CN104744308B - ISO-AHPPA derivative and preparation method thereof - Google Patents
ISO-AHPPA derivative and preparation method thereof Download PDFInfo
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- CN104744308B CN104744308B CN201510151735.9A CN201510151735A CN104744308B CN 104744308 B CN104744308 B CN 104744308B CN 201510151735 A CN201510151735 A CN 201510151735A CN 104744308 B CN104744308 B CN 104744308B
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- Prior art keywords
- ahppa
- iso
- preparation
- derivative
- present
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- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 13
- 238000000034 method Methods 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 abstract description 3
- HQWPLXHWEZZGKY-UHFFFAOYSA-N diethylzinc Chemical compound CC[Zn]CC HQWPLXHWEZZGKY-UHFFFAOYSA-N 0.000 abstract description 3
- 239000000203 mixture Substances 0.000 abstract description 3
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 abstract 2
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 abstract 2
- 238000009776 industrial production Methods 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- DFVFTMTWCUHJBL-BQBZGAKWSA-N statine Chemical compound CC(C)C[C@H](N)[C@@H](O)CC(O)=O DFVFTMTWCUHJBL-BQBZGAKWSA-N 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 229930014626 natural product Natural products 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- -1 amido aldehyde Chemical class 0.000 description 2
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- GHCBYDBRCQYPPL-XKSSXDPKSA-N (3r,4s,5s)-3-methoxy-5-methyl-4-(methylamino)heptanoic acid Chemical compound CC[C@H](C)[C@H](NC)[C@H](OC)CC(O)=O GHCBYDBRCQYPPL-XKSSXDPKSA-N 0.000 description 1
- 101710110426 Aspartyl protease inhibitor Proteins 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 238000005882 aldol condensation reaction Methods 0.000 description 1
- 239000003696 aspartic proteinase inhibitor Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 235000014121 butter Nutrition 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- JFOZKMSJYSPYLN-QHCPKHFHSA-N lifitegrast Chemical compound CS(=O)(=O)C1=CC=CC(C[C@H](NC(=O)C=2C(=C3CCN(CC3=CC=2Cl)C(=O)C=2C=C3OC=CC3=CC=2)Cl)C(O)=O)=C1 JFOZKMSJYSPYLN-QHCPKHFHSA-N 0.000 description 1
- 229950000964 pepstatin Drugs 0.000 description 1
- 108010091212 pepstatin Proteins 0.000 description 1
- FAXGPCHRFPCXOO-LXTPJMTPSA-N pepstatin A Chemical compound OC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](C(C)C)NC(=O)[C@H](C(C)C)NC(=O)CC(C)C FAXGPCHRFPCXOO-LXTPJMTPSA-N 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Catalysts (AREA)
Abstract
The invention discloses an ISO-AHPPA derivative and a preparation method thereof. According to the preparation method of the ISO-AHPPA derivative, a mixture of diethyl zinc and stannic chloride is used as the catalyst, wherein the mole ratio of the diethyl zinc and the stannic chloride is (2-4):1. The reaction temperature and the yield rate are improved in the preparation method of the ISO-AHPPA derivative, so that the preparation method of the ISO-AHPPA derivative is more suitable for industrial production.
Description
Technical field
The present invention relates to chemical technology field, it is specifically related to a kind of iso-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, iso-ahppa, ahmpa etc.
Deng.In view of the structure (especially stereochemical structure) of this kind of compound has important impact to the activity of parent compound, so seeking
The synthetic method looking for highly-solid selectively is to make up the rare important means of natural products, is also beneficial to these natural products are entered
Row transformation, strengthens activity, drops 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 iso-ahppa to spread out
Biology and preparation method thereof, improves 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 iso-ahppa derivative it is characterised in that the knot of described iso-ahppa derivative
Structure formula 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 iso-ahppa derivative it is characterised in that described
Preparation method include 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 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 is the dichloromethane and ether 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 2-4:1 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 1:3 respectively4(c2h5)2Zn's is mixed
Compound 1g, is pre-chilled to -30 DEG C more than 2 hours, by the dichloromethane for 1:1 for the volume ratio and ether be also pre-chilled to -30 DEG C 2 hours with
On, add reactant b, dcm and catalyst mixture under cryogenic conditions more successively, continue stirring after stirring, slowly
Add reactant a, after adding within 5 minutes, maintain -30 DEG C, reaction under stirring condition stops reaction in 1 hour afterwards, separates and obtains mesh
Mark product c.
Product is identified, obtains 0.56mmol target product (yield is 56%), anti selectively reaches more than 97%,
Syn 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 (4)
1. a kind of preparation method of iso-ahppa derivative, the structural formula of described iso-ahppa derivative is:
Wherein r1For ethyl；
It is characterized in that described preparation method includes reacting as follows:
Described reaction is carried out between -25 DEG C to -35 DEG C.
2. method according to claim 1, described r1For ethyl.
3. method according to claim 2 is it is characterised in that sncl in described reaction4(c2h5)2The mol ratio of zn is 1:
2-4.
4. method according to claim 3 is it is characterized in that sncl in described reaction4(c2h5)2The mol ratio of zn is 1:
3.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510151735.9A CN104744308B (en) | 2015-04-01 | 2015-04-01 | ISO-AHPPA derivative and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510151735.9A CN104744308B (en) | 2015-04-01 | 2015-04-01 | ISO-AHPPA derivative and preparation method thereof |
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| Publication Number | Publication Date |
|---|---|
| CN104744308A CN104744308A (en) | 2015-07-01 |
| CN104744308B true CN104744308B (en) | 2017-01-18 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN201510151735.9A Expired - Fee Related CN104744308B (en) | 2015-04-01 | 2015-04-01 | ISO-AHPPA derivative and preparation method thereof |
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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 CN201510151735.9A patent/CN104744308B/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 (3)
| 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 * |
| 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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| Publication number | Publication date |
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| CN104744308A (en) | 2015-07-01 |
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Granted publication date: 20170118 Termination date: 20170401 |