A process for the preparation of 6-((((9H-fluorenyl)methoxy)carbonyl)amino)quinoline-4-carboxylic acid
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- ASTATECH (CHENGDU) BIOPHARM CORP
- Filing Date
- 2024-12-30
- Publication Date
- 2026-06-30
AI Technical Summary
Existing technologies cannot provide a method for synthesizing 6-((((9H-fluorenyl)methoxy)carbonyl)amino)quinoline-4-carboxylic acid that is readily available, simple in steps, and low in cost, and suitable for industrial production.
Using 2-hydroxyquinoline-4-carboxylic acid as a raw material, a hydrogen source was introduced through a dehalogenation palladium carbon hydrogenation reaction, and triethylamine was used as an acid-binding agent to neutralize the generated hydrochloric acid, allowing the reaction to proceed in the forward direction. Subsequently, Fmoc-OSU was used as an amino-protecting agent to generate the target compound.
A synthetic route with readily available raw materials, simple steps, and low cost has been achieved, which is suitable for industrial production. The prepared compounds can be used to synthesize high-purity copper radiopharmaceuticals.
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Abstract
Description
Technical Field
[0001] This invention belongs to the field of pharmaceutical synthesis technology, specifically relating to a method for preparing 6-((((9H-fluorenyl)methoxy)carbonyl)amino)quinoline-4-carboxylic acid. Background Technology
[0002] Quinoline is a heterocyclic aromatic organic compound. Its derivatives are widely used in the synthesis of pharmaceuticals, dyes, and pesticides. For example, it is used as an intermediate in the synthesis of 8-hydroxy-7-iodo-5-quinoline sulfonic acid, a halogenated quinoline anti-amoebic drug, or as a fragment in the synthesis of S-2[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-1,2,3,4-tetrahydro-3-isoquinoline acid salt.
[0003] Patent application (WO2024064969) discloses a high-purity copper radiopharmaceutical that can be used to prepare a radioactive tracking agent, with a structure for treating malignant tumors using radioactive copper-61. The structure of compound 30 is shown below: This drug can treat malignant tumors using radioactive copper-61. 6-((((9H-fluorenyl)methoxy)carbonyl)amino)quinoline-4-carboxylic acid can serve as a quinoline fragment source for the synthesis of this drug. Therefore, developing a method for synthesizing 6-((((9H-fluorenyl)methoxy)carbonyl)amino)quinoline-4-carboxylic acid that uses readily available raw materials, involves simple steps, is low-cost, and is suitable for industrial production is of great significance. Summary of the Invention
[0004] The purpose of this invention is to provide a method for preparing 6-((((9H-fluorenyl)methoxy)carbonyl)amino)quinoline-4-carboxylic acid.
[0005] This invention provides a method for preparing 6-((((9H-fluorenyl)methoxy)carbonyl)amino)quinoline-4-carboxylic acid, the method comprising the following steps:
[0006]
[0007] Wherein, R is selected from hydrogen, carboxyl, C 1～6 alkyl;
[0008] (1) 2-hydroxyquinoline-4-carboxylic acid was reacted with concentrated nitric acid to give compound 2;
[0009] (2) Compound 2, catalyst, base and phosphorus oxychloride are reacted to obtain compound 3;
[0010] (3) Compound 3, base, catalyst and reducing agent are reacted to obtain compound 4;
[0011] (4) React compound 4, a base and an amino protecting agent to obtain 6-((((9H-fluorenyl)methoxy)carbonyl)amino)quinoline-4-carboxylic acid.
[0012] Furthermore, the R is selected from carboxyl groups.
[0013] Further, in step (1), the equivalent ratio of 2-hydroxyquinoline-4-carboxylic acid and concentrated nitric acid is 1:3 to 5; the solvent for the reaction is an organic solvent; the temperature of the reaction is -15 to 0°C, and the time is 1 to 5 hours.
[0014] Further, in step (1), the equivalent ratio of 2-hydroxyquinoline-4-carboxylic acid and concentrated nitric acid is 1:4 to 4.5; the solvent for the reaction is concentrated sulfuric acid; the reaction temperature is -15 to 0°C, and the reaction time is 2 to 4 hours.
[0015] Furthermore, after step (1) is completed, the following purification steps are also included: after the reaction is completed, ice water is added to quench the reaction, the temperature does not exceed 30°C, the mixture is filtered, the filter cake is rinsed with water and dried to obtain the final product.
[0016] Further, in step (2), the catalyst is N,N-dimethylformamide; the base is selected from N,N-diisopropylethylamine or triethylamine; the equivalent ratio of compound 2, catalyst, base and phosphorus oxychloride is 1:0.1-0.3:0.2-0.4:4-8; the solvent for the reaction is an organic solvent; the reaction temperature is 110-140℃ and the time is 2-8 hours.
[0017] Further, in step (2), the equivalent ratio of compound 2, catalyst, base and phosphorus oxychloride is 1:0.2:0.3:6; the solvent for the reaction is toluene; the reaction temperature is 120°C and the time is 4 to 6 hours.
[0018] Furthermore, after step (2), the following purification steps are also included: concentration to remove phosphorus oxychloride, quenching with water, ice bath, controlling the reaction temperature to not exceed 30°C, standing and separating, extraction, filtration and concentration, addition of tetrahydrofuran, reflux and stirring, ice bath, filtration while cold, drying, and the final product is obtained.
[0019] Further, in step (3), the base is selected from N,N-diisopropylethylamine or triethylamine; the catalyst is palladium on carbon; the reducing agent is hydrogen; the equivalent ratio of compound 3, base and catalyst is 1:2:0.4; the solvent for the reaction is a mixture of tetrahydrofuran and methanol in a volume ratio of 6:3 to 4; the reaction temperature is 10 to 40°C, the time is 5 to 20 hours, and the pressure is 0.5 to 2.0 MPa.
[0020] Further, in step (3), the equivalent ratio of compound 3, base and catalyst is 1:2:0.4; the solvent for the reaction is a mixture of tetrahydrofuran and methanol in a volume ratio of 1:1; the reaction temperature is 20-35°C, the time is 12-16 hours, and the pressure is 1.0-1.5 MPa.
[0021] Furthermore, after step (3) is completed, the following purification steps are also included: after the reaction is completed, sodium hydroxide solution (pH=9-12) is added, stirred and filtered, activated carbon is added and refluxed, cooled and filtered, pH is adjusted (4-6), stirred to precipitate crystals, filtered, and dried to obtain the product.
[0022] Further, in step (4), the base is selected from sodium bicarbonate or sodium carbonate; the amino protecting agent is Fmoc-OSU; the equivalent ratio of compound 4, base and amino protecting agent is 1:2 to 3:1; the solvent for the reaction is an organic solvent; the reaction temperature is 10 to 40°C and the time is 5 to 20 hours.
[0023] Further, in step (4), the equivalent ratio of compound 4, base and amino protecting agent is 1:2.5:1; the solvent for the reaction is tetrahydrofuran; the reaction temperature is 20-35°C and the reaction time is 16 hours.
[0024] Furthermore, after step (4) is completed, the following purification steps are also included: after the reaction is completed, adjust the pH, extract, stir to precipitate crystals, filter under reduced pressure, and dry to obtain the final product.
[0025] This invention uses 2-hydroxyquinoline-4-carboxylic acid as a raw material and develops a method that introduces a hydrogen source through catalytic hydrogenation via dehalogenation palladium on carbon, followed by neutralization of the generated hydrochloric acid using triethylamine as an acid-binding agent, thus advancing the reaction to obtain a 6-amino-quinoline-4-carboxylic acid intermediate. Fmoc-OSU then replaces the amino group to generate 6-((((9H-fluorenyl)methoxy)carbonyl)amino)quinoline-4-carboxylic acid. This invention further optimizes the reaction process conditions, obtaining the preferred process conditions shown in Example 1. The method of this invention has the advantages of readily available raw materials, simple steps, and low cost, making it suitable for industrial production and showing broad application prospects.
[0026] The 6-((((9H-fluorenyl)methoxy)carbonyl)amino)quinoline-4-carboxylic acid prepared by this invention can be used as a quinoline fragment source for the synthesis of high-purity copper radiopharmaceuticals as radioactive tracking agents, and has broad application prospects.
[0027] 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.
[0028] 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 embodiments. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention. Attached Figure Description
[0029] Figure 1 The 1H NMR spectrum of 2-hydroxy-6-nitro-quinoline-3-carboxylic acid.
[0030] Figure 2 The 1H NMR spectrum of 2-chloro-6-nitroquinoline-4-carboxylic acid.
[0031] Figure 3 The 1H NMR spectrum of 6-amino-quinoline-4-carboxylic acid.
[0032] Figure 4 The 1H NMR spectrum of 6-((((9H-fluorenyl)methoxy)carbonyl)amino)quinoline-4-carboxylic acid. Detailed Implementation
[0033] The raw materials and equipment used in this invention are all known products, obtained by purchasing commercially available products.
[0034] In this invention, "room temperature" refers to 25±10℃, and "overnight" refers to 12±5 hours.
[0035] 6-((((9H-fluorenyl)methoxy)carbonyl)amino)quinoline-4-carboxylic acid was prepared according to the following synthetic route:
[0036] Example 1: Synthesis of 6-((((9H-fluorenyl)methoxy)carbonyl)amino)quinoline-4-carboxylic acid
[0037] Step 1: Synthesis of 2-hydroxy-6-nitro-quinoline-3-carboxylic acid
[0038] 317 g of 2-hydroxyquinoline-4-carboxylic acid (1.68 mol, 1 eq) was added to 1600 mL of concentrated sulfuric acid. Stirring was started, and the reaction system was kept in an ice-salt bath to lower the temperature to approximately -10 °C. 422.36 g of 65% concentrated nitric acid (6.70 mol, 4 eq) and 320 mL of concentrated sulfuric acid were weighed and mixed thoroughly. After the temperature dropped to approximately -10 °C, the mixture was added dropwise to the reaction flask, maintaining the temperature between -15 °C and 0 °C. After the addition was complete, the reaction was maintained at 0 °C for 2 hours. After the reaction was complete, the reaction solution was slowly quenched in ice water, keeping the reaction temperature below 30 °C. The mixture was stirred for 20 minutes, filtered, and the filter cake was rinsed with water. The filter cake was then washed once with 3.5 L of water and stirred for 20 minutes before filtration. The filter cake was then washed again with 2.5 L of water for 30 minutes before filtration, rinsing with water, and drying at 55 °C to obtain 388 g of 2-hydroxy-6-nitro-quinoline-3-carboxylic acid, with a yield of 87%. 1 ¹H NMR (400MHz, DMSO) δ 9.86 (d, J = 2.7Hz, 1H), 8.39 (dd, J = 9.2, 2.7Hz, 1H), 8.03 (d, J = 9.2Hz, 1H), 7.75 (s, 1H). The ¹H NMR spectrum of 2-hydroxy-6-nitro-quinoline-3-carboxylic acid is shown below. Figure 1 As shown.
[0039] Step 2: Synthesis of 2-chloro-6-nitroquinoline-4-carboxylic acid
[0040] The 2-hydroxy-6-nitro-quinoline-3-carboxylic acid (375 g, 1.60 mol, 1 eq) obtained in step 1 was dissolved in 4 L of toluene. N,N-dimethylformamide (23.41 g, 320.29 mmol, 0.2 eq) and N,N-diisopropylethylamine (62.09 g, 480.43 mmol, 0.3 eq) were added, and the mixture was stirred until homogeneous. Phosphorus oxychloride (1.47 kg, 9.61 mol, 6 eq) was slowly added dropwise. After the addition was complete, the temperature was gradually increased to 120 °C and the reaction proceeded for 4–6 h. After the reaction was complete, the mixture was concentrated at 55 °C to remove phosphorus oxychloride. The precipitated solid was quenched in portions by adding it to 3 L of water in an ice-water bath, controlling the reaction temperature to not exceed 3 °C. After quenching at 0℃, stir for 30 min, let stand and separate the liquid. Extract the aqueous phase with methyl tert-butyl ether (MTBE) until there is almost no product in the aqueous phase. If there is still a small amount of undissolved solid, filter and dry. After THF is completely dissolved, filter again and mix the filtrate with the previous organic phase and concentrate together. Add 1.5V tetrahydrofuran, start stirring, and heat to 70℃ to generate reflux. After reflux, continue stirring for 20 minutes until the solid is completely dissolved. Remove the heat source and let it cool naturally to room temperature. Then, put it in an ice bath and cool it to about 10℃. Filter while cold, wash the filter cake with a small amount of tetrahydrofuran, and dry at 50℃ to obtain 225g of 2-chloro-6-nitroquinoline-4-carboxylic acid, with a yield of 55%. 1¹H NMR (400MHz, DMSO) δ 9.86 (d, J = 2.7Hz, 1H), 8.39 (dd, J = 9.2, 2.7Hz, 1H), 8.03 (d, J = 9.2Hz, 1H), 7.75 (s, 1H). The ¹H NMR spectrum of 2-chloro-6-nitroquinoline-4-carboxylic acid is as follows: Figure 2 As shown.
[0041] Step 3: Synthesis of 6-amino-quinoline-4-carboxylic acid
[0042] The 2-chloro-6-nitroquinoline-4-carboxylic acid (120 g, 475.04 mmol, 1 eq) obtained in step 2 was dissolved in 1.8 L of tetrahydrofuran and 1.8 L of methanol. Triethylamine (48.07 g, 475.04 mmol, 1 eq) and 5% dehalogenated palladium on carbon (23.08 g, 190.02 mmol, 0.4 eq) were added. The mixture was purged with hydrogen and the pressure was maintained at 1.0-1.5 MPa. The reaction was carried out overnight at room temperature. Then, triethylamine (48.07 g, 475.04 mmol, 1 eq) was added again. After the reaction was complete, diatomaceous earth was used as a base, and the mixture was filtered. The filter cake was added to a sodium hydroxide solution (pH = 9-12), stirred, and filtered. The two filtrates were combined and concentrated until almost no solid was produced. The mixture was stirred with activated carbon, heated to 60°C, refluxed for 2 hours, cooled, and filtered. The filter cake was rinsed with a small amount of water. The pH of the filtrate was adjusted to 4-6 with dilute hydrochloric acid, stirred, and crystallized. The solid was filtered, and the filter cake was rinsed with tetrahydrofuran. The filtrate was further concentrated until at least a small amount of solid precipitated. The pH was then adjusted to 4-6 with dilute hydrochloric acid, stirred, and crystallized. The solid was filtered, and the filter cake was rinsed with tetrahydrofuran and dried to obtain 60 g of 6-amino-quinoline-4-carboxylic acid, with a yield of 57%. 1 1H NMR (400MHz, DMSO) δ 8.8 (dd, J = 20.0, 3.5Hz, 2H), 7.8 (d, J = 4.4Hz, 1H), 7.8 (d, J = 7.4Hz, 2H). The 1H NMR spectrum of 6-amino-quinoline-4-carboxylic acid is shown below. Figure 3 As shown.
[0043] Step 4: Synthesis of 6-((((9H-fluorenyl)methoxy)carbonyl)amino)quinoline-4-carboxylic acid
[0044] The 6-amino-quinoline-4-carboxylic acid (52.2 g, 277.39 mmol, 1 eq) obtained in step 3 was added to water (250 ml, 5V), followed by NaHCO3 (58.26 g, 693.48 mmol, 2.5 eq), 9-fluorenylmethyl-N-succinimide carbonate (93.57 g, 277.39 mmol, 1 eq), and THF (250 ml, 5V). The mixture was reacted overnight at room temperature. After the reaction was complete, the pH was adjusted to 8-9 with 1N hydrochloric acid, and MTBE (100 ml, 2V) was added for extraction. The mixture was separated, and the pH of the aqueous phase was adjusted to 4-5 with 1N hydrochloric acid. Crystallization was carried out by stirring for 2 hours, during which a small amount of MTBE (20 ml) was added. The mixture was filtered under reduced pressure, washed with PE, and dried to obtain 82 g. 6-((((9H-fluorenyl)methoxy)carbonyl)amino)quinoline-4-carboxylic acid, yield 70%, purity = 98%; 1 H NMR (400M, DMSO): δ10.2(s,1H),8.8(d,J=2.3Hz,1H),8.8(d,J=4.5Hz,1H),8.0(d,J=9.0Hz,1H),7.8(d,J=7.4Hz,3H),7.8(d,J=4.3Hz,1H),7 .8(d,J=7.3Hz,2H),7.40(t,J=7.4Hz,2H),7.4(t,J=7.3Hz,2H),4.4(d,J=6.8Hz,2H),4.4(t,J=6.7Hz,1H),3.6~3.5(m,2H),1.8~1.6(m,2H). The 1H NMR spectrum of 6-((((9H-fluorenyl)methoxy)carbonyl)amino)quinoline-4-carboxylic acid is as follows: Figure 4 As shown.
[0045] In summary, this invention provides a method for preparing 6-((((9H-fluorenyl)methoxy)carbonyl)amino)quinoline-4-carboxylic acid, its application, and other uses. This invention uses 2-hydroxyquinoline-4-carboxylic acid as a raw material to prepare 6-((((9H-fluorenyl)methoxy)carbonyl)amino)quinoline-4-carboxylic acid. This method has the advantages of readily available raw materials, simple steps, and low cost, making it suitable for industrial production and showing broad application prospects.
Claims
1. A method for preparing 6-((((9H-fluorenyl)methoxy)carbonyl)amino)quinoline-4-carboxylic acid, characterized in that, The method includes the following steps: Wherein, R is selected from hydrogen, carboxyl, C 1～6 alkyl; (1) 2-hydroxyquinoline-4-carboxylic acid was reacted with concentrated nitric acid to give compound 2; (2) Compound 2, catalyst, base and phosphorus oxychloride are reacted to obtain compound 3; (3) Compound 3, base, catalyst and reducing agent are reacted to obtain compound 4; (4) React compound 4, a base and an amino protecting agent to obtain 6-((((9H-fluorenyl)methoxy)carbonyl)amino)quinoline-4-carboxylic acid.
2. The method according to claim 1, characterized in that, The R is selected from carboxyl groups.
3. The method according to claim 1, characterized in that, In step (1), the equivalent ratio of 2-hydroxyquinoline-4-carboxylic acid to concentrated nitric acid is 1:3 to 5; the solvent for the reaction is an organic solvent; the reaction temperature is -15 to 0°C, and the reaction time is 1 to 5 hours.
4. The method according to claim 3, characterized in that, In step (1), the equivalent ratio of 2-hydroxyquinoline-4-carboxylic acid to concentrated nitric acid is 1:4 to 4.5; the solvent for the reaction is concentrated sulfuric acid; the reaction temperature is -15 to 0°C, and the reaction time is 2 to 4 hours.
5. The method according to claim 1, characterized in that, In step (2), the catalyst is N,N-dimethylformamide; the base is selected from N,N-diisopropylethylamine or triethylamine; the equivalent ratio of compound 2, catalyst, base and phosphorus oxychloride is 1:0.1-0.3:0.2-0.4:4-8; the solvent for the reaction is an organic solvent; the reaction temperature is 110-140℃ and the time is 2-8 hours.
6. The method according to claim 5, characterized in that, In step (2), the equivalent ratio of compound 2, catalyst, base and phosphorus oxychloride is 1:0.2:0.3:6; the solvent for the reaction is toluene; the reaction temperature is 120°C and the time is 4 to 6 hours.
7. The method according to claim 1, characterized in that, In step (3), the base is selected from N,N-diisopropylethylamine or triethylamine; the catalyst is palladium on carbon; the reducing agent is hydrogen; the equivalent ratio of compound 3, base and catalyst is 1:2:0.4; the solvent for the reaction is a mixture of tetrahydrofuran and methanol in a volume ratio of 6:3 to 4; the reaction temperature is 10 to 40°C, the time is 5 to 20 hours, and the pressure is 0.5 to 2.0 MPa.
8. The method according to claim 7, characterized in that, In step (3), the equivalent ratio of compound 3, base and catalyst is 1:2:0.4; the solvent for the reaction is a mixture of tetrahydrofuran and methanol in a volume ratio of 1:1; the reaction temperature is 20-35°C, the time is 12-16 hours, and the pressure is 1.0-1.5 MPa.
9. The method according to claim 1, characterized in that, In step (4), the base is selected from sodium bicarbonate or sodium carbonate; the amino protecting agent is Fmoc-OSU; the equivalent ratio of compound 4, base and amino protecting agent is 1:2 to 3:1; the solvent for the reaction is an organic solvent; the reaction temperature is 10 to 40°C and the time is 5 to 20 hours.
10. The method according to claim 9, characterized in that, In step (4), the equivalent ratio of compound 4, base and amino protecting agent is 1:2.5:1; the solvent for the reaction is tetrahydrofuran; the reaction temperature is 20-35℃ and the reaction time is 16 hours.