* 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 1,3-bis-(diphenylphosphino)propane; palladium diacetate; triethylamine In N,N-dimethyl-formamide at 70℃; for 6 h; Autoclave
[00132] The benzofuranyl carbonyl moiety was prepared by protecting the hydroxyl groupof compound 13 by reacting with tert-butyldimethylsilyl chloride (1.0 equivalents) andtriethylamine (TEA, 1.1 equivalents) in acetone, to give compound 14 in 79percent yield. A solutionof compound 14 in methanol was then treated with sodium borohydride (1.0 equivalent) at roomtemperature overnight. The reaction was quenched with an addition of acetone, stirred at roomtemperature for a further 2.5 hours, aqueous HC1 (4N) was added with the temperature controlledto below 28 °C, tetrahydrofuran (THF) was added, and the solution stirred overnight under argonand in the absence of light. The product, compound 15, was isolated quantitatively by extractioninto methylene chloride, concentrated at low heat, and used without further purification. Thetriflate ester, compound 16, was produced in 69percent yield from compound 15 by reacting it with Nphenyl-bis(trifluoromethanesulfonimide) (1.0 equivalent) in methylene chloride for 72 hours.Compound 16 in a mixture of DMF, methanol, and triethylamine, was added to a preparedsolution of palladium acetate, 1,3-Bis(diphenylphosphino)propane (dppp), DMF and methanol inan autoclave. Carbon monoxide was charged into the autoclave to a pressure of 8 bar, and the reaction mixture was heated at 70 °C for 6 hours. After workup, compound 17 was isolated in 91percent yield. Lithium hydroxide (4 equivalents) in methanol and water was used to hydrolyze the ester and permit the isolation of compound 18’ in 97percent yield.
80%
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 70℃; for 24 h;
Step d: Methyl benzofuran-6-carboxylate; A mixture of benzofuran-6-yl trifluoromethanesulfonate (16.2 g, 61 mmol), 1,3- bis(diphenyl phosphino)propane (1.4 g, 3.3 mmol) and Pd(OAc)2 (756 mg, 3.3 mmol) in DIEA (16.2 g, 124 mmol), MeOH (153 mL) and DMF (153 mL) was stirred at 70 °C under atmosphere of CO for 24 h. The reaction mixture was diluted with water, and extracted with ethyl acetate. The combined organic layer was then washed with brine and dried over Na2SO4, filtered and concentrated to afford a crude mixture that was purified by column chromatography on silica gel (5-10percent ethyl acetate in petroleum ether) to yield methyl benzofuran-6-carboxylate (8.5 g, 80 percent yield). 1H NMR (300 MHz, CDCl3) δ: 8.21(s, IH), 7.96 (dd, J =8.1, 1.5, IH), 7.76 (d, J= 2.1, IH), 7.63 (d, J= 8.1, IH), 6.83-6.82 (m, IH), 3.95 (s, IH).
65%
With N-ethyl-N,N-diisopropylamine In DMF (N,N-dimethyl-formamide) at 65℃;
A mixture of 50 mmol of compound 1.9, 2.5 mmol of dppp (diphenylphosphine-1, 3-propane) and 2.5 mmol of Pd (OAc) 2 in 100 mmol of DIEA, 125 mL of dry DMF, and 125 mL of anhydrous MeOH was stirred at 65°C under an atmosphere of CO overnight. The solvent was removed and the residue was purified by column chromatography to give compound 1.10 in 65percent yield. IH NMR (400 MHz, CD13) : 8 8.23 (s, 1H), 7.99 (d, J= 8.3 Hz, 1H), 7.78 (s, 1H), 7.65 (d, J= 8. 3 Hz, 1H), 6. 85 (s, 1H), 3.97 (s, 3H) ppm; ESI-MS (mlz) : (M+1) 177.10.
Stage #1: With n-butyllithium In tetrahydrofuran at -65 - -60℃; for 4 h; Stage #2: at -65℃; for 5 h;
5.28 g (0.0268 mol) of 6-bromobenzofuran was added to a 250 mL three-necked flask, 80 ml of dry tetrahydrofuran was added, stirred and dissolved, then placed in a freezer to cool to -65 ° C, n-butyllithium was added dropwise (2M) 14.74mL, maintained the temperature at -60 °C during the addition process, and dropwise addition completion in 1h. After the reaction was continued for 3 hours, 2.89 g (0.0321 mol) of dimethyl carbonate was added dropwise under this reaction conditions, and the dropwise addition was completed in 1 hour, and the reaction temperature was controlled to -65 ° C. After the reaction for 4 hours, the reaction was completed. and the reaction was quenched by dropwise addition of a saturated ammonium chloride solution under a low temperature condition. The reaction was quenched by dropwise addition of a saturated ammonium chloride solution under a low temperature condition, after the solvent was evaporated under reduced pressure, residue was stirred by adding 100ml of water and 100 ml of dichloromethane , and then the layers were separated. The organic layer was washed twice with saturated brine, 100 mL each time, and the dichloromethane layer was dried over anhydrous magnesium sulfate and filtered, dichloromethane was evaporated under reduced pressure to obtain 6-methyl formate benzofuran 4.3g. yield 91.2percent and HPLC purity 97.2percent.
Reference：
[1] Patent: CN108129430, 2018, A, . Location in patent: Paragraph 0008; 0016; 0018; 0020
3
[ 478169-68-5 ]
[ 67-56-1 ]
[ 588703-29-1 ]
Yield
Reaction Conditions
Operation in experiment
70%
Stage #1: With copper(l) iodide In methanol at 75℃; for 3 h; Stage #2: With pyrographite In methanol at 20 - 95℃; Stage #3: With sodium hydroxide In ethanol at 20℃;
Methyl 3-hydroxy-4-[(trimethylsilyl)ethynyl]benzoate (4.15 g, 16.7 mmol) is dissolved in MeOH (45 ml) and treated with DIA (2.34 ml, 16.7 mmol). Copper iodide (159 mg, 0.84 mmol) is added portion-wise and the reaction is heated at 75° C. for 3 h. DARCO (2 g) is added and the reaction is stirred at 95° C. for an additional 2 h, then overnight at RT. The reaction is filtered, concentrated to a brown oil and the crude material is chromatographed over 300 g slurry-packed silica gel, eluting with 10percent EtOAc/hexane. The appropriate fractions are collected and concentrated to afford 2.05 g (70percent) of methyl 1-benzofuran-6-carboxylate as an orange crystalline solid. 1H NMR (400 MHz, CDCl3) δ3.97, 6.84, 7.65, 7.78, 7.98, 8.22 ppm.
With lithium hydroxide; water; In tetrahydrofuran; at 20℃; for 1h;
A mixture of 20 mmol of compound 1.10 and 80 mmol of LiOH-H20 in 60 mL of THF and 15 mL of H20 was stirred at room temperature for 1 hour, followed by adding 80 mL of 1. ON aq. HC1. The organic solvent was removed and the residue was diluted with 50 mL of brine. The mixture was then extracted with EtOAc, and the extract was dried with anyhydrous Na2S04. The solvent was removed and the residue was dried in vacuo to give a quantitative yield of compound 1. 11. 1H NMR (400 MHz, CD30D) : No. 8.14 (s, 1H), 7.92 (m, X2H), 7.67 (d, J=8. 5 Hz, 1H), 6.92 (s, 1H) ppm; ESI-MS (mlz) : (M+H 163.1.
97%
With water; lithium hydroxide; In methanol;
[00132] The benzofuranyl carbonyl moiety was prepared by protecting the hydroxyl groupof compound 13 by reacting with tert-butyldimethylsilyl chloride (1.0 equivalents) andtriethylamine (TEA, 1.1 equivalents) in acetone, to give compound 14 in 79% yield. A solutionof compound 14 in methanol was then treated with sodium borohydride (1.0 equivalent) at roomtemperature overnight. The reaction was quenched with an addition of acetone, stirred at roomtemperature for a further 2.5 hours, aqueous HC1 (4N) was added with the temperature controlledto below 28 C, tetrahydrofuran (THF) was added, and the solution stirred overnight under argonand in the absence of light. The product, compound 15, was isolated quantitatively by extractioninto methylene chloride, concentrated at low heat, and used without further purification. Thetriflate ester, compound 16, was produced in 69% yield from compound 15 by reacting it with Nphenyl-bis(trifluoromethanesulfonimide) (1.0 equivalent) in methylene chloride for 72 hours.Compound 16 in a mixture of DMF, methanol, and triethylamine, was added to a preparedsolution of palladium acetate, 1,3-Bis(diphenylphosphino)propane (dppp), DMF and methanol inan autoclave. Carbon monoxide was charged into the autoclave to a pressure of 8 bar, and the reaction mixture was heated at 70 C for 6 hours. After workup, compound 17 was isolated in 91% yield. Lithium hydroxide (4 equivalents) in methanol and water was used to hydrolyze the ester and permit the isolation of compound 18? in 97% yield.
95%
With hydrogenchloride; In dichloromethane; water; at 20℃; for 2h;
Methyl 6-formate benzofuran 15.3 g (0.0869 mol)Dissolved in 100mL of dichloromethane, dissolved and added with concentrated hydrochloric acid (37%) 20ml,After stirring at room temperature for 2 h, the reaction was completely monitored by TLC, and washed twice with saturated brine.After 100 mL of each time, the dichloromethane layer was dried over anhydrous magnesium sulfate, filtered, and dichloromethane evaporated.Obtaining 13.37 g of benzofuran 6-formic acid,Yield 95%, HPLC purity 98%,
A solution of <strong>[588703-29-1]methyl 1-benzofuran-6-carboxylate</strong> (J. Med. Chem. 1995, 38, 3094; 142 mg, 0.8 mmol) in THF (5 ml) was added dropwise to a stirred suspension of lithium aluminum hydride (92 mg, 2.4 mmol) in THF (2 mL) at -10 C. The mixture was stirred at room temperature for 30 min, cooled to 0 C. and treated slowly with water (1 mL). The mix was brought to pH 1 with 2N HCl and extracted with ethyl acetate (3*). The combined extracts were washed with water, brine, dried (MgSO4) and concentrated to give the final productproduct.
cis-methyl 2,3-dichloro-2,3-dihydro-1-benzofuran-6-carboxylate[ No CAS ]
trans-methyl 2,3-dichloro-2,3-dihydro-1-benzofuran-6-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
34%; 47%
With chlorine; In diethyl ether; at 0℃;
Methyl 1-benzofuran-6-carboxylate (1.90 g, 10.7 mmol) is dissolved in Et2O (50 ml) and cooled to 0 C. Chlorine gas is bubbled in for 5 min, and the reaction is stirred over the weekend, allowing the ice bath to expire. The volatiles are removed in vacuo, and the crude material is chromatographed over 300 g slurry-packed silica gel, eluting with 10% EtOAc/hexane. The appropriate fractions are collected and concentrated to afford 906 mg (34%) of cis-methyl 2,3-dichloro-2,3-dihydro-1-benzofuran-6-carboxylate as a pale oil. A second pool of fractions is collected and concentrated to afford 1.25 g (47%) of trans-methyl 2,3-dichloro-2,3-dihydro-1-benzofuran-6-carboxylate and as a yellow oil. trans-isomer: 1H NMR (400 MHz, CDCl3): delta3.93, 5.47, 6.53, 7.56, 7.69, 7.85 ppm. cis-isomer: 1H NMR (400 MHz, CDCl3): delta3.94, 5.68, 6.69, 7.49,7.63, 7.85 ppm
With 1,3-bis-(diphenylphosphino)propane; palladium diacetate; triethylamine; In N,N-dimethyl-formamide; at 70℃; under 6000.6 Torr; for 6h;Autoclave;
[00132] The benzofuranyl carbonyl moiety was prepared by protecting the hydroxyl groupof compound 13 by reacting with tert-butyldimethylsilyl chloride (1.0 equivalents) andtriethylamine (TEA, 1.1 equivalents) in acetone, to give compound 14 in 79% yield. A solutionof compound 14 in methanol was then treated with sodium borohydride (1.0 equivalent) at roomtemperature overnight. The reaction was quenched with an addition of acetone, stirred at roomtemperature for a further 2.5 hours, aqueous HC1 (4N) was added with the temperature controlledto below 28 C, tetrahydrofuran (THF) was added, and the solution stirred overnight under argonand in the absence of light. The product, compound 15, was isolated quantitatively by extractioninto methylene chloride, concentrated at low heat, and used without further purification. Thetriflate ester, compound 16, was produced in 69% yield from compound 15 by reacting it with Nphenyl-bis(trifluoromethanesulfonimide) (1.0 equivalent) in methylene chloride for 72 hours.Compound 16 in a mixture of DMF, methanol, and triethylamine, was added to a preparedsolution of palladium acetate, 1,3-Bis(diphenylphosphino)propane (dppp), DMF and methanol inan autoclave. Carbon monoxide was charged into the autoclave to a pressure of 8 bar, and the reaction mixture was heated at 70 C for 6 hours. After workup, compound 17 was isolated in 91% yield. Lithium hydroxide (4 equivalents) in methanol and water was used to hydrolyze the ester and permit the isolation of compound 18? in 97% yield.
80%
With N-ethyl-N,N-diisopropylamine;palladium diacetate; 1,3-bis-(diphenylphosphino)propane; In N,N-dimethyl-formamide; at 70℃; for 24h;
Step d: Methyl benzofuran-6-carboxylate; A mixture of benzofuran-6-yl trifluoromethanesulfonate (16.2 g, 61 mmol), 1,3- bis(diphenyl phosphino)propane (1.4 g, 3.3 mmol) and Pd(OAc)2 (756 mg, 3.3 mmol) in DIEA (16.2 g, 124 mmol), MeOH (153 mL) and DMF (153 mL) was stirred at 70 C under atmosphere of CO for 24 h. The reaction mixture was diluted with water, and extracted with ethyl acetate. The combined organic layer was then washed with brine and dried over Na2SO4, filtered and concentrated to afford a crude mixture that was purified by column chromatography on silica gel (5-10% ethyl acetate in petroleum ether) to yield methyl benzofuran-6-carboxylate (8.5 g, 80 % yield). 1H NMR (300 MHz, CDCl3) delta: 8.21(s, IH), 7.96 (dd, J =8.1, 1.5, IH), 7.76 (d, J= 2.1, IH), 7.63 (d, J= 8.1, IH), 6.83-6.82 (m, IH), 3.95 (s, IH).
65%
With N-ethyl-N,N-diisopropylamine;palladium diacetate; 1,3-bis-(diphenylphosphino)propane; In DMF (N,N-dimethyl-formamide); at 65℃;
A mixture of 50 mmol of compound 1.9, 2.5 mmol of dppp (diphenylphosphine-1, 3-propane) and 2.5 mmol of Pd (OAc) 2 in 100 mmol of DIEA, 125 mL of dry DMF, and 125 mL of anhydrous MeOH was stirred at 65C under an atmosphere of CO overnight. The solvent was removed and the residue was purified by column chromatography to give compound 1.10 in 65% yield. IH NMR (400 MHz, CD13) : 8 8.23 (s, 1H), 7.99 (d, J= 8.3 Hz, 1H), 7.78 (s, 1H), 7.65 (d, J= 8. 3 Hz, 1H), 6. 85 (s, 1H), 3.97 (s, 3H) ppm; ESI-MS (mlz) : (M+1) 177.10.
Methyl 3-hydroxy-4-[(trimethylsilyl)ethynyl]benzoate (4.15 g, 16.7 mmol) is dissolved in MeOH (45 ml) and treated with DIA (2.34 ml, 16.7 mmol). Copper iodide (159 mg, 0.84 mmol) is added portion-wise and the reaction is heated at 75° C. for 3 h. DARCO (2 g) is added and the reaction is stirred at 95° C. for an additional 2 h, then overnight at RT. The reaction is filtered, concentrated to a brown oil and the crude material is chromatographed over 300 g slurry-packed silica gel, eluting with 10percent EtOAc/hexane. The appropriate fractions are collected and concentrated to afford 2.05 g (70percent) of methyl 1-benzofuran-6-carboxylate as an orange crystalline solid. 1H NMR (400 MHz, CDCl3) delta3.97, 6.84, 7.65, 7.78, 7.98, 8.22 ppm.
dimethyl (2-(benzofuran-6-yl)-2-oxoethyl)phosphonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72.8%
Under nitrogen protection,In a round bottom flask,Dimethyl methylphosphonate (521 mg, 4.2 mmol, 2.0 equiv) was added and20 ml of anhydrous tetrahydrofuran,Cool in a dry ice-ethanol bath to -72C,A 2.5 M solution of n-butyllithium in n-hexane (2.5 mL, 6.3 mmol, 3.0 equiv) was added dropwise.Stir for an hour,Methyl benzofuran-6-carboxylate (0303-101) (370 mg, 2.1 mmol, 1.0 equiv) was added dropwise at -72CThe tetrahydrofuran solution was stirred for 2 hours.Add ammonium chloride solution and ethyl acetate to separateThe organic phase was dried over sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 2:1).The product was obtained as a slightly yellow oily liquid (2-(benzofuran-6-yl)-2-oxoethyl)phosphonate (410 mg, yield:72.8%)
5.28 g (0.0268 mol) of <strong>[128851-73-0]6-bromobenzofuran</strong> was added to a 250 mL three-necked flask, 80 ml of dry tetrahydrofuran was added, stirred and dissolved, then placed in a freezer to cool to -65 C, n-butyllithium was added dropwise (2M) 14.74mL, maintained the temperature at -60 C during the addition process, and dropwise addition completion in 1h. After the reaction was continued for 3 hours, 2.89 g (0.0321 mol) of dimethyl carbonate was added dropwise under this reaction conditions, and the dropwise addition was completed in 1 hour, and the reaction temperature was controlled to -65 C. After the reaction for 4 hours, the reaction was completed. and the reaction was quenched by dropwise addition of a saturated ammonium chloride solution under a low temperature condition. The reaction was quenched by dropwise addition of a saturated ammonium chloride solution under a low temperature condition, after the solvent was evaporated under reduced pressure, residue was stirred by adding 100ml of water and 100 ml of dichloromethane , and then the layers were separated. The organic layer was washed twice with saturated brine, 100 mL each time, and the dichloromethane layer was dried over anhydrous magnesium sulfate and filtered, dichloromethane was evaporated under reduced pressure to obtain 6-methyl formate benzofuran 4.3g. yield 91.2% and HPLC purity 97.2%.
With potassium tert-butylate; In tetrahydrofuran; at 0 - 5℃; for 1h;Inert atmosphere; Large scale;
3.Add compound IV1 (8.0kg, 44.41mol, 1.0eq) to the reaction kettle,Compound V (29.05 kg, 66.61 mol, 1.5 eq) and THF (80 L), protected by nitrogen.The temperature was lowered to 0 C, and potassium tert-butoxide was added dropwise to the reaction kettle.(8.26kg, 73.61mol, 1.65eq) in THF (1M),Control the temperature at 0 5 , stir for 30min, and continue adding potassium tert-butoxide (2.70 kg, 24.06mol, 0.54eq) THF to the reaction kettleThe solution (1M) was controlled at a temperature of 0 to 5 C and stirred for 1 hour.After the TLC analysis of the raw materials was consumed, 200 L of petroleum ether was added to the reaction solution to quench the reaction. Then add 200 L of petroleum ether,Insoluble matter was filtered. Concentrated to an oily liquid,200 L of petroleum ether was used for dispersion, and the reaction solution was filtered.The filter cake was beaten with petroleum ether (200L x 2), and the organic phases were combined.Concentrated to dryness. Continue to disperse 50L with petroleum ether,Filter to remove insolubles, filter cake using petroleum ether (50L x 3)Beating.The combined organic phases were concentrated to dryness to obtain 5.89 kg of compound VI1.HPLC purity reached95%Directly used in the next reaction.
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