CN107827869B - Preparation method of 4- (6-aminopyridine-3-yl) piperidine-1-tert-butyl formate - Google Patents
Preparation method of 4- (6-aminopyridine-3-yl) piperidine-1-tert-butyl formate Download PDFInfo
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Abstract
The invention discloses a preparation method of 4- (6-aminopyridine-3-yl) piperidine-1-tert-butyl formate. N- (5-bromo-pyridine-2-) -2, 2-dimethylpropionamide, N-tert-butoxycarbonyl-4-piperidone, Raney nickel and the like are taken as raw materials, and a target product, namely 4- (6-aminopyridine-3-yl) piperidine-1-tert-butyl formate is obtained through three-step reaction. The method has the advantages of simple and stable process operation, easy separation of products in each step, high yield, environmental friendliness, comprehensive yield of over 82 percent, obvious improvement compared with the yield of 42 percent in the prior art, cheap and easily available raw materials, great reduction of the production cost of the prior biological, medical and chemical intermediates, and contribution to industrial scale production.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemical synthesis, and particularly relates to a preparation method of 4- (6-aminopyridine-3-yl) piperidine-1-tert-butyl formate.
Background
4- (6-aminopyridin-3-yl) piperidine-1-carboxylic acid tert-butyl ester, english name: tert-Butyl-4- (6-a minoxidin-3-yl) piperidine-1-carboxylate, the molecular formula is C15H23N3O 2. The white powdery solid is a good biological, medical and chemical intermediate.
The synthesis of 4- (6-aminopyridin-3-yl) piperidine-1-carboxylic acid tert-butyl ester has few published documents, and the existing synthesis processes can be roughly divided into two types:
method one, 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:
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 materials are expensive, the catalyst dosage is as high as 0.1 equivalent, the yield after reaction is low, the reaction impurities are more caused due to the fact that diboron ester generated during coupling is partially complexed with pyridylamine to a great extent, the purification can be realized only by passing through a silica gel column after the post-treatment, and the heavy metal content in the product is difficult to effectively control to the level required by a drug intermediate. Therefore, the existing synthesis process has low yield, difficult purification and poor economic benefit.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides the preparation method of the 4- (6-aminopyridine-3-yl) piperidine-1-tert-butyl formate, 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.
The invention provides a preparation method of 4- (6-aminopyridine-3-yl) piperidine-1-tert-butyl formate, which has the following reaction equation:
the method is characterized in that 4- (6-aminopyridine-3-yl) piperidine-1-tert-butyl formate is obtained by starting from N- (5-bromo-pyridine-2-) -2, 2-dimethylpropionamide through three reactions of addition reaction, reduction reaction, deprotection reaction and the like, and comprises the following steps:
the first step is as follows: synthesis of 4- (6-pivaloylamino-3-pyridyl) -4-hydroxy-N-tert-butoxycarbonylpiperidine
Adding N-butyl lithium into N- (5-bromo-pyridine-2-) -2, 2-dimethylpropionamide solution at ultralow temperature, then adding N-tert-butoxycarbonyl-4-piperidone solution, and reacting to obtain 4- (6-trimethylacetamido-3-pyridyl) -4-hydroxy-N-tert-butoxycarbonylpiperidine.
In the step, the solution of N- (5-bromo-pyridine-2-) -2, 2-dimethylpropionamide is diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, N-hexane or a solution obtained by any combination of the solvents; the solution of N-tert-butoxycarbonyl-4-piperidone is a solution obtained by diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, N-hexane or any combination of the above solvents. The molar feeding proportion of N- (5-bromo-pyridine-2-) -2, 2-dimethylpropionamide, N-butyl lithium and N-tert-butyloxycarbonyl-4-piperidone is 1: 2.5-3.5: 1-1.2. Preferred organic solvents are tetrahydrofuran or 2-methyltetrahydrofuran.
The second step is that: synthesis of 4- (6-trimethylacetamido-3-pyridinyl) -N-tert-butoxycarbonylpiperidine
Adding 4- (6-trimethylacetamido-3-pyridyl) -4-hydroxy-N-tert-butyloxycarbonyl piperidine and Raney nickel into an alcohol solvent, and carrying out reflux reaction on a reaction solution to obtain the 4- (6-trimethylacetamido-3-pyridyl) -N-tert-butyloxycarbonyl piperidine.
In this step, the alcoholic solvent is selected from ethanol, methanol, isopropanol or any combination of the above solvents. The feeding molar ratio of the 4- (6-trimethylacetamido-3-pyridyl) -4-hydroxy-N-tert-butyloxycarbonylpiperidine to the raney nickel is 1: 1-1.5. Preferably, the solvent is ethanol.
The third step: synthesis of 4- (6-aminopyridin-3-yl) piperidine-1-carboxylic acid tert-butyl ester
Adding 4- (6-trimethylacetamido-3-pyridyl) -N-tert-butyloxycarbonylpiperidine into a mixed solution of an alkali liquor and an organic solvent, reacting, heating, selectively deprotecting to obtain 4- (6-aminopyridin-3-yl) piperidine-1-tert-butyl formate.
In this step, the alkali solution is sodium hydroxide aqueous solution, potassium hydroxide aqueous solution, lithium hydroxide aqueous solution or any combination of the above reagents; the organic solvent is methanol, ethanol, isopropanol, etc. The molar ratio of 4- (6-amino-3-pyridyl) -N-tert-butyloxycarbonylpiperidine to alkali liquor is 1: 5-10. Preferably, the solvent is methanol.
The invention has the beneficial effects that:
compared with the prior synthesis method, the invention has the following beneficial effects:
1) the comprehensive yield of the invention is more than 82 percent, which is obviously improved compared with the prior yield of 42 percent, and the production cost of the 4- (6-aminopyridine-3-yl) piperidine-1-tert-butyl formate is greatly reduced.
2) 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.
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 average room temperature described in the following examples of the present invention is 20-35 ℃. Unless otherwise indicated, the reagents are not specifically indicated and are all used without purification. All solvents were purchased from commercial suppliers, such as Aldrich (Aldrich), and used without treatment. The reaction was analyzed by TLC or by HPLC, and the termination of the reaction was judged by the consumption of starting material. Thin Layer Chromatography (TLC) for analysis was performed on glass plates (EMD Chemicals) precoated with silica gel 60F2540.25 mm plates, developed with UV light (254nm) or iodine on silica gel, or TLC stains such as alcoholic phosphomolybdic acid, ninhydrin solution, potassium permanganate solution, or cerium sulfate solution were heated together.
Example 1
The first step is as follows: synthesis of 4- (6-pivaloylamino-3-pyridyl) -4-hydroxy-N-tert-butoxycarbonylpiperidine
A solution of N-butyllithium (37.2mL, 93mmol) in N-hexane (2.5N) was slowly added to N- (5-bromo-pyridin-2-) -2, 2-dimethylpropionamide (7.94g, 31mmol) in ether (80mL) at-70 ℃ and the reaction mixture was stirred at this temperature for 1 hour. N-tert-Butoxycarbonyl-4-piperidone (6.15g, 31mmol) in diethyl ether (60mL) was added to the reaction mixture at-70 ℃ and stirred for 2 hours. After TLC monitoring reaction was complete, the reaction was quenched with aqueous ammonium chloride, extracted with ethyl acetate, the organic layer was spin dried and purified over a fast silica gel column to give 11.01g of a solid with 94.42% yield.
Mass spectrum detection, ESI/MS: 322.3[ MH ] m/z]+This solid was identified as 4- (6-trimethylacetamido-3-pyridyl) -4-hydroxy-N-tert-butoxycarbonylpiperidine.
The second step is that: synthesis of 4- (6-trimethylacetamido-3-pyridinyl) -N-tert-butoxycarbonylpiperidine
4- (6-trimethylacetamido-3-pyridyl) -4-hydroxy-N-t-butoxycarbonylpiperidine (5g,13.25mmol) and Raney's nickel (1g, 17.04mmol) were added to ethanol (180mL), and the reaction mixture was refluxed for 5 hours and then cooled to room temperature. The Raney nickel was filtered and the solution was spun dry to give 4.54g of solid in 94.78% yield.
Mass spectrum detection, ESI/MS: 306.3[ MH ] m/z]+This solid was identified as 4- (6-trimethylacetamido-3-pyridyl) -N-tert-butoxycarbonylpiperidine.
The third step: synthesis of 4- (6-aminopyridin-3-yl) piperidine-1-carboxylic acid tert-butyl ester
4- (6-trimethylacetamido-3-pyridyl) -N-tert-butoxycarbonylpiperidine (4g, 11.07mmol) was added to a mixed solution of 5N aqueous sodium hydroxide (11.07mL, 55.33mmol) and methanol (11mL), the reaction was refluxed and stirred for 20 minutes, the solution was extracted with ethyl acetate after cooling to room temperature, and the organic layers were combined, dried, filtered and dried to give 2.85g of a white solid, 99.2% by HPLC, and the yield was 92.84%.
HNMR(400MHz,MeOD):7.76(d,J＝2.3Hz,1H),7.38(dd,J＝8.6,2.3Hz,1H),6.56(d,J＝8.6Hz,1H),4.21-4.18(m,2H),2.84(brs,2H),2.60(m,1H),1.78-1.75(m,2H),1.58-1.57(m,2H),1.48(s,9H)；MSm/z278.2[MH]+.
The total yield of the three-step reaction is as follows: 83 percent.
Example 2
The first step is as follows: synthesis of 4- (6-pivaloylamino-3-pyridyl) -4-hydroxy-N-tert-butoxycarbonylpiperidine
A solution of N-butyllithium (1.94L, 4.85mol) in N-hexane (2.5N) was slowly added to N- (5-bromo-pyridin-2-) -2, 2-dimethylpropionamide (500g, 1.94mol) in tetrahydrofuran (1L) at-65 ℃ and the reaction mixture was stirred for 1 hour at-65 ℃ to-70 ℃. N-tert-Butoxycarbonyl-4-piperidone (465g, 2.33mol) in tetrahydrofuran (2L) was added to the reaction mixture at-65 ℃ and stirred for 2 hours. After TLC monitoring reaction was complete, the reaction was quenched with aqueous ammonium chloride, extracted with ethyl acetate, the organic layer was spin dried and purified over a fast silica gel column to give 704.6g of a solid with 96.0% yield.
Mass spectrum detection, ESI/MS: 322.3[ MH ] m/z]+This solid was identified as 4- (6-trimethylacetamido-3-pyridyl) -4-hydroxy-N-tert-butoxycarbonylpiperidine.
The second step is that: synthesis of 4- (6-trimethylacetamido-3-pyridinyl) -N-tert-butoxycarbonylpiperidine
4- (6-trimethylacetamido-3-pyridinyl) -4-hydroxy-N-tert-butoxycarbonylpiperidine
(700.0g,1.85mol) and Raney nickel (163.3g, 2.78mol) were added to methanol (3.5L), and the reaction mixture was refluxed for 5 hours and then cooled to room temperature. Raney nickel was filtered and the solution was spun dry to give 643g of solid in 95.9% yield.
Mass spectrum detection, ESI/MS: 306.3[ MH ] m/z]+This solid was identified as 4- (6-trimethylacetamido-3-pyridyl) -N-tert-butoxycarbonylpiperidine.
The third step: synthesis of 4- (6-aminopyridin-3-yl) piperidine-1-carboxylic acid tert-butyl ester
Adding 4- (6-trimethylacetamido-3-pyridyl) -N-tert-butyloxycarbonylpiperidine (600g, 1.66mol) into a mixed solution of 5N potassium hydroxide aqueous solution (3.32L, 16.60mol) and ethanol (3.3L), carrying out reaction reflux stirring for 20 minutes, cooling to room temperature, extracting the solution with ethyl acetate, combining organic layers, drying, filtering and spin-drying to obtain 432g of white solid, wherein the HPLC (high performance liquid chromatography) accounts for 99.4% and the yield is 93.83%;
the total yield of the three-step reaction is as follows: 86 percent.
Example 3
The first step is as follows: synthesis of 4- (6-pivaloylamino-3-pyridyl) -4-hydroxy-N-tert-butoxycarbonylpiperidine
A solution of N-butyllithium (46.6L, 116.67mol) in N-hexane (2.5N) was slowly added to N- (5-bromo-pyridin-2-) -2, 2-dimethylpropionamide (10kg, 38.89mol) in tetrahydrofuran (20L) at-78 ℃ and the reaction mixture was stirred for 1 hour at-78 ℃ to-70 ℃. N-tert-Butoxycarbonyl-4-piperidone (7.75kg, 38.89mol) in tetrahydrofuran (12L) was added to the reaction mixture at-78 ℃ and stirred for 2 hours. After TLC monitoring reaction, ammonium chloride aqueous solution quenching reaction, ethyl acetate extraction, organic layer spin drying and rapid silica gel column purification to obtain solid 13.79kg, yield 93.9%.
Mass spectrum detection, ESI/MS: 322.3[ MH ] m/z]+This solid was identified as 4- (6-trimethylacetamido-3-pyridyl) -4-hydroxy-N-tert-butoxycarbonylpiperidine.
The second step is that: synthesis of 4- (6-trimethylacetamido-3-pyridinyl) -N-tert-butoxycarbonylpiperidine
4- (6-trimethylacetamido-3-pyridyl) -4-hydroxy-N-t-butoxycarbonylpiperidine (12kg,31.79mmol) and Raney's nickel (1.87kg, 31.79mmol) were added to isopropanol (60L), and the reaction mixture was refluxed for 5 hours and then cooled to room temperature. The Raney nickel was filtered and the solution was spun dry to give 10.91kg of solid with 94.95% yield.
Mass spectrum detection, ESI/MS: 306.3[ MH ] m/z]+This solid was identified as 4- (6-trimethylacetamido-3-pyridyl) -N-tert-butoxycarbonylpiperidine.
The third step: synthesis of 4- (6-aminopyridin-3-yl) piperidine-1-carboxylic acid tert-butyl ester
4- (6-trimethylacetamido-3-pyridyl) -N-tert-butoxycarbonylpiperidine (10kg, 27.66mol) was added to a mixed solution of 5N lithium hydroxide aqueous solution (38.73L, 193.65mol) and isopropanol (38.73mL), the reaction was refluxed and stirred for 20 minutes, the solution was extracted with ethyl acetate after cooling to room temperature, and the organic layers were combined, dried, filtered and spin-dried to give 7.06kg of a white solid, 99.3% HPLC, yield 92.05%.
The total yield of the three-step reaction is as follows: 82 percent.
Comparative example 1 (literature example)
The synthetic route reported in document WO201324078a1 is as follows:
in the first step, 6-nitro-3 ',6' -dihydro-2 ' -hydro- [3,4' ] bipyridinyl-1 ' -carbonic acid tert-butyl ester is prepared.
5-bromo-2-nitropyridine (6.56g,32.3mmol, Eq ═ 1) and 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5, 6-dihydropyridine-1 (2-hydro) -carboxylic acid tert-butyl ester (10g,32.3mmol, Eq ═ 1) were added to a flask containing dioxane (160mL) to form a yellow solution. Cesium carbonate (21.1g,64.7mmol, Eq ═ 2) and water (6mL) were added to the solution, argon was replaced and bis (triphenylphosphine) palladium dichloride (2.27g,3.23mmol, Eq ═ 0.1) was added. The reaction mixture was heated to 80 ℃ and stirred for 15 hours. The reaction was poured into 500mL of water and extracted with ethyl acetate, the organic layer was washed with brine, dried over magnesium sulfate, filtered, spin-dried, and purified over a fast silica gel column to give a pink solid. The solid was slurried with diethyl ether and filtered to give 2.2g of product.
Second, preparation of 4- (6-aminopyridin-3-yl) piperidine-1-carboxylic acid tert-butyl ester
To ethanol (300mL) and ethyl acetate (75mL) was added 6-nitro-3 ',6' -dihydro-2 ' -hydro- [3,4' ] bipyridinyl-1 ' -carbonic acid tert-butyl ester (4.9g,16.0mmol, Eq ═ 1.00), followed by palladium on carbon (1.32g,1.24mmol, Eq ═ 0.0773). The reaction mixture was replaced with hydrogen 2 times and reacted under hydrogen overnight. The reaction was confirmed to be complete by LC/MS, filtered under nitrogen and the filter cake was washed with ethyl acetate. And (5) rotatably drying the filtrate to obtain a product.
Comparative example 2 (literature example)
The synthetic routes reported in the journal of medicinal chemistry,2010, vol.53, #22p.7938-7957 are as follows:
the first step is as follows: preparation of 6-amino-3 ',6' -dihydro-2 ' -hydro- [3,4' ] bipyridinyl-1 ' -carboxylic acid tert-butyl ester
To a mixture of 5-bromo-2-aminopyridine (26,0.67g,3.9mmol) and 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5, 6-dihydropyridine-1 (2-hydro) -carboxylic acid tert-butyl ester (27,1.20g,3.9mmol) was added tetrakis (triphenylphosphine) palladium (0.45g,0.39mmol) and potassium fluoride/aluminum trioxide (3.6 g); the reaction mixture was degassed for 0.5 hour and heated to 100 ℃ for 2 hours. The reaction mixture was diluted with ethyl acetate, filtered and the filter cake was washed with ethyl acetate. The filtrate was dried over sodium sulfate, filtered and spun-dried, and passed through a fast silica gel column to give 6-amino-3 ',6' -dihydro-2 ' -hydro- [3,4' ] bipyridinyl-1 ' -carboxylic acid tert-butyl ester as a brown solid (0.75g, 70%).
Second, preparation of 4- (6-aminopyridin-3-yl) piperidine-1-carboxylic acid tert-butyl ester
10% Palladium on carbon (0.2g) was added to a solution of 6-amino-3 ',6' -dihydro-2 ' -hydro- [3,4' ] bipyridinyl-1 ' -carboxylic acid tert-butyl ester (0.75g,2.7mmol) in ethanol (20mL), the reaction solution was hydrogenated under the action of a hydrogen balloon for 16 hours, the reaction mixture was filtered, and the filter cake was rinsed with ethanol (2-10 mL). The filtrate was spun dry and passed through a flash column of silica gel to give tert-butyl 4- (6-aminopyridin-3-yl) piperidine-1-carboxylate (0.45g, 60%) as a solid.
Claims (3)
1. A preparation method of 4- (6-aminopyridine-3-yl) piperidine-1-tert-butyl formate is characterized by comprising the following specific steps:
the first step is as follows: synthesis of 4- (6-pivaloylamino-3-pyridyl) -4-hydroxy-N-tert-butoxycarbonylpiperidine
37.2mL of a 2.5N N-butyllithium N-hexane solution was slowly added to 80mL of an ether solution of 7.94g N- (5-bromo-pyridin-2-) -2, 2-dimethylpropionamide at-70 ℃ and the reaction mixture was stirred at this temperature for 1 hour; 6.15g N-tert-Butoxycarbonyl-4-piperidone in 60mL of diethyl ether at-70 ℃ were added to the reaction mixture and stirred for 2 hours; after TLC monitoring reaction, quenching reaction by ammonium chloride aqueous solution, extracting by ethyl acetate, spin-drying an organic layer, and purifying by a rapid silica gel column to obtain 11.01g of solid which is determined to be 4- (6-trimethylacetamido-3-pyridyl) -4-hydroxy-N-tert-butyloxycarbonylpiperidine by mass spectrometry;
the second step is that: synthesis of 4- (6-trimethylacetamido-3-pyridinyl) -N-tert-butoxycarbonylpiperidine
Adding 5g of 4- (6-trimethylacetamido-3-pyridyl) -4-hydroxy-N-tert-butyloxycarbonylpiperidine and 1g of raney nickel into 180mL of ethanol, refluxing the reaction solution for 5 hours, and cooling to room temperature; filtering Raney nickel, spin-drying the solution to obtain 4.54g of solid, and determining the solid to be 4- (6-trimethylacetamido-3-pyridyl) -N-tert-butyloxycarbonylpiperidine by mass spectrometry;
the third step: synthesis of 4- (6-aminopyridin-3-yl) piperidine-1-carboxylic acid tert-butyl ester
Adding 4g of 4- (6-trimethylacetamido-3-pyridyl) -N-tert-butyloxycarbonylpiperidine into a mixed solution of 11.07mL of 5N sodium hydroxide aqueous solution and 11mL of methanol, carrying out reaction reflux and stirring for 20 minutes, cooling to room temperature, extracting the solution with ethyl acetate, combining organic layers, drying, filtering and spin-drying to obtain 2.85g of white solid, wherein HPLC (high performance liquid chromatography) is 99.2%; the total yield of the three-step reaction is 83 percent.
2. A preparation method of 4- (6-aminopyridine-3-yl) piperidine-1-tert-butyl formate is characterized by comprising the following specific steps:
the first step is as follows: synthesis of 4- (6-pivaloylamino-3-pyridyl) -4-hydroxy-N-tert-butoxycarbonylpiperidine
Slowly adding 1.94L of 2.5N N-butyllithium N-hexane solution into 1L of 500g N- (5-bromo-pyridine-2-) -2, 2-dimethylpropionamide tetrahydrofuran solution at-65 deg.C, and stirring the reaction mixture at-65 deg.C to-70 deg.C for 1 hr; 465g of 2L tetrahydrofuran solution of N-tert-butoxycarbonyl-4-piperidone was added to the reaction solution at-65 ℃ and stirred for 2 hours; after TLC monitoring reaction, quenching reaction by ammonium chloride aqueous solution, extracting by ethyl acetate, spin-drying an organic layer, purifying by a rapid silica gel column to obtain 704.6g of solid, and determining the solid to be 4- (6-trimethylacetamido-3-pyridyl) -4-hydroxy-N-tert-butyloxycarbonylpiperidine by mass spectrometry;
the second step is that: synthesis of 4- (6-trimethylacetamido-3-pyridinyl) -N-tert-butoxycarbonylpiperidine
700.0g of 4- (6-trimethylacetamido-3-pyridyl) -4-hydroxy-N-tert-butoxycarbonylpiperidine and 163.3g of Raney's nickel were added to 3.5L of methanol, and the reaction solution was refluxed for 5 hours and then cooled to room temperature; filtering raney nickel, spin-drying the solution to obtain 643g of solid, and determining the solid to be 4- (6-trimethylacetamido-3-pyridyl) -N-tert-butyloxycarbonylpiperidine by mass spectrum detection;
the third step: synthesis of 4- (6-aminopyridin-3-yl) piperidine-1-carboxylic acid tert-butyl ester
Adding 600g of 4- (6-trimethylacetamido-3-pyridyl) -N-tert-butyloxycarbonylpiperidine into a mixed solution of 3.32L of 5N potassium hydroxide aqueous solution and 3.3L of ethanol, carrying out reaction reflux and stirring for 20 minutes, cooling to room temperature, extracting the solution with ethyl acetate, combining organic layers, drying, filtering and spin-drying to obtain 432g of white solid, wherein HPLC (high performance liquid chromatography) accounts for 99.4%; the total yield of the three-step reaction is 86%.
3. A preparation method of 4- (6-aminopyridine-3-yl) piperidine-1-tert-butyl formate is characterized by comprising the following specific steps:
the first step is as follows: synthesis of 4- (6-pivaloylamino-3-pyridyl) -4-hydroxy-N-tert-butoxycarbonylpiperidine
Slowly adding 46.6L N-hexane solution 2.5N of N-butyllithium into 10kg tetrahydrofuran 20L solution of N- (5-bromo-pyridine-2-) -2, 2-dimethylpropionamide at-78 deg.C to-70 deg.C, and stirring the reaction mixture at-78 deg.C to-70 deg.C for 1 hr; 7.75kg of N-tert-butoxycarbonyl-4-piperidone in 12L of tetrahydrofuran was added to the reaction mixture at-78 ℃ and stirred for 2 hours; after TLC monitoring reaction, quenching reaction by ammonium chloride aqueous solution, extracting by ethyl acetate, spin-drying an organic layer, purifying by a rapid silica gel column to obtain 13.79kg of solid, and determining the solid to be 4- (6-trimethylacetamido-3-pyridyl) -4-hydroxy-N-tert-butyloxycarbonylpiperidine by mass spectrometry;
the second step is that: synthesis of 4- (6-trimethylacetamido-3-pyridinyl) -N-tert-butoxycarbonylpiperidine
Adding 12kg of 4- (6-trimethylacetamido-3-pyridyl) -4-hydroxy-N-tert-butyloxycarbonylpiperidine and 1.87kg of raney nickel into 60L of isopropanol, refluxing and reacting the reaction liquid for 5 hours, and cooling to room temperature; filtering Raney nickel, spin-drying the solution to obtain 10.91kg of solid, and determining the solid to be 4- (6-trimethylacetamido-3-pyridyl) -N-tert-butyloxycarbonylpiperidine by mass spectrometry;
the third step: synthesis of 4- (6-aminopyridin-3-yl) piperidine-1-carboxylic acid tert-butyl ester
Adding 10kg of 4- (6-trimethylacetamido-3-pyridyl) -N-tert-butyloxycarbonylpiperidine into a mixed solution of 38.73L of 5N lithium hydroxide aqueous solution and 38.73L of isopropanol, carrying out reaction reflux and stirring for 20 minutes, cooling to room temperature, extracting the solution with ethyl acetate, combining organic layers, drying, filtering and spin-drying to obtain 7.06kg of white solid, 99.3% of HPLC; the total yield of the three-step reaction is 82%.
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