CN104744307B - Isostatine derivant and preparation method thereof - Google Patents
Isostatine derivant and preparation method thereof Download PDFInfo
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- CN104744307B CN104744307B CN201510151514.1A CN201510151514A CN104744307B CN 104744307 B CN104744307 B CN 104744307B CN 201510151514 A CN201510151514 A CN 201510151514A CN 104744307 B CN104744307 B CN 104744307B
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Abstract
The invention discloses a kind of isostatine derivant and preparation method thereof, the diethyl zinc of method employing mol ratio 2 4:1 of the present invention and butter of tin mixture, as catalyst, improve reaction temperature and productivity, are more suitable for industrialized production.
Description
Technical field
The present invention relates to chemical technology field, be specifically related to a kind of isostatine derivant and preparation method thereof.
Background technology
20 century 70s, Japanese researchers Umezawa etc. is separated to aspartyl protease inhibitor pepstatin,
Its structure occurs in that a kind of brand-new beta-hydroxy-gamma-aminoacid (3S, 4S)-4-amino-3-hydroxyl-6-methyl first
Enanthic acid (statine). further investigation finds, statine is the required fragment of activity of parent compound, by simulation peptide chain enzymolysis
Tetrahedron transition state and play pharmacological action.
Later, people were found that statine and knot thereof the most successively in the multiple natural product with valuable pharmacological activity
Structure analog, these analog include isostatine, dolaisoleuine, dolaproine, AHPPA, AHMPA etc..Mirror
Structure (especially stereochemical structure) in this compounds has important impact to the activity of parent compound, so finding Gao Li
The selective synthetic method of body is to make up the important means that natural product is rare, is also beneficial to change these natural products
Make, to reaching to strengthen activity, drop hypotoxic purpose.
The method that there is substantial amounts of synthesis staine analog in prior art, such as Mikami etc. by amino with double benzyls
The amido aldehyde of protection, at EtAlCl2In the presence of, aldol condensation shows the anti selectivity of height；And amino is with Boc
The amido aldehyde of protection, at SnCl4Higher syn selectivity is then given under mediation.But the subject matter that the method exists is one
Aspect reaction needs to carry out at-78 DEG C, and productivity is also only capable of reaching about 41%, the most how to provide a kind of reaction condition more
Gentleness, it is that those skilled in the art's technology urgently to be resolved hurrily is asked that productivity is more capable of the preparation method of industrialized production purpose
Topic.
Summary of the invention
The present invention is directed to the deficiencies in the prior art, by the screening of several years and repeatedly test, it is provided that a kind of isostatine
Derivant and preparation method thereof, improves reaction temperature and productivity.In order to realize the purpose of the present invention, intend using following technical side
Case:
One aspect of the present invention relates to a kind of isostatine derivant, it is characterised in that described isostatine derivant
Structural formula is:
Wherein R1Selected from C1-C6Alkyl, it is preferred that described R1For ethyl.
In another aspect of this invention, the preparation method of above-mentioned isostatine derivant is further related to, it is characterised in that institute
The preparation method stated includes reacting as follows:
In a preferred embodiment of the present invention, it is characterised in that SnCl in described reaction4(C2H5)2Zn rubs
Your ratio is 1:2-4, preferably 1:3.
In a preferred embodiment of the present invention, it is characterised in that described reaction is to carry out in mixed solvent,
Described mixed solvent be volume ratio be dichloromethane and the ether of 1:1.
In a preferred embodiment of the present invention, it is characterised in that described reaction is entered between-25 DEG C to-35 DEG C
OK.
The method of the present invention uses the diethyl zinc of mol ratio 2-4:1 and butter of tin mixture as catalyst and to mix
Bonding solvent, improves reaction temperature and productivity, beneficially industrialized production.
Detailed description of the invention
If not specified, that technological means used in embodiment is well known to those skilled in the art conventional means,
Used is abbreviated as the abbreviation that this area is common.
Embodiment 1:
Take 1mmol reactant a and b, 1.5mmol DCM respectively and mol ratio is the SnCl of 1:34(C2H5)2Zn's is mixed
Compound 1g, is pre-chilled to-30 DEG C more than 2 hours, dichloromethane that volume ratio is 1:1 and ether are also pre-chilled to-30 DEG C 2 hours with
On, add reactant b, DCM and catalyst mixture the most again under cryogenic conditions, stir and continue stirring afterwards, slowly
Add reactant a, within 5 minutes, add and maintain-30 DEG C afterwards, stopped reaction after reacting 1 hour under stirring condition, isolated mesh
Mark product c.
Product is identified, obtains 0.62mmol target product (yield is 62%), and anti selectivity reaches more than 98%,
Syn selectivity is less than 2%.
The above is the preferred embodiments of the present invention, it is noted that come for those skilled in the art
Saying, on the premise of without departing from principle of the present invention, it is also possible to make some improvements and modifications, these improvements and modifications also should
It is considered as protection scope of the present invention.
Claims (3)
1. a preparation method for isostatine derivant, the structural formula of described isostatine derivant is:
Wherein R1For ethyl, it is characterised in that described preparation method includes reacting as follows:
Described reaction is carried out between-25 DEG C to-35 DEG C.
Preparation method the most according to claim 1, it is characterised in that SnCl in described reaction4(C2H5)2The mol ratio of Zn
It is 1:2-4.
Preparation method the most according to claim 2, it is characterised in that SnCl in described reaction4(C2H5)2The mol ratio of Zn
It is 1:3.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510151514.1A CN104744307B (en) | 2015-04-01 | 2015-04-01 | Isostatine derivant and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510151514.1A CN104744307B (en) | 2015-04-01 | 2015-04-01 | Isostatine derivant and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104744307A CN104744307A (en) | 2015-07-01 |
| CN104744307B true CN104744307B (en) | 2017-01-04 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN201510151514.1A Expired - Fee Related CN104744307B (en) | 2015-04-01 | 2015-04-01 | Isostatine derivant and preparation method thereof |
Country Status (1)
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4397786A (en) * | 1981-11-23 | 1983-08-09 | Merck & Co., Inc. | Method of preparing statine and derivatives |
| US4777286A (en) * | 1985-06-18 | 1988-10-11 | The Upjohn Company | Certain aryl or hetero-hydroxamic acid esters useful as renin inhibitors |
| CN1561332A (en) * | 2001-09-28 | 2005-01-05 | 弗·哈夫曼-拉罗切有限公司 | Preparation of HIV protease inhibitors |
-
2015
- 2015-04-01 CN CN201510151514.1A patent/CN104744307B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4397786A (en) * | 1981-11-23 | 1983-08-09 | Merck & Co., Inc. | Method of preparing statine and derivatives |
| US4777286A (en) * | 1985-06-18 | 1988-10-11 | The Upjohn Company | Certain aryl or hetero-hydroxamic acid esters useful as renin inhibitors |
| CN1561332A (en) * | 2001-09-28 | 2005-01-05 | 弗·哈夫曼-拉罗切有限公司 | Preparation of HIV protease inhibitors |
Non-Patent Citations (4)
| Title |
|---|
| A New Ligand Scaffold for Catalytic Asymmetric Alkylzinc Additions to Aldehydes;Peter Wipf等;《ORGANIC LETTERS》;20021231;第4卷(第7期);第1197-1200页 * |
| Aminoaldehyde-Ene Reaction:Stereoselective Route to B-Amino Alcohols;Kolchl Mikaml等;《Tetrahedron Letters》;19901231;第31卷(第27期);第3909-3912页 * |
| High Antiplasmodial Activity of Novel Plasmepsins I and II Inhibitors;Mario Dell’Agli等;《J. Med. Chem.》;20061231;第49卷;第7440-7449页 * |
| Statine及其类似物不对称合成研究进展;张伟等;《Chin. J. Org. Chem.》;20121231(第32期);第2203-2213页 * |
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| CN104744307A (en) | 2015-07-01 |
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