CN105440106A - Preparation method of carfilzomib - Google Patents
Preparation method of carfilzomib Download PDFInfo
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- CN105440106A CN105440106A CN201510955131.XA CN201510955131A CN105440106A CN 105440106 A CN105440106 A CN 105440106A CN 201510955131 A CN201510955131 A CN 201510955131A CN 105440106 A CN105440106 A CN 105440106A
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- 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
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Abstract
The invention discloses a preparation method of carfilzomib. According to the method, TBTU namely 2-(1H-benzotriazoleL-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate is taken as the condensing agent to carry out condensation. The method has the advantages that the reaction time is short, the nitrogen gas protection is not needed, the operation is convenient and feasible, the byproduct of condensing agent TBTU can be easily removed, the tedious steps such as column chromatography are not needed; a mixed solvent is cured in the post treatment to obtain the solid carfilzomib, the column chromatography is not needed, and the crude product is recrystallized by alcohol so as to obtain the refined product of carfilzomib. The preparation method can be applied to industrial production.
Description
Technical field
The present invention relates to organic drug synthesis technical field, particularly relate to the preparation method of a kind of antitumor drug Ka Feizuo meter.
Technical background
Ka Feizuo meter (Carfilzomib); chemical name is (2S)-N-((S)-1-((S)-4-methyl isophthalic acid-((R)-2-methyl oxirane-2-base)-1-oxo-pentane-2-base formamyl)-2-styroyl)-2-((S)-2-(2-morpholine acetamido)-4-phenylbutanamides base)-4-methylpentanamide; commodity are called Kyprolis, and molecular formula is C
40h
57n
5o
7, structure is as shown in formula I:
Ka Feizuo meter (Carfilzomib) is the proteinase inhibitor of OnyxPharmaceuticalsInc drugmaker of U.S. exploitation, trade(brand)name Kyprolis, this medicine is injection liquid, U.S. FDA approval listing is obtained, the treatment of multiple myeloma patients failed after treating for adopting other drug in July, 2012.Multiple myeloma is the Clonal disease of a kind of plasma cell dyscrasias, and sickness rate increases year by year, has occupied the second of neoplastic hematologic disorder, along with the raising for the treatment of level, although complete remission rate is higher, because recurrence rate is higher, makes the survival rate of patient still lower.Carfilzomib's is granted, is the multiple myeloma patients of recurrence after current therapy treatment, provides the selection of how a kind for the treatment of, many a hope of curing.
The above-mentioned cut-out mode of the many employings of the synthetic method of display card Fei Zuo meter in the open source information announced, namely compound ii and compound III condensation is adopted to obtain product Ka Feizuo meter, compound ii and compound III commercialization now, can easily from buying on the market.
In the preparation method of the Ka Feizuo meter announced; as patent US2005245435, WO2010108172, WO2009045497, WO2005105827 and WO2011109355 etc. report the synthetic method of Ka Feizuo meter; condensation condensing agent used mostly is PyBOP, HOBT, but PyBOP, HOBT long reaction time, require high to temperature control; dosing operation is complicated; severe reaction conditions, needs nitrogen protection, and by product is difficult to removing; need column chromatography to carry out purifying more, be not easy to industrial production.Preparation method of the present invention is simple to operate; reaction times is short; do not need nitrogen protection; the condensing agent TBTU byproduct of reaction adopted is easy to removing especially; do not need the loaded down with trivial details purification steps such as column chromatography, aftertreatment obtains Ka Feizuo meter solid crude product, crude product alcohols recrystallization and get Ka Feizuo meter solid fine work; especially, the present invention is particularly useful for suitability for industrialized production.
Summary of the invention
The object of the present invention is to provide the preparation method of a kind of Ka Feizuo meter.
For achieving the above object, the present invention adopts following technical scheme: in preparation process, condensing agent used is TBTU is (2-(1H-benzo trisazo-L-1-yl)-1,1,3,3-tetramethyl-urea Tetrafluoroboric acid ester).
Concrete, the preparation method of described Ka Feizuo meter, comprises the following steps:
With compound ii, compound III for raw material, be acid binding agent with organic amine, be that compound prepared by condensing agent with TBTU.
The preparation method of a kind of Ka Feizuo meter of the present invention, comprises the following steps:
Compound ii, compound III and TBTU are dissolved in methylene dichloride, be placed in ice-water bath, then the dichloromethane solution of organic amine is added, add the water-bath of recession deicing, stirring at room temperature 1-2h, obtains reaction solution, add sodium hydrogen carbonate solution to wash, again with saturated common salt washing, anhydrous sodium sulfate drying, obtains sticky thick product through concentrating under reduced pressure.
With the organic liquid mixture of certain volume ratio, target product Ka Feizuo beige solid is obtained to above-mentioned sticky thick product making beating purifying, namely obtain pure Ka Feizuo meter fine work with alcohols recrystallization.
In addition, the present invention also comprises following technical scheme:
Preferably, in Ka Feizuo meter synthesis, the equivalence ratio of compound ii, compound III, TBTU, organic amine is 1:(1.05-2.0): (1.05-2.0): (1.5-3.0).
Preferably, described temperature of reaction is-20 DEG C-50 DEG C, is more preferably-10 DEG C-30 DEG C.
Preferably, the described reaction times is 0.5h-5h, is more preferably 1h-2h.
Preferably, acid binding agent is triethylamine (TEA), pyridine, 2, 6-lutidine, DMAP (DMAP), N-methylmorpholine (NMM), N-ethylmorpholine (NEM), diisopropylethylamine (DIPEA), 1, 5-diazabicylo [4.3.0]--5-alkene in ninth of the ten Heavenly Stems (DBN), 1, 8-diazabicyclo [5.4.0]-ten one-7-alkene (DBU) or 1, 4-diazabicylo [2.2.2] octane (DABCO), preferred N-methylmorpholine (NMM) or diisopropylethylamine (DIPEA), be more preferably diisopropylethylamine (DIPEA).
Preferably, solvent is toluene, dimethylbenzene, ethyl acetate, isopropyl acetate, butylacetate, chloroform, methylene dichloride, methyl-sulphoxide, DMF or acetonitrile, preferred methylene dichloride, N, dinethylformamide or acetonitrile, be more preferably methylene dichloride.
Preferably, be dissolved in the first solvent by described Ka Feizuo meter viscous fluid, obtain Ka Feizuo meter solution, described first solvent comprises one or more in acetone, methylene dichloride and ethyl acetate;
Preferably, by described Ka Feizuo meter solution and the second solvent, crystallization, obtains Ka Feizuo meter sterling, and described second solvent comprises one or more in normal hexane, hexanaphthene, normal heptane.
Preferably, be dissolved in alcohol by described Ka Feizuo beige solid, described alcohol comprises one or more in methyl alcohol, ethanol, propyl alcohol.
Preparation method of the present invention is simple to operate; reaction times is short; do not need nitrogen protection; the condensing agent TBTU byproduct of reaction adopted is easy to removing especially; do not need the loaded down with trivial details purification steps such as column chromatography; get Ka Feizuo meter solid crude product instead can be analysed, crude product alcohols recrystallization and get Ka Feizuo meter solid fine work with adding the alkane such as normal hexane, normal heptane after the organic solvent dissolution such as ethyl acetate, methylene dichloride.The present invention can be applicable to suitability for industrialized production.
Embodiment
In order to further illustrate the present invention, below in conjunction with embodiment, the preparation method to Ka Feizuo meter provided by the invention is described, and protection scope of the present invention is not limited by the following examples.
In the preparation method of the Ka Feizuo meter provided in the present invention, raw materials used or reagent all can be buied by market.
Embodiment 1
By compound ii (10.4g, 50mmol), compound III (29.7g, 52.5mmol) with TBTU (19.3g, 60mmol) be dissolved in 200ml methylene dichloride, be placed in ice-water bath, then N is added, N-diisopropylethylamine (13.0g, dichloromethane solution 100mmol), add the water-bath of recession deicing, stirring at room temperature 2h, obtain reaction solution, the sodium hydrogen carbonate solution (500ml × 2) adding 2% is washed, saturated aqueous common salt (500ml × 2) is used to wash again, anhydrous sodium sulphate (10g) is dry, the thick product of thickness is obtained through concentrating under reduced pressure, then with the normal hexane of certain volume ratio and the mixed solution making beating 12h of ethyl acetate (volume ratio is 5:1), filter, be drying to obtain target product Ka Feizuo beige solid 32.0g, yield is 89.0%.
Embodiment 2
By compound ii (10.4g, 50mmol), compound III (29.7g, 52.5mmol) with TBTU (19.3g, 60mmol) be dissolved in 200ml methylene dichloride, be placed in ice-water bath, then triethylamine (10.1g is added, dichloromethane solution 100mmol), add the water-bath of recession deicing, stirring at room temperature 2h, obtain reaction solution, the sodium hydrogen carbonate solution (500ml × 2) adding 2% is washed, saturated aqueous common salt (500ml × 2) is used to wash again, anhydrous sodium sulphate (10g) is dry, the thick product of thickness is obtained through concentrating under reduced pressure, then with the normal hexane of certain volume ratio and the mixed solution making beating 12h of ethyl acetate (volume ratio is 5:1), filter, be drying to obtain target product Ka Feizuo beige solid 30.6g, yield is 86.0%.
Embodiment 3
Get above-mentioned obtained Ka Feizuo meter crude product 32.0g, be heated to 70-80 DEG C with ethanol (128ml), until molten clear after be cooled to less than 0 DEG C, filter after crystallization 3h, the a small amount of ethanol rinse of filter cake, filter cake in the air dry oven of 50 DEG C dry 26.9g, yield 84%.
Embodiment 4
Get above-mentioned obtained Ka Feizuo meter crude product 30.6g, be heated to 60-70 DEG C with methyl alcohol (122ml), until molten clear after be cooled to less than 0 DEG C, filter after crystallization 3h, the a small amount of ethanol rinse of filter cake, filter cake in the air dry oven of 50 DEG C dry 25.1g, yield 82%.
Claims (4)
1. the preparation method of Yi Zhong Ka Feizuo meter, be characterised in that: with compound ii, compound III and DIPEA be raw material, with TBTU for condensing agent, take organic amine as acid binding agent, prepare compound Ka Feizuo meter, compound ii, compound III are following structure:
TBTU is 2-(1H-benzo trisazo-L-1-yl)-1,1,3,3-tetramethyl-urea Tetrafluoroboric acid ester.
2. the preparation method of a kind of Ka Feizuo meter as claimed in claim 1, is characterised in that:
(1) in Ka Feizuo meter synthesis, the equivalence ratio of compound ii, compound III, TBTU, DIPEA is 1:(1.05-2.0): (1.05-2.0): (1.5-3.0);
(2) described temperature of reaction is-20 DEG C-50 DEG C, is more preferably-10 DEG C-30 DEG C;
(3) the described reaction times is 0.5h-5h, more elects 1h-2h as;
(4) acid binding agent of amidate action is triethylamine (TEA), pyridine, 2, 6-lutidine, DMAP (DMAP), N-methylmorpholine (NMM), N-ethylmorpholine (NEM), diisopropylethylamine (DIPEA), 1, 5-diazabicylo [4.3.0]--5-alkene in ninth of the ten Heavenly Stems (DBN), 1, 8-diazabicyclo [5.4.0]-ten one-7-alkene (DBU) or 1, 4-diazabicylo [2.2.2] octane (DABCO), preferred N-methylmorpholine (NMM) or diisopropylethylamine (DIPEA), be more preferably diisopropylethylamine (DIPEA),
(5) solvent of amidate action is toluene, dimethylbenzene, ethyl acetate, isopropyl acetate, butylacetate, chloroform, methylene dichloride, methyl-sulphoxide, N, dinethylformamide or acetonitrile, preferred methylene dichloride, DMF or acetonitrile, be more preferably methylene dichloride;
(6) described Ka Feizuo meter viscous fluid is dissolved in the first solvent, obtains Ka Feizuo meter solution, and described first solvent comprises one or more in acetone, methylene dichloride and ethyl acetate; Ka Feizuo meter solution and the second solvent, crystallization, obtains Ka Feizuo meter sterling, and described second solvent comprises one or more in normal hexane, hexanaphthene, normal heptane;
(7) described Ka Feizuo beige solid is dissolved in alcohol, and described alcohol comprises one or more in methyl alcohol, ethanol, propyl alcohol.
3. the preparation method of a kind of Ka Feizuo meter as claimed in claim 1, is characterised in that: aftertreatment mixed solvent solidification get Ka Feizuo meter solid, does not need column chromatography for separation.
4. the preparation method of a kind of Ka Feizuo meter as claimed in claim 1, is characterised in that: adopt alcohols to carry out recrystallization and namely obtain pure Ka Feizuo meter fine work.
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| CN201510955131.XA CN105440106A (en) | 2015-12-17 | 2015-12-17 | Preparation method of carfilzomib |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10364269B2 (en) | 2015-05-21 | 2019-07-30 | Laurus Labs Limited | Processes for the preparation of carfilzomib or pharmaceutically acceptable salts thereof |
| CN110759967A (en) * | 2019-09-05 | 2020-02-07 | 雅本化学股份有限公司 | Preparation method of carfilzomib |
| CN110964085A (en) * | 2018-09-28 | 2020-04-07 | 扬子江药业集团有限公司 | Preparation method of carfilzomib and derivatives thereof |
| CN113024637A (en) * | 2021-03-10 | 2021-06-25 | 江西师范大学 | Method for preparing carfilzomib by using water-soluble alkynylamide as condensing agent |
| 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 |
| CN116813710A (en) * | 2023-07-05 | 2023-09-29 | 重庆药友制药有限责任公司 | Preparation method of carfilzomib |
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| CN101006098A (en) * | 2004-04-15 | 2007-07-25 | 普罗特奥里克斯公司 | Compounds for proteasome enzyme inhibition |
| CN103641890A (en) * | 2013-12-19 | 2014-03-19 | 重庆泰濠制药有限公司 | Synthetic method of kyprolis |
| CN104086624A (en) * | 2014-03-21 | 2014-10-08 | 河南海汇药物研究有限公司 | Preparation method for carfilzomib |
| CN104356197A (en) * | 2014-09-30 | 2015-02-18 | 重庆泰濠制药有限公司 | Carfilzomib intermediate and preparation method thereof, as well as preparation method of carfilzomib |
| WO2015032622A1 (en) * | 2013-09-06 | 2015-03-12 | Sandoz Ag | Stereoselective synthesis of diols and triols by mannich reaction and their use in the synthesis of carfilzomib |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101006098A (en) * | 2004-04-15 | 2007-07-25 | 普罗特奥里克斯公司 | Compounds for proteasome enzyme inhibition |
| WO2015032622A1 (en) * | 2013-09-06 | 2015-03-12 | Sandoz Ag | Stereoselective synthesis of diols and triols by mannich reaction and their use in the synthesis of carfilzomib |
| CN103641890A (en) * | 2013-12-19 | 2014-03-19 | 重庆泰濠制药有限公司 | Synthetic method of kyprolis |
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| CN104356197A (en) * | 2014-09-30 | 2015-02-18 | 重庆泰濠制药有限公司 | Carfilzomib intermediate and preparation method thereof, as well as preparation method of carfilzomib |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10364269B2 (en) | 2015-05-21 | 2019-07-30 | Laurus Labs Limited | Processes for the preparation of carfilzomib or pharmaceutically acceptable salts thereof |
| US10800809B2 (en) | 2015-05-21 | 2020-10-13 | Laurus Labs Limited | Processes for the preparation of carfilzomib or pharmaceutically acceptable salts thereof |
| CN110964085A (en) * | 2018-09-28 | 2020-04-07 | 扬子江药业集团有限公司 | Preparation method of carfilzomib and derivatives thereof |
| CN110964085B (en) * | 2018-09-28 | 2023-07-07 | 扬子江药业集团有限公司 | Preparation method of carfilzomib and derivatives thereof |
| CN110759967A (en) * | 2019-09-05 | 2020-02-07 | 雅本化学股份有限公司 | Preparation method of carfilzomib |
| CN113024637A (en) * | 2021-03-10 | 2021-06-25 | 江西师范大学 | Method for preparing carfilzomib by using water-soluble alkynylamide as condensing agent |
| 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 |
| CN114249796B (en) * | 2021-12-29 | 2024-02-27 | 南京格亚医药科技有限公司 | Carfilzomib key intermediate impurity and preparation method thereof |
| CN116813710A (en) * | 2023-07-05 | 2023-09-29 | 重庆药友制药有限责任公司 | Preparation method of carfilzomib |
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Application publication date: 20160330 |