound. 1H-NMR (CDCl3); δ (ppm) 3.87 (3H, s), 6.42 (1H, d, J=2.4 Hz), 7.02-7.07 (2H, m), 7.27-7.32 (1H, m), 7.68-7.72 (2H, m), 8.01 (1H, d, J=2.4 Hz). MS (FAB); m/z 175 (M+H)+
179.4 mg
for 2 h; Reflux
200 mg of 2-methoxyphenylhydrazine hydrochloride was dissolved in 5 ml of ethanol and 189 μl of malonaldehyde bisdimethylacetal was added, followed by heating to reflux for 2 hours. To the reaction mixture was added 50 ml of water, followed by neutralizing with a saturated aqueous sodium carbonate solution and extracting with 60 ml of ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and subsequently the solvent was distilled off under reduced pressure to afford 179.4 mg of the title compound. 1H-NMR (CDCl3); δ (ppm) 3.87 (3H, s), 6.42 (1H, d, J=2.4 Hz), 7.02-7.07 (2H, m), 7.27-7.32 (1H, m), 7.68-7.72 (2H, m), 8.01 (1H, d, J=2.4 Hz). MS (FAB); m/z 175 (M+H)+
179.4 mg
for 2 h; Reflux
a) 1-(2-Methoxyphenyl)-1H-pyrazole [0154] 200 mg of 2-methoxyphenylhydrazine hydrochloride was dissolved in 5 ml of ethanol and 189 µl of malonaldehyde bisdimethylacetal was added, followed by heating to reflux for 2 hours. To the reaction mixture was added 50 ml of water, followed by neutralizing with a saturated aqueous sodium carbonate solution and extracting with 60 ml of ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and subsequently the solvent was distilled off under reduced pressure to afford 179.4 mg of the title compound. 1H-NMR(CDCl3); δ (ppm) 3.87 (3H,s), 6.42 (1H, d, J=2.4Hz), 7.02-7.07 (2H, m), 7.27-7.32 (1H, m), 7.68-7.72 (2H, m), 8.01 (1H, d, J=2.4Hz). MS (FAB); m/z 175 (M+H)+
200 mg of 2-methoxyphenylhydrazine hydrochloride was dissolved in 5 ml of ethanol and 189 μl of malonaldehyde bisdimethylacetal was added, followed by heating to reflux for 2 hours. To the reaction mixture was added 50 ml of water, followed by neutralizing with a saturated aqueous sodium carbonate solution and extracting with 60 ml of ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and subsequently the solvent was distilled off under reduced pressure to afford 179.4 mg of the title compound. 1H-NMR (CDCl3); δ (ppm) 3.87 (3H,s), 6.42 (1H, d, J=2.4Hz), 7.02-7.07 (2H, m), 7.27-7.32 (1H, m), 7.68-7.72 (2H, m), 8.01 (1H, d, J=2.4Hz). MS (FAB); m/z 175 (M+H)+
179.4 mg
for 2 h; Reflux
[0176] 200 mg of 2-methoxyphenylhydrazine hydrochloride was dissolved in 5 ml of ethanol and 189 μl of malonaldehyde bisdimethylacetal was added, followed by heating to reflux for 2 hours. To the reaction mixture was added 50 ml of water, followed by neutralizing with a saturated aqueous sodium carbonate solution and extracting with 60 ml of ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and subsequently the solvent was distilled off under reduced pressure to afford 179.4 mg of the title compound. [0177] 1H-NMR (CDCl3); δ (ppm) 3.87 (3H, s), 6.42 (1H, d, J=2.4 Hz), 7.02-7.07 (2H, m), 7.27-7.32 (1H, m), 7.68-7.72 (2H, m), 8.01 (1H, d, J=2.4 Hz). [0178] MS (FAB); m/z 175 (M+H)+
Reference：
[1] Zhurnal Obshchei Khimii, 1957, vol. 27, p. 57,58,61;engl.Ausg.S.65,67,68
28
[ 102-52-3 ]
[ 31230-17-8 ]
[ 116834-96-9 ]
Reference：
[1] Journal of Medicinal Chemistry, 1997, vol. 40, # 17, p. 2706 - 2725
29
[ 102-52-3 ]
[ 6825-71-4 ]
[ 1260169-02-5 ]
Yield
Reaction Conditions
Operation in experiment
58.1%
at 100℃; for 14 h;
To a solution of ethyl 3,5-diamino-lH-pyrazole-4-carboxylate (5.00 g, 29.38 mmol) in DMF (80 mL) were added 1 , 1 ,3,3-tetramethoxypropane (14.50 mL, 88.15 mmol) and AcOH (0.34 mL, 5.88 mmol). The reaction mixture was stirred at 100 °C for 14 h, and then concentrated in vacuo. The residue was partitioned between DCM (50 mL) and water (50 mL). The organic phase was separated and the aqueous phase was extracted with DCM (100 mL x 3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2S04, filtered and concentrated in vacuo. The residue was purified by a silica gel column chromatography (a solution of NH3in MeOH (7 M)/DCM (v/v) =1/100) to give the title compound as a pale yellow solid (3.52 g, 58.1percent).MS (ESI, pos. ion) m/z: 207.1 [M+H]+;H NMR (400 MHz, CDC1 ): δ (ppm) 8.60 (dd, J= 4.40 Hz, 1.76 Hz, 1H), 8.46 (dd, J = 6.76 Hz, 1.76 Hz, 1H), 6.86 (dd, J = 6.72 Hz, 4.40 Hz, 1H), 4.50 (q, J = 7.08 Hz, 2H), 1.47 (t, J = 7.08 Hz, 3H).
58.1%
With acetic acid In N,N-dimethyl-formamide at 100℃; for 14 h;
To a solution of ethyl 3,5-diamino-1 -hydro-pyrazole-4-carboxylate (5.00 g, 29.38 mmol)In N, N-dimethylformamide ((80 mL)1,1,3,3-tetramethoxypropane (14.50 mL, 88.15 mmol)And acetic acid (0.34 mL, 5.88 mmol).After the reaction mixture was stirred at 100 ° C for 14 hours,Concentrate under reduced pressure. The resulting residue was dispersed in a mixed system of dichloromethane (50 mL) and water (50 mL), the organic phase was separated and the aqueous phase was extracted with dichloromethane (100 mL x 3). The combined organic phases were washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH3 in methanol (7M) / methylene chloride (v / v) = 1/100) to give the title compound as a pale yellow solid (3.52 g, 58.1percent).
35.3%
With triethylamine In N,N-dimethyl-formamide at 100℃; for 14 h;
ethyl 2-aminopyrazolo[l ,5-a]pyrimidine-3-carboxylateA mixture of ethyl 3,5-diamino-l H-pyrazole-4-carboxylate (1.0 g, 5.9 mmol), 1,1,3,3- tetramethoxypropane (2.9 mL, 18 mmol), triethylamine (2 mL, 10 mmol), and DMF (15 mL) was heated at 100 0C for 14 hrs, then a further 2 mL of 1,1,3,3-tetramethoxypropane was added. After adding the additional 1,1,3,3-tetramethoxypropane, a significant by-product was noted and heating was stopped immediately. The reaction was cooled to room temperature and the DMF was removed in vacuo. The residue was partitioned between DCM and water, then the organic layer was concentrated and the residue purified by silica chromatography, eluting with 95:5 DCM: 2M methanolic ammonia solution to afford 420 mg (35percent) of ethyl 2-aminopyrazolo[l,5- a]pyrimidine-3-carboxylate. 1H NMR (500 MHz, CDCl3) δ 8.57 (dd, J = 4.3, 1.6, IH), 8.43 (dd, J = 6.7, 1.6, IH), 6.84 (dd, J = 6.7, 4.4, IH), 5.52 (s, 2H), 4.48 (q, J= 7.1, 2H), 1.45 (t, J= 7.1, 3H).
To chloroacetoamidine hydrochloride (19.7 g) was added 1,1,3,3-tetramethoxypropane (50 ml), and the mixture was stirred for 16 hours at 100°C. After cooling to room temperature, the mixture was added to water, extracted with methylene chloride, and dried over magnesium sulfate. The solvent was removed under reduced pressure to give 2-(chloromethyl)pyrimidine (2.0 g). 1H-NMR (200 MHz, CDCl3) delta 4.76 (2H, s), 7.27 to 7.30 (1H, m), 8.78 (1H, d, J = 5.2 Hz)
at 100℃; for 16h;
Step A: 2-(Chloromethyl)pyrimidineA suspension of Chloroacetamidine HCl (5 g, 38.76 mmol) in 1 ,1 ,3,3-tetramethoxy propane (12.5 mL) was heated at 100°C for 16 h. Reaction mixture was diluted with H20 (50 mL), the pH adjusted to ~8 using NaHC03and extracted with DCM (2x 50 mL). The organic layer was washed with brine (50 mL), then 4N Dioxane-HCI (2 mL) was added to the organic layer and stirred for 10 min. The organic layer was dried (Na2S0 ), filtered and evaporated in vacuo to give the crude product (10 g) which was employed in the next step without further purification.
2-amino-4-methoxypyrido[2,3-d]pyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
2.5 gm (40.5%)
With sodium hydrogencarbonate; In water; acetic acid;
EXAMPLE 73 2-Amino-4-methoxypyrido[2,3-d]pyrimidine A quantity of 4.94 gm of <strong>[3270-97-1]2,4-diamino-6-methoxypyrimidine</strong> is heated to boiling in 120 ml of glacial acetic acid and, after the addition of 6.4 ml of 1,1,3,3-tetramethoxypropane, left for a further 45 minutes at boiling temperature. Then, the glacial acetic acid is distilled off and evaporated several times with water, and the residue is taken up in 400 ml of water. After the addition of 5 gm of sodium bicarbonate, the residue is removed by suction filtration and discarded. The filtrate is extracted several times with chloroform, and the combined extracts are washed with sodium bicarbonate solution and then dried over sodium sulfate. The residue remaining after evaporation is purified on silica gel with chloroform and a chloroform/methanol mixture and then recrystallized from water. Yield: 2.5 gm (40.5%) of 2-amino-4-methoxy-pyrido[2,3-d]pyrimidine in the form of crystals, m.p.: 178-180 C. Elementary analysis Calc.: C 54.54 H 4.58 N 31.80. Found: 54.42 4.56 31.77.
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