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With oxalyl dichloride; N,N-dimethyl-formamide |
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With thionyl chloride at 60℃; for 1h; |
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With thionyl chloride |
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With thionyl chloride In toluene for 2h; Heating; |
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With thionyl chloride for 1h; Heating; |
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With thionyl chloride |
1 N-Methyl-3-phenyl-4-(4-trifluoromethylphenyl)-butanaminium chloride
EXAMPLE 1 N-Methyl-3-phenyl-4-(4-trifluoromethylphenyl)-butanaminium chloride To a 250 ml, round bottom flask fitted with a condenser were added 73.0 g (358 mmole) of p-trifluoromethylphenylacetic acid and 107 ml (1.5 mole) of thionyl chloride. The mixture was heated to reflux and stirred at that temperature for about 21/2 hours. The condenser was removed and the unreacted thionyl chloride was evaporated by vacuum distillation to provide a slurry consisting essentially of p-trifluoromethylphenylacetyl chloride. |
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With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 2.16667h; Inert atmosphere; |
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With oxalyl dichloride; N,N-dimethyl-formamide In tetrahydrofuran at 0 - 20℃; |
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With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane for 4h; |
3
4- (Trifluoromethyl) phenylacetic acid (1.79 g, 8.77 mmol) was dissolved in dichloromethane (20 ml) at room temperature. Oxalyl chloride (0.92 ml, 10.5 mmol) was added followed by DMF (2 drops). The reaction was stirred for 4 hours, after which time effervescence had ceased. The dichloromethane and excess OXALYL chloride were then evaporated. The acid chloride was redissolved in dichloromethane (20 ml) and poured in one go into a solution of sodium azide (0.63 g, 9.65 mmol) and tetrabutylammonium bromide (300 mg, 0.88 mmol) in water (15 ml). The mixture was stirred for 15 minutes, then the layers separated and the aqueous layer extracted with more dichloromethane (30 ml). The combined organic layers were dried (NA2SO4) and evaporated to give an oil which was purified by flash column (50% dichloromethane-hexane). The acyl azide (1.54 g) so produced was dissolved in dichloromethane (20 ml) and heated at reflux to quantitatively afford the title compound. The volume was adjusted to give a ca. 0. 33 M solution in dichloromethane for use in subsequent preparations. |
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With thionyl chloride In tetrachloromethane at 65℃; for 0.75h; |
2.A
Example 2; A. 2-Bromo-2-(4-(trifluoromethyl)phenyl)acetyl chloride. To a slurry of 2-(4-(trifluoromethyl)phenyl)acetic acid (10.21 g, 50.0 mmol) in CCl4 (5 mL) was added SOCl2 (14.6 mL, 200.6 mmol). The reaction was heated at 65° C. for 45 minutes then diluted with CCl4 (25 mL). N-Bromosuccinimide (10.70 g, 60.1 mmol) was added followed by 1 drop of 48% HBr. The temperature was then increased to 85° C. for an additional 2 hours. The reaction mixture was then cooled to room temperature and diluted with hexanes (250 mL). The solids were filtered off and the filtrate was evaporated in vacuo. The resulting residue was dissolved in hexanes (25 mL), filtered again and concentrated in vacuo to give Compound 2a in quantitative yield as a peach-colored liquid (15.29 g). 1H-NMR (CDCl3): δ 7.73-7.58 (m, 4H), 5.69 (s, 1H). |
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With thionyl chloride In tetrachloromethane at 65℃; for 0.75h; |
3.A Example 3
A. 2-Bromo-2-(4-(trifluoromethyl)phenyl)acetyl chloride. To a slurry of Compound 3a (10.21 g, 50.0 mmol) in CCl4 (5 mL) was added SOCl2 (14.6 mL, 200.6 mmol). The reaction was heated at 65° C. for 45 min then diluted with CCl4 (25 mL). N-Bromo succinimide (10.70 g, 60.1 mmol) was added followed by 1 drop of 48% HBr. The temperature was then increased to 85° C. for an additional 2 h. The reaction mixture was then cooled to room temperature and diluted with hexanes (250 mL). The solids were filtered away and the filtrate was evaporated in vacuo. The resulting residue was dissolved in hexanes (25 mL), filtered again, and concentrated in vacuo to give Compound 3b in quantitive yield as a peach-colored liquid (15.29 g). 1H NMR (CDCl3): δ 7.73-7.58 (m, 4H), 5.69 (s, 1H). |
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With oxalyl dichloride In dichloromethane at 20℃; for 1h; Inert atmosphere; |
15.E.h
p-Trifluoromethylphenylacetic acid (45 mg, 0.222 mmol, 1.3 eq) was dissolved in dry DCM (2 mL) under nitrogen atmosphere. Oxalyl chloride (0.028 mL, 0.333 mmol, 1.95 eq) and dry DMF (0.005 mL) were added and the mixture was stirred at room temperature for 1 h. The mixture was evaporated to dryness and kept under high vacuum for 1 h. The acid chloride was then dissolved in dry DCM (2 mL) under nitrogen and a solution of 3-(7-pyridin-4-yl- pyrazolo[5,1-b]thiazol-6-yl)-phenylamine (prepared as described in Example 13) (50 mg, 0.171 mmol, 1 eq) in dry DCM (1 mL) was added, followed by triethylamine (0.036 mL, 0.257 mmol, 1.5 eq) and the mixture was stirred at room temperature for 2 hours. It was then diluted with DCM, washed with saturated aqueous NaHCCb and brine, dried and concentrated to dryness. The crude product was purified by chromatography on silica gel (DCM/MeOH 98:2) to give 25 mg (30%) of N-[3-(7-pyridin-4-yl-pyrazolo[5,1-b]thiazol-6-yl)-phenyl]-2-(4-trifluoro-methyl-phenyl)- acetamideas off-white solid. HPLC (254 nm): R1: 6.36 min.1H-NMR (401MHz, DMSOd6) δ = 10.34 (s, 1 H), 8.51 (d, J = 6.0 Hz, 2 H), 8.38 (d, J = 4.1 Hz, 1 H), 7.83 (t, J = 1.8 Hz, 1 H), 7.65 - 7.73 (m, 3 H), 7.51 - 7.57 (m, 3 H), 7.38 (t, J = 7.9 Hz, 1 H), 7.18 - 7.22 (m, 2 H), 7.16 (dt, J = 1.2, 7.8 Hz, 1 H), 3.77 (s, 2 H). HRMS (ESI) calcd for C25H18F3N6O2S [M+H]+ 479.1148 found 479.1149. |
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With thionyl chloride for 3h; Inert atmosphere; Reflux; |
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With oxalyl dichloride; N,N-dimethyl-formamide In tetrahydrofuran at 0 - 80℃; for 0.25h; Inert atmosphere; |
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With thionyl chloride In dichloromethane at 80℃; for 2h; Inert atmosphere; |
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With oxalyl dichloride In dichloromethane at 0 - 20℃; for 4h; |
1
General procedure: Method-3A: A corresponding acid (2) (3.89 mmol) was dissolved in dichloromethane and cooled in an ice bath to +5 - 0°C. 0.66 ml (2 equivalents) of oxalyl chloride was dropped in dichloromethane while keeping the temperature at +5 - 0°C. After addition was complete the ice bath was removed and the mixture was allowed to warm to room temperature (RT). After stirring for 4 hours, the mixture was cooled to 0°C and the aniline (1 ) (3.89 mmol) was add- ed in dimethylacetamide (10 ml). The resulting mixture was stirred at RT and monitored by TLC. After completion of the reaction, the mixture was poured in ice water and extracted with dichloromethane. The Organic phase was washed with water and dried over Na2SO4 and evaporated to give (3). Intermediate (3) was purified by flash chromatography. |
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With thionyl chloride at 100℃; for 1.5h; Inert atmosphere; |
5.5-1 Synthesis Example 5-1
Under an argon atmosphere, to 4-trifluoromethylphenylacetic acid (51) (817 mg, 4.00 mmol) was added thionyl chloride (5.00 mL, 68.9 mmol), and heated to reflux (100° C.) for 1.5 h. After cooling to room temperature, the mixture was concentrated under reduced pressure to give 4-trifluoromethylphenylacetyl chloride (52) as a brown oily crude product, which was used in the next reaction without further purification. |
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With thionyl chloride In dichloromethane at 25℃; for 4h; Inert atmosphere; |
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With thionyl chloride |
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With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 1h; |
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With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 2h; |
2.1
Step 1: Oxalyl chloride (7.2 mmol, 7.2 mmol) was added dropwise to stirred solution of 4-(trifluoromethyl)phenylacetic acid (6 mmol, 6 mmol) in dichloromethane (20 mL), and 1 drop of dimethylformamide was added. The solution was stirred at room temperature for 2 hours and was then evaporated under reduced pressure to afford 4- (trifluoromethyl)phenylacetyl chloride, which was used directly without further purification |
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With thionyl chloride for 1h; Reflux; |
61.0 Reaction Step 0: 4-Trifluoromethylphenylacetyl chloride (50ELH121)
Reaction Step 0: 4-Trifluoromethylphenylacetyl chloride (50ELH121) (0434) 4-Trifluorophenylacetic acid (1.0 g) and thionyl chloride (15 ml) were refluxed for 1 h. The excess thionyl chloride was evaporated off. NMR showed complete conversion. |
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With thionyl chloride In dichloromethane; N,N-dimethyl-formamide |
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With thionyl chloride for 2h; Reflux; |
3.A Step A: 2-(4-(trifluoromethyl)phenyl)acetyl chloride
Step A: 2-(4-(trifluoromethyl)phenyl)acetyl chloride A solution of 2-(4-(trifluoromethyl)phenyl)acetic acid (50 g, 244 mmol) in thionyl chloride (160 mL) was refluxed for 2 h. The resulting mixture was concentrated in vacuo to give 2-(4-(trifluoromethyl)phenyl)acetyl chloride as an oil, which was used in the next step directly. |
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With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 1.16667h; |
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With oxalyl dichloride; N,N-dimethyl-formamide In tetrahydrofuran at 0℃; for 0.5h; Inert atmosphere; |
5.1.2. General procedure of the preparation of A-1~A-7
General procedure: Compound 1-4 (10 mmol, 2.5 g), ammonium chloride(10 mmol, 532 mg) and Fe (30 mmol, 1.67 g) were placed in adouble-neck flask, and 40 mL of THF and 8mL of H2Owere added tothe flask. The mixture was refluxed under nitrogen for 4 h. Whenthe reaction solution temperature cooled to room temperature,20 mL of H2O was added. The excess of Fe was filtered, and themixture was extracted with EtOAc (3 20 mL). The organic layerwas dried over anhydrous Na2SO4, filtered and concentrated toobtain the intermediate aminofuranone, which was used in thenext reaction without purification. The carboxylic acid (0.75 mmol)was added into a dry double-neck flask, and 5 mL of dry THF wasadded to the flask. N,N-Dimethylformamide (1.50 mmol, 0.15 mL)was added into the solution under nitrogen at 0 C. When thesewere completely dissolved, oxalyl chloride (3.75 mmol) was addedslowly. After 30 min, the solvent and excess oxalyl chloride werethen removed under reduced pressure to obtain an acyl chloride.The acyl chloride was kept dry. 100 mg of the intermediate aminofuranone was added into a dry double-neck flask, and 5 mL of dryTHFwas added to the flask. When these were completely dissolved,dry pyridine (1.06 mmol, 0.01 mL) was added under nitrogen at0 C. The THF solution of an acyl chloride (0.793 mmol) was addedinto the mixture slowly. After 30 min, 20 mL of saturated ammoniumchloride solution was slowly added into the mixture, and themixture was extracted three times with EtOAc (3 x 20 mL). Theorganic layer was dried over anhydrous Na2SO4, filtered andconcentrated to dryness, which was purified through silica gelcolumn (EA: PE 2: 1) to give A-1~A-7. |
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With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 2h; |
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In dichloromethane at 20 - 80℃; for 1h; |
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With thionyl chloride In dichloromethane at 55℃; Inert atmosphere; |
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With thionyl chloride for 3h; Reflux; |
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With thionyl chloride for 1h; Heating / reflux; |
61.0
Procedure as 50ELH14B.[0334] Reaction Step 0: 4-Trifluoromethyphenylacetyl chloride (50ELH12 l)[0335] 4-Trifluorophenylacetic acid (1.0 g) and thionyl chloride (15 ml) were refluxed for 1 h. The excess thionyl chloride was evaporated off. NMR showed complete conversion. |
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With thionyl chloride for 2h; Reflux; |
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With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 20℃; Inert atmosphere; |
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With thionyl chloride for 24h; Inert atmosphere; Reflux; |
4.1. General Procedures for The synthesis of Benzoyl Chloride and 2-Phenylacetyl Chloride Derivatives (1-12)
General procedure: Benzoic acid derivatives (1-6) and 2-phenylacetic acid derivatives (7-12) (6-10 mmol, 0.5 g) werereacted with thionyl chloride (68.9 mmol, 5 mL) under nitrogen atmosphere for 24 h to aord thecorresponding benzoyl chloride or 2-phenylacetyl chloride derivatives. The mixture was maintainedfor 15 min. at room temperature and then concentrated under vacuum to give the corresponding crudearoyl chloride derivatives, which were immediately used in the next reaction. |
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With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane for 2h; |
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With thionyl chloride In toluene at 80℃; Inert atmosphere; |
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With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane for 2h; Cooling with ice; |
5 Preparation of acid chloride:
add to a 100ml single-neck flask626mg 4-trifluoromethylphenylacetic acid and 25ml DCM,After stirring for a while, add (2eq) 0.513ml of oxalyl chloride in an ice bath,Two drops of DMF are used as a catalyst, and the reaction is very violent.Release a lot of gas, stir in an ice bath for 2 hours,Evaporate the solvent to obtain 4-trifluoromethylphenylacetyl chloride, which is ready for use. |
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With thionyl chloride at 20℃; for 2h; |
General procedure for compounds 4a-h
General procedure: Carboxylic acid (1a-h) (679.04 μmol) was dissolved inSOCl2 (2 mL). The mixture was stirred at room temperaturefor 2 h. After evaporation of the solvent, the intermediate(2a-h) was dissolved in anhydrous DCM (2 mL) and thenadded dropwise to another anhydrous DCM (10 mL) inwhich sulfonic aniline (3) (565.87 μmol) and DIPEA(188.94 μL) were dissolved. The mixture was stirred atroom temperature for 4 h and the precipitate was recoveredby vacuum filtration. The final compound was purified bycolumn chromatography using methanol/dichloromethane1:19 as eluents (4a, 4b, and 4g) or purified by stirring withthe ether (4c-f and 4h). |
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With oxalyl dichloride; N,N-dimethyl-formamide In N,N-dimethyl-formamide at 0 - 20℃; for 6h; Inert atmosphere; |
5.1.1. General procedure A: syntheses of compounds 16a-16f
General procedure: To a stirred solution of substituted or unsubstituted phenylaceticacid (14ae14f) (5.0 mmol, 1.0 eq) in anhydrous dichloromethane(20 mL)was successively added oxalyl chloride (6.0 mmol,1.2 eq) and DMF (0.5 mmol, 0.1 eq) at 0 C under argon atmosphere.The resulting mixture was subsequently warmed up to roomtemperature and stirred for 6 h. The reaction mixture wasconcentrated in vacuum to afford the corresponding phenylacetylchloride. The solution of the corresponding phenylacetyl chloridein anhydrous dichloromethane (10 mL) was slowly added to astirred solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (5.0 mmol,1.0 eq), pyridine (10.0 mmol, 2.0 eq) in anhydrous dichloromethane(10 mL) at 0 C under argon atmosphere. The resulting mixture wassubsequently warmed up to room temperature and stirred for 5 h.The reaction mixture was concentrated and the resulting residuewas dissolved in anhydrous ethanol (20 mL), and the mixture washeated to 80 C for additional 4 h. After cooling, the mixture wasconcentrated to dryness and distributed inwater and ethyl acetate.The organic layer was separated and washed with water and brinesuccessively, dried over anhydrous sodium sulfate and concentratedin vacuum. The resulting residue was purified by silica gelchromatography (petroleum ether/ethyl acetate, v/v, 99:1 to 90:10)to give the desired product. |
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