Alpha-aryl-beta-amino carboxylic ester as well as synthesis method and application thereof

Abstract

The invention belongs to the field of compound synthesis, and particularly relates to alpha-aryl-beta-amino carboxylic ester as well as a synthesis method and application thereof. According to the invention, the reaction product is synthesized into the alpha-aryl-beta-amino carboxylic ester by using a nickel / boron catalyzed alpha-amino-beta-bromo amino acid ester compound through a 1, 2-nitrogen migration-reduction cross-coupling method. The synthesis method has the advantages of simple reaction operation, cheap and easily available various adopted free radical precursors, mild and environment-friendly reaction system, high selectivity, simple conditions and high yield, and has great popularization and application values in the field of medicine synthesis.

Description

Technical Field

[0001] The present invention belongs to the field of compound synthesis, and particularly relates to an α-aryl-β-amino carboxylate, a synthesis method thereof, and uses thereof. Background Art

[0002] β-amino acid compounds have attracted extensive attention due to their significant pharmacological and biological activities, and are widely used in industries such as medicine, feed, food, and environmental applications. Therefore, research on the synthesis methods of such molecular skeletons will bring great economic benefits.

[0003] As an important class of organic compounds, α-aryl-β-amino carboxylates exhibit potential application values in many fields such as medicine and materials. In the medical field, compounds containing amino and ester groups are often used as key intermediates in drug synthesis. For example, many drug molecules with antiviral, anti-tumor and other biological activities contain similar functional group fragments in their structures. By modifying and derivatizing the structure of α-aryl-β-amino carboxylates, new drugs with better pharmacological activities and pharmacokinetic properties can be developed. In materials science, the active groups in their structures can participate in polymerization reactions to prepare polymer materials with special properties, such as polymers with specific optical and electrical properties, which have potential applications in fields such as electronics and optical devices.

[0004] However, there are still some limitations in the current synthesis methods of α-aryl-β-amino carboxylates. Although the traditional nucleophilic substitution reaction is relatively simple to operate, the reaction conditions are often relatively harsh, requiring the use of strong alkaline reagents or high temperatures, which may lead to poor selectivity of the substrate and easy occurrence of side reactions, affecting the yield and purity of the target product. In the reductive amination reaction, the stability of the imine intermediate is sometimes low, and the choice and dosage of the reducing agent in the reduction process have a great influence on the reaction result, and problems such as over-reduction may exist. Although the transition metal-catalyzed reaction has good selectivity and atom economy, the cost of transition metal catalysts is high, and the recovery and reuse of catalysts are difficult, which limits its large-scale industrial application.

[0005] Therefore, it is of great practical significance to develop a synthesis method of α-aryl-β-amino carboxylate with mild reaction conditions, high selectivity, good yield, low cost and environmental friendliness, which has a positive effect on promoting its application and development in fields such as medicine and materials. Summary of the Invention

[0006] Based on the above problems, the purpose of the present application is to overcome the deficiencies of the prior art, and provide a synthesis method of α-aryl-β-amino carboxylate with simple operation, mild reaction system, green environmental protection, high selectivity and high yield, and its application in the medical field.

[0007] To this end, the first technical solution of the present application discloses an α-aryl-β-amino carboxylate, which has the following structural formula:

[0008]

[0009] In the formula, R1 = 2,6-2(Me)2, R2 = 2,6-2(Me)2;

[0010] or R1 = 2,6-2(Cl)2, R2 = 2,6-2(Cl)2;

[0011] or R1 = 2,6-2(F)2, R2 = 2,6-2(Me)2.

[0012] And a synthesis method of the above α-aryl-β-amino carboxylate, including: using an α-amino-β-bromo amino acid ester compound and an aryl bromide as reaction substrates, NiBr2 as a catalyst, B2neo2 as a reducing agent, K2CO3 as a base, 2-(4,5-dihydro-1H-imidazol-2-yl)-4-methoxypyridine as a ligand, and acetonitrile as a solvent to react to obtain;

[0013] The α-amino-β-bromo amino acid ester compound has the following structural formula:

[0014]

[0015] In the formula, R1 = 2,6-2(Me)2, R2 = 2,6-2(Me)2;

[0016] or R1 = 2,6-2(Cl)2, R2 = 2,6-2(Cl)2;

[0017] or R1 = 2,6-2(F)2, R2 = 2,6-2(Me)2.

[0018] Further, when R1 = 2,6-2(Me)2, R2 = 2,6-2(Me)2, the aryl bromide is any one of 4-bromobenzophenone, 4-bromobenzophenone, 2-bromobenzonitrile, 1-bromo-3-(trifluoromethyl)benzene, bromobenzene, 6-bromobenzofuran, 4-(6-bromopyridin-3-yl)morpholine, methyl 2-methyl-5-bromobenzoate, 2-bromo-6-methylbenzonitrile, 4-bromophthalonitrile, 6-bromo-3H-isobenzofuran-1-one, 6-bromo-3H-isobenzofuran-1-one, 2-bromonaphthalene, 3-bromopyridine, 3-bromoquinoline, 5-bromo-2-cyanopyridine, 2-bromodibenzothiophene, 6-bromobenzothiazole, 5-bromobenzod[d][1,3]dioxole; when R1 = 2,6-2(Cl)2, R2 = 2,6-2(Cl)2, the aryl bromide is 5-bromobenzod[d][1,3]dioxole; when R 1When R1 = 2,6-2(F)2 and R2 = 2,6-2(Me)2, the aryl bromide is 4-bromobenzonitrile.

[0019] Furthermore, the reaction temperature is 50 °C and the reaction time is 24 h.

[0020] Furthermore, the α-amino-β-bromo amino acid ester compound is prepared by the following method:

[0021] S1. Mix DL-serine methyl ester hydrochloride, aromatic aldehyde with the corresponding substituent of R1, and triethylamine, react at room temperature, and then add a reducing agent under an ice-water bath condition to continue the reaction to obtain product A;

[0022] S2. React product A with acetonitrile, K2CO3, TBAI, and benzyl bromide with the corresponding substituent of R2 at 40 °C for more than 12 h to obtain product B;

[0023] S3. React product B with carbon tetrabromide, anhydrous tetrahydrofuran, and triphenylphosphine to obtain it.

[0024] Furthermore, the reaction is carried out in a nitrogen environment.

[0025] Furthermore, the molar ratio of the α-amino-β-bromo amino acid ester compound, aryl bromide, NiBr 2、 B2neo 2、 K2CO 3、 2-(4,5-dihydro-1H-imidazol-2-yl)-4-methoxypyridine is 1:1:0.1:2:2:0.12.

[0026] And the α-aryl-β-amino carboxylic acid ester obtained according to the above synthesis method.

[0027] The second technical solution of this application discloses the use of the above α-aryl-β-amino carboxylic acid ester in the preparation of an inhibitor of esophageal cancer cell ECa9706

[0028] The beneficial effects of this application are as follows: The synthesis method of the α-aryl-β-amino carboxylic acid ester of the present invention has simple reaction operation, the several radical precursors used are cheap and easily available, the reaction system is mild, green and environmentally friendly, has high selectivity, simple conditions, high yield, and has great popularization and application value in the field of pharmaceutical synthesis. Description of the Drawings

[0029] Figure 1 It is the synthesis reaction process diagram of the α-aryl-β-amino carboxylic acid ester of the present invention;

[0030] Figure 2 It is the synthesis reaction process diagram of the α-amino-β-bromo amino acid ester compound. Detailed Embodiments

[0031] The present invention will be further described in detail below with reference to specific embodiments. These embodiments are implemented on the premise of the technology of the present invention, and the detailed implementation manners and specific operation processes are given to illustrate the creativity of the present invention. However, the protection scope of the present invention is not limited to the following embodiments.

[0032] As Figure 1 shown, the reaction formula of a preferred embodiment for synthesizing α-aryl-β-amino carboxylate of the present application is disclosed; in the formula, α-aryl-β-amino carboxylate (1) and aryl bromide (Ar-Br) are reaction substrates, NiBr2 is a catalyst, B2neo2 is a reducing agent, and K2CO3 is used as a base; with 2-(4,5-dihydro-1H-imidazol-2-yl)-4-methoxypyridine as a ligand (L) and acetonitrile as a solvent, the reaction product α-aryl-β-amino carboxylate (2) is obtained.

[0033] The reaction product is synthesized by a method of nickel / boron-catalyzed 1,2-nitrogen migration-reductive cross-coupling of α-amino-β-bromo amino ester compounds to form α-aryl-β-amino carboxylate.

[0034] In the formula, the α-aryl-β-amino carboxylate compound has the following structural formula:

[0035]

[0036] In the formula, R1 = 2,6-2(Me)2, R2 = 2,6-2(Me)2;

[0037] or R1 = 2,6-2(Cl)2, R2 = 2,6-2(Cl)2;

[0038] or R1 = 2,6-2(F)2, R2 = 2,6-2(Me)2.

[0039] It should be noted that the aromatic bromide (Ar-Br) is added correspondingly according to the different α-aryl-β-amino carboxylates, specifically:

[0040] When R1 = 2,6-2(Me)2 and R2 = 2,6-2(Me)2, the aryl bromide is any one of 4-bromobenzophenone, 4-bromobenzophenone, 2-bromobenzonitrile, 1-bromo-3-(trifluoromethyl)benzene, bromobenzene, 6-bromobenzofuran, 4-(6-bromopyridin-3-yl)morpholine, methyl 2-methyl-5-bromobenzoate, 2-bromo-6-methylbenzonitrile, 4-bromophthalonitrile, 6-bromo-3H-isobenzofuran-1-one, 6-bromo-3H-isobenzofuran-1-one, 2-bromonaphthalene, 3-bromopyridine, 3-bromoquinoline, 5-bromo-2-cyanopyridine, 2-bromodibenzothiophene, 6-bromobenzothiazole, 5-bromobenzodioxole.

[0041] When R1 = 2,6-2(Cl)2 and R2 = 2,6-2(Cl)2, the aryl bromide is 5-bromobenzodioxole.

[0042] When R1 = 2,6-2(F)2 and R2 = 2,6-2(Me)2, the aryl bromide is 4-bromobenzonitrile.

[0043] In this embodiment, the reaction temperature is preferably 50 °C and the reaction time is preferably 24 h.

[0044] As Figure 2 shown, in a further preferred embodiment, a method for preparing α-aryl-β-amino carboxylate compounds is disclosed, specifically:

[0045] S1. DL-serine methyl ester hydrochloride and the aromatic aldehyde with the substituent corresponding to R1 are reacted under the conditions of using triethylamine as the base, sodium borohydride as the reducing agent, and methanol as the solvent to obtain product A ( Figure 2-1 );

[0046] S2. Product A and benzyl bromide with the substituent corresponding to R2 are reacted in acetonitrile as the solvent, K2CO3 as the base, and TBAI as the catalyst to obtain product B;

[0047] S3. Product B and carbon tetrabromide are reacted in anhydrous tetrahydrofuran as the solvent and triphenylphosphine as the ligand to obtain α-aryl-β-amino carboxylate compounds.

[0048] In the above embodiment, the aromatic aldehyde with the substituent corresponding to R1 and the benzyl bromide with the substituent corresponding to R2 respectively refer to those with R 1、Aromatic aldehydes with R2 functional groups and benzyl bromides. For example, when R1 = 2,6-2(Me)2, the aromatic aldehyde is: 2,6-dimethylbenzaldehyde; when R1 = 2,6-2(Cl)2, the aromatic aldehyde is: 2,6-dichlorobenzaldehyde; when R1 = 2,6-2(F)2, the aromatic aldehyde is: 2,6-difluorobenzaldehyde; when R2 = 2,6-2(Me)2, the benzyl bromide is: 2,6-dimethylbenzyl bromide; R 2 = 2,6-2(Cl)2, the benzyl bromide is 2,6-dichlorobenzyl bromide; R 2 = 2,6-2(Me)2, the benzyl bromide is 2,6-difluorobenzyl bromide.

[0049] All the reactions in the above embodiments are carried out under a nitrogen atmosphere.

[0050] In the above embodiments, the molar ratio of the α-amino-β-bromo amino acid ester compound, aryl bromide, NiBr 2、 B2neo 2、 K2CO 3、 2-(4,5-dihydro-1H-imidazol-2-yl)-4-methoxypyridine is 1:1:0.1:2:2:0.12.

[0051] It can be understood that after obtaining the reaction product in the above embodiments, the reaction product needs to be separated and purified. For example, the reaction product is extracted, dried, concentrated, column chromatographed, etc. to obtain the purified product, which is a conventional operation in the art and is not particularly limited in this application.

[0052] The synthesis method of this application and the application of the synthesized product will be illustrated by specific examples below.

[0053] Example 1

[0054] 1. Preparation of α-amino-β-bromo amino acid ester compounds

[0055] S1. Add a magnetic stir bar of appropriate size, DL-serine methyl ester hydrochloride (12 mmol), and 15 ml of anhydrous methanol as a solvent to a 100 mL round-bottom flask. Under magnetic stirring, add the corresponding aromatic aldehyde (10 mmol) and triethylamine (12 mmol) 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 condition; remove the ice-water bath and continue the reaction for 3 - 4 h. Then, quench the sodium borohydride with water, rotary evaporate for 15 min, extract with ethyl acetate, dry over anhydrous sodium sulfate, and then rotary evaporate to obtain product A for use in the subsequent steps.

[0056] S2. Add a magnetic stir bar of appropriate size, product A (10 mmol), and 12 mL of acetonitrile into a 100 mL round-bottom flask. Weigh K2CO3 (12 mmol), TBAI (0.6 mmol), and benzyl bromide with corresponding substituents (12 mmol) and add them into the reactor in sequence. Then, react overnight at 40 °C, filter to remove solid by-products, concentrate the filtrate, and finally purify to obtain B by column chromatography for use in subsequent steps.

[0057] S3. 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 keeping warm for 40 min, transfer the Schlenk tube to an oil bath at 40 °C and continue the reaction for 20 h. After the reaction is completed, filter to remove solid by-products, concentrate the filtrate, and finally purify to obtain 1 by column chromatography.

[0058] 2. Preparation of α-aryl-β-amino carboxylates; in a clean 25 ml Schlenk tube, add α-amino-β-bromo amino acid ester compounds (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-methoxypyridine (L, 0.024 mmol), and aryl bromide (0.2 mmol). Add 2 mL of the solvent acetonitrile and react at 50 °C for 24 h under a nitrogen atmosphere. After the reaction is completed, filter, extract with ethyl acetate, dry with anhydrous sodium sulfate, concentrate, and purify by column chromatography to obtain the reaction product α-aryl-β-amino carboxylates.

[0059] Among them, the α-amino-β-bromo amino acid ester compounds and aryl bromides are shown in Table 1.

[0060] Table 1

[0061]

[0062]

[0063] The structural formulas and NMR (1H NMR and 13C NMR) data of the reaction products prepared according to Table 1 are as follows:

[0064]

[0065]

[0066]

[0067]

[0068]

[0069]

[0070]

[0071] Example 2 Tumor Inhibition Experiment

[0072] Perform a tumor inhibition experiment on the a-t reaction product synthesized in Example 1. The experimental method is as follows: Select adherent esophageal cancer cells ECa9706 in the logarithmic growth phase. After digestion with trypsin, prepare a cell suspension of 5000 cells / ml with RPMI1640 medium containing 10% calf serum, inoculate it in a 96-well culture plate, 100 μl per well, and culture at 37°C and 5% CO2 until the cell monolayer covers the bottom of the well.

[0073] In the experimental group, replace with fresh medium containing different concentrations (2.2175×10 -4 , 3.5478×10 -4 , 5.4632×10 -4 , 8.5696×10 -4 , 11.2365×10 -4 , 16.5278×10 -4 , the unit is mol·L -1 ) of the a-t sample in Example. In the control group, replace with medium containing the same volume of solvent. Set 3 - 5 parallel wells in each group and culture at 37°C and 5% CO2 for 4 - 5 days.

[0074] Discard the supernatant, add 100 μl of freshly prepared serum-free medium containing 0.2 mg / ml MTT to each well. Continue to culture at 37°C for 4 h. Carefully discard the supernatant and add 100 μl of DMSO. After mixing with a micro ultrasonic oscillator, measure the optical density value on an enzyme-labeled instrument with a test wavelength of 570 nm and a reference wavelength of 450 nm.

[0075] Calculate the inhibition rate of the drug on tumor cell growth according to the following formula:

[0076] Tumor cell growth inhibition rate % = (1 - ODexperiment / ODcontrol) × 100%;

[0077] Plot the inhibition rate of tumor cell growth against different concentrations of the same sample to obtain a dose-response curve, and calculate the half-lethal concentration IC 50 of the sample from it; As shown in Table 2, the IC 50 value of the a-t compound on esophageal cancer cells ECa9706:

[0078] Table 2

[0079]

[0080] As can be seen from the above bioactivity test data, the synthesized α-aryl-β-amino carboxylate products 2a-2i of the present invention have a significant inhibitory effect on esophageal cancer cell ECa9706. The purpose of the blank control group is to eliminate the influence of the solvent on the experimental results. Since the blank control has no inhibitory effect on esophageal cancer cell ECa9706, the IC 50 .

[0081] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and not to limit them. Although the present invention has been described in detail with reference to the preferred embodiments, those of ordinary skill in the art should understand that the technical solutions of the present invention can be modified or equivalently replaced without departing from the purpose and scope of the technical solutions of the present invention, and they should all be covered by the scope of the claims of the present invention.

Claims

1. An α-aryl-β-aminocarboxylate, characterized in that It has the following structural formula: Wherein, R1=2,6-2(Me)2, R2=2,6-2(Me)2; Or R1=2,6-2(Cl)2,R2=2,6-2(Cl)2; Or R1=2,6-2(F)2,R2=2,6-2(Me)2.

2. A method for synthesizing the α-aryl-β-aminocarboxylate as claimed in claim 1, characterized in that: include: The α-amino-β-bromoamino acid ester compound and aryl bromide are used as reaction substrates, NiBr2 is used as a catalyst, B2neo2 is used as a reducing agent, K2CO3 is used as a base, 2-(4,5-dihydro-1H-imidazol-2-yl)-4-methoxypyridine is used as a ligand, and acetonitrile is used as a solvent to obtain the reaction product; The α-amino-β-bromoamino acid ester compound has the following structural formula: Wherein, R1=2,6-2(Me)2, R2=2,6-2(Me)2; Or R1=2,6-2(Cl)2,R2=2,6-2(Cl)2; Or R1=2,6-2(F)2,R2=2,6-2(Me)2.

3. The synthesis method according to claim 2, characterized in that: When R1=2,6-2(Me)2, R2=2,6-2(Me)2, the aromatic bromide is 4-bromobenzophenone, 4-bromobenzophenone, 2-bromobenzonitrile, 1-bromo-3-(trifluoromethyl)benzene, bromobenzene, 6-bromobenzofuran, 4-(6-bromopyridin-3-yl)morpholine, 2-methyl-5-bromobenzoic acid methyl ester, 2-bromo-6-methylbenzonitrile, 4-bromophthalonitrile, 6-bromo-3H-isobenzofuran-1-one, 6-bromo-3H-isobenzofuran-1-one, Any one of 2-bromonaphthalene, 3-bromopyridine, 3-bromoquinoline, 5-bromo-2-cyanopyridine, 2-bromodibenzothiophene, 6-bromobenzothiazole, and 5-bromobenzo[d][1,3]dioxole; when R1=2,6-2(Cl)2, R2=2,6-2(Cl)2, the aryl bromide is 5-bromobenzo[d][1,3]dioxole; when R1=2,6-2(F)2, R2=2,6-2(Me)2, the aryl bromide is 4-bromobenzonitrile.

4. The synthesis method according to claim 2, characterized in that: The reaction temperature is 40°C to 60°C, and the reaction time is 20 to 24 hours.

5. The synthesis method according to claim 2, characterized in that: The α-amino-β-bromoamino acid ester compound is prepared by the following method: S1. DL-serine methyl ester hydrochloride, an aromatic aldehyde corresponding to the substituent of R1, and triethylamine are mixed and reacted at room temperature, and then a reducing agent is added in an ice-water bath to continue the reaction to obtain product A; S2. reacting product A with acetonitrile, K2CO3, TBAI, and benzyl bromide corresponding to the substituent of R2 at 40°C for more than 12 hours to obtain product B; S3. The product B is reacted with carbon tetrabromide, dehydrated tetrahydrofuran and triphenylphosphine to obtain.

6. The synthesis method according to claim 2, characterized in that: The reaction was carried out under nitrogen atmosphere.

7. The synthesis method according to claim 2, characterized in that: The α-amino-β-bromoamino acid ester compound, aryl bromide, NiBr 2、 B2neo 2、 K2CO 3、 The molar ratio of 2-(4,5-dihydro-1H-imidazol-2-yl)-4-methoxypyridine is 1:1:0.1:2:2:0.

12.

8. An α-aryl-β-aminocarboxylate obtained according to any one of the synthesis methods of claims 1-6.

9. Use of the α-aryl-β-aminocarboxylate according to claim 1 or claim 8 in the preparation of an inhibitor of esophageal cancer cell ECa9706.

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