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CAS No. : | 327056-62-2 |
Formula : | C6H3FN2 |
M.W : | 122.10 |
SMILES Code : | FC1=CN=C(C#N)C=C1 |
MDL No. : | MFCD08741371 |
InChI Key : | BHXHRMVSUUPOLX-UHFFFAOYSA-N |
Pubchem ID : | 11332453 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H312-H319-H332 |
Precautionary Statements: | P280-P310-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 |
---|---|---|
95% | In tetrahydrofuran; diethyl ether; at -78 - 20℃; for 7.25h;Inert atmosphere; | To the solution of 5-fluoropyridine-2-carbonitrile (7.00 g, 57.3 mmol) in tetrahydrofuran (140 mL) cooled to -78 C under argon atmosphere 3 M methylmagnesium bromidesolution in diethyl ether (22.9 mL, 68.8 mmol) was added dropwise during 15 minutes. Reaction mixture was stirred at -78 C for 2 hours, and then at room temperature for 5 hours. A solid precipitated from the reaction mixture. To the reaction mixture 2 M hydrochloric acid solution was added until reaching pH = 6 and dissolution of the precipitate. Then to the mixture 6% sodium hydrogencarbonate solution (100 mL) wasadded. The mixture was extracted with dichloromethane (3 x 150 mL). Organic phases were combined, washed twice with water, brine, dried (Na2504) and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent:dichloromethane 100% to dichloromethane:acetone, 97:3, v/v) to obtain the product as a light yellow oil with a yield of 95% (7.57 g, 54.4 mmol). |
55% | a) l-(5-Fluoropyridin-2-yl)ethanone5-Fluoro-pyridine-2-carbonitrile (29 g, 240 mmol) was dissolved in THF (150 mL) under a nitrogen atmosphere. The reaction mixture was cooled to an internal temperature of -64 <n="30"/>C. Methyl magnesium bromide (3M in THF, 105 mL, 315 mmol) was added over 40 min. The reaction mixture was stirred at -65 0C for 1.5 h, then warmed to room temperature. THF (50 mL) was added and the mixture was stirred an additional 3 h. 2M hydrochloric acid (aq., 100 mL) was added until the mixture was slightly acidic and the reaction mixture was stirred at room temperature over night. Sodium bicarbonate was then added to neutralize the reaction mixture. The phases were separated and the aqueous phase was extracted with DCM. The combined organic extracts were washed with Brine, dried over sodium sulphate and concentrated in vacuo. The crude product was purified by flash column chromatography to yield 18 g (55% yield) of the title compound. 1R NMR (300 MHz, CDCl3): 8.50 (m, IH); 8.10 (m, IH); 7.52 (m, IH); 2.70 (s, 3H). | |
55% | a) l-(5-Fluoropyridin-2-yl)ethanone5-Fluoro-pyridine-2-carbonitrile (29 g, 240 mmol) was dissolved in THF (150 mL) under a nitrogen atmosphere. The reaction mixture was cooled to an internal temperature of -64 C. Methyl magnesium bromide (3M in THF, 105 mL, 315 mmol) was added over 40 min. The reaction mixture was stirred at -65 0C for 1.5 h, then it was warmed to room temperature. THF (50 mL) was added and the mixture was stirred an additional 3 h. 2M <n="34"/>hydrochloric acid (aq., 100 mL) was added until the mixture was slightly acidic and the reaction mixture was stirred at room temperature over night. Sodium bicarbonate was then added to neutralize the reaction mixture. The phases were separated and the aqueous phase was extracted with DCM. The combined organic extracts were washed with Brine, dried over sodium sulphate and concentrated in vacuo. The crude product was purified by flash column chromatography to yield 18 g (55% yield) of the title compound. 1H NMR (300 MHz, CDCl3): 8.50 (m, IH); 8.10 (m, IH); 7.52 (m, IH); 2.70 (s, 3H). |
54.5% | In tetrahydrofuran; at -65 - 20℃; for 4.5h; | To a stirred solution of <strong>[327056-62-2]5-fluoropicolinonitrile</strong> (EO, 2.9 g, 23.75 mmol) in THF (20 mL), methylmagnesium bromide (3M in THF, 10.2 mL, 30.87 mmol) was added at -65 C and stirred for 1.5 h. The reaction mixture was further stirred at RT for 3 h. 2M HC1 (10 mL) was added and the reaction mixture was further stirred at RT for 14 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with saturated aqueous NaHC03 solution and extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous Na2S04 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 15% EtOAc/hexane to afford compound EP (1.8 g, 54.5%) as a colorless liquid. LC-MS: m/z 140.00 [M+H]+. |
34% | 10(B) 1 -(5-Fluoro-pyridin-2-yl)-ethanone; To a solution of <strong>[327056-62-2]5-fluoro-pyridine-2-carbonitrile</strong> (2.6 g, 21.31 mmol) in dry THF (50 ml), cooled at - 20C, under nitrogen atmosphere, methylmagnesium bromide (3M solution in diethyl ether, 7.1 ml, 21.31 mmol) was added dropwise. After stirring overnight at - 20C, the reaction mixture was slowly allowed to warm to room temperature, and then a saturated solution of NH4Cl (aq.) was added to adjust the pH to 2. Ethyl acetate was added and the phases were separated. Evaporation of the solvent gave a crude solid that was purified through a silca gel cartridge (eluent: DCM/petroleum ether 1:1). The solid that was recovered from this purification was purified again by flash chromatography (silica gel, eluent: diethyl ether/petroleum ether 1 :9) to afford 1 g of l-(5-fiuoro-pyridin-2-yl)-ethanone. Yield: 34%; LCMS (RT): 3.4 min (Method F); MS (ES+) gave m/z: 140.0 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With ammonia; hydrogen;nickel; In ethanol; at 70℃; under 25858.1 Torr; for 16h; | Preparation 85; 2-Aminomethyl-5-fluoropyridine (dihydrochloride); Combine a mixture of <strong>[327056-62-2]2-cyano-5-fluoropyridine</strong> (63.2 g, 0.52 mol), 22.5 g of Raney nickel, and ethanol (1.5 L) saturated with ammonia and hydrogenate at 500 p. s. i. and 70 C for 16 h. Chromatograph the dark purple liquid over flash silica gel (methylene chloride/methanol/ammonia hydroxide-95: 4.5 : 0.5) to give, after concentration at 25-30 C, a yellow liquid of the pure desired free base, 25.0 g (44%); 'H NMR (DMSO-d6) 8 8.43 (d, J= 2.9 Hz, 1H), 7.66 (m, 1H), 7.50 (m, 1H), 3.77 (s, 2H), 2.10 (br, 2H); MS (ESI) m/z 127 (m+H). Add to a solution of the free base (20.0 g, 159.0 mmol) in 150 ml of 1,4-dioxane, 4N HC1 in dioxane (150 mL, 3.8 eq. ) and a white solid separates immediately. Dilute the solid with ethyl ether (300 mL) and filter. Dry the product at 20 mm Hg, 60 C, to give the pure dihydrochloride title compound, 30.0 g (95%) ; lH NMR (DMSO-d6) 6 8.61 (d, J= 2.9 Hz, 1H), 8.50 (brs, 3H), 7.82 (m, 1H), 7.62 (m, 1H), 7.50 (br, 1H), 4.18 (m, 2H); MS (ESI) m/z 127 (rn+H, free base). |
With hydrogenchloride; hydrogen;palladium 10% on activated carbon; In methanol; at 20℃; for 4h; | The mixture of <strong>[327056-62-2]5-fluoro-pyridine-2-carbonitrile</strong> (0.16 g,1.27mmol) and Pd/C (0.030 g, 10% wt) in 15 ml of MeOH and0.50 ml of concentrated HCl was placed under H2 which wasprovided by a balloon and stirred at RT for 4 h, filteredthrough Celite, condensed, the residue was purified byflash column chromatography. The titled compound wasobtained as a light yellowish solid. MS(ES+): 127.2 (freebase) (M+H)+ . Calc'd for C6H7FN2 (free base)- 126.13. | |
With hydrogenchloride; hydrogen;palladium 10% on activated carbon; In methanol; water; at 20℃; for 4h; | The mixture of <strong>[327056-62-2]5-fluoro-pyridine-2-carbonitrile</strong> (0.16 g, 1.27 mmol) and Pd/C (0.030 g, 10% wt) in 15 ml of MeOH and 0.50 ml of concentrated HCl was placed under H2 which was provided by a balloon and stirred at RT for 4 h, filtered through Celite, condensed, the residue was purified by flash column chromatography. The titled compound was obtained as a light yellowish solid. MS (ES+): 127.2 (free base)(M+H)+. Calc'd for C6H7FN2 (free base) 126.13. |
With hydrogenchloride; palladium 10% on activated carbon; hydrogen; In ethanol; under 2327.23 Torr; for 3.5h; | Example 32.2-(6-Fluoro-imidazo[l ,5-a]pyridin-l -yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3- cyano-azetidin- 1 -yl)- 1 -methyl-2- xo-ethyl]-amideStep 1(5 -Fluoro-pyridin-2-yl)-meth lamineIn a Parr pressure bottle, <strong>[327056-62-2]2-cyano-5-fluoropyridine</strong> (2.0 g, 16.4 mmol) was dissolved in ethanol (60 ml). Palladium on carbon, 10% Pd (wet) (574 mg, 5.39 mmol) was added followed by cone. HC1 (4.6 ml, 56.0 mmol). The bottle was placed on a Parr hydrogenator and shaken for 3.5 h under a 45 psi hydrogen atmosphere. The reaction mixture was filtered over Celite and rinsed with methanol. The filtrate was concentrated to a light yellow solid. The solid was taken up in dichloromethane, cooled to 0C, and basified with saturated aqueous NaHC03. The aqueous layer was extracted with dichloromethane (3x) and the combined organics were dried over sodium sulfate, filtered and concentrated to give 558 mg (27%) of (5-fluoro-pyridin-2-yl)- methylamine as a yellow oil which was used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium fluoride; In 1-methyl-pyrrolidin-2-one; at 175℃; for 18h; | The mixture of 5-bromo-pyridine-2-carbonitrile (0.50 g, 2.73mmol), and KF (0.48 g, 8.20 mmol) in 10 ml of 1-methyl-2-pyrrolidinone was stirred at 175 C for 18 h, cooled to RT,diluted with H2O, extracted with EtOAc, the combined organicportions were washed with H20, brine, dried with Na2S04,filtered, condensed, the crude compound was purified byflash column chromatography (5 to 20% of EtOAc in hexanes).The titled compound was obtained as an off-white solid. | |
With potassium fluoride; In 1-methyl-pyrrolidin-2-one; at 175℃; for 18h; | The mixture of 5-bromo-pyridine-2-carbonitrile (0.50 g, 2.73 mmol), and KF (0.48 g, 8.20 mmol) in 10 ml of 1-methyl-2-pyrrolidinone was stirred at 175 C. for 18 h, cooled to RT, diluted with H2O, extracted with EtOAc, the combined organic portions were washed with H2O, brine, dried with Na2SO4, filtered, condensed, the crude compound was purified by flash column chromatography (5 to 20% of EtOAc in hexanes). [1978] The titled compound was obtained as an off-white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | In 1-methyl-pyrrolidin-2-one; at 210 - 220℃; for 4h; | Preparation 84; 2-Cyano-5-fluoropyridine; Add in a 5-L 3-neck roundbottom equipped with overhead stirrer, reflux condenser, thermometer, and N2 line, 5-chloro-2-cyanopyridine (193.0 g, 1. 39 mol) and 1-methyl-2-pyrrolidinone (NMP, 2L). Heat the mixture and stir at 210-220 C for 4 h. Cool the reaction mixture to room temperature, stir overnight, and filter. Wash the filter cake with ethyl ether (1L). Extract the filtrate with water (6L) and ethyl ether (3 X 5L). Combine the organics and back-extract with water (8L) and dry over magnesium sulfate. Concentrate at 25-30 C to give an oily semi-solid, 193 g. Chromatograph over flash silica gel (5% ethyl acetate in hexanes gradually increasing to 10% ethyl acetate in hexanes) to provide the title compound as a white solid. Dissolve the solid in ethyl ether, filter, and add hexanes. Concentrate to low volume to provide a primary crop of pure title compound, 60 g. Repeat the process of crystallization on the filtrate to provide a second crop of highly pure title compound, 24.0 g. (Concentrate the final filtrate to a white solid of product of good quality, and re-chromatograph, conditions as above, to provide an additional 38.6 g of material. ) Obtain a total yield of title compound of 122.4 g, 72% ; 1H NMR (CDCl3) 5 8.59 (d, J= 3.0 Hz, 1H), 7.75 (m, 1H), 7.55 (m, 1H). |
425 mg (48%) | With potassium fluoride; In 1-methyl-pyrrolidin-2-one; | A mixture of 2-cyano-5-chloropyridine (1 g, 7.22 mmol) and potassium fluoride (1.26 g, 21.68 mmol) in 1-methyl-2-pyrrolidinone (25 mL) was heated at reflux for 18 hours. After cooling, the reaction was diluted with ethyl acetate and extracted with water and brine. The organic solvents were then removed in vacuo. Silica gel chromatography of the residue afforded 425 mg (48%) of 2-cyano-5-fluoropyridine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With pyridine; hydrogen fluoride; sodium nitrite; In water; at 0 - 80℃; for 2.75h; | 5-Fluoro-pyridine-2-carbonitrile; Sodium nitrite (8.7g, 126 mmol) was added portionwise to an ice-salt cooled solution of 5- amino-pyridine-2-carbonitrile (10.03g, 84.2 mmol) in 70% hydrogen fluoride-pyridine (Aldrich, 100g, 3.5 mol HF) (note: the reaction was carried out in the supplied bottle). The resulting dark red solution was stirred for 45 min in the ice-salt bath, then the bath was re- moved and the mixture stirred at ambient temperature for 30 min, followed by heating at 80C for 1. 5h. The reaction mixture was quenched by pouring onto ice/water mixture (-400g) in a separatory funnel and extracted with dichloromethane (6xl 50mL), dried (MgS04), filtered and evaporated the solvent in vacuo. The crude product (10.08g, 98%, orange solid) was sufficiently pure for use without further purification. lH NMR (CDC13, 300 MHz): 8 = 8.61 (d, 1H), 7. 78 (m, 1H), 7.58 (m, 1H). GC-MS M+122. |
84% | Plug-flow reactors were constructed from 1/16″ PFA tubing (0.03″ ID, Upchurch Scientific) and reagents and reaction streams were joined through connections with PEEK tee-mixers (0.04” ID, Upchurch Scientific). Pressure was regulated with a 100 psi backpressure regulator cartridge from Upchurch Scientific. Reagent streams were pumped with Harvard Apparatus PhD Ultra syringe pumps. A 20 μL (4.4 cm, 1 min tR) segment of PFA air-cooled tubing was used as a reactor for diazonium formation, and a 2.2 mL (482 cm, 10 min tR) coil of PFA tubing heated at 95 C in an oil bath was used for the thermal dediazoniation. 5-Amino-2-cyanopyridine (0.238 g, 2.00 mmol, 0.4 M), LiBF4 (0.562 g, 6.00 mmol), and TFA (154 μL, 2.00 mmol) were combined in a 5 mL volumetric flask and MeCN was added to reach a total volume of 5 mL. The orange solution was transferred to an 8 mL stainless steel syringe and pumped at 18.92 μL/min tBuONO (8.41 M) was added to a 2.5 mL glass syringe with luer lock adapter and pumped at 1.08 μL/min. A solution of LiBF4 (1.00 g, 10.7 mmol) in BMIMBF4 was made to 10 mL, added to a stainless-steel syringe, and pumped at 200 μL/min. After passing 5 residence volumes (1.10 mL) sample was collected for 2 min and 38 s (0.579 mL), diluted to 5 mL in MeCN, and analyzed by HPLC as described above. | |
64% | 1) 5-Fluoropyridine-2-carbonitrile 5-Amino-2-cyanopyridine (24.5 g) was added to hydrogen fluoride-pyridine (100 mL) under cooling on ice, and the mixture was stirred for 10 minutes. Sodium nitrite (15.6 g) was added to the reaction mixture, and the resultant mixture was stirred at room temperature for 10 minutes and at 50C for 2 hours and then cooled in air. The reaction mixture was partitioned between 20% aqueous sodium hydroxide and diethyl ether, and the organic layer was dried over sodium sulfate anhydrate. After a filtration step, the solvent was removed under reduced pressure, and the residue was purified through silica gel column chromatography (hexane - ethyl acetate), to thereby give 5-fluoropyridine-2-carbonitrile as a solid product (16.0 g, 64%). 1H-NMR (400MHz, CDCl3) δ:7.57 (1H, ddd, J=8.6, 8.6, 3.1Hz), 7.77 (1H, dd, J=8.6, 4.4Hz), 8.60 (1H, d, J=3.1Hz). MS (EI)m/z:122 (M+). |
64% | To hydrogen fluoride - pyridine (100 ml) was added 5-amino-2-cyanopyridine (24.5 g, 0.206 mol) under ice cooling. The resulting mixture was stirred for 10 minutes. To the reaction mixture was added sodium nitrite (15.6 g, 0.226 mol). The resulting mixture was stirred at room temperature for 10 minutes, and then stirred at 50C for 2 hours. To the reaction mixture was added a 20% aqueous solution of sodium hydroxide. The resulting mixture was extracted with diethyl ether. The organic layer thus obtained was dried over sodium sulfate, and concentrated under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate=3:1 eluate was concentrated under reduced pressure to give the title compound (16.0 g, 0.131 mmol, 64%) as colorless needle crystals. 1H-NMR(400MHz,CDCl3)δ: 7.57(1H,ddd,J=8.6,8.6,3.1Hz), 7.77(1H,dd,J=8.6,4.4Hz), 8.60(1H,d,J=3.1Hz). IR(ATR)cm-1: 3095, 2237, 1577, 1467, 1409, 1375, 1272, 1240, 1197, 1120, 1010. MSm/z: 122 (M+). EI-MS: 122.0293 (Calcd for C6H3FN2: 122.0280). | |
64% | 1) 5-Fluoropyridine-2-carbonitrile 5-Amino-2-cyanopyridine (24.5 g) was added to hydrogen fluoride-pyridine (100 mL) under ice cooling, and the resultant mixture was stirred for 10 minutes. Sodium nitrite (15.6 g) was added to the reaction solution, and the mixture was stirred at room temperature for 10 minutes, and then stirred at 50C for 2 hours. After air cooling, a 20% aqueous solution of sodium hydroxide and diethyl ether were added to the reaction solution, and the resultant mixture was partitioned. The organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and a residue thus obtained was purified by silica gel column chromatography (hexane-ethyl acetate), to obtain 5-fluoropyridine-2-carbonitrile (16.0 g, 64%) as a solid. 1H-NMR (400MHz, CDCl3) δ: 7.57 (1H, ddd, J=8.6, 8.6, 3.1Hz), 7.77 (1H, dd, J=8.6, 4.4Hz), 8.60 (1H, d, J=3.1Hz). MS (EI) m/z: 122 (M+). | |
52% | With pyridine hydrogenfluoride; sodium nitrite; at 0 - 65℃;Inert atmosphere; | To a 100 mL round bottom flask charged with 5-aminopicolinonitrile (285 mg, 2.44 mmol) at 0 C. was added HF-pyridine (5 mL) under N2. A pale brown solution was formed. In 4 aliquots, NaNO2 (250 mg, 3.62 mmol) was added with stirring. The solution turned green and a brown gas was liberated. After 20 min at 0 C., the solution was allowed to reach rt and stirred for an additional 20 min. A reflux condenser was attached and the reaction mixture was heated at 65 C. for 20 min then allowed to cool to rt. The orange slurry was quenched by the addition of crushed ice and the aqueous layer was extracted with DCM (3×10 mL). The combined organic portions were dried over Na2SO4, decanted and concentrated under reduced pressure to yield 5-fluoropicolinonitrile (152 mg, 52% yield) as a pale orange powder. LCMS: RT=0.63 min [M+H] 122.9 (2 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); HPLC: RT=0.99 min (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.2% PPA; 4 mL/min, monitoring at 220 nm, Purity 96%); NMR: 400 MHz 1H (CDCl3) ppm 8.52 (d, J=2.64 Hz, 1H), 7.70 (dd, J=4.4 and J=8.36 Hz, 1H), 7.50 (m, 1H). |
With pyridine hydrogenfluoride; sodium nitrite; at -10 - 80℃; for 2.75h; | EXAMPLE 10; Example 10 utilized a 5-fluoro-2-hydroxyamidinylpyridine as an intermediate to obtain the desired product. To a mixture of 5-amino-2-cyanopyridine (100 g, 840 rnmol) cooled to -1O0C was added HF-pyridine (50OmL, 70%v/v). Sodium nitrite (91g, 1.32mol) was added in portions. The reaction was then stirred at -100C for 45 minutes, room temperature for 30 minutes, and 800C for 90 minutes. Upon completion, the reaction was cooled to room temperature and quenched with ice/water. The aqueous solution was extracted with CH2Cl2, dried over magnesium sulfate and concentrated. The fluoropyridine (4Og, 328mmol) was treated with sodium carbonate (82g, 773mmol) and hydroxylamine- hydrochloride (45g, 652mmol) in methanol (30OmL). The reaction was allowed to stir for 24h and upon completion, the reaction was concentrated in vacuo, diluted with water, filtered and dried under vacuum.Example 10 was generated under similaτ reaction conditions described in the examples above and shown in Schemes 4 and 5. 1H NMR (DMSOd6, 500 MHz) δ 12.0 (s, IH), 8.79(s, IH), 8.23 (m, IH), 8.14 (m, IH), 7.97 (m, IH), 7.64 (m, IH), 7.26 (m, IH), 4.64 (m, IH), 3.56 (m, 2H); LCMS m/z 394 (M+Na). | |
With pyridine; hydrogen fluoride; sodium nitrite; at 0 - 80℃; for 2.75h; | EXAMPLE 17As shown in Scheme 6 a suspension of 5-amino-2-cyano pyridine (20.0 g, 0.168 mol) in HF-pyridine (100 g) in an Erlenmeyer flask cooled to O0C was added sodium nitrite (17.4 g, 0.25 mol) in four portions. After 45 min at O0C the reaction mixture was stirred at room temperature for 30 min and then heated to 8O0C for 90 min. The reaction mixture was quenched by pouring into ice/water mixture. The resulting mixture was extracted with DCM. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give the fluoropyridine as an orange solid.To a suspension of this fluoropyridine nitrile intermediate (16.0 g, 0.13 mol) in methanol (200 mL) was added hydroxylamine (9.63 mL, 0.16 mmol, 50% by wt). After stirring the reaction mixture at room temperature for 48 h, it was filtered through a fritted funnel. The precipitate was washed with ether and dried under vacuum to give the N-hydroxy amidine as a yellow solid.To a suspension of this amidine intermediate (5.32 g, 34.3 mmol) in anhydrous pyridine (10 mL) was added 4-chloro-4-oxo-methyl butyrate (5 mL, 41.2 mmol). The resulting reaction mixture was heated at 12O0C for 2 h. The mixture was cooled to RT and concentrated. The residue was dissolved in ethyl acetate and washed with IN HCl, water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give a dark brown solid. This material was purified by Biotage using 25%-60% ethyl acetate-hexanes gradient to give the heterobiaryl intermediate as a light yellow solid.To a solution of this ester intermediate (900 mg, 3.58 mmol) in THF (4 mL) was added methanol (2 mL) followed by 5N NaOH (1 mL). After 30 min, the reaction mixture was EPO <DP n="41"/>neutralized by the addition of IN HCl (5 mL). The reaction mixture was concentrated. The residue was extracted with ethyl acetate, and the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give a light yellow solid of the carboxylic acid.EXAMPLE 17 was prepared by reaction of the carboxylic acid described above and the intermediate prepared for EXAMPLE 2. 1H NMR (DMSOd6, 500 MHz) δ 10.95 (br s, IH), 8.75 (d, IH), 8.12 (dd, IH), 7.95-7.91 (m, IH) .50 (t, 2H), 3.31 (t, 2H), 3.03 (d, IH), 2.32- 2.21 (m, 3H), 1.75 (br s, 2H), 1.26-1.24 (m, lH)m 0.99 (d, 3H); LCMS m/z 372 (M+l). | |
With pyridine hydrogenfluoride; sodium nitrite; at 0 - 80℃; for 2.75h; | To a suspension of 5-amino-2-cyano pyridine (20-0 g, 0.168 mol) in HF-pyridine (100 g) in an Erlenmeyer flask cooled to 0 C. was added sodium nitrite (17.4 g, 0.251 mol) in four portions. After 45 min at 0 C. the reaction mixture was stirred at room temperature for 30 min and then heated to 80 C. for 90 min. The reaction mixture was quenched by pouring into an ice/water mixture. The resulting mixture was extracted with DCM. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give the fluoropyridine nitrile as an orange solid. To a suspension of this fluoropyridine nitrile intermediate (16.0 g, 0.131 mol) in methanol (200 mL) was added hydroxylamine (9.63 mL, 0.157 mmol, 50% by wt). After stirring the reaction mixture at room temperature for 48 h, it was filtered through a fritted funnel. The precipitate was washed with ether and dried under vacuum to give the N-hydroxyamidine as a yellow solid. To a suspension of this amidine intermediate (5.32 g, 34.32 mmol) in anhydrous pyridine (10 mL) was added 4-chloro-4-oxo-methyl butyrate (5 mL, 41.18 mmol). The resulting reaction mixture was heated at 120 C. for 2 h. The mixture was cooled to RT and concentrated. The residue was dissolved in ethyl acetate and washed with 1N HCl, water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give a dark brown solid. This material was purified by Biotage using 25%-60% ethyl acetate-hexanes gradient to give the heterobiaryl intermediate as a light yellow solid. To a solution of this ester intermediate (900 mg, 3.58 mmol) in dioxane (3 mL) was added ammonium hydroxide (3 mL) and the mixture was allowed to stir at room temperature for 12 hours. Upon completion, the mixture was concentrated, and the amide was purified via flash chromatography (Biotage 40M). To the amide (0.25 g, 1.0 mmol) in a degassed solution of dioxane (7 mL) was added the corresponding triflate (0.92 g, 2.1 mmol), cesium carbonate (1.0 g, 3.0 mmol), xantphos ligand (0.1 g, 0.2 mmol), and Pd2(dba)3 catalyst (0.09 g, 0.1 mmol), and the reaction mixture was heated to 75 C. for 6 hours. The mixture was cooled, filtered, concentrated in vacuo, and purified via flash chromatography (Biotage 40 M). To the desired cycloalkene (0.26 g, 0.5 mmol) in THF/H2O (1:1) was added sodium hydroxide (0.06 g, 1.5 mmol). The biphasic reaction mixture was allowed to stir for 12 hours at room temperature. The mixture was concentrated in vacuo and purified by reverse phase HPLC (Gilson) to afford the desired product Example 43. 1H NMR (DMSO-d6, 500 MHz) δ 11.46 (s, 1H), 8.76 (s, 1H), 8.12 (m, 1H), 7.94 (m, 1H), 7.41 (m, 1H), 6.87 (m, 1H), 3.43 (m, 2H), 3.26 (m, 2H), 2.89 (m, 2H), 2.18 (m, 1H), 2.11 (m, 2H) 1.88, (m, 1H), 1.30 (m, 3H); LCMS m/z 527 (M+Na). | |
With pyridine hydrogenfluoride; sodium nitrite; at 0 - 80℃; for 2.75h; | To a suspension of 5-amino-2-cyano pyridine (20.0 g, 0.168 mol) in HF-pyridine (100 g) in an Erlenmeyer flask cooled to 0 C. was added sodium nitrite (17.4 g, 0.251 mol) in four portions. After 45 min at 0 C. the reaction mixture was stirred at room temperature for 30 min and then heated to 80 C. for 90 min. The reaction mixture was quenched by pouring into ice/water mixture. The resulting mixture was extracted with DCM. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give the fluoropyridine as an orange solid. | |
With sodium nitrite; at 0 - 80℃; for 2.75h; | EXAMPLE 5; 6 2-[6-FLUORO-3-(2,3 ,6-TRIFLUOROBENZYL)lMIDAZO[ 1 ,5-o]PYRIDIN-l -YL]-5-PYRIDIN-3-YLPYRJMIDIN-4-AMINE; Step A; To a suspension of 5-amino-2-cyano pyridine (20.06 g, 168 mml) in a 2L Erlenmeyer flask in HF-pyridine (lOOg, 3.5 mol) cooled to 0C was added sodium nitrite (17.4 g, 251 mmol) in 4 portions. After 45 minutes at 0C the reaction was stirred at ambient temperature for 30 minutes, and then heated at 80C for 1.5 hours. The reaction mixture was cooled to room temperature and quenched by pouring into ice/water mixture (-400 mL). The resulting solution was extracted with DCM (6X150 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to yield an orange solid. LC-MS: m/z=T23.09 (M+H); rt=2.32 min (Method A). |
Yield | Reaction Conditions | Operation in experiment |
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20% | 5-Fluoro-pyridine-2-carbaldehyde p. 3600-35; DIBAL (1 M toluene solution, 8. 2 mL, 8.2 mmol) was added dropwise to a cold (-78 C) solution of <strong>[327056-62-2]5-fluoro-pyridine-2-carbonitrile</strong> (l. Og, 8.2 mmol) in CH2Cl2 (50 mL) and the resulting misture was stirred at-78 C for 3 h, with an additional 0.25 equivalents of DIBAL added after 0.5 and 1 h. The reaction was quenched with 1 N HCl (20 mL) and stirred for 2.5 h. The aqueous phase was basified with solid NaHCO3 and the product was extracted with CH2Cl2. (An emulsion formed that required filtration before extraction could be performed). The combined organics were washed with brine and dried (Na2SO4) and filtered. Purification was performed by flash column chromatography over silica gel, eluting with 2 % EtOAc/hexanes to yield the product (200 mg, 20 %, colourless solid which melts just above room temperature and was volatile under high vacuum resulting in a lower yield than expected). 1H NMR (CDC13, 300 MHz): 8 = 7. 59 (ddd, J = 8,2, 1 Hz, 1H), 8.04 (ddd, J = 8,5, 0.5 Hz, 1H), 8. 64 (d, J = 2 Hz, 1H), 10.00 (apparent dd, J = 1, 1 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
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With hydrogenchloride; water; for 4h;Heating / reflux; | 2) 2-[(5-Fluoropyridine-2-carbonyl)amino]malonic acid diethyl ester The above 5-fluoropyridine-2-carbonitrile (11.8 g) in 6N HCl (100 mL) was refluxed for 4 hours and then cooled in air. NaCl was added to the reaction mixture to saturate the mixture, and ethyl acetate was added thereto for partitioning the mixture. The organic layer was dried over sodium sulfate anhydrate. After a filtration step, the solvent was removed under reduced pressure, and the residue was dissolved in N,N-dimethylformamide (140 mL). 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (6.0 g), 1-hydroxybenzotriazole (770 mg), and aminomalonic acid diethyl ester hydrochloride (7.2 g) were added to the solution, and the mixture was stirred for 19.5 hours at room temperature. The reaction mixture was partitioned between water and ethyl acetate, and the organic layer was washed with saturated brine and then dried over sodium sulfate anhydrate. After a filtration step, the solvent was removed under reduced pressure, and the residue was purified through silica gel column chromatography (hexane - ethyl acetate), to thereby give 2-[(5-fluoropyridine-2-carbonyl)amino]malonic acid diethyl ester as a solid product (9.4 g, 53%). 1H-NMR (400MHz, CDCl3) δ:1.33 (6H, t, J=7.1Hz), 4.27-4.38(4H,m), 5.36 (1H, d, J=7.4Hz), 7.51-7.56 (1H, m), 8.20-8.21 (1H, m), 8.46 (1H, d, J=2.7Hz), 8.74 (1H, d, J=10.0Hz). | |
With hydrogenchloride; water; for 4h;Heating / reflux; | 2) 2-[(5-Fluoropyridine-2-carbonyl)amino]malonic acid diethyl ester A 6 N aqueous solution of hydrochloric acid (100 mL) containing the 5-fluoropyridine-2-carbonitrile (11.8 g) was heated to reflux for 4 hours. After air cooling, Nacl was added to the reaction solution for saturation, and ethyl acetate was further added thereto. The resultant mixture was partitioned, and the organic layer was dried over anhydrous sodium sulfate. After separating the organic layer by filtration, the solvent was evaporated under reduced pressure, and a residue thus obtained was dissolved in N,N-dimethylformamide (140mL). Then, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (6.0 g), 1-hydroxybenzotriazole (770mg), and aminomalonic acid diethyl ester hydrochloride (7.2 g) were added to the solution, and the resultant mixture was stirred at room temperature for 19.5 hours. Water and ethyl acetate were added to the reaction solution, and the mixture was partitioned. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. After separating the organic layer by filtration, the solvent was evaporated under reduced pressure, and a residue thus obtained was purified by silica gel column chromatography (hexane-ethyl acetate), to obtain 2-[(5-fluoropyridine-2-carbonyl)amino]malonic acid diethyl ester (9.4 g, 53%) as a solid. 1H-NMR (400MHz, CDCl3) δ: 1.33 (6H, t, J=7.1Hz), 4.27-4.38 (4H, m), 5.36 (1H, d, J=7.4Hz), 7.51-7.56 (1H, m), 8.20-8.21 (1H, m), 8.46 (1H, d, J=2.7Hz), 8.74 (1H, d, J=10.0Hz). |
Yield | Reaction Conditions | Operation in experiment |
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With hydrogenchloride; diisobutylaluminium hydride; In hexane; dichloromethane; at -75 - 20℃; for 3h; | Diisobutylaluminum hydride (a 1.01M hexane solution, 58 ml, 58.9 mmol) was added dropwise to a dichloromethane (150 ml) solution of 5-fluoropyridine-2-carbonitrile (6.54 g, 53.8 mmol) at -75C under an argon atmosphere. The reaction mixture was stirred for 3 hours. At the same temperature, hydrochloric acid (80 ml) (concentrated hydrochloric acid:water=1:3) was added, followed by heating to room temperature. From the reaction mixture, a dichloromethane layer was separated. To the water layer was then added sodium bicarbonate. The resulting mixture was extracted with diethyl ether. The organic layer thus obtained was dried over magnesium sulfate, and concentrated under reduced pressure. The dichloromethane layer obtained previously was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. To a benzene (150 ml) solution of the combined residues were added p-toluenesulfonic acid monohydrate (1.02 g, 5.36 mmol) and ethylene glycol (30 ml, 0.536 mol). Under heating under reflux, the resulting mixture was stirred for 2 hours. After cooling, a saturated aqueous solution of sodium bicarbonate was added and the resulting mixture was extracted with diethyl ether. The extract was washed with brine. The organic layer thus obtained was dried over magnesium sulfate, and concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate=4:1 eluate was concentrated under reduced pressure to give the title compound (3.33 g, 19.7 mmol, 37%) as a reddish brown oil. 1H-NMR(400MHz,CDCl3)δ: 4.02-4.21(4H,m), 5.85(1H,s), 7.45(1H,ddd,J=8.3,8.3,2.9Hz), 7.57(1H,dd,J=8.3,4.5Hz), 8.48(1H,d,J=2.9Hz). MSm/z: 170(M++H). |
Yield | Reaction Conditions | Operation in experiment |
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35% | N-( 1 -(5-Fluoropyridm-2-yl')vinyl')acetamide A solution of MeMgBr (170.3 ml, 510.98 mmol) in ether was diluted with 170 ml of anhydrous THF and cooled to 0 C. 5-Fluoropicolinontrile (Method 37, 53.6 g, 425.82 mmol) in THF (170 ml) was added dropwise. The reaction was stirred at 0 C for 30 minutes, then diluted with DCM (170 ml). Acetic anhydride (48.3 ml, 510.98 mmol) in DCM (100 ml) was added dropwise at 0 0C. After addition, the reaction was warmed to room temperature and stirred at room temperature for 8 hours. Saturated sodium bicarbonate solution (50 ml) was added and extracted with EtOAc (2 x 200 ml). The combined organic was dried over sodium sulfate. After removal of solvent, the resulted residue was purified by column chromatography (hexane-EtOAc = 2.5 : 1) to give the title compound as a white solid (26.6 g, 35%). 1H NMR (400 MHz) δ 9.37 (s, IH), 8.57 (d, J= 2.8 Hz, IH), 7.81 (m, 2H), 6.01 (s, IH), 5.52 (s, IH), 2.08 (s, 3H). MS: Calcd.: 180; Found: [M+H]+ 181 | |
35% | Intermediate 2: N-(1-(5-Fluoropyridin-2-yl)vinyl)acetamide. A solution of MeMgBr (170.3 ml, 510.98 mmol) in ether was diluted with 170 ml of anhydrous THF and cooled to 0 C. 5-Fluoropyridine-2-carbonitrile (Intermediate 1, 53.6 g, 425.82 mmol) in THF (170 ml) was added drop-wise. The reaction was stirred at 0 C for 30 minutes, then diluted with dichloromethane (170 ml). Acetic anhydride (48.3 ml, 510.98 mmol) in dichloromethane (100 ml) was added drop-wise at 0 0C. After addition, the reaction was warmed to room temperature and stirred at room temperature for 8 hours. Saturated sodium bicarbonate solution (50 ml) was added and extracted with EtOAc (2 x 200 ml). The combined organic was dried over sodium sulfate. After removal of solvent, the resulted residue was purified by column chromatography (hexane:EtOAc = 2.5 : 1) to give the title compound as a white solid (26.6 g, 35%). 1H NMR (400 MHz) δ 9.37 (s, 1 H), 8.57 (d, J= 2.8 Hz, 1 H), 7.81 (m, 2 H), 6.01 (s, 1 H), 5.52 (s, 1 H), 2.08 (s, 3 H). LCMS: 181 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
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72% | With zinc;1,1'-bis-(diphenylphosphino)ferrocene; tris-(dibenzylideneacetone)dipalladium(0); In ISOPROPYLAMIDE; at 95℃; for 3h; | 2-Bromo-5-fluoropyridine (93.0 g, 528 mmol), Zn dust (8.29 g, 127 mmol), zinc cyanide (40.3 g, 343 mmol), diphenylphosphinoferrocene (11.7 g, 21.1 mmol) and Pd2dba3 (9.68 g, 10.6 mmol) in anhydrous DMA (300 ml) was heated at 95 C for 3 hours. After cooled to room temperature, brine (100 ml) and ether (500 ml) was added. The solid formed was removed by filtration and washed with ether (300 ml). The organic layer was separated, washed with brine (200 ml) and dried over sodium sulfate, and concentrated. After removal of solvent, the resulted residue was purified by column chromatography (hexane-DCM = 1 : 1) to give the title compound as a white solid (49 g, 72%). 1H NMR (400 MHz) δ 8.82 (d, J= 2.8 Hz, IH), 8.21 (dd, J= 4.4 and 8.8 Hz, IH), 8.05 (dd, J= 2.8 and 8.8 Hz, IH). |
72% | With zinc;1,1'-bis-(diphenylphosphino)ferrocene; tris-(dibenzylideneacetone)dipalladium(0); In N,N-dimethyl acetamide; at 95℃; for 3h; | Intermediate 25-Fluoropyridine-2-carbonitrile2-Bromo-5-fluoropyridine (93.0 g, 528 mmol), Zn dust (8.29 g, 127 mmol), zinc cyanide (40.3 g, 343 mmol), dppf (11.7 g, 21.1 mmol) and Pd2dba3 (9.68 g, 10.6 mmol) in anhydrous DMAc (300 ml) were heated at 95 0C for 3 hours. After cooled to room temperature, brine (100 ml) and ether (500 ml) was added. The solid formed was removed by filtration and washed with ether (300 ml). The organic layer was separated, washed with brine (200 ml) and dried over sodium sulfate, <n="55"/>and concentrated. After removal of solvent, the resulted residue was purified by column chromatography (hexane-DCM = 1:1) to give the title compound as a white solid (49 g, 72%). 1H NMR (400 MHz) δ: 8.82 (d, IH), 8.21 (dd, IH), 8.05 (dd, IH). |
72% | With zinc;tris-(dibenzylideneacetone)dipalladium(0); 1,1'-bis(diphenylphosphino)ferrocene; In ISOPROPYLAMIDE; at 95℃; for 3h; | 2-Bromo-5-fluoropyridine (93.0 g, 528 mmol), Zn dust (8.29 g, 127 mmol), zinc cyanide (40.3 g,343 mmol), l,r-bis(diphenylphosphino)ferrocene (11.7 g, 21.1 mmol) and Pd2dba3 (9.68 g, 10.6 mmol) in anhydrous DMA (300 ml) were heated at 95 0C for 3 hours. After cooling to room temperature, brine (100 ml) and ether (500 ml) was added. The solid formed was removed by filtration and washed with ether (300 ml). The organic layer was separated, washed with brine(200 ml) and dried over sodium sulfate, and concentrated. After removal of solvent, the resulting residue was purified by column chromatography (hexane:DCM = 1:1), providing the title compound as a white solid (49 g, 72%).1H NMR (400 MHz) δ: 8.82 (d, IH), 8.21 (dd, IH), 8.05 (dd, IH). |
72% | With zinc;1,1'-bis-(diphenylphosphino)ferrocene; tris-(dibenzylideneacetone)dipalladium(0); In ISOPROPYLAMIDE; at 95℃; for 3h; | Intermediate 1: 5-Fluoropyridine-2-carbonitrile. 2-Bromo-5-fluoropyridine (93.0 g, 528 mmol), Zn dust (8.29 g, 127 mmol), zinc cyanide (40.3 g, 343 mmol), l ,l'-bis(diphenylphosphino)ferrocene (1 1.7 g, 21.1 mmol) and Pd2dba3 (9.68 g, 10.6 mmol) in anhydrous DMAc (300 ml) was heated at 95 0C for 3 hours. After cooled to room temperature, brine (100 ml) and ether (500 ml) was added. The solid formed was removed by filtration and washed with ether (300 ml). The organic layer was separated, washed with brine (200 ml) and dried over sodium sulfate, and concentrated. After removal of solvent, the resulted residue was purified by column chromatography (hexane:DCM = 1 : 1) to give the title compound as a white solid (49 g, 72%). 1H NMR (400 MHz) δ 8.82 (d, 1 H), 8.21 (dd, 1 H), 8.05 (dd, 1 H). |
72% | With zinc;1,1'-bis-(diphenylphosphino)ferrocene; tris-(dibenzylideneacetone)dipalladium(0); In ISOPROPYLAMIDE; at 95℃; for 3h; | Intermediate 35-Fluoropyridine-2-carbonitrile; 2-Bromo-5-fluoropyridine (93.0 g, 528 mmol), Zn dust (8.29 g, 127 mmol), zinc cyanide (40.3 g, 343 mmol), l,l'-bis(diphenylphosphino)ferrocene (11.7 g, 21.1 mmol) and Pd2dba3 (9.68 g, 10.6 mmol) in anhydrous DMA (300 ml) was heated at 95 0C for 3 hours. After cooled to room temperature, brine (100 ml) and ether (500 ml) was added. The solid formed was removed by filtration and washed with ether (300 ml). The organic layer was separated, washed with brine <n="50"/>(200 ml) and dried over sodium sulfate, and concentrated. After removal of solvent, the resulted residue was purified by column chromatography (hexane-DCM = 1:1) to give the title compound as a white solid (49 g, 72%). 1H NMR (400 MHz) δ 8.82 (d, IH), 8.21 (dd, IH), 8.05 (dd, IH). |
72% | With 1,1'-bis-(diphenylphosphino)ferrocene; zinc;tris-(dibenzylideneacetone)dipalladium(0); In N,N-dimethyl acetamide; at 95℃; for 3h; | Intermediate 115-Fluoropyridine-2-carbonitrile2-Bromo-5-fluoropyridine (93.0 g, 528 mmol), Zn dust (8.29 g, 127 mmol), zinc cyanide (40.3 g, <n="85"/>343 mmol), dppf (11.7 g, 21.1 mmol) and Pd2dba3 (9.68 g, 10.6 mmol) in anhydrous DMA (300 ml) were heated at 95 0C for 3 hours. After cooled to room temperature, brine (100 ml) and ether (500 ml) was added. The solid formed was removed by filtration and washed with ether (300 ml). The organic layer was separated, washed with brine (200 ml) and dried over sodium sulfate, and concentrated. After removal of solvent, the resulted residue was purified by column chromatography (hexane-DCM = 1:1) to give the title compound as a white solid (49 g, 72%). 1H NMR (400 MHz) δ: 8.82 (d, IH), 8.21 (dd, IH), 8.05 (dd, IH). |
72% | With zinc;1,1'-bis-(diphenylphosphino)ferrocene; tris-(dibenzylideneacetone)dipalladium(0); In ISOPROPYLAMIDE; at 95℃; for 3h; | Intermediate 15-Fluoropyridine-2-carbonitrile; 2-Bromo-5-fluoropyridine (93.0 g, 528 mmol), Zn dust (8.29 g, 127 mmol), zinc cyanide (40.3 g, 343 mmol), l,l'-bis(diphenylphosphino)ferrocene (11.7 g, 21.1 mmol) and Pd2dba3 (9.68 g, 10.6 mmol) in anhydrous DMAc (300 ml) was heated at 95 ºC for 3 hours. After cooled to room temperature, brine (100 ml) and ether (500 ml) was added. The solid formed was removed by filtration and washed with ether (300 ml). The organic layer was separated, washed with brine (200 ml) and dried over sodium sulfate, and concentrated. After removal of solvent, the resulted residue was purified by column chromatography (hexane-DCM = 1:1) to give the title compound <n="52"/>as a white solid (49 g, 72%). 1H NMR (400 MHz, OMSO-d6) δ 8.82 (d, J = 2.8 Hz, 1 H), 8.21 (dd, J= 4.4 and 8.8 Hz, 1 H), 8.05 (dd, J= 2.8 and 8.8 Hz, 1 H). |
72% | With zinc;1,1'-bis-(diphenylphosphino)ferrocene; tris-(dibenzylideneacetone)dipalladium(0); In ISOPROPYLAMIDE; at 95℃; for 3h;Product distribution / selectivity; | 2-Bromo-5-fluoiOpyridine (93.0 g, 528 mmol), Zn dust (8.29 g, 127 mmol), zinc cyanide (40.3 g, 343 mmol), l,r-bis(diphenylphosphino)ferrocene (11.7 g, 21.1 mmol) and Pd2dba3 (9.68 g, 10.6 mmol) in anhydrous DMA (300 ml) was heated at 95 0C for 3 hours. After cooled to room temperature, brine (100 ml) and ether (500 ml) was added. The solid formed was removed by filtration and washed with ether (300 ml). The organic layer was separated, washed with brine (200 ml) and dried over sodium sulfate, and concentrated. After removal of solvent, the resulted residue was purified by column chromatography (hexane- DCM = 1:1) to give the title compound as a white solid (49 g, 72%). 1H NMR (400 MHz) δ 8.82 (d, J= 2.8 Hz, IH), 8.21 (dd, J= 4.4 and 8.8 Hz, IH), 8.05 (dd, J= 2.8 and 8.8 Hz, IH). |
Examples; Example 1. Using zinc cyanide as cyanide source; 2-Bromo-5-fluoropyridine (280.43 mmol; 49.80 g; commercially available from Asymchem), zinc (11.27 mmol; 739.20 mg), zinc acetate (8.45 mmol; 1.55 g), 1,1'- bis(diphenylphosphino)ferrocene DPPF) (845.09 μmol; 483.00 mg), tris(dibenzylideneacetone)dipalladium(0) (281.74 μmol; 258.00 mg) were charged to an inerted reactor and dimethylformamide (98.00 mL; 92.64 g) warmed to 1050C was added. Zinc cyanide (155.49 mmol; 18.58 g) was added in 5 portions of equal size while keeping the temperature at 100+/-5C. The reaction mixture was cooled to ambient temperature and butyl acetate (175.00 mL; 154.14 g) was added. Ethylenediaminetetraacetic acid tetrasodium salt tetrahydrate (Na-EDTA) (259.10 mmol; 117.88 g) dissolved in water (300.00 mL) was added and the mixture was stirred for 1 hour. The mixture was clear filtered and the filter was rinsed with butyl acetate (25.00 mL; 22.02 g). The phases were allowed to separate and the aqueous phase was discarded. Ethanol (78.00 mL; 61.72 g) was added and hydroxylamine (309.74 mmol; 17.79 mL; 19.19g) was charged during 1 hour using a syringe pump. The precipitated product was isolated by filtration, washed with butyl acetate (10OmL) and dried under vacuum at 400C, obtaining 5-Fluoro-N-hydroxy-pyridine-2-carboxamidine, 180.58 mmol; 28.24 g in 64.40% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98.42% | With hydroxyamino hydrochloride; In methanol; at 20℃; for 10h; | To the solution of cyano compound (2) (10 g, 0.082 mol) was dissolved in 250 ml methyl alcohol to this added hydroxylamine hydrochloride (NH2OH.HCI) (8.52 g, 0.123 mol) in presence of TEA (12.44 g, 0.123 mol) and then the reaction mixture was stirred at RT for 10 h. Reaction was monitored by thin layer chromatography, under reduced pressure solvent was removed. Obtained residue was further dissolved in methylene dichloride (DCM) solvent and washed with water. By using separating funnel the organic layer was separated, again which is washed with the brine solution, separated organic layer was dried with anhydrous Na2SO4 and concentrated to get title compound (3). (0053) Colour: Off White crystalline solid; M.p.: 190-191 C; Yield: 98.42 %; *H-NMR (400 MHz, CDCI3, 5 ppm): 8.55 (d, 1H, .7=2,8 Hz, Ar-H), 7.89-7.92 (m, 1H, Ar-H), 7.72-7 ,77(m, 1H, Ar-H), 5.84(s, 2H, NH2); 13C NMR (100 MHz, CDCI3, 5 ppm): 163.1(1C, C=N-OH), 158.4(1C, Ar-H), 150.3(lC, Ar-H) 134.0(lC, Ar-C), 121.6(1C, Ar-C), 12O.6(1C, Ar-C); MS (m/z): 156.1 (M+); Anal, calcd. for C6H6FN3O: C, 46.45 ; H, 3.90; N, 27.09%; Found: C, 46.28; H, 3.92; N, 27.21%. |
98.42% | With hydroxyamino hydrochloride; In methanol; at 20℃; for 10h; | To the solution of cyano compound (2) (10 g, 0.082 mol) was dissolved in 250 ml methyl alcohol to this added hydroxylamine hydrochloride (NH2OH.HCI) (8.52 g, 0.123 mol) in presence of TEA (12.44 g, 0.123 mol) and then the reaction mixture was stirred at RT for 10 h. Reaction was monitored by thin layer chromatography, under reduced pressure solvent was removed. Obtained residue was further dissolved in methylene dichloride (DCM) solvent and washed with water. By using separating funnel the organic layer was separated, again which is washed with the brine solution, separated organic layer was dried with anhydrous Na2SO4 and concentrated to get title compound (3). (0053) Colour: Off White crystalline solid; M.p.: 190-191 C; Yield: 98.42 %; *H-NMR (400 MHz, CDCI3, 5 ppm): 8.55 (d, 1H, .7=2,8 Hz, Ar-H), 7.89-7.92 (m, 1H, Ar-H), 7.72-7 ,77(m, 1H, Ar-H), 5.84(s, 2H, NH2); 13C NMR (100 MHz, CDCI3, 5 ppm): 163.1(1C, C=N-OH), 158.4(1C, Ar-H), 150.3(lC, Ar-H) 134.0(lC, Ar-C), 121.6(1C, Ar-C), 12O.6(1C, Ar-C); MS (m/z): 156.1 (M+); Anal, calcd. for C6H6FN3O: C, 46.45 ; H, 3.90; N, 27.09%; Found: C, 46.28; H, 3.92; N, 27.21%. |
80% | With hydroxyamino hydrochloride; sodium hydroxide; In ethanol; water monomer; at 80℃; for 1h; | 5-Fluoropyridine-2-carbonitrile 4b (2.9 g, 23.8 mmol) 2 was treated with hydroxylamine (1M, 40 mL) (prepared from 1:1 mixture of hydroxylamine hydrochloride and sodium hydroxide in 1:1 water and ethanol) at 80C for 1h. The solvent was half evaporated and the precipitate was washed with 1:1 water:ethanol (100 mL) and water (100 mL x 2). After drying, 2.93 g (80% yield) of the title compound was obtained. 1H NMR (270 MHz, CDCl3) δ ppm: 8.41 (d, 1H), 7.94 (dd,1H), 7.44 (ddd,1H), 6.62 (br s,1H), 5.58 (br s, 2H). 1H NMR (300 MHz, DMSO-d6) δ ppm: 9.88 (s, 1 H), 8.54 (d, J=2.7 Hz, 1 H), 7.91 (dd, J=9.0, 4.7 Hz, 1 H), ), 7.73 (td, J=8.8, 2.8 Hz, 1 H), 5.79 (br. s., 2 H) |
330 mg (61%) | With sodium hydroxide; hydroxyamino hydrochloride; In ethanol; | Using the general procedure for the synthesis of amidoximes, <strong>[327056-62-2]2-cyano-5-fluoropyridine</strong> (425 mg, 3.48 mmol), 5M hydroxylamine hydrochloride (0.79 ml, 3.95 mmol) in ethanol (5 mL), and 10N sodium hydroxide (0.398 mL, 3.98 mmol) were heated at reflux for 24 hours. Standard work up afforded 330 mg (61%) of 5-fluoropyrid-2-ylamidoxime. |
With hydroxyamino hydrochloride; anhydrous sodium carbonate; In methanol; for 24h; | EXAMPLE 10; Example 10 utilized a 5-fluoro-2-hydroxyamidinylpyridine as an intermediate to obtain the desired product. To a mixture of 5-amino-2-cyanopyridine (100 g, 840 rnmol) cooled to -1O0C was added HF-pyridine (50OmL, 70%v/v). Sodium nitrite (91g, 1.32mol) was added in portions. The reaction was then stirred at -100C for 45 minutes, room temperature for 30 minutes, and 800C for 90 minutes. Upon completion, the reaction was cooled to room temperature and quenched with ice/water. The aqueous solution was extracted with CH2Cl2, dried over magnesium sulfate and concentrated. The fluoropyridine (4Og, 328mmol) was treated with sodium carbonate (82g, 773mmol) and hydroxylamine- hydrochloride (45g, 652mmol) in methanol (30OmL). The reaction was allowed to stir for 24h and upon completion, the reaction was concentrated in vacuo, diluted with water, filtered and dried under vacuum.Example 10 was generated under similaτ reaction conditions described in the examples above and shown in Schemes 4 and 5. 1H NMR (DMSOd6, 500 MHz) δ 12.0 (s, IH), 8.79(s, IH), 8.23 (m, IH), 8.14 (m, IH), 7.97 (m, IH), 7.64 (m, IH), 7.26 (m, IH), 4.64 (m, IH), 3.56 (m, 2H); LCMS m/z 394 (M+Na). | |
With hydroxylamine; In methanol; at 20℃; for 48h; | To a suspension of 5-amino-2-cyano pyridine (20-0 g, 0.168 mol) in HF-pyridine (100 g) in an Erlenmeyer flask cooled to 0 C. was added sodium nitrite (17.4 g, 0.251 mol) in four portions. After 45 min at 0 C. the reaction mixture was stirred at room temperature for 30 min and then heated to 80 C. for 90 min. The reaction mixture was quenched by pouring into an ice/water mixture. The resulting mixture was extracted with DCM. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give the fluoropyridine nitrile as an orange solid. To a suspension of this fluoropyridine nitrile intermediate (16.0 g, 0.131 mol) in methanol (200 mL) was added hydroxylamine (9.63 mL, 0.157 mmol, 50% by wt). After stirring the reaction mixture at room temperature for 48 h, it was filtered through a fritted funnel. The precipitate was washed with ether and dried under vacuum to give the N-hydroxyamidine as a yellow solid. To a suspension of this amidine intermediate (5.32 g, 34.32 mmol) in anhydrous pyridine (10 mL) was added 4-chloro-4-oxo-methyl butyrate (5 mL, 41.18 mmol). The resulting reaction mixture was heated at 120 C. for 2 h. The mixture was cooled to RT and concentrated. The residue was dissolved in ethyl acetate and washed with 1N HCl, water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give a dark brown solid. This material was purified by Biotage using 25%-60% ethyl acetate-hexanes gradient to give the heterobiaryl intermediate as a light yellow solid. To a solution of this ester intermediate (900 mg, 3.58 mmol) in dioxane (3 mL) was added ammonium hydroxide (3 mL) and the mixture was allowed to stir at room temperature for 12 hours. Upon completion, the mixture was concentrated, and the amide was purified via flash chromatography (Biotage 40M). To the amide (0.25 g, 1.0 mmol) in a degassed solution of dioxane (7 mL) was added the corresponding triflate (0.92 g, 2.1 mmol), cesium carbonate (1.0 g, 3.0 mmol), xantphos ligand (0.1 g, 0.2 mmol), and Pd2(dba)3 catalyst (0.09 g, 0.1 mmol), and the reaction mixture was heated to 75 C. for 6 hours. The mixture was cooled, filtered, concentrated in vacuo, and purified via flash chromatography (Biotage 40 M). To the desired cycloalkene (0.26 g, 0.5 mmol) in THF/H2O (1:1) was added sodium hydroxide (0.06 g, 1.5 mmol). The biphasic reaction mixture was allowed to stir for 12 hours at room temperature. The mixture was concentrated in vacuo and purified by reverse phase HPLC (Gilson) to afford the desired product Example 43. 1H NMR (DMSO-d6, 500 MHz) δ 11.46 (s, 1H), 8.76 (s, 1H), 8.12 (m, 1H), 7.94 (m, 1H), 7.41 (m, 1H), 6.87 (m, 1H), 3.43 (m, 2H), 3.26 (m, 2H), 2.89 (m, 2H), 2.18 (m, 1H), 2.11 (m, 2H) 1.88, (m, 1H), 1.30 (m, 3H); LCMS m/z 527 (M+Na). | |
With hydroxylamine; In methanol; at 20℃; for 48h; | To a suspension of this fluoropyridine nitrile intermediate (16.0 g, 0.131 mol) in methanol (200 mL) was added hydroxylamine (9.63 mL, 0.157 mmol, 50% by wt). After stirring the reaction at room temperature for 48 h, it was filtered through a fritted funnel. The precipitate was washed with ether and dried under vacuum to give the N-hydroxy amidine as a yellow solid. | |
With hydroxylamine; In ethanol; water monomer; for 1h;Reflux; | General procedure: 50 % Aq. Hydroxylamine (1.05 mmole) was added to a solution of nitrile (10, 1.0 mmole)in ethanol (10 vol) at room temperature. Reflux the reaction mass for 1 hr (TLC monitored).After completion of reaction, cooled to room temperature and concentrated under reducedpressure to get the corresponding amidoxime (7a-m) as a white to yellow colored solidwhich was used directly in the next step without further purification. | |
With hydroxylamine; In ethanol; water monomer;Reflux; | General procedure: To a stirred solution of nitrile (1.0 mmol.) in ethanol (10 vol), Hydroxylamine (1.05 mmol.) (50% aqueous solution) was added and refluxed. After completion of the reaction, as indicated by TLC, the reaction mixture was concentrated to get the corresponding amidoxime. | |
With hydroxylamine; In ethanol; water monomer;Reflux; | General procedure: To a stirred solution of nitrile (1.0 mmol.) in ethanol (10 vol), Hydroxylamine (1.05 mmol.) (50% aqueous solution) was added and refluxed. After completion of the reaction, as indicated by TLC, the reaction mixture was concentrated to get the corresponding amidoxime. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
304 mg (43%) | In methanol; sodium methylate; | A solution of 2-cyano-5-fluoropyridine (0.65 g, 5.3 mmol) in sodium methoxide (1.83 mL of 25% wt. solution in methanol, 7.95 mmol) was stirred at 0 C. for 1.5 hours and 2 hours at ambient temperature. The reaction was then diluted with ethyl acetate and washed with water and brine. Removal of the solvent in vacuo afforded 304 mg (43%) of 2-cyano-5-methoxypyridine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | Intermediate 3A^-(l-(5-Fluoropyridin-2-yl)vinyl)acetamideA solution of MeMgBr (170.3 ml, 510.98 mmol) in ether was diluted with 170 ml of anhydrousTHF and cooled to 0 0C. 5-Fluoropyridine-2-carbonitrile (Intermediate 2, 53.6 g, 425.82 mmol) in THF (170 ml) was added dropwise. The reaction was stirred at 0 0C for 30 minutes, then diluted with DCM (170 ml). Acetic anhydride (48.3 ml, 510.98 mmol) in DCM (100 ml) was added drop- wise at 0 0C. After addition, the reaction was warmed to room temperature and stirred at room temperature for 8 hours. Saturated sodium bicarbonate solution (50 ml) was added and the product was extracted with EtOAc (2 x 200 ml). The combined organic was dried over sodium sulfate. After removal of solvent, the resulting residue was purified by column chromatography (hexane-EtOAc = 2.5 : 1) to give the title compound as a white solid (26.6 g,35%).1H NMR (400 MHz) δ: 9.37 (s, IH), 8.57 (d, IH), 7.81 (m, 2H), 6.01 (s, IH), 5.52 (s, IH), 2.08(s, 3H).LC-MS: 181 [M+H]. | |
35% | A solution of MeMgBr (170.3 ml, 510.98 mmol) in ether was diluted with 170 ml of anhydrousTHF and cooled to 0 0C. 5-Fluoropyridine-2-carbonitrile (Intermediate 19, 53.6 g, 425.82 mmol) in THF (170 ml) was added drop-wise. The reaction mixture was stirred at 0 0C for 30 minutes, then diluted with DCM (170 ml). Acetic anhydride (48.3 ml, 510.98 mmol) in DCM(100 ml) was added drop-wise at 0 0C. After the addition, the reaction mixture was warmed to room temperature and stirred at room temperature for 8 hours. Saturated sodium bicarbonate solution (50 ml) was added and extracted with EtOAc (2 x 200 ml). The combined organic was dried over sodium sulfate. After removal of solvent, the resulted residue was purified by column chromatography (hexane-EtOAc = 2.5 : 1) to give the title compound as a white solid (26.6 g,35%).1H NMR (400 MHz) δ: 9.37 (s, IH), 8.57 (d, IH), 7.81 (m, 2H), 6.01 (s, IH), 5.52 (s, IH), 2.08(s, 3H).LC-MS: 181 [M+H]+. | |
35% | A solution of MeMgBr (170.3 ml, 510.98 mmol) in ether was diluted with 170 ml of anhydrous THF and cooled to 0 0C. 5-Fluoropyridine-2-carbonitrile (Intermediate 11, 53.6 g, 425.82 mmol) in THF (170 ml) was added dropwise. The reaction mixture was stirred at 0 0C for 30 minutes, then diluted with DCM (170 ml). Acetic anhydride (48.3 ml, 510.98 mmol) in DCM (100 ml) was added dropwise at 0 0C. After the addition, the reaction mixture was warmed to room temperature and stirred at room temperature for 8 hours. Saturated sodium bicarbonate solution (50 ml) was added and an extraction was carried out with EtOAc (2 x 200 ml). The combined organic layers were dried over sodium sulfate. After removal of solvent, the resulting residue was purified by column chromatography (hexane:EtOAc = 2.5 : 1), providing the title compound as a white solid (26.6 g, 35%). 1H νMR (400 MHz) δ: 9.37 (s, IH), 8.57 (d, J= 2.8 Hz, IH), 7.81 (m, 2H), 6.01 (s, IH), 5.52 (s, IH), 2.08 (s, 3H). |
35% | Intermediate 4N-( 1 -(5-Fluoropyridin-2-yl)vinyl)acetamide; A solution of MeMgBr (170.3 ml, 510.98 mmol) in ether was diluted with 170 ml of anhydrous THF and cooled to 0 0C. 5-Fluoropyridine-2-carbonitrile (Intermediate 3, 53.6 g, 425.82 mmol) in THF (170 ml) was added dropwise. The reaction was stirred at 0 0C for 30 minutes, then diluted with DCM (170 ml). Acetic anhydride (48.3 ml, 510.98 mmol) in DCM (100 ml) was added dropwise at 0 0C. After addition, the reaction was warmed to room temperature and stirred at room temperature for 8 hours. Saturated sodium bicarbonate solution (50 ml) was added and extracted with EtOAc (2 x 200 ml). The combined organic was dried over sodium sulfate. After removal of solvent, the resulted residue was purified by column chromatography (hexane : EtOAc = 2.5 : 1) to give the title compound as a white solid (26.6 g, 35%). 1H NMR (400 MHz) δ 9.37 (s, IH), 8.57 (d, J= 2.8 Hz, IH), 7.81 (m, 2H), 6.01 (s, IH), 5.52 (s, IH), 2.08 (s, 3H). MS: Calculated: 180; Found: [M+H]+ 181. | |
35% | Intermediate 12N-ri-(5-Fluoropyridin-2-yl)vinvHacetamideA solution of MeMgBr (170.3 ml, 510.98 mmol) in ether was diluted with 170 ml of anhydrous THF and cooled to 0 0C. 5-Fluoropyridine-2-carbonitrile (Intermediate 11, 53.6 g, 425.82 mmol) in THF (170 ml) was added dropwise. The reaction was stirred at 0 0C for 30 minutes, then diluted with DCM (170 ml). Acetic anhydride (48.3 ml, 510.98 mmol) in DCM (100 ml) was added drop-wise at 0 0C. After addition, the reaction was warmed to room temperature and stirred at room temperature for 8 hours. Saturated sodium bicarbonate solution (50 ml) was added and extracted with EtOAc (2 x 200 ml). The combined organic was dried over sodium sulfate. After removal of solvent, the resulted residue was purified by column chromatography (hexane : EtOAc = 2.5 : 1) to give the title compound as a white solid (26.6 g, 35%). 1H NMR (400 MHz) δ: 9.37 (s, IH), 8.57 (d, IH), 7.81 (m, 2H), 6.01 (s, IH), 5.52 (s, IH), 2.08 (s, 3H). LCMS: 181 [M+H]. | |
35% | Intermediate 2N-( 1 -(5-Fluoropyridin-2-yl)vinyl)acetamide; A solution of MeMgBr (170.3 ml, 510.98 mmol) in ether was diluted with 170 ml of anhydrous THF and cooled to 0 ºC. 5-fluoropyridine-2-carbonitrile (Intermediate 1, 53.6 g, 425.82 mmol) in THF (170 ml) was added dropwise. The reaction was stirred at 0 C for 30 minutes, then diluted with dichloromethane (170 ml). Acetic anhydride (48.3 ml, 510.98 mmol) in dichloromethane (100 ml) was added dropwise at 0 ºC. After addition, the reaction was warmed to room temperature and stirred at room temperature for 8 hours. Saturated sodium bicarbonate solution (50 ml) was added and extracted with EtOAc (2 x 200 ml). The combined organic was dried over sodium sulfate. After removal of solvent, the resulted residue was purified by column chromatography (hexane : EtOAc = 2.5 : 1) to give the title compound as a white solid (26.6 g, 35%). 1H NMR (400 MHz) δ 9.37 (s, 1 H), 8.57 (d, J= 2.8 Hz, 1 H), 7.81 (m, 2 H), 6.01 (s, 1 H), 5.52 (s, 1 H), 2.08 (s, 3 H). MS: Calculated: 180; Found: [M+H]+ 181. | |
35% | A solution of MeMgBr (170.3 ml, 510.98 mmol) in ether was diluted with 170 ml of anhydrous THF and cooled to 0 C. 5-Fluoropicolinontrile (Method 35; 53.6 g, 425.82 mmol) in THF (170 ml) was added dropwise. The reaction was stirred at 0 0C for 30 minutes, then diluted with DCM (170 ml). Acetic anhydride (48.3 ml, 510.98 mmol) in DCM (100 ml) was added dropwise at 0 C. After addition, the reaction was warmed to room temperature and stirred at room temperature for 8 hrs. Saturated sodium bicarbonate solution (50 ml) was added and extracted with EtOAc (2 x 200 ml). The combined organic was dried over sodium sulfate. After removal of solvent, the resulted residue was purified by column chromatography (hexane-EtOAc = 2.5 : 1) to give the title compound as a white solid (26.6 g, 35%). 1H NMR (400 MHz) δ 9.37 (s, IH), 8.57 (d, J= 2.8 Hz, IH), 7.81 (m, 2H), 6.01 (s, IH), 5.52 (s, IH), 2.08 (s, 3H). MS: Calcd.: 180; Found: [M+H]+ 181. | |
31% | PREPARATION 32 (R)-1-(5-Fluoropyridin-2-yl)ethanamine hydrochloride [Show Image]a) N-(1-(5-Fluoropyridin-2-yl)vinyl)acetamide: 5-Fluoropicolinonitrile (9.30 g, 76.2 mmol) in tetrahydrofuran (40 mL) was added dropwise to a cold (0 C), stirred solution of methylmagnesium bromide (3M in diethylether, 30.47 mL, 91.4 mmol) in tetrahydrofuran (40 mL). The mixture was stirred for 30 minutes at 0 C then diluted with dichloromethane (30 mL) and then acetic anhydride (8.64 mL, 91.4 mmol) in dichloromethane (2 mL) was added dropwise at 0 C. The mixture was warmed to room temperature and stirred overnight. 4% Aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate. The organic layer was dried (MgSO4), evaporated and the residue was purified by flash chromatography (3:1 hexanes/ethyl acetate) to give the title compound (4.30 g, 31%) as a yellow solid. LRMS (m/z): 181 (M+1)+.1H NMR (300 MHz, CDCl3) δ ppm 2.21 (s, 3H), 5.47 (s, 1H), 6.47 (s, 1H), 7.48 (m, 1H), 7.78 (m, 1H), 8.37 (m, 1H), 9.07 (br s, 1H). | |
31% | PREPARATION 32 (R)-1-(5-Fluoropyridin-2-yl)ethanamine hydrochloride a) N-(1-(5-Fluoropyridin-2-yl)vinyl)acetamide: 5-Fluoropicolinonitrile (9.30 g, 76.2 mmol) in tetrahydrofuran (40 mL) was added dropwise to a cold (0 C), stirred solution of methylmagnesium bromide (3M in diethylether, 30.47 mL, 91.4 mmol) in tetrahydrofuran (40 mL). The mixture was stirred for 30 minutes at 0 C then diluted with dichloromethane (30 mL) and then acetic anhydride (8.64 mL, 91.4 mmol) in dichloromethane (2 mL) was added dropwise at 0 C. The mixture was warmed to room temperature and stirred overnight. 4% Aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate. The organic layer was dried (MgSO4), evaporated and the residue was purified by flash chromatography (3:1 hexanes/ethyl acetate) to give the title compound (4.30 g, 31%) as a yellow solid. LRMS (m/z): 181 (M+1)+.1H NMR (300 MHz, CDCl3) δ ppm 2.21 (s, 3H), 5.47 (s, 1H), 6.47 (s, 1H), 7.48 (m, 1H), 7.78 (m, 1H), 8.37 (m, 1H), 9.07 (br s, 1H). | |
31% | a) N-(1-(5-Fluoropyridin-2-yl)vinyl)acetamide A solution of <strong>[327056-62-2]5-fluoropicolinonitrile</strong> (9.30 g, 76.2 mmol) in tetrahydrofuran (40 mL) was added dropwise to a cold (0 C), stirred solution of methylmagnesium bromide (3M solution in diethylether, 30.47 mL, 91.4 mmol) in tetrahydrofuran (40 mL). The mixture was stirred for 30 minutes at 0 C then diluted with dichloromethane (30 mL) and then acetic anhydride (8.64 mL, 91.4 mmol) in dichloromethane (2 mL) was added dropwise at 0 C. The mixture was warmed to ambient temperature and stirred overnight. 4% Aqueous sodium hydrogencarbonate solution was added and the mixture was extracted with ethyl acetate. The organic layer was separated, dried (MgSO4) evaporated and the residue was purified by flash chromatography (3:1 hexanes/ethyl acetate) to give the title compound (4.30 g, 31 %) as a yellow solid. LRMS (m/z): 181 (M+1)+. 1H NMR δ (300 MHz, CDCl3): 2.21 (s, 3H), 5.47 (s, 1H), 6.47 (s, 1H), 7.48 (m, 1H), 7.78 (m, 1H), 8.37 (m, 1H), 9.07 (br s, 1H). | |
a) yV-(1 -(5-Fluoropyridin-2-yl)vinyl)acetamideA solution of <strong>[327056-62-2]5-fluoropicolinonitrile</strong> (9.30 g, 76.2 mmol) in tetrahydrofuran (40 mL) was added dropwise to a cold (0 C), stirred solution of methylmagnesium bromide (3M solution in diethyl ether, 30.47 mL, 91 .4 mmol) in tetrahydrofuran (40 mL). The mixture was stirred for 30 minutes at 0 C then diluted with dichloromethane (30 mL) and then acetic anhydride (8.64 mL, 91 .4 mmol) in dichloromethane (2 mL) was added dropwise at 0 C. The mixture was warmed to ambient temperature and stirred overnight. 4% Aqueous sodium hydrogencarbonate solution was added and the mixture was extracted with ethyl acetate. The organic layer was separated, dried (MgS04), evaporated and the residue was purified by flash chromatography (3:1 hexanes/ethyl acetate) to give the title compound (4.30 g, 31 %) as a yellow solid.LRMS (m/z): 181 (M+1 )+.1H NMR δ (300 MHz, CDCI3): 2.21 (s, 3H), 5.47 (s, 1 H), 6.47 (s, 1 H), 7.48 (m, 1 H), 7.78 (m, 1 H), 8.37 (m, 1 H), 9.07 (br s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37.7% | With hydroxylamine hydrochloride; potassium carbonate; In ethanol; for 12h;Reflux; | General procedure: 2-cyanopyridine (2.5g, 24.01mmol) was dissolved in EtOH (60mL) treated with K2CO3 (5.97g; 43.22mmol; 1.8 equiv) and H2NOH·HCl (3.0g; 43.22mmol; 1.8 equiv) and heated to reflux for 12h. The mixture was diluted with diethyl ether when it was cooled to room temperature. The product was collected by filtration, washed with water, and dried under an infrared lamp. The compound was used without further purification. Yield: 1.5g (45.5%). |
With hydroxylamine; In methanol; at 20℃; for 48h; | EXAMPLE 17As shown in Scheme 6 a suspension of 5-amino-2-cyano pyridine (20.0 g, 0.168 mol) in HF-pyridine (100 g) in an Erlenmeyer flask cooled to O0C was added sodium nitrite (17.4 g, 0.25 mol) in four portions. After 45 min at O0C the reaction mixture was stirred at room temperature for 30 min and then heated to 8O0C for 90 min. The reaction mixture was quenched by pouring into ice/water mixture. The resulting mixture was extracted with DCM. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give the fluoropyridine as an orange solid.To a suspension of this fluoropyridine nitrile intermediate (16.0 g, 0.13 mol) in methanol (200 mL) was added hydroxylamine (9.63 mL, 0.16 mmol, 50% by wt). After stirring the reaction mixture at room temperature for 48 h, it was filtered through a fritted funnel. The precipitate was washed with ether and dried under vacuum to give the N-hydroxy amidine as a yellow solid.To a suspension of this amidine intermediate (5.32 g, 34.3 mmol) in anhydrous pyridine (10 mL) was added 4-chloro-4-oxo-methyl butyrate (5 mL, 41.2 mmol). The resulting reaction mixture was heated at 12O0C for 2 h. The mixture was cooled to RT and concentrated. The residue was dissolved in ethyl acetate and washed with IN HCl, water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give a dark brown solid. This material was purified by Biotage using 25%-60% ethyl acetate-hexanes gradient to give the heterobiaryl intermediate as a light yellow solid.To a solution of this ester intermediate (900 mg, 3.58 mmol) in THF (4 mL) was added methanol (2 mL) followed by 5N NaOH (1 mL). After 30 min, the reaction mixture was EPO <DP n="41"/>neutralized by the addition of IN HCl (5 mL). The reaction mixture was concentrated. The residue was extracted with ethyl acetate, and the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give a light yellow solid of the carboxylic acid.EXAMPLE 17 was prepared by reaction of the carboxylic acid described above and the intermediate prepared for EXAMPLE 2. 1H NMR (DMSOd6, 500 MHz) δ 10.95 (br s, IH), 8.75 (d, IH), 8.12 (dd, IH), 7.95-7.91 (m, IH) .50 (t, 2H), 3.31 (t, 2H), 3.03 (d, IH), 2.32- 2.21 (m, 3H), 1.75 (br s, 2H), 1.26-1.24 (m, lH)m 0.99 (d, 3H); LCMS m/z 372 (M+l). | |
With hydroxylamine; In ethanol; acetic acid butyl ester; water; N,N-dimethyl-formamide; at 25℃; for 1h;Product distribution / selectivity; | Examples; Example 1. Using zinc cyanide as cyanide source; 2-Bromo-5-fluoropyridine (280.43 mmol; 49.80 g; commercially available from Asymchem), zinc (11.27 mmol; 739.20 mg), zinc acetate (8.45 mmol; 1.55 g), 1,1'- bis(diphenylphosphino)ferrocene DPPF) (845.09 μmol; 483.00 mg), tris(dibenzylideneacetone)dipalladium(0) (281.74 μmol; 258.00 mg) were charged to an inerted reactor and dimethylformamide (98.00 mL; 92.64 g) warmed to 1050C was added. Zinc cyanide (155.49 mmol; 18.58 g) was added in 5 portions of equal size while keeping the temperature at 100+/-5C. The reaction mixture was cooled to ambient temperature and butyl acetate (175.00 mL; 154.14 g) was added. Ethylenediaminetetraacetic acid tetrasodium salt tetrahydrate (Na-EDTA) (259.10 mmol; 117.88 g) dissolved in water (300.00 mL) was added and the mixture was stirred for 1 hour. The mixture was clear filtered and the filter was rinsed with butyl acetate (25.00 mL; 22.02 g). The phases were allowed to separate and the aqueous phase was discarded. Ethanol (78.00 mL; 61.72 g) was added and hydroxylamine (309.74 mmol; 17.79 mL; 19.19g) was charged during 1 hour using a syringe pump. The precipitated product was isolated by filtration, washed with butyl acetate (10OmL) and dried under vacuum at 400C, obtaining 5-Fluoro-N-hydroxy-pyridine-2-carboxamidine, 180.58 mmol; 28.24 g in 64.40% yield. |
With hydroxylamine; In 1-methyl-pyrrolidin-2-one; ethanol; acetic acid butyl ester; water; at 25℃; for 1h;Product distribution / selectivity; | Example 2. Using acetone cyanohydrin as cyanide source and palladium2(dba)3 as palladium source and sodium carbonate as base; 2-Bromo-5-fluoropyridine (281.84 mmol; 50.00 g), sodium carbonate (154.86 mmol; 16.43 g), sodium acetate (22.57 μmol; 1.87 mg), l,r-bis(diphenylphosphino)ferτocene (DPPF) (839.84 μmol; 480.00 mg), tris(dibenzylideneacetone)dipalladium(0) (287.75 μmol; 310.00 mg), butyl acetate (50.00 mL; 44.04 g) and N-methylpyrrolidone (50.00 mL; 51.45 g) was mixed under nitrogen and was heated to 1050C. Acetone cyanohydrin (295.58 mmol; 27.34 mL; 25.41 g) was charged during 2 hours using a syringe pump. The mixture was cooled to ambient temperature and water (200.00 mL) was charged. The mixture was clear filtered and butyl acetate (150.00 mL; 132.12 g) was added, the phases were allowed to separate and the aqueous phase was discarded. Ethanol (80.00 mL; 63.30 g) was added and hydroxylamine (281.84 mmol; 17.10 mL; 18.43 g) was charged during 1 hour using a syringe pump. The precipitated product was isolated by filtration, washed with butyl acetate (10OmL) and dried under vacuum at 400C, obtaining 5-Fluoro-N-hydroxy-pyridine- 2-carboxamidine, 238.96 mmol; 37.37 g in 84.79% yield. | |
With hydroxylamine; In ethanol; acetic acid butyl ester; water; at 25℃; for 1h;Product distribution / selectivity; | Example 3. Using acetone cyanohydrin as cyanide source with palladium acetate as palladium source and triethanolamine as base; 2-Bromo-5-fluoropyridine (50.02g. 281.95 mmol), palladium acetate (129 mg, 565 μmol), 1,1 '-bis(diphenylphosphino)ferrocene (DPPF) (847 mg, 847 μmol), sodium acetate (1.87 g, 22.6 mmol), triethanolamine (43 ml, 312 mmol) and n-butyl acetate (100 ml) was mixed under nitrogen and heated to 1050C and acetone cyanohydrine (27.37 ml, 295.91 mmol) was added during 2 hours using a syringe pump. The resulting slurry was sampled for conversion control (result: 100% conversion) and was then cooled to O0C. The solids (triethanolamine hydrobromide) were removed by filtration, the reaction vessel and the salt was washed with cold n-butyl acetate (2x50 ml) and the washing liquor was pulled off from the salt and was combined with the mother liquor which was then washed with water (200 ml) and the water phase was discarded. To the mother liquor containing 5-Fluoro- pyridine-2-carbonitrile was added ethanol (78 ml) and hydroxylamine 50% aq. (21.87 ml, 310.15 mmol) was added during 1 hour at ambient temperature using a syringe pump. The resulting slurry was cooled to 00C and the product was isolated by filtration, was washed with cold n-butyl acetate (100 ml), the mother liquor was pulled off and the product was dried at 400C under reduced pressure obtaining 5-Fluoro-N-hydroxy-pyridine-2- carboxamidine 37.88g in 85.9% yield. |
Yield | Reaction Conditions | Operation in experiment |
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With sodium acetate; sodium carbonate;1,1'-bis-(diphenylphosphino)ferrocene; tris-(dibenzylideneacetone)dipalladium(0); In 1-methyl-pyrrolidin-2-one; acetic acid butyl ester; at 105℃; for 2h;Product distribution / selectivity; | Example 2. Using acetone cyanohydrin as cyanide source and palladium2(dba)3 as palladium source and sodium carbonate as base; 2-Bromo-5-fluoropyridine (281.84 mmol; 50.00 g), sodium carbonate (154.86 mmol; 16.43 g), sodium acetate (22.57 μmol; 1.87 mg), l,r-bis(diphenylphosphino)ferτocene (DPPF) (839.84 μmol; 480.00 mg), tris(dibenzylideneacetone)dipalladium(0) (287.75 μmol; 310.00 mg), butyl acetate (50.00 mL; 44.04 g) and N-methylpyrrolidone (50.00 mL; 51.45 g) was mixed under nitrogen and was heated to 1050C. Acetone cyanohydrin (295.58 mmol; 27.34 mL; 25.41 g) was charged during 2 hours using a syringe pump. The mixture was cooled to ambient temperature and water (200.00 mL) was charged. The mixture was clear filtered and butyl acetate (150.00 mL; 132.12 g) was added, the phases were allowed to separate and the aqueous phase was discarded. Ethanol (80.00 mL; 63.30 g) was added and hydroxylamine (281.84 mmol; 17.10 mL; 18.43 g) was charged during 1 hour using a syringe pump. The precipitated product was isolated by filtration, washed with butyl acetate (10OmL) and dried under vacuum at 400C, obtaining 5-Fluoro-N-hydroxy-pyridine- 2-carboxamidine, 238.96 mmol; 37.37 g in 84.79% yield. | |
With triethanolamine; sodium acetate;1,1'-bis-(diphenylphosphino)ferrocene; palladium diacetate; In acetic acid butyl ester; at 105℃; for 2h;Product distribution / selectivity; | Example 3. Using acetone cyanohydrin as cyanide source with palladium acetate as palladium source and triethanolamine as base; 2-Bromo-5-fluoropyridine (50.02g. 281.95 mmol), palladium acetate (129 mg, 565 μmol), 1,1 '-bis(diphenylphosphino)ferrocene (DPPF) (847 mg, 847 μmol), sodium acetate (1.87 g, 22.6 mmol), triethanolamine (43 ml, 312 mmol) and n-butyl acetate (100 ml) was mixed under nitrogen and heated to 1050C and acetone cyanohydrine (27.37 ml, 295.91 mmol) was added during 2 hours using a syringe pump. The resulting slurry was sampled for conversion control (result: 100% conversion) and was then cooled to O0C. The solids (triethanolamine hydrobromide) were removed by filtration, the reaction vessel and the salt was washed with cold n-butyl acetate (2x50 ml) and the washing liquor was pulled off from the salt and was combined with the mother liquor which was then washed with water (200 ml) and the water phase was discarded. To the mother liquor containing 5-Fluoro- pyridine-2-carbonitrile was added ethanol (78 ml) and hydroxylamine 50% aq. (21.87 ml, 310.15 mmol) was added during 1 hour at ambient temperature using a syringe pump. The resulting slurry was cooled to 00C and the product was isolated by filtration, was washed with cold n-butyl acetate (100 ml), the mother liquor was pulled off and the product was dried at 400C under reduced pressure obtaining 5-Fluoro-N-hydroxy-pyridine-2- carboxamidine 37.88g in 85.9% yield. |
Yield | Reaction Conditions | Operation in experiment |
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50% | In N,N-dimethyl-formamide; for 9h;Heating / reflux; | 10(A) 5-Fluoro-pyridine-2-carbonitrile; A solution of 2-bromo-5-fluoro-pyridine (5.0 g, 28.4 mmol), CuCN (2.01 g, 22.5 mmol) and NaCN (1.14 g, 23.2 mmol) in dry DMF (50 ml) was refluxed for 9h. The reaction mixture was allowed to cool down to room temperature and a solution of 2% K2CO3 (aq.) was added. Ethyl acetate was added and the phases were separated. The organic layer was dried over sodium sulphate and evaporated under reduced pressure to give a crude solid that was triturated from hexane. Yield: 50%; LCMS (RT): 2.5 min (Method G); MS (ES+) gave m/z: 122.9 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
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52% | With 3-chloro-benzenecarboperoxoic acid; In chloroform; for 96h;Reflux; | A solution of <strong>[327056-62-2]5-fluoropicolinonitrile</strong> (7.27 g, 59.5 mmol) in CHCl3 (60 mL) was added dropwise by addition funnel to a solution of m-CPBA (<77%, 22.00 g, 98 mmol) in CHCl3 160 mL). The solution was stirred at reflux for 4 days, at which time LCMS showed 85% conversion. The sample was allowed to cool, then sodium sulfite (12.4 g, 98 mmol) was added and the sample was stirred at room temperature for three hours, during which time the solution became thick with a white precipitate. The sample was diluted with DCM (300 mL) and filtered on a Buchner funnel, and the filter cake was washed with DCM (400 mL). A white material precipitated in the filtrate. The filtrate mixture was washed with saturated aqueous NaHCO3 (400 mL), during which the solids went into solution. The organic layer was washed with water (300 mL), then dried (MgSO4) and filtered. Silica gel was added and the mixture was evaporated under reduced pressure. The material was chromatographed by Biotage MPLC (340 g silica gel column) with 0 to 100% EtOAc in hexanes, with isocratic elution when peaks came off to provide <strong>[327056-62-2]2-cyano-5-fluoropyridine</strong> 1-oxide (4.28 g, 31.0 mmol, 52% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6): δ ppm 8.85-8.93 (m, 1H), 8.23 (dd, J=9.09, 6.74 Hz, 1H), 7.53-7.64 (m, 1H). LCMS (Method 1): Rt 0.57 min., m/z 138.9 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
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49% | An ether solution (2 mL) of <strong>[130723-13-6]1-bromo-3-fluoro-5-(trifluoromethyl)benzene</strong> (0.200 g, 0.826 mmol) was stirred in an oven-dried round bottom flask at -78 C. under Ar. To this solution, n-BuLi (2.0 M in cyclohexane, 0.41 mL, 0.82 mmol, 1.0 eq) was added dropwise. The resulting solution was stirred at -78 C. for 30 min. 5-Fluoropicolinonitrile (0.101 g, 0.828 mmol, 1.0 eq), prepared as described in Procedure 1, was added as a solid via addition funnel. The resulting red solution was stirred at -78 C. for 1 h. The reaction mixture was quenched with HCl (10 mL, 1.0 M) and extracted with EtOAc (3*10 mL). The combined organic portions were dried over Na2SO4, decanted and the volume was reduced to 5 mL under reduced pressure. The resulting oil was loaded directly onto a silica gel ISCO cartridge (40 g). Gradient elution from 0-70% EtOAc in hexane over 20 min yielded (3-fluoro-5-(trifluoromethyl)phenyl)(5-fluoropyridin-2-yl)methanone as a pale brown oil at a retention time of 7 min (0.117 g, 49% yield). LCMS: RT=1.91 min [M+H] 288.2 (2 min Phenomenex Luna C18 column, 4.6*30 mm eluding with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); HPLC: RT=3.69 min (Phenomenex Luna C18 column, 4.6*50 mm eluding with 10-90% MeOH/H2O over 4 minutes containing 0.2% PPA; 4 mL/min, monitoring at 220 nm, purity 97%); NMR: 400 MHz 1H (CDCl3) ppm 8.50 (d, J=2.4 Hz, 1H), 8.19 (dd, J=4.0 and J=8.0 Hz, 1H), 8.15 (s, 1H), 8.00 (d, J=8.0 Hz, 1H), 7.57 (ddd, J=3.08, J=2.4 and J=8.0 Hz). |
Yield | Reaction Conditions | Operation in experiment |
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72% | With zinc;1,1'-bis-(diphenylphosphino)ferrocene; tris-(dibenzylideneacetone)dipalladium(0); In ISOPROPYLAMIDE; at 95℃; for 3h; | A mixture of 2-bromo-5-fluoropyridine (93.0 g, 528 mmol), Zn dust (8.29 g, 127 mmol), zinc cyanide (40.3 g, 343 mmol), dppf (11.7 g, 21.1 mmol) and Pd2dba3 (9.68 g, 10.6 mmol) in anhydrous DMA (300 ml) were heated at 95 0C for 3 hours. After cooling to room temperature, brine (100 ml) and ether (500 ml) was added. The solid formed was removed by filtration and washed with ether (300 ml). The organic layer was separated, washed with brine (200 ml) and dried over sodium sulfate, and concentrated. After removal of solvent, the resulted residue was purified by column chromatography (hexane-DCM = 1 : 1) to give the title compound as a white solid (49 g, 72%). 1H NMR (400 MHz) δ: 8.82 (d, IH), 8.21 (dd, IH), 8.05 (dd, IH). |
Yield | Reaction Conditions | Operation in experiment |
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A solution of <strong>[327056-62-2]5-fluoropicolinonitrile</strong> (Method 35; 1875g 1 equivalent) in THF (3.7 volumes) was added to methyl magnesium chloride (3N in THF, 1.2 equivalents) maintaining the temperature at O0C. The reaction mixture was stirred for 30 minutes at O0C and then EPO <DP n="64"/>diluted with DCM (3.2 volumes) at O0C. Acetic anhydride (2.0 equivalents) in DCM (1.6 volumes.) was added at a rate to maintain the temperature at O0C. The batch was allowed to warm to room temperature and stirred overnight. Saturated, aqueous sodium hydrogen carbonate (13.9 volumes) was added and the product was extracted into EtOAc (1 x 0.53 volumes, 1 x 0.26 volumes). The combined extracts were dried, filtered and evaporated in vacuo and purification carried out by chromatography (5 w/w silica; 20-100 % DCM in hexane). The mixture of N-mono and N,N-di-acetylated compounds was treated with potassium carbonate (0.1 w/w on mixture) in methanol (5 volumes) for 30 minutes. The inorganic solids were filtered and washed with methanol. Silica was added to the methanol solution to remove residual potassium carbonate prior to evaporation. The product, pre- adsorbed on silica, was eluted through a silica pad (2 w/w silica; 90-100 % DCM in hexane) and evaporated to give an orange solid. Mp 61.0 - 62.20C, 636g, 23.0% theory. |
Yield | Reaction Conditions | Operation in experiment |
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62.9% | 2-Bromo-5-fluoiOpyridine (93.0 g, 528 mmol), Zn dust (8.29 g, 127 mmol), zinc cyanide (40.3 g, 343 mmol), l,r-bis(diphenylphosphino)ferrocene (11.7 g, 21.1 mmol) and Pd2dba3 (9.68 g, 10.6 mmol) in anhydrous DMA (300 ml) was heated at 95 0C for 3 hours. After cooled to room temperature, brine (100 ml) and ether (500 ml) was added. The solid formed was removed by filtration and washed with ether (300 ml). The organic layer was separated, washed with brine (200 ml) and dried over sodium sulfate, and concentrated. After removal of solvent, the resulted residue was purified by column chromatography (hexane- DCM = 1:1) to give the title compound as a white solid (49 g, 72%). 1H NMR (400 MHz) δ 8.82 (d, J= 2.8 Hz, IH), 8.21 (dd, J= 4.4 and 8.8 Hz, IH), 8.05 (dd, J= 2.8 and 8.8 Hz, IH). |
Yield | Reaction Conditions | Operation in experiment |
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With potassium carbonate; In dimethyl sulfoxide; at 100℃; for 5h; | 5-Fluoro-pyridine-2-carbonitrile (1.5 mmol), piperazine-1-carboxylic acid tert-butyl ester (1.5 mmol) and potassium carbonate are dissolved in dry dimethylsulfoxide (7 mL) and the resulting mixture is reacted for 5 hours at 1000C under stirring. The reaction is then cooled down to room temperature and is diluted with ethyl acetate (15 mL). The organic layer is then washed with aqueous saturated ammonium chloride solution (2 x 10 mL) and with aqueous saturated sodium chloride solution (10 mL). The organic layer is then dried over magnesium sulphate, filtered and concentrated under reduced pressure to afford the desired product |
Yield | Reaction Conditions | Operation in experiment |
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Example 78; Obtaining a library of [4-(quinolin-3-yl)-9H-carbazol-9-yl]-arylcarboxamides-application to the synthesis of 5-[4-(quinolin-3-yl)-9H-carbazol-9yl]pyridin-2-amide; A library of 40 various [4-(quinolin-3-yl)-9H-carbazol-9-yl]-arylcarboxamide type derivatives can be prepared according to the scheme below, and by carrying out the procedure according to the following protocol:; Stage 1:; In a 250 ml three-necked flask, under an argon atmosphere, 800 mg of sodium hydride at 60% in oil are stirred in 10 ml of heptane for 5 minutes, and then the mixture is allowed to separate by settling out for 15 minutes. The supernatant is removed with a pipette. 80 ml of anhydrous dimethylformamide are then added, followed, portionwise over 30 minutes, by 2.944 g of 4-(quinolin-3-yl)-9H-carbazole, obtained in stage 1 of Example 2. The reaction medium is stirred until no more hydrogen gas is given off. The solution obtained is divided up into 40 identical samples of 2 ml, which are each transferred into a 5 ml tube reactor. 0.25 mmol of a different aryl fluoride is added, under an argon atmosphere, to each tube. The tube reactors are septum-sealed, and then heated overnight at 60 C. 0.1 ml of trifluoroacetic acid is then added to each tube reactor. The 40 reaction media obtained are extracted, in parallel, by adding 20 ml of ethyl acetate, washing 10 ml of a 5% aqueous solution of sodium hydrogen carbonate, drying over a magnesium sulphate cartridge, and evaporating to dryness under reduced pressure. The 40 residues thus obtained are purified by supercritical chromatography in parallel, so as to give 40 [4-(quinolin-3-yl)-9H-carbazol-9-yl]arylnitriles, used in stage 2. |
Yield | Reaction Conditions | Operation in experiment |
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64% | To 5-fluoropyridine-2-carbonitrile (200 mg, 1.64 mmol) was added a solution of sodium methoxide in methanol (0.1 M, 1.7 ml, 0.1 eq.) and the solution heated under nitrogen in a 40-45 C oil-bath for 100 min. A solution of 2 -amino-4-(5 ' -{4"- memylpiperazm- '-yl)benziniidazol-2'-yl)anilme (277 mg, 0.86 mmol) in dry methanol (15 ml) and glacial acetic acid (0.19 ml, 3.3 mmol) was then added and the mixture gently refluxed under nitrogen overnight. After cooling the solvents were removed by rotary evaporator, the residue dissolved in water (10 ml) and basified to pH 8 with dilute ammonia solution (3.0 M). After stirring for 40 min the light brown suspension was centrifuged and the supernatant removed. Then solid was then treated with water (3 5 ml), followed by acetonitrile (4 x 3 ml) with centrifuging and removal of the supernatant between treatments. The remaining solid was dried under vacuum to give a brown glassy solid (270 mg). The material was then dissolved in methanol (2 ml) and applied to a silica cartridge (KP-Sil 25g) and eluted with methanol to give 5-fluoro-2-(5'-(5"-(4'"- memylpiperazm- "-yl)benziniida as a dull light yellow powder (235 mg, 64%), mp 196-199 C. fH nmr (500 MHz, dj-MeOH + 5 drops d-TFA) δ 3.00, s, 3H, 4"'-MeN; 3.21, t (J =12.0 Hz), 2H, NCH2; 3.34, m (obs), NCH2; 3.69, d (J = 12.0 Hz), 2H, NCH2; 3.96, d ( J = 13.5 Hz), 2H, NCH2; 7.32, d ( J = 1.5 Hz), 1H, H4"; 7.41, dd (J - 2.5, 9.0 Hz), 1H, H6"; 7.73, d (J = 9.0 Hz), 1H, H7"; 7.90, ddd (J = 3.0, 8.5, 8.5 Hz), 1H, H4; 8.02, dd (J = 0.5, 8.5 Hz), 1H, H7'; 8.14, dd (J = 1.8, 8.8 Hz), 1H, H6'; 8.46, dd (J = 4.0, 8.5 Hz), 1H, H3; 8.53, dd (J = 0.5, 1.5 Hz), 1H, H4'; 8.74, d (J = 3.0 Hz), 1H, H6. 13C nmr (125 MHz, d,- MeOH + 5 drops HOAc) δ 43.6, 4"'-MeN; 49.3, C2"'/6'"; 54.6, C3"'/5'"; 102.5, C4"; 115.0, 116.3, 116.8 (overlap), C4 C6", C7 C7"; 122.9, C6'; 124.0, C5'; 124.2, d (3JCT = 5 Hz), C3; 125.0, d (2JCF = 19 Hz), C4; 134.1, C7a"; 138.8, C3a' or C3a"; 139.0, d (2JCF = 25 Hz), C6; 140.3, C3a" or C3a'; 141.5, C7a'; 145.0, C2; 148.5, C5"; 152.7, 153.1, C2 C2"; 161.4, d ('JCF = 258 Hz), C5. MS (ESI +ve) m/z 428 (MH+, 100%). HRMS (ESI +ve) m/z 428.19934, C24H23FN7 requires 428.19935 (Δ = 0.0 ppm).Cytotoxicity and radioprotection resultsC50 = 537.5PF = 40.0DMFm = 2.46DMF10 = 2.20 |
Yield | Reaction Conditions | Operation in experiment |
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Example 1 Preparation of N-(4-(2-(5-tert-butylisoxazol-3-ylamino)-2-oxoethyl)phenyl)-5- (pyrrolidin-3-yloxy)picolinamide hydrochloride[00279] Step 1 : NaH (60% in mineral oil, 393 mg, 9.8 mmol) in 15 mL of DMF was stirred at rt in a round-bottom flask. tert-Butyl 3-hydroxypyrrolidine-l- carboxylate (1.84 g, 9.8 mmol) was added in portions and the resulting mixture was stirred at rt for 30 min. 5-Fluoro picolinonitrile (1.0 g, 8.2 mmol) in 5 mL of DMF was added dropwise. After stirring at rt for 2 h, LC-MS indicated that the reaction was complete. The reaction mixture was then partitioned between EtOAc (30 mL) and water (25 mL). The organic layer was washed with brine (10 mL), dried over MgS04, filtered, and concentrated under reduced pressure, and dried under high vacuum to give crude tert- vXy 3 -((6-cyanopyridin-3-yl)oxy)pyrrolidine-l -carboxylate (2.37 g) as an oil. LC-MS (ESI) m/z 290 (M +H)+. |
Yield | Reaction Conditions | Operation in experiment |
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76% | General procedure: Into an oven-dried flask equipped with a magnetic stir bar was added aryl fluoride (1.00 g, 1.0 eq.), Na2S (1.1 eq.) and DMF (5 mL) under argon. The reaction mixture was stirred at room temperature for 1 h. Then 1 M NaOH (50 mL) was added and was washed with CH2Cl2 (2 x 25 mL). The aqueous layer was acidified to pH ~ 1-2 with 6 N HCl and extracted with CH2Cl2 (2 x 50 mL). The combined organic layer was washed with brine (50 mL), dried over MgSO4, filtered and concentrated under reduced pressure to provide a crude residue. To the residue was added 10% HCl (40 mL) and cooled with an ice-water bath. Then zinc dust (4 g) was added and the mixture was stirred for 1 h. Then EtOAc (100 mL) was added and the mixture was stirred for an additional 30 minutes. The organic layer was separated and washed with water (40 mL) and brine (40 mL), dried over MgSO4, filtered and concentrated to provide the desired product with satisfactory purity. | |
41% | With sodium sulfide; In N,N-dimethyl-formamide; at 20℃; for 19h;Inert atmosphere; | A mixture of Na2S (2.25 g, 28.8 mmol) in deoxygenated (nitrogen sparged) DMF (75 mL) was treated with solution of <strong>[327056-62-2]5-fluoropicolinonitrile</strong> (3.22 g, 26.3 mmol) in deoxygenated DMF (25 mL) and stirred at rt for 19 h. The mixture was diluted with 1 N NaOH (aq) (50 mL) and extracted with DCM (2 x 100 mL) breaking up any emulsions that formed with brine. The pH of the aqueous phase was adjusted to ~4 with 1 N HCI (aq) (50 mL) and the precipitate that formed was collected by filtration and dried to give the title compound as a tan powder (1 .48 g, 41 % yield). 1H NMR (400 MHz, DMSO-cf6) δ: 8.67 (s, 1 H), 7.98 (d, J = 8.3 Hz, 1 H), 7.86 (d, J = 8.3 Hz, 1 H). MS (m/z) 136.7 (M+H+). |
With sodiumsulfide nonahydrate; In N,N-dimethyl-formamide; at 20℃; for 20h; | To a solution of <strong>[327056-62-2]5-fluoropicolinonitrile</strong> (5 g, 40.95 mmol) in DMF (200 mL) was added Na2S 9H20 (14.8 g, 61.43 mmol). The reaction was stirred at room temperature for 20 h. The mixture was added NaHS04 aq to adjust pH 4-5 and MTBE (100 ml) was added. The organic phase was washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulphate. Removal of solvent gave the desired product (4.5 g,crude). m/z calcd for [C6H4N2S]" [M-H]~: 135.0; found: 135.0. |
Yield | Reaction Conditions | Operation in experiment |
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A solution of the aniline component (1 mol-equivalent) and a strong base such as e.g. potassium-tert-butoxide (1 mol-equivalent) in DMSO was stirred for one hour at ambient temperature, then combined with the 4-fluoro-benzonitrile component (1 mol-equivalent) and stirred overnight at approx. 80 C. For working up the mixture was filtered through Alox and evaporated to dryness in vacuo. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17% | With ammonium chloride; In hydrogenchloride; diethyl ether; chloroform; toluene; | 5-Fluoro-pyridine-2-carboxamidine Trimethyl aluminum (3.54 g, 49.14 mmol) was added dropwise to a vigorously stirred solution of NH4Cl (2.63 g, 49.14 mmol) in dry toluene (20 ml) at 0 C. The mixture was warmed to room temperature and was stirred for 15 min. A solution of 5-fluoropyridine-2-carbonitrile (2.00 g, 16.38 mmol) in toluene (20 ml) was added dropwise. The reaction mixture was heated at 80 C. for 18 h. After cooling, the mixture was transferred to a vigorously stirred and cooled (0 C.) slurry of silica (20.0 g) in chloroform (150 ml) and was stirred for 10 min. The mixture was filtered and the filter cake was washed with MeOH (*3). The filtrate was concentrated in vacuo. The residue was dissolved in 1M HCl (150 ml) and Et2O (70 ml). The organic phase was separated and discarded. The aqueous phase was basified with saturated aqueous NaOH and extracted with chloroform (*2). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo to give the title compound (394 mg, 17%). The compound could not be detected by HPLCMS therefore structure was confirmed by 1H-NMR. |