Synthesis method and use of 1,2,3,4-tetrahydroisoquinoline-4-carboxylate

Abstract

The present invention discloses a method and use for synthesizing β-amino acid derivatives by nickel / bis-boron-catalyzed radical 1,2-nitrogen migration / C-H cyclization. The synthesized target compound has the structure shown by the following formula. The preparation method uses α-amino-β-bromo amino acid ester compounds as reaction substrates, NiBr2(dme) as a catalyst, B2neo2 (neopentyl glycol diborate) as a reducing agent, K2CO3 as a base, 2-(4,5-dihydro-1H-imidazol-2-yl)-4-methylpyridine (L1) as a ligand, and acetonitrile as a solvent. The reaction is carried out under a nitrogen atmosphere at a reaction temperature of 60 °C. After 20 hours of reaction, after filtration, concentration and other treatments, the target product 1,2,3,4-tetrahydroisoquinoline-4-carboxylate (2) is obtained by column chromatography or thin-layer chromatography separation and purification. The synthesis reaction has simple operation, cheap and easily available raw materials, a mild and green reaction system, high selectivity, simple conditions and high yield, and has great popularization and application value.

Description

Technical Field

[0001] The present invention relates to the field of organic chemistry, and particularly to a method and use for synthesizing 1,2,3,4-tetrahydroisoquinoline-4-carboxylate by nickel / bisboron-catalyzed radical 1,2-nitrogen migration / C-H cyclization. Background Art

[0002] 1,2,3,4-Tetrahydroisoquinoline-4-carboxylate (i.e., β-amino acid derivative) has attracted extensive attention due to its significant pharmacological and biological activities and exists in many medicinal molecules. Therefore, the research on the synthesis methods of such molecular skeletons will bring great economic benefits. For example, paclitaxel, betaine, and jasmonolide all have important medicinal values in medicine.

[0003]

[0004] This class of compounds is a kind of natural product parent nucleus and widely exists in natural alkaloids. The spiro compounds containing heteroatoms have unique action mechanisms and are not prone to drug resistance. At the same time, it is also a good pharmaceutical skeleton. If the synthesis technology of this class of compounds can be mastered, it will be of great help to human diseases.

[0005] At present, although many people have reported the synthesis methods of β-amino acids, there is still much room for improvement in the reactions. Organic chemists and medicinal chemists have shown great interest in the development of efficient and selective synthesis technologies for novel β-amino acid derivatives. In this regard, the synthesis method of preparing β-amino acids and their derivatives (e.g., 1,2,3,4-tetrahydroisoquinoline-4-carboxylate) through 1,2-nitrogen migration reaction from common α-amino acid substrates is a direct and efficient approach.

[0006] Currently, there is still no relevant literature report on the method for synthesizing 1,2,3,4-tetrahydroisoquinoline-4-carboxylate and its derivatives through 1,2-nitrogen migration / C-H cyclization. Recently, our research group found that in the presence of NiBr2(dme)2 and B2neo2 (neopentyl glycol diborate), α-amino-β-bromo acid esters can undergo radical reactions under mild reaction conditions, effectively undergoing 1,2-nitrogen migration to efficiently generate 1,2,3,4-tetrahydroisoquinoline-4-carboxylate. This synthesis method is simple and convenient, with a relatively high yield. It forms a ring in one step under the catalysis of nickel-boron reagents, showing the characteristics of "green" and "atom economy", so it has extremely high practical promotion value, and such compounds have great application prospects in the fields of medicine, pesticides, and organic materials. Summary of the Invention

[0007] The present invention overcomes the deficiencies of the prior art and provides a synthetic route for nickel- and boron-catalyzed induction of α-amino-β-bromo acid esters to obtain 1,2,3,4-tetrahydroisoquinoline-4-carboxylates through tandem 1,2-nitrogen migration / C-H cyclization. The structural formula of the synthesized product is as follows:

[0008]

[0009] The preparation scheme for the above nickel / diboron-catalyzed tandem radical 1,2-nitrogen migration / C-H cyclization to synthesize 1,2,3,4-tetrahydroisoquinoline-4-carboxylate (2) is as follows:

[0010] Using α-amino-β-bromo acid esters as reaction substrates, NiBr2(dme) as the catalyst, B2neo2 (neopentyl glycol diborate) as the reducing agent, K2CO3 as the base, 2-(4,5-dihydro-1H-imidazol-2-yl)-4-methylpyridine (L1) as the ligand, and acetonitrile as the solvent, the reaction is carried out under a nitrogen atmosphere at a reaction temperature of 60 °C for 20 hours to obtain the target product 2, with a yield between 37% and 75%. The reaction formula is as follows:

[0011]

[0012] In the reaction general formula, R 1 , R 2 , R 3 , R can be as shown in the following groups:

[0013] 2a: R 1 = H, R 2 = H, R 3 = H, R = Me

[0014] 2b: R 1 = 4-Me, R 2 = 4-Me, R 3 = H, R = Me

[0015] 2c: R 1 = 4-t-Bu, R 2 = 4-t-Bu, R 3 = H, R = Me

[0016] 2d: R 1 = 4-Cl, R 2 = 4-Cl, R 3 = H, R = Me

[0017] 2f: R 1 = 4-OMe, R2 = 4-OMe, R 3 = H, R = Me

[0018] 2g: R 1 = 2-F, R 2 = 2-F, R 3 = H, R = Me

[0019] 2h: R 1 = 3-Cl, R 2 = 3-Cl, R 3 = H, R = Me

[0020] 2i: R 1 = H, R 2 = H, R 3 = Me, R = Me

[0021] 2j: R 1 = H, R 2 = H, R 3 = Pr, R = Et

[0022] 2k: R 1 = H, R 2 = H, R 3 = i -Pr, R = Et

[0023] 2l: R 1 = H, R 2 = H, R 3 = Bu, R = Et

[0024] 2m: R 1 = 4-Me, R 2 = 4-Me, R 3 = Pr, R = Et

[0025] 2n: R 1 = 4-Cl, R 2 = 4-Cl, R 3 = Pr, R = Et

[0026] 2o: R 1 = 4-Ph, R 2 = 4-Ph, R 3 = H, R = Me

[0027] 2p: R 1 = H, R 2= 4-t-Bu, R 3 = H, R = Me

[0028] 2q: R 1 = 2-Me, 6-Me, R 2 = 4-Cl, R 3 = H, R = Me

[0029] In the above reaction: After the reaction is completed, filter, wash with ethyl acetate, dry, concentrate, and perform column chromatography to obtain the reaction product.

[0030] The method for synthesizing β-amino acid derivatives of the present invention has the advantages of simple reaction operation, cheap and easily available raw materials, mild and green reaction system, high selectivity, simple conditions, high yield, and great promotion and application value in medical drugs. Specific Embodiments

[0031] The present invention will be further specifically described below in conjunction with specific examples.

[0032] (1) Raw material synthesis

[0033] The preparation of the reaction raw material α-amino-β-bromo amino acid ester compound (1a) can be obtained from serine methyl ester hydrochloride as the starting material through the following three simple synthesis steps.

[0034]

[0035] Step 1

[0036] Add a magnetic stirrer bar of appropriate size, serine methyl ester hydrochloride (12 mmol), and 15 ml of anhydrous methanol as a solvent into a 100 mL round-bottom flask. Add benzaldehyde (10 mmol) and triethylamine (12 mmol) to this mixture under magnetic stirring and mix well. Plug the flask with a stopper and react at room temperature for 6 h under a magnetic stirrer. Then add 3 × 3.3 mmol of sodium borohydride as a reducing agent in three portions under an ice-water bath. Remove the ice-water bath and let the reaction continue for 3 - 4 h. Then add water as a reaction terminator. After 15 minutes, remove the reaction. Use ethyl acetate as the eluent and extract it with water. Dry to remove salts to obtain the intermediate crude product A for use in subsequent steps.

[0037] Step 2

[0038] Add a magnetic stir bar of appropriate size, the intermediate crude product A (10 mmol), and 12 mL of acetonitrile into a 100 mL round-bottom flask. Weigh K2CO3 (12 mmol) and tetrabutylammonium iodide (0.6 mmol) and add them into the reactor in sequence. Then, slowly add 12 mmol of benzyl bromide under stirring conditions. After that, react overnight at 40 °C. After the reaction is completed as detected by TLC plate, filter to remove the solid by-products, concentrate the filtrate, and finally purify it by column chromatography to obtain B with a yield of 88%.

[0039] Step 3

[0040] Add a magnetic stir bar of appropriate size into a 100 mL Schlenk tube. Weigh 5 mmol of B and 7.5 mmol of carbon tetrabromide and add them into the Schlenk tube in sequence. Then, add 8 mL of dehydrated tetrahydrofuran to dissolve, seal the Schlenk tube, and protect it with nitrogen. Weigh 7.5 mmol of triphenylphosphine and dissolve it in 2 mL of dehydrated tetrahydrofuran. Then, inject this mixed solution into the Schlenk tube at -5 °C. After reacting at this temperature for 40 min, transfer the reactor to an oil bath at 40 °C and continue to react for 20 h. After the reaction is completed, filter to remove the solid by-products, concentrate the filtrate, and finally purify it by column chromatography to obtain 1a with a yield of 63%.

[0041] (2)The target product provided by the present invention is methyl N-benzyl-2,3,4-tetrahydroisoquinoline-4-carboxylate (2a) obtained by 1,2-nitrogen migration / C-H cyclization of nickel / boron-catalyzed α-amino-β-bromo amino acid esters (1). Taking the preparation of methyl 2-benzyl-1,2,3,4-tetrahydroisoquinoline-4-carboxylate (2a) as an example:

[0042]

[0043] Add α-amino-β-bromo amino acid ester (0.2 mmol), NiBr2(dme) (0.02 mmol), neopentyl glycol diborate (0.4 mmol), K2CO3 (0.4 mmol), 2-(4,5-dihydro-1H-imidazol-2-yl)-4-methylpyridine (0.024 mmol) into a clean 10 mL Schlenk tube, and add 2 mL of acetonitrile. React in a nitrogen environment for 20 h. After the reaction is completed, filter, wash with ethyl acetate, dry, concentrate, and purify by column chromatography to obtain the reaction product methyl N-benzyl-1,2,3,4-tetrahydroisoquinoline-4-carboxylate (2a), which is a colorless oily liquid with a yield of 75%.

[0044] The structure of the product is determined according to the NMR ( 1 1H NMR and 13 13C NMR) data of the product, as well as high-resolution mass spectrometry.

[0045] Structural Characterization of Product Methyl 2-Benzyl-1,2,3,4-tetrahydroisoquinoline-4-carboxylate (2a) : Colorless oily liquid 1 HNMR (500 MHz, CDCl3) δ 7.42 – 7.34 (m, 4H), 7.33 – 7.28 (m, 1H), 7.23 (dd, J J = 5.8, 3.6 Hz, 3H), 7.11 – 7.05 (m, 1H), 3.90 (t, J J = 5.1 Hz, 1H), 3.86 –3.75 (m, 2H), 3.72 (s, 3H), 3.70 – 3.58 (m, 2H), 3.21 (dd, J J = 11.4, 5.5 Hz,1H), 2.87 (dd, J J = 11.5, 4.8 Hz, 1H). 13 C NMR (126 MHz, CDCl3) δ 173.7, 138.1,135.2, 131.4, 129.4, 129.0, 128.3, 127.2, 127.0, 126.7, 126.3, 62.2, 56.1,52.9, 52.1, 45.5. HRMS m / z (ESI-TOF) calcd for Chemical Formula: C 18 H 20 NO2 [M+H] + : 282.1489, found: 282.1489.

[0046] Tumor suppression assay:

[0047] Adherent breast cancer AU565 cells in the logarithmic growth phase were selected. After digestion with trypsin, a cell suspension of 5000 cells / ml was prepared with RPMI 1640 medium containing 10% fetal bovine serum. The cells were seeded in a 96-well culture plate, 100 μl per well, and cultured at 37°C and 5% CO2 until the cell monolayer covered the bottom of the well.

[0048] In the experimental group, the medium was replaced with a new medium containing the sample of the example at different concentrations, and in the control group, the medium was replaced with a medium containing the same volume of solvent. Each group had 3 - 5 parallel wells and was cultured at 37°C and 5% CO2 for 4 - 5 days.

[0049] The supernatant was discarded, and 100 μl of fresh serum-free medium containing 0.2 mg / ml MTT was added to each well. 37°C

[0050] Continue to culture for 4 h. Carefully discard the supernatant, add 100 μl of DMSO, mix well with a micro ultrasonic oscillator, and measure the optical density value on an enzyme-linked immunosorbent assay (ELISA) reader

[0051] at a test wavelength of 570 nm and a reference wavelength of 450 nm.

[0052] Calculate the inhibition rate of the drug on tumor cell growth according to the following formula:

[0053] Inhibition rate of tumor cell growth (%) = (1 - OD of experiment / OD of control) × 100%

[0054] Plot the inhibition rate of tumor cell growth against different concentrations of the same sample to obtain a dose-response curve, and calculate

[0055] the half-maximal inhibitory concentration (IC50) of the sample from it.

[0056] Table 1 shows the IC50 values of some compounds of the present invention against breast cancer AU565 cells:

[0057] Compound IC50 (μg / ml) 2a 31.5 2f 37.8 2g 18.4 2h 20.5 2q 36.7

[0058] As can be seen from the above, the compounds of the present invention have a significant tumor inhibitory effect.

[0059] The above are only the preferred embodiments of the present invention, and do not impose any form of limitation on the present invention. Any person skilled in the art can make many possible changes and modifications to the technical solution of the present invention by using the technical content disclosed above, or modify it into an equivalent embodiment with equivalent changes. Therefore, any simple modification, equivalent change and modification made to the above embodiments based on the technical essence of the present invention without departing from the technical solution of the present invention shall fall within the scope of protection of the technical solution of the present invention.

Claims

1. A method for synthesizing 1,2,3,4-tetrahydroisoquinoline-4-carboxylate by nickel / bisboron-catalyzed radical 1,2-nitrogen migration / C-H cyclization, characterized in that: Using α-amino-β-bromo amino acid ester 1 as the reaction substrate, NiBr2(dme) as the catalyst, B2neo2 as the reducing agent, K2CO3 as the base, 2-(4,5-dihydro-1H-imidazol-2-yl)-4-methylpyridine L1 as the ligand, and acetonitrile as the solvent, the reaction is carried out under a nitrogen atmosphere at a reaction temperature of 60 °C. After 20 hours of reaction, after filtration and concentration, the target product 1,2,3,4-tetrahydroisoquinoline-4-carboxylate 2 is obtained by column chromatography or thin-layer chromatography separation and purification. NiBr2(dme) is nickel(II) bromide bis(dimethyl ether), and B2neo2 is neopentyl glycol diborate. The reaction formula is as follows: Among them, R 1 and R 2 are each any one of 2-F, 3 / 4-Cl, 4-Me, 4-t-Bu, 4-OMe, 4-Ph, R 3 is any one of H, Me, Pr, i-Pr, and R is any one of Me, Et.

2. The synthesis method of 1,2,3,4-tetrahydroisoquinoline-4-carboxylate according to claim 1, characterized in that: The equivalent ratio of NiBr2(dme) to the reaction substrate α-amino-β-bromo amino acid ester 1 is 0.1, the molar ratio of 2-(4,5-dihydro-1H-imidazol-2-yl)-4-methylpyridine L1 to the reaction substrate α-amino-β-bromo amino acid ester 1 is 0.12, the molar ratio of B2neo2 to the reaction substrate α-amino-β-bromo amino acid ester 1 is 1.5, and the molar ratio of K2CO3 to the reaction substrate α-amino-β-bromo amino acid ester 1 is 2.

3. An application of a 1,2,3,4-tetrahydroisoquinoline-4-carboxylate compound in the preparation of an anti-breast cancer drug, characterized in that: The structure of this compound is as follows: 。

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