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Product Details of NAP-226-90

CAS No. :139306-10-8
Formula : C10H15NO
M.W : 165.23
SMILES Code : OC1=CC=CC([C@@H](N(C)C)C)=C1
MDL No. :MFCD06656491
InChI Key :GQZXRLWUYONVCP-QMMMGPOBSA-N
Pubchem ID :445892

Safety of NAP-226-90

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H335
Precautionary Statements:P261-P305+P351+P338

Application In Synthesis of NAP-226-90

* 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.

  • Downstream synthetic route of [ 139306-10-8 ]

[ 139306-10-8 ] Synthesis Path-Downstream   1~11

  • 1
  • [ 105601-04-5 ]
  • [ 851086-95-8 ]
  • [ 139306-10-8 ]
YieldReaction ConditionsOperation 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)
  • 2
  • [ 105601-04-5 ]
  • [ 139306-10-8 ]
YieldReaction ConditionsOperation 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%
  • 3
  • [ 42252-34-6 ]
  • [ 139306-10-8 ]
  • [ 123441-03-2 ]
YieldReaction ConditionsOperation 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.
Example-8: Preparation of Rivastigmine Base To a 100 ml. RB flask, MDC (5 ml), and NaH (0.36 g) were added. To the above reaction mixture, a solution of (1S)-3-(1-Dimethylamino-ethyl)-phenol (1.0 g) in MDC (15 ml) was added drop wise at 20-25 C. for about 5 min and followed by added drop wise N-Ethyl N-methyl carbamoyl chloride (0.88 g) at 20-25 C. for about 5 min. Heated the reaction mass to reflux for 4 to 5 hours and cooled to room temperature. Added DM water (5 ml) followed by adjusted the pH 1 to 2 by dil. HCl. Layers were separated and MDC layer was extracted with DM water (5 ml*2). Collected and combined all aqueous layers, basify the pH 12 to 13 with 25% KOH. Extracted the compound in EtOAc (5 ml) and evaporated to dryness to obtained 1.18 g of Rivastigmine base (Yield: 77.8%, HPLC: 91.42%, Chiral HPLC: 98.09%).

  • 4
  • 1-[(N-ethyl-(N-methyl)amino)carbonyl]-3-methyl-1H-imidazolium iodide [ No CAS ]
  • [ 139306-10-8 ]
  • [ 123441-03-2 ]
YieldReaction ConditionsOperation in experiment
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).
  • 5
  • 1-[[N-ethyl-(N-methyl)amino]carbonyl]-3-methyl-1H-imidazolium methyl sulfate [ No CAS ]
  • [ 139306-10-8 ]
  • [ 123441-03-2 ]
YieldReaction ConditionsOperation in experiment
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.
  • 6
  • [ 123441-03-2 ]
  • [ 139306-10-8 ]
  • 7
  • [ 139306-10-8 ]
  • [ 51493-02-8 ]
  • [ 123441-03-2 ]
  • 8
  • [ 123441-03-2 ]
  • [ 624-78-2 ]
  • [ 124-38-9 ]
  • [ 139306-10-8 ]
  • 9
  • [ 624-78-2 ]
  • [ 139306-10-8 ]
  • [ 530-62-1 ]
  • [ 123441-03-2 ]
YieldReaction ConditionsOperation 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).
  • 10
  • [ 624-78-2 ]
  • [ 139306-10-8 ]
  • [ 7693-46-1 ]
  • [ 123441-03-2 ]
YieldReaction ConditionsOperation 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).
  • 11
  • C5H8Cl3NO2 [ No CAS ]
  • [ 139306-10-8 ]
  • [ 123441-03-2 ]
 

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