* 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] Journal of Medicinal Chemistry, 1998, vol. 41, # 1, p. 96 - 101
[2] Patent: US5464781, 1995, A,
4
[ 39890-95-4 ]
[ 34486-06-1 ]
Yield
Reaction Conditions
Operation in experiment
80.8%
With potassium hydroxide In <i>tert</i>-butyl alcohol at 70℃; for 8 h;
(3), 1500 g of t-butanol, 140 g of potassium hydroxide and 2-chloro-6-trifluoromethylpyridine prepared in step (2) were added to a 3 L reaction flask, and the temperature was raised to 70 ° C,Insulation reaction 8 hours,After completion of the reaction, tert-butanol was removed under reduced pressure, 550 g of ethyl acetate and 550 g of water were added and stirred,The organic layer was washed with 370 g of saturated brine, dried over 100 g of anhydrous sodium sulfate, and the ethyl acetate was removed by steaming To give crude 172.4 g;(4), the crude product prepared in step (3) was added to 150 g of ethyl acetate, heated to 70 ° C, stirred and dissolved, and 1200 g of petroleum ether was added dropwise,After the addition of petroleum ether, the mixture was cooled to 2 ° C, solid crystals were precipitated, and the solid was filtered. The solid was washed with 50 g of petroleum ether and dried at 70 ° C,To obtain 131.2 g of 2-hydroxy-6-trifluoromethylpyridine as a pale yellow solid powder in a yield of 80.8percent.
Reference：
[1] Patent: CN106866512, 2017, A, . Location in patent: Paragraph 0014
[2] Patent: US5973159, 1999, A,
[3] Patent: CN107759513, 2018, A, . Location in patent: Paragraph 0017
5
[ 39890-95-4 ]
[ 34486-06-1 ]
Yield
Reaction Conditions
Operation in experiment
97%
With hydrogenchloride In water
EXAMPLE 8 This Example illustrates the preparation of 2-hydroxy-6-trifluoromethylpyridine by reacting a 95:5 mixture of 2-fluoro-6-trifluoromethylpyridine and 2-chloro-6-trifluoromethylpyridine with aqueous potassium hydroxide at 115-130° C. Potassium hydroxide flake (95percent, 25.9 g, 2.22 mole equivalents) and water (24.6 g, 6.84 mole equivalents) were charged to a 250 ml round bottomed flask fitted with a condenser, agitator and (contents thermometer. The contents were stirred to give a solution and heated to 130° C. (reflux). A mixture of 2-fluoro-6-trifluoromethylpyridine (99.2percent, 31.6 g, 0.95 mole equivalents) and 2-chloro-6-trifluoromethylpyridine (100percent, 1.8 g, 0.05 mole equivalents) was add d dropwise over 1 hour maintaining a gentle reflux (115-120° C.). When the addition was complete the reaction mixture was held for 4 hours at 115° C. (reflux). The reaction mixture was cooled to 50° C. and water (79 g) added. Hydrochloric acid (approximately 27.4 g, 36percent strength) was then added dropwise over 30 minutes maintaining a temperature of 50° C. to give a pH of 5. The resulting slurry was stirred for a further 10 minutes at 50° C. and then cooled to 0-5° C. and the pH readjusted to 5. The slurry was held for a further 30 minutes at 0-5° C. The product was filtered and displacement washed with water (37 g). The title product was then dried under vacuum at 40° C.: isolated dry weight 31.7 g, yield 97percent (assuming a product strength of 100percent).
Reference：
[1] Patent: US6143899, 2000, A,
[2] Patent: US6143899, 2000, A,
6
[ 7664-93-9 ]
[ 39890-95-4 ]
[ 34486-06-1 ]
Reference：
[1] Patent: US5973159, 1999, A,
7
[ 1929-82-4 ]
[ 39890-95-4 ]
Yield
Reaction Conditions
Operation in experiment
80%
at 330℃;
2-chloro-6-trichloromethyl pyridine (700 g, 3.03 moles, feed rate 1.24 g/min) and anhydrous hydrogen fluoride (936 g, 46.8 moles, feed rate 1.66 g/min) in the absence of inert gas were fed in to a tubular reactor packed with pre activated chromia- alumina catalyst (210 g) at 330°C. Reactor outlet material was collected in ice-cooled water and it was extracted with dichloromethane. Dichloromethane layer was washed with 10percent potassium hydroxide solution and the organic layer was separated out and it was concentrated to get 490.0 g of crude 2-chloro-6-trifluoromethypyridine. The purity of crude product was 95.03 percent by GC analysis. Reaction yield on the basis of crude product obtained is 89 percent. The crude product was purified by fractional distillation to obtain 2-chloro-6-trifluoromethlypyridine with the Purity (percent): 98.0 Yield (percent): 80.0
Stage #1: With hydrogenchloride In water at 70℃; for 1 h; Stage #2: at -2 - 2℃; Stage #3: With hydrogenchloride; copper(l) chloride In water at 65℃; for 2 h;
(1), 2000 g of reaction flask A was charged with 700 g of concentrated hydrochloric acid at a concentration of 36percent by weight and 162.1 g2-amino-6-trifluoromethylpyridine was heated to 70 ° C, stirred for 1 hour, after the completion of the reaction to -2 to 2 ° C, 177.5 g of a sodium nitrite solution having a concentration of 40percentDropping the diazonium salt solution;(2), 500 ml of a hydrochloric acid solution having a concentration of 18percent by weight and 129.4 g of cuprous chloride were added to another reaction flask B, and the mixture was heated to 65C. The resulting diazonium salt solution was added dropwise, Reaction for 2 hours,After the completion of the reaction, the pH of the reaction solution was adjusted to 10 with a sodium hydroxide solution having a concentration of 46percent by weight. Then, 550 g of ethyl acetate was added thereto, followed by stirring. The organic layer was extracted and extracted twice,The organic layer was combined and the organic layer was distilled off to remove ethyl acetate to give a pale yellow liquid. The pale yellow liquid was cooled to room temperature to give 186.3 g of solid 2-chloro-6-trifluoromethylpyridine.
Reference：
[1] Patent: CN106866512, 2017, A, . Location in patent: Paragraph 0014
9
[ 1929-82-4 ]
[ 39890-95-4 ]
Yield
Reaction Conditions
Operation in experiment
90.96 %Chromat.
at 160 - 180℃; for 22 h;
A 300 ml high pressure reactor equipped with overhead condenser with controlled valve, mechanical stirrer and pressure gauge was charged with 2-chloro-6-(trichloromethyl)pyridine (231 gm) and ferric chloride (11 gm). The mixture was heated and anhydrous hydrogen fluoride was added into the reaction mixture under agitation. The temperatures of the mixture was maintained at 170±10 °C and at a pressure of 20±5 kg/cm for 18 hours with continuous feeding of anhydrous hydrogen fluoride at the rate of 20 gm/hr. Reaction mixture was maintained further for 4 hours. The excess HF and hydrochloric acid gas generated were vented, scrubbed and separated as per conventional method and recycled. The completion of reaction was monitored by gas chromatography. After the completion of reaction, the reactor was depressurized to atmospheric pressure and flushed with nitrogen. Reaction product was distilled, diluted with water, neutralized with 5percent aqueous solution of sodium carbonate, layer separated and analysed. The results obtained as per gas chromatography were: 2-fluoro-6- (trifluoromethyl)pyridine: 90.96 percent; 2-chloro-6-(trifluoromethyl)pyridine: 7.67 percent; 2-chloro-6- (trichloromethyl)pyridine: 0.001 percent. The obtained product was distilled to obtain 2-fluoro-6- (trifluoromethyl)pyridine with 85percent yield and 99.97percent GC purity. The distillation residue containing partially fluorinated chlorofluoropyridine compounds was recycled back. The product was confirmed by mass spectroscopy and 1HNMR.
A 300 ml high pressure reactor equipped with overhead condenser with controlled valve, pressure gauge and mechanical stirrer was charged with 2-chloro-6-(trichloromethyl)pyridine (231 gm). The solution was heated and anhydrous hydrogen fluoride (260 gm) was added into the reaction mixture under agitation in approx 20 hours at 190±10 °C and 20-30 kg/cm pressure. Reaction mixture was maintained further for 8 hours. The excess HF and hydrochloric acid gas generated were vented, scrubbed and separated as per conventional method and recycled. The completion of reaction was monitored by gas chromatography. After the completion of reaction, the reactor was depressurized to atmospheric pressure and flushed with nitrogen. Reaction product was distilled, diluted with water, neutralized with 5percent aqueous solution of sodium carbonate and layer separated. The obtained product layer was analyzed by gas chromatography and the results obtained were: 2-fluoro-6- (trifluoromethyl)pyridine:- 51.87percent; 2-chloro-6-(trifluoromethyl)pyridine: 38.66percent; 2-chloro-6- (difluorochloromethyl)pyridine: 8.22percent. The obtained product was distilled to get 2-fluoro-6- (trifluoromethyl)pyridine with 99.97percent GC purity. The product was confirmed by mass spectroscopy and 1H NMR. The distillation residue containing partially fluorinated chlorofluoropyridine compound was recycled back.
40.28 %Chromat.
at 150 - 175℃; for 12 h;
A 300 ml high pressure reactor equipped with overhead condenser with controlled valve, mechanical stirrer and pressure gauge was charged with 2-chloro-6-(trichloromethyl)pyridine (1 16 gm). The solution was heated and anhydrous hydrogen fluoride (55 gm) was added into the reaction mixture in one lot under agitation. The reaction was maintained at a temperature 150-175 °C under autogenously developed pressure for 12 hours. After the completion of reaction, the reactor was depressurized to atmospheric pressure and flushed with nitrogen. The reaction product was diluted in ice water, neutralized with soda ash aqueous solution, followed by steam distillation and analysed. The results obtained as per gas chromatography were: 2-fluoro-6-(trifluoromethyl)pyridine: 40.28percent; 2-chloro-6-(trifluoromethylpyriidne: 48.49percent; 2-chloro-6-(difluorochloromethyl)pyrdine: 10.22percent; 2-chloro-6- (0063) (trichloromethyl)pyriditte: 0.01 1percent. The product was confirmed by mass spectroscopy and 1H NMR.
Reference：
[1] European Journal of Organic Chemistry, 2002, # 2, p. 327 - 330
12
[ 626-05-1 ]
[ 39890-95-4 ]
Reference：
[1] European Journal of Organic Chemistry, 2002, # 2, p. 327 - 330
13
[ 5140-72-7 ]
[ 39890-95-4 ]
Reference：
[1] European Journal of Organic Chemistry, 2002, # 2, p. 327 - 330
14
[ 39890-95-4 ]
[ 100366-74-3 ]
Reference：
[1] Journal of Organic Chemistry, 1986, vol. 51, # 6, p. 953 - 954
15
[ 39890-95-4 ]
[ 147149-98-2 ]
Reference：
[1] Journal of Medicinal Chemistry, 1993, vol. 36, # 6, p. 733 - 746
16
[ 39890-95-4 ]
[ 205444-22-0 ]
Yield
Reaction Conditions
Operation in experiment
42%
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -100℃; for 2 h; Inert atmosphere Stage #2: With iodine In tetrahydrofuran; hexane at -78℃; for 1 h; Inert atmosphere Stage #3: With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78℃; for 3 h; Inert atmosphere
To a cooled (-100°C) solution of diisopropylamine (14.5 mL, 104 mmol) in 80 mL of THF under inert atmosphere was added dropwise n-butyllithium (65 mL of a 1.6 M solution in hexanes, 104 mmol) followed by a lOmL of THF solution of 2-chloro-6- (trifluoromethyl) pyridine (9.5 g, 52 mmol). After two hours, the temperature was raised to -78°C and a 10 mL solution of iodine in THF (13 g, 52 mmol) was added. After 1 hour, the reaction was poured into water and extracted with DCM. The combined DCM layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo to provide 14.9 g of a mixture of 6-chloro-3-iodo-2-(trifluoromethyl)pyridine and 2-chloro-4-iodo-6- (trifluoromethyl)pyridine. This crude material was resubjected to LDA as follows. To a cooled (-78°C) solution of diisopropylamine (14.5 mL, 104 mmol) in 80 mL of THF under inert atmosphere was added dropwise n-butyllithium (65 mL of a 1.6 M solution in hexanes, 104 mmol) followed by a 30 mL solution of the preceding crude mixture in THF. After three hours, the reaction mixture was poured in water and extracted with DCM. The DCM layers were washed with brine, dried (MgSC^), concentrated in vacuo, and purified via silica gel chromatography (0-20percent EtOAc/hexanes) to afford Intermediate 9A as a white solid (6.9 g, 42percent). l NMR (CDC13): δ 7.96 (s, 1H), 7.95 (s, 1H).
Add palladium(II) acetate (200 mg, 2 w/wpercent) and l,l '-bis(diphenylphosphino)ferrocene (dppf) (400 mg, 4 w/wpercent) to a solution of 2-chloro-6-trifluoromethyl-pyridine (10.0 g, 55.1 mmol) in methanol (30 mL). To the orange solution add triethylamine (8.45 mL, 60.6 mmol). Purge the mixture with nitrogen and then maintain under an atmosphere of carbon monoxide (40 psig) at 60 0C for 17 h. Cool to ambient temperature and concentrate under a reduced pressure. Dissolve the solid in tert-butylmethyl ether (70 mL). Filter the resulting slurry over silica gel (10 g) and diatomaceous earth (10 g).Concentrate the filtrate to afford the title compound as a light orange solid (10.8 g, 96percent). 1H NMR (399.84 MHz, DMSO d6): 8.31-8.27 (m, IH), 8.14 (dd, J= 2.4, 6.4 Hz, 2H), 3.91 (s, 3H). HRMS (ESI) m/z (M+H)+ calcd for C8H7F3NO2: 206.0423, found 206.0422.
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 2 h; Stage #2: at -78 - 20℃; for 0.166667 h;
To a stirred solution of 2-chloro-6-(trifluoromethyl)pyridine (50.0 g, 1.0 eq.) in tetrahydrofuran (1.0 1) was added drop wise lithium diisopropylamide (LDA) (44.2 g, 1.5 eq.) at -78 °C. After 2 h dry carbondioxide (500 g) was added at -78 °C. The resulting reaction mixture was allowed to room temperature and stirred for 10 min. The reaction progress was monitored by TLC. After completion of reaction, the reaction mixture was acidified with 1N HCl up to pH 2 and extracted with ethyl acetate (2 x 500 mL). The combined organic layer was washed with water (500 mL), brine (500 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to get crude product which was triturated with pet ether to get pure 2-chloro-6-(trifiuoromethyl)nicotinic acid (Int-15) (40.0 g, 64.6 percent).
Reference：
[1] European Journal of Organic Chemistry, 2004, # 18, p. 3793 - 3798
[2] Patent: WO2013/64460, 2013, A1, . Location in patent: Page/Page column 125; 126
With hydrazine hydrate; In ethanol; at 80℃; for 14h;
[0628] to a solution of compound 59a (10 g, 55.08 mmol) in EtOH (30 ml) was added NH2NH2.H2O (32 ml, 550.80 mmol). After addition, the reaction mixture was stirred at 80 C for 14 hrs. The reaction mixture was concentrated and the residue was dissolved into 150 ml of EtOAc, the mixture was washed with water (50 ml) and brine (50 ml), then dried over Na2SO4 and concentrated in vacuum to afford compound 59b (9.7 g, yield 99.4%) as white solid. 1H NMR (400mhz, DMSO-d6) delta 8.02 (s, 1h), 7.71 - 7.53 (m, 1h), 7.03-6.79 (m, 2h), 4.23 (s, 2h).
With hydrazine hydrate; In ethanol; at 55℃; for 72h;
General procedure: 2-Chloropyridines were dissolved in EtOH and hydrazine hydrate added. The solution was heated in a thick walled sealed vial for 72h at 55 C, concentrated under a stream of nitrogen and purified by silica gel chromatography, (hexanes/ethylacetate).
6,6'-bis(trifluoromethyl)-2,2'-bipyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
With dibromobis(triphenylphosphine)nickel(II); tetrabutylammomium bromide; zinc; In N,N-dimethyl-formamide; at 55℃; for 12h;Inert atmosphere;
General procedure: A 100 mL oven-dried flask was charged with Ni(PPh3)2Br2 (520 mg, 0.7 mmol), zinc dust (137 mg, 2.1 mmol), tetrabutylammonium bromide (676 mg, 2.1 mmol) and 6-tert-butyl-2-chloro-pyridine (5a, 1.2 g, 7 mmol). After the flask was evacuated and refilled with argon, dry DMF (20 mL) was added and the suspension was stirred at 55 C. After the reaction was complete (monitored by TLC), the mixture was filtered through Celite and washed with Et2O (200 mL). The combined solution was then washed with water (100 mL x 3) and brine (100 mL), dried over anhydrous Na2SO4, concentrated and purified by column chromatography on silica gel (Hexane/EtOAc 30:1, v/v) to afford desired 6,6'-di-tert-Butyl-2,2'-bipyridine as a white solid, 488 mg, 52% yield.
8-fluoro-3-(6-trifluoromethylpyridin-2-yl)imidazo[1,2-a]pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
With caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 150℃; for 0.222222h;
n-Butyllithium (2.5 M in hexanes; 230 ml, 0.57 mol) was added to a solution of [1,] 4-diazabicyclo [2.2. [2]] octane (pre-dried by azeotropic removal of water with toluene) (63. [8] g, 0. [57] mol) in Et20 (2. [5 1)] holding the temperature between-20 [AND-30C.] After stirring for 1 h, the temperature was adjusted to-65C and a solution of 3-fluoropyridine (50.0 g, 0.52 mol) in [ET20] (250 [ML)] was added dropwise over 10 min and the mixture stirred for a further 1 h. A solution of hexachloroethane (136.5 g, 0. 58 mol) in [ET20] (350 [ML)] was then added dropwise over [15 MIN,] holding the temperature [BELOW-60C] and the mixture was stirred for 2 h, allowing the temperature to rise [TO-40C.] The reaction was quenched by addition of saturated aqueous [NH4CL] solution (250 ml), warmed to ambient temperature and separated. The aqueous phase was extracted with [ET20] (2 x 250 [ML)] and the combined organics washed with further saturated aq. NH4Cl (250 ml), dried over anhydrous [MGS04] and concentrated in uacuo. The residue was diluted with isohexane (150 ml) and washed with 2 N hydrochloric acid (3 x 100 ml), followed by 37% hydrochloric acid (3 x 50 ml). The acid washings were then extracted with isohexane (3 x 100 ml), basified to pH 14 by careful addition of 4 N aqueous [NAOH] solution (500 ml) and re-extracted with [CH2CL2] (3 x 150 ml). The organic fractions were dried over anhydrous [MGS04] and concentrated in vacuo. The residue was purified by distillation (bp 74-82C, 1 atm) to afford 2-chloro-3- fluoropyridine as a straw-coloured oil (42.6 g, 63%): 8H (400 MHz, [CDCL3)] 7. [25-7. 30 (1H, M), 7.] 47-7.51 [(1H,] m), 8. 24 [(1H,] dd, J 0. 8 and 4.7) ; m/z (ES+) 132 (100%, [MH] +). A mixture of 2-chloro-3-fluoropyridine (21.0 g, 0.16 mol), benzophenone imine (32.3 g, 0. 18 mol), Cs2CO3 (73.0 g, 0. [23 MOL), BINAP] (5.96 g, 9.6 mmol), palladium (II) acetate (1.45 g, 6.4 mmol) and toluene (370 ml) were heated to [95C] for 42 h, then cooled, filtered and the residue extracted with further toluene (2 x 210 ml). The filtrate was washed with 0.5 N hydrochloric acid (200 ml) and saturated aqueous [NAHCO3] [(200] ml), dried over anhydrous [MGS04] and concentrated [IN VACUO, AFFORDING] crude benzhydrylidene [(3-FLUOROPYRIDIN-2-YL)] amine as a brown oil (49.4 g) which was used directly without further purification : [M/Z] [(ES+)] 277 (100%, [ [MH] NU+)-] A mixture of crude benzhydrylidene (3-fluoropyridin-2-yl) amine (49.4 g), 2-bromoacetaldehyde diethyl acetal (56 ml, 0.37 mol), 48% hydrobromic acid (20 ml) and water (20 [ML)] were heated to [90C] for 20 min. On cooling, the mixture was diluted with isopropanol (450 ml), [NAHCO3] [(68] g) was added cautiously, and the mixture filtered. The residue was washed with further isopropanol (450 ml) and the combined organics were stirred and heated to [50C] for 18 h. On cooling, the solution was concentrated in vacuo and azeotroped with EtOAc (2 x 440 ml). The remaining mixture was suspended in EtOAc (400 ml), filtered and the residue washed with further EtOAc until the filtrate ran clear [(11).] The solid orange-coloured residue was then suspended between water (100 ml) and EtOAc (220 ml) and the aqueous phase pH adjusted to 8-9 by addition of saturated aqueous [NAHCO3] solution (450 ml). The phases were separated and the aqueous extracted with further EtOAc (2 x 220 ml). The combined organic extracts were dried over anhydrous MgS04 and concentrated in vacuo affording crude [8-FLUOROIMIDAZO [1, 2-A]] pyridine. Purification was achieved by dissolving the crude material in EtOAc [(11)] and extracting with 2 N hydrochloric acid (5 x 50 ml). The acid washings were back-extracted with EtOAc (3 x 100 ml), adjusted to pH 11-12 using 4 N aqueous sodium hydroxide solution and re-extracted with EtOAc (5 x 100 ml). The combined organic fractions were washed with brine, dried over anhydrous [MGS04] and concentrated in vacuo to afford 8- [FLUOROIMIDAZO] [1, 2-a] pyridine (11.4 g, 76% from 2-chloro-3-fluoropyridine): 8H (400 MHz, CDCl3) 6.69-6. 74 [(1H,] m), 6. [84-6. 87 (1H,] m), 7.65-7. 66 (2H, m), 7.97 [(1H,] dd, J 1.0 and 6.8) [; M/Z] (ES+) 137 [(100%,] [[MHJ+).] 8-Fluoroimidazo [1, 2-a] pyridine (68 mg, 0.50 mmol), 2-chloro-6- [TRIFLUOROMETHYLPYRIDINE] (182 mg, 1.0 [MMOL),] [CS2CO3] (326 mg, 1.0 mmol), tetrakis (triphenylphosphine) palladium (0) (57 mg, 0.05 mmol) and 1,4- dioxane (3 ml) were heated to [150C] for 800 s in a Smith Personal [SYNTHESISERTM] using microwave irradiation. On cooling, the mixture was partitioned between [CH2CL2] (2 ml) and water (2 ml), and the phases separated using a [WHATMAN 5, UM] teflon filter tube. The organics were concentrated in vacuo and purified by column chromatography (silica; 90% EtOAc/isohexane), yielding the title imidazopyridine as a white amorphous solid [(85] mg, 60%): 8H (400 MHz; DMSO) 7.19-7. 24 [(1H, M),] 7.38-7. 43 [(1H,] m), 7.83 [(1H,] d, [J 7.] 4), 8. 20 [(1H,] t, J 8. 2), 8.38 [(1H,] s), 8.64 [(1H,] s), 9.64 [(1H,] dd, J 1.2 and...
8-chloro-1-piperidin-4-yl-4H,6H-5-oxa-2,3,10b-triaza-benzo[e]azulene[ No CAS ]
[ 39890-95-4 ]
8-chloro-1-(6'-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-yl)-4H,6H-5-oxa-2,3,10b-triaza-benzo[e]azulene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 100℃; for 18h;
2-Chloro-6-trifluoromethyl-pyridine (55 mg, 0.30 MMOL) and potassium carbonate (41 mg, 0.30 MMOL) were added to a solution of the amine of preparation 29 (45 mg, 0.15 MMOL) in N, N-dimethylformamide (2 ml). The mixture was heated at 100 C for 18 hours before evaporation under reduced pressure. The residue was purified by chromatography on silica gel using methanol and ammonium hydroxide in DICHLOROMETHANE (5: 0.5 : 95) as eluant to afford the title compound (30 mg), as a brown foam. APCI MS M/Z 450 [M+H] +, 472 [M+Na] + 'H NMR (400MHZ, CD30D) : 5 1.88-2. 06 (m, 4H), 3.01 (bt, 2H), 3.40 (m, 1H), 4.44 (bs, 2H), 4.51 (d, 2H), 4.59 (s, 2H), 6.94 (d, 1H), 7.02 (d, 1H), 7.68 (t, 1H), 7.74-7. 78 (m, 4H).
With triethylamine; In DMF (N,N-dimethyl-formamide); at 100℃; for 4h;
A solution of <strong>[39890-95-4]2-chloro-6-(trifluoromethyl)pyridine</strong> (1.8 g, 9.9 mmol), tert-butyl [(3S)-1-(piperidin-4-ylcarbonyl)pyrrolidin-3-yl]carbamate (2.97 g, 10.0 mmol) and triethylamine (4.1 mL, 30 mmol) in DMF (50 mL) was heated at 100 C. for 4 hrs. After cooling down, ethyl acetate was added. The resulting solution was washed with brine several times, dried over Na2SO4 and concentrated. The residue was chromatographed on silica gel to give the title compound (1.3 g) as a yellow solid. MS (M+H) 443.2.
EXAMPLE 1 This Example illustrates the preparation of 2-hydroxy-6-trifluoromethylpyridine by reacting <strong>[39890-95-4]2-chloro-6-trifluoromethylpyridine</strong> with aqueous potassium hydroxide at 150° C. under autogenous pressure. 2-Chloro-6-trifluoromethylpyridine (10.0 g; 55.1 mmol; 1 equiv) was charged to a 100 ml Hastelloy C Parr reactor, the reactor sealed and pressure tested with nitrogen. When a sealed system had been achieved, the pressure was released, the reactor resealed, and heated to 150° C. Potassium hydroxide solution (10percent strength; 68.0 g; 121.1 mmol; 2.2 equiv) was added via an HPLC pump over 1 hour, while the mixture was maintained at 150° C. Addition of base caused the pressure to rise to 5 bar. The reaction mixture was held at this temperature and pressure for a further 5 hours. Following this period the reactor was cooled, dismantled and sodium chloride (5 g) added. The solution was cooled to 5° C., acidified to pH 5-6 by the addition of concentrated sulphuric acid, filtered and pulled dry. The filter cake was washed with water (10 g), pulled dry, discharged and allowed to dry overnight to afford 2-hydroxy-6-trifluoromethylpyridine as a colourless powder (9.5 g; 95percent strength; 92percent isolated yield).
With potassium hydroxide; In tert-butyl alcohol; at 70℃; for 8h;
(3), 1500 g of t-butanol, 140 g of potassium hydroxide and <strong>[39890-95-4]2-chloro-6-trifluoromethylpyridine</strong> prepared in step (2) were added to a 3 L reaction flask, and the temperature was raised to 70 ° C,Insulation reaction 8 hours,After completion of the reaction, tert-butanol was removed under reduced pressure, 550 g of ethyl acetate and 550 g of water were added and stirred,The organic layer was washed with 370 g of saturated brine, dried over 100 g of anhydrous sodium sulfate, and the ethyl acetate was removed by steaming To give crude 172.4 g;(4), the crude product prepared in step (3) was added to 150 g of ethyl acetate, heated to 70 ° C, stirred and dissolved, and 1200 g of petroleum ether was added dropwise,After the addition of petroleum ether, the mixture was cooled to 2 ° C, solid crystals were precipitated, and the solid was filtered. The solid was washed with 50 g of petroleum ether and dried at 70 ° C,To obtain 131.2 g of 2-hydroxy-6-trifluoromethylpyridine as a pale yellow solid powder in a yield of 80.8percent.
73%
With sodium hydroxide;
EXAMPLE 2 This Example illustrates the preparation of 2-hydroxy-6-trifluoromethylpyridine by reacting <strong>[39890-95-4]2-chloro-6-trifluoromethylpyridine</strong> with aqueous sodium hydroxide at 150° C. under autogenous pressure. 2-Chloro-6-trifluoromethylpyridine (8.05 g at 98percent strength; 43.2 mmol; 1 equiv) was charged to a Parr reactor, pressure tested at 100 psi. The pressure was released and the reactor heated to 150° C. Sodium hydroxide solution (9.823percent strength; 40.1 g; 98.5 mmol; 2.28 equiv) was added via an HPLC pump over 2 hours 20 minutes and the reaction mixture maintained at 150° C. for a further 4 hours. The mixture was cooled, unreacted <strong>[39890-95-4]2-chloro-6-trifluoromethylpyridine</strong> extracted with methylene chloride, and the aqueous phase acidified with hydrochloric acid and filtered to afford 2-hydroxy-6-trifluoromethylpyridine (5.615 g; 93percent strength; 73percent isolated yield). Further product was obtained by extraction of the filtrates with methylene chloride.
<strong>[39890-95-4]2-chloro-6-trifluoromethylpyridine</strong>(? 99percent) 750 kg (4.01 Kmol) and1100kg-2000kg water is added to the reactorThen add 950 kg (9.15 Kmol) of potassium hydroxide (95percent).Potassium hydroxide can also be first formulated into an aqueous solution and put into the reactor.Raise the temperature to 120-170°C and stir the reaction at a pressure of about 0.3-0.8 MPa for 8 hours.After the sample is qualified (the content of <strong>[39890-95-4]2-chloro-6-trifluoromethylpyridine</strong> is less than 0.1percent), it is transferred to the neutralizer.Transfer to the former neutralization kettle and add a certain amount of water first, and add 1500-3000kg of water to the medium capacity kettle.The amount of water added in the neutralization tank can be adjusted appropriately after the neutralization and the pulp concentration. The amount of water is too less than the pulp concentration is not conducive to stirring and discharging.The volume of water that has passed through the Ambassador has increased. After the material is transferred, it is neutralized with hydrochloric acid and the pH is 5-6.Neutralization process temperature control is less than 30 °C,After neutralization and cooling to 5-10°C,After centrifuging, the material enters the washing kettle.After adding 2000kg of water and water, it is centrifuged twice.The material is dried after the second centrifugation.Dry to give 2-hydroxy-6-trifluoromethylpyridine.
EXAMPLE 8 This Example illustrates the preparation of 2-hydroxy-6-trifluoromethylpyridine by reacting a 95:5 mixture of 2-fluoro-6-trifluoromethylpyridine and <strong>[39890-95-4]2-chloro-6-trifluoromethylpyridine</strong> with aqueous potassium hydroxide at 115-130° C. Potassium hydroxide flake (95percent, 25.9 g, 2.22 mole equivalents) and water (24.6 g, 6.84 mole equivalents) were charged to a 250 ml round bottomed flask fitted with a condenser, agitator and (contents thermometer. The contents were stirred to give a solution and heated to 130° C. (reflux). A mixture of 2-fluoro-6-trifluoromethylpyridine (99.2percent, 31.6 g, 0.95 mole equivalents) and <strong>[39890-95-4]2-chloro-6-trifluoromethylpyridine</strong> (100percent, 1.8 g, 0.05 mole equivalents) was add d dropwise over 1 hour maintaining a gentle reflux (115-120° C.). When the addition was complete the reaction mixture was held for 4 hours at 115° C. (reflux). The reaction mixture was cooled to 50° C. and water (79 g) added. Hydrochloric acid (approximately 27.4 g, 36percent strength) was then added dropwise over 30 minutes maintaining a temperature of 50° C. to give a pH of 5. The resulting slurry was stirred for a further 10 minutes at 50° C. and then cooled to 0-5° C. and the pH readjusted to 5. The slurry was held for a further 30 minutes at 0-5° C. The product was filtered and displacement washed with water (37 g). The title product was then dried under vacuum at 40° C.: isolated dry weight 31.7 g, yield 97percent (assuming a product strength of 100percent).
In water;
EXAMPLE 6 This Example illustrates the preparation of 2-hydroxy-6-trifluoromethylpyridine by reading a 50:50 mixture of 2-fluoro-6-trifluoromethylpyridine and <strong>[39890-95-4]2-chloro-6-trifluoromethylpyridine</strong> with aqueous potassium hydroxide at 150° C. Potassium hydroxide flake (95percent, 82.1 g, 13.9 mole equivalents) and water (19.5 g) were charged to a 250 ml round bottom flask fitted with a condenser, agitator and contents thermometer. The contents were stirred to give a solution. 2-Fluoro-6-trifluoromethyl-pyridine (99.7percent, 8.27 g, 0.5 mole equivalents) and <strong>[39890-95-4]2-chloro-6-trifluoromethylpyridine</strong> (99.0percent, 9.17 g, 0.5 mole equivalents) were added and the reaction mixture heated to 150° C. and held for 2 hours. The reaction mixture was sampled and analyzed and found to contain 0.6percent, 2-fluoro-6-trifluoromethylpyridine and 99.4percent 2-hydroxy-6-trifluoromethylpyridine.
(a) 2-Chloro-6-trifluoromethylpyridine (29.28 g; 0.16 mol) was treated with several portions of methyl hydrazine (7.9 g; 0.17 mol) and stirred under nitrogen at room temperature for 24 h. The mixture was treated with 5M aqueous NaOH to basify (pHil) and extracted with ethyl acetate. The organic extracts were dried and evaporated to leave an oil (30.12 g) which was flash-chromatographed over silica (eluent: 33% diethyl ether in hexane) to afford 1-[6-trifluoromethylpyrid-2-yl]-1-methyl hydrazine as a yellow oil (12.12 g; 38%).
2-trifluoromethyl-6-(4-methoxyphenoxy)pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With N,N,N,N,N,N-hexamethylphosphoric triamide; potassium hydroxide; In 1,2-dimethoxyethane; water;
Example V 2-Trifluoromethyl-6-(4-methoxyphenoxy)pyridine STR22 A mixture comprising 90.5 grams (0.5 mole) of <strong>[39890-95-4]2-chloro-6-trifluoromethylpyridine</strong>, 65 grams (0.55 mole) of 4-methoxyphenol and 36.4 grams (0.55 mole) of 85 percent potassium hydroxide was stirred in 1 liter of a 1:1 mixture of monoglyme and hexamethylphosphoramide for 1 hour at room temperature and thereafter heated overnight at reflux. The resulting mixture was diluted with water and extracted with hexane. The hexane extract was washed with a dilute sodium hydroxide solution followed by water washing. The extract was dried and concentrated under reduced pressure to give 127 grams (94 percent of theoretical) of 2-trifluoromethyl-6-(4-methoxyphenoxy)pyridine.
To a stirred solution of 7.1 ml of n-BuLi (1.6M in hexane, 11.3 mmol) in 7 ml THF under argon at -73 C. were added 1.6 ml of diisopropylamine (11.3 mmol) in 3 ml THF within 8 min. After 10 min stirring at the same temperature a solution of 1 g of <strong>[39890-95-4]2-chloro-6-(trifluoromethyl)-pyridine</strong> (5.51 mmol) in 5 ml THF was added within 15 min (temperature between -76 and -75 C.). The dark brown solution was stirred at -75 C. for 1 h 15 min. Finally a solution of 1.4 g of iodine (5.51 mmol) in 10 ml THF was added at -75 C. over 25 min. After additional 45 min stirring at the same temperature 12 ml 2M aqueous HCl were added within 2 min (temperature raised from -78 to -50 C. The cooling device was then removed, the reaction mixture diluted with diethylether. After separation of the organic phase, the aqueous phase was reextracted with diethylether. The combined organic phases were successively washed with 10 ml 1M sodium thiosulfate, saturated NaHCO3 and brine, dried over magnesium sulfate, filtered off and concentrated in vacuo to yield 1.54 (69%) of 6-chloro-3-iodo-2-trifluoromethyl-pyridine as a brown semisolid residue. MS: 307.0
a) 6-Chloro-3-iodo-2-(trifluoromethyl)pyridine A solution of LDA (1.8 M, 24.5 mL) in THF was cooled to -78 C. and a solution of <strong>[39890-95-4]2-chloro-6-(trifluoromethyl)pyridine</strong> (4 g, 22.0 mmol) in THF was added dropwise. The solution was stirred at -78 C. for 1.5 h. To the resulting mixture was then added a solution of iodine (5.6 g, 22.0 mmol) in THF dropwise over 30 min. The solution was stirred at -78 C. for 45 min, then quenched with 2M HCl. The resulting mixture was extracted with Et2O (2*). The combined organic extracts were washed with sodium thiosulfate, sat NaHCO3, brine and dried over Na2SO4 to yield 6-chloro-3-iodo-2-(trifluoromethyl)pyridine.
With iodine; lithium diisopropyl amide;
Step 1: 6-chloro-3-iodo-2-(trifluoromethyl)pyridine To a solution of lithium diisopropylamide (2 M in THF, 3.03 mmol) in tetrahydrofuran (15 ml) was added a solution of <strong>[39890-95-4]2-chloro-6-(trifluoromethyl)pyridine</strong> (500 mg, 2.75 mmol) in tetrahydrofuran (5 ml) at -65 C. under nitrogen atmosphere. The dark brown solution was stirred at -65 C. for 30 minutes. To the reaction mixture was added a solution of iodine (0.7 g, 2.75 mmol) in tetrahydrofuran (5 ml) was added at -65 C. within 20 minutes. After additional 20 minutes stirring at the same temperature, the reaction mixture was quenched with hydrochloride acid (2M, 6 ml) at 0 C. and stirred for 20 minutes. The reaction mixture was extracted with ethyl acetate (30 ml). The combined organic layers were washed with brine (30 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue which was purified by silica gel flash chromatography (eluted with 1% ethyl acetate in hexane) to afford 6-chloro-3-iodo-2-(trifluoromethyl)pyridine (316 mg, yield 37%) as brown oil.
ethyl 3-{3-isopropyl-1-[6-(trifluoromethyl)-2-pyridinyl]-1H-pyrazol-4-yl}propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
63%
Reference Example 301 To a mixture of ethyl3- (3-isopropyl-lH-pyrazol-4- yl) propanoate (0.63 g),2-chloro-6- (trifluoromethyl) pyridine (0.55 g) and N, N-dimethylformamide (10 ml) was added 60% sodium hydride (0.20 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- [6- (trifluoromethyl)-2-pyridinyl]-lH-pyrazol-4-yl} propanoate (0.67 g, yield63%) was obtained as a colorless oil from a fraction eluted with ethyl acetate- hexane (1: 9, volume ratio). 1H-NMR (CDC13) S : 1.28 (3H, t, J=7.2 Hz), 1.33 (6H, d, J=7.2 Hz), 2.63-2. 67 (2H, m), 2.83 (2H, t, J=8.0 Hz), 3.01-3. 07 (1H, m), 4.17 (2H, q, J=7.2 Hz), 7.44 (1H, d, J=7.6 Hz), 7.88-7. 92 (1H, m), 8.11 (1H, d, J=8.4 Hz), 8.30 (1H, s).
4-([4'-(Methylsulfonyl)-4-biphenylyl]oxy}methyl)piperidine hydrochloride (prepared as in Example 2, Step 1, 0.05 g, 0.14 mmol) was added to a solution of <strong>[39890-95-4]2-chloro-6-(trifluoromethyl)pyridine</strong> (0.01 g, 0.14 mmol) in DMSO (2 mL), followed by addition of NaO-t-Bu (0.3 g, 0.3 mmol), and a catalytic amount of Pd(P(o-Tol)3)2Cl2. The reaction mixture was heated at 200 C. for 10 min using microwave heating. The reaction was then purified by reverse-phase preparative HPLC using CH3CN:H2O gradient (0:100 to 90:10) with 0.05% TFA as a modifier to give the title compound (3 mg, 4%) as a white solid. 1H NMR (400 MHz, CDCl3): delta 7.97 (d, 2H, J=8.6 Hz), 7.72 (d, 2H, J=8.7 Hz), 7.60-7.53 (m, 3H), 7.00 (d, 2H, J=8.9 Hz), 6.94 (d, 1H, J=7.4 Hz), 6.86 (d, 1H, J=8.9 Hz), 4.46-4.40 (m, 2H), 3.90 (d, 2H, J=6.3 Hz), 3.09 (s, 3H), 3.00-2.92 (m, 2H), 2.01-1.95 (m, 3H), 1.51-1.40 (m, 2H); LRMS (ESI), m/z 491 (M+H).
1,5-anhydro-2,3-dideoxy-3-[{(1R,3S)-3-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-3-(1-hydroxycyclobutyl)cyclopentyl}amino]-4-O-methyl-D-erythro-pentitol dihydrochloride[ No CAS ]
[ 39890-95-4 ]
[ 1228111-95-2 ]
Yield
Reaction Conditions
Operation in experiment
With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 80℃; for 18h;
A solution of 93 mg (0.20 mmol) of 1 ,5-anhydro-2,3-dideoxy-3-[(1 R,3S)-3- [(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-ylcarbonyi]-3-(1- hydroxycyclobutyl)cycIopentyl]amino}-4-O-methyl-D-erythro-pentitol dihydrochloride, 91 mg (0.49 mmol) of 2-chIoro-6-trifluoromethyIpyridine, and 0.14 ml_ (0.80 mmol) of diisopropylethylamine in 0.5 ml_ of DMSO was heated at 80 C for 18 h, then cooled and partitioned between ethyl acetate and water. The organic phase was dried (Na2SO4) and concentrated under reduced pressure. The crude material was purified by preparative RP-HPLC using as the mobile phase acetonitrile-water containing 0.05% TFA. 1H NMR (400 MHz, CHLOROFORM-of) delta ppm 1.46 - 2.52 (m, 16 H) 3.26 - 3.54 (m, 8 H) 3.53 - 3.92 (m, 4 H) 4.02 (dd, JM 1.8, 4.3 Hz, 1 H) 4.22 (d, JM 3.0 Hz, 1 H) 5.01 (d, JM 4.3 Hz, 2 H) 6.47 (d, J=8.5 Hz, 1 H) 6.93 (d, J=7.5 Hz, 1 H) 7.56 (t, J=8.0 Hz1 1 H). HRMS calculated for C27H37N4O4F3: 539.2845; found: 539.2894.
(c) 2-Chloro-3-tributylstannyl-6-trifluoromethyl-pyridine. To a solution of diisopropylamine (5.5 mL, 39 mmol, Aldrich,) in THF (30 mL) was added n-BuLi (15.6 mL, 2.5 M in hexanes, 39 mmol, Aldrich) with stirring at -78 C. The mixture was stirred at -78 C. for 30 min and at room temperature for 15 min. The reaction mixture was cooled again to -78 C. and a solution of <strong>[39890-95-4]2-chloro-6-trifluoromethylpyridine</strong> (5.0 g, 27.5 mmol, Lancaster) in THF (20 mL) was added. The mixture was stirred at -78 C. for 1 h, tributyltin chloride (9 mL, 33 mmol, Aldrich) was added via a syringe, and stirring was continued for 2 h. The reaction mixture was allowed to reach 0 C., quenched with a sat. aqueous solution of NH4Cl, and extracted with Et2O (3*). The combined organic extracts were dried over MgSO4, filtered, and concentrated under reduced pressure. Purification of the residue by flash silica gel chromatography (gradient: 0-1% EtOAc/hexane) afforded the title compound as colorless oil. MS (ESI, pos. ion.) m/z: 471 (M+1).
(b) 2-Chloro-3-(tributylstannyl)-6-(trifluoromethyl)pyridine. To a solution of diisopropylamine (4.6 mL, 33 mmol, Aldrich) in anhydrous THF (40 mL) was added dropwise n-butyllithium (1.6 M in hexanes, 19 mL, 30 mmol, Aldrich) with stirring at -78 C. under N2. Upon complete addition, the reaction mixture was stirred at -78 C. for 10 min and at 0 C. for 10 min. The reaction mixture was cooled again to -78 C. and a solution of 2-Chloro-6-trifluoromethylpyridine (5.0 g, 28 mmol, Oakwood) in anhydrous THF (15 mL) was added dropwise. The mixture was stirred at -78 C. for 2 h, tributyltin chloride (8.2 mL, 30 mmol, Aldrich) was added, and the stirring was continued for 2 h at -78 C. The reaction mixture was allowed to warm to -10 C. over 2 h and was quenched with a sat. aqueous solution of NH4Cl (100 mL). The mixture was diluted with Et2O (100 mL) and the organic layer was separated, washed with satd NaCl (75 mL), dried over Na2SO4, filtered, and concentrated in vacuo to provide an oil. The oil was purified by silica gel column chromatography (gradient: 0-5% EtOAc/hexane) to give the title product as a colorless oil. MS (ESI, pos. ion.) m/z: 471 (M+1).
(b) 2-Chloro-3-(tributylstannyl)-6-(trifluoromethyl)pyridine. To a solution of diisopropylamine (4.6 mL, 33 mmol, Aldrich) in anhydrous THF (40 mL) was added dropwise n-butyllithium (1.6 M in hexanes, 19 mL, 30 mmol, Aldrich) with stirring at -78 C. under N2. Upon complete addition, the reaction mixture was stirred at -78 C. for 10 min, and at 0 C. for 10 min. The reaction mixture was cooled again to -78 C. and a solution of <strong>[39890-95-4]2-chloro-6-trifluoromethylpyridine</strong> (5.0 g, 28 mmol, Oakwood) in anhydrous THF (15 mL) was added dropwise. The mixture was stirred at -78 C. for 2 h, tributyltin chloride (8.2 mL, 30 mmol, Aldrich) was added, and the stirring was continued for 2 h at -78 C. The reaction mixture was allowed to warm to -10 C. over 2 h and was quenched with a sat. aqueous solution of NH4Cl (100 mL). The mixture was diluted with Et2O (100 mL) and the organic layer was separated, washed with satd NaCl (75 mL), dried over Na2SO4, filtered, and concentrated in vacuo to provide an oil. The oil was purified by silica gel column chromatography (gradient: 0-5% EtOAc/hexane) to give the title product as a colorless oil. MS (ESI, pos. ion.) m/z: 471 [M+1].
Example BlO; PXQP.aration of cpmpound.l 19[2R-(2a, 3aalpha, 12bbeta)] . C2HF3O2 (I:.) EPO <DP n="50"/>; A mixture of intermediate 3 (0.425 mmol) and <strong>[39890-95-4]2-chloro-6-(trifluoromethyl)-pyridine</strong> (1.275 mmol) in DMSO (5 ml) was stirred at 140 C for 45 minutes in a microwave oven at 300 Watt. Water was added and the reaction mixture was extracted with DCM. The separated organic layer was washed with brine, dried (Na2SO4), filtered and the solvent was evaporated. The residue was purified by high performance liquid chromatography over reversed phase. The desired fractions were collected and the solvent was evaporated. The residue was converted into the TFA salt, yielding compound 119.
(Intermediate 7 was prepared in a similar manner to the preparation described iaAngew. Chem. Int. Ed. 2003, 42, 5051). To a stirred solution of bis(dibenzylideneacetone)palladium (0) ("Pd2(dba)3", 100 mg, 0.11 mmol) and potassium t-butoxide (617 mg, 5.5 mmol) in toluene (11 mL) was added 2,8,9-tri-z- butyl-2,5,8,9-tetraza-l-phosphabicyclo[3.3.3]undecane (75mg, 0.22 mmol) in toluene (2 mL) followed by 2-chloro-6-(trifluoromethyl) pyridine (500 mg, 2.75 mmol). Upon completion of addition, the reaction mixture was stirred for 20 minutes. After this time, isobutyronitrile (0.30 mL) was added and the resulting mixture was heated at 90 0C for 5h. Upon completion of this period, the reaction mixture was poured into H2O (20 mL) and extracted with toluene (3 x 20 mL). The combined extracts were dried over Na2SO4, and filtered. The volatiles were removed under reduced pressure to provide a residue. The residue was subjected to chromatography on silica gel using 0 to 25% EtOAc/hexanes to provide Intermediate 7 as a clear oil. (120 mg, 20%).
With caesium carbonate; In N,N-dimethyl-formamide; at 150℃; for 1.5h;Microwave irradiation;
Example B27A mixture of intermediate 67 (0.21 g, 0.74 mmol), 2-chloro-6-(trifluomethyl)pyridine (0.54 g, 2.9 mmol), and Cs2CO3 (0.60 g, 1.85 mmol) in DMF was heated at 150 0C under microwave irradiation for 1.5 h. After cooling, H2O was added and the r.m. was extracted with EtOAc. The o.l. was washed with brine, dried (MgSO4), filtered and evaporated under reduced pressure. The residue was purified by columnchromatography over silica gel (eluent: DCM/MeOH from 100/0 to 97/3) The product fractions were isolated and evaporated under reduced pressure. The product was recrystallized from CH3CN and isolated by filtration as a white solid. Yield: 0.077 g of compound 236 (24.2 %).
With caesium carbonate;palladium diacetate; catacxium A; In water; toluene; at 100℃; for 18h;Inert atmosphere; Sealed tube;
2-Chloro-6-trifluoromethyl pyridine (451 mg, 2.5 mmol), ethyltrifluoroborate potassium salt (374 mg, 2.75 mmol), palladium acetate (1 1 mg, 0.05 mmol), di(1 -adamantyl)-n- butylphosphine (27 mg, 0.075 mmol), and cesium carbonate (2.4 g, 7.5 mmol) were suspended in a mixture of toluene and water (10:1 , 10 mL). After flushing the vessel under a stream of nitrogen gas for 5 minutes, the reaction tube was sealed and then heated at 100 C for 18 hours. On cooling, the mixture was partitioned between DCM (15 mL) and water (15 mL). The separated aqueous phase was extracted with DCM (2 x 15 mL) and the combined organic phases were passed through a phase separator and concentrated in vacuo, affording a yellow oil which was used without further purification (460 mg, crude)LCMS: major peak observed at 1.53 min; poor ionisation (method A)TLC Rf: 0.55 (EtOAc/hexane, 1 :9).
With caesium carbonate;palladium diacetate; catacxium A; In water; toluene; at 100℃; for 18h;Inert atmosphere; Sealed tube;
2-Chloro-6-trifluoromethyl pyridine (451 mg, 2.5 mmol), cyclopropyltrifluoroborate potassium salt (373 mg, 2.52 mmol), palladium acetate (1 1 mg, 0.05 mmol), di(1- adamantyl)-n-butylphosphine (27 mg, 0.075 mmol), and cesium carbonate (2.4 g, 7.5 mmol) were suspended in a mixture of toluene and water (10:1 , 10 mL). After flushing the vessel under a stream of nitrogen gas for 5 minutes, the reaction tube was sealed and then heated at 100 C for 18 hours. On cooling, the mixture was partitioned between DCM (15 mL) and water (15 mL). The separated aqueous phase was extracted with DCM (2 x 15 mL) and the combined organic phases were passed through a phase separator and concentrated in vacuo, affording a yellow oil which was used without further purification (423 mg, crude).LCMS: major peak observed at 1.77 min; poor ionisation (method A)TLC Rf: 0.6 (EtOAc/hexane, 1 :9).
iron(III)-acetylacetonate; In tetrahydrofuran; 1-methyl-pyrrolidin-2-one; diethyl ether; at 0 - 27℃; for 1.41667h;Inert atmosphere;
A mixture of <strong>[39890-95-4]2-chloro-6-(trifluoromethyl)pyridine</strong> (2.69 g, 14.8 mmol) and iron(lll)acetylacetonate (523 mg, 1.48 mmol) in THF (100 mL) and NMP (10 mL) was stirred at 0 C under N2 for 5 mins. Methyl-d3-magnesium iodide solution (18.0 mL, 1 M in diethyl ether, 18.0 mmol) was added drop-wise over 10 mins, and the mixture was stirred under N2 at 0 C for 5 mins, then ambient temperature for 75 mins. 1 M aqueous HCI (50 mL) was added and the mixture was stirred for 5 mins before addition of diethyl ether (50 mL) and separation of the phases. The organic phase was washed with 0.5 M aqueous HCI (50 mL) and water (50 mL) and the combined aqueous phases were extracted with diethyl ether (2 x 50 mL). The combined organic phases were concentrated to a volume of approximately 25 mL and short path distillation (bp 28-30 C at 35 mbar) yielded a clear oil to which was added DCM (5 mL) and H20 (5 mL). The phases were separated and the aqueous phase was extracted with DCM (2 x 5 mL); the combined organic phases were concentrated in vacuo to yield the title compound (639 mg, 26%) as a clear oil.1H NMR: (400 MHz, CDCI3) delta: 7.34 (d, J 7.8, 1 H), 7.49 (d, J 7.8, 1 H), 7.75 (t, J 7.8, 1 H). Bp: 28-30 C at 35 mbar
With lithium hexamethyldisilazane;chloro(2-di-t-butylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl]palladium(lI); In toluene; at 0 - 20℃; for 0.5h;Inert atmosphere;
·?, 1 -dimethyl ethyl [6-(trifluoromethyl)-2-pyridinyllacetateTo a stirred solution of tert-butyl acetate (1 .013 mL, 7.5 mmol), 2-chloro-6- (trifluoromethyl)pyridine (908 mg, 5.00 mmol), chloro(2-di-t-butylphosphino-2',4',6'-tri-i- propyl-1 ,1 '-biphenyl)[2-(2-aminoethyl)phenyl]palladium(ll) (343 mg, 0.500 mmol) in Toluene (10 mL) at 0 C in a 100-mL RBF under N2 was added a solution of LHMDS (1 M in toluene) (15.00 ml_, 15.00 mmol) prec-cooled to 0 C. The reaction was stirred for 30 min, but LCMS indicated the reaction was not complete, so the reaction was allowed to warm to room temperature overnight, and LCMS analysis indicated that the reaction was complete, so it was poured into ammonium chloride (aqueous, saturated) and water (1 :1 , 40 mL), and extracted with ethyl acetate (3 x 100 mL). The combined organics were dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (0-25% EtOAC in hexanes, 90-g column) to afford 1 , 1-dimethylethyl [6- (trifluoromethyl)-2-pyridinyl]acetate (701.3 mg, 53.7 % yield) as a pale yellow oil. LC- MS(ES) m/z = 206 [M+H-tBu]+. 1 H NMR (400 MHz, DMSO-d6) delta ppm 1 .41 (s, 9 H), 3.88 (s, 2 H), 7.61 - 7.71 (m, 1 H), 7.77 - 7.85 (m, 1 H), 8.02 - 8.1 1 (m, 1 H).
2-chloro-6-(trifluoromethyl)pyridine-4-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Step A. 2-Chloro-6-(trifluoromethyl)isonicotinic acid and 2-chloro-6- ( trifluoromethyl)nicotinic acid2-Chloro-6-(trifluoromethyl)pyridine (20.0 g, 110 mmol, Synquest) was dissolved in tetrahydrofuran (400 mL) and then 1.0 M lithium chloride - chloro(2,2,6,6- tetramethylpiperidin-l-yl)magnesium (1 : 1) in THF (132 mL, 132 mmol, Aldrich) was added. The reaction was stirred at room temperature for 1 hour and was then cooled to - 78 C, and 67 g of solid dry ice was added into the flask. The reaction was stirred at -78 C for 1 hour and subsequently allowed to slowly warm to room temperature. Upon reaching room temperature, the reaction was quenched with water, and was poured into IN NaOH and washed with diethyl ether. The aqueous phase was then acidified with c.HCl to pH~ 1 and extracted with diethyl ether. The combined extracts were washed with water, then sat'd NaCl, dried over Na2S04, filtered concentrated to afford a 1.2: 1 regioisomeric mixture of carboxylic acids (11.65 g, 47%). 1H NMR (400 MHz, CDCI3) delta 8.43 (dd, J= 7.9, 0.8 Hz, 1H), 8.17 (d, J= 1.1 Hz, 1H), 8.11 (dd, J= 1.1, 0.6 Hz, 1H), 7.71 (d, J= 7.9 Hz, 1H).
{trans-3-(4-[4-(1-hydroxy-1-methylethyl)-6-(trifluoromethyl)pyridin-2-yl]carbonyl}piperazin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl} acetonitrile[ No CAS ]
{trans-3-(4-[4-(1-hydroxy-1-methylethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile[ No CAS ]
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 160℃; for 1h;Inert atmosphere; Microwave irradiation;
General procedure: To an oven-dried microwave vial was added ethyl 2-amino-1,3-oxazole-5-carboxylate (546 mg, 3.50 mmol), Cs2CO3 (2279 mg, 6.99 mmol), Pd2(dba)3 (80 mg, 0.09 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (152 mg, 0.26 mmol) and the vial was capped and purged with nitrogen. 2,4-Dichloropyridine (0.378 mL, 3.50 mmol) was added via syringe, followed by 1,4-dioxane (18 mL) (degassed) and the reaction mixture was heated to 160 C for 1 h under microwave irradiation. CH2Cl2 (40 mL) was added to the crude reaction mixture together with silica (5 g). The solvents were removed under reduced pressure and the crude product was purified by flash silica chromatography with CH2Cl2 (containing 1% methanolic ammonia) as eluent.The resulting brown solid was triturated with Et2O to give ethyl 2-(4-chloropyridin-2-ylamino)oxazole-5-carboxylate (626 mg, 67%) as a pale yellow solid, which was collected by filtration and dried under vacuum.
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 160℃; for 1.0h;Inert atmosphere; Microwave irradiation;
General procedure: To an oven-dried microwave vial was added ethyl 2-amino-1,3-oxazole-5-carboxylate (546 mg, 3.50 mmol), Cs2CO3 (2279 mg, 6.99 mmol), Pd2(dba)3 (80 mg, 0.09 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (152 mg, 0.26 mmol) and the vial was capped and purged with nitrogen. 2,4-Dichloropyridine (0.378 mL, 3.50 mmol) was added via syringe, followed by 1,4-dioxane (18 mL) (degassed) and the reaction mixture was heated to 160 C for 1 h under microwave irradiation. CH2Cl2 (40 mL) was added to the crude reaction mixture together with silica (5 g). The solvents were removed under reduced pressure and the crude product was purified by flash silica chromatography with CH2Cl2 (containing 1% methanolic ammonia) as eluent.The resulting brown solid was triturated with Et2O to give ethyl 2-(4-chloropyridin-2-ylamino)oxazole-5-carboxylate (626 mg, 67%) as a pale yellow solid, which was collected by filtration and dried under vacuum.
{1-(cis-4-[4-[(ethylamino)methyl]-6-(trifluoromethyl)pyridin-2-yl]oxy}cyclohexyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile tris(trifluoroacetate)[ No CAS ]
2-Chloro-6-(trifluoromethyl)pyridine (20.0 g, 0.11 mol, Oakwood) was dissolved in tetrahydrofuran (397 mL) and then 1 ,0 M lithium chloride - chloro(2,2,6,6-tetramethylpiperidin-l-yl)magnesium (1 : 1) in THF (132.2 mL, 132.2 mmol, Aldrich) was added. The reaction was stirred at ambient temperature for 1 hour and was then cooled to -78 C, and then a solution of di-tert-Butyldicarbonate (48.1 g, 0.22 mol, Aldrich) in tetrahydrofuran (100 mL) was added. The reaction was stirred at -78 C for 1 hour and then allowed to warm to room temperature overnight. The reaction was quenched with water, then ammonium chloride was added. The layers were separated and the aqueous was extracted with two portions of ethyl acetate, The combined organic extracts were washed with water, then sat'd NaCl solution, dried over NajS04, filtered and concentrated. The crude product, which was a mixture of two regioisomers, was purified by flash chromatography, eluting with 2% EtOAc in hexanes, in 3 batches, each on a 330 g silica gel cartridge. The first product to elute was the desired regioisomer, which also contained some unreacted starting material, The product rystallized on standing and the oil, which contained some unreacted starting material, was decanted away, leaving a more pure crystalline product (9.58 g, 30%). 'H NMR (300 MHz, CDC13) delta 8.07 (d, J= 1.1 Hz, 1H), 8.02 - 7.99 (m, 1H), 1.62 (s, 9H). ,9F NMR (282 MHz, CDC13) delta -68.43 (s). LCMS (M-tBu+H)+: 225.9/227.9.
2-Chloro-6-(trifluoromethyl)pyridine (2.00 g, 1 1.0 mmol Oakwood Products) was dissolved in tetrahydrofuran (40 mL) and 1.0 M lithium chloride - chloro(2,2,6,6-tetramethylpiperidin- l -yl)magnesium ( 1 : 1) in THF ( 13.22 mL, 13.22 mmol, Aldrich Co.) was added at 25 C. The reaction was stirred at 25 C for 1 hour and was cooled to -78 C, and di-tert-butyldicarbonate (4 g, 18.3 mmol) in tetrahydrofuran (13.5 mL) was added. The reaction was stirred at -78 C for 1 hour at which time TLC analysis showed no change. Then the reaction was allowed to warm to room temperature at which time a new product with higher Rf value on TLC was identified. The reaction was stirred at 25 C and most of the starting material was gone. The reaction was quenched with saturated NH4Cl and extracted with EtOAc. The EtOAc extract was washed with I HCl, NaHC03, dried and evaporated in vacuo. NMR analysis of the crude showed residual BOC anhydride, t-BuOH and a mixture of the two esters in a ~3: 1 ratio and some starting material remaining. The crude was chromatographed on silica gel using 5% EtOAc hexanes to give the product contaminated with a small amount of impurity. This was allowed to crystallize and washed with 5% EtOAc/hexanes to give clean product. ? NMR (400 MHz, CDCl3) delta 7.07 (s, 1 H), 8.01 (s, 1 H), 1.47 (s, 9H).
With sodium carbonate; In dimethyl sulfoxide; at 100℃; for 96h;
Example 85[886] (7R,8a5)-7-[(5-chloropyridin-2-yl)oxy]-2-[6-(trifluoromethyl)pyridin-2-yl]- octahydropyrrolo[l,2-a]pyrazine[887] To a solution of Example 57 (76.2 mg, 0.3 mmol) in dimethyl sulfoxide (0.3 mL) was added <strong>[39890-95-4]2-chloro-6-(trifluoromethyl)pyridine</strong> (87 mg, 0.48 mmol) and sodium carbonate (64 mg, 0.6 mmol). The mixture was stirred at 100 C for 4 days and then concentrated. The residue was purified by chromatography on silica gel (ethylacetate/methanol =10: 1) to give the title compound. XH NMR (400 MHz, DMSO-i/6) ? ppm 1.90 (m, 2H), 2.22-2.36 (m, 3H), 2.58 (m, 1H), 2.90-3.08 (m, 2H), 3.62 (m, 1H), 4.30 (m, 1H), 4.44 (m, 1H), 5.31 (m, 1H), 6.83 (d, 1H, J = 7 Hz), 7.05 (d, 1H, J = 7 Hz), 7.15 (d, 1H, J = 7 Hz), 7.78 (m, 2H), 8.22 (s, 1H); MS (ESI) m/z 399 (M+H)+.
With sodium carbonate; In dimethyl sulfoxide; at 100℃; for 72h;
Example 18A[727] tert-butyl (75,8aS)-7- [6-(trifluoromethyl)pyridin-2-yl]amino}hexahydro- pyrrolo[ 1 ,2-a]pyrazine-2( lH)-carboxylate[728] To (75',8a5)-tert-butyl 7-aminohexahydropyrrolo[l,2-a]pyrazine-2(lH)- carboxylate (310 mg, 1.29 mmol) and sodium carbonate (0.26 g, 2.5 mmol) in dimethyl sulfoxide (1 mL) was added <strong>[39890-95-4]2-chloro-6-(trifluoromethyl)pyridine</strong> (0.35 g, 1.93 mmol). The mixture was stirred at 100 C for 3 days and then concentrated. The residue was purified by chromatography on silica gel (100% ethyl acetate) to provide the title compound. MS (ESI) m/z 387 (M+H)+.
With sodium carbonate; In dimethyl sulfoxide; at 100℃; for 72h;
Example 15A[0824] tert-butyl (75,,8a5)-7- [6-(trifluoromethyl)pyridin-2-yl]amino}hexahydro- pyrrolo[l,2-a]pyrazine-2(lH)-carboxylate[0825] To (75',8a5)-tert-butyl 7-aminohexahydropyrrolo[l,2-a]pyrazine-2(lH)- carboxylate (310 mg, 1.29 mmol) and sodium carbonate (0.26 g, 2.5 mmol) in dimethyl sulfoxide (1 mL) was added <strong>[39890-95-4]2-chloro-6-(trifluoromethyl)pyridine</strong> (0.35 g, 1.93 mmol). The mixture was stirred at 100 C for 3 days and then concentrated. The residue was purified by chromatography on silica gel (100% ethyl acetate) to provide the title compound. MS (ESI) m/z 387 (M+H)+.
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