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CAS No. : | 105601-04-5 |
Formula : | C10H15NO |
M.W : | 165.23 |
SMILES Code : | OC1=CC=CC(C(N(C)C)C)=C1 |
MDL No. : | MFCD08272688 |
InChI Key : | GQZXRLWUYONVCP-UHFFFAOYSA-N |
Pubchem ID : | 409441 |
GHS Pictogram: | ![]() ![]() |
Signal Word: | Danger |
Hazard Statements: | H301-H318-H412 |
Precautionary Statements: | P273-P280-P301+P310-P305+P351+P338-P310 |
Class: | 8(6.1) |
UN#: | 2923 |
Packing Group: | Ⅲ |
* 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 |
---|---|---|
60% | With sulfuric acid; DL-methionine; In water; at 110 - 120℃; for 28h; | Experimental procedure: To the solution of 50 % sulfuric acid in water (400.0 [ML),] was added at 10 to 15 C temperature, DL-methionine (124.9 gm, 0.837 moles) and stirred for 15 minutes. To this solution, was added [[1- (3-METHOXYPHENYL)] ethyl] dimethylamine (100.0 gm, 0.553 moles) at 10 to 15 C temperature within 2 hours and stirred for 30 minutes. Reaction mixture was then heated to 110 to 120C temperature for 28 hours. The reaction mixture was diluted with water, basified to pH 8.5 to 9.0 using ammonia solution and extracted with dichloromethane. Organic extract was then washed with water, charcoalized and concentrated. Hexane was then added to the residue and crude product filtered. b) Purification: Crude product was recrystallized from diisopropylether to give pure [1- (3- hydroxyphenyl) ethyl] dimethylamine (55.0 gm, 60 % yield, Purity->99%) melting range: 85 to [86C] temperature) |
With hydrogen bromide; In water; at 145 - 150℃; for 12h;Heating / reflux; | Preparation of 3- (L-DIMETHYLAMINOETHYL) PHENOL (IV) according to Literature 3 94 g of [1- (3-METHOXYPHENYL) ETHYL] dimethylamine (V) are dissolved in 285 ml of azeotropic hydrobromic acid and the resulting solution is refluxed under stirring using a reflux condenser for 12 hours (bath temperature 145-150 C). During boiling, the reaction mixture darkens. The solution is then left to cool down to room temperature. Excess hydrobromic acid is evaporated using a rotary vacuum evaporator and the evaporation residue is dissolved in 200 ml of water. The solution is extracted with 3x 100 ML ETHYLACETATE. The aqueous fraction is then gradually alkalized with the saturated solution of sodium carbonate with constant stirring (foam creation). The solution becomes milky turbid and it is extracted with 3x 200 ml ethylacetate. The ethylacetate fraction is shaken out lx with water, lx with brine and dried with anhydrous magnesium sulfate. Activated carbon is added before filtering off the desiccant and the desiccant along with the carbon are filtered off. The ethylacetate solution of compound (IV) is used for the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With potassium carbonate; In acetonitrile; at 70 - 80℃; | Condensation reaction of 3-(l-dimethylaminoethyl) phenol (10 gm) and ethylmethylcarbamoyl chloride (10gm) was carried in the presence of potassium carbonate (25 gm) and acetonitrile (150 ml) at 70-80 C. After completion of reaction, the reaction mixture was quenched in water (250 ml) at 30-35 C and extracted in ethyl acetate (100ml). Evaporation of ethyl acetate gave the desired compound in 70% yield. Yield: 80-85 gms. %Yield: 66.0% HPLC Purity: 99%. |
b) Preparation of 3-(1-(dimethylamino)ethyl)phenyl ethyl-(methyl) carbamate (rivastigmine base) An amount of 5.25 g (30.0 mmol) of 3-(1-dimethylaminoethyl)-phenol was dissolved in 70 ml of acetonitrile. To the solution was slowly added 1.30 g (32.5 mmol) of sodium hydride and stirred for 30 minutes. 6.20 g (51 mmol) of ethyl(methyl)-carbamic chloride were slowly added to the solution. The reaction mixture was stirred for 20 hours. The mixture was filtered and concentrated. 100 ml of water were added and the pH was adjusted with 0.1 M NaOH to pH 12, followed by extraction with ether (3x100 ml). The organic layer was then washed with 100 ml of brine, dried over sodium sulfate, filtered and concentrated. 6.20 g of an oily residue of rivastigmine base were obtained. | ||
An amount of 1.1 g (27.5 mmol, 60 %, 1.05 mole) of sodium hydride suspended in 15 ml of acetonitrile was added to 1.0 mole of the above obtained 3-(1-dimethylaminoethyl)phenol (as acetonitrile solution) within a period of 30 minutes while maintaining the reaction mixture at the room temperature. After the addition of sodium hydride an amount of 3.1 ml (3.44 g, 97 % 27.5 mmol, 1.05 molar equivalent) of ethyl(methyl)-carbamic chloride were added within a period of 30 minutes. The reaction mixture was stirred for 2 hours at room temperature and then the solvent was removed under vacuum at 50 mbar and 50C. 55 ml of ether and 35 ml of water were added to the residue, the pH was set to 11 with 0.1 M NaOH and stirred for 20 minutes. The layers were separated. The water phase was washed with 25 ml of ether and the organic phases were combined, dried with 2.0 g of Na2SO4 and filtered. The filtrate was concentrated to obtain 6.4 g of an oily substance of 3-(1-(dimethylamino)ethyl)phenyl ethyl(methyl)carbamate. Yield from 1-(3-hydroxyphenyl)-N,N-dimethyl-ethanaminium chloride was 85 %, purity of the product 97.7 area %. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With hydrogen;nickel; In methanol; at 80℃; under 7355.72 Torr; for 3 - 4h;Product distribution / selectivity; | Example 2: Preparation of alpha-m-hydroxy phenylethyldimethylamine; N-methylation was carried out on alpha-m-hydroxy phenylethylmethylamine (25g) with Paraformaldehyde (15g) in presence of Raney Nickel (3Og) in methanol(500ml) at 80C and 10kg /cm2 of lrydrogen pressure in an autoclave. After 3-4 hours the product was isolated by removing Raney nickel and concentrating the filtrate. The product was further <n="9"/>purified by dissolving the crude product in Toluene (50ml) and is crystallized by slow addition of Petroleum ether (150ml). Pure alpha-m-hydroxy phenylethyldimethylarnine is isolated (23g, Yield: 85%, purity 98%) by filtration.Characterization data:1H-NMR (DMSO): 9.25(1H, s), 7.05(1H, t), 6.60(3H, m), 3.08(1H5 q), 2.05(6H, s),1.19(3H, d)13C-NMR (DMSO): 158.0, 146.7, 129.8, 118.7, 114.8, 114.5, 65.8, 43.6, 20.9.Mass(Methanol) : 166.2 (M+l); Example 4: Preparation of alpha-m-hydroxy phenylethyldimethylamine; N-methylation was carried out on alpha-m-hydroxy phenylethylmethylamine (25g) with Paraformaldehyde (15g) in presence of Raney Nickel (30g) in methanol (500ml) at 80C and 10kg /cm of hydrogen pressure in an autoclave. After 3-4 hours the product was isolated by removing Raney nickel and concentrating the filtrate. The product was further purified by dissolving the crude product in Toluene (50ml) and is crystallized by slow addition of Petroleum ether (150ml). Pure alpha-m-hydroxy phenylethyldimethylamine is isolated (23g, Yield: 85%, purity 98%) by filtration.Characterization data: 1H-NMR (DMSO): 9.25(1H, s), 7.05(1H, t), 6.60(3H, m), 3.08(1H, q), 2.05(6H, s), 1.19(3H, d) 13C-NMR (DMSO): 158.0, 146.7, 129.8, 118.7, 114.8, 114.5, 65.8, 43.6, 20.9. <n="10"/>Mass(Methanol) : 166.2 (M+l) |
85% | With hydrogen;Raney nickel; In methanol; at 80℃; under 7355.72 Torr; for 3 - 4h;Product distribution / selectivity; | Example 2 Preparation of alpha-m-hydroxy phenylethyldimethylamine N-methylation was carried out on alpha-m-hydroxy phenylethylmethylamine (25 g) with Paraformaldehyde (15 g) in presence of Raney Nickel (30 g) in methanol (500 ml) at 80 C. and 10 kg/cm2 of hydrogen pressure in an autoclave. After 3-4 hours the product was isolated by removing Raney nickel and concentrating the filtrate. The product was further purified by dissolving the crude product in Toluene (50 ml) and is crystallized by slow addition of Petroleum ether (150 ml). Pure alpha-m-hydroxy phenylethyldimethylamine is isolated (23 g, Yield: 85%, purity 98%) by filtration. Characterization Data: 1H-NMR (DMSO): 9.25(1H, s), 7.05(1H, t), 6.60(3H, m), 3.08(1H, q), 2.05(6H, s), 1.19(3H, d) 13C-NMR (DMSO): 158.0, 146.7, 129.8, 118.7, 114.8, 114.5, 65.8, 43.6, 20.9. Mass (Methanol): 166.2 (M+1) Example 4Preparation of alpha-m-hydroxy phenylethyldimethylamineN-methylation was carried out on alpha-m-hydroxy phenylethylmethylamine (25 g) with Paraformaldehyde (15 g) in presence of Raney Nickel (30 g) in methanol (500 ml) at 80 C. and 10 kg/cm2 of hydrogen pressure in an autoclave. After 3-4 hours the product was isolated by removing Raney nickel and concentrating the filtrate. The product was further purified by dissolving the crude product in Toluene (50 ml) and is crystallized by slow addition of Petroleum ether (150 ml). Pure alpha-m-hydroxy phenylethyldimethylamine is isolated (23 g, Yield: 85%, purity 98%) by filtration.Characterization Data:1H-NMR (DMSO): 9.25(1H, s), 7.05(1H, t), 6.60(3H, m), 3.08(1H, q), 2.05(6H, s), 1.19(3H, d)13C-NMR (DMSO): 158.0, 146.7, 129.8, 118.7, 114.8, 114.5, 65.8, 43.6, 20.9.Mass (Methanol): 166.2 (M+1) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With formaldehyd; hydrogen; In methanol; aluminum nickel; toluene; Petroleum ether;Product distribution / selectivity; | Example 4 Preparation of alpha-m-hydroxy phenylethyldimethylamine N-methylation was carried out on alpha-m-hydroxy phenylethylmethylamine (25 g) with Paraformaldehyde (15 g) in presence of Raney Nickel (30 g) in methanol (500 ml) at 80 C. and 10 kg/cm2 of hydrogen pressure in an autoclave. After 3-4 hours the product was isolated by removing Raney nickel and concentrating the filtrate. The product was further purified by dissolving the crude product in Toluene (50 ml) and is crystallized by slow addition of Petroleum ether (150 ml). Pure alpha-m-hydroxy phenylethyldimethylamine is isolated (23 g, Yield: 85%, purity 98%) by filtration. Characterization Data: 1H-NMR (DMSO): 9.25(1H, s), 7.05(1H, t), 6.60(3H, m), 3.08(1H, q), 2.05(6H, s), 1.19(3H, d) 13C-NMR (DMSO): 158.0, 146.7, 129.8, 118.7, 114.8, 114.5, 65.8, 43.6, 20.9. Mass (Methanol): 166.2 (M+1) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; at 40 - 80℃; for 0.166667 - 1h;Resolution of racemate;Purification / work up; | Example 5Resolution of dl-alpha-m-HydroxyphenylethylmethylamineRacemic dl-alpha-m-Hydroxyphenylethylmethylamine (20 g) dissolved in Ethanol (300 ml) was added d-camphorsulphonic acid (33 g), and the reaction mixture was heated to 40-80 C. for 10-60 mins, and then Ethanol was distilled out completely under vacuum, the same operation was repeated twice with Ethanol (100 ml×2). Residual mass was added Ethyl acetate (250 ml) and distilled out. The residual mass was added i-Propanol (60 ml) and stirred for 2-3 days at 0-25 C. The precipitated solid was filtered (10-20 g).The camphorsulfonate thus obtained was dissolved in Sod. Carbonate soln and then extracted with Ethyl acetate (2×25 ml). Combined organic layer was distilled out and Cyclohexane (50 ml) was added to the residual mass and stirred for 10-30 mins. The solid material was then filtered and dried under vacuum at 40-80 C. (5-10 g) (m.p. 171 C. [alpha]D -68.0; c=5.0 in C5H5N) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 5: Resolution of dl-alpha-m-Hydroxyphenylethymethylamine:; Raceniic dl-alpha-m-Hydroxyphenylethylmethylamine (20 g) dissolved in Ethanol (300 ml) was added d-camphorsulphonic acid (33 g), and the reaction mixture was heated to 40- 8O0C for 10-60 mins, and then Ethanol was distilled out completely under vacuum, the same operation was repeated twice with Ethanol (100ml X 2). Residual mass was added Ethyl acetate (250 ml) and distilled out. The residual mass was added z-Propanol (60 ml) and stirred for 2-3 days at 0-25C. The precipitated solid was filtered (10-20 g). The camphorsulfonate thus obtained was dissolved in Sod. Carbonate soln and then extracted with Ethyl acetate (2x 25ml). Combined organic layer was distilled out and Cyclohexane (50ml) was added to the residual mass and stirred for 10-30 mins. The solid material was then filtered and dried under vacuum at 40-80C (5-1Og) (m.p. 1710C [alpha] D - 68.0; c= 5.0 in C5H5N) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at -78 - 5℃; for 3.08333 - 3.58333h;Product distribution / selectivity; | Comparative example 1; Reaction scheme :[0047] 1 g 3-(l-Dimethylamino)ethyl) phenol was dissolved in 20 ml dichloromethane (dried on CaCl2). The solution was cooled to -780C.[0048] 0.92 g Triethylamine was added. A solution of 1.22 g 4-nitrophenyl chloroformate in 5 ml dichloromethane (dried on CaCl2) was added dropwise over 5 minutes. The solution was stirred at -78C. Reaction progress was monitored by HPLC. After 3 hours at -780C, HPLC showed that there was still starting material present. A second addition of 0.61 g 4-nitrophenyl chloroformate in 2 ml dichloromethane (dried on CaCl2) was made. After 30 min at -78, the starting material was completely converted (ace. to HPLC). [0049] 715 mg N-Ethylmethylamine was added and the yellow reaction mixture was allowed to warm slowly to O0C. The reaction mixture was stirred for 40 hours at 40C. The reaction mixture was allowed to warm to room temperature and was then washed with 2x20 ml water. The organic phase was concentrated in vacuo. To the resulting yellow oil, 20 ml diethyl ether and 20 ml of a solution of hydrochloric acid (2 M) were added. The 2- phase system was stirred for 15 minutes. The acidic aqueous layer was washed with 20 ml diethyl ether. <n="15"/>[0050] 20 ml dichloromethane was added to the aqueous layer and a solution of sodium hydroxide (2 M) was added until pH~10-l 1 was reached. The organic layer was washed with 2x20 ml water, dried (Na2SO4), filtered and concentrated in vacuo. Isolated yield: 1.4 g (93%), yellow oilHPLC : 97.6% purity1H-NMR: confirmed the expected structure; The Comparative example 1 was repeated with the following solvents and reaction temperatures with the following results:; Example 1; Synthesis and isolation of compound VII-Ia-78' 5C[0052] 1 g 3-(l-Dimethylamino)ethyl) phenol was dissolved in 20 ml dichloromethane (dried on CaCl2). The solution was cooled to -780C. <n="16"/>[0053] 0.92 g triethylamine was added. A solution of 1.22 g4-nitrophenyl chloroformate in 5 mldichloromethane (dried on CaCl2) was added dropwise over 5 minutes. The mixture was stirred at -780C. Reaction progress was monitored with HPLC. After 3 hours at -78C, the reaction mixture was allowed to warm to ambient temperature and was then washed with 2x20 ml water, dried (Na2SO4), filtered and concentrated in vacuo.Isolated yield: 2.1 g, yellow oilHPLC : 83% purity1H- and 13C-NMR: confirmed the expected structure | |
With triethylamine; In ethyl acetate; at -20℃; for 3.58333h;Product distribution / selectivity; | Comparative example 1; Reaction scheme :[0047] 1 g 3-(l-Dimethylamino)ethyl) phenol was dissolved in 20 ml dichloromethane (dried on CaCl2). The solution was cooled to -780C.[0048] 0.92 g Triethylamine was added. A solution of 1.22 g 4-nitrophenyl chloroformate in 5 ml dichloromethane (dried on CaCl2) was added dropwise over 5 minutes. The solution was stirred at -78C. Reaction progress was monitored by HPLC. After 3 hours at -780C, HPLC showed that there was still starting material present. A second addition of 0.61 g 4-nitrophenyl chloroformate in 2 ml dichloromethane (dried on CaCl2) was made. After 30 min at -78, the starting material was completely converted (ace. to HPLC). [0049] 715 mg N-Ethylmethylamine was added and the yellow reaction mixture was allowed to warm slowly to O0C. The reaction mixture was stirred for 40 hours at 40C. The reaction mixture was allowed to warm to room temperature and was then washed with 2x20 ml water. The organic phase was concentrated in vacuo. To the resulting yellow oil, 20 ml diethyl ether and 20 ml of a solution of hydrochloric acid (2 M) were added. The 2- phase system was stirred for 15 minutes. The acidic aqueous layer was washed with 20 ml diethyl ether. <n="15"/>[0050] 20 ml dichloromethane was added to the aqueous layer and a solution of sodium hydroxide (2 M) was added until pH~10-l 1 was reached. The organic layer was washed with 2x20 ml water, dried (Na2SO4), filtered and concentrated in vacuo. Isolated yield: 1.4 g (93%), yellow oilHPLC : 97.6% purity1H-NMR: confirmed the expected structure; The Comparative example 1 was repeated with the following solvents and reaction temperatures with the following results: | |
With triethylamine; In chloroform; at -20℃; for 3.58333h;Product distribution / selectivity; | Comparative example 1; Reaction scheme :[0047] 1 g 3-(l-Dimethylamino)ethyl) phenol was dissolved in 20 ml dichloromethane (dried on CaCl2). The solution was cooled to -780C.[0048] 0.92 g Triethylamine was added. A solution of 1.22 g 4-nitrophenyl chloroformate in 5 ml dichloromethane (dried on CaCl2) was added dropwise over 5 minutes. The solution was stirred at -78C. Reaction progress was monitored by HPLC. After 3 hours at -780C, HPLC showed that there was still starting material present. A second addition of 0.61 g 4-nitrophenyl chloroformate in 2 ml dichloromethane (dried on CaCl2) was made. After 30 min at -78, the starting material was completely converted (ace. to HPLC). [0049] 715 mg N-Ethylmethylamine was added and the yellow reaction mixture was allowed to warm slowly to O0C. The reaction mixture was stirred for 40 hours at 40C. The reaction mixture was allowed to warm to room temperature and was then washed with 2x20 ml water. The organic phase was concentrated in vacuo. To the resulting yellow oil, 20 ml diethyl ether and 20 ml of a solution of hydrochloric acid (2 M) were added. The 2- phase system was stirred for 15 minutes. The acidic aqueous layer was washed with 20 ml diethyl ether. <n="15"/>[0050] 20 ml dichloromethane was added to the aqueous layer and a solution of sodium hydroxide (2 M) was added until pH~10-l 1 was reached. The organic layer was washed with 2x20 ml water, dried (Na2SO4), filtered and concentrated in vacuo. Isolated yield: 1.4 g (93%), yellow oilHPLC : 97.6% purity1H-NMR: confirmed the expected structure; The Comparative example 1 was repeated with the following solvents and reaction temperatures with the following results: |
With triethylamine; In acetonitrile; at -20℃; for 3.58333h;Product distribution / selectivity; | Comparative example 1; Reaction scheme :[0047] 1 g 3-(l-Dimethylamino)ethyl) phenol was dissolved in 20 ml dichloromethane (dried on CaCl2). The solution was cooled to -780C.[0048] 0.92 g Triethylamine was added. A solution of 1.22 g 4-nitrophenyl chloroformate in 5 ml dichloromethane (dried on CaCl2) was added dropwise over 5 minutes. The solution was stirred at -78C. Reaction progress was monitored by HPLC. After 3 hours at -780C, HPLC showed that there was still starting material present. A second addition of 0.61 g 4-nitrophenyl chloroformate in 2 ml dichloromethane (dried on CaCl2) was made. After 30 min at -78, the starting material was completely converted (ace. to HPLC). [0049] 715 mg N-Ethylmethylamine was added and the yellow reaction mixture was allowed to warm slowly to O0C. The reaction mixture was stirred for 40 hours at 40C. The reaction mixture was allowed to warm to room temperature and was then washed with 2x20 ml water. The organic phase was concentrated in vacuo. To the resulting yellow oil, 20 ml diethyl ether and 20 ml of a solution of hydrochloric acid (2 M) were added. The 2- phase system was stirred for 15 minutes. The acidic aqueous layer was washed with 20 ml diethyl ether. <n="15"/>[0050] 20 ml dichloromethane was added to the aqueous layer and a solution of sodium hydroxide (2 M) was added until pH~10-l 1 was reached. The organic layer was washed with 2x20 ml water, dried (Na2SO4), filtered and concentrated in vacuo. Isolated yield: 1.4 g (93%), yellow oilHPLC : 97.6% purity1H-NMR: confirmed the expected structure; The Comparative example 1 was repeated with the following solvents and reaction temperatures with the following results: | |
With triethylamine; In tetrahydrofuran; at -20℃; for 3.58333h;Product distribution / selectivity; | Comparative example 1; Reaction scheme :[0047] 1 g 3-(l-Dimethylamino)ethyl) phenol was dissolved in 20 ml dichloromethane (dried on CaCl2). The solution was cooled to -780C.[0048] 0.92 g Triethylamine was added. A solution of 1.22 g 4-nitrophenyl chloroformate in 5 ml dichloromethane (dried on CaCl2) was added dropwise over 5 minutes. The solution was stirred at -78C. Reaction progress was monitored by HPLC. After 3 hours at -780C, HPLC showed that there was still starting material present. A second addition of 0.61 g 4-nitrophenyl chloroformate in 2 ml dichloromethane (dried on CaCl2) was made. After 30 min at -78, the starting material was completely converted (ace. to HPLC). [0049] 715 mg N-Ethylmethylamine was added and the yellow reaction mixture was allowed to warm slowly to O0C. The reaction mixture was stirred for 40 hours at 40C. The reaction mixture was allowed to warm to room temperature and was then washed with 2x20 ml water. The organic phase was concentrated in vacuo. To the resulting yellow oil, 20 ml diethyl ether and 20 ml of a solution of hydrochloric acid (2 M) were added. The 2- phase system was stirred for 15 minutes. The acidic aqueous layer was washed with 20 ml diethyl ether. <n="15"/>[0050] 20 ml dichloromethane was added to the aqueous layer and a solution of sodium hydroxide (2 M) was added until pH~10-l 1 was reached. The organic layer was washed with 2x20 ml water, dried (Na2SO4), filtered and concentrated in vacuo. Isolated yield: 1.4 g (93%), yellow oilHPLC : 97.6% purity1H-NMR: confirmed the expected structure; The Comparative example 1 was repeated with the following solvents and reaction temperatures with the following results: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 0 - 20℃; for 2.5 - 4h;Product distribution / selectivity; | Example 4; Synthesis of the compound (L-R); Reaction scheme:Process:1 g 3-(l-(Dimethylamino)ethyl) phenol was dissolved in 20 ml dichloromethane (distilled from CaCl2). The solution was cooled with an ice-water bath (0-50C). 0.92 g trie thy lamine was added.2.21 g bis(4-nitrophenyl)carbonate was added. The yellow solution was stirred in an ice- water bath.[0062] Reaction progress was monitored by HPLC. After 4 hours, 715 mg N- ethylmethylamine was added and the yellow solution was stirred for 17 hours at 40C. The reaction mixture was allowed to warm to room temperature and was then washed with 2x20 ml water. The organic phase was concentrated in vacuo. To the resulting yellow oil, 20 ml diethyl ether and 20 ml of a solution of hydrochloric acid (2 M) were added. The 2- phase system was stirred for 15 minutes. The acidic aqueous layer was washed with 20 ml diethyl ether.[0063] 20 ml dichloromethane was added to the aqueous layer and a solution of sodium hydroxide (2 M) was added until pH~12 was reached. The organic layer was washed with 2x20 ml water, dried (Na2SO4), filtered and concentrated in vacuo. <n="19"/>Isolated yield: 1.37 g (90%), yellow oilHPLC: 98% purity1H-NMR: confirmed the expected structure; Example 5; Synthesis of the compound (JL-R); [0064] 1 g 3-(l-(Dimethylamino)ethyl) phenol was dissolved in 20 ml dichloromethane (distilled from CaCl2).[0065] 0.92 g triethylamine was added.[0066] 2.21 g bis(4-nitrophenyl)carbonate was added. The yellow solution was stirred at ambient temperature. [0067] Reaction progress was monitored by HPLC. After 2.5 hours, 715 mg JV- ethylmethylamine was added dropwise and the yellow solution was stirred for 1.5 hours at ambient temperature. The reaction mixture was washed with 2x20 ml water. The organic phase was concentrated in vacuo. To the resulting yellow oil, 20 ml diethyl ether and 20 ml of a solution of hydrochloric acid (2 M) were added. The 2-phase system was stirred for 15 minutes. The acidic aqueous layer was washed with 20 ml diethyl ether.[0068] 20 ml dichloromethane was added to the aqueous layer and a solution of sodium hydroxide (2 M) was added until pH~12 was reached. The organic layer was washed with 2x20 ml water, dried (Na2SO4), filtered and concentrated in vacuo.Isolated yield: 1.36 g (90%), yellow oil HPLC: 97% purity1H-NMR, 13CNMR: confirmed the expected structure Examples 6-9 | |
With triethylamine; In ethyl acetate; at 0 - 5℃; for 2.5h;Product distribution / selectivity; | Example 5; Synthesis of the compound (JL-R) [0064] 1 g 3-(l-(Dimethylamino)ethyl) phenol was dissolved in 20 ml dichloromethane (distilled from CaCl2).[0065] 0.92 g triethylamine was added.[0066] 2.21 g bis(4-nitrophenyl)carbonate was added. The yellow solution was stirred at ambient temperature. [0067] Reaction progress was monitored by HPLC. After 2.5 hours, 715 mg JV- ethylmethylamine was added dropwise and the yellow solution was stirred for 1.5 hours at ambient temperature. The reaction mixture was washed with 2x20 ml water. The organic phase was concentrated in vacuo. To the resulting yellow oil, 20 ml diethyl ether and 20 ml of a solution of hydrochloric acid (2 M) were added. The 2-phase system was stirred for 15 minutes. The acidic aqueous layer was washed with 20 ml diethyl ether.[0068] 20 ml dichloromethane was added to the aqueous layer and a solution of sodium hydroxide (2 M) was added until pH~12 was reached. The organic layer was washed with 2x20 ml water, dried (Na2SO4), filtered and concentrated in vacuo.Isolated yield: 1.36 g (90%), yellow oil HPLC: 97% purity1H-NMR, 13CNMR: confirmed the expected structure Examples 6-9; The Example 5 was repeated in the following solvents and with the following results: | |
With triethylamine; In acetonitrile; at 0 - 5℃; for 2.5h;Product distribution / selectivity; | Example 5; Synthesis of the compound (JL-R) [0064] 1 g 3-(l-(Dimethylamino)ethyl) phenol was dissolved in 20 ml dichloromethane (distilled from CaCl2).[0065] 0.92 g triethylamine was added.[0066] 2.21 g bis(4-nitrophenyl)carbonate was added. The yellow solution was stirred at ambient temperature. [0067] Reaction progress was monitored by HPLC. After 2.5 hours, 715 mg JV- ethylmethylamine was added dropwise and the yellow solution was stirred for 1.5 hours at ambient temperature. The reaction mixture was washed with 2x20 ml water. The organic phase was concentrated in vacuo. To the resulting yellow oil, 20 ml diethyl ether and 20 ml of a solution of hydrochloric acid (2 M) were added. The 2-phase system was stirred for 15 minutes. The acidic aqueous layer was washed with 20 ml diethyl ether.[0068] 20 ml dichloromethane was added to the aqueous layer and a solution of sodium hydroxide (2 M) was added until pH~12 was reached. The organic layer was washed with 2x20 ml water, dried (Na2SO4), filtered and concentrated in vacuo.Isolated yield: 1.36 g (90%), yellow oil HPLC: 97% purity1H-NMR, 13CNMR: confirmed the expected structure Examples 6-9; The Example 5 was repeated in the following solvents and with the following results: |
With triethylamine; In tetrahydrofuran; at 0 - 5℃; for 2.5h;Product distribution / selectivity; | Example 5; Synthesis of the compound (JL-R) [0064] 1 g 3-(l-(Dimethylamino)ethyl) phenol was dissolved in 20 ml dichloromethane (distilled from CaCl2).[0065] 0.92 g triethylamine was added.[0066] 2.21 g bis(4-nitrophenyl)carbonate was added. The yellow solution was stirred at ambient temperature. [0067] Reaction progress was monitored by HPLC. After 2.5 hours, 715 mg JV- ethylmethylamine was added dropwise and the yellow solution was stirred for 1.5 hours at ambient temperature. The reaction mixture was washed with 2x20 ml water. The organic phase was concentrated in vacuo. To the resulting yellow oil, 20 ml diethyl ether and 20 ml of a solution of hydrochloric acid (2 M) were added. The 2-phase system was stirred for 15 minutes. The acidic aqueous layer was washed with 20 ml diethyl ether.[0068] 20 ml dichloromethane was added to the aqueous layer and a solution of sodium hydroxide (2 M) was added until pH~12 was reached. The organic layer was washed with 2x20 ml water, dried (Na2SO4), filtered and concentrated in vacuo.Isolated yield: 1.36 g (90%), yellow oil HPLC: 97% purity1H-NMR, 13CNMR: confirmed the expected structure Examples 6-9; The Example 5 was repeated in the following solvents and with the following results: | |
With triethylamine; In acetone; at 0 - 5℃; for 2.5h;Product distribution / selectivity; | Example 5; Synthesis of the compound (JL-R) [0064] 1 g 3-(l-(Dimethylamino)ethyl) phenol was dissolved in 20 ml dichloromethane (distilled from CaCl2).[0065] 0.92 g triethylamine was added.[0066] 2.21 g bis(4-nitrophenyl)carbonate was added. The yellow solution was stirred at ambient temperature. [0067] Reaction progress was monitored by HPLC. After 2.5 hours, 715 mg JV- ethylmethylamine was added dropwise and the yellow solution was stirred for 1.5 hours at ambient temperature. The reaction mixture was washed with 2x20 ml water. The organic phase was concentrated in vacuo. To the resulting yellow oil, 20 ml diethyl ether and 20 ml of a solution of hydrochloric acid (2 M) were added. The 2-phase system was stirred for 15 minutes. The acidic aqueous layer was washed with 20 ml diethyl ether.[0068] 20 ml dichloromethane was added to the aqueous layer and a solution of sodium hydroxide (2 M) was added until pH~12 was reached. The organic layer was washed with 2x20 ml water, dried (Na2SO4), filtered and concentrated in vacuo.Isolated yield: 1.36 g (90%), yellow oil HPLC: 97% purity1H-NMR, 13CNMR: confirmed the expected structure Examples 6-9; The Example 5 was repeated in the following solvents and with the following results: | |
In dichloromethane; at 20℃; for 2h;Product distribution / selectivity; | Example 10; Synthesis of the compound (I-R); [0070] 0.5 g 3-(l-(Dimethylamino)ethyl) phenol was dissolved in 10 ml dichloromethane (distilled from CaCl2).[0071] 1.1 g bis(4-nitrophenyl)carbonate was added. The yellow solution was stirred at ambient temperature.[0072] Reaction progress was monitored with HPLC. After 2 hours, 358 mg N- ethylmethylamine was added dropwise and the yellow solution was stirred at ambient temperature for 16 hours. The reaction mixture was concentrated in vacuo. To the resulting yellow oil, 20 ml diethyl ether and 20 ml of a solution of hydrochloric acid (2 M) were added. The 2-phase system was stirred for 15 minutes. The acidic aqueous layer was washed with 20 ml diethyl ether.[0073] 20 ml dichloromethane was added to the aqueous layer and a solution of sodium hydroxide (2 M) was added until pH~12 was reached. The organic layer was washed with 2x20 ml water, dried (Na2SO4), filtered and concentrated in vacuo. Isolated yield: 0.62 g (82%), yellow oilHPLC: 97.4% purity | |
In acetone; at 20℃; for 1.5h;Product distribution / selectivity; | Example 11; Synthesis of the compound (I-R); [0074] 1.0 g 3-(l-(Dimethylamino)ethyl) phenol was dissolved in 20 ml acetone.[0075] 2.21 g bis(4-nitrophenyl)carbonate was added. The yellow solution was stirred at ambient temperature.[0076] Reaction progress was monitored with HPLC. After 1.5 hour, 537 mg N- ethylmethylamine was added dropwise and the yellow solution was stirred at ambient temperature for 1.5 hour. The reaction mixture was concentrated in vacuo. To the resulting yellow oil, 20 ml t-butylmethyl ether and 20 ml of a solution of hydrochloric acid (2 M) were added. The 2-phase system was stirred for 15 minutes. The acidic aqueous layer was washed with 20 ml t-butylmethyl ether.[0077] 20 ml t-Butylmethyl ether was added to the aqueous layer and a solution of sodium hydroxide (2 M) was added until pH~12 was reached. The organic layer was washed with 2x20 ml water, dried (Na2SO4), filtered and concentrated in vacuo.Isolated yield: 1.34 g (88%), yellow oilHPLC: 95.6% purity |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25.7 - 31.0% | In ethanol; ethyl acetate; at 5 - 70℃; | Preparation of S- (-)-3- (1-DIMETHYLAMINO) PHENOL (III) Resolving compound (IV) with an 1 equivalent amount OF S- (+)-CAMPHOR-10-SULFONIC acid A solution of compound (IV) in ethylacetate (0.505 mol) * in 500 ml of ethylacetate) is introduced into a 1-liter round flask with a magnetic stirrer and a solution OF S- (+)-CAMPHOR- 10-sulfonic acid (117.4 g (0.505 mol) IN 250 ml of anhydrous ethanol), prepared in warm conditions, is added. The solution is inoculated and left to stand in a refrigerator (+5 C) overnight. The precipitated crystals are sucked off through fritted glass and left to air dry overnight. 1) 82.2 g of white crystals with m. p. = 165-171 C are obtained, which are dissolved in 190 ml of absolute ethanol under reflux. 380 ml of ethylacetate are added under warm conditions and crystallization is performed according to the above-mentioned procedure. 2) 64.1 g of white crystals with m. p. = 174-176 C are obtained, which are dissolved in 150 ML OF ETHANOL (ABSOL. ) UNDER REFLUX AND 300 ML OF ETHYLACETATE ARE ADDED UNDER WARM conditions. 3) 56.5 g of white crystals with m. p. = 177-179 C are obtained, which are dissolved in 130 ML OF ETHANOL (ABSOL. ) UNDER REFLUX AND 260 ML OF ETHYLACETATE ARE ADDED UNDER WARM conditions. 4) 51.6 g of white crystals with m. p. = 179-181 C are obtained; i. e. 25.7 % of the theoretical amount. * the contents of compound (IV) was determined by titration Resolving compound (IV) with 0.6 equivalent amount OF S- (+)-CAMPHOR-10-SULFONIC acid 100 g (0.605 mol) of compound (IV) are dissolved in 600 ml of ethylacetate under stirring and reflux. A solution of S- (+)-CAMPHOR-10-SULFONIC acid (84.3 g (0.363 mol) in 125 ML of anhydrous ethanol) is added under stirring at 70 C. The solution is inoculated, left to cool down to room temperature under stirring, cooled down with brine to-10 up TO-15C and it is left to crystallize for at least 12 hours under exclusion of air humidity. The precipitated first fraction of crystals is sucked off and air dried. 1) 95.0 g of white crystals with m. p. =173-175 C are obtained, which are dissolved in 175 ml of ethanol under stirring and reflux and 350 ml of ethylacetate are added at a temperature of the solution between 60-70 C. The CAMPHORSULFONATE will start to crystallize and is left to crystallize at a temperature-5 up to-10 C for at least 12 hours. The precipitated fraction is sucked off, washed with 2x 50 ml of ethylacetate and air dried. 2) 79.5 g of the second fraction with m. p. 176-178 C are obtained, which are again recrystallized in a mixture of ethanol: ethylacetate (150 ML : 300 ml) following the above specified procedure. After being washed with 2x 50 ml of ethylacetate, the product is dried freely. 3) 74.6 g of the third fraction with m. p. =177-179 C are obtained; i. e. 31.0 % of the theoretical yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In dimethyl sulfoxide; at 90 - 110℃; for 35 - 40h; | 3- (1-dimethylaminoethyl) phenol (200gm, 1.21 moles), anhydrous potassium carbonate (252gm, 1.515 moles), N-ethyl-N-methyl-4-nitrophenyl carbamate (340gm, 1.82 moles) and dimethylsulfoxide [(1] liter) are mixed and heated at a temperature of about [90] to about [110C,] under nitrogen atmosphere, for 35-40 hours. The reaction mixture is cooled gradually to room temperature and filtered. The filtered solution is quenched in ice-water mixture and extracted with ethyl acetate to furnish racemic Rivastigmine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | [80] alpha-m-Hydroxyphenylethyldimethylamine (Formula 2, 50.0 g, 0.3 mol) was suspended in acetonitrile (250 ml), and then N-ethyl-N-methylcarbamoyl chloride (58.3 g, 0.48 mol) was added thereto. The reaction solution was cooled to 0C. To the cooled solution was added sodium hydroxide (14.4 g, 0.36 mol). The resulting mixture was gradually allowed to rise to room temperature, and stirred at this temperature for 24 hours. The completion of the reaction was confirmed by HPLC. Thereafter, the reaction mixture was filtered to remove salts, and the obtained filtrate was concentrated. The pH of the concentrate was adjusted to 11 using water and NaOH solution, followed by extraction with ether and concentration. To the concentrate were added water and cone. HCl. The mixture was stirred at room temperature for one hour, and washed twice with ether. The obtained aqueous layer was concentrated, and re- crystallized from ethylacetate, yielding racemic rivastigmine hydrochloride (50.6 g, 58%). The racemic rivastigmine hydrochloride (20 g, 69 mmol) was dissolved in water (60 ml), and then NaOH (3.3 g, 1.2 eq.) was added thereto. The mixture was stirred at room temperature for one hour. The resulting mixture was extracted five times with ether, dried over anhydrous MgSO , and concentrated under reduced pressure. Di-O, O'4-p-toluoyl tartaric acid monohydrate (DTTA, 26.5 g, 69 mmol) and a solution of methanol/water (2/1) (180 ml) were added to the concentrate, dissolved under heating, and gradually allowed to cool to room temperature to obtain a precipitate. The precipitate was filtered, and recrystallized four times to afford rivastigmine DTTA salt (11.4 g, 26% (from the racemic rivastigmine hydrochloride)). The obtained rivastigmine DTTA salt (4.7 g, 7.4 mmol) was suspended in a IM NaOH solution (8 ml) EPO <DP n="10"/>and dichloromethane (30 ml). The suspension was stirred for 30 minutes, followed by phase separation. The obtained organic layer was concentrated, and water and ether were added to the concentrate to separate layers. The obtained ether layer was dried over K CO , and concentrated. To the concentrate were added acetone (5 ml) and L- tartaric acid (1.1 g, 7.4 mmol, 1 eq.). The resulting mixture was refluxed for one hour, cooled to 0C, and filtered to obtain a solid. The solid was washed, and dried to afford (S)-rivastigmine tartrate salt (2.5 Ig, 99.7% ee, 85% (from the rivastigmine DTTA salt), 13% (from the alpha-m-hydroxyphenylethyldimethylamine). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With hydrogen;nickel; In methanol; at 80℃; under 7355.72 Torr; for 3 - 4h;Product distribution / selectivity; | Example 1: Preparation of alpha-m-hydroxy phenylethyldimethylamine; N-methylation was carried out on alpha-m-hydroxy phenylethylamine (25g) with Paraformaldehyde (33g) in presence of Raney Nickel (3Og) in methanol (500ml) at 800C and 10kg /cm2 of hydrogen pressure in an autoclave. After 3-4 hours the product was isolated by removing Raney nickel and concentrating the filtrate. The product was further purified by dissolving the crude product in Toluene (50ml) and is crystallized by slow addition of Petroleum ether (150ml). Pure alpha-m-hydroxy phenylethyldimethylamine is isolated (25g, Yield: 83%, purity 98%) by filtration.Characterization data:1H-NMR (DMSO): 9.25(1H, s)/ 7.05(1H, t), 6.60(3H, m), 3.08(1H, q), 2.05(6H, s), 1.19(3H, d) 13C-NMR (DMSO): 158.0, 146.7, 129.8, 118.7, 114.8, 114.5, 65.8, 43.6, 20.9. Mass(Methanol) : 166.2 (M+l) |
83% | With hydrogen;Raney Nickel; In methanol; at 80℃; under 7355.72 Torr; for 3 - 4h;Product distribution / selectivity; | Example 1 Preparation of alpha-m-hydroxy phenylethyldimethylamine N-methylation was carried out on alpha-m-hydroxy phenylethylamine (25 g) with Paraformaldehyde (33 g) in presence of Raney Nickel (30 g) in methanol (500 ml) at 80 C. and 10 kg/cm2 of hydrogen pressure in an autoclave. After 3-4 hours the product was isolated by removing Raney nickel and concentrating the filtrate. The product was further purified by dissolving the crude product in Toluene (50 ml) and is crystallized by slow addition of Petroleum ether (150 ml). Pure alpha-m-hydroxy phenylethyldimethylamine is isolated (25 g, Yield: 83%, purity 98%) by filtration. Characterization Data: 1H-NMR (DMSO): 9.25(1H, s), 7.05(1H, t), 6.60(3H, m), 3.08(1H, q), 2.05(6H, s), 1.19(3H, d) 13C-NMR (DMSO): 158.0, 146.7, 129.8, 118.7, 114.8, 114.5, 65.8, 43.6, 20.9. Mass (Methanol): 166.2 (M+1) |
70% | With formic acid; at 90℃; for 10 - 12h; | N-Alkylation was carried on 3-hydroxy-l-phenylethylamine (lOgm) with 2 eq. of formaldehyde and 4 eq. of formic acid. The reaction was carried at 9O0C for 10-12 hours. The reaction mixture was neutralized with caustic solution and extracted with ethyl acetate (3 X 50 1). Further concentration gave the desired product with 70% yield. Yield: 80-90 gms %Yield: 70% HPLC Purity: 97%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33.8% | With (1S)-10-camphorsulfonic acid; In ethanol; ethyl acetate; at 50℃; for 0.666667h; | 2 L ethyl acetate, 300.0 g (R,S)-<strong>[105601-04-5]3-(1-(dimethylamino)ethyl)phenol</strong>The raw materials were added to the reaction flask and stirred at 50 C., and the solution of S-(+)-camphorsulfonic acid ethanol (600 ml) was prepared (350 g of S-(+)-camphorsulfonic acid was dissolved in 850 ml of ethanol. ) Add the above reaction flask, stir and reflux for 40 min, the system is dissolved, then cooled to room temperature, cooled to 0 C., and stirred and crystallized for 3 h. After suction filtration and drying, a white solid is obtained. The obtained solid is added into a reaction flask, and then 700 ml of ethanol and 1100 ml of ethyl acetate are added, and the mixture is stirred under reflux. After 40 minutes, the mixture is naturally cooled to room temperature, cooled to 0 C., and crystallized for 3 hours. Solid g. The resulting solid was dissolved in 800 ml of water and dissolved by stirring to remove insoluble matter by filtration. Transfer the filtrate with sodium hydroxidepH to 11.5, cooling to 5-10 C crystallized for 4 hours. After suction filtration and drying, a white solid was obtained with a yield of 33.8% and the corresponding R isomer was 0.58%. |
25 - 30% | 3-(l-Dimethylaminoethyl) phenol (25g, 0.15mole) was added to Ethyl acetate (125ml) followed by D-(+)-10-camphor sulphonic acid (35 g, 0.15 mole). The reaction mass EPO <DP n="13"/>was heated to reflux temperature. Methanol (17ml) was added. The reaction mass was refluxed for 30 minutes and filtered at 100C to give compound of formula (V-a).Optionally, the salt was further recrystallized from a mixture of ethyl acetate and methanol. Yield: 6.25-7.5 gms%Yield: 25-30%HPLC Purity: 98% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With potassium carbonate; In N,N-dimethyl-formamide; for 24h;Heating / reflux; | {2-[3-(1-dimethylamino-ethyl)-phenoxy]-ethyl}-carbamic acid ter-butyl ester (19b). A solution of 19a was synthesized following the procedure described for the corresponding (R,S)-3-[[1-di-(2H3) methylamino]ethyl]phenol in: Ciszewska, Grazyna; Pfefferkorn, Heidi; Tang, Y. S.; Jones, Lawrence; Tarapata, Richard; Sunay, Ustun B. Synthesis of tritium, deuterium, and carbon-14 labeled (s)-n-ethyl-n-methyl-3-[1-(dimethylamino)ethyl]carbamic acid, phenyl ester, (1) -2,3-dihydroxybutanedioic acid salt (SDZ ENA 713 hta), an investigational drug for the treatment of Alzheimer's disease. Journal of Labeled Compounds & Radiopharmaceuticals 1997, 39, 651-668) (350 mg, 2.17 mmol) (3-chloro-propyl)-carbamic acid terbutyl ester (420 mg, 2.17 mmol) and K2CO3 (300 mg, 2.17 mmol) in DMF (10 mL) was stirred under reflux conditions for 24 h. Evaporation of the solvent afforded a residue which was purified by gravity column. Elution with CHCl3/MeOH/aqueous 30% ammonia solution (9:1:0.02) afforded lab as an oil: 65% yield, |
65% | With potassium carbonate; In N,N-dimethyl-formamide; for 24h;Reflux; | A solution of 14 (0.350 g, 2.17 mmol), tert-butyl 3-chloropropylcarbamate (0.420 g, 2.17 mmol) and K2CO3 (0.300 g, 2.17 mmol) in DMF (10 mL) was stirred under reflux conditions for 24 h. Evaporation of the solvent afforded a residue which was purified by gravity column. Elution with CHCl3/MeOH/aqueous 30% ammonia (9:1:0.02) afforded 15 (0.454 g, 65%) as an oil. 1H NMR (CDCl3, 200 MHz) delta 7.20 (t, J = 8.0 Hz, 1H), 6.79-6.89 (m, 3H), 4.92 (br s, 1H, exchangeable with D2O), 4.02 (t, J = 6.4 Hz, 2H), 3.20-3.33 (m, 3H), 2.20 (s, 6H), 1.93-1.99 (m, 2H), 1.44 (s, 9H), 1.35 (d, J = 6.6 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; water; In dichloromethane; for 0.333333 - 1.33333h;pH 9.7;Product distribution / selectivity; | Example 1: (i) Synthesis of rivastigmine base a) Preparation of 3-(1-dimethylaminoethyl)phenol An amount of 10.10 g (50.0 mmol) of 3-(1-dimethylaminoethyl)-phenol hydrochloride was dissolved in 75 ml of water and 100 ml of dichloromethane. 50 ml of 1 M NaOH were added dropwise to the mixture while stirring. The pH was adjusted to 9.7 with 1 M NaOH and the reaction mixture was stirred for another 20 minutes. The organic layer was separated and 50 ml of brine were added thereto and stirred for 20 minutes. The organic layer was separated, dried over Na2SO4 (7.0 g) and filtered. The organic layer was concentrated under reduced pressure to obtain 7.48 g of an oily residue of 3-(1-dimethylaminoethyl)phenol which rapidly crystallized. (ii) Synthesis of rivastigmine base (alternative) An amount of 6.06 g (30.0 mmol; 99.3 area %) of 3-(1-dimethylaminoethyl)phenol hydrochloride was dissolved in 45 ml of water and stirred for 10 minutes. 60 ml of dichloromethane was added and stirred for additional 10 minutes. 30 ml of 1 M NaOH was added dropwise in period of 30 minutes and the pH was set to 9.7 with 1 M NaOH. The reaction mixture was stirred for another 30 minutes. The layers were separated. The organic layer was dried with 2 g of Na2SO4, and filtered. After the filtration 30 ml of acetonitrile were added and concentrated at 600 mbar and a temperature of 50C twice. After the evaporation of the solvent, the pressure was slowly reduced to 350 mbar and maintained to complete the evaporation of dichloromethane. 3-(1-dimethylaminoethyl)phenol was obtained as a solution in acetonitrile. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of <strong>[105601-04-5]3-[1-(dimethylamino)ethyl]phenol</strong> (0.82 g, 5 mmoL) in acetonitrile (5 mL) was stirred under nitrogen and cooled using an ice-bath. 1,1'-Carbonyldiimidazole (1.0 g, 6 mmoL) was added and the resulting solution was stirred at room temperature for 1.5 h. The solution was re-cooled using an ice-bath and acetic acid (1.0 g, 16.7 mmoL) was added followed by N-ethylmethylamine (0.5 g, 8.3 mmoL). The solution was allowed to warm slowly to room temperature and stirred for 3 hours. The reaction mixture was evaporated and the residue was dissolved in diethyl ether (20 mL). Water (10 mL) was added to the solution and the pH of the aqueous layer was adjusted to >10 by the addition of aqueous NaOH. The organic layer was separated and the aqueous layer was extracted with diethyl ether. The combined organic extracts were washed with water and evaporated to dryness to give racemic Rivastigime (0.8 g) as a liquid. | ||
A mixture of <strong>[105601-04-5]3-[1-(dimethylamino)ethyl]phenol</strong> (0.41 g, 2.5 mmoL) in acetonitrile (5 mL) was stirred under nitrogen at room temperature. 1,1'-Carbonyldiimidazole (0.5 g, 3.0 mmoL) was added to the mixture and the resulting solution was stirred at room temperature for 1.5 h. The solution was cooled using an ice-bath and acetic acid (0.5 g, 8.3 mmoL) was added followed by aqueous 40% N-ethylmethylamine solution (0.6 g, 4 mmoL). The solution was allowed to warm slowly to room temperature and stirred overnight. The reaction mixture was evaporated and the residue was dissolved in diethyl ether (15 mL). Water (10 mL) was added to the solution and the pH of the aqueous layer was adjusted to >10 by the addition of aqueous NaOH solution. The organic layer was separated and the aqueous layer was extracted with diethyl ether. The combined ethereal extracts were washed with water and evaporated to dryness to give racemic Rivastigime (0.38 g) as a liquid. | ||
3-(l-dimethylaminoethyl) phenol (10 gm, 0.06 moles) was added to dichloromethane(50ml) followed by addition of carbonyl diimidazole (2Og, 0.123mole). The reaction mass was refluxed for 12 hours and the reaction mass was then cooled to 5-1O0C.Ethylmethyl amine (7.08gms; 2.0 moles) was added to the mixture and stirred for 4-6 hours till completion of reaction. Water (100 ml) was added to quench the reaction. The dichloromethane layer was separated and treated with 10% NaOH solution (50ml) at10-150C. The organic layer was then treated with dilute hydrochloric acid, neutralized with ammonia solution and extracted with Hexane. The hexane layer was concentrated to give compound (I). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of <strong>[105601-04-5]3-[1-(dimethylamino)ethyl]phenol</strong> (0.82 g, 5 mmoL) in acetonitrile (5 mL) was stirred under nitrogen and cooled using an ice-bath. 1,1'-Carbonyldiimidazole (1.1 g, 6.8 mmoL) was added and the resulting solution was stirred at room temperature for 2 h. The solution was re-cooled using an ice-bath and acetic acid (0.4 g, 8.3 mmoL) was added followed by N-ethylmethylamine hydrochloride (0.76 g, 10 mmoL) and triethylamine (1.0 g, 10 mmol). The solution was allowed to warm slowly to room temperature and stirred overnight. The reaction mixture was evaporated and the residue was dissolved in diethyl ether (20 mL). Water (10 mL) was added to the solution and the pH of the aqueous layer was adjusted to >10 by the addition of aqueous NaOH. The organic layer was separated and the aqueous layer was extracted with diethyl ether. The combined organic extracts were washed with water and evaporated to dryness to give racemic Rivastigime (0.6 g) as a liquid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A solution of <strong>[105601-04-5]3-[1-(dimethylamino)ethyl]phenol</strong> (0.41 g, 2.5 mmoL) and triethylamine (0.8 g, 7.9 mmoL) in dichloromethane (10 mL) was stirred under nitrogen and cooled using an ice-bath. 4-Nitrophenyl chloroformate (0.6 g, 3 mmoL) was added to the solution and the mixture was stirred for 1 h whereupon N-ethylmethylamine (0.24 g, 4 mmoL) was added and the solution was allowed to warm slowly to room temperature and stirred overnight. The reaction mixture was quenched by the addition of water (10 mL) and the pH of the aqueous layer was adjusted to >10 by the addition of aqueous NaOH solution. The organic layer was separated and the aqueous layer was extracted with additional dichloromethane. The combined extracts were washed with water and evaporated to dryness. The residue was dissolved in diethyl ether and extracted with dilute HCl solution. The pH of the aqueous solution was adjusted to >10 by the addition of aqueous NaOH and extracted with diethyl ether. The ethereal layers were washed with water and evaporated to dryness to give racemic Rivastigime (0.48 g) as a liquid. |
A151961 [139306-10-8]
(S)-3-(1-(Dimethylamino)ethyl)phenol
Similarity: 1.00
A231532 [851086-95-8]
(R)-3-(1-(Dimethylamino)ethyl)phenol
Similarity: 1.00
A231989 [60760-04-5]
3-((Dimethylamino)methyl)phenol
Similarity: 0.88
A166836 [856563-08-1]
(R)-3-(1-Aminoethyl)phenol hydrochloride
Similarity: 0.84
A151961 [139306-10-8]
(S)-3-(1-(Dimethylamino)ethyl)phenol
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