CN110540535B - Process suitable for preparing 4- (6-aminopyridin-3-yl) substituted piperidine in amplification way - Google Patents
Process suitable for preparing 4- (6-aminopyridin-3-yl) substituted piperidine in amplification way Download PDFInfo
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Abstract
The invention discloses a process method suitable for preparing 4- (6-aminopyridine-3-yl) substituted piperidine in an amplifying way, belonging to the field of synthesis of pharmaceutical intermediates. N-substituted piperidone, aryl sulfonyl hydrazide and 2-amino-5-bromopyridine are subjected to coupling reaction in the presence of a palladium catalyst, and then hydrogenation reaction is carried out to obtain the 4- (6-aminopyridine-3-yl) substituted piperidine ester. In the process, raw materials in pyridine do not need to be protected, condensation and coupling are carried out in the same reaction kettle, the operation cost is reduced, the steps of protection and deprotection in documents are avoided, the production cost of the conventional biological, medical and chemical intermediates is greatly reduced, the process is subjected to scale-up verification on a kilogram scale, the yield and the product purity are basically equivalent to a gram-scale, and the process can be used as a process for industrial scale production.
Description
Technical Field
The invention belongs to the field of synthesis of pharmaceutical intermediates, and particularly relates to a process method suitable for preparing 4- (6-aminopyridin-3-yl) substituted piperidine in an amplification way.
Background
In recent years, a plurality of series of selective CDK4/CDK6 inhibitors, such as palbociclib developed by Pfizer/Onyx, abemaciclib developed by Eli L illy and ribociclib developed by Novartis, have been developed by various pharmaceutical companies in the world, and are used for treating diseases such as cancer, cardiovascular disorders and inflammation.
WO2014183520 discloses a selective CDK4/CDK6 inhibitor of novel structure and finds that compounds having such structure exhibit excellent effects and actions, in particular excellent pharmacokinetic absorption activity, having the following structure:
among the inhibitors, 4- (6-aminopyridin-3-yl) substituted piperidines are important structural fragments, such as: 4- (6-aminopyridin-3-yl) piperidine-1-carboxylic acid tert-butyl ester, english name: tert-Butyl-4- (6-aminopyridin-3-yl) piperidine-1-carboxylate of formula C15H23N3O2White powdery solid, is a key intermediate of the novel structural selective CDK4/CDK6 inhibitor.
The synthesis of 4- (6-aminopyridin-3-yl) piperidine-1-carboxylic acid tert-butyl ester has few published documents, and the existing synthesis process can be roughly divided into three types:
the first method is that 2-nitro-5-bromopyridine and N-Boc-1,2,5, 6-tetrahydropyridine-4-boronic acid pinacol ester are coupled under the catalysis of metal palladium, and after column chromatography separation, the nitro group is simultaneously reduced while palladium/hydrocarbon double bond is adopted. The synthetic route is as follows:
method II, 2-nitro-5-bromopyridine and 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -5, 6-dihydropyridine-1 (2-hydrogen) -formic acid tert-butyl ester are coupled under the catalysis of metallic palladium, and then the double bond is hydrogenated by palladium carbon, and the nitro group is simultaneously reduced. The synthetic route is as follows:
in the two methods, the used raw material N-Boc-1,2,5, 6-tetrahydropyridine-4-boronic acid pinacol ester has more synthesis steps, the price is high when the N-Boc-1,2,5, 6-tetrahydropyridine-4-boronic acid pinacol ester is directly purchased in the market, the dosage of the catalyst is up to 10 percent, the yield after the reaction is low, the reaction impurities are more due to the fact that the diboron ester generated during the coupling is related to the complexation of the pyridylamine part to a great extent, the post-treatment can be purified by adopting a silica gel column, and the heavy metal content in.
Coupling 5-bromo-2- (2, 5-dimethyl-1H-pyrrole-1-yl) pyridine and N-benzyl piperidone under catalysis, removing a nitrogen protecting group by hydroxylamine hydrochloride, then hydrogenating a double bond by palladium carbon, removing a benzyl group, and finally protecting by Boc. The synthetic route is as follows:
in the method, pyrrole is adopted to protect amino and then coupling is carried out to remove the amino, and in actual operation, the steps of debenzylation and reduction need to be completed step by step, and impurities are difficult to purify and remove.
Therefore, in view of the low yield, difficult purification and poor economic benefit of the existing synthesis process, the existing process needs to be improved, and the process suitable for industrial amplification is developed by adopting cheaper and easily available raw materials.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides the preparation method which is simple, convenient and stable to operate, easy to separate products in each step, high in yield, environment-friendly, low in production cost and suitable for industrial large-scale production of the 4- (6-aminopyridin-3-yl) substituted piperidine.
The invention provides a preparation method of 5- (substituted piperidine-4-yl) pyridine-2-amine (4) suitable for industrial amplification, which has the following reaction equation:
n-substituted piperidone 1 and 2-amino-5-bromopyridine are used as raw materials, and 4- (6-aminopyridine-3-yl) substituted piperidine 4 is obtained through condensation reaction, coupling reaction and hydrogenation reaction, and the method specifically comprises the following steps:
adding N-protecting group piperidone and aryl sulfonyl hydrazide into an organic solvent for condensation reaction, then adding a palladium catalyst, a ligand, alkali and 2-amino-5-bromopyridine, and carrying out heating coupling reaction to obtain an intermediate 3; and adding palladium/hydrocarbon into the intermediate 3 for reduction to obtain the 5- (substituted piperidine-4-yl) pyridine-2-amine 4.
Further, in the above technical solution, the aryl sulfonyl hydrazide is selected from 2,4, 6-triisopropylbenzenesulfonyl hydrazide and p-methylbenzenesulfonyl hydrazide.
Further, in the above technical solution, the organic solvent is dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, or a solution obtained by any combination of the above solvents.
Further, in the technical scheme, the molar charging ratio of the N-substituted piperidone to the p-methylbenzenesulfonyl hydrazide or the 2,4, 6-triisopropylbenzenesulfonyl hydrazide to the 2-amino-5-bromopyridine is 1: 0.98-1.2: 1-2.
Further, in the above technical means, the protecting group is selected from methyl, ethyl, formyl, Boc, Cbz and the like.
Further, in the above technical scheme, the palladium catalyst is selected from the group consisting of tris (dibenzylideneacetone) dipalladium, [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex, tetrakistriphenylphosphine palladium and palladium acetate.
Furthermore, in the technical scheme, the molar ratio of the palladium catalyst to the 2-amino-5-bromopyridine is 0.002-0.01: 1.
Further, in the above technical scheme, the ligand is selected from 2-dicyclohexyl phosphonium-2, 4, 6-triisopropyl biphenyl, 4, 5-bis diphenyl phosphine-9, 9-dimethyl xanthene and tricyclohexyl phosphine.
Further, in the above technical solution, the base is selected from sodium tert-butoxide, potassium carbonate, sodium carbonate, cesium carbonate, and lithium tert-butoxide. When cesium carbonate is adopted, the molar ratio of the palladium catalyst to the 2-amino-5-bromopyridine is reduced to about 0.002 equivalent, and the yield is not obviously reduced.
Further, in the above technical solution, the palladium on carbon is selected from 5% or 10% palladium on carbon. The hydrogenation uses hydrogen or ammonium formate.
Further, in the technical scheme, the adding amount of the palladium-carbon is 2-6% of the weight of the intermediate 3.
In order to obtain the 4- (6-aminopyridin-3-yl) piperidine-1-carboxylic acid tert-butyl ester described in the background art, the following procedure can also be used:
adding N-protective group piperidone and aryl sulfonyl hydrazide into dioxane for condensation reaction, adding palladium catalyst, base and 2-amino-5-bromopyridine, heating for coupling reaction, and adding (Boc)2After O, hydrogenation reduction in the presence of palladium on carbon gives 4- (6-aminopyridin-3-yl) piperidine-1-carboxylic acid tert-butyl ester.
The invention has the beneficial effects that:
compared with the prior synthesis method, the invention has the following beneficial effects:
1. the invention adopts cheap raw materials to replace expensive boron reagent and palladium reagent, optimizes the preparation process, reduces the environmental pollution and greatly reduces the production cost. The method has strong universality and can be smoothly carried out on different substituted piperidone substrates.
2. The method has the advantages of short route steps and high yield. Taking 4- (6-aminopyridine-3-yl) piperidine-1-tert-butyl formate as an example, the total reaction yield is over 60 percent, and compared with the existing yield of 42 percent, the yield is obviously improved, and the production cost is greatly reduced.
Detailed Description
The invention will be further illustrated with reference to the following specific examples. These examples are to be construed as merely illustrative and not limitative of the remainder of the disclosure in any way whatsoever. After reading the description of the invention, one skilled in the art can make various changes and modifications to the invention, and such equivalent changes and modifications also fall into the scope of the invention defined by the claims.
The experimental methods of the present invention, in which specific conditions are not specified in the following examples, are generally carried out under conventional conditions.
The starting materials or reagents used in the following examples of the present invention are commercially available unless otherwise specified.
The reagents described in the following examples are used without purification unless otherwise specified, all solvents are purchased from commercial suppliers such as Aldrich (Aldrich) and can be used without treatment the reaction is judged for termination by consumption of starting material by analysis at T L C or by analysis at HP L C thin layer chromatography (T L C) for analysis is performed on glass plates (EMD Chemicals) precoated with silica gel 60F 2540.25 mm plates, developed with UV light (254nm) or iodine on silica gel, or T L C stains such as alcoholic phosphomolybdic acid, hydrindantin solution, potassium permanganate solution or cerium sulfate solution are heated together.
Example 1
The first step is as follows: preparation of 6-amino-3 ',6' -dihydro-2 ' -hydro- [3,4' ] bipyridinyl-1 ' -formyl tert-butyl ester
N-tert-Butoxycarbonyl-4-piperidone (1.45g), p-toluenesulfonylhydrazide (1.35g) and dioxane (31.2g) were charged into a flask, and nitrogen was purged three times with stirring, and the mixture was heated to 75 ℃ and stirred for reaction for 5 hours. After the point plate monitoring shows that the N-tert-butyloxycarbonyl-4-piperidone point disappears, 20g of solvent is distilled off, Xphos (0.11g) and [1,1' -bis (diphenylphosphino) ferrocene are added into a bottle in sequence under the protection of nitrogen]Palladium dichloride (0.029g), sodium tert-butoxide (1.34g) and 2-amino-5-bromopyridine (1g) are heated to 110 ℃ for reaction for 8h, cooled, filtered, added with 5ml of methyl tert-butyl ether, pulped for 10 min, and the solid obtained by filtering is dried to obtain 6-amino-3 ',6' -dihydro-2 '-hydrogen- [3,4']Bipyridyl-1' -formyl tert-butyl ester 1.30g, purity: 99.1%, yield: 82 percent.1H-NMR(400MHz,DMSO-d6):7.94(s,1H) ,7.46-7.43(dd ,J＝2.4and 8.8Hz,1H),6.39-6.37(d,8.8Hz,1H),5.94(s,2H),5.91(s,1H),3.93(s,2H),3.49-3.47(m,2H),2.36(m,2H),1.41(s,9H)。
The second step is that: preparation of tert-butyl 4- (6-aminopyridin-3-yl) piperidine-1-carboxylate
6-amino-3 ',6' -dihydro-2 ' -hydro- [3,4' was added to the flask ']Bipyridyl-1' -formyl tert-butyl ester (5g) and isopropanol (75m L), adding 10% palladium carbon (0.1g) and ammonium formate (10g) under the protection of nitrogen, carrying out hydrogenation reaction at 20-30 ℃ until the reaction is finished, filtering with diatomite, concentrating, adding 10ml of ethyl acetate, heating to 70 ℃ to ensure that the system is completely clear, slowly dropwise adding petroleum ether until the system is turbid, slowly cooling the system to 0 ℃, filtering, and drying under reduced pressure to obtain a product (4.81g), wherein the purity is 99.2% and the yield is 95.4%.1H-NMR(400MHz,DMSO-d6):7.74(d,J＝2.4Hz,1H),7.24-7.22(dd,J＝2.4and8.4Hz,1H),6.39(d,J＝8.4Hz,1H),5.65(s,2H),4.04-4.01(m,2H),2.74(m,2H),1.66-1.63(m,2H),1.42-1.33(m,11H)。
Overall yield of the two-step reaction: 78.2 percent.
Example 2
N-benzylpiperidone (1.38g), p-toluenesulfonylhydrazide (1.35g) and dioxane (31.2g) were added to a flask, and nitrogen was purged three times with stirring, and the mixture was heated to 75 ℃ and stirred for reaction for 5 hours. After the dot panel monitoring showed that the N-benzylpiperidone dot had disappeared, 20g of the solvent was distilled off, tricyclohexylphosphine (0.064g), tris (dibenzylideneacetone) dipalladium (0.0106g), cesium carbonate (1.34g) and 2-amino-5-bromopyridine (1g) were added in this order to a bottle under nitrogen protection, heated to 110 ℃ for reaction for 8 hours, and filtered to give 6-amino-3 ',6' -dihydro-2 '-hydro- [3,4']Bipyridyl-1' -benzyl solution with external standard content of 5.1%. Adding Boc anhydride (1.1g) into the reaction solution, adding 5% palladium carbon (0.06g), pumping hydrogen for three times under stirring, after the first stage of complete 20-30 ℃ hydrogenation reaction, heating to 50-80 ℃ until the reaction is finished, filtering and concentrating by using kieselguhr to obtain paste, pulping by using 20ml of methyl tert-butyl ether, filtering and airing to obtain solid 4- (6-aminopyridin-3-yl) piperidine-1-tert-butyl formate (1.03g) with purity: 99.3%, yield 64.2%.1H-NMR(400MHz,DMSO-d6):7.74(d,J＝2.4Hz,1H),7.24-7.22(dd,J＝2.4,8.4Hz,1H),6.39(d,J＝8.4Hz,1H),5.65(s,2H),4.04-4.01(m,2H),2.74(m,2H),1.66-1.63(m,2H),1.42-1.33(m,11H)。
Example 3
1-Cbz-4-piperidone (1.70g), p-toluenesulfonylhydrazide (1.35g) and dioxane (31.2g) were charged into a reaction flask, and nitrogen was purged three times with stirring, and the mixture was heated to 75 ℃ and stirred for reaction for 5 hours. After dot-panel monitoring indicated disappearance of the 1-Cbz-4-piperidone dots, the solvent was evaporated to dryness and 10g dioxane was added. Under the protection of nitrogen, 4, 5-bis (diphenylphosphino) -9, 9-dimethyl xanthene (0.13g) and [1,1' -bis (diphenylphosphino) ferrocene are sequentially added into a bottle]Palladium dichloride dichloromethane complex (0.047g), potassium carbonate (2.3g) and 2-amino-5-bromopyridine (1g) were heated to 110 ℃ to react for 8 hours and filtered to give 6-amino-3 ',6' -dihydro-2 '-hydro- [3,4']Bipyridyl-1' -CBZ solution, external standard content 5.0%, content yield: 83 percent. MS (M/z)310.3(M + H)+To this solution, isopropanol (25m L) was added and Boc anhydride was added(1.1g), adding 10% palladium carbon (0.05g) under the protection of nitrogen, pumping hydrogen for three times under stirring, after the first stage of complete hydrogenation reaction at 20-30 ℃, heating to 50-80 ℃ until the reaction is finished, filtering and concentrating by using kieselguhr to obtain paste, pulping by using 20ml of methyl tert-butyl ether, filtering and airing to obtain solid tert-butyl 4- (6-aminopyridin-3-yl) piperidine-1-carboxylate (1.25g) with the purity: 99.3% yield: 78.1% of the product1H-NMR confirmed the correct structure. .
Example 4
The first step is as follows: preparation of 6-amino-3 ',6' -dihydro-2 ' -hydro- [3,4' ] bipyridinyl-1 ' -methyl
N-methyl-4-piperidone (0.82g), 2,4, 6-triisopropylbenzenesulfonylhydrazide (1.72g) and dioxane (31.2g) were added to a reaction flask, nitrogen was purged three times with stirring, and the mixture was heated to 75 ℃ and stirred for reaction for 5 hours. After dot plate monitoring indicated disappearance of the N-methyl-4-piperidone dots, the solvent was evaporated to dryness and 10g dioxane was added. Adding tricyclohexylphosphine (0.064g), tetratriphenylphosphine palladium (0.047g), sodium carbonate (1.8g) and 2-amino-5-bromopyridine (1g) into a bottle in sequence under the protection of nitrogen, heating to 110 ℃ for reacting for 8h, filtering to evaporate a solvent, adding 5ml of methyl tert-butyl ether, pulping for 10 min, filtering to obtain a solid, and airing to obtain 6-amino-3 ',6' -dihydro-2 '-hydrogen- [3,4']Bipyridyl-1' -methyl 0.92g, purity: 99.4%, yield: 83.8 percent. MS (M/z)190.3(M + H)+.
The second step is that: preparation of 2-amino-5- (1-methyl-4-piperidinyl) pyridine
6-amino-3 ',6' -dihydro-2 ' -hydro- [3,4' was charged into a reaction flask ']Dipyridyl-1' -methyl (5g) and isopropanol (75M L), 10% palladium on carbon (0.25g) were added under nitrogen protection, hydrogen was purged three times with stirring, after completion of hydrogenation at 20-30 ℃ and filtration and concentration with celite to obtain a paste, which was slurried with 20ml of methyl tert-butyl ether, filtered and air-dried to obtain 2-amino-5- (1-methyl-4-piperidinyl) pyridine (4.8g) as a solid with a purity of 99.5% yield of 95.0% MS (M/z)192.2(M + H)+.
Example 5
N-benzyl piperidone (1.38kg), p-toluenesulfonylhydrazide (1.35kg) and dioxane (31.2kg) were added to a bottle, nitrogen was purged three times with stirring, and the mixture was heated to 75 ℃ and stirred for reaction for 5 hours. After the dot plate monitoring indicated disappearance of the N-benzylpiperidone dot, 20g of the solvent was distilled off, and Xphos (0.11kg), palladium acetate (0.009kg), potassium tert-butoxide (1.9kg) and 2-amino-5-bromopyridine (1kg) were added in this order to a flask under nitrogen atmosphere, heated to 110 ℃ for 8 hours to react, and filtered to give 6-amino-3 ',6' -dihydro-2 '-hydro- [3,4']5.5 percent of bipyridyl-1' -benzyl solution, adding Boc anhydride (1.1kg) into the solution, adding 5 percent of palladium carbon (0.06kg), pumping hydrogen for three times under stirring, heating to 50-80 ℃ until the reaction is finished after the first stage of hydrogenation reaction at 20-30 ℃, filtering and concentrating by using kieselguhr to obtain paste, pulping by using 20L methyl tert-butyl ether, filtering and airing to obtain solid 4- (6-aminopyridin-3-yl) piperidine-1-tert-butyl formate (1.05kg), wherein the purity is 99.3 percent, and the yield is 65.4 percent, and obtaining the product by purifying by using a solvent, namely methanol, ethanol, methanol, ethanol1H-NMR confirmed the correct structure.
Example 6
The first step is as follows: preparation of 6-amino-3 ',6' -dihydro-2 ' -hydro- [3,4' ] bipyridinyl-1 ' -benzyl
N-benzyl piperidone (1.38kg), p-toluenesulfonylhydrazide (1.35kg) and dioxane (31.2kg) were added to a bottle, nitrogen was purged three times with stirring, and the mixture was heated to 75 ℃ and stirred for reaction for 5 hours. After the point plate monitoring shows that the N-benzyl piperidone point disappears, tricyclohexylphosphine (0.064kg) and [1,1' -bis (diphenylphosphino) ferrocene are added into a bottle in sequence under the protection of nitrogen]Palladium dichloride (0.029kg), lithium tert-butoxide (1.34kg) and 2-amino-5-bromopyridine (1kg) are heated to 110 ℃ for reaction for 8h, filtered, the solvent is evaporated to 25kg, 5L methyl tert-butyl ether is added, the mixture is pulped for 10 min, and the solid obtained by filtering is dried to obtain 6-amino-3 ',6' -dihydro-2 '-hydrogen- [3,4']Bipyridyl-1' -benzyl 1.22kg, purity: 99.2 percent of the total weight of the mixture,yield: 81 percent.1H-NMR(400MHz,DMSO-d6):7.95(d,J＝2.4Hz,1H),7.46-7.44(dd,J＝2.4,8.8Hz,1H),7.33-7.32(m,4H),7.25-7.24(m,1H),6.41(d,J＝8.8Hz,1H),5.91(s,1H),5.90(s,2H),3.55(s,2H),2.99(d,J＝2.8Hz,2H),2.59-2.58(m,2H),2.38(m,2H).
The second step is that: preparation of 5- (piperidin-4-yl) pyridin-2-amine
6-amino-3 ',6' -dihydro-2 ' -hydro- [3,4' was added to the flask ']Dipyridyl-1' -benzyl (5kg) and isopropanol (75L), 10% palladium carbon (0.5kg) and Boc anhydride (3.48kg) were added under nitrogen protection, hydrogen was pumped three times with stirring, after the first stage of 20-30 ℃ hydrogenation reaction was complete, heating to 50-80 ℃ until the reaction was complete, filtering with celite, concentrating to give a paste, slurrying with 20L methyl tert-butyl ether, filtering and air drying to give 4.56g of solid tert-butyl 4- (6-aminopyridin-3-yl) piperidine-1-carboxylate with a purity of 99.3% and a yield of 87.2%.1H-NMR(400MHz,DMSO-d6):7.74(d,J＝2.4Hz,1H),7.24-7.22(dd,J＝2.4,8.4Hz,1H),6.39(d,J＝8.4Hz,1H),5.65(s,2H),4.04-4.01(m,2H),2.74(m,2H),1.66-1.63(m,2H),1.42-1.33(m,11H)。
Overall yield of the two-step reaction: 60 percent.
Comparative example 1 (literature example)
The synthetic route reported in document CN109384767 is as follows:
the first step is that compound 1(75.6g), TsNHNH2(74.4g) and ethanol (900m L) are added into a bottle, the mixture is stirred and reacted for 5 hours at 25 ℃, the solvent is evaporated to dryness under reduced pressure to obtain white solid 2(142g), the yield is 100%, the white solid is directly used for the next reaction, Xphos (1.9g), Pd2(dba)3(0.9g), lithium tert-butoxide (20.2g), 2(39.3g), 3(35.3g) and dioxane (500m L) are sequentially added into the bottle, argon is pumped out three times under the stirring condition, the mixture is heated to 110 ℃ under the protection of argon to react for 10 hours, water is added to quench the reaction, MTBE is extracted, saturated salt is added, magnesium sulfate is dried, filtered and evaporated to dryness, and then column chromatography separation is carried out to obtain compound 4(34g), the purity is 97.
And the second step, adding 4(180g), hydroxylamine hydrochloride (139g), ethanol (1.2L) and water (400m L) into a bottle, stirring and heating to 80 ℃ for reaction for 20h, adding a dot plate to show complete reaction, evaporating most of ethanol under reduced pressure, adding NaHCO3(200g) for neutralization, extracting with dichloromethane, combining organic phases, drying with magnesium sulfate, filtering, concentrating, and performing column chromatography to obtain 5(74g) with the purity of 98%.
And the third step, adding 5(20g), isopropanol (300m L) and palladium carbon (2g) into a bottle, pumping hydrogen for three times under stirring, filtering and spin-drying by using kieselguhr after the hydrogenation reaction is completed to obtain a product 6(12.4g), and directly using the product in the next step.
And a fourth step of adding the compound 6(5.3g), isopropanol (70m L) and DCM (70m L) into a bottle, stirring and dissolving, adding Boc anhydride (6.5g), reacting completely, adding MTBE, washing and separating layers with water, combining organic phases, washing with saturated sodium chloride, drying with anhydrous sodium sulfate, filtering, concentrating, and performing column chromatography to obtain 7(7.5g), wherein the purity is 99% and the total yield of the two steps is 84%.
Claims (9)
1. A process for the preparation of 5- (substituted piperidin-4-yl) pyridin-2-amines characterized by the following reaction equation:
the method comprises the following steps: adding N-protecting group piperidone 1 and aryl sulfonyl hydrazide into an organic solvent for condensation reaction, then adding a palladium catalyst, a ligand, alkali and 2-amino-5-bromopyridine, and carrying out heating coupling reaction to obtain an intermediate 3; the intermediate 3 is hydrogenated and reduced in the presence of a palladium carbon catalyst to obtain 5- (substituted piperidine-4-yl) pyridine-2-amine 4; wherein the protecting group is selected from methyl, ethyl, formyl, Boc or Cbz.
2. A process for the preparation of 5- (substituted piperidin-4-yl) pyridin-2-amines as claimed in claim 1 wherein: the organic solvent is dioxane, tetrahydrofuran, 2-methyltetrahydrofuran or a solution obtained by any combination of the solvents.
3. A process for the preparation of 5- (substituted piperidin-4-yl) pyridin-2-amines as claimed in claim 1 wherein: the molar charge ratio of the N-substituted piperidone to the aryl sulfonyl hydrazide to the 2-amino-5-bromopyridine is 1: 0.98-1.20: 1-2.
4. A process for the preparation of 5- (substituted piperidin-4-yl) pyridin-2-amines as claimed in claim 1 wherein: the palladium catalyst is selected from tris (dibenzylideneacetone) dipalladium, [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex, tetratriphenylphosphine palladium or palladium acetate, and the molar ratio of the catalyst to the 2-amino-5-bromopyridine is 0.002-0.01: 1.
5. a process for the preparation of 5- (substituted piperidin-4-yl) pyridin-2-amines as claimed in claim 1 wherein: the alkali is selected from sodium tert-butoxide, potassium carbonate, sodium carbonate or cesium carbonate, and when cesium carbonate is adopted, the dosage of the catalyst is reduced to 2 percent, and the yield is not obviously reduced.
6. A process for the preparation of 5- (substituted piperidin-4-yl) pyridin-2-amines as claimed in claim 1 wherein: the ligand is selected from 2-dicyclohexyl phosphorus-2, 4, 6-triisopropyl biphenyl, 4, 5-bis diphenyl phosphine-9, 9-dimethyl xanthene or tricyclohexyl phosphine.
7. A process for the preparation of 5- (substituted piperidin-4-yl) pyridin-2-amines as claimed in claim 1 wherein: the palladium carbon is selected from 5% or 10% palladium carbon; the hydrogenation uses hydrogen or ammonium formate.
8. A process for the preparation of 5- (substituted piperidin-4-yl) pyridin-2-amines as claimed in claim 1 wherein: the adding amount of the palladium-carbon is 2-6% of the weight of the intermediate 3.
9. A preparation method of 4- (6-aminopyridin-3-yl) piperidine-1-tert-butyl formate comprises the following steps:
it is characterized by comprising: adding N-protective group piperidone and aryl sulfonyl hydrazide into dioxane for condensation reaction, adding palladium catalyst, ligand, base and 2-amino-5-bromopyridine, heating for coupling reaction, and adding (Boc)2And O, hydrogenating and reducing in the presence of palladium carbon catalyst to obtain the 4- (6-aminopyridine-3-yl) piperidine-1-tert-butyl formate.
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