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CAS No. : | 139306-10-8 | MDL No. : | MFCD06656491 |
Formula : | C10H15NO | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | GQZXRLWUYONVCP-QMMMGPOBSA-N |
M.W : | 165.23 | Pubchem ID : | 445892 |
Synonyms : |
|
Num. heavy atoms : | 12 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.4 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 50.75 |
TPSA : | 23.47 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) : | -6.03 cm/s |
Log Po/w (iLOGP) : | 2.08 |
Log Po/w (XLOGP3) : | 1.8 |
Log Po/w (WLOGP) : | 1.69 |
Log Po/w (MLOGP) : | 1.83 |
Log Po/w (SILICOS-IT) : | 1.42 |
Consensus Log Po/w : | 1.76 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.24 |
Solubility : | 0.959 mg/ml ; 0.0058 mol/l |
Class : | Soluble |
Log S (Ali) : | -1.91 |
Solubility : | 2.02 mg/ml ; 0.0122 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -2.36 |
Solubility : | 0.721 mg/ml ; 0.00437 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.44 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-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 |
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With water; sodium hydrogencarbonate; | 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 |
---|---|---|
57% | In dichloromethane; at 20℃; for 1.5h;Product distribution / selectivity; | Example 2; Synthesis and isolation of the compound (VII-Ib); Reaction scheme:[0054] 0.5 g (S)-3-(l-(Dimethylamino)ethyl) phenol was dissolved (not completely) in 10 ml dichloromethane (distilled from CaCl2).[0055] 1. Ig bis(4-nitrophenyl)carbonate was added. The yellow solution was stirred at ambient temperature. Reaction progress was monitored with HPLC.[0056] 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. <n="17"/>[0057] 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: 0.57 g (57%), yellow oilHPLC: 84.2% purity; Example 12; Synthesis of rivastigmine (Ia); Reaction scheme:L NH <n="22"/>[0078] 0.5 g (S)-3-(l-(Dimethylamino)ethyl) phenol was dissolved in 10 ml dichloromethane (distilled from CaCl2).[0079] 1. Ig bis(4-nitrophenyl)carbonate was added. The yellow solution was stirred at ambient temperature.[0080] Reaction progress was monitored with HPLC. After 1.5 hour, 357 mg N- ethylmethylamine was added dropwise and the yellow solution was stirred at ambient temperature for 2.5 hours. The reaction mixture was concentrated in vacuo. To the resulting yellow oil, 10 ml diethyl ether and 10 ml of a solution of hydrochloric acid (2 M) were added. The 2-phase system was stirred for 10 minutes. The acidic aqueous layer was washed with 10 ml diethyl ether.[0081] 10 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 2x10 ml water, dried (Na2SO4), filtered and concentrated in vacuo.Isolated yield: 0.58 g (76%), yellow oilHPLC: 94 % purity; Example 13; Synthesis of Rivastigmine; [0082] 0.5 g (S)-3-(l-(Dimethylamino)ethyl) phenol was dissolved in 10 ml dichloromethane (distilled from CaCl2).[0083] 1.11 g bis(4-nitrophenyl)carbonate was added. The yellow solution was stirred at ambient temperature.[0084] Reaction progress was monitored by HPLC. After 1.5 hours, 357 mg N- ethylmethylamine was added dropwise and the yellow solution was stirred for 2.5 hours at <n="23"/>ambient temperature. The reaction mixture was concentrated in vacuo. To the resulting yellow oil, 10 ml diethyl ether and 10 ml of a solution of hydrochloric acid (2 M) were added. The 2-phase system was stirred for 10 minutes. The acidic aqueous layer was washed with 10 ml diethyl ether. [0085] 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 2x10 ml water, dried (Na2SO4), filtered and concentrated in vacuo. Isolated yield: 0.58 g (76%), yellow oilHPLC: 93.92% purity, 99% ee |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With sodium carbonate; In dichloromethane; water; for 1h; | 4 1 of water were introduced in a 10-1 thick-wall beaker with a KPG stirrer. 250 g of sodium carbonate were added and dissolved under stirring. Crystals of the CAMPHORSULFONATE (517.5 g) were added in parts under stirring. When about half of the total amount was added 2 liters of dichloromethane were added. The remainder of the camphorsulfonate was added under constant stirring. The addition period was about 0.5 hour. The resulting mixture was stirred for another 0.5 hour. Then, the layers were separated in a 10-liter separating funnel. The aqueous fraction was extracted with 2x 1.5 liter of dichloromethane. The combined organic fractions were extracted with 1.5 liter of water and dried with 600 g of anhydrous sodium sulfate. The desiccant was then filtered off and the filtrate was evaporated until dry. The resulting evaporation residue was then dried in a rotary vacuum evaporator until constant weight at 50 C and 2,7 kPa. A white crystalline substance forms (187.0 g; 87%), which is used without purification in the next stage, [A] D =-55. 7 ; c=1.55, methanol). <P>THE CONTENTS OF THE UNDESIRED (R) -ENANTIOMER < 0.4%-DETERMINED USING GC IN A CHIRAL column. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With sodium carbonate; In water; | (S)-3-(l-dimethylaminoethyl)phenol hydrochloride (hydrochloride salt of the compound of Formula 8, 60 g, 0.296 mol) was dissolved in water (100 ml), and then an aqueous solution of Na CO ? 1OH O (50.82 g, 0.178 mol) was slowly added dropwise thereto with stirring. The precipitated crystals were filtered, and dried to afford (S)-3-(l-dimethylaminoethyl)phenol (Formula 8, 44 g, 90%).[53] m.p of the compound of Formula 8: 116C[54] ' H NMR (CDCl3): 7.16 (IH, m), 6.77 (3H, m), 3.27 (IH, m), 2.23 (6H, s), 1.36(3H, d) |
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 |
---|---|---|
80.5% | Reference Example 1Preparation of S-(-)-Rivastigmine300 ml of tetrahydrofuran (THF) are placed in a 0.51-three-neck flask and sodium hydride as a 60% dispersion in oil (11.3 g) is added slowly under inert conditions (Ar or N2) and stirring. A suspension develops, to which alpha-m-hydroxy phenylethyldimethylamine (46.5 g, 0.281 mol) is added at room temperature. A solution of the phenolate forms, to which 35.7 g (0.281 mol) of carbamoylchloride are added dropwise over 10 minutes while slightly cooling down to 15 C. The reaction is slightly exothermic. The rate of dropping is kept such that the temperature of the reaction mixture does not exceed 30 C. After all the agent is added, the cooling system is put aside and the reaction mixture is mixed for 2 hours at room temperature. Thereafter, THF is evaporated in a rotary vacuum evaporator. The evaporation residue is partitioned between 200 ml IN NaOH and 500 ml of ether. The organic layer is separated and the aqueous fraction is shaken with additional 2×200 ml of ether. The combined ether layers are shaken out with 1×100 ml water and 1×50 ml brine. The organic fraction is dried over anhydrous sodium sulfate. The solvent is evaporated and the crude product is vacuum distilled.b.p.=135-140 C. at 13 Pa45.6 g of a colorless viscous oil are obtained, i.e. a 80.5% yield. Content GC 99.6% | |
74% | With potassium carbonate; In acetonitrile; | (S)-3-(l-dimethylaminoethyl) phenol (V-a; 25gm; 0.15mole) was reacted with Ethyl methyl carbamoyl chloride (20gm, 0.165 mole) in presence of anhydrous.potassium carbonate (31.5 gm, 0.228 moles) and acetonitrile (250ml) and heated. After completion of reaction the reaction mixture was filtered and the filtrate concentrated to give product. The product was optionally purified by acid base treatment. Yield: 27 gmYield: 74%Purity: 99% (by HPLC) |
With pyridine;tetrabutylammomium bromide; In 4-methyl-2-pentanone; at 30℃; for 15.75h; | EXAMPLE 5: PREPARATION OF (S)-N-ETHYL-N-METHYL-3-[1-DIMETHYL-AMINO)-ETHYL]-PHENYL CARBAMATE (FORMULA II); . 6 kg of S-(-)-[1-(3-hydroxyphenyl) ethyl] dimethyl amine of Formula III and 12 L of Methyl Isobutyl Ketone(MIBK) were charged and stirred for about 10 minutes. To this reaction solution 3.44 kg of pyridine, 1.18 kg of tetrabutylammonium bromide were charged and stirred for about 15 minutes to form clear solution. 3.97 kg of N-ethyl, N-methyl carbomyl chloride was added to the reaction mixture for about 30 minutes. Heated the contents to about 30C and stirred for about 15 hours. After completion of the reaction 48 lit of water was charged and pH was adjusted to about 1.5 using 3.72 lit of 36% aqueous hydrochloric acid. Stirred the contents for about 30 minutes at about 25C and aqueous layer was separated. The aqueous layers were then washed with MIBK (2x12 lit) and separate the aqueous layer. Aqueous layer pH was adjusted to 12.5 using 6 lit of 40% aqueous sodium hydroxide solution and stirred for about 15 minutes. The aqueous layer was then extracted with MIBK (2x12 lit) and separated the organic layer. Washed the organic layer with water (2x12 lit) and separated the organic layer. The obtained organic layer was distilled off completely at about 60C to afford residue. To the obtained residue 48 lit of ethyl acetate was added and pH of the reaction solution was adjusted to about 2 by adding about 6 lit of f 18% hydrochloride in isopropyl alcohol at about 5C and stirred for about 90 minutes for solid separation. The separated solid was filtered and washed with 6 lit of ethyl acetate. The obtained wet solid was again charged into a reaction containing 30 lit of water and adjusted the pH to about 12.5 using 1.8 lit of 40% aqueous sodium hydroxide solution(caustic lye). The reaction mass was extracted with MIBK (2x12 lit) and the combined organic layer was washed with water (2x12 lit). The organic layer was distilled completely at about 60C to afford residue. To the obtained residue 48 lit of ethyl acetate was added and pH of the reaction solution was adjusted to about 2 by adding about 6 lit of f 18% hydrochloride in isopropyl alcohol at about 5C and stirred for about 90 minutes for solid separation. The separated solid was filtered and washed with 6 lit of ethyl acetate. The obtained wet solid was again charged into a reaction containing 30 lit of water and adjusted the pH to about 12.5 using 1.8 lit of 40% aqueous sodium hydroxide solution. The reaction mass was extracted with MIBK (2x12 lit) and the combined organic layer was washed with water (2x121it). The organic layer was distilled completely at about 60C to afford the title compound Purity by HPLC. 99.33% |
With pyridine;tetrabutylammomium bromide; In 4-methyl-2-pentanone; at 30℃; for 15.75h; | Example 5; Preparation of (S)-N-Ethyl-N-Methyl-3-[1-Dimethyl-Amino)-Ethyl]-Phenyl Carbamate (Formula II); 6 kg of S- (-)-[1-(3-hydroxyphenyl)ethyl] dimethyl amine of Formula III and 12 L of Methyl Isobutyl Ketone(MIBK) were charged and stirred for about 10 minutes. To this reaction solution 3.44 kg of pyridine, 1.18 kg of tetrabutylammonium bromide were charged and stirred for about 15 minutes to form clear solution. 3.97 kg of N-ethyl, N-methyl carbornyl chloride was added to the reaction mixture for about 30 minutes. Heated the contents to about 30 C. and stirred for about 15 hours. After completion of the reaction 48 lit of water was charged and pH was adjusted to about 1.5 using 3.72 lit of 36% aqueous hydrochloric acid. Stirred the contents for about 30 minutes at about 25 C. and aqueous layer was separated. The aqueous layers were then washed with MIBK (2×12 lit) and separate the aqueous layer. Aqueous layer pH was adjusted to 12.5 using 6 lit of 40% aqueous sodium hydroxide solution and stirred for about 15 minutes. The aqueous layer was then extracted with MIBK (2×12 lit) and separated the organic layer. Washed the organic layer with water (2×12 lit) and separated the organic layer. The obtained organic layer was distilled off completely at about 60 C. to afford residue.To the obtained residue 48 lit of ethyl acetate was added and pH of the reaction solution was adjusted to about 2 by adding about 6 lit of 18% hydrochloride in isopropyl alcohol at about 5 C. and stirred for about 90 minutes for solid separation. The separated solid was filtered and washed with 6 lit of ethyl acetate. The obtained wet solid was again charged into a reaction containing 30 lit of water and adjusted the pH to about 12.5 using 1.8 lit of 40% aqueous sodium hydroxide solution (caustic lye). The reaction mass was extracted with MIBK (2×12 lit) and the combined organic layer was washed with water (2×12 lit). The organic layer was distilled completely at about 60 C. to afford residue.To the obtained residue 48 lit of ethyl acetate was added and pH of the reaction solution was adjusted to about 2 by adding about 6 lit of 18% hydrochloride in isopropyl alcohol at about 5 C. and stirred for about 90 minutes for solid separation. The separated solid was filtered and washed with 6 lit of ethyl acetate. The obtained wet solid was again charged into a reaction containing 30 lit of water and adjusted the pH to about 12.5 using 1.8 lit of 40% aqueous sodium hydroxide solution. The reaction mass was extracted with MIBK (2×12 lit) and the combined organic layer was washed with water (2×12 lit). The organic layer was distilled completely at about 60 C. to afford the title compound.Purity by HPLC. 99.33% | |
Example 6; Preparation of Rivastigmine25 gm of S-(-)-3-[(l-dimethylamino) ethylj-phenol was dissolved in 250 ml of THF and 12.5 gm of KOH was charged in a flask and stirred for 10 minutes. The reaction mixture was cooled to 10-15C under nitrogen atmosphere. 25 gm of N-methyl, N-ethyl carbamoyl chloride was added slowly for about 30 minutes and then stirred for 30 minutes. The reaction mixture temperature was allowed to 25-35 and stirred for about 5 hours. The reaction mixture was charged into a flask containing 200 ml of water which is cooled to 0-5C. The reaction mixture was extracted with toluene (200 ml). Total organic layer was extracted with 20 % aqueous HCl solution. The aqueous layer pH was adjusted to about 10 using aqueous sodium hydroxide solution. The aqueous layer was extracted with dichloromethane (200 ml). The total dichloromethane layer was washed with water and distilled off completely to get 34 gm of rivastigmine base. | ||
77.1 g | With sodium hydride; In tetrahydrofuran; at 0 - 20℃; for 3h; | 2L of tetrahydrofuran was added to the reaction flask, and 100 g of Intermediate 1 was dissolved with stirring. The ice-water bath was cooled to 13 C. and 30 g of sodium hydride was slowly added in portions. After the addition is completed, it is cooled to 0C. A solution of 80 g of N-ethyl-N-methylcarbamoyl chloride in tetrahydrofuran (80 g of N-ethyl-N-methylcarbamoyl chloride dissolved in 160 ml of tetrahydrofuran) was added dropwise, and the mixture was naturally heated toAt room temperature, the reaction was stopped for 3 hours. After the reaction was completed, 100 ml of water was slowly added to quench the reaction. The tetrahydrofuran was concentrated under reduced pressure, 800 ml of water was added to the system, pH was adjusted to 3.5 with concentrated hydrochloric acid, and dichloromethane (500 ml) was washed with 3*3. The organic layer was discarded. The aqueous phase was extracted with 2M NaOH solution adjusted to pH 11,600 ml*2 dichloromethane and the aqueous phase was discarded. The methylene chloride layer was washed once with 1 M sodium hydroxide solution, twice with water, and once with saturated brine. The dichloride layer was collected and concentrated to obtain 77.1 g of a pale yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 4: PREPARATION OF S-(-)-[1-(3-HYDROXYPHENYL) ETHYL] DIMETHYL AMINE (FORMULA III); 50 g of S-(-)-[1-(3-methoxyphenyl) ethyl] dimethyl amine of Formula IV and 283 g of 48% aqueous HBr solution were charged into a clean and round bottom flask followed by heating to about 110 C and stirred for about 6 hours. After completion of the reaction, the mixture was cooled to about 30C and charged 250 ml of water and pH was adjusted to about 10.5 using 162 ml caustic lye and the reaction mixture was extracted with ethyl acetate ((1x150 ml, 2x50 ml)). The organic layer thus obtained was washed with water (2x50 ml) and treated with activated charcoal. The organic layer is filtered through celite and washed with 100 ml of ethyl acetate. The filtrate was distilled completely at below 60 C under vacuum. To the residue charged 200 ml of n-heptane at about 50C and stirred for about 90 minutes at about 25C. The separated solid was filtered and washed the solid with n-heptane 50 ml and suck dried. The solid obtained was dried at about 50C for about 5 hours to yield 41.5 g of the title compound. Purity by HPLC: 99.07%. | ||
Example 4; Preparation of S-(-)-[1-(3-Hydroxyphenyl) Ethyl] Dimethyl Amine (Formula III); 50 g of S- (-)-[1-(3-methoxyphenyl)ethyl] dimethyl amine of Formula IV and 283 g of 48% aqueous HBr solution were charged into a clean and round bottom flask followed by heating to about 110 C. and stirred for about 6 hours. After completion of the reaction, the mixture was cooled to about 30 C. and charged 250 ml of water and pH was adjusted to about 10.5 using 162 ml caustic lye and the reaction mixture was extracted with ethyl acetate ((1×150 ml, 2×50 ml)). The organic layer thus obtained was washed with water (2×50 ml) and treated with activated charcoal. The organic layer is filtered through celite and washed with 100 ml of ethyl acetate. The filtrate was distilled completely at below 60 C. under vacuum. To the residue charged 200 ml of n-heptane at about 50 C. and stirred for about 90 minutes at about 25 C. The separated solid was filtered and washed the solid with n-heptane 50 ml and suck dried. The solid obtained was dried at about 50 C. for about 5 hours to yield 41.5 g of the title compound.Purity by HPLC: 99.07%. | ||
Example 4; Preparation of S- (- )- 3- [( 1 -dimethylamino) ethyl]-phenol15 gm of the residue obtained in Example 3 was charged in a flask containing 84 ml of 48% aqueous hydrogen bromide solution and heated to about 100-110C. The reaction mixture was stirred for about 10 hours at reflux. After completion of the reaction, the reaction mixture was cooled to 25-35C and quenched into 150 ml of water. The reaction mass was basified with 60 ml of 40 % aqueous sodium hydroxide solution. The reaction mixture was extracted with ethylacetate (75 ml X 1, 50 ml X 2). The total ethyl acetate organic layer was washed with 10% aqueous NaCl solution (75 ml). Finally the organic layer was treated with activated charcoal and then distilled off completely under vacuum. 5 ml of n-hexane was added to the residue and distilled off completely. Another 30 ml of n-hexane was added to the reaction mixture and stirred for about 1 hour at 25-35C. The solid was filtered and washed with hexane (5 ml) to obtain 12 gm of the titlecompound.R-isomer content by HPLC: 0.14%Example 5; Purification of S-(-)-3-[( 1-dimethylamino) ethyl]-phenol5 gm of S-(-)-3-[(l-dimethylamino) ethylj-phenol obtained in Example 4 was charged with 15 ml of dichloromethane, heated to reflux and stirred for about 45 minutes under reflux. The reaction mixture was then cooled to 25-35C and maintained for about 30 minutes. The reaction mixture was further cooled to 0-5C and stirred for about 45 minutes. The solid was filtered and washed with dichloromethane (2 ml) to obtain the title compound (4 gm).R-isomer content by HPLC: 0.05% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In dichloromethane;Product distribution / selectivity; | EXAMPLE 1: COMPOUND SYNTHESISCompounds of the invention are produced by coupling of Ra-phenol and Q-H using methods known to those skilled in the art. For example,wherein R3 represents the appropriate phenyl substituents for a stigmine, such as rivastigmine or physostigmine, and Q represents an amine-containing pharmacologically active agent. For example,Exemplary compounds are shown in Table A. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 1: COMPOUND SYNTHESISCompounds of the invention are produced by coupling of Ra-phenol and Q-H using methods known to those skilled in the art. For example,wherein R3 represents the appropriate phenyl substituents for a stigmine, such as rivastigmine or physostigmine, and Q represents an amine-containing pharmacologically active agent. For example,Exemplary compounds are shown in Table A. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In dichloromethane;Product distribution / selectivity; | EXAMPLE 1: COMPOUND SYNTHESISCompounds of the invention are produced by coupling of Ra-phenol and Q-H using methods known to those skilled in the art. For example,wherein R3 represents the appropriate phenyl substituents for a stigmine, such as rivastigmine or physostigmine, and Q represents an amine-containing pharmacologically active agent. For example,Exemplary compounds are shown in Table A. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 1: COMPOUND SYNTHESISCompounds of the invention are produced by coupling of Ra-phenol and Q-H using methods known to those skilled in the art. For example,wherein R3 represents the appropriate phenyl substituents for a stigmine, such as rivastigmine or physostigmine, and Q represents an amine-containing pharmacologically active agent. For example,Exemplary compounds are shown in Table A. | ||
In ethyl acetate; | Example 2Synthesis of Cholinesterase Inhibitors Synthesis of compounds 4a, 4b, 4c, and 4d was accomplished as shown above. Thus, (-)-3-hydroxyphenylethyldimethylamine 1 was reacted with carbonyl diimidazole in dry ethyl acetate to form the activated imidazolide. Addition of the amphetamine isomers (2a-d) gave access to the target carbamates 3a-d in good yields (40-60% after purification by column chromatography). Free base carbamates 3a-d were converted into the corresponding hydrochloride salts 4a-d by addition of hydrogen chloride in diethyl ether followed by removal of the solvents. The identity and purity of the resulting white solids was firmly established by 1H-NMR and HPLC analysis. | |
In ethyl acetate; at 20℃; for 20h;Product distribution / selectivity; | (S)-(-)-3'-hydroxyphenylethyldimethylamine (96 mg, 0.58 mmol) (1) was dissolved in 4 ml of dry ethyl acetate. N,N'-carbonyldiimidazole powder (283 mg , 1.74 mmol) was added and the mixture stirred at room temperature for 20 h. Acetic acid (313 mg, 5.22 mmol) was then added to the mixture, followed by the addition of 162 mg (-)-atomoxetine (4, 0.63 mmol). The resulting mixture was stirred at room temperature overnight. Saturated sodium bicarbonate solution was added to the mixture and the aqueous and organic layers separated. The aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, dried over NaHCO3, evaporated and purified with a silica gel column (eluted with 25% ethyl acetate in hexane with 1% triethylamine) to yield 101 mg of the carbamoyl ester (5) (0.23 mmol, 39.0% yield). The carbamoyl ester (5) was confirmed by NMR. 1H-NMR of the HCl salt (CDCl3, 400 MHz): delta 1.808 and 1.825 (d, 3H, J = 6.8 Hz, CH3), 2.090-2.320 (m, 2H), 2.262 (ma) and 2.325 (mi) (s, 3H, CH3), 2.506-2.541 (m, 3H, CH3), 2.658-2.698 (m, 3H, CH3), 3.002 (ma) and 3.082 (mi) (s, 3H, CH3), 3.520-3.575 (m, IH, CH), 3.662-3.700 and 3.892-3.961 (m, IH, CH), 4.048-4.123 (m, IH, CH), 5.180-5.252 (m, IH, CH), 6.535- 6.582 (m, IH, CH arom.), 6.729- 6.787 and 6.902-6.957 (m, 3H, 3xCH arom.), 7.007-7.086 (m, 2H, 2xCH arom.), 7.224-7.428 (m, 7H, 7xCH arom.), 12.620 (bs, IH, HCl). |
Yield | Reaction Conditions | Operation in experiment |
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32.7% | Scheme XI. Synthesis of a Carbamoyl Ester (S)-(-)-3'-hydroxyphenylethyldimethylamine (1) (145 mg, 0.88 mmol) was dissolved in 4 ml of dry ethyl acetate. N,N'-carbonyldiimidazole powder (356 mg, 2.20 mmol) was added and the mixture stirred at room temperature for 20 h. Acetic acid (395 mg, 6.58 mmol) was added, followed by the addition of 283 mg of 2-phenylethylamine (17, 2.34 mmol). The mixture was stirred at room temperature overnight. Water (10 ml) and 1M HCl (10 ml) added and the layers separated. The organic layer was extracted with 0.5M HCl. The aqueous layers were combined, washed with ether twice and basified with NaHCO3 and 0.5 N NaOH to pH ~11, followed by extraction with ether. The ether layer was dried over NaHCO3, evaporated and purified with a silica gel column. Elution with 25% ethyl acetate in hexane with 1% triethylamine to yield 90 mg of carbamoyl ester (18) (0.29 mmol, 32.7% yield). The carbamoyl ester (18) was confirmed by NMR. 1H-NMR (CDCl3, 300 MHz): delta 1.328 (d, 3H, J=6.7 Hz, CH3), 2.169 (s, 6H, 2*CH3), 2.860 (t, 2H, J=6.8 Hz, CH2), 3.231 (q, 1H, J=6.7 Hz, CH), 3.466-3.532 (m, 2H, CH2), 5.002 (bs, 1H, NH), 6.966 (dd, 1H, J=8.0 and 1.4 Hz, CH arom.), 7.030 (bs, 1H, CH arom.), 7.092 (bd, 1H, J=7.7 Hz, CH arom.) 7.183-7.334 (m, 6H, CH arom.). |
Yield | Reaction Conditions | Operation in experiment |
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39.0% | Scheme II. Synthesis of a Carbamoyl Ester (S)-(-)-3'-hydroxyphenylethyldimethylamine (96 mg, 0.58 mmol) (1) was dissolved in 4 ml of dry ethyl acetate. N,N'-carbonyldiimidazole powder (283 mg, 1.74 mmol) was added and the mixture stirred at room temperature for 20 h. Acetic acid (313 mg, 5.22 mmol) was then added to the mixture, followed by the addition of 162 mg (-)-atomoxetine (4, 0.63 mmol). The resulting mixture was stirred at room temperature overnight. Saturated sodium bicarbonate solution was added to the mixture and the aqueous and organic layers separated. The aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, dried over NaHCO3, evaporated and purified with a silica gel column (eluted with 25% ethyl acetate in hexane with 1% triethylamine) to yield 101 mg of the carbamoyl ester (5) (0.23 mmol, 39.0% yield). |
Yield | Reaction Conditions | Operation in experiment |
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46% | Scheme I. Synthesis of a Carbamoyl Ester Seventy three milligrams (73 mg) of NaH (60% dispersion in mineral oil) was added to a solution of 0.3 g (1.82 mmol) (-)-3'-hydroxyphenylethyldimethylamine (1) in 15 ml toluene. The solution was stirred at room temperature for 30 min and then 0.33 g of carbonyldiimidazole (CDI) (2.0 mmol) was added in one portion, and heated to 80 C. for 2 hours. dl-Amphetamine (2) sulfate (0.335 g, 1.82 mmol) was then added and the mixture was stirred at room temperature for 2 days. Distilled water (20 ml) and 15 ml of a 1M HC1 solution were added to the reaction mixture and the aqueous and organic layers separated. The aqueous layer was washed with chloroform, basified with 1 M NaOH to pH ~11 and extracted with ether. The ether layer was dried over sodium sulfate, evaporated and purified with a silica gel column (eluted with 3% methanol and 1% triethylamine in ethyl acetate) to yield 0.27 g of the carbamoyl ester (3) (0.83 mmol, 46% yield). The carbamoyl ester (3) was confirmed by NMR. 1H-NMR (CDCl3, 300 MHz): delta 1.146 (d, 3H, J=6.6 Hz, CH3), 1.312 (d, 3H, J=6.7 Hz, CH3), 2.153 (s, 6H, 2xCH3), 2.721 (dd, 1H, J=13.4 and 7.2 Hz, CHH), 2.866 (dd, 1H, J=13.4 and 5.9 Hz, CHH), 3.218 (q, 1H, J=6.6 Hz, CH), 3.960-4.936 (m, 1H, CH), 4.870 (bd, 1H, J=7.7 Hz, NH), 6.943 (bd, 1H, J=7.2 Hz, CH arom.), 6.993 (bs, 1H, CH arom.), 7.078 (bd, 1H, J=7.7 Hz, CH arom.) 7.156-7.291 (m, 6H, CH arom.). |
Yield | Reaction Conditions | Operation in experiment |
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39% | Scheme V. Synthesis of a Carbamoyl Ester (S)-(-)-3'-hydroxyphenylethyldimethylamine (1) (1.2 g, 7.3 mmol) was dissolved in 20 ml of dry ethyl acetate. N,N'-carbonyldiimidazole powder (2.37 g,14.6 mmol) was added and the mixture stirred at 85 C. overnight. After cooling to 0 C., 3.3 g of acetic acid (55.0 mmol) was added, followed by the addition of 2.8 g of 1-amphetamine (8) (20.7 mmol). The mixture was stirred at room temperature for 36 h. Water (20 ml) and 1M HCl (20 ml) were added and the aqueous and organic layers separated. The organic layer was extracted with 0.5M HCl. The aqueous layers were combined and washed with ether twice, basified with NaHCO3 and 0.5 N NaOH to pH ~11 and extracted with ether. The ether layer was dried over NaHCO3, evaporated and purified with silica gel chromatography. Elution with a mixture of 25% ethyl acetate with 1% triethylamine in hexane yielded 0.93 g of the carbamoyl ester (9) (2.85 mmol, 39% yield). | |
23.5% | Scheme IV. Synthesis of a Carbamoyl Ester At room temperature, diisopropylethylamine (5.16 g, 40 mmol) and CDI powder (6.48 g, 40 mmol) were added to a suspension of 7.34 g of 1-amphetamine sulfate (8) (40 mmol) in 140 ml of dichloromethane. The resulting mixture was stirred at room temperature for 1 h. (-)-alpha-3'-hydroxyphenylethyldimethylamine (1) (3.3 g, 20 mmol), which had been mixed with 0.8 g sodium hydride (60% dispersion in mineral oil) in dry toluene (120 ml) for 30 minutes, was added to the mixture and the dichloromethane removed under reduced pressure. The resulting suspension was heated to 85 C. overnight with stirring. The reaction mixture was extracted with 0.5 M HCl (200 ml). The aqueous layer was washed with ethyl acetate, basified at 0 C. to pH ~11 with sodium bicarbonate and 0.5 N NaOH and extracted with ethyl acetate (3*100 ml). The organic layers were combined, dried over sodium sulfate and evaporated. The residue was purified with a silica gel column. Elution with a mixture of 20-30% ethyl acetate with 1% triethylamine in hexane yielded 1.53 g of the carbamoyl ester (9) (4.7 mmol, 23.5% yield). The carbamoyl ester (9) was confirmed by NMR. 1H-NMR (CDCl3, 300 MHz): delta 1.179 (d, 3H, J=6.6 Hz, CH3), 1.331 (d, 3H, J=6.7 Hz, CH3), 2.174 (s, 6H, 2xCH3), 2.789 (dd, 1H, J=13.4 and 7.2 Hz, CHH), 2.832 (dd, 1H, J=13.4 and 5.9 Hz, CHH), 3.228 (q, 1H, J=6.7 Hz, CH), 3.980-4.062 (m, 1H, CH), 4.856 (bd, 1H, J=7.2 Hz, NH), 6.955 (bd, 1H, J=7.4 Hz, CH arom.), 7.018(bs, 1H, CH arom.), 7.095 (bd, 1H, J=7.7 Hz, CH arom.) 7.186-7.303 (m, 6H, CH arom.). |
Yield | Reaction Conditions | Operation in experiment |
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59.4% | Scheme XII. Synthesis of a Carbamoyl Ester (S)-(-)-3'-hydroxyphenylethyldimethylamine (1) (81 mg, 0.49 mmol) was dissolved in 4 ml of dry ethyl acetate. N,N'-carbonyldiimidazole powder (199 mg, 1.23 mmol) was added and the mixture was stirred at room temperature for 20 h. Acetic acid (184 mg, 3.07 mmol) was added, followed by the addition of 186 mg of d-amphetamine (19) acetate salt (0.96 mmol). The mixture was stirred at room temperature overnight. Water (5 ml) and 1M HCl (5 ml) were added and the aqueous and organic layers separated. The organic layer was extracted with 0.5M HCl. The aqueous layers were combined, washed with ether twice and basified with NaHCO3 and 0.5 N NaOH to pH ~11, followed by extraction with ether. The ether layer was dried over NaHCO3, evaporated and purified with a silica gel column (eluted with 25% ethyl acetate in hexane with 1% triethylamine) to yield 95 mg of carbamoyl ester (20) (0.29 mmol, 59.4% yield). The carbamoyl ester (20) was confirmed by NMR. 1H-NMR (CDCl3, 300 MHz): delta 1.192 (d, 3H, J=6.6 Hz, CH3), 1.367 (d, 3H, J=6.7 Hz, CH3), 2.205 (s, 6H, 2*CH3), 2.759 (dd, 1H, J=13.4 and 7.2 Hz, CHH), 2.896 (dd, 1H, J=13.4 and 5.9 Hz, CHH), 3.295 (q, 1H, J=6.6 Hz, CH), 3.990-4.044 (m, 1H, CH), 4.847 (bd, 1H, J=7.2 Hz, NH), 6.966 (bd, 1H, J=7.4 Hz, CH arom.), 6.976 (bs, 1H, CH arom.), 7.114 (bd, 1H, J=7.7 Hz, CH arom.) 7.191-7.324 (m, 6H, CH arom.). |
Yield | Reaction Conditions | Operation in experiment |
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61% | 4-nitrophenychloroformate powder (0.179 g, 0.86 mmol) was added to a solution of 0.12 g (0.72 mmol) (-)-3'-hydroxyphenylethyldimethylamine (1) and 0.22 g (2.17 mmol) triethylamine in 10 ml of dry dichloromethane (0.86 mmol) at 0 C. The solution was stirred at 0 C. for 5 min followed by stirring at room temperature for an additional 30 minutes. A solution of 0.107 g 1-methamphetamine (6) in 2 ml of dry dichloromethane was then added, and the resulting solution stirred at room temperature for 2 hours. The solvent was evaporated and the residue applied to a silica gel column. The carbamoyl ester (7) was eluted with 3% acetone in ethyl acetate containing 1% triethylamine. Fractions containing the carbamoyl ester (7) were combined and concentrated to yield 0.15 g of the carbamoyl ester (7) (0.44 mmol, 61% yield). The carbamoyl ester (7) was confirmed by NMR. 1H-NMR (CDCl3, 300 MHz): delta 1.192 (mi) and 1.275 (ma) (d, 3H, J=6.8 Hz, CH3), 1.305 and 1.326 (d, 3H, J=3.0 Hz, CH3), 2.162 and 2.167 (s, 6H, 2×CH3), 2.746 (dd, 1H, J=13.7 and 6.8 Hz, CHH), 2.850 (dd, 1H, J=13.7 and 6.8 Hz, CHH), 2.868 and 2.886(s, 3H, CH3), 3.165-3.217 (m, 1H, CH), 4.558-4.633 (m, 1H, CH), 6.665 and 6.855 (bd, 1H, J=7.9 Hz, CH arom.), 6.723 and 6.928 (bs, 1H, CH arom.), 7.065 (bd, 1H, J=7.2 Hz, CH arom.), 7.176-7.305 (m, 6H, CH arom.). | |
61% | 4-nitrophenychloroformate powder (0.179 g, 0.86 mmol) was added to a solution of 0.12 g (0.72 mmol) (-)-3'-hydroxyphenylethyldimethylamine (1) and 0.22g (2.17 mmol) triethylamine in 10 ml of dry dichloromethane (0.86 mmol) at O0C. The solution was stirred at O0C for 5 min followed by stirring at room temperature for an additional 30 minutes. A solution of 0.107 g 1-methamphetamine (6) in 2 ml of dry dichloromethane was then added, and the resulting solution stirred at room temperature for 2 hours. The solvent was evaporated and the residue applied to a silica gel column. The compound (7) was eluted with 3% acetone in ethyl acetate containing 1% triethylamine. Fractions containing compound (7) were combined and concentrated to yield 0.15 g of the compound (7) (0.44 mmol, 61% yield).The compound (7) was confirmed by NMR. 1H-NMR (CDC13, 300 MHz): delta 1.192 (mi) and 1.275 (ma) (d, 3H, J = 6.8 Hz, CH3), 1.305 and 1.326 (d, 3H, J = 3.0 Hz, CH3), 2.162 and 2.167 (s, 6H, 2xCH3), 2.746 (dd, IH, J = 13.7 and 6.8 Hz, CHH), 2.850 (dd, IH, J = 13.7 and 6.8 Hz, CHH), 2.868 and 2.886(s, 3Eta, CH3), 3.165-3.217 (m, IH, CH), 4.558- 4.633 (m, IH, CH), 6.665 and 6.855 (bd, IH, J = 7.9 Hz, CH arom.), 6.723 and 6.928 (bs, IH, CH arom.), 7.065 (bd, IH, J = 7.2 Hz, CH arom.), 7.176-7.305 (m, 6H, CH arom.). |
Yield | Reaction Conditions | Operation in experiment |
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92.3% | Scheme VI. Synthesis of a Carbamoyl Ester Triphosgene (85.5 mg, 0.28 mmol) was dissolved in 2 ml of dry dichloromethane. To this solution, a mixture of 145 mg of desmethylselegeline (10) (0.84 mmol) and 110 mg of diisopropylethylamine (DIEA) (0.85 mol) in 1 ml of dry dichloromethane was added at 0 C. and allowed to react for 10 minutes. The mixture was stirred at room temperature for 60 hours, and subsequently added to a suspension of (-)-alpha-3'-hydroxyphenylethyldimethylamine (1) (92 mg, 0.55 mmol) and sodium hydride (68 mg, 60% dispersion in mineral oil) in dry acetonitrile, which had been stirred at. room temperature for 1 hour. The resulting mixture was stirred at room temperature overnight. The solvents of the above mixture were removed under reduced pressure. The residue was dissolved in 0.5 M HCl and washed with ether. The aqueous layer was basified with sodium bicarbonate and extracted with ethyl acetate (3*20 ml). The organic layer was washed with 0.5 N NaOH (200 ml), dried over sodium sulfate and evaporated. The residue was purified with a silica gel column (eluted with 30-60% ethyl acetate in hexane with 1% triethylamine) to yield 185 mg of the carbamoyl ester (11) (0.508 mmol, 92.3% yield). The carbamoyl ester (11) was confirmed by NMR. 1H-NMR (CDCl3, 300 MHz): delta 1.339 (d, 3H, J=6.6 Hz, CH3), 1.327-1.415 (m, 3H, CH3), 2.187 (s, 6H, 2*CH3), 2.215-2.258 (m, 1H, CH), 2.843-2.870 (m, 1H, CH), 3.063 (dd, 1H, J=13.5 and 7.5 Hz, CHH), 3.230 (q, 1H, J=6.6 Hz, CH), 4.043-4.118 (m, 2H, 2*CH), 4.372-4.411 (m, 1H, CH), 6.846-7.024 (m, 2H, 2*CH arom.), 7.108 (bd, 1H, J=7.7 Hz, CH arom.), 7.202-7.313 (m, 6H, CH arom.). |
Yield | Reaction Conditions | Operation in experiment |
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EXAMPLE 4 Preparation of (S)-N-Ethyl-N-methyl-3-[1-(dimethylamino)ethyl]-phenyl carbamate from (S)-3-[1-(Dimethylamino)ethyl]phenol and 1-[(N-ethyl-methylamino)carbonyl]-3-methyl-1H-imidazolium iodide Triethylamine (14.7 g, 145.2 mmol) and 1-[[N-ethyl-(N-methyl)amino]carbonyl}-3-methyl-1H-imidazolium iodide (42.9 g, 145.25 mmol) were added slowly to the cooled solution of (S)-3-[1-(dimethylamino)ethyl]phenol (20 g, 121.0 mmol) in acetonitirile (60 mL). The reaction mixture was stirred at 75-80 C. until reaction completion as determined by 1H NMR. The reaction mixture was evaporated and the obtained residue was diluted with water (40 mL) and toluene (60 mL) and then basified with 50% aq. NaOH solution at <10 C. The phases were separated and the aqueous phase was extracted with toluene. The combined organic phases were washed with water. The organic solution was evaporated under vacuum to give (S)-N-ethyl-N-methyl-3-[1-(dimethylamino)ethyl]phenyl carbamate (Rivastigmine free base). 1H-NMR (CDCl3) delta 7.29 (t, J=7.80 Hz, 1H); 7.13-6.90 (m, 3H); 3.50-3.35 (m, 2H); 3.24 (q, J=6.7 Hz, 1H); 3.02 (ad, 3H); 2.20 (s, 6H); 1.36 (d, J=6.7 Hz, 3H); 1.26-1.15 (m, 3H). |
Yield | Reaction Conditions | Operation in experiment |
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EXAMPLE 7 Preparation of (S)-N-Ethyl-N-methyl-3-[1-(dimethylamino)ethyl]-phenyl carbamate (2R,3R)-hydrogen tartrate from (S)-3-[1-(Dimethylamino)ethyl]phenol and 1-[(N-ethyl-methylamino)carbonyl]-3-methyl-1H-imidazolium methyl sulfate Triethylamine (3.6 g, 35.4 mmol) and 1-{([N-ethyl-(N-methyl)amino]carbonyl}-3-methyl-1H-imidazolium methyl sulfate (9.1 g, 32.6 mmol) were added slowly to the cooled solution of (S)-3-[1-(dimethylamino)ethyl]phenol (4.5 g, 27.23 mmol) in acetonitirile (25 mL). The reaction mixture was stirred at 75-80 C. until reaction completion as determined by 1H NMR. The reaction mixture was evaporated and the obtained residue was diluted with water (30 mL) and toluene (30 mL) and then basified with 50% aq. NaOH solution at internal temperature below 10 C. The phases were separated and the aqueous phase was extracted with toluene. The combined organic phases were washed with water. The organic solution was evaporated under vacuum to give (S)-N-ethyl-N-methyl-3-[1-(dimethylamino)ethyl]phenyl carbamate. The residue dissolved in isopropanol (45 mL) and to the solution was added (2R,3R)-tartaric acid (4.08 g, 27.23 mmol) and heated to 70-80 C. The solution was cooled and the resulting suspension was filtered and dried to give (S)-N-Ethyl-N-methyl-3-[1-(dimethylamino)ethyl]-phenyl carbamate (2R,3R)-hydrogen tartrate (8.54 g, 78% yield). The 1H NMR spectrum of the product was identical to that of example 6. |
Yield | Reaction Conditions | Operation in experiment |
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Example 7; Preparation of CffH-VRivastigmine Tartrate; To a solution of lOOg of (S)-[I -(3 -hydroxyphenyl) ethyl] dimethylamine (VIII) in 500ml of acetone, pulverized potassium carbonate (125.2g) was added. The reaction mixture was heated to 40-450C for 1 hour. A solution of iV-ethyl-iV-methylcarbamoyl chloride (77.5 g) in acetone (300ml) was added to the reaction mixture and the temperature of the reaction mixture was raised to 55-600C followed by stirring at the same temperature for 8-10 hours. After the completion of the reaction, the reaction mixture was cooled and filtered. The solvent was then removed under reduced pressure, water (500ml) and toluene (300ml) were added followed by pH adjustment to 1 -2 using concentrated hydrochloric acid. After separating the organic layer, ethyl acetate (500ml) was added to the aqueous layer and pH was adjusted to 9-11 with liquid ammonia. The organic layer was separated and concentrated under reduced pressure to obtain oil. To this oily mass, acetone (750ml) and activated charcoal (5g) were added and stirred for 30 minutes. The reaction mixture was then filtered first through hyflo bed and then through micron filter. (L)-(+)-Tartaric acid was added to the filtrate and the reaction mixture was stirred for 4-5 hours and filtered. The solid thus obtained was washed with acetone and dried to obtain the title compound as solid | ||
Example 7 Preparation of (S)-(-)-Rivastigmine Tartrate To a solution of 100 g of (S)-[1-(3-hydroxyphenyl)ethyl]dimethylamine (VIII) in 500 ml of acetone, pulverized potassium carbonate (125.2 g) was added. The reaction mixture was heated to 40-45 C. for 1 hour. A solution of N-ethyl-N-methylcarbamoyl chloride (77.5 g) in acetone (300 ml) was added to the reaction mixture and the temperature of the reaction mixture was raised to 55-60 C. followed by stirring at the same temperature for 8-10 hours. After the completion of the reaction, the reaction mixture was cooled and filtered. The solvent was then removed under reduced pressure, water (500 ml) and toluene (300 ml) were added followed by pH adjustment to 1-2 using concentrated hydrochloric acid. After separating the organic layer, ethyl acetate (500 ml) was added to the aqueous layer and pH was adjusted to 9-11 with liquid ammonia. The organic layer was separated and concentrated under reduced pressure to obtain oil. To this oily mass, acetone (750 ml) and activated charcoal (5 g) were added and stirred for 30 minutes. The reaction mixture was then filtered first through hyflo bed and then through micron filter. (L)-(+)-Tartaric acid was added to the filtrate and the reaction mixture was stirred for 4-5 hours and filtered. The solid thus obtained was washed with acetone and dried to obtain the title compound as solid |
Yield | Reaction Conditions | Operation in experiment |
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With methanol; potassium hydroxide; at 10 - 20℃;Inert atmosphere; | Example 6; Preparation of CSy?-O-Hydroxyphenyl) ethyl. dimethylamine CVIII); 44.6g of KOH pellets was taken in 300 ml of methanol at room temperature under nitrogen atmosphere. The suspended solution was then cooled to 10-15C. To the resulting solution, methanolic solution of (iS)-[3-(l-Dimethylamino) ethyl] phenyl) p- toluenesulfonate (VII) obtained in Example 5 was added over 30 minutes. The reaction mixture was stirred for 2-3 hours at room temperature. After completion of the reaction, the reaction mixture was filtered and washed with methanol. Methanol was removed completely under reduced pressure and water was added to the resulting reaction mixture. The reaction mixture was cooled to 10-150C and pH was adjusted between 1-2 using concentrated hydrochloric acid. Water was then added and the layers"were mixed and separated. The aqueous layer was washed with toluene (3 x 200ml). To the aqueous layer, ethyl acetate was added, followed by the adjustment of pH to 9.5-11 with liquid ammonia. After separating and washing the aqueous layer with ethyl acetate, the combined organic layer was concentrated under reduced pressure. Cyclohexane (100ml) was then added and distilled off. Again 200ml of cyclohexane was added to the residue and heated to 80-85C for 30 minutes. The reaction mass was cooled to room temperature and stirred for 1 hour. The solid thus obtained was washed with cyclohexane and dried to obtain the title compound. | |
With methanol; potassium hydroxide; at 10 - 20℃;Inert atmosphere; | 44.6 g of KOH pellets were taken in 300 ml of methanol at room temperature under nitrogen atmosphere. The suspended solution was then cooled to 10-15C. To the resulting solution, methanolic solution of 5'-[3-(l-dimethylamino)ethyl]phenyl)- 7- toulenesuphonate (X) obtained in Example 10 was added over 30 minutes. The reaction mixture was stirred for 2-3 hours at room temperature. After completion of the reaction, the reaction mixture was filtered and washed with methanol. Methanol was removed completely under reduced pressure and water was added to the resulting reaction mixture. The reaction mixture was cooled to 10-15C and pH was adjusted between 1-2 using concentrated hydrochloric acid. Water was then added and the layers were mixed and aqueous separated. The aqueous layer was washed' with toluene (3 x 200 ml). To the aqueous layer, ethyl acetate was added, followed by the adjustment of pH to 9.5-1 1 with liquid ammonia. After separating and washing the aqueous layer with ethyl acetate, the combined organic layer was concentrated under reduced pressure. Cyclohexane (100 ml) was then added and distilled off. Again 200 ml of cyclohexane was added to the residue and heated to 80-85C for 30 minutes. The reaction mass was cooled to room temperature and stirred for 1 hour. The solid thus obtained Was washed with cyclohexane and dried to obtain the title compound, (XI) as a solid. | |
With methanol; potassium hydroxide; at 10 - 20℃;Inert atmosphere; | Example 6 Preparation of (S)-[1-(3-Hydroxyphenyl)ethyl]dimethylamine (VIII) 44.6 g of KOH pellets was taken in 300 ml of methanol at room temperature under nitrogen atmosphere. The suspended solution was then cooled to 10-15 C. To the resulting solution, methanolic solution of (S)-[3-(1-Dimethylamino)ethyl]phenyl)p-toluenesulfonate (VII) obtained in Example 5 was added over 30 minutes. The reaction mixture was stirred for 2-3 hours at room temperature. After completion of the reaction, the reaction mixture was filtered and washed with methanol. Methanol was removed completely under reduced pressure and water was added to the resulting reaction mixture. The reaction mixture was cooled to 10-15 C. and pH was adjusted between 1-2 using concentrated hydrochloric acid. Water was then added and the layers were mixed and separated. The aqueous layer was washed with toluene (3*200 ml). To the aqueous layer, ethyl acetate was added, followed by the adjustment of pH to 9.5-11 with liquid ammonia. After separating and washing the aqueous layer with ethyl acetate, the combined organic layer was concentrated under reduced pressure. Cyclohexane (100 ml) was then added and distilled off. Again 200 ml of cyclohexane was added to the residue and heated to 80-85 C. for 30 minutes. The reaction mass was cooled to room temperature and stirred for 1 hour. The solid thus obtained was washed with cyclohexane and dried to obtain the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88.5% | With sodium hydroxide; In water; at 90℃; for 2h; | To the crude product obtained in the previous step, 20 g of 30% NaOH solution was added and the system was heated to 90C. After 2 hours of reaction, the system clarifies the yellow homogeneous liquid from the emulsion. After the reaction is complete, the system is cooled to room temperature, the system is cooled with ice water bath, 3N HCl is added to the system, and the pH of the system is about 7-8. The system was extracted three times with ethyl acetate (60 mL x 3) and the organic phases were combined, washed once with saturated brine and dried over anhydrous sodium sulfate. After the removal of most of the solvent, adding n-hexane beating, precipitation of a large amount of white solid and then filtered to obtain white solid (S)-3-(1-dimethylaminoethyl)phenol 7.93g. The rate was 88.5% and the HPLC value was 99.8%. |
79% | Example 2; (S)-3-(1-Dimethylamino-ethyl)-phenol via dimesylate and aminomesylate; In a 0.75 L round-bottomed flask with mechanical stirring were placed 96.5 g methanesulfonic anhydride, 30.0 g of (R)-3-(1-Hydroxy-ethyl)-phenol, 0.27 g 4-dimethylaminopyridine and 270 g ethyl acetate under nitrogen. Stirring was continued at 20 C. for 15 min before cooling down to 0 C. 74.4 g N,N-Diisopropylethylamine (i.e. Huenig's base) was added at 0 C. (exothermic) within 3 h and stirring was continued for 30 min at about -5 C. before heating to 20 C. and further 30 min stirring of the resulting suspension.Sample of (R)-methanesulfonic acid 3-(1-methanesulfonyloxy-ethyl)-phenyl ester) drawn at this point:1H NMR (400 MHz, CDCl3, ppm): 1.70 (d, 3H); 2.84 (s, 3H); 3.18 (s, 3H); 5.75 (q, 1H); 7.30 (d, 1H); 7.38 (m, 2H); 7.49 (t, 1H).; 79.1 g gaseous dimethyl amine was added within >4 h at 15-25 C. into the gas phase from a laboratory lecture bottle. The reaction was moderately exothermic. The suspension was stirred for >10 h at 20 C. before conversion was checked. 60 g water was added dissolving the salts and ca. 100 g of the aqueous phase of the resulting biphasic solution was removed.100 g water was added. After stirring for 5 min ca. 100 g of the aqueous phase was removed.3 g Cellflock 40 PL filter aid was added, the solution was filtered and transferred to a second 0.75 L round-bottomed flask. Phases were separated and the aqueous phase was discarded.391 g ethyl acetate was removed by distillation.Sample of (S)-methanesulfonic acid 3-(1-dimethylamino-ethyl)-phenyl ester drawn at this point:1H NMR (400 MHz, CDCl3, ppm): 1.37 (d, 3H); 2.21 (s, 3H); 3.15 (s, 3H); 3.31 (q, 1H); 7.18 (d, 1H); 7.26 (m, 2H); 7.37 (t, 1H).IR (ATR, cm-1): 3631, 2979, 2941, 2820, 2773, 1607, 1584, 1484, 1443, 1369, 1179, 1128, 967, 917, 823, 804, 700.MS (ESI, m/z): 244 (100%, MH+), 199.80 g water was added and distillation was continued until water started to distill over. 87 g 30% aqueous NaOH was added and the resulting biphasic solution was heated to 90 C. with rapid stirring for 2 h. A clear, dark monophasic solution was obtained. Temperature was lowered to about 80 C. 174 g toluene was added and the pH was adjusted to 8.7 with 24 g orthophosphoric acid at about 80 C. The biphasic mixture was heated to a temperature of about 80 C. and phases were separated. The aqueous phase was discarded.The toluene phase was washed with 15 g water at 80 C. Ca. 100 g toluene was distilled off.3 g silica gel 60 was added and the suspension was filtered at 80 C. into a 0.25 L round-bottomed flask. The filter cake was washed with 17 g hot toluene. 20 mg of the (S)-3-(1-Dimethylamino-ethyl)-phenol suspended in 0.5 ml toluene was added at 70 C. resulting in crystallization. The suspension was held at 70 C. for 30 min, then the temperature was lowered to a temperature of about 0 C. within 3 h. Stirring was continued at this temperature for 2 h. The solids were filtered and washed twice with 44 g toluene each. The wet filter cake (29.5 g) was transferred to a 0.25 L round-bottomed flask. 78 g toluene was added. The suspension was heated to 100 C. to dissolve the (S)-3-(1-Dimethylamino-ethyl)-phenol and filtered hot over a plate filter into a preheated 0.25 L round-bottomed flask. Temperature was lowered to about 70 C. and 20 mg of (S)-3-(1-Dimethylamino-ethyl)-phenol suspended in 0.5 ml toluene was added at 70 C. resulting in crystallization. The suspension was held at 70 C. for 30 min, then the temperature was lowered to 0 C. within 3 h. Stirring was continued at this temperature for 2 h. The solids were filtered and washed twice with 25 g toluene each. The wet product (29.2 g) was dried at 45 C./50 mbar for at least 8 hours to give 28.5 g (79% yield of (R)-3-(1-Hydroxy-ethyl)-phenol and an, enantiomeric ratio >99.9:0.1 of (S)-3-(1-Dimethylamino-ethyl)-phenol as colorless crystals.1H NMR (400 MHz, CDCl3, ppm): 1.42 (d, 3H); 2.24 (s, 3H); 3.37 (q, 1H); 6.75 (m, 3H); 7.14 (m, 1H).IR (ATR, cm-1): 3004, 2974, 2874, 2839, 2795, 2672, 2552, 1595, 1465, 1454, 1465, 1454, 1373, 1335, 1270, 1206, 1163, 1082, 1059, 1019, 957, 911, 871, 810, 792, 706.MS (ESI, m/z): 166 (100%, MH+), 121, 79, 60, 46.; | |
80 g water was added and distillation was continued until water started to distill over. 87 g 30% aqueous NaOH was added and the resulting biphasic solution was heated to 90C with rapid stirring for 2 h. A clear, dark monophasic solution was obtained. Temperature was lowered to about 80C. 174 g toluene was added and the pH was adjusted to 8.7 with 24 g orthophosphoric acid at about 80C. The biphasic mixture was heated to a temperature of about 80C and phases were separated. The aqueous phase was discarded.The toluene phase was washed with 15 g water at 80C. Ca. 100 g toluene was distilled off.3 g silica gel 60 was added and the suspension was filtered at 80C into a 0.25 L round-bottomed flask. The filter cake was washed with 17 g hot toluene. 20 mg and then the (S)-3-(1-dimethylamino-ethyl)-phenol suspended in 0.5 ml toluene was added at 70C resulting in crystallization. The suspension was held at 70C for 30 min, then the temperature was lowered to a temperature of about 0C within 3 h. Stirring was continued at this temperature for 2 h. The solids were filtered and washed twice with 44 g toluene each. The wet filter cake (29.5 g) was transferred to a 0.25 L round-bottomed flask. 78 g toluene was added. The suspension was heated to 100C to dissolve the (S)-3-(1-Dimethylamino- ethyl)-phenol and filtered hot over a plate filter into a preheated 0.25 L round- bottomed flask. Temperature was lowered to about 70C and 20 mg of (S)-3-(1- Dimethylamino-ethyl)-phenol suspended in 0.5 ml toluene was added at 70C resulting in crystallization. The suspension was held at 70C for 30 min, then the temperature was lowered to 0C within 3 h. Stirring was continued at this temperature for 2 h. The solids were filtered and washed twice with 25 g toluene each. The wet product (29.2 g) was dried at 45C/50 mbar for at least 8 hours to give 28.5 g (79% yield of (R)-3-(1-Hydroxy-ethyl)-phenol and an, enantiomeric ratio >99.9:0.1 of (S)-3-(1-Dimethylamino-ethyl)-phenol as colorless crystals. H NMR (400 MHz, CDCI3, ppm): 1.42 (d, 3H); 2.24 (s, 3H); 3.37 (q, 1H); 6.75 (m, 3H); 7.14 (m, 1H).IR (ATR, cm"1): 3004, 2974, 2874, 2839, 2795, 2672, 2552, 1595, 1465, 1454, 1465, 1454, 1373, 1335, 1270, 1206, 1163, 1082, 1059, 1019, 957, 911 , 871, 810, 792, 706.MS (ESI, m/z): 166 (100%, MH+), 121, 79, 60, 46. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | Example 1APreparation of 3-((S)-1-(Dimethylamino)ethyl)phenyl methyl-((R)-1-phenylpropan-2 yl)carbamate Free Base (3d) In a 22 L 4-neck flask equipped with addition funnel, mechanical stirrer, ?distillation head? with reflux condenser and nitrogen inlet and a thermocouple 638 g (3.86 mol, 1.05 eq.) of (S)-rivaphenol IV and 1791 g (5.5 mol, 1.5 eq.) cesium carbonate were suspended in 9.2 L toluene and subsequently heated to reflux for 30 min. The first distillate (120 mL) contained about 1 mL of water and was discarded. Subsequently, 893 g (3.67 mol, 1.0 eq.) activated urea III (Example 1) was dissolved in 3.3 L of toluene (heated to 40 C. to facilitate dissolution) and slowly added to the reaction mixture at a rate that maintained adequate reflux (1 h). The addition funnel was rinsed with an additional 100 mL of toluene and this solution was added as well over 10 min. After completed addition the reaction mixture was maintained at reflux overnight. During this time an additional 1 mL of water was collected in the distillation still trap. The reaction mixture was cooled to 90 C. before 1.1 L of 1N sodium hydroxide solution was added. After heating for 3 h to 90 C. The mixture was allowed to cool to rt and transferred into an extraction funnel. The separated toluene layer was washed with 1.6 L of 1N sodium hydroxide before being extracted with aqueous 1N HCL (5.4×1 L+1×2.7 L). The combined acidic extracts were then basified with 10% sodium hydroxide solution to reach pH 12-13 and subsequently extracted with TBME (1×1 L+1×5 L). The combined ether extracts were washed with 11 L 1N sodium hydroxide, two times 1.6 L of water, and 1.1 L of saturated brine before being dried over sodium sulfate. Current chromatographic purity is 99.1% AUC. Solvent evaporation followed by high vacuum drying over weekend afforded 1150 g of the title compound VI (96%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of (S)-3-[1-(dimethylamino)ethyl]phenol (1.64 g, 10 mmoL) in acetonitrile (10 mL) was stirred under nitrogen at 0-5 C. 1,1'-Carbonyldiimidazole (2.2 g, 13.5 mmoL) was added to the mixture and the resulting solution was stirred at room temperature overnight. The solution was cooled using an ice-bath and acetic acid (0.82 g, 13.5 mmoL) was added followed by N-ethylmethylamine (1.13g, 15 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 (30 mL). Water (20 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 (S)-Rivastigime (1.8 g) as a liquid with enantiomeric purity >99.0% (chiral HPLC). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A solution of (S)-3-[1-(dimethylamino)ethyl]phenol (4.1 g, 25 mmoL) and triethylamine (8.0 g, 79 mmoL) in dichloromethane (40 mL) was stirred under nitrogen and cooled using an ice-bath. 4-Nitrophenyl chloroformate (6.0 g, 3 mmoL) was added to the solution and the mixture was stirred for 2 h whereupon N-ethylmethylamine (2.2 g, 37.5 mmoL) was added in portions and the solution was allowed to warm slowly to room temperature and stirred overnight. The reaction mixture was quenched by the addition of water (20 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 (S)-Rivastigime (4.2 g) as a liquid with enantiomeric purity >99.0% (chiral HPLC). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.3% | Triphosgene (85.5 mg , 0.28 mmoi) was dissolved in 2 mi of dry dichioromethane.To this solution, a mixture of 145 mg of desmethylselegiline (10) (0.84 mmol) and 110 mg of diisopropylethylamine (DIEA) (0.85 mol) in 1 ml of dry dichioromethane was added at O0C and allowed to react for 10 minutes. The mixture was stirred at room temperature for 60 hours, and subsequently added to a suspension of (-)-_ -3'-hydroxyphenylethyldimethylamine (1) (92 mg, 0.55 mmol) and sodium hydride (68 mg, 60% dispersion in mineral oil) in dry acetonitrile, which had been stirred at room temperature for 1 hour. The resulting mixture was stirred at room temperature overnight. The solvents of the above mixture were removed under reduced pressure. The residue was dissolved in 0.5 M HCl and washed with ether. The aqueous layer was basified with sodium bicarbonate and extracted with ethyl acetate (3x20 ml). The organic layer was washed with 0.5 N NaOH (200 ml), dried over sodium sulfate and evaporated. The residue was purified with a silica gel column (eluted with 30- 60% ethyl acetate in hexane with 1% triethylamine) to yield 185 mg of the carbamoyl ester (11) (0.508 mmol, 92.3% yield).The carbamoyl ester (11) was confirmed by NMR. 1H-NMR (CDC13, 300 MHz): delta 1.339 (d, 3H, J = 6.6 Hz, CH3), 1.327-1.415 (m, 3H, CH3), 2.187 (s, 6H, 2xCH3), 2.215-2.258 (m, IH, CH), 2.843-2.870 (m, IH, CH), 3.063 (dd, IH, J = 13.5 and 7.5 Hz, CHH), 3.230 (q, 1Eta, J = 6.6 Hz, CH), 4.043-4.118 (m, 2H, 2xCH), 4.372-4.411 (m, IH, CH), 6.846-7.024 (m, 2H, 2xCH arom.), 7.108 (bd, IH, J = 7.7 Hz, CH arom.), 7.202-7.313 (m, 6H, CH arom.). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23.5% | At room temperature, diisopropylethylamine (5.16 g, 40 mmol) and CDI powder (6.48 g , 40 mmol) were added to a suspension of 7.34 g of 1-amphetamine sulfate (8) (40 mmol) in 140 ml of dichloromethane. The resulting mixture was stirred at room temperature for 1 h. (-)-alpha -3'-hydroxyphenylethyldimethylamine (1) (3.3 g, 20 mmol), which had been mixed with 0.8 g sodium hydride (60% dispersion in mineral oil) in dry toluene (120 ml) for 30 minutes, was added to the mixture and the dichloromethane removed under reduced pressure. The resulting suspension was heated to 850C overnight with stirring. The reaction mixture was extracted with 0.5 M HCl (200 ml). The aqueous layer was washed with ethyl acetate, basified at 00C to pH ~11 with sodium bicarbonate and 0.5 N NaOH and extracted with ethyl acetate (3x100 ml). The organic layers were combined, dried over sodium sulfate and evaporated. The residue was purified with a silica gel column. Elution with a mixture of 20-30% ethyl acetate with 1% triethylamine in hexane yielded 1.53 g of the carbamoyl ester (9) (4.7 mmol, 23.5% yield). The carbamoyl ester (9) was confirmed by NMR. 1H-NMR (CDCB5 SOO MHZ): delta1.179 (d, 3H, J = 6.6 Hz, CH3), 1.331 (d, 3H, J = 6.7 Hz, CH3), 2.174 (s, 6H, 2xCH3), 2.789 (dd, IH, J = 13.4 and 7.2 Hz, CHH), 2.832 (dd, IH, J = 13.4 and 5.9 Hz, CHH), 3.228 (q, 1Eta, J = 6.7 Hz, CH), 3.980-4.062 (m, IH, CH), 4.856 (bd, IH, J = 7.2 Hz, NH), 6.955 (bd, IH, J = 7.4 Hz, CH arom.), 7.018(bs, IH, CH arom.), 7.095 (bd, IH, J = 7.7 Hz, CH arom.) 7.186- 7.303 (m, 6H, CH arom.). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With phosphoric acid; sodium hydroxide; In water; at 50℃; for 3h; | 6.5 g of sodium hydroxide was added to a 30 mL aqueous solution containing 13 g of phosphorous acid, (S)-3-(1-methylamino)ethyl)phenol was added 12 g, Stirring, at 50 C, dropping 40% formaldehyde solution 8 g, stirring 3 h, (S)-3-(1-methylamino)ethyl)phenol. After adding sodium hydroxide, adjust the pH to 7, add ethyl acetate and extract and crystallize to give (S)-3-(1- (dimethylamino) ethyl) phenol 11.8 g, ee value of 99.5%, yield: 90%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of 100 g of S- [1 -(3 -Hydroxyphenyl)ethyl] dimethyl amine (XI) obtained in Example 1 1 in 500 ml of acetone, pulverized potassium carbonate (125.2 g) was added. The reaction mixture was heated to 55-60C for 1 hour. A solution of N-ethyl- N-methyl carbamoyl chloride (77.5 g) was added to the reaction mixture followed by stirring at the same temperature for 8-10 hours. After the completion of the reaction, the reaction mixture was cooled and filtered. The solvent was then removed under reduced pressure, water (500 ml) and toluene (500 ml) were added followed by pH adjustment to 1-2 using concentrated hydrochloric acid. After separating the organic layer, toluene (500 ml) was added to the aqueous layer and pH was adjusted to 9-11 with 10% sodium hydroxide solution. The organic layer was separated and concentrated under reduced pressure to obtain oil. To this oily mass, acetone (750 ml) and activated charcoal (5 g) were added and stirred for 30 minutes. The reaction mixture was then first filtered through hyflo bed and then through micron filter. L-(+ -tartaric acid was added to the filtrate and the reaction mixture was stirred for 4-5 hours and filtered. The solid thus obtained was washed with acetone and dried to obtain the title compound as solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With polyphosphoric acid; at 80℃; for 0.25h; | General procedure: A mixture of 1.65 g (±)-3-(1-(dimethylamino)ethyl)phenol(10.0 mmol) (2) and 2.2 g 2-bromobenzoic acid (11.0 mmol) washeated in polyphosphoric acid at 80 C for 10-15 min. After completedisappearance of aminophenol derivative, checked by TLC,the reaction vessel was cooled. Then, 100 mL ethylacetate and100 mL water were added to reaction mixture, respectively, andpH of the content was adjusted to 8-9 using NaHCO3(s). Organicphase was separated and concentrated under reduced pressure togive oily ester product. Yield obtained: 78.0%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With Trimethyl borate; hydrogen; iodine; acetic acid; (R)-diMe-PipPhos; In tetrahydrofuran; acetonitrile; under 38002.6 Torr; for 20h;Autoclave; | In a 5 mL reaction flask,Add 27.2 mg (0.2 mmol) of m-hydroxyacetophenone,0.4 mmol of dimethylamine, 1 mL of acetonitrile,1mL tetrahydrofuran 25mg (0.24mmol) trimethyl borate,0.5mg (0.002mmol) molecular iodine,1.2 mg (0.02 mmol) of acetic acid and one percent of a catalyst prepared by complexing ruthenium with (R)-L1a. The reaction flask was placed in an autoclave and replaced with hydrogen for 2 times.The hydrogen was pressurized to 50 atm for 20 hours.TLC showed the reaction was complete. Add saturated sodium bicarbonate solution,The organic phase is separated. The organic phase is distilled under reduced pressure to obtain a crude product.Purified by column chromatography to give 3-[1-(dimethylamino)ethyl]phenol.The yield was 93%. The product was analyzed by chiral high performance liquid chromatography.Its stereoselectivity is 88%. |
Tags: 139306-10-8 synthesis path| 139306-10-8 SDS| 139306-10-8 COA| 139306-10-8 purity| 139306-10-8 application| 139306-10-8 NMR| 139306-10-8 COA| 139306-10-8 structure
[ 60760-04-5 ]
3-((Dimethylamino)methyl)phenol
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[ 856563-08-1 ]
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[ 82769-75-3 ]
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[ 60760-04-5 ]
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[ 856563-08-1 ]
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[ 82769-75-3 ]
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[ 90-72-2 ]
2,4,6-Tris(dimethylaminomethyl)phenol
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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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