CN1962624A - Method for synthesis of rivastigmine - Google Patents
Method for synthesis of rivastigmine Download PDFInfo
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- CN1962624A CN1962624A CN 200610123473 CN200610123473A CN1962624A CN 1962624 A CN1962624 A CN 1962624A CN 200610123473 CN200610123473 CN 200610123473 CN 200610123473 A CN200610123473 A CN 200610123473A CN 1962624 A CN1962624 A CN 1962624A
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- rivastigmine
- ethyl
- reaction
- dimethylamino
- phenol
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Abstract
The invention discloses a synthesizing method of (S)-N-ethyl-3-[(1-dimethylamino) acetyl]-N-methyl amido phenyl formate, which is characterized by the following: adopting m-hydroxy acetophenone as raw material; synthesizing intermediate 3-(1-(dimethylamino) ethyl) phenol; condensing 3-(1-(dimethylamino) ethyl) phenol and formyl chloride to produce the product with high receiving rate.
Description
Technical field
The present invention relates to the anti senile dementia drug rivastigmine, particularly a kind of rivastigmine ((S)-N-ethyl-3-[(1-diformazan ammonia) acetyl]-N-methyl carbamic acid phenyl ester) synthetic method.
Background technology
Rivastigmine (Rivastigmine) is a kind of acetylcholinesterase depressant (AchEI), in being used for the treatment of, slight senile dementia.The synthesis technique of existing rivastigmine has two classes, 1) conventional synthetic, chiral separation; 2) asymmetric synthesis.Method of asymmetric synthesis all needs to use comparatively expensive catalysts; conventional synthetic method is used all is general reagent; and generally all to synthesize and obtain racemic rivastigmine via important intermediate 3-(1-(dimethylamino) ethyl) phenol; mainly contain two kinds of method: a, be raw material for intermediate 3-(1-(dimethylamino) ethyl) phenol synthetic at present with the meta-methoxy methyl phenyl ketone; earlier synthetic 1-(3-p-methoxy-phenyl)-N; the N-dimethylethyl amine obtains through deprotection reaction again.B, be raw material, through become the oxime reaction with azanol after, utilize reductive agent that oxime is reduced into primary amine again, pass through the N-methylation reaction again, final synthetic obtaining with the m-hydroxy acetophenone.The a method will be passed through deprotection reaction, the also not supply on China market at present of meta-methoxy methyl phenyl ketone raw material, and the relative complicated operation of total synthesis technique, cost is higher.The b method obtains tertiary amine through three-step reaction is synthetic, complicated operation, and synthesis cycle is long, cost height, and poor selectivity, responsive substituted radicals such as the hydroxyl on the aromatic ring can be affected in the N-methylation reaction, so that overall yield is low, is about 18%.
Conventional achirality synthetic document operational path is as shown in the formula (I):
React the method for synthesizing tertiary amine compounds by Leuckart, existing in early days pertinent literature report (Bunnett J F.Marks J L.Preparation of tertiary amines by the Leuckart reaction.Journal of the American Chemical Society, 1949,71:1587-1589.), the Leuckart reaction is at first proposed in 1885 by people such as Leuckart, this reaction can be heated carbonyl compound as reductive agent with formic acid (or ammonium formiate, methane amide) together, makes primary amine, secondary amine and tertiary amine.When the catalyst-free catalyzed reaction, reaction yield is on the low side, utilizes MgCl
2, FeCl
3React Deng catalyst, and utilize the N of nascent state, N '-dialkylformamide is participated in reaction, can improve the productive rate of tertiary amine and reclaim productive rate, and technology is simple, and cost is low.
Summary of the invention
In order to overcome the shortcoming of above-mentioned prior art, the object of the present invention is to provide a kind of synthetic method of rivastigmine.This synthetic method has solved existing synthesis route length, not high, the cost problem of higher of yield.
Purpose of the present invention is achieved through the following technical solutions: a kind of synthetic method of rivastigmine comprises the steps:
(1) key intermediate 3-(1-(dimethylamino) ethyl) phenol is synthetic: under normal pressure, and m-hydroxy acetophenone and N, dinethylformamide (DMF) reacts, and the reaction times is 5～24 hours; Temperature of reaction is 155～170 ℃, and carbonyl is changed into tertiary amine, promptly makes 3-(1-(dimethylamino) ethyl) phenol; Described m-hydroxy acetophenone and N, the mol ratio of dinethylformamide is 1: 4～1: 800.
(2) rivastigmine is synthetic: 3-(1-(dimethylamino) ethyl) phenol becomes ester condensation to become rivastigmine ((S)-N-ethyl-3-[(1-diformazan ammonia) acetyl under the NaH effect with first and second urea chlorides]-N-methyl carbamic acid phenyl ester), the mol ratio of described 3-(1-(dimethylamino) ethyl) phenol and first and second urea chlorides is 1: 1.05.
In order to realize the present invention better, described step (1) can also be carried out as follows: under normal pressure, and m-hydroxy acetophenone and N, dinethylformamide (DMF) reacts, and the reaction times is 5～24 hours; Temperature of reaction is 155～170 ℃, after reaction finishes, reaction solution is poured in the water, about concentrated hydrochloric acid adjust pH to 1～2, filter, and extracted with diethyl ether, ether is used anhydrous magnesium sulfate drying mutually, the rotation evaporate to dryness; Water sodium bicarbonate adjust pH to 8.5, ethyl acetate extraction, the mutually anhydrous MgSO of ethyl acetate
4Drying, rotary evaporation is to doing, and vacuum-drying obtains 3-(1-(dimethylamino) ethyl) phenol.
Also can add catalyzer in the step (1) building-up reactions of intermediate 3-(1-(dimethylamino) ethyl) phenol (promptly), described catalyzer can be the lewis acid compounds; Described lewis acid compounds comprises MgCl
2Or FeCl
3Deng the lewis acid compounds; Described MgCl
2Or FeCl
3Mole dosage Deng catalyzer is 15～100% of a m-hydroxy acetophenone.
Add the productive rate that formic acid helps improving 3-(1-(dimethylamino) ethyl) phenol in the step (1), the mole dosage of formic acid is 100～1000% of a m-hydroxy acetophenone.
Described reaction reagent N, dinethylformamide also can adopt formic acid and dimethylamine agueous solution to react the N that makes nascent state, dinethylformamide, the N of the nascent state that makes, the dinethylformamide activity is higher, and the productive rate of reaction products therefrom is higher.Described N, dinethylformamide prepares as follows and gets: under condition of ice bath, slowly add dimethylamine agueous solution in formic acid, after adding finishes, add the thermal distillation steaming and dewater, promptly make the N of nascent state, dinethylformamide, described formic acid equates with the dimethylamine agueous solution amount of substance.
Reaction formula of the present invention is suc as formula (II), wherein the reaction type of synthetic intermediate 3-(1-(dimethylamino) ethyl) phenol belongs to the Leuckart reaction, with existing different through polystep reaction technology such as one-tenth oxime, reduction, aminations, the present invention is one-step synthesis intermediate 3-(1-(dimethylamino) ethyl) phenol, and then becomes ester condensation to become the free alkali of rivastigmine under the NaH effect with first and second urea chlorides:
The present invention compared with prior art has following advantage and beneficial effect:
(1) the present invention is a synthesis under normal pressure, and facility investment is few, and is easy to operate and safe.
(2) cost of the present invention is low, and raw material is simple, be easy to get, and used catalyzer all is commercially available conventional reagent.
(3) the present invention is environmentally friendly, pollution is few, and the three wastes are handled burden and obviously reduced, and have reached the requirement of cleaner production, help large-scale industrial production.
(4) reaction process difficulty of the present invention is low, easy and simple to handle, and product separates easily with unreacted raw material, just can separate with simple extracting and separating.
(5) good economy performance of the present invention, the reaction preference height, byproduct of reaction is few, and the hydroxyl sensitive group is all unaffected on the aromatic ring, and it is good to reclaim productive rate, and two step yields are 74%.The present invention is easy to operate and safe, reaction end of a period easily separated recovery of unreacted raw material and recycle.
Embodiment
The present invention is further described in detail below in conjunction with embodiment, but embodiments of the present invention are not limited thereto.
Embodiment 1
(1) under condition of ice bath, (20.9g in 250ml there-necked flask 0.4mol), slowly adds 33% dimethylamine agueous solution (54.5g to filling 88% formic acid, 0.4mol), after adding finishes, add thermal distillation, steaming about 46ml that dewaters makes nascent state N, dinethylformamide (DMF).Treat that temperature reduces to below 100 ℃, in this reaction flask, add m-hydroxy acetophenone (13.6g, 0.1mol), formic acid (concentration 88%) (4.6g, 0.1mol), MgCl
26H
2O (3g, 0.015mol).Directly temperature is risen to 170 ℃, reacting by heating 5h, after reaction finishes, reaction solution is poured in the 80ml water, combined behind about 5ml water cleaning reaction bottle, about concentrated hydrochloric acid adjust pH to 1～2, filter, extracted with diethyl ether, ether is used anhydrous magnesium sulfate drying mutually, the rotation evaporate to dryness gets solid material m-hydroxy acetophenone 6.47g and recycles.Water sodium bicarbonate adjust pH to 8.5, ethyl acetate extraction, the mutually anhydrous MgSO of ethyl acetate
4Drying, rotary evaporation is to doing, and vacuum-drying gets product 3-(1-(dimethylamino) ethyl) phenol (6.7g, productive rate: 40.9%; Reclaim productive rate: 78.0%).M.p.90-92 ℃ (literature value: 88-90 ℃, yield: 30%).
1H?NMR(400MHz，CDCl
3)δH?1.38(d，J＝6.72Hz，3H，-CH
3)，2.22(s，6H，-N(CH
3)
2)，3.26(q，J＝6.68Hz，1H，-CH)，6.26(br，1H，HO-Ar)，6.73(d，J＝8.06Hz，ArH)，6.77(d，J＝7.60Hz，ArH)6.81(s，ArH)，7.14(dd，J＝7.78Hz，J＝7.81Hz，ArH)；MS，m/z?166.5(MH
+)；IR(KBr)cm
-13039，2960，2521，2360，1582，1480，1287。
(2) in the 50ml flask, add 3-(1-(dimethylamino) ethyl) phenol (1.65g, 0.01mol), 60% NaH (0.42g, 0.0105mol), tetrahydrofuran (THF) (THF) 15ml is after fully mixing, (1.28g 0.0105mol), stirs 2h under the room temperature to add first and second urea chlorides, after reclaiming THF, the extraction that adds diethyl ether, 0.1mol/L NaOH solution washing, washing, boil off ether, after the vacuum-drying, get yellow liquid rivastigmine free alkali (2.34g, 93.6%).
1H?NMR(400?Hz，CDCl
3)δH1.23(m，3H)，1.35(d，J＝6.69Hz，3H)，2.20(s，6H，-N(CH
3)
2)，3.01(s，s，3H)，3.24(q，J＝6.62Hz，3H)，3.43(m，2H)，7.00(d，J＝7.83Hz，ArH)，7.07(s，ArH)，7.11(d，J＝7.67Hz，ArH)，7.28(t，J＝7.83HZ，ArH)；
13C?NMR(400?MHz，CDCl
3)δ12.6，19.8，33.8，43.4，65.4，77.0，120.3，123.9，128.6，145.5，151.4，154.2；MS，m/z?273(M+Na
+)。
Embodiment 2
(1) in the 100ml there-necked flask, and the adding m-hydroxy acetophenone (4g, 0.029mol), 88% formic acid (4ml, 0.093mol), N, dinethylformamide (DMF) (20ml, 0.26mol).Be heated to 155 ℃ of backflow 24h, about concentrated hydrochloric acid adjust pH to 1～2, filter, extracted with diethyl ether, ether is used anhydrous magnesium sulfate drying mutually, and ether is removed in common distillation earlier, and excessive DMF is removed in underpressure distillation again, gets solid material m-hydroxy acetophenone 2.55g.Water sodium bicarbonate adjust pH to 8.5, ethyl acetate extraction, anhydrous MgSO
4Drying, rotary evaporation concentrate, and raffinate is cold puts for residue, separates out solid, filter, vacuum-drying, product 3-(1-(dimethylamino) ethyl) phenol (0.65g, productive rate: 13.4%; Reclaim productive rate: 36.9%).
(2) with embodiment 1.
Embodiment 3
(1) with embodiment 1, (418g, in 2000ml there-necked flask 8mol), (1090g 8mol), after adding finishes, adds thermal distillation, and steaming dewaters, and makes nascent state N, dinethylformamide (DMF) slowly to add 33% dimethylamine agueous solution to filling 88% formic acid.Wait to be chilled to about 100 ℃, in this reaction flask, add m-hydroxy acetophenone (1.36g, 0.01mol), formic acid (concentration 88%) (4.6g, 0.1mol), MgCl
26H
2O (2g, 0.01mol).Directly temperature is risen to 170 ℃, reacting by heating 5h, after reaction finished, excessive DMF was removed in underpressure distillation, and raffinate is poured in the 10ml water.Other operations are with embodiment 1.Make 3-(1-(dimethylamino) ethyl) phenol (0.7g, productive rate: 42.4%; Reclaim productive rate: 79.0%).
(2) with embodiment 1.
Embodiment 4
(1) with FeCl
3Be catalyzer (this FeCl
3Consumption is 0.015mol), other experimental techniques and condition are with embodiment 1, and productive rate is 16.9%, reclaims productive rate 31%.
(2) with embodiment 1.
Embodiment 5
(1) with embodiment 2, in the experimentation, behind the reaction beginning 1h, disposable add 88% formic acid (4ml, 0.093mol), other experimental techniques and condition are with embodiment 2, productive rate is 29.1%, reclaims productive rate 41.5%.
(2) with embodiment 1.
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 (7)
1, a kind of synthetic method of rivastigmine is characterized in that comprising the steps:
(1) intermediate 3-(1-(dimethylamino) ethyl) phenol is synthetic: under normal pressure, and m-hydroxy acetophenone and N, dinethylformamide reacts, and the reaction times is 5～24 hours; Temperature of reaction is 155～170 ℃, promptly makes 3-(1-(dimethylamino) ethyl) phenol; Described m-hydroxy acetophenone and N, the mol ratio of dinethylformamide is 1: 4～1: 800;
(2) rivastigmine is synthetic: 3-(1-(dimethylamino) ethyl) phenol becomes ester condensation to become rivastigmine with first and second urea chlorides under the NaH effect, and the mol ratio of described 3-(1-(dimethylamino) ethyl) phenol and first and second urea chlorides is 1: 1.05.
2, according to the synthetic method of the described a kind of rivastigmine of claim 1, it is characterized in that: described step (1) is carried out as follows: under normal pressure, and m-hydroxy acetophenone and N, dinethylformamide reacts, and the reaction times is 5～24 hours; Temperature of reaction is 155～170 ℃, after reaction finishes, reaction solution is poured in the water, and filter concentrated hydrochloric acid adjust pH to 1～2, extracted with diethyl ether, and ether is used anhydrous magnesium sulfate drying mutually, the rotation evaporate to dryness; Water sodium bicarbonate adjust pH to 8.5, ethyl acetate extraction, the mutually anhydrous MgSO of ethyl acetate
4Drying, rotary evaporation is to doing, and vacuum-drying obtains 3-(1-(dimethylamino) ethyl) phenol.
3, according to the synthetic method of the described a kind of rivastigmine of claim 1, it is characterized in that: add catalyzer in the described step (1), described catalyzer is the lewis acid compounds.
4, according to the synthetic method of the described a kind of rivastigmine of claim 3, it is characterized in that: described lewis acid compounds is MgCl
2Or FeCl
3
5, according to the synthetic method of the described a kind of rivastigmine of claim 3, it is characterized in that: described MgCl
2Or FeCl
3Mole dosage be 15～100% of m-hydroxy acetophenone.
6, according to the synthetic method of the described a kind of rivastigmine of claim 1, it is characterized in that: add formic acid in the described step (1), the mole dosage of formic acid is 100～1000% of a m-hydroxy acetophenone.
7, according to the synthetic method of the described a kind of rivastigmine of claim 1, it is characterized in that: described N, dinethylformamide prepares as follows and gets: under condition of ice bath, in formic acid, add dimethylamine agueous solution, after adding finishes, add the thermal distillation steaming and dewater, promptly make N, dinethylformamide; Described formic acid equates with the dimethylamine agueous solution amount of substance.
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|---|---|---|---|
| CNB2006101234736A CN100457722C (en) | 2006-11-10 | 2006-11-10 | Method for synthesis of rivastigmine |
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|---|---|---|---|
| CNB2006101234736A CN100457722C (en) | 2006-11-10 | 2006-11-10 | Method for synthesis of rivastigmine |
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|---|---|
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| CN100457722C CN100457722C (en) | 2009-02-04 |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101134738B (en) * | 2007-09-29 | 2010-08-25 | 暨南大学 | Asymmetric synthesis method of (S)-rivastigmine |
| WO2010099745A1 (en) * | 2009-03-03 | 2010-09-10 | 江苏恩华药业股份有限公司 | Preparation methods of rivastigmine and its intermediate |
| CN103242191A (en) * | 2013-05-06 | 2013-08-14 | 暨南大学 | Compound for preventing and treating Alzheimer disease as well as preparation method and application thereof |
| CN104987294A (en) * | 2015-07-27 | 2015-10-21 | 浙江京新药业股份有限公司 | Method for preparing 3-[1-(dimethylamino)ethyl]phenol |
-
2006
- 2006-11-10 CN CNB2006101234736A patent/CN100457722C/en not_active Expired - Fee Related
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101134738B (en) * | 2007-09-29 | 2010-08-25 | 暨南大学 | Asymmetric synthesis method of (S)-rivastigmine |
| WO2010099745A1 (en) * | 2009-03-03 | 2010-09-10 | 江苏恩华药业股份有限公司 | Preparation methods of rivastigmine and its intermediate |
| CN103242191A (en) * | 2013-05-06 | 2013-08-14 | 暨南大学 | Compound for preventing and treating Alzheimer disease as well as preparation method and application thereof |
| CN103242191B (en) * | 2013-05-06 | 2015-05-20 | 暨南大学 | Compound for preventing and treating Alzheimer disease as well as preparation method and application thereof |
| CN104987294A (en) * | 2015-07-27 | 2015-10-21 | 浙江京新药业股份有限公司 | Method for preparing 3-[1-(dimethylamino)ethyl]phenol |
| CN104987294B (en) * | 2015-07-27 | 2017-08-15 | 浙江京新药业股份有限公司 | A kind of preparation method of 3 [1 (dimethylamino) ethyl] phenol |
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| Publication number | Publication date |
|---|---|
| CN100457722C (en) | 2009-02-04 |
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Granted publication date: 20090204 Termination date: 20111110 |