CN100404497C - A kind of method for reducing nitrile to prepare amine - Google Patents

Abstract

A method for preparing amines by reducing nitriles according to the present invention, the structural formula of the nitriles is as follows: wherein: R is a straight chain hydrocarbon group, a branched chain hydrocarbon group, a substituted hydrocarbon group, etc.; R' is a hydrocarbon group, a halogen, a hydroxyl group, an amino group, a carboxyl group wait. The invention relates to a method for efficiently reducing nitriles to corresponding primary amines by using borohydride as a reducing agent and Raney nickel as a catalyst. Can reduce 2-(1-hydroxycyclohexyl)-2-(4-methoxyphenyl) acetonitrile to 1-(2-amino-1-(4-methoxyphenyl) acetonitrile through the adjustment of system activity Base) cyclohexanol, this alcohol is the intermediate of preparation phenethylamine antidepressant venlafaxine hydrochloride. The use of borohydride as the reducing agent is economical and safe, and the reaction conditions are mild and carried out under normal pressure. No high-pressure equipment is needed, and protective gas such as _N2 is not needed. The yield of primary amine is more than 80%, the rate is fast, the operation is simple, the solvent is easy to recover and purify, the cost is low, and the pollution is small.

Description

A kind of method for reducing nitrile to prepare amine

technical field

The invention relates to a method for preparing amines by reducing nitriles.

Background technique

Amines are widely used as solvents, pesticides and pharmaceuticals, and the reduction of nitriles is a very important and commonly used method for the preparation of amines. However, the reduction of nitriles to amines will go through the imine stage, which is easy to form coupling products (secondary amines). Therefore, the selective reduction of nitriles to primary amines has become a hot spot in recent years. The method is usually to use lithium aluminum hydride or catalytic hydrogenation (see (1) Walker.ERHChem.Soc.Rev.1976,5,23-50; 2480-2483.) The reduction of nitriles by catalytic hydrogenation usually requires high temperature and high pressure. The main limitation of lithium aluminum hydride is that it decomposes and spontaneously ignites when it meets moisture, which is easy to cause fire, and the industrial production is dangerous. Factors such as the price of lithium aluminum hydride and large amount of solvent lead to its high cost of use. However, the activity of sodium borohydride is not enough _{to reduce} nitriles to amines. It is usually necessary to add some auxiliary reagents to enhance the activity of NaBH ₄ or capture the newly generated primary amines. Nitriles are primary amines (see Khurana JMKukreja G. Synthetic Communications 2002, 32(8), 1265-1269), but have no good effect on aliphatic nitriles. Stephen Caddickt et al. used acetic anhydride and (Boc) ₂ O to trap the formed primary amines so that they would not be coupled with imines (see (1) Stephen Caddick, Alexandra K.de K.Haynes, Duncan B.Judd and Meredith RVWilliams Tetrahedron Letters 2000, 41.3513-3516; (2) Stephen Caddick, Duncan B. Judd, Alexandra K.de K. Lewis, Melanie T.Reich and Meredith R.V. Williams Tetrahedron 2003, 59, 5417-5423), but to get Primary amines also require removal of these protecting groups. Raney nickel is a classic catalyst for catalytic hydrogenation, but in recent years there have also been non-hydrogen sources of hydrogen such as: Shankare Gowda etc. have obtained more than 70% yields with Raney nickel and hydrazine formic acid reduction of nitrile (see Shankare Gowda and D. Channe Gowda Tetrahedron 2002, 58, 2211-2213), however the toxicity of hydrazine and the moderate yield are drawbacks of this method.

Contents of the invention

The purpose of the present invention is to overcome the deficiencies in the prior art and provide a method for preparing primary amines by reducing nitriles with better selectivity, higher yield and lower cost using Raney nickel/borohydride system.

The structural formula of nitrile of the present invention is as follows:

Among them: R is a straight-chain hydrocarbon group, a branched chain hydrocarbon group, a substituted hydrocarbon group, etc.; R' is a hydrocarbon group, a halogen, a hydroxyl group, an amino group, a carboxyl group, etc.

The method that the reduction nitrile of the present invention is primary amine with Raney nickel/borohydride system is as follows:

(1) Add 5-80mmol borohydride (such as lithium borohydride, sodium borohydride, potassium borohydride, etc.) into a dry round bottom flask, carefully add 1-80mmol of Raney nickel, then add 0-80mL water, 80 mL of ethanol or methanol and 10 mmol of nitrile, stirred at -15 to 70°C for 45 to 120 minutes.

(2) Filter out Raney nickel, evaporate the filtrate to ethanol or methanol with a rotary evaporator, add 5-100mL of ethyl acetate or ether to dissolve the product, transfer it to a separatory funnel, wash with water 3 to 4 times, and transfer the organic phase to a circular Bottom flask, add anhydrous desiccant (Na ₂ SO ₄ or MgSO ₄ ) to dry overnight.

(3) Filter off the desiccant, evaporate ethyl acetate or ether with a rotary evaporator, and use aluminum oxide column chromatography (developing solvent is dichloromethane: methanol 20: 1) to obtain primary amine with a yield of 80%. ~92%.

The present invention has the following beneficial effects with Raney nickel/borohydride system reduction nitrile:

(1) The reducing agent borohydride is economical and safe;

(2) reaction conditions are mild and carried out under normal pressure, do not need high-pressure equipment, do not need protective gases such as _N ;

(3) The reaction primary amine yield is higher than 80%, the rate is fast, the solvent is easy to recover and purify, the cost is low, and the pollution is small.

Detailed ways

Embodiment 1: This embodiment prepares phenylethylamine, raw material is benzyl nitrile:

Add 5-80mmol KBH ₄ into the round bottom flask, put a magnetic stirring bar, add 0-80mL water, carefully add 1-80mmol Raney nickel, then add 5-80mL ethanol and 1.16mL (10mmol) phenylacetonitrile, Stir at -15 to 70°C. After 45 minutes, the Raney nickel was filtered off, and the filtrate was evaporated to remove ethanol with a rotary evaporator, and 50 mL of ethyl acetate was added to dissolve the product, transferred to a 125 mL separating funnel, washed with water for 3 to 4 times, and the organic phase was transferred to a 100 mL round bottom flask. Add anhydrous Na ₂ SO ₄ to dry overnight, filter off the desiccant, evaporate ethyl acetate with a rotary evaporator, and use aluminum oxide column chromatography (developing solvent: dichloromethane:methanol 20:1) to obtain light yellow Liquid phenethylamine, yield 92%.

Embodiment 2: This embodiment prepares p-methoxyphenethylamine, raw material is p-methoxyphenylacetonitrile

Add 5-80mmol KBH ₄ to the round bottom flask, put a magnetic stirring bar, add 0-80mL water, carefully add 1-80mmol Raney nickel, then add 5-80mL ethanol and 1.36mL (10mmol) p-methoxy Phenylacetonitrile, stirred at -15~70°C. After 45 minutes, the Raney nickel was filtered off, and the filtrate was evaporated to remove ethanol with a rotary evaporator, and 50 mL of ethyl acetate was added to dissolve the product, transferred to a 125 mL separating funnel, washed with water for 3 to 4 times, and the organic phase was transferred to a 100 mL round bottom flask. Add anhydrous _Na2SO4 to dry overnight, filter off _the desiccant, evaporate ethyl acetate with a rotary evaporator, and use aluminum oxide column chromatography (developing solvent: dichloromethane: methanol 20:1) to obtain a colorless Liquid p-methoxyphenethylamine, yield 86%.

Embodiment 3: This embodiment prepares p-chlorophenethylamine, raw material is p-chlorophenylacetonitrile

Add 5-80mmol KBH ₄ to the round bottom flask, put a magnetic stirring bar, add 0-80mL water, carefully add 1-80mmol Raney nickel, then add 5-80mL ethanol and 1.51g (10mmol) p-chlorobenzene Acetonitrile, stirred at -15～70°C. After 45 minutes, the Raney nickel was filtered off, and the filtrate was evaporated to remove ethanol with a rotary evaporator, and 50 mL of ethyl acetate was added to dissolve the product, transferred to a 125 mL separating funnel, washed with water for 3 to 4 times, and the organic phase was transferred to a 100 mL round bottom flask. Add anhydrous _Na2SO4 to dry overnight, filter off _the desiccant, evaporate ethyl acetate with a rotary evaporator, and use aluminum oxide column chromatography (developing solvent: dichloromethane: methanol 20:1) to obtain a colorless Liquid p-methoxyphenethylamine, the yield is 90%.

Embodiment 4: This embodiment prepares n-pentylamine, and the raw material is n-valeronitrile

Add 5-80mmol KBH ₄ into the round bottom flask, put a magnetic stirring bar, add 0-80mL water, carefully add 1-80mmol Raney nickel, then add 15mL methanol and 1.05mL (10mmol) n-valeronitrile, - Stir at 15-70°C. After 45 minutes, the Raney nickel was filtered off, the filtrate was carefully distilled off methanol with a rotary evaporator, and 50 mL of diethyl ether was added to dissolve the product, transferred to a 125 mL separating funnel, washed with water for 3 to 4 times, the organic phase was transferred to a 100 mL round bottom flask, and added Anhydrous Na ₂ SO ₄ was dried overnight, the desiccant was filtered off, the ether was evaporated with a rotary evaporator, and the column chromatography with aluminum oxide (developing solvent was dichloromethane:methanol 20:1) gave a light yellow liquid n-pentyl Amine, 80% yield.

Embodiment 5: This embodiment prepares p-n-dodecylamine, raw material is n-dodecyl nitrile

Add 5-80mmol KBH ₄ into the round bottom flask, put a magnetic stirring bar, add 0-80mL water, carefully add 1-80mmol Raney nickel, then add 5-80mL ethanol and 2.21mL (10mmol) n-12 Nitrile, stirred at -15～70°C. After 45 minutes, the Raney nickel was filtered off, and the filtrate was evaporated to remove ethanol with a rotary evaporator, and 50 mL of ethyl acetate was added to dissolve the product, transferred to a 125 mL separating funnel, washed with water for 3 to 4 times, and the organic phase was transferred to a 100 mL round bottom flask. Add anhydrous _Na2SO4 to dry overnight, filter off _the desiccant, evaporate ethyl acetate with a rotary evaporator, and use aluminum oxide column chromatography (developing solvent: dichloromethane: methanol 20:1) to obtain a white solid N-dodecylamine, yield 82%.

Embodiment 6: This embodiment prepares benzylamine, raw material is benzonitrile

Add 5-80mmol KBH ₄ to a round bottomed cauldron, put a magnetic stirrer, add 0-80mL water, carefully add 1-80mmol Raney nickel, then add 5-80mL ethanol and 1.02mL (10mmol) Benzene Nitrile, stirred at -15～70°C. After 45 minutes, the Raney nickel was filtered off, and the filtrate was evaporated to remove ethanol with a rotary evaporator, and 50 mL of ethyl acetate was added to dissolve the product, transferred to a 125 mL separating funnel, washed with water for 3 to 4 times, and the organic phase was transferred to a 100 mL round bottom flask. Add anhydrous Na ₂ SO ₄ to dry overnight, filter off the desiccant, evaporate ethyl acetate with a rotary evaporator, and use aluminum dioxide column chromatography (developing solvent: dichloromethane:methanol 20:1) to obtain light yellow Liquid benzylamine, yield 82%.

Embodiment 7: This embodiment prepares m-methylbenzylamine, raw material is m-benzonitrile

Add 5-80mmol KBH ₄ to the round bottom flask, put a magnetic stirring bar, add 0-80mL water, carefully add 1-80mmol Raney nickel, then add 5-80mL ethanol and 1.21mL (10mmol) m-methyl Benzonitrile, stirred at -15～70°C. After 45 minutes, the Raney nickel was filtered off, and the filtrate was evaporated to remove ethanol with a rotary evaporator, and 50 mL of ethyl acetate was added to dissolve the product, transferred to a 125 mL separating funnel, washed with water for 3 to 4 times, and the organic phase was transferred to a 100 mL round bottom flask. Add anhydrous Na ₂ SO ₄ to dry overnight, filter off the desiccant, evaporate ethyl acetate with a rotary evaporator, and use aluminum oxide column chromatography (developing solvent: dichloromethane:methanol 20:1) to obtain light yellow Liquid m-methylbenzylamine, yield 80%.

Embodiment 8: This embodiment prepares o-ethoxybenzylamine, and the raw material is o-ethoxybenzonitrile

Add 5-80mmol KBH ₄ into the round bottom flask, put a magnetic stirring bar, add 0-80mL water, carefully add 1-80mmol Raney nickel, then add 5-80mL ethanol and 1.47g (10mmol) o-ethoxy Base benzonitrile, stirring at -15~70°C. After 45 minutes, the Raney nickel was filtered off, and the filtrate was evaporated to remove ethanol with a rotary evaporator, and 50 mL of ethyl acetate was added to dissolve the product, transferred to a 125 mL separating funnel, washed with water for 3 to 4 times, and the organic phase was transferred to a 100 mL round bottom flask. Add anhydrous _Na2SO4 to dry overnight, filter off _the desiccant, evaporate ethyl acetate with a rotary evaporator, and use aluminum oxide column chromatography (developing solvent: dichloromethane: methanol 20:1) to obtain a white solid O-ethoxybenzylamine, yield 81%.

Example 9: This example prepares 1-(2-amino-1-(4-methoxyphenyl)ethyl)cyclohexanol, the raw material is 2-(1-hydroxycyclohexyl)-2-(4- Methoxyphenyl) acetonitrile

Add 5-80mmol KBH ₄ into the round bottom flask, put a magnetic stirring bar, add 0-80mL water, carefully add 1-80mmol Raney nickel, then add 5-80mL ethanol and 2.45g (10mmol) 2-( 1-Hydroxycyclohexyl)-2-(4-methoxyphenyl)acetonitrile, stirred at -15～70°C. After 3 hours, the Raney nickel was filtered off, and the filtrate was evaporated to remove ethanol with a rotary evaporator, and 50 mL of ethyl acetate was added to dissolve the product, transferred to a 125 mL separating funnel, washed with water for 3 to 4 times, and the organic phase was transferred to a 100 mL round bottom flask. Add anhydrous _Na2SO4 to dry overnight, filter off _the desiccant, evaporate ethyl acetate with a rotary evaporator, and use aluminum oxide column chromatography (developing solvent: dichloromethane: methanol 20:1) to obtain a white solid 1-(2-Amino-1-(4-methoxyphenyl)ethyl)cyclohexanol, 85% yield.

Claims (1)

1. a method for reducing nitrile to prepare amine, the structural formula of described nitrile is as follows:

Wherein: R is a straight-chain hydrocarbon group, a branched chain hydrocarbon group, a substituted hydrocarbon group: R' is a hydrocarbon group, a halogen, a hydroxyl group, an amino group, a carboxyl group, and it is characterized in that potassium borohydride is used as a reducing agent and Raney nickel is used as a catalyst to reduce nitrile to primary The amine method is as follows: (1) Add 5-80mmol potassium borohydride to a dry round bottom flask, carefully add 1-80mmol Raney nickel, then add 0-80mL water, 5-80mL ethanol or methanol and 10mmol nitrile, and stir at -15～70°C for 45 ~120 minutes; (2) Filter out Raney nickel, evaporate the filtrate to ethanol or methanol with a rotary evaporator, add 5-100mL of ethyl acetate or ether to dissolve the product, transfer it to a separatory funnel, wash with water 3 to 4 times, and transfer the organic phase to a circular Bottom flask, add anhydrous desiccant Na ₂ SO ₄ or MgSO ₄ to dry overnight; (3) The desiccant was filtered off, ethyl acetate or ether was evaporated with a rotary evaporator, and the primary amine was obtained by aluminum oxide column chromatography, and the developing solvent was dichloromethane:methanol 20:1.