CN114195784A - Pabociclib related substance, preparation method and application thereof - Google Patents
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Abstract
The invention provides a palbociclib related substance and a preparation method and application thereof, wherein the preparation process of the palbociclib related substance comprises the following steps: carrying out coupling reaction on the compound 1 and the compound 2, and separating and purifying to obtain an intermediate 3; carrying out suzuki coupling reaction on the intermediate 3 and the compound 4 to obtain a palbociclib related substance Pla-A; under the action of acid, the compound Pla-A Pabociclib-related substance Pla-B. The palbociclib related substances Pla-A and Pla-B synthesized by the method can be used as standard substances, and are expected to further improve the production quality standard of palbociclib by respectively carrying out quality control research on the preparation process and the raw material medicaments of the palbociclib key intermediate. The synthesis method provided by the invention has the advantages of low cost, short route and high yield and purity, and provides reliable substance guarantee for quality control research in the preparation process of the compounds Pla-A and Pla-B which are respectively used as a key intermediate and a raw material medicine of Pabociclib.
Description
Technical Field
The invention relates to the technical field of drug synthesis, in particular to a palbociclib related substance and a preparation method and application thereof.
Background
Palbociclib (Palbociclib), trade name: ibrance, developed by Aequorea, was approved by the FDA of America at month 2 of 2015, was the first globally approved inhibitor for the treatment of breast cancer with CDK4/6, which was experimentally, orally, targeted, CAS:571190-30-2, having the chemical name 4- [4- [4- [4- [ [ (3R,5R) -5- (2, 4-difluorophenyl) -5- (1,2, 4-triazol-1-ylmethyl) oxolan-3-yl ] methoxy ] phenyl ] piperazin-1-yl ] phenyl ] -2- [ (2S,3S) -2-hydroxypentan-3-yl ] -1,2, 4-triazol-3-one, and having the structural formula shown below:
patent documents WO2014128588, synthesis progress of a novel anti-breast cancer drug palbociclib, 2018,37(1), 242-251, and journal of new chinese drugs, 2019, 29 (4): 290-297 reported the synthesis of palbociclib, wherein one of the technical routes is as follows:
the substance A is used as a starting material, the substance A and the substance B are subjected to Heck coupling reaction to obtain a substance C with 75% yield, then the substance C is subjected to hydroxyethyl sulfonic acid catalyzed rearrangement and hydrolysis reaction with 86% yield, and the technical route development of the target product Palbociclb is obtained by two steps.
The current market price of compound A (cas:571188-82-4) is: 10g/842RMB, therefore, the cost advantage of the route is obvious, and the palbociclib can be simply synthesized by only two steps.
CN106970177B discloses a method for analyzing the palbociclib intermediate and its impurities, and this patent document discloses various impurity structures:
CN111239299A also discloses the following: currently, known impurities that are the main controls for the synthesis of palbociclib are: impurity SM1, impurity SM2, impurity a1, impurity Z7, impurity Z8, impurity Z12, impurity Z16, impurity Z21, impurity Z23, impurity Z25, impurity Z26, and impurity Z29.
Obviously, different palbociclib synthesis process routes need to control different impurities, and the quality of the medicine cannot be guaranteed only by the impurities.
Disclosure of Invention
Therefore, a palbociclib related substance, a preparation method and an application thereof are needed to be provided.
As shown in FIGS. 1 to 4, when the inventor team repeats the technical route of the above documents to synthesize palbociclib, the palbociclib crude product synthesized by the technical route always has an unavoidable related substance (Pal-B), and the related impurity Pal-B has similar properties to palbociclib, the solubility is very poor, and the subsequent process purification process is very difficult to avoid the generation of the impurity. Meanwhile, research on the reaction mechanism of the technical route shows that the Heck coupling reaction can generate a detectable palbociclib-related substance Pal-a besides a substance C obtained from a dominant product. The invention researches the directional synthesis method of the palbociclib-related substance for the first time and confirms the structure, and has important significance for further improving and perfecting the quality standard of palbociclib.
The invention adopts the following technical scheme:
the invention provides Palbociclib related substances Pal-B and Pal-A (cas:827022-35-5), which have the following structures:
the invention provides a preparation method of palbociclib related substance Pal-B, which comprises the following synthetic route:
according to the reaction route, dissolving the compound Pal-A in a mixture of an organic solvent and water, heating, adding acid, maintaining the temperature after the addition is finished, continuing the reaction until the compound Pal-A disappears, adjusting the pH value to 9-10 by using a sodium hydroxide aqueous solution (6M), filtering, washing, and drying at 40 ℃ in vacuum to obtain the compound Pal-B.
In this process step, the volume ratio of the organic solvent to water in the mixed solvent is preferably 1: (2-4). The organic solvent is one or more selected from methanol, acetone, and tetrahydrofuran, and can be mixed with water. The organic solvent is preferably acetone.
In some embodiments, 5-40 mL of mixed solvent, preferably 20mL of mixed solvent, is added to 1g of compound Pal-A.
In some of these embodiments, the reaction temperature is 30 to 60 ℃, preferably 45 to 55 ℃.
In some of these embodiments, the acid is selected from at least one of concentrated hydrochloric acid, trifluoromethanesulfonic acid, methanesulfonic acid, 2-hydroxyethylsulfonic acid, trifluoroacetic acid, preferably concentrated hydrochloric acid.
In some embodiments, the ratio of the compound Pal-A to the acid is 1 (10-20), preferably 1 (10-15).
The invention also provides a preparation method of the intermediate Pal-A, which comprises the following synthetic route:
according to the reaction route, dissolving the compound 4 and the compound 3 in a mixed solvent, replacing the mixed solvent with inert gas, sequentially adding alkali and a catalyst at room temperature, reacting within a certain temperature range after the addition is finished, detecting by TLC until the compound 4 disappears, cooling the temperature to room temperature, and concentrating to remove the solvent. And adding water into the reaction solution, extracting, drying by sodium sulfate, filtering, concentrating, and purifying by a column to obtain the compound Pal-A.
In the process steps, the mixed solvent is a mixture of an organic solvent and water, and the volume ratio of the organic solvent to the water is preferably 20 (1-6). The organic solvent is selected from one or more of dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, N-dimethylformamide, N-dimethylhexanamide, neopentyl alcohol, acetonitrile, dimethyl sulfoxide and toluene, and preferably dioxane.
In some of these examples, 1g of Compound 4 is added (10-20 mL of organic solvent, preferably 20mL of organic solvent). The reaction temperature is 50-120 ℃, preferably 90-100 ℃.
In some of these embodiments, the base is selected from one or more of potassium phosphate, potassium carbonate, sodium carbonate, cesium fluoride, diisopropylhexylamine, and potassium acetate, preferably potassium phosphate.
In some of the embodiments, the molar ratio of the compound 4, the base and the compound 3 is 1 (1.5-6) to (1.1-2.5). Preferably, the molar ratio of the compound 4 to the base to the compound 3 is 1 (2-3) to (1.5-2.5).
In some of these embodiments, the catalyst is selected from one or more of dichloro [1,1 '-bis (diphenylphosphino) ferrocene ] palladium and its solvent adduct, tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium chloride, methanesulfonic acid (2-dicyclohexylphosphino-2', 4',6' -tri-isopropyl-1, 1 '-biphenyl) (2' -amino-1, 1 '-biphenyl-2-yl) palladium (II) (Xphos-Pd-G3), preferably dichloro [1,1' -bis (diphenylphosphino) ferrocene ] palladium and its solvent adduct.
In one example, the route for the preparation of compound 3 is as follows:
according to the above reaction scheme, compound 1 and compound 2 are added to an organic solvent and replaced with an inert gas. Adding the catalyst in batches at 0-5 ℃, reacting at 0-100 ℃ after adding, detecting by TLC until the compound 1 disappears, adding water to quench the reaction, extracting, drying with sodium sulfate, filtering, concentrating, and purifying by a column to obtain a compound 3.
In this step, the organic solvent is selected from one or more of dioxane, N-dimethylformamide, N-dimethylhexanamide, dimethylsulfoxide, tetrahydrofuran, 2-methyltetrahydrofuran, neopentanol, vinyl N-butyl ether, toluene, etc., preferably toluene. 3 to 60mL of an organic solvent, preferably 20mL of the organic solvent is added to 1g of the compound 1.
In some of the embodiments, the molar ratio of the compound 1 to the compound 2 is 1 (1-20), and the preferred molar ratio is 1 (1-4).
In some of the embodiments, the reaction temperature is preferably 20 to 30 ℃.
In some of these embodiments, the catalyst for the reaction is selected from one or more of palladium acetate, tris (dibenzylideneacetone) dipalladium and its solvent adduct, bis (dibenzylideneacetone) dipalladium and its solvent adduct, palladium on carbon, dichloro [1,1' -bis (diphenylphosphino) ferrocene ] palladium and its solvent adduct, and preferably palladium acetate.
The invention also provides application of the palbociclib related substance Pal-B and the intermediate Pal-A in quality control of palbociclib medicaments.
The invention has the beneficial effects that:
compared with the prior art, the invention discovers and provides a palbociclib related substance Pal-B for the first time, and provides Pal-B and Pal-a as indexes for impurity control, thereby facilitating subsequent quality research.
Drawings
FIG. 1 is a liquid mass spectrum of Pabociclib (API) when the existing process route is repeated.
FIG. 2 is a mass spectrum of a related substance Pal-B liquid when the existing process route is repeated.
FIG. 3 is a liquid mass spectrum of Compound C when the prior art route is repeated.
FIG. 4 is a liquid mass spectrum of intermediate Pal-A when the existing process route is repeated.
FIG. 5 toxicological profiles of the compounds Pal-A and Pal-B.
Detailed Description
The present invention is further described in detail below with reference to specific examples so that those skilled in the art can more clearly understand the present invention.
The following examples are provided only for illustrating the present invention and are not intended to limit the scope of the present invention. All other embodiments obtained by a person skilled in the art based on the specific embodiments of the present invention without any inventive step are within the scope of the present invention.
In the examples of the present invention, all the raw material components are commercially available products well known to those skilled in the art, unless otherwise specified; in the examples of the present invention, unless otherwise specified, all technical means used are conventional means well known to those skilled in the art.
The progress of the reaction of the present invention can be monitored by conventional monitoring methods in the art (e.g., TLC, HPLC or NMR), and is generally at the end of the reaction when one of the reaction substrates is eliminated.
Example 1
This example provides compound 3, which is synthesized as follows:
the preparation method of the compound 3 of the embodiment comprises the following steps:
compound 1(5.00g, 39.0mmol) and compound 2(15.6g,156mmol) were dissolved in toluene (300mL), replaced with nitrogen for 3min, palladium acetate (43.8mg,0.195mmol) was added in 10 portions under nitrogen atmosphere at 0-5 ℃, and after the addition, the reaction was gradually returned to room temperature for 16 h.
TLC detection of compound 1 disappearance, to the reaction liquid adding water (50mL), liquid separation extraction, using anhydrous sodium sulfate drying organic layer, suction filtration, decompression evaporation to remove solvent, with petroleum ether (100%) column purification product of compound 3 pure product.
6.540g of colorless oil was obtained in 74.3% yield and 92.3% purity by this method.
The intermediate compound 3 prepared in this example was identified as follows:
1H NMR(400MHz,DMSO-d6)δ7.95(s,1H),6.93(d,J＝14.0Hz，1H),3.80-3.76(m,2H),1.65-1.50(m,2H),1.40-1.25(m,2H),1.17(s,12H),0.90-0.83(m,3H)。
example 2
This example provides a compound Pal-a, which is synthesized as follows:
the preparation method of the compound Pal-A of the embodiment comprises the following steps:
compound 4(1.00g, 1.68mmol) was dissolved in dioxane (20mL) and water (2mL), purged with nitrogen for 3 minutes, and potassium carbonate (462mg, 3.35mmol) and Pd (dppf) were added2(122mg, 0.17mmol), reaction at 80 ℃ for 16h until disappearance of Compound 4 by TLC.
The temperature was reduced to room temperature, water (10mL) was added to the reaction solution, followed by extraction with ethyl acetate (20mL × 3), washing with saturated sodium chloride (10mL × 2), drying over anhydrous sodium sulfate, filtration and concentration, and column purification (petroleum ether: ethyl acetate: 100%: 0% -50%: 50%) was performed to elute the compound Pal-a.
The yellow solid obtained by the method is 0.90g, the yield is 87.4 percent, and the purity is 99.3 percent.
The compound Pal-a prepared in this example was identified as follows:
ESI-MS(m/z):603.3；
1H NMR(400MHz,CDCl3)δ8.78(s,1H),8.60(d,J＝8Hz,1H),7.70-7.60(m,3H),5.94-5.88(m,1H),5.87(s,1H),4.00-3.90(m,2H),3.70-3.55(m,4H),3.40-3.10(m,4H),2.44(s,3H),2.40-1.65(m,11H),1.50(s,9H),1.49-1.38(m,2H),1.05-0.95(m,3H)。
example 3
This example provides a compound Pal-B, which is synthesized as follows:
the preparation method of the compound Pal-B of the embodiment comprises the following steps:
intermediate Pal-A (0.60g, 1.50mmol) prepared in example 2 was dissolved in acetone (5mL) and water (10mL), concentrated hydrochloric acid (1.25mL, 15mmol) was added dropwise at 50 deg.C, after addition, the reaction was carried out at 50 deg.C for 16h, and disappearance of compound Pal-A was detected by TLC.
And (3) spin-drying the reaction solution, adjusting the pH to 10-11 by using an aqueous solution (6M) of sodium hydroxide, performing suction filtration, washing (acetone: water is 2:2, heating the crude product by using acetone (5ml) and water (5ml) until reflux and pulping for 0.5h, cooling to room temperature, and filtering to obtain the compound Pal-B.
The compound Pal-B obtained by the method is 0.39g of light yellow solid, the yield is 87.1 percent, and the purity is 98.6 percent.
The compound Pal-B prepared in this example was identified as follows:
ESI-MS(m/z):447.3；
1H NMR(400MHz,CDCl3)δ14.30(s,1H),8.80(s,1H),8.75(d,J＝8Hz,1H),7.70-7.55(m,3H),5.91-5.88(m,1H),5.72(s,1H),3.55-3.31(m,4H),3.30-3.05(m,4H),2.53-1.57m,12H)。
example 4
This example provides compound 3, which is synthesized as follows:
the preparation method of the compound 3 of the embodiment comprises the following steps:
compound 1(5.00g, 39.0mmol) and compound 2(15.6g,156mmol) were dissolved in vinyl n-butyl ether (50mL) and replaced with nitrogen for 3 min. Under the condition of nitrogen atmosphere and 0-5 ℃, palladium acetate (43.8mg,0.195mmol) is added in 10 batches, and the mixture is gradually returned to room temperature for reaction for 16 hours after the addition. TLC detecting compound 1 disappearance, concentrating to remove solvent, purifying with pure petroleum ether column to obtain pure product of compound 3.
The colorless oil obtained by the method is 4.90g, the yield is 55.6%, and the purity is 89.3%.
Example 5
This example provides a compound Pal-a, which is synthesized as follows:
the preparation method of the compound Pal-A of the embodiment comprises the following steps:
compound 4(1.00G, 1.68mmol) was dissolved in dioxane (20mL) and water (2mL), purged with nitrogen for 3 minutes, potassium phosphate (710mg, 3.35mmol) and Xphos-Pd-G3(144mg,0.17mmol) were added, and reacted at 80 ℃ for 5h until disappearance of compound 4 was detected by TLC. Cooling to room temperature, concentrating to remove solvent, adding water (10mL), extracting with ethyl acetate (20mL × 3), washing with saturated sodium chloride (10mL × 2), drying with anhydrous sodium sulfate, filtering, concentrating, and eluting with column purification (petroleum ether: ethyl acetate: 100%: 0% -50%: 50%) to obtain the compound Pal-A.
The yellow solid obtained by the method is 0.95g, the yield is 92.1 percent, and the purity is as follows: 99.7 percent.
Example 6
This example provides a compound Pal-B, which is synthesized as follows:
the preparation method of the compound Pal-B of the embodiment comprises the following steps:
intermediate Pal-A (0.30g, 0.50mmol) prepared in example 5 was dissolved in acetone (5mL) and water (10mL), a mixed solution of methanesulfonic acid (0.24g, 2.5mmol) in acetone (1mL) and water (1mL) was added dropwise at 50 deg.C, after 10 minutes addition, the reaction was carried out at 50 deg.C for 16h, and the disappearance of compound Pal-A was detected by TLC. And (3) spin-drying the reaction solution, adjusting the pH to 10-11 by using an aqueous solution (6M) of sodium hydroxide, performing suction filtration, washing (acetone: water is 2:2, heating the crude product by using acetone (5ml) and water (5ml) until the crude product is refluxed and pulped for 0.5h, cooling to room temperature, and filtering to obtain the compound Pal-B.
The compound Pal-B obtained by the method is 0.14g of light yellow solid, the yield is 62.2%, and the purity is 96.3%.
EXAMPLE 7 toxicity test of Compounds Pal-A and Pal-B
Cytotoxicity studies using human embryonic kidney cells 293 cells (HEK293) are shown in fig. 5. Shows that: the compound Pal-A has certain cytotoxicity on HEK293 and IC thereof50The concentration was 31.1. mu.M. Meanwhile, the compound Pal-B also has a certain cytotoxic effect on HEK293, and the IC thereof506.2. mu.M.
The research results show that: the existence of the compounds Pal-A and Pal-B has potential toxic and side effects on human bodies, and the impurities need to be removed.
It should be noted that the above examples are only for further illustration and description of the technical solution of the present invention, and are not intended to further limit the technical solution of the present invention, and the method of the present invention is only a preferred embodiment, and is not intended to limit the protection scope of the present invention. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A palbociclib-related substance is a compound Pal-B having the structure as follows:
2. use of the palbociclib-related substance according to claim 1 for the quality control of palbociclib pharmaceuticals.
3. The use of claim 2, further comprising using compound Pal-a as an impurity control for palbociclib drug quality control, said compound Pal-a having the structure shown in the following formula:
4. a preparation method of palbociclib-related substances is characterized by comprising the following steps:
dissolving a compound Pal-A in a first solvent, heating to the temperature of 30-60 ℃, adding acid for reaction, detecting by TLC until the compound Pal-A disappears, adjusting the pH value to 9-10, filtering, washing, and drying in vacuum to obtain a compound Pal-B:
the structure of the compound Pal-A, Pal-B is shown as the following formula:
5. the method for preparing palbociclib-related substance as claimed in claim 4, wherein the first solvent is a mixed solvent of an organic solvent and water, and the organic solvent is one or more selected from methanol, acetone and tetrahydrofuran; and/or
The acid is selected from at least one of concentrated hydrochloric acid, trifluoromethanesulfonic acid, methanesulfonic acid, 2-hydroxyethyl sulfonic acid and trifluoroacetic acid; and/or
The dosage ratio of the compound Pal-A to the acid is 1 (10-20).
6. The method for preparing palbociclib-related substance as claimed in claim 4 or 5, wherein the reaction route of the compound Pal-a is:
dissolving the compound 4 and the compound 3 in a second solvent according to the reaction route, replacing the solvent with inert gas, sequentially adding alkali and a first catalyst at room temperature, reacting after the addition is finished, detecting by TLC until the compound 4 disappears, cooling the temperature to room temperature, and concentrating to remove the solvent; and adding water into the reaction solution, extracting by using an extracting agent, drying by using sodium sulfate, filtering, concentrating, and purifying by using a column to obtain the compound Pal-A.
7. The method of claim 6, wherein the molar ratio of the compound 4, the base and the compound 3 is 1 (1.5-6) to 1.1-2.5.
8. The method for preparing palbociclib-related substance as claimed in claim 7, wherein the base is selected from one or more of potassium phosphate, potassium carbonate, sodium carbonate, cesium fluoride, diisopropylhexylamine, and potassium acetate; and/or
The first catalyst is selected from one or more of dichloro [1,1' -bis (diphenylphosphino) ferrocene ] palladium and solvent adduct thereof, tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium chloride, methanesulfonic acid (2-dicyclohexylphosphino-2 ',4',6' -tri-isopropyl-1, 1' -biphenyl) (2' -amino-1, 1' -biphenyl-2-yl) palladium (II) (Xphos-Pd-G3).
9. The method for preparing palbociclib-related substance as claimed in claim 6, wherein the reaction route of the compound 3 is:
adding the compound 1 and the compound 2 into a third solvent according to the reaction route, and replacing the mixture by inert gas; adding a second catalyst in batches at 0-5 ℃, reacting at 0-100 ℃ after the addition is finished, detecting by TLC until the compound 1 disappears, and adding water to quench the reaction; the organic layer was extracted, dried over sodium sulfate, filtered, concentrated, and column purified to give compound 3.
10. The method for preparing palbociclib-related substance according to claim 9, wherein the third solvent is one or more selected from dioxane, N-dimethylformamide, N-dimethylformamide, dimethylsulfoxide, tetrahydrofuran, 2-methyltetrahydrofuran, neopentanol, vinyl N-butyl ether, toluene, etc.; and/or
The second catalyst is selected from one or more of palladium acetate, tris (dibenzylideneacetone) dipalladium and a solvent adduct thereof, bis (dibenzylideneacetone) already palladium and a solvent adduct thereof, palladium/carbon, dichloro [1,1' -bis (diphenylphosphino) ferrocene ] palladium and a solvent adduct thereof, and the like; and/or
The molar ratio of the compound 1 to the compound 2 is 1 (1-20).
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005005426A1 (en) * | 2003-07-11 | 2005-01-20 | Warner-Lambert Company Llc | Isethionate salt of a selective cdk4 inhibitor |
| WO2014128588A1 (en) * | 2013-02-21 | 2014-08-28 | Pfizer Inc. | Solid forms of a selective cdk4/6 inhibitor |
| CN106970177A (en) * | 2017-06-06 | 2017-07-21 | 北京元延医药科技股份有限公司 | The analyzing detecting method of Pa Boxini intermediates and its impurity |
| CN111297867A (en) * | 2020-03-31 | 2020-06-19 | 黄泳华 | Use of composition containing pyridylaminopyridopyrimidine derivative for preparing medicine for treating breast cancer |
-
2021
- 2021-12-29 CN CN202111642452.6A patent/CN114195784A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005005426A1 (en) * | 2003-07-11 | 2005-01-20 | Warner-Lambert Company Llc | Isethionate salt of a selective cdk4 inhibitor |
| WO2014128588A1 (en) * | 2013-02-21 | 2014-08-28 | Pfizer Inc. | Solid forms of a selective cdk4/6 inhibitor |
| CN106970177A (en) * | 2017-06-06 | 2017-07-21 | 北京元延医药科技股份有限公司 | The analyzing detecting method of Pa Boxini intermediates and its impurity |
| CN111297867A (en) * | 2020-03-31 | 2020-06-19 | 黄泳华 | Use of composition containing pyridylaminopyridopyrimidine derivative for preparing medicine for treating breast cancer |
Non-Patent Citations (4)
| Title |
|---|
| QIU LI, ET AL.: "Synthesis and antiproliferative evaluation of novel 8-cyclopentyl-7,8-dihydropteridin-6(5H)-one derivatives as potential anticancer agents", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
| 于治国主编: "《药物分析第3版》", 31 August 2017, 中国医药科技出版社 * |
| 赵斌: "小议在MTT法测细胞增殖抑制率中IC50的计算方法", 《安徽医药》 * |
| 马自超、陈文田、李海霞著: "《姜黄素 功能制备及应用研究》", 31 January 2020 * |
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