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USD 0.00
Limited Quantity
USD 15-60
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USD 80+
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Structure of 6482-24-2 * Storage: {[proInfo.prStorage]}
* 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] Chemical and Pharmaceutical Bulletin, 1993, vol. 41, # 1, p. 148 - 155
2
[ 109-86-4 ]
[ 6482-24-2 ]
Reference：
[1] Patent: WO2006/64897, 2006, A1, . Location in patent: Page/Page column 7-8
[2] Patent: WO2006/64897, 2006, A1, . Location in patent: Page/Page column 10
[3] Chemische Berichte, 1931, vol. 64, p. 798
[4] Candad.J.Res., 1932, vol. 7, p. 467[5] Chem. Zentralbl., 1933, vol. 104, # I, p. 1758
[6] Journal of Organic Chemistry, 1962, vol. 27, p. 806 - 814
[7] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1983, p. 1303 - 1310
[8] Synthesis, 2002, # 4, p. 479 - 482
[9] Patent: WO2006/64897, 2006, A1, . Location in patent: Page/Page column 8; 1/1
[10] Molecules, 2013, vol. 18, # 1, p. 50 - 73
[11] Patent: US2014/221495, 2014, A1, . Location in patent: Paragraph 0027
3
[ 77-78-1 ]
[ 540-51-2 ]
[ 6482-24-2 ]
Reference：
[1] Journal of the American Chemical Society, 1945, vol. 67, p. 290,292
4
[ 67-56-1 ]
[ 74-85-1 ]
[ 6482-24-2 ]
Reference：
[1] Journal of the American Chemical Society, 1978, vol. 100, p. 3506 - 3513
[2] Bulletin de la Societe Chimique de France, 1970, p. 2432 - 2439
Reference：
[1] Chem. Zentralbl., 1912, vol. 83, # II, p. 1269
10
[ 124-41-4 ]
[ 106-93-4 ]
[ 6482-24-2 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1983, p. 1303 - 1310
11
[ 2615-15-8 ]
[ 6482-24-2 ]
[ 4437-01-8 ]
Yield
Reaction Conditions
Operation in experiment
41%
With sodium hydride In tetrahydrofuran at 20℃; for 2 h;
To a solution of hexa(ethylene glycol)(10 g, 35 mmole) and 2-bromoethyl methyl ether (4.9 g, 35 mmole) in THF (100 mL) was slowly added sodium hydride (2.55 g, 106 mmole). The solution was stirred at room temperature for two hours. HPLC indicated that mPEG7-OH was formed in about 54percent yield. The reaction was then stopped by the addition of diluted hydrochloride acid to destroy excess sodium hydride. All solvents were removed using a rotary evaporator to give a brown sticky liquid. Pure mPEG7-OH was obtained as a colorless liquid (4.9 g, 41percent isolated yield) by using semi-preparative HPLC (20 cm.x.4 cm, C18 column, acetonitrile and water as mobile phases). 1H NMR (CDCl3): 2.57 ppm (triplet, 1 H, OH); 3.38 ppm (singlet, 3 H, CH3O); 3.62 ppm (multiplet, 30 H, OCH2CH2).
Stage #1: With potassium <i>tert</i>-butylate In tetrahydrofuran at 20℃; for 0.5 h; Stage #2: at 20℃;
Tetra(ethylene glycol) (55 mmol, 10.7 g) was dissolved in 100 mL of tetrahydrofuran ("THF") and to this solution was added KOtBu (55 mL, 1.0 M in THF) at room temperature. The resulting solution was stirred at room temperature for 30 minutes, followed by dropwise addition of CH3OCH2CH2Br (55 mmol, 5.17 mL in 50 mL THF). The reaction was stirred at room temperature overnight, followed by extraction with H2O (300 mL)/CH2Cl2 (3.x.300 mL). The organic extracts were combined and then dried over anhydrous Na2SO4. After filtering off the solid drying agent and removing the solvent by evaporation, the recovered crude residue was purified by column chromatography using a silica gel column (CH2Cl2:CH3OH=60:140:1) to give pure penta(ethylene glycol) monomethyl ether (yield 35percent). 1H NMR (CDCl3) δ 3.75-3.42 (m, 20 H, OCH2CH2O), 3.39 (s, 3H, MeO).
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 5 h;
[00546] To a solution of 4-nitrophenol (2.78 g, 20 mmol) and 2-bromoethyl methyl ether (3.6 g,26 mmol) in DMF (10 mL) were added K2C03 (5.52 g, 40 mmol) and the reaction was stirred at80°C for 5 h. The mixture was cooled down tort and then quenched with H20 (30 mL) andEtOAc ( 40 mL ). The layers were separated and the aqueous layer was extracted with EtOAc (2x 25 mL). The combined organic extracts were washed with brine (2 x 20 mL), dried (Na2S04)and concentrated to afford 1-(2-methoxyethoxy)-4-nitrobenzene (38) (3.9 g, 100percent) as a yellowsolid.
97.6%
With potassium carbonate In N,N-dimethyl-formamide at 65 - 70℃; for 4 h;
To a solution of 4-nitrophenol (18.2 g, 130 mmol) and 1-bromo-2-methoxyethane (20 g, 144 mmol) in DMF (60 ml), K2CO3 (36 g, 260 mmol) was added. The reaction mixture was stirred at 65~70°C for 4 h and then cooled to room temperature. Water (200 mL) was added and the mixture was extracted with ethyl acetate (200 mL x3). The combined organic layers were washed with water (200 ml x3), dried over Na2SO4. The solvent was removed under reduced pressure to yield the desired product (3) as white solid (25 g, 97.6percent yield), which was used for the next step without further purification.
Reference：
[1] Patent: WO2014/130693, 2014, A1, . Location in patent: Paragraph 00544; 00546
[2] Patent: WO2015/6754, 2015, A2, . Location in patent: Paragraph 00243; 00244
[3] European Journal of Medicinal Chemistry, 1980, vol. 15, # 5, p. 399 - 404
[4] Patent: US2005/277668, 2005, A1, . Location in patent: Page/Page column 17
EXAMPLES; a) 2-(l-pyrrolidino)-ethyl triphenyl phosphonium bromide is obtained by refluxing Triphenyl phosphine (300 gm, 1.14 mole) and 2-methoxy ethyl bromide (2QQgni, 1.43 rnole) in toluene (1 It) for 24 hours. Reaction mass was then cooled to 3O0C and filtered to obtain 2-Methoxy ethyl triphenyl phosphonium bromide (450gm, 78percent) which is further reacted <n="7"/>with pyrrolidine (96gm, 1.37 mole) in methanol (500ml) at 60 C for 2 hours. Distilled off methanol and the solid obtained was suspended in toluene (lit), then cooled to 300C and filtered to obtain 2-(l-pyrrolidino)- ethyl triphenyl phosphonium bromide (450gm, 91percent). NMR (D2O) δ : 1.67 (m,4H), 2.46 (m,4H), 2.78 (m,2H), 3.41 (m,2H), 7.68 (m, 15H)
With potassium carbonate In N,N-dimethyl-formamide at 60℃;
General procedure: K2CO3 (18 mmol, 2.5 g) was suspended in 15 mL of DMF. The phenol (6.0 mmol) and the alkyl halide (6.6 mmol) were added subsequentially and the suspension was stirred overnight at 60 °C. The reaction mixture was diluted with 50 mL demiwater and the resulting reaction mixture was extracted with with EtOAc (3 x 30 mL). The combined organic layers were, washed with brine (1 x 50 mL), dried over Na2SO4 and filtered. The solvent was evaporated under reduced pressure to give the product in high purity.
48%
With potassium carbonate In N,N-dimethyl-formamide at 20℃;
Step 1-Preparation 1-Bromo-4-(2-methoxy-ethoxy)-benzene (42)To a solution of 4-bromophenol (41, 5.0 g, 28.9 mmol) in dimethylformamide (15 mL) were added potassium carbonate (4.40 g, 31.8 mmol) and 1-bromo-2-methoxyethane (5.00 g, 36.0 mmol) under an atmosphere of nitrogen. The reaction mixture was stirred at ambient temperature overnight and concentrated under reduced pressure. The residue was slurried in ethyl acetate (50 mL) and filtered. The filtrate was washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and filtered. Silica gel column chromatography (0-10percent ethyl acetate in hexanes) gave the desired compound as a colorless oil (42, 3.2 g, 48percent).
48%
With potassium carbonate In N,N-dimethyl-formamide at 20℃;
To a solution of 4-bromophenol (646, 5.0 g, 28.9 mmol) in dimethylformamide (15 mL) were added potassium carbonate (4.40 g, 31.8 mmol) and l-bromo-2-methoxyethane (5.00 g, 36.0 mmol) under an atmosphere of nitrogen. The reaction mixture was stirred at ambient temperature overnight and concentrated under reduced pressure. The residue was slurried in ethyl acetate (50 mL) and filtered. The filtrate was washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and filtered. Silica gel column chromatography (0-10percent ethyl acetate in hexanes) gave the desired compound as a colorless oil (647, 3.2 g, 48percent).
Reference：
[1] European Journal of Medicinal Chemistry, 2012, vol. 47, # 1, p. 337 - 344
[2] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 6, p. 1659 - 1662
[3] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 16, p. 3670 - 3674
[4] Patent: US2008/167338, 2008, A1, . Location in patent: Page/Page column 41
[5] Patent: WO2007/2325, 2007, A1, . Location in patent: Page/Page column 216
[6] Bulletin of the Chemical Society of Japan, 1997, vol. 70, # 10, p. 2519 - 2523
[7] Patent: US2005/209278, 2005, A1,
[8] Patent: US2005/9838, 2005, A1, . Location in patent: Page 130
19
[ 6482-24-2 ]
[ 139-85-5 ]
[ 80407-64-3 ]
Yield
Reaction Conditions
Operation in experiment
98%
With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 2 h;
a) 3,4-bis (2-methoxyethoxy) benzaldehyde:; To 3, 4-dihydroxy benzaldehyde of the formula Il (25g, 0.1811 mole), potassium carbonate (6Og, 0.4347 mole) in N, N-dimethyl formamide (120ml) was added 2-bromoethylmethyl ether (50.4g, 0.3625 mole). The mixture was stirred at 1000C for 2 hours, cooled to room temperature, filtered inorganics. The clear filtrate was concentrated under vacuum and the residue was dissolved in methylene chloride, washed with water and dried over calcium chloride. ^Evaporation yielded 3,4-bis (2-methoxyethoxy) benzaldehyde of formula III (45g, 98percent).NMR spectrum (CDCI3): δ 3.46 (s, 6H), 3.81 (m, 4H), 4.22 (m, 4H), 7.00(d, 1 H), 7.43(s, 1 H), 7.45(d, 1 H) and 9.83(s, 1 H).
98%
With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 2 h;
a) 3,4-bis (2-methoxyethoxy) benzaldehyde:; To 3, 4-dihydroxy benzaldehyde of the formula Il (25g, 0.1811 mole), potassium carbonate (6Og, 0.4347 mole) in N, N-dmethyl formamide (120ml) was added 2-bromoethylmethyl ether (50.4g, 0.3625 mole). The mixture was stirred at 1000C for 2 hours, cooled to room temperature, filtered inorganics. The clear filtrate was concentrated under vacuum and the residue was dissolved in methylene chloride, washed with water and dried over calcium chloride. Evaporation yielded 3,4-bis (2- methoxyethoxy) benzaldehyde of formula III (45g, 98percent).NMR spectrum (CDCI3): δ 3.46 (s, 6H), 3.81 (m, 4H), 4.22 (m, 4H), 7.00(d, 1 H), 7.43(S1 1H)1 7.45(d, 1 H) and 9.83(s, 1 H).
With potassium carbonate; potassium iodide In acetone at 60℃; for 19 h; Inert atmosphere
(3) Preparation of Ethyl 3,4-dimethoxyethoxybenzoate 13 Ethyl 3,4-dihydroxy benzoate 12 (5 g, 27.45 mmol) is placed in a two-neck bottle of 250 ml, N2 is added at room temperature, and acetone (100 ml), potassium carbonate (9.48 g, 68.63 mmol), potassium iodide (0.5 g) and 2-Bromoethyl methyl ether (7.84 ml, 82.35 mmol) are added. Then heat refluxing is carried out at 60° C. for 19 hours. After the reaction is completed, the resultant of reaction is cooled at 5° C. and stirred for 30 minutes, then filtered and concentrated to dry. The solid is dried by oil-less pump for 22 hours to obtain khaki compound 13 (8.19 g, 100percent). 1H-NMR (CDCl3) spectrum: 1.32 (t, 3H, J=7 Hz), 3.41 (s, 6H), 3.76 (m, 4H), 4.15 (m, 4H), 4.29 (q, 2H, J=7 Hz), 6.85 (d, 1H, J=8.4 Hz), 7.53 (dd, 1H, J=8.4 Hz, J=2.3 Hz), 7.53 (m, 1H), 7.63 (dd, 1H, J=8.4 Hz, J=2.3 Hz).
93%
With potassium carbonate In acetone at 20 - 70℃; for 24 h;
3,4-Dihydroxy-benzoic acid ethyl ester (compound A') (2.0 g) was dissolved in acetone (20 ml). Potassium carbonate (4.3 g) and 1-bromo-2-methoxy-ethane (compound D) (5 ml) were added to the solution at room temperature, and the mixture was then stirred at 70°C for 24 hr. After the completion of the reaction, the reaction solution was allowed to stand for cooling at room temperature, and the reaction system was concentrated under the reduced pressure. Distilled water was added to the residue, and the mixture was then subjected to separatory extraction with chloroform. The organic layer was washed with saturated brine, was dried over sodium sulfate, and was then concentrated under the reduced pressure. The residue was purified by column chromatography using a hexane-acetone system to give 3,4-bis-(2-methoxy-ethoxy)-benzoic acid ethyl ester (3.06 g, yield 93percent).
93%
With tetra-(n-butyl)ammonium iodide; potassium carbonate In acetone for 64 h; Inert atmosphere; Reflux
To ethyl 3,4-dihydroxybenzoate (36.4 g, 0.200 mol), K2CO3 (60.8 g, 0.44 mol) and tetrabutylammonium iodide(750 mg) in degassed acetone (400 mL) was added 2-bromoethyl methyl ether (69.5 g, 47 mL). The mixture was stirred under N2 at reflux for 64 hours. Ether (600 mL) was added to the mixture and after stirring 30 minutes at 20 °C theprecipitated salts were removed by filtration. The filtrate was concentrated in vacuo and the residue was triturated withhexane (500 mL) for 30 minutes and the white solid ethyl 3,4-bis(2-methoxy-ethoxy)benzoate was filtered and dried invacuo (55.5 g; 93percent; M.P. 50-51 °C). A portion of this product (45.7 g, 0.158 mol) in acetic acid (150 mL) was treateddropwise with conc. HNO3 (40 mL) at 5°C and the solution stirred 24 hours before pouring into cold H2O (1.6 L). Themixture was extracted with ethyl acetate (1.1 L), and the organic phase was washed three times with 200 mL H2O, andbrine, dried over Na2SO4, filtered and concentrated in vacuo to afford ethyl 4,5-bis-(2-methoxy-ethoxy)-2-nitro-benzoate(54.3 g) as a brown oil. This nitro product (52.0 g, 0.15 mol) was dissolved in ethanol (1000 mL) containing 1 equivalentof HCl (generated in the ethanol by prior addition of 11 mL acetyl chloride), PtO2•H2O (1.0 g) was added, and the mixturewas hydrogenated under 45 psi H2 for 6 hours. The catalyst was removed by filtration through Celite, and the filtratewas concentrated in vacuo to a thick slurry which was diluted with ether (400 mL). The solid white hydrochloride salt ofethyl 2-amino-4,5-bis-(2-methoxy-ethoxy)benzoate was filtered and dried in vacuo (44.7 g; 88percent). A portion of this material(42 g, 0.12 mol) and ammonium formate (7.6 g, 0.12 mol) were disssolved in formamide (63 mL) and the stirred mixturewas heated to 160-165 °C under an atmosphere of N2 for 3 hours. H2O (200 mL) was added and after cooling theprecipitated crude title product was recovered by filtration, washed with cold H2O, and dried in vacuo. The filtrate wasextracted five times with CHCl3, and the pooled organic extracts were washed with brine, dried over Na2SO4, andconcentrated in vacuo. The residue and crude quinazolone precipitate were combined, triturated in hot acetonitrile (250mL) for 30 minutes, cooled to 20 °C and treated with ether (250 mL). After cooling to 4 °C the white solid was filteredand dried in vacuo (30.4 g, 86percent; GC-MS m/z 294 (M+)).
Reference：
[1] Patent: US2010/267949, 2010, A1, . Location in patent: Page/Page column 6
[2] Patent: EP1614676, 2006, A1, . Location in patent: Page/Page column 194
[3] Patent: EP2163546, 2016, B1, . Location in patent: Paragraph 0125
[4] European Journal of Medicinal Chemistry, 2008, vol. 43, # 7, p. 1478 - 1488
[5] Chemistry - A European Journal, 2015, vol. 21, # 41, p. 14342 - 14346
[6] Journal of Labelled Compounds and Radiopharmaceuticals, 2005, vol. 48, # 11, p. 829 - 843
[7] Molecules, 2006, vol. 11, # 4, p. 286 - 297
[8] European Journal of Medicinal Chemistry, 2013, vol. 67, p. 293 - 301
[9] Journal of Labelled Compounds and Radiopharmaceuticals, 2018, vol. 61, # 2, p. 42 - 53
21
[ 3943-89-3 ]
[ 6482-24-2 ]
[ 183322-16-9 ]
Reference：
[1] Patent: US5821246, 1998, A,
22
[ 6482-24-2 ]
[ 2096-10-8 ]
[ 473278-54-5 ]
Reference：
[1] Nucleosides, Nucleotides and Nucleic Acids, 2008, vol. 27, # 9, p. 1024 - 1033
23
[ 269410-08-4 ]
[ 6482-24-2 ]
[ 847818-71-7 ]
Yield
Reaction Conditions
Operation in experiment
90%
With potassium carbonate In N,N-dimethyl-formamide at 160℃; for 2 h; Microwave irradiation
A mixture of 4-(4,4,5 ,5 -tetramethyl- 1,3 ,2-dioxaborolan-2-yl)- 1H-pyrazole (1.94 g, 10 mmol), 2-bromoethyl methyl ether (1.68 g, 12 mmol) and K2C03 (2.76 g, 20 mmol) in DMF (16 mL) was stirred at 160 °C for 2 h in the microwave. The reaction mixture was concentrated and purified by silica gel chromatography (30percent EA:PE) to give 2.2 g (90percent) of the title compound as yellow oil. ‘H NMR (400 MHz, CDC13): ö 1.32 (12H, s), 3.32 (3H, s), 3.75 (2H, t, J= 5.2 Hz), 4.30 (2H, t, J= 5.2 Hz), 7.77 (1H, s), 7.79 (1H, s). [M+H] Calc’d for C,2H2,BN203, 253; Found, 253.
68%
With caesium carbonate In N,N-dimethyl-formamide at 150℃; for 0.5 h; Microwave irradiation
Example A68Preparation of intermediate 68: l-(2-Methoxy-ethyl)-4-(4,4,5,5-tetramethyl- [l,3,21dioxaborolan-2-yl)-7H-pyrazoleA mixture of 4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-7H-pyrazole (1 g, 5.15 mmol), 2-bromoethyl methyl ether (0.63 ml, 6.7 mmol) and cesium carbonate (2.52 g, 7.73 mmol) in N,N-dimethylformamide (7 ml) was stirred at 150 °C for 30 min. under microwave irradiation. The mixture was partitioned between water and diethyl ether. The organic layer was separated, dried (Na2S04), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; ethyl acetate in heptane 30/70). The desired fractions were collected and concentrated in vacuo to yield intermediate 68 (0.88 g, 68percent) as a pale yellow oil.
68%
With caesium carbonate In N,N-dimethyl-formamide at 150℃; for 0.5 h; microwave irradiation
Example A68 Preparation of intermediate 68: 1-(2-Methoxy-ethyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole A mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (1 g, 5.15 mmol), 2-bromoethyl methyl ether (0.63 ml, 6.7 mmol) and cesium carbonate (2.52 g, 7.73 mmol) in N,N-dimethylformamide (7 ml) was stirred at 150° C. for 30 min. under microwave irradiation. The mixture was partitioned between water and diethyl ether. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; ethyl acetate in heptane 30/70). The desired fractions were collected and concentrated in vacuo to yield intermediate 68 (0.88 g, 68percent) as a pale yellow oil.
57%
With caesium carbonate In N,N-dimethyl-formamide at 0 - 20℃;
2-Bromoethyl methyl ether (0.93 g, 6.70 mmol, 0.64 mL) was added to a mixture of 4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (1 .00 g, 5.15 mmol) and caesium carbonate (3.49 mg, 10.72 mmol) in dry N,N-dimethylformamide (20 mL) at 0°O. After stirring for 30 mm the ice-water bath was removed. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (150 mL) and washed with brine(3x100 mL). The organic layer was dried with sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (Method L7; 12 g; heptane, 10percent-30percent ethyl acetate) afforded 0.74 g (2.92 mmol; 57percent of theory) of the title compound.GO-MS (Method L9): R1 = 4.21 mm; m/z = 251 MH NMR (300 MHz, Ohloroform-d, Method M2) 6 7.79 (s, 1 H), 7.76 (s, 1 H), 4.29 (t, J = 5.3 Hz,2H), 3.75 (t, J = 5.3 Hz, 2H), 3.32 (s, 3H), 1.31 (s, 12H).
56%
Stage #1: With sodium hydride In N,N-dimethyl-formamide for 0.25 h; Stage #2: at 80℃; for 1 h; Microwave irradiation
General procedure: Preparation 122: 1 -(2-Methoxyethyl)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H- Method H NaH (60percent, 83 mg) was added to a solution of 4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 - -pyrazole (204 mg, 1 .05 mmol) in DMF (4 mL). After stirring for 15 minutes, 1 -bromo-2-methoxyethane (175 mg, 1 .26 mmol) in DMF (1 mL) was added. The resulting solution was stirred at 80°C under microwave irradiation for 60 minutes. The reaction mixture was diluted with brine and extracted with EtOAc. The combined organic layers were washed with water, dried with Na2S04j and concentrated in vacuo to afford the title compound as a yellow oil that was used directly in the next step (148 mg, 56percent). 1 H NMR (500 MHz, CDCI3): δ 7.80 (d, J = 0.7 Hz, 1 H), 7.77 (d, J = 0.7 Hz, 1 H), 4.31 (t, = 5.3 Hz, 2H), 3.76 (t, J = 5.3 Hz, 2H), 3.33 (s, 3H), 1.32 (s, 12H). LCMS (ESI) Rt = 2.17 minutes MS m/z 253 [M+H]+
26%
Stage #1: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 1 h; Stage #2: at 0 - 20℃; for 1 h;
To a solution of 4-(tetramethyl-1 ,3, 2-dioxaborolan-2-yl)-1H-pyrazole (1 .00 g, 5.1 mmol) in DMF (5 mL) was added sodium hydride (245 mg of a 60percent dispersion in mineral oil, 6.1 mmol) at room temperature. The mixture was then stirred at room temperature for 60 minutes. The mixture was cooled to 0 ° C and 2-bromoethyl methyl ether (0.72 mL, 7.7 mmol) was added drop wise via syringe. After complete addition, the mixture was allowed to warm to room temperature and stirred for an hour prior to addition of ethyl acetate (70 mL) and water (30 mL). The organic layer was separated, washed with water (2 x 30 mL) and brine (30 mL), dried (Na2S04), filtered and concentrated at reduced pressure. The residue was purified by Biotage Isolera™ chromatography [Biotage SNAP Cartridge KP-Sil 50 g; using a gradient of eluents, 0-50percent EtOAc in heptane] to give the title compound (333 mg, 26percent yield) as a colourless oil. 1H NMR (250 MHz, DMSO-d6) δ [ppm] 7.88 (s, 1 H), 7.57 (s, 1 H), 4.32 - 4.20 (m, 2H), 3.73 - 3.60 (m, 2H), 3.21 (s, 3H), 1 .25 (s, 12H). LCMS (Analytical Method A): Rt = 1 .01 mins, MS (ESIPos): m/z = 253 (M+H)\
20%
With potassium hydroxide In ethanol at 50℃; for 76 h;
Intermediate 1171 -[2-(Methyloxy)ethyl]-4-(4,4,5,5-tetrameth l-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazolA solution of 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (10 g, 51 .5 mmol) in ethanol (50 mL) was treated with KOH (3.47 g, 61 .8 mmol) and 1 -bromo-2- (methyloxy)ethane (5.81 mL, 61.8 mmol) at room temperature and the resulting mixture was stirred at 50°C under nitrogen for 16 h then cooled to room temeprature. 1 -Bromo-2- (methyloxy)ethane (2 ml_, 21 .3 mmol) was added and the resulting mixture was stirred at 50°C for 60 h then cooled to room temperature. The mixture was filtered through celite and the insoluble were washed with ethanol. The combined filtrate and washings were concentrated in vacuo. Purification of the residue on SP4 using a 100 G silica cartridge (gradient: 0 to 100percent AcOEt in Hexanes) gave 1 -[2-(methyloxy)ethyl]-4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 /-/-pyrazole (2.72 g, 10.25 mmol, 20percent) as a yellow oil. LCMS (method G): Retention time 0.87 min, [M+H]+ = 252.9
20%
With potassium hydroxide In ethanol at 50℃; for 66 h; Inert atmosphere
A solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (10 g, 51.5 mmol) in ethanol (50 mL) was treated with KOH (3.47 g, 61.8 mmol) and 1-bromo-2-(methyloxy)ethane (5.81 mL, 61.8 mmol) at room temperature and the resulting mixture was stirred at 50° C. under nitrogen for 16 h then cooled to room temperature. 1-Bromo-2-(methyloxy)ethane (2 mL, 21.3 mmol) was added and the resulting mixture was stirred at 50° C. for 60 h then cooled to room temperature. The mixture was filtered through celite and the insoluble were washed with ethanol. The combined filtrate and washings were concentrated in vacuo. Purification of the residue on SP4 using a 100 G silica cartridge (gradient: 0 to 100percent AcOEt in Hexanes) gave 1-[2-(methyloxy)ethyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.72 g, 10.25 mmol, 20percent) as a yellow oil. LCMS (method G): Retention time 0.87 min, [M+H]+=252.9
25.4 g
With caesium carbonate In N,N-dimethyl-formamide at 80℃;
4-(4,4,5,5-Tetramethyl-[1 ,3,2]clioxaborolan-2-yl)-1 H-pyrazole (19.4 g, 0.10 mol), 1- bromo-2-methoxy-ethane (14.18 ml, 0.15 mol), and caesium carbonate (32.58 g, 0.1 mol) are dissolved in DMF (200 ml). The suspension is stirred for 16 h at 80°C, filtered and the solvent is removed in vacuum. The residue is treated with tert-butyl methyl ether (200 ml), filtered over Celite and then the solvent is removed in vacuum; yield: 25.4 g 1-(2-methoxy-ethyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxa- borolan-2-yl)-1H-pyrazole; HPLC/MS: 1.82 min, [M+H] = 253.
1.31 g
With caesium carbonate In acetonitrile at 50℃; Inert atmosphere
1H-pyrazole-4-boronic acid pinacol ester (1.0 g, 5.155 mmol),2-Bromoethyl methyl ether (0.788 g, 5.669 mmol)And cesium carbonate (5.04 g, 15.469 mmol) were dissolved in acetonitrile (20 mL),The mixture was stirred under nitrogen at 50 ° C overnight,filter,Concentrate to dryness to give 1- (2-methoxyethyl) -1H-pyrazole-4-boronic acid pinacol ester (1.310 g).
With caesium carbonate In N,N-dimethyl-formamide at 60℃;
To a solution of lH-pyrazole-4-carbaldehyde (500 mg, 5.20 mmol) in DMF (20 mL) was added l-bromo-2-methoxyethane (713 mg, 5.2 mmol) and CS2CO3 (3.40 g, 10.4 mmol). After stirring at 60 °C overnight, water (20 mL) was added to the mixture and the mixture was extracted with EtOAc (50 ml x 3). The organic phase was washed with brine, dried over Na2S04 and concentrated to yield intermediate 50 (520 mg, 65percent> yield).
55%
With caesium carbonate In acetonitrile for 2 h; Reflux
1H-pyrazole-4-carbaldehyde (0.5 g; 5.2 mmol) and cesium carbonate (3.39 g; 10.4mmol) were diluted in ACN (10 mL). Then, 2-bromoethyl methyl ether (0.636 mL; 6.77 mmol) was added and the reaction mixture was refluxed for 2 hours. The reaction mixture was partitionned between a saturated solution of NaHCO3 and EtOAc. The organic layer was separated, dried over MgSO4, filtered and concentrated.The residue was purified by silica gel chromatography (irregular Si02, 120 g, DCM/MeOH: 100/0 to 95/5). The fractions containing the product were mixed andconcentrated to afford 439 mg (55percent) of intermediate 35.
With potassium carbonate In acetonitrile at 80℃; for 4 h;
[0223j To a mixture of 4-nitro-1H-pyrazole (113 mg, 1 mmol, 1.0 eq) in CH3CN (5 mL), 1-bromo-2-methoxyethane (138 mg, 1 mmol, 1.0 equiv) and K2C03 (276 mg, 2 mmol, 2.0 equiv) was added. The mixture was stirred at 80 °C for 4 h. After diluted with EtOAc (100 mL), the mixture was washed with water (50 mL x 2). The organic layer was concentrated and purified by silica gel column (petroleum ether/EtOAc = 10 : 1) to give 1-(2-methoxyethyl)-4-nitro-1H- pyrazole (170 mg, yield: 100percent) as a colorless oil. ESI-MS (M+H): 172.1. ‘H NMR (400 MHz, CDC13) (5: 8.23 (s, 1H), 8.07 (s, 1H), 4.31 (t, J= 5.2 Hz, 2H), 3.74 (t, J= 5.2 Hz, 2H), 3.35 (s, 3H).
97%
With potassium carbonate In acetonitrile at 90℃; for 5 h;
To a solution of 4-nitro-1H-pyrazole 12 (1.70 g, 15.03 mmol) in CH3CN (50 mL) was added K2C03 (3.11 g, 22.53 mmol) followed by addition of 1-bromo-2- methoxy-ethane (2.5 g, 18.0 mmol) at room temperature. The reaction mixture was heated to 90°C for 5 h. After completion of reaction (monitored by TLC), the solvent was evaporated, added water and extracted with EtOAc (3 x 200 mL). the combined organics was washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 2.50 g (97percent yield) of the title compound 16 as colorless liquid. 1H NMR (400 MHz, DMDO-d6): 3 8.85 (s, 1H), 8.27 (s, 1H), 4.36-4.33 (t, 2H), 3.77-3.72 (t, 2H), 3.23 (s, 3H). MS: 172.11 (M+H).
76%
With potassium carbonate In acetonitrile at 60℃; for 6 h;
A mixture of 4-nitro-1H-pyrazole (1 equiv), 1-bromo-2-methoxyethane (1.05 equiv), potassium carbonate (1.5 equiv) and acetonitrile (0.44 M) was stirred and heated to 60° C. for 6 h. The resultant mixture was evaporated and the residue was purified by flash chromatography (2.5percent MeOH in DCM) to afford the desired product as a yellow solid (76percent yield). 1H NMR (400 MHz, CHLOROFORM-d1) δ ppm 8.25 (s, 1H), 8.08 (s, 1H), 4.34-4.31 (t, J=4.8 Hz, 2H), 3.77-3.74 (t, J=4.8 Hz, 2H), 3.37 (s, 3H)
With potassium carbonate; In N,N-dimethyl-formamide; at 60℃;
General procedure: K2CO3 (18 mmol, 2.5 g) was suspended in 15 mL of DMF. The phenol (6.0 mmol) and the alkyl halide (6.6 mmol) were added subsequentially and the suspension was stirred overnight at 60 C. The reaction mixture was diluted with 50 mL demiwater and the resulting reaction mixture was extracted with with EtOAc (3 x 30 mL). The combined organic layers were, washed with brine (1 x 50 mL), dried over Na2SO4 and filtered. The solvent was evaporated under reduced pressure to give the product in high purity.
48%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;
Step 1-Preparation 1-Bromo-4-(2-methoxy-ethoxy)-benzene (42)To a solution of 4-bromophenol (41, 5.0 g, 28.9 mmol) in dimethylformamide (15 mL) were added potassium carbonate (4.40 g, 31.8 mmol) and 1-bromo-2-methoxyethane (5.00 g, 36.0 mmol) under an atmosphere of nitrogen. The reaction mixture was stirred at ambient temperature overnight and concentrated under reduced pressure. The residue was slurried in ethyl acetate (50 mL) and filtered. The filtrate was washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and filtered. Silica gel column chromatography (0-10% ethyl acetate in hexanes) gave the desired compound as a colorless oil (42, 3.2 g, 48%).
48%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;
To a solution of 4-bromophenol (646, 5.0 g, 28.9 mmol) in dimethylformamide (15 mL) were added potassium carbonate (4.40 g, 31.8 mmol) and l-bromo-2-methoxyethane (5.00 g, 36.0 mmol) under an atmosphere of nitrogen. The reaction mixture was stirred at ambient temperature overnight and concentrated under reduced pressure. The residue was slurried in ethyl acetate (50 mL) and filtered. The filtrate was washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and filtered. Silica gel column chromatography (0-10% ethyl acetate in hexanes) gave the desired compound as a colorless oil (647, 3.2 g, 48%).
With potassium carbonate; In ethyl acetate; N,N-dimethyl-formamide;
Part A: Preparation of 1-bromo-4-(2-methoxyethoxy)benzene To a room temperature solution of 4-bromophenol (5 g, 28.9 mmol) in 15 mL DMF under N2 was added 2-bromoethyl methyl ether (5 g, 36.4 mmol) and potassium carbonate (4.4 g, 31.8 mmol). The resulting solution was stirred overnight at ambient temperature under N2. Afterward, no starting material remained. The mixture was concentrated, partially dissolved in ethyl acetate (50 mL), and filtered. The filtrate was concentrated under reduced pressure, affording 5.6 g of crude oil. 1H NMR and mass spectrometry (MNa+=287.0) were consistent with the desired product.
With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 20℃;
To a room temperature solution of 4-bromophenol (5 g, 28.9 mmol) in 15 mL DMF under N2 was added 2-bromoethyl methyl ether (5 g, 36.4 mmol) and potassium carbonate (4.4 g, 31.8 mmol). The resulting solution was stirred overnight at ambient temperature under N2. Afterward, no starting material remained. The mixture was concentrated, partially dissolved in ethyl acetate (50 mL), and filtered. The filtrate was concentrated under reduced pressure, affording 5.6 g of crude oil. 1H NMR and mass spectrometry (MNa+=287.0) were consistent with the desired product.
With potassium carbonate; potassium iodide; In DMF (N,N-dimethyl-formamide); at 80℃; for 1h;
The starting material was prepared as follows: A mixture of 2-methoxy-5-nitrophenol (6 g, 35 mmol), 2-bromoethyl methyl ether (4 ml, 40 mmol), potassium carbonate (5.8 g, 40 mmol) and potassium iodide (0.5 g) in DMF (50 ml) was heated at 80 C. for 1 hour.. The mixture was allowed to cool and poured into water (400 ml).. The resulting precipitate was collected by filtration, washed with water and dried under vacuum to give 4-methoxy-3-(2-methoxyethoxy)nitrobenzene (7.75 g, 98%). 1H NMR Spectrum: (CDCl3) 3.46 (s, 3H); 3.82 (t, 2H); 3.96 (s, 3H); 4.25 (t, 2H); 6.91 (d, 1H); 7.79 (d, 1H); 7.92 (dd, 1H); MS-ESI: 227 [MH]+;
1-bromo-2-chloro-4-(2-methoxy-ethoxy)-benzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 90℃; for 24h;
Step 1: Combine <strong>[13631-21-5]4-<strong>[13631-21-5]bromo-3-chlorophenol</strong></strong> (2.00 g, 9.64 mmol), 2-bromoethyl methyl ether (1.28 g, 9.20 mmol) and K2CO3 (1.86 g, 13.5 mmol) in DMF (20 ml). Heat at 90 C. 24 h and allow to cool. Partition between 0.2N NaOH and ether. Wash with brine, dry (MgSO4) and concentrate to obtain the aryl ether as a yellow oi
With sodium hydride; In N,N-dimethyl-formamide; at 0 - 50℃;
Step B The Preparation of tert-butyl (3R)-3-(2-methoxyethoxy)piperidine-1-carboxylate To a solution of tert-butyl (3R)-3-hydroxypiperidin-1-carboxylate (300 mg, 1.5 mmol) in dry DMF (5 mL) was added sodium hydride (60%, 115 mg, 3.0 mmol) at 0 C. under nitrogen and the suspension was stirred at room temperature for 30 min. 1-Bromo-2-methoxyethane (0.17 mL, 1.8 mmol) was added to the reaction mixture and stirred over night at room temperature. The reaction mixture was heated at 50 C. and Sodium hydride (60%, 58 mg, 1.5 mmol) was added, then 1-bromo-2-methoxyethane (0.17 mL, 1.8 mmol). The reaction mixture was stirred at 50 C. for 2 hours. Sodium hydride (60%, 58 mg, 1.5 mmol) was added, then 1-bromo-2-methoxyethane (0.17 mL, 1.8 mmol). The reaction was stirred at 50 C. for 2 hours and then cooled to room temperature. The reaction was quenched with water (1 mL) at 0 C. The solvent was removed in vacuo and the residue was dissolved in dichloromethane (30 mL) and water (25 mL). The phases were separated and the aqueous was extracted with dichloromethane (2*30 ml). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The product was purified by column chromatography (50% heptane in ethyl acetate). The product was obtained as colourless oil (328 mg, 84%). 1H NMR (400 MHz, CHLOROFORM-D) delta ppm 1.38-1.53 (m, 4H), 1.46 (s, 9H), 1.68-1.79 (m, 1H), 1.93-2.03 (m, 1H), 2.89-3.00 (m, 2H), 3.27-3.35 (m, 1H), 3.39 (s, 3H), 3.51-3.56 (m, 2H), 3.59-3.73 (m, 2H).
3-hydroxy-N-[(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]adamantane-1-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In water; ethyl acetate; for 14h;Heating / reflux;
A mixtitie of 3-hydroxyadamantane-l -carboxylic acid (1000 mg, 5 10 mmo]) and l,r-caiotabonyldiimidazole (992 mg, 6.12 mmol) in EtOAc (25 mL) were stirred at ambient temperature Foi 4 hours. The mixture was treated with water (5 ml) and the product of Example 46A (13620 mg, 5 10 rnmol), then heated at reflux for 14 hours. The mixture was diluted with water and EtOAc and then the phases were separated The organic extract was washed with water (2X) and brine, dried over MgSO4, and concentrated- The solid was crystallized from hot EtOAc to afford 1430 rng (77%) of the title compound MS (DCI/NH3) m/z 365 (M+H) Anal Calculated foi C19H26N2O3S: C, 62.61 ; H, 7 74; N, 7 69, Found: C, 62,35; H, 8,08; N, 7,77.
3-([(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]amino}carbonyl)adamantane-1-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In tetrahydrofuran; at 0 - 65℃; for 6h;
Adamantane-l,3-dicarboxylic acid (1 0 g, 4 4 mmol) was dissolved in 5 mL thionyl chloride and heated to reflux for 1 5 hours The mixture was cooled to ambient temperatuie and then concentrated under reduced pressure To a solution of the unpurifed acid chloride and the pioduct of Example 46A (0 82 g, 4.4 mmol) in 20 ml of THF at 0 0C was added triethylamine (1.4 ml , 9 7 mmol) The mixture was warmed to 65 0C and stirred for 6 hours The mixture was diluted with ethyl acetate and washed with saturated potassium carbonate, water and brine The aqueous washings were combined and extracted with ethyl acetate The combined organic extracts were dried over magnesium sulfate and concentrated under reduced pressure <n="60"/>Purification by column chromatography (SiO?, 20-40% ethyl acetate/hexanes gradient) affoided the title compound. 1H NMR (DMSO-d, 300 MHz) delta ppm 1 62 (s,2 H), 1 69- 1 92 (m, 10 H), 2 08 (s, 2 H), 2 15 (s, 3 H), 2 20 (s, 3 H), 3 24 (s, 3 H),3 64 (t, ./=5 4 Hz, 2 H), 4 24 (t, ,/=5.4 Hz, 2 H), 12 01 (br s, 1 H); MS (DCI/NH3) m/z 393 (M+H)+ Anal Calculated foi C20H28N2O4S 0.3H2O: C, 60 37; H, 7 24; N, 7,04Found: C, 60.21 ; H, 7 15; N, 7 1 1
1-adamantan-2-yl-3-[(2Z)-3-(2-methoxyethyl)-4,5-dimethyl-1,3-thiazol-2(3H)-ylidene]urea[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In tetrahydrofuran; at 20 - 120℃; for 0.5h;Microwave irradiation;
To a solution of adamantan-2-ylamine (167mg, 1 00 mmol) in 19 mL of THF and 1 mL of N,N-diisopropylethylamine was added 4-nitrophenyI chloroformate (403 mg, 2 00 mmol) The solution was irradiated in a sealed tube placed in a single node microwave at 70 0C for 300 sec (maximum power 300W) with stirring The resulting <n="91"/>solution was cooled to room temperature and the product of Example 46A (300 mg, 1 10 mmol) was added. The sealed tube was irradiated at 120 0C for 1800 sec with stirring The mixture was cooled to ambient temperature and the solvent removed under reduced pressure. The residue was partitioned between water and ethyl acetate and the phases were separated. The organic extract was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. Purification by column chromatography (SiO;?, 0-70% ethyl acetate/hexanes gradient) afforded 153 mg (39%) of the title compound. 1H NMR (300 MHz, DMSO-d6) delta ppm 1.46 (d, /=14 Hz, 2 H), 1 68 (s, 2 H), 1.73 - 1.85 (m, 8 H), 2.00 (d, J=13 Hz, 2 H), 2 07 (s, 3 H), 2 12 (s, 3 H), 3.24 (s, 3 H), 3.57 (t, .7=6 Hz, 2 H), 3 74 (d, J=4 Hz, 1 H), 4.07 - 4.13 (m, 2 H), 6.59 (d, J=7 Hz, 1 H); MS (DCIYNH3) m/z 364 (M+H)+
With sodium hydride; In N,N-dimethyl-formamide; at 80℃; for 3h;
A solution of 4-amino-2-chloropyromidine-5-carbonitrile (0.101 g, 0.65 mmol) , bromoethyl methyl ether (0.09 mL, 0.98 mmol) , and NaH (60% suspension in mineral oil, 0.04 g, 0.98 mmol) in DMF (1 mL) is stirred at 80 C in an oil bath for 3 h. Water is added (2 mL) , and the aqueous phase is extracted with EtOAc (3 x) . The combined organic layers are washed with brine, dried over MgSO4, and evaporated to dryness. Purification of the crude material using a Biotage column (0 - 50% EtOAc/hexanes for 5 CV, and 50% EtOAc/hexanes for 10 CV) affords 0.0721 g of 2-Chloro-4- (2-methoxy-ethylamino) - pyrimidine-5-carbonitrile (52%) . LC/MS Calculated for C8H9ClN4O: m/z = 212.64. Found: m/z = 213 [M+H]+.
Example 12A 3-(2-Methoxyethyl)-4,5-dimethyl-3H-thiazol-2-ylideneamine hydrobromide A mixture of <strong>[2289-75-0]4,5-dimethylthiazol-2-ylamine</strong> (9.0 g, 70 mmol) and 2-bromoethyl methyl ether (7.9 mL, 84 mmol) were heated at 85 C. for 12 hours. The mixture was cooled to ambient temperature and then triturated with isopropanol. The solid was collected by filtration and dried under vacuum to provide 10 g (56%) of the title compound. 1H NMR (DMSO-d6, 300 MHz) delta ppm 2.17 (s, 3 H), 2.19 (s, 3 H), 3.25 (s, 3 H) 3.56 (t, J=5.1 Hz, 2 H) 4.16 (t, J=5.1 Hz, 2 H) 9.41 (s, 1 H); MS (DCI/NH3) m/z 129 (M+H)+.
56%
at 85℃; for 12h;
Example 82B 3-(2-Methoxyethyl)-4,5-dimethyl-3H-thiazol-2-ylideneamine hydrobromide A mixture of <strong>[2289-75-0]4,5-dimethylthiazol-2-ylamine</strong> (9.0 g, 70 mmol) and 2-bromoethyl methyl ether (7.9 mL, 84 mmol) were heated at 85 C. for 12 hours. The mixture was cooled to ambient temperature and then triturated with isopropanol. The solid was collected by filtration and dried under vacuum to provide 10 g (56%) of the title compound. 1H NMR (DMSO-d6, 300 MHz) delta ppm 2.17 (s, 3H), 2.19 (s, 3H), 3.25 (s, 3H) 3.56 (t, J=5.1 Hz, 2H) 4.16 (t, J=5.1 Hz, 2H) 9.41 (s, 1H).
56%
at 85℃; for 12h;
A mixture of <strong>[2289-75-0]4,5-dimethylthiazol-2-ylamine</strong> (9.0 g, 70 mmol) and 2-bromoethyl methyl ether (7.9 mL, 84 mmol) were heated at 85 0C for 12 hours. The mixture was cooled to ambient temperature and then triturated with isopropanol. The solid was collected by nitration and dried under vacuum to provide 10 g (56%) of the title compound. 1H NMR (DMSO-J6, 300 MHz) delta ppm 2.17 (s, 3 H), 2.19 (s, 3 H), 3.25 (s, 3 H) 3.56 (t, J=5.1 Hz, 2 H) 4.16 (t, J=5.1 Hz, 2 H) 9.41 (s, 1 H); MS (DCI/NH3) m/z 129 (M+H)+
With potassium carbonate; In DMF (N,N-dimethyl-formamide); for 20h;
Potassium carbonate (8. 25G, 60 mol) followed by 2-BROMOETHYL methyl ether (1.87 mL, 20 mmol) were added to a solution of <strong>[64080-15-5]2-bromo-4-ethyl-phenol</strong> (4g, 20 mmol, from step 1 of Example B (98) ) in DMF (25mL). The mixture was stirred for 20 hours and then partitioned between 1N HCI and EtOAc. The organic layers were washed with brine, dried over NA2SO4 and concentrated. The crude yellow oil was purified by flash column chromatography (0% to 10% EtOAc in hexanes) to give the desired product (4.63 g, 90%).'H NMR (400 MHz, CDCI3) : 6 1.20 (t, J=7.6 Hz, 3 H), 2.57 (q, J=7.6 Hz, 2 H), 3.48 (s, 3 H), 3.79 (t, J=5.1 Hz, 2 H), 4.15 (t, J=4.8 Hz, 2 H), . 6.85 (d, J=8.3 Hz, 1 H), 7.06 (dd, J=8.3, 2.3 Hz, 1 H), 7.37 (d, J=2.3 Hz, 1 H).
With cesium carbonate; In DMF (N,N-dimethyl-formamide); at 20 - 60℃; for 7h;
Cesium carbonate (14.88 g, 45.66 mmol) was added to a solution of 5-bromo-3- nitropyridin-2-ol (10.0 g, 45.7 mmol) and 2-BROMOETHYL methyl ether (4.29 mL, 45.66 mmol) in N, N-dimethylformamide (400 mL). After 3 h, additional 2-BROMOETHYL METHYL ether (4.29 mL, 45.7 mmol) was added, and the reaction was heated to 60 oC. After 4 h, water was added. The mixture was extracted with ethyl acetate (3x), and the combined organic extracts were washed with saturated brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% hexanes) 40% ethyl acetate/hexanes) gave the title compound (7.39 g). MS 277 (M).
9-fluorenyl-methoxycarbonyl-cyclohexyl alanine[ No CAS ]
[ 462-94-2 ]
[ 1458-98-6 ]
[ 78-77-3 ]
[ 1809-10-5 ]
[ 110-53-2 ]
[ 592-55-2 ]
[ 7328-91-8 ]
[ 871-76-1 ]
[ 105-83-9 ]
[ 144-48-9 ]
[ 929-59-9 ]
[ 107-59-5 ]
[ 5324-30-1 ]
[ 5428-54-6 ]
[ 27129-86-8 ]
[ 2417-72-3 ]
[ 2581-34-2 ]
[ 554-84-7 ]
[ 3385-21-5 ]
[ 126-38-5 ]
[ 636-93-1 ]
[ 88-30-2 ]
[ 620-13-3 ]
[ 823-78-9 ]
[ 5035-82-5 ]
[ 29022-11-5 ]
[ 539-48-0 ]
[ 35661-39-3 ]
[ 26759-46-6 ]
[ 20439-47-8 ]
[ 2615-25-0 ]
[ 6393-01-7 ]
[ 5372-81-6 ]
[ 35661-40-6 ]
[ 100-39-0 ]
[ 611-17-6 ]
[ 23915-07-3 ]
[ 71989-23-6 ]
[ 35737-15-6 ]
[ 2592-95-2 ]
[ 18880-00-7 ]
[ 88681-68-9 ]
[ 100063-22-7 ]
[ 75-03-6 ]
[ 106-94-5 ]
[ 104-81-4 ]
[ 589-10-6 ]
[ 107-15-3 ]
[ 109-76-2 ]
[ 110-60-1 ]
[ 7051-34-5 ]
[ 106-95-6 ]
[ 622-95-7 ]
[ 589-15-1 ]
[ 134-20-3 ]
[ 2550-36-9 ]
[ 89-92-9 ]
[ 456-41-7 ]
[ 766-80-3 ]
[ 459-46-1 ]
[ 874-98-6 ]
[ 402-49-3 ]
[ 870-63-3 ]
[ 85118-01-0 ]
[ 22115-41-9 ]
[ 3958-57-4 ]
[ 100-11-8 ]
[ 107-82-4 ]
[ 6482-24-2 ]
[ 3132-64-7 ]
[ 112883-41-7 ]
[ 3433-80-5 ]
[ 52727-57-8 ]
C18H15N2O3PolS[ No CAS ]
C20H20N3OPolS[ No CAS ]
C23H19N2O2PolS[ No CAS ]
C18H23ClN3OPolS[ No CAS ]
C22H26N3OPolS[ No CAS ]
C22H23N2O5PolS[ No CAS ]
C20H26ClN2O3PolS[ No CAS ]
C23H22ClN2O3PolS[ No CAS ]
C20H21FN3O3PolS[ No CAS ]
C22H29N2O3PolS[ No CAS ]
C21H28N3O3PolS[ No CAS ]
C19H26N3O4PolS2[ No CAS ]
C22H30N3OPolS[ No CAS ]
C21H28N3O4PolS[ No CAS ]
C26H26N3OPolS[ No CAS ]
C23H15ClF3N2O2PolS[ No CAS ]
C24H22N3O3PolS[ No CAS ]
C23H16ClF2N2O2PolS[ No CAS ]
C22H22Br2N3OPolS[ No CAS ]
C24H26FN2O5PolS[ No CAS ]
C25H22FN2O4PolS[ No CAS ]
C26H22N3O4PolS[ No CAS ]
C25H25ClN3O3PolS[ No CAS ]
C25H18ClF2N2O3PolS[ No CAS ]
C29H26N3O3PolS[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With piperidine; Carbonyldiimidazole; tin-2-ethylhexanoate dihydrate; potassium tert-butylate; water; N-ethyl-N,N-diisopropylamine; trifluoroacetic acid; diisopropyl-carbodiimide; dibromotriphenylphosphorane; In DMF (N,N-dimethyl-formamide); dichloromethane; N,N-dimethyl acetamide; 1,2-dichloro-ethane;Combinatorial reaction / High throughput screening (HTS);
EXAMPLE 1 [0213] This example shows the synthesis of a combinatorial library of thioquinazolinone derivatives. [0214] Step 1a: Preparation of Wang Bromide Resin [0215] 40 tea bags containing 2 g each of Wang resin (80 g, 120 mmol) was taken in a 5 L PP container. A solution of triphenylphosphine dibromide (152 g, 0.15 M, 3 eq., 360 mmol) in 2000 ml DCM was added and the solution was shaken at room temperature overnight. The resin was sequentially washed with DCM (4×, 1.5 L each) and diethylether (6×, 1.5 L each) and dried under vacuum, to give the bromo wang resin. [0216] Step 1b: Loading of the Nitrophenol on Bromo Wang [0217] 20 g of the Bromo wang resin (1.5 meq/g) was taken in a 2 L wide-mouthed glass container and 1000 mL DMA was addded to it followed by the addition of the nitro phenol (10 eq., 0.3M, 300 mmol). Potasium t-butoxide (33.46 g, 10 eq., 300 mmol) was then added to it and the bottles were heated at 50 C. overnight. The bags were washed alternatively with DMF (500 mL) and DCM (500 mL) 3 cycles followed by 6 cycles of MeOH (500 mL). The tea bags were then dried overnight in air. The following nitrophenols were used: [0218] 2-METHYL-5-NITROPHENOL [0219] 5-HYDROXY-2-NITROBENZOTRIFLUORIDE [0220] 3-METHYL-4-NITROPHENOL [0221] 2-METHOXY-5-NITROPHENOL [0222] M-NITROPHENOL [0223] Step 1c: Reduction of the Nitro Group to Amine [0224] A 2.0 M solution of tin-2-ethylhexanoate dihydrate was prepared in DMF containing 0.5% H2O. The tea bags were added and the solution is heated at 50 C. for 40 hours. After cooling the bags are washed with DMF/10% HOAc (3×), DMF (3×), 5% DIEA/DCM (2×), DCM (2×) and MeOH (2×) and dried in air overnight. [0225] Step 1d: Coupling N-FMOC Protected Amino Acid to Wang Resin. [0226] 20 g of Wang resin (1.5 meq/g) was placed in a porous polypropylene packet (Tea-bag, 60 mm×60 mm, 65mu) and taken in a 1000 mL plastic bottle. DMF (300 mL), DCM (300 mL), FMOC-Cyclohexyl alanine (70.82 g, 6 eq., 0.3M, 180 mmol), DIC (22.71 g, 6 eq., 180 mmol), HOBt (24.32 g, 6 eq., 180 mmol) were added sequentially. After shaking for 12 hours, the packet was washed alternatively with DMF (500 mL) and DCM (500 mL) 3 cycles followed by 6 cycles of MeOH (500 mL). The packet was then dried overnight in air. The tea bags containing the amino acids were then treated with 20% piperidine/DMF for 2 h at room temperature to deblock the FMOC group. The following amino acids were used: [0227] FMOC-GLY-OH [0228] FMOC-ALA-OH [0229] FMOC-L-ISOLEUCINE [0230] FMOC-L-PHENYLALANINE [0231] FMOC-D-NLE-OH [0232] FMOC-CHA-OH [0233] FMOC-L-TRYPTOPHAN [0234] Step 1e: Coupling of the Diamines to Wang Resin [0235] 20 g of Wang resin (1.5 meq/g) was placed in a porous polypropylene packet (Tea-bag, 60 mm×60 mm, 65mu) and taken in a 1000 mL Nalgene bottle. 600 mL of DCM was added followed by the addition of the carbonyl diimidazole (29.9 g, 6 eq., 0.3M, 180 mmol) and the flasks were shaken at room temperature for 3 hours after which they were decanted and washed with DCM (2×, 600 mL). To these Nalgene bottles were added the diamines (6 eq., 0.4M, 180 mmol) in 450 mL of DCM (0.4M) and they were shaken at room temperature overnight. The diamines used were as follows: [0236] 2,2-DIMETHYL-1,3-PROPANEDIAMINE [0237] 1,3-CYCLOHEXANEDIAMINE [0238] (1R,2R)-(-)-1,2-DIAMINOCYCLOHEXANE [0239] TRANS-1,4-DIAMINOCYCLOHEXANE [0240] P-XYLYLENEDIAMINE [0241] 1,4-BIS(3-AMINOPROPYL)PIPERAZINE [0242] ETHYLENEDIAMINE [0243] 1,3-DIAMINOPROPANE [0244] 1,8-DIAMINO-3,6-DIOXAOCTANE [0245] 1,4-DIAMINOBUTANE [0246] 1,5-DIAMINOPENTANE [0247] 1,6-HEXANEDIAMINE [0248] N,N-BIS(3-AMINOPROPYL)METHYLAMINE [0249] 2,2'-THIOBIS(ETHYLAMINE) [0250] 2,5-DIMETHYL-1,4-PHENYLENEDIAMINE [0251] After shaking overnight, the packets was washed alternatively with DMF (500 mL) and DCM (500 mL) 3 cycles followed by 6 cycles of MeOH (500 mL). The packet was then dried in air. [0252] Step 2: Formation of the Isothiocyanate [0253] The o-amino benzoate ester (136 g, 10 eq., 900 mmol) was taken in a 5 L wide-mouthed glass bottle and 2.7 L of dichloroethane was added to it (0.3M). The following esters were used: [0254] METHYL ANTHRANILATE [0255] METHYL 2-AMINO-4-CHLOROBENZOATE [0256] 2-AMINO-4,5-DIMETHOXYBENZOIC ACID [0257] METHYL ESTER [0258] METHYL 3,4,5-TRIMETHOXYANTHRANILATE [0259] DIMETHYL AMINOTEREPHTHALATE [0260] METHYL 2-AMINO-5-BROMOBENZOATE [0261] METHYL 3-AMINOTHIOPHENE-2-CARBOXYLATE [0262] METHYL 3-AMINO-5-PHENYLTHIOPHENE-2-CARBOXYLATE [0263] Thiocarbonyl diimidazole (160 g, 10 eq., 900 mmol) was added to it and the solution was heated at 55 C. overnight to form the isothiocyanate. [0264] Step 3: Formation of the Thioquinazolinone [0265] The next day the tea bags containing the amino acids, diamines and the amino phenols on wang resin (90 mmol) was added to the isothiocyanate solution from reaction 2 and the glass bottles were heated at 55 C. overnight. After cooling the bags was washed alternatively with DMF (2000 mL) and DCM (2000 mL) 3 cycles followed by 6 cycles of MeOH...
With potassium carbonate; In N,N-dimethyl-formamide; at 70℃; for 4h;
A mixture of <strong>[22510-08-3]2-fluoro-5-nitrophenol</strong> (10.0 g , 63.7 mmol), 2-bromoethyl methyl ether (15.0 g, 107.9 mmol) and potassium carbonate (26.5 g, 192 mmol) in 40 mL of N, N'-dimethylformamide is heated at 70 C. for 4 hours then cooled to room temperature and poured onto ice. The solid is collected by filtration washed with water and dried to provide 12.0 g of 2-fluoro-1-(2-methoxyethoxy)-4-nitrobenzene, mp 62-63 C. [0225] MS 216.02 (M+H)+[0226] Analysis for C9H10FNO4 [0227] Calcd: C, 50.24; H, 4.68; N, 6.51. [0228] Found: C, 50.24; H, 4.67; N, 6.49.
ethyl 7-(N-(2-methoxyethyl)amino)thieno[2,3-b]pyrazine-6-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
0.640 g (51%)
With potassium hexamethylsilazane; In tetrahydrofuran; toluene;
EXAMPLE 11A Ethyl 7-(N-(2-methoxyethyl)amino)thieno[2,3-b]pyrazine-6-carboxylate Ethyl 7-amino-thieno[2,3-b]pyrazine-6-carboxylate (1.0 g g, 4.48 mmol) prepared by the method of Schneller and Clough, J. Het. Chem., 12: 513 (1975), was treated with potassium bis(trimethylsilyl)amide (0.5M in toluene, 8.96 ml) in 15 ml THF at -70 C., and allowed to warm to room temperature. 2-Bromoethyl methyl ether (0.454 ml, 4.70 mmol) was added, and the reaction was stirred under N2 at 60 C. overnight. The mixture was cooled and evaporated, then purified by column chromatography on silica gel eluding with 1:9 ethyl acetate:hexanes to yield 0.640 g (51%) of the title compound as a yellow solid: 1 H NMR (300 MHz, DMSO-d6) d 1.32 (t, 3H), 3.3 (s, 3H), 3.56 (t, 2H), 4.25 (q, 2H), 4.32 (t, 2H), 7.70 (br t, 1H), 8.76 (s, 1H), 8.77 (s, 1H); MS (DCI/NH3) m/e 282 (M+H)+.
0.640 g (51%)
With potassium hexamethylsilazane; In tetrahydrofuran; toluene;
EXAMPLE 11A Ethyl 7-(N-(2-methoxyethyl)amino)thieno[2,3-b]pyrazine-6-carboxylate Ethyl 7-amino-thieno[2,3-b]pyrazine-6-carboxylate (1.0 g g, 4.48 mmol) prepared by the method of Schneller and Clough, J. Het. Chem., 12: 513 (1975), was treated with potassium bis(trimethylsilyl)amide (0.5M in toluene, 8.96 ml) in 15 ml THF at -70 C., and allowed to warm to room temperature. 2-Bromoethyl methyl ether (0.454 ml, 4.70 mmol) was added, and the reaction was stirred under N2 at 60 C. overnight. The mixture was cooled and evaporated, then purified by column chromatography on silica gel eluding with 1:9 ethyl acetate:hexanes to yield 0.640 g (51%) of the title compound as a yellow solid: 1 H NMR (300 MHz, DMSO-d6) d 1.32 (t, 3H), 3.3 (s, 3H), 3.56 (t, 2H), 4.25 (q, 2H), 4.32 (t, 2H), 7.70 (br t, 1H), 8.76 (s, 1H), 8.77 (s, 1H); MS (DCI/NH3) m/e 282 (M+H)+.
With hydrogenchloride; sodium hydroxide; In water; ethyl acetate; acetone;
A 4-(2-Methoxyethoxy)-1-nitrobenzene A mixture of 40 g of 4-nitrophenol, 41 g of 1-bromo-2-methoxyethane, 45 g of K2 CO3 and 80 ml of tris[2-(2-methoxyethoxy)ethyl]amine in 80 ml of acetone is refluxed for 20 hours. An insoluble material is filtered off and the filtrate is concentrated under vacuum. The residue is taken up with water and the precipitate formed is filtered off and washed with water. The precipitate is dissolved in AcOEt, washed with a 1N solution of NaOH, with water, with a 1N solution of HCl and with water and dried over Na2 SO4 and the solvent is evaporated off under vacuum to give 59 g of the expected product, which is used as such in the next step.
4-chloro-6-methoxy-7-(2-methoxyethoxy)quinoline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74%
With tetra-(n-butyl)ammonium iodide; potassium carbonate; In N,N-dimethyl-formamide;
Production Example 21: 4-Chloro-6-methoxy-7-(2-methoxyethoxy)quinoline 4-Chloro-6-methoxy-7-quinolinol (50 mg), potassium carbonate (40 mg), tetra-n-butylammonium iodide (9 mg), and 2-bromoethyl methyl ether (40 mg) were dissolved in N,N-dimethylformamide (10 ml). The solution was stirred at 70C overnight. The solvent was removed by distillation under the reduced pressure. A saturated aqueous sodium hydrogencarbonate solution was added to the residue, followed by extraction with chloroform. The chloroform layer was dried over sodium sulfate. Thesolvent was removed by distillation under the reduced pressure. The residue was purified by chromatography on silica gel by development with hexane/acetone/dichloromethane (6/2/1) to give 47 mg (yield 74%) of the title compound. 1H-NMR (CDCl3, 400 MHz): delta 3.49 (s, 3H), 3.88 - 3.90 (m, 2H), 4.04 (s, 3H), 4.32 - 4.35 (m, 2H), 7.35 (d, J = 4.9 Hz, 1H), 7.40 (s, 1H), 7.43 (s, 1H), 8.57 (d, J = 4.9 Hz, 1H)
With potassium carbonate; caesium carbonate; In acetone;Heating / reflux;
Example 1; Synthesis of 4-bromo-7-methoxy-6-(2-methoxy ethoxy)cinnoline; [00212] Step 1; Into a 1000 mL round bottom flask containing a solution of l-(3- hydroxy-4-methoxy-phenyl)ethanone (11 g, 66.27 mmol) in acetone (200 mL) was added K2CO3 (39 g, 282.61 mmol), l-bromo-2-methoxyethane (38 g, 273.40 mmol) and Cs2CO3 (3 g, 9.20 mmol). The resulting solution was stirred overnight while the temperature was maintained at reflux and the reaction progress was monitored by TLC (EtOAc/PE = 1:1). The reaction mixture was concentrated (rotary evaporator), taken up in H2O and extracted with EtOAc. The combined organic layers were dried over Na2Spsi4 and concentrated (rotary evaporator) to provide 15.28 g of crude l-(4-methoxy-3-(2-methoxyethoxy)phenyl)ethanone as a yellow solid.
4-[1-(2-Methoxy-ethyl)-piperidin-4-yl]-benzoic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
52.1%
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 40℃; for 18h;
A solution of methyl 4-(piperidin-4-yl)benzoate, HCl (1.279 g, 5 mmol), N-ethyl-N-propan-2-ylpropan-2-amine (3.49 mL, 20.00 mmol) and 1-bromo-2-methoxyethane (0.470 mL, 5.00 mmol) in dichloromethane (10 mL) was heated at 40 C. or 18 h. A few drops of DMF were added to aid solubility. The reaction mixture was cooled, diluted with DCM (30 ml) and washed with water (2×30 ml) and saturated sodium chloride solution (30 ml). This was dried over MgSO4, filtered and evaporated to dryness. The crude product was purified by silica column chromatography, eluting with a gradient of 0 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford methyl 4-(1-(2-methoxyethyl)piperidin-4-yl)benzoate (0.723 g, 52.1%) as a colourless oil. 1H NMR (399.9 MHz, CDCl3) delta 1.75 (1H, t), 1.81-1.90 (3H, m), 2.09-2.15 (2H, m), 2.55 (1H, q), 2.60-2.63 (2H, m), 3.08-3.11 (2H, m), 3.37 (3H, s), 3.53-3.56 (2H, m), 3.89-3.90 (3H, m), 7.27-7.31 (2H, m), 7.95-7.98 (2H, m). MS: m/z 278 (MH+).
With caesium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 30℃; for 2h;Inert atmosphere;
In a 25 m round-bottomed fiask, <strong>[52427-05-1]2-bromo-5-nitrophenol</strong> (600 mg, 2.75 mmol, Eq: 1.00), cesium carbonate (1.35 g, 4.13 mmol, Eq: 1.5) and potassium iodide (9 1.4 mg, 550 imol, Eq:0.2) were combined with dimethylformamide (10 ml) and under argon 1 -bromo-2- methoxyethane (574 mg, 388 jil, 4.13 mmol, Eq: 1.5) was added. The reaction mixture was stirred at 30 °C for 2 hours. The reaction mixture was concentrated in yacuo and water was added (40 ml). The reaction mixture was extracted with ethyl acetate (3 x 30 ml). The organie phase was dried oyer magnesium sulfate and concentrated in yacuo to yield 1-bromo-2-(2- methoxyethoxy)-4-nitrobenzene (?748 mg. 98percent) as a brown solid. 1H-NMR (ppm. 300 MHz. CDC13): 7.76-7.77 (m, 1H), 7.72-7.73 (m, 2 H), 4.29 (t, 2 H), 3.85 (t, 2 H), 3.49 (s, 3 H).
91%
potassium iodide; In N,N-dimethyl-formamide; at 70℃; for 4h;
Method 10 l-Bromo-2-(2-methoxyethoxy)-4-nitrobenzene. To a solution of <strong>[52427-05-1]2-bromo-5-nitrophenol</strong> (7.24 g, 33.2 mmol) (Method 9) in anhydrous DMF was added 2-methoxy-l-bromoethane (6.92 g, 49.8 mmol) and a catalytic amount of potassium iodide (~ 100 mg). The reaction was heated at 70 0C for 4 h before being allowed to cool to rt. The reaction was then poured into a separatory funnel and partitioned between EtOAc (~ 250 mL) and water (~ 250 mL). The organic phase was dried over Na2SO4 and cone in vacuo giving the crude title compound which was taken up in a minimum volume of warm EtOAc. The resulting solution was cooled in an ice bath and hexanes were slowly added to induce crystallization. The resulting precipitate was isolated via vacuum filtration through a fritted funnel and air dried to give pure title compound (8.3 g, 91percent). 1H NMR: (300 MHz) 7.87-7.92 (m, 2 H), 7.76 (dd, 1 H), 4.35 (t, 2 H), 3.73 (t, 2 H), 3.35 (s, 3 H).
91%
potassium iodide; In N,N-dimethyl-formamide; at 70℃; for 4h;
To a solution of <strong>[52427-05-1]2-bromo-5-nitrophenol</strong> (7.24 g, 33.2 mmol) (Method 9) in anhydrous DMF was added 2-methoxy-l-bromoethane (6.92 g, 49.8 mmol) and a catalytic amount of potassium iodide (~ 100 mg). The reaction was heated at 70 0C for 4 h before being allowed to cool to rt. The reaction was then poured into a separatory funnel and partitioned between EtOAc (~ 250 mL) and water (~ 250 mL). The organic phase was dried over Na2SO4 and cone in vacuo giving the crude title compound which was taken up in a minimum volume of warm EtOAc. The resulting solution was cooled in an ice bath and hexanes were slowly added to induce crystallization. The resulting precipitate was isolated via vacuum filtration through a fritted funnel and air dried to give pure title compound (8.3 g, 91percent). 1H NMR: (300 MHz) 7.87-7.92 (m, 2 H), 7.76 (dd, 1 H), 4.35 (t, 2 H), 3.73 (t, 2 H), 3.35 (s, 3 H)
theCompound (0. 48g, 3mmol) of PreparationExample 23a dissolved in 5mL of DMF, added Potassium carbonate (0. 83g, 6mmol)and under 50 C the reaction was stirred for 15min. added 2-bromoethyl methyl ether(0. 52g, 3. 6mmol) and continued at 50 C keep the reaction for 2h.in the reaction solution added 50mL ofwarer, the reaction solution was extracted with Ethyl acetate (15mLX3),combined the organic phases, washed with saturated brine (20 mLx2) and Driedover anhydrous sodium sulfate. Filtrated , concentrated and the residue wasseparated and purified with column chromatography (Eluent, petroleum ether:ethyl acetate = 2: 1, v / v) to obtain pale yellow solid 0.50g, yield 75%.
Sodium hydride (55% in mineral oil, 1.76 g, 40.5 mmol) was suspended in 100 mL tetrahydrofurane. 3-(Hydroxymethyl)benzonitrile (5.0 g, 36.5 mmol), dissolved in 200 mL tetrahydrofuran was added drop wise. The reaction mixture was stirred at room temperature for 1 h. 2-Bromoethylmethylether (7.0 mL, 76 mmol) was added and the reaction mixture was refluxed overnight. The reaction mixture was quenched with 3 mL 2N sodium carbonate solution and the solvent was evaporated. The residue was taken up in 100 mL water and extracted three times with ethyl acetate (100 mL each). The organic phases ware pooled, dried with sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 100:0?50:50 gradient). 3-(2-Methoxy-ethoxymethyl)-benzonitrile was obtained as a yellow liquid (2.63 g, 38%).
With potassium carbonate; In acetonitrile; at 80℃;
a- Synthesis of Int. 183: Methyl 4-bromo-3 -hydro xybenzoate (2g, 8.6mmol), 2-bromo ethyl methylether (0.9mL, 9.5mmol), K2C03 (1.8g, 13mmol) in ACN (40ml) at 80C overnight. Water and EtOAc were added, the mixture was extracted, the organic layer was separated, dried over MgS04, filtered and evaporated. The residue was purified by prep. LC on (Irregular SiOH 20-45muiotaeta 450g MATREX, Mobile phase: 85% heptane, 15% EtOAc). The pure fractions were collected and solvent was evaporated until dryness to give 2.1g of Int. 183 (84%).
With tetra-(n-butyl)ammonium iodide; potassium carbonate; In acetone; at 50 - 75℃; for 46h;
To a suspension of 59.38 mmol of dry K2CO3, <strong>[106291-80-9]methyl 4-bromo-3-hydroxybenzoate</strong> <n="36"/>[106291-80-9] and 2.12 mmol of TBAI in 200 ml_ of acetone are added dropwise 46.66 mmol of 2-bromoethyl methyl ether. The reaction mixture is stirred at 500C for 20 h. Additional 2-bromoethyl methyl ether (46.66 mmol) are added, and the reaction mixture is stirred at 75C for 3 h. Another portion of 2-bromoethyl methyl ether (46.66 mmol) is added, and the reaction mixture is stirred at 75C for 3 h. After adding another portion (46.66 mmol) of 2-bromoethyl methyl ether, the reaction mixture is stirred at 75C for 20 h, cooled to RT and filtered, washing the filter cake with acetone. The filtrate is concentrated under reduced pressure to afford the title compound as a pale yellow oil. Rf = 0.28 (EtOAc/heptane 1 :3); Rt = 4.45 (gradient I).
With potassium carbonate; potassium iodide; In dichloromethane; at 20 - 80℃;
To a mixture of 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenol (800 mg, 3.636 mmol) in DCM (20 ml) were added KI (1.2 g, 7.273 mmol), K2C03 (1.307g 10.091 mmol) and l-bromo-2-methoxyethane (1.01 g, 7.273 mmol) at room temperature. The mixture was stirred overnight at 80 C. The mixture was extracted with DCM (30 mL x 2) and the organic phase was dried with Na2S04 and concentrated under reduced pressure and the residue was purified by column chromatography to give the title compound (550 mg, yield 50%).
50%
With potassium carbonate; potassium iodide; In dichloromethane; at 80℃;
Example 137 2-(3-(2-methoxyethoxy)phenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane To a mixture of 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenol (800 mg, 3.636 mmol) in DCM (20 ml) were added KI (1.2 g, 7.273 mmol), K2C03 (1.307g 10.091 mmol) and l-bromo-2-methoxyethane (1.01 g, 7.273 mmol) at room temperature. The mixture was stirred overnight at 80 C. The mixture was extracted with DCM (30 mL x 2) and the organic phase was dried with Na2S04 and concentrated under reduced pressure and the residue was purified by column chromatography to give the title compound (550 mg, yield 50%).
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 1h;
Potassium carbonate (1.88 g, 13.65 mmol) was added to a solution of 3- hydroxyphenylboronic acid pinacol ester (Apollo, 1.0 g, 4.55 mmol) in DMF (10 ml_). 2- Bromoethyl methyl ether (0.41 ml_, 5.46 mmol) was added and the reaction mixture was heated to 100 C for 1 hr. The reaction mixture was allowed to coo. and then partitioned between ethyl acetate (50 mL), and water (150 ml_). The phases were separated and the organic phase was washed with brine (150 mL), dried over anhydrous sodium sulphate, filtered and the filtrate solvents removed in vacuo, to afford the title product as a light- brown oil (1.1 g) which was used without further purification. LCMS (Method A) RT = 1.42 min; m/z = no ionisation.
1-(2-methoxyethyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
52%
In acetonitrile; at 90℃; for 6h;
Intermediate B22: 1-(2-methoxyethyl)-<strong>[857530-80-4]3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong> (0421) (0422) To a solution of <strong>[857530-80-4]3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong> (0.68 mmol, 150 mg) in CH3CN (5 mL) was added 1-bromo-2-methoxyethane (0.95 mmol, 130.5 mg). The mixture was stirred at 90 C. for 6 h, concentrated under reduced pressure, purified by flash chromatography (silica gel, PE:EA=0-20%, UV254 & UV280 nm) to give the title compound (100 mg, 52%) as a yellow solid. LC-MS: [M+H]+=281.5.
52%
In acetonitrile; at 90℃; for 6h;
To a solution of 3,5-dimethyl-4-(4,4 ,5,5-tetramethyl-1 ,3 ,2-dioxaborolan-2-yl)- 1H-pyrazole (0.68 mmol, 150 mg) in CH3CN(5mL) was added 1-bromo-2-methoxyethane (0.95 mmol, 130.5mg). The mixture was stirred at 90 C for 6 h, concentrated underreduced pressure, purified by flash chromatography (silica gel, PE:EAO-20%, UV254 & UV280 nm) to give the title compound (100 mg, 52%) as a yellow solid. LC-MS: [M+H] =281.5.
With potassium carbonate; In N,N-dimethyl-formamide; at 160℃; for 2h;Microwave irradiation;
A mixture of 4-(4,4,5 ,5 -tetramethyl- 1,3 ,2-dioxaborolan-2-yl)- 1H-pyrazole (1.94 g, 10 mmol), 2-bromoethyl methyl ether (1.68 g, 12 mmol) and K2C03 (2.76 g, 20 mmol) in DMF (16 mL) was stirred at 160 °C for 2 h in the microwave. The reaction mixture was concentrated and purified by silica gel chromatography (30percent EA:PE) to give 2.2 g (90percent) of the title compound as yellow oil. ?H NMR (400 MHz, CDC13): oe 1.32 (12H, s), 3.32 (3H, s), 3.75 (2H, t, J= 5.2 Hz), 4.30 (2H, t, J= 5.2 Hz), 7.77 (1H, s), 7.79 (1H, s). [M+H] Calc?d for C,2H2,BN203, 253; Found, 253.
68%
With caesium carbonate; In N,N-dimethyl-formamide; at 150℃; for 0.5h;Microwave irradiation;
Example A68Preparation of intermediate 68: l-(2-Methoxy-ethyl)-4-(4,4,5,5-tetramethyl- [l,3,21dioxaborolan-2-yl)-7H-pyrazoleA mixture of 4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-7H-pyrazole (1 g, 5.15 mmol), 2-bromoethyl methyl ether (0.63 ml, 6.7 mmol) and cesium carbonate (2.52 g, 7.73 mmol) in N,N-dimethylformamide (7 ml) was stirred at 150 °C for 30 min. under microwave irradiation. The mixture was partitioned between water and diethyl ether. The organic layer was separated, dried (Na2S04), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; ethyl acetate in heptane 30/70). The desired fractions were collected and concentrated in vacuo to yield intermediate 68 (0.88 g, 68percent) as a pale yellow oil.
68%
With caesium carbonate; In N,N-dimethyl-formamide; at 150℃; for 0.5h;microwave irradiation;
Example A68Preparation of intermediate 68: 1-(2-Methoxy-ethyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazoleA mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (1 g, 5.15 mmol), 2-bromoethyl methyl ether (0.63 ml, 6.7 mmol) and cesium carbonate (2.52 g, 7.73 mmol) in N,N-dimethylformamide (7 ml) was stirred at 150° C. for 30 min. under microwave irradiation.The mixture was partitioned between water and diethyl ether.The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo.The crude product was purified by flash column chromatography (silica; ethyl acetate in heptane 30/70).The desired fractions were collected and concentrated in vacuo to yield intermediate 68 (0.88 g, 68percent) as a pale yellow oil.
57%
With caesium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃;
2-Bromoethyl methyl ether (0.93 g, 6.70 mmol, 0.64 mL) was added to a mixture of 4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (1 .00 g, 5.15 mmol) and caesium carbonate (3.49 mg, 10.72 mmol) in dry N,N-dimethylformamide (20 mL) at 0°O. After stirring for 30 mm the ice-water bath was removed. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (150 mL) and washed with brine(3x100 mL). The organic layer was dried with sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (Method L7; 12 g; heptane, 10percent-30percent ethyl acetate) afforded 0.74 g (2.92 mmol; 57percent of theory) of the title compound.GO-MS (Method L9): R1 = 4.21 mm; m/z = 251 MH NMR (300 MHz, Ohloroform-d, Method M2) 6 7.79 (s, 1 H), 7.76 (s, 1 H), 4.29 (t, J = 5.3 Hz,2H), 3.75 (t, J = 5.3 Hz, 2H), 3.32 (s, 3H), 1.31 (s, 12H).
56%
General procedure: Preparation 122: 1 -(2-Methoxyethyl)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H- Method H NaH (60percent, 83 mg) was added to a solution of 4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 - -pyrazole (204 mg, 1 .05 mmol) in DMF (4 mL). After stirring for 15 minutes, 1 -bromo-2-methoxyethane (175 mg, 1 .26 mmol) in DMF (1 mL) was added. The resulting solution was stirred at 80°C under microwave irradiation for 60 minutes. The reaction mixture was diluted with brine and extracted with EtOAc. The combined organic layers were washed with water, dried with Na2S04j and concentrated in vacuo to afford the title compound as a yellow oil that was used directly in the next step (148 mg, 56percent). 1 H NMR (500 MHz, CDCI3): delta 7.80 (d, J = 0.7 Hz, 1 H), 7.77 (d, J = 0.7 Hz, 1 H), 4.31 (t, = 5.3 Hz, 2H), 3.76 (t, J = 5.3 Hz, 2H), 3.33 (s, 3H), 1.32 (s, 12H). LCMS (ESI) Rt = 2.17 minutes MS m/z 253 [M+H]+
26%
To a solution of 4-(tetramethyl-1 ,3, 2-dioxaborolan-2-yl)-1H-pyrazole (1 .00 g, 5.1 mmol) in DMF (5 mL) was added sodium hydride (245 mg of a 60percent dispersion in mineral oil, 6.1 mmol) at room temperature. The mixture was then stirred at room temperature for 60 minutes. The mixture was cooled to 0 ° C and 2-bromoethyl methyl ether (0.72 mL, 7.7 mmol) was added drop wise via syringe. After complete addition, the mixture was allowed to warm to room temperature and stirred for an hour prior to addition of ethyl acetate (70 mL) and water (30 mL). The organic layer was separated, washed with water (2 x 30 mL) and brine (30 mL), dried (Na2S04), filtered and concentrated at reduced pressure. The residue was purified by Biotage Isolera? chromatography [Biotage SNAP Cartridge KP-Sil 50 g; using a gradient of eluents, 0-50percent EtOAc in heptane] to give the title compound (333 mg, 26percent yield) as a colourless oil. 1H NMR (250 MHz, DMSO-d6) delta [ppm] 7.88 (s, 1 H), 7.57 (s, 1 H), 4.32 - 4.20 (m, 2H), 3.73 - 3.60 (m, 2H), 3.21 (s, 3H), 1 .25 (s, 12H). LCMS (Analytical Method A): Rt = 1 .01 mins, MS (ESIPos): m/z = 253 (M+H)\
20%
With potassium hydroxide; In ethanol; at 50℃; for 76h;
Intermediate 1171 -[2-(Methyloxy)ethyl]-4-(4,4,5,5-tetrameth l-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazolA solution of 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (10 g, 51 .5 mmol) in ethanol (50 mL) was treated with KOH (3.47 g, 61 .8 mmol) and 1 -bromo-2- (methyloxy)ethane (5.81 mL, 61.8 mmol) at room temperature and the resulting mixture was stirred at 50°C under nitrogen for 16 h then cooled to room temeprature. 1 -Bromo-2- (methyloxy)ethane (2 ml_, 21 .3 mmol) was added and the resulting mixture was stirred at 50°C for 60 h then cooled to room temperature. The mixture was filtered through celite and the insoluble were washed with ethanol. The combined filtrate and washings were concentrated in vacuo. Purification of the residue on SP4 using a 100 G silica cartridge (gradient: 0 to 100percent AcOEt in Hexanes) gave 1 -[2-(methyloxy)ethyl]-4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 /-/-pyrazole (2.72 g, 10.25 mmol, 20percent) as a yellow oil. LCMS (method G): Retention time 0.87 min, [M+H]+ = 252.9
20%
With potassium hydroxide; In ethanol; at 50℃; for 66h;Inert atmosphere;
A solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (10 g, 51.5 mmol) in ethanol (50 mL) was treated with KOH (3.47 g, 61.8 mmol) and 1-bromo-2-(methyloxy)ethane (5.81 mL, 61.8 mmol) at room temperature and the resulting mixture was stirred at 50° C. under nitrogen for 16 h then cooled to room temperature. 1-Bromo-2-(methyloxy)ethane (2 mL, 21.3 mmol) was added and the resulting mixture was stirred at 50° C. for 60 h then cooled to room temperature. The mixture was filtered through celite and the insoluble were washed with ethanol. The combined filtrate and washings were concentrated in vacuo. Purification of the residue on SP4 using a 100 G silica cartridge (gradient: 0 to 100percent AcOEt in Hexanes) gave 1-[2-(methyloxy)ethyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.72 g, 10.25 mmol, 20percent) as a yellow oil. LCMS (method G): Retention time 0.87 min, [M+H]+=252.9
With caesium carbonate; In N,N-dimethyl-formamide; at 90℃; for 2h;microwave irradiation;
A solution of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (0.8 g, 4.1 mmol), cesium carbonate (2.0 g, 6.2 mmol), and l-bromo-2-methoxyethane (0.41 rnL, 4.3 mmol) in DMF (14 rnL) was heated in a microwave at 900C for 1 hr. After the initial heating, additional l-bromo-2-methoxyethane (0.41 rnL) was added to the reaction. Heating was repeated for an additional 1 hr. The crude reaction mixtures were then diluted with water (250 mL) and extracted with ethyl acetate (3 x 50 mL). Product was purified by silica gel column using DCM/EtOAc/MeOH (8/1.5/0.5) as eluent to give l-(2-methoxyethyl)-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (1.2 g) as a light yellow oil. ESI- MS :m/z 253.2 (M+H)+.
With caesium carbonate; In acetonitrile; at 90℃;
Step I : l-(2-methoxyethyl)-4-(4, 4, 5, 5-tetramethyl-L 3, 2-dioxaborolan-2-yl)-W-pyrazoIe; A mixture of [A] 4-(4,4,5s5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l H-pyrazole ( 100 mg, 0.5 mmol), 2-bromoethyl methyl ether (58 uL, 0.62 mmol, Aldrich, Cat. No. 238155), and cesium carbonate (500.0 mg, 1.5 mmol) in acetonitrile (1 mL) was stirred at 90 0C overnight. After cooling it was quenched with water, extracted with ethyl acetate. The extract was washed with water twice, brine once; dried over Na2SO4. After filtration the filtrate was concentrated to yield 90 mg of the product. LCMS (M+H)+: m/z = 253.1
With sodium hydride; In tetrahydrofuran; mineral oil; for 24h;Reflux;
ntermediate 1 1 1 -(2-methoxyethyl)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole[094] A mixture of 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (200 mg, 1 .03 mmol),1 -bromo-2-methoxyethane (280 mg, 2.01 mmol), and NaH (200 mg, 4 mmol) in THF (15 mL) was stirred at reflux for 24 hours, cooled to the ambient temperature, and concentrated in vacuo. The residue was treated with HCI(aq) and extracted with EtOAc. The insoluble solid was removed by filtration, and the organic solution was concentrated to give the title compound. MS (m/z): 253 (M.bul.H)+.
25.4 g
With caesium carbonate; In N,N-dimethyl-formamide; at 80℃;
4-(4,4,5,5-Tetramethyl-[1 ,3,2]clioxaborolan-2-yl)-1 H-pyrazole (19.4 g, 0.10 mol), 1- bromo-2-methoxy-ethane (14.18 ml, 0.15 mol), and caesium carbonate (32.58 g, 0.1 mol) are dissolved in DMF (200 ml). The suspension is stirred for 16 h at 80°C, filtered and the solvent is removed in vacuum. The residue is treated with tert-butyl methyl ether (200 ml), filtered over Celite and then the solvent is removed in vacuum; yield: 25.4 g 1-(2-methoxy-ethyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxa- borolan-2-yl)-1H-pyrazole; HPLC/MS: 1.82 min, [M+H] = 253.
With sodium hydride; In tetrahydrofuran; for 24h;Reflux;
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (200 mg, 1.03 mmol), 1-bromo-2-methoxyethane (280 mg, 2.01 mmol), and NaH (200 mg, 4 mmol) in THF (15 mL) was stirred at reflux for 24 hours, cooled to the ambient temperature, and concentrated in vacuo. The residue was treated with HCl(aq) and extracted with EtOAc. The insoluble solid was removed by filtration, and the organic solution was concentrated to give the title compound. MS (m/z): 253 (M+H)+.
1.31 g
With caesium carbonate; In acetonitrile; at 50℃;Inert atmosphere;
1H-pyrazole-4-boronic acid pinacol ester (1.0 g, 5.155 mmol),2-Bromoethyl methyl ether (0.788 g, 5.669 mmol)And cesium carbonate (5.04 g, 15.469 mmol) were dissolved in acetonitrile (20 mL),The mixture was stirred under nitrogen at 50 ° C overnight,filter,Concentrate to dryness to give 1- (2-methoxyethyl) -1H-pyrazole-4-boronic acid pinacol ester (1.310 g).
To a 0 0C suspension Of Cs2COs (18.73 g, 57.48 mmol) in 150 mL DMF was added 6-fluoropyridin-3- ol (5.0 g, 44.21 mmol). The cloudy brown mixture was stirred for 15 minutes, then 1-bromo- 2-methoxyethane (6.232 mL, 66.32 mmol) was added. The reaction mixture was heated in a 110 0C sand bath and stirred for 17 hours, after which it was cooled to ambient temperature and the DMF was removed in vacuo. The resulting residue was combined with saturated NH4Cl and the mixture was extracted with DCM. The combined extracts were dried (Na2SO4), filtered, and concentrated. The crude material was purified on silica gel (5-50% ethyl acetate in hexanes gradient) to give the desired product (7.00 g, 92.50 % yield) as a clear, colorless oil.
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 16h;
4-Nitro-1,2-phenol (3 g, 19.3 mmol)And 1-bromo-2-methoxyethane (5.9 g, 42.5 mmol)Dissolved in 10mL DMF,To a solution of potassium carbonate (8 g, 58 mmol)The reaction was carried out at 100 C for 16 h,After completion of the reaction, DMF was removed,And extracted with ethyl acetate to give a yellow oil 7a.
5.4 g
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃;Reflux;
In a reaction flask, <strong>[3316-09-4]4-nitrocatechol</strong> (3.1 g, 19.99 mmol) 2-bromoethyl methyl ether (6.12 g, 44.03 mmol), Potassium carbonate (8.29 g, 59.98 mmol) and DMF (10 mL), Heat to 100 C and reflux overnight. After cooling, The mixture was poured into a separatory funnel containing hydrochloric acid (1 mol / L, 200 mL) It was extracted with ethyl acetate (200 mL) After drying the organic layer over anhydrous sodium sulfate, Concentrated under reduced pressure, directly to the next step, A brown liquid (5.4 g,> 100%) was obtained.
With potassium carbonate; In acetone; for 48h;Reflux;
Description for D82-Methy l-4-[2-(methy loxy)ethy l]oxy}be nzo n itri Ie (D8)The mixture of <strong>[14143-26-1]4-hydroxy-2-methylbenzonitrile</strong> (100 mg), 2-bromoethyl methyl ether (209 mg) and potassium carbonate (311 mg) in acetone (8 mL) was heated to reflux for two days. The solid was filtered and the liquor was concentrated, purified by column to afford 2-methyl-4-[2-(methyloxy)ethyl]oxy}benzonitrile (D8) (100 mg). deltaH (CDCI3, 400MHz): 2.51 (3H, s), 3.46 (3H, s), 3.76 (2H, t), 4.15 (2H, t), 6.80 (1H, dd), 6.84 (1 H, d), 7.52 (1H, d). MS (ES): CnH13NO2 requires 191 ; found 192.1 (M+H+).
With potassium carbonate; In N,N-dimethyl-formamide; at 90℃;
A solution of 19a (lO.Og, 53.6mmol) in DMF (250ml) was treated with K2C03 (19.5g, 140mmol) and 2-bromoethyl methyl ether (16.7g, 120mmol) and stirred at 90 C overnight. The reaction was cooled to RT, concentrated and the residue partitioned between water and DCM. The organics were separated, dried and concentrated. Column chromatography (Si02; 4: 1 PE:ether) gave the title compound; (11.05g, 45mmol)NMR (CDCI3) delta 7.77 (IH, d, J 2.8), 7.39 (IH, dd, J 8.8, 2.8), 6.94 (IH, d, J 8.8), 4.17 (2H, m), 3.88 (3H, s), 3.78 (2H, m), 3.46 (3H, s)
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃;Inert atmosphere;
In 5 ml of anhydrous DMF, are added under argon 500 mg (2.7 mmol) of <strong>[4068-78-4]methyl 5-chloro-2-hydroxybenzoate</strong>, 277 mul (2.9 mmol) of 2-bromoethyl methyl ether and 1.3 g (4 mmol) of cesium carbonate. The mixture is stirred at ambient temperature overnight. The mixture is then diluted with diethyl ether, filtered on Celite and the Celite is washed several times with diethyl ether. The combined filtrates are evaporated under reduced pressure to give 580 mg of a yellow oil which crystallizes at ambient temperature. Crude product is used in the next step without further purification. Yield: 88%. 1H NMR (DMSO-d6, 300 MHz): delta 7.67 (d, J=2.7Hz, 1H); 7.56 (dd, J=2.7 and 8.9Hz, 1H); 7.67 (d, J=8.9Hz, 1H); 4.17 (t, J=4.5Hz, 2H); 3.79 (s, 3H); 3.65 (t, J=4.6Hz, 2H); 3.31 (s, 3H).
To a 0 C solution of 7-chloro-lH-pyrrolo[2,3-c]pyridine (1.3 g, 8.5 mmol) in DMF (40 mL) under nitrogen is added sodium hydride (60% suspension in oil, 0.51 g, 12.8 mmol). After stirring for 10 minutes at 0 C, 1- bromo-2-methoxy-ethane (1.8 g, 12.8 mmol) is added followed by a catalytic amount of NaT After stirring an additional 2h at 0 C the reaction is quenched with aqueous saturated NaHC03 solution and extracted with EtOAc. The combined organic layers are dried over MgS04, filtered and concentrated in vacuo. The crude material is purified on silica gel with 30%> EtOAc /heptanes as eluant to deliver the titled compound as a clear colorless oil 1.66 g (93%). 1H NMR (CDC13) delta 7.98 (d, J= 5.4 Hz, 1H), 7.45 (d, J = 5.4 Hz, 1H), 7.31 (d, J= 3.1 Hz, 1H), 6.52 (d, J= 3.1 Hz, 1H), 4.72 (t, J= 5.1 Hz, 2H), 3.76 (t, J= 5.1 Hz, 2H), 3.30 (s, 3H). LCMS m/z 211 (M+H).
To a suspension of NaH (0.51 g, 12.63 mmol) in DMF (lOmL) under Ar is added a suspension of lH-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester (2 g, 10.53 mmol) in DMF (9 mL). The reaction mixture is stirred for 20 min, and 2-methoxyethyl bromide (1.1 mL, 11.8 mmol) is added. The reaction mixture is stirred at room temperature overnight. The reaction mixture is poured into H20 and the resulting precipitate isolated by filtration. Purification by flash chromatography on Si02 eluting with 10%> EtOAc gives 1.27 g, (49%>) of the desired product. 1H-NMR (CDC13, 300 MHz) delta 8.5 (d, H), 8.0 (d, H), 7.2 (s, H), 7.15 (m, H), 5.0 (t, 2H), 4.4 (t, 2H), 3.75 (t, 2H), 3.3 (s,3H), 1.4(t, 3H). LCMS m/z 249 (M+H).
To a solution of lH-pyrrolo[3,2-b]pyridine-2-carboxylic acid ethyl ester (1.34 g, 7.04 mmol) [prepared according to the procedure by Lachance, N. et al. Synthesis 2005, 15, 2571 -2577] in N,N- dimethylacetamide at rt is added sodium hydride (210 mg, 8.31 mmol). The resulting mixture is stirred for 30 minutes at rt. 2-Bromoethylmethyl ether (1.4 mL, 14.15 mmol) is added and the resulting mixture is stirred at rt overnight. The mixture is diluted with water and EtOAc. The organic is separated and the aqueous phase is extracted with EtOAc. The organic phase is washed with brine then separated and dried (MgSO/t). The organic phase is concentrated in vacuo and the crude residue is flash chromatographed over Si02 (eluted with heptane:EtOAc = 85: 15) to afford 1.24 g (71percent) of the title compound as a yellow oil. lH NMR (CDC13, 300 MHz) delta 8.56 (m, 1H), 7.82 (d, 1H), 7.46 (s, 1H), 7.24-7.20 (m, 1H), 4.73 (m, 2H), 4.40 (m, 2H), 3.73 (m, 2H), 3.24 (m, 3H), 1.43 (m, 3H). LCMS m/z 249 (M+H).
To a solution of <strong>[55864-87-4]4-nitro-1H-pyrazole-3-carboxylic acid ethyl ester</strong> (100 mg, 0.54 mmol) in DMSO (1 mL) was added potassium carbonate (164 mg, 1.19 mmol) and the reaction mixture was stirred for 5 min. 1-Bromo-2-methoxyethane (110 mul, 1.19 mml) was added and the resulting reaction mixture was stirred at ambient temperature overnight. The reaction mixture was partitioned between ethyl acetate and water and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried and the solvent was evaporated. The product was obtained as a mixture of regioisomers which were separated by silica gel chromatography using a heptane /ethyl acetate gradient to yield 72 mg (55%) of the desired regioisomer and 33 mg (25%) of 2-(2-methoxyethyl)-4-nitro-2H-pyrazole-3-carboxylic acid ethyl ester. MS: M=244.3 (M+H)+
25%; 55%
To a solution of 4-nitro-lH-pyrazole-3-carboxylic acid ethyl ester (100 mg, 0.54 mmol) in DMSO ( 1 mL) was added potassium carbonate (164 mg, 1.19 mmol) and the reaction mixture was stirred for 5 min. l-Bromo-2-methoxyethane (110 mu, 1.19 mml) was added and the resulting reaction mixture was stirred at ambient temperature overnight. The reaction mixture was partitioned between ethyl acetate and water and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried and the solvent was evaporated. The product was obtained as a mixture of regioisomers which were separated by silica gel chromatography using a heptane/ethyl acetate gradient to yield 72 mg (55 %) of the desired regioisomer and 33 mg (25 %) of 2-(2-methoxyethyl)-4-nitro-2H-pyrazole-3-carboxylic acid ethyl ester.MS: M = 244.3 (M+H)+
Preparation of Compound 150Step 1:(S)-tert-Butyl (l-(2-methoxyethyl)-2-oxopiperidin-3-yl)carbamate. (5)-tert-Butyl (2- oxopiperidin-3-yl)carbamate (1.16 g, 5.42 mmol) was dissolved in DMSO (12 rnL). KOH (395 mg, 7.05 mmol) was added, followed by l-bromo-2-methoxyethane (660 mu,, 7.0 mmol) and the mixture stirred overnight. The reaction was quenched by addition of saturated aqueous NH4C1 (8 vol) and extracted with EtOAc (2 x 4 vol). The combined extracts were washed with brine, dried, filtered and evaporated. The desired product was isolated by silica gel chromatography to afford (S)-tert-butyl (l-(2-methoxyethyl)-2- oxopiperidin-3-yl)carbamate. Yield: (1.04g, 70.4%).
With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 16h;Inert atmosphere;
j0399j 2-Chloropyrimidin-5-ol (200 mg, 1.53 mmol), 1-bromo-2-methoxyethane (0.158 mL, 1.69 mmol) and potassium carbonate (423.5 mg 3.06 mmol) were suspended in anhydrous NN-dimethylformamicle (5 mL) and heated 10 50 °C in a nitrogen almosphere for 16 hours. The solvents were removed in vacuo and the residue was partitioned between ethyl acetate (50 mL) and water (30 mL), the aqueous was extracted with ethyl acetate (2 x 30 niL) and the conbilled organics washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound 244 mg (yield 85percent) as off-white translucent crystals. &i NMR (500 MHz, DMSO) 8.55 (s, 2F1), 4.37 ?4.21 (m, 2H), 3.78 ? 3.59 (m, 2H), 3.30 (s, 3H). Tr(METCRI278) = 1.36 mill, (Est) (M+Na)t 189.
With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 26h;
To a stirred solution of 2-chloropyrimidm-5-ol (Intermediate No.86 Step 2, 17.5 g, 134 mmol) in DMF (90 mL was added 2-bromoethyl methyl ether (17.6 mL, 1-87 mmol) followed by K2C03 (24.0 g, 174 mmol). The. resulting suspension was heated at 60 °C for 18 hr. In order to drive the reaction to completion, additional 2-bromoethyl methyl ether (16.0 mL, 170 mmol) and K2C03 (18.5 g, 134 mmol) were added, and- the heating was continued for approximately 8 hr. The reaction mixture was cooled and partitioned between 10percent aqueous sodium chloride (250 mL) and EtOAc (500 mL). The layers were separated and the organic layer was washed with 10percent aqueous sodium chloride (250 mL). The first aqueous layer was extracted with EtOAc (250 mL). The second aqueous layer was salted with solid NaCl, and extracted with EtOAc (250-mL). The combined organic layers were driecLover Na2S04, filtered, andconcentrated to a crude oil that was taken up into a minimal amount of DCM and purified by silica gel chromatography to afford 2-chIoro-5-(2-methoxyethoxy)pyrimidine as a white solid. LRMS (ESI) calc'd for C7H10C1N2O2 [M+Hf: 189. ; found 189.
With sodium hydride; In N,N-dimethyl-formamide; at 0 - 50℃;Inert atmosphere;
To a solution of <strong>[19520-74-2]methyl 3-hydroxy-5-methoxybenzoate</strong> (Example 1 , step i, 0.5 g, 2.7 mmol) in DMF (10 ml) was added NaH (0.2 g, 5.4 mmol) at 0 under a nitrogen atmosphere. After stirring for minutes, 1 -bromo-2-methoxy-ethane (0.75 g, 5.4 mmol) was added and the reaction mixture was stirred at 50 for 1 hour. The solution was poured into 100 ml ice water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2S04 and concentrated under reduced pressure to give methyl 3-methoxy-5-(2-methoxyethoxy)benzoate (0.5 g). The crude product was used in the next step without further purification,
With potassium carbonate; In ethyl acetate; N,N-dimethyl-formamide;
Step 1 <strong>[3336-43-4]1-chloroisoquinolin-4-ol</strong> (0.5 g, 2.78 mmol), 1-bromo-2-methoxyethane (0.318 mL, 3.34 mmol), and potassium carbonate (0.539 g, 3.90 mmol) were added to a solution of DMF (10 mL) and heated to 45 C. for 1 hr. Ater 45 min, the temp was raised to 55 C. for 45 min. One half of an equivalent of 1-bromo-2-methoxyethane (0.318 mL, 3.34 mmol) was then added and then stirred at 40 C. for overnight. The reaction was diluted with water and extracted with EtOAc. The organic layer was washed with brine, collected, dried over MgSO4, filtered and evaporated to give the crude product. Crude material purified via silica gel chromatography (10-60% EtOAc:Hex) to give the desired product 1-chloro-4-(2-methoxyethoxy)isoquinoline (368 mg, 1.548 mmol, 55.6% yield) as an orange solid. 1H NMR (400 MHz, CHLOROFORM-d) delta 8.33-8.24 (m, 2H), 7.83 (s, 1H), 7.81-7.68 (m, 2H), 4.40-4.32 (m, 2H), 3.95-3.84 (m, 2H), 3.52 (s, 3H). MS: MS m/z 238.15 (M++1).
55.6%
With potassium carbonate; In N,N-dimethyl-formamide; at 40 - 55℃;
<strong>[3336-43-4]1-chloroisoquinolin-4-ol</strong> (0.5 g, 2.78 mmol), 1-bromo-2-methoxyethane (0.318 mL, 3.34 mmol), and potassium carbonate (0.539 g, 3.90 mmol) were added to a solution of DMF (10 mL) and heated to 45 C. for 1 hr. Ater 45 min, the temp was raised to 55 C. for 45 min. One half of an equivalent of 1-bromo-2-methoxyethane (0.318 mL, 3.34 mmol) was then added and then stirred at 40 C. for overnight. The reaction was diluted with water and extracted with EtOAc. The organic layer was washed with brine, collected, dried over MgSO4, filtered and evaporated to give the crude product. Crude material purified via silica gel chromatography (10-60% EtOAc:Hex) to give the desired product 1-chloro-4-(2-methoxyethoxyl)isoquinoline (368 mg, 1.548 mmol, 55.6% yield) as an orange solid. 1H NMR (400 MHz, CHLOROFORM-d) delta 8.33-8.24 (m, 2H), 7.83 (s, 1H), 7.81-7.68 (m, 2H), 4.40-4.32 (m, 2H), 3.95-3.84 (m, 2H), 3.52 (s, 3H). MS: MS m/z 238.15 (M++1)
Example 1743-(2,6-difluoro-3,5-dimethoxyphenyl)-1- j1-(2-methoxyethyl)-1H-pyrazol-4-ylj -1,3,4,7-tetrahydro-2H-pyrazolo j4?,3? : 5,6j pyrido j4,3-dj pyrimidin-2-one Step 1: 1-(2-methoxyethyl)-JH-pyrazol-4-amine A mixture of 4-nitro-1H-pyrazole (0.5 g, 4 mmol), Ethane, 1-bromo-2-methoxy (0.84mL, 8.8 mmol), and potassium carbonate (1.2 g, 8.8 mmol) in N,N-dimethylformamide (8mL, 100 mmol) was stirred at 70 C for 1 hour. After cooling to room temperature, the mixture was diluted with water then extracted with EtOAc. The combined extracts were washed with water and brine. The organic layer was dried over Na2SO4, filtered then concentrated. The residue was dissolved in methanol (10 ml) then a catalytic amount ofpalladium (10 wt % on activated carbon) was added. The suspension was stirred under a balloon of H2 at room temperature for 2 hours then filtered and concentrated. The residue was used in the next step without further purification.
To a stirred solution of Scheme 52 compound 1 (1.00 g, 8.84 mmol) in dry DMF (5 mL) was added NaH (254 mg, 10.61 mmol, 50-60% in oil) portion wise, followed after 15 min of stirring by l-bromo-2-methoxyethane (1.23g, 8.84 mmol). The reaction mixture was stirred at 50 C for 12 h. After TLC showed the starting material was completely consumed, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (10 mL). The organic layer was washed with water (5 mL) and brine (5 mL) then dried over Na2S04 and concentrated to give a residue which was purified by flash chromatography on silica gel (eluting with CH2Cl2/MeOH 100/0 gradually increasing to 95/5) to give Scheme 52 compound 2 (800 mg, 53%) as a yellow solid. MS [ESI, MH+] = 172.07.
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 18h;
General procedure: 6-Hydroxy2-chloroquinoline (4 mmol) was added to a pressure vial. Next, bromoethylmethyl ether, 2-(2-bromoethoxy)-N-tritylethan-1-amine or 4-(3- bromopropyl)morpholine (4.4 mmol) dissolved in DMF (10 mL), and K2CO3 (6 mmol) were added and the solution was stirred at 80 C for 16 h. The reaction mixture was cooled to room temperature, diluted with EtOAc and extracted with water (x1) and brine (x3). The aqueous phase was washed with EtOAc (x1) and the organic phase was evaporated. The title compound was purified by flash chromatography.
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 16h;
General procedure: 6-Hydroxy2-chloroquinoline (4 mmol) was added to a pressure vial. Next, bromoethylmethyl ether, 2-(2-bromoethoxy)-N-tritylethan-1-amine or 4-(3- bromopropyl)morpholine (4.4 mmol) dissolved in DMF (10 mL), and K2CO3 (6 mmol) were added and the solution was stirred at 80 C for 16 h. The reaction mixture was cooled to room temperature, diluted with EtOAc and extracted with water (x1) and brine (x3). The aqueous phase was washed with EtOAc (x1) and the organic phase was evaporated. The title compound was purified by flash chromatography.
2-fluoro-4-(2-methoxyethoxy)benzaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 2h;
A solution of <strong>[348-27-6]2-fluoro-4-hydroxybenzaldehyde</strong> (200mg), K2C03 (592mg) and 1-bromo-2-methoxyethane in DMF (5m1) was stirred at 60C for 2h. . The reaction mixture was dilutedat rt with DCM and water. The layers were separated and the water phase was extracted with DCM. The combined org. layers were dried over Mg504, filtrated off and evaporated in vacuo. The crude brown oil (330mg) was used in the next step without purification LC-MS (A): tR = 0.72mm; [M+H]: 199.15.
With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 2h;Inert atmosphere;
Aldehyde 38: 2-Fluoro-4-(2-methoxyethoxy)benzaldehyde A solution of <strong>[348-27-6]2-fluoro-4-hydroxybenzaldehyde</strong> (200 mg), K2C03 (592 mg) and 1-bromo-2- methoxyethane in DMF (5 mL) was stirred at 60C for 2h. . The reaction mixture was diluted at rt with DCM and water. The layers were separated and the water phase was extracted with DCM. The combined org. layers were dried over MgS04, filtrated off and evaporated in vacuo. The crude brown oil (330 mg) was used in the next step without purification LC-MS (A): tR = 0.72 min; [M+H]+: 199.15.
With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 2h;
A solution of <strong>[348-27-6]2-fluoro-4-hydroxybenzaldehyde</strong> (200mg), bromo(methoxy)methane (0.201 ml)and K2C03 (592mg) in DMF (5ml) was stirred at 60C for 2h. The mixture was diluted with DCM and water. The layers were separated and the org. phase was washed with sat. aq. NaCI. The combined org. layers were dried over MgS04, filtrated off and evaporated in vacuo. The crude product (250mg of a yellow oil) was used in the next step without purification. LC-MS (A): tR = 0.72min; [M+H]+: 199.15.
1-bromo-3-chloro-5-(2-methoxyethoxyl)benzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 18h;
1-bromo-2-methoxyethane (136 ^L, 1.45 mmol) was added to a mixture of 3- bromo-5-chlorophenol (200 mg, 0.964 mmol), potassium iodide (240 mg, 1.45 mmol) and potassium carbonate (213 mg, 1.54 mmol) in DMF (1 mL). The reaction mixture was stirred at 100 oC for 18 h. Water and ethyl acetate were added. The phases were separated the organic layer was washed with 1N NaOH (2x), dried with sodium sulfate, filtered and evaporated under reduced pressure to give the title compound (170 mg, 0.67 mmol, 70percent).
70%
With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 100℃; for 18h;
1-bromo-2-methoxyethane (136 iL, 1.45 mmol) was added to a mixture of 3- bromo-5-chlorophenol (200 mg, 0.964 mmol), potassium iodide (240 mg, 1.45 mmol) and potassium carbonate (213 mg, 1.54 mmol) in DMF (1 mL). The reaction mixture was stirred at 100 C for 18 h. Water and ethyl acetate were added. The phases were separated the organic layer was washed with 1 N NaOH (2x), dried with sodium sulfate, filtered and evaporated under reduced pressure to give the title compound (170 mg, 0.67 mmol, 70percent).
17 g
With caesium carbonate; In acetonitrile; at 80℃; for 12h;
To a mixture of <strong>[56962-04-0]3-bromo-5-chloro-phenol</strong> (14.0 g, 67.5 mmol) in MeCN (150 mL) was added 1-bromo-2-methoxy-ethane (12.6 g, 90.7 mmol) and Cs2CO3 (34.1 g, 105 mmol). The resultant mixture was heated at 80° C. for 12 hours, and then cooled to room temperature and then filtered. The filtrate was evaporated under reduced pressure, and the residue was purified by column chromatography to give 1-bromo-3-chloro-5-(2-methoxyethoxyl)benzene (17.0 g) as colorless oil.
17 g
With caesium carbonate; In acetonitrile; at 80℃; for 12h;
Step 1: Preparation of l -bromo-3-ehloro-5-(2-inethoxyethoxy)benzene To a mixture o f 3 -bro mo -5 -ch lo ro -plietio 1 ( 14.0 g, 67.5 mmol) in MeCN ( 1 50 ml.) was added 1 -bro mo-2-met ho.x y-et ha ne ( 1 2.6 g, 90.7 mmol ) and CS2CO3 (34. 1 g, 105 mmol). The resultant mixture was heated at 80 °C for I 2 hours, and then cooled to room temperature and then filtered. The filtrate was evaporated under reduced pressure, and the residue was purified by column chromatography to give 1 -bromo-3-chloro-5-(2-metho.xyethoxy)bcnzene ( 1 7.0 g) as colorless oil.
17 g
With caesium carbonate; In acetonitrile; at 80℃; for 12h;
To a mixture of <strong>[56962-04-0]3-bromo-5-chloro-phenol</strong> (14.0 g, 67.5 mmol. Accel a) in MeCN (150 ml. ) was added 1 -bromo-2-methoxy-ethane (12.6 g, 90.7 mmol ) and CS2CO3(34.1 g, 105 mmol ). The resultant mixture was heated at 80 °C for 12 hours, and then cooled to room temperature and then filtered. The filtrate was evaporated under reduced pressure, and the residue was puri ied by column chromatography to give l -bromo-3-chloro-5-(2-methoxyethoxy)benzene (17.0 g) as a colorless oil.
(4-(dimethoxymethyl)-2-(2-methoxyethylsulfanyl)pyrimidine)[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1.51 g sodium methoxide (28.0 mmoi) was dissolved in 15 mL MeOH and cooled to 0C.2.44 g thiocarbamide (32.0 mol) was added portionwise and the mixture was stirred for 1hour. Then 3.46 g E)-4-(dimethylarnino)-t,i-dimethoxy-but-3-en-2-onc (Preparation9a1) (20.0 mol) was added dropwise at 0C, then it was heated to 80C and stirred there for 2 hours. It was cooled to room temperature, 4.17 g i-brorno-2-rnethoxy-ethane (30 mmol) was added and the mixture was stirred for 1 hour at 50C, then overnight at room temperature. It was filtered, the filtrate was concentrated under reduced pressure, diluted with EtOAe, washed with water and brine, The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified via flash chromatography using heptane and ethyl-acetate as eluents to give a light yellow oil (4-(dimethoxymethyl)-5 2-(2-methoxyethylsulfanyl)pyrirnidine).?H NMR (400 MT-Tz, DMSO-d6): 8.68 (d, IH), 7.24 (d, IH), 5.23 (s, 1T4), 3.59 (t, 2H), 3.33 (s, 6H), 3.32 (t, 2H), 3.28 (s, 3H).
4-formyl-3-(2-methoxy-ethoxy)-benzoic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1.88 g
With potassium carbonate; In N,N-dimethyl-formamide; at 75℃; for 18h;Inert atmosphere;
A mixture of <strong>[24589-98-8]4-formyl-3-hydroxy-benzoic acid methyl ester</strong> (1.80 g, 9.99 mmol) and K2CO3 (2.76 g, 19.97 mmol) in DMF (20 mL) was treated with 1-bromo-2-methoxy-ethane (1.20 mL, 12.77 mmol) and heated to 75 C. for 18 h under nitrogen. The reaction mixture was concentrated in vacuo and partitioned between EtOAc and water. The aqueous extract was further extracted with EtOAc (×2) and the combined organic extract was washed with water and brine, then dried (Na2SO4), filtered and concentrated in vacuo to give the title compound as an dark brown waxy solid (1.88 g).1H NMR (400 MHz, CDCl3) delta 10.56 (1H, d, J=0.5 Hz), 7.88 (1H, dd, J=7.8, 0.5 Hz), 7.70-7.69 (1H, m), 7.68 (1H, s), 4.39-4.28 (2H, m), 3.95 (3H, s), 3.85-4.81 (2H, m), 3.4 (3H, s).
2-fluoro-4-iodo-1-(2-methoxyethoxy)benzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75.3%
With caesium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 70℃; for 3h;
A mixture of cesium carbonate (3.50 g, 10.50 mmol) , potassium iodide (350 mg, 2.10 mmol) , <strong>[2713-28-2]2-fluoro-4-iodophenol</strong> (1.01 g, 4.20 mmol) and 1-bromo-2-methoxyethane (880 mg, 6.30 mmol) in DMF (15.00 mL) was stirred at 70 for 3 h and diluted with water (50 mL) , and then extracted with EtOAc (50 mL × 3) . The combined organic layers were concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with PE/EtOAc (v/v) 20/1 to give a colorless oily product (982 mg, 75.3) .[1148]MS (ESI, pos. ion) m/z: 297.0 [M+1]+ and[1149]1H NMR (400 MHz, CDCl3) : delta (ppm) 7.49-7.31 (m, 2H) , 6.74 (t, J 8.5 Hz, 1H) , 4.16 (t, J 4.8 Hz, 2H) , 3.75 (t, J 4.8 Hz, 2H) , 3.44 (s, 3H)
4-bromo-1-(2-methoxyethyl)-3-methyl-1H-pyrazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
30.1%
With caesium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 70℃; for 4h;
To a mixture of cesium carbonate (14.52 g, 46.58 mmol) , potassium iodide (1.62 g, 9.32 mmol) and <strong>[13808-64-5]4-bromo-3-methyl-1H-pyrazole</strong> (3.02 g, 18.64 mmol) were added 1-bromo-2-methoxyethane (3.92 g, 27.95 mmol) and DMF (30 mL) . The mixture was warmed to 70 and stirred for 4 h and cooled to rt, and then diluted with water (100 mL) . The resulting mixture was extracted with EtOAc (100 mL × 3) . The combined organic layers were dried over anhydrous Na2SO4and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with PE/EtOAc (v/v) 3/1 to give a cololess oily producnt (1.23 g, 30.1) .[1462]MS (ESI, pos. ion) m/z: 219.0 [M+1]+ and[1463]1H NMR (400 MHz, CDCl3) : delta (ppm) 7.42 (s, 1H) , 4.18 (d, J 5.2 Hz, 2H) , 3.69 (d, J 5.2 Hz, 2H) , 3.33 (s, 3H) , 2.23 (s, 3H)
2-bromo-4-(2-methoxyethoxy)-1-methylbenzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96.6%
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 8h;
A mixture of <strong>[60710-39-6]3-bromo-4-methylphenol</strong> (1.66 g, 8.87 mmol) , 1-bromo-2-methoxyethane (0.85 mL, 9.00 mmol) and cesium carbonate (3.5 g, 11.00 mmol) in DMF (15 mL) was stirred at rt for 8 h. The reaction mixture was diluted with water (50 mL) . The resulting mixture was extracted with DCM (50 mL × 3) . The combined organic layers were washed with saturated aqueous NaCl (15 mL) , dried over anhydrous Na2SO4and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with PE/EtOAc (v/v) 8/1 to give a light yellow liquid product (2.10 g, 96.60) .[1618]MS (ESI, pos. ion) m/z: 246.90 [M+1]+
j0317j To sodium hydride (60% in mineral oil, 131 mg, 3.26 mmol and methyl 5- hydroxypyridine-2-carboxylate (500 mg, 3.27 mmol) under nitrogen was added anhydrous N,N-dimethylformamide (5 mL) and the mixture stirred at room temperature for 15 minutes. A solution of 1 -bromo-2-methoxyethane (477 mg, 3.43 mmol) in N4Y-dimethylformamide (5 mL) was added slowly. The mixture was stirred at room temperature overnight and then heated at 65 C for 3.5 hours. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated to give the title compound 688 mg (quantitative yield) as a light brown oil. oH NMR (500 MHz, DMSO) 8.39 (d, I = 2.9 Hz, 1H), 8,03 (d, I = 8.7 Hz, 1H), 7.53 (dd, I = 8.7, 2.9 Hz, 1H), 4.31 -4.23 (m, 2H), 3.84 (s, 3H), 3.72-3.66 (m, 2H), 3.31 (s, 3H). Tr(METCR1278) = 1.25 mi (ESj(M±H)2l2.
2-bromo-5-(2-methoxyethoxy)-3-methylpyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
38%
With potassium carbonate; In acetonitrile; at 20℃;
(A) A mixture of <strong>[1003711-43-0]6-bromo-5-methylpyridin-3-ol</strong> (1 g, 5.32 mmol), 1-bromo-2- methoxyethane (730 mg, 5.25 mmol) and K2CO3 (1.5 g, 10.87 mmol) in MeCN (20 mL) was stirred at rt overnight, after which the reaction was quenched by the addition of water (100 mL). The resulting solution was extracted with EtOAc (2 x 100 mL) and the combined organic phase was dried (Na2SO4) and concentrated under reduced pressure. The resultant residue was purified by silica gel chromatography (0-15% EtOAc/petroleum ether) to afford 2-bromo-5-(2-methoxyethoxy)-3-methylpyridine (500 mg, 38 %) as colorless oil. LC/MS: mass calcd. for C9H12BrNO2: 246.10, found: 246.0 [M]+, 248.0 [M+2]+.
38%
With potassium carbonate; In acetonitrile; at 20℃;
(A) A mixture of <strong>[1003711-43-0]6-bromo-5-methylpyridin-3-ol</strong> (1 g, 5.32 mmol), 1-bromo-2-methoxyethane (730 mg, 5.25 mmol) and K2CO3 (1.5 g, 10.87 mmol) in MeCN (20 mL) was stirred at rt overnight, after which the reaction was quenched by the addition of water (100 mL). The resulting solution was extracted with EtOAc (2*100 mL) and the combined organic phase was dried (Na2SO4) and concentrated under reduced pressure. The resultant residue was purified by silica gel chromatography (0-15% EtOAc/petroleum ether) to afford 2-bromo-5-(2-methoxyethoxy)-3-methylpyridine (500 mg, 38%) as colorless oil. LC/MS: mass calcd. for C9H12BrNO2: 246.10, found: 246.0 [M]+, 248.0 [M+2]+.
38%
With potassium carbonate; In acetonitrile; at 20℃;
(A) A mixture of 552 <strong>[1003711-43-0]6-bromo-5-methylpyridin-3-ol</strong> (1 g, 5.32 mmol), 188 1-bromo-2-methoxyethane (730 mg, 5.25 mmol) and 149 K2CO3 (1.5 g, 10.87 mmol) in 16 MeCN (20 mL) was stirred at rt overnight, after which the reaction was quenched by the addition of 12 water (100 mL). The resulting solution was extracted with EtOAc (2×100 mL) and the combined organic phase was dried (Na2SO4) and concentrated under reduced pressure. The resultant residue was purified by silica gel chromatography (0-15% EtOAc/petroleum ether) to afford 553 2-bromo-5-(2-methoxyethoxy)-3-methylpyridine (500 mg, 38%) as colorless oil. LC/MS: mass calcd. for C9H12BrNO2: 246.10, found: 246.0 [M]+, 248.0 [M+2]+
<strong>[603-11-2]3-nitrophthalic acid</strong> 15.0g was dissolved in dimethyl sulfoxide 78 g, further sodium hydrogen carbonate 17.9 g, was stirred for 1.5 hours at 120. C. was added 2-bromo-methyl ether 21.7 g. Since the stirring and while cooling precipitation of the product to room temperature, was completely precipitate the product by then cooled to 0 , and the mixture was stirred for 30 minutes with vigorous room temperature poured into water 200g. The precipitate was collected by filtration, saturated sodium bicarbonate, washed successively with water, vacuum 13.8g (59 mole% equivalent) as a white powder nitrophthalic di (2-methoxy-ethyl) by drying was obtained.
2-bromo-1-(2-methoxyethyl)-1H-benzo[d]imidazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
Sodium hydride (60% dispersion in mineral oil, 0.665 g, 16.63 mmol) was added to a solution of <strong>[54624-57-6]2-bromo-1H-benzo[d]imidazole</strong> (2.73 g, 13.86 mmol) in DMF (30 mL), and the reaction stirred for 10 minutes at ambient temperature. 1-Bromo-2-methoxyethane (1.541 ml, 16.63 mmol) was added, and reaction stirred overnight at ambient temperature. The reaction was diluted with ethyl acetate and washed several times with brine. The organic layer was separated and dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified via column chromatography on a 100 gram silica gel column eluting with 20-40% ethyl acetate-hexane. The desired fractions were combined and concentrated to afford 2-bromo-1-(2-methoxyethyl)-1H-benzo[d]imidazole (2.9 g, 82%) as an orange oil. 1H NMR (300 MHz, DMSO-d6) delta ppm 7.54-7.67 (m, 2H) 7.14-7.34 (m, 2H) 4.42 (t, J=5.28 Hz, 2H) 3.67 (t, J=5.28 Hz, 2H) 3.20 (s, 3H).
82%
Sodium hydride (60% dispersion in mineral oil, 0.665 g, 16.63 mmol) was added to a solution of 2-bromo-lH-benzo[d]imidazole (2.73 g, 13.86 mmol) in DMF (30 mL), and the reaction stirred for 10 minutes at ambient temperature. l-Bromo-2-methoxy ethane (1.541 ml, 16.63 mmol) was added, and reaction stirred overnight at ambient temperature. The reaction was diluted with ethyl acetate and washed several times with brine. The organic layer was separated and dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified via column chromatography on a 100 gram silica gel column eluting with 20-40%) ethyl acetate- hexane. The desired fractions were combined and concentrated to afford 2-bromo-l-(2- methoxyethyl)-lH-benzo[d]imidazole (2.9 g, 82%) as an orange oil. 1H NMR (300 MHz, DMSO-i) delta ppm 7.54 - 7.67 (m, 2 H) 7.14 - 7.34 (m, 2 H) 4.42 (t, j=5.28 Hz, 2 H) 3.67 (t, J=5.28 Hz, 2 H) 3.20 (s, 3 H).
1-bromo-3-fluoro-2-(2-methoxyethoxy)benzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With potassium carbonate; acetonitrile; at 80℃; for 18h;
To a solution of <strong>[2040-89-3]2-bromo-6-fluorophenol</strong> (1 .0 g, 5.2 mmol) in MeCN (20 mL) was added K2003 (2.2 g, 15.7 mmol) followed by 1-bromo-2-methoxyethane (1.2 g, 7.9 mmol). The mixture was heated at 80 oC for 18 hrs then the mixture was cooled and water (50 mL) was added and the mixture extracted with DCM ( 2 x 75 mL). The combined extracts were dried (Mg504) then concentrated under reduced pressure to give the title compound as a colourless oil (1 .09 g, 85%).1H NMR (ppm)(400 MHz, CDCI3): 3.76 (2H, t, J=4.8 Hz), 3.45 (3H, s), 4.25 (2H, t, J4.8 Hz),6.95 -6.88 (1 H, m), 7.09 - 7.02 (1 H, m), 7.34 - 7.29 (1 H, m)
methyl 1-(2-methoxyethyl)-4-nitro-1H-pyrazole-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃; for 18h;
l-Bromo-2-methoxyethane (4.3g, 30.9mmol) was slowly added to a stirred solution of methyl 4- nitro-lH-pyrazole-3-carboxylate (6g, 28.9 mmol) in DMF (120mL) at 0 C. The reaction mass was stirred at room temperature for 18h. Quenched the reaction mass with ice cold water and extracted with ethyl acetate (3x25mL). The combined organic layer was washed with brine, dried over Na2S04, filtered and concentrated under vacuum to obtain crude residue. The residue was purified by silica gel column chromatography to afford the desired title compound (4g, 60%). 1HNMR (CDCI3, 300MHz): delta 8.25 (s, 1H), 4.35-4.32 (m, 2H), 3.98 (s, 3H), 3.75-3.71 (m, 3.35 (s, 3H).
With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 20℃; for 9h;Cooling with ice; Inert atmosphere;
Adenosine (7.0 g, 1 eq) was dissolved in 200 mL of anhydrous DMF, NaH (1.6 g, 1.5 eq), purity 60%, was added under ice-cooling with nitrogen and stirred well for 30 min.A solution of 2-bromoethyl methyl ether (2.9 mL, 1.2 eq) was added dropwise,After 30 min, the ice bath was removed and stirred at room temperature for 8 h.After the reaction, ice water (5 mL) was added and stirred for 10 min. The reaction solution was concentrated,O-MOE-adenosine (1.7 g, yield 20.3%) was isolated by silica gel column chromatography.
methyl 1-(2-methoxyethyl)-1H-indole-7-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
A solution of <strong>[93247-78-0]methyl 1H-indole-7-carboxylate</strong> (1 g, 5.71 mmol) in DMF (30 mL) was added NaH (274 mg, 6.86 mmol) at 0C. After stirring for 45 minutes, 1-bromo-2-methoxyethane (946 mg, 6.86 mmol) was added and stirred for 16 hours at a it was quenched with water, extracted with EA (x3), washed with brine (x2). The organic layer was dried, and concentrated to give the cmde methyl 1-(2-methoxyethyl)-1H-indole-7-carboxylate as a yellow oil (680 mg, 5 1%). ESI MS m/z = 233.9 [M+Hf
A solution of <strong>[93247-78-0]methyl 1H-indole-7-carboxylate</strong> (1 g, 5.71 mmol) in DMF (30 mL) was added NaH (274 mg, 6.86 mmol) at 0°C. After stirring for 45 minutes, 1-bromo-2-methoxyethane (946 mg, 6.86 mmol) was added and stirred for 16 hours at rt. It was quenched with water, extracted with EA (x3), washed with brine (x2). The organic layer was dried, and concentrated to give the crude methyl 1-(2-methoxyethyl)-1H-indole-7-carboxylate as a yellow oil (680 mg, 51percent). ESI MS m/z = 233.9 [M+H]+.
2-((2-methoxyethoxy)methyl)-1-methylimidazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50%
With sodium hydride; In tetrahydrofuran; at 0 - 20℃; for 20h;
5.00 g (44.6 mmol) of 2-hydroxymethyl-1-methylimidazole and 4.28 g (178 mmol) of sodium hydride were added to 70 mL of tetrahydrofuran and cooled to 0 .After 4.61 mL (49.0 mmol) of bromoethyl methyl ether was slowly added to the cooled reaction solution, the ice bath was removed, and the mixture was stirred at room temperature for 20 hours.After completion of the reaction, the reaction solution was distilled off under reduced pressure, dissolved in water, and then extracted several times with hexane. The water layer was collected and extracted several times with dichloromethane, and the organic layer was collected and magnesium sulfate was added.The magnesium sulfate was removed with a vacuum filter, and the obtained solution was collected by vacuum distillation and then purified by column chromatography using eluent dichloromethane: methanol = 95: 5 to obtain 3.28 g of the product (yield = 50%).NMR and mass measurement results of the obtained ionic liquid are as follows.
1-bromo-2-(2-methoxyethoxy)-4-(trifluoromethyl)benzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
97%
With caesium carbonate; In acetonitrile; at 80℃; for 16h;
A solution of <strong>[402-05-1]2-bromo-5-(trifluoromethyl)phenol</strong> (5g, 20.75 mmol), i-bromo-2- methoxyethane (5.77g, 41.5 mmol) and Cs2CO3 (20.28g, 62.2 mmol) in acetonitrile (10 ml) was heated to 80 °C for 1 6h. The reaction was quenched by the addition of water and the reaction mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over Na2SO4 and concentrated under vacuum. The crude was purified by columnchromatography to obtain the product as white gummy liquid (6g, 97percent).
ethyl 1-(2-methoxyethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68%
With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 23℃; for 16h;
To a solution of ethyl 3-(trifluoromethyl)-lH-pyrazole-5-carboxylate (8 g, 38.46 mmol, 1 eq) in DMF (150 ml) was added K2C03 (15.9 g, 115.38 mmol, 3 eq) and bromo ethyl methyl ether at 0C. The RM was stirred at RT for 16 h. The RM was diluted with ice water (200 ml) and extracted with EtOAc (3x 200 ml). The combined organic layers were washed with water (200 ml) and brine (200 ml), dried (N 2S0 ) and upon concentration provided the crude product, which upon flash chromatography (silica gel; EtOAc - PE; 0: 100? 4:96) afforded the title compound (7.0 g, 68%).
6-bromo-2-(2-methoxyethyl)-2,3-dihydro-1H-isoindol-1-one[ No CAS ]
6-bromo-2,3-bis(2-methoxyethyl)isoindolin-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 0 - 20℃; for 72h;Inert atmosphere;
Preparation 314: Mixture of 6-bromo-2-(2-methoxyethyl)isoindolin-1-one and 6-bromo- 2,3-bis(2-methoxyethyl)isoindolin-1 -one (2064) (2065) Sodium hydride (60% wt in mineral oil) (0.1 13 g, 2.83 mmol) was added to a stirred solution of <strong>[675109-26-9]6-bromoisoindolin-1-one</strong> (0.5 g, 2.358 mmol) and 1-bromo-2-methoxyethane (0.277 ml, 2.83 mmol) in DMF (12 mL) under nitrogen at 0 C. The resulting orange solution was allowed to warm slowly to room temperature and stirred for 3 days. The reaction was quenched with water (15 mL) and extracted with EtOAc (3 x 15 mL). The organic extracts were combined and washed with brine (50 mL), dried (MgS04), filtered, and concentrated in vacuo to afford a yellow oil. The crude product was purified by chromatography (S1O2, 24 g GRACE column, 0-100% EtOAc in isohexane) to afford a mixture of 6-bromo-2-(2-methoxyethyl)isoindolin-1-one (549 mg, 62.9%) and 6-bromo-2,3-bis(2-methoxyethyl)isoindolin-1-one as a yellow oil (~3: 1 ratio by LCMS and NMR analyses). Further purification by chromatography (S1O2, 24 g GRACE column, 0-10% MeOH in DCM) did not improve ratio of products, which was used without further purification in the next step. LCMS: [M+H]+ = 270 and 328.
5,7-dihydroxy-3-(2-methoxyethoxy)-2-(4-methoxyphenyl)-8-(3-methylbut-2-en-1-yl)-4H-chromen-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
55%
With potassium carbonate; In acetone;Reflux; Inert atmosphere;
A mixture of 3,5,7-trihydroxy-2- (4-methoxyphenyl)-8- (3-methylbut-2-enyl) -4H-chromen-4-one(400 mg, 1.09 mmol)And 1-bromo-2-methoxyethane (151 mg, 1.09 mmol)Dissolved in acetone solution (20mL),Then, anhydrous potassium carbonate (165 mg, 1.2 mmol) was added,The reaction mixture was heated under reflux with nitrogen under reflux overnight,Concentrated under reduced pressure.Add 20 mL of water,Extracted with ethyl acetate (30 mL x 3)The combined organic phases were washed with saturated sodium chloride solution (30 mL)Dried over anhydrous sodium sulfate,The residue was purified by silica gel column chromatography,The title compound was obtained as a yellow solid (255 mg, 55%).
benzyl 4-methoxyethyl-3-oxopiperazine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74.9%
N-Benzyloxycarbonyl-3-oxobutazine (350 mg, 1.50 mmol) was added to a three-necked flask and about 10 ml of anhydrousDMF was added under nitrogen, NaH (90 mg, 2.25 mmol) was added under stirring. After stirring for 60 min, 2-bromoethyl methyl ether (219 mg, 1.57 mmol) was added dropwise and reacted at room temperature overnight. The solvent was evaporated under reduced pressure, and the aqueous solution was concentrated twice, and the organic layer was concentrated. The column was chromatographed to 32711 ^ as a yield of 74.9%.
methyl 6-bromo-1-(2-methoxyethyl)-1H-indazole-4-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
16%
To a solution of <strong>[885518-49-0]methyl 6-bromo-1H-indazole-4-carboxylate</strong>(200 mg,0.79 mmol)in DMF(5 mL) was added NaH(40 mg,1.63 mmol),and the reaction was stirred for 30 minat RT. 1-Bromo-2-methoxyethane(165 mg,1.18 mmol) was added and the reaction wasstirred overnight. The reaction was quenched with MeOH at-78 C,then diluted withDCM/H20(60 mL,1:1),the organic layer was separated,the aqueous layer was extractedwith DCM(2 x 20 mL),the organic fractions combined,dried over MgS04,filtered,andconcentrated in vacuo. The crude reaction mixture was purified by flash chromatography(Combi-flash Rf,Hex/EtOAc = 0-100% gradient) to aHord the title compound(39 mg,16%).
1-(2-methoxyethyl)-N-(2, 6-dimethylphenyl)-2-piperidinecarboxamide hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78.1%
General procedure: General procedure for preparation of 4a-4q2-fluoroethylbromide (2.2 ml, 0.024 mol) was added to asuspension of N-(2, 6-dimethylphenyl)-2- piperidinecarboxamide(3) (5.0 g, 0.022 mol) and K2CO3 (3.6 g,0.26 mol) in DMF (50 ml). The mixture was stirred andheated at 80 C for 90 min and then allowed to cool to roomtemperature. The solid were filtered off and the DMFsolution was added to cold water (200 ml). 1-(2-fluoroethyl)-N-(2, 6-dimethyl phenyl)-2-piperidinecarboxamideprecipitated as a pale cream solid. It was dissolved inanhydrous ether and dried gas of hydrogen chloride wasadded at room temperature for 5 min, 1-(2-fluoroethyl)-<strong>[15883-20-2]N-(2, 6-dimethylphenyl)-2-piperidinecarboxamide</strong> was transformedinto 1-(2-fluoroethyl)-N-(2, 6-dimethylphenyl)-2-piperidine carboxamide hydrochloride (4a). Compounds4b-4q was prepared by following the same procedure.
With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 5h;
Potassium carbonate (1.44 g, 10.4 mmol) and 1-bromo-2-methoxyethane (0.545 mL, 5.72 mmol) were added to a solution of 1H-imidazole-2-carbaldehyde (0.500 g, 5.20 mmol) in N,N-dimethyl formamide (5.2 mL) at room temperature. The reaction liquid was stirred at 60 C. for 5 hours. The reaction liquid was cooled to room temperature. Ethyl acetate and distilled water were added to the reaction liquid and the reaction liquid was extracted with ethyl acetate. The organic layer was washed with a 10% aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, n-hexane/ethyl acetate) to obtain 1-(2-methoxyethyl)-1H-imidazole-2-carbaldehyde (0.113 g, 0.733 mmol, 14%) as a white solid. (0149) 1H-NMR (400 MHz, DMSO) delta: 3.21 (3H, s), 3.61 (2H, d, J=5.2 Hz), 4.53 (2H, d, J=5.2 Hz), 7.27 (1H, s), 7.62 (1H, s), 9.69 (1H, s). (0150) ESI-MS: m/z=155 (M+H)+.
4-(2-methoxyethylamino)-2-(trifluoromethyl)benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With caesium carbonate; potassium iodide; In acetonitrile; at 70℃; for 18h;
A solution of 4-amino-2-(trifluoromethyl)benzonitrile (2.00 g, 10.7 mmol), potassium iodide (1.79 g, 10.8 mmol), cesium carbonate (10.51 g, 32.26 mmol) and l-bromo-2- methoxyethane (7.47 g, 53.7 mmol) in acetonitrile (25 mL) stirred for 18 h at 70 C. The resulting mixture was cooled to room temperature and concentrated under vacuum. The residue was diluted with water (30 mL) and extracted with 3x30 mL of ethyl acetate. The combined organic phases were washed with 2x30 mL of brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via column chromatography with silica gel (eluting with ethyl acetate/petroleum ether (1 :3)) to give 4-(2- methoxyethylamino)-2-(trifluoromethyl)benzonitrile (2.1 g, 80%) as yellow oil. MS: (ESI, m/z): 243 [M-H]-.
1-(2-methoxyethyl)-5-methyl-3-nitro-1H-pyrazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
64%
With potassium carbonate; In acetonitrile; at 75℃; for 3h;
Add acetonitrile (35 mE) to a mixture of 5-methyi-3-nitro-1H-pyrazoie (095 g,7.1 minol), potassium carbonate (2.0 g, 2.0 eq), and I-brorno-2-methoxyethane (2.0 rnL,3.0 eq). Stir at 75 C for three hours. Cool to rt. Add diethyl ether (-35 mL) and filter. Rinse the solids with EtOAc (2 x 25 rnL). Concentrate the filtrate in vacuo to provide aresidue. Subject the residue to normal phase chromatography, eluting with a 0-100%EtOAc in hexanes gradient, to give the title compound as a yellow oil (1.1 g, 64%). MS(ES) m/z = 186 (M-i-H).
6-(4-aminophenyl)-2-(2-methoxyethyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
32%
To a solution of Intermediate 7 (2:00 g, 9.84 minol) in DMF (50 mL) sodium hydride 60% in mineral oil (472 mg, 10.8 minol) was added carefully at 0 C The ice bath was removed and the mixture was stirred for 30 min at room temperature. The resulting suspension was cooled at 000 and 1-bromo-2-methoxyethane (0.93 mL, 9.84 minol) was added. The reaction mixture was stirred over night at room temperature. The mixture was poured into water and extracted three times with ethyl acetate. The combined organic extracts were washes with brine, dried over Na2SO4 and evaporated. The crude material was purified by flash-chromatography on silica gel to yield the desired product (816 mg, 32%).1H-NMR (400MHz, DMSO-d6): oe [ppm]= 1.02 (d, 3H), 2.24 (dd, IH), 2.56-2.68 (m, IH), 3.23 (s,3H), 3.25 -3.32 (m, IH), 3.50 -3.57 (m, 2H), 3.67 (dt, IH), 3.99 -4.11 (m, IH), 5.56 (s, 2H),6.53 - 6.60 (m, 2H), 7.46 - 7.54 (m, 2H).UPLC (Method 7): R = 0.80; MS (ESIpos): mz [M÷H] 262.
2-bromo-1,3-dimethoxy-5-((2-methoxyethoxy)methyl)benzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
To a round bottom flask was added <strong>[61367-62-2](4-bromo-3,5-dimethoxyphenyl)methanol</strong> (0436) (compound 10, 1.95 g, 7.89 mmol) and NN-dimethylformamide (20 mL). The solution was cooled to 0 °C and sodium hydride (0.393 g of 60percent (w/w) in mineral oil, 10.3 mmol) was added and the reaction was stirred for 1 hour at room temperature. l-Bromo-2- methoxy ethane (0.89 mL, 9.47 mmol) was added and the reaction was stirred overnight at room temperature. The reaction was quenched with methanol and concentrated in vacuo. The residue was taken up in ethyl acetate and washed using water, then brine. The organic layer was dried using sodium sulfate, filtered and concentrated in vacuo. The resulting oil was purified on silica gel using ethyl acetate and hexanes as eluent. Product 2-Bromo-l,3- dimethoxy-5-((2-methoxyethoxy)methy)benzene (15, 2.22 g, 92percent yield) was isolated as a pale yellow oil. LC-MS: tR=2.11 min; m/z+ 23=327.0, 329.0. NM1HR (400 MHz, DMSO- d6) delta ppm 6.70 (s, 2 H) 4.48 (s, 2 H) 3.82 (s, 6 H) 3.53 - 3.62 (m, 2 H) 3.45 - 3.52 (m, 2 H) 3.26 (s, 3 H).
1-hexyl-3-(2-methoxyethyl)-1H-imidazol-3-ium bromide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
In toluene; at 80℃; for 0.333333h;Microwave irradiation;
General procedure: 1-Hexylimidazole (1 eq) and the appropriate alkyl halide (1 eq) were placed in a closed vessel and exposed to irradiation for 20 min at 80 C using a microwave irradiation. The product was then collected as described in the conventional procedure outlined earlier.
2,6-difluoro-4-(2-methoxyethoxy)benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
With potassium carbonate; In acetonitrile; at 80 - 85℃;Inert atmosphere; Large scale;
1-bromo-2-methoxyethane (9.6 kg, 69.06 mol) was added in one portion to <strong>[123843-57-2]2,6-difluoro-4-hydroxybenzonitrile</strong> (8.6 kg, 55.45 mol) and potassium carbonate (23 kg, 166.43 mol) in CH3CN (70.9 kg). The resulting solution was stirred at 80-85 C. for 8-10 hours. The reaction mixture was cooled to 40-45 C. and filtered. The cake was washed with CH3CN (13.4 kg). The combined filtrate was concentrated under vacuum to 34-43 L. Process water (92.0 kg) was added and the mixture was concentrated under vacuum to 77-85 L. The suspension was filtered to afford 2,6-difluoro-4-(2-methoxyethoxy)benzonitrile (13.70 kg, 100%) as a damp solid. 1H NMR (400 MHz. DMSO-d6) delta 3.29 (3H, s), 3.65-3.67 (2H, t), 4.24-4.26 (2H, t), 7.11 (1H, s), 7.14 (1H, s)
4-Amino-5-hydroxypyrimidine 53b (100.0 mg, 0.9 mmol) and anhydrous lithium hydroxide (65.0 mg, 2.7 mmol) were dissolved in N,N-dimethylformamide (3.0 mL).After stirring for 30 minutes, 1-bromo-2-methoxyethane (125.0 mg,0.9 mmol), the reaction was stirred at 60 C for 5 hours. The reaction solution was cooled to room temperature.filter. The filtrate was decomposed under reduced pressure to obtain a crude product.Purification by preparative silica gel plate (dichloromethane / methanol = 10:1) gave 5-(2-methoxyethoxy)-4-aminopyrimidine 53c (60.0 mg,0.36 mmol, colorless oily liquid), yield: 40%.
To a solution of tert-butyl 4,6-dihydropyrrolo[3,4- c]pyrazole-5(2H)-carboxylate (15.0 g, 71.8 mmol) in DMF (150 mL) was added NaH (60% in mineral oil) (8.6 g, 215.4 mmol) while the reaction mixture was cooled with an ice bath. When the addition was complete, the resulting mixture was allowed to warm to room temperature and was stirred at room temperature for 30 min. At this point, l-bromo-2- methoxyethane (19.8 g, 143.6 mmol) was added into the reaction mixture, and stirring was continued at room temperature for 2 h. The reaction mixture was then quenched with water (300 mL), and extracted with EtOAc (150 mL x 3). The combined organic layer was washed with brine (100 mL x 3), dried over anhydrous Na2S04 and then concentrated in vacuo. The residue was purified by column chromatography on silica gel (DCM : MeOH = 100 : 1 ~ 30 : 1) to give a mixture of 122 and 122-A (19.0 g, 99%) as a colorless oil. MS 268.2 [M + H]+. [0072] Synthesis of 123 and 123-A. To a solution of 122 and 122-A (6.5 g, 24.3 mmol) in DCM (60 mL) cooled with an ice bath was added TFA (30 mL). The reaction mixture was stirred at room temperature for 1 h, whereupon the solvent was removed in vacuo to give 123 and 123-A as a crude product mixture which was used directly in the next step without further purification. MS 168.1 [M+H]+. (0114) [0073] Synthesis of 124 and 124-A. To a solution of 123 and 123-A (24.3 mmol, crude product from last step) and A4 (9.3 g, 20.3 mmol) in DMSO (200 mL) was added Na2C03 (21.5 g, 203 mmol), and the reaction mixture was stirred at room temperature for 4 h. The mixture was then diluted with water (400 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (100 mL x 3), dried over anhydrous Na2S04 and then concentrated in vacuo. The residue was purified by column chromatography on silica gel (DCM : MeOH = 100 : 1 ~ 30 : 1) to give a mixture of 124 and 124-A (4.5 g, 50%) as a yellow solid. MS 411.0, 413.1 [M+H]+.
To a solution of tert-butyl 4,6-dihydropyrrolo[3,4- c]pyrazole-5(2H)-carboxylate (15.0 g, 71.8 mmol) in DMF (150 mL) was added NaH (60% in mineral oil) (8.6 g, 215.4 mmol) while the reaction mixture was cooled with an ice bath. When the addition was complete, the resulting mixture was allowed to warm to room temperature and was stirred at room temperature for 30 min. At this point, l-bromo-2- methoxyethane (19.8 g, 143.6 mmol) was added into the reaction mixture, and stirring was continued at room temperature for 2 h. The reaction mixture was then quenched with water (300 mL), and extracted with EtOAc (150 mL x 3). The combined organic layer was washed with brine (100 mL x 3), dried over anhydrous Na2S04 and then concentrated in vacuo. The residue was purified by column chromatography on silica gel (DCM : MeOH = 100 : 1 ~ 30 : 1) to give a mixture of 122 and 122-A (19.0 g, 99%) as a colorless oil. MS 268.2 [M + H]+. [0072] Synthesis of 123 and 123-A. To a solution of 122 and 122-A (6.5 g, 24.3 mmol) in DCM (60 mL) cooled with an ice bath was added TFA (30 mL). The reaction mixture was stirred at room temperature for 1 h, whereupon the solvent was removed in vacuo to give 123 and 123-A as a crude product mixture which was used directly in the next step without further purification. MS 168.1 [M+H]+. (0114) [0073] Synthesis of 124 and 124-A. To a solution of 123 and 123-A (24.3 mmol, crude product from last step) and A4 (9.3 g, 20.3 mmol) in DMSO (200 mL) was added Na2C03 (21.5 g, 203 mmol), and the reaction mixture was stirred at room temperature for 4 h. The mixture was then diluted with water (400 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (100 mL x 3), dried over anhydrous Na2S04 and then concentrated in vacuo. The residue was purified by column chromatography on silica gel (DCM : MeOH = 100 : 1 ~ 30 : 1) to give a mixture of 124 and 124-A (4.5 g, 50%) as a yellow solid. MS 411.0, 413.1 [M+H]+. (0115) [0074] Synthesis of 125 and 125- A . A mixture of 124 and 124-A (500 mg, 1.22 mmol), 5-chlorothiophen-2-ylboronic acid (237 mg, 1.46 mmol) and K2C03 (169 mg, 1.23 mmol) in dioxane/H20 (10 mL/2 mL) was treated with Pd(PPh3)4 (45 mg, 0.06 mmol) under a N2 atmosphere. The reaction mixture was stirred at 50 C for 3 h and then concentrated in vacuo. The residue was taken up in EtOAc (30 mL), and the resulting solution was washed with brine (10 mL x 3). The organic layer was then dried over anhydrous Na2S04 and concentrated in vacuo. The crude residue was purified by Prep-TLC (DCM : MeOH = 20: 1) to give a mixture of 125 and 125-A (450 mg, 82%) as a yellow solid. MS 449.2 [M + H]+.
To a solution of tert-butyl 4,6-dihydropyrrolo[3,4- c]pyrazole-5(2H)-carboxylate (15.0 g, 71.8 mmol) in DMF (150 mL) was added NaH (60% in mineral oil) (8.6 g, 215.4 mmol) while the reaction mixture was cooled with an ice bath. When the addition was complete, the resulting mixture was allowed to warm to room temperature and was stirred at room temperature for 30 min. At this point, l-bromo-2- methoxyethane (19.8 g, 143.6 mmol) was added into the reaction mixture, and stirring was continued at room temperature for 2 h. The reaction mixture was then quenched with water (300 mL), and extracted with EtOAc (150 mL x 3). The combined organic layer was washed with brine (100 mL x 3), dried over anhydrous Na2S04 and then concentrated in vacuo. The residue was purified by column chromatography on silica gel (DCM : MeOH = 100 : 1 ~ 30 : 1) to give a mixture of 122 and 122-A (19.0 g, 99%) as a colorless oil. MS 268.2 [M + H]+. [0072] Synthesis of 123 and 123-A. To a solution of 122 and 122-A (6.5 g, 24.3 mmol) in DCM (60 mL) cooled with an ice bath was added TFA (30 mL). The reaction mixture was stirred at room temperature for 1 h, whereupon the solvent was removed in vacuo to give 123 and 123-A as a crude product mixture which was used directly in the next step without further purification. MS 168.1 [M+H]+. (0114) [0073] Synthesis of 124 and 124-A. To a solution of 123 and 123-A (24.3 mmol, crude product from last step) and A4 (9.3 g, 20.3 mmol) in DMSO (200 mL) was added Na2C03 (21.5 g, 203 mmol), and the reaction mixture was stirred at room temperature for 4 h. The mixture was then diluted with water (400 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (100 mL x 3), dried over anhydrous Na2S04 and then concentrated in vacuo. The residue was purified by column chromatography on silica gel (DCM : MeOH = 100 : 1 ~ 30 : 1) to give a mixture of 124 and 124-A (4.5 g, 50%) as a yellow solid. MS 411.0, 413.1 [M+H]+. (0115) [0074] Synthesis of 125 and 125- A . A mixture of 124 and 124-A (500 mg, 1.22 mmol), 5-chlorothiophen-2-ylboronic acid (237 mg, 1.46 mmol) and K2C03 (169 mg, 1.23 mmol) in dioxane/H20 (10 mL/2 mL) was treated with Pd(PPh3)4 (45 mg, 0.06 mmol) under a N2 atmosphere. The reaction mixture was stirred at 50 C for 3 h and then concentrated in vacuo. The residue was taken up in EtOAc (30 mL), and the resulting solution was washed with brine (10 mL x 3). The organic layer was then dried over anhydrous Na2S04 and concentrated in vacuo. The crude residue was purified by Prep-TLC (DCM : MeOH = 20: 1) to give a mixture of 125 and 125-A (450 mg, 82%) as a yellow solid. MS 449.2 [M + H]+. (0116) [0075] Synthesis of Compound 6 and Compound 6A. A mixture of 125 and 125-A (450 mg, 1.0 mmol) and Raney Ni (100 mg) in DCM/MeOH (6mL/6 mL) was stirred at room temperature for 1 h under a H2 atmosphere. Raney Ni was then removed by filtration through Celite, the filtrate was concentrated en vacuo, and the residue was purified by Prep-TLC (DCM : MeOH = 10 : 1). The mixture of regioisomers was then separated by using chiral HPLC (Column: Chiralcel OD-3; Solvent: MeOH; Flow rate: 2 mL/min; RTi843 = 3.477 min, RTi843A = 4.142 min) to give Compound 6 (99 mg, 24%) as a white solid (MS 419.2 (0117) [M+H]+) and Compound 6A (50 mg, 12%) as a white solid. MS 419.2 [M+H]+.
To a solution of tert-butyl 4,6-dihydropyrrolo[3,4- c]pyrazole-5(2H)-carboxylate (15.0 g, 71.8 mmol) in DMF (150 mL) was added NaH (60% in mineral oil) (8.6 g, 215.4 mmol) while the reaction mixture was cooled with an ice bath. When the addition was complete, the resulting mixture was allowed to warm to room temperature and was stirred at room temperature for 30 min. At this point, l-bromo-2- methoxyethane (19.8 g, 143.6 mmol) was added into the reaction mixture, and stirring was continued at room temperature for 2 h. The reaction mixture was then quenched with water (300 mL), and extracted with EtOAc (150 mL x 3). The combined organic layer was washed with brine (100 mL x 3), dried over anhydrous Na2S04 and then concentrated in vacuo. The residue was purified by column chromatography on silica gel (DCM : MeOH = 100 : 1 ~ 30 : 1) to give a mixture of 122 and 122-A (19.0 g, 99%) as a colorless oil. MS 268.2 [M + H]+. [0072] Synthesis of 123 and 123-A. To a solution of 122 and 122-A (6.5 g, 24.3 mmol) in DCM (60 mL) cooled with an ice bath was added TFA (30 mL). The reaction mixture was stirred at room temperature for 1 h, whereupon the solvent was removed in vacuo to give 123 and 123-A as a crude product mixture which was used directly in the next step without further purification. MS 168.1 [M+H]+. (0114) [0073] Synthesis of 124 and 124-A. To a solution of 123 and 123-A (24.3 mmol, crude product from last step) and A4 (9.3 g, 20.3 mmol) in DMSO (200 mL) was added Na2C03 (21.5 g, 203 mmol), and the reaction mixture was stirred at room temperature for 4 h. The mixture was then diluted with water (400 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (100 mL x 3), dried over anhydrous Na2S04 and then concentrated in vacuo. The residue was purified by column chromatography on silica gel (DCM : MeOH = 100 : 1 ~ 30 : 1) to give a mixture of 124 and 124-A (4.5 g, 50%) as a yellow solid. MS 411.0, 413.1 [M+H]+. Example 8. Synthesis of Compound 8 (0126) (0127) [0081] Synthesis of 129 and 129-A. A mixture of 124 and 124-A (350 mg, 0.85 mmol), 2-fluorophenylboronic acid (143 mg, 1.02 mmol) and K2CO3 (352 mg, 2.55 mmol) in dioxane/H20 (10 mL/2 mL) was treated with Pd(PPh3)4 (49 mg, 0.04 mmol) under a N2 atmosphere. The reaction mixture was stirred at 90 C for 3 h and then concentrated in vacuo. The crude residue was taken up in EtOAc (30 niL), and the resulting solution was washed with brine (10 mL x 3). The organic layer was dried over anhydrous Na2S04 and then concentrated in vacuo. The residue was purified by Prep-TLC (PE : EA = 5: 1) to give a mixture of 129 and 129-A (300 mg, 83%) as a yellow solid. MS 427.2 [M + H]+.
To a solution of tert-butyl 4,6-dihydropyrrolo[3,4- c]pyrazole-5(2H)-carboxylate (15.0 g, 71.8 mmol) in DMF (150 mL) was added NaH (60% in mineral oil) (8.6 g, 215.4 mmol) while the reaction mixture was cooled with an ice bath. When the addition was complete, the resulting mixture was allowed to warm to room temperature and was stirred at room temperature for 30 min. At this point, l-bromo-2- methoxyethane (19.8 g, 143.6 mmol) was added into the reaction mixture, and stirring was continued at room temperature for 2 h. The reaction mixture was then quenched with water (300 mL), and extracted with EtOAc (150 mL x 3). The combined organic layer was washed with brine (100 mL x 3), dried over anhydrous Na2S04 and then concentrated in vacuo. The residue was purified by column chromatography on silica gel (DCM : MeOH = 100 : 1 ~ 30 : 1) to give a mixture of 122 and 122-A (19.0 g, 99%) as a colorless oil. MS 268.2 [M + H]+. [0072] Synthesis of 123 and 123-A. To a solution of 122 and 122-A (6.5 g, 24.3 mmol) in DCM (60 mL) cooled with an ice bath was added TFA (30 mL). The reaction mixture was stirred at room temperature for 1 h, whereupon the solvent was removed in vacuo to give 123 and 123-A as a crude product mixture which was used directly in the next step without further purification. MS 168.1 [M+H]+. (0114) [0073] Synthesis of 124 and 124-A. To a solution of 123 and 123-A (24.3 mmol, crude product from last step) and A4 (9.3 g, 20.3 mmol) in DMSO (200 mL) was added Na2C03 (21.5 g, 203 mmol), and the reaction mixture was stirred at room temperature for 4 h. The mixture was then diluted with water (400 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (100 mL x 3), dried over anhydrous Na2S04 and then concentrated in vacuo. The residue was purified by column chromatography on silica gel (DCM : MeOH = 100 : 1 ~ 30 : 1) to give a mixture of 124 and 124-A (4.5 g, 50%) as a yellow solid. MS 411.0, 413.1 [M+H]+. Example 8. Synthesis of Compound 8 (0126) (0127) [0081] Synthesis of 129 and 129-A. A mixture of 124 and 124-A (350 mg, 0.85 mmol), 2-fluorophenylboronic acid (143 mg, 1.02 mmol) and K2CO3 (352 mg, 2.55 mmol) in dioxane/H20 (10 mL/2 mL) was treated with Pd(PPh3)4 (49 mg, 0.04 mmol) under a N2 atmosphere. The reaction mixture was stirred at 90 C for 3 h and then concentrated in vacuo. The crude residue was taken up in EtOAc (30 niL), and the resulting solution was washed with brine (10 mL x 3). The organic layer was dried over anhydrous Na2S04 and then concentrated in vacuo. The residue was purified by Prep-TLC (PE : EA = 5: 1) to give a mixture of 129 and 129-A (300 mg, 83%) as a yellow solid. MS 427.2 [M + H]+. Synthesis of Compound 8 and Compound 8A. A mixture of 129 and 129-A (300 mg, 0.70 mmol) and Pd/C (80 mg) in DCM/MeOH (5mL/5 mL) was stirred at room temperature for 1 h under a H2 atmosphere. The Pd/C was then removed by filtration through Celite, the filtrate was concentrated, and the crude residue was purified by Prep-TLC (DCM : MeOH = 10 : 1). The mixture of regioisomers was then separated using chiral HPLC (0129) (Column: Chiralcel OJ-3; Solvent: MeOH; Flow rate: 2 mL/min; RTi849 = 1.201 min, RTi84gA = 2.244 min) to give 8 (105 mg, 37%) as a yellow solid (MS 397.2 [M+H]+) and 8A (98 mg, 35%) as a yellow solid. MS 397.2 [M+H]+.
To a solution of tert-butyl 4,6-dihydropyrrolo[3,4- c]pyrazole-5(2H)-carboxylate (15.0 g, 71.8 mmol) in DMF (150 mL) was added NaH (60% in mineral oil) (8.6 g, 215.4 mmol) while the reaction mixture was cooled with an ice bath. When the addition was complete, the resulting mixture was allowed to warm to room temperature and was stirred at room temperature for 30 min. At this point, l-bromo-2- methoxyethane (19.8 g, 143.6 mmol) was added into the reaction mixture, and stirring was continued at room temperature for 2 h. The reaction mixture was then quenched with water (300 mL), and extracted with EtOAc (150 mL x 3). The combined organic layer was washed with brine (100 mL x 3), dried over anhydrous Na2S04 and then concentrated in vacuo. The residue was purified by column chromatography on silica gel (DCM : MeOH = 100 : 1 ~ 30 : 1) to give a mixture of 122 and 122-A (19.0 g, 99%) as a colorless oil. MS 268.2 [M + H]+. [0072] Synthesis of 123 and 123-A. To a solution of 122 and 122-A (6.5 g, 24.3 mmol) in DCM (60 mL) cooled with an ice bath was added TFA (30 mL). The reaction mixture was stirred at room temperature for 1 h, whereupon the solvent was removed in vacuo to give 123 and 123-A as a crude product mixture which was used directly in the next step without further purification. MS 168.1 [M+H]+.
To a solution of tert-butyl 4,6-dihydropyrrolo[3,4- c]pyrazole-5(2H)-carboxylate (15.0 g, 71.8 mmol) in DMF (150 mL) was added NaH (60% in mineral oil) (8.6 g, 215.4 mmol) while the reaction mixture was cooled with an ice bath. When the addition was complete, the resulting mixture was allowed to warm to room temperature and was stirred at room temperature for 30 min. At this point, l-bromo-2- methoxyethane (19.8 g, 143.6 mmol) was added into the reaction mixture, and stirring was continued at room temperature for 2 h. The reaction mixture was then quenched with water (300 mL), and extracted with EtOAc (150 mL x 3). The combined organic layer was washed with brine (100 mL x 3), dried over anhydrous Na2S04 and then concentrated in vacuo. The residue was purified by column chromatography on silica gel (DCM : MeOH = 100 : 1 ~ 30 : 1) to give a mixture of 122 and 122-A (19.0 g, 99%) as a colorless oil. MS 268.2 [M + H]+.
With tetrabutyl-ammonium chloride; sodium hydroxide; In sulfolane; at 60 - 120℃;
139 g (1 mol) of 2-bromoethyl methyl ether was placed in the reaction flask.Triethanolamine borate 31.4g (0.2mol), tetrabutylammonium chloride 5.6g (0.02mol) and350 g of sulfolane, heated to 60 ° C,Start adding 32g (0.8mol) of sodium hydroxide in batches.After heating to 120 ° C for 3 to 4 hours, sampling GC detection,By rectification, 59.9 g of tris(3,6-dioxaheptyl)amine was obtained as a yellow oily liquid.Nuclear magnetic purity: 99.3percent, yield: 92.7percent.
6-bromo-1-(2-methoxyethyl)-1H-pyrrolo[3,2-c]pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With caesium carbonate; In N,N-dimethyl-formamide; at 20 - 50℃; for 16h;
General procedure: To a stirred solution of 6-bromo-1 H-pyrrolo[3,2-c]pyridine (1 g, 5.07 mmol) in DMF (25 mL), CS2CO3 (4.95 g, 15.21 mmol) and 4-(bromomethyl)pyridine hydrobromide (1 .92 g, 7.60 mmol) were added. The resulting suspension was allowed to stir at rt, and then heated to 50C for 16 h. The reaction mixture was poured into ice water and extracted with EtOAc (2 x 120 mL). The organic layer was washed with water and brine solution, dried over anhydrous Na2S04, and filtered. The resulting solution was concentrated under reduced pressure to get a crude residue that was purified by flash column chromatography in 230-400 silica gel 70 % EtOAc/ pet ether as an eluent to afford the title compound (800 mg, 57.7 %) of the title compound as a light brown solid.
3-bromo-1-(2-methoxyethyl)-1H-pyrazolo[4,3-b]pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
66%
To a stirred solution of 3-bromo-1 H-pyrazolo[4,3-b]pyridine (500 mg, 2.52 mmol) in DMF, NaH (60%) (201 mg, 5.04 mmol) was added at 0C and it was stirred for 15min. Then, 1 -bromo-2-methoxyethane (420 mg, 3.02 mmol) was added and the reaction mixture was stirred at rt for 2h. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was dried over anhydrous Na2S04, and it was concentrated under reduced pressure. The crude compound was purified by flash column chromatography on 230-400 silica using 45% EtOAc in pet ether as an eluent to afford the title compound (430 mg, 66%) as a gummy solid.LC-MS (method 24): R, = 2.63 min; m/z = 258.01 (M+2H+),
5-bromo-1-(2-methoxyethyl)-1H-pyrazolo[3,4-c]pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With caesium carbonate; In N,N-dimethyl-formamide; at 20 - 50℃; for 16h;
General procedure: To a stirred solution of 6-bromo-1 H-pyrrolo[3,2-c]pyridine (1 g, 5.07 mmol) in DMF (25 mL), CS2CO3 (4.95 g, 15.21 mmol) and 4-(bromomethyl)pyridine hydrobromide (1 .92 g, 7.60 mmol) were added. The resulting suspension was allowed to stir at rt, and then heated to 50C for 16 h. The reaction mixture was poured into ice water and extracted with EtOAc (2 x 120 mL). The organic layer was washed with water and brine solution, dried over anhydrous Na2S04, and filtered. The resulting solution was concentrated under reduced pressure to get a crude residue that was purified by flash column chromatography in 230-400 silica gel 70 % EtOAc/ pet ether as an eluent to afford the title compound (800 mg, 57.7 %) of the title compound as a light brown solid.
5-bromo-2-(2-methoxyethyl)-2H-pyrazolo[3,4-c]pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With caesium carbonate; In N,N-dimethyl-formamide; at 20 - 50℃; for 16h;
General procedure: To a stirred solution of 6-bromo-1 H-pyrrolo[3,2-c]pyridine (1 g, 5.07 mmol) in DMF (25 mL), CS2CO3 (4.95 g, 15.21 mmol) and 4-(bromomethyl)pyridine hydrobromide (1 .92 g, 7.60 mmol) were added. The resulting suspension was allowed to stir at rt, and then heated to 50C for 16 h. The reaction mixture was poured into ice water and extracted with EtOAc (2 x 120 mL). The organic layer was washed with water and brine solution, dried over anhydrous Na2S04, and filtered. The resulting solution was concentrated under reduced pressure to get a crude residue that was purified by flash column chromatography in 230-400 silica gel 70 % EtOAc/ pet ether as an eluent to afford the title compound (800 mg, 57.7 %) of the title compound as a light brown solid.
5-bromo-4-fluoro-1-(2-methoxyethyl)indazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 2h;
General procedure: Step 8-4. 5-Bromo-1-[(3R)-oxolan-3-yl]indazole (Compound 80 To a DMF (3.8 mL) solution of 5-bromo-1H-indazole (Compound 6j, 300 mg, 1.52 mmol) was added cesium carbonate (992 mg, 3.05 mmol) and Compound 8e (369 mg, 1.52 mmol) obtained in Step 8-3, and the mixture was stirred at 100 C. for 2 h. After cooling to room temperature, water was added to the reaction solution and extraction was performed using ethyl acetate. The organic layer was washed with water, and the solvent was removed by evaporation under reduced pressure. The resulting product was purified by silica gel column chromatography (ethyl acetate/hexane=1:1) to obtain the titled Compound 8f (198 mg, yield 49%) as a colorless oil-like product. LC/MS mass spectrometry: m/z 267 ([M+H]+).
5-bromo-1-(2-methoxyethyl)-3-methylbenzoimidazol-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 2h;
General procedure: Step 8-4. 5-Bromo-1-[(3R)-oxolan-3-yl]indazole (Compound 80 To a DMF (3.8 mL) solution of 5-bromo-1H-indazole (Compound 6j, 300 mg, 1.52 mmol) was added cesium carbonate (992 mg, 3.05 mmol) and Compound 8e (369 mg, 1.52 mmol) obtained in Step 8-3, and the mixture was stirred at 100 C. for 2 h. After cooling to room temperature, water was added to the reaction solution and extraction was performed using ethyl acetate. The organic layer was washed with water, and the solvent was removed by evaporation under reduced pressure. The resulting product was purified by silica gel column chromatography (ethyl acetate/hexane=1:1) to obtain the titled Compound 8f (198 mg, yield 49%) as a colorless oil-like product. LC/MS mass spectrometry: m/z 267 ([M+H]+).
3,5-dibromo-1-(2-methoxyethyl)-1,2,4-triazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
With triethylamine; In N,N-dimethyl acetamide; at 55℃; for 18h;
A solution of <strong>[7411-23-6]3,5-dibromo-1H-1,2,4-triazole</strong> (250 mg, 1.1 mmol), 2-bromoethyl methyl ether (0.17 mL, 2.2 mmol) and triethylamine (0.46 mL, 3.3 mmol) in DMA (5 mL) was stirred at 55 C for 18 h. The reaction mixture was filtered and the solvent removed in vacuo. The product was purified via silica column chromatography eluting with 0-100% EtOAc in Pet. Ether to yield 3,5-dibromo-1-(2-methoxyethyl)-1,2,4-triazole (260 mg, 0.91 mmol, 83% yield) as a colourless oil. UPLC-MS (ES+, Method A), 1.34 min, m/z 285.9 [M+H]+.
ethyl 1-(2-methoxyethyl)-3-(trifluoromethyl)-1H-pyrazole-4-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
To a stirred solution of <strong>[155377-19-8]ethyl 3-(trifluoromethyl)-1H-pyrazole-4-carboxylate</strong> (2.5 ml, 4.8 mmol) in THF (20 ml_) was added sodium hydride in oil (266 mg, 65 % purity, 7.21 mmol) at 0 C and the mixture was stirred at room temperature for 30 min. 1-bromo-2-methoxyethane (900 mI, 9.6 mmol) was added and the mixture was stirred at 60 C for 2 days. Water and an aqueous solution of sodium bicarbonate was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with a saturated sodium chloride solution, dried (sodium sulfate), filtered and the solvent was removed in vacuum. Silicagel chromatography gave 960 mg (75 % yield) of the title compound. LC-MS (Method 1 ): Rt = 1 .1 1 min; MS (ESIpos): m/z = 267 [M+H]+ 1H-NMR (400 MHz, DMSO-d6) d [ppm]: 1 .249 (7.26), 1 .267 (16.00), 1 .285 (7.34), 3.330 (3.16), 3.699 (2.95), 3.712 (4.23), 3.725 (3.18), 4.217 (2.24), 4.235 (7.27), 4.252 (7.14), 4.270 (2.13), 4.381 (2.57), 4.394 (3.86), 4.407 (2.36), 8.548 (3.50), 8.550 (3.44).
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃;
A mixture containing <strong>[936-44-7]3-phenylpyrrolidine</strong> (commercially available from Apollo Scientific, 300 mg), 1-bromo-2-methoxyethane (0.230 mL), N,N-diisopropylethylamine (0.532 mL)and acetonitrile (3 mL) was stirred at room temperature overnight. The reaction mixture was concentrated under a reduced pressure, ethyl acetate was added to the obtained residue, and the mixture was then sequentially washed with water and a saturated saline solution. The organic layer was dried over anhydrous sodium sulfate and then concentrated under a reduced pressure, the obtained residue was purified through silica gel column chromatography (elution solvent: dichloromethane-methanol), and thereby 1-(2-methoxyethyl)-<strong>[936-44-7]3-phenylpyrrolidine</strong> (135 mg)as a light brown oily substance was obtained.
2-methoxyethyl 2-(2-methoxyethoxy)-6-nitrobenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In N,N-dimethyl-formamide; at 80.0℃; for 16.0h;
To a mixture of <strong>[601-99-0]2-hydroxy-6-nitrobenzoic acid</strong> (2 g, 10.92 mmol) and (1533) 1-bromo-2-methoxy-ethane (4.55 g, 32.77 mmol, 3.08 mL) in DMF (20 mL) was added K2CO3 (3.02 g, 21.84 mmol). The mixture was stirred at 80 C for 16 h, cooled to room temperature, quenched by H2O (100 mL) and extracted with EtOAc (50 mL×2). The combined organic layers were washed by H2O (100 mL×3), brine (100 mL×2), dried over Na2SO4, concentrated under reduced pressure to provide the title compound (3.3 g, crude) as a yellow oil. The crude product was used for the next step reaction without further purification.1H NMR (400 MHz, DMSO-d6) d 7.80 (d, J = 8.0 Hz, 1H), 7.70 (t, J = 8.4 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 4.40 (t, J = 8.4 Hz, 2H), 4.27 (t, J = 8.4 Hz, 2H), 3.67-3.60 (m, 4H), 3.31 (s, 3H), 3.28 (s, 3H).
1-bromo-2,3-difluoro-4-(2-methoxyethoxy)benzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
With potassium carbonate; In N,N-dimethyl-formamide; at 60℃;
A mixture of 4-bromo-2, 3-difluorophenol (2 g, 9.56 mmol) , 1-bromo-2-methoxyethane (1.46 g, 10.52 mmol) and K2CO3(2.6 g, 19.12 mmol) in DMF (10 mL) was stirred at 60 C overnight. The reaction mixture was poured into H2O (30 mL) and extracted with EtOAc (20 mL x 3) . The combined organic layers were washed with brine, dried over Na2SO4, concentrated under high vacuum to give the target compound (2.55 g, 100%) as colorless oil.
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