CN116813710A - Preparation method of carfilzomib - Google Patents
Preparation method of carfilzomib Download PDFInfo
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- CN116813710A CN116813710A CN202310814325.2A CN202310814325A CN116813710A CN 116813710 A CN116813710 A CN 116813710A CN 202310814325 A CN202310814325 A CN 202310814325A CN 116813710 A CN116813710 A CN 116813710A
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- 108010021331 carfilzomib Proteins 0.000 title claims abstract description 35
- 229960002438 carfilzomib Drugs 0.000 title claims abstract description 34
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- 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 description 33
- 238000006243 chemical reaction Methods 0.000 claims abstract description 33
- 150000001875 compounds Chemical class 0.000 claims abstract description 33
- 238000000034 method Methods 0.000 claims abstract description 19
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 16
- GPIQOFWTZXXOOV-UHFFFAOYSA-N 2-chloro-4,6-dimethoxy-1,3,5-triazine Chemical compound COC1=NC(Cl)=NC(OC)=N1 GPIQOFWTZXXOOV-UHFFFAOYSA-N 0.000 claims abstract description 10
- 150000007530 organic bases Chemical class 0.000 claims abstract description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 34
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 33
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 30
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- 238000006482 condensation reaction Methods 0.000 claims description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- XTUVJUMINZSXGF-UHFFFAOYSA-N N-methylcyclohexylamine Chemical compound CNC1CCCCC1 XTUVJUMINZSXGF-UHFFFAOYSA-N 0.000 claims description 2
- PAMIQIKDUOTOBW-UHFFFAOYSA-N N-methylcyclohexylamine Natural products CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 claims description 2
- MGNCLNQXLYJVJD-UHFFFAOYSA-N cyanuric chloride Chemical compound ClC1=NC(Cl)=NC(Cl)=N1 MGNCLNQXLYJVJD-UHFFFAOYSA-N 0.000 claims description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 2
- OKDQKPLMQBXTNH-UHFFFAOYSA-N n,n-dimethyl-2h-pyridin-1-amine Chemical compound CN(C)N1CC=CC=C1 OKDQKPLMQBXTNH-UHFFFAOYSA-N 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- XKDFUXJROYAXAO-UHFFFAOYSA-N 2-chloro-4,6-bis(phenylmethoxy)-1,3,5-triazine Chemical compound N=1C(OCC=2C=CC=CC=2)=NC(Cl)=NC=1OCC1=CC=CC=C1 XKDFUXJROYAXAO-UHFFFAOYSA-N 0.000 claims 1
- WPAYYYDSSCOEHN-UHFFFAOYSA-N 2-chloro-4,6-diphenoxy-1,3,5-triazine Chemical compound N=1C(OC=2C=CC=CC=2)=NC(Cl)=NC=1OC1=CC=CC=C1 WPAYYYDSSCOEHN-UHFFFAOYSA-N 0.000 claims 1
- NCMONXLWVRSCBP-UHFFFAOYSA-N 2-methoxy-1,3,5-triazine Chemical compound COC1=NC=NC=N1 NCMONXLWVRSCBP-UHFFFAOYSA-N 0.000 claims 1
- VFRSADQPWYCXDG-LEUCUCNGSA-N ethyl (2s,5s)-5-methylpyrrolidine-2-carboxylate;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.CCOC(=O)[C@@H]1CC[C@H](C)N1 VFRSADQPWYCXDG-LEUCUCNGSA-N 0.000 claims 1
- 150000008054 sulfonate salts Chemical class 0.000 claims 1
- 239000012535 impurity Substances 0.000 abstract description 16
- 230000006340 racemization Effects 0.000 abstract description 9
- 238000009776 industrial production Methods 0.000 abstract description 5
- 239000006227 byproduct Substances 0.000 abstract description 4
- -1 carfilzomib compound Chemical class 0.000 abstract description 4
- 150000004677 hydrates Chemical class 0.000 abstract description 3
- 230000035484 reaction time Effects 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- 239000000047 product Substances 0.000 description 11
- 239000007787 solid Substances 0.000 description 9
- OWGGQBZQMQMPBI-DKXTVVGFSA-N (2s)-2-amino-4-methyl-1-[(2r)-2-methyloxiran-2-yl]pentan-1-one;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.CC(C)C[C@H](N)C(=O)[C@@]1(C)CO1 OWGGQBZQMQMPBI-DKXTVVGFSA-N 0.000 description 7
- 239000012065 filter cake Substances 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- 239000012295 chemical reaction liquid Substances 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 6
- 230000008025 crystallization Effects 0.000 description 6
- 238000004321 preservation Methods 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 239000004593 Epoxy Substances 0.000 description 3
- 239000012317 TBTU Substances 0.000 description 3
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- JKAPWXKZLYJQJJ-UHFFFAOYSA-N 2,4-dichloro-6-methoxy-1,3,5-triazine Chemical compound COC1=NC(Cl)=NC(Cl)=N1 JKAPWXKZLYJQJJ-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
- GOOHAUXETOMSMM-GSVOUGTGSA-N R-propylene oxide Chemical compound C[C@@H]1CO1 GOOHAUXETOMSMM-GSVOUGTGSA-N 0.000 description 1
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N epoxyketone group Chemical group O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229940000764 kyprolis Drugs 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of a carfilzomib compound, which comprises the steps of reacting a compound shown in a formula 1 with a compound shown in a formula 2 in a system containing organic base in the presence of condensing agents such as 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine (CDMT), 4- (4, 6-dimethoxy-1, 3, 5-triazine-2-yl) -4-methylmorpholine hydrochloride (DMTMM) and hydrates thereof. The method can effectively reduce the generation of racemization impurities, has the advantages of short reaction time, high raw material conversion rate, high yield, simple post-treatment, less byproducts and less three wastes, and is suitable for industrial production.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a preparation method of carfilzomib.
Background
Carfilzomib (Carfilzomib) is a second generation protease inhibitor containing a tetrapeptide epoxyketone structure developed by the company Onyx Pharma, and approved by the U.S. Food and Drug Administration (FDA) for the treatment of refractory multiple myeloma at 7, 2012 under the trade name kypro lis.
Carfilzomib is chemically named { (2S) -2- [ (morpholin-4-yl) acetamido ] -4-phenylbutyryl } -L-leucyl-N1- { (2S) -1[ (2R) -2-methyl-epoxy ethyl-2-yl ] -4-methyl-1-oxopentan-2-yl } -L-phenylalaninamide, and its chemical structure is shown in formula 3:
。
CN102286070B discloses a method for synthesizing carfilzomib, the reaction formula is as follows:
in the route, compound 1 and epoxy compound 2 are subjected to condensation reaction to obtain carfilzomib of compound 3. The method is a common route for synthesizing carfilzomib at present, but has a certain technical problem when the method is used for mass production. Firstly, the method uses expensive benzotriazol-1-yl-oxy-tripyrrolidinylphosphine hexafluorophosphate (PyBOP) as a condensing agent, the cost is high, and the condensing agent faces the problem of racemization of chiral carbon at a carboxyl position when long-chain polypeptide carboxylic acid is activated, and an additional racemization inhibitor and an extremely low reaction temperature are usually required to be added to reduce the generation of racemization impurities (the following compound 4).
The inventors of the present invention have found that when using PyBOP and similar O-benzotriazol-N, N' -tetramethylurea tetrafluoroborate (TBTU) as condensing agents to prepare carfilzomib in the course of developing a process for preparing carfilzomib with reference to the example of CN102286070, the purity of the reaction solution is low, the amount of by-products is large, the content of racemic impurities (compound 4) is high, and the yield of the target product is low. Meanwhile, the inventor adopts the condensing agent to react, and then drops the reaction solution into water for crystallization, so that a complex post-treatment process is expected to be eliminated, and high-yield and high-purity carfilzomib is obtained, but experiments find that the yield of the carfilzomib obtained by the operation mode is obviously lower, the purity is lower, and the racemization impurity content is higher (see comparative example 3 and comparative example 4). Therefore, the post-treatment mode adopting the condensing agent is difficult to simplify operation, multiple extraction and washing are needed, a large amount of three wastes are generated, and the method is not suitable for industrial production.
Therefore, the research and development of the carfilzomib synthesis method has the advantages of low cost, less racemization impurities, less byproducts, simple post-treatment process, less three wastes, high yield and great significance in being suitable for industrial production.
Disclosure of Invention
The invention develops a preparation method of a carfilzomib compound, which selects cheap and easily available 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine (CDMT) and 4- (4, 6-dimethoxy-1, 3, 5-triazine-2-yl) -4-methylmorpholine hydrochloride (DMTMM) as condensing agents, has high product purity, less racemization impurities, simple and convenient post-treatment operation, greatly reduces three wastes, improves the total yield, and is particularly suitable for industrial production.
To achieve the object of the present invention, the present invention provides the following embodiments:
in one embodiment, a method for preparing carfilzomib of the present invention is represented by the following formula:
the method comprises reacting a compound of formula 1 with a compound of formula 2 or a salt thereof in an organic solvent in the presence of an organic base and a condensing agent to produce carfilzomib (compound of formula 3), characterized in that: the condensing agent is selected from the group consisting of 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine, 4- (4, 6-dimethoxy-1, 3, 5-triazin-2-yl) -4-methylmorpholine hydrochloride and hydrates thereof, 4- (4, 6-dimethoxy-triazin-2-yl) -4-methylmorpholine tetrafluoroborate and hydrates thereof, 2,4, 6-trichloro-1, 3, 5-triazine, 2-methoxy-4, 6-dichloro-1, 3, 5-triazine, 4,6, -dibenzyloxy-2-chloro-1, 3, 5-triazine and 4,6, -diphenoxy-2-chloro-1, 3, 5-triazine.
Preferably, in the above method for preparing carfilzomib of the present invention, the salt of the compound of formula 2 is hydrochloride, trifluoroacetate or sulfonate, preferably hydrochloride or trifluoroacetate.
Preferably, the method for preparing carfilzomib of the present invention is characterized in that: the molar ratio of the condensing agent to the compound of formula 1 is at least 1.01:1, preferably (1.1 to 2.0): 1. The condensing agent is preferably 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine or 4- (4, 6-dimethoxy-1, 3, 5-triazin-2-yl) -4-methylmorpholine hydrochloride.
Preferably, in the method for preparing carfilzomib of the present invention, the molar ratio of the organic base to the compound of formula 1 is at least 1.01:1, preferably (2-10): 1. Preferably, the organic base is triethylamine, diethylamine, diisopropylethylamine, N-methylmorpholine, N-methylcyclohexylamine, N-dimethylaminopyridine or pyridine, more preferably N-methylmorpholine (NMM).
Preferably, in the preparation method of carfilzomib disclosed by the invention, the volume amount of the organic solvent is 0.1-50 times of the mass of the compound of formula 1, preferably 8-20 times of the mass of the compound of formula 1. Preferably, the organic solvent is dichloromethane, ethyl acetate, acetonitrile or N, N-dimethylformamide, more preferably N, N-Dimethylformamide (DMF).
Preferably, in the preparation method of carfilzomib disclosed by the invention, the temperature of the condensation reaction is-40-25 ℃, preferably-25-10 ℃; the condensation reaction time is 1 to 8 hours, preferably 1 to 4 hours.
The invention has the technical effects that: the preparation method of carfilzomib disclosed by the invention uses cheap CDMT, DMTMM and the like as condensing agents, has few reaction byproducts, few racemized impurities (compound 4), high purity, high yield, simple post-treatment, few three wastes and low cost, and is suitable for large-scale industrial production.
Detailed Description
The following examples are merely representative to aid in understanding and explaining the nature of the invention and are not intended to limit the scope of the invention in any way.
30.00g of (2S) -2-amino-4-methyl-1- ((2R) -2-methyl oxiranyl) -1-pentanone trifluoroacetate, 16.61g of CDMT (sodium chloride) 16.61g and 240ml of DMF (dimethyl formamide) are added into a reaction bottle, stirred and cooled to-25 to-15 ℃, 18.74g of NMM is dropwise added, the reaction is completed after the heat preservation for 1 hour, the temperature is controlled to 0-20 ℃, the reaction is dropwise added into 1440-ml water, crystallization and filtration are carried out, and the filter cake is recrystallized by acetonitrile/water to obtain 34.05g of white solid of a target product, the yield is 89.34%, the chromatographic purity is 99.93%, and the racemic impurity (compound 4) is not detected.
Example 2 preparation of carfilzomib
10.00g of (2S) -2-amino-4-methyl-1- ((2R) -2-methyl oxiranyl) -1-pentanone trifluoroacetate, 5.54g of CDMT 6.20g and 200ml of DMF are added into a reaction bottle, stirred and cooled to 0-10 ℃, 17.85g of NMM is dropwise added, the reaction is carried out for 1 hour after the completion of the dropwise addition, the temperature is controlled to 0-20 ℃, the reaction liquid is dropwise added into 1200ml of water, crystallization and filtration are carried out, and the filter cake is recrystallized by acetonitrile/water to obtain 11.29g of white solid of the target product, the yield is 88.87%, the chromatographic purity is 99.92%, and the racemized impurity (compound 4) is 0.01%.
Example 3 preparation of carfilzomib
10.00g of (2S) -2-amino-4-methyl-1- ((2R) -2-methyl epoxy ethyl) -1-pentanone hydrochloride, 4.03g of CDMT 4.03g and 100ml of DMF are added into a reaction bottle, stirred and cooled to-25 to-15 ℃, 7.14g of NMM is dropwise added, the reaction is carried out for 4 hours after the dropwise addition, the reaction is finished, the temperature is controlled to be 0-20 ℃, the reaction liquid is dropwise added into 900ml of water, crystallization and filtration are carried out, and the filter cake is recrystallized by acetonitrile/water to obtain 10.53g of white solid of a target product, the yield is 82.89%, the chromatographic purity is 99.81%, and the racemic impurities (compound 4) are not detected.
Example 4 preparation of carfilzomib
10.00g of (2S) -2-amino-4-methyl-1- ((2R) -2-methyl oxiranyl) -1-pentanone trifluoroacetate, 5.55g of DMTMM 6.35g and 100ml of DMF are added into a reaction bottle, stirred and cooled to-15-0 ℃, 3.57g of NMM is dropwise added, the reaction is completed after the completion of the heat preservation reaction for 2 hours, the temperature is controlled to 0-20 ℃, the reaction liquid is dropwise added into 600ml of water, crystallization and filtration are carried out, and the filter cake is recrystallized by acetonitrile/water to obtain 11.26g of white solid of a target product, the yield is 88.63%, the chromatographic purity is 99.85%, and the racemic impurities (compound 4) are not detected.
Example 5 preparation of carfilzomib
10.00g of (2S) -2-amino-4-methyl-1- ((2R) -2-methyl oxirane) -1-pentanone hydrochloride, 4.08g of DMTMM 8.79g and 150ml of DMF are added into a reaction bottle, stirred and cooled to-15-0 ℃, 4.46g of NMM is dropwise added, the reaction is carried out for 1 hour after the completion of the reaction, the temperature is controlled to 0-20 ℃, the reaction liquid is dropwise added into 1200ml of water, crystallization and filtration are carried out, and the filter cake is recrystallized by acetonitrile/water to obtain 11.39g of white solid of a target product, the yield is 89.66%, the chromatographic purity is 99.89%, and the racemic impurity (compound 4) is not detected.
Comparative example 1 preparation of carfilzomib
5.00g of a compound shown in the formula 1, 4.76g of 1-hydroxybenzotriazole and 50ml of methylene dichloride are added into a reaction bottle, stirred and cooled to-45 to-40 ℃, 2.71g of (2S) -2-amino-4-methyl-1- ((2R) -2-methyl oxiranyl) -1-pentanone trifluoroacetate and 5.96g of PyBOP are added, 6.26g of N, N-diisopropylethylamine is added dropwise, and after the dropwise addition, the temperature is raised to-20 to-15 ℃, and the reaction is carried out for 6 hours under heat preservation. After the reaction, the reaction mixture was sequentially washed with water, an aqueous phosphoric acid solution, an aqueous sodium hydrogencarbonate solution and saturated brine, the organic phase was concentrated, and the concentrate was recrystallized from acetonitrile/water to give 2.27g of a white solid of the objective product, yield 35.74%, chromatographic purity 99.07% and racemic impurity (compound 4) 0.09%.
Comparative example 2 preparation of carfilzomib
5.00g of a compound shown in the formula 1, 4.76g of 1-hydroxybenzotriazole and 50ml of methylene dichloride are added into a reaction bottle, stirred and cooled to-45 to-40 ℃, 2.73g of (2S) -2-amino-4-methyl-1- ((2R) -2-methyl oxiranyl) -1-pentanone trifluoroacetate and 3.67g of TBTU are added, 6.30g of N, N-diisopropylethylamine is added dropwise, and the temperature is raised to-20 to-15 ℃ after the dropwise addition, and the reaction is carried out for 6 hours under heat preservation. After the reaction, the reaction mixture was sequentially washed with water, an aqueous phosphoric acid solution, an aqueous sodium hydrogencarbonate solution and saturated brine, the organic phase was concentrated, and the concentrate was recrystallized from acetonitrile/water to give 3.83g of a white solid of the objective product, yield 60.30%, chromatographic purity 98.50% and racemic impurity (compound 4) 0.10%.
Comparative example 3 preparation of carfilzomib
5.00g of a compound shown in the formula 1, 4.78g of 1-hydroxybenzotriazole and 50ml of DMF are added into a reaction bottle, stirred and cooled to-45 to-35 ℃, 2.73g of (2S) -2-amino-4-methyl-1- ((2R) -2-methyl oxiranyl) -1-pentanone trifluoroacetate and 5.98g of PyBOP are added, 6.26g of N, N-diisopropylethylamine is added dropwise, and after the dropwise addition, the temperature is raised to-20 to-15 ℃, and the reaction is carried out for 4 hours under heat preservation. After the reaction is finished, controlling the temperature to be 0-20 ℃, dripping the reaction liquid into 300m water l, crystallizing, filtering, recrystallizing a filter cake by acetonitrile/water to obtain 2.60g of white solid of a target product, wherein the yield is 40.94%, the chromatographic purity is 89.87%, and the racemization impurity (compound 4) is 0.09%.
Comparative example 4 preparation of carfilzomib
5.00g of a compound shown in the formula 1, 4.77g of 1-hydroxybenzotriazole and 30ml of DMF are added into a reaction bottle, stirred and cooled to-40 to-30 ℃, 2.72g of (2S) -2-amino-4-methyl-1- ((2R) -2-methyl oxiranyl) -1-pentanone trifluoroacetate and 3.69g of TBTU are added, 6.28g of N, N-diisopropylethylamine is added dropwise, the temperature is raised to-20 to-15 ℃ after the dropwise addition, and the reaction is carried out for 5 hours under heat preservation. After the reaction is finished, controlling the temperature to be 0-20 ℃, dripping the reaction liquid into 180ml of water, crystallizing, filtering, recrystallizing a filter cake by acetonitrile/water to obtain 4.82g of white solid of a target product, wherein the yield is 75.88%, the chromatographic purity is 99.30%, and the racemization impurity (compound 4) is 0.16%.
The above embodiments are exemplary, and any simple modification or variation substantially within the spirit of the present invention is also included in the scope of the present invention.
Claims (10)
1. A method for preparing carfilzomib, the reaction formula is as follows:
the method comprises the steps of reacting a compound of formula 1 with a compound of formula 2 or a salt thereof in an organic solvent in the presence of an organic base and a condensing agent to prepare a compound of formula 3, carfilzomib, and is characterized in that: the condensing agent is selected from 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine, 4- (4, 6-dimethoxy-1, 3, 5-triazine-2-yl) -4-methylmorpholine hydrochloride and hydrate thereof, 4- (4, 6-dimethoxy-triazine-2-yl) -4-methylmorpholine tetrafluoroborate and hydrate thereof, 2,4, 6-trichloro-1, 3, 5-triazine, 2-methoxy1,3, 5-triazine, 4, 6-dibenzyloxy-2-chloro-1, 3, 5-triazine and 4, 6-diphenoxy-2-chloro-1, 3, 5-triazine.
2. The process according to claim 1, wherein the salt of the compound of formula 2 is a hydrochloride, trifluoroacetate or sulfonate salt, preferably a hydrochloride or trifluoroacetate salt.
3. The method of manufacturing according to claim 1, characterized in that: the condensing agent is 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine or 4- (4, 6-dimethoxy-1, 3, 5-triazine-2-yl) -4-methylmorpholine hydrochloride.
4. The process according to claim 1, wherein the organic base is triethylamine, diethylamine, diisopropylethylamine, N-methylmorpholine, N-methylcyclohexylamine, N-dimethylaminopyridine or pyridine, preferably N-methylmorpholine.
5. The preparation method according to claim 1, wherein the organic solvent is dichloromethane, ethyl acetate, acetonitrile or N, N-dimethylformamide, preferably N, N-dimethylformamide.
6. A process according to claim 1 or 3, wherein the molar ratio of condensing agent to compound of formula 1 is at least 1.01:1, preferably (1.1 to 2.0): 1.
7. The process according to claim 1, wherein the molar ratio of the organic base to the compound of formula 1 is at least 1.01:1, preferably (2-10): 1.
8. The preparation method according to claim 1, wherein the volume amount of the organic solvent is 0.1-50 times ml/g, preferably 8-20 times ml/g, of the mass of the compound of formula 1.
9. The preparation method according to claim 1, wherein the condensation reaction temperature is-40 to 25 ℃, preferably-25 to 10 ℃.
10. The preparation method according to claim 1, wherein the time of the condensation reaction is 1 to 8 hours, preferably 1 to 4 hours.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CA2991975A1 (en) * | 2015-08-10 | 2015-10-15 | Suzhou M-Conj Biotech Co., Ltd. | Novel linkers and their uses in specific conjugation of drugs to a biological molecule |
| CN105440106A (en) * | 2015-12-17 | 2016-03-30 | 昆明贵研药业有限公司 | Preparation method of carfilzomib |
| CA3209672A1 (en) * | 2016-02-04 | 2016-04-21 | Hangzhou Dac Biotech Co., Ltd. | Specific conjugation linkers, specific immunoconjugates thereof, methods of making and uses such conjugates thereof |
| CN108811499A (en) * | 2015-07-04 | 2018-11-13 | 苏州美康加生物科技有限公司 | Specific conjugation of cell binding molecules |
| CN110099682A (en) * | 2016-11-14 | 2019-08-06 | 杭州多禧生物科技有限公司 | It is coupled connector, cell-binding molecules-drug conjugates and its preparation and application containing this connector |
| WO2020257998A1 (en) * | 2019-06-24 | 2020-12-30 | Hangzhou Dac Biotech Co., Ltd | A conjugate of a cytotoxic agent to a cell binding molecule with branched linkers |
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Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108811499A (en) * | 2015-07-04 | 2018-11-13 | 苏州美康加生物科技有限公司 | Specific conjugation of cell binding molecules |
| CA2991975A1 (en) * | 2015-08-10 | 2015-10-15 | Suzhou M-Conj Biotech Co., Ltd. | Novel linkers and their uses in specific conjugation of drugs to a biological molecule |
| CN105440106A (en) * | 2015-12-17 | 2016-03-30 | 昆明贵研药业有限公司 | Preparation method of carfilzomib |
| CA3209672A1 (en) * | 2016-02-04 | 2016-04-21 | Hangzhou Dac Biotech Co., Ltd. | Specific conjugation linkers, specific immunoconjugates thereof, methods of making and uses such conjugates thereof |
| CN110099682A (en) * | 2016-11-14 | 2019-08-06 | 杭州多禧生物科技有限公司 | It is coupled connector, cell-binding molecules-drug conjugates and its preparation and application containing this connector |
| WO2020257998A1 (en) * | 2019-06-24 | 2020-12-30 | Hangzhou Dac Biotech Co., Ltd | A conjugate of a cytotoxic agent to a cell binding molecule with branched linkers |
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