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With thionyl chloride; for 1.5h;Heating / reflux; |
Preparative Example 1. EN = CO2Pr1 = CO2CH3 EPO <DP n="109"/>Methyl-2,3-dichloro pyridine 5- carboxylate 1 (methyl5,6-dichloronicotinate, BIONET) was prepared from <strong>[41667-95-2]5,6-Dichloronicotinic acid</strong> (ALDRICH), by converting to the acid chloride by treatment with excess SOCI2, and refluxed for 1.5 hours followed by methylation in methanol/pyridine as solvent in nearly quantitative yield. Ref. Musso et al, Bioorg. Med.Chem. Lett, 1997, I1 1-6.A round bottomed flask was charged with methyl 2,3-dichloro pyridine 5-carboxylate 1 (7g, 34 mmol), 2-S-ethyl piperazine (prepared as per Williams et al J. Med. Chem 1996, 39, 1345,) ( 75% active, 5.2 g, 34mmol), cesium carbonate (12.15 g, 68 mmol), DBPD (0.74 g, 2.48 mmol), palladium acetate ( 0.55 g, 2.48 mmol) and 1 ,4 dioxane (170 ml). The flask was equipped with a reflux condenser and heated to 8O0C. After 36 hours the reaction was cooled, diluted with methylene chloride (~ 200 ml), and washed with water (2 x 50 ml). The organic layer was dried over anhydrous magnesium sulfate and then concentrated to an oil. The crude product was purified by silica gel chromatography using a methanol/ methylene chloride eluent (3% to 10% MeOH) to afford 3 (8.2 g, 85%) of the title compound. MS: m/e, M+H = 283 |
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With hydrogenchloride; oxalyl dichloride; In 1,4-dioxane; dichloromethane; at 20℃; for 18h;Product distribution / selectivity; |
Oxalyl chloride (3.2 mL; 36.0 mmol) was added to a solution of 5,6 dichloronicotinic acid (5.76 g; 30.0 mmol) and 4M hydrogen chloride in dioxan (7.5 mL; 30.0 mmol) in DCM (50 mL). The mixture was stirred at RT for 18 hours, the DCM evaporated in vacuo, the residue azeotroped with toluene (2 x 15 mL) then added to a solution of pyrrolidine (3.0 mL; 36.0 mmol) and triethylamine (10.0 mL; 72 mmol) in DCM (150 mL). The mixture was stirred at RT for 6 hours, the DCM evaporated in vacuo, the residue partitioned between water (75 mL) and ethyl acetate (100 mL), the organic layer washed with brine, dried (MgSO4) and evaporated in vacuo. The residue was chromatographed on silica, eluting with 50% ethyl acetate in isohexane, to give the desired compound which was further purified by crystallisation from ethyl acetate and isohexane (6.88 g). 1H NMR delta (CDCl3): 1.9 (m, 4H), 3.4 (m, 2H), 3.6 (s, 3H), 7.9 (s, IH) and 8.4 (s, IH); m/z 245 (M+H)+.; Oxalyl chloride (3.2 mL; 36.0 mmol) was added to a solution of 5,6 dichloronicotinic acid (5.76 g; 30.0 mmol) and 4M hydrogen chloride in dioxane (7.5 mL; 30 mmol) in DCM (50 mL). The mixture was stirred at RT for 18 hours, the DCM evaporated in vacuo, the residue azeotroped with toluene (2 x 15 mL) and added to a solution of morpholine (3.1 mL; 36.0 mmol) and triethylamine (10.0 mL; 72 mmol) in DCM (150 mL). The mixture was stirred at RT for 18 hours, the DCM evaporated in vacuo, and the residue partitioned between water (75 mL) and ethyl acetate (100 mL). The organic layer was washed with brine, dried (MgSO4) and evaporated to a residue which was chromatographed on silica, eluting with 50% ethyl acetate in isohexane, to give the desired compound (7.1 g). 1H NMR delta (CDCl3): 3.3 - 3.8 (br, 8H), 7.8 (s, IH), 8.25 (s, IH); m/z 261 (M+H)+.; Oxalyl chloride (3.2 mL; 36.0 mmol) was added to a solution of 5,6 dichloronicotinic acid(5.76 g, 30.0 mmol) and 4M hydrogen chloride in dioxane (7.5 mL; 30.0 mmol) in DCM (50 mL). The mixture was stirred at RT for 18 hours, the DCM evaporated in vacuo, the residue azeotroped with toluene (2 x 15 mL) and added to a solution of 7- azabicyclo[2.2. l]heptane hydrochloride (4.75 g; 36.0 mmol) and triethylamine (15.1 mL; 108 mmol) in DCM (150 mL). The mixture was stirred at RT for 18 hours, the DCM evaporated in vacuo and the residue partitioned between water (75 mL) and ethyl acetate EPO <DP n="210"/>(150 mL). The organic layer was washed with brine, dried (MgSO4) and evaporated to give a solid which was crystallised from ethyl acetate to give the desired compound (5.45 g). 1H NMR delta (CDCl3): 1.5 (m, 4H), 1.85 (m, 4H), 4.0 (br, IH), 4.65 (br, IH), 7.9 (s, IH), 8.4 (s, lH); m/z 271 (M+H)+. |
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With thionyl chloride; at 70℃; for 4h; |
ii) (5,6-Dichloro-pyridin-3-yl)-(3-ethyl-piperidin-1-yl)-methanoneA mixture of 5,6 dichloronicotinic acid (1 g, 5.2 mmol) in SOCI2 (6 mL) was stirred at 700C for 4 hours. The solvent was removed in vacuo to give a beige oil (1.05 g) corresponding to the acid chloride. This oil was solublised in DCM (15 mL) and at 0C triethylamine (1.1 mL, 7.84 mmol) was added. Then, a solution of 3-ethyl piperidine (657 mg, 5.75 mmol) in DCM (5 mL) was added carefully drop-wise. At the end of the addition, the mixture was stirred at RT for 30 min. Water was added and the aqueous phase was extracted with DCM. The organic phases were combined, dried over sodium sulfate and concentrated in vacuo to (5,6- dichloro-pyridin-3-yl)-(3-ethyl-piperidin-1-yl)-methanone (1.2 g, 80%) as a yellow oil. (ES-MS: m/z 328.2/330.2 [M+CH3CN+ H]+, tR 5.48 min (system 2)). |
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With thionyl chloride; In N,N-dimethyl-formamide; at 80℃; for 5h; |
5,6-Dichloro-nicotinic Acid Methyl Ester A solution of 5,6-dichloro-nicotinic acid (55.0 g, 281 mmol) in SOCl2 (204 ml) was treated with DMF (0.1 ml) and the mixture was heated to 80 C. for 5 h. The excess of SOCl2 was evaporated and the crude product was taken up in MeOH (300 ml) and the resulting solution was heated to reflux for 1 h. The mixture was then allowed to cool slowly to RT. 5,6-Dichloro-nicotinic acid methyl ester precipitated and was collected by filtration (55.6 g, 96%). UPLC (5-100% CH3CN): tR=1.384 min, TLC (Hex/EtOAc 1:1): Rf=0.76. By analogy to the preparation of example 16, the following compounds can be made: |
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With thionyl chloride; In N,N-dimethyl-formamide; toluene; at 100℃; for 18h; |
7-Chloro-2-(5,6-dichloro-pyridin-3-yl)-1-propyl-1H-benzoimidazole A mixture of 5,6-dichloro-nicotinic acid (25 g, 128 mmol) and SOCl2 (10.6 ml, 146 mmol) in toluene (125 ml) was treated with DMF (197 mul, 2.55 mmol) at RT and the mixture was then heated to 100 C. for 18 h. The mixture was allowed to cool to RT and then concentrated in vacuo to give the crude acid chloride, which was diluted in anhydrous THF (500 ml) and treated with 3-chloro-N-2-propyl-benzene-1,2-diamine (24.6 g, 133 mmol). The solution was stirred at RT for 2 h, and then heated to 60 C. for 4 h. the mixture was cooled to RT and stirred for 18 h. The precipitate was filtered and dried in vacuo. The crude product was taken up in EtOAc and washed with a sat. aq. soln. of NaHCO3, dried over Na2SO4, filtered and concentrated in vacuo to give pure 7-chloro-2-(5,6-dichloro-pyridin-3-yl)-1-propyl-1H-benzoimidazole (30.3 g, 67%). HPLC (System 3, 30-100% CH3CN): tR=3.531 min, TLC (Hex/EtOAc 4:1): Rf=0.46. By analogy to example 53, the following compounds can be prepared: |
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With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 2h; |
5,6-Dichloronicotinoyl chloride was prepared by reaction of <strong>[41667-95-2]5,6-dichloronicotinic acid</strong> in DCM and one drop DMF with 1.1 equivalents oxalyl chloride at room temperature for 2 h. The orange solution was concentrated, and the resulting solid was used without further purification. To a solution of ethyl 2-(7-(N-hydroxycarbamimidoyl)-l, 2,3,4- tetrahydrocyclopenta[b]indol-3-yl)acetate (0.20 g, 0.664 mmol) in dioxane (4 mL) was added <n="96"/>5,6-dichloronicotinoyl chloride (0.140 g, 0.664 mmol) then triethylamine (0.324 mL, 2.323 mmol). The resulting suspension was stirred at 70 0C for 2.5 h. The solvent was removed under reduced pressure. The residue was purified by silica gel flash chromatography (15 to 100% EtOAc/hexanes) to give the title compound as a beige solid (159 mg). LCMS m/z = 457.2 [M + H]+. |
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With thionyl chloride;N,N-dimethyl-formamide; In 1,1-dichloroethane; at 75℃; for 3h; |
To a well stirred suspension of <strong>[41667-95-2]5,6-dichloronicotinic acid</strong> 5 (600 g, 3.125 mole, Sigma-Aldrich) and DMF (20.0 mL) in dichloroethane (1.2 L) was added drop wise with stirring thionyl chloride (743.56 g, 6.25 mole). The reaction mixture was set up for heating with reflux, fitted with a gas trap filled with saturated aqueous sodium bicarbonate and heated at a temperature of 75 C. until the reaction mixture formed a clear solution, about 3 h. LC/MS of a sample quenched in methanol showed only the presence of the methyl ester. The reaction mixture was cooled to a temperature of about 25 C. and concentrated under reduced pressure to provide 5,6-dichloronicotinoyl chloride 6 as a thick paste. |
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With thionyl chloride; N,N-dimethyl-formamide; In 1,2-dichloro-ethane;Reflux; |
To a well stirred suspension of <strong>[41667-95-2]5,6-dichloronicotinic acid</strong> 5 (600 g, 3.125 mole, Sigma-Aldrich) and DMF (20.0 mL) in dichloroethane (1.2 L) was added drop wise with stirring thionyl chloride (743.56 g, 6.25 mole). The reaction mixture was set up for heating with reflux, fitted with a gas trap filled with saturated aqueous sodium bicarbonate and heated at a temperature of 75 C. until the reaction mixture formed a clear solution, about 3 h. LC/MS of a sample quenched in methanol showed only the presence of the methyl ester. The reaction mixture was cooled to a temperature of about 25 C. and concentrated under reduced pressure to provide 5,6-dichloronicotinoyl chloride 6 as a thick paste. |
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With thionyl chloride; In 1,1-dichloroethane; N,N-dimethyl-formamide; at 75℃; |
To a well stirred suspension of <strong>[41667-95-2]5,6-dichloronicotinic acid</strong> 5 (600 g, 3.125 mole, Sigma-Aldrich) and DMF (20.0 mL) in dichloroethane (1.2 L) was added drop wise with stirring thionyl chloride (743.56 g, 6.25 mole). The reaction mixture was set up for heating with reflux, fitted with a gas trap filled with saturated aqueous sodium bicarbonate and heated at a temperature of 75 C. until the reaction mixture formed a clear solution, about 3 h. LC/MS of a sample quenched in methanol showed only the presence of the methyl ester. The reaction mixture was cooled to a temperature of about 25 C. and concentrated under reduced pressure to provide 5,6-dichloronicotinoyl chloride 6 as a thick paste. |
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With thionyl chloride; at 90℃; for 0.5h;Inert atmosphere; |
Preparation of 5,6-dichloro-N-meth-N-(2-pyrrolidin-1-ylethyl)nicotinamide Thionyl chloride (6 ml) was added to <strong>[41667-95-2]5,6-dichloronicotinic acid</strong> (600 mg, 3.13 mmol), and stirred under a nitrogen atmosphere at 90C for 30 minutes. The reaction solution was concentrated under reduced pressure, and with cooling with ice, triethylamine (1.31 ml, 9.38 mmol) and N-methyl-2-pyrrolidin-1-ylethanamine (481 mg, 3.75 mmol) were added to a tetrahydrofuran solution (4 ml) of the obtained residue, and stirred at room temperature for 3 minutes. Saturated saline water and chloroform were added to the reaction solution, the organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by amine-type silica gel column chromatography (Biotage NH, hexane:ethyl acetate = 4:1 to 1:1) to obtain 5,6-dichloro-N-methyl-N-(2-pyrrolidin-1-ylethyl)nicotinamide 967 mg) as an orange oil. |
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With oxalyl dichloride; In dichloromethane; N,N-dimethyl-formamide; |
Thetitle compound was prepared as a crystalline solid from comm.<strong>[41667-95-2]5,6-dichloronicotinic acid</strong> using the sequence; formation of the carboxylic acidchloride using oxalyl chloride and cat. DMF in dichloromethane followed byreduction with sodium borohydride in water, then reaction with phosphorusoxychloride/DMF in chloroform to give the chloromethylpyridine followed bysubstitution with thioacetic acid/potassium carbonate in acetone and finallychlorosulfonylation using NCS in acetonitrile/water/hydrochloric acid. H-nmrfor l -(5,6-dichloropyridin-3-yl)methanesulfonylchloride; (500 mHz, DMSO) delta3.83 (s, 2H), 8.07 (s, 1H), 8.30 (s, 1H) |
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With thionyl chloride; N,N-dimethyl-formamide; In toluene; for 3h;Reflux; |
To a solution of <strong>[41667-95-2]5,6-dichloronicotinic acid</strong> (14) (2.0 g, 1.83 mmol) in toluene (10 ml) were added SOCl2(1.14 ml, 15.6 mmol) and 0.01 equivalent of DMF (16 mul, 0.208 mmol) at 25 C. risen up to reflux temperature for 3 hrs. Then the reaction mixture was concentrated in vacuo. (0733) To a solution of ethyl carbonocyanidate (15) in EtOH (13 ml) and H2O (7.5 ml) were added NH2OHHCl (1.44 g, 20.7 mmol) and Na2CO3 (1.17 g, 11.1 mmol) at 25 C. After being stirred for 2 hrs, the reaction mixture was concentrated in vacuo. The residue was diluted with CH2Cl2, quenched with brine and extracted with CH2Cl2. The resulting organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. (0734) To a solution of (16) (1.27 g, 9.60 mmol) in CH2Cl2 was added NEt3 (6.65 ml, 48.0 mmol) and then dropwise added resulting 5,6-dichloronicotinoyl chloride (2) in toluene (3 ml) via a droping funnel 0 C. under nitrogen. After being stirred for 2 hrs, the reaction mixture was added to CHCl3/hexane. The resulting solid was filtered through a glass funnel, rinsed with hexane, and collected. (0735) To a solution of crude product in DMF (30 ml) was heated to reflux temperature under nitrogen. After being stirred for 2.5 hrs at the same temperature, the reaction mixture quenched with H2O and diluted with ethyl acetate. The resulting organic layer was separated and the aqueous layer was extracted with ethyl acetate, the combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was triturated with CHCl3/hexane. The resulting solid was filtered through a glass funnel, rinsed with hexane, and collected to afford 1.04 g of the desired product (18) in 40% yield as a white solid. 1H-NMR (DMSO-d6) delta: 9.13 (1H, s), 8.86 (1H, s), 4.47 (2H, q, J=6.91 Hz), 1.37 (3H, t, J=6.91 Hz). LC/MS (M+1): 288. |
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With thionyl chloride; In toluene; for 6h;Heating / reflux; |
S.Theta-Dichloro-S-pyridinecarboxylic acid (1.5g, 7.8mmol) was suspended in toluene (15ml) and thionyl chloride (4.5ml, 39mmol) added. The solution was refluxed under argon for 6 hours and then evaporated to a brown oil. The residue was stirred in dichloromethane (10ml) and pyridine (10ml) and 1-({5-chloro-2-[(2-methylpropyl)oxy]phenyl}methyl)-5- methyl-1H-pyrazol-3-amine (1.0g, 3.4mmol) added. The reaction was stirred for 1 hour then evaporated to a brown solid which was flash chromatographed with ethyl acetate/hexane (1/2). The product was stirred in ethanol (30ml ) and 2M sodium hydroxide (5ml) for 30 minutes then evaporated. The yellow oil was dissolved in ethyl acetate, washed with 2M sodium hydroxide and the organic layer separated, dried over magnesium sulphate and evaporated to give the title compound (1.082g). EPO <DP n="79"/>LC/MS Rt = 3.83min [MH+] 466, 468 and 470 |
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With thionyl chloride;N,N-dimethyl-formamide; In toluene; at 20 - 100℃; for 18h; |
7-Chloro-2-(5,6-dichloro-pyridin-3-yl)-1-propyl-1 H-benzoimidazoleA mixture of 5,6-dichloro-nicotinic acid (25 g, 128 mmol) and SOCI2 (10.6 ml, 146 mmol) in toluene (125 ml) was treated with DMF (197 mul, 2.55 mmol) at RT and the mixture was then heated to 100 0C for 18 h. |
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5,6-dichloronicotinoyl chloride. To a well stirred suspension of <strong>[41667-95-2]5,6-dichloronicotinic acid</strong> 112 (60Og. 3.125 mol) and yV.yV-dimethylformamide (20.0 mL) in dichloroethane (1.2 L) a temperature of about 250C was added drop wise with stirring thionyl chloride (743.56 g, 6.25 mol). In a reflux apparatus fitted with a gas trap filled with saturated aqueous sodium bicarbonate, the reaction mixture was heated and refluxed, at about to 750C, until the reaction mixture became a clear solution, after about 3 h. LC/MS analysis of a sample quenched in methanol showed only the presence of the methyl ester. The reaction mixture was cooled to a temperature of about 250C and concentrated under reduced pressure to provide 113 as a thick slurry. |
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To a well stirred suspension of S.-dichloronicotinic acid 11 (600 g, 3.125 mole) and N,N-dimethylformamide (20.0 mL) in dichloroethane (1.2 L) was added drop wise with stirring thionyl chloride (743.56 g, 6.25 mole). The reaction mixture was set up for heating with reflux, fitted with a gas trap filled with saturated aqueous sodium bicarbonate and heated at 75 0C until the reaction mixture formed a clear solution, about 3 h. LC/MS of a sample quenched in methanol showed only methyl ester. The reaction mixture was cooled to ambient and concentrated under reduced pressure to yield 5,6- dichloronicotinoyl chloride 12 as a thick paste.[0243] A suspension of N,O-dimethylhydroxylamine hydrochloride (350.53 g, 3.59 mole) in methylene chloride was cooled to 0 C (internal temp, Dry Ice/acetone bath), and triethyl amine (711.5 g, 7.03 mole) was added. The 5,6-dichloronicotinoyl chloride from above was dissolved in methylene chloride (2.4 L) and added to the mixture at a rate such that the internal temperature did not exceed 15 0C. After addition of the acid chloride, the reaction mixture was allowed to warm slowly to ambient overnight.[0244] The crude reaction mixture was poured into 2 L water, the layers were separated, and the aqueous was extracted 2 X 500 mL with methylene chloride. The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to yield a brown solid. The solid was then treated with 1 L of boiling hexanes and heated at reflux for ~ 10 min. The resulting pale orange solution was decanted from the dark yellow- brown tar and allowed to cool. This step was repeated with the tar 2 X 500 mL. The hexane mixtures were allowed to cool first to ambient then cooled on ice/water baths. The resulting yellow needles were collected by vacuum filtration and air dried to yield 730 g (99%) of the desired amide, which was suitable to be carried on to the next step. 1H NMR (400 MHz, CDCl3) delta 8.68 (m, IH), 8.18 (m, IH), 3.59 (OCH3, 3H), 3.40 (NCH3, 3H). |
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With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 3h; |
A suspension of 5,6 dichloropyridine-S-carboxylic acid (4.8g, 25 mmol) in DCM (50 ml) was treated with oxalyl chloride (10.9 ml, 125 mmol) and the mixture stirred at ambient temperature with the addition of DMF (one drop). Complete solution was attained, which was then stirred for approximately 3 hrs. The solvent was removed in vacuo and the residue azeotroped once with more DCM, and then dried under high vacuum. More solvent was added (DCM5 60 ml), followed by dimethylamine (14 ml of a 2M solution in THF, 27.5 ml) and triethylamine 10.5 ml, 75 mmol). The reaction mixture was left to stand overnight and then washed twice with water and once with brine, dried (Phase Separating paper) and evaporated to give 5,6-dichloro-N,N-dimethyl-pyridine-3-carboxamide (4.3 g) as a pale brown solid which contained some triethylamine. The solid was dissolved in ethyl acetate and the solution was washed twice with water and once with brine, dried (MgSO4) and evaporated to give 5,6-dichloro-N,N-dimethyl-pyridine-3-carboxamide (3.8g) as a pale brown solid, 1H NMR (400 MHz, DMSO) delta 2.94 (s, 3H), 3.00 (s, 3H), 8.24 (d, IH), 8.46 (d, IH), m/z 217 (M-H)", 219 (M+H+)+. |
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