* 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.
Reference：
[1] Journal of Chemical Research, Miniprint, 1991, # 3, p. 581 - 594
2
[ 496-16-2 ]
[ 35700-40-4 ]
Yield
Reaction Conditions
Operation in experiment
54.7%
With n-butyllithium; N,N,N,N,-tetramethylethylenediamine In hexane
a. Preparation of 2,3-dihydrobenzo[b]furan-7-carboxylic acid (15a) To a solution of n-BuLi (1.7 M, 123 ml, 0.21 mol) in 400 ml of hexane at room temperature was added 24.3 g (0.21 mol) of N,N,N',N'-tetramethylethylenediamine (TMEDA), followed by a hexane (40 ml) solution of 2,3-dihydrobenzo[b]furan (14) (12.56 g, 0.11 mol). The mixture was stirred under argon at room temperature for 4 hours, and then poured into dry ice (pre-washing with anhydrous ether). After stirring at ambient temperature overnight, the mixture was diluted with water (300 ml), and the layers separated. The aqueous layer was acidified with conc. HCl to pH 1, cooled and the precipitate collected on a filter. This was recrystallized from CH2 Cl2 to give 15a (9.43 g, 54.7percent) as a white solid, mp 167°-169.5° C.
54.7%
With n-butyllithium; N,N,N,N,-tetramethylethylenediamine In hexane
a. Preparation of 2,3-dihydrobenzo[b]furan-7-carboxylic acid (15a) To a solution of n-BuLi (1.7 M, 123 ml, 0.21 mol) in 400 ml of hexane at room temperature was added 24.3 g (0.21 mol) of N,N,N',N'-tetramethylethylenediamine (TMEDA), followed by a hexane (40 ml) solution of 2,3-dihydrobenzo[b]furan (14) (12.56 g, 0.11 mol). The mixture was stirred under argon at room temperature for 4 hours, and then poured into dry ice (pre-washing with anhydrous ether). After stirring at ambient temperature overnight, the mixture was diluted with water (300 ml), and the layers separated. The aqueous layer was acidified with conc. HCl to pH 1, cooled and the precipitate collected on a filter. This was recrystallized from CH2Cl2 to give 15a (9.43 g, 54.7percent) as a white solid, mp 167-169.5°C.
18%
With n-butyllithium; N,N,N,N,-tetramethylethylenediamine; carbon dioxide In tetrahydrofuran; sodium hydroxide
EXAMPLE 21 7-Carboxy-2,3-dihydrobenzofuran(22) To a stirred solution of 2,3-dihydrobenzofuran (1 g, 0.0083 mol) and dry TMEDA (1 eq.) in dry tetrahydrofuran (30 mL) at -10° C. under argon, was added n-BuLi (1.6 M hexane solution) (5 mL, 0.008 mol). The reaction mixture was maintained at this temperature for 20 min and then carbon dioxide was bubbled through the reaction mixture as it warmed to room temperature. The reaction mixture was concentrated in vacuo to afford a yellow oil. The oil was dissolved in 10percent sodium hydroxide (100 mL), washed with methylene chloride (2*25 mL), and acidified with HCl. The white solid product was filtered, washed with water and air-dried to afford the carboxylic acid (22) (0.22 g, 18percent). 1 H NMR (CDCl3) δ 7.35(1H,d), 7.11(1H,d), 6.59(1H,t), 4.37(2H,t), 2.99(2H,t).
Reference：
[1] Patent: US4888353, 1989, A,
[2] Patent: EP234872, 1991, B1,
[3] Patent: US5122361, 1992, A,
3
[ 496-16-2 ]
[ 124-38-9 ]
[ 35700-40-4 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 24, p. 5567 - 5573
[2] Zeitschrift fur Naturforschung - Section B Journal of Chemical Sciences, 1999, vol. 54, # 11, p. 1469 - 1473
[3] Journal of Medicinal Chemistry, 2014, vol. 57, # 13, p. 5579 - 5601
[4] Journal of Medicinal Chemistry, 1990, vol. 33, # 1, p. 171 - 178
[5] Monatshefte fuer Chemie, 1990, vol. 121, # 11, p. 883 - 891
4
[ 496-16-2 ]
[ 110-18-9 ]
[ 124-38-9 ]
[ 35700-40-4 ]
Reference：
[1] Patent: US5519034, 1996, A,
5
[ 75934-15-5 ]
[ 35700-40-4 ]
Reference：
[1] Journal of Organic Chemistry, 1981, vol. 46, # 4, p. 783 - 788
6
[ 119-36-8 ]
[ 35700-40-4 ]
Reference：
[1] Journal of Medicinal Chemistry, 1992, vol. 35, # 2, p. 310 - 319
[2] Journal of Organic Chemistry, 1981, vol. 46, # 4, p. 783 - 788
[3] Journal of Organic Chemistry, 1981, vol. 46, # 4, p. 783 - 788
7
[ 496-16-2 ]
[ 110-18-9 ]
[ 35700-40-4 ]
Reference：
[1] Patent: US6207678, 2001, B1,
8
[ 133844-95-8 ]
[ 35700-40-4 ]
Reference：
[1] Journal of Medicinal Chemistry, 1992, vol. 35, # 2, p. 310 - 319
9
[ 13661-90-0 ]
[ 35700-40-4 ]
Reference：
[1] Journal of Medicinal Chemistry, 1992, vol. 35, # 2, p. 310 - 319
10
[ 75855-24-2 ]
[ 35700-40-4 ]
Reference：
[1] Journal of Medicinal Chemistry, 1992, vol. 35, # 2, p. 310 - 319
11
[ 69-72-7 ]
[ 35700-40-4 ]
Reference：
[1] Journal of Medicinal Chemistry, 1992, vol. 35, # 2, p. 310 - 319
12
[ 6282-42-4 ]
[ 35700-40-4 ]
Reference：
[1] Journal of Organic Chemistry, 1981, vol. 46, # 4, p. 783 - 788
13
[ 75934-01-9 ]
[ 35700-40-4 ]
Reference：
[1] Journal of Organic Chemistry, 1981, vol. 46, # 4, p. 783 - 788
14
[ 75934-00-8 ]
[ 35700-40-4 ]
Reference：
[1] Journal of Organic Chemistry, 1981, vol. 46, # 4, p. 783 - 788
15
[ 75934-02-0 ]
[ 35700-40-4 ]
Reference：
[1] Journal of Organic Chemistry, 1981, vol. 46, # 4, p. 783 - 788
16
[ 75934-03-1 ]
[ 35700-40-4 ]
Reference：
[1] Journal of Organic Chemistry, 1981, vol. 46, # 4, p. 783 - 788
17
[ 75934-11-1 ]
[ 35700-40-4 ]
Reference：
[1] Journal of Organic Chemistry, 1981, vol. 46, # 4, p. 783 - 788
18
[ 31456-98-1 ]
[ 35700-40-4 ]
Reference：
[1] Journal of Organic Chemistry, 1981, vol. 46, # 4, p. 783 - 788
EXAMPLE 39; 2-[f2,3-Dihydro-benzofuran-7-carbonyl)-aminol-indan-2-carboxylic acid ethyl ester (39):To a solution of 2,3-dihydro-benzofuran-7-carboxylic acid (394mg, 2.4mmol) in DCM (1OmL) is added oxalyl chloride (0.85mL, 9.6mmol). The resulting solution is stirred at RT for 2h. After the removal of DCM and excess oxalyl chloride, the residue, 2-amino-indan-2- carboxylic acid ethyl ester (500mg, 2.4mmol) and DIPEA (3.17mL, 19.2mmol) are dissolved in DCM (2OmL). The resulting solution is stirred at RT overnight. The reaction solution is diluted with DCM (4OmL) and washed with water (I x 5mL) and brine (2 x 5mL). The67 <n="69"/>organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (12Og silica gel, gradient elution: 0%-20% EtOAc in heptane) to give a pure product (39) as white solid (635mg, 75%).1H NMR (CDCl3, 300MHz): delta 1.23(t, 3H), 3.22(t, 2H), 3.40(d, 2H), 3.77(d, 2H), 4.26(q, 2H), 4.67(t, 2H), 6.93(t, IH), 7.17-7.30(m, 6H), 7.87(d, IH), 8.18(s, H) LC/MS (ES+) m/z = 352.12
b. Preparation of 5-bromo-2,3-dihydrobenzo[b]furan-7-carboxylic acid (15b) To an ice-cooled acetic acid solution (5 ml) of 2,3-dihydrobenzo[b]furan-7-carboxylic acid (15a) (0.33 g, 2.0 mmol) there was added iron (8 mg, 0.14 mmol) and bromine (0.32 g, 2.0 mmol) in 1 ml of acetic acid. The mixture was stirred at room temperature for 18 hours and then poured into water (20 ml). After cooling in the freezer for 11/2 hours the product was collected on a filter, and recrystallized from ethyl acetate to give 0.24 g (50.3%) of 15b as a white crystalline solid, mp 228-229 C.
0.24 g (50.3%)
With bromine; iron; In acetic acid;
b. Preparation of 5-bromo-2,3-dihydrobenzo[b]furan-7-carboxylic acid (15b) To an ice-cooled acetic acid solution (5 ml) of 2,3-dihydrobenzo[b]furan-7-carboxylic acid (15a) (0.33 g, 2.0 mmol) there was added iron (8 mg, 0.14 mmol) and bromine (0.32 g, 2.0 mmol) in 1 ml of acetic acid. The mixture was stirred at room temperature for 18 hours and then poured into water (20 ml). After cooling in the freezer for 1 1/2 hours the product was collected on a filter, and recrystallized from ethyl acetate to give 0.24 g (50.3%) of 15b as a white crystalline solid, mp 228-229C.
5-{5-[4-(2-hydroxy-ethyl)-piperazine-1-sulfonyl]-2,3-dihydro-benzofuran-7-yl}-1-methyl-3-propyl-1,6-dihydro-pyrazolo[4,3-<i>d</i>]pyrimidin-7-one[ No CAS ]
With dmap; benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; for 18h;
A solution of 2,3-dihydrobenzofuran-7-carboxylic acid (1.0g, 6.09 mmol, 1.0 equiv.), dimethylmethoxyamine hydrochloride (654 mg, 6.7 mmol, 1.1 equiv.), diisopropylethylamine (DIEA) (2.35 ml, 13.4 mmol, 2.2 equiv.), benzotriazole-1-yl-oxy-tris-pyrrolidinophosphonium hexafluorophosphate (PyBOP) (3.48g, 6.7 mmol, 1.1equiv.) and 4-dimethylaminopyridine (DMAP) (74 mg, 0.67 mmol, .1 equiv.) in anhydrous THF (20 ml) was stirred for 18hr under argon. The reaction mixture was then diluted with EtOAc (100 ml) and washed with aqueous sat. NaHCO3 (2x150 ml) and aqueous 1N HCl (2 x 150 ml), the oragnic layer was dried over MgSO4, filtered and solvent removed. yield : 1.06 mg, 84 %. LS-MS calcd 207, found 208. To a solution of the amide (950 mg, 4.59 mmol, 1.0 equiv.) in anhydrous THF (20 ml) was cooled to -5C under argon, was slowly added 1.0 M LAH in THF (9.1 ml, 9.14 mmol, 1.5 equiv.), the reaction mixture was stirred for 1 hr at -5C- A solution of aqueous 1 N HCl (150 ml) was slowly added to the reaction mixture, and extracted with EtOAc (50 ml). The organic layer was washed with aqueous 1 N HCl (150 ml), the organic layer was collected and dried over MgSO4, filter and solvent removed under reduced pressure to yield the aldhyde. Yield: 620 mg, 91%. LR-MS calcd 148, found 149.
INTERMEDIATE 65 Methyl 2, 3-dihydro-1-benzofuran-7-carboxylate 2, 3-Dihydrobenzofuran-7-carboxylic acid (8 g, 48. 7 mmol) was dissolved in methanol (39.6 mL, 975 mmol) and concentrated sulfuric acid (2.6 mL, 48. 7 mmol) was slowly added. The mixture was refluxed at 80 C for 17 h. The solvent was evaporated and the residue was dissolved in ethyl acetate and washed with brine. The organic layer was evaporated to give the title compound as a beige solid. Yield: 8.6 g (99%). HPLC purity 93%, RT=1.72 min (System A; 10-97% MeCN over 3 min); 96%, RT=1.67 min (System B; 10-97% MeCN over 3 min). MS (ESI+) for CloHlo03 m/z 179 (M+H) +.
With borane-THF; In tetrahydrofuran; at 20 - 60℃; for 3.5h;
1M Borane-THF complex THF solution (193 mL, 193.35 mmol) was slowly added to a solution of 2,3-dihydrobenzofuran-7-carboxylic acid (10.58 g, 64.45 mmol) in THF (65 mL) over 30 min while the reaction solution was maintained at room temperature. The reaction mixture was stirred at 60C for 3.5 hr, and poured into ice (about 400 g). The mixture was stirred at room temperature for 30 min, and extracted three times with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give (2,3-dihydrobenzofuran-7-yl)methanol (9.76 g, 65.0 mmol, quant.) as a colorless oil.
77%
With diborane; In tetrahydrofuran; at 0 - 20℃;
A. 2,3-dihydro-l-benzofuran-7-ylmethanol [00878] Added BH3 (1M in THF, 9 mL) to a solution of 2,3-dihydro-l-benzofuran-7- carboxylic acid (481 mg, 2.93 mmol) in THF (7 mL) drop wise at 0C, thereto, the mixture was stirred at room temperature overnight. Extracted with ethyl acetate twice, and washed the organic phase with brine and dried with anhydrous Na2S04, concentrated to give the title compound (340 mg, 77%). 1H NMR (400 MHz, CDC13): delta 2.09 (1H, s), 3.22 (2H, t, J= 8.8 Hz), 4.61 (2H, t, J= 8.8 Hz), 4.67 (2H, s), 6.83 (1H, t, J= 7.6 Hz), 7.08 (1H, d, J= 7.2 Hz), 7.14 (1H, d, J= 7.2 Hz).
EXAMPLE 29A 2,3-dihydro-1-benzofuran-7-ylmethanol 2,3-Dihydrobenzofuran carboxylic acid (5.047 g, 30.77 mmol) in tetrahydrofuran at -10 C. was treated dropwise with a solution of 1.0 M borane-tetrahydrofuran (20 mL 20 mmol). The temperature was allowed to warm to room temperature overnight, and was then treated with additional 1.0 M borane-tetrahydrofuran (10 mL 10 mmol), and stirred at room temperature for 2 hours. The mixture was cooled to 5 C., slowly treated with methanol (20 mL), and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate (2*), saturated sodium chloride, dried (sodium sulfate), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (hexanes:ethyl acetate, 3:2) to provide the title compound. MS (DCI/NH3) M/Z 168 (M+NH4)+; 1H NMR (CDCl3) delta 3.21 (t, 2H), 4.60 (t, 2H), 4.68 (s, 2H), 6.83 (t, 1H), 7.08 (dd, 1H), 7.14 (dd, 1H).
With borane-THF; In tetrahydrofuran; at -10 - 20℃; for 2h;
2,3-Dihydrobenzofuran carboxylic acid (5.047g) in tetrahydrofuran at -1 0 C was treated dropwise with a solution of 1.0 M borane-tetrahydrofuran (20 mL). The temperature was allowed to warm to room temperature overnight, treated with additional 1.0 M borane-tetrahydrofuran (10 mL), and stirred at room temperature for 2 hours. The mixture was cooled to 5 C, slowly treated with methanol (20 mL), and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate (2x), saturated sodium chloride, dried (sodium sulfate), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (hexanes:ethyl acetate, 3: 2) to provide the title compound. MS (DCI/NH3) m/z 168 (M+NH4)+;1H NMR (CDC13) 5 3.21 (t, 2H), 4.60 (t, 2H), 4.68 (s, 2H), 6.83 (t, 1 H), 7.08 (dd, 1 H), 7.14 (dd, 1H).
[0359] 2,3-Dihydrobenzofuran-7-carboxylic acid (820 mg, 5 mmol) was dissolved inTHF (10 rtiL). To the solution was added TEA (0.7 mL, 5 mmol) and methylchloroformate (0.43 mL, 5 mmol). The solution was stirred for 0.5 hour. The white precipitates were removed by filtration, the filtrate was added to a solution OfNaBH4 (437 mg, 12.5 mmol) in H2O (5 mL). The resulting solution was stirred overnight. The reaction mixture was neutralized with 2 M aqueous HCl solution and then extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The crude alcohol was dissolved in DCM. To the solution was added PCC (1.83 g, 7.5 mmol). The mixture was stirred for 2 hours at room temperature and diluted with diethyl ether, then ether layers were decanted. Combined organic layer was filtered though a layer of Celite. The filtrate was concentrated to give crude product. The crude was purified from column with 10% EtOAc/hexane to afford 450 mg of 2,3-dihydrobenzofuran-7-carbaldehyde as a slightly yellow solid. HPLC 4.3 min.
EXAMPLE 82 N,N,N',N'-Tetramethylethylenediamine (231.4 g) was added at ambient temperature to a solution of n-butyl lithium (2.5M, 800 ml) in hexane (2.5 l) followed by a solution of 2,3-dihydrobenzo[b]furan (102 g) in hexane (25 ml). The mixture was stirred under nitrogen at ambient temperature for 5 hours. The resulting suspension was added slowly to dry ice (300 g) and hexane (500 ml) under nitrogen. After stirring at ambient temperature for 16 hours, the mixture was diluted with water (2 l), and the layers separated. The aqueous layer was washed with hexane, acidified to pH 1 with concentrated hydrochloric acid, cooled and the precipitate collected by filtration. This was washed with water and dichloromethane and dried at 80 C. in vacuo to give 2,3-dihydrobenzo[b]furan-7-carboxylic acid (39.6 g), m.p. 164-165 C. The hexane layer was filtered, dried over sodium sulphate and concentrated. On cooling, further product was obtained (32.7 g), m.p. 170 C.
Step A 2,3-Dihydrobenzofuran-7-carboxylic acid A solution of dihydrocoumarin (0.338 mL, 3.00 mmol) in dry diethyl ether (10 mL) was cooled to -78 C. and a solution of n-butyllithium in hexane (2.38M, 1.30 mL, 3.00 mmol) was slowly added. The reaction was stirred at 20 C. overnight. The reaction was cooled to -78 C. and carbon dioxide was bubbled through for 10 min. The reaction was warmed to 20 C. and partitioned between water and ether. A solution of 10% aqueous HCl was added to the aqueous phase until the pH was less than 1. The aqueous phase was washed with ether, and the ether washed with saturated sodium chloride solution. The title compound was obtained as a white solid (0.175 g). NMR (CDCl3, 300 MHz) delta 7.83 (1H, d, J=8 Hz), 7.42 (1H, d, J=8 Hz), 6.96 (1H, t, J=8 Hz), 4.80 (2H, t, J=8 Hz), 3.30 (2H, t, J=8 Hz).
50
3-aminomethyl-4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazole di-p-toluenesulfonate[ No CAS ]
[ 35700-40-4 ]
N-(4-(3-(2-Chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazol-3-ylmethyl)-2,3-dihydrobenzofuran-7-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
EXAMPLE 20 N-(4-(3-(2-Chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazol-3-ylmethyl)-2,3-dihydrobenzofuran-7-carboxamide (1.42 g) was obtained in the same manner as in Example 11 using 2,3-dihydrobenzofuran-7-carboxylic acid (0.902 g) and 3-aminomethyl-4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazole di-p-toluenesulfonate (3.70 g). m.p. 127-129 C.
With n-butyllithium; N,N,N,N,-tetramethylethylenediamine; In hexane;
a. Preparation of 2,3-dihydrobenzo[b]furan-7-carboxylic acid (15a) To a solution of n-BuLi (1.7 M, 123 ml, 0.21 mol) in 400 ml of hexane at room temperature was added 24.3 g (0.21 mol) of N,N,N',N'-tetramethylethylenediamine (TMEDA), followed by a hexane (40 ml) solution of 2,3-dihydrobenzo[b]furan (14) (12.56 g, 0.11 mol). The mixture was stirred under argon at room temperature for 4 hours, and then poured into dry ice (pre-washing with anhydrous ether). After stirring at ambient temperature overnight, the mixture was diluted with water (300 ml), and the layers separated. The aqueous layer was acidified with conc. HCl to pH 1, cooled and the precipitate collected on a filter. This was recrystallized from CH2 Cl2 to give 15a (9.43 g, 54.7%) as a white solid, mp 167-169.5 C.
54.7%
With n-butyllithium; N,N,N,N,-tetramethylethylenediamine; In hexane;
a. Preparation of 2,3-dihydrobenzo[b]furan-7-carboxylic acid (15a) To a solution of n-BuLi (1.7 M, 123 ml, 0.21 mol) in 400 ml of hexane at room temperature was added 24.3 g (0.21 mol) of N,N,N',N'-tetramethylethylenediamine (TMEDA), followed by a hexane (40 ml) solution of 2,3-dihydrobenzo[b]furan (14) (12.56 g, 0.11 mol). The mixture was stirred under argon at room temperature for 4 hours, and then poured into dry ice (pre-washing with anhydrous ether). After stirring at ambient temperature overnight, the mixture was diluted with water (300 ml), and the layers separated. The aqueous layer was acidified with conc. HCl to pH 1, cooled and the precipitate collected on a filter. This was recrystallized from CH2Cl2 to give 15a (9.43 g, 54.7%) as a white solid, mp 167-169.5C.
18%
With n-butyllithium; N,N,N,N,-tetramethylethylenediamine; carbon dioxide; In tetrahydrofuran; sodium hydroxide;
EXAMPLE 21 7-Carboxy-2,3-dihydrobenzofuran(22) To a stirred solution of 2,3-dihydrobenzofuran (1 g, 0.0083 mol) and dry TMEDA (1 eq.) in dry tetrahydrofuran (30 mL) at -10 C. under argon, was added n-BuLi (1.6 M hexane solution) (5 mL, 0.008 mol). The reaction mixture was maintained at this temperature for 20 min and then carbon dioxide was bubbled through the reaction mixture as it warmed to room temperature. The reaction mixture was concentrated in vacuo to afford a yellow oil. The oil was dissolved in 10% sodium hydroxide (100 mL), washed with methylene chloride (2*25 mL), and acidified with HCl. The white solid product was filtered, washed with water and air-dried to afford the carboxylic acid (22) (0.22 g, 18%). 1 H NMR (CDCl3) delta 7.35(1H,d), 7.11(1H,d), 6.59(1H,t), 4.37(2H,t), 2.99(2H,t).
c. Preparation of 5-nitro-2,3-dihydrobenzo[b]furan-7-carboxylic acid (15k) Method A: To an ice-cooled solution of 2,3-dihydrobenzo[b]furan-7-carboxylic acid (15a) (0.33 g, 2.0 mmol) in 3 ml of TFA there was added dropwise 0.6 ml of HNO3. At the end of 1 hour, the cooling bath was removed. After an additional 3 hours of stirring, the mixture was poured into ice-water. The precipitate was collected on a filter to give 0.22 g (52.6%) of crude 15k. This was recrystallized from ethyl acetate to provide 88 mg of acid 15k (21.4%), mp 249-251.5 C.
21.4%
With nitric acid; In trifluoroacetic acid;
Method A To an ice-cooled solution of 2,3-dihydrobenzo[b]furan-7-carboxylic acid (15a) (0.33 g, 2.0 mmol) in 3 ml of TFA there was added dropwise 0.6 ml of HNO3. At the end of 1 hour, the cooling bath was removed. After an additional 3 hours of stirring, the mixture was poured into ice-water. The precipitate was collected on a filter to give 0.22 g (52.6%) of crude 15k. This was recrystallized from ethyl acetate to provide 88 mg of acid 15k (21.4%), mp 249-251.5C.
With nitric acid; In acetic acid;
To an ice-cooled solution of 2,3-dihydrobenzo[b]furan-7-carboxylic acid (15a) (0.33 g, 2.0 mmol) in 3 ml of acetic acid there was added dropwise 0.6 ml of HNO3. The mixture was stirred in a warm oil bath (70 C.) for 24 hours, and then poured into water. After cooling, the product was collected on a filter to give 0.21 g of solid (50.2%). This was recrystallized from ethyl acetate to afford 0.14 g (33.5%) of 15k, mp 249-251.5 C.
With nitric acid; In acetic acid;
Method B To an ice-cooled solution of 2,3-dihydrobenzo[b]furan-7-carboxylic acid (15a) (0.33 g, 2.0 mmol) in 3 ml of acetic acid there was added dropwise 0.6 ml of HNO3. The mixture was stirred in a warm oil bath (70C) for 24 hours, and then poured into water. After cooling, the product was collected on a filter to give 0.21 g of solid (50.2%). This was recrystallized from ethyl acetate to afford 0.14 g (33.5%) of 15k , mp 249-251.5C.
With nitric acid; trifluoroacetic acid; In trifluoroacetic acid; at 0℃; for 4h;
Nitric acid (9 ml) was added to a cooled (ice bath) solution of 2,3-dihydrobenzo[b]furan-7-carboxylic acid (5.1 g, 31 mmol) in trifluoroacetic acid (45 ml). After 4 hours the mixture was quenched into ice-water (150 ml) and the mixture filtered to give 5-nitro-2,3-dihydrobenzo[b]furan-7-carboxylic acid, which was washed with water and used crude (wet) in the next stage. 1H NMR (delta, 250 MHz, CD3OD): 3.70 (2H, t, 8.7 Hz), 5.21 (2H, t, 8.9 Hz), 8.67 (1H, d, 2.7 Hz), 8.83 (1H, d, 2.4 Hz)
With nitric acid; trifluoroacetic acid; for 4h;
Nitric acid (9ml) was added to a cooled (ice bath) solution of 2,3-dihydrobenzo[b]furan-7-carboxylic acid (5.1g, 31mmol) in trifluoroacetic acid (45ml). After 4 hours the mixture was quenched into ice-water (150ml) and the mixture filtered to give 5-nitro-2,3-dihydrobenzo[b]furan-7-carboxylic acid, which was washed with water and used crude (wet) in the next stage.1H NMR (delta, 250MHz, CD3OD): 3.70 (2H, t, 8.7Hz), 5.21 (2H, t, 8.9Hz), 8.67 (1H, d, 2.7Hz), 8.83 (1H, d, 2.4Hz) The crude 5-nitro-2,3-dihydrobenzo[b]furan-7-carboxylic acid was dissolved in the minimum amount of methanol (1.3L) and nitrogen was bubbled through the solution for 20 minutes. A mixture of 5% palladium on charcoal (1.0g) in water (20ml) was added and the mixture loaded into a 2L autoclave. After 2 sequential evacuation-N2 purges the vessel was charged to 5 bar H2 and stirred for 4 days. The mixture was flushed with nitrogen, filtered through celite and concentrated to give 5-amino-2,3-dihydrobenzo[b]furan-7-carboxylic acid (3.5g, 19.5mmol, 63% over 2 steps)1H NMR (delta, 250MHz, CD3OD): 3.46 (2H, t, 8.5Hz), 4.85 (2H, t, 8.7Hz), 7.19 (1H, br s), 7.27 (1 H, br s) .
With thionyl chloride; triethylamine; In water; benzene;
Example 5 Detailed preparation and physical properties of 7aand its precursors. Preparation of 4-(2,3-dihydro-7-benzofurylamino)-1-methyl-3-propyl-5-pyrazole-carboxamide (4a, i.e.4wherein X1=CH2and X2=O): A mixture of 2,3-dihydrobenzofuran-7-carboxylic acid (1.5 g, 0.0091 mole) and SOCl2(8 ml) was refluxed (oil bath) for 3 h. Excess of SOCl2was removed in vacuo, and the residual acid chloride was treated with a solution of compound 1(1.4 g, 0.0077 mole) in anhydrous benzene (25 ml), followed by addition of NEt3(3 ml). The solid residue was soaked in cold water (40 ml), and the remaining solid product was collected by suction filtration, drained, washed with water (2 x 20 ml) and diethyl ether (2 x 10 ml) and dried, thereby yielding 4a. Product yield = 2.3 g (91%); M.p. = 173-174C; Elemental analysis = Calculated for C17H20N4O3(MW=328.37) C 62.18, H 6.14, N 17.06%. Found C 61.95, H 6.07, N 17.11%. 1H NMR (CDCl3): delta 0.86 (t, J=7.4 Hz, 3H, CH2CH2C H 3), 1.56 (m, 2H, CH2C H 2CH3), 2.46 (t, J=7.6 Hz, 2H, C H 2CH2CH3), 3.27 (t, J=8.5 Hz, 2H, C3'-H), 3.97 (s, 3H, N-C H 3), 4.73 (t, J=8.5 Hz, 2H, C2'-H), 6.94 (t, J=7.6 Hz, 1H, C5'-H), 7.34 (d, J=7.2 Hz, 1H, C4'-H), 6.26, 7.72 (2 br s, 1H each of CON H 2), 7.86 (d, J=8.1 Hz, 1H, C6'-H), 8.88 (br s, 1H, N H CO). 13C NMR (CDCl3) delta 13.7 (CH2CH2 C H3), 22.2 (CH2 C H2CH3), 27.5 (C H2CH2CH3), 28.9 (C-3'), 39.1 (N- C H3), 72.8 (C-2'), 114.5 (C-3), 115.6 (C-7'), 121.4 (C-5'), 128.0 (C-3'a), 129.35, 129.34 (C-4' and C-6'), 132.1 (C-4), 147.0 (C-5), 157.9 (C-7'a), 161.7 (NH C O), 165.8 (C ONH2).
With thionyl chloride; triethylamine; In water; benzene;
Preparation of 4-(2,3-dihydro-7-benzofurylamino)-1-methyl-3-propyl-5-pyrazole-carboxamide (4a, i.e. 4 wherein X1=CH2 and X2=O): A mixture of 2,3-dihydrobenzofuran-7-carboxylic acid (1.5 g, 0.0091 mole) and SOCl2 (8 ml) was refluxed (oil bath) for 3 h. Excess of SOCl2 was removed in vacuo, and the residual acid chloride was treated with a solution of compound 1 (1.4 g, 0.0077 mole) in anhydrous benzene (25 ml), followed by addition of NEt3 (3 ml). The solid residue was soaked in cold water (40 ml), and the remaining solid product was collected by suction filtration, drained, washed with water (2*20 ml) and diethyl ether (2*10 ml) and dried, thereby yielding 4a. Product yield=2.3 g (91%); M.p.=173-174 C.; Elemental analysis=Calculated for C17H20N4O3 (MW=328.37). C 62.18, H 6.14, N 17.06%. Found C 61.95, H 6.07, N 17.11%. 1H NMR (CDCl3): delta 0.86 (t, J=7.4 Hz, 3H, CH2CH2CH3), 1.56 (m, 2H, CH2CH2CH3), 2.46 (t, J=7.6 Hz, 2H, CH2CH2CH3), 3.27 (t, J=8.5 Hz, 2H, C3'-H), 3.97 (s, 3H, N-CH3), 4.73 (t, J=8.5 Hz, 2H, C2'-H), 6.94 (t, J=7.6 Hz, 1H, C5'-H), 7.34 (d, J=7.2 Hz, 1H, C4'-H), 6.26, 7.72 (2 br s, 1H each of CONH2), 7.86 (d, J=8.1 Hz, 1H, C6'-H), 8.88 (br s, 1H, NHCO). 13C NMR (CDCl3): delta 13.7 (CH2CH2CH3), 22.2 (CH2CH2CH3), 27.5 (CH2CH2CH3), 28.9 (C-3'), 39.1 (N-CH3), 72.8 (C-2'), 114.5 (C-3), 115.6 (C-7'), 121.4 (C-5'), 128.0 (C-3'a), 129.35, 129.34 (C-4' and C-6'), 132.1 (C-4), 147.0 (C-5), 157.9 (C-7'a), 161.7 (NHCO), 165.8 (CONH2).
PREPARATION 32 2,3-Dihydrobenzo[b]furan-7-oic acid N,N,N',N'-Tetramethylethylenediamine (38 ml) was dissolved in hexane (300 ml), cooled in an ice-bath and n-butyllithium (100 ml of a 2.5M solution in hexane) added. The mixture was stirred at 0 C. for 15 minutes before adding 2,3-dihydrobenzo[b]furan (30 g) dropwise over 30 minutes. The mixture was allowed to warm to room temperature over 30 minutes, stirred at room temperature for a further 4 hours, poured onto an excess of solid carbon dioxide and left to stand for 3 days by which time the solvent had evaporated off. The residue was partitioned between ethyl acetate (1L) and 4N aqueous hydrochloric acid solution (240 ml), the layers separated and the aqueous layer extracted with ethyl acetate (500 ml). The organic extracts were combined, dried over anhydrous sodium sulphate and the solvent removed under reduced pressure. The residue was then triturated with diethyl ether to give 2,3-dihydrobenzo[b]furan-7-oic acid as a white solid (21 g) 1H-NMR (CDCl3): delta=7.75 (1H d), 7.31 (1H, d), 6.88 (1H, t), 4.69 (2H, t), 3.20 (2H, t) ppm.
PREPARATION 35 2,3-Dihydrobenzo[b]furan-7-oyl chloride 2,3-Dihydrobenzo[b]furan-7-oic acid (3 g) (see Preparation 32) was suspended in anhydrous dichloromethane (30 ml) and oxalyl chloride (3.5 g) added, followed by addition of dimethylformamide (3 drops). The mixture was stirred at room temperature for 2.5 hours, the solvent then removed under reduced pressure, the resulting residue dissolved in dichloromethane and the solvent removed under reduced pressure. The residue was again dissolved in dichloromethane and the solvent removed under reduced pressure to give 2,3-dihydrobenzo[b]furan-7-oyl chloride as a pink solid (3.3 g).
With N-ethyl-N,N-diisopropylamine; ((3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)oxy)tri(pyrrolidin-1-yl)phosphonium hexafluorophosphate(V); In acetonitrile;
Following the general procedure of acid-amine coupling as shown in Example 23, Compound 8(25 mg, 0.033 mmol) was treated with 2,3-dihydro-benzofuran-7-carboxylic acid (7.4 mg, 0.045 mmol), DIEA (0.0163 mL, 0.094 mmol) and the coupling reagent PyAop (29.3 mg, 0.056 mmol) in acetonitrile (3 mL). After purification by Prep.HPLC column, a white solid was obtained as final 1:1 diastereomers (Compound 30) (18 mg, 70% yield). (Compound 30, 48110-188D): LC-MS (retention time: 1.547 minutes.), MS m/z 684(MH+).
[00323] 2,3-Dihydrobenzofuran-7-carboxylic acid (820 mg, 5 mmol) was dissolved inTHF (10 mL). To the solution was added TEA (0.7 mL, 5 mmol) and methylchloroformate (0.43 mL, 5 mmol). The solution was stirred for 0.5 hour. The white precipitates were removed by filtration, the filtrate was added to a solution OfNaBH4 (437 mg, 12.5 mmol) in H2O (5 mL). The resulting solution was stirred overnight. The reaction mixture was neutralized with 2 M aqueous HCl solution and then extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The crude alcohol was dissolved in DCM. To the solution was added PCC (1.83 g, 7.5 mmol). The mixture was stirred for 2 hours at room temperature and diluted with diethyl ether, then ether layers were decanted. Combined organic layer was filtered though a layer of Celite. The filtrate was concentrated to give crude product. The crude was purified from column EPO <DP n="307"/>with 10% EtOAc/hexane to afford 450 mg of 2,3-dihydrobenzofuran-7-carbaldehyde as a slightly yellow solid. HPLC 4.3 min.
A suspension of 2,3-dihydro-benzofiran-7-carboxylic acid, (TCI, 20.0 g, 121.8 mmol) in 600 mL of dry acetonitrile was cooled to 0 0C and treated with N,O-dirnethylhydroxylamine hydrochloride (14.25 g, 146.1 mmol). The reaction was allowed to stirfor 10 minutes and EDCI (24.6 g, 158.3 mmol) was added, followed by HOBT (3.2 g, 24.2 mmol) and the resulting mixture was allowed to stirfor 5 minutes. Triethylamine (365.4 mmol) was then added and the reaction mixture was allowed to stirfor 18 hours at room temperature, then diluted with aqueous IN HCl (250 mL) and extracted with ethyl acetate (1.0 L). The organic layer was sequentially washed with aqueous 10% potassium carbonate (200 mL), aqueous IN HCl (200 mL), and brine (200 mL). The organic layer was then dried over magnesium sulfate, filtered and concentrated in vacuo to provide compound 2A (23.37 g, 93 %) as a colorless oil. M.S. found for CnHnNO3: 230.1 1 (M^Na)+.
93%
Example 10; Preparation of Compound 59; Step A - Synthesis of Compound 59 A; A suspension of 2,3-dihydro-benzofuran-7-carboxylic acid, (TCI, 20.0 g, 121.8 mmol) in 600 mL of dry acetonitrile was cooled to 0 0C and treated with N,O-dimethylhydroxylamine hydrochloride (14.25 g, 146.1 mmol). The reaction was allowed to stirfor 10 minutes and EDCI (24.6 g, 158.3 mmol) was added, followed by HOBT (3.2 g, 24.2 mmol) and the resulting mixture was allowed to stirfor 5 minutes. Triethylamine (365.4 mmol) was then added and the reaction mixture was allowed to stirfor 18 hours at room temperature, then diluted with aqueous IN HCl (250 mL) and extracted with ethyl acetate (1.0 L). The organic layer was sequentially washed with aqueous 10% potassium carbonate (200 mL), aqueous IN HCl (200 mL), and brine (200 mL). The organic layer was then dried over magnesium sulfate, filtered and concentrated in vacuo to provide compound 59A (23.37 g, 93 %) as a colorless oil. M.S. found for CiHi3NO3: 230.11 (M+Na)+.
80.1%
2,3-Dihydrobenzofuran 7-carboxylic acid la(According to Bioorganic & Medicinal ChemistryLetters, 15 (24), 5567-5573; 2005) (10.8 g, 66 mmol)Dissolve in 30 mL of thionyl chloride and refluxThe reaction was carried out for 1 hour, and the reaction mixture was concentrated under reduced pressure and dried under vacuum for 1 hour. To the residue was added 50 mL of dichloromethane,N, O-dimethylhydroxylamine hydrochloride (7.7 g, 79 mmol) and 10 mL of N, N-diisopropylethylamine were added and reacted for 1 hour at room temperature. The reaction mixture was concentrated under reduced pressure, water (50 mL) was added and extracted with ethyl acetate (50 mL). The organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous magnesium sulfate and filtered The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel eluting with System A.The residue yielded the title product N-methoxy-N-methyl-2,3-dihydrobenzofuran-7-carboxylate lb (10.9 g, yellow solid)Yield: 80.1%.
N-[1-ethyl-6-methyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-2,3-dihydro-1-benzofuran-7-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
The carboxylic acid R'COOH (0.12 mmol) is treated with a solution of HATU (0.12 mmol) in DMF (0.25 ml) and DIPEA (0.052 ml, ca. 0.3 mmol) is added. The solution is shaken for 10 mins, and is treated with a solution of Intermediate 15 or 16 (0.1 mmol) in DMF (0.2 ml). The resulting solution is shaken for 10 mins and left to stand for 18 h (e.g. at room temperature), and then the DMF is removed in a Genevac vacuum centrifuge. The residue is dissolved in chloroform (0.3 ml), is applied to an SPE cartridge (1 g, aminopropyl) which has been pre-washed with chloroform (6 ml), and is eluted sequentially with chloroform (3 ml) and 10% methanol in ethyl acetate (3 ml). Fractions containing the desired product are concentrated in vacuo in a Genevac vacuum centrifuge, and where necessary the residue is purified by mass directed autoprep HPLC (e.g. acetonitrile/water). Where necessary, the compound(s) is/are dissolved in chloroform, and is/are further purified by loading onto a SPE cartridge (0.5 g, aminopropyl) which has been prewashed with chloroform, eluting with 10% methanol in ethyl acetate.
(1RS,2SR)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylamine hydrochloride[ No CAS ]
[ 35700-40-4 ]
N-((1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-2,3-dihydro-1-benzofuran-7-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
To a solution of 2,3-dihydro-1-benzofuran-7-carboxylic acid (106 mg, 0.64 mmol) in tetrahydrofuran (5 ml) were added oxalyl chloride (0.11 ml, 1.72 mmol) and N,N-dimethylformamide (0.01 ml) and the mixture was stirred at room temperature for 30 min. The reaction solution was evaporated under reduced pressure. To a solution of the residue in ethyl acetate (5 ml) were added (1RS,2SR)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylamine hydrochloride (150 mg, 0.43 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (50 ml), and extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (160 mg, 81%). mp 121-122C IR nu maxKBrcm-1: 1780, 1644, 15! 37. Anal. Calcd for C25H21F4NO3: C, 65.36; H, 4.61; N, 3.05 Found: C, 65.41; H, 4.38; N, 2.76.1H-NMR (CDCl3)delta: 2.76-3.00 (2H, m), 3.18-3.30 (2H, m), 4.12 (1H, d, J = 3.6 Hz), 4.48-4.76 (4H, m), 5.08 (1H, s), 6.90-7.16 (2H, m), 7.20-7.52 (6H, m), 7.60 (1H, d, J = 7.6 Hz), 7.85 (1H, d, J = 7.6 Hz).
With sodium tetrahydroborate; triethanolamine; 4,5-dichloro-1-phenylpyridazin-6-one; In tetrahydrofuran; water; ethyl acetate;
Preparation of 2,3-dihydrobenzofuran-7-carbaldehyde 2,3-Dihydrobenzofuran-7-carboxylic acid (820 mg, 5 mmol) was dissolved in THF (10 mL). To the solution was added TEA (0.7 mL, 5 mmol) and methylchloroformate (0.43 mL, 5 mmol). The solution was stirred for 0.5 hr. The white precipitates were removed by filtration, the filtrate was added to a solution of NaBH4 (437 mg, 12.5 mmol) in H2O (5 mL). The resulting solution was stirred overnight. The reaction mixture was neutralized with 2 M aqueous HCl solution and then extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The crude alcohol was dissolved in DGM. To the solution was added PCC (1.83 g, 7.5 mmol). The mixture was stirred for 2 hrs at room temperature and diluted with diethyl ether, then ether layers were decanted. Combined organic layer was filtered though a layer of Celite. The filtrate was concentrated to give crude product. The crude was purified from column with 10% EtOAc/hexane to afford 450 mg of 2,3-dihydrobenzofuran-7-carbaldehyde as a slightly yellow solid. HPLC 4.3 min.
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
