CN112608299A - Synthesis method of 4- (6-aminopyridine-3-yl) piperidine-1-tert-butyl formate - Google Patents
Synthesis method of 4- (6-aminopyridine-3-yl) piperidine-1-tert-butyl formate Download PDFInfo
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- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
The invention discloses a synthesis method of 4- (6-aminopyridine-3-yl) piperidine-1-tert-butyl formate. The method comprises the steps of generating a Grignard reagent by exchanging fluorine/magnesium with methyl N- (5-bromopyridine-2-yl) carbamate and isopropyl magnesium chloride-lithium chloride, then adding the Grignard reagent and N-tert-butyloxycarbonyl-4-piperidone, reducing the addition product by triethylsilane, and deprotecting under an alkaline condition to obtain a target product. The method has the advantages of simple steps, no special reactions such as ultralow temperature, high temperature and high pressure, catalytic hydrogenation and the like, low equipment requirement, high safety, cheap and easily-obtained raw materials, no need of expensive catalysts, high product purity and high yield, and is suitable for industrial production.
Description
Technical Field
The invention relates to a synthesis method of 4- (6-aminopyridine-3-yl) piperidine-1-tert-butyl formate, belonging to the technical field of organic synthesis.
Background
4- (6-aminopyridin-3-yl) piperidine-1-tert-butyl formate is an important medical intermediate, can be used as a key intermediate of some pyrimidine or pyridopyridone medicaments, and the medicaments can effectively and selectively inhibit the activity of cell Cycle Dependent Kinases (CDKs) CDK4 and CDK6 to play an anti-tumor role, thereby being attracted by much attention.
4- (6-Aminopyridin-3-yl) piperidine-1-carboxylic acid tert-butyl ester currently has the following synthetic method:
patent WO201324078 uses 5-bromo-2-nitropyridine and 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -5, 6-dihydropyridine-1 (2-hydro) -carboxylic acid tert-butyl ester as starting materials, catalytic coupling is carried out under palladium catalyst, and palladium carbon is then used for hydrogenation reduction of nitro and double bonds to obtain the product. The raw materials, catalysts, cesium carbonate and the like used in the method are high in price, the yield is low during coupling, more impurities are generated, the removal is difficult, palladium-carbon hydrogenation is needed, and the requirements on equipment safety and the like are high.
Document JMC,2010,53,22, 7938-.
Patent CN109384767A adopts cheaper N-benzyl piperidone and 5-bromo-2- (2, 5-dimethyl-1H-pyrrole-1-yl) pyridine as raw materials, and the raw materials are subjected to catalytic coupling by a palladium catalyst, deprotection, palladium-carbon hydrogenation reduction and Boc group loading to obtain a product, but the catalyst is expensive, the reaction steps are too long, the yield is low, palladium-carbon hydrogenation is still needed, and the requirements on equipment safety and the like are high.
Patent CN107759563A adopts 2-fluoro-5-bromopyridine to exchange with isopropyl Grignard reagent or n-butyl lithium to generate active metal reagent, and then the active metal reagent is added, substituted and reduced to obtain the product, which has the advantages of cheap raw material, short steps and the like, but the substitution requires high temperature and high pressure, the yield is not high, and the Raney nickel catalytic hydrogenation is flammable and explosive, and has great safety risk.
The patent CN107827869A adopts N- (5-bromo-pyridine-2-) -2, 2-dimethylpropionamide as a raw material, and the product is obtained by butyl lithium bromine extraction addition, reduction and deprotection, so that the cost is low, the yield is high, but the addition needs ultralow temperature, and the Raney nickel catalytic hydrogenation has high flammable and explosive safety risk and is not beneficial to industrial production.
Patent CN110540535A directly adopts cheaper 2-amino-5-bromopyridine as raw material on the basis of patent CN109384767A, and the product is obtained by catalytic coupling and reduction through a palladium catalyst, so that deprotection is not needed, impurities are less, cost is low, palladium-carbon catalytic hydrogenation is still needed, equipment requirement is high, and safety risk is high.
Disclosure of Invention
The invention overcomes the defects of the prior art and provides a synthetic method of 4- (6-aminopyridine-3-yl) piperidine-1-tert-butyl formate. The method comprises the steps of generating a Grignard reagent by exchanging fluorine/magnesium with methyl N- (5-bromopyridine-2-yl) carbamate and isopropyl magnesium chloride-lithium chloride, then adding the Grignard reagent and N-tert-butyloxycarbonyl-4-piperidone, reducing the addition product by triethylsilane, and deprotecting under an alkaline condition to obtain a target product. The method has the advantages of simple steps, no special reactions such as ultralow temperature, high temperature and high pressure, catalytic hydrogenation and the like, low equipment requirement, high safety, cheap and easily-obtained raw materials, no need of expensive catalysts, high product purity and high yield, and is suitable for industrial production.
The technical scheme of the invention is as follows: a synthetic method of 4- (6-aminopyridine-3-yl) piperidine-1-tert-butyl formate is characterized by comprising the following steps:
1) fluorenylmethyl N- (5-bromopyridine-2-yl) carbamate and isopropyl magnesium chloride-lithium chloride generate Grignard reagent through halogen/magnesium exchange, and then carry out addition reaction with N-tert-butyloxycarbonyl-4-piperidone to obtain 4- (6-fluorenylformylamino-3-pyridyl) -4-hydroxy-N-tert-butyloxycarbonyl piperidine;
2) reducing 4- (6-fluorenylformylamino-3-pyridyl) -4-hydroxy-N-tert-butyloxycarbonyl piperidine by triethylsilane, and deprotecting under alkaline condition to obtain 4- (6-aminopyridin-3-yl) piperidine-1-tert-butyl formate.
The reaction equation is shown below.
Remarking: fmoc is fluorenylmethoxycarbonyl.
Further, the step 2) is carried out with boron trifluoride diethyl etherate as a catalyst.
The method specifically comprises the following steps:
1) under the protection of nitrogen, adding fluorenylmethyl N- (5-bromopyridine-2-yl) carbamate into an organic solvent, dropwise adding an isopropyl magnesium chloride-lithium chloride solution to perform halogen/magnesium exchange to obtain an active format reagent, dropwise adding the active format reagent into an N-tert-butoxycarbonyl-4-piperidone solution, controlling the temperature to be 5-20 ℃, performing heat preservation reaction for 1-5 hours, and performing aftertreatment to obtain 4- (6-fluorenylformamido-3-pyridyl) -4-hydroxy-N-tert-butoxycarbonylpiperidine;
2) under the protection of nitrogen, adding 4- (6-fluorenylformylamino-3-pyridyl) -4-hydroxy-N-tert-butyloxycarbonylpiperidine and triethylsilane into an organic solvent, dropwise adding boron trifluoride diethyl etherate, controlling the temperature to be-10 to-5 ℃ after dropwise adding, carrying out reduction reaction for 1-3 h, then adding alkali liquor, stirring and reacting to remove fluorenylformylamino, and carrying out post-treatment to obtain a target product, namely 4- (6-aminopyridin-3-yl) piperidine-1-tert-butyl formate.
Further, the post-treatment of the step 1) is as follows: adding saturated ammonium chloride solution into the reaction solution, extracting with ethyl acetate, drying, steaming to dryness, adding methyl tert-butyl ether, refluxing, pulping, cooling to-5-0 ℃, performing suction filtration, and drying.
Further, the post-treatment of the step 2) is as follows: adding dichloromethane into the reaction liquid for extraction, drying, reducing steam to dryness, refluxing and pulping methyl tert-butyl ether, reducing the temperature to 0-5 ℃, performing suction filtration, and drying.
Preferably, the organic solvent in step 1) is one or more of tetrahydrofuran, dioxane and 2-methyltetrahydrofuran, and more preferably tetrahydrofuran.
Preferably, the molar charge ratio of fluorenylmethyl N- (5-bromopyridin-2-yl) carbamate, isopropyl magnesium chloride-lithium chloride and N-tert-butoxycarbonyl-4-piperidone in the step 1) is 1: 1.1-1.4: 0.9 to 1.0.
Preferably, the organic solvent of step 2) is one or more of tetrahydrofuran, dioxane, 2-methyltetrahydrofuran, acetonitrile, dichloromethane, isopropyl ether and methyl tert-butyl ether, and more preferably acetonitrile.
Preferably, the alkali liquor used in step 2) is one or more of aqueous solutions of sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, piperidine and triethylamine, and more preferably an aqueous solution of piperidine.
Preferably, the molar charge ratio of the 4- (6-fluorenylformamido-3-pyridyl) -4-hydroxy-N-tert-butyloxycarbonylpiperidine, the triethylsilane, the boron trifluoride diethyl etherate and the alkali in the alkali liquor in the step 2) is 1: 1.5-2.5: 0.7-1.0: 3 to 7.
The invention has the beneficial effects that:
1) the method has the advantages of cheap and easily obtained raw materials, no need of expensive boron reagent or palladium reagent, short steps (reduction and deprotection one-pot method), higher yield (total yield is more than or equal to 75 percent), and great reduction of the production cost of the 4- (6-aminopyridin-3-yl) piperidine-1-tert-butyl formate.
2) The method does not need special reactions such as ultralow temperature, high temperature and high pressure, catalytic hydrogenation and the like, has low requirement on equipment and high safety, and is particularly suitable for industrial production.
Detailed Description
The following examples are further illustrative of the present invention, but the present invention is not limited thereto.
Example 1:
(1) synthesis of 4- (6-fluorenylcarboxamido-3-pyridyl) -4-hydroxy-N-t-butoxycarbonylpiperidine
Under the protection of nitrogen, 39.5g of fluorenylmethyl N- (5-bromopyridin-2-yl) carbamate is added into 400ml of anhydrous THF, 100ml of isopropyl magnesium chloride lithium chloride solution (1.3M) is dripped into the anhydrous THF when the temperature is reduced to 0-5 ℃, and the reaction is carried out for 2h after dripping is finished, thus obtaining the Grignard reagent.
Under the protection of nitrogen, dissolving 17.9g N-tert-butoxycarbonyl-4-piperidone in 100ml of anhydrous THF, dropwise adding the Grignard reagent, controlling the temperature to be 10-15 ℃, and carrying out heat preservation reaction for 3 hours. And after TLC reaction, adding 500ml of saturated ammonium chloride solution and 300ml of ethyl acetate for extraction, drying, evaporating to dryness, adding 150ml of methyl tert-butyl ether, refluxing and pulping for 1h, cooling to-5-0 ℃, performing suction filtration, and drying to obtain 41.9g of a product, wherein the yield is 90.3%, and the purity is 98.6%.
(2) Synthesis of 4- (6-aminopyridin-3-yl) piperidine-1-carboxylic acid tert-butyl ester
Under the protection of nitrogen, 41.9g of 4- (6-fluorenylformamido-3-pyridyl) -4-hydroxy-N-tert-butyloxycarbonylpiperidine and 14.1g of triethylsilane are added into 500ml of acetonitrile, the temperature is controlled between minus 10 ℃ and minus 5 ℃, 9g of boron trifluoride diethyl etherate is added dropwise, and the reaction is carried out for 2 hours at the temperature after the dropwise addition. After TLC reaction is finished, 50g of sodium carbonate/400 g of water is dripped, reaction is carried out for 2h at 20-25 ℃, dichloromethane is added for extraction, drying and reduced evaporation are carried out until the mixture is dry, 60ml of methyl tert-butyl ether is refluxed and pulped for 1h, the temperature is reduced to 0-5 ℃, suction filtration is carried out, and drying is carried out to obtain 19.4g of a product, the yield is 86.2%, and the purity is 99.6%.
Example 2:
(1) synthesis of 4- (6-fluorenylcarboxamido-3-pyridyl) -4-hydroxy-N-t-butoxycarbonylpiperidine
Under the protection of nitrogen, 59.3g of fluorenylmethyl N- (5-bromopyridine-2-yl) carbamate is added into 600ml of anhydrous 2-methyltetrahydrofuran, the temperature is reduced to 0-5 ℃, 145ml of isopropyl magnesium chloride lithium chloride solution (1.3M) is dripped, and the Grignard reagent is obtained after the dripping and the heat preservation reaction for 2 hours.
Under the protection of nitrogen, 29.8g N-tert-butyloxycarbonyl-4-piperidone is dissolved in 150ml of anhydrous 2-methyltetrahydrofuran, the Grignard reagent is dripped, the temperature is controlled to be 5-10 ℃, the heat preservation reaction is carried out for 3h, after the TLC reaction is finished, 750ml of saturated ammonium chloride solution and 450ml of ethyl acetate are added for extraction, the mixture is dried and evaporated to dryness, 200ml of methyl tert-butyl ether is added for reflux pulping for 1h, the temperature is reduced to-5-0 ℃, the mixture is subjected to suction filtration and drying, and 70.3g of a product is obtained, the yield is 91.1%, and the purity is 98.7%.
(2) Synthesis of 4- (6-aminopyridin-3-yl) piperidine-1-carboxylic acid tert-butyl ester
Under the protection of nitrogen, 41.9g of 4- (6-fluorenylformamido-3-pyridyl) -4-hydroxy-N-tert-butyloxycarbonylpiperidine and 18.7g of triethylsilane are added into a mixed solution of 300ml of acetonitrile and 200ml of dichloromethane, the temperature is controlled between minus 10 ℃ and minus 5 ℃, 10g of boron trifluoride diethyl etherate is added dropwise, and the reaction is carried out for 2 hours at the temperature after the dropwise addition. After TLC reaction is finished, 43g of piperidine/400 g of water is dripped, reaction is carried out for 2h at 20-25 ℃, dichloromethane is added for extraction, drying and reduced evaporation are carried out until the mixture is dry, 60ml of methyl tert-butyl ether is refluxed and pulped for 1h, the temperature is reduced to 0-5 ℃, suction filtration is carried out, and drying is carried out to obtain 20.1g of product, the yield is 89.3%, and the purity is 99.5%.
Claims (10)
1. A synthetic method of 4- (6-aminopyridine-3-yl) piperidine-1-tert-butyl formate is characterized by comprising the following steps:
1) fluorenylmethyl N- (5-bromopyridine-2-yl) carbamate and isopropyl magnesium chloride-lithium chloride generate Grignard reagent through halogen/magnesium exchange, and then carry out addition reaction with N-tert-butyloxycarbonyl-4-piperidone to obtain 4- (6-fluorenylformylamino-3-pyridyl) -4-hydroxy-N-tert-butyloxycarbonyl piperidine;
2) reducing 4- (6-fluorenylformylamino-3-pyridyl) -4-hydroxy-N-tert-butyloxycarbonyl piperidine by triethylsilane, and deprotecting under alkaline condition to obtain 4- (6-aminopyridin-3-yl) piperidine-1-tert-butyl formate.
2. The method for synthesizing tert-butyl 4- (6-aminopyridin-3-yl) piperidine-1-carboxylate according to claim 1, wherein the step 2) is carried out by reduction reaction under catalysis of boron trifluoride diethyl etherate.
3. The method for synthesizing 4- (6-aminopyridin-3-yl) piperidine-1-carboxylic acid tert-butyl ester according to claim 2, which comprises the following steps:
1) under the protection of nitrogen, adding fluorenylmethyl N- (5-bromopyridine-2-yl) carbamate into an organic solvent, dropwise adding an isopropyl magnesium chloride-lithium chloride solution to perform halogen/magnesium exchange to obtain an active format reagent, dropwise adding the active format reagent into an N-tert-butoxycarbonyl-4-piperidone solution, controlling the temperature to be 5-20 ℃, performing heat preservation reaction for 1-5 hours, and performing aftertreatment to obtain 4- (6-fluorenylformamido-3-pyridyl) -4-hydroxy-N-tert-butoxycarbonylpiperidine;
2) under the protection of nitrogen, adding 4- (6-fluorenylformylamino-3-pyridyl) -4-hydroxy-N-tert-butyloxycarbonylpiperidine and triethylsilane into an organic solvent, dropwise adding boron trifluoride diethyl etherate, controlling the temperature to be-10 to-5 ℃ after dropwise adding, carrying out reduction reaction for 1-3 h, then adding alkali liquor, stirring and reacting to remove fluorenylformylamino, and carrying out post-treatment to obtain a target product, namely 4- (6-aminopyridin-3-yl) piperidine-1-tert-butyl formate.
4. The method for synthesizing 4- (6-aminopyridin-3-yl) piperidine-1-carboxylic acid tert-butyl ester according to claim 3, wherein the post-treatment in the step 1) is as follows: adding saturated ammonium chloride solution into the reaction solution, extracting with ethyl acetate, drying, steaming to dryness, adding methyl tert-butyl ether, refluxing, pulping, cooling to-5-0 ℃, performing suction filtration, and drying.
5. The method for synthesizing 4- (6-aminopyridin-3-yl) piperidine-1-carboxylic acid tert-butyl ester according to claim 3, wherein the post-treatment in the step 2) comprises the following steps: adding dichloromethane into the reaction liquid for extraction, drying, reducing steam to dryness, refluxing and pulping methyl tert-butyl ether, reducing the temperature to 0-5 ℃, performing suction filtration, and drying.
6. The method for synthesizing tert-butyl 4- (6-aminopyridin-3-yl) piperidine-1-carboxylate as claimed in claim 3, wherein the organic solvent in step 1) is one or more of tetrahydrofuran, dioxane and 2-methyltetrahydrofuran.
7. The method for synthesizing 4- (6-aminopyridin-3-yl) piperidine-1-carboxylic acid tert-butyl ester according to claim 3, wherein the molar ratio of fluorenylmethyl N- (5-bromopyridin-2-yl) carbamate, isopropylmagnesium chloride-lithium chloride and N-tert-butoxycarbonyl-4-piperidone in the step 1) is 1: 1.1-1.4: 0.9 to 1.0.
8. The method for synthesizing tert-butyl 4- (6-aminopyridin-3-yl) piperidine-1-carboxylate according to claim 3, wherein the organic solvent in step 2) is one or more of tetrahydrofuran, dioxane, 2-methyltetrahydrofuran, acetonitrile, dichloromethane, isopropyl ether and methyl tert-butyl ether.
9. The method for synthesizing 4- (6-aminopyridin-3-yl) piperidine-1-carboxylic acid tert-butyl ester according to claim 3, wherein the alkali solution used in the step 2) is one or more than two of aqueous solutions of sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, piperidine and triethylamine.
10. The method for synthesizing 4- (6-aminopyridin-3-yl) piperidine-1-carboxylic acid tert-butyl ester according to any one of claims 3 to 9, wherein the molar charge ratio of 4- (6-fluorenylcarboxamido-3-pyridyl) -4-hydroxy-N-tert-butoxycarbonylpiperidine, triethylsilane, boron trifluoride diethyl etherate and alkali in alkali liquor in the step 2) is 1: 1.5-2.5: 0.7-1.0: 3 to 7.
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