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CAS No. : | 34486-24-3 | MDL No. : | MFCD03093868 |
Formula : | C6H5F3N2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | NFYYDQMFURPHCC-UHFFFAOYSA-N |
M.W : | 162.11 | Pubchem ID : | 821024 |
Synonyms : |
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.17 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 33.64 |
TPSA : | 38.91 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.28 cm/s |
Log Po/w (iLOGP) : | 1.23 |
Log Po/w (XLOGP3) : | 1.42 |
Log Po/w (WLOGP) : | 2.84 |
Log Po/w (MLOGP) : | 1.33 |
Log Po/w (SILICOS-IT) : | 1.66 |
Consensus Log Po/w : | 1.7 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.08 |
Solubility : | 1.36 mg/ml ; 0.00837 mol/l |
Class : | Soluble |
Log S (Ali) : | -1.84 |
Solubility : | 2.33 mg/ml ; 0.0144 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -2.54 |
Solubility : | 0.465 mg/ml ; 0.00287 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.46 |
Signal Word: | Danger | Class: | 6.1 |
Precautionary Statements: | P264-P280-P301+P310-P305+P351+P338 | UN#: | 2811 |
Hazard Statements: | H300-H315-H317-H319-H335 | Packing Group: | Ⅲ |
GHS Pictogram: |
* 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 |
---|---|---|
186.3 g | Stage #1: With hydrogenchloride In water at 70℃; for 1 h; Stage #2: at -2 - 2℃; Stage #3: With hydrogenchloride; copper(l) chloride In water at 65℃; for 2 h; |
(1), 2000 g of reaction flask A was charged with 700 g of concentrated hydrochloric acid at a concentration of 36percent by weight and 162.1 g2-amino-6-trifluoromethylpyridine was heated to 70 ° C, stirred for 1 hour, after the completion of the reaction to -2 to 2 ° C, 177.5 g of a sodium nitrite solution having a concentration of 40percentDropping the diazonium salt solution;(2), 500 ml of a hydrochloric acid solution having a concentration of 18percent by weight and 129.4 g of cuprous chloride were added to another reaction flask B, and the mixture was heated to 65C. The resulting diazonium salt solution was added dropwise, Reaction for 2 hours,After the completion of the reaction, the pH of the reaction solution was adjusted to 10 with a sodium hydroxide solution having a concentration of 46percent by weight. Then, 550 g of ethyl acetate was added thereto, followed by stirring. The organic layer was extracted and extracted twice,The organic layer was combined and the organic layer was distilled off to remove ethyl acetate to give a pale yellow liquid. The pale yellow liquid was cooled to room temperature to give 186.3 g of solid 2-chloro-6-trifluoromethylpyridine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73.1% | With N-Bromosuccinimide In methanol at 0 - 20℃; Inert atmosphere | To a mixture of 6-(trifluoromethyl)pyridin-2-amine (600 mg, 3.7mmol) in MeOH (10 mL) was added NBS (659 mg, 3.7mmol) in portions at 0oC. The reaction mixture was stirred at r.t. overnight. The reaction mixture was concentrated under reduced pressure and the residue was purified by chromatography (eluted with PE:EA = 4:1) to afford the title compound (650 mg, 73.1percent yield) as a white solid. Retention time (LC-MS): 1.33 min. MH+ 241. |
44% | With N-Bromosuccinimide In chloroform for 2 h; Darkness | To a solution of 6-trifluoromethyl-pyridin-2-ylamine (10.0 g, 62.1 mmol, 1 eq) in CHCI3 (200 mL) was added NBS (12.0 g, 67.4 mmol, 1.08 eq). The solution was stirred in the dark for 2 h, at which time it was added to DCM (200 mL) and 1 N NaOH (200 mL). Upon mixing, the layers were separated and the organic layer was dried and concentrated. The residue was purified by silica gel column (EA/PE = 1/1, v/v) to give 5-bromo-6- trifluoromethyl-pyridin-2-ylamine (6.5 g, 44percent) as an orange solid. |
40.3% | at 0 - 20℃; for 3 h; | The 6 - (trifluoromethyl) pyridin -2 amine (972 mg, 6 . 0mmol) dissolved in chloroform (10 ml) in, cooling to 0 °C, adding N-bromo succinimide (1.28g, 7 . 2mmol), stir at room temperature 3 hours, concentrated, crude product by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) purification, to obtain solid title compound (0.58g, yield 40.3percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonia;copper(I) chloride; | a) A mixture of <strong>[39890-95-4]2-chloro-6-trifluoromethylpyridine</strong> (20.0 g), cuprous chloride (0.2 g) and ammonia (specific gravity 0.88, 75 ml) was heated at 170 C. in a pressure vessel for 18 hours. After cooling to ambient temperature, the mixture was extracted with dichloromethane (300 ml). The organic extract was dried and evaporated to give 6-trifluoromethylpyridin-2-amine, m.p. 74-79 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
b) A mixture of 6-trifluoromethylpyridin-2-amine (17.2 g) and diethyl ethoxymethylenemalonate (22.9 g) was heated at 95 C., under vacuum for 8 hours. The mixture was cooled and diluted with petroleum ether b.p. 60-80 C. (50 ml). The mixture was filtered and the residue was recrystallized from IMS to give diethyl 2-(6-trifluoromethyl-2-pyridylaminomethylene)malonate, m.p. 125-128 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N,N-dimethyl-formamide; at 80℃; for 3h; | To a solution of 1,1-dimethylethyl (2S)-2-(3-bromo-2-oxopropyl)-1-piperidinecarboxylate D2 (0.10 g, 0.32 mmol) in DMF (1 ml), <strong>[34486-24-3]6-(trifluoromethyl)-2-pyridinamine</strong> (0.077 g, 0.48 mmol) was added and the mixture heated at 80 C. for 3 h. The reaction was eluted through a SCX column. Collected fractions gave 0.070 g of an oil containing the N-Boc protected derivative contaminated with some residual <strong>[34486-24-3]6-(trifluoromethyl)-2-pyridinamine</strong>. [N-Boc derivative data: MS: (ES/+) m/z: 384 (M+1). C19H24F3N3O2 requires 383]. The crude was dissolved in DCM (4 ml) and the resulting solution cooled to 0 C. TFA (1 ml) was added dropwise, the reaction left under stirring for 1 h and then eluted through a SCX column. Collected fractions gave the title compound D17 (0.060 g, 0.21 mmol, 66% yield from D2, two steps). MS: (ES/+) m/z: 284 (M+1). C14H16F3N3 requires 283. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With titanium(IV) isopropylate; In dichloromethane; at 20℃; | 6-(Trifluoromethyl)-2-pyridinamine (24.91 mg, 0.154 mmol), (trans)-2-oxo-3-(3-pyridinyl)-1-oxa-3-azaspiro[4.5]decane-8-carbaldehyde (Intermediate 65, 40 mg, 0.154 mmol) and titanium(IV) isopropoxide (0.090 ml, 0.307 mmol) were collected in dichloromethane (2 ml) and shaken at r.t. overnight. Then sodium borohydride (17.44 mg, 0.461 mmol) and ethanol (2.0 ml) were added and the resulting mixture was shaken for 5 hours. It was then rinsed with DCM (20 ml), treated with NaHCO3 (5 ml) and filtered over a filter tube washing with DCM (2×5 ml). The collected organic phases were concentrated to afford 50 mg of crude compound. This was purified by MDAP system Fraction Lynx (method D) to afford (trans)-3-(3-pyridinyl)-8-([6-(trifluoromethyl)-2-pyridinyl]amino}methyl)-1-oxa-3-azaspiro[4.5]decan-2-one (8.5 mg).1H NMR (400 MHz, CDCl3): delta 8.62 (d, 1H), 8.40 (dd, 1H), 8.24 (dq, 1H), 7.54 (t, 1H), 7.32 (ddd, 1H), 6.93 (d, 1H), 6.54 (d, 1H), 4.82 (br s, 1H), 3.83 (s, 2H), 3.34 (t, 2H), 2.10-1.72 (m, 7H), 1.30-1.18 (m, 2H); UPLC-MS: 0.72 min, 407 [M+H]+.The above compound was dissolved in DCM (2 ml) and converted into the corresponding salt by reaction with 1M HCl in Et2O (2 eq) to afford the title compound as a colourless solid (12 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 1,2-dimethoxyethane; at 20℃; | ,3-dichloroacetone (0.01 mL, 0.11 mmol) was added dropwise to a solution of 6-trifluoromethyl-pyridin-2-ylamine (0.016 g, 0.10 mmol) in 1,2-dimethoxyethane (1.0 mL), and the mixture was left to stir at room temperature for 2 h. The solvent was removed in vacuo and the resulting residue re-dissolved in ethanol (1.0 mL). The reaction mixture was subsequently heated under reflux for 2 h, and the solvent was removed under reduced pressure. DIPEA (0.05 mL, 0.25 mmol) and 1-methyl-4 phenyl-1,3-dihydro-imidazole-2-thione (0.017 g, 0.09 mmol) were sequentially added to a solution of the crude product in DMF (1.0 mL). The reaction mixture was then heated at 60 C. for 2 h after which LC-MS showed complete consumption of the starting materials. The solvent was removed under reduced pressure and the crude product purified using preparative LC-MS to yield the title compound. LC-MS: m/z=389.1 (MH+), tR=0.52 min, method C. | |
Example 4; Preparation of 5-Methyl-2-(1 -methyl-4-phenyl-1 H-imidazol-2-ylsulfanylmethyl)- imidazo[1 ,2-a]pyridine 1 ,3-dichloroacetone (0.01 mL, 0.11 mmol) was added dropwise to a solution of 6- trifluoromethyl-pyridin-2-ylamine (0.016 g, 0.10 mmol) in 1 ,2-dimethoxyethane (1.0 mL), and the mixture was left to stir at room temperature for 2 h. The solvent was removed in vacuo and the resulting residue re-dissolved in ethanol (1.0 mL). The reaction mixture was subsequently heated under reflux for 2 h, and the solvent was removed under reduced pressure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With sodium t-butanolate; tert-butyl XPhos;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; tert-butyl alcohol; at 120℃; for 16h; | EXAMPLE 35 N2-(R)-Indan-1-yl-N6-(6-trifluoromethyl-pyridin-2-yl)-4H-benzo[d][1,3]oxazine-2,6-diamine A mixture of (6-bromo-4H-benzo[d][1,3]oxazin-2-yl)-(R)-indan-1-yl-amine (Example 32) (172 mg, 0.5 mmol), commercially available <strong>[34486-24-3]2-amino-6-trifluoromethyl-pyridine</strong> (162 mg, 1.0 mmol), tert-Bu-XPhos (34 mg, 0.08 mmol), Pd2dba3 (18 mg, 0.02 mmol), sodium tert.-butylate (53 mg, 0.55 mmol), tert-butanol (0.5 ml) and dioxane (3 ml) was heated in a sealed tube at 120 C. for 16 h. The reaction mixture was poured into water (15 ml) and extracted with ethyl acetate (2*30 ml). The combined organic layers were washed with water (20 ml) and brine (20 ml), dried (magnesium sulfate) and evaporated. Further purification of the crude product by flash chromatography on silica gel (ethyl acetate/heptane) yielded the title compound (127 mg, 60%) as light brown foam. MS (ISP): m/e=425.2 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 4-methyl-morpholine; In dichloromethane; for 0.333333h; | Example 226; 2-[3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-l-yl]-7V-[6-(trifluoromethyl)pyridin-2- yljacetamide; To a suspension of 2-(3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-l-yl)acetic acid (0.192 g, 0.578 mmol; Example 58D) in dichloromethane (3 mL) was added a catalytic amount of Lambda/,Lambda/-dimethylformamide followed by oxalyl dichloride (2.0 M in dichloromethane) (0.578 mL, 1.157 mmol). The reaction was stirred for 30 minutes than concentrated to give an oil. After drying under high vacuum for 20 minutes, the residue was dissolved in dichloromethane (1 mL) and <strong>[34486-24-3]6-(trifluoromethyl)pyridin-2-amine</strong> (0.075 g, 0.463 mmol) and 4-methylmorpholine (0.102 mL, 0.925 mmol) were added. After stirring for 20 minutes, the reaction was loaded onto a GraceResolv 40 g silica gel column (Grace Davison Discovery Sciences) and the product eluted with a gradient of 5% ethyl acetate/hexanes to 35% ethyl acetate/hexanes (Flow = 40 mL/minute) over 30 minutes to give the title compound. 1H NMR (300 MHz, CDCl3) delta 8.36 (s, IH), 8.32 (d, J= 8.5, IH), 7.86 (t, J= 8.0, IH), 7.43 (d, J = 7.3, IH), 7.36 - 7.29 (m, 4H), 7.06 - 6.96 (m, 4H), 4.22 (s, 2H), 3.54 (t, J= 6.5, 2H), 2.83 (t, J= 6.5, 2H); MS (ESI+) m/z 476.1 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42.9% | With bromine; In dichloromethane; at 20℃; | A solution of bromine (4.31 g, 27.0 mmo 1) in dichloromethane (10 mL) was added dropwise to a solution of 2-amino-6- (trifluoromethyl) pyridine (4.37 g, 27.0 mmo 1) In dichloromethane (70 mL) and the resulting mixture was stirred at room temperature overnight. Saturated aqueous sodium bicarbonate (40 mL) was added, the layers were separated and the organic layer was collected. The aqueous layer was extracted with dichloromethane (70 mL) and the combined organic layers were washed sequentially with saturated aqueous sodium thiosulfate (20 mL) and saturated brine (20 mL) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the product was purified by column chromatography (200~300 mesh silica gel, ethyl acetate: petroleum ether = 1:50~1:30) to give 3-bromo-6- (trifluoromethyl) Pyridin-2-amine (3) (2.79g). The yield was 42.9% |
24% | With bromine; In dichloromethane; at 0℃; for 25.5h; | a) 3-Bromo-<strong>[34486-24-3]6-(trifluoromethyl)pyridin-2-amine</strong>; A solution of <strong>[34486-24-3]6-(trifluoromethyl)pyridin-2-amine</strong> (200 mg, 1.23 mmol) in dichloromethane (2.47 ml) was cooled to 0 C. and bromine (197 mg, 63.4 mul, 1.23 mmol) was slowly added within 30 min. After 25 h at 0 C. the reaction mixture was extracted with saturated Na2S2O3 solution, water and brine, dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography over silica gel using CH2Cl2/MeOH (with 10% ammonia) as eluent. The title compound was obtained as a white solid (711 mg, 24%).1H NMR (CDCl3, 300 MHz): delta (ppm)=7.80-7.77 (m, 1H), 6.91-6.89 (m, 1H). |
24% | With bromine; In dichloromethane; at 0℃; for 25.5h; | A solution of <strong>[34486-24-3]6-(trifluoromethyl)pyridin-2-amine</strong> (200 mg, 1.23 mmol) in dichloromethane (2.47 ml) was cooled to 0C and bromine (197 mg, 63.4 mu, 1.23 mmol) was slowly added within 30 min. After 25 h at 0C the reaction mixture was extracted with saturated Na2S203 solution, water and brine, dried over Na2S04 and concentrated in vacuo.The crude material was purified by flash chromatography over silica gel using CH2Cl2/MeOH(with 10% ammonia) as eluent. The title compound was obtained as a white solid (711 mg, 24%). 1H NMR (CDCI3, 300 MHz): delta (ppm) = 7.80-7.77 (m, 1H), 6.91-6.89 (m, 1H). |
24% | With bromine; In dichloromethane; at 0℃; for 25.5h; | a) 3-Bromo-<strong>[34486-24-3]6-(trifluoromethyl)pyridin-2-amine</strong>; A solution of <strong>[34486-24-3]6-(trifluoromethyl)pyridin-2-amine</strong> (200 mg, 1.23 mmol) in dichlormethane (2.47 mL) was cooled to 0 C. and bromine (197 mg, 63.4 muL, 1.23 mmol) was slowly added within 30 minutes. After 25 hours at 0 C. the reaction mixture was extracted with saturated Na2S2O3 solution, water and brine, dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography over silica gel using CH2Cl2/MeOH (with 10% ammonia) as eluent. The title compound was obtained as a white solid (711 mg, 24%).1H NMR (CDCl3, 300 MHz): delta (ppm)=7.80-7.77 (m, 1H), 6.91-6.89 (m, 1H). |
24% | With bromine; In chloroform; at 0℃; for 25.5h; | A solution of <strong>[34486-24-3]6-(trifluoromethyl)pyridin-2-amine</strong> (200 mg, 1.23 mmol) in dichlormethane (2.47 mL) was cooled to 0 C and bromine (197 mg, 63.4 mu,, 1.23 mmol) was slowly added within 30 minutes. After 25 hours at 0 C the reaction mixture was extracted with saturated Na2S203 solution, water and brine, dried over Na2S04 and concentrated in vacuo. The crude material was purified by flash chromatography over silica gel using CH2Cl2/MeOH (with 10% ammonia) as eluent. The title compound was obtained as a white solid (711 mg, 24%).1H NMR (CDCls, 300 MHz): delta (ppm) = 7.80-7.77 (m, 1H), 6.91-6.89 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17% | With 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; sodium t-butanolate;bis(dibenzylideneacetone)-palladium(0); In toluene; at 140℃; for 0.333333h;Microwave irradiation; Inert atmosphere; | A 20-mL microwave vial was charged with ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (1.28 g, 5.67 mmol, 1 equiv), <strong>[34486-24-3]2-amino-6-(trifluoromethyl)pyridine</strong> (1.10 g, 6.81 mmol, 1.2 equiv), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (132 mg, 0.22 mmol, 4 mol %), tris(dibenzylideneacetone) dipalladium(0) (104 mg, 0.11 mmol, 2 mol %), sodium tert-butoxide (652 mg, 6.81 mmol, 1.2 equiv) and toluene (12 mL). The vial was sealed and the contents degassed, purged with argon and then heated in a microwave reactor at 140 C. for 20 minutes. After cooling, the mixture was diluted with ethyl acetate and filtered through a pad of Celite. The filtrate was washed with water and saturated aqueous sodium chloride solution, dried over anydrous sodium sulphate, filtered, and concentrated under vacuum. The resultant residue was purified by flash column chromatography on silica gel (gradient: 0 to 20% ethyl acetate in dichloromethane) to give 344 mg (17%) of ethyl 5-(6-(trifluoromethyl)pyridin-2-ylamino)pyrazolo[1,5-a]pyrimidine-3-carboxylate as an orange solid. LCMS (ESI) m+H=352.1; 1H NMR (300 MHz, DMSO-d6) delta: 11.06 (s, 1H), 9.16 (d, 1H), 8.94 (d, 1H), 8.39 (s, 1H), 8.10 (t, 1H), 7.57 (d, 1H), 7.05 (d, 1H), 4.31 (q, 2H), 1.40 (t, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73.1% | With N-Bromosuccinimide; In methanol; at 0 - 20℃;Inert atmosphere; | To a mixture of 6-(trifluoromethyl)pyridin-2-amine (600 mg, 3.7mmol) in MeOH (10 mL) was added NBS (659 mg, 3.7mmol) in portions at 0oC. The reaction mixture was stirred at r.t. overnight. The reaction mixture was concentrated under reduced pressure and the residue was purified by chromatography (eluted with PE:EA = 4:1) to afford the title compound (650 mg, 73.1% yield) as a white solid. Retention time (LC-MS): 1.33 min. MH+ 241. |
48.2% | With N-Bromosuccinimide; In methanol; at 0 - 20℃; for 10.0h; | To a stirred solution of 6-(trifluoromethyl)pyridin-2-amine (2 g, 12.34 mmol) in methanol (20 ml.) was added N-bromosuccinamide (2.19 g, 12.34 mmol) in portions at 0 C. Reaction mixture was then stirred at rt for 10 h. After completion of reaction (monitored by TLC) evaporated the solvent invacuo to dryness. Crude compound was purified by column chromatography using 0-50% EtOAc in n-hexanes to afford title compound 1 .4 g (48.2%), Rf = 0.55 (20% EtOAc in n-Hexane). 1 H NMR (300 MHz, Chloroform-d) d 7.68 (d, J = 8.6 Hz, 1 H), 6.53 (d, J = 8.7 Hz, 1 H), 4.71 (s, 2H). |
44% | With N-Bromosuccinimide; In chloroform; for 2.0h;Darkness; | To a solution of 6-trifluoromethyl-pyridin-2-ylamine (10.0 g, 62.1 mmol, 1 eq) in CHCI3 (200 mL) was added NBS (12.0 g, 67.4 mmol, 1.08 eq). The solution was stirred in the dark for 2 h, at which time it was added to DCM (200 mL) and 1 N NaOH (200 mL). Upon mixing, the layers were separated and the organic layer was dried and concentrated. The residue was purified by silica gel column (EA/PE = 1/1, v/v) to give 5-bromo-6- trifluoromethyl-pyridin-2-ylamine (6.5 g, 44%) as an orange solid. |
40.3% | With N-Bromosuccinimide; at 0 - 20℃; for 3.0h; | The 6 - (trifluoromethyl) pyridin -2 amine (972 mg, 6 . 0mmol) dissolved in chloroform (10 ml) in, cooling to 0 C, adding N-bromo succinimide (1.28g, 7 . 2mmol), stir at room temperature 3 hours, concentrated, crude product by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) purification, to obtain solid title compound (0.58g, yield 40.3%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | 366 mg of bis(trichloromethyl)carbonate (1.234 mmol) were dissolved in 7 ml of dichloromethane (DCM) and cooled to 0 C. To this mixture a solution of 400 mg 6-(trifluoromethyl)pyridin-2-amine (2.467 mmol) and 379 mul triethylamine (5.43 mmol) in 9.7 ml DCM was slowly added over 60 minutes at 0 C. and stirring was then continued for additional 60 minutes at 23 C. 550 mg <strong>[65340-73-0]6-bromoquinolin-4-amine</strong> (2.467 mmol) and 379 mul triethylamine (5.43 mmol) were suspended in 9.7 ml DCM and the suspension was slowly added to the reaction mixture at 23 C., which became a clear solution after 45 minutes. After stirring over night the reaction mixture was poured into ice water and stirred for 2 h. The precipitate formed was filtered off and dried in vacuo for 24 h. 810 mg of the desired product were obtained as off white powder (yield: 80%). The already quite pure raw material was used without further purification.1H NMR (DMSO-d6, 400 MHz): delta [ppm]: 10.26 (s, 1H), 9.70 (s, 1H), 8.79 (d, 1H), 8.44 (d, 1H), 8.28 (d, 1H), 8.19 (d, 1H), 8.09 (dd, 1H), 7.88 (dd, 1H), 7.93 (d, 1H), 7.57 (d, 1H)ESI-MS [M+H+]: 413.0 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | A solution of 6-(trifluoromethyl)pyridin-2-amine (0.668 g, 4.12 mmol) in DMF (5 mL) was added NaH (0.10 g, 4.18 mmol) and stirred for 0.5 h. To the mixture was added <strong>[933190-51-3]8-bromo-6-chloroimidazo[1,2-b]pyridazine</strong> (0.38 g, 1.65 mmol) under N2. The mixture was stirred at room temperature for 16 h then 100 mL of water was added and the precipitate collected by filtration and washed with water to give 6-chloro-N-(6-(trifluoromethyl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (0.513 g, 99%) as a light brown solid. LC-MS: [M+H]+, 314.1, tR=1.738 min. | |
99% | A solution of 6-(trifluoromethyl)pyridin-2-amine (0.668 g, 4.12 mmol) in DMF (5 mL) was added NaH (0.10 g, 4.18 mmol) and stirred for 0.5 h. To the mixture was added 8-bromo-6- chloroimidazo[l,2-b]pyridazine (0.38 g, 1.65 mmol) under N2. The mixture was stirred at room temperature for 16 h then 100 mL of water was added and the precipitate collected by filtration and washed with water to give 6-chloro-N-(6-(trifluoromethyl)pyridin-2-yl)imidazo[l,2- b]pyridazin-8-amine (0.513 g, 99 %) as a light brown solid. LC-MS: [M+H]+, 314.1 , tR = 1.738 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 6h; | 3-(3-chlorophenyl)imidazo[l ,2-b]pyridazine-6-carboxylic acid (150.0 mg, 0.55 mmol), 6- (trifluoromethyl)pyridin-2-amine (180.0 mg, 1.1 1 mmol), DIEA (142.0 mg, 1.1 1 mmol) and HATU (422.0 mg, 1.1 1 mmol) were dissolved in DMF (30.0 mL). The mixture was stirred at room temp for about 6 h, then poured into water and filtered. The solid was washed with water. Purification gave 3-(3-chlorophenyl)-N-(6-(trifluoromethyl)pyridin-2- yl)imidazo[l,2-b]pyridazine-6-carboxamide (62.0 mg, 28%). MS (ESI) calcd for CI9HI IC1F3N50: 417.06; found: 417.80 [M+H] . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
00205] Step 1: A mixture of tert-butyl {(lS,2i?)-2-[(4-chloro-5-cyanopyridin-2-yl)amino]cyclohexyl} carbamate (PrepEx 1.1) (80 mg, 0.23 mmol), <strong>[34486-24-3]2-amino-6-(trifluoromethyl)pyridine</strong> (37 mg, 0.23 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (16 mg, 0.034 mmol), Pd2(dba)3 (21 mg, 0.023 mmol), and cesium carbonate (149 mg, 0.456 mmol) in a flask was evacuated and backfilled with nitrogen (3x). Dioxane (1.5 mL) was added, and the reaction mixture was heated to 80C for 3 hours. The mixture was allowed to cool to room temperature. TFA (0.386 mL, 5.02 mmol) was added, and the suspension was heated to 65 C for 14 hours. The mixture was allowed to cool to room temperature, filtered, and concentrated under reduced pressure. The residue was dissolved in DMSO, filtered, and purified via reverse phase HPLC (acetonitrile/water with 0.1% TFA, linear gradient) to afford 6-[(li?,2S)-2-aminocyclohexyl]amino}-4-[6-(trifluoromethyl)pyridin-2-yl]amino}pyridine-3-carbonitrile. MS ESI calc'd. for CigH20F3N6 [M + H]+ 377, found 377. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With palladium diacetate; caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; for 1h;Reflux; | To a mixture of 6-chloro-1-(4-chlorobenzyl)-3-(2-methoxycarbonyl-2-methylpropyl)pyrimidine-2,4(1H, 3H)-dion (120 mg, 0.311 mmol) and dioxane (3 mL) were added <strong>[34486-24-3]6-trifluoromethylpyridine-2-yl-amine</strong> (76 mg, 0.47 mmol), palladium acetate(II) (7.0 mg, 0.031 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (27 mg, 0.047 mmol) and cesium carbonate (142 mg, 0.436 mmol), and the resulting mixture was heated at reflux for 1 hour. To the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The extract was washed by brine, dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give 1-(4-chlorobenzyl)-3-(2-methoxycarbonyl-2-methylpropyl)-6-(6-trifluoromethyl-2-pyrid ylamino)pyrimidine-2,4(1H, 3H)-dion (110 mg, Yield: 69%) as colorless solid. 1H-NMR (delta ppm TMS/DMSO-d6): 1.11 (6H, s), 3.50 (3H, s), 4.01 (2H, s), 5.30 (2H, s), 6.10 (1H, s), 7.24 (2H, d, J=8.0 Hz), 7.35 (3H, m), 7.48 (1H, d, J=7.6 Hz), 7.96 (1H, m), 9.41 (1H, s). |
69% | With palladium diacetate; caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; for 1h;Reflux; | To a mixture of 6-chloro-1-(4-chlorobenzyl)-3-(2-methoxycarbonyl-2-methylpropyl)pyrimidine-2,4(1H,3H)-dion (120 mg, 0.311 mmol) and dioxane (3 mL) were added <strong>[34486-24-3]6-trifluoromethylpyridine-2-yl-amine</strong> (76 mg, 0.47 mmol), palladium acetate(II) (7.0 mg, 0.031 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (27 mg, 0.047 mmol) and cesium carbonate (142 mg, 0.436 mmol), and the resulting mixture was heated at reflux for 1 hour. To the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The extract was washed by brine, dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give 1-(4-chlorobenzyl)-3-(2-methoxycarbonyl-2-methylpropyl)-6-(6-trifluoromethyl-2-pyrid ylamino)pyrimidine-2,4(1H,3H)-dion (110 mg, Yield: 69%) as colorless solid. 1H-NMR (delta ppm TMS/DMSO-d6): 1.11 (6H, s), 3.50 (3H, s), 4.01 (2H, s), 5.30 (2H, s), 6.10 (1H, s), 7.24 (2H, d, J=8.0 Hz), 7.35 (3H, m), 7.48 (1H, d, J=7.6 Hz), 7.96 (1H, m), 9.41 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12% | 6-(Trifluoromethyl)pyridin-2-amine (0.108g, 0.66 mmol) was added to a mixture of sodium hydride (0. 095 g, 3.96 mmol) and N,N-dimethylformamide (2.1 mL) under nitrogen gas at 15 - 20 C and the reaction mixture was stirred for 15 - 20 min. Compound of example 65 (0.238 g, 0.77 mmol) was added to the reaction mixture at 5 - 10 C and was stirred for 3 - 6 h. The reaction mixture was cooled to 10 C and methanol (0.4 mL) was added slowly. A solution of chilled 20 % ammonium chloride solution (3.1 mL) was added drop-wise to the reaction mixture at 10 C and was stirred for 25 - 30 min. The product was extracted in ethyl acetate (9 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound. Yield: 0.03 g (12 %); 1H NMR (300 MHz, DMSO-d6): delta 10.34 (s, 1 H), 8.58 (m, 2H), 8.06 (m, 1 H), 7.83 (m, 2H), 7.55 (d, 1 H), 7.47 (d, 1 H), 7.10 (d, 1 H), 7.10 (d, 1 H), 6.41 (s, 2H); MS (ES+): 361 .4 (M+1 ). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | 6-(Trifluoromethyl)-pyridin-2ylamine (0.7 g, 4.27 mmol) was added to a mixture of sodium hydride (1 .2 g, 49.7 mmol) and N,N-dimethylformamide (9.96 mL) under nitrogen gas at 25 - 30 C and the reaction mixture was stirred for 15 - 20 min. Compound of example 2 (1 .245 g, 4.97 mmol) was added to the reaction mixture and was stirred for 16 -18 h. The reaction mixture was cooled to 10 C and methanol (2.5 mL) was added slowly. A solution of chilled 20 % ammonium chloride solution (125 mL) was added drop-wise to the reaction mixture at 10 C and was stirred for 25 - 30 min. The precipitated product was filtered, and was washed with water followed by petroleum ether. The resulting product was dried at 45 - 50 C for 20 - 22 h. Yield: 1 .45 g (78 %); 1H NMR (300 MHz, DMSO-d6): delta 10.6 (s, 1 H), 8.8 (s, 1 H), 8.4 (s, 1 H), 8.0 (t, 1 H, 7.5 Hz), 7.9 (s, 1 H,), 7.6 (d, 2H, 7.2 Hz), 7.5 (d, 1 H, 7.5 Hz), 7.1 (d, 1 H, 8.7 Hz), 3.86 (s, 3H), 3.84 (s, 3H); MS (ES+): 377 (M+1 ). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23% | 6-(Trifluoromethyl)pyridin-2-amine (0.56 g, 3.46 mmol) was added to a mixture of sodium hydride (0.49 g, 20.7 mmol) and N,N-dimethylformamide (10 mL) under nitrogen gas at 1 5 - 20 C and the reaction mixture was stirred for 1 5 - 20 min. Compound of example 1 00 (1 .0 g, 4.01 mmol) was added to the reaction mixture at 5 - 1 0 C and was stirred for 3 - 6 h. The reaction mixture was cooled to 1 0 C and methanol (1 .7 mL) was added slowly. A solution of chilled 20 % ammonium chloride solution (1 5 mL) was added drop-wise to the reaction mixture at 1 0 C and was stirred for 25 - 30 min. The product was extracted in ethyl acetate (40 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound. Yield: 0.3 g (23 %) ; 1 H NMR (300 MHz, DMSO-d6) : delta 1 0.22 (s, 1 H), 8.55(m, 2H), 8.04 (m, 2H), 7.55 (d, 1 H), 7.44(d, 1 H), 6.70 (m, 2H), 3.90 (s, 3H), 3.85 (s, 3H) ; MS (ES+) : 377.2 (M+1 ). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | 6-(Trifluoromethyl)pyridin-2-amine (2.25 g, 13.9 mmol) was added to a mixture of sodium hydride (1 .74 g, 72.6 mmol) and N,N-dimethylformamide (22 mL) under nitrogen gas at 15 - 20 C and the reaction mixture was stirred for 15 - 20 min. Compound of example 104 (3.0 g, 12.1 mmol) was added to the reaction mixture at 5 - 10 C and was stirred for 3 - 6 h. The reaction mixture was cooled to 10 C and methanol (7.6 mL) was added slowly. A solution of chilled 20 % ammonium chloride solution (67 mL) was added drop-wise to the reaction mixture at 10 C and was stirred for 25 - 30 min. The product was extracted in ethyl acetate (2 x 22 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound. Yield: 2.2 g (43 %); 1H NMR (300 MHz, DMSO-d6): delta 10.70 (s, 1 H), 10.21 (s, 1 H), 8.81 (s, 1 H), 8.29 (s, 1 H), 7.98 (m, 3H), 7.70(d, 3H), 7.49 (d, 1 H), 2.10 (s, 3H); MS (ES+): 374.1 (M+1 ). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16% | 6-(Trifluoromethyl)pyridin-2-amine (1 .0 g, 6.1 7 mmol) was added to a mixture of sodium hydride (0.88 g, 37.0 mmol) and N,N-dimethylformamide (20 ml_) under nitrogen gas at 1 5 - 20 C and the reaction mixture was stirred for 1 5 - 20 min. Compound of example 1 07 (2.0 g, 7.1 mmol) was added to the reaction mixture at 5 - 1 0 C and was stirred for 3 - 6 h. The reaction mixture was cooled to 1 0 C and methanol (3.4 ml_) was added slowly. A solution of chilled 20 % ammonium chloride solution (30 ml_) was added drop-wise to the reaction mixture at 1 0 C and was stirred for 25 - 30 min. The product was extracted in ethyl acetate (2 x 40 ml_) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain title compound. Yield: 0.4 g (1 6 %) ; 1 H NMR (300 MHz, DMSO-d6) : delta 1 0.96 (s, 1 H), 8.85(s, 1 H), 8.53 (s, 2H), 8.38 (d, 1 H), 8.1 6(t, 1 H), 7.68 (d, 1 H), 7.51 (s, 1 H), 7.35 (d, 1 H), 3.99 (s, 3H); MS (ES+): 405.6 (M+1 ). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29% | 6-(Trifluoromethyl)pyridin-2-amine (0.146 g, 0.90 mmol) was added to a mixture of sodium hydride (0.129 g, 5.4 mmol) and N,N-dimethylformamide (3.0 mL) under nitrogen gas at 15 - 20 C and the reaction mixture was stirred for 15 - 20 min. Compound of example 31 (0.26 g, 1 .04 mmol) was added to the reaction mixture at 5 - 10 C and was stirred for 3 - 6 h. The reaction mixture was cooled to 10 C and methanol (0.5 mL) was added slowly. A solution of chilled 20 % ammonium chloride solution (4 mL) was added drop-wise to the reaction mixture at 10 C and was stirred for 25 - 30 min. The product was extracted in ethyl acetate (12 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain title compound. Yield: 0.1 g (29 %); 1H NMR (300 MHz, DMSO-d6): delta 10.57 (s, 1 H), 8.77(s, 1 H), 8.34 (s, 1 H), 8.19 (d 1 H), 7.99(m, 2H), 7.46 (d, 1 H), 6.69 (m, 2H), 3.84 (s, 6H); MS (ES+): 377.2 (M+1 ). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | 6-(Trifluoromethyl)pyridin-2-amine (0.19 g, 1 .17 mmol) was added to a mixture of sodium hydride (0.168 g, 7.02 mmol) and N,N-dimethylformamide (3.8 mL) under nitrogen gas at 15 - 20 C and the reaction mixture was stirred for 15 - 20 min. Compound of example 34 (0.339 g, 1 .35 mmol) was added to the reaction mixture at 5 - 10 C and was stirred for 3 - 6 h. The reaction mixture was cooled to 10 C and methanol (0.6 mL) was added slowly. A solution of chilled 20 % ammonium chloride solution (5 mL) was added drop-wise to the reaction mixture at 10 C and was stirred for 25 - 30 min. The product was extracted in ethyl acetate (15 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound. Yield: 0.1 g (22 %); 1H NMR (300 MHz, DMSO-d6): delta 10.74 (s, 1 H), 8.85 (s, 1 H), 8.50 (s, 1 H), 8.03 (m, 1 H), 7.91 (d, 1 H), 7.51 (d, 1 H), 7.22 (s, 2H), 6.68 (s, 1 H), 3.83 (s, 6H); MS (ES+): 377.2 (M+1 ). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | 6-(Trifluoromethyl)pyridin-2-amine (0.31 g, 1 .91 mmol) was added to a mixture of sodium hydride (0.275 g, 1 1 .4 mmol) and N,N-dimethylformamide (6.2 mL) under nitrogen gas at 15 - 20 C and the reaction mixture was stirred for 15 - 20 min. Compound of example 37 (0.48 g, 2.21 mmol) was added to the reaction mixture at 5 - 10 C and was stirred for 3 - 6 h. The reaction mixture was cooled to 10 C and methanol (1 .0 mL) was added slowly. A solution of chilled 20 % ammonium chloride solution (9 mL) was added drop-wise to the reaction mixture at 10 C and was stirred for 25 - 30 min. The product was extracted in ethyl acetate (25 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain title compound Yield: 0.3 g (45 %); 1 H NMR (300 MHz, DMSO-d6): delta 10.66 (s, 1 H), 8.8 (s, 1 H), 8.30 (s, 1 H), 8.03 (m, 4H), 7.48 (m, 1 H), 7.12 (d, 2H), 3.77 (s, 3H); MS (ES+): 347.4 (M+1 ). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12% | 6-(Trifluoromethyl)pyridin-2-amine (0.15 g, 0.92 mmol) was added to a mixture of sodium hydride (0. 13 g, 5.5 mmol) and N,N-dimethylformamide (3.0 mL) under nitrogen gas at 15 - 20 C and the reaction mixture was stirred for 15 - 20 min. Compound of example 40 (0.24 g, 1 .06 mmol) was added to the reaction mixture at 5 - 10 C and was stirred for 3 - 6 h. The reaction mixture was cooled to 10 C and methanol (0.5 mL) was added slowly. A solution of chilled 20 % ammonium chloride solution (4.5 mL) was added drop-wise to the reaction mixture at 10 C and was stirred for 25 - 30 min. The product was extracted in ethyl acetate (12 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain title compound. Yield: 0.04 g (12 %); 1H NMR (300 MHz, DMSO-d6): delta 10.68 (s, 1 H), 8.8 (s, 1 H), 8.29 (s, 1 H), 8.01 (m, 2H), 7.64 (d, 1 H), 7.53 (m, 3H), 7.1 1 (d, 1 H), 6.13 (s, 2H); MS (ES+): 361 .4 (M+1 ). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17% | 6-(Trifluoromethyl)pyridin-2-amine (0.56 g, 3.45 mmol) was added to a mixture of sodium hydride (0.25 g, 10.4 mmol) and N,N-dimethylformamide (1 1 .2 mL) under nitrogen gas at 15 - 20 C and the reaction mixture was stirred for 15 - 20 min. Compound of example 42 (1 .0 g, 4.0 mmol) was added to the reaction mixture at 5 - 10 C and was stirred for 3 - 6 h. The reaction mixture was cooled to 10 C and methanol (1 .9 mL) was added slowly. A solution of chilled 20 % ammonium chloride solution (15 mL) was added drop-wise to the reaction mixture at 10 C and was stirred for 25 - 30 min. The product was extracted in ethyl acetate (40 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound. Yield: 0.2 g (17 %); 1H NMR (300 MHz, DMSO-d6): delta 10.34 (s, 1 H), 8.66(d 1 H), 8.60 (d 1 H), 8.06 (m, 1 H), 7.87 (s, 1 H), 7.84 (d, 1 H), 7.60 (d, 1 H), 7.47 (d, 1 H), 7.13 (d, 1 H), 3.89 (s, 3H), 3.85 (s, 3H); MS (ES+): 377.2 (M+1 ). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | 6-(Trifluoromethyl)pyridin-2-amine (10 g, 61 .72 mmol) was added to a mixture of sodium hydride (4.44 g, 185.18 mmol) and N,N-dimethylformamide (100 ml_) under nitrogen gas at 0-5 C and the reaction mixture was stirred for 15 - 20 min. Compound of 4,6-dichloropyrimidine (10.1 1 g, 67.90 mmol) was added to the reaction mixture at 0-5 C, then allow the temperature to 25-30 C and stirred for 14-16 h. The reaction mixture was cooled to 0 -5 C and methanol (10 ml_) was added slowly. A solution of chilled 20 % ammonium chloride solution (20 ml_) was added drop-wise to the reaction mixture at 0-5 C and was stirred for 10-15 min. Further 100 ml_ of water was added drop wise, raise the temperature to 25-30 C and added ethyl acetate (100 ml_). The reaction mixture is stirred for 15-20 min and separated the layers. The aqueous layer was extracted with ethyl acetate (50 ml_). Combined both the organic layers and washed with 40% brine solution. The organic layer was dried over sodium sulphate and distilled out the solvent completely under vacuum at 40-45 C to get crude. It was further purified by column chromatography to obtain the title compound Yield: 8 g (80 %); 1 H NMR (300 MHz, DMSO-d6): delta 10.96 (s, 1 H), 8.64(s, 1 H), 8.07 (t, 1 H), 7.97 (d, 1 H), 7.86(s, 1 H), 7.54 (d, 1 H); MS (ES+): 275.4 (M+1 ). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 26 (3S)-2-((2R)-3-Cyclopentyl-2-[formyl(hydroxy)amino]methyl}propanoyl)-N-[6-(trifluoromethyl)-2-pyridinyl]-3-pyrazolidinecarboxamide 2-amino-6-trifluoromethylpyridine (49.5 mg, 0.305 mmol). LC/MS: (M+H)+: 458.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19% | In acetonitrile; at 120℃; for 24h; | Step 1 Ethyl 6-chloro-4-(6-(trifluoromethyl)pyridin-2-ylamino)pyridazine-3-carboxylate A mixture of ethyl 4,6-dichloropyridazine-3-carboxylate (400 mg, 1.81 mmol) and 6- (trifluoromethyl)pyridin-2-amine (587 mg, 3.62 mmol, available commercially from Aldrich), was dissolved in acetonitrile (3 mL) and heated at 120 C for 24 h. The mixture was cooled, concentrated, and the residue was adsorbed on silica gel and purified by chromatography (silica gel 45 muMu, 160g, Thomson, eluting with 0 to 20% acetone in dichloromethane over 20 min) to give the desired ethyl 6-chloro-4-(6-(trifluoromethyl)pyridin-2-ylamino)pyridazine-3- carboxylate (116 mg, 19 %). 1H NMR (CHLOROFORM-d) delta: 10.97 (s, 1H), 9.16 (s, 1H), 7.79 (t, J = 7.9 Hz, 1H), 7.33 (d, J = 7.6 Hz, 1H), 7.05 (d, J = 8.3 Hz, 1H), 4.51 (q, J = 7.2 Hz, 2H), 1.52 (br. s., 1H), 1.45 (t, J = 7.2 Hz, 3H); MS (EI/CI) m/z: 347.0 [M + H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With calcium carbonate; In dichloromethane; water; at 0 - 20℃;Inert atmosphere; | To a suspension of calcium carbonate (1.56 g, 15.6 mmol, Eq: 2.57) and thiophosgene (780 mg, 520 mu, 6.78 mmol, Eq: 1.12) in dichloromethane (10 ml)/water (10 ml) at 0, was added 6- (trifluoromethyl)pyridin-2-amine (985 mg, 6.08 mmol, Eq: 1.00). The reaction was gradually warmed to room temperature and stirred overnight. Separated organic layer and dried over sodium sulfate. Chromatography (40 g Analogix, 0 to 10% ethyl acetate/hexane) gave 965 mg (78%) of desired product as a colorless oil |
60% | With sodium hydrogencarbonate; In dichloromethane; at 0 - 20℃; for 1h; | 2-Isothiocyanato-6-(trifluoromethyl)pyridine. To a stirred solution of <strong>[34486-24-3]6-(trifluoromethyl)pyridin-2-amine</strong> (1 g, 6 mmol) in dichloromethane (25 mL) was added saturated sodium bicarbonate solution (25 mL). Thiophosgene (0.84 g, 7 mmol) was added dropwise at 0 C. The resulting reaction mixture was stirred at ambient temperature for 1 h. Completion of the reaction was confirmed by UPLC. The product was isolated to afford 2-isothiocyanato-6-(trifluoromethyl)pyridine (0.75 g, 60%) as a yellow liquid. MS (ESI) m/z 205 [M+1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61.4% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 16h; | (Formula 7-4: methyl 4-(((6-(trifluoromethyl)pyridin-2-yl)amino)methyl)benzoate)[1765][1766]Compound ofFormula 7-3(<strong>[34486-24-3]6-(trifluoromethyl)pyridin-2-amine</strong> (0.500 g, 3.084 mmol), methyl 4-(bromomethyl)benzoate (1.413 g, 6.169 mmol) and DIPEA(1.092 mL, 6.169 mmol) were dissolved in acetonitrile (10 mL) at room temperature and stirred at the same temperature for 16 hours. Then, water was poured into the reaction mixture, and the organic layer was extracted with ethyl acetate. Then, the organic layer was washed with saturated sodium chloride aqueous solution, dehydrated with anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (silica; ethyl acetate/hexane=20%) to give the desired compound ofFormula 7-4(0.588 g, 61.4%) in the form of a white solid. |
47% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 70℃; for 16h; | [ 1860] A solution of <strong>[34486-24-3]6-(trifluoromethyl)pyridin-2-amine</strong> ( 10.000 g, 61.687 mmol), methyl 4-(bromomethyl)benzoate ( 16.957 g, 74.024 mmol) and N,N-diisopropylethylamine ( 16.010 mL, 92.530 mmol) in acetonitrile ( 150 mL) was stirred at 70 C for 16 hr, and cooled down to the room temperature to terminate the reaction. Then, water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with aqueous saturated ammonium chloride solution, dried (anhydrous MgS04), filtered, and concentrated in vacuo. The concentrate was purified and concentrated by column chromatography (Si02, 120 g cartridge; ethyl acetate / hexane = 0 % to 15 %) to give the title compound methyl 4-(((6-(trifluoromethyl)pyridin-2-yl)amino)methyl)benzoate as white solid (9.000 g, 47.0 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.33 g | With pyridine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 70℃; for 2h; | Production Example 6 (1) A mixture of 0.81 g of 2-amino-6-trifluoromethylpyridine, 0.78 g of <strong>[57266-69-0]3-chloropicolinic acid</strong>, 1.15 g of EDCI hydrochloride, 0.06 g of HOBt and 10 mL of pyridine was stirred at 70C for 2 hours. A saturated aqueous sodium bicarbonate solution was poured to the cooled reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the resulting solid was washed with hexane and dried to obtain 1.33 g of 3-chloro-N-(6-trifluoromethylpyridin-2-yl)picolinamide. 3-Chloro-N-(6-trifluoromethylpyridin-2-yl)picolinamide 1H-NMR (CDCl3) delta: 10.60 (1H, brs), 8.66 (1H, d), 8.58 (1H, d), 7.97-7.87(2H, m), 7.53-7.43(2H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5% | With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 20℃; for 6h; | A mixture of (S)-4-(tert-butoxycarbonyl)morpholine-3 -carboxylic acid (530 mg,2.299 mmol, 1.0 eq), 6-(trifluoromethyl)pyridin-2-amine (447 mg, 2.758 mmol, 1.2 eq), andEDCI (1.32 g, 6.89 mmol, 3.0 eq) in pyridine (15 mL) was stirred at r.t. for 6 h. The reactionmixture was concentrated and the resulting residue was purified by prep-HPLC to give (S)tert-butyl 3 -((6-(trifluoromethyl)pyridin-2-yl)carb amoyl)morpholine-4-carboxylate (50 mg,5%) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 20℃; for 6h; | A mixture of (S)- 1 -((benzyloxy)carbonyl)-4-(tert-butoxycarbonyl)piperazine-2- carboxylic acid (1 g, 2.744 mmol, 1.0 eq), 6-(trifluoromethyl)pyridin-2-amine (667 mg, 4.116 mmol, 1.5 eq), and EDCI (1.58 1 g, 8.232 mmol, 3.0 eq) in pyridine (50 mL) was stirred at r.t. for 6 h. The mixture was concentrated and purified by chromatography on silica gel column (PE/EA = 5/1, v/v) to give the crude (S)-1-benzyl 4-tert-butyl 2-((6-(trifluoromethyl)pyridin- 2-yl)carbamoyl)piperazine-1,4-dicarboxylate (900 mg, 65%) as a brown solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
186.3 g | (1), 2000 g of reaction flask A was charged with 700 g of concentrated hydrochloric acid at a concentration of 36% by weight and 162.1 g2-amino-6-trifluoromethylpyridine was heated to 70 C, stirred for 1 hour, after the completion of the reaction to -2 to 2 C, 177.5 g of a sodium nitrite solution having a concentration of 40%Dropping the diazonium salt solution;(2), 500 ml of a hydrochloric acid solution having a concentration of 18% by weight and 129.4 g of cuprous chloride were added to another reaction flask B, and the mixture was heated to 65C. The resulting diazonium salt solution was added dropwise, Reaction for 2 hours,After the completion of the reaction, the pH of the reaction solution was adjusted to 10 with a sodium hydroxide solution having a concentration of 46% by weight. Then, 550 g of ethyl acetate was added thereto, followed by stirring. The organic layer was extracted and extracted twice,The organic layer was combined and the organic layer was distilled off to remove ethyl acetate to give a pale yellow liquid. The pale yellow liquid was cooled to room temperature to give 186.3 g of solid 2-chloro-6-trifluoromethylpyridine. |
Tags: 34486-24-3 synthesis path| 34486-24-3 SDS| 34486-24-3 COA| 34486-24-3 purity| 34486-24-3 application| 34486-24-3 NMR| 34486-24-3 COA| 34486-24-3 structure
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