* 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.
Reference：
[1] Chemical Communications, 2008, # 47, p. 6333 - 6335
2
[ 21739-93-5 ]
[ 27007-53-0 ]
Yield
Reaction Conditions
Operation in experiment
92%
With hydrogenchloride In methanol
Step 1. methyl 2-bromo-5-chlorobenzoate Into a stirred solution of 2-bromo-5-chlorobenzoic acid (11 g, 46.7 mmol, HPLC RT=2.99 min) in methanol (250 mL) at 0° C. was bubbled HCl gas. The reaction was allowed to warm to room temperature and stirred overnight. The reaction mixture was concentrated in vacuo to give an orange oil, which was purified by flash chromatography using hexanes as eluant to give methyl 2-bromo-5-chlorobenzoate as a colorless oil (10.7 g, 92percent yield). TLC Rf=0.6 (5percent EtOAc-hexanes); HPLC RT=3.48 min (Method A); 1H NMR (CDl3, 400 MHz) 7.78 ppm (d, 1H, J=2.6 Hz); 7.59 ppm (d, 1H, J=12.81 Hz);7.30 ppm (dd, 1H, J=8.6, 2.5 Hz); 3.94 ppm (s, 3H).
92%
With hydrogenchloride In methanol
Step 1. methyl 2-bromo-5-chlorobenzoate Into a stirred solution of 2-bromo-5-chlorobenzoic acid (11 g, 46.7 mmol, HPLC RT=2.99 min) in methanol (250 mL) at 0° C. was bubbled HCl gas. The reaction was allowed to warm to room temperature and stirred overnight. The reaction mixture was concentrated in vacuo to give an orange oil, which was purified by flash chromatography using hexanes as eluant to give methyl 2-bromo-5-chlorobenzoate as a colorless oil (10.7 g, 92percent yield). TLC Rf=0.6 (5percent EtOAc-hexanes); HPLC RT=3.48 min (Method A); 1H NMR (CDCl3, 400 MHz) 7.78 ppm (d, 1H, J=2.6 Hz); 7.59 ppm (d, 1H, J=12.81 Hz);7.30 ppm (dd, 1H, J=8.6, 2.5 Hz); 3.94 ppm (s, 3H).
92%
With hydrogenchloride In methanol
Step 1. Into a stirred solution of 2-bromo-5-chlorobenzoic acid (11 g, 46.7 mmol, HPLC RT=2.99 min) in methanol (250 mL) at 0° C. was bubbled HCl gas. The reaction was allowed to warm to room temperature and stirred overnight. The reaction mixture was concentrated in vacuo to give an orange oil, which was purified by flash chromatography using hexanes as eluant to give methyl 2-bromo-5-chlorobenzoate as a colorless oil (10.7 g, 92percent yield). TLC Rf=0.6 (5percent EtOAc-hexanes); HPLC RT=3.48 min, method A; 1H NMR (CDCl3, 400 MHz) 7.78 ppm (d, 1H, J=2.6 Hz); 7.59 ppm (d, 1H, J=12.81 Hz);7.30 ppm (dd, 1H, J=8.6,2.5 Hz); 3.94 ppm (s, 3H).
2-bromo-5-chlorobenzoic acid (4g, 0.Ol6mol) was dissolved in MeOH (20m1) and sulphuric acid (imI) was added. The reaction was refluxed for 3h then cooled at RT. Water (20m1) was added and the solid was filtered, dissolved in DCM and washed with saturated aqueous solution of NaHCO3. The organic solvent was dried (Na2SO4) and evaporated to obtain 4.17g of the title compound as oil.1HNMR (CDCl3) 5 ppm= 7.81(d,1H), 7.61(d,1H),7.33(dd,1H), 3.96 (s,3H).
4.17 g
for 3 h; Reflux
2-bromo-5-chlorobenzoic acid (4 g, 0.016 mol) was dissolved in MeOH (20 ml) and sulphuric acid (1 ml) was added. The reaction was refluxed for 3 h then cooled at RT. Water (20 ml) was added and the solid was filtered, dissolved in DCM and washed with saturated aqueous solution of NaHCO3. The organic solvent was dried (Na2SO4) and evaporated to obtain 4.17 g of the title compound as oil. 1HNMR (CDCl3) δ ppm=7.81 (d, 1H), 7.61 (d, 1H), 7.33 (dd, 1H), 3.96 (s, 3H).
4.17 g
for 3 h; Reflux
2-bromo-5-chlorobenzoic acid (4 g, 0.016 mol) was dissolved in MeOH (20 ml) and sulphuric acid (1 ml) was added. The reaction was refluxed for 3 h then cooled at RT. Water (20 ml) was added and the solid was filtered, dissolved in DCM and washed with saturated aqueous solution of NaHCO3. The organic solvent was dried (Na2SO4) and evaporated to obtain 4.17 g of the title compound as oil. 1HNMR (CDCl3) δ ppm=7.81 (d, 1H), 7.61 (d, 1H), 7.33 (dd, 1H), 3.96 (s, 3H).
(1) Synthesis of Intermediate [1-1] (methyl 2-bromo- 5-chlorobenzoate)With reference to a synthesis method described in Journal of Organic Chemistry 2003, 68, 11, 4588, 2-bromo-5- chlorobenzoic acid was used as a starting material and Intermediate [1-1] (methyl 2-bromo-5-chlorobenzoate) was synthesized.
4.17 g
With sulfuric acid; for 3h;Reflux;
2-bromo-5-chlorobenzoic acid (4g, 0.Ol6mol) was dissolved in MeOH (20m1) and sulphuric acid (imI) was added. The reaction was refluxed for 3h then cooled at RT. Water (20m1) was added and the solid was filtered, dissolved in DCM and washed with saturated aqueous solution of NaHCO3. The organic solvent was dried (Na2SO4) and evaporated to obtain 4.17g of the title compound as oil.1HNMR (CDCl3) 5 ppm= 7.81(d,1H), 7.61(d,1H),7.33(dd,1H), 3.96 (s,3H).
With sulfuric acid; In dichloromethane; water; at 20℃; for 3h;Reflux;
Example 26: preparation of intermediate 26: methyl 2-bromo-5-chlorobenzoateCI2-bromo-5-chlorobenzoic acid (4g, 0.01 6mol) was dissolved in MeOH (20m1) and25 sulphuric acid (imI) was added. The reaction was refluxed for 3h then cooled at RT. Water (20m1) was added and the solid was filtered, dissolved in DCM and washed with saturated aqueous solution of NaHCO3. The organic solvent was dried (Na2SO4) and evaporated to obtain 4.17g of the title compound as oil. 1 HNMR (CDCI3) 6 ppm= 7.81 (d,1 H), 7.61 (d,1 H),7.33(dd,1 H), 3.96 (s,3H).
With hydrogenchloride; at 20℃;
Step A: Preparation of 2-bromo-5-chlorobenzoate Through a solution of 2-bromo-5-chlorobenzoic acid (l lg, 46.7 mmol) in methanol (250ml) was bubbled HCl gas. The reaction was allowed to warm to room temperature and stirred overnight. The reaction mixture is concentrated in vacuo to give an orange oil, which is purified by flash chromatography (silica gel, hexane) to give the title compound as a colorless oil. 1H NMR (CDCI3, 400MHz): delta 7.78 (d, 1 H, J= 2.6 Hz); 7.59 (d, 1H, J= 12.81 Hz);7.30 (dd, 1 H, J= 8.6, 2.5 Hz); 3.94 (s, 3H)
4.17 g
With sulfuric acid; for 3h;Reflux;
2-bromo-5-chlorobenzoic acid (4 g, 0.016 mol) was dissolved in MeOH (20 ml) and sulphuric acid (1 ml) was added. The reaction was refluxed for 3 h then cooled at RT. Water (20 ml) was added and the solid was filtered, dissolved in DCM and washed with saturated aqueous solution of NaHCO3. The organic solvent was dried (Na2SO4) and evaporated to obtain 4.17 g of the title compound as oil. 1HNMR (CDCl3) delta ppm=7.81 (d, 1H), 7.61 (d, 1H), 7.33 (dd, 1H), 3.96 (s, 3H).
4.17 g
With sulfuric acid; for 3h;Reflux;
2-bromo-5-chlorobenzoic acid (4 g, 0.016 mol) was dissolved in MeOH (20 ml) and sulphuric acid (1 ml) was added. The reaction was refluxed for 3 h then cooled at RT. Water (20 ml) was added and the solid was filtered, dissolved in DCM and washed with saturated aqueous solution of NaHCO3. The organic solvent was dried (Na2SO4) and evaporated to obtain 4.17 g of the title compound as oil. 1HNMR (CDCl3) delta ppm=7.81 (d, 1H), 7.61 (d, 1H), 7.33 (dd, 1H), 3.96 (s, 3H).
With sulfuric acid; for 24h;Reflux;
General procedure: 4.2.1. General procedures I for the synthesis of starting materials 1 a-n. Compounds 1a-g, i-n were synthesized according to general procedures I. Compound 1h was commercially available. Method A:16, 17 A two-necked round-bottomed flask equipped with a reflux condenser and a magnetic stir bar was charged withthe 2-bromobenzoic acid (20 mmol) and freshly distilled methanol(25 mL). The solution was heated in a hot water bath, conc. H2SO4(8 mmol) was added slowly and the reaction mixture was refluxed for 24 h. After cooling to room temperature around half of theamount of the solvent was removed in vacuo and the residue was partitioned between water (50 mL) and diethyl ether (70 mL). The organic layer was separated and washed with saturated NaHCO3(250 mL), water (50 mL) and brine (50 mL), dried over anhydrous MgSO4 and the volatiles were removed under reduced pressure.The crude product thus obtained was purified by flash chromatographyon silica gel to afford the alkyl-2-halobenzoate.In a two-necked round-bottomed flask equipped with a reflux condenser and a magnetic stir bar the alkyl 2-halobenzoate(22.5 mmol) was dissolved in freshly distilled dry THF (30 mL) under argon. The solution was cooled to 0 C using an ice bath and NaH (60% in mineral oil, 15 mmol) was added portion wise. After stirring for 15 min a solution of the alkyl acetate (15 mmol) in dry THF (30 mL) was added dropwise to the reaction mixture at 0 C.The mixture was warmed up, stirred at room temperature for 2 h and heated under reflux for 24 h. After cooling to room temperature around half of the amount of the solvent was removed in vacuo and the reaction mixture was diluted with toluene (50 mL). The resulting mixture was washed with 2N HCl (50 mL), saturated NH4Cl (50 mL), dried over anhydrous MgSO4 and the volatiles were removed under reduced pressure. The crude product was purifiedby flash column chromatography on silica gel to afford the alkyl 3-(20-halophenyl)-3-oxo-propanoate 1.
With thionyl chloride; at 80℃;Cooling with ice;
To a mixture of 2-bromo-5-chlorobenzoic acid (10.4 g, 44.16 mmol, 1.0 eq) in MeOH (250 mL) at ice bath was added slowly SOCl2 (4.8 mL, 66.24 mmol, 1.5 eq). The reaction mixture was warm to RT and heated at 80C oil bath overnight. The completion of the reaction was monitored by analytical HPLC. When complete, the reaction mixture was cooled to RT and concentrated. The crude was dissolved with EtOAc and washed with Sat?d NaHCO3, brine and dried over Na2SO4. The organic layer was concentrated to obtain the desired product for the next step with no further purification.
4-(4-chloro-2-methoxycarbonyl-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
With potassium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In ethanol; N,N-dimethyl-formamide; at 20 - 90℃; for 5.08333 - 5.16667h;
A solution of <strong>[27007-53-0]2-bromo-5-chloro-benzoic acid methyl ester</strong> Compound 4-2 (5.08 g, 20.4 mmol), the boronate Compound 4-1 (6.00 g, 19.4 mmol), PdCl2dppf-CH2Cl2 (1.06 g, 1.30 mmol) and K2CO3 (8.9 g, 58.21 mmol) in DMF and EtOH (4:1, 90 mL) was prepared in a thick walled tube. The mixture was stirred under argon at rt for 5-10 min and the tube was closed and heated at 90 C. for 5 hrs (4-16 hrs for other examples). The mixture was cooled to rt then filtered thru a pad of Celite, washing with EtOAc. The solvent was evaporated and purified by flash chromatography (gradient elution with 5-50% EtOAc in heptane with 0.1% TEA). The desired product Compound 4-3 was isolated as yellow liquid (4.05 g, 60%). 1H NMR (300 MHz, CDCl3) delta 7.82 (d, J=2.2 Hz, 1H), 7.43 (d of d, J=8.2 and 2.2 Hz, 1H), 7.14 (d, J=8.2 Hz, 1H), 5.51 (br s, 1H), 4.02 (br s, 2H), 3.85 (s, 3H), 3.63 (t, J=5.6 Hz, 2H), 2.30 (br s, 2H), 1.50 (s, 9H); MS (ES+) m/z 374.0 (M+Na).
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at -10 - 90℃;
To a stirred solution of <strong>[27007-53-0]methyl 2-bromo-5-chlorobenzoate</strong> (10 g, 40.1 mmol) in 1,4-dioxane (50 mL) cooled to -10 C. was added bis(pinacolato)diboron (12.21 g, 48.1 mmol) and PdCl2(dppf) (1.466 g, 2.004 mmol) followed by potassium acetate (11.80 g, 120 mmol). The mixture was then heated to 90 C. overnight. The reaction mixture was cooled to room temperature, diluted with water (300 mL) and extracted with ethyl acetate (500 mL). The organic layer was separated and dried over sodium sulphate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (10% ethyl acetate in petroleum ether) to afford methyl 5-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (11.8 g, 39.8 mmol, 99% yield). LC/MS (ESI) m/e 297.2 [(M+H)+, calcd for C14H19BClO4, 297.1]; LC/MS retention time (Method A1): tR=2.32 min; 1H NMR (400 MHz, CHLOROFORM-d) delta 7.92 (d, J=2.0 Hz, 1H), 7.49 (dd, J=8.0, 2.0 Hz, 1H), 7.45-7.41 (m, 1H), 3.92 (s, 3H), 1.41 (s, 12H).
42%
With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 80℃;Microwave heating in sealed tube;
Example 46; 2'-(6-Carbamimidoyl-1-ethyl-1H-indol-3-ylmethyl)-4-chloro-5'-[(5-methyl-pyrazin-2-ylmethyl)-carbamoyl]-biphenyl-2-carboxylic acid; Part A. 5-chloro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester:; A mixture of <strong>[27007-53-0]methyl 2-bromo-5-chlorobenzoate</strong> (1.9 g, 7.65 mmol), bis(pinacolato)diboron (2.1 g, 8.41 mmol), potassium acetate (2.3 g, 22.94 mmol) and PdCl2(dppf) (0.25 g, 0.306 mmol) in 1,4-dioxane (40 mL) was degassed then heated in an 80 C. oil bath overnight under N2. The reaction mixture was filtered through a pad of Celite then diluted with EtOAc and washed with water and brine, dried and concentrated. Flash chromatography on silica gel provided the boronate (0.96 g, 42%). 1HNMR (400 MHz, CDCl3) delta 7.92 (m, 1H); 7.48 (m, 2H); 3.91 (s, 3H); 1.41 (s, 12H). LC/MS m/z 297.2 (M+H)+; 319.1 (M+Na)+.
Step 2. methyl 5-chloro-2-cyanobenzoate To a stirred solution of methyl 2-bromo-5-chlorobenzoate (11.5 g, 46 mmol) in degassed DMF (50 mL) was added zinc cyanide (2.82 g, 24.0 mmol) and palladium tetrakis-triphenylphosphine (1.0 g, 0.86 mmol) and the mixture was heated to 90 C. for 18 h. The reaction was partitioned between EtOAc (200 mL) and water (100 mL). The organic phase was concentrated in vacuo and the residue was purified by flash chromatography eluding with a gradient of 10%, 15%, 20% ethyl acetate in hexane yielding methyl 5-chloro-2-cyanobenzoate as a white solid (8.0 g, 88% yield). TLC Rf=0.4 (15% EtOAc-hexanes); HPLC RT=3.13 min (Method A); 1H NMR (CDCl3, 400 MHz) 8.13 ppm (d, 1H, J=1.83 Hz); 8.09 ppm (d, 1H, J=8.24 Hz); 7.29 ppm (dd, 1H, J=8.34, 2.10 Hz); 4.02 ppm (s, 3H). Step. 3 2-aminomethyl-5-chlorobenzyl Alcohol
88%
In hexane; ethyl acetate; N,N-dimethyl-formamide;
Step 2. methyl 5-chloro-2-cyanobenzoate To a stirred solution of methyl 2-bromo-5-chlorobenzoate (11.5 g, 46 mmol) in degassed DMF (50 mL) was added zinc cyanide (2.82 g, 24.0 mmol) and palladium tetrakis-triphenylphosphine (1.0 g, 0.86 mmol) and the mixture was heated to 90 C. for 18 h. The reaction was partitioned between EtOAc (200 mL) and water (100 mL). The organic phase was concentrated in vacuo and the residue was purified by flash chromatography eluding with a gradient of 10%, 15%, 20% ethyl acetate in hexane yielding methyl 5-chloro-2-cyanobenzoate as a white solid (8.0 g, 88% yield). TLC Rf=0.4 (15% EtOAc-hexanes); HPLC RT=3.13 min (Method A); 1H NMR (CDCl3, 400 MHz) 8.13 ppm (d, 1H, J=1.83 Hz); 8.09 ppm (d, 1H, J=8.24 Hz); 7.29 ppm (dd, 1H, J=8.34, 2.10 Hz); 4.02 ppm (s, 3H).
In hexane; ethyl acetate; N,N-dimethyl-formamide;
Step B Preparation of Methyl 5-chloro-2-cyanobenzoate To a solution of methyl 2-bromo-5-chlorobenzoate (1.15 g, 4.6 mmol) in degassed DMF was added zinc cyanide (282 mg, 2.40 mmol) and palladium tetrakis triphenylphosphine (100 mg, 0.086 mmol) and the reaction is stirred at 90 C. over night. The reaction was partitioned between ethyl acetate and water. The organic was concentrated in vacuo and purified by flash chromatography eluding a gradient to 10 to 25% ethyl acetate in hexane yielding a white solid (methyl 5-chloro-2-cyanobenzoate. 1H NMR (CDCl3, 400 MHz): delta 8.13 (d, 1H, J=1.83 Hz); 3.09 (d, 1H, J=8.24 Hz); 7.29 (dd, 1H, J=8.34, 2.10 Hz); 4.02 (s, 3H)
In hexane; ethyl acetate; N,N-dimethyl-formamide;
Step B. Methyl 5-chloro-2-cyanobenzoate To a solution of methyl 2-bromo-5-chlorobenzoate (1.15 g, 4.6 mmol) in degassed DMF was added zinc cyanide (282 mg, 2.40 mmol) and palladium tetrakis triphenylphosphine (100 mg, 0.086 mmol) and the reaction is stirred at 90 C. over night. The reaction was partitioned between ethyl acetate and water. The organic was concentrated in vacuo and purified by flash chromatography eluding a gradient to 10 to 25% ethyl acetate in hexane yielding a white solid (methyl 5-chloro-2-cyanobenzoate). H NMR (CDCl3, 400 MHz): delta8.13 (d, 1 H, J=1.83 Hz); 3.09 (d, 1 H, J=8.24 Hz); 7.29 (dd, 1 H, J=8.34, 2.10 Hz); 4.02 (s, 3 H)
In hexane; ethyl acetate; N,N-dimethyl-formamide;
Step B. Methyl 5-chloro-2-cyanobenzoate To a solution of methyl 2-bromo-5-chlorobenzoate (1.15 g, 4.6 mmol) in degassed DMF was added zinc cyanide (282 mg, 2.40 mmol) and palladium tetrakis triphenylphosphine (100 mg, 0.086 mmol) and the reaction is stirred at 90C over night. The reaction was partitioned between ethyl acetate and water. The organic was concentrated in vacuo and purified by flash chromatography eluding a gradient to 10 to 25% ethyl acetate in hexane yielding a white solid (methyl 5-chloro-2-cyanobenzoate). H NMR (CDCl3, 400 MHz): delta 8.13 (d, 1H, J=1.83 Hz); 3.09 (d, 1H, J=8.24 Hz); 7.29 (dd, 1H, J=8.34,2.10 Hz); 4.02(s, 3H).
In methanol; dichloromethane; N,N-dimethyl-formamide;
Example 80 6-(2-BROMO-5-CHLORO-PHENYL)-N-(4-CHLORO-PHENYL)-[1,3,5]TRIAZINE-2,4-DIAMINE To a suspension of <strong>[21739-93-5]2-bromo-5-chloro-benzoic acid</strong> (2.5 g, 10.6 mmol) in dichloromethane (50 ml) was added a solution of oxalyl chloride in dichloromethane (2 M, 6 ml, 12 mmol) followed by N,N-dimethylformamide (5 drops). After stirring for 30 minutes, methanol (10 ml) was added. After stirring for 3 hours, the mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (150 ml) and saturated aqueous potassium carbonate solution (100 ml). The organic layer was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluding with dichloromethane-hexane (1:2) to provide methyl 2-bromo-5-chloro-benzoate (2.1 g, 79% yield).
2-(4-chloro-2-methoxycarbonylphenyl)acrylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
66%
With tributyl-amine;palladium diacetate; In ethyl acetate; toluene;
Example 9 To a solution of <strong>[27007-53-0]methyl 2-bromo-5-chlorobenzoate</strong> (6.30 g), tri-o-tolylphosphine (P(o-tol)3) (770 mg), tri-n-butylamine (9.38 g) and acrylic acid (3.64 g) in toluene (20 mL) was added palladium acetate (284 mg) under nitrogen atmosphere, and the mixture was heated at 110 C. for 3 hours. The mixture was washed with 1N HCl, dried, filtered, and concentrated. The residue was purified by silica gel column chromatography, and the fractions containing the desired compound were combined, dissolved in ethyl acetate, and extracted with a saturated aqueous sodium hydrogen carbonate solution. The aqueous layer was acidified with hydrochloric acid, extracted with ethyl acetate, and the organic layer was dried, filtered, and concentrated to give 2-(4-chloro-2-methoxycarbonylphenyl)acrylic acid (4.0 g, 66%). 1H NMR (CDCl3, 400 MHz) delta 8.51 (d, 1H, J=15.9 Hz), 7.98 (d, 1H, J=1.9 Hz), 7.58 (d, 1H, J=8.4 Hz), 7.53 (dd, 1H, J=8.4 and 1.9 Hz), 6.31 (d, 1H, J=15.9 Hz), 3.95 (s, 3H).
66%
With tributyl-amine;palladium diacetate; In ethyl acetate; toluene;
(9-1) To a solution of <strong>[27007-53-0]methyl 2-bromo-5-chlorobenzoate</strong> (6.30 g), tri-o-tolylphosphine (P(o-tol)3) (770mg), tri-n-butylamine (9.38 g) and acrylic acid (3.64 g) in toluene (20 mL) was added palladium acetate (284 mg) under nitrogen atmosphere, and the mixture was heated at 110C for 3 hours. The mixture was washed with 1N HCl, dried, filtered, and concentrated. The residue was purified by silica gel column chromatography, and the fractions containing the desired compound were combined, dissolved in ethyl acetate, and extracted with a saturated aqueous sodium hydrogen carbonate solution. The aqueous layer was acidified with hydrochloric acid, extracted with ethyl acetate, and the organic layer was dried, filtered, and concentrated to give 2-(4-chloro-2-methoxycarbonylphenyl)acrylic acid (4.0 g, 66 %). 1H NMR (CDCl3, 400MHz) delta 8.51 (d, 1H, J=15.9Hz), 7.98 (d, 1H, J=1.9Hz), 7.58 (d, 1H, J=8.4Hz), 7.53 (dd, 1H, J=8.4 and 1.9Hz), 6.31 (d, 1H, J=15.9Hz), 3.95 (s, 3H).
Step 1. methyl 2-bromo-5-chlorobenzoate Into a stirred solution of 2-bromo-5-chlorobenzoic acid (11 g, 46.7 mmol, HPLC RT=2.99 min) in methanol (250 mL) at 0 C. was bubbled HCl gas. The reaction was allowed to warm to room temperature and stirred overnight. The reaction mixture was concentrated in vacuo to give an orange oil, which was purified by flash chromatography using hexanes as eluant to give methyl 2-bromo-5-chlorobenzoate as a colorless oil (10.7 g, 92% yield). TLC Rf=0.6 (5% EtOAc-hexanes); HPLC RT=3.48 min (Method A); 1H NMR (CDl3, 400 MHz) 7.78 ppm (d, 1H, J=2.6 Hz); 7.59 ppm (d, 1H, J=12.81 Hz);7.30 ppm (dd, 1H, J=8.6, 2.5 Hz); 3.94 ppm (s, 3H).
92%
With hydrogenchloride; In methanol;
Step 1. methyl 2-bromo-5-chlorobenzoate Into a stirred solution of 2-bromo-5-chlorobenzoic acid (11 g, 46.7 mmol, HPLC RT=2.99 min) in methanol (250 mL) at 0 C. was bubbled HCl gas. The reaction was allowed to warm to room temperature and stirred overnight. The reaction mixture was concentrated in vacuo to give an orange oil, which was purified by flash chromatography using hexanes as eluant to give methyl 2-bromo-5-chlorobenzoate as a colorless oil (10.7 g, 92% yield). TLC Rf=0.6 (5% EtOAc-hexanes); HPLC RT=3.48 min (Method A); 1H NMR (CDCl3, 400 MHz) 7.78 ppm (d, 1H, J=2.6 Hz); 7.59 ppm (d, 1H, J=12.81 Hz);7.30 ppm (dd, 1H, J=8.6, 2.5 Hz); 3.94 ppm (s, 3H).
92%
With hydrogenchloride; In methanol;
Step 1. Into a stirred solution of 2-bromo-5-chlorobenzoic acid (11 g, 46.7 mmol, HPLC RT=2.99 min) in methanol (250 mL) at 0 C. was bubbled HCl gas. The reaction was allowed to warm to room temperature and stirred overnight. The reaction mixture was concentrated in vacuo to give an orange oil, which was purified by flash chromatography using hexanes as eluant to give methyl 2-bromo-5-chlorobenzoate as a colorless oil (10.7 g, 92% yield). TLC Rf=0.6 (5% EtOAc-hexanes); HPLC RT=3.48 min, method A; 1H NMR (CDCl3, 400 MHz) 7.78 ppm (d, 1H, J=2.6 Hz); 7.59 ppm (d, 1H, J=12.81 Hz);7.30 ppm (dd, 1H, J=8.6,2.5 Hz); 3.94 ppm (s, 3H).
Stage #1: methyl-2-bromo-5-chlorobenzoate; butylamidine hydrochloride With caesium carbonate; <i>L</i>-proline In N,N-dimethyl-formamide at 20℃; for 0.5h; Inert atmosphere;
Stage #2: With copper(l) iodide In N,N-dimethyl-formamide at 20 - 80℃; for 20h; Inert atmosphere;
With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); triethylamine; at 50℃; for 4h;
Methyl 2-bromo-5-chlorobenzoate 10 g (40 mmol)Was dissolved in 20 ml of triethylamine,6 g (60 mmol) of ethynyltrimethylsilane, 2.3 g (2 mmol) of Pd (PPh3) 4 and 760 mg (4 mmol) of CuI were added dropwise. The reaction solution was stirred at 50 C for 4 hours, cooled to 0 C, diluted with diethyl ether, and neutralized with 1N HCl. The organic layer was separated with diethyl ether, dried over anhydrous magnesium sulfate, filtered under reduced pressure and distilled under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain intermediate 1-110.7 g (yield 99%) was obtained.
93%
[01671 ] Step 1 : Synthesis of methyl 5-chloro-2-[2-(trimethylsilyl)ethynyl]benzoate[01672] To a stirred solution of <strong>[27007-53-0]methyl 2-bromo-5-chlorobenzoate</strong> (14.8 g, 59 mmol) in triethylamine (124 ml, 890 mmol) was added copper iodide (339 mg, 1 .8 mmol) and triphenylphosphine (778 mg, 3.0 mmol) at room temperature, under nitrogen. This mixture was purged with nitrogen before the addition of ethynyl(trimethyl)silane (12.5 ml, 89 mmol) and Pd(OAc)2 (266 mg, 1 .2 mmol). The reaction mixture was stirred at 50 C for 20 hours and concentrated in-vacuo. The residue was dissolved in deionized water (50 ml) and EtOAc (50 ml) and filtered through Celite. The filter cake was washed with EtOAc (50 ml) before the phases were separated and the aqueous layer was extracted with EtOAc (2 x 50 ml). The combined organic extracts were dried over gS04, filtered and concentrated in vacuo. The residue was purified by flash column chromatography ( l Og Silica Isolute cartridge, 1 - 1 5% EtOAc:Heptanes) to give the title compound ( 16.2 g, 93%) as an orange solid. LC-MS 91 %, m/z = 267.4, 268.9; NMR (500 MHz, Ch.oroform-d) 5 ppm 7.90 (d, J=2.2 . Hz, 1 H) 7.52 (d, J=8.35 Hz, 1 H) 7.42 (dd, J=8.28, 2.29 Hz, 1 H) 3.93 (s, 3 H) 0.28 (s, 9H).
With copper(l) iodide; triethylamine; triphenylphosphine;palladium diacetate; at 20 - 50℃; for 20h;Inert atmosphere;
Step 1: Synthesis of methyl 5-chloro-2-[2-(trimethylsilyl)ethynyl]benzoate To a solution of <strong>[27007-53-0]methyl 2-bromo-5-chlorobenzoate</strong> (14.8 g, 59 mmol) in TEA (124 ml, 889.82 mmol) was added copper(I) iodide (338 mg, 1.78 mmol) and triphenylphosphine (778 mg, 2.97 mmol) at room temperature and under nitrogen. This mixture had nitrogen bubbled through it for 10 minutes before the addition of ethynyl(trimethyl)silane (12.45 ml, 89 mmol) and Pd(OAc)2 (266 mg, 1.19 mmol). The reaction mixture was stirred at 50 C. for 20 hours before being concentrated under reduced pressure. The residue was dissolved in deionized water (50 ml) and EtOAc (50 ml) and filtered through Celite. The filter cake was washed with EtOAc (50 ml) before the phases were separated and the aqueous layer was extracted with EtOAc (2*50 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by FCC (10 g silica, Isolute cartridge, gradient of eluents; 99:1 Heptane:EtOAc to 85:15 Heptane:EtOAc) to give 16.2 g (102.4%) of methyl 5-chloro-2-[2-(trimethylsilyl)ethynyl]benzoate as an orange oil that solidified upon standing. Sample contained heptane. LC-MS 91%, 2.57 min (3 minute LC-MS method), m/z=267.4/268.9, 1H NMR (500 MHz, Chloroform-d) delta ppm 7.89 (d, J=2.2 Hz, 1H), 7.51 (d, J=8.3 Hz, 1H), 7.41 (dd, J=8.3, 2.3 Hz, 1H), 3.92 (s, 3H), 0.27 (s, 9H).
With potassium phosphate;palladium diacetate; johnphos; In toluene; for 72h;Inert atmosphere; Reflux;
80.0 mg (0.254 mmol) of example IA, 75.9 mg (0.304 mmol) of <strong>[27007-53-0]methyl-2-bromo-5-chlorobenzoate</strong>[Pan, Fletcher, J. Med. Chem. 1970, 13, 567] and 75.4 mg (0.355 mmol) potassium phosphate were dissolved in 2.0 ml absolute toluene. The resultant solution was outgassed with argon. Then 5.1 mg (0.023 mmol) of palladium(II) acetate and 10.2 mg (0.034 mmol) of (2-biphenyl)di-tert.- butylphosphine were added. It was stirred for 72 h at the reflux temperature. Then 50 ml ethyl acetate was added and the solid residue was removed by filtration on kieselguhr. The resultant filtrate was concentrated by evaporation and the raw product was purified by preparative HPLC(eluent: acetonitrile/water, gradient 10:90 ? 90:10). This gave 59 mg (48% of theor.) of the target compound.LC-MS (method 2): R, = 2.56 min; MS (EIpos): m/z = 484 [M+H]+.1H-NMR (400 MHz, DMSO-D6): delta [ppm] = 2.19 (s, 3H), 2.49 (s, 3H), 3.81 (s, 3H), 6.50 (dd, IH), 7.18-7.29 (m, 2H), 7.29-7.35 (m, 2H), 7.44 (d, IH), 7.61 (d, IH), 7.98 (dd, IH), 8.06 (d, IH), 8.13 (d, IH), 8.89 (d, IH), 8.91 (d, IH), 9.21 (s, IH).
With N-ethyl-N,N-diisopropylamine;palladium diacetate; tris-(o-tolyl)phosphine; In acetonitrile; at 48 - 82℃;Inert atmosphere;
Method: 25%, 10 min/100%, 20 min/100%, 220 nm 1. In a 10-L reactor, equipped with a sparging instrument, was placed Methyl 2-Bromo-5-chlorobenzoate (1000 g; 1.00 equiv; 4.01 moles; 1.00 kg) and Acetonitrile (3.92 kg). Purged the colorless solution with Argon for 1 hr at 1 liter per minute (LPM), stirred at 120 RPM. 2. To the degassed solution was added Tri-o-tolylphosphine (243.99 g) to the light suspension was added Diisopropylethylamine (1621.64 g) and Butyl Vinyl Ether (802.92 g). A colorless light suspension was obtained. 3. Sparged the light suspension with Argon for 0.5 hr (at) 1 LPM (at) 15 C. to minimize loss of volatiles. 4. Under Argon (sparging instrument above surface), to the solution was added Pd(OAc)2 (27.00 g). An orange light suspension was obtained. 5. The solution was heated at 80-82 C. After 1 hour, reaction temp was 48 C. 6. When temperature reached 81 C., HPLC shows about 55 relative area percent to starting material. 7. Stirred under Argon at 80-82 C. for 0.75 hr. A complete conversion was observed. 8. The reaction mixture was stirred under Argon at 80-82 C. for 0.5 more hrs during analysis. 9. Allowed to cool at 35-45 C. 10. Using a 20-L evaporator, the acetonitrile was evaporated to a black oily solid mixture. 11. Added Toluene (2.18 kg) and reevaporate to a black oily solid mixture; large amount of dense solid consisting of diisopropylethylamine hydrobromide and palladium. 12. Added Toluene (4.36 kg).13. The suspension was stirred at 20-25 C. for 14 hrs. This stirring time favors complete precipitation of the salts. 14. Solids filtered on filter paper. Cake size: 32 cm i.d.×4 cm high, weight not measured. Cake washed with toluene, 2×1 L; last wash was pale red but showed minimal amount of product. Due to flask volume restriction, washes were concentrated to an oil and added to main solution.
(Z)-methyl 5-chloro-2-(2-cyanovinyl)benzoate[ No CAS ]
[ 1256592-86-5 ]
Yield
Reaction Conditions
Operation in experiment
With sodium acetate; tris-(o-tolyl)phosphine;palladium diacetate; In N,N-dimethyl-formamide; at 120℃; for 60h;
To an N,N-dimethylformamide solution (100 mL) of methyl 2-bromo-5- chlorobenzoate (25, 100 mmol) was added palladium(II) acetate (480mg, 2.1 mmol) tri(o tolyl)phosphine (1.2 g, 3.9 mmol), acrylonitrile (6g, 113 mmol), and anhydrous sodium acetate (1Og, 122 mmol). The mixture was heated at 1200C. Additional palladium(II) acetate (224 mg, 1 mmol) and tri(o-tolyl)phosphine (600 mg, 2 mmol) were added, after 36 hours. The mixture was heated at 120 0C for 24 hours. N,N-Dimethylformamide was removed in vacuo and the remaining mixture was quenched with 1 N EtaCl(aq) and extracted with ethyl acetate. The ethyl acetate extracts were concentrated and the residue was dissolved in 1:1 dichloromethane: methanol (50 mL). (Trimethylsilyl)diazomethane (30 mL, 2 N in diethyl ether, 60 mmol) was added dropwise. After stirring overnight, the mixture was quenched with acetic acid, concentrated under reduced pressure and purified by silica gel column chromatography eluting with 2:1 hexanes: ethyl acetate to afford the title compound(2: 1 EIZ isomers). 1H NuMR (E isomer, Example 45 A, 300 MHz, DMSO-J6) delta ppm 8.08 (d, J = 16.2 Hz, IH), 7.91 (d, J = 2.1 HZ, IH), 7.84 (d, J = 8.7 HZ, IH), 7.78 (dd, J = 2.1, 8.4 Hz, IH), 6.45 (d, J = 16.5 Hz, IH), and 3.88 (s, 3H).
EXAMPLE 83; 2-[5-CHLORO-3-(253,6-TRIFLUOROBENZYL)-lH-INDAZOL-l-YL]-5-(l-METHYL-l/J- IDINE-4,6-DiAMI E; Step A; To a solution of 2,3,-6 trifluoro phenyl acetic acid (5g, 26.3 mmol) and methyl 5-bromo-3-chloro benzoate in anhydrous THF (53 mL) cooled to -78C was added slowly NaHMDS (1 10 mL, 65.7 mmol, 0.6 M). The reaction was warmed to 0C. After stirring for 30 minutes it was quenched by the addition of IN HC1 (1 OOmL). The resulting mixture was stirred vigorously at roomtemperature for 1 hour and concentrated. The residue was extracted with EtOAc . The organic layer was washed with saturated sodium bicarbonate solution (2X), water and brine, then dried over sodium sulfate, filtered and concentrated. The crude material was carried on to the next step. NMR delta (ppm)(CH3CN-d6): 7.66-7.61 (2 H, m), 7.40 (1 H, dd, J - 8.58, 2.56 Hz), 7.25 (1 H5 qd, J = 9.52, 5.12 Hz), 6.98 (1 H, tdd, J - 9.04, 3.76, 2.25 Hz), 4,34 (2 H, s).
With sodium hexamethyldisilazane; In tetrahydrofuran; at -78 - 0℃;Inert atmosphere;
To a solution of 2,3,6 trifluorophenyl acetic acid (5 g, 26.3 mmol) and methyl 2-bromo-5-chloro benzoate in anhydrous THF (53 mL) cooled to -78 C was slowly added NaHMDS (1 10 mL, 65.7 mmol, 0.6 M). The reaction was then warmed to 0 C. After stirring for 30 minutes the reaction was quenched by adding aqueous IN HC1 (100 mL). The resulting mixture was stirred vigorously at room temperature for 1 hour. The reaction mixture was concentrated to remove the excess organic solvents. The solution was extracted with EtOAc. The organic layer was washed with saturated sodium bicarbonate solution (2X), water and brine. The organic layer was then dried over sodium sulfate, filtered and concentrated to give the indicated product. NMR (400 MHz, CD3CN): 6 7.66-7.61 (m, 2H); 7.40 (dd} J = 8.6, 2.6 Hz, IH); 7.25 (m, IH); 6.98 (m, IH); 4.34 (ss 2H).
With sodium hexamethyldisilazane; In tetrahydrofuran; at -78 - 0℃;
To a solution of 2,3,6 trifluorophenyl acetic acid (5g, 26.3 mmol) and methyl 2-bromo-5-chloro benzoate in anhydrous THF (53mL) cooled to -78C was slowly added NaHMDS (110 mL, 65.7 mmol, 0.6 M). The reaction was then warmed to 0C. After stirring for 30 minutes the reaction was quenched by adding aqueous 1N HCl (100mL). The resulting mixture was stirred vigorously at room temperature for 1 hour. The reaction mixture was concentrated to remove the excess organic solvents. The residue was extracted with EtOAc. The organic layer was washed with saturated sodium bicarbonate solution (2X), water and brine. The organic layer was then dried over sodium sulfate, filtered and concentrated to give the indicated product. 1H NMR (400 MHz, CD3CN): delta 7.66-7.61 (m, 2 H); 7.40 (dd, J = 8.6, 2.6 Hz, 1 H); 7.25 (m, 1 H); 6.98 (m, 1 H); 4.34 (s, 2 H). LC4 rt = 4.41 min, (M + H) not ionized.
With sodium hexamethyldisilazane; In tetrahydrofuran; at -78 - 0℃;Inert atmosphere;
A THF solution of sodium bis(trimethylsilyl)amide (1.0M, 194 mL, 194 mmol) was added dropwise to a -78 C THF (400 mL) solution containing methyl 2-bromo-5-chlorobenzoate (16.10 g, 64.5 mmol) and <strong>[406-93-9]4,4,4-trifluorobutyric acid</strong> (9.17 g, 64.5 mmol). After stirring for 15 minutes at -78 C the solution was warmed to 0 C and stirred for an additional 2 hours. The reaction was quenched with an excess of aqueous IN HCl (ca 400 mL) and stirred overnight at room temperature. The solution was concentrated to remove the majority of the THF. The solution was then diluted with EtOAc and washed with IN NaHC03 (twice) and brine. The organic phase was then dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography using a hexanes/EtOAc gradient to give the indicated compound (solid). NMR (500 MHz, CDC13): delta 7.58 (d5 J = 8.4 Hz, 1H); 7.41 (d, J= 2.5 Hz, 1H); 7.33 (dd, 3 = 8.5, 2.5 Hz, 1H); 3.22 (t, J = 7.8 Hz, 2H); 2.68-2.56 (m, 2H).
With sodium hexamethyldisilazane; In tetrahydrofuran; at -78 - 0℃; for 2.25h;
A THF solution of sodium bis(trimethylsilyl)amide (1.0M, 194mL, 194mmol) was added dropwise to a -78C THF (400mL) solution containing methyl 2-bromo-5-chlorobenzoate (16.10g, 64.5mmol) and <strong>[406-93-9]4,4,4-trifluorobutyric acid</strong> (9.17g, 64.5mmol). After stirring for 15min at -78C the solution was warmed to 0C and stirred for an additional 2 hours. The reaction was quenched with an excess of aqueous 1N HCl (ca 400mL) and stirred overnight at room temperature. The solution was concentrated to remove the majority of the THF. The solution was then diluted with EtOAc and washed with 1N NaHCO3 (twice) and brine. The organic phase was then dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography using a hexanes/EtOAc gradient to give the indicated compound (solid). 1H NMR (500 MHz, CDCl3): delta 7.58 (d, J = 8.4 Hz, 1 H); 7.41 (d, J = 2.5 Hz, 1 H); 7.33 (dd, J = 8.5, 2.5 Hz, 1 H); 3.22 (t, J = 7.8 Hz, 2 H); 2.68-2.56 (m, 2 H). LC4 rt = 4.25min, mlz = not ionized (M+H).
With palladium diacetate; caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100℃;Inert atmosphere;
General procedure: Method A: A sealed tube was charged with compound 4a,b (0.93 mmol), 5a-e (0.93 mmol), 5 mol % of Pd(OAc)2, 10 mol % of Xantphos, 2 equiv of Cs2CO3 (1.86 mmol) and 10 mL of 1,4-dioxane. The mixture was degassed and backfilled with argon, the reaction vessel was sealed with a Teflon tap and heated at 100 C for 12 h. The reaction mixture was cooled to rt and concentrated in vacuo. The residue was dissolved in chloroform, washed with 10% citric acid solution, brine solution, dried over anhydrous Na2SO4 and concentrated. The crude compound was purified by flash column chromatography using 3-5% of MeOH/CHCl3 as an eluent to give the title cyclized compound.Method B: To a thick-well borosilicate glass vial (5 mL) was added compound 4a,b (0.23 mmol), compound 5a-e (0.23 mmol), 5 mol % of Pd(OAc)2, 10 mol % of Xantphos, 2 equiv Cs2CO3 (0.46 mmol) and 1,4-dioxane (2 mL). The mixture was degassed and the reaction vial was sealed and placed in the CEM-DISCOVER microwave reactor and irradiated at 100 C for 15 min. After cooled to rt, the product was isolated as above described in method A.
With potassium dihydrogenphosphate; In 1,4-dioxane; methanol; at 80℃; for 4h;Inert atmosphere; Sealed vial;
[00468] Methyl 2-(5-(l-((tert-butoxycarbonyl)amino)cyclopropyl)-3-methylisoxazol-A re-sealable vial containing methyl 2-bromo-5- chlorobenzoate (0.205 g, 0.822 mmol), Pd(Ph3P)4 (0.042 g, 0.036 mmol), and anhydrous potassium phosphate, tribasic (0.275 g, 1.296 mmol) was evacuated and purged with N2 (g) (3x). To the solids was added a solution of tert-butyl l-(3-methyl-4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)isoxazol-5-yl)cyclopropylcarbamate (0.236 g, 0.648 mmol) in MeOH (2 x 1 mL, 2 mL total) and 1,4-Dioxane (2 x 1 mL, 2 mL total). The suspension was evacuated and purged with N2 (g) (3x), the vial was sealed, and the contents heated to 80 C. LC-MS analysis indicated complete conversion to desired product with in 4 h. After 4 h, the reaction mixture was cooled to room temperature and filtered over Celite. The filter cake was washed with MeOH (3x) and the filtrate was concentrated to give a brown oil. The oil was purified on Biotage system (5% EtOAc : 95% Hexanes to 30% EtOAc : 70% Hexanes, then isocratic 30% EtOAc : 70% Hexanes). The product methyl 2-(5-(l-(tert- butoxycarbonylamino)cyclopropyl)-3-methylisoxazol-4-yl)-5-chlorobenzoate (0.226 g, 0.555 mmol, 86 % yield) was isolated as a clear oil. LC/MS m/z 407 [M + H]++
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 80℃; for 12h;Inert atmosphere;
(3) Synthesis of Compound d-6; A nitrogen atmosphere was established in a 200-ml three-necked flask. After that, the following reagents and solvents were loaded into the flask.Compound d-4: 7.08 g (20.0 mmol)Compound d-5: 5.46 g (22.0 mmol)Sodium carbonate: 10.6 g (100 mmol)Toluene: 100 mlEthanol: 20 mlWater: 100 ml[0096] Next, the reaction solution was stirred at roomtemperature under a nitrogen atmosphere, and to the stirred solution were added 1.16 g of tetrakis (triphenylphosphine) palladium ( 0 ) . Next, the reaction solution was warmed to a temperature of 80 C and stirred at the same temperature (80C) for 12 hours. After the completion of the reaction, the organic layer was extracted with toluene, and the resultant organic layer was dried over anhydrous sodium sulfate. The organic layer was then concentrated under reduced pressure to give a crude product. Next, the resultant crude product was purified by silica gel columnchromatography (developing solvent: toluene-ethyl acetate mixed solvent) to afford 4.92 g of Compound d-6 as a white solid (yield: 62%).
With lithium chloride;bis-triphenylphosphine-palladium(II) chloride; In N,N-dimethyl-formamide; at 100℃; for 5h;
Preparation DMethyl 5-chloro-2-ethylbenzoateMethyl 2-bromo-5-chlorobenzoate (1.0 g, 4 mmol), lithium chloride (490 mg, 11.58 mmol), tetraethyltin (0.81 mL, 4.1 mmol) and bis(triphenylphosphine)-palladium(ll)chloride (100 mg, 0.13 mmol) were combined in DMF (20 mL) and heated at 100 C for 5 h. Solvent was removed at reduced pressure and the residue was diluted with water andEtOAc. The organic layer was separated, washed with water, dried over sodium sulfate and concentrated. Column chromatography on silica gel (0 to 10% EtOAc/hexane) provided the title compound (435 mg, 55%).1H NMR (400 MHz, DMSO- /6) delta ppm 1.15 (t, J=7A3 Hz, 3 H) 2.86 (q, J=7.45 Hz, 2 H) 3.84 (s, 3 H) 7.40 (d, J=8.30Hz, 1 H) 7.53 - 7.61 (m, 1 H) 7.75 (d, J=2.32 Hz, 1 H).
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; for 8h;Inert atmosphere; Reflux;
A stirred suspension of <strong>[27007-53-0]methyl 2-bromo-5-chlorobenzoate</strong> (10 g, 40.08 mmol), potassium trifluoro(vinyl)borate (8.05 g, 60.12 mmol), Pd(dppf)Cl2 (1.64 g, 2.0 mmol) and sodium carbonate (8.5 g, 80.16 mmol) in dioxane (150 mL) and water (15 mL) was refluxed for 8 hours under a nitrogen atmosphere. After cooling to RT, the mixture was filtered, concentrated, and the crude product was purified by column chromatography eluting with petroleum ether and ethyl acetate (PE/EtOAc=100:1-50:1 gradient) to give the title compound (31.4 g, 76.4%). 1H NMR (400 MHz, CDCl3) delta ppm 7.80 (d, J=2.0 Hz, 1H), 7.45 (d, J=8.0 Hz, 1H), 7.31-7.39 (m, 2H), 5.57 (d, J=17.6 Hz, 1H), 5.31 (d, J=10.8 Hz, 1H), 3.83 (s, 3H).
With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); cesium fluoride; In N,N-dimethyl-formamide; at 130℃; for 0.166667h;Microwave irradiation;
(D53) (2g, 8mmol) was dissolved dry DMF (15m1), then CsF (l6mmol), Cul (1.6 mmol), [Ph3P]4Pd (0.8mmol) and pyrimidine-2-tributylstannane (1 2mmol; prepared according to Eur. J. Org. Chem. 2003, 1711-1721)were added. The mixture was warmed at 13000 for 10 minutes (microwave), then poured in aqueous saturated solution of NH4CI andextracted with AcOEt (3x50m1). The organic layers were combined, dried (Na2SO4) and concentrated under vacuum; the crude mixture was purified by silica gel column chromatography (DCM to DCM/MeOH 9/1) to give 1.5g of the title compound as white solid.MS (ESI) m/z: 249 [M+H].1HNMR (CDCl3) 5 ppm= 8.82(d,2H), 8.07 (d,1H),, 7.71(d,1H),7.57(dd,1H), 7.27(t,1H),3.80 (s,3H).
1.5 g
With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); cesium fluoride; In N,N-dimethyl-formamide; at 130℃; for 0.166667h;Microwave irradiation;
Examjjle 27: preparation of intermediate 27: methyl 5-chloro-2-(pyrimidin-2- yl)benzoate5Intermediate 26 (2g, 8mmol) was dissolved dry DMF (15m1), then C5F (l6mmol), Cul (1.6 mmol), [Ph3P]4Pd (0.8mmol) and pyrimidine-2-tributylstannane (l2mmol;10 prepared according to Eur. J. Org. Chem. 2003, 1711-1721) were added. The mixture was warmed at 13000 for 10 minutes (microwave), then poured in aqueous saturated solution of NH4CI and extracted with AcOEt (3x50m1). The organic layers were combined, dried (Na2SO4) and concentrated under vacuum; crude product was purified by silica gel column chromatography (DCM to15 DCM/MeOH 9/1) to give 1 .5g of the title compound as white solid.MS (ES I) m/z: 249 [M+H]+.1HNMR (CDCI3) 6 ppm= 8.82(d,2H), 8.07 (d,1H),, 7.71(d,1H),7.57(dd,1H),7.27(t,1H), 3.80 (s,3H).
1.5 g
With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); cesium fluoride; In N,N-dimethyl-formamide; at 130℃; for 0.166667h;Microwave irradiation;
(D53) (2 g, 8 mmol) was dissolved dry DMF (15 ml), then CsF (16 mmol), CuI (1.6 mmol), [Ph3P]4Pd (0.8 mmol) and pyrimidine-2-tributylstannane (12 mmol; prepared according to Eur. J. Org. Chem. 2003, 1711-1721) were added. The mixture was warmed at 130 C. for 10 minutes (microwave), then poured in aqueous saturated solution of NH4Cl and extracted with AcOEt (3×50 ml). The organic layers were combined, dried (Na2SO4) and concentrated under vacuum; the crude mixture was purified by silica gel column chromatography (DCM to DCM/MeOH 9/1) to give 1.5 g of the title compound as white solid.MS (ESI) m/z: 249 [M+H]+. 1HNMR (CDCl3) 5 ppm=8.82 (d, 2H), 8.07 (d, 1H), 7.71 (d, 1H), 7.57 (dd, 1H), 7.27 (t, 1H), 3.80 (s, 3H).
1.5 g
With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); cesium fluoride; In N,N-dimethyl-formamide; at 130℃; for 0.166667h;Microwave irradiation;
Intermediate 26 (2 g, 8 mmol) was dissolved dry DMF (15 ml), then CsF (16 mmol), CuI (1.6 mmol), [Ph3P]4Pd (0.8 mmol) and pyrimidine-2-tributylstannane (12 mmol; prepared according to Eur. J. Org. Chem. 2003, 1711-1721) were added. The mixture was warmed at 130 C. for 10 minutes (microwave), then poured in aqueous saturated solution of NH4Cl and extracted with AcOEt (3×50 ml). The organic layers were combined, dried (Na2SO4) and concentrated under vacuum; crude product was purified by silica gel column chromatography (DCM to DCM/ MeOH 9/1) to give 1.5 g of the title compound as white solid.MS (ESI) m/z: 249 [M+H]+.1HNMR (CDCl3) delta ppm=8.82 (d, 2H), 8.07 (d, 1H), 7.71 (d, 1H), 7.57 (dd, 1H), 7.27 (t, 1H), 3.80 (s, 3H).
With potassium phosphate tribasic trihydrate; palladium diacetate; tricyclohexylphosphine; In water; toluene; at 20 - 110℃; for 5h;
Methyl 5-chloro-2-ethylbenzoate nto a 500 mL round bottom flask equipped wfth a stir bar, condenser and 3-way vave connected to argon andvacuum methyl 2-bromo-5-chlorobenzoate (15.0 g, 60 mmol), <strong>[4433-63-0]ethylboronic acid</strong> (5.3 g, 72 mmol), K3P04.3H20 (48.0g, 180 mmo), tricyclohexylphosphine (1,7 g, 6 mmo) and touene (250 mL) and water (12 mL) were charged at room temperature. The resuftng reacton mxture was degassed three times back fAhng wfth argon each time before beng charged Pd(OAc)2 (0.673 g, 3 mmo), The resuWng reacton mixture was degassed four tmes back fUhng wfth argon each tme and then warmed to 110 C for 5 h. The reaction mxture was cooed to room temperature, fNtered througha pad of Cehte, washed wfth EtOAc and the fNtrate was concentrated and then dNuted wfth EtOAc (400 mL) and water (300 mL), The two ayers were separated, and the aqueous ayer was extracted wfth EtOAc (100 mL). The combned organc fractions were dried over Na2SO4, fUtered and concentrated under reduced pressure. The resdue was purfled by flash chromatography (hexane/EtOAc 97/3) to afford the tUe compound (9.3 g, 78%).1HNMR (600 MHz, DMSO-d6) 7.74 (d, J = 2.4 Hz, 1 H), 7.57 (dd, J = 2.4, 8.4 Hz, 1 H), 7.39 (d, J = 8.2 Hz, 1 H), 3.84 (s, 3H), 2.85 (q, J= 7.4 Hz, 2 H), 1.15 (t, J= 7.4 Hz, 3 H).
With tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 90℃;
Step B: Preparation of Methyl 5-chloro-2-cyanobenzoate To a solution of methyl 2-bromo-5-chlorobenzoate (1.15g, 4.6 mmol) in degassed DMF was added zinc cyanide (282 mg, 2.40 mmol) and palladium tetrakis triphenylphosphine (lOOmg, 0.086 mmol) and the reaction is stirred at 90C over night. The reaction was partitioned between ethyl acetate and water. The organic was concentrated in vacuo and purified by flash chromatography eluting a gradient to 10 to 25% ethyl acetate in hexane yielding a white solid (methyl 5-chloro- 2-cyanobenzoate. H NMR (CDCI3, 400 MHz): delta 8.13 (d, 1 H, J= 1.83 Hz); 3.09 (d, 1 H, J= 8.24 Hz); 7.29 (dd, 1 H, J= 8.34, 2.10 Hz); 4.02 (s, 3 H)
With tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 90℃;
A mixture of methyl 2-bromo-5-chlorobenzoate (8.275 g, 33.17 mmol, 1.0 eq) and ZnCN (2.03 g, 17.25 mmol, 0.52 eq) in DMF( 40mL) was degassed, and then Pd(PPh3)4(0.767 g, 0.66 mmol, 0.02 eq) was added. The mixture was heated overnight at 90C at oil bath. The completion of the reaction was monitored by analytical HPLC. When complete, the reaction mixture was cooled to RT and concentrated to provide the crude which was purified by column chromatography on silica gel to obtain the desired product.
3-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridine[ No CAS ]
methyl 5-chloro-2-(3-fluoropyridin-4-yl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
41%
With potassium phosphate; tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 80℃; for 2h;Inert atmosphere;
To a solution of <strong>[27007-53-0]methyl 2-bromo-5-chlorobenzoate</strong> (1.15g, 4.61 mmol) in dioxane (2 mL), were added 3-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (1.234 g, 5.53 mmol), K3P04 (2.446 g, 11.52 mmol) and Pd(Ph3P)4 (0.266 g, 0.230 mmol) at rt. The reaction was stirred under argon at 80 C for 2 h. The reaction was cooled to rt. The reaction mixture was diluted with EtOAc, washed with 0 and brine. The organic phase was dried over sodium sulfate, filtered and concentrated. The crude product was purified by normal phase chromatography to afford Intermediate 17A as a clear colorless oil (0.50 g, 41%). LC-MS (ESI) m/z: 266.0 [M+H]+; XH NMR (400MHz, CDC13) delta 8.53 - 8.44 (m, 2H), 8.04 (d, J = 2.2 Hz, 1H), 7.60 (dd, J = 8.1, 2.2 Hz, 1H), 7.28 (d, J = 8.1 Hz, 1H), 7.22 (dd, J = 6.3, 5.0 Hz, 1H), 3.74 (s, 3H).
4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-N1,N1-diisobutylbenzene-1,2-diamine[ No CAS ]
methyl 3'-amino-4-chloro-4'-(diisobutylamino)-[1,1'-biphenyl]-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; at 100℃; for 20h;Inert atmosphere;
A. Methyl 3 ?-amino-4-chloro-4?-(diisobutylamino)- [1,1 ?-biphenyl] -2-carboxylate 4-(5,5 -Dimethyl- 1,3 ,2-dioxaborinan-2-yl)-N 1 ,N 1 -diisobutylbenzene- 1 ,2-diamine (4B) (128 mg, 0.385 mmol), <strong>[27007-53-0]methyl 2-bromo-5-chlorobenzoate</strong> (80 mg, 0.32 1 mmol), PdC12(dppf)-CH2Cl2Adduct (23.5 mg, 0.032 mmol) and potassium phosphate, tribasic (204 mg, 0.962 mmol) were added to a 2 dram vial which was then evacuated and filled with nitrogen 3x. Dioxane (2 mL) was added and the resultant mixture was purged withnitrogen for five minutes. The mixture was then heated at 100 C for 20h. The reaction was cooled to rt, filtered and concentrated in vacuo before being purified via ISCO Companion (12g silica gel column with 0-10% EtOAc/hexane gradient) to afford the title compound as a clear oil (99.4 mg, 75%). ?H NMR (500MHz, CDC13) oe 7.71 (d, J=2.2 Hz, 1H), 7.45 (dd, J=8.2, 2.1 Hz, 1H), 7.33 (d, J=8.0 Hz, 1H), 7.06 (d, J=8.0 Hz, 1H),6.66 (d, J=1.9 Hz, 1H), 6.60 (dd, J=8.0, 1.9 Hz, 1H), 4.17 (br. s., 2H), 2.65 (d, J=7.2 Hz,4H), 1.79 (m, 2H), 0.93 (d, J=6.7 Hz, 12H). MS(ES): m/z = 389 [M+H].
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In tetrahydrofuran; water; at 80℃; for 24h;Inert atmosphere;
50 g (200 mmol) of <strong>[27007-53-0]methyl-2-bromo-5-chlorobenzoate</strong> was dissolved in 0.5 L of tetrahydrofuran (THF) in anitrogen environment, 51 g (241 mmol) of dibenzofuran-2-yl boronic acid and 7.0 g (6.0 mmol) of tetrakis(triphenylphosphine)palladium were added thereto, and the mixture was agitated. 59 g (401 mmol) of potassium carbonate saturatedin water was added thereto, and the mixture was heated and refluxed at 80 C for 24 hours. When the reaction wasterminated, water was added to the reaction solution, and the mixture was extracted with dichloromethane (DCM) andtreated with anhydrous MgSO4 to remove moisture and then, filtered and concentrated under a reduced pressure. Theobtained residue was separated and purified through flash column chromatography, obtaining a compound I-5 (63.4 g,94 %). HRMS (70 eV, EI+): m/z calcd for C20H13ClO3: 336.0553, found: 336.1. Elemental Analysis: C, 71 %; H, 4 %
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In toluene; for 12h;Reflux; Inert atmosphere;
Round bottom flask was charged with 4-benzothiophene boronic acid 21.5g (94.3mmol), <strong>[27007-53-0]methyl 2-bromo-5-chlorobenzoate</strong> 23.5g(94.3mmol) and the mixture of the aqueous solution of potassium carbonate dissolved in 117ml 19.5g (141.5mmol) was dissolved was added to toluene (313ml)It was added and stirred. Here tetrakistriphenylphosphine-palladium was added to 1.09g (0.94mmol) Under nitrogen atmosphereIt was stirred at reflux for 12 hours. After the end of the reaction the ethyl acetate extract was extracted with gun with magnesium sulfateAnd concentrated under reduced pressure and the crude was filtered and the filtrate. The product n- hexane / ethyl acetate (9: 1 by volume) as a silica gel curlThe column of the desired compound intermediate M-25 was purified by chromatography to give the 31.6g (95% yield).
85%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In tetrahydrofuran; water; at 80℃; for 21h;Inert atmosphere;
50 g (200 mmol) of <strong>[27007-53-0]methyl-2-bromo-5-chlorobenzoate</strong> was dissolved in 0.5 L of tetrahydrofuran (THF) in a nitrogen environment, 50.2 g (220 mmol) of dibenzothiophene-4-ylboronic acid and 4.62 g (4.0 mmol) of tetrakis(triphenylphosphine)palladium were added thereto, and the mixture was agitated. 58.9 g (400 mmol) of potassium carbonate saturated in water was added thereto, and the mixture was heated and refluxed at 80 C for 21 hours. When the reaction was terminated, water was added to the reaction solution, and the mixture was extracted with dichloromethane (DCM) and treated with anhydrous MgSO4 to remove moisture and then, filtered and concentrated under a reduced pressure. The residue obtained therefrom was separated and purified through flash column chromatography, obtaining a compound I-5 (60 g and 85 %). HRMS (70 eV, EI+): m/z calcd for C20H13ClO2S: 352.0325, found: 352.0. Elemental Analysis: C, 68 %; H, 4 %
80%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In water; toluene; for 12h;Inert atmosphere; Reflux;
Intermediate (4-dibenzothiophenyl) boronic acid 30g (141.5mmol), <strong>[27007-53-0]methyl 2-bromo-5-chlorobenzoate</strong> (37.1 g (148.6 mmol), tetrakistriphenylphosphine palladium 8.2 g (7.1 mmol) into a flask under nitrogen atmosphere was dissolved in toluene 550 ml and then potassium carbonate (potassium carbonate) 104.2 g (707.51 mmol) dissolved in the aqueous solution was added to 353.8 ml after 12 hours under reflux agitation.The end of the reaction after drying the extract with ethyl magnesium sulfonic then extracted with acetate sulfite (magnesium sulphate), filtered and the filtrate was concentrated under reduced pressure. The product n- hexane / dichloromethane (7: 3 by volume) as a silica-gel column chromatography of Intermediate Compound M-4 to give the desired compound was obtained in a 38.2 g (yield 80%) as a white solid.
80%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In tetrahydrofuran; water; for 12h;Reflux;
Dibenzo [b, d] thiophene-4-Daily with acid (dibenzo [b, d] thiophen-4-ylboronic acid, 1-1) 50.3g (0.22mol) and <strong>[27007-53-0]methyl 2-bromo-5-chlorobenzoate</strong> benzoate (<strong>[27007-53-0]methyl 2-bromo-5-chlorobenzoate</strong>, 2-2) was dissolved in 50g (0.20mol) in tetrahydrofuran (THF) was allowed to warm 500mL was added to 125mL aqueous solution dissolved potassium carbonate (K2CO3) 83g (0.60mol) . At reflux tetrakis (triphenylphosphine) palladium (0) 2.3g (0.002mol) was stirred under reflux for 12 hours and then added. After cooling to room temperature after completion of the reaction by washing with water and extracted with ethyl acetate. Water the organic solution was collected by extraction with anhydrous magnesium sulfate was removed and concentrated under reduced pressure after filtration. A concentrated substance into the 100 mL of ethanol and stirred at room temperature after solidification by filtration to give the title compound 57g 2-3 (80%) of light brown.
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In toluene; for 12h;Reflux;
Round bottom flask was charged with 4-dibenzofuran boronic acid 20g (94.3mmol), <strong>[27007-53-0]methyl 2-bromo-5-chlorobenzoate</strong> 23.5g (94.3mmol) were placed toluene (313ml) was added dissolved in the addition of an aqueous solution of potassium carbonate dissolved in 117ml 19.5g (141.5mmol) to thenAnd it stirred. Followed by adding thereto tetrakis triphenylphosphine palladium 1.09g (0.94mmol) after 12 hours in a nitrogen atmosphere It was stirred while refluxing. After the reaction was filtered and the dried extract was then extracted with ethyl acetate and with magnesium sulfate High filtrate was concentrated under reduced pressure. The product n- hexane / ethyl acetate (9: 1 by volume) was purified by silica gel column in thatPurification by raepi to give the desired compound in the intermediate M-19 30g (94% yield)
81%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In tetrahydrofuran; water; at 80℃; for 24h;Inert atmosphere;
50 g (200 mmol) of <strong>[27007-53-0]methyl-2-bromo-5-chlorobenzoate</strong> was dissolved in of 0.5 L of tetrahydrofuran (THF) undera nitrogen environment, 51 g (241 mmol) of dibenzofuran-4-yl boronic acid and 7.0 g (6.0 mmol) of tetrakis(triphenylphosphine)palladium were added thereto, and the mixture was agitated. 59 g (401 mmol) of potassium carbonatesaturated in water was added thereto, and the resulting mixture was heated and refluxed at 80 C for 24 hours. Whenthe reaction was terminated, water was added to the reaction solution, and the obtained mixture was extracted withdichloromethane (DCM), treated with anhydrous MgSO4 to remove moisture and then, filtered and concentrated undera reduced pressure. The obtained residue was separated and purified through flash column chromatography, obtaininga compound I-1 (55 g, 81 %). HRMS (70 eV, EI+): m/z calcd for C20H13ClO3: 336.0553, found: 336.1. Elemental Analysis: C, 71 %; H, 4 %
80%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In water; toluene; for 12h;Inert atmosphere; Reflux;
(4-dibenzofuranyl) boronic acid, 30g (141.5mmol), <strong>[27007-53-0]methyl-2-bromo-5-chlorobenzoate</strong> 37.1g (148.6 mmol), tetrakistriphenylphosphine palladium 8.2 g (7.1 mmol) and the flask placed in a nitrogen atmosphere under a toluene 550 ml dissolution was then potassium carbonate (potassium carbonate) 104.2 g (707.51 mmol) was dissolved aqueous solution of 353.8 ml of after the addition was stirred under reflux for 12 hours. The end of the reaction after drying the extract with ethyl magnesium sulfonic then extracted with acetate sulfite (magnesium sulphate), filtered and the filtrate was concentrated under reduced pressure. The product n- hexane / dichloromethane (7: 3 by volume) as a silica-gel column chromatography of Intermediate Compound M-1 to give the desired compound was obtained in a 38.2 g (yield 80%) as a white solid.
80%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In water; toluene; for 12h;Inert atmosphere; Reflux;
(4-di benzohexa [...]) boronic acid ((4-dibenzofuranyl) boronic acid) 30 g (141.5 mmol), methyl-2-bromo-5-chloro-benzo benzoate (<strong>[27007-53-0]methyl-2-bromo-5-chlorobenzoate</strong>) 37.1 g (148.6 mmol), tetra kissing tree phenyl gun spin palladium 8.2 g (7.1 mmol) of multi function cap paste has better mouth feeling and nitrogen atmosphere, a polycarbonate potassium after dissolving in a 550 ml toluene (potassium carbonate) 104.2 g (707.51 mmol) 353.8 ml added aqueous solution senses a rotation velocity of the disk 12 after stirring the reflux time. Reaction after ethyl which has after extraction (magnesium sulphate) dried to extract magnesium sulfite, wherein the filtration of the slurry suspension was filtrate, concentrating it under reduced pressure. Product methane dichloro /-hexanediol n (volume ratio 7:3) silica gel column chromatography for purifying the thereby, a desired compound intermediates (G) 38.2 g (80% yield) a white solid are obtained for.
80%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In water; toluene; for 12h;Inert atmosphere; Reflux;
(4-Dibenzofuranyl) boronic acid ((4-dibenzofuranyl) boronic acid), 30 g (141.5 mmol), <strong>[27007-53-0]methyl-2-bromo-5-chlorobenzoate</strong> (<strong>[27007-53-0]methyl-2-bromo-5-chlorobenzoate</strong>), 37.1 g ( 148.6 mmol), tetrakistriphenylphosphine palladium 8.2 g (7.1 mmol) were added to flask placed in a nitrogen atmosphere and dissolved in toluene 550 ml, aqueous solution of 353.8 ml potassium carbonate (potassium carbonate) 104.2 g (707.51 mmol) dissolved in toluene 550 ml was added and the mixture was stirred under reflux for 12 hours. After the end of the reaction, the mixture was extracted with ethyl acetate, dried with magnesium sulfite (magnesium sulphate), filtered and the filtrate was concentrated under reduced pressure. The resulting product was purified by silica gel column chromatography using n-hexane/dichloromethane (7:3) to give the desired intermediate compound (G) of 38.2 g (80% yield) as a white solid.
78%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In tetrahydrofuran; water; for 12h;Reflux;
Dibenzo [b, d] furan-4-yl boronic acid (dibenzo [b, d] furan-4-ylboronic acid, 3-1) 50g (0.23mol) and <strong>[27007-53-0]methyl 2-bromo-5-chlorobenzoate</strong> ( <strong>[27007-53-0]methyl 2-bromo-5-chlorobenzoate</strong>, 2-2) was dissolved in 50g (0.20mol) in a tetrahydrofuran (THF) was allowed to warm 600mL was added to 150mL aqueous solution dissolved potassium carbonate (K2CO3) 93g (0.66mol). At reflux tetrakis (triphenylphosphine) palladium (0) 2.6g (0.002mol) was stirred under reflux for 12 hours and then added. After completion of the reaction treatment in the same manner as in the synthesis of compound 2-3 of Example 2 by reaction of a brown solid compound 3-2 to give 53g (78%).
74%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; water; toluene; for 8h;Inert atmosphere; Reflux;
Under argon atmosphere, dibenzofuran-4-boronic acid: 3.0g, <strong>[27007-53-0]2-bromo-5-chlorobenzoic acid methyl ester</strong>: 3.2g, tetrakis(triphenylphosphine)palladium(0): 0.3g, sodium carbonate: 4.1g, toluene: 30mL, 1,2-dimethoxyethane: 10ml, water: 10ml were added to the flask then heated with stirring under reflux for 8 hours. Cooled to room temperature (25C). The reaction solution was transferred to a separatory funnel and extracted with toluene. Then, the organic layer was dried over sodium sulfate, filtered, concentrated. The residue was purified by silica gel column chromatography to give a white solid 3.2g (74% yield).
7-chloropyrazolo[1,5-a]quinazolin-5(4H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
56%
With copper(l) iodide; caesium carbonate; In water; at 100℃; for 6h;Inert atmosphere;
General procedure: To a solution of Cs2CO3 (2 mmol) in H2O (5 mL) were added methyl 2-bromobenzoate (1a, 1 mmol), 1H-pyrazol-5-amine (2a, 1.2 mmol), and CuI (0.2 mmol). The mixture was stirred at 100 C under nitrogen atomasphere until a complete conversion as indicated by TLC. It was cooled to room temperature and then extracted with ethyl acetate. The combined organic phase was dried over anhydrous Na2SO4, and concentrated under vacuum. The crude product was purified by column chromatography eluting with petroleum ether/ethyl acetate (3:1) to give 3a. Products 3b-3t and 6 were obtained in a similar manner.
With copper(l) iodide; caesium carbonate; In water; at 100℃; for 6h;Inert atmosphere;
General procedure: To a solution of Cs2CO3 (2 mmol) in H2O (5 mL) were added methyl 2-bromobenzoate (1a, 1 mmol), 1H-pyrazol-5-amine (2a, 1.2 mmol), and CuI (0.2 mmol). The mixture was stirred at 100 C under nitrogen atomasphere until a complete conversion as indicated by TLC. It was cooled to room temperature and then extracted with ethyl acetate. The combined organic phase was dried over anhydrous Na2SO4, and concentrated under vacuum. The crude product was purified by column chromatography eluting with petroleum ether/ethyl acetate (3:1) to give 3a. Products 3b-3t and 6 were obtained in a similar manner.
7-chloro-2-phenylpyrazolo[1,5-a]quinazolin-5(4H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
57%
With copper(l) iodide; caesium carbonate; In water; at 100℃; for 6h;Inert atmosphere;
General procedure: To a solution of Cs2CO3 (2 mmol) in H2O (5 mL) were added methyl 2-bromobenzoate (1a, 1 mmol), 1H-pyrazol-5-amine (2a, 1.2 mmol), and CuI (0.2 mmol). The mixture was stirred at 100 C under nitrogen atomasphere until a complete conversion as indicated by TLC. It was cooled to room temperature and then extracted with ethyl acetate. The combined organic phase was dried over anhydrous Na2SO4, and concentrated under vacuum. The crude product was purified by column chromatography eluting with petroleum ether/ethyl acetate (3:1) to give 3a. Products 3b-3t and 6 were obtained in a similar manner.
General procedure: Method A:16,17 A two-necked round-bottomed flask equipped with a reflux condenser and a magnetic stir bar was charged with the 2-bromobenzoic acid (20mmol) and freshly distilled methanol (25mL). The solution was heated in a hot water bath, conc. H2SO4 (8mmol) was added slowly and the reaction mixture was refluxed for 24h. After cooling to room temperature around half of the amount of the solvent was removed in vacuo and the residue was partitioned between water (50mL) and diethyl ether (70mL). The organic layer was separated and washed with saturated NaHCO3 (2×50mL), water (50mL) and brine (50mL), dried over anhydrous MgSO4 and the volatiles were removed under reduced pressure. The crude product thus obtained was purified by flash chromatography on silica gel to afford the alkyl-2-halobenzoate. (0023) In a two-necked round-bottomed flask equipped with a reflux condenser and a magnetic stir bar the alkyl 2-halobenzoate (22.5mmol) was dissolved in freshly distilled dry THF (30mL) under argon. The solution was cooled to 0C using an ice bath and NaH (60% in mineral oil, 15mmol) was added portionwise. After stirring for 15min a solution of the alkyl acetate (15mmol) in dry THF (30mL) was added dropwise to the reaction mixture at 0C. The mixture was warmed up, stirred at room temperature for 2h and heated under reflux for 24h. After cooling to room temperature around half of the amount of the solvent was removed in vacuo and the reaction mixture was diluted with toluene (50mL). The resulting mixture was washed with 2N HCl (50mL), saturated NH4Cl (50mL), dried over anhydrous MgSO4 and the volatiles were removed under reduced pressure. The crude product was purified by flash column chromatography on silica gel to afford the alkyl 3-(2?-halophenyl)-3-oxo-propanoate 1.
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In tetrahydrofuran; water; at 70℃; for 8h;Inert atmosphere;
4 -phenoxathiinyl boronic acid 18.8g (76.88mmol),methyl-2-bromo-5-chloro-benzoate 21.1g (84.57mmol) and tetrakis triphenylphosphinepalladium0.89g (0.769mmol) were placed in a flask, and under a nitrogen atmosphere, itwas dissolved in tetrahydrofuran 257 ml, and then an aqueous solution 128ml of dissolvedpotassium carbonate 17g (115.3mmol) was added, and stirred at reflux at 70 C for 8 h. After completion of the reaction, it was extracted with ethyl acetate,the extract was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The product was purified by silica gelcolumn chromatography using n- hexane / ethyl acetate (9: 1 volume ratio) to obtain intermediate M-3 of the desired compound 26.1 g (92% yield).
(9,9-dimethyl-9H-xanthene-4-yl)boronic acid[ No CAS ]
C23H19ClO3[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In tetrahydrofuran; water; at 70℃; for 8h;Inert atmosphere;
19.5g (76.88mmol) Intermediate M-5,methyl-2-bromo-5-chloro-benzoate 21.1g (84.57mmol) and tetrakis triphenylphosphinepalladium0.89g (0.769mmol) were placed in a flask, and under a nitrogen atmosphere, itwas dissolved in tetrahydrofuran 257 ml, and then an aqueous solution 128ml of dissolved potassium carbonate 17g (115.3mmol) was added, and stirred at reflux at 70 C for 8 h. After completion of the reaction, it was extracted with ethyl acetate,the extract was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The product was purified by silica gel column chromatography using n-hexane / ethyl acetate (9: 1 volume ratio) to obtain intermediate M-6 of the desired compound 26.2 g (90% yield).
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In tetrahydrofuran; water; at 70℃; for 8h;Inert atmosphere;
20.8g (76.88mmol) Intermediate M-9,methyl-2-bromo-5-chloro-benzoate 21.1g (84.57mmol) and tetrakis triphenylphosphinepalladium0.89g (0.769mmol) were placed in a flask, and under a nitrogen atmosphere, it was dissolved in tetrahydrofuran 257 ml, and then an aqueous solution 128ml of dissolved potassium carbonate 17g (115.3mmol) was added, and stirred at reflux at 70 Cfor 8 h. After completion of the reaction, it was extracted with ethyl acetate,the extract was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The product was purified by silica gelcolumn chromatography using n- hexane / ethyl acetate (9: 1 volume ratio) to obtain intermediate M-10 of the desired compound 27 g (89% yield).
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In tetrahydrofuran; water; at 70℃; for 8h;Inert atmosphere;
20.8g (76.88mmol) Intermediate M-13, <strong>[27007-53-0]methyl-2-bromo-5-chlorobenzoate</strong> 21.1g (84.57mmol) and tetrakis triphenylphosphinepalladium 0.89g (0.769mmol) were placed in a flask, and under a nitrogen atmosphere, it was dissolved in tetrahydrofuran 257 ml, and then an aqueous solution 128ml of dissolved potassium carbonate 17g (115.3mmol) was added, and stirred at reflux at 70 Cfor 8 h. After completion of the reaction, it was extracted with ethyl acetate,the extract was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The product was purified by silica ge lcolumn chromatography using n-hexane / ethyl acetate (9: 1 volume ratio) to obtain intermediate M-26 of the desired compound 27.3 g (90% yield).
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In tetrahydrofuran; water; at 70℃; for 8h;Inert atmosphere;
Thianthrene-1-boronic acid 20g (76.88mmol),methyl-2-bromo-5-chloro-benzoate 21.1g (84.57mmol) and tetrakis triphenylphosphinepalladium0.89g (0.769mmol) were placed in a flask, and under a nitrogen atmosphere, it was dissolved in tetrahydrofuran 257 ml, and then an aqueous solution 128ml of dissolved potassium carbonate 17g (115.3mmol) was added, and stirred at reflux at 70 Cfor 8 h. After completion of the reaction, it was extracted with ethyl acetate,the extract was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The product was purified by silica gelcolumn chromatography using n- hexane / ethyl acetate (9: 1 by volume) to obtain intermediate M-1 of the desired compound 26.9 g (91% yield)
Under argon atmosphere, 4-bromodibenzofuran: 8.6g, tetrahydrofuran: 100mL were added in the flask and cooled to -30C. To this was slowly added butyllithium in hexane solution (1.6M): 26ml. After stirring for 30 minutes, warmed to 0C then stirred for 1 hour. Then, under an argon atmosphere was added <strong>[27007-53-0]2-bromo-5-chlorobenzoic acid methyl ester</strong>: 17.5g, tetrahydrofuran: 40mL. Previously prepared solution was added at 0C after warming to room temperature for 5 hours with stirring. Then, after aqueous ammonium chloride solution was added to the reaction solution, transferred to a separatory funnel then extracted with toluene. Then, the organic layer was dried over sodium sulfate, filtered, concentrated. The residue was purified by silica gel column chromatography to give 7.3 g of a white solid (yield 55%).
2-(dibenzo[b,e][1,4]dioxin-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane[ No CAS ]
methyl 5-chloro-2-(dibenzo[b,e][1,4]dioxan-2-yl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 70℃; for 8h;Inert atmosphere;
The step 1 2 obtained in 2-(dibenzo[b,e][1,4]dioxin-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (24g, 76.88mmol), <strong>[27007-53-0]methyl 2-bromo-5-chlorobenzoate</strong> (21.1g, 84.57mmol) and Pd (PPh3) 4 (0.89g, 0.769mmol) in a flask placed under nitrogen atmosphere was dissolved in 257mL THF was stirred at reflux for 8 hours after the 70 K2CO3 17g (115.3mmol) was added an aqueous solution of 128ml then dissolved. After completion of the reaction the obtained organic layer was dried over Na2SO4 and then extracted with ethyl acetate and was evaporated under reduced pressure and then purified by column chromatography to give the compound methyl 5-chloro-2-(dibenzo[b,e][1,4]dioxan-2-yl)benzoate to give the 24.7g (yield 91%).
91%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; for 8h;
The 2-(dibenzo[b,e][1,4]dioxin-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (73 g, 0.235 mol) obtained in , <strong>[27007-53-0]methyl 2-bromo-5-chlorobenzoate</strong> (70.3 g, 0.282 mol) and Pd(PPh3)4 (13.5 g, 0.011 mol) were placed in a flask, and dissolved by adding a saturated aqueous 2 M Na2CO3 solution (352 ml) and 1,4-dioxane (2 L) thereto, and then the result was heated and stirred for 8 hours. After the reaction was terminated, distilled water was introduced thereto, and the organic layer was extracted with ethyl acetate. The obtained organic layer was dried using Na2SO4, vacuum distilled, and then purified using column chromatography to obtain a methyl 5-chloro-2-(dibenzo[b,e][1,4]dioxin-2-yl)benzoate compound (75.4 g, yield 91%).
91%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; for 8h;Heating;
(Dibenzo [b, e] [1,4] dioxin-2-yl) -4,4,5,5-tetramethyl-1,3,2-Dioxaborolane (73 g, 0.235 mol),Methyl 2-bromo-5-chlorobenzoate (70.3 g, 0.282 mol) and Pd (PPh3) 4 (13.5 g, 0.011 mol)A saturated aqueous solution of 2M Na2CO3 (352 ml) and 1,4-dioxane (2 L) were added and dissolved, followed by heating and stirring for 8 hours. After completion of the reaction, distilled water was added and the organic layer was extracted with ethyl acetate. The obtained organic layer was dried over Na2SO4, distilled under reduced pressure, and then purified by column chromatography to obtain methyl 5-chloro-2- (dibenzo [b, e][1,4] dioxin-2-yl) benzoate (75.4 g, yield 91%).
methyl 2-(4-bromophenoxy)-5-chlorobenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
With pyridine; potassium carbonate; copper(II) oxide; at 130℃; for 5h;
Methyl 2-bromo-5-chlorobenzoate (10g) and 4-bromo-phenol (7g) and pyridine (50ml) and then diluted to theK 2 CO 3 (8.3g),CuO (3.8g) then added dropwise to the reaction the mixture was stirred at 130 for 5 hours.After cooling slowly to room temperature, conc the filtrate obtained after filtration under reduced pressure at 0 .After neutralization with HCl and extracted with ethyl acetate.The organic layer was dried over anhydrous magnesium sulfate, distilled under reduced pressure, the obtained residue was separated by purified by silica gel column chromatography to give the intermediate 5-1 (14g) quantitatively.
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In tetrahydrofuran; water; at 80℃; for 12h;Inert atmosphere;
In a nitrogen atmosphere, 100 g (282 mmol) of the compound I-1 was dissolved in 900 mL of tetrahydrofuran (THF), and thereto was added methyl 2-(77.4 g, 310 mmol) of <strong>[27007-53-0]methyl 2-bromo-5-chlorobenzoate</strong> and tetrakis (triphenylphosphine) palladium3.26 g (2.82 mmol) of tetrakis (triphenylphosphine) palladium was added thereto and stirred. Saturated potassium carbonate in water97.4 g (705 mmol) of nate were added, and the mixture was refluxed by heating at 80 DEG C for 21 hours. After completion of the reaction, water is added to the reaction solutionThe reaction mixture was extracted with dichloromethane (DCM), then dried over anhydrous MgSO 4, filtered, and concentrated under reduced pressure. Get thisThe residue was purified by flash column chromatography to obtain 112 g (94%) of compound I-5.
11-phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) 11H-benzo[a]carbazole[ No CAS ]
C30H20ClNO2[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
With tetrakis(triphenylphosphine) palladium(0); Aliquat 336; potassium carbonate; In water; toluene; for 24h;Reflux; Inert atmosphere;
Intermediate product (E) 16.0 g (38.16 mmol), <strong>[27007-53-0]methyl 2-bromo-5-chlorobenzoate</strong> 14.28 g (57.24 mmol) andK 2 CO 3 15.82 g (114.48mmol), Pd (PPh 3) 4 0.88 g (0.76 mmmol) and 150 ml of toluene, was suspended in 70 ml of distilled water was stirred and refluxed for 24 hours under a nitrogen stream.After completion of the reaction extract the reaction mixture with dichloromethane and filter with silica gel and then was evaporated under reduced pressure, and hexane: dichloromethane = 7: 3 (v / v) with a silica column one behind, the intermediate product was recrystallized with dichloromethane and normal hexane (F) 16.74g (yield: 95%) was obtained.
To a solution of Compound 42 (2g, 8.02mmol) in tetrahydrofuran (800uL) was added sufric acid (20ml, 8.02mmol)at -10C, the solution was stirred for 40 minutes. The reaction mixture was poured into ice water, and extracted withethyl acetate. The oranic layer was washed with water, dried with anhydrous sodium sulfate, and concentrated underreduced pressure. The residue was purified by silica gel chromatography (ethyl acetate / hexane) to yield the mixtureof Compound 43 and 44 (2.2g, yield: 93%). LC/MS Method: B, retention time: 2.18 min; To a solution of the mixture of Compound 43 and 44 (1.7g, 5.77 mmol) in tetrahydrofuran (20mL) was addeddiisobutylamuminium hydride (14.4ml, 14.4mmol) at -78C, and the solution was gradually warmed to 0C. The reactionmixture was poured into the mixed solvent of ethyl acetate and methanol, and then Rochelle salt aqueous solution wasadded to the solution. After extracted, the organic layer was washed with water, dried with anhydrous sodium sulfate,and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate / hexane)to yield the mixture of Compound 45 and 46 (1.65g, yield: quant).LC/MS Method: B, retention time: 1.79 min, 1.87 min; To a mixed solution of the mixture of Compound 45 and 46 (1.55g, 5.82mmol) in ethanol (10mL) and water(2.5mL) was added ammonium chloride (933mg, 17.45mmol) and iron (974mg, 17.45mmol), the solution was stirred at80C for 20 minutes. The reaction mixture was filtered, to the filtrate was added water, and extracted with ethyl acetate.The organic layer was dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residuewas purified by suspention with ethyl acetate / hexane to yield Compound 47 (620mg, yield: 45%) as a white solid.1H-NMR (DMSO-D6) delta: 6.74 (1H, d, J = 2.8 Hz), 6.69 (1H, d, J = 2.5 Hz), 5.58 (2H, s), 5.41 (1H, t, J = 5.6 Hz), 4.40(2H, d, J = 5.0 Hz).LC-MS: m/z=235. [M+H]+
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In tetrahydrofuran; water; at 80℃; for 12h;Inert atmosphere;
In a nitrogen atmosphere, 5.13 g (30 mmol) of <strong>[26076-46-0]thiophene-2,5-diyldiboronic acid</strong>, 7.472 g (30 mmol) of methyl 2-bromo-5-chlorobenzoate, 1.732 g (1.5 mmol) of Pd(PPh3)4, and 6.21 g (45 mmol) of K2CO3 were dissolved in 500 mL of a mixed solution of THF/H2O (at a volume ratio of 2/1), and then, stirred at a temperature of 80° C. for 12 hours. After the reaction solution was cooled to room temperature, 100 mL of water was added thereto and the resulting solution was extracted 3 times with 150 mL of ethylether. An organic solvent layer collected therefrom was dried with magnesium sulfate, and then, the residues obtained by evaporating the solvent were separated-purified by silica gel chromatography, so as to obtain 6.21 g (21 mmol, yield of: 83percent) of Intermediate A-1.
With copper(l) iodide; sodium hydroxide; In acetonitrile; at 100℃; for 24h;Sealed tube; Inert atmosphere;
General procedure: A sealed tube of 25 mL equipped with a magnetic stir bar was charged with alkynes (0.20 mmol), 2-bromobenzoic esters (0.22 mmol), CuI (0.02 mmol, 10 mol%), NaOH (0.4 mmol, 2 equiv) and CH3CN (1.0 mL). The reaction mixture was stirred at 100 C for 24 h. The reaction was monitored by GC or GC-MS. After completion of the reaction, the reaction mixture was cooled to room temperature, then washed with saturated NH4Cl aqueous solution (5.0 mL), and extracted with CHCl3 (3 * 5.0 mL). The combined organic phases were dried over Na2SO4 (anhydrous), concentrated in vacuum. The crude product was purified by flash column chromatography (eluent: ethyl acetate/petroleum ether = 1/20-1/10) on silica gel to afford the desired product.
With copper(l) iodide; sodium hydroxide; In acetonitrile; at 100℃; for 24h;Sealed tube; Inert atmosphere;
General procedure: A sealed tube of 25 mL equipped with a magnetic stir bar was charged with alkynes (0.20 mmol), 2-bromobenzoic esters (0.22 mmol), CuI (0.02 mmol, 10 mol%), NaOH (0.4 mmol, 2 equiv) and CH3CN (1.0 mL). The reaction mixture was stirred at 100 C for 24 h. The reaction was monitored by GC or GC-MS. After completion of the reaction, the reaction mixture was cooled to room temperature, then washed with saturated NH4Cl aqueous solution (5.0 mL), and extracted with CHCl3 (3 * 5.0 mL). The combined organic phases were dried over Na2SO4 (anhydrous), concentrated in vacuum. The crude product was purified by flash column chromatography (eluent: ethyl acetate/petroleum ether = 1/20-1/10) on silica gel to afford the desired product.
methyl 5-chloro-2-(4-fluoronaphthalen-1-yl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
150 g
With tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; for 4h;Inert atmosphere; Reflux;
In the nitrogen atmosphere,<strong>[182344-25-8]4-fluoronaphthalene-1-boronic acid</strong> (92.0 g)2-bromo-5-chlorobenzoate (120.0 g),Pd (PPh3) 4 (15.0 g), potassium phosphate (204.0 g),Toluene (800 ml),Ethanol (200 ml) and water (200 ml) was stirred at reflux temperature for 4 hours.The reaction solution was cooled to room temperature,After adding water for separation,Using silica gel column chromatography (expansion liquid:Toluene) for refining,To give methyl 5-chloro-2- (4-fluoronaphthalen-1-yl) benzoate (150.0 g).
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 90℃; for 8.5h;
E1 [ 20.0 g (80.2mmol) ] and E2 [ 15.4 g (120.2mmol) ] were put in 100 ml of toluene, 50 ml of ethanol, and a 150-ml 20 mass % sodium carbonate aqueous solution. 2.8 g (2.4mmol) of tetrakistriphenyl phosphinepalladium (0) was added, and it heated in temperature of 90 degrees C, and performed stirring for 8.5 hours. It extracted and condensed with toluene after cooling, and obtained 16.5g (81% of yield) of water-white liquids E3 by refining with silica gel column chromatography (mobile phase; heptane : toluene =3:1).
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; water; toluene; at 70 - 75℃; for 10h;Inert atmosphere;
In a 1L three-neck flask, phenanthroline-9-boronic acid (44.8 g, 0.20 mol), <strong>[27007-53-0]methyl 2-bromo-5-chlorobenzoate</strong> (52.4 g, 0.21) was added. (mol), potassium carbonate (55.2 g, 0.40 mol), 165.6 g of water, Pd(PPh3)4 (2.312 g, 2.0 mmol), toluene (300 mL), and absolute ethanol (100 mL), protected with nitrogen, and warmed to reflux.Incubate the reaction at 70-75C for 10h, stop the reaction, cool to 25C, separate the liquid, collect the organic phase, wash it to neutrality, and remove the solvent under reduced pressure in the organic phase. Purify by pure toluene column chromatography and recrystallize toluene and petroleum ether. Intermediate 1-I was obtained in a yield of 78.37%.
methyl 2-(benzo[c][1,2,5] thiadiazol-4-yl)-5-chlorobenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In 1,4-dioxane; water for 8h; Heating;
2.2 Step 2 Synthesis of 4-(2-nitrophenyl)benzo[c][1,2,5]thiadiazole
Benzo [c] [1,2,5] thiadiazole obtained in the above , and the 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan- Sol (72 g, 0.274 mol),1-Bromo-2-nitrobenzene (66 g, 0.326 mol)And Pd (PPh3) 4 (13.5 g, 0.011 mol) were placed in a flask,A saturated aqueous solution of 2M Na2CO3 (352 ml) and 1,4-dioxane (2 L) were added and dissolved, followed by heating and stirring for 8 hours. After completion of the reaction, distilled water was added thereto, and the organic layer was extracted with ethyl acetate.The obtained organic layer was dried over Na2SO4, distilled under reduced pressure,The crude product was purified by column chromatography to obtain 4- (2-nitrophenyl)benzo[c][1,2,5] thiadiazole (54.5 g, yield 77%).
2-(dibenzo[b,d]furan-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane[ No CAS ]
C20H13ClO3[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
With palladium diacetate; tris-(o-tolyl)phosphine; In 1,4-dioxane; water; toluene; for 16h;Reflux;
117.9 g (401 mmol) of starting material a,100 g (401 mmol) of starting material b and 203.1 g (882 mmol) of potassium phosphate monohydrate at 1.6 LMix and degas in toluene/water/dioxane (2:1:1).Adding palladium acetate to the mixture(0.9 g, 4 mmol) and tri-o-tolylphosphine (2.44 g, 8 mmol),The mixture was stirred at reflux for 16 hours.After the mixture was cooled to room temperature, phase separation was carried out.The aqueous phase was further extracted with ethyl acetate (2×300 mL).The combined organic phases were washed several times with water, dried over sodium sulfate and evaporated in vacuo.The crude product was filtered through a pad of EtOAc using EtOAc. After removal of the solvent in vacuo, an oil was obtained in quantitative yield.
100%
With potassium phosphate monohydrate; palladium diacetate; tris-(o-tolyl)phosphine; In 1,4-dioxane; water; toluene; for 16h;Reflux;
117.9 g (401 mmol) starting material a, 100 g (401 mmol) starting material b and 203.1 g (882 mmol) potassium phosphate monohydrate are mixed in 1.6 L toluene/water/dioxane (2:1 :1 ) and degassed. To the mixture, palladium acetate (0.9 g, 4 mmol) and tri-o/f/io-tolylphosphine (2.44 g, 8 mmol) are added and the mixture is stirred at reflux for 16 h. After cooling the mixture to room temperature, the phases are separated. The aqueous phase is further extracted with ethyl acetate (2 x 300 ml_). The combined organic phases are washed multiple times with water, dried over sodium sulfate and finally removed in vacuum. The crude is filtered over a plug of S1O2/AI2O3 using ethyl acetate as solvent. After removing the solvent in vacuum, an oil is obtained in quantitative yield.
100%
With potassium phosphate monohydrate; palladium diacetate; tris-(o-tolyl)phosphine; In 1,4-dioxane; water; toluene; for 16h;Reflux;
117.9 g (401 mmol) starting material a, 100 g (401 mmol) starting material b and 203.1 g (882 mmol) potassium phosphate monohydrate are mixed in 1.6 L toluene/water/dioxane (2:1 :1) and degassed. To the mixture, palladium acetate (0.9 g, 4 mmol) and tri-o/f/io-tolylphosphine (2.44 g, 8 mmol) are added and the mixture is stirred at reflux for 16 h. After cooling the mixture to room temperature, the phases are separated. The aqueous phase is further extracted with ethyl acetate (2 x 300 ml_). The combined organic phases are washed multiple times with water, dried over sodium sulfate and finally removed in vacuum. The crude is filtered over a plug of S1O2/AI2O3 using ethyl acetate as solvent. After removing the solvent in vacuum, an oil is obtained in quantitative yield.
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 90℃; for 5h;
4.0 Grams (16.0 mmol) of El and 4.3 g (16.0 mmol) of E2 were loaded into 50 ml of toluene, 25 ml of ethanol, and 25 ml of a 20 mass % aqueous solution of sodium carbonate. Further, 0.6 g (0.5 mmol) of tetrakistriphenylphosphine palladium(0) was added to the mixture, and the whole was heated to a temperature of 90 C. and stirred for 5 hours. The resultant was cooled, and was then extracted with toluene and concentrated. The residue was purified by silica gel colunm chromatography (mobile phase; heptane:ethyl acetate=9:l) to provide 4.0 g of a yellow liquid E3 (yield: 8 1%).
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; for 16h;Inert atmosphere; Reflux;
To a three-necked flask under argon atmosphere, 5.0 g (11.2 mmol) of a starting material (SM-2), 2.78 g (11.2 mmol) of <strong>[27007-53-0]2-bromo-5-methyl chlorobenzoate</strong>, 2.96 g (27.9 mmol) of sodium carbonate, 50 mL of 1,2-dimethoxyethane (DME), and 30 mL of water were added. Subsequently, 0.13 g (0.11 mmol) of tetrakis(triphenylphosphine)palladium was further added to the flask to provide a mixture solution. The mixture solution was heated for reflux with stirring for 16 hours. After the mixture solution was added with water at the room temperature, the mixture solution was filtered. The obtained residue was refined by silica-gel column chromatography (a mobile phase; hexane: ethyl acetate), so that an intermediate 5A was obtained. A yield of the obtained compound was 6.00 g and a yield rate thereof was 94%.
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In tetrahydrofuran; water; at 80℃; for 12h;
4-bromo-1-naphthaleneboronic acid 25.08g (100mmol),Methyl 5-chloro-2-bromo benzoate 24.95 g (100 mmol),After dissolving 5.77 g (0.5 mmol) of Pd(PPh3)4 and 27.64 g (200 mmol) of K2CO3 in 500 mL of THF / H2O (2/1 volume ratio) mixed solution,Stirred at 80 C. for 12 hours.After the reaction solution was cooled to room temperature, 200 mL of water was added and extracted three times with 150 mL of ethyl ether.The combined organic solvent layer was dried over magnesium sulfate and the solvent was evaporated.The obtained residue was separated and purified through silica gel column chromatography to obtain intermediate I-1 (29.29 g, yield 78%).
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In tetrahydrofuran; water at 120℃; for 12h;
4 Synthesis of Compound A27
Add 100mmol of 2-bromo-5-chlorobenzoic acid methyl ester, 100mmol of 4-carbazole boron ester, 41.4g of potassium carbonate (300mmol), 800ml of THF and 200ml of water into the reaction flask, and add 1mol% of Pd( PPh3)4, react at 120°C for 12h. After the completion of the reaction, the reaction was stopped, and the reactant was cooled to room temperature, water was added, filtered, and washed with water. The obtained solid was recrystallized and purified with toluene to obtain a white powder M1.
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In ethanol; water; toluene at 80℃; for 10h; Inert atmosphere;
1.1 Step 1: Synthesis of Intermediate 1-a
Put methyl 2-bromo-5-chlorobenzoate (24.9g, 100mmol) into a 500ml round bottom flask reaction flask, 2-methoxy-2-naphthaleneboronic acid (20.2, 100mmol), tetrakis(triphenylphosphine) palladium (3.4g, 0.29mmol), Potassium carbonate (30.2 g, 217.2 mmol), 300 mL of toluene, 100 mL of ethanol, and 100 mL of water were added. Under nitrogen conditions, the temperature of the reactor was increased to 80° C. and stirred for 10 hours. After the reaction was completed, the temperature of the reactor was lowered to room temperature, and the reactor was extracted with toluene and separated into several layers. The organic layer was concentrated under reduced pressure and separated by column chromatography to obtain Intermediate 1-a (26.1 g, yield, 80%).
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