| 68% |
With copper(l) iodide; caesium carbonate; trans-N,N'-dimethylcyclohexane-1,2-diamine; In N,N-dimethyl-formamide; at 100℃; for 4h;Inert atmosphere; |
1,2,3-triazole (3.45 g, 50 mmol), 2-iodo-5-methylbenzoic acid (5.24 g, 20 mmol), cesium carbonate (0.57 g, 3.6 mmol), cuprous iodide (0.38 g, 2 mmol), trans-N, N'-dimethyl-1,2-cyclohexanediamine (0.51 g, 3.6 mmol), N, N-dimethylformamide (30 mL)was added sequentially to a 100 mL single-necked round bottom flask and gradually heated under nitrogen to 100 C for 4 hours. The reaction was quenched, cooled, diluted with tap water and washed with ethyl acetate (200 mL x 2). The aqueous layer was acidified with concentrated hydrochloric acid (pH = 1~2) and extracted with ethyl acetate (200 mL x 2). The organic layers were combined and dried over anhydrous sodium sulfate. The filtrate was evaporated under reduced pressure and purified by column chromatography (dichloromethane / methanol (v/v) = 50/1) to give the title compound (yellow solid, 2.76 g, 68%). |
| 68% |
With copper(l) iodide; caesium carbonate; trans-N,N'-dimethylcyclohexane-1,2-diamine; In N,N-dimethyl-formamide; at 100℃; for 4h;Inert atmosphere; |
1,2,3-Triazole (3.45 g, 50 mmol),2-iodo-5-methylbenzoic acid (5.24 g, 20 mmol),Cesium carbonate (11.72 g, 36 mmol),Trans-N, N'-dimethyl-1,2-cyclohexanediamine (0.51 g, 3.6 mmol),Cuprous iodide (0.38 g, 2 mmol),N, N-dimethylformamide (30 mL) were sequentially added into a 100 mL single-necked round bottom flask, and the mixture was gradually heated to 100 C. under a nitrogen atmosphere for reaction for 4 hours. The reaction was stopped, cooled, diluted with tap water and extracted with ethyl acetate (200 mL x 2). The aqueous layer was acidified with concentrated hydrochloric acid (pH = 1-2) and extracted with ethyl acetate (200 mL x 2). The combined organic layers were combined and dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated to dryness under reduced pressure and subjected to column chromatography Purification (dichloromethane / methanol (v / v) = 50/1) afforded the title compound (yellow solid, 2.76 g, 68%). |
|
With (1S,2S)-N,N'-dimethyl-1,2-diaminocyclohexane; caesium carbonate;copper(l) iodide; In N,N-dimethyl-formamide; at 120℃; for 0.166667h;In a microwave reactor; |
A solution of 2-iodo-5-methylbenzoic acid (4.0 g, 15.3 mmol) in DMF (10 mL) was treated with 1,2,3-triazole (2.1 g, 30.5 mmol), CsCO3 (9.95 g, 30.5 mmol), CuI (0.145 g, 0.76 mmol) and trans-N,N'-dimethylcyclohexane-1,2-diamine (0.43 g, 3.05 mmol). The mixture was heated at 120 C. for 10 min in a microwave reactor. The reaction was cooled to room temperature, diluted with water, and washed with EtOAc. The aqueous phase was acidified with 1N HCl and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by gradient elution on SiO2 (MeOH in DCM with 0.1% AcOH) to give the faster eluting 2-(2H-1,2,3-triazol-2-yl)-5-methylbenzoic acid A-2, followed by the undesired regioisomer isomer, 2-(1H-1,2,3-triazol-2-yl)-5-methylbenzoic acid. Data for A-2: 1HNMR (500 MHz, DMSO-d6) delta 12.98 (br s, 1H), 8.04 (s, 2H), 7.72-7.45 (m, 3H), 2.41 (s, 3H) ppm. |
|
With trans-N,N'-dimethyl-1,2-cyclohexyldiamine; copper(l) iodide; caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 0.166667h;Microwave irradiation; |
A solution of 2-iodo-5-methylbenzoic acid (4.0 g, 15.3 mmol) in DMF (10 mL) was treated with 1 ,2,3-triazole (2.1 g, 30.5 mmol), CsCO3 (9.95 g, 30.5 mmol), CuI (0.145 g, 0.76 mmol) and trans-N,N'-dirnethylcyclohexane-l,2-diamine (0.43 g, 3.05 mmol). The mixture was heated at 120 0C for 10 min in a microwave reactor. The reaction was cooled to rt, diluted with water, and washed with EtOAc. The aqueous phase was acidified with IN HCl and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by gradient elution on SiO2 (0 to 50% EtOAc in water with 0.1% TFA) to give the desired A-3. A portion of this acid (0.1 1 g, 0.53 mmol) was treated with thionyl chloride (0.59 g, 5.3 mmol) in dichloromethane (5.0 mL) at rt. After stirring at RT for 1 h, the mixture was concentrated, azeotroping with benzene to yield acid chloride A-3. |
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With copper(l) iodide; caesium carbonate; N,N-dimethylethylenediamine; In N,N-dimethyl-formamide; at 125℃; for 0.25h;Microwave irradiation; |
Intermediate 3: 5-Methyl-2-(2H-l,2,3-triazol-2-yl)benzoic acid To the solution of 1,2,3-triazole (1.99 g, 28.93 mmol) in DMF (7.0 ml) at 0-10UC was added cesium carbonate (4.7 g, 14.45 mmol), N,N-dimethylethylenediamine (0.127 g, 1.45 mmol), copper(I) iodide (0.068 g, 0.36 mmol) and 2-iodo-5-methylbenzoic acid (3.79 g, 14.46 mmol). The reaction was subjected to microwave irradiation at 125 C for 15 minutes, and then poured into water (20 ml) and extracted with ethyl acetate. The combined organics were washed with brine, dried (sodium sulphate) and concentrated in vacuo. The crude product was purified by column chromatography (0-3 % methanol in dichloromethane) to afford the title compound.1H NMR (DMSO-i/6) delta ppm 2.42 (s, 3 Eta), 7.49 - 7.52 (m, 1 Eta), 7.58 - 7.64 (m, 2 Eta), 8.05 (s, 2 H), 13.01 (s, 1 H)MS ES+: 204 |
| 2.81 kg |
With copper(l) iodide; potassium carbonate; In tetrahydrofuran; N,N-dimethyl-formamide; at 40 - 65℃; for 0.5h;Large scale; |
The iodide 19 (6.04 kg, 23.0 mol), THF (45 E) and DMF (9.0 E) were charged to a vessel. Copper iodide (218 g, 1.15 mol) and potassium carbonate (7.94 kg, 57.4 mol) were added and the mixture heated to an internal temperature of40 C. 1,2,3-Triazole (3.16 kg, 46.0 mol) was added as asolution in THF (6.0 E) over half an hour (no exotherm) andheating continued to 65 C. (again no exotherm observed) and the reaction monitored by HPEC. Once complete N,Ndimethylethylenediamine (244 mE, 2.30 mol) was addedand mixture cooled to RT. Aqueous 3.6 M HC1 (36 E) wasadded (exotherm) and the mixture extracted twice with ethylacetate (2x30 E). The combined organics were washed with EiC1 solution (2x20 E). The acid solution assayed for 3.79 kg of 5 (81%) and 4.64 kg of 5 and 20 combined (99%). A solution of acids 5 and 20 (approx. 4.64 kg, 22.9 mol) in THF and EtOAc (approx. 110 E) was concentrated to lowvolume. THF (90 E) was added and the solvent composition checked by ?H NMR to ensure most ethyl acetate had been removed. Sodium tert-butoxide (2.42 kg, 25.2 mol) was added slowly as a solid over 1-2 h (slight exotherm), allowing the sodium salt to form and stirred overnight at RT. The liquors showed a 45:55 ratio of product:starting material and the solid was collected by filtration, washed with THF (2x20 E) and dried in a vacuum oven (T=40 C.) for 15 h to afford 4.22 kg of crude sodium salt. The crude sodium salt (4.22 kg, 14.9 mol) was charged to a 50 E vessel and 3.6 M HC1 (21.2 E) was added with cooling. The slurry was thenstirred at room temperature for 16 h and the off-white solidisolated by filtration. The cake was washed with water (11E) and iPAc/Heptane (2x5 E), then dried in a vacuum oven(T=35 C.) for 15 h to give 3.10 kg of crude acid 5 (97.9ECAP, 92 wt %, corrected weight 2.85 kg, 61% yield from19). The acid 5 (2.85 kg corrected, 14.0 mol) was chargedto a 50 E vessel and EtOAc (28 E) and dilute 0.22 M HC1 (14 E) were added and the mixture stirred until two clear phases resulted. The aqueous layer was removed and the organic layer filtered to remove any particulate matter. Theethyl acetate was reduced to about 8 E and then heptane (15.6 E) was added over 1 h and the liquors sampled to check for appropriate losses. The solid was isolated by filtration, washed with heptane:ethyl acetate (3:1, 4 E) and dried on the filter under nitrogen to give 2.81 kg of acid 5.m.p. 167.5 C. ?H NMR (400 MHz, d5-DMSO): oe 12.09 (brs, 1H), 8.04 (s, 1H), 7.62 (d, 1H, J=8.4 Hz), 7.58 (d, 1H, J=1.2 Hz), 7.49 (dd, 1H, J=8.4, 1.2 Hz), 2.41 (s, 3H). ?3C NMR (100.6 MHz, d5-DMSO): oe 168.0, 139.2, 136.4, 135.8, 132.5, 130.3, 128.7, 124.8, 20.9. HRMS (ESI): mlz [M+H] calcd for C,0H9N302: 204.0773; found: 204.0781. |
| 0.71 kg |
With copper(l) iodide; potassium carbonate; In acetone; at 70℃; for 5h;Reflux; Large scale; |
In the reactor,Add 250mL of acetone,Stirring,26.2 g of 2-iodo-5-methylbenzoic acid,Then 34.5 g of potassium carbonate was added,0.38 g copper iodide (Cul),1,2,3-triazole 7.6g.External temperature was raised to 70 C,During the heating process, a large amount of gas is generated,The reaction was refluxed for 5 hours.Then the reaction mixture was distilled under reduced pressure, the reaction system is more viscous, add 30mL of water, continue to reduce the steam distillation to no acetone (no acetone gas phase). 300mL of water was added to the residue after distillation, and 6mo 1 / L hydrochloric acid was added dropwise at room temperature to adjust the pH of the system to 1-2, resulting in a khaki-colored suspension liquid. Stirred for 15 minutes, filtered, washed with water three times,Each 50mL. The resulting solid was dried at 70 C in vacuo to dryness,Have pale green solid 19.45g,For crude compound (1-1), the purity was 95.20%.With stirring, 7.5 kg of acetone, 0.94 kg of crude compound (1-1) and 0.194 kg of sodium hydroxide were added to the reaction kettle. Stirred at 20 C-30 C for 14 hours. Centrifugation, The filter cake was washed 3 times with acetone, each time 3kg. The resulting solid was transferred to the reaction kettle , 5.65 kg of water was added, 0.14 kg of diatomaceous earth was added and stirred for 1 hour. Filtration, the filtrate was transferred to the reaction kettle, hydrochloric acid was added dropwise to adjust the pH to 1-2, a large amount of white solid formed and stirred for 1 hour. Filtered, the filter cake was washed with water three times, each time 3kg. The resulting solid was dried at 60 C in vacuo to dryness, 0.71 kg white solid, represents Compound (I-1), purity 99.97%, Isomeric compound (1-2) less than 0.1%. |
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