* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Journal of the American Chemical Society, 1942, vol. 64, p. 794,797
2
[ 4786-52-1 ]
[ 41103-17-7 ]
Yield
Reaction Conditions
Operation in experiment
99%
With thionyl chloride In tetrahydrofuran for 4 h; Heating / reflux
Ethyl 4-hydroxypyrimidine-5-carboxylate (380 mg, 2.26 mmol) was dissolved in THF (5 mL) and treated with thionyl chloride (1.65 ml, 22.6 mmol). The solution was heated to reflux for 4 h and then concentrated in vacuo, yielding 417 mg (99percent) of the crude product. This material was used without purification or characterization.
99%
With thionyl chloride In tetrahydrofuran for 4 h; Heating / reflux
Ethyl 4-hydroxypyπmιdιne-5-carboxylate (380 mg, 2.26 mmol) was dissolved in THF (5 mL) and treated with thionyl chloride (1.65 ml, 22.6 mmol). The solution was heated to reflux for 4 h and then concentrated in vacuo, yielding 417 mg (99percent) of the crude product This material was used without purification or characterization
99%
With thionyl chloride In tetrahydrofuran for 4 h; Heating / reflux
Ethyl 4-hydroxypyrimidine-5-carboxylate (380 mg, 2.26 mmol) was dissolved in THF (5 mL) and treated with thionyl chloride (1.65 ml, 22.6 mmol). The solution was heated to reflux for 4 h and then concentrated in vacuo, yielding 417 mg (99percent) of the crude product. This material was used without purification or characterization.
95%
at 120℃; for 5 h;
2 g of the compound obtained in step 1) above was dissolved in 3.5 mL of phosphorus oxychloride, and 18 mL of thionylchloride and 50 \\ih of dimethylformamide were added thereto. The mixture was stirred at 120°C under reflux for 5 hours. After the reaction was completed, the reaction mixture was distilled under a reduced pressure. 50 mL of toluene was added to the residue, the resulting residue was distilled under a reduced pressure (repeated twice) and the resulting solid was dried to obtain the title compound (2.1 g, yield: 95percent).1H-NMR (300MHz, DMSO-d6) δ 9.18 (s, 2H), 4.36 {dd, 2H), 1.33 (t, 3H).
77%
With N-ethyl-N,N-diisopropylamine; trichlorophosphate In toluene at 70℃; for 2 h;
To a suspension of ethyl 4-hydroxy-pyrimidine-5-carboxylate (3.0g, 17.6 mmol) in toluene (35ml) was added diisopropylethylamine (3.4 ml, 19.6mmol) and phosphorous oxychloride (1.8 ml, 19.6 mmol) dropwise under a nitrogen atmosphere. The reaction mixture was heated to 700C, and stirred for two hours then cooled to 5°C. A IM aqueous solution of sodium hydroxide (26 ml) was added and the mixture was diluted with water and extracted into ethyl acetate. The organic layer was washed with water, saturated sodium hydrogencarbonate, then dried over sodium sulfate, filtered and concentrated to give the title compound as a brown oil (2.56g, 77percent). 1H NMR (CDCl3, 400 MHz) 9.13 (s, IH), 9.08 (s, IH), 4.47 (q, J = 6.9 Hz, 2H), 1.44 (t, J = 6.9 Hz, 3H).
With sodium; In ethanol; for 3.0h;Heating / reflux;
To a pre-formed solution of sodium (1.70 g, 73.9 mmol) in absolute ethanol(300ml) was added 1,3,5-triazine (6.0 g, 74.1 mmol) and diethylmalonate (11.3 ml, 74.1 mmol). The reaction mixture was heated to reflux. After heating for 3h, the reaction mixture was cooled to room temperature and concentrated under reduced pressure to afford a residue. The residue was dissolved in water (300 ml), then cooled to 5C and acidified by addition of hydrochloric acid (6 ml). The mixture was aged for 48 hours at 5C and filtered. The resultant solid was washed with water, before being dried under reduced pressure to give the title compound as a beige solid (3.0g, 24%). 1H NMR (d6-DMSO, 400 MHz) 8.47 (s, IH), 8.37 (d, s, IH), 4.22 (q, J = 7.2 Hz, 2H), 1.26 (t, J = 7.2 Hz, 3H).
With sodium hydrogencarbonate; triethylamine; trichlorophosphate;
b) Ethyl 4-chloropyrimidine-5-carboxylate To a mixture of ethyl 3,4-dihydro-4-oxopyrimidine-5-carboxylate (3.54 g) (synthesised according to the method reported by A. R. Todd and F. Bergel on J. Chem. Soc., 364 (1937)) and triethylamine (2.13 g) was added dropwise under ice-cooling phosphorus oxychloride (21 ml), and the mixture was then heated for 1.5 hour under reflux. The reaction mixture was concentrated to dryness, which was poured into ice-water, followed by partitioning between chloroform and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and then dried. The solvent was distilled under reduced pressure. The residue was purified by column chromatography on silica gel to afford the title compound as a pale yellow oil (3.42 g, 86%). 1 H-NMR(200 MHz, CDCl3) delta: 1.44(3H,t), 4.47(2H,q), 9.08(1H,s), 9.13(1H,s).
Diethyl malonate (3.14 mL, 20.7 mmol) was combined with N, N', N"- methylidynetrisformamide (3.00 g, 20.7 mmol), and p-toluenesuifonic acid (356 mg, 2.07 mmol), and the reaction mixture was heated to 18O0C for 4 h. The resulting red oil was allowed to cool to rt overnight. The crude reaction mixture was dissolved in a minimum amount of water and allowed to crystallize overnight. The solids were collected by filtration, washed with water, and dried, yielding 822 mg (24%) of the desired product.
24%
With toluene-4-sulfonic acid; at 180℃; for 4.0h;
Diethyl malonate (3.14 mL, 20 7 mmol) was combined with N, N', N"- methylidynet?sformamide (3 00 g, 20.7 mmol), and p-toluenesulfonic acid (356 mg, 2.07 mmol), and the reaction mixture was heated to 180C for 4 h. The resulting red oil was allowed to cool to rt overnight The crude reaction mixture was dissolved in a minimum amount of water and allowed to crystallize overnight. The solids were collected by filtration, washed with water, and dried, yielding 822 mg (24%) of the desired product. 1H NMR (400 MHz, CD3OD) delta 1.38 (t, 3H), 4.32 (q, 2H), 8 32 (s, 1 H), 8 60 (s, 1 H)
24%
With toluene-4-sulfonic acid; at 180℃; for 4.0h;
Diethyl malonate (3.14 mL, 20.7 mmol) was combined with N, N', N"- methylidynetrisformamide (3.00 g, 20.7 mmol), and p-toluenesuifonic acid (356 mg, 2.07 mmol), and the reaction mixture was heated to 18O0C for 4 h. The resulting red oil was allowed to cool to rt overnight. The crude reaction mixture was dissolved in a minimum amount of water and allowed to crystallize overnight. The solids were collected by filtration, washed with water, and dried, yielding 822 mg (24%) of the desired product.
With thionyl chloride; In tetrahydrofuran; for 4h;Heating / reflux;
Ethyl 4-hydroxypyrimidine-5-carboxylate (380 mg, 2.26 mmol) was dissolved in THF (5 mL) and treated with thionyl chloride (1.65 ml, 22.6 mmol). The solution was heated to reflux for 4 h and then concentrated in vacuo, yielding 417 mg (99%) of the crude product. This material was used without purification or characterization.
99%
With thionyl chloride; In tetrahydrofuran; for 4h;Heating / reflux;
Ethyl 4-hydroxypy?miotadiotane-5-carboxylate (380 mg, 2.26 mmol) was dissolved in THF (5 mL) and treated with thionyl chloride (1.65 ml, 22.6 mmol). The solution was heated to reflux for 4 h and then concentrated in vacuo, yielding 417 mg (99%) of the crude product This material was used without purification or characterization
99%
With thionyl chloride; In tetrahydrofuran; for 4h;Heating / reflux;
Ethyl 4-hydroxypyrimidine-5-carboxylate (380 mg, 2.26 mmol) was dissolved in THF (5 mL) and treated with thionyl chloride (1.65 ml, 22.6 mmol). The solution was heated to reflux for 4 h and then concentrated in vacuo, yielding 417 mg (99%) of the crude product. This material was used without purification or characterization.
95%
With thionyl chloride; trichlorophosphate;N,N-dimethyl-formamide; at 120℃; for 5h;
2 g of the compound obtained in step 1) above was dissolved in 3.5 mL of phosphorus oxychloride, and 18 mL of thionylchloride and 50 ih of dimethylformamide were added thereto. The mixture was stirred at 120C under reflux for 5 hours. After the reaction was completed, the reaction mixture was distilled under a reduced pressure. 50 mL of toluene was added to the residue, the resulting residue was distilled under a reduced pressure (repeated twice) and the resulting solid was dried to obtain the title compound (2.1 g, yield: 95%).1H-NMR (300MHz, DMSO-d6) delta 9.18 (s, 2H), 4.36 {dd, 2H), 1.33 (t, 3H).
87.1%
With thionyl chloride; In dichloromethane; at 25 - 65℃; for 3.5h;
(3.0 g, 17.85 mmol) was dissolved in dichloromethane (40 mL).The temperature was raised to 65 C and stirred for 3.5 h.The remaining thionyl chloride was concentrated under reduced pressure to give a yellow oil.Add toluene (20 mL × 3) under reduced pressure and concentrate with water to dry.2.9 g of a yellow oil was obtained in a yield of 87.1%.The product was taken directly to the next step without further purification.
77%
With N-ethyl-N,N-diisopropylamine; trichlorophosphate; In toluene; at 70℃; for 2h;
To a suspension of ethyl 4-hydroxy-pyrimidine-5-carboxylate (3.0g, 17.6 mmol) in toluene (35ml) was added diisopropylethylamine (3.4 ml, 19.6mmol) and phosphorous oxychloride (1.8 ml, 19.6 mmol) dropwise under a nitrogen atmosphere. The reaction mixture was heated to 700C, and stirred for two hours then cooled to 5C. A IM aqueous solution of sodium hydroxide (26 ml) was added and the mixture was diluted with water and extracted into ethyl acetate. The organic layer was washed with water, saturated sodium hydrogencarbonate, then dried over sodium sulfate, filtered and concentrated to give the title compound as a brown oil (2.56g, 77%). 1H NMR (CDCl3, 400 MHz) 9.13 (s, IH), 9.08 (s, IH), 4.47 (q, J = 6.9 Hz, 2H), 1.44 (t, J = 6.9 Hz, 3H).
16 mL of 2-ethoxymethylene-malonate diethylester was mixed with 6.6 g of formamidine hydrochloride, and the mixture was stirred at 160C under reflux for 20 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, and the solid thus obtained by concentration was filtered under a reduced pressure and washed with acetone. The solid was dried under a reduced pressure to obtain the title compound (7.7 g, yield: 56%).1H-NMR (300MHz, CDCl3) delta 8.81 (s, 1H), 8.51 (s, 1H), 4.40 (dd, 2H), 1.35 (t,3H).
4-((1-(3-fluorobenzyl)-1H-indazol-5-yl)amino)-N-(5-(((4aS,7aS)-tetrahydro-2H-[1,4]dioxine[2,3-c]pyrrole-6(3H)-yl)methyl)thiazol-2-yl)pyrimidine-5-carboxamide[ No CAS ]
4-((1-(3-fluorobenzyl)-1H-indazol-5-yl)amino)-N-(5-(((4aR,7aS)-tetrahydro-2H-[1,4]dioxine[2,3-c]pyrrole-6(3H)-yl)methyl)thiazol-2-yl)pyrimidine-5-carboxamide[ No CAS ]
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