* 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.
A mixture of 4,5-dichloro-2-trimethylacetamido-pyridine (0.500 g, 2.02 mmol) and aqueous HCl (6N; 9.5 ml) was heated was heated at 100° C. for 17 h. The reaction mixture was allowed to cool to room temperature, diluted with ice-water (15 ml), and the pH of the mixture was adjusted to 7.0 with 10percent aqueous NaOH. The white precipitate was collected by filtration, washed with water (2.x.5 ml), and dried in vacuo over P2O5. The title compound was obtained as a white solid (0.284 g, 86percent); 1H-NMR (500 Mz, DMSO-d6) 6.44 (s, 2H, NH2, exchangeable with D2O), 6.64 (s, 1H), and 8.03 (s, 1H) (3-H, 6-H); LC-MS (ESI, m/z) 4.37 min-163, 165, 167 [(M+H)+, Cl2 isotopic pattern].
85%
With hydrogenchloride In water at 100℃; for 10 h;
A mixture of N-(4,5-dichloropyridin-2-yl)pivalamide (1.25 g, 5.04 mmol) in 6N HCl (20 mL) was stirred at 100° C. for 10 h. The mixture was cooled, combined with water (20 mL), and basified by the addition of sodium bicarbonate solution (20 mL). The mixture was extracted with ethyl acetate (3×40 mL), and the combined organic layers were dried over sodium sulfate, then evaporated under reduced pressure and purified by gradient column chromatography using ethyl acetate in n-hexane as eluent to afford 4,5-dichloropyridin-2-amine as a white solid (0.7 g, 85percent). 1HNMR (400 MHz, CDCl3): δ 8.06 (s, 1H), 6.60 (s, 1H), 4.48 (br s, 2H). LC-MS calcd exact mass 161.98, found m/z 162.8 [M+H]+.
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, 2011, A2, . Location in patent: Page/Page column 162-163
[7] Patent: WO2011/85126, , A1, . Location in patent: Page/Page column 162-163[7] Patent: , 2011, , . Location in patent: Page/Page column 162-163
[9] Patent: US2016/362407, 2016, A1,
With hydrogenchloride; In water; at 100℃; for 17h;
A mixture of 4,5-dichloro-2-trimethylacetamido-pyridine (0.500 g, 2.02 mmol) and aqueous HCl (6N; 9.5 ml) was heated was heated at 100 C. for 17 h. The reaction mixture was allowed to cool to room temperature, diluted with ice-water (15 ml), and the pH of the mixture was adjusted to 7.0 with 10% aqueous NaOH. The white precipitate was collected by filtration, washed with water (2×5 ml), and dried in vacuo over P2O5. The title compound was obtained as a white solid (0.284 g, 86%); 1H-NMR (500 Mz, DMSO-d6) 6.44 (s, 2H, NH2, exchangeable with D2O), 6.64 (s, 1H), and 8.03 (s, 1H) (3-H, 6-H); LC-MS (ESI, m/z) 4.37 min-163, 165, 167 [(M+H)+, Cl2 isotopic pattern].
85%
With hydrogenchloride; In water; at 100℃; for 10h;
A mixture of N-(4,5-dichloropyridin-2-yl)pivalamide (1.25 g, 5.04 mmol) in 6N HCl (20 mL) was stirred at 100 C. for 10 h. The mixture was cooled, combined with water (20 mL), and basified by the addition of sodium bicarbonate solution (20 mL). The mixture was extracted with ethyl acetate (3×40 mL), and the combined organic layers were dried over sodium sulfate, then evaporated under reduced pressure and purified by gradient column chromatography using ethyl acetate in n-hexane as eluent to afford 4,5-dichloropyridin-2-amine as a white solid (0.7 g, 85%). 1HNMR (400 MHz, CDCl3): delta 8.06 (s, 1H), 6.60 (s, 1H), 4.48 (br s, 2H). LC-MS calcd exact mass 161.98, found m/z 162.8 [M+H]+.
Description 76: 4,5-dichloro-2-pyridinamine (D76); N-(4,5-dichloro-2-pyridinyl)-2,2-dimethylpropanamide D75 (560 mg) was reacted with HCl (10 ml, 60.0 mmol) at 80 0C for 1 hour then it was purified over a 20 g SCX Strata column, washing with MeOH and eluting with 2M ammonia in MeOH, to give the title compound D76 (360 mg) as colourless solid. 1H NMR (400 MHz, CHLOROFORM-^) delta ppm 4.54 (br. s., 2 H) 6.63 (s, 1 H) 8.09 (s, 1 H)
With N-chloro-succinimide; In N,N-dimethyl-formamide; at -20 - 20℃; for 24h;
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, 69.0%).
66%
With N-chloro-succinimide; In ethyl acetate; at 20℃; for 28h;
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. 75% 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 (66%>) of brown solid. The product was pure enough (96%>) to be taken to the next step. 1H NMR (600 MHz, DMSO-d6) delta 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 28h;
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. 75% 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 (66%) of brown solid. The product was pure enough (96%) to be taken to the next step.1H NMR (600 MHz, DMSO-d6) delta 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.
BBM-001-049[ 0404 ] Preparation of 2-Amino-4,5-dichloropyridine (CAS 188577-68-6):[0405] 4-Chloro-2-aminopyridine (Matrix Scientific, cat. No.23809; 1.29 g, 0.01 mol) is dissolved by stirring in 500 ml of ethyl acetate. A thermometer is placed in the solution to monitor temperature. N-Chlorosuccinimide (13.3 g, 0.01 mol) is added in several portions to keep the solution at room temperature. The solution becomes dark in color and is stirred at room temperature overnight. The supernatant is decanted from the dark solids that formed and transferred to a separatory funnel. The organic solution is washed with 500 ml saturated aqueous sodium bisulfite and then 500 ml brine. The organic layer is dried with MgSC>4 and concentrated on a rotovap. The dark brown crude product is chromatographed on 500 g of flash silica-gel eluting with CH2C12. Concentration of the appropriate fractions on a rotovap gives a light tan solid. The solid is dissolved in EtOAc and decolorized with activated carbon. EtoAc is removed using a rotovap and the resulting solid is suspended in ice-cold CH2Q2 and filtered to give the product as a white solid. (MP 142-143 C).
To 30 mL 98% H2SO4 was added portionwise <strong>[188577-68-6]4,5-dichloropyridin-2-amine</strong> (1.0 g, 6.13 mmol) at -5 C. After the solid material was completely dissolved, 3.7 mL fuming HNO3 was added dropwise over 5 min maintaining internal temperature ?0 C. The mixture was allowed to warm to 50 C over 2 h, and then stirred for another 1 h at this temperature before poured onto 150 g crushed ice. The aqueous solution was basified to pH = 7.3 with ammonia and extracted with ethyl acetate. The combined extracts were dried, concentrated and purified by column chromatography to give 4,5-dichloro-3-nitropyridin-2-amine (0.80 g, 62.6%).
26%
With sulfuric acid; nitric acid; In water; at 0 - 55℃; for 1.11667h;Cooling with ice-bath;
To a 50 ml round-bottomed flask containing <strong>[188577-68-6]2-amino-4,5-dichloropyridine</strong> (0.275 g, 1.65 mmol) and cooled into an ice-bath was added conc. H2SO4 (2.79 g). The reaction mixture was stirred for 3 min and then HNO3 (70%; 0.186 g) was dropwise added. The reaction mixture was stirred at 0 C. (ice-bath) for 7 min, then heated to 55 C. and stirred at this temperature for 1 h, allowed to cool to room temperature, diluted with ice-water (15 ml) and the pH was adjusted to 7.5 with 10% aqueous NaOH. The yellow precipitate was collected by filtration, washed with water and dried in vacuo over P2O5, then absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column. Elution with 2% ethyl acetate in dichloromethane afforded the title compound as a yellow solid (0.090 g, 26%); 1H-NMR (250 Mz, DMSO-d6) 7.39 (s, 2H, NH2), 8.39 (s, 1H, 6-H); LC-MS (ESI, m/z) 6.54 min-208, 210, 212 [(M+H)+, Cl2 isotopic pattern].
11.7 g
INTERMEDIATE 2 4,5-Dichloro- V-nitropyridine-2-amine 4,5-Dichloropyridin-2-amine (INTERMEDIATE 1, 45.2 g, 283.0 mmol) was added to 270 mL of ice cold cone. H2SO4, in small portions over ca 20 min. When dissolved, cone. HNO3 (22 g) was added dropwise and the mixture was stirred at ca 5 C for 3.5 h. LCMS indicated total conversion to expected product. The cold mixture was poured on crushed ice/water mixture (3 L), stirred for ca 5 min and then filtered. The solid was collected and slurried in ice cold water (500 mL) and filtered. The procedure was repeated until neutral pH. When semi dry on the filter, the solid was dissolved in EtOAc (ca. 3 L) , washed with brine (ca. 100 mL) and the organic layer was dried with Na2S04, filtered, and evaporated to furnish 46.2 g (78%) of 97% pure title product as beige-orange solid. 1H NMR (600 MHz, CD3OD) delta ppm 8.47 (s, 1 H) 8.08 (s, 1 H). MS: (ESI+) m/z 208, 210, 212 [M+H]+, di-chlorine isotopic pattern. INTERMEDIATE 3 4,5-Dichloro-3-nitropyridine-2-amine 4,5-Dichloro-N-nitropyridin-2-amine (INTERMEDIATE 2, 20.0 g, 96.2 mmol) was added to 200 mL of cone. H2S04 at room temperature. After stirring at 40 C for 2.5 h the mixture was cooled to below room temperature and poured onto crushed ice (2 L) while stirring. After the ice had melted, the volume was adjusted to ca. 2 L with ice cold water and the yellow precipitate was collected by filtration and washed with ice cold water until neutral pH (3 x 250 mL). The solid was allowed to semi-dry on the filter and was then dissolved in EtOAc (ca. 800 mL). The organic phase was washed with 0.25 M NaOH (3x30 mL), water (3x15 mL) and brine (15 mL), dried (Na2S04), filtered and the solvent evaporated to furnish 11.7 g (59%) of 99% pure title product as yellow solid. 1H NMR (600 MHz, CD3OD) delta ppm 8.26 (s, 1 H). MS: (ESI+) m/z 208, 210, 212 [M+H]+ chlorine isotopic pattern.
A mixture of 4,5-dichloropyridin~2-amine (300 mg, 1.84 mmol) and morpholine (480 mg, 5.52 mmol) in DMA (3.6 mL) was heated at 2000C for 60 minutes by microwave irradiation. The mixture was purified by ion exchange chromatography on SCX-II acidic resin (2 g) eluting with methanol, then 2M ammonia-methanol. The basic fractions were combined and solvent was evaporated. Flash chromatography on silica, eluting with ethyl acetate - hexane (1:1) gave 5-chloro-4-morpholinopyridin-2-amine as a colourless solid (347 mg, 88%).1H NMR (500 MHz, (CD3)2CO) delta 3.07-3.09 (4H, m), 3.76-3.78 (4H, m), 5.39 (2H, s), 6.20 (1 H, s), 7.78 (1 H, s). LCMS (3) Rt 2.60 min; m/z (ESI+) 252 (MK+).
Description 77: 2,4,5-trichloropyridine (D77); 4,5-dichloro-2-pyridinamine D76 (360 mg) was dissolved in HCl (8 ml, 96 mmol) at O0C, then sodium nitrite (305 mg, 4.42 mmol) was added portionwise, and the resulting yellow mixture was stirred at 0 0C for 1 hour and then at room temperature for 1 hour. On the basis of HPLC/MS, starting material was consumed to give the required product and the corresponding pyridone.The reaction was then poured into ammonium hydroxide (10 ml) in ice and extracted with Et2O (3x150 ml). The collected organic phases were dried over Na2SO4, then filtered and carefully concentrated (max 200 mBar) to give the title compound D77 (200 mg) as yellow oil.UPLC (Acid GEN_QC_SS): rt = 0.86 minutes, peak observed: 184 (M+2) C5H2Cl3N requires 182.1H NMR (400 MHz, CHLOROFORM- d) delta ppm 7.48 (s, 1 H) 8.43 (s, 1 H)
[0928] To a solution of phosgene (20% solution in toluene,0.186 ml, 0.353 mmol) in THF (2 ml) was added triethylamine(0.141 ml, 1.01 mmol). To the resulting white suspensionwas added a solution of <strong>[204452-91-5]7-(dimethoxymethyl)-1,2,3,4-tetrahydro-1,8-naphthyridine</strong> (intermediate 4, 70 mg, 0.336mmol) in THF (2 ml) drop wise. The resulting yellow suspensionwas stirred at room temperature for 1 h. 4,5-dichloropyridin-2-amine (65.7 mg, 0.403 mmol) in THF (1 ml) wasadded to the mixture and stirred at room temperature for 16 h.The reaction mixture was filtered through a silica gel plug andwashed with heptanes/EtOAc 1:1 (35 ml), the filtrate wasconcentrated. The residue was dissolved in dioxane (1 ml)and treated with HCl (4 Min dioxane, 1 ml, 4.0 mmol). Themixture was stirred at room temperature for 2 h, diluted withDCM and quenched with saturated aqueous NaHC03 . Theorg. layer was collected and the water layer was extractedwith DCM. The combined org. layers were dried over anhydrousNa2S04 and concentrated under reduced pressure. Thecrude product was dissolved in acetonitrile/NMP/TFA, filteredthrough a syringe filter (0.2 f.tm) and purified by preparativereverse phase LC-MS (RP 1). The clean fractionswere combined and lyophilized to obtain the title compoundas an off white solid.
a solution of phosgene (20% solution in toluene, 0.186 ml, 0.353 mmol) in THF (2 ml) was added triethylamine (0.141 ml, 1.01 mmol). To the resulting white suspension was added a solution7-(dimethoxymethyl)-1 ,2,3,4-tetrahydro-1 ,8-naphthyridine (intermediate 4, 70 mg, 0.336 mmol) inTHF (2 ml) drop wise. The resulting yellow suspension was stirred at room temperature for I h. 4,5- dichloropyridin-2-amine (65.7 mg, 0.403 mmol) in THF (1 ml) was added to the mixture and stirredroom temperature for 16 h. The reaction mixture was filtered through a silica gel plug and washed with heptanes/EtOAc 1:1(35 ml), the filtrate was concentrated. The residue was dissolveddioxane (1 ml) and treated with HCI (4 M in dioxane, I ml, 4.0 mmol). The mixture was stirred atroom temperature for 2 h, diluted with DCM and quenched with saturated aqueous NaHCO3. The org. layer was collected and the water layer was extracted with DCM. The combined org. layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was dissolved in acetonitrile/NMP/TFA, filtered through a syringe filter (0.2 pm) and purified by preparative reverse phase LC-MS (RP 1). The clean fractions were combined and lyophilized toobtain the title compound as an off white solid.1H NMR (400 MHz, DMSO-d5) 5 13.73 (s, IH), 9.94 (s, IH), 8.56 (s, IH), 8.34 (s, IH), 7.94 (d, IH),7.68 (d, IH), 4.03-3.95 (m, 2H), 2.95 (t, 2H), 2.01-1.90 (m, 2H).(UPLC-MS 1) Sample prepared in MeOH; tR 1.15, 1.28 mm; ESl-MS 383.1 [M+MeOH+H], 351.0[M+H].
tert-butyl N-[(tert-butoxy)carbonyl]-N-(4,5-dichloropyridin-2-yl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃;
Production Example 9-1 tert-Butyl N-[(tert-butoxy)carbonyl]-N-(4,5-dichloropyridin-2-yl)carbamate To a solution of <strong>[188577-68-6]2-amino-4,5-dichloropyridine</strong> (0.10 g, 0.61 mmol) and diisopropylethylamine (0.26 mL, 1.5 mmol) in dichloromethane (10 mL), di-tert-butyldicarbonate (0.32 g, 1.5 mmol) was added, and the resulting mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with a saturated saline solution and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, and then the residue was separated and purified by silica gel column chromatography (ethyl acetate:heptane=1:5) to obtain the title compound (0.18 g, 80% yield). 1H-NMR Spectrum (400 MHz, CDCl3) delta (ppm): 1.48 (s, 18H), 7.46 (s, 1H), 8.46 (s, 1H).
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100℃; for 3h;Inert atmosphere;
To a stirred solution of ( <strong>[188577-68-6]4,5-dichloropyridin-2-amine</strong> (0.1 g, 0.61 mmol) in dioxane (5 mL) was added iodobenzene (0.25 g, 1.22 mmol), cesium carbonate (0.597 g, 1.83 mmol), and Xantphos (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; 0.035 g, 0.06 mmol). The mixture was degassed with argon for 10 min, then tris(dibenzylideneacetone)dipalladium(0) (0.029 g, 0.03 mmol) was added, and the mixture was degassed again with argon for 10 min. The mixture was stirred for 3 h at 100 C. The mixture was cooled, concentrated under reduced pressure, diluted with water (10 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by gradient column chromatography using ethyl acetate in hexane as eluent to afford 4,5-dichloro-N-phenylpyridin-2-amine as an off-white solid (82 mg, 56% yield). 1HNMR (400 MHz, CDCl3): delta 8.17 (s, 1H), 7.36 (t, J=7.2 Hz, 2H), 7.28 (s, 2H), 7.12 (t, J=7.6 Hz, 1H), 6.92 (s, 1H), 6.51 (br s, 1H). LC-MS calcd exact mass 238.01, found m/z 239.1 [M+H]+.
4,5-Dichloropyridin-2-amine (INTERMEDIATE 1, 45.2 g, 283.0 mmol) was added to 270 mL of ice cold conc. H2SO4, in small portions over ca 20 min. When dissolved, conc. HNO3 (22 g) was added dropwise and the mixture was stirred at ca 5 C for 3.5 h. LCMS indicated total conversion to expected product. The cold mixture was poured on crushed ice/water mixture (3 L), stirred for ca 5 min and then filtered. The solid was collected and slurried in ice cold water (500 mL) and filtered. The procedure was repeated until neutral pH. When semi dry on the filter, the solid was dissolved in EtOAc (ca.3 L), washed with brine (ca.100 mL) and the organic layer was dried with Na2SO4, filtered, and evaporated to furnish 46.2 g (78%) of 97% pure title product as beige-orange solid.1H NMR (600 MHz, CD3OD) delta^D) delta (600 MHz, CDaporated to furnish 46.2+) m/z 208, 210, 212 [M+H]+ , di-chlorine isotopic pattern.
To <strong>[188577-68-6]4,5-dichloropyridin-2-amine</strong> (0.25 g, 1.53mmol) in dichloromethane (25 mL) was added I,I'-thiocarbonyldipyridin-2(1H)-one (0.36 g, 1.56 mmol). The reactionwas stirred at 40 C. for 3 hours, then cooled to room temperature.The crude material was purified by chromatography(Biotage: 25-100% ethyl acetate/hexane) to yield 4,5dichloro-2-isothiocyanatopyridine (0.26 g, 1.27 mmol, 83%yield) as a yellow powder. The product was carried directly to the next step.
6,7-dichloro-2-(chloromethyl)imidazo[1,2-a]pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Example 188 Synthesis of 6,7-dichloro-2-(chloromethyl)imidazo[1,2-a]pyridine. The mixture of <strong>[188577-68-6]4,5-dichloropyridin-2-amine</strong> (1 g, 6.13 mmol) and 1,3-dichloropropan-2-one(10 g, 78.4 mmol) in DMF (20 mL) was stirred at 90 C. for 20 h. Then H2O (100 mL) was added and extracted with EtOAc (100 mL*2). The combined organic layers were concentrated to give the crude product which was purified by silica gel chromatography (PE/EtOAc=3/1) to give 6,7-dichloro-2-(chloromethyl)imidazo[1,2-a]pyridine (471 mg, yield: 33%) as a yellow solid. ESI-MS [M+H]+: 235.1
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