Process for the preparation of 2-acetyl-1,10-phenanthroline
By using the condensation and decarboxylation reaction of 2-formic acid-1,10-phenanthroline, the problems of long synthetic routes and low yields of 2-acetyl-1,10-phenanthroline in existing technologies have been solved, enabling efficient and low-cost large-scale production.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- ASTATECH (CHENGDU) BIOPHARM CORP
- Filing Date
- 2023-07-14
- Publication Date
- 2026-08-04
AI Technical Summary
The existing synthesis process for 2-acetyl-1,10-phenanthroline suffers from problems such as long route, low yield, high cost, and unsuitability for large-scale production.
Using 2-formic acid-1,10-phenanthroline as raw material, the reaction is carried out through condensation and decarboxylation reactions, using inexpensive and readily available reagents and room temperature conditions. The reaction is carried out using N,N'-carbonyldiimidazole, malonic acid monoester metal salt, anhydrous magnesium chloride and alkali, avoiding harsh equipment and low temperature conditions.
A high-yield and high-purity preparation of 2-acetyl-1,10-phenanthroline was achieved, which is suitable for large-scale production, low-cost, environmentally friendly, and easy to operate.
Smart Images
Figure CN117209493B_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of organic synthesis, specifically relating to a method for preparing 2-acetyl-1,10-phenanthroline. Background Technology
[0002] 2-Acetyl-1,10-phenanthroline, CAS: 72404-92-3, is a very important organic synthesis intermediate, and developing a safe and efficient production process for it is of great significance.
[0003]
[0004] 2-Acetyl-1,10-Phenanthroline
[0005] Currently, several synthetic processes for 2-acetyl-1,10-phenanthroline have been reported both domestically and internationally. For example, Chinese patent application CN112961154A discloses an addition reaction using 8-aminoquinoline as a starting material to obtain 4-oxo-3-(quinoline-8-amino)pentanal, followed by a cyclization reaction to obtain 2-acetyl-1,2-dihydrophenanthroline, and then an oxidation reaction to obtain 2-acetyl-1,10-phenanthroline. This method has a long route, long reaction time, and very low yield, making it unsuitable for scale-up. Patent CN102040608B discloses a process using 1,10-phenanthroline as a starting agent, involving methylation with lithium methylate, followed by oxidation to a carboxylic acid with potassium permanganate, and then reaction with lithium methylate to obtain the target product. This process requires the use of large amounts of permanganate, generating a large amount of wastewater, and also uses a large amount of expensive alkyl metal reagents. Furthermore, the reaction needs to be carried out under cryogenic conditions of -78°C, resulting in high raw material and production costs, which is not conducive to scale-up.
[0006] Chinese patent CN110003203A, published under publication number CN102040608B, made improvements to the previous patent. Using 1,10-phenanthroline as the starting material, it first obtains a cyano intermediate through a cyanidation reagent, and then reacts with methyllithium to obtain the target product. Although it avoids the use of potassium permanganate, it still requires expensive alkyl metal reagents and still needs to be reacted under cryogenic conditions of -78°C. The raw material cost and production cost are still relatively high, which is not conducive to scale-up. Moreover, its reaction selectivity is not high. To obtain the mono-substituted alkylated phenanthroline product, the yield is very low, the product is complex, and it is difficult to separate.
[0007] Chinese patent CN114940677A addresses the problems of Chinese patent CN110003203A by using continuous flow equipment to improve selectivity and other issues. However, it still requires a large amount of methylglycine reagents to participate in the reaction, which is not only costly and poses safety risks, but also too dependent on continuous flow equipment, resulting in high equipment investment.
[0008] Therefore, finding a simple, rapid, safe and efficient method for the scale-up production of 2-acetyl-1,10-phenanthroline is of great significance. Summary of the Invention
[0009] The purpose of this invention is to provide a method for preparing 2-acetyl-1,10-phenanthroline.
[0010] This invention provides a method for preparing 2-acetyl-1,10-phenanthroline, which includes the following steps:
[0011]
[0012] Wherein, R is selected from C1 to C4 alkyl groups;
[0013] Step 1: In a solvent, compound 1 reacts with a carboxyl activator to obtain compound 2;
[0014] Step 2: In a solvent, compound 2, malonic acid monoester metal salt, anhydrous magnesium chloride, and base react. The resulting solid reaction product is then reacted with acid to obtain compound 3.
[0015] Furthermore,
[0016] In step 1, the solvent is acetonitrile;
[0017] And / or, in step 1, the carboxyl activator is N,N'-carbonyldiimidazole, thionyl chloride, or phosphorus oxychloride;
[0018] And / or, in step 2, the solvent is acetonitrile;
[0019] And / or, in step 2, the malonic acid monoester metal salt is malonic acid monomethyl ester metal salt, malonic acid monoethyl ester metal salt, or malonic acid monotert-butyl ester metal salt.
[0020] And / or, in step 2, the base is an organic base;
[0021] And / or, in step 2, the acid is hydrochloric acid.
[0022] Furthermore,
[0023] In step 1, the carboxyl activator is N,N'-carbonyldiimidazole;
[0024] And / or, in step 2, the metal salt of the malondialdehyde monoester is selected from sodium salt, potassium salt, and lithium salt;
[0025] And / or, in step 2, the organic base is triethylamine, pyridine, or DIPEA;
[0026] And / or, in step 2, the hydrochloric acid is 10% hydrochloric acid;
[0027] Preferably,
[0028] In step 2, the malonic acid monoester metal salt is potassium monomethyl malonic acid.
[0029] And / or, in step 2, the organic base is triethylamine.
[0030] Furthermore,
[0031] In step 1, the equivalent ratio of compound 1 to carboxyl activator is 1:1 to 2;
[0032] And / or, in step 2, the equivalent ratio of the malonic acid monoester metal salt, anhydrous magnesium chloride, base and compound 1 in step 1 is 1-2:1-2:1-2:1;
[0033] And / or, in step 2, the mass-to-volume ratio of the solid reaction product to the acid is 1:2 to 20.
[0034] Furthermore,
[0035] In step 1, the equivalent ratio of compound 1 to the carboxyl activator is 1:1.1 to 1.2;
[0036] And / or, in step 2, the equivalent ratio of the malonic acid monoester metal salt, anhydrous magnesium chloride, base and compound 1 in step 1 is 1.05-1.2:1.05-1.2:1.05-1.2:1.
[0037] Furthermore,
[0038] In step 1, the reaction temperature is 20–30°C, and the reaction time is 1–5 hours.
[0039] And / or, in step 2, the reaction temperature of compound 2, the metal salt of malondialdehyde monoester, anhydrous magnesium chloride and the base is 70-80°C, and the reaction time is 1-5 hours;
[0040] And / or, in step 2, the temperature of the acid addition reaction is 70-75°C, and the reaction time is 12-16 hours.
[0041] Furthermore,
[0042] In step 1, the temperature is 20–30°C when the carboxyl activator is added;
[0043] And / or, in step 1, the compound 2 obtained after the reaction is not purified and directly enters step 2 to participate in the reaction.
[0044] Furthermore,
[0045] In step 2, after the reaction of compound 2, malonic acid monoester metal salt, anhydrous magnesium chloride and alkali, the temperature is lowered to 10-20°C, the reaction solution is poured into water, stirred, and then cooled to 5-10°C for 1-5 hours. After filtration, a solid reaction product is obtained.
[0046] And / or, in step 2, after the acid reaction, water is added to the reaction solution and the pH is adjusted to 9-10 until solid precipitates, then filtered and dried to obtain compound 3.
[0047] Furthermore, the pH adjustment is performed using a NaOH solution.
[0048] This invention also provides the use of the aforementioned method in the large-scale industrial production of 2-acetyl-1,10-phenanthroline. In this invention, large-scale industrial production refers to the production of 10 kg or more of the product.
[0049] Compared with the prior art, the beneficial effects of the present invention are as follows:
[0050] This invention provides a method for obtaining 2-acetyl-1,10-phenanthroline from 2-formic acid-1,10-phenanthroline via condensation and decarboxylation. The preparation of 2-acetyl-1,10-phenanthroline by this invention does not require special reagents, special equipment, or harsh reaction conditions. The raw materials are inexpensive and readily available, resulting in low cost, simple operation, and a green and safe reaction process that is environmentally friendly. The prepared product has a high overall yield and high purity, making it easy to scale up for production. This method is of great significance for the synthesis of 2-acetyl-1,10-phenanthroline and has broad application prospects.
[0051] Obviously, based on the above description of the present invention, and according to common technical knowledge and conventional methods in the field, various other modifications, substitutions or alterations can be made without departing from the basic technical concept of the present invention.
[0052] The following detailed embodiments further illustrate the above-described content of the present invention. However, this should not be construed as limiting the scope of the present invention to the following examples. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention. Attached Figure Description
[0053] Figure 1 The hydrogen spectrum of 2-acetyl-1,10-phenanthroline. Detailed Implementation
[0054] The raw materials and equipment used in the specific embodiments of the present invention are all known products, obtained by purchasing commercially available products.
[0055] The synthetic route for 2-acetyl-1,10-phenanthroline in this invention is as follows:
[0056]
[0057] Example 1: Preparation method of 2-acetyl-1,10-phenanthroline
[0058] S1. Using 2-carboxylic acid-1,10-phenanthroline (50 g, 1.0 eq) dissolved in acetonitrile (300 g) as a substrate, N,N'-carbonyldiimidazole (CDI, 39.77 g, 1.1 eq) was slowly added dropwise at 20 °C. After the addition was complete, the mixture was kept at 20–30 °C for 1.5 h. Once the reaction was complete, the mixture was set aside. Yield: 100%.
[0059] S2. Under an inert atmosphere, 37.27 g (1.07 eq) of potassium monomethyl malonate and 22.72 g (1.07 eq) of anhydrous magnesium chloride were suspended in acetonitrile (300 g). At 20 °C, 22.56 g (1.07 eq) of triethylamine was slowly added dropwise, followed by the rapid addition of the activated carboxylic acid from S1. After the addition was complete, the temperature was raised to 70–80 °C and maintained for 3 hours until the reaction was complete. The temperature was then lowered to 10–20 °C, and the reaction solution was transferred to 1800 g of water. The mixture was stirred thoroughly and then cooled to 5–10 °C and maintained for 1 hour. The mixture was then filtered to obtain a white solid magnesium salt. The obtained magnesium salt was directly added to 300 mL of 10% hydrochloric acid and heated to 70–75 °C for 12–16 h. After the reaction was complete, 500 mL of tap water was added to the reaction solution, and the pH was adjusted to 9–10 with 10% NaOH solution. A large amount of solid precipitated out, which was filtered and the filter cake was dried to obtain 42.24 g of the product 2-acetyl-1,10-phenanthroline, with a yield of 85.23% and an HPLC yield of 96.8%.
[0060] 1 H NMR (400M, DMSO): δ = 9.22 (dd, 1H), 8.67 (d, 1H), 8.56 (dd, 1H), 8.29 (d, 1H), 8.12 (t, 2H), 7.85 (dd, 1H), 2.90 (s, 3H).
[0061] Example 2: Preparation method of 2-acetyl-1,10-phenanthroline
[0062] S1. Using 2-carboxylic acid-1,10-phenanthroline (50 g, 1.0 eq) dissolved in acetonitrile (300 g) as a substrate, CDI (43.38 g, 1.2 eq) was slowly added dropwise at 20 °C. After the addition was complete, the mixture was kept at 20–30 °C for 1.5 h. Once the reaction was complete, the product was set aside. Yield: 100%.
[0063] S2. Under an inert atmosphere, 41.80 g (1.2 eq) of potassium monomethyl malonate and 25.48 g (1.2 eq) of anhydrous magnesium chloride were suspended in acetonitrile (300 g). At 20 °C, 25.30 g (1.2 eq) of triethylamine was slowly added dropwise, followed by the rapid addition of the activated carboxylic acid from S1. After the addition was complete, the temperature was raised to 70–80 °C and maintained for 3 hours until the reaction was complete. The temperature was then lowered to 10–20 °C, and the reaction solution was transferred to 1800 g of water. The mixture was stirred thoroughly and then cooled to 5–10 °C and maintained for 1 hour. The mixture was then filtered to obtain a white solid magnesium salt. The obtained magnesium salt was directly added to 300 mL of 10% hydrochloric acid and heated to 70–75 °C for 12–16 h. After the reaction was complete, 500 mL of tap water was added to the reaction solution, and the pH was adjusted to 9–10 with 10% NaOH solution. A large amount of solid precipitated out, which was filtered and the filter cake was dried to obtain 43.52 g of the product 2-acetyl-1,10-phenanthroline, with a yield of 87.82% and an HPLC yield of 97.2%.
[0064] 1 H NMR (400M, DMSO): δ = 9.22 (dd, 1H), 8.67 (d, 1H), 8.56 (dd, 1H), 8.29 (d, 1H), 8.12 (t, 2H), 7.85 (dd, 1H), 2.90 (s, 3H).
[0065] Example 3: Scale-up production of 2-acetyl-1,10-phenanthroline
[0066] S1. Using 2-carboxylic acid-1,10-phenanthroline (50 kg, 1.0 eq) dissolved in acetonitrile (200 kg) as a substrate, CDI (39.77 kg, 1.1 eq) was slowly added dropwise at 20 °C. After the addition was complete, the mixture was kept at 20–30 °C for 1.5 h. Once the reaction was complete, the mixture was set aside. Yield: 100%.
[0067] S2. Under an inert atmosphere, 36.57 kg (1.05 eq) of potassium monomethyl malonate and 22.29 kg (1.05 eq) of anhydrous magnesium chloride were suspended in acetonitrile (200 kg). At 20 °C, 23.19 kg (1.1 eq) of triethylamine were slowly added dropwise, followed by the rapid addition of the activated carboxylic acid from S1. After the addition was complete, the temperature was raised to 70–80 °C and maintained for 3 hours until the reaction was complete. The temperature was then lowered to 10–20 °C, and the reaction solution was transferred to 1800 kg of water. The mixture was stirred thoroughly and then cooled to 5–10 °C and maintained for 2 hours. The mixture was then filtered to obtain a white solid magnesium salt. The obtained magnesium salt was directly added to 10% hydrochloric acid (300 kg) and heated to 70-75℃ for 12-16 h. After the reaction was complete, 500 kg of tap water was added to the reaction solution, and the pH was adjusted to 9-10 with 10% NaOH solution. A large amount of solid precipitated out, which was filtered and the filter cake was dried to obtain 43.66 kg of the product 2-acetyl-1,10-phenanthroline, with a yield of 88.10% and an HPLC yield of 96.5%.
[0068] 1 H NMR (400M, DMSO): δ = 9.22 (dd, 1H), 8.67 (d, 1H), 8.56 (dd, 1H), 8.29 (d, 1H), 8.12 (t, 2H), 7.85 (dd, 1H), 2.90 (s, 3H).
[0069] The method for preparing 2-acetyl-1,10-phenanthroline of this invention can still achieve high yield and high purity during scale-up production, making it very suitable for large-scale production.
[0070] In summary, this invention provides a method for obtaining 2-acetyl-1,10-phenanthroline from 2-formic acid-1,10-phenanthroline via condensation and decarboxylation. This method for preparing 2-acetyl-1,10-phenanthroline does not require special reagents, special equipment, or stringent reaction conditions. The raw materials are inexpensive and readily available, resulting in low cost, simple operation, and a green and safe reaction process that is environmentally friendly. The prepared product has a high overall yield and high purity, making it easy to scale up for production. This method is of great significance for the synthesis of 2-acetyl-1,10-phenanthroline and has broad application prospects.
Claims
1. A process for the preparation of 2-acetyl-1,10-phenanthroline, characterized in that: It includes the following steps: Wherein, R is selected from C1~C4 alkyl groups; Step 1: In a solvent, compound 1 reacts with a carboxyl activator to obtain a carboxyl-activated intermediate; Step 2: In a solvent, the carboxyl-activated intermediate, the metal salt of malonate monoester, anhydrous magnesium chloride and base react to obtain solid reaction product compound 2. The solid reaction product is then reacted with acid to obtain compound 3. In step 1, the carboxyl activator is N,N'-carbonyldiimidazole; In step 2, the malonic acid monoester metal salt is potassium monomethyl malonic acid. In step 2, the base is triethylamine.
2. The method according to claim 1, characterized in that: In step 1, the solvent is acetonitrile; And / or, in step 2, the solvent is acetonitrile; And / or, in step 2, the acid is hydrochloric acid.
3. The method of claim 2, wherein: In step 2, the hydrochloric acid is 10% hydrochloric acid.
4. The method according to claim 1, characterized in that: In step 1, the equivalent ratio of compound 1 to carboxyl activator is 1:1~2; And / or, in step 2, the equivalent ratio of the malonic acid monoester metal salt, anhydrous magnesium chloride, base and compound 1 in step 1 is 1~2:1~2:1~2:1; And / or, in step 2, the mass-to-volume ratio of the solid reaction product to the acid is 1:2~20.
5. The method according to claim 4, characterized in that: In step 1, the equivalent ratio of compound 1 to the carboxyl activator is 1:1.1~1.2; And / or, in step 2, the equivalent ratio of the malonic acid monoester metal salt, anhydrous magnesium chloride, base and compound 1 in step 1 is 1.05~1.2:1.05~1.2:1.05~1.2:
1.
6. The method according to claim 1, characterized in that: In step 1, the reaction temperature is 20~30℃ and the reaction time is 1~5h; And / or, in step 2, the reaction temperature of the carboxyl-activated intermediate, the malonic acid monoester metal salt, the anhydrous magnesium chloride and the base is 70~80℃, and the reaction time is 1~5h; And / or, in step 2, the temperature of the acid addition reaction is 70~75℃, and the reaction time is 12~16h.
7. The method according to claim 1, characterized in that: In step 1, the temperature is 20~30℃ when the carboxyl activator is added; And / or, in step 1, the carboxyl-activated intermediate obtained after the reaction is not purified and directly enters step 2 to participate in the reaction.
8. The method according to claim 1, characterized in that: In step 2, the carboxyl-activated intermediate, malonic acid monoester metal salt, anhydrous magnesium chloride and alkali react and are then cooled to 10-20°C. The reaction solution is poured into water, stirred, and cooled to 5-10°C for 1-5 hours. After filtration, a solid reaction product is obtained. And / or, in step 2, after the acid reaction, water is added to the reaction solution and the pH is adjusted to 9-10 until solid precipitates, then filtered and dried to obtain compound 3.
9. The method of claim 8, wherein: The pH was adjusted using NaOH solution.
10. Use of the method according to any one of claims 1 to 9 in the large-scale industrial production of 2-acetyl-1,10-phenanthroline.