CN104817475B - AHPPA derivatives and preparation method thereof - Google Patents
AHPPA derivatives and preparation method thereof Download PDFInfo
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- CN104817475B CN104817475B CN201510151378.6A CN201510151378A CN104817475B CN 104817475 B CN104817475 B CN 104817475B CN 201510151378 A CN201510151378 A CN 201510151378A CN 104817475 B CN104817475 B CN 104817475B
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Abstract
The invention discloses AHPPA derivatives and a preparation method thereof. The preparation method utilizes a diethylzinc-stannic chloride mixture with a mole ratio of 1: 2-4 as a catalyst, improves a reaction temperature and a yield and is suitable for industrial production.
Description
Technical field
The present invention relates to chemical technology field, it is specifically related to a kind of ahppa derivative and preparation method thereof.
Background technology
20 century 70s, Japanese researchers umezawa etc. is separated to aspartyl protease inhibitor pepstatin,
A kind of brand-new beta-hydroxy-gamma-amino acid (3s, 4s) -4- amino -3- hydroxyl -6- methyl is occurred in that first in its structure
Enanthic acid (statine). further investigation finds, statine is the required fragment of activity of parent compound, by simulating peptide chain enzymolysis
Tetrahedron transition state and play pharmacological action.
Later, people were found that statine and its knot in multiple natural products with valuable pharmacological activity again successively
Structure analog, these analogs include isostatine, dolaisoleuine, dolaproine, ahppa, ahmpa etc..Mirror
Structure (especially stereochemical structure) in this kind of compound has important impact to the activity of parent compound, so finding Gao Li
The selective synthetic method of body is to make up the rare important means of natural products, is also beneficial to these natural products are changed
Make, strengthen activity, drop hypotoxic purpose to reaching.
The method that there is substantial amounts of synthesis statine analog in prior art, such as mikami etc. is by amino with double benzyls
The amido aldehyde of base protection, in etalcl2In the presence of, aldol condensation shows the anti of height selectively；And amino with
The amido aldehyde of boc protection, in sncl4Higher syn is then given selectively under mediation.But the subject matter that the method exists is
On the one hand reaction needs to carry out at -78 DEG C, and yield is also only capable of reaching 41% about, therefore how to provide a kind of reaction condition more
For gentle, the preparation method that yield is more capable of industrialized production purpose is that those skilled in the art's technology urgently to be resolved hurrily is asked
Topic.
Content of the invention
The present invention is directed to the deficiencies in the prior art, tests by the screening of several years and repeatedly, provides a kind of ahppa derivative
And preparation method thereof, improve reaction temperature and yield.In order to realize the purpose of the present invention, intend adopting the following technical scheme that
One aspect of the present invention is related to a kind of ahppa derivative it is characterised in that the structural formula of described ahppa derivative is:
Wherein r1Selected from c1-c6Alkyl it is preferred that described r1For ethyl.
In another aspect of this invention, further relate to the preparation method of above-mentioned ahppa derivative it is characterised in that described system
Preparation Method includes reacting as follows:
In a preferred embodiment of the present invention it is characterised in that described reaction in sncl4(c2h5)2Zn rubs
Your ratio is 2-4:1, preferably 3:1.
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 is the dichloromethane and hexamethylene that volume ratio is 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 adopts the diethyl zinc of mol ratio 1:2-4 and butter of tin mixture as catalyst and to mix
Bonding solvent, improves reaction temperature and yield, is conducive to industrialized production.
Specific embodiment
If not specified, the conventional meanses that in embodiment, technological means used is well known to those skilled in the art,
Adopted is abbreviated as the common abbreviation in this area.
Embodiment 1:
Take the sncl that 1mmol reactant a and b, 1.5mmol dcm and mol ratio are 3:1 respectively4(c2h5)2Zn's is mixed
Compound 1g, is pre-chilled to -30 DEG C more than 2 hours, and the dichloromethane for 1:1 for the volume ratio and hexamethylene are also pre-chilled to -30 DEG C 2 hours
More than, add reactant b, dcm and catalyst mixture under cryogenic conditions more successively, after stirring, continue stirring, delay
Slow addition reactant a, maintains -30 DEG C after adding within 5 minutes, and reaction under stirring condition stops reacting for 1 hour afterwards, separates and obtains
Target product c.
Product is identified, obtains 0.58mmol target product (yield is 58%), syn selectively reaches more than 97%,
Anti is selectively less than 3%.
The above is the preferred embodiments of the present invention it is noted that coming for those skilled in the art
Say, on the premise of without departing from principle of the present invention, some improvements and modifications can also be made, these improvements and modifications also should
It is considered as protection scope of the present invention.
Claims (3)
1. a kind of preparation method of ahppa derivative, the structural formula of described ahppa derivative 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.
2. preparation method according to claim 1 is it is characterised in that sncl in described reaction4(c2h5)2The mol ratio of zn
It is 2-4:1.
3. preparation method according to claim 2 is it is characterised in that sncl in described reaction4(c2h5)2The mol ratio of zn
It is 3:1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510151378.6A CN104817475B (en) | 2015-04-01 | 2015-04-01 | AHPPA derivatives and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510151378.6A CN104817475B (en) | 2015-04-01 | 2015-04-01 | AHPPA derivatives and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104817475A CN104817475A (en) | 2015-08-05 |
| CN104817475B true CN104817475B (en) | 2017-01-18 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN201510151378.6A Expired - Fee Related CN104817475B (en) | 2015-04-01 | 2015-04-01 | AHPPA derivatives and preparation method thereof |
Country Status (1)
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0202577A2 (en) * | 1985-05-15 | 1986-11-26 | G.D. Searle & Co. | N(Acyldipeptidyl)-aminoglycols |
| 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 CN201510151378.6A patent/CN104817475B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0202577A2 (en) * | 1985-05-15 | 1986-11-26 | G.D. Searle & Co. | N(Acyldipeptidyl)-aminoglycols |
| 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;Kolchi Mikami等;《Tetrahedron Letters》;19901231;第31卷(第27期);第3909-3912页 * |
| Exploring β‑Hydroxy γ‑Amino Acids (Statines) in the Design of Hybrid Peptide Foldamers;Anupam Bandyopadhyay等;《Org. Lett》;20131109;第16卷;第294-297页 * |
| Statine及其类似物不对称合成研究进展;张伟;《Chin. J. Org. Chem》;20121231;第32卷;第2203-2213页 * |
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|---|---|
| CN104817475A (en) | 2015-08-05 |
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