* 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 7: Preparation of 5,6-dichloro-nicotinic acid methyl ester (10)[284] 4.45 niL of sulfuric acid was added to 5.0 g of 5,6-dichloronicotinic acid (26 mmol) dissolved in 50 niL of methanol, and refluxed under heating and stirring for 18 hours. The mixture was cooled to 40C, neutralized with a saturated sodium bicarbonate solution, and methanol was concentrated under reduced pressure. The aqueous layer was extracted with ethyl acetate, and the organic layer was separated to be dried over magnesium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography (eluting solvent: chloroform/methanol=20/l) to obtain 5.2 g of white solid, 5,6-dichloro-nicotinic acid methyl ester (yield 97percent).[285] 1H NMR (CDCl3) δ: 8.86 (s, IH), 8.34 (s, IH), 3.96 (s, 3H)
97%
Stage #1: for 18 h; Reflux Stage #2: at 4℃;
Example 7Preparation of 5,6-dichloro-nicotinic acid methyl ester (10)4.45 mL of sulfuric acid was added to 5.0 g of 5,6-dichloronicotinic acid (26 mmol) dissolved in 50 mL of methanol, and refluxed under heating and stirring for 18 hours. The mixture was cooled to 4° C., neutralized with a saturated sodium bicarbonate solution, and methanol was concentrated under reduced pressure. The aqueous layer was extracted with ethyl acetate, and the organic layer was separated to be dried over magnesium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography (eluting solvent: chloroform/methanol=20/1) to obtain 5.2 g of white solid, 5,6-dichloro-nicotinic acid methyl ester (yield 97percent).1H NMR (CDCl3) δ: 8.86 (s, 1H), 8.34 (s, 1H), 3.96 (s, 3H)
96%
Stage #1: With thionyl chloride In N,N-dimethyl-formamide at 80℃; for 5 h; Stage #2: for 1 h; Heating / reflux
5,6-Dichloro-nicotinic acid methyl esterA solution of 5,6-dichloro-nicotinic acid (55.0 g, 281 mmol) in SOCI2 (204 ml) was treated with DMF (0.1 ml) and the mixture was heated to 80 0C for 5 h. The excess of SOCI2 was evaporated and the crude product was taken up in MeOH (300 ml) and the resulting solution was heated to reflux for 1 h. The mixture was then allowed to cool slowly to RT. 5,6-Dichloro- nicotinic acid methyl ester precipitated and was collected by filtration (55.6 g, 96percent). UPLC (5-100percent CH3CN): tR = 1.384 min, TLC (Hex/EtOAc 1 :1 ): Rf = 0.76.
34.7%
at 0℃; for 3 h; Reflux
Thionyl chloride (27.9 g, 234 mmol) was added dropwise to the solution of 5,6-dichloropyridine-3-carboxylic acid (18.0 g, 94 mmol) in MeOH (300 mL) at 0 °C. The resulting mixture was heated under reflux for 3 hours, cooled and concentrated under reduced pressure. The residue was purified by silica chromatography (hexane:EtOAc = 5:1 to 3:1) to give the title compound (6.7 g, 34.7percent yield) as a white solid. MS mlz 226.08 [M+Hjt
5 g
at 25℃;
A mixture of 5 6-dichloronicotinic acid (5 g) and sulfurous dichloride (3.10 g) in methanol (20 mL) was stirred at 25overnight. Cold water (100 mL) was added and the resulting mixture was neutralized with sat. NaHCO3solution. The aqueous layer was extracted with DCM (2×100 mL) and the combined organic layers were dried over Na2SO4. Aftet filtration the filtrate was concentrated in vacuo to give the title compound (5 g) as a white solid. MS (ESI) C7H5Cl2NO2requires 205 found 206 [M+H]+.
5 g
at 25℃;
A mixture of 5,6-dichloronicotinic acid (5 g) and sulfurous dichloride (3.10 g) in methanol (20 mL) was stirred overnight at 25°C. Cold water (100 mL) was added and the resulting mixture was neutralized with sat. NaHCO3 solution. The aqueous layer was extracted with DCM (2x 100 mL) and the combined organic layers were dried over Na2SO4. Aftet filtration, the filtrate was concentrated in vacuo to give the title compound (5 g) as white solid. MS (ESI): C7H5C12NO2requires 205; found 206 [M+H].
5 g
at 25℃;
Description 123Methyl 5,6-dichioronicotinate (P123) The mixture of 5,6-dichloronicotinic acid (5 g) and sulfurous dichloride (3.10 g) in methanol (20 mL) was stirred overnight at 25°C. Cold water (100 mL) was added and the resulted mixture wasneutralized with saturated NaHCO3 solution. The aqueous layer was extracted with DCM (2x 100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to afford the title compound (5 g) as white solid. MS (ESI): C7H5C12NO2 requires 205; found 206 [M+H].
5 g
at 25℃;
Take 5,6-dichloronicotinic acid (5 g) with thionyl chloride(sulfbrous dichloride) (3.10 g)In methanol (20 mL) was stirred at 25 ° C overnight. Add cold water (100 mL) and the resulting mixture was neutralized with saturated NaHCO3 solution. The aqueous layer was extracted with DCM (2 x 100 mL) and the combined organic layers were dehydrated by Na2S04. After filtration, the filtrate was concentrated in vacuo to give the title compound (5 g) as a white solid.
Stage #1: at 105℃; for 1 h; Stage #2: at 0 - 20℃; for 0.5 h;
5,6-Dichloro-nicotinic acid methyl esterA solution of 5,6-dichloro-nicotinic acid (10.0 g, 51.0 mmol) and DMF (7 μl) in SOCI2 (49.5 ml) was heated to 105°C for 1 h. The mixture was then concentrated in vacuo and treated with cooled MeOH (10 ml, 0°C ). The solution was allowed to warm slowly to rt over 30 min. The solvent was then evaporated in vacuo and the crude product was purified by flash chromatography (Hex/EtOAc 1 :1 ) to provide 5,6-dichloro-nicotinic acid methyl ester (10.3 g, 99percent). UPLC (5-100percent CH3CN): RT = 1.374 min.
To a 25OmL reaction vessel was added 5,6-dichloronicotinic acid (15.6mmol), toluene (5OmL), and methanol (50 mL). The reaction mixture was cooled to 00C and a 2M solution of trimethylsilyldiazomethane in hexanes (23.4mmol) was subsequently added dropwise followed by stirring for about 12-18 hours. Concentration of the reaction mixture to dryness afforded the desired product (3.2g) as an off-white solid; MW = 206.03, yield = 100percent, HPLC (min) = 3.96, LC-MS = 206, 208; dichloro fragment
100%
at 0℃; for 12 - 18 h;
Preparation B: Reaction 1 : Methyl 5, δ-dichloropyridine-S-carboxylateTo a 25OmL reaction vessel was added 5,6-dichloronicotinic acid (15.6mmol), toluene (5OmL), and methanol (50 mL). The reaction mixture was cooled to 0°C and a 2M solution of trimethylsilyldiazomethane in hexanes (23.4mmol) was subsequently added dropwise followed by stirring for about 1-2-18 hours. Concentration of the reaction mixture to EPO <DP n="46"/>dryness afforded the desired product (3.2g) as an off-white solid; MW = 206.03, yield = 100percent, HPLC (min) = 3.96, LC-MS = 206, 208; dichloro fragment.
5,6-Dichloro-nicotinic Acid Methyl Ester A solution of 5,6-dichloro-nicotinic acid (55.0 g, 281 mmol) in SOCl2 (204 ml) was treated with DMF (0.1 ml) and the mixture was heated to 80° C. for 5 h. The excess of SOCl2 was evaporated and the crude product was taken up in MeOH (300 ml) and the resulting solution was heated to reflux for 1 h. The mixture was then allowed to cool slowly to RT. 5,6-Dichloro-nicotinic acid methyl ester precipitated and was collected by filtration (55.6 g, 96percent). UPLC (5-100percent CH3CN): tR=1.384 min, TLC (Hex/EtOAc 1:1): Rf=0.76. By analogy to the preparation of example 16, the following compounds can be made:
Reference：
[1] Organic Process Research and Development, 2013, vol. 17, # 6, p. 940 - 945
8
[ 365413-29-2 ]
[ 73781-91-6 ]
[ 56055-54-0 ]
Reference：
[1] Organic Process Research and Development, 2013, vol. 17, # 6, p. 940 - 945
[2] Organic Process Research and Development, 2013, vol. 17, # 6, p. 940 - 945
9
[ 5006-66-6 ]
[ 56055-54-0 ]
Reference：
[1] Organic Process Research and Development, 2013, vol. 17, # 6, p. 940 - 945
10
[ 66171-50-4 ]
[ 56055-54-0 ]
Reference：
[1] Organic Process Research and Development, 2013, vol. 17, # 6, p. 940 - 945
11
[ 885950-46-9 ]
[ 56055-54-0 ]
Reference：
[1] Organic Process Research and Development, 2013, vol. 17, # 6, p. 940 - 945
12
[ 5006-66-6 ]
[ 73781-91-6 ]
[ 56055-54-0 ]
Reference：
[1] Organic Process Research and Development, 2013, vol. 17, # 6, p. 940 - 945
13
[ 66171-50-4 ]
[ 73781-91-6 ]
[ 56055-54-0 ]
Reference：
[1] Organic Process Research and Development, 2013, vol. 17, # 6, p. 940 - 945
14
[ 885950-46-9 ]
[ 73781-91-6 ]
[ 56055-54-0 ]
Reference：
[1] Organic Process Research and Development, 2013, vol. 17, # 6, p. 940 - 945
Preparative Example 1. EN = CO2Pr1 = CO2CH3 EPO <DP n="109"/>Methyl-2,3-dichloro pyridine 5- carboxylate 1 (methyl5,6-dichloronicotinate, BIONET) was prepared from 5,6-Dichloronicotinic acid (ALDRICH), by converting to the acid chloride by treatment with excess SOCI2, and refluxed for 1.5 hours followed by methylation in methanol/pyridine as solvent in nearly quantitative yield. Ref. Musso et al, Bioorg. Med.Chem. Lett, 1997, I1 1-6.A round bottomed flask was charged with methyl 2,3-dichloro pyridine 5-carboxylate 1 (7g, 34 mmol), 2-S-ethyl piperazine (prepared as per Williams et al J. Med. Chem 1996, 39, 1345,) ( 75% active, 5.2 g, 34mmol), cesium carbonate (12.15 g, 68 mmol), DBPD (0.74 g, 2.48 mmol), palladium acetate ( 0.55 g, 2.48 mmol) and 1 ,4 dioxane (170 ml). The flask was equipped with a reflux condenser and heated to 8O0C. After 36 hours the reaction was cooled, diluted with methylene chloride (~ 200 ml), and washed with water (2 x 50 ml). The organic layer was dried over anhydrous magnesium sulfate and then concentrated to an oil. The crude product was purified by silica gel chromatography using a methanol/ methylene chloride eluent (3% to 10% MeOH) to afford 3 (8.2 g, 85%) of the title compound. MS: m/e, M+H = 283
96%
for 1h;Heating / reflux;
5,6-Dichloro-nicotinic Acid Methyl Ester A solution of 5,6-dichloro-nicotinic acid (55.0 g, 281 mmol) in SOCl2 (204 ml) was treated with DMF (0.1 ml) and the mixture was heated to 80 C. for 5 h. The excess of SOCl2 was evaporated and the crude product was taken up in MeOH (300 ml) and the resulting solution was heated to reflux for 1 h. The mixture was then allowed to cool slowly to RT. 5,6-Dichloro-nicotinic acid methyl ester precipitated and was collected by filtration (55.6 g, 96%). UPLC (5-100% CH3CN): tR=1.384 min, TLC (Hex/EtOAc 1:1): Rf=0.76. By analogy to the preparation of example 16, the following compounds can be made:
Example 7: Preparation of 5,6-dichloro-nicotinic acid methyl ester (10)[284] 4.45 niL of sulfuric acid was added to 5.0 g of 5,6-dichloronicotinic acid (26 mmol) dissolved in 50 niL of methanol, and refluxed under heating and stirring for 18 hours. The mixture was cooled to 40C, neutralized with a saturated sodium bicarbonate solution, and methanol was concentrated under reduced pressure. The aqueous layer was extracted with ethyl acetate, and the organic layer was separated to be dried over magnesium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography (eluting solvent: chloroform/methanol=20/l) to obtain 5.2 g of white solid, 5,6-dichloro-nicotinic acid methyl ester (yield 97%).[285] 1H NMR (CDCl3) delta: 8.86 (s, IH), 8.34 (s, IH), 3.96 (s, 3H)
97%
Example 7Preparation of 5,6-dichloro-nicotinic acid methyl ester (10)4.45 mL of sulfuric acid was added to 5.0 g of 5,6-dichloronicotinic acid (26 mmol) dissolved in 50 mL of methanol, and refluxed under heating and stirring for 18 hours. The mixture was cooled to 4 C., neutralized with a saturated sodium bicarbonate solution, and methanol was concentrated under reduced pressure. The aqueous layer was extracted with ethyl acetate, and the organic layer was separated to be dried over magnesium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography (eluting solvent: chloroform/methanol=20/1) to obtain 5.2 g of white solid, 5,6-dichloro-nicotinic acid methyl ester (yield 97%).1H NMR (CDCl3) delta: 8.86 (s, 1H), 8.34 (s, 1H), 3.96 (s, 3H)
96%
5,6-Dichloro-nicotinic acid methyl esterA solution of 5,6-dichloro-nicotinic acid (55.0 g, 281 mmol) in SOCI2 (204 ml) was treated with DMF (0.1 ml) and the mixture was heated to 80 0C for 5 h. The excess of SOCI2 was evaporated and the crude product was taken up in MeOH (300 ml) and the resulting solution was heated to reflux for 1 h. The mixture was then allowed to cool slowly to RT. 5,6-Dichloro- nicotinic acid methyl ester precipitated and was collected by filtration (55.6 g, 96%). UPLC (5-100% CH3CN): tR = 1.384 min, TLC (Hex/EtOAc 1 :1 ): Rf = 0.76.
34.7%
With thionyl chloride; at 0℃; for 3h;Reflux;
Thionyl chloride (27.9 g, 234 mmol) was added dropwise to the solution of 5,6-dichloropyridine-3-carboxylic acid (18.0 g, 94 mmol) in MeOH (300 mL) at 0 C. The resulting mixture was heated under reflux for 3 hours, cooled and concentrated under reduced pressure. The residue was purified by silica chromatography (hexane:EtOAc = 5:1 to 3:1) to give the title compound (6.7 g, 34.7% yield) as a white solid. MS mlz 226.08 [M+Hjt
With toluene-4-sulfonic acid; for 25h;Heating / reflux;
Example 178 [5-CHLORO-6- (3R)-3-METHYL-4- [5-TRIFLUOROMETHYL-7- (3,] 4, [5-TRIFLUORO-PHENYL)-1 H-] [BENZOIMIDAZOL-2-YL]-PIPERAZIN-1-YL}-NICOTINIC] acid methyl ester. (a) 5,6-Dichloro-nicotinic acid methyl ester. A solution of 5, 6-dichloro-nicotinic acid (1.92 g, 10 mmol, Aldrich) [ANDP-] toluenesulfonic acid monohydrate (190 mg, 1.0 mmol, Aldrich) in methanol (5 mL, Aldrich) was heated at reflux for 25 h. The reaction mixture was cooled to room temperature, the solvent was removed in vacuo and the residue was dissolved in EtOAc (50 mL). The solution was washed with satd. [NAHC03] (20 mL) and brine (20 mL), dried over [NA2S04,] and filtered. The filtrate was evaporated in vacuo and the residue was purified by silica gel column chromatography, eluting with 30% EtOAc/hexane to give the title compound as a white solid. MS ESI, pos. ion) m/e: 205 [(M+1).]
Step 1: A mixture of compound 6-1 (4 g, 20.8 mmol) in DCM (100 mL) was added oxalyl chloride (10.5 g, 83.2 mmol) dropwise. The resulting mixture was stirred at room temperature for 12 hours. Then methanol (6.7 g, 208 mmol) was added into the above solution at 0 C. After being stirred at room temperature for another 0.5 hours, the mixture was washed with H20 (100 mL), extracted with DCM (100 mL x 2), the organic phase was dried over anhydrous Na2S04 and concentrated, purified by flash column chromatography to give product 6-2 as white solid.
5 g
With thionyl chloride; at 25℃;
A mixture of 5 6-dichloronicotinic acid (5 g) and sulfurous dichloride (3.10 g) in methanol (20 mL) was stirred at 25overnight. Cold water (100 mL) was added and the resulting mixture was neutralized with sat. NaHCO3solution. The aqueous layer was extracted with DCM (2×100 mL) and the combined organic layers were dried over Na2SO4. Aftet filtration the filtrate was concentrated in vacuo to give the title compound (5 g) as a white solid. MS (ESI) C7H5Cl2NO2requires 205 found 206 [M+H]+.
5 g
With thionyl chloride; at 25℃;
A mixture of 5,6-dichloronicotinic acid (5 g) and sulfurous dichloride (3.10 g) in methanol (20 mL) was stirred overnight at 25C. Cold water (100 mL) was added and the resulting mixture was neutralized with sat. NaHCO3 solution. The aqueous layer was extracted with DCM (2x 100 mL) and the combined organic layers were dried over Na2SO4. Aftet filtration, the filtrate was concentrated in vacuo to give the title compound (5 g) as white solid. MS (ESI): C7H5C12NO2requires 205; found 206 [M+H].
5 g
With thionyl chloride; at 25℃;
Description 123Methyl 5,6-dichioronicotinate (P123) The mixture of 5,6-dichloronicotinic acid (5 g) and sulfurous dichloride (3.10 g) in methanol (20 mL) was stirred overnight at 25C. Cold water (100 mL) was added and the resulted mixture wasneutralized with saturated NaHCO3 solution. The aqueous layer was extracted with DCM (2x 100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to afford the title compound (5 g) as white solid. MS (ESI): C7H5C12NO2 requires 205; found 206 [M+H].
5 g
With thionyl chloride; at 25℃;
Take 5,6-dichloronicotinic acid (5 g) with thionyl chloride(sulfbrous dichloride) (3.10 g)In methanol (20 mL) was stirred at 25 C overnight. Add cold water (100 mL) and the resulting mixture was neutralized with saturated NaHCO3 solution. The aqueous layer was extracted with DCM (2 x 100 mL) and the combined organic layers were dehydrated by Na2S04. After filtration, the filtrate was concentrated in vacuo to give the title compound (5 g) as a white solid.
With triethylamine; In N,N-dimethyl-formamide; at 120℃; for 2h;
Step D. A solution of (2-methylsulfanyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl)-(4-trifluoromethyl-phenyl)-amine (187 mg, 0.53 mmol), <strong>[56055-54-0]5,6-dichloro-nicotinic acid methyl ester</strong> (129 mg, 0.58 mmol), and Et3N (0.2 mL, 1.58 mmol) in DMF (1.2 mL) was heated at 120 C. for 2 h. The mixture was cooled to rt, diluted with water, and extracted with EtOAc. The combined organic layers were dried and concentrated. The residue was purified (FCC) to give the title compound (203 mg, 74%). MS (ESI): mass calcd. for C23H21ClF3N5O2S, 523.11; m/z found, 524.1 [M+H]+. 1H NMR (CDCl3): 8.57 (d, J=2.0 Hz, 1H), 8.00 (d, J=2.0 Hz, 1H), 7.59 (d, J=8.6 Hz, 2H), 7.48 (d, J=8.6 Hz, 2H), 6.73-6.59 (m, 1H), 3.89-3.65 (m, 7H), 3.19-3.07 (m, 2H), 2.95-2.87 (m, 2H), 2.40 (s, 3H).
5,6-Dichloro-nicotinic acid methyl esterA solution of 5,6-dichloro-nicotinic acid (10.0 g, 51.0 mmol) and DMF (7 mul) in SOCI2 (49.5 ml) was heated to 105C for 1 h. The mixture was then concentrated in vacuo and treated with cooled MeOH (10 ml, 0C ). The solution was allowed to warm slowly to rt over 30 min. The solvent was then evaporated in vacuo and the crude product was purified by flash chromatography (Hex/EtOAc 1 :1 ) to provide 5,6-dichloro-nicotinic acid methyl ester (10.3 g, 99%). UPLC (5-100% CH3CN): RT = 1.374 min.
5-Chloro-6-(4-chloro-phenylamino)-nicotinic acid methyl esterA solution of [Pd(OAc)2] (365 mg, 1.59 mmol) and rac-BINAP (1.02 g, 1.61 mmol) in degassed toluene (20 ml) was treated with a solution of <strong>[56055-54-0]5,6-dichloro-nicotinic acid methyl ester</strong> (10.3 g, 50.0 mmol) in de-gassed toluene (10 ml) and a solution of 4-chloroaniline (9.66 g, 75.0 mmol) in de-gassed toluene (10 ml). The mixture was stirred at rt for 15 min and K2CO3 (34.9 g, 250 mmol) was added. The suspension was heated to reflux for 16 h, and the solvent was then evaporated in vacuo. The residue was taken up in DCM, acidified with 1 N aq. HCI, and extracted with DCM. The combined organic layers were dried over Na2SO4, and concentrated in vacuo. Purification by flash chromatography (Hex/EtOAc 100:0 to 80:20) and crystallization in /-PrOH gave 5-chloro-6-(4-chloro-phenylamino)-nicotinic acid methyl ester (5.69 g, 38%). UPLC (5-100% CH3CN): RT = 1.755 min.
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; for 18h;Heating / reflux;
Example 8: Preparation of 3-chloro-6'-methyl-[2,3']bipyridyl-5-carboxylic acid methyl ester (12)[288] 0.29 of Na CO (0.273 mmol), 0.25 g of 6-methylpyridin-3-ylboronic acid (11)(0.18 mmol) and 0.11 g of Pd(PPh 3 ) 4 were added to 0.4 g of <strong>[56055-54-0]5,6-dichloro-nicotinic acid methyl ester</strong>(ltheta) (0.2 mmol) prepared in Example 7 dissolved in 14 mL of 1,2-dimethoxyethane and 7 mL of distilled water, and refluxed under heating and stirring for 18 hours. The mixture was cooled to room temperature, and concentrated about 50% under reduced pressure. The aqueous layer was extracted with ethyl acetate, and the organic layer was dried over magnesium sulfate, concentrated under reduced pressure. The residue was separated by column chromatography (eluting solvent: chloroform/methanol=10/l) to obtain 0.42 g of 3-chloro-6'-methyl-[2,3'] bipyridyl- 5-carboxylic acid methyl ester (yield 88%).[289] 1U NMR (CDCl ) delta: 9.16 (d, IH), 8.96 (s, IH), 8.40 (d, IH), 8.03 (dd, IH), 7.29 (d,IH), 4.00 (s, 3H), 2.65 (S, 3H)
81%
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; for 18h;Reflux;
Example 8Preparation of 3-chloro-6'-methyl-[2,3']bipyridyl-5-carboxylic acid methyl ester (12)0.29 of Na2CO3 (0.273 mmol), 0.25 g of 6-methylpyridin-3-ylboronic acid (11) (0.18 mmol) and 0.11 g of Pd(PPh3)4 were added to 0.4 g of <strong>[56055-54-0]5,6-dichloro-nicotinic acid methyl ester</strong> (10) (0.2 mmol) prepared in Example 7 dissolved in 14 mL of 1,2-dimethoxyethane and 7 mL of distilled water, and refluxed under heating and stirring for 18 hours. The mixture was cooled to room temperature, and concentrated about 50% under reduced pressure. The aqueous layer was extracted with ethyl acetate, and the organic layer was dried over magnesium sulfate, concentrated under reduced pressure. The residue was separated by column chromatography (eluting solvent: chloroform/methanol=10/1) to obtain 0.42 g of 3-chloro-6'-methyl-[2,3']bipyridyl-5-carboxylic acid methyl ester (yield 88%).1H NMR (CDCl3) delta: 9.16 (d, 1H), 8.96 (s, 1H), 8.40 (d, 1H), 8.03 (dd, 1H), 7.29 (d, 1H), 4.00 (s, 3H), 2.65 (S, 3H)
Step B: Methyl 5-chloro-6- (2, 2, 2-trifluoro-1-methylethoxy) nicotinate; To a solution of 630 mg (3.06 mmol) of <strong>[56055-54-0]methyl 5,6-dichloronicotinate</strong> (from Step A) and 349 muL (3.06 mmol) of 1, 1, l-trifluoro-2-propanol in 10 mL of THF at-78 C was added 3.1 mL (3.06 mmol) of sodium bis (trimethylsilyl) amide (1.0 M in THF). After stirring at-78 C for 30 min and at 0 C for 5 h, the reaction was quenched by adding 10 mL of saturated NH4Cl. The mixture was poured into brine and extracted with CH2C12 (3 x 20 mL). Organic layers were combined, dried over MgS04, and concentrated. Chromatography on a Biotage 40M cartridge using 3: 97 v/v Et20/hexanes as the eluant gave 627 mg of the title compound : 1H NMR (500 MHz, CDC13) 8 1.56 (d, J = 6.4, 3H), 3.93 (s, 3H), 5.86 (m, 1H), 8.27 (d, J = 2.1, 1H), 8. 67 (d, J = 2.0, 1H).
In methanol; hexanes; toluene; at 0℃; for 12 - 18h;
To a 25OmL reaction vessel was added 5,6-dichloronicotinic acid (15.6mmol), toluene (5OmL), and methanol (50 mL). The reaction mixture was cooled to 00C and a 2M solution of trimethylsilyldiazomethane in hexanes (23.4mmol) was subsequently added dropwise followed by stirring for about 12-18 hours. Concentration of the reaction mixture to dryness afforded the desired product (3.2g) as an off-white solid; MW = 206.03, yield = 100%, HPLC (min) = 3.96, LC-MS = 206, 208; dichloro fragment
100%
In methanol; hexanes; toluene; at 0℃; for 12 - 18h;
Preparation B: Reaction 1 : Methyl 5, delta-dichloropyridine-S-carboxylateTo a 25OmL reaction vessel was added 5,6-dichloronicotinic acid (15.6mmol), toluene (5OmL), and methanol (50 mL). The reaction mixture was cooled to 0C and a 2M solution of trimethylsilyldiazomethane in hexanes (23.4mmol) was subsequently added dropwise followed by stirring for about 1-2-18 hours. Concentration of the reaction mixture to EPO <DP n="46"/>dryness afforded the desired product (3.2g) as an off-white solid; MW = 206.03, yield = 100%, HPLC (min) = 3.96, LC-MS = 206, 208; dichloro fragment.
In methanol; hexanes; dichloromethane; at 20℃; for 0.5h;
CARBOXYLIC ACID 20; 5-Cyano-6- (2, 2, 2-trifluoro-l-methylethoxy) nicotinic acid; Step A: Methyl 5, 6-dichloronicotinate; To a solution of 2. 15 g (11. 2 mmol) of 5, 6-dichloronicotinic acid in 10 mL of v : v 1 : 1 CH2Cl2/CH3OH at rt was added dropwise 8.4 mL (16.8 mmol) of (trimethylsilyl) diazomethane (2.0 M in hexanes). The mixture was stirred at rt for 30 min and then concentrated. Chromatography on a Biotage 40M cartridge using 1: 19 v/v EtOAc/hexanes as the eluant gave 1.85 g of the title compound : 1H NMR (500 MHz, CDC13) 8 3.98 (s, 3H), 8.35 (d, J = 1.8, 1H), 8.88 (d, J = 1.8, 1H).
With caesium carbonate;palladium diacetate; johnphos; In 1,4-dioxane; at 80℃; for 36h;Heating / reflux;
Preparative Example 1. EN = CO2Pr1 = CO2CH3 EPO <DP n="109"/>Methyl-2,3-dichloro pyridine 5- carboxylate 1 (methyl5,6-dichloronicotinate, BIONET) was prepared from 5,6-Dichloronicotinic acid (ALDRICH), by converting to the acid chloride by treatment with excess SOCI2, and refluxed for 1.5 hours followed by methylation in methanol/pyridine as solvent in nearly quantitative yield. Ref. Musso et al, Bioorg. Med.Chem. Lett, 1997, I1 1-6.A round bottomed flask was charged with methyl 2,3-dichloro pyridine 5-carboxylate 1 (7g, 34 mmol), 2-S-ethyl piperazine (prepared as per Williams et al J. Med. Chem 1996, 39, 1345,) ( 75% active, 5.2 g, 34mmol), cesium carbonate (12.15 g, 68 mmol), DBPD (0.74 g, 2.48 mmol), palladium acetate ( 0.55 g, 2.48 mmol) and 1 ,4 dioxane (170 ml). The flask was equipped with a reflux condenser and heated to 8O0C. After 36 hours the reaction was cooled, diluted with methylene chloride (~ 200 ml), and washed with water (2 x 50 ml). The organic layer was dried over anhydrous magnesium sulfate and then concentrated to an oil. The crude product was purified by silica gel chromatography using a methanol/ methylene chloride eluent (3% to 10% MeOH) to afford 3 (8.2 g, 85%) of the title compound. MS: m/e, M+H = 283
With urea hydrogen peroxide adduct; trifluoroacetic anhydride; at 20℃; for 2h;
Preparative Example 34.; A round bottomed flask was charged with 5,6-Dichloro-nicotinic acid methyl ester (0.353 g, 1.72 mmol), urea hydrogen peroxide addition compound (0.340 g, 3.62 mmol), and trifluoroacetic anhydride (0.486 mL, 3.44 mmol). The mixture was stirred at room temperature for 2 hours. To the mixture was added an aqueous solution of sodium thiosulfate. After stirring for 15 min., the solution was poured into 0.5M HCI and extracted with methylene chloride. The organics were washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate, filtered and concentrated in vacuo. There was obtained 0.306 g of product 41. which was not purified further. 1 H NMR (300 MHz, CDCI3): 8.94 (s, 1 H), 8.03 (s, 1 H), 4.09 (s, 3H).
With potassium iodide; potassium carbonate; In dimethyl sulfoxide; ethyl acetate;
EXAMPLE 275B methyl 5-chloro-6-cyanonicotinate A mixture of Example 275A (2.0 g, 10 mmol), potassium iodide (830 mg, 5 mmol), K2CO3 (6.91 g, 50 mmol), and potassium cyanide (3.26 g, 50 mmol) in DMSO (20 mL) at 80 C. was stirred for 6 hours, cooled, treated with ethyl acetate, washed with water and brine, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 3:1/hexanes:ethyl acetate to provide the desired product.
With thionyl chloride; In methanol; ethyl acetate;
EXAMPLE 275A methyl 5,6-dichloronicotinate A solution of 5,6-dichloronicotinic acid (19.2 g, 100 mmol) in methanol (150 mL) at 0 C. was treated with thionyl chloride (10.9 mL, 150 mmol), warmed to room temperature over 18 hours, treated with ethyl acetate, washed sequentially with half-saturated NaHCO3, water, and brine, dried (Na2SO4), filtered, and concentrated to provide the desired product of sufficient purity for subsequent use without further purification.
To a 25OmL reaction vessel purged with nitrogen was added methyl 5,6- dichloropyridine-3-carboxylate (6.5mmol). Dry toluene (28mL) was added to the reaction vessel. The resulting suspension was stirred for a few minutes and N- (chloro(methyl)alumino)-4-(2-fluoro-3-(trifluoromethyl)phenyl)thiazol-2-amine (7.8mmol) was added in small portions. After addition was complete, the reaction was heated to 9O0C and stirred for about 24 hours. The reaction mixture was concentrated to dryness. To the resulting residue was added 1 M Rochelle salt (~50mL) and the mixture was stirred at room temperature for about 12-18 hours. The suspension was filtered, and the filter cake was dissolved in THF and filtered again. Concentration of the filtrate and flash column chromatography of the mixture afforded the desired product (1.78g) as a pale yellow solid ((Companion ReadySep 12Og, silica gel packed) using a 10 % EtOAc / hexanes solvent system). MW = 436.22, yield = 63%, HPLC = 7.03min (100%), LC-MS = 436, 438 (dichloro fragment pattern).; To a 25OmL reaction vessel purged with nitrogen was added 5,6-Dichloro-nicotinic acid methyl ester (6.5mmol). Dry toluene (28m L) was added to the reaction vessel. The resulting EPO <DP n="58"/>suspension was stirred for a few minutes and N-(chloro(methyI)alumino)-4-(2-fluoro-3- (trifluoromethyl)phenyl)thiazol-2-amine (7.8mmol) was added in small portions. After addition was complete, the reaction was heated to 9O0C and stirred for about 24 hours. The reaction mixture was concentrated to dryness. To the resulting residue was added 1 M Rochelle salt (~50mL ) and the mixture was stirred at room temperature for about 12-18 hours. The suspension was filtered, and the filter cake was dissolved in THF and filtered again. Concentration of the filtrate and flash column chromatography of the mixture afforded the desired product (1.78g) as a pale yellow solid ((Companion ReadySep 12Og, silica gel packed) using a 10 % EtOAc / hexanes solvent system). MW = 436.22, yield = 63%, HPLC (min) = 7.03, LC-MS (M+1 ) = 436, 438 (dichloro fragment pattern).; To a 25OmL reaction vessel purged with nitrogen was added 5,6-Dichloro-nicotinic acid methyl ester (6.5mmol). Dry toluene (28mL) was added to the reaction vessel. The resulting suspension was stirred for a few minutes and N-(chloro(methyl)alumino)-4-(2-fluoro-3- (trifluoromethyl)phenyl)thiazol-2-amine (7.8mmol) was added in small portions. After addition was complete, the reaction was heated to 90C and stirred for about 24 hours. The reaction mixture was concentrated to dryness. To the resulting residue was added 1 M Rochelle salt (~50mL ) and the mixture was stirred at room temperature for about 12-18 hours. The suspension was filtered, and the filter cake was dissolved in THF and filtered again. Concentration of the filtrate and flash column chromatography of the mixture afforded the desired product (1.78g) as a pale yellow solid ((Companion ReadySep 12Og, silica gel packed) using a 10 % EtOAc / hexanes solvent system). MW = 436.22, yield = 63%, HPLC (min) = 7.03, LC-MS = 436, 438 (dichloro fragment pattern).; To a 25OmL reaction vessel purged with nitrogen was added 6-Chloro-nicotinic acid methyl ester (6.5mmol). Dry toluene (28mL) was added to the reaction vessel. The resulting suspension was stirred for a few minutes and N-(chloro(methyl)alurnino)-4-(2-fluoro-3- (trifluoromethyl)phenyl)thiazol-2-amine (7.8mmol) was added in small portions. After addition was complete, the reaction was heated to 900C and stirred for about 24 hours. The reaction mixture was concentrated to dryness. To the resulting residue was added 1 M Rochelle salt (~50mL ) and the mixture was stirred at room temperature for about 12-18 hours. The suspension was filtered, and the filter cake was dissolved in THF and filtered again. Concentration of the filtrate and flash column chromatography of the mixture afforded the desired product (1.78g) as a pale yellow solid ((Companion ReadySep 12Og, silica gel packed) using a 10 % EtOAc / hexanes solvent system). MW = 436.22, yield = 63%, HPLC (min) = 7.03, LC-MS (M+1 ) = 436, 438 (dichloro fragment pattern).; To a 25OmL reaction vessel purged with nitrogen was added 6-Chloro-nicotinic acid methyl ester (6.5mmol). Dry toluene (28mL) was added to the reaction vessel. The resulting suspension was stirred for a few minutes and N-(chloro(methyl)alurnino)-4-(2-fluoro-3- (trifluoromethyl)phenyl)thiazol-2-amine (7.8mmol) was added in small portions. After addition was complete, the reaction was heated to 9O0C and stirred for about 24 hours. The reaction mixture was concentrated to dryness. To the resulting residue was added 1 M Rochelle salt (~50mL ) and the mixture was stirred at room temperature for about 12-18 hours. The suspension was filtered, and the filter cake was dissolved in THF and filtered again. Concentration of the filtrate and flash column chromatography of the mixture afforded the desired product (1.78g) as a pale yellow solid ((Companio...
EXAMPLE 9 To a solution of tert-butyl [(2R)-2-(3-chlorophenyl)-2-hydroxyethyl][2-(4-hydroxyphenyl)ethyl]carbamate (600 mg) and potassium carbonate (254 mg) in dimethylsulfoxide (6.0 ml) was added <strong>[56055-54-0]methyl 5,6-dichloro-3-pyridinecarboxylate</strong> (347 mg), and the mixture was stirred at room temperature for 12 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=2/1) to give methyl 6-[4-[2-[(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]phenoxy]-5-chloronicotinate (770 mg). (+)ESI-MS (m/z): 561 (M+H)+
With potassium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl;tris-(dibenzylideneacetone)dipalladium(0); In toluene; at 120℃; for 16h;
5-Chloro-6-(6-methyl-pyridin-3-ylamino)-nicotinic Acid Methyl Ester A suspension of <strong>[56055-54-0]5,6-dichloro-nicotinic acid methyl ester</strong> (50.0 g, 243 mmol), 3-amino-6-methylpyridine (40.2 g, 364 mmol), rac-BINAP (9.05 g, 14.5 mmol), Pd2(dba)3 (11.1 g, 12.1 mmol) and K2CO3 (101.0 g, 731 mmol) in toluene was heated to 120 C. for 16 h. The mixture was allowed to cool to RT and concentrated in vacuo. Purification by re-crystallization in Tol/EtOAc provided 5-chloro-6-(6-methyl-pyridin-3-ylamino)-nicotinic acid methyl ester (37.8 g, 56%). UPLC (5-100% CH3CN): tR=0.832 min, MS (ES+): 278 [M+1]
56%
With potassium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 120℃; for 16h;
5-Chloro-6-(6-methyl-pyridin-3-ylamino)-nicotinic acid methyl ester A suspension of <strong>[56055-54-0]5,6-dichloro-nicotinic acid methyl ester</strong> (50.0 g, 243 mmol), 3-amino-6- methylpyridine (40.2 g, 364 mmol), rac-BINAP (9.05 g, 14.5 mmol), Pd2(dba)3 (11.1 g, 12.1 mmol) and K2CO3 (101.0 g, 731 mmol) in toluene was heated to 120 0C for 16 h. The mixture was allowed to cool to RT and concentrated in vacuo. Purification by re-crystallization in Tol/EtOAc provided 5-chloro-6-(6-methyl-pyridin-3-ylamino)-nicotinic acid methyl ester (37.8 g, 56%). UPLC (5-100% CH3CN): tR = 0.832 min, MS (ES+): 278 [M+1]
Step 1: Methyl 5-chloro-6-(isopropylamino)nicotinate (75). A mixture of <strong>[56055-54-0]5,6-dichloronicotinic acid methyl ester</strong> 74 (6.0 g, 15.2 mmol) and isopropylamine (30 mL, 60.6 mmol) was stirred in a sealed vessel at 100 C. for 14 h. The reaction mixture was cooled to room temperature and concentrated. The residue was dissolved in ethyl acetate and washed with water, sat. NaCl, dried over Na2SO4, concentrated and purified by column chromatography to give 75 (4.4 g, 65. 9%).
5-chloro-6-[3-chloro-4-(3,3,3-trifluoro-2-hydroxy-1-methyl-2-quinoxalin-6-yl-propyl)-phenoxy]-nicotinic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With 1,4-diaza-bicyclo[2.2.2]octane; triethylamine; In HCOOH[aq]; N,N-dimethyl-formamide; acetonitrile;
Step 3: 5-Chloro-6-[3-chloro-4-(3,3,3-trifluoro-2-hydroxy-1-methyl-2-quinoxalin-6-yl-propyl)-phenoxy]-nicotinic acid DABCO (2 mg) was added to a mixture of <strong>[56055-54-0]methyl 5,6-dichloronicotinate</strong> (27 mg, CAS. Reg. No. 56055-54-0), 3-chloro-4-(3,3,3-trifluoro-2-hydroxy-1-methyl-2-quinoxalin-6-yl-propyl)-phenol (50 mg), and triethylamine (17 mg) in DMF (5 ml). The mixture was stirred at room temperature overnight. Aqueous LiOH solution (1N, 1 ml) was added and then stirred for 2 hours to hydrolyze the intermediate ester. The mixture was purified by prep. HPLC (C18-column, solvent gradient 20-98% CH3CN in 0.1% HCOOH[aq]) to give the title compound (10 mg) as a white foam. MS (m/e)=536.1 [M+H+].
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
