An azide-containing asymmetric o-diamine compound and its synthesis method

Abstract

The present invention discloses an azide-containing asymmetric ortho-diamine compound and its synthesis method, belonging to the field of organic synthesis. Under the action of adding a hypervalent iodine reagent and in an inert gas atmosphere, a three-component reaction of an olefin, a diaryl ketimine compound and an azide reagent is realized, completing the asymmetric diamination reaction of the olefin and simultaneously constructing a technical solution for two C-N bonds. The reaction conditions are extremely mild, the olefin raw materials are widely sourced and inexpensive and easily available, the experimental operation is simple and safe, and it is easy to apply and expand; commercially available benzophenone imine and azide reagent are used; the azide group and the imine can be further converted into primary amine compounds, which have very good application prospects in the synthesis of natural products and drug molecules, saving a large amount of research time and shortening the production cycle, and having a foreseeable market commercialization prospect.

Description

Technical Field

[0001] The present invention relates to an azide-containing asymmetric o-diamine compound and a synthesis method thereof, belonging to the field of organic synthesis. Background Art

[0002] O-diamine compounds widely exist in natural products, metal ligands and bioactive small molecules and have extensive applications in the pharmaceutical field. The following figure shows drug molecules with o-diamine structures as examples. However, currently, the synthesis methods of symmetric o-diamines have been intensively reported, while the synthesis methods of asymmetric o-diamine compounds have been less reported.

[0003] Drugs represented by o-diamines:

[0004]

[0005] Azide groups and benzophenone imines are common precursors for synthesizing amine compounds. Derivatives containing azide groups can be reduced to obtain primary amine compounds, and compounds with imine structures can also be hydrolyzed to obtain primary amines, and the two synthetic routes do not interfere with each other. Therefore, it is possible to control the synthesis of asymmetric o-diamine compounds, which have very good application prospects in the synthesis of drug molecules. However, the preparation of the above-mentioned imine functional molecules with β-azide groups is still very challenging. Summary of the Invention

[0006] Therefore, the purpose of the present invention is to provide an azide-containing asymmetric o-diamine compound and a synthesis method thereof.

[0007] Another purpose of the present invention is to provide a method for olefin radical diamination reaction without the participation of transition metals. This method can simultaneously construct two different C-N bonds under mild conditions and has the advantages of low raw material price, wide source, simple and safe experimental operation, and good substrate adaptability.

[0008] Thus, the β-azidoimine derivative of the present invention has the general formula of Formula I:

[0009]

[0010] Wherein:

[0011] R 1 is selected from various groups such as substituted and unsubstituted aryl, heteroaryl, alkynyl, alkyl, carbonyl, ester, amide, and cyano groups;

[0012] R 2 is selected from various groups such as substituted and unsubstituted aryl, heteroaryl, alkyl, cycloalkyl, and hydrogen atoms;

[0013] R 3 ,R4 Groups selected from substituted alkyl, hydrogen atom, and various other groups;

[0014] The present invention provides an azide-containing asymmetric o-diamine derivative and a synthesis method thereof. The method is characterized in that an alkene, an imine, and an azide reagent are mixed and stirred under the conditions of a base, a hypervalent iodine reagent, an organic solvent, and an argon or nitrogen atmosphere, and finally the product is purified.

[0015] In the synthesis method of the present invention, the general formula of the alkene is II:

[0016]

[0017] Wherein:

[0018] R 1 Selected from substituted and unsubstituted aryl, heteroaryl, alkynyl, alkyl, carbonyl, ester, amide, cyano and various other groups;

[0019] R 2 Selected from substituted and unsubstituted aryl, heteroaryl, alkyl, cycloalkyl, hydrogen atom and various other groups;

[0020] R 3 ,R 4 Selected from substituted alkyl, hydrogen atom and various other groups.

[0021] Another object of the present invention is to provide a synthesis method of a β-azido primary amine compound. This method synthesizes a primary amine compound containing an azide group from a purified or unpurified derivative containing an azide and an imine group represented by general formula I, and has the advantages of simple conditions and good yield.

[0022] The β-azido primary amine compound of the present invention has the general formula III:

[0023]

[0024] Wherein:

[0025] R 1 Selected from substituted and unsubstituted aryl, heteroaryl, alkynyl, alkyl, carbonyl, ester, amide, cyano and various other groups;

[0026] R 2 Selected from substituted and unsubstituted aryl, heteroaryl, alkyl, cycloalkyl, hydrogen atom and various other groups;

[0027] R 3 ,R 4 Selected from substituted alkyl, hydrogen atom and various other groups.

[0028] Synthesis method of the present invention. The imine reagent is one of benzophenone imine or substituted diaryl ketone imine. The azide reagent is one or several of trimethylsilyl azide (TMSN3), sodium azide (NaN3), 1-azido-1,2-benziodoxol-3(1H)-one (ABX). The hypervalent iodine reagent is one or several of 1-hydroxy-1,2-benziodoxol-3(1H)-one (BI-OH), 1-acetoxy-1,2-benziodoxol-3-(1H)-one (BI-OAc), hydroxy(tosyloxy)iodobenzene (HTIB), N-iodosuccinimide (NIS), iodobenzene diacetate (PIDA), bis(trifluoroacetic acid)iodobenzene (PIFA). The base is one or several of 4-dimethylaminopyridine (DMAP), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 2-tert-butyl-1,1,3,3-tetramethylguanidine (BTMG), triethylamine, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, lithium methoxide, sodium methoxide, sodium ethoxide, lithium hydroxide. The organic solvent is one or several of tetrahydrofuran, diethyl ether, 1,4-dioxane, ethyl acetate, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, n-hexane, cyclohexane, acetone, toluene, xylene, chlorobenzene, dichloromethane, 1,2-dichloroethane, methanol, ethanol, isopropanol. The molar ratio of the alkene, imine reagent, azide reagent, hypervalent iodine reagent, and base is 1.0:1.0 - 4.0:1.0 - 4.0:0 - 4.0:0 - 4.0; the reaction temperature is 0°C - 100°C; the atmosphere in the reaction vessel is an argon or nitrogen atmosphere; the reaction duration is 1 - 300 min.

[0029] The technical solution of the present invention has the following advantages:

[0030] (I) Under the action of the hypervalent iodine reagent and the base reagent, in an argon or nitrogen atmosphere, the present invention realizes the three-component reaction of an alkene, an imine compound, and an azide reagent, completes the asymmetric diamination reaction of the alkene, and constructs a technical solution for forming two different C-N bonds at the same time; (II) The reaction conditions are extremely mild, the raw materials are widely sourced and inexpensive and readily available, the experimental operation is simple and safe, and it is easy to apply and expand. This method uses commercially available benzophenone imine and azide reagent; (III) o-Diamine compounds widely exist in various drug molecules. The introduction of azide will change the biological activity of the molecule, and azide is a versatile synthetic intermediate, enabling the compound molecule to be better applied in industries such as biomedicine. This method can efficiently synthesize o-diamine derivatives containing azide groups, can be used for the synthesis of β-azido primary amines, saves a large amount of research time and shortens the production cycle, and has a foreseeable market commercialization prospect. Description of the Drawings

[0031] Figure 1 This is the reaction formula of the present invention using α-methylstyrene, benzophenone imine and TMSN3 as raw materials under standard conditions.

[0032] Figure 2 This is the hydrolysis and amidation reaction formula of the product obtained using α-methylstyrene as the raw material under standard reaction conditions.

[0033] Figures 1a - 6a 1H NMR spectra of some examples, Figures 1b - 6b This is the 13C NMR spectra of some examples. Detailed implementation manners

[0034] Now, the present invention will be further described in detail with reference to the following figures. These figures are all simplified schematic diagrams, only illustrating the basic structure of the present invention in a schematic manner, so they only show the components related to the present invention:

[0035]

[0036] Examples 1-9

[0037] Including the following steps:

[0038] (1) Add an alkene, an imine, an azide reagent, a base and an organic solvent into a reaction vessel;

[0039] (2) Under an inert gas atmosphere, add a hypervalent iodine reagent in batches and stir vigorously until no bubbles are generated;

[0040] (3) After the reaction is complete, purify to obtain the product.

[0041]

[0042] Examples 10-15

[0043] Including the following steps:

[0044] (1) Add a purified or unpurified β-azido imine derivative shown in general formula I, an acidic aqueous solution (acetic acid, sulfuric acid, hydrochloric acid or citric acid), and an organic solvent into a reaction vessel;

[0045] (2) Under an air atmosphere, after fully mixing the reactants, stir and react;

[0046] (3) After the reaction is complete, purify to obtain the product.

[0047] The present invention will be further described in detail below with reference to the accompanying drawings and examples.

[0048] The alkene, imine reagent, azide reagent, reaction conditions, reaction products and yields are shown in Table 1:

[0049] Table 1: Reactants and reaction conditions in Examples 1-9

[0050]

[0051]

[0052] The azide-containing diamine derivatives shown in General Formula I, reaction conditions, reaction products and yields are shown in Table 2 as follows:

[0053] Table 2: Reactants and reaction conditions in Examples 10-16

[0054]

[0055] The product synthesized by using the present invention (Example 1) can be further subjected to the following reactions, and o-diamine compounds can be prepared in good yields, providing a new method for synthesizing drug molecules containing 1,2-diamine. The reaction equation is as follows:

[0056]

[0057] The product synthesized by using the present invention (Example 1) can be further subjected to a click reaction with ethisterone to synthesize triazole compounds in excellent yields, and these compounds may have certain biological activities. The reaction equation is as follows:

[0058]

[0059] The NMR data of the products of some examples are as follows:

[0060] The NMR data of the product of Example 1 are as follows:

[0061] 1 H NMR(400MHz,CDCl3)δ(ppm)=7.63(d,J=7.0Hz,2H),7.38–7.29(m,3H),7.22–7.13(m,6H),7.07(t,J=7.6Hz,2H),6.56(d,J=7.5Hz,2H),3.85(d,J=11.9Hz,1H),3.36(d,J=11.8Hz,1H),1.36(s,3H).

[0062] 13 C NMR(100MHz,CDCl3)δ(ppm)=168.3,146.3,140.9,138.4,130.1,128.4,128.1,127.9,127.8,127.5,127.3,126.9,126.5,66.2,64.8,22.2.

[0063] The NMR data of the product of Example 2 are as follows:

[0064] 1 H NMR(400MHz,CDCl3)δ(ppm)=7.83–7.77(m,1H),7.73(d,J=8.6Hz,1H),7.71–7.63(m,3H),7.50–7.35(m,6H),7.34(dd,J=8.2,6.5Hz,2H),7.09(tt,J=7.5,1.3Hz,1H),6.92(t,J=7.6Hz,2H),6.53(d,J=7.4Hz,2H),3.96(d,J=11.9Hz,1H),3.44(d,J=11.9Hz,1H),1.48(s,3H).

[0065] 13 C NMR(100MHz,CDCl3)δ(ppm)=168.6,143.4,140.9,138.2,133.0,132.3,130.1,128.5,128.1,128.0,127.9,127.7,127.6,127.4,127.2,126.0,125.8,125.09,125.06,66.0,65.0,22.4.

[0066] The NMR data of the product of Example 3 are as follows:

[0067] 1 H NMR(400MHz,CDCl3)δ(ppm)=7.65–7.56(m,2H),7.53–7.45(m,2H),7.44–7.36(m,1H),7.32(t,J=7.4Hz,2H),7.30–7.23(m,2H),7.27–7.17(m,1H),7.11(t,J=7.6Hz,2H),6.57(dt,J=9.8,3.3Hz,2H),3.75(d,J=11.9Hz,1H),3.46(d,J=11.9Hz,1H),1.41(s,3H).

[0068] 13 C NMR(100MHz,CDCl3)δ(ppm)=169.2,151.4,140.3,138.0,131.8,130.5,128.4,128.0,127.9,127.6,127.47,127.46,118.7,110.7,65.4,64.7,22.5.

[0069] 1919F NMR (376 MHz, CDCl3) δ (ppm) = -59.3.

[0070] The NMR data of the product of Example 4 are as follows:

[0071] 1 1H NMR (400 MHz, CDCl3) δ (ppm) = 7.64–7.56 (m, 2H), 7.41–7.34 (m, 1H), 7.31 (dd, J = 8.2, 6.4 Hz, 2H), 7.25–7.18 (m, 1H), 7.10 (t, J = 7.6 Hz, 2H), 7.07–6.98 (m, 4H), 6.60 (d, J = 7.5 Hz, 2H), 3.82 (d, J = 12.2 Hz, 1H), 3.71 (d, J = 12.2 Hz, 1H), 2.33 (s, 3H), 2.06 (dq, J = 14.5, 7.3 Hz, 1H), 1.79 (dq, J = 14.6, 7.4 Hz, 1H), 0.93 (t, J = 7.3 Hz, 3H).

[0072] 13 13C NMR (100 MHz, CDCl3) δ (ppm) = 167.1, 143.1, 141.1, 138.7, 136.3, 129.9, 128.7, 128.3, 127.9, 127.5, 127.3, 127.2, 126.7, 66.3, 60.0, 27.6, 21.0, 8.5.

[0073] The NMR data of the product of Example 5 are as follows:

[0074] 1 1H NMR (400 MHz, CDCl3) δ (ppm) = 7.62–7.54 (m, 2H), 7.42–7.36 (m, 1H), 7.32 (dd, J = 8.3, 6.6 Hz, 2H), 7.24–7.16 (m, 6H), 7.09 (t, J = 7.6 Hz, 2H), 6.62 (d, J = 7.0 Hz, 2H), 3.67 (d, J = 12.1 Hz, 1H), 3.45 (d, J = 12.1 Hz, 1H), 1.15–1.06 (m, 2H), 0.97–0.89 (m, 1H), 0.70–0.60 (m, 1H), 0.58–0.49 (m, 1H).

[0075] 1313C NMR (100 MHz, CDCl3) δ (ppm) = 167.8, 146.7, 141.2, 138.8, 130.0, 128.3, 127.9, 127.8, 127.5, 127.3, 126.63, 126.60, 64.6, 58.5, 22.1, 3.2, 2.6.

[0076] The NMR data of the product of Example 6 are as follows:

[0077] 1 1H NMR (400 MHz, CDCl3) δ (ppm) = 7.69–7.63 (m, 2H), 7.63–7.56 (m, 2H), 7.49–7.41 (m, 4H), 7.41–7.30 (m, 4H), 7.20 (dd, J = 8.6, 6.9 Hz, 3H), 7.08 (t, J = 7.6 Hz, 2H), 6.62 (d, J = 7.4 Hz, 2H), 3.92 (d, J = 11.8 Hz, 1H), 3.42 (d, J = 11.8 Hz, 1H), 1.43 (s, 3H).

[0078] 13 13C NMR (100 MHz, CDCl3) δ (ppm) = 168.4, 145.1, 140.8, 140.7, 139.6, 138.4, 130.1, 128.8, 128.4, 128.0, 127.8, 127.5, 127.3, 126.98, 126.95, 126.7, 65.9, 64.6, 22.3.

[0079] The NMR data of the product of Example 7 are as follows:

[0080] 1 1H NMR (400 MHz, CDCl3) δ (ppm) = 7.74–7.68 (m, 2H), 7.42–7.38 (m, 1H), 7.34 (dd, J = 8.3, 6.4 Hz, 2H), 7.29–7.23 (m, 5H), 7.23–7.19 (m, 6H), 7.05 (t, J = 7.6 Hz, 2H), 6.52 (d, J = 6.8 Hz, 2H), 3.87 (s, 2H).

[0081] 13 13C NMR (100 MHz, CDCl3) δ (ppm) = 168.3, 146.2, 141.2, 138.2, 130.2, 128.5, 128.1, 128.0, 127.9, 127.41, 127.37, 127.2, 126.7, 69.9, 59.9.

[0082] The NMR data of the product of Example 8 are as follows:

[0083] 1 H NMR(400MHz,CDCl3)δ(ppm)=7.66–7.59(m,2H),7.43–7.37(m,1H),7.35–7.30(m,2H),7.16–7.08(m,4H),6.89(dd,J=9.8,7.7Hz,2H),6.64–6.53(m,2H),3.80(d,J=11.8Hz,1H),3.39(d,J=11.9Hz,1H),1.38(s,3H).

[0084] 13 C NMR(100MHz,CDCl3)δ(ppm)=168.5,161.74(d,J=246.0Hz),142.0(d,J=3.4Hz),140.7,138.3,137.4,130.2,128.4,128.2(d,J=7.9Hz),128.0,127.70,127.66,127.3,114.8(d,J=21.0Hz),66.0,64.3,22.4.

[0085] 19 F NMR(376MHz,CDCl3)δ(ppm)=-115.63.

[0086] The NMR data of the product of Example 9 are as follows:

[0087] 1 H NMR(400MHz,CDCl3)δ(ppm)=7.63–7.59(m,2H),7.38–7.30(m,8H),7.26–7.19(m,3H),7.12–7.08(m,2H),3.68–3.59(m,2H),1.60(s,3H).

[0088] 13 C NMR(100MHz,CDCl3)δ(ppm)=168.9,140.8,137.2,131.6,130.2,128.60,128.58,128.4,128.3,128.0,127.9,127.8,127.7,122.8,90.4,87.2,63.9,58.7,27.1.

[0089] The NMR data of the product of Example 10 are as follows:

[0090] 11H NMR (400 MHz, CDCl3) δ (ppm) = 7.69 (td, J = 7.7, 1.8 Hz, 1H), 7.35 (d, J = 7.8 Hz, 1H), 7.25–7.17 (m, 1H), 4.15 (dd, J = 7.3, 5.3 Hz, 1H), 3.66 (dd, J = 12.0, 5.3 Hz, 1H), 3.54 (dd, J = 12.0, 7.3 Hz, 1H), 1.92–1.81 (br, 2H).

[0091] 13 13C NMR (100 MHz, CDCl3) δ (ppm) = 160.9, 149.4, 136.8, 122.6, 121.6, 58.0, 56.6.

[0092] The NMR data of the product of Example 11 are as follows:

[0093] 1 1H NMR (400 MHz, CDCl3) δ (ppm) = 7.87–7.82 (m, 4H), 7.53–7.45 (m, 3H), 4.31 (dd, J = 8.4, 4.5 Hz, 1H), 3.62 (dd, J = 12.0, 4.5 Hz, 1H), 3.47 (dd, J = 12.1, 8.3 Hz, 1H), 1.97–1.90 (br, 2H).

[0094] 13 13C NMR (100 MHz, CDCl3) δ (ppm) = 139.4, 133.3, 133.0, 128.5, 127.9, 127.7, 126.3, 126.0, 125.3, 124.5, 58.9, 55.6.

[0095] The NMR data of the product of Example 12 are as follows:

[0096] 1 1H NMR (400 MHz, CDCl3) δ (ppm) = 7.62 (dd, J = 7.8, 1.8 Hz, 1H), 7.37 (dd, J = 7.7, 1.6 Hz, 1H), 7.32–7.17 (m, 2H), 3.99 (d, J = 12.1 Hz, 1H), 3.72 (d, J = 12.1 Hz, 1H), 2.25–1.85 (br, 2H), 1.62 (s, 3H). 13 13C NMR (100 MHz, CDCl3) δ (ppm) = 141.6, 132.1, 131.9, 128.8, 128.5, 127.1, 60.3, 56.9, 26.0.

[0097] The NMR data of the product of Example 13 are as follows:

[0098] 1 H NMR(400MHz,CDCl3)δ(ppm)=7.44–7.33(m,2H),6.96–6.81(m,2H),3.80(s,3H),3.51(d,J=11.9Hz,1H),3.42(d,J=11.9Hz,1H),1.84–1.75(m,2H),1.48(s,3H).

[0099] 13 C NMR(100MHz,CDCl3)δ(ppm)=158.5,137.5,126.4,113.6,63.9,55.3,55.2,28.2.

[0100] The NMR data of the product of Example 14 are as follows:

[0101] 1 H NMR(400MHz,CDCl3)δ(ppm)=8.13–7.73(m,2H),7.63–7.41(m,3H),6.85–6.28(m,1H),2.84–2.50(m,1H),2.45–2.21(m,2H),2.17–1.78(m,2H),1.78–1.59(m,1H),1.59–1.44(m,6H),1.44–1.19(m,1H),1.06–0.90(m,3H).

[0102] 13 C NMR(100MHz,CDCl3)δ(ppm)=206.1,204.5,167.3,166.9,134.1,133.5,132.1,131.9,130.1,128.8,128.7,128.4,127.02,126.95,69.3,68.0,67.6,66.8,49.5,48.2,36.0,33.7,32.1,30.5,29.6,28.5,23.0,22.9,22.6,22.5,22.0,19.6.

[0103] The NMR data of the product of Example 15 are as follows:

[0104] 11H NMR (400 MHz, CDCl3) δ (ppm) = 7.52–7.44 (m, 2H), 7.37 (dd, J = 8.6, 6.9 Hz, 2H), 7.32–7.24 (m, 1H), 3.55 (d, J = 11.9 Hz, 1H), 3.46 (d, J = 11.9 Hz, 1H), 1.72–1.67 (br, 2H), 1.50 (s, 3H).

[0105] 13 13C NMR (100 MHz, CDCl3) δ (ppm) = 145.6, 128.4, 127.1, 125.3, 63.9, 55.8, 28.2.

[0106] Note: The specific reaction equations and NMR spectra are shown in the attached drawings of the specification for details.

[0107] Taking the ideal embodiments of the present invention described above as inspiration, through the above description, relevant staff can completely make various changes and modifications without departing from the technical idea of this invention. The technical scope of this invention is not limited to the content in the specification, and its technical scope must be determined according to the scope of the claims.

Claims

1. A method for preparing a compound of formula I from an olefin, characterized in that, A three-component reaction of an alkene, an imine reagent, and an azide reagent is carried out by mixing them under the conditions of a base reagent, a hypervalent iodine reagent, an organic solvent, and an argon or nitrogen atmosphere, and finally the product is obtained by purification; The formula I is selected from any one of the following structural formulas: , , , , , , , , , , , , ; The imine reagent is benzophenone imine; the azide reagent is trimethylsilyl azide; the hypervalent iodine reagent is iodobenzene bis(trifluoroacetate); The base is 4-dimethylaminopyridine; The olefin is selected from any one of the following structural formulas: , , , , , , , , , , , , , ; The organic solvent is 1,4-dioxane.

2. The method according to claim 1, wherein The molar ratio of the alkene, the imine reagent, the azide reagent, the hypervalent iodine reagent, and the base is 0.2:0.3:0.6:0.5:0.4; the reaction temperature is 0 °C - 100 °C; the atmosphere in the reaction vessel is an argon or nitrogen atmosphere; the reaction time is 1 - 300 min.

3. A method for synthesizing β-azido primary amine compounds, characterized in that, The compound of formula 1 prepared by the method described in claim 1 is reacted by mixing under the conditions of an acidic aqueous solution, an organic solvent, and an air atmosphere, and the product is obtained by purification; The compound of Formula 1 is selected from any one of the following structures; , , , , , ; The product is selected from any one of the following structural formulas: , , , , , ; The acidic aqueous solution is one of acetic acid, sulfuric acid, hydrochloric acid, and citric acid.

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