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Structure of 535-11-5 * 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.
With potassium carbonate In N,N-dimethyl-formamide at 20 - 90℃; for 13.5 h; Cooling with ice
125 mM potassium carbonate was added to 100 mL of dry DMF (N, N-dimethylformamide)Add to it50 mM 2-amino-5-nitrophenol was stirred at room temperature for 1 h until it was completely dissolved.Under ice-cooling, a 50 mM solution of ethyl 2-bromopropionate in DMF was slowly added dropwise.After half an hour, the reaction solution was slowly warmed to room temperature and reacted at 90 ° C for 12 hours.After the reaction solution was cooled, part of the solvent was distilled off under reduced pressure,Slowly add ice water 300-500mL stirring with a solid precipitation,Stirring for half an hour under an ice bath, filtering,The filter cake was dried under vacuum to obtain pure intermediate product,6.28g as brown powder, yield 77.03percent.This intermediate was used directly in the next reaction without further purification.
Reference：
[1] Tetrahedron Letters, 2010, vol. 51, # 14, p. 1852 - 1855
[2] Chemistry - A European Journal, 2011, vol. 17, # 6, p. 1884 - 1893
[3] Tetrahedron, 2005, vol. 61, # 28, p. 6879 - 6885
[4] Patent: CN107459494, 2017, A, . Location in patent: Paragraph 0279; 0281-0283
(a)(ii) 2-Bromopropionic acid ethyl ester 1 M HCI in Et2O (5 mL) was added to a solution of 2-bromopropionic acid (25 g) in EtOH (200 mL). The mixture was refluxed over night and the solvents were then evaporated to give a yellow oil, 20.4 g (approximately 75percent yield).1 H NMR (500 MHz, CHLOROFORM-cQ δ ppm 4.36 (q, J=7.00 Hz, 1 H) 4.24 (qd, J=IAQ, 2.69 Hz, 2 H) 1.83 (d, J=7.08 Hz, 3 H) 1.31 (t, J=7.20 Hz, 3 H).
Reference：
[1] ACS Medicinal Chemistry Letters, 2017, vol. 8, # 3, p. 304 - 309
[2] Patent: WO2010/86613, 2010, A1, . Location in patent: Page/Page column 39
[3] Journal of the American Chemical Society, 2014, vol. 136, # 50, p. 17662 - 17668
[4] Justus Liebigs Annalen der Chemie, 1879, vol. 197, p. 13
[5] Monatshefte fuer Chemie, 1881, vol. 2, p. 546
[6] Justus Liebigs Annalen der Chemie, 1881, vol. 206, p. 319[7] Justus Liebigs Annalen der Chemie, 1882, vol. 214, p. 55
[8] Bulletin de la Societe Chimique de France, 1892, vol. <3>7, p. 359[9] Bulletin de la Societe Chimique de France, 1894, vol. 11, p. 297
[10] Justus Liebigs Annalen der Chemie, 1883, vol. 216, p. 32
[11] Justus Liebigs Annalen der Chemie, 1879, vol. 197, p. 13
[12] Monatshefte fuer Chemie, 1881, vol. 2, p. 546
[13] Justus Liebigs Annalen der Chemie, 1881, vol. 206, p. 319[14] Justus Liebigs Annalen der Chemie, 1882, vol. 214, p. 55
[15] Bulletin de la Societe Chimique de France, 1892, vol. <3>7, p. 359[16] Bulletin de la Societe Chimique de France, 1894, vol. 11, p. 297
[17] Justus Liebigs Annalen der Chemie, 1883, vol. 216, p. 32
[18] Patent: WO2004/58705, 2004, A2, . Location in patent: Page 58-59
4
[ 64-17-5 ]
[ 563-76-8 ]
[ 535-11-5 ]
Reference：
[1] Chemische Berichte, 1891, vol. 24, p. 2218
[2] Justus Liebigs Annalen der Chemie, 1894, vol. 280, p. 248
[3] Chemische Berichte, 1889, vol. 22, p. 62
[4] Journal of the Chemical Society, 1948, p. 642[5] Journal of the Chemical Society, 1934, p. 339
[6] Annales de Chimie (Cachan, France), 1935, vol. <11>3, p. 156,170,173[7] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1934, vol. 198, p. 2103
[8] Chemische Berichte, 1887, vol. 20, p. 2021
[9] Biochemical Pharmacology, 2005, vol. 69, # 9, p. 1351 - 1361
[10] Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 8, p. 2827 - 2836
[11] Organic and Biomolecular Chemistry, 2006, vol. 4, # 15, p. 2874 - 2882
[12] Asian Journal of Chemistry, 2012, vol. 24, # 2, p. 929 - 930
[13] Organic Letters, 2016, vol. 18, # 10, p. 2443 - 2446
[14] Synthesis (Germany), 2018, vol. 50, # 16, p. 3187 - 3196
5
[ 687-47-8 ]
[ 535-11-5 ]
Reference：
[1] Journal of Organic Chemistry, 1997, vol. 62, # 20, p. 7061 - 7064
6
[ 64-17-5 ]
[ 802294-64-0 ]
[ 535-11-5 ]
Reference：
[1] Molecules, 2018, vol. 23, # 9,
7
[ 21504-43-8 ]
[ 535-11-5 ]
Reference：
[1] Journal of the American Chemical Society, 1955, vol. 77, p. 3786,3789
8
[ 105-37-3 ]
[ 535-11-5 ]
Reference：
[1] Journal of Organic Chemistry, 1953, vol. 18, p. 649,651
9
[ 97-64-3 ]
[ 535-11-5 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1870, vol. 156, p. 176
Reference：
[1] Journal of the Chemical Society, 1948, p. 642[2] Journal of the Chemical Society, 1934, p. 339
[3] Annales de Chimie (Cachan, France), 1935, vol. <11>3, p. 156,170,173[4] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1934, vol. 198, p. 2103
13
[ 56-23-5 ]
[ 7726-95-6 ]
[ 21504-43-8 ]
[ 74-96-4 ]
[ 408325-87-1 ]
[ 535-11-5 ]
Reference：
[1] Journal of the American Chemical Society, 1952, vol. 74, p. 1816,1818
Reference：
[1] Zhurnal Obshchei Khimii, 1953, vol. 23, p. 737,740,741;engl.Ausg.S.769,770,772
17
[ 535-11-5 ]
[ 349-43-9 ]
Reference：
[1] Journal of Fluorine Chemistry, 1999, vol. 99, # 2, p. 115 - 117
[2] ACS Medicinal Chemistry Letters, 2017, vol. 8, # 3, p. 304 - 309
[3] Bulletin de la Societe Chimique de France, 1964, p. 2254 - 2257
[4] Comptes Rendus des Seances de l'Academie des Sciences, Serie C: Sciences Chimiques, 1969, vol. 268, p. 2352 - 2354
[5] Comptes Rendus des Seances de l'Academie des Sciences, Serie C: Sciences Chimiques, 1969, vol. 268, p. 2352 - 2354
[6] Journal of the American Chemical Society, 1961, vol. 83, p. 1945 - 1950
18
[ 535-11-5 ]
[ 3699-67-0 ]
Reference：
[1] Patent: US5162566, 1992, A,
19
[ 150-76-5 ]
[ 535-11-5 ]
[ 13794-15-5 ]
Reference：
[1] Bulletin of the Chemical Society of Japan, 2008, vol. 81, # 5, p. 617 - 622
20
[ 121-44-8 ]
[ 535-11-5 ]
[ 82614-48-0 ]
[ 71-91-0 ]
[ 636-70-4 ]
Reference：
[1] Danske Vid.Selsk.Mat.fys.Medd., 1943, vol. 20, # 13, p. 8,9[2] Chem.Abstr., 1945, p. 1844
21
[ 121-44-8 ]
[ 108-88-3 ]
[ 535-11-5 ]
[ 82614-48-0 ]
[ 71-91-0 ]
[ 636-70-4 ]
Reference：
[1] Danske Vid.Selsk.Mat.fys.Medd., 1943, vol. 20, # 13, p. 8,9[2] Chem.Abstr., 1945, p. 1844
22
[ 535-11-5 ]
[ 617-27-6 ]
Reference：
[1] Synthesis, 1985, # 2, p. 202 - 204
23
[ 603-35-0 ]
[ 535-11-5 ]
[ 30018-16-7 ]
Yield
Reaction Conditions
Operation in experiment
80.5%
at 20℃; for 24 h;
The 1g of triphenylphosphine were dissolved in 15mL ethyl acetate was added 2-bromopropionate ethyl ester0.55mL2-, the reaction was stirred at room temperature 24h, and gradually a large amount of white solid was suction filtered, rinsed with ethyl acetate to give 1.35 g of a white solid, yield rate of 80.5percent.
144 g
With potassium iodide In water; toluene at 20 - 75℃; for 15 h;
At 20-30°C,To a solution of triphenylphosphine (88 g) in toluene (the organic phase recovered in the first step of Example 3), an aqueous solution of potassium iodide (3 g) was added (the mother liquor from the first step of Example 3).Then alpha-bromo-propionic acid ethyl ester (60 g) is added,Reaction at 70-75 ° C for 15h;After the reaction is complete,Phase,Water cooling,Crystallization,Filtered to give the ethoxycarbonyl ethyl triphenylphosphonium bromide (144g);Organic phase recovery application,Aqueous mother liquor recovery application.
Reference：
[1] European Journal of Organic Chemistry, 2016, vol. 2016, # 12, p. 2110 - 2114
[2] Chemistry - A European Journal, 2015, vol. 21, # 20, p. 7408 - 7412
[3] Tetrahedron, 2010, vol. 66, # 26, p. 4745 - 4759
[4] Journal of Organic Chemistry, 1984, vol. 49, # 22, p. 4293 - 4295
[5] Patent: CN103864753, 2016, B, . Location in patent: Paragraph 0087; 0110-0111
[6] Angewandte Chemie - International Edition, 2018, vol. 57, # 24, p. 7240 - 7244[7] Angew. Chem., 2018, # 130, p. 7360 - 7364,5
[8] Tetrahedron, 1991, vol. 47, # 18-19, p. 2991 - 2998
[9] Journal of Fluorine Chemistry, 1985, vol. 29, p. 363 - 384
[10] Organic and Biomolecular Chemistry, 2004, vol. 2, # 10, p. 1456 - 1470
[11] Organic Letters, 2010, vol. 12, # 2, p. 240 - 243
[12] Advanced Synthesis and Catalysis, 2011, vol. 353, # 6, p. 913 - 917
[13] Chemistry - A European Journal, 2011, vol. 17, # 27, p. 7409 - 7413
[14] Chemistry - A European Journal, 2012, vol. 18, # 31, p. 9645 - 9650
[15] Organic Letters, 2016, vol. 18, # 10, p. 2443 - 2446
[16] Tetrahedron, 2016, vol. 72, # 37, p. 5707 - 5712
[17] Patent: JP5793025, 2015, B2, . Location in patent: Paragraph 0037
[18] Organic Letters, 2017, vol. 19, # 13, p. 3478 - 3481
[19] Patent: CN107759634, 2018, A, . Location in patent: Paragraph 0036; 0037; 0043; 0044
[20] Synthesis (Germany), 2018, vol. 50, # 16, p. 3187 - 3196
24
[ 269410-08-4 ]
[ 535-11-5 ]
[ 1220968-24-0 ]
Yield
Reaction Conditions
Operation in experiment
61%
With caesium carbonate In acetonitrile at 90℃; for 4 h;
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.40 g, 2.1 mmol, Aldrich, Cat. 525057), ethyl 2-bromopropanoate (290 μL, 2.3 mmol), and cesium carbonate (1.5 g, 4.6 mmol) in acetonitrile (8 mL) was stirred at 90° C. for 4 h. After cooling, the reaction mixture was worked up with aqueous Na2CO3, extracted with ethyl acetate (3.x.20 mL), and washed with brine. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-50percent) to afford the desired product (0.42 g, 61percent). LCMS (M+H)+: m/z=295.1.
21.6 g
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 14 h;
Step 9 Ethyl 2-[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-pyrazol-1-yl]propionate To a suspension of 4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (21.3 g) and potassium carbonate (20.7 g) in dimethylformamide (100 ml) was added ethyl 2-bromopropionate (13 ml), and the mixture was stirred at 80° C. for 14 hr. The reaction mixture was cooled to 0° C., and toluene (100 ml) and water (150 ml) were successively added dropwise. The mixture was partitioned, and the aqueous layer was extracted with toluene (50 ml). The combined organic layer was successively washed once with 10percent aqueous potassium carbonate solution (50 ml), twice with water (50 ml) and once with saturated brine (50 ml). The obtained organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the title compound (21.6 g). 1H-NMR (400 MHz, CDCl3) δ: 7.85 (1H, s), 7.81 (1H, s), 5.10 (1H, q, J=7.3 Hz), 4.19 (2H, q, J=7.1 Hz), 1.78 (3H, d, J=7.4 Hz), 1.32 (12H, s), 1.25 (3H, t, J=7.2 Hz).
The 1g of triphenylphosphine were dissolved in 15mL ethyl acetate was added 2-bromopropionate ethyl ester0.55mL2-, the reaction was stirred at room temperature 24h, and gradually a large amount of white solid was suction filtered, rinsed with ethyl acetate to give 1.35 g of a white solid, yield rate of 80.5%.
80%
at 50℃;Inert atmosphere;
In a 500 mL round-bottomed flask equipped with a magnetic stir bar was added triphenylphosphine (100 g, 381 mmol, 1.0 eq. ) and ethyl 2-bromopropionate (100 mL, 762 mmol, 2.0 eq. ) . The mixture was then heated to 50 under N 2 atmosphere overnight. After the white solid (PPh 3) was dissolved, a large amount of white solid was generated. Trituration with petroleum ether/EtOAc and filtration gave compound 95 as a white solid (135 g, 80%yield) . MS ESI m/z calcd for C 23H 24O 2P [M-Br] + 363.15, found 363.13.
In toluene; at 75℃;
A 500 mL flask was charged with PPh3 (26.2 g, 100 mmol) and 250 mL of toluene. To this solution was added ethyl 2-bromopropionate (100 mmol) over 40 minutes. The soultion was stirred for 8-9 hour at 75 C. The precipitate was filtered, washed with toluene (3×10 mL) and dried. The collected phosphonium salt was dissolved in H2O (400 mL) and 1drop of phenolphthalein solution was added. The mixture was cooled in an ice bath and saturated aqueous NaOH solution was added dropwise until a permanent pink color was obtained. The solid was filtered and washed with cold H2O, collected and dried in vacuo to afford 2d-1 (yield: 90%).
In water; at 75 - 80℃; for 4h;Inert atmosphere;
36.2 g (138 mmol) of triphenylphosphane and 400 ml of water were placed in a 500 ml four-necked flask equipped with a stirrer and a thermometer and purged with nitrogen, and 25.0 g (138 mmol) of ethyl 2-bromopropanoate was added to 75 To 80 C., and the mixture was stirred at 80 C. for 4 hours. The obtained aqueous solution was washed twice with 50 ml of toluene to obtain an aqueous solution of (1-ethoxycarbonylethyl) triphenylphosphonium bromide.
144 g
With potassium iodide; In water; toluene; at 20 - 75℃; for 15h;
At 20-30C,To a solution of triphenylphosphine (88 g) in toluene (the organic phase recovered in the first step of Example 3), an aqueous solution of potassium iodide (3 g) was added (the mother liquor from the first step of Example 3).Then alpha-bromo-propionic acid ethyl ester (60 g) is added,Reaction at 70-75 C for 15h;After the reaction is complete,Phase,Water cooling,Crystallization,Filtered to give the ethoxycarbonyl ethyl triphenylphosphonium bromide (144g);Organic phase recovery application,Aqueous mother liquor recovery application.
In chloroform; at 0 - 20℃;
General procedure: A dry two-necked flask was charged with a stirring bar, 3,5-dimethylphenol (1.22 g, 10 mmol), CH2Cl2 (30 mL), and pyridine (1.77 mL, 22 mmol). The mixture was cooled to 0 C, and bromoacetyl bromide (0.86 mL, 10 mmol) was added to the mixture slowly. The mixture was warmed to r.t. and stirred overnight. After the completion of the reaction (TLC monitoring), the mixture was washed with H2O (2 × 20 mL) and the organic phase was dried (Na2SO4). The solvent was removed and the residue was purified by flash chromatography on silicagel (c-Hex/EtOAc 10:1) to give 3,5-dimethylphenyl 2-bromoacetate (2.1 g, 86%) as a colorless oil. A dry two-neck flask was charged with PPh3 (786 mg, 3.0 mmol) and CHCl3 (10 mL). The solution was cooled to 0 C and the above prepared 3,5-dimethylphenyl 2-bromoacetate (729 mg, 3.0 mmol) was added. The reaction was warmed to r.t. and stirred overnight. The mixture was washed with aq 2 N NaOH (2 × 20 mL) and the collected organic phase was dried (Na2SO4). After removal of solvent under vacuum, the intermediate pure ylide was obtained as a white solid (1.20 g, 95%) and used in the next step without further purification. A dry Schlenk tube was charged with a stirring bar, CH2Cl2 (6 mL), the above prepared ylide (2.0 mmol), and Et3N (305 muL, 2.2 mmol). The mixture was cooled to 0 C in ice bath. A solution of acetyl chloride (2.2 mmol) in CH2Cl2 (2 mL) was added dropwise to the reaction mixture. The mixture was warmed to r.t. and stirred overnight. After the completion of the reaction (TLC monitoring), most of solvent was removed under vacuum, and Et2O (50 mL) was added to the flask, and the mixture was stirred for 0.5 h (Caution: longer reaction time may promote the isomerization of allenoate to the corresponding alkyl ester). The mixture was filtered and the organic phase was concentrated under vacuum. The residue was purified by flash chromatographyon silica gel (c-Hex/EtOAc 20:1) to give the allenoate 1e; yield: 147 mg (78%).
With potassium carbonate; potassium iodide; In acetone; for 15h;Reflux;
To a 50 mL round-bottom flask, <strong>[13020-57-0](3-hydroxyphenyl)(phenyl)methanone</strong>(6, 1 mmol, 198.2 mg), ethyl 2-bromopropanoate (7, 217.4 mg, 1.2mmol), KI (17 mg, 0.1 mmol), dry acetone (6 mL) and anhydrous K2CO3(276 mg, 2 mmol) were added, and refluxed for 15 h. The mixture was quenchedwith water (5 mL) and the solution was extracted dichoromethane (10 mL×3). The organic extracts were combined and dried with anhydrous MgSO4,filtered and concentrated to dryness reduced pressure by a rotary evaporator.Then the resulting residue was purified by column chromatography on silica gelto provide the desired product (8, light yellow solid, 285 mg,96% yield).
Step A Preparation of benzyl 4-(3-ethoxy-3-oxopropyl)-3-oxo-1-piperazine carboxylate Phenylmethyl 3-oxopiperazinecarboxylate (234 mg, 1.0 mmol) was dissolved in anhydrous DMF (5mL) and cooled to 0 C. To this solution was added NaH (44 mg, 1.1 mmol). The reaction mixture was stirred for 1 hour and allowed to warm to room temperature. The reaction was cooled to 0 C. and bromo ethyl propionate (0.144 ml, 1.1 mmol) was added. The reaction was stirred overnight and allowed to warm to room temperature. The reaction was poured into brine and extracted 3* with EtOAc. The organic layers were combined and the solvent evaporated. The resulting residue was purified by flash chromatography yielding 250 mg (75.0%) of the desired product. MS (ES) 335 (M+H)+
With sodium chloride; sodium hydrogencarbonate;potassium iodide; In ethanol;
(2-1) 1.5 g of <strong>[99365-69-2]7-nitro-1,2,3,4-tetrahydroisoquinoline hydrochloride</strong> was dissolved in 20 ml of ethanol, and 2.9 g of sodium hydrogencarbonate, 2.3 g of ethyl bromopropionate, and a catalytic amount of potassium iodide were added to the solution. The resulting solution was heated and stirred overnight under reflux. The resulting solution was extracted with ethyl acetate, washed with water and saturated aqueous solution of sodium chloride, and then dried with anhydrous sodium sulfate. After separating the desiccant by filtration, the product was purified by silica gel column chromatography to obtain 1.1 g of 2-(2-(ethoxycarbonyl)ethyl)-7-nitro-1,2,3,4-tetrahydroisoquinoline (yield: 57percent, oily product).
EXAMPLE 1 Triethyl Phosphonopropionate: Ethyl bromopropionate (92 g 0.5 mole) and triethyl phosphite (83 g, 0.5 mole) were stirred and heated to about 200 C. under a air cooled reflux condenser. The ethyl bromide that was evolved was collected with the aid of a cooling trap. After 1 hour of heating the pot temperature went up to 230 C. At this point the evolution of ethyl bromide ceased. The yellow oil was cooled to room temperature (RT) and then distilled under vacuum. There was obtained 112 g of phosphonate (93%) boiling at 105 /20 mm Hg as a colorless oil.
1-(Ethoxycarbonyl)ethyl Cinnoline-4-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In benzene;
1-(Ethoxycarbonyl)ethyl Cinnoline-4-carboxylate (32) A solution of 0.75 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in 20 ml of benzene was added to a stirred suspension of 0.87 g of 1 in 30 ml of benzene at room temperature. After one hour of stirring, 1.36 g of ethyl 2-bromopropionate was added and the mixture was heated at reflux for 6 hours. The mixture was cooled, diluted with 25 ml of benzene, washed with water, 1 N aqueous sodium bicarbonate, and brine. It then was dried (MgSO4), the solvent was evaporated and the residue was chromatographed on silica gel, using a 1:1 v:v mixture of cyclohexane and ethyl acetate as eluent, to give 32, as a yellow oil.
a. Formation of 2-methoxypropanoic acid A two liter flask equipped with a paddle stirrer, thermometer, condenser and nitrogen bubbler was charged with one liter of absolute methanol. Sodium metal (23.0 grams) was slowly added, when all of the metal was dissolved, the solution was cooled and starting at 8 C., 190 grams (1.05 mole) of ethyl 2-bromopropionate was added dropwise over a 55-minute period, the final temperature being 2 C. The solution was stirred for 45 minutes with ice bath cooling, then 250 milliliters of waters and 42 grams of sodium hydroxide pellets were added and the reaction mixture was stirred for an additional 75 minutes, while the temperature rose to 20 C. The reaction mixture was distilled at 90 C. to remove the methanol, then acidified with 85% phosphoric acid and extracted twice with 200 milliliters of chloroform (CHCl3). The extracts were combined and dried over anhydrous magnesium sulfate (MgSO4), filtered and then topped on a roto-vac at 50 C. to yield 81.1 grams of a colorless liquid of 2-methoxypropanoic acid.
1(a) Ethyl-2-(2-propylimidazol-1-yl)propanoate 2-Propylimidazole (5.5 g), ethyl 2-bromopropionate (9.95 g) and potassium carbonate (12.4 g) were stirred in refluxing acetonitrile (100 ml) for 72 hours. The suspension was allowed to cool, filtered and the solvent removed under reduced pressure, yielding the title compound as an off-white foam, 9.2 g [88%].
A mixture of 2-thiophenecarbonitrile (25.0 g), activated zinc (22.5 g) and CuBr2(0,2 g; 0.9 mmol) in benzene (350 mL) was heated to reflux temperature (83 C). Ethyl 2-bromopropionate (62.2 g) in benzene (150 mL) was added over 60 min. at 83 C. The resulting mixture was refluxed for 2 h and cooled to 0 C. 15 % Aqueous H2SO4(400 mL) was added over 60 mm. (temp. < 10 C) and the mixture was stirred for 20 h at 20 C. The mixture was filtered and the phases were separated. The aqueous phase was extracted with diethyl ether (2 x 500 mL) and the combined organic phases were dried (MgSO4) and evaporated in vacuo.Column chromatography (silica gel, eluent: ethyl acetate/n-heptane/methanol = 4:4:1) gave ethyl 2-methyl-3-(2-thienyl)-3-oxopropionate as an oil (35.0 g; 72 %).
With potassium carbonate; In dichloromethane; acetonitrile;
Example 3 3.51 g (0.01 mol) of 2-(2,6-difluorophenyl)-4-(4'-hydroxybiphenyl-4-yl)-1,3-oxazoline and 1.38 g (0.01 mol) of potassium carbonate are suspended in 50 ml of acetonitrile and, after addition of three drops of tris(3,6-dioxaheptyl)amine (TDA), 1.8 g (0.01 mol) of ethyl 2-bromopropionate are added. The reaction mixture is stirred at 65° C. for 18 hours and then concentrated. The residue is taken up in 100 ml of methylene chloride, and the mixture is washed with water, dried over sodium sulfate and concentrated. The oily residue is purified by column chromatography with methylene chloride as the mobile phase. 2.5 g (55.4percent of theory) of 2-(2,6-difluorophenyl)-4-[4'-(1-ethoxycarbonyl-eth-1-yl-oxy)-biphenyl-4-yl]-1,3-oxazoline with a log p=4.12 are obtained.
Step-j product (5 g, 0.018 mol) was dissolved in THF (22.5 mL) and 6N hydrochloric acid (22.5 mL) was added to it. The reaction mixture was stirred for 2 hours at ambient temperature. After total consumption of starting material the reaction mixture was diluted with water (50 mL) and extracted with 10percent ethyl acetate in hexane (3 x 50 mL). The combined organic layer was dried over magnesium sulfate and concentrated under reduced pressure.The crude compound was purified by column chromatography using 5percent ethyl acetate in hexane as eluent to afford 3.2 g pure compound.
H181 (150 mg, 1.0 mmol) was dissolved in DMF (10.0 mL) and cooled to 0 °C with ice bath. To this solution under nitrogen were added in sequence NaH (60percent in mineral oil, 160 mg, 4.0 mmol) and ethyl 2-bromopropanoate (0.51 mL, 4.0 mmol). The reaction mixture was stirred for 1 d then treated with 1.0 M HCl (10.0 mL). After extraction with ethyl acetate, the organic phase was washed with water and brine, and dried over anhydrous Na2S04. The residue after rotary evaporation was purified by column chromatography over silica gel to give the title compound (144 mg, 7percent yield). 1H NMR (300 MHz, DMSO-d6): delta 9.18 (s, 1H), 7.31 (d,J = 8.1 Hz, 1H), 7.14 (d, J = 2.4 Hz, 1H), 7.02 (dd, J = 8.4 2.7 Hz, 1H), 4.95-4.87 (m, 3H), 4.19-4.08 (m, 2H), 1.51 (d, J = 6.6 Hz, 3H) and 1.17 (t, J = 7.2 Hz, 3H) ppm; Mp: 65-67 °C.
ethyl 1-[(1E)-3-ethoxy-3-oxoprop-1-en-1-yl]-8,9-dimethoxy-2-(4-methoxyphenyl)-3-methyl-1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]isoquinoline-3-carboxylate[ No CAS ]
ethyl 1-[(1E)-3-ethoxy-3-oxoprop-1-en-1-yl]-8,9-dimethoxy-2-(4-methoxyphenyl)-3-methyl-1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]isoquinoline-3-carboxylate[ No CAS ]
With caesium carbonate; In acetonitrile; at 90.0℃; for 4.0h;
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.40 g, 2.1 mmol, Aldrich, Cat. 525057), ethyl 2-bromopropanoate (290 muL, 2.3 mmol), and cesium carbonate (1.5 g, 4.6 mmol) in acetonitrile (8 mL) was stirred at 90 C. for 4 h. After cooling, the reaction mixture was worked up with aqueous Na2CO3, extracted with ethyl acetate (3×20 mL), and washed with brine. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-50%) to afford the desired product (0.42 g, 61%). LCMS (M+H)+: m/z=295.1.
21.6 g
With potassium carbonate; In N,N-dimethyl-formamide; at 80.0℃; for 14.0h;
Step 9 Ethyl 2-[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-pyrazol-1-yl]propionate To a suspension of 4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (21.3 g) and potassium carbonate (20.7 g) in dimethylformamide (100 ml) was added ethyl 2-bromopropionate (13 ml), and the mixture was stirred at 80 C. for 14 hr. The reaction mixture was cooled to 0 C., and toluene (100 ml) and water (150 ml) were successively added dropwise. The mixture was partitioned, and the aqueous layer was extracted with toluene (50 ml). The combined organic layer was successively washed once with 10% aqueous potassium carbonate solution (50 ml), twice with water (50 ml) and once with saturated brine (50 ml). The obtained organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the title compound (21.6 g). 1H-NMR (400 MHz, CDCl3) delta: 7.85 (1H, s), 7.81 (1H, s), 5.10 (1H, q, J=7.3 Hz), 4.19 (2H, q, J=7.1 Hz), 1.78 (3H, d, J=7.4 Hz), 1.32 (12H, s), 1.25 (3H, t, J=7.2 Hz).
With caesium carbonate; In N,N-dimethyl-formamide; at 90℃;
As depicted above in Scheme 3, provided compounds can be synthesized from a variety of commercially available or previously prepared hydroxybenzoate derivatives. o-Alkylation of hydroxybenzoate E-7 with a suitable alkylating reagent (e.g., (3-bromopropyl)benzene) affords ether E-8. E-8 can then be transformed under suitable conditions in one or more steps to the desired benzaldehyde E-9. E-9 can be a test compound or can be further modified (e.g., via reaction with a suitable amine, Wittig reaction and/or a modification thereof selective for either the E or Z isomer, reduction, nucleophilic addition, etc.) to provide a test compound. As depicted above in Scheme 4, (R)- and (S)-1-(3,5-bis(trifluoromethyl)phenoxy)ethanol were synthesized from phenol E-10. Upon exposure to a suitable alkylating reagent, phenol E-10 was o-alkylated to afford ether E-11. The ethyl ester of E-11 was then reduced in the presence of a suitable reducing agent (e.g., a metal hydride such as LiAlH4) to the corresponding alcohol E-12. Acylation of racemic E-12 upon exposure to a suitable chiral derivative (e.g., (S)-campanic chloride) provided the corresponding ester as a diastereomeric mixture separable by column chromatography. Subsequent saponification of acylated E-12 provided compounds E-13a and E-13b. Alternatively, as depicted above in Scheme 5, one of skill in the art would appreciate that the steps of reduction and resolution can be reversed. For instance, one of skill in the art could envision accessing either of E-13a or E-13b by exposing the corresponding chiral precursor E-14a or E-14b to a suitable reducing agent (e.g., LiAlH4). E-13a and E-13b can then be oxidized using a suitable oxidant to afford the corresponding aldehydes, which can be taken on as shown in Scheme 1 (above) to provide chiral compounds E-15a and E-15b.
Example 9One pot synthesis of 3-(3-Methoxyphenyl)-2-methyl-pent-3-enoic acid ethyl ester from 3- Methoxy propiophenone[0079] Tetrahydrofuran (200 ml) and zinc metal (100 g) were taken under nitrogen atmosphere, the mixture was heated at 65+/-2C, followed by the addition of ethyl 2- bromopropionate (20 g) and then drop-wise addition of trimethylsilyl chloride (10 ml). A mixture of 3-methoxy propiophenone (100 g), ethyl 2-bromopropionate (120 g) and tetrahydrofuran (300 ml) was added to the above mixture while maintaining the temperature at 65-75 C. After complete addition of the above mixture, the reaction mass was refluxed for 1-2 hours and then cooled to 0-5C, followed by the addition of 15% dilute HC1 solution (200 ml) at below 20C. Toluene (300 ml) was added to the resulting mixture and then stirred for 30 minutes. The reaction mass was transferred into a separating funnel and then allowed to settle for 10-15 minutes, followed by the separation of the upper organic layer. The resulting aqueous layer was separated and then placed into a reaction flask. Toluene (200 ml) was added to the aqueous layer and the reaction mixture was stirred for 30 minutes, followed by transferring into the separating funnel and allowing it to settle for 10-15 minutes. The upper organic layer was separated. The entire extracted organic layer was combined and then washed with saturated sodium chloride solution (200 ml). The organic layer was dried over anhydrous sodium sulphate (50 g), followed by the distillation of solvents completely at 55C and further applying high vacuum (5mm/Hg) at 55C for 5-7 hours to produce 237 g of 3-(3- Methoxy-phenyl)-2-methyl-pent-3-enoic acid ethyl ester (Yield: 100%).
With chloro-trimethyl-silane; zinc; In tetrahydrofuran; at 65 - 75℃;Inert atmosphere; Reflux;Product distribution / selectivity;
Example 3Preparation of 3-Hydroxy-3-(3-methoxy-phenyl)-2-methyl-pentanoic acid ethyl ester[0073] Tetrahydrofuran (100 ml) and zinc metal (100 g) were taken under nitrogen atmosphere, the mixture was heated at 65+/-2C, followed by the addition of ethyl 2- bromopropionate (20 g) and then drop-wise addition of trimethylsilyl chloride (10 ml). A mixture of 3-methoxy propiophenone (100 g), ethyl 2-bromopropionate (120 g) and tetrahydrofuran (300 ml) was added to the resulting mixture, followed by maintaining at 65- 75 C. After complete addition of the above mixture the reaction mass was refluxed for 1-2 hours and then cooled to 0-5C. Saturated potassium bisulphate solution (250 ml) was added to the reaction mass at below 20C, followed by the addition of ethyl acetate (500 ml) and then stirring the reaction mass for 30 minutes. The reaction mass was transferred into a separating funnel and allowed it to settle for 10-15 minutes, followed by the separation of the upper organic layer. The resulting aqueous layer was separated and then placed into a flask, followed by the addition of ethyl acetate (500 ml). The reaction mixture was stirred for 30 minutes, followed by transferring into the separating funnel and allowing it to settle for 10-15 minutes. The upper organic layer was separated. The entire extracted organic layer was combined and washed with saturated sodium chloride solution (250 ml). The organic layer was dried over anhydrous sodium sulphate (50 g), followed by the distillation of solvent completely at 50+/-2C and further applying high vacuum at 50+/-2C for 30 minutes in order to distil out the solvent completely to produce 251 g of 3-hydroxy-3-(3-methoxy-phenyl)-2- methyl-pentanoic acid ethyl ester (Yield: 100%).
With potassium carbonate; In tetrahydrofuran; N,N-dimethyl-formamide; at 20 - 50℃;
a) A mixture of potassium carbonate (832 mg, 6.02 mmol), 2-methyl-5-(trifluoromethyl)-1H-imidazole (450 mg, 3.00 mmol) and ethyl 2-bromopropanoate (0.43 mL, 3.3 mmol) in dimethylformamide:tetrahydrofuran (2 mL:4 mL) was heated at 50 C. for 7 h with stirring and then at room temperature overnight. Most of the tetrahydrofuran was removed by gently blowing nitrogen over the reaction mixture. Ethyl acetate and water were then added and the layers were separated. The aqueous layer was extracted twice more with ethyl acetate. The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (SiO2, 17-50% ethyl acetate in hexanes) to afford the desired product (697 mg, 2.79 mmol, 93%).
With potassium carbonate; In tetrahydrofuran; N,N-dimethyl-formamide; at 45℃; for 16h;
A solution of ethyl 2-bromopropionate (3.98 g, 22 mmol), 4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazole (3.00 g, 20 mmol), and K2CO3 (5.53 g, 40 mmol) in THF/DMF (2:1, 39 mL) was allowed to stir at 45 C. for 16 h. The mixture was then concentrated in vacuo and diluted with EtOAc (70 mL). The organic layer was washed with water and brine, dried over MgSO4, filtered, and concentrated in vacuo to give the product (5.3 g) as a colorless oil that was used without further purification.
With triethylamine; In tetrahydrofuran; toluene;Reflux;
To <strong>[658-93-5]3,4</strong>-difluorophenyl acids (58 mmol) in toluene THF (100 ml), 2-bromopropionate (87 mmol) and triethylamine (35 mmol ) was added . And the mixture was heated to reflux 7-8h. The progress of the reaction was monitored by TLC, after the reaction completed, the mixture was cooled down to room temperature and filtered to remove the salt. The filtrate was concentrated to get crude product compound 10 as deep red transparent liquid.
With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 16h;
General procedure: To stirred solutions of the corresponding phenol (15.0 mmol)in DMF (25 mL) are added K2CO3 (2.60 g, 19 mmol) and ethyl 2-bromopropanoate (2.5 mL, 19 mmol). The mixtures were stirredat 50 C for 16 h, then cooled to room temperature and filtered toremove the inorganic solids. The filtrates were evaporated underhigh vacuum (<1 mmHg) to provide clear oils that were dissolvedin absolute ethanol (25 mL). Aqueous solutions of NaOH (2.0 M,12 mL, 24 mmol) were added, and the combined solutions heatedto reflux for 4 h. The resulting mixtures were cooled to room temperatureand evaporated under reduced pressure to provide residuesthat were dissolved in water (75 mL). The aqueous solutionswere acidified (pH 2) with aqueous HCl (2.0 M) to provide precipitatesthat were filtered, rinsed with water (20 mL), and driedunder vacuum to provide the products 11c-h.
2,2'-[(5-hydroxy-2-(4-methoxyphenyl)-8-(3-methylbut-2-en-1-yl)-4-oxo-4H-chromen-3,7-diyl)bis(oxy)]dipropionic acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
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.
2-[(5,7-dihydroxy-2-(4-methoxyphenyl)-8-(3-methylbut-2-en-1-yl)-4-oxo-4H-chromen-3-yl)oxy]propionic acid ethyl ester[ No CAS ]
2-[(3,5-dihydroxy-2-(4-methoxyphenyl)-8-(3-methylbut-2-en-1-yl)-4-oxo-4H-chromen-7-yl)oxy]propionic acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
40%; 10%
With potassium carbonate; 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.
ethyl 2-(3-cyano-4-methoxy-2-oxopyridin-1(2H)-yl)propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
6.12 g
With caesium carbonate; In N,N-dimethyl-formamide; at 50℃;
A) ethyl 2-(3-cyano-4-methoxy-2-oxopyridin-1(2H)-yl)propanoate (0796) A mixture of <strong>[21642-98-8]4-methoxy-2-oxo-1,2-dihydropyridine-3-carbonitrile</strong> (5.56 g), ethyl 2-bromopropanoate (10.1 g), cesium carbonate (36.2 g) and N,N-dimethylformamide (75 mL) was stirred at 50°C overnight. The reaction mixture was added to water, and the mixture was extracted 3 times with ethyl acetate. The extracts were combined, washed with water and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane). The obtained solid was washed with ethyl acetate/diisopropyl ether to give the title compound (6.12 g). MS (ESI+): [M+H]+ 250.8.
(rac)-ethyl 2-(4-iodo-1H-imidazol-1-yl)propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
To a round bottom flask was added <strong>[71759-89-2]4-iodo-1H-imidazole</strong> (2.29 g, 11.806 mrnol) and dimethylformamide (20 mL). The atmosphere was evacuate and purged thrice with nitrogen. Sodium hydride (0.59 g, 14.75 7 mmol) was added, and the reaction mixture was stirred at 25 C for 10 mm. Ethyl 2- bromopropanoate (2.201 g, 12.16 mmol) was added, and the reaction was stirred at roomtemperature overnight. The reaction mixture was poured into water and extracted twice with ethyl acetate (2 x 125 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography (eluting with hexanes and ethyl acetate) to provide the title compound as a clear yellow oil (2.829 g, 9.62 mmol, 8 1%). LCMS M/Z (M+H) 295.
ethyl 2-(4-fluoro-3-nitrophenoxy)propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With caesium carbonate; In N,N-dimethyl-formamide; at 20 - 60℃; for 2h;
<strong>[2105-96-6]4-<strong>[2105-96-6]fluoro-3-nitrophenol</strong></strong> (500 mg, 3.18 mmol) was dissolved in DMF (6.365 mL) at room temperature. Cesium carbonate (1244 mg, 3.82 mmol) was added followed by racemic ethyl 2-bromopropanoate (634 mg, 3.50 mmol). The mixture was stirred at 60 °C. After 2 hours, the reaction was then diluted with water and brine (1 : 1) and extracted with EtOAc. The organics were combined, dried with sodium sulfate, filtered, and concentrated in vacuo. The resulting tan oil was dried on high vac overnight to give 58 A (tan oil, 759 mg, 2.95 mmol, 93 percent yield). LC-MS Anal. Calc'd for C11H12FNO5 257.70, Tr = 0.91 min (Method A) (Note: product does not ionize well). NMR (400 MHz, chloroform-d) delta: 7.51 (dd, J=5.8, 3.0 Hz, IH), 7.11-7.23 (m, 2H), 4.75 (q, J=6.7 Hz, IH), 4.24 (qd, J=7.1, 1.7 Hz, 2H), 1.65 (d, J=6.7 Hz, 3H), 1.28 (t, J=7.2 Hz, 3H)
ethyl 2-(3-[[(tert-butoxy)carbonyl]amino]azetidin-1-yl)propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
44%
With triethylamine; In dichloromethane; at 20℃; for 13h;
To a soulution of <strong>[91188-13-5]tert-butyl N-(azetidin-3-yl)carbamate</strong> (475 mg, 2.76 mmol) in DCM (40 m) was added triethylamine (418 mg, 4.14 mmol) and ethyl 2-bromopropanoate (749 mg, 4.14 mmol) at room temperature. The resulting solution was stirred for 13 h at room temperature. When the reaction was done, it was quenched by the addition of water (10 mL). The resulting solution was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in hexane (0% to 50% gradient) to yield ethyl 2-(3- [[(tert-butoxy)carbonyljaminojazetidin-1-yl)propanoate as yellow oil (330 mg, 44%). MS: m/z = 259.3 [M+Hj.
ethyl 2-(1-(4-chlorophenyl)-3-pyrazolyloxy)propionate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 5h;
General procedure: The mixture of ethyl 2-bromopropanoate (11.00, 60.0 mmol), B/B? (9.93 g, 50.0 mmol) and potassium carbonate (5.60 g, 40.0 mmol) in N,N-dimethylformamide (DMF; 100 mL) was stirred at 100 C for about 5 h. After completion of the reaction (TLC), the reaction mixture was filtered. The filtrate was evaporated in vacuum to remove DMF and the residue was dissolved in ethyl acetate (50 mL). The organic phase was washed with water (20 mL), evaporated, and the crude product was further purified by recrystallization from ethanol to obtain D1: 12.06 g, yield 81.0%. White solid, m.p. 77-79 C. 1H NMR (300 MHz, CDCl3, 25 C, TMS): delta (ppm) 7.69 (d, J=3.0 Hz, 1H, pyrazol-5-H), 7.48 (d, J=8.7 Hz, 2H, 4-Cl-Ph-2,6-2H), 7.33 (d, J=8.7 Hz, 2H, 4-Cl-Ph-3,5-2H), 5.88 (d, J=2.7 Hz, 1H, pyrazol-4-H), 5.14 (q, J=6.9 Hz, 1H, CH), 4.23 (q, J=7.2 Hz, 2H, CH2), 1.63 (d, J=6.9 Hz, 3H, CH3), 1.26 (t, J=7.2 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3, 25 C, TMS): delta (ppm) 172.1, 163.0, 138.4, 130.4, 129.2, 127.6, 118.5, 94.5, 72.9, 61.0, 17.9, 14.1; MS (ESI+) Calcd for C14H15ClN2O3 (M+H)+, m/z 295.08, found, 295.1; Anal. Calcd for C14H15ClN2O3: C, 57.05, H, 5.13, N, 9.50, found, C, 57.00, H, 5.12, N, 9.52%.
81%
With potassium carbonate; In N,N-dimethyl-formamide; at 90 - 100℃; for 5h;
1-(4-chlorophenyl)-3-pyrazol9.9g (60mmol),Ethyl 2-bromopropionate11.0 g (60 mmol),Potassium carbonate 5.6g (40mmol)And 100 ml of N,N-dimethylformamide was put into a 250 mL three-neck bottle.The temperature was raised to 90 to 100 C and maintained for 5 hours.Thin layer chromatography (TLC) followed the progress of the reaction (n-hexane / ethyl acetate = 4:1). After the conversion of 1-(4-chlorophenyl)-3-pyrazol was completed, the material was filtered to remove the salt, and the filter cake was washed with 20 ml of fresh N,N-dimethylformamide. The filtrate was combined, and the solvent was removed by evaporation under reduced pressure. The residue was washed with 50 g of ethyl acetate and 20 g of water, and the oil phase was distilled under reduced pressure to remove solvent. The residue was recrystallized from ethanol,A solid of 12.0 g was obtained in a yield of 81.0% (based on 1-(4-chlorophenyl)-3-pyrazol).
81%
With potassium carbonate; In N,N-dimethyl-formamide; at 90 - 100℃; for 5h;
9.93 g (50 mmol) of <strong>[76205-19-1]1-(4-chlorophenyl)-3-pyrazolyl-ol</strong>, 11.00 g (60 mmol) of ethyl 2-bromopropionate, 5.60 g (40 mol) of potassium carbonate, and100 ml of N,N-dimethylformamide was placed in a 250 mL three-necked flask, and the temperature was raised to 90 to 100 C for 5 hours. Thin layer chromatography (TLC) followed the progress of the reaction (n-hexane / ethyl acetate = 4:1). After the conversion of <strong>[76205-19-1]1-(4-chlorophenyl)-3-pyrazolyl-ol</strong> was completed, the material was filtered to remove the salt and the filter cake was washed with 20 ml of fresh N,N-dimethylformamide. The filtrate was combined, and the solvent was removed by evaporation under reduced pressure. The residue was dissolved in 50 mL of ethyl acetate, washed with water, an oil phase was distilled under reduced pressure. The residue was recrystallized from ethanol to give a white solid 12.06 g. Yield 81.0% (based on <strong>[76205-19-1]1-(4-chlorophenyl)-3-pyrazolyl-ol</strong>).
ethyl 2-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With caesium carbonate; In acetonitrile; at 20 - 25℃; for 16h;
To a stirred solution of Compound 1g in ACN (100 ml) were added Cs2CO3 (125.6 g, 386.15 mmol) and ethyl 2-bromopropanoate (39.43 ml, 283.15 mmol) at 25° C. The mixture was stirred for 16 h at room temperature, The progress of the reaction was monitored by TLC (5percent MeOH in DCM, Rf=0.5, PMA active). After completion of the reaction, the reaction mixture was filtered and washed with EtOAc (300 ml). The filtrate was washed with water (2×200 ml), brine (2×200 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain 35 g crude product. The crude product was purified by normal phase column chromatography using silica (100-200 mesh), eluting with 2percent MeOH in DCM. The collected fractions were evaporated to obtain Compound 2g (30 g, 59.17percent) as a pale yellow liquid. The desired isomer was confirmed by NOE analysis. 1H NMR (400 MHz, DMSO-d6) delta ppm: 5.22-5.34 (m, 1H), 4.03-4.18 (m, 2H), 2.32 (s, 3H), 2.16 (s, 3H), 1.60 (d, J=7.23 Hz, 3H), 1.06-1.19 (m, 3H); LCMS: 75.07percent (198.17, M+H), RT=1.18 min.
At room temperature, to nortropin hydrochloride(8.1g, 50.0mmol)And TEA (20.0g, 200.0mmol)100mL MeCNEthyl 2-bromoacetate (10.0 g, 55.0 mmol) was added to the solution.The reaction was stirred at room temperature overnight.TLC showed the reaction was completed.The reaction system is poured into 500 mL of water.Extract with EA (200 mL x 3).The organic phase is washed twice with saturated brine.Dry anhydrous Na2SO4 and concentrate under reduced pressure to give 9.8 g(yield: 87percent) of the target compound,It is a light yellow oil.
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