* 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 sodium tetrahydroborate In ethanol; water at 20℃; for 1.5 h;
General procedure: TAPEHA-Pd (0.015 g) was added to a solution of nitroarenes (1.0 mmol) in EtOH/water (1/1) (20 mL). After NaBH4 (4.0 mmol) was slowly added to the mixture, the color of the reaction mixture turned gradually black in a few minutes, resulting in the formation of palladium nanoparticles (TAPEHA-PdNPs). 42 After being stirredfor 1.5 h at room temperature and atmospheric pressure, the catalyst was removed by ltering and the fitrate was extracted with 3 30 mL of EtOAc. The combined organic layers were dried over MgSO4 and concentrated in a vacuum.
97%
With sodium tetrahydroborate In ethanol; water at 20℃; for 4 h;
General procedure: SAC (300mg) and NaBH4 (4.0mmol) were added to a solution of nitroarenes (1.0mmol) in EtOH/water (1/1) (20ml). The reaction mixture was stirred for 4h at the temperature indicated in Table3. At the end of the reaction, the catalyst was removed by filtering and the filtrate was extracted with 3×70ml EtOAc. The combined organic layers were dried over MgSO4 and concentrated in a vacuum.
Reference：
[1] Turkish Journal of Chemistry, 2017, vol. 41, # 5, p. 784 - 792
[2] Catalysis Communications, 2015, vol. 67, p. 64 - 67
2
[ 2402-78-0 ]
[ 45644-21-1 ]
Yield
Reaction Conditions
Operation in experiment
70%
With ammonia In water at 150℃; for 6 h;
In a 600 mL autoclave equipped with a gas entrapment stirrer 240 g aqueous ammonia (28percent NH3 by weight) was added and mixed with 120 g of 2, 6-dichloropyridine. After purging with nitrogen, 48 g of liquid ammonia were added, and the reaction mixture was heated to 150°C for 6 h under stirring. The reaction mixture was allowed to cool to room temperature, and the pressure was brought back to atmospheric pressure . The product was isolated by filtration, washed with water and MeOH and dried. The yield for 2-chloro-6-amino pyridine was about 70percent, and the purity as determined by GC chromatography was 98percent.
Reference：
[1] Tetrahedron, 2002, vol. 58, # 3, p. 489 - 493
[2] Organic Process Research and Development, 2009, vol. 13, # 3, p. 555 - 566
[3] Patent: WO2009/18504, 2009, A1, . Location in patent: Page/Page column 18
[4] Journal of Medicinal Chemistry, 1987, vol. 30, # 11, p. 2047 - 2051
[5] Recueil des Travaux Chimiques des Pays-Bas, 1939, vol. 58, p. 709,721
[6] Patent: US2002/173490, 2002, A1,
[7] Patent: US6756360, 2004, B1, . Location in patent: Page column 145
[8] Patent: US6489476, 2002, B1,
3
[ 2402-78-0 ]
[ 141-86-6 ]
[ 45644-21-1 ]
Yield
Reaction Conditions
Operation in experiment
91 %Chromat.
With ammonium acetate; ammonia In water at 150℃; for 8 h;
In a 600 mL autoclave equipped with a gas entrapment stirrer, a solution of 5 g CuI in 120 g aqueous ammonia (30percent NH3 by weight) was added and mixed with 77 g ammonium acetate and 60 g of 2, 6-dichloropyridine. After purging with nitrogen, 24 g of liquid ammonia were added resulting in a pressure of about 150 psi (1.03 MPa). Subsequently, the reaction mixture was heated to 150°C for 8 h under stirring. Over the course of the reaction, the pressure decreased from an initial pressure of 680 psi (4.69 MPa) to 450 psi (3.10 MPa). The reaction mixture was allowed to cool to room temperature, and the pressure was brought back to atmospheric pressure. The reaction mixture was analyzed using a quantitative GC analytical method. The conversion of 2, 6-dichloropyridine was greater than 99.5percent. The reaction mixture contained 0.37 mol 2,6- diaminopyridine and 0.03 mol 2-chloro-6-amino pyridine. The yields for 2, 6-diaminopyridine and 2-chloro-6-amino pyridine were 91percent and 7percent, respectively.
72 %Chromat.
With ammonia In water at 150℃; for 8 h;
This reaction was conducted in the same manner as described in Example 1, but no ammonium acetate was added to the reaction mixture, demonstrating that lower selectivity is obtained in an unbuffered solution. The conversion of 2, 6-dichloropyridine was greater than 99.5percent. The reaction mixture contained 0.29 mol 2, 6-diaminopyridine and less than 0.005 mol 2-chloro-6-amino pyridine. The yield for 2, 6-diaminopyridine was 72percent.
Reference：
[1] Australian Journal of Chemistry, 1982, vol. 35, # 10, p. 2025 - 2034
19
[ 45644-21-1 ]
[ 98-80-6 ]
[ 39774-25-9 ]
Yield
Reaction Conditions
Operation in experiment
82%
With potassium phosphate; 1,1'-bis(di-tertbutylphosphino)ferrocene; palladium diacetate In 1,4-dioxane at 100℃; for 5 h; Inert atmosphere; Sealed tube
General procedure: To a solution of the requisite chloro-amino-substituted heteroaromatic in anhydrous 1,4-dioxane (30 volumes wrt chloride) in a sealed tube was introduced phenylboronic acid (1.5 equiv) and finely ground potassium phosphate (2.0 equiv). The solution was degassed (N2 bubbling) for 5 min, Pd(OAc)2 (5 mol percent wrt chloride) and di-tert-butylphosphinoferrocene (5 mol percent wrt chloride) introduced and degassing continued for a further 5 min. The tube was sealed under nitrogen and heated with rapid stirring at 100 °C for 5 h. After cooling, the reaction mixture was filtered in vacuo through a celite pad and the precipitated material washed with 1,4-dioxane. The combined filtrates were evaporated and purified by flash column chromatography (neat hexane to 1:1 hexane/EtOAc gradient containing 2.5percent by volume Et3N) to furnish the biarylanilines 13, 14 and 15.
Reference：
[1] Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 8, p. 2742 - 2750
[2] Tetrahedron Letters, 2005, vol. 46, # 20, p. 3573 - 3577
[3] New Journal of Chemistry, 2017, vol. 41, # 24, p. 15420 - 15432
20
[ 45644-21-1 ]
[ 73896-36-3 ]
Reference：
[1] Australian Journal of Chemistry, 1982, vol. 35, # 10, p. 2025 - 2034
21
[ 45644-21-1 ]
[ 76629-10-2 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 1980, vol. 17, # 6, p. 1225 - 1229
[2] Patent: EP3287441, 2018, A1,
22
[ 45644-21-1 ]
[ 15944-34-0 ]
Reference：
[1] Patent: WO2017/211759, 2017, A1,
23
[ 45644-21-1 ]
[ 3282-30-2 ]
[ 86847-84-9 ]
Yield
Reaction Conditions
Operation in experiment
98%
With triethylamine In dichloromethane at 0 - 20℃; for 5 h;
To a suspension of 6-chloro-pyridin-2-ylamine 13-1 (0.30 g, 2.33 mmol) and triethlyamine (0.41 mL, 2.92 mmol) in anhydrous methylene chloride at 0 °C was added a solution of trichloromethylacetyl chloride (0.32 mL, 2.57 mmol) in anhydrous methylene chloride. The mixture was stirred at 0 °C for 50 min, before allowing it to gradually warm up to room temperature. After 5 h, the reaction mixture was poured into water and the organic phase separated. The aqueous layer was extracted with methylene chloride and the combined organic phases were dried and concentrated. The product was purified by flash chromatography using Combiflash.(R). employing a gradient of 0-15percent EtOAc in Hexanes to afford 0.48 g (2.28 mmol, 98percent yield) of 13-2 as a white solid.
92%
With triethylamine In toluene at 20 - 50℃; for 22 h;
Example 2; l-({4-[([l,3]Oxathiolo[5,4-c]pyridin-6-ylmethyl)amino]-l- piperidinyl} methyl)- 1 ,2-dihydro-4H,9H-imidazo [1 ,2,3-ij ] -1 ,8-naphthyridine-4,9- dione hydrochloride; (a) λ/-(6-Chloro-2-pyridinyl)-2,2-dimethylpropanamide; A solution of 6-chloro-2-pyridinamine (13.776g, 107 mmol) in toluene (100ml) and triethylamine (16.28ml, 118 mmol) at 500C under argon was treated with 2,2- dimethylpropanoyl chloride (13.81ml, 112mmol). The reaction was then stirred at 500C for 4h and then at rt for 18h. 2M HCl (200ml) was then added and the mixture was extracted with diethyl ether (3 x 500ml). The organic extracts were dried (MgSO4), filtered and evaporated to give the product as a brown solid (21.005g, 92percent). MS (ES+) m/z 213/215 (MH+).
87%
With sodium hydrogencarbonate In toluene at 0 - 20℃; for 5 h;
To a solution of 2-amino-6-chloropyridine (10.7 g, 83.5 mmol) in toluene (103 mL) NaHCO3 (14 g, 167 mmol) and pivaloyl chloride (15.4 mL, 125.2 mmol) were added at 0°C. The resulting mixture was stirred at room temperature for 5 hours then the suspension was filtered and the solid was washed with DCM. The filtrates were concentrated undervacuum then heptane (22 mL) was added and the resulting mixture was concentrated. The solid was filtered, washed with heptane (15 mL) and dried under vacuum to afford the title intermediate (15.4 g, 72.4 mmol, 87percent yield). LC-MS (M-H) = 213.2
81%
Stage #1: With triethylamine In dichloromethane at 20℃; Cooling with ice Stage #2: With sodium hydrogencarbonate In dichloromethane; water
Synthesis of compound 3[0120] Pivaloyl chloride (18.7 mL, 151.6 mmol) was slowly added to an ice-cooled solution of 6-chloropyridin-2-amine (15 g, 116.7 mmol) and triethylamine (24.25 mL, 124.96 mmol) in DCM (180 mL). The mixture was stirred in an ice-bath for 15 min and then at rt for 6 h. The mixture was poured into water. The organic layer was washed with saturated aq NaHC03, brine, dried over anhydrous Na2S04; filtered and concentrated in vacuo to give N-(6- chloropyridin-2-yl)pivalamide (intermediate 5) (20.01 g, 81percent) as a yellow solid.
77.7%
With triethylamine In toluene at 60℃; for 16 h;
To a solution of 10.1 (7.0 g, 54.54 mmol, 1.0 equiv) and pivaloyl chloride (6.7 mL, 57.0 mmol, 1.05 equiv) in toluene was added Et3N (7.7 mL, 57.0 mmol, 2.5 equiv) and stirred at 60° C. for 16 hours. Upon completion, reaction mixture was poured into water (500 mL) and extracted with EtOAc (200 mL*3). Organic layers were combined, dried over sodium sulphate and concentrated under reduced pressure to obtain crude which was purified by column chromatography to provide pure 10.2 (9.0 g, 77.7percent). MS (ES): m/z 213.3 [M+H]+.
Reference：
[1] Patent: WO2011/50245, 2011, A1, . Location in patent: Page/Page column 118
[2] Patent: WO2008/128942, 2008, A1, . Location in patent: Page/Page column 33
[3] Journal of Medicinal Chemistry, 2000, vol. 43, # 16, p. 3134 - 3147
[4] Patent: WO2017/211759, 2017, A1, . Location in patent: Page/Page column 92
[5] Organic Process Research and Development, 2009, vol. 13, # 3, p. 555 - 566
[6] Patent: WO2012/3418, 2012, A2, . Location in patent: Page/Page column 47
[7] Journal of Organic Chemistry, 1983, vol. 48, # 20, p. 3401 - 3408
[8] Patent: US2016/251376, 2016, A1, . Location in patent: Paragraph 0431; 0432; 0433
[9] Journal of Organic Chemistry, 2005, vol. 70, # 5, p. 1771 - 1779
[10] Patent: WO2006/59164, 2006, A2, . Location in patent: Page/Page column 22
[11] Patent: WO2011/71725, 2011, A1, . Location in patent: Page/Page column 49
[12] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 23, p. 7107 - 7112
[13] Patent: CN105294688, 2016, A, . Location in patent: Paragraph 0031-0033
[14] Patent: WO2004/104001, 2004, A2, . Location in patent: Page 71
Conc. HNO3 (2.39 mL, 35.00 mmol) was added dropwise to a mixture of cone H2SO4 (56 mL, 1050 mmol) and 6-chloropyridin-2-amine (3.00 g, 23.34 mmol) at 0 °C. The mixture was stirred at 0 °C for 4 h and poured into ice-water. The mixture was extracted with EtOAc (3x100 mL). The combined organic layers were dried over anhydrous Na2S04 and concentrated. The residue was purified by chromatography to give the sub-title compound (1.38 g, 34 percent).
34%
at 0℃; for 4 h;
Cone. HNO3 (2.39 ml_, 35.00 mmol) was added dropwise to a mixture of cone H2SO4 (56 ml_, 1050 mmol) and 6-chloropyridin-2-amine (3.00 g, 23.34 mmol) at 0 °C. The mixture was stirred at 0 °C for 4 h and poured into ice-water. The mixture was extracted with EtOAc (3x100 ml_). The combined organic layers were dried over anhydrous Na2S04 and concentrated. The residue was purified by chromatography to give the sub-title compound (1.38 g, 34 percent).
Stage #1: With sodium hexamethyldisilazane In tetrahydrofuran at 20℃; Inert atmosphere Stage #2: With hydrogenchloride In water; ethyl acetate
tert-butyl (6-chloro-pyridin-2-yl)-carbamate Under a nitrogen atmosphere a solution of 32.7 g (0.15 mol) BOC anhydride in 100 mL THF was added dropwise at RT to 17.4 g (0.14 mol) 6-chloro-pyridin-2-ylamine and 300 mL (0.30 mol) of a 1 molar sodium hexamethyldisilazide solution in THF in 200 mL THF. The reaction mixture was stirred overnight at RT and then evaporated down. The residue was stirred between EtOAc and 1N aqueous hydrochloric acid solution. The organic phase was separated off and the aqueous phase was again extracted with EtOAc. The combined organic phases were washed with 300 mL saturated sodium hydrogen carbonate solution, dried and evaporated down. The residue was recrystallised from EtOH, the solid was suction filtered and dried.Yield: 29.2 g (95percent of theoretical)ESI-MS: m/z=228 (M+)Rt(HPLC): 1.70 min (method C)
95%
With sodium hexamethyldisilazane In tetrahydrofuran at 20℃; Inert atmosphere
Step 1: tert-butyl (6-chloro-pyridin-2-yl)-carbamate; Under a nitrogen atmosphere a solution of 32.7 g (0.150 mol) BOC-anhydride in 100 mL THF was added dropwise at RT to a mixture of 17.4 g (0.135 mol) 6-chloropyridin-2-ylamine and 300 mL (0.300 mol) of a sodium hexamethyldisilazide solution (1M in THF) in 200 mL of THF. The reaction mixture was stirred overnight at RT and evaporated down i.vac. The residue was stirred between EtOAc and 1N aqueous hydrochloric acid solution. The organic phase was separated off and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with saturated sodium hydrogen carbonate solution, dried and evaporated down. The residue was recrystallised from EtOH, the solid was suction filtered and dried.Yield: 29.2 g (95percent of theoretical)ESI-MS: m/z=228 (M+)Rt(HPLC): 1.70 min (method B)
95%
With sodium hexamethyldisilazane In tetrahydrofuran at 20℃; Inert atmosphere
Step 1: tert-butyl (6-chloro-pyridin-2-yl)-carbamate Under a nitrogen atmosphere a solution of 32.74 g (0.15 mol) BOC anhydride in 100 mL THF was added dropwise at RT to 17.36 g (0.14 mol) 6-chloro-pyridin-2-ylamine and 300 mL (0.30 mol) of a 1 molar sodium hexamethyldisilazide solution in THF in 200 mL THF. The reaction mixture was stirred overnight at RT and then evaporated down. The residue was stirred between EtOAc and 1 N aqueous hydrochloric acid solution. The organic phase was separated off and the aqueous phase was extracted again with EtOAc. The combined organic phases were washed with 300 mL saturated sodium hydrogen carbonate solution, dried and evaporated down. The residue was recrystallised from EtOH, the solid was suction filtered and dried overnight in the drying cupboard at 50° C.Yield: 29.20 g (95percent of theoretical)ESI-MS: m/z=228 (M+)Rt(HPLC): 1.70 min (method C)
88%
With sodium hexamethyldisilazane In tetrahydrofuran at 0 - 20℃; for 0.5 h;
Example 11A tert-Butyl (6-chloropyridin-2-yl)carbamate Under argon, 150 ml of THF were added to 23.4 g (181.8 mmol) of 2-chloro-5-aminopyridine, and the mixture was cooled to 0° C. 73.3 g (400 mmol) of sodium bis(trimethylsilyl)amide and 43.65 g (200 mmol) of di-tert-butyl dicarbonate, dissolved in 150 ml of THF, were added dropwise. After 15 min, the cooling bath was removed, and stirring was continued at RT for 15 min. The THF was removed using a rotary evaporator, ethyl acetate and 0.5 N hydrochloric acid were added to the residue and the mixture was extracted. The organic phase was separated off, dried over magnesium sulphate and concentrated using a rotary evaporator. The reaction mixture was chromatographed on silica gel (mobile phase dichloromethane/methanol 100percent-->100:3). This gave 36.54 g (88percent of theory) of the product as a solid. LCMS (method 3): Rt=2.41 min. (m/z=175 (M+H)+). 1H-NMR (400 MHz, DMSO-d6): δ=10.11 (s, 1H), 7.78 (d, 2H), 7.1 (t, 1H), 1.47 (s, 9H).
88%
With sodium hexamethyldisilazane In tetrahydrofuran at 0 - 20℃; Inert atmosphere
Example 105Atert-Butyl (6-chloropyridin-2-yl)carbamate 23.4 g (181.8 mmol) of 2-chloro-5-aminopyridine are mixed with 150 ml of THF under argon and cooled to 0° C. 73.3 g (400 mmol) of bis(trimethylsilyl)sodium amide and 43.65 g (200 mmol) of di-tert-butyl dicarbonate, dissolved in 150 ml of THF, are added dropwise. After 15 min, the cooling bath is removed and stirring is continued at RT for 15 min. The THF is removed in a rotary evaporator, and the residue is mixed and extracted with ethyl acetate and 0.5 N hydrochloric acid. The organic phase is separated off, dried over magnesium sulphate and concentrated in a rotary evaporator. The reaction mixture is chromatographed on silica gel (mobile phase dichloromethane/methanol 100percent-->100:3). 36.54 g (88percent of theory) of the product are obtained as a solid.LCMS (method 3): Rt=2.41 min. (m/z=175 (M+H)+).1H-NMR (400 MHz, DMSO-d6): d=10.11 (s, 1H), 7.78 (d, 2H), 7.1 (t, 1H), 1.47 (s, 9H).
88%
With sodium hexamethyldisilazane In tetrahydrofuran at 0 - 20℃; for 0.5 h; Inert atmosphere
Example 3Atert-Butyl(6-chloropyridin-2-yl)carbamate; Under argon, 150 ml of THF were added to 23.4 g (181.8 mmol) of 2-chloro-5-aminopyridine, and the mixture was cooled to 0° C. 73.3 g (400 mmol) of sodium bis(trimethylsilyl)amide and 43.65 g (200 mmol) of di-tert-butyl dicarbonate, dissolved in 150 ml of THF, were added dropwise. After 15 min, the cooling bath was removed and stirring was continued at RT for 15 min. The THF was removed on a rotary evaporator, ethyl acetate and 0.5N hydrochloric acid were added to the residue and the mixture was extracted. The organic phase was separated off, dried over magnesium sulfate and concentrated on a rotary evaporator. The reaction mixture was chromatographed on silica gel (mobile phase dichloromethane/methanol 100percent-->100:3). This gave 36.54 g (88percent of theory) of the product as a solid.LCMS (Method 3): Rt=2.41 min. (m/z=175 (M+H)+).1H-NMR (400 MHz, DMSO-d6): δ=10.11 (s, 1H), 7.78 (d, 2H), 7.1 (t, 1H), 1.47 (s, 9H).
88%
With sodium hexamethyldisilazane In tetrahydrofuran at 0 - 20℃; for 0.5 h; Inert atmosphere
Example 1A tert-Butyl (6-chloropyridin-2-yl)carbamate 23.4 g (181.8 mmol) of 2-chloro-5-aminopyridine were admixed with 150 ml of THF under argon and cooled to 0° C. 73.3 g (400 mmol) of sodium bis(trimethylsilyl)amide and 43.65 g (200 mmol) of di-tert-butyl dicarbonate, dissolved in 150 ml of THF, were added dropwise. After 15 min, the cooling bath was removed and the mixture was stirred at RT for a further 15 min. The THF was removed by rotary evaporation, and the residue was admixed and extracted with ethyl acetate and 0.5 N hydrochloric acid. The organic phase was removed, dried over magnesium sulphate and concentrated on a rotary evaporator. The reaction mixture was chromatographed on silica gel (eluent: dichloromethane/methanol 100percent→100:3). 36.54 g (88percent of theory) of the product were obtained in solid form. LCMS (method 3): Rt=2.41 min (m/z=175 (M+H)+). 1H NMR (400 MHz, DMSO-d6): δ=10.11 (s, 1H), 7.78 (d, 2H), 7.1 (t, 1H), 1.47 (s, 9H).
87.4%
Stage #1: With sodium hexamethyldisilazane In tetrahydrofuran at 0℃; for 0.0833333 h; Inert atmosphere Stage #2: at 0 - 20℃; for 1 h;
Sodium hexamethyl disilazane (63.03 g, 343 mmol) was added portion-wise to a stirred solution of 2-chloro-6-aminopyridine (20.0 g, 156.25 mmol) in THF (100 mL) at 0° C. under argon. After 5 minutes of stirring at the same temperature, di-tertiary-butyl dicarbonate (36.77 mL, 171 mmol) was added drop-wise into the reaction mixture. After 15 minutes of additional stirring at the same temperature, the reaction temperature was brought to room temperature and stirred until starting material was consumed completely (1 hour, monitored by silica gel TLC using ethyl acetate-hexanes, 1:9 as mobile phase). THF was distilled off under reduced pressure, the obtained residue was taken up in ethyl acetate (300 mL), washed with an aqueous solution of 0.5 M HCl (100 mL), water (2*75 mL), dried over anhydrous sodium sulfate, filtered and concentrated on the rotary evaporator to obtain a gummy mass, which was purified over silica gel column chromatography (eluant:EtOAc-hexanes, 1:19) to give (6-chloro-pyridin-2-yl)-carbamic acid tert-butyl ester as a white solid. (Yield 31.0 g, 87.4percent).
63.4%
Stage #1: With sodium hexamethyldisilazane In tetrahydrofuran at 0℃; Stage #2: at 0 - 20℃; for 1 h;
NaHMDS (351 ml, 0.7mol) in THF (300 ml) was cooled to 0 °C, a solution of 2-amino-6- chloropyridine (107; 40 g, 0.3 1 1 mol) in THF (300 ml) was added, followed by a solution of di- tert-butyl dicarbonate(68 g, 0.3 1 1 mol) in THF, ensuring the internal temperature remained below 0 °C. The resulting reaction mixture was aged for 1 h at room temp and then careful ly acidified to pH 3 by addition of 1 M hydrochloric acid, extracted with EtOAc, the combined organic layers were then washed sequentially with saturated aqueous NaHCCh and brine, dried over Na2S04, filtered, concentrated to afford crude product, Triturated with ether to afforded desired product tert-butyl 6-chloropyridin-2-ylcarbamate (108; 45g, yield 63.4percent). M S (ESI) calcd for C,oH,3CIN202 (m/z) 228.69.
To a solution of 2-amino-6-chloropyridine (15g, 116mmol) in chloroform (600ml) was added a solution of bromine (4.2g, 965mmol) in chloroform (50ml) at 0°C and the reaction mixture wasstirred at room temperature for 16h. After completion of reaction, the reaction was quenched over ice cold water; extracted to DCM and concentrated to obtain the crude compound. The crude compound was purified by silica gel column chromatography using 10percent ethyl acetate in hexane as eluent to afford the title compound (6.2g, 25.5percent). LCMS: m/z = 209.0 (M+1)+.
17%
With bromine In chloroform
A.1 3-Bromo-6-chloro-pyridin-2-ylamine[0328] 6-Chloro-pyridin-2-ylamine (5g, 38.89 mmol) is dissolved in chloroform (250 mL) and a solution of bromine (1.33 mL, 26 mmol) in chloroform (50 mL) is slowly added over a one hour period. During the addition a precipitate (hydrobromide salt of the starting material) forms. After stirring overnight the reaction mixture is filtered, the filtrate is evaporated and the residue is partitioned between ethyl acetate and 1 M sodium carbonate solution. The organic phase is separated, evaporated and the solid residue purified by flash chromatography (silica gel, 15 percent ethyl acetate in petroleum ether) affording the title compound (1.44 g, 17 percent) as a solid. The material is carried through the next three reaction steps.
With N-iodo-succinimide In N,N-dimethyl-formamide at 20℃; for 12 h;
To a solution of 6-chloropyridin-2-amine (50.0 g, 389 mmol) in DMF (700 mL) was added N-iodosuccinimide (105 g, 467 mmol). The brown solution was stirred at rt for 12 h. The mixture was poured into water (2.1 L) and filtered. The filter cake was washed with water (2*500 mL) and then dried under vacuum. Purification (FCC, SiO2; 5-20percent EtOAc/petroleum ether) afforded the title compound (83 g, 75percent) as a pink solid. MS (ESI): mass calcd. for C5H4ClIN2, 253.9; m/z found, 254.7 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J=8.0 Hz, 1H), 6.20 (d, J=8.0 Hz, 1H), 4.69 (br s, 2H).
73%
With N-iodo-succinimide In N,N-dimethyl-formamide for 43 h;
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). mp 154.3–155.9. 1H NMR (CDCl3) δ 7.75 (d, J=8.2Hz, 1H), 6.22 (d, J=8.2Hz, 1H). 13C NMR (CDCl3) δ 157.6, 151.6, 149.4, 108.8.
0.49 g
With N-iodo-succinimide In N,N-dimethyl-formamide at 20℃; for 16 h;
To an N,N-dimethylformamide (30 mL) solution of 2-amino-6-chloropyridine (1.0 g) was added N-iodosuccinimide (1.75 g) and the mixture stirred at room temperature for 16 hours. To the reaction mixture, water (200 mL) was added followed by extraction into ethyl acetate. The combined organic layers were dried, filtered and concentrated. The residue was triturated with dichloromethane and the resultant precipitate collected by filtration to give the title compound having the following physical properties (0.49 g). LC/MS tR 1.72 minutes; MS (ES+) m/z 254 (M+H) a.
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 5, p. 1697 - 1700
[2] Patent: US2018/111933, 2018, A1, . Location in patent: Paragraph 0243
[3] European Journal of Medicinal Chemistry, 2014, vol. 84, p. 404 - 416
[4] Patent: WO2013/93484, 2013, A1, . Location in patent: Page/Page column 243
[5] Patent: WO2016/168098, 2016, A1, . Location in patent: Page/Page column 50
33
[ 45644-21-1 ]
[ 1221398-11-3 ]
Yield
Reaction Conditions
Operation in experiment
6.1 g
at 80℃; for 4 h;
2-chloro-6-aminopyridine (23.0 g, 178 mmol) and potassium acetate (17.5 g, 178 mmol) were dissolved in 200 mL acetic acid and heated to 80° C. A solution of ICl (29.05 g, 178 mmol) in acetic acid (40 mL) was added dropwise and the reaction mixture was stirred at 80° C. for 4 h. The reaction mixture was cooled to room temperature and the acetic acid was removed under reduced pressure. The residue was dissolved in ethyl acetate and neutralized by saturated aq. NaHCO3solution. The organic layer was washed with saturated aq. NaHSO3, dried over Na2SO4, concentrated and purified by silica column using hexanes and ethyl acetate as eluent. Isolated 6.1 g of title compound.
In a 600 mL autoclave equipped with a gas entrapment stirrer 240 g aqueous ammonia (28% NH3 by weight) was added and mixed with 120 g of 2, 6-dichloropyridine. After purging with nitrogen, 48 g of liquid ammonia were added, and the reaction mixture was heated to 150C for 6 h under stirring. The reaction mixture was allowed to cool to room temperature, and the pressure was brought back to atmospheric pressure . The product was isolated by filtration, washed with water and MeOH and dried. The yield for 2-chloro-6-amino pyridine was about 70%, and the purity as determined by GC chromatography was 98%.
With ammonium hydroxide; In ethanol;
Step A. A solution of 2,6-dichloropyridine (120 mmol) in ethanol was treated with aqueous ammonia solution (28%, excess) at 160-165 C. for 60 h in a sealed tube. Extraction and chromatography gave 2-amino-6-chloropyridine as a white solid.
With ammonia; In ethanol; at 160 - 165℃; for 60h;
Step A. A solution of 2,6-dichloropyridine (120 mmol) in ethanol was treated with aqueous ammonia solution (28%, excess) at 160-165 C. for 60 h in a sealed tube.. Extraction and chromatography gave 2-amino-6-chloropyridine as a white solid.
With ammonium hydroxide; In ethanol;
Step A. A solution of 2,6-dichloropyridine (120 mmol) in ethanol was treated with aqueous ammonia solution (28%, excess) at 160-165 C. for 60 h in a sealed tube. Extraction and chromatography gave 2-amino-6-chloropyridine as a white solid.
With triethylamine; In dichloromethane; at 0 - 20℃; for 5h;
To a suspension of 6-chloro-pyridin-2-ylamine 13-1 (0.30 g, 2.33 mmol) and triethlyamine (0.41 mL, 2.92 mmol) in anhydrous methylene chloride at 0 C was added a solution of trichloromethylacetyl chloride (0.32 mL, 2.57 mmol) in anhydrous methylene chloride. The mixture was stirred at 0 C for 50 min, before allowing it to gradually warm up to room temperature. After 5 h, the reaction mixture was poured into water and the organic phase separated. The aqueous layer was extracted with methylene chloride and the combined organic phases were dried and concentrated. The product was purified by flash chromatography using Combiflash employing a gradient of 0-15% EtOAc in Hexanes to afford 0.48 g (2.28 mmol, 98% yield) of 13-2 as a white solid.
92%
With triethylamine; In toluene; at 20 - 50℃; for 22h;
Example 2; l-({4-[([l,3]Oxathiolo[5,4-c]pyridin-6-ylmethyl)amino]-l- piperidinyl} methyl)- 1 ,2-dihydro-4H,9H-imidazo [1 ,2,3-ij ] -1 ,8-naphthyridine-4,9- dione hydrochloride; (a) lambda/-(6-Chloro-2-pyridinyl)-2,2-dimethylpropanamide; A solution of 6-chloro-2-pyridinamine (13.776g, 107 mmol) in toluene (100ml) and triethylamine (16.28ml, 118 mmol) at 500C under argon was treated with 2,2- dimethylpropanoyl chloride (13.81ml, 112mmol). The reaction was then stirred at 500C for 4h and then at rt for 18h. 2M HCl (200ml) was then added and the mixture was extracted with diethyl ether (3 x 500ml). The organic extracts were dried (MgSO4), filtered and evaporated to give the product as a brown solid (21.005g, 92%). MS (ES+) m/z 213/215 (MH+).
87%
With sodium hydrogencarbonate; In toluene; at 0 - 20℃; for 5h;
To a solution of <strong>[45644-21-1]2-amino-6-chloropyridine</strong> (10.7 g, 83.5 mmol) in toluene (103 mL) NaHCO3 (14 g, 167 mmol) and pivaloyl chloride (15.4 mL, 125.2 mmol) were added at 0C. The resulting mixture was stirred at room temperature for 5 hours then the suspension was filtered and the solid was washed with DCM. The filtrates were concentrated undervacuum then heptane (22 mL) was added and the resulting mixture was concentrated. The solid was filtered, washed with heptane (15 mL) and dried under vacuum to afford the title intermediate (15.4 g, 72.4 mmol, 87% yield). LC-MS (M-H) = 213.2
81%
Synthesis of compound 3[0120] Pivaloyl chloride (18.7 mL, 151.6 mmol) was slowly added to an ice-cooled solution of <strong>[45644-21-1]6-chloropyridin-2-amine</strong> (15 g, 116.7 mmol) and triethylamine (24.25 mL, 124.96 mmol) in DCM (180 mL). The mixture was stirred in an ice-bath for 15 min and then at rt for 6 h. The mixture was poured into water. The organic layer was washed with saturated aq NaHC03, brine, dried over anhydrous Na2S04; filtered and concentrated in vacuo to give N-(6- chloropyridin-2-yl)pivalamide (intermediate 5) (20.01 g, 81%) as a yellow solid.
77.7%
With triethylamine; In toluene; at 60℃; for 16h;
To a solution of 10.1 (7.0 g, 54.54 mmol, 1.0 equiv) and pivaloyl chloride (6.7 mL, 57.0 mmol, 1.05 equiv) in toluene was added Et3N (7.7 mL, 57.0 mmol, 2.5 equiv) and stirred at 60 C. for 16 hours. Upon completion, reaction mixture was poured into water (500 mL) and extracted with EtOAc (200 mL*3). Organic layers were combined, dried over sodium sulphate and concentrated under reduced pressure to obtain crude which was purified by column chromatography to provide pure 10.2 (9.0 g, 77.7%). MS (ES): m/z 213.3 [M+H]+.
With triethylamine; In dichloromethane; at 0 - 20℃; for 5.83333h;
Preparation 9 : N-(6-Chloropyridin-2-yl)-2,2-dimethyl propionamide; To a solution of <strong>[45644-21-1]2-amino-6-chloropyridine</strong> (3.0g, 23.3mmol) in DCM (45mL) under argon was added triethylamine (4.1OmL, 29.2mmol) and the reaction cooled to O0C (ice bath). A solution of trimethylacetyl chloride (3.16mL, 25.7mmol) in DCM (1OmL) was added dropwise over 20min before stirring for 30min at O0C. The reaction was brought up to rt and stirred for a further 5h, then water (3OmL) was added. The organics were separated and washed with Na2CO3 solution (2x50mL), dried (MgSO4) and the solvent removed in vacuo. Purification by column chromatography (SiO2, DCM) gave the title compound, m/z (ES+) = 213.04 [M+ H]+.
With triethylamine; In dichloromethane; at 20℃; for 16h;
Step 1: Synthesis of N-(6-Chloropyridin-2-yl)-2,2-dimethylpropionamide To a solution of 6-chloro-2-aminopyidine (50 g, 389 mmol) and triethylamine (68 mL, 486 mmol) in dry CH2C12 (250 mL) at 0 C is added pivaloyl chloride (52 g, 428 mmol), dropwise. The reaction mixture is stirred at ambient temperature for 16 h. Saturated NH4CI solution (100 mL) is added and the mixture is extracted with CH2C12 (3 x 200 mL). The combined organic layers are washed with saturated NaHC03 solution, dried (Na2S04) and evaporated to afford the title compound as an off-white solid (70 g, 86%) which is used in the next step without purification.
In N,N-dimethyl-formamide; for 6h;
Pivaloyl chloride (18.7mL, 151.6mmol) and <strong>[45644-21-1]6-chloropyridin-2-amine</strong> (15g, 116.7mmol) were dissolved together in DMF (180 mL), and then stirring slowly dropping Stuttgart pivaloyl chloride (18.7mL, 151.6mmol). Stirring was continued for 6h, and then the system was Department poured into water, separated, the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated to dryness to give compound (2) to crude Product 15.8g. It was used directly in the next step
With triethylamine; In dichloromethane; at 0 - 20℃; for 5.83333h;
To a solution of <strong>[45644-21-1]2-amino-6-chloropyridine</strong> (3. 0G, 23. 3MMOL) in dichloromethane (45mL) under argon was added triethylamine (4. 10ML, 29. 2MMOL) and the reaction cooled to 0C (ice bath). A solution of trimethylacetyl chloride (3.16mL, 25. 7MMOL) in dichloromethane (lOmL) was added dropwise over 20min before stirring for 30min at 0C. The reaction was brought up to rt and stirred for a further 5h, then water (30mL) was added. The organics were separated and washed with Na2CO3 solution (2X50ML), dried (MGS04) and solvent removed in vacuo. Purification by column chromatography (SI02, CH2C12) gave the title compound. m/z (ES+) = 213.04 [M+ H] +.
With copper(II) sulfate In ethanol; water at 180 - 190℃; for 38h;
In water at 190℃; for 1h; Microwave;
10
The 2-amino-6-dimethylaminopyridine used as a starting material was prepared as follows :-A mixture of 2-amino-6-chloropyridine (0.4 g) and an aqueous solution of dimethylamine (40%, 1.41 ml) was stirred and heated to 19O0C for 1 hour in a microwave oven. The reaction mixture was purified by column chromatography on silica using a 20: 1 mixture of methylene chloride and methanol as eluent. There was thus obtained the required starting material (0.38 g); 1H NMR: (CDCl3) 3.02 (s, 6H), 4.15 (br s, 2H), 5.79 (d, IH), 5.9 (d, IH), 7.25 (t, IH); Mass Spectrum: M+H* 138.
tert-butyl (6-chloro-pyridin-2-yl)-carbamate Under a nitrogen atmosphere a solution of 32.7 g (0.15 mol) BOC anhydride in 100 mL THF was added dropwise at RT to 17.4 g (0.14 mol) 6-chloro-pyridin-2-ylamine and 300 mL (0.30 mol) of a 1 molar sodium hexamethyldisilazide solution in THF in 200 mL THF. The reaction mixture was stirred overnight at RT and then evaporated down. The residue was stirred between EtOAc and 1N aqueous hydrochloric acid solution. The organic phase was separated off and the aqueous phase was again extracted with EtOAc. The combined organic phases were washed with 300 mL saturated sodium hydrogen carbonate solution, dried and evaporated down. The residue was recrystallised from EtOH, the solid was suction filtered and dried.Yield: 29.2 g (95% of theoretical)ESI-MS: m/z=228 (M+)Rt(HPLC): 1.70 min (method C)
95%
With sodium hexamethyldisilazane; In tetrahydrofuran; at 20℃;Inert atmosphere;
Step 1: tert-butyl (6-chloro-pyridin-2-yl)-carbamate; Under a nitrogen atmosphere a solution of 32.7 g (0.150 mol) BOC-anhydride in 100 mL THF was added dropwise at RT to a mixture of 17.4 g (0.135 mol) <strong>[45644-21-1]6-chloropyridin-2-ylamine</strong> and 300 mL (0.300 mol) of a sodium hexamethyldisilazide solution (1M in THF) in 200 mL of THF. The reaction mixture was stirred overnight at RT and evaporated down i.vac. The residue was stirred between EtOAc and 1N aqueous hydrochloric acid solution. The organic phase was separated off and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with saturated sodium hydrogen carbonate solution, dried and evaporated down. The residue was recrystallised from EtOH, the solid was suction filtered and dried.Yield: 29.2 g (95% of theoretical)ESI-MS: m/z=228 (M+)Rt(HPLC): 1.70 min (method B)
95%
With sodium hexamethyldisilazane; In tetrahydrofuran; at 20℃;Inert atmosphere;
Step 1: tert-butyl (6-chloro-pyridin-2-yl)-carbamate Under a nitrogen atmosphere a solution of 32.74 g (0.15 mol) BOC anhydride in 100 mL THF was added dropwise at RT to 17.36 g (0.14 mol) 6-chloro-pyridin-2-ylamine and 300 mL (0.30 mol) of a 1 molar sodium hexamethyldisilazide solution in THF in 200 mL THF. The reaction mixture was stirred overnight at RT and then evaporated down. The residue was stirred between EtOAc and 1 N aqueous hydrochloric acid solution. The organic phase was separated off and the aqueous phase was extracted again with EtOAc. The combined organic phases were washed with 300 mL saturated sodium hydrogen carbonate solution, dried and evaporated down. The residue was recrystallised from EtOH, the solid was suction filtered and dried overnight in the drying cupboard at 50 C.Yield: 29.20 g (95% of theoretical)ESI-MS: m/z=228 (M+)Rt(HPLC): 1.70 min (method C)
88%
With sodium hexamethyldisilazane; In tetrahydrofuran; at 0 - 20℃; for 0.5h;
Example 11A tert-Butyl (6-chloropyridin-2-yl)carbamate Under argon, 150 ml of THF were added to 23.4 g (181.8 mmol) of 2-chloro-5-aminopyridine, and the mixture was cooled to 0 C. 73.3 g (400 mmol) of sodium bis(trimethylsilyl)amide and 43.65 g (200 mmol) of di-tert-butyl dicarbonate, dissolved in 150 ml of THF, were added dropwise. After 15 min, the cooling bath was removed, and stirring was continued at RT for 15 min. The THF was removed using a rotary evaporator, ethyl acetate and 0.5 N hydrochloric acid were added to the residue and the mixture was extracted. The organic phase was separated off, dried over magnesium sulphate and concentrated using a rotary evaporator. The reaction mixture was chromatographed on silica gel (mobile phase dichloromethane/methanol 100%?100:3). This gave 36.54 g (88% of theory) of the product as a solid. LCMS (method 3): Rt=2.41 min. (m/z=175 (M+H)+). 1H-NMR (400 MHz, DMSO-d6): delta=10.11 (s, 1H), 7.78 (d, 2H), 7.1 (t, 1H), 1.47 (s, 9H).
88%
With sodium hexamethyldisilazane; In tetrahydrofuran; at 0 - 20℃;Inert atmosphere;
Example 105Atert-Butyl (6-chloropyridin-2-yl)carbamate 23.4 g (181.8 mmol) of 2-chloro-5-aminopyridine are mixed with 150 ml of THF under argon and cooled to 0 C. 73.3 g (400 mmol) of bis(trimethylsilyl)sodium amide and 43.65 g (200 mmol) of di-tert-butyl dicarbonate, dissolved in 150 ml of THF, are added dropwise. After 15 min, the cooling bath is removed and stirring is continued at RT for 15 min. The THF is removed in a rotary evaporator, and the residue is mixed and extracted with ethyl acetate and 0.5 N hydrochloric acid. The organic phase is separated off, dried over magnesium sulphate and concentrated in a rotary evaporator. The reaction mixture is chromatographed on silica gel (mobile phase dichloromethane/methanol 100%?100:3). 36.54 g (88% of theory) of the product are obtained as a solid.LCMS (method 3): Rt=2.41 min. (m/z=175 (M+H)+).1H-NMR (400 MHz, DMSO-d6): d=10.11 (s, 1H), 7.78 (d, 2H), 7.1 (t, 1H), 1.47 (s, 9H).
88%
With sodium hexamethyldisilazane; In tetrahydrofuran; at 0 - 20℃; for 0.5h;Inert atmosphere;
Example 3Atert-Butyl(6-chloropyridin-2-yl)carbamate; Under argon, 150 ml of THF were added to 23.4 g (181.8 mmol) of 2-chloro-5-aminopyridine, and the mixture was cooled to 0 C. 73.3 g (400 mmol) of sodium bis(trimethylsilyl)amide and 43.65 g (200 mmol) of di-tert-butyl dicarbonate, dissolved in 150 ml of THF, were added dropwise. After 15 min, the cooling bath was removed and stirring was continued at RT for 15 min. The THF was removed on a rotary evaporator, ethyl acetate and 0.5N hydrochloric acid were added to the residue and the mixture was extracted. The organic phase was separated off, dried over magnesium sulfate and concentrated on a rotary evaporator. The reaction mixture was chromatographed on silica gel (mobile phase dichloromethane/methanol 100%?100:3). This gave 36.54 g (88% of theory) of the product as a solid.LCMS (Method 3): Rt=2.41 min. (m/z=175 (M+H)+).1H-NMR (400 MHz, DMSO-d6): delta=10.11 (s, 1H), 7.78 (d, 2H), 7.1 (t, 1H), 1.47 (s, 9H).
88%
With sodium hexamethyldisilazane; In tetrahydrofuran; at 0 - 20℃; for 0.5h;Inert atmosphere;
Example 1A tert-Butyl (6-chloropyridin-2-yl)carbamate 23.4 g (181.8 mmol) of 2-chloro-5-aminopyridine were admixed with 150 ml of THF under argon and cooled to 0 C. 73.3 g (400 mmol) of sodium bis(trimethylsilyl)amide and 43.65 g (200 mmol) of di-tert-butyl dicarbonate, dissolved in 150 ml of THF, were added dropwise. After 15 min, the cooling bath was removed and the mixture was stirred at RT for a further 15 min. The THF was removed by rotary evaporation, and the residue was admixed and extracted with ethyl acetate and 0.5 N hydrochloric acid. The organic phase was removed, dried over magnesium sulphate and concentrated on a rotary evaporator. The reaction mixture was chromatographed on silica gel (eluent: dichloromethane/methanol 100%?100:3). 36.54 g (88% of theory) of the product were obtained in solid form. LCMS (method 3): Rt=2.41 min (m/z=175 (M+H)+). 1H NMR (400 MHz, DMSO-d6): delta=10.11 (s, 1H), 7.78 (d, 2H), 7.1 (t, 1H), 1.47 (s, 9H).
87.4%
Sodium hexamethyl disilazane (63.03 g, 343 mmol) was added portion-wise to a stirred solution of <strong>[45644-21-1]2-chloro-6-aminopyridine</strong> (20.0 g, 156.25 mmol) in THF (100 mL) at 0 C. under argon. After 5 minutes of stirring at the same temperature, di-tertiary-butyl dicarbonate (36.77 mL, 171 mmol) was added drop-wise into the reaction mixture. After 15 minutes of additional stirring at the same temperature, the reaction temperature was brought to room temperature and stirred until starting material was consumed completely (1 hour, monitored by silica gel TLC using ethyl acetate-hexanes, 1:9 as mobile phase). THF was distilled off under reduced pressure, the obtained residue was taken up in ethyl acetate (300 mL), washed with an aqueous solution of 0.5 M HCl (100 mL), water (2*75 mL), dried over anhydrous sodium sulfate, filtered and concentrated on the rotary evaporator to obtain a gummy mass, which was purified over silica gel column chromatography (eluant:EtOAc-hexanes, 1:19) to give (6-chloro-pyridin-2-yl)-carbamic acid tert-butyl ester as a white solid. (Yield 31.0 g, 87.4%).
63.4%
NaHMDS (351 ml, 0.7mol) in THF (300 ml) was cooled to 0 C, a solution of 2-amino-6- chloropyridine (107; 40 g, 0.3 1 1 mol) in THF (300 ml) was added, followed by a solution of di- tert-butyl dicarbonate(68 g, 0.3 1 1 mol) in THF, ensuring the internal temperature remained below 0 C. The resulting reaction mixture was aged for 1 h at room temp and then careful ly acidified to pH 3 by addition of 1 M hydrochloric acid, extracted with EtOAc, the combined organic layers were then washed sequentially with saturated aqueous NaHCCh and brine, dried over Na2S04, filtered, concentrated to afford crude product, Triturated with ether to afforded desired product tert-butyl 6-chloropyridin-2-ylcarbamate (108; 45g, yield 63.4%). M S (ESI) calcd for C,oH,3CIN202 (m/z) 228.69.
56%
With lithium hexamethyldisilazane; In tetrahydrofuran; at 20℃;
Drop in a solution of <strong>[45644-21-1]2-amino-6-chloropyridine</strong> (40.0 g, 311 mmol) and bistrimethylsilylamide lithium (685 mL, 685 mmol, 1 M in tetrahydrofuran) in tetrahydrofuran (400 mL) Di-tert-butyl dicarbonate (74.7 g, 342 mmol) was added. The reaction system was stirred at room temperature overnight, then concentrated, diluted with ethyl acetate (400 mL), and the organic phase was washed with hydrochloric acid (1M), saturated aqueous sodium hydrogen carbonate and brine, The sodium was dried, filtered and concentrated, and the obtained residue was recrystallized from ethanol and filtered. The filter cake was dried to give compound 1.1 (39.5 g, yield: 56%) as a yellow solid.
With hydrogenchloride; In dichloromethane; water;
a) 2-tert-Butoxycarbonylamino-6-chloropyridine. A solution of 4.36 g (0.02 mol) of di-tert-butyl dicarbonate in 10 ml of methylene chloride is added dropwise to a solution of 2.57 g (0.02 mol) of <strong>[45644-21-1]2-amino-6-chloropyridine</strong> in 25 ml of methylene chloride. It is left at ambient temperature overnight, washed with a 1N solution of HCl and with water, and is dried over sodium sulphate and concentrated in vacuum to obtain 4.0 g of the compound referred to above, as a yellow oil.
With sodium hexamethyldisilazane; In tetrahydrofuran; for 24h;
To a solution of <strong>[45644-21-1]2-amino-6-chloropyridine</strong> (5.24 g, 40.8 mmol) and sodium hexamethyldisilazide (1.0 M, 89.8 mL, 89.8 mmol) in TEtaF (35 mL) was added a solution of di-tert-butyl dicarbonate (9.80 g, 44.9 mmol) in TEtaF (35 mL). After 24 h the reaction was concentrated and the residue was partitioned between EtOAc (30 mL) and IN HCl (100 mL). The aqueous layer was extracted further with EtOAc (2x). The combined organic layers were washed with NaEtaCOs, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of 20 to 100% dichloromethane: hexane to give the title compound (7.73 g). MS: m/z = 173.0 (M - 1Bu).
With sodium hexamethyldisilazane; In tetrahydrofuran; for 24h;
INTERMEDIATE 2; Spirorpiperidine-4.4'-pyridor2.3-6?ri.31oxazin1-2'd'H)-one; Step A. tot-Butyl (6-chloropyridin-2-yl)carbamate; To a solution of <strong>[45644-21-1]2-amino-6-chloropyridine</strong> (5.24 g, 40.8 mmol) and sodium hexamethyldisilazide (1.0 M, 89.8 mL, 89.8 mmol) in TEtaF (35 mL) was added a solution of di-tert-butyl dicarbonate (9.80 g, 44.9 mmol) in TEtaF (35 mL). After 24 h the reaction was concentrated and the residue was partitioned between EtOAc (30 mL) and IN HCl (100 mL). The aqueous layer was extracted further with EtOAc (2x). The combined organic layers were washed with NaHCO3, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel EPO <DP n="56"/>chromatography, eluting with a gradient of 20 to 100% dichloromethane: hexane to give the title compound (7.73 g). MS: mlz = 173.0 (M - 'Bu).
With sodium hexamethyldisilazane; In tetrahydrofuran; for 48h;
INTERMEDIATE 12 EPO <DP n="80"/> Spirorpirhoeridine-4.4'-pyrido|"2.3-Jiri31oxazin]-2'(rH)-one Step A. tert-Butyl f-chloropyridin^-yPcarbamate; To a solution of <strong>[45644-21-1]2-amino-6-chloropyridine</strong> (25.0 g, 194.5 mmol) and sodium hexamethyldisilazide (1.0 M; 427.8 mL, 427.8 mmol) in tetrahydrofuran (175 mL) was added a solution of di-tert-butyl dicarbonate (46.69 g, 213.9 mmol) in tetrahydrofuran (175 mL). After 48 h, the reaction mixture was concentrated and the residue was partitioned between ethyl acetate (150 mL) and IN HCl (500 mL). The aqueous layer was extracted further with ethyl acetate (2x). The combined organic layers were washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated. Recrystalization was accomplished by dissolving the crude residue in a minimal amount of ethanol at 60 0C. The solution was allowed to cool to ambient temperature and water was added. Precipitated solid was filtered and dried to give the title compound (33.45 g). MS: mlz = 173.0 (M - 1Bu).
With sodium hexamethyldisilazane; In tetrahydrofuran; for 24h;
To a solution of <strong>[45644-21-1]2-amino-6-chloropyridine</strong> (5.24 g, 40.8 mmol) and sodium hexamethyldisilazide (1.0 M, 89.8 mL, 89.8 mmol) in TEtaF (35 mL) was added a solution of di-tert-butyl dicarbonate (9.80 g, 44.9 mmol) in TEtaF (35 mL). After 24 h the reaction was concentrated and the residue was partitioned between EtOAc (30 mL) and IN HCl (100 mL). The aqueous layer was extracted further with EtOAc (2x). The combined organic layers were washed with NaHCO3, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of 20 to 100% dichloromethane: hexane to give the title compound (7.73 g). MS: mlz = 173.0 (M - 1Bu).
In tert-butyl methyl ether; at 35℃; for 6h;Green chemistry;
Starting with <strong>[45644-21-1]6-chloro-2-aminopyridine</strong> in methyl tert-butyl etherDi-tert-butyl dicarbonate is subjected to a condensation reaction in a stirred state,<strong>[45644-21-1]6-chloro-2-aminopyridine</strong>,Methyl tert-butyl ether and di-tert-butyl dicarbonate in a molar ratio of 1: 20:The condensation reaction temperature was 35 C,The condensation reaction time was 6 h,TLC plate to determine the reaction is completed,The reaction solution was distilled to dryness,To give 6-chloro-2-tert-butoxycarbonylaminopyridine, 6-chloro-2-tert-butoxycarbonylaminopyridine was added to a sodium hydroxide solution having a mass percentage of 4.2%Tetrabutylammonium bromide,P-xylene and water, and the hydrolysis reaction is carried out in a stirred state,6-chloro-2-tert-butoxycarbonylaminopyridine,The concentration of 4.2% sodium hydroxide solution,Tetrabutylammonium bromide,The molar ratio of p-xylene to water is 1: 1: 0.05: 0.06: 25: 50,The temperature of the hydrolysis reaction was 90 C,The hydrolysis time was 8 h,TLC plate to determine the reaction is completed,Down to room temperature,Adding methylene chloride and water,The organic phase is separated,First with water,And then washed with salt,And then dried with magnesium sulfate,Steamed to dry,The residue was purified by recrystallization from a methanol-isopropanol mixed solvent,To give 6-hydroxy-2-tert-butoxycarbonylaminopyridine as an off-white solid,Yield 88.7%The reaction of this step is the same as in Example 1;
With sodium hexamethyldisilazane; In tetrahydrofuran; at 20℃; for 20h;
<strong>[45644-21-1]2-amino-6-chloropyridine</strong> and sodium bis(trimethylsilyl)amide are dissolved in tetrahydrofuran. A solution of di-tert-butyl dicarbonate in tetrahydrofuran is added dropwise. The reaction mixture is stirred at room temperature for twenty hours. Water and ethyl acetate are added, and the product is extracted with ethyl acetate. The organic phases are combined, washed once with water and once with a saturated aqueous solution of sodium chloride, then dried over magnesium sulphate, filtered and concentrated under vacuum. (6-Chloro-pyridin-2-yl)-tert-butyl carbamate is obtained in the form of a brown solid.
With triethylamine; In chloroform; at 0 - 5℃; for 12h;Inert atmosphere;
General procedure: To a solution of theappropriate amine (31-44, 10 mmol) and triethylamine (10 mmol) in anhydrous chloroform was added dropwisechloroacetylcloride (30, 12 mmol) at0-5 C and the mixture was stirred for 12 h at the same temperature under N2.Then the solvent was removed under vacuum, and the residue dissolved in ethylacetate was once washed with water. The organic phase was stirred with 10%activated charcoal for 30 min and filtered through a neutral alumina bed.Finally, the solvent was distilled under vacuum. It is worth mentioning thatall the products obtained decompose rapidly, therefore they were used immediatelyin the next reaction.
With potassium phosphate; 1,1'-bis(di-tertbutylphosphino)ferrocene; palladium diacetate; In 1,4-dioxane; at 100℃; for 5h;Inert atmosphere; Sealed tube;
General procedure: To a solution of the requisite chloro-amino-substituted heteroaromatic in anhydrous 1,4-dioxane (30 volumes wrt chloride) in a sealed tube was introduced phenylboronic acid (1.5 equiv) and finely ground potassium phosphate (2.0 equiv). The solution was degassed (N2 bubbling) for 5 min, Pd(OAc)2 (5 mol % wrt chloride) and di-tert-butylphosphinoferrocene (5 mol % wrt chloride) introduced and degassing continued for a further 5 min. The tube was sealed under nitrogen and heated with rapid stirring at 100 C for 5 h. After cooling, the reaction mixture was filtered in vacuo through a celite pad and the precipitated material washed with 1,4-dioxane. The combined filtrates were evaporated and purified by flash column chromatography (neat hexane to 1:1 hexane/EtOAc gradient containing 2.5% by volume Et3N) to furnish the biarylanilines 13, 14 and 15.
Example 25-(Piperidin-4-yloxy)-imidazo[1 ,2-a]pyridine-2-carboxylic acid [5-(3-trifluoromethyl-phenyl)-1 H-benzoimidazol-2-yl]-amide trihydrochlorideStep 1. To 2-amino-6-chloropyridine (12.9 g) in ethanol (100 ml_) was added ethyl bromopyruvate (39.6 ml_) and stirred under reflux for 3 hours. The reaction mixture became a brown color. The reaction mixture was cooled to room temperature, and ethyl acetate was added to precipitate the product, which was filtered, washed with ethyl acetate and dried to give delta-chloro-imidazoli ^-ajpyridine^-carboxylic acid ethyl ester (17.2 g). LCMS (m/z): 225.2.
In ethanol;Heating / reflux;
An ethanol solution (300 mL) of 6-chloro-2-aminopyridine (14.88 g) and ethyl bromopyruvate (30 g) was refluxed overnight. The reaction solution was concentrated under reduced pressure, and extracted with water after addition of diethyl ether. The aqueous layer was made basic with aqueous sodium carbonate solution, and extracted with ethyl acetate-tetrahydrofuran. The extract was washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was recrystallized from diisopropyl ether to obtain ethyl 5-chloroimidazo[1,2-a]pyridine-2-carboxylate (19.69 g) as colorless crystals. 1H-NMR (CDCl3, 400MHz); delta 1.45 (3H, t, J=7.2Hz), 4.48 (2H, q, J=7.2Hz), 6.98 (1H, dd, J=0.8, 7.2Hz), 7.26 (1H, dd, J=7.2, 9.2Hz), 7.67 (1H, dt, J=0.8, 9.2Hz), 8.38 (1H, d, J=0.8Hz)
2-chloro-6-(2,5-dimethyl-1H-pyrrol-1-yl)pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96%
With toluene-4-sulfonic acid; In toluene; at 120℃; for 3h;Large scale;
2-chloro-6-(2,5-dimethyl-lH-pyrrol-l-yl)pyridine A solution of commercially available 6-chloropyridin-2 amine (1.0 g, 7.78 mmol, leq.), 2,5-butanedione (1.06 g, 9.33 mmol, 1.2 eq.) and p-toluenesulfonic acid monohydrate (9 mg, 0.093 mmol, 0.01 eq.) in toluene (10 mL) was heated at l20C with azeotropic removal of water for about 3 hours. After cooling to room temperature, the resulting mixture was diluted with EtOAc (10 mL), washed successively with a saturated solution of NaHCO , water and brine. The organic fraction was than dried with Na2S04. The reaction mixture was then concentrated under vacuum and the crude product was purified by chromatography on silica gel using a EtOAc / heptane: 1/8 as eluent to afford the expected product 2-chloro-6-(2,5-dimethyl-lH-pyrrol-l-yl)pyridine (1,542 g, 96 %). 1H-NMR (400 MHz, CDCI3): d 7.76 (t, 7= 7.8 Hz, 1H), 7.31 (d, 7= 7.8 Hz, 1H), 7.13 (d, 7= 7.8 Hz, 1H), 5.88 (s, 3H), 2.14 (s, 6H).13C-NMR (101 MHz, CDCb): d 151.9, 150.6, 140.3, 128.9, 122.8, 120.2, 107.7, 13.5
10
The 2-amino-6-methylaminopyridine used as a starting material was prepared as follows :- A mixture of 2-amino-6-chloropyridine (0.5 g) and an aqueous solution of methylamine(40%, 2.19 ml) was placed in a glass cylinder which was sealed and heated to 2000C for 2 hours. The reaction mixture was cooled to ambient temperature and purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and EPO methanol as eluent. There was thus obtained the required starting material (0.11 g); 1H NMR: (CDCl3) 2.84 (s, 3H), 4.15 (br s, 2H), 4.28 (br s, IH), 5.76 (d, IH), 5.83 (d, IH), 7.25 (t, IH).
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 0 - 25℃; for 2h;
Step 1. 4-Amino-N-(6-chloropyridin-2-yl)-1,2,5-oxadiazole-3-carboxamide A solution of <strong>[78350-50-2]4-amino-1,2,5-oxadiazole-3-carboxylic acid</strong> (0.4 g, 3.1 mmol) and 6-chloropyridin-2-amine (0.56 g, 4.3 mmol) in N,N-dimethylformamide (6.2 mL) was treated with N,N,N',N-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (1.4 g, 3.7 mmol) followed by N,N-diisopropylethylamine (0.76 mL, 4.3 mmol) at 0 C. The reaction mixture was stirred at 25 C. for 2 h, poured into saturated NaHCO3 (50 mL) and extracted with ethyl acetate (100 mL). The organic layer was separated and washed with brine (25 mL), dried with sodium sulfate, filtered, and concentrated to a crude solid. The crude solid was washed with ethyl acetate and filtered. The filtrate was concentrated and purified on silica gel to give the desired product with some impurities. The impurities were removed by washing the solid with chloroform to yield the desired product (65 mg, 9%). LCMS for C8H7ClN5O2 (M+H)+: m/z=240.1.
With sodium hydrogencarbonate In ethanol at 90℃; for 16h;
5-chloroimidazo[l,2-a]pyridine:
NaHCO3 (980.4 mg, 11.67 mmol) and 2- chloro acetaldehyde (1.22 g, 15.56 mmol) were added to a solution of 6-chloropyridin-2- amine (1.0 g, 7.78 mmol) in EtOH (15 mL) and the mixture stirred at 90°C for 16 hours. The reaction mixture was evaporated to dryness in vacuo and the residue extracted with EtOAc (2 x 20 mL). The organic phase was washed with brine (2 x 10 mL), dried (Na2S04) and and evaporated to dryness in vacuo. The residue was purified by column chromatography (petroleum ether/EtOAc; 1: 1) to afford the title compound as a yellow oil (524 mg, 44%). LCMS (ESI): [M+H] = 153.0; 1H NMR (500 MHz, MeOH-d4) d: 7.97-7.99 (m, 1H), 7.70- 7.73 (m, 1H), 7.59 (d, 7=9.0 Hz, 1H), 7.34-7.36 (m, 1H), 7.13 (d, 7=7.0 Hz, 1H).
With bromine; In chloroform; at 0 - 20℃; for 16.0h;
To a solution of 2-amino-6-chloropyridine (15g, 116mmol) in chloroform (600ml) was added a solution of bromine (4.2g, 965mmol) in chloroform (50ml) at 0C and the reaction mixture wasstirred at room temperature for 16h. After completion of reaction, the reaction was quenched over ice cold water; extracted to DCM and concentrated to obtain the crude compound. The crude compound was purified by silica gel column chromatography using 10% ethyl acetate in hexane as eluent to afford the title compound (6.2g, 25.5%). LCMS: m/z = 209.0 (M+1)+.
17%
With bromine; In chloroform;
A.1 3-Bromo-6-chloro-pyridin-2-ylamine[0328] 6-Chloro-pyridin-2-ylamine (5g, 38.89 mmol) is dissolved in chloroform (250 mL) and a solution of bromine (1.33 mL, 26 mmol) in chloroform (50 mL) is slowly added over a one hour period. During the addition a precipitate (hydrobromide salt of the starting material) forms. After stirring overnight the reaction mixture is filtered, the filtrate is evaporated and the residue is partitioned between ethyl acetate and 1 M sodium carbonate solution. The organic phase is separated, evaporated and the solid residue purified by flash chromatography (silica gel, 15 % ethyl acetate in petroleum ether) affording the title compound (1.44 g, 17 %) as a solid. The material is carried through the next three reaction steps.
With potassium carbonate; In dimethyl sulfoxide; at 190℃; for 10h;
A mixture containing 4-chloro-2-arninopyridine (164; 26g, 0.20 mol), K2CO3 (0.40 mol) and morpholine (48; 0.6 mol) in DMSO (150 mL) was stirred at 190 0C for 10 h. Upon cooling to room temperature, the reaction mixture was diluted with water (300 mL) and the resulting mixture was extracted with ethyl acetate (4 x 150 mL). The combined organic layers were washed with water (3 x 25 mL), dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by chromatography (petroleum ethe?ethyl acetate=10:l) to afford 6-morpholinopyridin-2-amine 165 (17 g, 47%) as a white solid
47%
With potassium carbonate; In dimethyl sulfoxide; at 190℃; for 10h;
Step 1) Preparation of 6-morpholinopyridin-2-amine (34):A mixture containing 4-chloro-2-aminopyridine (33; 26g g, 0.20 mol), K2CO3 (0.40 mol) and morpholine (0.6 mol) in DMSO (150 mL) was stirred at 190 0C for 10 h. Upon cooling to room temperature, the reaction mixture was diluted with water (300 mL) and the resulting mixture was extracted with ethyl acetate (4 x 150 mL). The combined organic layers were washed with water (3 x 25 mL), dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by chromatography (petroleum ethe?ethyl acetate = 10:1) to afford 6- morpholinopyridin-2-amine 34 (17 g, 47%)as a white solid.
47%
With potassium carbonate; In dimethyl sulfoxide; at 190℃; for 10h;
A mixture containing 4-chloro-2-aminopyridine (76; 26g g, 0.20 mol), K2CO3 (0.40 mol) and morpholine (0.6 mol) in DMSO (150 mL) was stirred at 1900C for 10 h. Upon cooling to room temperature, the reaction mixture was diluted with water (300 mL) and the resulting mixture was extracted with ethyl acetate (4 x 150 mL). The combined organic layers were washed with water (3 x 25 mL), dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by chromatography (petroleum ethe?ethyl acetate = 10:1) to afford 6- morpholinopyridin-2-amine 77 (17 g, 47%)as a white solid. MS (ESI) calcd for C9Hi3N3O (m/z): 179.2 found, 180 [M+H].
at 225℃; for 1h;
A mixture of <strong>[45644-21-1]2-amino-6-chloropyridine</strong> in 100 rnL of morpholine was heated at 225 C for 60 mins. The mixture was cooled and precipitate filtered off, the filtrate was concentrated to give the 17 gram product as a brown oil.
With potassium carbonate; In dimethyl sulfoxide; at 190℃; for 10h;
A mixture of 4-chloro-2-aminopyridine (13; 1 9.3 g, 1 50 mmol), K2CO3 (4 1 .7 g, 0.30 mol) and morpholine (38.9 mL, 450 mmol) in DM SO ( 1 50 mL) was stirred at 1 90 C (oi l bath) for 1 0 h. After cooling to room temperature, water (300 mL) was added and extracted with ethyl acetate (4 x 1 50 mL). The combined organic layers were washed with water (3 x 25 mL), dried over Na2S0 and concentrated in vacuo. The residue was puri fied by si lica gel chromatography ( 10: . petroleum ethenethyl acetate) to give 6-morpholinopyridin-2-amine as a white solid (14; 9.0 g, 54.8 mmol). MS (ESI) calcd for C9H 13N3O (m/z): 1 79. 1 1 , found 1 80 [M+H].
9 g
With potassium carbonate; In dimethyl sulfoxide; at 190℃; for 10h;
General procedure: A mixture of <strong>[45644-21-1]6-chloropyridin-2-amine</strong> (19.3 g, 150 mmol), K2C03 (41.7 g, 0.30 mol) and morpholine (38.9 mL, 450 mmol) in DMSO (150.0 mL) was stirred at 190 C (oil bath) for 10 h. After cooling to room temp, water (300.0 mL) was added and the mixture was extracted with ethyl acetate (4 x 150.0 mL). The combined organic layers were washed with water (3 x 25.0 mL), dried over Na2S04 and concentrated in vacuo. The residue was purified by silica gel chromatography (10: 1 petroleum ether : ethyl acetate) to give 6- morpholinopyridin-2-amine as a white solid (9.0 g, 54.8 mmol). MS (ESI) calcd for C9Hi3N30 (m/z): 179.11, found 180 [M+H].
at 200℃; for 2h;Microwave irradiation;
6-Chloropyridin-2-amine (244 mg, 1.90 mmol) and morpholine (0.827 mL, 9.49 mmol) were combined and heated for 2 hr at 200C via microwave irradiation. The reaction mixture was diluted with saturated aqueous ammonium chloride and DCM. The organics were separated, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (10-80% acetone/hexanes, linear gradient) to afford 6- (morpholin-4-yl)pyridin-2-amine. MS ESI calc'd. for C9Hi4N30 [M + H]+ 180, found 180. 1H NMR (500 MHz, CDC13) delta 7.29 (t, J= 7.9 Hz, 1H), 5.99 (d, J= 8.1 Hz, 1H), 5.91 (d, J= 7.8 Hz, 1H), 3.82 - 3.75 (m, 4H), 3.46 - 3.38 (m, 4H).
9 g
With potassium carbonate; In dimethyl sulfoxide; at 190℃; for 10h;
A mixture of <strong>[45644-21-1]6-chloropyridin-2-amine</strong> (19.3 g, 150 mmol), K2CO3 (41.7 g, 0.30 mol) and morpholine (38.9 niL, 450 mmol) in DMSO (150 niL) was stirred at 190 C (oil bath) for 10 h. After cooling to room temp, water (300 mL) was added and extracted with ethyl acetate (4 x 150 mL). The combined organic layers were washed with water (3 x 25 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (10:1 petroleum ether: ethyl acetate) to give 6-morpholinopyridin-2- amine as a white solid (9.0 g, 54.8 mmol). MS (ESI) calcd for C9H13N3O (m/z): 179.11; found 180 [M+H]
9 g
With potassium carbonate; In dimethyl sulfoxide; at 190℃; for 10h;
A mixture of <strong>[45644-21-1]6-chloropyridin-2-amine</strong> (19.3 g, 150 mmol), K2CO3 (41.7 g, 0.30 mol) and morpholine (38.9 mL, 450 mmol) in DMSO (150 mL) was stirred at 190 C (oil bath) for 10 h. After cooling to room temp, water (300 mL) was added and extracted with ethyl acetate (4 x 150 mL). The combined organic layers were washed with water (3 x 25 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (10:1 petroleum ether: ethyl acetate) to give 6-morpholinopyridin-2-amine as a white solid (9.0 g, 54.8 mmol). MS (ESI) calcd for C9H13N3O (m/z): 179.11; found 180 [M+H].
Into a 250 mL round bottom flask was added 3-methoxy-propanol (5.26 g, 58.4 mmol) and DMF (156 mL). Sodium hydride (60%, 4.67 g, 3 eq) was added slowly to the solution. After addition the mixture was heated to 90 C for one hour. 2-chloro-6-amino- pyridine was added and the mixture was heated to reflux for four hours. LCMS showed conversion to product. The reaction was cooled to room temperature and solvent was removed under vacuum. The residue was partitioned between water and ethyl acetate. Organic layer was separated and the aqueous was extracted three times with ethyl acetate (3x 50 mL). Organic layer dried over sodium sulfate and filtered; the solvent was removed under vacuum. The residue was dissolved with 2N HCl in MeOH and stirred for five hours at room temperature; the solvent was removed and the residue was purified by <n="213"/>column chromatography with 20% ethyl acetate in hexanes yeilding 3.12 g (45%) of the title compound as a yellow oil.
With ammonia;copper(l) iodide; In water; at 150℃; under 6050.79 - 21875.9 Torr; for 8h;Product distribution / selectivity;
This reaction was conducted in the same manner as described in Example 2, but no ammonium acetate was added to the reaction mixture. The conversion of 2-amino-6- chloropyridine was 99.5%, and the yield for 2,6- diaminopyridine was 69%.
81%Chromat.
With ammonium acetate; ammonia;copper(l) iodide; In water; at 150℃; under 6050.79 - 21875.9 Torr; for 8h;Product distribution / selectivity;
In a 300 mL Hastelloy autoclave a solution of 5.0 g CuI in 120 g aqueous ammonium hydroxide (28% wt. NH3) was added and mixed with 77 g ammonium acetate and 60 g of 2- amino-6-chloropyridine. After purging with nitrogen, 24 g of liquid ammonia was added resulting in a pressure of about 117 psi (0.807 MPa) . Subsequently, the reaction mixture was heated to 150C for 8 h. Over the course of the reaction, the pressure decreased from an initial pressure of 423 psi (2.92 MPa) to 340 psi (2.34 MPa). The reaction mixture was allowed to cool to room temperature, and the pressure was brought back to atmospheric pressure. The reaction mixture was analyzed using a quantitative GC analytical method. The conversion of 2-amino-6- chloropyridine was 99.0%. The yield for 2,6- dichloropyridine was 81%.
With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 5 - 20℃;
19.1 5-Bromo-6-chloro-pyridin-2-ylamine 6-chloro-pyridin-2-ylamine (purchased from Aldrich) (1.50 g, 11.7 mmol) is dissolved in 15 ml N,N-Dimethylformamide and cooled to 5 C. 1-bromo-pyrrolidine-2,5-dione (2.28 g, 12.8 mmol) is added and the mixture is slowly warmed to room temperature. The mixture is poured onto ice water and the precipitate is collected by filtration and dried under vacuum. Yield: 91% of theory Mass spectrometry (ESI-): m/z=207, 209 [M+H]+
86.5%
With N-Bromosuccinimide; In N,N-dimethyl acetamide; at 20℃; for 0.5h;
Weighing 6-chloro-pyridin-2-amine (2.58g, 20 . 06mmol), added to the N, N-dimethyl formamide (25 ml) in dissolved, weighing N-bromo succinimide (3.56g, 20 . 00mmol) is added to the above-mentioned solution, the reaction room temperature for 0.5 hours. Adding water, ethyl acetate extraction, organic stated and salt water washing, drying by anhydrous sodium sulfate, concentrated, crude product by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) purification, to obtain the title compound (3.60g, yield 86.5%).
72%
With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 20℃; for 2h;
Step a) Formation of5-bromo-<strong>[45644-21-1]6-chloropyridin-2-amine</strong>; N-bromosuccinimide (16.45 g; 92.41 mmol; 1.10 eq.) was added portionwise to a solution of <strong>[45644-21-1]2-amino-6-chloropyridine</strong> (10.80 g; 84.01 mmol; 1.0 eq.) in DMF (200 mL) at rt. The reaction mixture was stirred at rt for 2 hours. Solvents were removed under reduced pressure and the residue was taken up in EtOAc and aqueous ammonia. The organic phase was washed again with aqueous ammonia and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The black solid obtained was washed with pentane and dried under vacuum to give the title compound as a beige powder (12.5 g, 72%). HPLC, Rt: 2.81 min. (purity 95.8%).
24.79%
With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 20℃; for 2h;
To a solution of <strong>[45644-21-1]6-chloropyridin-2-amine</strong> 13A (reference: W02014055955A1) (1.0 g, 7.78 mmol) in DMF (10 mL) was added NBS (1.384 g, 7.78 mmol) portion-wise at room temperature and stirring was continued for 2 h. The reaction mixture was then evaporated under reduced pressure to give a crude residue. To this was added aqueous ammonia (60 mL, 25 % solution) and the mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was evaporated under reduced pressure to give cmde residue which was purified by silica gel chromatography (24 g RediSep column, eluting with a gradient of 27-29 % ethyl acetate in petroleum ether) to yield 5-bromo-<strong>[45644-21-1]6-chloropyridin-2-amine</strong> 15B (0.4 g, 1.928 mmol, 24.79 % yield) as a brown solid. LCMS: m/z = 207.0 [M+Hf?; ret. time 1.74 mm; condition-E. ?H NMR (400 MHz, DMSO-d6) oe ppm 7.63 (d, J=8.5 Hz, 1H), 6.59 (s, 2H), 6.36 (d, J9.0 Hz, 1H).
With N-Bromosuccinimide; In acetonitrile; at 20℃; for 13h;
6-Chloropyridin-2-amine (2.0 g) was dissolved in acetonitrile (40 ml). N-Bromosuccinimide (3.1 g) was added and the mixture was stirred under shading at room temperature for 13 hours. The reaction solution was concentrated and the resulting residue was purified by silica gel column chromatography (developed with ethyl acetate-hexane) to give the title compound (2.8 g).MS (ESI) m/z: 207 (M+H)+.
Stage #1: chloroacetaldehyde dimethyl acetal With toluene-4-sulfonic acid In ethanol; water at 20 - 65℃;
Stage #2: With sodium hydrogencarbonate In ethanol; water at 20℃;
Stage #3: 6-chloropyridin-2-amine In ethanol; water for 3h; Reflux;
17.X; X
To a solution of pTSA (103 mg, 0.65 mmol) in water (5 ml) and ethanol (20 ml) was added chloroacetaldehyde dimethyl acetal (2.0 g, 16.0 mmol) at room temperature. The reaction was stirred at 65 0C for 30 minutes and then cooled to room temperature and a saturated solution of NaHCOs was added dropwise until pH 7 was reached. 2-Amino-6-chloropyridine (2.1 g, 16 mmol) in 4:1 ethanohwater (20 ml) was then added and the reaction was heated at reflux for 3 hours. After cooling and concentrating at reduced pressure, the residue was purified by FCC (98:2 DCM/MeOH) to give the title compound (850 mg, 36%) as brown oil. LCMS data: Calculated MH+ (153/155); Found 97% (MH+) m/z 153/155, Rt = 3.35 min (High pH method). NMR data: 1H NMR (500 MHz, CDCl3) δ ppm 7.79 (1 H, s), 7.73 (1 H, s), 7.64 (1 H, d, J=9.2 Hz), 7.19 (1 H, dd, J=8.9, 7.3 Hz), 6.92 (1 H, d, J=7.3 Hz).
With N-iodo-succinimide; In N,N-dimethyl-formamide; at 20℃; for 12h;
To a solution of 6-chloropyridin-2-amine (50.0 g, 389 mmol) in DMF (700 mL) was added N-iodosuccinimide (105 g, 467 mmol). The brown solution was stirred at rt for 12 h. The mixture was poured into water (2.1 L) and filtered. The filter cake was washed with water (2*500 mL) and then dried under vacuum. Purification (FCC, SiO2; 5-20% EtOAc/petroleum ether) afforded the title compound (83 g, 75%) as a pink solid. MS (ESI): mass calcd. for C5H4ClIN2, 253.9; m/z found, 254.7 [M+H]+. 1H NMR (400 MHz, CDCl3) delta 7.74 (d, J=8.0 Hz, 1H), 6.20 (d, J=8.0 Hz, 1H), 4.69 (br s, 2H).
73%
With N-iodo-succinimide; In N,N-dimethyl-formamide; for 43h;
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, 73%). mp 154.3-155.9. 1H NMR (CDCl3) delta 7.75 (d, J=8.2Hz, 1H), 6.22 (d, J=8.2Hz, 1H). 13C NMR (CDCl3) delta 157.6, 151.6, 149.4, 108.8.
71%
With Iodine monochloride; acetic acid;
60 g of 6-chloro-2-aminopyridine was dissolved in 400 mL of glacial acetic acid, and 75.5 g of iodine chloride was added.The reaction mixture was stirred until the reaction was completed. Filtration, concentration to obtain fine products, the crude product was crystallized from ethanol to obtain 126.7 g of a product, the yield was 71%, and the purity of the product was determined by HPLC to be 99.5%.
0.49 g
With N-iodo-succinimide; In N,N-dimethyl-formamide; at 20℃; for 16h;
To an N,N-dimethylformamide (30 mL) solution of 2-amino-6-chloropyridine (1.0 g) was added N-iodosuccinimide (1.75 g) and the mixture stirred at room temperature for 16 hours. To the reaction mixture, water (200 mL) was added followed by extraction into ethyl acetate. The combined organic layers were dried, filtered and concentrated. The residue was triturated with dichloromethane and the resultant precipitate collected by filtration to give the title compound having the following physical properties (0.49 g). LC/MS tR 1.72 minutes; MS (ES+) m/z 254 (M+H) a.
With N-iodo-succinimide; In N,N-dimethyl-formamide; at 25℃; for 18h;Inert atmosphere;
Step 1 : 6-chloro-5-iodopyridin-2-amine To a solution of 6-chloropyridin-2-amine (10 g, 78 mmol) in DMF (100 mL) was added l-iodopyrrolidine-2,5-dione (17.50 g, 78 mmol). The reaction mixture was allowed to stir under N2 balloon at 25C for 18 h. LCMS showed some of the desired product. The reaction was then diluted with EtOAc (100 mL) and water (200 mL). The aqueous layer was extracted with EtOAc (3 x 100 mL). The combined organic phases were dried over Na2S04, and concentrated in vacuo. The residue was then washed with DCM (30 mL) and then dried to give the title compound. MS (ESI) m/z 254.8 (M+H).
To a solution of (S)-(2,2-dimethyl- 1 ,3-dioxolan-4-y l)methanol (19.5 g, 150 mmol) in dioxane (250 mL) was added NaH (6.0 g, 60%) at room temperature and stirred for 30 min. then 2- amino-6-chloropyridine (29; 6.43 g, 50 mmol) was added and the mixture was stirred under reflux for48h. Water was added and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with water (6 x 50 mL), dried over Na2SC , concentrated in vacuo and purified by silica gel chromatography (20:1 dichloromethane : methanol) to afford (S)-6- ((2,2-dimethyl-l,3-dioxolan-4-yl)methoxy)pyridin-2-amine as an oil (30; 5.7 g, 25.4 mmol, 51%). MS (ESI) calcd for CH^Os (m/z) 224.12, found 225 [M+H].
20.92%
To a stirred suspension of NaH (62.2 g, 1556 mmol) in N-Methyl-2-pyrrolidone (NMP) (800 mL), under nitrogen at 0C, was added a solution of (S)-(2,2-dimethyl-l,3-dioxolan- 4-yl)methanol (206 g, 1556 mmol) in N-Methyl-2-pyrrolidone (NMP) (300 mL) dropwise during 2 h. After stirring for another 10 min added a solution of <strong>[45644-21-1]6-chloropyridin-2-amine</strong> (200 g, 1556 mmol) in N-Methyl-2-pyrrolidone (NMP) (300 mL) dropwise during 30 min at 0C. The reaction mixture was stirred at 120 C for 48 hr. TLC indicated that starting material was. Reaction mixture was poured into ice cold water (2000 mL), aqueous layer was extracted with EtOAc (3 x 1000 mL). The combined organic layer was washed with water (3 x 1000 mL) to remove excess NMP. The organic layer was dried over Na2SC" , filtered and concentrated under reduced pressure to obtain crude product. Crude product was purified by column chromatography using 100-200 silica gel (eluent 12-15% EtOAc in pet ether) to obtain the desired pure product (S)-6-((2,2-dimethyl-l,3-dioxolan-4- yl)methoxy)pyridin-2-amine (75 g, 325 mmol, 20.92 % yield) as a yellow viscous liquid. LCMS (m/z): 225 [M+H]+.
With potassium phosphate;1,1'-bis(di-tertbutylphosphino)ferrocene; palladium diacetate; In 1,4-dioxane; for 4h;Inert atmosphere; Reflux;
a) 6-(4-Fluoro-phenyl)-pyridin-2-ylamine; 2-Amino-6-chloropyridine (128.6 mg, 1 mmol), 4-fluorobenzeneboronic acid (216.4 mg, 1.5 mmol) and potassium phosphate tribasic (433.2 mg, 2 mmol) were suspended in dioxane (3.9 mL) The suspension was evacuated and flushed with nitrogene for 3 times. Palladium (II) acetat (11.2 mg, 0.05 mmol) and (D-t-BPF) (1,1'-bis(di-tert.-butylphosphino) ferrocene, (24.2 mg, 0.05 mmol) were added and again the suspension was evacuated and flushed with nitrogen twice. The reaction was heated to reflux for 4 hours. After cooling to room temperature the reaction was partitionated between water and EtOAc and extracted once with EtOAc. The combined organic layers were washed with 1N aqueous NaOH solution and once with saturated aqueous NaCl solution, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography using CH2Cl2/MeOH (v/v 19:1) as eluent to yield the title compound as a light brown oil (142 mg, 68%).MS ISP (m/e): 189.4 (59) [(M+H)+], 173.2 (100).1H NMR (DMSO-D6, 300 MHz): delta (ppm)=8.01 (m, 2H), 7.45 (t, 1H), 7.24 (t, 2H), 7.03 (d, 1H), 6.41 (d, 1H), 5.98 (br s, 2H).
68%
With potassium phosphate;1,1'-bis(di-tertbutylphosphino)ferrocene; palladium diacetate; In 1,4-dioxane; for 4h;Inert atmosphere; Reflux;
2-Amino-6-chloropyridine (128.6 mg, 1 mmol), 4-fluorobenzeneboronic acid (216.4 mg, 1.5 mmol) and potassium phosphate tribasic (433.2 mg, 2 mmol) were suspended in dioxane (3.9 mL) The suspension was evacuated and flushed with nitrogene for 3 times. Palladium (II) acetat (11.2 mg, 0.05 mmol) and (D-t-BPF) (Iota,Gamma-bis (di-tert.-butylphosphino) ferrocene, (24.2 mg, 0.05 mmol) were added and again the suspension was evacuated and flushed with nitrogen twice. The reaction was heated to reflux for 4 hours. After cooling to room temperature the reaction was partitionated between water and EtOAc and extracted once with EtOAc. The combined organic layers were washed with IN aqueous NaOH solution and once with saturated aqueous NaCl solution, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography using CH2Cl2/MeOH (v/v 19: 1) as eluent to yield the title compound as a light brown oil (142 mg, 68%).MS ISP (m/e): 189.4 (59) [(M+H)+], 173.2 (100).1H NMR (DMSO-D6, 300 MHz): delta (ppm) = 8.01 (m, 2H), 7.45 (t, 1H), 7.24 (t, 2H), 7.03 (d, 1H), 6.41 (d, 1H), 5.98 (br s, 2H).
Stage #1: 6-chloropyridin-2-amine With sodium hydride In tetrahydrofuran; mineral oil for 0.333333h; Inert atmosphere; Cooling with ice;
Stage #2: 2-chloro-6-methylbenzo[d]thiazole In tetrahydrofuran; mineral oil at 20℃;
Stage #3: With ammonium chloride In tetrahydrofuran; water; mineral oil
Intermediate 1W-(6-chloro-2-pyridinyl)-6-methyl-1 ,3-benzothiazol-2-amineUnder an atmosphere of nitrogen, an ice-cooled solution of 6-chloro-2-pyridinamine (300mg, 2.33mmol) in tetrahydrofuran (15ml_) was treated portionwise with sodium hydride (60% w/w in oil) (121 mg, 3.03mmol). After 20 minutes, the mixture was treated with 2-chloro-6-methyl-1 ,3-benzothiazole (471 mg, 2.57mmol) and allowed to stir and warm to ambient temperature overnight. The mixture was then cautiously treated with saturated aqueous ammonium chloride (20ml_) and dichloromethane (50ml_). The organic phase was collected, evaporated to dryness and the product was purified by chromatography on silica using a gradient elution from 0 to 100% ethyl acetate in cyclohexane to afford the title compound (155mg, 0.56mmol, 24% yield). LCMS (Method A): Rt 1 .33 minutes; m/z 276 (MH+)
Stage #1: 6-chloropyridin-2-amine With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.166667h; Inert atmosphere; Cooling with ice;
Stage #2: 2-chloro-6-nitrobenzothiazole In tetrahydrofuran; mineral oil at 20 - 50℃;
Intermediate 14:N-(6-chloro-2-pyridinyl)-6-nitro-1 ,3-benzothiazol-2-Under an atmosphere of nitrogen, an ice-cooled solution of 6-chloro-2-pyridinamine (2g, 15.56mmol) in tetrahydrofuran (100mL) was treated portionwise with sodium hydride (60% w/w in oil, 0.81g, 20.2mmol) and the resulting mixture was stirred at 0°C for 10 minutes. The mixture was treated dropwise with a solution of 2-chloro-6-nitro-1 ,3- benzothiazole (4.01g, 18.7mmol) in tetrahydrofuran (150mL) and then the reaction mixture was allowed to warm to ambient temperature and stirred overnight. Additional sodium hydride (60% w/w in oil, 0.40g, 10.1 mmol) was added and reaction mixture was heated to 50°C for 2 hours. The cooled reaction mixture was treated cautiously with methanol and evaporated to dryness. The residual solid was stirred in dichloromethane overnight, filtered and dried to afford the title compound (1 .96g, 6.38mmol, 41 % yield). The filtrate was evaporated to dryness and the residual solid was stirred with dichloromethane to afford a second crop of the title compound (1 .06g, 3.44mmol, 22% yield). LCMS (Method A): Rt 1 .17 minutes; m/z 307 (MH+).
Intermediate 2-bromo-N-(6-chloro-2-pyridinyl)-1 ,3-benzothiazol-2-amineUnder an atmosphere of nitrogen, an ice-cooled solution of 6-chloro-2-pyridinamine (2.6g, 20.2mmol) in anhydrous tetrahydrofuran (50ml_) was treated portionwise with sodium hydride (60% in oil) (2.43g, 60.7mmol). The reaction mixture was stirred for 10 minutes and then 6-bromo-2-chloro-1 ,3-benzothiazole (5.53g, 22.3mmol) was added portionwise. The reaction mixture was stirred for a further 15 minutes then allowed to warm up to ambient temperature, then heated at 65C overnight. Water (100ml_) was added to the cooled reaction mixture which was then filtered; the filtered solid was washed with water and thoroughly dried to afford the title compound (7.16g, 21.1 mmol, quantitative yield). LCMS (Method B): Rt 3.45 minutes; m/z 340 (MH+).
1,3-bis[(diphenylphosphino)propane]dichloronickel(II); In 1,4-dioxane; toluene; for 16h;Inert atmosphere; Reflux;
A mixture of 6-chloro-2-aminopyridine (15.0 g, 1 16 mmol) and [1,3- bis(diphenylphosphino)propane]nickel(II) chloride (5.70 g, 10.5 mmol) in anhydrous 1,4- dioxane (450 mL) was treated with 1.1 M solution of diethylzinc in toluene (225 mL) and the reaction stirred, under a nitrogen atmosphere, at reflux for 16 h. After this time, the reaction was cooled to room temperature, treated with methanol (200 mL) and concentrated under reduced pressure. The resulting residue was diluted in brine (500 L) and extracted with a mixture of 9: 1 methylene chloride/methanol (3 x 300 mL). The combined organic layers were dried over sodium sulfate, filtered and the filtrate concentrated under reduced pressure to afford 6-ethylpyridin-2-amine as a brown gel, which was used in the next step without further purification: NMR (400 MHz, CDC13) d 7.36 (t, J = 7.6 Hz, 1 H), 6.53 (d, J= 7.6 Hz, 1H), 6.33 (d, J= 7.6 Hz, 1H), 4.41 (bs, 2H), 2.64 (q, J= 7.6 Hz, 2H), 1.26 (t, J= 7.6 Hz, 3H).
With [1,3-bis(diphenylphosphino)propane]nickel(II) chloride; In 1,4-dioxane; toluene; for 16h;Inert atmosphere; Reflux;
Example 14 Preparation of 6-ethylpyridin-2-amine A mixture of 6-chloro-2-aminopyridine (15.0 g, 116 mmol) and [1,3-bis(diphenylphosphino)propane]nickel(II) chloride (5.70 g, 10.5 mmol) in anhydrous 1,4-dioxane (450 mL) was treated with 1.1 M solution of diethylzinc in toluene (225 mL) and the reaction stirred, under a nitrogen atmosphere, at reflux for 16 h. After this time, the reaction was cooled to room temperature, treated with methanol (200 mL) and concentrated under reduced pressure. The resulting residue was diluted in brine (500 L) and extracted with a mixture of 9:1 methylene chloride/methanol (3*300 mL). The combined organic layers were dried over sodium sulfate, filtered and the filtrate concentrated under reduced pressure to afford 6-ethylpyridin-2-amine as a brown gel, which was used in the next step without further purification: 1H NMR (400 MHz, CDCl3) d 7.36 (t, J=7.6 Hz, 1H), 6.53 (d, J=7.6 Hz, 1H), 6.33 (d, J=7.6 Hz, 1H), 4.41 (bs, 2H), 2.64 (q, J=7.6 Hz, 2H), 1.26 (t, J=7.6 Hz, 3H).
With N-Bromosuccinimide In N,N-dimethyl-formamide at 0 - 20℃;
16
To a stirred solution of 6-chloropyridin-2-amine (50.0 g, 388 mmol) in N,N- dimethylformamide (500 mL) at 0 °C, was added N- bromosuccinimide (175 g, 972 mmol) portion wise during which an exotherm was observed. The mixture was allowed to warm to room temperature and stirred for 2h. After this time, the mixture was poured into ice water (2.0 L) and the resulting suspension was filtered. The filter cake was dissolved in methylene chloride, dried over sodium sulfate, filtered and the filtrate concentrated under reduced pressure. The resulting residue was dried under vacuum to a constant weight to afford 3,5- dibromo-6-chloropyridine-2-amine as a yellow solid: NMR (400 MHz, DMSO- ) d 8.09 (s, 1H), 6.88 (bs, 2H); MM MS m/z 286.8 [M + 2 + H]+.
With N-Bromosuccinimide In N,N-dimethyl-formamide at 0 - 20℃; for 2h;
Preparation of 3,5-dibromo-6-chloropyridine-2-amine
Preparation of 3,5-dibromo-6-chloropyridine-2-amine To a stirred solution of 6-chloropyridin-2-amine (50.0 g, 388 mmol) in N,N-dimethylformamide (500 mL) at 0° C., was added N-bromosuccinimide (175 g, 972 mmol) portion wise during which an exotherm was observed. The mixture was allowed to warm to room temperature and stirred for 2 h. After this time, the mixture was poured into ice water (2.0 L) and the resulting suspension was filtered. The filter cake was dissolved in methylene chloride, dried over sodium sulfate, filtered and the filtrate concentrated under reduced pressure. The resulting residue was dried under vacuum to a constant weight to afford 3,5-dibromo-6-chloropyridine-2-amine as a yellow solid: 1H NMR (400 MHz, DMSO-d6) d 8.09 (s, 1H), 6.88 (bs, 2H); MM MS m/z 286.8 [M+2+H]+.
With N-ethyl-N,N-diisopropylamine; In ethyl acetate; at -15 - -5℃; for 5.5h;
Example 864 mL of ethyl acetate were added to a reaction system and cooled to about -15 C. with a salt and ice bath followed by blowing in 10.6 g (107 millimoles) of phosgene. A mixed solution containing 5.5 g (42.8 millimoles) of 2-amino-6-chloropyridine, 11.1 g (85.6 millimoles) of N,N-diisopropylethylamine, 6.34 g (85.5 millimoles) of t-butanol and 43 mL of ethyl acetate were dropped into this phosgene solution over the course of 2.5 hours while holding the internal temperature at -15 C. to -5 C. Following completion of dropping, the solution was stirred for 3 hours at the same temperature range. Next, 50 mL of water and 23.2 g of 28% sodium hydroxide were sequentially added while holding the internal temperature at 0 C. or lower. The aqueous phase was extracted with ethyl acetate. The organic phase was washed with water and concentrated under reduced pressure. The resulting crude crystals were subjected to quantitative analysis by HPLC. The target (6-chloro-pyridin-2-yl)-carbamic acid tert-butyl ester was obtained at a yield of 93%. There was hardly any urea compound formed.
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 85℃; for 16h;
To a stirred mixture of <strong>[45644-21-1]2-amino-6-chloropyridine</strong> (0.26 g, 2.0 mmol ), (5-chloro- 2-hydroxy)benzene boronic acid (0.35 g, 2.0 mmol) and 2 M aqueous sodium carbonate (3 mL, 6 mmol) in p-dioxane (6 ml_) was added iefra/ /s(triphenylphosphine)palladium(0) (0.10 g, 0.086 mmol). The mixture was heated at 85 C for 16 h, allowed to cool to ambient temperature and diluted with ethyl acetate (50 mL) and water (20 mL). The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography eluting with a gradient of 25-50% ethyl acetate in hexanes to afford 2-(6-aminopyridin-2-yl)-4-chlorophenol as a yellow solid in 56% yield (0.25 g): 1H NMR (300 MHz, CDCI3) £7.67 (d, J = 2.4 Hz, 1 H), 7.57 (dd, J = 7.8, 7.8 Hz, 1 H), 7.22-7.13 (m, 2H), 6.89 (d, J = 8.7 Hz, 1 H), 6.46 (d, J = 8.4 Hz, 1 H), 4.53 (s, 2H).
5-chloroimidazo[1,2-a]pyridine hydrochloride[ No CAS ]
[ 63111-79-5 ]
Yield
Reaction Conditions
Operation in experiment
1: 39%
2: 45%
Stage #1: 2-chloroethanal; 6-chloropyridin-2-amine In ethanol; water for 5h; Reflux;
Stage #2: With sodium hydrogencarbonate In dichloromethane; water
23.A EXAMPLE 23 Synthesis of 4-chlorophenyl 4-(4-chloro-2-(imidazo[1 ,2-a]pyridin-5-yl)phenoxy)-2,5- difluorobenzenesulfonate
A. To a stirred solution of 2-amino-6-chloropyridine (20.00 g, 156 mmol) in ethanol (300 mL) at ambient temperature was added chloroacetaldehyde (26.1 mL of a 50% aqueous solution, 202 mmol). The reaction mixture was heated at refux for 5 h, allowed to cool to ambient temperature and concentrated in vacuo. The residue was treated with dichloromethane (400 ml.) and the dichloromethane layer was decanted. The resultant brown gummy solid was treated with a mixture of methanol (20 mL) and diethyl ether (500 mL). The colorless solid so obtained was collected by filtration to afford 5-chloroimidazo[1 ,2-a]pyridine hydrochloride (13.26 g, 45% yield). The filtrate was combined with the aforementioned dichloromethane layer and the mixture concentrated in vacuo. The residue was dissolved in dichloromethane (500 mL). The resulting solution was washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluting with a 40-95% gradient of ethyl acetate in hexanes to afford a second batch of 5-chloroimidazo[1 ,2-a]pyridine as a brown liquid in 39% yield (9.18 g): 1H NMR (300 MHz, DMSO-c/6) 8.02 (s, 1 H), 7.74 (s, 1 H), 7.65 (d, J = 9.0 Hz, 1 H), 7.31 (dd, J = 7.5, 7.5 Hz, 1 H), 7.19 (d, J = 7.2 Hz, 1 H); MS (ES+) m/z 153.0 (M.+ 1 ), 155.0 (M + 1).
6-Chloropyridin-2-amine (2.00 g, 15.6 mmol) and lH-l,2,3-triazole (3.22 g, 46.7 mmol) were combined in a 75 mL sealed flask and heated overnight at 180C. The reaction mixture was cooled to room temperature, and diluted with DCM and a solution of saturated aqeuous ammonium chloride. The organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0- 50% acetone in hexanes, linear gradient) to afford a 1 : 1 mixture of lHand 2Htriazole regioisomers. Further purification by HPLC afforded the separated regioisomers (15-30% acetonitrile/water with 0.1% ammonium hydroxide, linear gradient). MS ESI calc'd. for C7H N5 [M + H]+ 162, found 162. ? NMR (2H isomer, 500 MHz, DMSO-d6) delta 8.03 (s, 2H), 7.56 (t, J = 7.9 Hz, 1H), 7.03 (d, J= 7.6 Hz, 1H), 6.46 (d, J= 8.1 Hz, 1H), 6.39 (s, 2H).
With sodium ethanolate In ethanol at 25 - 140℃; for 81h; Sealed tube;
30.1 6-Ethoxypyridin-2-amine
Step 1 6-Ethoxypyridin-2-amine In a vial in a water bath, a 21% wt solution of sodium ethoxide in ethanol (1.08 g, 1.25 mL, 15.9 mmol) was diluted in ethanol (4 mL) and stirred at 25° C. for 10 min then 6-chloropyridin-2-amine (2.0 g, 15.6 mmol) was added in a single portion. After 3 h the reaction mixture was transferred to a sealed flask and was stirred at 130° C. for 18 h. A second portion of 21% wt solution of sodium ethoxide in ethanol (1.08 g, 1.25 mL, 15.9 mmol) was added and the reaction was stirred at 130° C. for another 36 h. Finally, a third portion of a 21% wt solution of sodium ethoxide in ethanol (3.18 g, 3.66 mL, 46.7 mmol) was added and the mixture stirred at 140° C. for 6 h then at 130° C. for 18 h. The mixture was cooled, concentrated onto silica gel, and purified by chromatography (silica, Analogix 120 g, 0 to 100% ethyl acetate in hexanes, 60 min) to give 6-ethoxypyridin-2-amine (819 mg, 36%) that was used directly without further purification. MS (EI/CI) m/z: 139 [M+H].
With bis-triphenylphosphine-palladium(II) chloride; caesium carbonate; In N,N-dimethyl-formamide; at 90℃;Inert atmosphere; Sealed tube;
A solution of 36 (200 mg, 0.819 mmol) and 37 (105.3 mg, 0.819 mmol) in DMF was added cesium carbonate (533.6 mg, 1.638 mmol). The reaction was purged and degassed with nitrogen for 10 min. Pd(PPh3)2Cl2 (28.7 mg, 0.0409 mmol) was added to the reaction and again degassed and purged with nitrogen for 10 min. Reaction was sealed and heated to 90 C. overnight. The reaction was allowed to cool to rt and diluted with dichloromethane and filtered through Celite bed. The organic layer was concentrated to get the crude product. The crude was purified through flash chromatography by using 100-200 mesh silica gel. The compound was eluted at 1% methanol in chloroform as pale yellow colour solid 38.
With sodium tetrahydroborate; In ethanol; water; at 20℃; under 760.051 Torr; for 1.5h;
General procedure: TAPEHA-Pd (0.015 g) was added to a solution of nitroarenes (1.0 mmol) in EtOH/water (1/1) (20 mL). After NaBH4 (4.0 mmol) was slowly added to the mixture, the color of the reaction mixture turned gradually black in a few minutes, resulting in the formation of palladium nanoparticles (TAPEHA-PdNPs). 42 After being stirredfor 1.5 h at room temperature and atmospheric pressure, the catalyst was removed by ltering and the fitrate was extracted with 3 30 mL of EtOAc. The combined organic layers were dried over MgSO4 and concentrated in a vacuum.
97%
With sodium tetrahydroborate; In ethanol; water; at 20℃; for 4h;
General procedure: SAC (300mg) and NaBH4 (4.0mmol) were added to a solution of nitroarenes (1.0mmol) in EtOH/water (1/1) (20ml). The reaction mixture was stirred for 4h at the temperature indicated in Table3. At the end of the reaction, the catalyst was removed by filtering and the filtrate was extracted with 3×70ml EtOAc. The combined organic layers were dried over MgSO4 and concentrated in a vacuum.
N-(6-chloropyridin-2-yl)-4-methylthiazole-2-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
27%
To a solution of <strong>[14542-16-6]4-methylthiazole-2-carboxylic acid</strong> 9 (25.0 mg, 0.17 mmol) and N-methylmorpholine (60.0 muL, 0.52 mmol) in THF (5.0 ml) at -78 C, isobutylchloroformate (30.0 muL, 0.23 mmol) was added. The mixture was stirred at -5 C for 30 minutes and a solution of 2-amino-6-chloropyridine (90.0 mg, 0.70 mmol) was added. The mixture was stirred at room temperature overnight. The subsequent solution was concentrated under reduced pressure and extracted with H2O/ethylacetate. The combined organic layer was dried over Na2SO4, concentrated under reduced pressure and purified by column chromatography on silica gel (hexane/ethyl acetate = 7:1) to afford N-(6-chloropyridin-2-yl)-4-methylthiazole-2-carboxamide 6ah (12.0 mg, 27%) as white solid: 1H-NMR (400MHz, CDCl3) delta 9.72(s, 1H), 8.26 (d, J = 8.12, 1H),7.74-7.70 (t, J = 7.94, 1H), 7.22 (d,J = 0.8, 1H), 7.11 (d, J = 7.72, 1H), 2.50 (d, J = 0.68, 3H). 13C-NMR (100MHz, CDCl3) delta 161.2, 157.8, 154.6, 150.5, 149.4, 141.0,120.9, 120.1, 112.1, 17.0. LC/MS (ESI-) 251.9 (M-H)+.
27%
<strong>[14542-16-6]4-methylthiazole-2-carboxylic acid</strong> (25.0 mg, 0.17 mmol) and N-methylmorpholine (60.0 muL, 0.52 mmol) were added to 5.0 mL of tetrahydrofuran (THF)Isobutyl chloroformate (30.0 [mu] L, 0.23 mmol) was added to the reaction solution.After stirring at -5 C for 30 minutes2-Amino-6-chloropyridine (90.0 mg, 0.70 mmol) was added thereto, followed by stirring at room temperature for 12 hours. After water was added, the mixture was extracted with ethyl acetate, and the organic layer was separated by distillation under reduced pressure. The organic layerThe organic layer was dried over anhydrous Na2SO4 and purified by column chromatography to obtain the desired compound (12.0 mg, yield 27%).
4-bromo-N-(6-chloropyridin-2-yl)thiazole-2-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
43%
To a solution of isobutyl chloroformate (17.0 muL, 0.14 mmol) in THF (4.0 mL) at -40 C, a mixtureof 4-bromo 1,3-thiazole 2-carboxylic acid 11(20.0 mg, 0.1 mmol) and N-methylmorpholine (27.0 muL, 0.25 mmol) in THF (1.00 mL) was added slowly. The resulting mixture was stirred at - 5 C for 30 minutes and a solution of 2-amino 6-bromopyridine (62.0 mg, 0.48 mmol) in THF (2.00 mL) was added. This solution was vigorously stirred at room temperature overnight and thenconcentrated under reduced pressure, extracted with water/ethyl acetate. The combined organic layer was dried over Na2SO4,concentrated under reduced pressure, and purified by column chromatography on silica gel (hexane/ethyl acetate = 10:1) to afford 4-bromo-N-(6-chloropyridin-2-yl)thiazole-2-carboxamide6bh (10.0 mg, 33%) as a white solid:1H-NMR (400MHz, CDCl3) delta 9.59(s, 1H), 8.24-8.22 (dd, J = 8, 0.4Hz, 1H), 7.75-7.71 (t, J = 8 Hz, 1H),7.57(s, 1H), 7.16-7.13 (dd, J = 8,0.4 Hz, 1H). 13C-NMR (100 MHz, CDCl3) delta 162.6, 156.4, 150.0, 149.5, 141.0, 126.3,124.4, 120.6, 112.2. LC/MS (ESI-) 315.9 (M-H)+.
4-bromo-N-(6-bromopyridin-2-yl)thiazole-2-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
46%
To a solution of isobutyl chloroformate (10.0 muL, 0.08 mmol) in THF (1.00mL) at -40 C, a mixture of 4-bromo 1,3-thiazole 2-carboxylic acid 11(16.0 mg, 0.08 mmol) and N-methylmorpholine(17.0 muL, 0.15 mmol) in THF (1.00 mL) was added slowly. The resulting mixture was stirred at - 5 C for 30 minutes and a solution of2-amino 6-bromopyridine (66.0 mg, 0.38 mmol) in THF (2 mL) was added. This solution was vigorously stirred at room temperature overnight and then concentrated under reduced pressure, extracted with water/ethyl acetate. The combined organic layer was dried over Na2SO4,concentrated under reduced pressure and purified by column chromatography onsilica gel (hexane/ethyl acetate = 10:1) to afford 4-bromo-N-(6-bromopyridin-2-yl)thiazole-2-carboxamide6bi (13.0 mg, 46%) as a white solid:1H-NMR (400MHz, CDCl3) delta 9.59(s, 1H), 8.27-8.25 (dd, J = 8, 0.4Hz, 1H), 7.64-7.60 (t, J = 8 Hz, 1H),7.60 (s, 1H) 7.30-7.28 (dd, J = 8,0.4 Hz, 1H). 13C-NMR (100 MHz, CDCl3) delta 162.6, 156.4, 150.2, 140.7, 139.8, 126.3,124.4, 124.3, 112.5. LC/MS (ESI-) 359.8 (M-H)+.
2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridine[ No CAS ]
6'-methyl-5'-(trifluoromethyl)-[2,3'-bipyridin]-6-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 90℃; for 4h;Inert atmosphere; Sealed tube;
To a solution of <strong>[45644-21-1]6-chloropyridin-2-amine</strong> (723 mg, 4.18 mmol) in dioxane (18 mL) in a sealed tube was added 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3- (trifluoromethyl)pyridine (1.20 g, 4.18 mmol) and aq. potassium carbonate (2M, 6.27 mL, 12.54 mmol). The reaction was degassed with argon for 5 min then Pd(PPh3)4 (242 mg, 0.209 mmol) was added. The reaction was heated at 90oC for 4 h, cooled to RT, diluted with water (100 mL) and extracted with EA (3x 75 mL). The combined organic layers were dried with MgSO4 and concentrated to a residue which was purified by chromatography eluted with EA/Hep (5:95 to 30:70) to give 6?-methyl-5?-(trifluoromethyl)-[2,3?-bipyridin]-6-amine (1.02 g, 96% yield) as a pale yellow solid. LCMS: MH+ 254 and Rt = 1.814 min.
With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; caesium carbonate In 1,4-dioxane at 95 - 105℃;
Coupling of Compound (O) with Compound (P-a) to form Compound (C)
Coupling of Compound (O) with Compound (P-a) to form Compound (C) To a mixture of Compound (O) (1.0 equiv), Compound (P-a) (1.0 equiv), PdCl2(PPh3)2(10 mol%), Cs2C03(2.0 equiv), and Cul (4.7 mol%) was charged dioxane (about 20 vols). The mixture was degassed and then heated to about 95 °C to about 105 °C. After a period of about 20 to about 40 hours, the mixture was cooled to ambient temperature. The reaction mixture was diluted with EtOAc (about 40 vols) and the organic layer was washed with water (about 40 vols) The layers of the biphasic mixture were separated and the aqueous phase was extracted with EtOAc (about 40 vols). The combined organic phases were concentrated in vacuo. To the residue was charged IPA (about 20 vols), and the resulting suspension was stirred at about 40 °C to about 50 °C for about 1 h and then stirred at ambient temperature for about 16 h. The suspension was cooled to about 5 °C, filtered and washed with cold IPA (about 4 vols). The resulting solids were dried at about 40 °C to afford Compound (C). 1H NMR (400 MHz, DMSO-d6): δ 8.77 (s, 1H), 7.51 (t, 1H, J= 8.0 Hz), 7.18 (d, 1H, J= 4.0 Hz), 6.53 (d, 1H, J= 8.0 Hz), 6.17 (s, 1H), 5.53 (sep, 1H, J= 8.0 Hz), 1.42 (d, 6H, J= 8.0 Hz).13C NMR (100 MHz, DMSO-d6): 159.59, 151.18, 146.25, 142.97, 138.41, 111.90, 108.88, 48.12, 23.55.
4-((6-aminopyridin-2-yl)oxy)-2-methylbutan-2-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
38.6%
To a stirred suspension of NaH (1.167 g, 29.2 mmol) in N-Methyl-2-pyrrolidone (NMP) (2 mL) under nitrogen at 0C was added a solution of 3-methylbutane-l,3-diol (3.04 g, 29.2 mmol) in N-Methyl-2-pyrrolidone (NMP) (2 mL) dropwise during 10 min at 0C. After 10 min added a solution of 6-chloropyridin-2-amine (2.5 g, 19.45 mmol) in N-Methyl-2- pyrrolidone ( MP) (2 mL) dropwise during 10 min at 0C. The reaction mixture was heated at 120 C for 16 hr. Progress of the reaction was monitored by TLC. Reaction mixture was poured into ice water and extracted with EtOAc (3X 30 ml), organic solvent was dried over Na2S04 and concentrated under vacuum to get crude. The crude was purified by column chromatography by using silica gel (100-200 mesh) by eluting with 50- 70% EtOAc in hexane to get 4-((6-aminopyridin-2-yl)oxy)-2-methylbutan-2-ol (1.5 g, 7.51 mmol, 38.6 % yield) as an off-white solid, LCMS (m/z): 197.29 [M+H]+.
6-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)pyridin-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
3-((tetrahydro-2H-pyran-2-yl)oxy)propan-l-ol (4.2 g, 26.2 mmol) in 1,4-Dioxane (20 mL) was added to a solution of NaH (1.307 g, 32.7 mmol) in 1,4-Dioxane (20 mL) at 0 C, and the reaction mixture was stirred for 30 min at 28 C. <strong>[45644-21-1]6-chloropyridin-2-amine</strong> (2.8g, 21.78 mmol) in 1,4-Dioxane (20 mL) was added to the reaction mixture at 0 C, and the reaction mixture was stirred for 10 hr at 100 C. The reaction mixture was partitioned between water (20 mL) and DCM (2 X 25 mL). DCM layer was washed with saturated NaHC03 solution, was separated and dried over anhydrous Na2S04, filtered and filtrate was evaporated to crude 6-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)pyridin-2-amine (5.5 g, 18.12 mmol, 83 % yield) as brown oil, LCMS (m/z): 253.2 [M+H]+.
With Pd(tris[2-(diphenylphosphino)ethyl]phosphine tetrasulfide)(dibenzylideneacetone); caesium carbonate; In isopropyl alcohol; at 80℃; for 9h;
General procedure: To a stirred solution of aryl halide (1.2mmol) and [Pd(pp3S4)(dba)] (1mol %) in isopropanol (2.5ml) was added nitrogen/oxygen nucleophile (1mmol) followed by Cs2CO3 (2mol %) in the atmosphere of air. The mixture was heated to 80C and the progress of the reaction was monitored by TLC. After completion, the solvent was evaporated through rotavapour and the crude mixture was washed with dichloromethane-H2O and the organic phase was separated and dried over Na2SO4. The dichloromethane was evaporated followed by flash column purification on silica gel of the crude to obtain the pure products. The products were characterized using 1H, 13C NMR spectroscopy and GC-MS spectroscopy. The characterization data were in good agreement with those described in the literature.
With Pd(tris[2-(diphenylphosphino)ethyl]phosphine tetrasulfide)(dibenzylideneacetone); caesium carbonate; In isopropyl alcohol; at 80℃; for 24h;
General procedure: To a stirred solution of aryl halide (1.2mmol) and [Pd(pp3S4)(dba)] (1mol %) in isopropanol (2.5ml) was added nitrogen/oxygen nucleophile (1mmol) followed by Cs2CO3 (2mol %) in the atmosphere of air. The mixture was heated to 80C and the progress of the reaction was monitored by TLC. After completion, the solvent was evaporated through rotavapour and the crude mixture was washed with dichloromethane-H2O and the organic phase was separated and dried over Na2SO4. The dichloromethane was evaporated followed by flash column purification on silica gel of the crude to obtain the pure products. The products were characterized using 1H, 13C NMR spectroscopy and GC-MS spectroscopy. The characterization data were in good agreement with those described in the literature.
With potassium acetate; Iodine monochloride; acetic acid; at 80℃; for 4h;
2-chloro-6-aminopyridine (23.0 g, 178 mmol) and potassium acetate (17.5 g, 178 mmol) were dissolved in 200 mL acetic acid and heated to 80 C. A solution of ICl (29.05 g, 178 mmol) in acetic acid (40 mL) was added dropwise and the reaction mixture was stirred at 80 C. for 4 h. The reaction mixture was cooled to room temperature and the acetic acid was removed under reduced pressure. The residue was dissolved in ethyl acetate and neutralized by saturated aq. NaHCO3solution. The organic layer was washed with saturated aq. NaHSO3, dried over Na2SO4, concentrated and purified by silica column using hexanes and ethyl acetate as eluent. Isolated 6.1 g of title compound.
With N-chloro-succinimide; In acetonitrile; at 80℃; for 18h;
A mixture of <strong>[45644-21-1]6-chloropyridin-2-amine</strong> (2.5 g, 19.4 mmol) and NCS (2.8 g, 21.3 mmol) in MeCN (40 mL) was stirred at 80 C for 18 hours. The reaction mixture was concentrated in vacuo to give a residue, which was purified by silica gel chromatography (ethyl acetate in petroleum ether = 0% to 30%) to afford 5,6-dichloropyridin-2-amine (2.1 g, 66% yield) as a white solid. LCMS m/z [M+H]+ = 162.8.
63%
With N-chloro-succinimide; In acetonitrile; at 80℃; for 18h;
Step 3: 5,6-dichloropyridin-2-amine To a solution of <strong>[45644-21-1]6-chloropyridin-2-amine</strong> (5 g, 38.9 mmol) in acetonitrile (50 ml) was added N- chlorosuccinimide (5.25 g, 39.3 mmol). The reaction was stirred for 18 h at 80 C and then concentrated in vacuo. The residue was purified by chromatography with ethyl acetate/petroleum ether (1/3) to afford 5,6- dichloropyridin-2-amine (4 g, 63%) as a white solid. LCMS (ESI): M+H+ = 163.0. NMR (300 MHz, CDC13) delta 7.42 (d, J = 4.0 Hz, 1H), 6.63 (d, J = 4.0 Hz, 1H), 5.10 (brs, 2H).
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,2-dimethoxyethane; water; at 80℃; for 18h;Inert atmosphere;
Example 79A methyl 4-(6-aminopyridin-2-yl)benzoate A mixture of 6-chloropyrid-2-amine (255.1 mg, 1.984 mmol) and methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (611.2 mg, 2.332 mmol) in dimethoxyethane (5 mL) and water (2.5 mL) was degassed under a N2 flow for 15 minutes. Potassium carbonate (581.9 mg, 4.21 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride (87.5 mg, 0.120 mmol) were added, and the mixture stirred at 80 C. for 18 hours. Water was then added to the reaction mixture (35 mL), and it was extracted with ethyl acetate (3*35 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography, eluted with 5% ethyl acetate in dichloromethane (Rf=0.28), to provide the title compound (344.5 mg, 76%). 1H NMR (400 MHZ), DMSO-d6) delta 8.16-8.09 (m, 2H), 8.05-7.96 (m, 2H), 7.50 (dd, J=8.2, 7.5 Hz, 1H), 7.18-7.11 (m, 1H), 6.49 (d, J=8.3 Hz, 1H), 6.08 (s, 2H), 3.87 (s, 3H): MS (ESI+) m/z 229 (M+H)+.
tert-butyl 3-(6-aminopyridin-2-yl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
62%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,2-dimethoxyethane; water; at 80℃; for 18h;Inert atmosphere;
Example 73A tert-butyl 3-(6-aminopyridin-2-yl)benzoate A mixture of 6-chloropyrid-2-amine (259.6 mg, 2.019 mmol) and <strong>[220210-56-0](3-(tert-butoxycarbonyl)phenyl)boronic acid</strong> (491.8 mg, 2.215 mmol) in dimethoxyethane (5 mL) and water (2.5 mL) was degassed under a N2 flow for 15 minutes. Potassium carbonate (621.0 mg, 4.49 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride (88.5 mg, 0.125 mmol) were added, and the mixture stirred at 80 C. for 18 hours. Water was then added to the reaction mixture (35 mL), and it was extracted with ethyl acetate (3*35 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography, eluted with 5% ethyl acetate in dichloromethane (Rf=0.43), to provide the title compound (340.5 mg, 62%). 1H NMR (400 MHz, DMSO-d6) delta 8.50 (t, J=1.7 Hz, 1H), 8.16 (dt, J=7.9, 1.4 Hz, 1H), 7.88 (dt, J=7.8, 1.3 Hz, 1H), 7.54 (t, J=7.7 Hz, 1H), 7.47 (t, J=7.8 Hz, 1H), 7.07 (d, J=7.4 Hz, 1H), 6.45 (d, J=8.2 Hz, 1H), 6.05 (s, 2H), 1.56 (s, 9H): MS (ESI+) m/z 271 (M+H)+.
ethyl 5-(6-aminopyridin-2-yl)thiophene-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
42%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,2-dimethoxyethane; water; at 80.0℃; for 18.0h;Inert atmosphere;
Example 82A ethyl 5-(6-aminopyridin-2-yl)thiophene-3-carboxylate A mixture of 6-chloropyrid-2-amine (257.2 mg, 2.001 mmol) and <strong>[960116-27-2]ethyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-3-carboxylate</strong> (528.1 mg, 1.872 mmol) in dimethoxyethane (5 mL) and water (2.5 mL) was degassed under a N2 flow for 15 minutes. Potassium carbonate (599.5 mg, 4.34 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride (95.2 mg, 0.130 mmol) were added, and the mixture stirred at 80 C. for 18 hours. Water was then added to the reaction mixture (35 mL), and it was extracted with ethyl acetate (3*35 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography, eluted with 5% ethyl acetate in dichloromethane (Rf=0.46), to provide the title compound (193.8 mg, 42%). 1H NMR (501 MHz, DMSO-d6) delta 8.27 (d, J=1.3 Hz, 1H), 7.90 (d, J=1.4 Hz, 1H), 7.42 (dd, J=8.2, 7.4 Hz, 1H), 7.10 (dd, J=7.4, 0.7 Hz, 1H), 6.39 (dd, J=8.2, 0.7 Hz, 1H), 6.07 (s, 2H), 4.28 (q, J=7.1 Hz, 2H), 1.31 (t, J=7.1 Hz, 3H): MS (ESI+) m/z 249 (M+H)+.
methyl 4-(6-aminopyridin-2-yl)-3-methylbenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
19%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,2-dimethoxyethane; water; at 80℃; for 17h;Inert atmosphere;
Example 120A methyl 4-(6-aminopyridin-2-yl)-3-methylbenzoate A mixture of 6-chloropyrid-2-amine (138.8 mg, 1.080 mmol) and <strong>[473596-87-1]methyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate</strong> (263.4 mg, 0.954 mmol) in dimethoxyethane (2.5 mL) and water (1.25 mL) was degassed under a N2 flow for 15 minutes. Potassium carbonate (352.2 mg, 2.67 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (40.2 mg, 0.055 mmol) were added, and the mixture stirred at 80 C. for 17 hours. Water was then added to the reaction mixture (35 mL), and extracted with ethyl acetate (3*35 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography, eluted with 5% ethyl acetate in dichloromethane (Rf=0.30), to provide the title compound (44.2 mg, 19%). 1H NMR (400 MHz, DMSO-d6) delta 7.85 (d, J=1.8 Hz, 1H), 7.81 (dd, J=8.0, 1.8 Hz, 1H), 7.50-7.42 (m, 2H), 6.61 (d, J=7.2 Hz, 1H), 6.45 (d, J=8.2 Hz, 1H), 6.00 (s, 2H), 3.86 (s, 3H), 2.38 (s, 3H). MS (ESI+) m/z 243 (M+H)+.
methyl 3-(6-aminopyridin-2-yl)-2-methylbenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,2-dimethoxyethane; water; at 80℃;
Example 122A methyl 3-(6-aminopyridin-2-yl)-2-methylbenzoate 6-chloropyridin-2-amine (0.257 g, 2 mmol), <strong>[955929-54-1]methyl 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate</strong> (0.607 g, 2.200 mmol), potassium carbonate (0.663 g, 4.80 mmol), and PdCl2dppf (0.073 g, 0.100 mmol) in dimethoxyethane (6 mL) and water (3 ml) were heated at 80 C. overnight. The mixture was diluted with ethyl acetate (20 mL) and washed with water (3*5 mL) and brine (5 mL) sequentially. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel, eluting with 10 to 60% ethyl acetate-heptanes. The title compound was obtained as a white solid (0.378 g, 78%). 1H NMR (400 MHz, DMSO-d6) delta 7.70 (dd, J=7.7, 1.5 Hz, 1H), 7.51-7.26 (m, 3H), 6.57-6.38 (m, 2H), 5.97 (s, 2H), 3.84 (s, 3H), 2.36 (s, 3H). MS (DCI+) m/z 243.0 (M+H).
methyl 4-(6-aminopyridin-2-yl)-3-fluorobenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
37%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,2-dimethoxyethane; water; at 80℃;
Example 123A methyl 4-(6-aminopyridin-2-yl)-3-fluorobenzoate 6-Chloropyridin-2-amine (0.257 g, 2 mmol), <strong>[603122-84-5](2-fluoro-4-(methoxycarbonyl)phenyl)boronic acid</strong> (0.436 g, 2.200 mmol), potassium carbonate (0.663 g, 4.80 mmol), and PdCl2dppf (0.073 g, 0.100 mmol) in dimethoxyethane (6 mL) and water (3 mL) were heated at 80 C. overnight. The mixture was diluted with ethyl acetate (25 mL) and washed with water (3*10 mL) and brine (10 mL) sequentially. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with 10 to 50% ethyl acetate-heptanes, to afford the title compound as a white solid (0.181 g, 37% yield). 1H NMR (400 MHz, DMSO-d6) delta 8.04 (t, J=8.0 Hz, 1H), 7.92-7.70 (m, 2H), 7.50 (dd, J=8.3, 7.4 Hz, 1H), 7.04-6.93 (m, 1H), 6.51 (dd, J=8.3, 0.8 Hz, 1H), 6.12 (s, 2H), 3.89 (s, 3H). MS (DCI+) m/z 246.9 (M+H).
ethyl 3-(6-aminopyridin-2-yl)-2-fluorobenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
47%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,2-dimethoxyethane; water at 80℃; for 17h; Inert atmosphere;
125.125A Example 125A ethyl 3-(6-aminopyridin-2-yl)-2-fluorobenzoate
Example 125A ethyl 3-(6-aminopyridin-2-yl)-2-fluorobenzoate A mixture of 6-chloropyrid-2-amine (259.6 mg, 2.019 mmol) and 2-fluoro-3-(ethoxycarbonyl)phenylboronic acid (438.0 mg, 2.066 mmol) in dimethoxyethane (5 mL) and water (2.5 mL) was degassed under a N2 flow for 15 minutes. Potassium carbonate (589.3 mg, 4.26 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride (83.9 mg, 0.115 mmol) were added, and the mixture was stirred at 80° C. for 17 hours. Water was then added to the reaction mixture (35 mL), and it was extracted with ethyl acetate (3*35 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography, eluted with 5% ethyl acetate in dichloromethane (Rf=0.28), to provide the title compound (246.6 mg, 47%). 1H NMR (400 MHz, DMSO-d6) δ 8.02 (td, J=7.4, 1.9 Hz, 1H), 7.85 (ddd, J=8.4, 6.7, 1.9 Hz, 1H), 7.48 (t, J=7.8 Hz, 1H), 7.38 (t, J=7.7 Hz, 1H), 6.89 (dd, J=7.3, 2.5 Hz, 1H), 6.49 (d, J=8.2 Hz, 1H), 6.07 (s, 2H), 4.34 (q, J=7.1 Hz, 2H), 1.33 (t, J=7.1 Hz, 3H). MS (ESI+) m/z 261 (M+H)+.
methyl 3-(6-aminopyridin-2-yl)-4-fluorobenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
47%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,2-dimethoxyethane; water; at 80.0℃; for 17.0h;Inert atmosphere;
Example 128A methyl 3-(6-aminopyridin-2-yl)-4-fluorobenzoate A mixture of 6-chloropyrid-2-amine (256.3 mg, 1.994 mmol) and <strong>[850568-04-6]2-fluoro-5-(methoxycarbonyl)phenylboronic acid</strong> (429.8 mg, 2.171 mmol) in dimethoxyethane (5 mL) and water (2.5 mL) was degassed under a N2 flow for 15 minutes. Potassium carbonate (621.0 mg, 4.49 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride (71.3 mg, 0.097 mmol) were added, and the mixture stirred at 80 C. for 17 hours. Water was then added to the reaction mixture (35 mL), and it was extracted with ethyl acetate (3*35 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography, eluted with 10% ethyl acetate in dichloromethane (Rf=0.31), to provide the title compound (246.6 mg, 47%). 1H NMR (400 MHz, DMSO-d6) delta 8.54 (dd, J=7.6, 2.4 Hz, 1H), 7.99 (ddd, J=8.6, 4.7, 2.4 Hz, 1H), 7.49 (dd, J=8.3, 7.4 Hz, 1H), 7.43 (dd, J=11.2, 8.6 Hz, 1H), 6.97 (ddd, J=7.5, 2.7, 0.8 Hz, 1H), 6.50 (dd, J=8.3, 0.8 Hz, 1H), 6.16 (s, 2H), 3.88 (s, 3H). MS (ESI+) m/z 247 (M+H)+.
methyl 3-(6-aminopyridin-2-yl)-4-methylbenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
35%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,2-dimethoxyethane; water; at 80℃;
Example 129A methyl 3-(6-aminopyridin-2-yl)-4-methylbenzoate 6-chloropyridin-2-amine (0.129 g, 1 mmol), <strong>[882679-40-5]methyl 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate</strong> (0.304 g, 1.100 mmol), potassium carbonate (0.332 g, 2.400 mmol), and PdCl2dppf (0.037 g, 0.050 mmol) in dimethoxyethane (3.4 mL) and water (1.7 mL) were heated at 80 C. overnight. The mixture was diluted with ethyl acetate (20 mL) and washed with water (3*5 mL) and brine (5 mL) sequentially. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The dark brown crude oil was purified by silica gel chromatography, eluting with 10 to 70% ethyl acetate-heptanes, to afford the title compound as a white solid (0.085 g, 35%). 1H NMR (500 MHz, DMSO-d6) delta 7.94-7.79 (m, 2H), 7.51-7.37 (m, 2H), 6.61 (dd, J=7.3, 0.9 Hz, 1H), 6.44 (dd, J=8.3, 0.9 Hz, 1H), 6.01 (s, 2H), 3.84 (s, 3H), 2.39 (s, 3H). MS (DCI+) m/z 243.0 (M+H).
With formic acid; In water; at 110℃; for 0.333333h;Green chemistry;
General procedure: Formic acid (98% aqueous solution, 0.1 mmol) was added to a mixture of heteroaryl amine (1 mmol), triethylorthoformate(1 mmol), and 2,3-dihydroxynaphthalene (1 mmol). The reaction mixture was magnetically stirred on a preheated oilbath at 110C for 20 min. The progress of the reaction was monitored by thin-layer chromatography (TLC). After completion,the reaction mixture was cooled down to room temperature, and CH3CN (5 mL) was added. The precipitate was filtered, washed with cold CH3CN, dried, and purifiedby recrystallization from ethyl acetate to give the pure products 4.
(1R,3S,4S)-tert-butyl 3-((6-chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate[ No CAS ]
(1R,3S,4S)-N-(6-chloropyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
With trifluoroacetic acid; In dichloromethane; at 0℃;
TFA (1.5 mL) was added dropwise to a solution of(1R,3S,4S)-tert-butyl 3-((6- chloropyridin-2-yl)carbamoyl)-2-azabicyclo[2.2. 1 ]heptane-2-carboxylate (100 mg, 0.3 mmol) in DCM (3.5 mL) at 0 C. After the addition was complete, the resulting mixture was stirred at 0 C overnight, then diluted with DCM (1 mL) and neutralized by the addition of saturated aqueous NaHCO3 (10 mL). The bi-layers were separated and the organic layer was dried over anhydrous Na2SO4 and concentrated in vacuum to provide (1R,3S,4S)-N-(6- chloropyridin-2-yl)-2-azabicyclo[2 .2.1 ]heptane-3 -carboxamide (70 mg, quant.) which was used in next step without further purification.
(S)-tert-butyl 3-((6-chloropyridin-2-yl)carbamoyl)morpholine-4-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
10%
With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 20℃;
A mixture of (S)-4-(tert-butoxycarbonyl)morpholine-3 -carboxylic acid (500 mg,2.17 mmol, 1.0 eq), 6-chloro-pyridin-2-ylamine (557 mg, 4.33 mmol, 2.0 eq), and EDCI (1.25 g, 6.5 mmol, 3.0 eq) in pyridine (80 mL) was stirred at r.t. overnight. The reaction was monitored by LC-MS. The mixture was concentrated and the resulting residue was purified by prep-HPLC to give (S)-tert-butyl 3 -((6-chloropyridin-2-yl)carbamoyl)morpholine-4- carboxylate (71 mg, 10%) as a white solid.
(S)-1-benzyl 4-tert-butyl 2-((6-chloropyridin-2-yl)carbamoyl)piperazine-1,4-dicarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 20℃; for 6h;
A mixture of (S)- 1 -((benzyloxy)carbonyl)-4-(tert-butoxycarbonyl)piperazine- 2- carboxylic acid (500 mg, 1.372 mmol, 1.0 eq), 6-chloro-pyridin-2-ylamine (265 mg, 2.058 mmol, 1.5 eq), and EDCI (790 mg, 4.116 mmol, 3.0 eq) in pyridine (25 mL) was stirred at r.t. for 6 h. The reaction was monitored by LC-MS and TLC. The mixture was concentrated and the resulting residue was purified by chromatography on silica gel column (PE/EA = 5/1, v/v) to give the crude (S)- 1-b enzyl 4-tert-butyl 2-((6-chloropyridin-2-yl)carbamoyl)piperazine- 1,4-dicarboxylate (400 mg, 61%) as a white solid.
To dry DMF (300 mL) taken in a sealed tube, was added NaOtBu (74.8 g, 777.85 minol) followed by phenylmethanethiol (91.1 mL, 777.85 minol) at rt and stirred for 30 min Then <strong>[45644-21-1]6-chloropyridin-2-amine</strong> (50.0 g, 388.92 minol) was added in portions for 15 min at rt, followed by KF (45.2 g, 777.85 minol). The reaction was sealed and heated at 80-90C for 36h. Then the reaction was quenched with water (1.5 L) and extracted with Et20 thrice. TheStep I. To dry DMF (300 mL) taken in a sealed tube, was added NaOtBu (74.8 g, 777.85 minol) followed by phenylmethanethiol (91.1 mL, 777.85 minol) at rt and stirred for 30 min Then <strong>[45644-21-1]6-chloropyridin-2-amine</strong> (50.0 g, 388.92 minol) was added in portions for 15 min at rt, followed by KF (45.2 g, 777.85 minol). The reaction was sealed and heated at 80-90C for 36h. Then the reaction was quenched with water (1.5 L) and extracted with Et20 thrice. Thecombined organic portion was washed with brine solution, dried over Na2SO4, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography on silica gel (60-120 mesh size) (15-20% EtOAc in Hexane) to afford 6- (benzylthio)pyridin-2-amine as yellowish oil (67.5 g, 80.2%). LC/MS, ESl-MS(): 2 1 7 . 4.1H NMR (300 MHz, CDCI3) O ppm 7.42 - 7.39 (m, 2H), 7.33 - 7.23 (m, 4H), 7.55 (d, J= 7.8 Hz, 1H), 7.21 (d, J= 8.1 Hz, 1H), 4.44 (brs, 2H), 4.36 (5, 2H).
A) N-(6-Chloropyridin-2-yl)-beta-alanine A mixture of 2-amino-6-chloropyridine (100 g), methyl acrylate methyl acrylate (117 g) and acetic acid (34 mL) was stirred at 120C for 72 hours. The reaction was cooled to room temperature. Then, a 6 N aqueous sodium hydroxide solution (375 mL) was added thereto, and the mixture was stirred under conditions of heating to reflux for 5 hours. The reaction mixture was cooled to room temperature, and then, unreacted 2-amino-6-chloropyridine starting material was extracted with diethyl ether. The remaining aqueous layer was adjusted to pH = 4 to 5 with 3 N hydrochloric acid, and the precipitate was collected by filtration. The solid collected by filtration was dissolved in ethyl acetate, washed with saturated brine and dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure to obtain the title compound (60 g). 1HNMR (300 MHz, MeOD) delta 2.58 (2H, t, J = 6.8 Hz), 3.54 (2H, t, J = 6.8 Hz), 6.38 (1H, dd, J = 8.4, 0.6 Hz), 6.49 (1H, dd, J = 7.2, 0.6 Hz), 7.33 (1H, dd, J = 8.4, 7.4 Hz).
Conc. HNO3 (2.39 mL, 35.00 mmol) was added dropwise to a mixture of cone H2SO4 (56 mL, 1050 mmol) and 6-chloropyridin-2-amine (3.00 g, 23.34 mmol) at 0 C. The mixture was stirred at 0 C for 4 h and poured into ice-water. The mixture was extracted with EtOAc (3x100 mL). The combined organic layers were dried over anhydrous Na2S04 and concentrated. The residue was purified by chromatography to give the sub-title compound (1.38 g, 34 %).
34%
With sulfuric acid; nitric acid; for 4.0h;
Cone. HNO3 (2.39 ml_, 35.00 mmol) was added dropwise to a mixture of cone H2SO4 (56 ml_, 1050 mmol) and 6-chloropyridin-2-amine (3.00 g, 23.34 mmol) at 0 C. The mixture was stirred at 0 C for 4 h and poured into ice-water. The mixture was extracted with EtOAc (3x100 ml_). The combined organic layers were dried over anhydrous Na2S04 and concentrated. The residue was purified by chromatography to give the sub-title compound (1.38 g, 34 %).
With pyridine; In dichloromethane; at 0 - 20℃; for 1.5h;
To a solution of <strong>[45644-21-1]6-chloropyridin-2-amine</strong> (1.04 g, 8.09 mmol) in pyridine/DCM (16.4 mL,1/4) was added isobutyryl chloride (0.91 mL, 8.49 mmol) dropwise at 0 C. The reaction was allowed to stir at 0 C for 30 mm and then rt for lh. The crude reaction was diluted with DCM and washed with aq. NH4C1 and brine. The organic layer was then dried over Na2504, filtered and concentrated. The crude residue was purified by chromatography on silica gel (0->20% acetone in hexanes) to provide N-(6-chloropyridin-2-yl)isobutyramide as white solid(1.523 g, 95%). ?H NMR (500 MHz, Chloroform-d) oe 8.19 (d, J= 8.2Hz, 1H), 7.85 (s, br,1H), 7.68 (t, J= 8.0 Hz, 1H), 7.08 (d, J= 7.8Hz, 1H), 2.62-2.48 (m, 1H), 1.29 (d, J 6.9Hz, 6H).
95%
With pyridine; In dichloromethane; at 0 - 20℃; for 1.5h;
To a solution of <strong>[45644-21-1]6-chloropyridin-2-amine</strong> (1.04 g, 8.09 mmol) in pyridine/DCM (16.4 mL, 1/4) was added isobutyryl chloride (0.91 mL, 8.49 mmol) dropwise at 0 C. The reaction was stirred at 0 C for 30 min and then at rt for 1h. The reaction was diluted with DCM and washed with aq. NH4Cl and brine. The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude residue was purified by chromatography on silica gel (0% acetone 20% acetone in hexanes) to provide N-(6-chloropyridin-2- yl)isobutyramide as white solid (1.5 g, 95%): 1H NMR (500 MHz, Chloroform-d) delta 8.19 (d, J = 8.2Hz, 1H), 7.85 (s, br, 1H), 7.68 (t, J = 8.0 Hz, 1H), 7.08 (d, J = 7.8Hz, 1H), 2.62- 2.48 (m, 1H), 1.29 (d, J = 6.9 Hz, 6H).
4-((6-chloropyridin-2-yl)carbamoyl)phenyl acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine In dichloromethane at 20℃; for 4h;
General procedure: To a solution of 2-amino-6-chloropyridine (2.1 mmol) in dried DCM(10 mL) were added Et3N (0.4 mL, 3.7 mmol) followed by dropwiseaddition of a solution of 4 (0.4 g, 2.3 mmol) in dried DCM (5 mL). Afterstirring the reaction mixture for 4 h at room temperature, the mixturewas concentrated under vacuo, and the crude product was purified bycolumn chromatography using DCM/acetone (20:1) to yield pure 4-((6-chloropyridin-2-yl)carbamoyl)phenyl acetate.
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In ethanol; water; toluene at 120℃; Inert atmosphere;
4.1.3. General Method B: Pd-Catalyzed Suzuki-Miyaura Cross-Coupling Using Pd(PPh3)4.Preparation of 5a, 5b, 35b-g, 45a, 45b
General procedure: Under argon a microwave vial was charged with the corresponding halogeno derivative(1.0 equiv.), the corresponding phenylboronic acid (1.2 equiv.), Pd(PPh3)4 (5 mol%),Na2CO3 (3.0 equiv.) and a mixture toluene:ethanol:water (5:1:1, 5.32 mL/mmol)). The vialwas capped properly, flushed with argon and heated to 120 C until complete conversionof the starting material. After it was cooled, the reaction mixture was concentrated undervacuum. The crude residue was diluted in water. The organic phase was extracted 3 timeswith EtOAc. The organic layers were combined, washed with brine, dried over Na2SO4,filtered, concentrated and purified by silica gel column chromatography, eluting with theappropriate hexane:EtOAc mixture.
Step 1: tert-butyl (6-chloropyridin-2-yl)carbamate 6-chloropyridin-2-amine (10g) was dissolved into dichloromethane (100mL). TEA(11.8g), DMAP (928mg) and (Boc)2O (25.4g) were added to the solution, and stirred overnight. After reaction of the solution was complete monitored through LC-MS, water (500mL) was poured into the solution, and the solution was extracted by dichloromethane (400mL∗3). The organic phase was washed by saturated sodium chloride, and dried by anhydrous sodium sulfate. Solvent was removed from the organic phase. After beating with PE:EA (10:1) and filtering, the product (8.0g) was obtained. LC-MS,(ES,m/z): [M+H]+=229.7
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