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Chemical Structure| 5305-40-8 Chemical Structure| 5305-40-8

Structure of 5305-40-8

Chemical Structure| 5305-40-8

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Product Details of [ 5305-40-8 ]

CAS No. :5305-40-8
Formula : C5H2Cl2N2O
M.W : 176.99
SMILES Code : O=CC1=C(Cl)N=CN=C1Cl
MDL No. :MFCD02257701
InChI Key :XQSJHQXYQAUDFC-UHFFFAOYSA-N
Pubchem ID :819691

Safety of [ 5305-40-8 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H317-H319
Precautionary Statements:P280-P305+P351+P338

Application In Synthesis of [ 5305-40-8 ]

* 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.

  • Downstream synthetic route of [ 5305-40-8 ]

[ 5305-40-8 ] Synthesis Path-Downstream   1~8

  • 1
  • [ 68-12-2 ]
  • [ 1193-24-4 ]
  • [ 5305-40-8 ]
YieldReaction ConditionsOperation in experiment
95% With trichlorophosphate; at 0 - 20℃; for 4.5h;Heating / reflux; A mixture of DMF (3.2 mL) and POCl3 (10 mL) at 0 C. 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 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, 1H), 8.90 (s, 1H).
95% With trichlorophosphate; at 0 - 20℃; for 4.5h;Heating / reflux; A mixture of DMF (3.2 mL) and POCl3 (10 mL) at 0 C. 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 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, 1H), 8.90 (s, 1H).
95% With trichlorophosphate; at 0 - 20℃; for 4.5h; 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 <strong>[1193-24-4]4,6-dihydroxypyrimidine</strong> (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, 95%). 1H NMR (CDCl3) delta 10.46 (s, 1H), 8.90 (s, 1H).
95% Amixture of DMF (3.2 mL, 41.34mmol) and POCl3 (10 mL,109,24mmol) at 0 C. was stirred for 1 h, treated with <strong>[1193-24-4]4,6-dihydroxypyrimidine</strong>(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, 95%).
94% With trichlorophosphate; at 70℃; for 24h; 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 70C 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, 94.0%) as a white solid. 1H NMR (300 MHz, CDCl3) delta ppm: 10.48(s, 1H), 8.91 (s, 1H).
85% 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 <strong>[1193-24-4]4,6-dihydroxypyrimidine</strong> 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: 85%). 1H NMR(300 MHz, CDCl3) delta 10.47 (s, 1H), 8.90 (s, 1H).
75% With trichlorophosphate; at 0 - 110℃; for 5h; 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, 75%) as a pale yellow solid.
75.4% With trichlorophosphate; for 3h;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,<strong>[1193-24-4]4,6-dihydroxypyrimidine</strong> (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 75.4%
74% 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, 74% of the desired compound as an orange solid. 1H NMR (500 MHz, CDCl3): delta 10.48 (s, 1H), 9.92 (s, 1H). 13C NMR (125 MHz, CDCl3): delta 185.61, 162.69, 159.58, 124.89.
72.7% The DMF 30ml of dimethylformamide and 80ml of phosphorus oxychloride were mixed and stirred at 0 30 minutes,Was added <strong>[1193-24-4]4,6-dihydroxypyrimidine</strong> 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 72.7%.
70% (1) Weigh POCl3 (4 eq) into the reaction flask, and under nitrogen protection, cool to about 0C. Add DMF (1.85 eq) to the feed solution. When adding, control the temperature at 08C, add it. Feed solution 0 ~ 10 C, stirring 1h,To the solution was added <strong>[1193-24-4]4,6-dihydroxypyrimidine</strong>. 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: 70%), which was used directly in the next reaction.
68% 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 <strong>[1193-24-4]4,6-dihydroxypyrimidine</strong> (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 (3×200 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, 68%) as a white solid, which was used for the next step without further purification. 1H NMR (400 MHz, CDCl3) delta 8.88 (s, 1H), 10.45 (s, 1H).
68.4% 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 <strong>[1193-24-4]4,6-dihydroxypyrimidine</strong> 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 <strong>[1193-24-4]4,6-dihydroxypyrimidine</strong> 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, 68.4%) 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) delta 10.46 (s, 1H), 8.89 (s, 1H) ppm.
58% With trichlorophosphate; at 0 - 20℃; for 3h;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 (58%) of 4,6- dichloro-5-formylpyrimidine (J. Med. Chem. 2002, 45, 3639).
57% 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 (5×100 mL), and the organic extracts were washed with aqueous saturated NaHCO3 (2×100 mL) and brine (100 mL), and dried over anhydrous sodium sulfate and concentrated in vacuo to provide Compound 15 (4.42 g, 57%) as a crude orange solid, which was used without further purification.
57% (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 <strong>[1193-24-4]4,6-dihydroxypyrimidine</strong> (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 (6×100 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, 57% yield). 1H NMR (CDCl3) delta 10.41 (s, 1H), 8.85 (s, 1H).
56% With trichlorophosphate; at 30℃; for 4.33333h;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, 56%); [1H] NMR [(CDC13)] 8 8. 89 (s, 1H), 10.46 (s, 1H).
55% With trichlorophosphate; at 0 - 20℃; for 4.5h;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 <strong>[1193-24-4]4,6-pyrimidinediol</strong> (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, 55%); LC-MS (ESI) m/z 177 [M+H]+.
40% 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 (10% 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 %).
Phosphorus Oxychoride (200 mL, 2184.8mmol) was added drop wise (additional funnel) in DMF at 0 C, and stirred for 1 hour, treated with 4,6 DIHYDROXYPYRIDIMIDINE (50. 0g, 446.1 mmol) and stirred for half hour at room temperature. The 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 chloroform and diethylether, wash with sodium bicarbonate and concentrate under high vacuum. The resulting mixture was purified on silica (CH2C12) to afford 4,6-dichloro- pyrimidine-5-carbaldehyde as a yellow solid (54.0 g). 'H NMR 400MHZ CDC13 6 (PPM) : 10.3 (s, 1H, aldehyde), 8.7 (s, lH, pyrimidine).
4,6-Dichloropyrimidine-5-carbaldehyde (9).; In a 5 L 4-neck flask equipped with mechanical stirrer, addition funnel, condenser, thermocouple, and a N2 sweep into an aqueous NaOH scrubbing solution, phosphorous oxychloride (1 L, 10.572 mol, 4.82 equiv) was cooled in an ice/salt bath. N,N-Dimethylformamide (DMF, 320 mL, 4.138 mol, 1.85 equiv) was added dropwise at 0+/-2 C. After addition of 100 mL of DMF (0.5 hr) crystallization occurred and the reaction temperature was increased from 0 to 10 C. Addition was stopped and the mixture was allowed to recool to 2 C. The remaining DMF was added over 2.5 hr at <8 C. The suspension became very thick making stirring difficult. When addition of DMF was complete, the mixture was stirred 0.5 hr at 3-5 C. <strong>[1193-24-4]4,6-dihydroxypyrimidine</strong> (8, 250 g, 2.232 mol) was added portion wise as a solid. After about one third of <strong>[1193-24-4]4,6-dihydroxypyrimidine</strong> was added the reaction mixture became more mobile and a slow exothermic phenomena occurred with the reaction temperature increasing to 12 C. over 0.5 hr. The remaining <strong>[1193-24-4]4,6-dihydroxypyrimidine</strong> was added portion wise over 0.25 hr 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 hr, 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 began and the reaction mixture gradually thinned and darkened. After about 0.5 hr a clear, brown solution developed with the reflux temperature slowly increasing to 115 C. over 1.25 hr. After a total of 2.5 hr at reflux, the reaction mixture was cooled to room temperature and stirred overnight. Excess 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, 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 (9, 270 g, 395 g theoretical, 68.4%) as yellow-orange solid. 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 (9) as a white solid that turned yellow on standing at room temperature. (On standing crude 9 undergoes slow hydrolysis with formation of HCl. Prior to use in the next step crude 9 was dissolved in a mixture of EtOAc and toluene and filtered to remove insoluble material. The filtrate washed with H2O, saturated NaHCO3 solution, brine, dried over Na2SO4, filtered, and concentrated under reduced pressure and the resulting yellow solid used the following day.) For 9: 1H NMR (CDCl3, 300 MHz) delta ppm 10.46 (s, 1H), 8.89 (s,1H).
DMF (40 mL) was added to a solution of POCl3 (400 ml, 4.4 mol) at 0 0C and the mixture was stirred for 1 hour at ambient temperature. Pyrimidine-4,6-diol 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 POCI3. The resulting residue was diluted with EtOAc and carefully quenched, while stirring, by the slow addition of ice. The isolated organic solution was sequentially washed with an aqueous saturated NaHCtheta3 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-carbaldehyde Compound Ib (60 g). MS 177 (MH+).
A mixture of DMF (64 niL) and POCl3 (200 mL) at 0 0C was stirred for 1 h, treated with <strong>[1193-24-4]4,6-dihydroxypyrimidine</strong> (50.0 g, 446 mmol), and stirred for 0.5 h at rt, and then the heterogeneous mixture was refluxed for 3 h. The volatiles were removed under reduced pressure, and the residue was poured into ice water and extracted six times with Et2O. The organic phase was washed with aq NaHCO3 and water, dried over Na2SO4, coned, and crystallized (EtO Ac-petroleum ether) to give 4,6-dichloropyrimidine-5-carbaldehyde. Mass Spectrum (ESI) m/e = 177 (M+l).
Dry DMF (1.3 L, 16.5 mol) was added dropwise to POCI3 (4 L, 42.9 mol) at 10-20 C with stirring. After the addition was completed, the slurry was further stirred at rt for 5 min. Pyrimidine-4,6-diol (1 Kg, 8.9 mol) was slowly added to the mixture. The resulting mixture was heated to reflux, stirred for 3 h, then slowly poured into crushed ice with stirring. The reaction mixture was stirred for another 5 min and then extracted with EtOAc (3 x3 L). The organic layers were combined and adjusted to pH 8 with saturated aqueous Na2C03. After washing with brine, the organic layer was dried over Na2SC>4, filtered, and concentrated to dryness under vacuum to give crude title intermediate (800 g, 53.3%) as a yellow solid.
With trichlorophosphate; at 20℃; for 3.5h;Reflux; A mixture of DMF (64 mL) and POCl3 (200 mL) at 0 C. was stirred for 1 h, treated with <strong>[1193-24-4]4,6-pyrimidinediol</strong> (50.0 g, 446 mmol), and stirred for 0.5 h at rt, and then refluxed for 3 h. The volatiles were removed under reduced pressure, and the residue was poured into ice water and extracted six times with Et2O. The organic phase was washed with satd. aq. NaHCO3 and water, dried over Na2SO4, concentrated, and crystallized (EtOAc-petroleum ether) to give 4,6-dichloro-5-pyrimidinecarbaldehyde; LC-MS (ESI) m/z 177 [M+H]+.
With trichlorophosphate; at 0 - 20℃; for 4.5h;Reflux; A mixture of DMF (64 mL) and POCl3 (200 mL) at 0 C was stirred for 1 h and then treated with <strong>[1193-24-4]4,6-pyrimidinediol</strong> (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 Et20. The organic phase was washed with aqueous NaHC03, water, dried over Na2S04, concentrated under reduced pressure, and crystallized (EtO Ac-petroleum ether) to give 4,6-dichloro-5- pyrimidinecarbaldehyde; LC-MS (ESI) m/z 177 [M+H]+.
With trichlorophosphate; at 20℃; for 3h;Inert atmosphere; Reflux; (1) Weigh POCl3 (4 eq) into the reaction flask, and under nitrogen protection, cool to about 0C.DMF (1.85 eq) was added to the feed solution. When the mixture was added dropwise, the temperature was controlled at 0 to 8C. After the addition, the feed solution was 0 to 10C.Stir 1h, add <strong>[1193-24-4]4,6-dihydroxypyrimidine</strong> to the feed solution, add the end, the liquid naturally warms to room temperature, stir for 1h,Then, the mixture was warmed to reflux and stirred for 2 h. The mixture was cooled and stirred overnight.The feed solution is evaporated under reduced pressure to remove excess POCl3, and the residue is slowly added to ice water.The product was extracted with ethyl acetate (2x volume*3) and the organic phases combined and washed with water (2 volumes).The solution was washed with saturated sodium bicarbonate solution (2 volumes), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude 4,6-dichloropyrimidine-5-carboxaldehyde (yield: 70%), which was used directly in the next step. reaction.
15.3 g 4,6-Dichloropyrimidine-5-carbaldehyde (26) 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 <strong>[1193-24-4]4,6-dihydroxypyrimidine</strong> 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 <strong>[1193-24-4]4,6-dihydroxypyrimidine</strong> 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, 68.4%) 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) delta 10.46 (s, 1H), 8.89 (s, 1H) ppm.

References: [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,p. 3353 - 3358.
[5]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,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,p. 5012 - 5024.
[15]Journal of Heterocyclic Chemistry,2015,vol. 52,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,p. 3639 - 3648.
[21]Patent: US2011/152296,2011,A1 .Location in patent: Page/Page column 14-15.
[22]European Journal of Organic Chemistry,2009,p. 5920 - 5926.
[23]Patent: WO2008/140947,2008,A1 .Location in patent: Page/Page column 37.
[24]Synthesis,2008,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,p. 7223 - 7226,4.
[33]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,p. 3052 - 3059.
[34]Patent: CN107759623,2018,A .Location in patent: Paragraph 0110.
[35]Patent: US2019/233392,2019,A1 .Location in patent: Paragraph 0125; 0126.
  • 2
  • [ 1193-24-4 ]
  • [ 5305-40-8 ]
YieldReaction ConditionsOperation in experiment
95% 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
  • [ 6971-45-5 ]
  • [ 5305-40-8 ]
  • [ 650628-21-0 ]
  • 4
  • [ 6971-45-5 ]
  • [ 5305-40-8 ]
  • [ 1429924-41-3 ]
  • 5
  • [ 51169-05-2 ]
  • [ 5305-40-8 ]
  • [ 1429924-51-5 ]
  • 6
  • [ 6971-45-5 ]
  • [ 5305-40-8 ]
  • 4,6-dichloro-5-[2-(2-methoxyphenyl)hydrazono]methyl}pyrimidine [ No CAS ]
YieldReaction ConditionsOperation in experiment
93% In N,N-dimethyl-formamide; at 20℃;Inert atmosphere; General procedure: To a 50 mL round-bottomed flask was added 1 (97%, 500 mg, 2.74mmol), 4-methoxyphenylhydrazine hydrochloride (2a; 456 mg,2.61 mmol), and DMF (10 mL). The reaction was allowed to stir undera N2 atmosphere at r.t. for 1 h. Ice (5 g) was added with stirring,followed by a solution of NaHCO3 (330 mg, 3.9 mmol) in H2O (5mL). The resultant precipitate was filtered, washed with H2O, anddried at 40-50 C under vacuum overnight to obtain 3a; yield: 678mg (87%)
  • 7
  • [ 68-11-1 ]
  • [ 5305-40-8 ]
  • [ 1668-54-8 ]
  • C12H10Cl2N6O2S [ No CAS ]
  • 8
  • [ 5305-40-8 ]
  • [ 60025-06-1 ]
 

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Technical Information

Categories

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