* 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] Bioorganic and Medicinal Chemistry, 2001, vol. 9, # 7, p. 1773 - 1780
[2] Organic Process Research and Development, 2001, vol. 5, # 5, p. 531 - 534
Reference：
[1] Chinese Journal of Chemistry, 2016, vol. 34, # 5, p. 481 - 484
11
[ 695-34-1 ]
[ 81565-18-6 ]
Reference：
[1] Patent: CN107151229, 2017, A,
12
[ 81565-18-6 ]
[ 89570-84-3 ]
Reference：
[1] ChemMedChem, 2018, vol. 13, # 10, p. 988 - 1003
[2] Journal of the Chemical Society, Chemical Communications, 1992, # 15, p. 1062 - 1064
13
[ 81565-18-6 ]
[ 106447-97-6 ]
Reference：
[1] Journal of Fluorine Chemistry, 1999, vol. 93, # 2, p. 153 - 157
[2] Journal of Medicinal Chemistry, 1998, vol. 41, # 1, p. 96 - 101
[3] Patent: US4762928, 1988, A,
[4] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 11, p. 3237 - 3242
14
[ 81565-18-6 ]
[ 50650-59-4 ]
Reference：
[1] Journal of Fluorine Chemistry, 1999, vol. 93, # 2, p. 153 - 157
15
[ 81565-18-6 ]
[ 175205-81-9 ]
Reference：
[1] European Journal of Organic Chemistry, 2003, # 8, p. 1559 - 1568
[2] Patent: US2006/4018, 2006, A1, . Location in patent: Page/Page column 33
16
[ 81565-18-6 ]
[ 158063-66-2 ]
Reference：
[1] European Journal of Organic Chemistry, 2003, # 8, p. 1559 - 1568
17
[ 124-41-4 ]
[ 81565-18-6 ]
[ 219715-34-1 ]
Yield
Reaction Conditions
Operation in experiment
92.1%
at 65℃;
The reaction bottle by adding 2 - chloro -4 - trifluoro methyl pyridine (45.5 g, 0 . 251 µM), the mass fraction is 30percent of the sodium methoxide solution (135.5 g, 0 . 753 µM) stirring after mixing, heating, in the 65 °C lower reaction, GC tracking to the raw reaction is complete, cooling to room temperature after completion of the reaction, filtration, vacuum recovering methanol, adding water and methylene chloride extraction layered, pressure reducing concentrated methylene chloride to obtain a pale yellow liquid 40.9 g, yield 92.1percent.
85%
for 4 h; Heating / reflux
(a) A solution having 5.05 g (27.8 mmol) of 2-chloro-4-trifluoromethylpyridine and 3.59 g (66.5 mmol) of sodium methoxide dissolved in 40 mL of methanol was stirred under reflux by heating for 4 hours. Water was added to terminate the reaction, and extraction with diethyl ether was carried out. Then, the organic layer was dried over anhydrous sodium sulfate and subjected to filtration on a silica gel cake. The solvent was distilled off under reduced pressure to obtain 4.19 g (yield 85percent) of 4-trifluoromethyl-2-methoxypyridine.1H-NMR(CDCl3, 400 MHz) : δ (ppm) = 3.96(s, 3H), 6.95(s, 1H), 7.05(d, 1H, J = 5.2 Hz), 8.29(d, 1H, J = 5.2 Hz)
Reference：
[1] Patent: CN108558744, 2018, A, . Location in patent: Paragraph 0052-0055
[2] Patent: EP1559320, 2005, A1, . Location in patent: Page/Page column 9
18
[ 67-56-1 ]
[ 124-41-4 ]
[ 81565-18-6 ]
[ 219715-34-1 ]
Yield
Reaction Conditions
Operation in experiment
85%
for 4 h; Heating / reflux
(a); A solution having 5.05 g (27.8 mmol) of 2-chloro-4-trifluoromethylpyridine and 3.59 g (66.5 mmol) of sodium methoxide dissolved in 40 ml of methanol was stirred under reflux with heating for 4 hours. Water was added to terminate the reaction, followed by extraction with diethyl ether. The organic layer was dried over anhydrous sodium sulfate and subjected to filtration on the pad of a silica gel cake. The solvent was distilled off under reduced pressure to obtain 4.19 g (yield: 85percent) of 4-trifluoromethyl-2-methoxypyridine. 1H-NMR(CDCl3, 400 MHz) : δ (ppm) = 3.96(s, 3H), 6.95(s, 1H), 7.05(d, 1H, J = 5.2 Hz), 8.29(d, 1H, J = 5.2 Hz)
General procedure: To 2-chloropyridine (1.1 mmol) in ethanol (5.0 mL) was added hydrazine hydrate (2 mL) dropwise at room temperature. The mixture was refluxed until completion as monitored by TLC. The reaction mixture was cooled, ethanol was removed by evaporation. Then, the residue was partitioned between ethyl acetate and water. The combined organic phase was dried over anhydrous sodium sulfate and concentrated to give the product, which was used for the following cyclization reaction without purification.
With nickel(II) chloride hexahydrate; triphenylphosphine; zinc; In N,N-dimethyl-formamide; at 80℃; for 72h;Inert atmosphere;
In a screw capped tube, NiCl2·6H2O, (238 mg, 1mmol) and PPh3, (524 mg, 2 mmol) were dissolved in 2 mL reagent grade DMF. This blue solution was sparged with argon for 30 min. Activated1 zinc dust (98 mg, 1.5 mmol) was added and the mixture was stirred with argon sparging for 1 h. To the resulting red-brown slurry, <strong>[81565-18-6]2-chloro-4-(trifluoromethyl)pyridine</strong> (1) (183 mg, 1 mmol) was added. The tube was capped and heated in an 80 C oil bath for 72 h at which time GC-MS showed full consumption of 1. The reaction mixture was then poured into a beaker containing 2 mL ammonia (24% aq) and 20 g ice. The mixture was extracted with diethyl ether. The diethyl ether phase was dried over MgSO4, filtered, and evaporated. The crude product was purified on a silica gel column (4:1 hexane/CH2Cl2) giving 129 mg (89%) of 2 as a white solid; mp 79-80 C. 1H NMR (500 MHz, CDCl3) delta 8.87 (d, J = 5.0 Hz, 2 H), 8.71 (s, 2 H), 7.57 (d, J = 5.0 Hz, 2 H); 13C NMR (125 MHz, CDCl3) delta 156.1, 150.3, 139.6 (q, J = 34 Hz), 122.8 (q, J = 273 Hz), 119.9 (q, J = 3.5 Hz), 117.1 (q, J = 3.8 Hz); 19F NMR (470 MHz, CDCl3) delta -64.9.
EXAMPLE 2 Preparation of 2-amino-4-trifluoromethylpyridine 14.5 g of <strong>[81565-18-6]2-chloro-4-trifluoromethylpyridine</strong> and 108 ml of 28% aqueous ammonia were charged in a 200-ml autoclave, and the mixture was reacted at 180 C. for 10 hours (internal pressure: about 20 atm). After the completion of the reaction, the reaction system was allowed to cool. The resultant crystals were washed with water and dried, thus obtaining 10.2 g of 2-amino-4-trifluoromethylpyridine (melting point: 69 to 70 C.).
With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -75℃; for 2h;
82%
Stage #1: 2-chloro-4-trifluoromethyl pyridine With lithium diisopropyl amide In tetrahydrofuran; hexane at -75℃; for 2h;
Stage #2: carbon dioxide In tetrahydrofuran; hexane at -75 - 25℃;
With trimethylsilyl bromide; In propiononitrile; for 22h;Heating / reflux;
A mixture of 2-chloro-4-(trifluoromethyl)pyridine (2.70 g, 14.9 mmol) and bromotrimethylsilane (3.90 mL, 29.6 mmol) in propanenitrile (15.0 mL) was heated under reflux for 22 h. The product (very volatile) was carefully rotary evaporated to give 4.07 g (propanenitrile contained) of thick light brown suspension w/o further purification. LC-MS calculated for C6H3BrF3N (M+H) 226.9; found 225.9/227.8.
With triethylamine; In DMF (N,N-dimethyl-formamide); at 100℃;
A solution of <strong>[81565-18-6]2-chloro-4-(trifluoromethyl)pyridine</strong> (2.0 g, 11 mmol), piperazine (3 g, 30 mmol) and triethylamine (3.1 mL, 22 mmol) in DMF (10 mL) was heated at 100 C. overnight and concentrated in vacuo. The residue was purified by column chromatography on silica gel (EtOAc to EtOAc/MeOH/Et3N=9/1/0.5) to give 1.09 g (43%) of pure product. MS calculated for C10H12F3N3: (M+H) 232; found 232.1.
REFERENCE EXAMPLE 11; 2-Methyl-2-(4-trifluoromethyl-2-pyridyloxy)propionic Acid; Step A: 2-f4-Triflupsilonoromethyl-2-pyridyloxy)propionic acid; To a suspension of lithium lactate (7.8 g, 81 mmol) in 100 mL of anhydrous dimethylformamide was added sodium hydride (60% dispersion in mineral oil, 3.2 g, 80 mmol). After stirring at room temperature for 30 min, 2-chloro-4-trifluromethyl-pyridine (10 g, 55 mmol) was added, and the mixture was heated at 1000C overnight. The reaction was cooled to room temperature, poured into 500 mL of water, and was washed with hexane (200 mL). The aqueous solution was acidified with concentrated hydrochloric acid (pH > 2), and was extracted with ether (2x500 mL). The combined extracts were washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness to give the title compound.
Reagents and conditions: (i) mCPBA, EtOAc; (ii) POCl3; (iii) PdPPh3) 2C12, Ba(OH)2, DME-H2O, 110 0C; (iv) 5-fluoro-lH- pyrazolo [3, 4-b] pyridin-3-amine, Pd(OAc)2, Xantphos, K2CO3, dioxane, 120 0C.[0054] Scheme III above shows a general synthetic route that is used for preparing the compounds III-5. Compounds of formula III-5 can be prepared from intermediate III-l. The formation of chloropyridine derivative III-2 is achieved by treating the corresponding pyridine III-l with m-CPBA in EtOAc followed by conversion of the corresponding N-oxide to the chloropyridine by treating it with POCl3. Intermediate III-2 is then reacted with the corresponding boronic acid derivative to yield compound III- 3 using Suzuki coupling conditions well known for those skilled in the art. This reaction is amenable to a variety of boronic acid derivatives. The pyridine III-3 is then converted in a chloropyridine derivative III-4 using the same two step procedures as used in step 1, m-CPBA oxidation followed by POCl3 treatment. Intermediate III-4 is then treated with 5-fluoro-lH- <n="25"/>pyrazolo [3, 4-b] pyridin-3-amine in the presence of Pd as a catalyst to yield the final compound III-5.
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 100℃; for 14h;
Intermediate 7 [ 2-R4-(METHVLTHIO) PHENYLL-4-(TRIFLUOROMETHYL)-PYRIDINE] To a mixture of 2-chloro-4- (trifluoromethyl) pyridine (19.9g, [0.] [11MOL),] 4- [(METHYLTHIO) PHENYLBORONIC] acid (21.9g, 0. [13MOL), 1M] aqueous sodium carbonate [(180ML)] and 1,2-dimethoxyethane (270mL) under an atmosphere of nitrogen was added palladium tetrakistriphenylphosphine (3.78g, 3. [3MMOL)] and the reaction heated at [100C] for 14 hours. After cooling and concentration in vacuo, the residue was partitioned between ethyl acetate (350mL) and water (400mL) and separated. The aqueous layer was further extracted with ethyl acetate (2 x [150ML)] and the combined organic layers were dried over sodium sulfate and [CONCENTRATED IN VACUO.] Filtration through a pad of silica gel (200g) eluting with a gradient of ethyl acetate in cyclohexane gave the title compound (29.4g) LC retention time 3.62mins, MS m/z 269 [(MH+).]
With sodium carbonate; In 1,2-dimethoxyethane; water; at 100℃; for 14h;
Example 3.1N-cvclohexvl-4- (trifluoromethyl)-6-f4- (methvlsulfonyl) phenvllpyridine-2-amine (i)2-f4- (methylthio) phenyll-4- (trifluoromethvl)-pyridine To a mixture of 2-chloro-4- (trifluoromethyl) pyridine (19. 9g, 0. 11mol), 4- (methylthio) phenylboronic acid (21.9g, 0. 13mol), 1M aqueous sodium carbonate(180mL) and 1,2-dimethoxyethane (270mL) under an atmosphere of nitrogen was added palladium tetrakistriphenylphosphine (3.78g, 3. 3mmol) and the reaction heated at100 C for 14 hours. After cooling and concentration in vacuo, the residue was partitioned between ethyl acetate (350mL) and water (400mL) and separated. The aqueous layer was further extracted with ethyl acetate (2 x150mL) and the combined organic layers were dried over sodium sulfate and concentrated in vacuo. Filtration through a pad of silica gel (200g) eluting with a <Desc/Clms Page number 39>gradient of ethyl acetate in cyclohexane gave the title compound (29. 4g) LC retention time 3.62mins, MS m/z 269 (MH+).
ethyl 3-{3-ethoxy-1-[4-(trifluoromethyl)-2-pyridinyl]-1H-pyrazol-4-yl}propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
With sodium hydride; In DMF (N,N-dimethyl-formamide); at 20℃;
Reference Example 238 A mixture of ethyl3- (3-ethoxy-lH-pyrazol-4-yl) propanoate (7.01 g), sodium hydride(60%, in oil, 1.59 g) and N, N- dimethylformamide (165 ml) was stirred at room temperature for <Desc/Clms Page number 236>30 minutes.2-Chloro-4- (trifluoromethyl) pyridine (6.00 g) was added and the mixture was stirred overnight. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried(MgS04) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl3- {3-ethoxy-l- [4-(trifluoromethyl)-2-pyridinyl]-lH-pyrazol-4-yl} propanoate (9.05 g, yield77%) was obtained as a pale-yellow oily substance from a fraction eluted with ethyl acetate-hexane (1: 9, volume ratio). 1H-NMR (CDC13) 8 : 1.26 (3H, t, J = 7. 0 Hz), 1.44 (3H, t, J = 7.0 Hz), 2.56-2. 66 (2H, m), 2. 70-2. 81 (2H, m), 4.15 (2H, q, J = 7. 0 Hz), 4.37 (2H, q, J = 7.0 Hz), 7.18-7. 24 (1H, m), 7.91 - 7. 94 (1H, m), 8.18 (1H, s), 8.45 (1H, d, J = 5.0 Hz).
The reaction bottle by adding 2 - chloro -4 - trifluoro methyl pyridine (45.5 g, 0 . 251 muM), the mass fraction is 30% of the sodium methoxide solution (135.5 g, 0 . 753 muM) stirring after mixing, heating, in the 65 C lower reaction, GC tracking to the raw reaction is complete, cooling to room temperature after completion of the reaction, filtration, vacuum recovering methanol, adding water and methylene chloride extraction layered, pressure reducing concentrated methylene chloride to obtain a pale yellow liquid 40.9 g, yield 92.1%.
85%
In methanol; for 4h;Heating / reflux;
(a) A solution having 5.05 g (27.8 mmol) of 2-chloro-4-trifluoromethylpyridine and 3.59 g (66.5 mmol) of sodium methoxide dissolved in 40 mL of methanol was stirred under reflux by heating for 4 hours. Water was added to terminate the reaction, and extraction with diethyl ether was carried out. Then, the organic layer was dried over anhydrous sodium sulfate and subjected to filtration on a silica gel cake. The solvent was distilled off under reduced pressure to obtain 4.19 g (yield 85%) of 4-trifluoromethyl-2-methoxypyridine.1H-NMR(CDCl3, 400 MHz) : delta (ppm) = 3.96(s, 3H), 6.95(s, 1H), 7.05(d, 1H, J = 5.2 Hz), 8.29(d, 1H, J = 5.2 Hz)
methyl 1-[4-(trifluoromethyl)pyridin-2-yl]-1H-imidazole-4-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
To a solution of methyl 1H-imidazole-4-carboxylate (417 mg, 3.3 mmol) in DMF (10 mL) was added sodium hydride (130 mg, 3.3 mmol). After being stir for 1 h at room temperature, <strong>[81565-18-6]2-chloro-4-(trifluoromethyl)pyridine</strong> (500 mg, 2.8 mmol) was added. The mixture was stirred at 80 C. overnight. After being cooled to room temperature, ethyl acetate was added. The solution was washed with brine several times, dried (MgSO4) and concentrated. Chromatography on silica gel eluting with EtOAc/hexanes (1:1) afforded the title compound (120 mg). MS (M+H) 272.1.
(a); A solution having 5.05 g (27.8 mmol) of 2-chloro-4-trifluoromethylpyridine and 3.59 g (66.5 mmol) of sodium methoxide dissolved in 40 ml of methanol was stirred under reflux with heating for 4 hours. Water was added to terminate the reaction, followed by extraction with diethyl ether. The organic layer was dried over anhydrous sodium sulfate and subjected to filtration on the pad of a silica gel cake. The solvent was distilled off under reduced pressure to obtain 4.19 g (yield: 85%) of 4-trifluoromethyl-2-methoxypyridine. 1H-NMR(CDCl3, 400 MHz) : delta (ppm) = 3.96(s, 3H), 6.95(s, 1H), 7.05(d, 1H, J = 5.2 Hz), 8.29(d, 1H, J = 5.2 Hz)
(E),(E)-methyl 2-[2-(4-trifluoromethylpyrid-2-yl-acetoximinomethyl)phenyl]-3-methoxypropenoate[ No CAS ]
[ 145948-12-5 ]
Yield
Reaction Conditions
Operation in experiment
35%
With potassium fluoride;bis(triphenylphosphine)palladium(II)-chloride; In N,N-dimethyl-formamide;
EXAMPLE 1 This Example illustrates the preparation of (E),(E)-methyl 2-[2-(4-trifluoromethylpyrid-2-yl-acetoximinomethyl)phenyl]-3-methoxypropenoate (Compound No. 4 of Table I). A solution of <strong>[81565-18-6]2-chloro-4-trifluoromethylpyridine</strong> (3.33 g), (1-ethoxyvinyl)tri-n-butyltin (5.95 g) and bis(triphenylphosphine)palladium(II) chloride (0.4 g) in DMF (40 ml) was heated at 70 C. for 16 hours. The reaction mixture was cooled to room temperature, potassium fluoride (60 ml of a 10% aqueous solution) was added and the resulting mixture was stirred for 1 hour then filtered through Hyflo supercel filter aid which was rinsed through with ether. The filtrate was extracted with ether (*2) and the combined extracts were washed with brine, then dried, concentrated and chromatographed using ether:hexane 1:4 as the eluant to give 1-ethoxy-1-(4-trifluoromethylpyrid-2-yl)-ethylene (1.4 g, 35% yield) as a pale yellow liquid; 1 H NMR (270 MHz): delta1.45(3H,t), 4.00(2H,q), 4.42(1H,d), 5.50(1H,d), 7.40(1H,d), 7.88(1H,s), 8.72(1H,d) ppm.
11. 2-Chloro-4-trifluoromethyl pyridine-1-oxide Prepared from <strong>[81565-18-6]2-chloro-4-trifluoromethyl pyridine</strong> (Fluorochem Limited, Wesley St., Old Glossop, Derbyshire SK13 9RY, United Kingdom). mp 44-46.
With 3-chloro-benzenecarboperoxoic acid; In chloroform; at 60℃; for 12h;
<Reference Production Example 4>To 22 ml of chloroform were added, 2 g of <strong>[81565-18-6]2-chloro-4-trifluoromethylpyridine</strong>, and 4.39 g of meta-chloroperbenzoic acid, and the mixture was stirred at 60C for 12 hours. Thereafter, the reaction solution was poured into an aqueous saturated sodium sulfite solution, followed by extraction with chloroform three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 1.5 g of <strong>[81565-18-6]2-chloro-4-trifluoromethylpyridine</strong>=N- oxide. 2-Chloro-4-trifluoromethylpyridine=N-oxide1H-NMR (DMSO-d6): 7.81 (dd, IH), 8.36 (d, IH), 8.62 (d, IH)
With dihydrogen peroxide; In water; trifluoroacetic acid; at 50℃;
To a solution of <strong>[81565-18-6]2-chloro-4-trifluoromethylpyridine</strong> (1.81 g, 10 mmol) in trifluoroacetic acid (12 mL) was added 30% hydrogen peroxide (8 mL), and the mixture was stirred at 500C over a weekend. The reaction mixture was poured into ice-cold water, neutralized with solid Na2CO3 with stirring, and extracted with ethyl acetate three times. The combined organic layer was dried over anhydrous Na2SO4, filtered, concentrated, and dried to give 1.67 g of analytically pure <strong>[81565-18-6]2-chloro-4-trifluoromethylpyridine</strong> N-oxide as a brown oil. 1H NMR (CDCl3): delta 8.45 (d, / = 6.9 Hz, IH), 7.77 (d, / = 2.4 Hz, IH), 7.47 (dd, / = 6.9, 2.4 Hz, IH). GC/MS: 197 [M]+.
1.67 g
With dihydrogen peroxide; trifluoroacetic acid; at 50℃;
2-Chloro-4-trifluoromethylpyridine N- oxide.To a solution of <strong>[81565-18-6]2-chloro-4-trifluoromethylpyridine</strong>(1.81g, 10mmol) in trifluoroacetic acid (12 mL), 30% hydrogenperoxide (8 mL) was added, and the mixture was stirred over the weekend at 50 C. The reaction mixture was poured into ice-cooled H2O, &neutralized with solid Na2CO3 with stirring, andextracted three times with EtOAc. The combined organic layers were dried overanhydrous Na2SO4, filtered, concentrated and dried togive analytically pure <strong>[81565-18-6]2-chloro-4-trifluoromethyl pyridine</strong> N- oxide (1.67 g) as a brown oil.
With potassium carbonate In acetonitrile for 51h; Heating / reflux;
35.1
Production Example 35-1: Methyl 4-(4-trifluoromethylpyridin-2-yloxy)benzenecarboxylate: 2-Chloro-4-trifluoromethylpyridine (1.0 g), methyl 4-hydroxybenzenecarboxylate (838.3 mg) and potassium carbonate (2.28 g) were suspended in acetonitrile (10 mL), heated under reflux for 27 hours, and methyl 4-hydroxybenzenecarboxylate (838.3 mg) was added thereto and further heated under reflux for 24 hours. Water (100 mL) was added to the reaction liquid, extracted with ethyl acetate (100 mL), and the organic layer was washed with aqueous 2 N sodium hydroxide solution (100 mL), water (100 mL) and saturated saline water (100 mL) in that order, dried with magnesium sulfate, and evaporated under reduced pressure to obtain a pale yellow oil. The resulting oil was purified through silica gel column chromatography (hexane/ethyl acetate= 8/2) to obtain the entitled compound (740 mg) as a colorless solid.
A mixture of <strong>[81565-18-6]2-chloro-4-trifluoromethylpyridine</strong> (16 g), tetrakis(triphenylphosphine) palladium(O) (2.0 g), trimethylaluminium (2.0 M in hexanes, 48 ml_) and 1,4-dioxane (300 ml_) was heated at reflux for 2.5 hours. The mixture was cooled to 0 0C, acidified by the addition 1.0 M aqueous hydrochloric acid and the organic phase dried over magnesium sulfate and then carefully concentrated to low bulk under atmospheric pressure. The residue was purified by column chromatography on silica gel to afford title compound, 1.5 g.1H NMR (CDCl3): delta 2.65 (s, 3H), 7.30 (m, 1H), 7.35 (s, 1H), 8.70 (d, J = 5.2 Hz, 1 H).
With barium dihydroxide;bis-triphenylphosphine-palladium(II) chloride; In 1,2-dimethoxyethane; water; at 110℃; for 1h;
Example 1 : <n="48"/>Step (i) :2- (2-chlorophenyl) -4- (trifluoromethyl) pyridine [00140] A mixture of 2-chloro-4- (trifluoromethyl) pyridine (4 g, 22.0 mmol), <strong>[3900-89-8]2-chlorophenylboronic acid</strong> (5.04 g, 24.2 mmol), Ba(OH)2 (12.5 g, 66.1 mmol) and Pd(PPh3)2Cl2 (464 mg, 0.66 mmol) in DME (140 mL) /water (35 mL) was heated at 110 0C for 1 h. The solids were filtered off and the mother liquor were concentrated to around 80 mL and extracted with EtOAc. The organic layer was washed with brine, then water, dried (MgSO4) , filtered and concentrated. Purification by column chromatography (1/1 Petroleum ether/EtOAc) gave the Suzuki adduct (5.05 g, 89percent) as a colourless oil. 1H NMR (400 MHz, CDCl3): 7.41-7.44 (2H, m) , 7.51-7.56 (2H, m) , 7.63-7.65 (IH, m) , 7.94 (IH, s), 8.94 (IH, d) .
With barium dihydroxide;bis-triphenylphosphine-palladium(II) chloride; In 1,2-dimethoxyethane; water; at 110℃;
Reagents and conditions: (i) mCPBA, EtOAc; (ii) POCl3; (iii) PdPPh3) 2C12, Ba(OH)2, DME-H2O, 110 0C; (iv) 5-fluoro-lH- pyrazolo [3, 4-b] pyridin-3-amine, Pd(OAc)2, Xantphos, K2CO3, dioxane, 120 0C.[0054] Scheme III above shows a general synthetic route that is used for preparing the compounds III-5. Compounds of formula III-5 can be prepared from intermediate III-l. The formation of chloropyridine derivative III-2 is achieved by treating the corresponding pyridine III-l with m-CPBA in EtOAc followed by conversion of the corresponding N-oxide to the chloropyridine by treating it with POCl3. Intermediate III-2 is then reacted with the corresponding boronic acid derivative to yield compound III- 3 using Suzuki coupling conditions well known for those skilled in the art. This reaction is amenable to a variety of boronic acid derivatives. The pyridine III-3 is then converted in a chloropyridine derivative III-4 using the same two step procedures as used in step 1, m-CPBA oxidation followed by POCl3 treatment. Intermediate III-4 is then treated with 5-fluoro-lH- <n="25"/>pyrazolo [3, 4-b] pyridin-3-amine in the presence of Pd as a catalyst to yield the final compound III-5.
With barium(II) hydroxide;bis-triphenylphosphine-palladium(II) chloride; In 1,2-dimethoxyethane; water; at 110℃; for 1h;
EXAMPLE 5: COMPOUND 1-32; Step (i): 2-(2-chlorophenyI)-4-(trifluoromethyl)pyridine; [00204] A mixture of 2-chloro-4-(trifluoromethyl)pyridine (4 g, 22.0 mmol), 2- chlorophenylboronic acid (5.04 g, 24.2 mmol), Ba(OH)2 (12.5 g, 66.1 mmol) and Pd(PPh3)2Cl2 (464 mg, 0.66 mmol) in DME (140 mL)/water (35 mL) was heated at 110 0C for 1 hour. The solids were filtered off and the mother liquors were concentrated to around 80 mL and extracted with EtOAc. The organic layer was washed with brine then water, dried (MgSO4), filtered and concentrated. Purification by column chromatography (1/1 Petroleum ether/EtOAc) gave the Suzuki adduct (5.05 g, 89percent) as a colourless oil. <n="57"/>1H NMR (400 MHz, CDCl3): 7.41-7.44 (2H, m), 7.51-7.56 (2H, m), 7.63-7.65 (IH, m), 7.94 (IH, s), 8.94 (IH, d).
(d); A hexane solution (11.4 ml) of n-butyllithium was dropwise added to a tetrahydrofuran (45 ml) solution of diisopropylamine (2.81 g) at 0 C., followed by stirring for 1 hour to prepare a tetrahydrofuran solution of lithium diisopropylamide. The solution was cooled to -50 C., and a tetrahydrofuran (7.5 ml) solution of <strong>[81565-18-6]2-chloro-4-trifluoromethylpyridine</strong> (2.81 g) was gradually added thereto, followed by stirring at the same temperature for 30 minutes. The solution was cooled to -78 C., and a tetrahydrofuran (37.5 ml) solution of 5-benzyloxy-4-methoxy-2-methylbenzaldehyde (3.97 g) was gradually added thereto, followed by stirring at the same temperature for 1 hour. A saturated aqueous ammonium chloride solution (50 ml) was added thereto, the temperature was raised to room temperature, the mixture was poured into a saturated aqueous sodium bicarbonate solution (50 ml), and extraction with ethyl acetate (150 ml) was carried out twice. The ethyl acetate phase was washed with an aqueous sodium chloride solution (100 ml) and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 6.48 g (yield 96%) of (5-benzyloxy-4-methoxy-2-methylphenyl)(2-chloro-4-trifluoromethyl-3-pyridyl)methanol as a red-yellow oily substance, and its structure was confirmed by nuclear magnetic resonance spectrum.
ethyl 3-{3-isopropyl-1-[4-(trifluoromethyl)-2-pyridinyl]-1H-pyrazol-4-yl} propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
64%
Reference Example 299 To a mixture of ethyl3- (3-isopropyl-lH-pyrazol-4- yl) propanoate (0.50 g),2-chloro-4- (trifluoromethyl) pyridine (0.43 g) andN, N-dimethylformamide (10 ml) was added 60% sodium hydride (0.19 g) at100 C and the mixture was stirred for 1 hour. The reaction mixture was poured into dilute hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried(MgS04) and concentrated. Ethanol (10 ml) andconc. sulfuric acid (0.05 ml) were added to the residue and the mixture was stirred at70 C for 2 hours. The reaction mixture was poured into an aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried(MgS04) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3- {3-isopropyl-1- [4- (trifluoromethyl)-2-pyridinyl]-lH-pyrazol-4-yl} propanoate (0.54 g, yield64%) was obtained as a colorless oil from a fraction eluted with ethyl acetate- hexane (1: 9, volume ratio). 1H-NMR (CDC13)8 : 1.26 (3H, t, J=7.2 Hz), 1.34 (6H, d, J=7.2 Hz), 2.62-2. 66 (2H, m), 2.81-2. 85 (2H, m), 3.01-3. 08(1H,m), 4.16 (2H, q, J=7. 2 Hz), 7.28(1H, dd, J=5.2, 1.2 Hz), 8.14 (1H, s), 8.27(1H, s), 8.50(1H, d, J=5.2 Hz).
(cis)-4-phenyl-1-[4-(trifluoromethyl)pyridin-2-yl]decahydroquinolin-4-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
20%
With 1,3-bis(2,6-diisopropylphenyl)-4,5-dihydro-1H-imidazolium tetrafluoroborate; potassium tert-butylate;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; at 100℃; for 17h;
To (cis)-4-phenyldecahydroquinolin-4-ol (25 mg, 0.108 mmol) was added 2-chloro-4- (trifluoromethyl)pyridine (21.6 mg, 0.119 mmol), potassium tertiary-butoxide (18.2 mg, 0.162 mmol), tris(dibenzylideneacetone)dipalladium(0) (9.9 mg, 0.011 mmol), and l,3-bis(2,6-di-i- propylphenyl)-4,5-dihydroimidazolium tetrafluoroborate (10.3 mg, 0.022 mmol). The mixture was taken up in 1 mL 1 ,4-dioxane, degassed by bubbling nitrogen through solution, and then heated to 100 C for 17 hours. The reaction mixture was filtered through a 0.45 mum syringe-tip filter, washing with CH2Cl2. The filtrate was evaporated under nitrogen and purified by reversed phase HPLC (5% to 75% CH3CN (0.1% TFA) in water (0.1% TFA) over 20 minutes at 20 mL/minute, 21.2 mm x 100 mm Phenomenex Gemini C 18). The desired fractions were free- based using a Phenomenex Strata X-C cartridge and concentrated in vacuo to give the title compound (10.2 mg, 20%).
With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In toluene; at 100℃; for 10h;
<Reference Production Example 16>To 21 ml of toluene were added 1.9 g of <strong>[81565-18-6]2-chloro-4-trifluoromethylpyridine</strong>, 1 g of cyclopropyl borate, 2.92 g of potassium carbonate and 0.26 g of [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium (II) dichloromethane complex (1 : 1), and the mixture was stirred at 100C for 10 hours. After allowing to cool, the reaction solution was poured into an aqueous saturated ammonium chloride solution, and the resultant solution was extracted with diethyl ether three times, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 1 g of 2-cyclopropyl-4-trifluoromethylpyridine. 2-Cyclopropyl-4-trifluoromethylpyridine 3 1H-NMR: 0.97-1.05 (m, 4H), 2.25-2.32 (m, IH), 7.47 (d, IH), 7.71 (s, IH), 8.66 (d, IH)
A tetrahydrofuran (200 ml) solution of 21.7 g of diisopropylamine was cooled to -70C and 114 ml of n-butyllithium was gradually added dropwise thereto. After continuously stirring at the same temperature for 15 minutes, 30 g of <strong>[81565-18-6]2-chloro-4-trifluoromethylpyridine</strong> was added dropwise, followed by stirring for 1 hour. Then, a tetrahydrofuran (30 ml) solution of 11.9 g of isobutyraldehyde was added dropwise, followed by continuously stirring at the same temperature for 2 hours. After completion of the reaction, the reaction solution was extracted with added an aqueous ammonium chloride solution and ethyl acetate. The organic layer was washed with water and saturated brine and then dried over anhydrous magnesium sulfate. The ethyl acetate was removed by evaporation under reduced pressure and the residue was purified by silica gel column chromatography (developing solvent: n-hexane/ethyl acetate = 4/1) to obtain 33 g (yield 79%) of the desired product as an oily substance.
(5-Chlorothieno[2,3-d]pyrimidin-4-yl)-{2-[3-methoxy-4-(4-trifluoromethylpyridin-2-yloxy)phenyl]ethyl}amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
33%
(5-Chlorothieno[2,3-d]pyrimidin-4-yl)-{2-[3-methoxy-4-(4-trifluoromethylpyridin-2-yloxy)phenyl]ethyl}amine To a solution of 60 percent sodium hydride / oil dispersion (31 mg, 0.78 mmol) in DMSO (3 mL) was added 4-{2-[(5-chlorothieno[2,3-d]pyrimidin-4-yl)amino]ethyl}-2-methoxyphenol (250 mg, 0.75 mmol). After stirring for 30 min, <strong>[81565-18-6]2-chloro-4-(trifluoromethyl)pyridine</strong> (141 mg, 0.78 mmol) was added and the reaction heated at 80 C. overnight. The reaction mixture was diluted with H2O and the precipitate collected by filtration. The filter cake washed with H2O and then dissolved in CH2Cl2. The organics were dried with (Na2SO4), filtered and the stripped in vacuo. The solid residue was triturated with a mixture of ether and pentane leaving a brown solid, 120 mg, 0.25 mmol, 33 percent yield.
33%
To a solution of 60 percent sodium hydride / oil dispersion (31 mg, 0.78 mmol) in DMSO (3 mL) was added 4-{2-[(5-chlorothieno[2,3-d]rhoyrimidin-4- yl)amino]ethyl}-2-methoxyphenol (250 mg, 0.75 mmol) . After stirring for 30min, <strong>[81565-18-6]2-chloro-4-(trifluoromethyl)pyridine</strong> (141 mg, 0.78 mmol) was added and the reaction heated at 80 C overnight. The reaction mixture was diluted with H2O and the precipitate collected by filtration. The filter cake washed with H2O and then dissolved in CH2Cl2. The organics were dried with (Na2SO4), filtered and the stripped in vacuo. The solid residue was triturated with a mixture of ether and pentane leaving a brown solid, 120 mg, 0.25 mmol, 33 percent yield.
A suspension of sodium hydride 60 % in mineral oil (1.65 g, 41 mmol) in anhydrous dioxane (36 ml_) was treated with diethylmalonate (6.3 ml_, 41 mmol) at 25C and heated to 600C for 30 min. Cuprous chloride (1.63 g, 17 mmol) was added, the mixture was heated to 800C and 2-chloro-4-(thfluoromethyl)-pyridine was added and the was heating increased to 100C for 16h.After cooling to 200C the mixture was acidified with 37 % HCI, diluted with water (120 ml_) and extracted with dichloromethane (2 x 60 ml_). The organic phase was dried and evaporated to give a crude oil that was purified by flash chromatography eluting with n-hexane/ethyl acetate from 95/5 to 60/40. 1.9 g (38 %) were obtained as a colourless oil. HPLC-MS (2F): Rt: 12.24 min MS (ESI pos): m/z = 306 (M+H)+.
(1S,4S)-2,5-diaza-bicyclo[2.2.1]heptan-2-yl((1S,3R)-1-ethyl-3-((3S,4R)-3-methoxy-tetrahydro-2H-pyran-4-ylamino)cyclopentyl)methanone hydrochloride[ No CAS ]
[ 81565-18-6 ]
[ 1228111-51-0 ]
Yield
Reaction Conditions
Operation in experiment
26%
With triethylamine; In dimethyl sulfoxide; at 120℃; for 15h;
To a solution of HCI salt of (1S,4S)-2,5-diaza-bicyclo[2.2.1Jheptan-2-yl((1S,3R)- 1-ethy.-3-((3S,4R)-3-methoxy-tetrahydro-2H-pyran-4- ylamino)cyelopentyl)methanone(118mg, 0.33mmol) in DMSO (2ml) was added triethylamine (0.15ml, 1.08mmol) and the <strong>[81565-18-6]2-chloro-4-(trifluoromethyl)pyridine</strong> (183mg, 1.01 mmol). The reaction was heated to 120sC for 15 hours. The reaction was cooled to room temperature, and added to stirring ice water. The mixture was extracted with ethyl acetate(3x). The combined organics were washed with brine, dried over MgSO4 concentrated under reduced pressure and purified with the Biotage (0-100% methanol/ethyl acetate, 15 column volumes) to give the product as a brown foam (40mg 26%). LC/MS (M+H) = 497.2739 exp, 497.2884 obs; 1H NMR (400 MHz, CDCI3) delta ppm 8.25-8.24 (1 H), 6.75-6.74 (1 H), 6.51 -6.45 (1 H), 5.13-4.76 (2H), 4.10-4.03 (1 H), 3.95-3.90 (1 H), 3.72-3.16 (11 H), 2.82-2.67 (1 H), 2.58-2.36 (1 H), 2.06-1.36 (12H), 0.86-0.67 (3H)
Step 2 To a solution of Compound 8 (228 mg, 0.800 mmol) obtained in Step 1 in dimethoxyethane (2 mL) was added sodium hydride (60%, 106 mg, 2.64 mmol) at 0 C., and the mixture was stirred for 1 hour at the same temperature, and then 2-fluorobenzonitrile (130 muL, 1.20 mmol) was added thereto and stirred for 2.5 hours at 80 C. The reaction solution was cooled to room temperature, and then poured into saturated brine and extracted with ethyl acetate, and dried over magnesium sulfate, and then a solvent was removed in vacuo. The residue was purified by column chromatography (n-hexane:ethyl acetate=60:40?50:50) using silica gel (12 g) to yield the desired compound Ic-3 (246 mg, yield 80%)1H-NMR (DMSO-d6) delta: 1.42-1.53 (m, 2H), 1.57-1.69 (m, 2H), 1.93-1.99 (m, 2H), 2.17-2.25 (m, 2H), 2.34-2.44 (m, 1H), 5.00-5.08 (m, 1H), 7.12 (t, 1H, J=74.4 Hz), 7.12-7.14 (m, 3H), 7.29 (d, 1H, J=4.8 Hz), 7.66 (d, 2H, J=8.8 Hz), 8.44 (d, 1H, J=4.8 Hz), 10.04 (s, 1H).
With 18-crown-6 ether; potassium hydroxide; In toluene; at 110℃; for 3h;
2-Chloro-4-trifluoromethyl-pyridine (97mg, 0.59mmol), KOH (26.4mg, 0.47 lmmol) and 18-crown-6-ether (156mg, 0.59mmol) were added to a solution of 7- hydroxy-2-(4-methyl-pyridin-3-yl)-3,4-dihydro-2H-isoquinolin- 1-one (35B: lOOmg, 0.393mmol) in toluene (3mL). The resulting mixture was heated to 110C for 3 hours. The reaction was monitored by TLC (50% ethylacetate in hexane). The reaction mixture was filtered and the filtrate was concentrated to afford the crude product. Purification by column chromatography on silica gel (30% ethylacetate in hexane) afforded 20mg of the product (12.8% yield). NMR (300 MHz, CDC13): delta 8.5-8.4 (bs, 2H), 8.35 (d, 1H), 7.95 (d, 1H), 7.48-7.20 (m, 5H), 4.2-4.0 (m, 1H), 3.90-3.73 (m, 1H), 3.39-3.10 (m, 2H), 2.3 (s, 3H) LCMS: 100%, m/z = 399.7 (M+l)HPLC: 95.8 %
12.8%
With 18-crown-6 ether; potassium hydroxide; In toluene; at 110℃; for 3h;
Preparation of 2-(4-Methyl-pyridin-3-yl)-7-(4-trifluoromethyl-pyridin-2-yloxy)-3,4-dihydro-2H-isoquinolin-1-one (35C) 2-Chloro-4-trifluoromethyl-pyridine (97 mg, 0.59 mmol), KOH (26.4 mg, 0.471 mmol) and 18-crown-6-ether (156 mg, 0.59 mmol) were added to a solution of 7-hydroxy-2-(4-methyl-pyridin-3-yl)-3,4-dihydro-2H-isoquinolin-1-one (35B: 100 mg, 0.393 mmol) in toluene (3 mL). The resulting mixture was heated to 110 C. for 3 hours. The reaction was monitored by TLC (50% ethylacetate in hexane). The reaction mixture was filtered and the filtrate was concentrated to afford the crude product. Purification by column chromatography on silica gel (30% ethylacetate in hexane) afforded 20 mg of the product (12.8% yield). 1H NMR (300 MHz, CDCl3): delta 8.5-8.4 (bs, 2H), 8.35 (d, 1H), 7.95 (d, 1H), 7.48-7.20 (m, 5H), 42-4.0 (m, 1H), 190-3.73 (m, 1H), 3.39-3.10 (m, 2H), 2.3 (s, 3H) LCMS: 100%, m/z=399.7 (M+1)
With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In 1,2-dimethoxyethane; water; at 90℃; for 1h;
To a degassed solution of 1,1-dimethylethyl (lR,4S,6R)-4-[(E/Z)-2-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)ethenyl]-3-azabicyclo[4.1.0]heptane-3-carboxylate D6 (100 mg) and <strong>[81565-18-6]2-chloro-4-(trifluoromethyl)pyridine</strong> (62.4 mg, 0.344 mmol) in DME (3 ml) and sodium carbonate 2M solution (1 ml, 0.286 mmol), bis(triphenylphosphine)palladium(II) chloride (20.10 mg, 0.029 mmol) was added and the mixture was heated to 90C and stirred at that temperature for 1 hour. The mixture was cooled down to room temperature then partitioned between water and EtOAc. Organic phase was dried over sodium sulphate, filtered and concentrated under reduced pressure. Crude was purified by Flash Chromatography on silica gel (Biotage SP1, SNAPlOg, eluentCy to Cy/EtOAc 8:2) affording the title compound D30 (51 mg).UPLC (GEN QC SS): rt = 1.03 min, peak observed: 369 (M+l). Ci9H23F3N202 requires 368.
2-chloro-3-iodo-4-methyl-pyridine n-Butyllithium (1.6M in hexanes, 13.3ml, 21.3mmol) was added dropwise to a solution of diisopropylamine (33ml, 23.3mmol) in tetrahydrofuran (7 ml) at -70 C (internal temp) and the resulting mixture was stirred for 30 min. 2-Chloro-4-trifluoromethyl-pyridine (2.5 ml, 3.52 g, 19.4mmol) was then added dropwise over 20 minutes and the mixture stirred for 2 hours at -70 C. This was then cannulated rapidly into a solution of iodine (5.2g, 20.4mmol) in tetrahydrofuran (3 ml) held at 0 C. The resulting mixture was stirred for 10 min, quenched with aqueous sodium metabisulfite and extracted with ethyl acetate. The organic layer was collected, washed with brine, dried over magnesium sulphate and evaporated. The crude mixture was purified by chromatography on silica, eluting with ethyl acetate in hexane, to give the desired compound (4.87 g, -82%) as a pale yellow solid contaminated with traces of starting material. deltaEta (CDC13) 8.50 (lH,d), 7.44 (1H, d)
With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 100℃;
Example 49 [(2R,3aR,6aR)-2-(4-phenylpiperidin-1-yl)hexahydropentalen-3a(1H)-yl]{(1S,4S)-5-[4-(trifluoromethyl)pyridin-2-yl]-2,5-diazabicyclo[2.2.1]hept-2-yl}methanone To a solution of compound in Example 48H (125 mg, 0.25 mmol) in DMSO (1 mL) was added <strong>[81565-18-6]2-chloro-4-trifluoromethyl-pyridine</strong> (114 mg, 0.63 mmol) and diisopropylethylamine (129 mg, 1.0 mmol). The mixture was heated at 100 C. overnight. After cooling to room temperature, the mixture was diluted with DMSO (2 mL) and purified by preparative HPLC (Column: Phenomenex Gemini C18 250*21.2 mm*8 mum; Mobile phase: from 70% acetonitrile in water (Ammonia(pH 10)) to 85% acetonitrile in water (Ammonia (pH 10)); Wavelength: 220 nm) to afford the title compound (35 mg, 26%) as a white solid. 1H NMR (400 MHz, CD3OD) delta (ppm): 8.18 (s, 1H), 7.10-7.30 (m, 5H), 6.68 (d, 1H), 6.44 (s, 1H), 4.60-5.10 (m, 2H), 3.20-3.80 (m, 9H), 1.20-2.90 (m, 17H); MS (ESI) m/z 539 (M+H)+.
26%
With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 100℃;
Example 49 [(2R,3aR,6aR)-2-(4-phenylpiperidin-l-yl)hexahydropentalen-3a(lH)-yl] {(lS,4S)-5-[4- (trifluoromethy l)pyridin-2-y 1] -2 , 5 -diazabicy clo [2.2.1] hept-2-y 1 } methanone To a solution of compound in Example 48H (125 mg, 0.25 mmol) in DMSO (1 mL) was added <strong>[81565-18-6]2-chloro-4-trifluoromethyl-pyridine</strong> (1 14 mg, 0.63 mmol) and diisopropylethylamine (129 mg, 1.0 mmol). The mixture was heated at 100C overnight. After cooling to room temperature, the mixture was diluted with DMSO (2 mL) and purified by preparative HPLC (Column: Phenomenex Gemini C18 250*21.2iotaetaiotaeta*8muiotaeta; Mobile phase: from 70% acetonitrile in water (Ammonia(pH 10)) to 85% acetonitrile in water (Ammonia (pH 10)); Wavelength: 220 nm) to afford the title compound (35 mg, 26%) as a white solid. 1H NMR (400 MHz, CD3OD) delta (ppm): 8.18 (s, 1H), 7.10-7.30 (m, 5H), 6.68 (d, 1H), 6.44 (s, 1H), 4.60-5.10 (m, 2H), 3.20-3.80 (m, 9H), 1.20-2.90 (m, 17H); MS (ESI) m/z 539 (M+H)+.
With triethylamine; In N,N-dimethyl-formamide; at 80℃; for 1h;Microwave irradiation;
Example 1F (1S,4S)-2-(4-(trifluoromethyl)pyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptane To a mixture of (1S,4S)-tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (0.6 g, 3.03 mmol) in DMF (5 mL) was added <strong>[81565-18-6]2-chloro-4-trifluoromethylpyridine</strong> (0.2 g, 1.1 mmol) and triethylamine (0.22 g, 2.2 mmol). The reaction mixture was heated at reflux for 1 hour in a microwave reactor at 80 C. Then the solvent was evaporated in vacuo. The crude product was purified by column chromatography on silica gel with eluent (petroleum ether:ethyl acetate from 50:1 to 10:1) to afford the intermediate (1S,4S)-tert-butyl 5-(4-(trifluoromethyl)pyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (0.1 g).
0.1 g
With triethylamine; In N,N-dimethyl-formamide; at 80℃; for 1h;Microwave irradiation;
Example IF (lS,4S)-2-(4-(trifluoromethyl)pyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptane To a mixture of (lS,4S)-tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (0.6 g, 3.03 mmol) in DMF (5 mL) was added <strong>[81565-18-6]2-chloro-4-trifluoromethylpyridine</strong> (0.2 g, 1.1 mmol) and triethylamine (0.22 g, 2.2 mmol). The reaction mixture was heated at reflux for 1 hour in a microwave reactor at 80 C. Then the solvent was evaporated in vacuo. The crude product was purified by column chromatography on silica gel with eluent (petroleum ether: ethyl acetate from 50: 1 to 10: 1) to afford the intermediate (lS,4S)-tert-butyl 5-(4- (trifluoromethyl)pyridin-2-yl)-2,5-diazabicyclo[2.2.1 ]heptane-2-carboxylate (0.1 g). A mixture of the above intermediate (0.1 g, 0.29 mmol) and a HC1 solution (4N, 10 mL) in 1 ,4-dioxane was stirred at room temperature overnight. The solvents were evaporated in vacuo. The crude product as hydrochloride salt was used in the next step without purification.
General procedure: To a solution of 4-iodophenol (200 g, 910 mmol) in A/,A/-dimethylformamide (1 L) was slowly added sodium hydride (47 g, 1.2 mol). The reaction was stirred for 30 min at room temperature, then <strong>[81565-18-6]2-chloro-4-trifluoromethylpyridine</strong> (165 g, 910 mmol) was added and the solution was stired at 1 10C for 4 h and 12 h at room temperature. The reaction solution was poured into water and extracted with methyl ferf-butylether (3x ). The combined organic layers were washed succesively with water, lithium chloride solution and 10% sodium hydroxide solution. The combined organic phases were then dried over sodium sulfate and the solvent was removed in vacuo to afford 91 % (303 g, 830 mmol) yield of 2-(4-iodophenoxy)-4-(trifluoromethyl)pyridine.
4-[[4-(trifluoromethyl)-2-pyridyl]oxy]phenol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
30%
General procedure: To a solution of 4-hydroxyphenol (20 g, 180 mmol) in N-methyl-2-pyrrolidone (500 mL) at 10Cwas added sodium hydride (7.3 g, 180 mmol). The reaction mixture was stirred at roomtemperature for 30 mm, then a solution of <strong>[81565-18-6]2-chloro-4-trifluoromethylpyridine</strong> (27 g, 150 mmol) inN-methyl-2-pyrrolidone (100 mL) was added and the solution was stirred for 2 h at 80C. Thereaction contents were then poured into water, extracted with methyl tert-butylether (3x). Thecombined organic layers were washed with water, dried over sodium sulfate and the solventwas the removed in vacuo. The crude residue was purified by flash silica gel columnchromatography (cyclohexane/ethyl acetate) to afford a 30% (12 g, 50 mmol) yield of 4-[[4-(trifl uoromethyl)-2-pyridyl]oxy]phenol.
With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 20℃; for 0.5h;
Step A: 2-methyl-4-((4-(trifluoromethyl)pyridin-2-yl)oxy)butan-2-ol (20-2)To a solution of <strong>[2568-33-4]3-methyl-butane-1,3-diol</strong> (1.6 g, 15 mmol) in DMF (50 mL) was added NaH(1.2 g, 30 mmol) in portions, and the mixture was stirred at room temperature for 30 minutes.Then the mixture was poured into 300 mL of water, extracted with EtOAc (100 mL x 2). TheEtOAc layers were combined and concentrated, the resulting residue was purified by columnchromatography on silica gel eluted with petroleum ether: ethyl acetate (2:1) to give compound20-2.
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 20h;
General procedure: A flask was charged with 2-formylpyrrole 1 (5.00 g, 52.6 mmol), K2CO3 (8.72 g, 63.1 mmol), 2-fluoropyridine 2 (9.0 mL, 105.2 mmol) and DMF (26 mL).The mixture was heated at 100 C for 20 h and then cooled to rt. The reaction mixturewas diluted with water, extracted with MTBE, and the organic phase was dried (MgSO4), filtered, and concentrated. The crude product was purified by chromatography on SiO2(hexanes/EtOAc, 95:5 to 85:15 v/v) to give the product 3 (5.71 g, 63%) as a tan solid.
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 110℃; for 1.5h;Inert atmosphere;
A mixture of <strong>[81565-18-6]2-chloro-4-(trifluoromethyl)pyridine</strong> (10 g, 55.2mmol), potassium vinyl trifluoroborate (1 lg ,82.8mmol), Pd(dppf)Cl2(500 mg) and K2C03 (15.2g, 110.4mmol) in the mixed solvent of dioxane (150mL) and H20 (15mL) was stirred at 110C for 1.5 hrs under a stream of N2 The reaction mixture was cooled to room temperature, filtered and evaporated to give a crude residue. The residue was purified by column chromatography on silica gel eluted with PE: EA= 10: 1 to afford 4- (trifluoromethyl)-2-vinylpyridine (4.5g , 47.4%).MS-ESI (m/z): 174.0(M+1) + (LC-MS method C; Ret. time: 0.94 min).
47.4%
With potassium carbonate; In 1,4-dioxane; water; at 110℃; for 1.5h;Inert atmosphere;
(a) 4-(trifluoromethyl)-2-vinylpyridine A mixture of <strong>[81565-18-6]2-chloro-4-(trifluoromethyl)pyridine</strong> (10 g, 55.2 mmol), potassium vinyl trifluoroborate (11 g, 82.8 mmol), Pd(dppf)Cl2 (500 mg) and K2CO3 (15.2 g, 110.4 mmol) in the mixed solvent of dioxane (150 mL) and H2O (15 mL) was stirred at 110 C. for 1.5 hrs under a stream of N2. The reaction mixture was cooled to room temperature, filtered and evaporated to give a crude residue. The residue was purified by column chromatography on silica gel eluted with PE: EA=10:1 to afford 4-(trifluoromethyl)-2-vinylpyridine (4.5 g, 47.4%). MS-ESI (m/z): 174.0 (M+1)+ (LC-MS method C; Ret. time: 0.94 min).
47.4%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 110℃; for 1.5h;Inert atmosphere;
A mixture of <strong>[81565-18-6]2-chloro-4-(trifluoromethyl)pyridine</strong> (10 g, 55.2 mmol), potassium vinyl trifluoroborate (11 g ,82.8 mmol), Pd(dppf)Cl2 (500 mg) and K2C03 (15.2 g, 110.4 mmol) in the mixed solvent of dioxane (150 mL) and H20 (15 mL) was stirred at 110 C for 1.5 hrs under a stream of N2. The reaction mixture was cooled to room temperature, filtered and evaporated to give a crude residue.. The residue was purified by column chromatography on silica gel eluted with PE: EA= 10: 1 to afford 4- (trifluoromethyl)-2-vinylpyridine (4.5g , 47.4%). MS-ESI (m/z): 174.0(M+1) + (Acq Method: 10-80AB_2min; Rt: 0.94 min)
(S)-4-(3-(3-cyclopropyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-8-yl)-8-((2,4-dimethoxybenzyl)amino)imidazo[1,5-a]pyrazin-1-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
42%
With potassium phosphate; dicyclohexyl-(2?,4?,6?-triisopropyl-3,6-dimethoxy-[1,1?-biphenyl]-2-yl)phosphine; ruphos; In tert-butyl alcohol; at 120℃;Inert atmosphere;
To a solution of (S)-4-(3-(3-cyclopropyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-8-yl)-8-((2,4-dimethoxybenzyl)amino)imidazo[1,5-a]pyrazin-1-yl)benzamide (60 mg, 0.1 mmol) in t-BuOH (4 mL) was added <strong>[81565-18-6]2-chloro-4-(trifluoromethyl)pyridine</strong> (38 mg, 0.2 mmol), K3PO4 (68 mg, 0.3 mmol), Brettphos precat (1 mg) and Ruphos (1 mg). The mixture was stirred at 120 C overnight under N2. The solvent was evaporated and the residue was purified by Pre-TLC to give (S)-4-(3-(3-cyclopropyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-8-yl)-8-((2,4-di methoxybenzyl)amino)imidazo[1,5-a]pyrazin-1-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide (30 mg, yield 42 %). MS-ESI (m/z): 710 (M+1) + (Acq Method: 10-80AB_2min; Rt: 1.06 min).
With iodine; diisopropylamine In tetrahydrofuran; hexane
3 2-chloro-3-iodo-4-methyl-pyridine
2-chloro-3-iodo-4-methyl-pyridine n-Butyllithium (1.6M in hexanes, 13.3 ml, 21.3 mmol) was added dropwise to a solution of diisopropylamine (33 ml, 23.3 mmol) in tetrahydrofuran (7 ml) at -70° C. (internal temp) and the resulting mixture was stirred for 30 min. 2-Chloro-4-trifluoromethyl-pyridine (2.5 ml, 3.52 g, 19.4 mmol) was then added dropwise over 20 minutes and the mixture stirred for 2 hours at -70° C. This was then cannulated rapidly into a solution of iodine (5.2 g, 20.4 mmol) in tetrahydrofuran (3 ml) held at 0° C. The resulting mixture was stirred for 10 min, quenched with aqueous sodium metabisulfite and extracted with ethyl acetate. The organic layer was collected, washed with brine, dried over magnesium sulphate and evaporated. The crude mixture was purified by chromatography on silica, eluting with ethyl acetate in hexane, to give the desired compound (4.87 g, ˜82%) as a pale yellow solid contaminated with traces of starting material. δH (CDCl3) 8.50 (1H, d), 7.44 (1H, d)
(S)-4-(3-(3-cyclopropyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-8-yl)-8-((2,4-dimethoxybenzyl)amino)imidazo[1,5-a]pyrazin-1-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
42%
With potassium phosphate; dicyclohexyl-(2?,4?,6?-triisopropyl-3,6-dimethoxy-[1,1?-biphenyl]-2-yl)phosphine; ruphos; In tert-butyl alcohol; at 120℃;Inert atmosphere;
To a solution of (,S)-4-(3-(3-cyclopropyl-5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3- a]pyridin-8-yl) -8-((2,4-dimethoxybenzyl)amino)imidazo[l,5-a]pyrazin-l-yl)benzamide (60 mg, 0.1 mmol) in t-BuOH (4 mL) was added <strong>[81565-18-6]2-chloro-4-(trifluoromethyl)pyridine</strong> (38 mg, 0.2 mmol), K3PO4 (68 mg, 0.3 mmol), Brettphos precat (1 mg) and Ruphos (1 mg). The mixture was stirred at 120 C overnight under N2. The solvent was evaporated and the residue was purified by Pre-TLC to give (,S)-4-(3-(3-cyclopropyl- 5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-a]pyridin-8-yl)-8-((2,4-di methoxybenzyl)amino)imidazo[ 1 ,5-a]pyrazin- 1 -yl)-N-(4-(trifluoromethyl)pyridin-2- yl)benzamide (30 mg, yield 42 %). MS-ESI (m/z): 710 (M+l) + (Acq Method: 10-80AB_2min; Rt: 1.06 min).
2-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-trifluoromethylpyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
94%
With (1,5-cyclooctadiene)(methoxy)iridium(I) dimer; 4,4'-di-tert-butyl-2,2'-bipyridine; In tetrahydrofuran; at 80℃; for 18h;Inert atmosphere; Glovebox;
Example 4Borylation of PyridinesBorylation of <strong>[81565-18-6]2-chloro-4-trifluoromethylpyridine</strong>An oven-dried 3 mL screw-cap Wheaton vial was charged inside a nitrogen-filled glovebox with [Ir(OMe)cod]2 (3.3 mg, 0.005 mmol) and dtbpy (2.7 mg, 0.01 mmol). THE (1.0 mL) was added followed by B2pin2 (127 mg, 0.5 mmol) and <strong>[81565-18-6]2-chloro-4-trifluoromethylpyridine</strong> (64 muL, 0.5 mmol). The vial was capped and heated outside of the glovebox at 80 C. for 18 h. The reaction solvent was removed by rotary evaporation. The residue was purified by flash column chromatography using pentane-EtOAc mixtures as eluent to provide 2-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-trifluoromethylpyridine as a colorless oil that solidified over time (145 mg, 94%): 1H NMR (500 MHz, CDCl3) delta 7.96 (s, 1H), 7.59 (s, 1H), 1.40 (s, 12H); 19F NMR (470 MHz, CDCl3) delta -64.75. The structure was confirmed by subjecting the compound to deuterodeborylation using [Ir(OMe)cod]2 (2 mol %) in methanol-d4 at 80 C.
With (1,5-cyclooctadiene)(methoxy)iridium(I) dimer; 4,4'-di-tert-butyl-2,2'-bipyridine; In tert-butyl methyl ether; at 120℃; for 1h;
General procedure: A solution of [Ir(COD)OMe]2 (5mol%), dtbpy (5 mol%) and B2pin2 (1.2mol %) in MTBE (0.4M) wasprepared in a sealed vial and an aliquot then added to a thick-walled microwave synthesis vial containing the starting pyridine . The vessel was sealed with a crimp top septum cap and shaken until allof the substrate was dissolved. The reaction mixture was stirred on a magnetic stirring block or irradiated in a microwave reactor for the stated time and temperature. Upon completion, the volatiles were removed in vacuo to afford the crude borylated product. To the crude mixture under N2, was added palladium catalyst (5 mol%), base (2 eq.), aryl halide (1.1 - 2eq.) and the stated solvent. The reaction was heated at the stated temperature for the stated time. The reaction mixture was diluted with water and extracted into EtOAc. The organic phase was dried over MgSO4, filtered and concentrated in vacuo to give the crude product. This was dry-loaded onto silica geland purified by silica gel flash column chromatography using the stated solvent system.
With propylamine; In tetrahydrofuran; at 20℃; for 15h;Inert atmosphere; Irradiation; Sealed tube;
Weigh 0.5 mM halogenated aromatic hydrocarbon in a reaction flask, add 2 mL of solvent, and nitrogen in the reaction flask.Deoxygenation for 30 minutes plus 50 muL during deoxygenationPropylamine.After that, the reaction vessel was sealed, placed over a light-emitting diode (LED) having a wavelength of 500 nm and a power of 25 W to be irradiated, and the reaction was stirred at room temperature for 15 hours.After that, the dehalogenation yield was characterized by gas chromatography-mass spectrometry. The yield of 4-trifluoromethylpyridine was 68%. The results of the GC-MS combination were shown in Figure 4. The halogenated aromatic hydrocarbon was 2-chlorobenzene. 4-trifluoromethylpyridine, the solvent is tetrahydrofuran
1-(4-(trifluoromethyl)pyridin-2-yl)guanidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
47%
With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 120℃; for 18h;
To a suspension of <strong>[81565-18-6]2-chloro-4-(trifluoromethyl)pyridine</strong> 4g (4.50g, 24.8mmol) and guanidine carbonate (13.4g, 74.4mmol) in NMP (45mL) was added K2CO3 (17.1g, 124mmol), and the mixture was heated to 120C and stirred for 18h. The mixture was filtered through a glass filter at approximately 100C, and the cake was washed with EtOAc (5×90mL). The combined filtrate was washed with H2O (45mL) and 10% aqueous NaCl (3×45mL), and concentrated in vacuo. The residue was suspended in EtOAc/hexane (1:2, 23mL), and the mixture was stirred at 50C for 1h. The mixture was cooled by ice bath and stirred for 1h, and then filtered. The obtained solids were suspended in H2O (13mL) and the slurry was stirred at 50C for 1h. The mixture was gradually cooled by ice bath and stirred for 1h, and then filtered to give 5g (2.39g, 47%) as a white solid. Mp 141-142C; 1H NMR (500MHz, DMSO-d6) delta 6.75 (s, 1H), 6.85 (dd, J=5.4, 1.6Hz, 1H), 6.92 (br s, 4H), 8.25 (d, J=5.4Hz, 1H); 13C NMR (125MHz, DMSO-d6) delta 107.5 (q, 3JCF=2.5Hz), 113.9 (q, 3JCF=3.8Hz), 123.2 (q, 1JCF=271.3Hz), 137.3 (q, 2JCF=32.5Hz), 147.7, 158.3, 164.2; IR (ATR) 3388, 3045, 1663, 1595, 1527, 1411, 1335, 1293, 1271, 1171, 1145, 1122, 1078, 980, 871, 817, 793, 758, 731, 689, 667, 561, 536, 467, 444, 421, 401cm-1; HRMS-ESI (m/z): [M+H]+ calcd for C7H8F3N4, 205.0701; found, 205.0693.
7-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridin-3-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Multi-step reaction with 3 steps
1: potassium carbonate / 1-methyl-pyrrolidin-2-one / 18 h / 120 °C
2: N-chloro-succinimide / methanol / 0.25 h / 40 °C
3: potassium carbonate / methanol; water / 0.5 h / 40 °C
2-(4-iodophenoxy)-4-(trifluoromethyl)pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91%
Example 1: Preparation of 2-(4-iodophenoxy)-4-(trifluoromethyl) pyridineTo a solution of 4-iodophenol (200 g, 910 mmol) in N,N-dimethylformamide (1 L) was slowlyadded sodium hydride (47 g, 1.2 mol). The reaction was stirred for 30 mm at roomtemperature, then <strong>[81565-18-6]2-chloro-4-trifluoromethylpyridine</strong> (165 g, 910 mmol) was added and thesolution was stired at 110C for 4 h and 12 h at room temperature. The reaction solution waspoured into water and extracted with methyl tert-butylether (3x). The combined organic layerswere washed succesively with water, lithium chloride solution and 10% sodium hydroxidesolution. The combined organic phases were then dried over sodium sulfate and the solventwas removed in vacuo to afford 91 % (303 g, 830 mmol) yield of 2-(4-iodophenoxy)-4-(trifl uoromethyl)pyrid me.
91%
To a solution of 4-iodophenol (200 g, 910 mmol) in N,N-dimethylformamide (1 L) was slowlyadded sodium hydride (47 g, 1 .2 mol). The reaction was stirred for 30 mm at roomtemperature, then <strong>[81565-18-6]2-chloro-4-trifluoromethylpyridine</strong> (165 g, 910 mmol) was added and the solution was stired at 110C for 4 h and 12 h at room temperature. The reaction solution was poured into water and extracted with methyl tert-butylether (3x). The combined organic layers were washed succesively with water, lithium chloride solution and 10% sodium hydroxidesolution. The combined organic phases were then dried over sodium sulfate and the solvent was removed in vacuoto afford 91% (303 g, 830 mmcl) yield of 2-(4-iodophenoxy)-4- (trifl uoromethyl)pyrid me.
1-(2,2-dimethoxy-1-methyl-ethyl)-1-methoxy-urea[ No CAS ]
[ 81565-18-6 ]
1-(2,2-dimethoxy-1-methyl-ethyl)-1-methoxy-3-[4-(trifluoromethyl)-2-pyridyl]urea[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
32%
With tris-(dibenzylideneacetone)dipalladium(0); potassium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 105℃; for 2h;Sealed tube;
Procedure for synthesis of 1 -(2,2-dimethoxy-1 -methyl-ethyl)-1 -methoxy-3-[4- (trifluorom 1-(2,2-dimethoxy-1-methyl-ethyl)-1-methoxy-urea (300 mg, 1.56 mmol), 2-chloro-4- (trifluoromethyl)pyridine (commercially available) (312 mg, 1 .1 equiv.), potassium carbonate (324 mg), tris(dibenzylideneacetone)dipalladium(0) (30 mg), 4,5-bis(diphenylphosphino)-9,9- dimethylxanthene (70 mg) were suspended in 1-4-dioxane (4 mL) and the mixture was then heated at 105C in a sealed vial for 2h. The mixture was allowed to cool to room temperature, diluted with EtOAc (6 mL), filtered, then chromatographed on silica eluting with 0-100% EtOAc in isohexane. Fractions containing product were evaporated to give the desired product as a yellow gum (170 mg, 32%). LC-MS: (positive ES MH+ 338).
32%
With tris-(dibenzylideneacetone)dipalladium(0); potassium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 105℃; for 2h;Sealed tube;
1 -(2,2-dimethoxy-1 -methyl-ethyl)-1 -nriethoxy-urea (300 mg, 1 .56 mmol), 2-chloro-4- (trifluoromethyl)pyridine (commercially available) (312 mg, 1 .1 equiv.), potassium carbonate (324 mg), tris(dibenzylideneacetone)dipalladium(0) (30 mg), 4,5-bis(diphenylphosphino)-9,9- dimethylxanthene (70 mg) were suspended in 1 -4-dioxane (4 mL) and the mixture was then heated at 105C in a sealed vial for 2h. The mixture was allowed to cool to room temperature, diluted with EtOAc (6 mL), filtered, then chromatographed on silica eluting with 0-100% EtOAc in isohexane. Fractions containing product were evaporated to give the desired product as a yellow gum (170 mg, 32%). LC-MS: (positive ES MH+ 338).
1-methyl-3-[4-(trifluoromethyl)-2-pyridyl]urea[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
55%
With tris-(dibenzylideneacetone)dipalladium(0); potassium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 75 - 80℃; for 3.5h;Inert atmosphere;
Procedure for synthesis of 4 1 -methyl-3-[4-(trifluoromethyl)-2-pyridyl]urea (Step-1) / A mixture of tris(dibenzylideneacetone)dipalladium(0) (0.202 g, 0.220 mmol), 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene (0.493 g, 0.826 mmol), potassium carbonate (1.93 g, 13.8 mmol) and methylurea (0.408 g, 5.51 mmol) in 1 ,4-dioxane (30 mL) was treated with 2- chloro-4-(trifluoromethyl)pyridine (commercially available) (1.0 g, 5.51 mmol), The mixture was warmed to 75-80C with stirring under a Nitrogen atmosphere for 3.5 h. The reaction mixture was diluted with EtOAc (20 mL) and water (20 mL) and filtered through a pad of celite, rinsing through with further small portions of EtOAc and water. The organic phase was separated and the aqueous further extracted with EtOAc (5 mL). The organic extracts were combined, washed with brine (10 mL), dried over MgS04, filtered and the filtrate evaporated giving an orange liquid. This was chromatographed (eluting with an EtOAc/iso-hexane gradient) and fractions containing product were evaporated and triturated with iso-hexane to give the desired product as a light yellow powder (0.669 g, 55%). H NMR (CDCI3): 9.44 (br.s, 1 H), 9.04 (br.s, 1 H), 8.32 (d, 1 H), 7.15 (s, 1 H), 7.06 (d, 1 H), 2.99 (d, 3H). LC-MS: (positive ES MH+ 220).
55%
With tris-(dibenzylideneacetone)dipalladium(0); potassium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 75 - 80℃; for 3.5h;Inert atmosphere;
A mixture of tris(dibenzylideneacetone)dipalladium(0) (0.202 g, 0.220 mmol), 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene (0.493 g, 0.826 mmol), potassium carbonate (1 .93 g, 13.8 mmol) and methylurea (0.408 g, 5.51 mmol) in 1 ,4-dioxane (30 mL) was treated with 2-chloro-4- (trifluoromethyl)pyridine (commercially available) (1 .0 g, 5.51 mmol), The mixture was warmed to 75- 80C with stirring under a Nitrogen atmosphere for 3.5 h. The reaction mixture was diluted with EtOAc (20 mL) and water (20 mL) and filtered through a pad of celite, rinsing through with further small portions of EtOAc and water. The organic phase was separated and the aqueous further extracted with EtOAc (5 mL). The organic extracts were combined, washed with brine (10 mL), dried over MgS04, filtered and the filtrate evaporated giving an orange liquid. This was chromatographed (eluting with an EtOAc/iso-hexane gradient) and fractions containing product were evaporated and triturated with iso-hexane to give the desired product as a light yellow powder (0.669 g, 55%). H NMR (CDCI3): 9.44 (br.s, 1 H), 9.04 (br.s, 1 H), 8.32 (d, 1 H), 7.15 (s, 1 H), 7.06 (d, 1 H), 2.99 (d, 3H). LC-MS: (positive ES MH+ 220).
1-(2,2-dimethoxy-1-methyl-ethyl)-1-methyl-urea[ No CAS ]
[ 81565-18-6 ]
1-(2,2-dimethoxy-1-methyl-ethyl)-1-methyl-3-[4-(trifluoromethyl)-2-pyridyl]urea[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
282 mg
With tris-(dibenzylideneacetone)dipalladium(0); potassium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 105℃; for 1h;Sealed tube;
Procedure for synthesis of 1-(2,2-dimethoxy-1-methyl-ethyl)-1-methyl-3-[4- (trifluoromethyl)-2-pyridyl]urea (Step 3) 1-(2,2-dimethoxy-1-methyl-ethyl)-1 -methyl-urea (220 mg, 1.249 mmol), 2-chloro-4- (trifluoromethyl)pyridine (commercially available) (272 mg, 1.2 equiv.), potassium carbonate (259 mg, 1.5 equiv.), tris(dibenzylideneacetone)dipalladium(0) (47 mg), 4,5-bis(diphenylphosphino)- 9,9-dimethylxanthene (1 1 1 mg) were suspended in 1-4-dioxane (6 mL) and the mixture was then heated at 105C in a sealed vial for 1 h. The mixture was allowed to cool to room temperature, diluted with EtOAc (6 mL), filtered then chromatographed on silica eluting with 0-100% EtOAc in isohexane. Fractions containing product were evaporated to give the desired product as a colourless gum (282 mg, 70%). LC-MS: (positive ES MH+ 322).
282 mg
With tris-(dibenzylideneacetone)dipalladium(0); potassium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 105℃; for 1h;Sealed tube;
1-(2,2-dimethoxy-1-methyl-ethyl)-1 -methyl-urea (220 mg, 1.249 mmol), 2-chloro-4- (trifluoromethyl)pyridine (commercially available) (272 mg, 1.2 equiv.), potassium carbonate (259 mg, 1.5 equiv.), tris(dibenzylideneacetone)dipalladium(0) (47 mg), 4,5-bis(diphenylphosphino)-9,9- dimethylxanthene (1 1 1 mg) were suspended in 1-4-dioxane (6 mL) and the mixture was then heated at 105C in a sealed vial for 1 h. The mixture was allowed to cool to room temperature, diluted with EtOAc (6 mL), filtered then chromatographed on silica eluting with 0-100% EtOAc in isohexane. Fractions containing product were evaporated to give the desired product as a colourless gum (282 mg, 70%). LC-MS: (positive ES MH+ 322).
2-(3-methylsulfanylpropoxy)-4-trifluoromethylpyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium tert-butylate; In tetrahydrofuran; at 100℃;
Step A.2-(3-Methylsulfanyl-propoxy)-4-trifluoromethyl-pyridine In a 250 mL round bottom flask, t-BuOK (9.3 g, 82.5 mmol) was added to a stirred mixture of <strong>[81565-18-6]2-chloro-4-trifluoromethyl-pyridine</strong> (10 g, 55 mmol) and 3-methylsulfanyl-propan- l- ol (8.7 g, 82.5 mmol) in dry THF (80 mL) .The mixture was allowed to stir at 100 C overnight. After the mixture was cooled to room temperature. The mixture was filtered, and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (PE/EA=5/1) to give the title compound. MS m/e (M+H+): 252.3.
With potassium tert-butylate; In tetrahydrofuran; at 100℃;
Step A.2-(3-Methylsulfanyl-propoxy)-4-trifluoromethyl-pyridine In a 250 mL round bottom flask, t-BuOK (9.3 g, 82.5 mmol) was added to a stirred mixture of <strong>[81565-18-6]2-chloro-4-trifluoromethyl-pyridine</strong> (10 g, 55 mmol) and 3-methylsulfanyl-propan- l- ol (8.7 g, 82.5 mmol) in dry THF (80 mL) .The mixture was allowed to stir at 100 C overnight. After the mixture was cooled to room temperature. The mixture was filtered, and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (PE/EA=5/1) to give the title compound. MS m/e (M+H+): 252.3.
2-[4-(trifluoromethyl)-2-pyridinyl]phenol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1.18 g
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; water; at 23 - 90℃; for 20.5h;
2-Chloro-4-trifluoromethylpyridine (1.0 g, 5.5 mmol) and 2-(4,4,5 ,5 -tetramethyl1,3 ,2-dioxaborolan-2-yl)phenol (1.57 g, 7.16 mmol) were combined in dimethoxyethane (18 mL) and water (1.8 mL). To this mixture were added sodium carbonate (2.28 g, 16.5mmol) and tetrakis(triphenylphosphine)palladium(0) (0.32 g, 0.27 mmol). The reaction was heated at 90 C for 2.5 h and allowed to stir at 23 C for 18 h. The mixture was diluted with water (20 mL) and dichloromethane (20 mL) and the layers separated. The aqueous layer was washed with dichloromethane (10 mL). The combined dichloromethane layers were washed with saturated aqueous sodium chloride solution (10 mL) and dried over sodiumsulfate. After filtration the organic layer was evaporated and the solid thus obtained wastriturated with hexanes (20 mL). The filtrate was concentrated to provide 1.18 g of the titlecompound as a yellow solid which was used in Step B without further purification.1H NMR oe 13.61 (s, 1H), 8.72 (d, 1H), 8.12 (s, 1H), 7.83 (d, 1H), 7.47 (m, 1H), 7.36 (s, 1H),7.06 (d, 1H), 6.96 (t, 1H).
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; water; at 23℃; for 2.5h;
[0350] 2-Chloro-4-trifluoromethylpyridine (1.0 g, 5.5 mmol) and 2-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl) phenol (1.57 g, 7.16 mmol) were combined in dimethoxyethane (18 mE) and water (1.8 mE). To this mixture were added sodium carbonate (2.28 g, 16.5 mmol) and tetrakis (triphenylphosphine)palladium(0) (0.32 g, 0.27 mmol). The reaction was heated at 90 C. for 2.5 h and allowed to stir at 23 C. for 18 h. The mixture was diluted with water (20 mE) and dichloromethane (20 mE) and the layers separated. The aqueous layer was washed with dichioromethane (10 mE). The combined dichloromethane layers were washed with saturated aqueous sodium chloride solution (10 mE) and dried over sodium sulfate. Afier filtration the organic layer was evaporated and the solid thus obtained was triturated with hexanes (20 mE). The filtrate was concentrated to provide 1.18 g of the title compound as a yellow solid which was used in Step B without thrther purification.10351] ?H NMR oe 13.61 (s, 1H), 8.72 (d, 1H), 8.12 (s, 1H),7.83 (d, 1H), 7.47 (m, 1H), 7.36 (s, 1H), 7.06 (d, 1H), 6.96 (t, 1H). [0351] ?H NMR oe 13.61 (s, 1H), 8.72 (d, 1H), 8.12 (s, 1H),7.83 (d, 1H), 7.47 (m, 1H), 7.36 (s, 1H), 7.06 (d, 1H), 6.96 (t, 1H).
With palladium diacetate; 1,2-bis-(diphenylphosphino)ethane; lithium tert-butoxide In 1,4-dioxane at 100℃; for 24h; Schlenk technique; Inert atmosphere;
tert-butyl 2-[4-(trifluoromethyl)-2-pyridyl]acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
31%
With [2-(di-tert-butylphosphino)-2?,4?,6?-triisopropyl-1,1?-biphenyl][2-((2-aminoethyl)phenyl)]palladium(II) chloride; lithium hexamethyldisilazane; In toluene; at 0 - 20℃;
[00311] Intermediate I 5a: tert-Butyl 2-[4-(trifluoromethyl)-2-pyridyl]acetate[00312] 2-Chloro-4-(trifluoromethyl)pyridine (0.35mL, 2.7Smmol), tert-butyl acetate (0.55mL,4.l3mmol) and tBuxphos Pd Gi (19mg, 0.O3mmol) were combined intoluene (lmL), stirred, and cooled to 0 C. LiHMDS 1 M in toluene (8.26mL, 8.26mmol) was then added slowly. The mixture was slowly allowed to warm to room temperature and stirred overnight. Sat. aq. NH4CI solution (l0mL) was added and the mixture extracted with EtOAc (3 x 50mL). The organics were combined, washed with brine (50mL), dried over Na2SO4, filtered then evaporated to dryness to give a brown oil. This was purified by column chromatography using an eluent of 0 to 40% EtOAc in heptane to give tert-butyl 2-[4-(trifluoromethyl)-2-pyridyl]acetate (220mg, 0.84mmol, 31% yield) as a yellow oil.1H NMR (CDCI3, 400MHz) O/ppm: 8.56 (1H, d, J= 5.2Hz), 7.35 (1H, 5), 7.23 (1H, d, J= 5.2Hz),3.67 (2H, 5), 1.25 (9H, 5).MS Method 2: RT: 1 .82 mi mlz 206.1 [MtBu+H]+Note: only the mass of the acid (205) is seen in the LCMS but t-butyl group can be seen in the NMR
With copper(l) iodide; trans-bis(triphenylphosphine)palladium dichloride; triphenylphosphine In triethylamine; N,N-dimethyl-formamide at 100℃; for 0.2h; Inert atmosphere; Microwave irradiation;
methyl (S)-3-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanoate[ No CAS ]
[ 81565-18-6 ]
methyl (S)-3-(4-((3-(trifluoromethyl)phenyl)sulfonyl)-6-(4-(trifluoromethyl)pyridin-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 90℃; for 2h;
A mixture of methyl (S)-3-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4- ((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanoate (150 mg, 0.27 mmol), <strong>[81565-18-6]2-chloro-4-(trifluoromethyl)pyridine</strong> (73.4 mg, 0.40 mmol), tetrakis(triphenylphosphine)palladium (15.6 mg, 0.01 mmol), sodium carbonate (85.9 mg), toluene (3 mL), ethanol (1 mL), and water (1 mL) was stirred for two hours at 90oC. Then, the mixture was partitioned between ethyl acetate and water. The organic layer was concentrated and the resulting residue was purified via MPLC eluting with 33% ethyl acetate in petroleum ether to afford methyl (S)-3-(4-((3-(trifluoromethyl)phenyl)sulfonyl)-6-(4- (trifluoromethyl)pyridin-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanoate (130 mg, 84%) as a white solid.
ethyl 2-amino-2-[4-(trifluoromethyl)-2-pyridyl]acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
13%
To a stirred suspension of sodium hydride (95%, 0.631 g, 25 mmol) in N,N-dimethylformamide (50 mL) cooled to 0 C was added ethyl 2-(benzhydrylideneamino)acetate (5.35 g, 20 mmol). After stirring the reaction for 30 min at 0 C, <strong>[81565-18-6]2-chloro-4-(trifluoromethyl)pyridine</strong> (4 g, 22 mmol) was added. The reaction mixture was warmed to RT and stirred for 4H. Hydrochloric acid (1 mol/L) in water (50 mL) was added, and the resulting mixture stirred at RT for 3 h. The mixture was diluted with isopropyl acetate (100 mL) and neutralized with saturated aqueous sodium bicarbonate (50 mL). The layers were separated, and the aqueous was extracted with isopropyl acetate (2 x 100 mL). The combined organics were dried over sodium sulfate, concentrated to dryness in vacuo, and purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% methanol in dichloromethane) affording ethyl 2-amino-2-[4-(trifluoromethyl)-2-pyridyl]acetate (0.630 g, the next step: LCMS RT = 0.93 min, m/z = 249 [M + H]+.
13%
To a stirred suspension of sodium hydride (95%, 0.631 g, 25 mmol) in N,Ndimethylformamide(50 mL) cooled to 0 C was added ethyl 2-(benzhydrylideneamino)acetate (5.35 g, 20 mmol). After stirring the reaction for 30 minat 0 C, <strong>[81565-18-6]2-chloro-4-(trifluoromethyl)pyridine</strong> (4 g, 22 mmol) was added. The reactionmixture was warmed to RT and stirred for 4 h. Hydrochloric acid (1 mol/L) in water (50mL) was added, and the resulting mixture stirred at RT for 3 h. The mixture was dilutedwith isopropyl acetate (100 mL) and neutralized with saturated aqueous sodiumbicarbonate (50 mL). The layers were separated, and the aqueous was extracted with isopropyl acetate (2 x 100 mL). The combined organics were dried over sodium sulfate,concentrated to dryness in vacuo, and purified by column chromatography (silica gel,100-200 mesh, 0 to 10% methanol in dichloromethane) affording ethyl 2-amino-2-[4-(trifluoromethyl)-2-pyridyl]acetate (0.630 g, 13%) used as is in the next step: LCMS (2.5min method) retention time = 0.93 min, m/z = 249 [M + H]+.
With hydrogen fluoride; at 200℃; under 37503.8 Torr;Autoclave; Industrial scale;
The third step of the reaction will be the second step of chlorination of the first round from the round-bottomed flask into the autoclave and the introduction of anhydrous hydrogen fluoride for fluorination.Hydrogen fluoride access to 250 grams, the control pot temperature was 200 , the control pressure of 5MPa reaction.This step produces the major product 2-chloro-4-trifluoromethylpyridine and by-product 2-fluoro-4-trifluoromethylpyridine. By-product 2-fluoro-4-trifluoromethylpyridine can be re-reacted by diazotization to produce 2-chloro-4-trifluoromethylpyridine.After the simple steam separation to give product 2-chloro-4-trifluoromethyl pyridine 345 g (content of 99%).
2-(benzofuran-2-yl)-4-(trifluoromethyl)pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
51%
With potassium phosphate; (DPEPhos)Ni(mesityl)Br; water; In 1,4-dioxane; benzene; at 25℃; for 16h;Inert atmosphere; Sealed tube;
General procedure: Unless otherwise specified, under an inert atmosphere C1 (12.7mg, 0.016 mmol, 2 mol %), aryl halide (0.8 mmol), boronic acid(1.6 mmol), and K3PO4 (679 mg, 3.2 mmol) were added to anoven-dried 4 dram vial containing a magnetic stir bar. 1,4-Dioxane (1.3 mL) and benzene (700 muL) were added, the vial wassealed with a screwcap featuring a PTFE/silicone septum andwas removed from the glovebox. Degassed water (86 muL) wasadded via a gas-tight syringe. The reaction mixture was magneticallystirred for 16 h at room temperature. Note: On severaloccasions the base became clumpy and stuck to the bottom ofthe reaction vial; in these cases it was noted that reactions weremore successful if efficient stirring was maintained. After 16 h,the reaction mixture was taken up in EtOAc (ca. 10 mL) andextracted with distilled water (3 × 10 mL). The organic layer wasdried over anhydrous Na2SO4, filtered, and concentrated withthe aid of a rotary evaporator.
2-(2-(4-(trifluoromethyl)pyridin-2-yl)naphthalen-1-yl)pyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With dichloro(eta6-2-phenoxyethanol)ruthenium(II) dimer; trisodium tris(3-sulfophenyl)phosphine; potassium pivalate; potassium carbonate; In water; at 120℃; for 24h;Inert atmosphere; Schlenk technique;
General procedure: A heating reaction vessel was charged with the prescribed amount of catalyst, naphthylpyrimidine (0.5 mmol), aryl chloride (0.6 mmol), K2CO3 (1.5 mmol), KO2CR (0.1 mmol), PAr3 (0.1 mmol) and water (3 mL) under nitrogen. The vessel was sealed and heated at 120 C (oil bath temperature) for 24 h. The resulting mixture was cooled to room temperature, and the aqueous layer was extracted with ethyl acetate, then the combined organic layers were washed with water, dried over MgSO4, filtered, and the solvent was removed on a rotary evaporator. The resulting residue was purified by flash chromatography to give the corresponding products 1-34.
2-(2-(4-(trifluoromethyl)pyridin-2-yl)naphthalen-3-yl)pyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78%
With dichloro(eta6-2-phenoxyethanol)ruthenium(II) dimer; trisodium tris(3-sulfophenyl)phosphine; potassium pivalate; potassium carbonate; In water; at 120℃; for 24h;Inert atmosphere; Schlenk technique;
General procedure: A heating reaction vessel was charged with the prescribed amount of catalyst, naphthylpyrimidine (0.5 mmol), aryl chloride (0.6 mmol), K2CO3 (1.5 mmol), KO2CR (0.1 mmol), PAr3 (0.1 mmol) and water (3 mL) under nitrogen. The vessel was sealed and heated at 120 C (oil bath temperature) for 24 h. The resulting mixture was cooled to room temperature, and the aqueous layer was extracted with ethyl acetate, then the combined organic layers were washed with water, dried over MgSO4, filtered, and the solvent was removed on a rotary evaporator. The resulting residue was purified by flash chromatography to give the corresponding products 1-34.
trimethyl-[2-[4-(trifluoromethyl)-2-pyridyl]ethynyl]silane[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
94.4%
With copper(l) iodide; triethylamine; triphenylphosphine; palladium dichloride; at 80℃; for 8h;Inert atmosphere; Cooling with ice;
In a nitrogen atmosphere, palladium(II) chloride (3.17 g, 17.9 mmol), triphenylphosphine (9.4 g, 35.8 mmol) and copper(I) iodide (5.5 g, 28.6 mmol) were sequentially added to a triethylamine (320 mL) solution of <strong>[81565-18-6]2-chloro-4-(trifluoromethyl)pyridine</strong> (65.0 g, 358.0 mmol), and trimethylsilylacetylene (42.2 g, 429.7 mmol) was added dropwise under ice cooling. After the completion of dropwise addition, the solution was stirred at 80 C. for 8 hours and filtered through Celite, and the filtrate was concentrated under reduced pressure. Subsequently, aqueous ammonia (30 mL) and water were added, and the resulting solution was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered to remove the white precipitate, and concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluting solvent: ethyl acetate/hexane=1:20) to afford the title compound (82.2 g, yield: 94.4%) as an orange oily product. 1HNMR Spectrum (CDCl3) sigma: 8.75 (1H, d, J=5.0 Hz), 7.67 (1H, s), 7.44 (1H, dd, J1=5.0 Hz, J2=0.9 Hz), 0.29 (9H, s).
94.4%
With copper(l) iodide; triethylamine; triphenylphosphine; palladium dichloride; at 80℃; for 8h;Inert atmosphere; Cooling with ice;
Under a nitrogen atmosphere,2-chloro-4- (trifluoromethyl) pyridine(65.0 g, 358.0 mmol) in triethylamine (320 mL) was added palladium (II) chloride(3.17 g, 17.9 mmol),Triphenylphosphine (9.4 g, 35.8 mmol),Iodized copper (I)(5.5 g, 28.6 mmol), and trimethylsilylacetylene (42.2 g, 429.7 mmol) was added dropwise under ice cooling.After completion of the dropwise addition,The mixture was stirred at 80 C. for 8 hours,Celite filtered. The filtrate was concentrated under reduced pressure,Ammonia water (30 mL) and water were added, the mixture was extracted with ethyl acetate,The organic layer was washed with saturated brine and then dried over sodium sulfate.After filtration, the white precipitate was removed, and after concentration under reduced pressure,The obtained crude product was purified by silica gel column chromatography (elution solvent: ethyl acetate / hexane = 1: 20)Obtained in the form of an orange oil (82.2 g, yield 94.4%).
1-((2-(trimethylsilyl)ethoxy)methyl)-5-(6-aminopyrimidin-4-ylamino)-6-methoxyindazole[ No CAS ]
[ 81565-18-6 ]
1-((2-(trimethylsilyl)ethoxy)methyl)-5-(6-((4-(trifluoromethyl)pyridin-2-yl)amino)pyrimidin-4-ylamino)-6-methoxyindazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
26%
With tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; sodium t-butanolate; In 1,4-dioxane; at 80℃; for 1h;Inert atmosphere; Microwave irradiation;
The compound 1-((2-(trimethylsilyl)ethoxy)methyl)-5-(6-aminopyrimidin-4-ylamino)-6-methoxyindazole 25a (15.0 mg, 0.039mmol),2-Chloro-4-(trifluoromethyl)pyridine (10.7 mg, 0.059 mmol)Mixed with 1,4-dioxane (1 mL),Tris(dibenzylideneacetone)dipalladium (3.6 mg, 0.004 mmol) was added under argon atmosphere.4,5-bisdiphenylphosphino-9,9-dimethylxanthenen (2.3 mg, 0.004 mmol)Sodium tert-butoxide (7.5 mg, 0.078 mmol) was reacted under microwave atmosphere at 80 C for 1 hour under argon atmosphere.After cooling to room temperature, the mixture was diluted with dichloromethane (10 mL) and filtered.The filtrate was de-dissolved under reduced pressure to give a crude material, which was purified by preparative liquid chromatography (water (0.2% formic acid), 40% to 60% acetonitrile, 15 min).The target product 1-((2-(trimethylsilyl)ethoxy)methyl)-5-(6-((4-(trifluoromethyl)pyridin-2-yl)amino)pyrimidine- 4-Aminoamino)-6-methoxyindazole 25b (5.5 mg, 0.01 mmol, white solid), yield: 26%.
2-methyl-4-[4-(trifluoromethyl)-2-pyridyl]-3-butyn-2-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88.4%
With copper(l) iodide; triethylamine; triphenylphosphine; palladium dichloride; at 80℃; for 7h;Inert atmosphere;
Under nitrogen atmosphere, palladium (II) chloride (1.5 g, 8.3 mmol), triphenylphosphine (2 g) was added to a solution of 2-chloro-4- (trifluoromethyl) pyridine (30.0 g, 165.3 mmol) in triethylamine (4.3 g, 16.5 mmol),Iodinated copper (I) (2.5 g, 13.2 mmol),2-methyl-3-butyn-2-ol(16.7 g, 198.3 mmol) were sequentially added,The mixture was stirred at 80 C. for 7 hours,Celite filtered.The filtrate was concentrated under reduced pressure,Ammonia water (30 mL) and water were added,Extraction with ethyl acetate,The organic layer was washed with saturated brine,And dried over sodium sulfate. Filter to remove white precipitate,After concentrating under reduced pressure, the obtained crude product was purified by silica gel column chromatography (elution solvent: ethyl acetate / hexane = 1: 20) to obtain the title compound as an orange oil (33.5 g, yield 88.4%) .
4-(trifluoromethyl)-2-(3,5-dimethyl-1H-pyrazol-1-yl)pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With potassium <i>tert</i>-butylate; C51H40BrCuN3OP2(1+)*F6P(1-) In 1,4-dioxane at 110℃; for 12h; Schlenk technique; Inert atmosphere;
General procedure for the amination
General procedure: In a Schlenk tube, a mixture of the catalyst 1 (0.5 mol%),2-N-heteroaryl chloride (1.0 mmol), pyrazole (1.1 mmol),and KOtBu (2.0 mmol) in dioxane (3 mL) was evacuatedand charged with nitrogen. The reaction mixture was heatedat 110 °C for 12 h. After being cooled and quenched withwater, the mixture was extracted with CH2Cl2. The solventwas evaporated and the resulting residue was purified by flash chromatography on silica gel.
44.1 Step 1
A solution of 2, 6-dichloro-4-(trifluoromethyl)pyridine (1 g, 4.6 mmol) in NH3 (30% aq., 17.5 mL, 137 mmol) was stirred at 120° C. for 24 h. After cooling to rt solvent was removed under reduced pressure and the crude residue was purified by column chromatography to give 6-chloro-4-(trifluoromethyl)pyridin-2-amine (583 mg, 64% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.01 (s, 2H) 6.80 (s, 1H) 6.65 (s, 1H).
Stage #1: 1,4-butanediol monovinyl ether; 2-chloro-4-trifluoromethyl pyridine With 1,3-bis-(diphenylphosphino)propane; palladium diacetate; anhydrous sodium carbonate at 120℃; for 3h; Inert atmosphere;
Stage #2: With hydrogenchloride In lithium hydroxide monohydrate at 110℃; for 1h; Inert atmosphere;
4.1 Step 1: 1-[4-(trifluoromethyl)-2-pyridyl]ethanone
To a solution of 2-chloro-4-(trifluoromethyl)pyridine (3.0 g, 16.52 mmol) in butane-2,3-diol (10 ml), 4-vinyloxybutan-1-ol (3.06 ml, 25 mmol) was added in one portion at 25 °C. Sodium carbonate (3.5 g, 33 mmol) was added and the reaction mixture was degassed for 20 min using N2 gas at 25 °C. Palladium acetate (0.186 g, 0.82 mmol) and 3-diphenylphosphanylpropyl(di- phenyl)phosphane (0.68 g, 2 mmol) were added and the reaction mixture was stirred for 3 h at 120 °C under N2. TLC showed the starting materials were consumed completely. The reaction mixture was cooled to 25 °C and to this 1 N HCI (10 ml) was added. The reaction mixture was again heated for 1 h at 110 °C. Reaction mixture was quenched with saturated solution of NaHCOs (50 ml) and filtered through Celite bed. The aqueous phase filtrate was extracted with ethyl acetate (EtOAc, 2x 20 ml). Combined organic layer was dried over Na2SC>4 and concentrated and purified by silica gel column (EtOAc: heptane = 20:80) to give 1-[4-(trifluoromethyl)- 2-pyridyl]ethanone (2.5 g, 80 %) as brown liquid. 1H NMR (500 MHz, DMSO-d6): 5 9.03 (s, 1 H), 8.15-8.10 (m, 1H), 8.09-8.08 (m,1H), 2.69 (s, 3H).
80%
Stage #1: 1,4-butanediol monovinyl ether; 2-chloro-4-trifluoromethyl pyridine With 1,3-bis-(diphenylphosphino)propane; palladium diacetate; anhydrous sodium carbonate at 120℃; for 3h; Inert atmosphere;
Stage #2: With hydrogenchloride In lithium hydroxide monohydrate at 110℃; for 1h; Inert atmosphere;
4.1 Step 1: 1-[4-(trifluoromethyl)-2-pyridyl]ethanone
To a solution of 2-chloro-4-(trifluoromethyl)pyridine (3.0 g, 16.52 mmol) in butane-2,3-diol (10 ml), 4-vinyloxybutan-1-ol (3.06 ml, 25 mmol) was added in one portion at 25 °C. Sodium carbonate (3.5 g, 33 mmol) was added and the reaction mixture was degassed for 20 min using N2 gas at 25 °C. Palladium acetate (0.186 g, 0.82 mmol) and 3-diphenylphosphanylpropyl(di- phenyl)phosphane (0.68 g, 2 mmol) were added and the reaction mixture was stirred for 3 h at 120 °C under N2. TLC showed the starting materials were consumed completely. The reaction mixture was cooled to 25 °C and to this 1 N HCI (10 ml) was added. The reaction mixture was again heated for 1 h at 110 °C. Reaction mixture was quenched with saturated solution of NaHCOs (50 ml) and filtered through Celite bed. The aqueous phase filtrate was extracted with ethyl acetate (EtOAc, 2x 20 ml). Combined organic layer was dried over Na2SC>4 and concentrated and purified by silica gel column (EtOAc: heptane = 20:80) to give 1-[4-(trifluoromethyl)- 2-pyridyl]ethanone (2.5 g, 80 %) as brown liquid. 1H NMR (500 MHz, DMSO-d6): 5 9.03 (s, 1 H), 8.15-8.10 (m, 1H), 8.09-8.08 (m,1H), 2.69 (s, 3H).
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