Preparation method of esostine
Through the new Elastin synthesis route, a series of specific reaction steps are used to solve the problem of multi-halogenated impurities in the prior art, improve product quality and yield, reduce costs, and is suitable for industrial production.
Patent Information
- Application Number
- CN202411825503.2
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-12
- Publication Date
- 2025-03-21
AI Technical Summary
The existing Elastin synthesis method has the production of multi-halogenated impurities, resulting in low product quality, low yield and high cost, making it difficult to meet the needs of industrial production.
Using a new synthesis route, 2-aminobenzoic acid is used as the starting material, through a series of reaction steps, including acylation and cyclization with propionic anhydride, high temperature reaction with o-aminophenylether and sodium hydroxide, oxidation of hydrogen peroxide, chlorination with methylsulfonyl chloride, reaction with mono-Boc piperidine and de-Boc protection, and finally obtain Elastin. This method avoids polybrominated substituted impurities produced by bromine, and improves overall yield and product purity.
The efficient preparation of Elastin is achieved, the generation of polyhalogenated impurities is avoided, the quality and yield of the product is improved, the cost is reduced, and it is suitable for industrial production.
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Abstract
Description
Technical Field
[0001] The invention relates to a preparation method of elastin, belonging to the technical field of drug synthesis. Background Art
[0002] Erastin, Chinese full name: 2-[1-[4-[2-(4-chlorophenoxy)acetyl]-1-piperazinyl]ethyl]-3-(2-ethoxyphenyl)-4-(3H)-quinazolinone; English name: 2-[1-[4-[2-(4-Chlorophenoxy)acetyl]-1-piperazinyl]ethyl]-3-(2-ethoxyphenyl)-4(3H)-Quinazolinone. As a ferroptosis inducer, it is named after the eradicator of RAS and small T (ST) antigen-expressing cells. Ferroptosis is a newly discovered cell death mode characterized by the accumulation of a large amount of iron ions and lipid peroxidation during cell death. Studies have shown that ferroptosis is closely related to tumors, iron metabolism diseases, nervous system diseases, kidney damage and other diseases. Therefore, the study of ferroptosis and its related compounds is of great significance.
[0003] Erastin is an anti-tumor ferroptosis inducer developed by the Whitehead Institute for Biomedical Research. It works by acting on mitochondrial VDAC and selectively acts on tumor cells carrying the oncogene RAS. Erastin can counteract the resistance of chemotherapy drugs through the ferroptosis pathway, inhibit the proliferation of acute myeloid leukemia cells, and significantly increase the anti-cancer activity of chemotherapy drugs.
[0004] At present, patent US2008 / 299076, 2008 discloses a general method for synthesizing an important intermediate of Erastin, which uses 2-aminobenzoic acid as the starting material, and is first acylated with propionic anhydride and then cyclized; then reacted with o-aminophenyl ether and sodium hydroxide at high temperature; then brominated with bromine; then substituted with piperidine to obtain the important intermediate of Erastin, 3-(2-ethoxyphenyl)-2-[1-(piperazin-1-yl)ethyl]quinazolin-4(3H)-one. The overall yield of the reaction process is low, and there are many impurities in the bromination process, which is not easy to purify. The reaction equation is as follows:
[0005]
[0006] In view of this, the object of the present invention is to provide a method for preparing elastin which can effectively improve the generation of polyhalogenated impurities occurring during the synthesis process, improve the quality of elastin products, increase the yield of elastin, and has relatively low cost and is suitable for industrial production. Summary of the invention
[0007] In order to achieve the above-mentioned invention object, the present invention provides a preparation method of elastin. 2-aminobenzoic acid is used as a starting material, and is acylated and cyclized with propionic anhydride to obtain compound 2; then, it is reacted with o-aminophenyl ether and sodium hydroxide at high temperature to obtain compound 3; then, it is oxidized with hydrogen peroxide to obtain nitrogen oxide compound 4; then, it is reacted with methanesulfonyl chloride to obtain compound 5; compound 6 is reacted with mono-Boc piperidine, and then Boc protection is removed to obtain compound 7; compound 5 is reacted with compound 7 to obtain compound 8 (elastin). The present invention avoids polybrominated impurities generated by bromination, improves the overall yield, has high product purity, and Pd residue is less than 5ppm.
[0008] The preparation method of Erastin of the present invention comprises the following steps:
[0009] Step 1: Mix 2-aminobenzoic acid and propionic anhydride, and heat to react to obtain compound 2;
[0010] Step 2: Compound 2 is reacted with o-aminophenyl ether in ethylene glycol dimethyl ether under reflux, and after the ethylene glycol dimethyl ether is concentrated, sodium hydroxide and ethylene glycol are added to react at high temperature to obtain compound 3;
[0011] Step 3: Compound 3 is mixed with phthalic anhydride and dichloromethane, and hydrogen peroxide is added dropwise to obtain compound 4;
[0012] Step 4: Chlorinate compound 4 with sulfonyl chloride to obtain compound 5;
[0013] Step 5: tert-butyl piperazine-1-carboxylate, DIPEA, dichloromethane and water were mixed, the temperature was lowered and a dichloromethane solution of compound 6 was added, the mixture was washed and concentrated, and then an acid was added to remove the Boc protection to obtain compound 7;
[0014] Step 6: dissolving compound 7 and compound 5 in an organic solvent, adding an acid-binding agent after cooling, and obtaining elastin through post-treatment.
[0015] The synthetic route of the present invention is expressed as follows using the reaction equation:
[0016]
[0017] Furthermore, in the first step, propionic anhydride is both a reactant and a solvent, and the mass of propionic anhydride is 3-4 times that of the raw material.
[0018] Furthermore, in the second step, the molar ratio of compound 2, o-aminophenyl ether and sodium hydroxide is 1:0.98-1.00:1.05-1.10.
[0019] Furthermore, in the third step, the molar ratio of compound 3, phthalic anhydride and hydrogen peroxide is 1:1.75-1.90:2.9-3.0.
[0020] Furthermore, in the fourth step, the molar ratio of compound 4 to methanesulfonyl chloride is 1:3.3-3.7.
[0021] Furthermore, in the fifth step, the molar ratio of tert-butyl piperazine-1-carboxylate, DIPEA and compound 6 is 1:1.50-1.80:1.0.
[0022] Furthermore, in the sixth step, the acid binding agent is selected from DIPEA or TEA.
[0023] Furthermore, in the sixth step, the organic solvent is selected from ethyl acetate or isopropyl acetate.
[0024] Furthermore, in the sixth step, the molar ratio of compound 7, compound 5 and acid binding agent is 1:1:3.5-4.5.
[0025] Advantageous Effects of the Invention
[0026] The present invention provides a new method for preparing elastin. Compared with the disclosed patented synthesis method, the synthesis method does not produce polyhalogenated impurities, has short operation steps and synthesis cycle, low cost, few by-products, and high product yield, which is conducive to the large-scale production of elastin and meets the needs of industrial production. DETAILED DESCRIPTION
[0027] The present invention is further illustrated by examples below. It should be correctly understood that the examples of the present invention are only used to illustrate the present invention, rather than to limit the present invention. Therefore, simple improvements to the present invention under the premise of the method of the present invention, unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which the present invention belongs. The terms used are only for describing specific embodiments and are not intended to limit the present invention.
[0028] Example 1
[0029]
[0030] 137.1 g (1 mol) of 2-aminobenzoic acid, 480 g of propionic anhydride and 100 g of N-methylpyrrolidone were mixed, heated to 125°C for reaction for 2 hours, and the remaining raw material was <0.3% by HPLC. The mixture was cooled to 70°C, concentrated under reduced pressure until no liquid flowed, cooled to 0°C, and n-heptane was added for pulping. The mixture was filtered, and the filter cake was washed with n-heptane and dried to obtain 168.7 g of compound 2 with a yield of 96.3% and an HPLC value of 98.7%. 1H NMR (400MHz, CDCl3): 8.15(dd,1H),7.79-7.75(m,1H),7.54(d,1H),7.50-7.45(m,1H),2.72(q,2H),1.35(t,3H).
[0031] Example 2
[0032]
[0033] Compound 2168.2g (0.96mol), o-aminophenyl ether 131.7g (0.96mol) and ethylene glycol dimethyl ether 1350mL were mixed and stirred, heated to 100°C for reaction for 32 hours, HPLC detected that the raw material was <1.0%, cooled to 55°C, concentrated under reduced pressure until no liquid flowed, ethylene glycol 350mL and xylene 350mL were added, sodium hydroxide 40.4g (1.01mol) was added in batches, heated to 135-140°C, refluxed and separated until no water was present, cooled to 5-10°C, the precipitated solid was filtered, the filter cake was washed with cold water and xylene respectively, and dried to obtain 253.5g of compound 3, with a yield of 89.7%, HPLC 97.9%. 1 H NMR(400MHz, CDCl3):8.14-8.10(m,1H),8.00-7.96(m,1H),7.62-7.49(m,3H),7.33-7.29(m,1H) ,7.20-7.05(m,2H),4.21-4.17(m,2H),2.83-2.79(m,2H),1.43-1.38(m,3H),1.34-1.29(m,3H).
[0034] Example 3
[0035]
[0036] Compound 3250.2g (0.85mol), phthalic anhydride 226.6g (1.53mol) and DCM 2600mL were mixed and stirred, and the temperature was raised to 35°C. 300.3g (2.5mol) of 30% hydrogen peroxide was slowly added dropwise. The reaction was continued for 10 hours. The raw material was detected by HPLC to be less than 1.0%. Water was added, and saturated sodium bisulfite solution was added dropwise to quench until the starch potassium iodide test paper showed colorless. The mixture was filtered, and the filtrate was allowed to stand for stratification. The aqueous layer was extracted with dichloromethane, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, replaced with n-heptane and pulped, filtered, and the filter cake was rinsed with n-heptane and dried to obtain 250.9g of compound 4, with a yield of 95.1% and an HPLC index of 98.9%. 1H NMR(400MHz, CDCl3):9.15-9.11(m,1H),8.39-8.35(m,1H),8.00-7.96(m,1H),7.60-7.47(m,2H) ,7.33-7.04(m,3H),4.39-4.35(m,2H),3.71-3.67(m,2H),1.69-1.65(m,3H),1.06-1.02(m,3H).
[0037] Example 4
[0038]
[0039] Compound 4248.3g (0.8mol) was added to MsCl 320.7g (2.8mol) in batches, and the temperature was raised to 80-90°C for reaction. The reaction was carried out for 8 hours. The residual raw material was <0.2% by HPLC. The reaction solution was added dropwise to cold water and filtered. The filter cake was slurried with 90% isopropanol at a temperature of 50°C, cooled and filtered, and the filter cake was rinsed with cold 90% isopropanol and dried to obtain compound 5233.6g with a yield of 88.8%. HPLC 99.3%. 1 H NMR(400MHz, CDCl3):8.29-8.25(m,1H),7.81-7.76(m,2H),7.56-7.31(m,2H) ,7.21-6.89(m,3H),4.69(q,1H),4.05(q,2H),2.00(d,3H),1.46-1.42(m,3H).
[0040] Example 5
[0041]
[0042] 130.4 g (0.7 mol) of tert-butyl piperazine-1-carboxylate, 106.2 g (1.05 mol) of triethylamine, 1300 mL of dichloromethane and 500 mL of water were mixed, cooled to 0-5°C, and a mixed solution of 143.5 g (0.7 mol) of compound 6 and 150 mL of dichloromethane was added, and the mixture was allowed to react for 2 hours after dropwise addition. The mixture was allowed to stand for stratification, and the aqueous phase was extracted with a small amount of dichloromethane. The organic phases were combined, washed with dilute hydrochloric acid and water, and the organic phase was concentrated under reduced pressure until no liquid flowed. Ethanol and water were added, and concentrated hydrochloric acid was added dropwise to raise the temperature to 50°C to react for 2 hours. Aqueous sodium hydroxide solution was added to adjust the pH to 9-10, and a solid was precipitated. The mixture was filtered, and the filter cake was rinsed with water and dried to obtain 161.9 g of compound 7; yield 90.8%, HPLC 99.6%. 1H NMR (400MHz, CDCl3): 7.25 (d, 2H), 6.91 (d, 2H), 4.69 (s, 2H), 3.59-3.53 (m, 4H), 3.43-3.39 (m, 4H), 1.07 (s, 1H).
[0043] Example 6
[0044]
[0045] 130.4 g (0.7 mol) of tert-butyl piperazine-1-carboxylate, 142.2 g (1.1 mol) of N,N-diisopropylethylamine, 1300 mL of dichloromethane and 500 mL of water were mixed, cooled to 0-5°C, and a mixed solution of 143.5 g (0.7 mol) of compound 6 and 150 mL of dichloromethane was added. After dropwise addition, the mixture was reacted for 2 hours, allowed to stand and stratified, the aqueous phase was extracted with a small amount of dichloromethane, the organic phases were combined, washed with dilute hydrochloric acid and water, dried with anhydrous sodium sulfate, trifluoroacetic acid was added, the temperature was raised to 35°C, and the reaction was carried out for 6 hours. Isopropanol and sodium hydroxide aqueous solution were added to adjust the pH to 9-10, solid precipitated, filtered, the filter cake was rinsed with water, and dried to obtain 165.3 g of compound 7; yield 92.7%, HPLC 99.1%.
[0046] Example 7
[0047]
[0048] Compound 5230.2g (0.7mol), compound 7178.3g (0.7mol) and ethyl acetate 1850mL were mixed, cooled to 0°C, N,N-diisopropylethylamine 316.6g (2.45mol) was added dropwise, and the temperature was raised to room temperature for overnight reaction. HPLC detected that the remaining raw material was less than 0.5%, washed with water, the organic phase was concentrated under reduced pressure, replaced with 95% ethanol, and recrystallized to obtain 344.6g of elastin. HPLC 99.7%, yield 90%. 1 H NMR(400MHz, CDCl3):8.30-8.27(m,1H),7.80-7.72(m,2H),7.50-7.40(m,2H),7.39-7.01(m,5H),6.84(d,2H),4.61 (s,2H),4.05-3.98(m,2H),3.55-3.30(m,5H),2.80-2.40(m,2H),2.25-1.95(m,2H),1.31(t,3H),1.23-1.17(m,3H).
[0049] The embodiments are described in detail, but the present invention is not limited to the above embodiments. Various changes can be made within the knowledge of ordinary technicians in the relevant technical field without departing from the purpose of the present invention. In addition, the embodiments of the present invention and the features in the embodiments can be combined with each other without conflict.
Claims
1. A method for preparing Erastin, characterized in that: The steps include: Step 1: Mix 2-aminobenzoic acid and propionic anhydride, and heat to react to obtain compound 2; Step 2: Compound 2 is reacted with o-aminophenyl ether in ethylene glycol dimethyl ether under reflux, and after DME is concentrated, sodium hydroxide and ethylene glycol are added to react at high temperature to obtain compound 3; Step 3: Compound 3 is mixed with phthalic anhydride and dichloromethane, and hydrogen peroxide is added dropwise to obtain compound 4; Step 4: Chlorinate compound 4 with sulfonyl chloride to obtain compound 5; Step 5: tert-butyl piperazine-1-carboxylate, DIPEA, dichloromethane and water were mixed, the temperature was lowered and a dichloromethane solution of compound 6 was added, the mixture was washed and concentrated, and then an acid was added to remove the Boc protection to obtain compound 7; Step 6: Dissolve compound 7 and compound 5 in an organic solvent, add an acid-binding agent after cooling, and obtain compound 8 through post-treatment.
2. The method for preparing Erastin according to claim 1, characterized in that: In the first step, propionic anhydride is both a reactant and a solvent, and the mass of propionic anhydride is 3.5 times that of the raw material.
3. The method for preparing Erastin according to claim 1, characterized in that: In the second step, the molar ratio of compound 2, o-aminophenyl ether and sodium hydroxide is 1:0.98-1.00:1.05-1.
10.
4. The method for preparing Erastin according to claim 1, characterized in that: In the third step, the molar ratio of compound 3, phthalic anhydride and hydrogen peroxide is 1:1.75-1.90:2.9-3.
0.
5. The method for preparing Erastin according to claim 1, characterized in that: In the fourth step, the molar ratio of compound 4 to methanesulfonyl chloride is 1:3.3-3.
7.
6. The method for preparing Erastin according to claim 1, characterized in that: In the fifth step, the molar ratio of tert-butyl piperazine-1-carboxylate, DIPEA and compound 6 is 1:1.50-1.80:1.
0.
7. The method for preparing Erastin according to claim 1, characterized in that: In the sixth step, the acid binding agent is DIPEA or TEA.
8. The method for preparing Erastin according to claim 1, characterized in that: In the sixth step, the organic solvent is selected from ethyl acetate or isopropyl acetate.
9. The method for preparing Erastin according to claim 1, characterized in that: In the sixth step, the molar ratio of compound 7, compound 5 and acid binding agent is 1:1:3.5-4.5.