* 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.
Stage #1: With sodium hydroxide In ethanol; water for 2 h; Heating / reflux Stage #2: Acidic aqueous solution
4-Amino-3-chloro-N-thiazol-2-yl-benzamide : 4-Amino-3-chloro-benzoic acid methyl ester (21.6 mmol) was saponified in EtOH (25 ml) and NaOH (1M, 25 ml) at reflux for 2h. The organic solvent was evaporated and pH adjusted to 4. The product was removed by filtration, washed with water and dried in vacuo. Yield: 92percent 1H NMR (D6-DMSO) : 6.15 (s, 2H); 6.79 (d, 1H); 7.59 (dd, 1H); 7.71 (d, 1H); 12.37 (br s, 1H).
92%
for 2 h; Heating / reflux
4-Amino-3-chloro-benzoic acid methyl ester (21.6 mmol) was saponified in EtOH (25 ml) and NaOH (IM5 25 ml) at reflux for 2h. The organic solvent was evaporated and pH adjusted to 4. The product was removed by filtration, washed with water and dried in vacuo to give A- amino-3-chloro-benzoic acid.Yield: 92percentIH NMR (D6-DMSO): 6.15 (s, 2H); 6.79 (d, IH); 7.59 (dd, IH); 7.71 (d, IH); 12.37 (br s,IH).
Example 1128-Chloro-3 ,3 -dimethyl-2- (3 -morpholin-4-yl-phenyl)- 1 ,2,3 ,4-tetrahydro-quinoline-6- carboxylic acidTo a stirred solution of 4-amino-3-chloro-benzoic acid (50 g, 291 mmol) in methanol (300 mL) was added thionyl chloride (45 mL, 605 mmol) dropewise at 0 °C. Then the mixture solution was refluxed for 12 hours before cooling to room temperature. Then the reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (500 mL), washed with saturated aqueous sodium bicarbonate solution (3 x 100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford 4-amino-3-chloro- benzoic acid methyl ester (54 g, quant.) as a pale-white solid: LC/MS m/e calcd for C8H8C1N02 (M+H)+: 186.61, observed: 185.9.
100%
at 0℃; for 12 h; Reflux
To a stirred solution of 4-amino-3-chloro-benzoic acid (50 g, 291 mmol) in methanol (300 mL) was added thionyl chloride (45 mL, 605 mmol) dropewise at 0° C. Then the mixture solution was refluxed for 12 hours before cooling to room temperature. Then the reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (500 mL), washed with saturated aqueous sodium bicarbonate solution (3.x.100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford 4-amino-3-chloro-benzoic acid methyl ester (54 g, quant.) as a pale-white solid: LC/MS m/e calcd for C8H8ClNO2 (M+H)+: 186.61, observed: 185.9.
97%
at 0 - 80℃; for 6 h;
To a stirring solution of 4-amino-3-chlorobenzoic acid (2.00 g, 1 1.7 mmol) in methanol (20.0 mL) at 0 °C was added concentrated H2S04 (2.00 mL) slowly. The resulting mixture was heated at 80 °C for 6 h. The reaction mixture was cooled to rt and then concentrated under reduced pressure. The residue was diluted with sat. aq. NaHC03 and extracted with ethyl acetate (2 x 50 mL). The combined organics were washed with brine, dried over anhydrous Na2S04 and then concentrated in vacuo to afford methyl 4-amino-3-chlorobenzoate (2.10 g, 97percent). -NMR (400 MHz, DMSO-c/6): δ ppm: 7.70 (d, J = 1.6 Hz, 1H), 7.58 (dd, J = 8.4, 2.0 Hz, 1H), 6.77 (d, J = 8.8 Hz, 1H), 6.24 (s, 2H), 3.73 (s, 3H)
Reference：
[1] Patent: WO2011/128251, 2011, A1, . Location in patent: Page/Page column 203
[2] Patent: US2011/257151, 2011, A1, . Location in patent: Page/Page column 75
[3] Patent: WO2018/157190, 2018, A1, . Location in patent: Paragraph 0337
[4] Journal of Cellular Biochemistry, 2017, vol. 118, # 8, p. 2420 - 2429
[5] Journal of Medicinal Chemistry, 2018, vol. 61, # 3, p. 666 - 680
[6] Patent: EP2697246, 2018, B1, . Location in patent: Paragraph 0262; 0263
4
[ 619-45-4 ]
[ 84228-44-4 ]
Yield
Reaction Conditions
Operation in experiment
83%
With copper(II) choride dihydrate; lithium chloride hydrate In ethanol for 48 h; Reflux
General procedure: A round-bottomed flask (25 mL) was charged with substrate (2 mmol), CuCl2·2H2O (6 mmol), LiCl·H2O (2 mmol) and EtOH (4 mL). The resulting reaction mixture was stirred at reflux. After the completion of the reaction monitored by TLC, EtOH was removed under reduced pressure. Then ammonium hydroxide (4 mL, 25percent) and water (10 mL) were added and the aqueous phase was extracted with ethyl acetate (10 mL×3). The combined organic phase was washed with brine (8 mL×3) and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. The crude mixture was purified by chromatography on silica gel to obtain the desired products.
Reference：
[1] Journal of Medicinal Chemistry, 1999, vol. 42, # 25, p. 5277 - 5283
6
[ 2486-71-7 ]
[ 77-76-9 ]
[ 84228-44-4 ]
Reference：
[1] Journal of Medicinal Chemistry, 1999, vol. 42, # 25, p. 5277 - 5283
7
[ 74-87-3 ]
[ 2486-71-7 ]
[ 84228-44-4 ]
Reference：
[1] Journal of Medicinal Chemistry, 2011, vol. 54, # 22, p. 7815 - 7833
8
[ 84228-44-4 ]
[ 214759-66-7 ]
Yield
Reaction Conditions
Operation in experiment
68%
Stage #1: With tert.-butylnitrite; boron trifluoride diethyl etherate In diethyl ether; dichloromethane at -20 - 20℃; for 72.5 h; Stage #2: at 0 - 20℃; for 18.5 h; Stage #3: With iron(III) chloride In water at 20℃; for 0.5 h;
A solution of methyl 4-amino-3-chlorobenzoate (5.0 g, 27 mmol) was stirred at -20°C in DCM (20 mL) and treated sequentially with a solution of BF3.0Et.2 (5.5 mL, 43 mmol) in anhydrous diethyl ether (10 mL) and ferf-butyl nitrite (6.0 mL, 46 mmol). The reaction mixture was stirred at -20°C for 30 min and then allowed to warm slowly to RT and stirred for 72 h. The reaction mixture was filtered and the precipitate was washed sequentially with DCM (50 mL), Et.20 (50 mL) and isohexane (50 mL) to afford the intermediate diazonium salt. The salt was dissolved in H2O (200 mL) and slowly added to a stirred mixture of potassium cyanide (1.98 g, 30.4 mmol) and copper (I) cyanide (2.73 g, (0572) 30.4 mmol) in H20 (300 mL) at 0-5°C. After the addition the mixture was stirred at 0-5°C for 0.5 h, then at RT for 18 h. The mixture was treated with 10percent aqueous FeC solution (200 mL) and stirred at RT for 30 min. The product was extracted with EtOAc (3 x 200 mL) and the combined organic extracts were washed with brine (400 mL), dried over MgSC , filtered and concentrated in vacuo. The product was purified by silica gel chromatography (120 g, 0-10percent EtOAc in isohexane) to afford the title compound (2) (3.56 g, 68percent) as an orange solid: m/z 196 [M+H]+ (ES+); 1 H NMR (400 MHz, DMSO-d6) δ: 8.17 - 8.14 (2H, m), 8.04 (1 H, dd), 3.91 (3H, s)
With copper(II) choride dihydrate; lithium chloride hydrate; In ethanol; for 48h;Reflux;
General procedure: A round-bottomed flask (25 mL) was charged with substrate (2 mmol), CuCl2·2H2O (6 mmol), LiCl·H2O (2 mmol) and EtOH (4 mL). The resulting reaction mixture was stirred at reflux. After the completion of the reaction monitored by TLC, EtOH was removed under reduced pressure. Then ammonium hydroxide (4 mL, 25%) and water (10 mL) were added and the aqueous phase was extracted with ethyl acetate (10 mL×3). The combined organic phase was washed with brine (8 mL×3) and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. The crude mixture was purified by chromatography on silica gel to obtain the desired products.
methyl 3-chloro-4-[(2-chloroacetyl)amido]benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 1h;
General procedure: N,N-Diisopropylethylamine (175muL, 1mmol) and then chloroacetyl chloride (78muL, 1mmol) were added dropwise to a solution of suitable substituted anilines (11-17) (1mmol) in dichloromethane (5mL). The mixture was stirred for 1h at room temperature. Successively, the reaction was quenched with a saturated NaHCO3 aqueous solution. The reaction mixture was extracted with ethyl acetate (3×10mL), dried over Na2SO4 and evaporated under reduced pressure. The residue was crystallized from ethanol.
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 1h;
General procedure: The desired compounds (5-19) were obtained following aprocedure previously reported by us.21Particularly, chloroacetyl chloride (78 ll, 1 mmol) and N,Ndiisopropylethylamine(175 ll, 1 mmol) were added dropwise to a solution of the appropriate substituted anilines in DCM (5 mL).The mixture was stirred for 1 h at room temperature. Successively,the reaction was quenched with a saturated NaHCO3 aqueous solution(5 mL). The reaction mixture was extracted with EtOAc (3 10 mL), dried over Na2SO4 and evaporated under reduced pressure.The residue was crystallized from EtOH or Et2O.
(S)-2-[3-Chloro-4-((R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionylamino)-benzoyl]-methyl-amino}-3-(1H-indol-3-yl)-propionic acid methyl ester[ No CAS ]
4-Amino-3-chloro-N-thiazol-2-yl-benzamide : 4-Amino-3-chloro-benzoic acid methyl ester (21.6 mmol) was saponified in EtOH (25 ml) and NaOH (1M, 25 ml) at reflux for 2h. The organic solvent was evaporated and pH adjusted to 4. The product was removed by filtration, washed with water and dried in vacuo. Yield: 92% 1H NMR (D6-DMSO) : 6.15 (s, 2H); 6.79 (d, 1H); 7.59 (dd, 1H); 7.71 (d, 1H); 12.37 (br s, 1H).
92%
With sodium hydroxide; ethanol; water; for 2h;Heating / reflux;
4-Amino-3-chloro-benzoic acid methyl ester (21.6 mmol) was saponified in EtOH (25 ml) and NaOH (IM5 25 ml) at reflux for 2h. The organic solvent was evaporated and pH adjusted to 4. The product was removed by filtration, washed with water and dried in vacuo to give A- amino-3-chloro-benzoic acid.Yield: 92%IH NMR (D6-DMSO): 6.15 (s, 2H); 6.79 (d, IH); 7.59 (dd, IH); 7.71 (d, IH); 12.37 (br s,IH).
With triethylamine; In tetrahydrofuran; at 0 - 50℃; for 22h;Heating / reflux;
A solution of 696 mul (0.84 g, 5.39 mmol) 5-chloro-pentanoylchloride in 10 ml THF is slowly added dropwise to 1.00 g (5.39 mmol) <strong>[84228-44-4]methyl 4-amino-3-chloro-benzoate</strong> in 20 ml THF with 1 ml TEA with stirring in the ice bath. After stirring for 16 hours at ambient temperature, for 3 hours at 50 C. and for 3 hours at reflux temperature the mixture is poured into water and extracted with ethyl acetate. After the organic phases have been dried over sodium sulphate the mixture is evaporated down i. vac. and the residue remaining is purified by chromatography on silica gel (eluant: petroleum ether/ethyl acetate 85:15). Yield: 300 mg (14.6%) 80% product C13H15Cl2NO3 (304.18) Mass spectrum: (M+H)+=304/306/308 (chlorine isotope) Rf value: 3.29 min
To a solution of compound 1 (200 mg, 1.077 mmol) and 2-iodopropane, (322uL, 3.23 mmol) in DMF (10 mL) was added DIEA (750uL, 4.31 mmol). The reaction mixture was heated to 80C and stirred overnight. The reaction was monitored by LC/MS. After the reaction was done it was cooled to room temperature. The reaction mixture was quenched with HCl (0.5N, 30 mL) and extracted with ethyl acetate (50 mL x 3). The organic layer was dried over sodium sulfate and concentrated and dried under high vacuum. The resulting residue was purified by reverse phase chromatography (using a mixture of acetonitrile and water) to give compound 2 (50 mg, 20%). [00442] To a solution of compound 2 (50mg, 0.22 mmol), in MEOH (1.0 mL) was added NaOH in water (1.0M, 330uL, 0.330minol). The reaction mixture was stirred at ambient temperature for 2 hours. The reaction was monitored by LC/MS. The reaction mixture was quenched with HCl (0.5N, 5 mL) and extracted with ethyl acetate (10 mL x 3). The organic layer was dried over sodium sulfate, and concentrated to give 2 (45 mg). LRMS (M-H+) m/z 212.0
20%
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 80℃;
[00185] To a solution of compound 4.1 (200 mg, 1.077 mmol) and 2-iodopropane (322 uL, 3.23 mmol) in DMF (10 mL) was added DIEA (750 uL, 4.31 mmol). The reaction mixture was heated to 800C and stirred overnight. When complete by LC/MS, the reaction was cooled to room temperature, quenched with HCl (0.5 N, 30 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were dried over sodium sulfate, concentrated and dried under high vacuum. The resulting residue was purified by reverse phase chromatography using a mixture of acetonitrile and water to give compound 4.2 (50 mg, 20%).
To methyl 4-amino-3-chlorobenzoate was added concentrated aqueous ammonia. The mixture was stirred overnight at 70C, then solvent was removed under reduced pressure. The resulting white solid contained 4-amino-3-chlorobenzoic acid but was without further purification. MS m/z: 171 (M+H)+. Step 2: 3-chloro-4-([(1-mesityl-1H-tetrazol-5-yl)thio]acetyl}amino)benzamide To a stirred suspension of [(1-mesityl-1H-tetrazol-5-yl)thio]acetic acid in DCM at 0C was added a solution of oxalyl chloride in DCM (2M, 1 eq.) and a few drops of DMF. The mixture was stirred for 15 minutes at 0C and then added to a solution of crude 4-amino-3-chlorobenzamide (1 eq) and Et3N (1 eq) in DCM at 0C. The mixture was stirred for 2 hours at 0C, after which the solvent was evaporated under reduced pressure. The product was purified by preparative RP-HPLC, using water (0.1 % TFA) and acetonitrile (0.1 % TFA) as eluants (column: C18). After lyophilization of the pooled product fractions the title compound was obtained as a white solid. ¹H NMR (400 MHz, DMSO-d6) No.: 10.08 (s, 1H), 8.02 (s, 1H), 8.00 (d, J= 1.8 Hz, 1H), 7.89 (d, J= 8.6, 1H), 7.82 (dd, J1= 8.6 Hz, J2= 1.8 Hz, 1H), 7.45 (s, 1H), 7.18 (s, 2H), 4.51 (s, 2H), 2.35 (s, 3H), 1.90 (s, 6H). MS m/z: 431 (M+H)+.
With dipotassium peroxodisulfate; sulfuric acid; In water; at 20℃; for 16h;
8.00 g (29.6 mmol) potassium peroxodisulphate are added to 6.0 ml of conc. sulphuric acid with stirring, stirred for 30 minutes at ambient temperature under a nitrogen atmosphere, the mixture is stirred into 50 g ice and neutralised with 14 g sodium carbonate. The solution obtained is combined with a suspension of 2.78 g (15.0 mmol) <strong>[84228-44-4]methyl 4-amino-3-chloro-benzoate</strong> in 300 ml of water and stirred for 16 hours at ambient temperature. The reaction mixture is suction filtered, the filter cake is washed with water, dried in the air and purified by chromatography on silica gel (eluant: petroleum ether/ethyl acetate 9:1). Yield: 1.00 g (33%) C8H6ClNO3 (199.59) Mass spectrum: (M+H)+=199/201 (chlorine isotope) Rf value: 0.55 (silica gel; petroleum ether/ethyl acetate=4:1)
With sodium bicarbonate; In tetrahydrofuran; water;
Reference Example 8 <strong>[84228-44-4]Methyl 4-amino-3-chlorobenzoate</strong> (5.65 g; synthesised in accordance with Synthesis, 1985, 669) was dissolved in tetrahydrofuran (112 ml) and admixed with a solution of sodium hydrogen carbonate (7.67 g) in water (84.8 ml) and benzyl chloroformate (39.1 ml) and the mixture was stirred under a nitrogen atmosphere at room temperature for 22.5 hours. The reaction mixture was extracted with ethyl acetate and the ethyl acetate layer was washed three times with water and then twice with saturated brine. The ethyl acetate layer was dried over magnesium sulfate and then the solvent was distilled off under reduced pressure, and then the residue was purified by column chromatography on silica gel (ethyl acetate/hexane=1:7). A desired fraction was concentrated under reduced pressure and the residue was crystallized from a mixture of ethyl acetate and diisopropyl ether to yield methyl 4-benzyloxycarbonylamino-3-chlorobenzoate (7.51 g) as white crystals. 1H-NMR (CDCl3) delta: 3.91 (3H, s), 5.25 (2H, s), 7.38-7.44 (6H, m), 7.95 (1H, dd, J=8.8 Hz, 2.0 Hz), 8.06 (1H, d, J=2.0 Hz), 8.33 (1H, d, J=8.8 Hz).
With methanol; potassium hydroxide; water; for 2h;Heating / reflux;
A mixture of <strong>[84228-44-4]methyl 4-amino-3-chlorobenzoate</strong>, MeOH and IN KOH in water (1 eq.), was stirred at reflux for 2 hours. The title compound was obtained as a creamy white precipitate, that was filtered, washed with diethyl ether and dried under vacuum. MS (EI+) 172 (M+H)+. MS (ES-) 170 (M+e)
2) Compounds of Formula V 2.1) methyl 3-chloro-4-hydrazino-benzoate (V.1) 31.99 g (0.172 mol) <strong>[84228-44-4]methyl-4-amino-3-chlorobenzoate</strong> are suspended in 160 mL conc. hydrochloric acid and cooled to -10 C. A solution of 11.98 g (0.174 mol) sodium nitrite and 160 mL water is added dropwise at -5 C. 170.98 g (0.759 mol) tin-(II)-chloride in 140 mL hydrochloric acid are added dropwise to the resulting solution. A thick precipitate is formed. The reaction mixture is frozen overnight. After thawing the suspension is made basic with 10 molar sodium hydroxide solution. After the addition of dichloromethane the product dissolves and is separated off with the organic phase. The latter is washed with water, dried and evaporated to dryness. The residue is purified by chromatography. Yield: 18.3 g (53%).
Production Example 11 To a solution of 5.43 g of 4-nitrophenyl chloroformate in 100 mL of dichloromethane was added 2.4 mL of pyridine under ice-cooling, and 5 g of <strong>[84228-44-4]methyl 4-amino-3-chlorobenzoate</strong> was added to the obtained mixture, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and ethyl acetate was added to the residue, followed by washing with 1 M hydrochloric acid, water, a saturated aqueous sodium hydrogen carbonate solution, water, and a saturated aqueous sodium chloride solution in this order. The organic layer was dried over anhydrous sodium sulfate, and after filtration, the filtrate was concentrated under reduced pressure. The obtained solid was dissolved in 200 mL of toluene under heating, and left to be cooled to room temperature, and further cooled in an ice bath. The precipitated solid was collected by filtration, and dried under reduced pressure to obtain 5.59 g of methyl 3-chloro-4-[(4-nitrophenoxy)carbonyl]amino}benzoate as a white solid.
With sodium methylate; formamide; In N,N-dimethyl-formamide; at 20 - 100℃;
EXAMPLE 17; 4-Amino-3-chlorobenzamide (17-2); An anhydrous DMF solution of 1.00 g (5.39 mmol) of <strong>[84228-44-4]methyl 4-amino-3-chlorobenzoate</strong> (17-1), 728 mg (16.16 mmol) of formamide and 204 mg (3.77 mmol) of 5.5M sodium methoxide was stirred for 1 hour at 100 C. and then stirred overnight at room temperature. The reaction was poured into 2-propanol (60 mL) and then evaporated off the solvent. The resultant crude oil was purified on a silica column and eluted with DCM:MeOH:NH4OH (95:5:0.5 to 9:1:0.1). Recovered the desired product 17-2. MS (M+1): measured 171.2; theoretical 170.0. 1H NMR (DMSO): 5.86(s,2H), 6.75(d,1H), 7.01(bs,1H), 7.56(dd,1H), 7.66(bs,1H), 7.75(m,1H).
With sodium hydroxide; sodium bromide; sodium nitrite; In water; hydrogen bromide;
ii) A solution of <strong>[84228-44-4]methyl 4-amino-3-chlorobenzoate</strong> (17.0 g) in 48% hydrobromic acid (200 ml) was stirred at 0. Sodium nitrite solution (6.3 g in 25 ml of water) was added dropwise over 45 minutes and the reaction mixture was maintained at 0-5C. The mixture was stirred at 0-5 for 2 hours. A solution of sodium metabisulphite (5.5 g) and sodium hydroxide (3.6 g) in water (40 ml) was added to a hot solution of copper (II) sulphate pentahydrate (25.5 g) and sodium bromide (12.3 g) in water (80 ml). The stirred suspension was maintained at 75 and the cold diazonium salt solution was added. The mixture was stirred for 15 minutes and 48% hydrobromic acid (30 ml) was added. The mixture was cooled to room temperature and extracted with diethyl ether. The ethereal extracts were washed with water and brine and dried over anhydrous magnesium sulphate. The solution was evaporated in vacuo . Methyl 4-bromo-3-chlorobenzoate (20.4 g) was obtained as a crystalline solid and was used without further purification. Gas-liquid chromatography (g.l.c.): OV-210 at 180 produced one peak. Nuclear magnetic resonance spectrum (N.M.R.) was as follows: 1H (p.p.m. from TMS in CDCl3, integral, number of peaks, J Hz): 3.80, 3H, s; 7.50, 2H, m; 7.90, 1H, m.
With n-Amyl nitrite; iodine; for 1h;Heating / reflux;
A mixture of <strong>[84228-44-4]methyl 4-amino-3-chlorobenzoate</strong> (1.0 g, 5.4 mmol), n-pentyl nitrite (0.95 g, 8.1 mmol) and iodine (1.78 g, 7.0 mmol) was stirred under refluxing for 1 h. The mixture was diluted with methylene chloride (30 ml). The purple solution was washed with saturated sodium thiosulfate solution, brine, and dried over sodium sulfate. The title compound was obtained after flash column using EtOAc:hexane/2:98 as the eluant.
Example 1: Ortho-bromo-Sulfonamides; [Show Image] 2-Bromobenzenesulfonyl chloride (1 eq) and pyridine (2 eq.) dissolved in dichloromethane (1 mL/ mmol of sulfonyl chloride) were introduced in a round bottomed flask. The reaction mixture was cooled to 0 C. The substituted-aniline (1 eq.) was slowly added. The resulting mixture was allowed to stir overnight. A 0.5 M solution of hydrochloric acid was added. The organic phase was separated and washed with water then brine. The organic phase was dried over sodium sulfate, filtered and evaporated to dryness. The residue was triturated in a minimal amount of methanol. The desired compound was obtained as a white solid.
A solution of diphenyl JV-cyanocarbonimidate (4.6 g, 0.0194 mol), 4-amino-3- chlorobenzoic acid methyl ester (3.6 g, 0.0194 mol) and pyridine (5 ml; p. a. dried on molecular sieves) was stirred for 45 minutes at 60 0C. An extra amount of pyridine (5 ml) was added and the reaction mixture was continued stirring for 2 hours at 60 0C. <n="51"/>The crude mixture (containing intermediate 13) was used as such in the next reaction step.
With sodium tris(acetoxy)borohydride; acetic acid; In dichloromethane; at 20℃; for 24h;
Sodium triacetoxyborohydride (3.47 g, 16.39 mmol) was added to a solution of <strong>[84228-44-4]methyl 4-amino-3-chlorobenzoate</strong> (1.014 g, 5.46 mmol), cyclopropanecarboxaldehyde (0.816 mL, 10.93 mmol), and acetic acid (1.876 mL, 32.78 mmol) in CH2Cl2 (40 mL). The reaction mixture was stirred at room temperature under nitrogen for 24 h. After concentration, the product was taken up with EtOAc (100 mL), washed with saturated NaHCO3 (3*20 mL), NaCl (20 mL) and dried over Na2SO4. The crude product was purified by MPLC on silica gel using Hex/EtOAc (4:1) to give 1.154 g (88%) of a colorless oil. 1H NMR (400 MHz, CHLOROFORM-D) delta 0.27-0.32 (m, 2H), 0.59-0.65 (m, 2H), 1.09-1.21 (m, 1H), 3.07 (dd, J=7.03, 5.08 Hz, 2H), 3.86 (s, 3H), 4.82-4.95 (m, 1H), 6.59 (d, J=8.59 Hz, 1H), 7.82 (dd, J=8.59, 1.95 Hz, 1H), 7.95 (d, J=1.95 Hz, 1H); MS (ESI) (M+H)+: 240.13.
With sodium tris(acetoxy)borohydride; acetic acid; In dichloromethane; at 20℃; for 48h;
Sodium triacetoxyborohydride (1.75 g, 8.24 mmol) was added to a solution of <strong>[84228-44-4]methyl 4-amino-3-chlorobenzoate</strong> (0.51 g, 2.75 mmol), cyclobutanone (0.41 mL, 0.39 g, 5.50 mmol), and acetic acid (0.16 mL, 0.17 g, 2.75 mmol) were mixed in CH2Cl2 (20 mL). The reaction mixture was stirred at room temperature under nitrogen for a weekend. After concentration, the product was taken up with EtOAc (100 mL), washed with saturated NaHCO3 (3*20 mL), NaCl (20 mL) and dried over Na2SO4. The crude product was purified by reverse-phase HPLC using high pH column 50-70% MeCN/H2O to give 0.332 g (50%) of a white solid as the title compound. 1H NMR (400 MHz, CHLOROFORM-D): delta 1.77-2.04 (m, 4H), 2.34-2.56 (m, 2H), 3.85 (s, 3H), 3.92-4.07 (m, 1H), 4.89 (d, J=5.47 Hz, 1H), 6.52 (d, J=8.59 Hz, 1H), 7.80 (dd, J=8.59, 1.56 Hz, 1H), 7.93 (d, J=1.95 Hz, 1H); MS (ESI) (M+H)+: 240.16.
Example 13-Chloro-4-{2-[2-(6-chloro-pyridin-3-yl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-acetylamino}-benzoic acid; The title compound was prepared by heating [2-(6-chloro-pyridin-3-yl)-5,6-difluoro-benzoimidazol-1-yl]-cyclohexylacetic acid (200 mg, 0.46 mmol) in 5 ml thionylchloride to 80 C. for 4 h. The solvent was evaporated and the residue taken up in dichloromethane. 4-Amino-3-chloro-benzoic acid methyl ester (85 mg, 0.46 mmol) were added and the reaction mixture stirred at rt overnight. The crude product was worked up by addition of a solution of 1 M NaHCO3 and extraction of the aqueous layer with dichloromethane. Organic layers were combined, dried over MgSO4 and evaporated to dryness. The residue was taken up in methanol (3 ml) and 1N NaOH (1 ml) added. The mixture was stirred at rt overnight, the solvent evaporated and the product isolated via preparative HPLC. MS (ES+): 560 (M+H).
With triethylamine; In dichloromethane; for 0.5h;Cooling with ice; Inert atmosphere;
9.1 3-Chloro-4-isocyanato-benzoic acid methyl ester; To an ice cold solution of triphosgene (59 mg, 200 mumol) in CH2Cl2 (1.5 ml) was added <strong>[84228-44-4]4-amino-3-chloro-benzoic acid methyl ester</strong> (100 mg, 540 mumol; [84228-44-4]) and a solution of Et3N (150 mul, 1.1 mmol) in CH2Cl2 (0.5 ml) under an argon atmosphere. The reaction mixture was stirred at ambient temperature for 30 min. The solvent was removed under reduced pressure. The residue was triturated with EtOAc, the solid was filtered off and the filtrate was evaporated to dryness under reduced pressure to give the title compound (111 mg, 520 mumol; 97%) as brown solid which was used in the next step without further purification. MS: m/e=228.9 [M+H+].
With iodine; silver nitrate; In ethanol; at 20℃; for 12h;
Preparation 149: 4-Amino-3-chloro-5-iodo-benzoic acid methyl ester; [1277] 4-Amino-3-chloro-benzoic acid methyl ester, iodine (21g, 82.7mmol) and silver nitrate (14g, 82.7mmol) were added to 1OmL of ethanol and reacted for 12 h at room temperature. After reaction, the solution was filtered through celite using ethanol. After filtration, 2OmL of sodium thiosulfate solution was added, and 2OmL of ethyl acetate was added. The organic layer was separated and dried over anhydrous magnesium sulfate. Ethyl acetate was thoroughly evaporated under reduced pressure. The product was solidified from hexane and dichloromethane, filtered and dried under nitrogen gas to give the title compound (8g, Yield 47%).[1278] NMR: 1H-NMR(CDCl3) delta 8.28(1H, d), 7.97(1H, d), 5.12(2H, s), 3.91 (3H, s) [1279] Mass(EI): 312(M++1)
With toluene-4-sulfonic acid; In toluene; for 12h;Reflux;
A mixture solution of <strong>[84228-44-4]4-amino-3-chloro-benzoic acid methyl ester</strong> (21 g, 113.2 mmol), 3- bromo-benzaldehyde (21 g, 113.2 mmol) and -toluenesulfonic acid (431mg, 2.2 mmol) in toluene (200 mL) was heated to reflux for 12 hours. Then the reaction mixture was cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 4-[(3-bromo-benzylidene)-amino] -3-chloro-benzoic acid methyl ester (39.8 g, quant.) as a pale-white solid: MS calcd. for Ci5HnBrClN02 353.62, obsd. (ESP) [(M+H)+] 351.9 & 353.9.
100%
toluene-4-sulfonic acid; In toluene; for 12h;Reflux;
A mixture solution of <strong>[84228-44-4]4-amino-3-chloro-benzoic acid methyl ester</strong> (21 g, 113.2 mmol), 3-bromo-benzaldehyde (21 g, 113.2 mmol) and p-toluenesulfonic acid (431 mg, 2.2 mmol) in toluene (200 mL) was heated to reflux for 12 hours. Then the reaction mixture was cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 4-[(3-bromo-benzylidene)-amino]-3-chloro-benzoic acid methyl ester (39.8 g, quant.) as a pale-white solid: MS calcd. for C15H11BrClNO2 353.62, obsd. (ESI+) [(M+H)+] 351.9 & 353.9.
Example 1128-Chloro-3 ,3 -dimethyl-2- (3 -morpholin-4-yl-phenyl)- 1 ,2,3 ,4-tetrahydro-quinoline-6- carboxylic acidTo a stirred solution of <strong>[2486-71-7]4-amino-3-chloro-benzoic acid</strong> (50 g, 291 mmol) in methanol (300 mL) was added thionyl chloride (45 mL, 605 mmol) dropewise at 0 C. Then the mixture solution was refluxed for 12 hours before cooling to room temperature. Then the reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (500 mL), washed with saturated aqueous sodium bicarbonate solution (3 x 100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford 4-amino-3-chloro- benzoic acid methyl ester (54 g, quant.) as a pale-white solid: LC/MS m/e calcd for C8H8C1N02 (M+H)+: 186.61, observed: 185.9.
100%
With thionyl chloride; at 0℃; for 12h;Reflux;
To a stirred solution of <strong>[2486-71-7]4-amino-3-chloro-benzoic acid</strong> (50 g, 291 mmol) in methanol (300 mL) was added thionyl chloride (45 mL, 605 mmol) dropewise at 0 C. Then the mixture solution was refluxed for 12 hours before cooling to room temperature. Then the reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (500 mL), washed with saturated aqueous sodium bicarbonate solution (3×100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford <strong>[2486-71-7]4-amino-3-chloro-benzoic acid</strong> methyl ester (54 g, quant.) as a pale-white solid: LC/MS m/e calcd for C8H8ClNO2 (M+H)+: 186.61, observed: 185.9.
97%
With sulfuric acid; at 0 - 80℃; for 6h;
To a stirring solution of <strong>[2486-71-7]4-amino-3-chlorobenzoic acid</strong> (2.00 g, 1 1.7 mmol) in methanol (20.0 mL) at 0 C was added concentrated H2S04 (2.00 mL) slowly. The resulting mixture was heated at 80 C for 6 h. The reaction mixture was cooled to rt and then concentrated under reduced pressure. The residue was diluted with sat. aq. NaHC03 and extracted with ethyl acetate (2 x 50 mL). The combined organics were washed with brine, dried over anhydrous Na2S04 and then concentrated in vacuo to afford methyl 4-amino-3-chlorobenzoate (2.10 g, 97%). -NMR (400 MHz, DMSO-c/6): delta ppm: 7.70 (d, J = 1.6 Hz, 1H), 7.58 (dd, J = 8.4, 2.0 Hz, 1H), 6.77 (d, J = 8.8 Hz, 1H), 6.24 (s, 2H), 3.73 (s, 3H)
With sulfuric acid;Dean-Stark;
<strong>[2486-71-7]4-amino-3-chlorobenzoic acid</strong> in Methanol (10 ml) was added H2SO4 c (0.3 ml) and the mixture refluxed in the presence of a deen stark for the week end. It was allowed to reach the room temperature, then diluted with dichloromethane. A saturated solution of NaHCO3 (12 ml) was added (12 ml) and transferred to a separatory funnel. The organic layer was washed with brine, dried with MgSO4 and the solvent was evaporated to dryness to get the desired ester.
To a stirring solution of <strong>[84228-44-4]methyl 4-amino-3-chlorobenzoate</strong> (1.00 g, 54.1 mmol) at 0 C was added sequentially concentrated HC1 (5.0 mL), water (3.0 mL) and NaN02 (440 mg, 64.86 mmol). The resulting mixture was stirred at 0 C for 1 h and then treated with acetic acid (7.0 mL), CuCl (27.0 mg, 0.27 mmol) and CuCl2 (460 mg, 3.40 mmol). Sulfur dioxide gas was then purged through the reaction mixture for 20 min. The resulting reaction mixture was stirred at 0 C for a further 1 h. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organics were washed with brine and dried over anhydrous Na2S04. The solvent was concentrated in vacuo. The crude material was purified over silica gel, eluting with 3% - 10% ethyl acetate in hexane to afford methyl 3-chloro-4- (chlorosulfonyl)benzoate (0.92 g, 64%). -NMR (400 MHz, CDC13): delta ppm: 8.27 (d, J = 2.0 Hz, 1H), 8.22 (d, J= 8.4 Hz, 1H), 8.1 1 (dd, J= 8.4, 2.0 Hz, 1H), 3.99 (s, 3H).
50%
To a suspension of <strong>[84228-44-4]methyl 4-amino-3-chlorobenzoate</strong> (33g, 146mmol, leq) in a 1 :1 mixture of concentrated HCl and water (140ml) cooling in an ice/ MeOH bath was added a solution of sodium nitrite (1 l.lg, lbetaOmmol, l.leq) in warm water (20ml) drop wise, ensuring that the reaction temperature was maintained below 5 0C. The mixture was filtered through a pad of Celite and the solids washed with water. The resulting filtrate was added portionwise to a mixture of sulphur dioxide (47g, 729mmol, 5eq) and copper (I) chloride (catalytic) in AcOH, maintaining the reaction temperature below 10 0C. The reaction mixture was extracted intoDCM (600ml), washed with water (600ml), dried over sodium sulphate, filtered and the solvent evaporated in vacuo. The residue was redissoved in DCM, washed with saturated sodium hydrogen carbonate, dried over sodium sulphate, filtered and evaporated in vacuo. The crude <n="217"/>material was purified by column chromatography eluting with 0-15% ethyl acetate: hexane then tritutated with hexane to yield the title compound (19.6g, 73.6mmol, 50%).[0464] 1HNMR (CDCl3): 4.0 (s, 3H), 8.1 (d, IH), 8.2 (d, IH), 8.25 (s, IH).
With potassium carbonate; In dichloromethane; at 20℃;
(a) Preparation of methyl 3-chloro-4-(furan-2-carboxamido)benzoate 3: To a mixture of <strong>[84228-44-4]methyl 4-amino-3-chlorobenzoate</strong> 2 (1.0 g, 5.38 mmol) and potassium carbonate (1.50 g, 11.0 mmol) in 10 mL of dichlorom ethane was added furan-2-carbonyl chloride 1 (0.70 g, 5.38 mmol) dropwise at ambient temperature. The reaction mixture was stirred at ambient temperature overnight. The solid was filtered off. The filtrate was concentrated. The residue was treated with methanol (10 mL) and stirred for 30 min. The solid was filtered to yield methyl 3-chloro-4-(furan-2-carboxamido)benzoate 3. Yield: 0.69 g, 45.8%. 1H- MR (300 Hz, CDC13) delta (ppm): 8.88 (brs, 1H), 8.68 (d, 1H), 8.11 (d, 1H), 8.00 (dd, 1H), 7.59 (m, 1H), 7.30 (dd, 1H), 6.60 (dd, 1H), 3.92 (s, 3H).
[0229] A mixture of <strong>[84228-44-4]methyl 4-amino-3-chlorobenzoate</strong> (881 mg, 4.75 mmol) and 1 ,2-oxathiane 2,2-dioxide (646 mg, 1 equiv) was heated at 100-1 10 C for 10 hrs. The mixture was cooled at room temperature and the desired product was obtained as brownish solid. Without work-up, the crude product was directly used for the following step.
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
