CN108689861A - A kind of preparation method of N- ethyls -3- phenylpropylamines - Google Patents
A kind of preparation method of N- ethyls -3- phenylpropylamines Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/44—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of carboxylic acids or esters thereof in presence of ammonia or amines, or by reduction of nitriles, carboxylic acid amides, imines or imino-ethers
- C07C209/52—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of carboxylic acids or esters thereof in presence of ammonia or amines, or by reduction of nitriles, carboxylic acid amides, imines or imino-ethers by reduction of imines or imino-ethers
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C249/02—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of compounds containing imino groups
Abstract
The present invention relates to a kind of preparation methods of N- ethyls -3- phenylpropylamines, belong to a kind of preparation method of compound.Under inert gas protection, 3- hydrocinnamicaldehydes are instilled in the alcoholic solution of ethylamine hydrochloride and is reacted;Up to after reaction end, into the reaction system, input metallic boron hydrides carries out reduction reaction;- 20 DEG C of temperature~15 DEG C are controlled, are slowly added to that solution is quenched into the reaction system, to terminate reaction, while hydrolyzing generated organic boride;To the target compound N- ethyl -3- phenylpropylamines generated or its corresponding salt, is detached, purified.Advantage is that of avoiding the generation of relevant tertiary amine and quaternary ammonium salt by-product;The influence of anti-response environment is reduced, there is environment-friendly advantage;Safe operation, simplicity, requirement to equipment and operating personnel is low, energy consumption is small, safe, is suitable for industrialization;High income, post-processing simplicity are preferably gone.
Description
Technical field
The invention belongs to a kind of preparation method of compound, in particular to it is a kind of cheap, mild, efficiently, be suitable for industrialization
N- ethyl -3- phenylpropylamines (Formulas I) preparation method.
Background technology
Alverine citrate (alverine citrate) is that have height by one kind that Norgine companies of Britain research and develop
The agents of calcium ion channel modulators of selectivity.It is listed for the first time in Britain within 1996, is mainly used for treating irritable bowel syndrome, intestines convulsion
The spasmic pain etc. that contraction, abdominal pain and the pain caused by diverticulosis, biliary spasm and urinary stone or infection cause.
Compound N-ethyl -3- phenylpropylamines (Formulas I) are the important intermediate (Scheme for synthesizing alverine citrate
Shown in 1, Ts=p-toluenesulfonyls, Ms=mesyls, Tf=trifyls).
Currently, the synthesis to compound N-ethyl -3- phenylpropylamines, mainly there is following three kinds of approach:
(1) by starting material 3- phenyl propanols (Formula II) in dense H2SO4With the bromo- 3- phenyl of 1- third is generated under the action of NaBr
Alkane (formula III), the bromo- 3- phenyl-propanes of 1- are reacted with ethylamine solution again, generation compound of formula I (document 1, Yang Dan, Zhang Yubin,
Wang Lanzhou, auspicious rigid, the synthesis of alverine citrate, Chinese Journal of Pharmaceuticals, 2012,43 (3):164-166;Document 2,
Zhang Yubin, auspicious rigid, Wang Lanzhou, a kind of new alverine citrate preparation method, application number:200910103386.8).
(2) it is generated through specific reducing agent (or specific reproducibility catalyst) reduction by 3- phenylpropionyls ethamine (formula IV)
Compound of formula I (document 3, William J.Horgan, Propylamine derivatives, GB 2246778A;Document 4,
Darren Willcox,Ben G.N.Chappell,Kirsten F.Hogg,Jonas Calleja,Adam P.Smalley,
Matthew J.Gaunt, A general catalytic β-C-H carbonylation of aliphatic amines to
β-lactams, Science, 2016,354 (6314):851-857;Document 5, Shiori Hanada, Toshiki Ishida,
Yukihiro Motoyama, Hideo Nagashima, The Ruthenium-Catalyzed Reduction and
Reductive N-Alkylation of Secondary Amides with Hydrosilanes:Practical
Synthesis of Secondary and Tertiary Amines by Judicious Choice of
Hydrosilanes, J.Org.Chem., 2007,72 (20):7551-7559).
(3) it using styrene as starting material, is reacted with diethylamide and metaformaldehyde, generation compound of formula I (document 6,
Theodore Cohen, Anatoli Onopchenko, Competing Hydride Transfer and Ene
Reactions in the Aminoalkylation of 1-Alkenes with N,N-Dimethylmethyl-
Eniminium Ions.A Literature Correction, J.Org.Chem., 1983,48 (24):4531-4537;Document
7, Manninen, Kalle, Karjalainen, Aira, Hydride transfer reaction products in the
Aminomethylation of styrene, Acta Chemica Scandinavica, Series B:Organic
Chemistry and Biochemistry, 1986, B40 (3):190-195).
Although the synthesis of compound of formula I it is existing excessively it is above-mentioned some report, synthesis technology be primarily present at present it is following not
Foot:
(1) severe reaction conditions, to equipment requirement height, energy consumption is big, seriously polluted, such as:Had using the concentrated sulfuric acid or acyl chlorides etc.
Corrosive reagents also need to be heated to 100 DEG C or 115 DEG C of high temperature are reacted, are unfavorable for industrialized production, are also unfavorable for energy-saving ring
It protects;(such as document 1-4 and 6).
(2) reducing catalyst used in individual method is rare metal Ru class catalyst, expensive and non-commercially available, is needed
Special, satisfied result (document 5) can just be obtained by also needing to match with reducing agent silicon hydrate costly.
(3) reducing agent used in some methods is LiAlH very sensitive to environment and easily spontaneous combustion4, reagent reaction
Acutely, it uses and operates and be difficult to control, it is higher to equipment, reaction condition and operator's level requirement, and have fire hazard (text
Offer 3 and 4).
(4) Main By product of some methods is more, complicated component, is unfavorable for the isolation and purification of succeeding target compound
(document 1,2 and 7).
(5) yield of individual method is also relatively low (being only 42%), unsatisfactory (document 6).
Invention content
The present invention provides a kind of preparation method of N- ethyls -3- phenylpropylamines, to solve the compounds process for production thereof at present
Present on above-mentioned deficiency.
The technical solution adopted by the present invention is that:Include the following steps:
(1), A is reacted:Under inert gas protection, 3- hydrocinnamicaldehydes are instilled in the alcoholic solution of ethylamine hydrochloride and is reacted;
Wherein, relative to 3- hydrocinnamicaldehydes, the dosage of ethylamine hydrochloride is its 0.5~100.0 molar equivalent;
(2), B is reacted:After reacting A up to reaction end, into the reaction system, input metallic boron hydrides is restored
Reaction;The dosage of the metallic boron hydrides, 0.25 times of the amount of no less than thrown reactant 3- hydrocinnamicaldehyde substances;
Or input restores class catalyst and reducing agent is added and carries out reduction reaction, the reduction class catalyst is:Transition
Metallic catalyst, the reducing agent are:Hydrogen or silicon hydrate;
(3), C is reacted:When reaction B reaches reaction end, -20 DEG C of temperature~15 DEG C are controlled, are delayed into the reaction system
Solution is quenched in slow be added, and to terminate reaction B, while hydrolyzing generated organic boride;
After reaction C reaches terminal, reaction is terminated, to the target compound N- ethyl -3- phenylpropylamines generated or its phase
The salt answered is detached, is purified.
The one kind of step (1) the of the present invention inert gas in nitrogen, argon gas or helium.
Alcoholic solvent used in step (1) of the present invention is selected from one or more of methanol, ethyl alcohol, isopropanol or n-butanol.
For step (1) of the present invention relative to 3- hydrocinnamicaldehydes, the dosage of ethylamine hydrochloride is its 1.0~20.0 molar equivalent.
Step (1) of the present invention:In reacting A systems, alkali is added before 3- hydrocinnamicaldehydes are added dropwise, the alkali is selected from
LiOH,NaOH,KOH,CsOH,Li2CO3,Na2CO3,K2CO3,Cs2CO3,Ca(OH)2Or Ba (OH)2One or more of;
For LiOH, NaOH, KOH, CsOH, the amount of the substance of alkali is no more than the substance of thrown reactant ethylamine hydrochloride
Amount;
For Li2CO3,Na2CO3,K2CO3,Cs2CO3,Ca(OH)2,Ba(OH)2, the amount of the substance of alkali, which is no more than, throws instead
Answer the amount of object ethylamine hydrochloride substance 0.5 times.
Step (1) of the present invention:In reacting A systems, dehydrating agent, the dehydrating agent is added before 3- hydrocinnamicaldehydes are added dropwise
For:One or more of anhydrous sodium sulfate, anhydrous magnesium sulfate, dead plaster, aluminium oxide, silica gel or molecular sieve mixture.
Step (2) input metallic boron hydrides of the present invention carries out reduction reaction, and the metallic boron hydrides is selected from NaBH4,
NaBH3CN,NaBH(OAc)3,KBH4,Zn(BH4)2Or LiBH4One or more of mixture.
Step (2) of the present invention:When the input metallic boron hydrides carries out reduction reaction, additive, the addition are put into
Agent uses:LiCl,CaCl2,MgCl2Or ZnCl2One or more of mixture.
Step (3) of the present invention:The solution that is quenched is selected from the aqueous solution of acid or the aqueous solution of the alcohol-water solution of acid, ammonium salt
Or the alcohol-water solution of ammonium salt, the aqueous solution of alkali or alcohol-water solution, water or the alcohol-water solution of alkali.
Step (3) of the present invention:Following methods are taken in separation, purifying:
Filtering, evaporated under reduced pressure solvent;
PH value is adjusted to alkalinity, pH=8~14;
With water insoluble solvent aqueous layer extracted 2~4 times, extractant is selected from ethyl acetate, n-butanol, benzene, toluene, diformazan
One or more of benzene, dichloromethane, chloroform mixed liquor;
Merge organic layer, using water and saturated salt solution successively, respectively extraction is primary, collected organic layer;
Dry, filtering, evaporated under reduced pressure solvent is to get target compound N- ethyl -3- phenylpropylamines.
The present invention mainly has following features compared with existing method:
1, it uses ethylamine hydrochloride and 3- hydrocinnamicaldehydes (Formula V) to be used as starting material for the first time, carrys out synthesising target compound N-
Ethyl -3- phenylpropylamines (Formulas I) --- from the angle convenient for quality control, this method can effectively avoid chemical combination shown in Formulas I
Crossing for object is alkylated, so as to avoid the generation of relevant tertiary amine and quaternary ammonium salt by-product;
2, reaction dissolvent is done using environmental-friendly alcohols solvent, reduces the influence of anti-response environment, have environmental protection excellent
Gesture;
3, reaction condition is mild, and using " one kettle way ", safe operation, simplicity, requirement to equipment and operating personnel is low, energy
Consume it is small, safe, be suitable for industrialization;
4, starting material used, reaction reagent and reaction dissolvent are commodity commercially available, cheap and easy to get, significantly reduce
Reaction cost;
5, target compound N- ethyl -3- phenylpropylamines (Formulas I) prepared by method provided by the present invention, high income (phase
For starting material 3- hydrocinnamicaldehydes (Formula V), the yield of target compound N- ethyl -3- phenylpropylamines (Formulas I) is up to 93%);
Post-processing simplicity is preferably gone, and is only handled through above-mentioned liquid-liquid extraction, and purity is i.e. up to 97%.
Specific implementation mode
Disclosed " one kettle way " is made of following reactions:1) with 3- hydrocinnamicaldehydes that are commercially available, cheap, being easy to get
(Formula V) and commercially available ethylamine hydrochloride that is cheap, stablizing safety are starting material, the reaction (note in cheap, environmentally friendly alcohols solvent
To react A.Such as in the reaction system, suitable alkali and/or dehydrating agent is added, then the step reaction reaction speed can faster,
Conversion ratio meeting higher);2) reduction reaction (being denoted as reaction B);3) hydrolysis (is denoted as reaction C.The product of B is such as reacted (as used
Boron hydride does reducing agent products therefrom) target compound N- ethyl -3- phenylpropylamines (Formulas I) must be discharged by hydrolyzing, then
It must carry out this step reaction).Later, by liquid-liquid extraction method, you can high yield obtains compound of formula I.
This method is suitable for prepare compound N- ethyl -3- phenylpropylamines (Formulas I).
Specifically, including the following steps:
(1), A is reacted:Under inert gas protection, 3- hydrocinnamicaldehydes (Formula V) are instilled in the alcoholic solution of ethylamine hydrochloride
Reaction;
Wherein:
The one kind of the inert gas in nitrogen, argon gas, helium;
Alcoholic solvent used is selected from one or more of methanol, ethyl alcohol, isopropanol and n-butanol mixed liquor;
Relative to 3- hydrocinnamicaldehydes (Formula V), the dosage of ethylamine hydrochloride can be its 0.5~100.0 molar equivalent, wherein
It is preferred that 1~20.0 molar equivalent, more preferable 1~10.0 molar equivalent;
The mass ratio of ethylamine hydrochloride and alcohol is 1 in ethylamine hydrochloride alcoholic solution:1~100, more preferable 1:5~50;
The molar equivalent is the ratio of two substance molal quantitys (amount of substance);
Further, suitable alkali can be added in reacting A systems, the reaction speed for reacting A can faster, conversion ratio meeting
Higher.The operation for wherein adding alkali, preferably before 3- hydrocinnamicaldehydes (Formula V) is added dropwise, then react A reaction speed can faster,
Conversion ratio meeting higher, by-product can be less;
The alkali is selected from LiOH, NaOH, KOH, CsOH, Li2CO3, Na2CO3, K2CO3, Cs2CO3, Ca (OH)2With Ba (OH)2
One or more of mixture.When the alkali is selected from LiOH, NaOH, KOH, any one or a few mixture in CsOH
When, the amount of the substance of alkali is no more than the amount of the substance of thrown reactant ethylamine hydrochloride;
When the alkali is selected from Li2CO3, Na2CO3, K2CO3, Cs2CO3, Ca (OH)2With Ba (OH)2In any one or a few
Mixture when, the amount of the substance of alkali is no more than 0.5 times of the amount of thrown reactant ethylamine hydrochloride substance;
Further, suitable dehydrating agent can be added in reacting A systems, after dehydrating agent is added, react the reaction speed of A
Degree can faster, and conversion ratio meeting higher is then reacted wherein dehydrating agent operation is added preferably before 3- hydrocinnamicaldehydes (Formula V) are added dropwise
The reaction speed of A can faster, and conversion ratio meeting higher, by-product can be less;
The dehydrating agent is in anhydrous sodium sulfate, anhydrous magnesium sulfate, dead plaster, aluminium oxide, silica gel and molecular sieve
One or more of mixtures;When the dehydrating agent is any one in anhydrous sodium sulfate, anhydrous magnesium sulfate, dead plaster
When kind or several mixtures, the amount of the substance of dehydrating agent is not less than the amount of the substance of thrown reactant ethylamine hydrochloride;Work as institute
Dehydrating agent is stated in silica gel, molecular sieve, aluminium oxide when any one or a few mixture, the dosage of dehydrating agent is not less than institute
Throw reactant ethylamine hydrochloride quality 5 times;
(2), B is reacted:Into reaction system, direct plunges into suitable metallic boron hydrides and carry out reduction reaction;Or it throws
Enter suitable reduction class catalyst, and suitable reducing agent is added and carries out reduction reaction.
The metallic boron hydrides is selected from NaBH4,NaBH3CN,NaBH(OAc)3,KBH4,Zn(BH4)2Or LiBH4In one
Kind or several mixtures;
The preferred transition-metal catalyst of the reduction class catalyst;
The preferred hydrogen of the reducing agent or silicon hydrate;
The considerations of for economic and ease-to-operate, is, it is preferable to use the metallic boron hydrides carrys out reduction reaction B.It is described
The dosage of metallic boron hydrides, 0.25 times of the amount of preferably no less than thrown reactant 3- hydrocinnamicaldehydes (Formula V) substance;
For details, reference can be made to following documents for step reaction:
Document 8, Michael B.Smith, Jerry March,"MARCH'S ADVANCED ORGANIC
CHEMISTRY,REACTIONS,MECHANISMS,AND STRUCTURE,SIXTH EDITION",A JOHN WILEY&
SONS,INC.,PUBLICATION,2007:1789~1869;
Document 9, FRANCIS A.CAREY, RICHARD J.SUNDBERG,"Advanced Organic Chemistry:
Part B:Reactions and Synthesis,FIFTH EDITION",Springer Science+Business
Media,2007:367~471;
Document 10, Katritzky, A.R., Laurenzo, K.S.:Alkylaminonitro-benzenes by
vicarious nucleophilic amination with 4-(alkylamino)-1,2,4-
Triazoles.J.Org.Chem.1988,53:3978–3982;
Document 11, A.R.Hajipour, M.Hantehzadeh, Asymmetric Reduction of Prochiral
Cyclic Imines to Alkaloid Derivatives by Novel Asymmetric Reducing Reagent in
THF or under Solid-State Conditions, J.Org.Chem.1999,64:8475~8478),
According to document 8~11, the metallic boron hydrides can be applied individually to any reaction B;
Further, it is possible to certain suitable additive use in conjunction, the additive is selected from LiCl, CaCl2,MgCl2Or
ZnCl2One or more of mixture, after use in conjunction, reduction effect is further promoted;
If using the metallic boron hydrides come reduction reaction B, need to carry out reaction C:Hydrolysis;
(3), C is reacted:When reaction B reaches reaction end, -20 DEG C of temperature~15 DEG C are controlled, are delayed into the reaction system
What slow addition was suitble to is quenched solution, to terminate reaction B, while hydrolyzing generated organic boride;
The alcohol-of the alcohol-water solution of the aqueous solution that solution is quenched selected from acid or acid, the aqueous solution of ammonium salt or ammonium salt is water-soluble
One kind in liquid, the alcohol-water solution of the aqueous solution of alkali or alkali, water or alcohol-water solution;
Can be HCl/water solution of the concentration no more than 2mol/L or alcohol solution, saturation NH4Cl aqueous solutions or alcohol are water-soluble
The alcohol solution of liquid or arbitrary proportion, it is mixed that the alcohol is selected from one or more of methanol, ethyl alcohol, isopropanol and n-butanol
Close liquid;
Reaction C reach terminal after, terminate reaction, the target compound N- ethyl -3- phenylpropylamines (Formulas I) generated or its
Corresponding salt, can according to document 12-13 (document 12, Shanghai Pharmaceutical Inst., Chinese Academy of Sciences write,"Chinese herbal medicine effective ingredients
It extracts and detaches (second edition)", Shanghai science tech publishing house, 1983;Document 13, Sun Yuqing chief editors, Wang Yancong associate editors,
"Modern chromatographic method and its application in medicine", People's Health Publisher, 1998) and it detached, purified.
It is preferred that taking following methods:Filtering, evaporated under reduced pressure solvent;PH is adjusted to alkalinity, preferably pH=8~14, with suitable
Water insoluble solvent aqueous layer extracted 2~4 times, extractant is selected from ethyl acetate, n-butanol, benzene,toluene,xylene, dichloro
One or more of methane, chloroform mixed liquor;Merge organic layer, after using water and saturated salt solution extraction successively, collects organic
Layer;Dry, filtering, evaporated under reduced pressure solvent is to get target compound N- ethyl -3- phenylpropylamines (Formulas I).
The spectroscopy data of target compound N- ethyl -3- phenylpropylamines (Formulas I) are as follows:
1H NMR (500MHz, CDCl3):δ 7.29-7.16 (5H, m), 2.67-2.62 (6H, m), 1.82 (2H, dt, J=
15.5Hz, 7.5Hz), 1.10 (3H, t, J=7.5Hz) 0.97 (1H, br.s).
13C NMR (125MHz, CDCl3):δ 142.2,128.3 (2C), 128.2 (2C), 125.7,49.4,44.1,33.7,
31.8 15.3.
EI-MS(m/z):163,148,117,91,77,65,58,51.
It is further illustrated the present invention below by specific embodiment.
Embodiment 1:
Under nitrogen protection, 20mmol ethylamine hydrochlorides are dissolved in 20mL methanol, stir 10min.In -40 DEG C, it is added dropwise
The 3- hydrocinnamicaldehydes (Formula V) of 20mmol.Reaction process is monitored with gas-chromatography.Up to after reaction end, in -40 DEG C, slowly put into
The NaBH of 5mmol4, continue to monitor reaction process with gas-chromatography.Up to after reaction end, -20 DEG C are warming up to, is slowly added to 20mL
Methanol-water (VMethanol:VWater=10:90) reaction is quenched in solution, and continues to stir, and reaction process is monitored with gas-chromatography.Eventually up to reaction
After point, reaction is terminated.
Embodiment 2:
The reaction solution of Example 1, filtering, evaporated under reduced pressure solvent adjust pH=8.Water layer is extracted with ethyl acetate 2 times,
Merge organic layer, using water and saturated salt solution successively, respectively extraction is primary, collected organic layer;It is dry, filtering, evaporated under reduced pressure solvent,
Up to target compound N- ethyl -3- phenylpropylamines (Formulas I, yield 72%, gas chromatographic detection its purity 85%).
Embodiment 3:
Under nitrogen protection, 20mmol ethylamine hydrochlorides are dissolved in 20mL methanol, after being slowly added to the LiOH of 2mmol,
Stir 10min.In -40 DEG C, the 3- hydrocinnamicaldehydes (Formula V) of 20mmol are added dropwise.Reaction process is monitored with gas-chromatography.Eventually up to reaction
After point, in -40 DEG C, the NaBH of 5mmol is slowly put into4, continue to monitor reaction process with gas-chromatography.Up to after reaction end, rise
Temperature is slowly added to 20mL methanol-waters (V to -20 DEG CMethanol:VWater=10:90) reaction is quenched in solution, and continues to stir, with gas phase color
Spectrum monitoring reaction process.Up to after reaction end, filtering, evaporated under reduced pressure solvent adjusts pH=8.Water layer is extracted with ethyl acetate 2 times,
Merge organic layer, using water and saturated salt solution successively, respectively extraction is primary, collected organic layer;It is dry, filtering, evaporated under reduced pressure solvent,
Up to target compound N- ethyl -3- phenylpropylamines (Formulas I, yield 75%, gas chromatographic detection its purity 90%)
Embodiment 4:
Under nitrogen protection, 20mmol ethylamine hydrochlorides are dissolved in 20mL methanol, are slowly added to input 20mmol dehydrations
Agent anhydrous sodium sulfate stirs 10min.In -40 DEG C, the 3- hydrocinnamicaldehydes (Formula V) of 20mmol are added dropwise.It is monitored and is reacted with gas-chromatography
Process.Up to after reaction end, in -40 DEG C, the NaBH of 5mmol is slowly put into4, continue to monitor reaction process with gas-chromatography.It reaches
After reaction end, -20 DEG C are warming up to, is slowly added to 20mL methanol-waters (VMethanol:VWater=10:90) reaction is quenched in solution, and continues
Stirring monitors reaction process with gas-chromatography.Up to after reaction end, filtering, evaporated under reduced pressure solvent adjusts pH=8.Use ethyl acetate
Aqueous layer extracted 2 times merges organic layer, and using water and saturated salt solution successively, respectively extraction is primary, collected organic layer;Dry, filtering subtracts
Press solvent evaporated to get target compound N- ethyl -3- phenylpropylamine (Formulas I, yield 76%, its purity of gas chromatographic detection
92%)
Embodiment 5:
Under nitrogen protection, 20mmol ethylamine hydrochlorides are dissolved in 20mL methanol, after being slowly added to the LiOH of 2mmol,
20mmol dehydrating agent anhydrous sodium sulfates are put into again, stir 10min.In -40 DEG C, the 3- hydrocinnamicaldehydes (Formula V) of 20mmol are added dropwise.With
Gas-chromatography monitors reaction process.Up to after reaction end, in -40 DEG C, the NaBH of 5mmol is slowly put into4, continue with gas-chromatography
Monitor reaction process.Up to after reaction end, -20 DEG C are warming up to, is slowly added to 20mL methanol-waters (VMethanol:VWater=10:90) solution
Reaction is quenched, and continues to stir, reaction process is monitored with gas-chromatography.Up to after reaction end, filtering, evaporated under reduced pressure solvent is adjusted
PH=8.Water layer is extracted with ethyl acetate 2 times, merges organic layer, primary, collected organic layer is extracted with water;It is dry, it filters, decompression
Solvent evaporated is to get target compound N- ethyl -3- phenylpropylamine (Formulas I, yield 85%, its purity of gas chromatographic detection
95%).
Embodiment 6:
Under protection of argon gas, 400mmol ethylamine hydrochlorides are dissolved in 600mL ethyl alcohol, are slowly added to 100mmol's
Na2CO3Afterwards, then 400mmol dehydrating agent dead plasters are put into, stirs 60min.In 0 DEG C, the 3- hydrocinnamicaldehydes of 2mol/L are added dropwise
(Formula V) ethanol solution 20mL.Reaction process is monitored with gas-chromatography.Up to after reaction end, in 0 DEG C, slowly put into 40mmol's
NaBH(OAc)3, continue to monitor reaction process with gas-chromatography.Up to after reaction end, in 0 DEG C, saturation NH is added4Cl aqueous solutions
Reaction is quenched in 40mL, and continues to stir, and reaction process is monitored with gas-chromatography.Up to reaction end.
Embodiment 7
The reaction solution of Example 6, filtering, evaporated under reduced pressure solvent adjust pH=12.With chloroform aqueous layer extracted 3 times, merge
Organic layer is extracted 3 times, collected organic layer with water;Dry, filtering, evaporated under reduced pressure solvent is to get target compound N- ethyls -3-
Phenylpropylamine (Formulas I, yield 86%, gas chromatographic detection its purity 96%).
Embodiment 8:
Under protection of argon gas, 200mmol ethylamine hydrochlorides are dissolved in 800mL n-butanols, are slowly added to the Ca of 100mmol
(OH)2Afterwards, then 82g dehydrating agent silica gel is put into, stirs 120min.In 15 DEG C, the 3- hydrocinnamicaldehydes (Formula V) of 0.5mol/L are being added dropwise just
Butanol solution 20mL.Reaction process is monitored with gas-chromatography.Up to after reaction end, in 15 DEG C, the LiBH of 40mmol is slowly put into4
And the LiCl of 20mmol, continue to monitor reaction process with gas-chromatography.Up to after reaction end, in 15 DEG C, it is slowly added to 0.5mol/
The HCl/water solution 50mL of L, is quenched reaction, and continue to stir, and reaction process is monitored with gas-chromatography.Up to after reaction end, mistake
Filter, evaporated under reduced pressure solvent adjust pH=14.With toluene aqueous layer extracted 4 times, merge organic layer, is extracted 2 times with water, collected organic layer;
Dry, filtering, evaporated under reduced pressure solvent is to get target compound N- ethyl -3- phenylpropylamine (Formulas I, yield 92%, gas-chromatography
Detect its purity 97%).
Embodiment 9:
Under protection of argon gas, 200mmol ethylamine hydrochlorides are dissolved in 800mL isopropanols, are slowly added to 80mmol's
K2CO3Afterwards, then 90g dehydrating agent 3A molecular sieves are put into, stirs 120min.In 15 DEG C, the 3- hydrocinnamicaldehyde (formulas of 0.5mol/L are added dropwise
V) aqueous isopropanol 20mL.Reaction process is monitored with gas-chromatography.Up to after reaction end, in 15 DEG C, slowly put into 40mmol's
LiBH4And the MgCl of 20mmol2, continue to monitor reaction process with gas-chromatography.Up to after reaction end, in 15 DEG C, it is slowly added to
The HCl/water solution 50mL of 1.0mol/L, is quenched reaction, and continue to stir, and reaction process is monitored with gas-chromatography.Up to reaction end
Afterwards, it filters, evaporated under reduced pressure solvent, adjusts pH=13.With dichloromethane aqueous layer extracted 4 times, merge organic layer, extracted 2 times with water, is received
Collect organic layer;It is dry, filtering, evaporated under reduced pressure solvent to get target compound N- ethyl -3- phenylpropylamines (Formulas I, yield 93%,
Gas chromatographic detection its purity 97%).
Claims (10)
1. a kind of preparation method of N- ethyls -3- phenylpropylamines, which is characterized in that include the following steps:
(1), A is reacted:Under inert gas protection, 3- hydrocinnamicaldehydes are instilled in the alcoholic solution of ethylamine hydrochloride and is reacted;
Wherein, relative to 3- hydrocinnamicaldehydes, the dosage of ethylamine hydrochloride is its 0.5~100.0 molar equivalent;
(2), B is reacted:After reacting A up to reaction end, into the reaction system, input metallic boron hydrides restore anti-
It answers;The dosage of the metallic boron hydrides, 0.25 times of the amount of no less than thrown reactant 3- hydrocinnamicaldehyde substances;
Or input restores class catalyst and reducing agent is added and carries out reduction reaction, the reduction class catalyst is:Transition metal
Catalyst, the reducing agent are:Hydrogen or silicon hydrate;
(3), C is reacted:When reaction B reaches reaction end, -20 DEG C of temperature~15 DEG C are controlled, are slowly added into the reaction system
Enter solution is quenched, to terminate reaction B, while hydrolyzing generated organic boride;
After reaction C reaches terminal, reaction is terminated, to the target compound N- ethyl -3- phenylpropylamines generated or it is corresponding
Salt is detached, is purified.
2. the preparation method of N- ethyls -3- phenylpropylamines according to claim 1, it is characterised in that:Step (1) is described lazy
The one kind of property gas in nitrogen, argon gas or helium.
3. the preparation method of N- ethyls -3- phenylpropylamines according to claim 1, it is characterised in that:Alcohol used in step (1)
Solvent is selected from one or more of methanol, ethyl alcohol, isopropanol or n-butanol.
4. the preparation method of N- ethyls -3- phenylpropylamines according to claim 1, it is characterised in that:Step (1) relative to
The dosage of 3- hydrocinnamicaldehydes, ethylamine hydrochloride is its 1.0~20.0 molar equivalent.
5. the preparation method of N- ethyls -3- phenylpropylamines according to claim 1, it is characterised in that:Step (1):Anti-
It answers in A systems, alkali is added before 3- hydrocinnamicaldehydes are added dropwise, the alkali is selected from LiOH, NaOH, KOH, CsOH, Li2CO3,
Na2CO3,K2CO3,Cs2CO3,Ca(OH)2Or Ba (OH)2One or more of;
For LiOH, NaOH, KOH, CsOH, the amount of the substance of alkali is no more than the amount of the substance of thrown reactant ethylamine hydrochloride;
For Li2CO3,Na2CO3,K2CO3,Cs2CO3,Ca(OH)2,Ba(OH)2, the amount of the substance of alkali is no more than thrown reactant second
0.5 times of the amount of amine hydrochlorate substance.
6. the preparation method of N- ethyls -3- phenylpropylamines according to claim 1, it is characterised in that:Step (1):Anti-
It answers in A systems, dehydrating agent is added before 3- hydrocinnamicaldehydes are added dropwise, the dehydrating agent is:Anhydrous sodium sulfate, anhydrous magnesium sulfate,
One or more of dead plaster, aluminium oxide, silica gel or molecular sieve mixture.
7. the preparation method of N- ethyls -3- phenylpropylamines according to claim 1, it is characterised in that:Step (2) input gold
Belong to boron hydride and carry out reduction reaction, the metallic boron hydrides is selected from NaBH4,NaBH3CN,NaBH(OAc)3,KBH4,Zn
(BH4)2Or LiBH4One or more of mixture.
8. the preparation method of N- ethyls -3- phenylpropylamines according to claim 1, it is characterised in that:Step (2):It is described
When putting into metallic boron hydrides progress reduction reaction, additive is put into, the additive uses:LiCl,CaCl2,MgCl2Or
ZnCl2One or more of mixture.
9. the preparation method of N- ethyls -3- phenylpropylamines according to claim 1, it is characterised in that:Step (3):It is described
Be quenched solution be selected from the aqueous solution of the acid or alcohol-water solution of acid, the aqueous solution of the ammonium salt or alcohol-water solution of ammonium salt, alkali it is water-soluble
The alcohol-water solution of liquid or alkali, water or alcohol-water solution.
10. the preparation method of N- ethyls -3- phenylpropylamines according to claim 1, it is characterised in that:Step (3):Point
From, purifying take following methods:
Filtering, evaporated under reduced pressure solvent;
PH value is adjusted to alkalinity, pH=8~14;
With water insoluble solvent aqueous layer extracted 2~4 times, extractant be selected from ethyl acetate, n-butanol, benzene,toluene,xylene,
One or more of dichloromethane, chloroform mixed liquor;
Merge organic layer, using water and saturated salt solution successively, respectively extraction is primary, collected organic layer;
Dry, filtering, evaporated under reduced pressure solvent is to get target compound N- ethyl -3- phenylpropylamines.
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