CN106831729A - A kind of purification process of AZD2171 - Google Patents
A kind of purification process of AZD2171 Download PDFInfo
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- CN106831729A CN106831729A CN201611174434.9A CN201611174434A CN106831729A CN 106831729 A CN106831729 A CN 106831729A CN 201611174434 A CN201611174434 A CN 201611174434A CN 106831729 A CN106831729 A CN 106831729A
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- Prior art keywords
- azd2171
- purification process
- silica gel
- crude product
- eluting solvent
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The present invention relates to a kind of purification process of AZD2171, comprise the following steps：（a）Prepared by chromatographic column, weigh silica gel, uses eluting solvent wet method dress post.（b）By AZD2171 dissolving crude product in strong solubility solvent, in addition silica gel column chromatography；（c）Eluted with the eluting solvent containing alkali, Fractional Collections eluent.（d）Eluent is tracked detection through HPLC, mixes precipitation, dries, and obtains sterling AZD2171.Purification process of the invention can remove a large amount of impurity, and the purity of AZD2171 can reach more than 99%, substantially increase yield, simplify AZD2171 process for refining, and organic solvent used in the present invention can be with recycling, it is adaptable to industrialized production.Meanwhile, the present invention also has nontoxic, Environmental Safety, the advantage of low production cost.
Description
Technical field
The present invention relates to a kind of purification process of AZD2171, belong to field of pharmaceutical chemistry technology.
Background technology
The chemical name of AZD2171 is：4- (the fluoro- 2 methyl indole -5- bases epoxides of 4-) -6- methoxyl groups -7- [3- (pyrroles
Alkane -1- bases) propoxyl group] quinazoline (I).
AZD2171 is a kind of oral antineoplastic, and the one kind researched and developed by Astrazeneca AB of the U.S. is possibly used for
The oral chemotherapeutics for the treatment of cancer.AZD2171 is a kind of oral small molecule Mutiple Targets acceptor TYR for treating cancer
Kinase inhibitor, there is certain antitumor action to Recurrent Ovarian Cancer, currently for other such as glioma, lung cancer, breast cancer
Multinomial clinical research with the solid tumor such as prostate cancer is still being carried out.
The synthetic method of a large amount of report AZD2171s existing at present, but AZD2171 is not reported in existing document specially
Method in terms of purifying.And conventional purification process is recrystallization, the solvent of recrystallization be usually tetrahydrofuran, methyl alcohol, ethanol,
Toluene.But it is susceptible to partially polymerized, formation dimer or polymer, conventional weight during the course of the reaction due to AZD2171
Method for crystallising can remove a part of impurity of AZD2171, and purity reaches more than 90%, but due to product and its polymer
Structure is similar, and chemical property is similar, does not have also a kind of effective purification process to enable to the purity of AZD2171 to reach so far
To 99% or higher purity.
Therefore it is badly in need of proposing that new technical scheme optimizes the purification process of AZD2171.
The content of the invention
It is an object of the present invention to provide a kind of purification process of new AZD2171.It is conventional based on silica gel column chromatography
Organic matter separation method, appearance tailing problem can effectively be suppressed by eluent of the selection containing organic base, obtain high-purity west
Ground Buddhist nun's cloth product.
To reach above-mentioned purpose, the present invention is adopted the following technical scheme that：
A prepared by () chromatographic column, weigh silica gel, use eluting solvent wet method dress post.
(b) by AZD2171 dissolving crude product in strong solubility solvent, add silica gel column chromatography in.
C () is eluted to eluting solvent of the addition containing alkali in chromatographic column, Fractional Collections eluent.
D () eluent is tracked detection through HPLC, mix precipitation, dries, and obtains sterling AZD2171.
Preferably, the silica gel described in step (a) refers to 100-500 mesh silica gel.
Preferably, the proper amount of silica gel described in step (a) refers to the weight of AZD2171 crude product and used silica gel
Than being 1：15-200.
Preferably, the strong solubility solvent described in step (b) is selected from tetrahydrofuran, ethyl acetate, dichloromethane, second
1~2 kind in nitrile and acetone.
Preferably, the strong solubility solvent quality described in step (b) is 1-100 times of AZD2171 crude product, preferably 1-10
Times.
Preferably, the eluting solvent in step (c) described in it is selected from dichloromethane, tetrahydrofuran, ethyl acetate, acetic acid
1~2 kind in butyl ester, acetone, ether, petroleum ether (60-90), n-hexane and pentane.
Preferably, the alkali described in step (c) is triethylamine, trimethylamine, tripropyl amine (TPA), tri-n-butylamine, diethyl isopropyl level
Amine, ammoniacal liquor or ammonia.
Preferably, the alkali and the volume ratio of eluting solvent described in step (c) are 1：10-1000, preferably 1：20-200.
Preferably, in step (d), the drying mode of described AZD2171 is vacuum drying, temperature 50-60 degree.
In the purification process of above-mentioned AZD2171, HPLC is tracked detection, precipitation collection and obtains most of qualified products,
Remaining a small amount of low-purity AZD2171 can proceed purifying as chromatographic materials.
The device have the advantages that：
Purification process of the invention can remove a large amount of impurity, greatly improve the purity and yield of AZD2171, and this
The used organic solvent of invention can be with recycling, it is adaptable to industrialized production.Meanwhile, the present invention also has nontoxic nothing
Evil, Environmental Safety, the advantage of low production cost.
Specific embodiment
With reference to specific embodiment, the present invention is described further, but protection scope of the present invention is not limited to that：
Embodiment one：
A prepared by () chromatographic column, weigh the 100 mesh silica gel of 60g, use petroleum ether wet method dress post.
B be dissolved in 2g AZD2171s crude product (purity 83.7%) in 2mL tetrahydrofuran solutions by (), add 2g silica gel, stirs
The silica gel solid mixture that uniform rear precipitation obtains AZD2171 crude product is mixed, then silica gel solid mixture carries out upper prop.
C () uses petroleum ether/dichloromethane (10：5) washed as eluting solvent (triethylamine of 1% (volume ratio) of addition)
It is de-.
D () point plate tracking product point occurs, continue to elute, and Fractional Collections is tracked detection purity with HPLC, merges and closes
Lattice collection liquid, is concentrated under reduced pressure into dry, recycling design, and it is (pure that dry (vacuum drying, 60 degree) obtains 1.20g white sterling AZD2171s
99%), yield is 71.7% to degree.Purified again as chromatographic materials after the component precipitation of low-purity.
Embodiment two：
A prepared by () chromatographic column, weigh the silica gel of 100g, use n-hexane wet method dress post.
B be dissolved in 2g AZD2171s crude product (purity 83.7%) in 4mL acetone solns by (), then uniformly drop to chromatography
Capital layer carries out upper prop.
C () uses n-hexane/acetone (10：3) eluted as eluting solvent (triethylamine of 5% (volume ratio) of addition).
D () point plate tracking product point occurs, continue to elute, and Fractional Collections is tracked detection purity with HPLC, merges and closes
Lattice collection liquid, is concentrated under reduced pressure into dry, recycling design, and it is (pure that dry (vacuum drying, 60 degree) obtains 1.11g white sterling AZD2171s
99%), yield is 66.3% to degree.Purified again as chromatographic materials after the component precipitation of low-purity.
Embodiment three：
A prepared by () chromatographic column, weigh the silica gel of 40g, use ethyl acetate wet method dress post.
B be dissolved in 2g AZD2171s crude product (purity 83.7%) in 10mL dichloromethane solutions by (), add 2g silica gel, stirs
The silica gel solid mixture that uniform rear precipitation obtains AZD2171 crude product is mixed, then silica gel solid mixture carries out upper prop.
C () is eluted with ethyl acetate as eluting solvent (ammoniacal liquor of 1% (volume ratio) of addition)..
D () point plate tracking product point occurs, continue to elute, and Fractional Collections is tracked detection purity with HPLC, merges and closes
Lattice collection liquid, is concentrated under reduced pressure into dry, recycling design, and it is (pure that dry (vacuum drying, 60 degree) obtains 0.95g white sterling AZD2171s
99%), yield is 56.7% to degree.Purified again as chromatographic materials after the component precipitation of low-purity.
Example IV：
A prepared by () chromatographic column, weigh the silica gel of 80g, use petroleum ether wet method dress post.
B be dissolved in 2g AZD2171s crude product (purity 83.7%) in 5mL tetrahydrofuran solutions by (), add 2g silica gel,
Precipitation obtains the silica gel solid mixture of AZD2171 crude product after stirring, and then silica gel solid mixture carries out upper prop..
C () uses petroleum ether/tetrahydrofuran (2：1) washed as eluting solvent (trimethylamine of 3% (volume ratio) of addition)
It is de-.
D () point plate tracking product point occurs, continue to elute, and Fractional Collections is tracked detection purity with HPLC, merges and closes
Lattice collection liquid, is concentrated under reduced pressure into dry, recycling design, and it is (pure that dry (vacuum drying, 60 degree) obtains 0.87g white sterling AZD2171s
99%), yield is 51.9 to degree.Purified again as chromatographic materials after the component precipitation of low-purity.
Embodiment five：
A prepared by () chromatographic column, weigh the silica gel of 50g, use petroleum ether wet method dress post.
B be dissolved in 2g AZD2171s crude product (purity 83.7%) in 12mL acetonitrile solutions by (), add 5g silica gel, and stirring is equal
Even rear precipitation obtains the silica gel solid mixture of AZD2171 crude product, and then silica gel solid mixture carries out upper prop.
C () uses petrol ether/ethyl acetate (1：1) washed as eluting solvent (tri-n-butylamine of 2% (volume ratio) of addition)
It is de-.
D () point plate tracking product point occurs, continue to elute, and Fractional Collections is tracked detection purity with HPLC, merges and closes
Lattice collection liquid, is concentrated under reduced pressure into dry, recycling design, and it is (pure that dry (vacuum drying, 60 degree) obtains 0.76g white sterling AZD2171s
99%), yield is 45.4% to degree.Purified again as chromatographic materials after the component precipitation of low-purity.
Embodiment six：
A prepared by () chromatographic column, weigh the silica gel of 60g, use butyl acetate wet method dress post.
B be dissolved in 2g AZD2171s crude product (purity 83.7%) in 5mL tetrahydrofuran solutions by (), add 2g silica gel, stirs
The silica gel solid mixture that uniform rear precipitation obtains AZD2171 crude product is mixed, then silica gel solid mixture carries out upper prop.
C () is eluted with butyl acetate as eluting solvent (ammoniacal liquor of 2% (volume ratio) of addition).
D () point plate tracking product point occurs, continue to elute, and Fractional Collections is tracked detection purity with HPLC, merges and closes
Lattice collection liquid, is concentrated under reduced pressure into dry, recycling design, and it is (pure that dry (vacuum drying, 60 degree) obtains 0.77g white sterling AZD2171s
99%), yield is 45.9% to degree.Purified again as chromatographic materials after the component precipitation of low-purity.
Embodiment seven：
A prepared by () chromatographic column, weigh the silica gel of 120g, use ethyl acetate wet method dress post.
B be dissolved in 2g AZD2171s crude product (purity 83.7%) in 5mL tetrahydrofuran solutions by (), add 2g silica gel, stirs
The silica gel solid mixture that uniform rear precipitation obtains AZD2171 crude product is mixed, then silica gel solid mixture carries out upper prop.
C () is eluted with ethyl acetate as eluting solvent (progressively adds 0.75%, 1%, 1.5%, 2%2% (body
Product ratio) triethylamine).
D () point plate tracking product point occurs, continue to elute, and Fractional Collections is tracked detection purity with HPLC, merges and closes
Lattice collection liquid, is concentrated under reduced pressure into dry, recycling design, and it is (pure that dry (vacuum drying, 60 degree) obtains 1.03g white sterling AZD2171s
99%), yield is 61.5% to degree.Purified again as chromatographic materials after the component precipitation of low-purity.
Below the preferred embodiments of the invention are only listed, protection scope of the present invention is not restricted to this, art technology
Any change that personnel are made within the scope of the invention as claimed is each fallen within the scope of the present invention.
Claims (9)
1. the present invention provides a kind of purification process of AZD2171 (I),
Characterized in that, the purification process is comprised the following steps：
A prepared by () chromatographic column, weigh silica gel, use eluting solvent wet method dress post；
(b) by AZD2171 dissolving crude product in strong solubility solvent, add silica gel column chromatography in；
C () is eluted to eluting solvent of the addition containing alkali in chromatographic column, Fractional Collections eluent；
D () eluent is tracked detection through HPLC, mix precipitation, dries, and obtains sterling AZD2171.
2. the purification process of AZD2171 according to claim 1, it is characterised in that the silica gel described in step (a) refers to
The silica gel of 100-500 mesh specifications.
3. the purification process of AZD2171 according to claim 1, it is characterised in that the proper amount of silicon described in step (a)
Glue refers to AZD2171 crude product and the weight ratio of used silica gel is 1：15-200.
4. the purification process of AZD2171 according to claim 1, it is characterised in that the strong solubility described in step (b) is molten
Agent is selected from 1~2 kind in tetrahydrofuran, ethyl acetate, dichloromethane, acetonitrile and acetone.
5. the purification process of AZD2171 according to claim 1, it is characterised in that the strong solubility described in step (b) is molten
Agent quality is 1-100 times of AZD2171 crude product.
6. the purification process of AZD2171 according to claim 1, it is characterised in that the eluting solvent choosing described in step (c)
From dichloromethane, tetrahydrofuran, ethyl acetate, butyl acetate, acetone, ether, petroleum ether (60-90), n-hexane and pentane
In 1~2 kind.
7. the purification process of AZD2171 according to claim 1, it is characterised in that the alkali described in step (c) is three second
Amine, trimethylamine, tripropyl amine (TPA), tri-n-butylamine, diethyl isopropyl level amine, ammoniacal liquor or ammonia.
8. the purification process of AZD2171 according to claim 1, it is characterised in that alkali described in step (c) with elute it is molten
The volume ratio of agent is 1：10-1000.
9. the purification process of AZD2171 according to claim 1, it is characterised in that AZD2171 described in step (d)
Drying mode is vacuum drying, temperature 50-60 degree.
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| CN201611174434.9A CN106831729A (en) | 2016-12-19 | 2016-12-19 | A kind of purification process of AZD2171 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115894300A (en) * | 2021-09-22 | 2023-04-04 | 中国科学院过程工程研究所 | Method for purifying 1,6-hexamethylene dicarbamate |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1346271A (en) * | 1999-02-10 | 2002-04-24 | 阿斯特拉曾尼卡有限公司 | Quinazoline derivatives as angiogenesis inhibitors |
| CN102603718A (en) * | 2012-02-08 | 2012-07-25 | 武汉嘉特利佰联创科技有限公司 | Synthesis method of cediranib |
| CN103275069A (en) * | 2013-05-22 | 2013-09-04 | 苏州明锐医药科技有限公司 | Preparation method of cediranib |
-
2016
- 2016-12-19 CN CN201611174434.9A patent/CN106831729A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1346271A (en) * | 1999-02-10 | 2002-04-24 | 阿斯特拉曾尼卡有限公司 | Quinazoline derivatives as angiogenesis inhibitors |
| CN102603718A (en) * | 2012-02-08 | 2012-07-25 | 武汉嘉特利佰联创科技有限公司 | Synthesis method of cediranib |
| CN103275069A (en) * | 2013-05-22 | 2013-09-04 | 苏州明锐医药科技有限公司 | Preparation method of cediranib |
Non-Patent Citations (1)
| Title |
|---|
| 李似姣著: "《现代色谱分析》", 30 June 2014, 北京：国防工业出版社 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115894300A (en) * | 2021-09-22 | 2023-04-04 | 中国科学院过程工程研究所 | Method for purifying 1,6-hexamethylene dicarbamate |
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