Structure of 1206972-45-3
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CAS No. : | 1206972-45-3 |
Formula : | C6H3ClF3NO |
M.W : | 197.54 |
SMILES Code : | FC(F)(F)OC1=CN=C(Cl)C=C1 |
MDL No. : | MFCD18257007 |
InChI Key : | PONLSAHALFQCNY-UHFFFAOYSA-N |
Pubchem ID : | 22000229 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 12 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.17 |
Num. rotatable bonds | 2 |
Num. H-bond acceptors | 5.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 35.93 |
TPSA ? Topological Polar Surface Area: Calculated from |
22.12 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.96 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.95 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
3.89 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.25 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.58 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.53 |
Log S (ESOL):? ESOL: Topological method implemented from |
-3.16 |
Solubility | 0.136 mg/ml ; 0.00069 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-3.08 |
Solubility | 0.165 mg/ml ; 0.000838 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.27 |
Solubility | 0.106 mg/ml ; 0.000535 mol/l |
Class? Solubility class: Log S scale |
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 |
Yes |
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) |
Yes |
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 |
-5.41 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 |
1.0 |
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 |
1.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.99 |
* 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 |
---|---|---|
81% | With trimethylsilyl bromide In propiononitrile for 24 h; Reflux | 2-Bromo-5-trifluoromethoxy pyridine (31); A solution of 2-chloro-5-trifluoromethoxy pyridine (6, 7.0 g, 35.4 mmol) and bromotrimethylsilane (10.8 g, 9.3 mL, 70.8 mmol, 2 eq) in propionitrile (35 mL) was heated under reflux for 24 h. GC monitoring indicated 100percent conversion. The mixture was distilled in vacuum to afford pure 2-bromo-4-trifluoromethoxy pyridine (31, 7.0 g, 28.7 mmol, 81percent) as a colorless oil; b.p. 63-66 0C / 14 mbar. 1H NMR (CDCl3, 300 MHz): δ = 8.34 (d, J = 2.8 Hz, 1 H), 7.56 (d, J = 8.7 Hz, 1 H), 7.45 (dd, J = 8.7, 2.8 Hz, 1 H). - 19F NMR (CDCl3, 282 MHz): δ = -58.8. - 13C NMR (CDCl3, 75 MHz): δ = 145.6, 143.1, 139.2, 131.4, 129.0, 120.1 (q, J = 260 Hz). - C6H3BrF3NO (241): calcd. (percent) C 29.78, H 1.25, N 5.79; found C 29.96, H 1.41, N 5.64. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | 2-Chloro-5-trifluoromethoxy-4-trimethylsilyl pyridine (25); At 0 0C, diisopropylamine (2.8 g, 3.9 mL, 27.8 mmol, 1.1 eq) was added dropwise to a solution of butyllithium (1.56 M in hexane, 17.8 mL, 27.8 mmol, 1.1 eq) in THF (40 mL). At -78 0C, a solution of 2-chloro-5-trifluoromethoxy pyridine (6, 5.0 g, 25.3 mmol, 1 eq) in THF (10 mL) was added dropwise and the reaction mixture was stirred for 2 h at this temperature. Chlorotrimethylsilane (3.0 g, 3.5 mL, 27.8 mmol, 1.1 eq) was then added and the mixture was allowed to reach 25 0C before being neutralized with water (40 mL) and extracted with diethylether (3 x 15 mL). The combined organic layers were dried over sodium sulfate before being evaporated. The crude product was distilled under vacuum to afford pure 2-chloro-5-trifluoromethoxy-4-trimethylsilyl pyridine (25, 6.3 g, 23.2 mmol, 92%) as a colorless oil; b.p. 96-98 0C / 14 mbar.1H NMR (CDCl3, 300 MHz): delta = 8.20 (s, 1 H), 7.28 (s, 1 H), 0.26 (s, 9 H). - 13C NMR (CDCl3, 75 MHz): delta = 149.9, 148.5, 146.2, 139.5, 130.0, 120.3 (q, J = 260 Hz), -1.9. -MS(EI): m/z = 269 [M+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); bis[2-(diphenylphosphino)phenyl] ether; In toluene; at 80℃; for 2h; | 2-Amino-5-trifluoromethoxy pyridine (34); 2-Chloro-5-trifluoromethoxypyridine (6, 1.0 g, 5.0 mmol), benzophenone imine (1.09 g, 6.0 mmol, 1.2 eq), NaOtBu (0.72 g, 7.5 mmol, 1.5 eq), DPEphos (0.03 g, 0.05mmol, 0.01 eq), Pd2dba3 (0.07 g, 0.1 mmol, 0.02 eq) were introduced in dry toluene (15 mL) and the reaction mixture was heated at 80 0C and vigorously stirred for 2 h. GC monitoring indicated 100% conversion. The mixture was allowed to cool to ambient temperature before being filtrated on celite and washed with ethyl acetate. The filtrate was poured onto a 10% aqueous solution of citric acid (30 mL) and the reaction mixture was then vigorously stirred for 16 h at room temperature. GC of the organic phase indicated disappearance of starting reagent and formation of diphenylketone. The aqueous phase was adjusted to pH 9-10 with 5% sodium hydroxide (40 mL) and extracted with ethyl acetate (5 x 20 mL). The combined organic layers were dried over sodium sulfate before being evaporated to afford a crude yellow powder. Crystallization in hexane provided pure 2-amino-5-trifluoromethoxy pyridine (34, 0.36 g, 2.0 mmol, 40%) as colorless needles; m.p. 71 -73 0C.1H NMR (CDCl3, 300 MHz): delta = 7.91 (d, J = 2.7 Hz, 1 H), 7.23 (dd, J = 2.7, 8.9 Hz, 1 H), 6.39 (d, J= 8.9 Hz, 1 H), 4.49 (bs, 2 H). - 19F NMR (CDCl3, 282 MHz): delta = -58.9 - 13C NMR (CDCl3, 75 MHz): delta = 157.1, 141.4, 138.7, 131.6, 120.6 (q, J = 256 Hz), 108.7. - C6H5F3N2O (178): calcd. (%) C 40.46, H 2.83, N 15.73; found C 40.46, H 2.90, N 16.02. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | 1. Functionalized 3-OCF3-pyridine:; 2-Chloro-5-trifluoromethoxy isonicotinic acid (17); At 0 0C, diisopropylamine (0.25 g, 0.35 mL, 2.5 mmol, 1 eq) was added dropwise to a solution of butyllithium (1.56 M in hexane, 1.6 mL, 2.5 mmol, 1 eq) in THF (4 mL). At -78 0C, a solution of <strong>[1206972-45-3]2-chloro-5-trifluoromethoxypyridine</strong> (6, 0.5 g, 2.5 mmol, 1 eq) in THF (2 mL) was added dropwise and the reaction mixture was stirred for 2 h at this temperature. Then, the mixture was poured onto an excess of freshly crushed dry ice and allowed to reach 25 0C before being treated with an aqueous solution of sodium hydroxide (5%, 5 mL). The resulting aqueous layer was collected, washed with diethylether (2 mL) and acidified to pH 4 by dropwise addition of hydrochloric acid (6 N, 1 mL) before being extracted with ethyl acetate (3 >< 3 mL). The combined organic layers were dried over sodium sulfate and the solvents evaporated to afford pure 2- chloro-5-trifluoromethoxy isonicotinic acid (17, 0.46 g, 1.9 mmol, 75%) as a white powder; m.p. 150-152 0C.1H NMR (CDCl3, 300 MHz): delta = 8.45 (s, 1 H), 7.84 (s, 1 H), 3.88 (br s, IH). - 19F NMR (CDCl3, 282 MHz): delta = -57.8. - 13C NMR (CDCl3, 75 MHz): delta = 150.3, 144.9, 142.5, 137.1, 133.8, 126.1, 120.3 (q, J = 260 Hz). - MS(APCI+): m/z = 241 [M+], 197 [M+-CO2]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With antimony(III) fluoride;antimonypentachloride; at 120 - 150℃; | 2-Chloro-5-trifluoromethoxypyridine (6); 2-Chloro-5-trichloromethoxypyridine (5, 7.4 g, 30.0 mmol) is added dropwise to a molten mixture of SbF3 (10.7 g, 60.0 mmol, 2.0 eq) and SbCl5 (1.4 g, 0.6 mL, 4.6 mmol, 0.15 eq) at 120 0C and stirred for 3 h at 150 0C. GC monitoring indicates 100% conversion and disappearance of byproduct OCF2Cl. The mixture is then cooled to 0 0C and dissolved in dichloromethane (100 mL). The solution is quenched with saturated aqueous solution of sodium hydrogencarbonate (100 mL) and potassium fluoride (20%, 50 mL), the aqueous layer is extracted with dichloromethane (2 x 50 mL). The combined organic layers are dried over sodium sulfate and the solvent is distilled. The crude product is distilled under vacuum to afford pure 2-chloro-5-trifluoromethoxypyridine (6, 3.6 g, 18.0 mmol, 60%) as a colorless oil; b.p. 41-43 C / 20 mbar.1H NMR (CDCl3, 300 MHz): delta = 8.35 (s, 1 H), 7.55 (d, J = 8.7 Hz, 1 H), 7.41 (d, J= 8.7 Hz, 1 H). - 13C NMR (CDCl3, 75 MHz): delta = 149.3, 142.7, 140.1, 131.3, 125.1, 120.2 (q, J= 259 Hz). - MS(EI): m/z = 197 [M+], 162 [M+-Cl]. |
40% | With antimonypentachloride; antimony(III) fluoride; at 120 - 175℃; for 18h; | Step 1: (0630) To antimony trifluoride (4.05 g, 23 mmol) and antimony pentachloride (0.22 mL, 1.7 mmol) at 120 C. was added the trichloromethyl ether prepared in step 1 of scheme 25 (2.80 g, 11 mmol). The reaction was warmed to 165 C. under nitrogen and stirred for 14 h and then warmed to 175 C. and stirred for an additional 4 h. The reaction was cooled to room temperature. The resulting solid mass was stirred vigorously with saturated NaHCO3 (aq.) [Gas evolution] and EtOAc. The mixture was filtered through a plug of Celite washing with EtOAc. The filtrate was extracted with EtOAc. The combined organic layers were washed with water and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (0-10% EtOAc/hex over 30 minutes) (0.90 g, 40%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With trimethylsilyl bromide; In propiononitrile; for 24h;Reflux; | 2-Bromo-5-trifluoromethoxy pyridine (31); A solution of 2-chloro-5-trifluoromethoxy pyridine (6, 7.0 g, 35.4 mmol) and bromotrimethylsilane (10.8 g, 9.3 mL, 70.8 mmol, 2 eq) in propionitrile (35 mL) was heated under reflux for 24 h. GC monitoring indicated 100% conversion. The mixture was distilled in vacuum to afford pure 2-bromo-4-trifluoromethoxy pyridine (31, 7.0 g, 28.7 mmol, 81%) as a colorless oil; b.p. 63-66 0C / 14 mbar. 1H NMR (CDCl3, 300 MHz): delta = 8.34 (d, J = 2.8 Hz, 1 H), 7.56 (d, J = 8.7 Hz, 1 H), 7.45 (dd, J = 8.7, 2.8 Hz, 1 H). - 19F NMR (CDCl3, 282 MHz): delta = -58.8. - 13C NMR (CDCl3, 75 MHz): delta = 145.6, 143.1, 139.2, 131.4, 129.0, 120.1 (q, J = 260 Hz). - C6H3BrF3NO (241): calcd. (%) C 29.78, H 1.25, N 5.79; found C 29.96, H 1.41, N 5.64. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | 2-Chloro-4-iodo-5-trifluoromethoxypyridine (28); At 0 0C, diisopropylamine (2.2 g, 3.1 mL, 22.2 mmol, 1.1 eq) was added dropwise to a solution of butyllithium (1.56 M in hexane, 14.2 mL, 22.2 mmol, 1.1 eq) in THF (35 mL). At -78 0C, a solution of <strong>[1206972-45-3]2-chloro-5-trifluoromethoxypyridine</strong> (6, 4.0 g, 20.2 mmol, 1 eq) in THF (10 mL) was added dropwise followed after 2 h by a solution of iodine (5.7 g, 22.2 mmol, 1.1 eq) in THF (10 mL). The reaction mixture was allowed to reach25 0C before being treated with a saturated aqueous solution of sodium sulfite (30 mL) and extracted with dichloromethane (3 x 20 mL). The combined organic layers were dried over sodium sulfate before being evaporated. The crude dark oil was distilled under vacuum (b.p. 95-97 C / 16 mbar) to afford pure 2-chloro-4-iodo-5- trifluoromethoxypyridine (28, 5.8 g, 18.0 mmol, 89%) as colorless needles; m.p. 85-870C.1H NMR (CDCl3, 300 MHz): delta = 8.17 (s, 1 H), 7.80 (s, 1 H). - 19F NMR (CDCl3, 282 MHz): delta = -58.0. - 13C NMR (CDCl3, 75 MHz): delta = 149.4, 146.6, 141.3, 134.9, 120.5 (q, J= 260 Hz), 103.5. | |
32% | [01258] LDA (7.6 mL, 2M in THF, 1.20 equiv) was added dropwise into a solution of 2-chloro-5- (trifluoromethoxy)pyridine (2.5 g, 12.65 mmol, 1.00 equiv) in tetrahydrofuran (20 mL) at -78C and the reaction mixture was stirred for 2 hours at -78C under nitrogen. To the above mixture was added a solution of ?2 (3.5 g, 13.79 mmol, 1.09 equiv) in tetrahydrofuran (20 mL) dropwise at -78C. After being stirred for 2 hours at room temperature the resulting mixture was then poured into water/ice, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel colunm eluting with dichloromethane/ethyl acetate (50/1) to afford the title compound (1.75 g, 32%) as a yellow solid. LCMS [M+H] 324. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With chloro-trimethyl-silane; sodium iodide; In propiononitrile; for 24h;Reflux; | 2-Iodo-5-trifluoromethoxypyridine (33); A suspension of <strong>[1206972-45-3]2-chloro-5-trifluoromethoxypyridine</strong> (6, 9.3 g, 47 mmol), chlorotrimethylsilane (5.1 g, 6.1 mL, 47 mmol, 1 eq) and sodium iodine (21.3 g, 142 mmol, 3 eq) in propionitrile (35 mL) was heated under reflux for 24 h. GC monitoring indicated 100% conversion. The reaction mixture was neutralized by addition of distilled water (100 mL) before being extracted with diethyl ether (3 x 40 mL). The combined organic layers were washed with a saturated aqueous solution of sodium sulfite (30 mL), dried over sodium sulfate before being evaporated. The crude dark oil was distilled under vacuum (90-93 0C / 26 mbar) to afford pure 2-iodo-4- trifluoromethoxypyridine (33, 6.7 g, 23.2 mmol, 49%) as a colorless oil which crystallized on standing.1H NMR (CDCl3, 300 MHz): delta = 8.25 (d, J = 2.6 Hz, 1 H), 7.69 (d, J = 8.6 Hz, 1 H),7.15 (dd, J = 8.6, 2.6 Hz, 1 H). - 19F NMR (CDCl3, 282 MHz): delta = -58.9. - 13C NMR (CDCl3, 75 MHz): delta = 146.3, 143.8, 135.7, 130.3, 120.1 (q, J= 259 Hz), 114.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | With antimony(III) fluoride;antimonypentachloride; at 120 - 140℃; | I-Chloro-S-trifluoromethoxypyridine (6); 5-(Bromodifluoromethoxy)-2-chloropyridine (16, 2.0 g, 10.1 mmol) is added dropwise to a molten mixture Of SbF3 (2.77 g, 15.0 mmol, 1.5 eq) and SbCl5 (1.5 g, 0.65 mL, 5.0 mmol, 0.5 eq) at 120 0C and stirred for 16 h at 140 0C. The mixture is then cooled to 0 0C and dissolved in dichloromethane (100 mL). The solution is washed with saturated aqueous solutions of sodium hydrogen carbonate and brine, the aqueous layer is extracted with dichloromethane (2 * 50 mL). The combined organic layers are dried over sodium sulfate before being evaporated. The crude product is distilled under vacuum to afford pure 2-chloro-5-trifluoromethoxypyridine (6, 0.5 g, 2.5 mmol, 25%) as a colorless oil; b.p. 41-43 0C / 20 mbar.1H NMR (CDCl3, 300 MHz): delta = 8.35 (s, 1 H), 7.55 (d, J= 8.7 Hz, 1 H), 7.41 (d, J= 8.7 Hz, 1 H). - 13C NMR (CDCl3, 75 MHz): delta = 149.3, 142.7, 140.1, 131.3, 120.2 (q, J= 259 Hz), 125.1. - MS(EI): m/z = 197 [M+], 162 [M+-Cl]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
24% | With tris-(dibenzylideneacetone)dipalladium(0); 2,8,9-tris(2-methylpropyl)-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane; In 1,4-dioxane; at 90℃; for 18h;Inert atmosphere; | Preparation 201tert-butyl cyano[5-(trifluoromethoxy) pyridin-2-yllacetate To a solution of <strong>[1206972-45-3]2-chloro-5-(trifluoromethoxy)pyridine</strong> (94 mg, 0.44 mmol) in dioxane (1 mL) was added tris(dibenzylideneacetone)dipalladium (0) (8.20 mg, 0.009 mmol). 2,8,9-tris(2- methylpropyl)-2,5,8,9-tetraaza-1 -phosphabicyclo[3.3.3]undecane (12 mg, 13 uL, 0.036 mmol) followed by tert-butylcyanoacetate (70 uL, 0.488 mmol) were added and the reaction degassedwith nitrogen before heating to 9000 for 18 hours. The reaction was cooled, concentrated in vacuo and diluted with DCM. The solution was washed with water, dried over sodium sulphate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 0-40% EtOAc in heptanes to afford the title compound (32 mg, 24%).MS mlz 301 [M-H] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | [01096] n-BuLi (20.2 mL, 2.5M in hexanes, 2.00 equiv) was added dropwise into a solution of iPr 2NH (6.38 g, 63.05 mmol, 2.49 equiv) in tetrahydrofuran (100 mL) at 0C under nitrogen. The resulting solution was stirred for 15 mm at 0C. To this was added <strong>[1206972-45-3]2-chloro-5-(trifluoromethoxy)pyridine</strong> (5 g, 25.311 mmol, 1.00 equiv) dropwise at -70C. The resulting solution was allowed to react for an additional 1 h while the temperature was maintained at -70C. To the mixture was added N,N-dimethylformamide (9.22 g, 126.14 mmol, 4.98 equiv) dropwise at -70C. The resulting solution was allowed to react for an additional 30 mm while the temperature was maintained at -70C. The reaction was then quenched by saturated NH4C1 solution, extracted with ethyl acetate, washed with hydrogen chloride (1M) and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. This resulted in the title compound (4.5 g, 79%) as light yellow oil.LCMS [M+H] 226. | |
79% | n-BuLi (20.2 mL, 2.5M in hexanes, 2.00 equiv) was added dropwise into a solution of i- Pr2NH (6.38 g, 63.05 mmol, 2.49 equiv) in tefrahydrofuran (100 mL) at 0 C under nitrogen. The resulting solution was stirred for 15 min at 0 C. To this was added 2-chloro-5- (trifluoromethoxy)pyridine (5 g, 25.311 mmol, 1.00 equiv) dropwise at -70 C. The resulting solution was allowed to react for an additional 1 h while the temperature was maintained at -70 C. To the mixture was added NN-dimethylformamide (9.22 g, 126.14 mmol, 4.98 equiv) dropwise at -70 C. The resulting solution was allowed to react for an additional 30 min while the temperature was maintained at -70 C. The reaction was then quenched by saturated NH4C1 solution, extracted with ethyl acetate, washed with hydrogen chloride (1M) and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. This resulted in the title compound (4.5 g, 79%) as light yellow oil. LCMS [M+H+] 226. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With Benzophenone imine; tris-(dibenzylideneacetone)dipalladium(0); bis[2-(diphenylphosphino)phenyl] ether; sodium t-butanolate; In toluene; at 80℃; for 2h;Inert atmosphere; | 2-Chloro-5-(trifluoromethoxy)pyridine (int-80) (1.0 g, 5.06 mmol), sodium tertbutoxide (0.97 g, 10.12 mmol) and benzophenone imine (int-81) (1.10 g, 6.07 mmol) were dissolved in toluene (15 mL). Then Pd2(dba)3 (92.60 mg, 0.10 mmol) and DPEPhos (109.0 mg, 0.20 mmol) were added under nitrogen atmosphere. The mixture was heated at 80 C for 2 h. Then it was filtered and washed with EtOAc (20 mL). The filtrate was treated with 3 M HC1 (50 mL) at 50 C for 4 h. The phases were separated and the aq. phase was basified with 10% NaOH to pH 10. The aq. phase was extracted with EtOAc (3 x 50 mL). The combined organic layers was dried over anhydrous Na2SO4 and concentrated in vacuo. Crude 5-(trifluoromethoxy)pyridin-2-amine (int-82) (400 mg, 44%) was used directly in the next step without further purification. MS (ESI): mlz 178.9 [M+H] . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 160℃; for 2h;Microwave irradiation; | A mixture of <strong>[1206972-45-3]2-chloro-5-(trifluoromethoxy)pyridine</strong> (0.99 g, 5 mmol), 4-methoxybenzylamine (2.6 mL, 20 mmol), DIEA (1.3 mL, 7.5 mmol), K2003 (1.0 g, 7.5 mmol) and DMF (13 mL) was stirred at 160 oC (microwave) for 2 hrs. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in DCM (100 mL) and H20 (25 mL). The organic layer was separated (phase separating cartridge) and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (Biotage SNAP 50 g column, 0 to 15% EtOAc/isohexane). The product was triturated with Et20 to give the title compound as a yellow oil(0.33 g, 40%).1H NMR (ppm)(400 MHz, CDCI3): 3.80 (3H, s), 4.42 (2H, d, J=5.8 Hz), 4.91 (IH, s), 6.35 (IH, d, J8.8 Hz), 6.90 - 6.87 (2H, m), 7.25 - 7.28 (3H, m), 8.04 (1 H, d, J=2.8 Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; sodium t-butanolate; In toluene; at 100 - 105℃; for 12h;Inert atmosphere; | 24 g (120 mmol) of <strong>[1206972-45-3]2-chloro-5-(trifluoromethoxy)pyridine</strong>, 19.1 g (150 mmol) of tert-butyl N-methylcarbamate and 17.5 g (180 mmol) of sodium tert-butoxide were dissolved in 400 ml of toluene, 2.8 g (3 mmol) of tris(dibenzylideneacetone)dipalladium(0) and 1.73 g (3 mmol) of Xantphos were added under argon, and the mixture was stirred at 100-105 C. for 12 h. Subsequently, the mixture was filtered through Celite and the solvent was distilled off under reduced pressure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With lithium carbonate; N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 155℃; for 4h; | [0186] N,N-diisopropylethylamine (0.1 mL, 0.58 mmol) was added to a suspension of 3-(7- chloro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine hydrochloride (25 mg, 0.06 mmol), <strong>[1206972-45-3]2-chloro-5-(trifluoromethoxy)pyridine</strong> (30 mg, 0.15 mmol), and Li2CO3 (20 mg, 0.27 mmol) in DMSO (5 mL) under magnetic stirring. The resulting mixture was stirred at 155 C for 4 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with brine and dried over MgSO4. The solvent was removed under reduced pressure and the residue was purified by HPLC (MeCN/H2O, with 1% TFA) to afford 3-(7- chloro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-5-(5-(trifluoromethoxy)pyridin-2-yl)-4,5,6,7- tetrahydro-2H-pyrazolo[4,3-c]pyridine .1H NMR (400 MHz, CDCl3) 8.49 (s, 1H), 8.09 (dd, J = 1.0, 2.9 Hz, 1H), 7.02 7.34 (m, 5H), 6.98 (dd, J = 8.0 Hz, 1H), 6.54 6.66 (m, 3H), 4.50 (s, 2H), 4.11 (t, J = 5.8 Hz, 2H), 3.05 (t, J = 5.8 Hz, 2H), 2.14 2.32 (br,m, 4H), 0.88 1.08 (br,m, 6H). MS: (ES) m/z calculated C30H28ClF3N5O [M + H]+ 566.2, found 566.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 80℃;Inert atmosphere; | General procedure: A mixture of (4-iodophenyl)(methyl)sulfane (Compound 4A) (500 mg, 2 mmol), 4-bromophenylboronic acid (400 mg, 2 mmol), Na2CCh (636 mg, 6 mmol), and Pd(PPh3)4 (115 mg, 0.1 mmol) in toluene/EtOH/H20 (20/10/4 mL) was stirred at 80 C under nitrogen overnight The mixture was concentrated under reduced pressure. The residue was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 10% v/v) to afford Compound 4B. LC-MS (ESI) m/z: non-ionizable compound under routine conditions used. - NMR (CDCb, 500 MHz): d (ppm) 2.52 (s, 3H), 7.32 (d, J= 8.5 Hz, 2H), 7.43 (d, J= 8.5 Hz, 2H), 7.48 (d, J= 8.5 Hz, 2H), 7.55 (d, J= 8.5 Hz, 2H). |
Tags: 1206972-45-3 synthesis path| 1206972-45-3 SDS| 1206972-45-3 COA| 1206972-45-3 purity| 1206972-45-3 application| 1206972-45-3 NMR| 1206972-45-3 COA| 1206972-45-3 structure
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