* 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 copper(l) iodide; TPGS-450-M; caesium carbonate In water at 20℃; for 12 h; Inert atmosphere; Green chemistry
General procedure: A two-neck round bottom flask was charged with a magnetic stirrer, evacuated and backfilled with nitrogen. Substituted 2-halobenzoic acid (1, 0.5 mmol) and amidine hydrochloride (2, 0.75 mmol) or bis(guanidine) sulphate (2, 0.38 mmol) in 2 wt percent TPGS-750-M (3 mL) were added under nitrogen atmosphere. After a 10-min stirring, Cs2CO3 (1 mmol, 326 mg) was added to the flask. 15 min later, CuI (0.1 mmol, 19 mg) was added to the flask. The mixture was allowed to stir under nitrogen atmosphere at the shown temperature for 12 h (see Table 3 in text). After completion of the reaction, the mixture was extracted with EtOAc (1 mL), and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using petroleum ether/ethyl acetate (3:1 to 1:1) as eluent to provide the desired product.
Reference：
[1] Journal of Organic Chemistry, 2010, vol. 75, # 10, p. 3311 - 3316
3
[ 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).
Compound 17-2 (0420) Compound 17-1 (5.0 g, 21.23 mmol) was added to BH3/THF (1 M, 85 mL) under nitrogen atmosphere at 10° C. After addition, the mixture was stirred at room temperature overnight, quenched with methanol (30 mL) at 0° C. and concentrated to dryness. The residue was dissolved in methanol (100 mL) and concentrated to dryness again. This operation was repeated twice to afford 17-2 as a white solid (4.7 g, quantitative yield).
98%
Stage #1: With borane-THF In tetrahydrofuran at 0 - 20℃; Inert atmosphere Stage #2: With hydrogenchloride In tetrahydrofuran; water at 0℃; for 1 h;
B.l. (2-bromo-5-chloro-phenyl)-methanol:Starting from 2-bromo-5-chlorobenzoic acid (158.0 g; commercial) and proceeding in analogy to Procedure I, the title compound was obtained, without additional purification, as a white solid (146.0 g; 98percent yield).1H NMR (d6-DMSO) δ: 7.58 (d, J = 8.5 Hz, 1H); 7.52-7.49 (d, J = 2.8 Hz, 1H); 7.26 (dd, J = 8.5, 2.8 Hz, 1H); 5.56 (t, J = 5.7 Hz, 1H); 4.47 (d, J = 5.7 Hz, 2H). Procedure I (reduction of carboxylic acid):A solution of the acid (1.0 mmol; 1.0 eq.) in dry THF (4 mL), under inert atmosphere (N2), is treated with a solution of borane-THF complex (IM in THF; 1.5 eq.) at 0°C. The reaction mixture is stirred at rt and monitored by LC-MS. Upon reaction completion, the reaction mixture is poured into an aq. 2N HC1 solution at 0°C. It is further stirred at 0°C for 1 h and THF is removed under reduced pressure. The obtained aq. layer is extracted with EA (3x) and the combined org. layers are washed with IN NaOH, water and brine, dried over Na2S04, filtered and concentrated under reduced pressure. Purification of the residue gives the desired product.
88%
Stage #1: With borane-THF In tetrahydrofuran at 0 - 20℃; Stage #2: With methanol In tetrahydrofuran
To a solution of 2-bromo-5-chlorobenzoic acid (5.49 g, 23.3 mmol) in anhydrous THF (70 mL) under nitrogen was added dropwise a BH3 THF solution (1.0 M, 55 mL) at 0° C. and the reaction mixture was stirred overnight at room temperature. Then the mixture was cooled on an ice bath and MeOH (20 mL) was added dropwise to decompose excess BH3. The resulting mixture was stirred until no bubble was released and then 10percent NaOH (10 mL) was added. The mixture was concentrated and the residue was mixed with water (200 mL) and extracted with EtOAc. The residue from rotary evaporation was purified by silica gel column chromatography (5:1 hexane/EtOAc) to give 2-bromo-5-chlorobenzyl alcohol as a white solid (4.58 g, 88percent): 1H NMR (300 MHz, DMSO-d6): δ (ppm) 7.57 (d, J=8.7 Hz, 1H), 7.50-7.49 (m, 1H), 7.28-7.24 (m, 1H), 5.59 (t, J=6.0 Hz, 1H), 4.46 (d, J=6.0 Hz, 2H).
88%
With borane-THF In tetrahydrofuran at 0 - 20℃;
To a solution of 2-bromo-5-chlorobenzoic acid (5.49 g, 23.3 mmol) in anhydrous THF (70 mL) under nitrogen was added dropwise a BH3 THF solution (1.0 M, 55 mL) at 0° C. and the reaction mixture was stirred overnight at room temperature. Then the mixture was cooled on an ice bath and MeOH (20 mL) was added dropwise to decompose excess BH3. The resulting mixture was stirred until no bubble was released and then 10percent NaOH (10 mL) was added. The mixture was concentrated and the residue was mixed with water (200 mL) and extracted with EtOAc. The residue from rotary evaporation was purified by silica gel column chromatography (5:1 hexane/EtOAc) to give 2-bromo-5-chlorobenzyl alcohol as a white solid (4.58 g, 88percent): 1H NMR (300 MHz, DMSO-d6): δ (ppm) 7.57 (d, J=8.7 Hz, 1H), 7.50-7.49 (m, 1H), 7.28-7.24 (m, 1H), 5.59 (t, J=6.0 Hz, 1H), 4.46 (d, J=6.0 Hz, 2H).
23.2 g
With borane-THF In tetrahydrofuran at 0 - 20℃; for 16 h; Inert atmosphere
Step 1 : Preparation of (2-bromo-5-chloro-phenyl)methanol (A) A solution of borane-tetrahydrofuran complex in THF (0.15 L, 1.5 eq) was added dropwise to a solution of 2-bromo-5-chlorobenzoic acid (24 g) in anhydrous tetrahydrofuran (0.24 L) at 0°C and under argon atmosphere. The reaction mixture was stirred at room temperature for 16 h, before being slowly poured onto 0.10 L of a 2N aqueous solution of hydrogen chloride at 0°C. The mixture was stirred for 15 minutes and the volatiles were removed under reduced pressure. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with a IN aqueous solution of sodium hydroxide and then water. After drying over sodium sulfate, filtration and concentration under reduced pressure, the crude product was purified by column chromatography; 23.2 g; M.p. 79-80 °C.
23.48 g
With borane-THF In tetrahydrofuran at 0 - 20℃; Inert atmosphere
A solution of the acid (1.0 mmol; 1.0 eq.) in dry THF (4 mL) in a round-bottomed flask, under inert atmosphere (N2), is treated with a solution of borane-THF complex (1M in THF; 1.5 eq.) at 0° C. The reaction mixture is stirred at rt and monitored by LC-MS. Upon reaction completion, the reaction mixture is concentrated under reduced pressureand diluted with EA and 1N HCl. The layers are separated and the aq. layer is extracted with EA (3×). The combined org. layers are washed with 1N HCl, 1M NaOH, water and brine, dried over MgSO4, filtered and concentrated under reduced pressure. Purification of the residue gives the desired product. S.1. (2-bromo-5-chloro-phenyl)-methanol Starting from 2-bromo-5-chlorobenzoic acid (25.0 g) and proceeding in analogy to Procedure AF, the title compound was obtained, without additional purification, as a white solid (23.48 g). 1H NMR (d6-DMSO) δ: 7.58 (d, J=8.5 Hz, 1H); 7.52-7.49 (d, J=2.8 Hz, 1H); 7.26 (dd, J=8.5, 2.8 Hz, 1H); 5.56 (t, J=5.7 Hz, 1H); 4.47 (d, J=5.7 Hz, 2H).
Reference：
[1] Patent: US9138427, 2015, B2, . Location in patent: Page/Page column 295
[2] Patent: WO2012/131588, 2012, A1, . Location in patent: Page/Page column 96; 108
[3] Chemical Communications, 2018, vol. 54, # 20, p. 2467 - 2470
[4] Journal of Medicinal Chemistry, 2006, vol. 49, # 15, p. 4447 - 4450
[5] Patent: US2007/265226, 2007, A1, . Location in patent: Page/Page column 58
[6] Patent: US2007/286822, 2007, A1, . Location in patent: Page/Page column 59
[7] Patent: US2007/293457, 2007, A1, . Location in patent: Page/Page column 39
[8] Journal of the American Chemical Society, 2011, vol. 133, # 20, p. 7916 - 7925
[9] Patent: WO2011/121555, 2011, A1, . Location in patent: Page/Page column 114-115
[10] Patent: WO2013/50591, 2013, A2, . Location in patent: Page/Page column 36; 37
[11] Patent: US2013/96119, 2013, A1, . Location in patent: Paragraph 0717; 0838; 0839
[12] Organic Letters, 2018, vol. 20, # 11, p. 3310 - 3313
[13] Patent: US2007/286822, 2007, A1, . Location in patent: Page/Page column 42-43
18
[ 21739-93-5 ]
[ 124-63-0 ]
[ 57381-37-0 ]
Reference：
[1] Patent: US5130318, 1992, A,
19
[ 21739-93-5 ]
[ 174265-12-4 ]
Reference：
[1] Journal of the American Chemical Society, 2011, vol. 133, # 20, p. 7916 - 7925
[2] Chemical Communications, 2018, vol. 54, # 20, p. 2467 - 2470
(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.
Compound 17-2 (0420) Compound 17-1 (5.0 g, 21.23 mmol) was added to BH3/THF (1 M, 85 mL) under nitrogen atmosphere at 10° C. After addition, the mixture was stirred at room temperature overnight, quenched with methanol (30 mL) at 0° C. and concentrated to dryness. The residue was dissolved in methanol (100 mL) and concentrated to dryness again. This operation was repeated twice to afford 17-2 as a white solid (4.7 g, quantitative yield).
98%
B.l. (2-bromo-5-chloro-phenyl)-methanol:Starting from 2-bromo-5-chlorobenzoic acid (158.0 g; commercial) and proceeding in analogy to Procedure I, the title compound was obtained, without additional purification, as a white solid (146.0 g; 98percent yield).1H NMR (d6-DMSO) delta: 7.58 (d, J = 8.5 Hz, 1H); 7.52-7.49 (d, J = 2.8 Hz, 1H); 7.26 (dd, J = 8.5, 2.8 Hz, 1H); 5.56 (t, J = 5.7 Hz, 1H); 4.47 (d, J = 5.7 Hz, 2H). Procedure I (reduction of carboxylic acid):A solution of the acid (1.0 mmol; 1.0 eq.) in dry THF (4 mL), under inert atmosphere (N2), is treated with a solution of borane-THF complex (IM in THF; 1.5 eq.) at 0°C. The reaction mixture is stirred at rt and monitored by LC-MS. Upon reaction completion, the reaction mixture is poured into an aq. 2N HC1 solution at 0°C. It is further stirred at 0°C for 1 h and THF is removed under reduced pressure. The obtained aq. layer is extracted with EA (3x) and the combined org. layers are washed with IN NaOH, water and brine, dried over Na2S04, filtered and concentrated under reduced pressure. Purification of the residue gives the desired product.
88%
To a solution of 2-bromo-5-chlorobenzoic acid (5.49 g, 23.3 mmol) in anhydrous THF (70 mL) under nitrogen was added dropwise a BH3 THF solution (1.0 M, 55 mL) at 0° C. and the reaction mixture was stirred overnight at room temperature. Then the mixture was cooled on an ice bath and MeOH (20 mL) was added dropwise to decompose excess BH3. The resulting mixture was stirred until no bubble was released and then 10percent NaOH (10 mL) was added. The mixture was concentrated and the residue was mixed with water (200 mL) and extracted with EtOAc. The residue from rotary evaporation was purified by silica gel column chromatography (5:1 hexane/EtOAc) to give 2-bromo-5-chlorobenzyl alcohol as a white solid (4.58 g, 88percent): 1H NMR (300 MHz, DMSO-d6): delta (ppm) 7.57 (d, J=8.7 Hz, 1H), 7.50-7.49 (m, 1H), 7.28-7.24 (m, 1H), 5.59 (t, J=6.0 Hz, 1H), 4.46 (d, J=6.0 Hz, 2H).
88%
With borane-THF; In tetrahydrofuran; at 0 - 20℃;
To a solution of 2-bromo-5-chlorobenzoic acid (5.49 g, 23.3 mmol) in anhydrous THF (70 mL) under nitrogen was added dropwise a BH3 THF solution (1.0 M, 55 mL) at 0° C. and the reaction mixture was stirred overnight at room temperature. Then the mixture was cooled on an ice bath and MeOH (20 mL) was added dropwise to decompose excess BH3. The resulting mixture was stirred until no bubble was released and then 10percent NaOH (10 mL) was added. The mixture was concentrated and the residue was mixed with water (200 mL) and extracted with EtOAc. The residue from rotary evaporation was purified by silica gel column chromatography (5:1 hexane/EtOAc) to give 2-bromo-5-chlorobenzyl alcohol as a white solid (4.58 g, 88percent): 1H NMR (300 MHz, DMSO-d6): delta (ppm) 7.57 (d, J=8.7 Hz, 1H), 7.50-7.49 (m, 1H), 7.28-7.24 (m, 1H), 5.59 (t, J=6.0 Hz, 1H), 4.46 (d, J=6.0 Hz, 2H).
To a solution of 1 (23.3 mmol) in anhydrous THF (70 mL) under nitrogen was added dropwise a BH3 THF solution (1.0 M, 55 mL, 55 mmol) at 0° C. and the reaction mixture was stirred overnight at room temperature. Then the mixture was cooled again with ice bath and MeOH (20 mL) was added dropwise to decompose excess BH3. The resulting mixture was stirred until no bubble was released and then 10percent NaOH (10 mL) was added. The mixture was concentrated and the residue was mixed with water (200 mL) and extracted with EtOAc. The residue from rotary evaporation was purified by flash column chromatography over silica gel to give 20.7 mmol of 3.
With borane-THF; In tetrahydrofuran; at 0 - 20℃;Inert atmosphere;
A solution of the acid (1.0 mmol; 1.0 eq.) in dry THF (4 mL) in a round-bottomed flask, under inert atmosphere (N2), is treated with a solution of borane-THF complex (IM in THF; 1.5 eq.) at 0°C. The reaction mixture is stirred at rt and monitored by LC-MS. Upon reaction completion, the reaction mixture is concentrated under reduced pressure and diluted with EA and IN HC1. The layers are separated and the aq. layer is extracted with EA (3x). The combined org. layers are washed with 1N HC1, l NaOH, water and brine, dried over MgS04, filtered and concentrated under reduced pressure. Purification of the residue gives the desired product. Starting from 2-bromo-5-chlorobenzoic acid (25.0 g) and proceeding in analogy to Procedure AF, the title compound was obtained, without additional purification, as a white solid (23.48 g). 1H NMR (d6-DMSO) delta: 7.58 (d, J = 8.5 Hz, 1H); 7.52-7.49 (d, J = 2.8 Hz, 1H); 7.26 (dd, J = 8.5, 2.8 Hz, 1H); 5.56 (t, J = 5.7 Hz, 1H); 4.47 (d, J = 5.7 Hz, 2H).
23.2 g
With borane-THF; In tetrahydrofuran; at 0 - 20℃; for 16h;Inert atmosphere;
Step 1 : Preparation of (2-bromo-5-chloro-phenyl)methanol (A) A solution of borane-tetrahydrofuran complex in THF (0.15 L, 1.5 eq) was added dropwise to a solution of 2-bromo-5-chlorobenzoic acid (24 g) in anhydrous tetrahydrofuran (0.24 L) at 0°C and under argon atmosphere. The reaction mixture was stirred at room temperature for 16 h, before being slowly poured onto 0.10 L of a 2N aqueous solution of hydrogen chloride at 0°C. The mixture was stirred for 15 minutes and the volatiles were removed under reduced pressure. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with a IN aqueous solution of sodium hydroxide and then water. After drying over sodium sulfate, filtration and concentration under reduced pressure, the crude product was purified by column chromatography; 23.2 g; M.p. 79-80 °C.
23.48 g
With borane-THF; In tetrahydrofuran; at 0 - 20℃;Inert atmosphere;
A solution of the acid (1.0 mmol; 1.0 eq.) in dry THF (4 mL) in a round-bottomed flask, under inert atmosphere (N2), is treated with a solution of borane-THF complex (1M in THF; 1.5 eq.) at 0° C. The reaction mixture is stirred at rt and monitored by LC-MS. Upon reaction completion, the reaction mixture is concentrated under reduced pressureand diluted with EA and 1N HCl. The layers are separated and the aq. layer is extracted with EA (3×). The combined org. layers are washed with 1N HCl, 1M NaOH, water and brine, dried over MgSO4, filtered and concentrated under reduced pressure. Purification of the residue gives the desired product.S.1. (2-bromo-5-chloro-phenyl)-methanol Starting from 2-bromo-5-chlorobenzoic acid (25.0 g) and proceeding in analogy to Procedure AF, the title compound was obtained, without additional purification, as a white solid (23.48 g). 1H NMR (d6-DMSO) delta: 7.58 (d, J=8.5 Hz, 1H); 7.52-7.49 (d, J=2.8 Hz, 1H); 7.26 (dd, J=8.5, 2.8 Hz, 1H); 5.56 (t, J=5.7 Hz, 1H); 4.47 (d, J=5.7 Hz, 2H).
To a solution of 1 (23.3 mmol) in anhydrous THF (70 mL) under nitrogen was added dropwise a BH3 THF solution (1.0 M, 55 mL, 55 mmol) at 0° C. and the reaction mixture was stirred overnight at room temperature. Then the mixture was cooled again with ice bath and MeOH (20 mL) was added dropwise to decompose excess BH3. The resulting mixture was stirred until no bubble was released and then 10percent NaOH (10 mL) was added. The mixture was concentrated and the residue was mixed with water (200 mL) and extracted with EtOAc. The residue from rotary evaporation was purified by flash column chromatography over silica gel to give 20.7 mmol of 3. 1.2.a 2-Bromo-5-chlorobenzyl Alcohol 1H NMR (300 MHz, DMSO-d6): delta 7.57 (d, J=8.7 Hz, 1H), 7.50-7.49 (m, 1H), 7.28-7.24 (m, 1H), 5.59 (t, J=6.0 Hz, 1H) and 4.46 (d, J=6.0 Hz, 2H) ppm.
(4-chloro-2-[2-(6-methyl-2-oxo-3-phenylmethanesulfonylamino-2<i>H</i>-pyridin-1-yl)-acetylamino]-methyl}-benzyl)-carbamic acid <i>tert</i>-butyl ester[ No CAS ]
A solution of <strong>[21739-93-5]2-bromo-5-chlorobenzoic acid</strong> in ethanol (10ml) and sulphuric acid (0. 5ml) was REFLUXED for 20 hours then cooled and evaporated. The residue was dissolved in diethyl ether/water and the organic layer dried (magnesium sulphate) and evaporated to give 516mg of light brown oil. 1H NMR (CDCl3) delta: 1.41 (3H, t), 4.40 (2H, q), 7.30 (1H, dd), 7.58, (1H, d), 7.65 (1H d).
With N-ethyl-N,N-diisopropylamine; HATU; In DMF (N,N-dimethyl-formamide); at 20℃; for 3h;
N,N-diisopropylethylamine (1.10 mL, 6.36 mmol) was added to a stirred solution of <strong>[21739-93-5]2-bromo-5-chlorobenzoic acid</strong> (3-1) (0.500 g, 2.12 mmol), N,O-dimethylhydroxylamine.HCl (0.310 g, 3.18 mmol), and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (1.21 g, 3.18 mmol) in N,N-dimethylformamide (8.5 mL) at ambient temperature. After 3 h, the reaction mixture was poured into water and extracted three times with ethyl acetate. The combined organic extracts were washed with saturated aqueous sodium bicarbonate, brine, dried (MgSO4) and concentrated in vacuo. Purification of the crude residue by flash chromatography on silica gel (gradient elution; 0-25% ethyl acetate/hexanes as eluent) gave 3-2 (0.56 g) as a colorless solid.
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).
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).
Step A. 2-bromo-5-chlorobenzoate Through a solution of <strong>[56961-26-3]2-bromo-chlorobenzoic acid</strong> 11 g, 46.7 mmol) in methanol (250 ml) 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 (CDCl3, 400MHz): delta7.78 (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)
With hydrogenchloride; In methanol;
Step A. 2-bromo-5-chlorobenzoate Through a solution of <strong>[56961-26-3]2-bromo-chlorobenzoic acid</strong> (11 g, 46.7 mmol) in methanol (250 ml) 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 (CDCl3, 400 MHz): delta 7.78 (d, 1H, J=2.6 Hz); 7.59 (d, 1H, J=12.81 Hz);7.30 (dd, 1H, J=8.6, 2.5 Hz); 3.94 (s, 3H)
EXAMPLE 213 5-Chloro-N-ethyl-2-(trimethylsilyl)benzamide <strong>[21739-93-5]2-Bromo-5-chlorobenzoic acid</strong> was converted to the acid chloride by the procedure of example b. The acid chloride was reacted with 70% aq ethylamine using General Method E1 to afford the amide. Purification by recrystallization from methylcyclohexane/ethyl acetate gave 4.69 g of 2-bromo-5-chloro-N-ethylbenzamide as a white solid in 75% yield. m.p. 98-99 C.
With pyridine; thionyl chloride; ammonia; In dichloromethane; chloroform;
(ii) Methanesulphonyl chloride (0.85 ml) was added to a solution of 2-bromo-5-chlorobenzoic acid (2.55 g) and pyridine (1.3 ml) in dichloromethane (5 ml) under an atmosphere of argon. The mixture was stirred for 1.5 hours and then gaseous ammonia was bubbled through for 5 minutes. Volatile material was removed by evaporation and the residue was suspended in chloroform (5 ml). Thionyl chloride (3 ml) was added and the mixture was heated under reflux for 20 hours. Volatile material was removed by evaporation and the residue was partitioned between dichloromethane (50 ml) and water (30 ml). The organic layer was separated, washed with water (30 ml) and dried (MgSO4). The solvent was removed by evaporation and the residue recrystallized from ethyl acetate/hexane (1:1 v/v) to give 2-bromo-5-chlorobenzonitrile (B) (1.64 g), m.p. 135-137 C.; NMR (CDCl3): 7.4(dd,1H), 7.6(d,1H), 7.65(d,1H).
The starting compound, m.p. 106-107 C, was prepared in analogy to the method described in Example 2 from <strong>[21739-93-5]2-bromo5-chloro-benzoic acid</strong> and 2,6-dihydroxy acetophenone via 3-hydroxy-4-acetyl-6-oxo-8-chloro-6H-dibenzo-[b,d]-pyran (m.p. 215-216 C).
Reference Example 8 To a suspension of <strong>[21739-93-5]2-bromo-5-chlorobenzoic acid</strong> (1.2g) in toluene (35ml) was added 3-trifluoromethoxyphenylacetonitrile (1.4g), followed by 60% sodium hydride (0.6g) and copper (I) bromide (0.09g). The reaction mixture was heated to reflux, under an inert atmosphere for 3.5 hours. After cooling to 70oC air was bubbled through the reaction mixture for 1 hour. The mixture was poured into water, the organic phase separated and the aqueous layer was washed with ether. The aqueous layer was then acidified to pH 2 with 2N hydrochloric acid and extracted with ethyl acetate. The combined ethyl acetate extracts were washed with brine, dried (MgSO4) and evaporated to yield 5-chloro-2-(3-trifluoromethoxybenzoyl)benzoic acid as a pale yellow solid (1.27g), NMR (DMSO d6) 7.6(2H,m), 7.65(2H,m), 7.8(2H,m), 7.9(1H,m), 13.7(1H,broad s).
To a solution of <strong>[21739-93-5]2-bromo-5-chlorobenzoic acid</strong> (2.35 g, 10.0 mmol) in tetrahydrofuran (THF) (15 mL) was added, a 1.6 M solution in hexane, n-butyllithium (20 mL, 32.0 mmol) slowly at-78C under nitrogen. After addition was complete the reaction mixture was kept on stirring at-78C for 3 h. Then a solution of 1-benzylpiperidin-4-one (3.78 g, 20.0 mmol) in THF (10 mL) was added slowly to the reaction mixture at-78C. After addition was complete the reaction temperature was raised to room temperature and the reaction mixture was kept on stirring at room temperature overnight. The reaction mixture was poured into a mixture of water (60 mL) and diethyl ether (60 mL), layers were separated. The aqueous layer was extracted with diethyl ether (2 x 20 mL). The aqueous layer was acidified with aqueous 6M hydrochloric acid (HCl) to pH 2 and boiled for 1 h, cooled to 0C, pH was adjusted to 10.0 by addition of aqueous sodium hydroxide (NaOH) (6M) and rapidly extracted with trichloromethane (CHCl3). The organic layer was washed with water, dried over sodium sulphate (Na2SO4), filtered and concentrated in vacuo to give the subtitled compound (1.22 g) and it was pure enough for the next step. 1H-NMR (CDCl3, 400 MHz): delta 7.85 (m, 1H) ; 7.65 (dd, J = 1.9, 8.2 Hz, 1H) ; 7.41-7.26-1.69 (m, 2H). APCI-MS: m/z 328 (MH+).
With copper(l) iodide; TPGS-450-M; caesium carbonate; In water; at 20℃; for 12h;Inert atmosphere; Green chemistry;
General procedure: A two-neck round bottom flask was charged with a magnetic stirrer, evacuated and backfilled with nitrogen. Substituted 2-halobenzoic acid (1, 0.5 mmol) and amidine hydrochloride (2, 0.75 mmol) or bis(guanidine) sulphate (2, 0.38 mmol) in 2 wt percent TPGS-750-M (3 mL) were added under nitrogen atmosphere. After a 10-min stirring, Cs2CO3 (1 mmol, 326 mg) was added to the flask. 15 min later, CuI (0.1 mmol, 19 mg) was added to the flask. The mixture was allowed to stir under nitrogen atmosphere at the shown temperature for 12 h (see Table 3 in text). After completion of the reaction, the mixture was extracted with EtOAc (1 mL), and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using petroleum ether/ethyl acetate (3:1 to 1:1) as eluent to provide the desired product.
With sodium; copper(I) bromide; In ethanol; for 3h;Reflux;
Sodium metal (138 mg, 6 mmol) was dissolved in 15 ml. of absolute ethanol. To this solution were added ethyl acetoacetate (555 mul_, 4 mmol), copper (I) bromide (286 mg, 2mmol) and <strong>[21739-93-5]2-bromo-5-chlorobenzoic acid</strong> (468 mg, 2 mmol). This mixture was heated at reflux for 3h, cooled at RT, and filtered through a celite pad. The solvent was removed in vacuum and the residue partitioned between 2N HCI and dichloromethane. The milky dichloromethane layer was separated and concentrated. The residue was adsorbed onto silica gel and purified by flash chromatography, eluting with dichloromethane-1 to 10% methanol (containing 10% acetic acid) to furnish 455 mg (94%) of 5-chloro-2-(2-ethoxy-2-oxoethyl)benzoic acid. ESI/APCI(-): 241 (M-H).
General procedure: A suspension of <strong>[3177-80-8]2-amino-3-methoxybenzoic acid</strong> (1.67 g, 10 mmol), 2-bromobenzoic acid derivative (11 mmol, 1.1 equiv), K2CO3 (2.77 g, 20 mmol, 2 equiv) and copper powder (0.125 g, 2 mmol, 0.2 equiv) was stirred in EtOH (20 mL) and heated to reflux for 1.5 h. The suspension was cooled to room temperature and H2O (20 mL) was added. The mixture was filtered on cellite to remove the copper. The filter bed was washed with H2O and the resulting solution was acidified with concentrated HCl to a pH of 2-3. The resulting suspension was stirred for 1 h at 10 C, the solid was filtered and washed with H2O. The product was recrystallized in EtOH/H2O and dried under vacuum.
General procedure: To a dried flask containing a magnetic stir bar under an atmosphere of dry argon was added 2-bromobenzoic acid (1.0 equiv) and dry THF (0.5 M). The solution was cooled to -78 C followed by drop-wise addition of n-BuLi (2.0 equiv, 2.5 M in hexane). The reaction mixture was stirred at -78 C for 30 min. Then the reaction mixture was drop-wise added with DMF (1.2 equiv), keep stirring for 3 - 4 hours, and quenched by saturated aqueous NH4Cl. The organic phase was extracted with EtOAc, washed with brine, dried over sodium sulfate, and concentrated in vacuo. The crude products were used directly for the next step without further purification.
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