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With triethylamine; trichlorophosphate; In toluene; at 50 - 80℃;
The 14.4g type IV compounds add 29 ml of toluene and 15.2g in triethylamine, heating to 50-80°C, dropwise 18.4g phosphorus oxychloride, the drop finishes, preserving heat and stirring reaction 5-7 hours, cooling to room temperature, adding water, separating, collecting the organic phase, organic phase is concentrated under reduced pressure, compound III namely type (strawcoloured liquid) 15.4g, molar yield is 95.0percent, HPLC purity of 95.8percent.
34%
With N,N-dimethyl-aniline; trichlorophosphate; at 110℃; for 1.5h;
43b2-Methoxy-5-fluorouracil (43a, 1.04g, 7.21 mmol) and N,N-dimethylaniline (1.80 mL) were heated in POCI3 at 11O0C for 90 minutes. After cooling, the reaction was added carefully to ice. The product was extracted with diethylether. The ether layer was washed with sequentially with 2N HCI, water, and brine followed by drying (MgSO4). The ether was carefully removed under reduced pressure to give 43b as a volatile liquid (0.39g, 34percent) which was used without further purification. Rf = 0.26 (10percent EtOAc/hexane). 1H NMR (400MHz, DMSO-d6): delta 3.91 (s, 3H), 8.79 (s, 1 H)
With acetic acid; In water; at 80℃; for 0.5h;microwave irradiation;
EXAMPLE AA1 : 5-(r(2S.5f?)-4-ethyl-2.5-dimethylpiperazin-1-vncarbonyl)-lambda/-(5-fluoro-2- methoxypyrimidin-4-yl)-6,6-dimethyl-1 ,4,5.6-tetrahvdropyrrolof3.4-clpyrazol-3-amine; A solution of 5-[(2S,5f?)-4-ethyl-2,5-dimethylpiperazin-1-yl]carbonyl}-6,6-dimethyl- 1 ,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine (289 mg, 0.9 mmol) and 4-chloro-5- fluoro-2-methoxypyrimidine (257 mg, 2 eq) in 5 ml_ of 50percent acetic acid in water was heated in a microwave for 30 min at 8O0C. Purification as described in Example AJ. afforded the title compound AA1 as a white powder (13.1 mg, 3percent). See Table 1 below for NMR data.
General conditions1: Chloropyrimidine 5 (0.45 mmol) and aminopyrazole 6 (0.30 mmol) were mixed in 1:1 acetic acid/water solution (1.4 mL) or in glacial acetic acid (1.4 mL) and stirred at 100 °C in an oil bath for 1 h (or 50 °C for 4 h or 25 °C for 18 h). The mixture was neutralized by the addition of ice-cold 5percent NaOH solution (10 mL) and extracted with methylene chloride (3 .x. 25 mL). Combined organic layers were dried and concentrated. The residue was further purified by normal phase flash chromatography (Biotage, for cPropylphenyl analogs R = C) or reversed phase preparative HPLC (analogs with free amines R = A or B), affording the desired aminopyrimidines (7-30).
With trichloromethyl chloroformate; In 1,4-dioxane; N,N-dimethyl-formamide; at 5 - 25℃;Inert atmosphere;
89 g (120 molpercent) of N,N-dimethylformamide and 200 ml of 1,4-dioxane were placed in a thermometer, reflux condenser,In a dropping funnel and a mechanically stirred 1000 ml three-necked flask, the reaction system temperature was lowered to 0 ° C and stirred for 1 hour.The double phosgene gas inlet speed was maintained at 2 g/min, and the reaction temperature was maintained at not more than 5 ° C, and 1.5 mol of diphosgene was introduced in common.Then, 144 g (1.0 mol) of 2-methoxy-4-hydroxy-5-fluoropyrimidine was added in portions, and the reaction temperature was controlled to not exceed 25 °C.After the reaction is completed, nitrogen gas is removed from the system to remove residual phosgene.To the reaction solution, 200 ml of water was added in portions and stirred for 50 minutes, and then the aqueous phase was separated by liquid separation.The aqueous phase was extracted with 200 ml of dichloromethane and the organic phase was combined twice.After isolation and purification, 160 g of a yellow oily liquid was obtained, yield 98.5percent.
91%
As shown in Fig. 1, 144 g (1.0 mol) of 2-methoxy-4-hydroxy-5-fluoropyrimidine, 61.1 g (50 molpercent) of 4-dimethylaminopyridine and 200 mL of nitrobenzene were charged into a single flask A three-necked 1000 mL flask equipped with a thermometer, a reflux condenser, a dropping funnel and a mechanical stirrer was slowly heated to 100 ° C and stirred for 30 minutes. Then the phosgene was started slowly, maintaining the flow rate of 7 g / min. The phosgene was introduced twice as much as the molar amount of 2-methoxy-4-hydroxy-5-fluoropyrimidine and the reaction was refluxed for 20 hours . After the reaction was completed, the phosgene was stopped and the temperature was lowered to room temperature and purged with nitrogen to remove phosgene from the system. Then, the solid was removed by filtration under reduced pressure, 100 mL of water was added to the filtrate and the mixture was stirred for 30 minutes, and then the aqueous phase was separated and separated. The aqueous phase was extracted with 100 mL of ethyl acetate and the organic phases were combined twice and dried over anhydrous sodium sulfate. The solvent was recovered under reduced pressure to give 147.4 g of a yellow oily product in 91percent yield.
To 100 ml dichloroethane and 25 ml acetonitrile as a solvent. Using dichloroethane as a solvent, the first 100 ml dichloroethane and 25 ml acetonitrile is poured into the 250 ml flask is, by adding 14.4g (0.1mol) of 2-methoxy-5-fluoro-4-hydroxy-pyrimidine. After dropwise 32.2g (0.3mol) of phosphorus oxychloride, within half an hour after the dropping, the stirring 10 minutes later, start dropwise triethylamine 21.2g (0.21mol), heating to 60 °C, stirring 2 hours later, cooling. In the reaction solution is poured into the crushed ice, to be layered. Applying the organic phase is 2-methoxy-4-chloro-5-fluoro pyrimidine dichloroethane solution.Then, 15 g of water and hydrazine were added dropwise thereto, and the mixture was heated to 70 ° C and reacted 2h, and the reaction was monitored by HPLC. The product was obtained as white needle crystals. 2-Methoxy-4-hydrazino-5-fluoro pyrimidine 11.98g (0.075 mol), m.p. 187 ° -188 ° C, product content 98.5percent, yield 77percent.
5-fluoro-4-hydrazino-2-methoxypyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
11.98 g
With hydrazine hydrate; In 1,2-dichloro-ethane; at 70℃; for 2h;
To 100 ml dichloroethane and 25 ml acetonitrile as a solvent. Using dichloroethane as a solvent, the first 100 ml dichloroethane and 25 ml acetonitrile is poured into the 250 ml flask is, by adding 14.4g (0.1mol) of 2-methoxy-5-fluoro-4-hydroxy-pyrimidine. After dropwise 32.2g (0.3mol) of phosphorus oxychloride, within half an hour after the dropping, the stirring 10 minutes later, start dropwise triethylamine 21.2g (0.21mol), heating to 60 °C, stirring 2 hours later, cooling. In the reaction solution is poured into the crushed ice, to be layered. Applying the organic phase is 2-methoxy-4-chloro-5-fluoro pyrimidine dichloroethane solution.Then, 15 g of hydrazine hydrate were added dropwise thereto, and the mixture was heated to 70 ° C and reacted 2h, and the reaction was monitored by HPLC. The product was obtained as white needle crystals. 2-Methoxy-4-hydrazino-5-fluoro pyrimidine 11.98g (0.075 mol), m.p. 187 ° -188 ° C, product content 98.5percent, yield 77percent.
The 32.5g formula III compound are added 170g10wt percent of the isopropyl alcohol solution of ammonia, heating to 40-60°C, stirring reaction 3-5 hours, natural cooling to room temperature, filtered, collecting solid, washing with isopropyl alcohol, drying, the compound of formula II is obtained (kind of white solid) 27.2g, molar yield is 95.0percent, HPLC purity of 99.0percent.
methyl 4-(5-fluoro-2-methoxypyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
<Step 1> Synthesis of methyl 4-(5-fluoro-2-methoxypyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylate Using 4-bromo-1-methyl-1H-pyrazole-5-carboxylic acid methyl ester (CAS No.: 514816-42-3, 2.52 g, 11.5 mmol) and <strong>[1801-06-5]4-chloro-5-fluoro-2-methoxypyrimidine</strong> (1.5 g), methyl 4-(5-fluoro-2-methoxypyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylate (1.6 g) was obtained as a pale yellow liquid using a method similar to that in <Step 1> in Working Example 3 or a method based on this method. (Physical property data) LC-MS: M=266, RT=0.91 (min), [M+H]+=267. 1H-NMR (300 MHz, CDCl3, delta ppm): 8.35 (1H, d, J=2 Hz), 7.86 (1H, d, J=1 Hz), 4.15 (3H, s), 4.00 (3H, s), 3.86 (3H, s).
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