CN102964295B - Preparation method of 2-substituted-4-(piperidylmethyl)pyridine - Google Patents
Preparation method of 2-substituted-4-(piperidylmethyl)pyridine Download PDFInfo
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- CN102964295B CN102964295B CN201210550211.3A CN201210550211A CN102964295B CN 102964295 B CN102964295 B CN 102964295B CN 201210550211 A CN201210550211 A CN 201210550211A CN 102964295 B CN102964295 B CN 102964295B
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- 0 *c1nccc(C(O)=O)c1 Chemical compound *c1nccc(C(O)=O)c1 0.000 description 4
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Abstract
The invention provides a preparation method of 2-substituted-4-(piperidylmethyl)pyridine, which comprises the following steps: mixing 2-substituted-isonicotinic acid, halogenation reagent, piperidine and solvent, and heating to react to obtain an amide compound dislcosed as Formula (II); and in the presence of catalyst, carrying out reduction reaction with alkali metal hydroborate to obtain the 2-substituted-4-(piperidylmethyl)pyridine.In the prior art, the 2-substituted-isonicotinic acid used as the raw material is subjected to esterification, reduction reaction, esterification with benzene sulfonyl chloride, and piperidine substitution reaction to obtain the 2-substituted-4-(piperidylmethyl)pyridine; and compared with the prior art, the invention performs amidation and catalytic reduction to obtain the target product. Firstly, the invention can obtain the target product by only two steps, and thus, the reaction steps are short and are simple to operate; secondly, the reaction steps are shortened, so that the reaction byproducts are reduced, thereby enhancing the yield of the target product; and thirdly, the catalytic hydrogenation reduction reaction has the advantages of mild conditions and lower raw material consumption, thereby lowering the cost of the target product.
Description
Technical field
The invention belongs to technical field of organic synthesis, relate in particular to a kind of 2-replacement-4-(piperidino methyl) preparation method of pyridine.
Background technology
Lafutidine; chemistry 2-[(2-furfuryl by name) sulfinyl] N-[(2Z)-4-[4-(piperidino methyl) oxygen base]-crotyl] ethanamide is a kind of potent, the long-acting s-generation histamine H that Japanese fuji (Fujirebio) and roc (Taiho) company develop jointly
2receptor antagonist, go on the market in April, 2000 in Japan, and commodity Storga by name and Protecadin, be mainly used in treating stomach ulcer and duodenal ulcer, can impel ulcer portion to form protective membrane, reduces the recurrence rate of ulcer.Compare with other similar drugs (as Cimitidine Type A/AB, Ranitidine HCL and famotidine), lafutidine to the blocking effect of H2 acceptor more effectively, lastingly, anti-gastric acid secretion effect is more lasting, the treatment that is mainly used in stomach ulcer, duodenal ulcer, reflux esophagitis, peptide ulceration, gastritis and other relevant diseases.
2-replacement-4-(piperidino methyl) pyridine is the important intermediate during lafutidine synthesizes, but the step of existing synthetic this intermediate is longer, complex operation, and yield is lower, causes the cost of lafutidine to increase.
The patent No. is all to disclose 2-replacement-4-(piperidino methyl in the European patent of EP0282077A2 and United States Patent (USP) that the patent No. is US4912101A) synthetic method of pyridine, the method be take 2-, and to replace γ-picolinic acid be raw material, through methanol esterification, sodium borohydride reduction obtains 2-replacement-4-4-hydroxymethylpiperidine, after reacting chloro with sulfur oxychloride again, obtain 2-replacement-4-chloromethylpyridine, chloro-product and pyridine condensation obtain 2-replacement-4-(piperidino methyl) pyridine, the method need just can obtain corresponding object product after four-step reaction, productive rate is lower, reaction scheme is as follows:
Wherein, X is halogen.
Yang Xuhua etc. have improved the synthesis technique of lafutidine, think that the productive rate of 2-replacement-4-4-hydroxymethylpiperidine chlorination reaction is low, therefore be only 15%, its synthesis technique carried out to corresponding improvement, to have improved intermediate 2-replacement-4-(piperidino methyl) productive rate of pyridine.This technique be take 2-equally, and to replace γ-picolinic acid be raw material, raw material is obtained to 2-replacement-4-4-hydroxymethylpiperidine through methanol esterification, sodium borohydride reduction, but in three-step reaction, by product 2-replacement-4-4-hydroxymethylpiperidine and benzene sulfonyl chloride esterification after reduction, and then carry out substitution reaction with piperidines, finally obtain 2-replacement-4-(piperidino methyl) pyridine, reaction scheme is as follows:
Wherein X is halogen.The method is by 2-replacement-4-(piperidino methyl) total recovery of pyridine is increased to 56%, but it exists step long equally, the problem that productive rate is lower.
Summary of the invention
In view of this, the technical problem to be solved in the present invention is to provide a kind of 2-replacement-4-(piperidino methyl) preparation method of pyridine, the method step is less and yield is higher.
The invention provides a kind of 2-replacement-4-(piperidino methyl) preparation method of pyridine, comprise the following steps:
A) 2-of formula (I) structure is replaced to γ-picolinic acid, halogenating agent, piperidines and solvent, reacting by heating, obtains the amide compound of formula (II) structure;
B) amide compound of described formula (II) structure is mixed with alkali metal borohydride, under the condition existing at catalyzer, carries out reduction reaction, obtain the 2-replacement-4-(piperidino methyl of formula (III) structure) pyridine;
Wherein, R is alkyl, aromatic base or the N heterocyclic radical of halogen, C1 ~ C10.
Preferably, described steps A) be specially:
A1) 2-of formula (I) structure is replaced to γ-picolinic acid, halogenating agent and solvent, reacting by heating obtains the acetyl halide compound of formula (IV) structure;
A2), by acetyl halide compound and the piperidines hybrid reaction of described formula (IV) structure, obtain the amide compound of formula (II) structure;
Wherein, X is halogen, and R is alkyl, aromatic base or the N heterocyclic radical of halogen, C1 ~ C10.
Preferably, the reaction described steps A 1) is back flow reaction.
The temperature of the reaction preferably, described steps A 2) is 5 ℃ ~ 30 ℃, and the time of reaction is 1 ~ 7h.
Preferably, described steps A 2) also add acid binding agent.
Preferably, described R is selected from fluorine atom, chlorine atom, bromine atoms, ethyl, phenyl or pyridyl.
Preferably, described halogenating agent is selected from a kind of in sulfur oxychloride, phosphorus trichloride, phosphorus pentachloride, phosgene, solid triphosgene, phosphorus tribromide and phosphorus pentabromide.
Preferably, the mol ratio of the amide compound of described alkali metal borohydride, catalyzer and formula (II) structure is: (1 ~ 5): (1 ~ 6): 1.
Preferably, described catalyzer is Lewis acid.
Preferably, described Lewis acid is selected from one or more in titanium tetrachloride, zinc chloride, aluminum chloride, nickelous chloride, iodine and methyl iodide.
The invention provides a kind of 2-replacement-4-(piperidino methyl) preparation method of pyridine, first the 2-of formula (I) structure is replaced to γ-picolinic acid, halogenating agent, piperidines and solvent, reacting by heating, obtains the amide compound of formula (II) structure; Under the condition existing at catalyzer again, carry out reduction reaction with alkali metal borohydride, obtain the 2-replacement-4-(piperidino methyl of formula (III) structure) pyridine.The 2-of take with prior art replaces γ-picolinic acid as raw material is through esterification, reduction reaction, obtain 2-replacement-4-(piperidino methyl with benzene sulfonyl chloride esterification, piperidines substitution reaction) pyridine compares, and the present invention obtains target product through amidation and catalytic reduction two-step reaction.First, the present invention only needs two steps can obtain target product, and reactions steps is shorter, simple to operate; Secondly, reactions steps shortens, and byproduct of reaction is reduced, and has improved the yield of target product; Again, the mild condition of catalytic hydrogenating reduction reaction, is used raw material to reduce, and has reduced the cost of target product.
Experimental result shows, by the inventive method, prepares 2-replacement-4-(piperidino methyl) productive rate of pyridine can reach 80% ~ 92%.
Embodiment
The invention provides a kind of 2-replacement-4-(piperidino methyl) preparation method of pyridine, comprise the following steps: A) 2-of formula (I) structure is replaced to γ-picolinic acid, halogenating agent, piperidines and solvent, reacting by heating, obtains the amide compound of formula (II) structure; B) amide compound of described formula (II) structure is mixed with alkali metal borohydride, under the condition existing at catalyzer, carries out reduction reaction, obtain the 2-replacement-4-(piperidino methyl of formula (III) structure) pyridine;
Reaction process is as follows:
Wherein, R is halogen, and the alkyl of C1 ~ C10 is preferably the alkyl of C1 ~ C5, more preferably the alkyl of C1 ~ C3, aromatic base or N heterocyclic radical.Described halogen is preferably F, Cl or Br, and described aromatic base is preferably phenyl, and described N heterocyclic radical is preferably pyridyl.
Described halogenating agent, for those skilled in the art know halogenating agent, there is no special restriction.In the present invention, described halogenating agent is preferably chlorinating agent or brominated reagent, more preferably sulfur oxychloride, phosphorus trichloride, phosgene, solid triphosgene, phosphorus tribromide or phosphorus pentabromide.
Described solvent is organic solvent well known to those skilled in the art, there is no special restriction.In the present invention, described solvent is preferably aromatic hydrocarbon solvent or chlorinated hydrocarbon solvent, more preferably toluene, dimethylbenzene, chloroform, 1,2-ethylene dichloride or tetracol phenixin.
According to the present invention, described steps A is specially: A1) 2-of formula (I) structure is replaced to γ-picolinic acid, halogenating agent and solvent, reacting by heating obtains the acetyl halide compound of formula (IV) structure; A2), by acetyl halide compound and the piperidines hybrid reaction of described formula (IV) structure, obtain the amide compound of formula (II) structure;
Wherein, X is halogen, is preferably Cl or Br, and R is identical with formula (I), formula (II), formula (III), does not repeat them here.
Described steps A 1) 2-of Chinese style (I) structure replaces γ-picolinic acid and halogenating agent generation substitution reaction, generates acetyl halide compound, and the condition of described substitution reaction is substitution reaction condition well known to those skilled in the art, there is no special restriction.In the present invention, described substitution reaction is preferably back flow reaction, and the time of described substitution reaction is preferably 2 ~ 10h, more preferably 4 ~ 8h.
Described steps A 2) in, the temperature of reaction is 5 ℃ ~ 30 ℃, is preferably 10 ℃ ~ 30 ℃, and the time of reaction is 1 ~ 7h, is preferably 3 ~ 5h.
According to steps A 1 of the present invention) reacted after, can steam the acetyl halide compound that solvent obtains formula (IV) structure, then it is carried out to described steps A 2 again with piperidines in solvent) in react, also can be without steaming solvent, directly be cooled to below 30 ℃, add piperidines to react, there is no special restriction.In the present invention in order to reduce operation steps, preferably directly by steps A 1) in the reaction solution that obtains after having reacted be directly cooled to below 30 ℃, be preferably 5 ℃ ~ 30 ℃, then add piperidines to react.
Take halogenating agent as chlorinating agent be example, steps A described in the present invention 2) acetyl halide compound of Chinese style (IV) structure and piperidines occur to react as follows:
Wherein, R is identical with formula (I), formula (II), formula (III), does not repeat them here.Because the acetyl halide compound of formula (IV) structure can produce the corresponding hydrogen halide of by product after reacting with piperidines, for reaction can be carried out smoothly, steps A described in the present invention 2) in, preferably also add acid binding agent, it is reacted with hydrogen halide.Described acid binding agent is acid binding agent well known to those skilled in the art, there is no special restriction, and acid binding agent described in the present invention is preferably the basic cpds such as salt of wormwood, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate.
According to the present invention, described steps A 2) also comprise: after reaction, add water and wash, and add siccative to remove the water in solvent layer, filter.Described siccative is siccative well known to those skilled in the art, there is no special restriction, and described in the present invention, siccative is preferably magnesium sulfate.
The solvent layer that gained contains product can steam solvent to remove, obtain the amide compound of formula (II) structure, and then add again alkali metal borohydride, catalyzer and solvent to carry out the reduction reaction in step B, the solvent now adding in step B can be from solvent phase in steps A with also can be different, can be the aromatic hydrocarbon solvents such as toluene, dimethylbenzene, the halohydrocarbon such as methylene dichloride, chloroform, also can be the ether solvents such as tetrahydrofuran (THF), methyltetrahydrofuran, there is no special restriction; Also can desolventize without steaming, directly add alkali metal borohydride and catalyzer, carry out the reduction reaction in step B, there is no special restriction.In the present invention, for reducing operation steps, reduce the use of organic reagent, reduce costs, preferably remove by filter after siccative, directly in solvent layer, add alkali metal borohydride and catalyzer to carry out reduction reaction.
Described alkali metal borohydride is alkali metal borohydride well known to those skilled in the art, there is no special restriction.Alkali metal borohydride described in the present invention is preferably sodium borohydride or POTASSIUM BOROHYDRIDE, more preferably sodium borohydride.
Described catalyzer is Lewis acid, and described Lewis acid is lewis acid catalyst well known to those skilled in the art, there is no special restriction.In the present invention, described Lewis acid is preferably one or more in titanium tetrachloride, zinc chloride, aluminum chloride, nickelous chloride, iodine and methyl iodide.
According to the present invention, the mol ratio of the amide compound of described alkali metal borohydride, catalyzer and formula (II) structure is: (1 ~ 5): (1 ~ 6): 1, be preferably (1.2 ~ 2.6): (1.5 ~ 3): 1.In reduction reaction, the consumption of solvent is preferably 1 ~ 10 times of amide compound amount of formula (II) structure, more preferably 2 ~ 4 times.
The temperature of described reduction reaction is controlled at 30 ℃ below, there is no special restriction, is preferably 5 ℃ ~ 30 ℃, more preferably 5 ℃ ~ 25 ℃ in the present invention.The time of described reduction reaction is 3 ~ 10h, is preferably 4 ~ 8h.
In the present invention, adopt alkali metal borohydride and lewis acid system to reduce to acid amides, avoided adopting also original reagent of lithium aluminum hydride inflammable and explosive or that toxicity is stronger or boranes, reductive condition is gentle, and easy to operate, safe ready, is beneficial to industrialization.
According to the present invention, in described step B, preferably also comprise: after reduction reaction, add alkaline aqueous solution to wash, after layering, solvent evaporated, obtains the 2-replacement-4-(piperidino methyl of formula (III) structure) pyridine.Alkaline aqueous solution described in the present invention is alkaline aqueous solution well known to those skilled in the art, there is no special restriction, is preferably saturated sodium bicarbonate solution, saturated sodium carbonate solution or saturated ammonium chloride solution.Adding of described alkaline aqueous solution can be passed through the excessive alkali metal borohydride of water destruct, so that aftertreatment, simultaneously also can catalyst neutralisation Lewis acid, and prevent that water layer acidity is compared with wastewater treatment strong and that cause.
The present invention only needs two steps can obtain target product, and reactions steps is shorter, simple to operate; Reactions steps shortens, and byproduct of reaction is reduced, and has improved the yield of target product.
Experimental result shows, by the inventive method, prepares 2-replacement-4-(piperidino methyl) productive rate of pyridine can reach 80% ~ 92%.
In order to further illustrate the present invention, below in conjunction with embodiment to a kind of 2-replacement-4-(piperidino methyl provided by the invention) preparation method of pyridine is described in detail.
In following examples, reagent used is commercially available.
Embodiment 1
50g 2-chloroisonicotinic acid, 45g sulfur oxychloride are mixed with 100ml toluene, be heated to reflux, reaction 8h, is then cooled to 30 ℃, adds 50g Anhydrous potassium carbonate and 30g piperidines, stirring reaction 2h, add after completion of the reaction 200ml water to wash, stratification, after adding anhydrous magnesium sulfate to be dried in toluene layer, filter, then add 70g TiCl
4with 14g NaBH
4, after 30 ℃ of insulation reaction 5h, add saturated sodium bicarbonate solution washing, layering, by toluene layer evaporated under reduced pressure, obtains the chloro-4-(piperidino methyl of 50g oily matter 2-) pyridine, yield is 80%.
Utilizing nucleus magnetic resonance to the chloro-4-(piperidino methyl of the 2-obtaining in embodiment 1) pyridine analyzes, and obtains its hydrogen nuclear magnetic resonance spectrogram, analyzes that to obtain result as follows:
1H?NMR（CDCl
3）δ:1.45（m,2H,piperidine?CH
2），1.56-1.64（m,4H,piperidine?CH
2），2.36（m,4H,piperidine?CH
2），3.44（s,2H,CH
2），7.20（d,1H,pyridine?H），7.33（s,1H,pyridine?H），8.30（d,1H,pyridine?H）。
Embodiment 2
50g 2-chloroisonicotinic acid, 45g sulfur oxychloride are mixed with 100ml toluene, be heated to reflux, reaction 4h, is then cooled to 20 ℃, add 60g Anhydrous potassium carbonate and 35g piperidines, stirring reaction 3h, adds 200ml water to wash, after repeated washing step after completion of the reaction, stratification, after adding anhydrous magnesium sulfate to be dried in toluene layer, filter, then add 60g ZnCl
2with 20g NaBH
4, after 30 ℃ of insulation reaction 8h, add saturated sodium bicarbonate solution washing, layering, by toluene layer evaporated under reduced pressure, obtains the chloro-4-(piperidino methyl of 55g oily matter 2-) pyridine, yield is 89%.
Embodiment 3
40g 2-bromine isonicotinic acid, 35g sulfur oxychloride are mixed with 75ml toluene, be heated to reflux, reaction 6h, is then cooled to 10 ℃, add 50g Anhydrous potassium carbonate and 28g piperidines, stirring reaction 5h, adds 200ml water to wash, after repeated washing step after completion of the reaction, stratification, after adding anhydrous magnesium sulfate to be dried in toluene layer, filter, then add 50g I
2with 18g NaBH
4, after 30 ℃ of insulation reaction 4h, add saturated sodium bicarbonate solution washing, layering, by toluene layer evaporated under reduced pressure, obtains the bromo-4-(piperidino methyl of 43.4g oily matter 2-) pyridine, yield is 92%.
Embodiment 4
40g 2-bromine isonicotinic acid, 28.2g sulfur oxychloride are mixed with 70ml toluene, be heated to reflux, reaction 7h, is then cooled to 15 ℃, adds 40g Anhydrous potassium carbonate and 20g piperidines, stirring reaction 5h, add after completion of the reaction 200ml water to wash, after repeated washing step, stratification, evaporated under reduced pressure toluene, then adds 200ml THF, 42g methyl iodide and 20g NaBH
4, after 25 ℃ of insulation reaction 5h, add saturated sodium bicarbonate solution washing, layering, evaporated under reduced pressure solvent, obtains the bromo-4-(piperidino methyl of 40g oily matter 2-) pyridine, yield is 85%.
The above is only the preferred embodiment of the present invention; it should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention; can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.
Claims (9)
1.2-replacement-4-(piperidino methyl) preparation method of pyridine, is characterized in that, comprises the following steps:
A) 2-of formula (I) structure is replaced to γ-picolinic acid, halogenating agent, piperidines and solvent, reacting by heating, obtains the amide compound of formula (II) structure;
B) amide compound of described formula (II) structure is mixed with alkali metal borohydride, under the condition existing at catalyzer, carries out reduction reaction, obtain the 2-replacement-4-(piperidino methyl of formula (III) structure) pyridine;
Wherein, R is chlorine atom or bromine atoms.
2. preparation method according to claim 1, is characterized in that, described steps A) be specially:
A1) 2-of formula (I) structure is replaced to γ-picolinic acid, halogenating agent and solvent, reacting by heating obtains the acetyl halide compound of formula (IV) structure;
A2), by acetyl halide compound and the piperidines hybrid reaction of described formula (IV) structure, obtain the amide compound of formula (II) structure;
Wherein, X is halogen, and R is chlorine atom or bromine atoms.
3. preparation method according to claim 2, is characterized in that, described steps A 1) in reaction be back flow reaction.
4. preparation method according to claim 2, is characterized in that, described steps A 2) in the temperature of reaction be 5 ℃～30 ℃, the time of reaction is 1～7h.
5. preparation method according to claim 2, is characterized in that, described steps A 2) also add acid binding agent.
6. preparation method according to claim 1, is characterized in that, described halogenating agent is selected from a kind of in sulfur oxychloride, phosphorus trichloride, phosphorus pentachloride, phosgene, solid triphosgene, phosphorus tribromide and phosphorus pentabromide.
7. preparation method according to claim 1, is characterized in that, the mol ratio of the amide compound of described alkali metal borohydride, catalyzer and formula (II) structure is: (1～5): (1～6): 1.
8. preparation method according to claim 1, is characterized in that, described catalyzer is Lewis acid.
9. preparation method according to claim 8, is characterized in that, described Lewis acid is selected from one or more in titanium tetrachloride, zinc chloride, aluminum chloride, nickelous chloride, iodine and methyl iodide.
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| US6645990B2 (en) * | 2000-08-15 | 2003-11-11 | Amgen Inc. | Thiazolyl urea compounds and methods of uses |
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| ES2120899A1 (en) * | 1996-10-07 | 1998-11-01 | Uriach & Cia Sa J | Process for the preparation of 8-chloro-6,11-dihydro-11[1- [(5-methyl-3-pyridenyl)methyl]-4-piperidinylideno]-5H- benzo[5,6]cyclohepta[1,2-b]pyridine |
| CN101553483A (en) * | 2006-12-13 | 2009-10-07 | 弗·哈夫曼-拉罗切有限公司 | 2-(piperidin-4-yl)-4-phenoxy-or phenylamino-pyrimidine derivatives as non-nucleoside reverse transcriptase inhibitors |
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