CN1978436A - Polypeptide synthetic condensation agent 3-hydroxy-4-oxy-3,4-dihydro-1,2,3-benzotriazozine synthesizing method - Google Patents
Polypeptide synthetic condensation agent 3-hydroxy-4-oxy-3,4-dihydro-1,2,3-benzotriazozine synthesizing method Download PDFInfo
- Publication number
- CN1978436A CN1978436A CN 200510126588 CN200510126588A CN1978436A CN 1978436 A CN1978436 A CN 1978436A CN 200510126588 CN200510126588 CN 200510126588 CN 200510126588 A CN200510126588 A CN 200510126588A CN 1978436 A CN1978436 A CN 1978436A
- Authority
- CN
- China
- Prior art keywords
- formula
- reaction
- dihydro
- iii
- naoh
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Landscapes
- Peptides Or Proteins (AREA)
Abstract
This invention discloses a composing method of polypeptide synthesis condensing agent that is 3-hydroxide radical-4-oxygen-3,4-dihydro-1,2,3- benzotriazin. This method uses methyl anthranilate as initiation factors. Target product is obtained by three step reaction with easily obtained raw material that is low poison. This invention has characteristics such as raw material is easily obtained, route is simple, noxious property is low, side reaction is little, it easily attributes, overall yield is suitable.
Description
Technical field:
The present invention relates to a kind of condensing agent for synthesizing polypeptide 3-hydroxyl-4-oxygen-3,4-dihydro-1,2,3-benzene a pair of horses going side by side three nitrogen piperazine (HOOBt) synthetic methods.
Background technology:
In the solid phase synthesis of polypeptide or peptide nucleic acid(PNA), the selection of condensing agent not only has influence on the condensation productive rate, and may influence the configuration of target.Therefore, select high reactivity, low side reaction, easily separated, condensing agent is a solid-phase peptide synthetic key always cheaply.
Nineteen fifty-five, sheehan and Hess are first with N, and it is synthetic that N-dicyclohexylcarbodiimide (DCC) is used for polypeptide, obtains good result.But DCC condensation active polypeptide intermediate is easily reset in the presence of triethylamine, and the danger that perhaps has racemization to take place causes condensation efficiency lower.
1966, Wiinsch and Dress found to add N-Hydroxysuccinimide (HOSu) in the DCC condensation reaction, have improved the polypeptide productive rate greatly, have suppressed racemization and rearrangement reaction.Therefore, on this basis, people further attempt and have developed a series of N-hydroxy derivatives.Wherein commonly used relatively with 1-hydroxyl benzotriazole (HOBt) and 3-hydroxyl-4-oxygen-3,4-dihydro-1,2,3-benzene a pair of horses going side by side three nitrogen piperazines (HOOBt).And (HOOBt) be the most effective coupling condenser agent that reduces racemization.
In addition, HBTU and the HATU (phosphorus-(7-pyridine triazol-1-yl)-1,1 of comparing, 3,3-tetramethyl-urea hexafluorophosphate) etc. urea salt is (HOOBt) not only with low cost, main is in the condensation reaction, not exist urea salt such as HBTU and HATU to generate the side reaction of guanidinesalt with primary amine reaction.Therefore, HOOBt is an ideal polypeptide synthetic condensation agent reagent.
Summary of the invention:
The object of the present invention is to provide a kind of ideal polypeptide synthetic condensation agent reagent 3-hydroxyl-4-oxygen-3,4-dihydro-1,2, the synthetic method of 3-benzene a pair of horses going side by side three nitrogen piperazines (HOOBt).
The present invention realizes by following measure:
3-hydroxyl-4-oxygen-3,4-dihydro-1,2, the structural formula of 3-benzene a pair of horses going side by side three nitrogen piperazines (HOOBt) are suc as formula (I) compound:
The present invention is initiator with the methyl o-aminobenzoate, and the raw material that is easy to get with other low toxicity obtains target compounds of formula (I) through three-step reaction.
A kind of condensing agent for synthesizing polypeptide 3-hydroxyl-4-oxygen-3,4-dihydro-1,2, the synthetic method of 3-benzene a pair of horses going side by side three nitrogen piperazines (HOOBt) is characterized in that this method may further comprise the steps successively:
A. use the NH of formula (II)
2NaOH reaction production (IV) NH of OHHCl and formula (III)
2OH
NH
2OH·HCl NaOH NH
2OH
II III IV
B. use the NH of formula (IV)
22-(the H of OH and formula V
2N) C
6H
4CO
2CH
3Reaction production (VI)
C. use the 2-(H of formula (VI)
2N) C
6H
4The NaNO of CONHOH and formula (VII)
2Reaction production (I)
In above-mentioned synthetic method, A step of the present invention, is reacted under 12～24 hours the condition of-5 ℃～room temperature reaction as reaction medium with water.
The NH of A step Chinese style of the present invention (II)
2The NaOH mol ratio of OHHCl and formula (III) is 1: 0.9～1.3.
In the A step of the present invention, the NH of formula (II)
2The mol ratio of OHHCl and reaction medium is 1: 0.9～3.3.
In above-mentioned synthetic method, B step of the present invention is with H
2O solution reacts under 48-96 hour condition of-5 ℃～room temperature reaction as reaction medium.
In the B step of the present invention, the NH of formula (IV)
22-(the H of OH and formula V
2N) C
6H
4CO
2CH
3Mol ratio is 1: 1.3～1.7.
In above-mentioned synthetic method, C step of the present invention is a reaction medium with the HCl aqueous solution, reacts under 1～3 hour the condition of-10 ℃～room temperature reaction.
In the C step of the present invention, the 2-(H of formula (VI)
2N) C
6H
4The NaNO of CONHOH and formula (VII)
2Mol ratio is 1: 1.2～1.5.
Involved in the present invention to the synthetic of HOOBt can represent with following chemical equation:
Raw material involved in the present invention such as methyl o-aminobenzoate, oxyammonia, Sodium Nitrite etc. are common economic reagent, toxicity is low; Synthetic route is simple, only needs for three steps can obtain target product; The reaction conditions gentleness, side reaction is few, and product is easy to separate, but normal temperature is deposited; Target product has the obvious characteristic infrared absorption peak, can determine by Infrared Characterization; The moderate characteristics such as (about 80%) of reaction overall yield.
Embodiment:
In order to understand the present invention better, describe by example.
Embodiment 1:
Get 48g sodium hydroxide and be dissolved in the 300ml water, be cooled to room temperature, add oxammonium hydrochloride 41.6g altogether under stirring in batches, drip 38.7ml 2-Methyl anthranilate and 30ml methyl alcohol mixed liquor.Reaction is 3 days under the room temperature.Underpressure distillation is to the sodium salt precipitation that white occurs (having the 100ml mother liquor this moment approximately).Cooling back suction filtration, the precipitation petroleum ether, dry that white solid is total to 38g.
Obtained white solid (1) is dissolved in the 60ml concentrated hydrochloric acid, with the dilution of 700ml water.Under temperature control 0-5 ℃ stirring, drip sodium nitrite solution (the 16g Sodium Nitrite is dissolved in the 500ml water), diazotization.Solution at room temperature continues stirring reaction 45min.Solution filters, and oven dry precipitates to such an extent that white solid (2) is total to 22.8g.
IR data characterization (the cm of target product
-1)
3423 ν
O-H VS
3091，3035 ν
N＝N＝N VS
1673，1636 ν
C＝O VS
1272 ν
N＝N S
Claims (7)
1, a kind of condensing agent for synthesizing polypeptide 3-hydroxyl-4-oxygen-3,4-dihydro-1,2,3-benzene a pair of horses going side by side three nitrogen piperazine (HOOBt) synthetic methods is characterized in that this method may further comprise the steps successively:
A. use the NH of formula (II)
2NaOH reaction production (IV) NH of OHHCl and formula (III)
2OH
NH
2OH·HCl NaOH NH
2OH
II III IV
B. use the NH of formula (IV)
22-(the H of OH and formula V
2N) C
6H
4CO
2CH
32-(the H of reaction production (VI)
2N) C
6H
4CONHOH
C. use the 2-(H of formula (VI)
2N) C
6H
4The NaNO of CONHOH and formula (VII)
2The HOOBt of reaction production (I)
NaNO
2
VII I
2, as the said method of claim 1, it is characterized in that the A step with water as reaction medium, react under 12～24 hours the condition of-5 ℃～room temperature reaction.
3,, it is characterized in that the NH of A step Chinese style (II) as the said method of claim 1
2The NaOH mol ratio of OH and formula (III) is 1: 0.9～1.3.
4, as the said method of claim 1, it is characterized in that the B step with water as reaction medium, react under 48-96 hour the condition of-5 ℃～room temperature reaction.
5,, it is characterized in that the NH of B step Chinese style (II) as the said method of claim 1
2The NaOH mol ratio of OH and formula (III) is 1: 0.9～1.3.
6,, it is characterized in that the C step is a reaction medium with the HCl aqueous solution, reacts under 1～3 hour the condition of-10 ℃～room temperature reaction as the said method of claim 1.
7,, it is characterized in that the 2-(H of C step formula (VI) as the said method of claim 1
2N) C
6H
4The NaNO of CONHOH and formula (VII)
2Mol ratio is 1: 1.2～1.5.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510126588 CN1978436A (en) | 2005-11-30 | 2005-11-30 | Polypeptide synthetic condensation agent 3-hydroxy-4-oxy-3,4-dihydro-1,2,3-benzotriazozine synthesizing method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510126588 CN1978436A (en) | 2005-11-30 | 2005-11-30 | Polypeptide synthetic condensation agent 3-hydroxy-4-oxy-3,4-dihydro-1,2,3-benzotriazozine synthesizing method |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1978436A true CN1978436A (en) | 2007-06-13 |
Family
ID=38129769
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200510126588 Pending CN1978436A (en) | 2005-11-30 | 2005-11-30 | Polypeptide synthetic condensation agent 3-hydroxy-4-oxy-3,4-dihydro-1,2,3-benzotriazozine synthesizing method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1978436A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103864885A (en) * | 2014-03-21 | 2014-06-18 | 河南师范大学 | Application of 1-hydroxy-1,2,3-phentriazine-4(3H)-one in polypeptide synthesis |
| CN103864705A (en) * | 2014-03-21 | 2014-06-18 | 河南师范大学 | Polypeptide condensating agent 1-hydroxy-1,2,3-phentriazine-4(3H)-one and preparation method thereof |
-
2005
- 2005-11-30 CN CN 200510126588 patent/CN1978436A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103864885A (en) * | 2014-03-21 | 2014-06-18 | 河南师范大学 | Application of 1-hydroxy-1,2,3-phentriazine-4(3H)-one in polypeptide synthesis |
| CN103864705A (en) * | 2014-03-21 | 2014-06-18 | 河南师范大学 | Polypeptide condensating agent 1-hydroxy-1,2,3-phentriazine-4(3H)-one and preparation method thereof |
| CN103864705B (en) * | 2014-03-21 | 2015-05-06 | 河南师范大学 | Polypeptide condensating agent 1-hydroxy-1,2,3-phentriazine-4(3H)-one and preparation method thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US7550591B2 (en) | Imatinib production process | |
| AU2010214305B2 (en) | Method for producing phenylacetamide compound | |
| CN110878084A (en) | Preparation method of nicosulfuron original drug | |
| CN102791677B (en) | Preparation method of 4-aminomethylbenzoic acid | |
| US9346772B2 (en) | Preparation method for an imine compound and reduction method for solid powder of a carbamic acid derivative | |
| CN1978436A (en) | Polypeptide synthetic condensation agent 3-hydroxy-4-oxy-3,4-dihydro-1,2,3-benzotriazozine synthesizing method | |
| CN107056756A (en) | A kind of method for preparing high-purity Losartan | |
| CN104011029A (en) | An improved process for the preparation of bendamustine hydrochloride | |
| CN110294768A (en) | A method of pinoxaden is synthesized by 2,6- diethyl -4- methylbenzene malonate | |
| CN109553539A (en) | A kind of preparation method of benzalkonium chloride | |
| TWI379830B (en) | Method for producing pyrimidinyl pyrazole compound | |
| JP4356111B2 (en) | Process for producing N- (2-amino-1,2-dicyanovinyl) formamidine | |
| CN109810052B (en) | Simple and convenient preparation method of high-selectivity apatinib | |
| CN103524483B (en) | A kind of preparation method of SYR-322 | |
| US20040053967A1 (en) | 3-(3-Amidinophenyl)-5-[({[1-(1-(iminoethyl)-4-piperidyl}amino)methyl]benzoic acid dihydrochloride and process for preparing the same | |
| CN109574951A (en) | A kind of preparation method of Febuxostat | |
| JP4838465B2 (en) | Process for producing 4-hydroxyphenylpyruvic acid | |
| US6620935B1 (en) | Process for producing benzylamine compound | |
| CN103242244B (en) | Canertinib preparation method | |
| JP2004137181A (en) | Method for producing n-aminopiperidine | |
| JP3959178B2 (en) | Method for producing hydrazine derivative, intermediate thereof and method for producing intermediate | |
| US20200071259A1 (en) | Method for Preparing Levobunolol Hydrochloride | |
| EP1963309B1 (en) | Method for producing metal salts of losartan | |
| JPS6054301B2 (en) | Alkyl carbazate production method | |
| CN102850395A (en) | Method for synthesizing glyphosate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |