* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With 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 ]
[ 288-36-8 ]
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
Reference:
[1] Russian Journal of Organic Chemistry, 2002, vol. 38, # 7, p. 1056 - 1059
11
[ 16681-70-2 ]
[ 288-36-8 ]
Yield
Reaction Conditions
Operation 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] Chemische Berichte, 1910, vol. 43, p. 2222
18
[ 155944-18-6 ]
[ 288-36-8 ]
Reference:
[1] Synlett, 1998, # 4, p. 431 - 433
19
[ 288-36-8 ]
[ 74-88-4 ]
[ 16681-65-5 ]
Yield
Reaction Conditions
Operation 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 ]
Yield
Reaction Conditions
Operation 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).
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.
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
[ 288-36-8 ]
[ 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 ]
[ 15294-81-2 ]
Yield
Reaction Conditions
Operation 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
28
[ 288-36-8 ]
[ 15294-81-2 ]
Reference:
[1] Justus Liebigs Annalen der Chemie, 1955, vol. 593, p. 200 - 207
29
[ 591-50-4 ]
[ 288-36-8 ]
[ 1453-81-2 ]
[ 51039-49-7 ]
Reference:
[1] Angewandte Chemie - International Edition, 2007, vol. 46, # 6, p. 934 - 936
[2] Inorganica Chimica Acta, 2012, vol. 388, p. 84 - 87
30
[ 108-86-1 ]
[ 288-36-8 ]
[ 51039-49-7 ]
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
[ 288-36-8 ]
[ 591-50-4 ]
[ 1453-81-2 ]
[ 51039-49-7 ]
Yield
Reaction Conditions
Operation 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] Advanced Synthesis and Catalysis, 2014, vol. 356, # 7, p. 1549 - 1554
33
[ 288-36-8 ]
[ 459-57-4 ]
[ 41498-10-6 ]
[ 179056-04-3 ]
Yield
Reaction Conditions
Operation 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
34
[ 1122-91-4 ]
[ 288-36-8 ]
[ 179056-04-3 ]
Reference:
[1] Angewandte Chemie - International Edition, 2011, vol. 50, # 38, p. 8944 - 8947
35
[ 288-36-8 ]
[ 22300-52-3 ]
Yield
Reaction Conditions
Operation 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]+.
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.
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
[ 52548-14-8 ]
[ 288-36-8 ]
[ 956317-36-5 ]
Yield
Reaction Conditions
Operation 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.
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)
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).
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).
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.
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 ]
Yield
Reaction Conditions
Operation 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.
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.
Example 120: Preparation of 4,5-dibromo-lH-pi,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 17h;
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.
With bromine; In water; at 20 - 50℃; for 41.5h;
Example 159: Preparation of 4,5-dibromo- IH-[1, 2,3 ItriazoleTo a solution of IH-[1, 2,3]triazole (1.26 ml, 21.7 mmol) in water (10 ml) at 50°C, was added bromine (1.5 ml, 29 mmol). The reaction mixture was stirred at 50°C 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 hour. 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 <n="113"/>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. 194.70C.
With bromine; In water; at 40℃; for 2h;
Bromine (2.2 mL, 43.4 mmol) was added cautiously to a solution of 1H-1,2,3- triazole (2 g, 29.0 mmol) in water (10 mL) at 40°C. The resulting mixture was stirred for 2 hrs at 40°C, then allowed to cool and stood overnight at room temperature. The precipitate was isolated by filtration, washed with water (2x10 mL), and dried in the vacuum oven to give 4,5- dibromo-lH-l,2,3-triazole as a light brown solid. (M+H 225.6; LCMS method 2).
With copper(l) iodide; (R,R)-N,N'-dimethyl-1,2-diaminocyclohexane; caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 4h;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 (rhoH- = 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, 67%)
2-iodobenzoic acid (1 g, 4.03 mmol), 2H-l,2,3-triazole (0.334 g, 4.84 mmol), copper(I) iodide (0.768 g, 4.03 mmol), cesium carbonate (2.63 g, 8.06 mmol) were reacted in DMF at 120 C under microwave irradiation for 20 minutes. Then the reaction was monitored confirming the presence of the required product. Large amount of starting material resulted left. The reaction was further irradiated for 20 minutes at 120 C. Solvent was then removed under vacuum, poured into water (100 ml) and neutralised with 37% HC1. Aqueous phase was extracted with Et20 (3x100 ml), and the collected organic phases were concentrated to give 1 g of crude material. This was purified with Biotage SP1 (over a 340g C18 column) eluting with a gradient of ACN and water (modified with 0.5% HCOOH). Fractions were collected and concentrated under vacuum to give the title compound D43 as colourless solid (140 mg). UPLC (GEN QC Basic): rt = 0.29 minutes, peak observed: 188 (M-l) C9H7N302 requires: 189. 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 6.47 (br. s., 1 H) 7.47 - 7.59 (m, 1 H) 7.66 (t, 1 H) 7.75 - 7.87 (m, 3 H) 7.91 (d, 1 H)
With copper(l) iodide; (R,R)-N,N'-dimethyl-1,2-diaminocyclohexane; caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 12h;
A solution of 2-iodobenzoic acid (3.0 g, 12.09 mmol) in DMF (1.0 mL) was treated with 1,2,3-triazole (1.5 g, 21.7 mmol), copper(I) iodide (0.25 g, 1.2 mmol), Cs2CO3 (7.08 g, 21.7 mmol), and trans-N,N?-dimethylcyclohexane-l ,2-diamine (0.31 g, 2.17 mmol). The mixture was heated at 120 CC for 12h. The reaction was cooled to ii, diluted with EtOAc, and filtered through Celite. The residue was purified by gradient elution on Si02 (0 to 10% MeOH in DCM with 0.1% AcOH) to give the title compound.?HNMR (500 MHz, DMSO-d6) 3 13.05 (br s, 1H), 8.12 (s, 2H), 7.81-7.52 (m, 4H) ppm. LRMS m/z (M+H) 190.2 found, 190.2.
With trans-N,N'-dimethyl-1,2-cyclohexyldiamine; copper(l) iodide; caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 0.166667h;Microwave irradiation;
To a solution of 2-iodobenzoic acid (3.0 g, 12.1 mmol) in DMF was added 1,2,3- triazole (1.5 g, 21.7 mmol), Cs2C03(7.1 g, 21.7 mmol), Cul (114 mg, 0.6 mmol), and trans-N,K- dimethylc)rclohexane-l,2-diamine (310 mg, 2.2 mmol). After heating at 120 C for 10 min in a microwave reactor, the mixture was cooled to room temperature, diluted with EtOAc, and filtered through Celite. The filtrate was concentrated in vacuo and the crude residue was purified by silica gel chromatography (MeOH in DCM with 0.1% AcOH) to give Intermediate H as the faster eluting isomer. 1H NMR (DMSO-d6 , 500MHz) delta 13.05 (brs, 1 H), 8.12 (s, 2H), 7.81-7.52 (m, 4H).
With trans-N,N'-dimethyl-1,2-cyclohexyldiamine; copper(l) iodide; caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 12h;
Intermediate A 2-(2H-l .2.3-Triazol-2-yl)benzoyl acid A solution of 2-iodobenzoic acid (3.0 g, 12.09 mmol) in DMF (1.0 mL) was treated with 1,2,3-triazole (1.5 g, 21.7 mmol), copper(I) iodide (0.25 g, 1.2 mmol), Cs2C03 (7.08 g, 21.7 mmol), and fras-N,N'-dimethylcyclohexane-l ,2-diamine (0.31 g, 2.17 mmol). The mixture was heated at 120 C for 12h. The reaction was cooled to rt, diluted with EtOAc, and filtered through Celite. The residue was purified by gradient elution on Si02 (0 to 10% MeOH in DCM with 0.1% AcOH) to give the title compound.1HNMR (500 MHz, DMSO-d6) delta 13.05 (br s, 1H), 8.12 (s, 2H), 7.81-7.52 (m, 4H) ppm. LRMS m/z (M+H) 190.2 found, 190.2.
With copper(l) iodide; (R,R)-N,N'-dimethyl-1,2-diaminocyclohexane; caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 0.166667h;Microwave irradiation;
To a solution of 2-iodobenzoic acid (3.0 g, 12.1 mmol) in DMF was added 1,2,3- triazole (1.5 g, 21.7 mmol), Cs2CO3 (7.1 g, 21.7 mmol), Cul (114 mg, 0.6 mmol), and trans-N,N?dimethylcyclohexane- 1 ,2-diamine (310 mg, 2.2 mmol). After heating at 120 C for 10 mm in amicrowave reactor, the mixture was cooled to room temperature, diluted with EtOAc, and filtered through Celite. The filtrate was concentrated in vacuo and the crude residue was purified by silica gel chromatography (MeOH in DCM with 0.1% AcOH) to give Intermediate N as the faster eluting isomer. ?H NMR (DMSO-d6, 500MHz) oe 13.05 (brs, 1 H), 8.12 (s, 2H), 7.8 1-7.52 (m, 4H).
With trans-N,N'-dimethyl-1,2-cyclohexyldiamine; caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 10h;Microwave irradiation;
A solution of 2-iodobenzoic acid (3.0 g, 12.09 mmol) in DMF (1.0 mL) was treated with 1,2,3-triazole (1.5 g, 21.7 mmol), CsCO3 (7.08 g, 21.7 mmol), and trans-N,N'- dimethylcyclohexane-l52-diamine (0.31 g, 2.17 mmol). The mixture was heated at 120 0C for 10 min in a microwave reactor. The reaction was cooled to rt, diluted with EtOAc5 and filtered through Celite. The residue was purified by gradient elution on SiO2 (0 to 10% MeOH in DCM with 0.1% AcOH) to give the faster eluting desired 2-(2H-l52,3-triazol-2-yl)benzoyl acid. Data for 2-triazolyl isomer: 1HNMR (500 MHz, DMSO-d6) delta 13.05 (br s , IH)5 8.12 (s, 2H), 7.81-7.52 (m, 4H) ppm. The undesired l-(2H-l,2,3-triazol-2-yl)benzoic acid eluted second. A portion of the desired acid (0.10 g, 0.53 mmol) was treated with thionyl chloride (0.59 g, 5.3 mmol) in dichloromethane (5.0 mL) at rt. After stirring at RT for 1 h, the mixture was concentrated, azeotroping with benzene to yield acid chloride A-3.
tris-(dibenzylideneacetone)dipalladium(0); triphenylphosphine; In tetrahydrofuran; at 50℃; for 2h;
Carbonic acid (1 S,4f?)-4-(2,6-dichloro -purin-9-yl)-cyclopent-2-enyl ester ethyl ester (1 .O g, 2.91 mmol) was dissolved in dry deoxygenated THF (20 ml_) under argon. Triphenyl phosphine (1 15 mg, 0.44 mmol, 0.15 equivalents), [1 ,2,3]triazole (200 muL, 238 mg, 3.45 mmol) and Pd2(dba)3 (133 mg, 0.146 mmol, 5 mol%) were added sequentially. The reaction mixture was stirred at 509C for 2 hours, and allowed to cool to room temperature, before the volatile components were removed under reduced pressure. The product was purified by flash column chromatography, using the Argonaut Flashmaster Personal. The residue was re-suspended in dichloromethane (5 ml_) before loading onto a 25 g lsolute Flash Si cartridge, presaturated with isohexane. The product was eluted after isohexane (500 ml_), isohexane :ethyl acetate 4:1 (250 ml_) and isohexane ethyl acetate 1 :1 (750 ml_). The solvent was removed from the fractions containing pure product under reduced pressure, and the product was re -crystallized from ethyl acetate, to give a beige solid (280 mg, 30% yield). LC-MS MH+ 321 .80
3-methyl-5-(2H-1,2,3-triazol-2-yl)benzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With trans-N,N'-dimethyl-1,2-cyclohexyldiamine; copper(l) iodide; caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 0.166667h;Microwave irradiation;
f+/-~) 2-f2H-1.2.3-Triazol-2-vn-5-methylbenzoic acid (A-51A solution of 2-iodo-5-methylbenzoic acid (4.0 g, 15.3 mmol) in DMF (10 mL) was treated with 1,2,3-triazole (2.1 g, 30.5 mmol), CsCO3 (9.95 g, 30.5 mmol), CuI (0.145 g, 0.76 mmol) and trans-N,N'-dimethylcyclohexane-l,2-diamine (0.43 g, 3.05 mmol). The mixture was heated at 120 0C for 10 min in a microwave reactor. The reaction was cooled to room temperature, diluted with water, and washed with EtOAc. The aqueous phase was acidified with IN HCl and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by gradient elution on SiO2 (0 to 10% MeOH in water <n="32"/>with 0.1% AcOH) to give the faster eluting 2-(2H-l,2,3-triazol-2-yl)-5-methylbenzoic acid A-5. followed by the undesired regioisomer isomer, l-(2H-l,2,3-triazol-2-yl)-5-rnethylbenzoic acid. Data for Az5: 1HNMR (500 MHz, DMSO-d*) d 12.98 (br s , IH), 8.04 (s, 2H), 7.72-7.45 (m, 3H), 2.41 (s, 3H) ppm.
With copper(l) iodide; caesium carbonate; N,N?-trans-dimethyl cyclohexane-1,2-diamine; In N,N-dimethyl-formamide; at 120℃; for 0.166667h;Microwave irradiation;
2-(2H-1.2,3-triazol-2-yl>5-methylbenzoic acid (A-3)A solution of 2-iodo-5-methylbenzoic acid (4.0 g, 15.3 mmol) in DMF (10 mL) was treated with 1,2,3-triazole (2.1 g, 30.5 mmol), CsCO3 (9.95 g, 30.5 mmol), CuI (0.145 g, 0.76 mmol) and trans-N,N'-dimethylcyclohexane-l,2-diamine (0.43 g, 3.05 mmol). The mixture was heated at 1200C for 10 min in a microwave reactor. The reaction was cooled to room temperature, diluted with water, and washed with EtOAc. The aqueous phase was acidified with IN HCl and extracted with EtOAc. The organic layer was dried over Na2SO^ filtered and concentrated. The residue was purified by gradient elution on Sitheta2 (0 to 10% MeOH in water with 0.1% AcOH) to give the faster eluting 2-(2H-l,2,3-triazol-2-yl)-5-methylbenzoic acid A-3, followed by the undesired regioisomer isomer, l-(2H-l,2,3-triazol-2-yl)-5-methylbenzoic acid. Data for A-3 : 1HNMR (500 MHz, DMSO-d6) d 12.98 (br s , IH), 8.04 (s, 2H), 7.72-7.45 (m, 3H), 2.41 (s, 3H) ppm.
With caesium carbonate;trans-N,N'-dimethyl-1,2-cyclohexyldiamine; copper(l) iodide; In N,N-dimethyl-formamide; at 120℃; for 0.166667h;microwave irradiation;
A solution of 2-iodo-5-methylbenzoic acid (4.0 g, 15.3 mmol) in DMF (10 mL) was treated with 1,2,3-triazole (2.1 g, 30.5 mmol), CsCO3 (9.95 g, 30.5 mmol), CuI (0.145 g, 0.76 mmol) and trans-N,N'-dimethylcyclohexane-l,2-diamine (0.43 g, 3.05 mmol). The mixture was heated at 120 0C for 10 min in a microwave reactor. The reaction was cooled to room temperature, diluted with water, and washed with EtOAc. The aqueous phase was acidified with IN HCl and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by gradient elution on SiO2 (0 to 10% MeOH in DCM with 0.1% AcOH) to give the faster eluting 2-(2H-l,2,3-triazol~2-yl)-5-methylbenzoic acid, followed by the undesired regioisomer isomer, I -(2H- 1 ,2,3-triazoI-2-yl)-5-methylbenzoic acid. A solution of the acid (3.56 g, 17.52 mmol) in 150 mL of DCM was stirred and cooled to O0C. The solution was treated with oxalyl chloride (1.9 mL, 21.9 mmol) and DMF (68 muL, .878 mmol). The solution was slowly warmed to room temperature and stirred overnight. Solvent was concentrated and the resulting solid was azetroped with DCM and concentrated to provide A-7 as a yellow solid.
With trans-N,N'-dimethyl-1,2-cyclohexyldiamine; caesium carbonate;copper(l) iodide; In N,N-dimethyl-formamide; at 120℃; for 0.166667h;microwave irradiation;
A solution of 2-iodo-5-methylbenzoic acid (4.0 g, 15.3 mmol) in DMF (10 mL) was treated with 1,2,3-triazole (2.1 g, 30.5 mmol), CsCO3 (9.95 g, 30.5 mmol), CuI (0.145 g, 0.76 mmol) and trans-N,N'-dimethylcyclohexane-l,2-diamine (0.43 g, 3.05 mmol). The mixture was heated at 120 0C for 10 min in a microwave reactor. The reaction was cooled to room temperature, diluted with water, and washed with EtOAc. The aqueous phase was acidified with IN HCl and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by gradient elution on SiO2 (0 to 10% MeOH in DCM with 0.1% AcOH) to give the faster eluting 2-(2H-l,2,3-triazol-2-yl)-5-methylbenzoic acid A-2, followed by the undesired regioisomer isomer, l-(2H-l,2,3-triazol-2-yl)-5-methylbenzoic acid. A solution of the acid (3.56 g, 17.52 mmol) in 150 mL of DCM was stirred and cooled to 00C. The solution was treated with oxalyl chloride (1.9 mL, 21.9 mmol) and DMF (68 muL, .878 mmol). The solution was slowly warmed to room temperature and stirred overnight. Solvent was concentrated and the resulting solid was azetroped with DCM and concentrated to provide A-4 as a yellow solid.
With copper(l) iodide; caesium carbonate; N,N?-trans-dimethyl cyclohexane-1,2-diamine; In N,N-dimethyl-formamide; at 120℃; for 0.166667h;Microwave irradiation;
2-(2H-l,2.3-triazol-2-vDbenzoic acid B-3A solution of 2-iodobenzoic acid (3.0 g, 12.09 mmol) in DMF was treated with (1.5 g, 21.7 mmol) 1,2,3-triazole, 7.08 g (21.7 mmol) CsCO3, 114 mg (0.60 mmol) CuI and 310 mg (2.17 mmol) trans-N,N'-dimethylcyclohexane-l,2-diamine. The mixture was heated at 120 0C for 10 min in a microwave reactor. The reaction was cooled to rt, diluted with EtOAc, and <n="35"/>filtered through CeIi te. The residue was purified by gradient elution on SiO2 (0 to 10% MeOH in DCM with 0.1% AcOH) to give the faster eluting desired 2-(2H-l,2,3-triazol-2-yl)benzoyl acid, B-3. Data for B-3: 1HNMR (500 MHz, DMSO-d6) delta 13.05 (br s , IH), 8.12 (s, 2H), 7.81-7.52 (m, 4H) ppm. The undesired l-(2H-l,2,3-triazol-2-yl)benzoic acid eluted second.
With potassium carbonate; In sulfolane; at 90℃; for 16h;
a) 3-Nitro-5-oxazol-2-yl-benzoic acid methyl esterTo a suspension of 20 g (87.9 mmol mono-methyl-5-nitroisophtalate in 300 ml toluene are added 300 mul DMF and 12.93 ml (175.9 mmol) thionylchloride and the reaction mixture is stirred at 80 0C for 7 hours. The reaction mixture is concentrated to give white crystals. The crystals are dissolved in 200 ml sulfolan, then 13.4 g (194 mmol) triazole is added, followed by 12.3 g (88.0 mmol) potassium carbonate. The reaction mixture is stirred at 90 0C for 16 hours. The reaction mixture is then filtered and diluted with diethyl ether and 0.1 N aq. HCI solution. The organic layer is washed with water, dried with sodium sulfate, filtered and <n="33"/>concentrated. The residue is purified by column chromatography using acetone and hexane in a ratio 1/6 to give the product.1H-NMR (400 MHz, CDCI3): 9.10 (s, 1 H), 9.04 (s, 1 H), 8.93 (s, 1 H), 7.83 (s, 1 H), 7.39 (s, 1 H), 4.03 (s, 3H).
1-(4-benzoyl-piperazin-1-yl)-2-(7-[1,2,3]triazol-2-yl-1H-pyrrolo[3,2-b]pyridin-3-yl)-ethane-1,2-dione[ No CAS ]
[ 619331-02-1 ]
Yield
Reaction Conditions
Operation in experiment
With copper; potassium carbonate; at 160℃; for 16h;
Example 205 and 206. In a sealed tube -(4-benzoyl-piperazin-1-yl)-2-(7-chloro-1H-pyrrolo[3,2-b]pyridin-3-yl)-ethane-1,2-dione (30 mg, 0.076 mmol), 1H1,2,3-triazole (160 mg, 2.3 mmol), Cu (0) (10 mg, 0.16 mmol) and K2CO3 (11 mg, 0.080 mmol) were heated at 160 C. for 16 h. The reaction mixture was diluted with MeOH, filtered through celite and concentrated. The reaction mixture was diluted with MeOH, filtered through celite and concentrated. The residue was purified by preparative HPLC to provide 1-(4-benzoyl-piperazin-1-yl)-2-(7-[1,2,3]triazol-2-yl-1H-pyrrolo[3,2-b]pyridin-3-yl)-ethane-1,2-dione: 1H NMR (300 MHz, CD3OD) delta8.79 (d, J=6.6 Hz, 1H), 8.79 (s, 1H), 8.48 (d, J=6.6 Hz, 1H), 8.40 (s, 2H), 7.48 (br s, 5H), 4.00-3.55 (m, 8H). MS m/z (M+H)+ calcd for C22H20N7O3: 430.15; found 430.29. HPLC retention time 0.91 min (Column G); and 1-(4-benzoyl-piperazin-1-yl)-2-(7-[1,2,3]triazol-1-yl-1H-pyrrolo[3,2-b]pyridin-3-yl)-ethane-1,2-dione: 1H NMR (300 MHz, CD3OD) delta8.97 (d, J=81.2 Hz, 1H), 8.70 (d, J=5.6 Hz, 1H), 8.48 (s, 1H), 8.06 (d, J=1.2 Hz, 1H), 7.80 (d, J=5.6 Hz, 1H), 7.47 (br s, 5H), 4.00-3.45 (m, 8H). MS m/z (M+H)+ calcd for C22H20N7O3: 430.15; found 430.29. HPLC retention time 0.90 min (Column G).
With copper; potassium carbonate; at 20 - 160℃; for 7h;
Reaction was carried in a 250 ml flask (foaming occurred upon heating and the big size flask is more convenient). A mixture of precursor 2i (3 g, 13.95 mmol), 1,2,3-triazole (15 g, 217.6 mmol, 15 eq), K2CO3 (1.9 g, 13.95 mmol, 1 eq) and Cu(0)(0.9 g, 13.9 mmol, 1 eq) was heated at 160 C. for 7 hr (from rt to 160 C. total 7 hr) under N2 (depending on the Cu(0) lot, reaction time may vary from 2 hr to 7 hr). The resulting mixture was diluted with MeOH, filtered through filter paper (to remove the copper). Washed with MeOH (20 ml) and water (30 ml). [1504] The filtrate was concentrated (remove solvent in rotovap) and diluted with ethylacetate. The aqueous layer was extracted with ethylacetate. The combined organic layer was dried over sodium sulfate, filtered and concentrated. The residue was dissolved in MeOH (20 ml), 7-80 (750 mg) crystallized from the methanol as a white solid and was collected by filtration. (Slow gradient volume, silica gel hex/AcOEt (0?18%) of the mother liquids usually affords 5-10% more of 7-80. [1505] 1HNMR (delta, CDCl3): 10.47 (bs, 1H), 8.76 (s, 1H), 7.94 (s, 1H), 7.89 (s, 1H), 7.53 (m, 1H), 6.78 (m, 1H); LCMS(M+1)+=204; rt=1.29 min
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃;
REFERENCE EXAMPLE 16 2-AMMO-3- (L- (L23-TNAZOLVL))-4- (4-CHLOROPHENVL) butane: Step A Benzyl 2- (1- (1, 2, 3-TRIAZOLYL)) acetate: A mixture of 1,2, 3-triazole (2.07 g, 30 mmol), phenyl bromoacetate (6.9 g, 30 mmol), and diisopropylethylamine (5,1 mL, 30 mmol) in 40 ML CH2C12 was stirred overnight at room temperature. This mixture was then diluted with ether until no further precipitate formed. The solid was filtered and washed with ether. The filtrate was concentrated and the residue was purified on silica gel using 10percent hexane in CH2C12 to give the title compound's isomer, benzyl 2- (2- (1, 2,3-triazolyl) acetate as amorphous solid. Further elution with a solvent mixture containing equal amounts of ether and CH2CI2 gave the title compound as amorphous solid. 1H NMR (400 MHz, CDC13) : 8 2.251 (s, 2H0, 7.267-7. 390 (m, 5H), 7.723 (s, 1H), 7.785 (s, LH)
N-allyl-2,3,4-tri-O-benzyl-6-triazolyl-D-gluco-δ-lactam[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 60℃; for 5h;
N-ALLYL-6-O-(P-TOLUENESULPHONYL)-2, 3, 4-TRI-O-BENZYL-D-GLUCO- -LACTAM (1 MMOL), prepared in Example 1, was dissolved in DMF. Triazole (2mmol) and K2CO3 (2mmol) were added to the solution. The reaction mixture was warmed to 60 C and stirred for an additional 5 hours at this temperature. The contents of the reaction mixture were poured into cold water (25 ml), and extracted with ethyl acetate (2 x 25 ml). The organic layer was dried and the residue was evaporated using column chromatography with ethyl acetate-hexane (7: 3) as eluent to yield a title compound in a semisolid state. The following spectral data was used to confirm product formation: IR (CH2C12) : v 1672 cm-1; 1HNMR (CDCl3) : # 3.37-3. 42 (dd, J=9Hz, 1H, CH), 3.46 (M, 1H, CH), 3.90 (M, 1H, CH), 3.98-4. 00 (d, J=6Hz, 1H, CH), 4.07 (M, 1H, CH), 4.18-4. 25 (M, 2H, 2xCH), 4.34-4. 39 (M, 1H, CH), 4.43-4. 45 (M, 3H, 2xCH+PhCH), 4.56-4. 59 (d, J=12HZ, 1H, PHCH), 5.10-5. 14 (d, J=12HZ, 1H, PHCH), 5.18-5. 27 (M, 2H, 2XPHCH), 5.70-5. 76 (M, 1H, CH), 7.15-7. 54 (M, 15H, ArH), 7.75 (s, 1H, TrH), 7.9 (s, 1H, TrH); Mass: M/Z 539 (M++1).
2,3,4-tri-O-benzyl-6-N-(2-chloroacetyl)-N-propyl-D-gluco-δ-lactam[ No CAS ]
[ 288-36-8 ]
2,3,4-tri-O-benzyl-6-N-(2-triazolylacetyl)-N-propyl-D-gluco-δ-lactam[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate;tetra-(n-butyl)ammonium iodide; In DMF (N,N-dimethyl-formamide); at 20℃; for 12h;
2,3, 4-TRI-0-BENZYL-6-N- {2- [CHLORO]-ACETYL}-N-PROPYL-D-GLUCO-5-LACTAM (LMMOL), prepared as described in Example 14 was dissolved in DMF. To this was added triazole (2 mmol), potassium carbonate (2 mmol) and tetrabutyl ammonium iodide (catalytic amount) and stirred the reaction mixture at room temperature for 12 hours. DMF was removed under vacuo and the residue was diluted with water (25 ml). The compound was extracted with ethylacetate (2 times, 25 ml), organic layer dried over NA2SO4 and solvent removed under reduced pressure. The product was purified by column chromatography using chloroform-methanol (9.5 : 0.5) as the eluent to yield the title compound in semisolid state. The following spectral information was used to confirm product formation: IR (CH2CL2) : V 1662 cm-1; 1HNMR (CDCl3) : # 0.86-0. 91 (t, J=7Hz 3H, CH3), 1.55-1. 58 (m, 2H, CH2), 2.91-2. 93 (m, 1H, NCH2), 3.24-3. 27 (m, 1H, NCH2), 3.52 (m, 1H, CH), 3.65-3. 71 (m, 3H, 3xCH), 3.85-3. 87 (m, 1H, CH), 3.99-. 4.01 (d, 1H, CH), 4.44-4. 55 (m, 3H, CH2+PhCH), 4.59-4. 72 (m, 4H, PHCH), 4.59-4. 72 (m, 4H, PHCH), 5.14-5. 19 (d, J=15Hz, 1H, PHCH), 6. 68 (BRM, 1H, NH), 7.14-7. 44 (M, 15H, ArH) 7. 81 (S, 1H, TRH), 8.07 (S, 1H, TrH) ; Mass : m/z 598 (M++L).
1,2,3-Triazole (19.00 kg, 275 mol) was charged over 30 minutes to a suspension of potassium carbonate (42.15 kg, 305 mol) in ethanol (80 L), and was rinsed in with ethanol (2 L). A solution of ethyl bromoacetate (45.8 kg, 274 mol) in ethanol (30 L) was added slowly and was rinsed in with ethanol (2L). During this time the reaction temperature was maintained at <20 C. The reaction mixture was then warmed to room temperature and stirred overnight. The suspension was filtered; washing the residue with ethanol (25 L and 17 L) and then the filtrate was concentrated under reduced pressure. The concentrate was dissolved in ethyl acetate (120 L) and the solution was washed with 1N hydrochloric acid (1×40 L, 7×20 L, 4×15 L). The aqueous washings were combined and extracted with ethyl acetate (3×21 L). The organic phases were combined, dried over magnesium sulphate, filtered and concentrated to dryness giving a mixture of the title compounds (25 kg). 1H NMR spectroscopic analysis indicated that this was a 6:5 mixture of N-2/N-1 isomers. 1H NMR (400 MHz, CDCl3): delta1.25 (m, 3H), 4.13 (q, 2H, N-1 isomer), 4.25 (q, 2H, N-2 isomer), 5.20 (s, 2H, N-1 isomer), 5.22 (s, 2H, N-2 isomer), 7.70 (s, 2H, N-2 isomer), 7.77 (s, 2H, N-1 isomer).
With potassium carbonate; In ethanol; at 20℃;
Preparation 17: [1 ,2,3]Triazol-1-yl-acetic acid ethyl ester and [1 ,2,3]triazol-2-yl-acetic acid ethyl ester. <strong>[288-36-8]1 ,2,3-Triazole</strong> (19.00 kg, 275 mol) was charged over 30 minutes to a suspension of potassium carbonate (42.15 kg, 305 mol) in ethanol (80 L), and was rinsed in with ethanol (2 L). A solution of ethyl bromoacetate (45.8 kg, 274 mol) in ethanol (30 L) was added slowly and was rinsed in with ethanol (2 L). During this time the reaction temperature was maintained at <20C. The reaction mixture was then warmed to room temperature and stirred overnight. The suspension was filtered; washing the residue with ethanol (25 L and 17 L), and then the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (120 L) and the solution was washed with 1N hydrochloric acid (1 x 40 L, 7 x 20 L, 4 x 15 L). The aqueous washings were combined and extracted with ethyl acetate (3 x 21 L). The organic phases were combined, dried over magnesium sulfate, and concentrated to in vacuo affording a mixture of the title compounds (25 kg). 1H NMR spectroscopic analysis indicated that this was a 6:5 mixture of N-2/N-1 isomers. 1H NMR (400MHz, CDCI3): delta 1.25 (m, 3H), 4.13 (q, 2H, N-1 isomer), 4.25 (q, 2H, N-2 isomer), 5.20 (s, 2H, N-1 isomer), 5.22 (s, 2H, N-2 isomer), 7.70 (s, 2H, N-2 isomer), 7.77 (s, 2H, N-1 isomer).
With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 20℃; for 18h;Product distribution / selectivity;
A mixture of the compound of preparation 8 (8 g, 26.5 mmol), triazole (3.7 g, 53 mmol) and potassium carbonate (5.2 g, 38 mmol) in N,N-dimethylformamide (60 ml) was stirred at room temperature for 18 hours. The mixture was then filtered, and the filtrate was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and brine, the layers were separated and the organic solution was dried over MgSO4 and concentrated under reduced pressure to afford the title compounds as a mixture of isomers. 1H NMR (400 MHz, CD3OD): delta 1.43 (s, 9H), 1.62-1.78 (m, 2H), 2.02 (m, 2H), 3.00 (m, 2H), 3.19 (m, 1H), 4.03 (m, 2H), 5.95, 5.99 (2xs, 2H), [7.77 (s), 7.80 (d), 8.18 (s) total 2H].
With potassium carbonate; In acetonitrile; at 20 - 50℃; for 1.5h;
A mixture of the compound of preparation 6 (2 g, 5.9 mmol), triazole (810 mg, 11.75 mmol) and potassium carbonate (1.2 g, 8.85 mmol) in acetonitrile (20 ml) was stirred at room temperature for 30 minutes, followed by a further hour at 50 C. The reaction mixture was filtered, washed through with ethyl acetate and the filtrate was concentrated under reduced pressure. The residual brown oil was partitioned between ethyl acetate and water, the layers were separated, and the organic phase was washed with additional water, then brine. The solution was dried over MgSO4 and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using dichloromethane:methanol (100:0 to 95:5) to afford the title compound, (202 mg). 1H NMR (400 MHz, CD3OD): delta 1.76-1.90 (m, 2H), 2.02 (m, 1H), 2.18 (m, 1H), 3.12-3.38 (m, 3H), 3.72 (m, 1H), 4.50 (m, 1H), 5.97 (s, 2H), 7.37 (dd, 1H), 7.41-7.51 (m, 3H), 7.78 (s, 2H). LRMS: m/z (ES+) 373, 375 [MH]+
With potassium carbonate; In acetonitrile; for 18h;Heating / reflux;
Preparation 32; Methyl 2H-1,2,3-triazol-2-ylacetate; A mixture of 1, 2, 3-triazole (10g, 144mmol), methyl bromoacetate (22g, 144mmol) and potassium carbonate (20g, 144mmol) in acetonitrile (100mL) was heated under reflux for 18 hours. The mixture was then diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate and concentrated in vacuo to afford the title compound in 56% yield, 11.4g.
With triethylamine; trichlorophosphate; In acetonitrile; at 5 - 20℃;
To a stirred solution of 4'-azido-arabino-uridine (15, 0.80 g, 2.84 mmol) in acetic anhydride (10 mL) and pyridine (10 mL) was added a trace of DMAP (catalytic) and the reaction mixture was stirred under N2 at RT overnight. The volatile substances were evaporated to dryness under reduced pressure. To a solution of the resulting residue and MeCN (30 mL) was added triazole (3.09 g, 44.87 mmol) and TEA (7.81 mL, 56.09 mmol). The reaction mixture was flushed with N2 and cooled to 5 C. in an ice bath. POCl3 (1.04 mL, 11.21 mmol) was added to the flask and the resulting mixture was left to stir at room temperature over night. The reaction mixture was evaporated to dryness under reduced pressure, dissolved in EtOAc (100 mL) and washed with saturated aqueous NaHCO3, dried (MgSO4) and evaporated to dryness to afford the protected triazole. NH4OH (2 mL) was added to a solution of the crude nucleoside in dioxane (5 mL). After stirring for 12 h the reaction mixture was evaporated to dryness. Preparative hplc chromatography (reverse phase ISCO column, H2O/MeCN) provided 0.21 g, (26%) of I (R1-R4=H) as a white solid.
(1) Production of 2-chloro-4-(2-2H-1,2,3-triazolyl)methylphenyl 2,2-di-methylpropanoate A mixture of 2.26 g of 2H-1,2,3-triazole, 1.31 g of sodium hydride (60% oil dispersion) and 100 ml of anhydrous N,N-dimethylformamide was stirred at 60 to 70 C. under a nitrogen atmosphere for 2 hours. After the evolution of hydrogen gas ceased, the mixture was cooled to 10 C. To this mixture was added dropwise an anhydrous N,N-di-methylformamide (150 ml) solution of 10 g of 4-bromomethyl-2-chlorophenyl 2,2-di-methylpropanoate at room temperature under stirring over 1 hour, and the mixture was stirred at 80 C. for 1 hour. After cooling, the reaction mixture was poured into ice water, which was extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution and then saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, which afforded 2-chloro-4-(2-2H-1,2,3-triazolyl)methylphenyl 2,2-dimethylpropanoate.
In N,N-dimethyl-formamide;
(1) Production of 2-chloro-4-(2-2H-1,2,3-triazolyl)methylphenyl 2,2-dimethylpropanoate A mixture of 2H-1,2,3-triazole (2.26 g), sodium hydride (60%, 1.31 g) and anhydrous N,N-dimethylformamide (100 ml) was stirred at 60 to 70 C. under a nitrogen atmosphere for 2 hours. After the evolution of hydrogen gas ceased, the mixture was cooled to 10 C. To this mixture was added dropwise an anhydrous N,N-dimethylformamide (150 ml) solution of 4-bromomethyl-2-chlorophenyl 2,2-dimethylpropanoate (10 g) at room temperature under stirring over 1 hour, and the mixture was stirred at 80 C. for 1 hour. After cooling, the reaction mixture was poured into ice water, which was extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution and then saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, which afforded 2-chloro-4-(2-2H-1,2,3-triazolyl)-methylphenyl 2,2-dimethylpropanoate.
4-(4-fluoro-phenoxy)-6-(pyridin-3-yloxy)-2-[1,2,4]triazol-1-yl-1H-benzimidazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium hydride; In N,N-dimethyl-formamide; at 160℃;
5.0 mg of sodium hydride was added to a dimethylformamide (0.5 ml) solution of 16 mg of 4-(4-fluoro-phenoxy)-2-methanesulfonyl-6-(pyridin-3-yloxy)-1H-benzimidazole, and then 10.4 mg of [1,2,4]-triazole was added to it, and the reaction liquid was stirred overnight at 160C. The reaction liquid was diluted with ethyl acetate, washed with water and saturated saline in order, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through partitioning thin-layer chromatography (Kieselgel 60F254, Art 5744 (by Merck), ethyl acetate) to obtain the entitled compound. 1HNMR(CDCl3)delta: 6.42(1H,s), 7.03-7.15(3H,m), 7.19(1H,s), 7.27-7.32(3H,m), 8.12(1H,s), 8.32-8.38(2H,m), 9.15(1H,s) ESI-MS(m/e):389[M+H]
With sodium hydride; In N,N-dimethyl-formamide; at 80℃; for 17h;
Sodium hydride (0.61 g) and 2H-1,2,3-triazole (0.7 mL) were added to a solution of tert-butyl 4-[2-fluoro-4-((5R )-5- { [(methylsulfonyl)oxy]methyl} -2-oxo- 1 ,3-oxazolidin- 3-yl)phenyl]piperazine-1-carboxylate (4 g) (which can be prepared according to Example 1 (h) of WO93/23384, page 13) in dry dimethylformamide (15 mL) and the reaction mixture was stirred at 80 C for about 17 hours. The reaction mixture was extracted with ethyl acetate and the organic layer was washed with water, dried over sodium sulfate and concentrated. The crude product thus obtained was purified by column chromatography using (3 %) methanol in dichloromethane as eluent to yield the title compound (0.9 g).
[F] 2-(2,3,5-Tri-O-acetyl-beta -D-ribofuranosyl)-1,2,3-triazole (19) and 1-(2,3,5-tri-O-acetyl-beta -D-ribofuranosyl)-1,2,3-triazole (20). A mixture of 1,2,3-triazole (166 g, 0.024 mol) and 1,2,3,5-tetra-O-acetyl-beta -D-ribofuranose (6.36 g, 0.020 mol) was heated in an oil bath at 145 until a melt was achieved. <strong>[645-15-8]Bis-(p-nitrophenyl)phosphate</strong> (20 mg) was added and heating was continued for 2 hrs. The syrup was cooled, dissolved in chloroform (75 ml) and washed with aqueous 5% sodium bicarbonate (25 ml). The chloroform layer was separated and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the solvent was removed. The syrup was applied to a silica gel column (2.5 * 80 cm) packed in methylene chloride. Elution was with methylene chloride-ethyl acetate (9:1, 4 liters) and fractions of 20 ml were collected. Fractions 50-62 provided 0.68 g of syrup which was shown by nmr to be 19 with a small amount of unreacted sugar: nmr (DMSO-d6) delta 6.34 (d, 1, J1',2' 3.0 Hz, 1'--H), 8.01 (s, 2;4,5--H); (CDCl3) delta 6.25 (d, 1, J1',2' 2.0 Hz, 1'--H), 7.68 (s, 2; 4,5--H).
3,10-dichloro-6-[1,2,3]triazol-2-ylmethyl-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
26%
With potassium carbonate; In dimethyl sulfoxide; at 20℃; for 2h;
EXAMPLE 10 3,10-Dichloro-6-[1,2,3]triazol-2-ylmethyl-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine To a solution of 6-bromomethyl-3,10-dichloro-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine (200 mg, 0.52 mmol) in DMSO (2 mL) was added at ambient temperature 1H-1,2,3-triazole (54 mg, 0.78 mmol) and potassium carbonate (86 mg, 0.62 mmol) and the reaction mixture was stirred for 2 h at this temperature. The resulting mixture was then treated with aqueous ammonium chloride (saturated, 0.5 mL), water (4 mL) and ice (2 g). After stirring for 15 min the suspension was filtered off and washed with water (3 mL). Purification by chromatography (SiO2, heptane:ethyl acetate:dichloromethane:methanol=40:50:10:0 to 0:85:10:5) afforded the title compound (50 mg, 26%) as a white solid. MS m/e: 372.9 [M+H]+.
To a mixture of methyl 6-methoxy-3-[(4-methyl-l-naphthoyl)amino]pyridine-2- carboxylate prepared in Example IE (1.8 g, 5.14 mmol) in CCl4 (100 ml) was added N- bromosuccinimide (0.96 g, 5.39 mmol) and benzoyl peroxide (0.125 g, 0.51 mmol). The reaction mixture was refluxed for 1.5 h under nitrogen. DMF (2.5 ml) and 1,2,3-triazole (2.98 ml, 51.4 mmol) was added, and the reaction mixture was refluxed overnight. After removal of solvents, the residue was suspended in cold water. The formed precipitate was collected, washed with water, air dried and purified by column chromatography on silica gel using first CH2Cl2 and then CH2Cl2MeOH (100:1) as eluent to give 1.55 g (72%) of methyl 6-methoxy-3 - { [4-(1H- 1 ,2,3-triazol- 1 -ylmethyl)-l naphthoyl] amino} pyridine-2- carboxylate. MS (ESI) (M+H)+ 418.13.
methyl 6-methoxy-3-[4-(1H-1,2,3-triazol-1-ylmethyl)-1-naphthoyl]amino}pyrazine-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
~ 39%
iV-Bromosuccinimine (456 mg, 2.56 mmol) and benzoylperoxide (61 mg, 0.25 mmol) was added to a warm (-77 0C) suspension of methyl 6-methoxy-3-[(4-methyl-l- 5 naphthoyl)amino]pyrazine-2-carboxylate, prepared in Example 25F or alternatively in Example 44E3 (883 mg, 2.51 mmol) in CCl4 (60 ml). The resulting reaction mixture was heated at reflux for 2.5 h. Additional amount of benzoylperoxide (catalytic, tip of a spatula) was added and reaction mixture was heated at reflux for a further 12 h. After removal of solvents, the residue was dissolved in EtOAc, washed with water and saturated 0 aqueous NaCl, dried (Na2SO4), and evaporated to give crude benzyl bromide (1.14 g). To this crude benzyl bromide (1.13 g) dissolved in acetonitrile (50 ml) at reflux was added 1,2,3-triazole (0.487 ml, 8.40 mmol) and the resulting mixture was heated at reflux over night (16 h). The solution was then evaporated under reduced pressure, and the residue was purified by revered-phase HPLC (30-»100% MeCN in 0.1M aqueous NH4OAc; followed 5 by 30-»100% MeCN in 0.15% aqueous TFA) to give methyl 6-methoxy-3 -[4-( IH- 1,2,3 - triazol-l-ylmethyl)-l-naphthoyl]amino}pyrazine-2-carboxylate as the corresponding TFA <n="95"/>salt (188 mg - pure and 333 mg - slightly contaminated, ~39% overall yield): MS (ESI) (M+H)+ 418.9.
methyl 5-chloro-6-methoxy-3-[4-(1H-1,2,3-triazol-1-ylmethyl)-1-naphthoyl]amino}pyrazine-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
21%
A mixture of methyl 5-chloro-6-methoxy-3-[(4-methyl-l-naphthoyl)amino]pyrazine-2- carboxylate prepared in Example 25E (0.258 g, 0.67 mmol, 1 eq.), JV-bromosuccinimide (0.123 g, 0.69 mmol, 1.0 eq.) and benzoyl peroxide (0.018 g, 0.07 mmol, 0.11 eq.) in 100 mL carbon tetrachloride was refluxed for 1 h until LC/MS showed that bromination was complete. The reaction mixture was cooled to 50 0C and 1,2,3-triazole (0.245 g, 3.55 mmol, 5.3 eq.) was added. The resulting mixture was stirred at 80 0C for 2 h until LC/MS showed that the reaction was complete. The solvents were removed in vacuo. The residue was dissolved in 10 mL dimethyl sulfoxide. The resulting dimethyl sulfoxide solution was purified by reversed-phase preparative HPLC. Freeze drying gave 0.062 g (21 %) of title compound.1H NMR (400 MHz, DMSO-*) delta (ppm) 3.80 (s, 3H), 4.01 (s, 3H), 5.72 (s, IH), 6.16 (s, 2H), 7.37 (d, J=7.2 Hz, IH), 7.63 (m, 2H), 7.71 (d, J=7.3 Hz, IH), 7.73 (s, IH), 8.18 (s, IH), 8.26 (m, 2H), 11.41 (br s, IH).
2,6-difluoro-N-(4-(oxazol-2-yl)-5-(3-(trifluoromethyl)phenyl)thiazol-2-yl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
73%
With sulfolane; potassium carbonate; at 110℃; for 5h;
Into a solution of acid chloride 69a (100 mg, 0.22 mmol) in 5 ml_ of sulfolane was added 1.2.3-triazole (83 mg, 0.26 mmol) and K2CO3 (70 mg, 0.5 mmol). The solution was stirred under N2 at 1100C for 5 hours, cooled and concentrated under reduced pressure. The residue was partitioned between CH2CI2 and water. The organic phase was dried (Na2SO4), concentrated under reduced pressure. Column chromatography on silica gel (10-100% ethyl acetate in hexanes) gave Compound 91 (74 mg, 73%) as a white solid.1H NMR (300 MHz, CDCI3) delta 10.8 (brs, 1H, NH), 7.83 (s, 1H), 7.78 (d, J = 8.0 Hz, 1 H), 7.70 (d, J = 8.0 Hz, 1 H), 7.58 (t, J = 8.0 Hz, 1 H), 7.52 (brs, 1 H), 7.45 (m, 1H), 7.11 (brs, 1H), 7.96 (t, J = 8.3 Hz, 2H).. MS (ESI) [M+H+]: 452.
With potassium carbonate; In tetrahydrofuran; at 20℃; for 3h;
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, 78%). 1 H NMR (400 MHz, CDCI3) deltappm 7.71 (s, 1 H), 7.55 (s, 1 H), 4.14 (s, 3H).
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃;
A mixture of 1,2, 3-triazole (2.07 g, 30 mmol), benzyl bromoacetate (6.9 g, 30 mmol), and diisopropylethylamine (5,1 ML, 30 mmol) in 40 mL CH2C12 was stirred overnight at room temperature. This mixture was then diluted with ether until no further precipitate formed. The solid was filtered and washed with ether. The filtrate was concentrated and the residue was purified on silica gel using 10% hexane in CH2C12 to give the title compound's isomer, benzyl 2- (2- (1, 2,3-triazolyl) acetate as amorphous solid. Further elution with a solvent mixture containing equal amounts of ether and CH2C12GAVE the title compound as amorphous solid. 1H NMR (400 MHz, CDC13) : 8 2. 251 (s, 2H0, 7.267-7. 390 (m, 5H), 7.723 (s, 1H), 7.785 (s, LH).
2-(1H-1,2,3-triazol-2-yl)-5-methyl-benzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With trans-N,N'-dimethyl-1,2-cyclohexyldiamine; copper(l) iodide; caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 0.166667h;Microwave irradiation;
2-(2H-1.2.3-Triazol-2-yl)-5-methylbenzoic acid (A-8)A solution of 2-iodo-5-methylbenzoic acid (4.0 g, 15.3 mmol) in DMF (10 mL) was treated with 1 ,2,3-triazole (2.1 g, 30.5 mmol), Cs2CO3 (9.95 g, 30.5 mmol), CuI (0.145 g, 0.76 mmol) and trans-N,N'-dimethylcyclohexane-l,2-diamine (0.43 g, 3.05 mmol). The mixture was heated at 120 0C for 10 min in a microwave reactor. The reaction was cooled to room temperature, diluted with water, and washed with EtOAc. The aqueous phase was acidified with IN HCl and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by gradient elution on SiO2 (0 to 10% MeOH in CH2Cl2 with 0.1% AcOH) to give the faster eluting 2-(2H-l,2,3-triazol-2-yl)-5-methylbenzoic acid A-8. followed by the undesired regioisomer isomer, l-(2H-l,2,3-triazol-2-yl)-5-methylbenzoic acid. Data for AJ5: IHNMR (500 MHz, DMSO-d6) d 12.98 (br s , IH), 8.04 (s, 2H), 1.12-1 AS (m, 3H), 2.41 (s, 3H) ppm.
With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 0℃;
Triazole (17 mul_, 0.30 mmol) is added to a chilled (O0C) mixture of NaH (60% dispersion in mineral oil, 11 mg, 0.28 mmol) in DMF (1 ml_). After bubbling ceases, the mixture is transferred via cannula into a vessel containing benzyl chloride 3a4 (110 mg, 0.20 mmol) in DMF (1 mL + 0.5 ml_ wash). The mixture is stirred for about 1 hour at O0C before being allowed to warm to RT and stirring continues for 5 hours. The reaction mixture is diluted in EtOAc and washed with 0.5 N aqueous KHSO4, saturated aqueous NaHCO3 and brine. The organic phase is dried with MgSO4 and filtered. Silica gel is added to the solution and then the mixture is concentrated. The dry packed compound on silica is purified by combiflash to afford the isomeric benzylic triazoles 6a1 and 6a2.
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃;
Alcohol 16a1 (10.5 g, 48 mmol) is combined with triazole (3.42 g, 48 mmol) and triphenylphosphine (14.3 g, 54 mmol) in anhydrous THF (500 mL). The mixture is chilled to O0C and DIAD (10.6 mL, 54 mmol) is added drop-wise. Stirring is continued at O0C for about 1 hour before the mixture is allowed to warm to ambient temperature. The mixture is then stirred overnight. The mixture is diluted in EtOAc and washed with water (500 mL) and brine (500 mL) before being dried of Na2SO4. The solvents are removed under reduced pressure and the residue is subjected to flash chromatography (1 :3 EtOAc/Hex) to afford benzylic triazole 16a2.
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃;
Step 3:Alcohol 16a2 (10.5 g, 48 mmol) is combined with triazole (3.42 g, 48 mmol) and triphenylphosphine (14.3 g, 54 mmol) in anhydrous THF (500 mL) The mixture is chilled to O0C and DIAD (10.6 mL, 54 mmol) is added drop-wise. Stirring continues at O0C for about 1 hour before the mixture is allowed to warm to ambient temperature and is then stirred overnight. The mixture is diluted in EtOAc and washed with water (500 mL) and brine (500 mL) before being dried over Na2SO4. The solvents are removed under reduced pressure and the residue is subject to flash chromatography (1 :3 EtOAc/Hex) to afford benzylic triazole 16a3.
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃;
Step 6:; Alcohol 5a5 (10.5 g, 48 mmol) is combined with triazole (3.42 g, 48 mmol) and triphenylphosphine (14.3 g, 54 mmol) in anhydrous THF (500 ml_). The mixture is chilled to 00C and DIAD (10.6 ml_, 54 mmol) is added dropwise. Stirring continues at O0C for about 1 h before the mixture is allowed to warm to RT and is then stirred overnight. The mixture is diluted in EtOAc and washed with water (500 mL) and brine (500 mL) before being dried over Na2SO4. The solvents are removed under reduced pressure and the residue is subjected to flash chromatography (1 :3 EtOAc/Hex) to afford benzylic triazole 5a7.
With caesium carbonate;copper (I) trifluoromethane sulfonate benzene; (1R,2R)-1,2-diaminocyclohexane; In N,N-dimethyl-formamide; at 120℃;Microwave irradiation; Inert atmosphere; Sealed tube;
Description 123: 3-(2H-l,2,3-triazol-2-yl)-2-pyridinecarbonitrile (D123); DMF (12 ml) was added to a mixture of <strong>[55758-02-6]3-bromo-2-pyridinecarbonitrile</strong> (1.18 g, 6.45 mmol), lH-l,2,3-triazole (0.748 ml, 12.90 mmol), (lR,2R)-N,N'-dimethyl-l,2- cyclohexanediamine (0.183 g, 1.290 mmol), copper(I) trifluoromethanesulfonate benzene complex (0.162 g, 0.322 mmol) and cesium carbonate (4.20 g, 12.90 mmol). The mixture was degassed via 3 vacuum/nitrogen cycles and heated in microwave at 120 0C for 45 minutes. Water was added and the aqueous extracted with EtOAc, the phases were separated on a hydrophobic filter and the combined organic solvent was removed to give the crude product. This was purified by a silica gel chromatography (100 g column, eluted with cyclohexane/EtOAc 0 to 40%) to give a first batch of the title compound D123 (896 mg) as a white solid.Material recovered from the column containing desired product (300 mg) was purified another time (silica gel chromatography 25 g column, eluted with cyclohexane/EtOAc 0 to 35%) to give a second batch of the title compound D123 (100 mg) as a white solid. UPLC (Basic GEN_QC): rt = 0.58 minutes, peak observed: 172 (M+ 1) C8H5N5 requires 171.
With copper(l) iodide; caesium carbonate; In N,N-dimethyl-formamide; at 20 - 120℃;
To a solution of <strong>[1123-99-5]2-iodobenzo[d]thiazole</strong> (130mg, 0.5mmol) and 1,2,3-trizole (35mg, 0.75mmol) in DMF (2ml) was added Cs2CO3 (0.33g, 1mmol) and CuI (19mg, 0.1mmol) at RT and then stirred at 120C for 40h. The reaction solution was extracted with ethyl acetate, washed with brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel column to give white solid (43mg, yield 42.6%). TLC Rf: 0.32 (Hexane/EtOAc=3/1).
With copper(I) trifluoromethanesulfonate benzene; (R,R)-N,N'-dimethyl-1,2-diaminocyclohexane; caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 4h;Inert atmosphere;
A solution of <strong>[717843-48-6]3-bromo-6-methylpyridine-2-carbonitrile</strong> (3 g, 15.23 mmol), lH-l,2,3-triazole (2.103 g, 30.5 mmol), (lR^^-^jV-dimethyl-l^-cyclohexanediamine (0.433 g, 3.05 mmol), cesium carbonate (9.92 g, 30.5 mmol) in dry DMF (30 ml) was degassed with argon bubbling for 5 minutes. Then bis(copper(I)trifluoromethanesulfonate)benzene complex (0.383 g, 0.761 mmol) was finally added and the resulting mixture was further de-gassed with argon bubbling for 30 seconds. Reaction mixture was heated at 120C for 4 hours. Reaction mixture was cooled down to room temperature and water (50 ml) was added. Mixture was taken up with EtOAc (100 ml). Emulsion formed, separation of phases was difficult, so further water 50 ml and EtOAc (50 ml) were added but separation still remained very difficult. Aqueous layer was back extracted with EtOAc (2x50 ml). Combined organic phases were washed with brine (30ml) and evaporated to dryness to get crude material (3.7 g) as thick brown oil that was purified over Si02 Biotage SNAP lOOg (eluting withCy/EtOAc 9/1 to 6/4). Evaporation of solvent afforded 3 fractions:6-methyl-2-pyridinecarbonitrile (0.4 g, 3.39 mmol, 22.24 % yield) as white solid;UPLC (IPQC): rt = 0.60 minutes peak observed: 119 (M+l);D45 6-methyl-3-(lH-l,2,3-triazol-l-yl)-2-pyridinecarbonitrile (0.68 g) as white solid UPLC (IPQC): rt = 0.58 minutes peak observed: 186 (M+l) C9H7N5 requires 185.1H NMR (400 MHz, CHLOROFORM-^ delta ppm 2.74 (s, 3 H) 7.62 (d, 1 H) 7.97 (d, 1 H) 8.22 (d, 1 H) 8.39 (d, 1 H)D46 6-methyl-3-(2H-l,2,3-triazol-2-yl)-2-pyridinecarbonitrile (1 g) as white solidUPLC (IPQC): rt = 0.74 minutes, peak observed: 186 (M+l) C9H7N5 requires 1851H NMR (400 MHz, CHLOROFORM-^ delta ppm 2.71 (s, 3 H) 7.54 (d, 1 H) 7.99 (s, 2 H) 8.34 (d, 1 H)
With N-Bromosuccinimide; potassium carbonate; In Isopropyl acetate; at 20℃; for 5h;
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 2% 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.
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 3h;
207 mg (corresponding to 3.00 mmol) of 1H-1,2,3-triazole was dissolved in 5 mL of dimethylformamide. Then, 200 mg (corresponding to 1.00 mmol) of 5-acetyl-2-bromopyridine and 414 mg (corresponding to 3.00 mmol) of potassium carbonate were added thereto. The resulting solution was heated at 100 C. for 3 hours. After the completion of the reaction, the reaction solution was cooled down to room temperature, supplemented with a saturated ammonium chloride aqueous solution and water, and extracted 3 times with dichloromethane. The combined dichloromethane layer was washed with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (elution solvent: dichloromethane/ethyl acetate=4/1), to obtain 31.9 mg (corresponding to 0.170 mmol) of 5-acetyl-2-(2H-1,2,3-triazole-2-yl)pyridine (FIG. 2, step 1). [0097] NMR apparatus employed: JNM-ECP-500 (manufactured by Japan Electron Optics Laboratory Co., Ltd. (JEOL)) [0098] 1H-NMR (solvent: chlorofolm-d1; resonance frequency: 500 MHz): delta 9.13 (d, J=2.3 Hz, 1H), 8.45 (dd, J=8.6, 2.3 Hz, 1H), 8.21 (d, J=8.6 Hz, 1H), 7.97 (s, 2H), 2.69 (s, 3H).
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 3h;
0073] 207 mg (corresponding to 3.00 mmol) of 1H-1,2,3-triazole was dissolved in 5 mL of dimethylformamide. Then, 200 mg (corresponding to 1.00 mmol) of 5-acetyl-2-bromopyridine and 414 mg (corresponding to 3.00 mmol) of potassium carbonate were added thereto. The resulting solution was heated at 100 C. for 3 hours. After the completion of the reaction, the reaction solution was cooled down to room temperature, supplemented with a saturated ammonium chloride aqueous solution and water, and extracted 3 times with dichloromethane. The combined dichloromethane layer was washed with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (elution solvent: dichloromethane/ethyl acetate=4/1), to obtain 57.2 mg (corresponding to 0.304 mmol) of 5-acetyl-2-(1H-1,2,3-triazole-1-yl)pyridine (FIG. 1, step 1). NMR apparatus employed: JNM-ECP-500 (manufactured by Japan Electron Optics Laboratory Co., Ltd. (JEOL)) [0075] 1H-NMR (solvent: chlorofolm-d1; resonance frequency: 500 MHz): b 9.05 (d, J=2.3 Hz, 1H), 8.65 (d, J=1.1 Hz, 1H), 8.46 (dd, J=8.7, 2.3 Hz, 1H), 8.34 (d, J=8.7 Hz, 1H), 7.86 (d, J=1.1 Hz, 1H), 2.68 (s, 3H)
With copper(l) iodide; potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 160℃; for 13h;Microwave irradiation;
A solution of 1 ,2,3-triazole (63.1 mg, 0.913 mmol), 5-bromo-2-fluorobenzoic acid (100 mg, 0.457 mmol), copper(I) iodide (8.70 mg, 0.046 mmol), and potassium carbonate (126 mg, 0.913 mmol) in NMP (2 mL) was heated to 160 C under microwave radiation for 13 h. The reaction mixture was filtered and purified by HPLC using a reversed phase C 18 column and eluting with a gradient of H20:CH3CN:CF3C02H - 90: 10:0.1 to 5:95:0.1. The desired fractions were concentrated to yield the title compounds in order of elution: 3-fluoro-5-(lH-l ,2,3-triazol- l-yl)benzoic acid [MS: m/z = 208 (M + 1)], 3-bromo-5-(lH-l ,2,3-triazol-l-yl)benzoic acid [MS: m/z = 268, 270 (M + 1)], and 3-fluoro-5-(2H-l ,2,3-triazol-2-yl)benzoic acid [MS: m/z = 208 (M + 1)].
(2-(2H)-1,2,3-triazol-2-yl)thiophene-3-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With copper(l) iodide; potassium carbonate; In N,N-dimethyl-formamide; at 75℃;Inert atmosphere;
EXAMPLE 18 2-(2-[(3i?,6i?)-6-methyl -[2 2H ,2,3-triazol-2-yl)thiophen-3-yl]carbonyl}piperidin-3- yl]oxy} pyridin-3 -yl)propan-2-ol 1 ,2,3-triazole, K2C03, Cul Step 1 : 2-(2H -l,2,3-Triazol-2-yl)thiophene-3-carboxylic acid (10) A solution of <strong>[24287-95-4]2-bromo-3-thiophene carboxylic acid</strong> (1.50 g, 7.24 mmol), 1Eta- 1,2,3-triazole (0.600 g, 8.69 mmol), potassium carbonate (2.00 g, 14.5 mmol), and copper iodide (0.138 g, 0.724 mmol) in DMF (36.2 mL) was purged subsurface with nitrogen and heated to 75 C for 4 nights. The reaction was diluted with water, washed with ether, and acidified with cone. HCl. The acidic aqueous solution was extracted 3x with ethyl acetate and the combined organic fractions were washed with brine, dried over magnesium sulfate, filtered, and concentrated. The crude material was purified by silica gel gradient chromatography [0-70% (1% acetic acid in ethyl acetate) in hexanes], providing the title compound as an off-white solid. LRMS m/z (M+H) 196.2 found, 196.1 required.
With copper(l) iodide; potassium carbonate; In N,N-dimethyl-formamide; at 75℃; for 96h;
A solution of <strong>[24287-95-4]2-bromo-3-thiophene carboxylic acid</strong> (1.50 g, 7.24 mmol), 1H- 1,2,3-triazole (0.600 g, 8.69 mmol), potassium carbonate (2.00 g, 14.5 mmol), and copper iodide (0.138 g, 0.724 mmol) in DMF (36.2 mL) was sparged with nitrogen and heated to 75 C for 96 h. The cooled reaction mixture was diluted with water, washed with ether, and acidified with cone. HCl. The acidic aqueous solution was extracted 3x with EtOAc and the combined organic fractions washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography [0-70% (1% acetic acid in EtOAc) in hexanes], to provide the title compound as an off-white solid. LRMS m/z (M+H) 196.2 found, 196.1 required.
With copper(l) iodide; potassium carbonate; In N,N-dimethyl-formamide; at 75℃; for 96h;Inert atmosphere;
A solution of <strong>[24287-95-4]2-bromo-3-thiophene carboxylic acid</strong> (1.50 g, 7.24 mmol), 1H- 1,2,3-triazole (0.600 g, 8.69 mmol), potassium carbonate (2.00 g, 14.5 mmol), and copper iodide (0.138 g, 0.724 mmol) in DMF (36.2 mL) was sparged with nitrogen and heated to 75C for 96 h. The cooled reaction mixture was diluted with water, washed with ether, and acidified with cone. HC1. The acidic aqueous solution was extracted 3x with EtOAc and the combined organic fractions washed with brine, dried over MgS04, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography [0-70% (1% acetic acid in EtOAc) in hexanes], to provide the title compound as an off-white solid. LRMS m/z (M+H) 196.2 found, 196.1 required.
A solution of <strong>[24287-95-4]2-bromo-3-thiophene carboxylic acid</strong> (1.50 g, 7.24 mmol), 1H-1,2,3- triazole (0.600 g, 8.69 mmol), potassium carbonate (2.00 g, 14.5 mmol), and copper iodide (0.138 g, 0.724 mmol) in DMF (36.2 mL) was purged subsurface with nitrogen and heated to 75 C for 96 h. The reaction was diluted with water, washed with ether, and acidified with cone. HCl. The acidic aqueous solution was extracted 3x with ethyl acetate and the combined organic fractions were washed with brine, dried over magnesium sulfate, filtered, and concentrated. The crude material was purified by silica gel gradient chromatography [0-70% (1% acetic acid in ethyl acetate) in hexanes], providing the title compound as an off-white solid. LRMS m/z (M+H) 196.2 found, 196.1 required.
With copper(l) iodide; potassium carbonate; In N,N-dimethyl-formamide; at 75℃; for 96h;Inert atmosphere;
A solution of <strong>[24287-95-4]2-bromo-3-thiophene carboxylic acid</strong> (1.50 g, 7.24 mmol), 1H-1,2,3-triazole(0.600 g, 8.69 mmol), potassium carbonate (2.00 g, 14.5 mmol), and copper iodide (0.138 g, 0.724 mmol) in DMF (36.2 mL) was purged subsurface with nitrogen and heated to 75C for 96 h. The reaction was diluted with water, washed with ether, and acidified with conc. HC1. The acidic aqueous solution was extracted 3x with EtOAc and the combined organic fractions were washed with brine, dried over magnesium sulfate, filtered, and concentrated. The crude material was purified by silicagel gradient chromatography [0-70% (1% acetic acid in EtOAc) in hexanes], providing the title compound as a solid. LRMS m/z (M+H) 196.2 found, 196.1 required.
With copper(l) iodide; potassium carbonate; In N,N-dimethyl-formamide; at 75℃; for 96h;Inert atmosphere;
A solution of <strong>[24287-95-4]2-bromo-3-thiophene carboxylic acid</strong> (1.50 g, 7.24 mmol), 1H- 1,2,3-triazole (0.600 g, 8.69 mmol), potassium carbonate (2.00 g, 14.5 mmol), and copper iodide (0.138 g, 0.724 mmol) in DMF (36.2 mL) was purged subsurface with nitrogen and heated at 75C for 96 h. The reaction was diluted with water, washed with ether, and acidified with cone. HCI. The acidic aqueous solution was extracted 3x with EtOAc and the combined organic fractions were washed with brine, dried over magnesium sulfate, filtered, and concentrated. The crude material was purified by silica gel gradient chromatography [0-70% (1% acetic acid in EtOAc) in hexanes], providing the title compound as a solid. LRMS m/z (M+H) 196.2 found, 196.1 required.
With copper(l) iodide; potassium carbonate; In N,N-dimethyl-formamide; at 75℃; for 96h;Inert atmosphere;
A solution of <strong>[24287-95-4]2-bromo-3-thiophene carboxylic acid</strong> (1.50 g, 7.24 minol), 111-1,2,3- triazole (0.600 g, 8.69 rnmol), potassium carbonate (2.00 g, 14.5 mmol), and copper iodide(0.138 g, 0.724 inmol) in DMF (36.2 mL) was purged subsurface with nitrogen and heated to75 C for 96 h. The reaction was diluted with water, washed with ether, and acidified with conc.HC1. The acidic aqueous solution was extracted 3x with EtOAc and the combined organic fractions were washed with brine, dried over magnesium sulfate, filtered, and concentrated. The crude material was purified by silica gel gradient chromatography [0-70% (1% acetic acid inEtOAc) in hexanesi, providing the title compound as an off-white solid. LRI?IS m/z (M+H)196.2 found, 196.1 required.
With copper(l) iodide; potassium carbonate; In N,N-dimethyl-formamide; at 75℃; for 96h;Inert atmosphere;
A solution of 2-bromo-3-thiophene carboxyhc acid(i.50 g, 7.24 rnmol), 1JJ 1,2,3-triazole (0.600 g, 8.69 mmoi), potassium carbonate (2.00 g, 14.5 mmol), and copper iodide (0138 g, 0.724 mmol) in DMF (36.2 mL) was purged subsurface with niLrogen and heated to75 C for 96 h. The reaction was diluted with water, washed with ether, and acidified with cone. HCI. The acidic aqueous solution was extracted 3x with EtOAc and the combined organic fractions were washed with brine, dried over magnesium sulfate, filtered, and concentrated, The crude material was purified by silica gel gradient chromatography [0-70% (1% acetic acid in EtOAc) in hexanesj, providing the title compound as a solid. LRMS rn/z (M+H) 196.2 found,196.1 required.
4-(2H-1,2,3-triazol-2-yl)thiophene-3-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With copper(l) iodide; (R,R)-N,N'-dimethyl-1,2-diaminocyclohexane; In N,N-dimethyl-formamide; at 110℃;
To a mixture of the product from step 2 (7.9 g, 38 mmol), cesium carbonate (24.8 g,76 mmol) and Cul (2.88 g, 7.6 mmol) in DMF (200 mL) were added 2H-[l,2,3]triazole (5.24 g,76 mmol) and ,N'-dimethyl-cyclohexane-l,2-diamine (0.9 g, 6.5 mmol) and the mixture was heated to 110C overnight. The cooled reaction mixture was adjusted to ~pH 12 with 1M sodium hydroxide and extracted with EtOAc (50 mL x 3). The aqueous layer was adjusted to ~pH 4 with 1M HCl and extracted with EtOAc (50 mLx4). The extracts was dried over Na2S04, filtered, the filtrate concentrated in vacuo and the residue purified by chromatography on silica (petroleum ether : EtOAc =10: 1) to provide the title compound. LRMS m/z (M+H) 196.0 found, 196.0 required.
With copper(l) iodide; caesium carbonate; cis-N,N'-dimethyl-1,2-diaminocyclohexane; In N,N-dimethyl-formamide; at 110℃;
To a mixture of the product from step 2 (7.9 g, 38 mmol), cesium carbonate (24.8 g,76 mmol) and Cul (2.88 g, 7.6 mmol) in DMF (200 mL) was added 2H-[l,2,3]triazole (5.24 g,76 mmol) and N,N'-dimethyl-cyclohexane-l,2-diamine (0.9 g, 6.5 mmol) and the mixture was stirred at 110C overnight. The cooling mixture was adjusted to ~pH 12 with 1 N NaOH and extracted with EtOAc (50 mL x 3). The aqueous layer was adjusted to ~pH 4 with 1 N HC1 and extracted with EtOAc (50 mL x 4). The combined extracts were dried over sodium sulfate and filtered; the filtrate was concentrated in vacuo and the residue purified by chromatography on silica gel (Petroleum ethenEtOAc =10: 1) to provide the title compound. LRMS m/z (M+H) 196.0 found, 196.0 required.
With (R,R)-N,N'-dimethyl-1,2-diaminocyclohexane; 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 Cul (5.27 g, 27.4 mmol) in DMF (200 mL) were added Nu,Nu'- dimethylcyclohexane-l,2-diamine (3.7 mL,23.3 mmol) and lH-l,2,3-triazole (18.92 g, 274 mmol). The resulting mixture was stirred at 110C 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 Na2S04, 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 as a yellow solid.LRMS m/z (M+H) 208.0 found, 208.0 required.
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 Cul (5.27 g, 27.4 mmol) in DMF (200mL) were added N,N?-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 110C overnight, cooled,concentrated in vacuo and diluted with water (150 mL). The aqueous layer was extracted with EtOAc (300 mLx 3). The aqueous layer was acidified with 2N HC1 and extracted with EtOAc (300mL x 4). The combined organic layers were washed with brine (150 mL x 3), dried over Na2S04, filtered and the filtrate concentrated in vacuo. The residue was purified by chromatography on silica gel (petroleum ether : EtOAc =100: 1 ~ 5 : l) to provide the title compound as a solid. LRMS m/z (M+H) 208.0 found, 208.0 required.
With copper(l) iodide; caesium carbonate; cis-N,N'-dimethyl-1,2-diaminocyclohexane; 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 Cul (5.27 g, 27.4 mmol) in DMF (200 mL) was added Nu,Nu'- dimethylcyclohexane-l,2-diamine (3.7 mL,23.3 mmol) and lH-l,2,3-triazole (18.92 g, 274 mmol). The resulting mixture was stirred at 110C 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 2 N HQ and extracted with EtOAc (300 mL x 4). The combined organic layers were washed with brine (150 mL x 3), dried over sodium sulfate, filtered, and the filtrate concentrated in vacuo. The residue was purified by chromatography on silica gel (petroleum ethenEtOAc = 100: 1 ~ 5: 1) to provide the title compound as a solid. LRMS m/z (M+H) 208.0 found, 208.0 required.
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.
5-fluoro-2-(1H-1,2,3-triazol-1-yl)benzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With copper(l) iodide; caesium carbonate; N,N-dimethylethylenediamine; In N,N-dimethyl-formamide; at 0 - 125℃; for 15h;Microwave irradiation;
Intermediate 20: 5-Fluoro-2-(lH-l,2,3-triazol-l-yl)benzoic acid To the solution of 1,2,3-triazole (4.0 g, 57.97 mmol ) in DMF (14.0 ml) was added cesium carbonate (18.84 g, 57.97 mmol), N,N-dimethylethylenediamine (0.510 g, 5.797 mmol), copper(I) iodide (0.276 g, 1.449 mmol) and <strong>[52548-63-7]2-iodo-5-fluorobenzoic acid</strong> (7.71 g, 28.98 mmol) at 0-10 C. The resulting reaction mixture was then heated with microwave irradiation at 125 C for 15 hours with stirring. The reaction mass was poured into water and the product was extracted into ethyl acetate. The combined organic layers were washed with brine, dried (sodium sulphate) and concentrated in vacuo. The crude mixture was separated by column chromatography (silica, 0-3 % methanol in dichloromethane) to obtain homogeneous 5-fluoro-2-(2H-l,2,3-triazol-2-yl)benzoic acid (also commercially available) and crude 5-fluoro-2-(lH-l,2,3-triazol-l-yl)benzoic acid.The crude compound obtained above was purified again by column chromatography (silica, 0-3 % methanol in dichloromethane) and further purified by preparative HPLC [Shimadzu CBM-20A.UFLC using a Waters 19mm id x 250mm long C18 column X Bridge 5muiotaeta materials at 12 ml/min. Mobile phase: acetonitrile / water (with 25 mM ammonium acetate)] to obtain the title compound. 1H NMR (DMSO-d6): delta ppm 7.41-7.45 (m, 1 H), 7.50-7.52 (m, 1 H), 7.57-7.60 (7.83-7.84 (d, 1 H), 8.42 (s, 1 H)MS ES+: 208
With copper(l) iodide; caesium carbonate; In N,N-dimethyl-formamide; at 40 - 70℃; for 0.5h;
2-lodo-5-methoxy benzoic acid (15.0 g; 53.9 mmol) is dissolved in anhydrous DMF (45 ml)followed by the addition of 1H-1,2,3-triazole (7.452 g; 108 mmol) and cesium carbonate (35.155 g; 108 mmol). By the addition of cesium carbonate the temperature of the reaction mixture increases to 4000 and gas evolved from the reaction mixture. Copper(l)iodide (514 mg; 2.7 mmol) is added. This triggers a strongly exothermic reaction and the temperature of the reaction mixture reaches 70°C within a few seconds. Stirring is continued for 30 minutes.Then the DMF is evaporated under reduced pressure followed by the addition of water (170 ml) and EtOAc (90 ml). The mixture is vigorously stirred and by the addition of citric acid monohydrate the pH is adjusted to 3-4. The precipitate is filtered off and washed with water and EtOAc and discarded. The filtrate is poured into a separation funnel and the phases are separated. The water phase is extracted again with EtOAc. The combined organic layers aredried over Mg504, filtered and the solvent is evaporated to give 7.1 g of 5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid as a white powder of 94percent purity (6 percent impurity is the regioisomerically Ni-linked triazolo-derivative); tR [mm] = 0.60; [M+H] = 220.21
With copper(l) iodide; caesium carbonate; In N,N-dimethyl-formamide; at 40 - 70℃; for 0.5h;
2-lodo-5-methoxy benzoic acid (15.0 g; 53.9 mmol) is dissolved in anhydrous DMF (45 ml) followed by the addition of 1H-1,2,3-triazole (7.452 g; 108 mmol) and cesium carbonate (35.155 g; 108 mmol). By the addition of cesium carbonate the temperature of the reaction mixture increases to 40°C and gas evolved from the reaction mixture. Copper(l)iodide (514 mg; 2.7 mmol) is added. This triggers a strongly exothermic reaction and the temperature ofthe reaction mixture reaches 70°C within a few seconds. Stirring is continued for 30 minutes. Then the DMF is evaporated under reduced pressure followed by the addition of water (170 ml) and EtOAc (90 ml). The mixture is vigorously stirred and by the addition of citric acid monohydrate the pH is adjusted to 3-4. The precipitate is filtered off and washed with water and EtOAc and discarded. The filtrate is poured into a separation funnel and the phases are separated. The water phase is extracted again with EtOAc. The combined organic layers are dried over MgSO4, filtered and the solvent is evaporated to give 7.1 g of 5-methoxy-2-(2H- 1 ,2,3-triazol-2-yl)benzoic acid as a white powder of 94percent purity (6 percent impurity is the regioisomerically Ni-linked triazolo-derivative); tR [mm] = 0.60; [M+H] = 220.21.
4-(dimethoxymethyl)-2-(1H-[1,2,3]triazol-1-yl)pyrimidine[ No CAS ]
4-(dimethoxymethyl)-2-(1H-[1,2,3]triazol-2-yl)pyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In acetone; at 20℃; for 2h;
To the solution of 829 mg 1H-[l,2,3ltriazolc (12.0 mmol) in acetone 2.07 g K2C03 (15.0 mmol), then Preparation 9a3 were added and the mixture was stirred for 2h at room temperature. The reaction mixture was filtered and concentrated under reduced pressure.The residue was purified via flash chromatography using heptane and ethyl-acetate aseluents to give 4-(dimethoxymethyl)-2-(lH-[l ,2,3]triazol-l-yl)pyrimidine as whitecrystals.111 NMR (400 MHz, DMSO-d6): 9.06 (d, 111), 8,89 (d, 111), 8.01 (d, 111), 7.70 (d, 111),5.44 (s, IH), 3.40 (s, 611). Note: 4-(dimethoxymethyl)-2-( 1H-[ 1 ,2,3]triazol-2-yl)pyrimidine was also obtained.?H NMR (400 MHz, DMSO-d6): 9.03 (d, 111), 8.24 (s, 2H), 7.66 (d, 111), 5.42 (s, 1H),(s, 611).
methyl 6-chloro-3-(2H-1,2,3-triazol-2-yl)picolinate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1.8 g
To a stirred suspension of <strong>[929000-66-8]3-bromo-6-chloropyridine-2-carboxylic acid</strong> (3.6 g, 15. mmol) in 1 ,4-dioxane (35 mL) was added (1 R,2R)-N,N-dimethylcyclohexane-1 ,2- diamine (220 mg, 1 .5 mol), Cs2C03 (10 g, 31 mmol), 1 H-1 ,2,3-triazole (2.1 g, 31 mmol), water (0.3 mL) and the mixture was degassed under nitrogen for 10 mins. Cul (295 mg, 1.6 mmol) was added and the mixture was heated at 100C for 6 hrs. The reaction mixture was then allowed to cool to ambient temperature, and concentrated in vacuo. MeOH (20 mL) was added to the residue and the mixture was acidified to pH 2 with 6N hydrochloric acid (approx 6 mL) and concentrated in vacuo. MeOH (20 mL) was added to the residue and concentrated in vacuo (x2). The residue was dissolved in MeOH (15 mL) and DCM (35 mL) and cooled to 0C. TMS diazomethane (39 mL, 77 mmol) was added dropwise (over 15 mins) and the reaction mixture was stirred at ambient temperature for 18 hrs. The reaction mixture was concentrated in vacuo. The crude product was purified by chromatography on the Biotage Isolera Four (100 g column, 10 to 80% EtOAc in heptane) to afford the title compound as an oil (1 .8 g). LCMS (Method G): 1 .03 min, 239 [M+H]+
With copper(l) iodide; caesium carbonate; cis-N,N'-dimethyl-1,2-diaminocyclohexane; In dimethyl sulfoxide; at 120℃;Inert atmosphere;
Step 1: 3-(211- I ,23-triazoi-2-yI)picolinic acidTo a solution of 3-brornonicotinic acid (1.4 g, 6.93 mrnoi) in DMS() (14 mL) wasadded 21-I-1,2,34riazole (0.718 g, 10.40 mmoi), cesium carbonate (4.74 g, 14.55 rnrnol), copper(1)iodide (0132 g, 0.693 mnioi), and Ni,N2-dimethyicyclohexane-i,2-diamine (0.099 g, 0.693mmoi) and the reaction mixture sparged with nitrogen and stirred at 120 C overnight. Thecooled reaction mixture was diluted with 1 N NaOH (15 mL) and washed with EtOAc (15 mL).The aqueous layer was acidified with 12 N HC1 and exLracted with ELOAc (4 x 20 mL). The combined organic layers were washed with brine, dried over NaSO4, filered, and the solvent was evaporated in vacuo. The crude product was purfied by chromatography on silica (0-100% (EtOAc 5% AcOH in ELOAc). The purified fractions were combined and azetroped withtoluene (3 x 100 mL) to give 3-(2H-i,2,3-triazol-2-yi)picoiinic acid as a solid. LSMS m/z (M+H)191.05 found, 191.05 required.
2-[2-(2H-1,2,3-triazol-2-yl)ethoxy]-1H-isoindole-1,3(2H)-dione[ No CAS ]
2-[2-(1H-1,2,3-triazol-1-yl)ethoxy]-1H-isoindole-1,3(2H)-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 17h;
To a clean dry flask containing suspension of 2-(2-bromoethoxy)isoindoline- l,3-dione (30 g, 0.111 mol), 1H- 1,2,3 triazole (7.66 g, 111 mmol) in dimethylformamide (150 ml) was added cesium carbonate ((36 g, 111 mmol) portion wise at room temperature under stirring. After 17 hours, the reaction mixture was filtered and filtrate was slowly poured into chilled water (1050 ml) under stirring. After 30 minutes of stirring, the separated precipitates were collected by filtration and washed with water (100 ml). The collected precipitates were dried at 40 C for 2 hours under high vacuum to obtain 18.5 g of a mixture of 2-[2-(2H- l,2,3-triazol-2-yl)ethoxy]- lH-isoindole- l,3(2H)-dione and 2-[2- (lH- l,2,3-triazol- l-yl)ethoxy]- lH-isoindole- l,3(2H)-dione as a white compound in 65% yield. Analysis: Mass: 259.2 (M+l); for Molecular weight: 258 and Molecular formula: C12H10N4O3
To a clean dry flask containing suspension of 2-(2-bromoethoxy)isoindoline- l,3-dione (30 g, 0.111 mol), 1H- 1,2,3 triazole (7.66 g, 111 mmol) in dimethylformamide (150 ml) was added cesium carbonate ((36 g, 111 mmol) portion wise at room temperature under stirring. After 17 hours, the reaction mixture was filtered and filtrate was slowly poured into chilled water (1050 ml) under stirring. After 30 minutes of stirring, the separated precipitates were collected by filtration and washed with water (100 ml). The collected precipitates were dried at 40 C for 2 hours under high vacuum to obtain 18.5 g of a mixture of 2-[2-(2H- l,2,3-triazol-2-yl)ethoxy]- lH-isoindole- l,3(2H)-dione and 2-[2- (lH- l,2,3-triazol- l-yl)ethoxy]- lH-isoindole- l,3(2H)-dione as a white compound in 65% yield. Analysis: Mass: 259.2 (M+l); for Molecular weight: 258 and Molecular formula: C12H10N4O3; To a solution of mixture of 2-(2-(2H-l,2,3-triazol-2- yl)ethoxy)isoindoline-l,3-dione and 2-(2-(lH-l,2,3-triazol-l-yl)ethoxy)isoindoline-l,3-dione (13 g, 50.3 mmol, obtained from Step 1) in dichloromethane (130 ml) was added hydrazine hydrate (3.7 ml, 75.7 mmol) under stirring at room temperature. After 2 hours, the progress of reaction was monitored by thin layer chromatography using mixture of chloroform and methanol as solvent system. After completion of the reaction the unwanted solid was filtered out and washed with dichloromethane (25 ml). The collective filtrates were concentrated at 40 C under high vacuum to dryness to provide 6.5 g of a mixture of 2-[2-(aminooxy)ethyl]-2H-l,2,3-triazole and l-[2- (aminooxy)ethyl]-lH-l,2,3-triazole, which was used as such in the next step without any further purification
sodium salt (2S,5R)-trans-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid[ No CAS ]
(2S,5R)-6-(benzyloxy)-7-oxo-N-[2-(2H-1,2,3-triazol-2-yl)ethoxy]-1,6-diazabicyclo[3.2.1]octane-2-carboxamide[ No CAS ]
(2S,5R)-6-(benzyloxy)-7-oxo-N-[2-(1H-1,2,3-triazol-1-yl)ethoxy]-1,6-diazabicyclo[3.2.1]octane-2-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
To a clean dry flask containing suspension of 2-(2-bromoethoxy)isoindoline- l,3-dione (30 g, 0.111 mol), 1H- 1,2,3 triazole (7.66 g, 111 mmol) in dimethylformamide (150 ml) was added cesium carbonate ((36 g, 111 mmol) portion wise at room temperature under stirring. After 17 hours, the reaction mixture was filtered and filtrate was slowly poured into chilled water (1050 ml) under stirring. After 30 minutes of stirring, the separated precipitates were collected by filtration and washed with water (100 ml). The collected precipitates were dried at 40 C for 2 hours under high vacuum to obtain 18.5 g of a mixture of 2-[2-(2H- l,2,3-triazol-2-yl)ethoxy]- lH-isoindole- l,3(2H)-dione and 2-[2- (lH- l,2,3-triazol- l-yl)ethoxy]- lH-isoindole- l,3(2H)-dione as a white compound in 65% yield. Analysis: Mass: 259.2 (M+l); for Molecular weight: 258 and Molecular formula: C12H10N4O3; To a solution of mixture of 2-(2-(2H-l,2,3-triazol-2- yl)ethoxy)isoindoline-l,3-dione and 2-(2-(lH-l,2,3-triazol-l-yl)ethoxy)isoindoline-l,3-dione (13 g, 50.3 mmol, obtained from Step 1) in dichloromethane (130 ml) was added hydrazine hydrate (3.7 ml, 75.7 mmol) under stirring at room temperature. After 2 hours, the progress of reaction was monitored by thin layer chromatography using mixture of chloroform and methanol as solvent system. After completion of the reaction the unwanted solid was filtered out and washed with dichloromethane (25 ml). The collective filtrates were concentrated at 40 C under high vacuum to dryness to provide 6.5 g of a mixture of 2-[2-(aminooxy)ethyl]-2H-l,2,3-triazole and l-[2- (aminooxy)ethyl]-lH-l,2,3-triazole, which was used as such in the next step without any further purification; To a solution of sodium salt of (25,5 ?)-6-(benzyloxy)-7-oxo-l,6-diaza-bicyclo[3.2.1]octane-2-carboxylic acid (15 g, 54.3 mmol, prepared as per the procedure disclosed in International Patent Application No. PCT/IB2013/059264) in dimethylformamide (75 ml) was added EDC.HC1 (15.6 g, 81.6 mmol) at ambient temperature under stirring. Then N-methyl morpholine (16.5 ml, 0.150 moles) was added followed by HOBT (7.73 g, 50.7 mmol) and reaction mixture was stirred for 5 minutes at ambient temperature. To this reaction mixture was added a solution of mixture of 2-[2-(aminooxy)ethyl]- 2H-l,2,3-triazole and l-[2-(aminooxy)ethyl]-lH-l,2,3-triazole (6.5 g, product from Step 2) in dimethylformamide (6.5 ml) under stirring at 15 C and then allowed to attain room temperature. The progress of reaction was monitored by thin layer chromatography using mixture of chloroform and methanol (9: 1) as solvent system. After completion of the reaction (17 hours), the resulted reaction mixture was slowly poured into chilled water (500 ml) and extracted with ethyl acetate (2x150 ml). The combined organic layer was washed with brine (75 ml) and organic layer was dried over anhydrous sodium sulfate, concentrated on rotavapour to provide 17.5 g of crude compound. It was purified by column chromatography (silica gel 60-120 mesh) using mixture of hexane and acetone as an eluent. The upper spot containing fractions were collected at 30-40% concentration of acetone in hexane and concentrated to dryness under vacuum to provide7.5 g of (25,5 ?)-6-(benzyloxy)-7-oxo-N-[2-(2H-l,2,3-triazol-2-yl)ethoxy]-l,6-diazabicyclo [3.2.1]octane-2- carboxamide. Similarly lower spot containing fractions collected at 40-50% concentration of acetone in hexane were concentrated to dryness under vacuum to provide 5.2 g of of (25,5 ?)-6- (benzyloxy)-7-oxo-N-[2-(lH-l,2,3-triazol-l-yl)ethoxy]-l,6-diazabicyclo[3.2.1]octane-2- carboxamide. In total, 12.7 g was obtained in 70% yield. Analysis: Mass: 385.3 (M-l); for Molecular weight: 386 and Molecular formula: C18H22N6O4.
1-(4-(4-(1H-1,2,4-triazol-1-yl)phenoxy)phenyl)-1Η-1,2,4-triazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; copper(II) oxide; at 80 - 200℃;
As described in the invention1- (4- (4- (1H-1,2,4-triazol-1-yl) phenoxy) phenyl) -1H-1,2,4-triazoleOf the preparation method, which is characterized by the "one pot"In a polar solvent, 1,1,2,2-tetrakis (4-bromophenyl) ethylene, triazole,Potassium carbonate and copper oxide in the heating conditions to prepare the organic compounds;The molar ratio of <strong>[2050-47-7]4,4'-dibromodiphenyl ether</strong>: triazole: potassium carbonate: copper oxide is 2: 10: 30: 1;The molar ratio of <strong>[2050-47-7]4,4'-dibromodiphenyl ether</strong>: triazole: potassium carbonate: copper oxide is 2: 10: 30: 1 in the present invention;Temperature 80-200 , reaction time 12-120 hours.The preparation of the present invention is as follows:Preparation of 1- (4- (4- (1H-1,2,4-triazol-1-yl) phenoxy) phenyl) -1H-1,2,4-triazoleThe method is characterized in that the organic compound is prepared by heating the <strong>[2050-47-7]4,4'-dibromodiphenyl ether</strong>, triazole, potassium carbonate and copper oxide under heating under a "one pot" method in a polar solvent;
With 1,1,2,2-tetrakis(4-bromophenyl)ethene; potassium carbonate; copper(II) oxide; at 150℃; for 12h;
he organic compound is prepared by heating 1,1,2,2-tetrakis(4-bromophenyl)ethylene, triazole, potassium carbonate, and copper oxide in a polar solvent; wherein 4,4?-dibromo The diphenyl ether: triazole: potassium carbonate: copper oxide molar ratio of 2:10:30:1; The reaction temperature was 150C and the reaction time was 12 hours
With 1,1,2,2-tetrakis(4-bromophenyl)ethene; potassium carbonate; copper(II) oxide; at 150℃; for 18h;
Preparation of 1-(4-(4-(1H-1,2,4-triazol-1-yl)phenoxy)phenyl)-1H-1,2,4-triazole according to the present invention The method is characterized by adopting a "one pot method" in which 1,1,2,2-tetrakis(4-bromophenyl)ethylene, triazole, potassium carbonate and copper oxide are prepared under heating conditions in a polar solvent. The organic compound; wherein 4,4 '- dibromodiphenyl ether: triazole: potassium carbonate: copper oxide molar ratio of 2:10:30:1; In a polar solvent, the organic compound is prepared using a "one pot method" of <strong>[2050-47-7]4,4'-dibromodiphenyl ether</strong>, triazole, potassium carbonate and copper oxide under heating conditions; preferably 4,4'-dibromo The molar ratio of diphenyl ether:triazole:potassium carbonate:copper oxide is 2:10:30:1; the reaction temperature is 150 C., and the reaction time is 18 hours.
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, 33%, based onsodium azide) was isolated by recondensation (5·10-3 mbar) at room temperature.
4-chloro-2-(1H-1,2,3-triazol-1-yl)benzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
0.345 g
With copper(l) iodide; (R,R)-N,N'-dimethyl-1,2-diaminocyclohexane; caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 0.166667h;Microwave irradiation;
A mixture of <strong>[936-08-3]2-bromo-4-chlorobenzoic acid</strong> (1.39 g), 1H-1,2,3-triazole (0.855 mL), copper(I) iodide (0.337 g), (1R,2R)-N,N'-dimethylcyclohexane-1,2-diamine (0.283 mL), cesium carbonate (3.85 g) and N,N-dimethylformamide (4 mL) was stirred in a microwave reactor at 100° C. for 10 min. To the reaction mixture was added 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. To the residue was added diisopropyl ether, and the obtained solid was collected by filtration to give the title compound (0.345 g). 1H NMR (300 MHz, DMSO-d6) delta 7.62-7.87 (2H, m), 7.87-8.03 (2H, m), 8.56 (1H, s), 13.30 (1H, brs).
With copper(l) iodide; N,N,N,N,-tetramethylethylenediamine; potassium carbonate; In N,N-dimethyl-formamide; at 100℃;
To a solution of <strong>[52548-63-7]5-fluoro-2-iodobenzoic acid</strong> (17 g) obtained in Step A of Reference Example 1, copper(I) iodide (2.434 g), potassium carbonate (26.5 g) and N,N,N?,N?tetramethylethylene diamine (3.83 mE) in N,N-dimethylformamide (200 mE) was added 1H-1,2,3-triazole (11.11 mE), and the mixture was stirred overnight at 1000 C. The reaction mixture was filtered through Celite, to the filtrate was added 6N aqueous hydrochloric acid solution at 0 C., and the mixture was extracted with ethyl acetate. The obtained organic layer was washed successively with saturated aqueous sodium thiosulfate solution and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ ethyl acetate) to give the title compound (5.6 g). 1H NMR (300 MHz, DMSO-d6) delta 7.52-7.69 (2H, m), 7.81 (1H, dd, J=8.7, 4.9 Hz), 8.08 (2H, s), 13.35 (1H,brs).
3-bromo-5-nitro-2-(2H-1,2,3-triazol-2-yl)pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
45.7%
With potassium carbonate; In acetonitrile; at 50℃; for 12h;
A solution of <strong>[5470-17-7]3-bromo-2-chloro-5-nitropyridine</strong> (1 g, 4.21 mmol), 1H-1,2,3-triazole (582 mg, 8.42 mmol), K2CO3 (1.74 g, 12.64 mmol) in CH3CN (30 mL) was stirred at 50 C. for 12 h. The mixture was concentrated under reduced pressure, the crude product was purified by column chromatography over silica gel (petroleum ether/ethyl acetate from 20:1 to 1:1). The desired fractions were collected and the solvent was concentrated under reduced pressure to afford 3-bromo-5-nitro-2-(2H-1,2,3-triazol-2-yl)pyridine, 139a (520 mg, 45.7%) as a yellow solid. LCMS (ESI) m/z M+1: 272.1.
5-phenylmethoxy-2-(triazol-1-yl)pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
39.7 mg
With copper(l) iodide; N,N`-dimethylethylenediamine; In N,N-dimethyl-formamide; at 120℃; for 1h;Inert atmosphere; Microwave irradiation;
(1) The compound (501 mg) obtained in Reference Example 1-1-(1), 1,2,3-triazole (196 mg), copper iodide (I) (72.3 mg), N,N'-dimethylethylenediamine (0.102 mL), and potassium phosphate (1.20 g) were suspended in N,N-dimethylformamide (9 mL), and the mixture was deaerated, so that the air in the container was purged with nitrogen. The mixture was stirred under microwave irradiation at 120C for 1 hour, cooled to room temperature, and then subjected to removal of insolubles by celite filtration and washing with ethyl acetate. The filtrate and washing solution were mixed, and the mixture was washed with an aqueous solution of saturated ammonium chloride, water, and then brine, and the organic layer was separated by a phase separator and then concentrated under reduced pressure. The obtained residue was purified by preparative HPLC and then preparative thin layer chromatography (n-hexane/ethyl acetate = 7:3) to give 5-phenylmethoxy-2-(triazol-1-yl)pyridine (39.7 mg) as a colorless powder.
6-chloro-4-methoxy-3-(2H-1,2,3-triazol-2-yl)pyridazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
41%
With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 180℃; for 2h;Microwave irradiation; Inert atmosphere;
DIPEA (3.9 mL, 22.4 mmol) was added to solution of <strong>[70952-62-4]3,6-dichloro-4-methoxypyridazine</strong> (2.0 g, 1 1.2 mmol) in DMSO (6 mL) followed by addition of 1H-1,2,3-triazole (930 mg, 13 mmol). The resulting mixture was heated at 180 C for 2 h in a microwave, until reaction was deemed completed as judged by TLC (~2 h), then diluted with water (30 mL). The aqueous layer was extracted with EtOAc (2 x 30 mL), the organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica (100-200 mesh), eluted at 3-5% MeOH in DCM which gave the title compound (1.0 g, 41 %) as a solid with 97.13% LCMS purity. MS (ES+) 212.16 [M+H]+.
5-chloro-2-[1,2,3]triazol-2-ylnicotinic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With copper(l) iodide; caesium carbonate; In 1,4-dioxane; water; at 100℃; for 12h;
A mixture of A-7.1 (9.50 g, 40.2 mmol), A-6.8 (3.33 g, 48.21 mmol), Cul (0.58 g, 4.02 mmol) andCsCO3 (14.26 g, 44.20 mmol) in Dioxane (200 mL) and water (10 mL) is heated to 10000 for 12h. The mixture is acidified with HCI (0.5 M aq. solution) to pH=2. The mixture is extracted with EA, the organic phase is washed with brine, dried and concentrated to give the crude product 5.0 g of A-7. ESI-MS: 225 [M+H] TLC (Rf): 0.1(silica gel; DCM/MeOH 10/1)
With copper(l) iodide; (R,R)-N,N'-dimethyl-1,2-diaminocyclohexane; caesium carbonate; In 1,4-dioxane; water; at 100℃; for 2.5h;
In a MW tube was added 4-fluoro-2-iodobenzoic acid (600 mg, 1.88 mmol), 1 H-1 ,2,3- Triazole (0.22 ml_, 3.76 mmol) and (1 R,2R)-N 1 ,N2-dimethylcyclohexane-1 ,2-diamine (0.06 ml_, 0.38 mmol). To these solids were added 1 ,4-Dioxane (2 ml_) and Water (0.2 ml_), then Cul (18 mg, 0.09 mmol) and finally Cs2C03 (1 .22 g, 3.76 mmol). The mixture was then warmed to 100 C for 2.5 hrs and left at RT O/N . HCI 6 N was added until pH 2, then volatiles were removed under vacuum and the crude material was purified by RP on C18 column (from H20/CH3CN 95:5 + 0.1 % of FA to H20/CH3CN 5:95 + 0.1 % of FA) affording 4-fluoro-2-(2H-1 ,2,3-triazol-2-yl)benzoic acid (p185, 250 mg, y= 64%) as white solid. MS (m/z): 206.3 [M-H]"