CN108264538A - The solid phase synthesis process of L-aminobutanedioic acid condensation product - Google Patents
The solid phase synthesis process of L-aminobutanedioic acid condensation product Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06104—Dipeptides with the first amino acid being acidic
- C07K5/06113—Asp- or Asn-amino acid
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
The present invention provides a kind of solid phase synthesis process of L-aminobutanedioic acid condensation product, includes the following steps：（1）Under deprotection agent effect, the protecting group of the immobilized amino acid of Wang resin is removed；（2）Under condensing agent effect, condensation reaction occurs for two kinds of protection type amino acid；（3）Under lytic reagent effect, deprotection base obtains L-aminobutanedioic acid condensation product.Solid phase synthesis process raw material provided by the invention is easy to get inexpensive, and synthesis cycle is short, and production cost is low, and easy post-processing, by-product is few, and product yield is high, is conducive to the extensive preparation of L-aminobutanedioic acid condensation product.
Description
Technical field
The present invention relates to technical field of organic synthesis more particularly to a kind of preparation methods of L-aminobutanedioic acid condensation product.
Background technology
Aspartic acid is mainly used for hypopotassaemia caused by treating a variety of causes, hypokalemia as electrolyte complementary medical
Arrhythmia cordis caused by periodical quadriplegia caused by disease and digitalis poisoning.Aspartic acid ornithine is mainly used for treating
The blood ammonia caused by acute and chronic hepatopathy increases, such as various hepatitis, hepatic sclerosis.Fatty liver and posthepatitic syndrome etc..It is particularly suitable
In the releasing of cental system neurological symptom caused by hepatopathy and the rescue of stupor.L-aminobutanedioic acid condensation product is door winter ammonia
The major impurity of sour potassium and aspartic acid ornithine.Its entitled 2- [(3- amino -3- pyruvic alcohols base) amino] succinic acid of chemistry,
Structural formula is as follows：
Chinese patent CN105566141A（Application number 201510965114.4）Disclose a kind of preparation of L-aminobutanedioic acid condensation product
Method occurs esterification using L-aminobutanedioic acid and alcohol, obtains L-aminobutanedioic acid diester, then with Boc-L- aspartic acid -1- benzyls
Ester condensation, then hydrolyze to obtain L-aminobutanedioic acid condensation product crude product, finally by column chromatography, it is recrystallized to give L-aminobutanedioic acid condensation product.
This method is cumbersome, and the reaction time is long, and it is all grease often to walk intermediate, it is difficult to purify, directly result in L-aminobutanedioic acid condensation
Containing a large amount of impurity in object crude product, the not high viscous solid of purity is also can only obtain even across column chromatography and after recrystallizing.
Americanized scholar Merrifield in 1963 is carrier with solid-phase resin, has invented the synthesis peptides chemical combination on resin
The method of object opens a brand-new field of Synthetic Organic Chemistry：Synthesis in solid state chemistry, the development to chemistry and life science
Important influence is produced, Nobel chemistry Prize was obtained in 1984.Synthesis in solid state is exactly to be connected to solid phase by certain mode
The chemical reaction that the chemical constituent of carrier is carried out by solvent medium with other chemical constituents.Reaction substrate is connected to table first
On solid phase carrier of the face Jing Guo functionalized modification, it is subsequently placed in solvent with other non-immobilized chemical constituents in solid-liquid intersection
It is chemically reacted.It is filtered after reaction by simple, after washing and drying, so that it may carry out next step reaction or by suitable
When reaction final product is cut down from solid phase carrier.
Compared with traditional liquid-phase chemical reaction, synthesis in solid state simplifies post-reaction treatment process, and filtered and washing is just
Remaining chemical reagent and soluble impurity in solution can be removed；Secondly, large excess of reaction reagent can be applied, improves conversion
Rate or by repeating identical reaction, makes reaction tend to be complete；Third, reaction substrate are fixed on stationary phase by linking group
It on carrier, limits and mutually collides between substrate molecule, also referred to as " false dilution effect ", avoid what reaction between substrate molecule generated
By-product.
Invention content
Of the existing technology to solve the problems, such as, the present invention provides a kind of solid phase synthesis process of L-aminobutanedioic acid condensation product.
This method raw material is easy to get inexpensive, and synthesis cycle is short, and production cost is low, and easy post-processing, by-product is few, and product yield is high, favorably
In the extensive preparation of L-aminobutanedioic acid condensation product.
A kind of solid phase synthesis process of L-aminobutanedioic acid condensation product, includes the following steps：
（1）Under deprotection agent effect, the protecting group of the immobilized amino acid of Wang resin is removed；
（2）Under condensing agent effect, condensation reaction occurs for two kinds of protection type amino acid；
（3）Under lytic reagent effect, deprotection base obtains L-aminobutanedioic acid condensation product.
Wherein, step（1）Concrete operations be：Resin is added in immersion 2h in DMF to be fully swollen, adds in deprotection agent,
45min is stirred, filtering is washed with DMF, takes out a small amount of resin, adds in reagent A and reagent B, boiling water bath heating 5min, if resin
For aubergine, then protecting group removing is complete, if resin is light red or yellow, needs to extend the deprotection time.
The resin be Fmoc-Asp (OtBu)-Wang resin, Fmoc-Asp-OAll-Wang Resin, the resin
Substitution degree be 0.3-0.8mmol/g.
The deprotection agent is the DMF solution of 25%PIP.
The ratio of the deprotection agent and the immobilized amino acid of Wang resin is preferably 20-80（ml：mmol）, further preferably
40-60（ml：mmol）.
The reagent A is the ethanol solution of 5% ninhydrin.
The reagent B is the ethanol solution of 80% phenol.
Wherein, step（2）Concrete operations be：Resin is added in DMF, adds in condensing agent C, condensing agent D, another protection
2h is stirred at room temperature in type L-aminobutanedioic acid, and filtering is washed with DMF, takes out a small amount of resin, adds in reagent A and reagent B, boiling water bath heating
5min, if resin is light red or yellow, condensation reaction is complete, if resin is aubergine, needs to extend the condensation time.
The another kind protection type amino acid is Ac-Asp-OtBu, Boc-Asp-OMe, Boc-Asp-OBzl, Boc-Asp-
OtBu。
The ratio of the another kind protection type amino acid and the immobilized amino acid of Wang resin is preferably 1-2（mmol：mmol）, into
One step is preferably 1-1.5（mmol：mmol）.
The condensing agent C is the DMF solution of 0.48mol/molHOBT.
The condensing agent D is the DMF solution of 0.48mol/molDIC.
The ratio of the condensing agent C and the immobilized amino acid of Wang resin is preferably 6-10（ml：mmol）, further preferably 8-
10（ml：mmol）.
The ratio of the condensing agent D and the immobilized amino acid of Wang resin is preferably 6-10（ml：mmol）, further preferably 8-
10（ml：mmol）.
The reagent A is the ethanol solution of 5% ninhydrin.
The reagent B is the ethanol solution of 80% phenol.
Wherein, step（3）Concrete operations be：Resin peptide is taken, lytic reagent is added in, 2h is stirred at room temperature, is filtered, filtrate adds
Enter in anhydrous ether, filter, anhydrous ether washing obtains L-aminobutanedioic acid condensation product.
The lytic reagent is TFA：Dithioglycol：Thioanisole：Phenol：Water=85：5：5：4：1.
The ratio of the lytic reagent and the immobilized amino acid of Wang resin is preferably 20-80（ml：mmol）, further preferably
40-60（ml：mmol）.
Specific embodiment
The meaning of english abbreviation used in specification and claims is listed in the following table.
| DMF | Dimethylformamide |
| Fmoc-Asp(OtBu)-Wang resin | N- fluorenylmethyloxycarbonyls-L-Aspartic acid 4- tert-butyl ester Wang resins |
| Fmoc-Asp-OAll-Wang Resin | N- fluorenylmethyloxycarbonyls-L-Aspartic acid 1- allyl ester Wang resins |
| PIP | Piperidines |
| Ac-Asp-OtBu | N- acetyl group-ASPARTIC ACID 1- methyl esters |
| Boc-Asp-OMe | N- tertbutyloxycarbonyls-ASPARTIC ACID 1- methyl esters |
| Boc-Asp-OBzl | N- tertbutyloxycarbonyls-ASPARTIC ACID 1- benzyl esters |
| Boc-Asp-OtBu | N- tertbutyloxycarbonyls-L-Aspartic acid 1- the tert-butyl esters |
| DIC | Diisopropylcarbodiimide |
| TFA | Trifluoroacetic acid |
The following examples are used to illustrate the present invention, but are not intended to limit the scope of the present invention..Unless otherwise specified, institute in embodiment
The conventional means that technological means is well known to those skilled in the art, raw materials used is commercial goods.
Embodiment 1
By Fmoc-Asp (OtBu)-Wang resin（Substitution degree 0.3mmol/g）1.00g is added in DMF15ml, is impregnated 2h and is filled
Divide swelling, add in deprotection agent 15ml, stir 45min, filtering is washed with DMF, takes out a small amount of resin, addition reagent A 0.02ml
With reagent B0.08ml, boiling water bath heating 5min, if resin is aubergine, protecting group removing is complete, if resin for light red or
Yellow then needs to extend the deprotection time.
After deprotection completely, deprotection resin is added in DMF15ml, adds in Ac-Asp-OtBu83mg
（0.36mmol）, 2h is stirred at room temperature in condensing agent C2.5ml, condensing agent D2.5ml, filters, is washed with DMF, take out a small amount of resin,
Reagent A and reagent B are added in, boiling water bath heating 5min, if resin is light red or yellow, condensation reaction is complete, if resin is
Aubergine then needs to extend the condensation time.
After condensation completely, resin peptide is taken, lytic reagent 15ml is added in, 2h is stirred at room temperature, is filtered, filtrate is added to anhydrous second
In ether 15ml, filtering, anhydrous ether washing obtains white solid 67mg, yield 90.1%.
Embodiment 2
By Fmoc-Asp-OAll-Wang Resin（Substitution degree 0.3mmol/g）1.00g is added in DMF15ml, is impregnated 2h and is filled
Divide swelling, add in deprotection agent 15ml, stir 45min, filtering is washed with DMF, takes out a small amount of resin, addition reagent A 0.02ml
With reagent B0.08ml, boiling water bath heating 5min, if resin is aubergine, protecting group removing is complete, if resin for light red or
Yellow then needs to extend the deprotection time.
After deprotection completely, deprotection resin is added in DMF15ml, adds in Boc-Asp-OMe89mg
（0.36mmol）, 2h is stirred at room temperature in condensing agent C2.5ml, condensing agent D2.5ml, filters, is washed with DMF, take out a small amount of resin,
Reagent A and reagent B are added in, boiling water bath heating 5min, if resin is light red or yellow, condensation reaction is complete, if resin is
Aubergine then needs to extend the condensation time.
After condensation completely, resin peptide is taken, lytic reagent 15ml is added in, 2h is stirred at room temperature, is filtered, filtrate is added to anhydrous second
In ether 15ml, filtering, anhydrous ether washing obtains white solid 64mg, yield 86.0%.
Embodiment 3
By Fmoc-Asp (OtBu)-Wang resin（Substitution degree 0.3mmol/g）100.00g is added in DMF1500ml, is impregnated
2h is fully swollen, and adds in deprotection agent 15ml, stirs 45min, and filtering is washed with DMF, takes out a small amount of resin, adds in reagent
A2ml and reagent B8ml, boiling water bath heating 5min, if resin is aubergine, protecting group removing is complete, if resin is light red
Or yellow, then it needs to extend the deprotection time.
After deprotection completely, deprotection resin is added in DMF1500ml, adds in Ac-Asp-OtBu8.32g
（36mmol）, condensing agent C250ml, condensing agent D250ml are stirred at room temperature 2h, filter, washed with DMF, take out a small amount of resin, add
Enter reagent A and reagent B, boiling water bath heating 5min, if resin is light red or yellow, condensation reaction is complete, if resin is purple
Red then needs to extend the condensation time.
After condensation completely, resin peptide is taken, lytic reagent 1500ml is added in, 2h is stirred at room temperature, is filtered, filtrate is added to anhydrous
In ether 150ml, filtering, anhydrous ether washing obtains white solid 7.06g, yield 94.9%.
Embodiment 4
By Fmoc-Asp-OAll-Wang Resin（Substitution degree 0.3mmol/g）100.00g is added in DMF1500ml, is impregnated
2h is fully swollen, and adds in deprotection agent 15ml, stirs 45min, and filtering is washed with DMF, takes out a small amount of resin, adds in reagent
A2ml and reagent B8ml, boiling water bath heating 5min, if resin is aubergine, protecting group removing is complete, if resin is light red
Or yellow, then it needs to extend the deprotection time.
After deprotection completely, deprotection resin is added in DMF1500ml, adds in Boc-Asp-OBzl11.63g
（36mmol）, condensing agent C250ml, condensing agent D250ml are stirred at room temperature 2h, filter, washed with DMF, take out a small amount of resin, add
Enter reagent A and reagent B, boiling water bath heating 5min, if resin is light red or yellow, condensation reaction is complete, if resin is purple
Red then needs to extend the condensation time.
After condensation completely, resin peptide is taken, lytic reagent 1500ml is added in, 2h is stirred at room temperature, is filtered, filtrate is added to anhydrous
In ether 150ml, filtering, anhydrous ether washing obtains white solid 6.74g, yield 90.6%.
Although above having used general explanation, specific embodiment and experiment, the present invention is done and has been retouched in detail
It states, but on the basis of the present invention, it can be modified and improved, this is apparent to those skilled in the art
's.Therefore, these modification and improvement done without departing from theon the basis of the spirit of the present invention, belong to claimed
Range.
Claims (7)
1. a kind of solid phase synthesis process of L-aminobutanedioic acid condensation product, which is characterized in that the solid phase synthesis process includes following step
Suddenly：
（1）Under deprotection agent effect, the protecting group of the immobilized amino acid of Wang resin is removed；
（2）Under condensing agent effect, condensation reaction occurs for two kinds of protection type amino acid；
（3）Under lytic reagent effect, deprotection base obtains L-aminobutanedioic acid condensation product.
2. preparation method according to claim 1, it is characterised in that：Step（1）Concrete operations be：Resin is added in
2h is impregnated in DMF to be fully swollen, adds in deprotection agent, stirs 45min, and filtering is washed with DMF, takes out a small amount of resin, adds in examination
Agent A and reagent B, boiling water bath heating 5min, if resin is aubergine, protecting group removing is complete, if resin is light red or Huang
Color then needs to extend the deprotection time.
3. preparation method according to claim 2, it is characterised in that：The resin is Fmoc-Asp (OtBu)-Wang
Resin, Fmoc-Asp-OAll-Wang Resin；
And/or the substitution degree of the resin is 0.3-0.8mmol/g；
And/or the DMF solution that the deprotection agent is 25%PIP；
And/or the ratio of the deprotection agent and the immobilized amino acid of Wang resin is 40-60（ml：mmol）；
And/or the ethanol solution that the reagent A is 5% ninhydrin；
And/or the ethanol solution that the reagent B is 80% phenol.
4. according to the preparation method described in claim 1-3, it is characterised in that：Step（2）Concrete operations be：Resin adds in
In DMF, condensing agent C, condensing agent D, another protection type L-aminobutanedioic acid are added in, 2h is stirred at room temperature, filters, is washed with DMF, takes out
A small amount of resin adds in reagent A and reagent B, and boiling water bath heating 5min, if resin is light red or yellow, condensation reaction is complete,
If resin is aubergine, need to extend the condensation time.
5. preparation method according to claim 4, it is characterised in that：The another kind protection type amino acid is Ac-Asp-
OtBu, Boc-Asp-OMe, Boc-Asp-OBzl, Boc-Asp-OtBu；
And/or the ratio of another protection type amino acid and the immobilized amino acid of Wang resin is 1-1.5（mmol：mmol）；
And/or the DMF solution that the condensing agent C is 0.48mol/molHOBT；
And/or the DMF solution that the condensing agent D is 0.48mol/molDIC；
And/or the ratio of the condensing agent C and the immobilized amino acid of Wang resin is 8-10（ml：mmol）；
And/or the ratio of the condensing agent D and the immobilized amino acid of Wang resin is 8-10（ml：mmol）；
And/or the ethanol solution that the reagent A is 5% ninhydrin；
And/or the ethanol solution that the reagent B is 80% phenol.
6. according to the preparation method described in claim 1-5, it is characterised in that：Step（3）Concrete operations be：Take resin peptide,
Lytic reagent is added in, 2h is stirred at room temperature, is filtered, filtrate is added in anhydrous ether, filtering, and anhydrous ether washing obtains winter ammonia
Sour condensation product.
7. preparation method according to claim 6, it is characterised in that：The lytic reagent is TFA：Dithioglycol：Fennel
Thioether：Phenol：Water=85：5：5：4：1；
And/or the ratio of the lytic reagent and the immobilized amino acid of Wang resin is 40-60（ml：mmol）.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710003723.0A CN108264538B (en) | 2017-01-04 | 2017-01-04 | Solid Phase Synthesis Method of Aspartic Acid Condensate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710003723.0A CN108264538B (en) | 2017-01-04 | 2017-01-04 | Solid Phase Synthesis Method of Aspartic Acid Condensate |
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| Publication Number | Publication Date |
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| CN108264538A true CN108264538A (en) | 2018-07-10 |
| CN108264538B CN108264538B (en) | 2023-08-29 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113354711A (en) * | 2021-06-04 | 2021-09-07 | 温州肯恩大学 | Anticancer bioactive peptide and synthesis method thereof |
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|---|---|---|---|---|
| WO2000071570A1 (en) * | 1999-05-20 | 2000-11-30 | Lipotec, S.A. | Solid phase peptide synthesis method |
| WO2005121181A1 (en) * | 2004-06-11 | 2005-12-22 | Beijing Jenkem Technology Co., Ltd. | Multi-drop tree branching polyethylene glycol-oligopeptides and active derivates and pharmaceutical compounds there of |
| CN102286092A (en) * | 2011-09-14 | 2011-12-21 | 深圳翰宇药业股份有限公司 | Solid-phase synthesis method of liraglutide |
| CN104262185A (en) * | 2014-10-09 | 2015-01-07 | 中国食品发酵工业研究院 | Method for solid-phase synthesis of potassium aspartate at room temperature |
| CN105566141A (en) * | 2015-12-17 | 2016-05-11 | 蚌埠丰原医药科技发展有限公司 | Method for preparing aspartate condensation compound |
-
2017
- 2017-01-04 CN CN201710003723.0A patent/CN108264538B/en active Active
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|---|---|---|---|---|
| WO2000071570A1 (en) * | 1999-05-20 | 2000-11-30 | Lipotec, S.A. | Solid phase peptide synthesis method |
| WO2005121181A1 (en) * | 2004-06-11 | 2005-12-22 | Beijing Jenkem Technology Co., Ltd. | Multi-drop tree branching polyethylene glycol-oligopeptides and active derivates and pharmaceutical compounds there of |
| CN102286092A (en) * | 2011-09-14 | 2011-12-21 | 深圳翰宇药业股份有限公司 | Solid-phase synthesis method of liraglutide |
| CN104262185A (en) * | 2014-10-09 | 2015-01-07 | 中国食品发酵工业研究院 | Method for solid-phase synthesis of potassium aspartate at room temperature |
| CN105566141A (en) * | 2015-12-17 | 2016-05-11 | 蚌埠丰原医药科技发展有限公司 | Method for preparing aspartate condensation compound |
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| RAYMOND BEHRENDT ET AL.: ""Advances in Fmoc solid-phase peptide synthesis"", 《J. PEPT. SCI.》 * |
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| CN113354711A (en) * | 2021-06-04 | 2021-09-07 | 温州肯恩大学 | Anticancer bioactive peptide and synthesis method thereof |
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