CN108689861B - Preparation method of N-ethyl-3-phenylpropylamine - Google Patents
Preparation method of N-ethyl-3-phenylpropylamine Download PDFInfo
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- C07—ORGANIC CHEMISTRY
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- 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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- 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 invention relates to a preparation method of N-ethyl-3-phenylpropylamine, belonging to a preparation method of a compound. Under the protection of inert gas, 3-phenylpropionaldehyde is dropped into the alcoholic solution of ethylamine hydrochloride for reaction; after the reaction end point is reached, adding metal borohydride into the reaction system to carry out reduction reaction; controlling the temperature to be-20-15 ℃, slowly adding a quenching solution into the reaction system to terminate the reaction, and hydrolyzing the generated organic boride; the produced target compound N-ethyl-3-phenylpropylamine or a corresponding salt thereof is separated and purified. The method has the advantages that the generation of related tertiary amine and quaternary ammonium salt byproducts is avoided; the influence of the reaction on the environment is reduced, and the method has the advantage of environmental protection; the operation is safe and simple, the requirements on equipment and operators are low, the energy consumption is low, the safety is high, and the method is suitable for industrialization; high yield and simple and convenient post-treatment.
Description
Technical Field
The invention belongs to a preparation method of a compound, and particularly relates to a preparation method of N-ethyl-3-phenylpropylamine (shown in a formula I), which is cheap, mild, efficient and suitable for industrialization.
Background
Alverine citrate (alverine citrate), a highly selective calcium channel modulator developed by Norgine, uk. It was first marketed in the uk in 1996 and is mainly used for treating irritable bowel syndrome, intestinal spasm, abdominal pain and pain caused by diverticulosis, biliary spasm, and spastic pain caused by urinary tract calculus or infection.
The compound N-ethyl-3-phenylpropylamine (formula I) is an important intermediate for synthesizing the citric acid alverine (shown in Scheme 1, Ts ═ p-toluenesulfonyl, Ms ═ methanesulfonyl, Tf ═ trifluoromethanesulfonyl).
Currently, there are three main routes for the synthesis of the compound N-ethyl-3-phenylpropylamine:
(1) starting from 3-phenylpropanol (formula II) in concentrated H2SO4And NaBr to generate 1-bromo-3-phenyl propane(formula III), 1-bromo-3-phenylpropane reacts with an ethylamine aqueous solution to generate a compound of formula I (document 1, Yandan, Zhangbin, Wanglan Wen, Jiqing gang, synthesis of Alverlin citrate, China journal of pharmaceutical industry 2012,43 (3): 164-166; document 2, Zhangbin, Jiqing Wen, Wanlang Wen, a new preparation method of Alverlin citrate, application number: 200910103386.8).
(2) Reduction of 3-phenylpropionamide (formula IV) with a specific reducing agent (or a specific reducing catalyst) to produce a compound of formula I (document 3, William J. Horgan, prophalamine derivatives, GB 2246778A; document 4, Darren Willcox, Ben G.N.Chappell, Kirsten F.Hogg, Jonas Calleja, AdP.Smalley, Matam The J.Gaunt, A genetic catalytic β -C-H carbonylation of aliphatic Amines to β -olefins, Science, 2016, 354 (6314): 857; document 5, Shiori Hanada, Toshishida, Yukihihimo Motoyama, Hideo Nagashi, The chemistry-catalyst, reaction N-reaction, reaction J.7559, reaction J.75. moisture and reaction J.75. moisture, reaction J.75. moisture and reaction J.72. moisture, moisture content, amino-reaction J.75. moisture and reaction J.75. moisture, moisture and reaction J..
(3) Styrene as a starting material was reacted with diethylamine and trioxymethylene to produce a compound of formula I (document 6, Theodere Cohen, Anatoli Onophenko, comparative Hydride Transfer and Ene Reactions in the amide alkylation of 1-aldehydes with N, N-dimethyl-imide ions. A lithium recovery, J.Org.Chem., 1983,48 (24): 4531-4537; document 7, Mannien, Kalle, Karjalainen, air, Hydride Transfer reaction products in the amide alkylation of styrene, Acta chemical Series, screens B: Organic Chemistry and Biochemistry, 1986, 40 (195): 195).
Although the synthesis of the compound of formula I has been reported above, the synthesis process thereof has the following defects:
(1) the reaction conditions are harsh, the requirements on equipment are high, the energy consumption is high, and the pollution is serious, such as: concentrated sulfuric acid, acyl chloride or other corrosive reagents are used, and the reaction is carried out by heating to 100 ℃ or 115 ℃, which is not beneficial to industrial production and energy conservation and environmental protection; (see documents 1 to 4 and 6).
(2) The reduction catalysts used in the individual methods are rare metal Ru catalysts, which are expensive, non-commercially available, specially made, and combined with the more expensive reducing agent, silicon hydride, to obtain satisfactory results (document 5).
(3) Some methods use LiAlH, which is very environment sensitive and highly pyrophoric, as the reducing agent4The reagent reacts violently, is difficult to control in use and operation, has high requirements on equipment, reaction conditions and operator level, and has fire hazard (documents 3 and 4).
(4) Some methods have a large number of main byproducts and complicated components, which are not favorable for the subsequent separation and purification of the target compound (documents 1,2 and 7).
(5) The yield of the individual processes is still low (only 42%) and is unsatisfactory (reference 6).
Disclosure of Invention
The invention provides a preparation method of N-ethyl-3-phenylpropylamine, which aims to solve the defects of the existing preparation method of the compound.
The technical scheme adopted by the invention is as follows: comprises the following steps:
(1) reaction A: under the protection of inert gas, 3-phenylpropionaldehyde is dropped into the alcoholic solution of ethylamine hydrochloride for reaction;
wherein, the dosage of the ethylamine hydrochloride is 0.5-100.0 molar equivalent relative to the 3-phenylpropionaldehyde;
(2) and reaction B: after the reaction A reaches the reaction end point, adding metal borohydride into the reaction system to carry out reduction reaction; the dosage of the metal borohydride is not less than 0.25 time of the dosage of the reactant 3-phenylpropionaldehyde substance;
or adding a reduction catalyst and adding a reducing agent to carry out reduction reaction, wherein the reduction catalyst is as follows: a transition metal catalyst, the reducing agent being: hydrogen or silicon hydride;
(3) and reaction C: when the reaction B reaches the reaction end point, controlling the temperature to be-20-15 ℃, slowly adding a quenching solution into the reaction system to terminate the reaction B, and hydrolyzing the generated organic boride;
and (3) stopping the reaction after the reaction C reaches the end point, and separating and purifying the generated target compound N-ethyl-3-phenylpropylamine or the corresponding salt thereof.
The inert gas in step (1) of the present invention is selected from one of nitrogen, argon or helium.
The alcohol solvent used in the step (1) of the invention is one or more selected from methanol, ethanol, isopropanol or n-butanol.
In the step (1), the dosage of the ethylamine hydrochloride is 1.0-20.0 molar equivalent relative to the 3-phenylpropionaldehyde.
Step (1) of the present invention: adding a base selected from LiOH, NaOH, KOH, CsOH and Li into the reaction system A before dropwise adding the 3-phenylpropionaldehyde2CO3、Na2CO3、K2CO3、Cs2CO3、Ca(OH)2Or Ba (OH)2One or more of the above;
for LiOH, NaOH, KOH, CsOH, the amount of substance of base does not exceed the amount of substance of reactant ethylamine hydrochloride dosed;
for Li2CO3、Na2CO3、K2CO3、Cs2CO3、Ca(OH)2、Ba(OH)2The amount of base material does not exceed 0.5 times the amount of the reactant ethylamine hydrochloride material dosed.
Step (1) of the present invention: in a reaction A system, adding a dehydrating agent before dropwise adding 3-phenylpropionaldehyde, wherein the dehydrating agent is as follows: one or a mixture of more of anhydrous sodium sulfate, anhydrous magnesium sulfate, anhydrous calcium sulfate, alumina, silica gel or molecular sieve.
In the step (2), metal borohydride is put into the reaction kettle to perform reduction reaction, and the metal borohydride is selected from NaBH4、NaBH3CN、NaBH(OAc)3、KBH4、Zn(BH4)2Or LiBH4One or a mixture of several of them.
Step (2) of the present invention: and adding an additive when the metal borohydride is added for reduction reaction, wherein the additive adopts the following formula: LiCl, CaCl2、MgCl2Or ZnCl2One or a mixture of several of them.
Step (3) of the present invention: the quenching solution is selected from aqueous acid solution or alcohol-aqueous acid solution, aqueous ammonium salt solution or alcohol-aqueous ammonium salt solution, aqueous base solution or alcohol-aqueous base solution, water or alcohol-aqueous solution.
Step (3) of the present invention: the following method is adopted for separation and purification:
filtering, and evaporating the solvent under reduced pressure;
adjusting the pH value to be alkaline, wherein the pH value is 8-14;
extracting the water layer for 2-4 times by using a water-insoluble solvent, wherein the extraction solvent is one or a mixture of ethyl acetate, n-butyl alcohol, benzene, toluene, xylene, dichloromethane and chloroform;
combining the organic layers, sequentially extracting with water and saturated saline solution once respectively, and collecting the organic layer;
drying, filtering, and evaporating the solvent under reduced pressure to obtain the target compound N-ethyl-3-phenylpropylamine.
Compared with the existing method, the method mainly has the following characteristics:
1. ethylamine hydrochloride and 3-phenylpropionaldehyde (formula V) are used as starting raw materials for synthesizing a target compound N-ethyl-3-phenylpropylamine (formula I), from the viewpoint of quality control, the method can effectively avoid over-alkylation of the compound shown in the formula I, so that the generation of related tertiary amine and quaternary ammonium salt byproducts is avoided;
2. the environment-friendly alcohol solvent is used as the reaction solvent, so that the influence of the reaction on the environment is reduced, and the method has the advantage of environmental protection;
3. the reaction condition is mild, and the one-pot method is adopted, so that the operation is safe and simple, the requirements on equipment and operators are low, the energy consumption is low, the safety is high, and the method is suitable for industrialization;
4. the used initial raw materials, reaction reagents and reaction solvents are all commercial products which are cheap and easy to obtain, so that the reaction cost is greatly reduced;
5. the target compound N-ethyl-3-phenylpropylamine (shown in the formula I) prepared by the method has high yield (relative to the initial raw material 3-phenylpropionaldehyde (shown in the formula V), the yield of the target compound N-ethyl-3-phenylpropylamine (shown in the formula I) can reach 93%); the post-treatment is simple and feasible, and the purity can reach 97 percent only by the liquid-liquid extraction treatment.
Detailed Description
The one-pot method disclosed by the invention comprises the following reactions: 1) the 3-phenylpropionaldehyde (formula V) which is available on the market, cheap and easily obtained and ethylamine hydrochloride which is available on the market, cheap, stable and safe are taken as starting materials to react in an alcohol solvent which is cheap and environment-friendly (marked as reaction A). If a proper amount of alkali and/or dehydrating agent is added into the reaction system, the reaction speed of the step is higher, and the conversion rate is higher); 2) reduction reaction (denoted as reaction B); 3) the hydrolysis reaction (denoted as reaction C. This is done if the product of reaction B (e.g., obtained using borohydride as the reducing agent) is hydrolyzed to release the target compound N-ethyl-3-phenylpropylamine (formula I). Then, the compound of the formula I can be obtained in high yield by a liquid-liquid extraction method.
This process is suitable for the preparation of the compound N-ethyl-3-phenylpropylamine (formula I).
Specifically, the method comprises the following steps:
(1) reaction A: under the protection of inert gas, 3-phenylpropionaldehyde (formula V) is dropped into alcohol solution of ethylamine hydrochloride for reaction;
wherein:
the inert gas is selected from one of nitrogen, argon and helium;
the alcohol solvent is selected from one or more of methanol, ethanol, isopropanol and n-butanol;
the amount of the ethylamine hydrochloride may be 0.5 to 100.0 molar equivalents, preferably 1 to 20.0 molar equivalents, and more preferably 1 to 10.0 molar equivalents, relative to 3-phenylpropionaldehyde (formula V);
the mass ratio of ethylamine hydrochloride to alcohol in the ethylamine hydrochloride alcohol solution is 1: 1 to 100, preferably 1:5 to 50;
the molar equivalent is the ratio of two substance moles (substance amount);
furthermore, a suitable alkali can be added into the reaction A system, the reaction speed of the reaction A is faster, and the conversion rate is higher. Wherein the addition of base, preferably before the dropwise addition of 3-phenylpropionaldehyde (formula V), results in a faster reaction rate, higher conversion and fewer by-products in reaction A;
the alkali is selected from LiOH, NaOH, KOH, CsOH and Li2CO3，Na2CO3，K2CO3，Cs2CO3，Ca(OH)2And Ba (OH)2One or a mixture of several of them. When the alkali is selected from any one or a mixture of LiOH, NaOH, KOH and CsOH, the amount of the substance of the alkali does not exceed the amount of the substance of the reactant ethylamine hydrochloride;
when the base is selected from Li2CO3，Na2CO3，K2CO3，Cs2CO3，Ca(OH)2And Ba (OH)2In any one or a mixture of several of them, the quantity of the alkali substance is not more than 0.5 times of the quantity of the reactant ethylamine hydrochloride substance;
furthermore, a proper dehydrating agent can be added into the reaction A system, after the dehydrating agent is added, the reaction speed of the reaction A is higher, and the conversion rate is higher, wherein the dehydrating agent is added, preferably before the 3-phenylpropionaldehyde (formula V) is dropwise added, the reaction speed of the reaction A is higher, the conversion rate is higher, and fewer byproducts are generated;
the dehydrating agent is one or a mixture of more of anhydrous sodium sulfate, anhydrous magnesium sulfate, anhydrous calcium sulfate, alumina, silica gel and a molecular sieve; when the dehydrating agent is selected from one or a mixture of more of anhydrous sodium sulfate, anhydrous magnesium sulfate and anhydrous calcium sulfate, the amount of the dehydrating agent is not less than that of the reactant ethylamine hydrochloride; when the dehydrating agent is selected from any one or a mixture of more than one of silica gel, molecular sieve and alumina, the dosage of the dehydrating agent is not less than 5 times of the mass of the added reactant ethylamine hydrochloride;
(2) and reaction B: directly adding proper metal borohydride into a reaction system to carry out reduction reaction; or adding a suitable reducing catalyst and adding a suitable reducing agent to carry out the reduction reaction.
The metal borohydride is selected from NaBH4、NaBH3CN、NaBH(OAc)3、KBH4、Zn(BH4)2Or LiBH4One or a mixture of several of them;
the reduction catalyst is preferably a transition metal catalyst;
the reducing agent is preferably hydrogen or silicon hydride;
for reasons of economy and ease of operation, it is preferred to use the metal borohydride for the reduction of reaction B. The dosage of the metal borohydride is preferably not less than 0.25 times of the dosage of the 3-phenylpropionaldehyde (formula V) substance;
the reaction of this step can be found in the following documents:
document 8, Michael b. smith, Jerry March, [ March' S ADVANCED ORGANIC CHEMISTRY, REACTIONS, MECHANISMS, AND stuctrure, sigth EDITION, a JOHN wide & SONS, inc., PUBLICATION, 2007: 1789 to 1869;
literature 9, FRANCIS a. carey, RICHARD j. sundberg, Advanced Organic Chemistry: part B Reactions and Synthesis, FIFTH identification, Springer Science + Business Media, 2007: 367 to 471;
document 10, katitzky, a.r., Laurenzo, k.s.: (iii) acrylamide nitro-benzenes by Vicarobacterium nuclephiic amino acid with 4- (acrylamide) -1,2, 4-triazole.J.org.chem.1988, 53: 3978-;
document 11, a.r.hajipout, m.hantehzadeh, asymmetry Reduction of progressive Cyclic Imines to alloid reductions by Novel asymmetry Reduction Reagent in THF or undide Solid-State Conditions, j.org.chem.1999, 64: 8475 to 8478) of a heat exchanger,
according to documents 8 to 11, the metal borohydride can be applied to the reaction B alone;
further, it can be used in combination with some suitable additives selected from LiCl, CaCl2、MgCl2Or ZnCl2After combined application, the reduction effect is further improved;
if the metal borohydride is used to reduce reaction B, reaction C is performed: carrying out hydrolysis reaction;
(3) and reaction C: when the reaction B reaches the reaction end point, controlling the temperature to be-20-15 ℃, slowly adding a proper quenching solution into the reaction system to terminate the reaction B, and hydrolyzing the generated organic boride;
the quenching solution is selected from one of aqueous acid solution or alcohol-aqueous acid solution, aqueous ammonium salt solution or alcohol-aqueous ammonium salt solution, aqueous base solution or alcohol-aqueous base solution, water or alcohol-aqueous solution;
can be HCl aqueous solution or alcohol aqueous solution with the concentration of not more than 2mol/L, saturated NH4Cl aqueous solution or alcohol aqueous solution with any proportion, wherein the alcohol is one or a mixture of methanol, ethanol, isopropanol and n-butanol;
after the reaction C is terminated, the reaction is terminated, and the target compound N-ethyl-3-phenylpropylamine (formula I) or a corresponding salt thereof is separated and purified according to documents 12 to 13 (document 12, written by Shanghai pharmaceutical research institute of Chinese academy of sciences, < extract and separation of effective components from Chinese herbs > (second edition), Shanghai scientific and technical Press, 1983, < document 13 >, Sunyuan celebration, auxiliary Wangdanzong, modern chromatography and its application in medicine, Min health Press, 1998).
The following method is preferably adopted: filtering, and evaporating the solvent under reduced pressure; adjusting the pH value to be alkaline, preferably 8-14, and extracting the water layer for 2-4 times by using a proper water-insoluble solvent, wherein the extraction solvent is one or a mixture of several of ethyl acetate, n-butanol, benzene, toluene, xylene, dichloromethane and chloroform; combining the organic layers, sequentially extracting with water and saturated salt solution, and collecting the organic layer; drying, filtering, and evaporating the solvent under reduced pressure to obtain the target compound N-ethyl-3-phenylpropylamine (formula I).
The spectral data of the target compound N-ethyl-3-phenylpropylamine (formula I) are as follows:
1H NMR(500MHz，CDCl3)：δ7.29-7.16(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)：δ142.2，128.3(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。
the invention is further illustrated by the following specific examples.
Example 1:
20mmol of ethylamine hydrochloride was dissolved in 20mL of methanol under nitrogen and stirred for 10 min. 20mmol of 3-phenylpropionaldehyde (formula V) are added dropwise at-40 ℃. The progress of the reaction was monitored by gas chromatography. After the reaction end point is reached, 5mmol of NaBH is slowly added at-40 DEG C4The reaction progress was monitored continuously by gas chromatography. After the reaction is finished, the temperature is raised to-20 ℃, and 20mL of methanol-water (V) is slowly addedMethanol：VWater (W)10:90) the reaction was quenched with continued stirring and the progress of the reaction was monitored by gas chromatography. After the reaction is completed, the reaction is terminated.
Example 2:
the reaction solution of example 1 was collected, filtered, and the solvent was evaporated under reduced pressure to adjust pH 8. Extracting the water layer with ethyl acetate for 2 times, mixing the organic layers, sequentially extracting with water and saturated saline solution once respectively, and collecting the organic layer; drying, filtering, and evaporating the solvent under reduced pressure to obtain the target compound N-ethyl-3-phenylpropylamine (formula I, yield 72%, purity 85% by gas chromatography).
Example 3:
20mmol of ethylamine hydrochloride are dissolved in 20mL of methanol under nitrogen, 2mmol of LiOH are slowly added, and the mixture is stirred for 10 min. 20mmol of 3-phenylpropionaldehyde (formula V) are added dropwise at-40 ℃. The progress of the reaction was monitored by gas chromatography. After the reaction end point is reached, 5mmol of NaBH is slowly added at-40 DEG C4The reaction progress was monitored continuously by gas chromatography. After the reaction is finished, the temperature is raised to-20 ℃, and 20mL of methanol-water (V) is slowly addedMethanol：VWater (W)10:90) the reaction was quenched with continued stirring and the progress of the reaction was monitored by gas chromatography. After the reaction was completed, the mixture was filtered, the solvent was evaporated under reduced pressure, and the pH was adjusted to 8. Extracting the water layer with ethyl acetate for 2 times, mixing the organic layers, sequentially extracting with water and saturated saline solution once respectively, and collecting the organic layer; drying, filtering, and evaporating the solvent under reduced pressure to obtain the target compound N-ethyl-3-phenylpropylamine (formula I, yield 75%, purity 90% by gas chromatography)
Example 4:
under the protection of nitrogen, 20mmol of ethylamine hydrochloride is dissolved in 20mL of methanol, 20mmol of dehydrating agent anhydrous sodium sulfate is slowly added, and stirring is carried out for 10 min. 20mmol of 3-phenylpropionaldehyde (formula V) are added dropwise at-40 ℃. The progress of the reaction was monitored by gas chromatography. After the reaction end point is reached, 5mmol of NaBH is slowly added at-40 DEG C4The reaction progress was monitored continuously by gas chromatography. After the reaction is finished, the temperature is raised to-20 ℃, and 20mL of methanol-water (V) is slowly addedMethanol：VWater (W)10:90) the reaction was quenched with continued stirring and the progress of the reaction was monitored by gas chromatography. After the reaction was completed, the mixture was filtered, the solvent was evaporated under reduced pressure, and the pH was adjusted to 8. Extracting the water layer with ethyl acetate for 2 times, mixing the organic layers, sequentially extracting with water and saturated saline solution once respectively, and collecting the organic layer; drying, filtering, and evaporating the solvent under reduced pressure to obtain the target compound N-ethyl-3-phenylpropylamine (formula I, yield 76%, purity 92% by gas chromatography)
Example 5:
20mmol of ethylamine hydrochloride are dissolved in 20mL of methanol under nitrogen protection, and 2mmol of L are slowly addedAfter iOH, 20mmol of dehydrating agent anhydrous sodium sulfate is added and stirred for 10 min. 20mmol of 3-phenylpropionaldehyde (formula V) are added dropwise at-40 ℃. The progress of the reaction was monitored by gas chromatography. After the reaction end point is reached, 5mmol of NaBH is slowly added at-40 DEG C4The reaction progress was monitored continuously by gas chromatography. After the reaction is finished, the temperature is raised to-20 ℃, and 20mL of methanol-water (V) is slowly addedMethanol：VWater (W)10:90) the reaction was quenched with continued stirring and the progress of the reaction was monitored by gas chromatography. After the reaction was completed, the mixture was filtered, the solvent was evaporated under reduced pressure, and the pH was adjusted to 8. Extracting the water layer with ethyl acetate for 2 times, mixing the organic layers, extracting with water for one time, and collecting the organic layer; drying, filtering, and evaporating the solvent under reduced pressure to obtain the target compound N-ethyl-3-phenylpropylamine (formula I, yield 85%, purity 95% by gas chromatography).
Example 6:
under the protection of argon, 400mmol of ethylamine hydrochloride are dissolved in 600mL of ethanol, and 100mmol of Na is slowly added2CO3Then, 400mmol of dehydrating agent anhydrous calcium sulfate is added and stirred for 60 min. 20mL of a 2mol/L ethanol solution of 3-phenylpropionaldehyde (formula V) was added dropwise at 0 ℃. The progress of the reaction was monitored by gas chromatography. After the end of the reaction, 40mmol of NaBH (OAc) are slowly added at 0 DEG C3The reaction progress was monitored continuously by gas chromatography. After the end of the reaction, saturated NH was added at 0 deg.C4The reaction was quenched with 40mL of aqueous Cl and continued to stir, with the progress of the reaction monitored by gas chromatography. The end point of the reaction is reached.
Example 7
The reaction solution of example 6 was collected, filtered, and the solvent was evaporated under reduced pressure to adjust pH 12. Extracting the water layer with chloroform for 3 times, mixing the organic layers, extracting with water for 3 times, and collecting the organic layer; drying, filtering, and evaporating the solvent under reduced pressure to obtain the target compound N-ethyl-3-phenylpropylamine (formula I, yield 86%, purity 96% by gas chromatography).
Example 8:
200mmol of ethylamine hydrochloride are dissolved in 800mL of n-butanol under argon protection, and 100mmol of Ca (OH) are slowly added2Then, 82g of dehydrating agent silica gel was added thereto, and the mixture was stirred for 120 min. 0.5mol/L of 3-20mL of phenylpropionaldehyde (formula V) n-butanol solution. The progress of the reaction was monitored by gas chromatography. After the reaction end point is reached, 40mmol of LiBH is slowly added at 15 DEG C4And 20mmol of LiCl, and the progress of the reaction was monitored by gas chromatography. After the end of the reaction, 50mL of 0.5mol/L aqueous HCl was slowly added at 15 ℃ to quench the reaction and continue stirring to monitor the progress of the reaction by gas chromatography. After the reaction was completed, the mixture was filtered, the solvent was evaporated under reduced pressure, and the pH was adjusted to 14. Extracting the water layer with toluene for 4 times, mixing the organic layers, extracting with water for 2 times, and collecting the organic layer; drying, filtering, and evaporating the solvent under reduced pressure to obtain the target compound N-ethyl-3-phenylpropylamine (formula I, yield 92%, purity 97% by gas chromatography).
Example 9:
200mmol of ethylamine hydrochloride are dissolved in 800mL of isopropanol under argon, and 80mmol of K are slowly added2CO3Then, 90g of dehydrating agent 3A molecular sieve is added and stirred for 120 min. 20mL of a 0.5mol/L isopropanol solution of 3-phenylpropionaldehyde (formula V) was added dropwise at 15 ℃. The progress of the reaction was monitored by gas chromatography. After the reaction end point is reached, 40mmol of LiBH is slowly added at 15 DEG C4And 20mmol of MgCl2The reaction progress was monitored continuously by gas chromatography. After the end of the reaction, 50mL of 1.0mol/L aqueous HCl was slowly added at 15 ℃ to quench the reaction and continue stirring to monitor the progress of the reaction by gas chromatography. After the reaction was completed, the mixture was filtered, the solvent was evaporated under reduced pressure, and the pH was adjusted to 13. Extracting the aqueous layer with dichloromethane for 4 times, mixing the organic layers, extracting with water for 2 times, and collecting the organic layer; drying, filtering, and evaporating the solvent under reduced pressure to obtain the target compound N-ethyl-3-phenylpropylamine (shown in formula I, yield 93%, purity 97% detected by gas chromatography).
Claims (5)
1. A preparation method of N-ethyl-3-phenylpropylamine is characterized by comprising the following steps:
(1) reaction A: under the protection of one of nitrogen, argon or helium, 3-phenylpropionaldehyde is dropped into the alcoholic solution of ethylamine hydrochloride to react;
wherein, the dosage of the ethylamine hydrochloride is 0.5-20.0 molar equivalent relative to the 3-phenylpropionaldehyde;
in the reaction A system:
adding a base selected from LiOH, NaOH, KOH, CsOH, Li before dropping 3-phenylpropionaldehyde2CO3、Na2CO3、K2CO3、Cs2CO3、Ca(OH)2Or Ba (OH)2One or more of the above;
for LiOH, NaOH, KOH, CsOH, the amount of substance of base does not exceed the amount of substance of reactant ethylamine hydrochloride dosed;
for Li2CO3、Na2CO3、K2CO3、Cs2CO3、Ca(OH)2、Ba(OH)2The amount of the substance of the base is not more than 0.5 times of the amount of the substance of the reactant ethylamine hydrochloride;
or adding a dehydrating agent before dropwise adding the 3-phenylpropionaldehyde, wherein the dehydrating agent is as follows: one or a mixture of more of anhydrous sodium sulfate, anhydrous magnesium sulfate, anhydrous calcium sulfate, alumina, silica gel or molecular sieve;
(2) and reaction B: after the reaction A reaches the reaction end point, adding metal borohydride into the reaction system to carry out reduction reaction; the dosage of the metal borohydride is not less than 0.25 time of the dosage of the reactant 3-phenylpropionaldehyde substance;
(3) and reaction C: when the reaction B reaches the reaction end point, controlling the temperature to be-20-15 ℃, slowly adding a quenching solution into the reaction system to terminate the reaction B, and hydrolyzing the generated organic boride;
after the reaction C reaches the end point, terminating the reaction, and separating and purifying the generated target compound N-ethyl-3-phenylpropylamine or the corresponding salt thereof;
the quenching solution is selected from aqueous acid solution or alcohol-aqueous acid solution, aqueous ammonium salt solution or alcohol-aqueous ammonium salt solution, aqueous base solution or alcohol-aqueous base solution, water or alcohol-aqueous solution.
2. The process for the preparation of N-ethyl-3-phenylpropylamine as claimed in claim 1, wherein: the alcohol solvent used in the step (1) is one or more selected from methanol, ethanol, isopropanol or n-butanol.
3. The process for the preparation of N-ethyl-3-phenylpropylamine as claimed in claim 1, wherein: putting metal borohydride selected from NaBH to perform reduction reaction in step (2)4、NaBH3CN、NaBH(OAc)3、KBH4、Zn(BH4)2Or LiBH4One or a mixture of several of them.
4. The process for the preparation of N-ethyl-3-phenylpropylamine as claimed in claim 1, wherein: step (2): and adding an additive when the metal borohydride is added for reduction reaction, wherein the additive adopts the following formula: LiCl, CaCl2、MgCl2Or ZnCl2One or a mixture of several of them.
5. The process for the preparation of N-ethyl-3-phenylpropylamine as claimed in claim 1, wherein: and (3): the following method is adopted for separation and purification:
filtering, and evaporating the solvent under reduced pressure;
adjusting the pH value to be alkaline, wherein the pH value is 8-14;
extracting the water layer for 2-4 times by using a water-insoluble solvent, wherein the extraction solvent is one or a mixture of ethyl acetate, n-butyl alcohol, benzene, toluene, xylene, dichloromethane and chloroform;
combining the organic layers, sequentially extracting with water and saturated saline solution once respectively, and collecting the organic layer;
drying, filtering, and evaporating the solvent under reduced pressure to obtain the target compound N-ethyl-3-phenylpropylamine.
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