Home Cart 0 Sign in  

[ CAS No. 530-62-1 ] {[proInfo.proName]}

,{[proInfo.pro_purity]}
Cat. No.: {[proInfo.prAm]}
HazMat Fee +

There will be a HazMat fee per item when shipping a dangerous goods. The HazMat fee will be charged to your UPS/DHL/FedEx collect account or added to the invoice unless the package is shipped via Ground service. Ship by air in Excepted Quantity (each bottle), which is up to 1g/1mL for class 6.1 packing group I or II, and up to 25g/25ml for all other HazMat items.

Type HazMat fee for 500 gram (Estimated)
Excepted Quantity USD 0.00
Limited Quantity USD 15-60
Inaccessible (Haz class 6.1), Domestic USD 80+
Inaccessible (Haz class 6.1), International USD 150+
Accessible (Haz class 3, 4, 5 or 8), Domestic USD 100+
Accessible (Haz class 3, 4, 5 or 8), International USD 200+
Chemical Structure| 530-62-1
Chemical Structure| 530-62-1
Structure of 530-62-1 * Storage: {[proInfo.prStorage]}
Cart0 Add to My Favorites Add to My Favorites Bulk Inquiry Inquiry Add To Cart

Quality Control of [ 530-62-1 ]

Related Doc. of [ 530-62-1 ]

Alternatived Products of [ 530-62-1 ]

Product Details of [ 530-62-1 ]

CAS No. :530-62-1 MDL No. :MFCD00005286
Formula : C7H6N4O Boiling Point : -
Linear Structure Formula :- InChI Key :PFKFTWBEEFSNDU-UHFFFAOYSA-N
M.W :162.15 Pubchem ID :68263
Synonyms :

Calculated chemistry of [ 530-62-1 ]

Physicochemical Properties

Num. heavy atoms : 12
Num. arom. heavy atoms : 10
Fraction Csp3 : 0.0
Num. rotatable bonds : 2
Num. H-bond acceptors : 3.0
Num. H-bond donors : 0.0
Molar Refractivity : 40.65
TPSA : 52.71 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -7.4 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.04
Log Po/w (XLOGP3) : -0.16
Log Po/w (WLOGP) : 0.6
Log Po/w (MLOGP) : -0.44
Log Po/w (SILICOS-IT) : -0.57
Consensus Log Po/w : 0.09

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -1.23
Solubility : 9.57 mg/ml ; 0.059 mol/l
Class : Very soluble
Log S (Ali) : -0.49
Solubility : 52.2 mg/ml ; 0.322 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -0.88
Solubility : 21.5 mg/ml ; 0.132 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.92

Safety of [ 530-62-1 ]

Signal Word:Danger Class:8
Precautionary Statements:P201-P202-P260-P264-P270-P280-P301+P312+P330-P301+P330+P331-P303+P361+P353-P304+P340+P310-P305+P351+P338+P310-P308+P313-P363-P405-P501 UN#:3263
Hazard Statements:H302-H314-H360 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 530-62-1 ]

* 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.

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

[ 530-62-1 ] Synthesis Path-Upstream   1~97

  • 1
  • [ 288-32-4 ]
  • [ 68-12-2 ]
  • [ 530-62-1 ]
YieldReaction ConditionsOperation in experiment
96% at 110℃; for 5 h; 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 ]
YieldReaction ConditionsOperation 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.
Reference: [1] Patent: US2002/111497, 2002, A1,
[2] Patent: WO2005/63718, 2005, A1, . Location in patent: Page/Page column 8-9
[3] Patent: EP1600444, 2005, A1, . Location in patent: Page/Page column 6
[4] Patent: WO2005/63718, 2005, A1, . Location in patent: Page/Page column 8; 9
[5] Patent: EP1600444, 2005, A1, . Location in patent: Page/Page column 6; 7
[6] Patent: EP1600444, 2005, A1, . Location in patent: Page/Page column 6-8
[7] Justus Liebigs Annalen der Chemie, 1957, vol. 609, p. 75,82
[8] Patent: US6353115, 2002, B1, . Location in patent: Page column 5
[9] Patent: US6353115, 2002, B1, . Location in patent: Page column 6
[10] Patent: US6353115, 2002, B1, . Location in patent: Page column 5
[11] Patent: US6353115, 2002, B1, . Location in patent: Page column 5
[12] Journal of Polymer Science, Part A: Polymer Chemistry, 2010, vol. 48, # 2, p. 417 - 424
  • 3
  • [ 288-32-4 ]
  • [ 75-44-5 ]
  • [ 530-62-1 ]
Reference: [1] Patent: US2002/111497, 2002, A1,
[2] Patent: US2002/111497, 2002, A1,
  • 4
  • [ 288-32-4 ]
  • [ 32315-10-9 ]
  • [ 530-62-1 ]
Reference: [1] Patent: US6455702, 2002, B1,
[2] Patent: US6455702, 2002, B1,
[3] Patent: US6455702, 2002, B1,
[4] Patent: US6455702, 2002, B1,
[5] Patent: US6455702, 2002, B1,
[6] Patent: US6455702, 2002, B1,
[7] Patent: US6455702, 2002, B1,
[8] Patent: US6455702, 2002, B1,
[9] Patent: US6455702, 2002, B1,
[10] Patent: US6455702, 2002, B1,
[11] Patent: US2012/53214, 2012, A1, . Location in patent: Page/Page column 9
  • 5
  • [ 288-32-4 ]
  • [ 75-44-5 ]
  • [ 6309-30-4 ]
  • [ 530-62-1 ]
Reference: [1] Patent: US6353115, 2002, B1, . Location in patent: Page column 5
  • 6
  • [ 288-32-4 ]
  • [ 503-38-8 ]
  • [ 530-62-1 ]
YieldReaction ConditionsOperation in experiment
85% at 20℃; for 2 h; 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.
Reference: [1] Patent: EP1731510, 2006, A1, . Location in patent: Page/Page column 5-6
  • 7
  • [ 288-32-4 ]
  • [ 75-44-5 ]
  • [ 1467-16-9 ]
  • [ 530-62-1 ]
YieldReaction ConditionsOperation in experiment
70% at 66 - 130℃; for 1.45 h; Example 2; Comparative in Analogy to Example 1 from WO-A-00/14072 In a flask, 68.22 g of imidazole are suspended in 505 g of xylene. The mixture is heated to reflux and dewatered by taking off 5 g of a xylene/water mixture. The temperature is reduced to 66° C. and over the course of 30 minutes 25.2 g of phosgene are metered in with an introduction rate of 50.4 g/h. After about 15 minutes the reaction mixture takes on a consistency like that of chewing gum. When the metering of phosgene is at an end the imidazole hydrochloride by-product is in the form of yellow balls. After a further hour of stirring at this temperature, this temperature is raised to 130° C., and the consistency of the imidazole hydrochloride changes to a brown melt. The melt is drained off at 130° C. It solidifies on cooling to a dark-green, solid mass. The supernatant xylene phase is cooled to 0° C. The precipitated crystals are filtered off and dried at 20 mbar and 50° C. This gives carbonylbisimidazole in the form of white crystals with black fractions (Hazen colour number: 489). The purity is 96.8percent, corresponding to a yield of 70percent of theory.
61.9% at 35 - 55℃; for 3.25 - 3.75 h; Example 3; Inventive; A flask is charged with 375.2 g of dry chloroform and 93.8 g of imidazole and this initial charge is heated to 35° C. At this temperature over the course of 1.75 hours 35.02 g of phosgene are added with an introduction rate of 20.0 g/h. The mixture thus obtained is subsequently stirred at the same temperature for 1.5 h. In order to ensure a phosgene-free reaction mixture, 28 g of distillate are taken off under a pressure of 280 mbar and at 30° C., an ammonia/water/isopropanol mixture is added to the distillate, and this mixture is discarded. The imidazole hydrochloride by-product (isolated dry weight: 72.1 g) is removed by filtration at 35° C., the filter cake being washed with twice 100 ml of warm chloroform at 35° C. 251.1 g of water-clear solution are distilled off from the combined organic phases at 280 mbar and 30° C. The remaining solution is cooled to 0° C., and a suspension forms. The precipitated carbonyl bisimidazole is separated off by filtration and additionally washed with 50 ml of chloroform conditioned to a temperature of 0° C. Drying of the crystals at 6 mbar and 30° C. gives 41.5 g of product in the form of white crystals having a Hazen colour number of 44. The purity of the product is 99.5percent, corresponding to a yield of 74.0percent of theory.; Example 4; Inventive; A flask is charged with 358.1 g of dry chloroform and 119.36 g of imidazole and this initial charge is heated to 55° C. At this temperature over the course of 1.75 hours 44.57 g of phosgene are added with an introduction rate of 25.5 g/h. The mixture thus obtained is subsequently stirred at the same temperature for 2 h. In order to ensure a phosgene-free reaction mixture, 5.4 g of distillate are taken off under a pressure of 630 mbar and at 35° C., an ammonia/water/isopropanol mixture is added to the distillate, and this mixture is discarded. The imidazole hydrochloride by-product (isolated dry weight: 96.0 g) is removed by filtration at 55° C., the filter cake being washed with twice 100 ml of warm chloroform at 55° C. The combined organic phases are cooled to 0° C., and a suspension forms. The precipitated carbonyl bisimidazole is separated off by filtration and additionally washed with 50 ml of chloroform conditioned to a temperature of 0° C. Drying of the residue at 4 mbar and 46° C. gives 44.3 g of product in crystalline form having a Hazen colour number of 49. The purity of the product is 99.0percent, corresponding to a yield of 61.9percent of theory.
59.9% at 35℃; for 3.25 h; Example 1; Inventive; A flask is charged with 531.5 g of dry dichloromethane and 93.8 g (1.37 mol) of imidazole and this initial charge is heated to 35° C. At this temperature over the course of 1.75 hours 36.04 g (0.36 mol) of phosgene are added with an introduction rate of 20.6 g/h. The mixture thus obtained is subsequently stirred at the same temperature for 1.5 h. In order to ensure a phosgene-free reaction mixture, 13.2 g of distillate are taken off under a pressure of 790 to 500 mbar and at 35-25° C., an ammonia/water/isopropanol mixture is added to the distillate, and this mixture is discarded. The imidazole hydrochloride by-product (isolated dry weight: 72.1 g) is removed by filtration at 35° C., the filter cake being washed with twice 100 ml of warm dichloromethane at 33° C. 250.1 g of water-clear solution are distilled off from the combined organic phases at 790 to 500 mbar and 35-25° C. The remaining solution is cooled to 0° C., and a suspension forms. The precipitated carbonyl bisimidazole is separated off by filtration and additionally washed with 50 ml of dichloromethane conditioned to a temperature of 0° C. Drying of the crystals at 4 mbar and 30° C. gives 40.0 g of product in the form of white crystals, Hazen colour number: 69.7. The purity of the product is 99.3percent, corresponding to a yield of 71.2percent of theory.; Example 5 Inventive with Recycling of the Mother Liquor 1st Phosgenation A flask is charged with 531.5 g of dry dichloromethane and 93.8 g (1.37 mol) of imidazole and this initial charge is heated to 35° C. At this temperature over the course of 1.75 hours 35.02 g (0.35 mol) of phosgene are added with an introduction rate of 20.0 g/h. The mixture thus obtained is subsequently stirred at the same temperature for 1.5 h. In order to ensure a phosgene-free reaction mixture, 8.4 g of distillate are taken off under a pressure of 750 to 500 mbar and at 35-20° C., an ammonia/water/isopropanol mixture is added to the distillate, and this mixture is discarded. The imidazole hydrochloride by-product (isolated dry weight: 80.3 g) is removed by filtration at 35° C., the filter cake being washed with twice 100 ml of warm dichloromethane at 33° C. The remaining solution is cooled to 0° C., and a suspension forms. The precipitated carbonyl bisimidazole is separated off by filtration and additionally washed with 50 ml of dichloromethane conditioned to a temperature of 0° C. After the solid carbonylbisimidazole has been filtered off, 553.0 g of mother liquor M1 are obtained. Drying of the crystals at 5 mbar and 20° C. gives 33.54 g of product in the form of white crystals with a Hazen colour number of 45.1. The purity of the product is 99.6percent. The yield therefore corresponds to 59.9percent of theory. 2nd Phosgenation A flask is charged with 531.5 g of dichloromethane-containing mother liquor M1 from the 1st phosgenation step and 93.8 g (1.37 mol) of imidazole and this initial charge is heated to 35° C. At this temperature over the course of 1.75 hours 35.02 g (0.35 mol) of phosgene are added with an introduction rate of 20.0 g/h. The mixture thus obtained is subsequently stirred at the same temperature for 1.5 h. In order to ensure a phosgene-free reaction mixture, 21.6 g of distillate are taken off under a pressure of 750 to 450 mbar and at 35-20° C., an ammonia/water/isopropanol mixture is added to the distillate, and this mixture is discarded. The imidazole hydrochloride by-product (isolated dry weight: 86.6 g) is removed by filtration at 35° C., the filter cake being washed with twice 100 ml of warm dichloromethane at 33° C. The remaining solution is cooled to 0° C., and a suspension forms. The precipitated carbonyl bisimidazole is separated off by filtration and additionally washed with 100 ml of dichloromethane conditioned to a temperature of 0° C. After the solid carbonylbisimidazole has been filtered off, 553.0 g of mother liquor M2 are obtained. Drying of the crystals at 6 mbar and 30° C. gives 39.4 g of product in the form of white crystals with a Hazen colour number of 33.2. The purity of the product is 98.7percent. The yield therefore corresponds to 70percent of theory. 3rd Phosgenation A flask is charged with 531.5 g of dichloromethane-containing mother liquor M2 from the 2nd phosgenation step and 93.8 g (1.37 mol) of imidazole and this initial charge is heated to 35° C. At this temperature over the course of 1.75 hours 35.02 g (0.35 mol) of phosgene are added with an introduction rate of 20.0 g/h. The mixture thus obtained is subsequently stirred at the same temperature for 1.5 h. In order to ensure a phosgene-free reaction mixture, 9.2 g of distillate are taken off under a pressure of 750 to 500 mbar and at 35-20° C., an ammonia/water/isopropanol mixture is added to the distillate, and this mixture is discarded. The imidazole hydrochloride by-product (isolated dry weight: 88.1 g) is removed by filtration at 35° C., the filter cake being washed with twice 100 ml of warm dichloromethane at 33° C. The remaining solution is cooled to 0° C., and a suspension forms. The precipitated carbonyl bisimidazole is separated off by filtration and additionally washed with 100 ml of dichloromethane conditioned to a temperature of 0° C. Drying of the crystals at 7 mbar and 20° C. gives 37.3 g of product in the form of white crystals with a Hazen colour number of 41.0. The purity of the product is 98.5percent. The yield therefore corresponds to 65.9percent of theory.
Reference: [1] Patent: US2005/272937, 2005, A1, . Location in patent: Page/Page column 4
[2] Patent: US2005/272937, 2005, A1, . Location in patent: Page/Page column 4
[3] Patent: US2005/272937, 2005, A1, . Location in patent: Page/Page column 3-4; 5
  • 8
  • [ 288-32-4 ]
  • [ 503-38-8 ]
  • [ 1467-16-9 ]
  • [ 530-62-1 ]
YieldReaction ConditionsOperation in experiment
90% at 20 - 55℃; for 4 h; To a 1000 ml flask were added 108.3 g (1.59 mol) of imidazole and 630 g of tetrahydrofuran. After the atmosphere of the system was replaced with nitrogen, the imidazole was dissolved under stirring. Thereto was added dropwise 39.3 g (0.2 mol) of diphosgene at room temperature over a period of 2 hours. After completion of the dropwise addition, the stirring was continued at room temperature for 1 hour and then the whole was heated to 55°C, followed by continuous stirring for another 1 hour. Imidazole hydrochloride yielded as a by-product was filtrated with heat and was then washed with 100 g of tetrahydrofuran. The imidazole hydrochloride filtrated off was dried under reduced pressure at 40°C to obtain 83.2 g (0.796 mol) of imidazole hydrochloride (recovery of 100percent). A filtrate containing CDI was concentrated and subjected to toluene-crystallization, and CDI was filtrated off under a nitrogen atmosphere. The CDI filtrated off was dried under reduced pressure at 40°C to obtain 58.0 g (0.358 mol) of CDI as white crystals (yield 90percent). M.p. 111.2 to 118.6°C.
Reference: [1] Patent: EP1731510, 2006, A1, . Location in patent: Page/Page column 5
  • 9
  • [ 288-32-4 ]
  • [ 32315-10-9 ]
  • [ 530-62-1 ]
Reference: [1] Patent: US6455702, 2002, B1,
  • 10
  • [ 74731-19-4 ]
  • [ 18156-74-6 ]
  • [ 530-62-1 ]
Reference: [1] J. Gen. Chem. USSR (Engl. Transl.), 1980, vol. 50, # 4, p. 705 - 711[2] Zhurnal Obshchei Khimii, 1980, vol. 50, # 4, p. 875 - 881
  • 11
  • [ 75-44-5 ]
  • [ 18156-74-6 ]
  • [ 74731-19-4 ]
  • [ 530-62-1 ]
Reference: [1] J. Gen. Chem. USSR (Engl. Transl.), 1980, vol. 50, # 4, p. 705 - 711[2] Zhurnal Obshchei Khimii, 1980, vol. 50, # 4, p. 875 - 881
[3] J. Gen. Chem. USSR (Engl. Transl.), 1980, vol. 50, # 4, p. 705 - 711[4] Zhurnal Obshchei Khimii, 1980, vol. 50, # 4, p. 875 - 881
  • 12
  • [ 288-32-4 ]
  • [ 75-44-5 ]
  • [ 530-62-1 ]
Reference: [1] Patent: US6353115, 2002, B1, . Location in patent: Page column 4
  • 13
  • [ 124-68-5 ]
  • [ 530-62-1 ]
  • [ 288-32-4 ]
  • [ 26654-39-7 ]
Reference: [1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1984, # 3, p. 481 - 486
  • 14
  • [ 3222-56-8 ]
  • [ 124-38-9 ]
  • [ 530-62-1 ]
  • [ 58539-65-4 ]
Reference: [1] Patent: US5616601, 1997, A,
  • 15
  • [ 2999-46-4 ]
  • [ 530-62-1 ]
  • [ 23012-14-8 ]
Reference: [1] Heterocycles, 2000, vol. 53, # 5, p. 1167 - 1170
  • 16
  • [ 64-17-5 ]
  • [ 530-62-1 ]
  • [ 19213-72-0 ]
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 ]
YieldReaction ConditionsOperation 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
  • 20
  • [ 16867-03-1 ]
  • [ 530-62-1 ]
  • [ 60832-72-6 ]
  • [ 1408253-36-0 ]
Reference: [1] Patent: US2014/113824, 2014, A1, . Location in patent: Paragraph 0293-0295; 0300-0303
  • 21
  • [ 40925-68-6 ]
  • [ 530-62-1 ]
  • [ 14733-73-4 ]
YieldReaction ConditionsOperation in experiment
100% at 20 - 25℃; for 1.5 h; Heating / reflux Reference Example 2
5-Bromo-1,3-benzoxazol-2(3H)-one
To a solution of 2-amino-4-bromophenol (3.50 g, 18.6 mmol) in tetrahydrofuran (100 mL) is added 1,1'-carbonyldiimidazole (3.62 g, 22.3 mmol) at 20-25°C, and the mixture is refluxed for 1.5 hour.
After the reaction, the reaction solution is cooled to 20-25°C, and thereto is added a 2N aqueous hydrochloric acid solution, and the mixture is extracted with ethyl acetate.
The resulting organic layer is washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated saline solution, and dried over anhydrous sodium sulfate.
The resultant is filtered, and the solvent is evaporated under reduced pressure to give 5-bromo-1,3-benzoxazol-2(3H)-one (3.89 g, quantitative).
IR (cm-1): 960, 1149, 1474, 1622, 1751
95% for 2 h; Reflux To a solution of 2-amino-4-phenylphenol (6.10 g, 32.9 mmol) in THF (150 mL) was added 1,1'-carbonyldiimidaziole (6.41 g, 39.5 mml) at room temperature.
The mixture was stirred at reflux for 2 h and cooled to room temperature.
The reaction was then quenched by adding 2 M HCl solution, and the mixture was extracted with EtOAc.
The organic layer was washed with brine and dried over anhydrous sodium sulfate.
After filtration, the solvent was removed in vacuo to give 11 (6.89 g, 99percent) as a white solid
95% at 20℃; for 2 h; Inert atmosphere 1,1′-Carbonyldiimidazole (46.5 g, 287 mmol) was added to a solutionof bromophenol 2 (49.0 g, 261 mmol) in THF (300 mL) at r.t.,and the mixture was stirred at r.t. for 2 h. The reaction was then quenched with 2 M aq HCl (700 mL), and the mixture was extracted with EtOAc (2 × 500 mL). The organic layers were combined, washed with brine (500 mL), dried (NaSO4), filtered, and concentrated in vacuo to give a brown solid; yield: 53.2 g (95percent).
91% at 120℃; for 3 h; a. A mixture of 2-amino-4-bromophenol (6.0 g, 31.9 mmol) and 1 ,1'- carbonyldiimidazole (6.2 g, 38.3 mmol) in p-dioxane (30 mL) was heated at 120 °C for 3 h, allowed to cool to ambient temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with 1N hydrochloric acid (3 20 mL), water (20 mL) and brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was triturated in hexanes/diethyl ether (1 :1 v/v, 50 mL) and washed with hexanes (20 mL) to afford 5- bromobenzo[d]oxazol-2(3H)-one in 91 percent yield (6.2 g) as a beige solid: 1H NMR (300 MHz, DMSO-d6) £ 11.85 (br s, 1 H), 7.28-7.25 (m, 3H); MS (ES+) m/z 212.0 (M + 1), 214.0 (M + 1).
63% at 80℃; for 17 h; Inert atmosphere To a solution of 14 (1.50 g. 7.98 mmol) in 1,4-dioxane (100 mL) was added Ι, Γ-carbonyldiimidazoie (1.55 g, 9.58 mmol). The reaction was heated at 80 "C for 17 h under nitrogen. The mixture was cooied to room temperature and 2N aq. HCI (40 mL) was added. The solution was diluted with ethyl acetate (200 mL) and washed with brine (2χ50 mL). The organic iayer was dried over sodium suifate, filtered and concentrated. Purification by chromatography (silica gel, 0-50percent ethyl acetate/hexanes) afforded 15 (1.08 g, 63percent) as an orange solid:XH M (5Q0 M Hz, DMSO-c/e) δ 11.81 (s, 1H), 7.27-7.25 (m, 3 H).

Reference: [1] Patent: EP1719761, 2006, A1, . Location in patent: Page/Page column 26
[2] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 18, p. 5568 - 5582
[3] Journal of Medicinal Chemistry, 2013, vol. 56, # 20, p. 8191 - 8195
[4] Synthesis (Germany), 2013, vol. 45, # 23, p. 3269 - 3275
[5] Patent: WO2013/64984, 2013, A1, . Location in patent: Page/Page column 125
[6] Patent: WO2015/2754, 2015, A2, . Location in patent: Paragraph 0198
[7] Journal of Medicinal Chemistry, 2015, vol. 58, # 23, p. 9258 - 9272
[8] RSC Advances, 2016, vol. 6, # 115, p. 114491 - 114499
[9] Patent: WO2016/198400, 2016, A1, . Location in patent: Page/Page column 61
[10] Patent: WO2018/148745, 2018, A1, . Location in patent: Page/Page column 82, 83
  • 22
  • [ 367-31-7 ]
  • [ 530-62-1 ]
  • [ 1544-75-8 ]
YieldReaction ConditionsOperation in experiment
88% at 20℃; Inert atmosphere; Cooling with ice A stirred solution of 4-fluorobenzene-1 ,2-diamine (15.1 g, 120 mmol) in THF (120 mL) under nitrogen was cooled using an ice-bath and then was treated with di(1 -/-imidazol-1 - yl)methanone (23.4 g, 144 mmol) portion-wise over 15 min. The resulting mixture was slowly warmed to room temperature then was concentrated in vacuo after 2.5 h. The residue was suspended in a mixture of water and DCM (250 mL each) and filtered off. This residue was then washed with water (50 mL) and DCM (50 mL), before being dried at 40 °C under vacuum for 16 h to give the title compound (16.0 g, 105 mmol, 88percent) as a brown solid. LCMS (high pH): Rt 0.57 min; [M-H+]" = 151.1 δΗ NMR (400 MHz, DMSO-d6) ppm 10.73 (br s, 1 H), 10.61 (br s, 1 H), 6.91-6.84 (m, 1 H), 6.78-6.70 (m, 2H).
78% at 150℃; for 0.333333 h; Microwave irradiation Intermediate 15: 5-Fluoro-1 ,3-dihvdro-2H-benzimidazol-2-one; A mixture of 4-fluoro-1 ,2-diaminobenzene (commercially available, 1.0 g, 7.9 mmol), carbonyldiimidazole (1.4 g) and THF (4 ml) was heated to 150 0C in a microwave reactor and stirred for 10 minutes. The mixture was heated to 150 0C and stirred for a further 10 <n="38"/>minutes. The mixture was cooled to room temperature and concentrated under vacuum. The residue was suspended in dilute hydrochloric acid and filtered. The filter-cake was washed with water and cyclohexane then dried under vacuum to give the title compound as a dark grey solid (0.95 g, 78percent). 1 H-NMR (400 MHz, DMSO-d6): δ 10.73 (1 H, br s), 10.62 (1 H, br s), 6.87 (1 H, dd, J 8.5, 5 Hz), 6.78-6.70 (2H, m). UPLC-MS: 0.47 min, m/z 153 [M+H]+.
52% at 20℃; a) 4-Fluorobenzene-1,2-diamine (2 g, 15.86 mmol) was dissolved in THF (49.4 ml) and 1,1'-Carbonyldiimidazole (2.83 g, 17.44 mmol) was added at RT. The reaction mixture was stirred overnight at RT. To this was added concentrated ammonia solution (1.5 ml) and the mixture stirred for 30 minutes and then diluted with water (100 ml). The resultant solid was collected by filtration, washed with water, followed by Et2O and then dried in vacuo to afford 5-fluoro-1H-benzo[d]imidazol-2(3H)-one (1.250 g, 52percent); 1H NMR (400 MHz, DMSO-d6) 6.66-6.79 (2H, m), 6.81-6.94 (1H, m), 10.64 (1H, s), 10.76 (1H, s); m/z: (ES+) MH+, 151.19.
Reference: [1] Patent: WO2016/62737, 2016, A1, . Location in patent: Page/Page column 24
[2] ACS Medicinal Chemistry Letters, 2016, vol. 7, # 6, p. 552 - 557
[3] ACS Medicinal Chemistry Letters, 2014, vol. 5, # 11, p. 1190 - 1195
[4] Journal of Medicinal Chemistry, 2006, vol. 49, # 12, p. 3719 - 3742
[5] Patent: WO2008/129007, 2008, A1, . Location in patent: Page/Page column 36-37
[6] Patent: US2011/306613, 2011, A1, . Location in patent: Page/Page column 37
  • 23
  • [ 95-83-0 ]
  • [ 530-62-1 ]
  • [ 2034-23-3 ]
YieldReaction ConditionsOperation in experiment
61.7% at 25℃; 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 ]
YieldReaction ConditionsOperation 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 ]
YieldReaction ConditionsOperation 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.
Reference: [1] Patent: US2003/187004, 2003, A1,
[2] Patent: EP1136099, 2001, A1,
[3] Patent: EP1136483, 2001, A1,
  • 30
  • [ 38875-53-5 ]
  • [ 530-62-1 ]
  • [ 148038-83-9 ]
YieldReaction ConditionsOperation in experiment
93% at 80℃; for 16 h; To a solution of 2,3-diamino-5-bromopyridine (5 g, 27 mmol) in THF (87 mL) was added CDI (3.02 g, 18.6 mmol), and the reaction mixture was stirred at 80 °C for 16 h. Then, water was added, and the mixture was filtered. The solids were collected by filtration, washed with water and Et2O, and dried under vacuum to afford the title compound (5.3 g, 25 mmol, 93percent), which was used in the next step without further purification. MS (ESI): mass calcd. for C6H4BrN3O, 212.95; m/z found, 214 [M+H]+.
92% at 20℃; Inert atmosphere Step 2 6-Bromo-lH-imidazo[4,5-b]pyridin-2(3H)-one. 5-Bromopyridine-2,3-diamine (2.45 g) was dissolved in THF (25 niL) and l,l'-carbonyldiimidazole (2.54 g, 1.2 eq) was added. The reaction was stirred at room temperature under nitrogen gas overnight. Water was then added to the mixture and the product was collected by filtration. The solid was dried under vacuum delivering product (2.57 g, 92percent yield). 1H-NMR (300 MHz, DMSOd6) δ 11.50 (s, IH), 11.00 (s, IH), 7.93 (s, 1 H), 7.39 (s, IH). MS (ES+) m/z 213.1 (M + 1).
Reference: [1] Patent: WO2018/67786, 2018, A1, . Location in patent: Page/Page column 106
[2] Patent: WO2010/121164, 2010, A2, . Location in patent: Page/Page column 61
[3] Patent: WO2011/149950, 2011, A2, . Location in patent: Page/Page column 104-105
  • 31
  • [ 4316-98-7 ]
  • [ 530-62-1 ]
  • [ 37527-48-3 ]
YieldReaction ConditionsOperation in experiment
96% for 0.833333 h; Reflux; Inert atmosphere 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] Patent: US2010/120801, 2010, A1, . Location in patent: Page/Page column 22
[2] Patent: WO2008/75110, 2008, A1, . Location in patent: Page/Page column 116-117
[3] Patent: WO2007/125315, 2007, A2, . Location in patent: Page/Page column 115-116
[4] Patent: WO2007/125325, 2007, A1, . Location in patent: Page/Page column 93
[5] Patent: WO2006/46023, 2006, A1, . Location in patent: Page/Page column 116
  • 32
  • [ 446-08-2 ]
  • [ 530-62-1 ]
  • [ 321-69-7 ]
Reference: [1] Organic Process Research and Development, 2008, vol. 12, # 5, p. 877 - 883
  • 33
  • [ 36692-49-6 ]
  • [ 530-62-1 ]
  • [ 106429-57-6 ]
YieldReaction ConditionsOperation in experiment
94% at 0℃; for 16 h; To a solution of 3,4-diamino-benzoic acid methyl ester (5.00 g, 30.1 mmol) and THF (40 ml_), was added carbonyl diimidazole (7.32 g, 45.1 mmol) at 0 0C. The mixture stirred for 16 h, and allowed to warm to 23 0C. A solution of 1 M aq. HCI (50 ml_) was added at 0 0C, followed by water (70 ml_) and the mixture was stirred for 1 h. The resulting precipitate was filtered and dried under reduced pressure for 18 h to yield the titled compound, which was used in the next step without further purification (5.45 g, 94 percent). MS (ESI/CI): mass calcd. for C9H8N2O3, 192.1 ; m/z found, 193.1 [M+H]+. 1H NMR (400 MHz, CDCI3): 11.01 (s, 1 H), 10.84 (s, 1 H), 7.63 (dd, J = 8.2, 1.6 Hz, 1 H), 7.47 (s, 1 H), 7.02 (d, J = 8.2 Hz, 1 H), 3.82 (s, 3H).
Reference: [1] Patent: WO2009/134750, 2009, A1, . Location in patent: Page/Page column 139
[2] Journal of Medicinal Chemistry, 2006, vol. 49, # 12, p. 3719 - 3742
[3] Patent: US2010/249124, 2010, A1, . Location in patent: Page/Page column 62
[4] Cell Chemical Biology, 2018, vol. 25, # 6, p. 677 - 12,690
  • 34
  • [ 67073-39-6 ]
  • [ 530-62-1 ]
  • [ 60713-78-2 ]
YieldReaction ConditionsOperation 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] Patent: WO2009/134750, 2009, A1, . Location in patent: Page/Page column 80
[2] Patent: WO2013/79505, 2013, A1, . Location in patent: Page/Page column 72
  • 35
  • [ 40851-95-4 ]
  • [ 530-62-1 ]
  • [ 40851-98-7 ]
Reference: [1] European Journal of Medicinal Chemistry, 1983, vol. 18, # 6, p. 501 - 506
  • 36
  • [ 530-62-1 ]
  • [ 75-65-0 ]
  • [ 49761-82-2 ]
Reference: [1] Tetrahedron Asymmetry, 2005, vol. 16, # 2, p. 297 - 301
[2] Soft Matter, 2012, vol. 8, # 4, p. 1096 - 1108
[3] Organic Letters, 1999, vol. 1, # 6, p. 933 - 936
[4] Tetrahedron Letters, 1982, vol. 23, # 20, p. 2113 - 2116
[5] Bulletin des Societes Chimiques Belges, 1982, vol. 91, # 10, p. 871 - 872
[6] Bulletin de la Societe Chimique de France, 1982, vol. 2, # 3-4, p. 111 - 115
[7] Tetrahedron, 1999, vol. 55, # 44, p. 12699 - 12710
[8] Macromolecules, 2003, vol. 36, # 26, p. 9704 - 9706
[9] Journal of the American Chemical Society, 2000, vol. 122, # 47, p. 11729 - 11730
[10] Organic Letters, 2000, vol. 2, # 14, p. 2117 - 2120
[11] Chemical Communications, 2009, # 21, p. 3095 - 3097
[12] Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 3, p. 1222 - 1235
[13] Green Chemistry, 2012, vol. 14, # 2, p. 326 - 329
[14] Tetrahedron Letters, 2012, vol. 53, # 19, p. 2373 - 2376
[15] Patent: WO2014/199174, 2014, A1, . Location in patent: Page/Page column 31; 32
[16] Soft Matter, 2015, vol. 11, # 35, p. 7005 - 7015
[17] Patent: WO2017/118842, 2017, A1, . Location in patent: Page/Page column 9-10
[18] Patent: WO2018/191719, 2018, A1, . Location in patent: Page/Page column 169-170
  • 37
  • [ 24424-99-5 ]
  • [ 530-62-1 ]
  • [ 49761-82-2 ]
Reference: [1] RSC Advances, 2017, vol. 7, # 67, p. 41955 - 41961
  • 38
  • [ 54-96-6 ]
  • [ 530-62-1 ]
  • [ 7397-68-4 ]
Reference: [1] Journal of Medicinal Chemistry, 2015, vol. 58, # 20, p. 8066 - 8096
  • 39
  • [ 5028-20-6 ]
  • [ 530-62-1 ]
  • [ 21991-39-9 ]
YieldReaction ConditionsOperation 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 ]
YieldReaction ConditionsOperation 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.
Reference: [1] Journal of Medicinal Chemistry, 2002, vol. 45, # 20, p. 4379 - 4382
[2] Patent: US2002/49204, 2002, A1,
[3] Patent: US2002/68735, 2002, A1,
[4] Patent: US6436929, 2002, B1,
[5] Patent: US6444668, 2002, B1,
[6] Patent: US2009/197878, 2009, A1, . Location in patent: Page/Page column 11
[7] Journal of Medicinal Chemistry, 2005, vol. 48, # 16, p. 5092 - 5095
  • 45
  • [ 40372-61-0 ]
  • [ 530-62-1 ]
  • [ 5579-85-1 ]
YieldReaction ConditionsOperation in experiment
82% at 80℃; for 3 h; 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.
Reference: [1] Patent: WO2015/91647, 2015, A1, . Location in patent: Page/Page column 42
  • 46
  • [ 50681-25-9 ]
  • [ 530-62-1 ]
  • [ 50901-46-7 ]
Reference: [1] Patent: EP1533304, 2005, A1, . Location in patent: Page/Page column 19
  • 47
  • [ 48108-93-6 ]
  • [ 530-62-1 ]
  • [ 41921-63-5 ]
YieldReaction ConditionsOperation in experiment
75% at 0 - 20℃; for 43 h; Heating / reflux 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+).
Reference: [1] Patent: WO2004/69245, 2004, A1, . Location in patent: Page/Page column 86
[2] Patent: WO2006/113432, 2006, A2, . Location in patent: Page/Page column 71; 36
  • 48
  • [ 530-62-1 ]
  • [ 2687-25-4 ]
  • [ 15965-57-8 ]
Reference: [1] Journal of the American Chemical Society, 2007, vol. 129, # 28, p. 8836 - 8844
  • 49
  • [ 5348-42-5 ]
  • [ 530-62-1 ]
  • [ 16865-11-5 ]
Reference: [1] Patent: US2005/54628, 2005, A1, . Location in patent: Page/Page column 31
  • 50
  • [ 399-97-3 ]
  • [ 530-62-1 ]
  • [ 13451-79-1 ]
YieldReaction ConditionsOperation in experiment
90% at 80℃; for 5 h; Inert atmosphere General procedure: The intermediates 4 were prepared as previously described [36] with some modification. Under the atmosphere of nitrogen, starting material aminophenol (1 equiv.) and N,N′-Carbonyldiimidazole (CDI) (1.2 equiv.) were mixed in DMF and stirred 80°C for 5h. The reaction mixture was allowed to cool to room temperature and the water was added to quench the reaction. The mixture was and extracted with ethyl acetate to afford the crude product that was purified by flash column chromatography on silica gel to yield 4a-d.
Reference: [1] European Journal of Medicinal Chemistry, 2017, vol. 138, p. 199 - 211
[2] Patent: WO2005/18529, 2005, A2, . Location in patent: Page/Page column 62
[3] Journal of Medicinal Chemistry, 2015, vol. 58, # 23, p. 9258 - 9272
[4] Organic and Biomolecular Chemistry, 2017, vol. 15, # 19, p. 4058 - 4063
[5] Patent: WO2005/18529, 2005, A2, . Location in patent: Page/Page column 62
  • 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
  • 52
  • [ 530-62-1 ]
  • [ 1759-53-1 ]
  • [ 21573-10-4 ]
Reference: [1] Patent: US2007/105909, 2007, A1, . Location in patent: Page/Page column 18
  • 53
  • [ 2941-78-8 ]
  • [ 530-62-1 ]
  • [ 40545-33-3 ]
Reference: [1] Patent: US5001157, 1991, A,
  • 54
  • [ 530-62-1 ]
  • [ 97582-88-2 ]
Reference: [1] Patent: US4579848, 1986, A,
  • 55
  • [ 288-32-4 ]
  • [ 75-44-5 ]
  • [ 1467-16-9 ]
  • [ 530-62-1 ]
YieldReaction ConditionsOperation in experiment
70% at 66 - 130℃; for 1.45 h; Example 2; Comparative in Analogy to Example 1 from WO-A-00/14072 In a flask, 68.22 g of imidazole are suspended in 505 g of xylene. The mixture is heated to reflux and dewatered by taking off 5 g of a xylene/water mixture. The temperature is reduced to 66° C. and over the course of 30 minutes 25.2 g of phosgene are metered in with an introduction rate of 50.4 g/h. After about 15 minutes the reaction mixture takes on a consistency like that of chewing gum. When the metering of phosgene is at an end the imidazole hydrochloride by-product is in the form of yellow balls. After a further hour of stirring at this temperature, this temperature is raised to 130° C., and the consistency of the imidazole hydrochloride changes to a brown melt. The melt is drained off at 130° C. It solidifies on cooling to a dark-green, solid mass. The supernatant xylene phase is cooled to 0° C. The precipitated crystals are filtered off and dried at 20 mbar and 50° C. This gives carbonylbisimidazole in the form of white crystals with black fractions (Hazen colour number: 489). The purity is 96.8percent, corresponding to a yield of 70percent of theory.
61.9% at 35 - 55℃; for 3.25 - 3.75 h; Example 3; Inventive; A flask is charged with 375.2 g of dry chloroform and 93.8 g of imidazole and this initial charge is heated to 35° C. At this temperature over the course of 1.75 hours 35.02 g of phosgene are added with an introduction rate of 20.0 g/h. The mixture thus obtained is subsequently stirred at the same temperature for 1.5 h. In order to ensure a phosgene-free reaction mixture, 28 g of distillate are taken off under a pressure of 280 mbar and at 30° C., an ammonia/water/isopropanol mixture is added to the distillate, and this mixture is discarded. The imidazole hydrochloride by-product (isolated dry weight: 72.1 g) is removed by filtration at 35° C., the filter cake being washed with twice 100 ml of warm chloroform at 35° C. 251.1 g of water-clear solution are distilled off from the combined organic phases at 280 mbar and 30° C. The remaining solution is cooled to 0° C., and a suspension forms. The precipitated carbonyl bisimidazole is separated off by filtration and additionally washed with 50 ml of chloroform conditioned to a temperature of 0° C. Drying of the crystals at 6 mbar and 30° C. gives 41.5 g of product in the form of white crystals having a Hazen colour number of 44. The purity of the product is 99.5percent, corresponding to a yield of 74.0percent of theory.; Example 4; Inventive; A flask is charged with 358.1 g of dry chloroform and 119.36 g of imidazole and this initial charge is heated to 55° C. At this temperature over the course of 1.75 hours 44.57 g of phosgene are added with an introduction rate of 25.5 g/h. The mixture thus obtained is subsequently stirred at the same temperature for 2 h. In order to ensure a phosgene-free reaction mixture, 5.4 g of distillate are taken off under a pressure of 630 mbar and at 35° C., an ammonia/water/isopropanol mixture is added to the distillate, and this mixture is discarded. The imidazole hydrochloride by-product (isolated dry weight: 96.0 g) is removed by filtration at 55° C., the filter cake being washed with twice 100 ml of warm chloroform at 55° C. The combined organic phases are cooled to 0° C., and a suspension forms. The precipitated carbonyl bisimidazole is separated off by filtration and additionally washed with 50 ml of chloroform conditioned to a temperature of 0° C. Drying of the residue at 4 mbar and 46° C. gives 44.3 g of product in crystalline form having a Hazen colour number of 49. The purity of the product is 99.0percent, corresponding to a yield of 61.9percent of theory.
59.9% at 35℃; for 3.25 h; Example 1; Inventive; A flask is charged with 531.5 g of dry dichloromethane and 93.8 g (1.37 mol) of imidazole and this initial charge is heated to 35° C. At this temperature over the course of 1.75 hours 36.04 g (0.36 mol) of phosgene are added with an introduction rate of 20.6 g/h. The mixture thus obtained is subsequently stirred at the same temperature for 1.5 h. In order to ensure a phosgene-free reaction mixture, 13.2 g of distillate are taken off under a pressure of 790 to 500 mbar and at 35-25° C., an ammonia/water/isopropanol mixture is added to the distillate, and this mixture is discarded. The imidazole hydrochloride by-product (isolated dry weight: 72.1 g) is removed by filtration at 35° C., the filter cake being washed with twice 100 ml of warm dichloromethane at 33° C. 250.1 g of water-clear solution are distilled off from the combined organic phases at 790 to 500 mbar and 35-25° C. The remaining solution is cooled to 0° C., and a suspension forms. The precipitated carbonyl bisimidazole is separated off by filtration and additionally washed with 50 ml of dichloromethane conditioned to a temperature of 0° C. Drying of the crystals at 4 mbar and 30° C. gives 40.0 g of product in the form of white crystals, Hazen colour number: 69.7. The purity of the product is 99.3percent, corresponding to a yield of 71.2percent of theory.; Example 5 Inventive with Recycling of the Mother Liquor 1st Phosgenation A flask is charged with 531.5 g of dry dichloromethane and 93.8 g (1.37 mol) of imidazole and this initial charge is heated to 35° C. At this temperature over the course of 1.75 hours 35.02 g (0.35 mol) of phosgene are added with an introduction rate of 20.0 g/h. The mixture thus obtained is subsequently stirred at the same temperature for 1.5 h. In order to ensure a phosgene-free reaction mixture, 8.4 g of distillate are taken off under a pressure of 750 to 500 mbar and at 35-20° C., an ammonia/water/isopropanol mixture is added to the distillate, and this mixture is discarded. The imidazole hydrochloride by-product (isolated dry weight: 80.3 g) is removed by filtration at 35° C., the filter cake being washed with twice 100 ml of warm dichloromethane at 33° C. The remaining solution is cooled to 0° C., and a suspension forms. The precipitated carbonyl bisimidazole is separated off by filtration and additionally washed with 50 ml of dichloromethane conditioned to a temperature of 0° C. After the solid carbonylbisimidazole has been filtered off, 553.0 g of mother liquor M1 are obtained. Drying of the crystals at 5 mbar and 20° C. gives 33.54 g of product in the form of white crystals with a Hazen colour number of 45.1. The purity of the product is 99.6percent. The yield therefore corresponds to 59.9percent of theory. 2nd Phosgenation A flask is charged with 531.5 g of dichloromethane-containing mother liquor M1 from the 1st phosgenation step and 93.8 g (1.37 mol) of imidazole and this initial charge is heated to 35° C. At this temperature over the course of 1.75 hours 35.02 g (0.35 mol) of phosgene are added with an introduction rate of 20.0 g/h. The mixture thus obtained is subsequently stirred at the same temperature for 1.5 h. In order to ensure a phosgene-free reaction mixture, 21.6 g of distillate are taken off under a pressure of 750 to 450 mbar and at 35-20° C., an ammonia/water/isopropanol mixture is added to the distillate, and this mixture is discarded. The imidazole hydrochloride by-product (isolated dry weight: 86.6 g) is removed by filtration at 35° C., the filter cake being washed with twice 100 ml of warm dichloromethane at 33° C. The remaining solution is cooled to 0° C., and a suspension forms. The precipitated carbonyl bisimidazole is separated off by filtration and additionally washed with 100 ml of dichloromethane conditioned to a temperature of 0° C. After the solid carbonylbisimidazole has been filtered off, 553.0 g of mother liquor M2 are obtained. Drying of the crystals at 6 mbar and 30° C. gives 39.4 g of product in the form of white crystals with a Hazen colour number of 33.2. The purity of the product is 98.7percent. The yield therefore corresponds to 70percent of theory. 3rd Phosgenation A flask is charged with 531.5 g of dichloromethane-containing mother liquor M2 from the 2nd phosgenation step and 93.8 g (1.37 mol) of imidazole and this initial charge is heated to 35° C. At this temperature over the course of 1.75 hours 35.02 g (0.35 mol) of phosgene are added with an introduction rate of 20.0 g/h. The mixture thus obtained is subsequently stirred at the same temperature for 1.5 h. In order to ensure a phosgene-free reaction mixture, 9.2 g of distillate are taken off under a pressure of 750 to 500 mbar and at 35-20° C., an ammonia/water/isopropanol mixture is added to the distillate, and this mixture is discarded. The imidazole hydrochloride by-product (isolated dry weight: 88.1 g) is removed by filtration at 35° C., the filter cake being washed with twice 100 ml of warm dichloromethane at 33° C. The remaining solution is cooled to 0° C., and a suspension forms. The precipitated carbonyl bisimidazole is separated off by filtration and additionally washed with 100 ml of dichloromethane conditioned to a temperature of 0° C. Drying of the crystals at 7 mbar and 20° C. gives 37.3 g of product in the form of white crystals with a Hazen colour number of 41.0. The purity of the product is 98.5percent. The yield therefore corresponds to 65.9percent of theory.
Reference: [1] Patent: US2005/272937, 2005, A1, . Location in patent: Page/Page column 4
[2] Patent: US2005/272937, 2005, A1, . Location in patent: Page/Page column 4
[3] Patent: US2005/272937, 2005, A1, . Location in patent: Page/Page column 3-4; 5
  • 56
  • [ 288-32-4 ]
  • [ 503-38-8 ]
  • [ 1467-16-9 ]
  • [ 530-62-1 ]
YieldReaction ConditionsOperation in experiment
90% at 20 - 55℃; for 4 h; To a 1000 ml flask were added 108.3 g (1.59 mol) of imidazole and 630 g of tetrahydrofuran. After the atmosphere of the system was replaced with nitrogen, the imidazole was dissolved under stirring. Thereto was added dropwise 39.3 g (0.2 mol) of diphosgene at room temperature over a period of 2 hours. After completion of the dropwise addition, the stirring was continued at room temperature for 1 hour and then the whole was heated to 55°C, followed by continuous stirring for another 1 hour. Imidazole hydrochloride yielded as a by-product was filtrated with heat and was then washed with 100 g of tetrahydrofuran. The imidazole hydrochloride filtrated off was dried under reduced pressure at 40°C to obtain 83.2 g (0.796 mol) of imidazole hydrochloride (recovery of 100percent). A filtrate containing CDI was concentrated and subjected to toluene-crystallization, and CDI was filtrated off under a nitrogen atmosphere. The CDI filtrated off was dried under reduced pressure at 40°C to obtain 58.0 g (0.358 mol) of CDI as white crystals (yield 90percent). M.p. 111.2 to 118.6°C.
Reference: [1] Patent: EP1731510, 2006, A1, . Location in patent: Page/Page column 5
  • 57
  • [ 530-62-1 ]
  • [ 619-17-0 ]
  • [ 63480-10-4 ]
Reference: [1] Journal of Medicinal Chemistry, 2010, vol. 53, # 22, p. 7979 - 7991
[2] Patent: US2011/263559, 2011, A1, . Location in patent: Page/Page column 20
  • 58
  • [ 79099-03-9 ]
  • [ 530-62-1 ]
  • [ 79098-75-2 ]
Reference: [1] Patent: WO2011/143444, 2011, A2, . Location in patent: Page/Page column 8; 87-90
  • 59
  • [ 4276-09-9 ]
  • [ 530-62-1 ]
  • [ 95530-58-8 ]
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 ]
YieldReaction ConditionsOperation 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).
Reference: [1] Patent: WO2004/808, 2003, A2, . Location in patent: Page 78
  • 62
  • [ 111-40-0 ]
  • [ 530-62-1 ]
  • [ 75-65-0 ]
  • [ 117499-16-8 ]
Reference: [1] Dalton Transactions, 2018, vol. 47, # 24, p. 7896 - 7904
  • 63
  • [ 3913-67-5 ]
  • [ 530-62-1 ]
  • [ 58311-53-8 ]
YieldReaction ConditionsOperation in experiment
45% 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.
Reference: [1] Patent: US2006/167245, 2006, A1, . Location in patent: Page/Page column 8
  • 64
  • [ 6638-79-5 ]
  • [ 530-62-1 ]
  • [ 139290-70-3 ]
YieldReaction ConditionsOperation in experiment
89% With sodium hydrogencarbonate In n-heptane; dichloromethane; water; toluene EXAMPLE 66
Scheme G, step b: 4-[(Methoxymethylamino)carbonyl]-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (15)
Into a 250-mL four-neck flask equipped with a mechanical stirrer, a nitrogen bubbler, a 125-mL addition funnel with a stopper, and a thermowell with a thermocouple was placed 1,1'-carbonyldiimidazole (7.2 g, 0.044 mol) and methylene chloride (20 g).
The addition funnel was charged with a solution of 1,4-piperidinedicarboxylic acid, 1-(1,1-dimethylethyl)ester (14) (10.0 g, 0.043 mol) and methylene chloride (75 g).
The solution was added to the reaction mixture over a 2 minute period, causing rapid CO2 evolution.
The reaction mixture was allowed to stir at 28° C. for 2 hours.
Into a 500-mL four-neck flask equipped with a mechanical stirrer, a nitrogen bubbler, a thermowell with a thermocouple, and a 125-mL addition funnel with a septum was placed N,O-dimethylhydroxylamine hydrochloride (4.9 g, 0.049 mol) and methylene chloride (38 g).
The imidazole amide intermediate/methylene chloride solution was added to the slurry of N,O-dimethylhydroxylamine hydrochloride and methylene chloride over a 20 minute period.
The resulting slurry was allowed to stir at 28° C. for 2 hours.
To the reaction mixture was added sodium bicarbonate (4.3 g) and water (75 g).
After stirring for 30 minutes at ambient temperature, the phases were allowed to stand and separate for 20 minutes.
The phases were separated and to the organic phase was added toluene (100 g).
The solution was concentrated and azeotropically dried by rotary evaporation (29 Hg, bath 60° C.) to afford the crude title compound as a thick oil.
The oil and heptane (25 g) were placed into a 100-mL jacketed-bottom-drain resin pot fitted with a four-joint head equipped with a mechanical stirrer, a thermowell with a thermocouple, a nitrogen bubbler, and a stopper.
The slurry was warmed to 60° C. before allowing it to slowly cool to 10° C. over a 2 hour period.
The solution was maintained at 10° C. for 1 hour (nucleation temperature) before cooling to 3° C. and stirring overnight.
The title compoundcompound was collected by suction filtration and washed with cold heptane (7 g, ~0° C.).
The wet cake was allowed to air dry for 24 hours to afford the title compound (15) as a white crystalline material (10.5 g, 89percent); m.p. 69-71° C.
1H NMR (CDCl3) δ 4.08 (m, 2H, CHN's), 3.66 (s, 3H, -OCH3), 3.13 (s, 3H, -NCH3), 2.76 (m, 3H), 1.51 (m, 4H, CH2's), 1.40 (s, 9H, t-Bu);
13C NMR (CDCl3) δ 175.5, 154.7, 121.6, 79.5, 61.6, 43.3, 36.1, 28.5, 28.0;
IR (KBr) 2973, 2935, 1694, 1663, 1421, 1367, 1289, 1133, 998, 870, 770 cm-1.
Reference: [1] Patent: US2005/261341, 2005, A1,
  • 65
  • [ 6638-79-5 ]
  • [ 530-62-1 ]
  • [ 139290-70-3 ]
YieldReaction ConditionsOperation in experiment
89% With sodium chloride; sodium hydrogencarbonate In n-heptane; dichloromethane; water EXAMPLE 67
Scheme G, step b: 4-[(Methoxymethylamino)carbonyl]-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (15)
A suitable reactor maintained under nitrogen was charged with 7.6 kg of 1,1'-carbonyldiimidazole and 15 L of methylene chloride.
A solution of 1,4-piperidinedicarboxylic acid, 1-(1,1-dimethylethyl)ester (14) (10.5 kg, 45.8 mol) in 62 L of methylene chloride was added over 30 minutes while maintaining a reaction temperature of 20° C.
After stirring the reaction mixture at ambient temperature for 2 hours, 0.1 kg of 1,1'-carbonyldiimidazole was added.
A solution of 4.55 kg of N,O-dimethylhydroxylamine hydrochloride in 32 L of methylene chloride was added to the mixture with stirring.
The reaction mixture was stirred at 28° C. for 24 hours, followed by the addition of 0.52 kg of N,O-dimethylhydroxylamine hydrochloride and 0.7 kg of 1,1'-carbonyldiimidazole.
Stirring was continued at 28° C. for 48 hours.
The stirred reaction mixture was diluted with a solution of sodium bicarbonate (4.5 kg, 53.6 mol) in 50 L of water.
The organic phase was separated and washed with a solution of sodium chloride (7 kg) in 46 L of water.
The organic phase was separated and dried with sodium sulfate (4 kg).
Drying agent was filtered off and washed with 2*5 L of methylene chloride.
Solvent was removed below 50° C. at 500 torr.
The residue was diluted with 5 L of heptane and solvent was removed below 50° C. at 500 torr.
A total of 40 L of heptane was added and the stirred solution was heated to 70° C. to obtain solution.
The stirred solution was cooled to ambient temperature over 18 hours, then cooled to and maintained at 10C for 12 hours, then cooled to 0° C.
Solid which crystallized was filtered off, then dried at ambient temperature to give 11.1 kg (89percent yield).
Reference: [1] Patent: US2005/261341, 2005, A1,
  • 66
  • [ 478408-77-4 ]
  • [ 6638-79-5 ]
  • [ 84358-13-4 ]
  • [ 530-62-1 ]
  • [ 139290-70-3 ]
YieldReaction ConditionsOperation in experiment
89% With sodium hydrogencarbonate In n-heptane; dichloromethane; water; toluene EXAMPLE 66
Scheme G, step b: 4-[(Methoxymethylamino)carbonyl]-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (15)
Into a 250-mL four-neck flask equipped with a mechanical stirrer, a nitrogen bubbler, a 125-mL addition funnel with a stopper, and a thermowell with a thermocouple was placed 1,1 '-carbonyldiimidazole (7.2 g, 0.044 mol) and methylene chloride (20 g).
The addition funnel was charged with a solution of 1,4-piperidinedicarboxylic acid, 1-(1,1-dimethylethyl)ester (14) (10.0 g, 0.043 mol) and methylene chloride (75 g).
The solution was added to the reaction mixture over a 2 minute period, causing rapid CO2 evolution.
The reaction mixture was allowed to stir at 28° C. for 2 hours.
Into a 500-mL four-neck flask equipped with a mechanical stirrer, a nitrogen bubbler, a thermowell with a thermocouple, and a 125-mL addition funnel with a septum was placed N,O-dimethylhydroxylamine hydrochloride (4.9 g, 0.049 mol) and methylene chloride (38 g).
The imidazole amide intermediate/methylene chloride solution was added to the slurry of N,O-dimethylhydroxylamine hydrochloride and methylene chloride over a 20 minute period.
The resulting slurry was allowed to stir at 28° C. for 2 hours.
To the reaction mixture was added sodium bicarbonate (4.3 g) and water (75 g).
After stirring for 30 minutes at ambient temperature, the phases were allowed to stand and separate for 20 minutes.
The phases were separated and to the organic phase was added toluene (100 g).
The solution was concentrated and azeotropically dried by rotary evaporation (29 Hg, bath 60° C.) to afford the crude title compound as a thick oil.
The oil and heptane (25 g) were placed into a 100-mL jacketed-bottom-drain resin pot fitted with a four-joint head equipped with a mechanical stirrer, a thermowell with a thermocouple, a nitrogen bubbler, and a stopper.
The slurry was warmed to 60° C. before allowing it to slowly cool to 10° C. over a 2 hour period.
The solution was maintained at 10C for 1 hour (nucleation temperature) before cooling to 3° C. and stirring overnight.
The title compoundcompound was collected by suction filtration and washed with cold heptane (7 g, 0° C.).
The wet cake was allowed to air dry for 24 hours to afford the title compound (15) as a white crystalline material (10.5 g, 89percent); m.p. 69-71° C.
1H NMR (CDCl3) δ 4.08 (m, 2H, CHN's), 3.66 (s, 3H, -OCH3), 3.13 (s, 3H, -NCH3), 2.76 (m, 3H), 1.51 (m, 4H, CH2's), 1.40 (s, 9H, t-Bu);
13C NMR (CDCl3) δ 175.5, 154.7, 121.6, 79.5, 61.6, 43.3, 36.1, 28.5, 28.0;
IR (KBr) 2973, 2935, 1694, 1663, 1421, 1367, 1289, 1133, 998, 870, 770 cm-1.
Reference: [1] Patent: US2002/151717, 2002, A1,
[2] Patent: US2002/151717, 2002, A1,
[3] Patent: US2002/151717, 2002, A1,
  • 67
  • [ 6638-79-5 ]
  • [ 84358-13-4 ]
  • [ 530-62-1 ]
  • [ 139290-70-3 ]
Reference: [1] Patent: US2005/261341, 2005, A1,
[2] Patent: US5371093, 1994, A,
  • 68
  • [ 6638-79-5 ]
  • [ 530-62-1 ]
  • [ 139290-70-3 ]
Reference: [1] Patent: US2005/261341, 2005, A1,
  • 69
  • [ 6638-79-5 ]
  • [ 530-62-1 ]
  • [ 139290-70-3 ]
Reference: [1] Patent: US2005/261341, 2005, A1,
  • 70
  • [ 530-62-1 ]
  • [ 118482-03-4 ]
  • [ 202859-73-2 ]
YieldReaction ConditionsOperation in experiment
45% 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 ]
YieldReaction ConditionsOperation in experiment
87.8% With triethylamine In N,N-dimethyl-formamide at 65℃; for 4 h; In a 250 ml reaction flask,Compound (4) (12.8 g, 50 mmol) was added,N, N'-carbonyldiimidazole (CDI) (8.9 g, 55 mmol),DMF 100 ml,Triethylamine (15.1 g, 0.15 mol),Temperature control at 65 ,The reaction was carried out for 4 hours,After completion of the reaction,To room temperature,Extraction with dichloromethane / water (V / V = 1: 1)The aqueous layer was washed twice with dichloromethane,The organic layers were combined,Dried over anhydrous sodium sulfate,And concentrated to give the compound (5) (9.3 g) in a total yield of 87.8percent.
Reference: [1] Patent: CN105859780, 2016, A, . Location in patent: Paragraph 0035
  • 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 ]
YieldReaction ConditionsOperation in experiment
88%
Stage #1: at 40 - 45℃;
Stage #2: for 4.5 h; Heating / reflux
To a round bottom flask equipped with a mechanical stirrer, a condenser, a nitrogen inlet and a heating mantel was charged with a mixture of acetonitrile (42 L) and N-(3-aminophthaloyl)-glutamine (2120 g, 7.28 moles). After the mixture was stirred and heated to 40-45° C., 1,1'-carbonyldiimidazole (1290 g, 7.95 moles) was added. The reaction mixture was stirred and refluxed for 4.5 hours. The progress of the reaction was monitored by HPLC using a Waters Nova-Pak C18 column (3.9.x.150 mm, particle size=4 micron, UV wavelength=240 nm, retention time=3.64 minutes) and a 20/80 mixture of acetonitrile and 0.1percent aqueous H3PO4 by volume as an eluent at a flow rate of 1 mL/min. After cooled to room temperature, the reaction mixture was filtered to yield a yellow solid which was subsequently washed with acetonitrile (6.5 L). The yellow solid was air dried and then dried in a vacuum oven at 60° C. and a pressure <1 mm to yield 1760 g (88percent) of the product. The product purity was found to be 99.57percent by HPLC using a Waters Nova-Pak C18 column (3.9.x.150 mm, particle size=4 micron, UV wavelength=240 nm, retention time=3.64 minutes) and a 20/80 mixture of acetonitrile and 0.1percent aqueous H3PO4 by volume as an eluent at a flow rate of 1 mL/min. The product in DMSO-d6 was characterized by a 1H NMR spectrum showing the following chemical shifts (δ in ppm): 11.10 (s, 1H), 7.47(t, J=7.9 Hz, 1H), 7.03-6.99 (dd, J=4.8 and 8.4 Hz, 2H), 6.52 (s, 2H), 5.09-5.02 (dd, J=5.3 and 12.4 Hz, 1H), 2.96-2.82 (m, 1H), 2.62-2.46 (m, 2H), 2.07-2.00 (m, 1H); and by a 13C NMR spectrum showing the following chemical shifts (δ in ppm): 172.82, 170.11, 168.57, 167-37, 146.71, 135.46, 131.99, 121.70, 110.97, 108.52, 48.47, 30.97, 22.14. The melting point of the product was found to be 315.5-317.5° C. An elemental analysis yielded the following results in weight percent: C, 56.98; H, 3.86; N, 15.35, which compared with calculated values for C13H11N3O4, in weight percent: 57.14; H, 4.06; N, 15.38.
Reference: [1] Patent: US2007/155791, 2007, A1, . Location in patent: Page/Page column 14-15
  • 74
  • [ 95-54-5 ]
  • [ 530-62-1 ]
  • [ 241809-79-0 ]
  • [ 209783-80-2 ]
YieldReaction ConditionsOperation in experiment
77 g
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.
Reference: [1] Patent: WO2017/81278, 2017, A1, . Location in patent: Page/Page column 15
  • 75
  • [ 337915-79-4 ]
  • [ 530-62-1 ]
  • [ 305790-48-1 ]
Reference: [1] Patent: WO2012/21382, 2012, A1, . Location in patent: Page/Page column 30
[2] Patent: WO2016/57834, 2016, A1, . Location in patent: Paragraph 000821; 000875
  • 76
  • [ 530-62-1 ]
  • [ 142266-62-4 ]
Reference: [1] Patent: US2018/334454, 2018, A1,
  • 77
  • [ 208925-08-0 ]
  • [ 530-62-1 ]
  • [ 452339-73-0 ]
YieldReaction ConditionsOperation in experiment
51% With triethylamine In chloroform at 20℃; 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).
Reference: [1] Patent: WO2006/122788, 2006, A1, . Location in patent: Page/Page column 54
  • 78
  • [ 446292-07-5 ]
  • [ 530-62-1 ]
  • [ 446292-08-6 ]
YieldReaction ConditionsOperation in experiment
97.9% at 19 - 60℃; for 1 h; Heating / reflux 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

Reference: [1] Patent: US2005/182055, 2005, A1, . Location in patent: Page/Page column 1; 3
[2] Patent: WO2014/102820, 2014, A2, . Location in patent: Paragraph 058
[3] Patent: WO2015/198259, 2015, A1, . Location in patent: Page/Page column 6
[4] Patent: WO2016/199027, 2016, A1, . Location in patent: Page/Page column 18-19
[5] Patent: WO2013/53739, 2013, A1, . Location in patent: Page/Page column 31
[6] Patent: WO2011/12321, 2011, A1, . Location in patent: Page/Page column 31
[7] Patent: WO2013/121436, 2013, A2, . Location in patent: Page/Page column 26; 27
[8] Patent: US2015/11756, 2015, A1, . Location in patent: Paragraph 0118
[9] Journal of Medicinal Chemistry, 2005, vol. 48, # 19, p. 5900 - 5908
[10] Patent: WO2012/41263, 2012, A2, . Location in patent: Page/Page column 9
[11] Patent: WO2013/120464, 2013, A1, . Location in patent: Page/Page column 8-9
[12] Patent: WO2012/32533, 2012, A2, . Location in patent: Page/Page column 15-16
[13] Patent: WO2013/98833, 2013, A2, . Location in patent: Page/Page column 41-42
[14] Patent: US2014/378682, 2014, A1, . Location in patent: Paragraph 0211; 0212
[15] Patent: WO2016/30669, 2016, A1, . Location in patent: Page/Page column 28; 29
  • 79
  • [ 446292-07-5 ]
  • [ 530-62-1 ]
  • [ 446292-08-6 ]
  • [ 1450876-94-4 ]
Reference: [1] Patent: WO2013/120464, 2013, A1, . Location in patent: Page/Page column 11
  • 80
  • [ 17626-40-3 ]
  • [ 530-62-1 ]
  • [ 221289-88-9 ]
YieldReaction ConditionsOperation in experiment
24% for 16 h; Inert atmosphere 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
  • 81
  • [ 289483-81-4 ]
  • [ 530-62-1 ]
  • [ 289483-82-5 ]
Reference: [1] Patent: US2002/128480, 2002, A1,
[2] Patent: EP1258252, 2002, A1,
[3] Patent: US2004/18192, 2004, A1,
  • 82
  • [ 762-04-9 ]
  • [ 530-62-1 ]
  • [ 618061-76-0 ]
YieldReaction ConditionsOperation in experiment
66.2%
Stage #1: at 40℃;
Stage #2: at 30 - 40℃; for 2 h;
(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 ]
YieldReaction ConditionsOperation 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] Patent: CN104876864, 2017, B, . Location in patent: Paragraph 0086; 0087; 0096; 0097
  • 84
  • [ 825619-30-5 ]
  • [ 530-62-1 ]
  • [ 765-30-0 ]
  • [ 896466-04-9 ]
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 ]
YieldReaction ConditionsOperation 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 ]
YieldReaction ConditionsOperation 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).
Reference: [1] Patent: WO2016/176457, 2016, A1, . Location in patent: Page/Page column 97
[2] Patent: WO2009/14620, 2009, A1, . Location in patent: Page/Page column 43; 23
  • 87
  • [ 446292-07-5 ]
  • [ 530-62-1 ]
  • [ 898543-06-1 ]
YieldReaction ConditionsOperation in experiment
89.1%
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
Reference: [1] Patent: CN104974105, 2017, B, . Location in patent: Paragraph 0074
  • 88
  • [ 1403383-55-0 ]
  • [ 530-62-1 ]
  • [ 898543-06-1 ]
YieldReaction ConditionsOperation in experiment
80.1%
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.
Reference: [1] Patent: WO2012/140061, 2012, A1, . Location in patent: Page/Page column 36
  • 89
  • [ 18645-88-0 ]
  • [ 530-62-1 ]
  • [ 256519-10-5 ]
YieldReaction ConditionsOperation in experiment
97% at 20 - 50℃; 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)+.
Reference: [1] Patent: US2011/306613, 2011, A1, . Location in patent: Page/Page column 31
[2] Patent: US8138168, 2012, B1, . Location in patent: Page/Page column 481-482
  • 90
  • [ 6638-79-5 ]
  • [ 61172-66-5 ]
  • [ 530-62-1 ]
  • [ 1172623-95-8 ]
YieldReaction ConditionsOperation in experiment
88.2%
Stage #1: at 0 - 10℃; for 1 h;
Stage #2: at 20℃;
1C (33 g, 0.155 mol) was dissolved in N, N-dimethylformamide (200 mL)Control the temperature is less than 10 ,N, N'-carbonyldiimidazole (32.58 g, 0.201 mol) was added,1 hour at 0 ,N, O-dimethylhydroxylamine hydrochloride (19.6 g, 0.186 mol) was added and stirred at room temperature overnight.Water (150 mL) was added dropwise to the reaction solution, stirred for 1 hour and extracted with ethyl acetate (100 mL x 2). The organic phases were combined and the organic phase was washed with saturated sodium bicarbonate solution (60 mL x 3), saturated sodium chloride (40 mL x 3), dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 10: 1) to give 1D (35 g , Yield 88.2percent).
Reference: [1] Patent: TW2017/8223, 2017, A, . Location in patent: Page/Page column 38
  • 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 ]
YieldReaction ConditionsOperation in experiment
63% at 20℃; Inert atmosphere Step-3: 2-chloro-9-methyl-7H-purin-8(9H)-one [0174] To a solution of 2-chloro-N4-methylpyrimidine-4,5-diamine (150 mg, 0.95 mmol) in anhydrous THF (20 mL) was added CDI (310 mg, 1.9 mmol) under N2. The reaction mixture was stirred at room temperature overnight. It was concentrated in vacuum and the residue was purified on ISCO (20 g silica gel column, MeOH/dichloromethane 0~10percent) to afford the title compound (0.11 g, 63percent).
Reference: [1] Patent: WO2016/171755, 2016, A1, . Location in patent: Paragraph 0174
[2] Patent: US2012/172347, 2012, A1, . Location in patent: Page/Page column 35
  • 93
  • [ 1373215-45-2 ]
  • [ 530-62-1 ]
  • [ 74-89-5 ]
  • [ 1373215-15-6 ]
YieldReaction ConditionsOperation in experiment
78%
Stage #1: at 20℃;
Stage #2: at 5℃; for 0.75 h;
To a solution of 4-fluoro-N-[(3R,4S)-3-hydroxy-6-[4-(oxetan-3-yl)piperazin-1-yl]chroman-4-yl]benzamide (72.0 g, 168 mmol) in THF (648 mL) add 1,1'-carbonyldiimidazole (35.5 g, 219 mmol) and stir the solution at room temperature overnight. Cool the mixture to 5° C. and add a solution of 2 M methylamine in THF (210 mL, 421 mmol, 2.5 eq) dropwise over a period of 15 min. Stir for 30 min. and pour over a mixture of water (720 mL) and methyl tert-butyl ether (216 mL). Stir the mixture for 30 min. and decant the phases. Extract the aqueous phase with dichloromethane (3.x.216 mL). Wash the combined organic phases with brine (3.x.100 mL), dry over anhydrous sodium sulfate, and concentrate in vacuo. Suspend the residue in ethyl acetate (720 mL), heat at reflux for 2 hr. and cool to 10° C. Collect the solid by filtration and dry under vacuum overnight to obtain the title compound (64.0 g, 78percent) as a white solid. LC-ES/MS m/z 485 [M+H]+.
Reference: [1] ACS Medicinal Chemistry Letters, 2014, vol. 5, # 10, p. 1138 - 1142
[2] Patent: US2012/95020, 2012, A1, . Location in patent: Page/Page column 17
  • 94
  • [ 1397836-41-7 ]
  • [ 530-62-1 ]
  • [ 1403474-70-3 ]
YieldReaction ConditionsOperation in experiment
95% With proton sponge In dimethyl sulfoxide at 20℃; for 3 h; Example 6Ethyl 2-ethoxy- l -((2'-(5-oxo-4,5-dihydro-l ,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)- lH- benzo[c/]imidazole-7-carboxylate of formula lbThe corresponding base (0. 1 g) was added to a mixture of ethyl 2-ethoxy- l -((2'- ((hydroxyamino)iminomethyl)biphenyl-4-yl)methyl)- l / -benzo[i ]imidazole-7-carboxylate (of formula Vb; 0.23 g, 0.5 mmol), DMSO (3 ml) and carbonyldiimidazole (0.1 g, 0,6 mmol) in a reaction vial under stirring and the mixture was stirred at the room temperature for 3 hours. Then, the content of the vial was poured into water (10 ml) and, after acidification with acetic acid, the separated solids were aspirated and washed with water. The yields and purity of the products are summarized in Table III. Table III - Yield and purity of the product of Example 6
Reference: [1] Organic Process Research and Development, 2013, vol. 17, # 1, p. 77 - 86
[2] Patent: WO2012/139536, 2012, A1, . Location in patent: Page/Page column 13-14
  • 95
  • [ 1397836-41-7 ]
  • [ 530-62-1 ]
  • [ 1403474-70-3 ]
YieldReaction ConditionsOperation in experiment
98.7 g With 1,8-diazabicyclo[5.4.0]undec-7-ene In tetrahydrofuran at 20℃; for 2 h; Example 1Prepared Synthesis of 2-ethoxy-3 - [[2 '- (N-benzyloxymethylidene) biphenyl-4-yl] methyl] benzimidazole-4-carboxylate,Into the reaction bottle,Add 209.8gCDI, 134ml DBU and 4.5L THF, room temperature reaction 2h, the reaction is completed. 4.5 L of water, 4.5 L of ethyl acetate was extracted and the organic phases were combined.Respectively, saturated NaHC03, saturated NaCl solution, dry anhydrous sodium sulfate organic phase, evaporated to dry organic solvent. Beaten with acetone, filtered and dried to obtain 98.7 g of a product.
Reference: [1] Patent: CN103664921, 2016, B, . Location in patent: Paragraph 0047-0049; 0050-0052
  • 96
  • [ 1451389-06-2 ]
  • [ 530-62-1 ]
  • [ 1245643-21-3 ]
YieldReaction ConditionsOperation in experiment
2.3 g at 60℃; Step 2: Into the solution of 2-(2-amino-4-bromophenyl)propan-2-ol (2.3 g) in THF (50 mL) was added CDI (1.95 g) at rt., then the mixture was warmed to 60° C. and stirred for overnight. After solvent removal, the residue was dissolved in ethyl acetate and washed with 1M of HCl(aq) and brine, and dried with dry agent. After removal of the solvent, the residue was crystallized from DCM and hexane to provide 2.3 g of 7-bromo-4,4-dimethyl-1H-benzo[d][1,3]oxazin-2(4H)-one 7.37 was synthesized.
Reference: [1] Patent: WO2013/124026, 2013, A1, . Location in patent: Page/Page column 173
[2] Patent: KR2016/37198, 2016, A, . Location in patent: Paragraph 3363-3364; 3367
  • 97
  • [ 624813-49-6 ]
  • [ 530-62-1 ]
  • [ 1207175-68-5 ]
YieldReaction ConditionsOperation in experiment
72% at 20 - 80℃; for 6 h; To a solution of compound 13 (0.90 g, 4.5 mmol) in THF(10 mL) at room temperature was CDI (0.80 g, 4.9 mmol)and the reaction was stirred at 80 °C for 6 hr. The mixturewas cooled to room temperature and the solid formed wasfiltered, washed with diethyl ether to afford 0.73 g (72percent) ofcompound 14 as off-white solid. IR (KBr) max. cm-1: 3308,3158 (NH), 3022 (Ar-H), 1682 (C=O), 1514, 1411 (C=C).1H NMR (500 MHz, DMSO-d6) = 5.25 (s, 2H, CH2); 6.82(d, 1H, J = 8.2 Hz, H-5); 7.42 (m, 2H, H-4, H-6); 10.29 (br.s, 1H, NH); 13C NMR (125.7 MHz, DMSO-d6) = 66.85(CH2), 113.70 (C-10), 115.70 (C-8), 121.03 (C-7), 127.52(C-6), 131.41 (C-5), 135.88 (C-9), 151.42 (C=O). Calculated(percent) for C8H7BrN2O (225.97); C: 42.32, H: 3.11, N: 12.34,found (percent); C: 42.27, H: 3.16, N: 12.28.
72% at 80℃; for 6 h; Example 4
Synthesis of 7-Bromo-3,4-dihydroquinazolin-2(1H)-one 13
To a solution of compound 12 (0.90 g, 4.5 mmol) in THF (10 mL) at room temperature was added CDI (0.80 g, 4.95 mmol), and the reaction was stirred at 80° C. for 6 hr.
The mixture was cooled to room temperature, and the solid formed was filtered, washed with diethyl ether to afford 0.73 g (72percent) of compound 13 as off-white solid. IR (KBr) νmax. cm-1: 3308, 3158 (NH), 3022 (Ar-H), 1682 (C=O), 1514, 1411 (C=C).
1H NMR (500 MHz, DMSO-d6) δ=5.25 (s, 2H, CH2); 6.82 (d, 1H, J=8.2 Hz, H-5); 7.42 (m, 2H, H-4, H-6); 10.29 (br. s, 1H, NH); 13C NMR (125.7 MHz, DMSO-d6) δ=66.85 (CH2), 113.70 (C-10), 115.70 (C-8), 121.03 (C-7), 127.52 (C-6), 131.41 (C-5), 135.88 (C-9), 151.42 (C=O).
Calculated (percent) for C8H7BrN2O (225.97); C, 42.32; H, 3.11; N, 12.34. found (percent); C, 42.27; H, 3.16; N, 12.28.
Reference: [1] Medicinal Chemistry, 2014, vol. 10, # 5, p. 484 - 496
[2] Patent: US8916704, 2014, B1, . Location in patent: Page/Page column 9
Same Skeleton Products
Historical Records

Similar Product of
[ 530-62-1 ]

Chemical Structure| 181517-09-9

A879598[ 181517-09-9 ]

Di(1H-imidazol-1-yl)methanone-13C

Reason: Stable Isotope