* 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.
With water; palladium diacetate; triethylamine; triphenylphosphine In 1,4-dioxane at 110℃; for 2 h; Flow reactor
General procedure: For a typical reaction, a Vapourtec 2R+ Series was used as the platform with a Vapourtec Gas/Liquid Membrane Reactor to load the carbon monoxide. The HPLC pump were both set at 0.125 mL/min, temperature of the reactor at 110 °C, pressure of CO at 15 bar with a back pressure regulator of 250 psi (17.24 bar). The system was left running for 2 h to reach steady state after which time the flow streams were switched to pass from the loops where the substrates and catalysts were loaded. The first loop (5 mL) was filled with a solution of palladium acetate (20 mg, 0.08 mmol), triphenylphosphine (48 mg, 0.168 mmol) in 6 mL of 1,4-dioxane while the second loop (5 mL) was filled with a solution made from the ortho-substituted iodoarene substrate (1.68 mmol), triethylamine (0.272 g, 0.374 mL, 2.69 mmol) and water (0.505 g, 28 mmol) in 5.8 mL of 1,4-dioxane. An Omnifit® column filled with 1.71 cm3 (r = 0.33 cm, h = 5.00 cm) of cotton was positioned just before the back pressure regulator to trap any particulate matter formed to avoid blocking of the back pressure regulator. After the substrates were passed through the system, the outlet of the flow stream was directed into a receptacle where the excess carbon monoxide gas was vented off in the fume cupboard. The reaction mixture was then evaporated to dryness, ethyl acetate (25 mL) and sodium carbonate solution (2 M, 10 mL) were added and transferred to a separating funnel. After collecting the aqueous layer, the organic layer was extracted with sodium carbonate solution (2 M, 2 × 10 mL). The combined aqueous layers were acidified by the addition of 2 M HCl solution which was then extracted with ethyl acetate (3 x 25 mL). The organic layer was dried over sodium sulfate, and the solvent evaporated under vacuum to give the crude product as a solid. The crude product was then recrystallised from the appropriate solvent.
Reference：
[1] Beilstein Journal of Organic Chemistry, 2016, vol. 12, p. 1503 - 1511
2
[ 95-72-7 ]
[ 7697-25-8 ]
Reference：
[1] Synthetic Communications, 2008, vol. 38, # 16, p. 2820 - 2825
[2] Bulletin de la Societe Chimique de France, 1958, p. 1418,1420
[3] Journal of Organic Chemistry, 1967, vol. 32, p. 134 - 136
[4] Patent: US4837333, 1989, A,
[5] Patent: EP150892, 1991, B1,
3
[ 21423-84-7 ]
[ 7697-25-8 ]
Reference：
[1] Journal of the Chemical Society, 1958, p. 4227,4230
[2] Journal fuer Praktische Chemie (Leipzig), 1889, vol. <2> 39, p. 496[3] Justus Liebigs Annalen der Chemie, 1891, vol. 265, p. 349
[4] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 21, p. 5936 - 5940
4
[ 615-65-6 ]
[ 7697-25-8 ]
Reference：
[1] Journal fuer Praktische Chemie (Leipzig), 1889, vol. <2> 39, p. 496[2] Justus Liebigs Annalen der Chemie, 1891, vol. 265, p. 349
[3] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 21, p. 5936 - 5940
5
[ 4395-80-6 ]
[ 7697-37-2 ]
[ 7697-25-8 ]
[ 1967-31-3 ]
[ 161622-06-6 ]
Reference：
[1] Gazzetta Chimica Italiana, 1886, vol. 16, p. 288
6
[ 7697-25-8 ]
[ 1967-31-3 ]
Reference：
[1] Bulletin de la Societe Chimique de France, 1958, p. 1418,1420
[2] Zeitschrift fuer Physikalische Chemie, Stoechiometrie und Verwandtschaftslehre, 1929, vol. <A> 143, p. 18
7
[ 4395-80-6 ]
[ 7697-37-2 ]
[ 7697-25-8 ]
[ 1967-31-3 ]
[ 161622-06-6 ]
Reference：
[1] Gazzetta Chimica Italiana, 1886, vol. 16, p. 288
8
[ 7697-25-8 ]
[ 55737-77-4 ]
Reference：
[1] Bulletin de la Societe Chimique de France, 1958, p. 1418,1420
9
[ 7697-25-8 ]
[ 1245643-61-1 ]
Reference：
[1] Journal of Medicinal Chemistry, 2014, vol. 57, # 14, p. 6128 - 6140
(a) 2-Chloro-4-methylbenzoic acid A suspension of 2-chloro-p-xylene (100 ml) in nitric acid (1000 ml of 45percent) was heated under reflux for 16 hours. On cooling the mixture was poured into ice water (4000 ml) and the resulting precipitate was filtered off. The crude solid was extracted into 1000 ml of a 1.5M potassium hydroxide solution, filtered and then acidified with hydrochloric acid. The resulting precipitate, which consisted of a mixture of the desired 2-chloro-4-methylbenzoic acid contaminated with 3-chloro-4-methylbenzoic acid, was filtered off and dried under vacuum.
With potassium hydroxide; In nitric acid;
a) 2-Chloro-4-methylbenzoic acid . A suspension of 2-chloro-p-xylene (100 ml) in nitric acid (1000 ml of 45percent) was heated under reflux for 16 hours. On cooling the mixture was poured into ice water (4000 ml) and the resulting precipitate was filtered off. The crude solid was extracted into 1000 ml of a 1.5M potassium hydroxide solution, filtered and then acidified with hydrochloric acid. The resulting precipitate, which consisted of a mixture of the desired 2-chloro-4-methylbenzoic acid contaminated with 3-chloro-4-methylbenzoic acid, was filtered off and dried under vacuum.
Under nitrogen, 1.86 g (10.0 mmol) of <strong>[7697-25-8]2-chloro-4-methylbenzoic acid</strong> was combined with 10 g of H2O. 1.11 g (15 mmol) of Ca(OH)2 was then added. The mixture was heated at 85° C. under stirring for 60 min, remaining under a nitrogen atmosphere. Separately, 43 mg of CuBr and 94 mg of rac-trans-N,N'-dimethylcyclohexane-1,2-diamine (Ligand F) were combined with 1 mL deionized water under nitrogen. The resulting mixture was stirred under an air atmosphere until the CuBr was dissolved to give a blue solution. This solution was added to the stirred reaction mixture via syringe at 80° C. under nitrogen and stirred for 24 h at 80° C. After cooling to 25° C., the reaction mixture was acidified with 15percent HCl, producing a white precipitate. The white precipitate was filtered and washed with water. After drying, a total of 1.45 g (9.5 mmol, 95percent yield) of 2-hydroxy-4-methylbenzoic acid was collected. The purity was determined by 1H NMR to be >99percent.
Preparation 18; Used to Prepare Example 71 (a) methyl 2-chloro-4-methylbenzoate<strong>[7697-25-8]2-chloro-4-methylbenzoic acid</strong> (500 mg, 2.93 mmol) was dissolved in Methanol (7 mL) and SOCl2 (0.215 mL, 2.93 mmol) was slowly added to the mixture and the reaction was left at room temperature overnight. Next morning HPLC showed completion. Volatiles were removed under vacuum to afford 526 mg of the title compound as brown oil.1H-NMR (delta ppm, DMSO): 7.71 (d, 1H), 7.40 (s, 1H), 7.25 (s, 1H), 3.81 (s, 3H), 2.33 (s, 3H).
With hydrogenchloride; In 1,4-dioxane; at 20℃;
Preparation 71 2-Chloro-4-methyl-benzoic acid methyl ester Add 4N hydrogen chloride in 1,4-dioxane (20 mL, 80 mmol) to <strong>[7697-25-8]2-chloro-4-methylbenzoic acid</strong> (5.0 g, 29.3 mmol) in methanol (60 mL). Stir the reaction mixture at room temperature over the weekend. Concentrate the reaction mixture and partition the residue between ethyl acetate and saturated aqueous sodium bicarbonate solution. Separate the organic layer and extract the aqueous with ethyl acetate (2*). Combine the organic layers, wash with brine, dry over sodium sulfate, and concentrate to provide the title compound as a brownish oil (4.7 g, 25.5 mmol). The following compounds are prepared essentially by the method of Preparation 71.
With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 80 - 86℃; for 16h;Large scale;
To a solution of 0.75 kg <strong>[7697-25-8]2-chloro-4-methylbenzoic acid</strong>(4.41 mol) in 7 dm3 DMF at 80 C was slowly added 0.94 kg NBS (5.3 mol) to maintain the temperature below86 C, and the reaction mixture was stirred for 16 h at80 C, and solvents were removed by rotaevaporation,cooled to room temperature, then de-ionized water wasadded, and then the resultant mixture was extracted withEtOAc, washed with de-ionized water and brine, dried withanhydrous sodium sulfate, and concentrated in vacuo.Subsequently it was recrystallized from 3 dm3 MeOH togive colorless crystals (1.03 kg, 94 percent). M.p.: 205?207 C;IR (KBr): m = 3878, 2951, 1749, 1482 cm-1; 1H NMR(300 MHz, CDCl3): d = 8.23 (s, 1H), 7.52 (s, 1H), 2.38 (s,3H) ppm; 13C NMR (100 MHz, CDCl3): d = 165.8, 145.6,135.2, 133.9, 131.2, 130.6, 122.6, 25.3 ppm; MS:m/z = 248 (M?), 271 ([M ? Na]?).
2.09 g
With bromine; iron; at 20℃; for 2h;Cooling with ice;
Bromine (7.5 mL, 132.3 mmol) was added to the reaction flask,Under ice-cooling was added iron powder (739mg, 13.2mmol),After stirring, <strong>[7697-25-8]2-chloro-4-methylbenzoic acid</strong> 1a (1.5 g, 8.8 mmol) was slowly added and the reaction was allowed to proceed at room temperature for 2 hours.The reaction solution was poured into 150 mL of sodium thiosulfate saturated solution cooled in an ice-water bath and extracted with ethyl acetate (200 mL). The organic phase was washed with water (50 mL) and saturated sodium chloride solution (50 mL) Dried over sodium sulfate, filtered and concentrated under reduced pressure. To the resulting residue was added 100 mL of ethyl acetate. The mixture was stirred uniformly and the insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure to give the crude title product Ib (2.09 g, pale yellow solid).The product is subjected to the next step without further purification.
4-((5-(2-chloro-4-methylphenyl)-1,3,4-oxadiazol-2-yl)thio)-butanoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
4-((5-(2chloro-4-methylphenyl)-1,3,4-oxadiazol-2-yl)thio)butanoic acid Compound 1000 is prepared by a method analogous to that described for 232120 starting with <strong>[7697-25-8]2-chloro-4-methylbenzoic acid</strong> instead of 2,4-dichlorobenzoic acid.
With N-iodo-succinimide; trifluorormethanesulfonic acid; In dichloromethane; at 0 - 20℃; for 0.666667h;
To a solution of <strong>[7697-25-8]4-methyl-2-chlorobenzoic acid</strong> 1 (2.50 g, 14.7 mmol) and(trifluoromethyl) sulfonic acid (65.0 mL, 73.3 mmol) in dichloromethane (20 mL) at 000was added N-iodosuccinimide (3.50 g, 15.4 mmol) portion wise over a period of 10minutes. The mixture was stirred at room temperature for 30 minutes, quenched withice, then water (60 mL) and extracted into EtOAc (100 mL). The layers were separated and the aqueous layer was washed with EtOAc (2 x 50 mL). The combined organic layers were washed with 10percent aqueous sodium sulfite solution (60 mL), dried over magnesium sulphate and concentrated in vacuo to afford the title compound (2.5 g,57percent).1H NMR (400MHz, MeOH-d4): O ppm 2.42 (s, 3H), 7.41 (s, 1H), 8.24 (s, 1H).
2-chloro-4-methyl-N-(2-methylquinolin-8-yl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
[00412] <strong>[7697-25-8]2-Chloro-4-methylbenzoic acid</strong> (171 mg, 1.0 mmol) and N-(3-dimethylaminopropyl)- N?-ethylcarbodiimide hydrochloride (230 mg, 1.2 mmol) were dissolved in dimethylformamide (5 mL). N,N-Diisopropylethylamine (260 jiL, 1.5 mmol) was added and the solution was stirred for 10 minutes. To this solution was added 8-aminoquinaldine (158 mg, 1.0 mmol) and the mixture was stirred for 20 hrs. The mixture was diluted with water and extracted with 2 volumes of ethyl acetate. The organic layers were collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a wateracetonitrile gradient to afford compound A17. ESI-MS: m/z 311 [M+H].
<strong>[7697-25-8]2-Chloro-4-methylbenzoic acid</strong> (171 mg, 1.0 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (230 mg, 1.2 mmol) were dissolved in dimethylformamide (5 mL). N,N-Diisopropylethylamine (260 muL, 1.5 mmol) was added and the solution was stirred for 10 minutes. To this solution was added 8-aminoquinaldine (158 mg, 1.0 mmol) and the mixture was stirred for 20 hrs. The mixture was diluted with water and extracted with 2 volumes of ethyl acetate. The organic layers were collected and the solvent was removed by rotary evaporation. The residue was purified by preparative reverse-phase HPLC using a water-acetonitrile gradient to afford compound A17. ESI-MS: m/z 311 [M+H]+.
With water; palladium diacetate; triethylamine; triphenylphosphine; In 1,4-dioxane; at 110℃; under 11251.1 Torr; for 2h;Flow reactor;
General procedure: For a typical reaction, a Vapourtec 2R+ Series was used as the platform with a Vapourtec Gas/Liquid Membrane Reactor to load the carbon monoxide. The HPLC pump were both set at 0.125 mL/min, temperature of the reactor at 110 °C, pressure of CO at 15 bar with a back pressure regulator of 250 psi (17.24 bar). The system was left running for 2 h to reach steady state after which time the flow streams were switched to pass from the loops where the substrates and catalysts were loaded. The first loop (5 mL) was filled with a solution of palladium acetate (20 mg, 0.08 mmol), triphenylphosphine (48 mg, 0.168 mmol) in 6 mL of 1,4-dioxane while the second loop (5 mL) was filled with a solution made from the ortho-substituted iodoarene substrate (1.68 mmol), triethylamine (0.272 g, 0.374 mL, 2.69 mmol) and water (0.505 g, 28 mmol) in 5.8 mL of 1,4-dioxane. An Omnifit® column filled with 1.71 cm3 (r = 0.33 cm, h = 5.00 cm) of cotton was positioned just before the back pressure regulator to trap any particulate matter formed to avoid blocking of the back pressure regulator. After the substrates were passed through the system, the outlet of the flow stream was directed into a receptacle where the excess carbon monoxide gas was vented off in the fume cupboard. The reaction mixture was then evaporated to dryness, ethyl acetate (25 mL) and sodium carbonate solution (2 M, 10 mL) were added and transferred to a separating funnel. After collecting the aqueous layer, the organic layer was extracted with sodium carbonate solution (2 M, 2 × 10 mL). The combined aqueous layers were acidified by the addition of 2 M HCl solution which was then extracted with ethyl acetate (3 x 25 mL). The organic layer was dried over sodium sulfate, and the solvent evaporated under vacuum to give the crude product as a solid. The crude product was then recrystallised from the appropriate solvent.
With potassium carbonate; In dimethyl sulfoxide; at 100℃; for 2h;Inert atmosphere; Sealed tube;
General procedure: 2-chlorobenzoic acids (1a, 0.2 mmol), pentane-2,4-dione (2a, 2 eq), Cu NPs (1.3 mg, 10 molpercent), K2CO3 (2.0 equiv) and 1.5 mL of DMSO were added into a 5-mL sealed tube under N2. The mixture was stirred at 100 °C for 2 h. The reaction mixture was then purified by flash column chromatography on silica gel (hexanes/EtOAc 15:1). Compound 3a was obtained in >92percent of yield.
With potassium carbonate; In dimethyl sulfoxide; at 100℃; for 8h;Inert atmosphere; Sealed tube;
General procedure: 2-chlorobenzoic acids (1a, 0.2 mmol), pentane-2,4-dione (2a, 2 eq), Cu NPs (1.3 mg, 10 molpercent), K2CO3 (2.0 equiv) and 1.5 mL of DMSO were added into a 5-mL sealed tube under N2. The mixture was stirred at 100 °C for 2 h. The reaction mixture was then purified by flash column chromatography on silica gel (hexanes/EtOAc 15:1). Compound 3a was obtained in >92percent of yield.
With potassium carbonate; In dimethyl sulfoxide; at 100℃; for 2h;Inert atmosphere; Sealed tube;
General procedure: 2-chlorobenzoic acids (1a, 0.2 mmol), pentane-2,4-dione (2a, 2 eq), Cu NPs (1.3 mg, 10 molpercent), K2CO3 (2.0 equiv) and 1.5 mL of DMSO were added into a 5-mL sealed tube under N2. The mixture was stirred at 100 °C for 2 h. The reaction mixture was then purified by flash column chromatography on silica gel (hexanes/EtOAc 15:1). Compound 3a was obtained in >92percent of yield.
With potassium carbonate; In dimethyl sulfoxide; at 100℃; for 2h;Inert atmosphere; Sealed tube;
General procedure: 2-chlorobenzoic acids (1a, 0.2 mmol), pentane-2,4-dione (2a, 2 eq), Cu NPs (1.3 mg, 10 molpercent), K2CO3 (2.0 equiv) and 1.5 mL of DMSO were added into a 5-mL sealed tube under N2. The mixture was stirred at 100 °C for 2 h. The reaction mixture was then purified by flash column chromatography on silica gel (hexanes/EtOAc 15:1). Compound 3a was obtained in >92percent of yield.
5-((2S,3S)-1-(4-(((tert-butoxycarbonyl)amino)methyl)-2-chloro-5-cyclopropylbenzoyl)-3-cyclohexylpyrrolidine-2-carboxamido)-1H-indole-2-carboxylic acid ethyl ester[ No CAS ]
5-((2S,3S)-1-(4-(((tert-butoxycarbonyl)amino)methyl)-2-chloro-5-cyclopropylbenzoyl)-3-cyclohexylpyrrolidine-2-carboxamido)-1H-indole-2-carboxylic acid[ No CAS ]
5-((2S,3S)-1-(4-(aminomethyl)-2-chloro-5-cyclopropylbenzoyl)-3-cyclohexylpyrrolidine-2-carboxamido)-1H-indole-2-carboxylic acid trifluoroacetic acid salt[ No CAS ]
With 1H-imidazole; copper ammonium sulphate hexahydrate; lithium tert-butoxide; In N,N-dimethyl-formamide; isopropyl alcohol; for 72h;Irradiation;
Step 1: Weigh out 85 mg (0.5 mmol) of <strong>[7697-25-8]2-chloro-4-methylbenzoic acid</strong>, respectively.Imidazole 34 mg (0.5 mmol), copper ammonium sulphate (hexahydrate) 24 mg (12 mmolpercent),Rose red 11mg (2mmolpercent),Lithium tert-butoxide lithium t-BuOli 72 mg (0.9 mmol) was placed in a quartz reaction tube.1.5 ml of each of isopropyl alcohol and DMF was added as a solvent.Step 2: The quartz reaction tube was exposed to ultraviolet light at 254 nm under air for 72 hours. The reaction formula is as follows:Step 3: The product was isolated by column chromatography after completion of the reaction in a yield of 85percent. The resulting product was p-toluic acid.
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