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CAS No. : | 93-40-3 | MDL No. : | MFCD00004335 |
Formula : | C10H12O4 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | WUAXWQRULBZETB-UHFFFAOYSA-N |
M.W : | 196.20 | Pubchem ID : | 7139 |
Synonyms : |
|
Num. heavy atoms : | 14 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.3 |
Num. rotatable bonds : | 4 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 50.97 |
TPSA : | 55.76 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.82 cm/s |
Log Po/w (iLOGP) : | 1.67 |
Log Po/w (XLOGP3) : | 0.95 |
Log Po/w (WLOGP) : | 1.33 |
Log Po/w (MLOGP) : | 1.09 |
Log Po/w (SILICOS-IT) : | 1.59 |
Consensus Log Po/w : | 1.33 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -1.71 |
Solubility : | 3.84 mg/ml ; 0.0196 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.71 |
Solubility : | 3.84 mg/ml ; 0.0196 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -2.44 |
Solubility : | 0.721 mg/ml ; 0.00367 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.62 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H319-H335 | Packing Group: | N/A |
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 |
---|---|---|
98.9% | With sodium tetrahydroborate; iodine In tetrahydrofuran at 20℃; for 0.583333 h; Cooling with ice | Take a dry and clean 100 mL round bottom flask, accurately weigh sodium borohydride (0.4 g, 7.65 mmol) and iodine (1.3 g, 5.10 mmol) in a bottle, add 10 mL of tetrahydrofuran, place in an ice bath, stir After 5 min, 21 (1.0 g, 5.10 mmol) was added in small portions. After the addition, the ice bath was removed and the reaction was carried out at room temperature. The reaction was monitored by TLC. After 30 min, the reaction was completed by TLC. 50 ml of a 5percent sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL × 3), and the organic phase was combined and washed with brine (10 mL × 3). The organic phase was separated, dried over anhydrous sodium sulfate, filtered and evaporatedThe title compound (22) was obtained as a yellow oil.The yield was 98.9percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | Reflux | Methyl 2-(3,4-dimethoxyphenyl)acetate SLA 28134 To a solution of 2-(3,4-dimethoxyphenyl)acetic acid (25.0 g, 127.4 mmol) in MeOH (100 mL) in a 500 mL round-bottomed flask equipped with a magnetic stirrer was added a catalytic amount of sulfuric acid (around 10 drops) and the mixture was stirred overnight under reflux. After cooling to RT, MeOH was removed at 40° C. under vacuum and the product was taken up in CH2Cl2 (250 mL), washed with water (5*20 mL), brine (20 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give methyl 2-(3,4-dimethoxyphenyl)acetate SLA 28134 as an orange oil (25.77 g, 96percent yield). MW: 210.23; Yield: 96percent; Orange oil. Rf: 0.25 (cyclohexane:EtOAc=3:1). 1H-NMR (CDCl3, δ): 3.56 (s, 2H, CH2), 3.70 (s, 3H, CH3), 3.87 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 6.82-6.83 (m, 3H, 3*ArH). 13C-NMR (CDCl3, δ): 40.6, 51.9, 55.8 (2*C), 111.2, 112.4, 121.4, 126.4, 148.2, 148.9, 172.2. MS-ESI m/z (percent rel. Int.): 233.2 ([M+Na]+, 3), 151.1 (100). |
93.3% | Stage #1: With 1,1'-carbonyldiimidazole In dichloromethane at 20℃; for 1 h; Stage #2: at 20℃; for 1 h; |
To a 1 L three-necked flask was added Compound 7a (50 g, 0.255 mol), 250 ml of dichloromethane,Stir at room temperature,Carbonyldiimidazole (62 g, 0.382 mol) was added in batches and reacted for 1 h at room temperature.Add 50ml of methanol, stir for 1h,The reaction solution was poured into a separatory funnel, 200 ml of water was added for extraction, and the organic layer was collected and dried over anhydrous sodium sulfate.The mixture was filtered and the filtrate was evaporated to dryness under reduced pressure to give 50 g of compound 6a in a yield of 93.3percent. |
88% | at 120℃; for 0.333333 h; Microwave irradiation | General procedure: In a typical reaction, AMA 2:3 (332 g, 0.6 mol), the corresponding carboxylicacid (1 mol), and alcohol (1.5–2 mol) were mixed in the provided reaction glass tubeequipped with a screw cap and magnetic agitation until a wet mixture was achieved.The reaction mixture was irradiated with microwaves (Anton Parr Monowave 300reactor) at 80 C for 8 min or 120 C for 20 min. On cooling, the mixture was diluted with dichloromethane (41 mL), filtered under gravity, and washed with dichloromethane;then the filtrate was washed with Na2CO3 (ss) and water. The organic layerwas dried over Na2SO4, filtered, and concentrated under reduced pressure to give theester. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | at 120℃; for 0.333333 h; Microwave irradiation | General procedure: In a typical reaction, AMA 2:3 (332 g, 0.6 mol), the corresponding carboxylicacid (1 mol), and alcohol (1.5–2 mol) were mixed in the provided reaction glass tubeequipped with a screw cap and magnetic agitation until a wet mixture was achieved.The reaction mixture was irradiated with microwaves (Anton Parr Monowave 300reactor) at 80 C for 8 min or 120 C for 20 min. On cooling, the mixture was diluted with dichloromethane (41 mL), filtered under gravity, and washed with dichloromethane;then the filtrate was washed with Na2CO3 (ss) and water. The organic layerwas dried over Na2SO4, filtered, and concentrated under reduced pressure to give theester. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | sulfuric acid; In dichloromethane;Reflux; | Methyl 2-(3,4-dimethoxyphenyl)acetate SLA 28134 To a solution of 2-(3,4-dimethoxyphenyl)acetic acid (25.0 g, 127.4 mmol) in MeOH (100 mL) in a 500 mL round-bottomed flask equipped with a magnetic stirrer was added a catalytic amount of sulfuric acid (around 10 drops) and the mixture was stirred overnight under reflux. After cooling to RT, MeOH was removed at 40 C. under vacuum and the product was taken up in CH2Cl2 (250 mL), washed with water (5*20 mL), brine (20 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give methyl 2-(3,4-dimethoxyphenyl)acetate SLA 28134 as an orange oil (25.77 g, 96% yield). MW: 210.23; Yield: 96%; Orange oil. Rf: 0.25 (cyclohexane:EtOAc=3:1). 1H-NMR (CDCl3, delta): 3.56 (s, 2H, CH2), 3.70 (s, 3H, CH3), 3.87 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 6.82-6.83 (m, 3H, 3*ArH). 13C-NMR (CDCl3, delta): 40.6, 51.9, 55.8 (2*C), 111.2, 112.4, 121.4, 126.4, 148.2, 148.9, 172.2. MS-ESI m/z (% rel. Int.): 233.2 ([M+Na]+, 3), 151.1 (100). |
93.3% | To a 1 L three-necked flask was added Compound 7a (50 g, 0.255 mol), 250 ml of dichloromethane,Stir at room temperature,Carbonyldiimidazole (62 g, 0.382 mol) was added in batches and reacted for 1 h at room temperature.Add 50ml of methanol, stir for 1h,The reaction solution was poured into a separatory funnel, 200 ml of water was added for extraction, and the organic layer was collected and dried over anhydrous sodium sulfate.The mixture was filtered and the filtrate was evaporated to dryness under reduced pressure to give 50 g of compound 6a in a yield of 93.3%. | |
88% | With alumina methanesulfonic acid; at 120℃; for 0.333333h;Microwave irradiation; | General procedure: In a typical reaction, AMA 2:3 (332 g, 0.6 mol), the corresponding carboxylicacid (1 mol), and alcohol (1.5-2 mol) were mixed in the provided reaction glass tubeequipped with a screw cap and magnetic agitation until a wet mixture was achieved.The reaction mixture was irradiated with microwaves (Anton Parr Monowave 300reactor) at 80 C for 8 min or 120 C for 20 min. On cooling, the mixture was diluted with dichloromethane (41 mL), filtered under gravity, and washed with dichloromethane;then the filtrate was washed with Na2CO3 (ss) and water. The organic layerwas dried over Na2SO4, filtered, and concentrated under reduced pressure to give theester. |
Acidic conditions; Heating / reflux; | A solution of 3,4-dimethoxyphenyl acetic acid (50 mM) in MeOH (100 mL) with concentrated sulfuric acid (conc. H2SO4, 1 mL) or concentrated hydrochloric acid (conc. HCl) was heated at reflux overnight. Concentration to dryness on a rotary evaporator and high vacuum pump overnight gave the ester as an oil which was used directly in the next step. | |
Acidic conditions; Heating / reflux; | EXAMPLE 1; Preparation of 4-[(3-chlorophenyl)amino]-5-(3,4-dimethoxyphenyl)nicotinitrile; A solution of 3,4-dimethoxyphenyl acetic acid (50 mM) in methanol (MeOH, 100 mL) with concentrated sulfuric acid (H2SO4, 1 mL) or concentrated hydrochloric acid (HCl) was heated at reflux overnight. Concentration to dryness on a rotary evaporator and high vacuum pump overnight gave 3,4-dimethoxy-phenyl)acetic acid methyl ester as an oil which was used directly in the next step. | |
With acetyl chloride; at 0 - 20℃;Inert atmosphere; | Methyl 2-diazo-2-(3,4-dimethoxyphenyl)acetate (2g)In a flame dried round bottom flask, 2-(3,4-dimethoxyphenyl) acetic acid (50 mmol, 1 eq.) was dissolved in MeOH (100 mL) and cooled to 0 C. Acetyl chloride (60 mmol, 1.2 eq.) was added drop wise at 0 C. The resultant reaction mixture was stirred at rt for overnight. The reaction mixture was poured in to a separation funnel having ethyl ether and saturated NH4C1 solution. Extracted twice; combined organic layers were washed with brine, dried over MgS04 and concentrated in vacuo. The crude methyl acetate mixture was taken to next step without further purification. | |
Manufacturing Example 1: Preparation of Methyl 2-(3,4-dimethoxyphenyl)acetate (32) carboxylic acid (1 equivalent) and anhydrous DMF (catalytic amount) were dissolved in anhydrous CH2Cl2 (0.1 M). After lowering the temperature of the mixture to 0C, oxalic acid (3 equivalent) was added drop by drop to the mixture. After stirring the mixture at room temperature for 30 minutes, anhydrous methanol (50 equivalent) was added drop by drop, followed by stirring again for 10 minutes. Then, the mixture was treated with water. The water layer was extracted with CH2Cl2 and the organic layer was dried over MgSO4, followed by filtering. After concentrating the mixture under reduced pressure, the residue was purified by flash column chromatography (EtOAc:n-hexane=1:3) to give the compound 32. 1H NMR (CDCl3, 300 MHz) delta 6.79 (s, 3H), 3.86 (s, 3H), 3.84 (s, 3H), 3.67 (s, 3H), 3.55 (s, 2H). | ||
carboxylic acid (1 equivalent) and anhydrous DMF (catalytic amount) were dissolved in anhydrous CH2Cl2 (0.1 M). After lowering the temperature of the mixture to 0 C., oxalic acid (3 equivalent) was added drop by drop to the mixture. After stirring the mixture at room temperature for 30 minutes, anhydrous methanol (50 equivalent) was added drop by drop, followed by stirring again for 10 minutes. Then, the mixture was treated with water. The water layer was extracted with CH2Cl2 and the organic layer was dried over MgSO4, followed by filtering. After concentrating the mixture under reduced pressure, the residue was purified by flash column chromatography (EtOAc:n-hexane=1:3) to give the compound 32. [0162] 1H NMR (CDCl3, 300 MHz) delta 6.79 (s, 3H), 3.86 (s, 3H), 3.84 (s, 3H), 3.67 (s, 3H), 3.55 (s, 2H) | ||
With thionyl chloride; at 65℃; | General procedure: To a solution of the aryl acetic acid (12.0 mmol, 1.00 equiv) in methanol (60 mL) was added thionyl chloride (2.63 mL, 36.0 mmol, 3.00 equiv). The solution was heated to reflux. Upon completion (as determined by TLC analysis), the solution was concentrated in vacuo and the crude residue was used without further purification.To a flame-dried round-bottom flask with a magnetic stir bar were added the aryl acetic acid ester (12.0 mmol, 1.00 equiv), p-ABSA (3.46 g, 14.4 mmol, 1.20 equiv), and dry acetonitrile (50 mL). The solution was stirred under nitrogen and cooled to 0 C using an ice water bath. DBU (1.97 mL, 13.2 mmol, 1.10 equiv) was added by syringe rapidly in one portion, and the reaction mixture was allowed to warm to 23 C and stir overnight. Upon completion (as determined by TLC analysis) or after 24 hours, whichever came first, the reaction mixture was quenched with saturated aqueous ammonium chloride (50 mL) and extracted with ether (3 x 50 mL). The combined organic layers were washed with brine (1 x 100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography using a mixture of hexanes and ethyl acetate as eluent. The aryl diazoacetates were obtained in 23-70% yield over two steps. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With alumina methanesulfonic acid; at 120℃; for 0.333333h;Microwave irradiation; | General procedure: In a typical reaction, AMA 2:3 (332 g, 0.6 mol), the corresponding carboxylicacid (1 mol), and alcohol (1.5-2 mol) were mixed in the provided reaction glass tubeequipped with a screw cap and magnetic agitation until a wet mixture was achieved.The reaction mixture was irradiated with microwaves (Anton Parr Monowave 300reactor) at 80 C for 8 min or 120 C for 20 min. On cooling, the mixture was diluted with dichloromethane (41 mL), filtered under gravity, and washed with dichloromethane;then the filtrate was washed with Na2CO3 (ss) and water. The organic layerwas dried over Na2SO4, filtered, and concentrated under reduced pressure to give theester. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.9% | With hydrogenchloride; acetic acid In water at 80℃; for 6h; | 1.1 (1) Add 520 g of a 10% by mass aqueous solution of dilute hydrochloric acid to the reaction vessel.Add 100g of 3,4-dimethoxyphenylacetic acid with stirring at room temperatureAnd 1.53g of glacial acetic acid;After the addition is completed, the reaction is carried out at 80 ° C for 6 h;Sampling, HPLC detection of the complete reaction of the raw materials;The reaction solution was lowered to 60 ° C, and water was distilled off under reduced pressure.Add 200 mL of isopropyl ether to the remaining oil.Then it was frozen in a refrigerator (0 ° C) overnight, a white solid precipitated, and filtered.The filter cake was washed with isopropyl ether.Drying at 55 ° C to obtain pure 3,4-dihydroxyphenylacetic acid,83.5 g, the yield was 96.9%. |
With phosphorus; hydrogen iodide | ||
With boron dimethyl-trifluoro sulphide In dichloromethane at 20℃; for 24h; Darkness; Cooling with ice; | 2-(3,4-dihydroxyphenyl)acetic acid (34) To an ice-cold solution of 2-(3,4-dimethoxyphenyl)acetic acid (10.2 mmol, 2.0 g) in dry CH2C12 (40 mL), BF3S(CH3)2 (101.9 mmol, 10.7 mL) was added dropwise. The reaction mixture was then stirred at ambient temperature, in the dark, for 24 h. Upon completion of the reaction, the solvent was evaporated under nitrogen flow. The desired product 34 was obtained as a yellowoil and used to the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With nitric acid at 0 - 5℃; | |
90% | With nitric acid In acetone at 10 - 25℃; for 3.08333h; | |
90% | With nitric acid; acetic acid at 10 - 25℃; for 3h; |
85% | With nitric acid In acetic acid at 0℃; for 2h; | |
82% | With nitric acid In tetrahydrofuran at 0 - 20℃; | |
79.3% | With nitric acid; acetic acid at 15 - 35℃; for 0.75h; | 1 Preparation of (E)-1, 3-dihydro-4-hydroxybenzylidene-5,6- dimethoxy- (lH)-indol-2-one.; 1) Synthesis of 2-nitro-4, 5-dimetoxvphenylacetic acid; 3, 4-Dimetoxyphenylacetic acid (45 g, 0. 23 moles, 1 eq. ) was dissolved in glacial acetic acid at 28°C-35°C, (100 mL, 2.2 volumes) under N2 atmosphere and with mechanical stirring. The solution was cooled to 15-20°C and a mixture of fuming nitric acid (98%, 33 mL) in glacial acetic acid (25 mL) was added in 45'. After completion of the addition, a red solid precipitated. The suspension was poured into ice-H2O (600 mL) and kept under stirring for 2 h. The solid was filtered, washed with H2O and dried at 60°C for 8 h. to obtain 44 g of the desired product. Yield 79.3% (mmoles/mmoles) TLC (Si02 ; ethyl acetate 10/AcOH 0.5) Rf acid = 0. 6 ; Rf product = 0. 5 M. p.: 199-202°C 'H-NMR, (DMSO): 3.9 ppm (s, 6H); 4.0 ppm (s. , 2H); 7.12 ppm (s. , 1H); 7.7 ppm (s. , 1H). |
79.3% | With nitric acid; acetic acid at 15 - 20℃; for 0.75h; | 1 3,4-Dimetoxyphenylacetic acid (45 g, 0.23 moles, 1 eq.) was dissolved in glacial acetic acid at 28° C.-35° C., (100 mL, 2.2 volumes) under N2 atmosphere and with mechanical stirring. The solution was cooled to 15-20° C. and a mixture of fuming nitric acid (98%, 33 mL) in glacial acetic acid (25 mL) was added in 45'. After completion of the addition, a red solid precipitated. The suspension was poured into ice-H2O (600 mL) and kept under stirring for 2 h. The solid was filtered, washed with H2O and dried at 60° C. for 8 h. to obtain 44 g of the desired product. Yield 79.3% (mmoles/mmoles) TLC (SiO2; ethyl acetate 10/AcOH 0.5) Rfacid=0.6; Rfproduct=0.5 M.p.: 199-202° C. 1H-NMR, (DMSO): 3.9 ppm (s, 6H); 4.0 ppm (s., 2H); 7.12 ppm (s., 1H); 7.7 ppm (s., 1H). |
With nitric acid | ||
With nitric acid; acetic acid | ||
With nitric acid In acetic acid | ||
With nitrating agent | ||
With nitric acid; acetic acid | 1.a 7-[2-(2-Aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]-3-[(1-(2-carboxymethyl-3-chloro-4,5-dihydroxyphenyl)tetrazol-5-yl)thiomethyl]ceph-3-em-4-carboxylic acid a) 3,4-Dimethoxyphenylacetic acid (7.84 g) was solubilized in ether (100 ml) and acetic acid (20 ml). Fuming nitric acid (1.68 ml) was added dropwise to the solution. Stirring was maintained at room temperature for 16 hours. The precipitate was collected by filtration, washed with ether and dried to give 4,5-dimethoxy-2-nitrophenylacetic acid (4.19 g); NMR (DMSO-d6) 3.88(s,3H); 3.80(s,3H); 3.97(s,2H); 7.15(s,1H); 7.70(s,1H). | |
In nitric acid | S.a (a) (a) 4,5-Dimethoxy-2-nitro-phenylacetic acid First, 3,4-dimethoxyphenylacetic acid (49.05 g, 0.25 mol) is added in batches to concentrated nitric acid (500 ml), with cooling, at 30° C. and stirred for a further 15 minutes with cooling. The reaction mixture is poured onto ice water (1.5 liters), the precipitate obtained is suction filtered, washed with ice water until neutral and dried. Yield: 56.4 g. Mp: 209°-211° C. | |
T.a (a) (a) 4,5-Dimethoxy-2-nitro-phenylacetic acid The title compound here is prepared from 3,4-dimethoxy phenylacetic acid (49.05 g, 0.25 mol) analogously to Example S(a). Yield: 56.4 g. Mp: 209°-211° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With bromine In dichloromethane | |
95% | With bromine; acetic acid at 20℃; for 3h; | 1.1 1) Synthesis of compound (2) Dissolve 72 g of 3,4-dimethoxyphenylacetic acid in 600 mL of glacial acetic acid.After stirring at room temperature for 1 h, 7.2 g of bromine in glacial acetic acid (60 mL) was added and the reaction was continued for 2 h.Add 200mL of ice water, a white precipitate is formed, and filtered.After the filter cake was recrystallized from methanol, 96 g of the compound (2) was obtained.The yield is about 95%. |
95% | With bromine; acetic acid at 20℃; for 3h; | 1.1 1) Synthesis of compound (2): Dissolve 72 g of 3,4-dimethoxyphenylacetic acid in 600 mL of glacial acetic acid.After stirring at room temperature for 1 h, 7.2 g of bromine in glacial acetic acid (60 mL) was added.After continuing to react for 2 hours, 200 mL of ice water was added and a white precipitate formed.After filtration, the filter cake was recrystallized from methanol to give 96 g of compound (2).The yield is about 95%. Compound (2) is a white solid. |
95% | Stage #1: (3,4-Dimethoxyphenyl)acetic acid With acetic acid at 20℃; for 1h; Stage #2: With bromine; acetic acid for 2h; | 1.1 Synthesis of compound (2): 72 g of 3,4-dimethoxyphenylacetic acid was dissolved in 600 mL of glacial acetic acid, and stirred at room temperature for 1 hour, then 7.2 g of bromine in glacial acetic acid (60 mL) was added. After the reaction was continued for 2 hours, 200 mL of ice water was added, and white was added. The precipitate formed, filtered, and the cake was recrystallized from methanol to give 96 g of Compound (2). |
95% | Stage #1: (3,4-Dimethoxyphenyl)acetic acid With acetic acid at 20℃; for 1h; Stage #2: With bromine; acetic acid at 20℃; for 2h; | 1.1 1) Synthesis of Compound (2): After 72g 3,4- dimethoxyphenylacetic acid was dissolved in 600mL of glacial acetic acid was added after stirring at room temperature 1h 7.2g bromine in glacial acetic acid (60 mL) solution, the reaction was continued for 2h, 200mL of ice water, white the resulting precipitate was filtered, the filter cake was recrystallized from methanol to give compound 96g (2), a yield of about 95%. |
91% | With bromine In acetic acid at 20℃; for 3h; | |
91% | With bromine; acetic acid at 0 - 60℃; for 1h; Inert atmosphere; | 2-(2-Bromo-4,5-dimethoxyphenyl)acetic acid (9) 2-(3,4-dimethoxyphenyl)acetic acid (5.00 g, 25.5 mmol) was dissolved in glacial acetic acid (10 mL) and cooled to 0 C. Br2(1.31 mL, 25.5 mmol) dissolved in glacial acetic acid (10 mL) was added dropwise. The ice bath was removed, and the reaction was heated at 60 C for 1 h. Upon completion, the reaction mixture was cooled, poured into ice water, and the precipitate was filtered off.This solid was washed with Na2S2O3 (sat., aq.) and H2O to afford the title compound 9 (6.41 g, 23.3 mmol, 91%) as white solid. Rf 0.48(EtOAc); 1H NMR (500 MHz, CDCl3) d 7.04 (s, 1H), 6.79 (s, 1H), 3.86(s, 3H), 3.86 (s, 3H), 3.77 (s, 2H); 13C NMR (126 MHz, CDCl3) d 176.4,149.1, 148.5,125.4, 115.5, 115.2,114.0, 56.3, 56.2, 41.0; IR (nmax/cm1)3550, 1688, 1417, 1281, 1189, 1144, 1045; HRMS (ES) calc. forC10H10O479Br [M H]e 272.9768, found 272.9767; mp 113e114 C. |
90% | With sodium hydroxide; bromine In water at 50℃; for 0.5h; | |
82% | With bromine | |
80.5% | With bromine In acetic acid for 3h; Ambient temperature; | |
80% | With bromine In chloroform for 2h; | |
With acetic acid durch Bromierung; | ||
With bromine | ||
With bromine; sodium acetate 2) 0 deg C, 30 min; Yield given. Multistep reaction; | ||
With bromine |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With N-iodo-succinimide; trifluoroacetic acid In acetonitrile at 20℃; | |
92% | With Iodine monochloride In acetic acid at 20℃; for 1.5h; | |
86% | With Iodine monochloride In dichloromethane; acetic acid |
82% | With Iodine monochloride In acetic acid at 20℃; for 2h; | |
79% | With Iodine monochloride; acetic acid In dichloromethane Inert atmosphere; | |
44.8% | With Iodine monochloride In acetic acid at 20℃; | 6.K.1 Step 1 Step 1 (2-iodo-4,5-dimethoxy-phenyl)-acetic acid 3,4-Dimethoxyphenylacetic acid (4.0 g, 20.4 mmol) was dissolved in 100 ml of glacial acetic acid. Iodine monochloride (1.35 eq, 1.38 ml) was added slowly and the mixture was allowed to stir at room temperature overnight. To the mixture was added 300 ml of a 10% aqueous solution of sodium bisulfite. The mixture was concentrated in vacuo to remove most of the acetic acid. The aqueous residue was extracted with EtOAc. The organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with diethyl ether and the solid was then filtered and dried to give (2-iodo-4,5-dimethoxy-phenyl)-acetic acid (2.94 g, 44.8%) as an off-white solid. |
With Iodine monochloride; acetic acid | ||
With Iodine monochloride | ||
With [bis(acetoxy)iodo]benzene; iodine; palladium diacetate In N,N-dimethyl-formamide at 60℃; for 12h; Darkness; | ||
With [bis(acetoxy)iodo]benzene; iodine; palladium diacetate In N,N-dimethyl-formamide at 60℃; for 24h; Inert atmosphere; | ||
With Iodine monochloride In acetic acid for 2h; | ||
With N-iodo-succinimide; sulfuric acid; acetic acid at 20℃; for 1h; Dean-Stark; | (2-Iodo-4,5-dimethoxyphenyl)acetic Acid (10) General procedure: To a solution of 3,4-dimethoxyphenylacetic acid (11; 2.00 g, 10.2 mmol) and N-iodosuccinimide (2.43 g, 10.8 mmol) in AcOH (32 mL) was added dropwise concd H2SO4 (1.08 mL) and the reaction mixture was stirred 1 h at r.t. The precipitate formed was filtered, washed with sat. aq Na2S2O3 and recrystallized from H2O/EtOH (20:1) and dried using azeotrope water distillation with benzene in a Dean-Stark apparatus. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With thionyl chloride In dichloromethane | |
100% | With oxalyl dichloride In N,N-dimethyl-formamide; toluene at 20℃; for 1.5h; Inert atmosphere; | |
96% | With oxalyl dichloride In benzene |
96% | With oxalyl dichloride In dichloromethane at 20℃; | |
96% | With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 27℃; for 2h; Cooling with ice; | 4.b b) (3,4-Dimethoxyphenyl)acetyl chloride b) (3,4-Dimethoxyphenyl)acetyl chloride 5 μl of dimethylformamide and then, dropwise, 10.93 ml (127.42 mmol) of oxalyl chloride are added to the solution of 5.00 g (25.48 mmol) of 3,4-dimethoxyphenylacetic acid in 100 ml of dichloromethane with ice-cooling and stirring, and, after removal of the cooling, the mixture is stirred at room temperature for two hours. The reaction mixture is subsequently evaporated to dryness in vacuo, the residue is taken up in 10 ml of toluene, the toluene is stripped off again, the residue is taken up again in 10 ml of toluene, and the toluene is stripped off again. The residue was finally taken up twice in 10 ml of diethyl ether each time, and the diethyl ether was stripped off again, giving 5.5 g (96%) of (3,4-dimethoxyphenyl)acetyl chloride, which is reacted further without additional purification. |
84% | With thionyl chloride | |
84% | With thionyl chloride In toluene for 1h; Heating; | |
81% | With thionyl chloride In dichloromethane for 1h; Heating; | |
81% | With thionyl chloride In ethanol | a (a) (a) 3,4-Dimethoxyphenylacetyl chloride 29.5 g of 3,4-dimethoxyphenyl-acetic acid are dissolved in 200 cc of anhydrous chloroform free from ethanol. There is then added 23.8 g of thionyl chloride. The mixture is warmed under reflux for four hours. The solvent and the excess of reagent are then removed under reduced pressure. The oily residue is distilled under reduced pressure (10 mmHg) collecting the fraction which distills at 170°-172° C. The pure acid chloride is thus obtained; 26 g, yield 81%. |
80% | With thionyl chloride In dichloromethane; N,N-dimethyl-formamide at 20℃; | |
79% | With thionyl chloride | |
With thionyl chloride; chloroform | ||
With thionyl chloride | ||
With thionyl chloride | ||
With thionyl chloride for 5h; Ambient temperature; | ||
With thionyl chloride In 1,2-dichloro-ethane at 80℃; for 3h; | ||
With thionyl chloride In benzene for 2h; Heating; | ||
With phosphorus pentachloride In dichloromethane | ||
With thionyl chloride In benzene Heating; | ||
With thionyl chloride In dichloromethane for 1h; Heating; | ||
With thionyl chloride In diethyl ether for 0.5h; Heating; | ||
With thionyl chloride for 1h; Heating; | ||
With oxalyl dichloride In benzene for 1h; Ambient temperature; | ||
With thionyl chloride at 20℃; for 3h; | ||
With oxalyl dichloride In benzene at 50 - 60℃; | ||
With thionyl chloride In chloroform | ||
With thionyl chloride In toluene for 3h; Heating; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane | ||
With thionyl chloride In chloroform Heating; | ||
With thionyl chloride for 2h; Heating; | ||
With thionyl chloride; N,N-dimethyl-formamide at 0℃; for 5h; | ||
With thionyl chloride for 1h; Heating; | ||
With pivaloyl chloride; triethylamine In tetrahydrofuran at -78℃; | ||
With thionyl chloride In tetrahydrofuran for 2h; Heating; | ||
With thionyl chloride; N,N-dimethyl-formamide In benzene for 3h; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In benzene at 20℃; for 2h; | ||
With oxalyl dichloride In ethyl acetate | ||
With thionyl chloride In toluene for 3h; Heating; | ||
With thionyl chloride In dichloromethane | 1.6 1.1.N-(2-Hydroxyphenyl)trifluoroacetamide. 1.6. 3,4-Dimethoxyphenylacetyl chloride. 103.7 ml (1.42 mol) of thionyl chloride are added to 95 g (0.48 mol) of 3,4-dimethoxyphenylacetic acid in solution in 200 ml of dichloromethane. The mixture is left with stirring at room temperature for 18 hours. The solvents are evaporated. 1.4 g of crude product are isolated in the form of a brownish oil. | |
With oxalyl dichloride In 1,2-dichloro-ethane; N,N-dimethyl-formamide at 20℃; for 1h; | (3,4-Dimethoxy-phenyl)-acetic acid was dissolved in 1,2-dichloroethant (7 mL) andDMF (0.07 nL). Oxalylchloride was added dropwise and the reaction mixture was stirred under argon for 1 h at room temperature. The solvent was removed in vacuo. The crude product was used without further purification. | |
With thionyl chloride In dichloromethane | A.a (a) (a) 3,4-Dimethoxy-phenylacetyl chloride Over a period of two hours, thionyl chloride (600 ml) is added dropwise, with stirring, to a suspension of 3,4-dimethoxy-phenylacetic acid (549.4 g) in methylene chloride (600 ml). After the development of gas has ended (16 hours) the mixture is refluxed for a further hour. After the highly volatile components have been removed the residue is distilled in vacuo. Yield: 486 g. Bp: 134°-136° C./1.95 mbar. | |
With thionyl chloride In dichloromethane | A.a (a) (a) 3,4-Dimethoxy-phenylacetic acid chloride First, thionyl chloride (600 ml) is added dropwise with stirring over a period of 2 hours to a suspension of 3,4-dimethoxy-phenylacetic acid (549.4 g) in methylene chloride (600 ml). After the evolution of gas has ended (16 hours) the mixture is refluxed for a further hour. After the volatile components have been eluminated the residue is distilled in vacuo. Yield: 486 g, Bp: 134°-136° C./1.95 mbar | |
With thionyl chloride In dichloromethane | A.a (a) (a) 3,4-Dimethoxyphenyl-acetic acid chloride 600 ml of thionyl chloride were added dropwise to a suspension of 549.4 gm of 3,4-dimethoxyphenyl-acetic acid in 600 ml of methylene chloride, while stirring, over a period of 2 hours. After the evolution of gas had ceased (16 hours), the mixture was refluxed for an hour. After the volatile components had been removed, the residue was distilled in vacuo. Yield: 486 gm (80.8% of theory). B.p.: 134°-136° C./1.95 mbar. | |
In benzene | 1 N-(3,4-Dimethoxyphenylacetyl)-5-aminoethyl-6-methylindan (VII) EXAMPLE 1 N-(3,4-Dimethoxyphenylacetyl)-5-aminoethyl-6-methylindan (VII) 3,4-Dimethoxyphenylacetic acid (6.47 g, 0.033 mole) was dissolved in 50 ml of dry benzene and refluxed for 2 hr. with excess thionyl chloride (25 ml). The solvent and SOCl2 were removed on a rotary evaporator. Two additional quantities of dry benzene were added to the residue, followed by rotary evaporation which yielded 3,4-dimethoxyphenylacetyl chloride. | |
With oxalyl dichloride In dichloromethane at 23℃; for 0.666667h; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In benzene at 20℃; for 1h; | ||
With thionyl chloride; N,N-dimethyl-formamide In benzene for 3h; | ||
With thionyl chloride In dichloromethane Reflux; | A Step A: (3,4-Dimethoxyphenyl)acetic acid chloride; Load into a reactor 135 g of (3,4-dimethoxyphenyl)acetic acid and 270 ml of dichloromethane and then bring the temperature of the reaction mixture to reflux and add, dropwise, 90 g of thionyl chloride. Stir the mixture at reflux for 3 hours. The solution obtained is used as such in the following Step. | |
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 2h; | ||
With thionyl chloride; N,N-dimethyl-formamide In dichloromethane at 22℃; | ||
With thionyl chloride for 2h; Reflux; Inert atmosphere; | ||
With thionyl chloride In dichloromethane at 20℃; for 8h; | ||
With thionyl chloride In dichloromethane at 25 - 50℃; for 0.75h; | 6 Example 6Charge 100.0 g of 3,4-Dimethoxy phenyl acetic acid (VI) and 110 ml of dichloromethane in a 500.0 ml 4-neck RB flask equipped with mechanical stirrer, condenser and thermometer pocket at 25°C. Slowly add 177.7 g of thionyl chloride at 25°C over period of 15 minutes and maintain for additional 15 minutes at 25°C. Heat it to 45-50°C and maintain for 15 minutes. Monitor the reaction by TLC for completion (Compound VI less than 1.0%, mobile phase - ethylacetate: hexane = 50:50). Distill off dichloromethane and excess thionyl chloride using normal distillation (vacuum at the end of the distillation for 5 min to remove the traces of thionyl chloride) to obtain a residue. Weight: 130.0 g | |
With oxalyl dichloride In benzene | ||
16.8 g | With thionyl chloride In dichloromethane for 1h; Reflux; | |
With thionyl chloride for 2h; Reflux; | ||
With thionyl chloride In toluene for 2h; Reflux; | AMD-7trans 2',3',4',9'-Tetrahydro-N,N-dimethyl-4-(3-fluorophenyl)-2'-(3,4-dimethoxybenzyl)carbonyl-spiro[cyclohexane-1,1'(1'H)-pyrido[3,4-b]indole]-4-amine (trans-diastereoisomer) 3,4-Dimethoxyphenylacetic acid (1 g, 5.1 mmol, 2.2 eq.) is suspended in 25 ml of abs. toluene, and thionyl chloride (0.84 ml, 11.6 mmol, 5.0 eq.) is added. Heating is carried out for 2 h under reflux, and the solvent is then removed. The residue was codistilled with abs. toluene (3*50 ml) and the crude product was dissolved in dichloromethane (37 ml) and transferred to a microwave vessel. Spiroamine AMN-2trans (0.875 mg, 2.32 mmol) and Hünig base (0.78 ml, 580 mmol, 250 eq.) were added, and the microwave vessel was closed and heated for 20 min at 120° C. in a microwave (Initiator Eight, Biotage). For working up, 17 ml of water and 17 ml of 1N sodium hydroxide solution were added to the reaction mixture. This mixture was stirred for 2 h at RT. The phases were then separated and the aqueous phase was extracted 3* with dichloromethane. The combined organic phases were washed with water and dried over sodium sulfate. After the solvent had been removed under reduced pressure, the residue was purified by column chromatography (silica gel; ethyl acetate/n-hexane 2:1). 0.236 g of product AMD-7trans (18%) was obtained. HPLC/MS analysis: R=5.45 min; Purity (UV 200-400 nm)>99%; m/z=555.8 | |
With oxalyl dichloride Reflux; | ||
With thionyl chloride In dichloromethane | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 6h; Inert atmosphere; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In tetrahydrofuran at 0 - 80℃; for 0.25h; Inert atmosphere; | ||
With thionyl chloride In dichloromethane Reflux; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In toluene at 20℃; for 2h; | ||
With thionyl chloride In dichloromethane at 20℃; for 18h; Inert atmosphere; | 1-(6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)-2-(3,4-dimethoxyphenyl)-ethanone (5b) (CAS no: 1021273-18-6)4 To 3,4-dimethoxyphenylacetic acid (980mg, 5.0mmol) in 10ml of CH2Cl2 was added SOCl2 (544μl, 7.5mmol) dropwise over 5 min under nitrogen atmosphere. The mixture was stirred at room temperature for 18 h. Excess SOCl2 and CH2Cl2 were removed in vacuo to afford crude (9b). | |
With trichlorophosphate In 1,2-dichloro-ethane for 3h; Reflux; | General procedure: Aralkanoic acid chlorides 2a-g were synthesized by the reaction of aralkanoic acid 1a-g (1 mmol) in the presence of 1,2-dichloroethane (12 mL) solvent and phosphorous oxychloride(0.4 mL) chlorinating agent under reflux for 3hours. Then, the resulting solution was cooled to room temperature, and the solvent was removed under reduced pressureto afford aralkanoic acid chloride 2a-g, which was directly used in the next step without further purification. Acid chloride 2a-g was dissolved in acetonitrile (80 mL), addeddropwise to a solution containing hydrazine hydrate(1 mmol), TEA (0.5 mL) and acetonitrile (20 mL) and allowed to reflux for 3 hours with monitoring by TLC. After consumption of the starting material, the reaction mixture was cooled to room temperature. Evaporation of the solvent under reduced pressure yielded crude acid hydrazide 3a-g as a white solid on cooling, which was purified by column chromatography and crystallized in methanol [46]. | |
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 3h; Inert atmosphere; | General procedure: To an over-dried 100 mL three-necked flask, the carboxylic acid (10 mmol), DMF (5 drops) and DCM (30 mL) were added under a N2 atmosphere. Oxalyl chloride (1.0 mL, 12 mmol) was added dropwise at 0 °C resulting in vigorous bubbling. The mixture was stirred for 3 h at room temperature, and the solvent was then removed in vacuo. The resulting acid chloride was used immediately without further purification. To a solution of the acid chloride in DCM (30 mL) ,a solution of 1,1,1,3,3,3-hexamethyldisilazane (30 mmol) in DCM (10 mL) was added dropwise at 0 °C, and the solution was then allowed to warm to room temperature. After stirring overnight, the reaction system was quenched with 1 M HCl aq. and saturated aqueous NH4Cl (excess amount) and the organic layer was separated. The aqueous layer was extracted with DCM (2x15 mL). The combined organic layers were washed with saturated aqueous NH4Cl (30 mL) and brine (30 mL), dried over MgSO4, filtered and evaporated in vacuo. The resulting crude material was purified by recrystallization from EtOAc and hexane. The resulting product (5 mmol), 8-bromomethylquinoline (6 mmol), Al2O3 (50 mmol), KOH (25 mmol) and dioxane (30 mL) were added to an over-dried 100 mL three-necked flask. The mixture was stirred for 8 h at 60 °C and then was filtered through a celite pad. The filtrate was washed with H2O (30 mL) and the organic layer was separated. The aqueous layer was extracted with EtOAc (2x15 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4, filtrated and evaporated in vacuo. The resulting crude amide was purified by column chromatography on silica gel (eluent: hexane/EtOAc = 1/1). | |
With thionyl chloride In chloroform for 2h; Reflux; | ||
With thionyl chloride In dichloromethane; N,N-dimethyl-formamide | ||
With thionyl chloride at 80℃; for 2h; | ||
With 4-methyl-morpholine; 1,3,5-trichloro-2,4,6-triazine at 20℃; for 0.166667h; | ||
With thionyl chloride at 80℃; for 4h; Inert atmosphere; | 3.3. Procedure for synthesis of phenylacetamides 1f-j General procedure: A dry flask containing the corresponding carboxylic acid (1 mmol) and SOCl2 (0.6 mL) was heated at 80 °C for 4 h under a nitrogen atmosphere. After the reaction period, the reaction mixture was concentrated under reduced pressure to remove the volatiles and then, the resultant crude reaction mixture was diluted with anhydrous DCM (2 mL). The DCM solution of corresponding acid chloride was slowly added to another RB flask containing the corresponding amine (1 mmol), Et3N (111 mg, 1.1mmol) and DCM (4 mL) under a nitrogen atmosphere. The resulting mixture was stirred at rt for 12 h. After this period, the reaction mixture was diluted with dichloromethane and washed with water and saturated aqueous NaHCO3 solution (twice). The combined organic layers were dried over anhydrous Na2SO4 and then, the solvent was evaporated in vacuo to afford a crude reaction mixture. Purification of the crude reaction mixture by column chromatography (neutral alumina (EtOAc/hexanes=25:75) furnished the corresponding products 1f-j. | |
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 25℃; for 2h; Inert atmosphere; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 2h; | ||
With thionyl chloride In 1,2-dichloro-ethane for 16h; Heating / reflux; | 7.A (3,4-Dimethoxy-phenyl)-acetic acid benzyl ester To a stirred mixture of commercially available 3,4-dimethoxyphenylacetic acid (100.0 g, 510 mmol) in anhydrous 1,2-dichioroethane (500 cm) at ambient temperature under an atmosphere of dry nitrogen was added thionyl chloride (112 cm3, 1.53 mol) portionwise over 20 minutes. The resulting solution was heated to reflux for 16 hours. The brown solution was cooled to ambient temperature and the volatile fractions removed in vacuo. Residual thionyl chloride was removed by an azeotrope with toluene (3*200 cm3) to afford a crude brown oil. The crude oil was dissolved in anhydrous dichloromethane (400 cm3) and cooled to 0 C. in an ice bath. To the cooled solution was added triethylamine (75 cm3, 535 mmol) dropwise over 10 minutes followed by a solution of benzyl alcohol (50 cm3, 485 mmol) dissolved in anhydrous dichloromethane (200 cm3). The mixture was stirred for 20 hours and warmed to ambient temperature. Water was added to the mixture (700 cm3) and the aqueous extracted with dichloromethane (2*100 cm3). The combined dichloromethane extracts were dried over sodium sulfate, vacuum filtered and the filtrate volatile fractions removed in vacuo to afford a crude brown oil. The crude product was purified by column chromatography (silica, eluting with hexane-ethyl acetate 1:0 to 1:1) to afford the title compound as a pale yellow viscous oil (83.4 g, 57.2%) with a positive ion ESI (M+H) +287.3. | |
With thionyl chloride at 100℃; | (a) SOCl2 method: Homoveratric acid (5g, 25.5 mmol) was added to freshly distilled thionyl chloride (15 mL) and refluxed at 100 °C for 3 h. Excessthionyl chloride was removed from reaction mixture by distillation and dry CHCl3 (10 mL) was added. Thissolution of acid chloride was added dropwise with stirring to an ice cold solution of homoveratryl amine (4.16g, 23.0 mmol) and K2CO3 (5.53 g 40 mmol) in dry CHCl3 (20 mL). This mixture was stirred for 12 h from 0 °C to r.t. Solvent was removed under vacuum and distilled water (50 mL) was added. The solid thus obtained wasfiltered and washed with water (20 mL X 3) and dried under vacuum. Analytically pure product 3 was obtainedas white amorphous solid in 76% (6.28 g) yield without any further purification. | |
With thionyl chloride at 25℃; Inert atmosphere; | ||
With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 20℃; Inert atmosphere; | ||
With thionyl chloride at 90℃; | ||
With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide for 2h; | ||
With thionyl chloride In dichloromethane | A.a (a) (a) 3,4-Dimethoxy-phenylacetic acid chloride Thionyl chloride (600 ml) is added dropwise, with stirring, over a period of 2 hours, to a suspension of 3,4-dimethoxy-phenylacetic acid (549.4 g) in methylene chloride (600 ml). After the development of gas has ended (16 hours) the mixture is refluxed for a further hour. After the highly volatile components have been removed the residue is distilled in vacuo. Yield: 486 g. Bp: 134°-136° C./1.95 mbar | |
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane for 2h; Inert atmosphere; Cooling with ice; | ||
With thionyl chloride In benzene at 20℃; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 6h; | ||
With thionyl chloride In benzene at 20 - 55℃; for 2.66667h; | 1,2-Diaryl-Substituted Ethanones General procedure: A mixture of arylacetic acid 11 (86 mmol) and SOCl2 (12.40 mL, 171 mmol) in absolute benzene (15 mL) was stirred at r.t. for 40 min and then at 55 °C for 2 h. Excess of SOCl2 and benzene were evaporated under low pressure. | |
With thionyl chloride In dichloromethane Reflux; | ||
With thionyl chloride at 85℃; for 3h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98.9% | With sodium tetrahydridoborate; iodine In tetrahydrofuran at 20℃; for 0.583333h; Cooling with ice; | 1.5 (5) Synthesis of Compound 22 Take a dry and clean 100 mL round bottom flask, accurately weigh sodium borohydride (0.4 g, 7.65 mmol) and iodine (1.3 g, 5.10 mmol) in a bottle, add 10 mL of tetrahydrofuran, place in an ice bath, stir After 5 min, 21 (1.0 g, 5.10 mmol) was added in small portions. After the addition, the ice bath was removed and the reaction was carried out at room temperature. The reaction was monitored by TLC. After 30 min, the reaction was completed by TLC. 50 ml of a 5% sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL × 3), and the organic phase was combined and washed with brine (10 mL × 3). The organic phase was separated, dried over anhydrous sodium sulfate, filtered and evaporatedThe title compound (22) was obtained as a yellow oil.The yield was 98.9%. |
98% | With lithium aluminium hydride In tetrahydrofuran at 0 - 70℃; for 0.5h; | 2-(3,4-Dimethoxyphenyl)ethan-1-ol (6) To a suspension of LiAIH4 (0.19 g, 5.07 mmol) in 3 mL dry THF, a solution of 2-(3,4-dimethoxyphenyl)acetic acid (0.50 g, 2.55 mmol) in 7 mL dry THF was added at 0 °C. The reaction mixture was gradually warmed to ambient temperature and then was refluxed for 30 min. A mixture of THF/H2O (1 : 1) was added at 0 °C and then was diluted with ethyl acetate. Na2S04 was added to the mixture and was stirred for 15 min. Finally, it was filtered through a pad of Celite and the filtrate was concentrated in vacuo giving the desired product as a white solid, (0.45 g, 98%). 1H NMR (600 MHz, CDCb) d : 6.82-6.75 (m, 3H, Ar H), 3.87 (s, 3H, -OC ft), 3.85 (s, 3H, -OC/fc), 3.83 (t, J= 6.5 Hz, 2H, -C//2OH), 2.80 (t, .7=6.5 Hz, 2H, -CCH2OH). 13C NMR (75 MHz, CDC13) d: 148.5, 147.2, 130.9, 120.6, 1 12.0, 1 1 1.1 , 63.3, 55.7, 55.4, 38.4. MS m/z: 182.82 (M+H) 204.96 (M+Na) +, 386.64 (2M+Na)+ |
97% | With lithium aluminium hydride In tetrahydrofuran at 0℃; Reflux; |
93% | With lithium aluminium hydride In tetrahydrofuran at 20℃; for 0.5h; | |
91.2% | With sodium tetrahydridoborate; iodine In tetrahydrofuran for 18h; Heating; | |
90% | With sodium tetrahydridoborate; iodine In tetrahydrofuran for 24h; Reflux; | |
86% | With dimethylsulfide borane complex In tetrahydrofuran for 1h; Inert atmosphere; Reflux; | |
With lithium aluminium hydride | ||
With lithium aluminium hydride | ||
With dimethylsulfide borane complex | ||
Multi-step reaction with 2 steps 1: sulfuric acid 2: sodium | ||
With lithium aluminium hydride In tetrahydrofuran at 0 - 20℃; | ||
With lithium aluminium hydride In tetrahydrofuran at 0℃; | ||
With lithium aluminium hydride Inert atmosphere; | ||
Multi-step reaction with 2 steps 1: sulfuric acid / 3 h / Reflux 2: diisobutylaluminium hydride / tetrahydrofuran; toluene / 20 °C | ||
Multi-step reaction with 2 steps 1: sulfuric acid / 0.5 h / Reflux 2: sodium tetrahydridoborate; calcium(II) chloride / ethanol / 16 h / 0 - 20 °C | ||
With lithium aluminium hydride In tetrahydrofuran at 0 - 20℃; for 3h; Inert atmosphere; Reflux; | ||
With borane-THF In tetrahydrofuran at 0 - 20℃; for 2h; | ||
With lithium aluminium hydride In tetrahydrofuran Inert atmosphere; | ||
With lithium aluminium hydride In tetrahydrofuran | ||
With sulfuric acid In tetrahydrofuran; lithium hydroxide monohydrate | Preparation of 2-(3,4-dimethoxyphenyl)ethanol Preparation of 2-(3,4-dimethoxyphenyl)ethanol To a solution of 3,4-dimethoxyphenylacetic acid (2 g) in anhydrous THF (40 ml) at 0° C. under N2 was added dropwise borane-methyl sulfide complex (10 M, 1.5 ml). The mixture was stirred at room temperature for further 4 hrs. Cold water (5 ml) was added to destroy any excess of borane followed by the addition of H2SO4 (1 M, 50 ml). The mixture was extracted three time with ethyl acetate (50 ml). The organic layer was separated and evaporated off to give a colourless liquid which was then purified by column chromatography to afford a colourless solid in quantitative yield. 1H-NMR: δ6.76-6.82 (3H, m), 3.87 (8H, m), 2.82 (2H, t, J=6 Hz). | |
With borane-THF In tetrahydrofuran at 0 - 20℃; for 2h; Inert atmosphere; | ||
With lithium aluminium hydride In tetrahydrofuran at 0℃; for 2h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium acetate |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | at 150℃; for 0.5h; Microwave irradiation; | |
97% | In o-xylene Reflux; | |
96% | at 180℃; for 1h; Inert atmosphere; Sealed tube; Microwave irradiation; |
95.2% | In xylene for 5h; Heating; | |
95% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃; for 12h; Inert atmosphere; | 4.7 General procedure for the preparation of compounds (25-32), (34-36), (39-40) General procedure: To a solution of an appropriate acid (0.12mmol) and related amine or alcohol (0.10mmol) in an anhydrous CH2Cl2 (50mL) was added EDC·HCl (0.13mmol) and DMAP (0.01mmol) at 0°C under N2 atmosphere. Then the mixture was stirred at room temperature for 12h. The mixture was diluted with CH2Cl2, washed with 1M HCl, saturated NaHCO3 and brine, dried over Na2SO4. After the solvent was distilled off under reduced pressure, the resulting residues were purified by flash chromatography to furnish compounds 25-32, 34-36, 39-40, respectively. |
95.03% | In 5,5-dimethyl-1,3-cyclohexadiene at 150℃; for 17h; | 2-(3,4-Dimethoxyphenyl)-N-[2-(3,4-dimethoxyphenyl)ethyl]acetamide (4). A mixture of 3,4-dimethoxyphenylacetic acid (2, 300 g, 1.66 mol) and 2-(3,4-dimethoxyphenyl)ethanamine (3, 325 g,1.66 mol) in xylene (3 L) was stirred at 150°C for 17 h with azeotropic removal of water [5]. The reaction was monitored by HPLC until initial compounds 2 and 3comprised less than 5% in total or until 95% conversion to amide 4 was attained. |
93% | With dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 24h; | |
92% | at 190 - 210℃; for 2h; | |
84% | at 190℃; for 3h; Inert atmosphere; | |
83% | at 180℃; for 1h; | N-(3,4-Dimethoxyphenethyl)-2-(3,4-dimethoxyphenyl)acetamide (11) A mixture of 3,4-dimethoxyphenethylamine 9 (9.2 mL, 55.8 mmol) and homoveratric acid 10 (9.4 g, 48mmol) was heated at 180 °C for 1 h. After cooled to room temperature, the residue was recrystallized fromEtOH (40 mL) to give amide 11 (14.4 g, 83%) as white solids of mp 122.0-124.0 °C.1H NMR: 2.68 (2H, t, J = 6.6), 3.45 (2H, dt, J = 6.6, 6.6 ), 3.48 (2H, s), 3.83 (6H, s), 3.86 (3H, s), 3.88 (3H,s), 5.40 (1H, br s), 6.52 (1H, d, J = 8.0), 6.62 (1H, s), 6.67-6.72 (3H, m), 6.80 (1H, d, J = 8.0). |
81% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0 - 20℃; for 24h; | N-(3,4-Dimethoxyphenethyl)-2-(3,4-dimethoxyphenyl)acetamide (3) (b) DCC coupling method: Homoveratric acid (5 g, 25.5 mmol), homoveratryl amine (4.62 g, 25.5 mmol) andDMAP (0.05 g) were added in dry CH2Cl2 (25 mL) and cooled to 0 °C. To this mixture, DCC (6.19 g, 30 mmol)was added and stirred from 0 °C to r.t. for 24 h. Water (1 mL) and dioxane (2 mL) was added to this and stirredfor 2 h. Solvent was removed under vacuum, CH2Cl2 (25 mL) was added, cooled to 0 °C and filtered. The filtratewas again cooled to 0 °C and filtered. The solvent was removed under vacuum and product 3 was obtained aswhite solid in 81% (7.41 g) yield without any further purification. |
79% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; for 18h; | N-(3,4-dimethoxyphenyl)-3,4-dimethoxybenzamide (2a) (CAS no: 59699-54-6)2 General procedure: To 3,4-dimethoxybenzoic acid (183mg, 1.0mmol) in 2ml of CH2Cl2 was added 3,4-dimethoxyaniline (168mg, 1.1mmol), triethylamine (152mg, 1.5mmol), 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide (288mg, 1.5mmol) and 1-hydroxybenzotriazole monohydrate (230mg, 1.5mmol). The reaction mixture was stirred at room temperature for 18 h, following which the precipitate was filtered under suction and washed with water and cold EtOAc to afford (2a) as a white solid, 62%. |
74% | With silica gel; toluene-4-sulfonic acid for 0.0833333h; microwave irradiation; | |
54% | at 180℃; for 4h; Inert atmosphere; | |
With tetralin | ||
at 200℃; | ||
With dicyclohexyl-carbodiimide In dichloromethane 1.) 0 deg C, 30 min, 2.) 25 deg C, 16 h; | ||
In xylene Heating; | ||
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; | 8.43 To the solution of A (650 mg, 3.31 mmol), B (630 mg, 3.48 mmol) in DCM (30 mL) was added EDCI (1.27 g, 6.62 mmol) and Et3N (1.0 g, 9.93 mmol) at 20° C. and the solution was stirred overnight. TLC analysis indicated the completion of the reaction. Water was added, and the organic layer was collected, dried and concentrated to give 1.0 g of C. | |
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; | 8.43 To the solution of A (650 mg, 3 31 mmol), B (630 mg, 3 48 mmol) m DCM(30 mL) was added EDCI (1 27 g, 6 62 mmol) and EtjN (1 0 g, 9 93 mmol) at 200C and the solution was stirred overnight TLC analysis indicated the completion of the reaction Water was added, and the organic layer was collected, dried and concentrated to give 1 0 g of C | |
at 190℃; for 3h; Inert atmosphere; | ||
In toluene for 12h; Reflux; | I.A.A1 3,4-Dimethoxyphenylacetic acid (50 g; 250 mmol) were suspended in toluene (250 ml) followed by the addition of homoveratrylamine (46.7 g; 250 mmol). The suspension was heated to reflux with a Dean-Stark trap (while being heated up, the starting materials dissolved) and kept at reflux temperature for 12 h. The reaction mixture was then transferred into an Erlenmeyer flask containing toluene (300 ml) and cooled to rt while being stirred. The product precipitated and was filtered off and washed with toluene. The filter cake was dried at high vacuum to give 2-(3,4-dimethoxy-pheny)-N-[2-(3,4-dimethoxy-phenyl)-ethyt]-acetamide. LC-MS; tR = 0.87 min; [M+H]+ = 360.26. | |
at 190℃; for 3h; Inert atmosphere; | ||
In toluene for 12h; Dean-Stark; Reflux; | ||
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide | ||
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; Inert atmosphere; | ||
In o-xylene Reflux; | ||
With boric acid In toluene for 12h; Reflux; | ||
at 100 - 170℃; for 2h; | 1.1; 2.1; 3.1 Preparation Example 3: Preparation of papaverine hydrochloride (1) Make 3,4-dimethoxy-β-phenyl-ethylamine108.7g (Mr181.2, 0.60mol)And 3,4-Dimethoxy-phenyl-acetic acid 117.7g (Mr=196.2, 0.60mol)It is melted by heating to 100110 (the methyl orange indicator shows approximately neutral value), the reaction mixture is stirred at 170 for another 2 hours, and then the main contentN-(3',4'-Dimethoxyphenylacetyl)-3,4-Dimethoxyphenyl-ethylamine(Substance F) is poured into homogeneous meltIn a mixture of 265g benzene, 16g chromium powder and 110g phosphorus oxychloride,Then the reaction mixture was refluxed for 2 hours; after removing the solvent,Decompose excess phosphorus oxychloride by adding 450 mL of absolute ethanol and filter out chromium powder;The filtrate mixture was allowed to stand for 8 hours under cooling,Then filter the precipitated crystals6,7,3',4'-Tetramethoxy-1-benzyl-dihydro-isoquinoline hydrochloride(Substance C hydrochloride), then washed with absolute ethanol;A product with an average water content of 8-15% is obtained (the yield of this step is 94.3%),It is used directly in the subsequent steps without drying; | |
1.0 g | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; | 8.43 [00245] To the solution of A (650 mg, 3.31 mmol), B (630 mg, 3.48 mmol) in DCM (30 mL) was added EDCI (1.27 g, 6.62 mmol) and Et3N (1.0 g, 9.93 mmol) at 20°C and the solution was stirred overnight. TLC analysis indicated the completion of the reaction. Water was added, and the organic layer was collected, dried and concentrated to give 1.0 g of C. |
In 5,5-dimethyl-1,3-cyclohexadiene at 130℃; for 10h; Dean-Stark; | 1-16 Example 1: Add 30g 3,4-dimethoxyphenethylamine, 32.5g 3,4-dimethoxyphenylacetic acid, and 300mL xylene to the reaction flask successively, heat to 130 and separate water with a water trap, and react for 10h The complete conversion of the raw materials was monitored by HPLC.Then lower the temperature to 70 and add 25.4g POCl3 to the reaction flask aafter the reaction was carried out for 2 hours, the reaction was monitored by HPLC and found that the conversion of the raw materials was completed. After cooling to room temperature, aqueous sodium hydroxide solution (0.01mol/L, 70mL) was added for washing.Finally, 11.3 g of Raney nickel was added to the reaction solution. At 110° C., the raw materials disappeared after 11 hours of reaction. After the reaction was completed, the Raney nickel was filtered and the xylene was concentrated to obtain 48 g of papaverine (purity 82%).Add the obtained papaverine to hydrochloric acid (14.36g of a 36% hydrochloric acid aqueous solution with a mass concentration of 36%) and absolute ethanol (240mL), and recrystallize to obtain 31g of papaverine hydrochloride, with a total yield of 50% (yield in this application = purity × product The molar mass ÷ the molar mass of the raw material×100%), and the purity is 99 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With hydrogenchloride; acetic acid for 1h; Heating; | |
84% | With hydrogenchloride In acetic acid for 1h; Heating; | |
83% | With hydrogenchloride; acetic acid In water at 120℃; for 1h; | 2.2.1 EXAMPLE 2Synthesis of Compounds Represented by Formula III According to the Invention by a Second Route Heat at 120° C. for 1 hour a mixture of 19.6 g (100 mmol) of 3,4-dimethoxyphenyl acetic acid (VII), 7.4 g (246 mmol) of paraformaldehyde and 20 ml of concentrated HCl in 100 ml of AcOH. Evaporate to dryness.Add 100 ml of H2O, and extract three times with 200 ml of CH2Cl2.Wash the organic phases with 50 ml of 0.5 N NaHCO3 and dry on Na2SO4.Evaporate to dryness.Allow to crystallize for 2 hours in 50 ml of Et2O. Filter and wash twice with 10 ml of Et2O and twice with 20 ml of pentane. Yield: 83%. M: 106-108° C. 1H-NMR (300 MHz, CDCl3): d 3.64 (s, 2H, CH2), 3.89 (s, 3H, OCH3), 3.90 (s, 3H, OCH3), 5.26 (s, 2H, CH2),6.71 (s, 1H Ar), 6.75 (s, 1H Ar). |
80% | With hydrogenchloride; acetic acid In water at 75℃; for 1h; | |
66% | With hydrogenchloride; acetic acid | |
61% | With hydrogenchloride In acetic acid at 90℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With trichlorophosphate for 5h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95.6% | Stage #1: (3,4-Dimethoxyphenyl)acetic acid With thionyl chloride for 1h; Reflux; Stage #2: With ammonium hydroxide at 0℃; for 0.5h; | 1.1; 2.1; 3.1 (1) Synthesis of 3 3,4-Dimethoxyphenylacetic acid (10.0 g, 50.97 mmol) was added to a 250 mL round bottom flask, and then 75 mL of thionyl chloride was added to dissolve it, and the reaction was refluxed. After 1h, it was detected by TLC and the reaction ended. The thionyl chloride was evaporated to dryness under reduced pressure to obtain a yellow oil, which was then dissolved with 20 mL of acetonitrile, added dropwise to 75 mL of ammonia water under ice bath, and reacted under ice bath conditions. After 0.5h, it was detected by TLC and the reaction was over. The acetonitrile was evaporated to dryness under reduced pressure, and a white solid was precipitated. It was filtered with suction, washed with water (50 mL×3), and dried to obtain 39.51 g of a white solid with a yield of 95.6%. |
With oxalyl dichloride; ammonia 1.) toluene, DMF, RT, 17 h, 2.) 4 h; Yield given. Multistep reaction; | ||
Multi-step reaction with 2 steps 1: SOCl2 2: aq. NH3 |
Multi-step reaction with 2 steps 1: hydrogen chloride 2: aqueous ammonia | ||
Multi-step reaction with 2 steps 1: sulfuric acid 2: aqueous ammonia | ||
Multi-step reaction with 2 steps 1: thionyl chloride / dichloromethane 2: ammonia / tetrahydrofuran | ||
Multi-step reaction with 2 steps 1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 3 h / 0 - 20 °C / Inert atmosphere 2: 1,1,1,3,3,3-hexamethyl-disilazane / dichloromethane / 0 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | Stage #1: (3,4-Dimethoxyphenyl)acetic acid; 2-hydroxy-5-methylbenzaldehyde With dicyclohexyl-carbodiimide In dimethyl sulfoxide at 110℃; for 24h; Inert atmosphere; Stage #2: With acetic acid In dimethyl sulfoxide at 20℃; for 2h; Inert atmosphere; | 4.2. Synthetic methodologies General procedure: A solution of ortho-hydroxybenzaldehyde (1.0 mmol), the correspondingarylacetic acid (1.25 mmol) and DCC (1.56 mmol), in DMSO(2.0 mL), was heated at 110 °C in an oil bath for 24 h. Ice (20 g). AcOH(3.0 mL) was added and the mixture was stirred at room temperaturefor 2 h, and then extracted with Et2O (3 Å~ 25 mL). The combinedorganic layer was washed with 5% aqueous NaHCO3 solution (50 mL)and H2O (20 mL) and dried (Na2SO4). The solvent was evaporatedunder vacuum and the residue was purified by flash chromatography(hexane-EtOAc, 9:1) to give the coumarins 9, 72-74, 75′ and 76.3-(3′,4′-Dimethoxyphenyl)-6-methylcoumarin (9). Yield: 71%; Mp149-150 °C. 1H NMR (CDCl3) δ: 2.40 (s, 3H, CH3), 3.92 (s, 3H, OCH3),3.94 (s, 3H, OCH3), 6.92 (d, 1H, H-5′, J = 8.3), 7.21-7.29 (m, 5H, H-5,H-7, H-8, H-2′, H-6′), 7.72 (s, 1H, H-4). 13C NMR (CDCl3) δ: 20.7, 55.8,55.9, 99.3, 110.8, 111.6, 115.9, 119.4, 121.1, 127.4, 127.5, 132.0,134.0, 138.7, 148.5, 149.5, 151.3, 160.8. MS m/z (%): 297 (28), 296(M+, 100). Anal. Elem. Calc. for C18H16O4: C, 72.96; H, 5.44. Found: C,72.90; H, 5.49. |
12% | With dicyclohexyl-carbodiimide In dimethyl sulfoxide at 100 - 110℃; for 48h; | |
With dicyclohexyl-carbodiimide In dimethyl sulfoxide at 110℃; for 24h; |
With dicyclohexyl-carbodiimide In dimethyl sulfoxide at 110℃; for 24h; | 2.1.1. General procedure for the preparation of methoxy-3-arylcoumarins General procedure: To a solution of the conveniently substituted ortho-hydroxybenzaldehyde (7.34 mmol) and the corresponding phenylacetic acid (9.18 mmol) in dimethyl sulfoxide (15 mL), N,N'-dicyclohexylcarbodiimide (11.46 mmol) was added. The mixture was heated at 110°C for 24 h. Then, ice (100 mL) and acetic acid (10 mL) were added to the reaction mixture. After keeping it at room temperature for 2 h, the mixture was extracted with ether (3*25 mL).The organic layers were combined and washed with sodium bicarbonate solution (50 mL, 5%) and water (20 mL). Subsequently, the solvent was evaporated under vacuum and the dry residue was purified by flash chromatography (hexane/ethyl acetate 9:1), to give the desired methoxy-3-arylcoumarins.23,28 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With 1,4-diaza-bicyclo[2.2.2]octane In neat (no solvent) at 180℃; for 1.66667h; | Synthesis of3-Arylcoumarins:GeneralProcedure General procedure: 2-Hydroxy-3,4,5-trimethoxybenzaldehyde (1c) was synthesizedfrom2,3,4-trimethoxy benzaldehydeaccordingtotheliterature.[29] A mixtureofsalicylaldehydederivative 1 (0.5 mmol), phenylaceticacidderivative 2 (1 mmol), andDABCO(3 mmol) was heatedat180 °C fortheappropriatetime (Table 1). Afterthecompletion ofthereaction (monitored bythin-layerchromatography,TLC),it wasdilutedwithicewaterandextractedwithdichloromethane (3 × 15 ml). Theorganic layerwasdriedoverNa2SO4, andthesolventwasevaporatedunderreducedpressure. Thecrudeproductwasrecrystallizedfromethanoltogivethepurecompound. Alltheproductswerecharacterizedusing 1H NMR, 13C NMR,andCHN analysis. 3-(3,4-Dimethoxyphenyl)-2H-chromen-2-one (3b). Yield: 81%, white crystals, mp 133-135 oC.IR (KBr): 1710 (C=O) cm-1. 1H NMR (500 MHz, CDCl3): δ = 3.94 (s, 3H, OCH3), 3.96 (s, 3H,OCH3), 6.95 (d, 1H, J = 8.2 Hz, H5'), 7.29-7.32 (m, 3H, H6, H8 H2' ), 7.37 (d, 1H, J = 8.2 Hz,H6'), 7.51-7.56 (m, 2H, H5, H7), 7.79 (s, 1H, H4). 13C NMR (125 MHz, CDCl3): δ = 55.8, 55.9,110.9, 111.7, 116.3, 119.7, 121.2, 124.4, 127.3, 127.7, 127.8, 131.0, 138.7, 148.6, 149.6, 154.12,159.3. Anal. calcd. for C17H14O4: C, 72.33; H, 5.00. Found: C, 72.51; H, 4.82. |
59% | With acetic anhydride; triethylamine at 120℃; for 8h; | General Procedure for the preparation of 3-arylcoumarin General procedure: A mixture of salicylaldehyde derivative (8 mmol), phenylacetic acid derivative (16 mmol), acetic anhydride (20 mL) and triethylamine (5 mL) were heated at 120 for eight hours. After cooling to room temperature, reaction mixture was slowly poured into ice-water (200 mL) with violent stirring. The precipitated solid was filtered off andrecrystallized from ethyl acetate to give 3-arylcoumarin. |
55% | With dicyclohexyl-carbodiimide In dimethyl sulfoxide Heating; |
20% | With dicyclohexyl-carbodiimide In dimethyl sulfoxide at 100 - 110℃; for 48h; | |
With potassium acetate; acetic anhydride for 4h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; for 72h; | |
60% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 20h; | |
30.3% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; | 178.1 00354] Intermediate 7: Synthesis of 2-(3,4-dimethoxyphenyl)-l-phenylethanone[00355] Step 1: A mixture of 2-(3,4-dimethoxyphenyl)acetic acid (1 g, 5.1 mmol),N, O-dimethylhydroxylamine hydrochloride (480 mg, 5.1 mmol), l-(3-dimethylaminopropyl)- 3-ethylcarbodiimide hydrochloride (978 mg, 5.1 mmol), hydroxybenzotriazole (690 mg, 5.1 mmol) and triethylamine (2.57 g, 25.5 mmol) in dichloromethane (30 mL) was stirred at room temperature overnight. The reaction mixture was diluted with water (30 mL), and extracted with EtOAc (30 mLx3). The combined organic layer was dried over Na2S04, concentrated in vacuo, and purified by column chromatography (PE: EtOAc=8: l) to afford 2- (3,4-dimethoxyphenyl)-N-methoxy-N-methylacetamide (370 mg, yield 30.3%). |
Stage #1: (3,4-Dimethoxyphenyl)acetic acid With 1,1'-carbonyldiimidazole In dichloromethane at 20℃; Stage #2: N,O-dimethylhydroxylamine*hydrochloride In dichloromethane at 20℃; | ||
31.2 g | Stage #1: (3,4-Dimethoxyphenyl)acetic acid With 1,1'-carbonyldiimidazole In dichloromethane at 0 - 20℃; for 2h; Stage #2: N,O-dimethylhydroxylamine*hydrochloride With triethylamine In dichloromethane at 0 - 20℃; | 96.1 Preparation of 2-(3,4-dimethoxyphenyl)-N-methoxy-N-methyl-acetamide To a solution of 2-(3,4-dimethoxyphenyl)acetic acid (25.2 g, 129 mmol) in CH2Cl2 (300 mL) was added di(imidazol-1-yl)methanone (25.1 g, 155 mmol) in portions at 0° C. The resultant mixture was stirred at 0° C. to room temperature for 2 hours. Then N,O-dimethylhydroxylamine hydrochloride (37.9 g, 387 mmol) was added at 0° C., and then Et3N (52.1 g, 516 mmol) was added to the mixture in dropwise. The resultant mixture was stirred at 0° C. at room temperature overnight. The reaction mixture was diluted with 2 M hydrochloric acid (100 mL) and extracted with EtOAc. The organic layer was washed with 2 M hydrochloric acid (50 mL*5) and brine, and then dried over anhydrous Na2SO4 and then concentrated to give 2-(3,4-dimethoxyphenyl)-N-methoxy-N-methyl-acetamide (31.2 g) as an orange oil. |
31.2 g | Stage #1: (3,4-Dimethoxyphenyl)acetic acid With 1,1'-carbonyldiimidazole In dichloromethane at 0℃; for 2h; Stage #2: N,O-dimethylhydroxylamine*hydrochloride With triethylamine In dichloromethane at 0 - 20℃; | 96.1; 211.1 Step 1 : Preparation of 2-(3,4-dimethox henyl)-iV-methoxy-iV-methyl-acetamide Step 1 : Preparation of 2-(3,4-dimethox henyl)-iV-methoxy-iV-methyl-acetamide To a solution of 2-(3,4-dimethoxyphenyl)acetic acid ( 25.2 g, 129 mmol) in CH2CI2 (300 m . ) was added di( imidazol- 1 -yl )methanone (25. 1 g, 1 55 mmol ) in portions at 0 °C. The resultant mixture was stirred at 0 °C to room temperature for 2 hours. Then A;, O-d i met h y 1 h yd ro x y 1 a m i n e hydrochloride (37.9 g, 387 mmol) was added at 0 °C, and then Et3N (52. 1 g, 5 16 mmol ) was added to the mixture in dropwise. The resultant mixture was stirred at 0 °C at room temperature overnight. The reaction mixture was diluted with 2 M hydrochloric acid ( 100 ml. ) and extracted with EtOAc. The organic layer was washed with 2 M hydrochloric acid (50 ml, x 5 ) and brine, and then dried over anhydrous a S().| and then concentrated to give 2-(3,4-dimetho.xyphenyl )- Λ'- met hox y-. V- met h y 1-acet am id e (31 .2 g) as an orange oil. |
28.3 g | Stage #1: (3,4-Dimethoxyphenyl)acetic acid With thionyl chloride In toluene at 70℃; for 2h; Inert atmosphere; Stage #2: N,O-dimethylhydroxylamine*hydrochloride With potassium carbonate In water; toluene at 0 - 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With oxygen; sodium carbonate In water at 49.85℃; for 2h; | ||
With sodium chlorite; Me-AZADO+Cl- In acetonitrile at 25℃; for 0.17h; aq. phosphate buffer; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With Lawessons reagent at 190℃; for 0.00833333h; microwave irradiation; | |
58% | at 210℃; for 1h; Microwave irradiation; | |
34% | Stage #1: (3,4-Dimethoxyphenyl)acetic acid With thionyl chloride In toluene at 85℃; for 2h; Inert atmosphere; Sealed tube; Stage #2: 2-amino-benzenethiol In toluene at 20℃; for 17h; Inert atmosphere; Cooling with ice; Sealed tube; | 2.2.1. 2-(3,4-Dimethoxybenzyl)-benzo[d]-thiazole 3,4-Dimethoxyphenylacetic acid (405mg, 2.06mmol, 1 equiv.) was dissolved in toluene (Thermo Fisher Scientific, Darmstadt, Germany) (5ml) in a pressure-proof reaction flask sealed with a screw cap under a nitrogen atmosphere. Thionylchloride (190µl, 2.62mmol, 1.27 equiv.) was added dropwise and the solution was heated for 2h to 85°C. Next, a stream of nitrogen was bubbled through the solution for 5min in order to remove the excess of thionylchloride. The reaction mixture was then cooled with an ice bath and 2-aminothiophenol (254 μl,2.06 mmol, 1 equiv.) was added dropwise. The solution was stirred for 1 h in the ice bath and subsequently for 16 h at room temperature. After monitoring with TLC on silica plates (60 F254) (Merck) (eluents: nhexane(VWR, Darmstadt, Germany)/ethyl acetate (Thermo FisherScientific), 3:2) reaction work-up was conducted. Saturated bicarbonate solution (Fluka Chemie, Buchs, Switzerland) (10 ml) was added and the mixture was stirred for 10 min. Then the mixture was transferred into a separation funnel and extracted after adding ethyl acetate (20 ml) andwater (10 ml). The aqueous phase was extracted two times more with ethyl acetate (10 ml each). The collected organic phases were washed with brine (Carl Roth, Karlsruhe, Germany) (10 ml), dried over sodium sulfate (Sigma-Aldrich), filtrated, mixed with a spatula of silica (FlukaChemie) (approx. 2 g) and evaporated to dryness using the rotary evaporator. The product loaded on silica was purified using MPLC (25 GUltra Snap column with a gradient from 100% n-hexane to 100% ethylacetate, Biotage, Uppsala, Sweden). Fractions were analyzed by TLC and product-containing fractions were combined and dried using the rotary evaporator.Yield 199 mg of a white solid (0.70 mmol, 34%). Rf-value: 0.48(TLC, n-hexane /ethyl acetate, 3:2).Molecular weight (C16H15NO2S): 285.4 Da, found (MH + ): 286 m/z.NMR: 1H NMR (500 MHz, DMSOZd6 (Deutero, Kastellaun,Germany)) 9 7.99 (d, J = 9.0 Hz, 1H), 7.96 - 7.92 (m, 1H), 7.48 (t,J = 5.5 Hz, 1H), 7.40 - 7.35 (m, 1H), 7.01 (s, 1H), 6.91 (d, J = 8.1 Hz,2H), 4.38 (s, 2H), 3.73 (s, 6H) ppm.13C NMR (126 MHz, DMSOZd6) 9 172.45, 153.50, 149.40, 148.56,135.62, 130.40, 126.61, 125.36, 122.83, 122.65, 121.89, 113.59,112.60, 56.08, 39.64 ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid; In methanol; | Step 1 3,4-Dimethoxyphenylacetic acid (80.0 grams, 0.41 mole), methanol (350 milliliters (mL)) and 2 mL of concentrated sulfuric acid were added to a reaction flask equipped with a Dean-Stark trap condensor and magnetic stirrer. The reaction mixture was maintained at reflux temperature overnight. After removal of unreacted methanol via a rotary evaporator, the product was dissolved in ether. The ether solution was washed twice in a sodium bicarbonate solution, washed twice with water and dried over anhydrous sodium sulfate. The ether was removed on a rotary evaporator, leaving 85 grams of methyl 3,4-dimethoxyphenylacetate as a viscous oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With boron trifluoride diethyl etherate at 100℃; for 1.66667h; | 1.1 2-Methyl resorcinol (62.2 g) and 3,4-methoxyphenyl acetic acid (92.3 g) were dried over P2O5 for 4 days. Boron trifluoride diethyl etherate (350 mL) was added to the solids in a round bottom flask and the mixture was stirred under nitrogen with heating to 100°C for 100 min. The solution was cooled to room temperature for 2 hours and the resulting precipitate was collected and washed with an excess of water to afford l-(2,4-dihydroxy-3- methylphenyl)-2-(3,4-dimethoxyphenyl)-ethanone as a brown solid (93 g, 65%). |
43% | With boron trifluoride diethyl etherate at 110℃; for 1.25h; | 2.1.1 Step 1.1 l-(2,4-dihydroxy-3-methyl-phenyl)-2-(3,4-dimethoxy-phenyl) ethanone; 2-Methylresorcinol (6.285g, lequivalent) and 3,4-dimethoxyphenylacetic acid (9.25 Ig, 1 equivalent) were added to a round bottom flask. The round bottom flask was attached to a condenser and placed in an oil bath, the whole system was kept under nitrogen. Distilled boron trifluoride diethyl etherate, BF3OEt2 (42ml, 5 equiv.) was added to the mixture while stirring. The mixture was refluxed (110° C). A yellow solid formed at 75 minutes indicating that the reaction had gone to completion. The reaction was heated for a further 10 minutes and cooled to room temperature. The yellow solid was collected by suction filtration and washed with distilled water (200ml) to remove any excess BF3OEt2 present. 1H NMR in d-DMSO indicated the yellow solid was l-(2,4-dihydroxy-3-methyl-phenyl)-2- EPO (3,4-dimethoxy-phenyl) ethanone in >95% purity. The solid was dried on a freeze dryer for 24hours (6.303g, 43%). |
With boron trifluoride diethyl etherate at 100℃; for 1.5h; Inert atmosphere; | 4.1.1. Synthesis of substituted 2-hydroxy-4-methoxy-3-methyldeoxy benzoins 14a-d General procedure: A mixture of 2-methylresorcinol 11(15 mmol) and substituted phenylacetic acids 12a-d (15 mmol) in BF3OEt2 (15 mL) was heated at 100 C under the atmosphere ofnitrogen for 1.5 h. Then the mixture was poured into ice cold H2O(500 mL) and allowed to stand at 4 C for 12 h. The formed precipitate was collected by filtration and re-crystallized fromEtOH to give compounds 13a-d. Then, to a solution of compounds13a-d (10 mmol) in anhydrous acetone (60 mL) were added K2CO3(10 mmol) and iodomethane (12 mmol). The resulting mixture was refluxed for 6 h and then filtered. The filtrate was concentrated under reduced pressure and the obtained residue was re-crystallizedfrom EtOH to give compounds 14a-d. |
With boron trifluoride diethyl etherate at 110℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 20℃; for 5h; | To an ice-cold solution of 3,4-dimethoxyphenylacetic acid (7.60 g, 38.7 mmol), -V5JV- dimethylaminopyridine (DMAP; 11.4 g, 93 mmol), and 4-piperidin-ethanol (5 g, 39 mmol) in dry dichloromethane (DCM; 80 mL) was added iV-(3-dimethylaminorhoropyl)-JV- ethylcarbodimide hydrochloride (EDACEtaC1; 9.65 g, 50.3 mmol) in one portion. The cooling bath was removed and the reaction was allowed to warm to room temperature. After five hours, HPLC analysis revealed the 3,4-dimethoxyphenylacetic acid was consumed. The reaction mixture was washed once with 1 N HCl(aq) (90 mL) and concentrated in vacuo. The residue was chromatographed to yield the title compound (A; 10.67 g, 90% yield) as viscous oil. 1H NMR (400 MHz5 CDCl3) 0.91 (br m, IH)5 1.04 (br m5 IH)5 1.44 (q, J = 6.6 Hz, 2H), 1.64 (m, 3H), 1.73 (br s, 2H), 2.56 (br m, IH), 2.92 (br m, IH)5 3.64 (m, 4H), 3.84 (s, 3H), 3.84 (s, 3H), 4.59 (br m, IH)5 6.73 (dd5 J= 2.O5 8.2 Hz5 IH)5 6.78 (d5 J= 2.0 Hz5 IH)5 6.79 (d, J = 8.2 Hz, IH). m/z 308 [M+l] +. |
90% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 20℃; for 5h; | The cooling bath was removed and the reaction was allowed to warm to room temperature. After five hours, HPLC analysis revealed the 3,4-dimethoxyphenylacetic acid was consumed. The reaction mixture was washed once with 1 nu HCl(aq) (90 mL) and concentrated in vacuo. The residue was chromatographed to yield the title compound(A; 10.67 g, 90% yield) as viscous oil.1H nuMR (400 MHz, CDCl3) 0.91 (br m, IH), 1.04 (br m, IH), 1.44 (q, J= 6.6 Hz, 2H),1.64 (m, 3H), 1.73 (br s, 2H), 2.56 (br m, IH), 2.92 (br m, IH), 3.64 (m, 4H), 3.84 (s, 3H), 3.84 (s, 3H), 4.59 (br m, IH), 6.73 (dd, J= 2.0, 8.2 Hz, IH), 6.78 (d, J = 2.0 Hz,IH), 6.79 (d, J= 8.2 Hz, IH). m/z 308 [M+l] +. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With boron trifluoride diethyl ether complex at 85℃; for 3h; | |
80% | With boron trifluoride diethyl ether complex at 90℃; for 1.5h; Inert atmosphere; | 4.2.1. 1-(2,4-Dihydroxyphenyl)-2-(3,4-dimethoxyphenyl)ethan-1-one (7b) 3,4-Dimethoxyphenylacetic acid (1.0 g, 5.1 mmol, 1.0 equiv.) andresorcinol (561 mg, 5.1 mmol, 1.0 equiv.) were added into 15mLboron trifluoride ethyl etherate. The mixturewas stirred at 90 °C for1.5 h under the protection of nitrogen. 30 mL cold water containing3.0 g sodium acetate was added into the reaction solution to precipitatethe product. The mixture was filtered and the solid waspurified by ethyl acetate to obtained 7b as a yellow solid (1.17 g,80%). 1H NMR (300 MHz, DMSO-d6) d 12.38 (s, 1H), 10.01 (s, 1H),8.03 (d, J 8.8 Hz, 1H), 6.91 (d, J 2.0 Hz, 1H), 6.89 (d, J 8.2 Hz,1H), 6.79 (dd, J 8.2, 2.0 Hz, 1H), 6.75 (d, J 2.4 Hz, 1H), 6.71 (dd,J 8.9, 2.4 Hz, 1H), 4.25 (s, 2H), 3.72 (s, 3H), 3.72 (s, 3H); ESI-MS m/z311.1 [MNa]. |
71.2% | With boron trifluoride diethyl ether complex at 80℃; for 2h; Inert atmosphere; |
69% | With boron trifluoride diethyl ether complex at 85℃; for 3h; Inert atmosphere; | |
62% | With trifluorormethanesulfonic acid at 60℃; for 1h; | |
52% | With boron trifluoride diethyl ether complex In N,N-dimethyl-formamide at 120℃; for 0.166667h; | |
52% | With boron trifluoride diethyl ether complex at 110℃; for 1.5h; Inert atmosphere; | |
19% | With boron trifluoride diethyl ether complex at 0 - 110℃; for 5h; | |
With boron trifluoride diethyl ether complex at 80 - 100℃; | ||
With boron trifluoride diethyl ether complex at 80℃; for 8h; | General procedure for synthesis of deoxybenzoin (3a-g) General Procedure: The mixture of p-methoxyphenyl acetic acid (500 mg, 3.08 mmol) in boron trifluoride etherate(0.6 ml) and resorcinol (280 mg, 3.00 mmol) were heated at 80 °C for 8 h. Reaction mixture was poured in water, extracted with ethyl acetate and dried over anhydrous sodium sulphate. Reaction mixture was concentratedto give crude product. Purification was done by column chromatography using silica gel as adsorbent and hexane, ethyl acetate as eluent to yield compound 3a. | |
With boron trifluoride diethyl ether complex at 80 - 90℃; Inert atmosphere; | ||
With boron trifluoride diethyl ether complex at 90℃; for 1.5h; Inert atmosphere; | 4.1.2.1. 1-(2,4-Dihydroxyphenyl)-2-(3,4-dimethoxyphenyl)Ethan-1-one (7) 3,4-Dimethoxyphenylacetic acid (5, 1.0 g, 5.1 mmol, 1.0 equiv.) and resorcinol (6, 561 mg, 5.1 mmol, 1.0 euqiv) were added into 0 mL boron trifluoride ethyl etherate. The mixture was stirred at 90 °C for1.5 h under the protection of nitrogen. 30 mL cold water containing3.0 g sodium acetate was added into the reaction solution to precipitate the product. The mixture was filtered and the solid was purified by ethyl acetate to obtained 7 as a yellow solid (1.17 g, 80%). 1H NMR(300 MHz, DMSO-d6) δ 12.59 (s, 1H), 10.67 (s, 1H), 7.96 (d,J = 8.9 Hz, 1H), 6.91 (d, J = 2.0 Hz, 1H), 6.87 (d, J = 8.2 Hz, 1H),6.80 (dd, J =8.2, 2.0 Hz, 1H), 6.40 (dd, J =8.9, 2.4 Hz, 1H), 6.26 (dd,J = 2.4 Hz, 1H), 4.20 (s, 2H), 3.72 (s, 6H); 13C NMR (75 MHz,DMSO-d6) δ 202.9, 165.4, 165.1, 149.1, 148.1, 134.0, 127.9, 122.0,113.8, 112.6, 112.3, 108.7, 102.9, 55.9, 55.9, 44.1; ESI-MS m/z 311.1[M + Na]+ | |
With boron trifluoride diethyl ether complex at 120℃; for 0.166667h; | 2.1 General processes for the synthesis of SIFs General procedure: The scheme of the synthetic procedure is shown in Fig. 1. The details concerning the synthesis of SIFs are described in the previous investigation (Goto et al., 2009). The mixture of compound 1 (7.8mmol), compound 2 (7.3mmol), and boron trifluoride-diethyl etherate (2.2ml) was heated at 120°C for 10min and cooled to room temperature. Then, N,N-dimethylformamide (9.9ml) was incorporated into the reaction mixture at 50°C for 10min. After adding methanesulfonyl chloride (5.9g), the mixture was heated at 80°C for 30min. After cooling to room temperature, cold water (240ml) was added. The product was extracted with diethylene and washed by brine and sodium bicarbonate. The sample was further purified with silica gel column chromatography to produce SIFs. The synthesized compounds included SIF-1 (3′,4′,7,8-tetrahydroxyisoflavone), SIF-2 (4′,7,8-trihydroxyisoflavone, 8-hydroxydaidzein), SIF-3 (3′,4′,7-trihydroxyisoflavone), SIF-4 (7,8-dihydroxy-3′,4′-dimethoxyisoflavone), SIF-5 (4′,7-dihydroxyisoflavone, daidzein), SIF-6 (7-hydroxy-3′,4′-dimethoxyisoflavone, cladrin), and SIF-7 (7-hydroxy-4′-methoxyisoflavone, formononetin, methoxy daidzein) (Fig. 1). The elucidation of SIF structures was established by 1H and 13C nuclear magnetic resonance (NMR) spectroscopy, and the data were in accordance with those reported earlier (Goto et al., 2009; Frasinyuk et al., 2015). The NMR spectra of SIFs were shown in Suppl. Material 1. The profiles and data about infrared (IR) spectrophotometry, ultraviolet (UV) spectrophotometry, NMR, and purity are depicted in Suppl. Material 2. The purity of SIF analogs was determined by high-performance liquid chromatography (HPLC). | |
With boron trifluoride diethyl ether complex at 120℃; for 0.166667h; | 2.1 General processes for the synthesis of SIFs General procedure: The scheme of the synthetic procedure is shown in Fig. 1. The details concerning the synthesis of SIFs are described in the previous investigation (Goto et al., 2009). The mixture of compound 1 (7.8mmol), compound 2 (7.3mmol), and boron trifluoride-diethyl etherate (2.2ml) was heated at 120°C for 10min and cooled to room temperature. Then, N,N-dimethylformamide (9.9ml) was incorporated into the reaction mixture at 50°C for 10min. After adding methanesulfonyl chloride (5.9g), the mixture was heated at 80°C for 30min. After cooling to room temperature, cold water (240ml) was added. The product was extracted with diethylene and washed by brine and sodium bicarbonate. The sample was further purified with silica gel column chromatography to produce SIFs. The synthesized compounds included SIF-1 (3′,4′,7,8-tetrahydroxyisoflavone), SIF-2 (4′,7,8-trihydroxyisoflavone, 8-hydroxydaidzein), SIF-3 (3′,4′,7-trihydroxyisoflavone), SIF-4 (7,8-dihydroxy-3′,4′-dimethoxyisoflavone), SIF-5 (4′,7-dihydroxyisoflavone, daidzein), SIF-6 (7-hydroxy-3′,4′-dimethoxyisoflavone, cladrin), and SIF-7 (7-hydroxy-4′-methoxyisoflavone, formononetin, methoxy daidzein) (Fig. 1). The elucidation of SIF structures was established by 1H and 13C nuclear magnetic resonance (NMR) spectroscopy, and the data were in accordance with those reported earlier (Goto et al., 2009; Frasinyuk et al., 2015). The NMR spectra of SIFs were shown in Suppl. Material 1. The profiles and data about infrared (IR) spectrophotometry, ultraviolet (UV) spectrophotometry, NMR, and purity are depicted in Suppl. Material 2. The purity of SIF analogs was determined by high-performance liquid chromatography (HPLC). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | Stage #1: (3,4-Dimethoxyphenyl)acetic acid With 4-methyl-morpholine; 1,3,5-trichloro-2,4,6-triazine In N,N-dimethyl-formamide at 20℃; for 0.166667h; Stage #2: 5-(sec-butyl)-4-hydroxybenzene-1,3-dicarbaldehyde In N,N-dimethyl-formamide at 110℃; for 0.833333h; | |
98% | Stage #1: (3,4-Dimethoxyphenyl)acetic acid With 4-methyl-morpholine; 1,3,5-trichloro-2,4,6-triazine In N,N-dimethyl-formamide at 20℃; for 0.166667h; Stage #2: 5-(sec-butyl)-4-hydroxybenzene-1,3-dicarbaldehyde In N,N-dimethyl-formamide for 0.75h; Reflux; | Generalsynthetic procedure for preparation of compounds (9-20): General procedure: To a mixture of cyanuric chloride (1.0equiv.) and N-methyl morpholine (1.5 equiv.) in DMF appropriatesubstituted phenyl acetic acid (1 equiv.) was added and stirred at roomtemperature for 10 min. After that, dicarbaldehyde (5-8, 1 mmol) was added, subsequently, the resulting reactionmixture was refluxed for 45 min (monitored by TLC). The reaction mixture wasdiluted with water and extracted with EtOAc. The combined organic layers weredried on Na2SO4, filtered, and concentrated to drynessunder reduced pressure. The residue was purified over columnchromatography (Al2O3, 70-230 mesh, neutral, hexane/ DCM)provided the purecompounds (9-20); 8-Sec-butyl-3-(3,4-dimethoxyphenyl)-2-oxo-2H-chromene-6-carbaldehyde(16)Light yellow solid; yield: 98%; mp: 140-142 C;IR (KBr): 3065, 1728, 1697, 1607, 1032 cm-1; 1H NMR (CDCl3,300 MHz) δ: 10.04(s, 1H), 7.93 (s, 2H), 7.86 (s, 1H), 7.33-7.29 (m, 2H), 6.96 (d, 1H, J = 8.6 Hz), 3.96 (s, 3H), 3.95 (s, 3H), 3.54-3.44 (m, 1H), 1.81-1.72 (m, 2H), 1.34 (d, 3H, J = 7.0 Hz), 0.91 (t, 3H, J= 7.4 Hz); 13C NMR(CDCl3, 75 MHz) δ:190.8, 160.0, 154.8, 150.2, 150.0, 138.6, 136.8, 132.8, 129.2, 128.8, 128.0,126.9, 121.4, 120.1, 111.9, 111.3, 56.2, 56.1, 33.5, 29.8, 20.6, 12.1; ESI-MS (m/z): 367 (M+H)+. |
98% | Stage #1: (3,4-Dimethoxyphenyl)acetic acid With 4-methyl-morpholine; 1,3,5-trichloro-2,4,6-triazine In N,N-dimethyl-formamide at 20℃; for 0.166667h; Stage #2: 5-(sec-butyl)-4-hydroxybenzene-1,3-dicarbaldehyde In N,N-dimethyl-formamide at 110℃; | General synthesis of 3-aryl coumarins (9a-9p): General procedure: To a mixture of cyanuric chloride (1.0 mmol), N-methyl morpholine (1.5 mmol) and substituted phenyl acetic acids (1.0 mmol) in DMF (5 mL), was stirred at room temperature for 10 min. after that 4-hydroxy-5-alkyl isophthalaldehyde (8a-8g, 1.0 mmol) was added. Subsequently, the resulting reaction mixture was refluxed for 30-90 min, after completion of the reaction (monitored by TLC) diluted with water (10 mL) and extracted 3-fold with EtOAc (15 mL). The combined organic layers were dried on Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was dissolved in methanol, the resulted solid was filtered and dried under vacuums to provide the pure compounds (9a-9p). |
59% | With dicyclohexyl-carbodiimide In dimethyl sulfoxide at 110℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | Stage #1: (3,4-Dimethoxyphenyl)acetic acid With 4-methyl-morpholine; 1,3,5-trichloro-2,4,6-triazine In N,N-dimethyl-formamide at 20℃; for 0.166667h; Stage #2: 4-hydroxy-5-methylisophthalaldehyde In N,N-dimethyl-formamide at 110℃; for 0.5h; | |
98% | Stage #1: (3,4-Dimethoxyphenyl)acetic acid With 4-methyl-morpholine; 1,3,5-trichloro-2,4,6-triazine In N,N-dimethyl-formamide at 20℃; for 0.166667h; Stage #2: 4-hydroxy-5-methylisophthalaldehyde In N,N-dimethyl-formamide for 0.75h; Reflux; | 5 5.1.4 Representative procedure for the synthesis of compounds (3a-d) General procedure: To a mixture of cyanuric chloride (1.0 equiv) and N-methyl morpholine (1.5 equiv) in DMF appropriate substituted phenyl acetic acid (1 equiv) was added and stirred at room temperature for 10 min. After that, aldehyde (2a/2b, 1 equiv) was added, subsequently, the resulting reaction mixture was refluxed for 45 min (monitored by TLC). The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried on Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified over column chromatography (Al2O3, 70-230 mesh, neutral, hexane/DCM) provided the pure compounds (3a-d). |
98% | Stage #1: (3,4-Dimethoxyphenyl)acetic acid With 4-methyl-morpholine; 1,3,5-trichloro-2,4,6-triazine In N,N-dimethyl-formamide at 20℃; for 0.166667h; Stage #2: 4-hydroxy-5-methylisophthalaldehyde In N,N-dimethyl-formamide for 0.75h; Reflux; | Generalsynthetic procedure for preparation of compounds (9-20): General procedure: To a mixture of cyanuric chloride (1.0equiv.) and N-methyl morpholine (1.5 equiv.) in DMF appropriatesubstituted phenyl acetic acid (1 equiv.) was added and stirred at roomtemperature for 10 min. After that, dicarbaldehyde (5-8, 1 mmol) was added, subsequently, the resulting reactionmixture was refluxed for 45 min (monitored by TLC). The reaction mixture wasdiluted with water and extracted with EtOAc. The combined organic layers weredried on Na2SO4, filtered, and concentrated to drynessunder reduced pressure. The residue was purified over columnchromatography (Al2O3, 70-230 mesh, neutral, hexane/ DCM)provided the purecompounds (9-20); 3-(3,4-Dimethoxyphenyl)-8-methyl-2-oxo-2H-chromene-6-carbaldehyde(10)Light yellow solid, yield: 98%; mp: 178-180C; IR (KBr): 3053, 1730, 1630, 1590, 1026; 1H NMR (CDCl3,300 MHz) δ: 2.56(s, 3H), 3.94 (s, 3H), 3.95 (s, 3H), 6.96 (d, 1H, J = 9.0 Hz), 7.32-7.29 (m, 2H), 7.84 (s, 1H), 7.88-7.91 (m, 2H), 10.01(s, 1H); 13C NMR(CDCl3, 75 MHz) δ:190.5, 159.9, 155.4, 150.2, 148.9, 138.2, 132.5, 132.4, 128.7, 128.0, 127.3,126.8, 121.4, 119.8, 111.2, 56.1, 56.0, 15.5. ESI-MS (m/z): 325 (M+H)+. |
98% | Stage #1: (3,4-Dimethoxyphenyl)acetic acid With 4-methyl-morpholine; 1,3,5-trichloro-2,4,6-triazine In N,N-dimethyl-formamide at 20℃; for 0.166667h; Stage #2: 4-hydroxy-5-methylisophthalaldehyde In N,N-dimethyl-formamide at 110℃; | General synthesis of 3-aryl coumarins (9a-9p): General procedure: To a mixture of cyanuric chloride (1.0 mmol), N-methyl morpholine (1.5 mmol) and substituted phenyl acetic acids (1.0 mmol) in DMF (5 mL), was stirred at room temperature for 10 min. after that 4-hydroxy-5-alkyl isophthalaldehyde (8a-8g, 1.0 mmol) was added. Subsequently, the resulting reaction mixture was refluxed for 30-90 min, after completion of the reaction (monitored by TLC) diluted with water (10 mL) and extracted 3-fold with EtOAc (15 mL). The combined organic layers were dried on Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was dissolved in methanol, the resulted solid was filtered and dried under vacuums to provide the pure compounds (9a-9p). |
60% | With dicyclohexyl-carbodiimide In dimethyl sulfoxide at 110℃; for 24h; | |
With 4-methyl-morpholine; 1,3,5-trichloro-2,4,6-triazine In N,N-dimethyl-formamide for 1h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 12h; | 4.3. General procedure for the esterification of alcohols syn-4b and anti-4b General procedure: Alcohol syn-4b (500 mg, 1.797 mmol, 1 equiv), DCC (445 mg, 2.16 mmol, 1.2 equiv), and DMAP (110 mg, 0.898 mmol, 0.5 equiv) were added to phenylacetic acid (294 mg, 2.16 mmol, 1.2 equiv) in CH2Cl2 (5 mL) at room temperature, under nitrogen. The mixture was stirred at room temperature for 12 h and the solvent was removed under reduced pressure. Et2O was added and the mixture was filtered. The filtrate was washed with sodium acetate buffer (pH=5) and the aqueous layer was extracted with Et2O. The organic layers were combined, dried over MgSO4, and concentrated under reduced pressure. The crude product was purified by flash chromatography (0-5% AcOEt/cyclohexane) to afford compound syn-9b (605 mg, 85%) as a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 18h; | General procedure: A mixture 2-amino-4,5-dimethylthiophene-3-carboxamide (340 mg, 2 mmol), 2-(1-naphthalen-1-yl)acetic acid (372 mg, 2 mol), EDC (458 mg, 2.4 mmol), HOBt (324 mg, 2.4 mmol), DIEA ( 1.1 mL, 6 mmol) in DMF (10 mL) was stirred at room temperature for 18 h. The reaction mixture was poured into 100 mL of water then extracted with ethyl acetate (150 mL). The organic layer was washed with saturated NaHCO3 solution (3 x 50 mL), brine (3 x 50 mL), water (3 x 50 mL) respectively. The ethyl acetate layer was dried over MgSO4 and concentrated. The residue was chromatographed over silica gel (30 to 40% ethyl acetate in haxane) to afford compound 1 (277 mg, 41%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With potassium carbonate In chloroform at 20℃; for 24h; Irradiation; Inert atmosphere; | |
94% | With 1H-imidazole; C17H16ClMnN2O2; tetrabutylammonium (meta)periodate In chloroform at 20℃; for 0.416667h; | |
94% | With tris(2,2′-bipyridine)ruthenium(II) dichloride hexahydrate; 1-butoxy-1λ3-benzo[d][1,2]iodaoxol-3(1H)-one In 2,2,2-trifluoroethanol at 40℃; for 3h; UV-irradiation; |
83% | With oxygen; Mn(dtbpy)<SUB>2</SUB>(OTf)<SUB>2</SUB> In acetonitrile at 45℃; for 12h; Irradiation; Schlenk technique; | |
73% | With copper(II) ferrite In dimethyl sulfoxide at 120℃; for 12h; Green chemistry; | |
70% | With Ag-Ag2S nanoparticles supported on cellulose In water monomer at 80℃; for 0.05h; Microwave irradiation; Green chemistry; | |
67% | With potassium peroxodisulfate In water monomer at 90℃; for 12h; Green chemistry; | General Procedure for the preparation of Aldehydes and Ketones from Aryl acetic acids General procedure: In an oven dried tube containing a mixture of 4-methyl phenyl acetic acid 1a (200 mg, 1.33mmol) and potassium persulfate (360 mg, 2.66 mmol), water (2 mL) was added and heated at 90 °C for 12 h. Upon completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature (24°C) and it was extracted with ethyl acetate (3 x 5 mL). The crude product was purified by column chromatography to furnish compound 2a as colorless liquid (136 mg, 85% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 60℃; for 1h; | 26.A Step A: Step A: To a pressure vessel were added, 4-fluoro-2-hydroxybenzaldehyde (0.5 g, 3.6 mmol), 2-(3,4-dimethoxyphenyl)acetic acid (1.4 g, 7.2 mmol), N-(3-dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride (1.5 g, 7.9 mmol), diisopropylethylamine (2.3 mL, 14.3 mmol) and CH2CI2 (10 mL). The mixture was stirred at 60 °C for 1 h, then quenched with an aqueous saturated NaHC03 solution (50 mL) and extracted with EtOAc three times. The combined extracts were dried over Na2S04 and concentrated under vacuum. The residue was purified by silica gel column chromatography (0-5% EtOAc in CH2C12) to give 3-(3,4-dimethoxyphenyl)-7- fluoro-2H-chromen-2-one (1.0 g, 95%). MS m/z 301.0 [M+H]+. |
95% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 60℃; for 1h; | 26.A Step A: To a pressure vessel were added, 4-fluoro-2-hydroxybenzaldehyde (0.5 g, 3.6 mmol), 2-(3,4-dimethoxyphenyl)acetic acid (1.4 g, 7.2 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.5 g, 7.9 mmol), diisopropylethylamine (2.3 mL, 14.3 mmol) and CH2Cl2 (10 mL). The mixture was stirred at 60° C. for 1 h, then quenched with an aqueous saturated NaHCO3 solution (50 mL) and extracted with EtOAc three times. The combined extracts were dried over Na2SO4 and concentrated under vacuum. The residue was purified by silica gel column chromatography (0-5% EtOAc in CH2Cl2) to give 3-(3,4-dimethoxyphenyl)-7-fluoro-2H-chromen-2-one (1.0 g, 95%). MS m/z 301.0 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 12h; | General procedure: Added compound 4 (1equiv.), appropriate acids (1.2equiv.), 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (1.2equiv.), Et3N (1.5equiv.) to anhydrous DMF (5mL) and stirred the solution at room temperature for 12h. The reaction mixture was poured into H2O (100mL). The precipitates were collected by filtration and washed with water to give the target compound 5a-r in a reasonable yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | Stage #1: (3,4-Dimethoxyphenyl)acetic acid With 4-methyl-morpholine; 1,3,5-trichloro-2,4,6-triazine In N,N-dimethyl-formamide at 20℃; for 0.166667h; Stage #2: 4-hydroxy-5-isopropylisophthalaldehyde In N,N-dimethyl-formamide at 110℃; | General synthesis of 3-aryl coumarins (9a-9p): General procedure: To a mixture of cyanuric chloride (1.0 mmol), N-methyl morpholine (1.5 mmol) and substituted phenyl acetic acids (1.0 mmol) in DMF (5 mL), was stirred at room temperature for 10 min. after that 4-hydroxy-5-alkyl isophthalaldehyde (8a-8g, 1.0 mmol) was added. Subsequently, the resulting reaction mixture was refluxed for 30-90 min, after completion of the reaction (monitored by TLC) diluted with water (10 mL) and extracted 3-fold with EtOAc (15 mL). The combined organic layers were dried on Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was dissolved in methanol, the resulted solid was filtered and dried under vacuums to provide the pure compounds (9a-9p). |
Stage #1: (3,4-Dimethoxyphenyl)acetic acid With 4-methyl-morpholine; 1,3,5-trichloro-2,4,6-triazine In N,N-dimethyl-formamide at 20℃; for 0.166667h; Stage #2: 4-hydroxy-5-isopropylisophthalaldehyde In N,N-dimethyl-formamide for 0.75h; Reflux; | ||
Stage #1: (3,4-Dimethoxyphenyl)acetic acid With 4-methyl-morpholine; 1,3,5-trichloro-2,4,6-triazine In N,N-dimethyl-formamide at 20℃; for 0.166667h; Stage #2: 4-hydroxy-5-isopropylisophthalaldehyde In N,N-dimethyl-formamide for 0.75h; Reflux; | Generalsynthetic procedure for preparation of compounds (9-20): General procedure: To a mixture of cyanuric chloride (1.0equiv.) and N-methyl morpholine (1.5 equiv.) in DMF appropriatesubstituted phenyl acetic acid (1 equiv.) was added and stirred at roomtemperature for 10 min. After that, dicarbaldehyde (5-8, 1 mmol) was added, subsequently, the resulting reactionmixture was refluxed for 45 min (monitored by TLC). The reaction mixture wasdiluted with water and extracted with EtOAc. The combined organic layers weredried on Na2SO4, filtered, and concentrated to drynessunder reduced pressure. The residue was purified over columnchromatography (Al2O3, 70-230 mesh, neutral, hexane/ DCM)provided the purecompounds (9-20); |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | Stage #1: (3,4-Dimethoxyphenyl)acetic acid With 4-methyl-morpholine; 1,3,5-trichloro-2,4,6-triazine In N,N-dimethyl-formamide at 20℃; for 0.166667h; Stage #2: 5-formyl-3-tert-butyl-2-hydroxybenzaldehyde In N,N-dimethyl-formamide at 110℃; | General synthesis of 3-aryl coumarins (9a-9p): General procedure: To a mixture of cyanuric chloride (1.0 mmol), N-methyl morpholine (1.5 mmol) and substituted phenyl acetic acids (1.0 mmol) in DMF (5 mL), was stirred at room temperature for 10 min. after that 4-hydroxy-5-alkyl isophthalaldehyde (8a-8g, 1.0 mmol) was added. Subsequently, the resulting reaction mixture was refluxed for 30-90 min, after completion of the reaction (monitored by TLC) diluted with water (10 mL) and extracted 3-fold with EtOAc (15 mL). The combined organic layers were dried on Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was dissolved in methanol, the resulted solid was filtered and dried under vacuums to provide the pure compounds (9a-9p). |
90% | Stage #1: (3,4-Dimethoxyphenyl)acetic acid With 4-methyl-morpholine; 1,3,5-trichloro-2,4,6-triazine In N,N-dimethyl-formamide at 20℃; for 0.166667h; Stage #2: 5-formyl-3-tert-butyl-2-hydroxybenzaldehyde In N,N-dimethyl-formamide for 0.75h; Reflux; | Generalsynthetic procedure for preparation of compounds (9-20): General procedure: To a mixture of cyanuric chloride (1.0equiv.) and N-methyl morpholine (1.5 equiv.) in DMF appropriatesubstituted phenyl acetic acid (1 equiv.) was added and stirred at roomtemperature for 10 min. After that, dicarbaldehyde (5-8, 1 mmol) was added, subsequently, the resulting reactionmixture was refluxed for 45 min (monitored by TLC). The reaction mixture wasdiluted with water and extracted with EtOAc. The combined organic layers weredried on Na2SO4, filtered, and concentrated to drynessunder reduced pressure. The residue was purified over columnchromatography (Al2O3, 70-230 mesh, neutral, hexane/ DCM)provided the purecompounds (9-20); 3-(4-Methoxyphenyl)-8-methyl-2-oxo-2H-chromene-6-carbaldehyde (9) Lightyellow solid, yield: 96%; mp: 148-150 C; IR (KBr): 3033, 1725, 1705, 1639,1021 cm-1; 8-tert-butyl-3-(3,4-dimethoxyphenyl)-2-oxo-2H-chromene-6-carbaldehyde(19)Light yellow solid; yield: 90%; mp: 152-153 C;IR (KBr): 3063, 1723, 1680, 1600, 1024 cm-1; 1H NMR (CDCl3,300 MHz) δ: 10.03(s, 1H), 8.02 (s, 1H), 7.93 (s, 1H), 7.83 (s, 1H), 7.36 (s, 1H), 7.26 (s, 1H),3.95 (s, 3H), 3.94 (s, 3H), 1.57 (s, 9H); ESI-MS (m/z): 367 (M+H)+. |
With 4-methyl-morpholine; 1,3,5-trichloro-2,4,6-triazine In N,N-dimethyl-formamide for 1h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine In tetrahydrofuran; chloroform at 70℃; for 20h; diastereoselective reaction; | (4) General procedure for β-lactam synthesis (Table 1 and Table 2) General procedure: The appropriate imine (0.762 mmol) and carboxylic acid (0.915 mmol, 1.2 eq.) were stirred in theappropriate solvent. NEt(i-Pr)2 (182 mg, 246 μL, 1.410 mmol, 1.85 eq.) and [T3P (364 mg, 1.14 mmol,1.5 eq. (728 mg of 50% wt. solution in THF)] were added by syringe and the reaction mixture stirred at70 °C for 20 h. The reaction was poured into sat. NaHCO3 (10 mL) and extracted with CH2Cl2 (3 × 10mL). The combined organic phases were dried (MgSO4), filtered, and concentrated to give the crudematerial. At this stage the diastereoselectivity was determined using 1H NMR. The material was purifiedby column chromatography (see individual entries for eluting solvent systems). |
61% | With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine In tetrahydrofuran; chloroform at 70℃; for 20h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With sodium acetate at 160℃; for 6h; Inert atmosphere; | |
65% | With sodium acetate at 160℃; for 6h; Inert atmosphere; | General procedure for synthesis of o-diacetoxy-3-phenylchromenones (4a-f) General procedure: A mixture of benzaldehyde (2a-d) (20 mmol), phenylacetic acids (3a-c) (20 mmol), and sodium acetate (50 mmol) was stirred in 40 mL acetic anhydride at 160 °C under N2 atmosphere for 6 h. On reaction completion, the mixture was poured into ice-cold water (200 mL). The crude product was filtered and recrystallized from ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80.5% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; Cooling with ice; | 2.25 2.1.1. General procedure for preparation of compounds b General procedure: Triphenylphosphine (1.5 mmol), 20,30-O-isopropylideneadenosine(1.0 mmol), and an appropriately substituted benzeneacetic acids(1.0 mmol) were dissolved in anhydrous THF (20 mL). After thesolution was cooled in an ice bath, diisopropyl azodicarboxylate(DIAD 2.0 mmol) was added dropwise, and the resulted mixturewas stirred at room temperature for several hours (monitored byTLC). Evaporation to dryness and flash chromatography (AcOEt/petroleum ether, from 5:1 to 3:1) afforded compounds b(Scheme 3). 2.1.25 ((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl 2-(3,4-dimethoxyphenyl)acetate (b12) White powder, 80.5%, mp 132-134 °C; 1H NMR (DMSO-d6): 1.33 (s, 6H, CH3); 1.55 (s, 6H, CH3); 3.64-3.74 (m, 2H, CH2); 4.18-4.22 (m, 1H, CH); 4.28-4.32 (m, 1H, CH); 4.36-4.40 (m, 1H, CH); 5.03-5.05 (m, 1H, CH); 5.43-5.45 (m, 1H, CH); 6.19 (d, J = 2.2 Hz, 1H, CH); 7.20-7.22 (m, 1H, ArH); 7.37 (s, 2H, NH2); 7.52-7.55 (m, 2H, ArH); 8.17 (d, J = 1.9 Hz, 1H, CHpurine); 8.30 (s, 1H, CHpurine). Anal. Calcd for C23H27N5O7: C, 56.90; H, 5.61; N, 14.43; Found: C, 56.83; H, 5.62; N, 14.47. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | Stage #1: (3,4-Dimethoxyphenyl)acetic acid; 1-Methoxynaphthalene With tetraphosphoric acid In acetonitrile at 20℃; for 0.166667h; Stage #2: With trifluoroacetic anhydride In acetonitrile at 20℃; for 8h; | 4.2. A representative synthetic procedure of skeleton 3 is as follows General procedure: PPA (H6P4O13, polyphosphoric acid, 1.7 g, 5.0 mmol) was added to a solution of substituted arenes (3.3 mmol) and phenylacetic acids (3.0 mmol) in MeCN (10 mL) at rt. The reaction mixture was stirred at rt for 10 min. TFAA (trifluoroacetic anhydride, 850 mg, 4.0 mmol) was added to the reaction mixture at rt. The reaction mixture was stirred at rt for 8 h. The solvent was concentrated. The residue was diluted with water (10 mL) and the mixture was extracted with CH2Cl2 (320 mL). The combined organic layers were washed with brine, dried, filtered and evaporated to afford crude product under reduced pressure. Purification on silica gel (hexanes/EtOAc=8/1-4/1) afforded 3. |
With trifluoroacetic acid; trifluoroacetic anhydride at 20℃; for 12h; | 8.1 Step 1: Add 1-methoxynaphthalene (1.5mmol), 3,4-dimethoxyphenylacetic acid (1.0mmol) and trifluoroacetic anhydride (2.0mmol), add 5ml of trifluoroacetic acid, and stir at room temperature for 12 hours, Spin dry, separate and purify with silica gel column chromatography to obtain 1-(4-methoxynaphthalen-1-yl)-2-(3,4-dimethoxyphenyl)ethane-1-one. | |
With trifluoroacetic acid; trifluoroacetic anhydride at 20℃; for 12h; | 4.1.1 General procedure for the synthesis of 3 General procedure: A mixture of 1 (12mmol, 1.90g), different phenylacetic acids 2 (8mmol), and TFAA (16mmol, 2.22mL) in TFA (5mL) was stirred at room temperature for overnight. After the completion of the reaction, the mixture was poured into 100mL of water and extracted with ethyl acetate (100mL×3). The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The residue was purified by chromatography to give the product 3. |
With trifluoroacetic acid; trifluoroacetic anhydride at 20℃; for 12h; | General Procedure for the Synthesis of 3a-3s General procedure: A mixtureof 1 (12 mmol), phenylacetic acids 2a-2s (8 mmol), andtrifluoroacetic anhydride (16 mmol) in trifluoroacetic acid(5 mL) was stirred at room temperature for overnight. Afterthe completion of the reaction, the content was poured intowater (100 mL) and extracted with ethyl acetate (100 mL × 3).The combined organic extracts were dried over Na2SO4, filtered,and concentrated. The residue was purified by chromatographyto give the product 3a-3s, which containing someimpurities. These compounds were used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In acetic anhydride; at 30℃; for 2h; | General procedure: General procedure A Step-a: Synthesis of 2-(4-fluorophenyl)-3-(4-((E)-3-methoxy-3-oxoprop-1-en-1-yl) phenyl) acrylic acid (C). A mixture of 4-fluorophenylacetic acid (2.5 g, 13.2 mmol) and methyl (E)-3-(4-formylphenyl)acrylate (2.03 g, 13.2 mmol) were dissolved under stirring with acetic anhydride (8 ml). To this mixture diisopropylethylamine (DIPEA) (3.4 ml, 19.7 mmol) was added and stirred at 30 C for 2 h. Upon completion (as monitored by TLC using 100% ethyl acetate as eluent), the reaction mixture was poured into water and the pH was adjusted to 1 using dil. HClaq (1:1). The aqueous layer was extracted with ethyl acetate (2 * 150 ml). The combined ethyl acetate layer was washed with water till the washings were neutral and dried over anhydrous Na2SO4. The ethyl acetate layer was evaporated to dryness to obtain a sticky compound, which was triturated with cold dichloromethane (DCM) to furnish a white solid. It was filtered and dried under vacuum to afford the title compound (2 g, 47%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; | N,N-dimethylformamide solution (3 ml) containing <strong>[16582-58-4]2-amino-6-iodobenzothiazole</strong> (200 mg, 0.723 mmol) and 3,4-dimethoxyphenylacetic acid (157 mg, 0.795 mmol) was added with N,N-diisopropylethylamine (139 mul, 0.803 mmol) and 0-(6-chlorobenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (360 mg, 0.870 mmol) and stirred over night at room temperature. After completion of the reaction, the solution was diluted with ethyl acetate and washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. The solution was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was recrystallized with ethanol and 167 mg of 2-(2-(3,4-dimethoxyphenyl)acetamide)-6-iodobenzothiazole was obtained in a yield of 50%. 1H NMR (DMSO-d6): delta 12.61 (s, 1H), 8.37 (s, 1H), 7.73-7.69 (m, 1H), 7.54 (d, J=8.0 Hz, 1H), 6.97-6.84 (m, 3H), 3.75-3.72 (m, 8H). MS (ESI) Found; 455[M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With pivaloyl chloride In toluene at 115℃; for 16h; | (S)-3-(2-(3,4-dimethoxyphenyl)acetyl)-4-isopropyloxazolidin-2-one (7). To a solution of (S)-4-isopropyloxazolidin-2-one (5.0 g, 38.76 mmol) and 3,4-Dimethoxy- phenylacetic acid (10.2 g,52.04 mmol) in dry toluene (250 mL) at 80°C was added PivCl (7.2 mL, 60.78 mmol) and the mixture was refluxed at 115°C for 16h. The reaction was quenched with 1M HCl and the aqueous layer was extracted with CH2Cl2, dried over Na2SO4 and concentrated. The crude residue was purified by flash column chromatography (PE-EtOAc, 4:1) to afford 7 (5.3 g,68 %) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 6.91 -6.79 (m, 1H), 4.47 - 4.40 (m, 0H), 4.29 (dd, J = 20.6, 11.7 Hz, 1H),4.22 - 4.13 (m, 1H), 3.86 (t, J = 5.2 Hz, 2H), 2.39 - 2.29 (m, 0H), 0.88(d, J = 7.0 Hz, 3H), 0.79 (d, J = 6.9 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; trichlorophosphate In diethyl ether at 0 - 20℃; for 6.16667h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 17.0h; | A mixture of 6?HCl (5.7 g, 15 mmol), homoveratric acid 10 (2.94 g, 15 mmol), HOBt (2.28 g, 16.8 mmol),EDC (3 mL, 16.8 mmol) and Et3N (6.3 mL, 45 mmol) in CH2Cl2 (300 mL) was stirred at room temperaturefor 17 h. The mixture was diluted with CH2Cl2 (100 mL) and was washed with 10% HCl (30 mL x 2), satdNaHCO3 (30 mL) and brine (30 mL), dried over Na2SO4, filtrated and evaporated to afford yellow solids.Recrystallization from EtOH (135 mL) gave amide 7 (6.96 g, 89%) as yellow solids of mp 148-150 C.1H NMR (the ratio of rotamer is 66/34): 2.49-2.61 (1.32H, m), 2.70 (0.34H, m), 2.92 (0.34H, m), 2.93(0.66H, dd, J = 8.0, 13.2), 2.98 (0.34H, dd, J = 5.2, 13.7), 3.02 (0.34H, d, J = 16.0), 3.07 (0.34H, dd, J = 9.2,13.7), 3.10 (0.66H, dd, J = 5.8, 13.2), 3.19 (0.34H, m), 3.24 (0.34H, d, J = 16.0), 3.38 (0.66H, m), 3.61(1.98H, s), 3.67 (1.02H, s), 3.68-3.73 (1.98H, m), 3.75 (1.98H, s), 3.80 (1.98H, s), 3.83-3.84 (6H, m), 3.86(1.02H, s), 3.87 (3H, s), 3.88 (1.02H, s), 4.82 (0.34H, m), 4.92 (0.34H, dd, J = 5.2, 9.2), 5.67 (0.66H, dd, J= 5.8, 8.0), 6.18 (0.66H, s), 6.39 (0.34H, s), 6.43-6.45 (0.68H, m), 6.15-6.52 (1.32H, m), 6.62-6.80 (4.66H,m), 6.84 (0.34 H, d, J = 8.6). 13C NMR: 27.9 (CH2), 28.3 (CH2), 35.2 (CH2), 39.6 (CH2), 41.1 (CH2), 41.2(CH2), 41.8 (CH2), 42.4 (CH), 54.0 (CH), 56.6 (CH3), 55.8 (CH3), 55.93 (CH3), 55.96 (CH3), 55.99 (CH3), 56.1 (CH3), 58.6 (CH), 110.1 (CH), 110.82 (CH), 110.89 (CH), 110.93 (CH), 111.2 (CH), 111.4 (CH), 111.5(CH), 111.6 (CH), 111.8 (CH), 111.9 (CH), 112.8 (CH), 112.9 (CH), 120.8 (CH), 120.9 (CH), 121.9 (CH),122.1 (CH), 125.6 (C), 126.7 (C), 127.5 (C), 127.7 (C), 128.0 (C), 128.3 (C), 130.5 (C), 130.7 (C), 147.0(C), 147.4 (C), 147.69 (C), 147.72 (C), 147.9 (C), 148.2 (C), 148.3 (C), 148.9 (C), 145.1 (C), 170.1 (C),170.4 (C). IR: 1630. HRMS-ESI m/z: [M+Na]+ calcd for C30H35NNaO7, 544.2311; found, 544.2300. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; for 6h; | 5.2.1 2-(3,4-dimethoxyphenyl)-N-(2-(thiophen-2-yl)ethyl)acetamide 6 To a solution of 2-(3,4-dimethoxyphenyl)acetic acid 5 (0.77g, 3.93mmol) in CH2Cl2, 2-thiophene ethylamine (0.50g, 3.93mmol), EDC-HCl (N-ethyl-N’-(3-dimethylaminopropyl)carbodiimide hydrochloride, 1.13g, 5.90mmol), HOBt (hydroxybenzotriazole, 0.69g, 5.11mmol) and triethylamine (0.40g, 3.93mmol) were added. The mixture was stirred for 6hat room temperature, washed with water and brine, dried over Na2SO4, filtered, and concentrated. The residue was recrystallized from ethyl acetate to afford 6 (1.6g, 86%) as a white solid. 1H NMR (400MHz, CDCl3) δ 7.12 (d, J=5.3Hz, 1H), 6.89-6.87 (m, 1H), 6.81 (d, J=8.0Hz, 1H), 6.74-6.67 (m, 3H), 5.53 (br, 1H), 3.88 (s, 3H), 3.85 (s, 3H), 3.50 (s, 2H), 3.49-3.42 (m, 2H), 2.97 (t, J=6.5Hz, 2H). LRMS (ESI) m/z: 306.1 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃; for 24h; | General method for the synthesis of monoesters/diesters A General procedure: To a stirred solution of 3,4-dimethoxyphenylacetic acid (0.19 g, 1.00 mmol) and thecorresponding alcohol (1.00 mmol)/diol (0.50 mmol) in CH2Cl2 (10 mL), 10% DMAP (0.01g, 0.10 mmol) was added and the mixture was cooled to 0°C. Then EDC (0.19 g, 1.00 mmol)was added and the reaction mixture was stirred at 0°C for 30 min and at room temperature for24 hours. Then CH2Cl2 (10 mL) and H2O (10 mL) were added and the organic phase wassuccessively washed with HCl 0.6 N (10 mL), H2O (10 mL), NaHCO3 5% (10 mL), H2O (10mL) and brine (10 mL), dried over Na2SO4 and the volatiles were removed in vacuo. Theresidue was purified with column chromatography using CH2Cl2/MeOH: 9.5/0.5 as eluent |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃; for 2h; | General method for the synthesis of amidoalcohols C General procedure: To a stirred solution of 3,4-dimethoxyphenylacetic acid (0.19 g, 1.00 mmol) and thecorresponding aminoalcohol(1.00 mmol) in CH2Cl2 (8 mL), HOBt (0.13 g, 1.00 mmol) wasadded and the mixture was cooled to 0°C. Then EDC (0.19 g, 1.00 mmol) was added and thereaction mixture was stirred at 0°C for 30 min and at room temperature for 2 hours. ThenCH2Cl2 (20 mL) and H2O (5 mL) were added and the organic phase was successively washedwith H2O (5 mL) and brine (10 mL), dried over Na2SO4 and the volatiles were removed invacuo. The residue was purified with column chromatography using CH2Cl2/MeOH: 9/1 aseluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | General procedure: A mixture of bromoacetic acid (2 mmol), HOBt (2 mmol) and EDC (2 mmol) in dichloromethane was stirred for 30 min at room temperature. Then 3a (2 mmol) was added to the solution. The reaction was stirred for 16 h at room temperature. Finally, reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL × 3). The organic layer was concentrated in vacuum and subjected to flash column chromatography to give compound 4a.A mixture of 2-(3,4-dimethoxyphenyl) acetic acid (2 mmol), HOBt (2 mmol) and EDC (2 mmol) in dichloromethane was stirred for 30 min at room temperature. Then 3a (2 mmol) was added to the solution. The reaction was stirred for 16 h at room temperature. Finally, reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL × 3). The organic layer was concentrated in vacuum and subjected to flash column chromatography to give compound 5a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | General procedure: A mixture of bromoacetic acid (2 mmol), HOBt (2 mmol) and EDC (2 mmol) in dichloromethane was stirred for 30 min at room temperature. Then 3a (2 mmol) was added to the solution. The reaction was stirred for 16 h at room temperature. Finally, reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL × 3). The organic layer was concentrated in vacuum and subjected to flash column chromatography to give compound 4a.A mixture of 2-(3,4-dimethoxyphenyl) acetic acid (2 mmol), HOBt (2 mmol) and EDC (2 mmol) in dichloromethane was stirred for 30 min at room temperature. Then 3a (2 mmol) was added to the solution. The reaction was stirred for 16 h at room temperature. Finally, reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL × 3). The organic layer was concentrated in vacuum and subjected to flash column chromatography to give compound 5a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83.4% | General procedure: A mixture of bromoacetic acid (2 mmol), HOBt (2 mmol) and EDC (2 mmol) in dichloromethane was stirred for 30 min at room temperature. Then 3a (2 mmol) was added to the solution. The reaction was stirred for 16 h at room temperature. Finally, reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL × 3). The organic layer was concentrated in vacuum and subjected to flash column chromatography to give compound 4a.A mixture of 2-(3,4-dimethoxyphenyl) acetic acid (2 mmol), HOBt (2 mmol) and EDC (2 mmol) in dichloromethane was stirred for 30 min at room temperature. Then 3a (2 mmol) was added to the solution. The reaction was stirred for 16 h at room temperature. Finally, reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL × 3). The organic layer was concentrated in vacuum and subjected to flash column chromatography to give compound 5a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With acetic anhydride; triethylamine; for 10h;Inert atmosphere; | In Reaction Scheme 1 above,Homobelatric acid represented by the chemical formula (a)(Homoveratric acid) and 4-butoxybenzaldehyde represented by the chemical formula (b)(4-butoxybenzaldehyde)Triethylamine (Et 3 N), Acetic anhydride (Ac 2 O), Reacted for 10 hours under N 2, allowed to cool, filtered through a filter and purified with EtOAc to give a yellow compound (Step 1 - 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | To a solution of compound 1 (10 g, 50.9 mmol., 1 equiv.) and N-Boc guanidine (8.5 g, 53.5 mmol., 1.05 equiv.) in DMF (100 mL) at 0 C, DIPEA (21.9 mL, 127.4 mmol., 2.5 equiv.) was added. The reaction mixture was allowed to stir for 30 min at the same temperature and then HATU (29 g, 76.5 mmol., 1.5 equiv.) was added in to it. The reaction mixture was allowed to stir overnight at room temperature. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was poured in to cold water and extracted twice with ethyl acetate. The combined organic layer was washed with brine and evaporated to dryness. The crude residue was purified through flash chromatography using hexane: ethyl acetate (80:20) as the eluent. Yield: 14 g (82%); 'H NMR (400 MHz, CDCb) d = 11.01 (brs, 1H), 8.81 (brs, 1H), 8.73 (brs, 1H), 6.88-6.91 (m, 2H), 6.80 (dd, J= 2.0 Hz, 6.0 Hz, 1H), 3.73 (d, J= 4.8 Hz, 6H), 3.55 (s, 1H), 1.38 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: o-Tolylacetic acid (0.59 g; 1.0 equiv; 3.77 mmol) and47.0 mg 4-DMAP (10 mol %; 0.38 mmol) were added to a100-mL round flask containing 1 g compound c (3.77 mmol) and stirred in an ice bath for 5 min after the addition of 20 mL methylene chloride. Afterward, 0.80 g DCC (1.0 equiv; 3.77 mmol) was added into the mixture and allowed to react for 3 h at room temperature, until the starting materials (TLC analysis) began to disappear. The resulting DHU was filtered under reduced pressure. The filtrate was extracted using 0.5 M HCl and a saturated solution of NaHCO3 in order. The solvent was removed under reduced pressure after dehydration using anhydrousMgSO4. The purified solid was obtained by recrystallization from ethanol as a light yellow solid. Synthesis of compounds 39-57 is shown in Scheme 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | Stage #1: (3,4-Dimethoxyphenyl)acetic acid With phosphoric acid; trifluoroacetic anhydride In acetonitrile at 25℃; for 0.5h; Stage #2: acetophenone In acetonitrile at 25℃; for 10h; | Synthesis of 3a′, 3a-x and 3aa-ag; General Procedure General procedure: Trifluoroacetic anhydride (TFAA, 230 mg, 1.1 mmol) and phosphoricacid (H3PO4, 110 mg, 1.1 mmol) were added to a solution of oxygenatedarylacetic acids 1a-d (1.0 mmol) in MeCN (15 mL) at 25 °C. The reactionmixture was stirred at 25 °C for 30 min. Ketone 2a-x or 2aa-ad(0.5 mmol) in MeCN (5 mL) was added to the reaction mixture at25 °C, and the reaction mixture was stirred at reflux (80 °C) for 20 h.The solvent of reaction mixture was concentrated, the residue was dilutedwith water (10 mL) and the mixture was extracted with CH2Cl2(3 × 20 mL). The combined organic layers were washed with brine,dried, filtered and evaporated to afford the crude product under reducedpressure. Purification on silica gel (hexanes/EtOAc = 10:1 to1:1) afforded compounds 3a′, 3a-x and 3aa-ag. 6,7-Dimethoxy-1-methyl-1-phenylisochroman-3-one (3a′)11For Table 1, entry 1. Yield: 87% (130 mg); colorless solid; mp 159-161 °C (recrystallizedfrom hexanes and EtOAc).1H NMR (400 MHz, CDCl3): = 7.26-7.19 (m, 3 H), 7.15-7.13 (m, 2 H),6.98 (s, 1 H), 6.65 (s, 1 H), 3.92 (s, 3 H), 3.86 (s, 3 H), 3.44 (d, J =18.4 Hz, 1 H), 3.07 (dd, J = 0.8, 18.4 Hz, 1 H), 2.00 (s, 3 H).13C{1H} NMR (100 MHz, CDCl3): = 171.0, 149.2, 147.9, 143.3, 130.1,128.3 (2C), 127.8, 125.2 (2C), 123.0, 110.4, 108.5, 85.9, 56.2, 55.9,36.2, 29.0.HRMS (ESI-TOF): m/z [M + H]+ calcd for C18H19O4: 299.1283; found:299.1288. |
74% | Stage #1: (3,4-Dimethoxyphenyl)acetic acid With trifluoroacetic anhydride In acetonitrile at 25℃; for 0.166667h; Green chemistry; Stage #2: acetophenone In acetonitrile at 25℃; for 10h; Green chemistry; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With dicyclohexyl-carbodiimide In dimethyl sulfoxide at 110℃; for 24h; | |
41% | Stage #1: (3,4-Dimethoxyphenyl)acetic acid; 3-ethoxysalicylaldehyde With dicyclohexyl-carbodiimide In dimethyl sulfoxide at 110℃; for 24h; Inert atmosphere; Stage #2: With acetic acid In dimethyl sulfoxide at 20℃; for 2h; Inert atmosphere; | 4.2. Synthetic methodologies General procedure: A solution of ortho-hydroxybenzaldehyde (1.0 mmol), the correspondingarylacetic acid (1.25 mmol) and DCC (1.56 mmol), in DMSO(2.0 mL), was heated at 110 °C in an oil bath for 24 h. Ice (20 g). AcOH(3.0 mL) was added and the mixture was stirred at room temperaturefor 2 h, and then extracted with Et2O (3 Å~ 25 mL). The combinedorganic layer was washed with 5% aqueous NaHCO3 solution (50 mL)and H2O (20 mL) and dried (Na2SO4). The solvent was evaporatedunder vacuum and the residue was purified by flash chromatography(hexane-EtOAc, 9:1) to give the coumarins 9, 72-74, 75′ and 76. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With 1,10-Phenanthroline; oxygen; copper(II) oxide; potassium ferrocyanide In dimethyl sulfoxide at 120℃; for 40h; Autoclave; | 2.2. General procedure for the conversion of arylacetic acids to aromatic nitriles General procedure: The reaction was carried out in a 40 mL stainless steel autoclave lined with Teflon. Typically, 0.5 mmol substrate, 0.6 mmol K4Fe(CN)6, 0.1mmol CuO, 0.5 mmol 1,10-phenanthroline and 2 mL DMSO were added into the reactor and 1.5MPa of oxygen was filled. Then the reaction system was heated under magnetic stirring at 120°C for 40h. Once the reaction time was reached, the mixture was cooled to room temperature. GC analysis of the reaction mixture provided the GC yields of the products. In addition, the crude product from another parallel experiment was purified by column chromatography, and identified by 1H NMR and 13C NMR. |
83% | With iron(III) trifluoromethanesulfonate; sodium nitrite In dimethyl sulfoxide at 50℃; for 10h; Inert atmosphere; Sealed tube; | Nitriles 2a-r: General Procedure General procedure: A tube of approximate volume 45 mL was charged with theappropriate arylacetic acid (0.5 mmol), NaNO2 (3 mmol),Fe(OTf)3 (1 mmol), and undried DMSO (2 mL), and the air in thetube was replaced by argon gas. The tube was sealed and themixture was heated with magnetic stirring at 50 °C for 10 h,then cooled to r.t. The solvent was evaporated, and the residuewas purified by column chromatography (silica gel). |
90 %Chromat. | With iron(III) chloride; sodium nitrite In dimethyl sulfoxide at 50℃; for 10h; Sealed tube; | 1-24 Example 1 Take magnetons, 2 mL of dimethyl sulfoxide, 0.5 mmol of 3,4-dimethoxyphenylacetic acid, 3 mmol of sodium nitrite, and 0.5 mmol of ferric chloride into the glass pressure-resistant reaction tube in order. The tube was sealed and placed in a heating tank at a temperature of 50 ° C, and a heating reaction was performed under magnetic stirring for 10 hours. After completion of the reaction, the reaction system was cooled to room temperature.After that, the above reaction product was subjected to internal standard quantitative analysis using a gas chromatograph, and the yield of the 3,4-dimethoxybenzonitrile product was measured to be 82%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Stage #1: (3,4-Dimethoxyphenyl)acetic acid With phosphoric acid; trifluoroacetic anhydride In acetonitrile at 25℃; for 0.5h; Stage #2: 1-(4-methoxyphenyl)ethanone In acetonitrile at 25 - 80℃; for 20h; | Synthesis of 3a′, 3a-x and 3aa-ag; General Procedure General procedure: Trifluoroacetic anhydride (TFAA, 230 mg, 1.1 mmol) and phosphoricacid (H3PO4, 110 mg, 1.1 mmol) were added to a solution of oxygenatedarylacetic acids 1a-d (1.0 mmol) in MeCN (15 mL) at 25 °C. The reactionmixture was stirred at 25 °C for 30 min. Ketone 2a-x or 2aa-ad(0.5 mmol) in MeCN (5 mL) was added to the reaction mixture at25 °C, and the reaction mixture was stirred at reflux (80 °C) for 20 h.The solvent of reaction mixture was concentrated, the residue was dilutedwith water (10 mL) and the mixture was extracted with CH2Cl2(3 × 20 mL). The combined organic layers were washed with brine,dried, filtered and evaporated to afford the crude product under reducedpressure. Purification on silica gel (hexanes/EtOAc = 10:1 to1:1) afforded compounds 3a′, 3a-x and 3aa-ag. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | Stage #1: (3,4-Dimethoxyphenyl)acetic acid With phosphoric acid; trifluoroacetic anhydride In acetonitrile at 25℃; for 0.5h; Stage #2: methyl 2-naphthyl ketone In acetonitrile at 25 - 80℃; | Synthesis of 3h-1, 3k-1, 3o-1, 3v-1 and 3w-1; General Procedure General procedure: Trifluoroacetic anhydride (TFAA, 230 mg, 1.1 mmol) and phosphoricacid (H3PO4, 110 mg, 1.1 mmol) were added to a solution of homoveratricacid (1a, 98 mg, 0.5 mmol) in MeCN (15 mL) at 25 °C. The reactionmixture was stirred at 25 °C for 30 min. Ketone 2h, 2k, 2o, 2v or2w (0.5 mmol) in MeCN (5 mL) was added to the reaction mixture at25 °C and the reaction mixture was stirred at reflux (80 °C) for 20 h.The solvent of reaction mixture was concentrated, the residue was dilutedwith water (10 mL) and the mixture was extracted with CH2Cl2(3 × 20 mL). The combined organic layers were washed with brine,dried, filtered and evaporated to afford crude product under reducedpressure. Purification on silica gel (hexanes/EtOAc = 10:1 to 1:1) affordedcompounds 3h-1, 3k-1, 3o-1, 3v-1 and 3w-1.6,7-Dimethoxy[1,2′]binaphthalenyl-3-ol (3h-1)Yield: 94% (155 mg); colorless liquid.1H NMR (400 MHz, CDCl3): = 7.94-7.90 (m, 3 H), 7.85-7.82 (m, 1 H),7.60 (dd, J = 1.2, 8.4 Hz, 1 H), 7.56-7.51 (m, 2 H), 7.18 (s, 1 H), 7.12 (d,J = 2.4 Hz, 1 H), 7.03 (d, J = 2.4 Hz, 1 H), 7.03 (s, 1 H), 5.99 (br s, 1 H),3.97 (s, 3 H), 3.73 (s, 3 H).13C{1H} NMR (100 MHz, CDCl3): = 152.0, 149.8, 147.7, 140.5, 138.1,133.4, 132.5, 131.1, 128.3, 128.0, 127.9, 127.70, 127.66, 126.3, 126.1,122.3, 117.0, 108.7, 105.6, 105.1, 55.7, 55.6.HRMS (ESI-TOF): m/z [M + H]+ calcd for C22H19O3: 331.1334; found:331.1339. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Stage #1: (3,4-Dimethoxyphenyl)acetic acid With phosphoric acid; trifluoroacetic anhydride In acetonitrile at 25℃; for 0.5h; Stage #2: 1-(3,4-dimethoxyphenyl)ethanone In acetonitrile at 25 - 80℃; for 20h; | Synthesis of 3a′, 3a-x and 3aa-ag; General Procedure General procedure: Trifluoroacetic anhydride (TFAA, 230 mg, 1.1 mmol) and phosphoricacid (H3PO4, 110 mg, 1.1 mmol) were added to a solution of oxygenatedarylacetic acids 1a-d (1.0 mmol) in MeCN (15 mL) at 25 °C. The reactionmixture was stirred at 25 °C for 30 min. Ketone 2a-x or 2aa-ad(0.5 mmol) in MeCN (5 mL) was added to the reaction mixture at25 °C, and the reaction mixture was stirred at reflux (80 °C) for 20 h.The solvent of reaction mixture was concentrated, the residue was dilutedwith water (10 mL) and the mixture was extracted with CH2Cl2(3 × 20 mL). The combined organic layers were washed with brine,dried, filtered and evaporated to afford the crude product under reducedpressure. Purification on silica gel (hexanes/EtOAc = 10:1 to1:1) afforded compounds 3a′, 3a-x and 3aa-ag. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | Stage #1: (3,4-Dimethoxyphenyl)acetic acid With phosphoric acid; trifluoroacetic anhydride In acetonitrile at 25℃; for 0.5h; Stage #2: methyl (3,4,5-trimethoxyphenyl) ketone In acetonitrile at 25 - 80℃; for 20h; | Synthesis of 3a′, 3a-x and 3aa-ag; General Procedure General procedure: Trifluoroacetic anhydride (TFAA, 230 mg, 1.1 mmol) and phosphoricacid (H3PO4, 110 mg, 1.1 mmol) were added to a solution of oxygenatedarylacetic acids 1a-d (1.0 mmol) in MeCN (15 mL) at 25 °C. The reactionmixture was stirred at 25 °C for 30 min. Ketone 2a-x or 2aa-ad(0.5 mmol) in MeCN (5 mL) was added to the reaction mixture at25 °C, and the reaction mixture was stirred at reflux (80 °C) for 20 h.The solvent of reaction mixture was concentrated, the residue was dilutedwith water (10 mL) and the mixture was extracted with CH2Cl2(3 × 20 mL). The combined organic layers were washed with brine,dried, filtered and evaporated to afford the crude product under reducedpressure. Purification on silica gel (hexanes/EtOAc = 10:1 to1:1) afforded compounds 3a′, 3a-x and 3aa-ag. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | Stage #1: (3,4-Dimethoxyphenyl)acetic acid With phosphoric acid; trifluoroacetic anhydride In acetonitrile at 25℃; for 0.5h; Stage #2: propiophenone In acetonitrile at 25 - 80℃; for 20h; | Synthesis of 3a′, 3a-x and 3aa-ag; General Procedure General procedure: Trifluoroacetic anhydride (TFAA, 230 mg, 1.1 mmol) and phosphoricacid (H3PO4, 110 mg, 1.1 mmol) were added to a solution of oxygenatedarylacetic acids 1a-d (1.0 mmol) in MeCN (15 mL) at 25 °C. The reactionmixture was stirred at 25 °C for 30 min. Ketone 2a-x or 2aa-ad(0.5 mmol) in MeCN (5 mL) was added to the reaction mixture at25 °C, and the reaction mixture was stirred at reflux (80 °C) for 20 h.The solvent of reaction mixture was concentrated, the residue was dilutedwith water (10 mL) and the mixture was extracted with CH2Cl2(3 × 20 mL). The combined organic layers were washed with brine,dried, filtered and evaporated to afford the crude product under reducedpressure. Purification on silica gel (hexanes/EtOAc = 10:1 to1:1) afforded compounds 3a′, 3a-x and 3aa-ag. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | Stage #1: (3,4-Dimethoxyphenyl)acetic acid With phosphoric acid; trifluoroacetic anhydride In acetonitrile at 25℃; for 0.5h; Stage #2: 1-(4-fluorophenyl)-2-phenylethanone In acetonitrile at 25 - 80℃; for 20h; | Synthesis of 3a′, 3a-x and 3aa-ag; General Procedure General procedure: Trifluoroacetic anhydride (TFAA, 230 mg, 1.1 mmol) and phosphoricacid (H3PO4, 110 mg, 1.1 mmol) were added to a solution of oxygenatedarylacetic acids 1a-d (1.0 mmol) in MeCN (15 mL) at 25 °C. The reactionmixture was stirred at 25 °C for 30 min. Ketone 2a-x or 2aa-ad(0.5 mmol) in MeCN (5 mL) was added to the reaction mixture at25 °C, and the reaction mixture was stirred at reflux (80 °C) for 20 h.The solvent of reaction mixture was concentrated, the residue was dilutedwith water (10 mL) and the mixture was extracted with CH2Cl2(3 × 20 mL). The combined organic layers were washed with brine,dried, filtered and evaporated to afford the crude product under reducedpressure. Purification on silica gel (hexanes/EtOAc = 10:1 to1:1) afforded compounds 3a′, 3a-x and 3aa-ag. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With HATU; potassium carbonate In N,N-dimethyl-formamide at 20℃; for 8h; | 4.1.42. 4-((4-Methylpiperazin-1-yl)methyl)-N-(4-methylthiazol-2-yl)-3-(trifluoromethyl)benzamide (51a) General procedure: To a solution of 50 (1 g, 2.3 mmol) in DMF (20 mL) were addedK2CO3 (3.2 g, 23 mmol), 4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzoic acid (0.84 g, 2.8 mmol) and HATU (1.1 g,3 mmol) in batches, and the reaction was allowed to be stirred at rtfor 8h. The mixture was extracted by DCM (100 mL 3) andwashed with water (100 mL 2) followed by brine (100 mL). Theorganic layers were dried over sodium sulfate, filtered, concentratedand purified by silica gel column chromatography (elutingwith 0e30% EtOAc in heptane) to afford 51a as a white solid (0.72 g,72%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With diphenyl phosphoryl azide; triethylamine In toluene at 120℃; Flow reactor; | General procedure for Curtius rearrangements in flow General procedure: In a similar manner as described before [Org. Process Res. Dev. 2020, in press;doi.org/10.1021/acs.oprd.0c00420] the carboxylic acid substrate (1.0 equiv), triethylamine(1.0 equiv.) and benzyl alcohol (1.8 equiv) are dissolved in toluene giving after agitation a clear solution(1 M). DPPA (0.9 equiv) is dissolved in toluene giving a second solution of equal volume (0.9 M). Bothsolutions are pumped at individual flow rates of 0.17 mL/min and mixed in a T-piece (1/8’’ PEEK)before entering a reactor coil mounted on a Vapourtec flow reactor (10 mL, PFA, 120 °C). Upon exitingthe reactor coil the crude Curtius reaction mixture passed a BPR (100 psi) before entering an Omnifitcolumn filled with a mixture of scavenger resin (A15/A21, ca. 50:50). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With triethylamine In acetic anhydride at 110℃; | 4.1.3. General procedure for the synthesis of 2a-2n General procedure: Cinnamaldehydes (10 mmol) and 2-phenylacetic acids(10 mmol) were dissolved in acetic anhydride (2.84 mL, 30 mmol),and then triethylamine (4.16 mL, 30 mmol) was added slowly. Themixture was stirred at 110 C overnight. After cooling to roomtemperature, ice-cold water was added and the mixture was acidifiedwith 12 N HCl. The precipitated crude product was collectedand was dissolved in 10% aq NaOH. After extracting with EtOAc, theaqueous layer was acidified with HCl to pH 6e7. The precipitatedcrude product was collected by filtration and washed with coldEtOAc to afford 2a-2n as a light yellow solid. 4.1.3.1. |
72% | With triethylamine In acetic anhydride at 110℃; | 4.1.3. General procedure for the synthesis of 2a-2n General procedure: Cinnamaldehydes (10 mmol) and 2-phenylacetic acids(10 mmol) were dissolved in acetic anhydride (2.84 mL, 30 mmol),and then triethylamine (4.16 mL, 30 mmol) was added slowly. Themixture was stirred at 110 C overnight. After cooling to roomtemperature, ice-cold water was added and the mixture was acidifiedwith 12 N HCl. The precipitated crude product was collectedand was dissolved in 10% aq NaOH. After extracting with EtOAc, theaqueous layer was acidified with HCl to pH 6e7. The precipitatedcrude product was collected by filtration and washed with coldEtOAc to afford 2a-2n as a light yellow solid. 4.1.3.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With trichlorophosphate at 80℃; for 8h; | 3.1. General Procedure for the Synthesis of 2,5-Disubstituted-1,3,4-oxadiazole General procedure: A mixture of benzoic acid (1a) (1 mmol), and concentrated sulfuric acid (1 mmol) in10 mL of ethanol was stirred and refluxed for 7 h. After completion of the reaction, thereaction mass was cooled and ethanol was removed by high vacuum pressure. Then, thereaction mixture was diluted with ethyl acetate and neutralized by bicarbonate solution.The organic layer was separated out and dried over anhydrous sodium sulphate, andconcentrated under vacuum; ethyl benzoate was obtained as a white solid. To the ethylbenzoate (2a) (1 mmol), hydrazine hydrate (1 mmol) and 15 mL of ethanol were addedand refluxed for 5 h. The completion of reaction was monitored by TLC and the traces ofhydrazine hydrate were washed with water; acid hydrazide was obtained as a solid. Toa mixture of acid hydrazide (3a) (1 mmol) and substituted acids (1 mmol), 6 mL of POCl3was added and refluxed at 80 C for 8 h. The completion of the reaction was monitoredby TLC. The reaction mass was quenched with crushed ice and neutralized by potassiumcarbonate to pH 8. The solid obtained was filtered, washed with water, and subjectedto column chromatography (hexane/ethyl acetate eluent)/recrystallized with suitablesolvents to obtain pure oxadiazoles. 4a-c (1 mmol), substituted aryl/het.aryl boronic acids(Ar/Het.Ar-B(OH)2) (1.2 mmol) and potassium carbonate (3 mmol) were taken in a sealedtube containing H2O:dioxane:EtOH (1:5:1) solvent. The above mixture was stirred for15 min at RT under an inert atmosphere (N2 atm). Then, a catalyst (Pd(dppf)Cl2) (0.1 mmol)was added to the above reaction mass and heated to 120 C for 45 min. Aryl-substituted1,3,4-oxadiazole (5a-x) was obtained and purified through the chromatographic techniqueusing hexane/ethyl acetate as an eluent. |
Tags: 93-40-3 synthesis path| 93-40-3 SDS| 93-40-3 COA| 93-40-3 purity| 93-40-3 application| 93-40-3 NMR| 93-40-3 COA| 93-40-3 structure
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P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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