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[ CAS No. 123441-03-2 ] {[proInfo.proName]}

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Chemical Structure| 123441-03-2
Chemical Structure| 123441-03-2
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Product Details of [ 123441-03-2 ]

CAS No. :123441-03-2 MDL No. :MFCD00871496
Formula : C14H22N2O2 Boiling Point : -
Linear Structure Formula :C14H22N2O2·C4H6O6 InChI Key :XSVMFMHYUFZWBK-NSHDSACASA-N
M.W : 250.34 Pubchem ID :77991
Synonyms :
S-Rivastigmine;SDZ-ENA 713;Exelon
Chemical Name :(S)-3-(1-(Dimethylamino)ethyl)phenyl ethyl(methyl)carbamate

Calculated chemistry of [ 123441-03-2 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 18
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.5
Num. rotatable bonds : 6
Num. H-bond acceptors : 3.0
Num. H-bond donors : 0.0
Molar Refractivity : 73.12
TPSA : 32.78 ?2

Pharmacokinetics

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) : -6.2 cm/s

Lipophilicity

Log Po/w (iLOGP) : 3.21
Log Po/w (XLOGP3) : 2.29
Log Po/w (WLOGP) : 2.44
Log Po/w (MLOGP) : 2.34
Log Po/w (SILICOS-IT) : 1.46
Consensus Log Po/w : 2.35

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 0.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -2.69
Solubility : 0.517 mg/ml ; 0.00206 mol/l
Class : Soluble
Log S (Ali) : -2.62
Solubility : 0.606 mg/ml ; 0.00242 mol/l
Class : Soluble
Log S (SILICOS-IT) : -3.15
Solubility : 0.176 mg/ml ; 0.000701 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 0.0
Synthetic accessibility : 2.73

Safety of [ 123441-03-2 ]

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:

Application In Synthesis of [ 123441-03-2 ]

* 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 [ 123441-03-2 ]

[ 123441-03-2 ] Synthesis Path-Downstream   1~19

  • 1
  • [ 1016225-06-1 ]
  • [ 624-78-2 ]
  • [ 123441-03-2 ]
YieldReaction ConditionsOperation in experiment
62% In dichloromethane; at 20℃; for 2.5 - 3h;Product distribution / selectivity; Example 4; Synthesis of the compound (L-R); Reaction scheme:Process:1 g 3-(l-(Dimethylamino)ethyl) phenol was dissolved in 20 ml dichloromethane (distilled from CaCl2). The solution was cooled with an ice-water bath (0-50C). 0.92 g trie thy lamine was added.2.21 g bis(4-nitrophenyl)carbonate was added. The yellow solution was stirred in an ice- water bath.[0062] Reaction progress was monitored by HPLC. After 4 hours, 715 mg N- ethylmethylamine was added and the yellow solution was stirred for 17 hours at 40C. The reaction mixture was allowed to warm to room temperature and was then washed with 2x20 ml water. The organic phase was concentrated in vacuo. To the resulting yellow oil, 20 ml diethyl ether and 20 ml of a solution of hydrochloric acid (2 M) were added. The 2- phase system was stirred for 15 minutes. The acidic aqueous layer was washed with 20 ml diethyl ether.[0063] 20 ml dichloromethane was added to the aqueous layer and a solution of sodium hydroxide (2 M) was added until pH~12 was reached. The organic layer was washed with 2x20 ml water, dried (Na2SO4), filtered and concentrated in vacuo. Isolated yield: 1.37 g (90%), yellow oilHPLC: 98% purity1H-NMR: confirmed the expected structure; 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
  • 2
  • [ 123441-03-2 ]
  • (S)-N-ethyl-N-methyl-3-[1-(dimethylamino)ethyl]carbamic acid phenyl-2-3H-ester [ No CAS ]
  • 3
  • [ 87-69-4 ]
  • [ 123441-03-2 ]
  • (S)-(-)-rivastigmine hydrogenartrate [ No CAS ]
YieldReaction ConditionsOperation in experiment
80% In methanol; acetone; 2.0 g of base (II) and 1.2 g of L- (+)-tartaric acid are dissolved in 5 ml of methanol at 60 C. The clear solution is left to cool down to room temperature and it is gradually precipitated with acetone (ca 50 ml). The resulting mixture is left to crystallize at +5 C overnight. The deposited crystals are sucked off using fritted glass and washed with acetone. They are dried in vacuo at 40 C and 2.4 g of white crystals (80% of the theoretical yield) with m. p. = 123-5 C are obtained. The obtained results differed according to the used method of resolving substance IV. The method with 1 equivalent amount of (S)- (+)-CAMPHOR-10-SULFONIC acid provided a total yield of 16.2 % based on compound IV and that with 0.6 equivalent provided a total yield of 19.5 % based on compound IV.
68.4 - 92.6% In ethanol; ethyl acetate; 8.86 g of the base (II) and 5.31 g of L- (+)-tartaric acid are dissolved under warm conditions and stirring in 20 ml of ethanol and the clear solution is precipitated with addition of ethylacetate (250 ml). The resulting mixture is left to cool down to +5 C. The precipitated crystals are sucked away and washed with ethylacetate. 9.7 g of desired <strong>[123441-03-2]rivastigmin</strong>e HYDROGENTARTRATE (I) RESULTS (I. E. , 68.4 % OF THE THEORETICAL YIELD) WITH M. P. = 124-126 C. THE CONTENTS OF THE UNDESIRED (R) -ENANTIOMER IN THIS FRACTION WAS 1 % (AS DETERMINED BY CAPILLARY electrophoresis). 0.3 g of the hydrogentartrate were recrystallized from a mixture ethanol/ethylacetate in the above specified manner and 0.24 g of a recrystallized fraction (I) were obtained (80 %). The CONTENTS OF THE UNDESIRED (R) -ENANTIOMER HAS DECREASED TO 0.69 % (CAPILLARY ELECTROPHORESIS). A total yield, based on the starting material (IV), of 12.5 % has been obtained. Preparation of S- (-)-RIVASTIGMINE (II) 300 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 crystalline compound (III) (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 1N NAOH and 500 ml of ether. The organic layer is separated and the aqueous fraction is shaken with additional 2x 200 ml of ether. The combined ether layers are shaken out with lx 100 ml water and lx 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 Pa 45.6 g of a colorless viscous oil are obtained, i. e. a 80.5% yield. content GC 99.6% Preparation of S- (-) <strong>[123441-03-2]rivastigmin</strong>e (II) 150 ml of diethylether are placed in a 0.51-three-neck flask and sodium hydride as a 60% dispersion in oil (0.48 g) is added slowly under inert conditions (Ar or N2) and stirring. A suspension develops, to which crystalline compound (III) (2.0 g, 0.012 mol) is added at room temperature. After stirring for one hour, a slightly turbid solution of the phenolate forms, to which 1.53 g (0.012 mol) OF N-ETHYL-N-METHYLCARBAMOYLCHLORIDE in 20 ml of ether are added dropwise at room temperature. The resulting reaction mixture is stirred at room temperature for 3 hours. Thereafter, it is diluted with 100 ml of water. The organic layer is separated and extracted with 2x 50 ml of a 0.1 N NAOH solution. The organic phase is extracted with 50 ml of water, dried with anhydrous magnesium sulfate, and concentrated in vacuo. 2.6 g of an oil are obtained (86.6% of the theoretical yield). Preparation of S- (-) <strong>[123441-03-2]rivastigmin</strong>e (II) 50 ml 1,2-dimethoxyethane are placed in a 0.251 round three-neck flask and compound (III) (2.0 g, 0.012 mol) is dissolved therein under stirring and under an inert (Ar or N2) at room temperature. Then, a 1.6M solution of n-butyllithium in hexane (7.5 ml) is added dropwise to the resulting solution. A slightly turbid solution of the phenolate develops, to which 1.53 g (0.012 mol) of N-ethyl-N-methylcarbamoylchloride in 20 ml of 1,2-dimethoxyethane are added dropwise at room temperature. The solvent is evaporated in a rotary vacuum evaporator. The evaporation residue is partitioned between 20 ml 1N NAOH and 50 ML of ether. The organic layer is separated and the aqueous fraction is shaken with additional 2x 20 ml of ether. The combined ether layers are shaken with lx 20 ml water and lx 20 ml brine. The organic fraction is dried over anhydrous sodium sulfate and concentrated in vacuo. 1.56 g of an oil are obtained (51.5% of the theoretical yield).
  • 4
  • (S)-rivastigmine di-p-toluoyl tartrate [ No CAS ]
  • [ 123441-03-2 ]
YieldReaction ConditionsOperation in experiment
With sodium hydroxide; In hexane; water; at 0 - 5℃; for 0.5h; To the solution of 200 gm (0.8 moles) [RACEMIC] Rivastigmine base in 2.0 L Methanol: [ WATER (2: 1), WAS ADDED 322.0 GM (0.8 MOLES) (+) -DI-P-TOLUOYL TARTARIC ACID] monohydrate and resulting slurry was heated to [60-65C] for 30 minutes to get clear solution. After cooling to [0-5C,] precipitated solid was filtered, dried at [50-55C] and recrystallized 4 times from minimum volumes of Methanol: water (2: 1) to get optically pure di-p-toluoyl tartrate salt of (S)-enantiomer of Rivastigmine. (Specific optical rotation=80-81. [5,] c=5 in Methanol) The above prepared salt was added in portions to a mixture of 1 N [NAOH] solution and n-hexane at [0-5C] temperature, stirred for 30 minutes, and organic phase was separated. Organic phase was then washed twice with water and concentrated [ COMPLETELY TO GET OPTICALLY PURE (S) -ENANTIOMER OF RIVASTIGMINE. (SPECIFIC OPTICAL] [ROTATION=-32,] c=5 in Methanol)
With sodium hydroxide; In water; at 5 - 30℃; for 0.416667h; Liberation of Rivasti; 12ml of aqueous 1N NaOH solution (0. 12mol) was charged to a flask equipped with a thermometer pocket and ice-bath. The solution was cooled to 5C and 2g (0. 0031mol) of the DPTTA salt obtained after three crystallisations above was charged to it. The ice-bath was removed and after 10 minutes of stirring the solution became turbid (at about 12C) and was allowed to come to 30C in about 15 minutes. It was extracted with diethyl ether (3 x 15ml) and the combined organic extracts were dried over sodium sulphate and concentrated to dryness on the rotavapor to obtain 750mg of rivastigmine (1). Yield: 750mg, 98.2%. [a] D (c=5 methanol)-30. 29.'H NMR: 8 1.16-1. 25 (2 x t, 3H, N-CH2CH3), 8 1.35 (d, 3H, PhCCH3), 8 2.2 (s, 6H, N- (CH3)), 8 2.90 and 3.00 (2 x s, 3H, N-CH3), 8 3.21-3. 27 (q, 2H, CHCH3), 8 3.39-3. 48 (2 x q, 2H, N- CH2CH3), 8 7.0 (d, 1H, Ar-H), 8 7. 06 (s, 1H, Ar-H), 8 7. 11 (d, 1H, Ar-H), 8 7.28 (t, 1H, Ar-H).
  • 5
  • C13H20N2O2*C18H18O6 [ No CAS ]
  • [ 123441-03-2 ]
YieldReaction ConditionsOperation in experiment
85% With sodium hydroxide; In dichloromethane; water; The salt of S- (-)-rivastigmine (II) with (+)-O, O'-DITOLUYLTARTARIC acid (33.0 g) is slowly added to the well mixed mixture of 150 ml of dichloromethane and 150 ml of IN NAOH solution. After all the solids are dissolved, the layers are separated; the dichloromethane layer is extracted twice with 100 ml of water, dried with magnesium sulfate. The solvent is evaporated in vacuo and the evaporation residue is distilled under vacuum (b. p. = 135-8 C, 40 Pa). 10.72 g of a colorless oil are obtained, which is 85% of the theoretical yield ( [A] D - 24. 5 ; C=3. 5, methanol).
  • 6
  • [ 42252-34-6 ]
  • [ 123441-03-2 ]
YieldReaction ConditionsOperation in experiment
86.6% 150 ml of diethylether are placed in a 0.51-three-neck flask and sodium hydride as a 60% dispersion in oil (0.48 g) is added slowly under inert conditions (Ar or N2) and stirring. A suspension develops, to which crystalline compound (III) (2.0 g, 0.012 mol) is added at room temperature. After stirring for one hour, a slightly turbid solution of the phenolate forms, to which 1.53 g (0.012 mol) OF N-ETHYL-N-METHYLCARBAMOYLCHLORIDE in 20 ml of ether are added dropwise at room temperature. The resulting reaction mixture is stirred at room temperature for 3 hours. Thereafter, it is diluted with 100 ml of water. The organic layer is separated and extracted with 2x 50 ml of a 0.1 N NAOH solution. The organic phase is extracted with 50 ml of water, dried with anhydrous magnesium sulfate, and concentrated in vacuo. 2.6 g of an oil are obtained (86.6% of the theoretical yield).
80.5% 300 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 crystalline compound (III) (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 1N NAOH and 500 ml of ether. The organic layer is separated and the aqueous fraction is shaken with additional 2x 200 ml of ether. The combined ether layers are shaken out with lx 100 ml water and lx 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 Pa 45.6 g of a colorless viscous oil are obtained, i. e. a 80.5% yield. content GC 99.6%
80.5% Reference example 1: Preparation of S-(-)-Rivastigmine; 300ml of tetrahydrofuran (THF) are placed in a 0.51 -three-neck flask and sodium hydride as a 60% dispersion in oil (11.3g) is added slowly under inert conditions (Ar or N2) and stirring. A suspension develops, to which alpha-m-hydroxy phenylethyldimethylamine (46.5g, 0.28 lmol) is added at room temperature. A solution of the phenolate forms, to which 35.7g (0.28 lmol) of carbamoylchloride are added dropwise over 10 minutes while slightly cooling down to 150C. The reaction is slightly exothermic. The rate of dropping is kept such that the temperature of the reaction mixture does not exceed 30C. 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 2x 200 ml of ether. The combined ether layers are shaken out with Ix 100 ml water and Ix 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. =135-140oC at l3 Pa 45.6 g of a colorless viscous oil are obtained, i.e. a 80.5% yield. Content GC 99.6%
51.5% 50 ml 1,2-dimethoxyethane are placed in a 0.251 round three-neck flask and compound (III) (2.0 g, 0.012 mol) is dissolved therein under stirring and under an inert (Ar or N2) at room temperature. Then, a 1.6M solution of n-butyllithium in hexane (7.5 ml) is added dropwise to the resulting solution. A slightly turbid solution of the phenolate develops, to which 1.53 g (0.012 mol) of N-ethyl-N-methylcarbamoylchloride in 20 ml of 1,2-dimethoxyethane are added dropwise at room temperature. The solvent is evaporated in a rotary vacuum evaporator. The evaporation residue is partitioned between 20 ml 1N NAOH and 50 ML of ether. The organic layer is separated and the aqueous fraction is shaken with additional 2x 20 ml of ether. The combined ether layers are shaken with lx 20 ml water and lx 20 ml brine. The organic fraction is dried over anhydrous sodium sulfate and concentrated in vacuo. 1.56 g of an oil are obtained (51.5% of the theoretical yield).

  • 7
  • [ 87-69-4 ]
  • [ 123441-03-2 ]
  • [ 123441-03-2 ]
YieldReaction ConditionsOperation in experiment
92.6% In ethanol; ethyl acetate; at 60 - 70℃; Reference example 2: Preparation of <strong>[123441-03-2]Rivastigmine</strong> hydrogentartrate; 45.6g of S-(-)-<strong>[123441-03-2]rivastigmin</strong>e and 27.4g of L- (+)-tartaric acid are dissolved in 125ml of anhydrous ethanol at 60-70C under stirring. At this temperature, 630ml of ethylacetate are gradually added to the solution. The solution is left to cool down to room temperature and to crystallize at +5C for at least 12 hours. The precipitated white crystalline product is sucked off, washed with 100ml of ethylacetate, and vacuum dried at 4O0C. 67.5g of the desired product with m.p.=125-126C (i.e. 92.6 % of the theoretical yield). ([a]D = +5.5; c=5, ethanol).
92.6% In ethanol; at 60 - 70℃; Reference Example 2Preparation of <strong>[123441-03-2]Rivastigmine</strong> Hydrogentartrate45.6 g of S-(-)-<strong>[123441-03-2]rivastigmin</strong>e and 27.4 g of L-(+)-tartaric acid are dissolved in 125 ml of anhydrous ethanol at 60-70 C. under stirring. At this temperature, 630 ml of ethylacetate are gradually added to the solution. The solution is left to cool down to room temperature and to crystallize at +5 C. for at least 12 hours. The precipitated white crystalline product is sucked off, washed with 100 ml of ethylacetate, and vacuum dried at 40 C. 67.5 g of the desired product with m.p.=125-126 C. (i.e. 92.6% of the theoretical yield). ([a]D=+5.5; c=5, ethanol).
91% In propylene glycol; at 90℃; (2) the 1 dissolved in the product 180ml1.2-propylene glycol, by adding L-(+) tartaric acid (18g, 0.12mol), heating 90 C stirring, to the clear reaction solution, for natural cooling to room temperature under stirring, separate products, filtering, drying the finished product weight tartaric acid of <strong>[123441-03-2]Rivastigmine</strong> 42.5g, yield 91%.
85% In acetone; at 60℃; for 1h; (-)-S-3-[l-(dimethylamino)ethyl]phenyl-N-ethyl-N-methylcarbamate (I) (100gms;1.0 mole) and L-tartaric acid (60gms; l.Omole) were added to acetone (1000ml) and the mixture heated at 600C for 1.0 hour to get a clear mixture, which was then cooled for EPO <DP n="14"/>complete precipitation of the tartrate salt of compound (I). The tartrate salt of compound was filtered and dried. Yield: 135 gms. %Yield: 85%. HPLC Purity: 99%.
83% In acetone; at 20℃; for 0.666667h;Reflux; Embodiment 22 The Preparation of <strong>[123441-03-2]Rivastigmine</strong> (Formula I) Mix 5.0 g (0.02 mol) (S)-3-(1-(dimethylamino)ethyl)phenyl ethyl(methyl)carbamate (formula X) with 20 ml acetone and 3.0 g L-tartaric acid (0.02 mol) at room temperature, heat the mixture until it refluxes, and let it react for 40 min. After it is cooled to 40 C., add seed crystals and stir it at room temperature for 2 hours. Use ice bath for insulation for 5 hours and set it in a refrigerator overnight. Filter it, and set it in a vacuum oven at 40 C. for 10 hours to receive 6.64 g white crystals with a yield of 83%. HPLC purity?99.8%, ee value of ?99.8%. Optical rotation [alpha]20D=+ 6.0 (C=5, ethanol); mp 123.8-124.5 C. 1HNMR (CDCl3) delta: 1.16, 1.24 (2*t, 3H), 1.67 (d, 3H), 2.65 (s, 6H), 2.96, 3.05 (2*s, 3H), 3.37, 3.45 (2*q, 2H), 4.34 (q, 1H), 4.47 (s, 2H), 7.14 (t, 1H), 7.20 (s, 1H), 7.28 (d, 1H), 7.39 (t, 1H); MS (ESI) m/z: 251.2 ([M+1]+).
83% In acetone; for 0.666667h;Reflux; Mix 5.0 g (0.02 mol) (S)-3-(1-(dimethylamino)ethyl)phenyl ethyl(methyl)carbamate (formulaX) with 20 ml acetone and 3.0 g L-tartaric acid (0.02 mol) at room temperature, heat the mixture until it refluxes, and let it react for 40 min. After it is cooled to 40 C, add seed crystals and stir it at room temperature for 2 hours. Use ice bath for insulation for 5 hours and set it in a refrigerator overnight. Filter it, and set it in a vacuum oven at 40 C for 10 hours to receive 6.64 g white crystals with a yield of 83%. HPLC purity > 99.8%, ee value of ? 99.8%. Optical rotation [alpha]20D = +6.0 (C = 5, ethanol); mp 123.8-124.5 C. 1HNMR (CDCl3) delta: 1.16,1.24 (2xt,3H), 1.67 (d,3H), 2.65 (s,6H), 2.96,3.05 (2xs,3H), 3.37,3.45 (2xq,2H), 4.34 (q,1H), 4.47 (s,2H), 7.14 (t,1H), 7.20 (s,1H), 7.28 (d,1H), 7.39 (t,1H); MS (ESI) m/z: 251.2 ([M+1]+).
81.5% In isopropyl alcohol;Heating; Add 350 ml of isopropanol, 76 g of intermediate 2, 51.4 g of L(+) tartaric acid to a 1L reaction flask, stir and heat untilflow. Then cooled to room temperature, crystallized 2h, suction filtration, filter cake rinsed with a small amount of isopropanol, to obtain crude <strong>[123441-03-2]rivastigmin</strong>e <strong>[123441-03-2]rivastigmin</strong>e. willThe solid wet product obtained in the previous step was added to a 1L reaction flask, 350 ml of acetone was added, and the mixture was stirred at room temperature for 1 hour. Then filter, filter cake with a small amountRinse with acetone and dry to give 99.1 g of a white solid. Yield 81.5%, R isomer 0.11%.
78% In methanol; acetone; at 40℃;Reflux; Example 10: Preparation of <strong>[123441-03-2]rivastigmin</strong>e (the compound represented by formula (VIII)); 117.5ml acetone and 2.83g (18.9mmol) L-tartaric acid were added into 4.72g (18.9mmol) the compound represented by formula (VII). The mixture was heated to 40C, followed by adding 11.8ml methanol, and refluxed for 40 min. After the mixture was cooled to 40C, seed crystal was added was and the mixture was stirred at room temperature for 2 hours. Then the mixture was settled in an ice bath for 5 hours followed by standing in a refrigerator overnight. After filtering and drying in a vacuum oven at 40C for 9 hours, white crystal (5.89g) was obtained with a yield of 78%. HPLC purity =99.8%, ee%=99.8% Optical rotation [alpha]20D = +6.0, C=5, ethanol; mp 122.3-124.1C. 1H NMR (CDCl3) delta ppm: 1.24, 1.16 (2×t, 3H), 1.67 (d, 3H), 2.65 (s, 6H), 2.96, 3.05(2xs, 3H), 3.37, 3.45(2×q, 2H), 4.34 (q, 1H), 4.47 (s, 2H), 7.14 (t, 1H), 7.20 (s, 1H), 7.28 (d, 1H), 7.39 (t, 1H); MS (ESI) m/z: 251.2.
77% In methanol; at 8 - 55℃;Product distribution / selectivity; Biva. rtigmine bydrogen tartrate (9); Methanol (0. 4ml) was taken in a glass vial and L- (+)-tartaric acid (0.204g, 1. 36mmol, leq) was added to it. It was warmed to about 40-45C to get a clear solution. This was added to a flask containing 0. 34g <strong>[123441-03-2]rivastigmin</strong>e (1) (1. 36mmol, leq). The clear solution was heated to 55C for about 5 minutes and kept at 30C for 2 hours and at 8-10C overnight. The solvent was evaporated to dryness and the oil so obtained was triturated with hexanes (1 x 5ml, 2 x 10ml) to obtain a solid that was filtered off under vacuum on a sintered funnel under an atmosphere of nitrogen. Yield: 419mg, 77%. [a] D (c=5 methanol) +5. 02.'H NMR: 8 1.05-1. 18 (2 x t, 3H, N-CH2CH3), 8 1.53 (d, 3H, PhCCH3), 8 2. 54 (s, 6H, N- (CH3) , 8 2.87 and 2.99 (2 x s, 3H, N-CH3), 8 3. 24-3.43 (2 x q, 2H, N-CH2CH3), 8 4.22-4. 29 (q, 2H, CHCH3), 8 7.15 (d, 1H, Ar-H), 8 7.22 (s, 1H, Ar-H), 8 7.31 (d, 1H, Ar-H), 8 7.46 (t, 1H, Ar-H).
76% In ethyl acetate; at 20 - 60℃; for 2h; L+Tartaric acid ( 8gm 0.052 mol) in Methanol 20 ml and Solution of III (13.5 gm 0.06 1 mol) inEthyl acetate 60 ml is added to above solution at 50-60C. The mass is stined for 2 hrs at 20-25C and filtered at 0-5C. The wet cake is refluxed in Acetone 100 ml. Final product is isolated after cooling to 0-5C followed by acetone wash. Obtained yield 76%.Chiral HPLC: R isomer 0.19% S Isomer 99.8% HPLC purity: 99.98% (figures 15 and 16).
In acetone; for 1h;Heating / reflux;Product distribution / selectivity; (S)-3-(l-dimethylaminoethyl)phenol hydrochloride (hydrochloride of the compound of Formula 8, 30 g, 0.148 mol) was suspended in acetonitrile (150 ml), and then N-ethyl-N-methylcarbamoyl chloride (36.1 g, 0.297 mol) was added thereto. The resulting solution was cooled to 0C. To the solution was added sodium hydride (29.7 g, 60%, 0.743 mol). The temperature was gradually allowed to rise to room temperature. The reaction mixture was stirred at room temperature for 24 hours. The completion of the reaction was confirmed by HPLC. The reaction mixture was extracted with ether, and organic layer was concentrated. Water and hydrochloric acid were added thereto. After the resulting mixture was stirred at room temperature for 2 hours, it was washed twice with ether. The obtained aqueous layer was concentrated and crystallized from ethylacetate, affording (S)-<strong>[123441-03-2]rivastigmin</strong>e hydrochloride (22.28g, 52%). The (S)-<strong>[123441-03-2]rivastigmin</strong>e hydrochloride (18.5 g, 64.5 mmol) was dissolved in water (60 ml), and then NaOH (2.58 g, 64.5 mmol, 1 eq.) was added thereto. The reaction mixture was stirred for 30 minutes. The mixture was extracted twice with ether, dried over anhydrous MgSO 4 , and concentrated under reduced pressure. The concentrate was distilled under vacuum at 116-128C to obtain <strong>[123441-03-2]rivastigmin</strong>e (10.7 g, 66.3%) as a pure distillate. To the distillate were sequentially added acetone (30 ml) and L-tartaric acid (6 g, 40 mmol, 1 eq.). The mixture was refluxed for one hour, cooled to 00C, and filtered to obtain a solid. The solid was washed, and dried to afford (S)-<strong>[123441-03-2]rivastigmin</strong>e tartrate salt*2 (16 g, 93.5% from the <strong>[123441-03-2]rivastigmin</strong>e hydrochloride, 99.8% ee).[59] In addition, the same results were obtained when(S)-3-(l-dimethylaminoethyl)phenol (Formula 8, Example 2) in the free-base form was used instead of (S)-3-(l-dimethylaminoethyl)phenol hydrochloride (hydrochloride salt of the compound of Formula 8).[60] n : (S)-<strong>[123441-03-2]rivastigmin</strong>e[61] ' H NuMR (CDCl3): 7.29 (IH, m), 7.01 (3H, m), 3.44 (2H, q), 3.24 (IH, q), 3.02(3H, d), 2.20 (6H, s), 1.35 (3H, d), 1.21 (3H, m)[62] *2 : (S)-<strong>[123441-03-2]rivastigmin</strong>e tartrate salt: m.p 124C
In acetone; at 30 - 60℃; for 2.5h;Heating / reflux; EXAMPLE 6: PREPARATION OF RIVASTIGMINE TARTRATE (FORMULA I); 3 kg of <strong>[123441-03-2]rivastigmin</strong>e freebase of Formula II in 105 lit of acetone, 1.8 kg of L-(+)-Tartaric acid was charged and heated to about 60 C followed by stirring for about 30 minutes for complete dissolution. The resulting reaction solutions was passed through celite and wash the bed with 13.5 lit acetone to made particle free. The obtained clear solution was distilled off up to 50% of the initial volume and cooled to 30C. 12 g of <strong>[123441-03-2]rivastigmin</strong>e hydrogen tartrate was added and stirred for about 60 minutes. The reaction mixture was heated to reflux and stirred for about 60 minutes and cooled to about 30C and stirred for about 60 minutes for solid separation. The separated solid was filtered and washed the solid with 3 lit of acetone. Solid obtained was dried at about 60 C for about 9 hours to afford 4.10 kg of the title compound. Purity by HPLC: 97.37%.
In acetone; at 30 - 60℃; for 2.5h;Heating / reflux; Example 6; Preparation Of <strong>[123441-03-2]Rivastigmine</strong> Tartrate (Formula I); 3 kg of <strong>[123441-03-2]rivastigmin</strong>e freebase of Formula II in 105 lit of acetone, 1.8 kg of L-(+)-Tartaric acid was charged and heated to about 60 C. followed by stirring for about 30 minutes for complete dissolution. The resulting reaction solutions was passed through celite and wash the bed with 13.5 lit acetone to made particle free. The obtained clear solution was distilled off up to 50% of the initial volume and cooled to 30 C. 12 g of <strong>[123441-03-2]rivastigmin</strong>e hydrogen tartrate was added and stirred for about 60 minutes. The reaction mixture was heated to reflux and stirred for about 60 minutes and cooled to about 30 C. and stirred for about 60 minutes for solid separation. The separated solid was filtered and washed the solid with 3 lit of acetone. Solid obtained was dried at about 60 C. for about 9 hours to afford 4.10 kg of the title compound.Purity by HPLC: 97.37%.
In isopropyl alcohol; at 20 - 80℃;Product distribution / selectivity; EXAMPLE 6; Preparation of crystalline form of (S)-N-Ethyl-N-methyl-3-[1-(dimethylamino)ethyl]-phenyl carbamate (2R,3R)-hydrogen tartrate; (2R,3R)-Tartaric acid (9.0 g, 60.0 mmol) was added to a solution of <strong>[123441-03-2](S)-N-ethyl-N-methyl-3-[1-(dimethylamino)ethyl]phenyl carbamate</strong> (15.0 g, 60.0 mmol) in isopropyl alcohol (75 mL). The resulting mixture was heated to 75-80 C. and then cooled to 20-25 C. The resulting suspension was filtered and washed with isopropanol and the solid was dried under vacuum at 40-50 C. to give crystalline (S)-N-Ethyl-N-methyl-3-[1-(dimethylamino)ethyl]-phenyl carbamate (2R,3R)-hydrogen tartrate (<strong>[123441-03-2]Rivastigmine</strong> hydrogen tartrate) 1H NMR (CDCl3) delta 8.50-7.50 (s, 4H); 7.41 (t, J=7.8 Hz 1H); 7.30-7.16 (m, 3H); 4.44 (s, 2H); 4.34 (q, J=6.5 Hz, 1H); 3.50-3.34 (m, 2H); 3.02 (ad, 3H); 2.66 (s, 6H); 1.70 (d, J=6.8 Hz); 1.26-1.15 (m, 3H). PXRD (FIG. 1).; 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 <strong>[123441-03-2](S)-N-ethyl-N-methyl-3-[1-(dimethylamino)ethyl]phenyl carbamate</strong>. 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. EXAMPLE 8 Preparation of amorphous form of (S)-N-Ethyl-N-methyl-3-[1-(dimethylamino)ethyl]phenyl carbamate hydrogen-(2R,3R)-tartrate The solution of (S)-N-Ethyl-N-methyl-3-[1-(dimethylamino)ethyl]-phenyl carbamate hydrogen-(2R,3R)-tartrate (<strong>[123441-03-2]Rivastigmine</strong> hydrogen tartrate) (2 g) in water (4 mL) was stirred at 20-25 C. for 0.5-1 hour. The mixture was evaporated at 45-60 C. under vacuum to give a white solid. The obtained material was further dried at 40-45 C. for 10-12 hours under vacuum to obtain amorphous <strong>[123441-03-2]Rivastigmine</strong> hydrogen tartrate.
In acetone; at 50℃; for 0.5h; Example 2: Preparation <strong>[123441-03-2]Rivastigmine</strong> Hydrogentartarate salt22 gm of the <strong>[123441-03-2]Rivastigmine</strong> (+) DPTTA salt obtained as 2nd crop in Example 1 Step (c) was charged in a flask containing 150 ml of water and pH was adjusted to about 11 using about 20 ml of aqueous ammonia. The reaction mixture was extracted with dichloromethane(DCM) (250 ml) and the organic layer was washed with water (100 ml). The final organic layer was distilled completely to obtain 9.5 gm of <strong>[123441-03-2]Rivastigmine</strong> base as residue.25 ml of acetone was added to the above obtained residue and stirred for dissolution. 5.7 gm of L(+) tartaric acid was added to the solution, heated to about 50 C and stirred for about 30 minutes. The reaction mixture was cooled to 10-150C and stirred for 1 hour. The solid was filtered and washed with acetone (10 ml). The solid was dried 50-600C to obtain 12.5 gm of the title compound.
In ethanol;Heating / reflux; (iii) Synthesis of <strong>[123441-03-2]rivastigmin</strong>e hydrogentartrate An amount of 1.30 g (5.2 mmol) of 3-(1-(dimethylamino)ethyl)-phenyl ethyl(methyl)carbamate as obtained in step (i) and 2.10 g (5.2 mmol) of (+)-di-p-toluoyl-D-tartaric acid monohydrate were dissolved in 13 ml of methanol/water (2:1) solution under heating. The reaction mixture was refluxed for 1 hour and cooled to room temperature. The precipitate was filtered and four times recrystallized in a minimal volume of methanol/water solution to obtain optically pure di-p-toluoyl tartrate salt of (S)-3-(1-(dimethylamino)ethyl)phenyl ethyl-(methyl)carbamate. The salt was dissolved in 1 M NaOH and extracted into ether to obtain an optically pure oily residue of (S)-3-(1-(dimethylamino)ethyl)phenyl ethyl(methyl)carbamate which was dissolved in ethanol, mixed with hydrogentartrate, refluxed and cooled to room temperature.
In acetone; at 4 - 60℃; for 19h; 2 g S-(-)-<strong>[123441-03-2]Rivastigmine</strong> and 1.2 g L-(+)-tartaric acid were added to 20 ml acetone and the mixture was heated at 600C for 1 hour to get a clear mixture. The solution was allowed to slowly cool to ambient temperature and was stirred for 18 hours at 4C until complete precipitation of the tartrate salt. The solid was isolated by filtration, washed with acetone, and dried for 22 hours under vacuum at 400C. Isolated yield: 2.72g, white solidXRPD pattern: comparable to Fig.l.
In acetone; at 0 - 50℃; for 1.5h; Example 7; Preparation of <strong>[123441-03-2]Rivastigmine</strong> hydrogentartrate salt170 ml of acetone was added to the above obtained residue and stirred for dissolution. 20.4 gm of L(+) tartaric acid was added to the solution, heated to about 50 C and stirred for about 30 minutes. The reaction mixture was cooled to 25-35 C and stirred for 30 minutes. The reaction mixture was further cooled to 0-5 C and stirred for 30 minutes. The solid was filtered and washed with acetone (20 ml). The solid was dried at 50-60C to obtain 46 gm of the title compound.Purity by HPLC: 99.84 %
2.5 g In acetone; at 60℃; for 1h; Example-9: Preparation of <strong>[123441-03-2]Rivastigmine</strong> Tartrate To a 250 ml. RB flask, <strong>[123441-03-2]Rivastigmine</strong> base (2.5 g), acetone (87.5 ml) and L-(+)-tartaric acid (1.5 g) were added. Heated the reaction mass at 60 C. for 1 hour and gradually cooled to room temperature. Filtered the reaction mass through hyflow bed and washed with acetone (12 ml). Evaporated half of the acetone volume and stirred at room temperature for 1 hour. Filtered the solid, washed with acetone and dried under vacuum to obtained 2.5 g of <strong>[123441-03-2]Rivastigmine</strong> Tartrate (Yield: 62.6%, HPLC: 99.48%, Chiral HPLC: 99.56%).

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  • 8
  • [ 727418-36-2 ]
  • [ 123441-03-2 ]
YieldReaction ConditionsOperation in experiment
66.3% With sodium hydroxide; In water; for 0.5h; [58] (S)-3-(l-dimethylaminoethyl)phenol hydrochloride (hydrochloride of the compound of Formula 8, 30 g, 0.148 mol) was suspended in acetonitrile (150 ml), and then N-ethyl-N-methylcarbamoyl chloride (36.1 g, 0.297 mol) was added thereto. The resulting solution was cooled to 0C. To the solution was added sodium hydride (29.7 g, 60%, 0.743 mol). The temperature was gradually allowed to rise to room temperature. The reaction mixture was stirred at room temperature for 24 hours. The completion of the reaction was confirmed by HPLC. The reaction mixture was extracted with ether, and organic layer was concentrated. Water and hydrochloric acid were added thereto. After the resulting mixture was stirred at room temperature for 2 hours, it was washed twice with ether. The obtained aqueous layer was concentrated and crystallized from ethylacetate, affording (S)-rivastigmine hydrochloride (22.28g, 52%). The (S)-rivastigmine hydrochloride (18.5 g, 64.5 mmol) was dissolved in water (60 ml), and then NaOH (2.58 g, 64.5 mmol, 1 eq.) was added thereto. The reaction mixture was stirred for 30 minutes. The mixture was extracted twice with ether, dried over anhydrous MgSO 4 , and concentrated under reduced pressure. The concentrate was distilled under vacuum at 116-128C to obtain rivastigmine (10.7 g, 66.3%) as a pure distillate. To the distillate were sequentially added acetone (30 ml) and L-tartaric acid (6 g, 40 mmol, 1 eq.). The mixture was refluxed for one hour, cooled to 00C, and filtered to obtain a solid. The solid was washed, and dried to afford (S)-rivastigmine tartrate salt*2 (16 g, 93.5% from the rivastigmine hydrochloride, 99.8% ee).[59] In addition, the same results were obtained when(S)-3-(l-dimethylaminoethyl)phenol (Formula 8, Example 2) in the free-base form was used instead of (S)-3-(l-dimethylaminoethyl)phenol hydrochloride (hydrochloride salt of the compound of Formula 8).[60] n : (S)-rivastigmine[61] ' H NuMR (CDCl3): 7.29 (IH, m), 7.01 (3H, m), 3.44 (2H, q), 3.24 (IH, q), 3.02(3H, d), 2.20 (6H, s), 1.35 (3H, d), 1.21 (3H, m)
  • 9
  • [ 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%).

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  • [ 399515-02-7 ]
  • [ 123441-03-2 ]
YieldReaction ConditionsOperation in experiment
With ammonia; In water;pH 11; Example 2: Preparation Rivastigmine Hydrogentartarate salt22 gm of the Rivastigmine (+) DPTTA salt obtained as 2nd crop in Example 1 Step (c) was charged in a flask containing 150 ml of water and pH was adjusted to about 11 using about 20 ml of aqueous ammonia. The reaction mixture was extracted with dichloromethane(DCM) (250 ml) and the organic layer was washed with water (100 ml). The final organic layer was distilled completely to obtain 9.5 gm of Rivastigmine base as residue.25 ml of acetone was added to the above obtained residue and stirred for dissolution. 5.7 gm of L(+) tartaric acid was added to the solution, heated to about 50 C and stirred for about 30 minutes. The reaction mixture was cooled to 10-150C and stirred for 1 hour. The solid was filtered and washed with acetone (10 ml). The solid was dried 50-600C to obtain 12.5 gm of the title compound.
With sodium hydroxide; water; (iii) Synthesis of rivastigmine hydrogentartrate An amount of 1.30 g (5.2 mmol) of 3-(1-(dimethylamino)ethyl)-phenyl ethyl(methyl)carbamate as obtained in step (i) and 2.10 g (5.2 mmol) of (+)-di-p-toluoyl-D-tartaric acid monohydrate were dissolved in 13 ml of methanol/water (2:1) solution under heating. The reaction mixture was refluxed for 1 hour and cooled to room temperature. The precipitate was filtered and four times recrystallized in a minimal volume of methanol/water solution to obtain optically pure di-p-toluoyl tartrate salt of (S)-3-(1-(dimethylamino)ethyl)phenyl ethyl-(methyl)carbamate. The salt was dissolved in 1 M NaOH and extracted into ether to obtain an optically pure oily residue of (S)-3-(1-(dimethylamino)ethyl)phenyl ethyl(methyl)carbamate which was dissolved in ethanol, mixed with hydrogentartrate, refluxed and cooled to room temperature.
Alkaline aqueous solution; The resolution of racemic compound (10gm) with (+)-O, O'-ditoluyltartaric acid (16gm) in methanol (20ml) and water (10ml) gave 6 gm of desired isomer under cold condition. The pure isomer was obtained after crystallization (thrice) in mixture of water and methanol (1:2). The tartrate salt (6 gm) was treated with caustic solution, extracted with dichloromethane and concentrated in vacuum to yield 2 gm of pale yellow oil. Yield: 20-25gms. %Yield: 20%(w/w). HPLC Purity: 99%.
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  • [ 50-00-0 ]
  • [ 923035-05-6 ]
  • [ 141-53-7 ]
  • [ 123441-03-2 ]
YieldReaction ConditionsOperation in experiment
Example 8; Obtaining (S)-N-ethyl-3-[1-(dimethylamino)ethyl]-N-methylphenylcarbamate [Rivastigmine] 2.5 mL of 98% formic acid, 0.4 g of sodium formiate and 1 mL of 37% formaldehyde aqueous solution are added to 0.5 g of the compound of formula (II) [Example 7]. The mixture is heated under reflux and maintained at this temperature until the end of the reaction. It is processed by adding 5 mL of methylene chloride and the mixture is adjusted to pH 8.7. The separated organic phase is distilled until obtaining a residue that is purified by column chromatography and is identified as the desired product. 1H NMR: delta 1.15-1.2 (2*t, 3H, N-CH2-CH3) ; delta 1.3 (d, 3H, -CH-CH3) ; delta 2.2 (s, 6H, N-CH3); delta 2.96-3.04 (2*s, 3H, OCN-CH3); 3.2 (q, 1H, -CH-CH3) ; delta 3.36-3. 44 (2*q, 2H, N-CH2-CH3) ; delta 6.96 (d, 1H, Ar-H); delta 7.05 (s, 1H, Ar-H); delta 7.10 (d, 1H, Ar-H); delta 7.3 (t, 1H, Ar-H)
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  • [ 50-00-0 ]
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  • [ 123441-03-2 ]
YieldReaction ConditionsOperation in experiment
79.3% Example 9: Preparation of N-methylethylcarbamino-3-[(S)-1-(dimethylamino) ethyl] phenyl ester (the compound represented by formula (VII)); 11.27g (39.2mmol) the compound represented by formula (VI) obtained in Example 4 and 7.22g (157mmol) formic acid were mixed at room temperature, and then 6.54g (78.4mmol) formaldehyde aqueous solution (37mass%) was added. The mixture was fluxed for 2 hours, and then cooled to room temperature. 50ml water was added, followed by adding sodium carbonate in batches to adjust pH to 8. The result was then extracted with 60ml ethyl acetate twice. The combined organic layers was washed with 15ml water, and then dried with anhydrous magnesium sulfate. Colorless liquid (11.3g) was obtained after filtering and recovering the solvent under a reduced pressure. Vacuum distillation: 1 to 1.5 kpa, the fraction at a temperature ranging from 128C to 133C is collected, and 7.77g product is obtained with a yield of 79.3%. Optical rotation [alpha]20D = -32.1, C=5, ethanol. 1H NMR (CDCl3) delta ppm: 1.22 (m, 3H), 1.35 (q, 3H), 2.20 (s, 6H), 3.02 (d, 3H), 3.25 (m, 1H), 3.44 (s, 2H), 7.05 (m, 3H), 7.27 (m, 1H); MS (ESI) m/z: 251.2(M++1).
Example 5; Obtaining (S)-N-ethyl-3-[1-(dimethylamino)ethyl]-N-methylphenylcarbamate [Rivastigmine] 1 g of the oil obtained in Example 4 is dissolved in 10 mL of methanol and 1.4 mL of acetic acid, cooling the mixture between 0C and -5 C. 0.32 g of sodium cyanoborohydride are added to this mixture, maintaining the temperature under 0C. Once the addition has been completed, 0.53 mL of a 37% formaldehyde aqueous solution in 10 mL of methanol are added and it is maintained stirring at room temperature until the end of the reaction. Then 10 mL of a 10% hydrochloric acid aqueous solution are added, the methanol residues are distilled at reduced pressure and extracted with 10 mL of methylene chloride. 20 mL of methylene chloride are added to the separated aqueous phase and the mixture is adjusted to pH 8.7 with sodium hydroxide aqueous solution. The separated organic phase is distilled at reduced pressure until obtaining a yellow oil weighing 0.8 g, and which is identified as the desired product. 1H NMR: delta 1.15-1.2 (2*t, 3H, N-CH2-CH3) ; delta 1.3 (d, 3H, -CH-CH3) ; delta 2.2 (s, 6H, N-CH3); delta 2.96- 3.04 (2*s, 3H, OCN-CH3); 3.2 (q, 1H, -CH-CH3) ; delta 3.36-3. 44 (2*q, 2H, N-CH2-CH3) ; delta 6.96 (d, 1H, Ar-H); delta 7.05 (s, 1H, Ar-H); delta 7.10 (d, 1H, Ar-H); delta 7.3 (t, 1H, Ar-H)
  • 13
  • 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).
  • 14
  • 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.
  • 15
  • (S)-3-[1-(dimethylamino)ethyl]phenol (1S)-10-camphorsulfonate [ No CAS ]
  • 1-[(N-ethyl-(N-methyl)amino)carbonyl]-3-methyl-1H-imidazolium iodide [ No CAS ]
  • [ 123441-03-2 ]
YieldReaction ConditionsOperation in experiment
EXAMPLE 5 Preparation of (S)-N-Ethyl-N-methyl-3-[1-(dimethylamino)ethyl]-phenyl carbamate from (S)-3-[1-(Dimethylamino)ethyl]phenol (1S)-10-Camphorsulfonate Triethylamine (12.7 g, 125.8 mmol) was added slowly to a solution of (S)-3-[1-(dimethylamino)ethyl]phenol (1S)-10-camphorsulfonate (20 g, 50.3 mmol) in acetonitirile (60 mL) while keeping the internal temperature below 10 C. The reaction mixture was stirred for 0.5-1 hour. A solution of 1-[[N-ethyl-(N-methyl)amino]carbonyl]-3-methyl-1H-imidazolium iodide (14.3 g, 55.3 mmol) was then added slowly while keeping the internal temperature below 10 C. The reaction mixture was warmed to 75-80 C. and maintained 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 subsequently 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 (Rivastigmine free base) (12.5 g). The 1H NMR spectrum of the product was identical to that of example 4.
YieldReaction ConditionsOperation in experiment
a compound for the treatment of Alzheimer's disease, in particular: an anticholinesterase, such as: donepezil, galantamine, rivastigmine,
  • 17
  • [ 856408-80-5 ]
  • [ 124-40-3 ]
  • [ 123441-03-2 ]
YieldReaction ConditionsOperation in experiment
87% Stage 3; Materials :- Mw Mass, g mMole Mole Ratio s Alcohol substrate from Stage 2 223 3.40 15.25 1.0 Triethylamine 101. 1 4.60 45. 75 3.0 Methane sulphonic Anhydride 174. 2 3.45 19.8 1. 3 Dimethylamine 45. 05 91. 5 6 THF 70mL Method:- The alcohol obtained in stage 2, without further purification, (3.40g, 15. 25mmol) was dissolved in dry THF (40ml) and cooled in an ice-water bath. Then, triethylamine (4.60g, 45. 75mmol) was added and the solution kept cooled. Methanesulfonic anhydride (3.45g, 19. 8mmol) was dissolved in dry THF (30ml) and added to the cold reaction mixture dropwise over 30 minutes. The reaction mixture was stirred at 0C for 2 hours until conversion was 100% (GC) and then dimethylamine (46mol, 2M solution in THF) was added and the reaction mixture allowed to reach room temperature. After 48 h stirring conversion was 70% (GC), additional dimethylamine (46mmol) was then added and 24 hours later the conversion achieved was 99%. The reaction mixture was poured into 1M HCl (aq) (350ml) and extracted with dichloromethane (350ml), the organic layer was extracted again with 1M HC) (aq) (200m .) and both aqueous layers were combined and neutralized with 2M NaOH (aq) until the pH was above 10, then extracted with dichloromethane (3x350ml), the organic layers combined, dried and the solvent distilled to obtain 3.34g (87%) of the final product as a reddish oil. The specific optical rotation of the product was measured at-31 (3% solution in MeOH) (lit. Rivastigmine-32, Helv. Chim. Acta, 73 (3), 1990,739-753).
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  • [ 123441-03-2 ]
  • [ 139306-10-8 ]
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  • [ 105601-04-5 ]
  • [ 123441-03-2 ]
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[ 123441-03-2 ]

Chemical Structure| 129101-54-8

A193069[ 129101-54-8 ]

(S)-3-(1-(Dimethylamino)ethyl)phenyl ethyl(methyl)carbamate (2R,3R)-2,3-dihydroxysuccinate

Reason: Free-salt

; ;