* 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.
In a four-necked flask equipped with a reflux condenser, the temperature was raised and stirred, and 228 g of 4,6-dihydroxypyrimidine was added by a constant pressure dropping funnel, the content was 98percent,and the content of 633 g of phosphorus oxychloride was 97percent.The temperature was raised to 40 to 45 ° C, and the content of 408 g of triethylamine was added dropwise with content of 99percent, after the addition was completed, the temperature was raised to 100 to 105 ° C and kept for 2 hours. HPLC (high performance liquid phase) analysis of 4,6-dihydroxypyrimidine was less than 0.2percent, and the reaction was completed. 880g of toluene was added and cooled tom 0~5 °C, 800g of ice water mixture was added, the ice was decomposed to room temperature, the organic phase was decomposed and the aqueous layer was extracted (200 ml of toluene), the organic phase was combined and washed with alkaline water until neutral. Toluene was concentrated. 697 g of toluene dichloropyrimidine solution was obtained, and the purity of 4, 6-dichloropyrimidine was 97.3percent, and the content was 39.91percent. The crude yield was 92percent. The 697 g crude solution was divided into three 240 g, 240 g, 217 g, respectively, as 1, 2, 3, to do the distillation experiment: The temperature of the top of the steam packed tower is required to reach 94 ° C ~ 96 ° C, when the temperature was reached, the concentrated organic phase was added dropwise, the feed rate was controlled, the balance was adjusted to prevent the stripper tower from cooling; The obtained organic phase, the quality of the aqueous phase and the purity and concentration of 4,6-dichloropyrimidine are shown in Table 1, the obtained organic phase was concentrated, cooled, crystallized, centrifuged or filtered to obtain a high purity product. The refined yield was as high as 98percent or more, and the appearance was white crystal. The experimental results are shown in Table 1.
97%
With bis(trichloromethyl) carbonate; sulfuric acid In N,N-dimethyl-formamide; 1,2-dichloro-benzene at 80℃; for 4.2 h; Industrial scale
In the reaction container (such as test flat glass reaction bottle) by adding 4,6-dihydroxypyrimidine 11.2 grams, sulfuric acid 20 ml, N, N-dimethylformamide 0.5 ml, mixed evenly, heated to 80 ° C, Mixed solution, 30 grams of triphosgene dissolved in 50 ml of dichlorobenzene, 1.2 hours slowly dropping added to the mixed solution, continued to heat after stirring for 3 hours, cooled to room temperature, pour ice water, the separation of organic Solvent layer and organic solvent layer, and then dried with anhydrous magnesium sulfate to obtain 4,6-dichloropyrimidine, the yield is 97percent, the mass content is more than 99percent (determined by high performance liquid phase method)
96.2%
With cobalt(II) phthalocyanine; bis(trichloromethyl) carbonate; Triphenylphosphine oxide In nitrobenzene at 90 - 95℃; for 5 h;
212 g of triphosgene (content 99percent, 0.71 mol) was dissolved in 500 mL of nitrobenzene for use.In a device equipped with a reflux condenser, a thermometer, a stirrer and a constant pressure dropping funnel,Add 4,6-dihydroxypyrimidine (114 g, content 98percent, 1 mol), triphenylphosphine oxide (8.4 g, content 99percent,0.03 mol), cobalt phthalocyanine (0.57 g, 0.001 mol), stirred and mixed evenly,The temperature was raised to 90-95 ° C, and a solution of triphosgene in nitrobenzene was added dropwise.After 5 hours of reaction, the sample was analyzed, and the content of 4,6-dihydroxypyrimidine was 0.25percent and the content of 4,6-dichloropyrimidine was 98.2percent by HPLC. The reaction was completed.Vacuum distillation reaction mixture (oil bath temperature 95 ° C, vacuum -0.095 Mpa),143.8 g (content 99.7percent) of 4,6-dichloropyrimidine was obtained in a yield of 96.2percent (based on 4,6-dihydroxypyrimidine).
94.9%
at 95 - 100℃; for 8 h; Large scale
In a device equipped with a reflux condenser, a thermometer, a stirrer and a constant pressure dropping funnel, 4,6-dihydroxypyrimidine(114.3 g, 98percent, 1 mol), phosphorus oxychloride (1140 g, 99percent) were stirred and mixed, the temperature was raised to 95-100 ° C,And slowly adding phosgene (220g, 99percent, 2.2mol) for 8 hours after the sample, HPLC analysis of 4,6 - dihydroxypyrimidine containing, The reaction was completed and the reaction mixture was distilled under reduced pressure (oil bath temperature 95 ° C,(Content 99percent); 4,6-dichloropyrimidine 142.8 g (content 99.0percent),The yield of 94.9percent (based on 4,6-dihydroxypyrimidine), where W (DCP) meansDCP quality, W (DHP) refers to the quality of DHP, the content refers to the mass content of DCP, 112 for DHP moleculesAnd 149 is the molecular weight of DCP.
94.9%
at 95 - 100℃; for 8 h; Large scale
With a reflux condenser, thermometer,In the device of the agitator and the constant pressure dropping funnel,Add 4,6-dihydroxypyrimidine (114.3 g, content 98percent, 1 mol), phosphorus oxychloride (1140 g, 99percent) and mix well.The temperature was raised to 95-100 ° C, and phosgene (220 g, 99percent, 2.2 mol) was slowly added to carry out the reaction, and the sample was taken after 8 hours.HPLC analysis of 4,6-dihydroxypyrimidine content of 0.9percent,The content of 4,6-dichloropyrimidine was 98.3percent, and the reaction was over.Vacuum distillation reaction mixture (oil bath temperature 95 ° C,Vacuum degree -0.095MPa),Obtained 1082 g of phosphorus oxychloride (content 99percent); 142.8 g of 4,6-dichloropyrimidine (content 99.0percent),Yield 94.9percent (based on 4,6-dihydroxypyrimidine), wherein W (DCP) refers to the mass of DCP, and W (DHP) refers to the mass of DHP.The content refers to the mass content of DCP, and 112 is the molecular weight of DHP.149 is the molecular weight of DCP.
78%
With pyridine; phosgene In chloroform at 50℃; for 3 h;
0.5 mol of 4,6-dihydroxypyrimidine was added to the reaction vessel,Solvents Trichloromethane,0.05 mol of pyridine catalyst,Then slowly into the phosgene 1.5mol,The reaction temperature was controlled within 50 ° C,After reaction for 3 h,After the completion of the reaction, the excess solvent chloroform was distilled off under reduced pressure,To give a 4,6-dichloropyrimidine solution,And then filtered, concentrated and crystallized to give 4,6-dichloropyrimidine as white needles.The yield of product 4,6-dichloropyrimidine prepared by the above method was 78percent and the purity was 80percent.
58%
With trichlorophosphate In water; <i>N</i>,<i>N</i>-dimethyl-aniline; chlorobenzene
Example 7 (for comparison) 460 g of phosphorus oxychloride and 62 g of N,N-dimethylaniline were mixed and 116 g of 4,6-dihydroxypyrimidine (98percent pure) were metered into the mixture with a screw at 100° C. in the course of 5 hours. Thereafter, the reaction mixture was subsequently stirred at 106° to 128° C. for 8 hours. It was diluted with 300 g of chlorobenzene and discharged onto 1.2 kg of ice. The organic phase was separated off, washed twice with 100 ml of water each time and then subjected to fractional distillation. 85.7 g of 4,6-dichloropyrimidine (=58percent of theory) are thus obtained.
Reference：
[1] Patent: CN108395409, 2018, A, . Location in patent: Paragraph 0039-0041; 0044
[2] Patent: CN105439963, 2016, A, . Location in patent: Paragraph 0011
[3] Patent: CN108341784, 2018, A, . Location in patent: Paragraph 0027; 0028; 0029; 0031-0033; 0039; 0040
[4] Patent: CN105732514, 2016, A, . Location in patent: Paragraph 0027; 0028
[5] Patent: CN108178749, 2018, A, . Location in patent: Paragraph 0027; 0028; 0030; 0032; 0034; 0036; 0038; 0040
[6] Synlett, 2010, # 14, p. 2179 - 2183
[7] Patent: CN105859637, 2016, A, . Location in patent: Paragraph 0023; 0024
[8] Patent: US5719285, 1998, A,
[9] Journal of Organic Chemistry, 2015, vol. 80, # 5, p. 2676 - 2699
[10] Patent: US2002/42514, 2002, A1,
[11] Beilstein Journal of Organic Chemistry, 2013, vol. 9, p. 2629 - 2634
[12] Patent: CN106045917, 2016, A, . Location in patent: Paragraph 0018; 0019
[13] Patent: CN106187913, 2016, A, . Location in patent: Paragraph 0014; 0015; 0016
[14] Patent: CN106187912, 2016, A, . Location in patent: Paragraph 0016; 0017
2
[ 75-44-5 ]
[ 1193-24-4 ]
[ 1193-21-1 ]
Yield
Reaction Conditions
Operation in experiment
80%
With 2,3-Dimethylaniline In dichloromethane; water
EXAMPLE 2 4,6-Dihydroxypyrimidine (20.5 g) was dispersed with agitation in dichloromethane (400 ml). Dimethylaniline (40.4 g) was added to the agitated mixture and the system was sealed (except for a vent line to a scrubber). Phosgene gas (56 g) was introduced from a cylinder and condensed onto a cold finger and collected in a pressure equalised dropping funnel. Once collected, the phosgene liquid was added to the reaction mixture over 15 minutes. The mixture was heated and agitated at reflux (29° C. approximately) for 17 hours after which time the mixture was cooled to room temperature and the excess phosgene removed by sparging with nitrogen. Water (400 ml) was added slowly to the agitated reaction mass with cooling to maintain the temperature at ambient. The organic layer was separated, and the aqueous was then extracted with dichloromethane (2*100 ml). The combined extracts were dried over anhydrous sodium sulphate and concentrated by rotary evaporation to give 4,6-dichloropyrimidine as an orange crystalline solid (27 g), equivalent to a yield of 80percent (hplc analysis).
Reference：
[1] Patent: US5750694, 1998, A,
[2] Patent: US5750694, 1998, A,
3
[ 104-90-5 ]
[ 1193-24-4 ]
[ 1193-21-1 ]
Reference：
[1] Patent: US5719285, 1998, A,
[2] Patent: US5719285, 1998, A,
4
[ 75-44-5 ]
[ 1122-58-3 ]
[ 1193-24-4 ]
[ 1193-21-1 ]
Reference：
[1] Patent: US5750694, 1998, A,
5
[ 288-32-4 ]
[ 75-44-5 ]
[ 1193-24-4 ]
[ 1193-21-1 ]
Reference：
[1] Patent: US5750694, 1998, A,
6
[ 75-44-5 ]
[ 1193-24-4 ]
[ 791-28-6 ]
[ 2526-64-9 ]
[ 1193-21-1 ]
Reference：
[1] Patent: US6160117, 2000, A,
7
[ 1193-24-4 ]
[ 1780-27-4 ]
Yield
Reaction Conditions
Operation in experiment
86%
With sulfuryl dichloride; triethylamine; trichlorophosphate In chlorobenzene at 40 - 83℃; for 19 h;
Example 2; To a 1000 mL four-neck flask, 89.7 g of 4,6-dihydroxypyrimidine and 179.3 g of chlorobenzene were added. The obtained mixture was adjusted at 40°C, and then, 129.6 g of sulfuryl chloride was added dropwise thereto over 1 hour. The obtained mixture was maintained at the same temperature for 6 hours. To the obtained reaction mixture, 269.9 g of phosphorus oxychloride was added at the same temperature. Further, 178.1 g of triethylamine was added dropwise thereto over 2 hours at an inner temperature of 40 to 80°C. After completion of the addition, the obtained mixture was maintained at 83°C for 10 hours. The obtained reaction mixture was cooled to room temperature. To another 100 mL four-neck flask, 269.0 g of water was added followed by adjusting at 40°C. To it, the obtained reaction mixture was added dropwise over 30 minutes. The inner temperature during the addition was 30 to 50°C. The obtained mixture was filtrated using Radiolite (registered trademark) and the obtained filtrate was separated to an organic layer and an aqueous layer. The aqueous layer was extracted with 44.8 g of chlorobenzene, and the obtained chlorobenzene layer was mixed with the previously obtained organic layer. The organic layer after mixing was washed with 44.8 g of water and then, concentrated under reduced pressure to obtain 169.2 g of black oily matter. The oily matter was analyzed by high performance liquid chromatography internal standard method, and 126.9 g of 4,5,6-trichlorpyrimidine was containd in the oily matter. The yield was 86percent.
Reference：
[1] Synthetic Communications, 1993, vol. 23, # 17, p. 2363 - 2369
[2] Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 18, p. 2419 - 2422
11
[ 77287-34-4 ]
[ 108-59-8 ]
[ 1193-24-4 ]
Yield
Reaction Conditions
Operation in experiment
82.5%
Stage #1: With sodium methylate In methanol at 95℃; for 1 h; Stage #2: With hydrogenchloride In water at 35℃;
80.0 g of dimethyl malonate and 60.0 g of formamide were mixed,At 100 excess sodium methoxide methanol solution was added, incubated for 1h,A mixture of 4,6-dihydroxypyrimidine sodium salt was obtained; subsequently, the temperature was lowered to 70CConcentrate the methanol and add water to continue to concentrate; then add water to dissolve4, 6-dihydroxypyrimidine sodium salt mixture to form 4,6-dihydroxypyrimidine reaction solution.The bipolar membrane was used to treat it until the pH of the bipolar membrane treatment solution was 9.0.The resulting bipolar membrane treatment solution was acidified with 131.9 g of 37percent strength by weight hydrochloric acid at 40 ° C,Acidified to a solution pH of 2.5, then the resulting acid solution was suction filtered and dried,55.9 g of 4,6-dihydroxypyrimidine product was obtained. After testing, the purity of the product was 98.2percentYield 82.1percent.
Reference：
[1] Patent: CN106883186, 2017, A, . Location in patent: Paragraph 0037; 0038; 0039; 0040; 0041; 0042; 0043-0052
[2] Patent: CN105859637, 2016, A, . Location in patent: Paragraph 0020; 0021; 0022
12
[ 108-59-8 ]
[ 1193-24-4 ]
Yield
Reaction Conditions
Operation in experiment
96%
With sulfuric acid; sodium methylate; formamide In methanol; water
EXAMPLE 1 To a stirred solution of sodium methoxide (140 g, 0.7 mol of a 27percent solution in methanol) under nitrogen was added formamide (27.0 g, 0.6 mol) over about 5 minutes. The resulting reaction mixture was heated to 50° C. and then dimethyl malonate (26.4 g, 0.2 mol) added dropwise over 1 hour. The resulting white suspension was held at 50° C. for a further hour and then cooled to ambient temperature. Water (100 ml) was added to dissolve all the solid and the resulting straw-coloured solution was stirred for about 15 minutes and then the methanol was removed under vacuum (final pot at 50° C. under 100 mmHg vacuum). Water (40 ml) was added and then 36percent sulphuric acid (90 g) added to give a final pH of 2.2. Once the acid had been added the temperature was kept at about 35° C. The yellow suspension was stirred for 1 hour, filtered and washed with water (2*25 g). The water-wet paste was dried overnight under vacuum at 50° C. to provide 4,6-dihydroxypyrimidine (16.2 g, 70percent yield, 96percent strength).
75.1%
With hydrogenchloride; sodium methylate; formamide In methanol; water
EXAMPLE 2 To a stirred solution of sodium methoxide (63 g of a 30percent solution in methanol containing 0.35 mol) under nitrogen was added formamide (13.5 g, 0.3 mol) over 5 minutes. The resulting reaction mixture was heated to 50° C. and then dimethyl malonate (13.2 g, 0.1 mol) added dropwise over 1 hour. The resulting white suspension was held at 50° C. for a further hour and then cooled to ambient temperature. Water (50 ml) was added to dissolve all the solid and the resulting straw-coloured solution was stirred for about 15 minutes and then methanol was removed under vacuum (final pot at 50° C. under 100 mmHg vacuum) until signs of solid could be seen. Water (20 ml) added and then 36percent hydrochloric acid added to give a final pH of 2.1. The resulting yellow suspension was stirred for 1 hour, filtered and washed with water (2*15 ml). The water-wet paste was dried overnight under vacuum at 50° C. to provide 4,6-dihydroxypyrimidine (8.75 g at 96.2percent strength, 75.1percent yield).
Reference：
[1] Patent: US6096892, 2000, A,
[2] Patent: US6096892, 2000, A,
[3] Patent: US6096892, 2000, A,
[4] Patent: US6096892, 2000, A,
13
[ 77287-34-4 ]
[ 105-53-3 ]
[ 1193-24-4 ]
Reference：
[1] Synlett, 2010, # 14, p. 2179 - 2183
[2] Journal of Labelled Compounds and Radiopharmaceuticals, 2008, vol. 51, # 1, p. 54 - 58
14
[ 289-95-2 ]
[ 1193-24-4 ]
Reference：
[1] Patent: CN107868057, 2018, A, . Location in patent: Paragraph 0018-0041
15
[ 143-37-3 ]
[ 105-53-3 ]
[ 1193-24-4 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 17, p. 5721 - 5726
Reference：
[1] Chemische Berichte, 1938, vol. 71, p. 87,99
[2] Journal of the Chemical Society, 1943, p. 388
[3] Journal of the American Chemical Society, 1940, vol. 62, p. 606
[4] Journal of the Chemical Society, 1943, p. 388
Stage #1: at 0℃; for 1 h; Stage #2: at 20℃; for 0.5 h;
EXAMPLE 1; 4-[6-Amino-5-(methoxyimino-methyl)-pyrimidin-4-yl]-piperazine-l-carboxylic acid (4-isopropoxy-phenyl)-amidea. 4,6-Dichloro-pyrimidine-5-carbaldehyde; A mixture of DMF (3.2 mL) and POCl3 (10 mL) at 0 0C was stirred for 1 h, treated with 4,6-dihydroxypyrimidine (2.5 g, 22.3 mmol), and stirred for 0.5 h at ambient EPO <DP n="48"/>temperature. The heterogeneous mixture was heated at reflux for 3 h and the volatiles were removed at reduced pressure. The residue was poured into ice water and extracted six times with ethyl ether. The organic phase was washed with aqueous NaHCO3, dried over Na2SO4 and concentrated to afford a yellow solid (3.7 g, 95percent). 1H NMR (CDCl3) δ 10.46 (s, IH), 8.90 (s, IH).
A mixture of DMF (3.2 mL) and POCl3 (10 mL) at 0° C. was stirred for 1 h, treated with 4,6-dihydroxypyrimidine (2.5 g, 22.3 mmol), and stirred for 0.5 h at ambient temperature. The heterogeneous mixture was heated at reflux for 3 h and the volatiles were removed at reduced pressure. The residue was poured into ice water and extracted six times with ethyl ether. The organic phase was washed with aqueous NaHCO3, dried over Na2SO4 and concentrated to afford a yellow solid (3.7 g, 95percent). 1H NMR (CDCl3) δ 10.46 (s, 1H), 8.90 (s, 1H).
95%
at 0 - 20℃; for 4.5 h; Heating / reflux
A mixture of DMF (3.2 mL) and POCl3 (10 mL) at 0° C. was stirred for 1 h, treated with 4,6-dihydroxypyrimidine (2.5 g, 22.3 mmol), and stirred for 0.5 h at ambient temperature. The heterogeneous mixture was heated at reflux for 3 h and the volatiles were removed at reduced pressure. The residue was poured into ice water and extracted six times with ethyl ether. The organic phase was washed with aqueous NaHCO3, dried over Na2SO4 and concentrated to afford a yellow solid (3.7 g, 95percent). 1H NMR (CDCl3) δ 10.46 (s, 1H), 8.90 (s, 1H).
95%
at 0 - 20℃; for 4.5 h;
b. 4,6-Dichloro-pyrimidine-5-carbaldehyde A mixture of DMF (3.2 mL) and POCl3 (10 mL) at 0° C. was stirred for 1 h, treated with 4,6-dihydroxypyrimidine (2.5 g, 22.3 mmol), and stirred for 0.5 h at ambient temperature. The heterogeneous mixture was heated at reflux for 3 h and the volatiles were removed at reduced pressure. The residue was poured into ice water and extracted six times with ethyl ether. The organic phase was washed with aqueous NaHCO3, dried over Na2SO4 and concentrated to afford a yellow solid (3.7 g, 95percent). 1H NMR (CDCl3) δ 10.46 (s, 1H), 8.90 (s, 1H).
95%
Stage #1: at 0℃; for 1 h; Stage #2: at 20℃; for 3.5 h; Reflux
Amixture of DMF (3.2 mL, 41.34mmol) and POCl3 (10 mL,109,24mmol) at 0° C. was stirred for 1 h, treated with 4,6-dihydroxypyrimidine(2.5 g, 22.3mmol), and stirred for 0.5 h at ambient temperature. Theheterogeneous mixture was heated at reflux for 3 h and the volatiles wereremoved at reduced pressure. The residue was poured into ice water andextracted six times with ethyl ether. The organic phase was washed with aqueousNaHCO3, dried over anhydrous Na2SO4 andconcentrated to afford a yellow solid (3.7 g, 95percent).
94%
at 70℃; for 24 h;
A 250mL three-necked flask was added POCl3 (91.4 mL, 1.12 mol) and cooledto -10 °C. With stirring, DMF (30.1 mL, 0.446 mol) was added in 30 min. then 3 (25 g, 0.223 mol) was added. Thereactor was heated to maintain at 70°C for 24 h. After being cooled to room temperature,the reaction mixture was poured into 500 mL of cold water (0-5 °C) withstirring. The resulting mixture was extracted with ethyl acetate (3×600 ml)., which was washed with brine (600 mL)and dried over Na2SO4. The organic phase was evaporatedto give the crude product, which was isolated by column chromatography onsilica gel (EtOAc-petroleum = 1:10, v/v) to give the title compound (37.1 g, 94.0percent) as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm: 10.48(s, 1H), 8.91 (s, 1H).
85%
Stage #1: at 0℃; for 1 h; Stage #2: at 0 - 20℃; for 3.5 h; Reflux
30 mL of phosphorylchloride (POCl3) was cooled down to 0° C., to which 9.6 mL of anhydrous dimethylformamide (DMF) was slowly added. 1 hour later, 7.85 g (70.0 mmol) of 4,6-dihydroxypyrimidine was added thereto. The reaction mixture was heated at room temperature, followed by stirring at room temperature for 30 minutes. The reaction mixture was refluxed for 3 hours. The mixture was cooled down to room temperature. The reaction mixture was slowly added to ice water, followed by extraction with ethylacetate. The extracted organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained solid was washed with hexane/diethyl ether (5/1, v/v) to give 10.5 g of 4,6-dichloropyrimidine-5-carbaldehyde as a white solid (5.95 mmol, yield: 85percent). 1H NMR(300 MHz, CDCl3) δ 10.47 (s, 1H), 8.90 (s, 1H).
75%
at 0 - 110℃; for 5 h;
To DMF (64 niL) at O0C was added POCl3 (200 niL) dropwise. After 1 hour, 2,4-dihydroxypyrimidine (50 g, 446 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour and then at HO0C for 3 hours. After cooling to room temperature the solution was poured into ice water portion wise, being careful to keep the mixture from becoming excessively exothermic. The mixture was extracted with ether (8X); the combined organic layer was washed with saturated NaHCO3, dried over Na2SO4, and concentrated in vacuo to provide compound 1.1 (58.6 g, 75percent) as a pale yellow solid.
75.4%
for 3 h; Cooling with ice; Reflux
DMF (5.50 mL, 71.34 mmol) was slowly added dropwise under ice-coolingPOCl3 (17.00 mL, 185.71 mmol),Stirring reaction 1h,Remove the ice bath,4,6-dihydroxypyrimidine (4.00 g, 35.68 mmol) was added,Temperature reflux 3h,Cooled to room temperature,Poured into ice water,Dichloromethane extraction,Concentrated under reduced pressure,Petroleum ether-ethyl acetate (P: E = 4: 1 (V: V)),4.74 g of a yellow solid,Yield 75.4percent
74%
Stage #1: at 0℃; for 1 h; Stage #2: for 3.5 h; Reflux
Example 1-Synthesis of 4, 6-dichloropyrimidine-5-carbaldehyde 1 This compound was synthesized similar to a patent. To POCl3 (107.3 mmol, 10 mL) cooled at 0° C. was added DMF (41.3 mmol, 3.2 mL) dropwise, and the mixture was stirred for 1 h. Then, 4, 6-dihydroxylpyrimidine (22.3 mmol, 2.50 g) was added, stirred for 30 minutes and refluxed for 3 h. After removing the volatiles at reduced pressure, it was poured into ice and extracted with ethyl acetate three times (3*200 mL). The combined ethyl acetate extracts were washed with 200 mL saturated NaHCO3, dried with Na2SO4, and concentrated under reduced pressure to afford 2.91 g, 74percent of the desired compound as an orange solid. 1H NMR (500 MHz, CDCl3): δ 10.48 (s, 1H), 9.92 (s, 1H). 13C NMR (125 MHz, CDCl3): δ 185.61, 162.69, 159.58, 124.89.
72.7%
Stage #1: at 0℃; for 0.5 h; Stage #2: at 120℃; for 5 h;
The DMF 30ml of dimethylformamide and 80ml of phosphorus oxychloride were mixed and stirred at 0 30 minutes,Was added 4,6-dihydroxypyrimidine and 20.0g (0.18mol). Heated to 120 , refluxed for 5 hours. Concentrated under reduced pressureTo dryness, the residue was poured into ice water, extracted three times with ethyl acetate, the combined organic phases, the organic phase was driedAnd concentrated to give a yellow solid 23.1g, yield 72.7percent.
70%
Stage #1: at 0 - 10℃; for 1 h; Inert atmosphere Stage #2: Inert atmosphere
(1) Weigh POCl3 (4 eq) into the reaction flask, and under nitrogen protection, cool to about 0°C. Add DMF (1.85 eq) to the feed solution. When adding, control the temperature at 08°C, add it. Feed solution 0 ~ 10 °C, stirring 1h,To the solution was added 4,6-dihydroxypyrimidine. After the addition was completed, the mixture was naturally warmed to room temperature and stirred for 1 hour. Then, the mixture was warmed to reflux and stirred for 2 hours. The mixture was cooled and stirred overnight.The feed solution was evaporated under reduced pressure to remove excess POCl3, the residue was slowly added to ice water, the product was extracted with ethyl acetate (2 volumes *3), the organic phases were combined, washed with water (2 volumes) and washed with saturated sodium bicarbonate solution (2 The volume of) was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude 4,6-dichloropyrimidine-5-carboxaldehyde (yield: 70percent), which was used directly in the next reaction.
68%
Stage #1: at 0℃; Inert atmosphere Stage #2: at 20 - 135℃; for 5 h; Reflux
Intermediate 16: 4,6-Dichloro-pyrimidine-5-carbaldehyde; Phosphorous oxychloride (249 mL, 671 mmol) was added slowly to dimethylformamide (75 mL) with continuous stirring at 0° C. under nitrogen. After the addition was complete, was added 4,6-dihydroxypyrimidine (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA 50.0 g, 446 mmol) and stirred at room temperature for 2 hours followed by refluxing (135° C.) for 3 hours. The reaction mixture was cooled to room temperature, poured into chilled water with stirring and extracted with diethyl ether (3.x.200 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo to give 4,6-dichloro-pyrimidine-5-carbaldehyde (54.0 g, 68percent) as a white solid, which was used for the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 8.88 (s, 1H), 10.45 (s, 1H).
68.4%
Stage #1: at 0 - 10℃; for 3.5 h; Inert atmosphere Stage #2: at 3 - 155℃; Inert atmosphere Stage #3: at 20℃;
4,6-Dichloropyrimidine-5-carbaldehyde (26) [0168] In a 5 L 4-neck flask equipped with a mechanical stirrer, an addition funnel, a condenser, a thermocouple, and a N2 sweep into an aqueous NaOH scrubbing solution, phosphorous oxychloride (POCl3, 1 L, 10.572 mol, 4.82 equiv) was charged and cooled in an ice/salt bath. N,N-Dimethylformamide (DMF, 320 mL, 4.138 mol, 1.85 equiv) was then added dropwise to the flask at 0±2° C. After addition of approximately 100 mL of DMF over approximately 0.5 h, crystallization occurred and the reaction temperature was increased from 0 to 10° C. Addition was stopped and the mixture was allowed to re-cool to approximately 2° C. The remaining DMF was added over 2.5 h at below 8° C. The suspension became very thick making stirring difficult. When addition of DMF was complete, the mixture was stirred at 3-5° C. for 0.5 h. 4,6-Dihydroxypyrimidine (250 g, 2.232 mol) was added portion wise as a solid. After about one third of 4,6-dihydroxypyrimidine was added, the reaction mixture became more mobile, and a slow exothermic phenomena occurred with the reaction temperature increasing to approximately 12° C. over 0.5 h. The remaining 4,6-dihydroxypyrimidine was added portion wise over 0.25 h with the reaction temperature increasing from 12 to 27° C. The reaction temperature was maintained at 25-27° C. with intermittent cooling during which time the yellow suspension became thinner, then thicker once again. After the exothermic phenomenon subsided in about 1 h, the reaction mixture was heated slowly. At about 55° C. the reaction mixture became extremely thick and the second mild exothermic phenomenon was occurred. The heating mantle was removed while the reaction temperature continued to increase to about 63° C. and remained at this temperature for several minutes before dropping. Heating of the mixture was resumed until gentle reflux (about 100° C.) was attained. At about 95° C. a steady, fairly rapid evolution of HCl gas began and the reaction mixture gradually thinned and darkened. After about 0.5 h, a clear brown solution developed with the reflux temperature slowly increasing to 115° C. over 1.25 h. After a total of 2.5 h at reflux, the reaction mixture was cooled to ambient temperature and stirred overnight at ambient temperature. Excess amount of POCl3 (as much as possible) was removed under reduced pressure (bath temperature 45-50° C.). The thick residual brown oil was poured very slowly into cold H2O (5 L) in a 20 L separation funnel, adding ice as needed to maintain the aqueous mixture near room temperature. The aqueous mixture was extracted with EtOAc (2×3 L followed by 1×2 L). The combined EtOAc extracts were washed with H2O (2×2.5 L), saturated NaHCO3 aqueous solution (1 L), brine (1 L), dried over Na2SO4, filtered, and concentrated under reduced pressure (bath temperature at 35° C.) to afford the crude 4,6-dichloropyrimidine-5-carbaldehyde (270 g, 395 g theoretical, 68.4percent) as yellow-orange solids. A 20 g portion of this crude material was purified by Kugelrohr distillation (oven temperature at 90-100° C., 225 mTorr) to give 15.3 g of pure 4,6-dichloropyrimidine-5-carbaldehyde as a white solid that turned yellow on standing at room temperature. 1H NMR (300 MHz, CDCl3) δ 10.46 (s, 1H), 8.89 (s, 1H) ppm.
58%
at 0 - 20℃; for 3 h; Heating / reflux
Dimethylformamide (31.82 mL, 413 mmol) was added dropwise to phosphorus oxychloride (100 mL, 1.07 mol) at O0C. To this mixture at O0C was added 4, 6- dihydroxypyrimidine (25 g, 223 mmol). The mixture was stirred at rt for 30 min and then at reflux for 2.5 h. The volatiles were removed in vacuo and the mixture was poured over ice water and extracted 6X with ether. The combined organics were washed with aqueous saturated sodium bicarbonate and dried over sodium sulfate to give 22.78 g (58percent) of 4,6- dichloro-5-formylpyrimidine (J. Med. Chem. 2002, 45, 3639).
57%
Stage #1: at 0℃; for 0.3 h; Stage #2: at 130℃; for 3.5 h;
To cooled (0° C.) phosphorus oxychloride (20.0 mL, 215 mmol, 4.8 equiv.) was added DMF (6.4 mL, 83 mmol, 1.9 equiv) dropwise over 3 min. The reaction mixture was stirred for fifteen min and the ice bath was removed. 4,6-Dihydroxypyrimidine (5.0 g, 44.6 mmol, 1.0 equiv.) was added and the reaction mixture was heated to 130° C. and stirred for 3.5 hr. The mixture was cooled to RT and concentrated. Ice was slowly added to the dark brown residue, followed by 600 mL of ice water. The aqueous mixture was extracted with diethyl ether (5.x.100 mL), and the organic extracts were washed with aqueous saturated NaHCO3 (2.x.100 mL) and brine (100 mL), and dried over anhydrous sodium sulfate and concentrated in vacuo to provide Compound 15 (4.42 g, 57percent) as a crude orange solid, which was used without further purification.
57%
Stage #1: at 0℃; for 1 h; Stage #2: at 20℃; for 3.5 h; Heating / reflux
(Ref: A. Gomtsyan, S. Didomenico, C-H. Lee, M. A. Matulenko, K. Kim, E. A. Kowaluk, C. T. Wismer, J. Mikusa, H. Yu, K. Kohlhass, M. F. Jarvis, S. S. Bhagwat; J. Med. Chem., 2002, 45, 3639-3648.) A mixture of DMF (32 mL) and POCl3 (100 mL) at 0° C. was stirred for 1 hour, treated with 4,6-dihydroxypyrimidine (25.0 g, 223 mmol), and stirred for 0.5 hour at room temperature. The heterogeneous mixture was then heated to refluxed and stirred for 3 hours. The reaction was cooled to room temperature and the resulting viscous, black liquid was poured onto ice water and extracted with diethyl ether (6.x.100 mL). The organic phase was subsequently washed with NaHCO3, and water, dried over MgSO4, and concentrated to give 25 as a yellow solid (20.0 g, 57percent yield). 1H NMR (CDCl3) δ 10.41 (s, 1H), 8.85 (s, 1H).
56%
at 30℃; for 4.33333 h; Heating / reflux
DMF (7 mL) was added dropwise to POC13 (22 mL) keeping the internal temperature below 30 °C. 4, [6-DIHYDROXYPYRIMIDINE] [(5. 0] g) was added maintaining the temperature below [30 °C.] The reaction mixture was stirred for 20 minutes and then heated to reflux for 4 hours. Excess POC13 was removed by evaporation and the resulting viscous mixture was poured into a stirred ice solution. The product was extracted with diethyl ether (6 x 50 mL). The combined organics were concentrated in vacuo and then purified by flash chromatography on silica eluting with hexane: EtOAc (7: 1 to 2: 1) to afford the title compound as [A] white crystalline solid (4.42 g, 56percent); [1H] NMR [(CDC13)] 8 8. 89 (s, 1H), 10.46 (s, 1H).
55%
at 0 - 20℃; for 4.5 h; Reflux
4,6-Dichloro-5-pyrimidinecarbaldehyde; A mixture of DMF (64 mL) and POCl3 (200 mL) at 0° C. was stirred for 1 h and then treated with 4,6-pyrimidinediol (50.0 g, 446 mmol), and further stirred for 0.5 h at rt. Then the heterogeneous mixture was heated under reflux for 3 h. The volatiles were removed under reduced pressure, and the residue was poured into ice water and extracted six times with diethyl ether. The organic phase was washed with aqueous NaHCO3 and water, dried over Na2SO4, concentrated under reduced pressure, and crystallized (EtOAc-petroleum ether) to give 4,6-dichloro-5-pyrimidinecarbaldehyde (43.5 g, 55percent); LC-MS (ESI) m/z 177 [M+H]+.
40%
Stage #1: at 0℃; for 1 h; Stage #2: at 0℃; for 4 h; Heating / reflux
Preparation 95-A; 4.6-Dichloropyrimidine-5-carbaldehvde; Charge DMF (8.9 mL, 1.3eq) in a round bottom flask and cool to 00C. Add POCl3 (32.6 mL, 4.0eq) to the reaction drop wise at 00C. Stir the reaction mass at 00C for Ih. Charge 4,6-dihydroxy pyrimidine (10.Og, l.Oeq) to the reaction mass and allowed it to come to room temperature slowly. Reflux the reaction mass for 4h and monitor the reaction by TLC (10percent acetone in DCM). Concentrate the reaction mass under vacuum and pour the concentrated reaction mass over crushed ice. Extract the product with diethyl ether and wash with saturated aq. sodium chloride. Dry the organic layer over anhydrous sodium sulfate and concentrate it under vacuum to get pale yellow solid as product (6.2g, 40 percent).
Reference：
[1] Patent: US2006/281700, 2006, A1, . Location in patent: Page/Page column 34
[2] Patent: US2006/281755, 2006, A1, . Location in patent: Page/Page column 40
[3] Patent: US2006/281764, 2006, A1, . Location in patent: Page/Page column 25
[4] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 16, p. 3353 - 3358
[5] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 12, p. 2936 - 2941
[6] Patent: US2018/105527, 2018, A1, . Location in patent: Paragraph 0797-0799
[7] Patent: WO2006/65703, 2006, A1, . Location in patent: Page/Page column 94
[8] Patent: CN107043366, 2017, A, . Location in patent: Paragraph 0085; 0086
[9] Patent: US2017/355700, 2017, A1, . Location in patent: Paragraph 0099
[10] Patent: CN105622613, 2016, A, . Location in patent: Paragraph 0109; 0148; 0149; 0150; 0151; 0152; 0153
[11] Patent: CN107759601, 2018, A, . Location in patent: Paragraph 0105-0109
[12] Patent: US2009/286812, 2009, A1, . Location in patent: Page/Page column 23
[13] Patent: US2014/256941, 2014, A1, . Location in patent: Paragraph 0168
[14] Journal of Medicinal Chemistry, 2010, vol. 53, # 13, p. 5012 - 5024
[15] Journal of Heterocyclic Chemistry, 2015, vol. 52, # 4, p. 1132 - 1135
[16] Patent: WO2006/90261, 2006, A1, . Location in patent: Page/Page column 78
[17] Patent: US2009/36419, 2009, A1, . Location in patent: Page/Page column 39
[18] Patent: US2007/72864, 2007, A1, . Location in patent: Page/Page column 33; 21
[19] Patent: WO2004/13141, 2004, A1, . Location in patent: Page 88
[20] Journal of Medicinal Chemistry, 2002, vol. 45, # 17, p. 3639 - 3648
[21] Patent: US2011/152296, 2011, A1, . Location in patent: Page/Page column 14-15
[22] European Journal of Organic Chemistry, 2009, # 34, p. 5920 - 5926
[23] Patent: WO2008/140947, 2008, A1, . Location in patent: Page/Page column 37
[24] Synthesis, 2008, # 6, p. 891 - 896
[25] Patent: WO2004/65380, 2004, A1, . Location in patent: Page 167
[26] Patent: US2010/190981, 2010, A1, . Location in patent: Page/Page column 101-102
[27] Patent: WO2007/84815, 2007, A2, . Location in patent: Page/Page column 41
[28] Patent: WO2010/151735, 2010, A2, . Location in patent: Page/Page column 56
[29] Patent: WO2011/29043, 2011, A1, . Location in patent: Page/Page column 126
[30] Patent: US2011/245257, 2011, A1, . Location in patent: Page/Page column 14
[31] Patent: WO2012/68343, 2012, A1, . Location in patent: Page/Page column 28
[32] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 23, p. 7223 - 7226,4
[33] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 13, p. 3052 - 3059
[34] Patent: CN107759623, 2018, A, . Location in patent: Paragraph 0110
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In ethanol; at 60℃;Heating / reflux;Product distribution / selectivity;
The title compound 10 was prepared by the method of Dauzonne, D.; Adam-Launay,A. Tetrahedron 1992, 48, 3069-3080. 4,6-Dihydroxypyrimidine (3.3 g, 29.4 mmol) and (2-Chloro-2-nitro-vinyl)-benzene (5.3 g, 26.7 mmol) were combined in EtOH (absolute, 110mL) and the mixture was heated at 60 C for 10 min to dissolve 4,6-Dihydroxypyrimidine.DBU (8.06 mL, 53.9 mmol) was then added drop-wise to the reaction. After addition of DBUthe deep green-brown solution was heated at reflux for 3 h then at 60 C over night. The deepred solution was then cooled to room temperature and concentrated to a thick red oil.Purification by flash chromatography (SiO2, gradient eluent: CH2C12 to 5% MeOH/CH2Cl2) toafford crude 10 as an orange-red semisolid/oil. This material was triturated with 1.75:1CH2Cl2/hexanes and solid 10 was isolated by Buchner filtration. Flash chromatography of themother liquors afforded a second crop of solid 3 (>90% pure). The two crops were combinedand concentrated to afford 10.; Step 2: 5-PhenyI-3H-furo[2,3-d]pyrimidin-4-one (162)[0389] The title compound was prepared by the method of Dauzonne, D.; Adam-Launay, A.Tetrahedron 1992, 48, 3069-3080. 4,6-Dihydroxypyrimidine 161 (3.3 g, 29.4 mmol) and 160(5.3 g, 26.7 mmol) were combined in EtOH (absolute, 110 mL) and the mixture was heated at60C for 10 min to dissolve 161. DBU (8.06 mL, 53.9 mmol) was then added drop-wise.After addition of DBU the deep green-brown solution was heated at reflux for 3 h then at60C over night. The deep red solution was then cooled to room temperature andconcentrated to a thick red oil. Purification by flash chromatography (SiO2, gradient eluent:CH2C12 to 5% MeOH/CH2Cl2) to afford as an orange-red semisolid/oil. This material wastriturated with 1.75:1 CH2Cl2/hexanes and solid 162 was isolated by Buchner filtration (~95% pure). Flash chromatography of the mother liquors afforded a second crop of solid 162(>90% pure). The two crops were combined and concentrated to afford 162 as a pale orangesolid (69% yield).
As in the procedure described in the literature [D. Dauzonne, Tetrahedron, 1992, 3069-3080], stir a suspension of 10.1 g (47.4 mmol) 1-[(Z)-2-chloro-2-nitrovinyl]-4-methoxybenzene and 5.8 g (52.2 mmol) <strong>[1193-24-4]4,6-dihydroxypyrimidine</strong> in 200 ml ethanol for ten minutes at 85 C. Next, slowly add 15.6 ml (15.9 g, 104.3 mmol) 1,8-diazabicyclo[5.4.0]undec-7-ene. Stir for 15 h at this temperature and then concentrate by vacuum evaporation. Take up the residue in dichloromethane and chromatograph on silica gel (solvent: dichloromethane/methanol 95:5). Mix the solid obtained with acetonitrile and then filter. 2.3 g (20% of theor.) of the target product is obtained. LC-MS (Method 2): Rt=1.57 min; m/z=290 (M+H)+ 1H-NMR (400 MHz, CDCl3): delta=12.66 (s, 1H), 8.15 (s, 1H), 8.14 (s, 1H), 7.92 (d, 2H), 6.98 (d, 2H), 3.79 (s, 3H).
20%
Example 15A 5-(4-Methoxyphenyl)furo[2,3-d]pyrimidin-4(3H)-one Analogously to a literature procedure [D. Dauzonne, Tetrahedron, 1992, 3069-3080], a suspension of 10.1 g (47.4 mmol) of 1-[(Z)-2-chloro-2-nitrovinyl]-4-methoxybenzene and 5.8 g (52.2 mmol) of <strong>[1193-24-4]4,6-dihydroxypyrimidine</strong> in 200 ml of ethanol is stirred at 85 C. for ten minutes. 15.6 ml (15.9 g, 104.3 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene are then added slowly. The mixture is stirred at this temperature for 15 h and then concentrated under reduced pressure. The residue is taken up in dichloromethane and chromatographed on silica gel (mobile phase: dichloromethane/methanol 95:5). The solid obtained is triturated with acetonitrile and filtered. This gives 2.3 g (20% of theory) of the target product. LC-MS (method 3): Rt=1.57 min.; m/z=290 (M+H)+ 1H-NMR (400 MHz, CDCl3): delta=12.66 (s, NH), 8.15 (s, 1H), 8.14 (s, 1H), 7.92 (d, 2H), 6.98 (d, 2H), 3.79 (s, 3H).
EXAMPLE 1; 4-[6-Amino-5-(methoxyimino-methyl)-pyrimidin-4-yl]-piperazine-l-carboxylic acid (4-isopropoxy-phenyl)-amidea. 4,6-Dichloro-pyrimidine-5-carbaldehyde; A mixture of DMF (3.2 mL) and POCl3 (10 mL) at 0 0C was stirred for 1 h, treated with <strong>[1193-24-4]4,6-dihydroxypyrimidine</strong> (2.5 g, 22.3 mmol), and stirred for 0.5 h at ambient EPO <DP n="48"/>temperature. The heterogeneous mixture was heated at reflux for 3 h and the volatiles were removed at reduced pressure. The residue was poured into ice water and extracted six times with ethyl ether. The organic phase was washed with aqueous NaHCO3, dried over Na2SO4 and concentrated to afford a yellow solid (3.7 g, 95%). 1H NMR (CDCl3) delta 10.46 (s, IH), 8.90 (s, IH).
Phosphorus oxychoride (200 mL, 2184. 8MMOL) was added drop wise (via additional funnel) to DMF cooled to 0C. After for 1 hour, 4,6 dihydroxypyridimidine (50.0 g, 446.1 mmol) was added and the mixture was allowed to warm to room temperature. The resulting heterogeneous mixture was refluxed for 3 hours. The volatiles were removed at reduce pressure, and the residue was poured in ice water and extract with CHC13/ET2O, wash with sodium bicarbonate and concentrate under high vacuum. Final product was purified by silica plug using CH2C12 to afford a yellow solid (54. 0 G), H NMR 400MHZ CDC13 8 (PPM) : 10.3 (s, 1H, ALDEHYDE), 8.7 (s, LH, pyrimidine).
With trichlorophosphate; In hexane; N,N-dimethyl-formamide;
(1) Phosphorus oxychloride (22ml, 236.5mmol) was dropwise added to DMF (7ml, 90.1mmol) at 10ØC. The mixture was stirred for 30 minutes at the same temperature, followed by adding portionwise <strong>[1193-24-4]4,6-dihydroxypyrimidine</strong> (4.8g, 42.9mmol). The mixture was stirred at room temperature for 2 hours and refluxed under heating for 3 hours. After cooling, the reaction mixture was portionwise added to iced water, and the mixture was extracted 3 times by ether. The ether extracts were combined, washed with aqueous sodium hydrogen carbonate, dried and concentrated by evaporation of the solvent. Hexane was added to the residue, and the crystals were collected by filtration to give 4,6-dichloro-5-formylpyrimidine (4.5g). 1H-NMR(CDCl3) delta 8.90(1H, s), 10.4(1H, s)
5.1 Example 1: Synthesis of Compound 1009 (a); Compound 1009 (a) was prepared according to the following scheme. The conversion of commercially available Compound 4 to Compound 6 was adapted from a procedure provided in J. Med. Chem., 45: 3639-3648 (2002).
DMF (40 mL) was added to a solution of POCl3 (400 mL, 4.4 mol) at 00C and the mixture was stirred for 1 hour at ambient temperature. 4,6-Dihydroxypyrimidine Compound Ia (50 g, 0.45 mol) was added to the reaction mixture at RT. After 1 hour, the reaction was heated at reflux for 3 hours. The reaction mixture was concentrated in vacuo to remove the excess POCl3. The remaining residue was diluted with ethyl acetate and carefully quenched, while stirring, by the slow addition of ice. The isolated organic solution was sequentially washed with an aqueous saturated NaHCO3 solution and brine. The organic layer was dried over Na2SO4, then filtered and concentrated to give a solid. The solid was extracted with hot hexanes and the solution evaporated down to yield 4,6-dichloro-pyrimidine-5-carboxaldehyde Compound Ib (60 g). MS 177 (MH+).
3-benzyl-6-(benzyloxy)-pyrimidin-4(3H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68%
With potassium carbonate; In DMF (N,N-dimethyl-formamide); for 4.5h;
<strong>[1193-24-4]4,6-dihydroxypyrimidine</strong> (25.0 G, 0.223 mol) and potassium carbonate (65.1 g, 0.471 mol) are combined in 0.5 L anhydrous dimethylformamide. Benzyl chloride (55. 7 g, 0.439 mol) is added dropwise over 30 minutes with stirring. After 4 h the solution is filtered, and the filtrate concentrated in vacuo. The residue is washed with acetonitrile, and the product is collected as a white solid by filtration (44.6 g, 68%). 1H-NMR (400 MHz, DMSO-D6) 6 8.06 (m, 2 H), 7.61 (quartet, J = 8.45 Hz, 1H), 7.30 (T, J = 10.37 Hz, LH), 7.12, (t, J = 8.45 Hz, 1H), 7.09 (d, J = 5.06 Hz, 2H), 5.14 (S, 2H). LC/MS tr = 5.29 minutes (0-95% acetonitrile/water, 0. 05% trifluoroacetic acid, over 6 minutes at 1 ml/min with detection at 215 nm, at 50oC) ES-MS M/Z 293 (M+H).
With triethylamine; trichlorophosphate; at 40 - 105℃; for 2h;
In a four-necked flask equipped with a reflux condenser, the temperature was raised and stirred, and 228 g of <strong>[1193-24-4]4,6-dihydroxypyrimidine</strong> was added by a constant pressure dropping funnel, the content was 98%,and the content of 633 g of phosphorus oxychloride was 97%.The temperature was raised to 40 to 45 C, and the content of 408 g of triethylamine was added dropwise with content of 99%, after the addition was completed, the temperature was raised to 100 to 105 C and kept for 2 hours. HPLC (high performance liquid phase) analysis of <strong>[1193-24-4]4,6-dihydroxypyrimidine</strong> was less than 0.2%, and the reaction was completed. 880g of toluene was added and cooled tom 0~5 C, 800g of ice water mixture was added, the ice was decomposed to room temperature, the organic phase was decomposed and the aqueous layer was extracted (200 ml of toluene), the organic phase was combined and washed with alkaline water until neutral. Toluene was concentrated. 697 g of toluene dichloropyrimidine solution was obtained, and the purity of 4, 6-dichloropyrimidine was 97.3%, and the content was 39.91%. The crude yield was 92%. The 697 g crude solution was divided into three 240 g, 240 g, 217 g, respectively, as 1, 2, 3, to do the distillation experiment: The temperature of the top of the steam packed tower is required to reach 94 C ~ 96 C, when the temperature was reached, the concentrated organic phase was added dropwise, the feed rate was controlled, the balance was adjusted to prevent the stripper tower from cooling; The obtained organic phase, the quality of the aqueous phase and the purity and concentration of 4,6-dichloropyrimidine are shown in Table 1, the obtained organic phase was concentrated, cooled, crystallized, centrifuged or filtered to obtain a high purity product. The refined yield was as high as 98% or more, and the appearance was white crystal. The experimental results are shown in Table 1.
97%
With bis(trichloromethyl) carbonate; sulfuric acid; In N,N-dimethyl-formamide; 1,2-dichloro-benzene; at 80℃; for 4.2h;Industrial scale;
In the reaction container (such as test flat glass reaction bottle) by adding <strong>[1193-24-4]4,6-dihydroxypyrimidine</strong> 11.2 grams, sulfuric acid 20 ml, N, N-dimethylformamide 0.5 ml, mixed evenly, heated to 80 C, Mixed solution, 30 grams of triphosgene dissolved in 50 ml of dichlorobenzene, 1.2 hours slowly dropping added to the mixed solution, continued to heat after stirring for 3 hours, cooled to room temperature, pour ice water, the separation of organic Solvent layer and organic solvent layer, and then dried with anhydrous magnesium sulfate to obtain 4,6-dichloropyrimidine, the yield is 97%, the mass content is more than 99% (determined by high performance liquid phase method)
96.2%
With cobalt(II) phthalocyanine; bis(trichloromethyl) carbonate; Triphenylphosphine oxide; In nitrobenzene; at 90 - 95℃; for 5h;
212 g of triphosgene (content 99%, 0.71 mol) was dissolved in 500 mL of nitrobenzene for use.In a device equipped with a reflux condenser, a thermometer, a stirrer and a constant pressure dropping funnel,Add <strong>[1193-24-4]4,6-dihydroxypyrimidine</strong> (114 g, content 98%, 1 mol), triphenylphosphine oxide (8.4 g, content 99%,0.03 mol), cobalt phthalocyanine (0.57 g, 0.001 mol), stirred and mixed evenly,The temperature was raised to 90-95 C, and a solution of triphosgene in nitrobenzene was added dropwise.After 5 hours of reaction, the sample was analyzed, and the content of <strong>[1193-24-4]4,6-dihydroxypyrimidine</strong> was 0.25% and the content of 4,6-dichloropyrimidine was 98.2% by HPLC. The reaction was completed.Vacuum distillation reaction mixture (oil bath temperature 95 C, vacuum -0.095 Mpa),143.8 g (content 99.7%) of 4,6-dichloropyrimidine was obtained in a yield of 96.2% (based on <strong>[1193-24-4]4,6-dihydroxypyrimidine</strong>).
94.9%
With phosgene; trichlorophosphate; at 95 - 100℃; for 8h;Large scale;
In a device equipped with a reflux condenser, a thermometer, a stirrer and a constant pressure dropping funnel, <strong>[1193-24-4]4,6-dihydroxypyrimidine</strong>(114.3 g, 98%, 1 mol), phosphorus oxychloride (1140 g, 99%) were stirred and mixed, the temperature was raised to 95-100 C,And slowly adding phosgene (220g, 99%, 2.2mol) for 8 hours after the sample, HPLC analysis of 4,6 - dihydroxypyrimidine containing, The reaction was completed and the reaction mixture was distilled under reduced pressure (oil bath temperature 95 C,(Content 99%); 4,6-dichloropyrimidine 142.8 g (content 99.0%),The yield of 94.9% (based on <strong>[1193-24-4]4,6-dihydroxypyrimidine</strong>), where W (DCP) meansDCP quality, W (DHP) refers to the quality of DHP, the content refers to the mass content of DCP, 112 for DHP moleculesAnd 149 is the molecular weight of DCP.
94.9%
With phosgene; trichlorophosphate; at 95 - 100℃; for 8h;Large scale;
With a reflux condenser, thermometer,In the device of the agitator and the constant pressure dropping funnel,Add <strong>[1193-24-4]4,6-dihydroxypyrimidine</strong> (114.3 g, content 98%, 1 mol), phosphorus oxychloride (1140 g, 99%) and mix well.The temperature was raised to 95-100 C, and phosgene (220 g, 99%, 2.2 mol) was slowly added to carry out the reaction, and the sample was taken after 8 hours.HPLC analysis of <strong>[1193-24-4]4,6-dihydroxypyrimidine</strong> content of 0.9%,The content of 4,6-dichloropyrimidine was 98.3%, and the reaction was over.Vacuum distillation reaction mixture (oil bath temperature 95 C,Vacuum degree -0.095MPa),Obtained 1082 g of phosphorus oxychloride (content 99%); 142.8 g of 4,6-dichloropyrimidine (content 99.0%),Yield 94.9% (based on <strong>[1193-24-4]4,6-dihydroxypyrimidine</strong>), wherein W (DCP) refers to the mass of DCP, and W (DHP) refers to the mass of DHP.The content refers to the mass content of DCP, and 112 is the molecular weight of DHP.149 is the molecular weight of DCP.
78%
With pyridine; phosgene; In chloroform; at 50℃; for 3h;
0.5 mol of <strong>[1193-24-4]4,6-dihydroxypyrimidine</strong> was added to the reaction vessel,Solvents Trichloromethane,0.05 mol of pyridine catalyst,Then slowly into the phosgene 1.5mol,The reaction temperature was controlled within 50 C,After reaction for 3 h,After the completion of the reaction, the excess solvent chloroform was distilled off under reduced pressure,To give a 4,6-dichloropyrimidine solution,And then filtered, concentrated and crystallized to give 4,6-dichloropyrimidine as white needles.The yield of product 4,6-dichloropyrimidine prepared by the above method was 78% and the purity was 80%.
58%
With trichlorophosphate; In water; N,N-dimethyl-aniline; chlorobenzene;
Example 7 (for comparison) 460 g of phosphorus oxychloride and 62 g of N,N-dimethylaniline were mixed and 116 g of <strong>[1193-24-4]4,6-dihydroxypyrimidine</strong> (98% pure) were metered into the mixture with a screw at 100 C. in the course of 5 hours. Thereafter, the reaction mixture was subsequently stirred at 106 to 128 C. for 8 hours. It was diluted with 300 g of chlorobenzene and discharged onto 1.2 kg of ice. The organic phase was separated off, washed twice with 100 ml of water each time and then subjected to fractional distillation. 85.7 g of 4,6-dichloropyrimidine (=58% of theory) are thus obtained.
EXAMPLES 1-6 General Procedure for Conversion of <strong>[1193-24-4]4,6-dihydroxypyrimidine</strong> (DHP) to 4,6-dichloropyrimidine (DCP): The reaction vessel is a Morton-type flask fitted with a heating mantle, a mechanical agitator, a temperature probe, a phosgene dip pipe (which also serves as a nitrogen inlet when phosgene is not being introduced to the reactor), and a dry ice condenser. The dry ice condenser is vented into a caustic scrubber. The reactor is charged with <strong>[1193-24-4]4,6-dihydroxypyrimidine</strong>, solvent, and catalyst, forming a slurry. The agitator is started and the mixture is heated to 105-110 C. When this temperature range is reached, phosgene gas is introduced subsurface to the reaction mixture via the dip pipe. Phosgene addition is continued over 3-5 hours. During the addition, phosgene escaping the reaction is condensed by the dry ice condenser and returned to the reactor. This reflux of phosgene begins shortly after the phosgene addition is begun, and continues throughout the course of the reaction.
With pyridine; phosgene; In chloroform; at 50℃;
One-step process for preparing 4, 6 - dichloro pyrimidine synthesis process, the synthesis process comprises the following steps: (1) input to the tower in the reactor 1 parts by weight of 4, 6 - dihydroxy pyrimidine and 3 parts by weight of chloroform, opening the stirrer stirring, continue adding 0.5 parts by weight of pyridine catalyst, and then open the jacket steam make the tower the temperature in the reactor is increased to 50 C, from the tower bottom of the reactor 1 parts by weight of phosgene, phosgene first of all through the reactor internal gas distributor, the gas distributor is triangle shape is placed in the bottom of the tower type reactor, gas distributor there are a lot of small holes is uniform and compact, phosgene is too high and the tower type reactor internal, then react with the material; (2) after the reaction, the bottom of the tower type reactor by nitrogen catches up with was mad, mixing the gas via the gas outlet of the tower the top of the reactor, into the collecting tank, the upper part of the collecting tank is provided with a ammonia-water spray system, the bottom of the traps the pot installed with a fan, when the gas enters into the collecting tank, by the fan gas into the ammonia-water spray system, so as to avoid the leakage of phosgene and hydrogen chloride gas; then the tower in the reactor in product transfer to the rectifying tower, are respectively arranged successively rectification temperature is 55 - 70 C, 105 - 125 C and 170 - 180 C, respectively collecting the corresponding temperature of the fraction, can be recycled chloroform solvent and pyridine catalyst, to a temperature of 170 - 180 C fraction is washed by water after cooling, drying, to obtain the 4, 6 - dichloro pyrimidine.
With pyridine; phosgene; In chloroform; at 50℃;
A kind of the improved 4, 6 - dichloro pyrimidine production process, characterized in that the production process comprises the following steps: (1) to the reaction kettle top feed port input 1 parts by weight of 4, 6 - dihydroxy pyrimidine and 3 parts by weight of chloroform, opening the stirrer stirring, continue adding 0.5 parts by weight of pyridine catalyst, and then open the jacket steam make the reaction kettle temperature to rise to 50 C, from the reactor into the bottom of the 1 parts by weight of phosgene to the phosgenation reaction, after the reaction is complete, to inject the nitrogen in the reactor catches up with was mad, at the same time the exhaust gas by the pipe into the absorption tower; (2) to be step 1 the product in the transfer to the rectifying tower, control rectification temperature is 65 C, collecting chloroform fraction, to be its after cooling to room temperature, the filling storage recycling; (3) collecting the step 2 in the remaining product, transferred to ice in the ice solution, slowly dropping concentration is 10% hydrochloric acid to adjust the pH of the solution to 5, standing the solution is layered, then methyl tert-butyl ether to the organic phase extraction, extraction 3 - 4 times, saturated copper sulfate solution for washing, until the copper sulfate solution is not color-changing, collecting pyridine circulation use; (4) the step 3 in the remaining product to filter, washing, and drying to obtain the target product 4, 6 - dichloro pyrimidine.The beneficial effects of the present invention: 1) using phosgene to replace the traditional process of phosphorus oxychloride, to avoid the emergence of phosphorus-containing by-product, the protection of the environment; 2) by adding pyridine catalyst, can accelerate the reaction of generating; 3) traditional use phosphorus oxychloride with 4, 6 - dihydroxy pyrimidine chloride obtained when the 4, 6 - two chlorine pyrimidine, easy to produce 3 different by-product, so that the trouble in processing after, and the yield of target product is not high, in the reaction of the present invention less by-products, and the yield of 4, 6 - dichloro pyrimidine higher; 4) by adjusting the solution pH, methyl tert-butyl ether extraction, and sulfuric acid copper and washing the collecting various pyridine, avoiding the traditional rectification, and steaming and method and the like caused by the leakage of pyridine, ensures the safety of the operators.
With trichlorophosphate; In N,N-dimethyl-formamide; toluene; at 120℃; for 3.5h;Reflux;
A 4,6-dichloropyrimidine production process,The production process includes the following steps:(1) To the reaction vessel was added 1 part by weight of <strong>[1193-24-4]4,6-dihydroxypyrimidine</strong>,2 parts by weight of phosphorus oxychloride and 5 parts by weight of toluene,Stir the stirrer,2 parts by weight of DMF was added dropwise with stirring,To ensure that in half an hour drop finished;(2) and then open the jacket steam to the reactor temperature rose to 120 reaction 2h,And then reflux reaction 3h,Until the solution appears stratified,When the thickness of the layer is no longer increased,Remove the upper solution,Transferred to the distillation tower,Atmospheric distillation,The control distillation temperature was 111 C and 150 C,Collect the fractions at these two temperatures,After cooling to room temperature,You can get toluene and DMF;(3) After the remaining product in step 2 is filtered,Transferred to the crystallization kettle for recrystallization,Collect crystalline solids,Washed,After drying, 4,6-dichloropyrimidine can be obtained,After crystallization of the mother liquor with a concentration of 10% sodium hydroxide solution to adjust the pH to 8,While reducing the solution temperature to 0 C,After crystallization,After centrifugation, the hydrated disodium hydrogen phosphate solid was collected.
With sulfuric acid; sodium methylate; formamide; In methanol; water;
EXAMPLE 1 To a stirred solution of sodium methoxide (140 g, 0.7 mol of a 27% solution in methanol) under nitrogen was added formamide (27.0 g, 0.6 mol) over about 5 minutes. The resulting reaction mixture was heated to 50 C. and then dimethyl malonate (26.4 g, 0.2 mol) added dropwise over 1 hour. The resulting white suspension was held at 50 C. for a further hour and then cooled to ambient temperature. Water (100 ml) was added to dissolve all the solid and the resulting straw-coloured solution was stirred for about 15 minutes and then the methanol was removed under vacuum (final pot at 50 C. under 100 mmHg vacuum). Water (40 ml) was added and then 36% sulphuric acid (90 g) added to give a final pH of 2.2. Once the acid had been added the temperature was kept at about 35 C. The yellow suspension was stirred for 1 hour, filtered and washed with water (2*25 g). The water-wet paste was dried overnight under vacuum at 50 C. to provide 4,6-dihydroxypyrimidine (16.2 g, 70% yield, 96% strength).
76.0%
With hydrogenchloride;
Acidification (c) A sample of the straw-coloured opaque solution (127.1 g, 0.143 mol based on dimethyl malonate starting material) was added dropwise to 36% hydrochloric acid (50 g) over 30 minutes. The pH at the end of addition was found to be 1.9. The very pale yellow slurry produced was agitated for an hour, filtered and washed with water (2*15 ml). The water-wet paste was dried overnight under vacuum at 50 C. to afford 4,6 -dihydroxypyrimidine (12.3 g at >99% strength, 76.0% yield).
75.1%
With hydrogenchloride; sodium methylate; formamide; In methanol; water;
EXAMPLE 2 To a stirred solution of sodium methoxide (63 g of a 30% solution in methanol containing 0.35 mol) under nitrogen was added formamide (13.5 g, 0.3 mol) over 5 minutes. The resulting reaction mixture was heated to 50 C. and then dimethyl malonate (13.2 g, 0.1 mol) added dropwise over 1 hour. The resulting white suspension was held at 50 C. for a further hour and then cooled to ambient temperature. Water (50 ml) was added to dissolve all the solid and the resulting straw-coloured solution was stirred for about 15 minutes and then methanol was removed under vacuum (final pot at 50 C. under 100 mmHg vacuum) until signs of solid could be seen. Water (20 ml) added and then 36% hydrochloric acid added to give a final pH of 2.1. The resulting yellow suspension was stirred for 1 hour, filtered and washed with water (2*15 ml). The water-wet paste was dried overnight under vacuum at 50 C. to provide 4,6-dihydroxypyrimidine (8.75 g at 96.2% strength, 75.1% yield).
74.8%
In water;
Acidification (b) A sample of the straw-coloured opaque solution (108.1 g, 0.122 mol based on dimethyl malonate starting material) was charged to a flask and water (50 ml) was added. The pH was then adjusted to 2.1 using 36% hydrochloric acid. The yellow slurry produced was agitated for an hour, filtered and washed with water (2*15 ml). The water-wet paste was dried overnight under vacuum at 50 C. to afford 4,6-dihydroxypyrimidine (10.4 g at 98.3% strength, 74.8% yield).
EXAMPLE 12 4,6-Dihydroxypyrimidine (0.5 g, 4.46 mmol) was suspended in chlorobenzene (10 ml) and dichlorotriphenylphosphorane (1.44 g, 4.46 mmol; previously prepared by the reaction of triphenylphosphine oxide with phosgene) was added as a solid. The mixture was stirred at 80 C. to 90 C. under a nitrogen atmosphere. Analysis by thin layer chromatography (tlc) of a sample removed after 90 minutes showed some 4,6-dichloropyrimidine formation. However, quite a lot of <strong>[1193-24-4]4,6-dihydroxypyrimidine</strong> remained out of solution. Another quantity of dichlorotriphenylphosphorane (1.44 g, 4.46 mmol) was added and stirring continued for a further hour at 110 C. A cloudy yellow solution was obtained with a solid residue. Analysis by tlc confirmed the formation of 4,6-dichloropyrimidine.
4,6-bis(4-nitro-3-hydroxy-2,5,6-trifluorophenoxy)pyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
94%
With hydrogenchloride; potassium carbonate; In nitrogen; water; dimethyl sulfoxide; ethyl acetate;
EXAMPLE 5 Preparation of 4,6-bis(4-nitro-3-hydroxy-2,5,6-trifluorophenoxy)pyrimidine STR12 11.2 g of <strong>[1193-24-4]4,6-dihydroxypyrimidine</strong> (0.1 mol) and 42.6 g of pentafluoronitrobenzene (0.2 mol) are dissolved in 400 ml of dimethyl sulfoxide in a 2 l three-neck flask fitted with nitrogen inlet and stirrer. 60 g of potassium carbonate (0.43 mol) are added in portions to the solution. The mixture is then stirred at room temperature for 24 hours and then heated in a temperature-controllable oil bath at 60 C. for 4 hours and, after the addition of 30 g of potassium hydrogen-carbonate (0.3 mol), for a further 6 hours. The reaction solution is then allowed to cool to room temperature, and the residue is filtered off via a Buchner funnel. After 500 ml of water and 300 ml of ethyl acetate has been added, concentrated hydrochloric acid is added drop wise until the solution is acidic. The organic phase is then washed three times with water, dried over sodium sulfate and evaporated to half in a rotary evaporator. After 2 days, the precipitated orange-brown crystals are filtered off, washed with petrol ether and dried for 48 hours under nitrogen at 40 C./10 mbar in a vacuum drying cabinet (yield: 94%). Characterization: Mass spectrum: molecular peak at 494
Example 2 2680 g of phosphorus oxychloride were initially introduced into the reaction vessel and 980 g of 2-methyl-5-ethyl-pyridine were added, while cooling. 460 g of <strong>[1193-24-4]4,6-dihydroxypyrimidine</strong> were then metered in over a period of 1 hour. Further reaction and working up were carried out as described in Example 1. 4,6-Dichloropyrimidine was obtained in a yield of virtually 100% and 88% by weight of the amount of amine employed was recovered.
98%
With trichlorophosphate;
Example 8 2680 g of phosphorus oxychloride were initially introduced into the reaction vessel and 980 g of 2-methyl-5-ethylpyridine were added, while cooling. 460 g of <strong>[1193-24-4]4,6-dihydroxypyrimidine</strong> were then metered in such that the temperature did not rise above 40 C. After an after-reaction at 40 to 45 C. for half an hour, first phosphorus oxychloride and then 4,6-dichloropyrimidine were distilled off as described in Example 1. 1390 g of phosphorus oxychloride and 595 g of 4,6-dichloropyrimidine (content 98.2%) were obtained, which corresponds to a yield of 98% of theory.
EXAMPLE 5 To a stirred mixture of <strong>[1193-24-4]4,6-dihydroxypyrimidine</strong> (5.18 g, 1 equivalent) and 4-(N,N,-dimethylamino)pyridine (0.55 g, 0.1 equivalent) in acetonitrile (100 ml) was added phosgene (28 g, 19.7 ml, 6.2 equivalents) in two aliquots. The resulting mixture was stirred for 10 minutes at room temperature and was then stirred for 4 hours at 55 C. The reaction mixture was purged with air after which water (200 ml) was added. The resulting mixture was extracted with dichloromethane (3*100 ml). The organic extracts were combined, washed with water (100 ml), dried over magnesium sulphate and evaporated to dryness to leave 4,6-dichloropyrimidine (4.63 g).
EXAMPLE 4 To a mixture of <strong>[1193-24-4]4,6-dihydroxypyrimidine</strong> (5.14 g, 1 equivalent) and imidazole (6.19 g, 2 equivalents) in acetonitrile (100 ml) was added phosgene (28 g, 6.2 equivalents). The resulting mixture was stirred for 21/4 hours at room temperature and for 1 hour at 50 C. The reaction mixture was purged with nitrogen overnight and then partitioned between water and dichloromethane. The organic layer was separated and the aqueous extracted twice more with dichloromethane. The organic extracts were combined, washed with water (twice), dried over magnesium sulphate and evaporated to dryness to leave 4,6-dichloropyrimidine as a pale yellow solid.
With 2,3-Dimethylaniline; In dichloromethane; water;
EXAMPLE 2 4,6-Dihydroxypyrimidine (20.5 g) was dispersed with agitation in dichloromethane (400 ml). Dimethylaniline (40.4 g) was added to the agitated mixture and the system was sealed (except for a vent line to a scrubber). Phosgene gas (56 g) was introduced from a cylinder and condensed onto a cold finger and collected in a pressure equalised dropping funnel. Once collected, the phosgene liquid was added to the reaction mixture over 15 minutes. The mixture was heated and agitated at reflux (29 C. approximately) for 17 hours after which time the mixture was cooled to room temperature and the excess phosgene removed by sparging with nitrogen. Water (400 ml) was added slowly to the agitated reaction mass with cooling to maintain the temperature at ambient. The organic layer was separated, and the aqueous was then extracted with dichloromethane (2*100 ml). The combined extracts were dried over anhydrous sodium sulphate and concentrated by rotary evaporation to give 4,6-dichloropyrimidine as an orange crystalline solid (27 g), equivalent to a yield of 80% (hplc analysis).
With N-ethyl-N,N-diisopropylamine; In water; acetonitrile;
EXAMPLE 6 To a stirred mixture of <strong>[1193-24-4]4,6-dihydroxypyrimidine</strong> (5.18 g, 1 equivalent) and N,N-diisopropylethylamine (11.75 g, 2 equivalents) in acetonitrile (100 ml) was added phosgene (28 g, 19.7 ml, 6.2 equivalents) in two aliquots. The resulting mixture was stirred for 10 minutes at room temperature and was then stirred for 4 hours at 55 C. The reaction mixture was sparged with air overnight after which water (100 ml) was added. The resulting mixture was extracted with dichloromethane (3*100 ml). The organic extracts were combined, washed with water (100 ml), dried over magnesium sulphate and evaporated to dryness to leave 4,6-dichloropyrimidine (6.35 g).
6-{3-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)-piperazin-1-yl]-propoxy}-pyrimidin-4-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In N,N-dimethyl-formamide; at 80℃; for 16h;
EXAMPLE 21:; 6-(3-f4-(2-terf-Butvl-6-cvclobutvl-pvrimidin-4-vl)-piperazin-1-vn-propoxv)-pyrimidin-4-ol; 1.5 g of 2-tert-Butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-cyclobutyl-pyrimidine (4.27 mmol), 0.72 g of <strong>[1193-24-4]pyrimidine-4,6-diol</strong> (6.4 mmol) and 1.31 g of triethylamine in 30 ml of dimethylformamide were stirred for 16 h at 80C. The mixture was extracted with water and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated to dryness. The crude product was purified by chromatography on silica gel using dichloromethane-methanol (1-10%). Fractions containing the product were combined. The solvents were evaporated and the oily residue was treated with acetonitrile. The precipitate was collected by filtration and dried to yield 0.27 g of the title compound.MS (ESI) m/z: 427.2 [M+H]+1H-NMR (DMSO): 5 [ppm] 8.1 (s, 1H), 6.4 (s, 1H), 5.5 (s, 1H), 4.15 (m, 2H), 3.6 (m, 4H), 3.4 (m, 2H), 2.4 (m, 6H), 2.25 (m, 2H), 2.15 (m, 2H), 1.95 (m, 1H), 1.85 (m, 2H), 1.8 (m, 1H), 1.3 (s, 9H).
With sulfuryl dichloride; triethylamine; trichlorophosphate; In chlorobenzene; at 40 - 83℃; for 19h;Product distribution / selectivity;
Example 2; To a 1000 mL four-neck flask, 89.7 g of <strong>[1193-24-4]4,6-dihydroxypyrimidine</strong> and 179.3 g of chlorobenzene were added. The obtained mixture was adjusted at 40C, and then, 129.6 g of sulfuryl chloride was added dropwise thereto over 1 hour. The obtained mixture was maintained at the same temperature for 6 hours. To the obtained reaction mixture, 269.9 g of phosphorus oxychloride was added at the same temperature. Further, 178.1 g of triethylamine was added dropwise thereto over 2 hours at an inner temperature of 40 to 80C. After completion of the addition, the obtained mixture was maintained at 83C for 10 hours. The obtained reaction mixture was cooled to room temperature. To another 100 mL four-neck flask, 269.0 g of water was added followed by adjusting at 40C. To it, the obtained reaction mixture was added dropwise over 30 minutes. The inner temperature during the addition was 30 to 50C. The obtained mixture was filtrated using Radiolite (registered trademark) and the obtained filtrate was separated to an organic layer and an aqueous layer. The aqueous layer was extracted with 44.8 g of chlorobenzene, and the obtained chlorobenzene layer was mixed with the previously obtained organic layer. The organic layer after mixing was washed with 44.8 g of water and then, concentrated under reduced pressure to obtain 169.2 g of black oily matter. The oily matter was analyzed by high performance liquid chromatography internal standard method, and 126.9 g of 4,5,6-trichlorpyrimidine was containd in the oily matter. The yield was 86%.
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃;Inert atmosphere;
To a 100 mL, three-necked flask fitted with a thermometer, a Dean-Stark trap with condenser, and a nitrogen inlet were added 1,3-dihydroxypyrimidine (5.00 g, 44.6 mmol), 4-nitrophthalonitrile (15.83 g, 91.4 mmol), powdered anhydrous K2CO3 (13.0 g, 94.2 mmol), and N,N-dimethylformamide (DMF) (100 mL). The resulting mixture was heated at 80 C. for 6-8 h. The mixture was allowed to cool to ambient temperature and poured into a 5% aqueous HCl solution resulting in the precipitation of a solid. The material was broken up and collected using a Buechner funnel. The white solid was washed with 200 mL of a 5% aqueous KOH solution, with 200 mL of distilled water until neutral, with 200 mL of a 5% aqueous HCl solution, and finally with 200 mL of water until neutral. The solvent was removed in vacuo and the solid was vacuum dried to yield the heteroaromatic phthalonitrile (14.4 g, 90% yield). IR [cm-1]: delta 3058 (CCH), 2231 (C?N), 1610 (CN), 1589 (CC), 1491 (aromatic), 1281 (CH3), 1248 (C-O), 1173 (C-O), 970 (C-O), 834 (aromatic).
Example 31A 5-(4-Ethylphenyl)furo[2,3-d]pyrimidin-4(3H)-one A mixture of 7.50 g (35.44 mmol) of 1-[(Z)-2-chloro-2-nitroethenyl]-4-ethylbenzene and 4.97 g (44.30 mmol) of <strong>[1193-24-4]4,6-dihydroxypyrimidine</strong> in 130 ml of isopropanol is heated at reflux. After 10 min, 13.22 ml (88.59 mmol) of 1,8-diazabicyclo[5.4.0]undecan-7-ene (DBU) are added dropwise, and the resulting reaction mixture is stirred under reflux for 4 h and then, after cooling, concentrated under reduced pressure. The residue is taken up in ethyl acetate and water. The phases are separated and the organic phase is washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate 1:2). This gives 2.8 g (32.9% of theory) of the title compound. HPLC (method 1): Rt=4.14 min. MS (DCI): m/z=241 (M+H)+. 1H-NMR (400 MHz, DMSO-d6): delta=12.68 (s, 1H), 8.19 (s, 1H), 8.17 (d, 1H), 7.88 (d, 2H), 7.28 (d, 2H), 2.63 (q, 2H), 1.22 (t, 3H).
Analogously to the literature method [D. Dauzonne, Tetrahedron, 1992, 3069-3080], stir a suspension of 11.9 g (85% purity, 47.6 mmol) of 1-[(Z)-2-chloro-2-nitrovinyl]-4-ethylbenzene and 5.9 g (52.3 mmol) of <strong>[1193-24-4]4,6-dihydroxypyrimidine</strong> in 200 ml of ethanol at 60-70 C. for 30 minutes. Then slowly add 14.4 ml (14.6 g, 96.1 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene. Stir the resulting reaction solution under reflux for six hours and then at 60 C. for 15 hours. After concentration under reduced pressure, take up the residue in dichloromethane and chromatograph it on silica gel (eluent: cyclohexane/ethyl acetate 1:1?1:5). Stir the resulting solid in diethyl ether and filter. 5.0 g (44% of theory) of the target compound are obtained. LC-MS (Method 8): Rt=2.14 min; m/z=241 (M+H)+ 1H-NMR (400 MHz, DMSO-d6): delta=12.68 (br. s, NH), 8.18 (d, 2H), 7.87 (d, 2H), 7.26 (d, 2H), 2.63 (q, 2H), 1.20 (t, 3H).
1,4-diaza-bicyclo[2.2.2]octane; In ethanol; at 80℃; for 18h;
Example 13:7-Amino-4-hydroxy-5-(3,4,5-trifluoro-phenyl)-5H-pyrano[2,3-d]pyrimidine-6-carbonitrile (13)(13)4,6-Dihydroxypyrimidine (493 mg, 4.4 mmol), 3-bromo-4,5-dimethoxy-benzaldehyde (1077 mg, 4.4 mmol) and malononitrile (295 mg, 4.4 mmol) were taken in 40 ml ethanol at room temperature, charged with DABCO (48.4 mu, 1.46 mmol) and then stirred at 80 C under LC-MS control for 18 h. The reaction mixture was then cooled down to room temperature. The mixture was diluted with water to about 100 ml, stirred at room temperature for lh and the precipitates were separated by filtration. It was washed well with 50 % aqueous ethanol and dried under vacuum (1.43 g, 3.53 mmol, 80 %).
80%
With 1,4-diaza-bicyclo[2.2.2]octane; In ethanol; at 20 - 80℃; for 18h;
4,6-Dihydroxypyrimidine (493 mg, 4.4 mmol), 3-bromo-4,5-dimethoxy-benzaldehyde (1077 mg, 4.4 mmol) and malononitrile (295 mg, 4.4 mmol) were taken in 40 ml ethanol at room temperature, charged with DABCO (48.4 mu, 1.46 mmol) and then stirred at 80 C under LC-MS control for 18 h. The reaction mixture was then cooled down to room temperature. The mixture was diluted with water to about 100 ml, stirred at room temperature for lh and the precipitates were separated by filtration. It was washed well with 50 % aqueous ethanol and dried under vacuum (1.43 g, 3.53 mmol, 80 %).
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