CN100448846C - Method for catalytic hydrogenation of acyl pyridine to preparing substituted pyridine compound hydrochlorate - Google Patents

Method for catalytic hydrogenation of acyl pyridine to preparing substituted pyridine compound hydrochlorate Download PDF

Info

Publication number
CN100448846C
CN100448846C CNB2006101443591A CN200610144359A CN100448846C CN 100448846 C CN100448846 C CN 100448846C CN B2006101443591 A CNB2006101443591 A CN B2006101443591A CN 200610144359 A CN200610144359 A CN 200610144359A CN 100448846 C CN100448846 C CN 100448846C
Authority
CN
China
Prior art keywords
alkyl
hydrochlorate
pyridine
hydrochloride
piperidine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
CNB2006101443591A
Other languages
Chinese (zh)
Other versions
CN1995017A (en
Inventor
胡跃飞
程传杰
王歆燕
邢立新
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Tsinghua University
Original Assignee
Tsinghua University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Tsinghua University filed Critical Tsinghua University
Priority to CNB2006101443591A priority Critical patent/CN100448846C/en
Publication of CN1995017A publication Critical patent/CN1995017A/en
Application granted granted Critical
Publication of CN100448846C publication Critical patent/CN100448846C/en
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Landscapes

  • Hydrogenated Pyridines (AREA)

Abstract

The invention discloses a catalytic acid hydrogenated based pyridine to replace piperidine compound hydrochlorate, which is characterized by the following: hydrogenating acyl pyridine with structural formula I or II catalyzed by Pd-C and dichloromethane condition; obtaining substituted piperidine composition hydrochlorate. R is H, alkyl or aryl; the general formula of dichloromethane is R1R2CCl2, wherein R1 and R2 is H, C1-C10 alkyl or subsituted C1-C10 alkyl by 1-5 chloride atom and or fluorine atom.

Description

A kind of catalytic hydrogenation of acyl pyridine is the method for preparing substituted pyridine compound hydrochlorate
Technical field
The present invention relates to the preparation method of compound, particularly relate to the method that a kind of catalytic hydrogenation of acyl pyridine is a preparing substituted pyridine compound hydrochlorate.
Background technology
Substituted piperidine and derivative thereof are important pharmacophore and the synthetic intermediates in the drug research.As follows: 4-substituted piperidine derivative 1 not only has potential CCR5 antagonistic activity, also demonstrates good anti-HIV-1 activity (Shinichi, I.; Takashi, I.; Youichi, N.et al.J.Med.Chem., 2006,49,2784-2793.); Ifenprodil (2) has antihypertensive active (Etsuo O.; Hitoshi T.; Hiroyuki H.et al.J.Med.Chem., 1993,36,417-420.); Similarly phenylbenzene amide derivatives 3 can be used as the retarding agent (IoannisR. of sodium-ion channel; Sheryl H.and Roy D.S.J.Med.Chem., 1996,39,1514-1520.).
Figure C20061014435900041
Using the 4-substituted pyridines under the catalytic hydrogenation condition pyridine ring to be carried out hydro-reduction as raw material is one of important method of preparation 4-substituted piperidine derivative.For example: the patent documentation report, phenylpyridyl ketone and derivative thereof reduce pyridine ring with the method for catalytic hydrogenation after hydrazine hydrate reduction obtains corresponding benzyl-pyridine compound again, obtain corresponding benzylpiperidine compound (Wick, A.; Frost, J.; Gaudilliere, B.; Bertin, J.; Dupont, R.; Rousseau, J.US Patent 4,690,931,1987).Again for example: α-phenyl-4-piconol uses higher relatively temperature (60-80 ℃) and pressure (8-10bar) to carry out the Pd-C catalytic hydrogenation in acetate solvate, and also pyridine ring being reduced when hydrogenolysis is removed hydroxyl becomes piperidine ring (Bela, A.; Agnes, P.; Gabor, T.; Laszlo, V.and Ferenc F.Eur.J.Org.Chem., 2004,3623-3632.).
But these two kinds of methods the most representative all have certain defective.For example: hydrazine hydrate itself has the bigger toxicity and the danger of operation; The hydrogenation that carries out in acetate solvate has lost eco-friendly characteristic basically, and not only aftertreatment is more loaded down with trivial details, and has to be low to moderate medium yield.
Summary of the invention
The purpose of this invention is to provide the method that a kind of catalytic hydrogenation of acyl pyridine is a preparing substituted pyridine compound hydrochlorate.
Catalytic hydrogenation of acyl pyridine provided by the present invention is the method for preparing substituted pyridine compound hydrochlorate, be that acyl pyridine with formula I or formula II structure is at the Pd-C catalyzer with in the presence of together with two enparas, carry out catalytic hydrogenation, obtain preparing substituted pyridine compound hydrochlorate;
Wherein, R is H, alkyl or aryl;
Described is R together with two enpara general formulas 1R 2CCl 2, wherein, R 1, R 2For the alkyl of H, C1-C10 or 1-5 chlorine atom arranged and/or C1-C10 alkyl that fluorine atom replaces.
In acyl pyridine, during the R alkyl, the preferably straight chained alkyl of C1-C20, branched-chain alkyl or cycloalkyl; The straight chained alkyl, branched-chain alkyl or the cycloalkyl that perhaps have the C1-C20 of alkoxyl group or aryl substituent.When R was aryl, preferred aryl groups was phenyl or substituted-phenyl, and substituting group is the alkyl of H, C1-C10, the alkoxyl group of C1-C10.
In the present invention, can be extensive stock reagent together with two enparas, commonly used have a methylene dichloride, 1,1-ethylene dichloride, vinyl trichloride, 1,1-two chloro-2-fluoroethanes, 1,1-two chloro-2,2,2-Halothane, 1, propylidene chloride 1,2,2-propylene dichloride, 1,1-two chloro-3,3-dimethylbutane, 1,1-dichloro pentamethylene and 1,1-dichloro hexanaphthene etc.; Be preferably 1,1-ethylene dichloride or 1,1-two chloro-3,3-dimethylbutane.
The present invention does not have particular requirement for reaction solvent, and reaction solvent commonly used is MeOH, EtOH, i-PrOH, t-BuOH or EtOAc; Be preferably MeOH or EtOH.
In the methods of the invention, Pd-C catalyzer and little for influencing of reaction together with the consumption of two enparas, but can influence the speed and the reaction times of reaction, generally, the Pd-C catalyst consumption is the 1-100% of described acyl pyridine weight; Described mol ratio together with two enparas and described acyl pyridine is more than 1: 1, even can be used as cosolvent, is preferably 1.1: 1.
Use the inventive method, the product preparing substituted pyridine compound hydrochlorate has two kinds sometimes: a kind of is the piperidines alcohol hydrochloride, and another kind is the Alkylpiperidine hydrochloride.Can adopt following condition to improve the selectivity of reaction:
When R is aryl, under the temperature (35-45 ℃) of normal pressure and a little higher than room temperature, can optionally obtain single 4-(arylmethyl) piperidine hydrochlorate.
When R is H or alkyl, under the hydrogen pressure of room temperature and 40-80psi, can optionally obtain single (alpha-alkyl) piperidine carbinols hydrochloride.
The present invention successfully pyridine ring is reduced to piperidine hydrochlorate under mild conditions, and the hydrochloride that is generated is that the separation and the purifying of product brings many convenience by adding together with two enparas in catalyst system.The inventive method productive rate height, selectivity is good, reaction conditions is gentle, and sepn process is easy.
Embodiment
In common Pd-C catalytic hydrogenation system, add together with dichloride (R 1R 2CCl 2); acyl pyridine [aryl pyridyl ketone (4) or Alkylpyridyl ketone (5)] almost can be quantitatively, highly chemistry optionally is converted into corresponding 4-(arylmethyl) piperidine hydrochlorate (6) or (alpha-alkyl) piperidine carbinols hydrochloride (9), and reaction equation is as follows:
Figure C20061014435900061
According to the result that experiment is followed the tracks of, we find that the ketone carbonyl in the acyl pyridine [aryl (4-pyridyl) ketone (4) and Alkylpyridyl ketone (5)] at first is reduced into and are piconol intermediate (10 and 11) in the Pd-C catalytic hydrogenation.Then, under Pd-C catalytic hydrogenation condition, the catalytic hydrogenation dechlorination reaction takes place together with dichloride.The hydrogenchloride that produces becomes hydrochloride (12 and 13) with piconol intermediate (10 and 11) converted in-situ.The influence that poisons of pyridine nitrogen atom pairs catalyzer has not only been removed in the generation of hydrochloride, and pyridine ring is further polarized, and fragrance stability is further reduced, and reaction mechanism is as follows.So, not only can be successfully under mild conditions with pyridine ring reduction becoming piperidine hydrochlorate, and the hydrochloride that generates brings many convenience for again the separation and the purifying of product, simple filtering can realize separating of product and raw material.And the reaction conditions of above-mentioned reaction can carry out being lower than under 35 ℃ and the 80psi hydrogen pressure as mild as a dove.
Figure C20061014435900062
Under experiment condition of the present invention, when-when R is aryl or alkyl, the reactive behavior of resulting piconol intermediate (10 and 11) shows significant difference: when-when R is aryl, hydroxyl in compound 10 molecules is owing to be subjected to the activation of continuous aryl, continue to take place the hydrogenolysis generation methylene radical of C-O key, optionally generate 4-(arylmethyl) piperidine hydrochlorate (6) at last.And when-when R was alkyl, the hydroxyl in compound 11 molecules linked to each other with alkane, can control the hydrogenolysis that the C-O key does not take place fully under reaction conditions of the present invention, optionally generated (alpha-alkyl) piperidine carbinols hydrochloride (9) at last.
In the present invention, together with dichloro-alkane (R 2R 1CCl 2) be meant the alkane that on a C atom, has two to replace the chlorine atoms, the R in the molecule 2And R 1Can be the alkyl (straight chained alkyl, branched-chain alkyl and cycloalkyl) of hydrogen atom or C1-C10, can have 1-5 chlorine atom or fluorine atom on together with any position beyond the dichloro carbon atom, to replace on these alkane chains.Preferably select for use 6 carbon atoms with interior together with dichloro-alkane, when aftertreatment, remove easily like this.Experiment showed, together with dichloro-alkane that under the Pd/C catalytic hydrogenation experiment condition that the present invention selects the reduction dechlorination reaction that is taken place is a process that is subjected to substrate control.When not having nitrogenous substrate to exist, the dechlorination that can not reduce reaction.When nitrogenous substrate exists, have only one reduction dechlorination reaction generation hydrogenchloride takes place together with two chlorine atoms in the dichloro-alkane.So whenever this reaction all can not produce excessive hydrogenchloride and catalyzer is poisoned.The most frequently used is those commodity compounds together with dichloro-alkane, for example: methylene dichloride, 1,1-ethylene dichloride, 1,1,2-trichloroethane, 1,1-two chloro-2-fluoroethanes, 1,1-two chloro-2,2,2-Halothane, 1, propylidene chloride 1,2,2-propylene dichloride, 1,1-two chloro-3, the 3-dimethylbutane, or the like 1,1-dichloro pentamethylene and 1,1-dichloro hexanaphthene or the like.Preferably use 1,1-ethylene dichloride or 1,1-two chloro-3, the 3-dimethylbutane because their boiling point is higher relatively, quantitatively carries out during operation easily.When they discharge the monochlor(in)ate compound that generates behind the chlorine atom boiling point lowering many, from system, remove easily again.In theory, be 1: 1 together with the mol ratio of dichloro-alkane and substrate, but preferably used 1.1: 1.Excessive does not have a negative impact together with the selectivity and the productive rate of dichloro-alkane to reaction.So the consumption together with dichloro-alkane in actually operating is random relatively.
In invention, the catalytic hydrogenation reduction reaction can be carried out in MeOH, EtOH, i-PrOH, t-BuOH and EtOAc equal solvent.Experimental results show that the productive rate of product and selectivity were best when MeOH and EtOH were solvent under the identical condition of catalyst levels, temperature of reaction, hydrogen pressure or the like, more preferably reaction solvent is MeOH.
Among the present invention, temperature of reaction is generally under the boiling point of reaction solvent; Under hot conditions, can fast reaction speed, need to select high boiling solvent this moment, carry out smoothly to guarantee reaction.In the reaction, H 2Pressure generally can be controlled in normal pressure to the 80psi scope, improves H 2Pressure also helps the carrying out that react, but the equipment of reaction is had special requirement.
First part: the hydro-reduction of aryl (4-pyridyl) ketone (4)
Be shown below: the available phenyl of reduction (4-pyridyl) ketone (4a) of aryl (4-pyridyl) ketone (4) illustrates for example.In the present invention, the content of Pd can get final product in the 1%-50% scope in the Pd-C catalyzer, and practical situation mainly are subjected to the influence of reaction pressure, temperature and time.Generally can select commercial 5% or 10% Pd-C catalyzer easily for use.Consider from the integrated condition of reaction, preferably select 10% Pd-C catalyzer for use.The 1-100% that the 10%Pd-C catalyst consumption is generally substrate weight gets final product, and is as shown in table 1.Consider from the angle of economy, preferably select 25% for use; Be less than 25% consumption and still can finish this reaction, but need to improve temperature of reaction or prolong the reaction times.Consider from the timesaving angle, laboratory operation is preferably selected 50% consumption for use.Use then can make to be reflected under the normal temperature and pressure when surpassing 100% consumption and carry out.
Figure C20061014435900081
Table 1.Pd/C catalyst levels is to the influence of 4a catalytic hydrogenation a
Figure C20061014435900082
A. hydrogen pressure=1 normal atmosphere.B. contain not salifiable mixture in the mother liquor.
In the present invention, (R) mainly refer to phenyl and substituted-phenyl, substituent scope comprises hydrogen atom (H) to the aryl in aryl (4-pyridyl) ketone; Alkyl is (R), comprising straight chained alkyl, branched-chain alkyl and the cycloalkyl of 1-10 carbon atom; Alkoxyl group (OR), the wherein straight chained alkyl of R=1-10 carbon atom, branched-chain alkyl and cycloalkyl.Substituting group can also can replace on these positions at ortho position, a position or the para-orientation of phenyl ring simultaneously.
If one or more fluorine atom is arranged on the phenyl ring, reaction is subjected to tangible influence.For example: (4-fluorophenyl) (4-pyridyl) ketone (4h) generates the mixture of 4-(4-fluorobenzene methyl) piperidine hydrochlorate (6h) and (4-fluorophenyl) (4-piperidyl) methylate hydrochlorate (8h) under same condition.This mainly is obviously to reduce because of the activation of phenyl ring to benzylalcohol, to such an extent as to the hydrogenolysis of hydroxyl can not take place reaction intermediate benzylalcohol fully.But, when using CH 2Cl 2During as the chlorine source, this reaction can generate single product (4-fluorophenyl) (4-piperidyl) methylate hydrochlorate (8h) (table 2) in chemo-selective ground.This mainly is because CH 2Cl 2Have higher hydrogenation dechlorination activity, can generate pyridine hydrochloride apace.In case pyridine hydrochloride is reduced into and is that piperidine hydrochlorate, benzyl alcohol originally just are converted to and is piperidyl methyl alcohol.Therefore, the C-O hydrogenolysis of alcoholic extract hydroxyl group just is prevented from fully.
Figure C20061014435900091
The selective catalytic hydrogenation reduction of table 24-(4-fluoro benzoyl) pyridine (4h) a
Figure C20061014435900092
The a.Pd-C catalyst levels is 50%w/w.B. test in the mother liquor of 1-4 and contain not salifiable mixture, but do not influence separation.
Under experiment condition of the present invention, the first step of aryl pyridyl reactive ketone is that carbonyl reduction is become hydroxyl, just produces two competing reactions then: a) pyridine ring is reduced into and is piperidine ring; B) hydroxyl is generated methylene radical by hydrogenolysis.The speed of reaction b does not produce any influence to reaction a.But reaction a at first finishes, and pyridine just disappears to the activation capacity of hydroxyl, reacts therefore that hydroxyl will be reduced significantly by the speed that hydrogenolysis generates methylene radical among the b.So, must keep suitable temperature of reaction, increase the hydrogenolysis ability of hydroxyl, could optionally obtain single 4-(arylmethyl) piperidine hydrochlorate (6).Under normal pressure, the reaction of carrying out between 35-55 ℃ provides optimal speed of response, selectivity and productive rate, 35 ℃ of first-selected uses.When being lower than 35 ℃, a spot of benzylalcohol compound is arranged in the product sometimes.Temperature is to the highly significant that influences of speed of response, for example: phenyl (4-pyridyl) ketone (4a) needed 12 hours to finish reaction in the time of 35 ℃, only needed 4.5 hours in the time of 55 ℃.Change suitable solvent if use higher temperature then need, in prepared in laboratory, there is no need.
The variation of hydrogen in reaction pressure also has significant influence to speed of response and product selectivity.If keep temperature of reaction between 35-55 ℃, the reaction of carrying out under hydrogen pressure between the 15-80psi does not all produce significantly influence to chemo-selective.But at room temperature, the variation of hydrogen pressure is quite obvious to the influence of reaction preference.For example: phenyl (4-pyridyl) ketone (4a) generates 1: 3 6a and the mixture of 8a under normal pressure; But generate single product 4-(phenmethyl) piperidine hydrochlorate (6a) under the 80psi hydrogen pressure quantitatively.
According to following experiment condition: with ClCH 2CHCl 2Or CH 2Cl 2As together with two enparas, MeOH is a solvent, and under 35 ℃, 1atm hydrogen pressure, aryl (4-pyridyl) ketone substrate molecule all can successfully be converted to and be 4-(arylmethyl) piperidine hydrochlorate (6).As shown in table 3, all transformations have the chemo-selective and the almost quantitative productive rate of height.
Figure C20061014435900101
The hydro-reduction of table 3. aryl (4-pyridyl) ketone (4) for example
Figure C20061014435900102
The a.Pd/C amount is 100%w/w; B.CH 2Cl 2Be used as the chlorine source.
The preparation of embodiment 1,4-benzyl piepridine hydrochloride (6a)
With the 4-benzoyl pyridine (4a, 366mg, 2.0mmol), 10%Pd-C (183mg; 50%w/w), and vinyl trichloride (320mg; 2.4mmol) suspension that in methyl alcohol (30mL), generates, behind the stirring 12h, absorption of hydrogen stops fully under 35 ℃ and atmospheric hydrogen pressure.After filtering out Pd-C, boil off the methyl alcohol in the filtrate, after the white solid of generation washs with anhydrous diethyl ether, through CH 3OH-Et 2The O recrystallization obtains the white crystal (42mg, 98%) of 4-benzyl piepridine hydrochloride (6a).
mp?180-181℃(MeOH-Et 2O)；
IR：v3427，3371，3026，2733，1595，1497，1471，1452，1074cm -1；
13C?NMR：δ140.0，129.4，128.6，126.4，44.1，41.5，35.1，28.2；
Calcd?for?C 12H 18ClN：C，68.07％；H，8.57％；N，6.62％；Found：C，67.94％；H，8.56％；N，6.51％.
The preparation of embodiment 2,4-(4-methyl-benzyl) piperidine hydrochlorate (6b)
According to the identical experimental procedure of embodiment 1, be raw material with (4-aminomethyl phenyl)-4-pyridyl ketone (4b), obtain 4-(4-methyl-benzyl) piperidine hydrochlorate (6b);
mp?218-220℃(MeOH-Et 2O)；
IR：v3448，3382，3035，2505，1593，1515，1473，1451cm -1；
13C?NMR：δ136.8，135.5，129.2，129.0，43.9，41.2，35.2，28.2，20.4；
Calcd?for?C 13H 20ClN：C，69.16％；H，8.93％；N，6.20％；Found：C，69.18％；H，8.93％；N，6.14％.
The preparation of embodiment 3,4-(2-methyl-benzyl) piperidine hydrochlorate (6c)
According to the identical experimental procedure of embodiment 1, obtain 4-(2-methyl-benzyl) piperidine hydrochlorate (6c) from (2-aminomethyl phenyl)-4-pyridyl ketone (4c);
mp?225-207℃(MeOH-Et 2O)；
IR：v3447，3374，2726，1635，1592，1494，1456cm -1；
13C?NMR：δ138.2，136.9，130.4，130.3，126.6，125.9，44.1，38.7，34.0，28.3，18.6；
Calcd?for?C 13H 20ClN：C，69.16％；H，8.93％；N，6.20％；Found：C，69.11％；H，8.89％；N，6.26％.
The preparation of embodiment 4,4-(4-methoxy-benzyl) piperidine hydrochlorate (6d)
According to the identical experimental procedure of embodiment 1, obtain 4-(4-methoxy-benzyl) piperidine hydrochlorate (6d) from (4-p-methoxy-phenyl)-4-pyridyl ketone (4d);
mp?172-174℃(MeOH-Et 2O)；
IR：v3448，2841，2723，1613，1593，1513，1455，1443，1246，1029cm -1；
13C?NMR：δ157.2，132.6，130.4，113.9，55.4，44.0，40.5，35.2，28.1；
Calcd?for?C 13H 20ClNO：C，64.59％；H，8.34％；N，5.79％；Found：C，64.48％；H，8.35％；N，5.66％.
The preparation of embodiment 5,4-(3-methoxy-benzyl) piperidine hydrochlorate (6e)
According to the identical experimental procedure of embodiment 1, obtain 4-(3-methoxy-benzyl) piperidine hydrochlorate (6e) from (3-p-methoxy-phenyl)-4-pyridyl ketone (4e);
mp?150-152℃(MeOH-Et 2O)；
IR：v3423，2840，2466，1611，1582，1488，1470，1454，1259，1046cm -1；
13C?NMR：δ158.9，141.8，129.7，122.2，114.8，111.7，55.3，44.0，41.5，35.0，28.2；
Calcd?for?C 13H 20ClNO：C，64.59％；H，8.34％；N，5.79％；Found：C，64.67％；H，8.28％；N，5.71％.
The preparation of embodiment 6,4-(2, the 4-dimethoxy-benzyl) piperidine hydrochlorate (6f)
According to the identical experimental procedure of embodiment 1, obtain 4-(2, the 4-dimethoxy-benzyl) piperidine hydrochlorate (6f) from (2, the 4-Dimethoxyphenyl)-4-pyridyl ketone (4f);
mp?178-180℃(MeOH-Et 2O)；
IR：v3449，2932，1611，1506，1464，1146cm -1；
13C?NMR：δ158.8，158.2，131.4，120.4，104.8，98.6，55.44，55.36，44.0，35.2，33.9，28.3；
Calcd?for?C 14H 22ClNO 2：C，61.87％；H，8.16％；N，5.15％；Found：C，61.68％；H，8.18％；N，5.21％.
The preparation of embodiment 7,4-(3, the 4-dimethyl benzyl) piperidine hydrochlorate (6g)
According to the identical experimental procedure of embodiment 1, obtain 4-(3, the 4-dimethyl benzyl) piperidine hydrochlorate (6g) from (3, the 4-3,5-dimethylphenyl)-4-pyridyl ketone (4g);
mp?218-219℃(MeOH-Et 2O)；
IR：v3420，2909，1586，12053420，2909，1586，1205cm -1；
13C?NMR：δ137.3，136.2，133.7，130.4，129.5，126.7，43.9，41.3，35.3，28.3，19.1，18.7；
Calcd?for?C 14H 22ClN：C，70.13％；H，9.25％；N，5.84％；Found：C，69.93％；H，9.18％；N，5.96％.
The preparation of embodiment 8,4-(3, the 5-dimethyl benzyl) piperidine hydrochlorate (6h)
According to the identical experimental procedure of embodiment 1, obtain 4-(3, the 5-dimethyl benzyl) piperidine hydrochlorate (6h) from (3, the 5-3,5-dimethylphenyl)-4-pyridyl ketone (4h);
mp?184-186℃(MeOH-Et 2O)；
IR：v3442，2955，2768，1607，1588，1450cm -1；
13C?NMR：δ139.8，137.5，127.4，127.0，43.9，41.7，35.2，28.3，20.8；
Calcd?for?C 14H 22ClNO 2：C，61.87％；H，8.16％；N，5.15％；Found：C，61.68％；H，8.18％；N，5.21％.
The preparation of embodiment 9, α-(4-fluorophenyl)-4-piperidine carbinols hydrochloride (6i)
According to the identical experimental procedure of embodiment 1, obtain α-(4-fluorophenyl)-4-piperidine carbinols hydrochloride (6i) from (4-fluorophenyl)-4-pyridyl ketone (4i);
mp?248-250℃(dec.)，(MeOH-Et 2O)；
IR：v3339，2950，2813，2718，1509，1223cm -1；
13C?NMR：δ163.8，160.6，137.5，128.7，128.5，115.5，115.2，76.6，43.9，43.8，40.1，25.1，25.0；
Calcd?for?C 12H 17ClFNO：C，58.66％；H，6.97％；N，5.70％；Found：C，58.67％；H，7.12％；N，5.55％.
Second section: the reduction of Alkylpyridyl ketone (5)
The reduction of Alkylpyridyl ketone (5) Application of Catalyst and together with on two of the dichloro-alkane with aryl (4-pyridyl) ketone (4) in statement in full accord.
In the present invention, substrate Alkylpyridyl ketone can be 2-or 4-Alkylpyridyl ketone, and alkyl wherein (R) can comprise hydrogen atom (H); The straight chained alkyl of 1-20 carbon atom, branched-chain alkyl and cycloalkyl wherein can have alkoxyl group to replace (OR on any carbon atom beyond two carbon atoms of distance ketone carbonyl 1, R wherein 1The straight chained alkyl of=1-10 carbon atom, branched-chain alkyl and cycloalkyl) and aryl replacement (Ar, wherein Ar=phenyl; The straight-chain paraffin, branched paraffin and the naphthenic hydrocarbon that on any position of phenyl ring, have 1-4 carbon atom; The straight chain alkoxyl group, branched alkoxy and the cycloalkyloxy that perhaps have 1-4 carbon atom on any position of phenyl ring).
As previously mentioned: when Alkylpyridyl ketone (5) is hydrogenated reduction when becoming pyridyl benzylalcohol (11), have two competing reactions in the subsequent reactions: a) pyridine ring is reduced into and is piperidine ring; B) benzylalcohol is generated methylene radical by hydrogenolysis.If reaction b takes place earlier, then generate Alkylpiperidine hydrochloride (7) at last.If reaction a takes place earlier, pyridyl benzylalcohol originally then becomes piperidyl alcohol.Therefore, alcoholic extract hydroxyl group loses fully by the possibility of hydrogenolysis, generates (alpha-alkyl) piperidine carbinols hydrochloride (9) at last.
According to foregoing reaction conditions, though the hydro-reduction overall yield of Alkylpyridyl ketone (5) is almost always quantitatively finished, the product that generates is the mixture of Alkylpiperidine hydrochloride (7) and (alpha-alkyl) piperidine carbinols hydrochloride (9).We find that the ratio of Alkylpiperidine hydrochloride (7) and (alpha-alkyl) piperidine carbinols hydrochloride (9) changes along with the variation of alkyl chain length in the mixture.As shown in table 4: the carbochain of alkyl is long more, and the ratio that generates (alpha-alkyl) piperidine carbinols hydrochloride (9) is high more.
Figure C20061014435900141
The Changing Pattern of table 4. Alkylpyridyl ketone (5) competing reaction in hydro-reduction
Figure C20061014435900142
In order to increase the chemo-selective of hydro-reduction product, be example with 4-pyridyl formaldehyde (5a), temperature of reaction is tested.The result shows: the rising temperature of reaction is fast reaction speed obviously.Though the trend that increases compound 7a ratio is arranged, 25% product 9a is still arranged in the time of 55 ℃.
Then the reaction pressure of substrate 5a is tested.The result shows: pressure is just in time opposite to the influence of reaction preference with temperature.Increase not only obvious fast reaction speed of reaction pressure, and have the trend of remarkable increase compound 9a ratio.Reaction when room temperature and 60psi has shown the chemo-selective of height, almost provides single product 9a quantitatively.
To the alkyl substrate (5a-d, table 4) long than short chain, the selectivity that lower temperature of reaction helps reacting, first-selected temperature is a room temperature.To the alkyl substrate long than long-chain, prepared in laboratory is best with room temperature.But consider from time saving angle, can more than room temperature, any temperature carry out, when temperature of reaction surpasses the methyl alcohol boiling point, can change high boiling solvent.For increasing chemo-selective than the long substrate of short chain (5a-d, table 4), must use certain hydrogen pressure, 80psi just can reach very satisfied effect with interior hydrogen pressure.The substrate long than long-chain just has very satisfied selectivity under normal pressure, but selects higher pressure to save time.
According to following experiment condition: with ClCH 2CHCl 2Or CH 2Cl 2As together with two enparas, MeOH is a solvent, and under the 15-80psi hydrogen pressure, Alkylpyridyl ketone substrate molecule (5) all can successfully be converted to and be (alpha-alkyl) piperidyl methyl alcohol hydrochloride (9).As shown in table 5, all hydro-reduction reactions all generate corresponding product with the chemo-selective and the almost quantitative productive rate of height.
The catalytic hydrogenation reduction of table 5. Alkylpyridyl ketone (5)
A.CH 2Cl 2Be used as the chlorine source, all reactions are carried out at normal temperatures.
The preparation of embodiment 10,4-piperidine carbinols hydrochloride (9a)
(2.0mmol), (163mg, 50%w/w), (after stirring 6.5h under the hydrogen pressure of 25 ℃ and 40psi, absorption of hydrogen stops methylene dichloride 10%Pd-C fully for 204mg, methyl alcohol 2.4mmol) (30mL) mixture for 5a, 214mg with 4-pyridyl formaldehyde.Filter out Pd-C, boil off the methyl alcohol in the filtrate, after the pale yellow colored solid body and function anhydrous diethyl ether washing of generation, through CH 3OH-Et 2The O recrystallization obtains the white crystal (297mg, 98%) of 4-piperidine carbinols hydrochloride (9a);
mp?128-130℃(MeOH-Et 2O)；
Figure C20061014435900161
v3261，2937，2888，2821，2731，2509，1617，1102，1016cm -1；
13C?NMR：δ65.5，43.8，35.4，25.1；
Calcd?for?C 6H 14ClNO：C，47.52％；H，9.31％；N，9.24％；Found：C，47.17％；H，9.41％；N，9.11％.
The preparation of embodiment 11, Alpha-Methyl-4-piperidine carbinols hydrochloride (9b)
According to the identical experimental procedure of embodiment 10, be raw material with 4-acetylpyridine (5b), vinyl trichloride is together with two enparas, reaction obtains Alpha-Methyl-4-piperidine carbinols hydrochloride (9b);
mp?108-110℃(MeOH-Et 2O)；
IR：v3404，2968，2812，2722，2496，1602，1453，1057cm -1；
13C?NMR：δ70.4，44.1，44.0，40.2，28.2，24.6，24.3，19.1；
Calcd?for?C 7H 16NOCl：C，50.75％；H，9.73％；N，8.46％；Found：C，50.66％；H，9.85％；N，8.44％.
The preparation of embodiment 12, α-ethyl-4-piperidine carbinols hydrochloride (9c)
According to the identical experimental procedure of embodiment 10, be raw material with 4-propionyl pyridine (5c), vinyl trichloride is together with two enparas, reaction obtains α-ethyl-4-piperidine carbinols hydrochloride (9c);
mp?106-108℃(MeOH-Et 2O)；
Figure C20061014435900162
v?3394，3068，2959，2936，2819，2715，1578，1378，994cm -1；
13C
Figure C20061014435900163
δ75.6，44.2，44.1，38.3，25.8，25.1，23.8，9.4；
Calcd?for?C 8H 18ClNO：C，53.47％；H，10.10％；N，7.80％；Found：C，53.52％；H，10.14％；N，7.78％.
The preparation of embodiment 13, α-normal-butyl-4-piperidine carbinols hydrochloride (9d)
(2.0mmol), (163mg, 50%w/w), (after stirring 6.5h under the hydrogen pressure of 25 ℃ and 40psi, absorption of hydrogen stops vinyl trichloride 10%Pd-C fully for 320mg, methyl alcohol 2.4mmol) (30mL) mixture for 5d, 326mg with 4-pentanoyl pyridine.Filter out Pd-C, boil off the methyl alcohol in the filtrate, after the pale yellow colored solid body and function anhydrous diethyl ether washing of generation, through CH 3OH-Et 2The O recrystallization obtains the white crystal (415mg, 100%) of α-normal-butyl-4-piperidine carbinols hydrochloride (9d);
mp?112-114℃(MeOH-Et 2O)；
IR：v?3392，2954，2928，2860，2818，2716，1579，1449，1380，994cm -1；
13C?NMR：δ74.1，44.3，44.2，38.9，32.8，27.5，25.2，23.8，22.4，138；
Calcd?for?C 10H 22ClNO：C，57.82％；H，10.67％；N，6.74％；Found：C，57.75％；H，10.79％；N，6.72％.
The preparation of embodiment 14, α-amyl group-4-piperidine carbinols hydrochloride (9e)
According to the identical experimental procedure of embodiment 13, be raw material with 4-caproyl pyridine (5e), reaction obtains α-amyl group-4-piperidine carbinols hydrochloride (9e);
mp?108-110℃(MeOH-Et 2O)；
IR：v3393，3070，2951，2924，2859，2819，2716，1580，1466，1448，1379cm -1；
13C?NMR：δ74.0，44.2，44.1，38.9，33.1，31.4，25.2，24.9，23.7，22.3，13.7；
Calcd?for?C 11H 24ClNO：C，59.57％；H，10.91％；N，6.32％；Found：C，59.68％；H，10.79％；N，6.47％.
The preparation of embodiment 15, α-hexyl-4-piperidine carbinols hydrochloride (9f)
According to the identical experimental procedure of embodiment 13, be raw material with 4-oenanthyl pyridine (5f), reaction obtains α-hexyl-4-piperidine carbinols hydrochloride (9f);
mp?98-100℃(MeOH-Et 2O)；
IR：v3394，3370，3064，2955，2925，2715，1133cm -1；
13C?NMR：δ74.0，44.2，38.9，33.1，31.4，28.8，25.2，23.7，22.3，13.7；
Calcd?for?C 12H 26ClNO：C，61.12；H，11.11；N，5.94；Found：C，61.28；H，11.07；N，5.87.
The preparation of embodiment 16, α-octyl group-4-piperidine carbinols hydrochloride (9g)
According to the identical experimental procedure of embodiment 13, be raw material with 4-nonanoyl pyridine (5g), reaction obtains α-octyl group-4-piperidine carbinols hydrochloride (9g);
mp?107-108℃(MeOH-Et 2O)；
IR：v3392，3366，3067，2955，2923，2716，1108cm -1；
13C?NMR：δ73.9，44.1，44.0，33.6，31.9，29.7，29.4，25.8，25.4，23.5，22.6，13.9.
Calcd?for?C 14H 30ClNO：C，63.73％；H，11.46％；N，5.31％；Found：C，63.47％；H，11.32％；N，5.29％.
The preparation of embodiment 17, α-(2-phenylethyl)-4-piperidine carbinols hydrochloride (9h)
According to the identical experimental procedure of embodiment 13, so that 4-(3-phenyl propionyl)-pyridine (5h) is a raw material, reaction obtains α-(2-phenylethyl)-4-piperidine carbinols hydrochloride (9h);
mp?170-171℃(MeOH-Et 2O)；
IR：v3628，3382，2947，2825，2802，2725，1578，1495，1450cm -1；
13C?NMR：δ142.5，128.7，126.0，73.2，44.1，44.0，39.0，35.3，31.7，25.2，23.5；
Calcd?for?C 14H 22ClNO：C，65.74％；H，8.67％；N，5.48％；Found：C，65.68％；H，8.44％；N，5.50％.
The preparation of embodiment 18, α-butyl-2-piperidine carbinols hydrochloride (9i)
According to the identical experimental procedure of embodiment 13, be raw material with 2-(pentanoyl) pyridine (5i), reaction obtains α-butyl-2-piperidine carbinols hydrochloride (9i);
mp?132-134℃(MeOH-Et 2O)；
IR：v3423，2956，2869，1486，1470，1447，1080cm -1；
13C?NMR：δ71.4，70.7，61.3，60.6，45.1，44.7，32.0，31.4，27.4，26.7，25.3，22.1，21.9，21.6，21.4，13.4；
Calcd?for?C 10H 22ClNO：C，57.82％；H，10.67％；N，6.74％；Found：C，57.94％；H，10.48％；N，6.87％.

Claims (11)

1, a kind of catalytic hydrogenation of acyl pyridine is the method for preparing substituted pyridine compound hydrochlorate, be acyl pyridine with formula I or formula II structure at the Pd-C catalyzer with in the presence of together with two enparas, carry out catalytic hydrogenation, obtain preparing substituted pyridine compound hydrochlorate;
(formula I)
Figure C2006101443590002C2
(formula II)
Wherein, R is H, alkyl or aryl;
Described is R together with two enpara general formulas 1R 2CCl 2, wherein, R 1, R 2For the alkyl of H, C1-C10 or 1-5 chlorine atom arranged and/or C1-C10 alkyl that fluorine atom replaces;
When R was H, described preparing substituted pyridine compound hydrochlorate was the piperidine carbinols hydrochloride; When R was alkyl, described preparing substituted pyridine compound hydrochlorate was an alpha-alkyl piperidine carbinols hydrochloride; When R was aryl, described preparing substituted pyridine compound hydrochlorate was 4-(arylmethyl) piperidine hydrochlorate.
2, method according to claim 1 is characterized in that: described alkyl is straight chained alkyl, branched-chain alkyl or the cycloalkyl of C1-C20, perhaps, and straight chained alkyl, branched-chain alkyl or the cycloalkyl of the C1-C20 that alkoxyl group or aryl replace.
3, method according to claim 1 is characterized in that: described aryl is phenyl or substituted-phenyl, and substituting group is the alkyl of H, C1-C10 or the alkoxyl group of C1-C10.
4, method according to claim 1 is characterized in that: described is methylene dichloride, 1 together with two enparas, 1-ethylene dichloride, 1,1,2-trichloroethane, 1,1-two chloro-2-fluoroethanes, 1,1-two chloro-2,2,2-Halothane, 1, propylidene chloride 1,2,2-propylene dichloride, 1,1-two chloro-3,3-dimethylbutane, 1,1-dichloro pentamethylene or 1,1-dichloro hexanaphthene.
5, method according to claim 4 is characterized in that: described is 1 together with two enparas, 1-ethylene dichloride or 1,1-two chloro-3,3-dimethylbutane.
6, method according to claim 1 is characterized in that: reaction solvent is MeOH, EtOH, i-PrOH, t-BuOH or EtOAc.
7, method according to claim 6 is characterized in that: described reaction solvent is MeOH or EtOH.
8, according to the arbitrary described method of claim 1-7, it is characterized in that: described Pd-C catalyst consumption is the 1-100% of described acyl pyridine weight; Described mol ratio together with two enparas and described acyl pyridine is more than 1: 1.
9, method according to claim 8 is characterized in that: described mol ratio together with two enparas and described acyl pyridine is 1.1: 1.
10, method according to claim 1 is characterized in that: when R was aryl, the condition that optionally obtains single 4-(arylmethyl) piperidine hydrochlorate was under normal pressure and 35-45 ℃.
11, method according to claim 1 is characterized in that: when R was H, the condition that optionally obtains single piperidine carbinols hydrochloride was under the hydrogen pressure of room temperature and 40-80psi; When R was alkyl, the condition that optionally obtains single alpha-alkyl piperidine carbinols hydrochloride was under the hydrogen pressure of room temperature and 40-80psi.
CNB2006101443591A 2006-12-04 2006-12-04 Method for catalytic hydrogenation of acyl pyridine to preparing substituted pyridine compound hydrochlorate Expired - Fee Related CN100448846C (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CNB2006101443591A CN100448846C (en) 2006-12-04 2006-12-04 Method for catalytic hydrogenation of acyl pyridine to preparing substituted pyridine compound hydrochlorate

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CNB2006101443591A CN100448846C (en) 2006-12-04 2006-12-04 Method for catalytic hydrogenation of acyl pyridine to preparing substituted pyridine compound hydrochlorate

Publications (2)

Publication Number Publication Date
CN1995017A CN1995017A (en) 2007-07-11
CN100448846C true CN100448846C (en) 2009-01-07

Family

ID=38250237

Family Applications (1)

Application Number Title Priority Date Filing Date
CNB2006101443591A Expired - Fee Related CN100448846C (en) 2006-12-04 2006-12-04 Method for catalytic hydrogenation of acyl pyridine to preparing substituted pyridine compound hydrochlorate

Country Status (1)

Country Link
CN (1) CN100448846C (en)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4690931A (en) * 1982-10-13 1987-09-01 Synthelabo Therapeutically useful 1-phenyl-2-piperidinoalkanol derivatives

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4690931A (en) * 1982-10-13 1987-09-01 Synthelabo Therapeutically useful 1-phenyl-2-piperidinoalkanol derivatives

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
哌啶催化合成工艺研究. 陈声宗.化学反应工程与工艺，第16卷第4期. 2002
哌啶催化合成工艺研究. 陈声宗.化学反应工程与工艺，第16卷第4期. 2002 *

Also Published As

Publication number Publication date
CN1995017A (en) 2007-07-11

Similar Documents

Publication Publication Date Title
JP5216065B2 (en) Pyridyltetrahydropyridines and pyridylpiperidines and methods for producing them
Blaser et al. The role of catalysis for the clean production of fine chemicals
US4605743A (en) Process for the production of 2,2,6,6-tetraalkyl-4-piperidylamines
US4089839A (en) 5-Chloro-2-(2'-hydroxy-5'-tert-octylphenyl)benzotriazole and polypropylene stabilized therewith
US4607104A (en) Process for the production of 2,2,6,6-tetraalkyl-4-piperidylamines
CA1205470A (en) Dihydropyridines
US3462441A (en) Bis(pyridylethyl)- and bis(piperidylethyl)-indoles
CN100448846C (en) Method for catalytic hydrogenation of acyl pyridine to preparing substituted pyridine compound hydrochlorate
HU220590B1 (en) Process for producing n-arilhydroxylamines and n-hetarylhydroxylamines
KR100691735B1 (en) New process for preparing 4-aminomethyl-3-alkoxyiminopyrrolidine methanesulphonate
HU182941B (en) Process for preparing new n-oxacyclyl-alkyl-piperidines further pharmaceutical compositions containing these compounds
JPS5910337B2 (en) Method for producing chlorinated phenylhydroxylamines
US5484918A (en) Process for the preparation of aqueous nicotinaldehyde
US5744648A (en) Process for the manufacture of 1, 3-cyclohexanedione
EP1221437B1 (en) Process for the preparation of primary and secondary amines from nitriles
WO2006061332A1 (en) Gleevec process
US3733338A (en) 1-oxo-isochromenes
US4208525A (en) Reduction of 4-oxo-tetraalkylpiperidines
US4722930A (en) 3-benzoyl-1-[(oxo or thioheteroaryl-ylalkyl)-piperid-4-yl]ureas and derivatives
US6258955B1 (en) Process for preparing 2-piperidineethanol compounds
CA2591894A1 (en) Process for producing 1-benzyl-4-[(5,6-dimethoxy-1-indanon­2-yl)methyl] piperidine or its salt thereof via novel intermediate
US20040116692A1 (en) Reductive alkylation of saturated cyclic amines
PL176708B1 (en) Method of obtaining high-purity buspyrone and its hydrochloride
TW393470B (en) Therapeutic heterocycles
Park et al. A new approch for catalyst optimization: Host/guest complexes of chiral bisphosphine bearing imidazolidinone and their application in Rh-catalyzed asymmetric hydrogenation

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
C17 Cessation of patent right
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20090107

Termination date: 20101204