CN114195741A - Preparation method of carfilzomib key intermediate isomer - Google Patents
Preparation method of carfilzomib key intermediate isomer Download PDFInfo
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- CN114195741A CN114195741A CN202111624606.9A CN202111624606A CN114195741A CN 114195741 A CN114195741 A CN 114195741A CN 202111624606 A CN202111624606 A CN 202111624606A CN 114195741 A CN114195741 A CN 114195741A
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- carfilzomib
- key intermediate
- isomer
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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 28
- 229960002438 carfilzomib Drugs 0.000 title claims abstract description 27
- 108010021331 carfilzomib Proteins 0.000 title claims abstract description 27
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims abstract description 24
- 150000001875 compounds Chemical class 0.000 claims abstract description 17
- 229940125904 compound 1 Drugs 0.000 claims abstract description 13
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims abstract description 12
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 12
- 229940125782 compound 2 Drugs 0.000 claims abstract description 11
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000005708 Sodium hypochlorite Substances 0.000 claims abstract description 6
- 230000009471 action Effects 0.000 claims abstract description 6
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims abstract description 6
- MDXGYYOJGPFFJL-MRVPVSSYSA-N (2r)-4-methyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]pentanoic acid Chemical compound CC(C)C[C@H](C(O)=O)NC(=O)OC(C)(C)C MDXGYYOJGPFFJL-MRVPVSSYSA-N 0.000 claims abstract description 5
- 239000007818 Grignard reagent Substances 0.000 claims abstract description 5
- 229940126214 compound 3 Drugs 0.000 claims abstract description 5
- 150000004795 grignard reagents Chemical class 0.000 claims abstract description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 14
- PHMRPWPDDRGGGF-UHFFFAOYSA-N 2-bromoprop-1-ene Chemical group CC(Br)=C PHMRPWPDDRGGGF-UHFFFAOYSA-N 0.000 claims description 8
- 239000003208 petroleum Substances 0.000 claims description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 239000007810 chemical reaction solvent Substances 0.000 claims description 6
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 5
- 239000011777 magnesium Substances 0.000 claims description 5
- 229910052749 magnesium Inorganic materials 0.000 claims description 5
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical group CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 3
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 3
- 229940011051 isopropyl acetate Drugs 0.000 claims description 3
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical group CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 3
- 239000012046 mixed solvent Substances 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 230000003647 oxidation Effects 0.000 claims 1
- 238000007254 oxidation reaction Methods 0.000 claims 1
- 238000011160 research Methods 0.000 abstract description 8
- 239000012535 impurity Substances 0.000 abstract description 6
- 238000003908 quality control method Methods 0.000 abstract description 3
- 230000001590 oxidative effect Effects 0.000 abstract description 2
- 238000001228 spectrum Methods 0.000 abstract description 2
- 238000012795 verification Methods 0.000 abstract description 2
- 239000000543 intermediate Substances 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- 239000003814 drug Substances 0.000 description 8
- 229940079593 drug Drugs 0.000 description 7
- 239000000243 solution Substances 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 206010035226 Plasma cell myeloma Diseases 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 208000034578 Multiple myelomas Diseases 0.000 description 3
- 229940079156 Proteasome inhibitor Drugs 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 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
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 239000007791 liquid phase Substances 0.000 description 3
- 239000003207 proteasome inhibitor Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 238000003756 stirring 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
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 239000007864 aqueous solution Substances 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
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000009104 chemotherapy regimen Methods 0.000 description 1
- 229940125898 compound 5 Drugs 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
- 239000013067 intermediate product Substances 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000002156 mixing Methods 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
- 239000012071 phase Substances 0.000 description 1
- 210000004180 plasmocyte Anatomy 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000004451 qualitative analysis Methods 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- DDMPMIMTLBGEHT-HZMBPMFUSA-N tert-butyl n-[(2s)-4-methyl-1-[(2s)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]carbamate Chemical class CC(C)(C)OC(=O)N[C@@H](CC(C)C)C(=O)[C@]1(C)CO1 DDMPMIMTLBGEHT-HZMBPMFUSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D301/00—Preparation of oxiranes
- C07D301/02—Synthesis of the oxirane ring
- C07D301/03—Synthesis of the oxirane ring by oxidation of unsaturated compounds, or of mixtures of unsaturated and saturated compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/36—Compounds containing oxirane rings with hydrocarbon radicals, substituted by nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a preparation method of a carfilzomib key intermediate isomer, which is characterized by comprising the following steps: (1) BOC-D-leucine (SM) is activated by pivaloyl chloride and condensed with morpholine under the action of N-methylmorpholine to obtain a compound 1; (2) reacting the compound 1 with a Grignard reagent under the action of isopropyl magnesium chloride to obtain a compound 2; (3) and oxidizing the compound 2 with sodium hypochlorite to obtain a compound 3 and a compound 4. The method can obtain isomers with high purity, and the purity can meet the requirements of structure identification, impurity spectrum research and methodology verification. Has important significance for the quality research and the quality control of the carfilzomib key intermediate compound 6 and the finished carfilzomib.
Description
Technical Field
The invention belongs to the technical field of medicines, and relates to a preparation method of a carfilzomib key intermediate isomer.
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. Carfilzomib has the structure compound 5:
the carfilzomib structure contains 5 chiral carbon molecules, so that the prepared isomer compound has important significance for the quality research and control of carfilzomib intermediate compounds and carfilzomib bulk drugs.
A key intermediate, compound 6, is required in the carfilzomib synthesis process and has the following structure:
in the synthesis process of the key intermediate compound 6, a chiral is introduced into a starting material and 1 chiral center is constructed, isomer impurities are mixed in an intermediate product, and in the synthesis process, 2 isomers, namely compounds 3 and 4, are found, and the structure is as follows:
if the content of the isomer compound 3 and the compound 4 in the intermediate compound 6 is relatively high, the isomer impurity is derived in the subsequent synthesis of the raw material drug carfilzomib, and the derived isomer impurity is difficult to remove in the raw material drug. The research on isomers of the raw material medicine carfilzomib is important, in the process of drug development, the quality control of an intermediate is an important link, and the establishment of a quality standard needs a certain amount of reference substances, so the development of a preparation method of the isomers is an important task of drug research.
The method has great significance for relevant research on the isomer of carfilzomib, and can be used for qualitative and quantitative analysis of impurities in production of carfilzomib intermediates, so that the quality standard of carfilzomib can be improved, and important guiding significance is provided for safe medication of people.
The invention aims to provide a preparation method of a key intermediate isomer of carfilzomib, which is simple to operate and mild in condition.
Disclosure of Invention
The invention provides a preparation method of a carfilzomib key intermediate isomer, which can obtain an isomer with higher purity, and the purity can meet the requirements of structure identification, impurity spectrum research and methodology verification. Has important significance for the quality research and the quality control of the carfilzomib key intermediate compound 6 and the finished carfilzomib.
The invention provides a preparation method of a carfilzomib key intermediate isomer, which has the advantages of mild reaction conditions in each step, 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 a carfilzomib key intermediate isomer, which is characterized by comprising the following steps:
(1) BOC-D-leucine (SM) is activated by pivaloyl chloride and condensed with morpholine under the action of N-methylmorpholine to obtain a compound 1;
(2) reacting the compound 1 with a Grignard reagent under the action of isopropyl magnesium chloride to obtain a compound 2;
(3) and oxidizing the compound 2 with sodium hypochlorite to obtain a compound 3 and a compound 4.
In the step (1), the molar ratio of the compound SM to the pivaloyl chloride is 1:1-1:1.2, the molar ratio of the compound SM to the N-methylmorpholine is 1:1-1:1.2, the molar ratio of the N-methylmorpholine to the morpholine is 1:1-1:2, and the reaction solvent is isopropyl acetate.
In the step (2), the molar ratio of the compound 1 to isopropyl magnesium chloride is 1:1-1:1.2, the grignard reagent is prepared from 2-bromopropylene and magnesium chips, the molar ratio of the compound 1 to 2-bromopropylene is 1:2, the molar ratio of the 2-bromopropylene to the magnesium chips is 1:1.15, and the reaction solvent is a mixed solvent of petroleum ether/tetrahydrofuran (v/v ═ 1/3).
In the step (3), the molar ratio of the compound 2 to sodium hypochlorite is 1:3, and the reaction solvent is N-methylpyrrolidone.
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 Compound 1
Adding 10g of SM and 60g of isopropyl acetate into a reaction bottle, replacing with nitrogen, cooling to-10-0 ℃, slowly adding 4.97g of pivaloyl chloride into the system, stirring at-10-0 ℃ for 10min, slowly adding 4.47g N-methylmorpholine, heating to 20-25 ℃, reacting, cooling to-10-0 ℃, slowly adding 3.85g of morpholine into the system, heating to 20-25 ℃ for reacting, dropwise adding 8mL of 1M sulfuric acid solution into the reaction bottle, separating, standing, adding a sodium hydroxide solution into an organic phase, separating, washing the organic phase with water and saturated salt water sequentially, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain 11g of a crude compound 1, wherein the yield is 84.7%.
Example 2
Preparation of Compound 2
Dissolving 21g of compound 1 in a mixed solvent of 42mL of petroleum ether and 126mL of tetrahydrofuran, carrying out nitrogen protection, cooling to below-10 ℃, adding 3.86g of magnesium chips, dropwise adding 41.2mL of isopropyl magnesium chloride, slowly heating after dropwise addition, dropwise adding a small amount of 2-bromopropene to initiate reaction, controlling the temperature to be 30-35 ℃, continuously dropwise adding 16.9g of 2-bromopropene, finishing the reaction, adding the reaction solution into a mixed solution of 30% citric acid aqueous solution (168mL) and petroleum ether (210mL), separating liquid, washing an organic phase twice with water, drying with anhydrous sodium sulfate, concentrating under reduced pressure, stirring a residue silica gel, purifying by column chromatography, and eluting with ethyl acetate/petroleum ether (1/100) to obtain 2.7g of compound 2, wherein the yield is 15.1%.
Example 3
Preparation of Compounds 3, 4
Adding 15.08g of compound 2 and 210mL of N-methylpyrrolidone into a reaction bottle, dropwise adding 140g of 10% sodium hypochlorite solution, controlling the temperature to be 0-10 ℃ for reaction after the dropwise adding is finished, adding 1L of 13% sodium thiosulfate solution to quench the reaction, extracting a water phase by 300mL of 2-heptane, combining organic phases, washing the organic phases once by 200mL of water, drying the anhydrous sodium sulfate, concentrating under reduced pressure, mixing the residue with silica gel, purifying by column chromatography, eluting by petroleum ether and ethyl acetate which are 50: 1-40: 1 to obtain 7g of compound 3, wherein the yield is 43.6%, and the liquid phase purity is 97.04%; petroleum ether and ethyl acetate 10:1 gave 1.27g of compound 4 in 7.9% yield and 99.23% liquid phase purity.
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 (4)
1. A preparation method of a carfilzomib key intermediate isomer is characterized by comprising the following steps:
(1) BOC-D-leucine (SM) is activated by pivaloyl chloride, and is condensed with morpholine under the action of N-methylmorpholine to obtain a compound 1:
(2) reacting the compound 1 with a Grignard reagent under the action of isopropyl magnesium chloride to obtain a compound 2:
(3) oxidation of compound 2 with sodium hypochlorite yielded compound 3 and compound 4:
2. the method for preparing the isomer of the carfilzomib key intermediate according to claim 1, which is characterized in that: in the step (1), the molar ratio of the compound SM to the pivaloyl chloride is 1:1-1:1.2, the molar ratio of the compound SM to the N-methylmorpholine is 1:1-1:1.2, the molar ratio of the N-methylmorpholine to the morpholine is 1:1-1:2, and the reaction solvent is isopropyl acetate.
3. The method for preparing the isomer of the carfilzomib key intermediate according to claim 1, which is characterized in that: in the step (2), the molar ratio of the compound 1 to isopropyl magnesium chloride is 1:1-1:1.2, the grignard reagent is prepared from 2-bromopropylene and magnesium chips, the molar ratio of the compound 1 to 2-bromopropylene is 1:2, the molar ratio of the 2-bromopropylene to the magnesium chips is 1:1.15, and the reaction solvent is a mixed solvent of petroleum ether/tetrahydrofuran (v/v ═ 1/3).
4. The method for preparing the isomer of the carfilzomib key intermediate according to claim 1, which is characterized in that: in the step (3), the molar ratio of the compound 2 to the sodium hypochlorite is 1:3, and the reaction solvent is N-methylpyrrolidone.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050256324A1 (en) * | 2004-05-10 | 2005-11-17 | Proteolix, Inc. | Synthesis of amino acid keto-epoxides |
| CN101883779A (en) * | 2007-10-04 | 2010-11-10 | 欧尼斯治疗公司 | Synthesizing of crystalline peptide epoxy ketone protease inhibitors and amino acid ketone-epoxide |
| CN109641863A (en) * | 2016-08-05 | 2019-04-16 | 美国安进公司 | (S) synthesis of-2- amino-4- methyl-1-((R)-2- methyl oxirane-2- base)-amyl- 1- ketone and its pharmaceutically acceptable salt |
-
2021
- 2021-12-28 CN CN202111624606.9A patent/CN114195741A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050256324A1 (en) * | 2004-05-10 | 2005-11-17 | Proteolix, Inc. | Synthesis of amino acid keto-epoxides |
| CN101883779A (en) * | 2007-10-04 | 2010-11-10 | 欧尼斯治疗公司 | Synthesizing of crystalline peptide epoxy ketone protease inhibitors and amino acid ketone-epoxide |
| CN109641863A (en) * | 2016-08-05 | 2019-04-16 | 美国安进公司 | (S) synthesis of-2- amino-4- methyl-1-((R)-2- methyl oxirane-2- base)-amyl- 1- ketone and its pharmaceutically acceptable salt |
Non-Patent Citations (1)
| Title |
|---|
| ANDREW J. MALONEY等: ""A Virtual Plant for Integrated Continuous Manufacturing of a Carfi lzomib Drug Substance Intermediate, Part 3: Manganese-Catalyzed Asymmetric Epoxidation, Crystallization, and Filtration"", ORG. PROCESS RES. DEV., vol. 24, pages 1891 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
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Application publication date: 20220318 |