| 80.7% |
In acetonitrile; at 0 - 45℃;Inert atmosphere; |
Under nitrogen protection,Compound A was added sequentially to a 1000 mL three-necked flask(100 g, 0.524 mol),Compound B (84 g, 0.583 mol),DMAP (5.2 g, 0.042 mol),Acetonitrile (250 mL),Cooling to 0 ~ 5 .Temperature control 0 ~ 30 ,Triethylamine was added dropwise to the system(150 mL, 1.079 mol).Cooling to 0 ~ 5 ,To the system, pivaloyl chloride was added dropwise(76 mL, 1.17 mol),Dropping temperature below 30 , plus complete,And the temperature was raised to 40 to 45C. 3 to 5 hours later,At the end of the reaction,Cooling to 25 ~ 30 .filter, The filter cake was washed twice with 200 mL of methyl tert-ether,The solvent was distilled off under reduced pressure (<30C) to 3-fold volume (viscous).600 mL of methylene chloride was added,The mixture was stirred for 5 minutes (25 to 30 C)Approximately 300 mL of 1.5 M hydrochloric acid was added dropwise over 15 minutes,Adjust the pH = 2 ~ 3.The DCM phase was washed with 100 mL of saturated brine, and the organic phase was evaporated in vacuo for 2 times the volume of the solvent (<15C)200 mL of n-heptane was added,The solvent was distilled off under reduced pressure (<15C)50 mL of ethyl acetate was added,Heptane 300 mL was beaten for 2 hours.Filtration,100 ml (n-heptane:Ethyl acetate = 10: 1)Dried to obtain 134.23 g of product,Yield 80.7%. |
| 65% |
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Meldrum's Adduct (19)2,4,5-Trifluorophenylacetic acid (500.0 gm, 2.63 mol) (18) was suspended in tetrahydrofuran (5.26 vol, 2.63 Ltr) at 25-30 C. and the reaction mixture was stirred for 10-15 minutes. To this clear solution, 1,1'-carbonyldiimidazole (1.5 eq, 639.68 gm) was charged in four lots and the reaction mixture was stirred for 2-3 hours at 25-30 C. After 2-3 hours stirring, Meldrum's acid (1.2 eq, 454.87 gm) was charged and the reaction mixture was heated for 6 hours at 50-55 C. After 6 hours heating at 50-55 C., the tetrahydrofuran was distilled out completely at 50-55 C. under reduced pressure to give a dark yellow coloured residue. The dark yellow residue was acidified by using a 1:1 mixture of 35% hydrochloric acid:water (0.5 vol, 250.0 ml) at 0-5 C. The product was extracted from the aqueous solution by using dichloromethane (3×5.0 vol, 3×2.5 Ltr). The combined dichloromethane layers were further washed with water (3×10.0 vol, 3×5.0 Ltr). After water washing, the dichloromethane was completely distilled under reduced pressure to give a dark yellow fluffy solid. The product was further washed with methanol (2.0 vol, 1.0 Ltr) at 0-5 C.Molar Yield: 60-65% (505.0 gm)Chemical Purity: 98-99.5% (as measured by HPLC) |
| 60.1% |
With 1,1'-carbonyldiimidazole; In tetrahydrofuran; at 50℃; for 5h; |
2,4,5-trifluorophenylacetic acid (30 g), tetrahydrofuran (360 ml_), 1 ,1 -carbonyl diimidazole (25.5 g) at about 5O0C, and meldrums acid (22.7 g) are combined. The mixture is stirred for about five hours at the same temperature. The reaction mass is then cooled to about 3O0C. Isopropyl acetate (180 ml_) and water (180 ml_) are added and stirred for about 30 minutes. The reaction mass is cooled to about O0C and pH is adjusted to about 2.4 using 36% aqueous hydrochloric acid. The organic layer is separated, washed with 0.1 N aqueous hydrochloric acid and distilled off completely. To the residue obtained, n-heptane (140 ml_) and isopropyl acetate (70 ml_) are charged at about 3O0C and stirred at about O0C for about 90 minutes. The separated solid is filtered and washed with a mixture of n-heptane (20 ml_) <n="30"/>and isopropyl acetate (10 ml_). The wet cake is dried at about 5O0C for about 4 hours to afford the title compound. (Yield: 60.1 %; purity by HPLC: 98.0%) |
| 60 - 65% |
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Meldrum's adduct (19)2,4,5-Trifluorophenylacetic acid (500.0 gm, 2.63 mol) (18) was suspended in tetrahydrofuran (5.26 vol, 2.63 Ltr) at 25-30C and the reaction mixture was stirred for 10- 15 minutes. To this clear solution, l,r-carbonyldmidazole (1.5 eq, 639.68 gm) was charged in four lots and the reaction mixture was stirred for 2-3 hours at 25-300C. After 2- 3 hours stirring, Meldrum's acid (1.2 eq, 454.87 gm) was charged and the reaction mixture was heated for 6 hours at 50-550C. After 6 hours heating at 50-55C, the tetrahydrofuran was distilled out completely at 50-55C under reduced pressure to give a dark yellow coloured residue. The dark yellow residue was acidified by using a 1:1 mixture of 35% hydrochloric acid : water (0.5 vol, 250.0 ml) at 0-50C. The product was extracted from the aqueous solution by using dichloromethane (3 x 5.0 vol, 3 x 2.5 Ltr). The combined dichloromethane layers were further washed with water (3 x 10.0 vol, 3 x 5.0 Ltr). After water washing, the dichloromethane was completely distilled under reduced pressure to give a dark yellow fluffy solid. The product was further washed with methanol (2.0 vol, 1.0 Ltr) at 0-50C.Molar Yield: 60-65% (505.0 gm) Chemical Purity: 98-99.5% (as measured by HPLC) |
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With dmap; pivaloyl chloride; N-ethyl-N,N-diisopropylamine; In ISOPROPYLAMIDE; at 0 - 40℃; for 2 - 3h; |
Step A: Preparation of 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4, 3- ALPYRAZIN-7 (8H)-YLL-1-(2, 4, 5-TRIFLUOROPHENYL) BUTAN-2-ONE (2-3) 2,4, 5-Trifluorophenylacetic acid (2-1) (150 g, 0.789 mol), Meldrum's acid (125 g, 0.868 mol), and 4- (dimethylamino) pyridine (DMAP) (7.7 g, 0063 mol) were charged into a 5 L three-neck flask. N, N-DIMETHYLACETAMIDE (DMAC) (525 ML) was added in one portion at room temperature to dissolve the solids. NN-DIISOPROPYLETHYLAMINE (282 mL, 1.62 mol) was added in one portion at room temperature while maintaining the temperature below 40 C. Pivaloyl chloride (107 ML, 0.868 mol) was added dropwise over 1 to 2 h while maintaining the temperature between 0 and 5 C. The reaction mixture was aged at 5 C for 1 h. Triazole hydrochloride 1-4 (180 g, 0.789 mol) was added in one portion at 40-50 C. The reaction solution was aged at 70 C for several h. 5% Aqueous sodium hydrogencarbonate solution (625 mL) was then added dropwise at 20-45 C. The batch was seeded and aged at 20-30 C for 1-2 h. Then an additional 525 ML of 5% aqueous sodium hydrogencarbonate solution was added dropwise over 2-3 h. After aging several h at room temperature, the slurry was cooled to 0-5 C and aged 1 h before filtering the solid. The wet cake was displacement-washed with 20% aqueous DMAC (300 mL), followed by an additional two batches of 20% aqueous DMAC (400 mL), and finally water (400 mL). The cake was suction-dried at room temperature. The isolated yield of final product 2-3 was 89%. |
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With dmap; pivaloyl chloride; N-ethyl-N,N-diisopropylamine; In ISOPROPYLAMIDE; at 0 - 5℃; for 2 - 3h; |
2,4,5-Trifluorophenylacetic acid (2-1) (150 g, 0.789 mol), Meldrum's acid (125 g, 0.868 mol), and 4- (dimethylamino)pyridine (7.7 g, 0063 mol) were charged into a 5 L three-neck flask. N,N-Dimethylacetamide (DMAc) (525 mL) was added in one portion at room temperature to dissolve the solids. N,N-diisopropylethylamine (282 mL, 1.62 mol) was added in one portion at room temperature while maintaining the temperature below 40 C. Pivaloyl chloride (107 mL, 0.868 mol) was added dropwise over 1 to 2 h while maintaining the temperature between 0 and 5 C. The reaction mixture was aged at 5 C for 1 h. Triazole hydrochloride 1-4 (180 g, 0.789 mol) was added in one portion at 40-50 C. The reaction solution was aged at 70 C for several h. 5% Aqueous sodium hydrogencarbonate solution (625 mL) was then added dropwise at 20 - 45 C. The batch was seeded and aged at 20 - 30 C for 1-2 h. Then an additional 525 mL of 5% aqueous sodium hydrogencarbonate solution was added dropwise over 2-3 h. After aging several h at room temperature, the slurry was cooled to 0 - 5 C and aged 1 h before filtering the solid. The wet cake was displacement-washed with 20% aqueous DMAc (300 mL), followed by an additional two batches of 20% aqueous DMAc (400 mL), and finally water (400 mL). The cake was suction-dried at room temperature. |
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With dmap; pivaloyl chloride; N-ethyl-N,N-diisopropylamine; In ISOPROPYLAMIDE; at 0 - 5℃; for 1h; |
2,4,5-Trifluorophenylacetic acid (24) (150 g, 0.789 mol), Meldrum's acid (125 g, 0.868 mol), and 4-(dimethylamino)pyridine (DMAP) (7.7 g, 0063 mol) were charged into a 5 L three-neck flask. NN-Dimethylacetamide (DMAc) (525 mL) was added in one portion at room temperature to dissolve the solids. NN-diisopropylethylamine (282 mL, 1.62 mol) was added in one portion at room temperature while maintaining the temperature below 40 0C. Pivaloyl chloride (107 mL, 0.868 mol) was added dropwise over 1 to 2 h while maintaining the temperature between 0 and 5 0C. The reaction mixture was aged at 5 0C for 1 h. |
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2,4,5-Trifluorophenylacetic acid (24) (150 g, 0.789 mol), Meldrum's acid (125 g, 0.868 mol), and 4-(dimethylammo)pyridine (DMAP) (7.7 g, 0063 mol) were charged into a 5 L three-neck flask. NN-Dimethylacetamide (DMAc) (525 mL) was added in one portion at room temperature to dissolve the solids. NN-diisopropylethylamine (282 mL, 1.62 mol) was added in one portion at room temperature while maintaining the temperature below 40 0C. Pivaloyl chloride (107 mL, 0.868 mol) was added dropwise over 1 to 2 h while maintaining the temperature between 0 and 5 0C. The reaction mixture was aged at 5 0C for 1 h. Triazole hydrochloric acid h4 (180 g, 0.789 mol) was added in one portion at 40-50 0C. The reaction solution was aged at 70 0C for several h. 5% Aqueous sodium hydrogencarbonate solution (625 mL) was then added dropwise at 20 - 45 0C. The batch was seeded and aged at 20 - 30 C for 1-2 h. Then an additional 525 mL of 5% aqueous sodium hydrogencarbonate solution was added dropwise over 2-3 h. After aging several h at room temperature, the slurry was cooled to 0 - 5 0C and aged 1 h before filtering the solid. The wet cake was displacement-washed with 20% aqueous DMAc (300 mL), followed by an additional two batches of 20% aqueous DMAc (400 mL), and finally water (400 mL). The cake was suction-dried at room temperature. |
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With dmap; pivaloyl chloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl acetamide; at 0 - 40℃; for 2 - 3h; |
2,4,5-Trifiuorophenylacetic acid QA) (150 g, 0.789 mol), Meldrum's acid (125 g, 0.868 mol), and 4-(dimethylamino)pyridine (DMAP) (7.7 g, 0063 mol) were charged into a 5 L three-neck flask. NN-Dimethylacetamide (DMAc) (525 mL) was added in one portion at room temperature to dissolve the solids. N,N-diisopropylethylamine (282 mL, 1.62 mol) was added in one portion at room temperature while maintaining the temperature below 40 C. Pivaloyl chloride (107 mL, 0.868 mol) was <n="36"/>added dropwise over 1 to 2 h while maintaining the temperature between 0 and 5 0C. The reaction mixture was aged at 5 0C for 1 h. Triazole hydrochloride Lambda (18O g, 0.789 mol) was added in one portion at 40-50 0C. The reaction solution was aged at 70 0C for several h. 5% Aqueous sodium hydrogencarbonate solution (625 mL) was then added dropwise at 20 - 45 0C. The batch was seeded and aged at 20 - 30 C for 1-2 h. Then an additional 525 mL of 5% aqueous sodium hydrogencarbonate solution was added dropwise over 2-3 h. After aging several h at room temperature, the slurry was cooled to 0 - 5 0C and aged 1 h before filtering the solid. The wet cake was displacement-washed with 20% aqueous DMAc (300 mL), followed by an additional two batches of 20% aqueous DMAc (400 mL), and finally water (400 mL). The cake was suction-dried at room temperature. |
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200 grris of 2,4,5-trifluropheriyl acetici.acid, 108 ml of oxalic acid, 10 ml of dimethyl formamide and 2000 ml of methylienedichloride were charged into a clean and dry round' bottom flask followed by stirring at about 25-30 0C for about 2-3 hours., the progress of the reaction was monitored by Thin layer chromatography as well as HPLC ,after the completion of the reaction, the reaction mass was cooled to about -5 0C. Pre- <n="24"/>reacted solution of 280 gm of 4-Dimethylamino pyridine and 226 gm of 2,2-dimethyl- l,3-dioxane-456-dione in 1000 ml of methylenedichloride was added to reaction mass between the temperature of -5~0C and 'maintained the reaction mixture at the same temperature till the completion of reaction , was monitored by TLC or HPLC . 300 gm of dried product of 5-[l-hydroxy-2-(2',4,'5-trifluorophenyl)ethylidene]-2,2-dimethyl- l,3-dioxane-4,6-dione (Formula VII) was obtained by the acidic aqueous workup followed by solid precipitation with Diisopropyl ether . The isolated compound has been characterized by Melting points, Mass 1H NMR and HPLC purity. Mass . : 315.31 [M-H]" 1H NMR(300 MHz5CDCB ) : 7.1,6.9 (2 H,m), 4.43 (2 H,s),1.7(6 H,s) Melting point :; [86.44 - 109.5] 0CHPLC purity : NLT = 98 %. , |
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With pivaloyl chloride; N-ethyl-N,N-diisopropylamine;dmap; In ISOPROPYLAMIDE; at 0 - 40℃; for 2 - 3h; |
2,4, 5-Trifluorophenylacetic acid (2-1) (150 g, 0.789 mol), Meldrum's acid (125 g, 0.868 mol), and 4- (dimethylamino) pyridine (DMAP) (7.7 g, 0063 mol) were charged into a 5 L three-neck flask. N, N-Dimethylacetamide (DMAc) (525 mL) was added in one portion at room temperature to dissolve the solids. N, N-diisopropylethylamine (282 mL, 1.62 mol) was added in one portion at room temperature while maintaining the temperature below 40 C. Pivaloyl chloride (107 mL, 0.868 mol) was added dropwise over 1 to 2 h while maintaining the temperature between 0 and 5 C. The reaction mixture was aged at 5 C for 1 h. Triazole hydrochloric acid 1-4 (180 g, 0. 789 mol) was added in one portion at 40-50 C. The reaction solution was aged at 70 C for several h. 5% Aqueous sodium hydrogencarbonate solution (625 mL) was then added dropwise at 20-45 C. The batch was seeded and aged at 20-30 C for 1- 2 h. Then an additional 525 mL of 5% aqueous sodium hydrogencarbonate solution was added dropwise over 2-3 h. After aging several h at room temperature, the slurry was cooled to 0-5 C and aged 1 h before filtering the solid. The wet cake was displacement-washed with 20% aqueous DMAc (300 mL), followed by an additional two batches of 20% aqueous DMAc (400 mL), and finally water (400 mL). The cake was suction-dried at room temperature. The isolated yield of final product 2-3 was 89%. |
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With dmap; pivaloyl chloride; N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20 - 55℃; for 3 - 5h; |
2,2-Dimethyl-5-r(2.4.5-trifluorophenyl)acetyl1-1.3-dioxan-4.6-dione(2-6) 2-6Trifluorophenylacetic acid (3.5 kG, 18.4 mol), Meldrum's acid (2.92 kG, 20.25 mol), and DMAP (225 g, 1.84 mol) were charged into a 72 L three-neck flask. MeCN (14 L) was added in one portion at room temperature to dissolve the solids. /Pr2NEt (7.06 L, 40.5 mol) was added in one portion at room temperature. Pivaloyl chloride (2.5 L, 20.25 mol) was then added dropwise over 1 to 2 h while the reaction temperature was maintained below 55 0C. The reaction was then aged at 50 0C for 2-3 h. The reaction was cooled to 20 0C and 7 L of 17.7 wt% aqueous phosphoric acid was charged to homogeneous solution over 1 h. The product crystallized out of solution and slurry was aged 1 h. Then an additional 21 L of 17.7 wt% phosphoric acid was charged and final pH of aqueous layer was 2.5. The slurry was filtered at ambient temperature and the mother liquors recycled to remove all solids from the flask. The cake was washed with 15 L of 2:3 MeCN/H2O and the wet cake stirred and then filtered. The cake was washed an additional two times with 15 L of 2:3 MeCN/H2O and filtered. The wet cake was then dried in vacuum oven at 40 0C for up to 5 d to afford Meldrum's adduct 2-6. 1H-NMR (400 MHz, CDCl3): ? 15.50 (s, IH), 7.14 (m, IH), 6.96 (m, IH), 4.45 (s, 2H), 1.76 (s, 6H) ppm; 13C-NMR (100 MHz, CDCl3): ? 192.76, 170.66, 160.42, 156.47 (ddd, JCF= 245.7, 9.6, 2.4 Hz), 149.79 (ddd, JCF = 251.4, 14.5, 12.0 Hz), 146.90 (ddd, JCF = 244.9, 12.0, 3.2 Hz), 119.40 (dd, JCF = 19.3, 5.6 Hz), 117,41, 105.63, 91.99, 34.59, 27.06 ppm. |
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EXAMPLESExample 1; PREPARATION OF 5-[1-HYDROXY-2-(2,4,5 TRIFLUOROPHENYL)ETHYLIDENE]-2,2-DIMETHYL-1,3-DIOXANE-4,6-DIONE200 gm of 2,4,5-trifluorophenyl acetic acid, 108 ml of oxalic acid, 10 ml of dimethyl formamide and 2000 ml of methylenedichloride were charged into a clean and dry round bottom flask followed by stifling at about 25-30 C. for about 2-3 hours., the progress of the reaction was monitored by thin layer chromatography (TLC) including high performance liquid chromatography (HPLC), after the completion of the reaction, the reaction mass was cooled to about -5 C. Pre-reacted solution of 280 gm of 4-dimethylamino pyridine and 226 gm of 2,2-dimethyl-1,3-dioxane-4,6-dione in 1000 ml of methylenedichloride was added to the reaction mass between the temperature of about -50 C. and maintained the reaction mixture at the same temperature until the completion of reaction, which was monitored by TLC or HPLC. 300 gm of dried product of 5-[1-hydroxy-2-(2,4,5-trifluorophenyl)ethylidene]-2,2-dimethyl-1,3-dioxane-4,6-dione (Formula VII) was obtained by the acidic aqueous workup followed by solid precipitation with diisopropyl ether. The isolated compound has been characterized by Melting points, Mass 1H NMR and HPLC purity. |
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300 gm of 2, 4, 5-trifluorophenyl acetic acid, 240 gm of oxalic acid, 15 ml of dimethylformamide (DMF) and 1500 ml of methylenedichloride were charged into a clean and dry round bottom flask by stirring at about 25-30C for about 2-3 hours, the progress of the reaction was monitored by thin layer chromatography (TLC) including high performance liquid chromatography (HPLC), after the completion of the reaction, the reaction mass was cooled to about -5C. Pre-reacted solution of 385.2 gm of 4- dimethylamino pyridine and 341 gm of 2, 2-dimethyl-l, 3-dioxane-4, 6-dione in 1500 ml of methylenedichloride was added to reaction mass between the temperature of about -5C and maintained the reaction mixture at the same temperature until the completion of reaction, which was monitored by TLC or HPLC. 420 gm of dried product of 5-[l- hydroxy-2-(2,4,5-trifluorophenyl)ethylidene]-2,2-dimethyl-l ,3-dioxane-4,6-dione (Formula X) was obtained by the acidic aqueous workup followed by solid precipitation with diisopropyl ether. The isolated compound has been characterized by Melting points, Mass, 'HNMR and HPLC purity.Mass : 315.31 [M-H]~ ' H NMPV(300 MHz,CDC13 ) : 7.1,6.9 (2 H,m), 4.43 (2 H,s), 1.7(6 H,s) Melting point : [86.44 - 109.5]CHPLC purity NLT = 98 %. |
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With dmap; pivaloyl chloride; N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20 - 50℃; for 2h; |
2,4,5-trifluorophenylacetic acid (50 g, 263 mmol) and meldrum's acid(42 g) were added to 125 ml of acetonitrile, and 6.6 ml of DMAP and 94 ml of N, N-diisopropylethylamine were added with stirring. 36 ml of pivaloyl chloride was added dropwise at room temperature. After the dropwise addition, the temperature was raised to 50 C for 2 hours, cooled to 0 C, poured into 300 ml of 1N hydrochloric acid solution, stirred for 30 minutes and filtered. The filter cake was dried in vacuo at 40 C to give 65 g of a yellow solid. 65 g of the yellow solid was added to 450 ml of acetonitrile, 23 g of benzyl alcohol was added at room temperature, and the mixture was heated to reflux for 2 hours, Then, 80 g of ammonium acetate was added and the reaction was continued for 2 hours. The mixture was cooled to 45 C and the acetonitrile was distilled off under reduced pressure. Then, 500 ml of ethyl acetate, 300 ml of water and 300 ml of saturated sodium carbonate were added and stirred for 15 minutes. The ethyl acetate layer was dried and concentrated under reduced pressure The To the concentrate was added tetrahydrofuran 500 ml, sodium borohydride 16 g, cooled to 0 C, slowly dropping concentrated sulfuric acid 42 g, dropwise after 0 ~ 5 C reaction for 3 hours, Slowly drop the water 300ml, dropping saturated sodium carbonate 100ml, ethyl acetate 150ml, layered. The organic layer was washed with 200 ml of saturated brine, dried and concentrated at 40 C under reduced pressure to give a brown oil. 3-Amino _4_ (2,4,5-dienobenzene Yl) butyrate (60 g, 185 mmol). Total yield: 70.5% |
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With dmap; pivaloyl chloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl acetamide; for 1h;Cooling with ice; |
2,4,5 - trifluorobenzoic acid (1.64 g), malonic acid cyclopentarolactone(1.37 g) and DMAP (80 mg)In DMAc (5.87 ml). N, N-diisopropylethylamine (2.23 g) was slowly added,Ice bath cooling, and then pivaloyl chloride(1.14 g) was slowly added dropwise to the reaction solution, and the mixture was stirred for 1 hour in an ice bath until the reaction solution became a yellow suspension, and the reaction was heatedThe mixture was stirred at 45 C for 30 minutes to give a solution of Compound V in DMAc without further separation. |
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With dmap; pivaloyl chloride; N-ethyl-N,N-diisopropylamine; In ISOPROPYLAMIDE; at 0 - 40℃; for 2 - 3h; |
2,4,5-Trifluorophenylacetic acid (2-1) (150 g, 0.789 mol), Meldrum's acid (125 g, 0.868 mol), and 4-(dimethylamino)pyridine (DMAP) (7.7 g, 0063 mol) were charged into a 5 L three-neck flask. NN-Dimethylacetamide (DMAc) (525 mL) was added in one portion at room temperature to dissolve the solids. N,N-diisopropylethylamine (282 mL, 1.62 mol) was added in one portion at room EPO <DP n="45"/>temperature while maintaining the temperature below 40 0C. Pivaloyl chloride (107 mL, 0.868 mol) was added drop wise over 1 to 2 h while maintaining the temperature between 0 and 5 0C. The reaction mixture was aged at 5 0C for 1 h. Triazole hydrochloride hA (180 g, 0.789 mol) was added in one portion at 40-50 0C. The reaction solution was aged at 70 0C for several h. 5% Aqueous sodium hydrogencarbonate solution (625 mL) was then added dropwise at 20 - 45 0C. The batch was seeded and aged at 20 - 30 0C for 1-2 h. Then an additional 525 mL of 5% aqueous sodium hydrogencarbonate solution was added dropwise over 2-3 h. After aging several h at room temperature, the slurry was cooled to 0 - 5 0C and aged 1 h before filtering the solid. The wet cake was displacement-washed with 20% aqueous DMAc (300 mL), followed by an additional two batches of 20% aqueous DMAc (400 mL), and finally water (400 mL). The cake was suction-dried at room temperature. |
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With dmap; pivaloyl chloride; N-ethyl-N,N-diisopropylamine; In ISOPROPYLAMIDE; at 5℃; for 2 - 3h; |
(2-3) 2,4, 5-TRIFLUOROPHENYLACETIC acid (2-1) (150 g, 0.789 mol), Meldrum's acid (125 g, 0. 868 mol), and 4- (DIMETHYLAMINO) pyridine (DMAP) (7.7 g, 0063 mol) were charged into a 5 L three-neck flask. N, N-DIMETHYLACETAMIDE (DMAC) (525 ML) was added in one portion at room temperature to dissolve the solids. N, N-diisopropylethylamine (282 ML, 1.62 mol) was added in one portion at room temperature while maintaining the temperature below 40 C. Pivaloyl chloride (107 ML, 0.868 mol) was added dropwise over 1 to 2 h while maintaining the temperature between 0 and 5 C. The reaction mixture was aged at 5 C for 1 h. Triazole hydrochloride 1-4 (180 g, 0.789 mol) was added in one portion at 40-50 C. The reaction solution was aged at 70 C for several h. 5% Aqueous sodium hydrogencarbonate solution (625 ML) was then added dropwise at 20-45 C. The batch was seeded and aged at 20-30 C for 1-2 h. Then an additional 525 mL of 5% aqueous sodium hydrogencarbonate solution was added dropwise over 2-3 h. After aging several h at room temperature, the slurry was cooled to 0-5 C and aged 1 h before filtering the solid. The wet cake was displacement-washed with 20% aqueous DMAC (300 mL), followed by an additional two batches of 20% aqueous DMAC (400 mL), and finally water (400 mL). The cake was suction-dried at room temperature. The isolated yield of final product 2-3 was 89%. |
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In a 250 mL three-necked flask, first add 120 mL of tetrahydrofuran., add 10g of 2,4,5-trifluorophenylacetic acid, stir until completely dissolved;12.8 g of N,N'-carbonyldiimidazoleand 0.96 g of 4-dimethylaminopyridine were slowly added in four portions at a constant temperature of 30 C.After stirring for 3 h, 9.1 g of Meldrum's acid was added, and then the temperature was raised to 50 C, and the reaction was terminated after 7 h of reaction;The reactant was subjected to rotary distillation to remove the solvent, and 50 mL of 10% hydrochloric acid was added to the residue, and extracted twice with 200 mL of dichloromethane.Combine the organic phase, and then steam to obtain a light yellow oil, which is a diketone compound; |
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With dmap; pivaloyl chloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl acetamide; at 5 - 40℃; for 3h;Inert atmosphere; |
A 5L 4-necks round-bottom flask was charged, under nitrogen atmosphere, with 2,4,5-Trifluorophenylacetic acid (II) (150 g, 0.789 mol), Meldrum's acid (VIII) (125 g, 0.868 mol), and 4-(dimethylamino)pyridine (DMAP) (7.7 g, 0063 mol). N,N-Dimethylacetamide (DMAc) (525 ml_) was added in one portion at room temperature to dissolve the solids. N,N- diisopropylethylamine (282 ml_, 1.62 mol) was added in one portion at room temperature while maintaining the temperature below 40 C. Pivaloyl chloride (107 ml_, 0.868 mol) was added dropwise aver 2 h while maintaining the temperature below 5 C. The reaction mixture was aged at 5 C for 1 h. Triazale hydrochloride (X) (180 g, 0.789 mal) was added at the same temperature. The reaction solution was aged at 70 C for 6h. Then 5% Aqueous sodium hydrogen carbonate solution (625 ml_) was added at 20- 45 C. The mixture was aged at 20-30 C for 2h. Then 525 ml_ of 5% aqueous sodium hydrogen carbonate solution was added over 3 h. After aging for 4 hours at room temperature, the slurry was cooled to 0- 5 C and aged 1 h before filtering the solid. The wet cake was washed with 20% aqueous DMAc (300 ml_), followed by an additional twice with 20% aqueous DMAc (400 ml_), and finally with water (400 ml_). The cake was dried at room temperature. |
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