CN114276412A - Preparation method of carfilzomib oxide impurities - Google Patents
Preparation method of carfilzomib oxide impurities Download PDFInfo
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- CN114276412A CN114276412A CN202111627135.7A CN202111627135A CN114276412A CN 114276412 A CN114276412 A CN 114276412A CN 202111627135 A CN202111627135 A CN 202111627135A CN 114276412 A CN114276412 A CN 114276412A
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- carfilzomib
- preparation
- oxide
- impurities
- oxide impurities
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- BLMPQMFVWMYDKT-NZTKNTHTSA-N carfilzomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)[C@]1(C)OC1)NC(=O)CN1CCOCC1)CC1=CC=CC=C1 BLMPQMFVWMYDKT-NZTKNTHTSA-N 0.000 title claims abstract description 27
- 229960002438 carfilzomib Drugs 0.000 title claims abstract description 26
- 108010021331 carfilzomib Proteins 0.000 title claims abstract description 26
- 239000012535 impurity Substances 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 8
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- 239000007810 chemical reaction solvent Substances 0.000 claims description 2
- 230000003647 oxidation Effects 0.000 claims 1
- 238000007254 oxidation reaction Methods 0.000 claims 1
- 238000011160 research Methods 0.000 abstract description 4
- 238000001228 spectrum Methods 0.000 abstract description 2
- 238000012795 verification Methods 0.000 abstract description 2
- 239000003814 drug Substances 0.000 description 5
- 206010035226 Plasma cell myeloma Diseases 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 208000034578 Multiple myelomas Diseases 0.000 description 3
- 229940079156 Proteasome inhibitor Drugs 0.000 description 3
- 229960001467 bortezomib Drugs 0.000 description 3
- GXJABQQUPOEUTA-RDJZCZTQSA-N bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 description 3
- 239000003207 proteasome inhibitor Substances 0.000 description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 208000010392 Bone Fractures Diseases 0.000 description 1
- 208000018240 Bone Marrow Failure disease Diseases 0.000 description 1
- 206010065553 Bone marrow failure Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 238000009104 chemotherapy regimen Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 201000005787 hematologic cancer Diseases 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 229940121354 immunomodulator Drugs 0.000 description 1
- 230000002584 immunomodulator Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 210000004180 plasmocyte Anatomy 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a preparation method of carfilzomib oxide impurities, which is characterized by comprising the following steps: the carfilzomib is oxidized by m-chloroperoxybenzoic acid to obtain the carfilzomib oxide impurity of the compound shown in the formula II. The oxide obtained by the method has high impurity purity, and can meet the requirements of structure identification, impurity spectrum research and methodology verification.
Description
Technical Field
The invention belongs to the technical field of medicines, and relates to a preparation method of carfilzomib oxide impurities.
Background
Carfilzomib, a proteasome inhibitor, is useful for treating multiple myeloma patients. Multiple Myeloma (MM) is a malignant tumor that originates from a B cell line and is characterized by clonal proliferation of malignant plasma cells in the bone marrow microenvironment, causing bone fractures and bone marrow failure, the second most common hematologic tumor worldwide and is not curable by traditional chemotherapy regimens. Bortezomib (brotezomib) is the first proteasome inhibitor and, due to its strong resistance and the ongoing studies on the mechanism of resistance, carfilzomib, followed by bortezomib, is approved by the FDA as a second proteasome inhibitor for the treatment of multiple myeloma patients who previously received at least 2 drugs, including bortezomib and immunomodulator therapy.
Carfilzomib is a specific, irreversible targeted inhibitor, originally developed by Proteolix corporation, produced by ornix (Onyx) pharmaceutical corporation, approved by FDA for marketing at 2012, 7/20. The carfilzomib structure is of formula i:
researchers find that the oxidized impurities of carfilzomib are key impurities of the raw material medicine carfilzomib and have important influence on the safety and the effectiveness of finally delivered medicines. Carfilzomib oxide impurity, a compound of formula ii, having the structure:
the method is important for researching the impurities of the carfilzomib oxides, is an important link in the process of drug development, and requires a certain amount of reference substances for establishing quality standards, so that the development of the preparation method of the carfilzomib open-loop impurities is an important task of drug research.
The invention aims to provide a preparation method for preparing carfilzomib oxide impurities, which is simple to operate and mild in conditions.
Disclosure of Invention
The invention provides a preparation method of carfilzomib oxide impurities, which can obtain oxide impurities with higher purity, and the purity can meet the requirements of structure identification, impurity spectrum research and methodology verification. The impurities of the oxides of carfilzomib have important significance for the quality research and the quality control of carfilzomib.
The preparation method of the carfilzomib oxide impurity provided by the invention has the advantages of mild reaction conditions, easiness in purification, simplicity in operation and higher yield, avoids a method obtained by liquid phase preparation, and greatly reduces the cost.
In order to achieve the purpose of the present invention, the present inventors finally obtained the following technical solutions through a large number of experimental studies:
the invention provides a preparation method of carfilzomib oxide impurities, which is characterized by comprising the following steps:
oxidizing carfilzomib with m-chloroperoxybenzoic acid to obtain a compound shown in a formula II, wherein the molar ratio of carfilzomib to m-chloroperoxybenzoic acid is 1:1-1:5, and a reaction solvent is dichloromethane.
Detailed Description
The following examples are presented to enable one of ordinary skill in the art to more fully understand the present invention and are not intended to limit the scope of the embodiments described herein.
Example 1
Preparation of Compounds of formula II
4.54g of potassium carbonate was dissolved in 40mL of water, and dissolved by stirring for use. Adding 1.0g of carfilzomib, 0.96g of m-chloroperoxybenzoic acid and 50mL of dichloromethane into a three-necked bottle, carrying out reflux reaction, cooling a reaction system to room temperature after the reaction is finished, washing a reaction solution by using a potassium carbonate solution, extracting by using n-butanol, combining organic phases, washing the organic phases once by using saturated saline solution, and carrying out reduced pressure concentration to obtain 0.99g of a compound shown as the formula II, wherein the purity is 97.78%, and the yield is 97%.
The foregoing shows and describes the general principles and features of the present invention, together with the advantages thereof. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are described in the specification and illustrated only to illustrate the principle of the present invention, but that various changes and modifications may be made therein without departing from the spirit and scope of the present invention, which fall within the scope of the invention as claimed. The scope of the invention is defined by the appended claims and equivalents thereof.
Claims (2)
1. A preparation method of carfilzomib oxide impurities is characterized by comprising the following steps:
(1) oxidation of carfilzomib with m-chloroperoxybenzoic acid affords compounds of formula ii:
2. the method of claim 1, wherein the method comprises the steps of: in the step (1), the molar ratio of carfilzomib to m-chloroperoxybenzoic acid is 1:2-1:5, and the reaction solvent is dichloromethane.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN202111627135.7A CN114276412A (en) | 2021-12-28 | 2021-12-28 | Preparation method of carfilzomib oxide impurities |
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| Application Number | Priority Date | Filing Date | Title |
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| CN202111627135.7A CN114276412A (en) | 2021-12-28 | 2021-12-28 | Preparation method of carfilzomib oxide impurities |
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| Publication Number | Publication Date |
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| CN114276412A true CN114276412A (en) | 2022-04-05 |
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| CN202111627135.7A Pending CN114276412A (en) | 2021-12-28 | 2021-12-28 | Preparation method of carfilzomib oxide impurities |
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105938123A (en) * | 2015-12-18 | 2016-09-14 | 重庆两江药物研发中心有限公司 | Detection method of impurity in carfilzomib intermediate |
| CN107548400A (en) * | 2014-12-02 | 2018-01-05 | 费森尤斯卡比肿瘤学有限公司 | The purification process of Carfilzomib |
| WO2020255059A1 (en) * | 2019-06-19 | 2020-12-24 | Laurus Labs Limited | Purification method of carfilzomib |
| CN114249796A (en) * | 2021-12-29 | 2022-03-29 | 南京格亚医药科技有限公司 | Carfilzomib key intermediate impurity and preparation method thereof |
| CN114262359A (en) * | 2021-11-26 | 2022-04-01 | 南京佰麦生物技术有限公司 | Preparation method of carfilzomib impurities |
| CN116023347A (en) * | 2022-10-09 | 2023-04-28 | 无锡紫杉药业股份有限公司 | Method for preparing carfilzomib side chain isomer |
-
2021
- 2021-12-28 CN CN202111627135.7A patent/CN114276412A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107548400A (en) * | 2014-12-02 | 2018-01-05 | 费森尤斯卡比肿瘤学有限公司 | The purification process of Carfilzomib |
| CN105938123A (en) * | 2015-12-18 | 2016-09-14 | 重庆两江药物研发中心有限公司 | Detection method of impurity in carfilzomib intermediate |
| WO2020255059A1 (en) * | 2019-06-19 | 2020-12-24 | Laurus Labs Limited | Purification method of carfilzomib |
| CN114262359A (en) * | 2021-11-26 | 2022-04-01 | 南京佰麦生物技术有限公司 | Preparation method of carfilzomib impurities |
| CN114249796A (en) * | 2021-12-29 | 2022-03-29 | 南京格亚医药科技有限公司 | Carfilzomib key intermediate impurity and preparation method thereof |
| CN116023347A (en) * | 2022-10-09 | 2023-04-28 | 无锡紫杉药业股份有限公司 | Method for preparing carfilzomib side chain isomer |
Non-Patent Citations (3)
| Title |
|---|
| SESTAK V, ET AL: "A UHPLC-UV-QTOF study on the stability of carfilzomib, a novel proteasome inhibitor.", 《J PHARM BIOMED ANAL》, vol. 124, pages 389 - 2 * |
| 刘娜等: "HPLC法测定注射用卡非佐米的含量", 《中国药师》, vol. 19, no. 10 * |
| 李海霞等: "卡非佐米中基因毒性杂质和吗啉乙酸的LC-MS/MS法测定", 《中国医药工业杂志》, vol. 47, no. 10 * |
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