* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Stage #1: for 6 h; Reflux Stage #2: With sodium hydrogencarbonate In water
PREPARATION 47 2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-amine [Show Image]a) methyl 2-methoxynicotinate Concentrated aqueous sulphuric acid (0.1 mL) was added to a solution of 2-methoxynicotinic acid (2.00 g, 13.1 mmol) in methanol (20 mL) and the mixture was stirred and heated to reflux. After 6 hours, a saturated aqueous solution of sodium hydrogen carbonate was added and the mixture was extracted with ethyl acetate. The organic layer was dried (MgSO4 and concentrated to give the title compound (1.85 g, 85percent) as a colourless oil. LRMS (m/z): 168 (M+1)+.1H NMR (300 MHz, DMSO-d6) δ ppm 3.81 (s, 3H), 3.92 (s, 3H), 7.11 (dd, 1H), 8.13 (dd, 1H), 8.38(dd, 1H).
85%
Stage #1: for 6 h; Reflux Stage #2: With sodium hydrogencarbonate In water
PREPARATION 47 2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-amine a) methyl 2-methoxynicotinate Concentrated aqueous sulphuric acid (0.1 mL) was added to a solution of 2-methoxynicotinic acid (2.00 g, 13.1 mmol) in methanol (20 mL) and the mixture was stirred and heated to reflux. After 6 hours, a saturated aqueous solution of sodium hydrogen carbonate was added and the mixture was extracted with ethyl acetate. The organic layer was dried (MgSO4 and concentrated to give the title compound (1.85 g, 85percent) as a colourless oil. LRMS (m/z): 168 (M+1)+.1H NMR (300 MHz, DMSO-d6) δ ppm 3.81 (s, 3H), 3.92 (s, 3H), 7.11 (dd, 1H), 8.13 (dd, 1H), 8.38(dd, 1H).
Reference：
[1] Journal of Medicinal Chemistry, 2000, vol. 43, # 18, p. 3386 - 3399
3
[ 16498-81-0 ]
[ 54916-66-4 ]
Yield
Reaction Conditions
Operation in experiment
82%
With bromine In water at 20℃;
To a solution of 2-methoxynicotinic acid (20 g, 130.60 mmol) in H20 (1500 mL), Br2 (20 mL, 375.45 mmol) was added at room temperature. The mixture was stirred at room temperature overnight. The reaction mixture was filtered, washed with water and dried to provide 5-bromo-2-methoxynicotinic acid (25 g, yield: 82percent). 1H- MR (DMSO, 400 MHz) δ 13.33 (br s, 1H), 8.47 (d, J= 2.4 Hz, 1H), 8.21 (d, J= 2.4 Hz, 1H), 3.90 (s, 3H). MS (M+H)+: 232 / 234.
82%
With bromine In water at 20℃;
Step 1-Synthesis of 5-bromo-2-methoxynicotinic acid To a solution of 2-methoxynicotinic acid (20 g, 130.60 mmol) in H2O (1500 mL), Br2 (20 mL, 375.45 mmol) was added at room temperature. The mixture was stirred at room temperature overnight. The reaction mixture was filtered, washed with water and dried to provide 5-bromo-2-methoxynicotinic acid (25 g, yield: 82percent). 1H-NMR (DMSO, 400 MHz) δ 13.33 (br s, 1H), 8.47 (d, J=2.4 Hz, 1H), 8.21 (d, J=2.4 Hz, 1H), 3.90 (s, 3H). MS (M+H)+: 232/234.
With hydrogenchloride In aqueous sodium hypochlorite
EXAMPLE 1 A 306 mg. (0.002 mole) sample of 2-methoxynicotinic acid (the product of Preparation A) was added in one portion to 20 ml. of well-stirred 5.25percent aqueous sodium hypochlorite solution (Clorox). The resulting mixture (now a solution) was then allowed to stir at room temperature (~20° C.) for a period of approximately 18 hours (i.e., overnight). Upon completion of this step, the reaction mixture was acidified with 10 ml. of 1N hydrochloric acid and the resulting precipitate was subsequently extracted with chloroform. The organic extracts were then combined, dried over anhydrous magnesium sulfate and filtered, and the resulting filtrate was subsequently concentrated in vacuo to afford 195 mg. (52percent) of pure 5-chloro-2-methoxynicotinic acid, m.p. 139°-141° C. (literature m.p. 149°-150° C., according to D. E. Kuhla et al. in U.S. Pat. No. 3,879,403). The pure product was further characterized by means of nuclear magnetic resonance data and mass spectroscopy.
PREPARATION B In a reaction flask equipped with a mechanical stirrer and dry ice condenser, there were placed 25.5 g. (0.166 mole) of <strong>[16498-81-0]2-methoxynicotinic acid</strong> (the product of Preparation A) and 1500 ml. of water. Stirring was then commenced and chlorine gas was bubbled into the resultant slurry until saturation of same was complete with respect to said gas. This step required a period of 30 minutes. At the end of this time, the reaction mixture was allowed to stir at room temperature (~20 C.) for a period of approximately 16 hours (i.e., overnight) and then was filtered to remove crude product. The latter material was then washed with water and air dried, prior to being taken up in chloroform. The chloroform solution was then washed once with saturated brine and dried over anhydrous magnesium sulfate. After removal of the drying agent by means of filtration and the solvent by means of evaporation under reduced pressure, there were ultimately obtained 26.2 g. (84%) of pure 5-chloro-<strong>[16498-81-0]2-methoxynicotinic acid</strong> in the form of a white solid material melting at 149-151 C. (literature m.p. 149-150 C., according to D. E.
195 mg. (52%)
With hydrogenchloride; In aqueous sodium hypochlorite;
EXAMPLE 1 A 306 mg. (0.002 mole) sample of <strong>[16498-81-0]2-methoxynicotinic acid</strong> (the product of Preparation A) was added in one portion to 20 ml. of well-stirred 5.25% aqueous sodium hypochlorite solution (Clorox). The resulting mixture (now a solution) was then allowed to stir at room temperature (~20 C.) for a period of approximately 18 hours (i.e., overnight). Upon completion of this step, the reaction mixture was acidified with 10 ml. of 1N hydrochloric acid and the resulting precipitate was subsequently extracted with chloroform. The organic extracts were then combined, dried over anhydrous magnesium sulfate and filtered, and the resulting filtrate was subsequently concentrated in vacuo to afford 195 mg. (52%) of pure 5-chloro-<strong>[16498-81-0]2-methoxynicotinic acid</strong>, m.p. 139-141 C. (literature m.p. 149-150 C., according to D. E. Kuhla et al. in U.S. Pat. No. 3,879,403). The pure product was further characterized by means of nuclear magnetic resonance data and mass spectroscopy.
In chloroform; water;
PREPARATION B In a reaction flask equipped with a mechanical stirrer and dry ice condenser, there were placed 25.5 g. (0.166 mole) of <strong>[16498-81-0]2-methoxynicotinic acid</strong> (the product of Preparation A) and 1500 ml. of water. Stirring was then commenced and chlorine gas was bubbled into the resultant slurry until saturation of same was complete with respect to said gas. This step required a period of 30 minutes. At the end of this time, the reaction mixture was allowed to stir at room temperature (~20C.) for a period of approximately 16 hours (i.e., overnight) and then was filtered to remove crude product. The latter material was then washed with water and air dried, prior to being taken up in chloroform. The chloroform solution was then washed once with saturated brine and dried over anhydrous magnesium sulfate. After removal of the drying agent by means of filtration and the solvent by means of evaporation under reduced pressure, there were ultimately obtained 26.2 g. (84%) of pure 5-chloro-<strong>[16498-81-0]2-methoxynicotinic acid</strong> in the form of a white solid material melting at 149-151C. (literature m.p. 149-150C., according to D.E.
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 0 - 27℃; for 2h;Inert atmosphere;
Step L 2MethoxynicotinoyI chloride: To a stirred solution of 2methoxynicotinic acid (2 g. 0.013 mol) in DCM (20 mL) under a N2 atmosphere was added oxalyl chloride (2mL, 0.026 mol) dropwise at 0 C followed by the addition of a catalytic amount of DMF(2 drops). The reaction mixture was stirred at room temperature for 2 h. Upon completion of the reaction, the solvent was removed under reduced pressure in an inert atmosphere toprovide title compound as a thick liquid (2.1 g, 98%).
98%
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 0 - 27℃; for 2h;Inert atmosphere;
Step 1. 2-Methoxy-nicotinoyl chloride To a stirred solution of <strong>[16498-81-0]2-methoxynicotinic acid</strong> (2 g, 0.013 mol) in DCM (20 mL) under a N2 atmosphere was added oxalyl chloride (2 mL, 0.026 mol) drop-wise at 0 C. followed by the addition of a catalytic amount of DMF (2 drops). The reaction mixture was stirred at room temperature for 2 h. Upon completion of the reaction, the solvent was removed under reduced pressure in an inert atmosphere to provide title compound as a thick liquid (2.1 g, 98%).
With thionyl chloride; In dichloromethane; for 2.5h;Heating / reflux;Product distribution / selectivity;
2-Methoxy-3-pyridinecarboxylic acid (0.028 mol) was dissolved in DCM (150 ml). Thionyl chloride (8.2 ml; 0.112 mol)) was added dropwise to this mixture and the mixture was refluxed for 2 hours and 30 minutes. The solvent was evaporated. Then DCM (150 ml) was added and the solvent was evaporated again. The crude compound was dissolved in DCM (150 ml). First l-(phenylmethyl)-3-pyrrolidinamine (0.028 mol) was added and then a saturated aqueous NaHCCb solution (75 ml) was added. The mixture was reacted for 2 hours. Then, the layers were separated. The separated organic layer was dried (MgSO4), filtered and the solvent was evaporated. The residue was purified by column chromatography (eluent: from 100 % CH2Cl2 till CH3OH/CH2C12 1/100). The product fractions were collected and the solvent was evaporated, yielding 7.97 g of intermediate (23); 2-Methoxy-3-pyridinecarboxylic acid (0.028 mol) was dissolved in DCM (150 ml). Thionyl cloride (8 ml; 0.112 mol) was added dropwise to this mixture and the mixture was refluxed for 2 hours and 30 minutes. The solvent was evaporated. Then DCM (150 ml) was added and the solvent was evaporated again. The crude compound was dissolved in DCM (150 ml). First N-methyl-N-(phenylmethyl)-l,3-propanediamine (0.028 mol) was added and then a saturated aqueous nuaHCtheta3 solution (75 ml) was added. The mixture was reacted for 2 hours. Then, the layers were separated. The separated organic layer was dried (MgSO4), filtered and the solvent was evaporated. The residue was purified by column chromatography (eluent: from 100 % CH2Cl2 till CH3OH/CH2C12 1/100). The product fractions were collected and the solvent was evaporated, yielding 8.7 Ig of intermediate (27); -Methoxy-3-pyridinecarboxylic acid (0.00485 mol) was dissolved in DCM (50 ml). Thionyl chloride (1.4 ml) was added dropwise to this mixture and the mixture was refluxed for 2 hours and 30 minutes. The solvent was evaporated. Then DCM (50 ml) was added and the solvent was evaporated again. The crude compound was dissolved in DCM (50 ml). First 4-(phenylmethyl)-2-morpholinemethanamine (0.00485 mol) was added and then a saturated aqueous NaHCO3 solution (25 ml) was added. The mixture was reacted for 2 hours. Then, the layers were separated. The separated organic layer was dried (MgSO4), filtered and the solvent was evaporated. The residue was purified by column chromatography (eluent : from 100 % CH2Cl2 till CH3OH/CH2C12 1/100). The product fractions were collected and the solvent was evaporated, yielding 1.6 g of intermediate (29); 2-Methoxy-3-pyridinecarboxylic acid (0.0269 mol) was dissolved in DCM (150 ml). Thionyl chloride (8 ml) was added dropwise to this mixture and the mixture was refluxed for 2 hours and 30 minutes. The solvent was evaporated. Then DCM (150 ml) was added and the solvent was evaporated again. The crude compound was dissolved in DCM (150 ml). First 4-aminohexahydro-lH-azepine-l-carboxylic acid, ethyl ester (0.0269 mol) was added and then a saturated aqueous NaetaCtheta3 solution (75 ml) was added. The mixture was reacted for 2 hours. Then, the layers were separated. The separated organic layer was dried (MgSO4), filtered and the solvent was evaporated. The residue was purified by column chromatography (eluent: from 100 % CH2CL) till CH3OH/CH2Cl2 1/100). The product fractions were collected and the solvent was evaporated, yielding 8.63 of intermediate (31).
With thionyl chloride; In dichloromethane;
) Preparation of J - ( - /~ N intermediate (41)First 2-methoxy-3-pyridinecarboxylic acid was turned into its acid chloride by refluxing the carboxylic acid in DCM (100 ml, p. a.) and thionyl chloride (7 ml). The solvent was evaporated. To a mixture of this residue (0.024 mol) in an aqueous saturated NaHCtheta3 solution (75 ml), a mixture of l-(phenylmethyl)-4-piperidinamine (0.024 mol) in DCM (150 ml) was added. The reaction mixture was stirred for 2 hours. The layers were separated. The separated organic layer was dried (MgSO4), filtered and the solvent was evaporated. The residue was purified by column chromatography (CH3OH/CH2CI2 1/99). The desired fractions were collected and the solvent was evaporated. The residue was triturated from diisopropyl ether, yielding 7.38 g of intermediate (41). EPO <DP n="39"/>b) Preparation of intermediate (42)
To a 100-mL round-bottomed flask was added <strong>[16498-81-0]2-methoxynicotinic acid</strong> (1.52 g, 9.93 mmol, Aldrich, St. Louis, MO) and borane methyl sulfide complex (3.77 mL, 39.7 mmol, Aldrich, St. Louis, MO) in tetrahydrofuran (30 mL). The reaction mixture was stirred at 70 C for 16 h. The mixture was cooled to 0 C and MeOH (10 mL) was added dropwise. After the addition was completed, the reaction mixture was stirred for further 20 min. The solvent was removed in vacuo and the residue was purified by silica gel chromatography, eluting with 60% EtOAc/hexanes to give (2-methoxy-3-pyridinyl)methanol (1.15 g) as a white solid.
150 mg
With borane-THF; In tetrahydrofuran; at 0 - 25℃; for 1h;Inert atmosphere;
A solution of <strong>[16498-81-0]2-methoxynicotinic acid</strong> (200.0 mg, 1.31mmol) and borane tetrahydrofuran complex solution (1 mol/L) (4 mL, 3.92 mmol) was stirred under nitrogen in tetrahydrofuran (5 mL) at 0 C. The resulting solution was stirred for 1 hour at 25 C. The reaction was quenched by methanol (2 mL). The solvent was concentrated under vacuum to afford 2-methoxy-3-pyridyl) methanol (150 mg, 1.08 mmol) as a yellow oil. LCMS (ESI) [M+H]+=139.2.
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃;
To a solution of 200mg (0.90mmol) of the compound obtained in the Example 6 in 3mL of dichloromethane were added to 165mg (l.OSmmol) of <strong>[16498-81-0]2-methoxynicotinic acid</strong> and 207mg (l.OSmmol) of l-ethyl-3-(3-dimethyl-aminopropyl) carbodiimide hydrochloride, and the mixture was stirred for over night at room temperature. After adding saturated sodium hydrogen carbonate aqueous solution, themixturewas extracted with dichloromethane.The organic layer was washed with water and saturated saline solution, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, then, 6mL of ethanol and 3mL of sodium hydroxide aqueous solution were added to the residue, and the mixture was refluxed for 9 hours. After the reaction mixture was cooled to the room temperature, water was added and the mixture was extracted with dichloromethane. The organic layer was washed with water and saturated saline solution, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate = 2/1) . The obtained product was recrystallized from the mixture solvent of ethyl acetate-hexane to give 78mg (26%) of the title compound.
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In ISOPROPYLAMIDE; at 60℃;
Examples 1 to 162 illustrated below were synthesised as a library. The following solutions were used: carboxylic acid, ZCO2H, was dissolved in dimethylacetamide (anhydrous) plus 3.75% triethylamine at 0.2M concentration. the amine of preparation 2a was dissolved in DMA (anhydrous) plus 3.75% triethylamine at 0.2M concentration. HBTU was dissolved in DMA (anhydrous) at 0.2M concentration. (N.B. Gentle sonication, in a warm water bath (temp <40 C.), was used to dissolve the monomers where necessary.) Experimental Procedure: The reaction Scale was between 20 and 30 micromoles per well (experimental details shown for 20 mumole reaction, scale can be adjusted accordingly within this range). Reactions were performed in a polypropylene 96 well plate. a) Amine solutions (0.1 ml, 20 mumoles, 1 eq.) were added to the wells b) Carboxylic acid solutions (0.15 ml, 30 mumoles, 1.5 eq.) were added to the wells c) HBTU Solution (0.15 ml, 30 mumoles, 1.5 eq.) was added to each well d) The polypropylene 96 well plate was sealed with a PTFE and Rubber gasket and clamped between a pair of metal plates. e) The plate was heated in an oven for 6 h at 60 C. and then left to cool down in the oven overnight. f) When cool, the plate was unclamped and placed in a Genevac to remove the solvent. g) The samples were re-dissolved in DMSO/water (9:1) (500 mul) and any particulate matter was removed by filtration. h) Purification was carried-out by RP-HPLC. HPLC Purification Conditions: Column: Phenomenex Luna C18, 10 um, 150×10 mm id Temperature: ambient Eluent A: 0.05% Diethylamine in water Eluent B: Acetonitrile Samples dissolved in: 90% Dimethylsulphoxide in water. Sample loaded using Gilson Autosampler with Injection Volume of 550 mul
With 4-methyl-morpholine; sodium borohydrid; In tetrahydrofuran; methanol; ethyl acetate;
a) 2-Methoxy-3-picolyl alcohol.HCl 20.0 g of <strong>[16498-81-0]2-methoxynicotinic acid</strong> (130.59 mmol) were introduced together with 28.7 ml of N-methylmorpholine (261.18 mmol) into THF at -10 C., and 25.4 ml of isobutyl chloroformate (195.89 mmol) in 50 ml of THF were rapidly added dropwise, during which a precipitate separated out. After stirring at 0 C. for one hour, 16.3 g of sodium borohydride (430.95 mmol) were added in portions and subsequently 250 ml of methanol were slowly added dropwise (vigorous evolution of gas and exothermic reaction). After the precipitated salt had been filtered off with suction, the filtrate was concentrated under reduced pressure in a rotary evaporator, and the residue was taken up in ethyl acetate, washed with water, dilute hydrochloric acid (pH=2), saturated brine (water phases were kept very small), dried over magnesium sulfate and concentrated in a rotary evaporator. The residue was taken up in ether, ethereal hydrochloric acid was added, and the precipitate was filtered off with suction and extracted by stirring with ether. 16.3 g (71%) of 2-methoxy-3-picolyl alcohol hydrochloride were obtained as a white salt.
N-[(1-tert-butoxycarbonyl-4-piperidyl)methyl]-2-methoxypyridine-3-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In thionyl chloride; dichloromethane; ethyl acetate; Petroleum ether;
EXAMPLE 26 <strong>[16498-81-0]2-Methoxypyridine-3-carboxylic acid</strong> (4.86 g) was added in portions to thionyl chloride (50 ml) then the mixture stirred and heated under reflux for 2 hours. After cooling, excess thionyl chloride was removed in vacuo and the residue dissolved in dichloromethane (100 ml). A solution of 4-(aminomethyl)-1 -tert-butoxycarbonylpiperidine (7.3 g) in dichloromethane (100 ml) was added and the mixture stirred at ambient temperature for 4 hours then poured into water (200 ml). The organic phase was washed with water (100 ml), aqueous oxalic acid solution (2 M; 2*100 ml), hydrochloric acid (1 M; 100 ml), aqueous sodium hydrogen carbonate solution (2 M; 2*150 ml), then water, and dried over magnesium sulphate. The solvent was removed in vacuo and the residue purified by flash chromatography over silica eluding with a 1:1 mixture of ethyl acetate and petroleum ether (b.p. 60-80 C.). Appropriate fractions were combined and the solvent removed in vacuo to give N-[(1-tert-butoxycarbonyl-4-piperidyl)methyl]-2-methoxypyridine-3-carboxamide (2.06 g)
PREPARATION 2 2-Methoxy-3-pyridinecarboxylic Acid A stainless steel stirred autoclave was charged sequentially with methanol (2.8 l.), sodium methoxide (259 g.) (in portions, keeping the temperature less than 35 C.), and 2-chloro-3-pyridinecarboxylic acid (190 g.). The autoclave was sealed and the reaction mixture heated at 110 C. (50 psig) for 48 hours. The reaction mixture was cooled to 25 C. and discharged from the autoclave. Solids were recovered by filtration. Concentration of the filtrate gave a second crop. These process steps were repeated until virtually all of the methanol had been removed. The several crops of solids were combined, taken up in 2.5 liters of water and acidified with conc. hydrochloric acid to pH 2.7 keeping the temperature below 20 C. The precipitated product was granulated for 30 minutes at 15 C. and recovered by filtration (141 g.). Purified title product was obtained by recrystallization from ethyl acetate-hexane (120.5 g., m.p. 148-150 C.).
(+)-10-amino-2-pyrimidin-4-yl-7,8,9,10-tetrahydropyrimido[1,2-a]azepin-4(6H)-one[ No CAS ]
[ 16498-81-0 ]
(+)-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydro-pyrimido[1,2-a]azepin-10-yl)-nicotinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
With diethyl cyanophosphonate; triethylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 16h;
3.7 (+) 2-Methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydro-pyrimido[1,2-a]azepin-10-yl)-nicotinamide To a solution of 3.50g (13.60 mmol) of (+) 10-amino-2-pyrimidin-4-yl-7,8,9,10-tetrahydropyrimido[1,2-a]azepin-4(6H)-one dissolved in 113 mL of dimethylformamide were added at 0C 2.083g (13.60 mmol) of <strong>[16498-81-0]2-methoxy nicotinic acid</strong>, 2.86g (13.60 mmol) of diethylcyanophosphonate and 1.9ml (13.60 mmol) of triethylamine. The resulting mixture was stirred at room temperature for 16h. Water and ethyl acetate were added and the mixture stirred for 8 h. The precipitate was filtered and refluxed with isopropanol. The residue was triturated with diisopropylether to give 3.745g (70%) of pure product obtained in the form of free base. Mp: 214-216C. [alpha]D20 = +5.04 (c=0.963, DMSO). RMN 1H (DMSO-d6; 200MHz) delta (ppm): 9.40 (d, 1H); 9.30 (s, 1H); 9.10 (d, 1H); 8.40-8.20 (m, 3H); 7.30-7.15 (m, 2H); 5.40 (dd, 1H); 5.00 (dd, 1H); 4.10 (s, 3H); 3.70 (dd, 1H); 2.25-2.10 (m, 1H); 2.09-1.80 (m, 3H); 1.80-1.60 (m, 1H); 1.40-1.20 (m, 1H).
With diethyl cyanophosphonate; triethylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 1h;
1.6 2-Methoxy-N-(1-methyl-6-oxo-1,6-dihydro-[4,4']bipyrimidinyl-2-ylmethyl)-nicotinamide To a solution of 0.08g (0.37 mmol) of 2-aminomethyl-1-methyl-1H-[4,4']bipyrimidinyl-6-one in 7.37mL of dimethylformamid was added 0.056g (0.37 mmol) of <strong>[16498-81-0]2-methoxy-nicotinic acid</strong> and 70muL (0.44 mmol) of diethyl phosphorocyanidate (DEPC). The resulting mixture was cooled at 0C and 60muL (0.41 mmol) of triethylamine was added. The reaction mixture was stirred at room temperature for 1 h. Water was added and the mixture extracted with dichloromethane. The extracts were dried and evaporated. The residue was triturated with diethyl ether and filtered to afford 0.088g (68%) of the desired compound as a white powder. Mp: 269-271 C. RMN 1H (DMSO-d6; 200 MHz) delta (ppm): 9.35 (s, 1 H); 9.10 (m, 2H); 8.50 - 8.20 (m, 3H); 7.35 (s, 1 H); 7.20 (m, 1 H); 4.80 (d, 2H); 4.10 (s,3H); 3.60 (s,3H).
With HATU; In N,N-dimethyl-formamide; at 20℃; for 72h;
12B. N-[4-chloro-3-(l,5-dimethylimidazol-2-yl)phenyl]-2-methoxy-pyridine-3-carboxamide; In a 10 mL vial was dissolved 4-chloro-3-(l,5-dimethyl-lH-imidazol-2-yl)aniline (0.06 g, 0.27 mmol), <strong>[16498-81-0]2-methoxynicotinic acid</strong> (0.27 mmol), and HATU (0.103 g, 0.27 mmol) in DMF (1.0 mL) to give a brown solution. HATU (0.103 g, 0.27 mmol) was added. The reaction was stirred at RT for 72 h and then concentrated in vacuo. The residue purified by Gilson HPLC (MeCN /10 mM NH4OAc in water). Collected fractions were concentrated to give the product (0.033 g, 34% yield). 1H NMR (DMSO-d6) delta 2.23 (s, 3 H), 3.35 (s, 3 H), 3.97 (s, 3 H), 6.77 (s, 1 H), 7.15 (dd, <n="48"/>1 H), 7.58 (d, 1 H), 7.87 (m, 2 H), 8.04 (dd, 1 H), 8.34 (dd, 1 H), 10.43 (s, 1 H). MS (M+H+) = 357.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 20h;
Example 47; Preparation ofN-(2-aminophenyl)-6-(2-(2-methoxynicotinamido)ethylamino)nicotinamide; <n="36"/> 2-Methoxynicotinic acid (153 mg, 1 mmol) and 8 ml of DMF were stirred at room temperature while 1 -ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (384 mg, 2 mmol), hydroxybenzotriazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and N-(2-aminophenyl)-6-(2-aminoethylamino)nicotinamide (284 mg, 1.05 mmol) were added. The mixture was stirred for 20 hours at room temperature. The mixture was diluted with 400 ml of brine and extracted with 200 ml of ethyl acetate. The ethyl acetate was removed under vacuum to give the title compound (207 mg, 51 %) as a brown solid. LC-MS (m/z) 407 (M+1 ).
N-[6-(1H-indol-4-yl)-1H-indazol-4-yl]-2-(methyloxy)-3-pyridinecarboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
2-(Methyloxy)-3-pyridinecarboxylic acid (33mg, 0.22mmol) was treated with HATU (84mg, 0.22mmol) in DMF (0.25ml) and DIPEA (0.069ml, 0.40mmol). The reaction mixture was shaken for 5mins prior to treatment with 6-(1H-indol-4-yl)-1 H-indazol-4-amine (25mg, 0.1 mmol) in DMF (0.25ml) and then left to stand at room temperature for 18h. Solvent was removed in vacuo and the product re-dissolved in chloroform (0.3ml) prior to application on to a pre-conditioned (methanol then chloroform) aminopropyl SPE cartridge (0.5g). Product was eluted after 2h with ethyl acetate / methanol (1 :1 , 3ml), and <n="124"/>concentrated under a stream of nitrogen using blow down apparatus. Purification by MDAP(Method D) afforded the title compound (2mg). LCMS (Method B) R1 = 1.06 min; MH+ = 384
With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 1h;
Example 15 (2S)-2-Methyl-1-[2-(methyloxy)-3-pyridinyl]carbonyl}-4-[4-(trifluoromethyl)phenyl]sulfonyl}piperazine To a solution of (3S)-3-methyl-1-[4-(trifluoromethyl)phenyl]sulfonyl}piperazine (Description 2) (100 mg, 0.324 mmol) in DMF (5 ml) was added HOBT.H2O (49.7 mg, 0.324 mmol), HBTU (123 mg, 0.324 mmol), <strong>[16498-81-0]2-(methyloxy)-3-pyridinecarboxylic acid</strong> (49.7 mg, 0.324 mmol) and DIPEA (0.170 ml, 0.973 mmol) and the reaction mixture was stirred for 1 h at room temperature. The reaction mixture was reduced in vacuo. The residue was dissolved in DCM (50 ml), transferred to a separating funnel and the solution was washed with NaHCO3 (5 ml), twice. The organic layer was dried with magnesium sulphate which was removed by filtration and the filtrate evaporated to dryness in vacuo. The residual oil was dissolved in 1:1 MeCN/DMSO (1.8 ml) and purified by MDAP in two batches. The fractions containing the desired product were combined and evaporated to dryness in vacuo to yield the the title compound (95 mg). m/z (API-ES) 443 [M+H]+ 1H NMR (400 MHz, CHLOROFORM-d) Rotameric mixture delta ppm 1.23-1.55 (m, 3H), 2.06-2.79 (m, 2H), 3.05-4.21 (m, 7H), 4.53+5.14 (m, 1H), 6.93 (br. s., 1H), 7.36-7.63 (m, 1H), 7.69-7.95 (m, 4H), 8.20 (d, J=4.8 Hz, 1H).
2-methoxynicotinamide 87 is prepared in a manner similar to the procedures in Bioorg. Med. Chem. Lett. 2007, 17, 2031 and /. Org. Chem. 1975, 40, 3554. To <strong>[16498-81-0]2-methoxynicotinic acid</strong> (86; 49 mmol) suspended dichloromethane (60 mL) and DMF (3 drops) is added oxalyl chloride (16.6 mL, 186 mmol) at room temperature. The mixture is stirred at room temperature for 1 h, then concentrated and redissolved in petroleum ether (60 mL). This mixture is then added at -350C to 250 mL of anhydrous acetonitrile that has been saturated with ammonia at -30 0C. After addition, the reaction is warmed to room temperature and allowed to stir 10 min. The mixture is concentrated and the residue taken up in hot ethyl acetate. This is filtered through diatomaceous earth, concentrated and followed by recrystallization from ethyl acetate to produce 2-methoxynicotinamide 87.
2-(4-((4-carbamimidoylphenylamino)hydrazinocarbonylmethyl)-2-ethoxyphenoxy)-N,N-dimethylacetamide dihydrochloride[ No CAS ]
[ 16498-81-0 ]
[ 76-05-1 ]
2-(4-(1-(4-carbamimidoylphenylamino)-2-(N'-(2-methoxypyridine-3-carbonyl)hydrazino)-2-oxoethyl)-2-ethoxyphenoxy)-N,N-dimethylacetamide trifluoroacetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
17%
(58c) 2-(4-(1-(4-Carbamimidoylphenylamino)-2-(N'-(2-methoxypyridine-3-carbonyl)hydrazino)-2-oxoethyl)-2-ethoxyphenoxy)-N,N-dimethylacetamide trifluoroacetate [Show Image] 2-Methoxynicotinic acid (6 mg, 0.039 mmol) was dissolved in N,N-dimethylformamide (0.28 ml) and cooled to 0C. To the reaction mixture were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (4 mg, 0.0209 mmol) and 1-hydroxybenzotriazole monohydrate (5 mg, 0.0326 mmol), followed by stirring for 1 hour and addition of a solution of 2-(4-((4-carbamimidoylphenylamino)hydrazinocarbonylmethyl)-2-ethoxyphenoxy)-N,N-dimethylacetamide dihydrochloride (10 mg, 0.015 mmol) prepared in Example 58b in N,N-dimethylformamide (0.1 ml). The reaction mixture was stirred overnight at room temperature and then directly purified by reversed-phase high performance liquid chromatography to give the title compound as a colorless solid (2.30 mg, yield: 17%). 1H-NMR (400 MHz, CD3OD) delta: 1.41 (t, J = 7.2 Hz, 3H), 2.96 (s, 3H), 3.11(s, 3H), 4.05 (s, 3H), 4.10-4.15 (m, 2H), 4.80 (s, 2H), 5.18 (s, 1H), 6.86 (d, J = 9.2 Hz, 2H), 6.93 (d, J = 8.4 Hz, 1H), 7.08-7.14 (m, 2H), 7.23 (d, J = 2.0 Hz, 1H), 7.62 (d, J = 9.2 Hz, 2H), 8.27-8.34 (m, 2H); Mass spectrum (ESI) m/z: 564 (M+H)+
10-(2-amino-ethyl)-7,8-dimethyl-10<i>H</i>-benzo[<i>g</i>]pteridine-2,4-dione[ No CAS ]
[ 16498-81-0 ]
[ 1262314-61-3 ]
Yield
Reaction Conditions
Operation in experiment
24%
Step 2 Preparation of N-[2-(7,8-Dimethyl-2,4-dioxo-3,4-dihvdro-2H-benzo[glpteridin- 10-vD-ethyll-2-methoxy-nicotinamide; [0116] 2-Methoxy-nicotinic acid (20 mg, 0.12 mmol) and Hunig's base (0.024 mL,0.14 mmol) are dissolved in DMF (1 mL) followed by addition of HATU (53 mg, 0.14 mmol) at room temperature and is stirred for one hour. 10-(2-Amino-ethyl)-7,8-dimethyl- 10H-benzo[g]pteridine-2,4-dione (39 mg, 0.14 mmol) (see Intermediate 1 for preparation) is dissolved in DMF (ImL) and added to the reaction mixture. After 3 h the reaction mixture is diluted with water (2 mL) and purification is performed using preparatory HPLC (Method 3). 3-[2-(7,8-Dimethyl-2,4-dioxo-3,4-dihydro-2H-benzo[g]pteridin-10- yl)-ethylamino] -benzoic acid (12 mg) is isolated following lyophilization of the appropriate fractions (Yield: 24%). 1H NMR (400 MHz, DMSO-d6) delta 11.37 (s, 1H), 8.48 (m, 1H), 8.28 (m, 1H)5 8.02 (m, 1H), 7.89 (m, 2H), 4.81 (m, 2H), 3.78 (m, 5H), 2.33 (s, 3H), 2.30 (s, 3H). LC-MS m/z 421.2 [M+H]+. Retention time = 5.31 min.
Example 11 : N- [2-(7.8-Dimethyl-2,4-dioxo-3.4-dihydro-2H-benzo [gl pteridin- 10-ylVethyll -2- methoxy-nicotinamide; Step 1 Preparation of 2-Methoxy-nicotinic acid; [0115] 2-Methoxy-nicotinic acid methyl ester (500 mg, 3.0 mmol) is dissolved in methanol (5 mL) and water (1 mL). Sodium hydroxide (600 mg, 15 mmol) is added and the reaction mixture is refluxed for 2 h. The solution is neutralized with IN HCl to pH 7 and concentrated under vacuum. The solid is washed with 30 mL of DCM/MeOH (1/1). The filtrate is concentrated under vacuum to yield 2-methoxy-nicotinic acid (407 mg) as a white solid (Yield: 88%). 1H NMR (400 MHz, DMSO-d6) delta 8.05 (m, 1H), 7.87 (m, 1H), 6.91 (m, 1H), 3.83 (s, 3H).
General procedure: Oxalyl chloride (1.85 mL, 21.88 mmol) was added to a suspensionof 6-methylpicolinic acid (2.50 g, 18.23 mmol) in DCM (75 mL,anhydrous) and DMF (1.3 mmol) at 20 C. The mixture was stirred at20 C for 1 h to give a colorless solution which was cooled to 0 C. N,ODimethylhydroxylaminehydrochloride (1.95 g, 20.1 mmol) andpyridine (3.25 mL, 40.11 mmol) were added sequentially and themixture was stirred at 20 C for 18 h, then partitioned between EtOAcand sat. aq. NaHCO3. Column chromatography with hexanes:EtOAc 1:1gave N-methoxy-N,6-dimethylpicolinamide as an oil (2.68 g, 82%).
61%
A solution of 6-methoxypicolinic acid (2.018g,13.2 mmol) in DCM (70 mL) was treated with DMF (0.1 mL, 1.3 mmol) and oxalylchloride (1.34 mL, 15.8 mmol), after 1 h the solution was cooled to 0 C and N,O-dimethylhydroxylamineHCl (1.42 g, 14.6 mmol) and pyridine (2.34 mL, 28.9 mmol) were added. Themixture was stirred at room temperature for 18 h, sat. aq. NaHCO3 (200mL) was added and the mixture was partitioned between DCM and water. Theorganic fractions were dried and evaporated, column chromatography (97.5:2.5DCM:MeOH) gave N,6-dimethoxy-N-methylpicolinamide (2.372 g, 92%) asan oil. 1H NMR (CD3SOCD3) delta 7.86 (dd, J = 8.3, 7.3 Hz, 1H), 7.66 (dd, J = 7.3, 0.7 Hz, 1H), 7.05 (dd, J = 8.3, 0.7 Hz, 1H), 3.90 (s, 3H), 3.28(bs, 3H). Found: [M+H] = 197.2.
51%
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; for 18h;Cooling;
To a stirred ice-cooled mixture of 2- methoxy-nicotinic acid (1.43 g, 9.31 mmol) and O.W-dimethyl-hydroxylaminehydrochloride (1.0 g, 10.3 mmol) in DCM (50 mL) was added DIPEA (6.4 mL, 37.3 mmol). EDCI (2.14 g, 11.1 mmol) was added portionwise over 5 minutes. After 18 hours, the reaction mixture was washed successively with saturated sodium bicarbonate and water. The organic layer was dried (Na2S04), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si02, gradient 50 to 75% EtOAc in cyclohexane) to afford the title compound (0.92 g, 51%) as a colourless oil. LCMS (Method A): RT = 2.48 min, [M+H]+ = 197.
(1) 2-Methoxynicotinic acid (3.0 g) was dissolved in chloroform (100 ml), N,O-dimethylhydroxylamine hydrochloride (3.82 g), N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (7.51 g), and triethylamine (27.3 ml) were added to the solution under ice cooling, and the resulting mixture was stirred at the same temperature for 6 hours. 4-Dimethylaminopyridine (0.1 g) was added to the reaction mixture at room temperature, and the resulting mixture was stirred overnight. Distilled water and ethyl acetate were added to the reaction mixture, and the layers were separated. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform to chloroform:methanol = 50:1) to obtain an amide compound (1.0 g).
With N-ethyl-N,N-diisopropylamine;2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; In tetrahydrofuran; ethyl acetate; at 60℃; for 18h;
Example 78 2-Methoxy-N-(2-phenylimidazo[1,2-a]pyrimidin-7-yl)nicotinamide A mixture of 2-phenylimidazo[1,2-a]pyrimidin-7-amine (200 mg, 951 mumol, Eq: 1.00), <strong>[16498-81-0]2-methoxynicotinic acid</strong> (146 mg, 951 mumol, Eq: 1.00), diisopropylethylamine (369 mg, 498 mul, 2.85 mmol, Eq: 3) and propylphosphonic anhydride in ethyl acetate 50% (1.21 g, 1.12 ml, 1.9 mmol, Eq: 2) in tetrahydrofuran (10 ml) is stirred for 18 hours at 60 C. The mixture is diluted with ethyl acetate and washed 2 times with water and once with brine, the organic layer was separated, dried over magnesium sulfate, filtrated and evaporated. The crude material was applied on silicagel and purified by flash chromatography over a 20 g silicagel column using ethyl acetate/methanol 0-10% as eluent affording 2-methoxy-N-(2-phenylimidazo[1,2-a]pyrimidin-7-yl)nicotinamide (36 mg, 11%) as a light yellow solid. MS: m/e=346.1 (M+H+), mp: 225-226 C.
A mixture of 2-phenylimidazo[l,2-a]pyrimidin-7-amine (200 mg, 951 muiotaetaomicron, Eq: 1.00), 2- methoxynicotinic acid (146 mg, 951 muetaiotaomicron, Eq: 1.00), diisopropylethylamine (369 mg, 498 mu, 2.85 mmol, Eq: 3) and propylphosphonic anhydride in ethyl acetate 50% (1.21 g, 1.12 ml, 1.9 mmol, Eq: 2) in tetrahydrofuran (10 ml) is stirred for 18 hours at 60 C. The mixture is diluted with ethyl acetate and washed 2 times with water and once with brine, the organic layer was separated, dried over magnesium sulfate, filtrated and evaporated. The crude material was ap lied on silicagel and purified by flash chromatography over a 20 g silicagel column using ethyl acetate / methanol 0-10 % as eluent affording 2-methoxy-N-(2-phenylimidazo[l,2- a]pyrimidin-7-yl)nicotinamide ( 36 mg, 11 %) as a light yellow solid. MS: m/e = 346.1 (M+H+), mp: 225-226 C
PREPARATION 47 2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-amine [Show Image]a) methyl 2-methoxynicotinate Concentrated aqueous sulphuric acid (0.1 mL) was added to a solution of 2-methoxynicotinic acid (2.00 g, 13.1 mmol) in methanol (20 mL) and the mixture was stirred and heated to reflux. After 6 hours, a saturated aqueous solution of sodium hydrogen carbonate was added and the mixture was extracted with ethyl acetate. The organic layer was dried (MgSO4 and concentrated to give the title compound (1.85 g, 85%) as a colourless oil. LRMS (m/z): 168 (M+1)+.1H NMR (300 MHz, DMSO-d6) delta ppm 3.81 (s, 3H), 3.92 (s, 3H), 7.11 (dd, 1H), 8.13 (dd, 1H), 8.38(dd, 1H).
85%
PREPARATION 47 2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-amine a) methyl 2-methoxynicotinate Concentrated aqueous sulphuric acid (0.1 mL) was added to a solution of 2-methoxynicotinic acid (2.00 g, 13.1 mmol) in methanol (20 mL) and the mixture was stirred and heated to reflux. After 6 hours, a saturated aqueous solution of sodium hydrogen carbonate was added and the mixture was extracted with ethyl acetate. The organic layer was dried (MgSO4 and concentrated to give the title compound (1.85 g, 85%) as a colourless oil. LRMS (m/z): 168 (M+1)+.1H NMR (300 MHz, DMSO-d6) delta ppm 3.81 (s, 3H), 3.92 (s, 3H), 7.11 (dd, 1H), 8.13 (dd, 1H), 8.38(dd, 1H).
With N-Bromosuccinimide; In water; at 20 - 25℃; for 16h;
Add 100 ml of water and 20 g of 2-methoxynicotinic acid to a 250 ml three-necked flask, then add 32 g of NBS.After 16 hours of reaction at a temperature of 20-25 degrees, a sample was taken for HPLC detection, and the reaction was terminated when HPLC detected that the starting material was less than 2%.After the end of the reaction, the mixture was filtered, and the solid was dried to give the product 2-methoxy-5-bromonicotinic acid, weight: 26.36 g, yield 87%.
82%
With bromine; In water; at 20℃;
To a solution of 2-methoxynicotinic acid (20 g, 130.60 mmol) in H20 (1500 mL), Br2 (20 mL, 375.45 mmol) was added at room temperature. The mixture was stirred at room temperature overnight. The reaction mixture was filtered, washed with water and dried to provide 5-bromo-2-methoxynicotinic acid (25 g, yield: 82%). 1H- MR (DMSO, 400 MHz) delta 13.33 (br s, 1H), 8.47 (d, J= 2.4 Hz, 1H), 8.21 (d, J= 2.4 Hz, 1H), 3.90 (s, 3H). MS (M+H)+: 232 / 234.
82%
With bromine; In water; at 20℃;
Step 1-Synthesis of 5-bromo-2-methoxynicotinic acid To a solution of 2-methoxynicotinic acid (20 g, 130.60 mmol) in H2O (1500 mL), Br2 (20 mL, 375.45 mmol) was added at room temperature. The mixture was stirred at room temperature overnight. The reaction mixture was filtered, washed with water and dried to provide 5-bromo-2-methoxynicotinic acid (25 g, yield: 82%). 1H-NMR (DMSO, 400 MHz) delta 13.33 (br s, 1H), 8.47 (d, J=2.4 Hz, 1H), 8.21 (d, J=2.4 Hz, 1H), 3.90 (s, 3H). MS (M+H)+: 232/234.
S-pyridin-2-yl 2-methoxypyridine-3-carbothioate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74%
With triphenylphosphine In tetrahydrofuran at 20℃; for 6h; Inert atmosphere;
15.1 Step 15.1: S-pyridin-2-yl 2-methoxypyridine-3-carbothioate
To a solution of 2-methoxynicotinic acid (4.59 g, 30 mmol) and 1,2-di(pyridin-2-yl)disulfane (6.74 g, 30 mmol) in THF (60 mL) was added under Ar triphenylphosphine and the reaction mixture was stirred for 6 h at RT. The reaction mixture was concentrated and the residual oil was purified by silica gel column chromatography (hexane/EtOAc 80:20 to 50:50) to afford the title product (6.6 g, 74% yield) as a white solid. Rf = 0.36 (hexane/EtOAc 1:1); tR: 0.803 min (UPLC 1); tR: 0.87 min (LC-MS 1); ESI-MS: 247 [M+H]+ (LC-MS 1); ); 1H NMR (400 MHz, CDCl3) δ ppm 4.05 (s, 3 H) 6.95 (dd, J=7.58, 4.89 Hz, 1 H) 7.26 (ddd, J=7.3, 4.9, 1.1 Hz, 1 H) 7.66 (d, J=8.6 Hz, 1 H) 7.7 (td, J=7.8, 1.8 Hz, 1 H) 8.12 (dd, J=7.6, 2.0 Hz, 1 H) 8.29 (dd, J=4.9, 1.8 Hz, 1 H) 8.58 - 8.64 (m, 1 H).
72%
With triphenylphosphine In tetrahydrofuran at 25℃; for 12h; Inert atmosphere;
10.1 Step 10.1: S-rvridin-2-vl 2-methoxvrvridine-3-carbothioate
To a solution of 2-methoxynicotinic acid (0.766 g, 5 mmcl) and 1,2-di(pyridin-2-yl)disulfane (1.124 gin THF (20 mL) was added under argon PPh3 (1.337 g, 5 mmcl) and the reaction mixture was stirred at 25 00 for 12 h. The reaction mixture was concentrated and the title product was obtained after silica gel column chromatography (hexane/EtOAc 80:20 to 50:50)(0.902 g, 72% yield) as a white solid. tR. 0.795 mm (UPLC 1); tR: 0.87 mm (LC-MS 1); ESI-MS:247 [M÷H] (LC-MS 1); R= 0.36 (hexane/EtOAc 1:1); 1H NMR (400 MHz, CDCI3) O ppm 8.61(ddd, J=4.9, 1.9, 0.9 Hz, I H), 8.29 (dd, J=4.9, 2.0 Hz, I H), 8.12 (dd, J=7.6, 2.0 Hz, I H), 7.76-7.62 (m, 2 H), 7.26 (ddd, J=7.4, 4.8, 1.3 Hz, I H), 6.95 (dd, J=7.6, 4.9 Hz, I H), 4.05 (s, 3 H).
With N-iodo-succinimide; acetic acid at 35℃; for 16h;
12 Example 12 Preparation of 2-methoxy-5-iodonicotinic acid
Add 100 acetic acid and 20 g of 2-methoxynicotinic acid to a 250 ml three-necked flask, then add 35.26 g of NIS at 35 °C.After 16 hours of reaction, a sample was taken for HPLC detection, and the reaction was terminated when HPLC detected that the starting material was less than 2%.After the reaction, the mixture was filtered, and the solid was dried to obtain 2-methoxy-5-iodonicotinic acid, the weight was 32.8 g, the yield was 90%, and the purity was 98.5%.
N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-2-methoxynicotinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
27%
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine In 1-methyl-pyrrolidin-2-one; ethyl acetate at 60℃; for 16h;
1 Example 1 : /V-(6-(4-Isopropyl-4//-l,2,4-triazol-3-yl)pyridin-2-yl)-2- methoxynicotinamide
A 2-dram vial was charged with 2-methoxynicotinic acid (37 mg, 0.18 mmol). A stock solution of 6-(4-isopropyl-4//-l ,2,4-triazol-3-yl)pyridin-2-aminc (17 mg, 0.08 mmol) in N- methyl-2-pyrrolidone and EtOAc (1:1 Vol%, 0.8 mL) and triethylamine (0.15 mL, 1.09 mmol) was prepared and added to the vial, followed by a T3P (propylphosphonic anhydride) solution (> 50 wt% in EtOAc, 0.32 mL, 0.54 mmol). The reaction solution was heated at 60 °C for 16 h and after this time the mixture was cooled to rt and diluted with water and EtOAc (1:1 Vol%, 4 mL). The separated aqueous layer was extracted with EtOAc (x2) and the combined organic extracts were evaporated to yield a solid. This crude material was subjected to reverse phase HPLC (using a Waters SunFire Prep C18 OBD, 5 pm, 19x100 mm column and using (0187) water/CH3CN (containing 0.1% TFA) from 95/5 to 30/70 as the mobile phase at a flow rate of 30 mL/min) to give the title compound (17.2 mg, 27%) as a slightly yellow solid. MS (ESI): 339.1 [M + H]+.
6-(trifluoromethyl)quinolin-4-yl 2-methoxypyridine-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
26%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 40℃;
General procedure for the synthesis of compounds 2a-2c
General procedure: Pyridine-3-carboxylic acids (1a-1c) (1.1 mmol) and 4-hydroxy-6-(trifluoromethyl)quinoline (A) (1.0 mmol) were dissolved in 3 mL of CH2Cl2, and the mixture was cooled to 0 °C. (1-(3-dimetylamiopropyl)-3-ethylcarbodiimide hydrochloride) (EDCI) (1.2 mmol) and dimethylaminopyridine (DMAP) (1.2 mmol) were added to the mixture separately. Then, the mixture was stirred for 15 h-20 h at 40 °C. When the reaction was completed, the mixture was washed with brine (2 × 2 mL) and water (2 × 2 mL), dried with Na2SO4, and filtered. The solvent was removed in vacuo, and the crude product was purified through column chromatography (eluent, petroleum ether/ethyl acetate, v/v=10:1-1:1) to obtain compounds 2a-2c.
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