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Structure of 530-62-1 * 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.
General procedure: Imidazole was chosen as the model substrate for theN-arylation reaction in presence of electrospun CuO NFsas catalyst. The reaction flask was packed with 0.1 mM ofCuO NFs, 5 ml of DMF followed by the charging of imidazole(1 mM) and bromobenzene (1 mM) at 110 C withconstant stirring. The progress of the reaction was monitoredby thin layer chromatography (TLC). After completion,the catalyst was separated by centrifuge and washedseveral times with water and ethyl acetate for re-use. Theproduct was isolated by evaporation of solvent in vacuumand purified. The obtained product was characterized withFT-IR for functional group identification and GC-MS for structural confirmation.
Reference：
[1] Journal of Nanoscience and Nanotechnology, 2018, vol. 18, # 1, p. 234 - 241
2
[ 288-32-4 ]
[ 75-44-5 ]
[ 530-62-1 ]
Yield
Reaction Conditions
Operation in experiment
88%
With sodium hydroxide In water; chlorobenzene
Example 16 286.0 g of imidazole were introduced into 1200 g of chlorobenzene in a flask fitted with water separator, and 320 g of 50percent strength aqueous sodium hydroxide solution were added dropwise. Water was then separated out until the distillate no longer separated into two phases. After 224 ml of water had been separated out in this way, 100 ml of chlorobenzene were removed by distillation. 202 g of phosgene were subsequently passed in at 80-85° C. over the course of one hour. When the addition was complete, the mixture was stirred at 90° C. for a further 1 hour while a vigorous stream of nitrogen was passed through the flask, and the precipitate then present was filtered off at 80° C. and rinsed with 200 g of chlorobenzene at 90° C. The filtrate and the washing liquid were combined and cooled to 0° C. The precipitate which deposited was filtered off, rinsed with 200 g of dry chlorobenzene, and dried at 60° C. under reduced pressure (50 mbar). 290.6 g of carbonyldiimidazole were thus obtained in the form of colorless crystals having a purity of 97percent. This corresponded to a yield of 88percent of theory.
Into a 500 ml flask were added the tetrahydrofuran containing 48.1 g (0.707 mol) of imidazole obtained in Example 2 and 140 g of tetrahydrofuran. After the atmosphere of the system was replaced with nitrogen, 18.5 g (0.094 mol) of diphosgene was added dropwise at room temperature over a period of 2 hours. Thereafter, the same operations as in Example 1 were conducted and white crystals of CDI were taken out. Yield 24.4 g (0.15 mol) (percent yield 85percent). M.p. 111.3 to 116.9°C.
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.
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] 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
17
[ 64-17-5 ]
[ 530-62-1 ]
[ 288-32-4 ]
[ 19213-72-0 ]
Reference：
[1] Synthetic Communications, 2000, vol. 30, # 1, p. 23 - 30
[2] Russian Journal of Applied Chemistry, 2012, vol. 85, # 3, p. 456 - 459
18
[ 585-70-6 ]
[ 530-62-1 ]
[ 2527-99-3 ]
Reference：
[1] Patent: US5693611, 1997, A,
19
[ 16867-03-1 ]
[ 530-62-1 ]
[ 60832-72-6 ]
Yield
Reaction Conditions
Operation in experiment
81%
at 70℃; for 14 h;
[00102] As shown in step 4-i of Scheme 4, l,l '-carbonyldiimidazole (57.4 g, 354.2 mmol) was added to a solution of 2-amino-3-hydroxypyridine (26.0 g, 236.1 mmol, obtained from Aldrich Chemical Co.) in THF (400 mL). The resulting reaction mixture was stirred at 70 0C for 14 h. The reaction mixture was cooled to RT and concentrated under reduced pressure. The residue was dissolved in DCM (500 mL) and washed with 2 N NaOH (3 x 100 mL). The combined aqueous layers were cooled to 0 0C and acidified to a pH of 6 with 6 N HCl. The precipitate that was formed was collected in a fritted funnel, washed with cold water (100 mL), and dried under vacuum to afford oxazolo[4,5-δ]pyridin-2(JH)-one (Compound 1011, 26.0 g, 81percent yield): ESMS (M+Η) 137; 1H NMR (DMSO-d6) δ 12.4 (br, 1Η), 8.0 (d, 1Η), 7.6 (d, 1Η), 7.1 (dd, 1Η).
81%
at 70℃; for 14 h;
As shown in step 4-i of Scheme 4, 1,1'-carbonyldiimidazole (57.4 g, 354.2 mmol) was added to a solution of 2-amino-3-hydroxypyridine (26.0 g, 236.1 mmol, obtained from Aldrich Chemical Co.) in THF (400 mL). The resulting reaction mixture was stirred at 70 0C for 14 h. The reaction mixture was cooled to RT and concentrated under reduced pressure. The residue was dissolved in DCM (500 mL) and washed with 2 N NaOH (3 x 100 mL). The combined aqueous layers were cooled to 0 0C and acidified to a pH of 6 with 6 N HCl. The precipitate that was formed was collected in a fritted funnel, washed with cold water (100 mL), and dried under vacuum to afford oxazolo[4,5-δ]pyridin-2(JH)-one (Compound 1011, 26.0 g, 81percent yield): ESMS (M+Η) 137; 1H NMR (DMSO-d6) δ 12.4 (br, 1Η), 8.0 (d, 1Η), 7.6 (d, 1Η), 7.1 (dd, 1Η).
79%
for 1 h; Heating / reflux
Carbonyldiimidazole (600 mmol) was added in several batches to a solution of 2-aminopyridin-3- ol (400 mmol) in tetrahydrofuran (600 ml) and the reaction was heated at reflux for 1 h. The mixture was concentrated and the residue was diluted with dichloromethane (500 ml). The solution was extracted with 1.5 N sodium hydroxide (3 x 200 ml). The pH of the aqueous layer was adjusted to 5 with 2 N hydrochloric acid and the precipitaed solids were collected by filtration to provide oxazolo[4,5-b]pyridin- 2(3H)-one in 79percent yield as a grey solid.
79%
Reflux
Intermediate 30: Synthesis of 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][l,4]oxazine-7-sulfonyl chloride.CCIICCHH2XCOOCCIINaHCO3 N' " 1. Synthesis of oxazolo[4,5-blpyridm-2(3H)-one.Carbonyldiimidazole (600 mmol) was added in several batches to a solution of 2- aminopyridin-3-ol (400 mmol) in tetrahydrofuran (600 ml) and the reaction was heated at reflux for 1 h. The mixture was concentrated and the residue was diluted with dichloromethane (500 ml). The solution was extracted with 1.5 N sodium hydroxide (3 x 200 ml). The pH of the aqueous layer was adjusted to 5 with 2 N hydrochloric acid and the precipitaed solids were collected by filtration to provide oxazolo[4,5-b]pyridin-2(3H)-one in 79percent yield as a grey solid.
79%
for 1 h; Reflux
Intermediate 30: Synthesis of 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][l,4]oxazine-7-sulfonyI chloride.CICH,COCI Pd/C, H- NaHCO, 1. Synthesis of oxazolo[4,5-b]pyridin-2('3//)-one.Carbonyldiimidazole (600 mmol) was added in several batches to a solution of 2- aminopyridin-3-ol (400 mmol) in tetrahydrofuran (600 ml) and the reaction was heated at reflux for 1 h. The mixture was concentrated and the residue was diluted with dichloromethane (500 ml). The solution was extracted with 1.5 N sodium hydroxide (3 x 200 ml). The pH of the aqueous layer was adjusted to 5 with 2 N hydrochloric acid and the precipitaed solids were collected by filtration to provide oxazolo[4,5-b]pyridin-2(3H)-one in 79percent yield as a grey solid.
73%
Reflux
Into a 3-L 3-necked round-bottom flask, was placed a solution of 2-aminopyridin-3-ol (100 g, 908.15 mmol, 1.00 equiv), 1-[(1H-imidazol-1-yl)carbonyl]-1H-imidazole (221.3 g, 1.36 mol, 1.50 equiv) in THF (1000 mL). The resulting solution was heated to reflux overnight. After cooling, the reaction was concentrated under vacuum. The residue was dissolved in 1000 mL of DCM and extracted with 1M NaOH (3*800 mL). The combined liquids were cooled with a water/ice bath and adjusted to pH 5-6 by adding 3M HCl. The solids were collected by filtration. The solid was dried in an oven under reduced pressure. This resulted in 90 g (73percent) of 2H,3H-[1,3]oxazolo[4,5-b]pyridin-2-one (1-10) as a gray solid.
71%
for 1.5 h; Reflux
A suspension of carbonyl diimidazole (118.2 mmol, 19.1 g) and 2-amino-3-hydroxy-pyridine (90.9 mmol, 10.00 g) in THF (100 mL) was heated at reflux for 1.5 hours. (0767) The mixture was cooled and concentrated under reduced pressure. The residue was taken up in dichloromethane and extracted with 2M aqueous sodium hydroxide solution. The aqueous phase was cooled (ice/water bath) and (0768) acidified to pH5 with concentrated hydrochloric acid. (0769) The resulting precipitate was isolated by filtration, washed with water and THF then dried under suction to give the title compound as a grey powder (8.81 g, 71percent).
0.5 g
for 16 h; Reflux
To a stirred solution of 2-amino 3-hydroxy pyridine 1 (2 g, 16.26 mmol) in THF (20 ml ) was added CDI (2.63 g ,16.26 mmol )and the total reaction mass stirred at reflux temperature for 16 h. Reaction mass was cooled to room temperature, THF was distilled and the crude material was partitioned between water and ethyl acetate. The organic layer was separated, dried over sodium sulphate and concentrated under vacuum to afford the desired compound 2 (0.5 g )
Reference：
[1] Patent: WO2007/67416, 2007, A2, . Location in patent: Page/Page column 56; 91
[2] Patent: WO2010/96389, 2010, A1, . Location in patent: Page/Page column 42; 44
[3] Patent: WO2010/135014, 2010, A1, . Location in patent: Page/Page column 50-51
[4] Journal of Medicinal Chemistry, 2015, vol. 58, # 20, p. 8066 - 8096
[5] Patent: WO2009/23844, 2009, A2, . Location in patent: Page/Page column 120
[6] Patent: WO2010/21797, 2010, A1, . Location in patent: Page/Page column 84-85
[7] Patent: WO2010/24980, 2010, A1, . Location in patent: Page/Page column 103
[8] Journal of Medicinal Chemistry, 1993, vol. 36, # 4, p. 497 - 503
[9] Patent: US2014/274926, 2014, A1, . Location in patent: Paragraph 0525; 0526
[10] Patent: WO2015/115673, 2015, A1, . Location in patent: Page/Page column 76
[11] Archiv der Pharmazie, 1999, vol. 332, # 2, p. 43 - 49
[12] Patent: WO2013/42035, 2013, A1, . Location in patent: Page/Page column 30-31
[13] Patent: WO2013/114332, 2013, A1, . Location in patent: Page/Page column 116; 117; 118
[14] Chemical Biology and Drug Design, 2016, vol. 87, # 6, p. 918 - 926
[15] Patent: WO2009/100536, 2009, A1, . Location in patent: Page/Page column 95
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
22
[ 367-31-7 ]
[ 530-62-1 ]
[ 1544-75-8 ]
Yield
Reaction Conditions
Operation 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.
EXAMPLE 66; H-(5-chloro-lH-benzordlimidazol-2-yl)-l-(9H-purin-6-yl)piperidin-4-yl)methanamine 66A. 5-chloro-lH-benzordlimidazol-2(3H)-one4-Chloro-l,2-phenylenediamine (20 g, 140.27 mmol) was dissolved in THF (250 mL), to this was added portionwise l,l'-Carbonyldiimidazole (27.3 g, 168.32 mmol) and the reaction was stirred overnight at 25 0C. The black reaction was evaporated to dryness, <n="170"/>quenched with 2.0N HCl (100 mL) and filtered. The obtained solid was dissolved in methanol and passed through a 50 g SCX column, to afford 5-chloro-lH- benzo[d]imidazol-2(3H)-one (14.6 g, 61.7 percent) as a yellow solid, m/z (ESI+) (M+H)+ = 169; HPLC tR = 1.14 min; IH NMR (399.902 MHz, DMSO) δ 6.91 (IH, d), 6.97 - 6.94 (2H, m), 10.74 (2H, s).
Reference：
[1] Journal of Medicinal Chemistry, 2006, vol. 49, # 12, p. 3719 - 3742
[2] Patent: WO2008/75109, 2008, A1, . Location in patent: Page/Page column 167-168
[3] Journal of Heterocyclic Chemistry, 1965, vol. 2, p. 41,43
[4] Archiv der Pharmazie, 2000, vol. 333, # 5, p. 123 - 129
[5] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 3, p. 719 - 723
[6] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 4, p. 1071 - 1074
24
[ 530-62-1 ]
[ 1575-37-7 ]
[ 39513-26-3 ]
Yield
Reaction Conditions
Operation in experiment
90%
at 80℃; for 5 h;
2.1a. 5-bromo-1,3-dihydrobenzimidazol-2-one 4.29 g (26.46 mmol) of carbonyldiimidazole (CDI) is added to a solution of 4.5 g (24.05 mmol) of 4-bromobenzene-1,2-diamine in 95 mL of DMF and the reaction mixture is stirred for 5 hours at 80° C. Then the reaction mixture is poured onto water and the precipitate formed is filtered off. The precipitate is washed three times with water and dried in the circulating air dryer at 60° C. Yield: 4.6 g (90percent of theoretical); C7H5BrN2O (M=213.03); calc.: molpeak (M+H)+: 213/215; found: molpeak(M+H)+: 213/215; Rf value: 0.5 (silica gel, DCM/MeOH 10:1).
70%
at 40℃; for 1 h;
Step 89a: 5-Bromo-lH-benzo[d]imidazol-2(3H)-one (Compound 0601-186)A mixture of 4-bromobenzene-l,2-diamine (3.74 g, 20 mmol), CDI (3.9 g, 24 mmol) in 1 ,4-dioxane(20 mL) was stirred for 1 hr at 40°C. The mixture was filtered and washed with petroleum ether and dichloromethane to get compound 0601-186 (3.0 g, 70percent>) as a white solid. LCMS: 213 [M+l]+, 1H NMR (400 MHz, DMSO-^ δ 6.86 (d, J= 8.0 Hz, 1H), 7.06(m, 1 H), 7.08 (m, 1H), 10.77 (s, 2H).
70%
at 40℃; for 1 h;
Step 89a: 5-Bromo-1H-benzo[d]imidazol-2(3H)-one (Compound 0601-186)[0593]A mixture of 4-bromobenzene-1,2-diamine (3.74 g, 20 mmol), CDI (3.9 g, 24 mmol) in 1,4-dioxane (20 mL) was stirred for 1 hr at 40° C. The mixture was filtered and washed with petroleum ether and dichloromethane to get compound 0601-186 (3.0 g, 70percent) as a white solid. LCMS: 213 [M+1]+, 1H NMR (400 MHz, DMSO-d6) δ 6.86 (d, J=8.0 Hz, 1H), 7.06 (m, 1H), 7.08 (m, 1H), 10.77 (s, 2H).
70%
at 40℃; for 1 h;
1,4-dioxane (20mL) solution of 4-bromo-1,2-diamine (3.74g, 20mmol), CDI (3.9g, 24mmol) and the mixture was stirred for 1 hour at 40 of. The mixture was washed and filtered with petroleum ether and dichloromethane to give the compound 0601-186 as a white solid (3.0g, 70percent).
4 g
at 80℃; for 4 h;
To a solution of 4-bromobenzene-1 ,2-diamine (3 g,16 mmol) in DMF (60 mL) was added CDI (3.1 g, 19.3mmol). The reaction was stirred at 80° C. for 4 h. After themixture was cooled toRT, water (100 mL) was added. Theprecipitate was collected by filtration and dried to give 4 gof 5-bromo-1,3-dihydro-28-benzo[d]imidazol-2-one as adark red solid. GC-MS: 212/214 (M).
Reference：
[1] Journal of Medicinal Chemistry, 2016, vol. 59, # 15, p. 7188 - 7211
[2] Patent: US2005/267115, 2005, A1, . Location in patent: Page/Page column 35
[3] Patent: WO2005/103029, 2005, A1, . Location in patent: Page/Page column 75
[4] Journal of Medicinal Chemistry, 2006, vol. 49, # 12, p. 3719 - 3742
[5] Patent: WO2011/130628, 2011, A1, . Location in patent: Page/Page column 231
[6] Patent: US2013/102595, 2013, A1, . Location in patent: Paragraph 0592; 0593
[7] Patent: JP2015/187145, 2015, A, . Location in patent: Paragraph 0503
[8] Patent: US2010/249124, 2010, A1, . Location in patent: Page/Page column 51
[9] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 4, p. 1071 - 1074
[10] Patent: WO2014/100695, 2014, A1, . Location in patent: Paragraph 00357
[11] Patent: WO2016/57834, 2016, A1, . Location in patent: Paragraph 000862
[12] Patent: US2018/258065, 2018, A1, . Location in patent: Paragraph 0267
25
[ 10349-57-2 ]
[ 530-62-1 ]
[ 38896-30-9 ]
Reference：
[1] Patent: US2004/122001, 2004, A1,
26
[ 23838-73-5 ]
[ 530-62-1 ]
[ 10045-45-1 ]
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
27
[ 530-62-1 ]
[ 6274-29-9 ]
[ 40925-65-3 ]
Reference：
[1] Patent: US4328235, 1982, A,
28
[ 530-62-1 ]
[ 102-51-2 ]
[ 2080-75-3 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 3, p. 719 - 723
29
[ 55-22-1 ]
[ 530-62-1 ]
[ 26377-17-3 ]
Yield
Reaction Conditions
Operation in experiment
74%
With magnesium chloride In tetrahydrofuran
1.1. Preparation of Ethyl 3-(4-pyridyl)-3-oxopropionate Isonicotinic acid (35.56 g, 289 mmol) was added to a solution of 1,1'-carbonylbis-1H-imidazole (46.98 g, 290 mmol) in tetrahydrofuran (700 ml), and the resulting solution was stirred for 1.5 hr at 50° C. After cooling to room temperature, malonic acid monoester potassium salt (51.7 g, 304 mmol) and magnesium chloride (34.33 g, 361 mmol) were added, and the mixture was refluxed for 1 hr and then heated at 50° C. for 6 hr. The solvent was removed under reduced pressure and the residue was quenched by the addition of dilute acetic acid. The organic layer was extracted with ethyl acetate (3 times) and the combined extracts were washed with dilute aqueous sodium bicarbonate and brine, and were concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; hexane/ethyl acetate=2/1 to 1/1) and recrystallization from hexane-ethyl acetate gave 41.52 g (74percent) of the title compound.
74%
With magnesium chloride In tetrahydrofuran
1.1. Preparation of Ethyl 3-(4-pyridyl)-3-oxopropionate Isonicotinic acid (35.56 g, 289 mmol) was added to a solution of 1,1'-carbonylbis-1H-imidazole (46.98 g, 290 mmol) in tetrahydrofuran (700ml), and the resulting solution was stirred for 1.5 hr at 50°C. After cooling to room temperature, malonic acid monoester potassium salt (51.7 g, 304 mmol) and magnesium chloride (34.33 g, 361 mmol) were added, and the mixture was refluxed for 1 hr and then heated at 50°C for 6 hr. The solvent was removed under reduced pressure and the residue was quenched by the addition of dilute acetic acid. The organic layer was extracted with ethyl acetate (3 times) and the combined extracts were washed with dilute aqueous sodium bicarbonate and brine, and were concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; hexane/ethyl acetate = 2/1 to 1/1) and recrystallization from hexane - ethyl acetate gave 41.52 g (74percent) of the title compound.
74%
With magnesium chloride In tetrahydrofuran
1.1. Preparation of Ethyl 3-(4-pyridyl)-3-oxopropionate Isonicotinic acid (35.56 g, 289 mmol) was added to a solution of 1,1'-carbonylbis-1H-imidazole (46.98 g, 290 mmol) in tetrahydrofuran (700ml), and the resulting solution was stirred for 1.5 hr at 50°C. After cooling to room temperature, malonic acid monoester potassium salt (51.7 g, 304 mmol) and magnesium chloride (34.33 g, 361 mmol) were added, and the mixture was refluxed for 1 hr and then heated at 50°C for 6 hr. The solvent was removed under reduced pressure and theresidue was quenched by the addition of dilute acetic acid. The organic layer was extracted with ethyl acetate (3 times) and the combined extracts were washed with dilute aqueous sodium bicarbonate and brine, and were concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; hexane/ethyl acetate = 2/1 to 1/1) and recrystallization from hexane - ethyl acetate gave 41.52 g (74percent) of the title compound.
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).
Preparation 131 6-Chloro-7,9-dihydro-purin-8-one Combine 6-chloro-pyrimidine-4,5-diamine (7.46 mmol; 1.08 g); 1,1'-carbonyldiimidazole (2 equiv; 14.92 mmol; 2.42 g) and 1,4-dioxane (20 mL) and heat to reflux under nitrogen for 50 min. Evaporate the yellow solution to an oil. Add DCM (80 mL), let sit 1 h, filter and dry in vacuum oven at 45° C. to provide the title compound (1.22 g; 7.15 mmol; 96percent) MS (ES+): m/z=169 (M-H).
86%
for 48 h; Heating / reflux
2D. 6-Chloro-7,9-dihydropurin-8-one; A mixture of the 5,6-diamino-4-chloropyrimidine of Example 6A (1.0 g, 6.92 mmol) and N,N'-carbonyldiimidazole (2.13 g, 13.2 mmol) in 1,4-dioxane (20 ml) was refluxed under <n="119"/>argon for 48 hours. The solution was concentrated to a brown oil, which was triturated and washed with dichloromethane to give an off-white solid (1.02 g, 86percent) LC/MS (LCTl): Rt 2.45 [M+H]+ 173, 171.
86%
for 48 h; Heating / reflux
13B. 6-Chloro-7,9-dihydropurin-8-one <n="118"/>A mixture of the 5,6-diamino-4-chloropyrimidine of Example 13A (1.0 g, 6.92 mmol) and N,N'-carbonyldiimidazole (2.13 g, 13.2 mmol) in 1,4-dioxane (20 ml) was refluxed under argon for 48 hours. The solution was concentrated to a brown oil, which was triturated and washed with dichloromethane to give an off-white solid (1.02 g, 86percent) LC/MS (LCT1): Rt 2.45 [M+H]+ 173, 171.
86%
for 48 h; Heating / reflux
6B. 6-Chloro-7,9-dihydropurin-8-oneA mixture of the 5,6-diamino-4-chloropyrimidine of Example 6A (1.0 g, 6.92 mmol) and N,N'-carbonyldiimidazole (2.13 g, 13.2 mmol) in 1,4-dioxane (20 ml) was refluxed under argon for 48 hours. The solution was concentrated to a brown oil, which was triturated and washed with dichloromethane to give an off-white solid (1.02 g, 86percent) LC/MS (LCTl): Rt2.45 [M+H]+ 173, 171.
Reference：
[1] Organic Process Research and Development, 2008, vol. 12, # 5, p. 877 - 883
33
[ 36692-49-6 ]
[ 530-62-1 ]
[ 106429-57-6 ]
Yield
Reaction Conditions
Operation 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
34
[ 67073-39-6 ]
[ 530-62-1 ]
[ 60713-78-2 ]
Yield
Reaction Conditions
Operation in experiment
76%
at 0 - 23℃;
To a solution of 4-chloro-5-nitro-benzene-1 ,2-diamine (8.34 g, 44.4 mmol) and THF (625 ml_) was added carbonyl diimidazole (8.65 g, 53.3 mmol) at 0 0C. The reaction mixture was allowed to warm to 23 0C and was stirred for 20 h at this temperature. The reaction mixture was concentrated to a volume of 300 ml_ and 500 ml_ aqueous 1 M HCI was added, followed by water (total volume 2 L). The resulting suspension was cooled at 0 0C for 2 h, and the precipitate was collected and dried on the filter. It was then triturated with cold EtOAc (20 ml_) and rinsed EtOAc (2 x 5 ml_) to yield the titled compound (7.26 g, 76percent yield). MS (ESI/CI): mass calcd. for C7H4CIN3O3, 213.0; m/z found, 214.0 [M+H]+.
Reference：
[1] Journal of Medicinal Chemistry, 2015, vol. 58, # 20, p. 8066 - 8096
39
[ 5028-20-6 ]
[ 530-62-1 ]
[ 21991-39-9 ]
Yield
Reaction Conditions
Operation in experiment
70%
at 23℃; for 15 h; Inert atmosphere
N2 -methylpyridine-2,3-diamine (66 mg, 0.54 mmol) and 1,1'-carbondiimidazole (130.3 mg, 0.80 mmol, 1.5eq) was dissolved in THF and stirred at RT under argon overnight. The solvent of the crude product mixture was evaporated under vacuum and the residue was recrystallized twice from water to give fluffy pink long crystals of the desired product (70percent)
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 5, p. 1117 - 1123
[2] Journal of Medicinal Chemistry, 2000, vol. 43, # 16, p. 3052 - 3066
[3] Patent: US2011/319394, 2011, A1, . Location in patent: Page/Page column 78-79
40
[ 104-15-4 ]
[ 530-62-1 ]
[ 2232-08-8 ]
Reference：
[1] Letters in Organic Chemistry, 2015, vol. 12, # 9, p. 637 - 644
41
[ 122-39-4 ]
[ 530-62-1 ]
[ 2875-79-8 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2012, vol. 10, # 31, p. 6420 - 6431
42
[ 7598-80-3 ]
[ 530-62-1 ]
[ 60628-96-8 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 16, p. 7715 - 7727
43
[ 530-62-1 ]
[ 27584-70-9 ]
Reference：
[1] Patent: US4728661, 1988, A,
44
[ 530-62-1 ]
[ 304853-89-2 ]
[ 21440-97-1 ]
Yield
Reaction Conditions
Operation in experiment
100%
at 50℃;
Step 2: 6-Bromo-4,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; This compound was prepared as described in U.S. Pat. No. 6,444,668. To a solution of 2-(2-amino-5-bromo-phenyl)-propan-2-ol (18 g, 78 mmol), prepared in the previous step, in dry THF (150 mL) was added 1,1'-carbonyldiimidazole (15.5 g, 94 mmol) under nitrogen. The reaction was heated at 50° C. overnight. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate (100 mL). The solution was washed with 1 N HCl (2.x.40 mL), brine (20 mL), dried over anhydrous MgSO4 and filtered. After removal of the solvent under reduced pressure 6-bromo-4,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (20 g, 100percent) was obtained as a white solid, mp 199-200° C.
Intermediate 8: 6-Bromo-5-chlo H)-one A mixture of 2-amino-5-bromo-4-chlorophenol (Intermediate 7, 8.4 g, 37.8 mmol), N,N-carbonyldiimidazole (12.2 g, 75.6 mmol) in THF (250 mL), was heated at 80 °C for 3 h. The solvent was removed under vacuum and the residue purified by column chromatography (silica: 200 - 400 mesh, 100 g) eluting with petroleum ether/ ethyl acetate from 9:1 to 5:1 ) to give 6-bromo-5-chlorobenzo[d]oxazol-2(3H)-one as an orange solid (7.7 g, 82percent). LCMS (A): Rt 1.49 min, MH+ 248/250.
To a solution of 2- (2-amino-ethyl)-phenylamine (5.6 g, 41 mmol) in tetrahydrofuran (400 ML) was added 1, 1#x0;-CARBONYLDIIMIDAZOLE (6.67 g, 41 mmol) at 0#x0C with stirring. The solution was stirred at 0 #x0;C for 1 h, then at room temperature for 18 h, and then refluxed for 24 h. The solid was removed by filtration. The filtrate was concentrated under vacuum, and the residue was purified by silica gel chromatography (2.5percent to 5percent of methanol in chloroform) to give the 1, 3,4, 5-tetrahydro-benzo [d] [1, 3] diazepin-2-one (Yield: 5.0 g, 75percent). 1H NMR (400 MHz, DMSO-d6) : 8 8.60 (s, 1H), 7.05 (m, 4H), 6.80 (t, 1H), 3.20 (m, 2H), 2.85 (m, 2H). MS: m/z 163 (MH+).
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
51
[ 492-41-1 ]
[ 530-62-1 ]
[ 16251-45-9 ]
Reference：
[1] European Journal of Organic Chemistry, 2001, # 3, p. 517 - 522
[2] Heterocycles, 2002, vol. 57, # 4, p. 637 - 648
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.
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] Journal of Organic Chemistry, 1987, vol. 52, # 14, p. 3168 - 3169
60
[ 530-62-1 ]
[ 85622-93-1 ]
Reference：
[1] Patent: WO2018/112589, 2018, A1,
61
[ 530-62-1 ]
[ 4042-35-7 ]
Yield
Reaction Conditions
Operation in experiment
67%
With triethylamine In tetrahydrofuran at 20 - 60℃;
Triethylamine (0.94 mL, 6.65 mmol) was added dropwise to a solution of L- alaninol (500 mg, 6.65 mmol) and [1,] 1-carbonyldiimidazole (1.29 g, 7.98 mmol) in dry THF (10 mL) at rt, under argon atmosphere. The reaction mixture was stirred overnight at [60°C.] The solvent was removed by evaporation under reduced pressure. Purification of the residue by silica gel column chromatography, eluting with 6percent methanol in dichloromethane, afforded the desired compound (450 mg, 67percent). Rf = 0.39 [(MEOH/CH2CL2] 6: 94). 1H NMR [(CDC13)] [S] 6.74 (m, 1H), 4.45-4. 34 (m, 1H), 4.98-4. 77 (m, 2H), 1.17 (m, 3H).
With N-ethyl-N,N-diisopropylamine In dichloromethane
To 50.2 mg of N-methyl-L-alanine suspended in 60 ml of CH2Cl2 was added 0.186 ml of DIPEA. After the solid mass had been broken up into a fine suspension by sonication, 82.6 mg of 1,1'-carbonyldiimidazole was added in 5 portions over 4 hours. The reaction was stirred over night, then filtered through a short silica column with dichloromethane. The filtrate was evaporated and crystallized with ether/hexane to afford 28 mg (45percent Yield) of product. 1H NMR (DMSO) 4.40 (1H, dd, J=7.0, 14.1 Hz, CH), 2.84 (3H, s, N-CH3), 1.38 (3H, d, J=7.1 Hz); 13C NMR 194.83, 184.18, 56.70, 27.97, 14.09; MS M-168.8 (M+K-1), 153.8 (M+Na-1). Compound Id can be prepared in a similar manor from N-methyl-D-alanine. Compound Ic can also be prepared by the reaction of phosgene on N-methyl-L-alanine.
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,
65
[ 6638-79-5 ]
[ 530-62-1 ]
[ 139290-70-3 ]
Yield
Reaction Conditions
Operation 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,
66
[ 478408-77-4 ]
[ 6638-79-5 ]
[ 84358-13-4 ]
[ 530-62-1 ]
[ 139290-70-3 ]
Yield
Reaction Conditions
Operation 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.
With pyridine In tetrahydrofuran at 65℃; for 3 h; Inert atmosphere
3. Synthesis of intermediate 107-3 Under a nitrogen atmosphere, the intermediate 107-2 (8.0 g, 54.0 mmol) as a raw material was dissolved in 100 mL of anhydrous tetrahydrofuran at room temperature in a 250 mL single-necked flask, followed by sequentially adding carbonyldiimidazole CDI (19.7 g, 108 mmol) and pyridine (8.54 g, 108 mmol) into the reaction system. Next, the reaction system was heated to 65°C, and then carried out for 3h. After detecting the reaction was completed, the reaction system was cooled to room temperature. The reaction mixture was poured into 100 mL of ice water to quench the reaction. The reaction system was washed with 300 mL of dichloromethane three times, and the organic phases were combined, washed with 300 mL of saturated brine three times, dried over anhydrous sodium sulfate and concentrated to dryness. The resulting residue was purified by silica gel column chromatography (eluent: EA/PE (1:10-1:5)), and the product was collected and concentrated to dryness to give 4.2 g of the intermediate 107-3 (45percent) as a white solid. LCMS: 175.1.
Reference：
[1] Patent: EP3216786, 2017, A1, . Location in patent: Paragraph 0553-0554
[2] Journal of Medicinal Chemistry, 1999, vol. 42, # 15, p. 2870 - 2880
[3] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 23, p. 6067 - 6070
[4] Patent: WO2015/65338, 2015, A1, . Location in patent: Page/Page column 49; 50
[5] Patent: WO2015/65336, 2015, A1, . Location in patent: Page/Page column 18
71
[ 530-62-1 ]
[ 149524-42-5 ]
Yield
Reaction Conditions
Operation 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
72
[ 15403-22-2 ]
[ 106-95-6 ]
[ 530-62-1 ]
[ 113100-86-0 ]
Reference：
[1] Patent: US2002/65308, 2002, A1,
73
[ 530-62-1 ]
[ 19171-19-8 ]
Yield
Reaction Conditions
Operation 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.
Stage #1: at 60℃; for 1.5 h; Stage #2: With trifluoroacetic acid In tetrahydrofuran at 20℃; for 14 h;
Step 2 The product from Step 1 was suspended in THF. Carbonyl diimidazole was added in portions within 30 minutes and the mixture heated to 60°C for 1.5 hours. According to TLC no starting material was detected. The mixture was cooled to room temperature and treated with o-phenyldiamine and TFA (added in one portion). The dark solution was stirred at RT for 14 hours. THF was evaporated and the residue portioned between ethyl acetate (1500 mL) and water (500 mL). The layers were separated and the water layer was extracted twice with 250 mL of ethyl acetate. The combined organics were dried and concentrated. The residue was suspended in dichloromethane (10 mL/g), stirred for 30 minutes, filtered and dried (this procedure was applied twice) resulting in77 g of Entinostat as a beige solid. The compound was analyzed by XRPD and resulted to be a mixture of form A and form B.
Intermediate 34. (/?)-5-(2,2-Dimethyl-4H-1 ,3-benzodioxin-6-yl)-1 ,3-oxazolidin-2-one; To a solution of (f?)-2-amino-1-(2,2-dimethyl-4H-1 ,3-benzodioxin-6-yl)ethanol (2.53 g, 11.3 mmol) in chloroform (12 ml.) was added carbonyldiimidazol (2.75 g, 17 mmol) and triethylamine (2.37 ml_, 17 mmol). The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue diluted with ethyl acetate (25 ml_). The organic layer was washed with water (2 x 10 ml_), brine (10 ml_), dried (Na2SO4), and the solvent reduced under reduced pressure. Purification by column chromatography with silica gel and n-hexane/ethyl acetate (1 :2) as eluent yielded the title compound (1.63 g, 51percent).1H NMR (300 MHz, CDCI3): 1.55 (s, 6 H); 3.54 (t, J=8.1 Hz, 1H); 3.94 (t, J=8.7 Hz, 1H); 4.86 (s, 2H); 5.10 (bs, 1H); 5.56 (t, J=8.1 Hz, 1H); 6.85 (d, J=8.5 Hz, 1H); 7.04-7.07 (m, 1H); 7.15-7.18 (m, 1H).
2641 g of 2-((2R)-2-hydroxy-3-[4-(3-oxo-4-morpholinyl)phenyl]amino}propyl)-1H-isoindole-1,3(2H)-dione (V) are suspended in 22 l of toluene and, at 19° C., 1300 g of N,N-carbonyl-diimidazole are added. The reaction mixture is subsequently heated under reflux for one hour and then, at 60° C., 4.5 l of ethanol are added. After cooling to 25 to 30° C., the precipitated reaction product is filtered off with suction, washed with ethanol and then dried. Yield: 2756 g; equivalent to 97.9percent of theory. Melting point: 220.5° C.
93.55%
at 25 - 30℃; for 8 h;
In a four neck round bottom flask, charged dichloromethane (3400ml), 2-((2R)-2-Hydroxy-3- [4-(3-oxo-4-morpholinyl)phenyl]amino}propyl)-lH-isoindole-l,3(2H)-dione (340 g) and Ν,Ν' -dicarbonyldiimidazole (209.13 g) at 25 to 30°C. The obtained reaction mass then stirred for 8hr. at 25 to 30°C. Reaction mass is concentrated under reduced pressure to obtain residue. Added tetrahydrofuran (1700 ml) to residue. The obtained mixture is heated to 40 to 45°C for 30 minutes followed by cooling to room temperature. Finally obtained solid is filtered off and washed by tetrahydrofuran(170 ml) Yield =93.55percent
93.8%
at 0 - 100℃; for 4 h; Large scale
This example relates to the preparation of 2-{(S)-2-oxo-3-[4-(3-oxo- morpholine-4-yl)phenyl]-oxazolidine-5-yl-methyl}-isoindol-1 ,3-dione, step b) of the process. 17.0 kg of the compound (III) obtained in example 1 , 170 kg of chlorobenzene and 8.5 kg of Ν,Ν-carbonyldiimidazole are loaded into a reactor. The mass is brought to about 100 °C and maintained at this temperature for 4 hours. At the end of the reaction, the mass is cooled to 0-10 °C then filtered by washing it with 34.0 kg of chlorobenzene and lastly oven-dried. 17.0 kg of the desired compound (IV) are obtained, with a reaction yield equal to 93.8percent.
93.8%
at 10 - 110℃; for 2 h;
To a 2 litre 4 Neck RBF, charge Toluene (830 ml), Compound (IV) (100 gms). Stirr the reaction mass and cool to 10-15°C. Charge N,N-carbonyl-diimidazole (82 gms). Reflux the reaction mass at 105-110°C for 2 hrs. Cool the reaction mass to 55-60°C and charge methanol (170 ml). Cool the reaction mass further to 25-30°C and filter. Wash the residue with Methanol (50 gms). Dry the solid under vacuum. Dry Wt: 100 gms (Theoretical yield: 93.80percent); Purity: 99.78percent
90.73%
for 4 h; Reflux
142.5 g (0.360 mol) of 2-((2R)-2-hydroxy-3-[4-(3-oxo-4-morpholinyl)phenyl]amino} propyl)-1 H-isoindole-1 , 3(2H)-dione (I), 175.32 g (1 .082 mol) of N,N- carbonyldiimidazole and 1425 mL of tetrahydrofuran were charged in a 3L flask and the reaction mass was heated to reflux for 4 hours. Then, the reaction mass was cooled down to 0 °C for 1 hour and the resulting solid was filtered off and dried under vacuum at 70 °C.Yield: 137.8 g. Molar yield: 90.73percent. HPLC purity: 99.74percent. M.P.: 223 °C. S.O.R.: [a ]D25 = -75.26° (c = 1 ,DMSO)
88.3%
for 3 h; Industry scale; Reflux
N,N-Carbonyldiimidazole (2.897kg , 1.47eq) was added to a suspension of compound according to d. ) (5.1kg, 12.114mol ) in toluene (49L) . The reaction mixture was refluxed for 3h, then at 60 0C, ethanol (14L) was added. After cooling to 25 0C, the precipitate was filtered and 4.8 kg of (S) -2- ( (2-oxo-3- (4- (3- oxomorpholino) phenyl) oxazolidin-5-yl) methyl) isoindoline- 1, 3-dione was obtained as a colorless solid (Yield 88,3 percent)
88.2%
With potassium carbonate In dichloromethane at 20℃; for 5 h;
To suspension of 2-[(2R)-2-hydroxy-3-[4-(3-oxomorpholin-4-yl)phenyl]amino}propyl]-1H-isoindole-1,3(2H)-dione (170 gm) and potassium carbonate (59.3 gm) in dichloromethane (1500 ml) was added 1,1’-carbonylbis(1H-imidazole) (153.4 gm) at room temperature. Reaction mass was then stirred for 5 hr at room temperature. After completion of reaction, inorganic base is removed by filtration. The obtained filtrate is concentrated under reduced pressure to yield solid. To this solid tetrahydrofuran (850 ml) was added followed by stirring and filtration. The obtained solid is dried under vacuum for 4 hr at 50 °C to obtain 2-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)-1H-isoindole-1,3(2H)-dione. [Yield = 160 gm (88.2 percent); Purity (HPLC) =99.65 percent]
88.2%
With potassium carbonate In dichloromethane at 20℃; for 5 h;
To suspension of 2-[(2R)-2-hydroxy-3-[4-(3-oxomorpholin-4-yl)phenyl]amino}propyl]-1H-isoindole-1,3(2H)-dione (170 gm) and potassium carbonate (59.3 gm) in dichloromethane (1500 ml) was added 1,1'-carbonylbis(1H-imidazole) (153.4 gm) at room temperature. Reaction mass was then stirred for 5 hr at room temperature. After completion of reaction, inorganic base is removed by filtration. The obtained filtrate is concentrated under reduced pressure to yield solid. To this solid tetrahydrofuran (850 ml) was added followed by stirring and filtration. The obtained solid is dried under vacuum for 4 hr at 50° C. to obtain 2-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)-1H-isoindole-1,3(2H)-dione. [Yield=160 gm (88.2percent); Purity (HPLC)=99.65percent]
85%
for 5 h; Reflux
Example 1 : Preparation of 2-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-l,3-oxazolidin- 5-yl}methyl)-lH-isoindol-l,3(2H)-dione, the compound of formula I(2R)-2-Hydro y-3-[4-(3-oxo-4-moφholinyl)phenyl]amino-propyl-lH-isoindol-l ,3(2H)- dione (10.0 g; 25 mmol), the compound of formula III, containing 1.0 percent of the (2S)-isomer was charged into a flask and tetrahydrofuran (200 ml) was added. NN-carbonyldiimidazole (4.1 g; 25 mmol) was added to the stirred mixture. The mixture was heated up to boil and refluxed for 5 hours.The white suspension was cooled to the temperature of 20°C, stirred for 1.5 hours, aspirated and washed with tetrahydrofuran (50 ml). The product was poured into a flask with 2- methoxyethanol (175 ml). The mixture was heated up to boil and stirred until dissolution. Active carbon (0.5 g) was added to the solution and filtered off while hot after 10 minutes and washed with 2-methoxyethanol (10 ml). The solution was cooled to the laboratory temperature and stirred for 1 hour. The resulting crystals were aspirated and washed with methanol (100 ml). The aspirated product was dried in a vacuum drier at a temperature up to 60°C. 9 g (85 percent of theory) of 2-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-l ,3-oxazolidin-5-yl} methyl)- lH-isoindol- l ,3(2H)-dione with the isomeric purity of 99.98percent were obtained, HPLC purity 99.7percent, m. p. = 221 - 223 °C. The polymorphous structure of the compound (I) was also characterized with the X-ray powder diffraction (Fig. 1) with the characteristic 2 theta angles 4.63; 12.00; 13.9; 15.3; 15.87 and 24.55.
73%
With dmap In tetrahydrofuran for 21 h; Reflux; Industrial scale
300 ml of THF were added to 20 g of 2-((2i?)-2-hydroxy-3-{ [4-(3-oxomorpholin-4- yl)phenyl]amino}propyl)- lH-isoindol-l ,3(2H)-dione (14, 0.0506 mol), 16 g of Ι , Γ- carbonyldiimidazole (0.09869 mol) and 0.1 g of 4-dimethylamino)pyridine. The suspension was stirred and heated to boiling for 7 hours, then slightly cooled and another portion of Ι , Γ-carbonyldiimidazole (0,09869 mol) was added. Then, the suspension was stirred under boiling for 14 hours. After that the mixture was cooled to 25°C, which was followed by filtration, washing of the cake with THF, with an ethanol/water mixture (9: 1) and drying. 15.6kg of an off-white powder was obtained that melted at the temperature of 216 to 217°C; HPLC 99.9percent, content of the (R)- isomer below 0.03percent, yield 73percent.
95 g
at 80 - 85℃; for 6 h;
100 gm (0.2531 moles) 2-((2R)-2-Hydroxy-3-[4-(3-oxo-4-morpholinyl) phenyl] amino} propyl) -lH-isoindole- 1, 3(2H)-dione (V) is added in 700 ml Dimethyl carbonate, 69.9 gm0 (0.4301 moles) Carbonyl diimidazole and 15.4 gm (0.1260 moles) Dimethylaminopyridine. Reaction mass is heated to 80-85°C for 6 hours. It is then cooled, chilled and filtered to get 2-({(5S)-2-Oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]- l,3- oxazolidiii-5-yl}methyl)- lH-isoindole- l,3(2H)-dione. it is washed with dimethyl carbonate followed by water. Wet Wt = 95 gm
To a stined solution of 3, 4-diammobenzanitrile (IC; 200 mg, 1.5 mmol) in THF (10 mL) under argon atmosphere was added carbonyl diimidazole (243 mg, 1.5 mmol) at RT and stirred for 16 h. The volatile were concentrated raider reduced pressure. The crude material was purified by silica gel column chromatography (eiuent: 40percent Acetone Hexane) to afford compound ID (60 mg, 0.37 mmol, 24percent) as an off-white solid. H NMR (400 MHz, DMSO- : δ 11.16 (b s; IH), 11.04 (br s, IH), 7.39 (dd, 7= 8. L 1.6 Hz, IH), 7.30 (s, IH), 7.06 (d, 7 = 8.2 Hz. IH).
1.5 g
at 0 - 25℃; for 18 h;
To a stirred solution of 3,4-diaminobenzonitrile (1 .40 g, 10.5 mmol) in tetrahydrofuran (70 mL) at 0 °C was added 1 ,1’-carbonyldiimidazole (2.22 g, 13.7 mmol), then the mixture was warmed to 25 °C and stirred for 18 h. The mixture was treated with ethyl acetate (100 mL), washed with 1 N HCI (20 mL x 2) and saturated aqueous sodium chloride solution (30 mL), then dried over anhydrous sodium sulfate,filtered and concentrated to give 2-oxo-1 ,3-dihydrobenzimidazole-5-carbonitrile (1 .50 g) as a pale yellow solid, which was used in next step directly.
0.211 g
at 125℃; for 2 h;
Step a. To a solution of 3,4-diaminobenzonitrile (CAS Number 17626-40-3; 0.400 g, 3.00 mmol) in toluene (5 ml) was added CDI (0.633 g, 3.907 mmol) at rt. The resulting reaction mixture was heated at 125°C for 2 h. The resulting reaction mixture was diluted with water (100 ml) and basified using 1M NaOH solution. The resulting mixture was extracted with EtOAc (3 x 100 ml) and the combined organic layer was dried over Na2S04, filtered and concentrated under reduced pressure yielding 2- oxo-2,3-dihydro-lH-benzo[d]imidazole-5-carbonitrile (0.211 g, 1.327 mmol). LCMS: Method F, 4.066 min, MS: ES- 158.00; NMR (400 MHz, DMSO-d6) δ ppm: 11.19 (s, 1 H), 11.06 (s, 1 H), 7.40 (dd, J=8.0, 1.2 Hz, 1 H), 7.31 (d, J=1.2 Hz, 1 H), 7.07 (d, J=8.0 Hz, 1 H).
Reference：
[1] Journal of Medicinal Chemistry, 2006, vol. 49, # 12, p. 3719 - 3742
[2] Patent: WO2017/117393, 2017, A1, . Location in patent: Page/Page column 263
[3] Patent: EP2003132, 2008, A1, . Location in patent: Page/Page column 23
[4] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 17, p. 5392 - 5395
[5] Patent: WO2018/81167, 2018, A1, . Location in patent: Page/Page column 244
[6] Patent: WO2018/60742, 2018, A1, . Location in patent: Page/Page column 62-63
(1) To a three-necked reaction flask was added 350 mL of tetrahydrofuran, and the mixture was stirred and 54.3 g of 1,1-dicarbonylimidazole was added as a white suspension. The temperature was raised to 40 ° C, 57.1 g of diethylphosphonic acid was dissolved in tetrahydrofuran, and the mixture was added dropwise to the mixture at 40 ° C for 30 to 45 minutes. The above reaction mixture is solution A; (2) To a three-necked reaction flask was added 420 mL of tetrahydrofuran, stirred and stirred, and 84.0 g of compound 6, for the green solution. The temperature is raised to 40 ° C. The solution is B, and the solution A is added dropwise to the solution B, and the internal temperature is reduced to 30 ° C. (3) stirring for 2 hours, the reaction is complete. 420 mL of methyl tert-butyl ether was added and cooled to room temperature. After stirring for 30 minutes, the above white suspension was filtered. (4) was washed with 420 mL (tetrahydrofuran / methyl tert-butyl ether = 1: 1, by volume) The solid was washed with 1.7 L of water. Filter to dry. Dried to give 82.0 g of compound 8 in a yield of 66.2percent.
Reference：
[1] Patent: CN106916147, 2017, A, . Location in patent: Paragraph 0052-0057
83
[ 530-62-1 ]
[ 765-30-0 ]
[ 417716-92-8 ]
Yield
Reaction Conditions
Operation in experiment
93.1%
With carbon dioxide; triethylamine In dichloromethane at 50℃; for 6 h;
To 600 ml of dichloromethane was added 60.0 g of 4- (4-amino-3-chlorophenoxy) -7-methoxyquinoline-6-carboxamide hydrochloride (E), 10.8 g of cyclopropylamine, 51.2 g N, N-carbonyldiimidazole and 47.8 g of triethylamine, CO2, and heated at 50 ° C under reflux for 6 hours.The reaction solution was washed with 900 ml of water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the methanol was recrystallized to give 62.1 g of the title compound (F) as white crystals.(Yield: 93.1percent)
Reference：
[1] Journal of Medicinal Chemistry, 2009, vol. 52, # 2, p. 379 - 388
85
[ 1072-67-9 ]
[ 530-62-1 ]
[ 286371-44-6 ]
[ 475108-18-0 ]
Yield
Reaction Conditions
Operation in experiment
87%
at 40℃; for 3 h;
3 - amino - 5 - methyl isoxazole (98 mg, 1 mmol) dissolved in anhydrous dichloromethane (5 ml) in, added under mixing N, N '- carbonyl diimidazole (356 mg, 2.2 mmol), then add 4 - [(4 (330 mg, 1 mmol) and tetrahydrofuran (5 ml) at 40 ° C under under stirring reaction 3 h, the reaction liquid under reducing pressure to dryness, re-dissolved in ethyl acetate (30 ml), and water extraction 3 times. The collection of ethyl acetate, reduced pressure to dryness, for column purification of silica gel chromatography (1 - 2percent methanol: dichloromethane). Collecting the corresponding elution component reducing dryness, methanol for refining, resulting in white or white solid powder for grips nepal fertile (394.6 mg, 87percent).
Reference：
[1] Patent: CN106967058, 2017, A, . Location in patent: Paragraph 0022; 0023; 0025
86
[ 851883-08-4 ]
[ 530-62-1 ]
[ 710348-69-9 ]
Yield
Reaction Conditions
Operation in experiment
63.2%
at 23℃; for 16 h;
Step B: 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydro-2H-benzo[d]imidazol- 2-one. To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene-1,2-diamine (17 mmol) in EtOAc (360 mL) was added 1,1'-carbonyldiimidazole (CDI) (3.0 g, 19 mmol). The resulting mixture was stirred at 23 °C for 16 h. The reaction mixture was diluted with DCM and the resulting white solid was filtered and washed with MeOH to afford the title compound (10.8 g, 63.2percent).
Stage #1: With dmap In tetrahydrofuran for 12 h; Reflux Stage #2: With hydrogenchloride In water at 20℃;
The resulting reaction flask was added 39.9g (0.101mol) of Intermediate VI, 100ml of tetrahydrofuran, 63.2g (0.39mol) N, N'- carbonyldiimidazole was stirred uniformly, added 5.0g of 4-dimethylaminopyridine (of DMAP), heated under reflux for 10 hours, TLC in the control (dichloromethane: methanol = 20: 1, volume ratio) reaction was complete, the reaction was stopped, cooled to room temperature after stirring for 1 hour, filtered, the filter cake was washed with 40ml of tetrahydrofuran and 70ml of 95percent ethanol washing, the resulting wet product directly into the reaction flask, and the aqueous solution was added 400ml of ethanol and 80ml of 95percent 30-33percent methylamine, stir, heated under reflux for 8 hours, TLC in the control (dichloromethane: methanol = 20: 1 , volume ratio) to complete the reaction, cooled to room temperature, treated with 37percent hydrochloric acid (V / V) to adjust to pH 1-2, to precipitate large amount of white solid was filtered, the filter cake was rinsed with 40ml of 95percent ethanol.Drying under reduced pressure, the obtained 29.3g (0.09mol) of an off-white solid hydrochloride salt of intermediate VII, prepared in molar yield intermediate VII VI hydrochloride thereof in between about 89.1percent, HPLC purity 99.4percent
Stage #1: With potassium carbonate In 4-methyl-2-pentanone at 4℃; Inert atmosphere; Reflux Stage #2: at 20℃; for 15 h; Stage #3: With hydrogenchloride In water; 4-methyl-2-pentanone
Example 19: [4-({S)-5-Aminomeihyl-2-oxo-oxazoiidm-3-yI)-pheriyl]-morphoiin-3-one; hydrochlorideUnder an atmosphere of nitrogen to a suspension of 2.00 g of 4-[4-((R)-3-amino-2-hydroxy- propylamino)-phenyi]-morphoiin-3-one hydrochloride (MW = 301.78; 1 eq.) in 100 mL of methylisobutylketone were added 3.85 g of potassium carbonate (MW = 138.21 ; 4.2 eq.) and the suspension was heated to reflux. The formed water was removed by azeotropic distillation. After refiuxing for 4 h and removing water by azeotropic distillation, the reaction mixture was cooled to room temperature and then 1.61 g of Ν,Ν'-carbonyidiimidazoi (MW = 162.15; 1.5 eq.) were added. After stirring at ambient temperature for 15 h, the reaction mixture was filtered. To the clear filtrate were added 5 mL of 6 M hydrochloric acid (1.5 eq.) and 50 mL of water and stirring was continued for 1 h. Then the mixture was concentrated in vacuo. To the solid residue were added 5.5 mL of water and 22 mL of 2-propanol. The resulting siurry was stirred for 1 h at ambient temperature and then cooled to 0 °C. After stirring in an ice bath for at least 2 h, the crystals were isolated by filtration, washed with 10 mL of 2-propanol and the wet product was dried in vacuo at 30 °C. The yield of isolated crystalline hydrochloride ( was 1.74 g (80.1percent).H-NMR (DMSO-dB, 300Mz) δ (ppm) = 3.21-3.26 (m, NCH2, 2H), 3.56-3.64 (m, CH2, 2H), 3.72 (m, CH2, 2H), 3.87 - 4.00 (m, CH2j CH, 3H), 4.20 (s, CHzCO, 2H), 3.21 (m, CH2, 1 H), 4.98 (m, CH, 1 H), 7.56 (d, CH, 2H, J 9.0Hz), 7.43 (d, CH, 2H, J 9.0Hz), 8.49 (3, NH, 3H). "C-NMR (DMSO-d6, 3Q0Mz) δ (ppm) - 48.10, 49.89, 55.99, 64.30, 68.51 , 70.27, 1 19.47, 126.88, 137.14, 138.06, 154.48, 167.02.
a) 3-Fluorobenzene-1,2-diamine (0.600 g, 4.76 mmol) was dissolved in THF (14.82 ml) and 1,1'-carbonyldiimidazole (0.848 g, 5.23 mmol) was added at RT. The reaction mixture was stirred overnight at RT and then heated for 24 hours at 50° C. The mixture was cooled to RT and ammonia in MeOH (1.5 ml) was added and the mixture stirred for 30 minutes. The mixture was dilued with water (40 ml) and the resultant brown solid was collected by filtration, washed with water and then dried in vacuo to afford 4-fluoro-1H-benzo[d]imidazol-2(3H)-one (0.700 g, 97percent) which was used in the next step without further purification; 1H NMR (400 MHz, DMSO-d6) 6.81 (2H, ddd), 6.88-6.95 (1H, m), 10.82 (1H, s), 11.08 (1H, s); m/z: (ES-) M-H-, 151.19.
66%
at 20℃;
Into a 25 mL round bottomed flask was added 2,3-diaminofluorobenzene (250 mg, 1.98 mmol) and THF (2 mL). CDI (386 mg, 2.38 mmol) in THF (6 mL) was added slowly via addition funnel. The reaction was stirred at room temperature overnight. The resultant precipitate was isolated by filtration on a Buchner funnel and washed with cold THF to give 4-fluoro-1H-benzo[d]imidazol-2(3H)-one (111A) as a white solid (200 mg, 66percent). ESI-MS:m/z 153.3 (M+H)+.
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
91
[ 530-62-1 ]
[ 7531-52-4 ]
[ 1166227-08-2 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 17, p. 3569 - 3574
92
[ 17587-95-0 ]
[ 530-62-1 ]
[ 1273315-11-9 ]
Yield
Reaction Conditions
Operation 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).
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]+.
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
95
[ 1397836-41-7 ]
[ 530-62-1 ]
[ 1403474-70-3 ]
Yield
Reaction Conditions
Operation 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.
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
97
[ 624813-49-6 ]
[ 530-62-1 ]
[ 1207175-68-5 ]
Yield
Reaction Conditions
Operation 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.
At 0 C,To 4-tert-butylbenzene-1,2-diamine (I-9, 5.02 g, 30.5 mmol)Add in tetrahydrofuran (400mL) solution1,1'-carbonyldiimidazole (CDI, 5.43 g, 33.6 mmol),The resulting solution was stirred at room temperature for 12 hours.Then diluted with diisopropyl ether (50 mL),The mixture was stirred for a further 30 minutes at room temperature.White precipitates gradually appear,Filter and collect products,Wash with diisopropyl ether (50 mL),Vacuum drying,4.05 g (yield: 70%) of 5-tert-butyl-1H-benzo[d]imidazole-2(3H)-one (IX-1),It is a white solid.
In tetrahydrofuran; dichloromethane; at 20℃; for 6.5h;
General procedure: To a solution of 4-methyl-1,2-phenylenediamine (25 g, 0.205 mol) in tetrahydrofuran (375 mL) was added dropwise a solution of 1,1'-carbonyldiimidazole (36.5 g, 0.225 mol) in dichloromethane (375 mL). After stirring for 6.5 h at ambient temperature, to the reaction mixture was added diisopropyl ether (375 mL). After stirring at ambient temperature, the resulting precipitates were collected by filtration. The precipitates were washed with diisopropyl ether and dried in vacuo to give 5-methyl-1,3-dihydrobenzimidazol-2-one (24.6 g, 70.1%).
N'-[(9H-fluoren-9-ylmethoxy)carbonyl]-1H-imidazole-1-carbohydrazide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In DMF (N,N-dimethyl-formamide); for 1h;
Starting from 200 mg resin (0.06 MMOL), following the general procedure of Example 1 c, except substituting Fmoc-Ala-OPfp for FMOC-GLY-OPFP. Formation of the semicarbazide bond was achieved by acylation with FMOC-NHNHCOLM. This was prepared just prior to use by reaction of FMOCNHNH2 (0.18 MMOL) and CDI (0.18 MMOL) in dry DMF (1 mL) for 1 h. The resulting solution was then added directly to the resin. Reaction time 16 h. The title compound was obtained as a white solid. Yield : 3.1 mg (19percent) ; HPLC : Rt = 2.42 min. (>99percent); ES-MS: mass calcd for C12H18N503 280.1 (MH+). Found M/Z 280.1
B. 6-Trifluoromethyl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one Add 1,1'-carbonyldiimidazole (1.0 g, 6.17 mmol)to a solution of <strong>[107867-51-6]5-trifluoromethyl-pyridine-2,3 diamine</strong> (0.90 g, 5.08 mmol) in CH2Cl2 (10 mL) and stir at room temperature for 18 hours. Heat the solution to reflux for 2 hours and filter the precipitate to obtain 6-trifluoromethyl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one.
1, 1'-Carbonyldiimidazole (11.4 g, 0.0703 mol) is added portionwise to a solution of <strong>[53981-23-0]2-amino-3-fluorophenol</strong> (Step 3, 8. 94 g, 0.0703 mol) in THF (200 ml) and warmed at 60°C for 2 h. The reaction mixture is diluted with ethyl acetate (200 ml), washed with 2N HC1 and saline, dried (MgS04), and evaporated to give product as a white solid suitable for use in the next step (10.6 g, 99percent); mp 131-3°C.
99%
In tetrahydrofuran; at 60℃; for 2h;
Step 4: Preparation of 4-fluoro-1,3-benzoxazol-2(3H)-one 1,1'-Carbonyldiimidazole (11.4 g, 0.0703 mol) is added portionwise to a solution of <strong>[53981-23-0]2-amino-3-fluorophenol</strong> (Step 3, 8.94 g, 0.0703 mol) in THF (200 ml) and warmed at 60° C. for 2 h.The reaction mixture is diluted with ethyl acetate (200 ml), washed with 2N HCl and saline, dried (MgSO4), and evaporated to give product as a white solid suitable for use in the next step (10.6 g, 99percent); mp 131-3° C.
59%
In tetrahydrofuran; at 20℃; for 16h;
To a solution of <strong>[53981-23-0]2-amino-3-fluorophenol</strong> (2.5g, 19.6mmol) in THF (5OmL) was added CDI (15.9g, 98.4mmol) at rt. The reaction mixture was stirred at rt for 16h. TLC showed the reaction to be complete. The reaction mixture was diluted with H20 (lOOmL) and extracted with EtOAc (3x lOOmL). The organics were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography using silica gel (100-200 mesh), eluting with 10percent EtOAc in hexane to afford 4-fluorobenzo[d]oxazol-2(3H)-one as a pale brown solid. Yield:1.8g (59percent); 1H NMR (400 MHz, DMSO-d6): 12.25 (bs, 1H), 7.12-7.19 (m, 1H),7.06-7.12 (m, 2H); MS (ESI-) for CHNOS m/z 151.90 [M-H].
A solution of (R) (-) -ibuprofen (3.45 g) in ethyl ether, cooled to 5°C, is treated, dropwise, with a 0.6 M solution of diazomethane in ethyl ether, up to a persistent yellow colour. The solvent is removed under vacuum; the residual oil is purified by flash chromatography to yield 3.3 g of methyl (R) (-) 2- (4APOS;-ISOBUTYLPHENYL)-PROPIONATE. Alternatively, 2.6 g of CARBONYLDIIMIDAZOLE are added under stirring to a solution of R (-) ibuprofen (3. 45 G) in LOML of THF. The mixture is stirred for 1 h, the solvent is evaporated under vacuum, and the residual oil is purified by flash chromatography to yield 4.05 g of (R) (-) 2- (4APOS;-ISOBUTYLPHENYL)-PROPIONYLIMIDAZOLIDE. In an inert-gas atmosphere, a solution of butyl lithium (1. 56 M ; 13. 3 ML, 0. 027 mol) in hexane is added dropwise to a solution of dimethyl methylphosphonate (3.69 g; 0.03 mol) in anhydrous THF (10 ML) cooled TO-70°C. The mixture is stirred for 15MIN before addition, dropwise, of a solution in anhydrous THF (10 ML) of methyl ester or of imidazolide, prepared as previously described. Upon completion of the dripping step, the reaction mixture is kept, under stirring, for 1 h at - 70°C and then for 1 h at room temperature. The mixture is then cooled TO-10°C, and 1.8 mL of glacial acetic acid is added dropwise. The solvent is removed under vacuum, the residue is diluted with water, and the mixture is repeatedly extracted with dichloromethane (4X50 mL). The organic extracts are dried on sodium sulfate; after evaporation of the solvent, the residue is purified on silica gel, eluted with AcOEt to yield, as a colourless oil, 3.02 g of (R) (-)-dimethyl 3- (4-ISOBUTYL)-2-OXOBUTAN-L-PHOSPHONATE. [A] D=-171° (C=L ; CH30H) ;APOS;H-NMR (CDC13) : 5 7.03 (s, 4H); 4.1-3. 9 (dd, 2H, J1=15HZ, J2=8HZ) ; 3.8 (s, 3H); 3.70 (m, 1H) ; 3.65 (s, 3H); 2.55 (d, 2H, J=8Hz); 1.75 (m, 1H); 1.50 (d, 3H, J=8Hz); 0.85 (d, 6H, J=7Hz).
In tetrahydrofuran; for 0.75 - 0.833333h;Heating / reflux;Product distribution / selectivity;
Step 2: Preparation of cyclopropanesulfonic acid (1-(R)-tert-butoxycarbonylamino-2-(S)-vinylcyclopropanecarbonyl)-amide A solution of the product of Step 1 (2.62 g, 11.5 mmol) and CDI (2.43 g, 15.0 mmol) in THF (40 mL) was heated at reflux for 50 minutes under nitrogen. The solution was cooled to room temperature and transferred by cannula to a solution of cyclopropylsulfonamide (1.82 g, 15.0 mmol) in THF (10 mL). To the resulting solution was added DBU (2.40 mL, 16.1 mmol) and stirring was continued for 20 hours. The mixture was quenched with 1N HCl to pH 1 and THF was concentrated in vacuo. The suspension was extracted with ethyl acetate (2.x.50 mL) and the combined organic extracts were dried (Na2SO4), filtered, and concentrated. Purification by recystallization from hexanes-ethyl acetate (1:1) afforded the title compound (2.4 g) as a white solid. The mother liquor was purified by a Biotage 40S column (eluted 9percent acetone in dichloromethane) to give a second batch of the title compound (1.1 g). Both batches were combined (total yield 92percent). 1H NMR (DMSO-d6) delta 0.96-1.10 (m, 4H), 1.22 (dd, J=5.5, 9.5 Hz, 1H), 1.39 (s, 9H), 1.70 (t, J=5.5 Hz, 1H), 2.19-2.24 (m, 1H), 2.90 (m, 1H), 5.08 (d, J=10 Hz, 1H), 5.23 (d, J=17 Hz, 1H), 5.45 (m, 1H), 6.85, 7.22 (s, NH (rotamers); LC-MS (retention time: 1.70 minutes, method B), MS m/z 331 (M++H).; 1b. Preparation of P1-P1' sulfamide derivative To a solution of (1R,2S) 1-tert-butoxycarbonylamino-2-vinyl-cyclopropanecarboxylic acid (217 mg, 1.194 mmol) in THF (5 mL), was added CDI (290 mg, 1.791 mmol) and the reaction mixture was heated under reflux for 45 minutes. In another round-bottomed flask, LiHMDS (1.0M solution in hexanes, 2.4 mL, 2.4 mmol) was added to a solution of N-ethylmethylsulfamide (330 mg, 2.388 mmol) in THF (5 mL) and the reaction mixture was stirred at room temperature for 1 hour. Two reaction mixtures were added together and stirred at room temperature for 2 hours. Water was added to quench the reaction and the reaction solution was extracted with ethyl acetate. The organic layer was separated and dried over MgSO4. Filtration and concentration of the solvent gave crude product which was purified by preparative HPLC to afford desired N-Boc protected N-acylsulfamide. The Boc protecting group was then removed as the compound was dissolved in 4N HCl solution in dioxane (2 mL) and stirred at room temperature for 4 hours. Evaporation of solution give brownish oil as the HCl salt. (112 mg, 33percent yield). 1H NMR (400 Mz, CD3OD) delta 1.16 (t, J=7.21 Hz, 3H), 1.68 (dd, J=10.03, 7.83 Hz, 1H), 2.15 (m, 1H), 2.37 (m, 1H), 2.89 (s, 3H), 3.30 (m, 2H), 5.31 (d, J=10.27 Hz, 1H), 5.42 (d, J=17.12 Hz, 3H), 5.68 (m, 1H). LC-MS (retention time: 0.883 minutes.), MS m/z 270 (M+Na+).; A solution of the product of Step 7a (2.62 g, 11.5 mmol) and CDI (2.43 g, 15.0 mmol) in THF (40 mL) was heated at reflux for 50 minutes under nitrogen. The solution was cooled to room temperature and transferred by cannula to a solution of cyclopropanesulfonic acid amide (1.82 g, 15.0 mmol) in THF (10 mL). To the resulting solution was added DBU (2.40 mL, 16.1 mmol) and stirring was continued for 20 hours. The mixture was quenched with 1N HCl to pH 1 and the THF was evaporated in vacuo. The suspension was extracted with ethyl acetate (2.x.50 mL) and the combined organic extracts dried (Na2SO4), filtered, and concentrated. Purification by recystallization from hexanes-ethyl acetate (1:1) provided the desired compound (2.4 g) as a white solid. The mother liquor was purified by a Biotage 40 S column (eluted 9percent acetone in dichloromethane) to provide a second batch of the desired compound (1.1 g). Both batches were combined (total yield 92percent). 1H NMR (DMSO-d6) delta 0.96-1.10 (m, 4H), 1.22 (dd, J=5.5, 9.5 Hz, 1H), 1.39 (s, 9H), 1.70 (t, J=5.5 Hz, 1H), 2.19-2.24 (m, 1H), 2.90 (m, 1H), 5.08 (d, J=10 Hz, 1H), 5.23 (d, J=17 Hz, 1H), 5.45 (m, 1H), 6.85, 7.22 (s, NH (rotamers); LC/MS (MH+, 331).;
In tetrahydrofuran; at 20℃; for 3h;Product distribution / selectivity;
Example 58 Preparation of Compound 58 Step 1. To a solution N-Boc-vinylcyclopropane carboxylic acid, the product of step 7a, Example 7, (1.83 g, 8.05 mmol) and THF (32 mL) was added 1,1'-carbonyldiimidazole (1.44 g, 8.86 mmol). After stirring at room temperature for 3 hours, the reaction mixture was treated with N,N-dimethylsulfamide (1.0 g, 8.05 mmol) followed by DBU (2.45 g, 16.1 mmol) and it was stirred at room temperature for an additional 15 hours. The reaction was then diluted with EtOAc (50 mL) and was washed with 2.x.25 mL 1N aqueous HCl. The aqueous layer was extracted with 2.x.50 mL EtOAc. The combined organic portion was washed with H2O (25 mL) and brine, dried over MgSO4, filtered, and concentrated to a light yellow solid (2.6 g, 97percent yield) which was used without further purification. LC-MS, MS m/z 356 (M++Na).
In tetrahydrofuran; for 0.833333h;Heating / reflux;
Preparation of 1(R)-tert-butoxycarbonylamino-2(S)-vinyl-cyclopropanecarboxylic acid To a solution of 1(R)-tert-butoxycarbonylamino-2(S)-vinyl-cyclopropanecarboxylic acid ethyl ester (3.28 g, 13.2 mmol) in THF (7 mL) and methanol (7 mL) was added a suspension of LiOH (1.27 g, 53.0 mmol) in water (14 mL). The mixture was stirred overnight at room temperature and quenched with 1N NaOH (15 mL) and water (20 mL). The resulting mixture was washed with ethyl acetate (20 mL), and the organic phase was extracted with 20 mL 0.5N NaOH. The combined aqueous phases were acidified with 1N HCl until pH 4 and extracted with ethyl acetate (3.x.40 mL). The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated to yield the title compound as a white solid (2.62 g, 87percent). 1H NMR: (DMSO-d6) delta 1.22-1.26 (m, 1H), 1.37 (s, 9H), 1.50-1.52 (m, 1H), 2.05 (q, J=9 Hz, 1H), 5.04 (d, J=10 Hz, 1H), 5.22 (d, J=17 Hz, 1H), 5.64-5.71 (m, 1H), 7.18, 7.53 (s, NH (rotamers), 12.4 (br s, 1H)); MS m/z 228 (M++H).
In tetrahydrofuran; for 1 - 2h;Heating / reflux;Product distribution / selectivity;
Step 1; [(lR,2S)-l-(2-Amino-benzenesulfonylaminocarbonyl)-2-vinyl-cyclopropyl]-carbamic acid tert-butyl ester; To a solution of 6.3 g (28 mmol) (lR,2S)-l-tert-Butoxycarbonylamino-2-vinyl-cyclopropane- <n="155"/>carboxylic acid (prepared according to WO 2000009558 Al) in 90 mL abs. THF is added 6.95 g (42 mmol) CDI and the mixture is refluxed for 2 h. After cooling to rt 5.1 g (29 mmol) 2-Aminobenzenesulfonamide and 6.5 g (42 mmol) DBU is added and stirring is continued for 45 min. The reaction mixture is diluted with 250 mL EtOAc and washed with 100 mL 0.5 N HCl and brine. The organic phase is dried with Na2SO4, filtered and the solvent is removed in vacuo. The residue is purified by FC on silica (eluent: CH2Cl2/Me0H 98:2) to give the title compound as a colorless solid. HPLC (method A) tR = 3.99 min TLC, Rf (CH2Cl2/Me0H 19:1) = 0.35 MS (method D): 382 [M+H]; Step 7; 12-{l-[((lR,2S)-l-tert-Butoxycarbonylamino-2-vinyl-cyclopropanecarbonyl)-su.famoyl]- cyclopropylj-dodecanoic acid methyl ester; <n="256"/>A mixture of 610 mg (2.7 mmol) (lR,2S)-l-tert-Butoxycarbonylamino-2-vinyl- cyclopropane-carboxylic acid and 687 mg (4.0 mmol) CDI in 20 mL THF is refluxed for 1 h. The reaction mixture is cooled to RT and 0.6 mL (4.0 mmol) DBU and a mixture of 806 mg (2.4 mmol) 12-(l-Sulfamoyl-cyclopropyl)-dodecanoic acid methyl ester in 5 mL THF is added. The mixture is stirred at RT overnight, concentrated in vacuo, taken up in EtOAc and washed with 0.1 M aq. HCl. The combined organic phases are dried over Na2SO4 and concentrated in vacuo. The residue is purified by FC on silica (Eluent: EtOAc/hexane 1:3) to give the title compound.LC-MS (method E) tR = 5.132 min, M-H = 543.3 HPLC (method C) tR = 4.472 min; Step 4; Methyl 12-[[({(lR,2S)-l-[(tert-butoxycarbonyl)amino]-2- vinylcyclopropyl}carbonyl)amino]-sulfonyl}(methyl)amino]dodecanoate; A mixture of 1.41 g (6.2 mmol) (lR,2S)-l-tert-Butoxycarbonylamino-2-vinyl-cyclopropane- carboxylic acid and 1.52 mg (9.31 mmol) CDI in 30 mL THF is refluxed for 1 h. In a second flask to a mixture of 3.0 g (9.31 mmol) of the title compound obtained in step 3 in 30 mL THF 9.3 mL (9.3 mmol) LiHMDS (1 M in THF) is added at 0°C and the mixture is stirred for 30 min. Both mixtures are combined and stirred at RT overnight. Water is added and the mixture is extracted with DCM (3x). The combined organic layers are dried over Na2SO4 and concentrated in vacuo. The residue is purified by FC (silica gel, eluent: EtOAc/hexane 1 :3) to give the title compound. LC-MS (method E) tR = 4.728 min, M-H = 530.2
3,5-dicarboxybenzyl methanethiosulfonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In N,N-dimethyl-formamide; tert-butyl alcohol;
3,5-Dicarboxybenzyl Methanethiosulfonate (1c). 1,1'-Carbonyldiimidazole (6.67 g, 0.0411 mol) was added to a solution of <strong>[499-49-0]toluene-3,5-dicarboxylic acid</strong> (2) (3.364 g, 0.0187 mol) in DMF (30 mL) and the resulting mixture stirred at 40° C. under N2. After 1.5 h DBU (6.15 mIL, 0.041 mol) and t-BuOH (7.7 mL, 0.0822 mol) were added. After 24 h the solution was cooled, ether (150 mL) added and the mixture acidified (HCl (aq.), 1.5 M). The ethereal layer was separated and the aqueous layer further extracted (ether, 150 mL). The organic fractions were combined, washed with water and 10percent K2CO3 (aq.), dried (MgSO4), filtered and the solvent removed. The residue was purified by flash chromatography (EtOAc:hexane, 1:50) to afford a colorless oil which solidified upon standing to give di-tert-butyl toluene-3,5-dicarboxylate (4.58 g, 84percent) as a white solid; mp 86.5-87.5° C. (hexane); IR (film) 1712 cm-1 (C=O), 1606, 1476 cm-1 (Ar C=C); 1H NMR (CDCl3) delta 1.60 (s, 18H, C(CH3)3), 2.43 (s, 3H, CH3), 7.95 (br s, 2H, H-2, H-6), 8.38 (br s, 1H, H-4); 13C NMR (CDCl3) delta 21.4 (CH3), 28.2 (C(H3)3), 81.4 ((CH3)3), 127.7, 132.1, 133.7, 138.1 (Ar), 165.2 (COO).
With N-ethyl-N,N-diisopropylamine; In N-methyl-acetamide;
Example 18 Preparation of N-(trans-4-methylcyclohexyl)isoquinoline-3-carboxamide (406) A solution of <strong>[6624-49-3]isoquinoline-3-carboxylic acid</strong> (346 mg, 2 mmol), and 1,1'-carbonyldiimidazole (325 mg, 2 mmol) in dimethylformamide (4 mL) was heated at 50° C. for 1 hour. After this time, trans-4-methylcyclohexylamine hydrochloride (300 mg, 2 mmol), and N,N-diisopropylethylamine (0.523 mL, 3 mmol) were added and the mixture heated at 50° C. for 16 hours. The reaction mixture was cooled, and diluted with ethyl acetate (20 mL). The organic solution was washed with water (3*15 mL), brine (20 mL), dried over anhydrous MgSO4, filtered and concentrated to afford 377 mg (70percent) of 406: rt=9.65 min.; m/z (rel. int.) 268 (M+, 9), 240 (6), 223 (16), 211 (17), 197 (13), 173 (22), 156 (55), 128 (100), 112 (38), 101 (15), 77 (10).
With sodium hydrogencarbonate; In dichloromethane; N,N-dimethyl-formamide;
(c) tert-Butyl 4-[2-({4-chloro-2-[2-(dimethylamino)-2-oxoethoxy]benzoyl}amino)ethyl]-1-piperazinecarboxylate The product from step (b) (0.7 g) and 1,1'-carbonyldiimidazole (0.62 g) were dissolved in N,N-dimethylformamide (10 ml) and stirred at room temperature for 1 hour. tert-Butyl 4-(2-aminoethyl)-1-piperazinecarboxylate (2.73 g) was added, the solution stirred for 16 hours and then evaporated to leave a gum. Dichloromethane and sodium bicarbonate solution were added, the organic phase was separated, dried and concentrated to a gum which was purified by chromatography (ethyl acetate:triethylamine, 10:1) to give the product as a solid (0.62 g), m.p. 139-140° C. MS: ESI: 469.22 (M+H).
a) 2-Chloro-5-hydroxy-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide To a solution of <strong>[56961-30-9]2-chloro-5-hydroxybenzoic acid</strong> (3.12 g) in N,N-dimethylformamide (50 ml) was added 1,1'-carbonyldiimidazole (3.0 g). The resulting reaction mixture was stirred for 2.5 h and then 1-adamantanemethylamine (3.0 g) was added. Stirring was continued for 14 h. The reaction mixture was partitioned between ethyl acetate and water and the organic layer was separated, washed with water and brine and then dried over sodium sulphate (Na2SO4). The organic layer was concentrated under reduced pressure to give a residue which was purified by silica gel chromatography (eluding with 3-10percent methanol in dichloromethane) to yield the subtitle compound as a white solid (0.15 g). MS (APCI+ve) 319/321 (M+H)+ 1H NMR (DMSO-d6) delta 9.85(1H,s), 8.25 (1H, t), 7.24(1H, d), 6.76-6.82(2H, m), 2.90 (2H,d), 1.93(3H, s), 1.67 (3H, d), 1.57 (3H, d), 1.51 (6H, s)
c) 2-Cyano-2-(4-fluorophenyl)-1 -(2-acetamido-4-pyridyl)ethanone (4); EPO <DP n="27"/>18.0 g of (3) are taken up in 50 ml of abs. dimethylformamide (DMF) and, after addition of 17.0 g of carbonyldiimidazole (CDI), stirred at room temperature for 45 min. Then 14.9 g of 4-fluoroacetonitrile and 14.6 g of potassium tert-butanolate are added, and the reaction mixture is heated at 1200C for 2 h. After cooling, the mixture is stirred at room temperature overnight. Ice is then added to the solution, and it is neutralized with cone. HCI. The precipitate of (4) which separates out is filtered off and dried in vacuo over P2O5. Yield: 18.1 g (65percent)
In N,N-dimethyl-formamide; at 20℃; for 0.75h;
18.0 g of (3) are taken up in 50 ml of abs. dimethylformamide (DMF) and, after addition of 17.0 g of carbonyldiimidazole (CDI), stirred at room temperature for 45 min. Then 14.9 g of 4-fluoroacetonitrile and 14.6 g of potassium tert-butanolate are added, and the reaction mixture is heated at 120°C for 2 h. After cooling, the mixture is stirred at room temperature overnight. Ice is then added to the solution, and it is neutralized with conc. HCl. The precipitate of (4) which separates out is filtered off and dried in vacuum over P2O5. Yield: 18.1 g (65percent)
8-fluoro-5-methyl-3-(5-morpholin-4-ylmethyl-1,2,4-oxadiazol-3-yl)-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With N-ethyl-N,N-diisopropylamine; In water; N,N-dimethyl-formamide; acetonitrile;
b) 0.38 ml (2.2 mmol) of N-ethyldiisopropylamine was added to a suspension of 0.4 g (2.2 mmol) of morpholin-4-yl-acetic acid hydrochloride in 4 ml of DMF. 390 mg (2.4 mmol) of 1,1'- carbonyldiimidazole were added portionwise at room temperature, whereupon the solution was stirred at 50° for 30 min. and then treated at room temperature with 0.58 g (2.0 mmol) of 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamidoxime. The reaction mixture was heated to 90° for 20 hrs. The solvent was removed in a vacuum, the residue was taken up in 15 ml of water and the solution was extracted several times with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered and evaporated. The crude material was purified by chromatography on silica gel (methylene chloride/methanol 19:1). The solvent was removed in a vacuum, the residue was dissolved in 5 ml of acetonitrile and the solution was made acid by the addition of ethereal HCl solution. The white crystals were filtered off under suction and recrystallized from acetonitrile. There was obtained 0.5 g (54percent) of 8-fluoro-5-methyl-3-(5-morpholin-4-ylmethyl-1,2,4-oxadiazol-3-yl)-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one hydrochloride (3:5) of m.p. 198°-205° (dec.).
With Imidazole hydrochloride; In tetrahydrofuran; at 50℃; for 4h;
General procedure: To a solution of carboxylic acid (0.1 mmol, 1 equiv.) in anhydrous THF (0.5 mL) in 2 dram screw cap vials was added imidazole hydrochloride (15.7 mg, 1.5 equiv.) and CDI (17.8 mg, 1.1 equiv.). The reactions were stirred for 4 h at 50 oC. A solution of pyrazole amide 23 (17.3 mg, 0.9 equiv.) in THF was added to each of the vials, and the reactions were agitated overnight at 50 oC. The solvent was removed, and the residue was dissolved in absolute EtOH (1 mL). To this was added a solution of NaOEt in EtOH (150 muL, 21percent w/w, 4 equiv.). The reactions were heated to 120 oC for 2 h in a sealed vial. The reactions were cooled to room temperature and 300 muL of 1M HCl was added, and the reactions were concentrated to precipitate the desired product. The solid was washed with 0.5 mL EtOAc and water to provide the final compounds.
EXAMPLE 20 9.8 g of <strong>[14190-59-1]thiazole-2-carboxylic acid</strong> and 12.3 g of 1,1'-carbonyldiimidazole were stirred at 70° for 1 hour in 35 ml of tetrahydrofuran. To this solution were then added dropwise 12.2 g of N-(t-butoxycarbonyl)ethylenediamine in 20 ml of tetrahydrofuran and the mixture was left to stir at 70° for a further 1/2 hour. The reaction mixture was subsequently cooled to room temperature and concentrated to about 1/4 of the volume on a rotary evaporator under reduced pressure, taken up in water and extracted three times with ethyl acetate. The ethyl acetate extracts, dried over magnesium sulfate, were evaporated completely, whereby t-butyl [2-(thiazole-2-carboxamido)ethyl]carbamate was obtained.
With triethylamine; In N-methyl-acetamide; propan-1-ol; dichloromethane;
EXAMPLE VII 6-[3-(p-Chlorobenzoyl)-3-thiocyanatopropionamido]penicillanic acid potassium salt. 3-(p-Chlorobenzoyl)-3-thiocyanatopropionic acid (1.40 grams, 5 millimole) was dissolved in 5 milliliter dimethylformamide. Carbonyl diimidazole (0.82 gram, 5 millimole) was added in one portion. The mixture was stirred under nitrogen for 1/2 hour and evacuated for 1/2 hour. To the above solution, chilled in an ice bath, was added a cold solution of 1.08 grams (5 millimole) <strong>[551-16-6]6-aminopenicillanic acid</strong> and 1.00 gram (10 millimole) of triethylamine in methylene chloride. The reaction mixture was stirred, in the ice bath for 2 hours, filtered, and concentrated in vacuo at 30°C. To the residue dissolved in methylene chloride was added a solution of 1 milliliter of a 2 Molar potassium salt of 2-ethyl hexanoate in propanol. Addition of anhydrous ether caused precipitation of the potassium salt, which was collected, washed with ether, and dried. Elemental Analysis for C19 H17 ClN3 O5 S2 K.H2 O:Calc'd: C, 43.55; H, 3.66; N, 8.02.Found: C, 43.85; H, 3.48; N, 8.63.
In tetrahydrofuran; dichloromethane; water; ethyl acetate; N,N-dimethyl-formamide;
14.1 1-[(5-methoxy-1H-indol-3-yl)methylcarbonyl]-4-(4-nitrophenyl)-piperazine In a 100 ml flask, 1.62 g (10 mmoles) of 1.1'-carbonyl-diimidazole is added to a solution of 2.05 g (10 mmoles) of 5-methoxyindole-3-acetic acid in 10 ml of THF. After one hour of agitation at ambient temperature, a solution of 1-(4-nitrophenyl)piperazine in 10 ml of DMF is added dropwise. Agitation is continued for 15 hours. The reaction medium is then concentrated under vacuum and the evaporation residue is precipitated from 50 ml of an ethyl acetate/water mixture (1/1). After filtration, the solid is rinsed successively with 50 ml of water, 50 ml of ethyl acetate and 50 ml of dichloromethane. After drying under vacuum, a yellow powder is obtained with a yield of 91percent. Melting point: 239-240° C. NMR 1H (100 MHz, DMSO d6, delta): 10.90 (m, 1H, NH); 7.63 (m, 4H, Ph-NO2); 7.40-7.15 (m, 3H, indol); 6.87 (dd, 1H indol, Jotho=8.7 Hz, Jmeta=2.8 Hz); 3.90 (s, 2H, CH2-CO); 3.88 (s, 3H, OCH3); 3.79 (m, 4H, piperazine); 3.50 (m, 4H, piperazine).
91%
14.1) 1-[(5-methoxy-1H-indol-3-yl)methylcarbonyl]-4-(4-nitrophenyl)piperazine: In a 100 ml flask, 1.62 g (10 mmoles) of 1.1'-carbonyl-diimidazole is added to a solution of 2.05 g (10 mmoles) of 5-methoxyindole-3-acetic acid in 10 ml of THF. After one hour of agitation at ambient temperature, a solution of 1-(4-nitrophenyl)piperazine in 10 ml of DMF is added dropwise. Agitation is continued for 15 hours. The reaction medium is then concentrated under vacuum and the evaporation residue is precipitated from 50 ml of an ethyl acetate/water mixture (1/1). After filtration, the solid is rinsed successively with 50 ml of water, 50 ml of ethyl acetate and 50 ml of dichloromethane. After drying under vacuum, a yellow powder is obtained with a yield of 91percent. Melting point: 239-240° C. NMR 1H (100 MHz, DMSO d6, delta): 10.90 (m, 1H, NH); 7.63 (m, 4H, Ph-NO2); 7.40-7.15 (m, 3H, indol); 6.87 (dd, 1H indol, Jortho=8.7 Hz, Jmeta=2.8 Hz); 3.90 (s, 2H, CH2-CO); 3.88 (s, 3H, OCH3); 3.79 (m, 4H, piperazine); 3.50 (m, 4H, piperazine).
Example 82(47?,6.S',9.S'.19-LS'.23aS)-9-t-Butyl-N-Cn/?,25r)-l-(r(cvclopropylsulfonvnaminolcarbonvU-2- vinylcvclopropyD-2.8.11 -trioxoicosahvdro-2H, 13H-4 J-methano- 1,12,3,7.10- benzodioxatriazacyclohenicosine-6-carboxamideStep 1 : Methyl (4i?)-4-r((r2-allylcvclohexylloxylcarbonyl)aminol-L-prolinate hydrochlorideetaN-S^O etaCI O^To a solution of racemic troens-2-allylcyclohexanol (200 mg, 1.42 mmol) in DMF (2 mL), CDI (0.23 g, 1.42 mmol) was added. After 1 hour, 1-f-butyl 2-methyl (2S,4R)-4- aminopyrrolidine-l,2-dicarboxylate (0.35 g, 1.42 mmol) was added, and the mixture was heated to 6O0C. After complete conversion, the mixture was extracted with EtOAc and Neta4Cl(aq.). The organic layer was dried over Na2SO4, and the solvent was removed in vacuo. The crude material was purified on SiO2 (gradient elution, 5-45percent EtOAc/hexanes) to yield 170 mg of 1-t-butyl 2- methyl (25',4i?)-4-([(2-allylcyclohexyl)oxy]carbonyl}amino)pypiOlidine-l,2-dicarboxylate. This material was dissolved in DCM/THF (5 mL), and HCl gas was bubbled through the mixture until complete removal of the Boc group. The solvent was then removed in vacuo to yield the title compound as a mixture of trans-diastereomers. LRMS ESI+ (M+H)+ 311.4.
Example 4; l-(3-tert-Butyl-phenyl)- 3-{4-[2-(3-Hydroxy-propylamino)-pyrimidin-4-yloxy]- phenyl}-urea172 mg (1.06 mmol) l.T-Carbonyl-diimidazol (CDI) were given to a solution of 144 mg (0.964 mmol) 3-t-butylaniline in 4.0 ml dichloromethane and stirred for 12 h. A solution of 263 mg (0.964 mmol) 3-[4-(4-Amino-phenoxy)-pyrimidin-2- ylamino]-propan-l-ol in 6.0 ml dichloromethane was added within 30 min. and the mixture stirred for 12 h at r.t. The reaction mixture was filtered, the filtrate evaporated and the residue purified by chromatography on silica gel (dichloromethane/methanol 95:5). The obtained material was washed with ether and the precipitate was isolated by filtration and dried. Yield: 170 mg (41percent) of the title compound. MS: 436.1 (ESI+), 434.07(ESI-).eta-NMR(400Hz, [DJDMSO): delta = 1.26(s, 9H, t-Bu), 1.59 (quintet, 2H, CH2-CH2- CH2), 3.2 (br, 2H, CH2-NH), 3.39 (br, 2H, CH2-OH), 4.37 (br, IH, OH), 6.04(br, IH, 5-H-pyrimidine), 7.00(d, IH, Ar-^-Bu), 7.04(br, IH, CH2NH), 7.08(d, 2H, 3- H/5-H-Ar-NH), 7.20(t, IH, 5-H-Ar-t-Bu), 7.29(d, IH, Ar-t-Bu), 7.46(s, IH, 2-H- Ar-t-Bu), 7.47(d, 2H, 2-H/6-H-Ar-NH), 8.12(d, IH, 6-H-pyrimidine), 8.64(s, IH, urea-NH), 8.68(s, IH, urea-NH).
N-(4-tert-butylpyridyl)-N'-(4-(4-chlorophenoxy)phenyl)-urea[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
9%
A solution of 4-tert-butyl-2-aminopyridine (0.177 g, 1.18 mmol, 1 equiv.) in 1.2 mL of anh. CH2Cl2 (1.2 mL) was added to CDI (0.200 g, 1.24 mmol, 1.05 equiv) and the 1-re w2s allowed to stir under argon at room temperature 1 d. To the resulting solution was added 4-(4-chlorophenoxy)aniline (0.259 g, 1.18 mmol, 1 equiv.) in one portion. The resulting mixture was stirred at room temperature for 1 d, then was treated with a 10percent citric acid solution (2 mL) and allowed to stir for 1 h. The resulting organic layer was extracted with EtOAc (3*5 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo. The resultant residue was treated with CH2Cl2 (10 mL) and a 1 N aqueous NaOH solution. This mixture was allowed to stir overnight. The resulting organic layer was extracted with CH2Cl2 (3*5 mL). The combined organic layers were (MgSO4) and concentrated in vacuo. The resultant solids were suspended in diethyl ether (10 mL) and sonicated for 15 minutes. The resulting white solids were dried to give N-(4-tert-butylpyridyl)-N'-(4-(4-chlorophenoxy)phenyl) urea (42 mg, 9percent): mp 198-199° C.
4-[([(4-[(tert-butoxycarbonyl)amino methyl}benzyl)oxy]carbonyl}amino) methyl]benzoic acid. To a suspension of CDI (340 mgd, 2.1 mmol) in THF (1.6 mL) was added tert-butyl [4-(hydroxymethyl)benzyl]carbamate (500 mg, 2.1 mmol)) in THF (0.7 mL) and the mixture was aged for 1 hour at ambient temperature. The resulting mixture was then added to a stirring solution of 4-(aminomethyl)benzoic acid (320 mg, 2.1 mmol), TEA (0.3 mL, 2.1 mmol), and DBU (0.3 mL, 2.1 mmol)) in THF (3.5 mL). After stirring at ambient temperature for 5 hours the reaction mixture was concentrated in vacuo, diluted with water, then acidified with HCl. The white precipitate was filtered away, washed with water then dissolved in DCM:EtOAc (some MeOH was added for solubility) dried over anhydrous MgSO4 and concentrated in vacuo to give the title compound. cal'd [M+Na]+437, exp. 437
A mixture of <strong>[17583-10-7]2-amino-5,6-dihydro-4H-benzothiazol-7-one</strong> (10 g, 59 mmol), DBU (18 mL, 0.12 mol) and CDI (24 g, 0.15 mol) in 400 mL acetonitrile is stirred for 5 h at 100 0C. Then dimethylamine (150 mL, 2M in TetaF) is added and the reaction mixture is stirred overnight at 100 0C. The reaction mixture is concentrated under reduced pressure and the residue is poured in water. The mixture is acidified to peta 5 with 6 M HCl in water and extracted with ethyl acetate. The combined organic phases are dried over MgSO4 and concentrated under reduced pressure. The residue is triturated with diethyl ether. Yield: 9.1 g.
6-fluoro-N-(E-1-hydroxyadamantan-4-yl)-3,4-dihydroquinoline-1(2H)-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
To a solution of N,N'-carbonyldiimidazole (185 mg) and triethylamine (159 mul) in chloroform (5 ml), E-4-aminoadamantan-1-ol obtained in Reference Example 2 (127 mg) and N,N-dimethylformamide (2 ml) were added and stirred at room temperature for 1 hour. To the reaction mixture, <strong>[59611-52-8]6-fluoro-1,2,3,4-tetrahydroquinoline</strong> obtained in Reference Example 5 (172 mg) was added and heated under reflux for 5.5 hours, followed by stirring overnight at room temperature. The reaction mixture was then heated under reflux for an additional 8.5 hours. After cooling at room temperature, the reaction mixture was diluted with 1M aqueous hydrochloric acid and extracted with chloroform. After distilling off the solvent under reduced pressure, the residue was diluted with ethyl acetate and washed sequentially with water and brine. The organic layer was dried over anhydrous sodium sulfate and then filtered to remove the desiccant, followed by distilling off the solvent under reduced pressure. The resulting residue was converted into a powder form by addition of chloroform and diethyl ether, and the crystal was collected by filtration to give the titled compound (Compound 2, 140 mg) as a light-brown powder. 1H NMR (300 MHz, CHLOROFORM-D) delta 1.35-1.57 (m, 5 H), 1.67-1.80 (m, 4 H), 1.83-1.99 (m, 4 H), 2.05-2.17 (m, 3 H), 2.75 (t, J=6.7 Hz, 2 H), 3.69-3.77 (m, 2 H), 3.91-3.99 (m, 1 H), 5.24 (d, J=7.0 Hz, 1 H), 6.86-6.95 (m, 2 H), 7.25-7.32 (m, 1 H).
Example 92; (lS.4S)-N-(5-((R)-2-(2.5-difluorophenvnpyrrolidin-l-vnpyrazolori.5-alpyrimidin-3- vD-Sigma-oxa-S-azabicvclo^^.?heptane-S-carboxamide; [00515] To a DCM (1.0 niL) solution of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-l- yl)pyrazolo[l,5-a]pyrimidin-3-amine (Preparation B; 50 mg, 0.16 mmol) was added CDI (51 mg, 0.32 mmol) at ambient temperature in one portion. After stirring 90 minutes, (lS,4S)-2- oxa-5-azabicyclo[2.2.1]heptane hydrochloride (43 mg, 0.32 mmol) was added in one portion, followed by DIEA (0.083 mL, 0.48 mmol). The reaction was stirred for 5 minutes before it was concentrated and directly purified by reverse-phase column chromatography, eluting with 0 to 60% acetonitrile/water to yield the final product as a pale-yellowish powder (60 mg, 86% yield). MS (apci) m/z = 441.2 (M+H).
With sodium chloride; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; water; dimethyl sulfoxide; N,N-dimethyl-formamide; mineral oil;
Steps 1 and 2: 5-[2-(2-Chloro-5-methoxy-phenyl)-acetyl]-1-methyl-1H-pyridin-2-one To a solution of <strong>[3719-45-7]1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid</strong> (7.95 g) in N,N-dimethylformamide (385 ml) was added 1,1'-carbonyldiimidazole (8.42 g). The mixture was stirred at 50° C. for 70 min. The mixture was cooled to -10° C. and (2-chloro-5-methoxy-phenyl)-acetic acid methyl ester (10.61 g) was added. Sodium hydride (60percent dispersion in mineral oil, 6.59 g) was added portionwise over 30 min. The mixture was slowly warmed to room temperature and stirred for 6 h. The mixture was poured into ice water (800 ml) and saturated aqueous ammonium chloride solution (250 ml) and was extracted with ethyl acetate (5*). The organic phase was washed with brine, dried (MgSO4), filtered and concentrated to dryness. The residue was dissolved in dimethylsulfoxide (100 ml). NaCl (3.15 g) and water (1.32 ml) were added and the mixture was heated to 140° C. for 5 h. After cooling to room temperature, ice water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried (MgSO4), filtered and concentrated to dryness to give a light brown solid. The solid was washed with cyclohexane and a small amount of dichloromethane to give the title compound as a colorless solid. More product could be obtained by chromatographic purification of the mother liquor ((SiO2, cyclohexane/EtOAc 7:3=>EtOAc). Colorless solid (9.37 g). MS (m/e)=292.1 [M+H+].
In tetrahydrofuran; at 20℃; for 2h;Inert atmosphere;
Step A:7-Nitro-1H-benzo[d][1,3]oxazine-2,4-dioneInto a 1000-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 2-amino-4-nitrobenzoic acid (54.6 g, 300.00 mmol, 1.00 equiv) in tetrahydrofuran (500 mL), di(1H-imidazol-1-yl)methanone (58.32 g, 360.00 mmol).The resulting solution was stirred for 2 h at 10° C.The solids were collected by filtration to yield 7-nitro-1H-benzo[d][1,3]oxazine-2,4-dione as a yellow solid.
Compound 2 (660 mg, 2.82 mmol) was dissolved in 10 mL of dry CH2Cl2.Then, N,N'-carbonyldiimidazole (915 mg, 5.64 mmol) was added, and the mixture was stirred at room temperature for 1-2 h under N2. After the reaction was completed, 40 ml of CH 2 Cl 2 was added, and the mixture was washed three times with an equal amount of 1 M HCl solution, and the organic phase was dried over anhydrous sodium sulfate.Concentrated under reduced pressure to give a white solid 787mg, yield 85%.
In dichloromethane; at 20℃; for 2h;
2.07 g of 1,1'-carbonyldiimidazole and 2.07 g of 4- (hydroxymethyl) phenylboronic pinicole ester(4- (hydroxymethyl) phenylboronic acid pinacol ester) was dissolved in 20 mL of dichloromethane (DCM)And allowed to react at room temperature for 2 hours. The product was named 1 and 1 was obtained by silica gel chromatography using an eluent of 1: 1 mixture of ethyl acetate and hexane.
3-Methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (2.00 g, 9.84 mmoL) was dissolved in 1,4-dioxane (10 ml), and di(1H-imidazol-1-yl)methanone (3.20 g, 19.68 mmoL) was added at 5 °C, followed by stirring at room temperature for 2 hours. The reaction mixture was poured into water and the precipitate was collected by filtration and dried. The obtained solid was dissolved in 1,4-dioxane (10 ml), and the <strong>[301673-16-5]tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate</strong> (1.53 g, 7.10 mmoL) was added. The reaction mixture was stirred at 80°C for 2 hours. To the mixture were added ethyl acetate (30 ml) and water (15 ml), and the mixture was partitioned between an organic layer and an aqueous layer. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure. The residue was purified by silica gel chromatography (MeOH/CHCl3:0percent-10percent) to afford the target compound (3.41 g, 87percent). LC-MS (Method E): 2.52 min, [M+H] =44623
Preparation of compound 48A: L-Ser(OtBu)-COOMe hydrochloride (500 mg,2.36 mmol) was dissolved in anhydrous DCM (5mL). CDI (421 mg, 2.6 mmol) and imidazole (177 mg, 2.6 mmol) was added and the mixture was stirred for 90 mins.Piperidine (350 uL, 3.54 mmol) was then added and stirring continued for another 16 hrs. The mixture was concentrated under reduced pressure. It was then dissolved in EtOAc and washed with 5percent citric acid aqueous solution (3X), saturated aqueous sodium bicarbonate solution and then saturated sodium chloride solution. The organic extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 48A (689 mg, 99percent). NMR (CDCh): delta 5.30 (m, 1H), 4.63 (m, 1H), 3.83 (m, 1H), 3.74 (s, 3H), 3.61 (m, 1H), 3.39 (m, 4H), 1.61 (m, 6H), 1.15 (s, 9H).
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In dimethyl sulfoxide; at 20℃; for 3h;Product distribution / selectivity;
Example 4Methyl 2-ethoxy- 1 -((2'-(5-oxo-4,5-dihydro- 1 (2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)- 1H- benzo[< ]imidazole-7-carboxylate of formula la l ,8-Diazabicyclo[5.4.0.]undec-7-ene (DBU; 0.1 g, 0.65 mmol) was added dropwise to a mixture of methyl 2-methoxy- l -((2'-((hydroxyamino)iminomethyl)biphenyl-4-yl)methyl)- lH- benzo[i ]imidazole-7-carboxylate (of formula Va; 0.22 g, 0.5 mmol), the corresponding solvent (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 I. Table I - Yield and purity of the product of Example 4* - Also contains 40.4 percent of the starting compound of formula Va; ** - Carbonyl-di- 1 ,2,4- triazole was used instead of carbonyldiimidazole.
68%
Example 2Preparation of methyl l-[[2'-(4, 5-dihydro-5-oxo-4H-l, 2, 4-oxadiazol-3-yl) biphenyl- 4-yl] methyl]-2-ethoxy-lH-benzimidazole-7-carboxyIate To a solution of methyl 2-ethoxy [[2'-(hydroxyamidino) biphenyl-4-yl] methyl]- lH-benzimidazole-7-carboxylate (25 g) in tetrahydrofuran (700 ml), N,N- carbonyldi imidazole (15 g) and l,8-diazabicyclo[5.4.0]undec-7-ene (DBU)(13 g) was added and resulting solution was stirred for 30-40 mins. at about 20-25°C. To the resulting solution ethyl acetate (700 ml) and saturated solution of sodium bisulphite (700 ml) was added. Organic layer was separated, washed with brine solution and evaporated under vacuum to concentrate the solution. Reaction mass was cooled to 20-25°C and cyclohexane was added to it and the solution was stirred for about 20-25°C. Product was filtered and dichloromethane was charged to it followed by stirring. The product was filtered, washed and dried to obtain title compound. (Yield: 17.8 g; 68percent (Purity: 96percent with desethyl impurity 0.1 1percent)
General procedure: A mixture of 4-chloro-3-(trifluoromethyl)aniline or its derivatives and CDI in dry CH2Cl2 (5mL) was stirred for 1h at room temperature, then compound 6 (194mg, 0.69mmol) or its derivatives was added. The mixture was allowed to stir for an additional 1h to afford white precipitates. The solid was collected by filtration under vacuum, washed with water for three times and dried under vaccum to give compound 7a?7m and 7p?7r [13], but 7m and 7n was synthesis by a condensation reaction between benzoic acid and compound 6 promoted by EDCI. The yields of all compounds were between 65.7percent and 82.4percent. The general synthetic route is depicted in Scheme 1.
Step 4 To a solution of <strong>[159622-10-3](1R,2S)-1-(tert-butoxycarbonylamino)-2-vinylcyclopropanecarboxylic acid</strong> (7.5 g, 33 mmol) in DMF (50 mL) was added 1,1'-carbonyldiimidazole ("CDI", 10.7 g, 66.0 mmol) and the reaction mass was heated at 55° C. for 4 h. To this reaction mass was added 1-fluoromethylcyclopropane-1-sulfonamide (6.5 g, 42.9 mmol) followed by 1,8-diazabicyclo[5.4.0]undec-7-ene ("DBU", 6.0 mL, 43 mmol). The reaction mixture was stirred at 55° C. for 18 h. The solvent was evaporated under reduced pressure and the residue was diluted with water and acidified to pH ?2 by using aq. 1.5 N HCl solution. The precipitated solid was isolated via filtration and washed with water to afford tert-butyl (1R,2S)-1-(1-(fluoromethyl)cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropylcarbamate as off-white solid (11.5 g, 96percent). MS: MS m/z 361.4 (M+-1).
96%
With hydrogenchloride; In N,N-dimethyl-formamide;
Step 4: Preparation of tert-butyl (1R,2S)-1-(1-(fluoromethyl)cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropylcarbamate To a solution of <strong>[159622-10-3](1R,2S)-1-(tert-butoxycarbonylamino)-2-vinylcyclopropanecarboxylic acid</strong> (7.5 g, 33 mmol) in DMF (50 mL) was added 1,1'-carbonyldiimidazole ("CDI", 10.7 g, 66.0 mmol) and the reaction mass was heated at 55° C. for 4 h. To this reaction mass was added 1-fluoromethylcyclopropane-1-sulfonamide (6.5 g, 42.9 mmol) followed by 1,8-diazabicyclo[5.4.0]undec-7-ene ("DBU", 6.0 mL, 43 mmol). The reaction mixture was stirred at 55° C. for 18 h. The solvent was evaporated under reduced pressure and the residue was diluted with water and acidified to pH ?2 by using aq. 1.5 N HCl solutions. The precipitated solid was isolated via filtration and washed with water to afford tert-butyl (1R,2S)-1-(1-(fluoromethyl)cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropylcarbamate as off-white solid (11.5 g, 96percent). MS:MS m/z 361.4 (M+-1).
With triethylamine; In tetrahydrofuran; for 5h;Reflux;
Preparation of compound V: 147 To a stirred suspension of 3H-spiro[isobenzofuran-1,4?-piperidine] hydrochloride (20mg, 0.O89mmol) in dry THF, was added triethylamine (18mg, 0.l78mmol) followed by the addition of CDI (15mg, 0.O9Ommol). The resulting solution was heated to reflux for 5 hours, the solvent removed under vacuum and the residue was purified by preparative TLC to afford 22 mg of the imidazoleintermediate (mle=284[M+H]j, Yield: 88percent.
Step 2 4-Amino-1,3-dihydrobenzoimidazol-2-one 0.53 g (6.5 mmol, 2 eq) of N-N'-carbonyliimidazole were added portionwise to 450.7 mg (3.24 mmol, 1 eq) of <strong>[608-32-2]benzene-1,2,3-triamine</strong> in solution in 30 ml of acetonitrile. The reaction medium was stirred at ambient temperature for 6 hours and then heated at 70° C. overnight. The reaction was stopped by adding 50 ml of water and then extracted with ethyl acetate. The organic phases were combined, and dried over sodium sulfate. The solvents were evaporated off and then the residue was purified by chromatography on silica gel (dichloromethane/methanol/aqueous ammonia: 95/5/2). 229.9 mg of 4-amino-1,3-dihydrobenzoimidazol-2-one were obtained. Yield=42percent.
1-(5-methoxypyridin-2-yl)-3-(3-methyl-1-phenyl-1H-pyrazol-5-yl)urea[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In acetonitrile; at 80℃; for 16h;
COMPOUND 111-(5-methoxypyridin-2-yl)-3-(3-methyl-1-phenyl-1H-pyrazol-5-yl)ureaTo a solution of 3 -methyl- 1 -phenyl- lH-pyrazol-5 -amine (50 mg, 0.29 mmol) in CH3CN (2 mL) was added 4-methoxypyridin-2-amine (43 mg, 0.35 mmol) and CDI (56 mg, 0.35 mmol). The mixture was stirred for 16 h at 80 °C. The reaction mixture was cooled, and concentrated, and the residue was purified by prep-HPLC using a reversed phase C18column and eluting with a gradient of H20:CH3CN:CF3C02H - 95:5:0.1 to 5:95:0.1, to give the title compound as a white solid. MS: m/z = 324 (M+H). 1H NMR (400 MHz, CDC13) delta 7.76-7.70 (m, 2H), 7.54-7.38 (m, 5H), 6.72 (m, 1H), 6.45 (s, 1H), 4.02 (s, 3H), 2.35 (s, 3H).
4-(4-(aminomethyl)-3-methylphenyl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine hydrochloride[ No CAS ]
[ 530-62-1 ]
N-(2-methyl-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-4-(trifluoromethyl)piperidine-1-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
52%
[01 82j To a solution of 4-(4-(aminomethyl)-3 -methylphenyl)-N-( 1-methyl-i H-pyrazol-4- yl)pyrimidin-2-amine (80 mg, 0.24 mmol, 1.0 equiv) in DMF (2 mL) was added TEA (48 mg, 0.48 mmol, 2.0 equiv), the mixture was stirred at rt for 10 mm. Then CDI (39 mg, 0.24 mmol,1.0 eq) was added and the reaction mixture was stirred at rt for 1 h before 4- (trifluoromethyl)piperidine (48 mg, 0.48 mmol, 2.0 eq) was added. The mixture was stirred at room temperature for another 12 h. The mixture was purified by prep-HPLC (Gradient: 5percent B increase to 95percent B, A: 0.5percent NH3 in water, B: CH3CN) to give N-(2-methyl-4-(2-((i-methyl-1H- pyrazol-4-yl)amino)pyrimidin-4-yl)benzyl)-<strong>[657-36-3]4-(trifluoromethyl)piperidine</strong>- 1 -carboxamide (68 mg, yield: 52percent) as a yellow solid. ESI-MS (M+H):474.2. ?H NMR (400 MHz, CDC13) 5: 8.41 (d, J 5.2 Hz, 1H), 7.86-7.82 (m, 3H), 7.53 (s, 1H), 7.36 (d, J= 7.6 Hz, 1H), 7.06-7.05 (m, 2H),4.67 (t, J 5.2 Hz, 1H), 4.47 (d, J 5.6 Hz, 2H), 4.10-4.06 (m, 2H), 3.90 (s, 3H), 2.85-2.78 (m,2H), 2.43 (s, 3H), 2.22-2.16 (m, 1H), 1.91-1.88 (m, 2H), 1.61-1.5 1 (m, 2H).
6-[trans-3-(methylamino)cyclobutyl]oxy}-2-(morpholin-4-yl)-4,5’-bipyrimidin-2’-amine hydrochloride[ No CAS ]
[ 530-62-1 ]
[ 153209-97-3 ]
1-(trans-3-[2’-amino-2-(morpholin-4-yl)-4,5’-bipyrimidin-6-yl]oxy}cyclobutyl)-1-methyl-3-[(3-methyloxetan-3-yl)methyl]urea[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In tetrahydrofuran; at 30℃; for 16h;
General procedure: The product of Example 2, Step 2, 6-[frans-3-(methylamino)cyclobutyl]oxy}-2- (morpholin-4-yl)-4,5'-bipyrimidin-2'-amine hydrochloride (75 pmol, 1 .0 eq) was dispensed to 8 mL vials. The amines monomers (75 pmol, 1 .0 eq), CDI (225 pmol, 3.0 eq) and THF (600 muIota_) were added, followed by triethylamine (450 pmol, 6.0 eq). The vials were capped and stirred at 30 °C for 16 hours. The solvent was evaporated by Speedvac and the residues were purified by preparative HPLC to give the desired product.
tert-butyl (2S,4R)-2-methoxycarbonyl-4-((methoxycarbonyl)amino)pyrrolidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
To a solution of triethylamine (136 mg, 1.35 mmol) and 1, 1?-carbonyldiimidazole (CDI) (175 mg, 1.08 mmol) in anhydrous DMF (2 mL) was added (2S, 4R) -1-tert-butyl 2-methyl 4-aminopyrrolidine-1, 2-dicarboxylate (220 mg, 0.90 mmol) at rt. The mixture was stirred at rt for 30 min, and then anhydrous methanol (5 mL) was added. The resulting mixture was stirred at 60 for 24 h, and concentrated. The residue was diluted with water (5 mL) , and extracted with EtOAc (10 mL × 3) . The combined organic layers were dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluted with Petroleum ether/EtOAc (v/v) 2/3 to give (2S, 4R) -1-tert-butyl 2-methyl 4- ( (methoxycarbonyl) amino) pyrrolidine-1, 2-dicarboxylate as a white solid (260 mg, 95) .1H NMR (600 MHz, CDCl3) : delta ppm 4.81-4.86 (m, 1H) , 4.26-4.38 (m, 2H) , 3.74-3.81 (m, 1H) , 3.73 (s, 3H) , 3.66 (s, 3H) , 3.25-3.38 (m, 1H) , 2.22 (m, 2H) , 1.45 (d, J 18.2 Hz, 9H) and MS-ESI: m/z 203.20 [M+H-100] +.
95%
Triethylamine (136mg, 1.35mmol), and N, N'- carbonyldiimidazole (CDI) (175mg, 1.08mmol) was dissolved indry DMF (2 mL), was added the compound (2S, 4R) -2- methoxycarbonyl-4-amino-pyrrolidine-1-carboxylate(220mg, 0.90mmol), stirred for 30min at room temperature After addition of anhydrous methanol (5mL), 60 °C the reaction is stopped after 24h the reaction, the solvent of DMF was removed, water (5mL), ethyl acetate (10mL × 3) was extracted, dried over anhydrous sodium sulfate, the solvent was removed concentrate wassubjected to column chromatography (eluent: Petroleumether / EtOAc (v / v) = 2/ 3) to give a white solid260mg: (2S, 4R) -2- methoxycarbonyl-4 - ((methoxycarbonyl) amino) pyrrolidine-1-carboxylate, yield: 95percent.
95%
Triethylamine (136 mg, 1.35 mmol)And N, N'-carbonyldiimidazole (CDI) (175 mg, 1.08 mmol) were dissolved in dry DMF (2 mL)Add compound(2S, 4R) -2-methoxycarbonyl-4-aminopyrrolidine-1-carboxylic acidTert-butyl ester (220 mg, 0.90 mmol)After stirring at room temperature for 30 min, anhydrous methanol (5 mL) was added,60 reaction after 24 hours to stop the reaction,(10 mL x 3), dried over anhydrous sodium sulfate, and the solvent was removed and the concentrate was subjected to column chromatography (eluent: petroleum ether / EtOAc (v / v) = 2/3) to afford 260 mg of a white solid: (2S, 4R) -2-methoxycarbonyl-4 - ((methoxycarbonyl) amino) pyrrolidine-Tert-butyl ester, yield: 95percent.
To a solution of triethylamine (670 mg, 6.5 mmol) and 1, 1'-carbonyldiimidazole (CDI) (2.6 g, 16.2 mmol) in anhydrous THF (5 mL) was added anhydrous methanol (520 mg, 16.2 mmol) at rt. The mixture was stirred at rt for 15 min, and tert-butyl 3- (hydroxymethyl) piperazine-1-carboxylate (700 mg, 3.2 mmol) was added. The resulting mixture was stirred at 65 for 6 h, and concentrated. The residue was diluted with water (5 mL) , and extracted with EtOAc (10 mL × 3) . The combined organic layers were dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluted with Petroleum ether/EtOAc (v/v) 3/1 to give tert-butyl 3-oxotetrahydro-1H-oxazolo [3, 4-a] pyrazine-7 (3H) -carboxylate as a white solid (202 mg, 26) .1H NMR (600 MHz, CDCl3) : delta ppm 4.41-4.44 (m, 1H) , 4.04-4.30 (m, 2H) , 3.92-3.95 (m, 1H) , 3.76-3.80 (m, 2H) , 2.97-3.02 (m, 1H) , 2.63-2.80 (m, 2H) , 1.46 (m, 9H) and MS-ESI: m/z 187.05 [M-55] +.
(S)-9-(4-fluorobenzyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid[ No CAS ]
[ 530-62-1 ]
[ 192130-34-0 ]
C31H36FN5O4[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
58%
1, 1-Carbonyl diimidazole (37 mg, 0.23 mmol) in DMF (0.5 mL) was added dropwise to a degassed solution of tert-Butyl 4-(2-aminoethyl) piperazine-1-carboxylate (53 mg, 0.23 mmol) and THF (0.5 mL). The mixture stirred at RT overnight. (S-9-(4-fluorobenzyl)-2,3,4,9- tetrahydro-1H-pyrido[3,4-bjindole-3-carboxylic acid (75 mg, 0.23 mmol) and DMF (1 mL) was added and heated at 95 °C overnight. The reaction cooled to RT and diluted with water. The mixture extracted with EtOAc (3 times). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography using 0-100 percent EtOAcIHx to afford (Dl) as a yellow solid (76 mg, 58 percent). LC-MS [M + H 562].
tert-butyl 2-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
97%
In dichloromethane; at 20℃;
Add 1,1 ?-carbonyldiimidazole (15.4 g, 93.3 mmol) to a solution of tert-butyl 4- amino-4-(aminomethyi)piperidine- I ?-carboxylate (21.4 g, 93.3 mmol) in DCM (1.10 L) and stir the resulting mixture at rt overnight, Add water (0.5 L) then stir the resulting mixture for 30 mm. Separate the two phases, dry the organic phase over Mg504, filter, and concentrate the filtrate under reduced pressure to afford the title compound (23.16 g, 97percent yield). ES/MS ,n/z 256 (M±H).
General procedure: (Step 1) The -amino methyl ester hydrochloride (1.0equiv.) and 1,1?-carbonylimidazole (CDI) (1.3 equiv.) were ground in a 12 mLstainless steel milling jar in a planetary ball-mill at 450 rpm for 40 minutes. (Step 2)The amine (1.6 equiv) and K2CO3 (3.6 equiv) were added and the mixture wasground at 450 rpm for two hours. Distilled water was added to the crude and thedesired compound was either precipitated and filtered over sintered glass, orextracted with ethyl acetate. The organic layer was washed with a 10percent aq. citric acidsolution (× 3) and brine (× 1), dried over MgSO4 and concentrated in vacuo. Only forcompounds 3b and 5b a purification by flash chromatography was performed on thecrude sample, respectively.
diethyl 2-((3-(1-methyl-1H-pyrazol-4-yl)ureido)methylene)malonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
66%
Step 1. Diethyl 2-((3-(1-methyl-1H-pyrazol-4-yl)ureido)methylene)malonate A mixture of 1-methyl-1H-pyrazol-4-amine (0.097 g, 1.0 mmol) and 1,1'-carbonyldiimidazole (0.178 g, 1.100 mmol) in DMSO (1 mL) was stirred at rt for 1 h, then diethyl 2-(aminomethylene)malonate (0.187 g, 1.00 mmol) was added to the solution. The reaction mixture was stirred at 80° C. overnight, cooled to rt, and directly purified via column chromatography (0percent to 100percent EtOAc in hexanes) to afford the product (0.204 g, 66percent). LCMS calcd for C13H19N4O5 (M+H)+: m/z=311.1. Found: 311.2.
(3aR,7aR)-4-(octahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-7H-pyrrolo[2.3-d]pyrimidine[ No CAS ]
[ 530-62-1 ]
[ 123986-64-1 ]
4-[(tert-butoxycarbonyl)amino]methyl}benzyl (3aR,7aR)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)octahydro-4-pyrrolo[3,2-b]pyridine-4-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
EXAMPLE 8-1 4- [(tert-butoxycarbonyl)amino]methyl} benzyl(3aR, 7aR)-1 -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)octahydro-4-pyrrolo[3,2-b]pyridine-4-carboxylate To a stirred solution of CDI (20 mg, 0.12 mmol) in THF (0.20 mL) was added <strong>[123986-64-1](4-hydroxymethyl-benzyl)-carbamic acid tert-butyl ester</strong> (29 mg, 0.12 mmol) in THF (0.20 mL) at -10 °C. The resulting suspension was allowed to stir for 1 hour at ambient temperature. In a separate flask, enantiomer 2 of Example 2 was dissolved in THF (0.20 mL) and DBU (0.019 mL, 0.12 mmol) followed by Et3N (0.017 mL, 0.12 mmol) was added and allowed to stir at ambient temperature for 5 minutes. The activated alcohol solution was added to the suspension of amine in DBU and the resulting suspension was allowed to stir at ambient temperature for 18 hours. The reaction mixture was partitioned between EtOAc (25 mL) and saturated aqueous sodium bicarbonate (25 mL). The layers were separated, and the organic layer was collected, dried over sodium sulfate, and concentrated in vacuo. The crude reaction mixture was purified by column chromatography on silica gel eluting with EtOAc/hexane (0-100percent) followed by DCM:MeOH (90:10). The product fractions were concentrated in vacuo to afford the desired product. LRMS calc'd for C27H34N6O4 [M+H]+, 507; found 507. Jak1 activity: +.
tert-butyl (2R)-3-phenyl-2-[4-(p-tolylsulfonylamino)phenyl]carbamoylamino}propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
52%
To a solution of 30 N-(4-aminophenyl)-4-methyl-benzenesulfonamide (0.119 g, 0.454 mmol) obtained by a method similar to that in Example 14 1, step 1, in 6 dichloromethane (4.5 mL) were added 16 triethylamine (0.316 mL, 2.27 mmol) and 17 carbonyldiimidazole (CDI) (0.0882 g, 0.544 mmol), and the mixture was stirred for 1 hr. To the reaction mixture was added 31 D-phenylalanine t-butylester hydrochloride (0.234 g, 0.907 mmol) and the mixture was stirred at room temperature overnight. To the reaction mixture was added 0.1N 10 hydrochloric acid (1.5 mL), and the mixture was extracted with dichloromethane. The solvent was evaporated and the obtained residue was purified by high performance liquid chromatography (water-acetonitrile (each containing 0.1percent 13 trifluoroacetic acid)) to give the 33 title compound (0.120 g, 0.236 mmol, 52percent). MS (ESI) m/z 510 (M+H)+ (1937) 1H NMR (400 MHz, DMSO-d6) delta 9.84 (s, 1H), 8.60 (s, 1H), 7.60-7.52 (m, 2H), 7.34-7.26 (m, 4H), 7.26-7.17 (m, 5H), 6.96-6.88 (m, 2H), 6.32 (d, J=8.0 Hz, 1H), 4.36 (m, 1H), 3.01-2.89 (m, 2H), 2.32 (s, 3H), 1.34 (s, 9H).
N-(4-amino-2-fluorophenyl)-4-methylbenzenesulfonamide[ No CAS ]
[ 3403-25-6 ]
[ 530-62-1 ]
tert-butyl (2R)-2-[3-fluoro-4-(p-tolylsulfonylamino)phenyl]carbamoylamino}-3-phenylpropanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
3%
To a solution of N-(4-amino-2-fluoro-phenyl)-4-methyl-benzenesulfonamide (42.7 mg, 0.152 mmol) obtained in step 63 2 in 6 dichloromethane (1.5 mL) were added 16 triethylamine (0.106 mL, 0.762 mmol) and 17 carbonyldiimidazole (29.6 mg, 0.183 mmol) and the mixture was stirred for 1 hr. To the reaction mixture was added 31 D-phenylalanine t-butylester hydrochloride (86.4 mg, 0.335 mmol) and the mixture was stirred at room temperature overnight. To the reaction mixture was added 0.1N 10 hydrochloric acid (0.5 mL), and the mixture was extracted with dichloromethane. The solvent was evaporated and the obtained residue was purified by high performance liquid chromatography (water-acetonitrile (each containing 0.1percent 13 trifluoroacetic acid)) to give the 65 title compound (2.2 mg, 0.00417 mmol, 3percent). (1954) MS (ESI) m/z 528 (M+H)+ (1955) 1H NMR (400 MHz, DMSO-d6) delta 9.75 (s, 1H), 8.90 (s, 1H), 7.61-7.50 (m, 2H), 7.39-7.28 (m, 5H), 7.28-7.15 (m, 3H), 7.02 (t, J=8.8 Hz, 1H), 6.94-6.84 (m, 1H), 6.45 (d, J=7.9 Hz, 1H), 4.45-4.31 (m, 1H), 3.01-2.93 (m, 2H), 2.36 (s, 3H), 1.35 (s, 9H).
The starting material 3-aminoisonicotinic acid (1000mg, 7.240mmol, 1.0eq) was dissolved in DMF (20mL), cooled to 0 deg.] C, was added portionwise CDI (2000mg, 12.334mmol, 1.7eq), slowly warmed to room temperature, the reaction overnight, complete reaction was monitored LC-MS, the reaction was cooled to room temperature, the reaction solution obtained without treatment, direct cast step.
6-chloro-2H-pyrido[3,4-d][1,3]oxazine-2,4(1H)-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In N,N-dimethyl-formamide; at 0 - 20℃;
5-amino-2-chloro isonicotinic acid (30g, 0.1738mol, 1.0eq), was dissolved in N,N-dimethylformamide (300 mL) in added portionwise at 0°C, N,N'-carbonyldiimidazole imidazole (48g, 0.2955mol, 1.7eq), was slowly warmed to room temperature overnight.LC-MS showed the reaction was complete, cooled to room temperature, the next step without treatment.
With triethylamine; In tetrahydrofuran; at 40℃; for 1.5h;
In 250 mL of tetrahydrofuran,14.3 g (about 0.1 mol) of 2-oxopyrrolidineacetic acid was added,17.7 g (about 0.11 mol) of CDI and 20.2 g (about 0.2 mol) of triethylamine, heated to 40 C, and reacted for 1.5 hours.Obtaining a solution containing an intermediate compound;
2-pyrolidinylmethanol (3g, 0.029 mole) was dissolved in dry toluene (100ml_) under an N2 atmosphere. Carbonyldiimidazole (9.6g, 0.059 mole) and 4-dimethylaminopyridine (0.36g, 0.002 mole) were added and the reaction mixture was refluxed at 100C for 2 hours. The crude reaction mixture was cooled to room temperature and concentrated. The crude solid was diluted with dichloromethane (200ml_) and washed with water (100ml_) follow by 1 M HCI(100ml_). The organic layer was dried over Na2S04 and concentrated to give the crude tetrahydro-1 H,3H-pyrrolo[1 ,2-c]oxazol-3-one (1.4g, 37.83%) which was used without further purification.
methyl (1S)-1-amino-7-fluoro-2,3-dihydro-1H-indene-4-carboxylate hydrochloride[ No CAS ]
[ 135242-93-2 ]
[ 530-62-1 ]
methyl (S)-7-fluoro-1-((((1-methyl-1H-1,2,4-triazol-3-yl)methoxy)carbonyl)amino)-2,3-dihydro-1H-indene-4-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81.8%
A mixture of carbonyldiimidazole (CDI, 4.62 g, 28.5 mmol), ( 1 -methyl- 1,2, 4-triazol- 3-yl)methanol (3.45g, 30.53 mmol), and 2-MeTHF (50 mL) was stirred at room temperature (20 C) for 3 hours. To the mixture was added methyl (5)-l-amino-7-fluoro-2,3-dihydro-lH- indene-4-carboxylate hydrochloride [lOa.HCl] (5.0 g, 20.35 mmol) followed by N,N- diisopropylethylamine (6.58 g, 50.9 mmol). The contents were heated to 60 C and stirred for 15 hours. The mixture was cooled to 20 C, charged with water (50 mL), and stirred for 30 min. The slurry was filtered, washed with 2-MeTHF (2 x 5 mL) and dried under vacuum to give methyl fV)-7-riuoro- 1 -(((( 1 -methyl- 1 H- 1.2.4-triazol-3-yl)methoy)carbonyl)amino)- 2,3-dihydro-lH-indene-4-carboxylate [11a] as white crystalline solid (5.8g, 81.8% yield). 'H NMR (400 MHz, DMSO-d6) d 8.41 (s, 1H), 7.87 (dd, J = 8.6, 5.0 Hz, 1H), 7.78 (d, J = 8.7 Hz, 1H), 7.11 (t, J = 8.8 Hz, 1H), 5.28-5.22 (m, 1H), 4.98 (q, J = 10 Hz, 2H), 3.82 (s, 3H), 3.80 (s, 3H), 3.31 (ddd, J = 17.6, 8.8, 5.5 Hz, 1H), 3.06 (ddd, J = 17.6, 8.7, 6.3 Hz, 1H), 2.44- 2.35 (m, 1H), 1.94-1.81 (m, 1H).
(S)-1-amino-N-(3-chloro-4-fluorophenyl)-7-fluoro-2,3-dihydro-1H-indene-4-carboxamide hydrochloride[ No CAS ]
[ 135242-93-2 ]
[ 530-62-1 ]
O-(1-methyl-1H-1,2,4-triazol-3-yl)methyl N-(S)-(4-((3-chloro-4-fluorophenyl)carbamoyl)-7-fluoro-2,3-dihydro-1H-inden-1-yl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
144.5 g
A mixture of carbonyldiimidazole (CDI) (97 g, 0.6 mol), (l-methyl-l,2,4-triazol-3- yl)methanol [8] (67.7 g, 0.6 mol), and 2-MeTHF (1150 mL) was stirred at room temperature (20 C) for 2 hours. The reaction mixture was added to a stirred mixture of (S)- 1 -amino-N- (3-chloro-4-fluorophenyl)-7-fluoro-2,3-dihydro-lH-indene-4-carboxamide hydrochloride [7.HC1] (143.3 g, 0.4 mol), 2-MeTHF (860 mL), and N,N-diisopropylethylamine (129 g, 1 mol). The mixture was heated to 60 C and the contents maintained at 60 C for 6 hours. (0248) The contents were cooled to 20 C, water (285 mL) was added, and the mixture was stirred for 15 min. The layers were separated and the organic layer was washed with water two times (285 mL each time). The organic layer was filtered through a pad of CELITE, and rinsed with 145 mL 2-MeTHF (1 volume). The solution was concentrated to about 700 mL under vacuum. 2-propanol (710 mL) was added and the mixture concentrated to about 700 mL. Additional 2-propanol (710 mL) was added and the mixture concentrated to (0249) approximately 1000 mL. The slurry was heated at 45 C for 2 hours and cooled to 20 C over 1 hour. The slurry was stirred at 20 C for 2 hours, and the product filtered. The product was washed with 2-propanol two times (286 mL each wash), and the wet product was dried under vacuum to give (l-methyl-lH-l,2,4-triazol-3-yl)methyl fV)-(4-((3-chloro-4- fluorophenyl)carbamoyl)-7-fluoro-2,3-dihydro-lH-inden-l-yl)carbamate [9] as solid (144.5 g, 78.4% yield). XH NMR (400 MHz, DMSO-d6) d 10.39 (s, 1H), 8.42 (s, 1H), 8.06-7.99 (m, (0250) 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.71-7.59 (m, 2H), 7.39 (t, J = 9.1 Hz, 1H), 7.14 (t, J = 8.8 Hz, 1H), 5.26 (q, J = 7.7 Hz, 1H), 4.99 (dd, J = 20.0, 12.0 Hz, 1H), 3.83 (s, 2H), 3.21 (ddd, J = 17.1, 8.8, 5.1 Hz, 1H), 3.04-2.96 (m, 1H), 2.46-2.33 (m, 1H), 1.92-1.83 (m, 1H). mp: 185.9- 186.9 C.
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