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Structure of 288-88-0 * Storage: {[proInfo.prStorage]}
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Step 1. 250 mmol of dimethyl carbonate was added to a mixture of 50 mmol of 1,2,4-triazole and 12.5 mmol of sodium carbonate, and the resulting suspension was stirred at 120 ° C under a nitrogen atmosphere and refluxed for 16 h. Volatilization in the residual liquid in the vacuumWashing the residue with chloroform, filtering solid impurities, and spinning the filtrate.4.74 g of 4-methyl-1,2,4-triazole was obtained as a colorless liquid.
Reference：
[1] Patent: CN108250227, 2018, A, . Location in patent: Paragraph 0025; 0028
Reference：
[1] Justus Liebigs Annalen der Chemie, 1957, vol. 609, p. 75,82
8
[ 288-88-0 ]
[ 75-03-6 ]
[ 16778-70-4 ]
Yield
Reaction Conditions
Operation in experiment
70%
With 1,8-diazabicyclo[5.4.0]undec-7-ene In tetrahydrofuran at 20℃; Cooling with ice
Example 3. Synthesis of 1 -Ethyl- 1 H- 1.2,4-triazole (26a).Scheme 6. Preparation of Intermediate 26a.\\16a 18a 26a[111] Step 1. l-Ethyl-lH-l,2,4-triazole d8a): To an ice-cold solution of 1,2,4- triazole (5 g, 72.4 mmol) in anhydrous TΗF (50 mL) was added ethyl iodide (7 mL, 86.9 mmol). DBU (10.8 mL, 72.4 mmol) was added dropwise to the cloudy system over 10-20 min. The reaction was allowed to slowly warm to room temperature and was stirred overnight. The mixture was filtered through a Celite pad and the filtrate was concentrated under reduced pressure to give 10 g of crude material as a yellow liquid. The crude material was Kugelrohr-distilled (at approximately 300 mtorr, 35- 40 0C) to provide 4.9 g (70percent) of 18a as clear liquid.
Reference：
[1] Patent: WO2011/5520, 2011, A1, . Location in patent: Page/Page column 31-32
[2] European Journal of Organic Chemistry, 2018, vol. 2018, # 31, p. 4331 - 4337
[3] Journal of Medicinal Chemistry, 2005, vol. 48, # 23, p. 7089 - 7092
[4] Patent: WO2010/67125, 2010, A1, . Location in patent: Page/Page column 85
9
[ 288-88-0 ]
[ 74-96-4 ]
[ 16778-70-4 ]
Yield
Reaction Conditions
Operation in experiment
4.47 g
Stage #1: With sodium ethanolate In ethanol at 30℃; for 0.666667 h; Stage #2: at 75℃; for 14 h;
adding 60 mmol of sodium ethoxide into 50 mmol of 1, 2, 4-triazole (shown in the formula II)) and 50 mL of ethanol solution, stirring for 40 minutes at the temperature of 30 DEG c, and dropwise adding 60 mmol of bromoethane, carrying out condensation reflux for 14 hours at the temperature of 75 DEG c, removing volatile matters in the reaction raffinate, washing the dichloromethane, and filtering the solid impurities, and carrying out rotary evaporation to remove the washing solvent to obtain colorless liquid 1-ethyl -1,2,4-triazole 4.47 g
Reference：
[1] Gazzetta Chimica Italiana, 1905, vol. 35 I, p. 378
[2] Journal of Organic Chemistry, 2013, vol. 78, # 8, p. 4196 - 4201
[3] Journal of Physical Chemistry B, 2014, vol. 118, # 33, p. 9944 - 9951
[4] Patent: CN108484654, 2018, A, . Location in patent: Paragraph 0027; 0030
With copper(II) acetate monohydrate; caesium carbonate In N,N-dimethyl-formamide at 110℃; for 24 h; Inert atmosphere
General procedure: To a solution of Cu(OAc)2*H2O (0.01 mmol) in DMF (2 mL) were added aryl iodide (1.2 mmol), nitrogen-containing heterocycle (1.0 mmol), and Cs2CO3 (2 mmol) under nitrogen atmosphere. The mixture was stirred at 110 °C for 24 h. After cooling to ambient temperature, the mixture was partitioned between water and ethyl acetate. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel.
With potassium phosphate; copper(l) iodide; N,N`-dimethylethylenediamine In N,N-dimethyl-formamide at 110℃; for 72 h; Inert atmosphere
General procedure: A mixture of CuI (0.10 g, 0.50 mmol), the required azole(10 mmol), K3PO4 (4.4 g, 20 mmol), the required halide (12 mmol)and N,N0-dimethylethylenediamine (0.11 mL, 1.0 mmol) in DMF(5 mL) was degased and heated under argon at 110 C for 72 h.After filtration over celite (washing using AcOEt) and removal ofthe solvents, the crude product is purified by chromatography oversilica gel (the eluent is given in the product description). 4.3.1 1-Phenyl-1H-1,2,4-triazole (2a) Compound 2a was prepared from 1,2,4-triazole (0.69 g) and iodobenzene (1.4 mL) using the general procedure 1, and was isolated (eluent: heptane/AcOEt 7:3) in 96percent yield as a yellow powder: mp 48 °C (lit. 28 46 °C); 1H NMR (CDCl3, 300 MHz) 7.42 (m, 1H), 7.53 (m, 2H), 7.71 (m, 2H), 8.15 (s, 1H), 8.74 (s, 1H); 13C NMR (CDCl3, 75 MHz) 120.1 (2CH), 128.3 (CH), 129.9 (2CH), 137.1 (C), 140.9 (CH), 152.7 (CH).
91%
With caesium carbonate In DMF (N,N-dimethyl-formamide) at 50 - 82℃; for 24 - 72 h;
Example 1.17 [0636] Preparation of 1-phenyl-1H-1,2,41 triazole [0637] Operating protocol A (82 C., 48 hours) was followed using 117 mg of Chxn-Py-Al (0.4 mmoles), 336 ?l of iodobenzene (3 mmoles), 138 mg of 1,2,4-triazole (2 mmoles), 1.042 g of caesium carbonate (3.2 mmoles) and 1.2 ml of DMF. [0638] The degree of transformation and selectivity were 100percent and 98percent respectively. [0639] The residue obtained following treatment was purified by silica gel chromatography (eluent: hexane/dichloromethane, 100/0 to 50/50). [0640] 264 mg of a dark yellow solid was obtained in a yield of 91percent. [0641] Pale yellow needles were obtained after re-crystallisation from chloroform. [0642] The compound obtained had the following formula: [CHEMMOL-00056] [0643] The characteristics were as follows: [0644] MPt: 46 C. (CHCl3) (Lit: 46-47 C. given by Micetich, R G; Spevak, P; Hall, T W; Bains, B K; Heterocycles 1985, 23, 1645-1649); [0645] H NMR/CDCl3:? 8.52 (wide s, 1H, HI), 8.04 (wide s, 1H, H2), 7.53-7.65 (m, 2H, H4,8), 7.26-7.51 (m, 3H, H5,6,7); [0646] 13C NMR/CDCl3: ? 152.55 (C1), 140.88 (C2), 139.96 (C3), 129.73 (C5 and C7), 128.15 (C6), 119.99 (C4 and C8); [0647] GC/MS: Rt=14.02 min, M/Z=145, purity=100percent; [0648] Rf=0.21 (eluent: dichloromethane/ethyl acetate, 90/10). Example 1.18 [0649] Preparation of 1-phenyl-1H-[1,2,4]triazole [0650] Operating protocol A (82 C., 24 hours) was followed using 117 mg of Chxn-Py-Al (0.4 mmoles), 336 ?l of iodobenzene (3 mmoles), 138 mg of 1,2,4-triazole (2 mmoles), 1.042 g of caesium carbonate (3.2 mmoles) and 1.2 ml of DMF. [0651] The degree of transformation and selectivity were 79percent and 99percent respectively. [CHEMMOL-00057] Example 1.19 [0652] Preparation of 1-phenyl-1H-[1,2,4]triazole Example 1.18 was repeated, operating at 50 C. (72 hours). The degree of transformation and selectivity for 1-phenyl-1H-[1,2,4-triazole] were 75percent and 99percent respectively. [0653] [CHEMMOL-00058]
91%
Stage #1: at 100℃; Stage #2: at 50 - 82℃; for 24 - 72 h;
Operating protocol A (82° C., 48 hours) was followed using 117 mg of Chxn-Py-Al (0.4 mmoles), 336 μl of iodobenzene (3 mmoles), 138 mg of 1,2,4-triazole (2 mmoles), 1.042 g of caesium carbonate (3.2 mmoles) and 1.2 ml of DMF. The degree of transformation and selectivity were 100percent and 98percent respectively. The residue obtained following treatment was purified by silica gel chromatography (eluent: hexane/dichloromethane, 100/0 to 50/50). 264 mg of a dark yellow solid was obtained in a yield of 91percent. Pale yellow needles were obtained after re-crystallisation from chloroform. The compound obtained had the following formula: The characteristics were as follows: MPt: 46° C. (CHCl3) (Lit: 46-47° C. given by Micetich, R G; Spevak, P; Hall, T W; Bains, B K; Heterocycles 1985, 23, 1645-1649); 1H NMR/CDCl3: δ8.52 (wide s, 1H, H1), 8.04 (wide s, 1H, H2), 7.53-7.65 (m, 2H, H4,8), 7.26-7.51 (m, 3H, H5,6,7); 13C NMR/CDCl3: δ 152.55 (C1), 140.88 (C2), 139.96 (C3), 129.73 (C5 and C7), 128.15 (C6), 119.99 (C4 and C8); GC/MS: Rt=14.02 min, M/Z=145, purity=100percent; Rf=0.21 (eluent: dichloromethane/ethyl acetate, 90/10). Example 1.18; Preparation of 1-phenyl-1H-[1,2,4]triazole; Operating protocol A (82° C., 24 hours) was followed using 117 mg of Chxn-Py-Al (0.4 mmoles), 336 μl of iodobenzene (3 mmoles), 138 mg of 1,2,4-triazole (2 mmoles), 1.042 g of caesium carbonate (3.2 mmoles) and 1.2 ml of DMF. The degree of transformation and selectivity were 79percent and 99percent respectively. ; Example 1.19; Preparation of 1-phenyl-1H-[1,2,4]triazole; Example 1.18 was repeated, operating at 50° C. (72 hours). The degree of transformation and selectivity for 1-phenyl-1H-[1,2,4-triazole] were 75percent and 99percent respectively.
83%
With caesium carbonate In N,N-dimethyl-formamide at 90℃; for 30 h; sealed tube
Preparation of 1-phenyl-1H-[1,2,4]triazole [0220] Following General Procedure A (90 0C, 30 hours), 1/-/-[1 ,2,4]triazole (104 mg, 1.5 mmol) is coupled with iodo-benzene (112 μL, 1.0 mmol). The crude brown oil is purified by flash chromatography on silica gel (eluent: dichloromethane/hexanes = 50/50) to provide 120 mg (83 percent isolated yield) of the desired product as a light yellow solid. <n="50"/>007/001836_ 49 -IdentificationMp: 460C.1H NMR (400 MHz, CDCI3): δ 8.49 (s, 1 H1 H8), 8.03 (s, 1H, H7), 7.58-7.61 (m, 2H, H2i6), 7.40-7.44 (t, 2H1 H3,5), 7.31-7.33 (t, 1 H, H4).13C NMR (100 MHz, CDCI3): δ 152.62 (C7), 140.91 (C8), 136.99 (C1), 129.77 (C3,5), 128.21 (C4), 120.04 (C2i6).IR (KBr) : v (cm'1) = 3105, 2924, 2852, 1600, 1514, 1416, 1359, 1278, 1223,1152, 1055, 981 , 876, 754, 681 , 671 , 503.GC/MS: rt = 15.28 min, M/Z = 145.HRMS: 146.0721 (M+H). Theoretical: 146.0718
71%
Stage #1: Inert atmosphere Stage #2: at 120℃; for 64 h; Inert atmosphere
A flask was charged with K2CO3 (12.1689 g, 88 mmol), 1H-1,2,4-triazole (2.0042 g, 29 mmol), Cu2O(430 mg, 3 mmol) and 1,10-phenanthroline (1.0452 g, 5.8 mmol) and then evacuated and back-filled with N2. Then, anhydrous DMF (20 ml) and iodobenzene (8.9764 g, 4.92 ml, 44 mmol) were added and the resulting mixture was heated to 120 °C for 64 h and then diluted with CH2Cl2 (40 ml). The mixture was filtered through a pad of Celite and the residue washed with CH2Cl2 (20 ml). The resulting organic layer was washed with water (20 ml) and brine (20 ml), dried over MgSO4 and concentrated under reduced pressure. The crude mixture was purified by column chromatography (cyclohexane/ethyl acetate 8/0→2/0) to yield the product as a pale yellow solid (2.986 g, 71percent).
65%
Stage #1: With phenanthroline monohydrate; potassium carbonate In N,N-dimethyl-formamideInert atmosphere Stage #2: at 100℃; for 48 h;
EXAMPLE 108 1-phenyltriazole 1 g (0.0145 mol) triazole 2, 0.21 g (0.00145 mol) copper(I)oxide, 0.29 g (0.00145 mol) phenantroline monohydrate and 6.01 g (0.044 mol) potassium carbonate are weighed into a Schlenk flask. After repeated evacuating and flushing with argon, 10 ml dry DMF is added. Evacuating and flushing with argon are repeated several times. Subsequently, 2.42 ml (4.43 g, 0.022 mol) of iodobenzene is added. The reaction mixture is stirred for 48 h at 100° C. under argon. After cooling 20 ml DCM is added and filtered. The solvent is removed in vacuum and the product is obtained after purification by column chromatography (KG 60, gradient petroleum ether/EtOAc 8:2 to EtOAc) as a yellowish-white solid.M 145.17 C8H7N3 Yield: 1.362 g (65percent)1H-NMR DM-94 (300 MHz/DMSO): (ppm)=7.41 (t, 1H, 6-H); 7.58 (t, 2H, 5/5'-H); 7.87 (d, 2H, 4-H); 8.25 (s, 1H, 1-H); 9.31 (s, 1H, 2-H)13C-NMR DM-94 (75.475 MHz/DMSO): (ppm)=119.37 (5/5'-C); 127.78 (6-C); 129.77 (4/4'-C); 136.74 (3-C); 142.27 (2-C); 152.39 (1-C)
Reference：
[1] Journal of the American Chemical Society, 2007, vol. 129, # 45, p. 13879 - 13886
[2] Journal of Organic Chemistry, 2007, vol. 72, # 8, p. 2737 - 2743
[3] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 19, p. 6355 - 6363
[4] RSC Advances, 2014, vol. 4, # 83, p. 44105 - 44116
[5] Journal of Organic Chemistry, 2004, vol. 69, # 17, p. 5578 - 5587
[6] Synlett, 2008, # 4, p. 614 - 620
[7] Organic and Biomolecular Chemistry, 2016, vol. 14, # 46, p. 10861 - 10865
[8] Chemistry - A European Journal, 2004, vol. 10, # 22, p. 5607 - 5622
[9] Patent: US2003/236413, 2003, A1, . Location in patent: Page 24-25
[10] Patent: US2005/234239, 2005, A1, . Location in patent: Page/Page column 23; 28-29
[11] Synthesis, 2008, # 11, p. 1707 - 1716
[12] ChemPlusChem, 2013, vol. 78, # 12, p. 1491 - 1502
[13] RSC Advances, 2014, vol. 4, # 14, p. 7321 - 7329
[14] Angewandte Chemie - International Edition, 2007, vol. 46, # 6, p. 934 - 936
[15] Patent: WO2008/4088, 2008, A2, . Location in patent: Page/Page column 48-49
[16] Synthesis, 2010, # 9, p. 1505 - 1511
[17] Chemistry - An Asian Journal, 2014, vol. 9, # 1, p. 166 - 178
[18] Advanced Synthesis and Catalysis, 2007, vol. 349, # 17-18, p. 2673 - 2676
[19] Tetrahedron, 2013, vol. 69, # 27-28, p. 5647 - 5659
[20] Journal of Organic Chemistry, 2011, vol. 76, # 1, p. 305 - 308
[21] Patent: US2011/105761, 2011, A1, . Location in patent: Page/Page column 38-39
[22] Asian Journal of Chemistry, 2013, vol. 25, # 10, p. 5647 - 5648
[23] Advanced Synthesis and Catalysis, 2008, vol. 350, # 9, p. 1253 - 1257
[24] Tetrahedron Letters, 2007, vol. 48, # 37, p. 6573 - 6576
15
[ 288-88-0 ]
[ 108-86-1 ]
[ 13423-60-4 ]
Yield
Reaction Conditions
Operation in experiment
93%
With copper(I) 3-metthylsalicylate; potassium carbonate In dimethyl sulfoxide at 110℃; for 3 h;
General procedure: A dry flask was charged with the nitrogen containing heterocycles (1.5 mmol), aryl halides (1 mmol), potassium carbonate(2 mmol) and CuMeSal (0.01 mmol)then anhydrous DMSO (5 ml) was added. The reaction mixture was stirred at 110°C, open to air, for 3h , cooled to room temperature, filtered, and the precipitate was washed with DMSO (2 ml) then stirred with ice water (30 ml) and extracted with ethyl acetate (3 × 50 ml),dried over sodium sulfate and the solvent was removed under reduced pressure.The residue was purified by chromatography or recrystallization as indicated with each compound.
6.32 g
Stage #1: With sodium methylate In methanol at 40℃; for 1 h; Stage #2: at 90℃; for 16 h;
, adding 50 mmol of sodium methoxide into 50 mmol of 1, 2, 4-triazole (shown in the formula II)) and 50 mL of methanol solution, stirring for 60 minutes at 40 DEG c, and dropwise adding 60 mmol of bromobenzene, carrying out condensation reflux for 16 hours at the temperature of 90 DEG c, removing volatile matters in the reaction raffinate, washing the carbon tetrachloride, and filtering the solid impurities, and carrying out rotary evaporation to remove the washing solvent to obtain colorless liquid 1-phenyl -1,2,4-triazole 6.32g
Reference：
[1] Journal of Organic Chemistry, 2008, vol. 73, # 22, p. 9121 - 9124
[2] Tetrahedron Letters, 2014, vol. 55, # 19, p. 3049 - 3051
[3] Green Chemistry, 2012, vol. 14, # 5, p. 1268 - 1271
[4] ChemCatChem, 2014, vol. 6, # 8, p. 2373 - 2383
[5] Journal of Organic Chemistry, 2007, vol. 72, # 22, p. 8535 - 8538
[6] Synthesis, 2008, # 11, p. 1707 - 1716
[7] Angewandte Chemie - International Edition, 2007, vol. 46, # 6, p. 934 - 936
[8] Dalton Transactions, 2015, vol. 44, # 18, p. 8433 - 8443
[9] Patent: CN108484654, 2018, A, . Location in patent: Paragraph 0057; 0060
16
[ 288-88-0 ]
[ 98-80-6 ]
[ 13423-60-4 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2018, vol. 16, # 46, p. 8984 - 8988
1-(p-toluenesulfonyl)-1,2,4-triazole (10) 1,2,4-triazole (9.28 g) was suspended in dichloromethane (110 mL) dried over molecular sieves. Triethylamine (13.6 g) was added; the triazole dissolved after triethylamine addition. Tosylchloride (25.62 g;) was added to the reaction mixture over approx. 30 min. The reaction mixture was stirred overnight. Precipitated salt was filtered off. Filtrate was washed with water and dried with Na2SO4. The drying agent was filtered off and filtrate was evaporated on rotary evaporator. Cyclohexane (300 mL) was added to the residue and the mixture was allowed to crystallise overnight. Product was separated by filtration, washed with cyclohexane (50 mL), and dried in oven at 50° C. to give the title compound as white crystalline powder, 25.1 g (83.7percent of theoretical yield; m.p. 105-107° C.
Reference：
[1] Carbohydrate Research, 2003, vol. 338, # 5, p. 451 - 453
[2] Journal of Organic Chemistry, 2010, vol. 75, # 8, p. 2722 - 2725
[3] Patent: US2008/76933, 2008, A1, . Location in patent: Page/Page column 3-5
[4] Patent: EP1258480, 2002, A1, . Location in patent: Page 37
[5] Journal of Chemical Research, 2016, vol. 40, # 2, p. 101 - 106
23
[ 288-88-0 ]
[ 824-79-3 ]
[ 13578-51-3 ]
Yield
Reaction Conditions
Operation in experiment
55%
With N-Bromosuccinimide In 1,4-dioxane at 25℃; for 12 h;
General procedure: Azoles 1 (0.5 mmol), sodium sulfinate 2 (1.0 mmol) and NBS (0.5 mmol) were dissolved in 2 mL of 1,4-dioxane solvent. the reaction mixture was stirred at room temperature under air for 12 h. After the reaction, the resulting mixture was extracted with EtOAc. The combined organic phase was dried over anhydrous Na2SO4 and the solvent was then removed under vacuum. The residue was purified by flash column chromatography on silica gel (petroleumether/ethyl acetate, 3:1) to afford the corresponding product.
Reference：
[1] Organic and Biomolecular Chemistry, 2015, vol. 14, # 2, p. 590 - 597
25
[ 288-88-0 ]
[ 30955-05-6 ]
[ 13578-51-3 ]
Reference：
[1] Nucleosides and Nucleotides, 1997, vol. 16, # 7-9, p. 1067 - 1071
26
[ 288-88-0 ]
[ 7411-23-6 ]
Yield
Reaction Conditions
Operation in experiment
90%
Stage #1: With bromine; sodium hydroxide In dichloromethane; water at 25℃; for 12 h; Stage #2: With hydrogenchloride In dichloromethane; water for 1 h;
To a solution of 1,2,4-triazole, 1 (27.6 g, 399.6 mmol) in dichloromethane (80 mL) was simultaneously added bromine in dichloromethane (50percentv/v, 80 mL) and an aqueous solution of sodium hydroxide (50percent w/v,96 mL). The rate of addition was such that the temperature of the reaction mass was maintained between 10-15°C. After the complete addition, the temperature was raised to 25°C and the stirring was continued for an additional 12 h. Into this was then added 6 N aq.HCl and stirring continued for 1 h.The solid thus precipitated was filtered, and dried under vacuum at 50°C to afford 2 as an off-white solid(80 g, 90percent). The product was used without further purification.
65%
With bromine; sodium hydroxide In dichloromethane; water at 0 - 20℃;
Intermediate 1 3,5-Dibromo-lH-l,2,4-triazole Solutions of bromine (6.1 mL, 119 mmol) in DCM (15 mL) and sodium hydroxide (6.78 g, 169 mmol) in water (20 mL) were simultaneously added dropwise to a stirred mixture of 1H-1,2,4- triazole (3.9 g, 56 mmol), water (50 mL) and DCM (15 mL) at 0°C while keeping the reaction temperature below 20°C. The mixture was stirred at ambient temperature over night. Hydrochloric acid (cone, 2.0 mL, 66 mmol) was added. The solid was isolated by filtration, washed with water and dried in vacuum to yield the title compound as a solid (8.3 g, 65percent). MS (ESI ) m/z 224 [M-H]".
65%
With bromine; sodium hydroxide In dichloromethane; water at 0 - 20℃;
Intermediate 1 3,5-Dibromo-lH-l,2,4-triazole lH-l,2,4-Triazole (3.9 g, 56 mmol) was mixed in water (50 mL) and DCM (15 mL) at 0°C. A solution of dibromine (6.1 mL, 119 mmol) in DCM (15 mL) and a solution of sodium hydroxide (6.78 g, 169 mmol) in water (20 mL) were added dropwise simultaneously while keeping the reaction temperature below 20°C. The mixture was stirred at ambient temperature over night. Hydrochloric acid (cone, 2.0 mL, 66 mmol) was added. The solid was isolated by filtration, washed with water and dried under vacuum to yield the title compound as a solid (8.3 g, 65percent). MS (ESI ) m/z 224 [M-H]".
Reference：
[1] Synthesis, 1998, # 9, p. 1357 - 1361
[2] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2014, vol. 53, # 5, p. 610 - 618
[3] Patent: WO2014/195321, 2014, A1, . Location in patent: Page/Page column 15; 16
[4] Patent: WO2014/195322, 2014, A1, . Location in patent: Page/Page column 15
[5] Patent: US2010/240619, 2010, A1, . Location in patent: Page/Page column 68
27
[ 288-88-0 ]
[ 459-57-4 ]
[ 27996-86-7 ]
Yield
Reaction Conditions
Operation in experiment
72%
With potassium carbonate In N,N-dimethyl-formamide at 110℃;
General procedure: A mixture of 4-fluoro acetophenone/4-fluorobenzaldehyde (10 mmol) and imidazole/triazole (10 mmol) were dissolved in dry DMF (20 mL). K2CO3 (12 mmol) was added in small portion within a period of 15 min to the above stirred solution. Mixture was stirred for 10-12 h at 110 °C. Heating discontinued, K2CO3 was filtered off, filtrate extracted with ethyl acetate (3 .x. 15 mL). Organic layer was washed with water (3 .x. 15 mL), dried over anhydrous sodium sulphate and concentrated to given an oil which was purified on silica gel column (60-120 mesh) taking methanol: chloroform (1:99) as an eluent.
65%
With potassium carbonate In N,N-dimethyl-formamide at 120℃; for 6 h;
Example 91Preparation of 4-(1H-1,2,4-triazol-1-yl)benzaldehyde (DI5); To a stiffing solution of 4-fluorobenzaldehyde (10.0 g, 80.6 mmol) in DMF (150 mL) were added K2CO3 (13.3 g, 96.7 mmol) and 1,2,4-triazole (6.67 g, 96.7 mmol) and the resultant reaction mixture was stirred at 120° C. for 6 h. After completion of reaction (by TLC), the reaction mixture was diluted with H2O and extracted with EtOAc (3.x.100 mL). The combined EtOAc layer was washed with H2O and brine, dried over Na2SO4, and concentrated under reduced pressure to afford the title compound as a solid (9.0 g, 65percent): mp 145-149° C.: 1H NMR (400 MHz, CDCl3) δ 10.08 (s, 1H), 8.70 (s, 1H), 8.16 (s, 1H), 8.06 (d, J=8.0 Hz, 2H), 7.92 (d, J=8.0 Hz, 2H); ESIMS m/z 173.9 ([M+H]+).
65%
With potassium carbonate In N,N-dimethyl-formamide
Example 91 Preparation of 4-(1H-1,2,4-triazol-1-yl)benzaldehyde (DI5) To a stirring solution of 4-fluorobenzaldehyde (10.0 g, 80.6 mmol) in DMF (150 mL) were added K2CO3 (13.3 g, 96.7 mmol) and 1,2,4-triazole (6.67 g, 96.7 mmol) and the resultant reaction mixture was stirred at 120° C. for 6 h. After completion of reaction (by TLC), the reaction mixture was diluted with water and extracted with EtOAc (3*100 mL). The combined EtOAc layer was washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure to afford the title compound as a solid (9.0 g, 65percent): mp 145-149° C.: 1H NMR (400 MHz, CDCl3) δ 10.08 (s, 1H), 8.70 (s, 1H), 8.16 (s, 1H), 8.06 (d, J=8.0 Hz, 2H), 7.92 (d, J=8.0 Hz, 2H); ESIMS m/z 173.9 ([M+H]+).
65%
With potassium carbonate In N,N-dimethyl-formamide at 120℃; for 6 h;
Example 91: Preparation of 4-(lH-l,2,4-triazol-l-yl)benzaldehyde (DI5) To a stirring solution of 4-fluorobenzaldehyde (10.0 g, 80.6 mmol) in DMF (150 mL) were added K2CO3 (13.3 g, 96.7 mmol) and 1,2,4- triazole (6.67 g, 96.7 mmol) and the resultant reaction mixture was stirred at 120 °C for 6 h. After completion of reaction (by TLC), the reaction mixture was diluted with H20 and extracted with EtOAc (3 xlOO mL). The combined EtOAc layer was washed with H20 and brine, dried over Na2S04, and concentrated under reduced pressure to afford the title compound as a solid (9.0 g, 65percent): mp 145-149 °C: ]H NMR (400 MHz, CDC13) δ 10.08 (s, IH), 8.70 (s, IH), 8.16 (s, IH), 8.06 (d, J = 8.0 Hz, 2H), 7.92 (d, J = 8.0 Hz, 2H); ESIMS m/z 173.9 ([M+H]+).
65%
With potassium carbonate In N,N-dimethyl-formamide at 120℃; for 6 h;
To a stiffing solution of 4-fluorobenzaldehyde (10.0 g, 80.6 mmol) in DMF (150 mL) were added K2CO3 (13.3 g, 96.7 mmol) and 1,2,4-triazole (6.67 g, 96.7 mmol) and the resultant reaction mixture was stirred at 120° C. for 6 h. After completion of reaction (by TLC), the reaction mixture was diluted with H2O and extracted with EtOAc (3×100 mL). The combined EtOAc layer was washed with H2O and brine, dried over Na2SO4, and concentrated under reduced pressure to afford the title compound as a solid (9.0 g, 65percent): mp 145-149° C.: 1H NMR (400 MHz, CDCl3) δ 10.08 (s, 1H), 8.70 (s, 1H), 8.16 (s, 1H), 8.06 (d, J=8.0 Hz, 2H), 7.92 (d, J=8.0 Hz, 2H); ESIMS m/z 173.9 ([M+H]+).
65%
With potassium carbonate In N,N-dimethyl-formamide at 120℃; for 6 h;
To a stiffing solution of 4-fluorobenzaldehyde (10.0 g, 80.6 mmol) in DMF (150 mL) were added K2CO3 (13.3 g, 96.7 mmol) and 1,2,4-triazole (6.67 g, 96.7 mmol) and the resultant reaction mixture was stirred at 120° C. for 6 h. After completion of reaction (by TLC), the reaction mixture was diluted with H2O and extracted with EtOAc (3*100 mL). The combined EtOAc layer was washed with H2O and brine, dried over Na2SO4, and concentrated under reduced pressure to afford the title compound as a solid (9.0 g, 65percent): mp 145-149° C.: 1H NMR (400 MHz, CDCl3) δ 10.08 (s, 1H), 8.70 (s, 1H), 8.16 (s, 1H), 8.06 (d, J=8.0 Hz, 2H), 7.92 (d, J=8.0 Hz, 2H); ESIMS m/z 173.9 ([M+H]+).
65%
With potassium carbonate In N,N-dimethyl-formamide at 120℃; for 6 h;
Example 91 Preparation of 4-(1H-1,2,4-triazol-1-yl)benzaldehyde (DI5) To a stirring solution of 4-fluorobenzaldehyde (10.0 g, 80.6 mmol) in DMF (150 mL) were added K2CO3 (13.3 g, 96.7 mmol) and 1,2,4-triazole (6.67 g, 96.7 mmol) and the resultant reaction mixture was stirred at 120° C. for 6 h. After completion of reaction (by TLC), the reaction mixture was diluted with water and extracted with EtOAc (3×100 mL). The combined EtOAc layer was washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure to afford the title compound as a solid (9.0 g, 65percent): mp 145-149° C.: 1H NMR (400 MHz, CDCl3) δ 10.08 (s, 1H), 8.70 (s, 1H), 8.16 (s, 1H), 8.06 (d, J=8.0 Hz, 2H), 7.92 (d, J=8.0 Hz, 2H); ESIMS m/z 173.9 ([M+H]+).
Reference：
[1] European Journal of Medicinal Chemistry, 2009, vol. 44, # 7, p. 2930 - 2935
[2] European Journal of Medicinal Chemistry, 2011, vol. 46, # 9, p. 4302 - 4310
[3] Patent: US2012/329649, 2012, A1, . Location in patent: Page/Page column 72
[4] Patent: US2014/171314, 2014, A1, . Location in patent: Page/Page column
[5] Patent: WO2014/100163, 2014, A1, . Location in patent: Page/Page column 131
[6] Patent: US2014/171308, 2014, A1, . Location in patent: Paragraph 0656-0657
[7] Patent: US2014/171312, 2014, A1, . Location in patent: Paragraph 0821; 0822
[8] Patent: US9211280, 2015, B2, . Location in patent: Page/Page column 132-133
[9] Tetrahedron, 2001, vol. 57, # 22, p. 4781 - 4785
[10] Journal of Medicinal Chemistry, 1998, vol. 41, # 13, p. 2390 - 2410
[11] Asian Journal of Chemistry, 2014, vol. 26, # 1, p. 257 - 260
[12] Crystal Growth and Design, 2012, vol. 12, # 9, p. 4663 - 4668
[13] Journal of Organic Chemistry, 2013, vol. 78, # 7, p. 3222 - 3234
[14] Patent: US2014/107094, 2014, A1, . Location in patent: Paragraph 0593; 0594
[15] Patent: US2015/105366, 2015, A1, . Location in patent: Paragraph 0567; 0568
[16] Patent: WO2015/57205, 2015, A1, . Location in patent: Page/Page column 158
[17] Medicinal Chemistry Research, 2017, vol. 26, # 7, p. 1506 - 1515
[18] Molecules, 2017, vol. 22, # 8,
[19] Patent: CN107056716, 2017, A, . Location in patent: Paragraph 0032; 0033
[20] Patent: CN104119286, 2017, B, . Location in patent: Paragraph 0033
28
[ 288-88-0 ]
[ 459-57-4 ]
[ 27996-86-7 ]
Reference：
[1] Patent: US6451973, 2002, B1,
[2] Patent: US5977075, 1999, A,
[3] Patent: US7138432, 2006, B1, . Location in patent: Page/Page column 44
[4] Patent: US5703106, 1997, A,
29
[ 459-57-4 ]
[ 288-88-0 ]
[ 27996-86-7 ]
Reference：
[1] Journal of Medicinal Chemistry, 1987, vol. 30, # 6, p. 1023 - 1029
[2] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 7, p. 1695 - 1697
30
[ 288-88-0 ]
[ 76-83-5 ]
[ 31250-99-4 ]
Yield
Reaction Conditions
Operation in experiment
93%
Stage #1: With triethylamine In N,N-dimethyl-formamide for 0.0833333 h;
j0185j Triethylamine (5.49 g, 54.30 mmol) is added to a solution of 1,2,4-triazole (3.0 g, 43.44 mmol) in DMF (50 mL) at rt. After stirring for 5 minutes, trityl chloride (12.11 g, 43.44 mmol) is added as a solid and the mixture is stirred overnight. The solvent is distilled off under reduced pressure and the crude is partitioned between dichloromethane (50 mL) and water (50 mL). The organic layer is separated and the aqueous layer is extracted with dichloromethane (3 x 50 mL). The combined organic layers are washed with water (3 x 40 mL). The organic layer is dried over Na2SO4 and concentrated under reduced pressure to afford the product 1-trytil-1H- 1,2,4-triazole (12.6 g, 93 percent). n-BuLi (4.5 mL, 11.24 mmol; 2.5 M solution in hexanes) is added to a solution of 1-trityl-1H-1,2,4-triazole (3.5 g, 11.24 mmol) in THF (120 mL) at -78°C and the solution is stirred for 45 mm. Bromine (1.76 g, 11.02 mmol) is added dropwise over a period of 5 minutes and the solution is stirred for 2 h allowed to warm to -20 °C and quenched by adding saturated NH4C1 solution (30 mL). The reaction mixture ias diluted with water (60 mL) and dichloromethane (40 mL). The organic layer is separated and the aqueous layer is extracted with CH2C12 (4 x 50 mL).The combined organic extract was dried over Na2SO4 and the solvent evaporated under reduced pressure to afford crude which is used as such for the next step (4.2 g, 95 percent). 7.09-7.16 (m, 6H), 7.27-7.40 (m, 9H), 7.86 (s, 1H).
Reference：
[1] Patent: WO2014/159248, 2014, A1, . Location in patent: Paragraph 0185
[2] European Journal of Medicinal Chemistry, 2009, vol. 44, # 7, p. 3064 - 3067
[3] Tetrahedron, 1997, vol. 53, # 30, p. 10289 - 10312
[4] MedChemComm, 2014, vol. 5, # 1, p. 72 - 81
[5] Patent: US6620841, 2003, B1,
[6] Patent: EP1219607, 2002, A1,
[7] Heterocycles, 1985, vol. 23, # 11, p. 2895 - 2906
[8] Patent: US5393732, 1995, A,
31
[ 288-88-0 ]
[ 76-83-5 ]
[ 136633-98-2 ]
[ 31250-99-4 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1991, vol. 110, # 9, p. 369 - 373
[2] Tetrahedron Letters, 2000, vol. 41, # 8, p. 1297 - 1301
32
[ 77287-34-4 ]
[ 302-01-2 ]
[ 288-88-0 ]
[ 628-36-4 ]
Reference：
[1] Journal of the American Chemical Society, 1955, vol. 77, p. 621,623
With sodium methylate In methanol for 4 h; Heating / reflux
[0061] Catalyst 1: Sodium 1,2,4-triazolate [0062] A three-necked-flask stirring apparatus with mechanical stirrer, internal thermometer and reflux condenser was charged under dry nitrogen with 200 ml of dry methanol and 45 ml of a 30percent strength methanolic solution of sodium methoxide, corresponding to 0.25 mol of sodium methoxide. 17.4 g (0.25 mol) of 1,2,4-triazole was added thereto in portions at room temperature. After the end of addition of the 1,2,4-triazole the reaction mixture was stirred at reflux temperature for 4 h. The solvent was subsequently distilled off under reduced pressure and the oily residue which remained was admixed at room temperature with 200 ml of methylene chloride. The mixture was stirred at room temperature for 15 min and the precipitated solid product was filtered off. This gave 22.5 g of sodium 1,2-4-triazolate (yield: 98percent of theory) in the form of a colourless powder. The product was pure according to its 1H-NMR spectrum and free of the 1,2,4-triazole used.
Reference：
[1] Liebigs Annalen der Chemie, 1994, # 2, p. 145 - 150
[2] Patent: US2004/49028, 2004, A1, . Location in patent: Page 5
[3] Chemistry of Heterocyclic Compounds, 1998, vol. 34, # 2, p. 252 - 253
[4] Journal of the American Chemical Society, 1927, vol. 49, p. 1999
[5] Patent: WO2005/105762, 2005, A1, . Location in patent: Page/Page column 8; 9-10
[6] Patent: US2003/13872, 2003, A1,
[7] Patent: WO2006/108155, 2006, A2, . Location in patent: Page/Page column 16-17
[8] Patent: US2010/143455, 2010, A1, . Location in patent: Page/Page column 9-10
[9] Patent: WO2006/137083, 2006, A1, . Location in patent: Abstract
[10] Patent: US2003/236419, 2003, A1, . Location in patent: Page 10
Step 1. Preparation of (1H-1,2,4-triazol-1-yl)methanol A mixture of 1H-1,2,4-triazole (7.04 g, 102 mmol), paraformaldehyde (3.06 g, 102 mmol) and catalytic amount of triethylamine was heated to molten condition and stirred at the same temperature (140° C.) for 0.5 hour. Reaction mixture was then cooled to 30° C. to obtain the product (9.0 g, 89percent) as white solid.
79%
at 20℃; for 13 h; Reflux
The compound was synthesized with some modifications compared to Ref. [14]: (1,2,4)-triazole [98 percent(Aldrich), 1,73 g, 25 mmol] in 20 ml of ethanol (absolute ethanol, ≥99.8 percent, Sigma-Aldrich) and 3.5 ml of formaldehyde solution (≥36,5 percent, Sigma-Aldrich) were stirred, refluxed for 1 h, and mixing was continued at room temperature for 12 h. After the elimination of the solvent under reduced pressure, the obtained residue was treated with cold water. A white solid appeared, which was collected by filtration, washed with diethyl ether (99 percent, Sigma-Aldrich) and dried under vacuum to yield the pure product (79 percent).
Reference：
[1] Heterocyclic Communications, 2001, vol. 7, # 6, p. 577 - 582
[2] Phosphorus and Sulfur and the Related Elements, 1987, vol. 33, p. 41 - 52
[3] Tetrahedron, 2010, vol. 66, # 47, p. 9145 - 9150
[4] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1980, vol. 16, # 2, p. 189 - 194[5] Khimiya Geterotsiklicheskikh Soedinenii, 1980, vol. 16, # 2, p. 251 - 256
[6] Patent: US2016/83380, 2016, A1, . Location in patent: Paragraph 0240; 0241
[7] Structural Chemistry, 2016, vol. 27, # 2, p. 697 - 704
38
[ 288-88-0 ]
[ 446-52-6 ]
[ 138479-53-5 ]
Reference：
[1] Australian Journal of Chemistry, 1991, vol. 44, # 8, p. 1097 - 1114
39
[ 288-88-0 ]
[ 451-46-7 ]
[ 143426-48-6 ]
Reference：
[1] European Journal of Medicinal Chemistry, 1992, vol. 27, # 3, p. 219 - 228
40
[ 288-88-0 ]
[ 451-46-7 ]
[ 167626-25-7 ]
[ 143426-48-6 ]
Reference：
[1] Patent: US6359134, 2002, B1, . Location in patent: Referential example 17
41
[ 288-88-0 ]
[ 461-82-5 ]
[ 103962-05-6 ]
Reference：
[1] Patent: US4925863, 1990, A,
42
[ 288-88-0 ]
[ 80443-63-6 ]
[ 107534-96-3 ]
Yield
Reaction Conditions
Operation in experiment
95%
at 108 - 128℃; for 15 h;
Into a clean 1000ml four-necked flask 200g of 2- (4-chlorophenethyl) -2-t-butyl ethylene oxide,200g triazole,90 g PEG-7000, 38 g KOH and 0.6 g 18-crown-6,To the dropping funnel, 400 g of 2- (4-chlorophenethyl) -2-t-butyl-oxirane were added dropwise.Turn on stirringWhen heated to 108 ° C,Begin with the dropwise addition of 2- (4-chlorophenethyl) -2-t-butyl-oxirane,Control the reaction flask temperature does not exceed 112 ,Dropping 2h, after the addition was completed,The reaction flask temperature was controlled at 108 ~ 112 ,Insulation 5h;Then warmed to 125 ~ 128 ,Insulation 8h, sample testing,Raw material peak is less than 0.5percent4-H isomer 0.3percentTo the reaction flask was added enough water and methylcyclohexane,Wherein the mass ratio of water and methylcyclohexane is 1: 3.5;After stratification, the water cooled crystallization of PEG,Suction filtered solid PEG recovery applied;The organic layer was cooled to crystallize tebuconazole, filtered with suction,Filter cake was washed to pH 7 to 8,The filter cake was dried to give 772 g of 1H-tebuconazole.
94%
With potassium hydroxide In neat (no solvent) at 130℃; for 7 h;
In 250ml three bottles,23.8 g of 2-tert-butyl-2- (4-chlorophenethyl) oxirane was added,2.0 g of potassium hydroxide and 800 g of PEG were added,And 8.0 g of 1,2,4-triazole was added,Temperature and control the temperature 130 ,Reaction for 7 hours,Stop the reaction.The filter mother liquor in Example 6 was added and the temperature was adjusted to 30 ° C for 3 hours and evacuated.The filter cake was dried to obtain 29.1 g of tebuconazole (white solid)Content of 98.1percent,Yield 94.0percent.
Reference：
[1] Patent: CN107176929, 2017, A, . Location in patent: Paragraph 0024; 0025; 0026; 0027; 0028; 0029; 0030-0040
[2] Patent: CN106588791, 2017, A, . Location in patent: Paragraph 0041; 0042
[3] Patent: US4668660, 1987, A,
43
[ 288-88-0 ]
[ 764-28-3 ]
[ 107534-96-3 ]
Reference：
[1] Patent: US4626594, 1986, A,
44
[ 288-88-0 ]
[ 226944-49-6 ]
[ 104206-82-8 ]
Reference：
[1] Patent: US6218579, 2001, B1,
45
[ 288-88-0 ]
[ 75-75-2 ]
[ 1175536-50-1 ]
Yield
Reaction Conditions
Operation in experiment
89.7%
Stage #1: for 1 h;
In the 1L added three-opening bottle 52.9g (0.24 µM) trimethyl protoiodide sulphone, 2.15g (0.014 µM) L - menthol, 6.3g (0.024 µM) triphenylphosphine, 9.6g (0.48 µM) LiOH, 350gTHF, nitrogen protection, stirring cooling to -20 °C, dropwise 64.8g compound III of the tetrahydrofuran solution, then completing, -20 °C insulation 20h, sampling HPLC detection, compound III 0.03percent, compound compound IV 99.8percent, ee value 99.3percent. The temperature to 20 °C, adding 16.5g (0.24 µM) 1, 2, 4 - triazole, thermal insulation 1h, adding 300g water, for 300g * 2 ethyl acetate extraction twice, combined with the organic phase, the organic phase is used for the 300g saturated sodium chloride washing, and organic 20g dried with anhydrous sodium sulfate 2h, filtering to remove the drying agent, the organic phase PH=8, to the organic adds by drops 50g methanesulfonic acid adjusting PH to strongly acidic, a large number of solid precipitation, filtering to obtain yellow solid 78.6g, HPLC purity 99percent, yield 89.7percent. Taking 23g the above yellow solid, adding 100g THF, stirring cooling to -10 °C, solid not soluble, dropping 19.3g triethylamine, dropped exothermic, needs to control the dripped under for the -5 °C, dropwise 10.8g a chloride, heat release during the dropping, temperature control of the -5 °C, then completing insulation 1h, system by large floc, the heat preservation finishes, no raw material remaining TLC ((Rf raw material=0.6, Rf (reaction solution)=0.7, developing solvent: toluene: ethanol=4:1, volume ratio)), to the system adds by drops 40g 10percent of sodium hydroxide solution, canada finishes clear system, thermal insulation 0.5h, liquid, organic uses 80g saturated sodium chloride wash, liquid, organic phase turns on lathe does (0.09 mpa, 50 °C) get 18g yellow solid, solid then 20percent ethanol solution of recrystallized a, shall be 13.4g white needle crystal compound V, HPLC purity 99.8percent, ee value 99.1percent, the overall yield 71percent (calculated to lactic acid methyl ester).
Reference：
[1] Patent: CN106749202, 2017, A, . Location in patent: Paragraph 0037; 0042; 0046
46
[ 288-88-0 ]
[ 75-75-2 ]
[ 1774-47-6 ]
[ 127001-03-0 ]
[ 1175536-50-1 ]
Reference：
[1] Organic Process Research and Development, 2009, vol. 13, # 4, p. 716 - 728
With sodium methylate; sodium; In methanol; dichloromethane; chloroform;
(a) To a stirred solution of sodium methoxide (from 5 g of sodium, 0.218 mol) in 120 ml of methanol under argon was added 1,2,4-triazole (15 g, 0.217 mol) at 0° C. and then 30.9 g (0.217 mol) of methyl iodide, and the mixture was stirred at room temperature for 24 h. The solvent was concencentrated in vacuo, the residue was extracted with 80 ml of hot benzene and then with chloroform (3*80 ml). Upon removal of the solvent in vacuo, 25.4 g of a white gum was isolated and the gum was dissolved in methylene chloride, filtered, and the filtrate was concentrated to yield an oil. The oil was distilled (80°-90° C./10-15 mm) to afford 10.5 g (58percent) of 1-methyl-1,2,4-triazole.
With sodium methylate; In methanol; benzene;
Preparation 20-1) To a solution of 1,2,4-triazole (100 g) in methanol (200 ml) was added 28percent sodium methoxide in methanol solution (278.3 ml), followed by iodomethane (205.5 g) and the solution was warmed to 40° C. for 18 hours. The solution was concentrated in vacuo to remove methanol then treated with benzene (150 ml), warmed to 70° C. and decanted. This was repeated with 3*150 ml portions of chloroform. The combined organic layer was concentrated in vacuo to ca. 100 ml and the white precipitate was removed by filtration. After evaporation of the filtrate the resulting red liquid residue was distilled at atmospheric pressure to give 1-methyl-1,2,4-triazole (71.45 g) as a colorless liquid that solidified in the refrigerator. bp: 175°-180° C. IR (Neat): 3100, 2950 cm-1NMR (CDCl3, delta): 3.95 (3H, s), 7.94 (1H, s), 8.05 (1H, s)EI-Mass (m/z): 83 (M+)
In tetrahydrofuran; methanol;
REFERENCE EXAMPLE 31 (S)2-Amino-4-methyl-(S)1-(1-methyl-1H-1,2,4-triazol-5-yl)-pentan-1-ol and (S)2-Amino-4-methyl-(R)1-(1-methyl-1H-1,2,4-triazol-5-yl)-pentan-1-ol To a suspension of 15.2 g of sodium hydride (60percent in oil) (washed with hexane) in 100 ml of tetrahydrofuran under argon was added slowly at 0° to 10° C. a solution of 25 g of 1,2,4-triazol in 100 ml of methanol. To this solution was added dropwise 25 ml of methyl iodide over 0.5 hour. The mixture was stirred at 0° C. for 1 hour and then refluxed for 15 minutes. The solution was concentrated under reduced pressure until sodium iodide began to precipitate. The mixture was diluted with 100 ml each of ether and dichloromethane, filtered and the filtrate concentrated to dryness. The residual solid was triturated with dichloromethane (100 ml) and filtered. The filtrate was dried over molecular sieves (3A) and passed through a thin pad of hydrous magnesium silicate. The solvent was removed under vacuum and the residue sublimed to give 7.72 g of 1-methyl-1,2,4-triazole, mp 18°-20° C.
In tetrahydrofuran; methanol;
Reference Example 60 (S)-2-Amino-4-methyl-(R)-1-(1-methyl-1H-1,2,4-triazol-5-yl)pentan-1-ol To a suspension of 15.2 g of sodium hydride (60percent in oil)(washed with hexane) in 100 ml of tetrahydrofuran under argon was added slowly at 0° to 10°C a solution of 25 g of 1,2,4-triazole in 100 ml of methanol. To this solution was added dropwise 25 ml of methyl iodide over 0.5 hour. The mixture was stirred at 0°C for one hour and then refluxed for 15 minutes. The solution was concentrated under reduced pressure until sodium iodide began to precipitate. The mixture was diluted with 100 ml each of ether and dichloromethane, filtered and the filtrate concentrated to dryness. The residual solid was triturated with dichloromethane (100 ml) and filtered. The filtrate was dried over molecular sieves (3A) and passed through a thin pad of hydrous magnesium silicate. The solvent was removed under vacuum and the residue sublimed to give 7.72 g of 1-methyl-1,2,4-triazole, mp 18-20°C.
With sodium; In methanol; chloroform; benzene;
1-Methyl-1,2,4-triazole Sodium (1.9 g, 83 mmol) was dissolved in MeOH (35 mL), allowed to cool to RT, then 1,2,4-triazole (5.7 g, 83 mmol) was added. The solution was cooled in an ice-water bath, then iodomethane (5.1 mL, 11.6 g, 82 mmol) was added dropwise. The reaction was allowed to warm to RT, stoppered, then heated at 38° C. overnight. The reaction was concentrated, then treated with hot benzene (25 mL) which resulted in the formation of white solids. Those solids were slurried in hot CHCl3 (25 ML) and filtered off. The CHCl3 slurry was repeated twice, the three filtrates combined, concentrated, and distlled (37-40° C./8 mm). Recovered 2.6 g (38percent). 1H NMR (CDCl3) delta8.05 (s, 1H), 7.93 (s, 1H), 3.96 (s, 3H).
Intermediate 281 -Methyl-1 H-1 ,2,4-triazole <n="101"/> In a microwave vial sodium methoxide (2.34g) was dissolved in methanol (10ml), 1 H- 1 ,2,4-triazole (3g) was added and the mixture was cooled to 5-1O0C. Methyl iodide (3.26ml) was added and the mixture was heated under microwave irradiation at 800C for 45min. The solvent was removed in vacuo. The oil was allowed to stand for 2h at RT until a solid was formed. To the solid, DCM was added, the DCM was decanted and the solvent was removed in vacuo. The residue was purified by flash chromatography on silica gel (100g silica) eluting with a gradient of 0-25percent methanol in DCM over 40min to give the title compound (1.19g) as a yellow oil. 1H NMR: (400MHz, DMSO) delta 8.45 (1 H, s), 7.95 (1 H, s), 3.85 (3H, s)
j0185j Triethylamine (5.49 g, 54.30 mmol) is added to a solution of 1,2,4-triazole (3.0 g, 43.44 mmol) in DMF (50 mL) at rt. After stirring for 5 minutes, trityl chloride (12.11 g, 43.44 mmol) is added as a solid and the mixture is stirred overnight. The solvent is distilled off under reduced pressure and the crude is partitioned between dichloromethane (50 mL) and water (50 mL). The organic layer is separated and the aqueous layer is extracted with dichloromethane (3 x 50 mL). The combined organic layers are washed with water (3 x 40 mL). The organic layer is dried over Na2SO4 and concentrated under reduced pressure to afford the product 1-trytil-1H- 1,2,4-triazole (12.6 g, 93 %). n-BuLi (4.5 mL, 11.24 mmol; 2.5 M solution in hexanes) is added to a solution of 1-trityl-1H-1,2,4-triazole (3.5 g, 11.24 mmol) in THF (120 mL) at -78C and the solution is stirred for 45 mm. Bromine (1.76 g, 11.02 mmol) is added dropwise over a period of 5 minutes and the solution is stirred for 2 h allowed to warm to -20 C and quenched by adding saturated NH4C1 solution (30 mL). The reaction mixture ias diluted with water (60 mL) and dichloromethane (40 mL). The organic layer is separated and the aqueous layer is extracted with CH2C12 (4 x 50 mL).The combined organic extract was dried over Na2SO4 and the solvent evaporated under reduced pressure to afford crude which is used as such for the next step (4.2 g, 95 %). 7.09-7.16 (m, 6H), 7.27-7.40 (m, 9H), 7.86 (s, 1H).
47%
In chloroform; water; N,N-dimethyl-formamide; mineral oil;
(1) Sodium hydride (60% dispersion in mineral oil, 13.8 g, 345 mmol) was washed with hexane and suspended in DMF (150 ml). At an ice bath temperature, 1,2,4-triazole (total; 20.7 g, 300 mmol) was added thereto in four divisions. After stirring for 30 minutes, to the mixture was added tritylchloride (total; 83.7 g, 300 mmol) in seven divisions and additionally added DMF (50 ml). After stirring for 1.5 hours at room temperature, to the reaction mixture was added water (600 ml). The precipitated crystal was collected by filteration, washed with water, dissolved in CHCl3 (800 ml) and dried. The solvent was evaporated. The obtained residue was chromatographed on silica gel (ethylacetate:CHCl3=1:2, v/v). The fraction of the objective was concentrated to give 1-trityl-1H-1,2,4-triazole (43.9 g). Yield: 47%.
47%
In chloroform; water; N,N-dimethyl-formamide; mineral oil;
(1) Sodium hydride (60% dispersion in mineral oil, 13.8 g, 345 mmol) was washed with hexane and suspended in DMF (150 ml). At an ice bath temperature, 1,2,4-triazole (total; 20.7 g, 300 mmol) was added thereto in four divisions. After stirring for 30 minutes, to the mixture was added tritylchloride (total; 83.7 g, 300 mmol) in seven divisions and additionally added DMF (50 ml). After stirring for 1.5 hours at room temperature, to the reaction mixture was added water (600 ml). The precipitated crystal was collected by filteration, washed with water, dissolved in CHCl3(800 ml) and dried. The solvent was evaporated. The obtained residue was chromatographed on silica gel (ethyl acetate: CHCl3= 1: 2, v/v). The fraction of the objective was concentrated to give 1-trityl-1H-1,2,4-triazole (43.9 g). Yield: 47%.
With triethylamine; In dichloromethane; N,N-dimethyl-formamide;
EXAMPLE 1 This Example illustrates the preparation of 1-trityl-1,2,4-triazole. A solution of trityl chloride (417.7 g) in dichloromethane (1.21) was added slowly over two hours, whilst maintaining the temperature below 50 C. by external cooling, to a solution of 1,2,4-triazole (103.5 g) and triethylamine (151.5 g, 209 ml) in N,N-dimethylformamide (500 ml). The mixture was then stirred for a further one hour, poured into water (21) and extracted with dichloromethane (5*500 ml). The extracts were dried over magnesium sulphate, evaporated under reduced pressure and the crude product triturated with ether (200 ml total) to give the title compound (425 g, m.p. 213-214 C.). NMR (CDCl3): delta7.1-7.4 (15H,m), 8.03(1H,s), 8.08(1H,s).
50 mmol of sodium methoxide was added to a mixture of 50 mmol of 1,2,4-triazole (a compound of the formula II) and 50 ml of a methanol solution, and the resulting suspension was stirred at 25 ° C for 30 min. Thereafter, 60 mmol of methyl bromide was added dropwise, and the mixture was refluxed at 70 ° C for 12 h. The volatiles in the reaction mixture were removed in vacuo, washed with chloroform, and solid impurities were filtered, after, rotary evaporation removal and the washing solvent, a colorless liquid of 1-methyl-1,2,4-triazole 3.90 g was obtained.
With potassium phosphate; copper(l) iodide; N,N`-dimethylethylenediamine; In N,N-dimethyl-formamide; at 110℃; for 72h;Inert atmosphere;
General procedure: A mixture of CuI (0.10 g, 0.50 mmol), the required azole(10 mmol), K3PO4 (4.4 g, 20 mmol), the required halide (12 mmol)and N,N0-dimethylethylenediamine (0.11 mL, 1.0 mmol) in DMF(5 mL) was degased and heated under argon at 110 C for 72 h.After filtration over celite (washing using AcOEt) and removal ofthe solvents, the crude product is purified by chromatography oversilica gel (the eluent is given in the product description). 4.3.1 1-Phenyl-1H-1,2,4-triazole (2a) Compound 2a was prepared from 1,2,4-triazole (0.69 g) and iodobenzene (1.4 mL) using the general procedure 1, and was isolated (eluent: heptane/AcOEt 7:3) in 96% yield as a yellow powder: mp 48 C (lit. 28 46 C); 1H NMR (CDCl3, 300 MHz) 7.42 (m, 1H), 7.53 (m, 2H), 7.71 (m, 2H), 8.15 (s, 1H), 8.74 (s, 1H); 13C NMR (CDCl3, 75 MHz) 120.1 (2CH), 128.3 (CH), 129.9 (2CH), 137.1 (C), 140.9 (CH), 152.7 (CH).
91%
With caesium carbonate;copper(I) oxide; trans-N,N'-bis(pyridin-2-ylmethylene)cyclohexane-1,2-diamine; In DMF (N,N-dimethyl-formamide); at 50 - 82℃; for 24 - 72h;Conversion of starting material;
Example 1.17 [0636] Preparation of 1-phenyl-1H-1,2,41 triazole [0637] Operating protocol A (82 C., 48 hours) was followed using 117 mg of Chxn-Py-Al (0.4 mmoles), 336 ?l of iodobenzene (3 mmoles), 138 mg of 1,2,4-triazole (2 mmoles), 1.042 g of caesium carbonate (3.2 mmoles) and 1.2 ml of DMF. [0638] The degree of transformation and selectivity were 100% and 98% respectively. [0639] The residue obtained following treatment was purified by silica gel chromatography (eluent: hexane/dichloromethane, 100/0 to 50/50). [0640] 264 mg of a dark yellow solid was obtained in a yield of 91%. [0641] Pale yellow needles were obtained after re-crystallisation from chloroform. [0642] The compound obtained had the following formula: [CHEMMOL-00056] [0643] The characteristics were as follows: [0644] MPt: 46 C. (CHCl3) (Lit: 46-47 C. given by Micetich, R G; Spevak, P; Hall, T W; Bains, B K; Heterocycles 1985, 23, 1645-1649); [0645] H NMR/CDCl3:? 8.52 (wide s, 1H, HI), 8.04 (wide s, 1H, H2), 7.53-7.65 (m, 2H, H4,8), 7.26-7.51 (m, 3H, H5,6,7); [0646] 13C NMR/CDCl3: ? 152.55 (C1), 140.88 (C2), 139.96 (C3), 129.73 (C5 and C7), 128.15 (C6), 119.99 (C4 and C8); [0647] GC/MS: Rt=14.02 min, M/Z=145, purity=100%; [0648] Rf=0.21 (eluent: dichloromethane/ethyl acetate, 90/10). Example 1.18 [0649] Preparation of 1-phenyl-1H-[1,2,4]triazole [0650] Operating protocol A (82 C., 24 hours) was followed using 117 mg of Chxn-Py-Al (0.4 mmoles), 336 ?l of iodobenzene (3 mmoles), 138 mg of 1,2,4-triazole (2 mmoles), 1.042 g of caesium carbonate (3.2 mmoles) and 1.2 ml of DMF. [0651] The degree of transformation and selectivity were 79% and 99% respectively. [CHEMMOL-00057] Example 1.19 [0652] Preparation of 1-phenyl-1H-[1,2,4]triazole Example 1.18 was repeated, operating at 50 C. (72 hours). The degree of transformation and selectivity for 1-phenyl-1H-[1,2,4-triazole] were 75% and 99% respectively. [0653] [CHEMMOL-00058]
91%
Operating protocol A (82 C., 48 hours) was followed using 117 mg of Chxn-Py-Al (0.4 mmoles), 336 mul of iodobenzene (3 mmoles), 138 mg of 1,2,4-triazole (2 mmoles), 1.042 g of caesium carbonate (3.2 mmoles) and 1.2 ml of DMF. The degree of transformation and selectivity were 100% and 98% respectively. The residue obtained following treatment was purified by silica gel chromatography (eluent: hexane/dichloromethane, 100/0 to 50/50). 264 mg of a dark yellow solid was obtained in a yield of 91%. Pale yellow needles were obtained after re-crystallisation from chloroform. The compound obtained had the following formula: The characteristics were as follows: MPt: 46 C. (CHCl3) (Lit: 46-47 C. given by Micetich, R G; Spevak, P; Hall, T W; Bains, B K; Heterocycles 1985, 23, 1645-1649); 1H NMR/CDCl3: delta8.52 (wide s, 1H, H1), 8.04 (wide s, 1H, H2), 7.53-7.65 (m, 2H, H4,8), 7.26-7.51 (m, 3H, H5,6,7); 13C NMR/CDCl3: delta 152.55 (C1), 140.88 (C2), 139.96 (C3), 129.73 (C5 and C7), 128.15 (C6), 119.99 (C4 and C8); GC/MS: Rt=14.02 min, M/Z=145, purity=100%; Rf=0.21 (eluent: dichloromethane/ethyl acetate, 90/10). Example 1.18; Preparation of 1-phenyl-1H-[1,2,4]triazole; Operating protocol A (82 C., 24 hours) was followed using 117 mg of Chxn-Py-Al (0.4 mmoles), 336 mul of iodobenzene (3 mmoles), 138 mg of 1,2,4-triazole (2 mmoles), 1.042 g of caesium carbonate (3.2 mmoles) and 1.2 ml of DMF. The degree of transformation and selectivity were 79% and 99% respectively. ; Example 1.19; Preparation of 1-phenyl-1H-[1,2,4]triazole; Example 1.18 was repeated, operating at 50 C. (72 hours). The degree of transformation and selectivity for 1-phenyl-1H-[1,2,4-triazole] were 75% and 99% respectively.
87%
With potassium phosphate; In N,N-dimethyl-formamide; at 110℃;
General procedure: 1 mmol of the compound of the formula II-1 and 2 mmol of the compound of the formula III are sequentially added to the reaction.0.5mmol% catalyst CS Cu2O,3mmol potassium phosphate and 0.5ml N,N-dimethylformamide solution, heated to 110 C to stir the reaction,After the TLC reaction was completed, the reaction was quenched with water and filtered for ethyl acetate.Washed with saturated brine, dried and concentrated.The product was obtained by silica gel column chromatography.
83%
With caesium carbonate;iron(III) acetylacetonate; copper(II) oxide; In N,N-dimethyl-formamide; at 90℃; for 30h;sealed tube;Conversion of starting material;
Preparation of 1-phenyl-1H-[1,2,4]triazole [0220] Following General Procedure A (90 0C, 30 hours), 1/-/-[1 ,2,4]triazole (104 mg, 1.5 mmol) is coupled with iodo-benzene (112 muL, 1.0 mmol). The crude brown oil is purified by flash chromatography on silica gel (eluent: dichloromethane/hexanes = 50/50) to provide 120 mg (83 % isolated yield) of the desired product as a light yellow solid. <n="50"/>007/001836_ 49 -IdentificationMp: 460C.1H NMR (400 MHz, CDCI3): delta 8.49 (s, 1 H1 H8), 8.03 (s, 1H, H7), 7.58-7.61 (m, 2H, H2i6), 7.40-7.44 (t, 2H1 H3,5), 7.31-7.33 (t, 1 H, H4).13C NMR (100 MHz, CDCI3): delta 152.62 (C7), 140.91 (C8), 136.99 (C1), 129.77 (C3,5), 128.21 (C4), 120.04 (C2i6).IR (KBr) : v (cm'1) = 3105, 2924, 2852, 1600, 1514, 1416, 1359, 1278, 1223,1152, 1055, 981 , 876, 754, 681 , 671 , 503.GC/MS: rt = 15.28 min, M/Z = 145.HRMS: 146.0721 (M+H). Theoretical: 146.0718
71%
A flask was charged with K2CO3 (12.1689 g, 88 mmol), 1H-1,2,4-triazole (2.0042 g, 29 mmol), Cu2O(430 mg, 3 mmol) and 1,10-phenanthroline (1.0452 g, 5.8 mmol) and then evacuated and back-filled with N2. Then, anhydrous DMF (20 ml) and iodobenzene (8.9764 g, 4.92 ml, 44 mmol) were added and the resulting mixture was heated to 120 C for 64 h and then diluted with CH2Cl2 (40 ml). The mixture was filtered through a pad of Celite and the residue washed with CH2Cl2 (20 ml). The resulting organic layer was washed with water (20 ml) and brine (20 ml), dried over MgSO4 and concentrated under reduced pressure. The crude mixture was purified by column chromatography (cyclohexane/ethyl acetate 8/0?2/0) to yield the product as a pale yellow solid (2.986 g, 71%).
65%
EXAMPLE 108 1-phenyltriazole 1 g (0.0145 mol) triazole 2, 0.21 g (0.00145 mol) copper(I)oxide, 0.29 g (0.00145 mol) phenantroline monohydrate and 6.01 g (0.044 mol) potassium carbonate are weighed into a Schlenk flask. After repeated evacuating and flushing with argon, 10 ml dry DMF is added. Evacuating and flushing with argon are repeated several times. Subsequently, 2.42 ml (4.43 g, 0.022 mol) of iodobenzene is added. The reaction mixture is stirred for 48 h at 100 C. under argon. After cooling 20 ml DCM is added and filtered. The solvent is removed in vacuum and the product is obtained after purification by column chromatography (KG 60, gradient petroleum ether/EtOAc 8:2 to EtOAc) as a yellowish-white solid.M 145.17 C8H7N3 Yield: 1.362 g (65%)1H-NMR DM-94 (300 MHz/DMSO): (ppm)=7.41 (t, 1H, 6-H); 7.58 (t, 2H, 5/5'-H); 7.87 (d, 2H, 4-H); 8.25 (s, 1H, 1-H); 9.31 (s, 1H, 2-H)13C-NMR DM-94 (75.475 MHz/DMSO): (ppm)=119.37 (5/5'-C); 127.78 (6-C); 129.77 (4/4'-C); 136.74 (3-C); 142.27 (2-C); 152.39 (1-C)
With copper(I) 3-metthylsalicylate; potassium carbonate; In dimethyl sulfoxide; at 110℃; for 3h;
General procedure: A dry flask was charged with the nitrogen containing heterocycles (1.5 mmol), aryl halides (1 mmol), potassium carbonate(2 mmol) and CuMeSal (0.01 mmol) then anhydrous DMSO (5 ml) was added. The reaction mixture was stirred at 110°C, open to air, for 3h , cooled to room temperature, filtered, and the precipitate was washed with DMSO (2 ml) then stirred with ice water (30 ml) and extracted with ethyl acetate (3 × 50 ml),dried over sodium sulfate and the solvent was removed under reduced pressure.The residue was purified by chromatography or recrystallization as indicated with each compound.
6.32 g
, adding 50 mmol of sodium methoxide into 50 mmol of 1, 2, 4-triazole (shown in the formula II)) and 50 mL of methanol solution, stirring for 60 minutes at 40 DEG c, and dropwise adding 60 mmol of bromobenzene, carrying out condensation reflux for 16 hours at the temperature of 90 DEG c, removing volatile matters in the reaction raffinate, washing the carbon tetrachloride, and filtering the solid impurities, and carrying out rotary evaporation to remove the washing solvent to obtain colorless liquid 1-phenyl -1,2,4-triazole 6.32g
Preparation Example 5 Preparation of 5-(4-chlorobenzyl)-2,2-dimethyl-1-(1H-1,2,4-triazol-1-ylmethyl)cyclopentanol 4.40 g (0.11 mol) of sodium hydroxide was charged in a 200 ml four-necked flask equipped with a condenser with a calcium chloride tube, a stirrer, a thermometer, a nitrogen inlet tube, and a water trap. 5 ml of water and 45 ml of N-methyl-2-pyrrolidone were added, and the mixture was stirred to dissolve the sodium hydroxide. Then, 7.60 g (0.11 mol) of 1H-1,2,4-triazole was added and dissolved, followed by the addition of 40 ml of toluene. The mixture was heated at 125 C. with stirring to evaporate and remove 7 ml of water from the reaction system while refluxing toluene, thus reducing the water content of the mixture in the reactor to about 1000 ppm. Then, 5.94 g (0.10 mol) of calcium oxide was added at the same temperature, followed by the addition of 5.61 g (0.10 mol) of potassium hydroxide powder. After further addition of 23.68 g (0.1 mol) of 5-(4-chlorobenzyl)-2,2-dimethylcyclopentanone, 25.95 g (0.15 mol) of <strong>[25596-24-1]trimethylsulfoxonium bromide</strong> was added in portions over 4 hours. The mixture was heated for a further 2 hours while stirring. After the reaction, the reaction mixture was cooled to room temperature and the precipitate was separated by filtration. The filtrate was poured into ice water and extracted with toluene, and the extract was washed with water. The toluene layer was dried over anhydrous sodium sulfate and toluene was evaporated under reduced pressure to obtain 29.50 g of an oily matter. This oily matter was purified by silica gel column chromatography, to obtain 20.47 g (yield: 64.0%) of the title compound.
2-(4-chlorobenzyl)-1-(1H-1,2,4-triazol-1-ylmethyl)cycloheptanol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium hydroxide; In water; toluene;
Preparation Example 14 Preparation of 2-(4-chlorobenzyl)-1-(1H-1,2,4-triazol-1-ylmethyl)cycloheptanol 4.40 g (0.11 mol) of sodium hydroxide was charged in a 200 ml four-necked flask equipped with a condenser with a calcium chloride tube, a stirrer, a thermometer, a nitrogen inlet tube, and a water trap. 5 ml of water and 45 ml of N-methyl-2-pyrrolidone were added, and the mixture was stirred to dissolve the sodium hydroxide. Then, 7.60 g (0.11 mol) of 1H-1,2,4-triazole was added and dissolved, followed by the addition of 40 ml of toluene. The mixture was heated at 125 C. with stirring to evaporate and remove 7 ml of water from the reaction system while refluxing toluene, thus reducing the water content of the mixture in the reactor to about 1000 ppm. Next, 15.3 g (0.10 mol) of barium oxide was added at the same temperature. After the addition of 23.68 g (0.1 mol) of 2-(4-chlorobenzyl)cycloheptanone, 22.49 g (0.13 mol) of <strong>[25596-24-1]trimethylsulfoxonium bromide</strong> was added in portions over 4 hours. The mixture was heated for a further 2 hours while stirring. After the reaction, the reaction mixture was cooled to room temperature and the precipitate was separated by filtration. The filtrate was poured into ice water and extracted with toluene, and the extract was washed with water. The toluene layer was dried over anhydrous sodium sulfate and toluene was evaporated under reduced pressure to obtain 29.44 g of an oily matter. This oily matter was purified by silica gel column chromatography, to obtain 20.79 g (yield: 65.0%) of the title compound.
Preparation Example 7 Preparation of 5-(4-chlorobenzyl)-2,2-dimethyl-1-(1H-1,2,4-triazol-1-ylmethyl)cyclopentanol 6.17 g (0.11 mol) of potassium hydroxide was charged in a 200 ml four-necked flask equipped with a condenser with a calcium chloride tube, a stirrer, a thermometer, a nitrogen inlet tube, and a water trap. 10 ml of water and 45 ml of N-methyl-2-pyrrolidone were added, and the mixture was stirred to dissolve the potassium hydroxide. Then, 7.60 g (0.11 mol) of 1H-1,2,4-triazole was added and dissolved, followed by the addition of 40 ml of toluene. The mixture was heated at 125 C. with stirring to evaporate and remove 12 ml of water from the reaction system while refluxing toluene, thus reducing the water content of the mixture in the reactor to about 1000 ppm. Then, 5.61 g (0.10 mol) of calcium oxide was added at the same temperature, followed by the addition of 4.0 g (0.10 mol) of sodium hydroxide powder. After further addition of 23.68 g (0.1 mol) of 5-(4-chlorobenzyl)-2,2-dimethylcyclopentanone, 25.95 g (0.15 mol) of <strong>[25596-24-1]trimethylsulfoxonium bromide</strong> was added in portions over 4 hours. The mixture was heated for a further 2 hours while stirring. After the reaction, the reaction mixture was cooled to room temperature and the precipitate was separated by filtration. The filtrate was poured into ice water and extracted with toluene, and the extract was washed with water. The toluene layer was dried over anhydrous sodium sulfate and toluene was evaporated under reduced pressure to obtain 30.50 g of an oily matter. This oily matter was purified by silica gel column chromatography, to obtain 23.0 g (yield: 72.0%) of the title compound.
2-(4-phenylbenzyl)-1-(1H-1,2,4-triazol-1-ylmethyl)-1-cyclopentanol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium hydroxide; In water; toluene;
Preparation Example 15 Preparation of 2-(4-phenylbenzyl)-1-(1H-1,2,4-triazol-1-ylmethyl)cyclopentanol 4.40 g (0.11 mol) of sodium hydroxide was charged in a 200 ml four-necked flask equipped with a condenser with a calcium chloride tube, a stirrer, a thermometer, a nitrogen inlet tube, and a water trap. 5 ml of water and 45 ml of N-methyl-2-pyrrolidone were added, and the mixture was stirred to dissolve the sodium hydroxide. Then, 7.60 g (0.11 mol) of 1H-1,2,4-triazole was added and dissolved, followed by the addition of 40 ml of toluene. The mixture was heated at 125 C. with stirring to evaporate and remove 7 ml of water from the reaction system while refluxing toluene, thus reducing the water content of the mixture in the reactor to about 1000 ppm. Next, 15.3 g (0.10 mol) of barium oxide was added at the same temperature. After the addition of 24.80 g (0.1 mol) of 2-(4-phenylbenzyl)cyclopentanone, 22.49 g (0.13 mol) of <strong>[25596-24-1]trimethylsulfoxonium bromide</strong> was added in portions over 4 hours. The mixture was heated for a further 2 hours while stirring. After the reaction, the reaction mixture was cooled to room temperature and the precipitate was separated by filtration. The filtrate was poured into ice water and extracted with toluene, and the extract was washed with water. The toluene layer was dried over anhydrous sodium sulfate and toluene was evaporated under reduced pressure to obtain 30.53 g of an oily matter. This oily matter was purified by silica gel column chromatography, to obtain 22.57 g (yield: 68.0%) of the title compound. m.p. 145-148 C.
Preparation Example 1 Preparation of 5-(4-chlorobenzyl)-2,2-dimethyl-1-(1H-1,2,4-triazol-1-ylmethyl)cyclopentanol 4.4 g (0.11 mol) of sodium hydroxide was charged in a 200 ml four-necked flask equipped with a condenser with a calcium chloride tube, a stirrer, a thermometer, a nitrogen inlet tube, and a water trap. 5 ml of water and 45 ml of N-methyl-2-pyrrolidone were added, and the mixture was stirred to dissolve the sodium hydroxide. Then, 7.60 g (0.11 mol) of 1H-1,2,4-triazole was added and dissolved, followed by the addition of 35 ml of toluene. The mixture was heated at 125 C. with stirring to evaporate and remove 7 ml of water from the reaction system while refluxing toluene, thus reducing the water content of the mixture in the reactor to about 1000 ppm. The reaction temperature was decreased to 115 C., and 15.3 g (0.10 mol) of barium oxide was added. After further addition of 23.68 g (0.1 mol) of 5-(4-chlorobenzyl)-2,2-dimethylcyclopentanone at the same temperature, 22.49 g (0.13 mol) of <strong>[25596-24-1]trimethylsulfoxonium bromide</strong> was added in portions over 4 hours. The mixture was heated for a further 2 hours while being stirred. After the reaction, the reaction mixture was cooled to room temperature and the precipitate was separated by filtration. The filtrate was poured into ice water and extracted with toluene, and the extract was washed with water. The toluene layer was dried over anhydrous sodium sulfate and toluene was evaporated under reduced pressure to obtain 32.50 g of an oily matter. This oily matter was purified by silica gel column chromatography, to obtain 23.04 g (yield: 72.03%) of the title compound. m.p. 113-115 C.
With sodium hydroxide; In water; toluene;
Preparation Example 2 Preparation of 5-(4-chlorobenzyl)-2,2-dimethyl-1-(1H-1,2,4-triazol-1-ylmethyl)cyclopentanol 4.40 g (0.11 mol) of sodium hydroxide was charged in a 200 ml four-necked flask equipped with a condenser with a calcium chloride tube, a stirrer, a thermometer, a nitrogen inlet tube, and a water trap. 5 ml of water and 45 ml of N-methyl-2-pyrrolidone were added, and the mixture was stirred to dissolve the sodium hydroxide. Then, 7.60 g (0.11 mol) of 1H-1,2,4-triazole was added and dissolved, followed by the addition of 40 ml of toluene. The mixture was heated at 125 C. with stirring to evaporate and remove 7 ml of water from the reaction system while refluxing toluene, thus reducing the water content of the mixture in the reactor to about 1000 ppm. Then, 5.61 g (0.10 mol) of calcium oxide was added at the same temperature, followed by the addition of 4.00 g (0.10 mol) of sodium hydroxide powder. After further addition of 23.68 g (0.1 mol) of 5-(4-chlorobenzyl)-2,2-dimethylcyclopentanone, 25.95 g (0.15 mol) of <strong>[25596-24-1]trimethylsulfoxonium bromide</strong> was added in portions over 4 hours. The mixture was heated for a further 2 hours while stirring. After the reaction, the reaction mixture was cooled to room temperature and the precipitate was separated by filtration. The filtrate was poured into ice water and extracted with toluene, and the extract was washed with water. The toluene layer was dried over anhydrous sodium sulfate and toluene was evaporated under reduced pressure to obtain 31.86 g of an oily matter. This oily matter was purified by silica gel column chromatography, to obtain 23.2 g (yield: 72.53%) of the title compound.
With sodium hydroxide; In water; toluene;
Preparation Example 3 Preparation of 5-(4-chlorobenzyl)-2,2-dimethyl-1-(1H-1,2,4-triazol-1-ylmethyl)cyclopentanol 4.00 g (0.1 mol) of sodium hydroxide was charged in a 200 ml four-necked flask equipped with a condenser with a calcium chloride tube, a stirrer, a thermometer, a nitrogen inlet tube, and a water trap. 5 ml of water and 45 ml of N-methyl-2-pyrrolidone were added, and the mixture was stirred to dissolve the sodium hydroxide. Then, 6.91 g (0.10 mol) of 1H-1,2,4-triazole was added and dissolved, followed by the addition of 35 ml of toluene. The mixture was heated at 125 C. with stirring to evaporate and remove 7 ml of water from the reaction system while refluxing toluene, thus reducing the water content of the mixture in the reactor to about 1000 ppm. Then, 4.03 g (0.10 mol) of magnesium oxide was added at the same temperature, followed by the addition of 4.00 g (0.10 mol) of sodium hydroxide powder. After further addition of 23.68 g (0.1 mol) of 5-(4-chlorobenzyl)-2,2-dimethylcyclopentanone, 25.95 g (0.15 mol) of <strong>[25596-24-1]trimethylsulfoxonium bromide</strong> was added in portions over 4 hours. The mixture was heated for a further 2 hours while stirring. After the reaction, the reaction mixture was cooled to room temperature and the precipitate was separated by filtration. The filtrate was poured into ice water and extracted with toluene, and the extract was washed with water. The toluene layer was dried over anhydrous sodium sulfate and toluene was evaporated under reduced pressure to obtain 29.75 g of an oily matter. This oily matter was purified by silica gel column chromatography, to obtain 22.07 g (yield: 69.0%) of the title compound.
With sodium hydroxide; In water; toluene;
Preparation Example 4 Preparation of 5-(4-chlorobenzyl)-2,2-dimethyl-1-(1H-1,2,4-triazol-1-ylmethyl)cyclopentanol 4.00 g (0.1 mol) of sodium hydroxide was charged in a 200 ml four-necked flask equipped with a condenser with a calcium chloride tube, a stirrer, a thermometer, a nitrogen inlet tube, and a water trap. 5 ml of water and 45 ml of N-methyl-2-pyrrolidone were added, and the mixture was stirred to dissolve the sodium hydroxide. Then, 6.91 g (0.10 mol) of 1H-1,2,4-triazole was added and dissolved, followed by the addition of 40 ml of toluene. The mixture was heated at 125 C. with stirring to evaporate and remove 7 ml of water from the reaction system while refluxing toluene, thus reducing the water content of the mixture in the reactor to about 1000 ppm. The reaction mixture was cooled to 115 C., and 5.61 g (0.10 mol) of calcium oxide was added, followed by the addition of 4.00 g (0.10 mol) of sodium hydroxide powder. After further addition of 23.68 g (0.1 mol) of 5-(4-chlorobenzyl)-2,2-dimethylcyclopentanone, 25.95 g (0.15 mol) of <strong>[25596-24-1]trimethylsulfoxonium bromide</strong> was added in portions over 4 hours. The mixture was heated for a further 3 hours while stirring. After the reaction, the reaction mixture was cooled to room temperature and the precipitate was separated by filtration. The filtrate was poured into ice water and extracted with toluene, and the extract was washed with water. The toluene layer was dried over anhydrous sodium sulfate and toluene was evaporated under reduced pressure to obtain 33.76 g of an oily matter. This oily matter was purified by silica gel column chromatography, to obtain 21.28 g (yield: 66.53%) of the title compound.
With sodium hydroxide; In water; toluene;
Preparation Example 8 Preparation of 5-(4-chlorobenzyl)-2,2-dimethyl-1-(1H-1,2,4-triazol-1-ylmethyl)cyclopentanol 4.40 g (0.11 mol) of sodium hydroxide was charged in a 200 ml four-necked flask equipped with a condenser with a calcium chloride tube, a stirrer, a thermometer, a nitrogen inlet tube, and a water trap. 5 ml of water and 45 ml of N-methyl-2-pyrrolidone were added, and the mixture was stirred to dissolve the sodium hydroxide. Then, 7.60 g (0.11 mol) of 1H-1,2,4-triazole was added and dissolved, followed by the addition of 40 ml of toluene. The mixture was heated at 125 C. with stirring to evaporate and remove 7 ml of water from the reaction system while refluxing toluene, thus reducing the water content of the mixture in the reactor to about 1000 ppm. Then, 5.61 g (0.10 mol) of calcium oxide and 15.3 g (0.10 mol) of barium oxide were added at the same temperature. After further addition of 23.68 g (0.1 mol) of 5-(4-chlorobenzyl)-2,2-dimethylcyclopentanone, 25.95 g (0.15 mol) of <strong>[25596-24-1]trimethylsulfoxonium bromide</strong> was added in portions over 4 hours. The mixture was heated for a further 2 hours while stirring. After the reaction, the the reaction mixture was cooled to room temperature and the precipitate was separated by filtration. The filtrate was poured into ice water and extracted with toluene, and the extract was washed with water. The toluene layer was dried over anhydrous sodium sulfate and toluene was evaporated under reduced pressure to obtain 33.57 g of an oily matter. This oily matter was purified by silica gel column chromatography, to obtain 23.35 g (yield: 73.0%) of the title compound.
2-(4-chlorobenzyl)-5-(1-methylethyl)cyclopentanone[ No CAS ]
[ 25596-24-1 ]
[ 125225-28-7 ]
Yield
Reaction Conditions
Operation in experiment
With sodium hydroxide; In water; toluene;
Preparation Example 11 Preparation of 2-(4-chlorobenzyl)-5-(1-methylethyl)-1-(1H-1,2,4-triazol-1-ylmethyl)cyclopentanol 4.40 g (0.11 mol) of sodium hydroxide was charged in a 200 ml four-necked flask equipped with a condenser with a calcium chloride tube, a stirrer, a thermometer, a nitrogen inlet tube, and a water trap. 5 ml of water and 45 ml of N-methyl-2-pyrrolidone were added, and the mixture was stirred to dissolve the sodium hydroxide. Then, 7.60 g (0.11 mol) of 1H-1,2,4-triazole was added and dissolved, followed by the addition of 40 ml of toluene. The mixture was heated at 125 C. with stirring to evaporate and remove 7 ml of water from the reaction system while refluxing toluene, thus reducing the water content of the mixture in the reactor to about 1000 ppm. Next, 5.61 g (0.10 mol) of calcium oxide was added at the same temperature, followed by the addition of 4.0 g (0.10 mol) of sodium hydroxide powder. After the addition of 25.08 g (0.1 mol) of 2-(4-chlorobenzyl)-5-(1-methylethyl)cyclopentanone, 25.95 g (0.15 mol) of <strong>[25596-24-1]trimethylsulfoxonium bromide</strong> was added in portions over 4 hours. The mixture was heated for a further 2 hours while stirring. After the reaction, the reaction mixture was cooled to room temperature and the precipitate was separated by filtration. The filtrate was poured into ice water and extracted with toluene, and the extract was washed with water. The toluene layer was dried over anhydrous sodium sulfate and toluene was evaporated under reduced pressure to obtain 33.44 g of an oily matter. This oily matter was purified by silica gel column chromatography, to obtain 23.3 g (yield: 70.0%) of the title compound.
With sodium hydroxide; In water; toluene;
Preparation Example 12 Preparation of 2-(4-chlorobenzyl)-5-(1-methylethyl)-1-(1H-1,2,4-triazol-1-ylmethyl)cyclopentanol 4.40 g (0.11 mol) of sodium hydroxide was charged in a 200 ml four-necked flask equipped with a condenser with a calcium chloride tube, a stirrer, a thermometer, a nitrogen inlet tube, and a water trap. 5 ml of water and 45 ml of N-methyl-2-pyrrolidone were added, and the mixture was stirred to dissolve the sodium hydroxide. Then, 7.60 g (0.11 mol) of 1H-1,2,4-triazole was added and dissolved, followed by the addition of 40 ml of toluene. The mixture was heated at 125 C. with stirring to evaporate and remove 7 ml of water from the reaction system while refluxing toluene, thus reducing the water content of the mixture in the reactor to about 1000 ppm. Next, 15.3 g (0.10 mol) of barium oxide was added at the same temperature. After the addition of 25.08 g (0.1 mol) of 2-(4-chlorobenzyl)-5-(1-methylethyl)cyclopentanone, 22.49 g (0.13 mol) of <strong>[25596-24-1]trimethylsulfoxonium bromide</strong> was added in portions over 4 hours. The mixture was heated for a further 2 hours while stirring. After the reaction, the reaction mixture was cooled to room temperature and the precipitate was separated by filtration. The filtrate was poured into ice water and extracted with toluene, and the extract was washed with water. The toluene layer was dried over anhydrous sodium sulfate and toluene was evaporated under reduced pressure to obtain 32.86 g of an oily matter. This oily matter was purified by silica gel column chromatography, to obtain 23.98 g (yield: 72.0%) of the title compound.
2-(4-chlorobenzyl)-1-(1H-1,2,4-triazol-1-ylmethyl)cyclohexanol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium hydroxide; In water; toluene;
Preparation Example 13 Preparation of 2-(4-chlorobenzyl)-1-(1H-1,2,4-triazol-1-ylmethyl)cyclohexanol 4.40 g (0.11 mol) of sodium hydroxide was charged in a 200 ml four-necked flask equipped with a condenser with a calcium chloride tube, a stirrer, a thermometer, a nitrogen inlet tube, and a water trap. 5 ml of water and 45 ml of N-methyl-2-pyrrolidone were added, and the mixture was stirred to dissolve the sodium hydroxide. Then, 7.60 g (0.11 mol) of 1H-1,2,4-triazole was added and dissolved, followed by the addition of 40 ml of toluene. The mixture was heated at 125 C. with stirring to evaporate and remove 7 ml of water from the reaction system while refluxing toluene, thus reducing the water content of the mixture in the reactor to about 1000 ppm. Next, 5.61 g (0.10 mol) of calcium oxide was added at the same temperature, followed by the further addition of 4.0 g (0.10 mol) of sodium hydroxide powder. After the addition of 22.27 g (0.1 mol) of 2-(4-chlorobenzyl)cyclohexanone, 25.99 g (0.15 mol) of <strong>[25596-24-1]trimethylsulfoxonium bromide</strong> was added in portions over 4 hours. The mixture was heated for a further 2 hours while stirring. After the reaction, the reaction mixture was cooled to room temperature and the precipitate was separated by filtration. The filtrate was poured into ice water and extracted with toluene, and the extract was washed with water. The toluene layer was dried over anhydrous sodium sulfate and toluene was evaporated under reduced pressure to obtain 32.51 g of an oily matter. This oily matter was purified by silica gel column chromatography, to obtain 23.2 g (yield: 65.0%) of the title compound.
With sodium hydroxide; In ISOPROPYLAMIDE; water; toluene;
Preparation Example 6 Preparation of 5-(4-chlorobenzyl)-2,2-dimethyl-1-(1H-1,2,4-triazol-1-ylmethyl)cyclopentanol 4.40 g (0.11 mol) of sodium hydroxide was charged in a 200 ml four-necked flask equipped with a condenser with a calcium chloride tube, a stirrer, a thermometer, a nitrogen inlet tube, and a water trap. 10 ml of water and 45 ml of dimethylacetamide were added, and the mixture was stirred to dissolve the sodium hydroxide. Then, 7.60 g (0.11 mol) of 1H-1,2,4-triazole was added and dissolved, followed by the addition of 40 ml of toluene. The mixture was heated at 120 C. with stirring to evaporate and remove 12 ml of water from the reaction system while refluxing toluene, thus reducing the water content of the mixture in the reactor to about 1000 ppm. Then, 15.3 g (0.10 mol) of barium oxide was added at the same temperature. After further addition of 23.68 g (0.1 mol) of 5-(4-chlorobenzyl)-2,2-dimethylcyclopentanone at the same temperature, 22.49 g (0.13 mol) of <strong>[25596-24-1]trimethylsulfoxonium bromide</strong> was added in portions over 4 hours. The mixture was heated for a further 2 hours while stirring. After the reaction, the reaction mixture was cooled to room temperature and the precipitate was separated by filtration. The filtrate was poured into ice water and extracted with toluene, and the extract was washed with water. The toluene layer was dried over anhydrous sodium sulfate and toluene was evaporated under reduced pressure to obtain 29.95 g of an oily matter. This oily matter was purified by silica gel column chromatography, to obtain 19.19 g (yield: 60.0%) of the title compound.
With potassium carbonate; In acetonitrile; at 60℃;
General procedure: A suspension of potassium carbonate (27.6 g, 0.20 mmol), 1H-1,2,4-triazole (9.8 g, 0.14 mol) and compound 3 (26.6 g, 0.14 mol) was stirred in acetonitrile (30 mL) at 60 C. After the reaction was completed (monitored by TLC, eluent, ethyl acetate/methanol, 15/1, V/V), the solvent was removed and the residue was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and filtered. After concentrating the filtrate, the crude product was purified by column chromatography on silica gel eluting with ethyl acetate/methanol (15/1, V/V) to give compound 4 (25.9 g) as white solid. Yield: 83.1%
With potassium carbonate; In isopropyl alcohol; at 75℃; for 16h;
702 ml of isopropanol and 50 g of 1-[2-(2,4-difluorophenyl)-oxiranyl methyl]-1H-1,2,4-triazole obtained above was taken into a round bottom flask. 22.5 g of 1,2,4-triazole and 63.7 g of potassium carbonate were added to the above reaction mass under stirring. The reaction mass was heated to 75 C. The reaction mass was maintained at 75 C. for 16 hours. Reaction completion was checked using thin layer chromatography. After completion of the reaction, the reaction mass was cooled to 30 C. The reaction mass was then filtered and the filter bed was washed with 70 ml of isopropanol in two equal lots. The filtrate was taken into a separate round bottom flask and distilled at 65 C. To the residue obtained 140.5 ml of deionized water was added. The reaction mass was maintained at 66 C. for 30 minutes. The reaction mass was then cooled to 10 C. The separated solid was filtered and washed with 14 ml of deionized water. The wet material was taken into a separate round bottom flask and 267 ml of deionized water was added to it. The reaction mass was heated to 98 C. 2.25 g of carbon was charged into the reaction mass and maintained at 98 C. for 30 minutes. The reaction mass was filtered and the carbon bed was washed with 32.5 ml of deionized water. The filtrate was cooled to 12 C. and maintained for 45 minutes. The separated solid was filtered and washed with 32.5 ml of deionized water. The wet material was taken into another round bottom flask and 1220 ml of chloroform was added to it. The reaction mass was checked for clear dissolution. 1030 ml of water, 51.5 g of citric acid, and 103 g of sodium chloride were taken into a separate round bottom flask and stirred for 5 minutes. The chloroform layer obtained above was washed with the above solution in 3 equal lots. The organic layer was then subjected to distillation under a vacuum of 300 mm Hg at 45 C. 103 ml of water was charged to the residue obtained and heating given to 96 C. 1.2 g of carbon was added to the reaction mass and maintained at 96 C. for 30 minutes. The reaction mass was then filtered under hot conditions and the carbon bed was washed with 32.5 ml of deionized water. The filtrate was cooled to 10 C. and maintained for 1 hour. The separated compound was filtered and washed with 26 ml of chilled deionized water. The wet compound was dried in oven at 65 C. for 2 hours to yield 34 g of the title compound. Purity by HPLC: 99.98%
With n-butyllithium; potassium carbonate; In N-methyl-acetamide; methanol; diethyl ether; hexane; dichloromethane; water; acetic acid;
EXAMPLE 1 A solution consisting of 960 mg. (0.005 mole) of 1-bromo-2,4-difluorobenzene dissolved in 10 ml. of diethyl ether was stirred at -78 C., while 3.23 ml. of 1.55 M n-butyl lithium (0.005 mole) in n-hexane was slowly added thereto over a period of three minutes. After the addition was complete, the mixture was stirred for a further period of ten minutes and then a solution consisting of 630 mg. (0.005 mole) of 1,3-dichloroacetone dissolved in 10 ml. of diethyl ether was added dropwise to the stirred etheral mixture over a period of three minutes. After the latter addition was complete, the reaction mixture was stirred for a further period of 30 minutes of -78 C., while a solution consisting of 330 mg. of glacial acetic acid dissolved in 5 ml. of diethyl ether was slowly added thereto at 0 C., followed by the addition of 10 ml. of water. Upon completion of this step, the organic layer was separated and the aqueous phase was extracted once with fresh diethyl ether. The combined ethereal extracts were then dried over anhydrous magnesium sulfate and filtered, and the resulting filtrate was subsequently evaporated under reduced pressure to afford a pale yellow oil as the residual liquid. The latter material, which consisted essentially of pure 1,3-bischloro-2-(2,4-difluorophenyl)propane-2-ol, was dissolved in 20 ml. of dimethylformamide and used as such in the next reaction step. To the solution prepared above, 1.72 g. (0.025 mole) of 1,2,4-triazole and 2.07 g. (0.015 mole) of anhydrous potassium carbonate were added and the resulting mixture was heated at 70 C. for a period of 18 hours. The reaction mixture thus obtained was then poured into 100 ml. of water and the resulting aqueous mixture was extracted twice with ethyl acetate. The combined organic extracts were then dried over anhydrous magnesium sulfate and filtered, and the resulting filtrate was subsequently evaporated under reduced pressure to give a gum. The latter material was then chromatographed on silica (270-400 mesh), using 3% methanol in methylene chloride as the eluant, to ultimately afford 400 mg. (26%) of pure 2-(2,4-difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)propan-2-ol in the form of a white solid, m.p. 138-140 C. after recrystallization from ethyl acetate/n-hexane.
EXAMPLE 3 According to the operation mode of Example 1, 280 ml of formamide are heated to 170° C., and a mixture of 1.2 mols of N,N'-<strong>[628-36-4]diformylhydrazine</strong> and 1.2 mols (94.8 g) of ammonium hydrogen carbonate is added. 16.9 g of water and formamide are distilled off. Yield: 89.9percent of 1,2,4-triazole, m.p. 116° C.
With thionyl chloride; potassium carbonate; In water; acetonitrile;
EXAMPLE 2 2-(2-Chloro-4-methanesulphonylbenzoyl)-1,3-cyclohexanedione from the acid chloride. 2-Chloro-4-methanesulphonylbenzoyl chloride (5 g) was prepared by the reaction of 2-chloro-4-methanesulphonylbenzoic acid with thionyl chloride. The acid chloride was dissolved in acetonitrile (40 ml). A mixture of 1,3-cyclohexanedione (2.24 g), potassium carbonate (6.9 g) and acetonitrile (40 ml) was stirred at room temperature for 4 hours. To this solution was added the acid chloride solution over 10 min and allowed to stir 1 hour. 1,2,4-Triazole (0.07 g) was then added and the mixture allowed to stir 16 hours at room temperature. The solvent was removed and the residue was dissolved in water and acidified. The product was extracted into dichloromethane and the solvent was dried then evaporated to give the desired product in 83.6percent yield.
2-Chloro-4-methanesulphonyl benzoyltriazolamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
57.4%
With thionyl chloride; In N-methyl-acetamide; toluene;
EXAMPLE 6 2-Chloro-4-methanesulphonyl benzoyltriazolamide 2-Chloro-4-methanesulphonylbenzoic acid (2.355 g) was suspended in toluene (150 ml) and dimethylformamide (0.1 ml) was added via a syringe. The suspension was heated to 75° C., then thionyl chloride (0.8 ml) in toluene (10 ml) added over 30 minutes. The suspension was heated for 1 hour to effect reaction, refluxed for 1 hour to remove acidic gases, then added via a cannula to a stirred suspension of 1,2,4-triazole (1.390 g) in toluene. The resultant suspension was stirred at room temperature for 48 hours then filtered. The precipitate was extracted with dichloromethane, and the solvent removed under reduced pressure to afford the title compound as a colourless powder (1.635 g, 57.4percent). Recrystalisation from ethyl acetate produced the compound as colourless spines. 1H NMR (200 MHz, CDCl3): 9.14 (1H,s,NCH), 8.12 (1H, d, J 1.5 Hz. H3) 8.09 (1H, s, NCH), 8.02 (1H.dd, J 8.1.J' 1.6 Hz, H5), 7.79 (1H,d,J 8.1 Hz, H6), 3.16 (3H,s,Me). 13C NMR (200 MHz, CDCl3): 163.82, 154.04, 144.65, 144.57, 136.32, 134.54, 130.78, 129.20, 125.77, 44.33.
With caesium carbonate; In dimethyl sulfoxide; at 55℃; for 1.5h;
A mixture of known <strong>[89284-61-7]4-chloro-nicotinonitrile</strong> (3.325 g, 24 mmol) (Tetrahedron Lett. 46:135-137, 2005), 1H-[1,2,4]triazole (1.99 g, 28.8 mmol), and CsCO3 (9.30 g, 28.5 mmol) in DMSO (5.0 mL) was stirred at 55 C. for 1.5 h. The resulting thin light brown slurry was shaken with water (50 mL) and extracted with DCM (1×50 mL, 2×25 mL). The organic layers were combined, dried (Na2SO4), and concentrated under vacuum at 90 C. to afford the title compound as a beige solid (3.38 g, 82%).
With potassium carbonate; In dimethyl sulfoxide; at 20℃; for 17h;
Step A: Preparation of 2-Methyl-3-nitro-6-(1H-1,2,4-triazol-1-yl)pyridine. A mixture of <strong>[22282-96-8]6-bromo-2-methyl-3-nitropyridine</strong> (5.0 g, 23 mmol), 1H-1,2,4-triazole (1.6 g, 23 mmol), and potassium carbonate (3.2 g, 23 mmol) in DMSO (10 mL) was stirred at room temperature for 17 h. The reaction mixture was poured into ice-water (1 L) and stirred until all the ice had melted. The ice-cold solution was filtered to give the title compound (3.4 g, 72%) as a dark purple solid. Exact mass calculated for C8H7N5O2: 205.1. Found: LCMS m/z=206.2 (M+H+).
With potassium carbonate; In dimethyl sulfoxide; at 20℃; for 36h;
Step 1: 2-Methyl-3-nitro-6-[1,2,4]triazol-1-yl-pyridine; A mixture of <strong>[22282-96-8]2-bromo-6-methyl-5-nitropyridine</strong> (ECA International Corporation, Palatine, Ill., USA; 2 g, 9.2 mmol), 1,2,4-triazole (Aldrich Chemical Company, Inc., Milwaukee, Wis., USA 0.64 g, 9.2 mmol) and potassium carbonate (1.27 g, 9.2 mmol) in dimethylsulfoxide (4 mL) was stirred at room temperature for 1.5 days and then poured into a mixture of ice and water (400 mL). The resulting mixture was stirred until all of the ice melted to give a dark purple slurry. The solid was filtered off to give 2-methyl-3-nitro-6-[1,2,4]triazol-1-yl-pyridine (1.34 g, 71%) as a purple solid with a purity estimated at 93% by LC-MS. This was used directly in the next step without further purification.
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 3h;
Step C; 1,2,4-triazoie (248 rog) is abeta to a solution of 4-fluoro~naphthalene-1- carbaldehyde (522 mg) and potassium carbonate (49? mg} in DMF (4 ml), After 3 hours at room temperature, the reaction is quenched with water {40 ml) and ethyi acetate (50 mi). The organic phase is separated and the aqueous phase is extracted two times with ethyi acetate. The organic phases are combined, extracted with water and with a saturated aqueous solution of NaCI, dried over Na2SO4 and concentrated in vacuo. The crude product is purified on a semi-preparative HPLC to yieid 4~[1,2,4]triazoi-1-ykiotaaphthaiene-1- carbaktehyde (480 mg) as beige crystals. MS (HPUC/MS): 224 (MH+), Retention ime: 2.97 min.
With potassium carbonate; In dimethyl sulfoxide; at 75℃; for 2h;Sealed tube; Inert atmosphere;
To a 100 mL dried sealed tube were added <strong>[454-16-0]1-fluoro-2-methoxy-4-nitrobenzene</strong> (0.6 g, 3.5 mmol), 1,2,4-triazole (0.36 g, 5.2 mmol) and potassium carbonate (0.9 g, 6.5 mmol), then DMSO (10 mL) was added. The sealed tube was sealed with teflon nut under nitrogen protection, then the mixture was heated to 75 °C and stirred for 2 h. The mixture was cooled to rt and to the residue was added water (60 mL). The mixture was stirred for 10 min and filtered. The filter cake was dried to give a light yellow solid (0.7 g, 90percent). MS(ESI, pos.ion) m/z: 221.1 (M+1);
With potassium carbonate; In N,N-dimethyl-formamide; at 75℃; for 1h;
A mixture of l-fluoro-2-methoxy-4-nitrobenzene (7 g, 40 mmol), IH-I, 2,4-triazole (4.28 g, 60 mmol), K2CO3 (8.3 Ig, 60 mmol) and DMF (50 ml) was stirred for 1 h at 75 0C. The solvent was evaporated and the residue was taken up in EtOAcZH2O. The aq. layer was extracted 3 times with EtOAc. The combined organic layers were dried (MgSO4), filtered and the solvent was evaporated in vacuo. Yield: 4.4 g of intermediate 13. The crude product was used as such in the next reaction step
2-(1H-1,2,4-triazol-1-yl)-5-nitropyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 0.5h;
Preparative Example 14aPreparation of tert-butyl f 6-( 1 H- 1 ,2,4-triazol- 1 -yl)pyridin-3 -yl]carbamateStep 1: 5-nitro-2-(lH-1,2,4-triazol-1-vDpvridine.<strong>[456-24-6]2-fluoro-5-nitropyridine</strong> (0.5g, 3.38mmol), 1,2,4-triazole (0.22g, 3.22mmol) were added in DMF (6.4mL), then cesium carbonate (3.14g, 9.65mmol) was added. The reaction was run at room temperature for 30 minutes. Water (5OmL) was added and product fell out of the solution. The solution was filtered and the solid was rinsed with ethyl acetate/water (1:1, 20mLx2), hot hexane(2OmL) to give the title compound as a white solid.LRMS calc: 191.15; obs: 192.15 (M+l).
With potassium carbonate; at 25℃; for 16h;
<strong>[456-24-6]2-fluoro-5-nitropyridine</strong> (30.g, 18.9 mmol) was added to a stirred solution of 1H-1,2,4-triazole (1.566 g, 22.7 mmol) and K2CO3 (5.14 g, 37.8 mmol) and stirred for 16 hrs at 25° C. Reaction mass was diluted with ice cold water and stirred for 15 min. The solid obtained was filtered and dried under vacuum to afford the desired product. MS (ESI): m/z 192 (M+H).
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃;
Example 23Preparation of N-(2- ( (JS, 2S)-2-\\ 1 -(5 -chloropyrimidin-2-yl)piperidin-4-yl] cyclopropyl } ethyl)-5 -( 1 H- 1 ,2,4-triazol- 1 -yl)pyrazin-2-amine,Step 1: 2-cMoro-5-flH--l.,2,4-triazol-1-yl')pyrazine.2,5-Dichloropyrazine (298mg, 2.0mmol) and 1,2,4-triazole (145mg, 2.1mmol) were added in DMF (1OmL), then cesium carbonate was added and the reaction was at room temperature over night. Water (2OmL) was added, extracted with ethyl acetate (3OmL), second wash with brine (2OmL). The organic phase was dried by magnesium sulfate, filtered, concentrated and purified by column chromatography through a 25 gram Biotage SNAP KP-Sil.(TM). silica gel cartridge eluting with 22percent ethyl acetate/hexanes to give the title compound as a white solid.LRMS calc: 181.58; obs: 182.21(M+1).
With potassium carbonate; In acetonitrile; at 80℃; for 0.0833333h;Sealed tube;
3-formyl-4-(lH-l,2,4-triazol-l-yl)benzonitrile In sealed microwave reactors, <strong>[146137-79-3]4-fluoro-3-formylbenzonitrile</strong> (850 mg, 5.7 mmol) was dissolved in acetonitrile (15 mL), lH-l,2,4-triazol (590 mg, 8.55 mmol, 1.5eq) and K2C03 (1575 mg, 11.39 mmol, 2 eq) were added to give a colorless suspension. Then the reaction mixture was stirred and heated at 80°C for 5min. The reaction mixture was poured into 20 mL of water, extracted with 2x 20 mL of EtOAc. The combined organic layers were washed with lx 20 mL of water, lx 20 mL of brine, dried over Na2S04, filtered and concentrated in vacuo to give an orange solid, m= 983mg. The solid was triturated with dichloromethane and petroleum ether, filtered and dried in vacuo at 45 °C overnight to give 493 mg of a brown powder (Yield : 43percent) APCI-MS: (M+H)+ =199 1H NMR (300 MHz, DMSO-d6) delta ppm: 10.01 (s, 1H), 9.33 (s, 1H), 8.46 - 8.29 (m, 3H), 8.05 (d, J = 9.0 Hz, 1H). 4-(lH-l,2,4-triazol-l-yl)nicotinaldehvde Aspect of the product: yellow solid (Yield: 49percent) APCI-MS: (M+H)+ =175 1H NMR (300 MHz, DMSO-d6) delta ppm: 10.20 (s, 1H), 9.39 (s, 1H), 8.99 - 8.91 (m, 2H), 8.39 (s, 1H), 7.90 (d, J = 5.5 Hz, 1H).
With potassium carbonate; In dimethyl sulfoxide; at 20 - 80℃;Microwave irradiation;
To a solution of <strong>[146137-79-3]5-cyano-2-fluorobenzaldehyde</strong> (200 mg, 1.34 mmol) in DMSO (8 mL) are added 1,2,4-triazole (139 mg, 2.01 mmol) and K2CO3 (370 mg, 2.7 mmol) at room temperature. The solution is heated to 80 °C for 5 minutes in a microwave reactor and then cooled down and washed with H20 (20 mL). The solution is extracted with EtOAc (3 x 15 mL). The combined organic layer is dried (MgS04), filtered and concentrated. The residue (120 mg, 45percent) is used in the next step of the synthesis without further purification.
With copper(II) acetate monohydrate; caesium carbonate; In N,N-dimethyl-formamide; at 110℃; for 24h;Inert atmosphere;
General procedure: To a solution of Cu(OAc)2·H2O (0.01 mmol) in DMF (2 mL) were added aryl iodide (1.2 mmol), nitrogen-containing heterocycle (1.0 mmol), and Cs2CO3 (2 mmol) under nitrogen atmosphere. The mixture was stirred at 110 C for 24 h. After cooling to ambient temperature, the mixture was partitioned between water and ethyl acetate. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel.
With hydrogen; nickel; In methanol; at 20℃; for 4h;
(2) Add 1,2,4 triazole 3 (5 g, 2.12 mol) to formaldehyde, sodium hydroxide,The substitution reaction occurs after hydrogen and nickel are mixed.Formation of 1-methyl-1,2,4triazole 4 (4.38 g, 2.9 mol) will give 1-methyl-1,2,4 triazole 4Add 50percent sodium hydroxide solution (100ml) to (4.38g, 2.9mol)And use chlorine gas for heating or lighting.The reaction produces 1-trichloromethyl-1,2,4 triazole 5 (3.9 g, 2.56 mol)
With potassium carbonate; In N,N-dimethyl-formamide; at 110℃; for 2h;Sealed tube;
A mixture of <strong>[454-16-0]1-fluoro-2-methoxy-4-nitrobenzene</strong> (3 g, 17.27 mmol), 1H-1,2,4-triazole (1.19 g, 17.27 mmol) and K2C03 (2.38 g, 17.27 mmol) in dimethlyformamide (20 ml) was stirred for 2h at 110°C in a sealed tube. The reaction mixture was cooled to 25°C, poured into ice cold water, and extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate, filtered, and evaporated in vacuum. The crude material thus obtained was diluted with DMSO, and filtered. The solid residue was washed with water and hexane. The filtrate was purified by prep-HPLC and combined with the solid to afford4-(2-methoxy-4-nitro-phenyl)-4H-[1, 2, 4] triazole (650 mg, 19percent) as light yellow solid. LC-MS(ESI): 221 [(M+H)+].
tert-butyl 4-(4H-1,2,4-triazol-4-yl)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
34%
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 110℃;Inert atmosphere;
Example 109, Step a: tert-butyl 4-(4H-1,2,4-triazol-4-yl)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate To a solution of Intermediate 2 (1.5 g, 5.6 mmol) in ACN (5 mL) was added 1,2,4 triazole (0.657 mL, 11.1 mmol) in one portion followed by Hunig's base (1.9 mL, 11.1 mmol). The mixture was stirred at 110 C. overnight. The solvents were removed in vacuo and chromatography on SiO2 eluting with EtOAc/Hex afforded the desired compound (579 mg, 34%). MS (ESI) mass calcd. C14H18N6O2, 302.1. m/z found 303.2 [M+H]+. 1H NMR (500 MHz, CDCl3): 9.04 (s, 1H), 7.98 (s, 2H), 4.81-4.75 (m, 2H), 3.75-3.69 (m, 2H), 3.29-3.22 (m, 2H), 1.51 (s, 9H).
tert-butyl 4-(1H-1,2,4-triazol-1-yl)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50%
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 110℃;Inert atmosphere;
Example 110, Step a: tert-butyl 4-(1H-1,2,4-triazol-1-yl)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate To a solution of Intermediate 2 (1.5 g, 5.6 mmol) in ACN (5 mL) was added 1,2,4 triazole (0.657 mL, 11.1 mmol) in one portion followed by Hunig's base (1.9 mL, 11.1 mmol). The mixture was stirred at 110 C. overnight. The solvents were removed in vacuo and chromatography on SiO2 eluting with EtOAc/Hex afforded the desired compound (855 mg, 50%). MS (ESI) mass calcd. C14H18N6O2, 302.1. m/z found 303.2 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.96 (s, 1H), 8.66-8.61 (m, 1H), 7.87-7.84 (m, 1H), 4.78 (s, 2H), 3.76-3.71 (m, 2H), 3.43-3.36 (m, 2H), 1.51 (s, 9H).
2-(4-chlorobenzyl)-8,8-dimethyl-7,9-dioxaspiro[4,5]decan-1-one[ No CAS ]
[ 25596-24-1 ]
[ 1447648-36-3 ]
Yield
Reaction Conditions
Operation in experiment
78.1%
Production Example 1 Synthesis of 2-(4-chlorobenzyl)-8,8-dimethyl-1-(1H-1,2,4-triazol-1-ylmethyl)-7,9-dioxaspiro[4,5]decan-1-ol (compound V-1; azole derivative (Vb) in which R3=CH3, R4=CH3, p=1, q=1, Xm=4-Cl, A=N) In dehydrated N,N-dimethylacetamide (6.18 mL), 1,2,4-triazole (compound I-1; compound (I) in which A=N) (15.0 mmol) was dissolved and the mixture was heated to 85 C. Thereafter, a 28% sodium methoxide methanol solution (15.0 mmol) was added thereto, and the mixture was heated and stirred at 85 C. for 3 hours. To the obtained reaction solution, 2-(4-chlorobenzyl)-8,8-dimethyl-7,9-dioxaspiro[4,5]decan-1-one (compound III-1; compound (IIIb) in which R3=CH3, R4=CH3, p=1, q=1, Xm=4-Cl) (10.0 mmol) and <strong>[25596-24-1]TMSOB</strong> (14.0 mmol) were then added, and a 28% sodium methoxide methanol solution (5.0 mmol) was divided and added in separate portions. After the mixture was heated and stirred at 85 C. for 100 minutes, the mixture was cooled to the room temperature, water was added, and extraction was performed using ethyl acetate. The organic layer was washed with water and a saturated salt solution, and dried with anhydrous sodium sulfate. The crude product was purified by means of silica gel chromatography, and the target compound V-1 was obtained. Product: 3.14 g Purity: 97.7% (0090) Yield: 78.1% (yield of the compound V-1 relative to the amount of the compound III-1) Properties: white solid
74.3%
[0089] First, after NaH (0.91 g (ca. 60% in mineral oil)) was suspended in N-methylpyrrolidone (NMP) (8 mL), 1,2,4-triazole (1.67 g) was added and stirred for 0.5 hours to produce a sodium salt. Next, compound (4) (5.00 g) was added.After this was heated to approximately 90C (bath temperature), <strong>[25596-24-1]trimethylsulfoxonium bromide</strong> (<strong>[25596-24-1]TMSOB</strong>) (4.20 g) andt-BuONa (0.77 g) were intermittently added over the course of 1.5 hours and then reacted for 1.5 hours. After the reactionsolution was further heated to approximately 125C (bath temperature) and reacted for 1 hour, saturated ammoniumchloride and water were added to the reaction solution and then extracted with ethyl acetate. After the organic layer wasdried with anhydrous sodium sulfate, the solvent was distilled out, and the crude product was purified by silica gel columnchromatography to obtain the target product (compound (5)) as an isomer mixture consisting of a 93:7 ratio of the cisformto the trans-form.Yield: 4.68 gYield rate: 74.3%
1,1,2,2-tetrakis-[4-(1H-1,2,4-triazol-1-yl)phenyl]ethylene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
With potassium carbonate; copper(II) oxide; In N,N-dimethyl-formamide; at 100℃; for 24h;
Equipped with a magnetic child within, a reflux condenser, a thermometer and three 50 mL round bottom flask were added CuO (0.5 mmol), potassium carbonate (15 mmol), lH-l, 2,4- triazole (5 mmol), l, l, 2,2- tetrakis (4-bromophenyl) ethylene (1 mmol of) and 20 mL DMF. Stirring at 100 ° C, reacted for 24 hours. After completion of the reaction, the reaction solution was cooled to room temperature, filtered and the filtrate was added 100 mL of water to precipitate a large number of precipitation, filtration, filter cake was collected, 1,1,2,2-tetrakis [4- (1Eta-1,2,4 - triazole-1-yl) phenyl] ethylene (L). Yield 60percent.
60%
With potassium carbonate; copper(II) oxide; at 100℃; for 48h;
The present invention is preferably <strong>[61326-44-1]1,1,2,2-tetrakis(4-bromophenyl)ethylene</strong>: 1H-1,2,4-triazole: potassium carbonate: copper oxide molar ratio of 2: 10-15: 30: 1; Reaction temperature of 100 deg.C. The reaction time was 48 hours. In a polar solvent, using the "one-pot method", <strong>[61326-44-1]1,1,2,2-tetrakis(4-bromophenyl)ethylene</strong>,1H-1,2,4-triazole, potassium carbonate and copper oxide under heating conditions 1,1,2,2-tetrakis[4-(1H-1,2,4-triazol-1-yl)phenyl]ethylene (L) is prepared. Yield 60percent.
60%
With potassium carbonate; copper(II) oxide; at 80 - 200℃; for 48h;
Using the polar solvent "one-pot synthesis", the 1, 1, 2, 2-tetra (4-bromophenyl) ethylene, 1H-1, 2, 4-triazole, potassium carbonate, and copper oxide in the preparation of the heating condition; wherein the 1, 1, 2, 2-tetra (4-bromophenyl) ethylene: 1H-1, 2, 4-triazole: potassium carbonate: copper oxide in a molar ratio of 2:10-15 : 30:1; the reaction temperature 80-200°C, reaction time 12-120 hours. The present invention is preferably 1, 1, 2, 2-tetra (4-bromophenyl) ethylene: 1H-1, 2, 4-triazole: potassium carbonate: copper oxide in a molar ratio of 2:10-15 : 30:1; the reaction temperature is 100 °C, the reaction time is 48 hours. In the polar solvent, the "one-pot synthesis", the 1, 1, 2, 2-tetra (4-bromophenyl) ethylene, 1H-1, 2, 4-triazole, potassium carbonate, and copper oxide under the heating condition preparing 1, 1, 2, 2-tetra [4 - (1H-1, 2, 4-triazole-1-yl) phenyl] ethylene (L). Yield 60percent
60%
With potassium carbonate; copper(II) oxide; at 100℃; for 48h;
The present invention is preferably 1,1,2,2-tetrakis (4-bromophenyl) ethylene:The molar ratio of 1H-1,2,4-triazole: potassium carbonate to cupric oxide was 2: 10-15: 30: 1. The reaction temperature was 100 and the reaction time was 48 hours. In the polar solvent, the "one-pot method"1,1,2,2-Tetrakis (4-bromophenyl) ethene, 1H-1,2,4-triazole, potassium carbonate and copper oxide were prepared by heating 1,1,2,2- 4- (1H-1,2,4-triazol-1-yl) phenyl] ethylene (L). Yield 60percent
60%
With potassium carbonate; copper(II) oxide; at 100℃; for 48h;
Preferred are 1,1,2,2-tetrakis (4-bromophenyl) ethene: 1H-1,2,4-triazole: potassium carbonate: copper oxide molar ratio of2: 10-15: 30: 1; reaction temperature 100 , reaction time 48 hours. In a polar solvent, the use of "one-pot method", 1,1,2,(4-bromophenyl) ethene, 1H-1,2,4-triazole, potassium carbonate and copper oxide were heated under heating to prepare 1,1,2,2-tetrakis [4-(1H-1,2,4-triazol-1-yl) phenyl] ethylene (L). Yield 60percent.
60%
With potassium carbonate; copper(II) oxide; at 100℃; for 48h;
Preferred are 1,1,2,2-tetrakis (4-bromophenyl) ethene: 1H-1,2,4-triazole: potassium carbonate: copper oxide molar ratio of2: 10-15: 30: 1; reaction temperature 100 , reaction time 48 hours. In a polar solvent, the use of "one-pot method", 1,1,2,(4-bromophenyl) ethene, 1H-1,2,4-triazole, potassium carbonate and copper oxide were heated under heating to produce 1,1,2,2-tetrakis [4-(1H-1,2,4-triazol-1-yl) phenyl] ethylene (L). Yield 60percent.
60%
With potassium carbonate; copper(II) oxide; at 100℃; for 48h;
In a polar solvent, 1,1,2,2-tetrakis (4-bromophenyl) ethylene, 1H-1,2,4-triazole, potassium carbonate andCopper oxide in the reaction conditions;(4-bromophenyl) ethylene: 1H-1,2,4-triazole: potassium carbonate:The molar ratio of copper oxide is 2: 10-15: 30: 1; the reaction temperature is 80-200 DEG C, the reaction time is 12-120 hours; 1,1,2,2-Tetrakis (4-bromophenyl) ethene 1H-1,2,4-triazole Preferred is 1,1,2,2-tetrakis (4-bromophenyl) The molar ratio of 1,2,4-triazole: potassium carbonate: copper oxide was:2: 10-15: 30: 1; reaction temperature 100 , reaction time 48 hours. In a polar solvent, the use of "one-pot method", 1,1,2,(4-bromophenyl) ethylene, 1H-1,2,4-triazole,Tetrakis [4- (1H-1,2,4-triazol-1-yl) phenyl] ethene (L) was prepared by heating potassium carbonate and cupric oxide under heating.Yield 60percent.
60%
With potassium carbonate; copper(II) oxide; at 100℃; for 48h;
The present invention is preferably 1, 1, 2, 2-tetra (4-bromophenyl) ethylene: 1H-1, 2, 4-triazole: potassium carbonate: copper oxide in a molar ratio of 2:10-15 : 30:1; the reaction temperature is 100 °C, the reaction time is 48 hours. In the polar solvent, the "one-pot synthesis", the 1, 1, 2, 2-tetra (4-bromophenyl) ethylene, 1H-1, 2, 4-triazole, potassium carbonate, and copper oxide under the heating condition preparing 1, 1, 2, 2-tetra [4 - (1H-1, 2, 4-triazole-1-yl) phenyl] ethylene (L). Yield 60percent. Elemental analysis (C34N6H24) theoretical value (percent): C, 79.05; H, 4.68 ; N, 16.27. Measured value: C, 79.02; H, 4.65 ; N, 16.25.
60%
With copper(I) oxide; potassium carbonate; at 100℃; for 48h;
In a polar solvent, 1,1,2,2-tetrakis (4-bromophenyl) ethylene, 1,1,2,2-tetrakis (4-bromophenyl)1H-1,2,4-triazole,Potassium carbonate andCopper oxide in the reaction conditions;Wherein 1,1,2,2-tetrakis (4-bromophenyl) ethylene:1H-1,2,4-triazole:Potassium carbonate:The molar ratio of copper oxide is 2: 10-15: 30: 1;The reaction temperature is 80-200 DEG C, the reaction time is 12-120 hoursThe present invention is preferably 1,1,2,2-tetrakis (4-bromophenyl) ethylene:1H-1,2,4-triazole:Potassium carbonate:The molar ratio of copper oxide was2: 10-15: 30: 1;Reaction temperature 100 ,The reaction time was 48 hours.In a polar solvent,Using the "one-pot method"1, 1, 2,(4-bromophenyl) ethene, 1H-1,2,4-triazole, potassium carbonate and copper oxide were heated under heating to produce 1,1,2,2-tetrakis [4-(1H-1,2,4-triazol-1-yl) phenyl] ethylene (L). Yield 60percent.
60%
With potassium carbonate;Heating;
Preferred are 1,1,2,2-tetrakis (4-bromophenyl) ethene: 1H-1,2,4-triazole: potassium carbonate: copper oxide molar ratio of 2: 10-15: 30: 1; reaction temperature 100°C , reaction time 48 hours. In a polar solvent, the use of "one-pot method", 1,1,2, (4-bromophenyl) ethene, 1H-1,2,4-triazole, potassium carbonate and copper oxide were heated under heating to produce 1,1,2,2-tetrakis [4- (1H-1,2,4-triazol-1-yl) phenyl] ethene (L). Yield 60percent. Elementary analysis (C34N6H24) Calcd. (percent): C, 79.05; H, 4.68; N, 16.27. Found: C, 79.02; H, 4.65; N, 16.25.
[iron(III)(protoporphyrin IX)1,2,4-triazole]+[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In methanol;Gas phase; Alkaline conditions;
General procedure: The sampled ions were generated in the gas-phase by directly infusing a slightly basic solution of FeIII(PPIX)Cl and azole ligand, both compounds 1 x 10-5 M in methanol, through a fused-silica capillary to the ESI source by a syringe pump at a flow rate of 10 muL/min. Typical values of declustering potential and entrance potential were 80 and 5 V, respectively. Full scan positive-ion ESI mass spectra of a 10-5 M 1:1 methanolic solution of FeIII(PPIX)Cl complexed with the five different azole ligands and the two model ligands N-Me-Im and Tri are reported in Figs. S1 and S2 in the Supplementary data. CID experiments at variable energy were carried out using an Applied Biosystems 2000 Q-Trap instrument, a commercial hybrid triple-quadrupole linear ion trap mass spectrometer (Q1q2QLIT). The ions were desolvated in the first region (Q0) at a temperature of 373 K using argonand then mass selected by the first quadrupole (Q1). They werethen allowed to collide with argon (3.1 105 mbar) in the q2 collision cell while monitoring the product ion abundance as a function of collision energy (Elab = 0-50 eV). There is only one dissociation channel for each complex of interest, involving the loss of the neutral azole ligand. The dissociation product pattern was monitored by scanning QLIT by using the enhanced mode of operation where the ions, formed in q2, are trapped in QLIT for 35 accumulation spectra in order to increase both resolution and signal intensity.
5-chloro-3-(1H-1,2,4-triazol-1-yl)pyrazin-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With copper(l) iodide; dimethylaminoacetic acid; caesium carbonate; In N,N-dimethyl-aniline; at 150℃; for 4h;
Intermediate C55-Chloro-3-(I H-I ,2,4-triazol-I -yI)pyrazin-2-amine A mixture of <strong>[76537-18-3]3-bromo-5-chloropyrazin-2-amine</strong> (5 g, 23.99 mmol), 1 H-i ,2,4-triazole (1.740 g,25.2 mmol), N,N-dimethylglycine (0.247 g, 2.399 mmol), Cs2003 (23.45 g, 72.0 mmol) andCul (0.457 g, 2.399 mmol) in dimethylaniline (120 ml) was heated at 150C for4 hours. Theresulting mixture was added to water (700 ml) and the product was extracted into EtOAc (2 x500m1). The combined organic extracts were washed with brine, dried over MgSO4 andconcentrated under reduced pressure. Purification by chromatography on silica eluting with a gradient of 0-10% [2M NH3 in MeOH] in DCM afforded the title compound as a yellow solid; LCMS: Rt 0.74 mins; MS mlz 197.1 [M+H]+; Method 2minLowpH.
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
93%
With potassium carbonate; copper(II) oxide; In N,N-dimethyl-formamide; at 100℃; for 24h;
4. 4' - dibromodiphenyl ether: 1H - 1,2, 4 - triazole: potassium carbonate: copper oxide in a molar ratio of 2:10: 30:1In the provided with a magneton, reflux condenser and a thermometer of the 50 ml round bottom flask in three separately adding CuO (0.5 mmol), potassium carbonate (15 mmol), 1H - 1,2, 4 - triazole (5 mmol), 4, 4' - dibromodiphenyl ether (1 mmol) and 20 ml DMF. Stir in 100oC, reaction 24 hours. After the reaction, the reaction liquid to room temperature, filtered, the filtrate by adding 100 ml water, separating out a large amount of precipitation, filtration, collection filter cake, 1 - (4 - (4 - (1H - 1,2, 4 - triazole -1 - yl) phenoxy) phenyl) - 1H - 1,2, 4 - triazole (L). Yield 60%.
60%
With potassium carbonate; copper(II) oxide; In N,N-dimethyl-formamide; at 100℃; for 24h;
(0.5 mmol), potassium carbonate (15 mmol), 1H-1,2,4-triazolium (5 mmol), 4,4 (5 mmol) were separately added to a 50 mL three-neck round bottom flask equipped with a magnetron, a reflux condenser and a thermometer, Apos; -dibromodiphenyl ether (1 mmol) and 20 mL of DMF. Stirring was started at 100oC for 24 hours. After the completion of the reaction, the reaction solution was cooled to room temperature, filtered, and the filtrate was added with 100 mL of water to precipitate a large amount of precipitate. The precipitate was collected by filtration and collected. 1- (4- (4- (1H-1,2,4-triazol- -) phenoxy) phenyl) -1H-1,2,4-triazole (L). Yield 60%.
60%
With potassium carbonate; copper(II) oxide; In N,N-dimethyl-formamide; at 100℃; for 24h;
Equipped with a magnetic promoter, were added to the three 50mL round bottom flask with a reflux condenser and a thermometer CuO (0.5mmol), potassium carbonate (15mmol), 1H-1,2,4- triazole (5mmol), 4,4 '- dibromo-diphenyl ether (1mmol) and 20mLDMF.Stirring at 100Othe C, reacted for 24 hours.After completion of the reaction, the reaction solution was cooled to room temperature, filtered and the filtrate was added 100mL of water, heavy precipitate precipitation, filtration, filter cake was collected 1- (4- (4- (1H- 1,2,4-triazole -1 - yl) phenoxy) phenyl) -1H-1,2,4- triazole (L).Yield 60%.
60%
With potassium carbonate; copper(II) oxide; In N,N-dimethyl-formamide; at 100℃; for 24h;Reflux;
Equipped with a magnetic promoter, were added to the three 50mL round bottom flask with a reflux condenser and a thermometer CuO (0.5mmol), potassium carbonate (15mmol), 1H-1,2,4- triazole (5mmol), 4,4 '- dibromo-diphenyl ether (1mmol) and 20mLDMF.Stirring at 100Othe C, reacted for 24 hours.After completion of the reaction, the reaction solution was cooled to room temperature, filtered and the filtrate was added 100mL of water, heavy precipitate precipitation, filtration, filter cake was collected, 1- (4- (4- (1H -1,2,4-triazole - 1- yl) phenoxy) phenyl) -1H-1,2,4- triazole (L).Yield 60%.
60%
With potassium carbonate; copper(II) oxide; In N,N-dimethyl-formamide; at 100℃; for 24h;
4,4 the diphenyl ether-dibromodiphenyl [...] : 1H-1, 2, 4-triazole: potassium carbonate: copper oxide in a molar ratio of 2:10:30:1 The magneton, of the reflux condenser and a thermometer 50 ml three port in the round-bottom flask by adding CuO (0.5mmol), potassium carbonate (15mmol), 1H-1, 2, 4-triazole (5mmol), 4,4 the diphenyl ether-dibromodiphenyl [...] (1mmol) and 20mLDMF. The stirring is started 100 o C, reaction 24 hours. After the reaction, the reaction liquid to room temperature, filtered, the filtrate by adding 100 ml water, precipitating a large amount of precipitation, filtration, collection filter cake, 1 - (4 - (4 - (1H-1, 2, 4-triazole-1-yl) phenoxy) phenyl) - 1H-1, 2, 4-triazole (L). Yield 60%.
60%
With potassium carbonate; copper(II) oxide; In N,N-dimethyl-formamide; at 100℃; for 24h;
The molar ratio of <strong>[2050-47-7]4,4'-dibromodiphenyl ether</strong>: 1H-1,2,4-triazole: potassium carbonate: copper oxide was 2: 10: 30: 1(0.5 mmol), potassium carbonate (15 mmol), 1H-1,2,4-triazolium (5 mmol), 4,4 (5 mmol) were separately added to a 50 mL three-neck round bottom flask equipped with a magnetron, a reflux condenser and a thermometer, Apos; -dibromodiphenyl ether (1 mmol) and 20 mL of DMF.Stirring at 100Othe C, reacted for 24 hours.After the completion of the reaction, the reaction solution was cooled to room temperature, filtered, and the filtrate was added with 100 mL of water to precipitate a large amount of precipitate. The precipitate was collected by filtration and collected. 1- (4- (4- (1H-1,2,4-triazol- -) phenoxy) phenyl) -1H-1,2,4-triazole (L).Yield 60%.
60%
With potassium carbonate; copper(II) oxide; In N,N-dimethyl-formamide; at 100℃; for 24h;
The molar ratio of <strong>[2050-47-7]4,4'-dibromodiphenyl ether</strong>: 1H-1,2,4-triazole: potassium carbonate: copper oxide was 2: 10: 30: A 50 mL three-necked round bottom flask equipped with a magnetic stirrer, a reflux condenser and a thermometer was charged with CuO (0.5 mmol)(15 mmol), 1H-1,2,4-triazole (5 mmol), <strong>[2050-47-7]4,4'-dibromodiphenyl ether</strong> (1 mmol) and 20 ML DMF. Start stirring at 100 C and react for 24 hours. After the reaction, the solution was cooled to room temperature, filtered and the filtrate was added with 100 mL of water, 1-(4-(4-(1H-1,2,4-triazol-1-yl)phenoxy)phenyl)-1H-1,2,4-triazole (L) was collected by filtration. Yield 60%.
60%
With potassium carbonate; copper(II) oxide; In N,N-dimethyl-formamide; at 100℃; for 24h;
4,4 '-Dibromodiphenyl ether:1H-1,2,4-triazole:Potassium carbonate:The molar ratio of copper oxide is 2: 10: 30: 1In the installation of magnetic son,Reflux condenser and thermometer50 mL three-necked round bottom flaskCuO (0.5Mmol), carbonic acid bell (15 mmol),1H-1,2,4-three-gas sitting(5 mmol),4,4'-dicarboxylic acid1 mmol) and 20ML DMF.Start stirring at 100 C,The reaction was carried out for 24 hours.After the reaction,The reaction solution was allowed to cool to room temperature,Filtration, the filtrate added100 mL of water,Precipitation a large number of precipitation, pumping filter,(1- (4- (4- (111-1,2,4-triazol-1-yl) phenoxy) phenyl) -1Hne-1,2,4-triazole (L) The Yield 60%.
60%
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 24h;
4,4 '- dibromodiphenyl ether:1H-1,2,4-triazole:Potassium carbonate:The molar ratio of copper oxide is 2: 10: 30: 1,A 50 mL three-necked round bottom flask equipped with a reflux condenser and a thermometer was charged with CuO (0.5 mmol)Carbonated bell(15 mmol),LH-L, 2,4 three gas sat(5 mmol),4,4'-dicarboxylate (1 mmol) and 20 mL of DMF.Start stirring at 100 C,The reaction was carried out for 24 hours.After completion of the reaction, the reaction solution was lowered to room temperature, filtered and the filtrate was added100 mL of water, precipitate a large amount of precipitate, filter, filter cake, 1- (4- (4- (111-1,2,4-triazol-1-yl) phenoxy) benzeneYl) -1Eta-1,2,4-triazole (L). Yield 60%.
60%
With potassium carbonate; copper(II) oxide; In N,N-dimethyl-formamide; at 100℃; for 24h;
<strong>[2050-47-7]4,4'-dibromodiphenyl ether</strong>: 1H-1,2,4-triazole: potassium carbonate: copper oxide molar ratio of 2: 10: 30: 1In a 50 mL three-necked round bottom flask equipped with a magnet, a reflux condenser and a thermometer, CuO (0.5Mmol, potassium carbonate (15 mmol), 1H-1,2,4-triazole (5 mmol), <strong>[2050-47-7]4,4'-dibromodiphenyl ether</strong> (1 mmol) and 20 mL DMF. Start stirring at 100 C for 24 hours. After completion of the reaction, the reaction solution was lowered to room temperature,Filter, add 100 mL of water to the filtrate, precipitate a large number of precipitation, filter, filter cake,1- (4- (4- (1H-1,2,4-triazol-1-yl) phenoxy) phenyl) -1H-1,2,4-triazole (L). Yield 60%.
60%
With potassium carbonate; copper(II) oxide; In N,N-dimethyl-formamide; at 100℃; for 24h;
CuO (0.5 mmol) was added to a 50 mL three-necked round bottom flask equipped with a magnet, a reflux condenser and a thermometer,Potassium carbonate (15 mmol), 1H-1,2,4-triazole (5 mmol),<strong>[2050-47-7]4,4'-dibromodiphenyl ether</strong> (1 mmol) and 20 mL of DMF.Start stirring at 100 C for 24 hours.After completion of the reaction, the reaction solution was lowered to room temperature, filtered, and 100 mL of water was added to the filtrate to precipitate a large amount of precipitate, and the filter cake was collected by filtration, 1- (4- (4- (1H-1,2,4-triazole -1-yl) phenoxy) phenyl) -1H-1,2,4-triazole (L). Yield 60%.
60%
With potassium carbonate; copper(II) oxide; In N,N-dimethyl-formamide; at 100℃; for 24h;
<strong>[2050-47-7]4,4'-dibromodiphenyl ether</strong>: 1H-1,2,4-triazole: potassium carbonate: copper oxide molar ratio of 2: 10: 30: 1CuO (0.5 mmol) was added to a 50 mL three-necked round bottom flask equipped with a magnet, a reflux condenser and a thermometer,Potassium carbonate (15 mmol),1H-1,2,4-triazole (5 mmol),<strong>[2050-47-7]4,4'-dibromodiphenyl ether</strong> (1 mmol) and 20 mL of DMF.Start stirring at 100 C for 24 hours. After the reaction,The reaction solution was allowed to cool to room temperature,The filtrate by adding 100 mL of water, precipitation a large number of precipitation, filter, filter cake,1- (4- (4- (1H-1,2,4-triazol-1-yl) phenoxy) phenyl) -1H-1,2,4-triazole (L). Yield 60%.
60%
With potassium carbonate; copper(II) oxide; In N,N-dimethyl-formamide; at 100℃; for 24h;
A 50 mL three-necked round bottom flask equipped with a reflux condenser and a thermometer was charged with CuO (0.5 mmol, potassium carbonate (15 mmol), 1H-1,2,4-triazole (5 mmol), <strong>[2050-47-7]4,4'-dibromodiphenyl ether</strong> (1 mmol) and 20 mL DMF. Start stirring at 100 C for 24 hours. After completion of the reaction, the reaction solution was lowered to room temperature, filtered, and 100 mL of water was added to the filtrate to precipitate a large amount of precipitate, 1- (4- (4- (1H-1,2,4-triazol-1-yl) phenoxy) phenyl) -1H-1,2,4-triazole (L). Yield 60%.
60%
With potassium carbonate; copper(II) oxide; In N,N-dimethyl-formamide; at 100℃; for 24h;
<strong>[2050-47-7]4,4'-dibromodiphenyl ether</strong>:1H-1,2,4-triazole:Potassium carbonate:Copper oxide molar ratio of 2: 10: 30: 1 in a magnetic device,A 50 mL three-necked round bottom flask equipped with a reflux condenser and a thermometer was charged with CuO (0.5 mmol),Potassium carbonate (15 mmol),1H-1,2,4-triazole (5 mmol),<strong>[2050-47-7]4,4'-dibromodiphenyl ether</strong> (1 mmol) and20 mL DMF.Start stirring at 100 oC,Reaction for 24 hours.After the reaction was completed, the reaction mixture was cooled to room temperature, filtered,The filtrate was added 100 mL of water, precipitated a large amount of precipitation, suction filtration,The filter cake 1- (4- (4- (1H-1,2,4-triazol-1-yl) phenoxy) phenyl) -1H-1,2,4-triazole (L) . Yield 60%.
60%
With potassium carbonate; copper(II) oxide; In N,N-dimethyl-formamide; at 100℃; for 24h;
<strong>[2050-47-7]4,4'-dibromodiphenyl ether</strong>: 1H-1,2,4-triazole: potassium carbonate: copper oxide in a molar ratio of 2: 10: 30: 1Equipped with a magnetic,A 50 mL three-necked round bottom flask equipped with a reflux condenser and a thermometer was charged with CuO (0.5 mmol),Potassium carbonate (15 mmol),1H-1,2,4-triazole (5 mmol),<strong>[2050-47-7]4,4'-dibromodiphenyl ether</strong> (1 mmol) and20 mL DMF.Start stirring at 100 oC, the reaction 24 hours.After the reaction was completed, the reaction mixture was cooled to room temperature, filtered,The filtrate was added 100 mL of water, precipitated a large amount of precipitation, suction filtration,Collect the filter cake,1- (4- (4- (1H-1,2,4-Triazol-1-yl) phenoxy) phenyl) -1H-1,2,4-triazole (L). Yield 60%.
60%
With potassium carbonate; copper(II) oxide; In N,N-dimethyl-formamide; at 100℃; for 24h;
<strong>[2050-47-7]4,4'-dibromodiphenyl ether</strong>: 1H-1,2,4-triazole: potassium carbonate: copper oxide in a molar ratio of 2: 10: 30: 1In the magnet,A 50 mL three-necked round bottom flask equipped with a reflux condenser and a thermometer was charged with CuO (0.5 mmol),Potassium carbonate (15 mmol),1H-1,2,4-triazole (5 mmol),<strong>[2050-47-7]4,4'-dibromodiphenyl ether</strong> (1 mmol) and 20 mL of DMF.Start stirring at 100 oC, the reaction 24 hours.After the reaction was completed, the reaction solution was cooled to room temperature, filtered and the filtrate was added00 mL water, precipitated a large amount of precipitation, suction filtration, collecting cake,1- (4- (4- (1H-1,2,4-triazol-1-yl) phenoxy) phenyl) -1H-1,2,4-triazole (L)Yield 60%.
60%
With potassium carbonate; copper(II) oxide; In N,N-dimethyl-formamide; at 100℃; for 24h;
4,4'-Dibromodiphenyl ether: 1H-1,2,4-triazole: Potassium carbonate: The molar ratio of copper oxide is 2:10:30:1Add CuO (0.5) to a 50 mL three-neck round bottom flask equipped with a magnet, a reflux condenser, and a thermometer.Methyl), potassium carbonate (15 mmol), 1H-1,2,4-triazole (5 mmol), <strong>[2050-47-7]4,4'-dibromodiphenyl ether</strong> (1 mmol) and 20 mL DMF. Start stirring at 100 C and react for 24 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and the filtrate was added to 100 mL of water to precipitate a large amount of precipitate, which was filtered with suction to collect a cake, 1-(4-(4-(1H-1,2,4-triazole) -1-yl)phenoxy)phenyl)-1H-1,2,4-triazole (L). The yield was 60%.
60%
With potassium carbonate; copper(II) oxide; In N,N-dimethyl-formamide; at 100℃; for 24h;
The molar ratio of copper oxide is 2:10:30:1CuO (0.5 mmol) was added to a 50 mL three-neck round bottom flask equipped with a magnet, a reflux condenser and a thermometer.Potassium carbonate (15 mmol), 1H-1,2,4-triazole (5 mmol), <strong>[2050-47-7]4,4'-dibromodiphenyl ether</strong> (1 mmol) and 20 mL DMF.Start stirring at 100 C and react for 24 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and the filtrate was added to 100 mL of water to precipitate a large amount of precipitate, which was filtered with suction to collect the filter cake 1-(4-(1H-1,2,4-triazole)- 1-yl)phenoxy)phenyl)-1H-1,2,4-triazole (L). The yield was 60%.
With potassium carbonate; copper(II) oxide; at 80 - 200℃;
The present invention is preferably 4,4'-dibromo-diphenyl ether: triazole: potassium carbonate: copper oxide molar ratio of 2: 10: 30: 1; the reaction temperature is 80-200 C, a reaction time of 12-120 hours. Cu (NO3)2 and 1-(4-(4-(1H-1,2,4-triazole-1-yl)phenoxy)phenyl)-1H-1,2,4-triazole (L), ratio of 1: 1; L(0.0304g,0.1mmol) Cu(NO3)2(0.0242 g, 0.1 mmol) in H2O (6 mL) and CH3OH (4 mL) a mixed solvent of was stirred at room temperature in a half hour and then filtered, the filtrate was yellow rod-like crystals at room temperature the volatiles X- ray diffraction analysis.Yield: 45% (calculated based on the L).
With potassium carbonate; copper(II) oxide; In N,N-dimethyl-formamide; at 450℃; for 25h;
(1) Using "one pot" , in DMF polar solvents, 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 reaction temperature was 450 C and the reaction time was 25 hours.
With potassium carbonate; In N,N-dimethyl-formamide; at 150℃; for 18h;
Preparation of 1- (4- (4- (1H-1,2,4-triazol-1-yl) phenoxy) phenyl) -1H-1,2,4-triazole (L)The organic compound is prepared by heating 1,1,2,2-tetrakis (4-bromophenyl) ethylene, triazole, potassium carbonate and copper oxide under heating in a DMF polar solvent;The molar ratio of <strong>[2050-47-7]4,4'-dibromodiphenyl ether</strong>: triazole: potassium carbonate: copper oxide is 2: 10: 30: 1;The reaction temperature was 150 C and the reaction time was 18 hours.
A 1-methyl -1, 2, 4-triazole preparation method comprises: in a 500 ml flask of the three-port adding 69g1, 2, 3-triazole, then adding 234g dimethyl carbonate, raising the temperature to 130 °C reaction 3 hour; After the reaction, the reaction mixture was cooled and vacuum distilled to collect fractions at 80 ° C to obtain 40 g of 1-methyl-2-methyl-2-methyl- -1,2,4-triazole.
tris(4-(1H-1,2,4-triazol-1-yl)phenyl)amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78.3%
With potassium carbonate; copper(II) oxide; In N,N-dimethyl-formamide; at 150℃; for 60h;
In the presence of a magnet,A reflux condenser and a thermometer were charged with CuO (0.5Mmol),Potassium carbonate (15 mmol),1H-1,2,4-triazole (5 mmol),Tris (4-iodobenzene) amine (1 mmol)And 20 mL of DMF.Start stirring at 150oC,For 60 hours.After completion of the reaction,The reaction solution was cooled to room temperature,filter,The filtrate was added with 100 mL of water,Precipitation a lot of precipitation,Filtration,Collecting filter cake,Tris (4-triazolyl) amine (L).Yield 78.3percent.
78.3%
With potassium carbonate; copper(II) oxide; In N,N-dimethyl-formamide; at 150℃; for 60h;
Example 1Tris (4-iodo-phenyl) amine: 1H-1,2,4- triazole: potassium carbonate: copper oxide molar ratio is 2: 15: 30: 1 Equipped with a magnetic promoter, were added to the three 50mL round bottom flask with a reflux condenser and a thermometer CuO (0.5 mmol), potassium carbonate (15mmol), 1H-1,2,4- triazole (5mmol), tris (4 - iodobenzene) amine (1mmol) and 20 mLDMF.Stirring at 150oC, for 60 hours.After completion of the reaction, the reaction solution was cooled to room temperature, filtered and the filtrate was added 100mL of water, heavy precipitate precipitation, filtration, filter cake was collected, tris (4-triazol-phenyl) amine (L).Yield 78.3percent.
78.3%
With potassium carbonate; copper(II) oxide; In N,N-dimethyl-formamide; at 150℃; for 60h;
The molar ratio of tris (4-iodobenzene) amine: 1H-1,2,4-triazole: potassium carbonate: copper oxide is 2: 15: 30: 1In the installation of magnetic son,Reflux condenser and thermometer50 mL three round bottom flask were addedCu (0.5 mmol), potassium carbonate (15 mmol), 1H-1,2,4-triazole (5 mmol), tris (4-iodobenzene) amine (1 mmol) and 20 ML DMF. Start stirring at 150 ° C for 60 hours. After completion of the reaction, the reaction solution was lowered to room temperature, filtered and the filtrate was added100 mL of water, precipitate a large number of precipitation, filter, filter cake, tris (4-triazolylphenyl) amine (L). Yield 78.3percent.
78.3%
With potassium carbonate; copper(II) oxide; In N,N-dimethyl-formamide; at 150℃; for 60h;
The method comprises the following steps: reacting tris(4-iodobenzene)amine: 1H-1,2,4-triazole: the molar ratio of the potassium carbonate to the copper oxide is 2: 15: 30: 1. On-site magnetic separator, the reflux condenser and the thermometer are respectively added with CuO (0.5 mmol)), potassium carbonate (15 mmol)), 1H-1,2,4-triazole (5 mmol)), and tris(4-iodobenzene)amine (1 mmol)) and 20 mL of DMF. The mixture is stirred at 150 DEG c and reacts for 60 hours. After the reaction is finished, the reaction liquid is cooled to room temperature and filtered, adding 100 mL of water into the filtrate, separating out a large amount of precipitates, carrying out suction filtration, and collecting a filter cake, tri(4-triazolephenyl))amine (amine). The yield is 78.3percent.
78.3%
With potassium carbonate; copper(II) oxide; In N,N-dimethyl-formamide; at 150℃; for 60h;
Three (4 - phenyl-iodide) amine: 1H - 1,2, 4 - triazole: potassium carbonate: copper oxide in a molar ratio of 2:15: 30:1In the provided with a magneton, reflux condenser and a thermometer of the 50 ml round bottom flask in three separately adding CuO (0.5 mmol), potassium carbonate (15 mmol), 1H - 1,2, 4 - triazole (5 mmol), three (4 - phenyl-iodide) amine (1 mmol) and 20 ml DMF. Stir in 150oC, reaction 60 hours. After the reaction, the reaction liquid to room temperature, filtered, the filtrate by adding 100 ml water, separating out a large amount of precipitation, filtration, collection filter cake, three (4 - triazole phenyl) amine (L). Yield 78.3percent.
With potassium carbonate; copper(II) oxide; at 80 - 200℃;
The present invention preferably tri (4-iodo-phenyl) amine: 1H-1,2,4- triazole: potassium carbonate: copper oxide molar ratio of 2: 15: 30: 1; the reaction temperature is 80-200 , reaction time 12-120 hours.In a polar solvent, a "one-pot", tris (4-iodo-phenyl) amine, 1H-1,2,4- triazole, potassium carbonate and copper oxide under heating preparing tris (4- three yl) amine) (L).
1-(4-(4-(1H-12,4-triazol-1-yl)phenoxy)phenyl)-1H-1,2,4-triazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
With potassium carbonate; copper(II) oxide; In N,N-dimethyl-formamide; at 100℃; for 24h;
Equipped with magnetic stirrer, 50 mL of reflux condenser and thermometer, A three round bottomed flask was charged with CuO (0.5Mmol), potassium carbonate(15 mmol), 1H-1,2,4-triazole (5mmol), <strong>[2050-47-7]4,4'-dibromodiphenyl ether</strong> (1 mmol) and 20 mL of DMF. Start stirring at 100 C and react for 24 hours. After completion of the reaction, the reaction solution was lowered to room temperature, filtered, and 100 mL of water was added to the filtrate to precipitate a large amount of precipitate, 1-(4-(4-(1H-1,2,4-triazol-1-yl)phenoxy)phenyl)-1H-1,2,4-triazole (L). Yield 60%.
In dichloromethane; N,N-dimethyl-formamide; at 20℃; for 3h;
35 mL of dichloromethane and To 6 mL of N, N-dimethylformamide (DMF) 2.4 g (40.6 mmol) of 1,2,4-triazole was dissolved. A solution prepared by dissolving 2.9 g (9.8 mmol) of <strong>[7158-32-9]4,4'-oxybisbenzoic acid chloride</strong> (mp 88-89 C.) in 15 mL of dichloromethane and 0.1 mL of DMF was added dropwise thereto at room temperature. The first one drop caused white turbidity. After stirring at room temperature for 3 hours, 100 mL of water was added and the mixture was separated, the dichloromethane layer was washed three times with water, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and vacuum dried at 80 C. for 1 hour to obtain a white 2.45 g (yield 69.4%) of 4,4'-biphenyl ether dicarbonyl ditriazole (OBBOTr) was obtained.
2-[2-(1H-1,2,4-triazol-1-yl)ethoxy]-1H-isoindole-1,3(2H)-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
55%
With caesium carbonate; In N,N-dimethyl-formamide; at 25 - 30℃; for 16h;
To a solution of 2-(2-bromoethoxy)isoindoline- l,3-dione (20 g, 7 mmol, step 1 product) in dimethylformamide (100 ml) was added 1H- 1,2,4 triazole (5.2 g, 7.52 mmol) and cesium carbonate (26.5 g, 8.13 mmol) under stirring at 25-30 C. After 16 hours of stirring, the reaction mixture was filtered through filter paper and the filtrate was slowly poured into chilled water (700 ml) under stirring. After 30 minutes, the separated precipitates were filtered and washed with water (50 ml). The filtered precipitates were dried at 40C for 2 hour under high vacuum to provide 10.5 g of 2-[2- (lH- l,2,4-triazol- l-yl)ethoxy]- lH-isoindole- l,3(2H)-dione as white solid in 55% yield. Analysis: Mass: 259.2 (M+l) for Molecular weight: 258 and for Molecular formula: C12H10N4O3
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; In N,N-dimethyl-formamide; at 150℃; for 18h;
Preparation of 1- (4- (4- (1H-1,2,4-triazol-1-yl) phenoxy) phenyl) -1H-1,2,4-triazole (L) _: The organic compound is prepared by heating 1,1,2,2-tetrakis (4-bromophenyl) ethylene, triazole, potassium carbonate and copper oxide under heating in a DMF polar solvent;The molar ratio of 4,4'-dibromodiphenyl ether: triazole: potassium carbonate: copper oxide is 2: 10: 30: 1;The reaction temperature was 150 ° C and the reaction time was 18 hours.
With potassium carbonate; In N,N-dimethyl-formamide; at 150℃; for 18h;
The 1- (4- (4- (1H-1,2,4-triazol-1-yl) phenoxy) phenyl) -1H-1,2,4-triazoleThe preparation method,Its characteristics in the use of "one pot"In DMF polar solvents,1,1,2,2-tetrakis (4-bromophenyl) ethylene, triazole,The molar ratio of 4,4'-dibromodiphenyl ether: triazole: potassium carbonate: copper oxide is 2: 10: 30: 1; the molar ratio of potassium carbonate and copper oxide is prepared under heating; _: The reaction temperature was 150 ° C and the reaction time was 18 hours.
an aqueous solution (10mL) containing 1,2,3-H3btc (21.0mg, 0.1mmol), Htrz (14.0mg, 0.2mmol), ZnO (12.2mg, 0.15mmol) was sealed in a stainless steel vessel (23mL) and heated to 180°C for three days. After the mixture was cooled to room temperature at a rate of 2.4°C/h, pale yellow block-shaped crystals 1 suitable for X-ray diffraction were obtained directly, washed with ethanol and dried in air (yield: 70percent based ZnO). Anal. calcd for C11H7Zn2N3O7: C, 31.16; H, 1.66; N, 9.91. Found: C, 31.11; H, 1.64; N, 9.94. IR (KBr, cm?1): 3412(vs), 1620(s), 1521(w), 1445(w), 1382(m), 1286(w), 1154(s), 1129(s), 1091(m), 1033(w), 1009(w), 988(m), 926(m), 765(w), 728(w), 671(w), 564(m
In dichloromethane; N,N-dimethyl-formamide; for 2.5h;
CH2Cl2 and DMF was dried over molecular sieves 4Aovernight. A solution of 3a (2.9 g, 9.8mmol) in CH2Cl2(15 mL) and DMF (1 mL) was added dropwise to asuspension of 1,2,4-triazole (2.8 g, 41mmol) in CH2Cl2(35 mL) and DMF (1 mL). The reaction mixture was stirredfor 2.5 h. Water (50 mL) was added and the organic layer wasseparated and the aqueous layer was extracted with CH2Cl2(15 mL). The combined organic layer was washed with water(50 mL) and sat. NaHCO3 aq (50mL x 2), dried overNa2SO4 and concentrated. The residue was dried at 80 Cfor 1 h to afford 3b (2.52 g, 71% yield) as white crystal.mp 163.0-163.8C; 1HNMR (400 MHz, DMSO-d6, 26 C):delta/ppm 9.44 (s, 2H, d), 8.39 (s, 2H, c), 8.258.21(m, 4H, a),7.357.31(m, 4H, b). 13CNMR (100 MHz, DMSO-d6,26 C): delta/ppm 164.6, 161.1, 154.5, 147.9, 135.4, 126.8,119.8. IR (ATR) upsilon/cm-1 3140 (C-H),3119 (C-H),1701(C=O), 1593 (C=C).
imidazo[1,2-c][1,2,4]triazolo[1,5-a]quinazoline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
37%
With potassium phosphate; 1,10-Phenanthroline; oxygen; copper dichloride; In N,N-dimethyl-formamide; at 120℃; for 24h;
General procedure: An oven-dried Schlenk tube equipped with a Teflon valve was charged with a magnetic stir bar, CuCl2 (7 mg, 0.05 mmol, 10 molpercent), K3PO4 (212 mg, 1 mmol), 1,10-phenanthroline monohydrate (20 mg, 0.1 mmol, 20 molpercent), 2-(2-bromophenyl)-1,4,5,6-tetrahydropyrimidine 1 or 2-(2-bromophenyl)- 1H-benzo[d]imidazole 4 (0.5 mmol), and N-heterocycle 2 (0.5 mmol). The Schlenk tube was evacuated and backfilled with O2 (this procedure was repeated three times). Under a counter flow of O2, DMF (2.0 mL) was added using a syringe. The reaction mixture was stirred at 110 °C for 24 h. After the reaction was completed, the mixture was extracted with dichloromethane (3 × 15 mL), and then the organic layer was washed with brine (3 × 10 mL) and dried over anhydrous Na2SO4. Subsequently, the solvent was removed, and the product was purified by column chromatography on silica gel using a mixture of dichloromethane and methanol as the eluent, affording the pure products.
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