Structure of 1446507-38-5
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CAS No. : | 1446507-38-5 |
Formula : | C9H5F3N4O2 |
M.W : | 258.16 |
SMILES Code : | O=C(N1)NC(C2=NC(C(F)(F)F)=CC=C2)=NC1=O |
MDL No. : | MFCD29044888 |
InChI Key : | JBXAKQJKSGOFNP-UHFFFAOYSA-N |
Pubchem ID : | 89677460 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 18 |
Num. arom. heavy atoms | 12 |
Fraction Csp3 | 0.11 |
Num. rotatable bonds | 2 |
Num. H-bond acceptors | 7.0 |
Num. H-bond donors | 2.0 |
Molar Refractivity | 53.71 |
TPSA ? Topological Polar Surface Area: Calculated from |
91.5 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.18 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
0.92 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.69 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.5 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.71 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.4 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.38 |
Solubility | 1.07 mg/ml ; 0.00415 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.43 |
Solubility | 0.965 mg/ml ; 0.00374 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-4.13 |
Solubility | 0.0192 mg/ml ; 0.0000743 mol/l |
Class? Solubility class: Log S scale |
Moderately soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
No |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-7.22 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
0.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
0.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<0.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
2.12 |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | 100801 Mixture of methyl 6-(trifluoromethyl)picolinate (50g, 244 mmol, 1.0 eq.) and biuret (30.2 g, 293 mmol, 1.20 eq.) in 750 mL EtOH was stirred at 30-35C for 10-20 mm. Titanium tetraethoxide (Ti(OEt)4, 27.8g, 122 mmol, 0.5 eq.) was added and stirred at 30-35C for 30-60 mi EtONa solution in EtOH (350 g, 19% wt, 978 mmol, 4.0 eq.) was added, and the reaction mixture was heated at 55-65C for 3 hours. The reaction mixture was concentrated, cooled to room temperature, and diluted with 700 mL water. Concentrated HC1 solution was added to adjust pH value to pH1. Methylene chloride (DCM, 700 mL) was charged, and the slurry was stirred 20-30C for 5-7 hours. Solid was collected by filtration, and the cake was sequentially washed twice with 6N HC1, twice with water, and once with DCM. The wet cake was dried at 50-60C under vacuum, yielding 6-(6-(trifluoromethyl)pyridin-2-yl)- 1,3 ,5-triazine-2,4( 1H,3H)- dione as off-white solid (45.0 g, 174 mmol, 71% yield). | |
47.5% | With sodium ethanolate; In ethanol; for 2h;Reflux; Inert atmosphere; | Step 2: 6-(6-trifluoromethylpyridin-2-yl)-1,3,5-triazine-2,4(1H,3H)-dione Under the protection of nitrogen gas, to a solution of sodium ethoxide (11.2 g, 165.0 mmol) in ethanol (200 mL) were successively added <strong>[155377-05-2]methyl 6-trifluoromethyl-pyridine-2-carboxylate</strong> (10.0 g, 48.7 mmol) and biuret (4.2 g, 40.7 mmol). The reaction mixture was heated at reflux for 2 hours, and then cooled to room temperature. The reaction solution was concentrated in vacuo, and the resulting residue was poured into water, and adjusted to pH 7 with 6 mol/L HCl solution. After the resulting solid was filtered, the filter cake was washed with water, and then dried to afford 6-(6-trifluoromethylpyridin-2-yl)-1,3,5-triazine-2,4(1H,3H)-dione (5.0 g, yield 47.5%). |
47.5% | With sodium ethanolate; In ethanol; for 2h;Inert atmosphere; Reflux; | To a solution of sodium ethoxide (11.2 g, 165.0 mmol) in ethanol (200 mL) were added in sequence <strong>[155377-05-2]methyl 6-trifluoromethyl-pyridine-2-carboxylate</strong> (10.0 g, 48.7 mmol) and biuret (4.2 g, 40.7 mmol) under the protection of nitrogen gas. The mixture was heated to reflux for 2 hours and then cooled to room temperature. Then the reaction solution was concentrated under vacuum and reduced pressure, and the resulting residue was poured into water and adjusted to pH 7 with 6N hydrochloric acid solution. The resulting solid was filtered, and the filter cake was washed with water and then dried to afford the title compound (5.0 g, yield: 47.5%). |
With ethanol; sodium; for 1h;Reflux; | General procedure: Step 2: Preparation of 6-(6-trifluomethylpyridin-2-yl)-1,3,5-triazine-2,4-dione To a solution of freshly prepared NaOEt from Na (3.84 g, 0.16 mol, 3 eq) in ethanol (500 mL) was added methyl 6-trifluoromethylpicolinate (33 g, 0.16 mol, 3 eq) and biuret (5.3 g, 0.052 mol). The resulting mixture was heated to reflux for 1 hr and then concentrated. The residue was poured into water and treated with Sat. aq. NaHCO3 to adjust pH to 7. The precipitated solid was collected by filtration and dried under air to give the desired compound. 1H NMR (400 MHz, DMSO-d6): delta 10.88 (s, 1H), 8.46 (d, J=7.4 Hz, 1H), 8.28 (t, J=7.3 Hz, 1H), 8.11 (d, J=7.4 Hz, 1H). LC-MS: m/z 259 (M+H)+. | |
With sodium ethanolate; In ethanol; for 1h;Reflux; | Step 2:Preparation of 6-(6- trfluomethylpyridin-2-yl)-1,3,5-triazine-2,4-dione. To a solution of freshly prepared NaOEt from Na (3.84 g, 0.16 mol, 3 eq) in ethanol (500 mL) was added methyl 6-trifluoromethylpicolinate (33 g, 0.16 mol, 3eq) and biuret (5.3 g, 0.052 mol). Theresultingmixture was heated to reflux for 1 hr and then concentrated. The residue was poured into water and treated with Sat. aq. NaHCO3 to adjust pH to 7. The precipitated solid was collected by filtration and dried under air to give the desired compound.?H NMR (400 MHz, DMSO-d6): 10.88 (s, 1H), 8.46 (d, J= 7.4 Hz, 1H), 8.28 (t, J 7.3 Hz, 1H), 8.11 (d, J= 7.4 Hz, 1H).LC-MS: m/z 259 (M+H). | |
Sodium metal (13.46 g, 0.585 mol) is added to ethanol (1.35 L) and the mixture is stirred at room temperature until the sodium dissolves completely. To the resulting sodium ethoxide solution is added biuret (15.1 g, 0.146 mol) at 50C and the solution is stirred at 50 C for 10 min, followed by addition of <strong>[155377-05-2]6-trifluoromethyl-pyridine-2-carboxylic acid methyl ester</strong> (90 g, 0.44 mol). The mixture is heated to reflux for 3 hours. The reaction mixture is concentrated and added to ice-water (1000 mL). Then concentrated HC1 (24.3 mL, 0.29 mol) is added to neutralize the mixture to a pH of between 7 and 8. The precipitated solid is collected by filtration and dried to give 6-(6-Trifluoromethyl -pyridin-2-yl)-lH-l ,3,5-triazine-2,4-dione, LCMS: m/z 259 (M+H)+. | ||
With sodium; In ethanol; at 50 - 80℃;Inert atmosphere; | 1 L absolute ethanol is charged to the reaction vessel under N2 atmosphere and Sodium Metal (11.2 g, 0.488 mol) is added in portions under N2 atmosphere at below 50 C. The reaction is stirred for 5-10 minutes, then heated to 50-55 C. Dried Biuret (12.5 g, 0.122 mol) is added to the reaction vessel under N2 atmosphere at 50-55 C temperature, and stirred 10-15 minutes. While maintaining 50-55 C <strong>[155377-05-2]6-trifluoromethyl-pyridine-2-carboxylic acid methyl ester</strong> (50.0 g, 0.244 mol) is added. The reaction mixture is heated to reflux (75-80 C) and maintained for 1.5-2 hours. Then cooled to 35-40 C, and concentrated at 45-50 C under vacuum. Water is added and the mixture is concentrated under vacuum then cooled to 35-40 C more water is added and the mixture cooled to 0 -5 C. pH is adjusted to 7-8 by slow addition of 6N HC1, and solid precipitated out and is centrifuged and rinsed with water and centrifuged again. The off white to light brown solid of 6-(6-Trifluoromethyl-pyridin-2-yl)-lH-l,3,5-triazine-2,4-dione is dried under vacuum for 8 to 10 hrs at 50 C to 60 C under 600mm/Hg pressure to provide 6-(6- Trifluoromethyl-pyridin-2-yl)- 1H- 1 ,3,5-triazine-2,4-dione. | |
[00271j 1 L absolute ethanol is charged to the reaction vessel under N2 atmosphere and Sodium Metal (11.2 g, 0.488 mol) is added in portions under N2 atmosphere at below 50 C. The reaction is stirred for 5-10 minutes, then heated to 50-55 C. Dried Biuret (12.5 g, 0.122 mol) is added to the reaction vessel under N2 atmosphere at 50-55 C temperature, and stirred 10-15 minutes. While maintaining 50-55 C <strong>[155377-05-2]6-trifluoromethyl-pyridine-2-carboxylic acid methyl ester</strong> (50.0 g, 0.244 mol) is added. The reaction mixture is heated to reflux (75-80 C) and maintained for 1.5-2 hours. Then cooled to 35-40 C, and concentrated at 45-50 C under vacuum. Water is added and the mixture is concentrated under vacuum then cooled to 35-40 C more water is added and the mixture cooled to 0 -5 C. pH is adjusted to 7-8 by slow addition of 6N HC1, and solid precipitated out and is centrifuged and rinsed with water and centrifuged again. The off white to light brown solid of 6-(6-Trifluoromethyl-pyridin-2-yl)- 1 H- 1,3,5 -triazine-2,4-dione is dried under vacuum for 8 to 10 hrs at 50 C to 60 C under 600mmlHg pressure to provide 6-(6- Trifluoromethyl-pyridin-2-yl)- 1 H- 1,3,5 -triazine-2,4-dione. | ||
1 L absolute ethanol is charged to the reaction vessel under N2 atmosphere and Sodium Metal (11.2 g, 0.488 mol) is added in portions under N2 atmosphere at below 50 C. The reaction is stirred for 5-10 minutes, then heated to 50-55 C. Dried Biuret (12.5 g, 0.122 mol) is added to the reaction vessel under N2 atmosphere at 50-55 C temperature, and stirred 10- 15 minutes. While maintaining 50-55 C <strong>[155377-05-2]6-trifluoromethyl-pyridine-2-carboxylic acid methyl ester</strong> (50.0 g, 0.244 mol) is added. The reaction mixture is heated to reflux (75-80 C) and maintained for 1.5-2 hours. Then cooled to 35-40 C, and concentrated at 45-50 C under vacuum. Water is added and the mixture is concentrated under vacuum then cooled to 35-40 C more water is added and the mixture cooled to 0 -5 C. pH is adjusted to 7-8 by slow addition of 6N HC1, and solid precipitated out and is centrifuged and rinsed with water and centrifuged again. The off white to light brown solid of 6-(6-Trifluoromethyl-pyridin-2-yl)- lH-l,3,5-triazine-2,4-dione is dried under vacuum for 8 to 10 hrs at 50 C to 60 C under 600mm/Hg pressure to provide 6-(6-Trifluoromethyl-pyridin-2-yl)-lH-l,3,5-triazine-2,4- dione. | ||
1 L absolute ethanol was charged to the reaction vessel under N2 atmosphere and sodium metal (11.2 g, 0.488 mol) was added in portions under N2 atmosphere at below 50C. The reaction was stirred for 5-10 minutes, then heated to 50-55C. Dried Biuret (12.5 g,0.122 mol) was added to the reaction vessel under N2 atmosphere at 50-55C temperature, and stirred for 10-15 minutes. While maintaining 50-55C <strong>[155377-05-2]6-trifluoromethyl-pyridine-2-carboxylic acid methyl ester</strong> (50.0 g, 0.244 mol) was added. The reaction mixture was heated to reflux (75- 80C) and maintained for 1.5-2 hours, then cooled to 35-40C, and concentrated at 45-50C under vacuum. Water was added and the mixture was concentrated under vacuum then cooled to 3 5-40 C, more water was added and the mixture was cooled to 0 -5C. pH was adjusted to 7-8 by slow addition of 6N HC1, a solid precipitated which was centrifuged and rinsed with water and centrifuged again. The off white to light brown solid of 6-(6-trifluoromethyl-pyridin-2-yl)- 1H-1,3,5-triazine-2,4-dione was dried under vacuum for 8 to 10 hrs at 50C to 60C under 600 mm/Hg pressure to provide 6-(6- trifluoromethyl-pyridin-2-yl)-1H- 1,3,5 -triazine-2,4-dione. | ||
1 L absolute ethanol was charged to the reaction vessel under N2 atmosphere and sodium metal (11.2 g, 0.488 mol) was added in portions under N2 atmosphere at below 50 C. The reaction was stirred for 5-10 minutes, then heated to 50-55 C. Dried Biuret (12.5 g, 0.122 mol) was added to the reaction vessel under N2 atmosphere at 50-55 C. temperature, and stirred for 10-15 minutes. While maintaining 50-55 C. <strong>[155377-05-2]6-trifluoromethyl-pyridine-2-carboxylic acid methyl ester</strong> (50.0 g, 0.244 mol) was added. The reaction mixture was heated to reflux (75-80 C.) and maintained for 1.5-2 hours, then cooled to 35-40 C., and concentrated at 45-50 C. under vacuum. Water was added and the mixture was concentrated under vacuum then cooled to 35-40 C., more water was added and the mixture was cooled to 0-5 C. pH was adjusted to 7-8 by slow addition of 6N HCl, a solid precipitated which was centrifuged and rinsed with water and centrifuged again. The off white to light brown solid of 6-(6-trifluoromethyl-pyridin-2-yl)-1H-1,3,5-triazine-2,4-dione was dried under vacuum for 8 to 10 hrs at 50 C. to 60 C. under 600 mm/Hg pressure to provide 6-(6-trifluoromethyl-pyridin-2-yl)-1H-1,3,5-triazine-2,4-dione. | ||
Example 2, Step 3: Preparation of 6-(6-trifluoromethyl-pyridin-2-yl)-l H-1,3,5-triazine-2,4-dione 1 L absolute ethanol was charged to the reaction vessel under N2 atmosphere and sodium metal (11.2 g, 0.488 mol) was added in portions under N2 atmosphere at below 50 C. The reaction was stirred for 5-10 minutes, then heated to 50-55 C. Dried Biuret (12.5 g, 0.122 mol) was added to the reaction vessel under N2 atmosphere at 50-55 C. temperature, and stirred for 10-15 minutes. While maintaining 50-55 C. <strong>[155377-05-2]6-trifluoromethyl-pyridine-2-carboxylic acid methyl ester</strong> (50.0 g, 0.244 mol) was added. The reaction mixture was heated to reflux (75-80 C.) and maintained for 1.5-2 hours, then cooled to 35-40 C., and concentrated at 45-50 C. under vacuum. Water was added and the mixture was concentrated under vacuum then cooled to 35-40 C., more water was added and the mixture was cooled to 0-5 C. pH was adjusted to 7-8 by slow addition of 6N HCl, a solid precipitated which was centrifuged and rinsed with water and centrifuged again. The off white to light brown solid of 6-(6-trifluoromethyl-pyridin-2-yl)-1H-1,3,5-triazine-2,4-dione was dried under vacuum for 8 to 10 hrs at 50 C. to 60 C. under 600 mm/Hg pressure to provide 6-(6-trifluoromethyl-pyridin-2-yl)-1H-1,3,5-triazine-2,4-dione. | ||
The biuret (13 g, 126.3 mmol) was dissolved in 300 mL of ethylene glycol dimethyl ether.Sodium hydride (42 g, 1053 mmol) was added portionwise and stirred at 50 C for 1 h.Add 6-(trifluoromethyl)-picolinic acid methyl ester (21.6 g, 105.3 mmol),The reaction was heated at 85 C for 16 h. The reaction solution was poured into water, and the pH was adjusted with concentrated hydrochloric acid.Filtration and drying of the filter cake gave the title compound. | ||
Biuret (13 g, 126.3 mmol) was dissolved in 300 mL of ethylene glycol dimethyl ether, and sodium hydride (42 g, 1053 mmol) was added in batches. The mixture was stirred at 50 C for 1 h. Methyl 6-(trifluoromethyl)picolinate (21.6 g, 105.3 mmol) was added and the mixture was heated at 85 C for 16 h. The resultant solution was poured into water, and the pH was adjusted with concentrated hydrochloric acid. The resultant was filtered, and the filter cake was dried to give the title compound. | ||
The biuret (13 g, 126.3 mmol) was dissolved in 300 mL of ethylene glycol dimethyl ether.Sodium hydride (42 g, 1053 mmol) was added portionwise.Stir at 50 C for 1 h.Methyl 6-(trifluoromethyl)-picolinate (21.6 g, 105.3 mmol) was added and the mixture was heated at 85 C for 16 h. The reaction solution was poured into water, and the pH was adjusted with concentrated hydrochloric acid.Filter, filter cake to dry,The title compound was obtained. | ||
With sodium hydride; In 1,2-dimethoxyethane; mineral oil; at 50 - 85℃; for 16h; | The biuret (13 g, 126.3 mmol) was dissolved in 300 mL of ethylene glycol dimethyl ether.Sodium hydride (42 g, 1053 mmol) was added portionwise and stirred at 50 C for 1 h.Add 6-(trifluoromethyl)-picolinic acid methyl ester (21.6 g, 105.3 mmol),heatingThe reaction was carried out at 85 C for 16 h.The reaction solution was poured into water, the pH was adjusted with concentrated hydrochloric acid, filtered, and the filter cake was dried.The title compound was obtained. | |
The biuret (13 g, 126.3 mmol) was dissolved in 300 mL of ethylene glycol dimethyl ether, sodium hydride (42 g, 1053 mmol) was added portionwise, and stirred at 50 C for 1 h. Methyl 6-(trifluoromethyl)-picolinate (21.6 g, 105.3 mmol) was added and the mixture was heated at 85 C for 16 h. The reaction solution was poured into water, the pH was adjusted with concentrated hydrochloric acid, filtered, and then filtered to give the title compound. | ||
With sodium hydride; In 1,2-dimethoxyethane; at 50 - 85℃; for 16h; | The biuret (13 g, 126.3 mmol) was dissolved in 300 mL of ethylene glycol dimethyl ether, sodium hydride (42 g, 1053 mmol) was added portionwise, and stirred at 50 C for 1 h. Methyl 6-(trifluoromethyl)-picolinate (21.6 g, 105.3 mmol) was added and the mixture was heated at 85 C for 16 h. The reaction solution was poured into water, the pH was adjusted with concentrated hydrochloric acid, filtered, and then filtered to give the title compound. |
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