4-CHLORO-3-(TRIFLUOROMETHYL)BENZOIC ACID

off-white powder

General procedure: In a glovebox, Cu(IPr)Cl catalyst and PMC (62.8 mg, 0.55 mmol, 1.1 equiv) were charged to a glass reaction tube. A solution of 3(0.50 mmol) in THF (1.5 mL) was added, the tube was sealed, taken out of the glovebox, and heated at 70 °C for 16 h. After cooling tor.t., H2O (2 mL) was added and the reaction mixture was acidified with aqueous HCl (1 M), and saturated with sodium chloride. After extraction with EtOAc (3 × 5 mL), the organic phase was dried overanhydrous sodium sulfate and concentrated under vacuo. The product was purified by silica gel column chromatography.The feed pump 1 starts feeding with the feed pump 2 at the same time, and the material is mixed with the reaction temperature (30-100 C) reaction time (5-10 min), the feed pump 3 starts to feed, and the material passes through the module and starts to react with the above. Liquid mixed reaction temperature (30 ~ 100 C) reaction time (3 ~ 10min) reaction node, feed pump is turned on for quenching, receiving compound III solution, treated to obtain sorafenib, after treatment yield of 88%At 0 C, Ultra-dry solvent DCM (5 mL), compound L1 (112 mg, 0.5 mmol) and N, N'-carbonyldiimidazole (97.2 mg, 0.6 mmol) were added to a nitrogen-protected, dry-broiled vial, and reacted for 2.5 h (TLC tracking) Then, 8-methyl-2, 8-diazaspiro[4.5]decane (92.4 mg, 0.6 mmol) was added, and the reaction was carried out for 12 h at room temperature (TLC tracking), which was adjusted with 1 mol/L sodium hydroxide solution. The pH of the system was 10, then it was extracted with DCM (15 mL), washed with water (10 mL), washed with saturated sodium hydrogen carbonate (10 mL) and brine (10 mL). The organic phase was filtered, and the obtained filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: methylene chloride:methanol = 5:1, v/v) to afford white solid compound L (177.5 mg, The yieldi 98.61%).General procedure: Trimethylacetyl chloride (2.42 mL, 20 mmol) and Et3N (4.60 mL, 30 mmol) were added to a mixture of 4-fluorobenzoic acid(20 mmol) in dry CH2Cl2 (80 mL). The resulting mixture was stirredat room temperature for 0.5e1 h until a clear solution wasobserved. A solution of piperazine (3.44 g, 40 mmol) in EtOH(80 mL) was added, and the mixture was further stirred for 3 h.Then the reaction solution was evaporated to remove solvents. Theresidue was dissolved in 20 mL H2O, and concd HCl (4 mL) wasadded. The resulting mixture was extracted with CH2Cl2 (5 mL) toremove bisadduct. NaOH (8 g) was added to the aqueous solutionand then extracted with CH2Cl2 (30 mL 3). The organic extractwas further washed with H2O (30 mL) and then dried over Na2SO4.Evaporation of the solvent at reduced pressure yielded the residuewhich was further used in next step. EI-MS (m/z) 208[M].The intermediates 5b-5e were prepared by commercially benzoicacids bearing different substituents and piperazine using thesame method as described above.General procedure: 4-fluorobenzoic acid (15 mmol), carbonyldiimidazole (2.92 g, 18 mmol) were dissolved in 60 mL anhydrous ACN, and was stirredfor 1 h at room temperature. In a separate dry 50 mL round bottomflask, fitted with an addition funnel, was placed 10 mL (150 mmol)of ethylenediamine. The activated 4-fluorobenzoic acid was transferredto the addition funnel and added dropwise to the ethylenediamine.The reaction was stirred at room temperature for 3 h.Then CH3CN was evaporated, and 40 mL HCl solution (6 mol/L) wasadded to the residue. The mixture was extracted with CH2Cl2(10 mL) to remove diacylated product. The aqueous layerwas adjustto PH 8e9 with 10 g NaOH, and extracted with CH2Cl2 (30 mL 3).Then the organic solution was combined, dried over Na2SO4 overnight, concentrated by rotary evaporation to afford the crudeproduct which can be directly used in the next step. EI-MS (m/z)183[MH].The intermediates 2b-2e were prepared by ethylenediamineand commercially benzoic acids with different substituents usingthe same procedure as described above.

Molecular Weight:224.56
XLogP3:3.7
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:1
Exact Mass:223.9851915
Monoisotopic Mass:223.9851915
Topological Polar Surface Area:37.3
Heavy Atom Count:14
Complexity:229
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes