CN112724078A - Method for removing impurities of piparide intermediate - Google Patents

Method for removing impurities of piparide intermediate Download PDF

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CN112724078A
CN112724078A CN202110044759.XA CN202110044759A CN112724078A CN 112724078 A CN112724078 A CN 112724078A CN 202110044759 A CN202110044759 A CN 202110044759A CN 112724078 A CN112724078 A CN 112724078A
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piperazine
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removing impurities
aminopyridin
butyl
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CN112724078B (en
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任传栋
杨波
林泉生
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Shandong Zouping Dazhan New Material Co ltd
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    • 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
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates

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Abstract

The invention relates to a method for removing impurities of a piparib-cypress-cilaride intermediate, belonging to the technical field of medical chemistry. The invention uses methanol and water as refined solvent, adds active carbon, and after stirring and heat preservation, the methanol is evaporated, and the 4- (6-aminopyridine-3-yl) piperazine-1-carboxylic acid tert-butyl ester is obtained after filtration and drying. The refining method can effectively remove azo impurities in the crude product of the 4- (6-aminopyridine-3-yl) piperazine-1-carboxylic acid tert-butyl ester, and obtain a solid with a white-like or bright yellow appearance, wherein the purity of the product reaches more than 99.9 percent.

Description

Method for removing impurities of piparide intermediate
Technical Field
The invention belongs to the technical field of medical chemistry, and particularly relates to a method for removing impurities of a piparib-cypress-cilley intermediate.
Background
Piparib (Palbociclib) is a drug for treating breast cancer marketed in 2015 and by the company picrorhiza americana. 4- (6-aminopyridin-3-yl) piperazine-1-carboxylic acid tert-butyl ester is a key intermediate for the chemical synthesis of piperaziril. Synthesis of 4- (6-aminopyridin-3-yl) piperazine-1-carboxylic acid tert-butyl ester is carried out by butt-jointing N-Boc-piperazine- (N-tert-butoxycarbonyl-piperazine) and 5-bromo-2-nitropyridine to synthesize 1-Boc-4- (6-nitro-3-pyridyl) piperazine, and then reducing with hydrogen. In the process of reducing 1-Boc-4- (6-nitro-3-pyridyl) piperazine by hydrogen, azo impurities A and impurities B are generated, and the specific structure is as follows:
Figure BDA0002896739330000011
the reaction liquid and the product have darker colors due to the existence of the impurity A and the impurity B, and further research finds that the impurity A and the impurity B are easy to separate out together with the product in the crystallization process and are not easy to remove. This affects the appearance and purity of the product.
Disclosure of Invention
Aiming at the problem that the impurity A and the impurity B are not easy to remove in the prior art, the invention provides a method for removing impurities of a piparib-cypress-cilley intermediate, so as to solve the problem. In the course of the research, the inventors found that when purifying tert-butyl 4- (6-aminopyridin-3-yl) piperazine-1-carboxylate by using a single solvent, impurities a and B were easily eluted together with the product, and were not easily removed even by adsorption on activated carbon. Further research shows that the impurities are easy to be removed by activated carbon adsorption in a mixed system of alcohol and water, so that the appearance and the purity of the product can be greatly improved.
The technical scheme of the invention is as follows:
the method for removing impurities in the piparix besiili intermediate is realized by the following steps: taking a crude product of the 4- (6-aminopyridine-3-yl) piperazine-1-carboxylic acid tert-butyl ester, adding methanol, and stirring to dissolve; then slowly adding water; adding activated carbon after the addition is finished, heating to 35-50 ℃, stirring for 2-3 h, and filtering; and (3) carrying out reduced pressure distillation to remove the methanol, cooling, stirring, filtering and drying to obtain the 4- (6-aminopyridine-3-yl) piperazine-1-carboxylic acid tert-butyl ester.
Preferably, the using amount of the methanol is 2-4 ml/g based on the charging amount of the crude tert-butyl 4- (6-aminopyridin-3-yl) piperazine-1-carboxylate.
Preferably, the amount of the water is 1-1.5 ml/g based on the charging amount of the crude tert-butyl 4- (6-aminopyridin-3-yl) piperazine-1-carboxylate.
Preferably, the using amount of the activated carbon is 0.05-0.15 g/g based on the charging amount of the crude product of the 4- (6-aminopyridin-3-yl) piperazine-1-carboxylic acid tert-butyl ester.
Preferably, the crude tert-butyl 4- (6-aminopyridin-3-yl) piperazine-1-carboxylate is prepared by:
Figure BDA0002896739330000021
the specific method comprises the following steps:
taking 1-Boc-4- (6-nitro-3-pyridyl) piperazine, adding dichloromethane, stirring to dissolve and clear, and adding platinum carbon; then, the mixture was transferred to an autoclave, and after three nitrogen replacements, three hydrogen replacements were performed to start hydrogenation reduction. Filtering after the reaction is finished, concentrating the filtrate, adding n-heptane into the concentrated solution for crystallization, filtering and drying to obtain a crude product of the 4- (6-aminopyridin-3-yl) piperazine-1-carboxylic acid tert-butyl ester.
Preferably, the amount of the dichloromethane is 4-5 g/g based on the charging amount of the 1-Boc-4- (6-nitro-3-pyridyl) piperazine.
Preferably, the effective content of the platinum carbon is 5-10%, and the dosage of the platinum carbon is 1.0-1.5% of the dosage of 1-Boc-4- (6-nitro-3-pyridyl) piperazine.
Preferably, the pressure of the hydrogenation reduction reaction is 0.2-0.6 MPa; the reaction temperature is 25-35 ℃.
Preferably, the n-heptane is used in an amount of 2-2.5 g/g based on the charging amount of 1-Boc-4- (6-nitro-3-pyridyl) piperazine.
The invention has the beneficial effects that:
the refining method can effectively remove azo impurities in the crude product of the 4- (6-aminopyridin-3-yl) piperazine-1-carboxylic acid tert-butyl ester. The appearance of 4- (6-aminopyridin-3-yl) piperazine-1-carboxylic acid tert-butyl ester of the impurity A and the impurity B which are not removed is brownish red or purple, and the content of the impurity A and the impurity B is about 3 percent in total. After the refining of the invention, the solid with the appearance of white-like or bright yellow can be obtained, and the purity of the product reaches more than 99.9 percent.
Drawings
In order to more clearly illustrate the embodiments or technical solutions in the prior art of the present invention, the drawings used in the description of the embodiments or prior art will be briefly described below, and it is obvious for those skilled in the art that other drawings can be obtained based on these drawings without creative efforts.
FIG. 1 is an HPLC chromatogram of crude tert-butyl 4- (6-aminopyridin-3-yl) piperazine-1-carboxylate prepared in example 1;
FIG. 2 is an HPLC chromatogram of tert-butyl 4- (6-aminopyridin-3-yl) piperazine-1-carboxylate after purification according to example 2;
FIG. 3 is an HPLC chromatogram of tert-butyl 4- (6-aminopyridin-3-yl) piperazine-1-carboxylate after purification in example 3;
FIG. 4 is an HPLC chromatogram of tert-butyl 4- (6-aminopyridin-3-yl) piperazine-1-carboxylate after purification of comparative example 1;
FIG. 5 is an HPLC chromatogram of purified tert-butyl 4- (6-aminopyridin-3-yl) piperazine-1-carboxylate according to comparative example 2.
Detailed Description
In order to make those skilled in the art better understand the technical solution of the present invention, the technical solution in the embodiment of the present invention will be clearly and completely described below with reference to the drawings in the embodiment of the present invention, and it is obvious that the described embodiment is only a part of the embodiment of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
Preparation of crude tert-butyl 4- (6-aminopyridin-3-yl) piperazine-1-carboxylate
920kg of dichloromethane was added to a 2000L autoclave, and 230kg of 1-Boc-4- (6-nitro-3-pyridyl) piperazine was added with stirring; stirring and dissolving, and adding 2.875kg of platinum carbon; after stirring uniformly, replacing the mixture with nitrogen for three times, then replacing the mixture with hydrogen for three times, controlling the pressure of the high-pressure kettle to be 0.2-0.6 MPa, and controlling the temperature to be 25-35 ℃ for reaction; the reaction was checked by TLC. And (3) after the reaction is finished, performing pressure filtration, performing reduced pressure distillation on the filtrate, cooling to 20 ℃ after 750kg of dichloromethane is evaporated, slowly adding 460kg of n-heptane, stirring and crystallizing for 0.5h after the addition is finished, centrifuging, and drying to obtain 200.8kg of crude 4- (6-aminopyridin-3-yl) piperazine-1-carboxylic acid tert-butyl ester, wherein the yield is 96.7%. The crude product prepared in example 1 was subjected to HPLC analysis with the following results in Table 1:
TABLE 1 crude detection results
Peak number Substance(s) Retention time Peak height Area of Percentage of area
1 Product(s) 15.118 29033296 220733612 96.9320％
2 17.030 7023 41669 0.0183％
3 18.680 4645 25438 0.0112％
4 24.179 12086 76864 0.0338％
5 Impurity A 24.873 884660 5461065 2.3981％
6 Impurity B 26.024 221854 1381332 0.6066％
Total of 30163564 227719980 100.0000％
The crude product was tested for molecular weight of impurities at RT-24.873 and RT-26.024 using LC-MS, where:
the impurities at RT-24.873 are: LC-MS (ESI) M/z 553.3([ M + H)]+) (ii) a The molecular weight of the product is consistent with that of the impurity A;
the impurities at RT-26.024 are: LC-MS (ESI) with M/z 591.3([ M + Na ]]+) (ii) a Consistent with the molecular weight of impurity B.
Example 2
Purification of crude tert-butyl 4- (6-aminopyridin-3-yl) piperazine-1-carboxylate
Taking 100g of the crude product prepared in the example 1, adding 300ml of methanol, and stirring to dissolve the mixture to be clear; then slowly adding 100ml of water, then adding 10g of active carbon, heating to 50 ℃, and stirring for 2 hours; after the reaction is finished, cooling the reaction liquid to 20 ℃, and performing suction filtration; distilling the methanol in the filtrate under reduced pressure, controlling the temperature to be 20 ℃, stirring for 10min, filtering, drying to obtain 88.6g of off-white product with the yield of 88.6 percent. The product prepared in example 2 was subjected to HPLC analysis with the following results in Table 2:
TABLE 2 results of product detection
Peak number Substance(s) Retention time Peak height Area of Percentage of area
1 Product of 15.172 14163681 92857586 99.9630
2 Impurity B 26.038 6304 34364 0.0370
Total of 14169985 92891950 100.0000
As can be seen from the results of the examination in Table 2, the purification method of the present invention can effectively remove the impurity A and the impurity B.
Example 3
Purification of crude tert-butyl 4- (6-aminopyridin-3-yl) piperazine-1-carboxylate
Adding 475kg of methanol into a 1000L reaction kettle, then adding 200kg of the crude product prepared in the example 1, and stirring to dissolve the solution; then slowly adding 200kg of water, then adding 20kg of active carbon, heating to 50 ℃, and stirring for 2 hours; after the reaction is finished, cooling the reaction solution to 20 ℃, and performing filter pressing; distilling off methanol in the filtrate under reduced pressure, controlling the temperature at 22 ℃, stirring for 20min, centrifuging, and drying to obtain 180.6kg of off-white product with the yield of 90.3%. The product prepared in example 3 was subjected to HPLC analysis with the following results in Table 3 below:
TABLE 3 results of product detection
Peak number Substance(s) Retention time Peak height Area of Percentage of area
1 Product of 14.686 18985972 145218106 99.9234
2 Impurity B 25.829 16610 111274 0.0766
Total of 19002582 145329380 100.0000
From the yield and the detection result of example 3, it can be seen that the purification process of the present invention is stable even when the process is scaled up to 200 kg/batch, and is effective in removing the impurities a and B.
Comparative example 1
Purification of crude tert-butyl 4- (6-aminopyridin-3-yl) piperazine-1-carboxylate
50g of the crude product prepared in example 1 is taken, 150ml of methanol is added, and the mixture is stirred to be dissolved; then adding 5g of active carbon, heating to 50 ℃, and stirring for 2 hours; after the reaction is finished, cooling the reaction liquid to 20 ℃, and performing suction filtration; the filtrate was evaporated to dryness under reduced pressure to give 48.8g of a light brown product with a yield of 97.6%. The HPLC assay of the product prepared in comparative example 1 gave the following results in Table 4:
TABLE 4 results of product detection
Figure BDA0002896739330000041
Figure BDA0002896739330000051
As can be seen from the detection results in table 4, in the case of using a single solvent (methanol), the impurities a and B were not effectively removed.
Comparative example 2
Purification of crude tert-butyl 4- (6-aminopyridin-3-yl) piperazine-1-carboxylate
50g of the crude product prepared in example 1 is taken, 150ml of methanol is added, and the mixture is stirred to be dissolved; then slowly adding 100ml of water, heating to 50 ℃, and stirring for 2 hours; after the reaction is finished, cooling the reaction liquid to 20 ℃, and performing suction filtration; and (3) carrying out reduced pressure evaporation to remove methanol in the filtrate, controlling the temperature at 20 ℃ after the reduced pressure evaporation is finished, stirring for 10min, carrying out suction filtration, and drying to obtain a light purple product 44.6g, wherein the yield is 89.2%. HPLC analysis of the product prepared in comparative example 2 gave the following results in Table 5:
TABLE 5 results of product detection
Peak number Substance(s) Retention time Peak height Area of Percentage of area
1 Product of 15.167 23616666 166541384 99.4534
2 Impurity A 24.242 24867 150694 0.0900
3 Impurity B 26.082 127462 764664 0.4566
Total of 23768995 167456742 100.0000
As can be seen from the results of the tests in table 5, impurities a and B could not be effectively removed without using activated carbon.
Although the present invention has been described in detail by referring to the drawings in connection with the preferred embodiments, the present invention is not limited thereto. Various equivalent modifications or substitutions can be made on the embodiments of the present invention by those skilled in the art without departing from the spirit and scope of the present invention, and these modifications or substitutions are within the scope of the present invention/any person skilled in the art can easily conceive of the changes or substitutions within the technical scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the claims.

Claims (9)

1. The method for removing impurities in the piparix besiili intermediate is characterized by comprising the following steps: taking a crude product of the 4- (6-aminopyridine-3-yl) piperazine-1-carboxylic acid tert-butyl ester, adding methanol, and stirring to dissolve; then slowly adding water; adding activated carbon after the addition is finished, heating to 35-50 ℃, and stirring for 2-3 hours; and (3) carrying out reduced pressure distillation to remove the methanol, cooling, stirring, filtering and drying to obtain the 4- (6-aminopyridine-3-yl) piperazine-1-carboxylic acid tert-butyl ester.
2. The method for removing impurities from an intermediate of pipariril as claimed in claim 1, wherein the amount of the methanol is 2-4 ml/g based on the amount of a crude tert-butyl 4- (6-aminopyridin-3-yl) piperazine-1-carboxylate.
3. The method for removing impurities from an intermediate of pipariril as claimed in claim 1, wherein the amount of the water is 1 to 1.5ml/g based on the amount of the crude tert-butyl 4- (6-aminopyridin-3-yl) piperazine-1-carboxylate.
4. The method for removing impurities from an intermediate of pipariril as claimed in claim 1, wherein the amount of the activated carbon is 0.05-0.15 g/g based on the amount of a crude tert-butyl 4- (6-aminopyridin-3-yl) piperazine-1-carboxylate.
5. The method of removing impurities from an intermediate of piparix according to claim 1, wherein the crude tert-butyl 4- (6-aminopyridin-3-yl) piperazine-1-carboxylate is prepared by:
Figure FDA0002896739320000011
the specific method comprises the following steps:
taking 1-Boc-4- (6-nitro-3-pyridyl) piperazine, adding dichloromethane, stirring to dissolve and clear, and adding platinum carbon; then transferring the mixture into a high-pressure kettle, replacing the mixture with nitrogen for three times, then replacing the mixture with hydrogen for three times, and starting hydrogenation reduction; filtering after the reaction is finished, concentrating the filtrate, adding n-heptane into the concentrated solution for crystallization, filtering and drying to obtain a crude product of the 4- (6-aminopyridin-3-yl) piperazine-1-carboxylic acid tert-butyl ester.
6. The method for removing impurities from an intermediate of piparix according to claim 5, wherein the amount of dichloromethane is 4 to 5g/g based on the amount of 1-Boc-4- (6-nitro-3-pyridyl) piperazine charged.
7. The method for removing impurities from an intermediate of piparix in claim 1, wherein the effective content of the platinum carbon is 5 to 10% and the amount of the platinum carbon is 1.0 to 1.5% based on the amount of 1-Boc-4- (6-nitro-3-pyridyl) piperazine charged.
8. The method for removing piparix intermediate impurities according to claim 5, wherein the pressure of the hydrogenation reduction reaction is 0.2 to 0.6 MPa; the reaction temperature is 25-35 ℃.
9. The method for removing impurities from an intermediate of pipariril as claimed in claim 5, wherein the amount of n-heptane used is 2 to 2.5g/g based on the amount of 1-Boc-4- (6-nitro-3-pyridyl) piperazine charged.
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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

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