Method for carbon-nitrogen bond breakage ring-opening alkylation of proline derivative

Abstract

The invention discloses a method for carbon-nitrogen bond breakage ring-opening alkylation of proline derivatives, and belongs to the field of organic synthesis. A three-step method is adopted, firstly, L-proline and benzoyl chloride serve as raw materials, (S)-N-benzoyl proline is obtained under the action of alkali, then (S)-N-benzoyl proline and aniline are subjected to condensation, and (S)-N-benzoyl proline aniline is obtained; then, the obtained (S)-N-benzoyl proline aniline and olefin are used as raw materials, and under the action of borane, mercaptan, a free radical initiator and an additive, carbon-nitrogen bond breakage ring-opening alkylation of the proline derivative is achieved. Compared with the reported ring-opening reaction of tetrahydropyrrole, the method provided by the invention has the advantages of excellent atom economy, no need of using expensive transition metal, no need of using excessive oxidant and super-stoichiometric additive and the like.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of organic synthesis, and particularly relates to a method for breaking a carbon-nitrogen bond of a proline derivative and ring-opening alkylation. BACKGROUND

[0002] Due to the unique properties of nitrogen atoms, organic amine molecules have important application values in many fields such as drug research and development, pesticide chemistry, polymer chemistry and material science. Therefore, scientific researchers are committed to developing new synthesis methods of nitrogen-containing compounds, and have made significant progress. However, developing innovative strategies for efficiently constructing nitrogen-containing skeletons is still a core topic in the field of synthetic chemistry.

[0003] As a renewable natural amino acid with biological activity, the high-value conversion of the tetrahydropyrrole skeleton of proline has been an important research direction in the field of organic synthesis. Although the carbon-hydrogen bond functionalization of tetrahydropyrrole derivatives has been widely studied, due to the inherent low ring strain characteristics of the five-membered ring, the selective cleavage of the carbon-nitrogen bond for ring-opening conversion still faces significant challenges. In particular, for the ring-opening alkylation reaction of the tetrahydropyrrole structure, there has been no report so far.

[0004] Currently, the following representative methods have successfully achieved the carbon-nitrogen bond cleavage and ring-opening functionalization of the tetrahydropyrrole ring. Among them, the ring-opening hydrogenation reaction of the tetrahydropyrrole structure can be achieved by using transition metals or strong reducing agents (Honda T., Chem. Commun., 1999, 12, 1065-1066.), while the ring-opening oxidation reaction of the tetrahydropyrrole structure can be achieved by using strong oxidizing agents (Sarpong R., Nature, 2018, 564, 244-248.) or electrochemical oxidation (Ruan Z., Nat. Commun., 2024, 15, 5181.). By adding an activating agent to convert the cyclic amine into a quaternary ammonium ion, followed by nucleophilic substitution reaction with a negative ion, the carbon-nitrogen bond cleavage and ring-opening halogenation (Seo S., Nat. Commun., 2020, 11, 4761.), sulfuration and phenolation (Song Q., ACS Cent. Sci., 2020, 6, 1819-1826.) reactions can be achieved. Under photocatalytic conditions, using carbon dioxide (Yu D., Angew. Chem. Int. Ed., 2023, 62, e202217918.) or a transition metal photocatalyst (Yamaguchi J., J. Am. Chem. Soc., 2024, 146, 30698-30707.) can achieve the ring-opening carboxylation or alkenylation reaction of the tetrahydropyrrole ring.

[0005] Although some progress has been made in the ring-opening reaction of tetrahydropyrrole, the use of noble metal catalysts, excess oxidizing agents and reducing agents, or superstoichiometric additives limits the application of these strategies. More importantly, the methods commonly used to achieve direct alkylation are through radical addition to alkenes followed by hydrogen atom transfer to obtain the product, but the radical intermediates are difficult to exist stably under the strong redox conditions described above. Therefore, it is of great significance to develop a method suitable for proline derivatives and capable of intermolecular reaction with alkenes to generate ring-opening alkylation products. SUMMARY

[0006] The present application aims at the deficiencies of the prior art and provides a method for breaking the carbon-nitrogen bond of proline derivatives and ring-opening alkylation. The present application designs and realizes Lewis acid activation, Lewis base-boron radical-mediated C-N bond cleavage and ring-opening alkylation of proline derivatives. This method does not require the use of photocatalysts and transition metals, has relatively mild reaction conditions, good regioselectivity, and a wide range of substrates.

[0007] The method for breaking the carbon-nitrogen bond of proline derivatives and ring-opening alkylation of the present application adopts a three-step method, including the following steps:

[0008] Step 1: Under a nitrogen atmosphere, proline substrate and base 1 are added to solvent 1, then benzoyl chloride is added dropwise to the system under an ice water bath environment, the reaction endpoint is determined by thin layer chromatography, the reaction is quenched by adding water, the aqueous phase is extracted with dichloromethane, the combined organic phase is dried over anhydrous sodium sulfate, concentrated by rotary evaporation, and then purified by column chromatography to obtain (S)-N-benzoyl proline.

[0009] In step 1, the proline substrate is L-proline, the base 1 is triethylamine, and the solvent 1 is dichloromethane.

[0010] Further, the molar ratio of proline substrate, benzoyl chloride and base is 1.0:1.1:1.1.

[0011] The synthetic route of this step is as follows:

[0012] .

[0013] Step 2: Under a nitrogen atmosphere, (S)-N-benzoyl proline obtained in step 1, a condensing agent and base 2 are added to solvent 1, then an aromatic amine is added dropwise to the system under an ice water bath environment, the reaction endpoint is determined by thin layer chromatography, and then purified by silica gel column chromatography to obtain (S)-N-benzoyl proline aniline.

[0014] In step 2, the condensing agent is 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride, the base 2 is 4-dimethylaminopyridine, and the aromatic amine is aniline.

[0015] Further, the molar ratio of (S)-N-benzoyl proline, arylamine, condensing agent and base 2 is 1.0:0.95:1.2:0.1.

[0016] The synthetic route of this step is shown as follows:

[0017] .

[0018] Step 3: (S)-N-benzoyl proline and olefin, borane, thiol, initiator and additive obtained in step 2 are added into solvent 2 under nitrogen atmosphere, and reacted at 120°C for 18 hours. The reaction solution is rotary evaporated to obtain a crude product, which is separated and purified by column chromatography to obtain the ring-opening alkylated product.

[0019] In step 3, the borane is p-dimethylaminopyridine-borane; the thiol is 2,6-dimethylbenzenethiol or methyl 2-mercaptobenzoate; the initiator is di-tert-butyl peroxide; the additive is magnesium trifluoromethanesulfonate; and the solvent 2 is acetonitrile.

[0020] Further, the molar ratio of (S)-N-benzoyl proline, arylamine, condensing agent and base 2 is 1.0:0.95:1.2:0.1.

[0021] Further, the concentration of (S)-N-benzoyl proline in the reaction system is controlled at 0.1 mol / L.

[0022] The synthetic route of this step is shown as follows:

[0023]

[0024] wherein: R is selected from one or more of substituted or unsubstituted aryl, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl. The substituents include one or more of alkyl substitution, alkoxy substitution, cycloalkyl substitution, heteroatom substitution (N, O, S, etc.), ester substitution. When R is substituted or unsubstituted aryl, it is generally more favorable to the reaction. When R is alkoxy, cycloalkyl or alkyl, the efficiency of the ring-opening alkylation reaction will be reduced to some extent.

[0025] Further, the olefin is 4-methoxystyrene, 4-aminostyrene, 4-vinylbenzocyclobutene, 5-vinyl-2,3-dihydrobenzofuran, 5-vinyl-1H-indole, 1,1-diphenylethylene, N-vinylcarbazole, vinyl n-butyl ether, ethyl 4-methylene cyclohexanecarboxylate, n-decene or (8R,9S,13S,14S,17S)-17-methoxy-13-methyl-3-vinyl-6H-cyclopenta[a]pentalenophane.

[0026] The general synthetic route is shown as follows:

[0027]

[0028] The present application develops a unique boron radical-promoted ring-opening alkylation strategy for proline derivatives, which utilizes magnesium salt as a Lewis acid to activate the reaction substrate, and achieves carbon-nitrogen bond cleavage through a radical center transfer mechanism. The types and equivalent ratios of the components are very important, for example, when the amount of borane, olefin or additive is changed, the reaction yield will be greatly reduced or even the reaction cannot occur; when the olefin is replaced from aryl olefin to alkyl olefin, the reaction effect will be obviously worse, and at this time, replacing the thiol from 2,6-dimethylbenzenethiol to 2-mercaptobenzoic acid methyl ester can improve the reaction yield to a certain extent. Such boron radical-mediated ring-opening functionalization strategy is expected to have a broader application prospect in the field of organic synthesis and medicinal chemistry. The compounds generated by the method can be obtained by subsequent steps to synthesize key intermediates of HDAC inhibitors. DETAILED DESCRIPTION

[0029] The organic synthesis technical solutions involved in the embodiments of the present application will be described in more detail and clearly below. Obviously, the following series of embodiments are only a part of the present application, not all embodiments. Other embodiments obtained by ordinary skilled in the art without creative labor on the basis of any reported embodiments of the present application all belong to the protection scope of the present application.

[0030] Example 1:

[0031] 1. The synthesis of (S)-N-benzoyl proline aniline is as follows:

[0032]

[0033] Under a nitrogen atmosphere, L-proline (20.1 mmol) and triethylamine (1.1 equivalent) were added to 100 mL of dichloromethane, and benzoyl chloride was added dropwise under an ice-water bath environment, and the reaction was continued at room temperature after the dropwise addition was completed. The reaction endpoint was determined by thin layer chromatography point plate, and the reaction was quenched with water, and the water phase was extracted with dichloromethane, and the obtained organic phase was dried over anhydrous sodium sulfate, concentrated by rotary evaporation, and then preliminarily purified by column chromatography (using ethyl acetate as the eluent) to obtain the crude product of the intermediate.

[0034] Add 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.2 equivalents) and 4-dimethylaminopyridine (0.1 equivalents) to the crude product, then dissolve in dichloromethane (0.5 M). Place the reaction mixture in an ice-water bath and slowly add aniline (0.95 equivalents) dropwise while stirring. After the addition is complete, stir at room temperature until TLC monitoring shows complete consumption of aniline. Transfer the reaction mixture to rotary evaporation to obtain the crude product to be purified, and purify by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1, V / V) to give (S)-N-benzoylprolylaniline. The overall yield was 57%; the product was a white solid.

[0035] 1 H NMR (500 MHz, CDCl3) δ 9.56 (1H, s), 7.58-7.56 (2H, m), 7.53-7.51(2H, m), 7.46-7.41 (3H, m), 7.31-7.28 (2H, m), 7.09-7.06 (1H, m), 5.01-4.98(1H, m), 3.59-3.49 (2H, m), 2.72-2.66 (1H, m), 2.15-2.00 (2H, m), 1.92-1.85(1H, m); 13 C NMR (125 MHz, CDCl3) δ 172.0, 168.5, 135.8, 135.5, 130.5, 128.9,128.5, 127.1, 124.0, 119.8, 60.7, 50.6, 26.2, 25.4.

[0036] 2. The synthetic steps of N-[6-(4-methoxyphenyl)-4-(phenylcarbamoyl)hexyl]benzamide are as follows:

[0037]

[0038] (S)-N-benzoylprolylaniline (0.3000 mmol), 4-methoxystyrene (12.0 equivalents), p-dimethylaminopyridine-borane (3.0 equivalents), di-tert-butylperoxide (1.5 equivalents), 2,6-dimethylbenzylthiophenol (0.5 equivalents), and magnesium trifluoromethanesulfonate (0.5 equivalents) were added under a nitrogen atmosphere and dissolved in 3 mL of acetonitrile. The reaction mixture was reacted at 120 °C for 18 hours. The reaction solution was rotary evaporated and then purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) to give N-[6-(4-methoxyphenyl)-4-(phenylcarbamoyl)hexyl]benzamide. The yield was 80%; the product was a white solid.

[0039] 1H NMR (500 MHz, CDCl3) δ 7.81 (1H, s), 7.76 (2H, d, J = 7.5 Hz), 7.60(2H, d, J = 8.0 Hz), 7.51-7.48 (1H, m), 7.44-7.41 (2H, m), 7.32-7.29 (2H, m),7.11-7.07 (3H, m), 6.82 (2H, d, J = 9.0 Hz), 6.38 (1H, t, J = 5.5 Hz), 3.78(3H, s), 3.63-3.56 (1H, m), 3.36-3.30 (1H, m), 2.74-2.68 (1H, m), 2.57-2.51(1H, m), 2.42-2.38 (1H, m), 2.12-2.05 (1H, m), 1.84-1.72 (2H, m), 1.69-1.64(2H, m), 1.59-1.52 (1H, m); 13 C NMR (100 MHz, CDCl3) δ 174.2, 168.0, 157.8,138.2, 134.3, 133.6, 131.5, 129.2, 128.8, 128.5, 126.9, 124.0, 119.8, 113.8,55.2, 46.4, 39.1, 34.3, 32.7, 29.9, 27.4。

[0040] Example 2:

[0041] The synthesis of N-[6-(4-aminophenyl)-4-(phenylcarbamoyl)hexyl]benzamide in this example is as follows:

[0042]

[0043] (S)-N-benzoylprolinamide (0.2990 mmol), 4-aminostyrene (12.0 eq), p-dimethylaminopyridine-borane (3.0 eq), di-tert-butyl peroxide (1.5 eq), 2,6-dimethylbenzenethiol (0.5 eq) and magnesium triflate (0.5 eq) were added under nitrogen atmosphere, dissolved in 3 mL of acetonitrile, and reacted at 120 °C for 18 hours. The reaction solution was rotary evaporated, and then purified using a silica gel column (petroleum ether / ethyl acetate = 3:1), to finally obtain N-[6-(4-aminophenyl)-4-(phenylcarbamoyl)hexyl]benzamide. The isolated yield was 77%; the product was a brown solid.

[0044] 1 H NMR (400 MHz, CD3OD) δ 7.75-7.73 (2H, m), 7.54-7.52 (2H, m), 7.45-7.41 (1H, m), 7.38-7.34 (2H, m), 7.26-7.22 (2H, m), 7.05-7.01 (1H, m), 6.88-6.86 (2H, m), 6.62-6.59 (2H, m), 3.38-3.29 (2H, m), 2.48-2.35 (3H, m), 1.93-1.84 (1H, m), 1.73-1.49 (5H, m); 13 C NMR (125 MHz, CD3OD) δ 177.1, 170.3,146.2, 139.6, 135.8, 132.9, 132.5, 130.0, 129.8, 129.5, 128.2, 125.3, 121.6,117.0, 48.1, 40.9, 36.2, 34.0, 31.6, 28.5。

[0045] Example 3:

[0046] The synthesis of N-[6-(benzocyclobutene-3-yl)-4-(phenylaminocarbonyl)hexyl]benzamide in this example is as follows:

[0047]

[0048] (S)-N-benzoylprolinamide (0.2888 mmol), 4-vinylbenzocyclobutene (12.0 eq), p-dimethylaminopyridine-borane (3.0 eq), di-tert-butyl peroxide (1.5 eq), 2,6-dimethylbenzenethiol (0.5 eq) and magnesium triflate (0.5 eq) were added under nitrogen atmosphere, dissolved in 3 mL of acetonitrile, and reacted at 120 °C for 18 hours. The reaction solution was rotary evaporated, and then purified using a silica gel column (petroleum ether / ethyl acetate = 3:1) to finally obtain N-[6-(benzocyclobutene-3-yl)-4-(phenylaminocarbonyl)hexyl]benzamide. The isolated yield was 65%. The product was a white solid.

[0049] 1H NMR (400 MHz, CDC13) δ 7.90 (1H, s), 7.77 (2H, d, J = 7.6 Hz), 7.59 (2H, d, J = 8.0 Hz), 7.51-7.47 (1H, m), 7.43-7.39 (2H, m), 7.32-7.28 (2H, m), 7.10-7.07 (1H, m), 7.01-6.93 (2H, m), 6.89 (1H, s), 6.50 (1H, s br), 3.60-3.52 (1H, m), 3.37-3.29 (1H, m), 3.12 (4H, s), 2.75-2.68 (1H, m), 2.60-2.52 (1H, m), 2.43-2.36 (1H, m), 2.12-2.03 (1H, m), 1.85-1.75 (2H, m), 1.69-1.60 (2H, m), 1.58-1.49 (1H, m); 13 C NMR (100 MHz, CDC13) δ 174.1, 168.0, 146.0, 143.3, 140.2, 138.1, 134.3, 131.5, 128.9, 128.6, 126.9, 126.9, 124.1, 122.6, 122.4, 119.8, 46.5, 39.1, 34.6, 34.3, 29.9, 29.3, 29.2, 27.4.

[0050] Example 4:

[0051] The synthesis of N-[6-(2,3-dihydro-5-benzofuranyl)-4-(phenylcarbamoyl)hexyl]benzamide in this example is as follows:

[0052]

[0053] (S)-N-benzoylprolinamide (0.2969 mmol), 5-vinyl-2,3-dihydrobenzofuran (12.0 eq), p-dimethylaminopyridine-borane (3.0 eq), di-tert-butyl peroxide (1.5 eq), 2,6-dimethylbenzenethiol (0.5 eq), and magnesium triflate (0.5 eq) were added under nitrogen atmosphere, dissolved in 3 mL of acetonitrile, and reacted at 120 °C for 18 hours. The reaction solution was rotary evaporated and then purified using a silica gel column (petroleum ether / ethyl acetate = 3:1) to finally obtain N-[6-(2,3-dihydro-5-benzofuranyl)-4-(phenylaminocarbonyl)hexyl]benzamide. The isolated yield was 75%; the product was a light yellow solid.

[0054] 1 H NMR (400 MHz, CDCl3) δ 8.04 (1H, s), 7.76 (2H, d, J = 7.2 Hz), 7.60(2H, d, J = 7.6 Hz), 7.50-7.46 (1H, m), 7.42-7.38 (2H, m), 7.31-7.27 (2H, m),7.10-7.06 (1H, m), 7.00 (1H, s), 6.88 (1H, d, J = 8.0 Hz), 6.68 (1H, d, J =8.0 Hz), 6.56 (1H, t, J = 5.6 Hz), 4.51 (2H, t, J = 8.6 Hz), 3.59-3.49 (1H,m), 3.35-3.27 (1H, m), 3.13 (2H, t, J = 8.6 Hz), 2.69-2.62 (1H, m), 2.55-2.48(1H, m), 2.44-2.37 (1H, m), 2.10-2.00 (1H, m), 1.82-1.70 (2H, m), 1.68-1.59(2H, m), 1.56-1.50 (1H, m); 13 C NMR (100 MHz, CDCl3) δ 174.2, 168.0, 158.3,138.2, 134.3, 133.5, 131.5, 128.9, 128.6, 127.7, 127.1, 126.9, 124.9, 124.0,119.8, 108.9, 71.1, 46.4, 39.1, 34.5, 33.1, 29.9, 29.7, 27.4。

[0055] Example 5:

[0056] The synthesis of N-[6-(lH-indol-5-yl)-4-(phenylcarbamoyl)hexyl]benzamide in this example is as follows:

[0057]

[0058] (S)-N-benzoylprolinamide (0.2959 mmol), 5-vinyl-lH-indole (12.0 eq), p-dimethylaminopyridine-borane (3.0 eq), di-tert-butyl peroxide (1.5 eq), 2,6-dimethylbenzenethiol (0.5 eq), and magnesium triflate (0.5 eq) were added under nitrogen atmosphere, dissolved in 3 mL of acetonitrile, and reacted at 120 °C for 18 hours. The reaction solution was rotary evaporated and then purified using a silica gel column (petroleum ether / ethyl acetate = 2: 1), and finally N-[6-(lH-indol-5-yl)-4-(phenylcarbamoyl)hexyl]benzamide was obtained. The isolated yield was 60%; the product was a yellow solid.

[0059] 1 H NMR (500 MHz, CDCl3) δ 8.16 (1H, s), 7.76-7.75 (2H, m), 7.59-7.55(3H, m), 7.50-7.47 (1H, m), 7.44-7.40 (3H, m), 7.33-7.29 (3H, m), 7.20-7.19(1H, m), 7.11-7.08 (1H, m), 7.04 (1H, dd, J = 8.3 1.3 Hz), 6.49 (1H, m), 6.36(1H, m), 3.57-3.50 (1H, m), 3.38-3.31 (1H, m), 2.90-2.85 (1H, m), 2.73-2.67(1H, m), 2.39-2.34 (1H, m), 2.19-2.11 (1H, m), 1.91-1.81 (2H, m), 1.71-1.61(2H, m), 1.58-1.54 (1H, m); 13 C NMR (125 MHz, CDCl3) δ 174.2, 167.8, 138.1,134.5, 134.4, 132.7, 131.5, 128.9, 128.6, 128.1, 126.9, 124.5, 124.1, 122.9,120.0, 119.7, 111.0, 102.3, 46.4, 39.1, 34.7, 33.6, 29.9, 27.4。

[0060] Example 6:

[0061] The synthesis of N-[6,6-diphenyl-4-(phenylcarbamoyl)hexyl]benzamide in this example is as follows:

[0062]

[0063] (S)-N-benzoylprolinamide (0.2979 mmol), 1,1-diphenylethylene (12.0 eq), p-dimethylaminopyridine-borane (3.0 eq), di-tert-butyl peroxide (1.5 eq), 2,6-dimethylbenzenethiol (0.5 eq), and magnesium triflate (0.5 eq) were added under nitrogen atmosphere, dissolved in 3 mL of acetonitrile, and reacted at 120 °C for 18 hours. The reaction solution was rotary evaporated and then purified using a silica gel column (petroleum ether / ethyl acetate = 3:1) to finally obtain N-[6,6-diphenyl-4-(phenylcarbamoyl)hexyl]benzamide. The isolated yield was 64%; the product was a white solid.

[0064] 1 H NMR (400 MHz, CDCl3) δ 7.78-7.74 (3H, m), 7.58 (2H, d, J = 7.6 Hz),7.53-7.49 (1H, m), 7.45-7.34 (6H, m), 7.32-7.28 (5H, m), 7.26-7.24 (2H, m),7.20-7.12 (2H, m), 6.56 (1H, t, J = 5.8 Hz), 4.04-4.00 (1H, m), 3.47-3.40(1H, m), 3.33-3.26 (1H, m), 2.56-2.49 (1H, m), 2.34-2.23 (2H, m), 1.88-1.81(1H, m), 1.68-1.55 (3H, m); 13 C NMR (100 MHz, CDCl3) δ 173.8, 167.8, 144.7,143.4, 138.0, 134.3, 131.5, 128.9, 128.7, 128.5, 128.4, 128.1, 127.5, 126.9,126.6, 126.2, 124.1, 119.7, 49.1, 45.2, 39.0, 38.4, 30.1, 27.3。

[0065] Example 7:

[0066] The synthesis of N-[6-(9H-carbazol-9-yl)-4-(phenylcarbamoyl)hexyl]benzamide in this example is as follows:

[0067]

[0068] (S)-N-benzoylprolinamide (0.2895 mmol), N-vinylcarbazole (12.0 eq), p-dimethylaminopyridine-borane (3.0 eq), di-tert-butyl peroxide (1.5 eq), 2,6-dimethylbenzenethiol (0.5 eq), and magnesium triflate (0.5 eq) were added under nitrogen atmosphere, dissolved in 3 mL of acetonitrile, and reacted at 120 °C for 18 hours. The reaction solution was rotary evaporated, and then purified using a silica gel column (petroleum ether / ethyl acetate = 3:1) to finally obtain N-[6-(9H-carbazol-9-yl)-4-(phenylcarbamoyl)hexyl]benzamide. The isolated yield was 41%; the product was a light yellow solid.

[0069] 1 H NMR (500 MHz, CDCl3) δ 8.16 (1H, s), 8.08 (2H, d, J = 7.5 Hz), 7.70(2H, d, J = 7.5 Hz), 7.61 (2H, d, J = 8.0 Hz), 7.49-7.37 (7H, m), 7.33-7.30(2H, m), 7.24-7.20 (2H, m), 7.12-7.09 (1H, m), 6.34 (1H, t, J = 5.8 Hz),4.43-4.31 (2H, m), 3.55-3.48 (1H, m), 3.17-3.11 (1H, m), 2.45-2.34 (2H, m),2.05-1.97 (1H, m), 1.78-1.71 (1H, m), 1.58-1.46 (3H, m); 13 C NMR (125 MHz,CDCl3) δ 173.3, 168.2, 140.2, 138.3, 134.1, 131.7, 128.9, 128.6, 126.8,125.7, 124.0, 122.9, 120.3, 119.7, 118.9, 108.8, 43.4, 41.0, 38.4, 30.3,30.1, 27.3。

[0070] Example 8:

[0071] The synthesis of N-[6-butoxy-4-(phenylcarbamoyl)hexyl]benzamide in this example is as follows:

[0072]

[0073] (S)-N-benzoylprolylphenylamide (0.2918 mmol), n-butyl vinyl ether (12.0 eq), p-dimethylaminopyridine-borane (3.0 eq), di-tert-butyl peroxide (1.5 eq), methyl 2-mercaptobenzoate (0.5 eq), and magnesium triflate (0.5 eq) were added under nitrogen atmosphere, dissolved in 3 mL of acetonitrile, and reacted at 120 °C for 18 hours. The reaction solution was rotary evaporated, and then purified using a silica gel column (petroleum ether / ethyl acetate = 3:1) to finally obtain N-[6-butoxy-4-(phenylcarbamoyl)hexyl]benzamide. The isolated yield was 34%; the product was a yellow solid.

[0074] 1 H NMR (500 MHz, CDCl3) δ 8.22 (1H, s), 7.80 (2H, d, J = 7.5 Hz), 7.57(2H, d, J = 8.0 Hz), 7.49-7.46 (1H, m), 7.42-7.39 (2H, m), 7.31-7.28 (2H, m),7.09-7.06 (1H, m), 6.64 (1H, s br), 3.60-3.53 (1H, m), 3.51-3.36 (5H, m),2.66-2.60 (1H, m), 1.96-1.77 (3H, m), 1.74-1.63 (2H, m), 1.59-1.50 (3H, m),1.41-1.33 (2H, m), 0.91 (3H, t, J = 7.5 Hz); 13 C NMR (100 MHz, CDCl3) δ 174.1,167.8, 138.3, 134.4, 131.4, 128.9, 128.5, 126.9, 123.9, 119.6, 70.9, 68.4,43.7, 39.2, 32.7, 31.8, 29.4, 27.3, 19.4, 13.9。

[0075] Example 9:

[0076] The synthesis of 4-[5-(benzamide)-2-(phenylcarbamoyl)pentyl]cyclohexane ethyl ester in this example is as follows:

[0077]

[0078] (S)-N-benzoylprolinamide (0.2945 mmol), ethyl 4-methylene cyclohexanecarboxylate (12.0 eq), p-dimethylaminopyridine-borane (3.0 eq), di-tert-butyl peroxide (1.5 eq), methyl 2-mercaptobenzoate (0.5 eq) and magnesium triflate (0.5 eq) were added under nitrogen atmosphere, dissolved in 3 mL of acetonitrile and reacted at 120 °C for 18 hours. The reaction was evaporated and then purified using a silica gel column (petroleum ether / ethyl acetate = 3:1) to finally obtain ethyl 4-[5-(benzamido)-2-(phenylcarbamoyl)pentyl]cyclohexanecarboxylate. The isolated yield was 33%; the product was a white solid.

[0079] 1 H NMR (400 MHz, CDCl3) δ 8.41 (1H, s), 7.78-7.76 (2H, m), 7.62-7.59(2H, m), 7.50-7.46 (1H, m), 7.42-7.38 (2H, m), 7.29-7.25 (2H, m), 7.08-7.04(1H, m), 6.67-6.65 (1H, m), 4.14-4.06 (2H, m), 3.67-3.59 (1H, m), 3.36-3.28(1H, m), 2.61-2.54 (1H, m), 2.20-2.12 (1H, m), 1.95-1.89 (4H, m), 1.77-1.61(5H, m), 1.53-1.41 (2H, m), 1.39-1.29 (2H, m), 1.24-1.21 (3H, m), 0.98-0.83(2H, m); 13 C NMR (100 MHz, CDCl3) δ 176.1, 174.6, 168.1, 138.3, 134.2, 131.6,128.8, 128.6, 126.9, 123.9, 119.8, 60.1, 43.9, 43.3, 39.6, 38.8, 35.0, 32.7,32.0, 30.2, 28.8, 28.7, 27.3, 14.2。

[0080] Example 10:

[0081] The synthesis of N-[4-(phenylcarbamoyl)tetradecyl]benzamide in this example was as follows:

[0082]

[0083] (S)-N-benzoylprolinamide (0.2969 mmol), n-decene (12.0 eq), p-dimethylaminopyridine-borane (3.0 eq), di-tert-butyl peroxide (1.5 eq), methyl 2-mercaptobenzoate (0.5 eq) and magnesium triflate (0.5 eq) were added under nitrogen atmosphere, dissolved in 3 mL of acetonitrile, and reacted at 120 °C for 18 hours. The reaction solution was rotary evaporated, and then purified using a silica gel column (petroleum ether / ethyl acetate = 3:1), to finally obtain N-[4-(phenylcarbamoyl)tetradecyl]benzamide. The isolated yield was 25%; the product was a light yellow solid.

[0084] 1 H NMR (400 MHz, CDCl3) δ 8.10 (1H, s), 7.78-7.76 (2H, m), 7.62-7.60(2H, m), 7.51-7.46 (1H, m), 7.43-7.39 (2H, m), 7.30-7.26 (2H, m), 7.09-7.05(1H, m), 6.57 (1H, t, J = 5.8 Hz), 3.64-3.56 (1H, m), 3.38-3.30 (1H, m),2.42-2.35 (1H, m), 1.79-1.60 (4H, m), 1.54-1.39 (2H, m), 1.30-1.23 (16H, m),0.87 (3H, t, J = 6.8 Hz); 13 C NMR (100 MHz, CDCl3) δ 174.6, 168.0, 138.2,134.3, 131.5, 128.8, 128.6, 126.9, 124.0, 119.8, 47.3, 39.1, 32.8, 31.9,29.8, 29.7, 29.6, 29.6, 29.5, 29.3, 27.7, 27.4, 22.7, 14.1。

[0085] Example 11:

[0086] The synthesis of N-[6-((8R,9S,13S,14S,17S)-17-methoxy-13-methyl-6H- cyclopenta[a]pentalenophan-3-yl)-4-(phenylcarbamoyl)hexyl]benzamide in this example was as follows:

[0087]

[0088] (S)-N-benzoylprolinamide (0.2755 mmol), (8R,9S,13S,14S,17S)-17-methoxy-13- methyl-3-vinyl-6H-cyclopenta[a]phenanthrene (9.0 eq), p-dimethylaminopyridine- borane (3.0 eq), di-tert-butyl peroxide (1.5 eq), 2,6-dimethylbenzenethiol (0.5 eq), and magnesium triflate (0.5 eq) were dissolved in 3 mL of acetonitrile and reacted at 120 °C for 18 hours under a nitrogen atmosphere. The reaction solution was rotary evaporated and then purified using a silica gel column (petroleum ether / ethyl acetate = 3:1) to finally obtain N-[6-((8R,9S,13S,14S,17S)-17-methoxy-13-methyl-6H- cyclopenta[a]phenanthren-3-yl)-4-(phenylaminocarbonyl)hexyl]benzamide. The isolated yield was 83%; the product was a white solid.

[0089] 1 H NMR (400 MHz, CDCl3) δ 8.13 (1H, s), 7.78-7.76 (2H, m), 7.60 (2H,d, J = 7.6 Hz), 7.50-7.46 (1H, m), 7.41-7.38 (2H, m), 7.31-7.27 (2H, m), 7.19(1H, d, J = 7.6 Hz), 7.10-7.06 (1H, m), 6.94 (1H, d, J = 8.0 Hz), 6.89 (1H,s), 6.66 (1H, t, J = 5.8 Hz), 3.59-3.51 (1H, m), 3.38 (3H, s), 3.35-3.26 (2H,m), 2.83-2.78 (2H, m), 2.69-2.62 (1H, m), 2.55-2.48 (1H, m), 2.45-2.38 (1H,m), 2.31-2.27 (1H, m), 2.23-2.16 (1H, m), 2.12-2.04 (3H, m), 1.89-1.84 (1H,m), 1.82-1.72 (2H, m), 1.71-1.59 (3H, m), 1.57-1.47 (3H, m), 1.46-1.39 (2H,m), 1.38-1.30 (2H, m), 1.24-1.16 (1H, m), 0.79 (3H, s); 13C NMR (100 MHz, CDC13) δ 174.2, 167.9, 138.7, 138.2, 138.0, 136.7, 134.3, 131.5, 128.9, 128.8, 128.5, 126.9, 125.6, 125.4, 124.0, 119.8, 90.7, 57.8, 50.3, 46.6, 44.2, 43.1, 39.1, 38.4, 38.0, 34.2, 33.1, 29.9, 29.5, 27.7, 27.4, 27.2, 26.2, 23.0, 11.5.

Claims

1. A method for cleavage of the carbon-nitrogen bond of a proline derivative followed by ring opening alkylation, characterized in that Comprising the following steps: Step 1: under nitrogen atmosphere, the proline substrate and base 1 are added into solvent 1, then benzoyl chloride is added dropwise into the system under ice water bath environment, TLC spot plate is used to determine the end point of the reaction, water is added to quench the reaction, the aqueous phase is extracted with dichloromethane, the obtained organic phases are combined and dried over anhydrous sodium sulfate, concentrated by rotary evaporation, and then purified by column chromatography to obtain (S)-N-benzoyl proline; Step 2: under nitrogen atmosphere, (S)-N-benzoyl proline obtained in step 1, condensing agent and base 2 are added into solvent 1, then an aromatic amine is added dropwise into the system under ice water bath environment, TLC spot plate is used to determine the end point of the reaction, and then purified by silica gel column chromatography to obtain (S)-N-benzoyl proline aniline; Step 3: under nitrogen atmosphere, (S)-N-benzoyl proline aniline obtained in step 2 and olefin, borane, thiol, initiator and additive are added into solvent 2, and the reaction is carried out at 120°C, after the reaction is completed, the reaction liquid is concentrated by rotary evaporation to obtain a crude product, and then purified by column chromatography to obtain the ring-opening alkylated product; The synthesis route is as follows: 。 2. The method of claim 1, characterized in that: In step 1, the proline substrate is L-proline, and the base 1 is triethylamine.

3. The method of claim 1 or 2, characterized in that: The molar ratio of the proline substrate, benzoyl chloride and base 1 is 1.0:1.1:1.

1.

4. The method of claim 1, characterized in that: In step 2, the condensing agent is 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride, the base 2 is 4-dimethylaminopyridine, and the aromatic amine is aniline.

5. The method of claim 1 or 4, characterized in that: The molar ratio of (S)-N-benzoyl proline, aromatic amine, condensing agent and base 2 is 1.0:0.95:1.2:0.

1.

6. The method of claim 1, characterized in that: In step 3, the borane is p-dimethylaminopyridine-borane; the thiol is 2,6-dimethylbenzenethiol or methyl 2-mercaptobenzoate; the initiator is di-t-butyl peroxide; and the additive is magnesium triflate.

7. The method of claim 1, characterized in that: In Step 3, the olefin has the general formula where R is selected from one or more of substituted or unsubstituted aryl, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl; the substituents include one or more of alkyl substitution, alkoxy substitution, cycloalkyl substitution, heteroatom substitution, ester substitution.

8. The method of claim 7, characterized in that: The olefin is 4-methoxystyrene, 4-aminostyrene, 4-vinylbenzocyclobutene, 5-vinyl-2,3-dihydrobenzofuran, 5-vinyl-1H-indole, 1,1-diphenylethylene, N-vinylcarbazole, vinyl n-butyl ether, ethyl 4-methylene cyclohexanecarboxylate, n-decene or (8R,9S,13S,14S,17S)-17-methoxy-13-methyl-3-vinyl-6H-cyclopenta[a]pentalophane.

9. The method of claim 1 or 6 or 7 or 8, characterized in that: The molar ratio of (S)-N-benzoyl proline aniline, olefin, borane, initiator, thiol and additive is 1.0:12.0:3.0:1.5:0.5:0.5.

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