An acylsilane reagent, its preparation method and use
By preparing acylsilyl reagents and reacting them with amine compounds, the shortcomings of existing amide bond formation methods have been overcome, enabling the efficient synthesis of amide compounds under mild conditions. This method is applicable to the synthesis of a variety of compounds, especially peptides and polymers, meeting the application needs of pharmaceuticals and materials.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- SUN YAT SEN UNIV
- Filing Date
- 2024-07-10
- Publication Date
- 2026-05-19
AI Technical Summary
Existing methods for amide bond formation suffer from problems such as poor chemoselectivity, water incompatibility, difficulty in product purification, high reagent toxicity, poor stability, and slow reaction rate. In particular, the linkage of potassium acyl trifluoroborate is carried out under strongly acidic conditions and the reaction rate is slow at dilute concentrations, which prevents its widespread application.
An acylsilane reagent and its preparation method are provided. The acylsilane reagent is prepared by reacting compound a with a compound containing an X group under specific solvent and conditions, and then reacting it with an amine compound in an anhydrous or organic solvent aqueous solution, using a desilylation reagent to generate an amide compound.
Acylsilane reagents react with a variety of amine compounds to form amide compounds. They have a wide range of applicable substrates, high selectivity, fast reaction speed, and high yield, making them suitable for the synthesis of peptides and polymeric amide compounds, meeting the needs of pharmaceuticals, agrochemicals, polymers, and materials.
Smart Images
Figure QLYQS_1 
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Abstract
Description
Technical Field
[0001] This invention relates to the field of organic synthesis technology, and in particular to an acylsilane reagent, its preparation method, and its application. Background Technology
[0002] Amide bonds are among the most common functional groups in nature, serving as fundamental structural units in small organic molecules, peptides, proteins, and other natural macromolecules. They are ubiquitous in pharmaceuticals, agrochemicals, polymers, materials, and other fine chemicals. Currently, the primary method for forming amide bonds is the dehydration coupling of carboxylic acids and amines with the assistance of coupling reagents. Many amide coupling reagents are now commercially available, such as 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU), O-benzotriazole-tetramethylurea hexafluorophosphate (HBTU), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), and dicyclohexylcarbodiimide (DCC). However, these coupling reagents still have several drawbacks, including poor chemoselectivity, water incompatibility, difficulty in product purification, poor reagent toxicity and stability, and the generation of large amounts of organic waste.
[0003] Numerous non-classical amide bond formation reactions have been reported, overcoming the limitations of traditional methods. Among these, natural chemical linkages (NCL), α-keto acid-hydroxylamine linkages (KAHAligation), potassium acyltrifluoroborate linkages (KATligation), and acylsilane linkages (ASHAligation) have been widely used in peptide and protein chemistry, as well as in the discovery of biobinding and inhibitors. These reactions exhibit high chemoselectivity and can occur under mild aqueous conditions. However, the application of NCL and KAHAligation is limited by their slow reaction rates. KAT linkages are fast and can occur at dilute concentrations of equimolar reactants, but their wider application is limited by strong acidic reaction conditions and the lack of rapid methods for obtaining various KATs. ASHA linkages require acidic conditions, and the method is slow at dilute concentrations; at a concentration of 2 mmol, the reaction yield is only 36% even after 3 days at 40°C. Furthermore, this method cannot react with aniline and secondary amines, nor can it synthesize dipeptides or polypeptides. Summary of the Invention
[0004] This invention aims to at least solve one of the aforementioned technical problems existing in the prior art. To this end, one objective of this invention is to provide an acylsilane reagent; a second objective is to provide a method for preparing such an acylsilane reagent; a third objective is to provide an application of such an acylsilane reagent; and a fourth objective is to provide a method for synthesizing an amide compound. To achieve the above objectives, the technical solution adopted by this invention is:
[0005] A first aspect of the present invention provides an acylsilane reagent with the structural formula shown in Formula I:
[0006]
[0007] Among them, R 1 and R 2 Each group is independently selected from alkyl, aryl, heteroatom, heterocyclic, carboxyl, ester, or hydrogen groups;
[0008] R 3 R 4 and R 5 Each is independently selected from alkyl and aryl groups;
[0009] X is selected from halogen, ester group, cyano group, hydroxyl group, alkoxy group, thioether chain, tertiary amine group, any substituted sulfonic acid group, and any substituted sulfonyl group.
[0010] Preferably, the halogen includes F, Cl, Br, and I.
[0011] Preferably, any substituted sulfonic acid group includes a sulfonic acid group or a trifluoroformate group;
[0012] Preferably, any substituted sulfonyl group includes sulfonyl, sulfinyl, and p-benzenesulfonyloxy.
[0013] Preferably, the acylsilane reagent includes, but is not limited to, the following structures:
[0014]
[0015] A second aspect of the present invention provides a method for preparing the acylsilane reagent described in the first aspect of the present invention, comprising the following steps:
[0016] Compound a The acylsilane reagent is obtained by reacting a compound containing an X group in a solvent; wherein, R... 1 R 2 R 3 R 4 R 5 And X as defined by compound I.
[0017] Preferably, the compounds containing the X group include, but are not limited to, elemental bromine, sulfonyl chloride, N-bromosuccinimide, and N-chlorosuccinimide; other chemical reagents that can introduce a leaving group at the ortho position of the carbonyl group can also be used as compounds containing the X group to participate in the preparation of the acylsilane reagent.
[0018] Preferably, the reaction includes at least one of the following conditions:
[0019] 1) The molar ratio of compound a to the compound containing the X group is 1:(0.8-4);
[0020] 2) The reaction is carried out in an ether-based organic solvent;
[0021] 3) The reaction temperature is 20–25°C;
[0022] 4) The reaction time is 15-17 hours.
[0023] The third aspect of the present invention provides the use of the acylsilane reagent described in the first aspect of the present invention in the preparation of amide compounds.
[0024] A fourth aspect of the present invention provides a method for synthesizing an amide compound, comprising reacting an acylsilyl reagent described in the first aspect of the present invention with an amine compound to obtain the amide compound.
[0025] Preferably, the amine compound includes, but is not limited to, the following structures:
[0026]
[0027] Preferably, the reaction is carried out under solvent conditions.
[0028] Preferably, the solvent includes one of anhydrous organic solvent and aqueous solution of organic solvent.
[0029] Preferably, the organic solvent includes at least one of tetrahydrofuran (THF), dimethyl sulfoxide, 1,4-dioxane, tert-butanol, and acetonitrile.
[0030] Preferably, the water content of the organic solvent aqueous solution is 10-25%; more preferably, the water content of the organic solvent aqueous solution is 10-20%.
[0031] Preferably, the molar ratio of the acylsilane reagent to the amine compound is (1-20):1.
[0032] Preferably, the reaction further includes the use of a desilication reagent; more preferably, the desilication reagent includes one of potassium fluoride (KF) and tetrabutylammonium fluoride (TBAF).
[0033] Preferably, the molar ratio of the desilylation reagent to the acylsilane reagent is (1-2):1.
[0034] Preferably, the reaction temperature is 20–25°C.
[0035] Preferably, the reaction time is 5 to 540 minutes.
[0036] Preferably, the product obtained by the synthesis method of the amide compound includes amide derivatives, dipeptides, and high molecular weight amide compounds; the weight-average molecular weight of the high molecular weight amide compound is greater than 30,000.
[0037] Preferably, the product obtained by the synthesis method of the amide compound includes, but is not limited to, the following structures:
[0038]
[0039] Compared with the prior art, the beneficial effects of the present invention are:
[0040] The acylsilane reagent provided by this invention has reducible chemical groups such as halogen and ester groups, and can react with a variety of amine compounds to generate amide compounds. It has a wide range of applicable substrates and high selectivity. The synthesis method of the amide compounds provided by this invention is simple in steps. The acylsilane reagent and amine compounds can efficiently and selectively synthesize amide compounds such as peptides and polymers under anhydrous organic solvent or aqueous organic solvent conditions, with high yield of amide compounds. Attached Figure Description
[0041] Figure 1 The 1H NMR spectrum of amide compound c1 in Example 1;
[0042] Figure 2 The image shows the carbon NMR spectrum of amide compound c1 in Example 1.
[0043] Figure 3 The 1H NMR spectrum of amide compound c2 in Example 2;
[0044] Figure 4 The image shows the carbon NMR spectrum of amide compound c2 in Example 2.
[0045] Figure 5 This is the gel permeation chromatogram of amide compound C3 in Example 3;
[0046] Figure 6 The gel permeation chromatogram of amide compound C4 in Example 6.
[0047] Figure 7 This is the high-resolution mass spectrum of amide compound C5 in Example 7. Detailed Implementation
[0048] The present invention will be further described in detail below through specific embodiments. Unless otherwise specified, the raw materials, reagents, or apparatus used in the embodiments can be obtained from conventional commercial sources or by existing technical methods. Unless otherwise specified, the experimental or testing methods are conventional methods in the art.
[0049] Example 1
[0050] This embodiment provides an acylsilane reagent, and the specific steps are as follows:
[0051] One equivalent of bromine was slowly added to a 2.5 mol / L diethyl ether solution of compound a1, and the reaction was carried out at 25 °C for 16 h. The acylsilane reagent b1 was then obtained by column chromatography.
[0052] The synthesis route is shown below:
[0053]
[0054] An amide compound was synthesized using acylsilane reagent b1 and benzylamine as raw materials. The reaction was carried out under aqueous organic solvent conditions, and the specific steps are as follows:
[0055] Add 0.2 mmol of acylsilane reagent b1, 1.6 mL of tetrahydrofuran, 0.4 mL of water, 1 equivalent of benzylamine, and 1 equivalent of potassium fluoride to a reaction flask in an air atmosphere. React at 25 °C for 5 min, and the amide compound c1 can be obtained by column chromatography.
[0056] The synthesis route is shown below:
[0057]
[0058] Figure 1 The image shows the 1H NMR spectrum of amide compound c1 in Example 1. Figure 2 The image shown is the carbon NMR spectrum of amide compound c1 in Example 1. Figure 1 and Figure 2 It can be seen that amide compound C1 is an amide compound synthesized using bromine as a reducible chemical group and acylsilane as a substrate. The yield of amide compound C1 is calculated to be 89%.
[0059] Example 2
[0060] This embodiment provides an acylsilane reagent, and the specific steps are as follows:
[0061] One equivalent of bromine was slowly added to a 2.5 mol / L diethyl ether solution of compound a2, and the reaction was carried out at 25 °C for 16 h. The acylsilane reagent b2 was then obtained by column chromatography.
[0062] The synthesis route is shown below:
[0063]
[0064] An amide compound was synthesized from acylsilane reagent b2 and L-proline methyl ester. The reaction was carried out under anhydrous organic solvent conditions, and the specific steps are as follows:
[0065] Add 0.2 mmol of acylsilane reagent b2, 2 mL of anhydrous tetrahydrofuran, 1 equivalent of L-proline methyl ester and 1 equivalent of tetrabutylammonium fluoride to a reaction flask in an air atmosphere, react at 25 °C for 120 min, and obtain amide compound c2 by column chromatography.
[0066] The synthesis route is shown below:
[0067]
[0068] Figure 3 The image shows the 1H NMR spectrum of amide compound c2 in Example 2. Figure 4 The image shown is the carbon NMR spectrum of amide compound c2 in Example 2. Figure 3 and Figure 4 It is known that amide compound C2 is a dipeptide protected by phthaloyl with bromine as a reducible chemical group and acylsilane as a substrate. The yield of amide compound C2 is calculated to be 75%.
[0069] Example 3
[0070] This embodiment provides an acylsilane reagent, and the specific steps are as follows:
[0071] In a 2.5 mol / L solution of compound a3 in diethyl ether, 4 equivalents of bromine were slowly added, and the reaction was carried out at 25 °C for 16 h. Then, the acylsilane reagent b3 was obtained by column chromatography.
[0072] The synthesis route is shown below:
[0073]
[0074] An amide compound was synthesized using acylsilane reagent b3 and hexamethylenediamine as raw materials. The reaction was carried out under anhydrous organic solvent conditions, and the specific steps are as follows:
[0075] Add 0.2 mmol of acylsilane reagent b3, 2 mL of anhydrous tetrahydrofuran, 1 equivalent of hexamethylenediamine and 2 equivalents of tetrabutylammonium fluoride to a reaction flask in an air atmosphere, react at 25 °C for 360 min, filter, and wash successively with water, n-hexane and tetrahydrofuran to obtain amide compound c3.
[0076] The synthesis route is shown below:
[0077]
[0078] Figure 5 This is the gel permeation chromatogram of amide compound C3 in Example 3, obtained by... Figure 5 It can be seen that amide compound C3 is a high molecular weight amide compound with a number-average molecular weight Mn of 27341, a weight-average molecular weight Mw of 31733, a peak molecular weight Mp of 27245, a z-average molecular weight Mz of 36895, a polydispersity index of 1.160634, and a yield of 78%.
[0079] Example 4
[0080] In this embodiment, an amide compound was synthesized using acylsilane reagent b1 and benzylamine as raw materials. The reaction was carried out under conditions of an aqueous organic solvent, and the specific steps are as follows:
[0081] Add 0.1 mmol of acylsilane reagent b1, 80 mL of tetrahydrofuran, 20 mL of water, 2 equivalents of benzylamine, and 1 equivalent of potassium fluoride to a reaction flask in an air atmosphere. React at 25 °C for 30 min, and the amide compound c1 can be obtained by column chromatography.
[0082] The synthesis route is shown below:
[0083]
[0084] The yield of compound c1 was calculated to be 95% at a concentration of 1 mmol / L.
[0085] Example 5
[0086] In this embodiment, an amide compound was synthesized using acylsilane reagent b1 and benzylamine as raw materials. The reaction was carried out under conditions of an aqueous organic solvent, and the specific steps are as follows:
[0087] Add 0.01 mmol of acylsilane reagent b1, 80 mL of tetrahydrofuran, 20 mL of water, 2 equivalents of benzylamine, and 1 equivalent of potassium fluoride to a reaction flask in an air atmosphere. React at 25 °C for 270 min, and the amide compound c1 can be obtained by column chromatography.
[0088] The synthesis route is shown below:
[0089]
[0090] The yield of compound c1 was calculated to be 84% at a concentration of 0.1 mmol / L.
[0091] In existing acylsilane linkage techniques, when the concentration is 2 mmol / L and the reaction is carried out at 40°C for 3 days, the yield of amide compounds can only reach 36%. However, the synthesis method of acylsilane reagent and amide compounds provided by this invention can achieve a yield of more than 80% of amide compounds within 10 hours under low concentrations of 0.1 mmol / L and 1 mmol / L and room temperature conditions.
[0092] Example 6
[0093] This embodiment provides an acylsilane reagent, and the specific steps are as follows:
[0094] Two equivalents of bromine were slowly added to a 2.5 mol / L diethyl ether solution of compound a4, and the reaction was carried out at 25 °C for 16 h. The acylsilane reagent b4 was then obtained by column chromatography.
[0095] The synthesis route is shown below:
[0096]
[0097] An amide compound was synthesized using acylsilane reagent b4 and hexamethylenediamine as raw materials. The reaction was carried out under anhydrous organic solvent conditions, and the specific steps are as follows:
[0098] Add 0.2 mmol of acylsilane reagent b5, 2 mL of anhydrous tetrahydrofuran, 1 equivalent of hexamethylenediamine, and 2 equivalents of tetrabutylammonium fluoride to a reaction flask in an air atmosphere. React at 25 °C for 360 min, filter, and wash successively with water, n-hexane, and tetrahydrofuran to obtain amide compound c4.
[0099] The synthesis route is shown below:
[0100]
[0101] Figure 6 This is the gel permeation chromatogram of amide compound C4 in Example 6, obtained by... Figure 6 It can be seen that amide compound C4 is a high molecular weight amide compound with a number-average molecular weight Mn of 105,146, a weight-average molecular weight Mw of 136,654, a peak molecular weight Mp of 69,132, a z-average molecular weight Mz of 199,446, a polydispersity index of 1.299666, and a yield of 85%.
[0102] Example 7
[0103] In this embodiment, an amide compound was synthesized using acylsilane reagent B1 and polymyxin B as raw materials. The reaction was carried out under conditions of an aqueous organic solvent, and the specific steps are as follows:
[0104] Add 0.2 mmol of acylsilane reagent B1, 1.8 mL of acetonitrile, 0.2 mL of water, 0.01 mmol of polymyxin B, and 0.2 mmol of potassium fluoride to a reaction flask in an air atmosphere. React at 25 °C for 180 min. The amide compound C5 can be obtained by reverse preparative chromatography.
[0105]
[0106]
[0107] Figure 7 This is the high-resolution mass spectrum of amide compound C5 from Example 7. Figure 7 It is known that amide compound C5 is a modified product of polymyxin B. Using polymyxin B as a substrate, the yield of amide compound C5 was calculated to be 66%.
[0108] The acylsilane reagent provided by this invention can react with amine compounds to generate amide compounds. Using the synthesis method of amide compounds provided by this invention, the acylsilane reagent can react with various amine compounds in anhydrous organic solvents or aqueous solutions of organic solvents to obtain amide compounds including dipeptides and high molecular weight compounds. It has a wide range of applicable substrates, fast reaction speed, high selectivity, and high product yield. The obtained peptides and high molecular weight amide compounds can meet the application needs of pharmaceuticals, agrochemicals, polymers, materials and other fine chemicals.
Claims
1. A method for synthesizing an amide compound, characterized in that, This includes reacting an acylsilane reagent as shown in Formula b1 with an amine compound in the presence of a desilylation agent to obtain an amide compound; The structural formula of the acylsilane reagent is as follows: ; The amine compound is selected from benzylamine; The desilication reagent is selected from potassium fluoride; The reaction was carried out under conditions of an aqueous organic solvent; The water content of the organic solvent aqueous solution is 10%~25%; The molar ratio of the acylsilane reagent to the amine compound is (1~2):1; The molar ratio of the desilylation reagent to the acylsilane reagent is (1~2): 1; The reaction temperature is 20~25℃; the reaction time is 5~270 min.
2. The method for synthesizing the amide compound according to claim 1, characterized in that, The acylsilane reagent shown in formula b1 is prepared by a method comprising the following steps: Compound a1 It reacts with elemental bromine to give the acylsilane reagent shown in formula b1.
3. The method for synthesizing the amide compound according to claim 2, characterized in that, The acylsilane reagent of formula b1 is prepared by a reaction comprising at least one of the following conditions: 1) The molar ratio of compound a1 to elemental bromine is 1:(0.8~4); 2) The reaction is carried out in an ether-based organic solvent; 3) The reaction temperature is 20~25℃; 4) The reaction time is 15-17 h.
4. The method for synthesizing the amide compound according to claim 1, characterized in that, The organic solvent includes at least one of tetrahydrofuran, dimethyl sulfoxide, 1,4-dioxane, tert-butanol, and acetonitrile.