CN101016257A - Intermediate of rivastigmine, preparation and application thereof - Google Patents
Intermediate of rivastigmine, preparation and application thereof Download PDFInfo
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- CN101016257A CN101016257A CN 200710067343 CN200710067343A CN101016257A CN 101016257 A CN101016257 A CN 101016257A CN 200710067343 CN200710067343 CN 200710067343 CN 200710067343 A CN200710067343 A CN 200710067343A CN 101016257 A CN101016257 A CN 101016257A
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- ethyl
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Abstract
The invention discloses a new making method of carbalatin as Alzheimer's disease drug and application, which is N, N-ethyl methyl-amino aminic acid 3-(1-methylamino ethyl) phenyl ester (II). The method improves receiving rate and product quality effectively, which is fit industrial manufacturing.
Description
(1) technical field
The present invention relates to be used to prepare the novel substance of Alzheimer's disease medicine rivastigmine: N, N-ethyl-methyl-carboxylamine 3-(1-methylamino ethyl) phenyl ester and preparation thereof and application.
(2) background technology
Tartrate rivastigmine (Rivastigmine Hydrogen tartrate) is that a kind of selectively acting by Switzerland Novartis company development is in the carbamate acetylcholinesteraseinhibitors inhibitors of brain, be used for the treatment of light moderate AD (Alzheimer's disease), in December, 1997 is in Switzerland's Initial Public Offering.
The chemical name of rivastigmine is: (S)-N, N-ethyl-methyl-carboxylamine 3-(1-(dimethylin) ethyl) phenyl ester, structural formula is as follows:
U.S. Pat 4948807 and US5602176 disclose the method (Scheme 1) for preparing rivastigmine: 3-(1-(dimethyl amido) ethyl) phenol jointly and N-ethyl-N-methyl formyl chloride reacts generation racemic modification compound N in the presence of sodium hydrogen, N-ethyl-methyl-carboxylamine 3-(1-(dimethylin) ethyl) phenyl ester (patent US4948807), this outer body and function (+)-two pair toluyl tartrate monohydrate that disappears splits and makes rivastigmine (patent US5602176).The shortcoming of this method is: 1) final step splits to reach through the method for recrystallization repeatedly increases enantiomeric excess (ee value); 2) total recovery is low, can not guarantee high ee value.
Scheme?1
(3) summary of the invention
The purpose of this invention is to provide a kind of novel substance for preparing rivastigmine yield height, operational safety, is beneficial to suitability for industrialized production: N, N-ethyl-methyl-carboxylamine 3-(1-methylamino ethyl) phenyl ester and preparation thereof and application.
For reaching goal of the invention the technical solution used in the present invention be:
N, N-ethyl-methyl-carboxylamine 3-(1-methylamino ethyl) phenyl ester, structure is suc as formula shown in (II):
Especially, described N, N-ethyl-methyl-carboxylamine 3-(1-methylamino ethyl) phenyl ester molecular structure is the S type, i.e. (S) N, N-ethyl-methyl-carboxylamine 3-(1-methylamino ethyl) phenyl ester, structure is suc as formula shown in (III):
N, the preparation method of N-ethyl-methyl-carboxylamine 3-(1-methylamino ethyl) phenyl ester, described method is as follows: with the N shown in the formula (I), N-ethyl-methyl-carboxylamine 3-ethanoyl phenyl ester is a raw material, carry out the amination reduction reaction, obtain described N, N-ethyl-methyl-carboxylamine 3-(1-methylamino ethyl) phenyl ester;
Described amination reduction reaction can use conventional amination method of reducing to carry out, and the amination reduction reaction is preferably carried out in the presence of titanium isopropylate, methylamine, sodium borohydride among the present invention.N, the ratio of N-ethyl-methyl-carboxylamine 3-ethanoyl phenyl ester, titanium isopropylate, methylamine, sodium borohydride amount of substance is preferably: 1: 0.5～3.0: 1.0～10.0: 0.5～3.0.
Described (S) N, N-ethyl-methyl-carboxylamine 3-(1-methylamino ethyl) phenyl ester can be prepared by following method: with the racemic modification compound shown in the optics active acid split-type (II): N, N-ethyl-methyl-carboxylamine 3-(1-methylamino ethyl) phenyl ester, obtain the optically active compound shown in the formula (III): (S) N, N-ethyl-methyl-carboxylamine 3-(1-methylamino ethyl) phenyl ester or its acid additional salt; Described optical activity acid is one of following: 1. tartrate, 2. lactic acid, 3. bisnapthylphosphoricacid acid, 4. camphorsulfonic acid, 5. amygdalic acid, 6. oxysuccinic acid, 7. 2-phenoxy propionic acid, 8. dibenzoyl tartaric acid, 9. two pairs of toluyl tartrate.
Described fractionation is carried out in organic solvent usually, described organic solvent can be one of following or two or more mixture wherein, or mixture one of following and water: the ketone of the alcohol of C1～C10, the ester of C3～C12, C3～C12, the ether of C2～C12, described N, the ratio of the amount of N-ethyl-methyl-carboxylamine 3-(1-methylamino ethyl) phenyl ester and optical activity acid substance is 1: 0.4～1.1.
Described organic solvent is preferably the alcohol of C1～C10, or the mixture of the alcohol of C1～C10 and water.
The invention still further relates to N, the application of N-ethyl-methyl-carboxylamine 3-(1-methylamino ethyl) phenyl ester in the preparation rivastigmine.Especially its S configuration body is (S) N, the application of N-ethyl-methyl-carboxylamine 3-(1-methylamino ethyl) phenyl ester in the preparation rivastigmine.With (S) N, N-ethyl-methyl-carboxylamine 3-(1-methylamino ethyl) phenyl ester is that raw material carries out methylation reaction, get final product rivastigmine, i.e. (S)-N, N-ethyl-methyl-carboxylamine 3-(1-(dimethylin) ethyl) phenyl ester.
Described methylation reaction has following two kinds of methods:
Method one: in the presence of reductive agent, the N-that utilizes formaldehyde to carry out reductibility methylates, concrete grammar is as follows: with (S) N, N-ethyl-methyl-carboxylamine 3-(1-methylamino ethyl) phenyl ester is a raw material, hydroborate or formic acid with I family or II family metal are reductive agent, carry out reductibility N-methylation reaction with formaldehyde, obtain (S)-N, N-ethyl-methyl-carboxylamine 3-(1-(dimethylin) ethyl) phenyl ester.When being reductive agent with the hydroborate of I family or II family metal, usually described being reflected in the aqueous solution carried out, with acetate and sodium acetate as buffer reagent, under cooling, with (S) N, the reaction mixture of N-ethyl-methyl-carboxylamine 3-(1-methylamino ethyl) phenyl ester and formaldehyde adds to react in the hydroborate in batches and gets final product; When being reductive agent with formic acid, described reaction is the Eschweiler-Clarke reaction, and this technology is simple, is this area conventional techniques means.
Method two: with (S) N, N-ethyl-methyl-carboxylamine 3-(1-methylamino ethyl) phenyl ester is a raw material, with methyl iodide or methyl-sulfate is methylating reagent, carries out methylation reaction and obtains (S)-N, N-ethyl-methyl-carboxylamine 3-(1-(dimethylin) ethyl) phenyl ester.Methyl iodide or methyl-sulfate are methylating reagent commonly used, and this method also belongs to this area conventional techniques means.
The principle of the invention is as follows: N; N-ethyl-methyl-carboxylamine 3-ethanoyl phenyl ester (I) carries out the amination reduction; then to gained N; N-ethyl-methyl-carboxylamine 3-(1-methylamino ethyl) (II) phenyl ester carries out optical resolution and (obtains earlier the optical activity acid salt (IV) of compound (II) with the optical activity acid-respons; the optics active acid of dissociating again); make (S) N; N-ethyl-methyl-carboxylamine 3-(1-methylamino ethyl) phenyl ester; (S) N; N-ethyl-methyl-carboxylamine 3-(1-methylamino ethyl) phenyl ester obtains described rivastigmine again through methylating: (S)-N, N-ethyl-methyl-carboxylamine 3-(1-(dimethylin) ethyl) phenyl ester.
Beneficial effect of the present invention is mainly reflected in: a kind of novel substance that can be used for preparing rivastigmine: N is provided, N-ethyl-methyl-carboxylamine 3-(1-methylamino ethyl) phenyl ester, a yield height, quality product height are provided, cost is low, easy and simple to handle, be fit to industrial rivastigmine synthetic route.
(4) embodiment
The present invention is described further below in conjunction with specific embodiment, but protection scope of the present invention is not limited in this:
Embodiment 1:N, the preparation of N-ethyl-methyl-carboxylamine 3-(1-methylamino ethyl) phenyl ester
Titanium isopropylate (20ml, 66mmol 1.3eq) are dissolved in the 75ml methylamine alcohol solution, add N, and N-ethyl-methyl-carboxylamine 3-ethanoyl phenyl ester (13g, 84.8%, 50mmol, 1eq) stirring reaction is 6 hours, adds NaBH under the ice bath in batches
4(3g, 78.9mmol, 1.6eq), stirring at room 2 hours adds shrend and goes out, and washes with ethyl acetate and saturated common salt behind the suction filtration, separatory, it is 1～3 that organic phase is transferred pH with 1N HCl, washes with ethyl acetate again, the water intaking phase, transferring pH with 2N NaOH solution is 10～12, ethyl acetate extraction, 40 mL water washings, anhydrous sodium sulfate drying, rotary evaporation get 11g (46.6mmol) yellow oil after being spin-dried for ethyl acetate, thick yield 93.2%.ESI-MSm/z237[M+H
+]
1H?NMR(DMSO-d
6，400MHz)δ(ppm)：1.15-1.26(2
*t，3H，N-CH
2C
H 3，J＝7.2Hz)，1.33(d，1H，PhCHC
H 3，J＝6.4Hz)，2.28(s，3H，NH-C
H 3)，2.94?and?3.04(2
*s，3H，NH-C
H 3)，3.36-3.47(2
*q，2H，N-C
H 2CH
3，J＝7.2Hz)，3.60-3.64(q，1H，CHC
H 3，J＝6.8Hz)，7.00(d，1H，Ar-
H，J＝7.2Hz)，7.05(s，1H，Ar-
H)，7.11(d，1H，Ar-
H，J＝7.6Hz)，7.29(t，1H，Ar-
H，J＝8.0Hz)
Embodiment 2:(S)-and N, the preparation of N-ethyl-methyl-carboxylamine 3-(1-methylamino ethyl) phenyl ester
N, N-ethyl-methyl-carboxylamine 3-(1-methylamino ethyl) phenyl ester (7.9g, 33.5mmol) be dissolved in 20ml solvent (methyl alcohol: water=2: 1, volume ratio), two pairs of toluyl D-tartrate (10.3g, 26.8mmol, 0.8eq)) are dissolved in 15ml solvent (methyl alcohol: water=2: 1), both mix, reflux is cooled to room temperature after whole clarifications, add 100mg left and right sides crystal seed, in 0 ℃ place 2 hours after, separate out a large amount of white solids, suction filtration, 10ml washed with isopropyl alcohol, 40 ℃ of following vacuum-dryings got 10g (16.1mmol) white solid after 1 hour.Salify yield 48%.
Above-mentioned white solid is carried out recrystallization, white solid (3g, 4.8mmol), yield 75%.
Get above-mentioned 3g (4.8mmol, 1eq) white solid places 50ml single port flask, add 20ml 2N NaOH (40mmol, 8.3eq), ice bath stirs down, adds extracted with diethyl ether, the saturated common salt washing, washing, anhydrous sodium sulfate drying, rotary evaporation get 1.1g (4.7mmol) light yellow oil after being spin-dried for ether.Yield 97.9%.High-efficient liquid phase analysis: S: R=100: 1.2.
Embodiment 3:(S)-and N, the preparation of N-ethyl-methyl-carboxylamine 3-(1-methylamino ethyl) phenyl ester
Make resolving agent with the D-amygdalic acid, N, the mol ratio of N-ethyl-methyl-carboxylamine 3-(1-methylamino ethyl) phenyl ester and D-amygdalic acid is 1: 0.7, presses the method operation of embodiment 2.
Embodiment 4: the preparation of rivastigmine (methylating with formaldehyde in formic acid)
(S)-and N, (1.6g 6.8mmol) is dissolved in 4ml formic acid to N-ethyl-methyl-carboxylamine 3-(1-methylamino ethyl) phenyl ester, the formalin of 1.8ml37%, after the reflux 4 hours, transferring pH with 10%NaOH is 10-12, separatory, use ethyl acetate extraction, use the saturated common salt water washing again, anhydrous sodium sulfate drying, rotary evaporation get light yellow oil (1.4g after being spin-dried for solvent, 5.6mmol), yield 82.4%.
Embodiment 5: the preparation of rivastigmine (methylating with formaldehyde in the presence of sodium borohydride)
(S)-N, N-ethyl-methyl-carboxylamine 3-(1-methylamino ethyl) phenyl ester (3.7g, 15.8mmol), anhydrous sodium acetate (3.3g, 40mmol), the 17ml glacial acetic acid, the mixture of the formalin of 10ml 37% and 50ml distilled water is cooled to 0 ℃, short run adds sodium borohydride (4.7g subsequently, 0.11mmol), low temperature stirred 1 hour, and transferring pH with 10%NaOH solution is 10-12, separatory, use ethyl acetate extraction, saturated common salt water washing, anhydrous sodium sulfate drying, rotary evaporation get light yellow oil (3.64g after being spin-dried for solvent, 14.58mmol), yield 92.3%.
Embodiment 6: the preparation of rivastigmine (methylating with methyl iodide)
(S)-N, N-ethyl-methyl-carboxylamine 3-(1-methylamino ethyl) phenyl ester (2.21g, 9.4mmol), methyl iodide (1.33g, 9.4mmol) and salt of wormwood (3.89g 28.2mmol) stirred in 20ml methyl alcohol 8 hours.Subsequently, add 20ml distilled water to mixture, the extraction of first and second acetoacetic esters, the saturated common salt water washing, anhydrous sodium sulfate drying, rotary evaporation get light yellow oil (1.83g, 7.3mmol) (yield 78%) after being spin-dried for solvent
Embodiment 7: the preparation of rivastigmine tartrate
(0.60g 4mmol) is dissolved in the 4ml methyl alcohol L-(+)-tartrate, adds rivastigmine (1.0g, 4mmol 1.0eq), is heated to 60oC, 2 hours postcooling continue to stir 1 hour to room temperature, and rotary evaporation gets oily matter after being spin-dried for solvent, add normal hexane, stir, be spin-dried for, get white solid, add the normal hexane suction filtration again, get 1.2g (3mmol) white solid, yield 75%.
Claims (10)
1.N, N-ethyl-methyl-carboxylamine 3-(1-methylamino ethyl) phenyl ester, structure is suc as formula shown in (II):
2. N as claimed in claim 1, N-ethyl-methyl-carboxylamine 3-(1-methylamino ethyl) phenyl ester, it is characterized in that described N, N-ethyl-methyl-carboxylamine 3-(1-methylamino ethyl) phenyl ester is (S) N, N-ethyl-methyl-carboxylamine 3-(1-methylamino ethyl) phenyl ester, structure is suc as formula shown in (III):
3. prepare N as claimed in claim 1, the method of N-ethyl-methyl-carboxylamine 3-(1-methylamino ethyl) phenyl ester, described method is: with the N shown in the formula (I), N-ethyl-methyl-carboxylamine 3-ethanoyl phenyl ester is a raw material, carry out the amination reduction reaction, obtain described N, N-ethyl-methyl-carboxylamine 3-(1-methylamino ethyl) phenyl ester;
4. N as claimed in claim 3, the preparation method of N-ethyl-methyl-carboxylamine 3-(1-methylamino ethyl) phenyl ester is characterized in that described amination reduction reaction carries out in the presence of titanium isopropylate, methylamine, sodium borohydride.
5. method as claimed in claim 4, it is characterized in that: described N, N-ethyl-methyl-carboxylamine 3-(1-methylamino ethyl) phenyl ester is (S) N, N-ethyl-methyl-carboxylamine 3-(1-methylamino ethyl) phenyl ester, described method is: with the racemic modification compound shown in the optics active acid split-type (II): N, N-ethyl-methyl-carboxylamine 3-(1-methylamino ethyl) phenyl ester, obtain the optically active compound shown in the formula (III): (S) N, N-ethyl-methyl-carboxylamine 3-(1-methylamino ethyl) phenyl ester or its acid additional salt; Described optical activity acid is one of following: 1. tartrate, 2. lactic acid, 3. bisnapthylphosphoricacid acid, 4. camphorsulfonic acid, 5. amygdalic acid, 6. oxysuccinic acid, 7. 2-phenoxy propionic acid, 8. dibenzoyl tartaric acid, 9. two pairs of toluyl tartrate.
6. method as claimed in claim 5, it is characterized in that described fractionation carries out in organic solvent, described organic solvent is one of following or two or more mixture wherein, or mixture one of following and water: the ketone of the alcohol of C1～C10, the ester of C3～C12, C3～C12, the ether of C2～C12, described N, the ratio of the amount of N-ethyl-methyl-carboxylamine 3-(1-methylamino ethyl) phenyl ester and optical activity acid substance is 1: 0.4～1.1.
7.N, the application of N-ethyl-methyl-carboxylamine 3-(1-methylamino ethyl) phenyl ester in the preparation rivastigmine.
8. application as claimed in claim 7 is characterized in that described N, and N-ethyl-methyl-carboxylamine 3-(1-methylamino ethyl) phenyl ester is (S) N, N-ethyl-methyl-carboxylamine 3-(1-methylamino ethyl) phenyl ester.
9. application as claimed in claim 8, it is characterized in that described rivastigmine is prepared by following method: with (S) N, N-ethyl-methyl-carboxylamine 3-(1-methylamino ethyl) phenyl ester is a raw material, hydroborate or formic acid with I family or II family metal are reductive agent, carry out reductibility N-methylation reaction with formaldehyde, obtain (S)-N, N-ethyl-methyl-carboxylamine 3-(1-(dimethylin) ethyl) phenyl ester.
10. application as claimed in claim 8, it is characterized in that described rivastigmine is prepared by following method: with (S) N, N-ethyl-methyl-carboxylamine 3-(1-methylamino ethyl) phenyl ester is a raw material, with methyl iodide or methyl-sulfate is methylating reagent, carry out methylation reaction and obtain (S)-N, N-ethyl-methyl-carboxylamine 3-(1-(dimethylin) ethyl) phenyl ester.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009086705A1 (en) * | 2008-01-10 | 2009-07-16 | Shanghai Institute Of Pharmaceutical Industry | Preparation method of rivastigmine, its intermediates and preparation method of the intermediates |
| CN102134206A (en) * | 2010-01-27 | 2011-07-27 | 上海京新生物医药有限公司 | Method for preparing rivastigmine |
| CN102786441A (en) * | 2011-05-18 | 2012-11-21 | 浙江海正药业股份有限公司 | Preparation method of rivastigmine, intermediates and preparation method of intermediates |
| CN103073456A (en) * | 2011-10-26 | 2013-05-01 | 连云港润众制药有限公司 | Preparation method for rivastigmine intermediate |
| CN103304447A (en) * | 2013-06-09 | 2013-09-18 | 无锡佰翱得生物科学有限公司 | Synthesis process of (S)-rivastigmine |
| CN105254513A (en) * | 2015-10-29 | 2016-01-20 | 无锡福祈制药有限公司 | Resolution method of (S)-3-[1-(dimethylamino) ethyl] phenol (III) |
| CN106187820A (en) * | 2016-07-02 | 2016-12-07 | 深圳市康立生生物科技有限公司 | A kind of preparation method of bambuterol impurity B |
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2007
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101910110B (en) * | 2008-01-10 | 2013-05-22 | 上海医药工业研究院 | Preparation method of rivastigmine, its intermediates and preparation method of the intermediates |
| CN101910110A (en) * | 2008-01-10 | 2010-12-08 | 上海医药工业研究院 | The bright preparation method of Li Fansi, its intermediate and intermediates preparation |
| WO2009086705A1 (en) * | 2008-01-10 | 2009-07-16 | Shanghai Institute Of Pharmaceutical Industry | Preparation method of rivastigmine, its intermediates and preparation method of the intermediates |
| US8324429B2 (en) | 2008-01-10 | 2012-12-04 | Shanghai Institute Of Pharmaceutical Industry | Preparation method of rivastigmine, its intermediates and preparation method of the intermediates |
| CN102134206A (en) * | 2010-01-27 | 2011-07-27 | 上海京新生物医药有限公司 | Method for preparing rivastigmine |
| CN102786441A (en) * | 2011-05-18 | 2012-11-21 | 浙江海正药业股份有限公司 | Preparation method of rivastigmine, intermediates and preparation method of intermediates |
| CN102786441B (en) * | 2011-05-18 | 2013-11-13 | 浙江海正药业股份有限公司 | Preparation method of rivastigmine, intermediates and preparation method of intermediates |
| CN103073456A (en) * | 2011-10-26 | 2013-05-01 | 连云港润众制药有限公司 | Preparation method for rivastigmine intermediate |
| CN103073456B (en) * | 2011-10-26 | 2014-03-19 | 连云港润众制药有限公司 | Preparation method for rivastigmine intermediate |
| CN103304447A (en) * | 2013-06-09 | 2013-09-18 | 无锡佰翱得生物科学有限公司 | Synthesis process of (S)-rivastigmine |
| CN103304447B (en) * | 2013-06-09 | 2015-12-09 | 无锡佰翱得生物科学有限公司 | (S) synthesis technique of-rivastigmine |
| CN105254513A (en) * | 2015-10-29 | 2016-01-20 | 无锡福祈制药有限公司 | Resolution method of (S)-3-[1-(dimethylamino) ethyl] phenol (III) |
| CN106187820A (en) * | 2016-07-02 | 2016-12-07 | 深圳市康立生生物科技有限公司 | A kind of preparation method of bambuterol impurity B |
| CN106187820B (en) * | 2016-07-02 | 2017-09-19 | 深圳市康立生生物科技有限公司 | A kind of preparation method of bambuterol impurity B |
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