CN1865221A - Method for reducing nitroxylbenzyl amine compound to amino-benzylamine hydrochloride - Google Patents
Method for reducing nitroxylbenzyl amine compound to amino-benzylamine hydrochloride Download PDFInfo
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Abstract
This invention discloses a method for reducing the nitrabenzylamine compound to be nitrabenzylamine hydrochlorate whichreduces the nitrabenzylamine compound under hydrogen gas atmosphere by catalytic hydrogenation, using Pd-C/HCl catalytic system. This invention reduces the reaction activity of Pd-C catalyst by adding HCl or hydrochloric acid or CHCl3 which can produce HCl during the reaction to the reaction system, to entitle the Pd-C catalyst with the activity of catalyzing the nitro group of hydrogenated nitrobenzylamine compound to be amidol, without benzyl hydrogenolysis. This invention is characterized of simple operation, mild reaction condition, convenient treatment of post-production material, and broad application future.
Description
Technical field
The present invention relates to a kind of nitro-benzylamine compound that reduces is the method for amino-benzylamine hydrochloride.
Background technology
The Pd-metal catalyst is being brought into play important effect in functional group's transition process of modern organic synthesis.Have the chemical functional group optionally the Pd-metal catalyst very special using value is arranged, for example: Lindler catalyzer [Pd-CaCO
3-Pb (OAc)
2] can optionally the acetylene bond reduction be become the cis ethylene linkage; Rosenmund catalyzer (Pd-BaSO
4) can be optionally with acyl chlorides reduction becoming aldehyde.
The Pd-C catalyzer is one of Pd-metal catalyst of the easiest preparation, also is a kind of Pd-metal catalyst the most frequently used in the organic synthesis.In the presence of the Pd-C catalyzer, use clean hydrogen not only can make many organo-functional groups take place effectively to change, and have that productive rate height, aftertreatment are simple, atom economy and eco-friendly characteristics.For example: under Pd-C shortening condition, aromatic nitro compound can almost transform into aromatic amine compound quantitatively under room temperature and normal pressure, and this reaction is that most important functional group one of changes in the organic synthesis; Again for example: under Pd-C catalytic hydrogenolysis condition, the hydrogenolysis fracture of benzyl C-N key can almost take place in N, N-dialkyl benzylamine quantitatively under room temperature and normal pressure, and this reaction is the most normal reaction of selecting for use when going to protect of benzylamine protecting group.
Because the Pd-C catalyzer can reduce nitro and hydrogenolysis benzyl under condition much at one, so up to the present, the N that can't replace from nitro by the method for Pd-C shortening, the N-dialkyl benzylamine obtains amino-N effectively, N-dialkyl benzylamine (reference: Shiraishi, M.; Aramaki, Y.; Seto, M.et al.J.Med.Chem., 2000,43,2049-2063.).For example: in first non-peptide CCR5 receptor antagonist (formula I) synthetic, can use SnCl
2In hydrochloric acid, N-methyl-N-(tetrahydrochysene-4H-pyrans-4-yl)-4-nitro-benzylamine (formula II) is reduced, almost obtain key intermediate N-methyl-N-(tetrahydrochysene-4H-pyrans-4-yl)-4-amino-benzylamine dihydrochloride (formula III) quantitatively.But,, then almost all obtain 4-monomethylaniline (formula IV) and N-methyl-(tetrahydrochysene-4H-pyrans-4-yl) amine (formula V) (reference: Hashimoto, H. if use the method for Pd-C shortening that formula II compound is reduced; Ikemoto, T.; Itoh, T.et al.Org.Process Res.Dev., 2002,6,70-73.), this mainly is that when nitro was reduced, the hydrogenolysis fracture had also taken place the C-N key of benzylamine because when using the Pd-C catalyzer to reduce, reaction formula is as follows:
Summary of the invention
The purpose of this invention is to provide a kind of nitro-benzylamine compound that reduces is the method for amino-benzylamine hydrochloride.
Method provided by the present invention is that the nitro-benzylamine compound is carried out the catalytic hydrogenation reduction reaction under nitrogen atmosphere, and wherein, the catalyst system therefor system is the Pd-C/HCl catalyst system.
In the present invention, the Pd-C/HCl catalyst system is to add HCl gas, CHCl in the Pd-C catalyzer
3Or hydrochloric acid.Wherein, in non-aqueous system, HCl gas and CHCl
3Source as HCl; Wherein, the mole number of HCl gas be in the product in the amino and Pd-C catalyzer 1-2 of the molar equivalent sum of Pd doubly be preferably 1-1.1 times; CHCl
3Mole number be in the product in the amino and Pd-C catalyzer 0.34-0.68 times of the molar equivalent sum of Pd.In Aquo System, hydrochloric acid is as the source of HCl, and wherein the mole number of HCl is at least in the product in the amino and Pd-C catalyzer 1.1 times of the molar equivalent sum of Pd in the hydrochloric acid.
The weight percentage of Pd is 1-50% in the described Pd-C catalyzer.
In the present invention, the solvent of hydro-reduction reaction is methyl alcohol, ethanol, Virahol, butanols, ether, tetrahydrofuran (THF) or 1, the 2-ethylene dichloride; Be preferably methyl alcohol.The hydro-reduction temperature of reaction is 0 a ℃-solvent refluxing temperature; Be preferably normal temperature.The hydro-reduction reaction pressure is that normal pressure is to the 50PSI hydrogen pressure; Be preferably normal pressure.
The inventive method is applicable to the nitro-benzylamine compound of different structure, suc as formula the N of VI, and the N-dialkyl benzylamine, three (nitrobenzyl) amine of formula VII structure, or the N-alkylbenzylamine of formula VIII structure etc.;
(formula VI) (formula VII) (formula VIII)
Wherein, R, R among the formula VI
1Be straight chained alkyl, branched-chain alkyl or the cycloalkyl of 1-18 carbon atom, perhaps for containing straight chained alkyl, branched-chain alkyl or the cycloalkyl of aryl; Perhaps for containing straight chained alkyl, branched-chain alkyl or the cycloalkyl of ehter bond; Perhaps be pyrrolidyl, piperidyl, piperazinyl or morphine quinoline base; Perhaps be substituted pyrrolidinyl, piperidyl, piperazinyl or the morphine quinoline base of straight chained alkyl, branched-chain alkyl or the cycloalkyl of 1-18 carbon atom for substituting group;
R is straight chained alkyl, branched-chain alkyl or the cycloalkyl of 1-18 carbon atom among the formula VIII, perhaps for containing straight chained alkyl, branched-chain alkyl or the cycloalkyl of aryl; Perhaps for containing straight chained alkyl, branched-chain alkyl or the cycloalkyl of ehter bond.
Nitro the position of substitution (2-, 3-or 4-position) on the aromatic ring of benzylamine is to the selectivity and the not significantly influence of productive rate of reaction.
The present invention reduces the reactive behavior of Pd-C catalyzer by add HCl in reaction system, makes the Pd-C catalyzer both have the activity of the nitro of catalytic hydrogenation nitro-benzylamine compound for amino, and the benzyl hydrogenolysis does not take place again.The inventive method is simple to operate, the reaction conditions gentleness, and product postprocessing is convenient, has a extensive future.
Embodiment
The inventive method adopts optionally Pd-C/HCl catalyst system of a kind of height chemical functional group, can be under condition as mild as a dove, and high selectivity ground becomes amino-benzylamine hydrochloride with multiple nitro-benzylamine direct hydrogenation reduction.The Pd-C/HCl catalyst system of this high selectivity is made up of Pd-C catalyzer and HCl, its optionally major cause be that HCl has the active ability of Pd-C catalyst reaction that reduces, the Pd-C catalyzer that is lowered after the reactive behavior still can be with aromatic nitro reduction becoming aromatic amine under the hydro-reduction condition, but lost the ability of C-N key in the hydrogenolysis fracture benzylamine fully, the product that generates is captured the back with the HCl in the reaction system and is generated corresponding hydrochloride, has brought many convenience for aftertreatment again.
In the Pd-C/HCl catalytic reduction system, the content of palladium metal gets final product between 1%-50% (weight ratio) in the Pd-C catalyzer, uses high-load palladium metal can add the speed of fast response.The Pd-C catalyst consumption is that the 0.1%-25% (weight ratio) of substrate gets final product, and uses a high proportion of catalyzer can add the speed of fast response, but can promote the cost of reaction.
In the suspension of Pd-C catalyzer, produce an amount of HCl and can form the Pd-C/HCl catalyst system:
In non-aqueous system, can directly add HCl gas, its mole dosage for the 1-2 that generates amido and the molar equivalent sum of Pd in the product doubly, be preferably in 1-1.1 times, excessively can cause the further inactivation of Pd-C catalyzer to the HCl more than 2.0 times, even lose the ability of reduction nitro.The method that also has a kind of HCl of generation is to add proper C HCl in reaction system
3, CHCl
3The de-chlorine hydride reaction takes place in the Pd-C catalytic hydrogenation, and original position is emitted hydrogenchloride (Secrist III, J.A.; Logue, M.W.J.Org.Chem., 1972,37,335-336.).CHCl
3Consumption be more than 0.34 times or of substrate mole number as dissolvant of reaction system and cosolvent.Look Pd-C activity of such catalysts and consumption, CHCl
3Three chlorine atoms in the molecule all are reduced and generate HCl or partly be reduced into HCl.The HCl part of these generations is used for " poisoning " Pd-C catalyzer, and another part is used for generating corresponding hydrochloride with product.
In Aquo System, the aqueous hydrochloric acid of different concns (1%-37%, weight ratio) can be used as the source of HCl.The molar equivalent number that the consumption of hydrochloric acid surpasses amido in the product adds that the summation of the molar equivalent number of Pd gets final product.Wherein, a part of hydrochloric acid is used for generating corresponding hydrochloride with product, and another part hydrochloric acid is used for " poisoning " Pd-C catalyzer.Excessive hydrochloric acid can not produce significantly influence to activity of such catalysts, but there is no need.Preferably use 37% concentrated hydrochloric acid, reduce the water that is brought in the system, help the salify of product.
The hydro-reduction reaction of using the Pd-C/HCl catalytic reduction system to carry out can be carried out in the 2-ethylene dichloride equal solvent at methyl alcohol, ethanol, Virahol, butanols, ether, tetrahydrofuran (THF), 1, and particular methanol is a solvent.The hydro-reduction reaction can be carried out to the reflux temperature of solvent at 0 ℃, uses low temperature need prolong the time of reaction, but is to use reflux temperature can reduce the selectivity of reaction, preferably at room temperature carries out.The hydro-reduction reaction can be carried out under normal pressure to 50 PSI hydrogen pressure, and high pressure can add the speed of fast response, but preferably selects normal pressure for use.
When hydrochloric acid was used as the HCl source, it was sign that the terminal point of reaction generally stops with suction hydrogen.Work as CHCl
3When being used as the HCl source, inhaling the terminal point of hydrogen and need determine by condition experiment.So the influence that the reaction times is subjected to reaction conditions is very big, can be between 1 minute to 50 hours.
In the experiment, use HCl and CHCl
3As HCl source, product can be slightly different: CHCl
3As HCl source, can contain a small amount of benzylic hydrogens hydrolysis products in the product; And directly with HCl as the HCl source, then do not have this phenomenon.This is because at reaction initial period, CHCl
3The hydrogenation de-chlorine hydride reaction of itself just begins, and does not have enough HCl to reduce the reactive behavior of Pd-C catalyzer.So, the catalytic benzyl hydrogenolysis of Pd-C has taken place inevitably at the incunabulum of reaction.Below two contrast experiments can confirm this point.
Experiment one:
Under room temperature and normal pressure, with 10% Pd-C catalyzer (10%, weight ratio) and 4-nitro-N, N-dimethyl benzylamine (formula VI/a) is at MeOH and CHCl
3The middle mixture that generates stirred 2 hours under nitrogen atmosphere, obtained a white solid through normal aftertreatment then.Warp
1H NMR and
13C NMR atlas analysis shows that it is 4-amino-N, the mixture of N-dimethyl benzylamine dihydrochloride (formula IX/a, 91%) and 4-methylaniline hydrochloride (X, 3%) and dimethyl amine hydrochloride (XI, 3%), and overall yield is 94%.
Experiment two:
Under room temperature and normal pressure, with 10% Pd-C catalyzer (10%, weight ratio), 4-nitro-N, the mixture that N-dimethyl benzylamine (formula VI/a) and an amount of concentrated hydrochloric acid generate in MeOH is stirred to suction hydrogen and stops 15 minutes fully under nitrogen atmosphere).But obtain single product 4-amino-N of 98% through normal aftertreatment then, N-dimethyl benzylamine dihydrochloride (formula IX/a) uses
1H NMR and
13C NMR detects demonstration to thick product and is generated by the product of hydrogenolysis without any benzylamine.
Under same condition, N-[(4-nitrophenyl) methyl]-tetrahydrochysene-N-methyl-2H-pyrans-4-amine (formula VI/i) optionally finished the hydro-reduction reaction of nitro, generates the single product (formula IX/i, 100%) of expection quantitatively in 10 minutes.
The inventive method is fit to the selective hydrogenation reduction of the nitro-benzylamine of number of different types:
One, the N of the nitro of formula VI structure replacement, the N-dialkyl benzylamine
a：4-NO
2，R＝R
1＝Me f：4-NO
2，R，R
1＝-(CH
2)
4-
b：4-NO
2，R＝R
1＝Et g：4-NO
2，R，R
1＝-(CH
2)
5-
c：4-NO
2，R＝R
1＝
iPr h：4-NO
2，R，R
1＝-(CH
2)
2-O-(CH
2)
2-
D:4-NO
2, R=R
1=
nBu i:4-NO
2, R=Me, R
1=4-THP trtrahydropyranyl
E:4-NO
2, R=R
1=cyclohexyl j:2-NO
2, R=Me, R
1=Me
Nitro the position of substitution (2-, 3-or 4-position) on the aromatic ring of benzylamine is to the selectivity and the not significantly influence of productive rate of reaction.
N, two straight chained alkyl, branched paraffin or cycloalkyl that alkyl can be respectively a 1-18 carbon atom in the N-dialkyl benzylamine, contain straight chained alkyl, branched-chain alkyl or cycloalkyl that aryl replaces, contain straight chained alkyl, branched-chain alkyl or the cycloalkyl of 1-18 carbon atom of ehter bond; Can also be pyrrolidyl, piperidyl, piperazinyl or morphine quinoline base, also can be straight chained alkyl, branched-chain alkyl, the cycloalkyl that different positions is substituted with 1-18 carbon atom on tetramethyleneimine, piperidines, piperazine or these groups of morphine quinoline, perhaps contain the derivative of straight chained alkyl, branched-chain alkyl or cycloalkyl substituted of 1-18 carbon atom of ehter bond.
When also containing other amidine functional group on the amido substituting group in the reaction substrate, other amidine functional group also is transformed into corresponding hydrochloride.For example: N-(4-nitrobenzyl)-N '-methylpiperazine (formula VI/k) is hydrogenated reduction with this understanding, generates the tri hydrochloride (formula IX/k) of corresponding N-(4-aminobenzyl)-N '-methylpiperazine automatically.
Two, three of formula VII structure (nitrobenzyl) amine
When using three (nitrobenzyl) amine (formula VII) as reaction substrate, nitro is hydrogenated reduction needs the long reaction times.But no matter nitro is in 2-, 3-or 4-position, and all selectivity and the productive rate to reaction do not produce tangible influence.For example: three (4-nitrobenzyl) amine obtains 95% three (4-aminobenzyl) amine, four hydrochlorides through 6 hours hydro-reduction:
Three, the N-alkylbenzylamine of the nitro of formula VIII structure replacement
M:R
3=
iPr; N:R
3=
nBu; O:R
3=
tBu; P:R
3=Bn; Q:R
3=cyclohexyl
The N-alkylbenzylamine that the nitro of number of different types replaces is also generated the hydrochloride of the corresponding amino N-alkylbenzylamine that replaces by the selectivity hydro-reduction under above-mentioned reaction conditions.
Nitro the position of substitution (2-, 3-or 4-position) on the benzylamine aromatic ring is to the selectivity and the not significantly influence of productive rate of reaction.Alkyl in the N-alkylbenzylamine can be straight-chain paraffin, branched paraffin or the naphthenic hydrocarbon of 1-18 carbon atom, contain straight-chain paraffin, branched paraffin or naphthenic hydrocarbon that aryl replaces, contain straight-chain paraffin and the branched paraffin or the naphthenic hydrocarbon of 1-18 carbon atom of ehter bond.
Embodiment 1, use CHCl
3Source as HCl prepares 4-amino-N, N-dimethyl benzylamine dihydrochloride (formula IX/a)
At 25 ℃, with 4-nitro-N, the N-dimethyl benzylamine (formula VI/a, 450mg, 2.5mmol), 10% Pd/C (45mg, 10% weight ratio) and CHCl
3(2mL) suspension that generates in methyl alcohol (30mL) filters out the Pd/C catalyzer behind hydrogenation 2h under the normal pressure.Filtrate under reduced pressure boils off methyl alcohol, obtains the thick product of yellow crystals.With a small amount of ether washing yellow crystals, remove any not salifiable material then.After MeOH/Et
2The O recrystallization obtains lurid crystalline compounds 4-amino-N, N-dimethyl benzylamine dihydrochloride (formula IX/a, 510mg, 91%).
m.p.198-200℃(MeOH/Et
2O)；
13C?NMR(CD
3OH)：δ133.7，133.0，130.5，123.7，60.1，42.0；
Ultimate analysis (C
9H
16N
2Cl
2): C, 48.44; H, 7.23; N, 12.55; Found:C, 48.20; H, 7.24; N, 12.32.
Embodiment 2, use concentrated hydrochloric acid prepare 4-amino-N, N-dimethyl benzylamine dihydrochloride (formula IX/a) as the source of HCl
At 25 ℃, with 4-nitro-N, N-dimethyl benzylamine (formula VI/a, 450mg, 2.5mmol), 10% Pd/C (45mg, 10% weight ratio) and 37% concentrated hydrochloric acid (1mL, the HCl that contains 8mmol approximately) suspension that generates in methyl alcohol (30mL), is inhaled hydrogen and is stopped fully after 15 minutes at hydrogenation under the normal pressure.Filter out the Pd/C catalyzer, filtrate under reduced pressure boils off methyl alcohol, obtains the thick product of yellow crystals.With a small amount of ether washing yellow crystals, remove any not salifiable material then.After MeOH/Et
2The O recrystallization obtains lurid crystalline compounds 4-amino-N, N-dimethyl benzylamine dihydrochloride (formula IX/a, 550mg, 98%).Physical data is identical with embodiment 1.
Embodiment 3, preparation 4-amino-N, N-diethyl benzylamine dihydrochloride (formula IX/b)
Under the identical condition of embodiment 2, with 4-nitro-N, N-diethyl benzylamine (formula VI/b) reacts, and inhaled hydrogen and stop fully after 15 minutes.Crude product is from MeOH/Et
2Recrystallization obtains lurid crystalline compounds 4-amino-N among the O, N-diethyl benzylamine dihydrochloride (formula IX/b, 100%).
m.p.180-182℃(MeOH/Et
2O)；
13C?NMR(CD
3OH)：δ150.0，132.2，117.3，115.1，56.2，46.4，8.1；
Ultimate analysis (C
11H
20N
2Cl
2): C, 52.60; H, 8.03; N, 11.15; Found:C, 52.48; H, 8.03; N, 11.17.
Embodiment 4, preparation 4-amino-N, N-di-isopropyl benzylamine dihydrochloride (formula IX/c)
Under the identical condition of embodiment 2, with 4-nitro-N, N-di-isopropyl benzylamine (formula VI/c) reacts, and inhaled hydrogen and stop fully after 9 minutes.Crude product is from MeOH/Et
2Recrystallization obtains lurid crystalline compounds 4-amino-N among the O, N-di-isopropyl benzylamine dihydrochloride (formula IX/c, 100%).
m.p.196-198℃(MeOH/Et
2O)；
13C?NMR(CD
3OH)：δ132.7，132.0，124.1，55.6，49.9，18.1，17.3；
Ultimate analysis (C
13H
24N
2Cl
2): C, 55.91; H, 8.66; N, 10.03; Found:C, 55.89; H, 8.60; N, 10.00.
Embodiment 5, preparation 4-amino-N, N-dibutyl benzylamine dihydrochloride (formula IX/d)
Under the identical condition of embodiment 2, with 4-nitro-N, N-dibutyl benzylamine (formula VI/d) reacts, and inhaled hydrogen and stop fully after 13 minutes.Crude product is from MeOH/Et
2Recrystallization obtains lurid crystalline compounds 4-amino-N among the O, N-dibutyl benzylamine dihydrochloride (formula IX/d, 100%).
m.p.＞250℃(MeOH/Et
2O)；
13C?NMR(CD
3OH)：δ133.1，133.0，130.8，123.9，56.2，52.6，25.5，19.9，12.9；
Ultimate analysis (C
15H
28N
2C
L2): C, 58.63; H, 9.18; N, 9.12.Found:C, 58.52; H, 9.10; N, 9.14.
Embodiment 6, preparation 4-amino-N, N-dicyclohexyl benzylamine dihydrochloride (formula IX/e)
Under the identical condition of embodiment 2, with 4-nitro-N, N-dicyclohexyl benzylamine (formula VI/e) reacts, and inhaled hydrogen and stop fully after 11 minutes.Crude product is from MeOH/Et
2Recrystallization obtains lurid crystalline compounds 4-amino-N among the O, N-dicyclohexyl benzylamine dihydrochloride (formula IX/e, 100%).
m.p.＞250℃(MeOH/Et
2O)；
13C?NMR(CD
3OH)：δ133.0，132.6，132.1，124.0，63.5，50.8，28.7，28.0，25.4，25.1，24.9；
Ultimate analysis (C
19H
32N
2Cl
2): C, 63.50; H, 8.98; N, 7.79; Found:C, 63.56; H, 8.94; N, 7.85.
Embodiment 7, preparation 4-(1-pyrrolidyl methyl) aniline dihydrochloride (formula IX/f)
Under the identical condition of embodiment 2, react with 4-(1-pyrrolidyl methyl) oil of mirbane (formula VI/f), after 20 minutes, inhale hydrogen and stop fully.Crude product is from MeOH/Et
2Recrystallization obtains lurid crystalline compounds 4-(1-pyrrolidyl methyl) aniline dihydrochloride (formula IX/f, 97%) among the O.
m.p.192-194℃(MeOH/Et
2O)；
13C?NMR(CD
3OH)：δ149.8，131.6，118.9，115.0，58.0，53.0，22.7；
Ultimate analysis (C
11H
18N
2Cl
2): C, 53.02; H, 7.28; N, 11.24.Found:C, 53.03; H, 7.29; N, 11.22.
Embodiment 8, preparation 4-(piperidino methyl) aniline dihydrochloride (formula IX/g)
Under the identical condition of embodiment 2, react with 4-(piperidino methyl) oil of mirbane (formula VI/g), after 60 minutes, inhale hydrogen and stop fully.Crude product is from MeOH/Et
2Recrystallization obtains lurid crystalline compounds 4-(piperidino methyl) aniline dihydrochloride (formula IX/g, 95%) among the O.
m.p.193-195℃(MeOH/Et
2O)；
13C?NMR(CD
3OH)：δ150.2，132.5，116.9，115.0，60.9，52.4，23.1，21.8；
Ultimate analysis (C
12H
20N
2Cl
2): C, 54.76; H, 7.66; N, 10.64.Found:C, 54.55; H, 7.58; N, 10.53.
Embodiment 9, preparation 4-(4-morphine quinoline ylmethyl) aniline dihydrochloride (formula IX/h)
Under the identical condition of embodiment 2, react with 4-(4-morphine quinoline ylmethyl) oil of mirbane (formula VI/h), after 45 minutes, inhale hydrogen and stop fully.Crude product is from MeOH/Et
2Recrystallization obtains lurid crystalline compounds 4-(4-morphine quinoline ylmethyl) aniline dihydrochloride (formula IX/h, 96%) among the O.
m.p.190-192℃(MeOH/Et
2O)；
13C?NMR(CD
3OH)：δ150.2，132.6，116.3，115.0，63.9，61.1，51.3。
Ultimate analysis (C
11H
18ON
2Cl
2): C, 49.82; H, 6.84; N, 10.56; Found:C, 49.60; H, 6.65; N, 10.45.
Embodiment 10, preparation N-[(4-aminophenyl) methyl]-tetrahydrochysene-N-methyl-2H-pyrans-4-amine dihydrochloride (formula IX/i)
Under the identical condition of embodiment 2, with the N-[(4-nitrophenyl) methyl]-tetrahydrochysene-N-methyl-2H-pyrans-4-amine (formula VI/i) reacts, inhaled hydrogen and stop fully after 10 minutes.Crude product is from MeOH/Et
2Recrystallization obtains lurid crystalline compounds among the O, the N-[(4-aminophenyl) methyl]-tetrahydrochysene-N-methyl-2H-pyrans-4-amine dihydrochloride (formula IX/i, 100%).
m.p.177-179℃(MeOH/Et
2O)；
13C?NMR(CD
3OH)：δ133.4，132.9，131.1，124.1，66.2，62.9，55.8，35.3，28.0，27.0；
Ultimate analysis (C
13H
22ON
2Cl
2): C, 53.25; H, 7.56; N, 9.55.Found:C, 53.23; H, 7.57; N, 9.54.
Embodiment 11, preparation 2-amino-N, N-dimethyl benzylamine dihydrochloride (formula IX/j)
Under the identical condition of embodiment 2, with 2-nitro-N, N-dimethyl benzylamine (formula VI/j) reacts, and inhaled hydrogen and stop fully after 10 minutes.Crude product is from MeOH/E
tRecrystallization obtains lurid crystalline compounds among the 2O, 2-amino-N, N-dimethyl benzylamine dihydrochloride (formula IX/j, 92%).
m.p.142-143℃(MeOH/Et
2O)；
13C?NMR(CD
3OH)：δ147.8，132.8，131.3，118.2，117.2，114.3，57.5，41.9；
Ultimate analysis (C
9H
16N
2Cl
2): C, 48.44; H, 7.23; N, 12.55; Found:C, 48.23; H, 7.14; N, 12.47.
Embodiment 12, preparation 4-[(4-methylpiperazine base) methyl] aniline tri hydrochloride (formula IX/k)
Under the identical condition of embodiment 2, with 4-[(4-methylpiperazine base) methyl] oil of mirbane (formula VI/k) reacts, inhaled hydrogen and stop fully after 45 minutes.Crude product is from MeOH/Et
2Recrystallization obtains lurid crystalline compounds among the O, 4-[(4-methylpiperazine base) methyl] aniline tri hydrochloride (formula IX/k, 96%).
m.p.139-141℃(MeOH/Et
2O)；
13C?NMR(CD
3OH)：δ140.2，129.3，123.1，50.1，42.8，41.0。
Ultimate analysis (C
11H
22N
3Cl
3): C, 45.80; H, 7.05; N, 13.35.Found:C, 45.91; H, 7.04; N, 13.57.
Embodiment 13, preparation three (4-aminobenzyl) amine four hydrochlorides (formula IX/l)
Under the identical condition of embodiment 2, react with three (4-nitrobenzyl) amine (formula VII/l), after 180 minutes, inhale hydrogen and stop fully.Crude product is from MeOH/Et
2Recrystallization obtains lurid crystalline compounds among the O, three (4-aminobenzyl) amine four hydrochlorides (formula IX/l, 95%).
m.p.＞250℃(MeOH)；
13C?NMR(D
2O)：δ131.7，131.6，131.5，123.8，50.0；
Ultimate analysis (C
21H
28N
4Cl
4): C, 52.74; H, 5.90; N, 11.71; Found:C, 52.86; H, 5.89; N, 11.80.
Embodiment 14, preparation 4-amino-N-isopropyl benzylamine dihydrochloride (formula IX/m)
Under the identical condition of embodiment 2, react with 4-nitro-N-isopropyl benzylamine (formula VIII/m), after 11 minutes, inhale hydrogen and stop fully.Crude product is from MeOH/Et
2Recrystallization obtains lurid crystalline compounds among the O, 4-amino-N-isopropyl benzylamine dihydrochloride (formula IX/m, 100%).
m.p.196-198℃(MeOH/Et
2O)；
13C?NMR(CD
3OH)：δ133.0，132.2，132.0，124.0，51.3，47.8，18.3；
Ultimate analysis (C
10H
18N
2Cl
2): C, 50.64; H, 7.65; N, 11.81; Found:C, 50.52; H, 7.66; N, 11.83.
Embodiment 15, preparation 4-amino-N-butyl benzylamine dihydrochloride (formula IX/n)
Under the identical condition of embodiment 2, react with 4-nitro-N-butyl benzylamine (formula VIII/n), after 9 minutes, inhale hydrogen and stop fully.Crude product is from MeOH/Et
2Recrystallization obtains lurid crystalline compounds among the O, 4-amino-N-butyl benzylamine dihydrochloride (formula IX/n, 99%).
m.p.202-203℃(MeOH/Et
2O)；
13C?NMR(CD
3OH)：δ132.8，132.1，124.0，50.4，47.7，28.1，19.8，12.9；
Ultimate analysis (C
11H
20N
2Cl
2): C, 52.60; H, 8.03; N, 11.15.Found:C, 56.62; H, 8.01; N, 11.24.
Embodiment 16, preparation 4-amino-N-tert-butyl benzyl amine dihydrochloride (formula IX/o)
Under the identical condition of embodiment 2,4-nitro-N-tert-butyl benzyl amine (formula VIII/o) was inhaled hydrogen and is stopped fully after 8 minutes.Crude product is from MeOH/Et
2Recrystallization obtains lurid crystalline compounds among the O, 4-amino-N-tert-butyl benzyl amine dihydrochloride (formula IX/o, 98%).
m.p.250℃(MeOH/Et
2O)；
13C?NMR(CD
3OH)：δ133.3，132.2，132.0，124.0，58.1，44.7，24.9；
Ultimate analysis (C
11H
20N
2C1
2): C, 52.60; H, 8.03; N, 11.15.Found:C, 52.49; H, 7.92; N, 11.26.
Embodiment 17, preparation 4-amino-N-benzyl benzylamine dihydrochloride (formula IX/p)
Under the identical condition of embodiment 2, react with 4-nitro-N-benzyl benzylamine (formula VIII/p), after 14 minutes, inhale hydrogen and stop fully.Crude product is from MeOH/Et
2Recrystallization obtains lurid crystalline compounds among the O, 4-amino-N-benzyl benzylamine dihydrochloride (formula IX/p, 98%).
m.p.198-199℃(MeOH/Et
2O)；
13C?NMR(CD
3OH)：δ132.6，132.3，132.2，131.3，130.2，129.7，129.3，123.9，51.3，50.2；
Ultimate analysis (C
14H
18N
2Cl
2): C, 58.96; H, 6.36; N, 9.82; Found:C, 58.88; H, 6.45; N, 9.91.
Embodiment 18, preparation 4-amino-N-cyclohexyl benzylamine dihydrochloride (formula IX/q)
Under the identical condition of embodiment 2, react with 4-nitro-N-cyclohexyl benzylamine (formula VIII/q), after 10 minutes, inhale hydrogen and stop fully.Crude product is from MeOH/Et
2Recrystallization obtains lurid crystalline compounds among the O, 4-amino-N-cyclohexyl benzylamine dihydrochloride (formula IX/q, 99%).
m.p.203-205℃(MeOH/Et
2O)；
13C?NMR(CD
3OH)：δ133.1，132.1，131.9，124.0，57.8，47.4，29.2，25.0，24.5；
Ultimate analysis (C
13H
22N
2Cl
2): C, 56.32; H, 8.00; N, 10.10; Found:C, 56.20; H, 8.02; N, 10.21.
Claims (9)
1, a kind of nitro-benzylamine compound that reduces is the method for amino-benzylamine hydrochloride, is that the nitro-benzylamine compound is carried out the catalytic hydrogenation reduction reaction under nitrogen atmosphere, and it is characterized in that: the catalyst system therefor system is the Pd-C/HCl catalyst system.
2, method according to claim 1 is characterized in that: described Pd-C/HCl catalyst system is to add HCl gas, CHCl in the Pd-C catalyzer
3Or hydrochloric acid.
3, method according to claim 2 is characterized in that: in non-aqueous system, and HCl gas and CHCl
3Source as HCl; Wherein, the mole number of HCl gas be in the product in the amino and Pd-C catalyzer 1-2 of the molar equivalent sum of Pd doubly be preferably 1-1.1 times; CHCl
3Mole number be in the product in the amino and Pd-C catalyzer 0.34-0.68 times of the molar equivalent sum of Pd.
4, method according to claim 2 is characterized in that: in Aquo System, hydrochloric acid is as the source of HCl, and wherein, the mole number of HCl is at least in the product in the amino and Pd-C catalyzer 1.1 times of the molar equivalent sum of Pd in the hydrochloric acid.
5, method according to claim 2 is characterized in that: the weight percentage of Pd is 1-50% in the described Pd-C catalyzer.
6, method according to claim 1 is characterized in that: the solvent of hydro-reduction reaction is methyl alcohol, ethanol, Virahol, butanols, ether, tetrahydrofuran (THF) or 1, the 2-ethylene dichloride; Be preferably methyl alcohol.
7, method according to claim 1 is characterized in that: the hydro-reduction temperature of reaction is 0 a ℃-solvent refluxing temperature; Be preferably normal temperature.
8, method according to claim 1 is characterized in that: the hydro-reduction reaction pressure is that normal pressure is to the 50PSI hydrogen pressure; Be preferably normal pressure.
9, according to the arbitrary described method of claim 1-8, it is characterized in that: described nitro-benzylamine compound is the N of structure suc as formula VI, N-dialkyl benzylamine, three (nitrobenzyl) amine of formula VII structure, or the N-alkylbenzylamine of formula VIII structure;
(formula VI) (formula VII) (formula VIII)
Wherein, R, R among the formula VI
1Be straight chained alkyl, branched-chain alkyl or the cycloalkyl of 1-18 carbon atom, perhaps for containing straight chained alkyl, branched-chain alkyl or the cycloalkyl of aryl; Perhaps for containing straight chained alkyl, branched-chain alkyl or the cycloalkyl of ehter bond; Perhaps be pyrrolidyl, piperidyl, piperazinyl or morphine quinoline base; Perhaps be substituted pyrrolidinyl, piperidyl, piperazinyl or the morphine quinoline base of straight chained alkyl, branched-chain alkyl or the cycloalkyl of 1-18 carbon atom for substituting group;
R among the formula VIII
3Be straight chained alkyl, branched-chain alkyl or the cycloalkyl of 1-18 carbon atom, perhaps for containing straight chained alkyl, branched-chain alkyl or the cycloalkyl of aryl; Perhaps for containing straight chained alkyl, branched-chain alkyl or the cycloalkyl of ehter bond.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101735071A (en) * | 2009-12-04 | 2010-06-16 | 大连凯飞精细化工有限公司 | Method for producing 4-N,N-dimethylamino methylaniline |
| JP2015522537A (en) * | 2012-05-18 | 2015-08-06 | ウニヴァーシテテット イ オスロ | Tertiary amines used in the treatment of heart disorders |
| CN105001096A (en) * | 2015-07-21 | 2015-10-28 | 沈阳化工研究院有限公司 | 4-amino-N-alkyl benzylamine preparation methood |
| US9585880B2 (en) | 2013-11-20 | 2017-03-07 | Universitetet I Oslo | Cyclic amino compounds for use in the treatment of cardiac disorders |
-
2006
- 2006-06-12 CN CNB2006100122076A patent/CN100383112C/en not_active Expired - Fee Related
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101735071A (en) * | 2009-12-04 | 2010-06-16 | 大连凯飞精细化工有限公司 | Method for producing 4-N,N-dimethylamino methylaniline |
| JP2015522537A (en) * | 2012-05-18 | 2015-08-06 | ウニヴァーシテテット イ オスロ | Tertiary amines used in the treatment of heart disorders |
| US9556111B2 (en) | 2012-05-18 | 2017-01-31 | Universitetet I Oslo | Tertiary amines for use in the treatment of cardiac disorders |
| US9951033B2 (en) | 2012-05-18 | 2018-04-24 | Universitetet I Oslo | Tertiary amines for use in the treatment of cardiac disorders |
| US9585880B2 (en) | 2013-11-20 | 2017-03-07 | Universitetet I Oslo | Cyclic amino compounds for use in the treatment of cardiac disorders |
| CN105001096A (en) * | 2015-07-21 | 2015-10-28 | 沈阳化工研究院有限公司 | 4-amino-N-alkyl benzylamine preparation methood |
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