* 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.
0.13 mol of 6-hydroxynicotinic acid (18.2 g), 2.6 ml of anhydrous hydrofluoric acid (concentration of 95 wtpercent or more) (0.13 mol) and 42.1 g (0.39 mol) of sulfur tetrafluoride were charged into a stainless steel pressure canister And heated to 100 ° C and reacted at 0.15 MPa for 12 hours. The gaseous product was treated with an exhaust gas absorbing device. The remaining product was transferred to a polytetrafluoroethylene container and heated to 40 ° C to remove traces of hydrogen fluoride.The resulting product was added to 150 ml of water, adjusted to pH 6.8-7.2 with saturated sodium carbonate solution, extracted with chloroform, dried, filtered and dried to give 15.3 g (0.094 mol) of 2-hydroxy- 5-trifluoromethylpyridine, , Yield 72percent.
Reference：
[1] Angewandte Chemie, International Edition, 2015, vol. 54, # 1, p. 280 - 284[2] Angewandte Chemie, 2015, vol. 127, # 1, p. 282 - 286,5
8
[ 33252-63-0 ]
[ 76041-72-0 ]
Reference：
[1] Angewandte Chemie, International Edition, 2015, vol. 54, # 1, p. 280 - 284[2] Angewandte Chemie, 2015, vol. 127, # 1, p. 282 - 286,5
[3] Chemical Communications, 2017, vol. 53, # 44, p. 5997 - 6000
9
[ 33252-63-0 ]
[ 76041-71-9 ]
Yield
Reaction Conditions
Operation in experiment
92%
With N-chloro-succinimide In 1-methyl-pyrrolidin-2-one; N,N-dimethyl-formamide at 20℃; for 8 h;
0.094 mol of 2-hydroxy-5-trifluoromethylpyridine (15.3 g) and 14.4 g of N-chlorosuccinimide (0.108 mol) were added to 50 ml of anhydrous DMF / nitromethylpyrrolidone, The reaction was carried out at room temperature for 8 hours with stirring.The reaction was slowly added to 250 ml of water to give a pale yellow precipitate.The resulting precipitate was filtered and dried to give 17.1 g (0.087 mol) of 3-chloro-5-trifluoromethyl-2-hydroxypyridine in a yield of 92percent.
Stage #1: at 0 - 65℃; for 25 h; Stage #2: With sodium hydroxide In water at 20℃;
2-Hydroxy-5-trifluoromethylpyridine (10.0 g, 61.3 mmol) was dissolved in sulfuric acid (50 ml) and cooled to 00C. Fuming nitric acid (14 ml, 92 mmol) was slowly added and the reaction was stirred at 00C for 1 hour before stirring at 65°C for 24 hours. The reaction was then cooled to room temperature and mixed with ice (300 g) before slow addition of NaOH (85 ml, 50percent aq). The aqueous phase was extracted with EtOAc (4*200 ml) and combined organics were dried over MgSO4 and evaporated to give 7.4 g (58 percent) of 2-hydroxy-3-nitro-5-trifluoromethylpyridine as yellow solids. 1H NMR (CDCl3): δ 8.66 (s, IH), 8.29 (s, IH).
28%
at 80 - 85℃;
(1) 100g compound 1 was dissolved in 400ml of concentrated sulfuric acid was added 2L three-necked flask,Heated to an internal temperature rose to 80 degrees;110g of concentrated nitric acid with a dropping funnel slowly added dropwise to the reaction system,System began to heat up,At this point the reaction flask from the hot bath to the air bath,Control dropping speed,So that the internal temperature maintained at 80-85 degrees (high temperature, the yield will be reduced, you can use a cold water bath temperature control),About 50 minutes dripping finished (40-60 minutes can be)Then the oil bath incubated for 50 minutes (40-60 minutes can be);TLC showed that most of the raw materials reacted, stop heating,Quickly dropped to room temperature, the reaction solution was poured into 1,000g of ice on the cloudy liquid,It was then extracted with ethyl acetate (EA) (500 ml * 2)The organic phase was washed again with saturated brine, dried and concentrated to give the crude product,The crude product was added to dichloromethane (DCM) (80ml), stirred for 5min, a small amount of unreacted raw material was dissolved and filtered. The filter cake was first washed with a small amount of DCM and then with EA and petroleum ether,The filter cake was dried to give compound 2 as a pale yellow solid.TLC information: UV color, raw Rf = 0.5, product Rf = 0.1.Developing solvent: EA / 1-2 drops of ammonia or DCM / MeOH = 10/1 plus 1-2 drops of ammonia.35 g of the product was obtained as a light yellow solid in a yield of 28percent.
Stage #1: With bromine; sodium acetate In acetic acid at 20 - 80℃; for 2.5 h; Stage #2: With sodium hydrogencarbonate In water
To a solution of 5-(trifluoromethyl)pyridin-2-ol (10.52 g, 62 mmol) and sodium acetate (5.29 g, 64 mmol) in glacial acetic acid (38 mL) was added bromine (3.36 mL, 65 mmol) at room temperature. The white cloudy solution slowly turned into a clear brown solution, which was heated at 80° C. for 2.5 h. The mixture was allowed to cool to room temperature and then evaporated under reduced pressure. The residue was neutralized with saturated NaHCO3 solution to pH=8. The resulting solution was extracted with EtOAc three times. The combined extracts were dried over MgSO4, filtered, and evaporated in vacuo to yield 15.1 g (99.8percent) of the crude product (15.1 g, 98.8percent) as a white solid. LC-MS calculated for C6H3BrF3NO: (M+H)+241.9; found 241.9/243.9. Step A-2
98%
With bromine; sodium acetate In acetic acid at 80℃; for 2.5 h;
To a solution of 5-trifluoromethyl-2-pyridinal (51 g, 310 mmol) and sodium acetate (26. 2G, 319 mmol) in glacial acetic acid (200 mL) was added bromine (16.7 ML, 325 mmol) and the resulting mixture was heated at 80 °C for 2.5 h. The reaction was allow to cool to room temperature and then was evaporated under reduced pressure. The residue was neutralized with saturated NaHC03 solution and extracted with ethyl acetate (3 x 200 mL). The organics were combined, dried over MGS04, filtered, and evaporated in vacuo to yield 74.45 g (98percent) of the crude product. 1H NMR (400 MHz, CDC13) 8 8.04 (d, J=2.6 Hz, 1H), 7.89 (m, 1H).
98.7%
With bromine; sodium acetate In acetic acid at 80℃; for 2.5 h;
To a solution of 5-TRIFLUOROMETHYL-2-PYRIDINOL (51. 0 g, 307 mmol) and sodium acetate (26.2 g, 319 mmol) in glacial acetic acid (200 mL) was added bromine (16.7 mL, 325 mmol) and the resulting mixture was heated at 80 °C for 2.5 hours. The reaction was allow to cool to room temperature and then was evaporated under reduced pressure. The residue was neutralized with saturated NAHC03 solution and extracted with ethyl acetate (3 x 200 mL). The organic layers were combined, dried over MgS04, filtered, and evaporated in vacuo to yield 74.45 g (98.7percent) of the crude PRODUCT. H NMR (400 MHz, CD) 5 8.04 (d, J=2.6 Hz, 1H), 7.89 (m, 1H).
98.7%
Stage #1: at 80℃; for 2.5 h; Stage #2: at 20℃;
INTERMEDIATE 2; Step A; To a solution of 5-trifluoromethyl-2-pyridinol (51.0 g, 307 mmol) and sodium acetate (26.2 g, 319 mmol) in glacial acetic acid (200 mL) was added bromine (16.7 mL, 325 mmol) and the resulting mixture was heated at 80° C. for 2.5 hours. The reaction was allow to cool to room temperature and then was evaporated under reduced pressure. The residue was neutralized with saturated NaHCO3 solution and extracted with ethyl acetate (3.x.200 mL). The organic layers were combined, dried over MgSO4, filtered, and evaporated in vacuo to yield 74.45 g (98.7percent) of the crude product. 1H NMR (400 MHz, CDCl3) δ 8.04 (d, J=2.6 Hz, 1H), 7.89 (m, 1H).
98%
With bromine; sodium acetate In acetic acid at 80℃; for 2.5 h;
To a solution of 5-trifluoromethyl-2-pyridinal (51 g, 310 mmol) and sodium acetate (26.2 g, 319 mmol) in glacial acetic acid (200 mL) was added bromine (16.7 mL, 325 mmol) and the resulting mixture was heated at 80° C. for 2.5 h. The reaction was allowed to cool to room temperature and then was evaporated under reduced pressure. The residue was neutralized with saturated NaHCO3 solution and extracted with ethyl acetate (3.x.200 mL). The organics were combined, dried over MgSO4, filtered, and evaporated in vacuo to yield 74.45 g (98percent) of the crude product. 1H NMR (400 MHz, CDCl3) δ 8.04 (d, J=2.6 Hz, 1H), 7.89 (m, 1H).
98.7%
With bromine; sodium acetate In acetic acid at 80℃; for 2.5 h;
To a solution of 5-trifluoromethyl-2-pyridinol (51.0 g, 307 mmol) and sodium acetate (26.2 g, 319 mmol) in glacial acetic acid (200 mL) was added bromine (16.7 mL, 325 mmol) and the resulting mixture was heated at 80° C. for 2.5 hours. The reaction was allow to cool to room temperature and then was evaporated under reduced pressure. The residue was neutralized with saturated NaHCO3 solution and extracted with ethyl acetate (3.x.200 mL). The organic layers were combined, dried over MgSO4, filtered, and evaporated in vacuo to yield 74.45 g (98.7percent) of the crude product. 1H NMR (400 MHz, CDCl3) δ 8.04 (d, J=2.6 Hz, 1H), 7.89 (m, 1H).
95%
With bromine; sodium acetate In acetic acid at 80℃; for 2 h;
To a solution of 5-TRIFLUOROMETHYL-2-PYRIDINOL (21.37 g, 131 mmol), and sodium acetate (11.23 g , 107 mmol) in glacial acetic acid was added bromine (6.94 ml, 135 mmol), and the resulting mixture stirred at 80 ° C for 2 hours. The cooled reaction mixture was evaporated and the residue basified by the addition of saturated NAHC03 (500 ml), and extracted with ethyl acetate (3 x 300 ml); the combined ethyl acetate layers were dried over MGS04, filtered and evaporated in vacuo to give the product (30.21 g, 95percent) ; IH NMR 500MHZ (CDC13) 8 = 8.00 (1H, d, J = 2.29 Hz), 8.16 (LH, d, J=2. 29HZ).
85%
With N-Bromosuccinimide In N,N-dimethyl-formamide for 2 h;
λ/-bromosuccinimide (NBS, 39.0Og, 0.22 mol) is added portionwise to a solution of 5-(trifluoromethyl)pyridin-2-ol (30.0Og, 0.18 mol) in DMF (180 ml_), and the resulting mixture is stirred for 2 hours. The mixture is poured into water (1200 mL) and the precipitate was collected by filtration. The crystal is dried in vacuo to give the product as a white solid (1st crystal : 28.1Og). The filtrate is extracted with EtOAc, and the organic layer is concentrated.The residue is poured into water and the precipitate is collected by filtration. The crystal is dried in vacuo to give 3-bromo-5-(trifluoromethyl)pyridin-2-ol (2nd crystal : 9.65 g, total:37.75g, 85 percent yield) as a yellow solid.1H-NMR (400MHz, CDCI3), δ (ppm): 7.86 (d, 1H), 8.02 (d, 1H), 13.17 (br, 1H).
INTERMEDIATE 7 Step A; To a solution of 5-trifluoromethyl-2-pyridinal (51 g, 310 mmol) and sodium acetate (26.2g, 319 mmol) in glacial acetic acid (200 mL) was added bromine (16.7 mL, 325 mmol) and the resulting mixture was heated at 80 °C for 2.5 h. The reaction was allow to cool to room temperature and then was evaporated under reduced pressure. The residue was neutralized with saturated NaHC03 solution and extracted with ethyl acetate (3 x 200 mL). The organics were combined, dried over MgS04, filtered, and evaporated in vacuo to yield 74.45 g (98percent) of the crude product. 1H NMR (400 MHz, CDC13) 8 8.04 (d, J=2.6 Hz, 1H), 7.89 (m, 1H).
98%
at 80℃; for 2.5 h;
INTERMEDIATE 7; Step A; To a solution of 5-trifluoromethyl-2-pyridinal (51 g, 310 mmol) and sodium acetate (26.2g, 319 mmol) in glacial acetic acid (200 mL) was added bromine (16.7 mL, 325 mmol) and the resulting mixture was heated at 80 °C for 2.5 h. The reaction was allow to cool to room temperature and then was evaporated under reduced pressure. The residue was neutralized with saturated NaHC03 solution and extracted with ethyl acetate (3 x 200 mL). The organics were combined, dried over MgS04, filtered, and evaporated ilz vacuo to yield 74.45 g (98percent) of the crude product.
With caesium carbonate; In acetonitrile; at 65 - 70℃; for 14h;
Step 1: Preparation of ethyl 2-methyl-2-((5-(trifluoromethyl)pyridin-2- y l)oxy)propanoate .To <strong>[33252-63-0]5-(trifluoromethyl)pyridin-2-ol</strong> (2.5 g, 15 mmol) in ACN (25 mL), Cesium carbonate (9.98 g, 30 mmol) followed by ethyl 2-bromo-2-methylpropanoate (2.27 mL, 15 mmol) was added and the reaction mixture was heated at 65-70 C for 14 h. The progress of reaction was checked by TLC using mobile phase 50 % ethyl acetate in pet ether. The reaction mixture was cooled to 30-35 C, solvents were evaporated on a rotatory evaporator under reduced pressure to afford the semisolid brown compound. The suspension was diluted with water and then extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous Na2S04 and solvents were evaporated on a rotatory evaporator under reduced pressure to afford tert-butyl 2-((4- oxo-3,4-dihydrophthalazin-l-yl) methyl)-6,7-dihydrothieno[3, 2-c] pyridine-5(4H)- carboxylate as liquid compound (1.4 g, 32 %).
With caesium carbonate; In acetonitrile; at 5℃;
A mixture of <strong>[33252-63-0]2-hydroxy-5-trifluoromethylpyridine</strong> (5.73 g, 39 mmol), ethyl 2- bromoisobutyrate (5.7 mL, 39 mmol) and cesium carbonate (25 g, 77 mmol) in 50 mL acetonitrile was heated at 5 0C overnight. The volatile materials were removed by concentrating on a rotary evaporator, EPO <DP n="36"/>and the residue was partitioned between water (100 mL) and EtOAc (100 mL). The organic layer was separated and the aqueous layer extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated to dryness, and the residue was purified by flash column chromatography on silica gel eluted with 5% EtOAc in hexane to give the title compound. 1H NMR (500 MHz, CD3OD): delta 7.99 (d, IH), 7.67 (dd, IH), 6.68 (d, IH), 4.13 (q, 2H),1.64 (s, 6H), 1.14 (t, 3H). LC-MS: m/e 244 (M + H)+ (3.41 min).
With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 20℃;
[0200] To a solution of 5- (trifluoromethyl)-2-pyridinol 98 (2.11 g, 12.9 mmol) in DMF (20 mL) was added K2CO3 (2.68 g, 19.4 mmol) followed by bromide 79 (4.68 g, 15.0 mol). The resulting mixture was stirred at room temperature overnight, diluted with EtOAc, and washed with water. The organic layer was washed with sat. NaHCO3 and brine, dried over Na2S04, concentrated in vacuo, and purified by flash chromatography on silica gel (5: 95 EtOAc/ hexanes) to afford ester 99 (0.61 g, 12%) as a pale-yellow liquid. To a solution of ester 99 (0.61 g, 1.55 mmol) in THF/H20 (10 mL/3 mL) at room temperature was added lithium hydroxide monohydrate (0.31 g, 7.39 mmol). The resulting solution was stirred at room temperature for 2 h. The reaction was quenched with 1N aqueous HC1 and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na2S04 and concentrated in vacuo to afford acid 100 (0.53 g, 94%) as a brown liquids NMR (400 MHz, DMSO-d6) : 5 8.55 (1H, s), 8.08 (1H, dd, J= 8.8, 2.6 Hz), 7.89 (1H, s), 7.86 (1H, d, J= 8.0 Hz), 7.71 (1H, d, J= 8. 0 Hz), 7.61 (1H, d, J= 7.6 Hz), 7.14 (1H, d, J= 8.0 Hz), 6.19 (1H, s) ppm.
dibutyltin dilaurate; In tetrahydrofuran; at 20℃; for 2h;
11 g of 5-trifluoromethyl-2-pyridinol was dissolved in 200 mL of THF. 24.7 g of 3-triethoxysilylpropyl isocyanate and 0.6 g of dibutyltin dilaurate were added. Reaction was performed for 2 hours while stirring at room temperature and under nitrogen atmosphere. After the reaction was completed, the solvent was removed under reduced pressure. The product was dried in vacuum. 33 g of silane coupling agent C represented by Formula 4 below was obtained. The yield was 92%. The resultant compound was colorless liquid. NMR analysis result was as follows. 1H NMR (CDCl3, 300 MHz): 0.72 (t, 2H), 1.24 (t, 9H) 1.76 (m, 2H), 3.43 (m, 2H), 3.83 (q, 6H), 6.45 (t, 1H), 6.72 (d, 1H), 8.39 (m, 1H), 10.64 (s, 1H). 13C NMR (CDCl3, 300 MHz): 2.50, 12.97, 17.56, 38.22, 42.55, 53.10, 101.43, 116.28, 126.67, 135.13, 145.11, 159.87.
92%
dibutyltin dilaurate; In tetrahydrofuran; at 20℃; for 2h;
11 g of 5-trifluoromethyl-2-pyridinol was dissolved in 200 mL of THF. 24.7 g of 3-triethoxysilylpropyl isocyanate and 0.6 g of dibutyltin dilaurate were added. Reaction was performed for 2 hours while stirring at room temperature and under nitrogen atmosphere. [49] After the reaction was completed, the solvent was removed under reduced pressure. The product was dried in vacuum. 33 g of silane coupling agent C represented by Formula 4 below was obtained. The yield was 92 %. [50] ChemistryFigure 4 [51] The resultant compound was colorless liquid. NMR analysis result was as follows. [52] ¹H NMR (CDCl3,300 MHz) : 0.72 (t, 2H), 1.24(t, 9H), 1.76(m, 2H), 3.43 (m, 3.83 (q, 6.45 (t, 6.72 (d, 8.39 (m, 10.64 (s, [53] ¹3C NMR (CDCl3,300 MHz) : 2.50,12.97, 17.56,38.22, 42.55, 53.10, 101.43, 116.28, 126.67, 135.13, 145.11, 159.87.
{2-[3-chloro-5-(3,3-dichloro-allyloxy)-2-methoxy-phenyl]-4,5-dihydro-oxazol-4-yl}-methanol[ No CAS ]
[ 33252-63-0 ]
2-{2-[3-chloro-5-(3,3-dichloro-allyloxy)-2-methoxy-phenyl]-4,5-dihydro-oxazol-4-ylmethoxy}-5-trifluoromethyl-pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triphenylphosphine; In 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran;
b) 2-{2-[3-chloro-5-(3,3-dichloro-allyloxy)-2-methoxy-phenyl]-4,5-dihydro-oxazol-4-ylmethoxy}-5-trifluoromethyl-pyridine 45 mg (0.12 mMol) {2-[3-chloro-5-(3,3-dichloro-allyloxy)-2-methoxy-phenyl]-4,5-dihydro-oxazol-4-yl}-methanol and 22 mg (0.13 mMol) of <strong>[33252-63-0]2-hydroxy-5-trifluoromethylpyridine</strong> is dissolved in 5 ml of absolute DCM under nitrogen together with 38 mg (0.14 mMol) of triphenylphosphine. Diethyl azodicarboxylate (DEAD) is subsequently added drop by drop into 1 ml of absolute DCM. The preparation is stirred overnight at room temperature. After concentration to dryness, the remaining residue is purified by means of preparative HPLC. One obtains 14.5 mg (22% of the theory) of the 2-{2-[3-chloro-5-(3,3-dichloro-allyloxy)-2-methoxy-phenyl]4,5-dihydro-oxazol-4-ylmethoxy}-5-trifluoromethyl-pyridine in addition to 12.2 mg (19% of the theory) of the 1-{2-[3-chloro-5-(3,3-dichloro-allyloxy)-2-methoxy-phenyl]-4,5-dihydro-oxazol-4-ylmethyl}-5-trifluoromethyl-1H-pyridin-2-one. MS(ES+)=510 (purity: 100% according to LC-MS). 1H-NMR: CDCl3, delta=3.9 (s, 3H, OCH3); 4.4 (t, 1H, CH2-oxzolin); 4.5 (dd, 1H, CH2OPy); 4.6 (t, 1H, CH2-oxzolin); 4.66 (m, 3H, CH2OPy and -CH-C=CCl2); 4.7 (m, 1H, CH); 6.1 (t, 1H, CH2--C=CCl2); 6.8 (d, 1H, Py); 7.1 (d, 1H, aryl); 7.2 (d, 1H, aryl); 7.8 (dd, 1H, Py); 8.4 (s, 1H, Py).
2-Hydroxy-5-trifluoromethylpyridine (10.0 g, 61.3 mmol) was dissolved in sulfuric acid (50 ml) and cooled to 00C. Fuming nitric acid (14 ml, 92 mmol) was slowly added and the reaction was stirred at 00C for 1 hour before stirring at 65C for 24 hours. The reaction was then cooled to room temperature and mixed with ice (300 g) before slow addition of NaOH (85 ml, 50% aq). The aqueous phase was extracted with EtOAc (4*200 ml) and combined organics were dried over MgSO4 and evaporated to give 7.4 g (58 %) of 2-hydroxy-3-nitro-5-trifluoromethylpyridine as yellow solids. 1H NMR (CDCl3): delta 8.66 (s, IH), 8.29 (s, IH).
28%
With sulfuric acid; nitric acid; at 80 - 85℃;
(1) 100g compound 1 was dissolved in 400ml of concentrated sulfuric acid was added 2L three-necked flask,Heated to an internal temperature rose to 80 degrees;110g of concentrated nitric acid with a dropping funnel slowly added dropwise to the reaction system,System began to heat up,At this point the reaction flask from the hot bath to the air bath,Control dropping speed,So that the internal temperature maintained at 80-85 degrees (high temperature, the yield will be reduced, you can use a cold water bath temperature control),About 50 minutes dripping finished (40-60 minutes can be)Then the oil bath incubated for 50 minutes (40-60 minutes can be);TLC showed that most of the raw materials reacted, stop heating,Quickly dropped to room temperature, the reaction solution was poured into 1,000g of ice on the cloudy liquid,It was then extracted with ethyl acetate (EA) (500 ml * 2)The organic phase was washed again with saturated brine, dried and concentrated to give the crude product,The crude product was added to dichloromethane (DCM) (80ml), stirred for 5min, a small amount of unreacted raw material was dissolved and filtered. The filter cake was first washed with a small amount of DCM and then with EA and petroleum ether,The filter cake was dried to give compound 2 as a pale yellow solid.TLC information: UV color, raw Rf = 0.5, product Rf = 0.1.Developing solvent: EA / 1-2 drops of ammonia or DCM / MeOH = 10/1 plus 1-2 drops of ammonia.35 g of the product was obtained as a light yellow solid in a yield of 28%.
With sulfuric acid; potassium nitrate; at 0 - 65℃; for 4h;
5-(Trifluoromethyl)pyridin-2-ol (10.0 g, 61.31 mmol) was added to a stirring concentrated sulfuric acid (50.0 mL) at room temperature. The resulting clear solution was placed in an ice water bath, and potassium nitrate (12.4 g, 123 mmol) was added slowly while maintaining the temperature at 0 C. The resulting mixture was heated at 65 C. for 4 h before pouring onto ice and treated carefully with 50% NaOH (83 mL) until pH=8. The aqueous solution was extracted with EtOAc three times. The combined extracts were dried, filtered and concentrated to give 9.78 (77%) of crude product (>90% purity) as a yellow solid. Further purification by trituration with EtOAc gave 8.40 g of pure product. LC-MS calculated for C6H3F3N2O3: (M+H) 209; found 209.0.
With sulfuric acid; nitric acid; In water; at 80℃; for 1h;
Reference Production Example 1 To a mixture of 9.84 g of 2-hydroxy-5- (trifluoromethyl ) pyridine and 40 ml of concentrated sulfuric acid, 10.9 g of 70% nitric acid was dropped at 80C. This mixture was stirred at 80C for 1 hour. The reaction mixture was cooled down to room temperature, then, the reaction mixture was poured into ice water. The deposited solid was collected by filtration. This solid was washed with ice water, then, dissolved in ethyl acetate, and washed with saturated saline. The organic layer was dried over magnesium sulfate, then, concentrated under reducedpressure, to obtain 5.22 g of 2-hydroxy-3-nitro-5- (trifluoromethyl ) pyridine .1 H-NMR (DMSO-d6) delta : 13.54 (br s, 1H) , 8.67 (d, J=2.7 Hz, 1H) , 8.48-8.45 (m, 1H)
3-methyl-1-[methyl(phenyl)amino]carbonyl}-1H-imidazol-3-ium iodide[ No CAS ]
[ 548766-53-6 ]
Yield
Reaction Conditions
Operation in experiment
66%
With triethylamine; In acetonitrile;
Example 255 Methyl-phenyl-carbamic Acid 5-trifluoromethyl-pyridin-2-yl Ester A solution of <strong>[33252-63-0]2-hydroxy-5-(trifluoromethyl)pyridine</strong> (0.49 g, 3.00 mmol), 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (1.03 g, 3.00 mmol) and triethylamine (0.42 ml, 3.00 mmol) in acetonitrile (15 ml) was stirred at room temperature for 18 hours. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (15:85)) yielding the title compound (0.59 g, 66% yield) as a white solid. 1H NMR (300 MHz, CDCl3): t3.43 (br.s, 3H), 7.23 (br.s, 1H), 7.28 (m, 1H), 7.37 (m, 4H), 7.94 (br.d, 1H), 8.62 (br.s, 1H); HPLC-MS (Method A): m/z=319 (M+Na); Rt=3.85 min.
EXAMPLE 3 N-Methyl-5-trifluoromethylpyridone A stirred mixture of <strong>[33252-63-0]5-(trifluoromethyl)-2-pyridinol</strong> (34.8 g, 0.213 mmol), potassium carbonate (101 g, 0.730 mol) and iodomethane (48.7 mL, 0.783 mol) in dry acetone (750 mL) in a sealed bottle was heated at 59 C. for 7 h then cooled to ambient temperature. The reaction mixture was filtered and concentrated to dryness to give a yellow solid. The crude product was purified by column chromatography (1 kg silica gel) eluted with hexanes:EtOAc (1:1) to give a white solid. The solid was dried in vacuo at room temperature for 2 h to give 34.3 g (90% yield). Additional reactions were performed to give a total of 86.9 g of similar product.
4-[(2,2,2-trifluoroethyl)(2-[5-(trifluoromethyl)-2-pyridinyl]oxy}ethyl)amino]-2-(trifluoromethyl)benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Example 46; 4-[(2,2,2-Trifluoroethyl)(2-[5-(trifluoromethyl)-2-pyridinyl]oxy}ethyl)amino]-2- (trifluoromethyl)benzonitrile; Synthesized as described in Example 1C from 4-[(2-hydroxyethyl)(2,2,2- trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile and 5-trifluoromethyl-2-pyridinol, using dry DME as reaction solvent: MS (ESI) m/z 458 (M+1).
With hydrogen;platinum(IV) oxide; In acetic acid; under 2585.81 Torr; for 9h;
1 g (6.13 mmol) of 5-trifluoromethyl-2-piridinol was dissolved in 20 mL of acetic acid. A reaction was conducted with 300 mg of platinum oxide under a pressure of 50 psi of hydrogen (g) for 9 hours. The reaction solution was filtered by Celite and distilled off under reduced pressure, then the residue was purified by column chromatography to give 920 mg (5.50 mmol) of the title compound in a yield of 89%.[451] NMR: 1H-NMR(CDCl ) delta 3.56~3.51(1H, m), 3.42~3.36(1H, m), 2.59~2.53(2H, m),2.45~2.41(1H, m), 2.19~2.13(1H, m), 1.95~1.87(1H, m)[452] Mass(EI) 168(M++.)
EXAMPLE 4 To a stainless steel pressure vessel is added 22 g of 2-hydroxy-5-carboxypyridine, 2.2 g of water and 20 cc of sulfur tetrafluoride. The sealed vessel was heated to 140 C. for 10 hours and cooled to 25 C. and vented. The liquid contents were dissolved in 200 cc of water, the pH adjusted to 7.1 with sodium carbonate and the neutral solution extracted with chloroform to give 2-hydroxy-5-trifluoromethylpyridine upon evaporation.
5 g of this <strong>[33252-63-0]2-hydroxy-5-trifluoromethylpyridine</strong> was added to 25 g of phosphorus pentachloride and heated for 120 C. for 6 hours. The cooled reaction mixture was added slowly to 200 cc of water and the pH adjusted to 5.5 with sodium carbonate. The solution was extracted three times with 100 cc of chloroform each time to give on evaporation 2-chloro-5-trifluoromethylpyridine.
With trichlorophosphate; In N-methyl-acetamide; water;
EXAMPLE 5 To 10 g of <strong>[33252-63-0]2-hydroxy-5-trifluoromethylpyridine</strong> obtained as in Example 1 was added 20 cc of dimethylformamide and 30 g of phosphorus oxychloride. The resulting solution was heated to 140 C. for 3 hours, cooled to room temperature and slowly diluted with 200 cc of cold water. The acid solution was slowly neutralized with sodium carbonate and extracted three times with 200 cc of pentane. The pentane was removed by evaporation to give 2-chloro-5-trifluoromethylpyridine as a yellow oil.
EXAMPLE 1 STR6 9.4 g (0.05 mole) of O,O-diethyl thionpphosphatechloride were added dropwise to a suspension of 8.2 g (0.05 mole) of <strong>[33252-63-0]2-hydroxy-5-trifluoromethylpyridine</strong> and 8 g (0.058 mole) of potassium carbonate in 80 ml of acetonitrile at 20 C. The mixture was then stirred at 70 C. for 2 hours, cooled and filtered. The filtrate was concentrated and the residue was subjected to incipient distillation. 15 g (96% of theory) of O,O-diethyl O-(5-trifluoromethylpyrid-2-yl)thionophosphate were obtained in the form of a yellow oil with a refractive index n22 of 1.4718.
4-(2-methoxy-3-chloro-5-triisopropylsilyloxy-phenyl)-2-hydroxyethyl-thiazole[ No CAS ]
[ 33252-63-0 ]
[ 796119-23-8 ]
Yield
Reaction Conditions
Operation in experiment
With triphenylphosphine; In tetrahydrofuran;
g) Production of 2-{2-[4-(3-chloro-2-methoxy-5-triisopropylsilanyloxy-phenyl)-thiazol-2-yl]-ethoxy}-5-trifluoromethyl-pyridine The production takes place analogously to the instructions according to Example (I-4) with 300 mg (0.68 mMol) of 4-(2-methoxy-3-chloro-5-triisopropylsilyloxy-phenyl)-2-hydroxyethyl-thiazole, 111 mg (0.68 mMol) of 5-trifluoromethyl-2-pyridinol, 356 mg (1.36 mMol) of triphenylphosphane, 236 mg (1.36 mMol) of azodicarboxylic acid diethyl ester and 15 ml of THF. After the residue was chromatographed over silica gel, one obtains 240 mg (purity 53%, 32% of the theory)2-{2-[4-(3-chloro-2-methoxy-5-triisopropylsilanyloxy-phenyl)-thiazol-2-yl]-ethoxy}-5-trifluoromethyl-pyridine. MS (ES+): 587.
Preparation 16 Tert-Butyl 4-[5-(trifluoromethyl)-2-pyridyl]oxy}-1-piperidinecarboxylate The title compound was obtained from tert-butyl 4-hydroxy-1-piperidinecarboxylate and <strong>[33252-63-0]5-trifluoromethyl-2-hydroxypyridine</strong> in the same manner as in Preparation 13. 1H-NMR (300 MHz, CDCl3) delta 8.40(br s, 1H), 7.76(dd, J=2,8 Hz, 1H), 6.69(d, J=8 Hz, 1H), 5.33-5.23(m, 1H), 3.84-3.70(m, 2H), 3.35-3.23(m, 2H), 2.05-1.92(m, 2H), 1.80-1.66(m, 2H), 1.48(s, 9H).
20.1 2-[(5-trifluoromethyl)pyridin-2-yl)oxy]ethanol The compound is prepared according to a method similar to that described in Example 19.1, from 2-bromoethanol and <strong>[33252-63-0]2-hydroxy-5-(trifluoromethyl)pyridine</strong>.
(SR)-1-[(3SR,4RS)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethanol[ No CAS ]
[ 33252-63-0 ]
2-{(SR)-1-[(3RS,4SR)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethoxy}-5-trifluoromethyl-pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78%
a) 2-{(SR)-1-[(3RS,4SR)-1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethoxy}-5-trifluoromethyl-pyridine (XI-B-4) To a suspension of PPh3 (PPh3 polymer bound, 3 mmol PPh3/g resin) (0.77 g) in THF (25 mL) at 0 C. were added 5-trifluoromethyl-pyridin-2-ol (0.28 g, 1.75 mmol) and then DBAD (0.43 g). After 5 minutes was added (RS)-1-[(3RS,4SR)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethanol (0.41 g, 1.17 mmol, described herein above). The reaction mixture was stirred over night at RT, filtered on celite and concentrated under vacuo. Extraction with EtOAc/aq.NaOH 1M, followed by column chromatography (SiO2, EtOAc/H, 1:4) yielded 0.45 g (78%) of the title compound as a colorless oil. ES-MS m/e: 495.8 (M+H+).
78%
To a suspension of PPh3 (PPh3 polymer bound, 3 mmol PPh3/g resin) (0.77 g) in THF (25 mL) at 0 C. were added 5-trifluoromethyl-pyridin-2-ol (0.28 g, 1.75 mmol) and then DBAD (0.43 g). After 5 minutes was added (RS)-1-[(3RS,4SR)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethanol (0.41 g, 1.17 mmol, described herein above). The reaction mixture was stirred over night at RT, filtered on celite and concentrated under vacuo. Extraction with EtOAc/aq.NaOH 1M, followed by column chromatography (SiO2, EtOAc/H, 1,4) yielded 0.45 g (78%) of the title compound as a colorless oil. ES-MS m/e: 495.8 (M+H+).
With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 20 - 50℃; for 2.5h;
To a solution of (5-methyl-3-phenyl-isoxazol-4-yl)-methanol (95 mg, 0.50 mmol) in THF (6 mL) was added <strong>[33252-63-0]2-hydroxy-5-trifluoromethylpyridine</strong> (90 mg, 0.55 mmol) and triphenylphosphine (197 mg, 0.75 mmol) at ambient temperature under an argon atmosphere. Then diethyl azodicarboxylate (120 muL, 0.75 mmol) was added and the reaction mixture was stirred for 2.5 h at 50 C. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=95:5 to 0:100) afforded the title compound (86 mg, 51%) as a colourless oil. MS: m/e=335.3 [M+H]+.
2-bromo-N-(3-tert-butyl-isoxazol-5-yl)-2-methyl-propionamide[ No CAS ]
[ 33252-63-0 ]
[ 1184177-82-9 ]
Yield
Reaction Conditions
Operation in experiment
5%
With silver(l) oxide; In water; acetonitrile; at 60℃; for 18h;
Method B+, Step 2: Synthesis of N-(3-tert-Butyl-isoxazol-5-yl)-2-methyl-2-(5- trifluoromethyl-pyridin-2-yloxy)-propionamide (Example 8); To a solution of 2-bromo-N-(3-tert-butyl-isoxazol-5-yl)-2-methyl-propionamide (0.53 g, 1.78 mmol) and 5-trifluoromethyl-2-pyridinol (0.30 g, 1.84 mmol) in acetonitrile/water (95/5, 15 mL) is added silver (I) oxide (0.85 g, 3.68 mmol). The reaction is heated to 60 0C for 18 h. After cooling, the reaction mixture is filtered through a plug of NaiSCVcotton wool. The filtrate is concentrated under reduced pressure to give a brown oil, which is triturated with heptanes/ethyl acetate to afford a grey powder. Further purification by column chromatography (silica, eluent heptanes, 2.5-20% ethyl acetate) afforded N-(3-tert-butyl- isoxazol-5-yl)-2-methyl-2-(5-trifluoromethyl-pyridin-2-yloxy)-propionamide as a white solid (33 mg, 5%). m/z 372 [M+H+]Examples in Table 2, Method B are prepared according to a similar procedure.
(RS)-1-[(3RS,4SR)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethanol[ No CAS ]
[ 33252-63-0 ]
2-{(SR)-1-[(3RS,4SR)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethoxy}-5-trifluoromethyl-pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78%
a) 2-{(SR)-1-[(3RS,4SR)-1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethoxy}-5-trifluoromethyl-pyridine; To a suspension of PPh3 (PPh3 polymer bound, 3 mmol PPh3/g resin) (0.77 g) in THF (25 mL) at 0 C. were added 5-trifluoromethyl-pyridin-2-ol (0.28 g, 1.75 mmol) and then DBAD (0.43 g). After 5 minutes was added (RS)-1-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethanol (V-B-1) (0.41 g, 1.17 mmol, described herein above). The reaction mixture was stirred over night at RT, filtered on celite and concentrated under vacuo. Extraction with EtOAc/aq.NaOH 1M, followed by column chromatography (SiO2, EtOAc/H, 1:4) yielded 0.45 g (78%) of the title compound as a colorless oil. ES-MS m/e: 495.8 (M+H+).
With potassium carbonate; In acetone; at 20℃; for 20h;
K2CO3 (107 mg, 0.78 mmol) was added to a solution of 1-adamantyl bromomethyl ketone (100 mg, 0.39 mmol) and 5-tri(fluoromethyl)-2-pyridinol (64 mg, 0.39 mmol) in acetone (5 mL) at room temperature. The reaction was stirred for 2Oh at room temperature then was quenched by addition of water. The extraction was conducted with EtOAc (x2) then the organic phase was washed with brine and dried over MgSO4. The crude residue was the purified by flash chromatography (hexane/EtOAc 0-20% gradient) to afford the title compound (118.6 mg, 90%) as white solid. TLC single spot at R/ 0.22 (hexane/EtOAc 7:3); Mp = [101.7-103.5 0C]; 1H NMR (270 MHz, CDCl3): £2.65-2.83 (m, 2H), 1.93 (d, J = 2.7 Hz, 6H), 2.08 (br s, 3H), 4.85 (s, 2H), 6.58 (d br, J = 10.4 Hz, IH), 7.48-7.40 (m, 2H); LC/MS (APCI) m/z 338 (M+-H), 339 (M+); Accurate Mass: calculated (M++H) 340.1519; found 340.1521; HPLC tr = 2.20 min (100%) in 10% water-acetonitrile.
With triethylamine; In tetrahydrofuran; at 0℃; for 7h;Inert atmosphere;
General procedure: 2-naphthol (0.13 g, 0.90 mmol) was dissolved in dry THF (10 mL). Ethyl dichlorophosphate (0.11 mL, 0.91 mmol) was slowly added to the THF solution, followed by triethylamine (0.15 mL, 1.10 mmol). The reaction mixture was stirred under an atmosphere of nitrogen at 0C for 7 hours. The reaction was monitored by TLC (mobile phase petroleum ether/ethylacetate 5:1). Upon completion of the reaction as judged by TLC, the intermediate phosphorochloridate was reacted in situ with an appropriate amine as follows: To the reaction flask containing the phosphorochloridate, was added a further 10 mL of THF. Isopropylamine (0.08 mL, 0.91 mmol) was injected into the flask along with triethylamine (0.15 mL (1.10 mmol). The reaction was stirred under an atmosphere of nitrogen at room temperature for 8 hours. The reaction was monitored by TLC (mobile phase petroleum ether/ethylacetate 5:1). Upon completion of the reaction as judged by TLC, the reaction mixture was filtered, the solvent removed in vacuo and the residue purified by flash column chromatography on silica gel (eluant: petroleum ether:ethyl acetate) to yield phosphoramidate 19. A similar procedure was performed for thiophosphoramidates, employing ethyl dichlorothiophosphate instead of ethyl dichlorophosphate and toluene instead of THF, and the general procedure was also applied to pyridine, indole, quinoline or isoquinoline analogues.
With triethylamine; In toluene; at 0℃; for 7h;Inert atmosphere;
General procedure: 2-naphthol (0.13 g, 0.90 mmol) was dissolved in dry THF (10 mL). Ethyl dichlorophosphate (0.11 mL, 0.91 mmol) was slowly added to the THF solution, followed by triethylamine (0.15 mL, 1.10 mmol). The reaction mixture was stirred under an atmosphere of nitrogen at 0C for 7 hours. The reaction was monitored by TLC (mobile phase petroleum ether/ethylacetate 5:1). Upon completion of the reaction as judged by TLC, the intermediate phosphorochloridate was reacted in situ with an appropriate amine as follows: To the reaction flask containing the phosphorochloridate, was added a further 10 mL of THF. Isopropylamine (0.08 mL, 0.91 mmol) was injected into the flask along with triethylamine (0.15 mL (1.10 mmol). The reaction was stirred under an atmosphere of nitrogen at room temperature for 8 hours. The reaction was monitored by TLC (mobile phase petroleum ether/ethylacetate 5:1). Upon completion of the reaction as judged by TLC, the reaction mixture was filtered, the solvent removed in vacuo and the residue purified by flash column chromatography on silica gel (eluant: petroleum ether:ethyl acetate) to yield phosphoramidate 19. A similar procedure was performed for thiophosphoramidates, employing ethyl dichlorothiophosphate instead of ethyl dichlorophosphate and toluene instead of THF, and the general procedure was also applied to pyridine, indole, quinoline or isoquinoline analogues.
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 70℃; for 48h;
General procedure: To a stirred solution of 1-(1-benzyl-2,5-dimethyl-1H-pyrrol-3-yl)-2-chloroethanone (50 mg, 0.191 mmol) in DMF (2.5mL) were added sequentially DIPEA (66 muL, 0.38 mmol) and 2-hydroxy-5-trifluoromethyl pyridine (62 mg, 0.38 mmol). The reaction was stirred 48 h at 70C. The mixture was diluted in water and extracted with ethyl acetate (4×50ml). The combined organic phase was washed with brine (2×50mL) and concentrated under reduced pressure. The mixture was purified by column chromatography using DCM/MeOH to yield 20 mg (0.052 mmol, 27%) of product as a pale yellow powder.
(E)-3-(4-chloro-2-((5-methyl-2H-tetrazol-2-yl)methyl)phenyl)-1-(4-hydroxypiperidin-1-yl)prop-2-en-1-one[ No CAS ]
[ 33252-63-0 ]
(E)-3-(4-chloro-2-((5-methyl-2H-tetrazol-2-yl)methyl)phenyl)-1-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)piperidin-1-yl)prop-2-en-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With di-tert-butyl-diazodicarboxylate; In dichloromethane; at 0 - 20℃; for 18h;
To polymer bound triphenylphosphine (461 mg, 1.382 mmol) in DCM (5528 p1) at 000 was added di-tert-butyl azodicarboxylate (255 mg, 1.106 mmol) followed by 5-(trifluoromethyl) pyridin-2-ol (commercially available) (45.1 mg, 0.276 mmol) and (E)-3-(4-Chloro-2-((5- methyl-2 H-tetrazol-2-yl)methyl)phenyl)- 1 -(4-hydroxypi peridi n-i -yl)prop-2-en- 1-one (100 mg,0.276 mmol). The reaction was stirred at room temperature for 18 h. The reaction mixture was filtered under vacuum and the solvent was removed under reduced pressure. TFA (1 mL) was added to the filtrate and the mixture was stirred for 10 minutes. The solvent was removed under reduced pressure. The residue was diluted in DCM and washed with HCI (1 M). The organic portion was dried over a phase separating column and the solventremoved under reduced pressure. The crude material was purified by preparative HPLCunder the following conditions:Prep Run 50-98% Gradient low pH 8.5mm UV only triggerWaters Sunfire 018, 150 x 30 mm, 5 micA=0.i% TFA in Water, B=0.i% TFA in MeCN0.0-0.5mm 50%B 3OmL/min0.5-1.0mm 50%B 30-5OmL/min1.0-7.25mm 50-98%B, 7.25-8.3mm 98%B, 8.3-8.5min98-50%B SOmLIminThe product fractions were concentrated under high vacuum to afford the title compound;LC-MS: Rt = 5.8smins; [M+H] 507.6, Method lominLowpH.
tert-butyl N-[(tert-butoxy)carbonyl]-N-{4,6-dimethyl-5-[({2-[(4-[2-oxo-5-(trifluoromethyl)-1,2-dihydropyridin-1-yl]methyl}phenyl)methyl]-2H-pyrazolo[3,4-d]pyrimidin-4-yl}amino)methyl]pyridin-2-yl}carbamate[ No CAS ]
1-(4-((4-(((6-amino-2,4-dimethylpyridin-3-yl)methyl)amino)-2H-pyrazolo[3,4-d]pyrimidin-2-yl)methyl)benzyl)-5-(trifluoromethyl)pyridin-2(1H)-one[ No CAS ]
1-[4-(hydroxymethyl)phenyl]methyl}-5-(trifluoromethyl)-1,2-dihydropyridin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
0.82 g
With potassium carbonate; In acetonitrile; at 40℃; for 16h;
1-(4-(hydroxymethyl)benzyl)-5-(trifluoromethyl)pyridin-2(1H)-one[4-(chloromethyl)phenyl]methanol (0.50 g; 3.19 mmol; 1.00 eq.) and <strong>[33252-63-0]5-(trifluoromethyl)-2-pyridinol</strong> (0.57 g; 3.51 mmol; 1.10 eq.) were suspended in acetonitrile (9 ml). Potassium carbonate (1.32 g; 9.58 mmol; 3.00 eq.) was added and the reaction was stirred in a heat block at 40 C. After 16 h, the mixture was filtered, evaporated and purified by silica gel chromatography (ethyl acetate/DCM gradient) to give 1-(4-(hydroxymethyl)benzyl)-5-(trifluoromethyl)pyridin-2(1H)-one (0.82 g) as a yellow solid.MS (M+H)+ found for C14H12F3NO2: 284.1.
N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methyl-3-((5-(trifluoromethyl)pyridin-2-yl)oxy)propanamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
29%
General procedure: To a mixture of NaH (60% in mineral oil, 0.050 g, 1.23 mmol) in anhydrous THF (2 mL) at 0 C under Ar atmosphere was added a solution of the differently substituted phenol or thiophenol (1.11 mmol) in 1 mL of anhydrous THF. This mixture was stirred at r.t. for 20 min. A solution of the different intermediate 17-21 (0.74 mmol) in anhydrous THF (3 mL) was added slowly. The reaction mixture was stirred at r.t. o.n. The mixture was then diluted with ethyl acetate (30 mL), washed with brine (15 mL) and water (30 mL), dried over Na2SO4 and concentrated under vacuum. The crude residue was purified by flash column chromatography.
2-hydroxy-2-methyl-N-(4-nitro-3-(trifluoromethyl)phenyl)-3-((5-(trifluoromethyl)pyridin-2-yl)oxy)propanamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
67%
General procedure: To a mixture of NaH (60% in mineral oil, 0.050 g, 1.23 mmol) in anhydrous THF (2 mL) at 0 C under Ar atmosphere was added a solution of the differently substituted phenol or thiophenol (1.11 mmol) in 1 mL of anhydrous THF. This mixture was stirred at r.t. for 20 min. A solution of the different intermediate 17-21 (0.74 mmol) in anhydrous THF (3 mL) was added slowly. The reaction mixture was stirred at r.t. o.n. The mixture was then diluted with ethyl acetate (30 mL), washed with brine (15 mL) and water (30 mL), dried over Na2SO4 and concentrated under vacuum. The crude residue was purified by flash column chromatography.
N-(4-cyano-2-(trifluoromethyl)phenyl)-2-methyloxirane-2-carboxamide[ No CAS ]
[ 33252-63-0 ]
N-(4-cyano-2-(trifluoromethyl)phenyl)-2-hydroxy-2-methyl-3-(3-((5-trifluoromethyl)pyridine-2-yl)oxy)propanamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
35%
General procedure: To a mixture of NaH (60% in mineral oil, 0.050 g, 1.23 mmol) in anhydrous THF (2 mL) at 0 C under Ar atmosphere was added a solution of the differently substituted phenol or thiophenol (1.11 mmol) in 1 mL of anhydrous THF. This mixture was stirred at r.t. for 20 min. A solution of the different intermediate 17-21 (0.74 mmol) in anhydrous THF (3 mL) was added slowly. The reaction mixture was stirred at r.t. o.n. The mixture was then diluted with ethyl acetate (30 mL), washed with brine (15 mL) and water (30 mL), dried over Na2SO4 and concentrated under vacuum. The crude residue was purified by flash column chromatography.
With copper diacetate; triethylamine; for 6h;Reflux;
adding the product of the previous step (9.16 mmol) to methanol,Substituted 5-trifluoromethylpyridine-2(1H)-one (4.58 mmol),After Et3N (18.32 mmol) and Cu(OAC) 2 (0.458 mmol) were heated and refluxed for 6 hours, the reaction solution was concentrated, dissolved in dichloromethane, and respectively, with 5% sodium hydroxide solution,Wash with saturated brine and dry with anhydrous sodium sulfate.After concentration and spin drying, the column was purified to give a white solid which was used for the next step.
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