* 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.
Stage #1: With sulfuric acid In water at 100℃; for 4 h; Stage #2: With sodium hydroxide In water at 20℃;
iV-(4-Iodo-pyridin-3-yl)-2,2-dimethyl-propionamide (20.00 g, 65.76 mmol) was charged to a 2 L round-bottom flask and 24percent sulfuric acid in water (640 mL) was added carefully. The mixture was heated to 100 °C for 4 hours. The reaction was determined complete by analyitical HPLC. The mixture was allowed to cool to room temperature and then carefully adjusted to pH 7-8 with 4Ν NaOH (approximately 700 mL). Saturated sodium bicarbonate was added to the mixture and the product extracted into dichloromethane (3 X 500 mL). The organic layers were combined and concentrated to give 3-amino-4-iodo- pyridine (13.3 g, 92percent).
90%
With sulfuric acid In water for 1 h; Heating / reflux
The product of preparation 22 (4.69g, 15.4mmol) and dilute sulphuric acid (24percent, 120mL) were heated under reflux for 1 hour. The mixture was then cooled, basified with solid sodium hydrogen carbonate to pH8 and extracted with dichloromethane (3x200mL). The combined organic solutions were dried over magnesium sulfate and concentrated in vacuo. Purification of the residue by column chromatography on silica gel, eluding with dichloromethane:methanol, 100:0 to 90:10, afforded the title compound as a brown solid in 90percent yield, 3.04g. 1H-NMR(CDCl3, 400MHz) δ: 4.11 (bs, 2H), 7.56(d, 1H), 7.61 (d, 1H), 8.05(s, 1H) MS APCI+ m/z 221 [MH]+
75%
Stage #1: With sulfuric acid In water at 80℃; for 8 h; Inert atmosphere Stage #2: With sodium hydroxide In water at -10 - 10℃;
The reaction was performed according to a procedure in the literature (Tetrahedron Lett. 2005, 46, 6363). A 1 L three-neck round-bottom flask was equipped with a mechanical stirrer, thermocouple, nitrogen inlet, and drying tube and placed in a heating mantle. The flask was charged with N-(4-iodo(3-pyridyl))-2,2-dimethylpropanamide (43, 45 g) and 25percent sulfuric acid (270 mL). The solubility of starting material in 25percent sulfuric acid was very high and formed light yellow clear solution. The reaction mixture was heated to 80° C. for 8 h. The reaction mixture was stirred continually at 80° C. until deemed to be complete, i.e., upon complete disappearance of starting material (N-(4-iodo(3-pyridyl))-2,2-dimethylpropanamide, 43). If reaction was not complete, stirring was continued at 80° C. for additional 6 h then monitored again, and repeated until complete. Typically, reaction was complete within 4-6 h. The reaction was monitored by TLC (SiO2, 100percent EtOAc, UV) by partitioning an aliquot of reaction mixture (1 mL) between 50percent NaOH solution (2 mL) and EtOAc (4 mL), agitating, allowing the layers to separate, and spotting the organic layer on TLC. The starting material (N-(4-iodo(3-pyridyl))-2,2-dimethylpropanamide, 43) had an RF of 0.55, and the product (4-iodo-3-pyridylamine, 44) had an RF of 0.35. Materials used to synthesize 4-iodo-3-pyridylamine (44) are shown in Table 35.To isolate the product (4-iodo-3-pyridylamine, 44), the flask was cooled to -10° C. and the mixture was cautiously basified (pH 10-11) with 50percent NaOH solution (45 g) while maintaining a temperature below 10° C. Additional ethyl acetate (200 mL) was added, the reaction was stirred for 10 minutes, and the layers were allowed to separate. The organic layer was collected, and the aqueous layer was extracted with ethyl acetate (2.x.50 mL). The combined organic layer was dried over MgSO4 and charcoal, filtered through a glass fiber filter paper, and concentrated to dryness. The residue was diluted with MTBE (50 mL) and the solids were filtered, rinsing with MTBE (10 mL). The product was air-dried for 2 h and then dried under high vacuum at room temperature to constant weight.4-Iodo-3-pyridylamine (44, lot No. 1358-86-1) was an off-white solid, synthesized with a yield of 24 g (75percent). 4-Iodo-3-pyridylamine (44) was analyzed using HPLC (PLX-LC3, 220), and according to results, it was 100percent pure. 1H-NMR (300 MHz, CDCl3) was used to confirm the identity of 4-iodo-3-pyridylamine (44).
Reference：
[1] Journal of Medicinal Chemistry, 2007, vol. 50, # 26, p. 6519 - 6534
[2] Patent: WO2006/86609, 2006, A2, . Location in patent: Page/Page column 154
[3] Patent: EP1595881, 2005, A1, . Location in patent: Page/Page column 57
[4] Journal of Heterocyclic Chemistry, 1994, vol. 31, # 1, p. 11 - 16
[5] Tetrahedron Letters, 2004, vol. 45, # 46, p. 8569 - 8573
[6] Patent: US2009/306121, 2009, A1, . Location in patent: Page/Page column 25-26; sheet 16
[7] Patent: WO2006/86609, 2006, A2, . Location in patent: Page/Page column 155
[8] Dalton Transactions, 2011, vol. 40, # 16, p. 4217 - 4222
[9] Patent: US2012/232051, 2012, A1, . Location in patent: Page/Page column 61
[10] Patent: WO2012/117000, 2012, A1, . Location in patent: Page/Page column 128
[11] Chemistry - A European Journal, 2012, vol. 18, # 51, p. 16358 - 16368
5
[ 239137-39-4 ]
[ 105752-11-2 ]
Reference：
[1] Chemistry and Biology, 2009, vol. 16, # 12, p. 1225 - 1229
Into a 100-mL round-bottom flask, was placed 4-iodopyridin-3 -amine (2 g, 9.09 mmol, 1.00 equiv), Boc20 (2.4 g, 1 1.00 mmol, 1.21 equiv), 4-dimethylaminopyridine (1 g, 8.19 mmol, 0.90 equiv), dichloromethane (50 mL). The resulting solution was stirred for 1 overnight at room temperature. The resulting solution was extracted with of ethyl acetate and the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (I : 10). This resulted in 1.9 g (65percent) of the title compound as an off- white solid. Analytical Data: LC-MS: (ES, m/z): RT = 0.719min, LCMS45 : m/z =321 [M+l].
iV-(4-Iodo-pyridin-3-yl)-2,2-dimethyl-propionamide (20.00 g, 65.76 mmol) was charged to a 2 L round-bottom flask and 24% sulfuric acid in water (640 mL) was added carefully. The mixture was heated to 100 C for 4 hours. The reaction was determined complete by analyitical HPLC. The mixture was allowed to cool to room temperature and then carefully adjusted to pH 7-8 with 4Nu NaOH (approximately 700 mL). Saturated sodium bicarbonate was added to the mixture and the product extracted into dichloromethane (3 X 500 mL). The organic layers were combined and concentrated to give 3-amino-4-iodo- pyridine (13.3 g, 92%).
90%
With sulfuric acid; In water; for 1h;Heating / reflux;
The product of preparation 22 (4.69g, 15.4mmol) and dilute sulphuric acid (24%, 120mL) were heated under reflux for 1 hour. The mixture was then cooled, basified with solid sodium hydrogen carbonate to pH8 and extracted with dichloromethane (3x200mL). The combined organic solutions were dried over magnesium sulfate and concentrated in vacuo. Purification of the residue by column chromatography on silica gel, eluding with dichloromethane:methanol, 100:0 to 90:10, afforded the title compound as a brown solid in 90% yield, 3.04g. 1H-NMR(CDCl3, 400MHz) delta: 4.11 (bs, 2H), 7.56(d, 1H), 7.61 (d, 1H), 8.05(s, 1H) MS APCI+ m/z 221 [MH]+
75%
The reaction was performed according to a procedure in the literature (Tetrahedron Lett. 2005, 46, 6363). A 1 L three-neck round-bottom flask was equipped with a mechanical stirrer, thermocouple, nitrogen inlet, and drying tube and placed in a heating mantle. The flask was charged with N-(4-iodo(3-pyridyl))-2,2-dimethylpropanamide (43, 45 g) and 25% sulfuric acid (270 mL). The solubility of starting material in 25% sulfuric acid was very high and formed light yellow clear solution. The reaction mixture was heated to 80 C. for 8 h. The reaction mixture was stirred continually at 80 C. until deemed to be complete, i.e., upon complete disappearance of starting material (N-(4-iodo(3-pyridyl))-2,2-dimethylpropanamide, 43). If reaction was not complete, stirring was continued at 80 C. for additional 6 h then monitored again, and repeated until complete. Typically, reaction was complete within 4-6 h. The reaction was monitored by TLC (SiO2, 100% EtOAc, UV) by partitioning an aliquot of reaction mixture (1 mL) between 50% NaOH solution (2 mL) and EtOAc (4 mL), agitating, allowing the layers to separate, and spotting the organic layer on TLC. The starting material (N-(4-iodo(3-pyridyl))-2,2-dimethylpropanamide, 43) had an RF of 0.55, and the product (4-iodo-3-pyridylamine, 44) had an RF of 0.35. Materials used to synthesize 4-iodo-3-pyridylamine (44) are shown in Table 35.To isolate the product (4-iodo-3-pyridylamine, 44), the flask was cooled to -10 C. and the mixture was cautiously basified (pH 10-11) with 50% NaOH solution (45 g) while maintaining a temperature below 10 C. Additional ethyl acetate (200 mL) was added, the reaction was stirred for 10 minutes, and the layers were allowed to separate. The organic layer was collected, and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layer was dried over MgSO4 and charcoal, filtered through a glass fiber filter paper, and concentrated to dryness. The residue was diluted with MTBE (50 mL) and the solids were filtered, rinsing with MTBE (10 mL). The product was air-dried for 2 h and then dried under high vacuum at room temperature to constant weight.4-Iodo-3-pyridylamine (44, lot No. 1358-86-1) was an off-white solid, synthesized with a yield of 24 g (75%). 4-Iodo-3-pyridylamine (44) was analyzed using HPLC (PLX-LC3, 220), and according to results, it was 100% pure. 1H-NMR (300 MHz, CDCl3) was used to confirm the identity of 4-iodo-3-pyridylamine (44).
3-(tert-Butylcarbonylamino)-4-iodo-pyridine (20.00 g, 65.76 mmol) was charged to a 2 L round-bottom flask, and sulfuric acid, 24% in water (640 mL) was carefully added. The reaction was heated to 100 0C. After 4 hours, the reaction was shown to be complete as determined by HPLC. After cooling to room temperature, the solution was carefully neutralized with 4 M NaOH until a pH of 7-8 was achieved. Saturated bicarbonate was added to the reaction mixture, and the product extracted into dichloromethane (3 X 500 mL). The organic layers were combined and concentrated to give 13.3 g of 3-amino-4-iodo-pyridine.
A solution of N-(4-iodo-pyridin-3-yl)-2,2-dimethyl-propionamide (6 g, 19.73 mmol) in aqueous 3M HCl (50 mL) was heated to 100 C. for 18 hours. After the completion of reaction, the reaction mass was washed with EtOAc. Under cooling the pH of the aqueous layer was adjusted to pH 9 using solid Na2CO3 and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford 4-iodo-pyridin-3-ylamine (3.2 g crude, 73%) as a brown sticky solid that was used in the next step without further purification.
A solution of N-(4-iodo-pyridin-3-yl)-2,2-dimethyl-propionamide (6 g, 19.73 mmol) in aqueous 3M HC1 (50 mL) was heated to 100 C for 18 hours. After the completion of reaction, the reaction mass was washed with EtOAc. Under cooling the pH of the aqueous layer was adjusted to pH 9 using solid Na2C03 and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2S04, filtered, and concentrated in vacuo to afford 4-iodo-pyridin-3-ylamine (3.2g crude, 73%) as a brown sticky solid that was used in the next step without further purification.
With sodium carbonate; lithium chloride;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; at 90℃; for 24h;
IN a pressure tube, a solution of iodopyridine (1.80 g, 8.18 mmol) in 20 mL OF DMF was treated with 2-butyne (1.5 mL, 19.1 mmol), Pd (DPPP2CL2CH2CL2 (357 mg, 0.438 mmol), lithium chloride (367 mg, 8. 71 mmol), and sodium carbonate (1. 82 g, 17.2 mmol). The tube was sealed and heated to 90 C. After 24 hours, the tube was cooled and opened. The resulting mixture was diluted with 20 mL of ethyl acetate and 20 mL of saturated aqueous ammonium chloride solution. The phases were separated and the aqueous layer was extracted with three 50 mL portions of ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (CH2C12 to 10% MeOH in CH2C12, gradient) afforded the title product as a brown solid (920 mg, 77% yield).
With triethylamine;palladium diacetate; tris-(o-tolyl)phosphine; In DMF (N,N-dimethyl-formamide); at 80℃; for 3h;
The product of preparation 23 (1.1g, 5mmol), ethyl acrylate (0.65mL, 6mmol), palladium acetate (112mg, 0.5mmol), tri-(O-tolyl) phosphine (3.04mg, 1mmol), triethylamine (0.84mL, 6mmol) and N,N-dimethylformamide (10mL) were mixed together and heated at 80C for 3 hours. The reaction mixture was then cooled to 25C and was partitioned between ethyl acetate (20mL) and water (20mL). The phases were separated and the aqueous phase was extracted with ethyl acetate (20mL). The combined organic solutions were washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluding with dichloromethane:methanol, 100:0 to 95:5, to afford the title product as a dark brown oil in 67% yield, 648mg. 1H-NMR(CDCl3, 400MHz) delta: 1.34(t, 3H), 3.96(bs, 2H), 4.28(q, 2H), 6.48(d, 1H), 7.18(d, 1H), 7.70(d, 1H), 8.03(d, 1H), 8.15(s, 1H) MS APCI+ m/z 193 [MH]+
57%
With palladium diacetate; N-ethyl-N,N-diisopropylamine; tris-(o-tolyl)phosphine; In N,N-dimethyl-formamide; at 85℃; for 12h;Inert atmosphere;
To a mixture of <strong>[105752-11-2]4-iodopyridin-3-amine</strong> (40 g, 182 mmol) and ethyl acrylate (27 g, 272 mmol) in DMF (300 mL), DIPEA (28 g, 218 mmol) was added. Then Pd(OAc)2 (4 g, 18 mmol) and P(o-tol)3 (11 g, 36 mmol) were added quickly under N2 atmosphere. The mixture was stirred at 85 C for 12 h under N2 atmosphere. After cooling down, the solvent was removed under reduced pressure. The residue was purified by silica gel column (DCM/ MeOH = 20/1) to give ethyl (E)-3-(3-aminopyridin-4-yl)acrylate (20 g, yield: 57%) as a yellow oil. ESI-MS (M+H): 193.1. ?H NMR (400 MHz, CDC13) (5: 8.15 (s, 1H), 8.02-7.98 (m, 1H), 7.72 (d, J= 16.4 Hz, 1H), 7.18 (d, J= 5.2 Hz, 1H), 6.48 (d, J= 16Hz, 1H), 4.27 (q, J= 7.2 Hz, 2H), 4.07 (s, 2H), 1.34 (t, J= 7.2Hz, 3H).
3-Amino-4-iodo-pyridine (15.0 g, 68.2 mmol) was charged to a 1 L round-bottom flask and then dichloromethane (200 mL) and triethylamine (21.1 mL, 152 mmol) were added. The mixture was cooled to 5 0C in an ice bath and methanesulfonyl chloride (11.61 mL, 17.18 g) was added via an addition funnel. The reaction was determined greater than 95% after 30 minutes by analytical HPLC. The mixture was quenched with saturated NH4Cl (300 mL) and extracted with ethyl acetate (1 L). The organic layer was filtered through a silica gel plug with ethyl acetate as eluant and concentrated to give crude 4-iodo-3-(fos- methylsulfonylammo)-pyridine (25.0 g, 97%) which was used in the next step without purification. 1H NMR (400 MHz, DMSO) delta 8.25 (d, IH, J= 5.5 Hz), 8.07 (d, IH, J= 0.8 Hz), 7.68 (dd, IH, J= 0.8, 5.5 Hz )
With sodium carbonate; lithium chloride;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In N,N-dimethyl-formamide; at 100℃; for 24h;
To triethylsilylcyclohexylacetylene (1.36 g, 6.20 mmol) synthesized as described in Tet. Lett. 41: 907 (2000) and <strong>[105752-11-2]4-iodo-pyridin-3-ylamine</strong> (1.62 g, 2.27 mmol) in anhydrous DMF (62 mL) was added Pd(dppf)Cl2-CH2Cl2 (253 mg, 0.31 mmol) followed by anhydrous LiCl (263 mg, 6.20 mmol) and Na2CO3 (1.31 g, 12.40 mmol). The reaction mixture was heated to 100 C. for 24 h after which the reaction was diluted with H2O and EtOAc and filtered over celite. The organics were separated, washed with saturated aqueous NaHCO3, and dried over sodium sulfate. After removal of solvent, the crude product was purified by column chromatography on silica (3:2 ethyl acetate/hexanes) to provide 590 mgs (30%) of desired product
With potassium phosphate;bis-triphenylphosphine-palladium(II) chloride; In 1,4-dioxane; water; at 95℃;Inert atmosphere;
A 1 L three-necked round-bottomed flask was equipped with a mechanical stirrer, thermometer, glass immersion tube for bubbling nitrogen, reflux condenser connected to a bubbler with silicone or mineral oil to monitor that a positive pressure of nitrogen was maintained in the reaction flask throughout the synthesis, and a heating mantle. The flask was charged with <strong>[105752-11-2]3-amino-4-iodopyridine</strong> (44, 12.5 g), 5-chloro-2-propoxy-4-pyridinylboronic acid (45, 18.4 g), and dioxane (538 mL). Stirring was initiated. The resulting yellow solution was degassed by bubbling an intensive stream of nitrogen through the mixture for 10 minutes. Bubbling of nitrogen was maintained throughout the entire synthesis. A solution of K3PO4 (36.18 g) and water (175 mL) was charged. The resulting solution was degassed by bubbling an intensive stream of nitrogen through the mixture for 10 minutes. PdCl2(PPh3)2 (4 g) was charged. The nitrogen flow was reduced, and the resulting orange color solution was heated to reflux (at approximately 95 C.) with bubbling of nitrogen. The reaction mixture was stirred at reflux for a minimum of 24 hours. The reaction mixture was continued to be stirred at 95 C. until the reaction was deemed to be complete, i.e., when <10% starting material was observed by TLC. If reaction was not complete, stirring was continued at 80 C. for an additional 6 h. Typically, reaction was complete within 24 h. The reaction was monitored by TLC (SiO2, [5:95], MeOH:DCM:2-3 drops of aqueous NH3, UV, three developments) by spotting an aliquot of reaction mixture directly on a TLC plate at various time points. The starting material had an RF of 0.45, while the product had an RF of 0.5, which was a fluorescent spot. The materials used to synthesize 4-(5-Chloro-2-propoxy-4-pyridyl)-3-pyridyl amine (46) are shown in Table 36. To isolate the product (4-(5-chloro-2-propoxy-4-pyridyl)-3-pyridyl amine, 46), the reaction mixture was cooled to 40 C. The reaction mixture was concentrated under reduced pressure at 40 C. to remove the majority of dioxane. The residue was diluted with water (125 mL) and EtOAc (300 mL), and the mixture was stirred at ambient temperature for 20 minutes. The reaction mixture was transferred to a separation funnel, the layers were allowed to separate, and the aqueous layer was extracted with EtOAc (2×100 mL). The organic layers were combined, washed with brine (200 mL), dried over MgSO4 and charcoal, and filtered through a glass fiber filter. The filtrate was concentrated under vacuum to dryness (semi-solid, 30 g). The crude semisolid was loaded on top of a silica plug (300 g) packed with DCM, using further DCM for loading. The column was eluted under gravity sequentially with DCM (1 L), 0.5% MeOH in DCM (0.5 L), 1% MeOH in DCM (0.5 L), and 1.5% MeOH in DCM (3 L) and collecting fractions of 3 L. Increasing the methanol percentage in small increments helped facilitate effective purification. The column was eluted under gravity with 2% MeOH in DCM until complete removal of the clean product was observed by TLC analysis. All fractions containing clean product were combined and concentrated under reduced pressure to give an off-white solid.4-(5-Chloro-2-propoxy-4-pyridyl)-3-pyridyl amine (46, lot No. 1458-20-1) was an off-white solid, synthesized with a yield of 7.6 g (51%). 4-(5-Chloro-2-propoxy-4-pyridyl)-3-pyridyl amine (46) was analyzed using HPLC (PLX-LC3, 220), and according to results, it was 96% pure. 1H-NMR (300 MHz, CDCl3) was used to confirm the identity of 4-(5-chloro-2-propoxy-4-pyridyl)-3-pyridyl amine (46).
With copper(l) iodide; trans-bis(triphenylphosphine)palladium dichloride; triethylamine; In 1,4-dioxane; N,N-dimethyl-formamide; at 70℃; for 1h;
Step 1: 4-[(2-fluorophenyl)ethvnyl]pyridin-3-amineTo a solution of <strong>[105752-11-2]3-amino-4-iodopyridine</strong> in Dioxane/DMF (1 :1, 0.7M) were sequentially added NEt3 (5eq.), CuI (0.04 eq.), trans-bis(triphenylphosphine) palladium(II) chloride (0.02 eq.) and l-ethynyl-2-fluorobenzene (2 eq.). After heating for 1 h at 70 0C, water was added and the mixture was extracted with Et2O. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel, eluting with PE/EtOAc (50:50), affording the title compound(80%) as a solid. 1H NMR (400 MHz, OMSO-d6 + TFA, 300K) delta, 7.26-7.33 (dd, 2H, J = 7.6 Hz, J= 8 Hz), 7.52-7.53 (m, IH), 7.78 (d, IH, J= 8 Hz), 7.83 (t, IH, J= 6.4 Hz), 7.7 (d, IH, J= 5.6 Hz), 8.21 (s, IH); MS (ES+) m/z 213 (M +H)+.
A mixture of 4-bromo-pyridin-3-ylamine (2 g, 11.56 mmol, CAS RN 239137-39-4) in trimethyl orthoformate (19 mL, 173.4 mmol, CAS RN 149-73-5) and a catalytic amount of TFA (1 drop) was heated to reflux for 2 hours. Volatiles were removed in vacuo, the resultant dark brown material was dissolved in THF (40 mL), treated portionwise with LiAlH4 (440 mg, 11.56 mmol) at 0 C. and then left stirring at 0 C. for 30 minutes. The reaction mixture was quenched with saturated aqueous NH4Cl solution (15 mL), filtered through a bed of celite, and the residue further washed with EtOAc (30 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and evaporated off in vacuo. The residue was purified by column chromatography over alumina (10% EtOAc in n-hexane) to afford the title compound. Light yellow oil (875 mg, 40%). MS (ESI): m/z=187.2 [M+H]+.
A dry 100 mL Schlenk-type flask was charged with a suspension of zinc (5g/0.1 L suspension in THF, 16.37 mL, 12.44 mmol, Rieke Metals Inc.). This material was treated with a solution of 4-iodo-5- methylisoxazole (2.0 g, 9.57 mmol, Maybridge Chemical Co.) dissolved in dry THF (5 mL). The slurry was stirred for 96 h at RT under an Ar atmosphere. The slurry was charged to a dry, 100 mL stainless steel N2 pressure filtration apparatus fitted with a 0.22 muiotaeta PTFE syringe filter. A dry, 100 mL, one neck round bottom flask was charged with <strong>[105752-11-2]3-amino-4-iodopyridine</strong> (1.92 g, 8.73 mmol, Alfa Aesar) (vacuum dried at RT for 96 h), a stirbar, A-Phos (1.02 g, 1.44 mmol, Sigma-Aldrich) and THF (20 mL). The flask was fitted with a septa/ Ar inlet pierced with a PTFE addition needle. The system was briefly flushed with Ar (the end of the PTFE addition needle was left open). The PFTE addition needle was then fitted to the outlet of the syringe filter/pressure filtration device. The slurry was N2-pressure filtered into the 100 mL round bottom flask over a 5 h period. The reaction was stirred at RT overnight. A second batch of organic zinc reagent was synthesized as described above (4-iodo-5-methyl-isoxazole (3.0 g, 14.36 mmol, Maybridge Chemical Co.), zinc (5 g/ 0.1L suspension in THF, 25.2 mL, 19.14 mmol, Rieke Metals Inc.) and stirred for 2 h at RT. This slurry was added using the pressure filtration device described above over a 3 h period. The reaction was cautiously poured onto a stirring, N2 covered, 0.56 M solution of EDTA (pH adjusted to 7.6 with LiOH) (177 mL, 96 mmol, MP Biomedical). The mixture was concentrated under a stream of N2 to remove most of the THF. The mixture was extracted with 1% 1,1, 1-3,3, 3-hexafluoro- 2-propanol in CHCI3 (4 x 100 mL), and the combined extraction volume was washed with 5% NaHC03 (1 x 50 mL). The organic phase was passed through an unbuffered, Varian Chem Elute (CE1020). The solvent was removed in vacuo, and the residue was transferred to a 500 mL, one neck, round bottom flask. The flask was charged with dry THF (150 mL), Si-TAAcONa (0.49 mmol/g loading, 13.0 g, 6.37 mmol, Silicycle), and a stirbar. The flask was fitted with a reflux condenser/ Ar inlet and heated at 60 C overnight. The slurry was cooled, and the solvent was removed in vacuo. The powder was further dried under vacuum at 45 C for 2 h (final pressure = 0.5 mm Hg). The reddish powder was loaded into a 25 x 300 mm column with 10 muetaiota PTFE support bed. The silica was eluted with CHCI3 (250 mL) and dry THF (250 mL). The total elution volume was combined, and the solvent was removed in vacuo. The residue was purified by silica gel chromatography (11% EtOH in CHC13) to afford 4-(5-methylisoxazol-4- yl)pyridin-3 -amine (1.12 g, 6.38 mmol, 67 % yield). MS (ESI, pos. ion) m/z: 176.0(M+l). .H NMR (400 MHz, THF-d8) delta ppm 2.40 (d, J=0.78 Hz, 3 H) 4.66 (br. s., 2 H) 6.88 (dd, J=4.89, 0.59 Hz, 1 H) 7.84 (d, J=4.70 Hz, 1 H) 8.07 (d, J=0.39 Hz, 1 H) 8.36 (q, J=0.60 Hz, 1 H).
With sodium acetate;bis[di-t-butyl(p-dimethylaminophenyl)phosphino]palladium (II) Dichloride; bis[di-tert-butyl-(4-dimethylaminophenyl)phosphine]palladium (II) dichloride; In 1,4-dioxane; water; at 120℃; for 1.5h;Sealed tube; microwave irradiation;
A 10 mL CEM microwave vessel was charged with <strong>[105752-11-2]3-amino-4-iodopyridine</strong> (139 mg, 0.63 mmol, Alfa Aesar), 3,6-dihydro-2H-pyridine-l-A^-boc-4-boronic acid pinacol ester (236 mg, 0.76 mmol, Frontier Scientific Inc.), NaOAc (155 mg, 1.90 mmol) and a stirbar. The vessel was sealed, and transferred into a glove box using a standard antichamber evacuate-refill cycle (3 times). The vessel was charged with A-Phos (45 mg, 0.063 mmol, Sigma-Aldrich), and sealed. The vessel was then transferred to a standard hood, and treated with dioxane (4 mL), and water (0.4 mL). The slurry was sonicated and was then heated in a microwave using a CEM explorer at 120 C for 30 min. The solution was treated with a second aliquat of 3,6-dihydro-2H-pyridine-l-A x>c-4-boronic acid pinacol ester (236 mg, 0.76 mmol, Frontier Scientific Inc.) and was then heated in a microwave using a CEM explorer at 120 C for 30 min The solution was treated with dichlorobis(di-?er?-butylphenylphosphine)palladium(II) (20 mg, 0.032 mmol, Alfa Aesar) and was then heated in a microwave using a CEM explorer at 120 C for 30 min. The solution was cooled to RT overnight under a stream of N2. The residue was treated with dry THF (5 mL) and SiliaMetS TAAcOH (1.29 g, 0.63 mmol, Silicycle). The vessel was crimped with a PTFE lined seal, and heated at 60 C for 3 h. The slurry was N2- pressure filtered through a glass frit (10 mL Bohdan) fitted with a 0.22 muiotaeta PTFE, 25 mm syringe filter unit (Millipore, SLFG025NK). The silica was washed with dry THF (5 x 5 mL), and concentrated in vacuo. The crude material was purified by silica gel chromatography (10% EtOH in DCE) to afford teri-butyl 3'-amino-5,6-dihydro-[4,4'- bipyridine]-l(2H)-carboxylate (77 mg, 0.28 mmol, 44 % yield). MS (ESI, pos. ion) m/z: 276.0 (M+l).
bis[di-tert-butyl-(4-dimethylaminophenyl)phosphine]palladium (II) dichloride; In tetrahydrofuran; at 20℃; for 48h;Inert atmosphere;
A dry, 50 mL, one neck round bottom flask was charged with freshly sublimed <strong>[105752-11-2]3-amino-4-iodopyridine</strong> (1.17 g, 5.32 mmol, Alfa Aesar), A-Phos (565 mg, 0.80 mmol), and a stirbar in a glove box. The flask was sealed with a septa, and moved to a standard fume hood. The septa was pierced with an Ar inlet, and the solids were treated with a 0.61 M THF solution of (3,5- dimethylisoxazol-4-yl)zinc(II) iodide (3.83 g, 13.29 mmol), The reaction was stirred at RT for 48 h. The reaction was carefully poured onto an aqueous 0.54 M EDTA, pH adjusted to 7.6 with LiOH (29.5 ml, 15.95 mmol, MP Biomedicals) solution. The transfer was quantitated with dry THF (3 x 20 mL). The mixture was stirred for 1 h, and the bulk of organic solvent was removed using a rotary evaporator. The aqueous mixture was extracted with 1% l,l,l,3,3,3-hexafluoro-2-propanol in CHCI3 (4 x 60 mL) and each extract was sequentially passed through an unbuffered Varian Chem Elut (CEIOIO). The total elution volume was concentrated in vacuo. The residue was transferred to a 100 mL round bottom flask, and treated with SiliaMetS TAAcOH (0.49 mmol/g loading, 10.85 g, 5.32 mmol, Silicycle). The flask was then charged with dry THF (40 mL), and a stirbar. The flask was fitted with a reflux condenser/ Ar inlet and heated at 70 C for 1 h. The solution was cooled over a 30 minute period, and the solvent was removed in vacuo. The powder was further dried at reduced pressure overnight (final pressure = 0.10 mm Hg). The silica was loaded onto a silica gel column and the crude material was purified by silica gel chromatography (10% EtOH in DCE). The crude material was treated wtih acetone (5 mL), and stirred in an ice-water bath. The slurry was N2-pressure filtered through a glass frit (10 mL Bohdan) fitted with a 0.22 muiotaeta PTFE, 25 mm syringe filter unit (Millipore, SLFG025NK). The solids were washed with cold acetone (3 x 2 mL) and discarded. The solvent was removed under reduced pressure, and the oily residue was dried at RT and 0.1 mm Hg vacuum for 2 h to afford 4-(3,5-dimethylisoxazol-4- yl)pyridin-3-amine (1.15 g, 6.08 mmol, 114 % yield). MS (ESI, pos. ion) m/z: 190.1 (M+l).
With copper(l) iodide; (R,R)-N,N'-dimethyl-1,2-diaminocyclohexane; caesium carbonate; In 1,4-dioxane; at 100℃;Inert atmosphere;
General procedure: a suspension of 3-iodo-4-aminopyridine (1 mmol), methyl 2-mercaptoacetate (1.5 equiv), copper (I) iodide (0.05 mmol), trans-N,N'-dimethylcyclohexane-1,2-diamine (0.1 mmol) and cesium carbonate(2 equiv) in dry 1,4-dioxane (4 mL) in a vial was degassed by bubbling N2 into the suspension for 3 min while stirring. The vial was then capped tightly. The mixture was heated at 100 C (oil bath temperature) for 15 h. After coolingto rt, filtration was carried out. The combined filtrates were concentrated on rotavap and the residue was subjected to silica gel column chromatographpurification (5% methanol in methylene chloride) furnishing 3b as a beige solid.
N-(4-iodopyrid-3-yl)-2-nitroisonicotinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 20h;
N-(4-iodopyrid-3-yl)-2-nitroisonicotinamideA 100 mL round-bottomed flask was charged with 2-nitroisonicotinic acid (0.545 g, 3.24 mmol) in methylene chloride (12 mL) to give a white suspension, dimethylformamide (0.025 mL, 0.324 mmol) was added, followed by oxalyl chloride (0.312 mL, 3.57 mmol) (addeddropwise under nitrogen). The solids dissolved within 20 min and the mixture became a tan solution. After stirring at rt for 40 min, LCMS showed complete conversion to the acid chloride (as methyl ester). 4-iodopyridin-3 -amine (0.856 g, 3.89 mmol) was suspended in 10ml methylene chloride and cooled at 0 C. The acid chloride solution was slowly added by canuulation, followed by addition of Hunig's base (1.132 mL, 6.48 mmol). The resulting mixture was stirred at it for 20 h, It was diluted with water and ethyl acetate. The gray solid (0.569 g) was filtered and proved to be the desired product by LCMS. The layers were separated. The organic layer was washed with brine, dried and concentrated. The residue was purified using silica gel flash chromatography, eluting with 50% ethyl acetate hexane. The combined product (0.699 g, 58%) was used without further purification: MS (ESI) (m/z): 371 (M+H)+.
2-(cyclopropanecarboxamido)-N-(4-iodopyridin-3-yl)isonicotinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
Example 192-(cyclopropanecarboxamido)-N-(4-iodopyridin-3-yl)isonicotinamideA 250 mL round-bottom flask was charged with 2-(cyclopropanecarboxamido)isonicotinic acid (776.5 mg, 3.77 mmol) in methylene chloride (30 mL) to give a white suspension. After cooling to 0 C, dimethylformamide (0.029 mL, 0.377 mmol) and oxalyl chloride (0.363 mL, 4.14 mmol) were added. The mixture was stirred at 0 C for 2 h. 4-Iodopyridin-3-amine (829 mg, 3.77 mmol) was added at 0 C, followed by triethylamine (2.1 mL, 15.06 mmol). The mixture became homogenous. It was then concentrated to give a tan oil. The residue was purified by flash column chiOmatography on silica gel, eluting with 0 - 10% methanol/methylene chloride (containing 1% acetic acid), giving a tan solid (100%) which was used without further characterization.
4-(3,6-dihydro-2H-pyran-4-yl)pyridin-3-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
8%
With potassium phosphate; chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) methyl tert-butyl ether; In 1,4-dioxane; water; at 80℃; for 2.5h;
4-(3,6-Dihydro-2H-pyran-4-yl)pyridin-3-amine. The mixture of 4-iodopyridin-3- amine (0.316 g, 1.437 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (0.3019 g, 1.437 mmol), XPhos precatalyst (0.045 g, 0.057 mmol) and Phosphoric acid, potassium salt (0.5 M aq) (5.75 mL, 2.87 mmol) in dioxane (3.0 mL) was heat at 80 C for 2.5 hours. The reaction was cooled to room temperature and diluted with ethyl acetate. The organic layer was washed with water three times before dried (Na2S04), filtered and concentrated. The product was purified by flash column eluted with ethyl acetate in hexane from 0 to 100% and eluted with 100% of ethyl acetate until the purple fraction (desired product ) was eluted out (0.020g, 8% yield). 1H NMR (400MHz, CHLOROFORM-d) 5 8.10 (s, IH), 8.00 (d, J=5.0 Hz, IH), 6.90 (d, J=5.0 Hz, IH), 5.97 (dt, J=3.0, 1.3 Hz, IH), 4.32 (q, J=2.8 Hz, 2H), 3.95 (t, J=5.4 Hz, 2H), 3.83 (br. s., 2H), 2.45 - 2.38 (m, 2H). MS(ES+) m/e 177 [M+H]+.
With potassium phosphate; chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) methyl tert-butyl ether; In tetrahydrofuran; water; at 20℃; for 24h;
4-(Cyclohex-l-en-l-yl)pyridin-3-amine.The mixture of 4-iodopyridin-3 -amine (0.161 g, 0.734 mmol),cyclohex-l-en-l-ylboronic acid (0.0924 g, 0.734 mmol), XPhos precatalyst (0.023g, 0.029 mmol), Phosphoric acid, potassium salt (2M aq) (0.550 mL, 1.100 mmol)in THF (3.0 mL) was stirred at room temperature for 24 hours. The reaction wasdiluted with ethyl acetate and washed with water three times. The ethyl acetatelayer was separated, dried (Na2SC"4), filtered and concentrated. Flashcolumn eluted with ethyl acetate in hexane from 0 to 100% gave the desiredproduct (33 mg, 25% yield). MS(ES+) m/e 175 MS[M+H]+; 1H NMR (400MHz,CHLOROFORM-d) delta 8.06 (s, 1H), 7.95 (d, J=5.0 Hz, 1H), 6.89 - 6.85 (m, 1H), 5.86(dt, J=3.8, 1.9 Hz, 1H), 3.80 (br. s., 2H), 2.26 - 2.15 (m, 4H), 1.81 - 1.74(m, 2H), 1.73 - 1.64 (m, 2H).
3-(2-(benzyloxy)ethyl)-2-(trimethylsilyl)-1H-pyrrolo[2,3-c]pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
2.5 g
A reselable pressure tube was charged with 4-iodopyridin-3 -amine (2.3 g, 10.5 mmol), (4-(benzyloxy)but-l-yn-l-yl)trimethlysilane (6.1 g, 26.1 mmol), lithium chloride (0.44 g, 10.5 mmol), sodium carbonate (2.21 g, 20.9 mmol) and 1,1 '- bis(diphenylphosphino)ferrocenopalladium(II) dichloride, toluene (0.43 g, 0.52 mmol), the tube was sealed and heated on a 100 C oil bath for ~20h. The reaction mixture was cooled to ambient temperature, diluted with EtOAc (75 mL) and ether (75 mL). Water (150 mL) was added and the biphasic mixture was filtered through celite. The filtrate was transferred to a separatory funnel and the phases were separated and the aqueous fraction extracted twice more with ethyl acetate. The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered and evaporated. The crude was purified by silica gel chromatography, eluting with 5-20% (9: 1 MeOH/NH40H)/chloroform, affording 3- (2-(benzyloxy)ethyl)-2-(trimethylsilyl)-lH-pyrrolo[2,3-c]pyridine, as a mixture with some of the de-silylated regioisomer (4 g, 118% yield, contains some residual DMF). LCMS method A: retention time of major component = 4.08 min, M+H = 325.5. The mixture was dissolved in THF (100 mL) and treated with TBAF (12.3 mL of a 1.0M solution in THF, 12.3 mmol) at room temperature for ~lh. No change was observed by TLC. The mixture was evaporated and re-purified by silica gel chromatography under the same conditions as before to afford 3-(2-(benzyloxy)ethyl)-2- (trimethylsilyl)-lH-pyrrolo[2,3-c]pyridine, essentially free of the regioisomer (2.5 g, 63% yield). 1H NMR (400MHz, CHLOROFORM-d) delta = 8.80 (s, 1H), 8.44 - 8.32 (m 1H), 8.22 (d, J=5.5 Hz, 1H), 7.58 - 7.47 (m, 1H), 7.41 - 7.30 (m, 5H), 4.56 (s, 2H), 3.69 (t, J=7.7 Hz, 2H), 3.18 (t, J=7.7 Hz, 2H), 0.42 (s, 9H).
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