CN113636973A - Industrial preparation method of 4- (6-aminopyridine-3-yl) piperazine-1-carboxylic acid tert-butyl ester - Google Patents
Industrial preparation method of 4- (6-aminopyridine-3-yl) piperazine-1-carboxylic acid tert-butyl ester Download PDFInfo
- Publication number
- CN113636973A CN113636973A CN202111047083.6A CN202111047083A CN113636973A CN 113636973 A CN113636973 A CN 113636973A CN 202111047083 A CN202111047083 A CN 202111047083A CN 113636973 A CN113636973 A CN 113636973A
- Authority
- CN
- China
- Prior art keywords
- acid
- piperazine
- water
- formula
- solvent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention discloses an industrial preparation method of 4- (6-aminopyridine-3-yl) piperazine-1-tert-butyl carboxylate, the method adopts 5-bromine-2-nitropyridine and piperazine as initial raw materials, in a mixed solvent of an alcohol organic solvent and water, preparing high-purity 1- (6-nitropyridine-3-yl) piperazine by nucleophilic substitution reaction with acid as a catalyst, reacting the piperazine with Boc anhydride in the presence of an organic solvent and water, the high-purity 4- (6-nitropyridine-3-yl) piperazine-1-carboxylic acid tert-butyl ester is prepared by taking weak base as an acid-binding agent, and then the high-purity and light-color 4- (6-aminopyridine-3-yl) piperazine-1-carboxylic acid tert-butyl ester is obtained by catalytic hydrogenation and refining decoloration. The method has the advantages of simple operation, little environmental pollution, high yield, low cost and good product quality, and is more suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to an industrial preparation method of 4- (6-aminopyridine-3-yl) piperazine-1-carboxylic acid tert-butyl ester.
Background
The Palbociclib (Palbociclib), the chemical name of which is 2- [ (4-piperidyl) benzyl ] -6-acetyl-8-cyclopentyl-5-methylpyridine [2,3-d ] pyrimidine-7 (8H) -ketone, is developed by the company Peucedanum, is approved to be marketed in the United states at 2 months in 2015, is an inhibitor of cyclin-dependent kinases (CDKs) 4 and 6, prevents cells from the G1 stage to the S stage to inhibit DNA synthesis mainly by regulating the cell cycle and inhibiting the activities of the (CDKs) 4 and 6, and is mainly clinically used for treating patients with advanced breast cancer.
Tert-butyl 4- (6-aminopyridin-3-yl) piperazine-1-carboxylate (formula (1)) is a key intermediate for the synthesis of palbociclib, CAS number 571188-59-5, structural formula:
the literature reports that the synthesis method of the 4- (6-aminopyridin-3-yl) piperazine-1-carboxylic acid tert-butyl ester mainly comprises the following two methods:
the method comprises the following steps: imaeda, Yasuhiro et al (Bioorganic & Medicinal Chemistry,16(6), 3125-3140; 2008) used 5-bromo-2-nitropyridine to react with 1-Boc-piperazine in N-methylpyrrolidone to give tert-butyl 4- (6-nitropyridin-3-yl) piperazine-1-carboxylate, followed by catalytic hydrogenation of the nitro group with palladium on carbon in ethanol to give the desired product, as follows:
the synthetic method has the advantages of short route and high yield, but the reaction cost is high because the prepared 1-Boc-piperazine (piperazine reacts with Boc anhydride) has low yield, high Boc anhydride has low utilization rate and more three wastes, and is not beneficial to environmental protection requirements, so that the 1-Boc-piperazine is high in price, contains a large amount of di-Boc-piperazine and has low purity.
The second method comprises the following steps: JV Carlinni et al reported in Chinese patent CN105384741B that 5-chloro-2-nitropyridine first reacted with piperazine in n-butanol through nucleophilic substitution to obtain 1- (6-nitropyridine-3-yl) piperazine hydrochloride, then reacted with Boc anhydride in tetrahydrofuran with potassium carbonate as an acid-binding agent, and then catalytically reduced to obtain 4- (6-aminopyridin-3-yl) piperazine-1-carboxylic acid tert-butyl ester, wherein the reaction route is as follows:
this route is a procedure for the preparation of 1- (6-nitropyridin-3-yl) piperazine hydrochloride, which, although giving a yield of 82.3% and a melting point range (mp > 230 ℃), is prone to potential side reactions with bimolecular halopyridines at the piperazine ends under basic conditions, generating bimolecular condensation by-products (Tetrahedron Letters 39(1998) 617-620).
In the actual preparation process, we observed 2 piperazine disubstituted impurities, impurity formula (4) and impurity formula (5), the reaction route is as follows:
although impurity formula (4) and impurity formula (5) do not react with Boc piperazine, but have relatively low solubility in both n-butanol and water, while impurity formula (4) and impurity formula (5) are mostly removed by filtration in step 2 in patent CN105384741B, they are carried into tert-butyl 4- (6-nitropyridin-3-yl) piperazine-1-carboxylate due to their solubility in tetrahydrofuran, and are reduced by hydrogenation to obtain their derivatives impurity formula (6) and impurity formula (7):
both impurity formula (6) and impurity formula (7) are difficult to remove from tert-butyl 4- (6-aminopyridin-3-yl) piperazine-1-carboxylate, and thus a high purity product cannot be obtained.
In the process of researching palladium-carbon catalytic reduction of nitro, a trace amount of impurity shown in formula (5) is found, and in the process of palladium-carbon reduction, a debromination reaction occurs to generate a trace amount of hydrobromic acid, so that Boc group of tert-butyl 4- (6-aminopyridin-3-yl) piperazine-1-carboxylate is promoted to be hydrolyzed to generate a series of impurities, wherein the impurities comprise impurities with potential genotoxicity, and the quality of a product is further influenced.
In addition, the color of the 4- (6-aminopyridin-3-yl) piperazine-1-carboxylic acid tert-butyl ester reported in the literature is a brown yellow solid, and no white to off-white solid is reported. However, as an enterprise mainly comprising pharmaceutical raw material drugs and intermediates, customers put forward the requirements of light yellow solid to us.
The dosage of the palbociclib serving as a heavy bomb grade new drug is large, and the dosage of the key intermediate, namely the 4- (6-amino-3-pyridyl) piperazine-1-carboxylic acid tert-butyl ester is increased year by year. With the increasing awareness of pharmaceutical and chemical enterprises on environmental protection year by year, and in order to meet the requirements of customers pursuing high-quality products, the problem to be solved currently is to develop a synthetic method of 4- (6-aminopyridine-3-yl) piperazine-1-tert-butyl carboxylate, which has low cost, high yield, high purity, low toxicity and environmental friendliness.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides an industrial preparation method of 4- (6-aminopyridine-3-yl) piperazine-1-carboxylic acid tert-butyl ester, the method adopts 5-bromo-2-nitropyridine and piperazine as starting materials, and comprises the steps of dissolving the starting materials in a mixed solvent of n-butanol and water, preparing high-purity 1- (6-nitropyridine-3-yl) piperazine by nucleophilic substitution reaction with acid as a catalyst, reacting the piperazine with Boc anhydride in the presence of an organic solvent and water, the high-purity 4- (6-nitropyridine-3-yl) piperazine-1-carboxylic acid tert-butyl ester is prepared by taking weak base as an acid-binding agent, and then the high-purity and light-color 4- (6-aminopyridine-3-yl) piperazine-1-carboxylic acid tert-butyl ester is obtained by catalytic hydrogenation and refining decoloration. The method has the advantages of simple operation, little environmental pollution, high yield, low cost and good product quality, and is more suitable for industrial production.
The technical scheme of the invention is as follows: an industrial preparation method of 4- (6-aminopyridin-3-yl) piperazine-1-carboxylic acid tert-butyl ester is characterized by comprising the following steps:
s1: in a mixed solvent of an alcohol organic solvent and water, using acid as a catalyst, reacting 5-bromo-2-nitropyridine with piperazine to generate an acid salt of a compound shown in a formula (2), adding water after the reaction is finished, recovering the solvent through azeotropic distillation to obtain an aqueous solution containing the acid salt of the compound shown in the formula (2), removing insoluble impurities through filtration, adjusting the pH value to be above 10 with alkali, and centrifuging to obtain a high-purity wet product of the compound shown in the formula (2);
s2: reacting a wet product of the compound shown in the formula (2) with Boc anhydride in a mixed solvent of an organic solvent and water in the presence of an acid-binding agent, and carrying out aftertreatment on a reaction liquid to obtain a compound shown in the formula (3);
s3: the compound of the formula (3) is subjected to catalytic hydrogenation in a polar solvent in the presence of a catalyst and an acid-binding agent, and a crude product of the compound of the formula (1) is generated after the post-treatment;
s4: adding the crude product of the compound shown in the formula (1) into water, adding acid to dissolve the solid, decoloring with activated carbon, adjusting pH to be alkaline with sodium hydroxide solution, and performing crystallization, centrifugation, washing and drying to obtain the 4- (6-aminopyridin-3-yl) piperazine-1-carboxylic acid tert-butyl ester with high purity (more than or equal to 99.8%) and white to light yellow color.
The synthetic route is as follows:
wherein the content of the first and second substances,
the acid in step S1 is one or a mixture of two of hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, acetic acid, citric acid, etc., preferably hydrobromic acid, and the molar ratio of the acid to piperazine used is 0.5 to 1.5:1, more preferably 1:1. One end of the amino group of piperazine is protected by the way that piperazine becomes monoacid salt, so that the generation of bipiperazine substitution products is prevented.
The alcohol organic solvent of the step S1 is one of n-butanol, n-pentanol, isoamyl alcohol, tert-butanol, sec-butanol and 1-propanol, and preferably n-butanol; the ratio of the water to the water is 10: 0.3-5 (V/V), preferably 10: 0.5-2, and more preferably 10: 1.
The molar ratio of 5-bromo-2-nitropyridine to piperazine in step S1 is 1:1.2 to 2, preferably 1: 1.2. The amount of piperazine is increased, which is beneficial to the generation of mono-substituted products of piperazine and the reduction of di-substituted products of piperazine, but from the viewpoint of environmental protection, the amount of piperazine is reduced as much as possible on the premise of not influencing the reaction result, which is beneficial to the treatment of three wastes and the requirement of environmental protection.
The reaction temperature in step S1 is 50-100 ℃, preferably 60-65 ℃.
And (4) recovering the solvent azeotropically in the step S1, obtaining a mixture of the solvent and water through azeotropic distillation in a mode of supplementing water in batches, separating out the organic solvent and the water through liquid separation, wherein the organic solvent is directly used for the next batch of reaction, and the water is used for the azeotropic distillation of the materials in the next batch, so that zero emission of the solvent is realized.
In step S1, dimeric impurities of formula (4) and formula (5) are removed by filtration, and the resulting mixture is made alkaline with a base to obtain a high-purity compound of formula (2).
The piperazine disubstituted impurities generated in the reaction process, namely the impurities shown in the formula (4) and the impurities shown in the formula (5), are slightly dissolved in an organic solvent under an acidic condition and are insoluble in water. The method comprises the steps of replacing reaction liquid with water by adopting an azeotropic organic solvent removal mode, dissolving intermediate formula (2) acid salt in water, directly removing a small amount of piperazine disubstituted impurities through filtration, adjusting the pH value of the reaction liquid to be more than 10 by adopting the characteristic that a compound of formula (2) has low solubility in strong alkali, separating out intermediate formula (2), obtaining an intermediate formula (2) wet product through centrifugation, and directly carrying out next reaction without drying.
The acid-binding agent in the step S2 is one of sodium carbonate, potassium carbonate, triethylamine, diisopropylethylamine, sodium acetate, sodium hydroxide and potassium hydroxide, preferably sodium carbonate, and the molar ratio of the compound of formula (2) to the acid-binding agent and Boc anhydride is 1: 1.2-1.8: 1.0-1.5.
The organic solvent in step S2 is one of dichloromethane, chloroform, toluene, tetrahydrofuran, and dioxane, preferably toluene and dichloromethane.
The post-processing in step S2 is: heating until the solid is dissolved, standing for liquid separation, separating out an aqueous layer, washing an organic layer, concentrating under reduced pressure, and recrystallizing.
The catalyst in the step S3 is one of palladium carbon, platinum carbon, and raney nickel, preferably platinum carbon, and the mass ratio of the compound of formula (3) to the catalyst is 1: 0.01-1: 0.05, preferably 1: 0.03.
The acid-binding agent in step S3 is one of sodium acetate, potassium acetate, triethylamine, ammonia water, sodium carbonate, and sodium bicarbonate, preferably sodium acetate. The molar ratio of the compound of the formula (3) to the acid-binding agent is 1:0.01 to 0.1, preferably 1:0.01 to 0.05, and more preferably 1: 0.02. Catalytic hydrogenation reduction of nitro, debromination reaction of trace impurity of formula (5), dissolving generated hydrogen bromide in water generated by hydrogenation reduction, leading reaction liquid to have certain acidity, leading Boc group to have trace degradation, leading to generation of a plurality of trace impurities in compound of formula (1), wherein the trace impurities comprise impurities with genetic toxicity warning structures. And a small amount of acid binding agent is added to neutralize generated hydrobromic acid so as to prevent degradation of Boc groups, and the purity and quality of the product are improved.
The polar solvent in step S3 is one of methanol, ethanol, isopropanol, and n-butanol, preferably methanol. The methanol is more beneficial to recovery and treatment, the economic cost is lower, and meanwhile, the methanol also has certain solubility on the acid-binding agent sodium acetate.
The reaction temperature in step S3 is 10-60 ℃, preferably 10-30 ℃.
The post-processing of step S3 is: filtering, concentrating the filtrate under reduced pressure to dryness, and recrystallizing with n-heptane.
The acid of step S4 is one of acetic acid, formic acid, citric acid, oxalic acid, and propionic acid, preferably acetic acid.
The invention has the technical characteristics and beneficial effects that:
1. the invention uses 5-bromo-2-nitropyridine and piperazine, uses organic solvent such as n-butyl alcohol and water as mixed solvent, uses hydrobromic acid and the like as catalyst to prepare acid salt of 1- (6-nitropyridin-3-yl) piperazine, realizes the recycling of the solvent through azeotropic distillation, removes the generated micro-piperazine double substitution through filtration, and obtains high-purity 1- (6-nitropyridin-3-yl) piperazine (formula (2)) through alkali adjustment. The reaction condition of the step is mild, the post-treatment is simple, the product does not need to be dried, the quality is good, the yield is high, and the material feeding is directly carried out according to 100 percent. The organic solvent can be repeatedly used, and the wastewater is inorganic salt, is easy to treat and is more suitable for industrial production.
2. According to the invention, a 1- (6-nitropyridin-3-yl) piperazine wet product is directly adopted to react with Boc anhydride in a two-phase system, inorganic substances are removed through liquid separation and washing, reduced pressure distillation and recrystallization are carried out to obtain high-purity 4- (6-nitropyridin-3-yl) piperazine-1-tert-butyl carboxylate (formula (3)), and the evaporated organic solvent can be directly recycled and reused.
3. The invention prepares the 4- (6-aminopyridin-3-yl) piperazine-1-carboxylic acid tert-butyl ester (formula (1)) by adding an acid-binding agent such as sodium acetate and adopting cheaper platinum carbon and the like as a catalyst to carry out hydrogenation reduction on nitro. The addition of the acid-binding agent prevents degradation of Boc group, prevents generation of potential genotoxic impurities, improves safety of the product, and further improves safety of the palbociclib.
4. The invention creatively removes high molecular groups influencing the color by the characteristic that the 4- (6-aminopyridine-3-yl) piperazine-1-carboxylic acid tert-butyl ester is dissolved in weak acid and adopting an activated carbon decoloring mode, and obtains the high-purity and light-color 4- (6-amino-3-pyridyl) piperazine-1-carboxylic acid tert-butyl ester by adjusting alkali.
In sum, the invention provides a preparation method which is suitable for industrial production and has high quality, low cost, environmental friendliness, high yield (more than or equal to 85 percent) and high purity (the purity can reach 99.9 percent) for synthesizing the 4- (6-aminopyridin-3-yl) piperazine-1-tert-butyl carboxylate.
Detailed Description
The present invention will be further described with reference to specific examples so that those skilled in the art may better understand the present invention, but the present invention is not limited thereto.
Example 1: laboratory preparation of 1- (6-nitropyridin-3-yl) piperazine (compound of formula (2))
In a 2000ml reaction flask, 101.5g (0.5mol) of 5-bromo-2-nitropyridine, 51.6g (0.6mol) of anhydrous piperazine, 1000ml of n-butanol, 100ml of water and 100g of hydrobromic acid (48%) are added, and the reaction is stirred for 24 hours at 60-65 ℃. After the reaction, 300ml of water is added, reduced pressure distillation is carried out, 1200ml of water is supplemented in a stage supplementing mode, and distillation is carried out until distillate becomes clear. Insoluble solids were removed by filtration and the mother liquor was adjusted to pH12 with 30% sodium hydroxide to precipitate a bright yellow solid. Filtering, collecting solid to obtain 1- (6-nitro-3-pyridyl) piperazine wet product, calculating the yield by 100%, directly putting the wet product into the next step for reaction, and the HPLC purity is more than or equal to 99.5%.
Example 2: laboratory preparation of 4- (6-nitropyridin-3-yl) piperazine-1-carboxylic acid tert-butyl ester (compound of formula (3))
And adding 1000ml of toluene, 500ml of water and 79.5g (0.75mol) of sodium carbonate into a 2000ml reaction bottle, slowly adding 131g (0.6mol) of Boc anhydride into the reaction bottle under the condition of controlling the reaction temperature to be 10-30 ℃, continuing to react for 1h after the addition is finished, and detecting by TLC until the raw materials disappear. After the reaction is finished, heating to 95 ℃, standing and separating liquid after the solid is dissolved, separating a water layer, adding 500ml of water into an organic layer, keeping the temperature at 90-95 ℃, washing once, evaporating to remove about 500ml of toluene under reduced pressure, cooling to 0-10 ℃, stirring, crystallizing, filtering, and drying to obtain 142g of bright yellow solid, wherein the yield of the two steps is 92.2%, and the purity is 99.8% (HPLC).
Example 3: industrial preparation of 1- (6-nitropyridin-3-yl) piperazine (compound of formula (2))
1000L of n-butanol, 100kg of water, 100kg of hydrobromic acid (48%), 101.5kg of 5-bromo-2-nitropyridine and 51.6kg of anhydrous piperazine are sequentially added into a 2000L glass lining reaction kettle, and stirred and reacted for 24 hours at the temperature of 60-65 ℃. After the reaction, 300kg of purified water was added, the distillation was carried out under reduced pressure, 1200kg of purified water was further added, and the distillation was stopped after the distillate was observed to be no longer turbid. Filter-pressing by using a bag filter, washing by 50kg of water, adjusting the pH value of filtrate to 12 by using 30% sodium hydroxide, cooling to 0-10 ℃, centrifuging to obtain 135kg of bright yellow solid (wet weight), wherein the HPLC purity is 99.7%, and the bright yellow solid is directly put into the next step for reaction according to 100%.
Example 4: industrial production of 4- (6-nitropyridin-3-yl) piperazine-1-carboxylic acid tert-butyl ester (compound of formula (3))
1000L of dichloromethane, 500kg of water, 80kg of sodium carbonate and 135kg of the wet 1- (6-nitropyridine-3-yl) piperazine product prepared in the previous step are sequentially added into a 2000L stainless steel reaction kettle, the temperature is reduced to 10 ℃, 131kg of Boc anhydride is slowly added, the reaction is continued for 1 hour after the addition is finished, and the TLC controls the reaction end point. After the reaction, the mixture was allowed to stand for delamination, the organic layer was washed once with 500kg of water, methylene chloride was recovered by atmospheric distillation, and the residual solvent was distilled under reduced pressure. Adding 500L of toluene, heating until the solid is dissolved, cooling to 0-10 ℃, stirring, crystallizing, centrifuging, and drying to obtain 145kg of bright yellow solid, wherein the yield of the two steps is 94.2%, and the purity is 99.9% (HPLC).
Example 5: industrial production of 4- (6-aminopyridin-3-yl) piperazine-1-carboxylic acid tert-butyl ester (compound of formula (1))
Into a 2000L autoclave, 1000L of anhydrous methanol, 145kg of tert-butyl 4- (6-nitropyridin-3-yl) piperazine-1-carboxylate and 0.77kg of sodium acetate were charged, and the mixture was purged with nitrogen 3 times, and 5kg of platinum carbon was dispersed in 100L of methanol and charged into the autoclave. The nitrogen is replaced three times, and hydrogen is introduced for reaction for 3 hours. Filter pressing, washing with 100L of methanol, collecting platinum carbon, recycling, concentrating the filtrate under reduced pressure to dryness, adding 1000L of n-heptane, cooling to room temperature, stirring for crystallization, centrifuging, washing with n-heptane, and drying to obtain 126kg of brown solid with yield of 96.3% and purity of 99.7%.
2000kg of water, 126kg of crude tert-butyl 4- (6-aminopyridin-3-yl) piperazine-1-carboxylate and 30kg of acetic acid were charged into a 3000L reactor, and stirred at room temperature until the solid was dissolved, 3kg of activated carbon (Egret's japonicus) was added, and stirring was continued for 1 hour, followed by filtration and washing with 100kg of water. Adjusting the pH value of the mother liquor to 10 by using 10% sodium hydroxide, cooling to 0-10 ℃ for crystallization for 2h, centrifuging, washing with water, and drying to obtain 122kg of off-white solid, wherein the refining yield is 96.8%, and the purity is 99.9% (HPLC).
Claims (9)
1. An industrial preparation method of 4- (6-aminopyridin-3-yl) piperazine-1-carboxylic acid tert-butyl ester is characterized by comprising the following steps:
s1: in a mixed solvent of an alcohol organic solvent and water, using acid as a catalyst, reacting 5-bromo-2-nitropyridine with piperazine to generate an acid salt of a compound shown in a formula (2), adding water after the reaction is finished, recovering the solvent through azeotropic distillation to obtain an aqueous solution containing the acid salt of the compound shown in the formula (2), removing insoluble impurities through filtration, adjusting the pH value to be above 10 with alkali, and centrifuging to obtain a high-purity wet product of the compound shown in the formula (2);
s2: reacting a wet product of the compound shown in the formula (2) with Boc anhydride in a mixed solvent of an organic solvent and water in the presence of an acid-binding agent, and carrying out aftertreatment on a reaction liquid to obtain a compound shown in the formula (3);
s3: carrying out catalytic hydrogenation on the compound of the formula (3) in a polar solvent in the presence of a catalyst and an acid-binding agent, and carrying out aftertreatment to generate a crude product of the 4- (6-aminopyridin-3-yl) piperazine-1-carboxylic acid tert-butyl ester;
s4: adding the crude product into water, adding acid to dissolve the solid, decoloring the solid by using activated carbon, adjusting the pH value to be alkaline by using an alkali solution, and performing crystallization, centrifugation, washing and drying to obtain a pure 4- (6-aminopyridin-3-yl) piperazine-1-carboxylic acid tert-butyl ester product;
the structural formulas of the compound of the formula (2) and the compound of the formula (3) are as follows:
2. the industrial process according to claim 1, wherein in step S1,
the acid is one or the mixture of two of hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, acetic acid, citric acid and the like;
the alcohol organic solvent is one of n-butyl alcohol, n-amyl alcohol, isoamyl alcohol, tertiary butyl alcohol, sec-butyl alcohol and 1-propanol; the volume ratio of the water to the water is 10: 0.3-5.
3. The industrial process according to claim 1, wherein in step S1,
the reaction temperature is 50-100 ℃;
the azeotropic recovery of the solvent is carried out in a mode of supplementing water in batches, a mixture of the solvent and water is obtained by azeotropic distillation, the organic solvent and water are separated by liquid separation, the organic solvent is directly used for the next batch of reaction, and the water is used for the azeotropic distillation of the materials in the next batch.
4. The industrial process according to claim 1, wherein in step S2,
the acid-binding agent is one of sodium carbonate, potassium carbonate, triethylamine, diisopropylethylamine, sodium acetate, sodium hydroxide and potassium hydroxide;
the organic solvent is one of dichloromethane, trichloromethane, toluene, tetrahydrofuran and dioxane.
5. The industrial process according to claim 1, wherein the post-treatment in step S2 is: heating until the solid is dissolved, standing for liquid separation, separating out an aqueous layer, washing an organic layer, concentrating under reduced pressure, and recrystallizing.
6. The industrial process according to claim 1, wherein in step S3,
the catalyst is one of palladium carbon, platinum carbon and Raney nickel;
the acid-binding agent is one of sodium acetate, potassium acetate, triethylamine, ammonia water, sodium carbonate and sodium bicarbonate.
7. The industrial process according to claim 1, wherein in step S3,
the polar solvent is one of methanol, ethanol, isopropanol and n-butanol;
the reaction temperature is 10-60 ℃.
8. The industrial process according to claim 1, wherein the post-treatment of step S3 is: filtering, concentrating the filtrate under reduced pressure to dryness, and recrystallizing with n-heptane.
9. The industrial production method according to any one of claims 1 to 8, wherein the acid of step S4 is one of acetic acid, formic acid, citric acid, oxalic acid, and propionic acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111047083.6A CN113636973B (en) | 2021-09-07 | 2021-09-07 | Industrial preparation method of 4- (6-aminopyridine-3-yl) piperazine-1-carboxylic acid tert-butyl ester |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111047083.6A CN113636973B (en) | 2021-09-07 | 2021-09-07 | Industrial preparation method of 4- (6-aminopyridine-3-yl) piperazine-1-carboxylic acid tert-butyl ester |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN113636973A true CN113636973A (en) | 2021-11-12 |
| CN113636973B CN113636973B (en) | 2023-04-07 |
Family
ID=78425280
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202111047083.6A Active CN113636973B (en) | 2021-09-07 | 2021-09-07 | Industrial preparation method of 4- (6-aminopyridine-3-yl) piperazine-1-carboxylic acid tert-butyl ester |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113636973B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112724078A (en) * | 2021-01-13 | 2021-04-30 | 山东邹平大展新材料有限公司 | Method for removing impurities of piparide intermediate |
| CN114805194A (en) * | 2022-06-29 | 2022-07-29 | 南京威凯尔生物医药科技有限公司 | Continuous hydrogenation method of 2-nitropyridine derivative and application thereof |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101671297A (en) * | 2008-09-11 | 2010-03-17 | 上海药明康德新药开发有限公司 | Method for synthesizing 4-(3-iodo-2-pyridinyl) piperazine compound |
| CN103168039A (en) * | 2010-03-11 | 2013-06-19 | 吉利德康涅狄格公司 | Imidazopyridines syk inhibitors |
| CN103201275A (en) * | 2010-11-10 | 2013-07-10 | 诺华有限公司 | Salt(s) of 7-cyclopentyl-2 -(5-piperazin-1-yl-pyridin-2-ylamino)-7h-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide and processes of making thereof |
| WO2017045648A1 (en) * | 2015-09-18 | 2017-03-23 | 正大天晴药业集团股份有限公司 | Preparation method for deuterated compound |
| WO2017211245A1 (en) * | 2016-06-06 | 2017-12-14 | 深圳市塔吉瑞生物医药有限公司 | Substituted pyrrolopyrimidine compound and application thereof |
| CN109369517A (en) * | 2018-10-24 | 2019-02-22 | 郑传花 | A kind of preparation method for treating breast cancer medicines intermediate |
| CN110036012A (en) * | 2016-11-28 | 2019-07-19 | 帝人制药株式会社 | Pyrido [3,4-d] pyrimidine derivatives and its pharmaceutically acceptable salt |
-
2021
- 2021-09-07 CN CN202111047083.6A patent/CN113636973B/en active Active
Patent Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101671297A (en) * | 2008-09-11 | 2010-03-17 | 上海药明康德新药开发有限公司 | Method for synthesizing 4-(3-iodo-2-pyridinyl) piperazine compound |
| CN103168039A (en) * | 2010-03-11 | 2013-06-19 | 吉利德康涅狄格公司 | Imidazopyridines syk inhibitors |
| CN103201275A (en) * | 2010-11-10 | 2013-07-10 | 诺华有限公司 | Salt(s) of 7-cyclopentyl-2 -(5-piperazin-1-yl-pyridin-2-ylamino)-7h-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide and processes of making thereof |
| CN105384741A (en) * | 2010-11-10 | 2016-03-09 | 诺华有限公司 | Salt(s) of cell cycle regulatory protein dependent kinase inhibitor and processes of making thereof |
| WO2017045648A1 (en) * | 2015-09-18 | 2017-03-23 | 正大天晴药业集团股份有限公司 | Preparation method for deuterated compound |
| WO2017211245A1 (en) * | 2016-06-06 | 2017-12-14 | 深圳市塔吉瑞生物医药有限公司 | Substituted pyrrolopyrimidine compound and application thereof |
| CN108290899A (en) * | 2016-06-06 | 2018-07-17 | 深圳市塔吉瑞生物医药有限公司 | A kind of substituted Pyrrolopyrimidine compounds and its application |
| CN110036012A (en) * | 2016-11-28 | 2019-07-19 | 帝人制药株式会社 | Pyrido [3,4-d] pyrimidine derivatives and its pharmaceutically acceptable salt |
| CN109369517A (en) * | 2018-10-24 | 2019-02-22 | 郑传花 | A kind of preparation method for treating breast cancer medicines intermediate |
Non-Patent Citations (1)
| Title |
|---|
| SOLOMON TADESSE等: "Highly Potent,Selective,and Orally Bioavailable 4-Thiazol-N-(pyridine-2-yl)pyrimidin-2-amine Cyclin-Dependent Kinases 4 and 6 Inhibitors as Anticancer Drug Candidates:Design,Synthesis,and Evaluation", 《J.MED.CHEM.》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112724078A (en) * | 2021-01-13 | 2021-04-30 | 山东邹平大展新材料有限公司 | Method for removing impurities of piparide intermediate |
| CN114805194A (en) * | 2022-06-29 | 2022-07-29 | 南京威凯尔生物医药科技有限公司 | Continuous hydrogenation method of 2-nitropyridine derivative and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN113636973B (en) | 2023-04-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN113636973B (en) | Industrial preparation method of 4- (6-aminopyridine-3-yl) piperazine-1-carboxylic acid tert-butyl ester | |
| CN107793418B (en) | Industrial production method of tofacitinib citrate | |
| CN105017260B (en) | Preparation method of sitagliptin intermediate triazolopyrazine derivative | |
| CN111470983B (en) | Preparation method of bromhexine hydrochloride | |
| CN112062726B (en) | Preparation method of 2-amino-4, 6-dichloro-5-formamido pyrimidine | |
| CN105440034A (en) | Preparation method of linagliptin and intermediate thereof | |
| CN105153169B (en) | A kind of synthetic method of epinastine hydrochloride | |
| CN106674084A (en) | Preparation method of 2-isopropoxy-5-methyl-4-(piperidine-4-yl) aniline dihydrochloride | |
| CN113278021B (en) | Preparation method of 1, 7-diazaspiro [3.5] nonane-7-tert-butyl formate and oxalate thereof | |
| CN115960059A (en) | Method for synthesizing furosemide impurity D with high yield and high purity | |
| CN112661753B (en) | Preparation method of palbociclib intermediate | |
| KR101485418B1 (en) | A synthetic method of high purity mirtazapine | |
| CN110483388B (en) | Preparation method of nicotinic acid derivative | |
| JP6947354B2 (en) | How to make linagliptin | |
| CN111233864B (en) | Method for industrially producing doxofylline | |
| CN111574463A (en) | Riagliptin intermediate compound IV | |
| CN112552299B (en) | Preparation method of linagliptin for treating type II diabetes | |
| CN112176011B (en) | Method for preparing valaciclovir hydrochloride through enzyme catalysis | |
| CN111606929B (en) | Preparation method of Degatinib | |
| CN111574540B (en) | Preparation method of Degatinib | |
| CN109970725B (en) | Preparation method of posaconazole | |
| CN109535025B (en) | Preparation method of Evonib intermediate 3, 3-difluorocyclobutylamine hydrochloride | |
| CN108623608B (en) | Preparation method of zabucfloxacin intermediate | |
| CN114560862A (en) | Synthesis method of pyrrolo [1,2-A ] quinoxaline-4 (5H) -ketone and derivative thereof | |
| CN114685510A (en) | Tofacitinib intermediate and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| CB02 | Change of applicant information |
Address after: 251400 No. 12, Taixing East Street, Jibei Economic Development Zone, Jiyang District, Jinan City, Shandong Province Applicant after: Shandong Baoyuan Pharmaceutical Co.,Ltd. Address before: Strong in Jiyang County of Ji'nan City, 251400 North Street, Shandong Province Economic Development Zone Applicant before: SHANDONG BOYUAN PHARMACEUTICAL Co.,Ltd. |
|
| CB02 | Change of applicant information | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |