* 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 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
[ 67-56-1 ]
[ 1666-28-0 ]
[ 22717-56-2 ]
Yield
Reaction Conditions
Operation in experiment
73%
at 0 - 65℃; for 16 h;
Step-1: Methyl 4-bromo-2-hydroxybenzoate (0246) (0247) 4-Bromo-2-hydroxybenzoic acid (10.0 g, 46.08 mmol, 1.0 equiv) and MeOH (50 mL) were placed in a 250-mL round-bottom flask. This was followed by the addition of sulfuric acid (20 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 16 h at 65° C. in an oil bath, then concentrated under vacuum. The residue was dissolved in EtOAc (300 mL) and washed with H2O (3×100 mL) and aq. 2N NaHCO3 (3×100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel chromatography (EtOAc/pet. ether, 1:20) to afford methyl 4-bromo-2-hydroxybenzoate as a light yellow solid (7.80 g, 73percent yield). MS: (ES, m/z): 231 [M+H]+.
58%
at 75℃; for 12 h;
(10) To a solution of 4-bromo-2-hydroxy benzoic acid (1 eq) in Methanol (0.2 M) at tt was added sulfuric acid (1 eq) . The dark red brown solution was heated to 75 for 12 h. LCMS confirms product. The rxtt was concentrated and crude residue was partitioned between EfOAe: water (1 : 1 }. The organic layer was washed wiih NaHCO.? faq), water and dried (MgSC ). After filtration, the organic layer was concentrated to give a tan solid (58percent).
14.2 g
at 70℃; Inert atmosphere; Cooling with ice
A) methyl 4-bromo-2-hydroxybenzoate To a solution of 4-bromo-2-hydroxybenzoic acid (15.0 g) in methanol (150 mL) was added dropwise thionyl chloride (10.1 mL) under ice-cooling, and the mixture was stirred overnight at 70°C under argon atmosphere. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title Compound (14.2 g) , XH NMR (300 MHz, DMSO-d6) δ 3.88 (3H, s) , 7.10-7.18 (1H, m) , 7.21-7.28 (1H, m) , 7.69 (1H, d, J.= 8.3 Hz), 10.65 (1H, s).
5.31 g
for 24 h; Reflux
2-hydroxy-4-bromobenzoic acid (5.0 g, 23.1 mmol) was dissolved in 20 mL of anhydrous methanol,Add 1.7mL sulfuric acid.The reaction solution was stirred and refluxed for 24 h.The reaction solution was added to ice water, the methanol was removed by concentration, the EA was extracted, the organic phase was washed with saturated NaHCO3 solution, dried over anhydrous sodium sulfate,Concentrated a total of reddish brown solid2-hydroxy-4-bromobenzoic acid methyl ester12, 5.31 g,Directly for the next step.
Stage #1: With sulfuric acid In methanol for 24 h; Heating / reflux
Reference Example 52 methyl 4-bromo-2-[[(dimethylamino)carbothioyl]oxy]benzoate 4-Bromosalicylic acid (15.5 g, 71 mmol) was dissolved in methanol (500 ml), and concentrated sulfuric acid (9.7 g, 99 mmol) was added thereto.. The reaction mixture was refluxed for 24 hrs, and the solvent was evaporated.. The residue was neutralized with 2 N aqueous sodium hydroxide solution and extracted with ethyl acetate.. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate.. The solvent was evaporated.. The residue was subjected to a silica gel column chromatography.. The fractions eluted with ethyl acetate-hexane (1:20, v/v) were collected and concentrated to give methyl 4-bromosalicylate (8.7 g, 52 percent)..
To a mixture of 4-bromo-2-hydroxybenzoic acid (5.0 g) in toluene (80 mL) -methanol (20 mL) was added dropwise 0.6 M(diazomethyl ) trimethylsilane (38 mL) under ice-cooling. The' reaction mixture was stirred at the same temperature for 2 hr. The reaction mixture was acidified with acetic acid (0.35 mL) , and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethylacetate/hexane) to give the title compound (4.83 g) .XH NMR (300 MHz, CDC13) δ 3.95 (3 H, s) , 7.02 (1 H, dd, J = 8.7, 1.9 Hz), 7.18 (1 H, d, J = 1.9 Hz), 7.68 (1 H, d, J = 8.3 Hz), 10.82 (1 H, s) .
methyl 4-bromo-2-(difluoromethoxy)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
23%
With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 60℃; for 66h;
Production Example 54 Mothyl 4-bromo-2-(difluoromethoxy)benzoate To a 70 ml dimethylformamide solution of 5.0 g (21.7 mmol) of <strong>[22717-56-2]methyl 4-bromo-2-hydroxybenzoate</strong>, 3.4 ml (32.6 mmol) of methyl chlorodifluoroacetate and 3.0 g (21.7 mmol) of potassium carbonate were added.. The mixture was stirred at 60C for 6 hours and at room temperature for 60 hours.. Then, water was added to the reaction mixture, and the mixture was extracted with ether.. The organic layer was washed with water and a saturated aqueous solution of sodium chloride.. The washed system was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure.. The residue was purified by silica gel column chromatography (hexane/ethyl acetate = 8/1) to obtain 1.4 g (23%) of the captioned compound.
Reference Example 52 methyl 4-bromo-2-[[(dimethylamino)carbothioyl]oxy]benzoate 4-Bromosalicylic acid (15.5 g, 71 mmol) was dissolved in methanol (500 ml), and concentrated sulfuric acid (9.7 g, 99 mmol) was added thereto.. The reaction mixture was refluxed for 24 hrs, and the solvent was evaporated.. The residue was neutralized with 2 N aqueous sodium hydroxide solution and extracted with ethyl acetate.. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate.. The solvent was evaporated.. The residue was subjected to a silica gel column chromatography.. The fractions eluted with ethyl acetate-hexane (1:20, v/v) were collected and concentrated to give methyl 4-bromosalicylate (8.7 g, 52 %)..
With sulfuric acid; In methanol; at 75℃; for 7h;
A solution of 4-bromo-2-hydroxybenzoic acid (1. Og) in methanol (10ml) was treated cautiously with conc. sulphuric acid (0. 5ml) then stirred at 75'under nitrogen for 7h. The mixture was concentrated under vacuum and the residue was partitioned between ethyl acetate (30ml) and water (30ml). The aqueous layer was re-extracted with ethyl acetate (30ml) and the combined organic extracts were washed with saturated aqueous sodium bicarbonate (2x50ml) and water (50ml). The dried (MgS04) extracts were concentrated under vacuum to give the title compound as a beige solid (0.7g). LCMS: Rt 3. 42min.
With 1,4-diaza-bicyclo[2.2.2]octane; In DMF (N,N-dimethyl-formamide); at 20℃; for 24h;
<strong>[22717-56-2]methyl 4-bromosalicylate</strong> (8.7 g, 37 mmol) and N,N-dimethylthiocarbamoyl chloride (6.0 g, 48 mmol) were dissolved in DMF (80 ml), and 1,4-diazabicyclo[2.2.2]octane (5.5 g, 49 mmol) was added thereto.. The reaction mixture was stirred at room temperature for 24 hrs.. The reaction mixture was combined with ethyl acetate and water.. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate.. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography.. The fractions eluted with ethyl acetate-hexane (1:4, v/v) were collected, concentrated and recrystallized from ethyl acetate-hexane to give the titled compound (10.6 g, 88 %) as white crystals. mp. 117.5-118.3 C1H-NMR (CDCl3) delta: 3.38 (3H, s), 3.45 (3H, s), 3.83 (3H, s), 7.31 (1H, d, J = 1.9 Hz), 7.45 (1H, dd, J = 1.9, 8.4 Hz), 7.86 (1H, d, J = 8.4 Hz). IR(KBr): 2947, 1712, 1595, 1550, 1394, 1286, 1207, 1116 cm-1
With 1,4-diaza-bicyclo[2.2.2]octane; In N,N-dimethyl-formamide; at 20℃;
EXAMPLE 5; [(7-bromo-4-hydroxy-2-oxo-2H-thiochromene-3-carbonyl)-amino]-acetic acid a) 4-Bromo-2-dimethylthiocarbamoyloxy-benzoic acid methyl ester[0206] To a mixture of 4-bromo-2 -hydroxy-benzoic acid methyl ester (Mori, N. et al, Bull Chem. Soc. Jpn. 1969, 42(2), 488-491) (29.3 g, 127 mmol) and dimethylthiocarbamoyl chloride (17.2 g, 140 mmol) in DMF at room temperature was added DABCO (21.3 g, 190 mmol). The resulting mixture, after being stirred at room temperature overnight, was diluted with water (1.25 L) and acidified to a pH of around 4 using 1 N HCl. The precipitate was collected, rinsed with water and dried in vacuo to provide 4-bromo-2-dimethylthiocarbamoyloxy-benzoic acid methyl ester as an off-white solid (36.8 g). 1H NMR (200 MHz, CDCl3): delta (ppm) = 7.84 (d, J = 8.2 Hz, 1 H), 7.43 (dd, J = 8.6, 2.0 Hz, 1 H), 7.29 (d, J = 2.0 Hz, 1 H), 3.83 (s, 3 H), 3.45 (s, 3 H), 3.38 (s, 3 H).
With sodium hydroxide; hydroxylamine hydrochloride; In 1,4-dioxane; water; at 20℃; for 18h;
A solution of <strong>[22717-56-2]methyl 4-bromo-2-hydroxybenzoate</strong> (Intermediate 22) (0.7g) in dioxan (5ml) was added dropwise to a solution of hydroxylamine hydrochloride (0.32g) and sodium hydroxide (0.42g) in water (10ml) then stirred at room temp. for 18h. The dioxan was removed under vacuum and the residue was stirred with 2N hydrochloric acid to give a precipitate which was collected by filtration, washed with water and dried to give the title compound as an off-white solid (0.63g). LCMS: Rt 2. 64min.
With hydroxylamine hydrochloride; sodium hydroxide; In 1,4-dioxane; water; at 20℃; for 18h;
(11) To a solution of hydroxy laraiiie hydrochloride (1.5 eqjand NaOH (3.5 eq) in water (0,25 M) was added Methyl 4-bromc-2-hydroxyben2oate (1 eq)in L4-dioxae (2,0 M) dropwise. The reaction turns light yellow shortly after addition. The solution is stirred at rt for 1 8hrs. 1 ,4-dioxane was removed in vacuo and HQ (2N) was added until a precipitate was formed. The heterogenous mixture was filtered and washed with water. The solid was dried overnight in a vacuum oven to give the title compound.
Step II - Preparation of Methyl 2-allyloxy-4-bromobenzoate-Intermediate (N) 139 g of ground potassium carbonate, 470 ml of acetonitrile, 16 g of benzyltributylammonium chloride and 136 g of allyl bromide were introduced into a 3-liter round-bottomed flask and 236 g of ground <strong>[22717-56-2]methyl 4-bromosalicylate</strong> were added in small amounts. The contents were heated under reflux with vigorous stirring, for 5 hours and then a part of the acetonitrile was distilled off under slight vacuum and the residue was taken up with water. A precipitate of methyl 2-allyloxy-4-bromobenzoate was obtained, which was drained, washed with water and air-dried. Weight obtained: 280 g (m.p.=62 C.).
With potassium carbonate;potassium iodide; In N,N-dimethyl-formamide; at 65℃; for 7h;
A mixture of <strong>[22717-56-2]4-bromo-2-hydroxybenzoic acid methyl ester</strong> (30 g, 130 mmol, CAS:22717-56- 2), 1-chloromethylnaphthalene (25 g, 142 mmol, CAS:86-52-2), Kl (1.7g, 10 mmol) and K2CO3 (27 g, 195 mmol) in DMF (300 mL) is stirred at 65 C for 7 h. After cooling down to room temperature, the reaction mixture is diluted with EtOAc. The organic layers are washed with H2O, dried over MgSO4 and concentrated under reduced pressure. The resulting residue is suspended in Et2O/hexanes and stirred at room temperature overnight. Educt 1.2 is obtained as pale yellow solid after filtration; ES-MS: [M+Na]+ = 394: tRet = 3.16 min.
With dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 12h;
General procedure: A solution of compound 3, substituted methyl salicylate (4a-4t), 1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (EDC.HCl), N-Hydroxybenzotriazole (HOBt) and 4-dimethylaminopyridine (DMAP) in DMF (50 mL) was stirred for 12 h at room temperature. Then, compounds 5a-5t were obtained by subsequent purification with flash chromatography (acetate: petroleum ether = 1:5-1:2).
Example I-XIVPreparation of Compound 317General Procedure I-DQTo a solution of <strong>[22717-56-2]methyl 4-bromo-2-hydroxybenzoate</strong> (4.6 g, 20.0 mmol) in DMF (50 mL) was added sodium hydride (60% dispersion in mineral oil, 1.2 g, 30.0 mmol) at 0 C. and the mixture was stirred for 30 minutes at the same temperature. After that, 3-bromo-propyne (3.5 g, 30.0 mmol) in DMF (5 ml) was added dropwise at 0 C. and the mixture was stirred at r.t. for 6 hours. The solvent was removed and the residue was dissolved in ethyl acetate, washed with water, brine and dried over sodium sulfate. The solvent was removed under reduced pressure to afford compound I-XIVa (4.8 g, yield 91%) as yellow oil. 1H NMR (400 MHz, CDCl3) delta 7.68 (d, 1H), 7.26 (d, 1H), 7.18 (d, 1H), 4.76 (s, 1H), 3.85 (s, 3H), 2.55 (s, 1H).
At room temperature, 300 g of methanol was added to the three-necked flask, 90 g of 4-bromosalicylic acid was added, and 6 g of thionyl chloride was slowly added under stirring, and the temperature was raised to 30 C, and the mixture was stirred for 5 hours. The reaction was complete by TLC. 300 g of water was added to the reaction flask and stirred for 20 minutes. It was suction filtered and dried at 70 C to obtain 93.8 g. Yield 98.0%, purity: 98.2%.
93.932%
With thionyl chloride; In N,N-dimethyl-formamide; for 12h;Cooling with ice; Reflux;
To a three-neck flask were added 4-bromo-2-hydroxybenzoic acid (20 g, 92.16 mmol) and CH3OH (200 mL). After the mixture was stirred well, to the mixture was added DMF (0.5 mL). The reaction mixture was cooled in an ice-bath, then thionyl chloride (8.02 mL, 111 mmol) was added dropwise slowly into the mixture. After addition, the resulting mixture was heated to refl ux and stirred for 12 hours. After the reaction was completed, the mixture was concentrated in vacuo, and the residue was diluted with water (300 mL) and EtOAc (500 mL), then the resulting mixture was stiring, and 5% aqueous sodium hydroxide solution was then added to adjust pH to 6-8, then the mixture was stood for partition. The separated organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo to give the title compound as a pale brown solid (20 g, 93.932%).N MR (400 M Hz, CD Cl3): 10.83 (s, 1 H), 7.70 (d, J = 8.53 Hz, 1 H), 7.20 (s, 1 H), 7.04 (d, J = 8.50 Hz, 1 H), 3.97 (s, 3H).
73%
With sulfuric acid; at 0 - 65℃; for 16h;
Step-1: Methyl 4-bromo-2-hydroxybenzoate (0246) (0247) 4-Bromo-2-hydroxybenzoic acid (10.0 g, 46.08 mmol, 1.0 equiv) and MeOH (50 mL) were placed in a 250-mL round-bottom flask. This was followed by the addition of sulfuric acid (20 mL) dropwise with stirring at 0 C. The resulting solution was stirred for 16 h at 65 C. in an oil bath, then concentrated under vacuum. The residue was dissolved in EtOAc (300 mL) and washed with H2O (3×100 mL) and aq. 2N NaHCO3 (3×100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel chromatography (EtOAc/pet. ether, 1:20) to afford methyl 4-bromo-2-hydroxybenzoate as a light yellow solid (7.80 g, 73% yield). MS: (ES, m/z): 231 [M+H]+.
58%
With sulfuric acid; at 75℃; for 12h;
(10) To a solution of 4-bromo-2-hydroxy benzoic acid (1 eq) in Methanol (0.2 M) at tt was added sulfuric acid (1 eq) . The dark red brown solution was heated to 75 for 12 h. LCMS confirms product. The rxtt was concentrated and crude residue was partitioned between EfOAe: water (1 : 1 }. The organic layer was washed wiih NaHCO.? faq), water and dried (MgSC ). After filtration, the organic layer was concentrated to give a tan solid (58%).
14.2 g
With thionyl chloride; at 70℃;Inert atmosphere; Cooling with ice;
A) methyl 4-bromo-2-hydroxybenzoate To a solution of 4-bromo-2-hydroxybenzoic acid (15.0 g) in methanol (150 mL) was added dropwise thionyl chloride (10.1 mL) under ice-cooling, and the mixture was stirred overnight at 70C under argon atmosphere. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title Compound (14.2 g) , XH NMR (300 MHz, DMSO-d6) delta 3.88 (3H, s) , 7.10-7.18 (1H, m) , 7.21-7.28 (1H, m) , 7.69 (1H, d, J.= 8.3 Hz), 10.65 (1H, s).
5.31 g
With sulfuric acid; for 24h;Reflux;
2-hydroxy-4-bromobenzoic acid (5.0 g, 23.1 mmol) was dissolved in 20 mL of anhydrous methanol,Add 1.7mL sulfuric acid.The reaction solution was stirred and refluxed for 24 h.The reaction solution was added to ice water, the methanol was removed by concentration, the EA was extracted, the organic phase was washed with saturated NaHCO3 solution, dried over anhydrous sodium sulfate,Concentrated a total of reddish brown solid2-hydroxy-4-bromobenzoic acid methyl ester12, 5.31 g,Directly for the next step.
With thionyl chloride; at 0 - 65℃; for 48.16h;
General procedure: Methyl 4-bromosalicylate (1 mol) was dissolved in methanol(25 mL), and thionyl chloride was added dropwise under ice-cooling,after 10 min, The mixture was stirred at 65 C for 48 h. and monitoredby TLC. After the reaction was completed, excess methanol was evaporated,the residue was extracted with ethyl acetate and aqueous sodiumcarbonate, and the organic phase was added to anhydrous sodiumsulfate and concentrated to obtain intermediate 6a.The compounds 6b-6h were prepared analogously.
With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 70℃; for 18h;
Step 1: Methyl 4-bromo-2-isopropoxybenzoate:To a solution of <strong>[22717-56-2]methyl 4-bromo-2-hydroxybenzoate</strong> (3 g, 12.98 mmol) in DMF (15 ml) was added K2C03 (2.153 g, 15.58 mmol), Kl (0.022 g, 0.130 mmol) and 2-iodopropane (1 .95 ml, 19.48 mmol). After stirring at 70 C for 18 h, the mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc, and the combined organic extracts were washed with water, dried (MgS04) and concentrated in vacuo to afford the title compound as a brown liquid (3.0 g, 85%).1H NMR (500 MHz, CDCI3): 7.57-7.56 (1 H, d), 7.05 (1 H, d), 7.03-7.01 (1 H, dd), 4.53-4.46 (1 H, sept), 3.79 (3H, s), 1 .32-1 .30 (6H, d).
With ammonium hydroxide; In isopropyl alcohol; at 20℃;Inert atmosphere;
Step 1 : To a solution of 4-bromo-2-hydroxy-benzoic acid methyl ester (4.62 g, 20.0 mmol) in isopropanol (40 mL) under nitrogen was added ammonium hydroxide (80 mL). The reaction mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure to give 4-bromo-2-hydroxy-benzamide (2.6 g; 60%). The material was used as is in the next step.
With ammonia; In isopropyl alcohol; at 50℃;
A solution of <strong>[22717-56-2]methyl 4-bromo-2-hydroxybenzoate</strong> (4.6 g) was dissolved in isopropanol (20 mL)Then add ammonia (40 mL)50 C after 5 h reaction to dry to obtain the crude product 4-bromo-2-hydroxybenzamide directly for the next step.
methyl 2-(2-((tert-butoxycarbonyl)amino)ethoxy)-4-bromobenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
62%
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran;Inert atmosphere;
General procedure: Methyl 2-(2-((tert-butoxycarbonyl)amino)ethoxy)-4-fluorobenzoate. To a solution of 300 mg (1.76 mmol, 1.0 eq) of Methyl 4-fluoro-2-hydroxybenzoate, 196 muL (1.76 mmol, 1.0 eq) boc-ethanolamine and 578 mg (2.20 mmol, 1.25 eq) triphenyl phosphine in 10 mL of dry THF was added 578 mg (2.20 mmol, 1.25 eq) of DIAD and the reaction mixture was left stirring overnight under nitrogen atmosphere. The reaction mixture was evaporated and without further processing was loaded on a silica column.
With potassium carbonate; In acetonitrile; for 4h;Reflux;
Step 1: Synthesis of intermediate 1-35.1 To methyl 4-bromo-2-hydroxy-benzoate (4.3 g, 18.61 mmol) in acetonitrile (50 mL) are added bromomethylbenzene (2.23 mL, 19.54 mmol) and potassium carbonate (3.86 g, 27.92 mmol) and stirred for 4h at reflux. The reaction mixture is cooled down to r.t., diluted with water and extracted with ethyl acetate. The organic layer is separated, dried over MgS04 and concentrated. The crude residue is purified over silica gel (eluent: cyclohexane/ethyl acetate 95:5). Yield 75%
75%
With potassium carbonate; In acetonitrile; for 4h;Reflux;
To methyl 4-bromo-2-hydroxy-benzoate (4.3 g, 18.61 mmol) in acetonitrile (50 mL) are added bromomethylbenzene (2.23 mL, 19.54 mmol) and potassium carbonate (3.86 g, 27.92 mmol) and stirred for 4 h at reflux. The reaction mixture is cooled down to r.t., diluted with water and extracted with ethyl acetate. The organic layer is separated, dried over MgSO4 and concentrated. The crude is residue is purified over silica gel (eluent: cyclohexane/ethyl acetate 95:5). Yield 75%.
General procedure: The appropriate bromo derivatives (1 eq.) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.1 eq.) and KAc (3.0 eq.) were dissolved in dioxane, and the three resulting mixtures were deoxygenated under a stream of N2. After 10 min, PdCl2(dppf) (0.05 eq.) was added, and each mixture was brought to 60-80 C andstirred under N2 for 2-4 h until the reaction was complete, followedby detection using TLC. After the reaction was finished,without further treatment the crude product was subjected to asecond coupling reaction.
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 140℃; for 0.333333h;Microwave irradiation;
In a microwave vial, <strong>[22717-56-2]methyl 4-bromo-2-hydroxybenzoate</strong> (250 mg, 1.08 mmol),bis(pinacolato)diboron (330 mg, 1.30 mmol), potassium acetate (425 mg, 4.33 mmol),PdCI2(dppf)-CH2CI2 adduct (44.2 mg, 0.05 mmol) and 1 ,4-dioxane (6 ml) were combined. The reaction vial was then irradiated at 140 00 for 20 minutes in microwave reactor.The reaction mixture was then cooled to room temperature, diluted with EtOAc and brine (10 ml) and filtered through a 0.45 uM PTFE frit. The layers were then separated and the organiclayer was passed through a hydrophobic frit, concentrated and purified via 5i02 chromatogaphy (ISCO Combiflash Rf and eluted with 0 to 10% methanol in DCM over 20 minutes, 25 g column) to yield the desired compound. MS (mlz) 279.1.
With boron tribromide; In dichloromethane; at 0℃; for 1.83333h;
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 94%).
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;
INTERMEDIATE 26: methyl 4-bromo-2-ethoxybenzoate lodoethane (6.12 ml, 76 mmol) was added dropwise to a mixture of methyl 4- bromo-2-hydroxybenzoate (5 g, 21.6 mmol) and potassium carbonate (8.97 g, 64.9 mmol)in N,N-dimethylformamide (80 ml) and the reaction mixture stirred at room temperature overnight. The mixture was then filtered, diluted with EtOAc and the organic layer washed twice with water. The organic layer was separated and then concentrated to give the title compound (5.61 g, 100% yield). MS (mlz) 261.0 (M+2).
100%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;
Iodoethane (6.12 ml, 76 mmol) was added dropwise to a mixture of <strong>[22717-56-2]methyl 4-bromo-2-hydroxybenzoate</strong> (5 g, 21.6 mmol) and potassium carbonate (8.97 g, 64.9 mmol) in N,N-dimethylformamide (80 ml) and the reaction mixture stirred at room temperature overnight. The mixture was then filtered, diluted with EtOAc and the organic layer washed twice with water. The organic layer was separated and then concentrated to give the title compound (5.61 g, 100% yield). MS (m/z) 261.0 (M+2+).
100%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;
lodoethane (6.12 ml, 76 mmol) was added dropwise to a mixture of methyl 4-bromo- 2-hydroxybenzoate (5.0 g, 21.6 mmol) and potassium carbonate (8.97 g, 64.9 mmol) in DMF(80 ml) and the reaction mixture stirred at room temperature overnight. The mixture was then filtered, diluted with EtOAc and washed twice with water. The organic layer was separated and then concentrated to give the title compound (5.61 g, 100% yield). MS (mlz) 261.0 (M+2).
With bis-triphenylphosphine-palladium(II) chloride; lithium chloride; In N,N-dimethyl-formamide; at 90℃; for 2h;Inert atmosphere;
B) methyl 2-hydroxy-4-vinylbenzoate To a solution of <strong>[22717-56-2]methyl 4-bromo-2-hydroxybenzoate</strong> (3.0 g) in DMF (50.0 mL) were added tributylvinyltin (6.18 g) , bis (triphenylphosphine) palladium ( II ) chloride (0.46 g) and lithium chloride (4.07 g) , and the mixture was stirred at 90C for 2 hr under argon atmosphere. To the reaction mixture was added aqueous potassium fluoride solution, and the precipitated insoluble substance was removed by filtration through Celite. The filtrate was diluted with ethyl acetate, and the mixture was washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound. This compound was used in the next step without an additional purification.
With bis-triphenylphosphine-palladium(II) chloride; lithium chloride; In N,N-dimethyl-formamide; at 90℃; for 2h;
A mixture of <strong>[22717-56-2]methyl 4-bromo-2-hydroxybenzoate</strong> (3.0 g) , tributylvinyltin (6.18 g) ,dichlorobis (triphenylphosphine) palladium (II) (0.46 g) , lithium chloride (4.07 g) and DMF (50 mL) was stirred under an argon atmosphere at 90C for 2 hr. To the reaction mixture was added aqueous potassium fluoride solution, and the precipitated insoluble material was filtered off through celite. Thefiltrate was diluted with ethyl acetate, and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound. This was used in the next step without further purification .
With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In toluene; at 100℃;Inert atmosphere;
B) methyl 4-cyclopropyl-2-hydroxybenzoate To a solution of <strong>[22717-56-2]methyl 4-bromo-2-hydroxybenzoate</strong> (3.00 g) in toluene (30.0 mL) were added tris (dibenzylideneacetone) dipalladium (0) (0.60 g) , 2- dicyclohexylphosphino-2 ' , 6 ' -dimethoxybiphenyl (0.53 g) , cyclopropylboronic acid (2.79 g) and sodium carbonate (3.44 g), and the mixture was stirred overnight at 100C under argon atmosphere. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water and saturated brine. The organic layer was dried over anhydrous sodium ? sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.80 g) . XH NMR (300 MHz, DMSO-d6) delta 0.70-0.80 (2H, m) , 0.97-1.07 (2H, m) , 1.85-1.99 (1H, m) , 3.87 (3H, s) , 6.61-6.73 (2H, m) , 7.65 (1H, d, J = 7.9 Hz), 10.50 (1H, s) .
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; ruphos; In toluene; at 98℃;Inert atmosphere;
Step 1: To a solution of compound 1 (1.5 g, 6.5 mmol) and Boc-piperazine (3.6 g, 19.4 mmol) in toluene (30 ml) was added Pd2(dba)3 (0.6 g, 0.65 mmol), RuPhos (0.3 g, 0.65 mmol), and Cs2C03 (8.4 g, 25.9 mmol). The mixture was stirred overnight at 98 C under N2atmosphere. After completion of the reaction, the mixture was filtered, and then extracted by EA, washed with PE, the solvent was evaporated off to afford the target compound 4 as a yellow solid (2 g, 80%).
methyl 4-bromo-2-(3-(tert-butoxycarbonylamino)propoxy)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In acetone; at 60℃; for 16h;
Step-2: Methyl 4-bromo-2-(3-(tert-butoxycarbonylamino)propoxy)benzoate (0248) (0249) Methyl 4-bromo-2-hydroxybenzoate (3.00 g, 12.98 mmol, 1.0 equiv) in propan-2-one (15 mL), potassium carbonate (5.40 g, 39.07 mmol, 3.0 equiv) and tert-butyl N-(3-bromopropyl)carbamate (3.7 g, 15.54 mmol, 1.20 equiv) were place in a 100-mL round-bottom flask. The resulting mixture was stirred for 16 h at 60 C. in an oil bath, then concentrated under vacuum. The residue was dissolved in EtOAc (200 mL) and washed with H2O (3×100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to afford methyl 4-bromo-2-(3-(tert-butoxycarbonylamino)propoxy)benzoate as a light yellow oil (5.89 g). This material was used without further purification. MS: (ES, m/z): 388 [M+H]+.
methyl 4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-2-hydroxybenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95 mg
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; ruphos; In toluene; at 100℃;
A mixture of methyl 4-bromo-2-hydroxy-benzoate (100 mg, 0.43 mmol), 1,4-dioxa-8-azaspiro[4.5]decane (74 mg, 0.52 mmol), Cs2CO3 (280 mg, 0.86 mmol), Pd2(dba)3 (8 mg, 0.009mmol) and Ru-Phos (8 mg, 0.018 mmol) in toluene (10 mL) was heated with stirring at 100 Covernight. The reaction mixture was cooled to rt, diluted with water (20 mL) and extracted withEA (20 mL) for three times. The combined organic layer was washed with brine, dried overanhydrous Na2SO4 and concentrated in vacuo to give methyl 4-(1,4-dioxa-8-azaspiro[4.5]decan- 8-yl)-2-hydroxy-benzoate (95 mg), which was used in the next step directly without further purification.
To a mixture of 4-bromo-2-hydroxybenzoic acid (5.0 g) in toluene (80 mL) -methanol (20 mL) was added dropwise 0.6 M(diazomethyl ) trimethylsilane (38 mL) under ice-cooling. The' reaction mixture was stirred at the same temperature for 2 hr. The reaction mixture was acidified with acetic acid (0.35 mL) , and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethylacetate/hexane) to give the title compound (4.83 g) .XH NMR (300 MHz, CDC13) delta 3.95 (3 H, s) , 7.02 (1 H, dd, J = 8.7, 1.9 Hz), 7.18 (1 H, d, J = 1.9 Hz), 7.68 (1 H, d, J = 8.3 Hz), 10.82 (1 H, s) .
With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 80℃;
To a stirred solution of methyl 4- bromo-2-hydroxybenzoate (1.5 g, 6.49 mmol), KI (108 mg, 0.65 mmol) and K2C03 (2.69 g, 19.47 mmol) in DMF (30 mL) was added 1- bromo-2-methyloethane (902mg, 6.49 mmol). The mixture was heated to 80 C overnight and water was added (150 mL).The mixture was extracted with EA (150 mL x3) and the combined organic phase was washed with water, brine and dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel chromatography (PE/EA = 5/1) to give the desired compound as a yellow solid (1.7 g, 90%). ESI-MS m/z: 289.1 [M+Hf
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In toluene; at 100℃; for 16h;Inert atmosphere;
A solution of methyl 4-bromo-2-hydroxybenzoate (600 mg, 2.8 mmol) and<strong>[28741-08-4]octylboronic acid</strong> (874 mg, 5.6 mmol), Pd(PPh3)4 (320 mg, 0.28 mmol) and K2C03 (1.15 g, 8.3mmol) in toluene (16 mL) was stirred at 100C under N2 for 16 h. The volatiles were removed and the residue was purified by silica gel flash column to give methyl 2-hydroxy-4- octylbenzoate (706 mg, 96.6% yield) as colorless oil.
With palladium diacetate; potassium carbonate; triphenylphosphine; In 1,2-dimethoxyethane; water; at 20℃; for 12h;Inert atmosphere;
To a solution of <strong>[22717-56-2]methyl 4-bromo-2-hydroxybenzoate</strong> (307 mg, 1.3 mmol) in (CH3OCH2)2/H2O (10 mL, 1:1) was added (4-(methoxycarbonyl)phenyl)boronic acid (287 mg, 1.6 mmol), Pd(OAc)2 (15 mg, 0.07 mmol), PPh3 (17 mg, 0.07 mmol) and K2CO3 (551 mg, 4 mmol). The mixture was stirred at room temperature under argon protection for 12 h. The solution was neutralized by 1N HCl, diluted with EtOAc, wash with H2O, brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel flash column chromatography (hexane/EtOAc=5:1) to afford compound 15 (363 mg, 98%). Yellow solid; 1H NMR (500 MHz, CDCl3) delta 10.82 (s, 1H), 8.12 (d, J=8.2 Hz, 2H), 7.92 (d, J=8.3 Hz, 1H), 7.68 (d, J=8.2 Hz, 2H), 7.24 (d, J=1.3 Hz, 1H), 7.15 (dd, J=8.3, 1.3 Hz, 1H), 3.98 (s, 3H), 3.95 (s, 3H).
94%
With palladium diacetate; potassium carbonate; triphenylphosphine; In 1,2-dimethoxyethane; water; at 20℃; for 12h;Inert atmosphere;
General procedure: To a solution of <strong>[22717-56-2]methyl 4-bromo-2-hydroxybenzoate</strong> (463 mg, 2 mmol) in (CH3OCH2)2/H2O (10 mL, 1:1) was added (4-(methoxycarbonyl)phenyl)boronic acid (432 mg, 2.4 mmol), Pd(OAc)2 (23 mg, 0.1 mmol), PPh3 (26 mg, 0.1 mmol) and K2CO3 (829 mg, 6 mmol). The mixture was stirred at room temperature under argon protection for 12h. The solution was neutralized with 1N HCl and the aqueous phase was extracted with EtOAc (5mL×3). The combined organic layer was wash with H2O, brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel flash column chromatography (hexanes/EtOAc=5:1) to afford compound 1 (537 mg, 94 %). Yellow solid; 1H NMR (500MHz, CDCl3) delta 10.82 (s, 1H), 8.12 (d, J=8.2Hz, 2H), 7.92 (d, J=8.3Hz, 1H), 7.68 (d, J=8.2Hz, 2H), 7.24 (d, J=1.3Hz, 1H), 7.15 (dd, J=8.3, 1.3Hz, 1H), 3.98 (s, 3H), 3.95 (s, 3H); ESI-MS calcd for C16H15O5 287.1 [M + H+], found 287.1.
Methyl 4-bromo-2-((2-(trifluoromethyl)benzyl)oxy)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
51%
With di-tert-butyl-diazodicarboxylate; triphenylphosphine; In dichloromethane; at 0 - 20℃;
2.3 g of G, 0.75 mL of F and 2.62 g of PPh3 were dissolved in 40 mL of methylene chloride and the reaction flask was placed in an ice-water mixture. Then 2.25 mL of DBAD (di-t-butyl azodicarboxylate, density 1.020 g / mL)was mixed with 10 mL of methylene chloride and the mixture was added dropwise to the reaction flask. After the addition, the reaction flask was removed from the ice-water bath and stirred overnight at room temperature. The reaction solution was clarified, concentrated and then separated by silica gel column chromatography. The eluent was ethyl acetate: petroleumether = 1: 7, and finally, H1.98 g was obtained as a white solid in 51percent yield.
With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In tetrahydrofuran; at 60℃; for 5h;
General procedure: A mixture of V-01 (922 mg, 4.292 mmol), ethynyltrimethylsilane (506 mg, 5.153 mmol), Pd(PPh3)2Cl2 (150 mg, 0.214 mmol), CuI (25 mg, 0.131 mmol), TEA (1.73 g, 17.16 mmol) was dissolved in anhydrous THF (20 mL). The mixture was stirred at 60 for 5 h. The solvent was removed under reduced pressure. The residue was partitioned between ethyl ether and water. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and then the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography with PE/EA (50/1-20/1) to give 0.9 g (90.4%) of V-13 as a brown oil.
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃;Cooling with ice;
To a mixture of <strong>[22717-56-2]methyl 4-bromo-2-hydroxybenzoate</strong> (10 g, 43 mmol) and diisopropylethylamine (11.0 mL, 65 mmol) in dichloromethane (100 mL) was added dropwise chloromethyl methyl ether (4.9 mL, 65 mmol) under an ice bath condition. Then the reaction mixture was warmed to rt and stirred overnight. The reaction was quenched with water (200 mL), and the resulting mixture was extracted with dichloromethane (150 mLx2). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluted with PE/EA (v/v = 20/1) to give the title compound as colourless oil (10 g, 84 %).
methyl 4-bromo-2-(4-bromobutoxy)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
With potassium hydroxide; In dimethyl sulfoxide; for 1.16667h;
General procedure: Method B: powdered KOH (60 mmol) was added to DMSO (40 mL). The obtained suspension wasstirred for 5 min. Appropriate phenol (20 mmol) was added, followed by 1,4-dibromobutane (40mmol) after further 10 min. After stirring for 1 h, the reaction mixture was poured into water andextracted with ethyl acetate (3 × 100 mL). The combined organic extracts were washed with brine (2× 100 mL) and dried over anhydrous sodium sulfate. After rotary evaporation, the residue waspurified by flash chromatography using mixtures of cyclohexane /ethyl acetate. By use of thisprocedure, the following compounds were prepared.
tert-butyl (5-hydroxypentan-2-yl)(4-methoxybenzyl)carbamate[ No CAS ]
methyl 4-bromo-2-((4-((tert-butoxycarbonyl)(4-methoxybenzyl)amino)pentyl)oxy)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
69%
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 28℃; for 3h;
To a solution of <strong>[22717-56-2]methyl 4-bromo-2-hydroxybenzoate</strong> (10 g, 43.3 mmol) in tetrahydrofuran (150 mL) was added rac-tert-butyl (5-hydroxypentan-2-yl)(4- methoxybenzyl)carbamate (21 g, 64.9 mmol) and PPh3 (17.0 g, 64.9 mmol) and the mixture was cooled to 0 C and treated with DIAD (13.6 mL, 69.2 mmol) dropwise via syringe. The mixture was stirred at 28 C for 3 h and after this time the reaction was concentrated and petroleum ether/EtOAc (50 mL, 5/1) was added. The mixture was stirred at 28 C for 15 min, filtered and concentrated to give the crude. The crude was purified by column chromatography on silica gel using petroleum ether/EtOAc (100/1 to 10/1) as an eluent to give the title compound (17 g, 69%) as a yellow gum. MS (ESI): 558.1 [(M + Na) (79Br)]+.
methyl 4-bromo-2-(4-((tert-butoxycarbonyl)amino)butoxy)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
52%
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 28℃; for 2h;
To a solution of <strong>[22717-56-2]methyl 4-bromo-2-hydroxybenzoate</strong> (5 g, 21.6 mmol) in THF (30 mL) was added ieri-butyl (4-hydroxybutyl)carbamate (4.91 g, 26 mmol) and PPh3 (6.81 g, 26 mmol) and the mixture was stirred at 28 C for 10 min. After this time DIAD (5.5 mL, 28.1 mmol) was added dropwise over 1 min and the mixture was stirred at 28 C for 2 h. After this time, the mixture was concentrated and petroleum ether/EtOAc (20 mL, 5/1) was added. The mixture was filtered and the filtrate was concentrated to give the crude product (5 g), which was purified by chromatography on silica gel using DCM/MeOH (100/1 to 10/1) as eluent to give the title compound (4.5 g, 52%) as an oil. MS (ESI): 403.8 [(M + H) (81Br)]+.
methyl 4-bromo-2-(2-hydroxyethoxy)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
62%
NaH (101 mg, 4.2 mmol) is added portionwise to a 0C solution of <strong>[22717-56-2]methyl 4-bromo-2-hydroxybenzoate</strong> (500 mg, 2.1 mmol) in DMF (5 mL). The RM is stirred for a few minutes at 0C, then 2-bromoethanol (0.235 mL, 3.15 mmol) is added and the RM is stirred at 90C for 2h45, then cooled to RT. Water is added to the RM and it is extracted twice with EtOAc. The combined organic layers are washed with brine, dried over MgSC>4, filtered and concentrated under reduced pressure. The residue is purified by FC (heptane/EtOAc, 1 :0 to 6:4), affording the title compound as a colorless oil (358 mg, 62%). LC-MS B: tR = 0.77 min; [M+H]+ = 275.14.
62%
NaH (101 mg, 4.2 mmol) is added portionwise to a 0C solution of <strong>[22717-56-2]methyl 4-bromo-2-hydroxybenzoate</strong> (500 mg, 2.1 mmol) in DMF (5 mL). The RM is stirred for a few minutes at 0C, then 2-bromoethanol (0.235 mL, 3.15 mmol) is added and the RM is stirred at 90C for 2h45, then cooled to RT. Water is added to the RM and it is extracted twice with EtOAc. The combined organic layers are washed with brine, dried over MgS04, filtered and concentrated under reduced pressure. The residue is purified by FC (heptane/EtOAc, 1 :0 to 6:4), affording the title compound as a colorless oil (358 mg, 62%). LC-MS B: tR = 0.77 min; [M+H]+ = 275.14.
62%
NaH (101 mg, 4.2 mmol) is added portionwise to a 0C solution of <strong>[22717-56-2]methyl 4-bromo-2-hydroxybenzoate</strong> (500 mg, 2.1 mmol) in DMF (5 mL). The RM is stirred for a few minutes at 0C, then 2-bromoethanol (0.235 mL, 3.15 mmol) is added and the RM is stirred at 90C for 2h45, then cooled to RT. Water is added to the RM and it is extracted twice with EtOAc. The combined organic layers are washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue is purified by FC(heptane/EtOAc, 1:0 to 6:4), affording the title compound as a colorless oil (358 mg, 62%). LC-MS B: tR =0.77 mm; [M+H] = 275.14.
62%
NaH (101 mg, 4.2 mmol) is added portionwise to a 0C solution of <strong>[22717-56-2]methyl 4-bromo-2-hydroxybenzoate</strong> (500 mg, 2.1 mmol) in DMF (5 mL). The RM is stirred for a few minutes at 0C, then 2-bromoethanol (0.235 mL, 3.15 mmol) is added and the RM is stirred at 90C for 2h45, then cooled to RT. Water is added to the RM and it is extracted twice with EtOAc. The combined organic layers are washed with brine, dried over MgSC>4, filtered and concentrated under reduced pressure. The residue is purified by FC (heptane/EtOAc, 1 :0 to 6:4), affording the title compound as a colorless oil (358 mg, 62%). LC-MS B: tR = 0.77 min; [M+H]+ = 275.14.
methyl 5-bromo-2-(cyclopentyloxy)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 19h;
To a solution of <strong>[22717-56-2]methyl 4-bromo-2-hydroxybenzoate</strong> (2.00 g, 8.4 mmol) in DMF (20 mL), bromocyclobutane (1.01 mL, 9.24 mmol) and K2CO3 (1.74 g, 12.6 mmol) aere added. The RM is stirred at 80C for 19h, cooled to RT, and partitioned between water and EbO. Organic layers are combined and washed with additional water, dried over MgS04 and concentrated to dryness. The crude product is purified by FC, eluting with Heptane/DCM (100:0 to 40:60) to the product as a colourless oil (1.88 g, 75%). LC-MS A: tR = 0.97 min; [M+H]+ = 298.89.
methyl 4-bromo-2-(2-chloroethoxy)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
With caesium carbonate; In N,N-dimethyl-formamide; at 65℃; for 2h;Inert atmosphere;
To a solution of <strong>[22717-56-2]methyl 4-bromo-2-hydroxybenzoate</strong> (5.000 g, 21.00 mmol) in anh. DMF (30 mL) at RT are added cesium carbonate (10.363 g, 31.50 mmol) and 2-chloroethyl p-toluenesulfonate (4.71 mL, 25.20 mmol) and the mixture is heated to 65C, under nitrogen, for 2h. The RM is allowed to cool to RT, water andEt20 are added, and the layers are separated. The aqueous layer is extracted three times with Et20 and the combined organic layers are washed with brine, dried over anh. Mg504, filtered and concentrated under reduced pressure. Purification by FC (from heptane to heptane/EtOAc = 4/1) affords methyl 4-bromo-2-(2- chloroethoxy)benzoate as a colorless solid (5.840 g, 95%). LC-MS B: tR = 0.96 mm; [M+H] = 293.10.
With potassium carbonate; In acetonitrile; at 80℃; for 12h;
To a 1 L single-neck flask were added <strong>[22717-56-2]methyl 4-bromo-2-hydroxybenzoate</strong> (44.5 g, 193 mmol) and CH3CN (450 mL). After the solid was dissolved completely by stirring, K2C03 (39.9 g, 289 mmol) and 1-bromo-3-methoxypropane (45.1 g, 289 mmol) were added in turn. The resulting mixture was heated to 80 C and stirred for 12 hours at 80 C. After the reaction was completed, the reaction mixture was cooled to 25 C and filtered. The filter cake was washed with acetonitrile (100 mL). The combined filtrates was concentrated in vacuo, and the residue was diluted with EtOAc (500 mL). The mixture was washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound as orange oil (58 g, 99.3%).MS (ESI, pos.ion) m/z: 303.2 [M÷H] .
With di-isopropyl azodicarboxylate; triphenylphosphine; In N,N-dimethyl-formamide; at 0℃; for 2.5h;Inert atmosphere;
[00513] A mixture of Example 96a (1.0 g, 4.3 mmol), Example 96b (1.0 g, 4.3 mmol) and PPh3 (1.69 g, 6.45 mmol) in dry DMF (10 mL) was stirred at 0C under N2 atmosphere. To the above mixture was injected DIAD (1.04g, 5.16 mmol), which was stirred for another 2.5 h. The mixture was diluted with H20 (20 mL) and then extracted with EtOAc (40 mL). The organic layer was dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM/MeOH = 7/3) to give the desired product Example 96c (700 mg, yield 37%) as yellow oil, which turned into a yellow solid after staying overnight. LCMS [M+l] + = 445.9/447.9.
1‐(4‐bromo-2-hydroxyphenyl)‐2‐(3‐bromo-6-methoxypyridine-2‐yl)ethanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91.2%
Add 250g of tetrahydrofuran to a three-necked flask at room temperature, add 85g of <strong>[126717-59-7]3-bromo-6-methoxy-2-methylpyridine</strong>, add 25.2g of sodium hydroxide in batches with stirring, warm to 60 C, stir for 40 minutes, slowly a mixed solution of 97.2 g of methyl 4-bromosalicylate and 97.2 g of tetrahydrofuran was added dropwise, and the temperature was controlled at 60 C, and the reaction was stirred for 6 hours with stirring. The reaction was complete by TLC. The temperature was lowered, and the reaction liquid was poured into 1 L of water, suction filtered, and dried to give 153.6 g. Yield 91.2%, purity: 96.0%.
2-chloro-1-nitro-4-(trifluoromethoxy)benzene[ No CAS ]
methyl 4-bromo-2-(2-nitro-5-(trifluoromethoxy)phenoxy)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
46%
With potassium carbonate; In N,N-dimethyl-formamide; at 70℃;
Methyl 4-bromo-2- hydroxybenzoate (478 mg, 2.07 mmol) was added to a solution of 2-chloro-l-nitro-4- (trifluoromethoxy)benzene (500 mg, 2.07 mmol) and K2CO3 (372 mg, 2.69 mmol) in DMF (10.0 mL). The resulting reaction mixture was stirred at 70 C overnight, after which LC-MS analysis showed completion. Reaction mixture was diluted with EtOAc and washed with brine twice, dried over MgS04, filtered and concentrated. Crude mixture was purified by flash column chromatography: silica gel with a gradient of 3- 15% EtOAc in Hex to afford methyl 4-bromo-2-(2-nitro-5-(trifluoromethoxy)phenoxy)benzoate (415 mg, (0794) 46.0 % yield), which was used without further purification in the next step. NMR (400 MHz, DMSO-ck) 5 8.27 (d, .7 = 9.1 Hz, 1H), 7.92 - 7.87 (m, 1H), 7.70 - 7.65 (m, 2H), 7.35 (ddq, J= 9.1, 2.6, 1.3 Hz, 1H), 7.02 (dd, J= 2.5, 0.7 Hz, 1H), 3.68 (s, 3H). 19F NMR (376 MHz, DMSO-ifc) d -56.91 (s, 3F). LCMS RT (Method 2) = 3.663 min, m/z 437.9 [M+].
methyl 4-bromo-2-(2-nitro-4-(trifluoromethoxy)phenoxy)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
With potassium carbonate; In N,N-dimethyl-formamide; at 60℃;
methyl 4-bromo-2- hydroxybenzoate (0.950 g, 4.11 mmol) was added to a solution of l-fluoro-2-nitro-4- (0788) (trifluoromethoxy)benzene (600 pL, 4.11 mmol) and K2CO3 (0.739 g, 5.35 mmol) in DMF (12.0 mL). The resulting reaction mixture was stirred at 60 C overnight, after which LC-MS analysis showed completion. Reaction mixture was allowed to cool to RT and then poured over ice H2O, vigorously stirred for 30 min and insoluble material filtered, washed generously with H2O and air dried to afford methyl 4-bromo-2-(2-nitro-4- (trifluoromethoxy)phenoxy)benzoate (1.55 g, 86.0 % yield) as a slightly yellow powder, which was used without further purification. NMR (400 MHz, DMSO-cfe) d 8.21 (d, J= 2.9 Hz, 1H), 7.90 (d, J= 8.9 Hz, 1H), 7.72 - 7.63 (m, 3H), 7.11 (d, .7= 9.2 Hz, 1H), 3.69 (s, 3H). 19F NMR (376 MHz, DMSO-ifc) d -57.51 (s, 3F). LCMS RT (Method 2) = 3.719 min, m/z 894.9 [2M+Na+]
2-[4-(2-bromo-ethoxy)-phenyl]-5,6,7-trimethoxy-chromen-4-one[ No CAS ]
4-bromo-2-{2-[4-(5,6,7-trimethoxy-4-oxo-4H-chromen-2-yl)-phenoxy]-ethoxy}-benzoic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
47%
With potassium carbonate; potassium iodide; In acetone; at 60℃;
General procedure: The intermediates 6a and 4a were dissolved in acetone (30mL), and a catalytic amount of anhydrous potassium carbonate was added to this solution at 60C for 48h (the reaction was monitored by TLC). After completion of the reaction, the solvent was evaporated, the residue was extracted with ethyl acetate and water, the organic phase was treated with anhydrous sodium sulfate, and then concentrated. The final target product 7a was purified by flash column chromatography on silica gel, and eluted with a solution of methanol and dichloromethane (v/v, 1:100) and recrystallized from anhydrous ethanol. (0027) Compounds 7b-7x were prepared similarly.
2-[4-(3-bromo-propoxy)-phenyl]-5,6,7-trimethoxy-chromen-4-one[ No CAS ]
[ 22717-56-2 ]
4-bromo-2-{3-[4-(5,6,7-trimethoxy-4-oxo-4H-chromen-2-yl)-phenoxy]-propoxy}-benzoic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
59.5%
With potassium carbonate; potassium iodide; In acetone; at 60℃;
General procedure: The intermediates 6a and 4a were dissolved in acetone (30mL), and a catalytic amount of anhydrous potassium carbonate was added to this solution at 60C for 48h (the reaction was monitored by TLC). After completion of the reaction, the solvent was evaporated, the residue was extracted with ethyl acetate and water, the organic phase was treated with anhydrous sodium sulfate, and then concentrated. The final target product 7a was purified by flash column chromatography on silica gel, and eluted with a solution of methanol and dichloromethane (v/v, 1:100) and recrystallized from anhydrous ethanol. (0027) Compounds 7b-7x were prepared similarly.
2-[4-(4-bromo-butoxy)-phenyl]-5,6,7-trimethoxy-chromen-4-one[ No CAS ]
[ 22717-56-2 ]
4-bromo-2-{4-[4-(5,6,7-trimethoxy-4-oxo-4H-chromen-2-yl)-phenoxy]-butoxy}-benzoic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
58.2%
With potassium carbonate; potassium iodide; In acetone; at 60℃;
General procedure: The intermediates 6a and 4a were dissolved in acetone (30mL), and a catalytic amount of anhydrous potassium carbonate was added to this solution at 60C for 48h (the reaction was monitored by TLC). After completion of the reaction, the solvent was evaporated, the residue was extracted with ethyl acetate and water, the organic phase was treated with anhydrous sodium sulfate, and then concentrated. The final target product 7a was purified by flash column chromatography on silica gel, and eluted with a solution of methanol and dichloromethane (v/v, 1:100) and recrystallized from anhydrous ethanol. (0027) Compounds 7b-7x were prepared similarly.
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 4h;
Add <strong>[22717-56-2]4-bromo-2-hydroxybenzoic acid methyl ester</strong> (15g, 64.92mmol), allyl bromide (15.8g, 131mmol), DMF (100mL) and potassium carbonate (18g, 130.242mmol) to the reaction flask, and warm up to Reaction at 80 for 4h.After the reaction was detected by TLC, the reaction solution was poured into water (200 mL), extracted with ethyl acetate (200 mL×2), the combined organic phase was washed with saturated sodium chloride solution (200 mL×3), dried over sodium sulfate, and concentrated under reduced pressure The title compound was obtained as a yellow solid product (17g, 62.70mmol, 97%).
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
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110K+ Compounds
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