CN111675666B - (tetrazol-1-yl) -N, N, N ', N' -tetramethylurea hexafluorophosphate and preparation method thereof - Google Patents
(tetrazol-1-yl) -N, N, N ', N' -tetramethylurea hexafluorophosphate and preparation method thereof Download PDFInfo
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- CN111675666B CN111675666B CN202010701486.7A CN202010701486A CN111675666B CN 111675666 B CN111675666 B CN 111675666B CN 202010701486 A CN202010701486 A CN 202010701486A CN 111675666 B CN111675666 B CN 111675666B
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- C—CHEMISTRY; METALLURGY
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- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
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- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/02—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length in solution
- C07K1/026—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length in solution by fragment condensation in solution
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- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
- C07K5/06165—Dipeptides with the first amino acid being heterocyclic and Pro-amino acid; Derivatives thereof
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- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0821—Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp
- C07K5/0823—Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp and Pro-amino acid; Derivatives thereof
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Abstract
The invention provides (tetrazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate, a polypeptide condensing agent and a preparation method thereof, wherein the preparation method of the (tetrazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate comprises the following steps: and carrying out nucleophilic substitution reaction on the N, N, N ', N' -tetramethyl chloroformamidine hexafluorophosphate and tetrazole in a solvent under the action of alkali to obtain the (tetrazole-1-yl) -N, N, N ', N' -tetramethylurea hexafluorophosphate. The invention develops a novel compound (tetrazole-1-yl) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HTTU), which can be used as a polypeptide condensing agent, polypeptide condensation is carried out by using the novel compound (tetrazole-1-yl) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HTTU), the generated racemization isomer is less, the yield is high, the preparation method uses TCFH and tetrazole as raw materials, the compound (tetrazole-1-yl) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HTTU) is obtained through nucleophilic substitution reaction, the synthetic route is short, and the yield can reach 80%.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to (tetrazole-1-yl) -N, N, N ', N' -tetramethylurea hexafluorophosphate, a polypeptide condensing agent and a preparation method thereof.
Background
Many natural polypeptides exist in the human body and are involved in the regulation of various physiological functions. The polypeptide is easy to synthesize, modify and optimize, the medicinal value can be quickly determined, and the medicine approval time and the success probability are superior to those of small molecule medicines. The specific advantages of the polypeptide enable the polypeptide to show specific advantages and have clinical application value in drug development, so the polypeptide has very important development value in clinical application.
Despite the great therapeutic potential of polypeptide drugs, their widespread use is still limited by several technical factors. Where the key step is the formation of a peptide bond, there are two main synthetic approaches: (a) in situ activation of carboxylic acids; (b) the prepared substance for activating amino acid is realized. The first is the most convenient synthetic method to date. For this reason, there is a need for a polypeptide condensing agent with good properties which on the one hand increases the yield of peptide bond formation and on the other hand ensures the integrity of the configuration, i.e. no racemization.
At present, as a condensing agent widely used at low cost and easily available, DCC, DIC, EDC and the like are included, but disadvantages thereof including racemization, low yield and the like are inevitable. In recent years, an ammonium sulfite or urea salt substance has been introduced as a polypeptide condensing agent, and the effect thereof is better than that of a conventional condensing agent. Although these agents are under investigation, they are rarely used in industrial production.
Therefore, it is important to develop a novel polypeptide condensing agent which can be industrially used.
Disclosure of Invention
In view of the above, the present invention aims to provide a novel compound, namely, (tetrazol-1-yl) -N, N' -tetramethyluronium hexafluorophosphate.
The present invention also aims to provide a polypeptide condensing agent containing the above novel compound.
The invention also aims to provide a preparation method of the (tetrazole-1-yl) -N, N, N ', N' -tetramethylurea hexafluorophosphate.
In order to solve the technical problems, the invention adopts the following technical scheme:
the chemical structural formula of the (tetrazol-1-yl) -N, N' -tetramethylurea hexafluorophosphate according to the embodiment of the first aspect of the present invention is shown in the following formula (1).
The polypeptide condensing agent according to the second aspect of the present invention contains (tetrazol-1-yl) -N, N' -tetramethyluronium hexafluorophosphate as described in the first aspect of the present invention.
A method for preparing (tetrazol-1-yl) -N, N' -tetramethylurea hexafluorophosphate according to an embodiment of the third aspect of the present invention comprises:
carrying out nucleophilic substitution reaction on N, N, N ', N' -tetramethyl chloroformamidine hexafluorophosphate (TCFH) and tetrazole in a solvent under the action of alkali to obtain the (tetrazole-1-yl) -N, N, N ', N' -tetramethylurea hexafluorophosphate.
According to some embodiments of the invention, the solvent is one or more selected from acetonitrile, N-dimethylformamide, tetrahydrofuran.
According to some embodiments of the invention, the base is one or more selected from triethylamine, N-methylmorpholine, N-diisopropylethylamine. According to some embodiments of the invention, the N, N' -tetramethylchloroformamidine hexafluorophosphate: tetrazole: the molar ratio of the alkali is 1: (1.0-1.5): (1-2). Wherein the N, N, N ', N' -tetramethylchlorformamidine hexafluorophosphate: tetrazole: the molar ratio of the bases is preferably 1: 1: 1.1.
according to some embodiments of the invention, the reaction temperature of the nucleophilic substitution reaction is 10 to 55 ℃.
Further, the reaction time of the nucleophilic substitution reaction is 1-10 hours. Preferably, the reaction time is 3 hours.
According to the present invention, the (tetrazol-1-yl) -N, N' -tetramethyluronium hexafluorophosphate obtained after the nucleophilic substitution reaction was completed was also purified according to the present invention.
Further, the purifying comprises:
the reaction system was suction-filtered and the filtrate was concentrated under reduced pressure to distill off the solvent, after which a beating treatment was performed by methanol.
The technical scheme of the invention at least has one of the following beneficial effects:
the present invention has developed a novel compound (tetrazol-1-yl) -N, N' -tetramethyluronium Hexafluorophosphate (HTTU), which can be used as a polypeptide condensing agent, and which produces less racemic isomers and high yield by performing polypeptide condensation using the same;
according to the preparation method provided by the embodiment of the invention, TCFH and tetrazole are used as raw materials, and a compound (tetrazole-1-yl) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HTTU) is obtained through nucleophilic substitution reaction, so that the synthetic route is short, and the yield can reach 80%;
according to the preparation method provided by the embodiment of the invention, the related operation is simple and convenient, and the conditions are easy to control.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. It is to be understood that the embodiments described are only a few embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the description of the embodiments of the invention given above, are within the scope of protection of the invention.
Hereinafter, a method for synthesizing HTTU according to an embodiment of the present invention will be described in detail with reference to specific examples.
The starting materials used in the examples which follow are all commercially available, chemically pure or analytically pure.
Example 1
In a single-mouth bottle, 3g of tetrazole and 12g of TCFH are dissolved in 70mL of acetonitrile, 4.76g of triethylamine is added in an ice water bath, and after reaction for 3 hours, TLC detects that the raw materials are completely reacted.
Suction filtration, filtrate concentration under reduced pressure, then use 40mL methanol two times beating. (tetrazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate was obtained in an amount of 10.6g, with a yield of 78%.
1H NMR(500MHz,CD3CN)δ9.47(s,1H),3.45(s,6H),2.95(s,6H).
Example 2
In a single-mouth bottle, 3g of tetrazole and 12g of TCFH are dissolved in 70mL of DMF, 4.76g of triethylamine is added at room temperature, and after reaction for 3 hours, TLC detects that the raw materials are completely reacted.
Suction filtration, filtrate concentration under reduced pressure, then use 40mL methanol two times beating. (tetrazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate was obtained in 8.8g, yield 65%.
1H NMR(500MHz,CD3CN)δ9.47(s,1H),3.45(s,6H),2.95(s,6H).
Example 3
In a single-mouth bottle, 3g of tetrazole and 12g of TCFH are dissolved in 70mL of tetrahydrofuran, 4.76g of triethylamine is added in an ice water bath, and after reaction for 3 hours, TLC detects that the raw materials are completely reacted.
Suction filtration, filtrate concentration under reduced pressure, then use 40mL methanol two times beating. (tetrazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate was obtained in 9.2g, yield 68%.
1H NMR(500MHz,CD3CN)δ9.47(s,1H),3.45(s,6H),2.95(s,6H).
In addition, in order to evaluate the polypeptide condensation property of (tetrazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate prepared according to the present invention, it was tried to synthesize a polypeptide. Meanwhile, as a control example, polypeptide synthesis was also performed under the same conditions using a conventional polypeptide condensing agent, and the yield and the racemization ratio thereof were evaluated.
Application example 1 dipeptide Z-Phg-Pro-NH2Synthesis of (2)
HTTU obtained in example 1 was used for the test of condensing two amino acids in solution without causing their racemability.
Reacting Z-Phg-OH with H-Pro-NH2Condensing in acetonitrile in the presence of a condensing agent and a base to obtain Z-Phg-Pro-NH2. The extent of racemization of the Phg residues was tested.
Table 1 gives the name of the condensing agent, the type and amount of base, the yield of the condensation reaction and the formation of Z-Phg-Pro-NH in acetonitrile2Racemization caused during (solution phase synthesis).
TABLE 1 Synthesis of the dipeptide Z-Phg-Pro-NH with different condensing Agents2Performance test of
| Polypeptide condensing agent | Base (equivalent) | Yield (%) | DL(％) |
| HATU | 2,4, 6-trimethylpyridine (2) | 92.2 | 4.3 |
| HBTU | 2,4, 6-trimethylpyridine (2) | 90.9 | 6.3 |
| HTTU (example 1) | 2,4, 6-trimethylpyridine (2) | 92.4 | 1.9 |
HATU 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate
HBTU O-benzotriazole-tetramethyluronium hexafluorophosphate
Application example 2 tripeptide Z-Phe-Val-Pro-NH2Synthesis of (2)
HTTU obtained in example 3 was used for the condensation of Z-Phe-Val-OH with H-Pro-NH in acetonitrile in the presence of a condensing agent and a base2Without causing a test of its racemability. The reaction is condensed to obtain Z-Phe-Val-Pro-NH2. The extent of racemization of valine residues was tested.
Table 2 gives the name of the condensing agent, the type and amount of base, the yield of the condensation reaction and the formation of Z-Phe-Val-Pro-NH in acetonitrile2(2+1) (solution phase synthesis) racemization.
TABLE 2 Synthesis of the tripeptide Z-Phe-Val-Pro-NH under different condensing Agents2Performance test of
| Polypeptide condensing agent | Base (equivalent) | Yield (%) | LDL(％) |
| HATU | 2,4, 6-trimethylpyridine (2) | 94.4 | 5.3 |
| HBTU | 2,4, 6-trimethylpyridine (2) | 86.9 | 10.2 |
| HOTU | 2,4, 6-trimethylpyridine (2) | 96.9 | 3.2 |
| HTTU (example 3) | 2,4, 6-trimethylpyridine (2) | 96.7 | 1.4 |
HATU 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate
HBTU O-benzotriazole-tetramethyluronium hexafluorophosphate
HOTU: o- [ (ethoxycarbonyl) cyanomethylamine ] -N, N, N ', N' -tetramethylthiourea hexafluorophosphate
As is clear from tables 1 and 2, the (tetrazol-1-yl) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HTTU) salt according to the present invention has advantages of high yield, good condensation performance, low racemization degree, etc., when it is used for polypeptide condensation.
While the foregoing is directed to the preferred embodiment of the present invention, it will be understood by those skilled in the art that various changes and modifications may be made without departing from the spirit and scope of the invention as defined in the appended claims.
Claims (10)
1. A (tetrazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate having a chemical structural formula shown by the following formula (1)
2. A polypeptide condensing agent comprising (tetrazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate according to claim 1.
3. A method for preparing (tetrazol-1-yl) -N, N' -tetramethyluronium hexafluorophosphate comprising:
and carrying out nucleophilic substitution reaction on the N, N, N ', N' -tetramethyl chloroformamidine hexafluorophosphate and tetrazole in a solvent under the action of alkali to obtain the (tetrazole-1-yl) -N, N, N ', N' -tetramethylurea hexafluorophosphate.
4. The method according to claim 3, wherein the solvent is one or more selected from acetonitrile, N-dimethylformamide, and tetrahydrofuran.
5. The method according to claim 3, wherein the base is one or more selected from triethylamine, N-methylmorpholine, and N, N-diisopropylethylamine.
6. The method according to claim 3, wherein the N, N, N ', N' -tetramethylchloroformamidine hexafluorophosphate: tetrazole: the molar ratio of the alkali is 1: (1.0-1.5): (1-2).
7. The preparation method according to claim 3, wherein the reaction temperature of the nucleophilic substitution reaction is 10 to 55 ℃.
8. The method according to claim 3, wherein the reaction time of the nucleophilic substitution reaction is 1 to 10 hours.
9. The method according to claim 3, wherein the obtained (tetrazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate is further purified after the nucleophilic substitution reaction is completed.
10. The method of claim 9, wherein the purifying comprises:
the reaction system was suction-filtered and the filtrate was concentrated under reduced pressure to distill off the solvent, after which a beating treatment was performed by methanol.
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| CN202010701486.7A CN111675666B (en) | 2020-07-20 | 2020-07-20 | (tetrazol-1-yl) -N, N, N ', N' -tetramethylurea hexafluorophosphate and preparation method thereof |
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| CN111675666B true CN111675666B (en) | 2022-05-17 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101525370A (en) * | 2008-03-06 | 2009-09-09 | 海南建邦制药科技有限公司 | Novel efficient condensing agent for synthesizing polypeptide |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101525370A (en) * | 2008-03-06 | 2009-09-09 | 海南建邦制药科技有限公司 | Novel efficient condensing agent for synthesizing polypeptide |
Non-Patent Citations (2)
| Title |
|---|
| 多肽固相合成缩合试剂-HBTU合成方法的改进;潘和平 等;《化学试剂》;19961228;第18卷(第6期);第362-363页 * |
| 苯并三氮唑－N，N，N"，N"－四甲基脲六氟磷酸盐的合成工艺研究;刘洪杰 等;《现代化工》;20180331;第38卷(第3期);第173-177页 * |
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