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With Dess-Martin periodane In dichloromethane at 20℃; for 0.166667 h;
Step 3 - Preparation of2-chloro-4,5-difluoro-benzaldehyde (110)[0182] To (2-chloro-4,5-difluoro-phenyl)-methanol (120, 2 40 g, 0 0134 mol) in dichloromethane (40 0 mL) was added Dcss-Martin peπodmane (6.84 g, 0 0161 mol) The reaction was stirred at room temperature for 10 minutes. The reaction was poured into aqueous potassium carbonate and extracted with ethyl acetate The organic layer was dried over anhydrous sodium sulfate and filtered The filtrate was concentrated and puπfied by silica gel column chromatography elutmg with 30percent ethyl acetate in hexane to give a white solid (110, 1.7 g, 71.6percent).
EXAMPLE 2 87 g of potassium fluoride in 225 ml of tetramethylene sulphone were placed in a stirred apparatus and partially distilled at 20 mbar for the purpose of drying. 96.5 g of 2,4-dichloro-5-fluorobenzaldehyde and 5 g of tetraphenylphosphonium bromide were then added and the mixture was heated for 5 hours at 190 C. while stirring. The reaction mixture was subsequently distilled at 20 mbar. This gave 68 g of distillate containing 78% by weight of 2,4,5-trifluorobenzaldehyde and 9.4% by weight of 2-chloro-4,5-difluorobenzaldehyde.
Fraction distillation gave 51.5 g of 2,4,5-trifluorobenzaldehyde having a boiling point of from 65 to 67 C./20 mbar and 51.2 g of <strong>[165047-23-4]2-chloro-4,5-difluorobenzaldehyde</strong> having a boiling point of from 90 to 92 C./20 mbar.
With ammonium acetate; acetic acid; at 95℃; for 4.0h;
Example 19B; 1-chloro-4,5-difluoro-2-[(E)-2-nitrovinyl]benzene To a solution of (2-chloro-4,5-difluorophenyl)methanol (1.7 g, 22 mmol) in CH2Cl2, TPAP (1.0 mmol), NMO (32 mmol), and 4 A molecular sieves (10.75 g) were added. The solution was stirred and filtered. The unpurified material was added to a solution of acetic acid (50 mL), nitromethane (10 mL) and ammonium acetate (2.7 g, 35 mmol). The solution was heated at 95 C. for 4 hours and concentrated under reduced pressure. The residue was partitioned between ethyl ether and water. The organics were dried, concentrated under reduced pressure and purified over silica gel to provide the title compound. 1H NMR (300 MHz, CDCl3) delta ppm 8.28 (d, J=13.8 Hz, 1H), 7.50 (d, J=13.8 Hz, 1H), 7.34-7.43 (m, 2).
With Dess-Martin periodane; In dichloromethane; at 20℃; for 0.166667h;
Step 3 - Preparation of2-chloro-4,5-difluoro-benzaldehyde (110)[0182] To (2-chloro-4,5-difluoro-phenyl)-methanol (120, 2 40 g, 0 0134 mol) in dichloromethane (40 0 mL) was added Dcss-Martin pe?odmane (6.84 g, 0 0161 mol) The reaction was stirred at room temperature for 10 minutes. The reaction was poured into aqueous potassium carbonate and extracted with ethyl acetate The organic layer was dried over anhydrous sodium sulfate and filtered The filtrate was concentrated and pu?fied by silica gel column chromatography elutmg with 30% ethyl acetate in hexane to give a white solid (110, 1.7 g, 71.6%).
With tetrapropylammonium perruthennate; 4-methylmorpholine N-oxide; In dichloromethane;Molecular sieves 4A;
Example 19B; 1-chloro-4,5-difluoro-2-[(E)-2-nitrovinyl]benzene To a solution of (2-chloro-4,5-difluorophenyl)methanol (1.7 g, 22 mmol) in CH2Cl2, TPAP (1.0 mmol), NMO (32 mmol), and 4 A molecular sieves (10.75 g) were added. The solution was stirred and filtered. The unpurified material was added to a solution of acetic acid (50 mL), nitromethane (10 mL) and ammonium acetate (2.7 g, 35 mmol). The solution was heated at 95 C. for 4 hours and concentrated under reduced pressure. The residue was partitioned between ethyl ether and water. The organics were dried, concentrated under reduced pressure and purified over silica gel to provide the title compound. 1H NMR (300 MHz, CDCl3) delta ppm 8.28 (d, J=13.8 Hz, 1H), 7.50 (d, J=13.8 Hz, 1H), 7.34-7.43 (m, 2).
With caesium carbonate; In N,N-dimethyl-formamide; at 90℃;
Step 4 - Preparation of2-chloro-5-fluoro-4-[2-(2-methoxy-ethoxy)-ethoxy]-benzaldehyde (121) [0183] To <strong>[165047-23-4]2-chloro-4,5-difluoro-benzaldehyde</strong> (110, 0.40 g, 0.0023 mol) in N1N- dimcthylformamide (10.0 mL), 2-(2-methoxyethoxy)-ethanol (0 327 g, 2 72 mmol) and cesium carbonate (0.886 g, 2.72 mmol) were added. The reaction was stirred at 90 0C overnight The reaction was poured into water, acidified to pH around 5, and extracted with ethyl acetate The organic layer was dried over anhydrous sodium sulfate and filtered The filtrate was concentrated and purified by silica gel column chromatography elutmg with 30% ethyl acetate in hexane to give a white solid (121, 0.15 g, 24.C
Example 15: Synthesis of 2-chloro-5-fluoro-4-hydroxy-benzaldehyde 111.[0184] 2-Chloro-5-fiuoro-4-hydroxy-benzaldehyde 111 was synthesized in one step from 2-chloro- 4,5-difluoro-bcnzaldchydc 110 as shown in Scheme 37.Step 1 - Preparation of2-chloro-5-fluoro-4-hydroxy-benzaldehyde (111)[0185] To <strong>[165047-23-4]2-chloro-4,5-difluoro-benzaldehyde</strong> (110, 0.40 g, 2.30 mmol, prepared as described in Example 14) in N,N-dimethylformamide (10 0 mL) were added 2-(2-methoxyethoxy)-ethanol, (0 327 g, 2 72 mmol) and cesium carbonate (0 886 g, 2 72 mmol) The reaction was stirred at 90 0C overnight The reaction was poured into water, acidified to pH around 5, and extracted with ethyl acetate The organic layer was dried over anhydrous sodium sulfate and filtered The filtrate was concentrated and purified by silica gel column chromatography elutmg with 30% ethyl acetate in <n="79"/>hexane to give a white solid (111. 0 24 g, 61 0%) MS (ESI) [M-H"] = 173 1
4-((3-chloro-4-fluorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carbohydrazide[ No CAS ]
(E)-N’-(2-chloro-4,5-difluorobenzylidene)-4-((3-chloro-4-fluorophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carbohydrazide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68.3%
In ethanol; for 1.0h;Reflux;
General procedure: To the solution of 4-(phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carbohydrazide (6a-c) (0.3mmol) and substituted benzaldehyde (6mmol) were dissolved in anhydrous ethanol (2mL). The reaction mixture was heated at reflux. After completion of reaction, the mixture was cooled and filtrated to give target compounds 7a-j, 8a-j and 9a-j.
41.6%
In ethanol;Reflux;
Add intermediate M4 to 10 times the amount of ethanol (v/m), then add 1 equivalent of <strong>[165047-23-4]2-chloro-4,5-difluorobenzaldehyde</strong>.The reflux reaction. Direct filtration to give Example 11 in a yield of 41.6%.