CN100448846C - A kind of catalytic hydrogenation acylpyridine is the method for substituted piperidine compound hydrochloride - Google Patents

Abstract

The invention discloses a method for catalyzing the hydrogenation of acylpyridines into substituted piperidine compound hydrochlorides. The method of the invention is to use the acylpyridines with the structure of formula I or formula II in the presence of Pd-C catalyst and gem-dichloroalkane, Carry out catalytic hydrogenation reaction to obtain substituted piperidine compound hydrochloride; wherein, R is H, alkyl or aryl; the general formula of the geminal dichloroalkane is R ¹ R ² CCl ₂ , wherein R ¹ and R ² are H, C1-C10 alkyl or C1-C10 alkyl substituted by 1-5 chlorine atoms and/or fluorine atoms. The invention successfully reduces the pyridine ring to piperidine hydrochloride under mild conditions by adding gem-dichloroalkane into the catalytic system, and the generated hydrochloride brings many conveniences to the separation and purification of products. The method of the invention has high yield, good selectivity, mild reaction conditions and simple and convenient separation process.

Description

A kind of catalytic hydrogenation acylpyridine is the method for substituted piperidine compound hydrochloride

technical field

The invention relates to a compound preparation method, in particular to a method for catalyzing the hydrogenation of acylpyridines to substituted piperidine compound hydrochlorides.

Background technique

Substituted piperidines and their derivatives are important pharmacophores and synthetic intermediates in drug research. As shown below: 4-substituted piperidine derivative 1 not only has potential CCR5 antagonistic activity, but also shows good anti-HIV-1 activity (Shinichi, I.; Takashi, I.; Youichi, N.et al.J .Med.Chem., 2006,49,2784-2793.); Ifenprodil (2) has antihypertensive activity (Etsuo O.; Hitoshi T.; Hiroyuki H.et al.J.Med.Chem., 1993,36 , 417-420.); similar diphenylamide derivatives 3 can be used as blockers of sodium ion channels (IoannisR.; Sheryl H. and Roy D.S.J.Med.Chem., 1996, 39, 1514-1520.).

Using 4-substituted pyridines as raw materials to carry out hydrogenation reduction of pyridine rings under catalytic hydrogenation conditions is one of the important methods for preparing 4-substituted piperidine derivatives. For example: patent literature reports, after phenylpyridyl ketone and derivative thereof obtain corresponding benzylpyridine compound through the reduction of hydrazine hydrate, then use the method for catalytic hydrogenation to reduce pyridine ring, obtain corresponding benzylpiperidine compound (Wick, A.; Frost, J.; Gaudilliere, B.; Bertin, J.; Dupont, R.; Rousseau, J. US Patent 4,690,931, 1987). Another example: α-phenyl-4-pyridinemethanol uses relatively high temperature (60-80°C) and pressure (8-10bar) to carry out catalytic hydrogenation of Pd-C in acetic acid solvent. Reduction of pyridine rings to piperidine rings (Bela, A.; Agnes, P.; Gabor, T.; Laszlo, V. and Ferenc F. Eur. J. Org. Chem., 2004, 3623-3632.).

However, both of these two most representative methods have certain defects. For example: hydrazine hydrate itself has great toxicity and danger of operation; the hydrogenation reaction carried out in acetic acid solvent basically loses the characteristics of environmental friendliness, not only the post-treatment is cumbersome, but also only obtains low to medium yield .

Contents of the invention

The object of the present invention is to provide a method for catalytic hydrogenation of acylpyridines to be substituted piperidine compound hydrochlorides.

The catalytic hydrogenation of acylpyridine provided by the present invention is a method for substituted piperidine compound hydrochloride, which is to carry out the catalytic hydrogenation reaction of the acylpyridine with the structure of formula I or formula II in the presence of Pd-C catalyst and gem-dichloroalkane, Obtain substituted piperidine compound hydrochloride;

Wherein, R is H, alkyl or aryl;

The general formula of the gem-dichloroalkane is R ¹ R ² CCl ₂ , wherein R ¹ and R ² are H, C1-C10 alkyl or C1-C10 substituted with 1-5 chlorine atoms and/or fluorine atoms alkyl.

In acylpyridine, when R is an alkyl group, it is preferably a C1-C20 straight-chain alkyl, branched-chain alkyl or cycloalkyl; or a C1-C20 straight-chain alkane with an alkoxy or aryl substituent radical, branched alkyl or cycloalkyl. When R is an aryl group, the preferred aryl group is phenyl or substituted phenyl, and the substituents are H, C1-C10 alkyl, and C1-C10 alkoxy.

In the present invention, gem-dichloroalkane can be various commercial reagents, commonly used have dichloromethane, 1,1-dichloroethane, 1,1,2-trichloroethane, 1,1-dichloro -2-fluoroethane, 1,1-dichloro-2,2,2-trifluoroethane, 1,1-dichloropropane, 2,2-dichloropropane, 1,1-dichloro-3, 3-Dimethylbutane, 1,1-dichlorocyclopentane and 1,1-dichlorocyclohexane, etc.; preferably 1,1-dichloroethane or 1,1-dichloro-3,3 - Dimethylbutane.

The present invention has no special requirements for the reaction solvent, and the commonly used reaction solvents are MeOH, EtOH, i-PrOH, t-BuOH or EtOAc; preferably MeOH or EtOH.

In the method of the present invention, the amount of Pd-C catalyst and gem-dichloroalkane has little effect on the reaction, but can affect the speed and reaction time of the reaction. Usually, the amount of Pd-C catalyst is about 100% of the acylpyridine 1-100% by weight; the molar ratio of the gem-dichloroalkane to the acylpyridine is more than 1:1, and can even be used as a co-solvent, preferably 1.1:1.

Applying the method of the present invention, the product substituted piperidine compound hydrochloride sometimes has two kinds: one is piperidinol hydrochloride, and the other is alkyl piperidine hydrochloride. The following conditions can be used to improve the selectivity of the reaction:

When R is an aryl group, a single 4-(arylmethyl)piperidine hydrochloride can be selectively obtained under normal pressure and a temperature slightly higher than room temperature (35-45° C.).

When R is H or an alkyl group, a single (α-alkyl) piperidinemethanol hydrochloride can be selectively obtained at room temperature and a hydrogen pressure of 40-80 psi.

The invention successfully reduces the pyridine ring to piperidine hydrochloride under mild conditions by adding gem-dichloroalkane into the catalytic system, and the generated hydrochloride brings many conveniences to the separation and purification of products. The method of the invention has high yield, good selectivity, mild reaction conditions and simple and convenient separation process.

Detailed ways

Adding gem dichloride (R ¹ R ² CCl ₂ ) to the usual Pd-C catalytic hydrogenation reaction system, the acylpyridine [aryl pyridyl ketone (4) or alkyl pyridyl ketone (5)] can be almost quantitatively , highly chemoselectively converted into corresponding 4-(arylmethyl)piperidine hydrochloride (6) or (α-alkyl)piperidinemethanol hydrochloride (9), the reaction equation is as follows:

According to the results of the experiment follow-up, we found that the ketone carbonyl in the acylpyridin [aryl(4-pyridyl) ketone (4) and alkylpyridyl ketone (5)] was first reduced to Pyridinemethanol intermediate (10 and 11). Then, the gem dichloride undergoes a catalytic hydrodechlorination reaction under the condition of Pd-C catalytic hydrogenation. The resulting hydrogen chloride converts the pyridinemethanol intermediates (10 and 11) to the hydrochloride salts (12 and 13) in situ. The generation of hydrochloride not only removes the poisoning effect of the pyridine nitrogen atom on the catalyst, but also further polarizes the pyridine ring, which further reduces the aromatic stability. The reaction process is as follows. Therefore, not only can the pyridine ring be successfully reduced to piperidine hydrochloride under mild conditions, but the generated hydrochloride brings a lot of convenience to the separation and purification of the product. Simple filtration can realize the separation of the product and the raw material. separate. Moreover, the reaction conditions of the above reaction are very mild, and can be carried out under 35° C. and 80 psi hydrogen pressure.

Under the experimental conditions of the present invention, when -R is an aryl group or an alkyl group, the reactivity of the obtained pyridinemethanol intermediates (10 and 11) shows a significant difference: when -R is an aryl group, the compound 10 molecule The hydroxyl group in is activated by the connected aryl group, and the hydrogenolysis reaction of the C-O bond continues to generate methylene, and finally selectively generates 4-(arylmethyl)piperidine hydrochloride (6). And when -R is an alkyl group, the hydroxyl group in the compound 11 molecule is connected with the alkane, and under the reaction conditions of the present invention, the hydrogenolysis reaction of the C-O bond can be controlled completely, and finally selectively generate (α-alkyl) piperidine Methanol hydrochloride (9).

In the present invention, gem-dichloroalkane (R ² R ¹ CCl ₂ ) refers to an alkane with two substituted chlorine atoms on one C atom, and R ² and R ¹ in the molecule can be hydrogen atoms or C1-C10 Alkyl groups (straight-chain alkyl, branched-chain alkyl and cycloalkyl), in these alkane chains may have 1-5 chlorine atoms or fluorine atoms substituted at any position other than the geminal dichloro carbon atom. It is best to use gem-dichloroalkanes with less than 6 carbon atoms, which are easy to remove during post-processing. Experiments prove that under the selected Pd/C catalytic hydrogenation experimental conditions of the present invention, the reductive dechlorination reaction of gem-dichloroalkanes is a process controlled by the substrate. In the absence of nitrogenous substrates, reductive dechlorination does not occur. In the presence of nitrogen-containing substrates, only one of the two chlorine atoms in the gem-dichloroalkane undergoes a reductive dechlorination reaction to generate hydrogen chloride. Therefore, the reaction does not generate excess hydrogen chloride at any time to poison the catalyst. The most commonly used gem-dichloroalkanes are those commercial compounds such as: dichloromethane, 1,1-dichloroethane, 1,1,2-trichloroethane, 1,1-dichloro-2-fluoroethane alkanes, 1,1-dichloro-2,2,2-trifluoroethane, 1,1-dichloropropane, 2,2-dichloropropane, 1,1-dichloro-3,3-dimethyl Butane, etc. 1,1-dichlorocyclopentane and 1,1-dichlorocyclohexane, etc. It is best to use 1,1-dichloroethane or 1,1-dichloro-3,3-dimethylbutane because of their relatively high boiling point and easy quantification during operation. When they release a chlorine atom, the boiling point of the monochlorine compound generated is much lower, and it is easy to remove from the system. Theoretically, the molar ratio of gem-dichloroalkane to substrate is 1:1, but preferably 1.1:1 is used. An excess of gem-dichloroalkane does not negatively affect the selectivity and yield of the reaction. Therefore, in actual operation, the amount of gem-dichloroalkane is relatively arbitrary.

In the invention, the catalytic hydrogenation reduction reaction can be carried out in solvents such as MeOH, EtOH, i-PrOH, t-BuOH and EtOAc. Experiments have shown that under the same conditions of catalyst consumption, reaction temperature, hydrogen pressure, etc., the yield and selectivity of the product are the best when MeOH and EtOH are solvents, and the more preferred reaction solvent is MeOH.

In the present invention, the reaction temperature is generally below the boiling point of the reaction solvent; under high temperature conditions, the reaction speed can be accelerated. At this time, a high boiling point solvent needs to be selected to ensure the smooth progress of the reaction. During the reaction, the H ₂ pressure can generally be controlled within the range of normal pressure to 80 psi, increasing the H ₂ pressure is also beneficial to the reaction, but there are special requirements for the reaction equipment.

Part 1: Hydrogenation reduction of aryl(4-pyridyl)ketones (4)

As shown in the following formula: the reduction of aryl (4-pyridyl) ketone (4) can be illustrated with phenyl (4-pyridyl) ketone (4a) as an example. In the present invention, the content of Pd in the Pd-C catalyst can be in the range of 1%-50%, and the actual situation is mainly affected by reaction pressure, temperature and time. Generally, a commercially available 5% or 10% Pd-C catalyst can be conveniently selected. Considering the comprehensive conditions of the reaction, it is best to use 10% Pd-C catalyst. The dosage of the 10% Pd-C catalyst is generally 1-100% of the weight of the substrate, as shown in Table 1. From an economic point of view, it is best to select 25%; the amount of less than 25% can still complete the reaction, but it needs to increase the reaction temperature or prolong the reaction time. From the perspective of saving time, it is best to use 50% of the dosage for laboratory operations. When the amount exceeds 100%, the reaction can be carried out at normal temperature and pressure.

Table 1. Effect of Pd/C catalyst dosage on 4a catalytic hydrogenation ^a

a. Hydrogen pressure = 1 atmosphere. b. The mother liquor contains a non-salt-forming mixture.

In the present invention, aryl (-R) in aryl (4-pyridyl) ketone mainly refers to phenyl and substituted phenyl, and the scope of substituent includes hydrogen atom (H); Alkyl (-R), wherein Including straight-chain alkyl, branched-chain alkyl and cycloalkyl of 1-10 carbon atoms; alkoxy (-OR), wherein R = straight-chain alkyl, branched-chain alkyl and Cycloalkyl. The substituents may be substituted at the ortho, meta, or para positions of the benzene ring, or may be substituted at these positions simultaneously.

If there are one or more fluorine atoms on the benzene ring, the reaction is significantly affected. For example: (4-fluorophenyl) (4-pyridyl) ketone (4h) generates 4-(4-fluorobenzyl) piperidine hydrochloride (6h) and (4-fluorophenyl ) (4-piperidinyl)methanol hydrochloride (8h) mixture. This is mainly because the activation of benzyl alcohol by the benzene ring is significantly reduced, so that the reaction intermediate benzyl alcohol cannot completely undergo the hydrogenolysis reaction of the hydroxyl group. However, when _CH2Cl2 was used as _the chlorine source, the reaction could chemoselectively yield the single product (4-fluorophenyl)(4-piperidinyl)methanol hydrochloride (8h) (Table 2). This is mainly because CH ₂ Cl ₂ has a higher hydrodechlorination activity and can quickly generate pyridine hydrochloride. Once pyridine hydrochloride is reduced to piperidine hydrochloride, the original benzyl alcohol is converted to piperidinylmethanol. Therefore, the CO hydrogenolysis reaction of alcoholic hydroxyl groups is completely prevented.

Selective catalytic hydrogenation reduction of table 24-(4-fluorobenzoyl)pyridine (4h) ^a

a. Pd-C catalyst dosage is 50% w/w. b. The mother liquor of experiments 1-4 contains a non-salt-forming mixture, but it does not affect the separation.

Under the experimental conditions of the present invention, the first step of the aryl pyridyl ketone reaction is to reduce the carbonyl to a hydroxyl group, and then two competing reactions are produced: a) the pyridine ring is reduced to a piperidine ring; b) the hydroxyl group is hydrogenolyzed Generate methylene. The speed of reaction b has no effect on reaction a. However, if reaction a is completed first, the activation ability of pyridine to hydroxyl will disappear, so the rate of hydrogenolysis of hydroxyl to form methylene in reaction b will be greatly reduced. Therefore, it is necessary to maintain an appropriate reaction temperature and increase the hydrogenolysis ability of the hydroxyl group to selectively obtain a single 4-(arylmethyl)piperidine hydrochloride (6). Under normal pressure, the reaction between 35-55°C gives the most ideal reaction speed, selectivity, and yield, and 35°C is preferred. When the temperature is lower than 35°C, sometimes there is a small amount of benzyl alcohol compound in the product. The influence of temperature on the reaction rate is very significant, for example: phenyl (4-pyridyl) ketone (4a) needs 12 hours to complete the reaction at 35°C, but only 4.5 hours at 55°C. If a higher temperature is applied, the appropriate solvent needs to be changed, which is not necessary in laboratory preparation.

The change of hydrogen pressure in the reaction also has a significant impact on the reaction rate and product selectivity. If the reaction temperature is kept between 35-55°C, the reactions carried out under the hydrogen pressure between 15-80psi have no obvious influence on the chemoselectivity. But at room temperature, the influence of the change of hydrogen pressure on the reaction selectivity is quite obvious. For example: phenyl (4-pyridyl) ketone (4a) generates a 1:3 mixture of 6a and 8a under normal pressure; however, a single product 4-(benzyl) piperidinium salt is quantitatively generated under 80 psi hydrogen pressure salt (6a).

According to the following experimental conditions: using ClCH ₂ CHCl ₂ or CH ₂ Cl ₂ as gem-dichloroalkane, MeOH as solvent, at 35°C and 1 atm hydrogen pressure, aryl (4-pyridyl) ketone substrate molecules can be successfully It is converted into 4-(arylmethyl)piperidine hydrochloride (6). As shown in Table 3, all transformations were highly chemoselective and almost quantitative in yield.

Table 3. Examples of hydrogenation reduction of aryl (4-pyridyl) ketones (4)

_a . Pd/C amount is 100% w/w; b. _CH2Cl2 is used as chlorine source.

The preparation of embodiment 1,4-benzylpiperidine hydrochloride (6a)

4-Benzoylpyridine (4a, 366 mg, 2.0 mmol), 10% Pd-C (183 mg, 50% w/w), and 1,1,2-trichloroethane (320 mg, 2.4 mmol) were dissolved in methanol (30 mL), after stirring the resulting suspension at 35 °C under 1 atmosphere of hydrogen pressure for 12 h, hydrogen uptake completely ceased. After filtering out Pd-C, the methanol in the filtrate was distilled off, and the resulting white solid was washed with anhydrous ether, and then recrystallized from CH ₃ OH-Et ₂ O to obtain the white 4-benzylpiperidine hydrochloride (6a). Crystals (42 mg, 98%).

mp 180-181°C (MeOH- _Et2O );

IR: v3427, 3371, 3026, 2733, 1595, 1497, 1471, 1452, ^1074cm-1 ;

¹³ C NMR: δ140.0, 129.4, 128.6, 126.4, 44.1, 41.5, 35.1, 28.2;

Calcd for C ₁₂ H ₁₈ ClN: 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-methylbenzyl)piperidine hydrochloride (6b)

According to the same experimental procedure as in Example 1, using (4-methylphenyl)-4-pyridyl ketone (4b) as a raw material, 4-(4-methylbenzyl)piperidine hydrochloride (6b) was obtained;

mp 218-220°C (MeOH- _Et2O );

IR: v3448, 3382, 3035, 2505, 1593, 1515, 1473, 1451cm ^-1 ;

¹³ C NMR: δ136.8, 135.5, 129.2, 129.0, 43.9, 41.2, 35.2, 28.2, 20.4;

Calcd for C ₁₃ H ₂₀ ClN: 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-methylbenzyl)piperidine hydrochloride (6c)

According to the same experimental procedure as in Example 1, 4-(2-methylbenzyl)piperidine hydrochloride (6c) was obtained from (2-methylphenyl)-4-pyridylketone (4c);

mp 225-207°C (MeOH- _Et2O );

IR: v3447, 3374, 2726, 1635, 1592, 1494, ^1456cm-1 ;

¹³ C 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 ₁₃ H ₂₀ ClN: 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-methoxybenzyl)piperidine hydrochloride (6d)

According to the same experimental procedure as in Example 1, 4-(4-methoxybenzyl)piperidine hydrochloride (6d) was obtained from (4-methoxyphenyl)-4-pyridylketone (4d);

mp 172-174°C (MeOH- _Et2O );

IR: v3448, 2841, 2723, 1613, 1593, 1513, 1455, 1443, 1246, 1029cm ^-1 ;

¹³ C NMR: δ157.2, 132.6, 130.4, 113.9, 55.4, 44.0, 40.5, 35.2, 28.1;

Calcd for C ₁₃ H ₂₀ ClNO: 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-methoxybenzyl)piperidine hydrochloride (6e)

According to the same experimental procedure as in Example 1, 4-(3-methoxybenzyl)piperidine hydrochloride (6e) was obtained from (3-methoxyphenyl)-4-pyridylketone (4e);

mp 150-152°C (MeOH- _Et2O );

IR: v3423, 2840, 2466, 1611, 1582, 1488, 1470, 1454, 1259, 1046cm ^-1 ;

¹³ C 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 ₁₃ H ₂₀ ClNO: 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-(2,4-dimethoxybenzyl)piperidine hydrochloride (6f)

According to the same experimental procedure as in Example 1, 4-(2,4-dimethoxybenzyl) piperidine hydrochloride was obtained from (2,4-dimethoxyphenyl)-4-pyridyl ketone (4f) salt (6f);

mp 178-180°C (MeOH- _Et2O );

IR: v3449, 2932, 1611, 1506, 1464, 1146cm ^-1 ;

¹³ C 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 ₁₄ H ₂₂ ClNO 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-(3,4-dimethylbenzyl)piperidine hydrochloride (6g)

According to the same experimental procedure as in Example 1, 4-(3,4-dimethylbenzyl) piperidine hydrochloride was obtained from (3,4-dimethylphenyl)-4-pyridyl ketone (4g) ( 6g);

mp 218-219°C (MeOH- _Et2O );

IR: v3420, 2909, 1586, 12053420, 2909, 1586, ^1205cm-1 ;

¹³ C 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 ₁₄ H ₂₂ ClN: C, 70.13%; H, 9.25%; N, 5.84%; Found: C, 69.93%; H, 9.18%; N, 5.96%.

Embodiment 8, the preparation of 4-(3,5-dimethylbenzyl)piperidine hydrochloride (6h)

According to the same experimental procedure as in Example 1, 4-(3,5-dimethylbenzyl) piperidine hydrochloride was obtained from (3,5-dimethylphenyl)-4-pyridyl ketone (4h) ( 6h);

mp 184-186°C (MeOH- _Et2O );

IR: v3442, 2955, 2768, 1607, 1588, 1450cm ^-1 ;

¹³ C NMR: δ139.8, 137.5, 127.4, 127.0, 43.9, 41.7, 35.2, 28.3, 20.8;

Calcd for C ₁₄ H ₂₂ ClNO ₂ : C, 61.87%; H, 8.16%; N, 5.15%; Found: C, 61.68%; H, 8.18%; N, 5.21%.

Example 9, Preparation of α-(4-fluorophenyl)-4-piperidinemethanol hydrochloride (6i)

According to the same experimental procedure as in Example 1, α-(4-fluorophenyl)-4-piperidinemethanol hydrochloride (6i) was obtained from (4-fluorophenyl)-4-pyridylketone (4i);

mp 248-250°C (dec.), (MeOH-Et ₂ O);

IR: v3339, 2950, 2813, 2718, 1509, 1223cm ^-1 ;

¹³ C 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 ₁₂ H ₁₇ ClFNO: C, 58.66%; H, 6.97%; N, 5.70%; Found: C, 58.67%; H, 7.12%; N, 5.55%.

Part II: Reduction of alkyl pyridyl ketones (5)

The reduction of alkyl pyridyl ketones (5) is exactly the same as that of aryl (4-pyridyl) ketones (4) in terms of the use of catalysts and gem-dichloroalkanes.

In the present invention, the substrate alkyl pyridyl ketone can be 2- or 4-alkyl pyridyl ketone, wherein the alkyl (-R) can include a hydrogen atom (H); a straight chain of 1-20 carbon atoms Alkyl, branched chain alkyl and cycloalkyl, wherein there may be alkoxy substitution on any carbon atom other than two carbon atoms from the ketone carbonyl group (-OR ¹ , wherein R ¹ = straight chain of 1-10 carbon atoms chain alkyl, branched chain alkyl and cycloalkyl) and aryl substitution (-Ar, where Ar = phenyl; straight-chain alkanes, branched-chain alkanes and cycloalkane; or straight-chain alkoxy, branched-chain alkoxy and cycloalkoxy with 1-4 carbon atoms at any position of the benzene ring).

As mentioned above: when the alkyl pyridyl ketone (5) is hydrogenated and reduced to pyridyl benzyl alcohol (11), there are two competing reactions in the subsequent reaction: a) the pyridine ring is reduced to a piperidine ring; b) Benzyl alcohol is hydrogenolyzed to form methylene. If reaction b occurs first, the alkylpiperidine hydrochloride (7) is finally formed. If reaction a occurs first, the original pyridyl benzyl alcohol becomes piperidyl alcohol. Therefore, the alcoholic hydroxyl group completely loses the possibility of being hydrogenolyzed, and finally generates (α-alkyl)piperidinemethanol hydrochloride (9).

According to the reaction conditions described above, although the overall yield of the hydrogenation reduction of alkylpyridyl ketones (5) is almost always quantitative, the products generated are all alkylpiperidine hydrochlorides (7) and (α-alkane base) mixtures of piperidinemethanol hydrochloride (9). We found that the ratio of alkylpiperidine hydrochloride (7) and (α-alkyl)piperidinemethanol hydrochloride (9) in the mixture varied with the alkyl chain length. As shown in Table 4: the longer the carbon chain of the alkyl group, the higher the ratio of (α-alkyl) piperidinemethanol hydrochloride (9) is generated.

Table 4. Variation of competition reaction of alkylpyridinyl ketone (5) in hydrogenation reduction

In order to increase the chemoselectivity of hydrogenated reduction products, the reaction temperature was tested by taking 4-pyridylcarbaldehyde (5a) as an example. The results show that increasing the reaction temperature can significantly speed up the reaction rate. Although there was a tendency to increase the proportion of compound 7a, there was still 25% product 9a at 55 °C.

Then the reaction pressure of substrate 5a was tested. The results showed that the effects of pressure and temperature on the reaction selectivity were opposite. Increasing the reaction pressure can not only significantly speed up the reaction rate, but also has a tendency to significantly increase the proportion of compound 9a. The reaction at room temperature and 60 psi already showed a high degree of chemoselectivity, giving almost quantitatively the single product 9a.

For alkyl substrates with shorter chain lengths (5a-d, Table 4), lower reaction temperatures favor the selectivity of the reaction, with room temperature being the preferred temperature. For alkyl substrates with longer chain lengths, room temperature is best for laboratory preparation. However, from the perspective of saving time, it can be carried out at any temperature above room temperature, and the high boiling point solvent can be replaced when the reaction temperature exceeds the boiling point of methanol. In order to increase the chemoselectivity of shorter chain length substrates (5a-d, Table 4), a certain hydrogen pressure must be used, and a hydrogen pressure within 80 psi can achieve very satisfactory results. Substrates with longer chain lengths have very satisfactory selectivity at normal pressure, but choosing a higher pressure can save time.

According to the following experimental conditions: using ClCH ₂ CHCl ₂ or CH ₂ Cl ₂ as gem-dichloroalkane, MeOH as solvent, and under 15-80 psi hydrogen pressure, the alkyl pyridyl ketone substrate molecule (5) can be successfully converted It becomes (α-alkyl)piperidinylmethanol hydrochloride (9). As shown in Table 5, all hydrogenation reduction reactions lead to the corresponding products in highly chemoselective and almost quantitative yields.

Table 5. Catalytic hydrogenation reduction of alkylpyridyl ketones (5)

a. CH ₂ Cl ₂ was used as chlorine source, and all reactions were carried out at room temperature.

The preparation of embodiment 10, 4-piperidinemethanol hydrochloride (9a)

4-pyridyl formaldehyde (5a, 214 mg, 2.0 mmol), 10% Pd-C (163 mg, 50% w/w), dichloromethane (204 mg, 2.4 mmol) in methanol (30 mL) mixture, at 25 ° C and After stirring for 6.5 h under a hydrogen pressure of 40 psi, hydrogen uptake completely ceased. Pd-C was filtered off, methanol in the filtrate was distilled off, and the resulting pale yellow solid was washed with anhydrous ether, then recrystallized from CH ₃ OH-Et ₂ O to obtain white crystals of 4-piperidinemethanol hydrochloride (9a) (297mg, 98%);

mp 128-130°C (MeOH- _Et2O );

v3261，2937，2888，2821，2731，2509，1617，1102，1016cm^-1；

v3261, 2937, 2888, 2821, 2731, 2509, 1617, 1102, 1016cm ^-1 ;

¹³ C NMR: δ65.5, 43.8, 35.4, 25.1;

Calcd for C ₆ H ₁₄ ClNO: C, 47.52%; H, 9.31%; N, 9.24%; Found: C, 47.17%; H, 9.41%; N, 9.11%.

Embodiment 11, the preparation of α-methyl-4-piperidinemethanol hydrochloride (9b)

According to the same experimental procedure as in Example 10, using 4-acetylpyridine (5b) as a raw material, and 1,1,2-trichloroethane as a geminal dichloroalkane, the reaction gives α-methyl-4-piperidine methoxide acid salt (9b);

mp 108-110°C (MeOH- _Et2O );

IR: v3404, 2968, 2812, 2722, 2496, 1602, 1453, 1057cm ^-1 ;

¹³ C NMR: δ70.4, 44.1, 44.0, 40.2, 28.2, 24.6, 24.3, 19.1;

Calcd for C ₇ H ₁₆ NOCl: C, 50.75%; H, 9.73%; N, 8.46%; Found: C, 50.66%; H, 9.85%; N, 8.44%.

Example 12, the preparation of α-ethyl-4-piperidinemethanol hydrochloride (9c)

According to the same experimental procedure as in Example 10, using 4-propionylpyridine (5c) as a raw material, and 1,1,2-trichloroethane as a geminal dichloroalkane, the reaction gives α-ethyl-4-piperidine methoxide acid salt (9c);

mp 106-108°C (MeOH- _Et2O );

v 3394，3068，2959，2936，2819，2715，1578，1378，994cm^-1；

v 3394, 3068, 2959, 2936, 2819, 2715, 1578, 1378, ^994cm-1 ;

δ75.6，44.2，44.1，38.3，25.8，25.1，23.8，9.4； ^13C

δ75.6, 44.2, 44.1, 38.3, 25.8, 25.1, 23.8, 9.4;

Calcd for C ₈ H ₁₈ ClNO: C, 53.47%; H, 10.10%; N, 7.80%; Found: C, 53.52%; H, 10.14%; N, 7.78%.

Example 13, Preparation of α-n-butyl-4-piperidinemethanol hydrochloride (9d)

4-pentanoylpyridine (5d, 326 mg, 2.0 mmol), 10% Pd-C (163 mg, 50% w/w), 1,1,2-trichloroethane (320 mg, 2.4 mmol) in methanol (30 mL ) mixture, after stirring for 6.5 h at 25° C. under a hydrogen pressure of 40 psi, hydrogen uptake completely ceased. Filter out Pd-C, evaporate the methanol in the filtrate, wash the resulting light yellow solid with anhydrous ether, and recrystallize from CH ₃ OH-Et ₂ O to obtain α-n-butyl-4-piperidinemethanol hydrochloride White crystals of (9d) (415 mg, 100%);

mp 112-114°C (MeOH- _Et2O );

IR: v 3392, 2954, 2928, 2860, 2818, 2716, 1579, 1449, 1380, 994cm ^-1 ;

¹³ C NMR: δ74.1, 44.3, 44.2, 38.9, 32.8, 27.5, 25.2, 23.8, 22.4, 138;

Calcd for C ₁₀ H ₂₂ ClNO: C, 57.82%; H, 10.67%; N, 6.74%; Found: C, 57.75%; H, 10.79%; N, 6.72%.

Example 14, Preparation of α-pentyl-4-piperidinemethanol hydrochloride (9e)

According to the same experimental procedure as in Example 13, using 4-hexanoylpyridine (5e) as a raw material, the reaction gave α-pentyl-4-piperidinemethanol hydrochloride (9e);

mp 108-110°C (MeOH- _Et2O );

IR: v3393, 3070, 2951, 2924, 2859, 2819, 2716, 1580, 1466, 1448, 1379cm ^-1 ;

¹³ C 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 ₁₁ H ₂₄ ClNO: C, 59.57%; H, 10.91%; N, 6.32%; Found: C, 59.68%; H, 10.79%; N, 6.47%.

Example 15, Preparation of α-hexyl-4-piperidinemethanol hydrochloride (9f)

According to the same experimental procedure as in Example 13, 4-heptanoylpyridine (5f) was used as a raw material to react to obtain α-hexyl-4-piperidinemethanol hydrochloride (9f);

mp 98-100°C (MeOH- _Et2O );

IR: v3394, 3370, 3064, 2955, 2925, 2715, 1133cm ^-1 ;

¹³ C NMR: δ74.0, 44.2, 38.9, 33.1, 31.4, 28.8, 25.2, 23.7, 22.3, 13.7;

Calcd for C ₁₂ H ₂₆ ClNO: C, 61.12; H, 11.11; N, 5.94; Found: C, 61.28; H, 11.07; N, 5.87.

Embodiment 16, the preparation of α-octyl-4-piperidinemethanol hydrochloride (9g)

According to the same experimental procedure as in Example 13, 4-nonanoylpyridine (5 g) was used as a raw material to react to obtain α-octyl-4-piperidinemethanol hydrochloride (9 g);

mp 107-108°C (MeOH- _Et2O );

IR: v3392, 3366, 3067, 2955, 2923, 2716, ^1108cm-1 ;

¹³ C 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 ₁₄ H ₃₀ ClNO: C, 63.73%; H, 11.46%; N, 5.31%; Found: C, 63.47%; H, 11.32%; N, 5.29%.

Example 17, Preparation of α-(2-phenylethyl)-4-piperidinemethanol hydrochloride (9h)

According to the same experimental procedure as in Example 13, 4-(3-phenylpropionyl)-pyridine (5h) was used as raw material to react to obtain α-(2-phenylethyl)-4-piperidinemethanol hydrochloride ( 9h);

mp 170-171°C (MeOH- _Et2O );

IR: v3628, 3382, 2947, 2825, 2802, 2725, 1578, 1495, ^1450cm-1 ;

¹³ C 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 ₁₄ H ₂₂ ClNO: C, 65.74%; H, 8.67%; N, 5.48%; Found: C, 65.68%; H, 8.44%; N, 5.50%.

Example 18, Preparation of α-butyl-2-piperidinemethanol hydrochloride (9i)

According to the same experimental procedure as in Example 13, using 2-(valeryl)pyridine (5i) as a raw material, the reaction gave α-butyl-2-piperidinemethanol hydrochloride (9i);

mp 132-134°C (MeOH- _Et2O );

IR: v3423, 2956, 2869, 1486, 1470, 1447, ^1080cm-1 ;

¹³ C 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 ₁₀ H ₂₂ ClNO: 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 acylpyridine is the method for substituted piperidine compound hydrochloride, is that the acylpyridine of formula I or formula II structure is carried out catalytic hydrogenation reaction under the presence of Pd-C catalyst and gem dichloroalkane, obtains Substituted piperidine compound hydrochloride; (Formula I)

(Formula II) Wherein, R is H, alkyl or aryl; The general formula of the gem-dichloroalkane is R ¹ R ² CCl ₂ , wherein R ¹ and R ² are H, C1-C10 alkyl or C1-C10 substituted with 1-5 chlorine atoms and/or fluorine atoms alkyl; When R is H, the substituted piperidine compound hydrochloride is piperidine methanol hydrochloride; when R is an alkyl group, the substituted piperidine compound hydrochloride is α-alkylpiperidine methanol hydrochloride ; When R is an aryl group, the substituted piperidine compound hydrochloride is 4-(arylmethyl)piperidine hydrochloride. 2. The method according to claim 1, characterized in that: the alkyl group is C1-C20 straight-chain alkyl, branched-chain alkyl or cycloalkyl, or C1- C20 straight chain alkyl, branched chain alkyl or cycloalkyl. 3. The method according to claim 1, wherein the aryl group is phenyl or substituted phenyl, and the substituent is H, C1-C10 alkyl or C1-C10 alkoxy. 4. The method according to claim 1, characterized in that: the gem-dichloroalkane is dichloromethane, 1,1-dichloroethane, 1,1,2-trichloroethane, 1,1- Dichloro-2-fluoroethane, 1,1-dichloro-2,2,2-trifluoroethane, 1,1-dichloropropane, 2,2-dichloropropane, 1,1-dichloro- 3,3-Dimethylbutane, 1,1-dichlorocyclopentane or 1,1-dichlorocyclohexane. 5. The method according to claim 4, wherein the gem-dichloroalkane is 1,1-dichloroethane or 1,1-dichloro-3,3-dimethylbutane. 6. The method according to claim 1, wherein the reaction solvent is MeOH, EtOH, i-PrOH, t-BuOH or EtOAc. 7. The method according to claim 6, characterized in that: the reaction solvent is MeOH or EtOH. 8. The method according to any one of claims 1-7, characterized in that: the amount of the Pd-C catalyst is 1-100% of the weight of the acylpyridine; the gem-dichloroalkane and the acylpyridine The molar ratio is above 1:1. 9. The method according to claim 8, characterized in that the molar ratio of said gem-dichloroalkane to said acylpyridine is 1.1:1. 10. The method according to claim 1, characterized in that: when R is an aryl group, the condition for selectively obtaining a single 4-(arylmethyl)piperidine hydrochloride is at normal pressure and 35-45 ℃. 11. The method according to claim 1, characterized in that: when R is H, the conditions for selectively obtaining a single piperidinemethanol hydrochloride are at room temperature and a hydrogen pressure of 40-80psi; when R is In the case of an alkyl group, the conditions for selectively obtaining a single α-alkylpiperidinemethanol hydrochloride are at room temperature and a hydrogen pressure of 40-80 psi.