* 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: WO2005/28429, 2005, A2, . Location in patent: Page/Page column 81
[3] Patent: WO2010/59393, 2010, A1, . Location in patent: Page/Page column 89
[4] Patent: WO2006/34004, 2006, A2, . Location in patent: Page/Page column 71
2
[ 124-38-9 ]
[ 189278-27-1 ]
[ 131747-42-7 ]
Yield
Reaction Conditions
Operation in experiment
35%
Stage #1: With n-butyllithium In hexanes; diethyl ether at -70 - -40℃; Stage #2: at -70 - 20℃; Stage #3: With hydrogenchloride In water
Preparation C4: Synthesis of 6-(trifluoromethyl)picolinic Acid Preparation C4, Step 1: 2-bromo-6-(trifluoromethyl)-pyridine (100 mg, 0.44 mmol, 1 eq.) was dissolved in diethyl ether at room temperature under nitrogen then cooled to -70° C. Added 1.6M n-Butyllithium in hexanes (0.28 mL, 0.44 mmol, 1 eq.) dropwise via an addition funnel. Stirred at -40° C. for 15 minutes then cooled to -70° C. and bubbled in CO2 gas for 10 minutes. Allowed to warm to room temperature. Added water then rinsed 3 times with diethyl ether. The aqueous pH was adjusted to=3 with conc. HCl. Extracted the acidic aqueous layer 3 times with ethyl acetate. The ethyl acetate layers were combined, dried over sodium sulfate and stripped to give 6-(trifluoromethyl)picolinic acid (30 mg) as a white solid. Yield=35percent. LCMS detects (M+H)+=192.06.
Reference：
[1] European Journal of Organic Chemistry, 2003, # 8, p. 1559 - 1568
[2] Patent: US2005/54626, 2005, A1, . Location in patent: Page/Page column 36
3
[ 124-38-9 ]
[ 131747-42-7 ]
Yield
Reaction Conditions
Operation in experiment
35%
Stage #1: With n-butyllithium In diethyl ether; hexane at -70 - -40℃; for 0.25 h; Stage #2: at -70 - 20℃; Stage #3: With hydrogenchloride In water
2-bromo-6-(trifluoromethyl)-pyridine (100 mg, 0.44 mmol, 1 eq.) was dissolved in diethyl ether at room temperature under nitrogen then cooled to -70° C. Added 1.6M n-Butyllithium in hexanes (0.28 mL, 0.44 mmol, 1 eq.) dropwise via an addition funnel. Stirred at -40° C. for 15 minutes then cooled to 70° C. and bubbled in CO2 gas for 10 minutes. Allowed to warm to room temperature. Added water then rinsed 3 times with diethyl ether. The aqueous pH was adjusted to=3 with conc. HCl. Extracted the acidic aqueous layer 3 times with ethyl acetate. The ethyl acetate layers were combined, dried over sodium sulfate and stripped to give 6-(trifluoromethyl)picolinic acid (30 mg) as a white solid. Yield=35percent. LCMS detects (M+H)+=192.06.
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1990, vol. 38, # 9, p. 2446 - 2458
7
[ 1824-81-3 ]
[ 131747-42-7 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1990, vol. 38, # 9, p. 2446 - 2458
8
[ 5315-25-3 ]
[ 131747-42-7 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1990, vol. 38, # 9, p. 2446 - 2458
9
[ 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
10
[ 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
11
[ 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
12
[ 67-56-1 ]
[ 131747-42-7 ]
[ 155377-05-2 ]
Yield
Reaction Conditions
Operation in experiment
21 g
for 14 h; Reflux
To a solution of 6-trifluoromethyl-pyridine-2-carboxylic acid (22 g, 1 equiv.) in methanol (200 mL) was added concentrated H2S04 (0.3 mL). The mixture was stirred at reflux for 14 hours and then cooled to ambient. Solid NaHCO3 (10 g) was added and the suspension was stirred for 30 minutes. The mixture was filtered and the filtrate was concentrated to remove the volatile. The crude product was diluted with ethyl acetated (200 mL) and dried with anhydrous Na2504. The mixture was filtered and concentrated to give 6-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (2) as a waxy solid (21 g).
2-bromo-6-(trifluoromethyl)-pyridine (100 mg, 0.44 mmol, 1 eq.) was dissolved in diethyl ether at room temperature under nitrogen then cooled to -70 C. Added 1.6M n-Butyllithium in hexanes (0.28 mL, 0.44 mmol, 1 eq.) dropwise via an addition funnel. Stirred at -40 C. for 15 minutes then cooled to 70 C. and bubbled in CO2 gas for 10 minutes. Allowed to warm to room temperature. Added water then rinsed 3 times with diethyl ether. The aqueous pH was adjusted to=3 with conc. HCl. Extracted the acidic aqueous layer 3 times with ethyl acetate. The ethyl acetate layers were combined, dried over sodium sulfate and stripped to give 6-(trifluoromethyl)picolinic acid (30 mg) as a white solid. Yield=35%. LCMS detects (M+H)+=192.06.
methyl 4-chloro-6-(trifluoromethyl)pyridine-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With dihydrogen peroxide; sodium hydrogencarbonate; In hydrogenchloride; methanol; trifluoroacetic acid;
A. Methyl 4-Chloro-6-trifluoromethylpyridine-2-carboxylate To a solution of 6-trifluoromethylpicolinic acid (8.6 g, 45 mmol; prepared from the corresponding 6-trifluoromethyl-2-cyanopyridine) in 25 mL of TFA was added 30% H2O2 (7.8 g, 67.5 mmol). Reaction mixture was stirred at 70 C. for 18 h and concentrated to give 8.0 g of the N-oxide. This material was stirred in HCl/MeOH solution for 18 hr. The reaction mixture was concentrated to give an oily residue which was partitioned between Et2O and saturated NaHCO3. The organic layer was dried over MgSO4, filtered and concentrated to give 5.0 g of a yellow oil. Neat POC13 was added and stirred at reflux for 2 hr. The mixture was allowed to cool, added carefully to saturated NaHCO3 and extracted (3*) with Et2O. The organic layer was dried over MgSO4, filtered and concentrated to give a brown solid. This material was purified via flash column chromatograph to give 2.64 g of product as a white solid; mp 62-3 C.
1-(3-amino-benzyl)-piperidine-4-carboxylic acid cyclohexylamide[ No CAS ]
[ 131747-42-7 ]
6-trifluoromethyl-pyridine-2-carboxylic acid [3-(4-cyclohexylcarbamoyl-piperidin-1-ylmethyl)-phenyl]-amide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With trichlorophosphate; In N,N-dimethyl-formamide; at 20 - 80℃; for 1.5h;
Example 1.002: 6-Trifluoromethyl-pyridine-2-carboxylic acid [3-(4- cyclohexylcarbamoyl-piperidin-1 -ylmethyl)-phenyl]-amide Method B A solution of <strong>[131747-42-7]6-trifluoromethylpyridine-2-carboxylic acid</strong> (19.1 mg, 0.1 mmol) in DMF (0.5 mL) is treated successively with a solution of 1-(3-Amino-benzyl)-piperidine-4-carboxylic acid cyclohexylamide BB-1 (36.3 mg, 0.1 mmol) in DMF (0.5 mL) and with POCI3 (0.01 mL, 0.1 1 mmol) at RT. The resulting solution is stirred at RT for 30 min and heated at 80C for 1 h. The reaction mixture is treated with water (0.2 mL) and evaporated under HV. The title compound is obtained by prep. HPLC F as a colorless powder: LC-MS B: tR = 1 .21 min; [M+H]+ = 440.1. 1H-NMR (CDCI3): 1 -1 .3 (m, 6 H), 1 .5-2.1 (m, 12 H), 2.3-2.4 (m, 1 H), 3.0- 3.1 (m, 2 H), 3.4-3.5 (m, 1 H) 5.4 (s broad, 1 H), 7.16 (d, J = 7, 1 H), 7.37 (t, J = 7, 1 H), 7.67 (s, 1 H), 7.79 (d, J = 7.5, 1 H), 7.90 (d, J = 7.5, 1 H), 8.15 (t, J = 8, 1 H), 8.53 (d, J = 8, 1 H) 9.81 (s, 1 H).
With trichlorophosphate; In N,N-dimethyl-formamide; at 20 - 80℃; for 1.5h;Inert atmosphere;
Method B A solution of <strong>[131747-42-7]6-trifluoromethylpyridine-2-carboxylic acid</strong> (19.1 mg, 0.1 mmol) in DMF (0.5 mL) is treated successively with a solution of 1-(3-amino-benzyl)-piperidine-4-carboxylic acid cyclohexylamide BB-1 (36.3 mg, 0.1 mmol) in DMF (0.5 mL) and with POCl3 (0.01 mL, 01.1 mmol) at RT. The resulting solution is stirred at RT for 30 min and heated at 80 C. for 1 h. The reaction mixture is treated with water (0.2 mL) and evaporated under HV. The title compound is obtained by prep. HPLC (F) as a colorless powder: LC-MS B: tR=1.21 min; [M+H]+=440.1. 1H-NMR (CDCl3): 1-1.3 (m, 6H), 1.5-2.1 (m, 12H), 2.3-2.4 (m, 1H), 3.0-3.1 (m, 2H), 3.4-3.5 (m, 1H) 5.4 (s broad, 1H), 7.16 (d, J=7, 1H), 7.37 (t, J=7, 1H), 7.67 (s, 1H), 7.79 (d, J=7.5, 1H), 7.90 (d, J=7.5, 1H), 8.15 (t, J=8, 1H), 8.53 (d, J=8, 1H) 9.81 (s, 1H).
1-oxy-6-trifluoromethylpyridine-2-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With dihydrogen peroxide; trifluoroacetic acid; In water; at 100℃;
1-Oxy-<strong>[131747-42-7]6-trifluoromethyl-pyridine-2-carboxylic acid</strong> CC-1 6-Trifluoromethylpyridine-2-carboxylic acid (500 mg, 2.62 mmol) Is added to a solution obtained form trifluoroacetic acid 98% (4 mL) and aqueous hydrogen peroxide 35% (8 mL). The mixture is stirred overnight at 100C. The RM is evaporated to dryness. The title compound is obtained as a yellowish solid LC-MS A: tR = 0.57 min; [M+H]+ = 208.20.
With dihydrogen peroxide; trifluoroacetic acid; In water; at 70℃; for 16h;
To a solution of 6- (trifluoromethyl)pyridine-2 -carboxylic acid (1.0 g, 5.23 mmol) in trifluoroacetic acid (10 mL) was added hydrogen peroxide (0.9 g, 26.4 mmol, 30% in water) dropwise at rt. The mixture was stirred at 70 C for 16 h and then concentrated to afford the title compound (0.7 g, crude) as a light yellow solid.
2-methyl-1-[(4-[6-(trifluoromethyl)pyridin-2-yl]-6-[2-(trifluoromethyl)pyridin-4-yl]amino}-1,3,5-triazin-2-yl)amino]propan-2-ol methanesulfonate[ No CAS ]
2-methyl-1-[(4-[6-(trifluoromethyl)pyridin-2-yl]-6-[2-(trifluoromethyl)pyridin-4-yl]amino}-1,3,5-triazin-2-yl)amino]propan-2-ol methanesulfonate[ No CAS ]
The solution of <strong>[131747-42-7]6-trifluoromethyl-pyridine-2-carboxylic acid</strong> (229.33 mg, 1.2 mmol, 1.2 eq) in thionyl chloride was refluxed for 80 C. 3 h, and thionyl chloride was evaporated to dryness under reduced pressure to give 6-(trifluoromethyl Methyl) pyridine-2-carboxylic acid chloride as colorless oil
With thionyl chloride; at 70℃; for 2h;
A solution of <strong>[131747-42-7]6-(trifluoromethyl)picolinic acid</strong> (250 mg, 1.31 mmol) in thionyl chloride (4.75 mL, 65.4 mmol) was heated at 70 C for 2 h. The mixture was concentrated and the crude product was used directly without purification.
2-methyl-1-[(4-[6-(trifluoromethyl)pyridin-2-yl]-6-[2-(trifluoromethyl)pyridin-4-yl]amino}-1,3,5-triazin-2-yl)amino] propan-2-ol methanesulfonate[ No CAS ]
2-(5-amino-6-methyl-2H-indazol-2-yl)-1-(4-benzoylpiperazin-1-yl)ethanone[ No CAS ]
[ 131747-42-7 ]
N-{2-[2-(4-benzoylpiperazin-1-yl)-2-oxoethyl]-6-methyl-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In tetrahydrofuran; N,N-dimethyl-formamide; at 25℃; for 24h;
General procedure: EXAMPLES General Procedure 1a (1420) 1.0 equivalent of the respective intermediate, 1.0 equivalent of 1-hydroxy-1H-benzotriazole hydrate, 2.0 equivalents of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 5.0 equivalents of triethylamine and 1.5 equivalents of the carboxylic acid in question were stirred in tetrahydrofuran at 25 C. for 24 h. Water and ethyl acetate were added to the reaction mixture. The resulting precipitate was filtered off, washed with water and diethyl ether and dried.
2-(5-amino-6-methoxy-2H-indazol-2-yl)-1-[4-(2-hydroxypropan-2-yl)piperidin-1-yl]ethanone[ No CAS ]
[ 131747-42-7 ]
N-(2-{2-[4-(2-hydroxypropan-2-yl)piperidin-1-yl]-2-oxoethyl}-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
51%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In tetrahydrofuran; at 25℃; for 24h;
General procedure: General Procedure 1c (1422) 1.0 equivalent of the respective intermediate, 1.0 equivalent of 1-hydroxy-1H-benzotriazole hydrate, 2.0 equivalents of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 5.0 equivalents of triethylamine and 1.3 equivalents of the carboxylic acid in question were stirred in tetrahydrofuran at 25 C. for 24 h. Water was added and the reaction mixture was extracted repeatedly with ethyl acetate. The combined organic phases were concentrated and the residue was purified by preparative HPLC according to Method P1.
2-[5-amino-6-(trifluoromethoxy)-2H-indazol-2-yl]-1-(4-methylpiperazin-1-yl)ethanone[ No CAS ]
[ 131747-42-7 ]
N-{2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-6-(trifluoromethoxy)-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
47%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In tetrahydrofuran; at 25℃; for 24h;
General procedure: General Procedure 1d (1423) 1.0 equivalent of the respective intermediate, 1.0 equivalent of 1-hydroxy-1H-benzotriazole hydrate, 2.0 equivalents of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 3.0 equivalents of triethylamine and 1.2 equivalents of the carboxylic acid in question were stirred in 1 ml of N,N-dimethylformamide at 25 C. for 24 h. The reaction mixture was diluted with a further 1.5 ml of N,N-dimethylformamide and purified by preparative HPLC according to Method P1.
2-(5-amino-6-bromo-2H-indazol-2-yl)-1-(4-methylpiperazin-1-yl)ethanone[ No CAS ]
[ 131747-42-7 ]
N-{2-[1-(4-benzoylpiperazin-1-yl)-1-oxopropan-2-yl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
98 mg
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In tetrahydrofuran; at 20℃;
100 mg of 2-(5-amino-2H-indazol-2-yl)- 1-(4-benzoylpiperazin-1-yl)propan-1-one (Intermediate 6-19) and 76 mg of 6- (trifluoromethyl)pyridine-2-carboxylic acid were reacted with EDC, HOBt and triethylamine in THF at room temperature overnight. After addition of water, extraction with ethyl acetate and concentration, the product was purified by preparative HPLC according to Method P1. This gave 98 mg of the exemplary compound. 1H NMR (400 MHz, DMSO-d6): delta = 1.68 1.08 (d, 3H), 3.1-3.7 (broad signals, superimposed), 5.91 (br. s., 1H), 7.34- 7.45 (m, 5H), 7.52-7.61 (m, 2H), 8.14 (dd, 1H), 8.26-8.39 (m, 3H), 8.43 (s, 1H), 10.34 (s, 1H).
2-(5-amino-6-bromo-2H-indazol-2-yl)-1-(4-methylpiperazin-1-yl)ethanone[ No CAS ]
[ 131747-42-7 ]
N-{6-bromo-2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In tetrahydrofuran; at 25℃; for 24h;
General procedure: General Procedure 1e (1424) 1.0 equivalent of the respective intermediate, 1.0 equivalent of 1-hydroxy-1H-benzotriazole hydrate, 2.0 equivalents of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 4.0 equivalents of triethylamine and 1.2 equivalents of the carboxylic acid in question were stirred in 1 ml of tetrahydrofuran at 25 C. for 24 h. The reaction mixture was poured into 25 ml of water. The precipitate formed was filtered off, washed twice with diethyl ether and dried in a drying cabinet.
2-(5-amino-3-methyl-2H-indazol-2-yl)-1-(4-benzoylpiperazin-1-yl)ethanone[ No CAS ]
[ 131747-42-7 ]
N-{2-[2-(4-benzoylpiperazin-1-yl)-2-oxoethyl]-3-methyl-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
43 mg
at 25℃; for 24h;
Example 72 N-{2-[2-(4-Benzoylpiperazin-1-yl)-2-oxoethyl]-3-methyl-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide (1477) (1478) Analogously to Intermediate 8-1, 103 mg (0.27 mmol) of 2-(5-amino-3-methyl-2H-indazol-2-yl)-1-(4-benzoylpiperazin-1-yl)ethanone (Intermediate 6-15, crude product) were reacted with 78 mg (0.41 mmol) of <strong>[131747-42-7]6-(trifluoromethyl)pyridine-2-carboxylic acid</strong>. After 24 h at 25 C., water was added. The solid was filtered off, washed with water and diethyl ether and dried under reduced pressure. This gave 43 mg (29% of theory) of the title compound. (1479) UPLC-MS (Method A1): Rt=1.12 min (1480) MS (ESIpos): m/z=551 (M+H)+. (1481) 1H-NMR (300 MHz, DMSO-d6): delta=3.34-3.73 (m, 8H), 5.48 (br. s., 2H), 7.42-7.58 (m, 7H), 8.14-8.23 (m, 2H), 8.32-8.43 (m, 2H), 10.35 (s, 1H).
ethyl (5-amino-6-fluoro-2H-indazol-2-yl)acetate[ No CAS ]
[ 131747-42-7 ]
ethyl [6-fluoro-5-([6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
Intermediate 8-1 Ethyl [6-fluoro-5-([6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]acetate (1039) (1040) 221 mg (1.16 mmol) of <strong>[131747-42-7]6-(trifluoromethyl)pyridine-2-carboxylic acid</strong>, 177 mg (1.16 mmol) of 1-hydroxy-1H-benzotriazole hydrate and 444 mg (2.32 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 5.5 ml of dimethylformamide were stirred at 25 C. for 30 min 250 mg (1.05 mmol) of ethyl (5-amino-6-fluoro-2H-indazol-2-yl)acetate (Intermediate 7-1) were added and the mixture was stirred at 25 C. for 30 min. The mixture was poured into 150 ml of water, filtered off with suction, washed with water and dried. This gave 366 mg (84% of theory) of the title compound. (1041) UPLC-MS (Method A1): Rt=1.23 min (1042) MS (ESIpos): m/z=411 (M+H)+ (1043) 1H-NMR (300 MHz, DMSO-d6): delta=1.22 (t, 3H), 4.18 (q, 2H), 5.41 (s, 2H), 7.55 (d, 1H), 8.21 (m, 1H), 8.36-8.51 (m, 4H), 10.27 (m, 1H).
ethyl [5-amino-6-(benzyloxy)-2H-indazol-2-yl]acetate[ No CAS ]
[ 131747-42-7 ]
ethyl [6-(benzyloxy)-5-([6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In tetrahydrofuran; at 25℃; for 24h;
Intermediate 8-6 Ethyl [6-(benzyloxy)-5-([6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]acetate (1060) (1061) 1.79 g (5.5 mmol) of ethyl [5-amino-6-(benzyloxy)-2H-indazol-2-yl]acetate (Intermediate 7-2), 1.26 g (6.6 mmol) of <strong>[131747-42-7]6-(trifluoromethyl)pyridine-2-carboxylic acid</strong>, 842 mg (5.5 mmol) of 1-hydroxy-1H-benzotriazole hydrate, 2.11 g (11.0 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 2.3 ml (16.5 mmol) of triethylamine were stirred in 75 ml of tetrahydrofuran at 25 C. for 24 h. The reaction mixture was concentrated and water was added to the residue. The resulting solid was filtered off with suction and washed twice with water and twice with diethyl ether. The yellow solid was dried under reduced pressure. This gave 2.44 g (89% of theory) of product. (1062) UPLC-MS (Method A1): Rt=1.42 min (1063) MS (ESIpos): m/z=499 (M+H)+ (1064) 1H-NMR (400 MHz, DMSO-d6): delta=1.23 (t, 3H), 4.18 (q, 2H), 5.31 (s, 2H), 5.33 (s, 2H), 7.32 (s, 1H), 7.34-7.47 (m, 3H), 7.54-7.61 (m, 2H), 8.18 (d, 1H), 8.32-8.42 (m, 2H), 8.43-8.52 (m, 1H), 8.81 (s, 1H), 10.47 (s, 1H).
tert-butyl 5-amino-6-chloro-1H-indazole-1-carboxylate[ No CAS ]
[ 131747-42-7 ]
tert-butyl 6-chloro-5-([6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-1H-indazole-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
98%
In N,N-dimethyl-formamide; at 25℃; for 72h;
Intermediate 13 tert-Butyl 6-chloro-5-([6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-1H-indazole-1-carboxylate (1282) (1283) Analogously to Intermediate 5-1, 1.23 g (4.59 mmol) of tert-butyl 5-amino-6-chloro-1H-indazole-1-carboxylate (Intermediate 12-1) in 20 ml of N,N-dimethylformamide were stirred with 1.14 g (5.97 mmol) of <strong>[131747-42-7]6-(trifluoromethyl)pyridine-2-carboxylic acid</strong> at 25 C. for 72 h. Water was added, the mixture was stirred for 15 min and the solid was filtered off with suction, washed three times with water and dried under reduced pressure. This gave 2.02 g (98% of theory) of the title compound. (1284) UPLC-MS (Method A1): Rt=1.57 min (1285) MS (ESIpos): m/z=441 (M+H)+ (1286) 1H-NMR (300 MHz, DMSO-d6): delta=1.65 (s, 9H), 8.19-8.27 (m, 2H), 8.37-8.53 (m, 3H), 8.75 (s, 1H), 10.59 (s, 1H).
N-(6-ethoxy-1H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
64%
In tetrahydrofuran; at 20℃; for 18h;
Intermediate 14-3 N-(6-Ethoxy-1H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide (1297) (1298) Analogously to Intermediate 5-1, 1.00 g (5.64 mmol) of 6-ethoxy-1H-indazole-5-amine and 1.29 g (6.77 mmol) of <strong>[131747-42-7]6-(trifluoromethyl)pyridine-2-carboxylic acid</strong> were reacted in 50 ml of tetrahydrofuran at room temperature for 18 h. Work-up and purification by column chromatography using the Isolera flash purification system (Biotage) (SNAP cartridge (100 g; KP-Sil), mobile phase: hexane/ethyl acetate; gradient: isocratic 100:0 (1 CV), 100:0->50:50 (10 CV), isocratic 50:50 (4.7 CV), 50:50->3:97 (9.4 CV)) gave 1.30 g (64% of theory) of the title compound. (1299) UPLC-MS (Method A1): Rt=1.18 min (1300) MS (ESIpos): m/z=351 (M+H)+ (1301) 1H-NMR (500 MHz, DMSO-d6): delta=1.51 (t, 3H), 4.24 (q, 2H), 7.10 (s, 1H), 8.00 (s, 1H), 8.20 (dd, 1H), 8.39-8.43 (m, 1H), 8.46-8.48 (m, 1H), 8.79 (s, 1H), 10.67 (s, 1H), 12.87 (s, 1H).
methyl 5-([6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-1H-indazole-6-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
99%
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 0 - 5℃; for 2h;
To a solution of methyl 5-amino-1H-indazole-6-carboxylate (7.20 g, 37.6 mmol), <strong>[131747-42-7]6-(trifluoromethyl)pyridine-2-carboxylic acid</strong> (6.48 g, 33.9 mmol, CAS131747-42-7) and DIPEA (7.35 g, 56.8 mmol) in THF (70 mL) was added T3P (47.9 g, 44.8 mL, 50 wt %) slowly at 0 C. Then the mixture was stirred at 0-5 C. for 2 hours. On completion, the reaction was quenched with cold water (0.1 mL). The mixture was diluted with water (280 mL), and stirred at 25 C. for 0.5 hour. The mixture was filtered and the filter cake was washed with water (30 mL). The filter cake was collected and dried in vacuo to give the title compound (12.3 g, 99% yield) as yellow solid. 1H NMR (400 MHz, DMSO-d6) delta 12.58 (s, 1H), 9.15 (s, 1H), 8.47 (d, J=7.6 Hz, 1H), 8.39 (t, J=7.6 Hz, 1H), 8.30 (s, 1H), 8.25 (s, 1H), 8.20 (d, J=8.0 Hz, 1H), 3.97 (s, 3H).
96%
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; ethyl acetate; at 0 - 5℃; for 2.5h;Large scale;
Example 1 Methyl 5-([6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-lH-indazole-6-carboxylate (VI) (0341) 2000 g (10.46 mol) methyl 5-amino-lH-indazole-6-carboxylate, 1899 g (9.94 mol) <strong>[131747-42-7]6-(trifluoromethyl)pyridine-2-carboxylic acid</strong> und 2028 g (15.69 mol) N,N-diisopropylethylamine are mixed in 14.2 kg THF. At O to 5C, 13.3 kg of a solution of T3P in ethyl acetate (50 w%) is added dropwise within 30 min. Stirring is continued for 2 h at the same temperature. Work-Up: (0342) The reaction mixture is warmed to ambient temperature (20C). 3000 g of water are added while the temperature is kept at 20 to 25 C. Stirring is continued for 10 min. The pH is adjusted to ca. 7.4 (7 - 8) using 4 N aq. sodium carbonate solution. Stirring is continued for 10 min. If necessary the pH is again adjusted to 7.4 using 4 N aq. sodium carbonate solution. The solvents (THF/ethyl acetate) are evaporated under reduced pressure (appr. 200 mbar, 45 - 50C internal temperature) until the limit of stirring is reached. A mixture of 4.7 kg ethanol and 14.0 kg water is added and the pH is again adjusted to pH 7.4 (7 - 8) using 4 N aq. sodium carbonate solution. (0343) The mixture is stirred for 1 h at 50 C, subsequently cooled to 20 to 25 C. Stirring is continued for 10 min at the same temperature. The precipitated crystals are filtered, washed with a mixture of ethanol and water (1.3 kg ethanol with 4 kg water) and dried under vacuum in a drying oven (45C, N2 flux, at least 12 h). (0344) According to the above described procedure four batches using 2 kg of starting material (methyl 5-amino-lH-indazole-6-carboxylate) were produced in the technical laboratory: Yields: (0345) Batch 1: 3476 g (95%) (0346) Batch 2: 3449 g (95%) (0347) Batch 3: 3476 g (95%) (0348) Batch 4: 3494 g (96%) The purities of all batches were determined to be > 98 area% (HPLC). HPLC (Method A): t = 6.5 min. MS (ESI pos): m/z = 365 (M+H)+ (0349) XH NMR (500 MHz, DMSO-d6): delta [ppm]: 3.98 (s, 3 H), 8.21 (d, 1H), 8.25 (s, 1H), 8.31 (s, 1H), 8.39 (t, 1H), 8.48 (d, 1H), 9.16 (s, 1H), 12.57 (s, 1H), 13.45 (br s, 1H). (0350) XH NMR (300 MHz, DMSO-d6): delta [ppm] = 3.97 (s, 3 H), 8.13 - 8.27 (m, 2 H), 8.30 (s, 1 H), 8.33 - 8.45 (m, 1 H), 8.45 - 8.51 (m, 1 H), 9.15 (s, 1 H), 12.57 (s, 1 H), 13.44 (br s, 1 H).
96%
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; ethyl acetate; at 0 - 5℃; for 2.5h;Large scale;
Variant 22000 g (10,46 mol) methyl 5-amino-1H-indazole-6-carboxylate (XII), 1899 g (9.94 mol)6-(trifluoromethyl)pyridinee-2-carboxylic acid (Xl) und 2028 g (15.69 mol) N,Ndiisopropylethylamine were mixed in 14.2 kg THE. At 0- 5 C, 13.3 kg of a solution of T3P in ethyl acetate (50 wt%) was added dropwise within 30 mm. Stirring was continued for 2 h at the sametemperature.Work-Up:The reaction mixture was warmed to ambient temperature (20 C). 3000 g of water were added while the temperature was kept at 20 - 25 C. Stirring was continued for 10 mm. The pH was adjusted to ca. 7.4 (7-8) using 4 N aq. sodium carbonate solution. Stirring was continued for 10mm. If necessary the pH was again adjusted to 7.4 using 4 N aq. sodium carbonate solution.The solvents (THE/ethyl acetate) were evaporated under reduced pressure (? 200 mbar, 45-50 C internal temperature) until the limit of stirring was reached. A mixture of 4.7 kg ethanol and 14.0 kg water was added and the pH was again adjusted to pH 7.4 (7-8) using 4 N aq. sodium carbonate solution.The mixture was stirred for 1 h at 50 C, subsequently cooled to 20 - 25 C. Stirring was continued for 10 mm at the same temperature. The precipitated crystals were filtered, washed with a mixture of ethanol and water (1.3 kg ethanol with 4 kg water) and dried under vacuum in a drying oven (45 C, N2 flux, at least 12 h).According to the above described procedure, four batches using 2 kg of starting material (methyl5-amino-1H-indazole-6-carboxylate) were produced in the technical laboratory:Yields:Batch 1: 3476 g (95 %)Batch 2: 3449 g (95 %)Batch 3: 3476 g (95%)Batch 4: 3494 g (96%)The purities of all batches were determined to be >98 area% (HPLC).HPLC (Method A): Rt = 6.5 mm.MS (ESI pos): m/z = 365 (M÷H)?H NMR (500 MHz, DMSO-d6): oe [ppm]: 3.98 (s, 3 H), 8.21 (d, 1H), 8.25 (s, 1H), 8.31 (s, 1H), 8.39 (t, 1H), 8.48 (d, 1H), 9.16 (s, 1H), 12.57 (s, 1H), 13.45 (br s, 1H).?H NMR (300 MHz, DMSO-d6): oe [ppm] = 3.97 (s, 3 H), 8.13 - 8.27 (m, 2 H), 8.30 (s, 1 H), 8.33 - 8.45 (m, 1 H), 8.45 -8.51 (m, 1 H), 9.15 (s, 1 H), 12.57 (s, 1 H), 13.44 (br s, 1 H).
84%
Intermediate 14-9 Methyl 5-([6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-1H-indazole-6-carboxylate (1323) (1324) 4.5 g (23.53 mmol) of methyl 5-amino-1H-indazole-6-carboxylate (Intermediate 1-6) were dissolved in 45 ml of tetrahydrofuran, 9.07 g (28.24 mmol) of 0-(benzotriazol-1-yl)-N,N,N?,N?-tetramethyluronium tetrafluoroborate and 4.92 ml (28.24 mmol) of N,N-diisopropylethylamine were added and the mixture was stirred at 25 C. for 30 minutes. 4.95 g (25.89 mmol) of <strong>[131747-42-7]6-(trifluoromethyl)pyridine-2-carboxylic acid</strong> (CAS No. 21190-87-4) were added, and the mixture was stirred at 25 C. for a further 24 h. The reaction mixture was filtered off with suction through a membrane filter, washed with tetrahydrofuran and water and dried at 50 C. in a vacuum drying cabinet for 24 h. The filtrate was concentrated with acetonitrile and the resulting precipitate was filtered off with suction, washed and dried. This gave 8.60 g (84% of theory) of the title compound. (1325) UPLC-MS (Method A1): Rt=1.21 min (1326) MS (ESIpos): m/z=365 (M+H)+ (1327) 1H-NMR (300 MHz, DMSO-d6): delta=3.97 (s, 3H), 8.13-8.27 (m, 2H), 8.30 (s, 1H), 8.33-8.45 (m, 1H), 8.45-8.51 (m, 1H), 9.15 (s, 1H), 12.57 (s, 1H), 13.44 (s, 1H).
7.6 g
4.95 g (25.9 mmol) of <strong>[131747-42-7]6-(trifluoromethyl)pyridine-2-carboxylic acid</strong> were initially charged in 45 ml of TH F. 9.07 g (28.2 mmol) of 0-(benzotriazol-l-yl)-N,N;N',N'-tetramethyluronium tetrafluoroborate and 4.92 ml (28.2 mmol) of N-ethyl-N-isopropylpropan-2-amine were added and the mixture was stirred at 25C for 30 min. Subsequently, 4.50 g (23.5 mmol) of methyl 5-amino-lH-indazole-6-carboxylate (Intermediate 2-1) were added and the mixture was stirred at 25C for 24 h. The reaction mixture was filtered with suction through a membrane filter and washed with THF and with water, and dried in a drying cabinet overnight. 7.60 g of the title compound were obtained. UPLC-MS (Method A2): Rt = 1.16 min MS (ESIpos): m/z = 365 (M+H)+ *H N MR (400 MHz, DMSO-d6): delta [ppm] = 3.97 (s, 3 H), 8.13 - 8.27 (m, 2 H), 8.30 (s, 1 H), 8.33 - 8.45 (m, 1 H), 8.45 - 8.51 (m, 1 H), 9.15 (s, 1 H), 12.57 (s, 1 H), 13.44 (s, 1 H).
7.60 g
4.95 g (25.9 mmol) of <strong>[131747-42-7]6-(trifluoromethyl)pyridine-2-carboxylic acid</strong> were in itially charged in 45 ml of THF. 9.07 g (28.2 mmol) of 0-(benzotriazol-l-yl)-N;N,N';N'-tetramethyluronium tetrafluoroborate and 4.92 ml (28.2 mmol) of N-ethyl-N-isopropylpropan-2-amine were added and the mixture was stirred at 25C for 30 min. Subsequently, 4.50 g (23.5 mmol) of methyl 5- amino-lH-indazole-6-carboxylate (Intermediate 2-1) were added and the mixtu re was stirred at 25C for 24 h. The reaction mixture was filtered with suction through a membrane filter and washed with THF and with water, and dried in a drying cabinet overnight. 7.60 g of the title compound were obtained . (0239) UPLC-MS (Method A2): , = 1.16 min (0240) MS (ESIpos): m/z = 365 (M+H)+ (0241) :H NMR (400 MHz, DMSO-d6): delta [ppm] = 3.97 (s, 3 H), 8.13 - 8.27 (m, 2 H), 8.30 (s, 1 H), 8.33 - 8.45 (m, 1 H), 8.45 - 8.51 (m, 1 H), 9.15 (s, 1 H), 12.57 (s, 1 H), 13.44 (s, 1 H).
7.6 g
Intermediate 3-1 Methyl 5-([6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-1H-indazole-6-carboxylate (0246) (0247) 4.95 g (25.9 mmol) of <strong>[131747-42-7]6-(trifluoromethyl)pyridine-2-carboxylic acid</strong> were initially charged in 45 ml of THF. 9.07 g (28.2 mmol) of O-(benzotriazol-1-yl)-N,N,N?,N?-tetramethyluronium tetrafluoroborate and 4.92 ml (28.2 mmol) of N-ethyl-N-isopropylpropan-2-amine were added and the mixture was stirred at 25 C. for 30 min. Subsequently, 4.50 g (23.5 mmol) of methyl 5-amino-1H-indazole-6-carboxylate (Intermediate 2-1) were added and the mixture was stirred at 25 C. for 24 h. The reaction mixture was filtered with suction through a membrane filter and the solids were washed with THF and with water, and dried in a drying cabinet overnight. 7.60 g of the title compound were obtained. (0248) UPLC-MS (Method A2): Rt=1.16 min (0249) MS (ESIpos): m/z=365 (M+H)+ (0250) 1H NMR (400 MHz, DMSO-d6): delta [ppm]=3.97 (s, 3H), 8.13-8.27 (m, 2H), 8.30 (s, 1H), 8.33-8.45 (m, 1H), 8.45-8.51 (m, 1H), 9.15 (s, 1H), 12.57 (s, 1H), 13.44 (s, 1H).
7.60 g
4.95 g (25.9 mmol) of <strong>[131747-42-7]6-(trifluoromethyl)pyridine-2-carboxylic acid</strong> were initially charged in 45 ml of THF. 9.07 g (28.2 mmol) of O-(benzotriazol-1-yl)-N,N,N?,N?-tetramethyluronium tetrafluoroborate and 4.92 ml (28.2 mmol) of N-ethyl-N-isopropylpropan-2-amine were added and the mixture was stirred at 25C for 30 mm. Subsequently, 4.50 g (23.5 mmol) of methyl 5-amino-1H-indazole-6-carboxylate (Intermediate 2-1) were added and the mixture was stirred at 25C for24 h. The reaction mixture was filtered with suction through a membrane filter and the solids were washed with THF and with water, and dried in a drying cabinet overnight. 7.60 g of the title compound were obtained.UPLC-MS (Method A2): R = 1.16 mm MS (ESIpos): mlz = 365 (M+H)?H NMR (400 MHz, DMSO-d6): [ppm] = 3.97 (s, 3 H), 8.13 - 8.27 (m, 2 H), 8.30 (s, 1 H), 8.33 - 8.45 (m, 1 H), 8.45 - 8.51 (m, 1 H), 9.15 (s, 1 H), 12.57 (s, 1 H), 13.44 (s, 1 H).
methyl 5-([6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-1H-indazole-6-carboxylate[ No CAS ]
[ 86864-60-0 ]
[ 131747-42-7 ]
methyl 2-(2-[tert-butyl(dimethyl)silyl]oxy}ethyl)-5-([6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
400 mg
1.00 g (2.66 mmol, 97%) of methyl 5-([6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)- lH-indazole-6-carboxylate (Intermediate 3-1) was initially charged in 50 ml of DMF, 1.10 g (7.99 mmol) of potassium carbonate and 221 mg (1.33 mmol) of potassium iodide were added while stirring, and the mixture was stirred at 25C for 30 min. Subsequently, 857 muIota (3.99 mmol) of (2-bromoethoxy)(tert-butyl)dimethylsilane were added and the mixture was stirred at 25C for 24 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic phases were filtered through a hydrophobic filter and concentrated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate). This gave 400 mg of the title compound. UPLC-MS (Method Al): Rt = 1.58 min MS (ESIpos): m/z = 523(M+H)+ ^ N MR (300 MHz, DMSO-d6): delta [ppm] = -0.18 - -0.13 (m, 6 H), 0.74 (s, 9 H), 3.96 (s, 3 H), 4.08 (t, 2 H), 4.57 (t, 2 H), 8.15 - 8.25 (m, 1 H), 8.32 - 8.43 (m, 1 H), 8.43 - 8.52 (m, 3 H), 9.07 (s, 1 H), 12.53 (s, 1 H).
methyl 5-amino-2-(3-hydroxy-3-methylbutyl)-2H-indazole-6-carboxylate[ No CAS ]
[ 131747-42-7 ]
methyl 2-(3-hydroxy-3-methylbutyl)-5-([6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
2.79 g
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 25℃; for 20.5h;
1.95 g (7.03 mmol) of methyl 5-amino-2-(3-hydroxy-3-methylbutyl)-2H-indazole-6- carboxylate (Intermediate 7-1) were initially charged in 30 ml of TH F. 1.45 g (7.73 mmol) of <strong>[131747-42-7]6-(trifluoromethyl)pyridine-2-carboxylic acid</strong>, 2.71 g (8.44 mmol) of 0-(benzotriazol-l- yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate and 1.47 ml (8.44 mmol) of N-ethyl- N-isopropylpropan-2-amine were added and the mixture was stirred at 25C for 20.5 h. Water was added, the mixture was extracted three times with ethyl acetate and the extracts were washed with sodium chloride solution, filtered through a hydrophobic filter and concentrated. The residue was separated by column chromatography on silica gel (hexane/ethyl acetate). This gave 2.79 g of the title compound. UPLC-MS (Method Al): Rt = 1.23 min (UV detector: TIC), mass found 450.00.
2.79 g
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 25℃; for 20.5h;
1.95 g (7.03 mmol) of methyl 5-amino-2-(3-hydroxy-3-methylbutyl)-2H-indazole-6-carboxylate (Intermediate 7-1) were initially charged in 30 ml of THF. 1.45 g (7.73 mmol) of 6- (trifluoromethyl)pyridine-2-carboxylic acid, 2.71 g (8.44 mmol) of O-(benzotriazol-l-yl)- Nu,Nu,Nu',Nu'-tetramethylu ronium tetrafluoroborate and 1.47 ml (8.44 mmol) of N-ethyl-N- isopropylpropan-2-amine were added and the mixture was stirred at 25C for 20.5 h. Water was added, the mixture was extracted three times with ethyl acetate and the extracts were washed with sodium chloride solution, filtered through a hydrophobic filter and concentrated. The residue was separated by column chromatography on silica gel (hexane/ethyl acetate). This gave 2.79 g of the title compound. (0277) UPLC-MS (Method Al): R, = 1.23 min (UV detector: TIC), mass found 450.00.
2.79 g
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 25℃; for 20.5h;
Preparation Method 2 (0277) 1.95 g (7.03 mmol) of methyl 5-amino-2-(3-hydroxy-3-methylbutyl)-2H-indazole-6-carboxylate (Intermediate 7-1) were initially charged in 30 ml of THF. 1.48 g (7.73 mmol) of <strong>[131747-42-7]6-(trifluoromethyl)pyridine-2-carboxylic acid</strong>, 2.71 g (8.44 mmol) of O-(benzotriazol-1-yl)-N,N,N?,N?-tetramethyluronium tetrafluoroborate and 1.47 ml (8.44 mmol) of N-ethyl-N-isopropylpropan-2-amine were added and the mixture was stirred at 25 C. for 20.5 h. Water was added, the mixture was extracted three times with ethyl acetate and the extracts were washed with sodium chloride solution, filtered through a hydrophobic filter and concentrated. The residue was separated by column chromatography on silica gel (hexane/ethyl acetate gradient). 2.79 g of the title compound were obtained. (0278) UPLC-MS (Method A1): Rt=1.23 min (UV detector: TIC), mass found 450.00.
2.79 g
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 25℃; for 20.5h;
1.95 g (7.03 mmol) of methyl 5-amino-2-(3 -hydroxy-3 -methylbutyl)-2H-indazole-6-carboxylate(Intermediate 7-1) were initially charged in 30 ml of THF. 1.48 g (7.73 mmol) of 6- (trifluoromethyl)pyridine-2-carboxylic acid, 2.71 g (8.44 mmol) of O-(benzotriazol-1-yl)- N,N,N?,N?-tetramethyluronium tetrafluoroborate and 1.47 ml (8.44 mmol) of N-ethyl-Nisopropylpropan-2-amine were added and the mixture was stirred at 25C for 20.5 h. Water was added, the mixture was extracted three times with ethyl acetate and the extracts were washed withsodium chloride solution, filtered through a hydrophobic filter and concentrated. The residue was separated by column chromatography on silica gel (hexane/ethyl acetate gradient). 2.79 g of the title compound were obtained.UPLC-MS (Method Al): R = 1.23 mm (UV detector: TIC), mass found 450.00.
rac-4-(5-amino-6-methoxy-2H-indazol-2-yl)pyrrolidin-2-one[ No CAS ]
[ 131747-42-7 ]
N-[6-methoxy-2-(5-oxopyrrolidin-3-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
64 mg
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 18h;
Example 22 N-[6-Methoxy-2-(5-oxopyrrolidin-3-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide A mixture of 119 mg (0.483 mmol) of 4-(5-amino-6-methoxy-2H-indazol-2-yl)pyrrolidin-2-one (Intermediate 41), 92 mg (0.483 mmol) of <strong>[131747-42-7]6-(trifluoromethyl)pyridine-2-carboxylic acid</strong> and 193 mg (0.507 mmol) of HATU in 5 ml of DMF and 0.168 ml (0.966 mmol) of N,N-diisopropylethylamine was stirred at room temperature for 18 h. Water and ethyl acetate were added, then the solvent was partly removed under reduced pressure, water was added, and extraction was effected with a mixture of methanol/dichloromethane. The mixture was filtered and concentrated. Thereafter, the crude product was recrystallized from hot ethanol. This gave 64 mg of the title compound. 1H-NMR (400 MHz, DMSO-d6): d=2.65 (dd, 1H), 2.83 (dd, 1H), 3.48 (dd, 1H), 3.82 (dd, 1H), 3.96 (s, 3H), 5.34-5.42 (m, 1H), 7.18 (s, 1H), 7.83 (s, 1H), 8.19 (dd, 1H), 8.37-8.46 (m, 3H), 8.67 (s, 1H), 10.48 (s, 1H).
methyl 5-amino-2-(tetrahydro-2H-pyran-4-yl)-2H-indazole-6-carboxylate[ No CAS ]
[ 131747-42-7 ]
methyl 2-(tetrahydro-2H-pyran-4-yl)-5-([6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
677 mg
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 24h;
To a solution of 450 mg of methyl 5-amino-2-(tetrahydro-2H-pyran-4-yl)-2H-indazole-6-carboxylate (Intermediate 4J) in 10 ml of DMF were added 406 mg of <strong>[131747-42-7]6-(trifluoromethyl)pyridine-2-carboxylic acid</strong>, 684 mg of HATU and 307 microlitres of N-ethyl-N-isopropylpropan-2-amine, and the mixture was stirred at room temperature for 24 h. The mixture was admixed with water and the precipitate was filtered off with suction and washed three times with water and three times with diethyl ether. After drying, 677 mg of the title compound were obtained. UPLC-MS (Method C): Rt=1.27 min; mass found 448.00. 1H-NMR (400 MHz, DMSO-d6): delta [ppm]=2.07-2.24 (m, 4H), 3.49-3.63 (m, 2H), 3.97 (s, 3H), 3.99-4.11 (m, 2H), 4.78-4.92 (m, 1H), 8.18-8.28 (m, 1H), 8.37-8.55 (m, 3H), 8.64 (s, 1H), 9.08 (s, 1H), 12.55 (s, 1H).
(R)-4-(3-trifluoromethyl-3-hydroxypyrrol-1-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridine 4-yl)-1,3,5-triazin-2-amine[ No CAS ]
(S)-4-(3-trifluoromethyl-3-hydroxypyrrol-1-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)-N-(2-(trifluoromethyl)pyridine 4-yl)-1,3,5-triazin-2-amine[ No CAS ]
6-methoxy-2-(tetrahydro-2H-pyran-4-yl)-2H-indazol-5-amine[ No CAS ]
[ 131747-42-7 ]
N-[6-methoxy-2-(tetrahydro-2H-pyran-4-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
290 mg
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 64h;
To a mixture of 260 mg (1.05 mmol) of 6-methoxy-2-(tetrahydro-2H-pyran-4-yl)-2H-indazol-5-amine (Intermediate 4A), 201 mg (1.05 mmol) of <strong>[131747-42-7]6-(trifluoromethyl)pyridine-2-carboxylic acid</strong> [CAS 131747-42-7] and 440 mg (1.2 mmol) of O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) [148893-10-1] in 5 ml of anhydrous dimethylformamide was added 0.366 ml (2.1 mmol) of N,N-diisopropylethylamine, and the mixture was stirred at room temperature for 64 h. Ethyl acetate and water were added to the reaction, the organic phase was removed and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with sodium chloride solution, dried over sodium sulphate, filtered and concentrated under reduced pressure. After purification (Biotage Isolera, 50 g silica gel column, cyclohexane/ethyl acetate), 290 mg (0.69 mmol) of the title compound were obtained. LC-MS (Method B): Rt=4.51 min; m/z=421 (M+H)+ 1H-NMR (400 MHz, DMSO-d6): delta=2.02-2.11 (m, 4H), 3.47-3.54 (m, 2H), 3.95-4.00 (m, 5H), 4.59-4.69 (m, 1H), 7.15 (s, 1H), 8.19 (dd, 1H), 8.35-8.45 (m, 3H), 8.67 (s, 1H), 10.48 (s, 1H)
tert-butyl 4-(5-amino-6-methoxy-2H-indazol-2-yl)piperidine-1-carboxylate[ No CAS ]
[ 131747-42-7 ]
tert-butyl 4-[6-methoxy-5-([6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 25℃; for 0.5h;
To a solution of <strong>[131747-42-7]6-(trifluoromethyl)pyridine-2-carboxylic acid</strong> (198.60 mg, 1.04 mmol, 1.2 eq) in N,N-dimethylformamide (5 mL) was added HATU (395.1 mg, 1.04 mmol, 1.2 eq), N,N-diisopropylethylamine (335.77 mg, 2.60 mmol, 452.52 muL, 3 eq) and tert-butyl 4-(5-amino-6-methoxy-indazol-2-yl)piperidine-1-carboxylate (0.3 g, 866 mumol, 1 eq). The mixture was stirred at 25 C. for 0.5 hour. The reaction mixture was quenched by the addition of water (20 mL) at 25 C., and then diluted with ethyl acetate (50 mL). The mixture was then extracted with ethyl acetate (50 mL×2). The combined organic layers were washed with brine (50 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography to yield tert-butyl 4-[6-methoxy-5-[[6-(trifluoromethyl)pyridine-2-carbonyl]amino]indazol-2-yl]piperidine-1-carboxylate (0.36 g, 693 mumol, 80.0% yield), obtained as a white solid. 1H NMR (400 MHz, CDCl3) delta: 10.72 (s, 1H), 8.83 (s, 1H), 8.49 (d, J=10.4, 1H), 8.12 (t, J=10.4, 1H), 7.80 (s, 1H), 7.80 (d, J=10.4, 1H), 7.06 (s, 1H), 4.48 (m, 1H), 4.32 (m, 2H), 4.04 (s,3H), 2.96 (m, 2H), 2.20 (m, 2H), 2.10 (m, 2H), 1.49 (s, 9H).
1.13 g
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 16h;
To a mixture of 913 mg (2.6 mmol) of tert-butyl 4-(5-amino-6-methoxy-2H-indazol-2-yl)piperidine-1-carboxylate (Intermediate 4B), 500 mg (2.6 mmol) of <strong>[131747-42-7]6-(trifluoromethyl)pyridine-2-carboxylic acid</strong> [131747-42-7] and 1.1 g (2.9 mmol) of O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) [148893-10-1] in 10 ml of anhydrous dimethylformamide was added 0.918 ml (5.3 mmol) of N,N-diisopropylethylamine, and the mixture was stirred at room temperature for 16 h. Ethyl acetate and water were added, the organic phase was removed and extracted twice with ethyl acetate, and the organic phases were combined, washed with sodium chloride solution, dried over sodium sulphate, filtered and concentrated under reduced pressure. After purification by column chromatography (Biotage Isolera, 50 g silica gel column, cyclohexane/ethyl acetate), 1.13 g (2.2 mmol) of tert-butyl 4-[6-methoxy-5-([6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]piperidine-1-carboxylate were obtained. LC-MS (Method A): Rt=4.49 min; m/z=464 (M-(tBu+H))+ 1H-NMR (300 MHz, CDCl3): delta=1.49 (s, 9H), 2.05-2.26 (m, 4H), 2.88-2.99 (m, 2H), 4.03 (s, 3H), 4.26-4.35 (m, 2H), 4.46-4.56 (m, 1H), 7.07 (s, 1H), 7.83-7.88 (m, 2H), 8.12 (dd, 1H), 8.49 (d, 1H), 8.82 (s, 1H), 10.70 (s, 1H)
2-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-6-methoxy-2H-indazol-5-amine[ No CAS ]
[ 131747-42-7 ]
N-[2-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-6-methoxy-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
2.57 g
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 15h;
To a mixture of 2.55 g (8.6 mmol) of 2-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-6-methoxy-2H-indazol-5-amine (Intermediate 4C), 1.73 g (9.1 mmol) of <strong>[131747-42-7]6-(trifluoromethyl)pyridine-2-carboxylic acid</strong> [131747-42-7] and 3.45 g (9.1 mmol) of O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) [148893-10-1] in 30 ml of DMF were added 3 ml (17.3 mmol) of N-ethyl-N-isopropylpropan-2-amine, and the mixture was stirred at room temperature for 15 h. Ethyl acetate and water were added, the organic phase was removed and extracted three times with ethyl acetate, and the organic phases were combined, washed with sodium chloride solution, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was admixed with dichloromethane, and the resultant solid was extracted by stirring with 100 ml of ethyl acetate. The solvent was concentrated under reduced pressure, and the residue was dried at 60 C. for 24 h and at 90 C. for 24 h. This gave 2.57 g (5.5 mmol) of the title compound. LC-MS (Method B): Rt=4.29 min; m/z=469 (M+H)+ 1H-NMR (400 MHz, DMSO-d6): delta=2.40 (dd, 2H), 2.49-2.61 (m, 2H), 3.21-3.25 (m, 2H), 3.44 (t, 2H), 3.96 (s, 3H), 4.80-4.89 (m, 1H), 7.17 (s, 1H), 8.19 (dd, 1H), 8.37-8.45 (m, 3H), 8.67 (s, 1H), 10.48 (s, 1H)
6-Methoxy-2-(1-oxidotetrahydro-2H-thiopyran-4-yl)-2H-indazol-5-amine[ No CAS ]
[ 131747-42-7 ]
N-[6-methoxy-2-(1-oxidotetrahydro-2H-thiopyran-4-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
560 mg
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 23h;
To a mixture of 426 mg (1.52 mmol) of rac-6-methoxy-2-(1-oxidotetrahydro-2H-thiopyran-4-yl)-2H-indazol-5-amine (Intermediate 4D), 306 mg (1.6 mmol) of <strong>[131747-42-7]6-(trifluoromethyl)pyridine-2-carboxylic acid</strong> [131747-42-7] and 609 mg (1.6 mmol) of O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) [148893-10-1] in 10 ml of dimethylformamide was added 0.531 ml (3.0 mmol) of N,N-diisopropylethylamine, and then the mixture was stirred at room temperature for 23 h. Ethyl acetate and water were added to the reaction, the organic phase was removed and extracted three times with ethyl acetate, and the organic phases were combined, washed with sodium chloride solution, dried over sodium sulphate and filtered, and the solvent was concentrated under reduced pressure. After purification (Biotage Isolera, 50 g silica gel column, dichloromethane/methanol), 560 mg (1.2 mmol) of the title compound were obtained. LC-MS (Method A): Rt=3.42 & 3.47 min; m/z=453 (M+H)+ 1H-NMR (300 MHz, CDCl3): delta=2.31-2.47 (m, 2H), 2.66-3.02 (m, 4H), 3.24-3.29 (m, 1H), 3.39-3.49 (m, 1H), 4.04 (d, 3H), 4.62-4.70 (m, 1H), 7.05 (d, 1H), 7.85-7.89 (m, 2H), 8.12 (dd, 1H), 8.49 (d, 1H), 8.84 (d, 1H), 10.71 (s, 1H)
tert-butyl 5-(5-amino-6-methoxy-2H-indazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate[ No CAS ]
[ 131747-42-7 ]
tert-butyl 5-[6-methoxy-5-([6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]-2-azabicyclo[2.2.1]heptane-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
151 mg
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 16h;
To a mixture of 150 mg (0.418 mmol) of tert-butyl rel-(1S,4S,5R)-5-(5-amino-6-methoxy-2H-indazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (Intermediate 4E), 84 mg (0.439 mmol) of <strong>[131747-42-7]6-(trifluoromethyl)pyridine-2-carboxylic acid</strong> [131747-42-7] and 167 mg (0.439 mmol) of O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) [148893-10-1] in 3 ml of DMF was added 0.146 ml (0.84 mmol) of N-ethyl-N-isopropylpropan-2-amine, and the mixture was stirred at room temperature for 16 h. Water and ethyl acetate were added, the organic phase was removed and extracted twice with ethyl acetate, and the combined organic phases were washed with sodium chloride solution, dried over sodium sulphate, filtered and concentrated. After purification (Biotage Isolera (25 g silica gel column), cyclohexane/ethyl acetate), 151 mg (0.284 mmol) of tert-butyl rel-(1S,4S,5R)-5-[6-methoxy-5-([6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]-2-azabicyclo[2.2.1]heptane-2-carboxylate were obtained. LC-MS (Method A): Rt=4.62 min; m/z=532 (M+H)+ 1H-NMR (300 MHz, CDCl3): delta=1.50 (s, 9H), 1.81-1.72 (m, 1H), 2.28-2.43 (m, 3H), 2.93 (d, 1H), 3.14-3.40 (m, 2H), 4.03 (s, 3H), 4.41 (d, 1H), 4.64-4.69 (m, 1H), 7.06 (s, 1H), 7.83-7.91 (m, 2H), 8.11 (dd, 1H), 8.49 (d, 1H), 8.81 (s, 1H), 10.70 (s, 1H).
tert-butyl 5-(5-amino-6-methoxy-2H-indazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate[ No CAS ]
[ 131747-42-7 ]
tert-butyl 5-[6-methoxy-5-([6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]-2-azabicyclo[2.2.1]heptane-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
383 mg
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 17h;
Stage A tert-Butyl rel-(1S,4S,5S)-5-[6-methoxy-5-([6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]-2-azabicyclo[2.2.1]heptane-2-carboxylate To a mixture of 297 mg (0.829 mmol) of tert-butyl rel-(1S,4S,5S)-5-(5-amino-6-methoxy-2H-indazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (Intermediate 4F), 166 mg (0.87 mmol) of <strong>[131747-42-7]6-(trifluoromethyl)pyridine-2-carboxylic acid</strong> [131747-42-7] and 331 mg (0.87 mmol) of O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) [148893-10-1] in 3 ml of DMF was added 0.289 ml (1.66 mmol) of N-ethyl-N-isopropylpropan-2-amine, and the mixture was stirred at room temperature for 17 h. Ethyl acetate and water were added, the organic phase was removed, the aqueous phase was extracted twice with ethyl acetate, the organic phases were combined, washed with sodium chloride solution, dried over sodium sulphate and filtered, and the solvents were removed under reduced pressure. After purification (Biotage Isolera (25 g silica gel column), cyclohexane/ethyl acetate), 383 mg (0.721 mmol) of tert-butyl rel-(1S,4S,5S)-5-[6-methoxy-5-([6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]-2-azabicyclo[2.2.1]heptane-2-carboxylate were obtained. LC-MS (Method A): Rt=4.47 min; m/z=532 (M+H)+ 1H-NMR (300 MHz, CDCl3): delta=1.50 (d, 9H), 1.80 (d, 1H), 1.88-1.95 (m, 1H), 2.32-2.42 (m, 2H), 2.53 (d, 0.5H), 2.98 (d, 0.5H), 3.13-3.21 (m, 2H), 4.04 (s, 3H), 4.38 (d, 1H), 5.07-5.07 (m, 1H), 7.04 (s, 1H), 7.83-7.91 (m, 2H), 8.12 (dd, 1H), 8.50 (d, 1H), 8.81 (s, 1H), 10.68-10.73 (m, 1H)
6-chloro-2-(tetrahydro-2H-pyran-4-yl)-2H-indazol-5-amine[ No CAS ]
[ 131747-42-7 ]
N-[6-chloro-2-(tetrahydro-2H-pyran-4-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
21 mg
With benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; triethylamine; In tetrahydrofuran; at 20℃; for 17h;
General procedure: To a mixture of 80 mg of 6-methoxy-2-(tetrahydro-2H-pyran-4-yl)-2H-indazol-5-amine (Intermediate 4A), 73 mg of 6-(difluoromethyl)pyridine-2-carboxylic acid [1256824-41-5] and 124 mg of N-[3-(dimethylamino)propyl]-N'-ethylcarbodiimide (EDC, CAS 1892-57-5) and 50 mg of 1H-benzotriazol-1-ol hydrate (1:1) (HOBt, CAS123333-53-9] in 2.5 ml of dimethylformamide were added 135 microlitres of triethylamine, and the mixture was stirred at room temperature for 17 h. Ethyl acetate and water were added to the reaction, the organic phase was removed and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were concentrated and the residue was purified by preparative HPLC. This gave 56 mg of the title compound. UPLC-MS (Method C): Rt=1.11 min; mass found 402.15. 1H-NMR (400 MHz, DMSO-d6): delta [ppm]=2.02-2.16 (m, 4H), 3.46-3.57 (m, 2H), 3.95-4.04 (m, 5H), 4.60-4.70 (m, 1H), 7.14 (t, 1H), 7.16 (s, 1H), 7.97-8.00 (m, 1H), 8.27-8.37 (m, 3H), 8.69 (s, 1H), 10.55 (s, 1H).
methyl 5-amino-2-[(3S)-tetrahydrofuran-3-yl]-2H-indazole-6-carboxylate[ No CAS ]
[ 131747-42-7 ]
methyl 2-[(3S)-tetrahydrofuran-3-yl]-5-([6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
824 mg
With N-ethyl-N,N-diisopropylamine; O?(1H?benzotriazol?1?yl)?N,N,N?,N??tetramethyluronium tetrafluoroborate; In tetrahydrofuran; at 20℃; for 18h;
To a solution of 759 mg of methyl 5-amino-2-[(3S)-tetrahydrofuran-3-yl]-2H-indazole-6-carboxylate (Intermediate 4L) in 10 ml of THF were added 666 mg of <strong>[131747-42-7]6-(trifluoromethyl)pyridine-2-carboxylic acid</strong>, 1.12 g of O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU, CAS 125700-67-6) and 0.61 ml of N-ethyl-N-isopropylpropan-2-amine, and the mixture was stirred at room temperature for 18 h. Water was added, the mixture was extracted three times with ethyl acetate, and the extracts were washed with sodium chloride solution, filtered through a hydrophobic filter and concentrated. Purification of the crude product by column chromatography on silica gel (Isolera, hexane/ethyl acetate) gave 824 mg of the title compound. UPLC-MS (Method C): Rt=1.24 min; mass found 434.00. 1H-NMR (400 MHz, DMSO-d6, selected signals from the crude product): delta [ppm]=2.38-2.59 (m, masked by solvent signal), 3.85-3.98 (m, 4H), 4.03-4.14 (m, 3H), 5.38-5.46 (m, 1H), 8.17-8.22 (m, 1H), 8.35-8.41 (m, 1H), 8.44-8.48 (m, 2H), 8.58 (s, 1H), 9.05 (s, 1H), 12.51 (s, 1H).
methyl 5-amino-2-[(3S)-tetrahydrofuran-3-yl]-2H-indazole-6-carboxylate[ No CAS ]
[ 131747-42-7 ]
methyl 2-[(3S)-tetrahydrothiophen-3-yl]-5-([6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50 mg
With N-ethyl-N,N-diisopropylamine; O?(1H?benzotriazol?1?yl)?N,N,N?,N??tetramethyluronium tetrafluoroborate; In tetrahydrofuran; at 20℃; for 23h;
General procedure: To a solution of 759 mg of methyl 5-amino-2-[(3S)-tetrahydrofuran-3-yl]-2H-indazole-6-carboxylate (Intermediate 4L) in 10 ml of THF were added 666 mg of <strong>[131747-42-7]6-(trifluoromethyl)pyridine-2-carboxylic acid</strong>, 1.12 g of O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU, CAS 125700-67-6) and 0.61 ml of N-ethyl-N-isopropylpropan-2-amine, and the mixture was stirred at room temperature for 18 h. Water was added, the mixture was extracted three times with ethyl acetate, and the extracts were washed with sodium chloride solution, filtered through a hydrophobic filter and concentrated. Purification of the crude product by column chromatography on silica gel (Isolera, hexane/ethyl acetate) gave 824 mg of the title compound. UPLC-MS (Method C): Rt=1.24 min; mass found 434.00. 1H-NMR (400 MHz, DMSO-d6, selected signals from the crude product): delta [ppm]=2.38-2.59 (m, masked by solvent signal), 3.85-3.98 (m, 4H), 4.03-4.14 (m, 3H), 5.38-5.46 (m, 1H), 8.17-8.22 (m, 1H), 8.35-8.41 (m, 1H), 8.44-8.48 (m, 2H), 8.58 (s, 1H), 9.05 (s, 1H), 12.51 (s, 1H).
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