* 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.
Stage #1: With N,N-Dimethylcarbamoyl chloride In N,N-dimethyl-formamide at 5 - 10℃; for 1 h; Stage #2: at 50℃; for 2 h;
Take 3-(4-pyridyl)-5-(1-oxo-4-pyridinyl)-1,2,4-triazole p-toluenesulfonic acid 200g, 1.5 liters of DMF, and put it into a 3-liter three-necked flask.Add 120 ml of N,N-dimethylformyl chloride and stir at 5-10 ° C for 1 h.95 ml of trimethylsilyl cyanide was added dropwise, and the mixture was heated to 50 ° C.Stir the reaction for 2 h, until the temperature drops below 30 °C,2N potassium carbonate solution was added dropwise to ph=7.5, stirred for 1 h, and filtered.It was obtained as a white solid, dried under vacuum at 55 ° C for 8 h, and obtained 10 g of topisita.The yield was 90.4percent.
Reference：
[1] Patent: CN108250184, 2018, A, . Location in patent: Paragraph 0033; 0040; 0041; 0052
2
[ 100-48-1 ]
[ 135048-32-7 ]
[ 577778-58-6 ]
Yield
Reaction Conditions
Operation in experiment
87.1%
Stage #1: at 25℃; for 1 h; Stage #2: for 0.166667 h; Stage #3: at 80℃; for 7 h; Reflux
100 ml of anhydrous ethanol was put into a 500 ml reaction flask, and sliced sodium was added.Stir the reaction to prepare sodium ethoxide. After the reaction is complete, continue stirring for 1 hour. Add 10.8 g of 4-cyanopyridine, control the temperature at 25°C and stir for 1 hour. Add acetic acid to adjust the pH to 5.0.Stir for 10 minutes,Added 14 g of the intermediate 2-cyanoisonicotinic acid hydrazide prepared in Example 1,Start oil bath heating and circulation, reflux temperature 80 °C, reflux 7h, HPLC monitoring,When the raw material 2-cyanoisonicotinic acid hydrazide obtained by the peak area normalization method is ≤ 0.5percent,Stop the heating and circulation, release the heat transfer oil in the jacket, wait until the temperature drops below 30°C, feed and centrifuge, and filter cake is rinsed twice with 50 ml of ethanol. The filter cake was transferred to an enamel baking dish and dried under reduced pressure (80°C/<-0.9 MPa/8h) to obtain 18 g of solid with a yield of 87.1percent.
85.6%
With sodium methylate In methanol for 8 h; Reflux
The 4-cyano pyridine 11.5g (110mmol) dissolved in 500 ml methanol, then adding sodium methoxide 3.5g, stir to dissolve. Then add 2-cyano [...] 16.2g (100mmol), heating reflux for 8 hours. After the reaction, the separated solid filter, vacuum drying after washing with methanol, to obtain he holds a department 21.4g, yield 85.6percent, purity 99.5percent (HPLC).
78%
With sodium methylate In methanol for 10 h; Reflux
A solution of 1.04 g (10 mmol) of the compound of the formula (2) in 50 ml of methanol was added with sodium methoxide 50mg, stirring to dissolve. Then, 1.62 g (10 mmol) of the compound of the formula (3) 2-cyanoisoniazide was added and the mixture was refluxed for 10 hours Time. After the completion of the reaction, the precipitated solid was filtered off, washed with methanol and dried with vacuum chestnut to give a yellow powdery product Pisitatum (1.93 g, yield 78percent, HPLC purity (normalized method): 98.5percent.
Reference：
[1] Patent: CN107573330, 2018, A, . Location in patent: Paragraph 0039; 0040-0042; 0065; 0067; 0069; 0071; 0073-0076
[2] Patent: CN105566301, 2016, A, . Location in patent: Paragraph 0064; 0065
[3] Patent: CN104151297, 2016, B, . Location in patent: Paragraph 0049; 0050
3
[ 577778-88-2 ]
[ 577778-58-6 ]
Yield
Reaction Conditions
Operation in experiment
95%
at 20℃;
Compound (2) (2 g, 10 mmol) was added to 10 ml of ethanol and 10 ml of water, stirred at room temperature and dissolved. A solution of sodium hydrogencarbonate (sodium hydrogencarbonate 0.84 g in 10 ml of water) was added, and stirred at room temperature for 2 hours. The crystals were obtained by filtration, washed with water and ethanol, abd vacuum-dried to obtain 2.39 g of the objective compound as pale yellow crystals, i.e., the compound of the formula (1).
Stage #1: pyridine-4-carbonitrile at 20℃; for 1h;
Stage #2: 2-cyanoisonicotinic acid hydrazide for 37h; reflux;
12.4 Example 12. 5-(2-Cyano-4-pyridyl)-3-(4-pyridyl)-1,2,4-triazole4) Production of the object compound
Example 12. 5-(2-Cyano-4-pyridyl)-3-(4-pyridyl)-1,2,4-triazole4) Production of the object compound 2.67 g of 4-cyanopyridine was dissolved in 40 ml of methanol, 0.83 g of sodium methoxide was added thereto, and the mixture was stirred at room temperature for one hour. Then 4.15 g of the crystal obtained in 3) was added and the mixture was refluxed for 37 hours. After the reaction completed, the precipitated solid was filtered, washed with methanol and dried with a vacuum pump to yield 3.66 g of the object compound as a yellow powder.1H-NMR (DMSO-d6) δ ppm: 8.01(2H, dd, J=4.54, 1.57Hz), 8.31(1H, dd, J=5.11, 1.65Hz), 8.53 (1H, dd, J=1.65, 0.50Hz), 8.80(2H, dd, J =4.54, 1.57Hz), 8.93(1H, dd, J=5.11, 0.50 Hz)
10 Preparation of compound of formula (1) 4-[5-(pyridin-4-yl)-1H-1,2,4-triazol-3-yl]pyridine-2-carbonitrile
Compound (2) (2 g, 10 mmol) was added to 10 ml of ethanol and 10 ml of water, stirred at room temperature and dissolved. A solution of sodium hydrogencarbonate (sodium hydrogencarbonate 0.84 g in 10 ml of water) was added, and stirred at room temperature for 2 hours. The crystals were obtained by filtration, washed with water and ethanol, abd vacuum-dried to obtain 2.39 g of the objective compound as pale yellow crystals, i.e., the compound of the formula (1).
With phosphoric acid In water; iso-butanol at 80℃; for 8h;
3 Example 3 Synthesis of 4-[5-(pyridin-4-yl)-1H-1,2,4-triazol-3-yl]pyridine-2-carbonitrile (1)
Example 3 Synthesis of 4-[5-(pyridin-4-yl)-1H-1,2,4-triazol-3-yl]pyridine-2-carbonitrile (1) Water (82 mL), 2-butanol (8.2 mL), and phosphoric acid (4.00 g) were added to 4-pyridinecarboxylic acid N'-(2-cyanopyridine-4-carbonimidoyl)hydrazide (4) (9.25 g), and the mixture was stirred at 80°C for 8 hours. The reaction mixture was cooled to room temperature, and precipitated crystals were recovered through filtration. The crystals were washed with a water-2-butanol (10 : 1) mixture (92.5 mL). The thus-washed crystal were dried at 80°C for 13 hours under reduced pressure, to thereby yield 7.89 g of 4-[5-(pyridin-4-yl)-1H-1,2,4-triazol-3-yl]pyridine-2-carbonitrile (1). 1H-NMR (DMSO-d6)δ(ppm): 8.02(dd, 2H, J=4.59, 1.62 Hz), 8.32(dd, 1H, J=5.13, 1.62 Hz), 8.55(dd, 1H, J=1.62, 1.08 Hz), 8.80(dd, 2H, J=4.59, 1.62 Hz), 8.93(dd, 1H, 5.13, 1.08 Hz) MS m/z: 247 [M-H]-
24 Example 24:
Example 24: Reaction vessel was added 3kg [Formula (IV), 4- pyridine-formic hydrazide -N '- (2- cyano-4-imino-carbonyl)], 30L of water,Stirring warming up to 80 ~ 100C , the reaction was kept for 6 hours. Reaction to complete, down to room temperature, filtered, the filter cake was washed, dried under reduced pressure to 80 , was topiroxostat 2.6kg, white solid, yield: 93%. 99.87% purity,
92%
With sodium ethanolate at 78℃; for 6h;
13 Example 13: Preparation of Topiroxostat crude (5-(2-Cyano-4-pyridyl)-3-(4-pyridyl)-1,2,4-triazole)
30 g of ethanol was sequentially added to a 100 mL reaction vessel.Sodium ethoxide 0.18g,Formula (4) 2-cyano-N-(imino(pyridin-4-yl)methyl)isonicotinoxime 5.2 g, stirring;Turn on heating;Control temperature 78 ° C, reaction 6h;Stop the reaction and filter; at 40 ° C ~ 50 ° C,-0.095Mpa, vacuum drying for 6-8h;Obtaining 4.45 g of a yellow solid with a molar yield of about 92%;HPLC purity (normalization method): 99.05%;
90.2%
With acetic acid In ethanol for 12h; Reflux; Large scale;
4 Example 4 Synthesis of 4-[5-(pyridin-4-yl)-1H-1,2,4-triazol-3-yl]-2-cyanide
1.20 kg of the intermediate IV was added to a 1 L single-mouth flask, 14 L of ethanol and 280 ml of acetic acid were added, and the mixture was stirred at reflux temperature for 12 h.The reaction solution was cooled to room temperature, filtered, and rinsed with a small amount of ethanol.The resulting solid was dried in vacuo at 80° C. to give 1.01 Kg of 4-[5-(pyridin-4-yl)-1H-1,,2,4-triazol-3-yl]-2-cyanide in a yield of 90.2%.HPLC 99.4%.
84.7%
With phosphoric acid In water; iso-butanol at 80℃; for 8h;
2-cyano -N '- (imino (pyridin-4-yl) methyl) Isoniazid (1.0g, 3.75mmol) placed in a reaction flask and water was added 9ml, 2- butanol 1ml, stirring, phosphoric acid was added 0.8g, 80 heating, the reaction 8h, cooled with stirring ice water bath, filtration, 2-butanol mixture 1ml + 10ml water wash, wash 10ml of ethanol, to obtain a solid, and dried in vacuo, dry weight 0.8g, yield: 84.7 %.
84.7%
With phosphoric acid In water; butan-1-ol at 80℃; for 8h;
5.1 Example 5: Implementation of 5- (2-cyano-4-pyridyl) -3- (4-pyridyl) 1,2,4-triazole (topiramate orlistat)
:1) 2-cyano--N '- (imino (pyridin-4-yl) methyl) Isoniazid (1.0g, 3.75mmol) placed in a reaction vial was added water9ml, 2-butanol 1ml, with stirring, phosphoric acid was added 0.8g, 80 heating, the reaction 8h, cooled with stirring ice water bath, filtration, 2-butoxyAlcohol mixture 1ml + 10ml water wash, wash 10ml of ethanol, to obtain a solid, and dried in vacuo, dry weight 0.8g, Yield: 84.7%.
5.489 kg
In butan-1-ol at 115 - 125℃; for 4h; Large scale;
1-3; 1-2
Add Intermediate II and 230kg n-butanol to a 500L reactor, heat to 115125 for 3h with stirring, cool to 2030, stir for 1h, shake and filter, rinse the filter cake with n-butanol, and spin dry. The filter cake was dried in a blast oven at 6570°C for 6 hours, and the filter cake was weighed 11.48kg; the filter cake was dissolved in 55kg of 2mol/L hydrochloric acid methanol, heated to 60°C, and then concentrated under reduced pressure to 2/5. Then add 118kg DMF, heat to 6070 with stirring, keep for 1h; reduce to 2030, stir for 1h, shake filter, wash the filter cake with 11kg DMF, spin dry, then rinse the filter cake with (3×15kg) methanol and spin dry As for drying in a blast oven at 6575 for 6 hours, 8.401kg of topistat hydrochloride is obtained.Add topicastat hydrochloride into 183kg of 5% methanol aqueous solution, control the temperature at 45 under stirring, add 7.742kg of sodium carbonate in batches, add 300g of activated carbon, stir for 30 minutes, filter with suction, and add 45kg of filtrate under stirring to dissolve 4.191kg of concentration. The aqueous solution of hydrochloric acid was dripped and stirred at 35-45°C for 1 hour; filtered by shaking, the filter cake was washed with (3×45kg) water and dried, the purity was 98.9%, and the chloride ion content was 0.08% by ion chromatography.Add 221kg of 20% methanol aqueous solution to the solid obtained in the previous step, heat to 70 with stirring for 1h, add 300g activated carbon and stir for 30min, filter 25kg of 20% methanol water to wash, the filtrate is slowly cooled to room temperature, shake filter, filter cake is used (3 ×45kg) Rinse with water, spin-dry, then rinse with (3×15kg) acetonitrile, spin-dry, and place the filter cake in a blast oven at 6575°C for 6h to obtain 5.940kg of solid, then dissolve the solid into 74.3kg of acetonitrile , Heat to 50±2 for 30 minutes under stirring; reduce to 2030, shake filter, wash the filter cake with 15kg acetonitrile, spin dry, put the filter cake in a vacuum oven at 6575 for 6h, weigh it Topipristat is 5.489 kg, the yield is 92.4%, the purity is 99.9%, and the chloride ion content is 0.02% as determined by ion chromatography.
In methanol; water at 85℃; Large scale;
1 Preparation of compound I crude product:
Add methanol, purified water and 11.5 kg (41.2 mol) of compound II to the reaction kettle while stirring, raise the temperature to 85°C and stir for 5 hours, cool down to 20-30°C, keep stirring for 3 hours, centrifuge, and rinse the filter cake with purified water. After drying, 10kg of crude topicastat I was obtained, with a yield of 93.7%.
Multi-step reaction with 4 steps
1.1: hydrazine hydrate / methanol / 2 h / 60 °C / Inert atmosphere
2.1: sodium methylate / methanol / 2 h / 40 °C / Inert atmosphere
2.2: 3 h
3.1: carbamic chloride / N,N-dimethyl-formamide / 1 h / 40 °C / Inert atmosphere
3.2: 1.5 h / 5 °C
4.1: phosphoric acid / water; iso-butanol / 8 h / 80 °C
Multi-step reaction with 4 steps
1.1: hydrazine hydrate / methanol / 2 h / 60 °C / Inert atmosphere
2.1: sodium methylate / methanol / 2 h / 40 °C / Inert atmosphere
2.2: 3 h
3.1: N,N-Dimethylcarbamoyl chloride / N,N-dimethyl-formamide / 1 h / 40 °C
3.2: 1.5 h
4.1: phosphoric acid / water; butan-1-ol / 8 h / 80 °C
Multi-step reaction with 4 steps
1.1: hydrazine hydrate / methanol / 2 h / 60 °C / Inert atmosphere
2.1: sodium methylate / methanol / 2 h / 40 °C / Inert atmosphere
2.2: 3 h
3.1: N,N-Dimethylcarbamoyl chloride / N,N-dimethyl-formamide / 1 h / 40 °C
3.2: 1.5 h
4.1: phosphoric acid / water; butan-1-ol / 8 h / 80 °C
Multi-step reaction with 3 steps
1: N,N-Dimethylcarbamoyl chloride; copper(l) iodide / acetonitrile / 5 h / 80 °C
2: hydrazine hydrate / ethanol / 5 h / 80 °C
3: sodium methylate / methanol / 10 h / Reflux
Multi-step reaction with 3 steps
1: N,N-Dimethylcarbamoyl chloride; copper(l) iodide / acetonitrile / 7 h / 90 °C
2: hydrazine hydrate / ethanol / 5 h / 80 °C
3: sodium methylate / methanol / 10 h / Reflux
Multi-step reaction with 3 steps
1: N,N-Dimethylcarbamoyl chloride; copper(l) iodide / acetonitrile / 8 h / 90 °C
2: hydrazine hydrate / ethanol / 5 h / 80 °C
3: sodium methylate / methanol / 10 h / Reflux
Multi-step reaction with 4 steps
1.1: hydrazine hydrate / methanol / 8 h / 50 °C / Large scale
2.1: sodium methylate / methanol / 1 h / 20 °C
2.2: 20 h / 90 °C
3.1: isopropyl alcohol / 2 h / Reflux
4.1: N,N-Dimethylcarbamoyl chloride / N,N-dimethyl-formamide / 1 h / 5 - 10 °C
4.2: 2 h / 50 °C
Multi-step reaction with 3 steps
1.1: sodium methylate / methanol / 2 h / 40 °C / Inert atmosphere
1.2: 3 h
2.1: carbamic chloride / N,N-dimethyl-formamide / 1 h / 40 °C / Inert atmosphere
2.2: 1.5 h / 5 °C
3.1: phosphoric acid / water; iso-butanol / 8 h / 80 °C
Multi-step reaction with 3 steps
1.1: sodium methylate / methanol / 2 h / 40 °C / Inert atmosphere
1.2: 3 h
2.1: N,N-Dimethylcarbamoyl chloride / N,N-dimethyl-formamide / 1 h / 40 °C
2.2: 1.5 h
3.1: phosphoric acid / water; butan-1-ol / 8 h / 80 °C
Multi-step reaction with 3 steps
1.1: sodium methylate / methanol / 2 h / 40 °C / Inert atmosphere
1.2: 3 h
2.1: N,N-Dimethylcarbamoyl chloride / N,N-dimethyl-formamide / 1 h / 40 °C
2.2: 1.5 h
3.1: phosphoric acid / water; butan-1-ol / 8 h / 80 °C
Multi-step reaction with 3 steps
1.1: sodium methylate / methanol / 1 h / 20 °C
1.2: 20 h / 90 °C
2.1: isopropyl alcohol / 2 h / Reflux
3.1: N,N-Dimethylcarbamoyl chloride / N,N-dimethyl-formamide / 1 h / 5 - 10 °C
3.2: 2 h / 50 °C
Stage #1: pyridine-4-carbonitrile With sodium ethanolate at 25℃; for 1h;
Stage #2: With acetic acid for 0.166667h;
Stage #3: 2-cyanoisonicotinic acid hydrazide at 80℃; for 7h; Reflux;
2 Example 2
100 ml of anhydrous ethanol was put into a 500 ml reaction flask, and sliced sodium was added.Stir the reaction to prepare sodium ethoxide. After the reaction is complete, continue stirring for 1 hour. Add 10.8 g of 4-cyanopyridine, control the temperature at 25°C and stir for 1 hour. Add acetic acid to adjust the pH to 5.0.Stir for 10 minutes,Added 14 g of the intermediate 2-cyanoisonicotinic acid hydrazide prepared in Example 1,Start oil bath heating and circulation, reflux temperature 80 °C, reflux 7h, HPLC monitoring,When the raw material 2-cyanoisonicotinic acid hydrazide obtained by the peak area normalization method is ≤ 0.5%,Stop the heating and circulation, release the heat transfer oil in the jacket, wait until the temperature drops below 30°C, feed and centrifuge, and filter cake is rinsed twice with 50 ml of ethanol. The filter cake was transferred to an enamel baking dish and dried under reduced pressure (80°C/
85.6%
With sodium methylate In methanol for 8h; Reflux;
10 Embodiment 10:he holds a department synthesis of
The 4-cyano pyridine 11.5g (110mmol) dissolved in 500 ml methanol, then adding sodium methoxide 3.5g, stir to dissolve. Then add 2-cyano [...] 16.2g (100mmol), heating reflux for 8 hours. After the reaction, the separated solid filter, vacuum drying after washing with methanol, to obtain he holds a department 21.4g, yield 85.6%, purity 99.5% (HPLC).
78%
With sodium methylate In methanol for 10h; Reflux;
7
A solution of 1.04 g (10 mmol) of the compound of the formula (2) in 50 ml of methanol was added with sodium methoxide 50mg, stirring to dissolve. Then, 1.62 g (10 mmol) of the compound of the formula (3) 2-cyanoisoniazide was added and the mixture was refluxed for 10 hours Time. After the completion of the reaction, the precipitated solid was filtered off, washed with methanol and dried with vacuum chestnut to give a yellow powdery product Pisitatum (1.93 g, yield 78%, HPLC purity (normalized method): 98.5%.
The 2 - cyano-isonicotinic acid methyl ester by adding (487.1g, 3 muM) soluble in 1L in the ethanol in the reactor, stirring at the room temperature, dropping hydrazine hydrate (187.9g, 3 muM), then heating to 40 C stirring 4h, TLC detection reaction (ethyl acetate: petroleum ether=1:2), the reaction is finished. Then adding sodium methoxide (28g, 0.5 muM), stirring 20min to dissolve, then the compound is added 4 - cyanopyridine (312.33g, 3 muM), 80 C reaction 10h, TLC detection (ethyl acetate: petroleum ether=1:4), after the reaction, cooling the room-temperature crystallization, the separated solid filtering, for 500 ml ethanol after cleaning, vacuum drying to obtain a pale yellow powdery product holds a department he 405.5g, yield 63%.
With hydrogenchloride; potassium carbonate In water; iso-butanol at 20℃; for 5h;
3
7.6 g of Topiroxostat TFA salt are dissolved in 71 ml mixture of D.M. water/2-butanol (9:1) (pH=4) and 7.2 g of K2C03 are added in portions at room temperature (pH=l0). 12.9 ml of HCI (6N) (pH=7) are dropwise at room temperature. The reaction mixture is left under stirring for 5 hours. The reaction is monitored with TLC and after completion the yellow pale solid is filtered off, washed with 2x50 ml of cold water and dried at 80 °C under vacuum to afford Topiroxostat as crystal type 1.1H-NMR (500MHz, DMSO) 6 8.90 (d, 2H), 8.79 (d, 2H), 8.52 (s, 1H), 8.30 (d, 1H),8.01(d, 2H).13C-NMR (125MHz, DMSO) 6 152.2, 150.7, 133.6, 125.1, 123.7, 120.2, 117.2.
5
10 g of Topiroxostat HC1 salt are added under stirring to 60m1 Na2CO3 saturated solution over a period of 1 hour maintaining pH above 7. The resulting suspension is filtered off, washed with 2x50 ml of cold water and dried at 80 °C under vacuum to afford 7.1 g of Topiroxo stat as crystal type II.
Multi-step reaction with 3 steps
1.1: sulfuric acid; ammonium persulfate / acetonitrile; water / 1.17 h / 60 - 75 °C
2.1: methanol / 2 h / 20 °C
2.2: 90 - 100 °C / 3000.3 Torr
3.1: triethylamine; trifluoroacetic anhydride / tetrahydrofuran / 1 h / 0 - 20 °C
Multi-step reaction with 4 steps
1.1: sulfuric acid; ammonium persulfate / acetonitrile; water / 1.17 h / 60 - 75 °C
2.1: methanol / 2 h / 20 °C
2.2: 90 - 100 °C / 3000.3 Torr
3.1: trichlorophosphate / toluene / 100 - 105 °C
4.1: sodium carbonate / pH > 7
Multi-step reaction with 4 steps
1.1: sulfuric acid; ammonium persulfate / acetonitrile; water / 1.17 h / 60 - 75 °C
2.1: methanol / 2 h / 20 °C
2.2: 90 - 100 °C / 3000.3 Torr
3.1: triethylamine / tetrahydrofuran / 0 - 20 °C
4.1: potassium carbonate; hydrogenchloride / water; iso-butanol / 5 h / 20 °C
Multi-step reaction with 3 steps
1.1: sodium methylate / ethanol / 9 h / 40 °C / Large scale
1.2: 1 h / 20 °C / Large scale
2.1: benzotriazol-1-ol; diisopropyl-carbodiimide / N,N-dimethyl-formamide / 12 h / 20 °C / Large scale
3.1: acetic acid / ethanol / 12 h / Reflux; Large scale
Multi-step reaction with 3 steps
1.1: sodium methylate / ethanol / 25 °C / Large scale
1.2: 25 °C / Large scale
2.1: benzotriazol-1-ol; diisopropyl-carbodiimide / N,N-dimethyl-formamide / 6 h / 20 °C / Large scale
3.1: acetic acid / 3 h / Reflux; Large scale
Multi-step reaction with 4 steps
1.1: sodium methylate / ethanol / 3 h / 25 °C / Large scale
1.2: 12 h / 0 - 10 °C / Large scale
2.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / N,N-dimethyl-formamide / 0.5 h / Large scale
2.2: 10 - 20 °C / Large scale
3.1: Dimethylcarbamic chloride / N,N-dimethyl-formamide / 1 h / 40 °C / Inert atmosphere
3.2: 1.5 h / Inert atmosphere
4.1: acetic acid / 3 h / Heating; Reflux
Multi-step reaction with 5 steps
1.1: sulfuric acid; dipotassium peroxodisulfate / acetonitrile / 30 min / 50 °C
2.1: sodium methylate / methanol / 3 h / 10 °C
2.2: 2 h / 10 °C / pH 7
3.1: dicyclohexyl-carbodiimide; dmap / dimethyl sulfoxide / 16 h / 30 °C
4.1: phosphoric acid / methanol / 24 h / 40 °C
5.1: trifluoroacetic anhydride; pyridine / 2-methyltetrahydrofuran / 0.5 h / 30 °C
5.2: 80 °C
5.3: 80 °C
Multi-step reaction with 5 steps
1.1: sulfuric acid; dipotassium peroxodisulfate / acetonitrile / 30 min / 50 °C
2.1: sodium methylate / methanol / 3 h / 10 °C
2.2: 2 h / 10 °C / pH 7
3.1: dicyclohexyl-carbodiimide; dmap / dimethyl sulfoxide / 16 h / 30 °C
4.1: phosphoric acid / methanol / 24 h / 40 °C
5.1: trifluoroacetic anhydride; 1H-imidazole / dichloromethane / 2 h / 0 °C
5.2: 70 °C
5.3: 85 °C
With triethylamine; trifluoroacetic anhydride In tetrahydrofuran at 0 - 20℃; for 1h;
4 Example 4 Preparation of Topiroxostat
A 250ml 3-necked r.b. flask equipped with a magnetic bar and a thermometer is charged with 1 O.Og of 4-(5-(pyridin-4-yl)- 1 H-i ,2,4-triazol-3-yl)picolinamide (7) dissolved in 60m1 of THF. 27 ml of Triethylamine are added. The reaction mixture is cooled down at 0 °C and 14 ml of Trifluoroacetic anhydride (TFAA) are added dropwise. After the addition of TFAA the reaction mixture is left under stirring atroom temperature for 1 hour. The reaction is monitored with TLC and after completion solvents are evaporated and crude API is formed. Above mentioned crude solid is dissolved in 50 ml DCM and heated at 40 °C for 1 h. Suspension is cooled down at room temperature and filtered off. Wet cake is washed with 10 ml DCM and dried under vacuum to afford 6.5 g of Topiroxostat as crystal type I.1H-NMR (500MHz, DMSO) ö 8.90 (d, 2H), 8.79 (d, 2H), 8.52 (s, 1H), 8.30 (d, 1H),8.O1(d, 2H).13C-NMR(125MHz,DMSO)ö 152.2, 150.7, 133.6, 125.1, 123.7, 120.2, 117.2.
Multi-step reaction with 2 steps
1: triethylamine / tetrahydrofuran / 0 - 20 °C
2: potassium carbonate; hydrogenchloride / water; iso-butanol / 5 h / 20 °C
97.1 %
Stage #1: 4-(5-(pyridin-4-yl)-1H-1,2,4-triazol-3-yl)picolinamide With 1H-imidazole; trifluoroacetic anhydride In dichloromethane at 0℃;
Stage #2: With hydrogen bromide In dichloromethane; water at 70℃;
Stage #3: In iso-butanol at 85℃;
1.5-1.6; 3.5-3.6
(5) Add 47.3g of compound V, 470mL of dichloromethane, 140g of imidazole and 94.0mL of trifluoroacetic anhydride into the reaction flask, and the reaction is complete when the reaction is carried out at 0°C for 2h under stirring conditions; the obtained product system is concentrated to dryness, Add 1600mL of water and 33mL of hydrobromic acid with a mass concentration of 40% to the obtained residue, dissolve it at 70°C with stirring, then cool down to 10°C to precipitate crystallization, filter, and dry the obtained filter cake to obtain the compound 50.1 g of VI (that is, the hydrobromide salt of topinastat) has a molar yield of 85.6%. (6) Add 50.1g of the compound VI, 1000mL of water and 200mL of 2-butanol into the reaction flask, dissolve it at 85°C with stirring, then cool down to 10°C for crystallization, and add 4% Potassium bicarbonate aqueous solution adjusted the pH value to 7, filtered, and dried the obtained filter cake to obtain 36.7 g of compound VII (namely topicastat) with a molar yield of 97.1% and a total molar yield of 51.3%.
77.2 %
With triethylamine; trifluoroacetic anhydride In tetrahydrofuran at 0 - 20℃;
13 Example 13
Compound 5 (3.2g, 12mmol) was added to tetrahydrofuran (20mL), stirred and triethylamine (9mL) was added dropwise, the reaction solution was cooled to 0°C and trifluoroacetic anhydride (5mL) was added dropwise, after the addition was complete, The reaction solution was stirred at room temperature for 3-4 hours. After the completion of the reaction monitored by TLC, the pH was adjusted to 6-7, and filtered. The resulting filter cake was slurried with N,N-dimethylformamide (5mL)/methanol (15mL) for 1 to 2 hours, filtered with suction, washed with methanol (5mL) and dried in vacuo to obtain compound 6 (i.e. Topiroxostat, 2.3 g, yield 77.2%), HPLC purity 99.77%.
1 Embodiment 1: preparation of holds a department he process impurities
Are respectively takes holds a department he 24.8g (0.1 µM), methanol 300 ml, sodium methoxide 57g (0.15 µM), into 1000 ml three flasks, stirring, add 2 - cyano isoniazid 16.2g (0.1 µM), reaction 3h, TLC detection reaction progress, display reaction finishes. steams solvent, adding 200 ml water, 100 ml × 3 dichloromethane extraction liquid. The merger methylene chloride, anhydrous magnesium sulfate drying, filtering of the drying agent, the organic phase is concentrated to get yellow solid, chloroform/hexane (1:2) re-crystallizing mixed solvent to get the yellow solid, namely holds a department he process impurity 28.7g. Yield: 73.2%.
With copper(l) iodide; sodium carbonate; potassium iodide; N,N`-dimethylethylenediamine In N,N-dimethyl-formamide at 140℃; for 8h; Inert atmosphere;
3 Example 3
In a 2500 ml reaction flask,Add 180 g of compound of formula 5,Add catalyst CuI 13.3g,Ligand DMEDA 18.5g,KI 35g K4[Fe(CN)6]257.7g,Na2CO3148.4g,N,N-Dimethylformamide 1080ml,Under nitrogen protection,Warm up to 140°C,Insulation 8hCool to room temperatureSuction filtrationThe filter cake is rinsed with water.drying,White to pale yellow solid,That is, product of tolsetstat,The yield was 81.5%.
With sodium ethanolate In 1,4-dioxane; water at 35 - 40℃; for 1h;
9 Example 2
100 ml of anhydrous ethanol was put into a 500 ml reaction flask, and sliced sodium was added.Stir the reaction to prepare sodium ethoxide. After the reaction is complete, continue stirring for 1 hour. Add 10.8 g of 4-cyanopyridine, control the temperature at 25°C and stir for 1 hour. Add acetic acid to adjust the pH to 5.0.Stir for 10 minutes,Added 14 g of the intermediate 2-cyanoisonicotinic acid hydrazide prepared in Example 1,Start oil bath heating and circulation, reflux temperature 80 °C, reflux 7h, HPLC monitoring,When the raw material 2-cyanoisonicotinic acid hydrazide obtained by the peak area normalization method is ≤ 0.5%,Stop the heating and circulation, release the heat transfer oil in the jacket, wait until the temperature drops below 30°C, feed and centrifuge, and filter cake is rinsed twice with 50 ml of ethanol. The filter cake was transferred to an enamel baking dish and dried under reduced pressure (80°C/<-0.9 MPa/8h) to obtain 18 g of solid with a yield of 87.1%.
Stage #1: 3-(4-pyridinyl)-5-(1-oxo-4-pyridyl)-1,2,4-triazole p-toluenesulfonic acid salt With N,N-Dimethylcarbamoyl chloride In N,N-dimethyl-formamide at 5 - 10℃; for 1h;
Stage #2: trimethylsilyl cyanide In N,N-dimethyl-formamide at 50℃; for 2h;
1.4 4) Preparation of tosistatin
Take 3-(4-pyridyl)-5-(1-oxo-4-pyridinyl)-1,2,4-triazole p-toluenesulfonic acid 200g, 1.5 liters of DMF, and put it into a 3-liter three-necked flask.Add 120 ml of N,N-dimethylformyl chloride and stir at 5-10 ° C for 1 h.95 ml of trimethylsilyl cyanide was added dropwise, and the mixture was heated to 50 ° C.Stir the reaction for 2 h, until the temperature drops below 30 °C,2N potassium carbonate solution was added dropwise to ph=7.5, stirred for 1 h, and filtered.It was obtained as a white solid, dried under vacuum at 55 ° C for 8 h, and obtained 10 g of topisita.The yield was 90.4%.
With hydrogen bromide In ethanol; water at 30 - 85℃;
16 Example 16: Preparation of Topiroxostat hydrobromide (5-(2-Cyano-4-pyridyl)-3-(4-pyridyl)-1,2,4-triazole hydrobromide)
797g of ethanol was sequentially added to the 3L reactor.793g of purified water,Hydrogen bromide 135g,(3) Toposestat-crude (5-(2-cyano-4-pyridyl)-3-(4-pyridyl)-1,2,4-triazole) 79 g;Temperature control 30 ° C, stirring 0.5h;Control the temperature to 85 ° C, stir for 20 ~ 30min, until the solution is clear;The filtrate was cooled to 20 ° C and stirred for 3 h;Filtration, the filter cake was washed with a mixed solution of 937 g of ethanol and 135 g of purified water;The filter cake was dried under vacuum at 40-50 ° C, -0.095 Mpa for 6 h.Obtaining an off-white solid 94.8 g, a molar yield of about 90.5%;HPLC purity (normalization method): 99.48%;
With sodium carbonate In water; isopropyl alcohol at 8 - 80℃; for 2h;
18 Example 18: Preparation of a Topiroxostat product
700 g of isopropanol was sequentially added to a 500 mL reaction vessel.Purified water 701g,Topotestat hydrobromide 70g;Temperature control to 80 ° C,Until the solution is clear;Hot filtrationCool down to 8 ° C;Adding NaCO3 to a mass of 35g,Purified water 535g;10 ° C, stirring for 2 h;Filtered, the filter cake was washed with 150 g of ethanol;Drying at 40 ° C, -0.095 Mpa for 5 h;49.6 g of a white crystalline powder was obtained.The molar yield is about 94.1%;HPLC purity (normalization method): 99.80%,The single impurity is less than 0.1%, and the total amount is less than 0.5%.
Stage #1: strontium nitrate; [14C]-Topiroxostat; water; copper(II) acetate monohydrate at 20℃; for 0.25h;
Stage #2: ammonium hydroxide at 160℃; for 72h; Autoclave; High pressure;
2.2.1. Synthesis of Mg(H2O)6.[Cu2Mg(L)4(H2O)4].4H2O (1)
General procedure: A mixture of Cu(OAc)2.H2O (10.0 mg, 0.05 mmol), Mg(NO3)2.6H2O (25.6 mg, 0.1 mmol),topiroxostat (24.8 mg, 0.1 mmol), and deionized water (6 mL) was stirred for 15 min at room temperature. An aqueous NH3 solution (25%, 0.4 mL) was dropped into the mixture to generate a clear solution. The resultant solution was transfered to a 15mL Teflon-lined stainless steel container. The container was heated to 160 °C and held at that teperature for 3 days, then cooled to room temperature at a rate of 5 K.h-1.Purple needle crystals of 1 suitable for X-ray diffraction were collected in ca. 43% yield(18.1 mg, based on copper acetate).
Stage #1: magnesium(II) nitrate hexahydrate; [14C]-Topiroxostat; water; copper(II) acetate monohydrate at 20℃; for 0.25h;
Stage #2: ammonium hydroxide at 160℃; for 72h; Autoclave; High pressure;
2.2.1. Synthesis of Mg(H2O)6.[Cu2Mg(L)4(H2O)4].4H2O (1)
A mixture of Cu(OAc)2.H2O (10.0 mg, 0.05 mmol), Mg(NO3)2.6H2O (25.6 mg, 0.1 mmol),topiroxostat (24.8 mg, 0.1 mmol), and deionized water (6 mL) was stirred for 15 min at room temperature. An aqueous NH3 solution (25%, 0.4 mL) was dropped into the mixture to generate a clear solution. The resultant solution was transfered to a 15mL Teflon-lined stainless steel container. The container was heated to 160 °C and held at that teperature for 3 days, then cooled to room temperature at a rate of 5 K.h-1.Purple needle crystals of 1 suitable for X-ray diffraction were collected in ca. 43% yield(18.1 mg, based on copper acetate). Anal. Calcd. for C52H64Cu2Mg2N20O26 (%): C, 40.01;H, 4.13; N, 17.95. Found: C, 40.61; H, 4.14; N, 17.78. IR (cm-1, KBr): 3442 br, 1610s,1459 w, 1405s, 1313 w, 1265 w, 1158 w, 1123 w, 1009 w, 762 w, 717 w, 583 w.
Stage #1: calcium(II) nitrate tetrahydrate; [14C]-Topiroxostat; water; copper(II) acetate monohydrate at 20℃; for 0.25h;
Stage #2: ammonium hydroxide at 160℃; for 72h; Autoclave; High pressure;
2.2.1. Synthesis of Mg(H2O)6.[Cu2Mg(L)4(H2O)4].4H2O (1)
General procedure: A mixture of Cu(OAc)2.H2O (10.0 mg, 0.05 mmol), Mg(NO3)2.6H2O (25.6 mg, 0.1 mmol),topiroxostat (24.8 mg, 0.1 mmol), and deionized water (6 mL) was stirred for 15 min at room temperature. An aqueous NH3 solution (25%, 0.4 mL) was dropped into the mixture to generate a clear solution. The resultant solution was transfered to a 15mL Teflon-lined stainless steel container. The container was heated to 160 °C and held at that teperature for 3 days, then cooled to room temperature at a rate of 5 K.h-1.Purple needle crystals of 1 suitable for X-ray diffraction were collected in ca. 43% yield(18.1 mg, based on copper acetate).
6
add 150g (0.575mol) of Intermediate 4 to a 2L reaction flask, add 1.5L acetic acid, heat and reflux for 3h, cool to room temperature, filter to obtain 132g of pale yellow to off-white solid, yield 95% , The purity is 99%
94%
With acetic acid for 3h; Reflux; Large scale;
1; 6 This embodiment provides a method for synthesizing topicastat from Intermediate 2. The chemical reaction formula is as follows:
Add 0.50kg (1.92mol) of Intermediate 2 to a 10L reaction flask, add 5L of acetic acid, heat and reflux for 3h, cool to room temperature, filter, and air-dried at 60 to obtain 0.43kg of light yellow to off-white crystals (crystal form I), the yield is 94%, and the purity is 99.9%
Stage #1: 4-(5-(pyridin-4-yl)-1H-1,2,4-triazol-3-yl)picolinamide With pyridine; trifluoroacetic anhydride In 2-methyltetrahydrofuran at 30℃;
Stage #2: toluene-4-sulfonic acid In 2-methyltetrahydrofuran at 80℃;
Stage #3: In ethanol; water at 80℃;
2.5-2.6
(5) Add 7.4g of the compound V, 250mL of 2-methyl-tetrahydrofuran, 48mL of pyridine and 24mL of trifluoroacetic anhydride into the reaction flask, and react completely at 30°C for 0.5h under stirring conditions; Concentrate to dryness, add 1400mL of water and 47g of p-toluenesulfonic acid to the obtained residue, dissolve it at 80°C with stirring, then cool down to 20°C to precipitate crystallization, filter, and dry the obtained filter cake to obtain the compound VI (ie p-toluenesulfonate of topinostat) was 65.0 g, and the molar yield was 86.9%.(6) Add 65.0g of the compound VI, 650mL of water and 450mL of ethanol to the reaction flask, dissolve it at 80°C with stirring, then cool down to 20°C for crystallization, and then add sodium carbonate with a mass concentration of 4%. The pH value of the aqueous solution was adjusted to 7, filtered, and the resulting filter cake was dried to obtain 36.8 g of compound VII (ie, topicastat) with a molar yield of 95.9% and a total molar yield of 51.4%.
Multi-step reaction with 2 steps
1.1: phosphoric acid / methanol / 24 h / 40 °C
2.1: trifluoroacetic anhydride; pyridine / 2-methyltetrahydrofuran / 0.5 h / 30 °C
2.2: 80 °C
2.3: 80 °C
3 Preparation of Topicastat I:
Add 2-butanol, purified water, 100g (0.403mol) topicastat I crude product and 83.7g (0.44mol) p-toluenesulfonic acid monohydrate successively under stirring in the reactor,Stir at 80°C for 1 hour, slowly cool down to 25-30°C, centrifuge, rinse the filter cake with 2-butanol and water, and centrifuge and dry to obtain 145g (0.345mol) of topinastat p-toluenesulfonate, with a yield of 85.6 %.
With potassium carbonate In ethanol; water at 20 - 30℃;
3
Add ethanol, purified water, and 120g (0.87mol) of anhydrous potassium carbonate to the reaction kettle in sequence while stirring, dissolve at a temperature of 20-30°C, add 145g (0.345mol) of topinastat p-toluenesulfonate, and stir to dissolve Clear, add activated carbon slurry, stir for 0.5h to decolorize,Press filter, control temperature at 20-30°C, add 2.2L of 6M hydrochloric acid to the filtrate, continue to stir for 5h, centrifuge, wash the filter cake with purified water, and dry at 80°C to obtain 79.4g (0.32mol) topicastat of crystal form I 1, yield 92.8%.The HPLC spectrum is shown in Fig. 3, the purity of topicastat I is 99.769%, the content of impurity A is 0.071%, and the content of impurity II is 0.059%.
2 Preparation of Topicastat I:
Add 2-butanol, purified water, 100g (0.403mol) crude product of topicastat I and 102.2g (0.44mol) camphorsulfonic acid successively to the reaction kettle under stirring, keep stirring at 80°C for 1h, and slowly cool down to 25~ Stir at 30°C for 3 hours, centrifuge, add 2-butanol and water to the filter cake to make a slurry, centrifuge, and dry at 80°C to obtain 159g (0.331mol) of topinastat camphorsulfonate, with a yield of 82.1%.
With potassium carbonate In ethanol; water at 20 - 30℃;
2
Add ethanol, purified water, and 114g (0.828mol) of anhydrous potassium carbonate to the reaction kettle in sequence while stirring, and dissolve at a temperature of 20 to 30°C, add 159g (0.331mol) of topinastat camphorsulfonate, and stir to dissolve , add 1.1g (0.0033mol) EDTA-2Na and activated carbon slurry, stir for 0.5h to decolorize, press filter, control the temperature at 20-30°C, add 6M hydrochloric acid to the filtrate to adjust the pH value to 6.5-7.0, continue stirring for 5h, centrifuge, filter The cake was beaten with purified water, and the filter cake was beaten with isopropanol. After drying at 80° C., 76.7 g (0.309 mol) of I crystal form topicastat I was obtained, with a yield of 93.3%.All mutagenic impurities were not detected.
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