CN101475491A - N-substituted 1,2-diphenylethylamine compounds and synthesizing method thereof - Google Patents
N-substituted 1,2-diphenylethylamine compounds and synthesizing method thereof Download PDFInfo
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Abstract
The invention provides N-substituted 1,2-diphenylethylamine compounds and a synthesis method thereof. The synthesis method comprises: firstly, making aromatic aldehyde and hydroxylamine derivatives react in an organic solvent for 3 to 96 hours according to the mol ratio of between 1:1 and 1:5 at a temperature of between 0 and 150 DEG C under the protection of nitrogen, performing extraction and separation and obtaining nitrone; secondly, making the nitrone and an organic metal reagent react in an aprotic solvent for 0.01 to 10 hours according to the mol ratio of between 1:1 and 1:5 at a temperature of between 80 DEG C below zero and 100 DEG C under the protection of the nitrogen, performing extraction and separation and obtaining hydroxylamine; and thirdly, reducing the hydroxylamine into the target compounds under the action of a reducing agent, or reducing the hydroxylamine into the target compounds through hydrogenation under the catalysis of transition metals. The method has the advantages of easily obtained raw materials, mild reaction conditions, convenient operation, high yield and the like.
Description
Technical field
The invention belongs to chemosynthesis technical field, relate to a kind of synthetic method of phenpromethamine compounds, relate in particular to 1 of a kind of N-replacement, 2-phenpromethamine compounds and synthetic method thereof.
Background technology
1,2-phenpromethamine compounds is the important intermediate of chemical industry and medicine industry, has pharmacological action widely.N-benzyl-1-phenylethylamine is key intermediate (the 2S)-6-fluoro-4-oxo-3 of synthetic fidarestat, the important resolving agent of 4-dihydro-2H-chromene-2-formic acid.4-anisole ethamine has the psychosis activity of plan and antineoplastic action; Uteramin (having another name called tyrasamine) has the pharmacological action [meticulous and specialty chemicals, 2004,12 (12): 5-7.] of rising blood pressure, and 2, the 4-dimethoxy-phenylethylamine has spasmolysis; 3,4-dimethoxy-N-Methylphenethylamine is intermediate (the Tetrahedron Lett. of the medicines such as tetrahydropalmatine of synthesizing methyl Dopamine HCL phenol, opium poppy alkali and treatment of arthritis, 1989,869), can also be as the raw material of antihypertensive drug, slow dose of bronchial smooth muscle, gastric secretion inhibitors etc., and can cough-relieving, anti-epileptic [United States Patent (USP): US5840981,1998-11-24], also being a kind of important Organic Chemicals simultaneously, is the main raw material of synthetic receptor blocking agent of new generation.2, the 5-dimethoxy-phenylethylamine is the main raw material [J.Med.Chem., 1994,37 (13): 1929-1935] of synthetic serotonine (5-HT) compounds.2, the tyrosine that 5-dimethoxy-phenylethylamine derivative can be used as in cancer therapy activates enzyme inhibitors [Japanese Patent: JP8742923,1987-02-24].1-phenyl-2-p-methoxyphenyl ethamine and 1-phenyl-2-can prevent the mitotic division of hen embryo development medium effectively to phenelyl ethamine.Contain 1, the 2-phenpromethamine can treat impotence (world patent: WO/2001/005401), the treatment cancer (WO/2007/017652).Beta-hydroxy 1, the 2-phenpromethamine has significant analgesia role (Nature, 154,514) to inoperable tumour patient.
At present in industrial production and the experimental study main adopt 1,2-phenpromethamine compounds synthetic route roughly can be divided into three classes: the one, by the addition reaction preparation (OrganicSyntheses of Grignard reagent with corresponding imines, Coll.Vol.4, p.605 (1963); Vol.34, p.64 (1954)); The one, the imine compound method of reducing prepares (Russ.J.Org.Chem., 2005,41,807); One is that phenyl aldehyde that replaces and the method that Nitromethane 99Min. condensation generation nitrostyrolene restores prepare the phenylethylamine compounds again.
Summary of the invention
The purpose of this invention is to provide 1 of a kind of N-replacement, 2-phenpromethamine compounds;
Another object of the present invention provides 1 of a kind of N-replacement, the synthetic method of 2-phenpromethamine compounds.
(1) 1 of the N-replacement, 2-phenpromethamine compounds
1 of N-replacement of the present invention, 2-phenpromethamine compounds, its structure is as follows:
R
1Be hydrogen, hydroxyl, ethanoyl, benzoyl, tertbutyloxycarbonyl, carbobenzoxy-(Cbz), a kind of in the fluorenylmethyloxycarbonyl;
R
2Be hydrogen, alkyl, aromatic base, arylmethyl, vinyl, allyl group, alkynyl, any in the propargyl;
R
3Be hydrogen, alkyl, alkoxyl group, vinyl, allyl group, alkynyl, any in propargyl, the halogen;
R
4Be hydrogen, alkyl, alkoxyl group, vinyl, allyl group, alkynyl, any in propargyl, the halogen.
R wherein
2, R
3, R
4Alkyl be C1～C20 alkyl, as methyl, ethyl, propyl group, sec.-propyl, normal-butyl, sec-butyl, the tertiary butyl etc.
R
2The aromatic base group that to be ortho position, a position or contraposition replaced by halogen, alkoxyl group or alkyl.
(2) 1 of the N-replacement, the synthetic method of 2-phenpromethamine compounds
1 of N-replacement of the present invention, the preparation method of 2-phenpromethamine compounds comprises following processing step:
1. with aromatic aldehyde and the hydroxylamine derivative mol ratio with 1:1～1:5, under nitrogen protection, in organic solvent, 0～150 ℃ of reaction 3～96 hours down, separates and obtains nitrone extraction.
Its reaction formula is as follows:
Wherein, R
3Be hydrogen, alkyl, alkoxyl group, vinyl, allyl group, alkynyl, any in propargyl, the halogen.
R
2Be hydrogen, alkyl, aromatic base, arylmethyl, vinyl, allyl group, alkynyl, any in the propargyl.
The condensation reaction of aromatic aldehyde and hydroxylamine derivative can be carried out in protic solvents such as water, acetate, methyl alcohol, ethanol, propyl alcohol, also can be at tetrahydrofuran (THF), chloroform, methylene dichloride, trichloromethane, 1, carry out in the aprotic solvent such as 4-dioxane.
2. with nitrone and organometallic reagent mol ratio, under nitrogen protection, in aprotic solvent,, extraction, separate and obtain azanol-80～100 ℃ of reactions 0.01～10 hour down with 1:1～1:5.
Its reaction equation is as follows:
Wherein, R
2, R
3The same, R
4Be hydrogen, alkyl, alkoxyl group, vinyl, allyl group, alkynyl, any in propargyl, the halogen;
M is magnesium, lithium;
X is a halogen, i.e. halide-ionss such as chlorine, bromine, iodine.
The reaction of nitrone and organometallic reagent can be at ether, tetrahydrofuran (THF), and N, N-dimethyl formamide, methylene dichloride, hexanaphthene carries out in the aprotic solvent such as glycol dimethyl ether.The organometallic reagent that adopts is magnesium, lithium.
3. with azanol under the effect of metallic reducing agent, under nitrogen protection, in aprotic solvent, 0～100 ℃ of down reaction 3～48 hours, extract, separate target compound; Or azanol down added reductive agent transition metal-catalyzed, in aprotic solvent, 0～100 ℃ of reaction 3～48 hours down, extract, separate target compound.
Its reaction equation is as follows:
When reducing under the effect of metallic reducing agent, metallic reducing agent adopts zinc, tin grain, tin protochloride or cuprous halide; The consumption of metallic reducing agent is 1～20 times of azanol molar weight.
When adopting transition metal to reduce as catalyzer, transition metal is palladium charcoal, Raney's nickel and the metal-salt that contains palladium, nickel, cobalt, ruthenium, platinum, and its consumption is 0.1～200% of an azanol molar weight; Reductive agent can adopt hydrogen, formic acid, ammonium formiate or hydrazine, and the consumption of reductive agent is 1～200 times of azanol molar weight.
The reduction reaction of azanol can be at ether, tetrahydrofuran (THF), and N, N-dimethyl formamide, methylene dichloride, hexanaphthene carries out in the aprotic solvent such as glycol dimethyl ether.
Advantage of the present invention and beneficial effect are as follows:
1, utilize the reaction of nitrone cheap and easy to get and organic-magnesium or organolithium reagent to obtain 1 by high productivity, 2-diphenyl-ethyl azanol, again its reduction can be prepared at an easy rate 1 of N-replacement, 2-phenpromethamine compounds, compounds provides a succinct synthetic method for this reason.
2, the present invention has that raw material is easy to get, the reaction conditions gentleness, and is easy to operate, cost is low, the productive rate advantages of higher.
Embodiment
Below by specific embodiment compound of the present invention and synthetic method thereof are described further.
Synthesizing of embodiment 1:N-(1, the 2-diphenyl-ethyl) aniline
The first step: α-phenyl-N-phenyl nitrone synthetic
With N-Phenylhydroxylamine (1.09 grams; 10.0 mmole) with phenyl aldehyde (1.22 grams; 11.5 mmole) be dissolved in 20 milliliters the tetrahydrofuran (THF); under protection of nitrogen gas; be heated to about 65 ℃; reacted 6 hours, the pressure reducing and steaming solvent, column chromatography for separation gets α-phenyl-N-phenyl nitrone product 1.69 grams.Productive rate 83%.Fusing point: 110 ℃.
Its reaction formula is as follows:
Second step: N-(1, the 2-diphenyl-ethyl)-N-Phenylhydroxylamine synthetic
α-phenyl-N-phenyl the nitrone of above-mentioned preparation (2.36 gram 12mmol) is dissolved in 20 milliliters of the tetrahydrofuran (THF)s, joins in 100 milliliters the three-necked bottle, under nitrogen atmosphere, the ice-water bath cooling.Slowly add benzylmagnesium chloride solution (1.0M, 20 milliliters), reacted 30 minutes, the mixed solution that adds 10 milliliters of ether and 15 milliliters of saturated ammonium chloride compositions then in three-necked bottle carries out cancellation, tells organic phase, water 15mL extracted with diethyl ether, merge organic phase, use anhydrous magnesium sulfate drying, boil off to use column chromatography behind the solvent and obtain product N-(1, the 2-diphenyl-ethyl)-and N-Phenylhydroxylamine 2.8 grams, productive rate 82%.The stationary phase of column chromatography for separation is a silica gel, and moving phase is the mixed solution of sherwood oil or sherwood oil and ethyl acetate composition.
Its reaction formula is as follows:
Spectroscopic data:
1H?NMR(CDCl
3)δ(ppm)：3.28(brs，1H，CH
2)，3.4(brs，1H，CH
2)，4.4(brs，1H，OH)，4.78(brs，1H，CH)，4.91(brs，1H，NOH)，6.90-7.40(m，15H，ArH)。
The 3rd step: N-(1,2-two styroyls) aniline synthetic
In 100 milliliters round-bottomed flask with N-(1, the 2-diphenyl-ethyl)-N-Phenylhydroxylamine (1.16 grams, 4 mmoles) be dissolved in 20 milliliters the dichloromethane solution, the aqueous acetic acid that adds 20 milliliters of mass concentrations 80% respectively, zinc powder (2.6 grams, 40 mmoles), venus crystals (0.36 gram, 4 mmoles), the stirring at room reaction is after 4 hours, and TLC shows that raw material reacts completely; After adding 20 milliliters of methylene dichloride and 20 ml waters, organic phase is through 40 milliliters of washings, 20 milliliters of saturated sodium bicarbonate solutions are washed, water extracts 3 times with 20 milliliters of dichloromethane solutions, after the merging organic phase, and anhydrous sodium sulfate drying, column chromatography for separation behind the pressure reducing and steaming solvent, obtain product N-(1,2-two styroyls) aniline 0.86 gram, productive rate: 78%.
Its reaction formula is as follows:
Spectroscopic data:
1H?NMR(CDCl
3)δ(ppm)：2.98(dd，J＝14.0，8.4Hz，1H)，3.12(dd，J＝14.0，8.4Hz，1H)，4.09(s，1H)，4.56(t，J＝6.0Hz，1H)，6.44(d，J＝8.4Hz，2H)，6.60(t，J＝7.6Hz，1H)，7.03(t，J＝7.6Hz，2H)，7.08-7.31(m，10H)。
Synthesizing of embodiment 2:N-phenyl-1-(4-methoxyphenyl)-2-phenylethylamine
Synthesizing of the first step: α-(4-methoxyphenyl)-N-phenyl nitrone
With N-Phenylhydroxylamine (1.09 grams; 10.0 mmole) with aubepine (1.56 grams; 11.5 mmole) be dissolved in 20 milliliters the tetrahydrofuran (THF); heating is about 65 ℃ under protection of nitrogen gas; reacted 6 hours; pressure reducing and steaming solvent, column chromatography for separation get product α-(4-methoxyphenyl)-N-phenyl nitrone 2.08 grams.Fusing point: 115～116 ℃.
Its reaction formula is as follows:
Spectroscopic data:
1HNMR(CDCl
3)，δ(ppm)：3.88(s，3H)，7.00(d，J＝8.8Hz，2H)，7.40-7.52(m，3H)，7.74-7.80(m，2H)，7.86(s，1H)，8.40(dt，J＝8.8，2.8Hz，2H)。
Second step: N-(1, the 2-diphenyl-ethyl)-N-Phenylhydroxylamine synthetic
Under nitrogen atmosphere, in 100 milliliters three-necked bottle, add α-(4-the methoxyphenyl)-N-phenyl nitrone (1.40 gram 6mmol) that is dissolved in the tetrahydrofuran (THF) (20 milliliters), the ice-water bath cooling.Slowly add benzylmagnesium chloride solution (1.0M, 10 milliliters) then, reacted 30 minutes, the mixed solution that adds 10 milliliters of ether and 15 milliliters of saturated ammonium chloride compositions then in three-necked bottle carries out cancellation.Tell organic phase, water 15mL extracted with diethyl ether merges organic phase, use anhydrous magnesium sulfate drying, boils off to use column chromatography behind the solvent to obtain product 1.42 and restrain productive rate 74%.The stationary phase of column chromatography for separation is a silica gel, and moving phase is the mixed solution of sherwood oil or sherwood oil and ethyl acetate composition.
Its reaction formula is as follows:
Spectroscopic data:
1H?NMR(400MHz，CDCl
3)δ(ppm)：3.28(brs，1H，CH
2)，3.38(brs，1H，CH
2)，3.75(s，3H)，4.70(brs，1H)，4.95(brs，1H)，6.76(brs，2H)，6.92(brs，1H)，7.0-7.4(bm，11H)。
The 3rd step: N-phenyl-1-(4-methoxyphenyl)-2-phenylethylamine
In 100 milliliters round-bottomed flask with N-(1, the 2-diphenyl-ethyl)-N-Phenylhydroxylamine (1.28 grams, 4 mmoles) be dissolved in 20 milliliters the dichloromethane solution, the aqueous acetic acid that adds 20 milliliters of mass concentrations 80% respectively, zinc powder (2.6 grams, 40 mmoles), venus crystals (0.36 gram, 4 mmoles), the stirring at room reaction is after 4 hours, TLC shows that raw material reacts completely, after adding 20 milliliters of methylene dichloride and 20 ml waters, organic phase is through 40 milliliters of washings, and 20 milliliters of saturated sodium bicarbonate solutions are washed, water extracts 3 times with 20 milliliters of dichloromethane solutions, after merging organic phase, anhydrous sodium sulfate drying, column chromatography for separation behind the pressure reducing and steaming solvent, obtain product N-phenyl-1-(4-methoxyphenyl)-2-phenylethylamine 1.04 grams, productive rate: 86%.
Its reaction formula is as follows:
Spectroscopic data:
1HNMR(CDCl
3)，δ(ppm)：2.98(dd，J＝14.0，5.6Hz，1H)，3.10(dd，J＝14.0，5.6Hz，1H)，3.78(s，3H)，4.09(brs，1H，NH)，4.54(t，J＝7.2Hz，1H)，6.45(dt，J＝8.4，0.8Hz，2H)，6.20(td，J＝7.6，0.8Hz，1H)，6.83(d，J＝8.4Hz，2H)，7.05(t，J＝7.2Hz，2H)，7.11(d，J＝7.2Hz，2H)，7.19-7.31(m，5H)。
Synthesizing of embodiment 3:N-(1-(2-chloro-phenyl-)-2-phenylethyl) aniline
Synthesizing of the first step: α-(2-chloro-phenyl-)-N-phenyl nitrone
With N-Phenylhydroxylamine (1.09 grams; 10.0 mmole) with o-chlorobenzaldehyde (1.54 grams; 11 mmoles) be dissolved in 20 milliliters the tetrahydrofuran (THF); heating (65 ℃) refluxed 6 hours under protection of nitrogen gas; pressure reducing and steaming solvent, column chromatography for separation get α-(2-chloro-phenyl-)-N-phenyl nitrone product 1.83 grams.
Its reaction formula is as follows:
Spectroscopic data:
1HNMR(CDCl
3)，δ(ppm)：7.35-7.58(m，6H)，7.70-7.82(m，2H)，8.43(s，1H)，9.53(dd，J＝7.6，2.0Hz，1H)。
Second step: N-[1-(2-chloro-phenyl-)-2-phenylethyl)-N-Phenylhydroxylamine synthetic
Under nitrogen atmosphere, in 100 milliliters three-necked bottle, add α-(2-the chloro-phenyl-)-N-phenyl nitrone (1.38 gram 6mmol) that is dissolved in the tetrahydrofuran (THF) (20 milliliters), the ice-water bath cooling.Slowly add benzylmagnesium chloride solution (1M, 15 milliliters), reacted 30 minutes, the mixed solution that adds 10 milliliters of ether and 15 milliliters of saturated ammonium chloride compositions then in reaction flask carries out cancellation, tell organic phase, water 15mL extracted with diethyl ether merges organic phase, use anhydrous magnesium sulfate drying, use column chromatography product after boiling off solvent.Stationary phase is a silica gel, and moving phase is that the mixed solution of sherwood oil or sherwood oil and ethyl acetate composition obtains product N-[1-(2-chloro-phenyl-)-2-phenylethyl)-N-Phenylhydroxylamine 1.63 grams, productive rate 84%.
Its reaction formula is as follows:
Spectroscopic data:
1HNMR(CDCl
3)，δ(ppm)：3.30(brs，2H)，5.16(brs，1H)，5.49(brs，1H)，6.70-7.00(brm，2H)，7.00-7.40(brm，11H)，7.78(brs，1H)。
The 3rd step: N-(1-(2-chloro-phenyl-)-2-phenylethyl) aniline synthetic
(1.49 restrain with N-(1-(2-chloro-phenyl-)-2-phenylethyl) N-Phenylhydroxylamine in 100 milliliters round-bottomed flask, 4.6 mmole) be dissolved in 20 milliliters the dichloromethane solution, the aqueous acetic acid that adds 20 milliliters of mass concentrations 80% respectively, zinc powder (2.6 grams, 40 mmoles), venus crystals (0.36 gram, 4 mmoles), after the stirring at room reaction 4 hours, TLC shows that raw material reacts completely, add 20 milliliters of methylene dichloride and 20 ml waters after, organic phase is through 40 milliliters of washings, 20 milliliters of saturated sodium bicarbonate solutions are washed, and water extracts 3 times with 20 milliliters of dichloromethane solutions, after the merging organic phase, anhydrous sodium sulfate drying, column chromatography for separation behind the pressure reducing and steaming solvent obtains product N-[1-(2-chloro-phenyl-)-2-phenylethyl) aniline 1.13 grams, productive rate: 81%.
Its reaction formula is as follows:
Spectroscopic data:
1HNMR(CDCl
3)，δ(ppm)：2.82(dd，J＝14.4，9.2Hz，1H)，3.31(dd，J＝14.4，3.6Hz，1H)，4.46(s，1H)，5.07(dd，J＝9.2，4.0Hz，1H)，6.40(d，J＝8.8Hz，4H)，6.64(td，J＝7.2，1.2Hz，1H)，7.06(t，J＝7.4Hz，2H)，7.20(tt，J＝4.7，1.0Hz，2H)，7.22-7.29(m，3H)，7.39-7.40(m，3H)，7.40-7.46(m，1H)。
Embodiment 4:N-[1-(4-chloro-phenyl-)-4-phenylethyl) aniline is synthetic
Synthesizing of the first step: α-(4-chloro-phenyl-)-N-phenyl nitrone
With N-Phenylhydroxylamine (1.09 grams; 10.0 mmole) with 4-chloro-benzaldehyde (1.54 grams; 11 mmoles) be dissolved in 20 milliliters the tetrahydrofuran (THF); heating (65 ℃) refluxed 6 hours under protection of nitrogen gas; pressure reducing and steaming solvent, column chromatography for separation get α-(4-chloro-phenyl-)-N-phenyl nitrone product 2.03 grams.Fusing point: 152-153 ℃.
Its reaction formula is as follows:
Spectroscopic data:
1HNMR(CDCl
3)，δ(ppm)：7.44-7.50(m，5H)，7.74-7.78(m，2H)，7.91(s，1H)，8.36(dt，J＝8.4，2.4Hz，2H)。
Second step: N-(1-(4-chloro-phenyl-)-2-phenylethyl) N-Phenylhydroxylamine synthetic
Under nitrogen atmosphere, (1.38 grams, 6mmol), ice-water bath cools off to add α-(4-the chloro-phenyl-)-N-phenyl nitrone that is dissolved in the tetrahydrofuran (THF) (20 milliliters) in 100 milliliters three-necked bottle.Slowly add benzylmagnesium chloride solution (1M, 15 milliliters), reacted 30 minutes, the mixed solution that adds 10 milliliters of ether and 15 milliliters of saturated ammonium chloride compositions then in reaction flask carries out cancellation, tells organic phase, water 15mL extracted with diethyl ether, merge organic phase, use anhydrous magnesium sulfate drying, boil off and use column chromatography product behind the solvent and obtain product N-(1-(4-chloro-phenyl-)-2-phenylethyl) N-Phenylhydroxylamine 1.69 grams, productive rate 87%.The stationary phase of column chromatography for separation is a silica gel, and moving phase is the mixed solution of sherwood oil or sherwood oil and ethyl acetate composition.
Its reaction formula is as follows:
Spectroscopic data:
1HNMR(CDCl
3)，δ(ppm)：3.20(brs，1H)，3.33brs，1H)，4.64(brs，1H)，5.38(brs，1H)，6.9-7.4(brm，14H)。
The 3rd step: the synthetic of N-(1-(4-chloro-phenyl-)-2 phenylethyls) aniline is synthetic
(1.60 restrain with N-(1-(4-chloro-phenyl-)-2-phenylethyl) N-Phenylhydroxylamine in 100 milliliters round-bottomed flask, 5.2 mmole) be dissolved in 20 milliliters the dichloromethane solution, the aqueous acetic acid that adds 20 milliliters of mass concentrations 80% respectively, zinc powder (3.3 grams, 50 mmoles), venus crystals (0.45 gram, 5 mmoles), after the stirring at room reaction 4 hours, TLC shows that raw material reacts completely, add 20 milliliters of methylene dichloride and 20 ml waters after, organic phase is through 40 milliliters of washings, 20 milliliters of saturated sodium bicarbonate solutions are washed, and water extracts 3 times with 20 milliliters of dichloromethane solutions, after the merging organic phase, anhydrous sodium sulfate drying, column chromatography for separation behind the pressure reducing and steaming solvent obtains product N-(1-(4-chloro-phenyl-)-2 phenylethyls) aniline 1.39 grams, productive rate: 83%.
Its reaction formula is as follows:
Spectroscopic data:
1HNMR(CDCl
3)，δ(ppm)：2.99(dd，J＝13.6，8.0Hz，1H)，3.07(dd，J＝13.6，6.0Hz，1H)，4.11(s，1H)，4.55(t，J＝7.6Hz，1H)，6.42(d，J＝8.8Hz，2H)，6.64(td，J＝7.2，1.2Hz，1H)，7.02-7.10(m，4H)，7.20-7.32(m，7H)。
Embodiment 5:N-[1-(3,4, the 5-trimethoxyphenyl)-2-phenylethyl] aniline synthetic
Synthesizing of the first step: α-(3,4, the 5-trimethoxyphenyl)-N-phenyl nitrone
With N-phenyl-C-azanol (1.09 grams; 10.0 mmole) with 3; 4; 5-TMB (2.16 gram, 11 mmoles) is dissolved in 20 milliliters the tetrahydrofuran (THF), and heating (65 ℃) refluxed 6 hours under protection of nitrogen gas; the pressure reducing and steaming solvent; column chromatography for separation gets α-(3,4, the 5-trimethoxyphenyl)-N-phenyl nitrone product 2.42 grams.
Its reaction formula is as follows:
Spectroscopic data:
1HNMR(CDCl
3)，δ(ppm)：3.94(s，3H)，3.94(s，6H)，7.46-7.52(m，3H)，7.77(d，J＝1.6Hz，1H)，7.79(brs，3H)，7.88(s，1H)。
Second step: N-(1-(3,4, the 5-trimethoxyphenyl)-2-phenylethyl) N-Phenylhydroxylamine synthetic
Under nitrogen atmosphere, in 100 milliliters three-necked bottle, add α-(3,4, the 5-the trimethoxyphenyl)-N-phenyl nitrone (1.72 gram 6.0mmol) that is dissolved in the tetrahydrofuran (THF) (20 milliliters), the ice-water bath cooling.Slowly add benzylmagnesium chloride solution (1M, 15 milliliters), reacted 30 minutes, the mixed solution that adds 10 milliliters of ether and 15 milliliters of saturated ammonium chloride compositions then in reaction flask carries out cancellation, tell organic phase, water 15mL extracted with diethyl ether merges organic phase, uses anhydrous magnesium sulfate drying, boil off to use column chromatography behind the solvent and obtain N-(1-(3,4, the 5-trimethoxyphenyl)-the 2-phenylethyl) N-Phenylhydroxylamine product 1.19 grams, productive rate 84%.The stationary phase of column chromatography for separation is a silica gel, and moving phase is the mixed solution of sherwood oil or sherwood oil and ethyl acetate composition.
Its reaction formula is as follows:
Spectroscopic data:
1HNMR(CDCl
3)，δ(ppm)：3.35(brs，1H)，3.45(brs，1H)，3.73(s，6H)，3.83(s，3H)，4.70(brs，1H)，4.93(brs，1H)，6.45(brs，2H)，6.94-7.53(m，10H)。
The 3rd step: the synthetic of N-(1-(3,4, the 5-trimethoxyphenyl)-2 phenylethyls) aniline is synthetic
(1-(3 with N-in 100 milliliters round-bottomed flask, 4, the 5-trimethoxyphenyl)-and the 2-phenylethyl) N-Phenylhydroxylamine (1.36 grams, 3.6 mmole) be dissolved in 20 milliliters the dichloromethane solution, add the aqueous acetic acid of 20 milliliters of mass concentrations 80% respectively, zinc powder (2.38 grams, 36 mmoles), venus crystals (0.27 gram, 3 mmoles), the stirring at room reaction is after 4 hours, TLC shows that raw material reacts completely, after adding 20 milliliters of methylene dichloride and 20 ml waters, organic phase is through 40 milliliters of washings, and 20 milliliters of saturated sodium bicarbonate solutions are washed, water extracts 3 times with 20 milliliters of dichloromethane solutions, after merging organic phase, anhydrous sodium sulfate drying, column chromatography for separation behind the pressure reducing and steaming solvent, (1-(3 to obtain product N-, 4, the 5-trimethoxyphenyl)-2 phenylethyls) aniline 1.0 grams, productive rate: 76%.
Its reaction formula is as follows:
Spectroscopic data:
1HNMR(CDCl
3)，δ(ppm)：3.03(dd，J＝14.0，8.0Hz，1H)，3.11(dd，J＝14.0，6.0Hz，1H)，3.74-3.80(m，1H)，3.78(s，6H)，3.84(s，3H)，3.94(d，J＝7.6Hz，1H)，6.45-6.55(m，3H)，6.67(t，J＝7.2Hz，1H)，7.05-7.20(m，3H)，7.20-7.35(m，3H)，7.35-7.43(m，2H)。
Claims (10)
1,1 of the N-replacement, 2-phenpromethamine compounds, its structure is shown below:
R
1Be hydrogen, hydroxyl, ethanoyl, benzoyl, tertbutyloxycarbonyl, carbobenzoxy-(Cbz), a kind of in the fluorenylmethyloxycarbonyl;
R
2Be hydrogen, alkyl, aromatic base, arylmethyl, vinyl, allyl group, alkynyl, any in the propargyl;
R
3Be hydrogen, alkyl, alkoxyl group, vinyl, allyl group, alkynyl, any in propargyl, the halogen;
R
4Be hydrogen, alkyl, alkoxyl group, vinyl, allyl group, alkynyl, any in propargyl, the halogen.
2, according to claim 1 N-replace 1,2-phenpromethamine compounds is characterized in that: described alkyl is C1～C10 alkyl.
3, according to claim 1 N-replace 1,2-phenpromethamine compounds is characterized in that: described R
2The aromatic base group that to be ortho position, a position or contraposition replaced by halogen, alkoxyl group or alkyl.
4, according to claim 1 N-replace 1, the preparation method of 2-phenpromethamine compounds comprises following processing step:
1. with aromatic aldehyde and hydroxylamine derivative mol ratio, under nitrogen protection, in organic solvent,, extraction, separate and obtain nitrone 0～150 ℃ of reaction 3～96 hours down with 1:1～1:5; Described organic solvent is protic solvent or aprotic solvent;
2. with nitrone and organometallic reagent mol ratio, under nitrogen protection, in aprotic solvent,, extraction, separate and obtain azanol-80～100 ℃ of reactions 0.01～10 hour down with 1:1～1:5;
3. with azanol under the effect of metallic reducing agent, under nitrogen protection, in aprotic solvent,, extraction, separate 0～100 ℃ of down reaction 3～48 hours, target compound; Or azanol down added reductive agent transition metal-catalyzed, in organic solvent, 0～100 ℃ of reaction 3～48 hours down, extract, separate target compound.
5, as N-as described in the claim 4 replace 1, the preparation method of 2-phenpromethamine compounds is characterized in that: the step 1. structure of described aromatic aldehyde is as follows:
R
3Be hydrogen, alkyl, alkoxyl group, vinyl, allyl group, alkynyl, any in propargyl, the halogen.
6, as N-as described in the claim 4 replace 1, the preparation method of 2-phenpromethamine compounds is characterized in that: the step 1. structure of described hydroxylamine derivative is as follows:
R
2Be hydrogen, alkyl, aromatic base, arylmethyl, vinyl, allyl group, alkynyl, any in the propargyl.
7, as N-as described in the claim 4 replace 1, the preparation method of 2-phenpromethamine compounds is characterized in that: the 2. described organometallic reagent of step is magnesium or lithium.
8, as N-as described in the claim 4 replace 1, the preparation method of 2-phenpromethamine compounds is characterized in that: the 3. described metallic reducing agent of step is zinc granule, tin grain, tin protochloride or cuprous halide; The consumption of metallic reducing agent is 1～20 times of azanol molar weight.
9, as N-as described in the claim 4 replace 1, the preparation method of 2-phenpromethamine compounds, it is characterized in that: the 3. described transition-metal catalyst of step is palladium charcoal, Raney's nickel and the metal-salt that contains palladium, nickel, cobalt, ruthenium, platinum, and its consumption is 0.1～200% of an azanol molar weight.
10, as N-as described in the claim 4 replace 1, the preparation method of 2-phenpromethamine compounds is characterized in that: the 3. described reductive agent of step is hydrogen, formic acid, ammonium formiate or hydrazine; The consumption of reductive agent is 1～200 times of azanol molar weight.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103755843A (en) * | 2013-12-11 | 2014-04-30 | 清华大学 | N-9-fluorenylmethoxycarbonyl hydrazine base resin, preparation method and application thereof |
| CN111704619A (en) * | 2020-07-30 | 2020-09-25 | 四川大学 | Preparation method of Forodesine |
| CN115304507A (en) * | 2022-09-19 | 2022-11-08 | 兰州石化职业技术大学 | Synthesis method of N-substituted aryl formamide |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103755843A (en) * | 2013-12-11 | 2014-04-30 | 清华大学 | N-9-fluorenylmethoxycarbonyl hydrazine base resin, preparation method and application thereof |
| CN103755843B (en) * | 2013-12-11 | 2016-06-01 | 清华大学 | N-9-fluorenylmethyloxycarbonyl hydrazine base resin and its preparation method and application |
| CN111704619A (en) * | 2020-07-30 | 2020-09-25 | 四川大学 | Preparation method of Forodesine |
| CN111704619B (en) * | 2020-07-30 | 2021-10-19 | 四川大学 | Preparation method of Forodesine |
| CN115304507A (en) * | 2022-09-19 | 2022-11-08 | 兰州石化职业技术大学 | Synthesis method of N-substituted aryl formamide |
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