* 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.
To a solution of 4-bromobenzenmine (40g, 0.232mol) and Et3N (32mL) in CH2Cl2 (200mL), benzenepropanoylchoride (37.5g, 0.223mol) was added dropwise at 0°C, and the mixture was stirred overnight at room temperature. Then, the mixture was poured out into water and 10percent HCl was added. The slurry of white solid which formed was stirred with ice-bath cooling for 1 hour. The solid was separated by filtration, washed with diethyl ether and air dried to give 62g (92percent yield) of compound 1.
87%
With triethylamine In dichloromethane at 20℃;
Benzenepropanoyl chloride (0.488 mol) was added dropwise at room temperature to a solution of 4-bromo benzenamine (0.407 mol) in Et3N (70ml) and DCM (700ml) and the mixture was stirred at room temperature overnight The mixture was poured out into water and concentrated NH40H, and extracted with DCM. The organic layer was dried (MgSO4), filtered, and the solvent was evaporated. The residue was crystallized from diethyl ether. The residue (119. 67g) was taken up in DCM and washed with HCI IN. The organic layer was dried (MgS04), filtered, and the solvent was evaporated, yielding 107.67g of intermediate 1 (87percent).
87%
With triethylamine In dichloromethane at 20℃;
Example A2; a) Preparation of intermediate 4; Benzene propanoyl chloride (0.488 mol) was added dropwise at room temperature to a solution of 4-bromobenzenamine (0.407 mol) in Et3N (70 ml) and CH2Cl2 (700 ml) and the mixture was stirred at room temperature overnight. The mixture was poured out into water and concentrated NH4OH, and extracted with CH2Cl2. The organic layer was dried (MgSO4), filtered, and the solvent was evaporated. The residue was crystallized from diethyl ether. The residue (119.67 g) was taken up in CH2Cl2 and washed with HCl IN. The organic layer was dried (MgSO4), filtered, and the solvent was evaporated. Yield: 107.67 g of intermediate 4 (87 percent).
87%
With triethylamine In dichloromethane at 20℃;
Example A1: Preparation of intermediate 1. Benzenepropanoyl chloride (0.488 mol) was added dropwise at room temperature to a solution of 4-bromo benzenamine (0.407 mol) in Et3N (70ml) and DCM (700ml) and the mixture was stirred at room temperature overnight. The mixture was poured out into water and concentrated NH4OH, and extracted with DCM. The organic layer was dried (MgSO4), filtered, and the solvent was evaporated. The residue was crystallized from diethyl ether. The residue (119.67g) was taken up in DCM and washed with HCl 1N. The organic layer was dried (MgSO4), filtered, and the solvent was evaporated, yielding 107.67g of intermediate 1 (87percent).
81%
With triethylamine In dichloromethane at 0 - 20℃; for 4 h;
Preparation ofN-(4-Bromo phenyl )-3-phenyl propionamide; Hydrocmnamoyl chloride (19.6 g, 168.5 mmol) was added to a mixture of 4-bromoanline (10.0 g, 116.3 mmol) and triethylamine (23 5 g, 232.5 mmol) in dry dichloromethane (200 ml) at 0 0C, the mixture was stirred, and allowing it to warm up to room temperature during 4 brs The reaction mixture was poured mto ice-water mixture, the organic layer was separated, washed with 10percent aqueous solution of hydrochloric acid, water and brme, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was triturated with hexane to furnish the pure product (11.0 g, 81percent) as a off white solid, Mp 149-151°C. 1H NMR (400 MHz, CDCl3) δ 2.64 (t, J = 8.0 Hz, 2 H), 3.04 (t, J = 8 0 Hz, 2 H), 7.01 (br s, 1 H, D2O exchangeable), 6.88-7.30 (m, 3 H), 7.26-7.33 (m, 4 H), 7.36-7.43 (m, 2 H). (M+H)+= 302, 304.
Reference：
[1] Chemical Science, 2016, vol. 7, # 2, p. 1276 - 1280
[2] Journal of Chemical Research - Part S, 2003, # 1, p. 10 - 11
[3] Patent: WO2010/36316, 2010, A1, . Location in patent: Page/Page column 47-48
[4] Patent: EP2371819, 2011, A1, . Location in patent: Page/Page column 6
[5] Journal of Medicinal Chemistry, 2013, vol. 56, # 9, p. 3568 - 3581
3
[ 90878-19-6 ]
[ 2493-02-9 ]
[ 316146-27-7 ]
Reference：
[1] Angewandte Chemie - International Edition, 2018, vol. 57, # 37, p. 12126 - 12130[2] Angew. Chem., 2018, vol. 130, # 37, p. 12302 - 12306,5
4
[ 68-12-2 ]
[ 316146-27-7 ]
[ 654655-68-2 ]
Yield
Reaction Conditions
Operation in experiment
67%
at 10 - 80℃;
Phosphoric trichloride (1.225 mol) was added dropwise at 10°C to DMF (0.525 mol). Then intermediate 1 (0.175 mol) was added at room temperature. The mixture was stirred overnight at 80°C, poured out on ice and extracted with DCM. The organic layer was dried (MgS04), filtered, and the solvent was evaporated. The product was used without further purification, yielding 77.62 g of intermediate 2 (67percent).
67%
at 20 - 80℃;
Example A2; Preparation of intermediate 2; The reaction was carried out twice. POC13 (1.225 mol) was added dropwise at 10 °C to DMF (0.525 mol). Then intermediate 1 (0.175 mol) was added at room temperature . The mixture was stirred overnight at 80 °C, poured out on ice and extracted with CH2CI2. The organic layer was dried (MgSO4), filtered, and the solvent was evaporated, yielding 77.62 g (67percent) of intermediate 2. The product was used without further purification.
67%
at 10 - 80℃;
b) Preparation of intermediate 11; The reaction was carried out twice. POCl3 (1.225 mol) was added dropwise at 10°C to DMF (0.525 mol). Then intermediate 10 (0.175 mol) was added at room temperature. The mixture was stirred overnight at 8O0C, poured out on ice and extracted with CH2CI2. The organic layer was dried (MgSO4), filtered, and the solvent was evaporated. Yield: 77.62 g of intermediate 11 (67percent).
67%
Stage #1: at 10 - 20℃; Stage #2: at 20 - 80℃;
b. Preparation of intermediate 10; The reaction was carried out twice . POCl3 (1.225 mol) was added dropwise at 10°C to DMF (0.525 mol) . Then intermediate 9 (0.175 mol) was added at room temperature . The mixture was stirred overnight at 80°C, poured out on ice and extracted with CH2Cl2 . The organic layer was dried (MgSO4), filtered, and the solvent was evaporated . Yield: 77.62 g of intermediate 10 (67 percent).
67%
at 10 - 80℃;
b) Preparation of intermediate 5; The reaction was carried out twice. POCl3 (1.225 mol) was added dropwise at 10°C to DMF (0.525 mol). Then intermediate 4 (0.175 mol) was added at room temperature. The mixture was stirred overnight at 80°C, poured out on ice and extracted with CH2Cl2. The organic layer was dried (MgSO4), filtered, and the solvent was evaporated. The product was used without further purification. Yield: 77.62 g of intermediate 5 (67 percent).
67%
Stage #1: at 10℃; Stage #2: at 20 - 80℃;
Intermediate 2 The reaction was carried out twice . POCI3 (1.225 mol) was added dropwise at 10 0C to DMF (0.525 mol) . Then intermediate 1 (0.175 mol) was added at room temperature. The mixture was stirred overnight at 80 0C, poured out on ice and extracted with CH2CI2 . The organic layer was dried (MgSO/t), filtered, and the solvent was evaporated, yielding 77.62 g (67percent) of intermediate 2. The product was used without further purification.
With trichlorophosphate In N,N-dimethyl-formamide at 80℃; Inert atmosphere
POCl3 (129 g, 0.840 mol) was added dropwise into DMF (32.6 ml, 0.420 mol) at 0°C. After 1h of vigorous agitation under room temperature, compound 1 (32 g, 0.105 mol) and CH3CN (50mL) was added into the mixture, followed by being stirred overnight at 80°C. After solvent was partially removed, the residue was poured out into ice water (300mL) with rapid stirring and crude compound 2 precipitates gradually. Then the solid was filtrated and washed with portions of cold CH3OH. Finally, compound 2 (25g, 71percent) can be recrystallized from CH2Cl2 and CH3OH.
Reference：
[1] Chinese Chemical Letters, 2015, vol. 26, # 6, p. 790 - 792
6
[ 316146-27-7 ]
[ 654655-68-2 ]
Yield
Reaction Conditions
Operation in experiment
67%
Stage #1: at 10℃; Stage #2: at 20 - 80℃;
The reaction was carried out twice . POCl3 (1.225 mol) was added dropwise at 10°C to iV,iV-dimethylformamide (DMF) (0.525 mol) . Then intermediate compound 1 (prepared according Al) (0.175 mol) was added at room temperature . The mixture was stirred overnight at 80°C, poured out on ice and extracted with CH2CI2 . The organic layer was dried (MgSO4), filtered, and the solvent was evaporated . The product was used without further purification. Yield : 77.62g of intermediate compound 2 (67percent).
67%
With trichlorophosphate In DMF (N,N-dimethyl-formamide) at 80℃;
The reaction was carried out twice. POC13 (1.225 mol) was added dropwise at [10C] to DMF (0.525 mol). Then intermediate compound 1 (prepared according [A1)] (0.175 mol) was added at room temperature. The mixture was stirred overnight at [80C,] poured out on ice and extracted with CH2C12. The organic layer was dried [(MgS04),] filtered, and the solvent was evaporated. The product was used without further purification. Yielding : (77.62g ; Yield=67percent).
67%
at 10 - 80℃;
b) Preparation of intermediate compound 4b; The reaction was carried out twice. POCl3 (1.225 mol) was added dropwise at 10°C to iV,iV-dimethylformamide (0.525 mol). Then intermediate compound 4a (0.175 mol) was EPO <DP n="39"/>added at room temperature. The mixture was stirred overnight at 80°C, poured out on ice and extracted with CH2CI2. The organic layer was dried (MgSO4), filtered, and the solvent was evaporated. The product was used without further purification. Yield: 77.62 g (67 percent) of intermediate compound 4b.
67%
at 20 - 80℃;
Example A2; Preparation of intermediate 2. Phosphoric trichloride (1.225 mol) was added dropwise at 10°C to DMF (0.525 mol). Then intermediate 1 (0.175 mol) was added at room temperature. The mixture was stirred overnight at 80°C, poured out on ice and extracted with DCM. The organic layer was dried (MgSO4), filtered, and the solvent was evaporated. The product was used without iurther purification, yielding 77.62 g of intermediate 2 (67percent).
64%
With cetyltrimethylammonim bromide; N,N-dimethyl-formamide; trichlorophosphate In acetonitrile at 5 - 80℃; for 8 h;
Preparation of3-Benzyl-6-bromo-2-chloro-quinoline; Phosphorus oxychloπde (30.0 g, 196 9 mmol) was added dropwise to JV, JV-Dimethylformamide (14 34 g, 196.18 mmol) at 5 0C, the mixture was allowed to warm up to room temperature and stirred for 20 mm. The above reagent was added to a suspension of7V-(4-Bromo phenyl)-3-phenyl propionamide (3.0 g, 9.86 mmol) and cetyltrimethylammomum bromide (CTAB, 0.04 g, 0.10 mmol) m acetomtπle at 5 0C. The reaction mixture was heated at 80 0C for 8 h, cooled to room temperature, poured into 100 ml of 3percent hypo solution at 0 0C, extracted with dichloromethane, the organic layer was washed with water until the water extracts became neutral to pH paper followed by brme, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude product was purified by column chromatography on silica gel (100-200) eluted with hexane - ethyl acetate (97:3) to afford the title compound (2.0 g, 64percent yield) as a white crystalline solid, Mp 102°C-104°C. 1H NMR (400 MHz, CDCL3). δ 4.22 (s, 2 H), 7.20-7.24 (m, 2 <n="24"/>H), 7 26-7 31 (m, 1 H), 7 32-7 38 (m, 2 H), 7 65 (s, 1 H), 7 72 (dd, /= 12 0, 4 0 Hz, 1 H), 7 84-7 88 (m, 2H). [M+H]+ = 332, 335.
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃;
General procedures:; Scheme 2; An acid (1 equiv), HATU (1 equiv) and DIEA (3 equiv) were added to a solution of 4-bromo-aniline (1 equiv) in DMF. The mixture was stirred at room temperature until the starting material disappeared (detection by LC-MS). The solution was diluted with EtOAc and washed with saturated aqueous NaHCO3. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude bromide 2-1. The bromide 2-1 (1 equiv) and the boronic acid ester (1.5 equiv) were dissolved in degassed dioxane/H2O (5:1 by volume) in a sealed tube. Pd(PPh3)4 (0.03 equiv) and 2M solution Of K2CO3 (3 equiv) were added sequentially. The mixture was heated at 95 0C for 2h. After cooling to room temperature, the mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate and concentrated in vacuo. The residue was then purified by preparative HPLC to give the product 2-2 as a solid (65percent-80percent yield in two steps).; Example 27. N-(4-(lH-pyrazol-4-yl)phenv0-3-phenylpropanamide; Procedures in Scheme 2 were utilized to synthesize this compound. LC/MS: Ci8HnN3O (M+l) 292. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
With thionyl chloride;Reflux;
Case 1 Obtaining intermediate compound Va; [Show Image] To a boiling mixture of the 230 grams of the hydrocinnamic acid and 270 grams of the 4-bromoaniline in 1 liter of the toluol 160 ml of the thionyl chloride are added by drops; then 1 liter of water and 50 ml of the aqueous ammonia are added by drops. The sediment after cooling is filtered and dried. Yield: 405 grams of the intermediate compound Va.
To a solution of 4-bromobenzenmine (40g, 0.232mol) and Et3N (32mL) in CH2Cl2 (200mL), benzenepropanoylchoride (37.5g, 0.223mol) was added dropwise at 0C, and the mixture was stirred overnight at room temperature. Then, the mixture was poured out into water and 10% HCl was added. The slurry of white solid which formed was stirred with ice-bath cooling for 1 hour. The solid was separated by filtration, washed with diethyl ether and air dried to give 62g (92% yield) of compound 1.
87%
With triethylamine; In dichloromethane; at 20℃;
Benzenepropanoyl chloride (0.488 mol) was added dropwise at room temperature to a solution of 4-bromo benzenamine (0.407 mol) in Et3N (70ml) and DCM (700ml) and the mixture was stirred at room temperature overnight The mixture was poured out into water and concentrated NH40H, and extracted with DCM. The organic layer was dried (MgSO4), filtered, and the solvent was evaporated. The residue was crystallized from diethyl ether. The residue (119. 67g) was taken up in DCM and washed with HCI IN. The organic layer was dried (MgS04), filtered, and the solvent was evaporated, yielding 107.67g of intermediate 1 (87%).
87%
With triethylamine; In dichloromethane; at 20℃;
Example A2; a) Preparation of intermediate 4; Benzene propanoyl chloride (0.488 mol) was added dropwise at room temperature to a solution of 4-bromobenzenamine (0.407 mol) in Et3N (70 ml) and CH2Cl2 (700 ml) and the mixture was stirred at room temperature overnight. The mixture was poured out into water and concentrated NH4OH, and extracted with CH2Cl2. The organic layer was dried (MgSO4), filtered, and the solvent was evaporated. The residue was crystallized from diethyl ether. The residue (119.67 g) was taken up in CH2Cl2 and washed with HCl IN. The organic layer was dried (MgSO4), filtered, and the solvent was evaporated. Yield: 107.67 g of intermediate 4 (87 %).
87%
With triethylamine; In dichloromethane; at 20℃;
Example A1: Preparation of intermediate 1. Benzenepropanoyl chloride (0.488 mol) was added dropwise at room temperature to a solution of 4-bromo benzenamine (0.407 mol) in Et3N (70ml) and DCM (700ml) and the mixture was stirred at room temperature overnight. The mixture was poured out into water and concentrated NH4OH, and extracted with DCM. The organic layer was dried (MgSO4), filtered, and the solvent was evaporated. The residue was crystallized from diethyl ether. The residue (119.67g) was taken up in DCM and washed with HCl 1N. The organic layer was dried (MgSO4), filtered, and the solvent was evaporated, yielding 107.67g of intermediate 1 (87%).
81%
With triethylamine; In dichloromethane; at 0 - 20℃; for 4h;
Preparation ofN-(4-Bromo phenyl )-3-phenyl propionamide; Hydrocmnamoyl chloride (19.6 g, 168.5 mmol) was added to a mixture of 4-bromoanline (10.0 g, 116.3 mmol) and triethylamine (23 5 g, 232.5 mmol) in dry dichloromethane (200 ml) at 0 0C, the mixture was stirred, and allowing it to warm up to room temperature during 4 brs The reaction mixture was poured mto ice-water mixture, the organic layer was separated, washed with 10% aqueous solution of hydrochloric acid, water and brme, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was triturated with hexane to furnish the pure product (11.0 g, 81%) as a off white solid, Mp 149-151C. 1H NMR (400 MHz, CDCl3) delta 2.64 (t, J = 8.0 Hz, 2 H), 3.04 (t, J = 8 0 Hz, 2 H), 7.01 (br s, 1 H, D2O exchangeable), 6.88-7.30 (m, 3 H), 7.26-7.33 (m, 4 H), 7.36-7.43 (m, 2 H). (M+H)+= 302, 304.
Benzenepropanoylchloride (0.488 mol) was added dropwise at room temperature to a solution of 4-bromobenzenamine (0.407 mol) in Et3N (70ml) and CH2Cl2 (700ml) and the mixture was stirred at room temperature overnight. The mixture was poured out into water and concentrated NH4OH, and extracted with CH2Cl2 . The organic layer was dried (MgSO4), filtered, and the solvent was evaporated . The residue was crystallized from diethyl ether . The residue (119.67g) was taken up in CH2Cl2 and washed with HCl IN . The organic layer was dried (MgSO4), filtered, and the solvent was evaporated. Yield: 107.67g of intermediate compound 1.
With triethylamine; In dichloromethane; at 25℃;
Benzenepropanoylchloride (0.488 mol) was added dropwise at room temperature to a solution [OF4-BROMOBENZENAMINE] (0.407 mol) in Et3N (70ml) and CH2C12 [(700ML)] and the mixture was stirred at room temperature overnight. The mixture was poured out into water and concentrated [NH40H,] and extracted with [CH2C12.] The organic layer was dried [(MGS04),] filtered, and the solvent was evaporated. The residue was crystallized from diethyl ether. The residue [(119.] 67g) was taken up in [CH2CL2] and washed with HCl [1N.] The organic layer was dried [(MGS04),] filtered, and the solvent was evaporated. Yielding: 107.67g of intermediate compound 1.
With triethylamine; In dichloromethane; at 20℃;
Example Al; Preparation of intermediate 1 Intermediate 1; Benzenepropanoylchloride (0.488 mol) was added dropwise at room temperature to a solution of 4-bromobenzenamine (0.407 mol) in Et3N (70 ml) and Cl-I2CI2 (700 ml) and the mixture was stirred at room temperature overnight. The mixture was poured out into water and concentrated NH40H, and extracted with CH2C12. The organic layer was dried (MgSO4), filtered, and the solvent was evaporated. The residue was crystallized from diethyl ether. The residue (119.67 g) was taken up in CH2C12 and washed with HC1 IN. The organic layer was dried (MgSO4), filtered, and the solvent was evaporated. Yield: 107. 67 g of intermediate 1.
With triethylamine; In dichloromethane; at 20℃;
Synthesis of compound LCompound L was synthesized according to the following schemeSynthesis of intermediate compound 4 a) Preparation of intermediate compound 4a; Benzenepropanoyl chloride (0.488 mol) was added dropwise at room temperature to a solution of 4-bromobenzenamine (0.407 mol) in Et3N (70 ml) and CH2Cl2 (700 ml) and the mixture was stirred at room temperature overnight. The mixture was poured out into water and concentrated NH4OH, and extracted with CH2Cl2. The organic layer was dried (MgSO4), filtered, and the solvent was evaporated. The residue was crystallized from diethyl ether. The residue (119.67 g) was taken up in CH2Cl2 and washed with HCl IN. The organic layer was dried (MgSO4), filtered, and the solvent was evaporated. Yield: 107.67 g of intermediate compound 4a.
With triethylamine; In dichloromethane; at 20℃;
Example A4; a) Preparation of intermediate 10; Benzenepropanoyl chloride (0.488 mol) was added dropwise at room temperature to a solution of 4-bromobenzenamine (0.407 mol) in Et3N (70 ml) and CH2Cl2 (700 ml) and the mixture was stirred at room temperature overnight. The mixture was poured out EPO <DP n="46"/>into water and concentrated NH4OH, and extracted with CH2CI2. The organic layer was dried (MgSO4), filtered, and the solvent was evaporated. The residue was crystallized from diethyl ether. The residue (119.67 g) was taken up in CH2CI2 and washed with HCl IN. The organic layer was dried (MgSO4), filtered, and the solvent was evaporated. Yield: 107.67 g of intermediate 10.
With triethylamine; In dichloromethane; at 5 - 20℃;
Example A4; a. Preparation of intermediate 9; Benzenepropanoylchloride (0.488 mol) was added dropwise at room temperature to a solution of 4-bromobenzenamine (0.407 mol) in Et3N (70 ml) and CH2Cl2 (700 ml) and the mixture was stirred at room temperature overnight. The mixture was poured out into water and concentrated NH4OH, and extracted with CH2Cl2 . The organic layer was dried (MgSO4), filtered, and the solvent was evaporated . The residue was crystallized from diethyl ether . The residue (119.67 g) was taken up in CH2Cl2 and washed with HCl IN . The organic layer was dried (MgSO4), filtered, and the solvent was evaporated. Yield: 107.67 g of intermediate 9 .
Benzenepropanoylchloride (0.488 mol) was added dropwise at room temperature to a solution of 4-bromobenzenamine (0.407 mol) in Et3N (70 ml) and CH2Cl2 (700 ml) and EPO <DP n="35"/>the mixture was stirred at room temperature overnight. The mixture was poured out into water and concentrated NH4OH, and extracted with CH2CI2 . The organic layer was dried (MgSO/t), filtered, and the solvent was evaporated . The residue was crystallized from diethyl ether . The residue (119.67 g) was taken up in CH2CI2 and washed with HCl IN . The organic layer was dried (MgSO/t), filtered, and the solvent was evaporated. Yield: 107.67 g of intermediate 1.
The reaction was carried out twice . POCl3 (1.225 mol) was added dropwise at 10°C to iV,iV-dimethylformamide (DMF) (0.525 mol) . Then intermediate compound 1 (prepared according Al) (0.175 mol) was added at room temperature . The mixture was stirred overnight at 80°C, poured out on ice and extracted with CH2CI2 . The organic layer was dried (MgSO4), filtered, and the solvent was evaporated . The product was used without further purification. Yield : 77.62g of intermediate compound 2 (67percent).
67%
With trichlorophosphate; In DMF (N,N-dimethyl-formamide); at 80℃;
The reaction was carried out twice. POC13 (1.225 mol) was added dropwise at [10C] to DMF (0.525 mol). Then intermediate compound 1 (prepared according [A1)] (0.175 mol) was added at room temperature. The mixture was stirred overnight at [80C,] poured out on ice and extracted with CH2C12. The organic layer was dried [(MgS04),] filtered, and the solvent was evaporated. The product was used without further purification. Yielding : (77.62g ; Yield=67percent).
67%
With N,N-dimethyl-formamide; trichlorophosphate; at 10 - 80℃;
b) Preparation of intermediate compound 4b; The reaction was carried out twice. POCl3 (1.225 mol) was added dropwise at 10°C to iV,iV-dimethylformamide (0.525 mol). Then intermediate compound 4a (0.175 mol) was EPO <DP n="39"/>added at room temperature. The mixture was stirred overnight at 80°C, poured out on ice and extracted with CH2CI2. The organic layer was dried (MgSO4), filtered, and the solvent was evaporated. The product was used without further purification. Yield: 77.62 g (67 percent) of intermediate compound 4b.
67%
With N,N-dimethyl-formamide; trichlorophosphate; at 20 - 80℃;
Example A2; Preparation of intermediate 2. Phosphoric trichloride (1.225 mol) was added dropwise at 10°C to DMF (0.525 mol). Then intermediate 1 (0.175 mol) was added at room temperature. The mixture was stirred overnight at 80°C, poured out on ice and extracted with DCM. The organic layer was dried (MgSO4), filtered, and the solvent was evaporated. The product was used without iurther purification, yielding 77.62 g of intermediate 2 (67percent).
64%
With cetyltrimethylammonim bromide; N,N-dimethyl-formamide; trichlorophosphate; In acetonitrile; at 5 - 80℃; for 8h;Product distribution / selectivity;
Preparation of3-Benzyl-6-bromo-2-chloro-quinoline; Phosphorus oxychlopide (30.0 g, 196 9 mmol) was added dropwise to JV, JV-Dimethylformamide (14 34 g, 196.18 mmol) at 5 0C, the mixture was allowed to warm up to room temperature and stirred for 20 mm. The above reagent was added to a suspension of7V-(4-Bromo phenyl)-3-phenyl propionamide (3.0 g, 9.86 mmol) and cetyltrimethylammomum bromide (CTAB, 0.04 g, 0.10 mmol) m acetomtpile at 5 0C. The reaction mixture was heated at 80 0C for 8 h, cooled to room temperature, poured into 100 ml of 3percent hypo solution at 0 0C, extracted with dichloromethane, the organic layer was washed with water until the water extracts became neutral to pH paper followed by brme, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude product was purified by column chromatography on silica gel (100-200) eluted with hexane - ethyl acetate (97:3) to afford the title compound (2.0 g, 64percent yield) as a white crystalline solid, Mp 102°C-104°C. 1H NMR (400 MHz, CDCL3). delta 4.22 (s, 2 H), 7.20-7.24 (m, 2 <n="24"/>H), 7 26-7 31 (m, 1 H), 7 32-7 38 (m, 2 H), 7 65 (s, 1 H), 7 72 (dd, /= 12 0, 4 0 Hz, 1 H), 7 84-7 88 (m, 2H). [M+H]+ = 332, 335.
Phosphoric trichloride (1.225 mol) was added dropwise at 10°C to DMF (0.525 mol). Then intermediate 1 (0.175 mol) was added at room temperature. The mixture was stirred overnight at 80°C, poured out on ice and extracted with DCM. The organic layer was dried (MgS04), filtered, and the solvent was evaporated. The product was used without further purification, yielding 77.62 g of intermediate 2 (67percent).
67%
With trichlorophosphate; at 20 - 80℃;
Example A2; Preparation of intermediate 2; The reaction was carried out twice. POC13 (1.225 mol) was added dropwise at 10 °C to DMF (0.525 mol). Then intermediate 1 (0.175 mol) was added at room temperature . The mixture was stirred overnight at 80 °C, poured out on ice and extracted with CH2CI2. The organic layer was dried (MgSO4), filtered, and the solvent was evaporated, yielding 77.62 g (67percent) of intermediate 2. The product was used without further purification.
67%
With trichlorophosphate; at 10 - 80℃;
b) Preparation of intermediate 11; The reaction was carried out twice. POCl3 (1.225 mol) was added dropwise at 10°C to DMF (0.525 mol). Then intermediate 10 (0.175 mol) was added at room temperature. The mixture was stirred overnight at 8O0C, poured out on ice and extracted with CH2CI2. The organic layer was dried (MgSO4), filtered, and the solvent was evaporated. Yield: 77.62 g of intermediate 11 (67percent).
67%
b. Preparation of intermediate 10; The reaction was carried out twice . POCl3 (1.225 mol) was added dropwise at 10°C to DMF (0.525 mol) . Then intermediate 9 (0.175 mol) was added at room temperature . The mixture was stirred overnight at 80°C, poured out on ice and extracted with CH2Cl2 . The organic layer was dried (MgSO4), filtered, and the solvent was evaporated . Yield: 77.62 g of intermediate 10 (67 percent).
67%
With trichlorophosphate; at 10 - 80℃;
b) Preparation of intermediate 5; The reaction was carried out twice. POCl3 (1.225 mol) was added dropwise at 10°C to DMF (0.525 mol). Then intermediate 4 (0.175 mol) was added at room temperature. The mixture was stirred overnight at 80°C, poured out on ice and extracted with CH2Cl2. The organic layer was dried (MgSO4), filtered, and the solvent was evaporated. The product was used without further purification. Yield: 77.62 g of intermediate 5 (67 percent).
67%
Intermediate 2 The reaction was carried out twice . POCI3 (1.225 mol) was added dropwise at 10 0C to DMF (0.525 mol) . Then intermediate 1 (0.175 mol) was added at room temperature. The mixture was stirred overnight at 80 0C, poured out on ice and extracted with CH2CI2 . The organic layer was dried (MgSO/t), filtered, and the solvent was evaporated, yielding 77.62 g (67percent) of intermediate 2. The product was used without further purification.
With trichlorophosphate; In chloroform; at 10℃;Reflux;
Case 2 Obtaining intermediate compound IIIa; [Show Image] To the cooled down to 10°C mixture of the 84 grams of the dimethyl formamide and 200 grams of the intermediate compound Va in 600 ml of chloroform, 400 ml of the phosphorous oxychloride are added by drops; then the mixture is boiled during the night. The mixture is then cooled and poured out into 2 kgs of ice; the organic layer is flushed with water, dried above MgSO4, and filtered; the solvent is vacuum distilled. The residue is crystallized from the methanol. Yield: 163 grams of the intermediate compound IIIa.
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 95℃; for 2h;sealed tube;
General procedures:; Scheme 2; An acid (1 equiv), HATU (1 equiv) and DIEA (3 equiv) were added to a solution of 4-bromo-aniline (1 equiv) in DMF. The mixture was stirred at room temperature until the starting material disappeared (detection by LC-MS). The solution was diluted with EtOAc and washed with saturated aqueous NaHCO3. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude bromide 2-1. The bromide 2-1 (1 equiv) and the boronic acid ester (1.5 equiv) were dissolved in degassed dioxane/H2O (5:1 by volume) in a sealed tube. Pd(PPh3)4 (0.03 equiv) and 2M solution Of K2CO3 (3 equiv) were added sequentially. The mixture was heated at 95 0C for 2h. After cooling to room temperature, the mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate and concentrated in vacuo. The residue was then purified by preparative HPLC to give the product 2-2 as a solid (65percent-80percent yield in two steps).; Example 27. N-(4-(lH-pyrazol-4-yl)phenv0-3-phenylpropanamide; Procedures in Scheme 2 were utilized to synthesize this compound. LC/MS: Ci8HnN3O (M+l) 292. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
With trichlorophosphate; In N,N-dimethyl-formamide; at 80℃;Inert atmosphere;
POCl3 (129 g, 0.840 mol) was added dropwise into DMF (32.6 ml, 0.420 mol) at 0°C. After 1h of vigorous agitation under room temperature, compound 1 (32 g, 0.105 mol) and CH3CN (50mL) was added into the mixture, followed by being stirred overnight at 80°C. After solvent was partially removed, the residue was poured out into ice water (300mL) with rapid stirring and crude compound 2 precipitates gradually. Then the solid was filtrated and washed with portions of cold CH3OH. Finally, compound 2 (25g, 71percent) can be recrystallized from CH2Cl2 and CH3OH.
General procedure: Here, a description will be given of the general synthetic procedure for the synthesis of amide in the dehydration azeotropic reflux. First of all, in a round-bottom flask, put a carboxylic acid, a catalyst and a solvent. In some cases, also put additives. The flask, put a Teflon-coated magnetic stirrer bar (registered trademark), attaching the side tube with a dropping funnel was charged with cotton plug and molecular sieves 4A (pellet). On the dropping funnel is attached a reflux condenser. The mixture was stirred at room temperature for 5 minutes, then added dropwise amine. Heating a predetermined period of time while removing the water in the mixture dehydration azeotropic reflux conditions. The reaction mixture was cooled to room temperature, then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to give the amide of interest. Incidentally, molecular sieves 4A will use those previously well dried. According to a general experimental procedure, as shown in the upper row of Table 4, by dehydration condensation reaction of 3-phenylpropionic acid (0.5 mmol) and aniline (0.5 mmol)The corresponding amide was synthesized.These are examples in which a carboxylic acid having two hydrogen atoms in the alpha position is used as a carboxylic acid. As a catalyst, phenylboronic acid was used in an amount of 5 molpercent based on the carboxylic acid. In Experimental Example 4-1, no additives were added, and in Experimental Examples 4-2 to 4-4, DMAPO, PPYO, and DMAP were added in equimolar amounts as catalysts, respectively.As is apparent from the yield shown in Table 4, in Experimental Examples 4-2 to 4-4 to which additives were added, the yield of amide was improved as compared with Experimental Example 4-1 in which no additive was added did.That is, the reaction promoting effect by the additive was recognized.In addition, the N - oxide such as DMAPO and PPYO had a remarkable reaction promoting effect as compared with DMAP.
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