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Product Details of [ 288-36-8 ]

CAS No. :288-36-8 MDL No. :MFCD00014490
Formula : C2H3N3 Boiling Point : -
Linear Structure Formula :- InChI Key :QWENRTYMTSOGBR-UHFFFAOYSA-N
M.W : 69.07 Pubchem ID :67516
Synonyms :

Calculated chemistry of [ 288-36-8 ]

Physicochemical Properties

Num. heavy atoms : 5
Num. arom. heavy atoms : 5
Fraction Csp3 : 0.0
Num. rotatable bonds : 0
Num. H-bond acceptors : 2.0
Num. H-bond donors : 1.0
Molar Refractivity : 16.38
TPSA : 41.57 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.96 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.0
Log Po/w (XLOGP3) : -0.33
Log Po/w (WLOGP) : -0.2
Log Po/w (MLOGP) : -1.1
Log Po/w (SILICOS-IT) : 1.21
Consensus Log Po/w : -0.08

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 2.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -0.8
Solubility : 10.9 mg/ml ; 0.158 mol/l
Class : Very soluble
Log S (Ali) : -0.08
Solubility : 57.2 mg/ml ; 0.828 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -0.71
Solubility : 13.3 mg/ml ; 0.193 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.32

Safety of [ 288-36-8 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 288-36-8 ]

* 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 [ 288-36-8 ]
  • Downstream synthetic route of [ 288-36-8 ]

[ 288-36-8 ] Synthesis Path-Upstream   1~55

  • 1
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  • [ 288-36-8 ]
YieldReaction ConditionsOperation in experiment
96.25% With N-ethyl-N,N-diisopropylamine In water at 100 - 110℃; for 1 h; Into 2000mL four-necked flask into 1250mL of pure water,157.08 g (1.0 mol) of 1H-1,2,3-triazole-4,5-dicarboxylic acid,4.71 g (3percent by weight of 1H-1,2,3-triazole-4,5-dicarboxylic acid) of N, N-diisopropylethylamine,Atmospheric pressure 100 ~ 110 reflux to clarify the reaction liquid,Continue to reflow 1h,To be detected by HPLC 1H-1,2,3-triazole-4,5-dicarboxylic acid residues less than 1percent, the reaction was terminated;Filtration, the use of vacuum pump to remove the filtrate most of the water, the replacement of mechanical pump, high vacuum vacuum dehydration dehydration, four bottles installed on the distillation column, and then vacuum distillation,66.48 g of 1H-1,2,3-triazole were obtained,Its molar yield was 96.25percent, GC purity was 99.56percent
95.2% With pyridine In N,N-dimethyl-formamide at 120℃; for 4 h; Large scale 1H-1,2,3- triazole for compound (c):
In 5000L glass lined reactor, was added N,N'-dimethylformamide 3800L, compound (b) 300 Gongjin stirring, then dropping 1L pyridine, heated to 120°C, the reaction 4.0h, after completion of the reaction followed by HPLC cooled to room temperature, filter, the filtrate was passed through a short distillation column, short distillation column length 3m, vacuum recovery of N, N- dimethylformamide, under reduced pressure and then the residue was collected compound (c) of the crude product, the compound (c) crude was purified by vacuum distillation column fractions collected colorless and transparent, to give the compound (c) finished 131.4 kg, purity 99.6percent (GC), moisture 0.2percent, molar yield of 95.2percent.
Reference: [1] Patent: CN106946803, 2017, A, . Location in patent: Paragraph 0035; 0040; 0041; 0045; 0046; 0050; 0051
[2] Patent: CN105330607, 2016, A, . Location in patent: Paragraph 0033; 0034
[3] Chemische Berichte, 1893, vol. 26, p. 2737
  • 2
  • [ 4368-68-7 ]
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Reference: [1] Journal of the Chemical Society - Perkin Transactions 1, 1996, # 12, p. 1341 - 1347
[2] Journal of Organic Chemistry, 1956, vol. 21, p. 190
[3] Journal of Organic Chemistry, 1956, vol. 21, p. 190
[4] Journal of the American Chemical Society, 1983, vol. 105, # 26, p. 7681 - 7685
[5] Liebigs Annales, 1996, # 7, p. 1041 - 1053
[6] Journal of the Chemical Society - Perkin Transactions 1, 1996, # 13, p. 1535 - 1543
[7] Patent: WO2015/37013, 2015, A1, . Location in patent: Page/Page column 6
  • 3
  • [ 6921-27-3 ]
  • [ 107-19-7 ]
  • [ 106-96-7 ]
  • [ 288-36-8 ]
Reference: [1] Patent: US2012/101096, 2012, A1,
  • 4
  • [ 76950-47-5 ]
  • [ 288-36-8 ]
Reference: [1] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1981, vol. 17, # 5, p. 510 - 515[2] Khimiya Geterotsiklicheskikh Soedinenii, 1981, # 5, p. 688 - 693
  • 5
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  • [ 288-36-8 ]
Reference: [1] Patent: EP2711367, 2014, A1, . Location in patent: Page/Page column
  • 6
  • [ 96042-30-7 ]
  • [ 288-36-8 ]
Reference: [1] Patent: US2015/240006, 2015, A1,
  • 7
  • [ 16712-16-6 ]
  • [ 288-36-8 ]
Reference: [1] Patent: CN107162992, 2017, A, . Location in patent: Paragraph 0019
  • 8
  • [ 31794-11-3 ]
  • [ 288-36-8 ]
Reference: [1] Journal of Organic Chemistry, 1997, vol. 62, # 26, p. 9177 - 9181
  • 9
  • [ 56020-01-0 ]
  • [ 288-36-8 ]
Reference: [1] Heterocycles, 1998, vol. 48, # 4, p. 695 - 702
  • 10
  • [ 74-86-2 ]
  • [ 288-36-8 ]
  • [ 41917-22-0 ]
Reference: [1] Russian Journal of Organic Chemistry, 2002, vol. 38, # 7, p. 1056 - 1059
  • 11
  • [ 16681-70-2 ]
  • [ 288-36-8 ]
YieldReaction ConditionsOperation in experiment
4.18 g at 300℃; 3-Bromo-1-propyne (1a, 23.8 g, 0.200mol) was dissolved in methanol (100 mL), charged with sodium azide (11.8 g, 0.1815 mol) inwater (50 mL), and stirred at room temperature for 14 h. The mixture was added to a solution of sodium hydroxide (36.3 g, 0.908 mol) in methanol (700 mL) and heated under reflux for 2 h. Themethanol was evaporated and the residue diluted with water (400 mL). Potassium hydroxide (17.7g, 0.315 mol) was added to the solution, which was charged in portions with potassium permanganate (41.1 g, 0.259 mol). The mixture was stirred for 12 h at room temperature and,thereafter, heated at 70 °C for 3 h. The suspension was filtered and the clear filtrate dissolved in hydrochloric acid. During the evaporation of the volatiles, carboxylic acid 1269 crystallized in thecold solution. The solid was separated by filtration and heated at 300 °C in an open apparatus of recondensation to remove carbon dioxide. The triazole 13 (4.18 g, 60.5 mmol, 33percent, based onsodium azide) was isolated by recondensation (5·10−3 mbar) at room temperature.
Reference: [1] Arkivoc, 2016, vol. 2016, # 5, p. 338 - 361
  • 12
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Reference: [1] Patent: US2012/93795, 2012, A1,
  • 13
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Reference: [1] Patent: US2015/225388, 2015, A1,
  • 14
  • [ 6921-27-3 ]
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Reference: [1] Patent: US10125116, 2018, B2,
  • 15
  • [ 2101-86-2 ]
  • [ 105-56-6 ]
  • [ 288-36-8 ]
  • [ 72680-08-1 ]
Reference: [1] Patent: US4223032, 1980, A,
  • 16
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Reference: [1] Synlett, 1998, # 4, p. 431 - 433
  • 17
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Reference: [1] Chemische Berichte, 1910, vol. 43, p. 2222
  • 18
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  • [ 288-36-8 ]
Reference: [1] Synlett, 1998, # 4, p. 431 - 433
  • 19
  • [ 288-36-8 ]
  • [ 74-88-4 ]
  • [ 16681-65-5 ]
YieldReaction ConditionsOperation in experiment
71% With potassium carbonate In tetrahydrofuran at 20℃; for 3 h; Inert atmosphere Step A: A solution of lH-l,2,3-triazole (1.0 g, 14.5 mmol), methyl iodide (3.1 g, 21.7 mmol) and K2CO3 (4.0 g, 28.9 mmol) in THF (15 mL) was stirred at room temperature for 3 hours. EtOAc (20 mL) and H20 (10 mL) were added, separated. The solvent was concentrated under vacuum. The crude residue was purified by silica gel chromatography eluting with 10percent MeOH/DCM to afford l-methyl-lH-l,2,3-triazole (860 mg, 10.4 mmol, 71percent yield) as yellow oil.
71% With potassium carbonate In tetrahydrofuran at 20℃; for 3 h; A solution of lH-l ,2,3-triazole (1.0 g, 14.5 mmol), methyl iodide (3.1 g, 21.7 mmol) and K2C03 (4.0 g, 28.9 mmol) in THF (15 mL) was stirred at room temperature for 3 hours. EtOAc (20 mL) and H20 (10 mL) were added, separated. The solvent was concentrated under vacuum. The crude residue was purified by silica gel chromatography eluting with 10percent MeOH/DCM to afford 1 -methyl- lH-l ,2,3-triazole (860 mg, 10.4 mmol, 71 percent yield) as yellow oil.
42%
Stage #1: With sodium methylate In methanol at 0℃; for 0.5 h;
Stage #2: at 20℃; for 24 h;
Sodium methoxide, prepared from sodium (1.8 g, 79.8 mmol) and methanol (30 ml) was added to a cooled solution of 1 H-1 ,2,3-triazole (5 g, 72.5 mmol) and stirred at O0C for 30 minutes, lodomethane (5 ml, 79.8 mmol) was then added dropwise and the reaction warmed to room temperature and stirred for 24 hours. The reaction was concentrated in vacuo and the residue partitioned between dichloromethane and 1 M aqueous NaOH. The organic extract was dried over MgSO4 and concentrated in vacuo to afford the title compound as a yellow oil (2.5 g, 42percent yield). 1HNMR (CDCI3): 4.11 (s, 3H), 7.53 (s, 1 H), 7.69 (s, 1 H)
Reference: [1] Crystal Growth and Design, 2015, vol. 15, # 2, p. 752 - 758
[2] Chemistry - A European Journal, 2017, vol. 23, # 71, p. 17870 - 17873
[3] Patent: WO2015/142903, 2015, A2, . Location in patent: Page/Page column 102
[4] Patent: WO2015/140133, 2015, A1, . Location in patent: Page/Page column 115
[5] ACS Medicinal Chemistry Letters, 2015, vol. 6, # 6, p. 650 - 654
[6] Patent: WO2008/135826, 2008, A2, . Location in patent: Page/Page column 157
[7] Patent: WO2016/29454, 2016, A1, . Location in patent: Page/Page column 51
  • 20
  • [ 288-36-8 ]
  • [ 74-88-4 ]
  • [ 16681-65-5 ]
YieldReaction ConditionsOperation in experiment
78% With potassium carbonate In tetrahydrofuran at 20℃; for 3 h; To a solution of 1 ,2,3-trazole (10 g, 145 mmol) in 150 ml of THF were added potassium carbonate (40 g, 290 mmol) and MeI (13.58 ml, 217 mmol). The resulting reaction mixture was stirred at rt for 3hr. The reaction mixture was filtered and the filtrate was concentrated to afford the title compound (9.2 g, 78percent). 1 H NMR (400 MHz, CDCI3) δppm 7.71 (s, 1 H), 7.55 (s, 1 H), 4.14 (s, 3H).
Reference: [1] Patent: WO2008/98104, 2008, A1, . Location in patent: Page/Page column 94
  • 21
  • [ 288-36-8 ]
  • [ 67-56-1 ]
  • [ 124-41-4 ]
  • [ 74-88-4 ]
  • [ 16681-65-5 ]
YieldReaction ConditionsOperation in experiment
22% at 0 - 20℃; for 2 h; Example 58:; N-[6-(3-MethyI-3H-[l,2,3]triazol-4-yl)-2,4-dioxo-7-trifluoromethyl-l,4-dihydro-2H- qninazoIin-3-yI]-methanesulfonamide; 1 -Methyl-1H-[1 ,2,3]triazole; To a solution of NaOMe (3.91 g, 72.4 mmol) in MeOH (50 mL) was added 1,2,3-lH-triazole (5 g, 72.4 mmol). The mixture was then cooled to 0 0C and MeI (4.53 mL, 72.4 mmol) was added dropwise. The mixture was stirred allowed to warm up to r.t. and stirred at this temperature for 2 h. The solvent was removed in vacuo, the residue was treated with hot toluene (40 mL) and then filtered to afford a yellow paste. This paste was slurried in hot CHCl3 and the solid was filtered off. The solid was washed with hot CHCl3 (2 X). The filtrates were combined, concentrated in vacuo and the residue distilled (112-116 0C, water pump) to afford a mixture of starting material and final product. The distillate was dissolved in THF and NaH was added portionwise. The insoluble material was filtered off, washed with Et2O and concentrated in vacuo to afford l-methyl-lH-[l,2,3]triazole (1.33 g, 22percent) as a yellow syrup.
Reference: [1] Patent: WO2006/108591, 2006, A1, . Location in patent: Page/Page column 117-118
  • 22
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Reference: [1] Organic Letters, 2010, vol. 12, # 20, p. 4632 - 4635
  • 23
  • [ 288-36-8 ]
  • [ 77-78-1 ]
  • [ 18922-69-5 ]
  • [ 16681-65-5 ]
Reference: [1] Acta Chemica Scandinavica, 1990, vol. 44, # 10, p. 1050 - 1057
[2] Justus Liebigs Annalen der Chemie, 1955, vol. 593, p. 200 - 207
  • 24
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Reference: [1] Acta Chemica Scandinavica (1947-1973), 1959, vol. 13, p. 888,890
  • 25
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  • [ 584-14-5 ]
YieldReaction ConditionsOperation in experiment
57% With potassium carbonate; hydroxylamine-O-sulfonic acid In ethanol; water REFERENCE EXAMPLE 14
Synthesis of 1-amino-1,2,3-triazole
In 20 ml of distilled water were dissolved 2.76 g(20 mmol) of potassium carbonate and 1.38 g(20 mmol) of 1H-1,2,3-triazole and 2.26 g(20 mmol) of hydroxylamine-O-sulfonic acid was added thereto.
The mixture was stirred at room temperature for 9 hours, concentrated under the reduced pressure and ethanol was added to give a precipitate, which was filtered off.
The filtrate was concentrated under the reduced pressure and crystallized from tetrahydrofuran/diethyl ether/chloroform to give 0.96 g of the desired product(57percent).
m.p. =51° C.
NMR (DMSO-d6 +D2 O, δ)
Reference: [1] Patent: US5336673, 1994, A,
  • 26
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  • [ 584-14-5 ]
Reference: [1] Journal of Organic Chemistry USSR (English Translation), 1992, vol. 28, # 6.2, p. 1042[2] Zhurnal Organicheskoi Khimii, 1993, vol. 28, # 6, p. 1320 - 1321
  • 27
  • [ 288-36-8 ]
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YieldReaction ConditionsOperation in experiment
93% With bromine In water at 50℃; for 41.5 h; Example 120: Preparation of 4,5-dibromo-lH-π,2,31triazoleRr Br. BrN^ NH *" ' \\V NVNH <n="69"/>To a solution of IH-[1, 2,3]triazole (1.26 ml, 21.7 mmol) in water (10 ml) at 5tfC, was added bromine (1.5 ml, 29 mmol). The reaction mixture was stirred at 5CPC for 1.5 hours. The white solid (2.375 g) was isolated via filtration and washed with water (5 ml). To the combined filtrates was added more bromine (1.5 ml, 29 mmol). The reaction mixture was stirred at room temperature for 20 hours. More white solid (1.83 g) was isolated via filtration and washed with water (5 ml). To the combined filtrates was added more bromine (1.5 ml, 29 mmol). The reaction mixture was stirred at room temperature for 20 hours. More white solid (375 mg) was isolated via filtration and washed with water (5ml). The white solids were combined and dried to give 4,5-dibromo- IH-[1, 2,3]- triazole (4.92 g, 93percent yield). M.p. 194.7C.
90.39% With bromine In water at 25 - 45℃; for 17 h; Intermediate 14f (0556) 4,5-Dibromo-lH-triazole (0557) Br2 (930 g, 5.82 mol) was added dropwise to a stirred solution of lH-triazole (300.00 g, 4.34 mol, 252.10 mL) in H20 (2 L) at 40 to 45 °C. The resulting solution was stirred for a further 1 hour. The precipitate was filtered off and further Br2 (617.28 g, 3.86 mol) was added to the filtrate, then it was kept at 25 °C for 16 hours. A second precipitate was filtered off. The combined filtered off solids were washed with water (1 L x 3), dried under vacuum and re-crystallized from MeOH (-400 mL) to give 4,5-dibromo-lH-triazole (Intermediate 14f; 890 g, 90.39percent yield) as an off-white solid, m/z (ES+) [M+H]+ (0558) 226/228/230.
Reference: [1] Journal of the Chemical Society - Perkin Transactions 1, 1996, # 12, p. 1341 - 1347
[2] Patent: WO2007/96576, 2007, A1, . Location in patent: Example I20
[3] Patent: WO2017/80980, 2017, A1, . Location in patent: Page/Page column 68-69
[4] Justus Liebigs Annalen der Chemie, 1947, vol. 558, p. 34,41
[5] Journal of the Chemical Society - Perkin Transactions 1, 1996, # 13, p. 1535 - 1543
[6] Patent: WO2007/71900, 2007, A1, . Location in patent: Page/Page column 111-112
[7] Patent: WO2012/138648, 2012, A1, . Location in patent: Page/Page column 82-83
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Reference: [1] Justus Liebigs Annalen der Chemie, 1955, vol. 593, p. 200 - 207
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  • [ 1453-81-2 ]
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Reference: [1] Angewandte Chemie - International Edition, 2007, vol. 46, # 6, p. 934 - 936
[2] Inorganica Chimica Acta, 2012, vol. 388, p. 84 - 87
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Reference: [1] Angewandte Chemie - International Edition, 2011, vol. 50, # 38, p. 8944 - 8947
[2] Journal of Organic Chemistry, 2012, vol. 77, # 5, p. 2543 - 2547
[3] Organic and Biomolecular Chemistry, 2013, vol. 11, # 45, p. 7830 - 7833
[4] Angewandte Chemie - International Edition, 2007, vol. 46, # 6, p. 934 - 936
  • 31
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YieldReaction ConditionsOperation in experiment
41% With caesium carbonate In N,N-dimethyl-formamide at 90℃; for 30 h; sealed tube Following General Procedure A (90 0C, 30 hours), 1/-/-[1 ,2,3]triazole (87 μL, 1.5 mmol) is coupled with iodo-benzene (112 μL, 1.0 mmol). The crude brown oil was purified by flash chromatography on silica gel (eluent: dichloromethane/hexanes = 50/50 then pure dichloro- methane) to provide 60 mg of 2-phenyl-2H-[1 ,2,3]triazole (41 percent yield) as an uncolored oil and 70 mg of 1-phenyl-1 H-[1 ,2,3]triazole (48 percent isolated yield) as a light yellow solid. Identification1H NMR (400 MHz, CDCI3): δ 7.99-8.02 (m, 2H, H7>8), 7.72 (s, 2H, H2l6),7.38-7.42 (m, 2H, H3,5), 7.24-7.28 (m, 1 H, H4).13C NMR (100 MHz, CDCI3): δ 139.90 (C1), 135.51 (C7,8), 129.30 (C3,5),127.56 (C4), 118.97 (C2l6).IR (KBr): v (cm'1) = 3125, 3060, 2926, 2854, 1598, 1500, 1410, 1376, 1260, 1215, 1149, 1069, 950, 821, 756, 695, 669, 509, 457. <n="51"/>GC/MS: rt = 13.50 min, M/Z = 145.HRMS: 146.0721 (M+H). Theoretical: 146.0718.Mp: 560C.1H NMR (400 MHz, CDCI3): δ 7.94 (d, 1H, H8), 7.78 (d, 1H1 H7), 7.66-7.69 (m, 2H, H2,β), 7.44-7.48 (m, 2H1 H3|6), 7.35-7.40 (m, 1 H1 H4).13C NMR (100 MHz, CDCI3): δ 137.06 (C1), 134.54 (C7), 129.79 (C8), 128.80 (C3i5), 121.78 (C4), 120.70 (C2,β).IR (KBr): v (cm"1) = 3147, 3130, 3065, 1596, 1503, 1463, 1319, 1229, 1176, 1092, 1038, 982, 910, 793, 762, 684, 640, 509, 440. GC/MS: rt = 16.58 min, M/Z = 145.HRMS: 146.0719 (M+H). Theoretical: 146.0718.
Reference: [1] Patent: WO2008/4088, 2008, A2, . Location in patent: Page/Page column 49-50
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Reference: [1] Advanced Synthesis and Catalysis, 2014, vol. 356, # 7, p. 1549 - 1554
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YieldReaction ConditionsOperation in experiment
29% With potassium carbonate In N,N-dimethyl-formamide at 20 - 100℃; for 5 h; Inert atmosphere [000338] Synthesis of 4-(2H-1, 2, 3-triazol-2-yl) benzaldehyde & 4-(1H-1, 2, 3-triazol-1-yl) benzaldehyde (418 & 419): To a stirred solution of 4-fluorobenzaldehyde 417 (2 g, 16 mmol) in DMF (50 mL) under argon atmosphere were added 1H-1, 2, 3-triazole 417 (1.32 g, 19.2 mmol), potassium carbonate (3.3 g, 24 mmol) at RT; heated to 100 °C and stirred for 5 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice cold water (35 mL) and extracted with EtOAc (2 x 40 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 20percent EtOAc/ hexanes to afford compound 418 (800 mg, 29percent) and using 40percent EtOAc/ hexanes to afford compound 419 (1 g, 36percent) as yellow solids.
Reference: [1] Journal of Medicinal Chemistry, 1998, vol. 41, # 13, p. 2390 - 2410
[2] Patent: WO2015/138895, 2015, A1, . Location in patent: Paragraph 000338
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Reference: [1] Angewandte Chemie - International Edition, 2011, vol. 50, # 38, p. 8944 - 8947
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YieldReaction ConditionsOperation in experiment
95% With bromine In water at 50℃; Into a 3000-mL 3-necked round-bottom flask, was placed 2H-1,2,3-triazole (100 g, 1.45 mol, 1.00 equiv), water (1000 mL), Br2 (522 g, 3.27 mol, 2.25 equiv). The resulting solution was stirred overnight at 50° C. in an oil bath. The reaction was then quenched by the addition of 1000 mL of Na2SO3 (aq). The solid was collected by filtration and dried in an oven under reduced pressure. This resulted in 313 g (95percent) of 4,5-dibromo-2H-1,2,3-triazole as a white solid.
60.8% With bromine In water at 0 - 20℃; 4,5-dibromo-2H-l,2,3-triazole. Bromine (15 mL) was added dropwise to a stirred solution of 2H-l,2,3-triazole (15.0 g, 217 mmol) in water (200 mL) at 0°C. Once addition was completed, the mixture was stirred for 12 hours at room temperature. The resultant mixture was filtered off and washed with water, dried over sodium sulfate and recrystallized from methanol to afford 4,5-dibromo-2H-l,2,3-triazole as a dark brown solid (29.8 g, 60.8percent).
49% With bromine In water at 0 - 20℃; [0260] Bromine (11.59 g, 73.35 mmol) was added dropwise to a 0 °C solution of 2H-l,2,3-triazole (5.00 g, 72.46 mmol) in water (50 mL), and the resulting solution was allowed to warm to room temperature and stir overnight. The precipitate was collected by filtration and dried to afford 4,5- dibromo-2H-l ,2,3-triazole (8.00 g, 49percent) as a white solid. MS (ESI, pos. ion) m/z 228, 226, 230 [M+H]+.
Reference: [1] Organic Letters, 2010, vol. 12, # 20, p. 4632 - 4635
[2] Patent: US2017/166584, 2017, A1, . Location in patent: Paragraph 0718; 0719
[3] Patent: WO2012/151512, 2012, A2, . Location in patent: Page/Page column 151
[4] Patent: WO2015/74064, 2015, A2, . Location in patent: Paragraph 0260
[5] Patent: WO2018/111803, 2018, A1, . Location in patent: Page/Page column 24
  • 36
  • [ 288-36-8 ]
  • [ 22300-52-3 ]
YieldReaction ConditionsOperation in experiment
70.8 g With N-Bromosuccinimide; potassium carbonate In Isopropyl acetate at 20℃; for 5 h; Example 2
Preparation of 4,5-dibromo-2H-1,2,3-triazole
NBS (123 g, 690 mmol), K2CO3 (0.8 g, 5.8 mmol) and IPAc (300 mL) are added into a round bottom flask with the internal temperature of the flask keep at 20° C. Then, 1H-1,2,3-triazole (19 mL, 330 mmol) is slowly added in the flask by keeping internal temperature of the reaction mixture below 40° C.
The reaction mixture is stirred at 20° C. for 5 h, and then filtered.
The filter cake is washed with IPAc (30 mL), and then the filter cake is discarded.
The filtrate is washed with 2percent NaS2O3 (100 mL).
The solvent of the resulting organic layer is distilled under vacuum and the internal temperature of the solvent is kept below 45° C.
After the distillation, the obtained product is recrystallized by hexanes (600 mL).
The resulting solid is filtered, and the filter cake is washed with hexanes (60 mL).
The resulting solid is dried under vacuum at a temperature of no more than 35° C. to afford 70.8 grams of the product.
Other R1 heterocycles as contemplated in the present invention can be brominated via similar preparation procedures as outlined above.
Reference: [1] Patent: US8410091, 2013, B1, . Location in patent: Paragraph 0062; 0063
  • 37
  • [ 288-36-8 ]
  • [ 52548-14-8 ]
  • [ 956317-36-5 ]
YieldReaction ConditionsOperation in experiment
68% With copper(l) iodide; (1R,2R)-N,N-dimethylcyclohexane-1,2-diamine; caesium carbonate In N,N-dimethyl-formamide at 100℃; for 4 h; The 1, 2, 3-triazole (3.45g, 50mmol), 2-iodo-5-methyl benzoic acid (5.24g, 20mmol), cesium carbonate (11.72g, 36mmol), trans-N, N '-dimethyl -1 , 2-cyclohexanediamine (0.51g, 3. 6mmol), cuprous iodide (0.38g, 2mmol) and N, N-dimethyl formamide (30 ml) are sequentially added to the 100 ml round bottom flask in a single port, the resulting reaction mixture under the protection of nitrogen is gradually heated up to 100 ° C, reaction 4 hours. Stop the reaction, cooling to room temperature to be reacted, water (150 ml) is diluted, and using ethyl acetate (200 ml × 2) extraction . Remove organic layer, the aqueous layer with concentrated hydrochloric acid (the mass fraction is 36.5percent) acidified to pH to 1-2, then using ethyl acetate (200 ml × 2) extraction, and combined with the organic layer dried with anhydrous sodium sulfate. Filtering, the filtrate concentrated under reduced pressure, the resulting residue is purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 50/1) to obtain the title compound as yellow solid (2.76g, 68percent) .
68% With copper(l) iodide; (R,R)-N,N'-dimethyl-1,2-diaminocyclohexane; caesium carbonate In N,N-dimethyl-formamide at 100℃; for 4 h; Inert atmosphere 1, 2, 3-Triazole (3.45 g, 50 mmol) , 2-iodo-5-methylbenzoic acid (5.24 g, 20 mmol) , cesium carbonate (11.72 g, 36 mmol) , trans-N, N'-dimethyl-1, 2-cyclohexanediamine (0.51 g, 3.60 mmol) , cuprous iodide (0.38 g, 2 mmol) and N, N-dimethylformamide (30 mL) were added sequentially to a 100 mL of single-necked round-bottomed flask under nitrogen, and the mixture was warmed gradually to 100 and reacted for 4 h. The reaction mixture was cooled, diluted with water, and extracted with ethyl acetate (200 mL x 2) . The aqueous layer was acidified to pH 12 with concentrated hydrochloric acid, and the resulting mixture was extracted with ethyl acetate (200 mL x 2) . The combined organic layers were dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography on silica gel eluted with (dichloromethane/methanol (v/v) 50/1) to give the title compound (as a yellow solid, 2.76 g, 68) .[MS (ESI, neg. ion) m/z: 202.1 [M-H]- and1H NMR (CD3OD, 600 MHz) δ (ppm) : 7.88 (s, 2H) , 7.66 (d, 1H) , 7.59 (d, J 8.2 Hz, 1H) , 7.507.48 (dd, J 8.1 Hz, 1.1 Hz, 1H) , 2.45 (s, 3H) .13C NMR (CD3OD, 151 MHz) δ (ppm) : 169.8, 140.7, 137.5, 136.7, 133.5, 131.5, 129.3, 126.0, 21.0.
68% With copper(l) iodide; caesium carbonate; trans-N,N'-dimethylcyclohexane-1,2-diamine In N,N-dimethyl-formamide at 100℃; for 4 h; Inert atmosphere 1,2,3-triazole (3.45 g, 50 mmol), 2-iodo-5-methylbenzoic acid (5.24 g, 20 mmol), cesium carbonate (0.57 g, 3.6 mmol), cuprous iodide (0.38 g, 2 mmol), trans-N, N'-dimethyl-1,2-cyclohexanediamine (0.51 g, 3.6 mmol), N, N-dimethylformamide (30 mL)was added sequentially to a 100 mL single-necked round bottom flask and gradually heated under nitrogen to 100 ° C for 4 hours. The reaction was quenched, cooled, diluted with tap water and washed with ethyl acetate (200 mL x 2). The aqueous layer was acidified with concentrated hydrochloric acid (pH = 1~2) and extracted with ethyl acetate (200 mL x 2). The organic layers were combined and dried over anhydrous sodium sulfate. The filtrate was evaporated under reduced pressure and purified by column chromatography (dichloromethane / methanol (v/v) = 50/1) to give the title compound (yellow solid, 2.76 g, 68percent).
68% With copper(l) iodide; caesium carbonate; trans-N,N'-dimethylcyclohexane-1,2-diamine In N,N-dimethyl-formamide at 100℃; for 4 h; Inert atmosphere 1,2,3-Triazole (3.45 g, 50 mmol),2-iodo-5-methylbenzoic acid (5.24 g, 20 mmol),Cesium carbonate (11.72 g, 36 mmol),Trans-N, N'-dimethyl-1,2-cyclohexanediamine (0.51 g, 3.6 mmol),Cuprous iodide (0.38 g, 2 mmol),N, N-dimethylformamide (30 mL) were sequentially added into a 100 mL single-necked round bottom flask, and the mixture was gradually heated to 100 ° C. under a nitrogen atmosphere for reaction for 4 hours. The reaction was stopped, cooled, diluted with tap water and extracted with ethyl acetate (200 mL x 2). The aqueous layer was acidified with concentrated hydrochloric acid (pH = 1-2) and extracted with ethyl acetate (200 mL x 2). The combined organic layers were combined and dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated to dryness under reduced pressure and subjected to column chromatography Purification (dichloromethane / methanol (v / v) = 50/1) afforded the title compound (yellow solid, 2.76 g, 68percent).
2.81 kg With copper(l) iodide; potassium carbonate In tetrahydrofuran; N,N-dimethyl-formamide at 40 - 65℃; for 0.5 h; Large scale The iodide 19 (6.04 kg, 23.0 mol), THF (45 E) and DMF (9.0 E) were charged to a vessel. Copper iodide (218 g, 1.15 mol) and potassium carbonate (7.94 kg, 57.4 mol) were added and the mixture heated to an internal temperature of40° C. 1,2,3-Triazole (3.16 kg, 46.0 mol) was added as asolution in THF (6.0 E) over half an hour (no exotherm) andheating continued to 65° C. (again no exotherm observed) and the reaction monitored by HPEC. Once complete N,Ndimethylethylenediamine (244 mE, 2.30 mol) was addedand mixture cooled to RT. Aqueous 3.6 M HC1 (36 E) wasadded (exotherm) and the mixture extracted twice with ethylacetate (2x30 E). The combined organics were washed with EiC1 solution (2x20 E). The acid solution assayed for 3.79 kg of 5 (81percent) and 4.64 kg of 5 and 20 combined (99percent). A solution of acids 5 and 20 (approx. 4.64 kg, 22.9 mol) in THF and EtOAc (approx. 110 E) was concentrated to lowvolume. THF (90 E) was added and the solvent composition checked by ‘H NMR to ensure most ethyl acetate had been removed. Sodium tert-butoxide (2.42 kg, 25.2 mol) was added slowly as a solid over 1-2 h (slight exotherm), allowing the sodium salt to form and stirred overnight at RT. The liquors showed a 45:55 ratio of product:starting material and the solid was collected by filtration, washed with THF (2x20 E) and dried in a vacuum oven (T=40° C.) for 15 h to afford 4.22 kg of crude sodium salt. The crude sodium salt (4.22 kg, 14.9 mol) was charged to a 50 E vessel and 3.6 M HC1 (21.2 E) was added with cooling. The slurry was thenstirred at room temperature for 16 h and the off-white solidisolated by filtration. The cake was washed with water (11E) and iPAc/Heptane (2x5 E), then dried in a vacuum oven(T=35° C.) for 15 h to give 3.10 kg of crude acid 5 (97.9ECAP, 92 wt percent, corrected weight 2.85 kg, 61percent yield from19). The acid 5 (2.85 kg corrected, 14.0 mol) was chargedto a 50 E vessel and EtOAc (28 E) and dilute 0.22 M HC1 (14 E) were added and the mixture stirred until two clear phases resulted. The aqueous layer was removed and the organic layer filtered to remove any particulate matter. Theethyl acetate was reduced to about 8 E and then heptane (15.6 E) was added over 1 h and the liquors sampled to check for appropriate losses. The solid was isolated by filtration, washed with heptane:ethyl acetate (3:1, 4 E) and dried on the filter under nitrogen to give 2.81 kg of acid 5.m.p. 167.5° C. ‘H NMR (400 MHz, d5-DMSO): ö 12.09 (brs, 1H), 8.04 (s, 1H), 7.62 (d, 1H, J=8.4 Hz), 7.58 (d, 1H, J=1.2 Hz), 7.49 (dd, 1H, J=8.4, 1.2 Hz), 2.41 (s, 3H). ‘3C NMR (100.6 MHz, d5-DMSO): ö 168.0, 139.2, 136.4, 135.8, 132.5, 130.3, 128.7, 124.8, 20.9. HRMS (ESI): mlz [M+H] calcd for C,0H9N302: 204.0773; found: 204.0781.
0.71 kg With copper(l) iodide; potassium carbonate In acetone at 70℃; for 5 h; Reflux; Large scale In the reactor,Add 250mL of acetone,Stirring,26.2 g of 2-iodo-5-methylbenzoic acid,Then 34.5 g of potassium carbonate was added,0.38 g copper iodide (Cul),1,2,3-triazole 7.6g.External temperature was raised to 70 ° C,During the heating process, a large amount of gas is generated,The reaction was refluxed for 5 hours.Then the reaction mixture was distilled under reduced pressure, the reaction system is more viscous, add 30mL of water, continue to reduce the steam distillation to no acetone (no acetone gas phase). 300mL of water was added to the residue after distillation, and 6mo 1 / L hydrochloric acid was added dropwise at room temperature to adjust the pH of the system to 1-2, resulting in a khaki-colored suspension liquid. Stirred for 15 minutes, filtered, washed with water three times,Each 50mL. The resulting solid was dried at 70 ° C in vacuo to dryness,Have pale green solid 19.45g,For crude compound (1-1), the purity was 95.20percent.With stirring, 7.5 kg of acetone, 0.94 kg of crude compound (1-1) and 0.194 kg of sodium hydroxide were added to the reaction kettle. Stirred at 20 ° C-30 ° C for 14 hours. Centrifugation, The filter cake was washed 3 times with acetone, each time 3kg. The resulting solid was transferred to the reaction kettle , 5.65 kg of water was added, 0.14 kg of diatomaceous earth was added and stirred for 1 hour. Filtration, the filtrate was transferred to the reaction kettle, hydrochloric acid was added dropwise to adjust the pH to 1-2, a large amount of white solid formed and stirred for 1 hour. Filtered, the filter cake was washed with water three times, each time 3kg. The resulting solid was dried at 60 ° C in vacuo to dryness, 0.71 kg white solid, represents Compound (I-1), purity 99.97percent, Isomeric compound (1-2) less than 0.1percent.

Reference: [1] Patent: CN105461699, 2016, A, . Location in patent: Paragraph 0239; 0240; 0241; 0242
[2] Patent: WO2017/12502, 2017, A1, . Location in patent: Page/Page column 53
[3] Patent: CN106986859, 2017, A, . Location in patent: Paragraph 0185; 0186
[4] Patent: CN105949203, 2016, A, . Location in patent: Paragraph 0179; 0193; 0194
[5] Angewandte Chemie - International Edition, 2011, vol. 50, # 48, p. 11511 - 11515
[6] Chinese Chemical Letters, 2015, vol. 26, # 1, p. 103 - 107
[7] Journal of Medicinal Chemistry, 2015, vol. 58, # 14, p. 5620 - 5636
[8] Patent: US2008/132490, 2008, A1, . Location in patent: Page/Page column 12-13
[9] Patent: WO2009/11775, 2009, A1, . Location in patent: Page/Page column 31
[10] Patent: WO2015/55994, 2015, A1, . Location in patent: Page/Page column 59
[11] Patent: US9441254, 2016, B2, . Location in patent: Page/Page column 13; 14
[12] Patent: CN104649983, 2018, B, . Location in patent: Paragraph 0037; 0038
  • 38
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  • [ 956317-36-5 ]
YieldReaction ConditionsOperation in experiment
68% With copper(l) iodide; (R,R)-N,N'-dimethyl-1,2-diaminocyclohexane; caesium carbonate In N,N-dimethyl-formamide at 100℃; for 4 h; Inert atmosphere 2H-1,2,3-triazole (3.45 g, 50 mmol),2-iodo-5-methylbenzoic acid (5.24 g, 20 mmol)Cesium carbonate (11.72 g, 36 mmol),Trans-N, N'-dimethyl-1,2-cyclohexanediamine (0.51 g, 3.6 mmol)Cuprous iodide (0.38 g, 2 mmol),N, N-dimethylformamide (30 mL) were successively added to a 100 mL single-necked round bottom flask,Under the protection of nitrogen gradually heated to 100 ,Reaction for 4 hours.Stop the reaction,cool down,Diluted with tap water and extracted with ethyl acetate (200 mL x 2).The aqueous layer was acidified with concentrated hydrochloric acid to pH = 1 to 2 and extracted with ethyl acetate (200 mL x 2)The combined organic layers were combined and dried over anhydrous sodium sulphate,filter,The filtrate was evaporated under reduced pressure and purified by column chromatography (dichloromethane / methanol (v / v) = 50 / 1) to afford the title compound (yellow solid, 2.76 g, 68percent).
68% With copper(l) iodide; caesium carbonate; trans-N,N'-dimethylcyclohexane-1,2-diamine In N,N-dimethyl-formamide at 100℃; Inert atmosphere Step 1) Synthesis of 5-methyl-2- (2H-1, 2, 3-triazol-2-yl) benzoic acid To a solution of N, N-dimethylformamide (30 mL) were added sequentially 2H-1, 2, 3-triazole (3.45 g, 50 mmol) , 2-iodo-5-methyl benzoic acid (5.24 g, 20 mmol) , cesium carbonate (11.72 g, 36 mmol) , trans-N, N'-dimethyl-1, 2-cyclohexanediamine (0.51 g, 3.6 mmol) and cuprous iodide (0.38 g, 2 mmol) . The reaction was heated to 100 ? under N2. After reaction for 4 hours, the reaction mixture was cooled to rt, diluted with water (60 mL) and extracted with ethyl acetate (200 mL × 2) . The aqueous layer was acidified to pH 1 to 2 with concentrated hydrochloric acid, and then extracted with ethyl acetate (200 mL × 2) . The combined organic layers were dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (DCM/methanol (v/v) =50/1) to give the title compound as a yellow solid (2.76 g, 68 percent) .MS (ESI, neg. ion) m/z: 202.1 [M-H] -;1H NMR (CD3OD, 600 MHz) d (ppm) : 7.88 (s, 2H) , 7.66 (d, 1H) , 7.59 (d, J= 8.2 Hz, 1H) , 7.50-7.48 (dd, J = 8.1 Hz, 1.1 Hz, 1H) , 2.45 (s, 3H) ; and13C NMR (CD3OD, 151 MHz) d (ppm) : 169.8, 140.7, 137.5, 136.7, 133.5, 131.5, 129.3, 126.0, 21.0.
68% With trans-N,N'-dimethyl-1,2-cyclohexyldiamine; copper(l) iodide; caesium carbonate In N,N-dimethyl-formamide at 100℃; for 4 h; Inert atmosphere The 2 H - 1, 2, 3 - triazole (3.45 g, 50 mmol), 2 - iodo -5 - methyl benzoic acid (5.24 g, 20 mmol), cesium carbonate (11.72 g, 36 mmol), trans - N, N' - dimethyl - 1, 2 - diaminocyclohexane (0.51 g, 3.6 mmol), cuprous iodide (0.38 g, 2 mmol) and N, N - dimethyl formamide (30 ml) are added to the 100 ml round bottom flask in a single port, under the protection of nitrogen reaction solution gradually raising the temperature to 100 °C reaction 4 hours. Stopping the reaction, cooling, liquid water (60 ml) diluted with water and ethyl acetate (200 ml × 2) extraction. The water layer is acidified to pH concentrated hydrochloric acid for 1 - 2, then adding ethyl acetate (200 ml × 2) extraction, the resulting organic layer dried with anhydrous sodium sulfate, filtered, filtrate turns on lathe does after separation and purification by column chromatography (dichloromethane/methanol (v/v)=50/1) to obtain the title compound (yellow solid, 2.76 g, 68percent).
19.48 g With copper(l) iodide; potassium carbonate In acetone at 70℃; for 5 h; Reflux In the reactor,Add 90percent acetone (volume fraction) 400mL,Stirring,26.2 g of compound (01)Then 34.5 g of potassium carbonate powder was added,0.38 g copper iodide (CuI),1,2,3-triazole.External temperature was raised to 70 ,During the heating process, a large amount of gas is generated,The reaction was stirred at reflux for 5 hours.The reaction mixture was then distilled under reduced pressure at 40 ° C,When the reaction system is more viscous, add 45mL of water and continue to reduce the steam to distillate without acetone (no acetone in the gas phase). Distilled residue was added 300mL of water, 25percent sulfuric acid was added dropwise at room temperature to adjust the pH to 1-2, a yellow suspension.Stir for 30 minutes, filter, and the solids are washed three times with water, 60 mL each. The resulting solid was dried to dryness at 70 ° C in vacuo,Have pale green solid 19.48g,Compound (1), purity 95.06percent.

Reference: [1] Patent: CN106243052, 2016, A, . Location in patent: Paragraph 0238; 0239; 0240; 0241; 0242
[2] Patent: WO2017/88759, 2017, A1, . Location in patent: Paragraph 00182
[3] Patent: CN107759620, 2018, A, . Location in patent: Paragraph 0183-0187
[4] Patent: WO2010/48014, 2010, A1, . Location in patent: Page/Page column 33-34
[5] Patent: WO2010/48017, 2010, A1, . Location in patent: Page/Page column 38
[6] Patent: WO2012/89606, 2012, A1, . Location in patent: Page/Page column 46
[7] Patent: WO2012/148553, 2012, A1, . Location in patent: Page/Page column 48-49
[8] Patent: US2015/232460, 2015, A1, . Location in patent: Paragraph 0441-0444
[9] Patent: CN104557744, 2017, B, . Location in patent: Paragraph 0011; 0032-0037; 0038; 0039; 0040-0041
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[2] Patent: WO2010/48010, 2010, A1, . Location in patent: Page/Page column 38
[3] Patent: WO2010/48016, 2010, A1, . Location in patent: Page/Page column 33
[4] Journal of the American Society for Mass Spectrometry, 2018, vol. 29, # 4, p. 694 - 703
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Reference: [1] Journal of Medicinal Chemistry, 2010, vol. 53, # 14, p. 5320 - 5332
[2] Patent: WO2009/58238, 2009, A1, . Location in patent: Page/Page column 35
[3] Organic Process Research and Development, 2011, vol. 15, # 2, p. 367 - 375
[4] Organic Letters, 2012, vol. 14, # 13, p. 3458 - 3461
[5] Patent: WO2013/59163, 2013, A1, . Location in patent: Page/Page column 37-38
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Reference: [1] Patent: WO2008/8517, 2008, A2, . Location in patent: Page/Page column 30; 31
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Reference: [1] Patent: WO2008/147518, 2008, A1, . Location in patent: Page/Page column 32; 34
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Reference: [1] Patent: WO2013/119639, 2013, A1, . Location in patent: Page/Page column 153; 154
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Reference: [1] Patent: EP2349270, 2015, B1, . Location in patent: Paragraph 0061; 0067
  • 45
  • [ 88-67-5 ]
  • [ 288-36-8 ]
  • [ 1001401-62-2 ]
YieldReaction ConditionsOperation in experiment
67% With copper(l) iodide; (R,R)-N,N'-dimethyl-1,2-diaminocyclohexane; caesium carbonate In N,N-dimethyl-formamide at 100℃; for 4 h; Inert atmosphere 1,2,3-triazole(0.7 ), 2-iodo-benzoic acid (1.0 ), cesium carbonate (2.36 g, 7.20 mmol)Trans-N, N'-dimethyl-1,2-cyclohexanediamine (0.10 g, 0.75 mmol), cuprous iodide (0.08 g, 0.40 mmo 1), N, N-dimethyl Amide (18 mL)Were successively added to a 100 mL single-necked round bottom flask and gradually warmed to 100 ° C for 4 hours under nitrogen protection.The reaction was quenched, cooled, diluted with tap water and extracted with ethyl acetate (200 mL X).The aqueous layer was acidified with concentrated hydrochloric acid (ρH- = 1 ~ 2) and extracted with ethyl acetate (200 mL x 2). The combined organic layers were dried and dried over anhydrous sodium sulfate. The filtrate was evaporated under reduced pressure and purified by column chromatography. (Dichloromethane / methanol (v / v) = 30/1) gave the title compound (yellow solid, 0.511 g, 67percent)
Reference: [1] Patent: CN106674207, 2017, A, . Location in patent: Paragraph 0217-0220
[2] Patent: WO2012/89606, 2012, A1, . Location in patent: Page/Page column 45-46
[3] Patent: WO2016/100157, 2016, A2, . Location in patent: Page/Page column 30; 31
[4] Patent: WO2016/85784, 2016, A1, . Location in patent: Page/Page column 38-39
[5] Patent: WO2016/100161, 2016, A1, . Location in patent: Page/Page column 32
[6] Patent: WO2016/85783, 2016, A1, . Location in patent: Page/Page column 47
[7] Patent: WO2007/126934, 2007, A2, . Location in patent: Page/Page column 32
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Reference: [1] Angewandte Chemie - International Edition, 2016, vol. 55, # 41, p. 12632 - 12636[2] Angew. Chem., 2016, vol. 128, p. 12822 - 12826,5
[3] Patent: US2008/132490, 2008, A1, . Location in patent: Page/Page column 12-13
[4] Journal of Medicinal Chemistry, 2010, vol. 53, # 14, p. 5320 - 5332
[5] Patent: WO2015/95111, 2015, A1, . Location in patent: Page/Page column 35-36
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Reference: [1] Patent: WO2008/143856, 2008, A1, . Location in patent: Page/Page column 30
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Reference: [1] Patent: WO2008/8518, 2008, A1, . Location in patent: Page/Page column 33-34
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  • [ 626-01-7 ]
  • [ 626248-56-4 ]
  • [ 16279-73-5 ]
YieldReaction ConditionsOperation in experiment
68% With potassium phosphate; copper(l) iodide; ethylenediamine In 1,4-dioxane; dimethyl sulfoxide for 72 h; Reflux The mixture of 3-iodoaniline (3.70 g, 16.9 mmol), 1,2,3-triazole (3.91 mL, 67.6 mmol), K3PO4 (7.17 g, 33.8 mmol), fine powder Cul (1.61 g, 8.45 mmol), ethylenediamine (0.60 mL, 8.45 mmol) in 30 mL dioxane and 15 mL DMSO were refluxed for three days to yield major product 3-(2H-l,2,3-triazol-2-yl)aniline and minor product 3-(lH-l,2,3-triazol-l-yl)aniline in ratio of about 3:1. The mixture was diluted with 400 mL EtOAc, vigorously stirred, filtered through celite, washed with brine twice, concentrated in vacuo, and subjected to flash column to isolate 3-(2H-l,2,3-triazol-2-yl)aniline (1.86 g, 68percent yield).
68% With potassium phosphate; copper(l) iodide; ethylenediamine In 1,4-dioxane; dimethyl sulfoxideReflux The mixture of 3-iodoaniline (3.70 g, 16.9 mmol), 1,2,3-triazole (3.91 mL, 67.6 mmol), K3P04 (7.17 g, 33.8 mmol), fine powder CuT (1.61 g, 8.45 mmol), ethylenediamine (0.60 mL, 8.45 mmol) in 30 mL dioxane and 15 mL DMSO were refluxed for three days to yield as the major product 3-(2H-1,2,3-triazol-2-yl)aniline and as the minor product 3-(1H- 1,2,3 -triazol- 1 -yl)aniline in ratio of about 3:1. The mixture was diluted with 400 mL EtOAc, vigorously stirred, filtered through celite, washed with brine twice, concentrated in vacuo, and subjected to flash column to isolate 3-(2H-1,2,3-triazol-2-yl)aniline (1.86 g, 68percent yield).
Reference: [1] Patent: WO2013/78468, 2013, A1, . Location in patent: Paragraph 0314; 0315
[2] Patent: WO2014/152768, 2014, A1, . Location in patent: Paragraph 0124
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  • [ 1186050-58-7 ]
YieldReaction ConditionsOperation in experiment
80% With copper(l) iodide; (R,R)-N,N'-dimethyl-1,2-diaminocyclohexane; caesium carbonate In 1,4-dioxane; water at 60 - 100℃; for 4 h; Inert atmosphere Method B: 2-Fluoro-6-[1 ,2,3]triazol-2-yl-benzoic acid. To a 2 L, 3- necked, round-bottomed flask equipped with an overhead mechanical stirrer, thermocouple probe, heating mantle, reflux condenser, and nitrogen inlet were added 2-fluoro-6-iodobenzoic acid (127.6 g, 480 mmol), copper iodide (4.57 g, 24 mmol), and Cs2C03 (312.6 g, 959 mmol). To these solids were added dioxane (640 mL), then water (2.6 mL, 144 mmol), then 1 H-1 ,2,3-triazole (55.6 mL, 959 mmol), and finally frans-1 ,2-dimethylcyclohexane-1 ,2-diamine (15.1 mL, 96 mmol). The mixture was then warmed to 60 °C for 30 min, then to 83 °C for 30 min, and then to 100 °C for 3 h. After the 3 h at 100 °C, the mixture was cooled and then 1 L of MTBE and 1 L of water were added. After vigorous mixing, the layers were separated and the bottom aqueous layer was acidified to pH 1 .72 with -148 mL of concentrated hydrochloric acid. The aqueous was then extracted twice with EtOAc. The combined organic layers were dried over Na2S04, filtered, and concentrated to provide a dark oil. The oil was stirred overnight in EtOAc (450 mL) and the resulting precipitate was removed by filtration. The mother-liquors were concentrated to a brown solid (106.21 g, 75 wtpercent by quantitative HPLC, 79.7 g, 80percent). 1H NMR (400 MHz, DMSO-d6): 8.22 - 8.13 (bs, 2H), 7.84-7.80 (m, 1 H), 7.74 - 7.65 (m, 1 H), 7.50 - 7.41 (m, 1 H).
Reference: [1] Patent: WO2012/145581, 2012, A1, . Location in patent: Page/Page column 50
  • 51
  • [ 288-36-8 ]
  • [ 111771-08-5 ]
  • [ 1186050-58-7 ]
YieldReaction ConditionsOperation in experiment
140 mg With copper(l) iodide; (1R,2R)-N,N-dimethylcyclohexane-1,2-diamine; caesium carbonate In 1,4-dioxane; water at 18 - 100℃; for 18 h; Inert atmosphere; Sealed tube A suspension of 2-fluoro-6-iodobenzoic acid (300 mg, 1 .1 mmol), (1 R,2R)-N,N- dimethylcyclohexane-1 ,2-diamine (32 mg, 0.23 mmol), Cs2C03 (735 mg, 2.3 mmol), 1 H- 1 ,2,3-triazole (0.13 mL, 2.3 mmol), water (0.01 mL) in 1 ,4-dioxane (5 mL) was degassed under nitrogen for 10 mins. Cul (10.7 mg, 0.06 mmol) was added and the mixture was further degassed under nitrogen for 10 mins. The pressure tube was sealed and the mixture was heated to 100 for 18 hrs. After cooling, the reaction mixture was quenched with 13percentwt NaCI in 2.5M hydrochloric acid (50 mL) and extracted with EtOAc. The combined organics were dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on the Biotage Isolera Four™ (25 g column, 0 to 75percent (10percent AcOH in EtOAc) in heptane) to afford the title compound as an oil (140 mg). 1H NMR (250 MHz, MeOD) 7.94 (s, 2 H), 7.80 (m, 1 H), 7.62 (m, 1 H), 7.29 (m, 1 H).
445.6 mg With copper(l) iodide; (R,R)-N,N'-dimethyl-1,2-diaminocyclohexane; caesium carbonate In N,N-dimethyl-formamide at 100℃; for 0.5 h; To a solution of 2-fluoro-6-iodobenzoic acid (502.5 mg), copper(I) iodide (36.5 mg), cesium carbonate (1.25 g) and trans-N,N'-dimethylcyclohexane-1,2-diamine (0.047 mL) in N,N-dimethylformamide (2.0 mL) was added 1H-1,2,3-triazole (330.3 mg), and the mixture was stirred at 100° C. for 0.5 hr. To the reaction mixture were added ethyl acetate and water. The obtained aqueous layer was neutralized with 1N aqueous hydrogen chloride solution, and extracted with ethyl acetate. The obtained organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (445.6 mg). MS: [M+H]+ 208.1.
Reference: [1] Journal of Medicinal Chemistry, 2015, vol. 58, # 14, p. 5620 - 5636
[2] Patent: WO2016/34882, 2016, A1, . Location in patent: Page/Page column 119; 120
[3] Patent: US2018/155333, 2018, A1, . Location in patent: Paragraph 1763; 1764; 1765
  • 52
  • [ 111771-08-5 ]
  • [ 288-36-8 ]
  • [ 1186050-58-7 ]
Reference: [1] Patent: WO2015/55994, 2015, A1, . Location in patent: Page/Page column 79
  • 53
  • [ 288-36-8 ]
  • [ 60468-36-2 ]
  • [ 1157938-97-0 ]
YieldReaction ConditionsOperation in experiment
73% With copper(l) iodide; potassium carbonate In N,N-dimethyl-formamide at 80℃; for 10 h; A) to the reactor were added successively 1mol difluorophenyl chloride, 1.2mol triazole, 0.15molCuI, 1.5mol potassium carbonate and 0.8LDMF (N, N- dimethylformamide), heated to 80 stirred 10 hours, TLC (thin layer chromatography) to detect the reaction was complete; the filtrate was filtered, concentrated under reduced pressure recovery DMF, the residue is recrystallized from ethyl acetate-white solid, that is the first product in a yield of 73percent ;
Reference: [1] Patent: CN105777740, 2016, A, . Location in patent: Paragraph 0019; 0023
  • 54
  • [ 1006-41-3 ]
  • [ 288-36-8 ]
  • [ 1293284-50-0 ]
YieldReaction ConditionsOperation in experiment
18.13 g With copper(l) iodide; (R,R)-N,N'-dimethyl-1,2-diaminocyclohexane; caesium carbonate In N,N-dimethyl-formamide at 110℃; To a mixture of2-bromo-4-fluorobenzoic acid (30 g, 137 mmol), cesiumcarbonate (89.26 g, 274 mmol) and Cui (5.27 g, 27.4 mmol) in DMF (200 mL) were addedN,N' -dimethylcyclohexane-1,2-diamine (3.7 mL,23.3 mmol) and 1H-1,2,3-triazole (18.92 g, 27430 mmol). The resulting mixture was stirred at 110 °C overnight, cooled, concentrated in vacuo anddiluted with water (150 mL). The aqueous layer was extracted with EtOAc (300 mL x 3). The aqueous layer was acidified with 2N HCl and extracted with EtOAc (300 mL x 4). Thecombined organic layers were washed with brine (150 mL x 3), dried over Na2S04, filtered andthe filtrate concentrated in vacuo. The residue was purified by chromatography on silica gel(petroleum ether: EtOAc = 100: 1 ~ 5 : 1) to provide the title compound (18.13 g) as a yellow5 solid. LRMS m/z (M+H) 208.0 found, 208.0 required.
18.13 g With trans-N,N'-dimethyl-1,2-cyclohexyldiamine; copper(l) iodide; caesium carbonate In N,N-dimethyl-formamide at 110℃; To a mixture of 2-bromo-4-fluorobenzoic acid (30 g, 137 mmol), cesium carbonate (89.26 g, 274 mmol) and CuI (5.27 g, 27.4 mmol) in DMF (200 mL) were added Ν,Ν'-dimethylcyclohexane-1,2-diamine (3.7 mL,23.3 mmol) and 1H-1,2,3-triazole (18.92 g, 274 mmol). The resulting mixture was stirred at 110 °C overnight, cooled, concentrated in vacuo and diluted with water (150 mL). The aqueous layer was extracted with EtOAc (300 mL x 3). The aqueous layer was acidified with 2N HCl and extracted with EtOAc (300 mL x 4). The combined organic layers were washed with brine (150 mL x 3), dried over Na2SO4, filtered and the filtrate concentrated in vacuo. The residue was purified by chromatography on silica gel (petroleum ether : EtOAc = 100: 1 - 5 : 1) to provide the title compound (18.13 g) as a yellow solid. LRMS m/z (M+H) 208.0 found, 208.0 required.
Reference: [1] Patent: WO2015/18027, 2015, A1, . Location in patent: Page/Page column 48; 49
[2] Patent: WO2015/18029, 2015, A1, . Location in patent: Page/Page column 34; 35
[3] Patent: WO2015/20930, 2015, A1, . Location in patent: Page/Page column 40
[4] Patent: WO2016/100157, 2016, A2, . Location in patent: Paragraph 36; 37
[5] Patent: WO2016/100162, 2016, A2, . Location in patent: Page/Page column 31
[6] Patent: WO2016/89721, 2016, A1, . Location in patent: Page/Page column 42
[7] Patent: WO2016/100161, 2016, A1, . Location in patent: Page/Page column 37-38
[8] Patent: WO2016/100156, 2016, A1, . Location in patent: Page/Page column 34
[9] Patent: WO2016/101118, 2016, A1, . Location in patent: Page/Page column 30-31
[10] Patent: WO2016/95204, 2016, A1, . Location in patent: Page/Page column 35
  • 55
  • [ 288-36-8 ]
  • [ 1006-41-3 ]
  • [ 1293284-50-0 ]
YieldReaction ConditionsOperation in experiment
18.13 g With copper(l) iodide; (R,R)-N,N'-dimethyl-1,2-diaminocyclohexane; caesium carbonate In N,N-dimethyl-formamide at 110℃; To a mixture of 2hromo4-fiuorohenzoic acid (30 g, 137 mmoi), cesium carbonate (89.26 g, 274 mmol) and Cul (5.27 g, 27.4 mmol) in I)MF (200 mL) were added N,N’dimethyicyciohexane—i,2-diamine (3.7 mL,23.3 mnioi) and 1H-L2,34riazoie (18.92 g, 274 mmoi). The resulting mixture was stirred at 110 °C overnight, cooling, concentrated in vacuo and diluted with water (150 mL). The aqueous layer was extracted with ELOAc (300 mL x 3).The aqueous layer was acidified with 2N HCI and extracted with EtOAc (300 mL x 4). The combined organic layers were washed with brine (150 mL x 3), dried over Na2SO4, filtered and the filtrate concentrated in vacuo. The residue was purified by chromatography on silica gel (petroleum ether: EtOAc = 100: 1 5 : 1) to provide the title compound (18.13 g as a yellow solid. LRMS m/z (M+H) 20. () found, 208.0 required.
Reference: [1] Patent: WO2015/20933, 2015, A1, . Location in patent: Page/Page column 51
[2] Patent: WO2016/65585, 2016, A1, . Location in patent: Page/Page column 48-49
[3] Patent: WO2016/69510, 2016, A1, . Location in patent: Page/Page column 47
[4] Patent: WO2016/101119, 2016, A1, . Location in patent: Page/Page column 41
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