* 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.
EXAMPLE 1 SPC3 100 g (0.51 mol) of 2,6-dichloro-3-chloromethylpyridine, 500 g of 97percent strength sulphuric acid, 5 g of Hg(NO3)2 and 2.5 g of CuSO4. 5H2 O are warmed to 120°C, whilst stirring vigorously, in a 2.5 liter sulphonation flask equipped with a stirrer, thermometer and gas outlet tube. 190 ml (280 g) of fuming nitric acid are then added dropwise over the course of 3.5 hours in such a way that the internal temperature does not exceed 150°C. After completion of the addition of HNO3, the reaction mixture is cooled to 40°C and poured onto 600 g of ice, whilst stirring. After half an hour, the acid which has precipitated is filtered off, well pressed out and suspended in 500 ml of water. The acid is then dissolved at pH 10 by adding Na2 CO3. The resulting, somewhat turbid solution is filtered and strongly acidified with concentrated hydrochloric acid, whereupon 2,6-dichloronicotinic acid again precipitates. It is filtered off and dried. 72 g of pure 2,6-dichloronicotinic acid (74percent of theory) of melting point 146°-148°C are obtained. Analysis for C6 H3 O2 Cl2 N (molecular weight 192): Calculated: C, 37.53 H, 1.57 Cl, 36.93 N, 7.30percent. Found: C, 37.21 H, 1.52 Cl, 36.66 N, 7.24percent.
Reference：
[1] Patent: US3956340, 1976, A,
2
[ 2402-78-0 ]
[ 38496-18-3 ]
Reference：
[1] Patent: US2004/142930, 2004, A1,
3
[ 2402-78-0 ]
[ 124-38-9 ]
[ 38496-18-3 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2002, vol. 10, # 6, p. 1793 - 1804
4
[ 2402-78-0 ]
[ 124-38-9 ]
[ 38496-18-3 ]
[ 5398-44-7 ]
Reference：
[1] Journal of Labelled Compounds and Radiopharmaceuticals, 2001, vol. 44, # 6, p. 451 - 457
5
[ 67-56-1 ]
[ 55366-30-8 ]
[ 38496-18-3 ]
[ 65515-33-5 ]
[ 503000-87-1 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1988, p. 227 - 234
Reference：
[1] Journal of Labelled Compounds and Radiopharmaceuticals, 2001, vol. 44, # 6, p. 451 - 457
9
[ 67-56-1 ]
[ 38496-18-3 ]
[ 65515-28-8 ]
Yield
Reaction Conditions
Operation in experiment
100%
Heating / reflux
To a solution of 2,6-dichloronicotinic acid (5.0 g, 26 mmol) in MeOH (100 mL) was added SOCl2 (0.1 mL). The reaction mixture was heated to reflux overnight. The solvent was removed by evaporation. The residue was dissolved in ethyl acetate and washed with saturated NaHCO3 and brine; dried over anhydrous Na2SO4 and concentrated to afford 2,6-dichloronicotinic acid methyl ester (5.37 g, 100percent); 1HNMR:(300 MHz, CDCl3) δ 8.13 (d, J=8.1 Hz, 1H), 7.33 (d. J=8.1 Hz, 1H), 3.94 (s, 3H).
100%
Heating / reflux
To a solution of 2,6-dichloronicotinic acid (5.0 g, 26 mmol) in MeOH (100 mL)was added SOCl2 (0.1mL). The reaction mixture was heated to reflux overnight. The solvent was removed by evaporation. The residue was dissolved in ethyl acetate and washed with saturated NaHCO3 and brine; dried over anhydrous Na2SO4 and concentrated to afford 2,6-dichloronicotinic acid methyl ester (5.37 g, 100percent); 1HNMR:(300 MHz, CDCI3) ;5 8.13 (d, J= 8.1 Hz, 1H), 7.33 (d. J= 8.1 Hz, 1H), 3.94 (s, 3H).
100%
for 4 h; Heating / reflux
To a solution of 2,6-dichloronicotinic acid (5Og, 0.26 mol) in methanol (250 ml_) was added thionyl chloride (22.7 mL, 0.312 mol) slowly. The mixture was refluxed for 4 hours and concentrated to give methyl 2,6-dichloronicotinate as a white solid in quantitative yield.
97%
at 0 - 20℃; for 48 h;
A solution of 2,5-dichloronicotinic acid (20.2 g, 0.105 mol) in methanol (500 mL) was cooled to 0 0C and neat thionyl chloride (38 mL, 63 g, 0.525 mol) was added over -30 min. The reaction mixture was stirred at 00C for 1 hour. The cooling bath was removed, the reaction temperature was allowed to warm to room temperature, and the reaction was allowed to stir for an additional 2 days at room temperature. The solvent was removed under reduced pressure to give an off-white residue. The residue was dissolved in Et2O (-500 mL) and the resulting solution was washed successively with saturated aqueous NaHCO3 solution (-300 mL), water (-300 mL), and brine (-300 mL). The organic layer was separated, dried over anhydrous MgSO4, and filtered. Removal of the solvent under reduced pressure yielded methyl 2,5-dichloronicotinate (21.0 g, 97percent) as a white solid
97%
at 0 - 20℃; for 49.5 h;
Preparative Example 45. Lithium 2-amino-6-chloronicotinate (58).; A solution of 2,5-dichloronicotinic acid (20.2 g, 0.105 mol, Aldrich) in methanol (500 mL) was cooled to 0°C and neat thionyl chloride (38 mL, 63 g, EPO <DP n="135"/>0.525 mol) was added over -30 min. The reaction mixture was stirred at 00C for 1 hour. The cooling bath was removed, the reaction temperature was allowed to warm to room temperature, and the reaction was allowed to stir for an additional 2 days at room temperature. The solvent was removed under reduced pressure to give an off-white residue. The residue was dissolved in ether (-500 mL) and the resulting solution was washed successively with saturated aqueous sodium bicarbonate solution (-300 mL), water (-300 mL), and brine (-300 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, and filtered. Removal of the solvent under reduced pressure yielded methyl 2,5-dichloronicotinate (21.0 g, 97percent yield) as a white solid.
97%
at 0 - 25℃; for 49.5 h;
A solution of 2,6-dichloronicotinic acid (20.2 g, 0.105 mol) in MeOH (500 mL) was cooled to 0 ° C. and neat thionyl chloride (38 mL, 63 g, 0.525 mol) was added over ~0.5 hours. The reaction mixture was stirred at 0° C. for 1 hour. The cooling bath was removed, the reaction temperature was allowed to warm to 25° C., and the reaction was allowed to stir for an additional 2 days at 25° C. The solvent was removed under reduced pressure to give an off-white residue. The residue was dissolved in Et2O (~500 mL) and the resulting solution was washed successively with saturated aqueous NaHCO3 solution (~300 mL), water (~300 mL), and brine solution (~300 mL). The organic layer was separated, dried over anhydrous MgSO4, and filtered. Removal of the solvent under reduced pressure yielded methyl 2,6-dichloronicotinate (21.0 g, 97percent) as a white solid.
97%
With diazomethyl-trimethyl-silane In 1,4-dioxane; diethyl ether
Dichlorocarboxylic acid 1.1 (2.0 g, 10 mmol) was diluted with 10 mL each of 1,4-dioxane and methanol, then treated with a 2.0M TMSCHN2 in diethyl ether solution (7.5 mL, 15 mmol) resulting in vigorous gas evolution and a light green solution. After stirring overnight the reaction was checked by UPLC which showed complete conversion to the desired product. The reaction was concentrated to near dryness, then diluted with water and stirred vigorously. The resulting granular precipitate was then filtered and dried under vacuum affording the desired methyl ester as a light beige solid (2.01 g, 97percent). MS found for C7H5Cl2NO2 as (M+H)+ 206.0, 208.0. UV λ=276.
97%
With diazomethyl-trimethyl-silane In 1,4-dioxane; diethyl ether
0483] Dichlorocarboxylic acid X.l (2.0 g, 10 mmol) was diluted with 10 mL each of 1,4- dioxane and methanol, then treated with a 2.0M TMSCHN2 in diethyl ether solution (7.5 mL, 15 mmol) resulting in vigorous gas evolution and a light green solution. After stirring overnight the reaction was checked by UPLC which showed complete conversion to the desired product. The reaction was concentrated to near dryness, then diluted with water and stirred vigorously. The resulting granular precipitate was then filtered and dried under vacuum affording the desired methyl ester as a light beige solid (2.01 g, 97percent). MS found for C7H5C12N02 a s(M+H)+ 206.0, 208.0. UV λ = 276
93%
Stage #1: With oxalyl dichloride In dichloromethane for 2 h; Stage #2: at 0 - 20℃;
The starting material, 5-[5-(3,5-bistrifluoromethylphenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-imidazo[1,2-a]pyridine-8-carboxylic acid, was prepared as follows: a. Oxalyl chloride (11.1 mL) was added to a solution of 2,6-dichloronicotinic acid (8 g) in a mixture of DCM (300 mL) and DMF (0.2 mL). After stirring 2 hours, the mixture was concentrated under reduced pressure to give a residue that was treated with MeOH (300 mL) at 0° C. The mixture was stirred at to room temperature and then was concentrated under reduced pressure to give a residue that was diluted with water and EA, neutralized with a saturated aqueous solution of sodium bicarbonate solution and extracted three times with EA. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 2,6-dichloronicotinic acid methyl ester (8 g, 93percent). 1H NMR (400 MHz, CHLOROFORM-d): 3.96 (s, 3H), 7.36 (d, J=8.2 Hz, 1H), 8.16 (d, J=8.0 Hz, 1H).
91%
With diazomethyl-trimethyl-silane In tetrahydrofuran; methanol; diethyl ether at 20℃; for 1 h;
A 2.0 M ether solution of (trimethylsilyl)diazomethane (30 mL, 60.0 mmol) was added dropwise to a solution of 2,6-dichloronicotinic acid (8.00 g, 37.5 mmol) in THF (100 mL) and MeOH (25 mL) in a room temperature water bath. After 1 h, HOAc (4 mL) was added. The mixture was stirred until bubbling stopped and concentrated. The resulting solid was dissolved in minimum amount of ethyl acetate, diluted with hexanes, and partially concentrated in vacuo. A white crystalline solid <n="90"/>precipitated out and was collected by filtration. This process was repeated three times to give 4.553 g of the desired product. The mother liquor was concentrated and purified by silica gel chromatography, eluting with 0-20percent EtOAc in hexanes, to give additional product (2.48 g). The total amount of the product was 7.033 g (91percent yield). MS (ES+) m/z: 206 (M+H); LC retention time: 2.99 min (analytical HPLC Method A).
90%
at 80℃;
To a solution of 2,6-dichloropyridine-3-carboxylic acid (300 mg, 1.56 mmol) in methanol (2 mL) was added three drops of concentrated sulfuric acid and the reaction was heated to eighty degrees Celsius overnight. The solution was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was washed with water and brine and dried over magnesium sulfate. The material was filtered and concentrated to provide the methyl ester as a beige solid (290 mg, 90percent yield).
87%
Stage #1: for 12 h; Heating / reflux Stage #2: With sodium carbonate In water; ethyl acetate
To a solution of 2,6-dichloronicotinic acid (30 g, 0.16 mol) in 150 mL methanol was added 3 mL of con. H2SO4 and the mixture was refluxed for 12 h. The methanol was evaporated off and the residue was dissolved in ethyl acetate, washed with water, 10percent sodium carbonate solution, brine, dried with sodium sulfate and evaporated to yield the desired product (29.0 g, 87percent) as white solid.
75%
Stage #1: for 20 h; Reflux Stage #2: With sodium hydrogencarbonate In methanol; water at 20℃;
Preparation 10: methyl 2-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)nicotinate; Step 1 : methyl 2,6-dichloronicotjnate; To a solution of 2,6-dichloronicotinic acid (130 g, 0.67 mol) in methanol (907 ml_) was added sulfuric acid (18.76M, 22 g, 0.22 mol) and the mixture was refluxed for 20 h. The reaction was cooled to room temperature and poured slowly into a solution of sodium bicarbonate (42 g, 0.5 mol) in water (1 L). The mixture was concentrated to remove the methanol. The residue was diluted with ethyl acetate (1 L) and extracted with water (500 mL). The organic layer was washed with 5percent aqueous sodium chloride (150 mL). The organic layer was concentrated to an oil. Heptane (150 mL) was added and the mixture was concentrated. To the residue was added heptane (580 mL) and the mixture was heated to 70°C. The solution was cooled to room temperature and stirred for 2 h. The resulting solid was collected by filtration and dried to yield the title compound as a white pale yellow solid (105 g, 75percent). 1 H NMR (400 MHz, DMSO-dβ) δ ppm 2.52 (1 H, d, J=1.8 Hz), 3.89 (3 H, s), 7.72 (1 H, d, J=8.0 Hz).
75%
for 20 h; Reflux
To a solution of acid 9 (130 g, 0.67 mol) in methanol (907 mL) was added sulfuric acid (18.76M, 22 g, 0.22 mol) and the mixture was heated under reflux for 20 h. After cooling to room temperature, the mixture was poured slowly into a solution of sodium bicarbonate (42 g, 0.5 mol) in water (1 L) then concentrated to remove the methanol. The residue was diluted with ethyl acetate (1 L) and washed with water (500 mL). The organic layer was washed with 5percent aqueous sodium chloride (150 mL) and concentrated. Heptane (150 mL) was added and the mixture was concentrated. The residue was taken up in hot heptane (580 mL, 70C) then cooled to room temperature and stirred for 2 h. The resulting solid was collected by filtration and dried to yield 10 as a pale yellow solid (105 g, 75percent). 1H NMR (400 MHz, CDCl3) δ 8.14 (1H, d, J= 8.0 Hz), 7.34 (1H, d, J=8.0 Hz), 3.95 (3H, s).
With potassium carbonate In acetone at 20℃; for 16 h;
[Example 23] Synthesis of 2,6-dichloro-nicotinic acid methyl ester To the mixture of 2,6-dichloro-nicotinic acid (4.7 g, 22 mmol) and acetone (22 ml), potassium carbonate (4.6 g, 33 mmol) and dimethylsulfate (2.4 ml, 24 mmol) were sequentially added at room temperature, and the obtained reaction mixture was stirred at room temperature for 16 hours. Impurities were removed by filtration, and the solvents were evaporated under reduced pressure from the filtrate. Dichloromethane was added to the obtained residue, followed by washing with a saturated sodium bicarbonate aqueous solution. The obtained organic layer was dried using anhydrous sodium sulfate, and the solvents were evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography (heptane: ethyl acetate = 10:1 1 to 1:1), thereby obtaining the entitled compound (4.0 g, 87percent). 1H-NMR Spectrum (CDCl3) δ(ppm): 3.96(3H, s), 7.36(1H, d, J=8.0Hz), 8.16(1H, d, J=8.0Hz)
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1988, p. 227 - 234
19
[ 38496-18-3 ]
[ 64-17-5 ]
[ 58584-86-4 ]
Yield
Reaction Conditions
Operation in experiment
85.2%
for 40 h; Reflux; Inert atmosphere
Esterification of 2,6-dichloronicotinic acid (25.5 g, 0.1328 mmol) in EtOH (200 proof, 200 mL) catalyzed with 96percent H2SO4 (1.7 g) at refluxing temperature for 40 h under N2 gave the desired ethyl 2,6-dichloronicotinate as grey solid (24.89 g, 0.1131 mmol, yield 85.2percent) after a normal work-up. (0723) 1H NMR (300 MHz, DMSO-d6): δ 8.30 (d, J=8.1 Hz, 1H), 7.71 (d, J=8.1 Hz, 1H), 4.33 (q, J=7.2 Hz, 2H) and 1.30 (t, J=7.2 Hz, 3H) ppm.
67%
at 85℃; for 72 h;
A mixture 2,6-dichloronicotinic acid (5.0 g, 26.2 mmol) and concentrated H2SO4 (1 ml.) in EtOH (30 ml.) is heated at 85 0C for 3 days. Upon cooling to room temperature, the reaction mixture is diluted with dichloromethane (200 ml_), washed with saturated NaHCO3 solution (2x100 ml.) and brine (50 ml_). The organic layer is dried, concentrated and the crude residue is purified by flash column with EtOAC/heptanes (2/8) to afford the desired product as a white solid (3.8 g, 67 percent). LC-MS ( (ESI) m/z 220.0 (M+1 ). 1H NMR (400 MHz, CD2CI2) δ ppm 7.38 (s, 1 H), 7.36 (s, 1 H), 4.39 (q, J=7.1 Hz, 2 H), 1.39 (t, J=IA Hz, 3 H).
65%
for 16 h; Reflux
Preparation 30: ethyl 2-ethoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)nicotinate; Step 1 : ethyl 2,6-dichloronjcotjnate; To a solution of 2,6-dichloronicotinic acid (10 g, 52.08 mmol) in ethanol (50 mL) was added concentrated sulfuric acid (1.0 mL) and the mixture was heated to refluxed for 16 h. The reaction was concentrated. The solid residue was diluted with ethyl acetate (50 mL) and washed with water (50 mL), 1M aqueous sodium carbonate (50 mL) and saturated aqueous sodium chloride. The organic layer was dried over magnesium sulfate, filtered, and concentrated to give the title compound (7.38 g, 65percent) as a light orange solid. 1 H NMR (500 MHz, DMSO-Cf6) δ ppm 1.32 (t, J=7.07 Hz, 3 H) 4.35 (q, J=7.24 Hz, 2 H) 7.72 (d, J=8.05 Hz, 1 H) 8.31 (d, J=8.05 Hz, 1 H). Step 2: ethyl 6-chloiO-2-ethoxynicotinate
Reference：
[1] Chemical and Pharmaceutical Bulletin, 2000, vol. 48, # 12, p. 1847 - 1853
[2] Chemical and Pharmaceutical Bulletin, 2000, vol. 48, # 12, p. 1847 - 1853
[3] Tetrahedron Letters, 2011, vol. 52, # 52, p. 7025 - 7029
[4] Patent: WO2016/54807, 2016, A1,
[5] ChemMedChem, 2016, vol. 11, # 8, p. 827 - 833
23
[ 67-56-1 ]
[ 38496-18-3 ]
[ 65515-32-4 ]
[ 65515-26-6 ]
Reference：
[1] Synlett, 2011, # 2, p. 203 - 206
24
[ 38496-18-3 ]
[ 65515-26-6 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 2000, vol. 48, # 12, p. 1847 - 1853
25
[ 67-56-1 ]
[ 38496-18-3 ]
[ 65515-32-4 ]
[ 65515-26-6 ]
Reference：
[1] Synlett, 2011, # 2, p. 203 - 206
26
[ 67-56-1 ]
[ 38496-18-3 ]
[ 65515-33-5 ]
[ 16727-43-8 ]
[ 503000-87-1 ]
Reference：
[1] Synlett, 2011, # 2, p. 203 - 206
27
[ 38496-18-3 ]
[ 40381-90-6 ]
Reference：
[1] European Journal of Organic Chemistry, 2012, # 35, p. 6940 - 6952
28
[ 38496-18-3 ]
[ 58584-92-2 ]
Yield
Reaction Conditions
Operation in experiment
93%
at 130℃; for 12 h; Sealed tube
A solution of 2,6-dichloropyridine-3-carboxylic acid (3 g, 0.0157 mol) in aqueous ammonia (30 mL) was heated in a sealed tube at 130°C for 12 h. The reaction mixture was concentrated and the resulting crude solid was triturated with diethyl ether to afford the title compound (2.5 g, 93percent). δΗ (400 MHz, DMSO-de) 8.02 (d, J 8.0 Hz, IH), 7.55 (s, 2H), 6.62 (d, J 8.0 Hz, IH). LCMS: mlz 173 (97.70percent)
90%
Stage #1: at 130℃; for 16 h; Stage #2: With hydrogenchloride In water at 0 - 20℃; for 0.5 h;
Intermediates:; a) 2-Amino-6-chloronicotinic acid (Inter. 2); To 2,6-dichloronicotinic acid (Inter. I)(I equiv) was added liquid ammonia (sufficient to make a 0.6M solution of substrate in ammonia). The suspension was sealed in a pressure vessel which was then heated slowly to 130°C. It was noted that at this temperature a pressure of 18 bar was observed. This temperature and pressure was maintained for a further 16 hours whereupon the mixture was cooled to room temperature. The pressure vessel was opened and the reaction poured into ice cold water (1 reaction volume). The resulting solution was acidified to pH 1-2 using concentrated HCl which caused a precipitate to form. The acidic mixture was allowed to warm to room temperature and was stirred like this for a further 30 minutes. The suspension was then extracted with diethyl ether (3 x 400 ml). The combined organic extracts were then filtered and the filtrate concentrated in vacuo to give a white solid which was dried further over P2O5 to give the title compound (90percent yield and 96percent pure) in suitably pure form to be used without any further purification, m/z (LC-MS5 ESP): 173 [M+H]+ R/T = 3.63 mins
90%
at 130℃; for 16 h;
To the appropriate amino acid (1 equiv) was added liquid ammonia (sufficient to make a 0.6M solution of substrate in ammonia). The suspension was sealed in a pressure vessel which was then heated slowly to 130 0C. It was noted that at this temperature a pressure of 18 bar was observed. This . temperature and pressure was maintained for a further 16 hours whereupon the mixture was cooled to room temperature. The pressure vessel was opened and the reaction poured into ice cold water (1 reaction volume). The resulting solution was acidified to pH 1-2 using concentrated HCl which caused a precipitate to form. The acidic mixture was allowed to warm to room temperature and was stirred like this for a further 30 min The suspension was then extracted with diethyl ether (3 X 400 ml). The combined organic extracts were then filtered and the filtrate concentrated in vacuo to give a white solid which was dried further over P2O5 to give the title compound (typically 80-90 percent yield and 90 percent+ pure) in suitably pure form to be used without any further purification.2-amino-6-chloronicotinic acid - X=N, Y=C, Z=C: (90 percent yield, 96 percent purity) m/z (LC-MS5 ESP): 173 [M+H]+ R/T = 3.63 min
90%
With hydrogenchloride In ammonia
2-Amino-6-chloronicotinic Acid (Inter. 2) To 2,6-dichloronicotinic acid (Inter. 1) (1 equiv) was added liquid ammonia (sufficient to make a 0.6M solution of substrate in ammonia). The suspension was sealed in a pressure vessel which was then heated slowly to 130° C. It was noted that at this temperature a pressure of 18 bar was observed. This temperature and pressure was maintained for a further 16 hours whereupon the mixture was cooled to room temperature. The pressure vessel was opened and the reaction poured into ice cold water (1 reaction volume). The resulting solution was acidified to pH 1-2 using concentrated HCl which caused a precipitate to form. The acidic mixture was allowed to warm to room temperature and was stirred like this for a further 30 minutes. The suspension was then extracted with diethyl ether (3*400 ml). The combined organic extracts were then filtered and the filtrate concentrated in vacuo to give a white solid which was dried further over P2O5 to give the title compound (90percent yield and 96percent pure) in suitably pure form to be used without any further purification. m/z (LC-MS, ESP): 173 [M+H]+R/T=3.63 mins
75%
With ammonia In water at 130℃; for 24 h;
Example 140A 2-Amino-6-chloro-nicotinic Acid A mixture of 2,6-dichloro-nicotonic acid (17.77 g, 92.6 mmol) in concenterated aqueous ammonia (173 mL) at 200 psi, was heated to 130° C. for 24 h. The mixture evaporated and the residue was taken into water (200 mL) and neuteralized with conc HCl then extracted into ether (200 ml). The ether was evaporated off to yield 12 g of product (75percent). MS (DCI/NH3) m/z 173 (M+1)+.
72%
With ammonia In methanol at -78 - 125℃; for 39.5 h; Sealed tube
Preparation Example A-1. 2-Amino-6-chloro-nicotinic acid To liquid ammonia (approximately 20mL) was added 2,6-dichloro-nicotinic acid (0.38g, 2mmol) and copper(l) iodide (720mg, 3.8mmol) at -78°C in a sealed tube, and the solution was heated for 25 hours (the temperature of the oil bath was 115°C). The temperature of the oil bath was raised to 125°C, which was further heated for 14 hours 30 minutes. The reaction mixture was allowed to room temperature, and ammonia was evaporated. Methanol was added, insoluble matter was removed by filtration, and the filtrate was concentrated to obtain the title compound (0.25g, 1.45mmol, 72percent) as a solid. 1H-NMR Spectrum (DMSO-d6) δ (ppm): 6.63 (1H, d, J=8.0 Hz), 7.55 (2H, brs), 8.02 (1 H, d, J=8.0 Hz).
72%
at -78 - 125℃; for 39.5 h;
2,6-Dichloronicotinic acid (0.38 g, 2 mmol) and copper (I) iodide (720 mg, 3.8 mmol) were added to liquid ammonia (approx. 20 mL) in a sealed tube at -78°C, which was heated for 25 hours (oil bath temperature: 115°C). The oil bath temperature was raised to 125°C followed by additionally heating for 14 hours 30 minutes. The reaction mixture was allowed to return to room temperature followed by distilling off the ammonia. The insoluble material that precipitated following addition of methanol was filtered out and the filtrate was concentrated to obtain the title compound (0.25 g, 1.45 mmol, 72percent) as a solid. 1H-NMR spectrum (DMSO-d6) δ (ppm): 6.63 (1 H, d, J=8.0 Hz), 7.55 (2H, brs), 8.02 (1H, d, J=8.0 Hz).
72%
at -78 - 125℃; for 39.5 h;
To liquid ammonia (approximately 20mL) was added 2,6-dichloro-nicotinic acid (0.38g, 2mmol) and copper(I) iodide (720mg, 3.8mmol) at -78°C in a sealed tube, and the solution was heated for 25 hours (the temperature of the oil bath was 115°C). The temperature of the oil bath was raised to 125°C, which was further heated for 14 hours 30 minutes. The reaction mixture was allowed to room temperature, and ammonia was evaporated. Methanol was added, insoluble matter was removed by filtration, and the filtrate was concentrated to obtain the title compound (0.25g, 1.45mmol, 72percent) as a solid. 1H-NMR Spectrum (DMSO-d6) δ(ppm) : 6.63 (1H, d, J=8.0 Hz), 7.55 (2H, brs), 8.02 (1 H, d, J=8.0 Hz).
67.5%
With ammonia In water at 130℃; for 68 h;
2.1: 2-Amino-6-chloronicotinic acid 9.6 g (50 mm) of 2,6-dichloronicotinic acid are mixed in a glass autoclave with 60 ml of 32percent aqueous ammonia solution. The reaction medium is immersed in an oil bath preheated to 130° C. and heating is carried out at this temperature for 68 h. The solution is allowed to return to ambient temperature. The reaction medium is concentrated under reduced pressure. The residue is taken up in 200 ml of water and ice and acidified to pH 2 with a concentrated HCl of solution. Ethyl acetate is added and the medium is then stirred for 5 minutes and filtered. The aqueous phase is separated by settling and the organic phase is washed with a saturated in NaCl solution. The organic phase is dried over sodium sulphate and filtered, and the solvent is evaporated. 5.83 g of product (Yd: 67.5percent) are obtained (LC/MS; MH+ 173, tr=6.03 min).
49%
Stage #1: With ammonia In water at 135℃; for 10 h; Stage #2: at 0℃;
Manufacturing Example 26-1-1 2-Amino-6-chloro-nicotinic acid; A mixture of 2,6-dichloro-nicotinic acid (31 g, 0.14 mol) and 28percent aqueous ammonia solution (200 mL) was stirred in a sealed tube for 10 hours at 135° C. This reaction solution was cooled to room temperature, and the excess ammonia gas was removed under a reduced pressure. Water was added to the residue to a total of 1000 mL, the mixture was cooled to 0° C., and citric acid was added to a pH being about 6. The precipitated solids were filtered out to obtain the title compound (12 g, 49percent).1H-NMR Spectrum (DMSO-d6) δ (ppm); 6.63 (1H, d, J=8.1 Hz), 7.55 (2H, brs), 8.02 (1H, d, J=8.1 Hz).
49%
Stage #1: With ammonia In water at 135℃; for 10 h; Stage #2: With citric acid In water at 0℃;
A mixture of 2,6-dichloro-nicotinic acid (31 g, 0.14 mol) and 28percent aqueous ammonia solution (200 mL) was stirred in a sealed tube for 10 hours at 135° C. This reaction solution was cooled to room temperature, and the excess ammonia gas was removed under a reduced pressure. Water was added to the residue to a total of 1000 mL, the mixture was cooled to 0° C., and citric acid was added to a pH being about 6. The precipitated solids were filtered out to obtain the title compound (12 g, 49percent). 1H-NMR Spectrum (DMSO-d6) δ (ppm): 6.63 (1H, d, J=8.1 Hz), 7.55 (2H, brs), 8.02 (1H, d, J=8.1 Hz).
34%
at 130 - 160℃; for 24 - 48 h;
Example 2 2-Amino-6-chloro-nicotinic acid A solution of 2,6-dichloronicotinic acid (10 g, 46.9 mmol, Aldrich 90percent) was dissolved in concentrated ammonium hydroxide (100 mL, 29.4percent, Fisher) and heated at 130-160° C. in a pressure bottle for 1-2 days before solvent was removed in vacuo. The residue was treated with water and the pH was lowered to ~8 with concentrated hydrochloric acid. The resulting mixture was extracted with ethyl acetate and the combined organic extracts were washed with brine, dried, concentrated and the crude product was recrystallized from ethyl acetate to give 2-Amino-6-chloro-nicotinic acid as white crystalline (2.74g, 34 percent yield). HRMS, observed: 172.0042, Calcd for M+: 172.0040
4.5%
Stage #1: With acetamide; Tris(3,6-dioxaheptyl)amine; potassium carbonate; copper(l) chloride In xylene at 145℃; Stage #2: With water In xylene at 105℃; for 1 h;
Preparation Example A-4. 2-Amino-6-chloronicotinic acid Tris(2-(2-methoxyethoxy)ethyl)amine (3.0mL, 9.4mmol) was added to a mixture of 2,6-dichloronicotinic acid (40g (90percentpurity), 0.19 mol), acetamide (80g, 1.4mol), potassium carbonate (78g, 0.56mol), copper(I) chloride (0.93g, 9.4mmol) and xylene (80mL), which was stirred overnight at 145°C. After cooling, copper(I) chloride (0.46g, 4.6mmol) was added to the reaction solution, which was stirred overnight at 145°C. After cooling the reaction solution to 105°C, water (1 00mL) was added, the solution was stirred for 1 hour at the same temperature, and cooled down to room temperature. 5N hydrochloric acid (150mL) was added, the solution was neutralized with a citric acid aqueous solution, then, ethyl acetate was added, and the solution was filtered through Celite pad. The organic layer was washed with brine, then, the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate), recrystallization by the ethyl acetate-hexane was carried out to obtain the title compound (1.4g, 8.3mmol, 4.5percent) as white crystal. 1H-NMR Spectrum (DMSO-d6) δ (ppm): 6.61 (1H, d, J=8.1 Hz), 7.53 (2H, brs), 8.01 (1 H, d, J=8.1 Hz).
4.5%
Stage #1: With acetamide; Tris(3,6-dioxaheptyl)amine; potassium carbonate In xylene at 145℃; Stage #2: With water In xylene at 105℃; for 1 h; Stage #3: With hydrogenchloride; citric acid In water; xylene at 20℃;
Tris(2-(2-methoxyethoxy)ethyl)amine (3.0mL, 9.4mmol) was added to a mixture of 2,6-dichloronicotinic acid (40g (90percentpurity), 0.19 mol), acetamide (80g, 1.4mol), potassium carbonate (78g, 0.56mol), copper(I) chloride (0.93g, 9.4mmol) and xylene (80mL), which was stirred overnight at 145°C. After cooling, copper(I) chloride (0.46g, 4.6mmol) was added to the reaction solution, which was stirred overnight at 145°C. After cooling the reaction solution to 105°C, water (100mL) was added, the solution was stirred for 1 hour at the same temperature, and cooled down to room temperature. 5N hydrochloric acid (150mL) was added, the solution was neutralized with a citric acid aqueous solution, then, ethyl acetate was added, and the solution was filtered through Celite pad. The organic layer was washed with brine, then, the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate), recrystallization by the ethyl acetate-hexane was carried out to obtain the title compound (1.4g, 8.3mmol, 4.5percent) as white crystal. 1H-NMR Spectrum (DMSO-d6) δ(ppm) : 6.61 (1H, d, J=8.1 Hz), 7.53 (2H, brs), 8.01 (1H, d, J=8.1 Hz).
Stage #1: With Tris(3,6-dioxaheptyl)amine; potassium carbonate; copper(l) chloride In xylene at 145℃; Stage #2: With copper(l) chloride In xylene at 145℃;
[Production Example 4-1-1B] 2-Amino-6-chloro-nicotinic acid To a mixture of 2,6-dichloronicotinic acid (40 g (purity: 90percent), 0.19 mol), acetoamide (80 g, 1.4 mol), potassium carbonate (78 g, 0.56 mol), copper (I) chloride (0.93 g, 9.4 mmol) and xylene (80 mL) was added tris(2-(2-methoxyethoxy)ethyl)amine (3.0 mL, 9.4 mmol), which was stirred overnight at 145°C. After allowing to cool on standing, to the reaction mixture was added copper (I) chloride (0.46 g, 4.6 mmol), followed by stirring overnight at 145°C. After cooling the reaction mixture to 105°C, water (100 mL) was added followed by stirring for 1 hour at the same temperature and allowing to cool to room temperature on standing. After neutralizing the reaction mixture with 5 N hydrochloric acid (150 mL) and aqueous citric acid, ethyl acetate was added. This mixture was filtered through Celite. After separating the organic phase and washing with sat. NaCl, the solvent was concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from an ethyl acetate-hexane system to obtain the title compound (1.4 g, 8.3 mmol, 4.5percent) as white crystals. 1H-NMR spectrum (DMSO-d6) δ (ppm): 6.61 (H1, d, J=8.1 Hz), 7.53 (2H, brs), 8.01 (1 H, d, J=8.1 Hz).
Stage #1: With borane-THF In tetrahydrofuran at 0 - 20℃; Stage #2: With water; potassium carbonate In tetrahydrofuran for 2 h;
Dissolve 2,6-dichloronicotinic acid (1000 mg, 5.21 mmol) in anhydrous tetrahydrofuran (5 niL). Cool to 0 0C. Add borane-tetrahydrofuran complex (7.82 mL5 7.82 mmol, 1.0 M in tetrahydrofuran) slowly. Stir the mixture at room temperature overnight. Add water (1 niL) and potassium carbonate, stir for 2 hours, filter and concentrate to give a residue. Chromatograph the residue on silica gel eluting with 10:90 to 20:80 ethyl acetate:hexanes to give (2,6-dichloropyridin-3-yl)-methanol (876 mg, 94percent). 1H NMR (400 MHz5 MeOH-d4) δ 7.96 (d, IH, J = 8.0 Hz), 7.45 (d, IH, J = 8.0 Hz), 4.64 (s, 2H).
80%
With sodium tetrahydroborate; boron trifluoride diethyl etherate In tetrahydrofuran at 0 - 20℃; for 10 h;
To a solution of 2,6-dichloronicotinic acid (1 g, 5.2 mmol) in THF (10 mL) was added NaBH4 (591 mg, 15.6 mmol) at 0°C. The mixture was stirred for 30 min and then BF3.OEt2 (2.2g, 15.6 mmol) was added drop wise at 0°C. After addition was complete, the mixture was stirred at room temperature for 10 hr, until the reaction was completed. The reaction mixture was quenched by the addition of saturated NH4C1 solution (50 mL) and extracted with ethyl acetate (3x30 mL). The combined organic layers were washed with brine (30 mL), dried over Na2S04 and concentrated to give the desired product as a white solid which was used in next step without further purification. (820 mg, Yield 80percent).
Reference：
[1] Journal of Medicinal Chemistry, 2003, vol. 46, # 5, p. 702 - 715
[2] Chemical and Pharmaceutical Bulletin, 2000, vol. 48, # 12, p. 1847 - 1853
[3] Chemical and Pharmaceutical Bulletin, 2000, vol. 48, # 12, p. 1847 - 1853
[4] Patent: US2012/172391, 2012, A1,
[5] Journal of Medicinal Chemistry, 2014, vol. 57, # 13, p. 5620 - 5637
[6] Journal of Medicinal Chemistry, 2017, vol. 60, # 17, p. 7315 - 7332
[7] Patent: WO2017/192304, 2017, A1,
[8] Patent: WO2008/76425, 2008, A1,
37
[ 38496-18-3 ]
[ 64321-24-0 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 5, p. 1212 - 1216
38
[ 38496-18-3 ]
[ 38025-90-0 ]
Yield
Reaction Conditions
Operation in experiment
88%
at 129℃; for 4 h;
Step a 2-chloro-6-oxo-1 ,6-dιhydropyrιdιne-3-carboxylιc acιd; ° A 500-mL round-bottom flask was charged with 2,6-dιchloronιcotιnιc acid (25 0 g 130 mmol), NaOH solution (325 ml_, 2N) and the solution was refluxed at 1290C for 4 hours The reaction mixture was cooled to room temperature and acidified with a 6N aq HCI solution The resulting precipitate was filtered and dried under reduced pressure yielding to the desired product (19 87g, 88percent)
4 g
Stage #1: at 120℃; for 4 h; Inert atmosphere Stage #2: With hydrogenchloride In water at 20℃;
2,6-Dichloronicotinic acid (6 g) was placed in a 250 mL round bottom flask, and sodium hydroxide solution (80 mL) was added.The mixture was heated to 120 ° C for 4 hours. After the reaction was completed, it was cooled to room temperature, acidified with 6N hydrochloric acid, and the solid was precipitated, filtered, and dried to give the title compound (4 g).
Reference：
[1] Patent: WO2010/108652, 2010, A1, . Location in patent: Page/Page column 97
[2] Patent: WO2008/125820, 2008, A1, . Location in patent: Page/Page column 33
[3] Patent: CN108314645, 2018, A, . Location in patent: Paragraph 0094; 0095; 0096; 0097
39
[ 38496-18-3 ]
[ 869357-63-1 ]
Reference：
[1] Patent: WO2008/125820, 2008, A1,
40
[ 38496-18-3 ]
[ 938443-20-0 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 5, p. 1212 - 1216
To a solution of 2,6-dichloronicotinic acid (5.0 g, 26 mmol) in MeOH (100 mL) was added SOCl2 (0.1 mL). The reaction mixture was heated to reflux overnight. The solvent was removed by evaporation. The residue was dissolved in ethyl acetate and washed with saturated NaHCO3 and brine; dried over anhydrous Na2SO4 and concentrated to afford 2,6-dichloronicotinic acid methyl ester (5.37 g, 100%); 1HNMR:(300 MHz, CDCl3) delta 8.13 (d, J=8.1 Hz, 1H), 7.33 (d. J=8.1 Hz, 1H), 3.94 (s, 3H).
100%
With thionyl chloride;Heating / reflux;
To a solution of 2,6-dichloronicotinic acid (5.0 g, 26 mmol) in MeOH (100 mL)was added SOCl2 (0.1mL). The reaction mixture was heated to reflux overnight. The solvent was removed by evaporation. The residue was dissolved in ethyl acetate and washed with saturated NaHCO3 and brine; dried over anhydrous Na2SO4 and concentrated to afford 2,6-dichloronicotinic acid methyl ester (5.37 g, 100%); 1HNMR:(300 MHz, CDCI3) ;5 8.13 (d, J= 8.1 Hz, 1H), 7.33 (d. J= 8.1 Hz, 1H), 3.94 (s, 3H).
100%
With thionyl chloride; for 4h;Heating / reflux;
To a solution of 2,6-dichloronicotinic acid (5Og, 0.26 mol) in methanol (250 ml_) was added thionyl chloride (22.7 mL, 0.312 mol) slowly. The mixture was refluxed for 4 hours and concentrated to give methyl 2,6-dichloronicotinate as a white solid in quantitative yield.
97%
With thionyl chloride; at 0 - 20℃; for 48h;
A solution of 2,5-dichloronicotinic acid (20.2 g, 0.105 mol) in methanol (500 mL) was cooled to 0 0C and neat thionyl chloride (38 mL, 63 g, 0.525 mol) was added over -30 min. The reaction mixture was stirred at 00C for 1 hour. The cooling bath was removed, the reaction temperature was allowed to warm to room temperature, and the reaction was allowed to stir for an additional 2 days at room temperature. The solvent was removed under reduced pressure to give an off-white residue. The residue was dissolved in Et2O (-500 mL) and the resulting solution was washed successively with saturated aqueous NaHCO3 solution (-300 mL), water (-300 mL), and brine (-300 mL). The organic layer was separated, dried over anhydrous MgSO4, and filtered. Removal of the solvent under reduced pressure yielded methyl 2,5-dichloronicotinate (21.0 g, 97%) as a white solid
97%
With thionyl chloride; at 0 - 20℃; for 49.5h;
Preparative Example 45. Lithium 2-amino-6-chloronicotinate (58).; A solution of 2,5-dichloronicotinic acid (20.2 g, 0.105 mol, Aldrich) in methanol (500 mL) was cooled to 0C and neat thionyl chloride (38 mL, 63 g, EPO <DP n="135"/>0.525 mol) was added over -30 min. The reaction mixture was stirred at 00C for 1 hour. The cooling bath was removed, the reaction temperature was allowed to warm to room temperature, and the reaction was allowed to stir for an additional 2 days at room temperature. The solvent was removed under reduced pressure to give an off-white residue. The residue was dissolved in ether (-500 mL) and the resulting solution was washed successively with saturated aqueous sodium bicarbonate solution (-300 mL), water (-300 mL), and brine (-300 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, and filtered. Removal of the solvent under reduced pressure yielded methyl 2,5-dichloronicotinate (21.0 g, 97% yield) as a white solid.
97%
With thionyl chloride; at 0 - 25℃; for 49.5h;
A solution of 2,6-dichloronicotinic acid (20.2 g, 0.105 mol) in MeOH (500 mL) was cooled to 0 C. and neat thionyl chloride (38 mL, 63 g, 0.525 mol) was added over ~0.5 hours. The reaction mixture was stirred at 0 C. for 1 hour. The cooling bath was removed, the reaction temperature was allowed to warm to 25 C., and the reaction was allowed to stir for an additional 2 days at 25 C. The solvent was removed under reduced pressure to give an off-white residue. The residue was dissolved in Et2O (~500 mL) and the resulting solution was washed successively with saturated aqueous NaHCO3 solution (~300 mL), water (~300 mL), and brine solution (~300 mL). The organic layer was separated, dried over anhydrous MgSO4, and filtered. Removal of the solvent under reduced pressure yielded methyl 2,6-dichloronicotinate (21.0 g, 97%) as a white solid.
97%
With diazomethyl-trimethyl-silane; In 1,4-dioxane; diethyl ether;
Dichlorocarboxylic acid 1.1 (2.0 g, 10 mmol) was diluted with 10 mL each of 1,4-dioxane and methanol, then treated with a 2.0M TMSCHN2 in diethyl ether solution (7.5 mL, 15 mmol) resulting in vigorous gas evolution and a light green solution. After stirring overnight the reaction was checked by UPLC which showed complete conversion to the desired product. The reaction was concentrated to near dryness, then diluted with water and stirred vigorously. The resulting granular precipitate was then filtered and dried under vacuum affording the desired methyl ester as a light beige solid (2.01 g, 97%). MS found for C7H5Cl2NO2 as (M+H)+ 206.0, 208.0. UV lambda=276.
97%
With diazomethyl-trimethyl-silane; In 1,4-dioxane; diethyl ether;
0483] Dichlorocarboxylic acid X.l (2.0 g, 10 mmol) was diluted with 10 mL each of 1,4- dioxane and methanol, then treated with a 2.0M TMSCHN2 in diethyl ether solution (7.5 mL, 15 mmol) resulting in vigorous gas evolution and a light green solution. After stirring overnight the reaction was checked by UPLC which showed complete conversion to the desired product. The reaction was concentrated to near dryness, then diluted with water and stirred vigorously. The resulting granular precipitate was then filtered and dried under vacuum affording the desired methyl ester as a light beige solid (2.01 g, 97%). MS found for C7H5C12N02 a s(M+H)+ 206.0, 208.0. UV lambda = 276
93%
The starting material, 5-[5-(3,5-bistrifluoromethylphenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-imidazo[1,2-a]pyridine-8-carboxylic acid, was prepared as follows: a. Oxalyl chloride (11.1 mL) was added to a solution of 2,6-dichloronicotinic acid (8 g) in a mixture of DCM (300 mL) and DMF (0.2 mL). After stirring 2 hours, the mixture was concentrated under reduced pressure to give a residue that was treated with MeOH (300 mL) at 0 C. The mixture was stirred at to room temperature and then was concentrated under reduced pressure to give a residue that was diluted with water and EA, neutralized with a saturated aqueous solution of sodium bicarbonate solution and extracted three times with EA. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 2,6-dichloronicotinic acid methyl ester (8 g, 93%). 1H NMR (400 MHz, CHLOROFORM-d): 3.96 (s, 3H), 7.36 (d, J=8.2 Hz, 1H), 8.16 (d, J=8.0 Hz, 1H).
91%
With diazomethyl-trimethyl-silane; In tetrahydrofuran; methanol; diethyl ether; at 20℃; for 1h;
A 2.0 M ether solution of (trimethylsilyl)diazomethane (30 mL, 60.0 mmol) was added dropwise to a solution of 2,6-dichloronicotinic acid (8.00 g, 37.5 mmol) in THF (100 mL) and MeOH (25 mL) in a room temperature water bath. After 1 h, HOAc (4 mL) was added. The mixture was stirred until bubbling stopped and concentrated. The resulting solid was dissolved in minimum amount of ethyl acetate, diluted with hexanes, and partially concentrated in vacuo. A white crystalline solid <n="90"/>precipitated out and was collected by filtration. This process was repeated three times to give 4.553 g of the desired product. The mother liquor was concentrated and purified by silica gel chromatography, eluting with 0-20% EtOAc in hexanes, to give additional product (2.48 g). The total amount of the product was 7.033 g (91% yield). MS (ES+) m/z: 206 (M+H); LC retention time: 2.99 min (analytical HPLC Method A).
90%
With sulfuric acid; at 80℃;
To a solution of 2,6-dichloropyridine-3-carboxylic acid (300 mg, 1.56 mmol) in methanol (2 mL) was added three drops of concentrated sulfuric acid and the reaction was heated to eighty degrees Celsius overnight. The solution was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was washed with water and brine and dried over magnesium sulfate. The material was filtered and concentrated to provide the methyl ester as a beige solid (290 mg, 90% yield).
87%
To a solution of 2,6-dichloronicotinic acid (30 g, 0.16 mol) in 150 mL methanol was added 3 mL of con. H2SO4 and the mixture was refluxed for 12 h. The methanol was evaporated off and the residue was dissolved in ethyl acetate, washed with water, 10% sodium carbonate solution, brine, dried with sodium sulfate and evaporated to yield the desired product (29.0 g, 87%) as white solid.
75%
Preparation 10: methyl 2-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)nicotinate; Step 1 : methyl 2,6-dichloronicotjnate; To a solution of 2,6-dichloronicotinic acid (130 g, 0.67 mol) in methanol (907 ml_) was added sulfuric acid (18.76M, 22 g, 0.22 mol) and the mixture was refluxed for 20 h. The reaction was cooled to room temperature and poured slowly into a solution of sodium bicarbonate (42 g, 0.5 mol) in water (1 L). The mixture was concentrated to remove the methanol. The residue was diluted with ethyl acetate (1 L) and extracted with water (500 mL). The organic layer was washed with 5% aqueous sodium chloride (150 mL). The organic layer was concentrated to an oil. Heptane (150 mL) was added and the mixture was concentrated. To the residue was added heptane (580 mL) and the mixture was heated to 70C. The solution was cooled to room temperature and stirred for 2 h. The resulting solid was collected by filtration and dried to yield the title compound as a white pale yellow solid (105 g, 75%). 1 H NMR (400 MHz, DMSO-dbeta) delta ppm 2.52 (1 H, d, J=1.8 Hz), 3.89 (3 H, s), 7.72 (1 H, d, J=8.0 Hz).
75%
With sulfuric acid; for 20h;Reflux;
To a solution of acid 9 (130 g, 0.67 mol) in methanol (907 mL) was added sulfuric acid (18.76M, 22 g, 0.22 mol) and the mixture was heated under reflux for 20 h. After cooling to room temperature, the mixture was poured slowly into a solution of sodium bicarbonate (42 g, 0.5 mol) in water (1 L) then concentrated to remove the methanol. The residue was diluted with ethyl acetate (1 L) and washed with water (500 mL). The organic layer was washed with 5% aqueous sodium chloride (150 mL) and concentrated. Heptane (150 mL) was added and the mixture was concentrated. The residue was taken up in hot heptane (580 mL, 70C) then cooled to room temperature and stirred for 2 h. The resulting solid was collected by filtration and dried to yield 10 as a pale yellow solid (105 g, 75%). 1H NMR (400 MHz, CDCl3) delta 8.14 (1H, d, J= 8.0 Hz), 7.34 (1H, d, J=8.0 Hz), 3.95 (3H, s).
sulfuric acid; at 60℃; for 8 - 14h;Product distribution / selectivity;
Alternate Method of Synthesizing Example 14(2S)-2-({6-chloro-3-[6-(4-chlorophenoxy)-2-propylpyridin-3-yl]-l,2- benzisoxazol-5-yl}oxy)propanoic acid, which is the compound of Example 14, has also been made by the following multi-step route. It is S-14 in steps 9 and 10 of the sequence below:Steps 1 and 2. Esterification and aryl ether formationTo a solution of 2,6-dichloronicotinic acid (1) (19.2 g, 0.10 mol) in MeOH(100 mL) was added 5.56 mL (0.10 mol) of concentrated H2SO4 dropwise. An ~15 0C temperature increase was observed. The resulting solution was heated at 60 0C for 8 - 14 hrs.The reaction mixture was allowed to cool to RT and then poured into a biphasic mixture containing IPAc (220 mL) and aq. K2CO3 (20.7 g in 117.3 g water) at RT with stirring. The organic layer was separated, washed with sat. NaHCO3 (80 mL), and then water (80 mL). The isolated IPAc solution was subjected to a solvent switch to DMF (80 mL) in vacuo.
With sulfuric acid; for 10h;Reflux;
To a mixture of 2, 6-dichloronicotinic acid (10.0 g, 52.1 mmol) in methanol (21.1 mL, 521 mmol) at ambient temperature was added concentrated H2SO4(18 M, 27.8 mL, 521 mmol) , and the resulting mixture was heated at reflux for 10 h. The reaction was cooled and poured slowly into saturated aqueous NaHCO3 solution. The resulting precipitate was filtered and the solid was washed with water and dried to give the title compound.1H NMR (400 MHz, CDCl3) delta 8.15 (d, J 8.0 Hz, 1 H) , 7.35 (d, J 8.5 Hz, 1 H) , 3.95 (s, 3 H) . MS (ESI) m/z: 206 (M + H+) .
Esterifcation and aryl ether formationTo a solution of 2,6-dichloronicotinic acid (1) (19.2 g, 0.10 mol) inMeOH (100 mL) was added 5.56 mL (0.10 mol) of concentrated H2SO4 dropwise. An ~15 0C temperature increase was observed. The resulting solution was heated at 60 0C for 8 - 14 hrs.The reaction mixture was allowed to cool to RT and then poured into a biphasic mixture containing IPAc (220 mL) and aq. K2CO3 (20.7 g in 117.3 g water) at RT with stirring. The organic layer was separated, washed with sat. NaHCO3 (80 mL), and then water (80 mL). The isolated IPAc solution was subjected to a solvent switch to DMF (80 mL) in vacuo.A solution of 4-chlororhohenol (12.2 g, 0.095 mol) in 36.6 mL of DMF was added at room temperature to the above solution (19.6 g of ester 2, 0.095 mol), followed by addition of triethylamine (17.3 mL, 0.124 mol) at 20-22 0C over 15 min. Solid DABCO (1.6 g, 14.2 mmol) was added to the resulting solution in one portion. A temperature increase of ~3 0C was observed. A water bath was used to maintain the reaction temperature. The reaction was stirred at 22-24 0C for 4-5 h while monitoring by LC until all of the 4-chlorophenol was consumed, resulting in a light slurry. AcOH (2.72 mL, 47.5 mmol) and EPA (57.5 mL) were added to the light slurry, followed by cold water (30 mL) to maintain the internal temperature at 20-25 0C. When the water was added, a clear solution first formed, and then a <n="9"/>slurry of product formed. After stirring at RT for 0.5 h, additional water (86 mL) was added over 0.5 h. After the slurry was stirred at RT for 1-2 h, it was filtered. The filter cake was washed with mixed solvents (60 mL OfIPAiH2O = 1:1). The isolated solid was dried in a vacuum-oven at 50 0C for 8 h to provide the product as white cotton-like solid.
With sulfuric acid; at 60℃; for 8 - 14h;
EXAMPLE 1; Synthesis of (2S)-2-f{6-chloro-3-[6-(4-chlorophenoxy)-2-propylpyridin-3-yl3- 1 ,2-benzisoxazol- 5-yl}oxy)propanoic acid (Compound I)Compound I is made by the multi-step process shown in Schemes 1 and 2 below. The process is described in detail in the description after the examples. Compound I as the free acid is (5)-14 in the schemes and description below. <n="8"/>Synthesis of Hydroxybenzisoxazole Intermediate 1010 <n="9"/>Synthesis of Chiral Acid 14TsCI1 Et3N, DABCOHO CO2IVIeTsO CO2Me (R)-11 12Steps I and 2. Esterification and aryl ether formationMeOH DABCO (15%)/ H2SO4 (cat.) TEA/DM F/RTTo a solution of 2,6-dichloronicotinic acid (1) (19.2 g, 0.10 mol) in MeOH (100 mL) was added 5.56 mL (0.10 mol) of concentrated H2SO4 dropwise. An -15 0C temperature increase was observed. The resulting solution was heated at 60 0C for 8 - 14 hrs.The reaction mixture was allowed to cool to RT and then poured into a biphasic mixture containing IPAc (220 mL) and aq. K2CO3 (20.7 g in 117.3 g water) at RT with stirring. The organic layer was separated, washed with sat. NaHCO3 (80 mL), and then water (80 mL). The isolated IPAc solution was subjected to a solvent switch to DMF (80 mL) in vacuo.
Example 40 Synthesis of (S)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-6-methoxy-2-phenylnicotinamide Compound 86a. To a solution of 2,6-dichloronicotinic acid (2.0 g, 10.41 mmol, 1.0 equiv) in MeOH (50 mL) was added compound potassium tert-butoxide (4.7 g, 41.66 mmol, 4.0 equiv), and resulting reaction mixture was heated at 70 C. for 3 h. Product formation was confirmed by LCMS and TLC. After the completion of reaction, the reaction mixture was concentrated and diluted with water (50 ml). Aqueous layer extracted with ethyl acetate (30 mL*3). Combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4 and concentrated. The crude product obtained was purified by flash chromatography (5% MeOH in DCM as an eluent) to obtain 2-chloro-6-methoxynicotinic acid (1.8 g, 96.4%) as white solid LCMS 188 [M+H]+ 1H NMR 1H NMR (400 MHz, DMSO-d6) delta 13.33 (br. s., 1H), 8.06-8.24 (m, 1H), 6.92 (d, J=8.77 Hz, 1H), 3.91 (s, 3H).
86%
With potassium tert-butylate; for 48h;Reflux;
2,6-Dichloronicotinic acid (10 g, 52.1 mmol, 1.0 eq) was dissolved in methanol (460 mL) and potassium t-butoxide was added.(23.37 g, 208.3 mmol, 4.0 eq), heated to reflux for 48 hours.The reaction was completely detected by LC-MS. The mixture was evaporated to room temperature, and concentrated under reduced pressure.A large amount of white solid precipitated, suction filtration,The filter cake is washed with water (300mL×3),Drying to a white solid product (8.5 g, yield: 86%
84%
2-Chloro-6-methoxypyridine-3-carboxylic acid [00213] A mixture of 2,6-dichloropyndme-3-carboxyhc acid (6 5 g, 33mmol), potassium tert- butoxide (11 4 g, 0 10 mol), and anhydrous methanol (30OmL) was heated to reflux for 4 days and cooled to room temperature After evaporation of the solvent, the residue was diluted with water and acidified with 35% aqueous hydrochloric acid The resulting solid was collected by filtration, washed with water, and dried to give 4 8 g (84%) of 2-chloro-6-methoxypyridine-3-carboxyhc acid as a white solid[00214] 1H NMR (DMSO-(Z5, 400MHz) delta 13 33 (brs, 1H, OH, exchangeable with D2O), 8 19 (d, J=8 5Hz, 1H), 6 92 (d, J=8 5Hz, 1H), 3 92 (s, 3H)
52%
With potassium tert-butylate; at 60℃; for 1h;
[752] Step A: 2-chloro-6-methoxy-nicotinic acid [753] Potassium botoxide (483 mg, 4.31 mmol) and MeOH (8 mL) were added to 2,6-dichloro-nicotinicacid (207 mg, 1.07 mmol), and the mixture was stirred usingmicrowave at 60 for 1 hour.After the termination of the reaction, the reactant was filtered, and 1N HClwas added thereto at 0 to adjust the pH to 3. Thesolid was dried by N2 gas to obtain the title compound (106 mg,52%).[754] 1H-NMR (DMSO-d6) delta 8.17(1H, d), 6.92(1H, d),3.92(3H, s)
3.15 g
With potassium tert-butylate; for 10h;Reflux;
To a solution (250 mL) of 2,6-dichloronicotinic acid (5.00 g) in methanol was added potassium tert-butoxide (8.77 g), and the mixture was heated under reflux for 10 hr. The solvent in the reaction mixture was evaporated under reduced pressure, and the residue was suspended in water and neutralized with 1N HCl. The precipitate was collected by filtration to give the title compound (3.15 g) as a white solid. (1368) MS (ESI+): [M+H]+ 188.0.
With potassium tert-butylate; at 65℃; for 96h;
Into a 250-mL round-bottom flask, was placed 2,6-dichloropyridine-3-carboxylic acid (5.0 g, 26.04 mmol), methanol (30 mL) and (tert-butoxy)potassium (5.86 g, 52.22 mmol). The resulting solution was stirred for 4 days at 65 C in an oil bath. The resulting mixture was concentrated under vacuum. The residue was dissolved in 30 mL of water and the pH value of the solution adjusted to 3-4 with HC1. The resulting precipitate was collected by filtration resulting in 4.6 g (94%) of 2-chloro-6- methoxypyridine-3-carboxylic acid as a white crude solid.
Example 11; [0163] (a) I-Chloro--methoxynicotinic acid. A mixture of 2,6- dichloronicotinic acid (50 g, 0.26 mol) and potassium tert-butoxide (87.7 g, 0.783 mol) in MeOH (2300 mL) was heated at reflux for 48 hours. After evaporation of the solvent, the residue was diluted with H2O and acidified with concentrated HCl. The solid precipitate was filtered, washed with water, and dried in vacuo to give the title compound as a white solid.
Under argon, 1500 ml of THF were initially charged and 2,6-dichloronicotinic acid (200 g, 1.04 mol) was added. 4-Dimethylaminopyridine (63.6 g, 521 mmol) and 1,1?-carbonyldiimidazole (253 g, 1.56 mol) were added a little at a time (evolution of gas). The mixture was stirred at room temperature for 24 h. A precipitate formed (suspension 1). In another flask, potassium 3-ethoxy-3-oxopropanoate (266 g, 1.56 mol) was initially charged in 1000 ml of THF, and magnesium chloride (179 g, 1.87 mol) was added. The suspension was stirred at 50 C. for 24 h (suspension 2). Suspension 2 was subsequently added to suspension 1 and stirred at room temperature for 24 h. The mixture was then stirred into 5 l of ice and about 20 l of water and adjusted to pH 4 using about 500 ml of hydrochloric acid/water (1:1). The mixture was subsequently extracted twice with ethyl acetate. The org. phase was washed with 10% strength NaCl solution. The phases were separated, dried over magnesium sulphate, concentrated by evaporation and dried under high vacuum. This gave 255 g of the target compound (93.5% of theory).
A solution of carbonyldiimidazole (CDI) (16.4 kg) in tetrahydrofuran (THF) was added to a slurry of 2,6-dichloronicotinic acid (Compound A) (16 kg) in THF. After about 2 hr, <strong>[6148-64-7]ethyl potassium malonate</strong> (Et02CCH2C02K) (19.4 kg), triethylamine (25.9 kg) and magnesium chloride (11.9 kg) were added and the reaction stirred for about 24 hr. The reaction mixture was quenched with dilute HC1 and extracted with ethyl acetate. The organic layer was concentrated, washed with a mixture of aqueous NaCl and NaHC03. The organic layer was diluted with methylcyclohexane and dried by vacuum distillation. The solution was treated with triethylortho formate (17.1 kg) and acetic anhydride (59 kg) at about 90 to 110 C. After the reaction was judged to be complete, the excess acetic anhydride was removed by distillations with methylcyclohexane. The crude product was treated with a solution of 2-aminothiazole (8.2 kg) in THF. After about 2 hr, the reaction mixture was treated with potassium carbonate (13.6 kg) and the mixture stirred for about 6 hr. The product was precipitated by the addition of water, isolated by filtration, washed with ACN-water, ACN, and dried to give Compound 1 (13.1 kg).
[Production Example 4-1-1B] 2-Amino-6-chloro-nicotinic acid To a mixture of 2,6-dichloronicotinic acid (40 g (purity: 90percent), 0.19 mol), acetoamide (80 g, 1.4 mol), potassium carbonate (78 g, 0.56 mol), copper (I) chloride (0.93 g, 9.4 mmol) and xylene (80 mL) was added tris(2-(2-methoxyethoxy)ethyl)amine (3.0 mL, 9.4 mmol), which was stirred overnight at 145°C. After allowing to cool on standing, to the reaction mixture was added copper (I) chloride (0.46 g, 4.6 mmol), followed by stirring overnight at 145°C. After cooling the reaction mixture to 105°C, water (100 mL) was added followed by stirring for 1 hour at the same temperature and allowing to cool to room temperature on standing. After neutralizing the reaction mixture with 5 N hydrochloric acid (150 mL) and aqueous citric acid, ethyl acetate was added. This mixture was filtered through Celite. After separating the organic phase and washing with sat. NaCl, the solvent was concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from an ethyl acetate-hexane system to obtain the title compound (1.4 g, 8.3 mmol, 4.5percent) as white crystals. 1H-NMR spectrum (DMSO-d6) delta (ppm): 6.61 (H1, d, J=8.1 Hz), 7.53 (2H, brs), 8.01 (1 H, d, J=8.1 Hz).
With 1-methyl-pyrrolidin-2-one; potassium carbonate; copper(I) bromide at 120℃; for 2.5h;
R.2.2 REFERENCE EXAMPLE 2
(2) A mixture of the compound (500 mg) obtained in (1) above, 3-chloro-4-methoxybenzylamine (638 mg), potassium carbonate (817 mg), copper bromide (313 mg) and 1-methyl-2-pyrrolidinone (10 ml) is stirred at 120 C for 2.5 hours. After the mixture is cooled to room temperature, a mixture of ethyl acetate and aqueous 1N hydrochloric acid solution is added to the mixture. The organic layer is separated and washed with water (x2) and brine, and dried over sodium sulfate. Sodium sulfate is removed by filtration and the filtrate is concentrated in vacuo. The residue is purified by column chromatography (silica gel, 30 g; solvent, chloroform ? chloroform:methanol = 70:1) to give 2-(3-chloro-4-methoxybenzylamino)-6-chloronicotic acid (471 mg) as colorless crystals. M.p. 184-185.5 C. MS (m/z): 325 (M-H)-.
With ammonium hydroxide; at 130℃; for 12h;Sealed tube;
A solution of 2,6-dichloropyridine-3-carboxylic acid (3 g, 0.0157 mol) in aqueous ammonia (30 mL) was heated in a sealed tube at 130°C for 12 h. The reaction mixture was concentrated and the resulting crude solid was triturated with diethyl ether to afford the title compound (2.5 g, 93percent). deltaEta (400 MHz, DMSO-de) 8.02 (d, J 8.0 Hz, IH), 7.55 (s, 2H), 6.62 (d, J 8.0 Hz, IH). LCMS: mlz 173 (97.70percent)
90%
Intermediates:; a) 2-Amino-6-chloronicotinic acid (Inter. 2); To 2,6-dichloronicotinic acid (Inter. I)(I equiv) was added liquid ammonia (sufficient to make a 0.6M solution of substrate in ammonia). The suspension was sealed in a pressure vessel which was then heated slowly to 130°C. It was noted that at this temperature a pressure of 18 bar was observed. This temperature and pressure was maintained for a further 16 hours whereupon the mixture was cooled to room temperature. The pressure vessel was opened and the reaction poured into ice cold water (1 reaction volume). The resulting solution was acidified to pH 1-2 using concentrated HCl which caused a precipitate to form. The acidic mixture was allowed to warm to room temperature and was stirred like this for a further 30 minutes. The suspension was then extracted with diethyl ether (3 x 400 ml). The combined organic extracts were then filtered and the filtrate concentrated in vacuo to give a white solid which was dried further over P2O5 to give the title compound (90percent yield and 96percent pure) in suitably pure form to be used without any further purification, m/z (LC-MS5 ESP): 173 [M+H]+ R/T = 3.63 mins
90%
With ammonia; at 130℃; under 13501.4 Torr; for 16h;
To the appropriate amino acid (1 equiv) was added liquid ammonia (sufficient to make a 0.6M solution of substrate in ammonia). The suspension was sealed in a pressure vessel which was then heated slowly to 130 0C. It was noted that at this temperature a pressure of 18 bar was observed. This . temperature and pressure was maintained for a further 16 hours whereupon the mixture was cooled to room temperature. The pressure vessel was opened and the reaction poured into ice cold water (1 reaction volume). The resulting solution was acidified to pH 1-2 using concentrated HCl which caused a precipitate to form. The acidic mixture was allowed to warm to room temperature and was stirred like this for a further 30 min The suspension was then extracted with diethyl ether (3 X 400 ml). The combined organic extracts were then filtered and the filtrate concentrated in vacuo to give a white solid which was dried further over P2O5 to give the title compound (typically 80-90 percent yield and 90 percent+ pure) in suitably pure form to be used without any further purification.2-amino-6-chloronicotinic acid - X=N, Y=C, Z=C: (90 percent yield, 96 percent purity) m/z (LC-MS5 ESP): 173 [M+H]+ R/T = 3.63 min
90%
With hydrogenchloride; In ammonia;
2-Amino-6-chloronicotinic Acid (Inter. 2) To 2,6-dichloronicotinic acid (Inter. 1) (1 equiv) was added liquid ammonia (sufficient to make a 0.6M solution of substrate in ammonia). The suspension was sealed in a pressure vessel which was then heated slowly to 130° C. It was noted that at this temperature a pressure of 18 bar was observed. This temperature and pressure was maintained for a further 16 hours whereupon the mixture was cooled to room temperature. The pressure vessel was opened and the reaction poured into ice cold water (1 reaction volume). The resulting solution was acidified to pH 1-2 using concentrated HCl which caused a precipitate to form. The acidic mixture was allowed to warm to room temperature and was stirred like this for a further 30 minutes. The suspension was then extracted with diethyl ether (3*400 ml). The combined organic extracts were then filtered and the filtrate concentrated in vacuo to give a white solid which was dried further over P2O5 to give the title compound (90percent yield and 96percent pure) in suitably pure form to be used without any further purification. m/z (LC-MS, ESP): 173 [M+H]+R/T=3.63 mins
75%
With ammonia; In water; at 130℃; under 10343.2 Torr; for 24h;
Example 140A 2-Amino-6-chloro-nicotinic Acid A mixture of 2,6-dichloro-nicotonic acid (17.77 g, 92.6 mmol) in concenterated aqueous ammonia (173 mL) at 200 psi, was heated to 130° C. for 24 h. The mixture evaporated and the residue was taken into water (200 mL) and neuteralized with conc HCl then extracted into ether (200 ml). The ether was evaporated off to yield 12 g of product (75percent). MS (DCI/NH3) m/z 173 (M+1)+.
72%
With ammonia;copper(l) iodide; In methanol; at -78 - 125℃; for 39.5h;Sealed tube;
Preparation Example A-1. 2-Amino-6-chloro-nicotinic acid To liquid ammonia (approximately 20mL) was added 2,6-dichloro-nicotinic acid (0.38g, 2mmol) and copper(l) iodide (720mg, 3.8mmol) at -78°C in a sealed tube, and the solution was heated for 25 hours (the temperature of the oil bath was 115°C). The temperature of the oil bath was raised to 125°C, which was further heated for 14 hours 30 minutes. The reaction mixture was allowed to room temperature, and ammonia was evaporated. Methanol was added, insoluble matter was removed by filtration, and the filtrate was concentrated to obtain the title compound (0.25g, 1.45mmol, 72percent) as a solid. 1H-NMR Spectrum (DMSO-d6) delta (ppm): 6.63 (1H, d, J=8.0 Hz), 7.55 (2H, brs), 8.02 (1 H, d, J=8.0 Hz).
72%
With copper(l) iodide; ammonia; at -78 - 125℃; for 39.5h;Product distribution / selectivity;
2,6-Dichloronicotinic acid (0.38 g, 2 mmol) and copper (I) iodide (720 mg, 3.8 mmol) were added to liquid ammonia (approx. 20 mL) in a sealed tube at -78°C, which was heated for 25 hours (oil bath temperature: 115°C). The oil bath temperature was raised to 125°C followed by additionally heating for 14 hours 30 minutes. The reaction mixture was allowed to return to room temperature followed by distilling off the ammonia. The insoluble material that precipitated following addition of methanol was filtered out and the filtrate was concentrated to obtain the title compound (0.25 g, 1.45 mmol, 72percent) as a solid. 1H-NMR spectrum (DMSO-d6) delta (ppm): 6.63 (1 H, d, J=8.0 Hz), 7.55 (2H, brs), 8.02 (1H, d, J=8.0 Hz).
72%
With ammonia;copper(l) iodide; at -78 - 125℃; for 39.5h;Product distribution / selectivity;
To liquid ammonia (approximately 20mL) was added 2,6-dichloro-nicotinic acid (0.38g, 2mmol) and copper(I) iodide (720mg, 3.8mmol) at -78°C in a sealed tube, and the solution was heated for 25 hours (the temperature of the oil bath was 115°C). The temperature of the oil bath was raised to 125°C, which was further heated for 14 hours 30 minutes. The reaction mixture was allowed to room temperature, and ammonia was evaporated. Methanol was added, insoluble matter was removed by filtration, and the filtrate was concentrated to obtain the title compound (0.25g, 1.45mmol, 72percent) as a solid. 1H-NMR Spectrum (DMSO-d6) delta(ppm) : 6.63 (1H, d, J=8.0 Hz), 7.55 (2H, brs), 8.02 (1 H, d, J=8.0 Hz).
67.5%
With ammonia; In water; at 130℃; for 68h;
2.1: 2-Amino-6-chloronicotinic acid 9.6 g (50 mm) of 2,6-dichloronicotinic acid are mixed in a glass autoclave with 60 ml of 32percent aqueous ammonia solution. The reaction medium is immersed in an oil bath preheated to 130° C. and heating is carried out at this temperature for 68 h. The solution is allowed to return to ambient temperature. The reaction medium is concentrated under reduced pressure. The residue is taken up in 200 ml of water and ice and acidified to pH 2 with a concentrated HCl of solution. Ethyl acetate is added and the medium is then stirred for 5 minutes and filtered. The aqueous phase is separated by settling and the organic phase is washed with a saturated in NaCl solution. The organic phase is dried over sodium sulphate and filtered, and the solvent is evaporated. 5.83 g of product (Yd: 67.5percent) are obtained (LC/MS; MH+ 173, tr=6.03 min).
49%
Manufacturing Example 26-1-1 2-Amino-6-chloro-nicotinic acid; A mixture of 2,6-dichloro-nicotinic acid (31 g, 0.14 mol) and 28percent aqueous ammonia solution (200 mL) was stirred in a sealed tube for 10 hours at 135° C. This reaction solution was cooled to room temperature, and the excess ammonia gas was removed under a reduced pressure. Water was added to the residue to a total of 1000 mL, the mixture was cooled to 0° C., and citric acid was added to a pH being about 6. The precipitated solids were filtered out to obtain the title compound (12 g, 49percent).1H-NMR Spectrum (DMSO-d6) delta (ppm); 6.63 (1H, d, J=8.1 Hz), 7.55 (2H, brs), 8.02 (1H, d, J=8.1 Hz).
49%
A mixture of 2,6-dichloro-nicotinic acid (31 g, 0.14 mol) and 28percent aqueous ammonia solution (200 mL) was stirred in a sealed tube for 10 hours at 135° C. This reaction solution was cooled to room temperature, and the excess ammonia gas was removed under a reduced pressure. Water was added to the residue to a total of 1000 mL, the mixture was cooled to 0° C., and citric acid was added to a pH being about 6. The precipitated solids were filtered out to obtain the title compound (12 g, 49percent). 1H-NMR Spectrum (DMSO-d6) delta (ppm): 6.63 (1H, d, J=8.1 Hz), 7.55 (2H, brs), 8.02 (1H, d, J=8.1 Hz).
34%
With ammonium hydroxide; at 130 - 160℃; for 24 - 48h;
Example 2 2-Amino-6-chloro-nicotinic acid A solution of 2,6-dichloronicotinic acid (10 g, 46.9 mmol, Aldrich 90percent) was dissolved in concentrated ammonium hydroxide (100 mL, 29.4percent, Fisher) and heated at 130-160° C. in a pressure bottle for 1-2 days before solvent was removed in vacuo. The residue was treated with water and the pH was lowered to ~8 with concentrated hydrochloric acid. The resulting mixture was extracted with ethyl acetate and the combined organic extracts were washed with brine, dried, concentrated and the crude product was recrystallized from ethyl acetate to give 2-Amino-6-chloro-nicotinic acid as white crystalline (2.74g, 34 percent yield). HRMS, observed: 172.0042, Calcd for M+: 172.0040
4.5%
Preparation Example A-4. 2-Amino-6-chloronicotinic acid Tris(2-(2-methoxyethoxy)ethyl)amine (3.0mL, 9.4mmol) was added to a mixture of 2,6-dichloronicotinic acid (40g (90percentpurity), 0.19 mol), acetamide (80g, 1.4mol), potassium carbonate (78g, 0.56mol), copper(I) chloride (0.93g, 9.4mmol) and xylene (80mL), which was stirred overnight at 145°C. After cooling, copper(I) chloride (0.46g, 4.6mmol) was added to the reaction solution, which was stirred overnight at 145°C. After cooling the reaction solution to 105°C, water (1 00mL) was added, the solution was stirred for 1 hour at the same temperature, and cooled down to room temperature. 5N hydrochloric acid (150mL) was added, the solution was neutralized with a citric acid aqueous solution, then, ethyl acetate was added, and the solution was filtered through Celite pad. The organic layer was washed with brine, then, the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate), recrystallization by the ethyl acetate-hexane was carried out to obtain the title compound (1.4g, 8.3mmol, 4.5percent) as white crystal. 1H-NMR Spectrum (DMSO-d6) delta (ppm): 6.61 (1H, d, J=8.1 Hz), 7.53 (2H, brs), 8.01 (1 H, d, J=8.1 Hz).
4.5%
Tris(2-(2-methoxyethoxy)ethyl)amine (3.0mL, 9.4mmol) was added to a mixture of 2,6-dichloronicotinic acid (40g (90percentpurity), 0.19 mol), acetamide (80g, 1.4mol), potassium carbonate (78g, 0.56mol), copper(I) chloride (0.93g, 9.4mmol) and xylene (80mL), which was stirred overnight at 145°C. After cooling, copper(I) chloride (0.46g, 4.6mmol) was added to the reaction solution, which was stirred overnight at 145°C. After cooling the reaction solution to 105°C, water (100mL) was added, the solution was stirred for 1 hour at the same temperature, and cooled down to room temperature. 5N hydrochloric acid (150mL) was added, the solution was neutralized with a citric acid aqueous solution, then, ethyl acetate was added, and the solution was filtered through Celite pad. The organic layer was washed with brine, then, the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate), recrystallization by the ethyl acetate-hexane was carried out to obtain the title compound (1.4g, 8.3mmol, 4.5percent) as white crystal. 1H-NMR Spectrum (DMSO-d6) delta(ppm) : 6.61 (1H, d, J=8.1 Hz), 7.53 (2H, brs), 8.01 (1H, d, J=8.1 Hz).
Manufacturing Example 11-1: 2-Amino-6-chloro-nicotinic acid To a mixture of 2,6-dichloronicotinic acid (36 g), acetamide (80 g), potassium carbonate (78 g), copper(I) chloride (0.93 g), and xylene (80 mL) was added tris(2-(2-methoxyethoxy)ethyl)amine (3.0 mL), which was stirred overnight at 145°C. The reaction mixture was cooled to room temperature, after which copper(I) chloride (0.46 g) was added to the reaction mixture at the same temperature, and then stirred overnight at 145°C. The reaction mixture was cooled to 105°C, after which water (100 mL) was added at the same temperature, and then stirred for 1 hour at the same temperature. The reaction mixture was cooled to room temperature, 5N hydrochloric acid (150 mL) was added thereto at the same temperature, and then the reaction mixture was neutralized with an aqueous citric acid solution. Ethyl acetate was added to the reaction mixture, which was filtered through Celite. The organic layer was washed with saturated brine, after which the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate), after which recrystallization was performed from an ethyl acetate-hexane system to obtain the titled compound (1.4 g). 1H-NMR spectrum (DMSO-d6) delta (ppm): 6.61 (1H, d, J = 8.1 Hz), 7.53 (2H, brs), 8.01 (1 H, d, J = 8.1 Hz).
Intermediate 62; 2-Amino-6-chloronicotinic acidA solution of 2,6-dichloronicotinic acid (10 g, 52.08 mmol) and (2,4- dimethoxyphenyl)methanamine (15.65 ml, 104.17 mmol) in pyridine (21.06 ml, 260.42 mmol) was heated at 100 0C overnight. The reaction mixture was concentrated under vacuum and partitioned between water and DCM. Evaporation of the organic layer provided a dark brown residue, which was dissolved in TFA (8.78 ml, 113.93 mmol) and the resulting mixture was stirred for 30 minutes. The precipitate formed was discarded via filtration and concentration of the filtrate under reduced pressure gave a residue. This residue was dissolved in HCl (IN, 200 mL) and the aqueous solution was washed with Et2O and evaporated under reduced pressure to give a solid. This solid was washed with DCM/Hexanes, dried in a vacuum oven overnight and characterized as the title product (6.8g) LCMS: 172.2 [M+H]+.
With ammonia; In water; for 5h;Autoclave;
Reference production example 74 5.0 g of 2,6-dichloronicotinic acid and 40 ml of 28percent aqueous ammonia were added to an autoclave, and they were then stirred under pressure for 5 hours. Thereafter, concentrated hydrochloric acid was added to the reaction mixture, so that the pH was adjusted to be pH 1. The resultant was extracted with ethyl acetate, and it was washed with a saturated saline solution and was then dried over anhydrous sodium sulfate. Thereafter, the resultant was concentrated under reduced pressure, so as to obtain 4.2 g of 2-amino-6-chloronicotinic acid.2-amino-6-chloronicotinic acid [Show Image] [Show Image] 1H-NMR (DMSO-D6) delta: 6.63 (1H, d, J = 8.2 Hz), 7.55 (2H, br s), 8.03 (1H, d, J = 8.2 Hz).
With sulfuric acid; for 40h;Reflux; Inert atmosphere;
Esterification of 2,6-dichloronicotinic acid (25.5 g, 0.1328 mmol) in EtOH (200 proof, 200 mL) catalyzed with 96% H2SO4 (1.7 g) at refluxing temperature for 40 h under N2 gave the desired ethyl 2,6-dichloronicotinate as grey solid (24.89 g, 0.1131 mmol, yield 85.2%) after a normal work-up. (0723) 1H NMR (300 MHz, DMSO-d6): delta 8.30 (d, J=8.1 Hz, 1H), 7.71 (d, J=8.1 Hz, 1H), 4.33 (q, J=7.2 Hz, 2H) and 1.30 (t, J=7.2 Hz, 3H) ppm.
67%
With sulfuric acid; at 85℃; for 72h;
A mixture 2,6-dichloronicotinic acid (5.0 g, 26.2 mmol) and concentrated H2SO4 (1 ml.) in EtOH (30 ml.) is heated at 85 0C for 3 days. Upon cooling to room temperature, the reaction mixture is diluted with dichloromethane (200 ml_), washed with saturated NaHCO3 solution (2x100 ml.) and brine (50 ml_). The organic layer is dried, concentrated and the crude residue is purified by flash column with EtOAC/heptanes (2/8) to afford the desired product as a white solid (3.8 g, 67 %). LC-MS ( (ESI) m/z 220.0 (M+1 ). 1H NMR (400 MHz, CD2CI2) delta ppm 7.38 (s, 1 H), 7.36 (s, 1 H), 4.39 (q, J=7.1 Hz, 2 H), 1.39 (t, J=IA Hz, 3 H).
65%
With sulfuric acid; for 16h;Reflux;
Preparation 30: ethyl 2-ethoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)nicotinate; Step 1 : ethyl 2,6-dichloronjcotjnate; To a solution of 2,6-dichloronicotinic acid (10 g, 52.08 mmol) in ethanol (50 mL) was added concentrated sulfuric acid (1.0 mL) and the mixture was heated to refluxed for 16 h. The reaction was concentrated. The solid residue was diluted with ethyl acetate (50 mL) and washed with water (50 mL), 1M aqueous sodium carbonate (50 mL) and saturated aqueous sodium chloride. The organic layer was dried over magnesium sulfate, filtered, and concentrated to give the title compound (7.38 g, 65%) as a light orange solid. 1 H NMR (500 MHz, DMSO-Cf6) delta ppm 1.32 (t, J=7.07 Hz, 3 H) 4.35 (q, J=7.24 Hz, 2 H) 7.72 (d, J=8.05 Hz, 1 H) 8.31 (d, J=8.05 Hz, 1 H). Step 2: ethyl 6-chloiO-2-ethoxynicotinate
Intermediate 21; Preparation of 2-chloro-6-(cyclopropylethynyl)nicotinic acid; Ethyl 2,6-dichloropyridine-3-carboxylate 2,6-dichloropyridine-3-carboxylic acid (2.0 g, 10.42 mmol) was placed in 100 mL EtOH, 2 mL conc. H2SO4 was added and the mixture was refluxed for 18 h. The reaction mixture was cooled and the pH adjusted to 5 with satd. aqueous NaHCO3 and then extracted with EtOAc. The organic layer was separated and dried (Na2SO4). Removal of solvent in vacuo furnished 2.1 g of the ethyl ester which was used in the next step without further purification. m/z=220.6 (M+1).
Sulfuric acid was added to an ethanol solution of 2,6-dichloronicotinic acid and heated under reflux for 24 hours. After adding saturated sodium bicarbonate aqueous solution thereto, ethanol was evaporated under a reduced pressure. The residue was extracted with ethyl acetate and the organic layer was concentrated under a reduced pressure. Potassium carbonate was added to a DMF solution of the obtained ethyl 2,6-dichloronicotinate, and cyclopentylamine was added thereto, followed by stirring at 0C for 1 hour and at room temperature for 6 hours. By post-treating the reaction liquid, ethyl 6-chloro-2-[(cyclopropylmethyl)amino]nicotinate was obtained.
To a solution of 2,6-dichloronicotinic acid (37g) in 200 mL ethanol was added 4 mL of con. H2SO4 and the mixture was refluxed overnight. The ethanol was evaporated off and the EPO <DP n="68"/>residue was dissolved in ethyl acetate, washed with water, 10% sodium carbonate solution, brine, dried with sodium sulfate, filtered and evaporated to yield the desired product (37.29g) as white solid (Rf : 1.553min., Condition B, M+H+ : 220).
EXAMPLE 25 2-Chloro-7-(4-methoxy-phenyl)-[1,6]naphthyridin-5-1 (Method F) Elemental sodium (173 mg, 7.5 mmol) was added to 40 mL of absolute EtOH stirring under nitrogen. After all of the sodium reacted, 4-methoxyacetophenone (1.44 g, 7.5 mmol) was added, and the reaction stirred an additional 15 minutes. 2,6-Dichloronicotinic acid (1 g, 5.2 mmol) and copper acetate (80 mg, 0.65 mmol) was added and the reaction was stirred at reflux for 16 hours. The reaction was cooled to room temperature and quenched with 1 mL concentrated acetic acid. The mixture was concentrated to a solid, and redissolved in EtOAc. A small portion of fine inorganic precipitate was filtered off. The organic layer was extracted with 3*100 mL 1N NaOH. This was acidified with 1 N HCl to a pH of ~4. A precipitate formed and was collected by vacuum filtration, yielding 6-chloro-2-[2-(4-methoxyphenyl)-2-oxo-ethyl]-nicotinic acid (1 g, 63%) as a tan solid.
Dissolve 2,6-dichloronicotinic acid (1000 mg, 5.21 mmol) in anhydrous tetrahydrofuran (5 niL). Cool to 0 0C. Add borane-tetrahydrofuran complex (7.82 mL5 7.82 mmol, 1.0 M in tetrahydrofuran) slowly. Stir the mixture at room temperature overnight. Add water (1 niL) and potassium carbonate, stir for 2 hours, filter and concentrate to give a residue. Chromatograph the residue on silica gel eluting with 10:90 to 20:80 ethyl acetate:hexanes to give (2,6-dichloropyridin-3-yl)-methanol (876 mg, 94%). 1H NMR (400 MHz5 MeOH-d4) delta 7.96 (d, IH, J = 8.0 Hz), 7.45 (d, IH, J = 8.0 Hz), 4.64 (s, 2H).
80%
With sodium tetrahydroborate; boron trifluoride diethyl etherate; In tetrahydrofuran; at 0 - 20℃; for 10.0h;
To a solution of 2,6-dichloronicotinic acid (1 g, 5.2 mmol) in THF (10 mL) was added NaBH4 (591 mg, 15.6 mmol) at 0C. The mixture was stirred for 30 min and then BF3.OEt2 (2.2g, 15.6 mmol) was added drop wise at 0C. After addition was complete, the mixture was stirred at room temperature for 10 hr, until the reaction was completed. The reaction mixture was quenched by the addition of saturated NH4C1 solution (50 mL) and extracted with ethyl acetate (3x30 mL). The combined organic layers were washed with brine (30 mL), dried over Na2S04 and concentrated to give the desired product as a white solid which was used in next step without further purification. (820 mg, Yield 80%).
Synthesis of 2,6-dichloropyridin-3-yl)methanolTo a solution of the compound 2,6-dichloronicotinic acid (0.5g, 2.6mmol) in tetrahydrofuran (10ml) at 00C was added sodium borohydride (0.29g, 7.8mmol) portion wise and stirred the reaction mixture at room temperature for 30 minutes. The resulting reaction mixture was again cooled to 0C followed by the addition of etheral solution of boron trifmoride (1.1 ml, 7.8 mmole) dropwise and stirred the mixture at room temperature for overnight. The reaction mixture was quenched with aqueous sodium hydroxide (IN) and the solvent was evaporated under reduced pressure to furnish the title compound. The residue thus obtained was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to furnish the title compound. Yield: 0.44g.
In tetrahydrofuran; methanol;
PREPARATION EXAMPLE 23-1 Lithium aluminum hydride (1.78 g) was suspended in dry tetrahydrofuran (10 ml), and 2,6-dichloronicotinic acid was added under ice-cooling at an inside temperature of not more than 10 C. The mixture was stirred under ice-cooling for 1 hr and 28% aqueous amonia was added dropwise to the reaction mixture until foams disappeared. Methanol was added and the mixture was stirred at room temperature for 3 hr, and filtered through celite. The mother liquor was concentrated and the residue was applied to flash silica gel column chromatography (silica gel, 200 ml) and eluted with chloroform:ethyl acetate=8:1 to give 2,6-dichloro-3-hydroxymethylpyridine as colorless crystals (2.89 g). 1H-NMR (CDCl3): 2.11 (1H, t, J=7 Hz), 4.77 (2H, d, J=7 Hz), 7.32 (1H, d, J=8 Hz), 7.87 (1H, d, J=8 Hz). MASS (ESI): m/z 176 (M-1).
(a) 19.1 g (0.1 mole) of 2,6-dichloronicotinic acid [Guthzeit and Laska, J. pr. Ch. 58 [2], 425 (1898)] are suspended in 250 ml of methanol and, while stirring and cooling with ice, hydrogen chloride gas is introduced until the mixture is saturated. The reaction mixture is allowed to stand for 48 hours at room temperature and subsequently heated for 3 hours to reflux temperature. It is then evaporated to dryness in a high vacuum at 40 C and the residue is dried in a high vacuum at 40 C. The brown crystalline product is recrystallized from ether-pentane to yield methyl 2,6-dichloronicotinate with a melting point of 53-54 C.
With thionyl chloride; In methanol; dichloromethane; water;
[I] 33 g of 2,6-dichloronicotinic acid and l00 ml of thionyl chloride were mixed and reacted in the reflux condition for about 3 hours. After the completion of the reaction, excessive thionyl chloride was distilled off at reduced pressure, and 500 ml of methylene chloride was added thereto. Anhydrous methanol was dropped in the mixture in the range of room temperature to 40C. After dropping, the resultant mixture was reacted in the reflux condition for about an hour. After the completion of the reaction, the reacted solution was added to 500 ml of water and separated with methylene chloride. After the residue was washed with water and dried with anhydrous sodium sulfate, methylene chloride was distilled off at reduced pressure. The residue was purified by a silica gel column chromatography to prepare 27 g of methyl 2,6-dichloronicotinate having a melting point of 45.5 to 48.0C.
With sulfuric acid; In ethanol; at 150℃; for 0.25h;Microwave irradiation;
(a) Ethyl2,6-dichloronicotinate 2,6-Dichloronicitinic acid (3.84 g, 20 mmol) was dissolved in EtOH (16 mL), sulfuric acid (1.96 g, 20 mmol) and triethyl ortoformate (4.45 g, 30 mmol) were added. The reaction mixture was heated in a microwave oven (single node heating) at 150 C. for 15 min. The mixture was extracted with EtOAc (3*20 mL) from 10% Na2CO3 (20 mL). The combined organic phases were extracted with water (50 mL), dried (Na2SO4), filtered and concentrated in vacuo to give ethyl2,6-dichloronicotinate. The crude material was used in the next step without further purification.
sulfuric acid; at 150℃; for 0.25h;Microwave irradiation;
Example 104Ethyl 2-[(2-acetamidoethyl)thio]-5-chloro-6-(4-[(4- chlorobenzytysulfonyljcarbamoytypiperidin-l-ytymcotmate30 <n="186"/>(a) Ethyl 2,6-dichloronicotinate2,6-Dichloronicitinic acid (3.84 g, 20 mmol) was dissolved in EtOH (16 mL), sulfuric acid (1.96 g, 20 mmol) and triethyl ortoformate (4.45 g, 30 mmol) were added. The reaction mixture was heated in a microwave owen (single node heating) at 150 0C for 15 min. The mixture was extracted with EtOAc (3x20 mL) from 10% Na2CO3 (20 mL). The combined organic phases were extracted with water (50 mL), dried (Na2SO4), filtered and concentrated in vacuo to give ethyl 2,6-dichloronicotinate. The crude material was used in the next step without further purification.
Step a 2-chloro-6-oxo-1 ,6-diotahydropyriotadiotane-3-carboxyliotac aciotad; A 500-mL round-bottom flask was charged with 2,6-diotachloroniotacotiotaniotac acid (25 0 g 130 mmol), NaOH solution (325 ml_, 2N) and the solution was refluxed at 1290C for 4 hours The reaction mixture was cooled to room temperature and acidified with a 6N aq HCI solution The resulting precipitate was filtered and dried under reduced pressure yielding to the desired product (19 87g, 88%)
48%
2- Chloro--oxo-l ^-dihydro-pyridine-S-carboxylic acid was prepared from dichloronicotinic acid (3.00 g, 15.6 mmol, Aldrich) according to the procedure described in U.S. Patent No. 3,682,932 to yield 1.31 g (48%) of the desired product.
4 g
2,6-Dichloronicotinic acid (6 g) was placed in a 250 mL round bottom flask, and sodium hydroxide solution (80 mL) was added.The mixture was heated to 120 C for 4 hours. After the reaction was completed, it was cooled to room temperature, acidified with 6N hydrochloric acid, and the solid was precipitated, filtered, and dried to give the title compound (4 g).
Example 19 Step i'; Preparation of 2,6-dichloro-7V-[5-(3,5-difluorobenzyl)-lH-indazol-3-yl]pyridine-3- carboxamide 2,6-dichloropyridine-3-carboxylic acid (480 mg, 2.5 mmol) and thionyl chloride (0.28 mL, 3.75 mmol) were heated in toluene dry (120 mL) and a few drops of dry DMF at 900C for 2 hours Volatiles were evaporated and the residue dissolved in dry pyridine <n="141"/>(15 mL) at 00C under nitrogen atmosphere. A solution of 5-(3,5-difluoro-benzyl)-lH- indazol-3-ylamine (518 mg, 2 mmol) in dry pyridine (7 mL) was added to the cooled reaction mixture. The resulting mixture was allowed to react overnight at room temperature, then the solvent removed under reduced pressure. The residue was taken- up with EtOAc and washed with acqueous NaHCOs sat.sol., water and brine. Organic phase was dried over sodium sulfate and evaporated to dryness. The crude was purified by flash chromatography on silica gel using DCM/EtOH 100:4 as the eluant, affording 300 mg of the title compound. IH-NMR (400 MHz), delta (ppm, DMSO-J6): 4.09 (s, 2H) 6.93 - 7.01 (m, 2H) 7.04 (tt, J=9.39, 2.32 Hz, IH) 7.29 (dd, J=8.54, 1.34 Hz, IH) 7.45 (d, J=8.54 Hz, IH) 7.70 (s, IH) 7.75 (d, J=8.05 Hz, IH) 8.24 (d, J=7.93 Hz, IH) 11.04 (s, IH) 12.80 (s, IH)
With potassium carbonate; In acetone; at 20℃; for 16h;
[Example 23] Synthesis of 2,6-dichloro-nicotinic acid methyl ester To the mixture of 2,6-dichloro-nicotinic acid (4.7 g, 22 mmol) and acetone (22 ml), potassium carbonate (4.6 g, 33 mmol) and dimethylsulfate (2.4 ml, 24 mmol) were sequentially added at room temperature, and the obtained reaction mixture was stirred at room temperature for 16 hours. Impurities were removed by filtration, and the solvents were evaporated under reduced pressure from the filtrate. Dichloromethane was added to the obtained residue, followed by washing with a saturated sodium bicarbonate aqueous solution. The obtained organic layer was dried using anhydrous sodium sulfate, and the solvents were evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography (heptane: ethyl acetate = 10:1 1 to 1:1), thereby obtaining the entitled compound (4.0 g, 87%). 1H-NMR Spectrum (CDCl3) delta(ppm): 3.96(3H, s), 7.36(1H, d, J=8.0Hz), 8.16(1H, d, J=8.0Hz)
Stage #1: 2,6-dichloropyridine-3-carboxylic acid With thionyl chloride at 100℃; for 2h;
Stage #2: 4-(ethoxycarbonyl)phenylzinc iodide In tetrahydrofuran at 20℃; for 3h;
Stage #3: With ammonium chloride In tetrahydrofuran; water
Example 19: Ethyl 4- (6-5-r (ethvlamino) carbonvll-2-methvlphenvl-1H-pyrazolor3, 4- blpvridin-3-vl) benzoate; 2, 6-Dichloronicotinic acid (3.4g, Aldrich) in thionyl chloride (15ml) was heated at 100°C for 2h. The excess thionyl chloride was removed under vacuum, the residual oil was dissolved in dry THF (36ml) and tetrakis (triphenylphosphine) palladium (90mg) was added to the solution. An aliquot (2ml) of the resulting mixture was treated with (4- ethoxycarbonyl) phenylzinc i odide, 0.5M i n T HF, 2. 3ml, A Idrich) a nd s tirred for 3 h a t room temperature. The reaction mixture was treated with aqueous ammonium chloride, extracted with DCM and the organic layer was filtered through a silica column (2g). The solvent was evaporated and the residues was dissolved in ethyl acetate/methanol and passed through an aminopropyl SPE cartridge (1g) washing with further ethyl acetate/methanol. The combined filtrate and washings were reduced to dryness under a stream of nitrogen to give the crude ketone intermediate which was used without further purification. The ketone was mixed with N-ethyl-4-methyl-3- (4, 4,5, 5-tetramethyl-1, 3,2- dioxaborolan-2-yl) benzamide (Intermediate 28,20. 6mg), tetrakis (triphenylphosphine) palladium (-1 mg), aqueous sodium hydrogen carbonate (1 M, 0. 21ml) and isopropanol (1ml) then heated at 90°C under nitrogen for 1.5h. The reaction was allowed to cool, diluted with ethyl acetate, and the solution was filtered through a silica column (0.5g). The filtrate was reduced to dryness under a stream of nitrogen and the residue was used without further purification. The crude intermediate was dissolved in in THF (1 ml), hydrazine hydrate (0. 1 ml) was added and the solution was heated at 60°C for 4h. The reaction mixture was allowed to cool, partitioned between chloroform and water and the organic phase was applied to an SCX SPE cartridge (1g). The cartridge was eluted with methanol followed by a solution of ammonia (0.88) in methanol (10%). The solvent was evaporated and the crude residue was purified on a silica column (1g) eluting sequentially with cyclohexane/ether, ether, ethyl acetate and methanol. The resultant product was triturated with ether to give the title compound as a cream solid. LC-MS: Rt 3.42min, MH+ 429
Stage #1: 2,6-dichloropyridine-3-carboxylic acid With thionyl chloride for 2h; Heating / reflux;
Stage #2: 4-methoxyphenylzinc iodide In tetrahydrofuran at 20℃; for 0.333333h;
Stage #3: With ammonium chloride In diethyl ether; water
Intermediate 15: (2. 6-Dichloro-3-pyridinvl) [4- (methyloxv) Phenyl] methanone; 2, 6-Dichloronicotinic acid (2g) in thionyl chloride (5ml) was heated at reflux for 2h, then left to cool to room temperature. The excess thionyl chloride was evaporated under vacuum and the resulting yellow oil was dissolved in anhydrous THF (10ml). Tetrakis (triphenylphosphine) palladium (120mg) and 4-methoxyphenylzinc iodide (0.5M, 17ml, Aldrich) were added to the solution which was stirred at room temperature for 20min. The reaction mixture was partitioned between ether and aquous saturated ammonium solution and the organic phase was washed with ammonium chloride and brine. The solution was dried through a hydrophobic filter tube then concentrated under vacuum to give the title compound as an orange oil. NMR: [8H d6-DMSO] 8.09 (1 H, d), 7.77 (3H, m), 7.09 (2H, d), 3.87 (3H, s)
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 100℃; for 4h;
A mixture of 1.0 g of 2,6-dichloronicotinic acid, 1.3 g of WSC, 1.3 g of <strong>[107622-80-0]4-phenoxybenzylamine</strong> and 5 ml of DMF was stirred at 100C for 4 hours. After, water was added to the reaction mixture, it was then extracted with ethyl acetate. The organic layer was successively washed with water and a saturated saline solution, and it was then dried over magnesium sulfate, followed by concentration under reduced pressure. The obtained residue was subjected to silica gel column chromatography, so as to obtain 0.37 g of N-(4-phenoxyphenyl)methyl-2,6-dichloronicotinic acid amide. [Show Image] 1H-NMR (CDCl3) delta: 4.64 (2H, d, J = 5.8 Hz), 6.79 (1H, br s), 6.98-7.03 (4H, m), 7.10-7.14 (1H, m), 7.31-7.37 (4H, m), 7.39 (1H, d, J = 8.0 Hz), 8.15 (1H, d, J = 8.0 Hz).
EXAMPLE 1; (R)-tert-Butyl l-(5-carbamoyl-6-(4-(morpholine-4-carbonyl)phenylamino)pyridin-2- yl)piperidin-3 -ylcarbamateA. 6-Chloro-2-(4-(morpholine-4-carbonyl)phenylamino)nicotinic acid[00157] To a suspension of <strong>[51207-86-4](4-aminophenyl)(morpholino)methanone</strong> (9.02 g, 43.8 mmol) in THF (20 mL) was added lithium bis(trimethylsilyl)amide (66.7 mL, 66.7 mmol, IM solution in THF) dropwise over 15 min. at -78C under nitrogen. The reaction mixture was stirred for one hour at -78C. To the resulting brown solution was added a solution of 2,6-dichloronicotinic acid (4 g, 20.83 mmol) in THF (12 ml) dropwise at -78C. The reaction mixture was removed from the dry ice bath and stirred overnight at rt. The resulting dark solids were washed with a small amount of THF to remove <strong>[51207-86-4](4-aminophenyl)(morpholino)methanone</strong> on the surface, followed by the addition of water and 18 ml of 6N HCl (pH of 2). The solids were filtered and the resulting pink filter cake was washed with water (~1L) until the filter cake was white powder and the filtrate was colorless. The filter cake was transferred to a flask with MeOH and CH2Cl2, and dried on a rotary evaporator with MeOH to give 6.60 g of 6- chloro-2-(4-(morpholine-4-carbonyl)phenylamino)nicotinic acid as a white solid. LCMS: (M+H)+ = 362.02, 364.03 (Cl pattern).
2,6-Dichloronicotinic acid (1 .20 g, 6.25 mmol), 3-(te/t-butoxycarbonyl)benzene boronic acid (2.08 g, 9.10 mmol), potassium carbonate (2.60 g, 18.8 mmol), tetrakis(triphenylphosphine)palladium (0.72 g, 0.62 mmol), degassed 1 ,2- dimethoxyethane (30 ml_) and water (0.5 ml_) were combined under an argon atmosphere and the mixture heated at 90 C overnight. The reaction mixture was then cooled to room temperature, diluted with water (100 ml_) and extracted with ethyl acetate (2 x 150 ml_). The aqueous layer was acidified to pH 3-4 using 2N HCI solution and extracted with ethyl acetate (2 x 200 ml_). The combined organic portions were dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (silica gel, 20% methanol/dichloromethane) and the product containing fractions concentrated to give a solid, which was triturated with 2:1 heptane/ethyl acetate to give pure 6-(3-(tert- butoxycarbonyl)phenyl)-2-chloronicotinic acid (1 .4 g, 67 %) as an off-white foam. 1H NMR (400 MHz, CD3OD) delta ppm 8.64 (s, 1 H), 8.34 (d, 1 H), 8.29 (d, 1 H), 8.04 (d, 1 H), 7.95 (d, 1 H), 7.59 (t, 1 H), 1 .60 (s, 9H); m/z 334 [M+H].
With potassium tert-butylate; In methanol; at 80℃; for 24h;Inert atmosphere;
Synthesis of 2-chloro-6-methoxynicotinic acid (2) (0685) To a suspension of 2,6-dichloronicotinic acid (1, 20.0 g, 105.2 mmol) in methanol (250 mL) under nitrogen, potassium tert-butoxide (35.0 g, 316.0 mol) was added at room temperature. The reaction mixture was allowed to stir at 80 C. for 24 h. After completion, solvent was removed under reduced pressure and crude was treated with 6 M hydrogen chloride. Precipitated solid was filtered and dried under vacuum to afford 2-chloro-6-methoxynicotinic acid (2) as white solid. Yield: 20.0 g, crude; MS (ESI) m/z 188.06[M+1]+.
Step A: 2,6-Dichloronicotinic acid (30g, 156.3 mmol) was dissolved in methanol (300 mL) at room temperature. Sodium ethoxide (5.4 M in MeOH, 781.3 mmol, 145 mL) was added slowly at the same temperature. The reaction mixture was stirred at 70 C for 5 hours and cooled to room temperature. The precipitated solid from reaction mixture was filtered off and the mother liquor was concentrated under vacuum. All solid collected was dissolved in water (300 mL) and the solution was acidified with 6N HC1 solution to pH 6 at 0 C. The aqueous layer was extracted with ethyl acetate five times. The combined organic layers were dried over MgS04. The organic layer was filtered off and concentrated to give a 1 : 1 mixture of 6-chloro-2- methoxynicotinic acid and 2-chloro-6-methoxynicotinic acid (20.22g, 69%). MS m/z 188 [M+H]+.
Step A: 2,6-Dichloronicotinic acid (30g, 156.3 mmol) was dissolved in methanol (300 mL) at room temperature. Sodium ethoxide (5.4 M in MeOH, 781.3 mmol, 145 mL) was added slowly at the same temperature. The reaction mixture was stirred at 70 C for 5 hours and cooled to room temperature. The precipitated solid from reaction mixture was filtered off and the mother liquor was concentrated under vacuum. All solid collected was dissolved in water (300 mL) and the solution was acidified with 6N HC1 solution to pH 6 at 0 C. The aqueous layer was extracted with ethyl acetate five times. The combined organic layers were dried over MgS04. The organic layer was filtered off and concentrated to give a 1 : 1 mixture of 6-chloro-2- methoxynicotinic acid and 2-chloro-6-methoxynicotinic acid (20.22g, 69%). MS m/z 188 [M+H]+. Step B: The mixture obtained above (11.48g, 61.2 mmol) was dissolved in THF (50 mL) and cooled to 0 C. Borane-THF complex (1.0 M in THF, 200 mL) was added slowly at 0 C. The reaction mixture was stirred at room temperature for 1 hour and cooled back to 0 C. Aqueous 6N HC1 (15 mL) was added very slowly at 0 C. The aqueous layer was neutralized with a saturated NaHC03 solution to pH 7. Dichloromethane was added and the aqueous layer was extracted. The combined organic layers were dried over K2C03, filtered and concentrated under vacuum to yield 10.6 g of corresponding alcohols. The residue can be used directly in the oxidation step or purified on silica gel with the mixture of ethyl acetate and hexane. TLC Rf 0.31 (30% EtOAc in hexane). MS m/z 174 [M+H]+.
Step A: 2,6-Dichloronicotinic acid (30g, 156.3 mmol) was dissolved in methanol (300 mL) at room temperature. Sodium ethoxide (5.4 M in MeOH, 781.3 mmol, 145 mL) was added slowly at the same temperature. The reaction mixture was stirred at 70 C for 5 hours and cooled to room temperature. The precipitated solid from reaction mixture was filtered off and the mother liquor was concentrated under vacuum. All solid collected was dissolved in water (300 mL) and the solution was acidified with 6N HC1 solution to pH 6 at 0 C. The aqueous layer was extracted with ethyl acetate five times. The combined organic layers were dried over MgS04. The organic layer was filtered off and concentrated to give a 1 : 1 mixture of 6-chloro-2- methoxynicotinic acid and 2-chloro-6-methoxynicotinic acid (20.22g, 69%). MS m/z 188 [M+H]+. Step B: The mixture obtained above (11.48g, 61.2 mmol) was dissolved in THF (50 mL) and cooled to 0 C. Borane-THF complex (1.0 M in THF, 200 mL) was added slowly at 0 C. The reaction mixture was stirred at room temperature for 1 hour and cooled back to 0 C. Aqueous 6N HC1 (15 mL) was added very slowly at 0 C. The aqueous layer was neutralized with a saturated NaHC03 solution to pH 7. Dichloromethane was added and the aqueous layer was extracted. The combined organic layers were dried over K2C03, filtered and concentrated under vacuum to yield 10.6 g of corresponding alcohols. The residue can be used directly in the oxidation step or purified on silica gel with the mixture of ethyl acetate and hexane. TLC Rf 0.31 (30% EtOAc in hexane). MS m/z 174 [M+H]+. The isolated alcohols (3.9g, 22.7 mmol) were dissolved in dichloromethane (110 mL) and cooled to 0 C. Dess-Martin Periodinane (11.6 g, 27.3 mmol) was added portionwise. The reaction mixture was stirred at 0 C for 30 min. The reaction was quenched with a saturated NaHC03 solution and extracted with dichloromethane. The combined organic layers were dried over K2C03, filtered and concentrated to give a mixture of 3.53 g of 6-chloro-2- methoxynicotinaldehyde and 2-chloro-6-methoxynicotinaldehyde (91%).
N-((6-aminopyridin-2-yl)sulfonyl)-2,6-dichloronicotinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
16%
2,6-dichloro-pyridine-3-carboxylic acid (20.2 g, 105 mmol) was dissolved in N,N-dimethylformamide (200 mL) and stirred under nitrogen and CDI (25.5 g, 158 mmol) was added in one portion. The reaction was warmed to 65 C. and heated for 1 h. In a separate vessel, <strong>[75903-58-1]6-aminopyridine-2-sulfonamide</strong> (18.2 g, 105 mmol) was dissolved in N,N-dimethylformamide (100 mL) under nitrogen and NaH (4.40 g, 60%, 110 mmol) was added in portions to mitigate gas evolution and the reaction was stirred for 1 h. The two reactions were combined in one portion at 65 C. The reaction was stirred for 30 min and evaporated to remove most of N,N-dimethylformamide. The residue was poured over ice and made acidic (pH=3) by the addition of 6M HCl. Solid was collected by filtration and washed with water (100 mL) and methanol (30 mL) and combined to the following crude material after dried. The filtrate and washing were combined and extracted with ethyl acetate (3×500 mL). The organics were washed once with brine (500 mL), dried over sodium sulfate and evaporated. The crude material was suspended in a mixture solvent of dichloromethane/ethyl acetate/methanol (30/30/30 mL), the suspension sonicated for 30 min, and filtered. The solid washed with ether (2×150 mL) and dried to give 19.8 g white solid (54%). The filtrate was further concentrated to afford 6.0 g (16%) of product. LCMS: 347 [M+11]+; 1H NMR (DMSO-d6, 250 MHz): 8.11 (d, J=7.5 Hz, 1H), 7.80-7.55 (m, 2H), 7.19 (d, J=7.2 Hz, 1H), 6.75 (d, J=8.5 Hz, 1H), 6.71 (s, 2H) ppm
With lithium hydroxide monohydrate; In tetrahydrofuran; at 20℃; for 12h;
To a stirred solution of 292 2,6-dichloronicotinic acid (20.0 g, 104.16 mmol, 1.0 eq) in 165 THF (80 mL) and 30 MeOH (40 mL) was added LiOH.H2O (13.11 g, 312.49 mmol, 3.0 eq) at rt. The resulting mixture was stirred at same temperature for 12 h. Progress of reaction was monitored by LCMS. After completion of reaction, mixture was concentrated and diluted with water (100 mL), followed by dropwise addition of 1N 31 HCl (50 mL), the formation of white precipitate was observed which was filtered and dried under vacuum to afford 293 6-chloro-2-methoxynicotinic acid as white solid (19.0 g, 97.23%). (0415) LCMS: 188 [M+1]+
General procedure: The corresponding onium triflate precursors of radiolabeled active esters, [ F]8 and [ F]9, were prepared by the reaction of 2,3,5,6-tetrafluorophenyl 6-chloro-2- or -4- methoxynicotinates (13 and 14, respectively) with Me3N followed by anion metathesis usingTMSOTf (Fig. 3). 13 and 14 were synthesized from the appropriate chloroanhydrides [obtained by the treatment of 6-chloro-2- or -4-methoxynicotinic acids (17 and 18, respectively) with oxalyl chloride in the presence of DMF traces] and 2, 3,5,6- tetrafluorophenol using Et3N as a base. 17 and 18 were prepared from 2,6- and 2,4- dichloronicotinic acids, respectively, by the reaction with MeONa, generated in situ from MeOH and NaH.[16]Similarly, the precursor of 2-EtO-6-[18F]FNic-OTfp (16) was prepared.
6-chloro-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
66%
Stage #1: Mesitol With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 5℃; for 0.25h;
Stage #2: 2,6-dichloropyridine-3-carboxylic acid In N,N-dimethyl-formamide; mineral oil at 20 - 80℃;
15.1 Step 1: 6-chloro-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxylic acid
To a solution of 2,4, (13.6 g, 100 mmol) in N,N-dimethylformamide (300 mL) at 0-5° C., was carefully added NaH solid (60% in mineral oil, 8.80 g, 220 mmol). After the resultant suspension was stirred at the same temperature for 15 min, solid 2,6-dichloronicotinic acid (19.2 g, 100 mmol) was added. The reaction mixture was stirred at room temperature for 20 min and then at 80° C. overnight. The mixture was cooled to room temperature before it was poured into a cold NaHSO4 solution (24.0 g in 200 mL water). The resultant suspension was stirred at room temperature for 30 min. The precipitate was collected by filtration, washed with water, followed by Et2O/hexanes (200/500 mL), and dried at 40° C. under vacuum to give 6-chloro-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxylic acid as a brownish solid (19.2 g, 66%). 1H NMR (400 MHz, DMSO) δ 13.38 (s, 1H), 8.28 (d, J=7.9 Hz, 1H), 7.27 (d, J=7.9 Hz, 1H), 6.94 (d, J=1.1 Hz, 2H), 2.27 (s, 3H), 1.99 (s, 6H). ESI-MS m/z calc. 291.1. found 292.0 (M+1)+. Retention time: 2.34 min (3 min run).
66%
Stage #1: Mesitol With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 5℃; for 0.25h;
Stage #2: 2,6-dichloropyridine-3-carboxylic acid In N,N-dimethyl-formamide; mineral oil at 20 - 80℃;
15.1 Step 1: 6-Chloro-2-(2,4,6-trimethylphenoxy)pyridine-3-carboxylic acid
To the solution of 2,4,6-trimethylphenol (13.6g, 100mmol) in N,N-dimethylformamide (300mL) at 0-5, carefully add NaH solid (60% in mineral In oil, 8.80g, 220mmol). After stirring the resulting suspension at the same temperature for 15 minutes, solid 2,6-dichloro-nicotinic acid (19.2 g, 100 mmol) was added. The reaction mixture was stirred at room temperature for 20 minutes and then at 80°C overnight. The mixture was cooled to room temperature, then it was poured into a cold NaHSO4 solution (24.0 g in 200 mL water). The resulting suspension was stirred at room temperature for 30 minutes. The precipitate was collected by filtration, washed with water, then Et2 O/hexane (200/500mL), and dried under vacuum at 40°C to obtain 6-chloro-2-(2,4,6) as a brownish solid -Trimethylphenoxy)pyridine-3-carboxylic acid (19.2 g, 66%).
2-chloro-7-hydroxy-6,11-dihydro-5H-benzo[b]pyrido[2,3-e][1,4]diazepin-5-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
at 150℃; for 5h;
Step 1: To a flask was added <strong>[59649-56-8]2,3-diaminophenol</strong> (1.0 g, 8.1 mmol), 2,6-dichioro-nicotinic acid(1.6 g, 8.1 mmol) and 2-butoxyethanol (10 mL) and the mixture was heated to 150°C for 5 h.Upon cooling to room temperature, the mixture was diluted with ethyl acetate (20 mL), andwashed with water (2x). The organic layer was dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by column chromatography onsilica gel (petroleum ether/ethyl acetate, 5:1 ratio) to afford 2-chloro-7-hydroxy-6, 11 -dihydro5H-benzo [b]pyrido [2,3 -e] [1 ,4]diazepin-5 -one.
at 150℃; for 5h;
To a flask was added <strong>[59649-56-8]2,3-diaminophenol</strong> (1.0 g, 8.1 mmol), 2,6-dichloro-nicotinic acid (1.6 g, 8.1 mmol) and 2-butoxyethanol (10 mL) and the mixture was heated to 150°Cfor 5 h. Upon cooling to room temperature, the mixture was diluted with ethyl acetate (20 mL), and washed with water (2x). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate, 5 :1 ratio) to afford 2-chloro-7-hydroxy-6,l 1-dihydro- 5 H-benzo [b]pyrido [2 , 3 -e] [ 1 ,4 ] diazepin-5 -one .
To the solution of 2,6-dichloronicotinic acid (2.0gm, 10.4lmmol) in THF (20 mL), was added CH3MgBr (12 mL) drop wise at 0C which was stined at RT for 12h. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer waswashed with water and brine solution; dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain crude compound (1.lg).?HNMR (300MHz, DMSO-d6): oe 8.25-8.23(d, 1H), 7.72-7.69 (d, 1H), 2.59 (s, 3H). LCMS:mlz = 190.0 (M-1)
Multi-step reaction with 5 steps
1.1: dmap / tetrahydrofuran / 20 °C / Large scale
2.1: potassium carbonate; 1,4-diaza-bicyclo[2.2.2]octane / N,N-dimethyl-formamide / 16 h / 20 °C / Large scale
3.1: hydrogenchloride / water; isopropyl alcohol / 3 h / Reflux; Large scale
4.1: 1,1'-carbonyldiimidazole / tetrahydrofuran / 20 °C / Large scale
4.2: 4 h / 20 °C / Large scale
5.1: potassium carbonate / monoethylene glycol diethyl ether / 16 h / 120 °C / Large scale
Multi-step reaction with 5 steps
1.1: dmap / tetrahydrofuran / 20 °C
2.1: 1,4-diaza-bicyclo[2.2.2]octane; potassium carbonate / N,N-dimethyl-formamide / 16 h / 20 °C
3.1: hydrogenchloride / water; isopropyl alcohol / Reflux
4.1: 1,1'-carbonyldiimidazole / tetrahydrofuran / 20 °C
4.2: 4 h / 20 - 60 °C
5.1: potassium carbonate / dimethyl sulfoxide; monoethylene glycol diethyl ether / 120 °C
Multi-step reaction with 5 steps
1.1: dmap / tetrahydrofuran / 20 °C
2.1: potassium carbonate; 1,4-diaza-bicyclo[2.2.2]octane / N,N-dimethyl-formamide / 16 h / 20 °C
3.1: hydrogenchloride; water / isopropyl alcohol / 3 h / Reflux
4.1: 1,1'-carbonyldiimidazole / tetrahydrofuran / 1 h / 18 - 21 °C
4.2: 16 h / 19 - 35 °C
5.1: potassium carbonate / dimethyl sulfoxide; monoethylene glycol diethyl ether / 16 h / 120 °C
Multi-step reaction with 5 steps
1.1: dmap / tetrahydrofuran / 20 °C
1.2: 0.17 h
2.1: potassium carbonate; 1,4-diaza-bicyclo[2.2.2]octane / N,N-dimethyl-formamide / 16 h / 20 °C
3.1: hydrogenchloride / isopropyl alcohol / 3 h / Reflux
4.1: 1,8-diazabicyclo[5.4.0]undec-7-ene; 1,1'-carbonyldiimidazole / tetrahydrofuran / 5 h / 20 - 60 °C
5.1: potassium carbonate / dimethyl sulfoxide; monoethylene glycol diethyl ether / 120 °C
Multi-step reaction with 5 steps
1.1: dmap / tetrahydrofuran / 20 °C
1.2: 0.17 h
2.1: 1,4-diaza-bicyclo[2.2.2]octane; potassium carbonate / N,N-dimethyl-formamide / 16 h / 20 °C
3.1: hydrogenchloride / isopropyl alcohol; water / 3 h / Reflux
4.1: 1,1'-carbonyldiimidazole / tetrahydrofuran / 20 °C
4.2: 4 h / 20 - 60 °C
5.1: potassium carbonate / dimethyl sulfoxide; 1,2-dimethoxyethane / 16 h / 120 °C
6-chloro-2-(6-azaspiro[2.5]octan-6-yl)nicotinic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
44%
With N-ethyl-N,N-diisopropylamine In 1,4-dioxane at 60℃; for 18h;
Intermediate 54: 6-chloro-2-(6-azaspiro[2.5]octan-6-yl)nicotinic acid.
A mixture of 2,6-dichloronicotinic acid (4.2 g, 21.9 mmol), 6-azaspiro[2.5]octane (2.4 g, 21.9 mmol) and 1,4-dioxane (40 mL). Hunig's base (7.7 mL, 44.1 mmol) was added and the brown solution was stirred at 60 °C for 18 h. The mixture was diluted with EtOAc (80 mL) and washed with water (2 x 10 mL) followed by brine (5 mL). The organic phase was concentrated and the residue was purified on a silica gel column (0.25% AcOH mediated 50% to 100% EtOAc/hexanes) to title compound (54, 2.60 g, 44% yield) as a tan solid. NMR (400MHz, CHLOROLORM-d) d = 8.52 (d, .7=8.2 Hz, 1H), 7.40 (d, .7=8.0 Hz, 1H), 3.21 (t, .7=5.4 Hz, 4H), 1.69 (br. s., 4H), 0.47 (s, 4H). -C02H was not observed. m/z (ESI): 267.0 (M+H)+.
6-chloro-2-(4,4,4-trifluorobutoxy)nicotinic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
Stage #1: 4,4,4-trifluorobutanol With sodium hydride In tetrahydrofuran at 50℃; for 0.5h;
Stage #2: 2,6-dichloropyridine-3-carboxylic acid In tetrahydrofuran at 70℃; for 3h; regioselective reaction;
3 Example 3
Example 3 Chemical Synthesis of Protected PD6 Prodrug Comprising Cholesterol Chemical synthesis of a protected PD6 prodrug comprising cholesterol is synthesized using the following protocol. First, Intermediate 1: 2,6-dichloro-3-carboxypyridine was treated with trimethylsilylethanol in THF followed by reduction with borane dimethylsulfide complex. Then, Intermediate 2: Intermediate 1 was treated with Dess-Martin Reagent. Then, Intermediate 3: 4-hydroxy-2,3-dihydro-1H-inden-2-one was treated with imidazole and tert-Butyldimethylsilyl chloride in DCM. Then, Intermediate 4: Intermediate 3 was treated with R(+)-2-methyl-CBS-oxaborolidine and borane dimethylsulfide in toluene. Then, Intermediate 5: Intermediate 4 was combined with Intermediate 2, palladium acetate, tBuXPHos, and cesium carbonate in toluene top. Then, Intermediate 6: Intermediate 5 was treated with TBAF in THF at -78° C. for 15 minutes followed by triflic anhydride, trimethylamine, and DMAP in DCM at room temperature. Then, Intermediate 7: Intermediate 6 was treated with B2Pin2, Pd-dppt and potassium acetate in dioxane. Then, Intermediate 8: Intermediate 7 was treated with 1,3-dibromo-2-chlorobenzene, Pd(dppt)Cl2, and Potassium acetate. Then, Intermediate 9: Intermediate 8 was treated with Palau-CI and 20% TFA in DCM/DMF. Then, Intermediate 10: Intermediate 9 was treated with cesium fluoride in DMF at 60 C followed by methyl iodide and potassium carbonate. Then, Intermediate 11: Intermediate 10 was treated with 4,4,5,5-tetramethyl-2-(4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)phenyl)-1,3,2-dioxaborolane and palladium triphenylphosphine. Then, Intermediate 12: Intermediate 11 was treated with 3-azetidine carboxylic acid, potassium acetate, and triacetoxysodium borohydride. Then, Intermediate 13: The ketal in intermediate 12 was hydrolyzed to the aldehyde with HCl in dioxane, then the aldehyde was converted with s-aminomethylpyrrolidin-2-one, potassium acetate, and sodium triacetoxyborohydride. Then, Intermediate 14: Intermediate 13 was converted the BOC derivative by treatment with BOO anhydride, followed by EDC mediated esterification with cholesterol, then removal of the BOC group with HCl in dioxane to yield the final PD6 Prodrug. ().
4 Example 4
Example 4 Chemical Synthesis of Protected PD6 Prodrug Comprising DPPG Chemical synthesis of a protected PD6 Prodrug comprising DPPG is synthesized using the following protocol. First, Intermediate 1: 2,6-dichloro-3-carboxypyridine was treated with trimethylsilylethanol in THF followed by reduction with borane dimethylsulfide complex. Then, Intermediate 2: Intermediate 1 was treated with Dess-Martin Reagent. Then, Intermediate 3: 4-hydroxy-2,3-dihydro-1H-inden-2-one was treated with imidazole and tert-Butyldimethylsilyl chloride in DCM. Then, Intermediate 4: Intermediate 3 was treated with R(+)-2-methyl-CBS-oxaborolidine and borane dimethylsulfide in toluene. Then, Intermediate 5: Intermediate 4 was combined with Intermediate 2, palladium acetate, tBuXPHos, and cesium carbonate in toluene top. Then, Intermediate 6: Intermediate 5 was treated with TBAF in THF at -78° C. for 15 minutes followed by triflic anhydride, trimethylamine, and DMAP in DCM at room temperature. Then, Intermediate 7: Intermediate 6 was treated with B2Pin2, Pd-dppt and potassium acetate in dioxane. Then, Intermediate 8: Intermediate 7 was treated with 1,3-dibromo-2-chlorobenzene, Pd(dppt)Cl2, and Potassium acetate. Then, Intermediate 9: Intermediate 8 was treated with Palau-CI and 20% TFA in DCM/DMF. Then, Intermediate 10: Intermediate 9 was treated with cesium fluoride in DMF at 60 C followed by methyl iodide and potassium carbonate. Then, Intermediate 11: Intermediate 10 was treated with 4,4,5,5-tetramethyl-2-(4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)phenyl)-1,3,2-dioxaborolane and palladium triphenylphosphine. Then, Intermediate 12: Intermediate 11 was treated with 3-azetidine carboxylic acid, potassium acetate, and triacetoxysodium borohydride. Then, Intermediate 13: The ketal in intermediate 12 was hydrolyzed to the aldehyde with HCl in dioxane, then the aldehyde was converted with s-aminomethylpyrrolidin-2-one, potassium acetate, and sodium triacetoxyborohydride. Then, Intermediate 14: Intermediate 13 was converted the BOC derivative by treatment with BOC anhydride, followed by EDC mediated esterification with DPPG, then removal of the BOC group with HCl in dioxane to yield the final PD6 Prodrug. ().
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