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Structure of 922-67-8 * 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 hydrazine hydrate In methanol at 20℃; for 0.5 h; Cooling with ice
Hydrazine hydrate (3.62 mL, 48.53 mmol) was added dropwise to a cooled (ice bath) solution of methyl propiolate (4.23 mL, 47.58 mmol) in methanol (40 mL). The reaction was allowed to stir for 30 min at room temperature. Brine (10 mL) was added and then the methanol was removed under vacuum. The remaining aqueous layer was extracted with EtOAc (4.x.75 mL) and the combined organic layers were dried (MgSO4), filtered and concentrated in vacuo to yield the title compound (44, 3.82 g, 95percent) as a cream solid; δH (400 MHz, DMSO): 5.44 (1H, d, J 2.27 Hz), 7.35 (1H, d, J 2.23 Hz), 9.50 (1H, br s, NH), 11.45 (1H, br s, NH); δC (101 MHz, DMSO): 89.25, 129.71, 160.73; m/z (ES+) 85.04 (100, MH+); HRMS (ESI): MH+, found 85.03951. C3H5N2O requires 85.03964.
66%
With hydrazine hydrate In methanol at 0 - 25℃; for 0.5 h;
To a solution of methyl prop-2-ynoate (150 g, 1785.7 mmol) in MeOH (1500 mL) was added hydrazine hydrate (89.2 g, 1784.0 mmol) dropwise at 0° C. The reaction was stirred at r.t. for 30 min. Saturated aqueous sodium chloride (400 mL) was added, and then methanol was removed under vacuum. The aqueous layer was extracted with EtOAc (3×500 mL), and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to afford 1,2-dihydropyrazol-3-one (99.5 g, 66percent) as a white solid. m/z: ES+[M+H]+ 85.
62%
With hydrazine hydrate In methanol at 20℃; for 0.5 h; Cooling with ice
The compound of hydrazine monohydrate (85percent, 4.81g, 95.2mrnol) was added dropwise to a cooled (ice bath) solution of 92 (8g, 96.2mmol) in methanol (5OmL). The reaction was allowed to stir for 30 minutes at room temperature, then, the solvent was removed under vacuo. Theremaining aqueous layer was extracted with Et0Ac(5mL5) and the combined organic layerswere dried (MgSO4), filtered and concentrated in vacuo to yield the title product 93 (5g, yield:62?/o)1HNIS’iR (400 MHz, DMSO.-d6): ö5.40 (s, 2H), 7.32 (s, 2 H).
Stage #1: With pyridine; N-chloro-succinimide In chloroform at 5 - 20℃; for 0.166667 h; Stage #2: With triethylamine In chloroform at 15 - 18℃; for 0.333333 h;
To a solution of N-chlorosuccinimide (2.67 g, 20 mmol) and pyridine (0.1 mL) in chloroform (18 mL), was added, portionwise, acetaldehyde oxime (1.18 g, 20 mmol), at about 5°C. After complete addition the mixture was stirred at rt for about 10 min and then methyl propiolate (2.22 mL, 25 mmol) was added. Subsequently, a solution of triethylamine (2.92 mL, 21 mmol) in chloroform (3 mL) was added dropwise, at such a rate that the temperature was maintained between 15 and 18° C. After complete addition the mixture was stirred at about 18° C. for about 20 min, then water (15 mL) was added. The layers were separated and the organic layer was washed with water (15 mL), dried (MgSO4), filtered, and concentrated in vacuo. The residue was treated with diethyl ether (20 mL) and the formed precipitate was collected by filtration and dried to give methyl 3-methylisoxazole-5-carboxylate (1.75 g, 12.4 mmol, 62percent) as a brown solid which was used as such: 1H-NMR (CDCl3, Bruker 400 MHz) 2.38 (3H, s); 3.96 (3H, s); 6.80 (1H, s).
Reference：
[1] Journal of the Chemical Society, Chemical Communications, 1991, # 23, p. 1671 - 1672
[2] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1994, # 4, p. 413 - 418
Reference：
[1] Chemical Communications, 2005, # 39, p. 4955 - 4957
22
[ 39687-95-1 ]
[ 922-67-8 ]
[ 2818-07-7 ]
Yield
Reaction Conditions
Operation in experiment
48%
With copper(I) oxide; 1,10-Phenanthroline In 1,4-dioxane at 100℃; for 2 h;
Step A: To a solution of cuprous oxide (832 mg, 5.9 mmol) and 1,10- phenanthroline (2.14 g, 11.89 mmol) in dioxane (200 mL) were added methyl propiolate (10 g, 118.9 mmol) and methyl isocyanoacetate (8.95 g, 98.6 mmol). The reaction mixture was heated at 100 0C for 2 h. The mixture was filtered through Celite, solvents were evaporated, and the residue was purified by silica gel chromatography using a mixture of EtOAc-hexanes as eluent. The isolated product was sonicated with DCM to afford dimethyl lH-pyrrole-2,4-dicarboxylate (8.6 gm, 48 percent).) as a solid. 1H NMR : (300 MHz, DMSCwZ6) δ 12.55 (s, IH), 7.60 (s, IH), 7.10 (s, IH), 3.92 (s, 3H)5 3.90 (s, 3H); LC-MS (ESI) m/z 184 (M+H)+.
Reference：
[1] Molecules, 2005, vol. 10, # 11, p. 1413 - 1418
[2] Journal of the American Chemical Society, 1988, vol. 110, p. 3965
[3] Journal of the Chemical Society, 1925, vol. 127, p. 1205
[4] Organic Letters, 2018, vol. 20, # 13, p. 4023 - 4027
24
[ 67-56-1 ]
[ 802294-64-0 ]
[ 922-67-8 ]
Reference：
[1] Journal of the American Chemical Society, 1984, vol. 106, # 4, p. 1029 - 1040
Reference：
[1] Journal of Heterocyclic Chemistry, 2009, vol. 46, # 1, p. 131 - 133
40
[ 922-67-8 ]
[ 63875-18-3 ]
Reference：
[1] Heterocycles, 1977, vol. 6, p. 933 - 939
[2] Journal of Heterocyclic Chemistry, 1979, vol. 16, p. 1009 - 1015
41
[ 61539-61-5 ]
[ 922-67-8 ]
[ 28478-46-8 ]
Reference：
[1] Journal of the American Chemical Society, 1979, vol. 101, p. 7001 - 7008
42
[ 922-67-8 ]
[ 7341-96-0 ]
Yield
Reaction Conditions
Operation in experiment
95.4%
With ammonia In water at -30 - 30℃; for 0.333333 h;
Example 164; N-Isoxazol-5-yl-4-(4-phenyl-1,3-thiazol-2-yl)piperazine-1-carboxamide; (1) Propiolamide; Methyl propiolate (25 ml, 281 mmol) was added dropwise to conc. aqueous ammonia (25 ml, 281 mmol) at 30°C and the mixture was stirred at -30°C for 20 minutes. The solvent was distilled off under reduced pressure, ether (200 ml) was added to the residue, the mixture was filtered and the filtrate was concentrated to obtain the desired product (18.5 g, 95.4percent) as a solid. 1H-NMR (DMSO-d6) δ; 4.08 (1H, s), 7.62 (1H, br s), 8.08 (1H, br s).
94%
With ammonia In water at -78℃; for 2 h;
Propiolamide (3): Methyl propiolate (2.0 mL, 22.5 mmol) was added to liquid ammonia at -78 °C and stirred for 2 hours. Evaporation at room temperature yielded compound 3 as white crystals (1.46 g, 94percent). mp 58-61°C (lit.[5], 61-62°C); 1H NMR (D2O) δ 3.50 (s, 1H), 4.43 (bs, 2H).
92%
at -60 - -50℃; for 1.33333 h;
Example 1.1: Propiolamide; o'NH2Methyl propioate (5 mL, 55 mmol) was added to ammonium hydroxide (15 mL) at -50 to -60" C over 20 minutes. The reaction mixture was stirred at this temperature for 1 hour. The solvent was evaporated and the residue dried under vacuum to give the product (3.7 g, 92 percent). 1H NMR (300 MHz, CDCI3): δ (ppm) 6.35 (bs, 1H), 5.97 (bsf 1H), 2.88 r 1H).
92%
With ammonia In water at -60 - -50℃; for 1.33333 h;
Example 1.1: Propiolamide; Methyl propioate (5 mL, 55 mmol) was added to ammonium hydroxide (15 ml_) at -50 to -60° C over 20 min. The reaction mixture was stirred at this temperature for 1 hour. The solvent was evaporated and the residue dried under vacuum to give the product (3.7 g, 92percent). 1H NMR (300 MHz, CDCI3): δ (ppm) 6.35 (bs, 1H), 5.97 (bs, 1H), 2.88 (s, 1H).
89%
With ammonia In water at -30℃;
Example 5Synthesis of Compound (IV)Propiolamide; Methyl propiolate (IV) (72 g, 0.86 mol) is slowly dropped into a 33percent ammonia aqueous solution (240 ml) cooled at -30° C. The reaction mixture is kept under stirring at the same temperature for 1 hour, then slowly brought again to about 25° C. The reaction is concentrated under reduced pressure to a residue, which is then taken up with methyl tert-butyl ether (350 ml) and the solution is dried over Na2SO4, then filtered and concentrated under reduced pressure to obtain 53 g of a yellow solid which is not purified but directly used in the subsequent reaction. Yield: 89percent.
89%
With ammonia In water at -30℃;
Example 5; Synthesis of compound (IV): Propiolamide Methyl propiolate (IV) (72 g, 0.86 mol) is slowly dropped into a 33percent ammonia aqueous solution (240 ml) cooled at -30°C. The reaction mixture is kept under stirring at the same temperature for 1 hour, then slowly brought again to about 25°C. The reaction is concentrated under reduced pressure to a residue, which is then taken up with methyl tert-butyl ether (350 ml) and the solution is dried over Na2SO4, then filtered and concentrated under reduced pressure to obtain 53 g of a yellow solid which is not purified but directly used in the subsequent reaction. Yield: 89percent.
72%
With ammonium hydroxide In water at 0℃; for 2.5 h;
Propynamide: To a solution of 30 mL of water and 7.15 g (105 mmol) ammonia (25-28 wt percent in water) is added dropwise 8.4 g (100 mmol) methyl propiolate at 0° C. for 30 minutes. The mixture was stirred for 2 h at 0° C., then acetic acid (2 mL) was added. The mixture was stirred for another 10 minutes and saturated with NaCl, followed by extraction with ethyl acetate (3*40 mL). The combined organic phase was washed with saturated aqueous solution of NaH-CO3 (20 mL), dried over Na2SO4, and removed by rotary evaporation to give product (5.0 g, yield 72percent, purity 99percent by GC). 1H NMR (400 MHz, DMSO-d6) δ 8.07 (1H, s), 7.61 (1H, s), 4.05 (1H, s).
72%
With ammonia In water at 0℃; for 2.5 h;
To a solution of 30 mL of water and 7.15 g (105 mmol) ammonia (25-28 wt percent in water) is added dropwise 8.4 g (100 mmol) methyl propiolate at 0 °C for 30 mins. The mixture was stirred for 2 h at 0 °C, then acetic acid (2 mL) was added. The mixture was stirred for another 10 mins and saturated with NaCI, followed by extraction with ethyl acetate (3 χ 40 mL). The combined organic phase was washed with saturated aqueous solution of NaHC03 (20 mL), dried over Na2S04, and removed by rotary evaporation to give product (5.0 g, yield 72percent, purity 99percent by GC).1H NMR (400 MHz, DMSO-d6) δ 8.07 (1 H, s), 7.61 (1 H, s), 4.05 (1 H, s).
Reference：
[1] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 1, p. 360 - 367
[2] Tetrahedron, 2004, vol. 60, # 31, p. 6665 - 6677
[3] Patent: EP1813606, 2007, A1, . Location in patent: Page/Page column 88
[4] Journal of the American Chemical Society, 2001, vol. 123, # 49, p. 12353 - 12363
[5] Patent: EP1007509, 2004, B1, . Location in patent: Page 6-7
[6] Advanced Synthesis and Catalysis, 2013, vol. 355, # 9, p. 1799 - 1807
[7] Patent: WO2008/9125, 2008, A1, . Location in patent: Page/Page column 55
[8] Patent: WO2009/79765, 2009, A1, . Location in patent: Page/Page column 65
[9] Patent: US2010/234616, 2010, A1, . Location in patent: Page/Page column 3-4
[10] Patent: EP2230234, 2010, A1, . Location in patent: Page/Page column 6
[11] Journal of Organic Chemistry, 1998, vol. 63, # 15, p. 5050 - 5058
[12] Patent: US2014/66655, 2014, A1, . Location in patent: Paragraph 0033; 0034
[13] Patent: WO2014/37308, 2014, A1, . Location in patent: Page/Page column 5
[14] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1910, vol. 151, p. 946[15] Annales de Chimie (Cachan, France), 1920, vol. <9>14, p. 51
[16] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1989, p. 1007 - 1011
[17] Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 8, p. 2527 - 2534
[18] Patent: WO2003/76436, 2003, A1, . Location in patent: Page/Page column 69
[19] Patent: EP1595881, 2005, A1, . Location in patent: Page/Page column 49
[20] Patent: WO2012/45196, 2012, A1, . Location in patent: Page/Page column 77
[21] Organic Process Research and Development, 2014, vol. 18, # 11, p. 1567 - 1570
[22] Chemistry - A European Journal, 2018, vol. 24, # 11, p. 2776 - 2784
43
[ 922-67-8 ]
[ 23680-40-2 ]
Yield
Reaction Conditions
Operation in experiment
98%
With N-Bromosuccinimide; silver nitrate In acetone at 20 - 32℃;
To methyl propiolate (60 g, 713.6 mmol) dissolved in acetone (2 L) was added N- bromosuccinimide (147.22 g, 827.13 mmol), followed by silver nitrate (12.12 g, 71 .37 mmol). A slight exotherm was observed with the reaction temperature increasing from 21 - 32 °C before the reaction mixture was left to stir at room temperature overnight. The resulting grey suspension was evaporated to dryness in vacuo, pentane added (100 ml_) and filtered through Celite®, washing through with more pentane. This procedure was carried out twice more and then the combined filtrates evaporated in vacuo to give 1 13 g of methyl 3-bromopropiolate (98percent yield) containing approximately 10percent of starting material.1H NMR (400 MHz, CDCI3) δ ppm 3.78 (s, 3 H).
88%
With N-Bromosuccinimide; silver nitrate In acetone at 20℃; for 6 h;
[1067] Methyl propiolate (52 ml, 0.583 mole) is combined with recrystallized N-bromo-succinimide (120 g, 0.674 mole) in 1,700 ml acetone under nitrogen. The solution is treated with silver nitrate (9.9 g, 0.0583 mole) neat in a single lot and the reaction is stirred 6 h at RT. The acetone is removed under reduced pressure (25° C., bath temperature) to provide a gray slurry. The slurry is washed with 2.x.200 ml hexane, the gray solid is removed by filtration, and the filtrate is concentrated in vacuo to provide 95 g of a pale yellow oily residue. The crude material was distilled via short path under reduced pressure (65° C., about 25 mm Hg) into a dry ice/acetone cooled receiver to give 83.7 g (88percent) of methyl-3-bromo-propiolate as a pale yellow oil. Anal. calc'd for C4H3BrO2: C, 29.48; H, 1.86. Found: C, 29.09; H, 1.97.
88%
With N-Bromosuccinimide; silver nitrate In acetone at 20℃; for 6 h;
Methyl propiolate (52 ml, 0.583 mole) is combined with recrystallized N-bromo-succinimide (120 g, 0.674 mole) in 1,700 ml acetone under nitrogen. The solution is treated with silver nitrate (9.9 g, 0.0583 mole) neat in a single lot and the reaction is stirred 6 h at RT. The acetone is removed under reduced pressure (25° C., bath temperature) to provide a gray slurry. The slurry is washed with 2.x.200 ml hexane, the gray solid is removed by filtration, and the filtrate is concentrated in vacuo to provide 95 g of a pale yellow oily residue. The crude material was distilled via short path under reduced pressure (65° C., about 25 mm Hg) into a dry ice/acetone cooled receiver to give 83.7 g (88percent) of methyl-3-bromo-propiolate as a pale yellow oil. Anal. calc'd for C4H3BrO2: C, 29.48; H, 1.86. Found: C, 29.09; H, 1.97.
88%
With N-Bromosuccinimide In acetone at 20℃; for 6 h;
Methyl propiolate (52 ml, 0.583 mol) is combined with recrystallized N- BROMO-SUCCINIMIDE (120 g, 0.674 mol) in 1,700 ml acetone under nitrogen. The solution is treated with silver nitrate (9.9 g, 0.0583 mol) neat in a single lot and the reaction is stirred 6 h at RT. The acetone is removed under reduced pressure (25°C, bath temperature) to provide a gray slurry. The slurry is washed with 2 x 200 ML hexane, the gray solid is removed by filtration, and the filtrate is concentrated in vacuo to provide 95 g of a pale yellow oily residue. The crude material is distilled via short path under reduced pressure (65°C, about 25 mm Hg) into a dry ice/acetone cooled receiver to give 83.7 g (88percent) of methyl-3-bromo-propiolate as a pale yellow oil. Anal. calc'd for C4H3BR02 : C, 29.48 ; H, 1.86. Found: C, 29.09 ; H, 1.97
88%
With N-Bromosuccinimide; silver nitrate In acetone at 20℃; for 6 h; Inert atmosphere
An alternate procedure for the bromination using methyl propiolate is described in a 2003 US patent publication US2003/236270 A1. Methyl propiolate (52 ml, 0.583 mol) is combined with recrystallized N-bromo-succinimide (120 g, 0.674 mol) in 1,700 ml acetone under nitrogen. The solution is treated with silver nitrate (9.9 g, 0.0583 mol) neat in a single lot and the reaction is stirred 6 h at RT. The acetone is removed under reduced pressure (25° C., bath temperature) to provide a gray slurry. The slurry is washed with 2×200 ml hexane, the gray solid is removed by filtration, and the filtrate is concentrated in vacuo to provide 95 g of a pale yellow oily residue. The crude material was distilled via short path under reduced pressure (65° C., about 25 mm Hg) into a dry ice/acetone cooled receiver to give 83.7 g (88percent) of methyl-3-bromo-propiolate as a pale yellow oil
83%
With N-Bromosuccinimide; silver nitrate In acetone at 0 - 20℃; for 4.5 h; Inert atmosphere
To a stirred solution of methyl propiolate (50 g, 594 mmol, Spectrochem) in dry acetone(300 mL), silver nitrate (1.01 g, 5.94 mmol, Spectrochem) was added and cooled to 0 00 under N2 atmosphere. N-bromo succinimide (116 g, 654 mmol, Spectrochem) was added in portions over 30 mm and allowed to warm to room temperature. Reaction mixture was allowed to stir at RT for 4 h. The reaction mixture was concentrated and taken up in hexane and filtered through celite bed. The filtrate was concentrated in Rota-evaporator and residue obtained was purified by distillation to get the titled compound as colorless liquid (81 g, 83percent). 1H NMR (400 MHz, CDCI3): 6 3.78 (s, 3H).
83%
With N-Bromosuccinimide; silver nitrate In acetone at 0 - 20℃; Inert atmosphere
Step 1: Bromo-propynoic acid methyl ester To a stirred solution of methyl propiolate (50 g, 594 mmol, Spectrochem) in dry acetone (300 mL), silver nitrate (1.01 g, 5.94 mmol, Spectrochem) was added and cooled to 0 °C under N2 atmosphere. N-bromo succinimide (116 g, 654 mmol, Spectrochem) was added in portions over 30 min and allowed to warm to room temperature. Reaction mixture was allowed to stir at RT for 4 h. The reaction mixture was concentrated and taken up in hexane and filtered through celite bed. The filtrate was concentrated in Rota-evaporator and residue obtained was purified by distillation to get the titled compound as colorless liquid (81 g, 83percent). 1H NMR (400 MHz, CDCl3): δ 3.78 (s, 3H).
72.3%
Stage #1: With silver nitrate In acetone at 20℃; for 0.166667 h; Inert atmosphere Stage #2: With N-Bromosuccinimide In acetone at 20℃; for 2 h;
To a solution of S1 (100.0 g, 1.19 mol) in acetone (1.5 L) was added AgNO3 (202.2 g, 1.19 mol) at room temperature. After stirring for 10 min, NBS (243.6 g, 1.37 mol) was added. Then the reaction mixture was stirred at room temperature for additional 2 hrs. The reaction mixture was filtered and the filtrate was evaporated in vacuo to afford crude product, which was further purified by distilled (10 mmHg, 85~90 oC) to afford S2 as yellow oil (210.0 g, yield: 72.3percent). 1H NMR (400MHz, CHLOROFORM-d): δ 3.80 (s, 3H).
49%
With N-Bromosuccinimide; silver nitrate In [(2)H6]acetone at 20℃; for 20 h;
Into a 250-mL round-bottom flask, was placed a solution of methyl prop-2-ynoate (1) (4.9 g, 58.28 mmol, 1.00 equiv) in acetone (dried over magnesium sulfate) (120 mL). NBS (15 g, 84.28 mmol, 1.40 equiv) and AgNO3 (1.0 g, 0.10 equiv) were added to the reaction. The resulting solution was stirred for 20 h at room temperature. The solids were filtered out. The resulting mixture was concentrated under vacuum. The crude product was purified by distillation and the fraction was collected at 40-55° C. This provided 4.7 g (49percent) of methyl 3-bromoprop-2-ynoate (2) as a colorless oil.
Reference：
[1] Patent: WO2015/166373, 2015, A1, . Location in patent: Page/Page column 148
[2] Organic Syntheses, 1997, vol. 74, p. 212 - 212
[3] Synthetic Communications, 1992, vol. 22, # 4, p. 567 - 572
[4] Patent: US2003/236264, 2003, A1, . Location in patent: Page 44
[5] Patent: US2003/236270, 2003, A1, . Location in patent: Page 33
[6] Patent: WO2004/52889, 2004, A1, . Location in patent: Page 52-53
[7] Patent: US2015/329554, 2015, A1, . Location in patent: Paragraph 0372
[8] Patent: WO2014/198808, 2014, A1, . Location in patent: Page/Page column 100
[9] Patent: EP2813505, 2014, A1, . Location in patent: Paragraph 0105
[10] European Journal of Organic Chemistry, 2017, vol. 2017, # 1, p. 138 - 148
[11] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 22, p. 4979 - 4984
[12] Chemistry--A European Journal, 2014, vol. 20, # 35, p. 11101 - 11110,10
[13] Patent: US2015/141465, 2015, A1, . Location in patent: Paragraph 0342
[14] Annales de Chimie (Cachan, France), 1957, vol. <13> 2, p. 819,861, 862
[15] Tetrahedron, 2006, vol. 62, # 50, p. 11635 - 11644
[16] Tetrahedron, 2007, vol. 63, # 13, p. 2888 - 2900
[17] Journal of the American Chemical Society, 2007, vol. 129, # 2, p. 441 - 449
[18] Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 15, p. 5262 - 5274
[19] Patent: WO2009/55331, 2009, A2, . Location in patent: Page/Page column 201
[20] Organic Letters, 2014, vol. 16, # 11, p. 3024 - 3027
[21] Tetrahedron Letters, 2014, vol. 55, # 38, p. 5302 - 5305
[22] Advanced Synthesis and Catalysis, 2015, vol. 357, # 4, p. 719 - 726
[23] Patent: WO2018/118838, 2018, A1, . Location in patent: Paragraph 001667; 001668
44
[ 128-08-5 ]
[ 922-67-8 ]
[ 23680-40-2 ]
Yield
Reaction Conditions
Operation in experiment
88%
With silver nitrate In acetone at 20℃; for 6 h;
Methyl propiolate (52 ml, 0.583 mol) is combined with recrystallized N- bromo-succinimide (120 g, 0.674 mol) in 1,700 ml acetone under nitrogen. The solution is treated with silver nitrate (9.9 g, 0.0583 mol) neat in a single lot and the reaction is stirred 6 h at RT. The acetone is removed under reduced pressure (25C, bath temperature) to provide a gray slurry. The slurry is washed with 2 x 200 ml hexane, the gray solid is removed by filtration, and the filtrate is concentrated in vacuo to provide 95 g of a pale yellow oily residue. The crude material is distilled via short path under reduced pressure (65C, about 25 mm Hg) into a dry ICE/ACETONE cooled receiver to give 83.7 g (88percent) of methyl-3-bromo-propiolate as a pale yellow oil. Anal. calc'd for C4H3BRO2 : C, 29.48 ; H, 1.86. Found: C, 29.09 ; H, 1.97.
15g (178mmol) Methyl propiolate and 26.3g (196mmol) Lithium iodide are dissolved in 178 mL of acetic acid, stir at 70 ° C for 11 h and add the 900 mL of water with stirring for quench the reaction, the reaction solution is neutralized with K2C03 until there is no C02 gas generated. Extracted three times with ether, and the combined organic phases were washed three times with saturated brine, dried over anhydrous sodium sulfate, after that filter, the filtrate has been concentrated and the resulting residue was purified by column chromatography (petroleum ether: ethyl acetate = 30: 1), than we get 32.4g light yellow oily liquid of (Z) -3-iodo-2-methyl acrylate (4), yield 89percent
89%
at 70℃; for 11 h; Inert atmosphere
A mixture of methyl propiolate (15.0 g, 178 mmol) and LiI (26.3 g, 196 mmol) in acetic acid (178 mL) was stirred and heated at 70. The reaction was monitored by GC-Ms (after neutralization). After 11 h, water (900 mL) was added and neutralized with solid K2CO3 until no CO2 was evolved and then extracted with ether (1.8 L x 3). The extracts were dried over anhydrous Na2SO4 andconcentrated in vacuo to afford a crude oil, which was purified by silica gel column chromatography (PE/EA = 30/1) to afford(Z)-methyl 3-iodoacrylate 7 (32.36 g, 89percent) as a pale yellow oil.
58%
With sodium iodide In acetic acid at 115℃;
The synthesis of the polyene chains of different lengths began with the treatment of methyl propiolate 11 with sodium iodide in acetic acid(23, 24) to provide Z-iodoacrylate 12 in 58percent yield and 100 percent stereoselectivity.
Reference：
[1] Journal of the American Chemical Society, 2004, vol. 126, # 32, p. 9926 - 9927
[2] Chemistry - A European Journal, 2014, vol. 20, # 28, p. 8594 - 8598
[3] Journal of Organic Chemistry, 2007, vol. 72, # 7, p. 2525 - 2532
[4] Tetrahedron, 2009, vol. 65, # 40, p. 8418 - 8427
[5] Angewandte Chemie - International Edition, 2015, vol. 54, # 34, p. 9958 - 9962[6] Angew. Chem., 2015, vol. 127, p. 10096 - 10100,5
[7] Tetrahedron Letters, 1996, vol. 37, # 49, p. 8949 - 8952
[8] European Journal of Organic Chemistry, 2016, vol. 2016, # 12, p. 2110 - 2114
[9] Tetrahedron, 2004, vol. 60, # 31, p. 6665 - 6677
[10] Organic and Biomolecular Chemistry, 2015, vol. 13, # 4, p. 1225 - 1233
[11] Journal of Organic Chemistry, 1992, vol. 57, # 2, p. 709 - 713
[12] Organic and Biomolecular Chemistry, 2010, vol. 8, # 15, p. 3509 - 3517
[13] Organic Letters, 2015, vol. 17, # 4, p. 948 - 951
[14] Patent: CN106008164, 2016, A, . Location in patent: Paragraph 0047; 0048
[15] Chinese Chemical Letters, 2017, vol. 28, # 5, p. 1035 - 1038
[16] Journal of Natural Products, 2008, vol. 71, # 5, p. 898 - 901
[17] Organic Letters, 2011, vol. 13, # 4, p. 748 - 751
[18] Canadian Journal of Chemistry, 1994, vol. 72, # 8, p. 1816 - 1819
[19] Chemistry (Weinheim an der Bergstrasse, Germany), 2001, vol. 7, # 24, p. 5286 - 5298
[20] Tetrahedron Letters, 1991, vol. 32, # 39, p. 5329 - 5332
[21] Journal of the American Chemical Society, 2016, vol. 138, # 7, p. 2126 - 2129
[22] Organic Letters, 2005, vol. 7, # 10, p. 1939 - 1942
[23] Patent: WO2012/76842, 2012, A1, . Location in patent: Page/Page column 33-34
[24] Organic Letters, 2009, vol. 11, # 3, p. 657 - 660
[25] Organic Letters, 2015, vol. 17, # 3, p. 520 - 523
[26] Patent: WO2015/119899, 2015, A1, . Location in patent: Page/Page column 109; 110
[27] Organic Letters, 2016, vol. 18, # 5, p. 1162 - 1165
[28] Journal of the American Chemical Society, 2018, vol. 140, # 27, p. 8415 - 8419
Reference：
[1] Journal of Heterocyclic Chemistry, 1989, vol. 26, p. 1739 - 1745
[2] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 21, p. 6122 - 6126
59
[ 55899-02-0 ]
[ 922-67-8 ]
[ 127717-19-5 ]
[ 127717-18-4 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 1989, vol. 26, p. 1739 - 1745
[2] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 21, p. 6122 - 6126
60
[ 55899-13-3 ]
[ 922-67-8 ]
[ 1062368-71-1 ]
[ 1062368-70-0 ]
Yield
Reaction Conditions
Operation in experiment
42%
Stage #1: With triethylamine In tetrahydrofuran; water at 30℃; for 0.00861111 h; Flow reactor Stage #2: at 90℃; for 0.0333333 h; Flow reactor
In contrast to the other examples, only the cyclisation reaction was performed in flow. TheVapourtec R-series was equipped with three pumps. MSH 1 (2 g, 71 percent damp solid, 6.60 mmol)1 and 3-bromopyridine 2a (1.04 g, 6.60 mmol) were dissolved together in THF/H2O (1:1, 33 mL, 0.2 M). Triethylamine (0.92mL, 6.60 mmol) dissolved in THF (8.25 mL, 0.8 M) was mixed with the first inlet via a Y-piece with flow rates of2.86 mL/min and 1.07 mL/min respectively (1.5 eq of triethylamine). Methyl propiolate 4a (0.56 g, 6.60 mmol) wasdissolved in THF (8.25 mL, 0.8 M) and introduced in a second Y-piece at flow rate 1.07 mL/min (1.5 eq of methylpropiolate). The system solvent was THF. The PFA reactor coils, with volumes 2 mL and 10 mL respectively, were setto temperatures 30 °C and 90 °C respectively. The reaction mixture from the first two inlet streams spent 31 secondsresidency time in the first reactor and then 2 minutes residency time in the second reactor. The operating pressure was7.5 bar with 3 pumps. The reaction set-up was flushed afterwards with 33 percent HCl (conc.) in MeOH followed by IPA.The total flow rate at the outlet was 5 mL/min. The outlet stream (40 mL, collected over 8 minutes) was concentratedin vacuo to remove the THF and then diluted with EtOAc (250 mL) and brine (100 mL). The organic layer wasseparated and the aqueous phase washed twice more with EtOAc (2 x 200 mL). The combined organic layers weredried over anhydrous sodium sulfate and concentrated in vacuo to give a dark red oil.The crude material was purified by column chromatography on a 100 g silica column using the Biotage machine anda gradient from 7 to 60 percent EtOAc/heptane. 5a eluted first from the column. Pale red solid (0.43 g, 8 min collectiontime, 42 percent). 1H NMR (400 MHz, d6-DMSO) 4.10 (3H, s, CH3), 7.79 (1H, d, J = 8 Hz, ArH), 8.26 (1H, d, J = 8 Hz,ArH), 8.73 (1H, s, ArH), 9.56 (1H, s, ArH) ppm. 13C NMR (101 MHz, d6-DMSO) 51.2, 103.3, 108.1, 118.8, 130.3,131.4, 138.7, 144.6, 162.6 ppm. HRMS (FAB) calcd for C9H8O2N2Br 254.97637, found 254.97636/256.97421.5b eluted second from the column. Pale yellow solid. (0.14 g, 8 min collection time, 14 percent). 1H NMR (400 MHz, d6-DMSO) 3.82 (3H, s, CH3), 7.06 (1H, dd, J = 4 and 4 Hz, ArH), 7.87 (1H, d, J = 4 Hz, ArH), 8.50 (1H, s, ArH), 8.93(1H, d, J = 4 Hz, ArH) ppm. 13C NMR (101 MHz, d6-DMSO) 51.3, 104.7, 109.8, 114.4, 129.8, 132.8, 137.6, 145.6,161.9 ppm. HRMS (FAB) calcd for C9H8O2N2Br 254.97637, found 254.97638/256.97424
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 15, p. 4388 - 4392
63
[ 106308-60-5 ]
[ 922-67-8 ]
[ 217448-86-7 ]
Yield
Reaction Conditions
Operation in experiment
94%
With ascorbic acid In ethanol; water at 25℃;
Example 7Synthesis of Compound (II)Methyl 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxylate; 2,6-Difluorobenzyl azide (3.0 g, 17.7 mmoles) is suspended in ethanol (30 ml), then methyl propiolate (IV) (1.6 g, 19.6 mmoles), ascorbic acid (317 mg, 1.8 mmoles) and CuSO4 pentahydrate (50 mg, 0.18 mmole) are added. The reaction mixture is kept at 25° C. under stirring overnight. The mixture is concentrated, taken up with ethyl acetate and washed with an ammonia diluted solution. The organic phase is dried, filtered, concentrated under reduced pressure. A crystalline white solid is obtained in 94percent yield.1H NMR (400 MHz, DMSO-d6), δ ppm: 8.86 (s, 1H), 7.52 (m, 1H), 7.27-7.12 (m, 2H), 5.74 (s, 2H), 3.83 (s, 3H).
94%
With ascorbic acid In ethanol at 25℃;
Example 7; Synthesis of compound (II): Methyl 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxylate 2,6-Difluorobenzyl azide (3.0 g, 17.7 mmoles) is suspended in ethanol (30 ml), then methyl propiolate (IV) (1.6 g, 19.6 mmoles), ascorbic acid (317 mg, 1.8 mmoles) and CuSO4 pentahydrate (50 mg, 0.18 mmole) are added. The reaction mixture is kept at 25°C under stirring overnight. The mixture is concentrated, taken up with ethyl acetate and washed with an ammonia diluted solution. The organic phase is dried, filtered, concentrated under reduced pressure. A crystalline white solid is obtained in 94percent yield. 1H NMR (400 MHz, DMSO-d6), δ ppm: 8.86 (s, 1 H), 7.52 (m, 1H), 7.27-7.12 (m, 2H), 5.74 (s, 2H), 3.83 (s, 3H).
With triethylamine In dichloromethane at 0 - 20℃; for 12 h;
To a stirred solution Z (8 g, 34.17 mmol) in dry CH2CI2 (100 mL) under inert atmosphere were added triethylamine (5.38 mL, 101.19 mmol) and methylpropiolate (3.05 mL, 34.17 mmol) dropwise at 0 °C. The reaction was warmed to RT and stirred for 12 h. After complete consumption of the starting material, the reaction mass was diluted with water (50 mL) and the compound was extracted with (( (3x50 mL). The combined organic extracts were washed with water (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude. The crude was purified by silica gel column chromatography eluting with 8-10percent EtOAc/hexanes to afford DG (3.1 g, 32percent) as an off- white solid. *H NMR (400 MHz, CDC13): δ 7.70 (d, / = 8.0 Hz, 2H), 7.62 (d, / = 8.4 Hz, 2H), 7.23 (s, 1H), 4.00 (s, 3H).
With N-Bromosuccinimide; silver nitrate; In acetone; at 20 - 32℃;
To methyl propiolate (60 g, 713.6 mmol) dissolved in acetone (2 L) was added N- bromosuccinimide (147.22 g, 827.13 mmol), followed by silver nitrate (12.12 g, 71 .37 mmol). A slight exotherm was observed with the reaction temperature increasing from 21 - 32 C before the reaction mixture was left to stir at room temperature overnight. The resulting grey suspension was evaporated to dryness in vacuo, pentane added (100 ml_) and filtered through Celite, washing through with more pentane. This procedure was carried out twice more and then the combined filtrates evaporated in vacuo to give 1 13 g of methyl 3-bromopropiolate (98% yield) containing approximately 10% of starting material.1H NMR (400 MHz, CDCI3) delta ppm 3.78 (s, 3 H).
88%
With N-Bromosuccinimide; silver nitrate; In acetone; at 20℃; for 6h;
[1067] Methyl propiolate (52 ml, 0.583 mole) is combined with recrystallized N-bromo-succinimide (120 g, 0.674 mole) in 1,700 ml acetone under nitrogen. The solution is treated with silver nitrate (9.9 g, 0.0583 mole) neat in a single lot and the reaction is stirred 6 h at RT. The acetone is removed under reduced pressure (25 C., bath temperature) to provide a gray slurry. The slurry is washed with 2×200 ml hexane, the gray solid is removed by filtration, and the filtrate is concentrated in vacuo to provide 95 g of a pale yellow oily residue. The crude material was distilled via short path under reduced pressure (65 C., about 25 mm Hg) into a dry ice/acetone cooled receiver to give 83.7 g (88%) of methyl-3-bromo-propiolate as a pale yellow oil. Anal. calc'd for C4H3BrO2: C, 29.48; H, 1.86. Found: C, 29.09; H, 1.97.
88%
With N-Bromosuccinimide; silver nitrate; In acetone; at 20℃; for 6h;
Methyl propiolate (52 ml, 0.583 mole) is combined with recrystallized N-bromo-succinimide (120 g, 0.674 mole) in 1,700 ml acetone under nitrogen. The solution is treated with silver nitrate (9.9 g, 0.0583 mole) neat in a single lot and the reaction is stirred 6 h at RT. The acetone is removed under reduced pressure (25 C., bath temperature) to provide a gray slurry. The slurry is washed with 2×200 ml hexane, the gray solid is removed by filtration, and the filtrate is concentrated in vacuo to provide 95 g of a pale yellow oily residue. The crude material was distilled via short path under reduced pressure (65 C., about 25 mm Hg) into a dry ice/acetone cooled receiver to give 83.7 g (88%) of methyl-3-bromo-propiolate as a pale yellow oil. Anal. calc'd for C4H3BrO2: C, 29.48; H, 1.86. Found: C, 29.09; H, 1.97.
88%
With N-Bromosuccinimide;silver nitrate; In acetone; at 20℃; for 6h;
Methyl propiolate (52 ml, 0.583 mol) is combined with recrystallized N- BROMO-SUCCINIMIDE (120 g, 0.674 mol) in 1,700 ml acetone under nitrogen. The solution is treated with silver nitrate (9.9 g, 0.0583 mol) neat in a single lot and the reaction is stirred 6 h at RT. The acetone is removed under reduced pressure (25C, bath temperature) to provide a gray slurry. The slurry is washed with 2 x 200 ML hexane, the gray solid is removed by filtration, and the filtrate is concentrated in vacuo to provide 95 g of a pale yellow oily residue. The crude material is distilled via short path under reduced pressure (65C, about 25 mm Hg) into a dry ice/acetone cooled receiver to give 83.7 g (88%) of methyl-3-bromo-propiolate as a pale yellow oil. Anal. calc'd for C4H3BR02 : C, 29.48 ; H, 1.86. Found: C, 29.09 ; H, 1.97
88%
With N-Bromosuccinimide; silver nitrate; In acetone; at 20℃; for 6h;Inert atmosphere;
An alternate procedure for the bromination using methyl propiolate is described in a 2003 US patent publication US2003/236270 A1. Methyl propiolate (52 ml, 0.583 mol) is combined with recrystallized N-bromo-succinimide (120 g, 0.674 mol) in 1,700 ml acetone under nitrogen. The solution is treated with silver nitrate (9.9 g, 0.0583 mol) neat in a single lot and the reaction is stirred 6 h at RT. The acetone is removed under reduced pressure (25 C., bath temperature) to provide a gray slurry. The slurry is washed with 2×200 ml hexane, the gray solid is removed by filtration, and the filtrate is concentrated in vacuo to provide 95 g of a pale yellow oily residue. The crude material was distilled via short path under reduced pressure (65 C., about 25 mm Hg) into a dry ice/acetone cooled receiver to give 83.7 g (88%) of methyl-3-bromo-propiolate as a pale yellow oil
83%
With N-Bromosuccinimide; silver nitrate; In acetone; at 0 - 20℃; for 4.5h;Inert atmosphere;
To a stirred solution of methyl propiolate (50 g, 594 mmol, Spectrochem) in dry acetone(300 mL), silver nitrate (1.01 g, 5.94 mmol, Spectrochem) was added and cooled to 0 00 under N2 atmosphere. N-bromo succinimide (116 g, 654 mmol, Spectrochem) was added in portions over 30 mm and allowed to warm to room temperature. Reaction mixture was allowed to stir at RT for 4 h. The reaction mixture was concentrated and taken up in hexane and filtered through celite bed. The filtrate was concentrated in Rota-evaporator and residue obtained was purified by distillation to get the titled compound as colorless liquid (81 g, 83%). 1H NMR (400 MHz, CDCI3): 6 3.78 (s, 3H).
83%
With N-Bromosuccinimide; silver nitrate; In acetone; at 0 - 20℃;Inert atmosphere;
Step 1: Bromo-propynoic acid methyl ester To a stirred solution of methyl propiolate (50 g, 594 mmol, Spectrochem) in dry acetone (300 mL), silver nitrate (1.01 g, 5.94 mmol, Spectrochem) was added and cooled to 0 C under N2 atmosphere. N-bromo succinimide (116 g, 654 mmol, Spectrochem) was added in portions over 30 min and allowed to warm to room temperature. Reaction mixture was allowed to stir at RT for 4 h. The reaction mixture was concentrated and taken up in hexane and filtered through celite bed. The filtrate was concentrated in Rota-evaporator and residue obtained was purified by distillation to get the titled compound as colorless liquid (81 g, 83%). 1H NMR (400 MHz, CDCl3): delta 3.78 (s, 3H).
72.3%
To a solution of S1 (100.0 g, 1.19 mol) in acetone (1.5 L) was added AgNO3 (202.2 g, 1.19 mol) at room temperature. After stirring for 10 min, NBS (243.6 g, 1.37 mol) was added. Then the reaction mixture was stirred at room temperature for additional 2 hrs. The reaction mixture was filtered and the filtrate was evaporated in vacuo to afford crude product, which was further purified by distilled (10 mmHg, 85~90 oC) to afford S2 as yellow oil (210.0 g, yield: 72.3%). 1H NMR (400MHz, CHLOROFORM-d): delta 3.80 (s, 3H).
49%
With N-Bromosuccinimide; silver nitrate; In [(2)H6]acetone; at 20℃; for 20h;
Into a 250-mL round-bottom flask, was placed a solution of methyl prop-2-ynoate (1) (4.9 g, 58.28 mmol, 1.00 equiv) in acetone (dried over magnesium sulfate) (120 mL). NBS (15 g, 84.28 mmol, 1.40 equiv) and AgNO3 (1.0 g, 0.10 equiv) were added to the reaction. The resulting solution was stirred for 20 h at room temperature. The solids were filtered out. The resulting mixture was concentrated under vacuum. The crude product was purified by distillation and the fraction was collected at 40-55 C. This provided 4.7 g (49%) of methyl 3-bromoprop-2-ynoate (2) as a colorless oil.
With N-Bromosuccinimide;silver nitrate; In acetone; for 22h;
Methyi propioiate ( 10.Og, 1 18mmol), N-bromosuccinimide (21.2g, 1 19mmol) and AgXO3 (0.2Og, 1.2mmol) were combined in acetone (60 mL). The mixture was stirred 22 hours, filtered, concentrated, taken up in hexane, and filtered. The filtrate was concentrated in vacuo and the residue obtained was purified using Kugelrohr distillation to provide compound 7OB as a yellow oil.
The starting methyl 3-bromopropiolate 2 was synthesized according to the reported method.1 In a 200 mL, one necked, round-bottomed flask is placed 30 mmol of the corresponding alkyne in 60 mL of acetone. To the solution at room temperature was added 3.0 mmol of silver nitrate. After 5 min, 45 mmol of NBS was added. The mixture was stirred for 2 h, and the solids were filtered off on a pad of silica, which was washed several times with Et2O. After rotary evaporation of the acetone, the residue was purified bybulb-to-bulb distillation (oven temp. 80-90 C, 25 torr) to afford 2 as colorless oil.
With N-Bromosuccinimide; silver nitrate; In acetone; at 20℃;
To a solution of methyl propiolate, Compound 180A, (5.0 g, 59.5 mmol) in acetone (170 mL) was added NBS (12.2 g, 68.4 mmol) and AgNO3 (1.0 g, 5.95 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to furnish Compound 180B. ?H-NIVIR (CDC13, 400 IVIHz):(5(ppm) 3.75 (s, 3H).
To a stirring solution of methyl propiolate (200 g, 2.38 mol, 198 mL) in acetone (2.50 L) was added AgN03(36.4 g, 214 mmol, 36.0 mL). After 5 min, NBS (445 g, 2.50 mol) was added portionwise, and the reaction mixture was stirred at 25 C for 12 h. The reaction mixture was filtered, the filtrate was concentrated, and the residue was triturated with 10% EtOAc/PE (1500 mL), and the filtrate was concentrated again. The residue was purified by column chromatography (0-5% EtOAc/PE) to give methyl 3-bromopropiolate (1 b) as a yellow oil which was used for the next step directly.
Azide 1a, 5.7 g (0.2 mol), was cooled to -20C, and 8.2 mL (0.1 mol) of ester 2c in 80 mL of benzene was quickly added. The reactor was hermetically closed, and the mixture was vigorously stirred for 48 h. The solvent was evaporated to leave a mixture of triazoles 3c and 4a at a ratio of 9 : 1. The pure products were isolated by column chroma-tography.
With trimethylsilylazide; In methanol; at 105℃; for 72h;
Methylpropiolate (20 g) and trimethylsilyl azide (68.6 g) were added to a pressure-resistant tube, and the mixture was stirred for 72 hours at 105°C. After allowing the mixture to be cooled to room temperature, methanol was added to the mixture, and the solvent was removed under reduced pressure, and the obtained residue was washed with diethylether/methanol to give methyl 1,2,3-triazole-4-carboxylate (22.7 g). 1H-NMR (200 MHz, CDCl3) delta 3.87 (3H, s), 8.57 (1H, m)
Methyl propiolate (52 ml, 0.583 mol) is combined with recrystallized N- bromo-succinimide (120 g, 0.674 mol) in 1,700 ml acetone under nitrogen. The solution is treated with silver nitrate (9.9 g, 0.0583 mol) neat in a single lot and the reaction is stirred 6 h at RT. The acetone is removed under reduced pressure (25C, bath temperature) to provide a gray slurry. The slurry is washed with 2 x 200 ml hexane, the gray solid is removed by filtration, and the filtrate is concentrated in vacuo to provide 95 g of a pale yellow oily residue. The crude material is distilled via short path under reduced pressure (65C, about 25 mm Hg) into a dry ICE/ACETONE cooled receiver to give 83.7 g (88%) of methyl-3-bromo-propiolate as a pale yellow oil. Anal. calc'd for C4H3BRO2 : C, 29.48 ; H, 1.86. Found: C, 29.09 ; H, 1.97.
Preparation 10b; Preparation of 4-ethenyl-8-fluoro-6-(methyloxy)quinoline; a) 8-Fluoro-6-methoxy-quinolin-4-ol; 2-Fluoro-4-methoxyphenylamine (3.8Og, 26.7 mmole) and methyl propiolate (2.37ml, 0.267 mole) in methanol (100ml) was stirred for 72 hours at room temperature, then heated at 5O0C for 24 hours. It was evaporated and the product purified by chromatography on silica gel (dichloromethane) to give a solid (1.66g), a portion of which was recrystallised from dichloromethane-hexane. The unsaturated ester (0.96g) in warm Dowtherm A (5ml) was added over 3 minutes to refluxing Dowtherm A (15ml), and after a further 20 minutes at reflux the mixture was cooled and poured into diethyl ether. The precipate was filtered to give the title compound (0.50 g, 61percent). MS (ES) m/e 196 (M+H)+.
<strong>[458-52-6]2-Fluoro-4-methoxy-phenylamine</strong> (3.80g, 26.7mmol) and methyl propiolate (2. 37ml, 0. 267mol) in methanol (100ml) was stirred for 72 hours at room temperature, then heated at 50°C for 24 hours. It was evaporated and the product purified by chromatography on silica gel (dichloromethane) to give a solid (1.66g), a portion of which was recrystallised from dichloromethane-hexane. The unsaturated ester (0.96g) in warm Dowtherm A (5ml) was added over 3 minutes to refluxing Dowtherm A (15ml), and after a further 20 minutes at reflux the mixture was cooled and poured into diethyl ether. The precipate was filtered to give the title compound (0. 50g, 61percent)
In potassium tert-butylate; water; tert-butyl alcohol;
1.b 1-(4-Chlorophenyl)-3-hydroxypyrazole A solution of 57.5 g of 4-chlorophenylhydrazine hydrosulfate in 1,000 ml of tert-butanol was first treated in portions with 100.8 g of potassium tert-butoxide and then (after stirring for 10 min) in the course of 45 min at 45° C.-50° C. with a solution of 27.7 g of methyl propiolate in 90 ml of tertbutanol. After 1 h at boiling point, the mixture was allowed to cool and the solvent was removed under reduced pressure. The residue thus obtained was dissolved in 1,200 ml of water. The aqueous phase was first washed with methylene chloride and then acidified, the product being deposited as a solid. 47.6 g of the title compound were obtained, m.p.: 185°-187° C.
(a) 8-Fluoro-6-methoxy-quinolin-4-ol <strong>[458-52-6]2-Fluoro-4-methoxy-phenylamine</strong> (3.80 g, 26.7 mmol) and methyl propiolate (2.37 ml, 0.267 mol) in methanol (1.0 ml) was stirred for 72 hours at room temperature, then heated at 50 C. for 24 hours. It was evaporated and the product purified by chromatography on silica gel (dichloromethane) to give a solid (1.66 g), a portion of which was recrystallized from dichloromethane-hexane. The unsaturated ester (0.96 g) in warm Dowtherm A (5 ml) was added over 3 minutes to refluxing Dowtherm A (15 ml), and after a further 20 minutes at reflux the mixture was cooled and poured into ether. The precipitate was filtered to give the title compound (0.50 g, 61%).
61%
In methanol;
(a) 8-Fluoro-6-methoxyquinolin-4-ol <strong>[458-52-6]2-Fluoro-4-methoxy-phenylamine</strong> (3.80 g;26.7 mmol) and methyl propiolate (2.37 ml, 0.267 mol) in methanol (100 ml) was stirred for 72 hours at room temperature, then heated at 50 C. for 24 hours. It was evaporated and the product purified by chromatography on silica gel (dichloromethane) to give a solid (1.66 g), a portion of which was recrystallized from dichloromethane-hexane. The unsaturated ester (0.96 g) in warm Dowtherm A (5 ml) was added over 3 minutes to refluxing Dowtherm A (15 ml), and after a further 20 minutes at reflux the mixture was cooled and poured into ether. The precipate was filtered to give the title compound (0.50 g, 61%)
With ascorbic acid;copper(ll) sulfate pentahydrate; In ethanol; water; at 25℃;
Example 7Synthesis of Compound (II)Methyl 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxylate; 2,6-Difluorobenzyl azide (3.0 g, 17.7 mmoles) is suspended in ethanol (30 ml), then methyl propiolate (IV) (1.6 g, 19.6 mmoles), ascorbic acid (317 mg, 1.8 mmoles) and CuSO4 pentahydrate (50 mg, 0.18 mmole) are added. The reaction mixture is kept at 25 C. under stirring overnight. The mixture is concentrated, taken up with ethyl acetate and washed with an ammonia diluted solution. The organic phase is dried, filtered, concentrated under reduced pressure. A crystalline white solid is obtained in 94% yield.1H NMR (400 MHz, DMSO-d6), delta ppm: 8.86 (s, 1H), 7.52 (m, 1H), 7.27-7.12 (m, 2H), 5.74 (s, 2H), 3.83 (s, 3H).
94%
With ascorbic acid;copper(ll) sulfate pentahydrate; In ethanol; at 25℃;
Example 7; Synthesis of compound (II): Methyl 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxylate 2,6-Difluorobenzyl azide (3.0 g, 17.7 mmoles) is suspended in ethanol (30 ml), then methyl propiolate (IV) (1.6 g, 19.6 mmoles), ascorbic acid (317 mg, 1.8 mmoles) and CuSO4 pentahydrate (50 mg, 0.18 mmole) are added. The reaction mixture is kept at 25C under stirring overnight. The mixture is concentrated, taken up with ethyl acetate and washed with an ammonia diluted solution. The organic phase is dried, filtered, concentrated under reduced pressure. A crystalline white solid is obtained in 94% yield. 1H NMR (400 MHz, DMSO-d6), delta ppm: 8.86 (s, 1 H), 7.52 (m, 1H), 7.27-7.12 (m, 2H), 5.74 (s, 2H), 3.83 (s, 3H).
In water; at 20 - 65℃;Product distribution / selectivity;
In a 250 ml round bottom flask, 2,6-difluorobenzylbromide (0.024 mol, 5 g), sodium azide (0.026 mol, 1.72 g) and water (50 ml) were added. The reaction mixture was heated to 700C to 750C for 30 hours and formation of the azide intermediate was monitored by thin layer chromatography (TLC). After the completion of reaction, the reaction contents were cooled to room temperature and then to this methyl propiolate (0.024 mol, 2.1 ml) was added dropwise, maintaining the contents at room temperature. On complete addition, the mixture was again heated at 600C to 650C for 4 to 5 hours. After the reaction was completed, the contents were cooled to room temperature and to this 25% aqueous ammonia (40 ml) solution was added dropwise. The reaction contents were heated to 700C to 750C for 4 to 5 hours and then gradually cooled to room temperature. The solid obtained was filtered and washed with water. The product was dried under vacuum at 700C - 750C to give 3.0 g of rufinamide.
With potassium carbonate; In N,N-dimethyl-formamide; for 24h;
Preparation 26-Bromo-pyrazolo[1 ,5-a]pyridine[00118] To a freshly prepared solution of hydroxylamine-O-sulfonic acid (8g, 70.7 mmol) in 50 ml_ of ice water 3-bromopyridine (6.9 ml_, 70.7 mmol) is added. The mixture is heated at 90 0C for 30 min, then cooled to room temperature and K2CO3 (9.7 g, 70.7 mmol) is added. The water is evaporated (bath temperature 30-40 0C) and the crude product is treated with EtOH (100 imL). The precipitate is filtered and the filtrate is concentrated to small volume (2OmL) and HI (5.4 mL) is added. The reaction mixture is then evaporated to dryness in vacuo. The residue is dissolved in dry DMF (50 mL) and anhydrous K2CO3 (11.7 g, 84.8 mmol) is added. Methyl propiolate (7 ml, 84.8 mmol) is then added dropwise. The mixture is stirred in open flask for 24 h, then diluted with water (50 mL) and extracted with EtOAc (2x150 mL). The organic layers are combined, washed with brine (2x100ml), dried over Na2SO4. The residue is purified by column chromatography (hexane : EtOAc 8:1 ) to give 6-bromo-pyrazolo[1 ,5-a]pyridine-3- carboxylic acid methyl ester and 4-bromo-pyrazolo[1 ,5-a]pyridine-3-carboxylic acid methyl ester in ca. 1 :1 ratio.
With hydrazine hydrate; In methanol; at 20℃; for 0.5h;Cooling with ice;
Hydrazine hydrate (3.62 mL, 48.53 mmol) was added dropwise to a cooled (ice bath) solution of methyl propiolate (4.23 mL, 47.58 mmol) in methanol (40 mL). The reaction was allowed to stir for 30 min at room temperature. Brine (10 mL) was added and then the methanol was removed under vacuum. The remaining aqueous layer was extracted with EtOAc (4×75 mL) and the combined organic layers were dried (MgSO4), filtered and concentrated in vacuo to yield the title compound (44, 3.82 g, 95%) as a cream solid; deltaH (400 MHz, DMSO): 5.44 (1H, d, J 2.27 Hz), 7.35 (1H, d, J 2.23 Hz), 9.50 (1H, br s, NH), 11.45 (1H, br s, NH); deltaC (101 MHz, DMSO): 89.25, 129.71, 160.73; m/z (ES+) 85.04 (100, MH+); HRMS (ESI): MH+, found 85.03951. C3H5N2O requires 85.03964.
78%
With hydrazine hydrate; In methanol; at 0 - 20℃; for 0.5h;
To a solution of methyl propiolate (4.2 mL, 47.58 mmol, 1 equiv) in methanol (40 mL) was added hydrazine hydrate (3.6 mL, 47.58 mmol, 1 equiv) dropwise at 0C. The reaction mixture was allowed to be stirred at room temperature for 30 mins. Brine (10 mL) was added and then methanol was removed under vacuum. The remaining aqueous layer was extracted with EtOAc (4*75 mL). The combined organic phase was dried over anhydrous MgSCri, filtered and concentrated in vacuo to afford the title compound lH-pyrazol-3(2H)- one as a white solid (3.2 g, 78% yield). NMR (400 MHz, DMSO-de) d: 10.68 (br. s., 2H), 7.40 (d, J = 4.0 Hz, 1H), 5.50 (d, J = 4.0 Hz, 1H).
66%
With hydrazine hydrate; In methanol; at 0 - 25℃; for 0.5h;
To a solution of methyl prop-2-ynoate (150 g, 1785.7 mmol) in MeOH (1500 mL) was added hydrazine hydrate (89.2 g, 1784.0 mmol) dropwise at 0 C. The reaction was stirred at r.t. for 30 min. Saturated aqueous sodium chloride (400 mL) was added, and then methanol was removed under vacuum. The aqueous layer was extracted with EtOAc (3×500 mL), and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to afford 1,2-dihydropyrazol-3-one (99.5 g, 66%) as a white solid. m/z: ES+[M+H]+ 85.
62%
With hydrazine hydrate; In methanol; at 20℃; for 0.5h;Cooling with ice;
The compound of hydrazine monohydrate (85%, 4.81g, 95.2mrnol) was added dropwise to a cooled (ice bath) solution of 92 (8g, 96.2mmol) in methanol (5OmL). The reaction was allowed to stir for 30 minutes at room temperature, then, the solvent was removed under vacuo. Theremaining aqueous layer was extracted with Et0Ac(5mL5) and the combined organic layerswere dried (MgSO4), filtered and concentrated in vacuo to yield the title product 93 (5g, yield:62?/o)1HNIS?iR (400 MHz, DMSO.-d6): oe5.40 (s, 2H), 7.32 (s, 2 H).
allyl 2-amino-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
54%
With caesium carbonate; In ethanol; at 20℃;
Preparation 6: lH-benzo[< ] [l,2,3]triazol-l-yl 2-amino-5-( 2- (dimethylamino)ethoxy)pyrazolo[l,5-]pyrimidine-3-carboxylate 6e Step 1: allyl 2-amino-5-(2-(dimethylamino)ethoxy)pyrazolo[l,5-a]pyrimidine-3-carboxylate 4e [00264] To a suspension of allyl 3,5-diamino-lH-pyrazole-4-carboxylate 3 (1.0 g, 5.4 mmol) and CS2CO3 (2.5g, 7.6 mmol) in EtOH (10 niL) was added methyl prop-2-ynoate (553.0 mg, 586.0mu1, 6.5 mmol), dropwise over 15 minutes and the reaction mixture was stirred overnight at room temperature. The deep orange mixture was filtered. The filtrate was cooled on an ice-bath and ether (lOOmL) was slowly added with stirring. The mixture was stirred at 0C for 20 minutes by which time a yellow solid had precipitated out of solution. The solid was filtered, further triturated in ether (20mL) and filtered. The yellow solid was dried to afford allyl 2-amino-5-oxo-4,5-dihydropyrazolo[l,5-a]pyrimidine-3-carboxylate (700mg, 54% yield). [00265] To a mixture of allyl 2-amino-5-oxo-4H-pyrazolo[l,5-a]pyrimidine-3-carboxylate (1 g, 4.270 mmol) in MeCN (15 mL) was added 2,3,4,6,7,8,9, 10-octahydropyrimido[l,2- ajazepine (975.1 mg, 957.9 mu, 6.405 mmol) and benzotriazol-l-yloxy(tripyrrolidin-l- yl)phosphonium (Phosphorus Hexafluoride Ion) (2.666 g, 5.124 mmol). After 5 minutes, 2- dimethylaminoethanol (3.806 g, 4.291 mL, 42.70 mmol) and cesium carbonate (5g) were added and the mixture was stirred at room temperature for 30 minutes, followed by heating to 50C for 30 minutes. After cooling to room temperature the mixture was filtered and the solid was rinsed with acetonitrile. The filtrate was concentrated in vacuo to an orange oil and purified by column chromatography using 4% MeOH/DCM as eluant. Solvent evaporations in vacuo afforded allyl 2-amino-5-(2-(dimethylamino)ethoxy)pyrazolo[l,5-a]pyrimidine-3- carboxylate as a light orange solid. (450 mg, 35% yield).
With caesium carbonate; In ethanol; at 20℃;
Preparation 4: 2-amino-5-(2-(dimethylamino)ethoxy)pyrazolo[l,5-]pyrimidine-3- carboxylic acid 5b 5b Step 1: allyl 2-amino-5-oxo-4,5-dihydropyrazolo[l,5-a]pyrimidine-3-carboxylate [00240] To a mixture of allyl 3,5-diamino-lH-pyrazole-4-carboxylate 3 (1 g, 5.489 mmol) and Cs2C03 (2.504 g, 7.685 mmol) in EtOH (10 mL) was added methyl prop-2-ynoate (553.8 mg, 586.0 mu, 6.587 mmol), dropwise, over 15 minutes. The reaction mixture was stirred overnight at room temperature. The deep red reaction mixture was then filtered, washing through with a small amount of ethanol. The filtrate was cooled on an ice-bath and ether (100ml) was slowly added; the mixture stirred at 0C for 20 mins. A yellow solid precipitated out of solution and was filtered off to afford a solid which was triturated in ether and filtered (3 cycles) to yield pure product as a yellow solid (yield 54%) LC-MS (M+H)+= 235.1
In neat (no solvent); at 100℃; for 0.25h;Microwave irradiation; Sealed tube;
General procedure: A mixture of benzotriazole 1 (0.06 g, 5 mmol) and methyl propiolate 2 (0.8 g, 1.0 ml, 0.01 mol) was made in a dried heavy wall Pyrex tube. The tube was sealed and then exposed to microwave oven. After 15 min irradiation at 200 W (100 °C) power, the mixture was cooled to room temperature. The residue of compounds was evaporated under air and reduced pressure. An off-white solid was afforded. The product 3 can be recrystallized from dried diethyl ether.
methyl 3-(2-acetamido-5-chloroquinolin-1(2H)-yl)acrylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With tetra-n-butylphosphonium acetate; In tetrahydrofuran; at 25℃; for 12h;
General procedure: To a stirred solution of amide (1.5 mmol), propiolate (1.0mmol), and TBPA (20 mol%) in THF (3 mL), the N-heterocycle(1.0 mmol) was added slowly at 25 C (for 10 min), and theresulting mixture was stirred at ambient temperature for 12 h.After completion of the reaction (monitored by TLC), themixture was evaporated in vacuo followed by addition of H2O(10 mL), and the pH was adjusted to 2 using concentrated HCl.Afterwards, CH2Cl2 (5 mL) was added, the mixture was stirredfor an additional 30 min, and two layers were separated. Theaqueous layer was extracted with CH2Cl2 (3 × 10 mL), the combinedorganic layers were dried over MgSO4, filtered, and concentratedin vacuo to yield the crude product (purity 75-82%).
methyl 3-(2-acetamido-7-chloroquinolin-1(2H)-yl)acrylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With tetra-n-butylphosphonium acetate; In tetrahydrofuran; at 25℃; for 12h;
General procedure: To a stirred solution of amide (1.5 mmol), propiolate (1.0mmol), and TBPA (20 mol%) in THF (3 mL), the N-heterocycle(1.0 mmol) was added slowly at 25 C (for 10 min), and theresulting mixture was stirred at ambient temperature for 12 h.After completion of the reaction (monitored by TLC), themixture was evaporated in vacuo followed by addition of H2O(10 mL), and the pH was adjusted to 2 using concentrated HCl.Afterwards, CH2Cl2 (5 mL) was added, the mixture was stirredfor an additional 30 min, and two layers were separated. Theaqueous layer was extracted with CH2Cl2 (3 × 10 mL), the combinedorganic layers were dried over MgSO4, filtered, and concentratedin vacuo to yield the crude product (purity 75-82%).
methyl 6-chloro-4-(2-fluorophenyl)quinoline-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
With tert-butylammonium hexafluorophosphate(V); calcium(II) trifluoromethanesulfonate; In neat (no solvent); at 110℃; for 2.5h;Green chemistry;
General procedure: A mixture of suitable 2-amino benzophenone (1.0 mmol) and ethyl propiolate 2a (1.2 mmol) was heated at 110 oC in the presence of Ca(OTf)2/Bu4NPF6 (10/10 mol%) for 3h. After completion of reaction (monitored by TLC), the reaction mixture was diluted with water, extracted with EtOAc thrice; the combined organic layers were washed with brine solution and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the desired product 3a in 76% yield.
methyl 7-bromo-4-oxo-2-phenyl-4H-quinolizine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74%
General procedure: An oven-dried screw cap test tube was charged with a magnetic stir bar, Pd(PPh3)2Cl2 (2 mol%), CuI (4 mol%), and K2CO3 (0.4mmol). The tube was then evacuated and backfilled with argon.The evacuated/backfill sequence was repeated two additional times. Under a counter-flow of argon, DMF (1 mL), iodoarene(1a, 0.2 mmol), and methyl propiolate (2a, 0.3 mmol) were added. The tube was placed in a preheated oil bath at 80 C, andthe mixture was stirred vigorously for 10 min. Then the screwcap was opened and 2-pyridyl ethyl ester (3a, 0.2 mmol) wasadded in air at 80 C. The mixture was allowed to react for another 8 h at 80 C in air atmosphere. After the reaction was finished, water (5 mL) was added, and the solution wasextracted with ethyl acetate (3 × 5 mL), the combined extractwas dried with anhydrous MgSO4. Solvent was removed, andthe residue was separated by column chromatography (petroleumether/ethyl acetate, 2:1) to give 4a (50 mg, 86%) as ayellow solid.
ethyl 2-(3,4-difluorophenyl)-4-oxo-4H-quinolizine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
General procedure: An oven-dried screw cap test tube was charged with a magnetic stir bar, Pd(PPh3)2Cl2 (2 mol%), CuI (4 mol%), and K2CO3 (0.4mmol). The tube was then evacuated and backfilled with argon.The evacuated/backfill sequence was repeated two additional times. Under a counter-flow of argon, DMF (1 mL), iodoarene(1a, 0.2 mmol), and methyl propiolate (2a, 0.3 mmol) were added. The tube was placed in a preheated oil bath at 80 C, andthe mixture was stirred vigorously for 10 min. Then the screwcap was opened and 2-pyridyl ethyl ester (3a, 0.2 mmol) wasadded in air at 80 C. The mixture was allowed to react for another 8 h at 80 C in air atmosphere. After the reaction was finished, water (5 mL) was added, and the solution wasextracted with ethyl acetate (3 × 5 mL), the combined extractwas dried with anhydrous MgSO4. Solvent was removed, andthe residue was separated by column chromatography (petroleumether/ethyl acetate, 2:1) to give 4a (50 mg, 86%) as ayellow solid.
methyl 6-methoxypyrazolo[1,5-b]pyridazine-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
13%
To a stirred solution of hydroxylamine-O-sulfonic acid (4.06 g, 36.0 mmol) in water (12.5 mL) was added potassium bicarbonate until the pH = 5 - 6. 3-Methoxypyridazine (prepared as described in J. Med. Chem, 2004, 47(19), 4716 -4730) (2.42 g, 22.0 mmol) was added and the resulting solution was placed in a preheated aluminium heating block at 70 00 forh, After cooling, the pH was adjusted to 7 - 8 using potassium bicarbonate and the solution was concentrated in vacuo. The residue was suspended in DMF (18 mL) and methyl propiolate (1.60 mL, 18 mmol) was added followed by the portion wise addition of potassium carbonate (6.07 g, 44.0 mmol), the mixture was stirred at r.t. for 36 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organiclayers were washed with brine, dried (MgSO4) and concentrated. The residue was purified by FCC eluting with 10-50% ethyl acetate in petrol to give the title compound (346 mg, 13%).LCMS (Method 4): Rt 2.22 mi mlz 208, 209 [MH].
(E)-methyl 3-(2-formyl-3-methylphenoxy)acrylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
69%
With 4-methyl-morpholine; In dichloromethane; at 0 - 20℃; for 20h;
General procedure: To a solution of 2-hydroxybenzaldehyde (s1) (539 mg, 4.41 mmol) in CH2Cl2 (15.2 mL) weresuccessively added methyl propiolate (0.50 mL, 4.55 mmol) and N-methylmorpholine (20 muL, 0.22mmol) at 0 C. After being stirred for 20 h at room temperature, the reaction mixture wereconcentrated in vacuo The residue was purified by column chromatography (silica gel,hexane/EtOAc = 6/1) to give 1a (800 mg, 88%) as white solid.
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In tetrahydrofuran; at 20 - 60℃; for 25h;Cooling with ice;
In a 100 mL three-necked flask, tetrahydrofuran (THF)6.25 g, <strong>[372-29-2]ethyl 3-amino-4,4,4-trifluorocrotonate</strong> 25 g (136 mmol),Diazabicyclo- [5,4,0] -7-undecene (DBU)11.5 g (75.5 mmol) were added with stirring.Next, under cooling with ice water, 6.25 g (74.3 mmol) of methyl propiolate was added dropwise so that the internal temperature did not exceed 20 C.After stirring for 1 hour, the temperature was raised to 60 C. After stirring for 24 hours,After separating the contents, drying and filtering with anhydrous sodium sulfate,
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