* 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 lithium borohydride In tetrahydrofuran at 60℃; for 16 h; Inert atmosphere
To a solution of methyl 4-bromo-2-methoxybenzoate (7.14g, 29mmol) in THF (35mL) was added a 2M solution of LiBH4 in THF (35mL, 70mmol, 2.4equiv). The solution was heated at 60°C for 16h. The reaction was then cooled to room temperature, and the solvent was removed under vacuum. The residue was stirred in a 5percent aqueous acetic acid solution (pH 6) for 15min. The aqueous layer was extracted with EtOAc (2×50mL), then the combined organic extracts were washed with brine, dried (MgSO4), filtered, and concentrated to yield the crude product as a tan oil. The oil was purified by flash chromatography using 5percent EtOAc in hexanes to provide 5.96g (94percent) of the product as a white solid: Rf 0.30 (10percent EtOAc/hexane); 1H NMR (CDCl3) δ 7.30 (d, 1H), 7.14 (d, 1H), 7.11 (s, 1H), 5.09 (t, 1H), 4.42 (d, 2H,), 3.77 (s, 3H).
Reference：
[1] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 1, p. 419 - 434
[2] Journal of Medicinal Chemistry, 1992, vol. 35, # 4, p. 734 - 740
[3] Patent: WO2006/60461, 2006, A1, . Location in patent: Page/Page column 197
[4] ChemMedChem, 2010, vol. 5, # 1, p. 65 - 78
[5] Patent: WO2012/66335, 2012, A1, . Location in patent: Page/Page column 54
2
[ 139102-34-4 ]
[ 22717-56-2 ]
Yield
Reaction Conditions
Operation in experiment
94%
With boron tribromide In dichloromethane at 0℃; for 1.83333 h;
A 1.0 M solution of boron tribromide (44.0 mL, 44 mmol) in DCM (20 mL) was cooled to 0C. Then, a solution of compound D (17.4 mmol) in DCM (120 mL) was slowly added over during 20 minutes. The reaction mixture was vigorously stirred for 1.5h at 0C. Water was added and the organic phase was separated. The aqueous phase was extracted with DCM and EtOAc. The combined organic phases were dried (MgSO4) and evaporated under reduced pressure to give a white powder. The crude solid was purified by flash chromatography (hexane:ethylacetate 9:1) to give the desired product E (yield 94percent).
Reference：
[1] European Journal of Organic Chemistry, 2017, vol. 2017, # 22, p. 3288 - 3300
[2] Tetrahedron, 2015, vol. 71, # 26-27, p. 4535 - 4542
3
[ 1666-28-0 ]
[ 74-88-4 ]
[ 139102-34-4 ]
Yield
Reaction Conditions
Operation in experiment
85%
With potassium carbonate In acetoneHeating / reflux
4-Bromo-2-hydroxybenzoic acid (1.00 g, 4.61 mmol) was dissolved in acetone (25 mL), and iodomethane (1.15 mL, 18.4 mmol) and K2CO3 (2.55 g, 18.4 mmol) were added. The reaction was heated at reflux overnight. Upon cooling to rt, the reaction mixture was filtered, and the filtrate was concentrated in vacuo. The crude material was purified by flash chromatography (Biotage.(R). column; 10percent EtOAc / Hexanes), yielding 0.955 g (85percent) of the desired product as a yellow oil. LC/MS m/z 245.0 (MH+); retention time 3.13 min. 1H NMR (400 MHz, CD2Cl2) δ 3.84 (s, 3H), 3.90 (s, 3H), 7.12-7.20 (m, 2H), 7.62 (d, IH).
Reference：
[1] Journal of Medicinal Chemistry, 1992, vol. 35, # 4, p. 734 - 740
[2] Patent: WO2006/44775, 2006, A2, . Location in patent: Page/Page column 17
[3] Patent: EP1445249, 2004, A1, . Location in patent: Page 138
4
[ 1666-28-0 ]
[ 77-78-1 ]
[ 139102-34-4 ]
Yield
Reaction Conditions
Operation in experiment
96.4%
Stage #1: With potassium carbonate In acetone for 1 h; Reflux; Large scale Stage #2: for 6.5 h; Reflux; Large scale
3.06 kg (22.12 mol) of potassium carbonate were initially charged in 3.6 1 of acetone and heated to reflux. To this suspension were added 1.2 kg of 4-bromo-2-hydroxy- benzoic acid (5.53 mol), suspended in 7.8 1 of acetone, and were rinsed in with 0.6 1 of acetone. The suspension was heated under reflux for 1 hour (vigorous evolution of gas).2.65 kg (21.01 mol) of dimethyl sulphate were then added over 4 hours while boiling. The mixture was subsequently stirred under reflux for 2.5 hours. The solvent was largely distilled oil (to the point of stirrability) and 12 1 of toluene were added and the residual acetone was then distilled off at 110° C. About 3 1 of distillate were distilled off, this being supplemented by addition of a further 3 1 of toluene to the mixture. The mixture was allowed to cool to 20° C. and 10.8of water were added and vigorously stirred in. The organic phase was separated off and the aqueous phase was extracted once more with 6.1 1 of toluene. The combined organic phases were washed with 3 1 of saturated sodium chloride solution and the toluene phase is concentrated to about 4 1. Determination of the content by evaporation of a portion resulted in a converted yield of 1.306 kg (96.4percent of theory). The solution was used directly in the subsequent stage. HPLC method A: RT about 11.9 mm. MS (Elpos): mlz=245 [M+H] ‘H NMR (400 MHz, CD2C12): ö=3.84 (s, 3H), 3.90 (s, 3H), 7.12-7.20 (m, 2H), 7.62 (d, 1H).
96.4%
Stage #1: With potassium carbonate In acetone for 1 h; Reflux; Large scale Stage #2: for 6.5 h; Reflux; Large scale
3.06 kg (22.12 mol) of potassium carbonate were initially charged in 3.6 1 of acetone and heated to reflux. To this suspension were added 1.2 kg of 4-bromo-2-hydroxy- benzoic acid (5.53 mol), suspended in 7.8 1 of acetone, and the latter was rinsed in with 0.6 1 of acetone. The suspension was heated under reflux for 1 hour (vigorous evolution of gas). 2.65 kg (21.01 mol) of dimethyl sulphate were then added over 4 hours while boiling. The mixture was subsequently stirred under reflux for 2.5 hours. The solvent was largely distilled oil (to the point of stirrability) and 12 1 of toluene were added and the residual acetone was then distilled off at 1100 C. About 3 1 of distillate were distilled off, this being supplemented by addition of a further 3 1 of toluene to the mixture. The mixture was allowed to cool to 20° C. and 10.8 1 of water were added and vigorously stirred in. The organic phase was separated off and the aqueous phase was extracted once more with 6.11 of toluene. The combined organic phases were washed with 3 1 of saturated sodium chloride solution and the toluene phase is concentrated to about 4 1. Determination of the content by evaporation of a portion resulted in a converted yield of 1.306 kg (96.4percent of theory). The solution was used directly in the subsequent stage. HPLC-Method A: RT ca. 11,9 mm. MS (Elpos): mlz=245 [M+H] ‘H NMR (400 MHz, CD2C12): ö=3.84 (s, 3H), 3.90 (s, 3H), 7.12-7.20 (m, 2H), 7.62 (d, 1H).
Reference：
[1] Journal of Medicinal Chemistry, 2012, vol. 55, # 7, p. 3228 - 3241
[2] ChemMedChem, 2010, vol. 5, # 1, p. 65 - 78
6
[ 67-56-1 ]
[ 72135-36-5 ]
[ 139102-34-4 ]
Reference：
[1] Patent: WO2017/143011, 2017, A1, . Location in patent: Paragraph 0467-0469
[2] Journal of Medicinal Chemistry, 2018, vol. 61, # 3, p. 666 - 680
7
[ 72135-36-5 ]
[ 74-88-4 ]
[ 139102-34-4 ]
Reference：
[1] Journal of Medicinal Chemistry, 2008, vol. 51, # 6, p. 1925 - 1944
8
[ 1666-28-0 ]
[ 139102-34-4 ]
Reference：
[1] Journal of Medicinal Chemistry, 2012, vol. 55, # 7, p. 3228 - 3241
9
[ 139102-34-4 ]
[ 43192-33-2 ]
Yield
Reaction Conditions
Operation in experiment
94.1%
With 1-methyl-piperazine; sodium bis(2-methoxyethoxy)aluminium dihydride In toluene at -8 - 0℃; for 1.5 h; Large scale
1.936 kg (6.22 mol) of a 65percent Red-Al solution in toluene were charged with 1.25 1 of toluene at -5° C. To this solution was added 0.66 kg (6.59 mol) of 1-methylpiperazine, which was rinsed in with 150 ml of toluene, keeping the temperature between -7 and -5° C. The mixture was then left to stir at 0° C. for 30 minutes. This solution was then added to a solution of 1.261 kg (5.147 mol) of methyl 4-bromo-2-methoxybenzoate (XV), dissolved in 41 of toluene, keeping the temperature at -8 to 0° C. After rinsing in twice with 0.7 1 of toluene, the mixture was then stirred at 0° C. for 1.5 hours. For the work-up, the solution was added to cold aqueous sulphuric acid at 0° C. (12.5 1 of water+1.4 kg of conc. sulphuric acid). The temperature was to increase to a maximum to 10° C. (slow addition). The pH was adjusted to pH 1, if necessary, by addition of further sulphuric acid. The organic phase was separated off and the aqueous phase was extracted with 7.6 1 of toluene. The combined organic phases were washed with 5.1 1 of water and then substantially concentrated and the residue taken up in 10 l of DMF. The solution was again concentrated to a volume of about 5 l. Determination of the content by evaporation of a portion resulted in a converted yield of 1.041 kg (94.1percent of theory). The solution was used directly in the subsequent stage. HPLC-Method A: RT ca. 12.1 min. MS (Elpos): m/z=162 [M+H]+ 1H-NMR (CDCl3, 400MHz): δ=3.93 (3H, s), 7.17 (2H, m), 7.68 (1H, d), 10.40 (1H, s)
94.1%
With 1-methyl-piperazine; sodium bis(2-methoxyethoxy)aluminium dihydride In toluene at -8 - 0℃; for 1.5 h; Large scale
1.936 kg (6.22 mol) of a 65percent Red-Al solution in toluene were charged with 1.25 l of toluene at -5° C. To this solution was added 0.66 kg (6.59 mol) of 1-methylpiperazine, which was rinsed in with 150 ml of toluene, keeping the temperature between -7 and -5° C. The mixture was then left to stir at 0° C. for 30 minutes. This solution was then added to a solution of 1.261 kg (5.147 mol) of methyl 4-bromo-2-methoxybenzoate (XV), dissolved in 4 l of toluene, keeping the temperature at -8 to 0° C. After rinsing in twice with 0.7 l of toluene, the mixture was then stirred at 0° C. for 1.5 hours. For the work-up, the solution was added to cold aqueous sulphuric acid at 0° C. (12.5 l of water+1.4 kg of conc. sulphuric acid). The temperature should increase at maximum to 10° C. (slow addition). The pH was adjusted to pH 1, if necessary, by addition of further sulphuric acid. The organic phase was separated off and the aqueous phase was extracted with 7.6 l of toluene. The combined organic phases were washed with 5.1 l of water and then substantially concentrated and the residue taken up in 10 l of DMF. The solution was again concentrated to a volume of about 5 l. Determination of the content by evaporation of a portion resulted in a converted yield of 1.041 kg (94.1percent of theory). The solution was used directly in the subsequent stage. HPLC method A: RT about 12.1 mm. MS (Elpos): mlz=162 [M+H]. 1H NMR (CDC13, 400MHz): ö=3.93 (3H, s), 7.17 (2H, m), 7.68 (1H, d), 10.40 (1H, s)
Reference：
[1] Patent: US2018/244668, 2018, A1, . Location in patent: Paragraph 0174; 0175; 0176; 0177
[2] Patent: US2018/244670, 2018, A1, . Location in patent: Paragraph 0178-0182
[3] Journal of Medicinal Chemistry, 1992, vol. 35, # 4, p. 734 - 740
[4] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 1, p. 419 - 434
[5] Patent: US2017/217957, 2017, A1, . Location in patent: Paragraph 0143-0146
10
[ 139102-34-4 ]
[ 72135-36-5 ]
Yield
Reaction Conditions
Operation in experiment
2.74 g
With methanol; lithium hydroxide In water at 20℃; for 3 h;
A mixture of Compound I (3.0 g), 2N aqueous lithium hydroxide solution (18 mL) and methanol (55 mL) was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and to the residue was added water, and the mixture was extracted with diisopropylether. The aqueous layer was acidified with 4N hydrochloric acid, and extracted with chloroform. The chloroform layer was dried over magnesium sulfate, and then concentrated under reduced pressure to give Compound II (2.74 g)
With lithium borohydride; In tetrahydrofuran; at 60℃; for 16h;Inert atmosphere;
To a solution of <strong>[139102-34-4]methyl 4-bromo-2-methoxybenzoate</strong> (7.14g, 29mmol) in THF (35mL) was added a 2M solution of LiBH4 in THF (35mL, 70mmol, 2.4equiv). The solution was heated at 60°C for 16h. The reaction was then cooled to room temperature, and the solvent was removed under vacuum. The residue was stirred in a 5percent aqueous acetic acid solution (pH 6) for 15min. The aqueous layer was extracted with EtOAc (2×50mL), then the combined organic extracts were washed with brine, dried (MgSO4), filtered, and concentrated to yield the crude product as a tan oil. The oil was purified by flash chromatography using 5percent EtOAc in hexanes to provide 5.96g (94percent) of the product as a white solid: Rf 0.30 (10percent EtOAc/hexane); 1H NMR (CDCl3) delta 7.30 (d, 1H), 7.14 (d, 1H), 7.11 (s, 1H), 5.09 (t, 1H), 4.42 (d, 2H,), 3.77 (s, 3H).
With lithium borohydride; In tetrahydrofuran; ethanol; at 20℃; for 20h;
Preparation of Example 389; Step i:; To <strong>[139102-34-4]methyl-4-bromo-2-methoxybenzoate</strong> (Aldrich) (1.0 g, 4.1 mmol) in THF(10 ml_), was added LiBH4 (0.13 g, 6.1 mmol). Ethanol (2 mL) was added dropwise. The resulting reaction mixture was stirred at room temperature for 20 h. 1 N NaOH was added, and the mixture was extracted with EtOAc. The organic layers were combined and washed with water and brine, then dried (MgSO4), filtered, and concentrated in vacuoXo provide the corresponfing benzyl alcohol (0.86 g, 4.0 mmol).
With lithium borohydride; ethanol; In tetrahydrofuran; for 18h;
L1BH4 (0.66 g) was added portion- wise to a solution of methyl 4-bromo-2- methoxybenzoate (5 g) in dry THF (50 mL) and EtOH (10 mL) was added. The reaction was stirred for 18h. The mixture was then poured into aq. NaOH (1M, 300 mL) and extracted with EtOAc. The organics were combined, washed with water then sat. brine before being dried (MgS04), and concentrated in vacuo to give the sub-title compound (4.4 g) as a gum; 1H NMR: 7.30 (d, 1H), 7.17-7.11 (m, 2H), 5.10 (t, 1H), 4.43 (d, 2H), 3.79 (s, 3H).
With potassium phosphate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; methanol; at 20 - 80℃; for 3h;
To a degassed solution of <strong>[139102-34-4]methyl 4-bromo-2-methoxybenzoate</strong> (0.70 g, 2.86 mmol) in 1,4-dioxane (10 mL) and MeOH (2.5 mL) at room temperature under nitrogen blanketing is added 4-chlorophenyl boronic acid (0.536 g, 3.43 mmol), Pd(dppf)Cl2 (0.233 g, 0.286 mmol) and K3PO4 (0.728 g, 3.43 mmol). The resulting suspension is heated to 80 C. and stirred for 3 hours after which the reaction is cooled to room temperature and filtered through Celite. The collected solids are washed with additional MeOH and the filtrate concentrated under reduced pressure. The crude material is purified over silica (hexanes:EtOAc gradient 6:1 to 4:1) to afford 0.614 g (78% yield) of the desired product as orange crystals. 1H NMR (400 MHz, CDCl3) delta ppm 7.89 (1H, d, J=8.0 Hz), 7.52-7.56 (2H, m), 7.44 (2H, d, J=8.7 Hz), 7.17 (1H, d, J=8.0 Hz), 7.12 (1H, d, J=1.6 Hz), 3.99 (3H, s), 3.92 (3H, s). HPLC-MS: m/z 277 [M+H]+
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 90℃; for 3h;Sealed tube; Inert atmosphere;
Step 1: Methyl 2-methoxy-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzoateTo a 100 mL round-bottomed flask equipped with a stir bar was added methyl 4- bromo-2-methoxybenzoate (1.79 g, 7.30 mmol), 4,4,4?,4?,5 ,5 ,5?,5?-octamethyl-2,2?- bi(1,3,2-dioxaborolane) (2.78 g, 10.9 mmol), PdCl2(dppf) (0.267 g, 0.365 mmol), and potassium acetate (2.15 g, 21.9 mmol) at ambient temperature. The flask was sealed witha septum, dioxane (36.5 ml) was added, and the atmosphere was purged with N2 (g). The reaction was then heated to 90 C with stirring for 3 h and cooled to room temperature. The reaction was concentrated, the residue was dissolved in EtOAc and washed with 1 M aq. HC1 and sat. aq. NaC1. The organics were dried (Na2504), filtered, and concentrated. The residue was purified by silica gel column chromatography (Teledyne ISCOCombiFlash Rf, gradient of 0% to 100% using solvent A/B=CH2C12/EtOAc over 15 column volumes, RediSep 5i02 80 g, loaded as DCM solution) to afford (methyl 2- methoxy-4-(4,4,5 ,5 -tetramethyl- 1,3 ,2-dioxaborolan-2-yl)benzoate (1 .87 g, 88 %) as a tan solid: ?H NMR (400 MHz, CDC13) oe 7.76 (d, J=7.7 Hz, 1 H), 7.42 (dd, J=7.7, 0.9 Hz, 1 H), 7.39 (s, 1 H), 3.96 (s, 3 H), 3.90 (s, 3 H), 1.36 (s, 12 H); HPLC: RT=1.284 mm(Waters Acquity BEH C,8 1.7 urn 2.0 x 50 mm, CH3CN/H20/0. 1% TFA, 1.5 mill gradient, wavelength=254 nm); MS (ES): mlz= 293 [M+1].
With potassium acetate;dichlorobis(triphenylphosphine)palladium[II]; In 1,4-dioxane;
Preparation 13 To a solution of <strong>[139102-34-4]methyl 4-bromo-2-methoxybenzoate</strong> (2.0 g) in 1,4-dioxane (40 ml) was added bis(pinacolato)diboron (2.07 g), dichlorobis(triphenylphosphine)palladium(II) (286 mg) and potassium acetate (2.4 g), and the mixture was stirred at 95 C. for 10 hours under nitrogen. The mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=3/1) to give methyl 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (2.0 g). (+)ESI-MS (m/z): 293 (M+H)+
With potassium acetate;palladium diacetate; In N,N-dimethyl-formamide; at 20 - 80℃; for 4.5h;
A mixture of bis(pinacolato)diboron (1.40 g, 5.51 mmol), methyl 4-bromo-2- methoxybenzoate (1.35 g, 5.51 mmol), palladium(II) acetate (0.04 g, 0.17 mmol), and KOAc (1.62 g, 16.5 mmol) in DMF (10 mL) was degassed with argon for 30 min at it. The mixture was then heated at 80C for 4 h. After the mixture was cooled to rt, N-(4-bromo-2-fluorophenyl)-6-fluoro-l,3- benzothiazol-2-amine (1.88 g, 5.51 mmol), tetrakis(triphe?ylrhohospliine)palladium(0) (0.19 g, 0.17 mmol), and saturated aqueous NaHCO3 (5 mL) were added. The mixture was heated at 85C overnight. The mixture was poured into ice water and extracted with EtOAc. The combined organic phases were dried over MgSO4, concentrated in vacuo, and purified by column chromatography (25% EtOAc in hexanes). This yielded 0.431 g (18%) of the title compound. LC/MS m/z 427.3 (MH+), retention time 3.82 min. 1H NMR (400 MHz, CD2Cl2) delta 3.81 (s, 3H), 4.03 (s, 3H), 7.19-7.23 (m, 3H), 7.41-7.64 (m, 4H), 7.82 (d, IH), 8.31 (t, IH).
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 20 - 90℃; for 3h;Inert atmosphere; Sealed tube;
To a 100 mL round-bottomed flask equipped with a stir bar was added <strong>[139102-34-4]methyl 4-bromo-2-methoxybenzoate</strong> (1.79 g, 7.30 mmol), 4,4,4?,4?,5,5,5?,5?-octamethyl-2,2?-bi(1,3,2-dioxaborolane) (2.78 g, 10.9 mmol), PdCl2(dppf) (0.267 g, 0.365 mmol), and potassium acetate (2.15 g, 21.9 mmol) at ambient temperature. The flask was sealed with a septum, dioxane (36.5 ml) was added, and the atmosphere was purged with N2 (g). The reaction was then heated to 90 C. with stirring for 3 h and cooled to room temperature. The reaction was concentrated, the residue was dissolved in EtOAc and washed with 1M aq. HCl and sat. aq. NaCl. The organics were dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel column chromatography (Teledyne ISCO CombiFlash Rf, gradient of 0% to 100% using solvent A/B=CH2Cl2/EtOAc over 15 column volumes, RediSep SiO2 80 g, loaded as DCM solution) to afford (methyl 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (1.87 g, 88%) as a tan solid: 1H NMR (400 MHz, CDCl3) delta 7.76 (d, J=7.7 Hz, 1H), 7.42 (dd, J=0.7, 0.9 Hz, 1H), 7.39 (s, 1H), 3.96 (s, 3H), 3.90 (s, 3H), 1.36 (s, 12H); HPLC: RT=1.284 min (Waters Acquity BEH C18 1.7 um 2.0×50 mm, CH3CN/H2O/0.1% TFA, 1.5 min gradient, wavelength=254 nm); MS (ES): m/z=293 [M+1]+.
With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; toluene; for 3h;Heating / reflux;
To a solution of <strong>[139102-34-4]methyl 4-bromo-2-methoxybenzoate</strong> (0.95 g, 3.9 mmol) and 4- nitrophenylboronic acid (1.29 g, 7.75 mmol) in toluene (10 mL) was added Na2CO3 (1.85 g, 17.4 mmol), l,r-bis(diphenylphospMno)ferrocenepalladium(IT) chloride complex with dichloromethane (0.06 g, 0.08 mmol), 1,4-dioxane (5 mL), and water (5 mL). The mixture was heated at reflux for 3 h and then allowed to cool to it. The mixture was diluted with EtOAc and water, and the organic layer was isolated, dried over MgSO4, and concentrated in vacuo. The material was purified by column chromatography (25% EtOAc in hexanes), yielding 0.675 g (61%) of the title compound. LC/MS m/z 287.9 (MH+); retention time 3.14 min.
With copper(l) iodide; triethylamine;bis-triphenylphosphine-palladium(II) chloride; at 100℃; for 16h;
Intermediate 25; Preparation of 4-(3,3-dimethylbut-1-ynyl)-2-methoxybenzoic acid; Methyl 2-methoxy-4-(3,3-dimethylbut-1-ynyl)benzoate A mixture of <strong>[139102-34-4]methyl 4-bromo-2-methoxybenzoate</strong> (1.2 g, 0.0049 mol), copper(I) iodide (0.093 g, 0.00049 mol), 3,3-dimethyl-1-butyne (0.70 mL, 0.0059 mol) and bis(triphenylphosphine)palladium(II) chloride (0.34 g, 0.00049 mol) in Et3N (10 mL) was heated at 100 C. in a 50 mL sealed reaction vessel for 16 hours. After cooling, the mixture was filtered through Celite and the filter cake was washed repeatedly with ethyl acetate. The filtrate was concentrated under vacuum and the residue was purified by column chromatography on silica gel to give a viscous oil (1.10 g, 91%).
[00197] Step 1: A mixture of <strong>[139102-34-4]methyl 4-bromo-2-methoxybenzoate</strong> (2.66 g, 10.85 mmol), 28% ammonium hydroxide (25 mL, 642 mmol) and ammonium chloride (2.0 g, 37.4 mmol) was stirred at RT for 20 min and then at 50 0C. Once the material converted forms to an oil (ca. 20 min), the mixture was cooled to RT and more ammonium hydroxide (25 mL, 642 mmol) and ammonium chloride (2.0 g, 37.4 mmol) were added. Upon completion of addition, the reaction mixture was stirred at RT overnight. After this time, the mixture was heated to reflux in an open flask to drive off the excess ammonia and then cooled to RT. The mixture was neutralized with cone. HCl and then extracted with ethyl acetate. The extract was dried (Na2SO4) and then concentrated to give a residue. The residue was purified by flash chromatography (40 g silica gel cartridge; EtO Ac/Hex) to give 4-bromo-2- methoxybenzamide (510 mg, 2.22 mmol, 20 % yield) as a white solid.
With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1-methyl-pyrrolidin-2-one; at 40 - 110℃; for 16h;
Reaction under nitrogen flow. 1 -Methyl-2-pyrrolidinone (32 ml) was added to a mixture of <strong>[139102-34-4]4-bromo-2-methoxybenzoic acid methyl ester</strong> (98%) (0.032 mol) and morpholine (0.038 mol). The mixture was stirred until complete dissolution. Then Cs2CO3 (0.048 mol) was added. The reaction mixture was heated to 4O0C. Then Pd2(dba)3 (0.00032 mol) and BINAP (98%) (0.00096 mol) were added. Then the reaction mixture was stirred for 16 hours at 110C. The reaction mixture was cooled to room temperature and then poured out in water (200ml). Then the reaction mixture was extracted with ethyl acetate (2 cycles). The solvent of the separated organic layer was evaporated. The residue was taken up in CH2Cl2, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2C12/CH3OH from 100/0 to 98/2). The product fractions were collected and the solvent was evaporated. The residue was crystallized from DIPE. The precipitate was filtered off and dried (vacuum), yielding 3.8 g of intermediate (54).
With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1-methyl-pyrrolidin-2-one; at 40 - 110℃;
A solution of <strong>[139102-34-4]4-bromo-2-methoxybenzoic acid methyl ester</strong> (0.1 mol) and tetrahydro- 2H"-pyran-4-amine (0.3 mol) in 1 -methyl-2-pyrrolidinone (800 ml) was stirred at 400C. Cs2CO3 (0.2 mol) was added. The reaction mixture was stirred for 5 minutes. Pd2(dba)3 (0.002 mol) and BINAP (0.003 mol) were added. The reaction solution was degassed by applying alternating nitrogen atmosphere and vacuum. The reaction mixture was stirred overnight at 110C. The 1 -methyl-2-pyrrolidinone solvent was evaporated. The residue was purified by high-performance liquid chromatography. The product fractions were collected and the solvent was evaporated, yielding 13 g of intermediate (29).
Reaction under nitrogen flow. 1 -Methyl-2-pyrrolidinone (40 ml) was added to a mixture of <strong>[139102-34-4]4-bromo-2-methoxybenzoic acid methyl ester</strong> (0.040 mol) and l-(tert- butyloxycarbonyl)piperazine (0.048 mol). The mixture was stirred until complete dissolution. Then Cs2CO3 (0.06 mol) was added. The reaction mixture was heated to 4O0C. Then Pd2(dba)3 (0.0004 mol) and 98% BINAP (0.0012 mol) were added. Then the reaction mixture was stirred vigorously for 16 hours at 1100C. The reaction mixture was cooled to room temperature and then poured out in water (200 ml). Then the <n="32"/>reaction mixture was extracted with ethyl acetate (2 cycles). The solvent of the separated organic layer was evaporated. The residue was taken up in CH2Cl2. Then the mixture was dried, filtered and the CH2Cl2 was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2C12/CH3OH from 100/0 to 98/2). The product fractions were collected and the solvent was evaporated. The residue was recrystallized from DIPE. The precipitate was filtered off and dried (vacuum), yielding 8 g of intermediate (43).
With potassium phosphate;2?-(dimethylamino)-2-biphenylyl-palladium(II)chloride dinorbornylphosphine complex; at 100℃; for 18h;
Example 14; N-Cyclopropyl-2-methoxy-4-{4-[3-(1H-pyrazol-4-yl)pyrrolidine-1-carbonyl]-3,4-dihydro-2H-quinoxalin-1-yl}benzamide (Example No. 78); 14.1: 4-(3-Methoxy-4-(methoxycarbonyl)phenyl)-3,4-dihydro-2H-quinoxaline-1-carboxylic Acid Tert-Butyl Ester; 0.64 g of 3,4-dihydro-2H-quinoxaline-1-carboxylic acid tert-butyl ester, 1.44 g of potassium phosphate and 0.15 g of Solvias I catalyst (Palladium, [bis(bicyclo[2.2.1]hept-2-yl)phosphine]chloro[2'-(dimethylamino-kappaN)[1,1'-biphenyl]-2-yl-kappaC] (9Cl)) are introduced into a 50 ml three-necked flask. The mixture is degassed and placed under a nitrogen atmosphere. 1 g of <strong>[139102-34-4]methyl 4-bromo-2-methoxybenzoate</strong> and 14 ml of dimethoxyethane are added. The reaction medium is again degassed, then placed under a nitrogen atmosphere and stirred at 100 C. for 18 h. It is poured onto ice-cold water, neutralized by addition of solid ammonium chloride and extracted with ethyl acetate. The organic phase is washed with water and a saturated sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on a silica column eluted with a heptane/ethyl acetate 96/4 to 60/40 gradient. 1.1 g of 4-(3-methoxy-4-(methoxycarbonyl)phenyl)-3,4-dihydro-2H-quinoxaline-1-carboxylic acid tert-butyl ester are obtained in the form of a colorless oil.M+H+=399
(-)-1-[(4chlorophenyl)-phenylmethyl]piperazine[ No CAS ]
[ 139102-34-4 ]
[ 1228780-41-3 ]
Yield
Reaction Conditions
Operation in experiment
With potassium phosphate;tris-(dibenzylideneacetone)dipalladium(0); johnphos; In 1,2-dimethoxyethane; at 80℃; for 24h;
EXAMPLE 17A methyl 4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin- 1 -yl)-2-methoxybenzoate; Methyl 4-bromo-2-methoxybenzoic acid (700 mg), EXAMPLE IB (983 mg), K3PO4 (909 mg), tris(dibenzylideneacetone)dipalladium(0) (78 mg), and 2-(di-t- butylphosphino)biphenyl (102 mg) were stirred in 1 ,2-dimethoxyethane (10 mL) at 8O0C for 24 hours. The reaction mixture was chromatographed on silica gel with 20-50% ethyl acetate/hexanes.
With potassium phosphate;tris-(dibenzylideneacetone)dipalladium(0); johnphos; In 1,2-dimethoxyethane; at 80℃; for 24h;
Example 25A methyl 4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-methoxybenzoate Methyl 4-bromo-2-methoxybenzoate (700 mg), EXAMPLE 7B (983 mg), K3PO4 (909 mg), tris(dibenzylideneacetone)dipalladium(0) (78 mg), and 2-(di-t-butylphosphino)biphenyl (102 mg) were stirred in 1,2-dimethoxyethane (10 mL) at 80 C. for 24 hours. The reaction mixture was chromatographed on silica gel with 20-50% ethyl acetate/hexanes.
Preparation 29: methyl 4-(3-cyclopentylacryloyl)-2-methoxybenzoate; Step 1 : methyl 4-(1-ethoxyvinyl)-2-methoxybenzoate; A solution of <strong>[139102-34-4]methyl 4-bromo-2-methoxybenzoate</strong> (5.0 g, 20 mmol), tributyl(1- ethoxyvinyl)stannane (8.10 g, 22.4 mmol), bis(triphenylphosphine)palladium Il chloride (0.438 g, 0.612 mmol), and N,N-dimethylformamide (50 ml_), was stirred at 80 0C under nitrogen for 1 h. The reaction mixture was cooled to room temperature, diluted with diethyl ether (50 ml_) and treated with a 10% aqueous potassium fluoride (50 mL). After stirring at room temperature for 1 h, the mixture was filtered. The solid was washed with diethyl ether. The filtrate was extracted 2 times with water (80 mL). The organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography eluting with 30% ethyl acetate / heptane to yield the title compound (3.38 g, 70%) as a clear oil. 1 H NMR (400 MHz, DMSO-d6) delta ppm 1.44 (3 H, t, J=7.0 Hz), 3.78 (3 H, s), 3.80 (3 H, s) 3.91 (2 H, q), 4.30 (1 H, d, J=2.9 Hz), 4.74 (1 H, d, J=2.7 Hz), 7.24 (2 H, m), 7.79 (1 H, d, J=8.4 Hz). Step 2: methyl 4-acetyl-2-methoxybeetazoate
With copper(l) iodide; triethylamine;tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; at 100℃; for 6h;Inert atmosphere of nitrogen;
4-(te/t-Butyldimethylsiloxy)butyne (3.7 g) and <strong>[139102-34-4]methyl 4-bromo-2-methoxybenzoate</strong> (4.0 g) were dissolved in THF (30 mL purged with N2) and CuI (0.61 g), Pd(PPh3)4 (1.8 g) and triethylamine (4.1 mL) were added. The mixture was then heated to 1000C for 6 h, cooled and diluted with EtOAc (10 mL). The solution was washed with 0.2N HCl (2 x 10 mL), sat. NaHCO3 (2 x 10 mL) and brine. The organic phase was dried and concentrated by evaporation. The resulting residue was purified by FCC to give the subtitle compound as colourless oil (5.6 g); 1H NMR: 7.61 (IH, d), 7.08 (IH, d), 6.99 (IH, dd), 3.80-3.75 (8H, m), 2.63 (2H, t), 0.87 (9H, s), 0.06 (6H, s); ESI m/z 349 (M+l).
With potassium carbonate;copper(l) iodide; N,N`-dimethylethylenediamine; In toluene; for 8h;Reflux;
To a mixture of <strong>[139102-34-4]methyl 4-bromo-2-methoxybenzoate</strong> (5.8 mL), (R)-4-methyloxazolidin-2-one (2 g) described in Preparation Example 25, potassium carbonate (2.8 g) and copper (I) iodide (760 mg) were added toluene (10 mL) and N,N'-dimethylethylenediamine (880 muL), and the mixture was refluxed for 8 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give methyl (R)-2-methoxy-4-(4-methyl-2-oxooxazolidin-3-yl)benzoate (2.1 g). Methyl (R)-2-methoxy-4-(4-methyl-2-oxooxazolidin-3-yl)benzoate (2.1 g) was dissolved in methanol (8 mL) and tetrahydrofuran (8 mL), 1N aqueous sodium hydroxide solution (16 mL) was added, and the mixture was stirred at room temperature for 3 hr. 1N hydrochloric acid (16 mL) was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated. The title compound (2.2 g) was obtained.
With palladium diacetate; caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100℃; for 15h;Inert atmosphere;
General procedure for coupling reaction: An oven-dried resealable Schlenk tube were charged with Pd(OAc)2 (6.7 mg, 0.03 mmol), Xantphos (34.7 mg, 0.06 mmol), 2-methylpropane-2-sulfinamide (145 mg, 1.2 mmol) and Cs2CO3 (650 mg, 2.0 mmol). The Schlenk tube was evacuated and back-filled with argon. 4-bromo-2-methylbenzonitrile (196 mg, 1.0 mmol) and dioxane (3 ml) were added and the Schlenk tube was then sealed with a Teflon screw cap and placed in a preheated oil bath at 100oC for 15 h. After cooling of the reaction mixture to room temperature, water was added and the reaction mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The product was purified by flash chromatography. Yield: 228 mg, 97 % [table-1, entry-5].
A -[1 -Cyclopropylcarbonyl)-3( ?S)^yrrolidinyl]methyl}-3-methyloxy-A -methyl-4- biphenylcarboxamide(a) 3-(Methyloxy)-4-biphenylcarboxylic acidMethyl 4-bromo-2-(methyloxy)benzoate ( 845 mg, 3.45 mmol) was dissolved in DMF and the solution sparged with N2 for 5 minutes. Next, Pd(PPh3)4 (398 mg, 0.345 mmol) was added and the suspension sparged with N2 for an additional 10 minutes. Phenylboronic acid (589 mg, 4.83 mmol) and Na2C03 (731 mg, 6.9 mmol), dissolved in water, were added to the reaction and the suspension allowed to stir for 3d at 80 C. After cooling to room temperature the reaction was diluted with water, brine (50 mL) and the product extracted with ethyl acetate. The organic extracts were filtered through a plug of celite and concentrated under vacuum to a yellow oil. The oil was dissolved in equal parts THF/water and sodium hydroxide (1.8 mL, 50%) was added to hydrolyze the methyl ester. After stirring for 18 h the reaction was diluted with brine and the pH adjusted to 2. The product was extracted with ethyl acetate, the combined organic extracts were dried over MgS04, filtered, concentrated under vacuum and dried under hi-vacuum to afford the titled compound as a brown oil. LCMS m/z 227 (M-H).
(+)-3-benzyloxymethyl-1,2-thiazolidine 1,1-dioxide[ No CAS ]
[ 139102-34-4 ]
[ 1346123-14-5 ]
Yield
Reaction Conditions
Operation in experiment
380 mg
With copper(l) iodide; potassium carbonate; potassium iodide; N,N`-dimethylethylenediamine; In toluene; for 8h;Reflux;
[0174] Preparation Example 12: Preparation of methyl (S)-4-(3-benzyloxymethyl-1,1-dioxo-1lambda6-isothiazolidin-2-yl)-2-methoxybenzoate[0175][0176] To a mixture of <strong>[139102-34-4]methyl 4-bromo-2-methoxybenzoate</strong> (245 mg), (S)-3-benzyloxymethylisothiazolidine 1,1-dioxide(241 mg) described in Preparation Example 1, potassium carbonate (276 mg), potassium iodide (166 mg) and copper(I) iodide (95 mg) were added toluene (3 mL) and N,N?-dimethylethylenediamine (110 mL), and the mixture was stirredwith heating under reflux for 8 hr. The reaction mixture was cooled, water was added, and the mixture was extractedwith ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtainedresidue was purified by column chromatography (hexane:ethyl acetate) to give the title compound (380 mg).MS(ESI)m/z:406(M+H)+.
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 5h;Inert atmosphere;
11 A. 4-(3-Methoxy-4-methoxycarbonyl-henyl)-36-dihydro-2H-yridine-1 -carboxylic acid tert-butyl esterA solution of 4-bromo-2-methoxy-benzoic acid methyl ester (4.0 g, 16.5 mmol), 1-Boc- piperidine-4-boronic acid pinacol ester (5.1 g, 16.5 mmol) and K2C03 (6.6 g, 49.5mmol) in DMF (25 mL) was degassed with nitrogen for 15 minutes. PdCI2(dppf).DCM(1 .0 g, 0.6 mmol) was added at room temperature then the mixture was heated to90C and stirring continued for 5 hours. Water (100 mL) was added and the mixtureextracted with EtOAc (2 x 50 mL) then the combined organic extracts were washedwith brine (50 mL), dried (Na2504) and evaporated under reduced pressure. Theresidue was purified by column chromatography on neutral silica gel using 10-15% EtOAc/hexanes as the eluent to give the title compound (5.0 g, 87%).
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