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CN101161634B - Method for preparing optical active 1-(3-methoxy phenyl) ethylamine - Google Patents

Method for preparing optical active 1-(3-methoxy phenyl) ethylamine Download PDF

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Publication number
CN101161634B
CN101161634B CN2006101169493A CN200610116949A CN101161634B CN 101161634 B CN101161634 B CN 101161634B CN 2006101169493 A CN2006101169493 A CN 2006101169493A CN 200610116949 A CN200610116949 A CN 200610116949A CN 101161634 B CN101161634 B CN 101161634B
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optically active
reaction
titanate
methoxyacetophenone
ethylamine
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CN101161634A (en
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张福利
胡猛
谢美华
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Shanghai Institute of Pharmaceutical Industry
Zhejiang Hisun Pharmaceutical Co Ltd
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Shanghai Institute of Pharmaceutical Industry
Zhejiang Hisun Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

本发明公开了中间体化合物光学活性的1-(3-甲氧基苯基)乙胺的制备方法，包括使间甲氧基苯乙酮和光学活性的苯乙胺在组合还原体系下在有机溶剂中进行不对称还原胺化反应的步骤。本发明方法的总收率达75％以上，光学纯度大于99％，制备方法易实现规模生产。The invention discloses a preparation method of optically active 1-(3-methoxyphenyl)ethylamine as an intermediate compound, comprising making m-methoxyacetophenone and optically active phenylethylamine under a combined reducing system in an organic The step of carrying out the asymmetric reductive amination reaction in a solvent. The total yield of the method of the invention reaches more than 75%, the optical purity is greater than 99%, and the preparation method is easy to realize large-scale production.

Description

The preparation method of optically active 1-(3-p-methoxy-phenyl) ethamine
Technical field
The present invention relates to the pharmaceutical chemistry field, be specifically related to treat the preparation method of the optically active 1-of bright key intermediate (3-p-methoxy-phenyl) ethamine of Alzheimer medicine-Li Fansi.
Background technology
Li Fansi bright (rivastigmine) is a kind of acetylcholinesterase depressant, and trade(brand)name Exelon is produced by U.S. Novartis.FDA is used for the treatment of alzheimer's disease in the oral liquid and the capsule listing of approval on April 21st, 2000 this product.This medicine is sold at 70 state approvals such as European Union member countries, Switzerland, New Zealand, Australia, Canada and Mexico.
Synthesizing of the optically active 1-of bright key intermediate (3-p-methoxy-phenyl) ethamine of Li Fansi, document Bull.Chem.Soc.Jpn., 66,3414-3418 report method is to split with 1-(3-p-methoxy-phenyl) ethamine of S-amygdalic acid to racemization, and synthetic route is as follows:
Figure G061B6949320061030D000011
Comparatively speaking, there is following shortcoming in this method:
The S-amygdalic acid that uses is as resolving agent, and effect is undesirable, and yield is low, only is 21.7%.
Summary of the invention
For overcoming the above-mentioned defective that prior art exists, make preparation technology more help the industrialization operation, the object of the present invention is to provide the preparation method of the optically active 1-of bright key intermediate (3-p-methoxy-phenyl) ethamine of a kind of new Li Fansi, this method comprises makes meta-methoxy methyl phenyl ketone and optically active phenylethylamine carry out the step of asymmetric reduction amination reaction under the combination reduction system in organic solvent.Carry out debenzylation reaction subsequently and obtain optically active 1-(3-p-methoxy-phenyl) ethamine, synthetic route is as follows:
Figure G061B6949320061030D000021
Described combination reduction system is tetralkyl titanate/Raney-Ni/H 2
Concrete preparation method comprises the steps:
Make meta-methoxy methyl phenyl ketone and optically active phenylethylamine and tetralkyl titanate in organic solvent, under certain pressure, carry out the asymmetric reduction amination reaction in the presence of the Raney-Ni, reaction finishes back filtering Raney-Ni catalyzer, add the neutralization of 1N aqueous sodium hydroxide solution, reclaim organic solvent behind the separatory, take off benzyl with palladium charcoal hydrogenation catalyst subsequently, filtering palladium charcoal hydrogenation catalyst again, reclaim organic solvent, collect the optically active 1-of target product (3-p-methoxy-phenyl) ethamine, yield reaches more than 75%, and optical purity is greater than 99%.
Described tetralkyl titanate comprises titanium isopropylate, tetraethyl titanate, tetrabutyl titanate, metatitanic acid orthocarbonate etc.
Described organic solvent comprises alcohols (such as methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, the trimethyl carbinol), ester class (such as ethyl acetate, butylacetate), ethers (such as ether, isopropyl ether, tetrahydrofuran (THF)), hydro carbons (such as benzene,toluene,xylene, hexanaphthene, hexane, sherwood oil), any mixture of halogenated hydrocarbon (such as methylene dichloride, chloroform) and above-mentioned solvent.
Described optically active 1-(3-p-methoxy-phenyl) ethamine comprises R and two kinds of optical isomers of S.
Described optically active phenylethylamine comprises R and two kinds of optical isomers of S.
Described palladium charcoal hydrogenation catalyst is 5%～30% palladium charcoal hydrogenation catalyst, is preferably 5% or 10% palladium charcoal hydrogenation catalyst.
The temperature of reaction of this method is 0～150 ℃, preferred 30～100 ℃; Reaction pressure is 1～30atm, preferred 3～20atm.
Meta-methoxy methyl phenyl ketone: optically active phenylethylamine: the mol ratio of tetralkyl titanate is 1: 1～2: 0.5～10, be preferably 1: 1～1.5: 1～and 5, the weight ratio of meta-methoxy methyl phenyl ketone: Raney-Ni is 1: 0.1～3, be preferably 1: 0.3～2.
Adopting method of the present invention to prepare optically active 1-(3-p-methoxy-phenyl) ethamine has the following advantages:
1. use tetralkyl titanate/Raney-Ni/H 2Combined system carries out carrying out debenzylation reaction behind the asymmetric reduction amination reaction and prepares optically active 1-(3-p-methoxy-phenyl) ethamine, and total recovery reaches more than 75%.
2.1-the optical purity of (3-p-methoxy-phenyl) ethamine is greater than 99%.
New preparation method's mild condition that the present invention adopts, aftertreatment is simple, reaction yield height, good product purity.The preparation method easily realizes scale production.
Embodiment
The present invention is further elaborated below in conjunction with embodiment, but these embodiment do not constitute any restriction to the present invention.1H-NMR AM 400 type nuclear magnetic resonance analyser records, chemical shift is represented with δ (ppm).Mass spectrum is measured with Shimadzu LCMS-2010 mass spectrograph, and specific rotation is measured with the Perkin-Elmer341 polarimeter.
Embodiment 1
With meta-methoxy methyl phenyl ketone 6g (0.04mol) and S-phenylethylamine 4.84g (0.04mol) and titanium isopropylate 11.36g (0.04mol) input hydrogenation still, add 100ml methyl alcohol and Raney-Ni1.8g, under 80 ℃ of pressure 3atm of interior temperature, react to pressure and do not descend, discharging removes by filter Raney-Ni, filtrate is reclaimed methyl alcohol after adding 1N sodium hydroxide 40ml, residuum extracts with ethyl acetate 50ml, add 50ml methyl alcohol and 10%Pd/C1.2g after reclaiming ethyl acetate, under 60 ℃ of 3atm, take off benzyl, back filtering Pd/C catalyzer reacts completely, collect target product S-1-(3-p-methoxy-phenyl) ethamine 4.53g, yield 75% after reclaiming solvent. 1HNMR(CDCl 3)δ：1.36(d，2H，)，3.80(S，3H)，4.05(q，1H，)，6.76～7.22(m，4H)；ESI(m/z)：152(M+1)； (C2，MeOH)。
Embodiment 2
With meta-methoxy methyl phenyl ketone 12g (0.08mol) and S-phenylethylamine 11.62g (0.096mol) and tetraethyl titanate 36.48g (0.16mol) input hydrogenation still, add 200m ethyl acetate and Raney-Ni7.2g, under 60 ℃ of pressure 5atm of interior temperature, react to pressure and do not descend, discharging removes by filter Raney-Ni, separatory behind the filtrate adding 1N sodium hydroxide 80ml, add 200ml ethanol and 5%Pd/C4.8g after reclaiming ethyl acetate, under 60 ℃ of 3atm, take off benzyl, back filtering Pd/C catalyzer reacts completely, collect target product S-1-(3-p-methoxy-phenyl) ethamine 9.66g, yield 80% after reclaiming solvent.
Embodiment 3
With meta-methoxy methyl phenyl ketone 6g (0.04mol) and R-phenylethylamine 6.3g (0.052mol) and tetrabutyl titanate 68g (0.2mol) input hydrogenation still, add 100ml tetrahydrofuran (THF) and Raney-Ni6g, under 70 ℃ of pressure 10atm of interior temperature, react to pressure and do not descend, discharging removes by filter Raney-Ni, filtrate is reclaimed tetrahydrofuran (THF) after adding 1N sodium hydroxide 200ml, residuum extracts with ethyl acetate 50ml, add 50ml methyl alcohol and 10%Pd/C 1.2g after reclaiming ethyl acetate, under 60 ℃ of 3atm, take off benzyl, back filtering Pd/C catalyzer reacts completely, collect target product R-1-(3-p-methoxy-phenyl) ethamine 4.59g, yield 76% after reclaiming solvent.
1HNMR(CDCl 3)δ：1.37(d，2H，)，3.80(S，3H)，4.08(q，1H，)，6.76～7.22(m，4H)；ESI(m/z)：152(M+1)； (C2，MeOH)。
Embodiment 4
With meta-methoxy methyl phenyl ketone 6g (0.04mol) and R-phenylethylamine 5.08g (0.042mol) and titanium isopropylate 34.08g (0.12mol) input hydrogenation still, add 100ml toluene and Raney-Ni12g, under 100 ℃ of pressure 15atm of interior temperature, react to pressure and do not descend, discharging removes by filter Raney-Ni, separatory behind the filtrate adding 1N sodium hydroxide 120ml, add 50ml methyl alcohol and 5%Pd/C2.4g after reclaiming toluene, under 60 ℃ of 3atm, take off benzyl, back filtering Pd/C catalyzer reacts completely, collect target product R-1-(3-p-methoxy-phenyl) ethamine 4.65g, yield 77% after reclaiming solvent.
Embodiment 5
With meta-methoxy methyl phenyl ketone 6g (0.04mol) and S-phenylethylamine 7.26g (0.06mol) and metatitanic acid orthocarbonate 45.44g (0.16mol) input hydrogenation still, add 100m methylene dichloride and Raney-Ni9g, under 30 ℃ of pressure 20atm of interior temperature, react to pressure and do not descend, discharging removes by filter Raney-Ni, separatory behind the filtrate adding 1N sodium hydroxide 160ml, add 50ml ethanol and 10%Pd/C1.2g after reclaiming methylene dichloride, under 60 ℃ of 3atm, take off benzyl, back filtering Pd/C catalyzer reacts completely, collect target product S-1-(3-p-methoxy-phenyl) ethamine 4.77g, yield 79% after reclaiming solvent.
More than show and described ultimate principle of the present invention and principal character and advantage of the present invention.The technician of the industry should understand; the present invention is not restricted to the described embodiments; that describes in the foregoing description and the specification sheets just illustrates principle of the present invention; the present invention also has various changes and modifications without departing from the spirit and scope of the present invention, and these changes and improvements all fall in the claimed scope of the invention.The claimed scope of the present invention is defined by appending claims and equivalent thereof.

Claims (13)

1.中间体化合物光学活性的1-(3-甲氧基苯基)乙胺的制备方法，其特征在于，该方法包括使间甲氧基苯乙酮和光学活性的苯乙胺在组合还原体系下在有机溶剂中于一定压力下进行不对称还原胺化反应的步骤，且不对称还原胺化反应后进行脱苄反应，得到光学活性的1-(3-甲氧基苯基)乙胺，所述脱苄反应中所用催化剂为钯炭加氢催化剂。1. The preparation method of the optically active 1-(3-methoxyphenyl) ethylamine of the intermediate compound, is characterized in that, the method comprises making m-methoxyacetophenone and optically active phenylethylamine in combined reduction The step of performing an asymmetric reductive amination reaction in an organic solvent under a certain pressure under the system, and performing a debenzylation reaction after the asymmetric reductive amination reaction to obtain optically active 1-(3-methoxyphenyl)ethylamine , the catalyst used in the debenzylation reaction is palladium carbon hydrogenation catalyst. 2.根据权利要求1所述的方法，其特征在于，所述的组合还原体系为钛酸四烷基酯/Raney-Ni/H2。2 . The method according to claim 1 , wherein the combined reducing system is tetraalkyl titanate/Raney-Ni/H 2 . 3.根据权利要求2所述的方法，其特征在于，所述的钛酸四烷基酯包括钛酸四异丙酯、钛酸四乙酯、钛酸四丁酯和钛酸四丙酯。3. The method according to claim 2, wherein the tetraalkyl titanate comprises tetraisopropyl titanate, tetraethyl titanate, tetrabutyl titanate and tetrapropyl titanate. 4.根据权利要求1所述的方法，其特征在于，脱苄反应中所用催化剂为5％～30％的钯炭加氢催化剂。4. The method according to claim 1, characterized in that the catalyst used in the debenzylation reaction is a 5% to 30% palladium carbon hydrogenation catalyst. 5.根据权利要求4所述的方法，其特征在于，所述的催化剂为5％或10％的钯炭加氢催化剂。5. method according to claim 4, is characterized in that, described catalyzer is 5% or 10% palladium carbon hydrogenation catalyst. 6.根据权利要求1所述的方法，其特征在于，所述的有机溶剂为醇类、酯类、醚类、烃类、卤代烃类或这些溶剂的任意混合物。6. The method according to claim 1, characterized in that, the organic solvent is alcohols, esters, ethers, hydrocarbons, halogenated hydrocarbons or any mixture of these solvents. 7.根据权利要求6所述的方法，其特征在于，所述的醇类为甲醇、乙醇、丙醇、异丙醇、丁醇、叔丁醇；所述的酯类为乙酸乙酯、乙酸丁酯；所述的醚类为乙醚、异丙醚、四氢呋喃；所述的烃类为苯、甲苯、二甲苯、环己烷、己烷、石油醚；所述的卤代烃类为二氯甲烷、氯仿。7. method according to claim 6 is characterized in that, described alcohols are methyl alcohol, ethanol, propanol, Virahol, butanol, tert-butanol; Described esters are ethyl acetate, acetic acid Butyl esters; the ethers are diethyl ether, isopropyl ether, tetrahydrofuran; the hydrocarbons are benzene, toluene, xylene, cyclohexane, hexane, petroleum ether; the halogenated hydrocarbons are dichloro Methane, chloroform. 8.根据权利要求1所述的方法，其特征在于，所述的光学活性的1-(3-甲氧基苯基)乙胺包括R及S两种光学异构体。8. The method according to claim 1, wherein the optically active 1-(3-methoxyphenyl)ethylamine includes two optical isomers, R and S. 9.根据权利要求1所述的方法，其特征在于，所述的光学活性的苯乙胺包括R及S两种光学异构体。9. The method according to claim 1, wherein the optically active phenethylamine includes two optical isomers of R and S. 10.根据权利要求1所述的方法，其特征在于，所述的不对称还原胺化反应的反应温度为0～150℃，反应压力为1～30atm。10. The method according to claim 1, characterized in that, the reaction temperature of the asymmetric reductive amination reaction is 0-150° C., and the reaction pressure is 1-30 atm. 11.根据权利要求10所述的方法，其特征在于，所述的不对称还原胺化反应的反应温度为30～100℃，反应压力为3～20atm。11. The method according to claim 10, characterized in that, the reaction temperature of the asymmetric reductive amination reaction is 30-100° C., and the reaction pressure is 3-20 atm. 12.根据权利要求2所述的方法，其特征在于，间甲氧基苯乙酮：光学活性的苯乙胺∶钛酸四烷基酯的摩尔比为1∶1～2∶0.5～10，间甲氧基苯乙酮∶Raney-Ni的重量比为1∶0.1～3。12. The method according to claim 2, characterized in that, m-methoxyacetophenone: optically active phenylethylamine: the molar ratio of tetraalkyl titanate is 1: 1～2: 0.5～10, The weight ratio of m-methoxyacetophenone:Raney-Ni is 1:0.1-3. 13.根据权利要求12所述的方法，其特征在于，间甲氧基苯乙酮：光学活性的苯乙胺∶钛酸四烷基酯的摩尔比为1∶1～1.5∶1～5，间甲氧基苯乙酮∶Raney-Ni的重量比为1∶0.3～2。13. The method according to claim 12, characterized in that, m-methoxyacetophenone: optically active phenylethylamine: the mol ratio of tetraalkyl titanate is 1: 1～1.5: 1～5, The weight ratio of m-methoxyacetophenone:Raney-Ni is 1:0.3-2.
CN2006101169493A 2006-10-09 2006-10-09 Method for preparing optical active 1-(3-methoxy phenyl) ethylamine Expired - Fee Related CN101161634B (en)

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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
CN114561440B (en) * 2022-04-27 2022-07-29 天津全和诚科技有限责任公司 A kind of preparation method of high-purity (R)-(+)-1-(4-methoxyphenyl)ethylamine monomer
CN114804989B (en) * 2022-05-06 2023-12-26 华中科技大学 Purification method and racemization recycling of key chiral intermediates of rivastigmine

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