| 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; |
|
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