CN115873012A - Biotin-perfluorocarboxylic acid compound and preparation method thereof - Google Patents
Biotin-perfluorocarboxylic acid compound and preparation method thereof Download PDFInfo
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- CN115873012A CN115873012A CN202211539528.7A CN202211539528A CN115873012A CN 115873012 A CN115873012 A CN 115873012A CN 202211539528 A CN202211539528 A CN 202211539528A CN 115873012 A CN115873012 A CN 115873012A
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- perfluorocarboxylic acid
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- -1 Biotin-perfluorocarboxylic acid compound Chemical class 0.000 title claims abstract description 51
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 claims abstract description 71
- 229960002685 biotin Drugs 0.000 claims abstract description 35
- 235000020958 biotin Nutrition 0.000 claims abstract description 35
- 239000011616 biotin Substances 0.000 claims abstract description 35
- 238000006243 chemical reaction Methods 0.000 claims abstract description 21
- 238000000034 method Methods 0.000 claims abstract description 15
- 150000001875 compounds Chemical class 0.000 claims description 120
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 72
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 27
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 24
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 claims description 22
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 13
- 238000006482 condensation reaction Methods 0.000 claims description 10
- 238000003756 stirring Methods 0.000 claims description 9
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 claims description 8
- 239000004593 Epoxy Substances 0.000 claims description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 6
- 239000011259 mixed solution Substances 0.000 claims description 4
- 125000006755 (C2-C20) alkyl group Chemical group 0.000 claims description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- ABDBNWQRPYOPDF-UHFFFAOYSA-N carbonofluoridic acid Chemical compound OC(F)=O ABDBNWQRPYOPDF-UHFFFAOYSA-N 0.000 abstract description 15
- 239000003344 environmental pollutant Substances 0.000 abstract description 9
- 239000002904 solvent Substances 0.000 abstract description 4
- 230000002085 persistent effect Effects 0.000 abstract description 3
- 231100000719 pollutant Toxicity 0.000 abstract description 3
- 238000002372 labelling Methods 0.000 abstract 1
- SNGREZUHAYWORS-UHFFFAOYSA-N perfluorooctanoic acid Chemical compound OC(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F SNGREZUHAYWORS-UHFFFAOYSA-N 0.000 description 13
- 239000000243 solution Substances 0.000 description 12
- JCEZOHLWDIONSP-UHFFFAOYSA-N 3-[2-[2-(3-aminopropoxy)ethoxy]ethoxy]propan-1-amine Chemical compound NCCCOCCOCCOCCCN JCEZOHLWDIONSP-UHFFFAOYSA-N 0.000 description 9
- 238000004090 dissolution Methods 0.000 description 9
- 231100000331 toxic Toxicity 0.000 description 9
- 230000002588 toxic effect Effects 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 8
- 230000002349 favourable effect Effects 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 239000012267 brine Substances 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- 239000000203 mixture Substances 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 4
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- 238000001228 spectrum Methods 0.000 description 4
- VQNDBXJTIJKJPV-UHFFFAOYSA-N 2h-triazolo[4,5-b]pyridine Chemical compound C1=CC=NC2=NNN=C21 VQNDBXJTIJKJPV-UHFFFAOYSA-N 0.000 description 3
- 239000007821 HATU Substances 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
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- 238000005516 engineering process Methods 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
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- 238000001914 filtration Methods 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 238000007738 vacuum evaporation Methods 0.000 description 2
- 238000003828 vacuum filtration Methods 0.000 description 2
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000024799 Thyroid disease Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 210000004381 amniotic fluid Anatomy 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 239000003599 detergent Substances 0.000 description 1
- 150000004985 diamines Chemical class 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000006221 furniture coating Substances 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 208000026278 immune system disease Diseases 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 239000010985 leather Substances 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
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- 150000002894 organic compounds Chemical class 0.000 description 1
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- 239000002994 raw material Substances 0.000 description 1
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- 229960005322 streptomycin Drugs 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000041 toxicology testing Toxicity 0.000 description 1
Images
Classifications
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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
Abstract
The invention provides a biotin-perfluorocarboxylic acid compound and a preparation method thereof, wherein the biotin-perfluorocarboxylic acid compound has a structure shown in the following formula (1):
formula (1). The biotin and perfluorocarboxylic acid compound are mixed, stirred to react in a solvent, and purified after the reaction is finished to obtain the biotin and perfluorocarboxylic acid compound, so that the high-efficiency biotin labeling of perfluorocarboxylic acid pollutants is realized, and a new method is provided for the research of direct acting targets of perfluorocarboxylic acid persistent environmental pollutants.
Description
Technical Field
The invention belongs to the field of crossing of organic compound preparation technology and environmental science, and particularly relates to a biotin-perfluorocarboxylic acid compound and a preparation method thereof.
Background
The perfluorocarboxylic acid compounds have the characteristics of water resistance and fat repellency, and simultaneously have the characteristics of incombustibility, stability and non-volatility, so that the perfluorocarboxylic acid compounds become excellent raw materials of non-stick pan coatings, furniture coatings, leather protection, emulsion detergents and waterproof and anti-stain materials and are widely used in human life. However, the widespread use of such substances makes them abundantly available in the environment and, due to their persistence and stability, accumulate continuously in the environment, in wild animals and in man. The presence of such substances is detected in human samples such as blood, milk, amniotic fluid and the like. As a persistent organic pollutant, the half-life period of the perfluorocarboxylic acid compound in a human body is as long as several years to several decades, and the perfluorocarboxylic acid compound causes persistent damage to the organism. Toxicology studies show that the compounds can cause body immune disorders, thyroid diseases, liver diseases, lipid and insulin imbalance, reproductive development toxicity, cancers and the like, however, compared with the study on toxic effects, the study on toxic action modes and toxic action targets needs to be promoted, so that data support is provided for the toxic intervention of the compounds.
Disclosure of Invention
In view of the above, the main object of the present invention is to provide biotin-linked-perfluorocarboxylic acid compounds and a preparation method thereof, so as to at least partially solve at least one of the above-mentioned technical problems.
In order to realize the purpose, the technical scheme of the invention is as follows:
in a first aspect of the present invention, there is provided a biotin-linked perfluorocarboxylic acid compound having a structure represented by the following formula (1):
wherein X is C2-C20 alkyl ether;
r is any one of the following structural formulas:
m is an integer of 3 to 15, 17, 19, and n is an integer of 1 to 5.
As a second aspect of the present invention, there is provided a method for producing biotin-linked perfluorocarboxylic acid compounds, comprising:
reacting the compound M1, the compound M2 and the compound M3 to obtain a biotin perfluorocarboxylic acid compound with a structure shown in a formula (1);
based on the technical scheme, the biotin-perfluorocarboxylic acid compound and the preparation method provided by the invention at least have the following beneficial effects:
the invention provides a biotin-linked perfluorocarboxylic acid compound, which is characterized in that a diamine compound is used as a connecting bridge to mark biotin on the perfluorocarboxylic acid compound, the synthetic steps are simple, only four-step reaction is needed, and the reaction conditions are mild. According to the position of the biotin label, the direct toxic effect target of the perfluorocarboxylic acid compounds as the environmental pollutants on organisms can be accurately obtained, the high-efficiency biotin label of the perfluorocarboxylic acid pollutants is realized, and a new method is provided for the research of the direct target and key molecular events of the perfluorocarboxylic acid persistent environmental pollutants.
Drawings
FIG. 1 is a liquid chromatogram of biotin-perfluorooctanoic acid compound prepared in an example of the present invention;
FIG. 2 is a molecular weight mass spectrum of a biotin-perfluorooctanoic acid compound prepared according to an example of the present invention;
FIG. 3 is a nuclear magnetic hydrogen spectrum of a biotin-perfluorooctanoic acid compound prepared according to an example of the present invention;
FIG. 4 is the nuclear magnetic fluorine spectrum of the biotin-perfluorooctanoic acid compound prepared in the example of the present invention.
Detailed Description
In order that the objects, technical solutions and advantages of the present invention will become more apparent, the present invention will be further described in detail with reference to the accompanying drawings in conjunction with the following specific embodiments.
In the process of realizing the invention, the technical difficulty of researching the toxic action of the perfluorocarboxylic acid pollutants is found how to identify the direct action target of the perfluorocarboxylic acid environmental pollutants in the environment. The invention provides a biotin-perfluorocarboxylic acid compound and a preparation method thereof, wherein biotin, diamine and perfluorocarboxylic acid compounds are mixed, stirred to react in a solvent, and purified after the reaction is finished to obtain the biotin-perfluorocarboxylic acid compound.
To further illustrate the present invention, the following preferred embodiments of the present invention are described in conjunction with examples, but it should be understood that these descriptions are only for further illustrating the features and advantages of the present invention, and not for limiting the claims of the present invention, and that all other examples obtained by one of ordinary skill in the art without inventive faculty are within the scope of protection of the present invention.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are intended to be exemplary only.
Specifically, according to an embodiment of the present invention, there is provided a biotin-perfluorocarboxylic acid compound having a structure represented by formula (1):
wherein X is C2-C20 alkyl ether;
r is any one of the following structural formulas:
m is an integer of 3 to 15, 17 or 19, and n is an integer of 1 to 5.
According to the embodiment of the invention, the compound formed by connecting the amino groups at the two ends by X is a diamine compound, and the amino groups at the two ends are beneficial to accelerating the reaction rate of biotin, the diamine compound and the perfluorocarboxylic acid compound, so that the biotin can be efficiently marked on the perfluorocarboxylic acid compound. In addition, the diamine compound is used as a connecting bridge to mark biotin on the perfluorocarboxylic acid compound, so that the biotin mark is firmer and is not easy to fall off, and favorable conditions are provided for subsequent toxic target effect analysis.
According to the embodiment of the invention, the direct toxic effect target of the perfluorocarboxylic acid compounds as the environmental pollutants on organisms can be accurately obtained according to the position of the biotin label. In addition, biotin end of the biotin and perfluorocarboxylic acid compounds is favorable for being combined with streptomycin, and target protein of the compounds is favorably extracted through the connection effect of diamine compounds and the combination effect of the perfluorocarboxylic acid compounds and specific target protein, so that toxic target effect analysis is favorably realized, and a new method is provided for direct target and key molecular event research of environmental pollutants.
According to an embodiment of the present invention, the biotin-linked-perfluorocarboxylic acid compound has a structural formula of one of the following formulae:
wherein, the structure of X is a straight chain structure.
According to the embodiment of the invention, the linear structure is favorable for accelerating the speed of connecting biotin and perfluorocarboxylic acid compounds, simplifying the connection process, and is more favorable for connection compared with a structure containing a branched chain.
According to an embodiment of the present invention, there is also provided a method for preparing the biotin-linked perfluorocarboxylic acid compound, including:
reacting the compound M1, the compound M2 and the compound M3 to obtain a biotin perfluorocarboxylic acid compound with a structure shown in a formula (1);
according to the embodiment of the present invention, reacting the compound M1, the compound M2 and the compound M3 to obtain the biotin-perfluorocarboxylic acid compound having the structure represented by the formula (1) includes:
reacting the compound M1 with di-tert-butyl dicarbonate to obtain a compound M4,
carrying out condensation reaction on the compound M2 and the compound M4 to obtain a compound M5,
mixing the compound M5 and 1,4 epoxy hexacyclic ring of hydrochloric acid, stirring, reacting to obtain a compound M6,
the compound M6 and the compound M3 are subjected to condensation reaction to obtain the biotin-perfluorocarboxylic acid compound with the structure shown in the formula (1).
According to an embodiment of the present invention, reacting compound M1 with di-tert-butyl dicarbonate to produce compound M4 comprises:
after the compound (M1) and triethylamine are dissolved in an organic solvent at a dissolution temperature of-1 ℃ to 1 ℃, di-tert-butyl dicarbonate is added dropwise to react and obtain the compound (M4), more preferably at a dissolution temperature of 0 ℃.
Preferably, the molar ratio of the compound M1, triethylamine and di-tert-butyl dicarbonate is (5-7) to 3, the reaction temperature is 15-35 ℃, and the reaction time is 16-24 hours. Under the optimized reaction condition, the method is favorable for regulating and controlling the generation of the mono boc protected compound M4, and the unprotected amino group in the compound M4 can participate in the subsequent reaction.
According to an embodiment of the present invention, more specifically, compound M1 and triethylamine (Et) are taken at a dissolution temperature of-1 ℃ to 1 ℃ 3 N) was added to Dichloromethane (DCM) and dissolved, and di-tert-butyl dicarbonate ((Boc) was added dropwise to the solution 2 O), water was added to the solution that completed the reaction and extracted with DCM, the combined organics were washed with brine, dried, filtered, concentrated, and the residue was purified by silica gel column chromatography with DCM/methanol (MeOH) (100. Wherein, if the dissolution temperature is too high, the dissolution releases heat, and the safety of the operation process cannot be ensured, and if the dissolution temperature is too low, the compound M1 and triethylamine (Et) 3 N) dissolution is incomplete, and therefore, the dissolution temperature should be in the range of-1 ℃ to 1 ℃, more preferably, the dissolution temperature is 0 ℃.
According to the embodiment of the present invention, if the compound M1 is added in a molar ratio that is too high or too low, it is not favorable for the compound M4 to be generated. Therefore, the molar ratio of the compound M1, triethylamine and di-tert-butyl dicarbonate is (5 to 7) to 3. The reaction temperature is 15 to 35 ℃, for example, 15 ℃,20 ℃, 25 ℃, 30 ℃, 35 ℃ and the like, and the reaction time is 16 to 24 hours, for example, 16 hours, 18 hours, 20 hours, 22 hours, 24 hours and the like. Wherein, the temperature range of 15 ℃ to 35 ℃ is easier to reach and better control than other over-high or over-low temperature ranges while ensuring the reaction to be carried out.
According to an embodiment of the present invention, obtaining compound M5 by condensation reaction of compound M2 and compound M4 comprises:
and (3) dropwise adding the compound M4 into the mixed solution of the compound M2, N-methylmorpholine and isobutyl chloroformate to obtain a compound M5 through condensation reaction.
Preferably, the molar ratio of the compound M2, the N-methylmorpholine, the isobutyl chloroformate and the compound M4 is (0.5-1.5) to 2.
According to the embodiments of the present invention, furtherIn bulk, compound M2 and N-methylmorpholine were dissolved in anhydrous DCM, the solution was cooled to-15 deg.C, isobutyl chloroformate was added, after stirring for 10 minutes, compound M4 in anhydrous DCM was added dropwise to the reaction mixture, the reaction-completed solution was washed with dilute hydrochloric acid, brine and distilled water, over MgSO 4 Drying, vacuum filtration and vacuum evaporation gave a crude product which was purified by silica gel column chromatography with DCM/MeOH (vol 100.
According to the embodiment of the present invention, if the molar ratio of compound M2 added is too high or too low, it is not favorable for generating compound M5, therefore, the molar ratio of compound M2, N-methylmorpholine, isobutyl chloroformate and compound M4 is (0.5-1.5): 1. The reaction temperature is 15 to 35 ℃, for example, 15 ℃,20 ℃, 25 ℃, 30 ℃, 35 ℃ and the like, and the reaction time is 16 to 24 hours, for example, 16 hours, 18 hours, 20 hours, 22 hours, 24 hours and the like. Wherein, the temperature range of 15 ℃ to 35 ℃ is easier to reach and better control than other over-high or over-low temperature ranges while ensuring the reaction to be carried out.
According to the embodiment of the invention, the compound M5 and 1,4 epoxy hexacyclic hydrochloride are mixed and stirred to react to obtain a compound M6, which comprises the following components:
adding 1,4 epoxy hexacyclic ring hydrochloride into the mixed solution containing the compound M5 and the organic solvent at the temperature of 15-35 ℃, stirring for 3-10 hours, and reacting to obtain a compound M6.
According to an embodiment of the present invention, more specifically, 1,4 epoxy hexacyclic hydrochloride is added to a DCM solution containing compound M5, and the mixture is stirred at a temperature of 15 ℃ to 35 ℃ for 3 to 10 hours, after evaporation of the solvent, DCM is added to the residue and the precipitated crude compound M6 is collected by filtration and used in the next reaction without purification.
According to the embodiment of the present invention, the compound M5 and 1,4 dioxane hydrochloride are stirred at 15 to 35 ℃ such as 15 ℃,20 ℃, 25 ℃, 30 ℃, 35 ℃ and the like for 3 to 10 hours such as 3 hours, 5 hours, 8 hours, 10 hours and the like.
According to the embodiment of the invention, the biotin-linked perfluorocarboxylic acid compound having the structure shown in the formula (1) obtained by the condensation reaction of the compound M6 and the compound M3 comprises:
adding the compound M6, the compound M3 and 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate into N, N-diisopropylethylamine, and stirring to react to obtain the biotin perfluorocarboxylic acid compound with the structure shown in the formula (1).
Preferably, the molar ratio of the compound M6, the compound M3, the 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate to the N, N-diisopropylethylamine is 1 (0.5-1.5) to 1.5, the reaction temperature is 15-35 ℃, and the reaction time is 16-24 hours.
According to the embodiment of the present invention, more specifically, compound M6, compound M3, 2- (7-azabenzotriazole) -N, N' -tetramethyluronium Hexafluorophosphate (HATU) and N, N-Diisopropylethylamine (DIPEA) are added to N, N-Dimethylformamide (DMF) and stirred, DCM is added to the reacted solution and extracted with water, washed with brine, dried, filtered, concentrated, and the residue is purified by silica gel column chromatography using DCM/MeOH (volume ratio 100-94).
According to the embodiment of the present invention, if the molar ratio of the compound M3 added is too high or too low, the reaction is not favored to obtain the biotin-perfluorocarboxylic acid compound having the structure shown in formula (1). Therefore, the molar ratio of the compound M6, the compound M3, the 2- (7-azabenzotriazole) -N, N '-tetramethylurea hexafluorophosphate to N, N-diisopropylethylamine is 1 (0.5-1.5): 1.5, preferably, the molar ratio of the compound M6, the compound M3, the 2- (7-azabenzotriazole) -N, N' -tetramethylurea hexafluorophosphate to N, N-diisopropylethylamine is 1.
According to the embodiment of the invention, in the process of preparing the biotin-perfluorocarboxylic acid compound, the organic solvent is at least one selected from dichloromethane, dichloroethane, toluene, acetone and methanol.
Reagents and sources
In each of the following examples, perfluorooctanoic acid, a product of sigma aldrich trade ltd; n-methylmorpholine, triethylamine, N-diisopropylethylamine, dichloromethane, shanghai Allantin Biotechnology Ltd; hydrochloric acid 1,4 epoxy hexacyclic, a product of Beijing YinuoKai science and technology Limited; di-tert-butyl dicarbonate, isobutyl chloroformate, 4,7, 10-trioxa-1, 13-tridecanediamine, biotin, 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU), N, N-dimethylformamide, and other unrecited reagents and drugs are commercially available from Shanghai Michelin Biochemical Co., ltd.
Example 1
Preparation of compound M4:
4,7,10-Trioxa-1, 13-tridecanediamine (Compound M1) (60.0g, 272mmol) and triethylamine (9.19g, 90.8mmol) were taken to be dissolved in DCM (600 mL) at 0 ℃ and (Boc) 2O (9.90g, 45.4 mmol) was added dropwise thereto, and the resulting mixture was stirred at room temperature for 16 hours. Water (800 mL) was added and extracted with DCM (3X 200 mL), and the organic mixture was washed with brine (2X 200 mL), dried, filtered, and concentrated. The residue was purified by column chromatography on silica gel with DCM/MeOH (vol.100-90: 10) to give compound M4 (5.53 g, yield: 44.2%) as represented by the formula (2) and compound M4 was obtained as a pale yellow oil.
The obtained product was subjected to nuclear magnetic resonance analysis, and the results were as follows:
1 H NMR(400MHz,CDCl 3 )δ5.14(d,J＝39.5Hz,1H),3.74–3.47(m,12H),3.22(d,J＝5.8Hz,2H),2.88–2.72(m,2H),1.84–1.67(m,4H),1.57(d,J＝17.6Hz,2H),1.44(s,9H).
preparation of compound M5:
perfluorooctanoic acid (compound M2) (3.11g, 6.71mmol) and N-methylmorpholine (1.36g, 13.4mmol) were taken and dissolved in anhydrous DCM (30 mL) and the solution was cooled to-15 ℃ before isobutyl chloroformate (916mg, 6.71mmol) was added. After stirring the mixture for 10 min, compound M4 (2.15g, 6.71mmol) in 10mL of anhydrous DCM was added dropwise to the reaction mixture. The reaction mixture was stirred at room temperature for 16 hours, and the solution was washed with dilute HCl, brine and distilled water, over MgSO 4 Drying, vacuum filtration and vacuum evaporation gave the crude product. The crude product was purified by column chromatography on silica gel with DCM/MeOH (vol.100: 0-98).
Preparation of compound M6:
to a solution of compound M5 (2.32g, 3.03mmol) in DCM (20 mL) was added 1,4 epoxyhexacyclic hydrochloride (4mL, 4M). The mixture was stirred at room temperature for 3 hours. After evaporation of the solvent, DCM (50 mL) was added to the residue and the precipitated crude product was collected by filtration as a white solid (2.40 g) which was compound M6, reaction formula shown in formula (4). The crude compound M6 was used in the next reaction without purification.
Preparation of biotin-perfluorooctanoic acid compound:
compound M6 (2.40g, 3.41mmol), biotin (compound M3) (833mg, 3.41mmol), 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU) (1.95g, 5.12mmol) and DIPEA (2.65g, 20.5 mmol) were taken in DMF (30 mL) and the solution was stirred at room temperature for 16h. DCM (200 mL) was added and extracted with water (3X 100 mL), and the combined organics were washed with brine (2X 50 mL), dried, filtered, and concentrated. The residue was purified by column chromatography on silica gel with DCM/MeOH (vol. 100-94). The biotin with perfluorooctanoic acid obtained was a pale reddish brown solid.
The obtained product biotin with perfluorooctanoic acid is subjected to nuclear magnetic resonance analysis, and the result is as follows:
LC-MS(ESI)[M+H]+893.2.1H NMR(400MHz,CDCl3)δ7.88(s,1H),6.43(t,J＝5.2Hz,1H),5.91(s,1H),5.07(s,1H),4.54–4.44(m,1H),4.34–4.28(m,1H),3.64–3.49(m,15H),3.35(dd,J＝12.1,6.1Hz,2H),3.15(td,J＝7.4,4.7Hz,1H),2.92(dd,J＝12.8,4.9Hz,1H),2.73(d,J＝12.8Hz,1H),2.19(t,J＝7.1Hz,2H),1.86(dt,J＝11.5,5.7Hz,2H),1.75–1.56(m,5H),1.44(dd,J＝15.0,7.2Hz,2H).
structural characterization of biotin with perfluorooctanoic acid:
the liquid chromatogram of the obtained biotin-perfluorooctanoic acid compound is shown in FIG. 1. From FIG. 1, it can be confirmed that the purity thereof is 95 to 98%.
The molecular weight mass spectrum of the obtained biotin-perfluorooctanoic acid compound is shown in FIG. 2. From FIG. 2, the molecular weight can be determined.
The nuclear magnetic hydrogen spectrum of the obtained biotin-perfluorooctanoic acid compound is shown in FIG. 3. The molecular structural formula can be determined from fig. 3.
The nuclear magnetic fluorine spectrum of the obtained biotin-perfluorooctanoic acid compound is shown in fig. 4. The molecular structural formula can be determined from fig. 4.
The above-mentioned embodiments are intended to illustrate the objects, technical solutions and advantages of the present invention in further detail, and it should be understood that the above-mentioned embodiments are only exemplary embodiments of the present invention and are not intended to limit the present invention, and any modifications, equivalents, improvements and the like made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (9)
1. A biotin-perfluorocarboxylic acid compound having a structure represented by the following formula (1):
wherein X is C2-C20 alkyl ether;
r is any one of the following structural formulas:
2. The biotin-linked-perfluorocarboxylic acid compound of claim 1, wherein X is represented by one of the following structural formulae:
3. a method for producing biotin-perfluorocarboxylic acids as described in claim 1 or 2, which comprises:
reacting the compound (M1), the compound (M2) and the compound (M3) to obtain a biotin-linked perfluorocarboxylic acid compound having a structure represented by formula (1);
4. the production method according to claim 3, wherein the reaction of the compound (M1), the compound (M2) and the compound (M3) to obtain the biotin-to-perfluorocarboxylic acid-based compound having the structure represented by the formula (1) comprises:
reacting the compound (M1) with di-tert-butyl dicarbonate to obtain a compound (M4),
subjecting the compound (M2) and the compound (M4) to a condensation reaction to obtain a compound (M5),
mixing the compound (M5) with 1,4 epoxy hexacyclic ring hydrochloride, stirring, reacting to obtain a compound (M6),
and (3) carrying out condensation reaction on the compound (M6) and the compound (M3) to obtain the biotin-linked perfluorocarboxylic acid compound with the structure shown in the formula (1).
5. The method according to claim 4, wherein the reacting the compound (M1) and di-tert-butyl dicarbonate to obtain the compound (M4) comprises:
dissolving the compound (M1) and triethylamine in an organic solvent at a dissolving temperature of-1 ℃, and then dropwise adding di-tert-butyl dicarbonate to react to obtain the compound (M4), wherein the dissolving temperature is more preferably 0 ℃;
preferably, the molar ratio of the compound (M1), triethylamine and di-tert-butyl dicarbonate is (5-7) to 3, the reaction temperature is 15-35 ℃, and the reaction time is 16-24 hours.
6. The method according to claim 4, wherein the step of subjecting the compound (M2) and the compound (M4) to a condensation reaction to obtain the compound (M5) comprises:
dropwise adding the compound (M4) into the mixed solution of the compound (M2), N-methylmorpholine and isobutyl chloroformate to obtain a compound (M5) through condensation reaction;
preferably, the molar ratio of the compound (M2), N-methylmorpholine, isobutyl chloroformate and the compound (M4) is (0.5-1.5): 2.
7. The preparation method according to claim 4, wherein the mixing and stirring of the compound (M5) and the 1,4 epoxy hexacyclic hydrochloride to obtain the compound (M6) comprises:
adding 1,4 epoxy hexacyclic ring hydrochloride into the mixed solution containing the compound (M5) and the organic solvent at the temperature of 15-35 ℃, stirring for 3-10 hours, and reacting to obtain the compound (M6).
8. The method according to claim 4, wherein the step of subjecting the compound (M6) and the compound (M3) to condensation reaction to obtain the biotin-linked perfluorocarboxylic acid compound having the structure represented by formula (1) comprises:
adding the compound (M6), the compound (M3) and 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate into N, N-diisopropylethylamine, stirring, and reacting to obtain the biotin perfluorocarboxylic acid compound with the structure shown in the formula (1);
preferably, the molar ratio of the compound (M6), the compound (M3), the 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate to the N, N-diisopropylethylamine is 1 (0.5-1.5) to 1.5, the reaction temperature is 15-35 ℃, and the reaction time is 16-24 hours.
9. The method according to claim 5 or 7, wherein the organic solvent is at least one selected from the group consisting of dichloromethane, dichloroethane, toluene, acetone, and methanol.
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| CN1518536A (en) * | 2001-05-04 | 2004-08-04 | ��¡���ӹɷ�����˾ | Labelling reagents, method for synthesis of said reagents and methods for detecting biological molecules |
| US20090208451A1 (en) * | 2003-10-17 | 2009-08-20 | Integrigen, Inc. | Halogen phosphonate monoesters |
| WO2021124032A1 (en) * | 2019-12-19 | 2021-06-24 | 3M Innovative Properties Company | Fluorinated coumarins |
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| CN1518536A (en) * | 2001-05-04 | 2004-08-04 | ��¡���ӹɷ�����˾ | Labelling reagents, method for synthesis of said reagents and methods for detecting biological molecules |
| US20090208451A1 (en) * | 2003-10-17 | 2009-08-20 | Integrigen, Inc. | Halogen phosphonate monoesters |
| WO2021124032A1 (en) * | 2019-12-19 | 2021-06-24 | 3M Innovative Properties Company | Fluorinated coumarins |
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