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Structure of 2969-81-5 * 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] Journal of Medicinal Chemistry, 2017, vol. 60, # 2, p. 608 - 626
[2] U.S.Atomic Energy Comm.WADC-TR-56-540 <1957>25,
[3] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1886, vol. 102, p. 369[4] Bulletin de la Societe Chimique de France, 1886, vol. <2>46, p. 65
[5] Journal of the Chemical Society, 1937, p. 1977
[6] Journal of the American Chemical Society, 1933, vol. 55, p. 1233 - 1241
[7] ACS Chemical Neuroscience, 2017, vol. 8, # 9, p. 1949 - 1959
5
[ 64-17-5 ]
[ 927-58-2 ]
[ 2969-81-5 ]
Reference:
[1] Journal of the Chemical Society, 1950, p. 1474,1476
[2] Patent: EP1953148, 2008, A1, . Location in patent: Page/Page column 122
6
[ 2623-87-2 ]
[ 2969-81-5 ]
Yield
Reaction Conditions
Operation in experiment
85.5%
With hydrogenchloride In 1,4-dioxane; ethanol; dichloromethane
Part A Preparation of ethyl 4-bromobutyrate To a solution of 4-bromobutyric acid (3 g, 18 mmol) in ethanol (30 mL) was added 5 mL of 4N HCl in dioxane. The reaction mixture was stirred for 16 hours at room temperature, and then the volatile components were removed under vacuum. The concentrated residue was brought up in 150 mL of methylene chloride. The organic solution was washed with saturated aqueous NaHCO3 (1 x 150 mL), brine (1*150 mL), dried over MgSO4, filtered, and the filtrate was concentrated at reduced pressure. The concentrated residue was dried in vacuo to give 3 g (85.5percent) of the known product as a yellow oil. 1 H NMR (300 MHz/CDCl3): δ 1.22 (t, 3H, J=7.15 Hz), 2.13 (overlapping t, 2H, J=6.80 Hz), 2.45 (t, 2H, J=7.15 Hz), 3.43 (t, 2H, J=6.44 Hz), 4.10 (q, 2H, J=7.25 Hz).
Reference:
[1] Patent: US5753660, 1998, A,
7
[ 96-48-0 ]
[ 64-17-5 ]
[ 2969-81-5 ]
Reference:
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1981, p. 336 - 343
[2] Journal of the American Chemical Society, 1952, vol. 74, p. 4960
[3] Journal of the Chemical Society, 1958, p. 3377,3382
[4] Journal of the Chemical Society, 1957, p. 2312
[5] Journal of the Chemical Society, 1953, p. 3502
[6] Org.Synth.Coll.Vol. V <1973>545,
[7] U.S.Atomic Energy Comm.WADC-TR-56-540 <1957>25,
[8] Journal of Organic Chemistry, 1951, vol. 16, p. 1417,1418
[9] Tetrahedron, 1960, vol. 11, p. 154 - 157
[10] Journal of pharmaceutical sciences, 1972, vol. 61, # 12, p. 1936 - 1940
[11] The Journal of organic chemistry, 1972, vol. 37, # 26, p. 4396 - 4399
8
[ 1191-95-3 ]
[ 1801-77-0 ]
[ 2969-81-5 ]
Reference:
[1] Journal of Organic Chemistry, 1991, vol. 56, # 6, p. 2264 - 2266
9
[ 64-17-5 ]
[ 5332-06-9 ]
[ 2969-81-5 ]
Reference:
[1] Journal of the American Chemical Society, 1956, vol. 78, p. 4030
[2] U.S.Atomic Energy Comm.WADC-TR-56-540 <1957>25,
10
[ 58258-01-8 ]
[ 2969-81-5 ]
[ 125602-76-8 ]
Reference:
[1] Patent: US4929618, 1990, A,
11
[ 125603-02-3 ]
[ 2969-81-5 ]
Reference:
[1] Patent: US4929618, 1990, A,
12
[ 88535-96-0 ]
[ 2969-81-5 ]
Reference:
[1] Patent: US4929618, 1990, A,
13
[ 125603-01-2 ]
[ 125602-78-0 ]
[ 2969-81-5 ]
Reference:
[1] Patent: US4929618, 1990, A,
14
[ 125603-04-5 ]
[ 2969-81-5 ]
Reference:
[1] Patent: US4929618, 1990, A,
15
[ 999-10-0 ]
[ 2969-81-5 ]
Reference:
[1] Journal of Medicinal Chemistry, 2014, vol. 57, # 9, p. 3874 - 3883
16
[ 1617-18-1 ]
[ 2969-81-5 ]
Reference:
17
[ 64-17-5 ]
[ 56489-06-6 ]
[ 2969-81-5 ]
Reference:
[1] Collection of Czechoslovak Chemical Communications, 1956, vol. 21, p. 1602,1605
18
[ 36847-51-5 ]
[ 2969-81-5 ]
[ 4606-07-9 ]
[ 105-54-4 ]
Reference:
[1] Journal of Chemical Research, Miniprint, 1983, # 11, p. 2401 - 2416
19
[ 1617-18-1 ]
[ 10035-10-6 ]
[ 2969-81-5 ]
Reference:
20
[ 2969-81-5 ]
[ 7425-53-8 ]
Yield
Reaction Conditions
Operation in experiment
87%
With potassium iodide In acetone for 12 h; Reflux
In a 100 ml round bottom flask, ethyl4-bromobutyrate (6.0 ml, 40.2 mmol: 1H NMR (300 MHz, CDCl3) δ 4.14(q, J = 7.2 Hz, 2H), 3.47 (t, J = 6.5 Hz, 2H), 2.49 (t, J = 7.2 Hz, 2H), 2.17(m, 2H), 1.26 (t, J = 7.1 Hz, 3H).) was dissolved in 40 ml acetone. Potassium iodide (13.35 g, 80.4 mmol,2.0 equiv.) was added, a reflux condenser was attached, and the reaction was heated at reflux for 12h. Thesolution was cooled, filtered through a course fritted funnel, and concentrated in vacuo. The resultingyellow oil with fine particulates was taken up in ca 50 ml of 1:1 Hex:Et2O and filtered through neutralaluminum to remove color. After flushing with an additional 100 ml 1:1 Hex:Et2O, the solution wasconcentrated to yield 8.44 g (87percent) of ethyl 4-iodobutyrate 12. 1H NMR (300 MHz, CDCl3) δ 4.14 (q, J =7.2 Hz, 2H), 3.24 (t, J = 6.8 Hz, 2H), 2.44 (t, J = 7.1 Hz, 2H), 2.13 (m, 2H), 1.26 (t, J = 7.2 Hz, 3H). A 50ml Schlenk flask was flame dried under vacuum, cooled to 23 °C, and charged with ethyl 4-iodobutyrate(8.4 g, 34.7 mmol) and copper(I) iodide (10 mg, 0.05 mmol). After sealing with a greased ground glassstopper, the flask was evacuated and refilled with Ar. The stopper was replaced with a rubber septum andneat diethyl zinc (14 ml, 137 mmol, 4 equiv) was added via syringe. The reaction was heated at 40 °C for12 h. The excess diethyl zinc and ethyl iodide were removed under vacuum for 2 h into a trap withmethanol cooled to -78 °C with dry ice and acetone. (CAUTION: A trap cooled with liquid nitrogeneasily clogs so dry ice/acetone cooling is preferred. Methanol quenches the excess diethyl zinc, but careshould be taken when cleaning the trap as some diethyl zinc may remain.) After backfilling with Ar, THF(5 ml) was added to the reaction vessel and heated at 40 °C for 1 h under Ar. The reaction vessel wasevacuated for 1 h. This step was repeated another two times. After cooling to 23 °C, the generated bis(4-ethoxy-4-oxobutyl)zinc was diluted with 15 ml of THF and this solution was used directly in thedesymmetrization reaction.
Reference:
[1] Synthetic Communications, 2009, vol. 39, # 1, p. 61 - 69
[2] Journal of Organic Chemistry, 2004, vol. 69, # 9, p. 3025 - 3035
[3] Advanced Synthesis and Catalysis, 2007, vol. 349, # 8-9, p. 1533 - 1536
[4] Journal of Organic Chemistry, 2007, vol. 72, # 18, p. 6816 - 6823
[5] Synthesis (Germany), 2018, vol. 50, # 22, p. 4343 - 4350
[6] Tetrahedron, 1996, vol. 52, # 45, p. 14081 - 14102
[7] Journal of the American Chemical Society, 2016, vol. 138, # 24, p. 7528 - 7531
[8] Tetrahedron, 1960, vol. 11, p. 154 - 157
[9] Journal of Organic Chemistry, 1989, vol. 54, # 4, p. 890 - 896
[10] Tetrahedron Letters, 1987, vol. 28, # 37, p. 4243 - 4246
[11] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1985, p. 2677 - 2688
[12] Tetrahedron, 1999, vol. 55, # 18, p. 5741 - 5758
[13] Journal of the American Chemical Society, 2000, vol. 122, # 40, p. 9600 - 9609
[14] Synthetic Communications, 2009, vol. 39, # 9, p. 1690 - 1690
[15] Patent: EP1612201, 2006, A1, . Location in patent: Page/Page column 26-28
[16] Advanced Synthesis and Catalysis, 2012, vol. 354, # 13, p. 2521 - 2530,10
[17] Advanced Synthesis and Catalysis, 2012, vol. 354, # 13, p. 2521 - 2530
21
[ 2969-81-5 ]
[ 14402-93-8 ]
[ 123-29-5 ]
Reference:
[1] Journal of Organic Chemistry, 2002, vol. 67, # 1, p. 79 - 85
Reference:
[1] Advanced Synthesis and Catalysis, 2008, vol. 350, # 10, p. 1484 - 1488
24
[ 2969-81-5 ]
[ 541-41-3 ]
[ 818-38-2 ]
Reference:
[1] Journal of Organic Chemistry, 1990, vol. 55, # 3, p. 788 - 790
25
[ 2969-81-5 ]
[ 26496-94-6 ]
Reference:
[1] Patent: US4804658, 1989, A,
26
[ 2969-81-5 ]
[ 106-48-9 ]
[ 59227-79-1 ]
Yield
Reaction Conditions
Operation in experiment
92%
With potassium carbonate In acetonitrile for 8 h; Reflux
To a solution of 4-chlorophenol (2.0 g, 15.556 mmol, 1 equiv) in acetonitrile (60 mL) was added anhydrous potassium carbonate (4.3 g, 31 .1 13 mmol, 2 equiv) and ethyl 4-bromobutanoate (3.56 mL, 24.891 mmol, 1 .6 equiv). The reaction mixture was heated to reflux and stirred for 8 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was allowed to cool to 27 °C, filtered the solid and washed with ethyl acetate (100 mL). The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography using 10percent ethyl acetate in hexane as eluent to obtain the title compound ethyl 4-(4-chlorophenoxy)butanoate (3.5 g, 92 percent yield) as colourless liquid. LCMS (ES) m/z = 242.9 [M+H]+. NMR (400 MHz, CDCI3): δ ppm 1 .25 (t, J = 6.8 Hz, 3 H), 2.06 - 2.06 (m, 2 H), 2.49 (t, J = 6.8 Hz, 2 H), 3.97 (t, J = 6.0 Hz, 2 H), 4.1 1 - 4.17 (m, 2 H), 6.80 (d, J = 8.4 Hz, 2 H), 7.21 (d, J = 8.8 Hz, 2 H).
89%
With potassium carbonate In N,N-dimethyl-formamide at 140℃; for 4 h;
To a solution of 4-chlorophenol (10 g, 77.784 mmol, 1 equiv) in N,N- dimethylformamide (100 mL) was added anhydrous potassium carbonate (21 .5 g, 1 16.6 mmol, 2 equiv) and ethyl 4-bromobutanoate (16.7 mL, 1 16.677 mmol, 1 .5 equiv). The reaction mixture was heated to 140 °C and stirred for 4 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was allowed to cool to 27 °C, filtered the solid and washed with ethyl acetate (700 mL). The filtrate was washed with water (2 x 200 mL), brine solution (100 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography using 10 percent ethyl acetate in hexane as eluent to obtain ethyl 4-(4-chlorophenoxy)butanoate (17.0 g, 89 percent yield) as white solid. LCMS (ES) m/z = 243.1 [M+H]+. NMR (400 MHz, CDCI3): δ ppm 1 .25 (t, J = 7.2 Hz, 3 H), 2.06 - 2.12 (m, 2 H), 2.49 (t, J = 7.6 Hz, 2 H), 3.97 (t, J = 6.0 Hz, 2 H), 4.1 1 - 4.17 (m, 2 H), 6.80 (d, J = 8.8 Hz, 2 H), 7.21 (d, J = 8.8 Hz, 2 H).
83%
With potassium carbonate In acetoneReflux
General procedure: General synthetic procedure for phenoxy acetic/butyric acid ethyl ester derivatives (3a-l) A mixture of substituted phenols 1a-f (0.05 mol) and 2a-b (0.075 mol) in dry acetone (40 ml) with anhydrous potassium carbonate (0.075 mol) were refluxed for 8-10 h. The reaction mixture was cooled and solvent removed by distillation. The residual mass was triturated with cold water to remove potassium carbonate, and extracted with ether (3 * 30 ml). The ether layer was washed with 10percent sodium hydroxide solution (3 * 30 ml) followed by water (3 * 30 ml) and then dried over anhydrous sodium sulfate and evaporated to afford compounds 3a-l. 4-(4-Chloro-phenoxy)-butyric acid ethyl ester (3b) Yield 83percent; FT-IR (cm-1): 1738 (C=O), 1281 (C-O-C); 1H NMR (CDCl3): δ 1.35 (t, 3H, CH3 of ester), 2.26 (m, 2H, CH2), 2.75 (t, 2H, COCH2), 4.07 (t, 2H, OCH2), 4.31 (q, 2H, CH2 of ester), 6.88 (d, J = 8.80 Hz, 2H, Ar-H), 7.27 (d, J = 8.85 Hz, 2H, Ar-H); LC-MS m/z 243 (M + 1). Anal. Calcd. for C12H15ClO3: C, 59.39; H, 6.23. Found: C, 59.50; H, 6.16percent.
Reference:
[1] Patent: WO2017/212425, 2017, A1, . Location in patent: Page/Page column 112
[2] Patent: WO2017/212423, 2017, A1, . Location in patent: Page/Page column 126
[3] Bioorganic Chemistry, 2015, vol. 60, p. 136 - 146
[4] Journal of Agricultural and Food Chemistry, 2016, vol. 64, # 37, p. 6911 - 6915
[5] Indian Journal of Heterocyclic Chemistry, 2018, vol. 28, # 3, p. 379 - 384
27
[ 117704-88-8 ]
[ 2969-81-5 ]
[ 19999-64-5 ]
Reference:
[1] Patent: US5102890, 1992, A,
28
[ 2969-81-5 ]
[ 52763-21-0 ]
Reference:
[1] Organic Process Research and Development, 2003, vol. 7, # 3, p. 418 - 425
29
[ 106-41-2 ]
[ 2969-81-5 ]
[ 55580-08-0 ]
Reference:
[1] Patent: US6166006, 2000, A,
30
[ 106-41-2 ]
[ 2969-81-5 ]
[ 157245-87-9 ]
Yield
Reaction Conditions
Operation in experiment
81%
With potassium carbonate In acetoneReflux
General procedure: General synthetic procedure for phenoxy acetic/butyric acid ethyl ester derivatives (3a-l) A mixture of substituted phenols 1a-f (0.05 mol) and 2a-b (0.075 mol) in dry acetone (40 ml) with anhydrous potassium carbonate (0.075 mol) were refluxed for 8-10 h. The reaction mixture was cooled and solvent removed by distillation. The residual mass was triturated with cold water to remove potassium carbonate, and extracted with ether (3 * 30 ml). The ether layer was washed with 10percent sodium hydroxide solution (3 * 30 ml) followed by water (3 * 30 ml) and then dried over anhydrous sodium sulfate and evaporated to afford compounds 3a-l. 4-(4-Bromo-phenoxy)-butyric acid ethyl ester (3d) Yield 81percent; FT-IR (cm-1): 1733 (C=O), 1287 (C-O-C); 1H NMR (CDCl3): δ 1.34 (t, 3H, CH3 of ester), 2.26 (m, 2H, CH2), 2.72 (t, 2H, COCH2), 4.05 (t, 2H, OCH2), 4.31 (q, 2H, CH2 of ester), 6.83 (d, J = 8.80 Hz, 2H, Ar-H), 7.35 (d, J = 8.85 Hz, 2H, Ar-H); LC-MS m/z 288 (M + 1). Anal. Calcd. for C12H15BrO3: C, 50.19; H, 5.27. Found: C, 50.29; H, 5.18percent.
Reference:
[1] Bioorganic Chemistry, 2015, vol. 60, p. 136 - 146
[2] Journal of Medicinal Chemistry, 2000, vol. 43, # 10, p. 2049 - 2063
[3] Patent: WO2016/25932, 2016, A1, . Location in patent: Page/Page column 150
[4] Chemistry - A European Journal, 2016, vol. 22, # 29, p. 9971 - 9974
[5] Indian Journal of Heterocyclic Chemistry, 2018, vol. 28, # 3, p. 379 - 384
31
[ 2969-81-5 ]
[ 95-01-2 ]
[ 152942-06-8 ]
Reference:
[1] Journal of the American Chemical Society, 2018, vol. 140, # 44, p. 15114 - 15123
[2] Organic letters, 2000, vol. 2, # 13, p. 1787 - 1790
[3] Patent: US5994378, 1999, A,
With potassium carbonate; In acetonitrile; at 20 - 90℃;
Step 2: ethyl 4-[(benzyl-(2-ethoxycarbonyl-ethyl)-amino]-propanecarboxylate 70.6 g (0.36 mol) ethyl 4-bromobutyrate were slowly added dropwise at RT to 50 g (0.24 mol) ethyl 3-benzylamino-propionate and 83 g (0.60 mol) potassium carbonate in 1.0 L acetonitrile. Then the reaction mixture was stirred for 12 h at 90 C. After cooling the reaction mixture was diluted with EtOAc and the organic phase was separated off. It was washed with water and saturated sodium chloride solution and then dried on sodium sulphate. After filtration the filtrate was evaporated down and the residue was purified by flash chromatography (on aluminium oxide). Yield: 55.00 g (68% of theoretical) Rf: 0.7 (silica gel, EtOAc/PE 2%)
With potassium carbonate; In acetonitrile; at 20 - 90℃; for 12h;
Step 2: ethyl 4-[(benzyl-(2-ethoxycarbonyl-ethyl)-amino]-propanecarboxylate 71 g (0.36 mol) ethyl 4-bromobutyrate were slowly added dropwise at RT to 50 g (0.24 mol) ethyl 3-benzylamino-propionate and 83 g (0.60 mol) potassium carbonate in 1.0 L acetonitrile. Then the reaction mixture was stirred for 12 h at 90 C. After cooling the reaction mixture was diluted with EtOAc and the organic phase was separated off. This was washed with water and saturated sodium chloride solution and then dried on sodium sulphate. After filtration the filtrate was evaporated down and the residue was purified by flash chromatography (on aluminium oxide). Yield: 55 g (68% of theory) Rf: 0.7 (silica gel, EtOAc/PE 2%)
benzyl 2-(4-ethoxy-4-oxobutyloxy)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In acetonitrile;Reflux;
General procedure: The corresponding alkyl bromide (2.0eq) and potassium carbonate (2.0eq) were added to a solution of benzyl 2-hydroxybenzoate (1.0eq) in CH3CN, and the mixture was refluxed. After completion of the reaction, the residue was purified by silica gel column chromatography (EtOAc/Hexane) to afford the product.
With 2,6-dimethylpyridine; sodium iodide; In N,N-dimethyl-formamide; at 80℃; for 14h;
To a mixture of <strong>[46004-37-9]methyl 4-amino-2-chlorobenzoate</strong> (0.500 g) and sodium iodide (0.404 g) in N,N-dimethylformamide (8.0 mL) were successively added 2, 6-lutidine (0.433 g) and ethyl 4-bromobutylate (0.578 g) at room temperature, and the solution was stirred at an external temperature of 80 C for 14 hours. To the solution were added water and ethyl acetate at room temperature. The organic layer was separated. The organic layer was successively washed with water and brine, dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The obtained crude product was purified by column chromatography on aminopropylsilylated silica gel (eluent:ethyl acetate-hexane) to give methyl 2-chloro-4-(3-ethoxycarbonylpropylamino) benzoate (0.178 g). ethoxycarbonylpropylamino)benzoate (0.178 g). 1H-NMR(CDCl3) delta ppm: 1.26 (3H, t, J=7.2Hz), 1.90-2.00 (2H, m), 2.43 (2H, t, J=6.9Hz), 3.15-3.25 (2H, m), 3.85 (3H, s), 4.15 (2H, q, J=7.2Hz), 4.35-4.45(1H, br), 6.44 (1H, dd, J=8.7, 2.4Hz), 6.59 (1H, d, J=2.4Hz), 7.79 (1H, d, J=8.7Hz). MS(ESI, m/z) : 300 (M+H)+
With potassium carbonate; In butanone; for 20h;Heating / reflux;
A 200 ml 3-neck round bottom flask equipped with a magnetic stirrer bar and a reflux condenser was charged with 4.42 g (34 mmol) of 2-fluoro-4-rnethylphenol, 7.58g (37 mmol) ethyl 4-bromobutyrate, 5.67g (41 mmol) potassium carbonate and 130 mL of 2-butanone. After stirring for 20 hr at reflux, the reaction mixture was cooled to 250C and diluted with ethyl acetate and distilled water. The layers were separated. The organic layer was washed with distilled water and brine. It was dried over potassium carbonate, transferred to a 1000 ml flask and concentrated. The precipitate was dissolved in distilled water. The solution was mixed with 40 ml (80mmol) 2N aqueous sodium hydroxide. The reaction mixture was heated to reflux for 30 min until the ester was hydrolyzed (determined by HPLC). The mixture was cooled to 25 0C using an ice bath. The amber solution was acidified with 45 ml of 2N aqueous hydrochloric acid. The resulting white solid was isolated by filtration washing with water twice followed by hexanes twice to yield 4.88g (68%) of the desired product. Combustion analysis: Found: C: 62.07%, H: 6.4%; Calculated: C: 62.26%, H: 6.4%. IHNMR (d6-DMS O): 612.1, s, IH (COOH); delta 6.8-6.9, m, 3H (aryl H); 63.8, t, 2H, (CH2 alpha to ArO); delta2.3, t, 2H (CH2 alpha COOH); delta 2.1, s, 3H, (CH3 meta to F); 61.8, m, 2H (CH2 beta to COOH).
With potassium carbonate; In butanone; for 14.5h;Heating / reflux;
A 200ml 3-neck round bottom flask equipped with a magnetic stirrer bar and a reflux condenser was charged with 4.99 g (40 mmol) of 2-fluoro- 5 -methyl phenol, 9.01 g (44 mmol) of ethyl 4-bromobutyrate5 6.63 g (48 mmol) potassium carbonate and 120 mL of 2- butanone. The slurry heated to reflux. After stirring for 14.5 hr at reflux, the reaction mixture was cooled to 250C, filtered and concentrated. The residue was taken up in water (200 ml) and treated with 42 ml (84 mmol) 2N aqueous sodium hydroxide. The reaction mixture was heated to reflux for 2 hours and cooled to 250C. The yellow solution was acidified with 45 ml 2N aqueous hydrochloric acid. The resulting white solid was isolated by filtration washing with twice with water then twice with hexanes to yield 7.64 g (90%), mp 62-640C. Combustion analysis: Found: C 62.2%, H 6.19 %; Calculated: C: 62.26%, H: 6.17%. IHNMR analysis (d6- DMSO): delta 12.2, broad s, IH, (COOH); delta 7.0, m, 2H (aryl H); delta 6.7, s, IH (aryl H); delta 4.0, t, 2H (CH2 alpha ArO); delta 2.4, t, 2H (CH2 alpha COOH); delta 2.21, s, 3H (CH3 para F); delta 1.90, m} 2H (CH2 beta COOH).
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;
The mixture of ethyl 4-bromobutyrate (0.400 g, 2.05 mmole), <strong>[10199-68-5]4-phenyl-1H-pyrazole</strong> (0.296 g, 2.05 mmole) and K2CO3 (0.567 g, 4.10 mmole) in DMF (10 ml) was stirred at room temperature overnight. The reaction mixture was diluted with water (100 ml) and extracted with ethyl acetate (2×). The combined organic phases were washed with water and then brine, dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by preparative to afford the desired product (73 mg, 52%) as colorless oil. LCMS calculated for C15H19N2O2 (M+H): 259; found: 259.1.
With potassium carbonate; In N,N-dimethyl-formamide;
2a 4-(4-Chloro-2-methyl-pyrrolo[2,3-d]pyrimidin-7-yl)-butyric Acid Ethyl Ester 0.5 g (3 mmol) of <strong>[71149-52-5]4-chloro-2-methyl-7H-pyrrolo[2,3-d]pyrimidine</strong> (prepared according to West and Beauchamp, J. Org. Chem. 26 (1961) 3809) was dissolved in 3 ml DMF and 2.06 g (15 mmol) of potassium carbonate was added to this solution. 0.431 ml (3 mmol) of 4-bromobutyric acid ethyl ester was added and the mixture was stirred at 50 C. for 45 minutes. The reaction mixture was diluted with 50 ml EE and washed three times with water, dried over MgSO4, filtered and the solvent was removed in vacuo. Yield: 0.8 g. MS (ES+): m/e=282.1 (M+H+, 100%); 284.1 (30%).
With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 80℃; for 40h;
A mixture of 2-formylimidazole (5.17 g), ethyl 4-bromobutyrate (9.2 ml) and potassium carbonate (11.1 g) in DMF (50 ml) was stirred for 40 hours at 80C. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethyl acetate:hexane 1:1), to give ethyl 4-(2-formyl-1H-imidazol-1-yl) butyrate (8.36 g) as pale yellow oil. 1H-NMR (200 MHz, CDCl3) delta 1.26 (3H, t, J = 7.2 Hz), 2.08 to 2.19 (2H, m), 2.29 to 2.36 (2H, m), 4.14 (2H, q, J = 7.2 Hz), 4.47 (2H, t, J = 7.1 Hz), 7.18 (1H, d, J = 1.1 Hz), 2.30 (1H, d, J = 1.1 Hz), 9.81 (1H, s). IR (neat) 1732, 1682, 1476, 1412, 1337, 1188, 1159, 772 cm-1
Reference Example 12 Production of 4-(5-methoxybenzimidazole-2-ylthio)butanoate ester hydrogen bromide salt 6.48 g (33.2 mmol) of 4-bromobutanoate ethyl ester were added to 10 ml of an ethanol solution containing 5.0 g (27.7 mmol) of 5-methoxybenzimidazole-2-thiol followed by stirring for 1 hour at 80 C. and adding 90 ml of ethyl acetate. The reaction solution was returned to room temperature and the formed crystals were filtered out followed by drying to obtain 9.34 g of the target compound (yield: 90%). 1H-NMR (270 MHz, CDCl3) (ppm): 7.65 (d, 1H, J=8.91 Hz), 7.24 (s, 1H), 7.00 (dd, 1H, J=2.43, 8.91 Hz), 4.21 (q, 2H, J=7.29 Hz), 3.83 (s, 3H), 3.74 (m, 2H), 2.61 (m, 2H), 2.10 (m, 2H), 1.30 (t, 3H, J=7.29 Hz)
90%
In ethanol; at 80℃; for 1h;
[0176] 6.48 g (33.2 mmol) of 4-bromobutanoate ethyl ester were added to 10 ml of an ethanol solution containing 5.0 g (27.7 mmol) of 5-methoxybenzimidazole-2-thiol followed by stirring for 1 hour at 80 C. and adding 90 ml of ethyl acetate. The reaction solution was returned to room temperature and the formed crystals were filtered out followed by drying to obtain 9.34 g of the target compound (yield: 90%). [0177] 1H-NMR (270 MHz, CDCl3) (ppm): 7.65 (d, 1H, J=8.91 Hz), 7.24 (s, 1H), 7.00 (dd, 1H, J=2.43, 8.91 Hz), 4.21 (q, 2H, J=7.29 Hz), 3.83 (s, 3H), 3.74 (m, 2H), 2.61 (m, 2H), 2.10 (m, 2H), 1.30 (t, 3H, J=7.29 Hz)
90%
In ethanol; ethyl acetate;
[Reference Example 7] Production of 4-(5-methoxybenzimidazole-2-ylthio)butanoate ester hydrogen bromide salt 6.48 g (33.2 mmol) of 4-bromobutanoate ethyl ester were added to 10 ml of an ethanol solution containing 5.0 g (27.7 mmol) of 5-methoxybenzimidazole-2-thiol followed by stirring for 1 hour at 80C and adding 90 ml of ethyl acetate. The reaction solution was returned to room temperature and the formed crystals were filtered out followed by drying to obtain 9.34 g of the target compound (yield: 90%). 1H-NMR (270 MHz, CDCl3) (ppm): 7.65 (d,1H,J=8.91 Hz), 7.24 (S,1H), 7.00 (dd,1H,J=2.43, 8.91 Hz), 4.21 (q,2H,J=7.29 Hz), 3.83 (s,3H), 3.74 (m,2H), 2.61 (m,2H), 2.10 (m,2H), 1.30 (t,3H,J=7.29 Hz)
a tert-Butyl (2S)-2-Benzyloxycarbonylamino-3-(4-(3-ethoxycarbonylpropyloxy)phenyl)propionate 7.42 g (0.02 mol) of N-benzyloxycarbonyl-L-tyrosine tert-butyl ester were refluxed for 6 h together with 9.77 g(0.03 mol) of cesium carbonate and 3.9 g (0.02 mol) of ethyl 4-bromo-butyrate in about 60 ml of acetone. After cooling the reaction mixture, the solvent was removed in vacuo. The residue was partitioned between ethyl acetate and water (1/1). After separation of the phases, the organic phase was washed two times each with water and saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The oily crude product was purified by flash chromatography on silica gel (dichloromethane/acetonitrile 25/1). Yield: 9.4 g (97%) of viscous oil. Rf=0.36 (silica gel, dichloromethane/methanol 9911).
In sodium hydroxide; (CH2)3 COOEt; N,N-dimethyl-formamide;
EXAMPLE 2 1-(4-hydroxybutyl)-3-butyl xanthine (Method B, xanthine no. 21) 11.3 g (0. 05 mole) of 1-butyl-5-formylamino-6-aminouracil (II) (R1 =butyl, R8 =H) are dissolved under nitrogen in 200 ml of DMF. 10.6 ml (0.075 mole) of ethyl 4-bromobutyrate are added, after which 2 g (0.05 mole) of solid powder-form NaOH is added with thorough stirring in portions of 0.5 g at intervals of 1 hour. On completion of the addition, the mixture is left to react overnight. The solvent is then evaporated and the oily residue of (IV) (substituent in the 1-position=(CH2)3 COOEt) is dissolved in 100 ml of 10% NaOH. This solution is then heated under reflux for 0.5 hour and then cooled, neutralized to pH 5 with acetic acid and filtered. The precipitate formed is dried. Yield: 9.2 g (60%) of crude xanthine (V) (substituent in the 1-position=(CH2)3 COOH, R3 =butyl, R8 =H).
9.2 g (60%)
In sodium hydroxide; N,N-dimethyl-formamide;
EXAMPLE 2 1-(4-Hydroxybutyl)-3-butylxanthine (Method B, compound No. 21) 11.3 g (0.05 mole) of 1-butyl-5-formylamino-6-aminouracil (II) (R3 =butyl, R2 =H) are dissolved under nitrogen in 200 ml of DMF. 10.6 ml (0.075 mole) of ethyl 4-bromobutyrate are added, followed, with good stirring, by 2 g of (0.05 mole) of powdered solid NaOH in hourly 0.5 g portions. When the addition has been completed, the mixture is left to react overnight again. The solvent is evaporated off and the oily residue of (IV) (substituent in the 1 position=--(CH2)3 COOEt) is dissolved in 100 ml of 10% NaOH. This solution is refluxed for 1/2 hour. It is cooled, neutralized with acetic acid to pH 5, and the precipitate formed is filtered off and dried. Yield: 9.2 g (60%) of crude xanthine (V) (substituent in the 1 position=--(CH2)3 COOH, R3 =butyl, R2 =H).
4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidine-1-yl]butyric acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
6.26 g (91%)
With potassium carbonate; In methanol; chloroform; acetone;
EXAMPLE 26 After 4.98 g (16.45 mmol) of 4-[(4-chlorophenyl)-2-pyridylmethoxy]piperidine and 3.85 g (19.74 mmol) of ethyl 4-bromobutanoate were dissolved in 35 ml of acetone, 2.73 g (19.75 mmol) of potassium carbonate was added to the mixed solution, and the mixture was stirred under reflux by heating for 4 hours. The insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography using a solvent mixture of chloroform and methanol in the volume ratio of 30:1 as an eluent. The desired fraction was concentrated under reduced pressure to give 6.26 g (91%) of ethyl 4-[4-[(4-chlorophenyl)-2-pyridylmethoxy]-1-piperidyl]-butanoate as an oil. Mass analysis value: EI-MS M+ no peak, CI-MS m/e=417(M+ +1). 1 H-NMR(CDCl3): delta(ppm)=1.13(3H,t), 1.10-1.98(6H,b,m), 2.12(2H,b), 2.33(4H,t), 2.70(2H,b), 3.45(1H,m), 4.11(2H,q), 5.59(1H,s), 7.12-7.72(7H,m), 8.50(1H,m).
6-Bromo-2-(3-carboxypropyl)phthalazin-1(2H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium hydroxide; In ethanol; dimethyl sulfoxide;
Step a 6-Bromo-2-(3-carboxypropyl)phthalazin-1(2H)-one To a slurry of 56 gm <strong>[75884-70-7]6-bromophthalazin-1(2H)-one</strong> (0.25 mole) in 600 ml DMSO was added 110 ml 45% KOH followed by 58.5 gm ethyl 4-bromobutyrate. The temperature of the mildly exothermic reaction was moderated with a water bath (ca. 25 C.) and was stirred for 20 hours. Ethanol (750 ml) was added, then the mixture was acidified with 125 ml concentrated HCl, diluted with 2500 ml water over about 30 minutes, stirred an additional 30 minutes, filtered, washed with water and isopropanol and dried. The product weighed 63.6 gm. A tlc of the product showed product, Rf =0.43 plus a trace of starting material, Rf =0.63.
With potassium hydroxide; In ethanol; dimethyl sulfoxide;
Step a 6-Bromo-2-(3-carboxypropyl)phthalazin-1(2H)-one To a slurry of 56 gm <strong>[75884-70-7]6-bromophthalazin-1(2H)-one</strong> (0.25 mole) in 600 ml DMSO was added 110 ml 45% KOH followed by 58.5 gm ethyl 4-bromobutyrate. The temperature of the mildly exothermic reaction was moderated with a water bath (ca. 25C) and was stirred for 20 hours. Ethanol (750 ml) was added, then the mixture was acidified with 125 ml concentrated HCl, diluted with 2500 ml water over about 30 minutes, stirred an additional 30 minutes, filtered, washed with water and isopropanol and dried. The product weighed 63.6 g. A tlc of the product showed product, Rf = 0.43 plus a trace of starting material, Rf = 0.63.
With hydrogenchloride; potassium hydroxide; In water;
EXAMPLE 42 In a similar manner to that described above in Example 17 ethyl 4-(3-piperidinomethylphenoxy)butyrate (b.p. 190°-200° C./0.005 mm Hg) was prepared from N-3-hydroxybenzylpiperidine and ethyl 4-bromobutyrate. The resulting ester (21.4 g) was then hydrolyzed by heating under reflux with potassium hydroxide (3.6 g), water (210 ml) and industrial methylated spirit (210 ml) for 30 minutes. 5N Hydrochloric acid (13.7 ml) was then added and the solvent removed by evaporation in vacuo. The residue was dried by azeotropic distillation with toluene and then with ethanol. The residue was digested with ethanol (420 ml). The ethanolic liquor was filtered and the solvent removed from the filtrate to give a yellow oil which was crystallized from a mixture of methanol and ether to give 4-(3-piperidinomethylphenoxy)butyric acid (m.p. 73°-77° C.).
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;
Reference Example 142-Chloropyrimidin-5-ol (3.89g) is dissolved in N,N- dimethylformamide (50ml) and thereto are added potassium carbonate (4.98g) and tert-butyl 4-bromo-butyrate (7.36g) and the mixture is stirred at room temperature overnight. To the reaction solution are added ethyl <n="169"/>acetate and water, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate - 24: 1-->4: 1) to give tert-butyl 4-(2-chloropyrimidin-5-yloxy)bromobutyrate (6.22g). MS (m/z): 273 [M+H]+
With potassium carbonate; In butanone; for 48h;Heating / reflux;
a) 4-((R)-2-Methyl-pyrrolidin-l-yl)-bntyric acid ethyl ester(R)-2-methyl-pypi.Olidine hydrochloride (1.0 g, 8.2 mmol, 1.1 eq) was dissolved in 2-butanone (25 niL) and potassium carbonate (2.2 g, 15.7 mmol, 2.1 eq) was added. Ethyl 4-bromobutyrate (1.07 niL, 7.5 mmol, 1.0 eq) was added and the reaction mixture was refluxed for 2 days. The mixture was allowed to cool to room temperature and solid was filtered off and washed with ether. The filtrate was concentrated under reduced pressure to give 1.5 g of the title compound (yield 99percent) which was used in the next step without further purification.C1 1H21NO2IH-NMR (dmso-d6): 0.95 (3H, d, J=6.0 Hz); 1.15 (3H, t, J=7.2 Hz); 1.20-1.27 (IH, m); 1.56-1.64 (4H, m); 1.77-1.86 (IH, m); 1.91-1.99 (2H, m); 2.15-2.22 (lH,m); 2.25-2.30 (2H, m); 2.62-2.69 (IH, m); 2.97-3.01 (IH, m); 4.01 (2H, q, J=7.2 Hz).
With sodium carbonate;sodium iodide; In acetonitrile; for 72h;Reflux; Inert atmosphere;
A 500 ml_ round-bottom flask was set up with a magnetic stir bar, a reflux condenser, and a nitrogen line. The flask was charged with 7-methoxy-2,2,4- trimethyl-1 ,2-dihydro-quinoline (43 g, 0.21 mol), ethyl 4-bromobutyrate (44 g, 0.22 mol), <n="41"/>sodium iodide (11 g, 0.073 mol), acetonitrile (150 ml_, 2.9 mol), and sodium carbonate (26 g, 0.24 mol). The flask was heated at reflux with stirring for 72 hours. The progress of the reaction was monitored by thin layer chromatography (silica-gel plates, CH2CI2 as eluent, Rf starting compound = 0.29; Rf product = 0.20). After 20 hours the conversion was about 50%. Additional ethyl 4-bromobutyrate (44 g) and sodium carbonate (26 g) were added to the reaction mixture and reflux was continued for additional 48 hours. TLC analysis showed about 85% conversion.[0091] The reaction mixture was filtered and the acetonitrile was removed with a rotary evaporator. The unreacted starting compound was removed from the product by vacuum distillation using an oil pump. The recovery of 7-methoxy-2,2,4- trimethyl-1 ,2-dihydro-quinoline was 7 g (16%, b.p.120-125C, 0.7 Torr). The viscous yellow residue in the distillation flask was the pure product. The yield was 53.0 g oil (79% of theoretical yield).[0092] Analysis. 1H NMR (CDCI3, 300 MHz) delta 1.25-1.30 (m, 9H, 2*CH3,CH3), 1.92-1.94 (m, 5H, CH3, CH2), 2.38 (t, 2H, 3JH-H = 6.9 Hz, CH2CO2CH2CH3), 3.23 (distorted t, 2H, CH2N), 3.79 (s, 3H, CH3O), 4.16 (q, 3JH-H = 7.2 Hz), 5.11 (s, 1 H, CH), 6.12-6.15 (m, 2H), 6.97 (d, 1 H, 3JN-H = 8.1 Hz). 13C NMR (CDCI3, 75 MHz) delta 14.2, 18.6, 23.4, 28.3, 31.7, 43.4, 55.1 , 56.8, 60.4, 98.0, 99.4, 116.9, 124.4, 127.1 , 127.5, 145.2, 160.6, 173.2.
With calcium carbonate; In N,N-dimethyl-formamide; at 120℃; for 72h;
j0061] Calcium carbonate (6.01 g, 60 mmols) and ethyl 4-bromobutyrate (9.75 g, 50 mmols) were added to a solution of compound 1 7-methoxy-2,2,4-trimethyl-1 ,2-dihyd- roquinoline (8.12 g, 40 mmols) in anhydrous DMF (100 ml). The mixture was stirred at 120 C. for 3 days (reaction was monitored by TLC: hexane/ethyl acetate, 4/1). The solvent was removed under vacuum. The residue was redissolved in ethyl acetate (200 mL) and filtered through celite. The solvent was removed under vacuum to give crude ester 2.
With caesium carbonate; In N,N-dimethyl-formamide; at 20 - 80℃;
To a solution of 1 H-indazole-5-carbonitrile (1.2 g, 8.38 mmol) (Description 29) in DMF (60 mL) was added cesium carbonate (4.10 g, 12.57 mmol) and ethyl 4- bromobutanoate (2.422 mL, 16.77 mmol). The reaction mixture was then heated at 80C for 1 h, then left stirring at rt overnight. The mixture was then diluted with ethyl acetate (ca. 100 mL), washed with water (ca. 80 mL) and the aqueous phase re- extracted with ethyl acetate (3 x 100 mL). The organic phases were combined, dried over magnesium sulfate, filtered and reduced in vacuo. Purification by chromatography on silica gel, eluting with 0-50% ethyl acetate in isohexane afforded the title compound as a colourless oif which (1.24 g). LCMS (A) m/z: 258 [M+1]+, Rt 1.06 min (acidic).
With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 1h;
Description 44: Ethyl 4-(5-cyano-1H-indazol-1-yl)butanoate To a solution of <strong>[74626-47-4]1H-indazole-5-carbonitrile</strong> (1.2 g, 8.38 mmol) (Description 29) in DMF (60 mL) was added cesium carbonate (4.10 g, 12.57 mmol) and ethyl 4-bromobutanoate (2.422 mL, 16.77 mmol). The reaction mixture was then heated at 80 C. for 1 h, then left stirring at rt overnight. The mixture was then diluted with ethyl acetate (ca. 100 mL), washed with water (ca. 80 mL) and the aqueous phase re-extracted with ethyl acetate (3*100 mL). The organic phases were combined, dried over magnesium sulfate, filtered and reduced in vacuo. Purification by chromatography on silica gel, eluting with 0-50% ethyl acetate in isohexane afforded the title compound as a colourless oil which (1.24 g). LCMS (A) m/z: 258 [M+1]+, Rt 1.06 min (acidic).
General procedure: Constant current electrolyses (I = 25 mA cm-2) were performed under a nitrogen atmosphere, at 20C, using an Amel Model 552 potentiostat equipped with an AmelModel 731 integrator. All the experiments were carried out in a divided glass cell separated through a porous glass plug filled up with a layer of gel (i.e., methylcellulose 0.5% vol dissolved in DMF-Et4NPF6 1.0 mol dm-3); Pt spirals (apparent areas 0.8 cm2) were used both as cathode and anode. MeCN-Et4NPF6 0.1 mol dm-3 was used as solvent-supporting electrolyte system (catholite: 20 cm3; anolite: 5 cm3).1 mmol of substrate was present in the catholyte (except for D-<strong>[68-41-7]cycloserine</strong>, which was added to the catholyte after the end of the electrolysis). After 145 C (if not otherwise stated) were passed, the current was switched off and 1 mmol of alkylating agent was added to the catholyte. The solution was kept under stirring at room temperature for 2 hours, than the solvent was evaporated under reduced pressure and the residue was extracted three times with diethyl ether. The products were purified by flash column chromatography, using a mixture of ethyl acetate/light petroleum ether 2/8 in volume. The reactions on D-<strong>[68-41-7]cycloserine</strong> were carried out following the general method, but the substrate was added to the catholyte after the end of the electrolysis. After 15 minutes at room temperature, the alkylating agent was added and the solution was kept under stirring at rt for 2 hours. The solvent was evaporated under reduced pressure and the residue was treated with 1 cm3 of saturated acqueous NaHCO3 and 1 mmol of ethyl chloroformate, at 0C, for 2 h. The solution was then acidified with diluted HCl (pH 4) and extracted with diethyl ether. The products were purified by flash column chromatography.
With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 2h;
Step 26b: Ethyl 4-(4-(fert-butoxycarbonylamino)phenoxy)butanoate (Compound 1003-29)To a solution of 1002-29 (5.00 g, 23.90 mmol) in DMF (40 mL) was added K2CO3 (5.30 g, 38.35 mmol) and ethyl 4-bromobutanoate (8.20 g, 42.04 mmol). The reaction mixture was stirred at 50C for 2 h. The mixture was extracted with ethyl acetate. The organic layer was washed with water (20 mL x 5) and brine, dried over with Na2SO4, and concentrated. The residue was purified by flash column (ethyl acetate in petroleum ether 10% v/v) to afford product 1003-29 (4 g, 55 %) as a white solid: LCMS: 268 [M+l]+. 1H NMR (400 MHz, DMSO-d6): delta 1.18 (t, J= 7.2 Hz, <n="82"/>3H), 1.45 (s, 9H), 1.93 (m, 2H), 2.43 (t, J= 7.2 Hz, IH), 3.91 (t, J= 6 Hz, IH), 4.07 (q, J= 7.2 Hz, IH), 6.81 (d, J= 8.8 Hz, 2H), 7.32 (d, J= 8.4 Hz, 2H), 9.11 (s, IH).
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 96h;Inert atmosphere;
Preparation Example 27 Under an argon atmosphere, to a mixed liquid of 1.06 g of 1-isopropylpiperidin-4-amine, 1.00 g of potassium carbonate, and 5.0 mL of DMF was added dropwise a mixture of 0.70 g of ethyl 4-bromobutyrate and 2.0 mL of DMF under ice-cooling, followed by washing with 3.0 mL of DMF. After stirring at room temperature for 96 hours, the reaction mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (aqueous ammonia-methanol-chloroform) to obtain 0.47 g of ethyl 4-[(1-isopropylpiperidin-4-yl)amino]butyrate as a yellow oily substance.
ethyl 4-(4-(tert-butyl)pyridin-2-yl)butanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50%
General procedure: In a well-ventilated fume hood, a 15 mL round-bottomed flaskequipped with a Teflon-coated magnetic stirrer bar was chargedwith NiBr2·3H2O (40.9 mg, 0.150 mmol, 0.05 equiv), bathophenanthroline(4; 49.9 mg, 0.150 mmol, 0.05 equiv), DMF (2.0 mL), andalkyl bromide 2 (3.3 mmol, 1.1 equiv). The vessel was stopperedwith a rubber septum and heated to 40 C in a fume hood until agreen homogeneous solution formed (~20 min). The vessel wasthen removed from the heat and 2-halopyridine 1 (3.00 mmol, 1.00equiv) and manganese(0) (-325 mesh; 330 mg, 6.00 mmol, 2.00equiv) were added. The vessel was resealed with the septum, purgedwith argon, and heated again to 40 C while the progress of the reactionwas monitored by GC analysis of aliquots of the crude reactionmixture. In general, the mixtures turned dark brown or blackwhen the reaction was complete. Upon completion of the reaction,the mixture was cooled to r.t., diluted with Et2O (10 mL), and filteredthrough a short pad of Celite 545 (approx. 1 × 1 × 1 inch) wettedwith Et2O (~10 mL) to remove metal salts. The Celite pad waswashed with additional Et2O (2 × 10 mL), and the filtrate was transferredto a separatory funnel and washed with 1 M aq NH4Cl (10mL). The layers were separated and the aqueous layer was washedwith additional Et2O (3 × 10 mL). The organic extracts were combined,washed with brine (10 mL), dried (MgSO4), filtered, and concentratedunder reduced pressure. The crude products were purifiedby flash column chromatography on silica gel.
ethyl 3-(3-(trifluoromethoxy)phenoxy)propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92.1%
With potassium carbonate; In acetone; at 20℃;
Step 1 ethyl 3-(3-(trifluoromethoxy)phenoxy)propanoate To a solution of ethyl 4-bromobutanoate (2 g, 10.26 mmol) in acetone (20 mL) was added 3- (trifluoromethoxy)phenol (1.52 g, 8.54 mmol), followed by potassium carbonate (3.5 g, 25.36 mmol). The reaction was stirred at room temperature overnight. The mixture was partitioned between DCM and water. The organic phase was washed with brine, dried over sodium sulfate, and concentrated to give a crude product which was purified by silica gel chromatography eluting with petroleum/ ethyl acetate (10: 1 to 5: 1) to give ethyl 3-(3- (trifluoromethoxy)phenoxy)propanoate (2.3 g, 92.1 percent yield) as a colorless oil.
4-(4-bromo-2,3-difluorophenoxy)butyric acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76%
4-Bromo-2,3-difluorophenol (0.45 g, 2 mmol) was dissolved in 10 mL of DMF and the solution was cooled to 0. NaH (60% in mineral oil, 0.11 g, 2.6 mmol) was added thereto and the mixture was stirred for 30 minutes. 4-Bromo-butyric acid ethyl ester (0.37 mL, 2.4 mmol) was added thereto, and the reaction mixture was stirred for16 hours at room temperature. The mixture was concentrated under reduced pressure, added with aqueous solution of ammonium chloride and extracted with EtOAc. Separated organic layer was dried with MgSO and purified by column chromatography to obtain the title compound (0.533 g, 76 %). 1H NMR (CDCl) delta 7.19 (1H, m), 6.66 (1H, m), 4.16 (2H, q), 4.09 (2H, t), 2.52 (2H, t), 2.14 (2H, m), 1.26 (3H, t)
4-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
63%
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 18h;
2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol obtained from Step A (0.56 g, 2.3 mmol), 4-bromo-butyric acid ethyl ester (0.34 mL, 2.3 mmol) and CsCO (0.92 g, 2.8 mmol) were dissolved in 8 mL of DMF. The reaction mixture was stirred for 16 hours at room temperature. The mixture was concentrated and purified by column chromatography to obtain the title compound (0.52 g, 63 %). 1H NMR (CDCl) delta 7.49 (2H, m), 6.93 (1H, t), 4.15 (2H, t), 4.10 (2H, q), 2.53 (2H, t), 2.15 (2H, m), 1.33 (12H, s), 1.25 (3H, t)
63%
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 16h;
2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (0.56 g, 2.3 mmol) obtained in Step A, 4-bromobutyricacid ethyl ester (0.34 mL, 2.3 mmol) and Cs2CO3 (0.92 g, 2.8 mmol) were dissolved in 8 mL of DMF, and stirredat room temperature for 16 hours. The reaction solution was concentrated and purified by column chromatography toobtain the title compound (0.52 g, 63 %).1H NMR (CDCl3) delta 7.49 (2H, m), 6.93 (1H, t), 4.15 (2H, t), 4.10 (2H, q), 2.53 (2H, t), 2.15 (2H, m), 1.33 (12H, s), 1.25 (3H, t)
4-[(5,7-dihydroxy-2-(4-methoxyphenyl)-8-(3-methylbut-2-en-1-yl)-4-oxo-4H-chromen-3-yl)oxy]butyric acid ethyl ester[ No CAS ]
4-[(3,5-dihydroxy-2-(4-methoxyphenyl)-8-(3-methylbut-2-en-1-yl)-4-oxo-4H-chromen-7-yl)oxy]butyric acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
10%; 26%
In acetone; for 6h;Reflux;
General procedure: Different bromo-carboxylic acid ethyl ester (1.0e1.5 equiv.) wasadded into a mixture of <strong>[118525-40-9]icaritin</strong> (1.0 equiv.) and anhydrous K2CO3 (1.0e1.5 equiv.) in dry acetone and stirred under reflux for 6 h. After removing the solvent under reduced pressure, the residue was dissolved in EtOAc and sequentially washed with 1% aqueous HCl solution, distilled water and dried over anhydrous Na2SO4. The crude product was purified by HPLC using CH3CN/H2O (v/v, 80:20or 85:15, based on the polarity of the final product) to afford compounds 2g-2o.
4,4'-[(5-hydroxy-2-(4-methoxyphenyl)-8-(3-methylbut-2-en-1-yl)-4-oxo-4H-chromen-3,7-diyl)bis(oxy)]dibutyric acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With potassium carbonate; In acetone; for 6h;Reflux;
General procedure: Specific bromo-carboxylic acid ethyl ester (2.5-4.0 equiv.) was added into a mixture of <strong>[118525-40-9]icaritin</strong> (1.0 equiv.) and anhydrous K2CO3 (2.5-4.0 equiv.) in dry acetone and stirred under reflux for 6 h. After removing the solvent under reduced pressure, the residue was dissolved in EtOAc and sequentially washed with 1% aqueous HCl solution, distilled water and dried over anhydrous Na2SO4. The crude product was purified by silica gel CC, eluted with petroleum/acetone (v/v from 20:1 to 4:1, based on the polarity of the final product) or HPLC using CH3CN/H2O (v/v, 80:20 or 85:15, based on the polarity of the final product) to afford compounds 2a-2f.
4-(5-bromo-6-methylpyridin-2-yloxy)butyric acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In N,N-dimethyl-formamide; at 110.0℃; for 16.0h;Inert atmosphere;
Step B.4-(5-Bromo-6-methyl-pyridin-2-yloxy)-butyric acid, ethyl ester A mixture of <strong>[54923-31-8]5-bromo-6-methyl-pyridin-2-ol</strong> (1.3 g, 6.9 mmol), 4-bromo-butyric acid ethyl ester (2.7 g, 13.8 mmol) and K2C03 (2.8 g, 20.7 mmol) in DMF (20 mL) was heated at 110C under a dry N2 atmosphere for 16 h. After cooling, the mixture was diluted with 200 mL of H2O, and twice extracted with ethyl acetate. The combined organic phase was washed with brine, dried over anhydrous Na2S04 and concentrated. The residue was purified by flash column chromatography on silica gel (EA/PE=1/10) to give the title compound.
4-(4-bromo-2-chloro-6-fluorophenoxy)butanoic acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
97%
With potassium carbonate; In N,N-dimethyl-formamide; at 80.0℃; for 5.0h;
After addition of 15 mL of DMF, <strong>[161045-79-0]4-bromo-2-chloro-6-fluoro-phenol</strong> (2.25 g, 10.0 mmol), K2CO3 (2.07 g, 15.0mmol) and 4-bromobutanoic acid ethyl ester (1.95 g, 10.0 mmol) were stirred at 80C for 5 hours. The reaction solutionwas cooled to room temperature. After addition of water, the reaction solution was extracted with EtOAc. The organiclayer was dried with anhydrous magnesium sulfate and purified by column chromatography to obtain the title compound(3.29 g, 97 %).1H-NMR (CDCl3) delta 7.32 (1H, m), 7.18 (1H, m), 4.12 (4H, m), 2.60 (2H, t), 2.10 (2H, m), 1.27 (3H, t)
ethyl 4-(2-(pyridin-2-yloxy)phenyl)butanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
62%
With dichlorobis(4-methylisopropylphenyl)ruthenium; 1-Adamantanecarboxylic acid; potassium carbonate; In benzene; at 120℃; for 24h;Inert atmosphere; Sealed tube;
34 mg (0.2 mmol) of <strong>[4783-68-0]2-phenoxypyridine</strong> was added to a 20 mL pressure-resistant reaction tube,117 mg (0.6 mmol) of ethyl 4-bromobutyrate,6 mg (0.01 mmol) of dichlorobis (4-methylisopropylphenyl) ruthenium,55 mg (0.4 mmol) of potassium carbonate,11 mg (0.06 mmol) of 1-adamantanecarboxylic acid,1.5mL benzene,Sealed under nitrogen,Heated to 120 reaction,Stirred for 24 hours,After reaction,Column chromatography,The desired product 4- (2- (2-pyridyloxy) phenylbutyric acid ethyl ester 35mg,The yield is 62%.
ethyl 1-(4-ethoxy-4-oxobutyl)-4-methyl-1H-pyrrole-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Compound (Ia) (4 g, 26.1 mmol) was dissolved in N,N-dimethylformamide (60 mL). Cesium carbonate (21.3 g, 65.3 mmol) was added thereto, and the mixture was stirred for 30 minutes. Ethyl 4-bromobutyrate (5.91 mL, 39.2 mmol) was added thereto at room temperature, followed by reaction for 3 days. When the reaction was completed, the solid was removed by filtration, and the filtrate was concentrated under reduced pressure and extracted with methylene chloride. The water was dried with anhydrous magnesium sulfate and filtered.The filtrate was concentrated under reduced pressure to obtain (IIa).The resulting compound was used as such in the next reaction without further purification.
9,10-bis-(4-ethoxy-4-oxobutoxy)anthracene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
5.4 g
With tetrabutylammomium bromide; potassium carbonate; In water; N,N-dimethyl-formamide; at 20 - 30℃; for 1h;Inert atmosphere;
Stirrer,In a 100 ml four-necked flask with a thermometer,Under nitrogen atmosphere,catalyst0.77 g (1.19 mmol) of a 50percent aqueous solution of tetrabutylammonium bromide inEthyl 4-bromobutyrate12.1 g (61.8 mmol),5.0 g (23.8 mmol) of <strong>[4981-66-2]9,10-anthracenediol</strong>,9.9 g (71.4 mmol) of potassium carbonate,40 g of solvent N, N-dimethylformamide was added.The mixture was stirred for 1 hour while maintaining the temperature of the reaction system at 20 to 30 ° C.after that,The anthraquinone is removed by suction filtration.The resulting filtrate is dissolved in toluene,Washed twice with water.The solution was concentrated with an evaporator.When left overnight,As the whole solution solidified,Add methanol,Heat to 50 ° C,It was dissolved.The undissolved anthraquinone is removed by suction filtration.The filtrate was cooled in a freezer to precipitate crystals. By further suction-filtering the precipitated crystals,A yield of 5.4 g (crude yield 51 molpercent) of yellow crystals was obtained.
Adding dimethylformamide (DMF) and sodium hydride (NaH) to <strong>[3380-34-5]triclosan</strong>, the ratio of <strong>[3380-34-5]triclosan</strong>, DMF and NaH is1000 mg: 30 ml: 50 mg, and reacting at room temperature for 15 min to obtain a reaction solution; was added 200mg 4- bromobutyrate, 40reaction conditions oil bath, 25ml extracted with ethyl acetate, evaporated to dryness, the residue was added 12mL of ethyl acetate was dissolved, weighed twice the weightamount of silica gel was added thereto, It was evaporated to dryness and prepared for silica gel column loading.The mixed silica gel sample was sampled by dry sample loading, rinsed with petroleum ether: ethyl acetate system, and the eluent was collected to collect the rotary product.
ethyl 2-deutero-3-butyrate-5-nitrotoluene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
73%
With potassium dihydrogenphosphate; norbornene; potassium acetate; palladium diacetate; sodium formate; triphenylphosphine; In N,N-dimethyl-formamide; at 50℃; for 16h;Inert atmosphere;
Palladium acetate palladium (44.9 mg, 0.2 mmol) was added to a 25 mL eggplant bottle.Triphenylphosphine (52.4 mg, 0.2 mmol),Sodium formate (276 mg, 4 mmol),Norbornene (188 mg, 2 mmol),Potassium phosphate (2.544 g, 12 mmol),Potassium acetate (392 mg, 4 mmol),<strong>[5326-38-5]2-iodo-5-nitrotoluene</strong> (526 mg, 2 mmol),Ethyl bromobutyrate (1.56 g, 8 mmol) and dimethylformamide (10 ml).High-purity nitrogen was replaced three times, after reacting at 50oC for 16 hours,The mixture is extracted with dichloromethane and water, and the organic phases are combined.The organic solvent is concentrated, and the product is further purified by column chromatography.Ethyl 2-deutero-3-butyrate-5-nitrotoluene was obtained in a yield of 73%
ethyl 4-(5-formyl-4-methyl-1H-imidazol-1-yl)butanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
47.3%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 18h;
K2CO3 (579 mg, 1 mmol) was added into a mixture of 4-methyl-1H-imidazole-5- carbaldehyde (1.1 g, 10 mmol) and ethyl 4-bromobutanoate (2.14 g , 11 mmol) in DMF (20 mL). The resulting mixture was stirred at rt for 18 hours and concentrated under high vacuum to afford a residue. The resulting residue was purified by normal phase column chromatography (MeOH in DCM from 0% to 5%) to afford ethyl 4-(5-formyl-4-methyl-1H- imidazol-1-yl)butanoate (1.06 g, 47.3%) as a yellow oil. LCMS (m/z) 225 (M+H)+, retention time: 0.744 min, LCMS Method 4.
1 g of compound 1 was dissolved in 50 ml of methanol solution, and stirred at 157 C. for the night after adding 157 mg MeONa, and then the compound 1 was gotten. 1.20 g of compound 2 was dissolved 30 ml DMF, and added 1.20 mg Ethyl 4-bromobutyrate stir at 80 C. for the night, and then the mixture 2 was gotten. The step 4 is to concentrate the obtained mixture 2 and then purify it with a silica gel column to obtain compound 3. The 800 mg compound 3 was dissolved into 3 mL tetrahydrofuran and 1 mL water, adding 180 mg 1-hydrated lithium hydroxide, adjusting pH to 4-6, and stirring at room temperature overnight to get mixture 4. The aqueous solution layer with ethylamine from mixture 4 was extracted, and the organic layer was combined, washing with salt water, drying with anhydrous sodium sulfate and being concentrated to obtain <strong>[71125-38-7]meloxicam</strong> hapten. (0087) The products of compound 3 and haptens are calculated. (0088) Compound 3 production rate of 53.3%, the yield of the hapten was 66.4%.