CN101314574B - Process for synthesizing acylations enamine - Google Patents

Abstract

The invention relates to a synthetic method of acylated enamine, which comprises the steps as follows: mixing dicarbonyl compound and amine compound, and adding pure water (6-10mL/5mmol dicarbonyl compound) as a solvent; adding 0.005-0.015 equivalent weight of phosphotungstic acid as a catalyst to the mixture, and stirring and reacting at 5-60 DEG C for 2-12 hours, wherein the mole ratio of dicarbonyl compound to amine compound to catalyst of 1:1.1:(0.005-0.015); extracting the reaction solution with ethyl acetate after the reaction is finished; mixing the organic layers, separating and removing the water layer; sequentially washing the organic layer with a saturated sodium carbonate solution and a saturated sodium chloride solution, drying by anhydrous magnesium sulfate, filtering, removing the solvent under the reduced pressure to obtain a coarse product; and separating by the column chromatography to obtain the purified product of acylated enamine.

Description

The compound method of acylated enamine

Technical field

The present invention relates to a kind of compound method of acylated enamine, particularly a kind ofly in pure water, make dicarbonyl compound and aminated compounds condensation obtain the compound method of acylated enamine by catalysis of phosphotungstic acid.

Background technology

The method of existing preparation acylated enamine has: dicarbonyl compound and aminated compounds azeotropic dehydration (like Synthesis 1983,902) etc. in the aromaticity solvent.The defective that these class methods exist is: the use of organic solvent brings environment unfriendly (its volatility causes topsoil, and inflammableness causes potential safety hazard); Long reaction time; Productive rate is not high.

Summary of the invention

The objective of the invention is to overcome deficiency of the prior art, provide a kind of and in pure water, make dicarbonyl compound and aminated compounds condensation get the compound method of acylated enamine by catalysis of phosphotungstic acid.

In order to solve the problems of the technologies described above, the present invention realizes through following technical scheme.

A kind of compound method of acylated enamine may further comprise the steps:

(1) dicarbonyl compound is mixed with aminated compounds, add pure water, the pure water solvent of the corresponding 6～10mL of every 5mmol dicarbonyl compound as solvent; In said mixture, add 0.005～0.015 equivalent phospho-wolframic acid as catalyzer, stirring reaction is 2～12 hours under 5 ℃～60 ℃ temperature; The mol ratio of dicarbonyl compound, aminated compounds and catalyzer is 1: 1.1: 0.005～1: 1.1: 0.015;

Its reaction formula is following:

R in the reaction formula (1) ¹Be alkyl or aryl, R ²Be alkyl, aryl or alkoxyl group, R ³Be hydrogen, alkyl or halogen group, R ⁴Be alkyl or aryl;

(2) question response finishes, and with ETHYLE ACETATE above-mentioned reaction solution is extracted, and merges organic layer, and separatory is abandoned water layer; Organic layer is washed with saturated sodium carbonate solution, saturated nacl aqueous solution successively, use anhydrous magnesium sulfate drying then, filter, the decompression precipitation obtains crude product; This crude product is separated with column chromatography, obtain the pure article of acylated enamine.

As a kind of improvement, R in the raw material dicarbonyl compound in the said reaction formula (1) ¹During for aryl, said aryl is substituted-phenyl, naphthyl or benzyl; Wherein substituted-phenyl be p-methoxyphenyl, p-methylphenyl, phenyl, to fluorophenyl, adjacent fluorophenyl, rubigan, Chloro-O-Phenyl, to bromophenyl, o-bromophenyl, right-(trifluoromethyl) phenyl, right-(N; The TMSDMA N dimethylamine base) phenyl, o-methyl-phenyl-, an aminomethyl phenyl or 3; 4-3,5-dimethylphenyl, naphthyl are Alpha-Naphthyl or betanaphthyl.

As a kind of improvement, R in the raw material dicarbonyl compound in the said reaction formula (1) ²During for aryl, said aryl is substituted-phenyl, naphthyl or benzyl; Wherein substituted-phenyl be p-methoxyphenyl, p-methylphenyl, phenyl, to fluorophenyl, adjacent fluorophenyl, rubigan, Chloro-O-Phenyl, to bromophenyl, o-bromophenyl, right-(trifluoromethyl) phenyl, right-(N; The TMSDMA N dimethylamine base) phenyl, o-methyl-phenyl-, an aminomethyl phenyl or 3; 4-3,5-dimethylphenyl, naphthyl are Alpha-Naphthyl or betanaphthyl.

As a kind of improvement, substituent R in the raw material aminated compounds in the said reaction formula (1) ⁴During for aryl, said aryl is substituted-phenyl, naphthyl or benzyl; Wherein substituted-phenyl be p-methoxyphenyl, p-methylphenyl, phenyl, to fluorophenyl, adjacent fluorophenyl, rubigan, Chloro-O-Phenyl, to bromophenyl, o-bromophenyl, right-(trifluoromethyl) phenyl, right-(N; The TMSDMA N dimethylamine base) phenyl, o-methyl-phenyl-, an aminomethyl phenyl or 3; 4-3,5-dimethylphenyl, naphthyl are Alpha-Naphthyl or betanaphthyl.

The invention has the beneficial effects as follows: products made thereby of the present invention is one type of important biological material, has important effect the synthetic of medicine with in using; This compound method mild condition, productive rate is higher; Make solvent with pure water, environmental friendliness; Reaction raw materials is easy to get, and is easy and simple to handle, is applicable to prepared in laboratory and industrial-scale production.

Embodiment

Embodiment 1

Dicarbonyl compound 1a (5mmol, 500mg) (5.5mmol, 512mg) in pure water (6m1), (0.025mmol, stir and reacted 12 hours to add 0.005 equivalent phospho-wolframic acid with aminated compounds 2a by 72mg) 25 ℃ (being room temperature).Reaction finishes, and reaction solution is used ethyl acetate extraction, merges organic layer, and separatory is abandoned water layer; Organic layer washs with saturated sodium carbonate solution, saturated nacl aqueous solution successively, and anhydrous magnesium sulfate drying filters, and the decompression precipitation obtains crude product; This crude product is separated with column chromatography, obtain white solid 3a (630mg, 72%).

Attach: 3a: ¹H NMR (CDCl ₃): d 2.289 (s, 3H, CH ₃), 2.294 (s, 3H, CH ₃), 6.00 (s, 1H, CH), 7.37-7.42 (m, 4H, Ph). ¹³C NMR (CDCl ₃): d 12.62,13.70,107.57,125.99,129.34,133.04,138.74,139.60,149.56.MS (ESI) m/z 208 ([M+H] ⁺).

Embodiment 2

Dicarbonyl compound 1a (5mmol, 500mg) (5.5mmol, 512mg) in pure water (6ml), (0.05mmol, stir and reacted 12 hours to add 0.01 equivalent phospho-wolframic acid with aminated compounds 2a by 114mg) 25 ℃ (being room temperature).Reaction finishes, and reaction solution is used ethyl acetate extraction, merges organic layer, and separatory is abandoned water layer; Organic layer washs with saturated sodium carbonate solution, saturated nacl aqueous solution successively, and anhydrous magnesium sulfate drying filters, and the decompression precipitation obtains crude product; This crude product is separated with column chromatography, obtain white solid 3a (788mg, 90%).

Embodiment 3

Dicarbonyl compound 1a (5mmol, 500mg) (5.5mmol, 512mg) in pure water (6ml), (0.075mmol, stir and reacted 12 hours to add 0.015 equivalent phospho-wolframic acid with aminated compounds 2a by 216mg) 25 ℃ (being room temperature).Reaction finishes, and reaction solution is used ethyl acetate extraction, merges organic layer, and separatory is abandoned water layer; Organic layer washs with saturated sodium carbonate solution, saturated nacl aqueous solution successively, and anhydrous magnesium sulfate drying filters, and the decompression precipitation obtains crude product; This crude product is separated with column chromatography, obtain white solid 3a (788mg, 90%).

Embodiment 4

Dicarbonyl compound 1a (5mmol, 500mg) (5.5mmol, 512mg) in pure water (6ml), (0.05mmol, stir and reacted 6 hours to add 0.01 equivalent phospho-wolframic acid with aminated compounds 2a by 114mg) 25 ℃ (being room temperature).Reaction finishes, and reaction solution is used ethyl acetate extraction, merges organic layer, and separatory is abandoned water layer; Organic layer washs with saturated sodium carbonate solution, saturated nacl aqueous solution successively, and anhydrous magnesium sulfate drying filters, and the decompression precipitation obtains crude product; This crude product is separated with column chromatography, obtain white solid 3a (718mg, 82%).

Embodiment 5

Dicarbonyl compound 1a (5mmol, 500mg) (5.5mmol, 512mg) in pure water (6ml), (0.05mmol, stir and reacted 2 hours to add 0.01 equivalent phospho-wolframic acid with aminated compounds 2a by 114mg) 25 ℃ (being room temperature).Reaction finishes, and reaction solution is used ethyl acetate extraction, merges organic layer, and separatory is abandoned water layer; Organic layer washs with saturated sodium carbonate solution, saturated nacl aqueous solution successively, and anhydrous magnesium sulfate drying filters, and the decompression precipitation obtains crude product; This crude product is separated with column chromatography, obtain white solid 3a (569mg, 65%).

Embodiment 6

Dicarbonyl compound 1a (5mmol, 500mg) (5.5mmol, 512mg) in pure water (6ml), (0.025mmol, 72mg) reacted 12 hours to add 0.005 equivalent phospho-wolframic acid with aminated compounds 2a by 5 ℃ of stirrings.Reaction finishes, and reaction solution is used ethyl acetate extraction, merges organic layer, and separatory is abandoned water layer; Organic layer washs with saturated sodium carbonate solution, saturated nacl aqueous solution successively, and anhydrous magnesium sulfate drying filters, and the decompression precipitation obtains crude product; This crude product is separated with column chromatography, obtain white solid 3a (516mg, 59%).

Embodiment 7

Dicarbonyl compound 1a (5mmol, 500mg) (5.5mmol, 512mg) in pure water (6ml), (0.05mmol, 114mg) reacted 4 hours to add 0.01 equivalent phospho-wolframic acid with aminated compounds 2a by 40 ℃ of stirrings.Reaction finishes, cooling reaction liquid, and reaction solution is used ethyl acetate extraction, merges organic layer, and separatory is abandoned water layer; Organic layer washs with saturated sodium carbonate solution, saturated nacl aqueous solution successively, and anhydrous magnesium sulfate drying filters, and the decompression precipitation obtains crude product; This crude product is separated with column chromatography, obtain white solid 3a (788mg, 90%).

Embodiment 8

Dicarbonyl compound 1a (5mmol, 500mg) (5.5mmol, 512mg) in pure water (6ml), (0.05mmol, 114mg) reacted 2 hours to add 0.01 equivalent phospho-wolframic acid with aminated compounds 2a by 60 ℃ of stirrings.Reaction finishes, cooling reaction liquid, and reaction solution is used ethyl acetate extraction, merges organic layer, and separatory is abandoned water layer; Organic layer washs with saturated sodium carbonate solution, saturated nacl aqueous solution successively, and anhydrous magnesium sulfate drying filters, and the decompression precipitation obtains crude product; This crude product is separated with column chromatography, obtain white solid 3a (796mg, 91%).

Embodiment 9

Dicarbonyl compound 1b (5mmol, 650mg) (5.5mmol, 589mg) in pure water (8ml), (0.05mmol, stir and reacted 12 hours to add 0.01 equivalent phospho-wolframic acid with aminated compounds 2b by 114mg) 25 ℃ (being room temperature).Reaction finishes, and reaction solution is used ethyl acetate extraction, merges organic layer, and separatory is abandoned water layer; Organic layer washs with saturated sodium carbonate solution, saturated nacl aqueous solution successively, and anhydrous magnesium sulfate drying filters, and the decompression precipitation obtains crude product; This crude product is separated with column chromatography, obtain yellow oily liquid 3b (925mg, 89%).

Attach: 3b: ¹H NMR (CDCl ₃): d 1.25-1.28 (t, J=7.0Hz, 3H, CH ₃), 1.92 (s, 3H, CH ₃), 4.09-4.13 (q, J=7.1Hz, 2H, CH ₂), 4.43-4.44 (d, J=6.4Hz, 2H, CH ₂), 4.55 (s, 1H, CH), 7.26-7.36 (m, 5H, Ph), 8.96 (s, 1H, NH). ¹³C NMR (CDCl ₃): d 14.83,19.54,47.00,58.57,83.45,126.92,127.54,128.98,138.98,161.97,170.79.MS (ESI) m/z 220 ([M+H] ⁺).

Embodiment 10

Dicarbonyl compound 1b (5mmol, 650mg) (5.5mmol, 589mg) in pure water (10ml), (0.05mmol, stir and reacted 12 hours to add 0.01 equivalent phospho-wolframic acid with aminated compounds 2b by 114mg) 25 ℃ (being room temperature).Reaction finishes, and reaction solution is used ethyl acetate extraction, merges organic layer, and separatory is abandoned water layer; Organic layer washs with saturated sodium carbonate solution, saturated nacl aqueous solution successively, and anhydrous magnesium sulfate drying filters, and the decompression precipitation obtains crude product; This crude product is separated with column chromatography, obtain yellow oily liquid 3b (925mg, 89%).

At last, it is also to be noted that what more than enumerate only is specific embodiment of the present invention.Obviously, the invention is not restricted to above embodiment, many distortion can also be arranged.All distortion that those of ordinary skill in the art can directly derive or associate from content disclosed by the invention all should be thought protection scope of the present invention.

Claims (1)

1. the compound method of an acylated enamine may further comprise the steps:

(1) dicarbonyl compound is mixed with aminated compounds, add pure water, the pure water solvent of the corresponding 6～10mL of every 5mmol dicarbonyl compound as solvent; In said mixture, add 0.005～0.015 equivalent phospho-wolframic acid as catalyzer, stirring reaction is 2～12 hours under 5 ℃～60 ℃ temperature; The mol ratio of dicarbonyl compound, aminated compounds and catalyzer is 1: 1.1: 0.005～1: 1.1: 0.015;

Its reaction formula is following:

R in the reaction formula (1) ¹Be alkyl, R ²Be alkyl or alkoxyl group, R ³Be hydrogen, alkyl or halogen group, R ⁴Be alkyl or aryl;

R ⁴During for aryl, said aryl is substituted-phenyl, naphthyl or benzyl; Wherein substituted-phenyl be p-methoxyphenyl, p-methylphenyl, phenyl, to fluorophenyl, adjacent fluorophenyl, rubigan, Chloro-O-Phenyl, to bromophenyl, o-bromophenyl, right-(trifluoromethyl) phenyl, right-(N; The TMSDMA N dimethylamine base) phenyl, o-methyl-phenyl-, an aminomethyl phenyl or 3; 4-3,5-dimethylphenyl, naphthyl are Alpha-Naphthyl or betanaphthyl;

(2) question response finishes, and with ETHYLE ACETATE above-mentioned reaction solution is extracted, and merges organic layer, and separatory is abandoned water layer; Organic layer is washed with saturated sodium carbonate solution, saturated nacl aqueous solution successively, use anhydrous magnesium sulfate drying then, filter, the decompression precipitation obtains crude product; This crude product is separated with column chromatography, obtain the pure article of acylated enamine.