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CAS No. : | 175205-81-9 |
Formula : | C6H3BrF3N |
M.W : | 225.99 |
SMILES Code : | FC(C1=CC(Br)=NC=C1)(F)F |
MDL No. : | MFCD00153085 |
InChI Key : | WZVHLUMAQLUNTJ-UHFFFAOYSA-N |
Pubchem ID : | 2781543 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P301+P312-P302+P352-P304+P340-P305+P351+P338 |
* 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 |
---|---|---|
With trimethylsilyl bromide; In propiononitrile; for 22h;Heating / reflux; | A mixture of 2-chloro-4-(trifluoromethyl)pyridine (2.70 g, 14.9 mmol) and bromotrimethylsilane (3.90 mL, 29.6 mmol) in propanenitrile (15.0 mL) was heated under reflux for 22 h. The product (very volatile) was carefully rotary evaporated to give 4.07 g (propanenitrile contained) of thick light brown suspension w/o further purification. LC-MS calculated for C6H3BrF3N (M+H) 226.9; found 225.9/227.8. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | To Diisopropylamine ( 1 equi) dissolved in THF( 30 mL) added BuLi ( 2.5 M solution in hexane, 9 mL, 1 equi.) and stirred the mixture at room temperature for 30 min. A solution of the bromo pyridine, 1 (5 gm, 1 equi.) in THF (50 mL) was cooled down to -78°C and added the pre- generated LDA to it via a canula. The reaction mixture was continued to stirr at -78°C for further one hour and poured to an excess of crushed dry ice immersed in THF (~ 50 mL). The stirring was continued for 30min allowing the temperature to rise to ice temperature. Evaporated off all the volatiles to obtain 5.8gm (97percent) of 2 which was used for further step without purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 165℃; for 0.333333h;Irradiation; | A mixture of [1- (4-METHANESULFONYL-PHENYL)-LH-PYRAZOLO [3, 4-d] pyrimidin-4-yl]-piperidin-4-yl- amine (100 mg, 0. 24 mmol), <strong>[175205-81-9]2-bromo-4-trifluoromethylpyridine</strong> (166 mg, 0. 73 mmol), and potassium carbonate (102 mg, 0. 73 mmol) in DMF (1. 0 mL) was heated under microwave irradiation for 20 minutes at 165 °C. The crude mixture was purified by HPLC to provide compound A128 as a white solid (41 mg, 32 percent). Exact mass calculated for C23H22F3N702S 517. 15, found 518. 2 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With triethylamine; In dimethyl sulfoxide; at 120℃; for 17h; | tert-Butyl {l-[4-(trifluoromethyl)pyridin-2-yl]piperidin"4-yl}carbamate; A solution of <strong>[175205-81-9]2-bromo-4-trifluoromethylpyridine</strong> (1.0Og, 4.42mmol), tert-butyl piperidine-4- ylcarbamate (0.93g, 4.65mmol) and TEA (0.67mL, 4.86mmol) in DMSO (5mL) was heated at 1200C for 17h. The reaction mixture was evaporated to dryness, Et2O was added, and the organic phase was washed with water, brine and evaporated to dryness. The residue was purified using the Biotage Horizon HRFC system eluting with 22percent EtOAc in petroleum ether EPO <DP n="195"/>(40-60°C) to give the title compound (1.08g, 71percent) as a solid. 1H NMR(500MHz, CDCl3): 8.30 (d, IH), 6.82 (s, IH), 6.77 (d, IH), 4.49 (bs, IH), 4.36-4.22 (m, 2H), 3.74 (bs, IH), 3.06 (td, 2H), 2.10-2.04 (m, 2H), 1.56-1.38 (m, 11H); 13C NMR(CDCl3): 159.4, 155.4, 149.5, 140.1, 139.9, 124.5,122.4, 108.1, 102.7, 79.8, 48.3, 44.4, 32.3, 28.6; Mass Spectrum: M+H 5 346. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With hydrogen bromide; In dichloromethane; at 20℃;Product distribution / selectivity; | Dry HBr gas was introduced at room temperature into a solution of 5 g of 5-ethoxy-3-hydroxy-3-(trifluoro-methyl)pent-4-enenitrile in 100 ml of dichloromethane. The conversion was then monitored by HPLC and, once the content of product in the reaction mixture did not increase any further, the mixture was isolated and purified by aqueous workup and distillation. Yield: 3.9 g (73percent). |
32% | With hydrogen bromide; In acetic acid; at 0 - 5℃; for 1h; | 100 g of hydrogen bromide were initially charged in glacial acetic acid (33percent) and cooled to from 0 to 5° C. by external cooling with ice. 10 g of 5-ethoxy-3-hydroxy-3-(trifluoromethyl)pent-4-enenitrile were then slowly added dropwise to this mixture within 1 h. The conversion was then monitored by HPLC and, once the content of product in the reaction mixture did not increase any further, the mixture was isolated and purified by aqueous workup, extraction and distillation as in the previous examples. 3.5 g (32percent) of product were thus obtained, whose structure was confirmed with the aid of the mass spectrum and by comparison with the spectroscopic data of the analogous chlorine compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; at 20℃; for 19h; | Preparation 11a: 3-(4-trifluoromethylpyridin-2-yl)propionic acid ethyl ester; A solution of 3-ethoxy-3-oxopropylzinc bromide in tetrahydrofuran (0.5 M, 67 mL) was added dropwise over a period of 1 hour to a mixture of <strong>[175205-81-9]2-bromo-4-trifluoromethylpyridine</strong> (6.9 g), tetrakis(triphenylphosphine)palladium(0), (0.60 g) and tetrahydrofuran (20 mL) at room temperature. The resulting mixture was stirred at room temperature for 18 hours, diluted with water (150 mL) and extracted with methyl tert-butyl ether. The combined extracts were dried over magnesium sulphate and the solvent removed under reduced pressure. Purification of the residue by column chromatography on silica gel, eluting with a mixture of pentane, dichloromethane and ethyl acetate (1:1:0, 0:1:0 and 0:5:1 by volume), gave title compound as a yellow oil, 4.2 g.1H NMR (CDCl3): delta 1.25 (t, J=7.0 Hz, 3H), 2.85 (t, J=7.3 Hz, 2H), 3.20 (t, J=7.3 Hz, 2H), 4.10 (q, J=7.0 Hz, 2H), 7.35 (d, J=4.7 Hz, 1H), 7.40 (s, 1H), 8.70 (d, J=4.7 Hz, 1H).MS: ESI (+ve) (Method B): 248 (M+H)+, Retention time 3.33 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With iodobenzene;tris-(dibenzylideneacetone)dipalladium(0); trifuran-2-yl-phosphane; In tetrahydrofuran; at 20 - 65℃; for 2.16667h; | In a separate flask, Pd2(dba)3 (45 mg, 0.05 mmol), P(2-furyl)3 (46 mg, 0.2 mmol) and <strong>[175205-81-9]2-bromo-4-(trifluoromethyl)pyridine</strong> (1.36 mg, 6 mmol) were mixed in THF (1 mL) under N2 for 10 min. This mixture was added to the organozinc reagent solution mentioned above, followed by iodobenzene (1.36 g, 6 mmol) in THF (10 mL). The mixture was heated at 65 °C for 2 h, then cooled, diluted with ethyl acetate and filtered over celite. The filtrate was washed with NaHCO3 (x2), brine (xl) and concentrated. The crude was purified by column chromatography to give the desired product tert-butyl 3-(4-(trifluoromethyl)pyridin-2- yl)azetidine-l-carboxylate (554 mg, 37percent yield): 1H NMR (400 MHz, CDCl3): delta 8.15(d, IH), 7.42 (s, IH), 7.42(d, IH), 4.34 (t, 2H), 4.19 (dd, 2H), 3.95 (dq, IH) 1.47 (s, 9H); MS (ESI) m/z: Calculated for C14HnF3N2O2: 302.29; found: 247.0 (M-1Bu)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Step 1: ferf-Butyl 3-oxo-4-r4-(trifluoromethyl)pyridin-2-yllpiperazine-l-carboxylate (II)A mixture of l-Boc-3-oxopiperazine (1.0 eq.), <strong>[175205-81-9]2-bromo-4-(trifluoromethyl)pyridine</strong> (1.5 eq.) and Cs2CO3 (1.5 eq.) in 1,4-dioxane (0.5M) was degassed under Argon flow for 30 min, then Pd(OAc)2 (0.1 eq.) and Xantphos (0.15 eq.) were added, the vial was sealed and stirring was continued at 1100C for 18 hr. Reaction mixture was diluted with EtOAc and filtered through a pad of SolcaFloc.(R). 200 FCC. After removal of the solvent, the crude product was purified by flash column chromatography on silica gel using 10- 40percent EtO Ac/Petroleum ether as eluent to afford the desired product Il as yellow solid (92percent yield). 1R NMR (400 MHz, CDCl3, 300K) delta 8.57 (IH, d, J = 4.8 Hz), 8.40 (IH, bs), 7.32 (IH, d, J = 4.8 Hz), 4.31 (2H, s), 4.17 (2H, t, J = 5.3 Hz), 3.76 (2H, t, J = 5.3 Hz), 1.50 (9H, s). MS (ES) Ci5Hi8F3N3 O3 requires: 345, found: 346 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With palladium diacetate; potassium carbonate; at 120℃; for 48h;Inert atmosphere; | General procedure: 2-Iodopyrazine (5.00 g, 24.3 mmol), PdII(OAc)2 (34 mg, 0.151 mmol), K2CO3 (3.4 g, 24.6 mmol) and poly(ethylene glycol) (Mw 4000, 24.0 g) were combined in an argon-purged flask. The mixture was gradually heated to 120 C and the temperature maintained for 48 h with stirring. The mixture was cooled to ca. 80 C and warm water (30 mL) was added to prevent solidification. On cooling to room temperature, further water (100 mL) was added and the suspension exhaustively extracted with ethyl acetate. The combined extracts were washed once with saturated aqueous Na2S2O3 and then thrice with brine. The organic layer was dried over MgSO4 and solvent removed under vacuum. The residue was triturated with n-pentane and the white crystalline solid filtered off, washed with n-pentane and dried. Yield: 1.35 g (70%). |
52% | 2.2 Synthesis of 4,4'-bis(trifluoromethyl)-2,2'-bipyridine 2-Bromo-4-trifluoromethyl pyridine (1.2 g, 5.31 mmol) was placed in a round bottom flask with 7.14 g of activated copper bronze. The reaction flask was then flushed with N2 and a reflux condenser was affixed. The reaction was then heated to 190 C for 16 h. The reaction was then cooled to room temperature and the ligand extracted with acetone and chloroform (?100 mL). The organic fraction was then extracted with 1.2 N HCl. Once the aq. fraction turned blue, the organic fraction was extracted then evaporated to afford a yellow oil. The ligand was then purified by vacuum sublimation (52% yield). Spectroscopic data matched literature values [12] . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66.6% | To an oven-dried round bottomed flask was added nBuLi (2.5 M in hexanes, 0.95 ml, 2.38 mmol, 1.17 eq) at -60° C. under N2. An Et2O solution (5 mL) of <strong>[175205-81-9]2-bromo-4-trifluoromethylpyridine</strong> (448 mg, 2.0 mmol) was added dropwise at -60 to -55° C. The resulting solution was stirred at the above temperate for 30 min. The mixture was cooled to -78° C., an Et2O solution (2 mL) of 3-fluoro-5-trifluoromethyl-benzonitrile (390 g, 2.06 mmol) was added dropwise. The resulting solution was stirred -78 to -70° C. for 1.5 h. Pretreated TMSCl (0.26 ml) was added dropwise at -78° C. The mixture was stirred at -78° C. for 15 min, and then warmed up to r.t. for 45 min. It was cooled back to -78° C., and benzyl magnesium chloride (1.0 ml, 2.0 mmol) was added dropwise. The resulting mixture was stirred at -78° C. for 1 h, and then at r.t. for 0.5 h. It was quenched by adding sat'd NH4Cl and 1N HCl, and stirred for 10 min. It was extracted with EtOAc, washed with 1N NaOH, sat'd NaHCO3, H2O, brine, dried (MgSO4), filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, hexanes/EtOAc) to give 1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenyl-1-(4-(trifluoromethyl)pyridin-2-yl)ethanamine as light brownish gum (0.57 g, yield: 66.6percent). LC-MS ESI (10-90percent MeOH in H2O with 0.1percent TFA in a 4-min run), retention time=3.32 min, 429.13 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | trans-bis(triphenylphosphine)palladium dichloride; In 1,4-dioxane; at 140℃; for 3h;Microwave irradiation; Inert atmosphere; Sealed; | Step 1In a microwave vial <strong>[175205-81-9]2-bromo-4-(trifluoromethyl)pyridine</strong> (330 mg, 1.46 mmol), bis(tributylyln) (1.44 mL, 2.85 mmol), and PdCl2(PPh3)2 (51 mg, 0.073 mmol) were suspended in 1,4-dioxane (15 mL).The mixture was degassed with a gentle stream of N2 for 15 min then the vial was then sealed and heated in a microwave reactor at 140° C. for 3 h.The reaction mixture was cooled to room temperature and concentrated.The residue was purified by SiO2 chromatography (5-20percent EtOAc/hexane) to give 229 mg (36percent) of 2-tributylstannanyl-4-trifluoromethyl-pyridine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With lithium chloride;copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; at 100℃; for 1h;Microwave irradiation; Inert atmosphere; | Example 18A microwave vial equipped with a magnetic stirrer was charged with 1 -(4-methoxybenzyl)- 6-methyl-N-(tetrahydro-2H-pyran-4-yl)-3-(trimethylstannyl)-1 H-pyrazolo[4,3-c]pyridin-4- amine (190 mg, 0.369 mmol), <strong>[175205-81-9]2-bromo-4-(trifluoromethyl)pyridine</strong> (167 mg, 0.738 mmol), LiCI (64 mg, 1.48 mmol), Cul (7 mg, 0.037 mmol), Pd(PPh3)4 (43 mg, 0.037 mmol), and THF (10 mL). After three cycles of vacuum/argon flash, the reaction mixture was heated at 100 °C for 1 h under microwave irradiation. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by reverse-phase Combi-flash eluting with 0.3percent NH4HC03 in 1 :3water/CH3CN to afford 1-(4-methoxybenzyl)-6-methyl-N-(tetrahydro-2H-pyran-4-yl)-3-(4- (trifluoromethyl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-4-amine as a yellow solid (55 mg). m/z (ES+APCI)+ : 498 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: Aryl or heteroaryl bromide (4 mmol) was charged in oven dried Radley's synthesis tube that was equipped with a stir bar under a stream of nitrogen. Anhydrous diethyl ether was added and the reaction mixture was cooled to -78 °C. n-BuLi (1.6 M in hexanes, 2.5 mL, 4.00 mmol) was added dropwise and the reaction mixture was stirred at -78 °C for 10 min. A solution of aryl or heteroaryl nitrile in THF (4 mmol) was added dropwise and the reaction mixture was stirred at -78 °C for 2 h. TMSCl (0.550 mL, 4.00 mmol) was added to the reaction mixture at -78 °C and the reaction mixture was allowed to warm up to 0 °C. The reaction mixture was cooled to -78 °C, benzylmagnesium chloride in either THF or ether (2 mmol) or benzyl zinc(II) bromide in ether (2 mmol), was added dropwise, stirred at -78 °C for 2 h, and then stirred at rt for 12 h. The reaction mixture was worked up and purified as in general procedure 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16% | Step B:; A solution of (4a'S,9a,R)-2-amino-7'-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan- -y -l'^'^'^'^a'^a'-hexahydro-SH-spirofoxazole^^'-xanthenJ- '-ol (0.025 g, 0.062 mmol), <strong>[175205-81-9]2-bromo-4-(trifluoromethyl)pyridine</strong> (0.017 g, 0.075 mmol), Pd(PPh3)4 (0.004 g, 0.003 mmol), Na2C03 (2.0 M aq, 0.10 mL, 0.19 mmol) in dioxane (0.62 mL) was degassed with nitrogen for 5 minutes, sealed in a vial and stirred at 80°C for lday. The reaction mixture was filtered through GF/F paper, washing with methanol. The filtrate was concentrated, redissolved in MeOH and purified by CI 8 semi-prep HPLC eluting with 5-75percent ACN/H20 + 0.1percentTFA to afford (2'S,4a'S,9a'R)-2-amino-7*-(4-(trifluoromethyl)pyridin-2-yl)-l,,2,,3',4',4a',9a,-hexahydro- 5H-spiro[oxazole-4,9'-xanthen]-2'-ol trifluoroacetic acid salt: (6 mg, 0.010 mmol, 16percent; racemic mixture of 2:1 mixture of diastereomers at oxazoline). m/z (APCI-pos) M+l = 420.1 (100percent).[00293] Major diastereomer: 1H NMR (CD3OD) delta 8.83 (m, 1H), 8.33 (m, 1H), 8.04 (m, 1H), 7.59 (m, 1H), 6.99 (d, J = 8.6 Hz, 1H), 5.23 (d, J = 9.8 Hz, 1H), 4.69 (d, J = 9.8 Hz, 1H), 4.06 (td, J = 11, 5.0 Hz, 1H), 3.74 (m, 1H), 2.33 (m, 1H), 2.17 (m, 2H), 2.10 (m, 1H), 1.70 (m, 1H), 1.51 (m, 1H), 1.41 (m, 1H).[00294] Minor diastereomer: 1H NMR (CD3OD) delta 8.84 (m, 1H), 8.30 (m, 1H), 8.04 (m, 1H), 7.59 (m, 1H), 7.03 (d, J = 8.6 Hz, 1H), 5.23 (d, J = 9.8 Hz, 1H), 5.02 (d, J = 9.8 Hz, 1H), 3.92 (td, J = 11, 5.0 Hz, 1H), 3.83 (m, 1H), 2.33 (m, 1H), 2.17 (m, 2H), 2.10 (m, 1H), 1.70 (m, 1H), 1.41 (m, 1H), 1.26 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | N*1*-(4-Trifluoromethyl-pyridin-2-yl)-ethane-1,2-diamine2-Bromo-4-(trifluoromethyl)pyridine (500 mg, 2.2 mmol) and ethane-1,2-diamine (12.5 ml, 187.5 mmol) were heated under reflux for 2 h.After cooling, the mixture was concentrated in vacuo and the residue was partitioned between DCM and water.The aqueous phase was extracted with DCM and the combined organic phases were washed with water, dried (MgSO4) and concentrated in vacuo to give the title compound (330 mg, 72percent) which was used without further purification.The compound could not be detected by HPLCMS therefore structure was confirmed by NMR. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: Pyridines substituted at the 2-position with halides shown in Tables 2 and 3 are stirred in a mixture of toluene (900 mL) and anhydrous ether (600 mL). The resulting solutions were cooled to < -100 °C for 20 min at which point n-BuLi/hexane was added slowly over 22 min. After maintaining the temperature below -100 °C for 20 min, triisopropylborate was added dropwise, and then the reaction mixture was stirred below -70 °C. After stirring for 4 h, ether (500 mL) was added and the solution was allowed to stand overnight at room temp. Isopropanol was added (30mL), then the reaction mixture was stirred for 30 min, the allowed to stand without stirring for an additional 2 h. The resulting precipitate was collected by filtration then washed with ethyl ether and dried under nitrogen atmosphere for 1.5 h. The resulting triisopropoxy analog was treated with a mixture of acetone and water (450 mL/50 mL) to remove any contaminating n-butylborate lithium salt. The solids were collected by filtration, washed with acetone/water (9:1, 300 mL), and dried in air for 2h, then lyophilized overnight to afford product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With cesium fluoride; In dimethyl sulfoxide; at 120℃; for 18h; | Step : 1 Preparation of tert-butyl (1S,4S)-5-(4-(trifluoromethyl)pyridin-2-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate [Show Image] <strong>[175205-81-9]2-bromo-4-(trifluoromethyl)pyridine</strong> (0.5 g, 2.21 mmol), cesium fluoride (0.33 g, 2.21 mmol) and tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (1.3 g, 6.63 mmol) were added in DMSO (5 mL). The reaction was then heated to 120°C for 18 hours. The reaction mass was diluted with water and extracted with DCM (3 X 100 mL). The organic layer was washed with water, brine solution, dried over anhydrous MgSO4 and concentrated to get the crude product which was dissolved in DCM. The title intermediate was precipitated by the addition of n-hexane as an off white solid (0.4 g, 66 percent). 1HNMR (DMSO-d6, 400 MHz): delta 8.27 (s, 1 H), 6.82-6.83 (m, 2H), 4.91 (s, 1 H), 4.42-4.52 (m, 1 H), 3.84 (s, 1 H), 3.36-3.59 (m, 1 H), 3.34-3.34 (m, 1 H), 3.14-3.16 (m, 1 H), 1.89 (s, 2H), 1.36 (s, 9H). LCMS (Method D): Mass found (M+ 344.0), Rt (min): 3.58, Area (percent) 97.2 (Max), 98.9 (254 nm). |
With cesium fluoride; In dimethyl sulfoxide; at 120℃; for 18h; | Step : 1 Preparation of tert-butyl (1S,4S)-5-[4-(trifluoromethyl)pyridin-2-yl]-2,5- diazabicyclo[2.2.1 ]heptane-2-carboxylate<strong>[175205-81-9]2-bromo-4-(trifluoromethyl)pyridine</strong> (0.5 g, 2.21 mmol), cesium fluoride (0.33 g, 2.21 mmol) and tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (1.3 g, 6.63 mmol) were added in DMSO (5 ml_). The reaction was then heated to 120°C for 18 hours. The reaction mass was diluted with water and extracted with DCM (3 X 100 mL). The organic layer was washed with water, brine solution, dried over anhydrous MgS04 and concentrated to get the crude product which was dissolved in DCM. The title intermediate was precipitated by the addition of n-hexane as an off white solid (0.4 g, 66 percent). HNMR (DMSO-d6, 400 MHz): delta 8.27 (s, 1 H), 6.82-6.83 (m, 2H), 4.91 (s, 1 H), 4.42-4.52 (m, 1 H), 3.84 (s, 1 H), 3.36-3.59 (m, 1 H), 3.34-3.34 (m, 1 H), 3.14-3.16 (m, 1 H), 1.89 (s, 2H), 1.36 (s, 9H). LCMS (Method D): Mass found (M+ 344.0), Rt (min): 3.58, Area (percent) 97.2 (Max), 98.9 (254 nm). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; at 85℃; for 3h;Inert atmosphere; | General procedure: To a solution of 2-ethynylquinoline 9 (50 mg, 0.33 mmol) in triethylamine (0.4 mL) was added PdCl2(PPh3)2 (12 mg, 0.02 mmol), copper(I) iodide 98percent (6 mg, 0.03 mmol) and 2- bromo-3-trifluoromethylpyridine (110 mg, 0.5 mmol). After the reaction was stirred at 85 °C for 3 h, it was allowed to cool to room temperature and filtered through a pad of Celite by the aid of EtOAc. The filtrate was treated with water and extracted with EtOAc (3 x 10 mL). The organic layer was washed with water and brine, dried over anhydrous MgSO4, and concentrated under reduced pressure. The crude oil was purified by column chromatography on silica gel (EtOAc/hexane = 1:1) to give 2-((3-(trifluoromethyl)pyridin-2-yl)ethynyl) quinoline 6a (48 mg, 49percent) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; toluene; at 100℃; for 2h; | <strong>[175205-81-9]2-bromo-4-(trifluoromethyl)pyridine</strong> (2.0 g, 8.85 mmol) was added to a mixture of 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.85 g,9.73 mmol,) tetrakis(triphenylphosphine)palladium(0) (511 mg, 0.44 mmol,) and potassium carbonate (3.67 g 26.55 mmol,) in ethanol (10 mL) and toluene (10 mL). The mixture was stirred at 100°C for 2h. The reaction was cooled down and water was added. The aqueous phase was extracted with 3X50 mL of dichloromethane. The organic phase was dried with MgSO4, filtered and concentrated. Purification by flash chromatography (100percent heptane to 100percent ethyl acetategradient, 40 g column) afforded 2.34 g (89percent) of 2-(2-tetrahydropyran-2-ylpyrazol-3-yl)-4-(trifluoromethyl)pyridine as a yellow oil. LCMS (Method Shimadzu): RT = 1.45 min, m+H = 298.1. 1H NMR (400 MHz, Chloroform-d) delta 8.87 (d, J = 5.0 Hz, I H), 7.86 (d, J = 1.5 Hz, 1H), 7.63 (dd, J = 14.6,2.2Hz, 1H), 7.48 (dd, J = 5.2, 1.6 Hz, 1H), 6.70 (d, J = 1.9 Hz, 1H), 6.14 (dd, J = 10.0,2.5Hz, 1H),4.04(ddt,J= 11.5,4.3,2.1 Hz, 1H),3.61 (td,J= 11.4,2.6Hz, 1H),2.63-2.48(m, 1H),2.17-1.99 (m, 2H), 1.83 - 1.62 (m, 2H), 1.58 (s, 1H). |
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 90℃; for 2h; | General procedure: Pd(PPh3)4 (9.23 g, 7.99 mmol) and a 2 mol/L aqueous Na2CO3solution (2.4 L) were added to an EtOH (1.6 L)/ toluene (1.6 L)mixed solution of 1 (500 g, 1.8 mol) and 2-bromo-5-fluoropyridine(281.2 g, 1.60 mol), and the mixture was heated to 90 C and stirredfor 2 h. After standing to cool at 0 C, water was added to thereaction mixture, followed by extraction with EtOAc. The extractedorganic layer was distilled off under reduced pressure. Theobtained residue was stirred in EtOAc (1.2 L), and NH silica gelwas added thereto. The mixture was stirred at room temperaturefor 1 h. Then, the silica gel was filtered off, and the solvent was distilledoff under reduced pressure to obtain 5-fluoro-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyridine as a brown oil.A 4 mol/L HCl?EtOAc solution (1.2 L) was added to a solution of5-fluoro-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyridinein MeOH (1.0 L), and the mixture was stirred at room temperaturefor 5 h. The deposited solid was then collected by filtration. Theobtained solid was stirred in water (2.0 L), and an 8 mol/L aqueousNaOH solution (0.3 L) was added thereto under ice cooling. Themixture was extracted with EtOAc, and the solvent was distilledoff under reduced pressure. The obtained residue was stirred for1 h in Et2O. Then, the deposited solid was collected by filtrationand dried by heating under reduced pressure to obtain the titlecompound 2a as a colorless powder (185 g, 71percent over 2 steps). |
Yield | Reaction Conditions | Operation in experiment |
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With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; In toluene; at 70℃; for 12h;Inert atmosphere; | Example 21.rac- (5 -(4-fluorophenyl)-2-methylthiazol-4-yl)((2S,3 R)-3 -methyl-2-(((4- (trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin- 1 -yl)methanoneA mixture of ((2S,3 R)-2-(aminomethyl)-3 -methylpiperidin- 1 -yl)(5-(4-fluorophenyl)- 2-methylthiazol-4-yl)methanone, <strong>[175205-81-9]2-bromo-4-(trifluoromethyl)pyridine</strong>, Pd2dba3, BII?AP, and NaOtBu in toluene was purged with argon, and then stirred at 70 °C for 12h. The reaction was cooled, filtered through a pad of silica gel and concentrated in vacuo. The crude reactionmixture was purified by reverse-phase preparative HPLC to afford the title compound. MS(ESI) 492.97 (M+H). |