CN101134738B - Asymmetric synthesis method of (S)-rivastigmine - Google Patents

Asymmetric synthesis method of (S)-rivastigmine Download PDF

Info

Publication number
CN101134738B
CN101134738B CN2007100306587A CN200710030658A CN101134738B CN 101134738 B CN101134738 B CN 101134738B CN 2007100306587 A CN2007100306587 A CN 2007100306587A CN 200710030658 A CN200710030658 A CN 200710030658A CN 101134738 B CN101134738 B CN 101134738B
Authority
CN
China
Prior art keywords
phenyl
ethyl
reaction
tertiary butyl
add
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
CN2007100306587A
Other languages
Chinese (zh)
Other versions
CN101134738A (en
Inventor
陈卫民
文富华
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Jinan University
University of Jinan
Original Assignee
Jinan University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Jinan University filed Critical Jinan University
Priority to CN2007100306587A priority Critical patent/CN101134738B/en
Publication of CN101134738A publication Critical patent/CN101134738A/en
Application granted granted Critical
Publication of CN101134738B publication Critical patent/CN101134738B/en
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Abstract

The present invention is asymmetrical (S)-carbalatine synthesizing process including the following steps: protecting the phenolic hydroxyl group of m-hydroxy benzaldehyde, reacting with chiral tert-butyl sulfonamide to produce (R, E)-3-methoxyl-phenyl methylene tert-butyl sulfonamide, addition reacting with methyl Grignard reagent, hydrolyzing, Eschweiler-Clarke methylation reaction, demethylating BBr3 to synthesize important intermediate (S)-1-(3-hydroxy phenyl)-N, N-dimethyl ethyl amine, and esterification with methyl ethyl carbamyl chloride to obtain (S)-carbalatine. The present invention has less reaction steps, high yield, total yield up to 21.85 %, and low cost.

Description

A kind of method of asymmetric synthesis of (S)-rivastigmine
Technical field
The invention belongs to the chiral drug synthesis technical field, the particularly method of pure (the S)-rivastigmine of synthesizing optical specifically is meant a kind of method of asymmetric synthesis of (S)-rivastigmine.
Background technology
Rivastigmine (Rivastigmine) is the novel anti medicine for senile dementia, because rivastigmine is to contain a chirality carbon compound, have (R)-and (S)-two kind of enantiomer.(S)-rivastigmine is its activeconstituents.Its synthetic method has two classes: 1) racemize splits; 2) asymmetric synthesis.Existing synthetic method is synthesized with the racemize Split Method mostly.Represent document to have: " Preparation and use ofphenylcarbamate cholinergic agonists as central nervous agents (being preparation and the purposes of phenylcarbamate comparison cholinergic agonist) " (Albert as the nervus centralis medicine, E.DE 3805744,1988); " study on the synthesis of tartrate rivastigmine " (Jiang Yongwen, Hua Zhengmao, Xie Lihua, Princeisaac K.A. Yang Li apple.East China Normal University's journal, 2001,1,61-65); " Process for preparing (-)-(S)-3-[1-(dimethylamino) ethyl] preparation technology of phenyl N-ethyl-N-methylcarbamate (rivastigmine) (i.e. (-)-(S)-N-ethyl-N-methyl carbamic acid (3-[1-(dimethylamino) ethyl] phenyl) ester (rivastigmine)) " (Stepankova, H.; Hajicek, J.; Simek, S.CZ293014,2004.); " Process for the preparation of aminoalkylphenyl carbamates inparticular rivastigmine hydrogentartrate (being the preparation technology of rivastigmine tartrate and carboxylamine (aminoalkyl group phenyl) ester) " (Gaitonde, A.; Mangle, M.GB 2409453,2005.).Above-mentioned this class racemize Split Method technology makes productive rate lower owing to repeatedly splitting, and production cost is higher.
The document of asymmetric synthesis method has " Stereoselective process for the preparation oftertiary amines attached to a secondary carbon center using a chiral transitionmetal transfer hydrogenation catalyst (using the secondary carbon center of chiral transition metal transfer hydrogenation catalyzer attack stereoselectivity to prepare the technology of tertiary amine) " (Fieldhouse, R.WO 2005058804,2005.); " Synthesis of Tritium; Deuterium; and Carbon-14 Labeled (S)-N-Ethyl-N-methyl-3-[1-(dimethylamino) ethyl] carbamic acid; phenyl ester; (L)-2; 3-dihydroxybutanedioic acid salt (SDZ ENA 713 hta), an InvestigationalDrug for the Treatment of Alzheimer ' s Disease (is a tritium, deuterium, (the S)-N-ethyl-N-methyl carbamic acid of carbon-14 mark (3-[1-(dimethylamino) ethyl] phenyl) ester (L)-2, synthesizing of the probe medicine of 3-dyhydrobutanedioic acid salt (SDZ ENA 713 hta) treatment Alzheimer disease) " (Ciszewska, G; Pfefferkom, H.; Tang, Y.S.; Jones, L.; Tarapata, R.; Sunay, U.B.Journal ofLabelled Compounds and Radiopharmaceuticals, 1997,39,651-668.).Above-mentioned this class asymmetric synthesis technology all exists some problems, and as: expensive raw material price, be not easy to obtain, the condition harshness is difficult to realize in industrialization etc.
Chirality tertiary butyl sulfinyl amine is the new chiral source of being found by professor Ellman in 1997; Equivalent for Chiral Amine; have advantages such as high asymmetric induction and reaction back tertiary butyl sulfinyl are easy to remove, in asymmetric synthesis, have in recent years widely and use.But do not see and be used for rivastigmine synthetic bibliographical information.
Summary of the invention
In order to solve above-mentioned the deficiencies in the prior art part, the object of the present invention is to provide the method for asymmetric synthesis of a kind of synthesis of chiral (S)-rivastigmine, the chirality that the present invention prepares (S)-rivastigmine reaches optical purity, meet drug standard, and cost descends greatly.
The present invention is starting raw material with the m-hydroxybenzaldehyde; after the phenolic hydroxyl group protection; with chirality tertiary butyl sulfinyl amine serves as that guiding reagent carries out asymmetric synthesis; generate (S)-1-(3-hydroxy phenyl)-N; the N-dimethyl amine; carry out esterification with the intermediate first and second amido formyl chlorides again, final synthetic (S)-rivastigmine.
Purpose of the present invention is achieved through the following technical solutions: a kind of method of asymmetric synthesis of (S)-rivastigmine; comprise the steps: that with m-hydroxybenzaldehyde (2) be starting raw material; carry out obtaining 3-methoxybenzaldehyde (3) after the phenolic hydroxyl group protection; generate (R with the reaction of chirality tertiary butyl sulfinyl amine; E)-3-methoxyl group-Ben Yajiaji tertiary butyl sulphonamide (4); again with methyl Grignard reagent generation addition reaction; generation has optically active (R)-N-((S)-1-(3-p-methoxy-phenyl) ethyl)-2-tertiary butyl sulphonamide (5) is more successively through hydrolysis; Eschweiler-Clarke methylation reaction and BBr 3Demethylation synthesizes important intermediate (S)-1-(3-hydroxy phenyl)-N, N-dimethyl amine (8), carry out esterification with first and second urea chlorides again, obtain (-)-(S)-N-ethyl-N-methyl carbamic acid (3-[1-(dimethylamino) ethyl] phenyl) ester (i.e. (S)-rivastigmine (1)), concrete synthetic route is as follows:
Figure DEST_PATH_GSB00000036506000011
The method of asymmetric synthesis of above-mentioned (S)-rivastigmine comprises the steps:
(1) 3-methoxybenzaldehyde (3) is synthetic
3-hydroxy benzaldehyde (2) is heated to 50~70 ℃ under magnetic agitation, drip methyl-sulfate simultaneously; Add the back and continue stirring reaction 10~30h, be cooled to room temperature; Extraction is dry, the rotation evaporate to dryness, and column chromatography gets 3-methoxybenzaldehyde (3); The mol ratio of described 3-hydroxy benzaldehyde and methyl-sulfate is 1: 1~1: 2.
(2) (R, E)-3-methoxyl group-Ben Yajiaji tertiary butyl sulphonamide (4) synthetic
Under nitrogen protection, in tertiary butyl sulfinyl amine, add anhydrous cupric sulfate, described tertiary butyl sulfinyl amine and anhydrous cupric sulfate mol ratio are 1: 2~1: 4, add 3-methoxybenzaldehyde (3) at last, stirring at room reaction 10~30h; Filter then, the rotation evaporate to dryness, column chromatography, (R, E)-3-methoxyl group-Ben Yajiaji tertiary butyl sulphonamide (4); The mol ratio of described 3-methoxybenzaldehyde and tertiary butyl sulfinyl amine is 2: 1~1: 1.
(3) (R)-N-((S)-1-(3-p-methoxy-phenyl) ethyl)-2-tertiary butyl sulphonamide (5) synthetic
Will (R, E)-3-methoxyl group-Ben Yajiaji tertiary butyl sulphonamide (4) is added drop-wise under-78~0 ℃ of stirring in the methyl magnesium iodide Grignard reagent, and continuation stirring reaction 4~6h, makes it rise to room temperature naturally then, and stirring reaction spends the night; With the reaction solution extraction, drying, the rotation evaporate to dryness, column chromatography gets (R)-N-((S)-1-(3-p-methoxy-phenyl) ethyl)-2-tertiary butyl sulphonamide (5); Described (R, E)-3-methoxyl group-Ben Yajiaji tertiary butyl sulphonamide (4) is 1: 1~1: 10 with the mol ratio of methyl magnesium iodide Grignard reagent.
(4) (S)-1-(3-methoxyl group) phenyl-ethyl amine (6) synthetic
Hydrochloric acid is added in (R)-N-((S)-1-(3-p-methoxy-phenyl) ethyl)-2-tertiary butyl sulphonamide (5), the mol ratio of described (R)-N-((S)-1-(3-p-methoxy-phenyl) ethyl)-2-tertiary butyl sulphonamide and hydrochloric acid is 1: 1~1: 5; Stirring at room reaction 0.1~2h; Concentrating under reduced pressure adds hydrochloric acid, washes 2~3 times with methylene dichloride, merges organic phase, with the hydrochloric acid soln extraction, merges water, and with ammoniacal liquor accent pH to 8~11, the extraction back merges organic phase, drying, and the rotation evaporate to dryness gets (S)-1-(3-methoxyl group) phenyl-ethyl amine (6).
(5) (S)-and 1-(3-p-methoxy-phenyl)-N, N-dimethyl amine (7) synthetic
In (S)-1-(3-methoxyl group) phenyl-ethyl amine (6), add formic acid and formaldehyde, 90 ℃ of left and right sides of oil bath stirring reaction 0.5~5h, and then add formaldehyde, continue reaction 5~30h; Stopped reaction is cooled to room temperature; Add hydrochloric acid soln and stirring, wash 2~3 times with methylene dichloride, merge organic phase, organic phase with the hydrochloric acid soln extraction, merges water again; Transfer pH to 8~11 with ammoniacal liquor, extraction merges organic phase, drying, and the rotation evaporate to dryness gets (S)-1-(3-p-methoxy-phenyl)-N, N-dimethyl amine (7); Described (S)-1-(3-methoxyl group) phenyl-ethyl amine (6): formaldehyde: the mol ratio of formic acid is 1: 2: 10~1: 100: 500.
(6) (S)-and 1-(3-hydroxy phenyl)-N, N-dimethyl amine (8) synthetic
With (S)-1-(3-p-methoxy-phenyl)-N, N-dimethyl amine (7) is cooled to-78 ℃ under the nitrogen protection, stirs down to add boron tribromide, continues to keep stirring 0.5~2h under this temperature; Be warming up to-30~-10 ℃ then, stirring reaction 2~6h is warming up to about-10 ℃ again, adds saturated sodium bicarbonate cancellation reaction; Extraction then, drying, column chromatography gets (S)-1-(3-hydroxy phenyl)-N, N-dimethyl amine (8); Described (S)-1-(3-p-methoxy-phenyl)-N, N-dimethyl amine (7) is 1: 1~1: 10 with the mol ratio of boron tribromide.
(7) (-)-(S)-N-ethyl-N-methyl carbamic acid (3-[1-(dimethylamino) ethyl] phenyl) ester ((S)-rivastigmine) synthetic
(S)-1-(3-hydroxy phenyl)-N, add the first and second amido formyl chlorides in the N-dimethyl amine (8), the described first and second amido formyl chlorides with (S)-1-(3-hydroxy phenyl)-N, the mol ratio of N-dimethyl amine is 1: 1~1: 2, stirring at room reaction 2~4h; The extraction that adds diethyl ether then, NaOH solution washing, washing, drying; Behind the rotation evaporate to dryness, (-)-(S)-N-ethyl-N-methyl carbamic acid (3-[1-(dimethylamino) ethyl] phenyl) ester (i.e. (S)-rivastigmine (1)).
In order to realize the present invention better, the 3-methoxybenzaldehyde (3) of described step (1) is preferably synthetic as follows: 50mmol 3-hydroxy benzaldehyde and 15ml methanol solution are being heated under the magnetic agitation about 65 ℃, drip 75mmol methyl-sulfate and 90mmol potassium hydroxide solution simultaneously, add the back and continue stirring reaction 24h, stopped reaction, be cooled to room temperature, ethyl acetate extraction, anhydrous sodium sulfate drying, rotation evaporate to dryness, column chromatography gets 3-methoxybenzaldehyde (3).
(the R of described step (2); E)-3-methoxyl group-Ben Yajiaji tertiary butyl sulphonamide (4) is preferably synthetic as follows: under nitrogen protection; 20mmol tertiary butyl sulfinyl amine is added the 30ml methylene dichloride; add the 44mmol anhydrous cupric sulfate under the magnetic agitation; add the 22mmol 3-methoxybenzaldehyde that is dissolved in the 10ml methylene dichloride at last; stirring at room reaction 24h; stop to stir; the sand core funnel filters; the rotation evaporate to dryness; column chromatography, (R, E)-3-methoxyl group-Ben Yajiaji tertiary butyl sulphonamide (4).
(the R)-N-of described step (3) ((S)-1-(3-p-methoxy-phenyl) ethyl)-2-tertiary butyl sulphonamide (5) is preferably synthetic as follows:
40.6mmol magnesium sheet and catalytic amount iodine are added the 10ml anhydrous diethyl ether under nitrogen protection, add several (about 0.5ml) methyl iodide diethyl ether solutions then, question response causes, after the yellow of iodine is decorporated, start magnetic agitation, and at 29~31 ℃ of mixed solutions that slowly drip 40mmol methyl iodide and 20ml ether down, drip the back and continue stirring reaction to the magnesium completely dissolve, obtain methyl magnesium iodide Grignard reagent;
The above-mentioned methyl magnesium iodide Grignard reagent that makes is cooled to-48 ℃, stir and slowly drip 6.69mmol (R down, E)-the 33ml dichloromethane solution of 3-methoxyl group-Ben Yajiaji tertiary butyl sulphonamide (4), add the back and keep-48 ℃ of following stirring reaction 4~6h, make it rise to room temperature naturally then, stirring reaction spends the night.Reaction solution is poured in the 200ml saturated ammonium chloride solution, used ethyl acetate extraction, anhydrous magnesium sulfate drying, the rotation evaporate to dryness, column chromatography gets (R)-N-((S)-1-(3-p-methoxy-phenyl) ethyl)-2-tertiary butyl sulphonamide (5).
(the S)-1-of described step (4) (3-methoxyl group) phenyl-ethyl amine (6) is preferably synthetic as follows: with 2.14ml methyl alcohol and hydrochloric acid/1,4-dioxane solution (2.14ml, 6.4mmol) be added in 3.2mmol (R)-N-((S)-1-(3-p-methoxy-phenyl) ethyl)-2-tertiary butyl sulphonamide (5), stirring at room reaction 0.5h, concentrating under reduced pressure, add 10ml hydrochloric acid, wash 3 times, merge organic phase with methylene dichloride, extract with the 2mol/L hydrochloric acid soln, merge water, transfer about pH to 9, use dichloromethane extraction with ammoniacal liquor, merge organic phase, anhydrous magnesium sulfate drying, the rotation evaporate to dryness gets (S)-1-(3-methoxyl group) phenyl-ethyl amine (6).
(the S)-1-of described step (5) (3-p-methoxy-phenyl)-N, N-dimethyl amine (7) is preferably synthetic as follows: adding 191mmol commodity concentration is that 88% formic acid and 50mmol commodity concentration are 38% formaldehyde in 1.66mmol (S)-1-(3-methoxyl group) phenyl-ethyl amine (6), 90 ℃ of left and right sides of oil bath stirring reaction 1h, and then adding 48mmol volumetric concentration is 38% formaldehyde, continue reaction 26h, stopped reaction is cooled to room temperature, add 10ml3 mol/L hydrochloric acid soln, and stir; Wash 3 times with methylene dichloride, merge organic phase, organic phase with the extraction of 2mol/L hydrochloric acid soln, merges water again; Transfer about pH to 9 with ammoniacal liquor, use dichloromethane extraction, merge organic phase, anhydrous magnesium sulfate drying, the rotation evaporate to dryness gets (S)-1-(3-p-methoxy-phenyl)-N, N-dimethyl amine (7).
(the S)-1-of described step (6) (3-hydroxy phenyl)-N, N-dimethyl amine (8) is preferably synthetic as follows: with 0.6mmol (S)-1-(3-p-methoxy-phenyl)-N, N-dimethyl amine (7) is dissolved in the 13ml methylene dichloride, under nitrogen protection, be cooled to-78 ℃, stir and add the 3.6mmol boron tribromide down, continue to keep stirring 0.5h under this temperature, be warming up to-20 ℃ then, stirring reaction 4h, be warming up to-12 ℃ again, add 20ml saturated sodium bicarbonate cancellation reaction, use ethyl acetate extraction, and use anhydrous sodium sulfate drying; Column chromatography gets (S)-1-(3-hydroxy phenyl)-N, N-dimethyl amine (8).
(S)-N-ethyl of described step (7)-3-[(1-diformazan ammonia) acetyl]-N-methyl carbamic acid phenyl ester ((S)-rivastigmine, (1)) preferably synthetic as follows: at 0.12mmol (S)-1-(3-hydroxy phenyl)-N, add 0.25ml THF in the N-dimethyl amine (8), add 0.13mmol NaH then, behind the thorough mixing, add the 0.13mmol first and second amido formyl chlorides, stirring at room reaction 2h, after reclaiming THF, extraction adds diethyl ether, 0.1mol/L NaOH solution washing, washing, anhydrous magnesium sulfate drying, behind the rotation evaporate to dryness, (-)-(S)-N-ethyl-N-methyl carbamic acid (3-[1-(dimethylamino) ethyl] phenyl) ester (i.e. (S)-rivastigmine (1)).
The present invention compared with prior art has following advantage and beneficial effect:
1, the present invention adopts method of asymmetric synthesis, and reactions steps is few, and each step reaction yield is all higher, and all about 90%, optical yields is 80.7% basically.
2, the whole synthetic route yield of rivastigmine reaches 21.85%, is higher than the racemize Split Method far away and closes route productive rate (6.23%), has reduced cost comparatively speaking, has reduced waste.
3, the inventive method is compared with existing asymmetric synthesis method, has also that raw material is easy to get, low price; Reaction conditions is gentle, and simple operation and other advantages all can realize in suitability for industrialized production.
Embodiment
The present invention is described in further detail below in conjunction with embodiment, but embodiments of the present invention are not limited thereto.
Embodiment 1
(1) 3-methoxybenzaldehyde (3) is synthetic
In the 250ml three-necked bottle, (6.10g is 50mmol) with the 15ml methanol solution to add the 3-hydroxy benzaldehyde, be heated under the magnetic agitation about 65 ℃, drip simultaneously methyl-sulfate (7.41ml, 75mmol) and potassium hydroxide solution (KOH (5.04g, 90mmol), 8ml water).Add the back and continue stirring reaction 24h, stopped reaction is cooled to room temperature.Ethyl acetate extraction (15ml * 3), anhydrous sodium sulfate drying, the rotation evaporate to dryness, column chromatography gets yellow oil 3-methoxybenzaldehyde (3) (5.76g, yield: 84.1%).
(2) (R, E)-3-methoxyl group-Ben Yajiaji tertiary butyl sulphonamide (4) synthetic
Under nitrogen protection; take by weighing tertiary butyl sulfinyl amine (2.40g; 20mmol) and anhydrous cupric sulfate (7.00g; 44mmol), tertiary butyl sulfinyl amine is put into the 100ml three-necked bottle, add the 30ml methylene dichloride; add anhydrous cupric sulfate under the magnetic agitation; (3.2g 22mmol) adds in the above-mentioned three-necked bottle, stirring at room reaction 24h will to be dissolved in the 3-methoxybenzaldehyde of 10ml methylene dichloride at last.Stop to stir, the sand core funnel filters, the rotation evaporate to dryness, column chromatography, yellow oil (R, E)-3-methoxyl group-Ben Yajiaji tertiary butyl sulphonamide (4) (4.48g, yield: 93.7%). 1H?NMR(CDCl 3)δ1.25(s,9H,CH 3),3.85(s,3H,OCH 3),7.06(dd,1H,ArH),7.39(m,3H,ArH),8.24(s,1H,CH);MS,m/z240.2(M+H +)。
(3) (R)-N-((S)-1-(3-p-methoxy-phenyl) ethyl)-2-tertiary butyl sulphonamide (5) synthetic
With the magnesium sheet (0.97g that polishes and shred; 40.6mmol) and catalytic amount iodine, put into the 250ml three-necked bottle, nitrogen protection adds the 10ml anhydrous diethyl ether down; add several (about 0.5ml) methyl iodide diethyl ether solutions then; question response causes, and after the yellow of iodine is decorporated, starts magnetic agitation; and at 29~31 ℃ of slow down methyl iodide (5.74g that drip; 40mmol) with the mixed solution of ether (20ml), drip the back and continue stirring reaction to the magnesium completely dissolve, obtain methyl magnesium iodide Grignard reagent.
The above-mentioned methyl magnesium iodide Grignard reagent that makes is cooled to-48 ℃, stir and slowly drip (R down, E)-3-methoxyl group-Ben Yajiaji tertiary butyl sulphonamide (4) (1.60g, 6.69mmol) methylene dichloride (33ml) solution, add the back and keep-48 ℃ of following stirring reaction 4~6h, make it rise to room temperature naturally then, stirring reaction spends the night.Reaction solution is poured in the 200ml saturated ammonium chloride solution, with ethyl acetate extraction (10ml * 3), anhydrous magnesium sulfate drying, the rotation evaporate to dryness, column chromatography gets white solid (R)-N-((S)-1-(3-p-methoxy-phenyl) ethyl)-2-tertiary butyl sulphonamide (5) (1.57g, yield: 91.8%); 1H NMR (CDCl 3) δ 1.11 (s, 9H, CH 3), 1.43 (d, J=6.7Hz, 3H, CH 3), 3.44 (d, J=3.4Hz, 1H, NH), 3.68 (s, 3H, OCH 3), 4.37 (q, J=6.6Hz, 1H, CH), 6.69 (m, 1H, ArH), 6.72 (s, 1H, ArH), 6.82 (d, J=7.4Hz, 1H, ArH), 7.14 (t, J=7.8Hz, 1H, ArH); 13C NMR (CDCl 3) δ 22.5,25.1,54.7,55.1,55.5,76.7,77.0,77.3,112.5,112.8,119.2,129.5,145.2,159.7; MS, m/z 256.4 (M+H +); Ultimate analysis calculated value: (C 13H 21O 2SN) C:61.14%; H:8.29%; N:5.48%; S:12.56%); Measured value: C, 61.88%; H, 8.73%; N, 5.46%; S, 12.53%.
(4) (S)-1-(3-methoxyl group) phenyl-ethyl amine (6) synthetic
With 2.14ml methyl alcohol and hydrochloric acid/1,4-dioxane solution (2.14ml, 6.4mmol) be added to fill (R)-N-((S)-1-(3-p-methoxy-phenyl) ethyl)-2-tertiary butyl sulphonamide (5) (0.82g, in the single neck bottle of 3.2mmol) 100ml, stirring at room reaction 0.5h.Concentrating under reduced pressure adds 10ml hydrochloric acid (3mol/L), washes 3 times with methylene dichloride (10ml * 3), merge organic phase, with hydrochloric acid soln (2mol/L, 10ml * 3) extraction, merge water, transfer about pH to 9 with ammoniacal liquor,, merge organic phase with methylene dichloride (10ml * 5) extraction, anhydrous magnesium sulfate drying, the rotation evaporate to dryness gets yellow oil (S)-1-(3-methoxyl group) phenyl-ethyl amine (6) (0.47g, yield: 97.9%); 1H NMR (CDCl 3) δ 1.36 (d, J=6.6Hz, 3H, CH 3), 1.57 (s, 2H, NH 2), 3.79 (s, 3H, OCH 3), 4.07 (q, J=6.6Hz, 1H, CH), 6.76 (m, 1H, ArH), 6.91 (m, 2H, ArH), 7.24 (m, 1H, ArH); MS, m/z 152.2 (M+H +).
(5) (S)-and 1-(3-p-methoxy-phenyl)-N, N-dimethyl amine (7) synthetic
Filling (S)-1-(3-methoxyl group) phenyl-ethyl amine 6 (0.25g, 1.66mmol) the 100ml three-necked bottle in to add concentration be the formic acid (10ml of 88% (percent by volume), be 38% (percent by volume) formaldehyde (4ml 191mmol) with concentration, 50mmol), 90 ℃ of left and right sides of oil bath stirring reaction 1h, and then adding concentration is that (3.8ml 48mmol), continues reaction 26h to 38% (percent by volume) formaldehyde.Stopped reaction is cooled to room temperature.Add 10ml hydrochloric acid soln (3mol/L), and stir.Wash 3 times with methylene dichloride (10ml * 3), merge organic phase, organic phase is used hydrochloric acid soln (2mol/L, 10ml * 3) extraction again, merges water.With about ammoniacal liquor accent pH to 9, with methylene dichloride (10ml * 5) extraction, merge organic phase, anhydrous magnesium sulfate drying, the rotation evaporate to dryness gets yellow oil (S)-1-(3-p-methoxy-phenyl)-N, N-dimethyl amine (7) (0.25g, yield: 84.2%); 1H NMR (CDCl 3) δ 1.35 (d, J=6.65Hz, 3H, CH 3), 2.21 (s, 6H, NCH 3), 3.19 (q, J=6.67Hz, 1H, CH), 3.80 (s, 3H ,-OCH 3), 6.77 (m, 1H, CH), 6.85 (s, 1H, CH), 6.87 (d, 1H, CH), 7.23 (m, 1H, CH); M/S, m/z 179.8 (M+H +).
(6) (S)-and 1-(3-hydroxy phenyl)-N, N-dimethyl amine (8) synthetic
With (S)-1-(3-p-methoxy-phenyl)-N, (0.11g 0.6mmol) is dissolved in the 13ml methylene dichloride N-dimethyl amine (7), and pours in the 100ml three-necked bottle.Be cooled to-78 ℃ under the nitrogen protection, (0.34ml 3.6mmol), continues to keep stirring 0.5h under this temperature to stir rapid down adding boron tribromide.Be warming up to-20 ℃ then, stirring reaction 4h is warming up to-12 ℃ again, adds 20ml saturated sodium bicarbonate cancellation reaction.With ethyl acetate (10ml * 4) extraction, and use anhydrous sodium sulfate drying.Column chromatography gets white crystal (S)-1-(3-hydroxy phenyl)-N, N-dimethyl amine (8) (0.08g, yield: 80.8%), reclaim raw material (S)-1-(3-p-methoxy-phenyl)-N, N-dimethyl amine (7) 0.01g (recovery productive rate: 90.9%); 1H NMR (CDCl 3) δ 1.39 (d, J=6.8Hz, 3H, CH 3), 2.23 (s, 6H, N (CH 3) 2), 3.28 (q, J=6.8Hz, 1H, CH), 6.74 (m, 2H, ArH), 6.83 (s, 1H, ArH), 7.15 (t, 1H, J=7.8Hz, ArH).
(7) (-)-(S)-N-ethyl-N-methyl carbamic acid (3-[1-(dimethylamino) ethyl] phenyl) ester (rivastigmine, (1)) synthetic
With (S)-1-(3-hydroxy phenyl)-N, N-dimethyl amine (8) (0.02g, 0.12mmol) pour in the 50ml round-bottomed flask, add 0.25ml THF, add then NaH (0.0051g, 0.13mmol), behind the thorough mixing, (0.0155g, 0.13mmol), stirring at room is reacted 2h to add the first and second amido formyl chlorides.After reclaiming THF, the extraction that adds diethyl ether, 0.1mol/L NaOH solution washing, washing, anhydrous magnesium sulfate drying.Behind the rotation evaporate to dryness, get yellow oil (S)-rivastigmine (1) (0.0272g, yield: 89.8%); 1H NMR (CDCl 3) δ 1.21 (m, 3H, CH 3), 1.36 (d, J=6.8Hz, 3H, CH 3), 2.20 (s, 6H, N (CH 3) 2), 3.02 (s, s, 3H, NCH 3), 3.25 (q, J=6.7,1H, 1H), 3.43 (m, 2H, CH 2), 7.01 (d, J=8.4Hz, 1H, ArH), 7.07 (s, 1H, ArH), 7.11 (d, J=7.6Hz, 1H, ArH), 7.28 (m, 1H, ArH); M/S, m/z 251.3 (M+H +).
The foregoing description is a preferred implementation of the present invention; but embodiments of the present invention are not restricted to the described embodiments; other any do not deviate from change, the modification done under spirit of the present invention and the principle, substitutes, combination, simplify; all should be the substitute mode of equivalence, be included within protection scope of the present invention.

Claims (9)

1. the method for asymmetric synthesis of (S)-rivastigmine; it is characterized in that comprising the steps: with the m-hydroxybenzaldehyde to be starting raw material; carry out obtaining the 3-methoxybenzaldehyde after the phenolic hydroxyl group protection; generate (R with the reaction of chirality tertiary butyl sulfinyl amine; E)-3-methoxyl group-Ben Yajiaji tertiary butyl sulphonamide; again with methyl Grignard reagent generation addition reaction; generation has optically active (R)-N-((S)-1-(3-p-methoxy-phenyl) ethyl)-2-tertiary butyl sulphonamide is more successively through hydrolysis, Eschweiler-Clarke methylation reaction and BBr 3Demethylation synthesizes important intermediate (S)-1-(3-hydroxy phenyl)-N, the N-dimethyl amine, carry out esterification with first and second urea chlorides again, obtain (-)-(S)-N-ethyl-N-methyl carbamic acid (3-[1-(dimethylamino) ethyl] phenyl) ester, i.e. (S)-rivastigmine.
2. the method for asymmetric synthesis of a kind of (S)-rivastigmine according to claim 1 is characterized in that comprising the steps:
(1) the 3-methoxybenzaldehyde is synthetic
The 3-hydroxy benzaldehyde is heated to 50~70 ℃ under magnetic agitation, drip methyl-sulfate simultaneously; Add the back and continue stirring reaction 10~30h, be cooled to room temperature; Extraction is dry, the rotation evaporate to dryness, and column chromatography gets the 3-methoxybenzaldehyde; The mol ratio of described 3-hydroxy benzaldehyde and methyl-sulfate is 1: 1~1: 2;
(2) (R, E)-3-methoxyl group-Ben Yajiaji tertiary butyl sulphonamide synthetic
Under nitrogen protection, in tertiary butyl sulfinyl amine, add anhydrous cupric sulfate, described tertiary butyl sulfinyl amine and anhydrous cupric sulfate mol ratio are 1: 2~1: 4, add the 3-methoxybenzaldehyde at last, stirring at room reaction 10~30h; Filter then, the rotation evaporate to dryness, column chromatography, (R, E)-3-methoxyl group-Ben Yajiaji tertiary butyl sulphonamide; The mol ratio of described 3-methoxybenzaldehyde and tertiary butyl sulfinyl amine is 2: 1~1: 1;
(3) (R)-N-((S)-1-(3-p-methoxy-phenyl) ethyl)-2-tertiary butyl sulphonamide synthetic
Will (R, E)-3-methoxyl group-Ben Yajiaji tertiary butyl sulphonamide is added drop-wise under-78~0 ℃ of stirring in the methyl magnesium iodide Grignard reagent, and continuation stirring reaction 4~6h, makes it rise to room temperature naturally then, and stirring reaction spends the night; With the reaction solution extraction, drying, the rotation evaporate to dryness, column chromatography gets (R)-N-((S)-1-(3-p-methoxy-phenyl) ethyl)-2-tertiary butyl sulphonamide; Described (R, E)-mol ratio of 3-methoxyl group-Ben Yajiaji tertiary butyl sulphonamide and methyl magnesium iodide Grignard reagent is 1: 1~1: 10;
(4) (S)-1-(3-methoxyl group) phenyl-ethyl amine synthetic
Hydrochloric acid is added in (R)-N-((S)-1-(3-p-methoxy-phenyl) ethyl)-2-tertiary butyl sulphonamide, the mol ratio of described (R)-N-((S)-1-(3-p-methoxy-phenyl) ethyl)-2-tertiary butyl sulphonamide and hydrochloric acid is 1: 1~1: 5; Stirring at room reaction 0.1~2h; Concentrating under reduced pressure adds hydrochloric acid, washes 2~3 times with methylene dichloride, merges organic phase, with the hydrochloric acid soln extraction, merges water, and with ammoniacal liquor accent pH to 8~11, the extraction back merges organic phase, drying, and the rotation evaporate to dryness gets (S)-1-(3-methoxyl group) phenyl-ethyl amine;
(5) (S)-and 1-(3-p-methoxy-phenyl)-N, N-dimethyl amine synthetic
In (S)-1-(3-methoxyl group) phenyl-ethyl amine, add formic acid and formaldehyde, 90 ℃ of stirring reaction 0.5~5h of oil bath, and then add formaldehyde, continue reaction 5~30h; Stopped reaction is cooled to room temperature; Add hydrochloric acid soln and stirring, wash 2~3 times with methylene dichloride, merge organic phase, organic phase with the hydrochloric acid soln extraction, merges water again; Transfer pH to 8~11 with ammoniacal liquor, extraction merges organic phase, drying, and the rotation evaporate to dryness gets (S)-1-(3-p-methoxy-phenyl)-N, the N-dimethyl amine; Described (S)-1-(3-methoxyl group) phenyl-ethyl amine: formaldehyde: the mol ratio of formic acid is 1: 2: 10~1: 100: 500;
(6) (S)-and 1-(3-hydroxy phenyl)-N, N-dimethyl amine synthetic
With (S)-1-(3-p-methoxy-phenyl)-N, the N-dimethyl amine is cooled to-78 ℃ under the nitrogen protection, stirs down to add boron tribromide, continues to keep stirring 0.5~2h under this temperature; Be warming up to-30~-10 ℃ then, stirring reaction 2~6h is warming up to-10 ℃ again, adds saturated sodium bicarbonate cancellation reaction; Extraction then, drying, column chromatography gets (S)-1-(3-hydroxy phenyl)-N, the N-dimethyl amine; Described (S)-1-(3-p-methoxy-phenyl)-N, the mol ratio of N-dimethyl amine and boron tribromide is 1: 1~1: 10;
(7) (-)-(S)-N-ethyl-N-methyl carbamic acid (3-[1-(dimethylamino) ethyl] phenyl) ester i.e. (S)-rivastigmine synthetic
(S)-1-(3-hydroxy phenyl)-N, add the first and second amido formyl chlorides in the N-dimethyl amine, the described first and second amido formyl chlorides with (S)-1-(3-hydroxy phenyl)-N, the mol ratio of N-dimethyl amine is 1: 1~1: 2, stirring at room reaction 2~4h; The extraction that adds diethyl ether then, NaOH solution washing, washing, drying; Behind the rotation evaporate to dryness, (-)-(S)-N-ethyl-N-methyl carbamic acid (3-[1-(dimethylamino) ethyl] phenyl) ester, i.e. (S)-rivastigmine.
3. the method for asymmetric synthesis of a kind of (S)-rivastigmine according to claim 2, it is characterized in that, the 3-methoxybenzaldehyde of described step (1) is synthetic as follows: 50mmol 3-hydroxy benzaldehyde and 15ml methanol solution are heated to 65 ℃ under magnetic agitation, drip 75mmol methyl-sulfate and 90mmol potassium hydroxide solution simultaneously, add the back and continue stirring reaction 24h, stopped reaction, be cooled to room temperature, ethyl acetate extraction, anhydrous sodium sulfate drying, the rotation evaporate to dryness, column chromatography gets the 3-methoxybenzaldehyde.
4. the method for asymmetric synthesis of a kind of (S)-rivastigmine according to claim 2; it is characterized in that; (the R of described step (2); E)-3-methoxyl group-Ben Yajiaji tertiary butyl sulphonamide is synthetic as follows: under nitrogen protection; 20mmol tertiary butyl sulfinyl amine is added the 30ml methylene dichloride; add the 44mmol anhydrous cupric sulfate under the magnetic agitation; add the 22mmol 3-methoxybenzaldehyde that is dissolved in the 10ml methylene dichloride at last; stirring at room reaction 24h stops to stir, and the sand core funnel filters; the rotation evaporate to dryness; column chromatography, (R, E)-3-methoxyl group-Ben Yajiaji tertiary butyl sulphonamide.
5. the method for asymmetric synthesis of a kind of (S)-rivastigmine according to claim 2 is characterized in that, (the R)-N-of described step (3) ((S)-1-(3-p-methoxy-phenyl) ethyl)-2-tertiary butyl sulphonamide is synthetic as follows:
40.6mmol magnesium sheet and catalytic amount iodine are added the 10ml anhydrous diethyl ether under nitrogen protection, add 0.5ml methyl iodide diethyl ether solution then, question response causes, after the yellow of iodine is decorporated, start magnetic agitation, and at 29~31 ℃ of mixed solutions that drip 40mmol methyl iodide and 20ml ether down, drip the back and continue stirring reaction to the magnesium completely dissolve, obtain methyl magnesium iodide Grignard reagent;
The above-mentioned methyl magnesium iodide Grignard reagent that makes is cooled to-48 ℃, stir and slowly drip 6.69mmol (R down, E)-the 33ml dichloromethane solution of 3-methoxyl group-Ben Yajiaji tertiary butyl sulphonamide, add the back and keep-48 ℃ of following stirring reaction 4~6h, make it rise to room temperature naturally then, stirring reaction spends the night.Reaction solution is poured in the 200ml saturated ammonium chloride solution, used ethyl acetate extraction, anhydrous magnesium sulfate drying, the rotation evaporate to dryness, column chromatography gets (R)-N-((S)-1-(3-p-methoxy-phenyl) ethyl)-2-tertiary butyl sulphonamide.
6. the method for asymmetric synthesis of a kind of (S)-rivastigmine according to claim 2, it is characterized in that, (the S)-1-of described step (4) (3-methoxyl group) phenyl-ethyl amine is synthetic as follows: with 2.14ml methyl alcohol and hydrochloric acid/1,4-dioxane solution 6.4mmol is added in 3.2mmol (R)-N-((S)-1-(3-p-methoxy-phenyl) ethyl)-2-tertiary butyl sulphonamide, stirring at room reaction 0.5h, concentrating under reduced pressure, add 10ml hydrochloric acid, wash 3 times with methylene dichloride, merge organic phase,, merge water with the extraction of 2mol/L hydrochloric acid soln, transfer pH to 9 with ammoniacal liquor, use dichloromethane extraction, merge organic phase, anhydrous magnesium sulfate drying, the rotation evaporate to dryness gets (S)-1-(3-methoxyl group) phenyl-ethyl amine.
7. the method for asymmetric synthesis of a kind of (S)-rivastigmine according to claim 2, it is characterized in that, (the S)-1-of described step (5) (3-p-methoxy-phenyl)-N, the N-dimethyl amine is synthetic as follows: adding 191mmol concentration is that 88% formic acid and 50mmol concentration are 38% formaldehyde in 1.66mmol (S)-1-(3-methoxyl group) phenyl-ethyl amine, 90 ℃ of stirring reaction 1h of oil bath, and then adding 48mmol concentration is 38% formaldehyde, continue reaction 26h, stopped reaction, be cooled to room temperature, add 10ml 3mol/L hydrochloric acid soln, and stir; Wash 3 times with methylene dichloride, merge organic phase, organic phase with the extraction of 2mol/L hydrochloric acid soln, merges water again; Transfer pH to 9 with ammoniacal liquor, use dichloromethane extraction, merge organic phase, anhydrous magnesium sulfate drying, the rotation evaporate to dryness gets (S)-1-(3-p-methoxy-phenyl)-N, the N-dimethyl amine.
8. the method for asymmetric synthesis of a kind of (S)-rivastigmine according to claim 2, it is characterized in that, (the S)-1-of described step (6) (3-hydroxy phenyl)-N, the N-dimethyl amine is synthetic as follows: with 0.6mmol (S)-1-(3-p-methoxy-phenyl)-N, the N-dimethyl amine is dissolved in the 13ml methylene dichloride, under nitrogen protection, be cooled to-78 ℃, stir and add the 3.6mmol boron tribromide down, continue to keep stirring 0.5h under this temperature, be warming up to-20 ℃ then, stirring reaction 4h, be warming up to-12 ℃ again, add 20ml saturated sodium bicarbonate cancellation reaction, use ethyl acetate extraction, and use anhydrous sodium sulfate drying; Column chromatography gets (S)-1-(3-hydroxy phenyl)-N, the N-dimethyl amine.
9. the method for asymmetric synthesis of a kind of (S)-rivastigmine according to claim 2, it is characterized in that, (S)-N-ethyl of described step (7)-3-[(1-diformazan ammonia) acetyl]-promptly (S)-rivastigmine is synthetic as follows for N-methyl carbamic acid phenyl ester: at 0.12mmol (S)-1-(3-hydroxy phenyl)-N, add 0.25ml THF in the N-dimethyl amine, add 0.13mmol NaH then, behind the thorough mixing, add the 0.13mmol first and second amido formyl chlorides, stirring at room reaction 2h, after reclaiming THF, extraction adds diethyl ether, 0.1mol/L NaOH solution washing, washing, anhydrous magnesium sulfate drying, behind the rotation evaporate to dryness, i.e. (the S)-rivastigmine of (-)-(S)-N-ethyl-N-methyl carbamic acid (3-[1-(dimethylamino) ethyl] phenyl) ester.
CN2007100306587A 2007-09-29 2007-09-29 Asymmetric synthesis method of (S)-rivastigmine Expired - Fee Related CN101134738B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN2007100306587A CN101134738B (en) 2007-09-29 2007-09-29 Asymmetric synthesis method of (S)-rivastigmine

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN2007100306587A CN101134738B (en) 2007-09-29 2007-09-29 Asymmetric synthesis method of (S)-rivastigmine

Publications (2)

Publication Number Publication Date
CN101134738A CN101134738A (en) 2008-03-05
CN101134738B true CN101134738B (en) 2010-08-25

Family

ID=39159091

Family Applications (1)

Application Number Title Priority Date Filing Date
CN2007100306587A Expired - Fee Related CN101134738B (en) 2007-09-29 2007-09-29 Asymmetric synthesis method of (S)-rivastigmine

Country Status (1)

Country Link
CN (1) CN101134738B (en)

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101580482B (en) * 2009-05-27 2014-04-23 沈阳药科大学 Method for preparing rivastigmine hydrogen tartrate and application thereof
CN102285904B (en) * 2011-07-11 2013-06-05 中国科学院成都生物研究所 Method for preparing rivastigmine
CN103073456B (en) * 2011-10-26 2014-03-19 连云港润众制药有限公司 Preparation method for rivastigmine intermediate
CN102690175A (en) * 2012-06-18 2012-09-26 潍坊杜得利化学工业有限公司 Preparation method of 3-methoxybenzyl chloride
CN103012154B (en) * 2012-12-18 2014-10-08 浙江大学 Method for preparing organic amine through benzsulfamide derivative ammonolysis
CN103319374B (en) * 2013-06-09 2015-04-22 无锡佰翱得生物科学有限公司 Asymmetric synthetic method of (S)-rivastigmine
CN103420941B (en) * 2013-08-26 2015-09-23 浙江大学 2-p-methoxy-phenyl-dimethylin carbamate derivatives and preparation and purposes
CN104098487A (en) * 2014-07-31 2014-10-15 天津民祥生物医药科技有限公司 Method for preparing N-tert-butyloxycarbonyl-3-hydroxy-1-adamantyl-d-glycine
CN104098505A (en) * 2014-07-31 2014-10-15 天津民祥生物医药科技有限公司 Preparation method for saxagliptin
CN106397227B (en) * 2016-08-19 2018-07-06 山东省药学科学院 A kind of preparation method of Dapoxetine hydrochloride hydrochloride

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1962624A (en) * 2006-11-10 2007-05-16 暨南大学 Method for synthesis of rivastigmine

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1962624A (en) * 2006-11-10 2007-05-16 暨南大学 Method for synthesis of rivastigmine

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
龙湘俊 等.酒石酸卡巴拉汀的合成研究进展.中南药学4 5.2006,4(5),369-371.
龙湘俊等.酒石酸卡巴拉汀的合成研究进展.中南药学4 5.2006,4(5),369-371. *

Also Published As

Publication number Publication date
CN101134738A (en) 2008-03-05

Similar Documents

Publication Publication Date Title
CN101134738B (en) Asymmetric synthesis method of (S)-rivastigmine
CN104557572B (en) Levalbuterol intermediate and levalbuterol hydrochloride synthesis method
CN101580482B (en) Method for preparing rivastigmine hydrogen tartrate and application thereof
CN105732533A (en) Substituted n-pentanamide compounds as well as preparation method and use thereof
CN104072398B (en) A kind of method of synthesizing Ezetimibe
CN101585519B (en) Method for preparing <15>N-hydroxylamine hydrochloride by hydrolyzing <15>N-nitromethane
CN102010400B (en) S-5-substituted-N-2'-(thiofuran-2-yl-) ethyl-1,2,3,4-tetranap-2-amine or chiral hydrochloric acid and application thereof to preparation of rotigotine
CN101143815B (en) Method for preparing felbinac
CN104072381A (en) Preparation method for optically pure aminoalcohol hydrochloride
CN106831441B (en) A kind of preparation method of cinacalcet hydrochloride
CN107778234A (en) A kind of preparation method of neuromuscular blocking agent intermediate
CN100457722C (en) Method for synthesis of rivastigmine
CN103435505A (en) Method for synthesizing (R)-salmeterol
CN106397227A (en) Preparation method of dapoxetine hydrochloride
CN113861066B (en) Deuterated fluvoxamine maleate and synthesis method thereof
CN101481333A (en) Novel rivastigmine preparation
CN107857710A (en) A kind of preparation method of antiepileptic Pregabalin
CN102010327A (en) Splitting method of (+/-)-2-(3-benzoyl)-phenylpropionic acid
CN103102280B (en) The preparation method of optical voidness 1-(alpha-amido benzyl)-beta naphthal
CN101481334B (en) Rivastigmine preparation suitable for industrial production
CN107382751A (en) The preparation method of dapoxetine hydrochloride
CN103319374B (en) Asymmetric synthetic method of (S)-rivastigmine
CN101735070A (en) Resolution method of R-(+)-1-(1-naphthyl) ethylamine
CN101481335A (en) Rivastigmine intermediate preparation
CN102115431B (en) Synthesis method of 2, 2-ethoxyethanol

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
C17 Cessation of patent right
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20100825

Termination date: 20130929