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[ CAS No. 530-62-1 ]

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Chemical Structure| 530-62-1
Chemical Structure| 530-62-1
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CAS No. :530-62-1 MDL No. :MFCD00005286
Formula : C7H6N4O Boiling Point : 394.6°C at 760 mmHg
Linear Structure Formula :- InChI Key :N/A
M.W :162.15 g/mol Pubchem ID :68263
Synonyms :

Safety of [ 530-62-1 ]

Signal Word:Danger Class:8
Precautionary Statements:P201-P202-P260-P264-P270-P280-P301+P312+P330-P301+P330+P331-P303+P361+P353-P304+P340+P310-P305+P351+P338+P310-P308+P313-P363-P405-P501 UN#:3263
Hazard Statements:H302-H314-H360 Packing Group:
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Application In Synthesis of [ 530-62-1 ]

  • Upstream synthesis route of [ 530-62-1 ]
  • Downstream synthetic route of [ 530-62-1 ]

[ 530-62-1 ] Synthesis Path-Upstream   1~32

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Reference: [1] Nucleosides and Nucleotides, 1999, vol. 18, # 9, p. 2109 - 2120
[2] Tetrahedron Letters, 1982, vol. 23, # 20, p. 2113 - 2116
[3] Gazzetta Chimica Italiana, 1993, vol. 123, # 10, p. 559 - 562
[4] Green Chemistry, 2012, vol. 14, # 2, p. 326 - 329
[5] Tetrahedron Letters, 2012, vol. 53, # 19, p. 2373 - 2376
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Reference: [1] Synthetic Communications, 2000, vol. 30, # 1, p. 23 - 30
[2] Russian Journal of Applied Chemistry, 2012, vol. 85, # 3, p. 456 - 459
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  • [ 530-62-1 ]
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YieldReaction ConditionsOperation in experiment
100% at 20 - 25℃; for 1.5 h; Heating / reflux Reference Example 2
5-Bromo-1,3-benzoxazol-2(3H)-one
To a solution of 2-amino-4-bromophenol (3.50 g, 18.6 mmol) in tetrahydrofuran (100 mL) is added 1,1'-carbonyldiimidazole (3.62 g, 22.3 mmol) at 20-25°C, and the mixture is refluxed for 1.5 hour.
After the reaction, the reaction solution is cooled to 20-25°C, and thereto is added a 2N aqueous hydrochloric acid solution, and the mixture is extracted with ethyl acetate.
The resulting organic layer is washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated saline solution, and dried over anhydrous sodium sulfate.
The resultant is filtered, and the solvent is evaporated under reduced pressure to give 5-bromo-1,3-benzoxazol-2(3H)-one (3.89 g, quantitative).
IR (cm-1): 960, 1149, 1474, 1622, 1751
95% for 2 h; Reflux To a solution of 2-amino-4-phenylphenol (6.10 g, 32.9 mmol) in THF (150 mL) was added 1,1'-carbonyldiimidaziole (6.41 g, 39.5 mml) at room temperature.
The mixture was stirred at reflux for 2 h and cooled to room temperature.
The reaction was then quenched by adding 2 M HCl solution, and the mixture was extracted with EtOAc.
The organic layer was washed with brine and dried over anhydrous sodium sulfate.
After filtration, the solvent was removed in vacuo to give 11 (6.89 g, 99percent) as a white solid
95% at 20℃; for 2 h; Inert atmosphere 1,1′-Carbonyldiimidazole (46.5 g, 287 mmol) was added to a solutionof bromophenol 2 (49.0 g, 261 mmol) in THF (300 mL) at r.t.,and the mixture was stirred at r.t. for 2 h. The reaction was then quenched with 2 M aq HCl (700 mL), and the mixture was extracted with EtOAc (2 × 500 mL). The organic layers were combined, washed with brine (500 mL), dried (NaSO4), filtered, and concentrated in vacuo to give a brown solid; yield: 53.2 g (95percent).
91% at 120℃; for 3 h; a. A mixture of 2-amino-4-bromophenol (6.0 g, 31.9 mmol) and 1 ,1'- carbonyldiimidazole (6.2 g, 38.3 mmol) in p-dioxane (30 mL) was heated at 120 °C for 3 h, allowed to cool to ambient temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with 1N hydrochloric acid (3 20 mL), water (20 mL) and brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was triturated in hexanes/diethyl ether (1 :1 v/v, 50 mL) and washed with hexanes (20 mL) to afford 5- bromobenzo[d]oxazol-2(3H)-one in 91 percent yield (6.2 g) as a beige solid: 1H NMR (300 MHz, DMSO-d6) £ 11.85 (br s, 1 H), 7.28-7.25 (m, 3H); MS (ES+) m/z 212.0 (M + 1), 214.0 (M + 1).
63% at 80℃; for 17 h; Inert atmosphere To a solution of 14 (1.50 g. 7.98 mmol) in 1,4-dioxane (100 mL) was added Ι, Γ-carbonyldiimidazoie (1.55 g, 9.58 mmol). The reaction was heated at 80 "C for 17 h under nitrogen. The mixture was cooied to room temperature and 2N aq. HCI (40 mL) was added. The solution was diluted with ethyl acetate (200 mL) and washed with brine (2χ50 mL). The organic iayer was dried over sodium suifate, filtered and concentrated. Purification by chromatography (silica gel, 0-50percent ethyl acetate/hexanes) afforded 15 (1.08 g, 63percent) as an orange solid:XH M (5Q0 M Hz, DMSO-c/e) δ 11.81 (s, 1H), 7.27-7.25 (m, 3 H).

Reference: [1] Patent: EP1719761, 2006, A1, . Location in patent: Page/Page column 26
[2] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 18, p. 5568 - 5582
[3] Journal of Medicinal Chemistry, 2013, vol. 56, # 20, p. 8191 - 8195
[4] Synthesis (Germany), 2013, vol. 45, # 23, p. 3269 - 3275
[5] Patent: WO2013/64984, 2013, A1, . Location in patent: Page/Page column 125
[6] Patent: WO2015/2754, 2015, A2, . Location in patent: Paragraph 0198
[7] Journal of Medicinal Chemistry, 2015, vol. 58, # 23, p. 9258 - 9272
[8] RSC Advances, 2016, vol. 6, # 115, p. 114491 - 114499
[9] Patent: WO2016/198400, 2016, A1, . Location in patent: Page/Page column 61
[10] Patent: WO2018/148745, 2018, A1, . Location in patent: Page/Page column 82, 83
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YieldReaction ConditionsOperation in experiment
88% at 20℃; Inert atmosphere; Cooling with ice A stirred solution of 4-fluorobenzene-1 ,2-diamine (15.1 g, 120 mmol) in THF (120 mL) under nitrogen was cooled using an ice-bath and then was treated with di(1 -/-imidazol-1 - yl)methanone (23.4 g, 144 mmol) portion-wise over 15 min. The resulting mixture was slowly warmed to room temperature then was concentrated in vacuo after 2.5 h. The residue was suspended in a mixture of water and DCM (250 mL each) and filtered off. This residue was then washed with water (50 mL) and DCM (50 mL), before being dried at 40 °C under vacuum for 16 h to give the title compound (16.0 g, 105 mmol, 88percent) as a brown solid. LCMS (high pH): Rt 0.57 min; [M-H+]" = 151.1 δΗ NMR (400 MHz, DMSO-d6) ppm 10.73 (br s, 1 H), 10.61 (br s, 1 H), 6.91-6.84 (m, 1 H), 6.78-6.70 (m, 2H).
78% at 150℃; for 0.333333 h; Microwave irradiation Intermediate 15: 5-Fluoro-1 ,3-dihvdro-2H-benzimidazol-2-one; A mixture of 4-fluoro-1 ,2-diaminobenzene (commercially available, 1.0 g, 7.9 mmol), carbonyldiimidazole (1.4 g) and THF (4 ml) was heated to 150 0C in a microwave reactor and stirred for 10 minutes. The mixture was heated to 150 0C and stirred for a further 10 <n="38"/>minutes. The mixture was cooled to room temperature and concentrated under vacuum. The residue was suspended in dilute hydrochloric acid and filtered. The filter-cake was washed with water and cyclohexane then dried under vacuum to give the title compound as a dark grey solid (0.95 g, 78percent). 1 H-NMR (400 MHz, DMSO-d6): δ 10.73 (1 H, br s), 10.62 (1 H, br s), 6.87 (1 H, dd, J 8.5, 5 Hz), 6.78-6.70 (2H, m). UPLC-MS: 0.47 min, m/z 153 [M+H]+.
52% at 20℃; a) 4-Fluorobenzene-1,2-diamine (2 g, 15.86 mmol) was dissolved in THF (49.4 ml) and 1,1'-Carbonyldiimidazole (2.83 g, 17.44 mmol) was added at RT. The reaction mixture was stirred overnight at RT. To this was added concentrated ammonia solution (1.5 ml) and the mixture stirred for 30 minutes and then diluted with water (100 ml). The resultant solid was collected by filtration, washed with water, followed by Et2O and then dried in vacuo to afford 5-fluoro-1H-benzo[d]imidazol-2(3H)-one (1.250 g, 52percent); 1H NMR (400 MHz, DMSO-d6) 6.66-6.79 (2H, m), 6.81-6.94 (1H, m), 10.64 (1H, s), 10.76 (1H, s); m/z: (ES+) MH+, 151.19.
Reference: [1] Patent: WO2016/62737, 2016, A1, . Location in patent: Page/Page column 24
[2] ACS Medicinal Chemistry Letters, 2016, vol. 7, # 6, p. 552 - 557
[3] ACS Medicinal Chemistry Letters, 2014, vol. 5, # 11, p. 1190 - 1195
[4] Journal of Medicinal Chemistry, 2006, vol. 49, # 12, p. 3719 - 3742
[5] Patent: WO2008/129007, 2008, A1, . Location in patent: Page/Page column 36-37
[6] Patent: US2011/306613, 2011, A1, . Location in patent: Page/Page column 37
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Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 23, p. 6067 - 6070
[2] Journal of Medicinal Chemistry, 2009, vol. 52, # 18, p. 5703 - 5711
[3] Patent: US2007/72928, 2007, A1, . Location in patent: Page/Page column 26
[4] Patent: WO2011/92293, 2011, A2, . Location in patent: Page/Page column 92
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YieldReaction ConditionsOperation in experiment
93% at 80℃; for 16 h; To a solution of 2,3-diamino-5-bromopyridine (5 g, 27 mmol) in THF (87 mL) was added CDI (3.02 g, 18.6 mmol), and the reaction mixture was stirred at 80 °C for 16 h. Then, water was added, and the mixture was filtered. The solids were collected by filtration, washed with water and Et2O, and dried under vacuum to afford the title compound (5.3 g, 25 mmol, 93percent), which was used in the next step without further purification. MS (ESI): mass calcd. for C6H4BrN3O, 212.95; m/z found, 214 [M+H]+.
92% at 20℃; Inert atmosphere Step 2 6-Bromo-lH-imidazo[4,5-b]pyridin-2(3H)-one. 5-Bromopyridine-2,3-diamine (2.45 g) was dissolved in THF (25 niL) and l,l'-carbonyldiimidazole (2.54 g, 1.2 eq) was added. The reaction was stirred at room temperature under nitrogen gas overnight. Water was then added to the mixture and the product was collected by filtration. The solid was dried under vacuum delivering product (2.57 g, 92percent yield). 1H-NMR (300 MHz, DMSOd6) δ 11.50 (s, IH), 11.00 (s, IH), 7.93 (s, 1 H), 7.39 (s, IH). MS (ES+) m/z 213.1 (M + 1).
Reference: [1] Patent: WO2018/67786, 2018, A1, . Location in patent: Page/Page column 106
[2] Patent: WO2010/121164, 2010, A2, . Location in patent: Page/Page column 61
[3] Patent: WO2011/149950, 2011, A2, . Location in patent: Page/Page column 104-105
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YieldReaction ConditionsOperation in experiment
94% at 0℃; for 16 h; To a solution of 3,4-diamino-benzoic acid methyl ester (5.00 g, 30.1 mmol) and THF (40 ml_), was added carbonyl diimidazole (7.32 g, 45.1 mmol) at 0 0C. The mixture stirred for 16 h, and allowed to warm to 23 0C. A solution of 1 M aq. HCI (50 ml_) was added at 0 0C, followed by water (70 ml_) and the mixture was stirred for 1 h. The resulting precipitate was filtered and dried under reduced pressure for 18 h to yield the titled compound, which was used in the next step without further purification (5.45 g, 94 percent). MS (ESI/CI): mass calcd. for C9H8N2O3, 192.1 ; m/z found, 193.1 [M+H]+. 1H NMR (400 MHz, CDCI3): 11.01 (s, 1 H), 10.84 (s, 1 H), 7.63 (dd, J = 8.2, 1.6 Hz, 1 H), 7.47 (s, 1 H), 7.02 (d, J = 8.2 Hz, 1 H), 3.82 (s, 3H).
Reference: [1] Patent: WO2009/134750, 2009, A1, . Location in patent: Page/Page column 139
[2] Journal of Medicinal Chemistry, 2006, vol. 49, # 12, p. 3719 - 3742
[3] Patent: US2010/249124, 2010, A1, . Location in patent: Page/Page column 62
[4] Cell Chemical Biology, 2018, vol. 25, # 6, p. 677 - 12,690
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Reference: [1] Journal of the American Chemical Society, 2007, vol. 129, # 28, p. 8836 - 8844
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Reference: [1] Patent: US2005/54628, 2005, A1, . Location in patent: Page/Page column 31
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YieldReaction ConditionsOperation in experiment
90% at 80℃; for 5 h; Inert atmosphere General procedure: The intermediates 4 were prepared as previously described [36] with some modification. Under the atmosphere of nitrogen, starting material aminophenol (1 equiv.) and N,N′-Carbonyldiimidazole (CDI) (1.2 equiv.) were mixed in DMF and stirred 80°C for 5h. The reaction mixture was allowed to cool to room temperature and the water was added to quench the reaction. The mixture was and extracted with ethyl acetate to afford the crude product that was purified by flash column chromatography on silica gel to yield 4a-d.
Reference: [1] European Journal of Medicinal Chemistry, 2017, vol. 138, p. 199 - 211
[2] Patent: WO2005/18529, 2005, A2, . Location in patent: Page/Page column 62
[3] Journal of Medicinal Chemistry, 2015, vol. 58, # 23, p. 9258 - 9272
[4] Organic and Biomolecular Chemistry, 2017, vol. 15, # 19, p. 4058 - 4063
[5] Patent: WO2005/18529, 2005, A2, . Location in patent: Page/Page column 62
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Reference: [1] European Journal of Organic Chemistry, 2001, # 3, p. 517 - 522
[2] Heterocycles, 2002, vol. 57, # 4, p. 637 - 648
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YieldReaction ConditionsOperation in experiment
70% at 66 - 130℃; for 1.45 h; Example 2; Comparative in Analogy to Example 1 from WO-A-00/14072 In a flask, 68.22 g of imidazole are suspended in 505 g of xylene. The mixture is heated to reflux and dewatered by taking off 5 g of a xylene/water mixture. The temperature is reduced to 66° C. and over the course of 30 minutes 25.2 g of phosgene are metered in with an introduction rate of 50.4 g/h. After about 15 minutes the reaction mixture takes on a consistency like that of chewing gum. When the metering of phosgene is at an end the imidazole hydrochloride by-product is in the form of yellow balls. After a further hour of stirring at this temperature, this temperature is raised to 130° C., and the consistency of the imidazole hydrochloride changes to a brown melt. The melt is drained off at 130° C. It solidifies on cooling to a dark-green, solid mass. The supernatant xylene phase is cooled to 0° C. The precipitated crystals are filtered off and dried at 20 mbar and 50° C. This gives carbonylbisimidazole in the form of white crystals with black fractions (Hazen colour number: 489). The purity is 96.8percent, corresponding to a yield of 70percent of theory.
61.9% at 35 - 55℃; for 3.25 - 3.75 h; Example 3; Inventive; A flask is charged with 375.2 g of dry chloroform and 93.8 g of imidazole and this initial charge is heated to 35° C. At this temperature over the course of 1.75 hours 35.02 g of phosgene are added with an introduction rate of 20.0 g/h. The mixture thus obtained is subsequently stirred at the same temperature for 1.5 h. In order to ensure a phosgene-free reaction mixture, 28 g of distillate are taken off under a pressure of 280 mbar and at 30° C., an ammonia/water/isopropanol mixture is added to the distillate, and this mixture is discarded. The imidazole hydrochloride by-product (isolated dry weight: 72.1 g) is removed by filtration at 35° C., the filter cake being washed with twice 100 ml of warm chloroform at 35° C. 251.1 g of water-clear solution are distilled off from the combined organic phases at 280 mbar and 30° C. The remaining solution is cooled to 0° C., and a suspension forms. The precipitated carbonyl bisimidazole is separated off by filtration and additionally washed with 50 ml of chloroform conditioned to a temperature of 0° C. Drying of the crystals at 6 mbar and 30° C. gives 41.5 g of product in the form of white crystals having a Hazen colour number of 44. The purity of the product is 99.5percent, corresponding to a yield of 74.0percent of theory.; Example 4; Inventive; A flask is charged with 358.1 g of dry chloroform and 119.36 g of imidazole and this initial charge is heated to 55° C. At this temperature over the course of 1.75 hours 44.57 g of phosgene are added with an introduction rate of 25.5 g/h. The mixture thus obtained is subsequently stirred at the same temperature for 2 h. In order to ensure a phosgene-free reaction mixture, 5.4 g of distillate are taken off under a pressure of 630 mbar and at 35° C., an ammonia/water/isopropanol mixture is added to the distillate, and this mixture is discarded. The imidazole hydrochloride by-product (isolated dry weight: 96.0 g) is removed by filtration at 55° C., the filter cake being washed with twice 100 ml of warm chloroform at 55° C. The combined organic phases are cooled to 0° C., and a suspension forms. The precipitated carbonyl bisimidazole is separated off by filtration and additionally washed with 50 ml of chloroform conditioned to a temperature of 0° C. Drying of the residue at 4 mbar and 46° C. gives 44.3 g of product in crystalline form having a Hazen colour number of 49. The purity of the product is 99.0percent, corresponding to a yield of 61.9percent of theory.
59.9% at 35℃; for 3.25 h; Example 1; Inventive; A flask is charged with 531.5 g of dry dichloromethane and 93.8 g (1.37 mol) of imidazole and this initial charge is heated to 35° C. At this temperature over the course of 1.75 hours 36.04 g (0.36 mol) of phosgene are added with an introduction rate of 20.6 g/h. The mixture thus obtained is subsequently stirred at the same temperature for 1.5 h. In order to ensure a phosgene-free reaction mixture, 13.2 g of distillate are taken off under a pressure of 790 to 500 mbar and at 35-25° C., an ammonia/water/isopropanol mixture is added to the distillate, and this mixture is discarded. The imidazole hydrochloride by-product (isolated dry weight: 72.1 g) is removed by filtration at 35° C., the filter cake being washed with twice 100 ml of warm dichloromethane at 33° C. 250.1 g of water-clear solution are distilled off from the combined organic phases at 790 to 500 mbar and 35-25° C. The remaining solution is cooled to 0° C., and a suspension forms. The precipitated carbonyl bisimidazole is separated off by filtration and additionally washed with 50 ml of dichloromethane conditioned to a temperature of 0° C. Drying of the crystals at 4 mbar and 30° C. gives 40.0 g of product in the form of white crystals, Hazen colour number: 69.7. The purity of the product is 99.3percent, corresponding to a yield of 71.2percent of theory.; Example 5 Inventive with Recycling of the Mother Liquor 1st Phosgenation A flask is charged with 531.5 g of dry dichloromethane and 93.8 g (1.37 mol) of imidazole and this initial charge is heated to 35° C. At this temperature over the course of 1.75 hours 35.02 g (0.35 mol) of phosgene are added with an introduction rate of 20.0 g/h. The mixture thus obtained is subsequently stirred at the same temperature for 1.5 h. In order to ensure a phosgene-free reaction mixture, 8.4 g of distillate are taken off under a pressure of 750 to 500 mbar and at 35-20° C., an ammonia/water/isopropanol mixture is added to the distillate, and this mixture is discarded. The imidazole hydrochloride by-product (isolated dry weight: 80.3 g) is removed by filtration at 35° C., the filter cake being washed with twice 100 ml of warm dichloromethane at 33° C. The remaining solution is cooled to 0° C., and a suspension forms. The precipitated carbonyl bisimidazole is separated off by filtration and additionally washed with 50 ml of dichloromethane conditioned to a temperature of 0° C. After the solid carbonylbisimidazole has been filtered off, 553.0 g of mother liquor M1 are obtained. Drying of the crystals at 5 mbar and 20° C. gives 33.54 g of product in the form of white crystals with a Hazen colour number of 45.1. The purity of the product is 99.6percent. The yield therefore corresponds to 59.9percent of theory. 2nd Phosgenation A flask is charged with 531.5 g of dichloromethane-containing mother liquor M1 from the 1st phosgenation step and 93.8 g (1.37 mol) of imidazole and this initial charge is heated to 35° C. At this temperature over the course of 1.75 hours 35.02 g (0.35 mol) of phosgene are added with an introduction rate of 20.0 g/h. The mixture thus obtained is subsequently stirred at the same temperature for 1.5 h. In order to ensure a phosgene-free reaction mixture, 21.6 g of distillate are taken off under a pressure of 750 to 450 mbar and at 35-20° C., an ammonia/water/isopropanol mixture is added to the distillate, and this mixture is discarded. The imidazole hydrochloride by-product (isolated dry weight: 86.6 g) is removed by filtration at 35° C., the filter cake being washed with twice 100 ml of warm dichloromethane at 33° C. The remaining solution is cooled to 0° C., and a suspension forms. The precipitated carbonyl bisimidazole is separated off by filtration and additionally washed with 100 ml of dichloromethane conditioned to a temperature of 0° C. After the solid carbonylbisimidazole has been filtered off, 553.0 g of mother liquor M2 are obtained. Drying of the crystals at 6 mbar and 30° C. gives 39.4 g of product in the form of white crystals with a Hazen colour number of 33.2. The purity of the product is 98.7percent. The yield therefore corresponds to 70percent of theory. 3rd Phosgenation A flask is charged with 531.5 g of dichloromethane-containing mother liquor M2 from the 2nd phosgenation step and 93.8 g (1.37 mol) of imidazole and this initial charge is heated to 35° C. At this temperature over the course of 1.75 hours 35.02 g (0.35 mol) of phosgene are added with an introduction rate of 20.0 g/h. The mixture thus obtained is subsequently stirred at the same temperature for 1.5 h. In order to ensure a phosgene-free reaction mixture, 9.2 g of distillate are taken off under a pressure of 750 to 500 mbar and at 35-20° C., an ammonia/water/isopropanol mixture is added to the distillate, and this mixture is discarded. The imidazole hydrochloride by-product (isolated dry weight: 88.1 g) is removed by filtration at 35° C., the filter cake being washed with twice 100 ml of warm dichloromethane at 33° C. The remaining solution is cooled to 0° C., and a suspension forms. The precipitated carbonyl bisimidazole is separated off by filtration and additionally washed with 100 ml of dichloromethane conditioned to a temperature of 0° C. Drying of the crystals at 7 mbar and 20° C. gives 37.3 g of product in the form of white crystals with a Hazen colour number of 41.0. The purity of the product is 98.5percent. The yield therefore corresponds to 65.9percent of theory.
Reference: [1] Patent: US2005/272937, 2005, A1, . Location in patent: Page/Page column 4
[2] Patent: US2005/272937, 2005, A1, . Location in patent: Page/Page column 4
[3] Patent: US2005/272937, 2005, A1, . Location in patent: Page/Page column 3-4; 5
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YieldReaction ConditionsOperation in experiment
90% at 20 - 55℃; for 4 h; To a 1000 ml flask were added 108.3 g (1.59 mol) of imidazole and 630 g of tetrahydrofuran. After the atmosphere of the system was replaced with nitrogen, the imidazole was dissolved under stirring. Thereto was added dropwise 39.3 g (0.2 mol) of diphosgene at room temperature over a period of 2 hours. After completion of the dropwise addition, the stirring was continued at room temperature for 1 hour and then the whole was heated to 55°C, followed by continuous stirring for another 1 hour. Imidazole hydrochloride yielded as a by-product was filtrated with heat and was then washed with 100 g of tetrahydrofuran. The imidazole hydrochloride filtrated off was dried under reduced pressure at 40°C to obtain 83.2 g (0.796 mol) of imidazole hydrochloride (recovery of 100percent). A filtrate containing CDI was concentrated and subjected to toluene-crystallization, and CDI was filtrated off under a nitrogen atmosphere. The CDI filtrated off was dried under reduced pressure at 40°C to obtain 58.0 g (0.358 mol) of CDI as white crystals (yield 90percent). M.p. 111.2 to 118.6°C.
Reference: [1] Patent: EP1731510, 2006, A1, . Location in patent: Page/Page column 5
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Reference: [1] Dalton Transactions, 2018, vol. 47, # 24, p. 7896 - 7904
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YieldReaction ConditionsOperation in experiment
89% With sodium hydrogencarbonate In n-heptane; dichloromethane; water; toluene EXAMPLE 66
Scheme G, step b: 4-[(Methoxymethylamino)carbonyl]-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (15)
Into a 250-mL four-neck flask equipped with a mechanical stirrer, a nitrogen bubbler, a 125-mL addition funnel with a stopper, and a thermowell with a thermocouple was placed 1,1'-carbonyldiimidazole (7.2 g, 0.044 mol) and methylene chloride (20 g).
The addition funnel was charged with a solution of 1,4-piperidinedicarboxylic acid, 1-(1,1-dimethylethyl)ester (14) (10.0 g, 0.043 mol) and methylene chloride (75 g).
The solution was added to the reaction mixture over a 2 minute period, causing rapid CO2 evolution.
The reaction mixture was allowed to stir at 28° C. for 2 hours.
Into a 500-mL four-neck flask equipped with a mechanical stirrer, a nitrogen bubbler, a thermowell with a thermocouple, and a 125-mL addition funnel with a septum was placed N,O-dimethylhydroxylamine hydrochloride (4.9 g, 0.049 mol) and methylene chloride (38 g).
The imidazole amide intermediate/methylene chloride solution was added to the slurry of N,O-dimethylhydroxylamine hydrochloride and methylene chloride over a 20 minute period.
The resulting slurry was allowed to stir at 28° C. for 2 hours.
To the reaction mixture was added sodium bicarbonate (4.3 g) and water (75 g).
After stirring for 30 minutes at ambient temperature, the phases were allowed to stand and separate for 20 minutes.
The phases were separated and to the organic phase was added toluene (100 g).
The solution was concentrated and azeotropically dried by rotary evaporation (29 Hg, bath 60° C.) to afford the crude title compound as a thick oil.
The oil and heptane (25 g) were placed into a 100-mL jacketed-bottom-drain resin pot fitted with a four-joint head equipped with a mechanical stirrer, a thermowell with a thermocouple, a nitrogen bubbler, and a stopper.
The slurry was warmed to 60° C. before allowing it to slowly cool to 10° C. over a 2 hour period.
The solution was maintained at 10° C. for 1 hour (nucleation temperature) before cooling to 3° C. and stirring overnight.
The title compoundcompound was collected by suction filtration and washed with cold heptane (7 g, ~0° C.).
The wet cake was allowed to air dry for 24 hours to afford the title compound (15) as a white crystalline material (10.5 g, 89percent); m.p. 69-71° C.
1H NMR (CDCl3) δ 4.08 (m, 2H, CHN's), 3.66 (s, 3H, -OCH3), 3.13 (s, 3H, -NCH3), 2.76 (m, 3H), 1.51 (m, 4H, CH2's), 1.40 (s, 9H, t-Bu);
13C NMR (CDCl3) δ 175.5, 154.7, 121.6, 79.5, 61.6, 43.3, 36.1, 28.5, 28.0;
IR (KBr) 2973, 2935, 1694, 1663, 1421, 1367, 1289, 1133, 998, 870, 770 cm-1.
Reference: [1] Patent: US2005/261341, 2005, A1,
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YieldReaction ConditionsOperation in experiment
89% With sodium chloride; sodium hydrogencarbonate In n-heptane; dichloromethane; water EXAMPLE 67
Scheme G, step b: 4-[(Methoxymethylamino)carbonyl]-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (15)
A suitable reactor maintained under nitrogen was charged with 7.6 kg of 1,1'-carbonyldiimidazole and 15 L of methylene chloride.
A solution of 1,4-piperidinedicarboxylic acid, 1-(1,1-dimethylethyl)ester (14) (10.5 kg, 45.8 mol) in 62 L of methylene chloride was added over 30 minutes while maintaining a reaction temperature of 20° C.
After stirring the reaction mixture at ambient temperature for 2 hours, 0.1 kg of 1,1'-carbonyldiimidazole was added.
A solution of 4.55 kg of N,O-dimethylhydroxylamine hydrochloride in 32 L of methylene chloride was added to the mixture with stirring.
The reaction mixture was stirred at 28° C. for 24 hours, followed by the addition of 0.52 kg of N,O-dimethylhydroxylamine hydrochloride and 0.7 kg of 1,1'-carbonyldiimidazole.
Stirring was continued at 28° C. for 48 hours.
The stirred reaction mixture was diluted with a solution of sodium bicarbonate (4.5 kg, 53.6 mol) in 50 L of water.
The organic phase was separated and washed with a solution of sodium chloride (7 kg) in 46 L of water.
The organic phase was separated and dried with sodium sulfate (4 kg).
Drying agent was filtered off and washed with 2*5 L of methylene chloride.
Solvent was removed below 50° C. at 500 torr.
The residue was diluted with 5 L of heptane and solvent was removed below 50° C. at 500 torr.
A total of 40 L of heptane was added and the stirred solution was heated to 70° C. to obtain solution.
The stirred solution was cooled to ambient temperature over 18 hours, then cooled to and maintained at 10C for 12 hours, then cooled to 0° C.
Solid which crystallized was filtered off, then dried at ambient temperature to give 11.1 kg (89percent yield).
Reference: [1] Patent: US2005/261341, 2005, A1,
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YieldReaction ConditionsOperation in experiment
89% With sodium hydrogencarbonate In n-heptane; dichloromethane; water; toluene EXAMPLE 66
Scheme G, step b: 4-[(Methoxymethylamino)carbonyl]-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (15)
Into a 250-mL four-neck flask equipped with a mechanical stirrer, a nitrogen bubbler, a 125-mL addition funnel with a stopper, and a thermowell with a thermocouple was placed 1,1 '-carbonyldiimidazole (7.2 g, 0.044 mol) and methylene chloride (20 g).
The addition funnel was charged with a solution of 1,4-piperidinedicarboxylic acid, 1-(1,1-dimethylethyl)ester (14) (10.0 g, 0.043 mol) and methylene chloride (75 g).
The solution was added to the reaction mixture over a 2 minute period, causing rapid CO2 evolution.
The reaction mixture was allowed to stir at 28° C. for 2 hours.
Into a 500-mL four-neck flask equipped with a mechanical stirrer, a nitrogen bubbler, a thermowell with a thermocouple, and a 125-mL addition funnel with a septum was placed N,O-dimethylhydroxylamine hydrochloride (4.9 g, 0.049 mol) and methylene chloride (38 g).
The imidazole amide intermediate/methylene chloride solution was added to the slurry of N,O-dimethylhydroxylamine hydrochloride and methylene chloride over a 20 minute period.
The resulting slurry was allowed to stir at 28° C. for 2 hours.
To the reaction mixture was added sodium bicarbonate (4.3 g) and water (75 g).
After stirring for 30 minutes at ambient temperature, the phases were allowed to stand and separate for 20 minutes.
The phases were separated and to the organic phase was added toluene (100 g).
The solution was concentrated and azeotropically dried by rotary evaporation (29 Hg, bath 60° C.) to afford the crude title compound as a thick oil.
The oil and heptane (25 g) were placed into a 100-mL jacketed-bottom-drain resin pot fitted with a four-joint head equipped with a mechanical stirrer, a thermowell with a thermocouple, a nitrogen bubbler, and a stopper.
The slurry was warmed to 60° C. before allowing it to slowly cool to 10° C. over a 2 hour period.
The solution was maintained at 10C for 1 hour (nucleation temperature) before cooling to 3° C. and stirring overnight.
The title compoundcompound was collected by suction filtration and washed with cold heptane (7 g, 0° C.).
The wet cake was allowed to air dry for 24 hours to afford the title compound (15) as a white crystalline material (10.5 g, 89percent); m.p. 69-71° C.
1H NMR (CDCl3) δ 4.08 (m, 2H, CHN's), 3.66 (s, 3H, -OCH3), 3.13 (s, 3H, -NCH3), 2.76 (m, 3H), 1.51 (m, 4H, CH2's), 1.40 (s, 9H, t-Bu);
13C NMR (CDCl3) δ 175.5, 154.7, 121.6, 79.5, 61.6, 43.3, 36.1, 28.5, 28.0;
IR (KBr) 2973, 2935, 1694, 1663, 1421, 1367, 1289, 1133, 998, 870, 770 cm-1.
Reference: [1] Patent: US2002/151717, 2002, A1,
[2] Patent: US2002/151717, 2002, A1,
[3] Patent: US2002/151717, 2002, A1,
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  • [ 139290-70-3 ]
Reference: [1] Patent: US2005/261341, 2005, A1,
[2] Patent: US5371093, 1994, A,
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  • [ 139290-70-3 ]
Reference: [1] Patent: US2005/261341, 2005, A1,
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  • [ 139290-70-3 ]
Reference: [1] Patent: US2005/261341, 2005, A1,
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  • [ 149524-42-5 ]
YieldReaction ConditionsOperation in experiment
87.8% With triethylamine In N,N-dimethyl-formamide at 65℃; for 4 h; In a 250 ml reaction flask,Compound (4) (12.8 g, 50 mmol) was added,N, N'-carbonyldiimidazole (CDI) (8.9 g, 55 mmol),DMF 100 ml,Triethylamine (15.1 g, 0.15 mol),Temperature control at 65 ,The reaction was carried out for 4 hours,After completion of the reaction,To room temperature,Extraction with dichloromethane / water (V / V = 1: 1)The aqueous layer was washed twice with dichloromethane,The organic layers were combined,Dried over anhydrous sodium sulfate,And concentrated to give the compound (5) (9.3 g) in a total yield of 87.8percent.
Reference: [1] Patent: CN105859780, 2016, A, . Location in patent: Paragraph 0035
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  • [ 113100-86-0 ]
Reference: [1] Patent: US2002/65308, 2002, A1,
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  • [ 19171-19-8 ]
YieldReaction ConditionsOperation in experiment
88%
Stage #1: at 40 - 45℃;
Stage #2: for 4.5 h; Heating / reflux
To a round bottom flask equipped with a mechanical stirrer, a condenser, a nitrogen inlet and a heating mantel was charged with a mixture of acetonitrile (42 L) and N-(3-aminophthaloyl)-glutamine (2120 g, 7.28 moles). After the mixture was stirred and heated to 40-45° C., 1,1'-carbonyldiimidazole (1290 g, 7.95 moles) was added. The reaction mixture was stirred and refluxed for 4.5 hours. The progress of the reaction was monitored by HPLC using a Waters Nova-Pak C18 column (3.9.x.150 mm, particle size=4 micron, UV wavelength=240 nm, retention time=3.64 minutes) and a 20/80 mixture of acetonitrile and 0.1percent aqueous H3PO4 by volume as an eluent at a flow rate of 1 mL/min. After cooled to room temperature, the reaction mixture was filtered to yield a yellow solid which was subsequently washed with acetonitrile (6.5 L). The yellow solid was air dried and then dried in a vacuum oven at 60° C. and a pressure <1 mm to yield 1760 g (88percent) of the product. The product purity was found to be 99.57percent by HPLC using a Waters Nova-Pak C18 column (3.9.x.150 mm, particle size=4 micron, UV wavelength=240 nm, retention time=3.64 minutes) and a 20/80 mixture of acetonitrile and 0.1percent aqueous H3PO4 by volume as an eluent at a flow rate of 1 mL/min. The product in DMSO-d6 was characterized by a 1H NMR spectrum showing the following chemical shifts (δ in ppm): 11.10 (s, 1H), 7.47(t, J=7.9 Hz, 1H), 7.03-6.99 (dd, J=4.8 and 8.4 Hz, 2H), 6.52 (s, 2H), 5.09-5.02 (dd, J=5.3 and 12.4 Hz, 1H), 2.96-2.82 (m, 1H), 2.62-2.46 (m, 2H), 2.07-2.00 (m, 1H); and by a 13C NMR spectrum showing the following chemical shifts (δ in ppm): 172.82, 170.11, 168.57, 167-37, 146.71, 135.46, 131.99, 121.70, 110.97, 108.52, 48.47, 30.97, 22.14. The melting point of the product was found to be 315.5-317.5° C. An elemental analysis yielded the following results in weight percent: C, 56.98; H, 3.86; N, 15.35, which compared with calculated values for C13H11N3O4, in weight percent: 57.14; H, 4.06; N, 15.38.
Reference: [1] Patent: US2007/155791, 2007, A1, . Location in patent: Page/Page column 14-15
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Reference: [1] Patent: US2018/334454, 2018, A1,
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YieldReaction ConditionsOperation in experiment
88.2%
Stage #1: at 0 - 10℃; for 1 h;
Stage #2: at 20℃;
1C (33 g, 0.155 mol) was dissolved in N, N-dimethylformamide (200 mL)Control the temperature is less than 10 ,N, N'-carbonyldiimidazole (32.58 g, 0.201 mol) was added,1 hour at 0 ,N, O-dimethylhydroxylamine hydrochloride (19.6 g, 0.186 mol) was added and stirred at room temperature overnight.Water (150 mL) was added dropwise to the reaction solution, stirred for 1 hour and extracted with ethyl acetate (100 mL x 2). The organic phases were combined and the organic phase was washed with saturated sodium bicarbonate solution (60 mL x 3), saturated sodium chloride (40 mL x 3), dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 10: 1) to give 1D (35 g , Yield 88.2percent).
Reference: [1] Patent: TW2017/8223, 2017, A, . Location in patent: Page/Page column 38
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Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 17, p. 3569 - 3574
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YieldReaction ConditionsOperation in experiment
63% at 20℃; Inert atmosphere Step-3: 2-chloro-9-methyl-7H-purin-8(9H)-one [0174] To a solution of 2-chloro-N4-methylpyrimidine-4,5-diamine (150 mg, 0.95 mmol) in anhydrous THF (20 mL) was added CDI (310 mg, 1.9 mmol) under N2. The reaction mixture was stirred at room temperature overnight. It was concentrated in vacuum and the residue was purified on ISCO (20 g silica gel column, MeOH/dichloromethane 0~10percent) to afford the title compound (0.11 g, 63percent).
Reference: [1] Patent: WO2016/171755, 2016, A1, . Location in patent: Paragraph 0174
[2] Patent: US2012/172347, 2012, A1, . Location in patent: Page/Page column 35
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YieldReaction ConditionsOperation in experiment
78%
Stage #1: at 20℃;
Stage #2: at 5℃; for 0.75 h;
To a solution of 4-fluoro-N-[(3R,4S)-3-hydroxy-6-[4-(oxetan-3-yl)piperazin-1-yl]chroman-4-yl]benzamide (72.0 g, 168 mmol) in THF (648 mL) add 1,1'-carbonyldiimidazole (35.5 g, 219 mmol) and stir the solution at room temperature overnight. Cool the mixture to 5° C. and add a solution of 2 M methylamine in THF (210 mL, 421 mmol, 2.5 eq) dropwise over a period of 15 min. Stir for 30 min. and pour over a mixture of water (720 mL) and methyl tert-butyl ether (216 mL). Stir the mixture for 30 min. and decant the phases. Extract the aqueous phase with dichloromethane (3.x.216 mL). Wash the combined organic phases with brine (3.x.100 mL), dry over anhydrous sodium sulfate, and concentrate in vacuo. Suspend the residue in ethyl acetate (720 mL), heat at reflux for 2 hr. and cool to 10° C. Collect the solid by filtration and dry under vacuum overnight to obtain the title compound (64.0 g, 78percent) as a white solid. LC-ES/MS m/z 485 [M+H]+.
Reference: [1] ACS Medicinal Chemistry Letters, 2014, vol. 5, # 10, p. 1138 - 1142
[2] Patent: US2012/95020, 2012, A1, . Location in patent: Page/Page column 17
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YieldReaction ConditionsOperation in experiment
95% With proton sponge In dimethyl sulfoxide at 20℃; for 3 h; Example 6Ethyl 2-ethoxy- l -((2'-(5-oxo-4,5-dihydro-l ,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)- lH- benzo[c/]imidazole-7-carboxylate of formula lbThe corresponding base (0. 1 g) was added to a mixture of ethyl 2-ethoxy- l -((2'- ((hydroxyamino)iminomethyl)biphenyl-4-yl)methyl)- l / -benzo[i ]imidazole-7-carboxylate (of formula Vb; 0.23 g, 0.5 mmol), DMSO (3 ml) and carbonyldiimidazole (0.1 g, 0,6 mmol) in a reaction vial under stirring and the mixture was stirred at the room temperature for 3 hours. Then, the content of the vial was poured into water (10 ml) and, after acidification with acetic acid, the separated solids were aspirated and washed with water. The yields and purity of the products are summarized in Table III. Table III - Yield and purity of the product of Example 6
Reference: [1] Organic Process Research and Development, 2013, vol. 17, # 1, p. 77 - 86
[2] Patent: WO2012/139536, 2012, A1, . Location in patent: Page/Page column 13-14
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YieldReaction ConditionsOperation in experiment
98.7 g With 1,8-diazabicyclo[5.4.0]undec-7-ene In tetrahydrofuran at 20℃; for 2 h; Example 1Prepared Synthesis of 2-ethoxy-3 - [[2 '- (N-benzyloxymethylidene) biphenyl-4-yl] methyl] benzimidazole-4-carboxylate,Into the reaction bottle,Add 209.8gCDI, 134ml DBU and 4.5L THF, room temperature reaction 2h, the reaction is completed. 4.5 L of water, 4.5 L of ethyl acetate was extracted and the organic phases were combined.Respectively, saturated NaHC03, saturated NaCl solution, dry anhydrous sodium sulfate organic phase, evaporated to dry organic solvent. Beaten with acetone, filtered and dried to obtain 98.7 g of a product.
Reference: [1] Patent: CN103664921, 2016, B, . Location in patent: Paragraph 0047-0049; 0050-0052
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YieldReaction ConditionsOperation in experiment
2.3 g at 60℃; Step 2: Into the solution of 2-(2-amino-4-bromophenyl)propan-2-ol (2.3 g) in THF (50 mL) was added CDI (1.95 g) at rt., then the mixture was warmed to 60° C. and stirred for overnight. After solvent removal, the residue was dissolved in ethyl acetate and washed with 1M of HCl(aq) and brine, and dried with dry agent. After removal of the solvent, the residue was crystallized from DCM and hexane to provide 2.3 g of 7-bromo-4,4-dimethyl-1H-benzo[d][1,3]oxazin-2(4H)-one 7.37 was synthesized.
Reference: [1] Patent: WO2013/124026, 2013, A1, . Location in patent: Page/Page column 173
[2] Patent: KR2016/37198, 2016, A, . Location in patent: Paragraph 3363-3364; 3367
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YieldReaction ConditionsOperation in experiment
72% at 20 - 80℃; for 6 h; To a solution of compound 13 (0.90 g, 4.5 mmol) in THF(10 mL) at room temperature was CDI (0.80 g, 4.9 mmol)and the reaction was stirred at 80 °C for 6 hr. The mixturewas cooled to room temperature and the solid formed wasfiltered, washed with diethyl ether to afford 0.73 g (72percent) ofcompound 14 as off-white solid. IR (KBr) max. cm-1: 3308,3158 (NH), 3022 (Ar-H), 1682 (C=O), 1514, 1411 (C=C).1H NMR (500 MHz, DMSO-d6) = 5.25 (s, 2H, CH2); 6.82(d, 1H, J = 8.2 Hz, H-5); 7.42 (m, 2H, H-4, H-6); 10.29 (br.s, 1H, NH); 13C NMR (125.7 MHz, DMSO-d6) = 66.85(CH2), 113.70 (C-10), 115.70 (C-8), 121.03 (C-7), 127.52(C-6), 131.41 (C-5), 135.88 (C-9), 151.42 (C=O). Calculated(percent) for C8H7BrN2O (225.97); C: 42.32, H: 3.11, N: 12.34,found (percent); C: 42.27, H: 3.16, N: 12.28.
72% at 80℃; for 6 h; Example 4
Synthesis of 7-Bromo-3,4-dihydroquinazolin-2(1H)-one 13
To a solution of compound 12 (0.90 g, 4.5 mmol) in THF (10 mL) at room temperature was added CDI (0.80 g, 4.95 mmol), and the reaction was stirred at 80° C. for 6 hr.
The mixture was cooled to room temperature, and the solid formed was filtered, washed with diethyl ether to afford 0.73 g (72percent) of compound 13 as off-white solid. IR (KBr) νmax. cm-1: 3308, 3158 (NH), 3022 (Ar-H), 1682 (C=O), 1514, 1411 (C=C).
1H NMR (500 MHz, DMSO-d6) δ=5.25 (s, 2H, CH2); 6.82 (d, 1H, J=8.2 Hz, H-5); 7.42 (m, 2H, H-4, H-6); 10.29 (br. s, 1H, NH); 13C NMR (125.7 MHz, DMSO-d6) δ=66.85 (CH2), 113.70 (C-10), 115.70 (C-8), 121.03 (C-7), 127.52 (C-6), 131.41 (C-5), 135.88 (C-9), 151.42 (C=O).
Calculated (percent) for C8H7BrN2O (225.97); C, 42.32; H, 3.11; N, 12.34. found (percent); C, 42.27; H, 3.16; N, 12.28.
Reference: [1] Medicinal Chemistry, 2014, vol. 10, # 5, p. 484 - 496
[2] Patent: US8916704, 2014, B1, . Location in patent: Page/Page column 9
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