* 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.
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1990, vol. 38, # 9, p. 2446 - 2458
[2] Patent: WO2012/87519, 2012, A1,
2
[ 131747-43-8 ]
[ 131747-57-4 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1990, vol. 38, # 9, p. 2446 - 2458
[2] Patent: WO2012/87519, 2012, A1, . Location in patent: Page/Page column 123
[3] Organic Letters, 2017, vol. 19, # 14, p. 3895 - 3898
3
[ 124-38-9 ]
[ 368-48-9 ]
[ 131747-42-7 ]
[ 131747-41-6 ]
[ 131747-43-8 ]
[ 231291-22-8 ]
Reference：
[1] European Journal of Organic Chemistry, 2003, # 8, p. 1569 - 1575
4
[ 124-38-9 ]
[ 368-48-9 ]
[ 131747-42-7 ]
[ 131747-41-6 ]
[ 131747-43-8 ]
[ 231291-22-8 ]
Reference：
[1] European Journal of Organic Chemistry, 2003, # 8, p. 1569 - 1575
5
[ 208517-35-5 ]
[ 131747-43-8 ]
Yield
Reaction Conditions
Operation in experiment
97%
With sodium hydroxide In neat (no solvent) at 100℃; for 1 h;
In a 250ml flask, sodium hydroxide solution (310 g, 7 percent) and ethyl 2-trifluoromethyl nicotinate (lOOg) were taken. The temperature of the reaction mass was raised to 100°C and was maintained for 1 hours. The progress of the reaction was monitored by gas chromatography. After 99percent conversion, the reaction mass was cooled and neutralized with hydrochloric acid (61 g, 30 percent). It was then filtered and washed with water to obtain title compound. (0068) Yield (percent) = 97 (0069) Purity (percent) = 99.5
Reference：
[1] European Journal of Organic Chemistry, 2003, # 8, p. 1559 - 1568
[2] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 16, p. 4555 - 4559
7
[ 124-38-9 ]
[ 368-48-9 ]
[ 131747-43-8 ]
Reference：
[1] Synlett, 2010, # 14, p. 2133 - 2135
[2] European Journal of Organic Chemistry, 2003, # 8, p. 1569 - 1575
8
[ 2942-59-8 ]
[ 77152-08-0 ]
[ 131747-43-8 ]
Reference：
[1] Journal of Organic Chemistry, 2013, vol. 78, # 22, p. 11126 - 11146
9
[ 1620-78-6 ]
[ 131747-43-8 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1990, vol. 38, # 9, p. 2446 - 2458
10
[ 52200-48-3 ]
[ 131747-43-8 ]
Reference：
[1] European Journal of Organic Chemistry, 2003, # 8, p. 1559 - 1568
[2] European Journal of Organic Chemistry, 2003, # 8, p. 1559 - 1568
11
[ 77332-76-4 ]
[ 131747-43-8 ]
Reference：
[1] European Journal of Organic Chemistry, 2003, # 8, p. 1559 - 1568
[2] European Journal of Organic Chemistry, 2003, # 8, p. 1559 - 1568
12
[ 13534-89-9 ]
[ 131747-43-8 ]
Reference：
[1] European Journal of Organic Chemistry, 2003, # 8, p. 1559 - 1568
13
[ 408502-43-2 ]
[ 131747-43-8 ]
Reference：
[1] European Journal of Organic Chemistry, 2003, # 8, p. 1559 - 1568
14
[ 1603-40-3 ]
[ 131747-43-8 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1990, vol. 38, # 9, p. 2446 - 2458
15
[ 3430-17-9 ]
[ 131747-43-8 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1990, vol. 38, # 9, p. 2446 - 2458
16
[ 124-38-9 ]
[ 368-48-9 ]
[ 131747-42-7 ]
[ 131747-41-6 ]
[ 131747-43-8 ]
[ 231291-22-8 ]
Reference：
[1] European Journal of Organic Chemistry, 2003, # 8, p. 1569 - 1575
17
[ 124-38-9 ]
[ 368-48-9 ]
[ 131747-42-7 ]
[ 131747-41-6 ]
[ 131747-43-8 ]
[ 231291-22-8 ]
Reference：
[1] European Journal of Organic Chemistry, 2003, # 8, p. 1569 - 1575
18
[ 131747-43-8 ]
[ 1018678-39-1 ]
Yield
Reaction Conditions
Operation in experiment
94%
Stage #1: With 2,2,6,6-tetramethyl-piperidine; n-butyllithium In tetrahydrofuran; hexanes at -78 - -50℃; for 1.33333 h; Stage #2: With hexachloroethane In tetrahydrofuran; hexanes at -15 - 20℃;
Preparation of 4-Chloro-2-(trifluoromethyl)nicotinic acid; To a stirred solution of 2,2,6,6-tetramethylpiperidine (21.0 mL, 124 mmol) in dry THF (200 mL) in a -78° C. bath is added n-Butyl lithium (66.2 mL of a 2.5M solution in hexanes, 166 mmol). The solution is stirred at -78° C. for 30 minutes, followed by the addition of a solution of 2-(trifluoromethyl)nicotinic acid (7.90 g, 41.4 mmol) in THF (35 mL) via canula. The solution is stirred at -78° C. for 20 minutes, followed by warming to -50° C. for 1 hour (to provide the corresponding lithiated pyridine). In a separate flask, hexachloroethane (29.4 g, 124 mmol) is dissolved in THF (200 mL) and cooled to -15° C. and stirred rapidly. The solution containing the lithiated pyridine is added to the hexachloroethane solution via canula. After complete addition, the mixture is allowed to ward to room temperature. Water (ca 200 mL) is added, followed by removal of the tetrathydrofuran in vacuo. The remaining aqueous residue is extracted with ether-pentane (1:1, 100 mL). The organic layer was discarded. The aqueous layer is acidified with hydrochloric acid (ca. 50 mL of a 1.0 M solution). The aqueous layer is extracted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford 8.75 g (94percent) of the title compound as a tan solid: 1H NMR (400 MHz, CD3OD), 8.63 (d, 1H), 7.79 (d, 1H). LC/MS (M+1)=226.1; [see: Schlosser et al., Eur. J. Org. Chem. 2003, 1559].
88%
Stage #1: With 2,2,6,6-tetramethyl-piperidine; n-butyllithium In tetrahydrofuran at -70 - -50℃; for 1.33333 h; Stage #2: With hexachloroethane In tetrahydrofuran at -15 - 20℃; for 0.5 h; Enzymatic reaction
To a solution of Example 42b (22.1 g, 157.1 mmol) in THF (250 mL) was added nBuLi (84 mL, 209.4 mmol, 2.5 M in THF) at -70°C, followed, after 0.5 h, by the addition of asolution of Example 42a (10 g, 52.3 mmol) in THF (40 mL). The solution was stirred at -70°Cfor 20 mm, followed by warming to -50°C for 1 h. In a separate flask, C2C16 (37.2 g, 157.1mmol) was dissolved in THF (250 mL) and cooled to -15°C. The solution containing the lithiated pyridine was added to the C2C16 solution. After complete addition, the mixture was warmed to r.t. and stirred for 0.5 h. The reaction was quenched with water (250 mL), followed by removal of THF in vacuo. The aqueous residue was extracted with MTBE (250 mL). The aqueous layer was acidified with HC1 (1 M, 60 mL), extracted with EtOAc (250 mL*2). The combined organic phase was washed with brine, dried over Na2SO4, filtrated and the filtrate was concentrated under reduced pressure to give the desired product (Example 42c, 10.4 g, yield 88percent) as a yellow solid. LCMS [M+1] = 225.9.’HNIVIR (400 MHz, DMSO-d6) 8.78 (d, J5.3 Hz, 1H), 8.04 (d, J 5.3 Hz, 1H).
Reference：
[1] Patent: US2008/85887, 2008, A1, . Location in patent: Page/Page column 18
[2] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 16, p. 4555 - 4559
[3] Patent: WO2018/31680, 2018, A1, . Location in patent: Paragraph 00405
[4] Patent: EP2889291, 2015, A1, . Location in patent: Paragraph 0295
A solution of 2- (trifluoromethyl)nicotinic acid (5g, 26.2 mml) in dry tetrahydrofuran (50 mL) was cooled to - 10C and then treated with LiAlH4 (39 mL, of a 1M solution in THF) by very slow addition. The reaction mixture was stirred at room temperature for 14 hours. The reaction was then cooled to -10 C and quenched with a very slow drop wise addition of water (2 mL) and 6N HC1 (1.2 mL). The reaction mixture was further diluted with water and extracted with dietyl ether (3 x 100 mL). The organics were combined and washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude oily residue was purified by silica gel chromatography with a gradient of 0-10% ethyl acetate- dichloromethane to yield (2-(trifluoromethyl)pyridin-3- yl)methanol (I-29A) as pale yellow oil. 1H-NMR (400 MHz, CDC13) delta 8.61 (d, J = 4.8 Hz, 1H), 8.15 (dd, J = 8.0, and 0.8 Hz, 1H), 7.55 (dd, J = 8.0 and 4.4 Hz, 1H), 4.95 (d, J = 6.0 Hz, 2H), 2.02 (t, J = 6.0 Hz, 1H). MS m/z 178.0 (M + 1).
Preparation of 4-Chloro-2-(trifluoromethyl)nicotinic acid; To a stirred solution of 2,2,6,6-tetramethylpiperidine (21.0 mL, 124 mmol) in dry THF (200 mL) in a -78 C. bath is added n-Butyl lithium (66.2 mL of a 2.5M solution in hexanes, 166 mmol). The solution is stirred at -78 C. for 30 minutes, followed by the addition of a solution of 2-(trifluoromethyl)nicotinic acid (7.90 g, 41.4 mmol) in THF (35 mL) via canula. The solution is stirred at -78 C. for 20 minutes, followed by warming to -50 C. for 1 hour (to provide the corresponding lithiated pyridine). In a separate flask, hexachloroethane (29.4 g, 124 mmol) is dissolved in THF (200 mL) and cooled to -15 C. and stirred rapidly. The solution containing the lithiated pyridine is added to the hexachloroethane solution via canula. After complete addition, the mixture is allowed to ward to room temperature. Water (ca 200 mL) is added, followed by removal of the tetrathydrofuran in vacuo. The remaining aqueous residue is extracted with ether-pentane (1:1, 100 mL). The organic layer was discarded. The aqueous layer is acidified with hydrochloric acid (ca. 50 mL of a 1.0 M solution). The aqueous layer is extracted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford 8.75 g (94%) of the title compound as a tan solid: 1H NMR (400 MHz, CD3OD), 8.63 (d, 1H), 7.79 (d, 1H). LC/MS (M+1)=226.1; [see: Schlosser et al., Eur. J. Org. Chem. 2003, 1559].
88%
To a solution of Example 42b (22.1 g, 157.1 mmol) in THF (250 mL) was added nBuLi (84 mL, 209.4 mmol, 2.5 M in THF) at -70C, followed, after 0.5 h, by the addition of asolution of Example 42a (10 g, 52.3 mmol) in THF (40 mL). The solution was stirred at -70Cfor 20 mm, followed by warming to -50C for 1 h. In a separate flask, C2C16 (37.2 g, 157.1mmol) was dissolved in THF (250 mL) and cooled to -15C. The solution containing the lithiated pyridine was added to the C2C16 solution. After complete addition, the mixture was warmed to r.t. and stirred for 0.5 h. The reaction was quenched with water (250 mL), followed by removal of THF in vacuo. The aqueous residue was extracted with MTBE (250 mL). The aqueous layer was acidified with HC1 (1 M, 60 mL), extracted with EtOAc (250 mL*2). The combined organic phase was washed with brine, dried over Na2SO4, filtrated and the filtrate was concentrated under reduced pressure to give the desired product (Example 42c, 10.4 g, yield 88%) as a yellow solid. LCMS [M+1] = 225.9.?HNIVIR (400 MHz, DMSO-d6) 8.78 (d, J5.3 Hz, 1H), 8.04 (d, J 5.3 Hz, 1H).
63.57%
With 2,2,6,6-tetramethyl-piperidine; n-butyllithium; In tetrahydrofuran; hexane; hexachloroethane; at -78 - 20℃; for 2.5h;
To a cooled solution of 2,2,6,6-tetramethylpiperidine (4.43 g, 31.39 mmol) in anhydrous THF (50 mL) was added n-BuLi (2.5M in hexane, 16.74 mL, 41 .86 mmol) dropwise over 5 min at -78C and the resulting solution was stirred for 30 minutes at - 78C. Then 2-(trifluoromethyl)nicotinic acid (2.0 g, 10.46 mmol) in anhydrous THF (20 mL) was added dropwise over 5 min at -78C and the resulting solution was stirred for 20 minutes at -78C, followed by -50C for 1 hour. Hexachloroethane (7.43 g, 31.39 mmol) in anhydrous THF (30 mL) was then added dropwise over 5 min at -78C. The reaction mixture was allowed to warm to rt and stirred for 1 h at rt .The reaction mixture was then quenched with water, the THF was removed by reduced pressure, to the resulting aquous layer was washed with 50% diethyl ether in pentane (50 mL ) and adjusted pH 4-5 using 1.0 M solution of HCI and extracted with EtOAc (100 mL X 3), combined organic phases were dried over sodium sulphate, evaporated under reduced pressure to afford a title compound as tan solid (1 .50g, 63.57 %), Rf = 0.1 (5 % methanol in Dichloromethane) 1 H NMR (300 MHz, DMSO-d6) d 8.80 (d, J = 5.3 Hz, 1 H), 8.06 (d, J = 5.3 Hz, 1 H); LC-MS m/z 225.95 [M+H]+, retention time = 0.32 min (Method A).
To a solution of 2,2,6,6-tetramethylpiperidine (11.1 g) in THF (100 mL) was added dropwise 1.6 M n-butyllithium hexane solution (65.4 mL) at -78C and the mixture was stirred at the same temperature for 30 min. Then a solution of 2-(trifluoromethyl)nicotinic acid (5.0 g) in THF (80 mL) was added dropwise at -78C. After stirring at the same temperature for 20 min, the mixture was warmed to -50C, and the mixture was further stirred for 1 hr. This solution was added dropwise to a solution of hexachloroethane (15.5 g) in THF (20 mL), which was separately stirring at -15C, and the mixture was warmed to room temperature and stirred overnight. Water was added to the reaction mixture and the solvent was evaporated under reduced pressure. Water was added to the residue, diethyl ether was further added, and the obtained aqueous layer was neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound. This was used without purification for the next step. 1H NMR (300 MHz, DMSO-d6) delta 8.06 (1H, d, J = 5.3 Hz), 8.80 (1H, d, J = 5.3 Hz).
With N-ethyl-N,N-diisopropylamine; bromo-tris(1-pyrrolidinyl)phosphonium hexafluorophosphate; In dichloromethane; at 20℃; for 20h;
A solution of 204 mg (1 mmol) of 2-trifluormethyl nicotinic acid, 200 mg (0.9 mmol) of 2-(3-chloro-5-trifluormethyl-pyridin-2-yl)-ethylamine and 620 mg (1.3 mmol) of bromotripyrrolidinophosphonium hexafluorophosphate and 230 mg (1.8 mmol) N,N-Diisopropylethylamine in 8 ml methylene chloride is stirred for 20 h at room temperature. The mixture is diluted with 10 ml water, separated and the methylene chloride phase is washed with sat. NH4Cl solution and water.. The organic phase is dried over sodium sulfate.. After evaporation of the solvent the residue is purified by column chromatography over silica-gel (eluant:hexane/ethylacetate = 10:1 to 1:1). Yield: 370 mg (98%).
P1a : 4-Trifluoromethylnicotinic acid chloride 18.7 g of trifluoromethylnicotinic acid are mixed together with a few drops of dimethyl-formamide and heated to 85 C. At this temperature, 17.46 g of thionyl chloride are added dropwise, and afterwards stirring is effected for a further 5 hours at 85 C. Then, the excess thionyl chloride is evaporated off and the product distilled at approximately 100 C. and 40 mbar. 4-Trifluoromethylnicotinic acid chloride is obtained as a colourless oil.
The following compounds, for example, are illustrative: ... 2-chloroisonicotinic acid, 4-methylnicotinic acid, 3-methylisonicotinic acid, 3-methylthioisonicotinic acid, 2-trifluoromethylnicotinic acid, 3,5-dichloroisonicotinic acid, 2-chloro-4-methylnicoticic acid, 2,4-dimethylnicotinic acid, ...
20
[ 923288-56-6 ]
[ 131747-43-8 ]
[ 923288-07-7 ]
Yield
Reaction Conditions
Operation in experiment
78%
Example 64. a) To a stirred solution of 2-trifiuoromethyl nicotinic acid (0.38 g, 2 mmol) in dimethylformamide (10 mL) at room temperature was added 1,1-carbonyldiimidazole (0.34 g, 2.10 mmol) in one portion. The resulting yellow mixture was allowed to stir for ninety minutes whereupon 3,4-bis(benzyloxy)-N'-hydroxy-5-nitrobenzamidine (0.79 g, 2 mmol) was added in one portion. The resulting mixture was stirred at room temperature for two hours and then poured onto water (100 mL). The resulting precipitate was filtered off, washed with water and dried. After recrystallisation from dichloromethane/isopropanol 3 ,4-bis(benzyloxy)-5-nitro-N'-(2- (trifluoromethyl)nicotinoyloxy)benzimidamide was obtained, as a light yellow solid, 0.88 g (78%).
Alternate coupling procedure:Combine 4-(4,5-dimethyl-6-(4-(methylamino)piperidin-l-yl)pyridazin-3- yl)benzonitrile (300 mg, 0.93 mmol), <strong>[131747-43-8]2-(trifluoromethyl)nicotinic acid</strong> (210 mg, 1.12 mmol) and diisopropylethylamine (0.79 mL, 4.51 mmol) in a 4: 1 mixture of DMF and DMSO (20 mL). Heat the mixture briefly at 60 0C to dissolve the solids, and then cool to 0 0C. Add a solution of perfluorophenyl diphenylphosphinate (750 mg, 1.96 mmol) in a 4: 1 mixture of DMF and DMSO (1 mL) dropwise. Heat the resulting mixture at 60 0C overnight. Partition the reaction mixture between aqueous NaHCO3 solution and CH2Cl2. Wash the organic layer with brine, dry over Na2SO4, filter, and concentrate under reduced pressure. Purify the resulting residue by flash silica gel chromatography (20:5: 1 hexanes: EtOAc: 2 M NH3/MeOH) to provide the free base of the title compound (346 mg, 75%). ES/MS m/z 495.2 (M+l). Form the HCl salt as described above.
Intermediate F To a 50 ml_ fiask containing 20 mL of DMF was added 1 mL of oxaiy. chloride siowiy and stirred for 10 min at RT. 100 rng of 2-trifluoromethyl nicotinic acid was dissolved in 2 mL of the above solution and stirred for 5 min at RT. Then 50 mg of 2-cyano-5- aminopy?dine was dissolved in 1 mL pyridine and added to the above solution. The reaction was completed in 5 min at RT and quenched with 1 mL NH4OH. The solvent was then evaporated under vacuum and the residue was used directly in the next step. The nitrile was dissolved in methanol (10 mL) and water (10 mL). Sodium hydroxide (300mg) was added to the above solution and the solution heated at 700C for 16 h. The reaction mixture was quenched with 1 N HCI (10 mL), and extracted with EtOAc four times (15 mL). Volatiles were evaporated and the intermediate F used without further purification in the next steps
Example 26To a 50 mL flask containing 20 imL of DMF was added 1 mL of oxalyl chloride siowiy and stirred for 10 min at RT. 100 mg of the carboxyiic acid was dissolved in 2 mL of the above solution and stirred for 5 min at RT. Then 50 mg of P was dissolved in 1 mL pyridine and added to the above solution. The reaction was completed in 5 min at RT and quenched with 1 mL NH4OH. The solvent was then evaporated under vacuum and the residue dissolved in CH3CN and water and purified with prep HPLC (0% to 95% water/ Acetonitrile) to afford 26 (26.7 mg, 54%).1H-NMR (DMSO, 300 MHz): delta 8.52 (d, J = 3.9 Hz, 1 H), 7.87 (d, J = 7.5 Hz, 1 H), 7.72 (d, J = 7.5 Hz, 1 H), 7.64-7.43 (m, 3H), 7.24 (t, J = 7.5 Hz, 1 H)5 7.15 (t, J = 8.1 Hz, 1 H)1 7.08 (t, J = 7.2 Hz, 1 H), 6.90 (d, J = 7.5 Hz, 1 H), 4.86-4.81 (m, 1 H), 3.34-3.04 (m, 3H), 2.84-2.78 (m, 1 H), 0.65 (m, 2H), 0.51 (m, 2H).LCMS m/z [M+H]+ C30H22F4N4O3S requires: 595.58. Found 595.00 HPLC Tr (min), purity %: 3.33, 98%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 0 - 20℃; for 3h;
Step 5: ?-??1 -(4-chlorothiazol-2-yl)cvclopropyllmethyll-2-(trifluoromethyl)pyridine-3- carboxamide (Compound A21 )To a solution of [1-(4-chlorothiazol-2-yl)cyclopropyl]methanamine (0.153 g, 0.747 mmol) in dry dichloromethane (3.0 mL) was added, under argon, NEt3 (0.210 ml_, 1 .49 mmol), then the mixture was cooled down to 0C. HOBT H20 (0.204 g, 1 .49 mmol), EDC HCL (0.287 g, 1.49 mmol), and <strong>[131747-43-8]2-(trifluoromethyl)pyridine-3-carboxylic acid</strong> (0.143 g, 0.747 mmol,) were successively added and the reaction mixture was stirred 3h. at R.T. Water was added, the aqueous solution was extracted with dichloromethane (3 times), the combined organic layers were washed by NaCI, dried over Na2S04, filtrated and evaporated under reduced pressure. A white solid was obtained (387 mg). It was purified by flash chromatography (Cyclohexane to Cyclohexane/AcOEt :1/1 ) to afford the desired product as a white solid (102 mg).1H-NMR (CDCI3): 8.77 (dd, 1 H), 7.92 (dd, 1 H), 7.56 (dd, 1 H), 6.97 (bs, 1 H), 6.9 (s, 1 H), 3.86 (d, 2H), 1.42 (m, 2H), 1.18 (m, 2H).
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃;
Step 5: N-rri-(4,6-dichloro-3-pyridyl)cvclopropyllmethyll-2-(trifluoromethyl)pyridine-3- carboxamide (Compound A1 18)[1-(4,6-Dichloro-3-pyridyl)cyclopropyl]methanamine (0.300 g, 0.691 mmol) was stirred in CH2CI2 (3.1 mL). At rt triethylamine (0.385 mL, 2.76 mmol) was added, to give a pale yellow suspension. At rt 2-(Trifluoromethyl)pyridine-3-carboxylic acid (0.132 g, 0.691 mmol) was added, then HOBT hydrate (0.187 g, 1.38 mmol) and finally EDCI.HCI (0.265 g, 1.38 mmol) to give a yellow solution. The solution was stirred at rt overnight. The solution was evaporated. The residue was dissolved in AcOEt and water. The phases were separated. The organic phase was washed with brine. The organic phase was dried with Na2SC>4, filtrated and the filtrate evaporated. A crude material was obtained as a yellow gum (286 mg). It was purified by flash chromatography (Solvent: Cyclohexane /EtOAc gradient from 2/1 to 1/2). The desired product was isolated as a white solid (55 mg).1H-NMR (CDCIs): 8.77 (d, 1 H), 8.2 (s, 1 H), 7.77 (d, 1 H), 7.56 (dd, 1 H), 7.38 (s, 1 H), 6.1 (bs, 1 H), 3.69 (d, 2H), 1.2 (m, 2H), 0.93 (m, 2H).
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃;
Step 7: N-rri-(3,5-difluoro-4-pyridyl)cvclopropyllmethyll-2-(trifluoromethyl)pyridine-3- carboxamide (Compound A126)[1-(3,5-Difluoro-4-pyridyl)cyclopropyl]methanamine (0.14 g, 0.760 mmol) was dissolved in CH2CI2 (3.5 ml_). At rt triethylamine (0.423 ml_, 3.040 mmol) was added. Then 2- (trifluoromethyl)pyridine-3-carboxylic acid (0.14526 g, 0.760 mmol), HOBT hydrate (0.20541 g, 1 .520 mmol) and finally EDCI.HCI (0.29143 g, 1 .520 mmol) were successively added at r.t. The solution was stirred at rt overnight. The solution was evaporated. The residue was dissolved in ethyl acetate and water. The phases were separeted. The organic phase was washed with brine. The organic phase was dried with filtrated and the filtrate evaporated which gave 268 mg of a yellow gum. The crude material was purified by flash chromatography (Solvent: Cyclohexane /EtOAc gradient from 2/1 to 1/2). The desired product was isolated as a white solid (188 mg).1H-NMR (CDCI3): 8.75 (dd, 1 H), 8.38 (s, 1 H), 7.78 (d, 1 H), 7.53 (dd, 1 H), 6.15 (bs, 1 H), 3.6 (d, 2H), 1 .17 (m, 2H), 1 .0 (m, 2H).
With thionyl chloride; In N,N-dimethyl-formamide; toluene; at 110℃; for 2h;
Step 2: N-[2-(2-fluoro-4-trifluoromethyl-phenyl)-ethyl1-2-trifluoromethyl-nicotinamide (Compound A.001 ) To a suspension of <strong>[131747-43-8]2-trifluoromethyl-nicotinic acid</strong> (4.20 g, 22.0 mmol) in toluene (22 ml) was added sequentially thionyl chloride (4.8 ml, 66 mmol) and DMF (two drops). The reaction mixture was heated at 1 10 C for 2 h. After the gas evolution ceased, the reaction mixture was concentrated in vacuo to give 2-trifluoromethyl-nicotinoyl chloride (4.65 g, 22.0 mmol) as a brown liquid which was directly used in the preparation of N-[2-(4-chloro-2-fluoro-phenyl)-ethyl]-2-trifluoromethyl-nicotinamide described below. To a solution of 2-(2-fluoro-4-trifluoromethyl-phenyl)-ethylamine hydrochloride (5.00 g, 20.5 mmol) and triethylamine (8.7 ml, 62 mmol) in 41 ml of dichloromethane at 0 C was added slowly 2- trifluoromethyl-nicotinoyl chloride (4.52 g, 21 .5 mmol). The reaction mixture was stirred at 0 C for 30 min. Then water was added, the phases were separated and the water phase was extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The crude material obtained was purified by Combiflash chromatography using dichloromethane as the eluent to afford N-[2-(2-fluoro-4-trifluoromethyl-phenyl)- ethyl]-2-trifluoromethyl-nicotinamide as a beige powder. 1 H NMR (CDCI3, 400MHz) delta 3.00-3.10 (2H, m); 3.70-3.80 (2H, m); 5.75-5.90 (1 H, br s); 7.30 (1 H, d, J = 10); 7.35-7.45 (2H, m); 7.50-7.60 (1 H, m); 7.82 (1 H, d); 8.20-8.30 (1 H, m).
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 18h;
a. Preparation of N-[2-(2,4-difluorophenyl)cvclobuten-1 -yl1-2-(trifluoromethyl)pyridine-3-carboxamide2-(Trifluoromethyl)pyridine-3-carbonyl chloride solution: To a stirred solution of <strong>[131747-43-8]2-(trifluoromethyl)pyridine-3-carboxylic acid</strong> (1 .7 g, 8.9 mmol) and a catalytic amount ofdimethylformamide in dichloromethane (10 ml), was added dropwise oxalylchloride (0.83 ml). The reaction mixture was stirred at room temperature for 18 hours, evaporated in vacuo and disolved again in dichloromethane (10ml).2-(Trifluoromethyl)pyridine-3-carbonyl chloride solution (5.6 mmol, 2.2 equivalents) was added dropwise to a stirred suspension of N-[2-(2,4-difluorophenyl)cyclobuten-1 -yl]formamide (537 mg) in toluene (8 ml) at 0C followed by addition of triethyl amine (0.79ml). The reaction mixture was stirred at 0C for 90 minutes and at 40C for 1 hour. Another portion of 2-(trifluoromethyl)pyridine-3-carbonyl chloride solution (2.6 mmol, 1 equivalent), triethyl amine (0.4 ml) and a catalytic amount of 4-dimethylaminopyridine were added and the reaction mixture was stirred at room temperature for aditional 16 hours.LC/MS analysis reveals the presence of N-[2-(2,4-difluorophenyl)cyclobuten-1 -yl]-N-formyl-2-(trifluoromethyl)pyridine-3-carboxamide intermediate:LC-MS (ES+): m/z = 383 (M+H) RT=1 .69 (method G).The mixture was taken up into ethyl acetate and the ethyl acetate solution was washed with saturated NaHC03, NH4CI, brine and it was dried (Na2S04). Filtration and concentration by rotary evaporation gave a brown oil. It was dissolved in methanol (6 ml). Potassium carbonate (289 mmol) was added and the mixture was stirred for 75 minutes at room temperature, filtered and evaporated. The mixture was taken up into ethyl acetate and the ethyl acetate solution was washed with saturated NH4CI, brine and it was dried (Na2S04). Filtration and concentration by rotary evaporation gave a brown solid.N-[2-(2,4-difluorophenyl)cyclobuten-1 -yl]-2-(trifluoromethyl)pyridine-3-carboxamide was isolated by column chromatography over silica gel (hexanes:ethyl acetate gradient) as an off-white solid . m.p. 171 -178 CH-NMR (CDCI3, 400Mhz):5 = 8.82 (d, 1 H, J=4.4Hz), 8.07 (bd, 1 H, J=12.8Hz), 7.99 (d, 1 H, J=7.7Hz), 7.59-7.64 (m, 1 H), 7.1 1 -7.18 (m, 1 H), 6.85-6.92 (m, 1 H), 6.73-6.81 (m, 1 H), 3.20-3.25 (m, 2H), 2.64-2.69 (m, 2H).
N-(1S,2S)-2-(2,4-dichlorophenyl)cyclobutamine hydrochloride[ No CAS ]
[ 131747-43-8 ]
N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]-2-(trifluoromethyl)pyridine-3-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃;
d. Preparation of N-[(1 S,2S)-2-(2,4-dichlorophenyl)cvclobutyl1-2-(trifluoromethyl)pyridine-3-carboxamideN-(1 S,2S)-2-(2,4-dichlorophenyl)cyclobutylamine hydrochloride (9.6g, 38 mmol) was dissolved in 100 ml DMF, N-hydroxy-benztriazole. hydrate (1 1 g, 76 mmol), EDCI hydrochloride (15 g, 76 mmol), and <strong>[131747-43-8]2-trifluoromethylnicotinic acid</strong> (8.7 g, 46 mmol) were added. Triethylamine (12 g, 1 10 mmol) was added to give a weak exotherm, and a slight suspension. It was stirred overnight at RT. The mixture was shaken between ether and water, washed with brine, dried with Na2S04, and evaporated. The crude was stirred with hexane and the crystals filtered off, washed with hexane, and dried in vacuo to yield pure product. It was analyzed via chiral HPLC (method C) which showed an ee of 99.7 % in favour of the desired enantiomer eluting at 4.81 min (minor enantiomer eluting at 9.32 min).m.p. 122-124 C.1 H-NMR (CDCI3) 2.07 (1 H, m); 2.38 (2H, m); 2.12 (1 H, m); 2.62 (1 H, m); 4.26 (m, 1 H); 5.05 (1 H, m); 5.45 (1 H, br d, NH); 7.28 (3H, m); 7.48 (1 H, dd); 7.63 (1 H, d); 8.68 (1 H, d).
(1R,3S)-5-[3-({4-methyl-5-[2-(trifluoromethyl)pyridin-3-yl]-4H-1,2,4-triazol-3-yl}sulfanyl)propyl]-1-[4-(trifluoromethyl)phenyl]-5-azaspiro[2.4]heptane dihydrochloride[ No CAS ]
3-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-1,2,4-thiadiazol-5-amine[ No CAS ]
[ 131747-43-8 ]
N-{3-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-1,2,4-thiadiazol-5-yl}-2-(trifluoromethyl)nicotinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65 mg
With N-ethyl-N,N-diisopropylamine; bromo-tris(1-pyrrolidinyl)phosphonium hexafluorophosphate; In dichloromethane; at 20℃;
Synthesis Example 14 N-{3-[3-Chloro-5-(trifluoromethyl)pyridin-2-yl]-l,2,4-thiadiazol-5-yl}-2- (trifluoromethyl)nicotinamide (Compound 1-2-3 in Table 2) 2-(Trifluoromethyl)nicotinic acid (168 mg), bromo-tris-pyrrolidino phosphoniumhexafluorophosphate (513 mg) and 3-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-l,2,4-thiadiazol-5-amine (206 mg) and diisopropylethylamine (189 mg) were placed in dichloromethane (7 mL). The reaction mixture was stirred overnight at room temperature. Some water was added. After extraction with dichloromethane the organic phase was dried and evaporated. The residue obtained was purified first by silica gel chromatography and then by preparative HPLC. This afforded 65 mg of the title compound. HPLC-MS: mass (m/z): 353.9 (M+H) 'H-NMR (400.0 MHz, d6-DMSO): see peak list for compound 1-2-3 (Table 2)
With sodium hydroxide; In neat (no solvent); at 100℃; for 1h;
In a 250ml flask, sodium hydroxide solution (310 g, 7 %) and ethyl 2-trifluoromethyl nicotinate (lOOg) were taken. The temperature of the reaction mass was raised to 100C and was maintained for 1 hours. The progress of the reaction was monitored by gas chromatography. After 99% conversion, the reaction mass was cooled and neutralized with hydrochloric acid (61 g, 30 %). It was then filtered and washed with water to obtain title compound. (0068) Yield (%) = 97 (0069) Purity (%) = 99.5
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 25℃; for 2.5h;
<strong>[131747-43-8]2-trifluoromethylpyridine-3-carboxylic acid</strong> (0.191 g, 1.0 mmol)And aminoacetonitrile hydrochloride (0.081 g, 1.0 mmol)Dissolved in 25 mL of dichloromethane,Add triethylamine (0.202 g, 2.0 mmol),Then EDCI (0.287 mg, 1.5 mmol) was added.HOBt (0.20g, 1.5mmol),Reaction at 25 C for 2.5 h,TLC detects the reaction completely,The reaction solution was washed with water (20 ml*2),Saturated saline solution (20ml*1),Dry over anhydrous sodium sulfate,Desolvent, get crude,Crude column chromatography gave an off-white solid.M.p. 90-93 C, yield: 79.5%.
N-{5-[(5R)-7-chloro-4,4-difluoro-5-hydroxy-5-(hydroxymethyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-1-carbonyl]pyridin-2-yl}-2-(trifluoromethyl)pyridine-3-carboxamide[ No CAS ]
6-[2-(trifluoromethyl)pyridin-3-amido]pyridine-3-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
11.21 g
To a suspension of <strong>[131747-43-8]2-(trifluoromethyl)pyridine-3-carboxylic acid</strong> (9.76 g) in DCM (200 mL) were added (COC1)2 (13.41 mL) and DMF (0.119 mL) at 0C, and the mixture was stirred at 0C for 1 hour, followed by stirring at 30-40C for 2 hours. The reaction solution was concentrated, and then the concentrate was diluted with DCM. The resulted solution was added to a suspension of methyl 6-aminonicotinate (7.77 g) in Pyr (20.65 mL) and DCM (200 mL). The mixture was stirred at room temperature for 2 hours, and then DCM was removed under reduced pressure. Water was added to the residue, and the mixture was extracted with AcOEt. The organic layer was dried over anhydrous Na2SO4, and then filtered and concentrated. The resulted residue was dissolved in MeOH-THF (4:1; 200 mL), and then thereto was added SN aqueous NaOH solution (20.43 mL), and the mixture was stirred at 60C for 2 hours. The reaction solution was concentrated and MeOH was removed. Then, the residue was diluted with water and adjusted to pH (4-5) by addition of HC1 aq. The precipitated solid was filtered and washed with water to give6- [2-(trifluoromethyl)pyridin-3-amidojpyridine-3-carboxylic acid (11.21 g).
3-(2,6-difluorophenyl)-1,2,4-oxadiazol-5-amine[ No CAS ]
[ 131747-43-8 ]
N-[3-(2,6-difluorophenyl)-1,2,4-oxadiazol-5-yl]-2-(trifluoromethyl)nicotinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74.2 g
To <strong>[131747-43-8]2-(trifluoromethyl)nicotinic acid</strong> (155 mg) in dimethylformamide (1.5 mL) was added 1- [bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate) (HATU) (309 mg) and diisopropylethylamine (0.265 mL). The reaction mixture was stirred at room temperature for 15 minutes. Amine (II-l) (100 mg) was added. The reaction was heated 3 hours to 80 C. The reaction mixture was cooled down. HPLC purification afforded 74.2 mg of the title compound.HPLC-MS: mass (m/z): 371.0 (M+H)+1H-NMR (400.0 MHz, d6-DMSO): d = 8.91 (d, 1H), 8.37 (d, 1H), 7.88 (m, 1H), 7.73 (m, 1H), 7.36 (t, 2H).
2-[2-chloro-4-[4-[3-chloro-5-(trifluoromethyl)pyridin-2-yloxy]phenyl]ethynyl]phenyl-2,2-difluoro-1-methylethylamine[ No CAS ]
[ 131747-43-8 ]
N-[2-[2-chloro-4-[4-[3-chloro-5-(trifluoromethyl)pyridin-2-yloxy]phenylethynyl]phenyl]-2,2-difluoro-1-methylethyl]-2-(trifluoromethyl)nicotinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77 mg
With dmap; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; In N,N-dimethyl-formamide; at 20℃; for 12h;
2- [2-Chloro-4- [4- [3-chloro-5- (trifluoromethyl) pyridin-2-yloxy] phenylethynyl] phenyl-2,2-difluoro-1-methylethylamine 104 mg N, N -In a 2 ml solution of dimethylformamide, 65 mg of triethylamine, 5 mg of 4- (N, N-dimethylamino) pyridine and O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate 82 mg of lato, 3 mg of 4- (N, N-dimethylamino) pyridine and 49 mg of 2- (trifluoromethyl) nicotinic acid were added and stirred at room temperature for 12 hours. After completion of the reaction, 3 ml of water was added and extracted with ethyl acetate (5 ml × 1). The organic layer was dehydrated and dried in the order of saturated brine and then anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate-hexane (gradient from 0:10 to 2: 8) to obtain 77 mg of the objective product as a colorless dendritic substance.
2-[2-chloro-4-[[6-(trifluoromethyl)pyridine-3-yl]ethynyl]phenyl]-2,2-difluoro-1-(methyl)ethylamine[ No CAS ]
[ 131747-43-8 ]
N-[2-[2-chloro-4-[[6-(trifluoromethyl)pyridine-3-yl]ethynyl]phenyl]-2,2-difluoro-1-methylethyl]-2-(trifluoromethyl)nicotinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
45 mg
With dmap; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine; In dichloromethane; at 20℃; for 16h;
To a stirred solution of 2-[2-chloro-4-[[6- (trifluoromethyl)pyridine-3-yl]ethynyl]phenyl]-2,2-difluoro-1-(methyl)ethylamine (130mg), 2- (trifluoromethyl)nicotinic acid (74mg), triethylamine (0.5ml) and 4-(dimethylamino)pyridine (5mg) in dichloromethane (1 ml) was added 0-(benzotriazol-1-yl)-1 ,1 ,3,3-tetramethyluronium tetrafluoroborate (170mg). After stirring at room temperature for 16h, water (10ml) was added, and then extracted with ethyl acetate (10ml x 1 ). The organic extracts were washed with 1 M aqueous hydrochloric acid (10ml x 2) and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with ethyl acetate-hexane (0:100 to 25:75 gradient composition) to afford the title compound as a colorless resin (45mg). NMR (CDCIs, Me4Si, 300MHz) 68.8-8.85 (m, 1 H), 8.7-8.75 (m, 1 H), 7.95-8.25 (m, 1 H), 7.65-7.75 (m, 3H), 7.55-7.6 (m, 1 H), 7.5-7.55 (m, 2H), 5.9-6.05 (m, 1 H), 5.35-5.55 (m, 1 H), 1.34 (d, J=6.7Hz, 3H).
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