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CAS No. : | 701-99-5 | MDL No. : | MFCD00000726 |
Formula : | C8H7ClO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | PKUPAJQAJXVUEK-UHFFFAOYSA-N |
M.W : | 170.59 | Pubchem ID : | 69703 |
Synonyms : |
|
Signal Word: | Danger | Class: | 8 |
Precautionary Statements: | P260-P261-P264-P271-P280-P301+P310+P330+P331-P303+P361+P353+P310-P304+P340+P310-P305+P351+P338+P310-P363-P403+P233-P405-P501 | UN#: | 3265 |
Hazard Statements: | H314-H335 | Packing Group: | Ⅱ |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Stage #1: With sodium hydrogencarbonate In water; acetone at 10 - 15℃; for 0.333333 h; Stage #2: With potassium 2-ethylhexanoate In butan-1-ol |
To a cooled and stirred solution of 2.76 g (12.5 mmol) of 6-APA in 60 mL of water containing 5.25 g (62.5 mmol) of sodium bicarbonate, a solution of 2.76 g (16.2 mmol) phenoxyacetyl chloride in 5 mL of acetone was added in one minute. The resulting mixture was stirred vigorously during 20 min while the temperature was kept at 10-15 °C. The clear solution was extracted twice with 15 mL portions of methyl isobutyl ketone (MIBK). The clear aqueous solution was cooled to 5-10 °C and acidified to pH 2 with a cold 5.0 mol/L sulfuric acid solution. The acidified aqueous solution was extracted with 50 mL MIBK twice. The MIBK extract was separated, washed with cold water, and dried for 10 min over anhydrous sodium sulfate. After filtration, 10 mL of a 25percent solution of potassium 2-ethylhexanoate in butanol was added. The white crystalline material was collected by filtration, washed on the filter with dry acetone and dried in vacuum, yield 3.5 g (80percent) penicillin V as a white solid. Mp: 210-211 °C (dec.). 1H NMR (400 MHz, DMSO-d6): δ 8.42 (d, 1H, J = 8.0 Hz), 7.27 (m, 2H), 6.92 (m, 3H), 5.42 (dd, 1H, J = 8.0 Hz, 4.0 Hz), 5.40 (d, 1H, J = 4.0 Hz), 4.62 (d, 2H, J = 2.2 Hz), 3.88 (s, 1H), 1.52 (s, 3H), 1.46 (s, 3H); 13C NMR (100 MHz, DMSO-d6): δ 172.8, 169.0, 168.1, 158.1, 130.0, 121.7, 115.0, 74.6, 67.3, 66.7, 65.0, 57.8, 32.7, 27.8; HRMS (FAB) calcd. for C16H18KN2O5S [M+H]+: m/z 389.0584; found: 389.0995. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With thionyl chloride; N,N-dimethyl-formamide for 5h; Reflux; | |
38% | With thionyl chloride In chloroform for 3h; Heating; | |
With thionyl chloride |
With thionyl chloride at 35 - 45℃; | ||
With phosphorus(V) chloride | ||
With phosphorus(V) chloride; benzene | ||
With thionyl chloride | ||
With thionyl chloride Heating; | ||
With Carbon tetrachloride; cross-linked polymer (containing 2.50 mmol of phosphine/g) In 1,2-dichloro-ethane for 4h; Heating; | ||
With thionyl chloride In benzene at 80℃; for 1h; | ||
With thionyl chloride In ethyl acetate; benzene for 8h; Heating; | ||
With thionyl chloride at 90℃; for 3h; | ||
With pyridine; oxalyl dichloride In dichloromethane for 2.5h; | ||
5.5 g | With thionyl chloride for 16h; Ambient temperature; | |
With thionyl chloride In methanol; ethyl acetate for 7h; Heating; | ||
With thionyl chloride for 8h; Heating; | ||
With oxalyl dichloride In N,N-dimethyl-formamide; benzene for 18h; | ||
With thionyl chloride In methanol; ethyl acetate; benzene for 8h; Heating; | ||
With thionyl chloride for 8h; Heating; | ||
With thionyl chloride for 1h; Heating; | ||
With thionyl chloride In benzene at 80℃; for 1h; | ||
With thionyl chloride In benzene for 1h; Heating; | ||
With thionyl chloride In benzene at 80℃; for 3h; | ||
With thionyl chloride In benzene Heating; | ||
With phosphorus(V) chloride In dichloromethane at 0℃; for 0.5h; | ||
With thionyl chloride for 1.5h; Heating; | ||
With PS-Ph3P resin; trichloroacetonitrile In dichloromethane at 20℃; | ||
With 1,1,1,3,3,3-hexachloro-propan-2-one; triethyl phosphite In dichloromethane at 0℃; for 0.5h; | ||
With Wang resin-CH2-O-(...)-[4-(2,6-dichloro-1,3,5-triazine)]; triethylamine In dichloromethane at 20℃; | ||
With thionyl chloride Heating; | ||
With thionyl chloride at 80℃; for 1h; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 1h; | ||
With thionyl chloride In benzene for 2.5h; Heating; | ||
With thionyl chloride | XI Phenoxy acetyl chloride EXAMPLE XI Phenoxy acetyl chloride Phenoxyacetic acid (d5) was treated with 25 ml of thionyl chloride and stirred for 18 hours at room temperature. After the end of the reaction, the reaction mixture was concentrated under vacuum at 30° C. to provide phenoxyacetyl chloride (4.8 g). | |
With thionyl chloride | XI Phenoxy Acetyl Chloride: EXAMPLE XI Phenoxy Acetyl Chloride: Phenoxyacetic acid (d5) was treated with 25 ml of thionyl chloride and stirred for 18 hours at room temperature. After the 5 end of the reaction, the reaction mixture was concentrated under vacuum at 300 C to provide phenoxyacetyl chloride (4.8 g). | |
With thionyl chloride at 80℃; for 1h; | ||
With thionyl chloride for 2h; Reflux; | ||
With phosphorus(V) chloride In dichloromethane for 0.5h; Reflux; Inert atmosphere; | ||
With dmap; thionyl chloride In dichloromethane for 2h; Reflux; | ||
With thionyl chloride | ||
With thionyl chloride In dichloromethane at 80℃; | General Procedure for preparation of Acetyl Chlorides: 1.2 molar equivalent of thionyl chloride (12 g, 7.4 mL, 0.1 mol) was added dropwise to a solution of acetoxy acetic acid (10 g, 0.08 mol) in CH2Cl2 (100 mL), and then left to stir on reflux in oil bath at about 80oC. The evolution of SO2 gas was monitored by connecting the flask to a bubbler containing hexane. When the production of SO2 stopped, the excess thionyl chloride was distilled off. The resulting acyl chloride appears as colorless oil. | |
With thionyl chloride | ||
With thionyl chloride for 6h; Reflux; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; Inert atmosphere; | ||
With thionyl chloride | ||
With thionyl chloride In chloroform for 72h; Reflux; | ||
With thionyl chloride; N,N-dimethyl-formamide In toluene at 20℃; | ||
With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 20℃; | ||
With thionyl chloride for 4h; Reflux; | General Procedure forSynthesis of Compounds 51-54 General procedure: Phenoxyaceticacids (50 mmol) was added to thionylchloride (50 mL) at room temperature under a calcium chloride tube.The mixture was then heated under reflux for 4 h. After cooling to roomtemperature, the mixture was evaporated in vacuo. The residue was dissolved in50 mL of dichloromethaneand aluminium chloride (13 g, 98 mmol) was addedslowly to the solution at 0°C. After stirring at 0°C for 15min, the reactionstirred at room temperature for 30min. The mixture was then poured into icewater, extracted with portions of ethyl acetate (3×50 mL). The organic layerwas washed with brine, dried over anhydrous sodium sulfate and the solventremoved in vacuo. The residue was purified by column chromatography to get theproduct. | |
With thionyl chloride; N,N-dimethyl-formamide In tetrahydrofuran at 50℃; for 5h; | General procedure for the synthesis of HY-1a-HY-1f General procedure: A mixture of aryloxyl acid (5a-f) (10 mmol), thionyl chloride(15 mmol), tetrahydrofuran (50 ml) and dimethylformamide(1 ml) was stirred at 50 C for 5 h. Then tetrahydrofuran and thionylchloride were removed in vacuo. Yellow liquid (6a-f) obtainedand pyridine (2.5 ml) were then added to a solution of 10 (10 mmolin 25 ml tetrahydrofuran). The solution was stirred at 50 C for 3 h.When the reaction was completed, the solution was poured intohydrochloric acid (1 mol/L) and extracted with CH2Cl2(20 ml 3). The combined organic phase was washed with brine(20 ml 3), dried over Na2SO4, concentrated to afford yellow solid.Purification by silica gel column chromatography (PE:EA = 15:1) yielded the isoflavone amide derivatives HY-1a-HY-1f | |
With phosphorus(V) chloride In benzene at 60℃; for 1h; | General procedure for the preparation of compounds 1-4 General procedure: To a solution of the corresponding DL-2-phenoxypropionic acid (6.02 mmol) in anhydrous benzene (40 mL) was added phosphorous pentachloride (9.62 mmol) and stirred at 60 °C for 1 h. Evaporation of the solvent gave acid chloride which was washed with anhydrous benzene. This acid chloride was dissolved in anhydrous benzene (40 mL) and added to a solution of methyl anthranilate (5.42 mmol) in benzene (20 mL) and then the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was added with water, extracted with ethyl acetate and the organic extracts were dried with anhydrous MgSO4 and filtered. The filtrate was concentrated to yield crude precipitate which was recrystallized with ethyl acetate and n-hexane to afford 1-4 as a white powder. | |
With thionyl chloride for 5h; Reflux; | General procedure for preparation of 5-R-4-R1-2-nitrobenzoylchlorides 12a-c and 2-phenoxyacetyl chlorides 16a-e General procedure: Substituted benzoyl and phenoxyacetyl chlorides 12a-c and 16a-e were obtained by refluxing for 5 h the appropriate acid derivatives (0.01 mol) with thionyl chloride (7.25 mL). After evaporation under reduced pressure, the crude liquid residue was used for subsequent reactions without purification. | |
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 3h; | General synthetic procedure for compounds 8-11 and 13-36 General procedure: To a stirred suspension of various carboxylic acid 4a, 4b, 6a and 8a (1.0 equiv) in CH2Cl2 (25 mL) was added oxalyl chloride (3.0 equiv) and a catalytic amount of DMF. After stirring at room temperature for 3 h, the reaction was concentrated under reduced pressure to afford a yellow oil crude acyl chloride. To a solution of methyl 2-(4-amino-2-fluorophenoxy)acetate 3a (1.0 equiv) in CH2Cl2(25 mL) was added Et3N (1.5 equiv), and this mixture was cooled to -5 °C. Subsequently, the crude acyl chloride obtained above was added in dropwise at a rate to ensure that the temperature did not exceed 0 °C. The solution was stirred for another 2 hrs at 25 °C, then washed successively with 10% HCl (2 × 25 mL), 10% NaHCO3 (2 × 25 mL) and brine (2 × 20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and the solvent was then evaporated to give the impure amide which was recrystallized from ethanol to give the desired products as colorless crystals. To a solution of the obtained crystals (1.0 equiv)in 2:3:1 THF/MeOH/H2O (18 ml) was added LiOH·H2O (1.5 equiv). After stirring at room temperature for 4 h, the volatiles were removed under reduced pressure. The residue was acidified with 1N hydrochloric acid solution, and then filtered and the filter cake was washed with 5 mL of water, dried in vacuum to afford a white powder. Recrystallization from 75% EtOH gave the desired compounds 8-11 and 13-36 as colorless crystals. | |
With thionyl chloride Reflux; | General procedure: The 2-amino-5-mercapto-1,3,4-thiadiazole 1 (5 mmol) was dissolved in NaOH(5 mmol, 15 mL) at room temperature. Ethyl 2-bromopropionate (5 mmol) was addedto the solution obtained and the mixture was stirred for 20 min. After that, the solid precipitatewas filtered off, washed with cold water, air dried, and then recrystallized from ethanolto give 2-(5-amino-1,3,4-thiadiazol-2-ylthio) propanoate 2 in 78% yield as pale yellowsolid. Mp 79-80C; 1H NMR(CDCl3, 400 MHz) δH: 1.25-1.28 (t, 3H, CH3, J = 6.0 Hz),1.57-1.59 (d, 3H, CH3, J = 8.0 Hz), 4.03-4.08 (q, 1H, SCH, J = 12.0 Hz), 4.16-4.22(q, 2H, OCH2, J = 16.0 Hz).4.35 (s, 2H, NH2); 13C NMR (CDCl3, 400 MHz) δC: 14.0,17.5, 46.0, 61.8, 150.0, 170.9, 171.4; IR (KBr) ν: 3266 (NH2), 1736 (OC O), 1501,1449, 1321, 1094 (C N N C S) cm-1; Anal. calcd for C7H11N3O2S2: C36.04, H 4.75,N 18.01; found C 36.10, H 4.77, N 17.93.To a 50 mL round-bottom flask was added phenoxyalkanoic acid 4 (5 mmol) andSOCl2 (5 mL). The mixture was refluxed for 4 h, and the excess SOCl2 was removedunder vacuum. The crude diacyl chloride was dissolved in CH3CN (5 mL) and addeddropwise through a dropping funnel to themixture of 2-(5-amino-1,3,4-thiadiazol-2-ylthio)propanoate 2 (4.5 mmol) and Et3N (4.2 mL, 30 mmol) in CH3CN (15 mL) on an ice bath.This mixture was vigorously stirred at room temperature for an additional 12 h aftercompletion of the addition. The product was evaporated under reduced pressure washedwith water and brine, dried and recrystallized from ethanol to give the title compounds 6. | |
With thionyl chloride for 4h; Reflux; | 2.4 Synthesis of phenoxyacetamide (2d) A solutionof 2-phenoxyacetic acid (3.04 g, 0,020 mol) in thionyl chloride (10 mL) was heated at reflux for 4 h. After removal of thionyl chloride under reduced pressure, dry CH2Cl2 (10 mL) was added to the residue. To the solution was added dropwise a solution of NH4OH (0.78 g, 0.022 mol) in CH2Cl2 (10 mL) at 0 °C and the reaction mixture was stirred at reflux for 4 h. The reaction mixture was allowed to cool to rt. After removal of the solvent under reduced pressure, ethylacetate (15 mL) was added tot he residue and the mixture was washed successively with 30 % NaHCO3 (10 mL) , and water (10 mL) and dried over MgSO4. Evaporation of the solvent gave a solid, which was recrystallized from dehydrated ethanol to afford phenoxyacetamide 2d as a white solid (2.41 g, 80%). | |
With thionyl chloride at 65 - 70℃; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 3h; | ||
With thionyl chloride for 3h; Reflux; Inert atmosphere; | ||
With phosgene; N,N-dimethyl-formamide In dichloromethane for 0.333333h; Cooling; | 1 7-phenoxyacetamidocephalosporanic acid (1) Phenoxyacetic acid (0.50 g, 3.3 mmol) was dissolved in 5 mL of methylene chloride and the solution was cooled in an ice/water bath. (COCl)2 was added to the solution followed by 3 drops of DMF. The reaction mixture was stirred for 20 min in the bath before the solvent was removed in vacuo. The residue was dissolved in toluene, which was removed in vacuo. The residue was then dissolved in 5 mL of dioxane and added dropwise to a stirred and ice/water bath-cooled mixture of 7-aminocephalosporanic acid (0.60 g, 2.2 mmol), 1 M Et3NH2CO3 buffer (13.5 mL, 13.5 mmol) and dioxane (5 mL). After the reaction mixture was stirred overnight at rt, the solvent was removed in vacuo. The residue was dissolved in water, which was removed in vacuo. The residue was dissolved in chloroform and loaded onto a silica gel column. The resulting solution was eluted using chloroform:methanol:acetic acid (6:2:0.1). The product-containing fractions were concentrated. The residue was dissolved in toluene, which was removed in vacuo. The residue was dissolved in 50 mL of 10% HCl and extracted with ethyl acetate (3×30 mL). The combined extracts were washed with water (2×20 mL), brine (20 mL), and dried over sodium sulfate. After filtering, the solvent was removed in vacuo to yield 1 (0.676 g, 76%). | |
With thionyl chloride; N,N-dimethyl-formamide for 5h; Reflux; | ||
With thionyl chloride | 1 0.3mol of chloroacetic acid dissolved in 60ml water, adjusted to pH 9 with sodium hydroxide, then add 0.2mol phenol, 100 ° C reflux,To give compound T1,Followed by addition of thionyl chloride for chlorination reaction to obtain compound T2,The thionyl chloride solvent was evaporated to give a brown liquid,And then with anthranilic acid condensation reaction,Get T3, PPA and then preheated to 130 ° C by adding T3 to compound, to obtain compound T4,The T4 was reacted with thionyl chloride at 80 ° C under reflux to give compound T5,The purified T5 was then added to a single-necked flask and phenol was added at 60 ° C overnight, followed by addition of 1,4-butanediamine at 120 ° C for 12 h,Finally, the product was purified by silica gel column to give compound 2T6. | |
With thionyl chloride Reflux; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 2.5h; | 6 At 0 ,A solution of phenoxyacetic acid (0.304 g, 2 mmol)Placed in a 25 mL two-necked round bottom flask and added dropwise with 2 drops of DMFDissolved in 10 mL of CH2Cl2, oxalyl chloride (0.2 mL, 4.0 mmol) was added with a disposable syringe; a mouth of a two-necked round bottom flaskWith rubber stopper plug, the other end of the exhaust gas absorption device; ice bath after 30min gradually returned to room temperature, stirring at room temperature for 2h,After completion of the reaction, the unreacted oxalyl chloride was removed by distillation under reduced pressure to dryness; The product was dissolved in 2 mL of CH2Cl2,This was added to 10 mL of a solution containing 4-chloromethyl-7-hydroxycoumarin (0.315 g, 1.5 mmol) andTriethylamine (0.208 g, 1.8 mmol)CH2Cl2 mixture, room temperature reaction 3h;After completion of the reaction, the pH of the reaction solution was adjusted to neutral with 1M HCl, extracted three times with 15 mL of dichloromethane, the organic phases were combined, washed with saturated sodium bicarbonate solution,And then washed twice with saturated brine. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated to give the crude product. The crude product was purified on a silica gel column to a 6: 1 by volume petroleum ether-ethyl acetate mixture As eluent,To give 0.413 g of the final product as a pale yellow solid,4-chloromethyl-7-phenoxyacetoxycoumarin (Compound K5) in 80% yield. | |
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 3h; Inert atmosphere; | ||
With phosphorus(V) chloride In dichloromethane for 0.5h; Reflux; | To a solution of phosphorus pentachloride (0.126 g, 0.610 mmol) in dichloromethane (11 mL), phenoxyacetic acid (0.092 g, 0.610 mmol) was added with stirring and the mixture refluxed for 30-40 minutes. After cooling, 4-methyl-1,2,5-oxadiazol-3-amine (0.060 g, 0.610 mmol) was added and the solution refluxed for 2-2.5 hours. The solvent was removed under reduced pressure and the residue quenched with water (50 mL). The solid was collected by vacuum filtration and washed with saturated sodium bicarbonate solution followed by water to afford compound 19 (0.103 g, 73%) | |
With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃; for 12h; | 1 3.8 g of compound 3 was dissolved in 50 mL of dichloromethane, cooled to 0 ° C in an ice bath, and 6.3 g of oxalyl chloride and 1 were added.N,N-dimethylformamide was added dropwise and stirred at room temperature for 12 h. Compound 4 was obtained by spinning off the solvent under reduced pressure. Compound 4 is not purifiedThen proceed to the next reaction. Subsequently, 1.6 g of compound 5 was dissolved in 20 mL of dichloromethane, and cooled to 0 ° C in an ice bath.Compound 4, 1.9 g of triethylamine and 0.15 g of 4-dimethylamine pyridine were added, and the reaction mixture was stirred at room temperature for 12 h. TLC tracking reaction, antiAfter completion, the reaction system was added to 50 mL of ice water, and the organic phase was separated. The aqueous phase was extracted twice with 50 mL of dichloromethane.The organic phase was washed with 20 mL of diluted hydrochloric acid (1 mol/L), brine, and dried over anhydrous sodium sulfate. Dry solvent under reduced pressureThe latter 3.25 g of white solid 6 was used directly in the next step without isolation and purification. | |
With thionyl chloride for 5h; Reflux; | 3.1 4.1.2. General procedure for preparation of 2-nitrobenzoyl chlorides (25a-c) The 3-phenylpropanoyl, 2-phenoxyacetyl and cinnamoyl chlorides 25a-c, were obtained by refluxing for 5 h the appropriate acid derivatives 24a-c (0.01 mol) with thionyl chloride (7.25 ml). After evaporationunder reduced pressure, the crude liquid residue was used forsubsequent reactions without purification. | |
With thionyl chloride | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 12h; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0℃; for 3h; | 5.1.30. General procedures for the synthesis 28a-g General procedure: To a solution of the acid (22a-g) (1.2 eq.) in DCM, oxalyl chlorideand 1 drop DMF were added dropwise at 0 C. After 3 h, DCM wasremoved by rotary evaporation. The resulting acyl chloride dissolvedin THF and pyridine was added dropwise into a solution of26 (1.0 eq.) in THF at 0 C, then slowly warmed to r.t. and continuedstirring for 5e6 h. 1 M HCl was added and extracted with ethylacetate for three times. The organic layer was combined, washedwith brine for once, dried over anhydrous Na2SO4 and concentratedto afford compounds 27a-g. To the solution of 27a-g in ethyl acetate,HCl gaswas added for 0.5 h, and the resulting solidwas filteredto obtain desired compounds 28a-g. | |
With thionyl chloride for 4h; Reflux; | ||
With thionyl chloride for 2h; Reflux; | ||
With thionyl chloride at 80℃; for 2h; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; | Acyl chlorides General procedure: The acid (5 mmol) was dissolved in anhydrous CH2Cl2 (10 mL) and DMF (a few drops) added.Oxalyl chloride (6 mmol, 1.2 equiv.) was added dropwise to the solution, that was cooled in an icewater bath. The resulting mixture was allowed to stir at room temperature for an additional 4 h andthe solvent was evaporated to afford the crude acyl chloride, which was used directly in the nextstep. | |
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 0.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With sodium hydroxide In lithium hydroxide monohydrate at 0℃; for 1h; | |
36% | With sodium oxide In lithium hydroxide monohydrate at 0℃; for 0.5h; | Intermediate 2-1 Anthranilic acid (7.0 g, 51.0 mmol) was added to of 60 mL of 2.5 M sodium oxide aqueous solution at 0 °C, and phenoxyacetyl chloride (8.71 g, 51.0 mmol) was added dropwise there. The mixture was stirred at 0 °C for 30 mm. The reaction mixture was quenched with 1 M hydrogen chloride to give a solid. The solid was collected by filtration, and it was dissolved in ethyl acetate. The solution was dried with MgSO4, and concentrated to give a solid. The crude product was recrystallized with ethanol to yield 5.60 g (36%) of intermediate 2-1 as a white solid. The product was used for the next reaction without further purification |
With sodium hydroxide |
In acetonitrile for 1h; Heating; Yield given; | ||
With sodium hydroxide In lithium hydroxide monohydrate at 20℃; for 3h; | ||
With sodium hydroxide In lithium hydroxide monohydrate at 0℃; | ||
With sodium hydroxide In lithium hydroxide monohydrate | ||
With sodium hydroxide In lithium hydroxide monohydrate | ||
With sodium hydroxide In lithium hydroxide monohydrate | ||
With sodium hydroxide In lithium hydroxide monohydrate for 2h; | ||
With sodium hydroxide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In benzene |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | Stage #1: G With pyridine; chloro-trimethyl-silane In dichloromethane for 2h; Stage #2: Phenoxyacetyl chloride In dichloromethane at 0℃; for 3h; Stage #3: With methanol In dichloromethane at 20℃; for 12h; | |
With pyridine; chloro-trimethyl-silane; benzotriazol-1-ol 1.) 45 min, 2.) acetonitrile, 55 deg C, 5 h; Yield given. Multistep reaction; | ||
150.2 g | Stage #1: G With pyridine; chloro-trimethyl-silane In dichloromethane at 0 - 20℃; for 3h; Inert atmosphere; Stage #2: Phenoxyacetyl chloride In dichloromethane for 3h; Cooling with ice; | 1.1 Step 1: Production of N2-(phenoxyacetyl)guanosine Reference Example 1 N9-{(2R,6S)-6-(Hydroxymethyl)morpholin-2-yl}-N2-(phenoxyacetyl) guanine p-toluenesulfone Step 1: Production of N2-(phenoxyacetyl)guanosine Guanosine, 100 g, was dried at 80° C. under reduced pressure for 24 hours. After 500 mL of pyridine (anhydrous) and 500 mL of dichloromethane (anhydrous) were added thereto, 401 mL of chlorotrimethylsilane was dropwise added to the mixture under an argon atmosphere at 0° C., followed by stirring at room temperature for 3 hours. The mixture was again ice-cooled and 66.3 g of phenoxyacetyl chloride was dropwise added thereto. Under ice cooling, the mixture was stirred further for 3 hours. To the reaction solution was added 500 ml of methanol, and the mixture was stirred at room temperature overnight. The solvent was then removed by distillation under reduced pressure. To the residue was added 500 mL of methanol, and concentration under reduced pressure was performed 3 times. To the residue was added 4 L of water, and the mixture was stirred for an hour under ice cooling. The precipitates formed were taken out by filtration, washed sequentially with water and cold methanol and then dried to give 150.2 g of the objective compound (cf.: Org. Lett. (2004), Vol. 6, No. 15, 2225-2557). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With triethylamine; In acetonitrile; at 0℃; | To a solution of phenoxyacetyl chloride (available from Aldrich 5.0 g) and triethylamine (Et3N) (3 g) in 50 mL of CH3CN was added a solution of the [2- (P-TOLYLSULFONYL)] ethanol (5.0 g) at [0C.] Thereafter water was added and the reaction mixture was extracted with [CH2C12.] The combined organic layers were washed with 1 N HCl and with saturated [NAHC03] solution, dried over anhydrous MgS04, and concentrated to give 8.0 g (97%) of the ester (Intermediate 3) as a light-yellow solid. 'H NMR (CDC13, 400 MHz) [82.] 41 (s, 3 H), 3.47 (t, 2 H), 4.40 (s, 2 H), 4.53 (t, 2 H), 6.83 (d, [2 H),] 7. 01 (m, [1] H), 7.29 (d, [2 H),] 7.36 (d, [2 H),] 7.81 (d, 2 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With triethylamine; In tetrahydrofuran; at 0 - 25℃; for 2.25h; | A solution of L-tert-Leucine tert-butyl ester hydrochloride (0.20 g, 0.90 mmol) in THF (9 mL) at 0 C. was treated with triethylamine (0.38 mL, 2.73 mmol) and phenoxyacetyl chloride (0.14 mL, 1.01 mmol), stirred at 0 C. for 15 minutes and then at 25 C. for 2 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine and dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-10% ethyl acetate/chloroform to give the title compound (0.23 g, 80% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.76 g (93%) | In tetrahydrofuran; methanol; diethyl ether; | N-[2-(2,6-Dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-2-phenoxy-acetamide I-53 To a suspension of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (0.55 g, 2 mmol) in THF (30 ml) was added phenoxyacetyl chloride (0.55 ml, 4 mmol). The mixture was heated to reflux for 18 hours. The reaction was cooled to room temperature, methanol (2 ml) was added, and the mixture stirred for 1 hour. The solvent was evaporated in vacuo leaving a solid which was slurried in diethyl ether (20 ml) and filtered to give 0.76 g (93%) of product as an off-white solid: mp 236-238 C.; 1H NMR (DMSO-d6) d 11.19 (s, 1H), 10.53 (s, 1H), 8.73 (d, J=8.4 Hz, 1H), 7.88 (t, J=7.6 Hz, 1H), 7.64 (d, J=7.3 Hz, 1H), 7.38 (t, J=7.6 Hz, 2H) 7.14-7.01 (m, 3H), 5.21 (dd, J=5.3 and 12.6 Hz, 1H), 4.81 (s, 2H), 3.00-2.86 (m, 1H), 2.67-2.51 (m, 2H), 2.13-2.09 (m, 1H); 13C NMR (DMSO-d6) d 172.77, 169.77, 168.37, 167.59, 166.67, 156.85, 136.58, 135.84, 131.28, 129.74, 124.45, 121.91, 118.50, 116.28, 114.86, 67.03, 49.02, 30.96, 21.93; Anal. Calcd. For C21, H17N3O6: C, 61.92; H, 4.21; N, 10.31. Found: C, 61.87; H, 4.27; N, 10.25. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With methyloxirane; In N-methyl-acetamide; acetone; | EXAMPLE 24 (S)-2-Oxo-3-[(phenoxyacetyl)amino]-1-azetidinesulfonic acid, potassium salt (S)-3-Amino-2-oxo-1-azetidinesulfonic acid, tetrabutylammonium salt (1.5 g; see Example 6A) in 100 ml of dry dimethylformamide is cooled to 0 C. Propylene oxide (2 ml) is added and 1 g of phenoxyacetyl chloride is added dropwise with stirring. The reaction is completed within 1 hour. The solvent is removed in vacuo and the residue is treated with an equivalent amount of potassium perfluorobutane sulfonate in 20 ml of acetone. On addition of ether the title compound (1 g) crystallizes and is filtered off and dried. After recrystallization from boiling water the title compound has a melting point of 176-180 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With triethylamine In dichloromethane at 20℃; for 16h; | 1.5 Step 5. A solution of (R)-2-[4-(4-chloro-phenyl)-thiazol-2-yl]-piperidinium trifluoroacetate (0.077 g, 0.20 mmol) in dry dichloromethane (2 mL) under argon was treated with triethylamine (0.079 g, 0.11 mL), dimethylaminopyridine (0.002 g, 0.020 mmol) and phenoxyacetyl chloride (0.033 g, 0.20 mmol). The mixture was stirred at room temperature for 16 h. The mixture was washed with water and saturated sodium chloride. The organic phase was dried over sodium sulphate and evaporated. The residual oil was purified by preparative HPLC: Column: YMC-Pack Pro C18 RS, 20×50 mm, S-5 um, 8 nm, No 200504707(W); Gradient: 0-0.4 min: 30% acetonitrile in (water+0.1% HCO2H), 0.4-2 min: increse of acetonitrile fraction from 30% to 95%, 2.4-3.7 min: 95% acetonitrile, 3.7-3.8 min: decrease of acetonitrile fraction from 95% to 30%; Program end at 4 min; Flow: 30 ml/min. 1-{(R)-2-[4-(4-Chloro-phenyl)-thiazol-2-yl]-piperidin-1-yl}-2-phenoxy-ethanone was obtained after lyophilization as a light yellow oil (0.037 g, 46%), MS (ISP): 413.1, 415.4 (M+H)+.. 1H-NMR (CDCl3, 300 MHz): 7.81 (2H, d), 7.38 (3H, m), 7.27 (2H, m), 6.98 (3H, m), 6.11+5.58 (1H, bs), 4.82 (2H, m), 4.56+3.91 (1H, bd), 3.36+2.86 (1H, bt), 2.59 (1H, m), 1.75 (5H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With triethylamine In dichloromethane at 20℃; for 4h; | 24.5 Step 5. A solution of 3-((R)-4-piperidin-2-yl-thiazol-2-yl)-benzoic acid methyl ester (0.048 g, 0.16 mmol) in dry dichloromethane (2 mL) under argon was treated with triethylamine (0.064 g, 0.09 ml.), dimethylaminopyridine (0.002 g, 0.020 mmol) and phenoxyacetyl chloride (0.027 g, 0.16 mmol). The mixture was stirred at room temperature for 4 h. The mixture was washed with water and saturated sodium chloride. The organic phase was dried over sodium sulphate and evaporated. The residual oil was purified by preparative HPLC: Column: YMC-Pack Pro C18 RS, 20×50 mm, S-5 um, 8 nm, No200504707(W); Gradient: 0-0.4 min: 30% acetonitrile in (water+0.1% HCO2H), 0.4-2.4 min: increse of acetonitrile fraction from 30% to 95%, 2.4-4.7 min: 95% acetonitrile, 4.7-4.8 min: decrease of acetonitrile fraction from 95% to 30%; Program end at 4.87 min; Flow: 30 ml/min. 3-{4-[(R)-1-(2-Phenoxy-acetyl)-piperidin-2-yl]-thiazol-2-yl}-benzoic acid methyl ester was obtained after lyophilization as a light yellow oil (0.033 g, 48%),MS (ISP): 437.3 (M+H)+.. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With triethylamine In dichloromethane at 20℃; Cooling with ice; | General Procedure 1 (GP1) for the synthesis of propargylamides 1a-z General procedure: Method A (from acyl chloride). A stirred solution of propargylamine (10 mmol, 0.551 g) in dichloromethane (25 mL) was cooled in an ice bath, triethylamine (20 mmol, 2.024 g) was added followed by a slow addition of corresponding acyl chloride (10 mmol). The mixture was stirredat room temperature overnight, washed with water (20 mL), brine (20 mL) and sat. aq. NaHCO3 (20 mL). The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel using appropriate eluent. |
With triethylamine In acetonitrile Inert atmosphere; | ||
With dmap; triethylamine In dichloromethane at 0 - 20℃; for 3.5h; |
With dmap; triethylamine In dichloromethane at 0 - 20℃; for 5.25h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With pyridine In N,N-dimethyl-formamide at 20℃; for 2h; | 332 To a solution of 2-amino-4-(N-piperazin-1-yl)-6-phenyl-thieno[2,3-d]pyrimidine (48 mg, 0.15 mmol) and pyridine (15 μl, 0.18 mmol) in DMF (1 ml) was added phenoxyacetyl chloride (0.17 mmol). The reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was quenched with water, extracted with EtOAc, brine and was dried over Na2SO4. After removing the solvents, the crude residue was purified by flash chromatography on silica (CH2Cl2/MeOH 100:1) to yield the title compound as a white solid (39 mg, 58%).MS m/z (%): 446 ([M+H]+, 100) |
58% | With pyridine In N,N-dimethyl-formamide at 20℃; for 2h; | 332 Example 332 Synthesis of 1-(4-(2-amino-6-phenylthieno[2,3-d]pyrimidin-4-yl)piperazin-1-yl)-2-phenoxyethanone Example 332 Synthesis of 1-(4-(2-amino-6-phenylthieno[2,3-d]pyrimidin-4-yl)piperazin-1-yl)-2-phenoxyethanone To a solution of 2-amino-4-(N-piperazin-1-yl)-6-phenyl-thieno[2,3-d]pyrimidine (48 mg, 0.15 mmol) and pyridine (15 μl, 0.18 mmol) in DMF (1 ml) was added phenoxyacetyl chloride (0.17 mmol). The reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was quenched with water, extracted with EtOAc, brine and was dried over Na2SO4. After removing the solvents, the crude residue was purified by flash chromatography on silica (CH2Cl2/MeOH 100:1) to yield the title compound as a white solid (39 mg, 58%). MS m/z (%): 446 ([M+H]+, 100) |
58% | With pyridine In N,N-dimethyl-formamide at 20℃; for 2h; | 332 Synthesis of 1-(4-(2-amino-6-phenylthieno[2,3d]pyrimidin-4-yl)piperazin-1-yl)-2-phenoxyethanone Example 332 Synthesis of 1-(4-(2-amino-6-phenylthieno[2,3d]pyrimidin-4-yl)piperazin-1-yl)-2-phenoxyethanone To a solution of 2-amino-4-(N-piperazin-1-yl)-6-phenyl-thieno[2,3-d]pyrimidine (48 mg, 0.15 mmol) and pyridine (15 μl, 0.18 mmol) in DMF (1 ml) was added phenoxyacetyl chloride (0.17 mmol). The reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was quenched with water, extracted with EtOAc, brine and was dried over Na2SO4. After removing the solvents, the crude residue was purified by flash chromatography on silica (CH2Cl2/MeOH 100:1) to yield the title compound as a white solid (39 mg, 58%). MS m/z (%): 446 ([M+H]+, 100) |
With triethylamine In N,N-dimethyl-formamide at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | Stage #1: (±)-1-(4-chlorophenyl)-2-(1H-imidazol-1-yl)ethanol With sodium hydride In acetonitrile at 20℃; for 2h; Stage #2: Phenoxyacetyl chloride In acetonitrile at 20℃; | 4.1.4.1. Example: Synthesis of (+/-)1-(4-fluorophenyl)-2-(1H-imidazol-1-yl)ethyl phenoxyacetate (7b) General procedure: To a stirred suspension of 1-(4-fluorophenyl)-2-(1H-imidazol-1-yl)ethanol (2b) (0.53 mmol) in dry acetonitrile (5 mL) was added sodium hydride (0.53 mmol). The reaction mixture was stirred for 2 h at rt, then phenoxyacetyl chloride (1.59 mmol) was dropwise added and the reaction mixture was over night stirred at rt. The solvent was removed under reduced pressure and the obtained residue was dissolved in dichloromethane and washed with aqueous saturated potassium carbonate.The separated organic layer was dried over anhydrous sodium sulphate and evaporated under reduced pressure. The solid residue was crystallized from ethylacetate to give pure 7b in 95%. |
95% | Stage #1: (±)-1-(4-chlorophenyl)-2-(1H-imidazol-1-yl)ethanol With sodium hydride In acetonitrile at 20℃; for 2h; Stage #2: Phenoxyacetyl chloride In acetonitrile at 20℃; | 4.1.1 (±)-1-(4-chlorophenyl)-2-(1H-imidazol-1-yl)ethyl-2-phenoxyacetate (1) Sodium hydride (13mg, 0.54mmol) was added to a suspension of (±)-1-(4-chlorophenyl)-2-(1H-imidazol-1-yl)ethanol (120mg, 0.54mmol) in dry CH3CN (5mL). After 2hat RT, the phenoxyacetyl chloride (220μL, 1.59mmol) was dropwise added and the reaction mixture was stirred overnight at RT. The solvent was removed under reduced pressure and the obtained residue was dissolved in CH2Cl2 (10mL) and washed with saturated Na2CO3 solution (2×10mL). The separated organic layer was dried over Na2SO4 and evaporated under reduced pressure. The residue was crystallized from EtOAc to give pure 1 as a white solid (183mg, 95%); mp: 103-105°C; IR (neat, cm-1): 1751(C=O); 1H NMR (400MHz, DMSO-d6) δ (ppm): 4.42 (d, J=5.5Hz, 2H), 4.83 (d, J=16.7Hz, 1H), 4.91 (d, J=16.7Hz, 1H), 6.11 (t, J=5.5Hz, 1H), 6.82-6.87 (m, 3H), 6.97 (t, J=7.4Hz, 1H), 7.13 (s, 1H), 7.27 (dd, J=8.5, 7.4Hz, 2H), 7.35 (d, J=8.5Hz, 2H), 7.43 (d, J=8.5Hz, 2H), 7.54 (s, 1H); MS (ESI): m/z calcd for C19H17ClN2O3: 357.10 [M+H]+, found 356.90; Anal. calcd for C19H17ClN2O3: C 63.96, H 4.80, N 7.85, found: C 63.86, H 4.81, N 7.83. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With triethylamine In chloroform at 2 - 20℃; | 15 General synthesis of title compounds 5a-q General procedure: A solution of substituted phenoxyacetyl chloride 2 (0.011 mol) in chloroform (15 mL) was added to stirred mixture of 1-hydroxycyclophosphonate 4 (0.01 mol) and triethylamine (0.011 mol) in chloroform (15 mL) at 2-4 ∘C. The resulting mixture was stirred at ambient temperature for 2-3 h, then washed with 0.1 mol/L HCl, saturated NaHCO3 and brine separately, dried and evaporated. The residue was chromatographed on silica gel using acetone-petroleum ether (1:4) as the eluent to afford the compounds 5a-q as a yellow oil or white solid. |
With triethylamine |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With triethylamine In chloroform at 2 - 20℃; | 16 General synthesis of title compounds 5a-q General procedure: A solution of substituted phenoxyacetyl chloride 2 (0.011 mol) in chloroform (15 mL) was added to stirred mixture of 1-hydroxycyclophosphonate 4 (0.01 mol) and triethylamine (0.011 mol) in chloroform (15 mL) at 2-4 ∘C. The resulting mixture was stirred at ambient temperature for 2-3 h, then washed with 0.1 mol/L HCl, saturated NaHCO3 and brine separately, dried and evaporated. The residue was chromatographed on silica gel using acetone-petroleum ether (1:4) as the eluent to afford the compounds 5a-q as a yellow oil or white solid. |
With triethylamine |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With triethylamine In chloroform at 2 - 20℃; | 14 General synthesis of title compounds 5a-q General procedure: A solution of substituted phenoxyacetyl chloride 2 (0.011 mol) in chloroform (15 mL) was added to stirred mixture of 1-hydroxycyclophosphonate 4 (0.01 mol) and triethylamine (0.011 mol) in chloroform (15 mL) at 2-4 ∘C. The resulting mixture was stirred at ambient temperature for 2-3 h, then washed with 0.1 mol/L HCl, saturated NaHCO3 and brine separately, dried and evaporated. The residue was chromatographed on silica gel using acetone-petroleum ether (1:4) as the eluent to afford the compounds 5a-q as a yellow oil or white solid. |
With triethylamine |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With benzotriazol-1-ol In pyridine at 20℃; for 21h; Inert atmosphere; | 2-(2-methylthioethyl)-6-phenoxyacetylamino-9-[2-deoxy-3’,5’-O-bis-(tert-butyldimethylsilyl)-b-D-ribofuranosyl]purine To a solution of 4 (303 mg, 0.547 mmol) in dry CH3CN (4.00 mL) was added 1-hydroxybenzotriazole (374 mg, 2.77 mmol) in dry pyridine solution (1.4mL) and phenoxyacetylchloride (0.380 mL, 2.75 mmol) under argon at room temperature. The reaction mixture was stirred for 21 h, diluted with chloroform, and washed with saturated aqueous NaHCO3 and brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (chloroform:ethyl acetate 100:0à8:1, v/v) to give 6-amino protected derivative as a colorless foam (351 mg, 0.510 mmol, 93%): 1H NMR (400 MHz, CDCl3) d 0.09-0.12 (m, 12H), 0.91 (s, 9H), 0.93 (s, 9H), 2.16 (s, 3H), 2.42-2.46 (m, 1H), 2.70 (ddd, J = 5.9, 5.9, 13.6 Hz, 1H), 3.05 (t, J = 7.8 Hz, 2H), 3.29 (t, J = 7.8 Hz, 2H), 3.77 (dd, J = 2.9, 11.2 Hz, 1H), 3.86 (dd, J = 3.9, 11.2 Hz, 1H), 4.01-4.03 (m, 1H), 4.62-4.64 (m, 1H), 4.97 (brs, 2H), 6.47 (t, J = 6.8 Hz, 1H), 7.03-7.05 (m, 3H), 7.34 (t, J = 7.8 Hz, 2H), 8.25 (s, 1H), 9.06 (brs, 1H); 13C NMR (100 MHz, CDCl3) d -5.5, -5.4, -4.8, -4.7, 15.5, 18.0, 18.4, 25.7, 25.9, 32.6, 38.9, 40.9, 62.8, 68.3, 71.9, 84.4, 87.9, 114.7, 114.9, 122.1, 129.4, 129.7, 141.8, 147.8, 152.2, 157.3, 163.4; HRMS (ESI, positive) m/z [M+Na]+ calcd for C33H53N5O5SSi2Na 710.3198, found 710.3197. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | To a cooled and stirred solution of 2.76 g (12.5 mmol) of 6-APA in 60 mL of water containing 5.25 g (62.5 mmol) of sodium bicarbonate, a solution of 2.76 g (16.2 mmol) phenoxyacetyl chloride in 5 mL of acetone was added in one minute. The resulting mixture was stirred vigorously during 20 min while the temperature was kept at 10-15 C. The clear solution was extracted twice with 15 mL portions of methyl isobutyl ketone (MIBK). The clear aqueous solution was cooled to 5-10 C and acidified to pH 2 with a cold 5.0 mol/L sulfuric acid solution. The acidified aqueous solution was extracted with 50 mL MIBK twice. The MIBK extract was separated, washed with cold water, and dried for 10 min over anhydrous sodium sulfate. After filtration, 10 mL of a 25% solution of potassium 2-ethylhexanoate in butanol was added. The white crystalline material was collected by filtration, washed on the filter with dry acetone and dried in vacuum, yield 3.5 g (80%) penicillin V as a white solid. Mp: 210-211 C (dec.). 1H NMR (400 MHz, DMSO-d6): delta 8.42 (d, 1H, J = 8.0 Hz), 7.27 (m, 2H), 6.92 (m, 3H), 5.42 (dd, 1H, J = 8.0 Hz, 4.0 Hz), 5.40 (d, 1H, J = 4.0 Hz), 4.62 (d, 2H, J = 2.2 Hz), 3.88 (s, 1H), 1.52 (s, 3H), 1.46 (s, 3H); 13C NMR (100 MHz, DMSO-d6): delta 172.8, 169.0, 168.1, 158.1, 130.0, 121.7, 115.0, 74.6, 67.3, 66.7, 65.0, 57.8, 32.7, 27.8; HRMS (FAB) calcd. for C16H18KN2O5S [M+H]+: m/z 389.0584; found: 389.0995. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With potassium carbonate; In benzene; at 20℃; for 1.0h; | General procedure: Phenoxyacetyl chloride (21 mmol) was dropwise added to the mixture of K2CO3 (15.2 mmol, 1.6 g),3-methyl-3,4-dihydro-2H-1,4-benzoxazine (14 mmol) and benzene (34 mL) at room temperature for 1 h.Then the mixture was filtered, and the filtrate was washed and dried over magnesium sulfate anhydrous.The benzene was removed under vacuum. The crude products were recrystallized with EtOAc and lightpetroleum. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With potassium carbonate; In benzene; at 20℃; for 1.0h; | General procedure: Phenoxyacetyl chloride (21 mmol) was dropwise added to the mixture of K2CO3 (15.2 mmol, 1.6 g),3-methyl-3,4-dihydro-2H-1,4-benzoxazine (14 mmol) and benzene (34 mL) at room temperature for 1 h.Then the mixture was filtered, and the filtrate was washed and dried over magnesium sulfate anhydrous.The benzene was removed under vacuum. The crude products were recrystallized with EtOAc and lightpetroleum. |
77.1% | With potassium carbonate; In toluene; at 20 - 25℃; for 1.5h; | General procedure: The phenoxyacetyl chloride (21 mmol) was added dropwise to the 3-methyl-3,4-dihydro-2H-1,4-benzoxazine 3 (14 mmol) dissolved in toluene (30 mL) with anhydrous K2CO3 as the attaching acid agent at 20~25C, and the mixture was stirred for 1.5 h. On completion of the reaction (TLC monitored), the mixture was filtered and washed with water. The organic layer was dried over anhydrous MgSO4 and filtered. After removal of the solvent, the residue was purified by column chromatography on silica gel using petroleum ether/EtOAc as eluent to obtain the target compounds 4a and 4b. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With pyridine; at 0 - 5℃; for 24.5h; | General procedure: To a cold (0-5 C) stirred suspension of aminobenzamides 15a-f and 20a,b (0.016 mol) in pyridine (13 mL), 0.016 mol of the appropriate phenoxyacetyl chloride 16a-e was added over 30 min. After addition was complete, the solution was stirred for24 h and then poured onto crushed ice. The precipitate was removed by filtration, washed with water, and crystallized from the indicated solvent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | With pyridine; at 0 - 5℃; for 24.5h; | General procedure: To a cold (0?5 °C) stirred suspension of aminobenzamides 15a?f and 20a,b (0.016 mol) in pyridine (13 mL), 0.016 mol of the appropriate phenoxyacetyl chloride 16a?e was added over 30 min. After addition was complete, the solution was stirred for24 h and then poured onto crushed ice. The precipitate was removed by filtration, washed with water, and crystallized from the indicated solvent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With pyridine; at 0 - 5℃; for 24.5h; | General procedure: To a cold (0-5 C) stirred suspension of aminobenzamides 15a-f and 20a,b (0.016 mol) in pyridine (13 mL), 0.016 mol of the appropriate phenoxyacetyl chloride 16a-e was added over 30 min. After addition was complete, the solution was stirred for24 h and then poured onto crushed ice. The precipitate was removed by filtration, washed with water, and crystallized from the indicated solvent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With triethylamine In dichloromethane at 20℃; for 2h; | 7-19 Preparation of N-(5-benzyloxy-3,4,6-trimethylpyridine-2-yl)-2-phenoxyacetamide (7s) Example 7-19 Preparation of N-(5-benzyloxy-3,4,6-trimethylpyridine-2-yl)-2-phenoxyacetamide (7s) 0.161 mL (1.155 mmol) of triethylamine and 0.140 mL (0.990 mmol) of phenoxyacetyl chloride were sequentially added to 10 mL of CH2Cl2 containing 200 mg (0.825 mmol) of Compound 6, and then, the mixed solution was stirred at room temperature for 2 hours. The reaction solution was diluted with 100 mL of CH2Cl2, and then, washed with 10 mL of saturated sodium hydrogencarbonate aqueous solution twice and 10 mL of water twice. The CH2Cl2 solution was washed with saturated brine, dried with anhydrous MgSO4, filtered, and then, concentrated under reduced pressure. The residues were purified by column chromatography (EtOAC:Hex=1:2), thereby obtaining 263 mg (85%) of white solids, i.e., Compound 7s. 1H-NMR (250 MHz, CHCl3-d) δ 8.53 (br s, 1H), 7.29-7.47 (m, 7H), 6.94-7.05 (m, 3H), 4.76 (s, 2H), 4.64 (s, 2H), 2.44 (s, 3H), 2.25 (s, 3H), 2.12 (s, 3H) ppm |
85% | With triethylamine In dichloromethane at 20℃; for 2h; | 7-19 Preparation of N-(5-benzyloxy-3,4,6-trimethylpyridine-2-yl)-2-phenoxyacetamide (7s) 0.161 mL (1.155 mmol) of triethylamine and 0.140 mL (0.990 mmol) of phenoxyacetyl chloride were sequentially added to 10 mL of CH2Cl2 containing 200 mg (0.825 mmol) of Compound 6, and then, the mixed solution was stirred at room temperature for 2 hours. The reaction solution was diluted with 100 mL of CH2Cl2, and then, washed with 10 mL of saturated sodium hydrogencarbonate aqueous solution twice and 10 mL of water twice. The CH2Cl2 solution was washed with saturated brine, dried with anhydrous MgSO4, filtered, and then, concentrated under reduced pressure. The residues were purified by column chromatography (EtOAC:Hex=1:2), thereby obtaining 263 mg (85%) of white solids, i.e., Compound 7s. |
85% | With triethylamine In dichloromethane at 20℃; | General procedure for N-(5-hydroxy-3,4,6-trimethylpyridin-2-yl)amides (2) General procedure: Amide formation: To a solution of 8 (1.0 equiv.) in CH2Cl2 (6 mL per 1.0 mmol of 8) was addedEt3N (1.4 equiv.), acid chloride (1.2 equiv.), and the mixture was stirred at room temperature.The mixture was diluted with CH2Cl2 and the aqueous layer was extracted with CH2Cl2. Thecombined organic solution was washed with saturated sodium bicarbonate, water, and brine.The organic solution was then dried over MgSO4, filtered and the filtrate was concentrated invacuo. The residue was purified by silica gel column chromatography to give 9. Debenzylationmethod1: To a solution of 9 in methanol (10 mL per 1.0 mmol of 9) was added palladium (10%on activated carbon, 20 mg per 100 mg of 9). The mixture was stirred with hydrogen balloonat room temperature. The solid in the reaction mixture was filtered through a Celite pad andthe filtrate was filtered again with a syringe membrane filter. The filtrate was concentrated togive 2. Debenzylation-method 2: To a cooled solution of 9 in CH2Cl2 (10 mL per 1.0 mmol of9) was added pentamethylbenzene (3 equiv.) and 1.0 M BCl3 (2 equiv.) at an ice-bath. Themixture was stirred at iced bath. The reaction mixture was quenched with a solution of 10%methanol in chloroform (1 mL) and stirred for additional 1 h at room temperature. The reactionsolution was concentrated and the residue was purified by silica gel column chromatographyto give 2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.103 g | In dichloromethane for 2h; Reflux; | N-(4-Methyl-1,2,5-oxadiazol-3-yl)-2-phenoxyacetamide To a solution of phosphorus pentachloride (0.126 g, 0.610 mmol) in dichloromethane (11 mL), phenoxyacetic acid (0.092 g, 0.610 mmol) was added with stirring and the mixture refluxed for 30-40 minutes. After cooling, 4-methyl-1,2,5-oxadiazol-3-amine (0.060 g, 0.610 mmol) was added and the solution refluxed for 2-2.5 hours. The solvent was removed under reduced pressure and the residue quenched with water (50 mL). The solid was collected by vacuum filtration and washed with saturated sodium bicarbonate solution followed by water to afford compound 19 (0.103 g, 73%), mp 132-134 °C. 1H NMR (500 MHz, CDCl3): δ 8.61 (s, 1H), 7.37 (t, J = 8.25, 2H), 7.10 (t, J = 6.5, 1H), 6.98 (dd, J = 9.0, 1.0, 2H), 4.70 (s, 2H), 2.45 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 167.1, 156.7, 149.8, 148.1, 130.2, 123.1, 114.9, 67.3, 9.53. LRMS (ESI): m/z 256.0 (M+Na)+. HRMS (ESI): (M+H)+ calcd for C11H12N3O3+, 234.0878; found, 234.0878. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With triethylamine In dichloromethane at 20℃; for 2h; | N-(6-(((tert-Butyldimethylsi IyI)oxy)methyl)pyridin-2-yI)-2-phenoxyacetam ide Cl Phenoxyacetyl chloride (0.58 mL, 4.2 mmol) was added to a stirred solution of 6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-amine B (1.0 g, 5.0 mmol) and triethylamine (0.59 mL,4.2 mmol) in DCM (15 mL). After 2 h the reaction mixture was concentrated in vacuo and theresidue was chromatographed on silica (25 g Biotage KP-Sil cartridge) eluting with 10-60%EtOAc I PE to give N-(6-(((tert-butyldimethylsilyl)oxy) methyl) pyridi n-2-yl)-2-phenoxyacetam ideCl (1.5 g, 98%) as a colourless oil.1H NMR (500 MHz, ODd3) O 8.83 (5, 1H), 8.13 (d, J= 8.2 Hz, 1H), 7.75 (t, J= 7.9 Hz, 1H),7.35 (t, J= 8.0 Hz, 2H), 7.29 (d, J= 7.6 Hz, 1H), 7.05 (t, J= 7.4 Hz, 1H), 7.01 (d, J= 8.0 Hz,2H), 4.73 (5, 2H), 4.62 (5, 2H), 0.96 (5, 9H), 0.12 (5, 6H); LCMS (method A): 4.23 mm (374.6,MH). |
98% | With triethylamine In dichloromethane for 2h; | N-(6-(((tert-Butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-2-phenoxyacetamide C2 Phenoxyacetyl chloride (0.58 mL, 4.2 mmol) was added to a stirred solution of 6-(((tert- butyldimethylsilyl)oxy)methyl)pyridin-2-amine B (1.0 g, 5.0 mmol) and triethylamine (0.59 mL, 4.2 mmol) in DCM (15 mL). After 2 hours the reaction mixture was concentrated in vacuo and the residue was chromatographed on silica eluting with 10-60% EtOAc / PE to give Λ/-(6- (((fe/f-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-2-phenoxyacetamide C2 (1.5 g, 98%) as a colourless oil. 1H NMR (500 MHz, CDCb) δ 8.83 (s, 1H), 8.13 (d, J = 8.2 Hz, 1H), 7.75 (t, J = 7.9 Hz, 1H), 7.35 (t, J = 8.0 Hz, 2H), 7.29 (d, J = 7.6 Hz, 1H), 7.05 (t, J = 7.4 Hz, 1H), 7.01 (d, J = 8.0 Hz, 2H), 4.73 (s, 2H), 4.62 (s, 2H), 0.96 (s, 9H), 0.12 (s, 6H); LCMS (method A): 4.23 min (374.6, MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.6% | With triethylamine In dichloromethane at 0 - 20℃; | General procedure for the preparation of enaminoamides 6a-l General procedure: To a mixture of formamidine 4a (0.723 g, 3 mmol), triethylamine (1.214 g, 12 mmol), and CH2Cl2 (3 mL),a solution of phenoxyacetyl chloride 5a (0.768 g, 4.5 mmol) in CH2Cl2 (3 mL) was added over a period of30 min at 0 oC with stirring. The reaction mixture was allowed to warm-up to room temperature and stirred further overnight. The reaction mixture was washed with water (5 mL x 3) and dried over Na2SO4.The solution was passed through short column or by crystallization from MeOH to give pure enaminoamide 6a. |
81.3% | With potassium carbonate In tetrachloromethane at -5 - 20℃; | 1 (E)-N'-(2-Bromophenyl)-N,N-dimethylformamidine (9.08 g, 0.04 mol, CAS No. 53746-69-3),Carbon tetrachloride (30 mL), potassium carbonate (5.53 g, 0.04 mol) and a magnetic particle were added to a 100 mL one-neck round bottom flask.The magnetic stirrer was turned on and the reaction flask was placed in a cold bath at -5 °C.The entire dropwise addition of 2-phenoxyacetyl chloride (10.2 g, 0.06 mol) was slowly added dropwise with a syringe for about 50 minutes.After the addition was completed, the reaction mixture was stirred at room temperature overnight.The solvent was removed by rotary evaporation.Ethyl acetate (20 mL) and water (20 mL) were then added to the reaction flask and stirred for 10 minutes, transferred to a separatory funnel, and the lower inorganic phase was separated.The inorganic phase was extracted with ethyl acetate (10 mL).The organic phases were combined and washed with brine (20 mL) and water (20 mL).The organic phase was dried over anhydrous sodium sulfate.After recovering the solvent by rotary distillation, the residue was applied to silica gel column chromatography (ethyl acetate/hexane: 1:7, v/v)The product (Z)-N-(2-bromophenyl)-3-(dimethylamino)-2-phenoxyacrylamide 0.292 g, yield: 81.3%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86.5% | With piperidine In dichloromethane at 20℃; for 24h; | 9 Example 9: Preparation of 7-phenoxyacetoxy-4'-methoxyisoflavone (I9): 7-Hydroxy-4'-methoxyisoflavone (A9) (0.27 g, 1.0 mmol) was added to the phenoxyacetyl chloride (B3) (0.50 g, 2.0 mmol)In a solution of CH2Cl2 (5 mL),The dried piperidine (200 μL) was then added in portions,Stir at room temperature for 24 h, the reaction was complete by TLC.The solvent was removed, 100 mL of a 1% NaOH solution was added thereto, filtered, washed with distilled water and a small amount of ethanol until pH = 7, and dried.The filter cake was recrystallized from ethanol and water to give 7-phenoxyacetoxy-4'-methoxyisoflavone (I9)0.34g, yield 86.5%, |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With triethylamine In toluene at 0 - 100℃; for 5h; Inert atmosphere; | 4.1.2 General method II: synthesis of 2-azetidinones (Staudinger reaction) General procedure: The appropriate imine (5mmol) and the appropriate acid chloride (7mmol) were dissolved in dry toluene (50mL), under nitrogen with stirring at 0°C. The solution was allowed to reach room temperature and then warmed to 100°C. Dry triethylamine TEA (9mmol) was added dropwise. The mixture was warmed at 100°C for 5h and stirred at room temperature overnight until the starting material had disappeared as monitored by TLC. The reaction mixture was washed with water (2 100mL), dried over anhydrous Na2SO4 and solvent was removed by evaporation in vacuo. The crude product was purified by flash chromatography over silica gel (eluent: 5:1; n-hexane: ethyl acetate). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With triethylamine In toluene at 0 - 100℃; for 5h; Inert atmosphere; | 4.1.2 General method II: synthesis of 2-azetidinones (Staudinger reaction) General procedure: The appropriate imine (5mmol) and the appropriate acid chloride (7mmol) were dissolved in dry toluene (50mL), under nitrogen with stirring at 0°C. The solution was allowed to reach room temperature and then warmed to 100°C. Dry triethylamine TEA (9mmol) was added dropwise. The mixture was warmed at 100°C for 5h and stirred at room temperature overnight until the starting material had disappeared as monitored by TLC. The reaction mixture was washed with water (2 100mL), dried over anhydrous Na2SO4 and solvent was removed by evaporation in vacuo. The crude product was purified by flash chromatography over silica gel (eluent: 5:1; n-hexane: ethyl acetate). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With triethylamine In toluene at 0 - 100℃; for 5h; Inert atmosphere; | 4.1.2 General method II: synthesis of 2-azetidinones (Staudinger reaction) General procedure: The appropriate imine (5mmol) and the appropriate acid chloride (7mmol) were dissolved in dry toluene (50mL), under nitrogen with stirring at 0°C. The solution was allowed to reach room temperature and then warmed to 100°C. Dry triethylamine TEA (9mmol) was added dropwise. The mixture was warmed at 100°C for 5h and stirred at room temperature overnight until the starting material had disappeared as monitored by TLC. The reaction mixture was washed with water (2 100mL), dried over anhydrous Na2SO4 and solvent was removed by evaporation in vacuo. The crude product was purified by flash chromatography over silica gel (eluent: 5:1; n-hexane: ethyl acetate). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | General procedure: To an ice-cooled suspension of sodium hydride (60% in mineral oil, 2 equiv) in CH2Cl2 (10 mL) was added dropwise a solution of compound 3 (1 equiv), in CH2Cl2 (15 mL). After stirring 15 min phenoxyacetyl chloride 4 (2 equiv) was added. The reaction mixture was stirred for 1 h at 0 C, and the temperature was raised to room temperature during 3 h. 20 mL of saturated solution of NaHCO3 was carefully added. The aqueous layer was extracted with CH2Cl2 (3 20 mL). The combined organic phases were dried over MgSO4, and concentrated in vacuum. The crude product was purified by crystallisation (ether petroleum/ethyl acetate (8:2)). tert-Butyl 4-(2-phenoxy-N-phenylacetamido) piperidine-1-carboxylate (5a). Following the general procedure, sodium hydride (60% in mineral oil, 0.723 g, 18.1 mmol) in CH2Cl2 (10 mL) was added dropwise a solution of compound 3a (2.5 g, 9.05 mmol), in CH2Cl2 (15 mL). After stirring 15 min phenoxyacetyl chloride (2.5 mL, 18.1 mmol) was added to give compound 5a (3.06 g, 82%). 1H-NMR (CDCl3): 1.25(m, 2H, CH2); 1.4 (s, 9H); 1.8 (m, 2H, CH2); 2.9 (m, 2H, CH2); 4.1 (m, 2H, CH2); 4.25 (m, 2H, CH2); 4.8 (m, 1H, CH); 6.7-7.5 (m, 10H aromatic). 13C-NMR (CDCl3) : 28.456 (3 CH3, C(CH3)3); 30.32 (2CH2); 43.315 (2 CH2); 52.96 (CH); 66.7 (CH2); 79.73 (C); 114.8 (2 CHAr); 121.47 (CHAr); 129.34 (CH);129.46 (2 CHAr); 129.88 (2 CHAr); 130.09 (2 CHAr); 136.89 (C); 154.63 (C); 158.14 (C); 167.6 (C). ESI(m/z) calcd for C24H30N2O4 410, 2 found 411.1 [M + 1], IR cm-1: 1744.95 (CO carbamate); 1652.06 (CO,amide). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | Stage #1: tert-butyl 4-((3-fluorophenyl)amino)piperidine-1-carboxylate With sodium hydride In dichloromethane; mineral oil for 0.25h; Cooling with ice; Stage #2: Phenoxyacetyl chloride In dichloromethane; mineral oil at 0 - 20℃; for 4h; | 3.2.2. General Procedure for the Coupling with Phenoxyacetyl chloride: Synthesis of Compounds 5a-b General procedure: To an ice-cooled suspension of sodium hydride (60% in mineral oil, 2 equiv) in CH2Cl2 (10 mL) was added dropwise a solution of compound 3 (1 equiv), in CH2Cl2 (15 mL). After stirring 15 min phenoxyacetyl chloride 4 (2 equiv) was added. The reaction mixture was stirred for 1 h at 0 °C, and the temperature was raised to room temperature during 3 h. 20 mL of saturated solution of NaHCO3 was carefully added. The aqueous layer was extracted with CH2Cl2 (3 20 mL). The combined organic phases were dried over MgSO4, and concentrated in vacuum. The crude product was purified by crystallisation (ether petroleum/ethyl acetate (8:2)). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With triethylamine In dichloromethane at 0 - 20℃; for 5.5h; Inert atmosphere; | 1-(2-Benzoyl-1-pyrrolidinyl)-3-phenoxy-4,4-diphenyl-2-azetidinone (12) To a solution of 2-acyl pyrrolidine 4a (70.9 mg, 0.20 mmol) and Et3N (66.9 mL, 0.48 mmol) in CH2Cl2 (2.0 mL) was added dropwise phenoxyacetyl chloride (55.0 mL, 0.40 mmol) in CH2Cl2 (0.40 mL) at 0 °C under an argon atmosphere. After being stirred at room temperature for 5.5 h, the reaction mixture was quenched with H2O (3 mL) and extracted with CHCl3. The organic phase was dried over MgSO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography (nhexane/AcOEt = 10/1 to 1/1) to afford 12 (97.0 mg, 99 % yield, dr = 6 : 1) as a white solid. IR (KBr) nmax 1753, 1696 cm-1; 1H NMR (300 MHz, CDCl3) δ: 7.79-6.78 (m, 20H), 5.61 (s, 1/7H), 5.55 (s, 6/7Hz), 5.31 (dd, J = 10.5, 4.0 Hz, 1/7H), 4.97 (dd, J = 10.0, 3.5 Hz, 6/7H), 3.81-3.64 (m, 12/7H), 3.53-3.45 (m, 1/7H), 3.29-3.22 (m, 1/7H), 2.65-2.47 (m, 1H), 2.21-1.78 (m, 3H); 13C NMR (75 MHz, CDCl3) δ: 198.2 (2C), 165.9, 165.6, 157.2 (2C), 139.3, 138.7, 137.7, 137.5, 135.21, 135.16, 133.0, 132.9, 129.32, 129.28, 129.1, 128.5, 128.44, 128.38, 128.3, 128.2, 128.1, 128.0, 127.9, 127.8, 127.5, 127.3, 122.5, 122.4, 116.8, 116.4, 84.7, 84.5, 76.4, 76.0, 69.0, 68.9, 56.7, 55.4, 30.8, 30.3, 24.5, 24.2; HRMS (ESI) m/z: [M + H]+ Calcd for C32H29O3N2 489.2173; Found 489.2170. Four of aromatic carbons overlapped with other aromatic carbons in 13C NMR spectrum. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With potassium hydrogenfluoride; tetrabutyl-ammonium chloride; water In dichloromethane at 20℃; for 0.333333h; Cooling with ice; | Preparation of Acyl Fluorides 2; General Procedure General procedure: A 250 mL round-bottomed flask was charged with potassium bifluoride(15.62 g, 200 mmol) and water (40.17 g), and stirred at ambienttemperature for 1 h. Then tetrabutylammonium chloride (0.279 g, 1.0mmol, 1 mol%), DCM (used in two-fold volume of acyl chloride) andacyl chloride (1a-y; 100 mmol) were added, and the mixture wasstirred (1400 rpm) with a magnetic bar (fish; 15 × 33 mm) at r.t. forthe time given in the characterization data. The mixture was thentransferred to a separatory funnel, separated, and the aqueous phasewas extracted with DCM (50 mL). The combined organic phases werewashed with brine (50 mL), and dried with MgSO4. The mixture wasfiltered and evaporated, and the residue was distilled under reducedpressure to obtain product 2a-y. |
Tags: 701-99-5 synthesis path| 701-99-5 SDS| 701-99-5 COA| 701-99-5 purity| 701-99-5 application| 701-99-5 NMR| 701-99-5 COA| 701-99-5 structure
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