* 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.
With N-chloro-succinimide In N,N-dimethyl-formamide at -20 - 20℃; for 24 h;
5.2.2.30 7,8-Dichloro-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (30) To a solution of 2-amino-4-chloropyridine (1.28 g, 10.0 mmol) in DMF (40 mL) at -20 °C was added NCS (2.67 g, 20.0 mmol). This mixture was allowed to warm to room temperature and stirred for 24 h, and then poured into 300 mL ice-water and extracted with ethyl acetate. The extracts were washed with 1 M NaOH and brine, dried and evaporated. The residue was purified by column chromatography on silica gel to give 4,5-dichloropyridin-2-amine (1.12 g, 69.0percent).
66%
With N-chloro-succinimide In ethyl acetate at 20℃; for 28 h;
INTERMEDIATE 1 4,5-Dichloropyridin-2-amine To a solution of 4-chloropyridine-2-amine (50.00 g, 0.389 mol) in EtOAc (400 mL) was added N-chloro succinimide (53.50 g, 0.401 mol) in one portion. The mixture was stirred over night (28 h) at room temperature, and was then filtered to remove precipitated succinimide. The filtrate was washed with aqueous 0.5M NaOH (8x50 mL), water (2x50 mL) and brine (2x50 mL). The organic phase was dried (Na2S04), filtered and evaporated to furnish 59.4 g of crude light brown powder after vacuum drying. The dry isolated crude (with a purity of ca. 75percent of the title compound) was slurried in hexane (800 mL) and stirred at reflux temperature for 15 min. The mixture was allowed to cool to 35 °C and was then filtered using a G3 glass frit filter. The filter cake was washed with hexane (ca. 200 mL) and dried on the filter to furnish 42.1 g (66percent>) of brown solid. The product was pure enough (96percent>) to be taken to the next step. 1H NMR (600 MHz, DMSO-d6) δ ppm 8.02 (s, 1 H) 6.65 (s, 1 H) 6.42 (s, 2 H). MS: (ESI+) m z 163, 165, 167 [M+H]+, di-chlorine isotopic pattern.
66%
With N-chloro-succinimide In ethyl acetate at 20℃; for 28 h;
To a solution of 4-chloropyridine-2-amine (50.00 g, 0.389 mol) in EtOAc (400 mL) was added N-chloro succinimide (53.50 g, 0.401 mol) in one portion. The mixture was stirred over night (28 h) at room temperature, and was then filtered to remove precipitated succinimide. The filtrate was washed with aqueous 0.5M NaOH (8x50 mL), water (2x50 mL) and brine (2x50 mL). The organic phase was dried (Na2SO4), filtered and evaporated to furnish 59.4 g of crude light brown powder after vacuum drying. The dry isolated crude (with a purity of ca. 75percent of the title compound) was slurried in hexane (800 mL) and stirred at reflux temperature for 15 min. The mixture was allowed to cool to 35 C and was then filtered using a G3 glass frit filter. The filter cake was washed with hexane (ca.200 mL) and dried on the filter to furnish 42.1 g (66percent) of brown solid. The product was pure enough (96percent) to be taken to the next step.1H NMR (600 MHz, DMSO-d6) δ ppm 8.02 (s, 1 H) 6.65 (s, 1 H) 6.42 (s, 2 H). MS: (ESI+) m/z 163, 165, 167 [M+H]+ , di-chlorine isotopic pattern.
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 1, p. 60 - 67
[2] European Journal of Medicinal Chemistry, 2016, vol. 117, p. 19 - 32
[3] Patent: WO2016/124553, 2016, A1, . Location in patent: Page/Page column 71-72
[4] Patent: WO2018/11138, 2018, A1, . Location in patent: Page/Page column 69-70
[5] Synthetic Communications, 1997, vol. 27, # 5, p. 861 - 870
[6] Patent: WO2011/85126, , A1, . Location in patent: Page/Page column 162-163[6] Patent: , 2011, , . Location in patent: Page/Page column 162-163
[8] Patent: US2016/362407, 2016, A1,
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In ethanol; water; toluene at 90℃; for 14 h; Sealed tube; Inert atmosphere
A mixture of 4-chloropyridin-2-amine (64 g, 498 mmol), phenyl boronic acid (61 g, 500 mmol), Na2CO3 (159 g, 1.5 mol), Pd(PPh3)4 (6.4 g) in H20/EtOH/toluene (500 mL) was heated to 90 °C in sealed vessel for 14 h. The crude mixture was cooled, filtered, and concentrated under reduced pressure. Purification (FCC, 5i02,PE:EtOAc (100:1) afforded the title Compound (64 g, 75percent).
With N-iodo-succinimide In N,N-dimethyl-formamide for 43 h;
General procedure: 36 (1.00g, 7.78mmol) was dissolved in DMF (40mL), the reaction flask was covered with aluminium foil, and NIS (970mg, 4.28mmol) was added. The reaction mixture was stirred for 19h before additional NIS (970mg, 4.28mmol) was added, and the reaction mixture was stirred for another 24h. H2O (200mL) was added, and the mixture was extracted with EtOAc (2×250mL). The combined organic layer was washed with H2O (2×200mL) and brine (200mL), dried over Na2SO4, and evaporated under vacuum. Recrystallization from EtOH followed by recrystallization of the mother liquor afforded the product as orange, needle-shaped crystals (1.45g, 73percent).
70%
With N-iodo-succinimide In N,N-dimethyl-formamide at 40℃;
A mixture of 4-chloropyridin-2-amine (2 g, 15.6 mmol) and N-iodosuccinimide (4.2 g, 18.7 mmol) in DMF (20 mL) was heated at 40°C overnight. The reaction mixture was diluted by H20 (80 mL), extracted by EtOAc (40 mL*3). The combined organic solutions were dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using Petroleum Ether:EtOAc (4: 1 ) as eluting solvents to afford 4-chloro-5-iodopyridin-2-amine as a red solid (2.8 g, 70percent). MS (ESI) m/z: 255 [M+H]+.
62%
With N-iodo-succinimide In N,N-dimethyl-formamide at 20℃; for 18 h;
To a solution of 2-amino-4-chloropyridine (150 g, 0.78 mol) in DMF (1.5 L) was added NIS (341 g, 1.52 mol) and the reaction mixture stirred at RT for 18 h before being concentrated in vacuo to 300 mL volume. The resultant residue was poured into 10percent aqueous sodium thiosulfate solution (1.2 L), stirred for 15 min and the precipitate formed collected by filtration, washed with water then dried at 35° C. in vacuo to give the title compound as a pale brown solid (185 g, 62percent). 1H NMR 400 MHz (CDCl3) δ: 8.33 (1H, s), 6.68 (1H, s), 4.52 (2H, s).
60%
With N-iodo-succinimide In N,N-dimethyl-formamide at 20℃; for 18 h;
(A. Tsuruoka, T. Matsushima, K. Miyazaki, J. Kamata, Y. Fukuda, K. Takahashi and M. Matsukura, Int. Pat. Appl. WO 200420434, 2005): N-iodosuccinimide (9.10 g, 40.4 mmol) was added to a solution of 2-amino-4- chloropyridine (i) (4.00 g, 31.1 mmol) in DMF (40 mL). The reaction mixture was stirred at room temperature for 18 h and partitioned between EtOAc (150 mL) and aqueous sodium thiosulfate solution (1M, 100 mL). The organic fraction was separated, washed successively with water (2 x 100 mL) and brine (50 mL), dried (MgS04) and reduced in vacuo to give the crude product as a light orange solid. Column chromatography (Si02), eluting with 5: 1 Petrol-EtOAc to 2: 1 Petrol-EtOAc, afforded compound ii. (4.65 g, 18.4 mmol, 60percent) as colourless needles, [M+H]+ m/z = 254.8.
60%
With N-iodo-succinimide In N,N-dimethyl-formamide at 20℃; for 18 h;
N-Iodosuccinimide (9.10 g, 40.4 mmol) was added to a solution of 2-amino-4-chloropyridine 29 (4.00 g, 31.1 mmol) in DMF (40 mL). The reaction mixture was stirred at room temperature for 18 h and partitioned between EtOAc (150 mL) and aqueous sodium thiosulfate solution (1M, 100 mL). The organic fraction was separated, washed successively with water (2 × 100 mL) and brine (50 mL), dried (MgSO4) and reduced in vacuo to give the crude product as a light orange solid. Column chromatography (SiO2), eluting with 5:1 Petrol–EtOAc to 2:1 Petrol–EtOAc, afforded the title compound16 (4.65 g, 18.4 mmol, 60percent) as colourless needles, m.p. 117-120 °C (from EtOH–water); Rf 0.57 (1:1 Petrol–EtOAc); (Found: C, 24.1; H, 1.50; N, 11.4; C5H4ClIN2 requires C, 23.6; H, 1.55; N, 11.0percent); δH (300 MHz, DMSO-d6); 8.21 (1H, s, 6-H), 6.69 (1H, s, 3-H), 6.43 (2H, br s, 2-NH2); δC (75 MHz, DMSO-d6); 160.8 (2-C), 156.2 (6-C), 146.3 (4-C), 108.7 (5-C), 79.4 (3-C); νmax/cm-1 (solid); 3436, 3284, 3121, 1629 and 1576; m/z (ES) 254.8 (100percent, MH+); (Found MH+, 254.9182. C5H4ClIN2 requires MH 254.9180); LC-MS; RT= 1.37min, m/z (ES+) found MH+, 254.8.
Reference：
[1] European Journal of Medicinal Chemistry, 2014, vol. 84, p. 404 - 416
[2] Patent: WO2015/100609, 2015, A1, . Location in patent: Page/Page column 47
[3] Patent: US2012/245144, 2012, A1, . Location in patent: Page/Page column 125-126
[4] Journal of Medicinal Chemistry, 2016, vol. 59, # 3, p. 985 - 1002
[5] Patent: WO2013/91011, 2013, A1, . Location in patent: Page/Page column 64
[6] European Journal of Medicinal Chemistry, 2014, vol. 86, p. 31 - 38
[7] Patent: EP1522540, 2005, A1, . Location in patent: Page/Page column 125
5
[ 19798-80-2 ]
[ 942947-95-7 ]
Reference：
[1] Journal of Medicinal Chemistry, 2012, vol. 55, # 20, p. 8721 - 8734,14
[2] Journal of Medicinal Chemistry, 2012, vol. 55, # 20, p. 8721 - 8734
[3] Patent: WO2013/190320, 2013, A1,
[4] European Journal of Medicinal Chemistry, 2016, vol. 117, p. 19 - 32
The 2-amino-4-pyrrolidin-l-ylpyridine used as a starting material was prepared as follows :-A mixture of 2-amino-4-chloropyridine (1 g) and pyrrolidine (2.59 ml) was heated to205C in a microwave oven for 30 minutes. The reaction mixture was purified by column chromatography on silica using a 10: 1 mixture of methylene chloride and a 3M methanolic ammonia solution as eluent. There was thus obtained the required starting material (1.05 g);1H NMR: (CDCl3) 2.0 (m, 4H), 3.28 (m, 4H), 4.49 (br s, 2H), 5.56 (m, IH), 5.95 (m, IH), 7.69(d, IH); Mass Spectrum: M+If" 164.
With sodium hydrogencarbonate; In ethanol; water; at 20℃; for 20h;Reflux;
Synthesis of 7-Chloroimidazo[1 , 2-a]pyridine (compound 65-3)[0000229] To a suspension of compound 65-2 (HC1) in ethanol (15 mL) was added sodium bicarbonate powder (3.3g, 38.4 mmol, 4 equiv) and a 50% solution of chloroacetaldehyde in water (2.26 g, 14.4 mmol, 1.5 equiv) . The reaction was heated at reflux for 4 hours and stirred at room temperature for 16 hours. The reaction was concentrated under reduced pressure and the residue was dissolved in water (10 mL) and ethyl acetate (10 mL) . The layers were separated and the aqueous phase was extracted with ethyl acetate (2 x 5 mL) . The organic layers were combined, dried over sodium sulfate, filtered and concentrated to give compound 65-3 as a dark yellow oil (980 mg, 89% yield)
85%
In ethanol; water; for 2h;Reflux;
(2a) 7-Chloroimidazo[1,2-a]pyridine Into ethanol (50 mL), 2-amino-4-chloropyridine (643 mg, 5.00 mmol) was dissolved, to which a 40% aqueous solution of chloroacetaldehyde (8.25 mL, 50 mmol) was added, followed by heating under reflux for two hours. The resulting mixture was left to cool, and the solvent was distilled off under reduced pressure. The residue thus obtained was purified by basic silica gel column chromatography (dichloromethane) to give the desired title compound (645 mg, yield 85%). 1H-NMR (CDCl3) delta: 6.79 (1H, dd, J = 7.4, 2.3 Hz), 7.57 (1H, s), 7.63 (2H, br s), 8.05 (1H, d, J = 7.4 Hz).
79%
In water; butan-1-ol; at 130℃; for 12h;
General procedure: 2-aminopyridine (15 g, 0.159 M) was dissolved in 1-butanol (64 mL) in a 250 mL round bottom flask affixed with a magnetic stir bar. 2-chloroacetaldehyde 50% solution in water (24.3 mL, 0.191 M) was added hitherto and the reaction was heated to 130 C for 12 h.The reaction solvent was condensed in vacuo and the crude product was adsorbed onto silica. The product was purified via flash chromatography utilizing a DCM/MeOH gradient and isolated as a light, yellow oil (17 g, 90%).
With sodium hydrogencarbonate; In ethanol; for 6h;Heating / reflux;
General Route A; Procedure A1 - General im idazopyridine ring formation; To a solution of 4-Chloro-pyridin-2-ylamine (12.8 g, 100 mmol, 1.0 equiv) in EtOH (170 ml) was added NaHCO3 (16.8 g, 200 mmol, 2.0 equiv) followed by chloroacetaldehyde (19.0 ml, 150 <n="95"/>mmol, 1.5 equiv). The mixture was refluxed for 6 h. Solvents removed under reduced pressure and the crude mixture was partitioned between water and EtOAc. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The product was purified by column chromatography (SiO2, eluted with 50% EtOAC-petrol) to afford 13.2 g of product.
With sodium hydrogencarbonate; In ethanol; for 6h;Heating / reflux;
To a solution of 4-Chloro-pyridin-2-ylamine (12.8 g, 100 mmol, 1.0 equiv) in EtOH (170 ml) was added NaHCO3 (16.8 g, 200 mmol, 2.0 equiv) followed by chloroacetaldehyde (19.0 ml, 150 mmol, 1.5 equiv). The mixture was refluxed <n="112"/>for 6 h. Solvents removed under reduced pressure and the crude mixture was partitioned between water and EtOAc. The organic layer was washed with brine, dried (MgSO4) and concentrated under reduced pressure. The product was purified by column chromatography (SiO2, eluted with 50% EtOAC-petrol) to afford 13.2 g of product. MS: [M+H]+ 153
With sodium hydrogencarbonate; In ethanol; for 17h;Heating / reflux;
4-Chloro-pyridin-2-ylamine (1 eq, 38.9 mmol, 5 g) is added to a solution of chloroacetic aldehyde (3 eq, 117 mmol, 15.1 ml) in EtOH (60 ml). NaHCO3 (2 eq, 77.8 mmol, 6.53 g) is added and the reaction mixture is heated at reflux for 17 h. The solvent is removed in vacuo and the product is purified by flash column chromatography eluting with 8:2 DCM/MeOH to afford 7-chloro-imidazo- [1,2-a]- pyridine as a red solid; [M+H]+ = 153
With sodium hydrogencarbonate; In ethanol; water; for 10h;Reflux;
To a mixture of 4-chloropyridin-2-amine (1.0 g, 7.78 mmol, 1.0 eq) and NaHCCb (1.31 g, 15.56 mmol, 2.0 eq) in EtOH (18 mL) was added chloroacetaldehyde, 50% wt in water, (1.48 mL, 11.67 mmol, 1.5 eq). The reaction mixture was heated to reflux. After 10 h, the solvent was removed under reduced pressure and the residue was partitioned between EtOAc: H20 (1 : 1, 100 mL). The organic layer was washed with Brine (50 mL), dried (MgS04), filtered and concentrated. The material was taken through without further purification. (0243) LCMS: RT = 0.123 min, >98% 215 and 254 nM, m/z = 153.0 [M + H]+.
With sodium hydrogencarbonate; In ethanol; for 6h;Reflux;
To a solution of 4-Chloro-pyridin-2-ylamine (12.8 g, 100 mmol, 1.0 equiv) in EtOH (170 ml) was added NaHCO3 (16.8 g, 200 mmol, 2.0 equiv) followed by chloroacetaldehyde (19.0 ml, 150 mmol, 1.5 equiv). The mixture was refluxed for 6 h. Solvents removed under reduced pressure and the crude mixture was partitioned between water and EtOAc. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The product was purified by column chromatography (SiO2, eluted with 50% EtOAC-petrol) to afford 13.2 g of product. MS: [M+H]+ = 153.
4-(Methylthio)pyridin-2-amine A mixture of 4-chloropyridin-2-amine (3.00 g, 23.3 mmol) and sodium thiomethoxide (4.9 g, 70.0 mmol) in ethanol (37.3 mL) and water (9.3 mL) was heated at 140 C in a sealed tube for 18 h. The solvent was evaporated and the residue was triturated with water (20 mL) and Et2O (5 mL). The mixture was filtered and washed with water followed by Et2O. <n="50"/>The solid was dried under high vacuum to afford the title product. MS (ESI, Q+) m/z 141 (M +1)
In methanol; for 1h;Inert atmosphere; Reflux; Dien-Stark condenser;
To a suspension of 5-formylthiophene-2-carboxylic acid (22g, 141 mmol) in toluene (220mL) was added 4-chloropyridin-2-amine ( 1 8.05g, 141 mmol) and MeOH (20mL) under nitrogen atmosphere at room temperature and the resulting reaction mixture was heated to reflux using Dien-Stark condenser for 1 h. The reaction mixture wasconcentrated under reduced pressure. To the resulting solid residue MeOH (220mL) was added, the mixture was cooled to 0°C and then treated with NaBH3CN ( 13.29g, 210mmol) which was added portion wise over a period of 10 min. The resulting mixture was stirred at room temperature for 1 5h. The reaction was quenched by addition of IN HCI until pH = 5-6 and concentrated under reduced pressure. The gummy residue was diluted with water ( l OOmL, note: gummy residue was insoluble) to which additional few drops of I N HCI to bring pH to 5 were added, before collection of the solid by filtration. Resulting solid was dried to afford the crude compound (30 g). The final product was obtained by recrystallizing twice from ethanol (10 volumes). 5-[(4-chloropyridin-2- ylamino)methyl]thiophene-2-carboxylic acid ( 12.5 g) was obtained as an off-white solid.
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 90℃; for 14.0h;Sealed tube; Inert atmosphere;
A mixture of 4-chloropyridin-2-amine (64 g, 498 mmol), phenyl boronic acid (61 g, 500 mmol), Na2CO3 (159 g, 1.5 mol), Pd(PPh3)4 (6.4 g) in H20/EtOH/toluene (500 mL) was heated to 90 C in sealed vessel for 14 h. The crude mixture was cooled, filtered, and concentrated under reduced pressure. Purification (FCC, 5i02,PE:EtOAc (100:1) afforded the title Compound (64 g, 75%).
tert-butyl ((1-(2-aminopyridin-4-yl)azetidin-3-yl)methyl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96%
With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 120℃; for 24.0h;Sealed tube;
For isopropyl alcohol / N, N-diisopropylethylamine (50mL / 25mL)4-chloropyridin-2-amine 8-1 (2.50 g, 19.5 mmol) solution inTert-butyl (azetidin-3-ylmethyl) carbamate hydrochloride 8-2 (5.60 g, 25.4 mmol) was added. The reaction mixture was heated in a sealed tube at 120 C for 24 hours.The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was distinguished between EtOAc and saturated sodium bicarbonate solution.The layers were separated; the organic layer was dried over sodium sulfate, filtered and concentrated. The residue was washed with hexane to obtain((1- (2-aminopyridin-4-yl) azetidin-3-yl) methyl) t-butylaminoformate 8-3 (5.2 g, 96%),An off-white solid, which was used directly in the next step without further purification.
With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 120℃; for 24.0h;Sealed tube;
To a solution of 4~chloropyridin~2 -amine 8-1 (2.50 g, 19.5 mrnol) in isopropanoyNN-diisopropylethylamine (50 mL/25 mL) was added /erf-butyl(azetidin-3- ylmethyl)carbamate hydrochloride 8-2 (5.60 g. 25.4 mmol). The reaction mixture was heated at 120 C in a sealed tube for 24 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between EtOAd and saturated sodium bicarbonate solution. The layers were separated; the organic layer was dried over sodium sulphate, filtered and concentrated . Hie residue was washed with hexanes to provide /en-butyl ((l -(2-aminopyridin-4-yl)azetidm-3- yl)methyl)carbamate 8-3 (5.2 g, 96%) as an off-white solid, which was used for next step without further purification. ESHAPCI-MS m/z 279 M - S i j .
Step 1: To the stirred solution of 4-chloropyridin-2-ylamine, 41(1.0 eq) in ethanol was added a solution of 2-chloro-3-oxo-propionicacid ethyl ester, 40 (1.2 eq) in benzene and the reaction mixture wasstirred at 60 C for 16 h. After completion of the reaction, the solventwas removed, and the crude was diluted with ethyl acetate, washedwith aqueous NaHCO3 followed by water and brine. The organic layerswere dried over anhyd. Na2SO4, filtered and concentrated under vacuo.The crude product was purified by column chromatography eluted withethyl acetate:hexane (2:8) to yield compound 42. To the stirred solution of OX2 (1.0 eq) in the mixture of DME andwater (4:1) (15 mL/ mmol) was added Pd(PPh3)4 (0.1 eq) under argonatmosphere and argon was bubbled for 10 min. 4-fluorophenylboronic acid (1.1 eq) was added followed by the addition of Na2CO3 (2.5 eq),and the reaction mixture was stirred at 80 C for 16 h. The reactionmixture was cooled, filtered and the filtrate was diluted with ethylacetate and washed with water. The organic layers were washed withbrine, dried over anhydrous Na2SO4, filtered and concentrated undervacuo. The crude was purified by column chromatography eluted withethyl acetate:hexane (2:8) to yield the pure product. . To the stirred solution of compounds 5 and 7 (1.0 eq) in themixture of THF and water (2:1) was added lithium hydroxide monohydrate(2.2 eq), and the reaction mixture was stirred at room temperaturefor 4 h. The reaction mixture was concentrated under vacuo and diluted with water, acidified with an aqueous solution of citric acidup to pH-4 ~ 5. The compound was extracted with ethyl acetate, andthe combined organic layers were washed with brine, dried over anhyd.Na2SO4, filtered and concentrated under vacuo to afford acids 6 and 8. To the stirred solution of carboxylic acid (3 and 4) (1.0 eq) in DCM(10 mL/ mmol) was added carbonyldiimidazole (CDI) (1.1 eq) and thereaction mixture was stirred for 30 min. N-hydroxybenzamidine, 2(1.0 eq) was added to this mixture and was stirred at room temperaturefor 6 h. After completion, the reaction mixture was diluted with DCM,washed with water and brine, dried over anhyd. Na2SO4, filtered andconcentrated under vacuo. The crude product was dissolved in tolueneand refluxed for 16 h. After completion of the reaction (monitored byTLC), the reaction mixture was cooled, and the solvent was removedunder vacuo. The product was purified by column chromatographyeluted with ethyl acetate:hexane (2:8) to yield the pure product.
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