A method for preparing a substituted pyridine carboxylic acid intermediate
By using an alkaline solvent pyridine and an aqueous phase system in the preparation of substituted pyridine carboxylic acids, the problems of thermal management instability and toxic solvent pollution are solved, realizing a high-purity and environmentally friendly preparation method that is suitable for the industrial production of pharmaceutical synthesis intermediates.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- HEFEI OUCHUANG GENE BIOTECHNOLOGY CO LTD
- Filing Date
- 2026-05-25
- Publication Date
- 2026-07-31
AI Technical Summary
In existing technologies, the preparation methods of substituted pyridine carboxylic acids have problems such as thermal management instability leading to side reactions and the use of toxic solvents increasing the risk of environmental pollution.
Using pyridine as the basic solvent as the reaction medium, the reaction conditions were optimized by using an aqueous system instead of the toxic solvent dioxane through acylation, oxidation and deprotection reactions, and controlling the reaction temperature and time.
It improves the purity and safety of the reaction, reduces the risk of environmental pollution, simplifies post-processing operations, and provides an environmentally friendly and feasible solution for industrial production.
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Figure CN122482986A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to a method for preparing a substituted pyridine carboxylic acid intermediate, belonging to the fields of pharmaceutical and chemical technology. Background Technology
[0002] Substituted pyridine carboxylic acids are important organic synthesis intermediates. For example, methyl 4-amino-6-chloropyridine-2-carboxylic acid (CAS: 1235475-17-8), a methyl ester derivative of 4-amino-6-chloropyridine-2-carboxylic acid, can be used in the synthesis of MALT1, BTK, and JAK2 inhibitors.
[0003] 4-Amino-6-chloropyridine-2-carboxylic acid is an important organic synthetic intermediate. Patent CN117486790 A discloses a synthetic method, and the reaction route is as follows:
[0004]
[0005] This reaction uses concentrated sulfuric acid and dioxane as catalysts and solvents, respectively. The mixing process releases a large amount of heat. Although the system temperature is controlled to not exceed 10°C during the reaction, localized overheating may lead to side reactions or decomposition of the raw materials. Furthermore, the large-scale use of highly toxic dioxane as a solvent increases the difficulty and cost of subsequent solvent recovery and waste treatment. Summary of the Invention
[0006] In view of the above technical background and to solve the problems in the prior art, the present invention provides a novel method for preparing substituted pyridine carboxylic acid intermediates.
[0007] The first aspect of this invention provides a method for preparing a substituted pyridine carboxylic acid intermediate, comprising the following steps:
[0008]
[0009] (1) Compound 1 was reacted with an acylation reagent under alkaline conditions to prepare compound 2;
[0010] (2) Compound 2 was reacted with an oxidizing agent to prepare compound 3;
[0011] (3) Compound 3 was deprotected to give compound 4;
[0012] Among them, R1 and R2 are independently selected from H and C. 1~3 Alkyl groups, preferably H, methyl groups, more preferably H;
[0013] R3 is selected from C 1~6 Primary or secondary alkyl groups, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, n-pentyl, isopentyl, neopentyl, and more preferably methyl;
[0014] R4 is an amino protecting group, which is selected from one of acetyl Ac, benzoyl Bz, trifluoroacetyl Tfa, benzyloxycarbonyl Cbz, tert-butoxycarbonyl Boc, 9-fluorenylmethoxycarbonyl Fmoc, p-toluenesulfonyl Ts or methanesulfonyl Ms, preferably acetyl Ac, benzoyl Bz, or trifluoroacetyl Tfa, and more preferably acetyl Ac;
[0015] X is selected from one of Cl, Br, I, p-toluenesulfonyloxy OTs, methanesulfonyloxy OMs, or trifluoromethanesulfonyloxy OTf; preferably Cl, Br, or I, more preferably Cl.
[0016] Further, in step (1), compound 2 is prepared by reacting with an acylation reagent in an alkaline solvent. The alkaline solvent is selected from one or any combination of pyridine, triethylamine, 2,6-dimethylpyridine, 4-dimethylaminopyridine or quinoline, preferably pyridine.
[0017] Further, in step (1), compound 1 is reacted with an acylation reagent in a solvent under the action of an inorganic base to prepare compound 2. The inorganic base is selected from one or any combination of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate or potassium bicarbonate, preferably sodium hydroxide. The solvent is selected from water or a mixture of water and an organic solvent. The organic solvent is selected from one or any combination of dichloromethane, chloroform, dichloroethane, diethyl ether, toluene, benzene, xylene, chlorobenzene, carbon tetrachloride, tetrahydrofuran, preferably a mixture of water and dichloromethane.
[0018] Further, in step (1), the acylation reagent may be selected from one of acetic anhydride, acetyl chloride, benzoyl chloride, benzoic anhydride, trifluoroacetic anhydride, benzyl chloroformate, ditert-butyl dicarbonate, fluorenyl chloroformate, p-toluenesulfonyl chloride or methanesulfonyl chloride, preferably acetic anhydride;
[0019] Further, in step (1), the molar ratio of compound 1 to the acylation reagent is 1:1~2, preferably 1:1~1.5, more preferably 1:1.1;
[0020] Further, in step (1), the molar ratio of compound 1 to the base is 1:8~15, preferably 1:10~13, more preferably 1:11;
[0021] Furthermore, the reaction temperature in step (1) is 70 ℃~120 ℃, preferably 100 ℃; the reaction time is 3~12 hours, preferably 6 hours.
[0022] Further, the oxidizing agent in step (2) can be selected from one or any combination of potassium permanganate, potassium dichromate or sodium dichromate, preferably potassium permanganate;
[0023] Further, in step (2), the molar ratio of compound 2 to the oxidizing agent is 1:1~3, preferably 1:1~1.5, and most preferably 1:1;
[0024] Furthermore, the reaction temperature in step (2) is 50 ℃~100 ℃, preferably 70 ℃; the reaction time is 24~48 hours, preferably 36 hours;
[0025] Further, step (2) is carried out in water or a mixture of water and an organic solvent; the organic solvent is selected from one or any combination of tert-butanol, acetone, acetic acid, acetonitrile, dichloromethane, and chloroform, preferably tert-butanol;
[0026] Furthermore, step (2) is carried out in water;
[0027] Furthermore, in step (2), the volume of solvent used (mL) is 10 to 30 times the mass of compound 2 (g), preferably 15 to 25 times, and more preferably 20 times.
[0028] Furthermore, the deprotection in step (3) can be carried out under strong acid, strong base or hydrogenation conditions, and the appropriate removal conditions are selected according to the specific protecting group; strong acid is preferred.
[0029] Further, in step (3), the strong acid can be selected from sulfuric acid, hydrochloric acid or hydrobromic acid, with sulfuric acid being preferred; the strong base can be selected from sodium hydroxide or potassium hydroxide, with sodium hydroxide being preferred; the catalyst under hydrogenation conditions is selected from Pd / C, Pd(OH)2 / C, Pd black, Pd-DIAION, with Pd / C being preferred;
[0030] Furthermore, in step (3), the molar ratio of compound 3 to a strong acid or strong base is 1:2~3, preferably 1:2.4;
[0031] Further, in step (3), the mass ratio of compound 3 to catalyst is 1:0.1~2; preferably 1:0.1~1, more preferably 1:0.1~0.5;
[0032] Furthermore, when step (3) is carried out under strong acid or strong base conditions, the reaction temperature is 70 ℃~120 ℃, preferably 100 ℃; the reaction time is 12~36 hours, preferably 24 hours.
[0033] Furthermore, when step (3) is carried out under hydrogenation conditions, the reaction temperature is 25~60 ℃, preferably 25~40 ℃; the reaction time is 2~24 hours, preferably 2~16 hours.
[0034] Furthermore, the deprotection step (3) can be carried out in different solvents, and the appropriate reaction solvent can be selected according to the specific protecting group;
[0035] Further, step (3) is carried out in water, an organic solvent, or a mixture of water and an organic solvent; the organic solvent is selected from alcohols, aromatic hydrocarbons, and halogenated hydrocarbon solvents; further, the alcohol solvent is selected from methanol, ethanol, n-propanol, n-butanol, or benzyl alcohol, or any combination thereof, preferably methanol; the aromatic hydrocarbon solvent is selected from toluene, xylene, or ethylbenzene, or any combination thereof, preferably toluene; the halogenated hydrocarbon solvent is selected from dichloromethane, chloroform, carbon tetrachloride, dichloroethane, or trichloroethane, or any combination thereof, preferably dichloromethane; further, step (3) is carried out in water;
[0036] Furthermore, in step (3), the volume of solvent used (mL) is 3 to 10 times the mass of compound 3 (g), preferably 6 times;
[0037] In some implementation schemes, high-purity target compounds can be selectively obtained through post-processing methods such as concentration, drying, and extraction;
[0038] In some implementations, the reaction product can be purified by washing with ethyl acetate after the reaction is complete.
[0039] A second aspect of the present invention provides a compound 2 or compound 3, as shown below:
[0040] , ;
[0041] Among them, R1 and R2 are independently selected from H and C. 1~3 alkyl;
[0042] R3 is selected from C 1~6 Primary or secondary alkyl groups;
[0043] R4 is selected from one of acetyl Ac, benzoyl Bz, trifluoroacetyl Tfa, 9-fluorenylmethoxycarbonyl Fmoc, p-toluenesulfonyl Ts, or methanesulfonyl Ms;
[0044] X is selected from one of Cl, Br, I, p-toluenesulfonyloxy OTs, methanesulfonyloxy OMs, or trifluoromethanesulfonyloxy OTf;
[0045] Furthermore, R1 and R2 are independently selected from H and methyl.
[0046] Furthermore, R3 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, n-pentyl, isopentyl, and neopentyl.
[0047] Furthermore, R4 is selected from acetyl Ac, benzoyl Bz, and trifluoroacetyl Tfa;
[0048] Furthermore, X is selected from Cl, Br, and I.
[0049] Furthermore, R1 and R2 are H, R3 is methyl, R4 is acetyl Ac, and X is Cl; specifically, a compound having the structure shown in formula (2-1) or formula (3-1) is provided:
[0050] , .
[0051] Furthermore, the present invention provides the use of the above-described compound 2 or compound 3 in the preparation of 4-amino-6-chloropyridine-2-carboxylic acid ester derivatives.
[0052] The third aspect of the present invention provides a method for preparing 4-amino-6-chloropyridine-2-carboxylic acid ester derivatives, and particularly provides a method for preparing methyl 4-amino-6-chloropyridine-2-carboxylic acid, the method comprising using the preparation method described in any one of the first aspects of the present invention, and / or compound 2 or compound 3 described in the second aspect of the present invention as a raw material or intermediate.
[0053] Beneficial technical effects of the present invention:
[0054] 1. This invention provides a novel method for preparing the substituted pyridine carboxylic acid intermediate 4-amino-6-chloropyridine-2-carboxylic acid, and provides two novel intermediate compounds 2 and 3, offering new ideas for the synthesis of substituted pyridine carboxylic acid intermediates.
[0055] 2. In step (1) of the present invention, pyridine is used as a base and solvent, which can effectively improve the protection efficiency of the amino group and ensure that the reaction can be carried out completely by neutralizing the acidic byproducts generated during the reaction. The purity of the final product is ≥99%.
[0056] 3. In the preparation method of this invention, steps 2 and 3, the oxidation reaction and the deprotection reaction, both use an aqueous system as the reaction medium. This eliminates the practice of using large amounts of toxic and harmful organic solvents such as dioxane as solvents in the prior art, greatly reducing the risk of environmental pollution, simplifying post-processing operations, and providing a more feasible and environmentally friendly solution for large-scale industrial production. Attached Figure Description
[0057] Figure 1 Compound 2-1 of Example 1 of this invention 1 H NMR spectrum;
[0058] Figure 2 The LCMS spectrum of compound 2-1 in Example 1 of this invention;
[0059] Figure 3 Compound 3-1 of Example 2 of this invention 1H NMR spectrum;
[0060] Figure 4 The LCMS spectrum of compound 3-1 in Example 2 of this invention;
[0061] Figure 5 Compound 4-1 of Example 3 of this invention 1 H NMR spectrum;
[0062] Figure 6 This is the LCMS spectrum of compound 4-1 in Example 3 of the present invention. Detailed Implementation
[0063] The preparation method of the present invention will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection intended by the present invention.
[0064] Unless otherwise specified, the experimental methods used in the following examples are conventional methods; unless otherwise specified, the reagents and materials used in the following examples are commercially available.
[0065] Example 1:
[0066]
[0067] Compound 1-1 (50.0 g, 0.35 mol), pyridine (300 mL), and acetic anhydride (36.13 mL) were added sequentially to a reaction vessel and magnetically stirred. The reaction was carried out at 100 °C for 6 hours. After the reaction was completed, the pyridine and unreacted acetic anhydride in the system were removed by vacuum concentration. Subsequently, water (300 mL) was added to the system and vacuum concentration was continued. This process was repeated three times. Finally, the mixture was dried with an oil pump to obtain a brownish-red oily compound 2-1 (60.0 g, yield 92.68%, purity: 99.9% (214 nm), 99.7% (254 nm)), with a mass-to-charge ratio (m / z) of 183 [MH] in negative ion mode. - ,That 1 H NMR spectrum as shown Figure 1 As shown, the LCMS spectrum is as follows Figure 2 As shown.
[0068] 1 H NMR(400 MHz, DMSO) δ 10.44(s, 1H), 7.54(d, J=1.7 Hz, 1H), 7.29 (d,J=1.7 Hz, 1H), 2.38 (s, 3H), 2.09 (s, 3H).
[0069] Example 2:
[0070]
[0071] Compound 2-1 (60.0 g, 0.325 mol), water (1200 mL), and potassium permanganate (KMnO4) (51.36 g) were added sequentially to a reaction vessel and magnetically stirred. The reaction was carried out at 70 °C for 36 hours. After the color of the reaction solution faded, the solution was cooled to room temperature. The pH of the reaction solution was adjusted to 8-9 with 2N sodium hydroxide aqueous solution, and the mixture was magnetically stirred for 30 min. The solution was then filtered. The filter cake was washed three times with 500 mL of water, and the filtrates were combined and separated. The aqueous phase was extracted six times with 500 mL of ethyl acetate, and then the pH of the aqueous phase was adjusted to 2-3 with 2N HCl aqueous solution. After drying with an oil pump, the solid was dissolved in methanol, filtered to remove salt, and concentrated under reduced pressure. The obtained solid was washed with 200 mL of ethyl acetate and dried to obtain a white powder solid (50.0 g, yield 71.69%, purity: 99.5% (214 nm), 99.8% (254 nm)), with a mass-to-charge ratio (m / z) of 213 [MH] in negative ion mode. - ,That 1 H NMR spectrum as shown Figure 3 As shown, the LCMS spectrum is as follows Figure 4 As shown.
[0072] 1 H NMR (400 MHz, DMSO) δ 10.86 (s, 1H), 8.11 (d, J=1.7 Hz, 1H), 7.92 (d, J=1.8 Hz, 1H), 2.13 (s, 3H).
[0073] Example 3:
[0074]
[0075] Compound 3-1 (50.0 g, 0.233 mol) and water (300 mL) were added sequentially to a reaction vessel and magnetically stirred. Sulfuric acid (30 mL, 98%) was slowly added during stirring, and the mixture was heated to 100 °C and reacted for 24 hours. After the reaction was complete, the reaction solution was cooled to room temperature, and water (700 mL) was added. The mixture was concentrated under reduced pressure to half its original volume, and water (500 mL) was added again. This process was repeated three times. The pH of the system was adjusted to 10-11 with 2N NaOH solution, and the mixture was concentrated under reduced pressure to approximately 300 mL. The pH was then adjusted to 2-3 with 2N HCl aqueous solution, resulting in the precipitation of a large amount of solid. The solid was filtered and washed with ethyl acetate (100 mL), and dried to obtain a white powder solid (32 g, yield 79.59%, purity: 99.3% (214 nm), 99.9% (254 nm)), with a mass-to-charge ratio (m / z) of 171 in negative ion mode [MH]. - ,That 1 H NMR spectrum as shown Figure 5 As shown, the LCMS spectrum is as follows Figure 6 As shown.
[0076] 1 H NMR (400MHz, DMSO) δ 7.20 (d, J=1.9 Hz, 1H), 6.70 (s, 2H), 6.63 (d,J=1.9 Hz, 1H).
Claims
1. A method for preparing compound 4, characterized in that, Includes the following steps: (1) Compound 1 was reacted with an acylation reagent under alkaline conditions to prepare compound 2; (2) Compound 2 was reacted with an oxidizing agent to prepare compound 3; (3) Compound 3 was deprotected to give compound 4; wherein R1, R2are independently selected from H, C 1~3 alkyl, preferably H, methyl, more preferably H; R3 is selected from C 1~6 Primary or secondary alkyl groups, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, n-pentyl, isopentyl, neopentyl, and more preferably methyl; R4 is an amino protecting group, which is selected from one of acetyl Ac, benzoyl Bz, trifluoroacetyl Tfa, benzyloxycarbonyl Cbz, tert-butoxycarbonyl Boc, 9-fluorenylmethoxycarbonyl Fmoc, p-toluenesulfonyl Ts or methanesulfonyl Ms, preferably acetyl Ac, benzoyl Bz, or trifluoroacetyl Tfa, and more preferably acetyl Ac; X is selected from one of Cl, Br, I, p-toluenesulfonyloxy OTs, methanesulfonyloxy OMs or trifluoromethanesulfonyloxy OTf, preferably Cl, Br, I, and more preferably Cl.
2. The preparation method according to claim 1, characterized in that, The preparation method satisfies at least one of the following conditions: In step (1), compound 1 is reacted with an acylation reagent in an alkaline solvent to prepare compound 2. The alkaline solvent is selected from one or any combination of pyridine, triethylamine, 2,6-dimethylpyridine, 4-dimethylaminopyridine or quinoline, preferably pyridine; or compound 1 is prepared with an acylation reagent in a solvent in the presence of an inorganic base to obtain compound 2. The inorganic base is selected from one or any combination of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate or potassium bicarbonate, preferably sodium hydroxide. The solvent is selected from water or a mixture of water and an organic solvent. The organic solvent is selected from one or any combination of dichloromethane, chloroform, dichloroethane, diethyl ether, toluene, benzene, xylene, chlorobenzene, carbon tetrachloride, tetrahydrofuran, preferably a mixture of water and dichloromethane. In step (1), the acylation reagent is selected from one of acetic anhydride, acetyl chloride, benzoyl chloride, benzoic anhydride, trifluoroacetic anhydride, benzyl chloroformate, ditert-butyl dicarbonate, fluorenyl chloroformate, p-toluenesulfonyl chloride or methanesulfonyl chloride, with acetic anhydride being preferred.
3. The preparation method according to any one of claims 1 to 2, characterized in that, The reaction conditions in step (1) satisfy at least one of the following conditions: The molar ratio of compound 1 to the acylation reagent is 1:1~2, preferably 1:1~1.5, and more preferably 1:1.1; The molar ratio of compound 1 to the base is 1:8~15, preferably 1:10~13, and more preferably 1:11; In step (1), the reaction temperature is 70 ℃~120 ℃, preferably 100 ℃; the reaction time is 3~12 hours, preferably 6 hours.
4. The preparation method according to claim 1, characterized in that, In step (2), the oxidizing agent is selected from one or any combination of potassium permanganate, potassium dichromate or sodium dichromate, with potassium permanganate being preferred.
5. The preparation method according to any one of claims 1 or 4, characterized in that, The reaction conditions in step (2) satisfy at least one of the following conditions: The molar ratio of compound 2 to the oxidizing agent is 1:1~3, preferably 1:1~1.5, and most preferably 1:1; In step (2), the reaction temperature is 50 ℃~100 ℃, preferably 70 ℃; the reaction time is 24~48 hours, preferably 36 hours. The step (2) is carried out in water or a mixture of water and an organic solvent; the organic solvent is selected from one or any combination of tert-butanol, acetone, acetic acid, acetonitrile, dichloromethane, and chloroform, preferably tert-butanol; In step (2), the volume of solvent used (mL) is 10 to 30 times the mass of compound 2 (g), preferably 15 to 25 times, and more preferably 20 times.
6. The preparation method according to claim 1, characterized in that, Step (3) is carried out under strong acid, strong base or hydrogenation conditions, preferably strong acid.
7. The preparation method according to any one of claims 1 or 6, characterized in that, The reaction conditions in step (3) satisfy at least one of the following conditions: The strong acid is selected from sulfuric acid, hydrochloric acid, or hydrobromic acid, with sulfuric acid being preferred. The strong base is selected from sodium hydroxide or potassium hydroxide, preferably sodium hydroxide; The catalyst under the hydrogenation conditions is selected from Pd / C, Pd(OH)2 / C, Pd black, and Pd-DIAION, with Pd / C being preferred. The molar ratio of compound 3 to a strong acid or strong base is 1:2~3, preferably 1:2.4; The mass ratio of compound 3 to catalyst is 1:0.1~2; preferably 1:0.1~1, more preferably 1:0.1~0.5; When step (3) is carried out under strong acid or strong base conditions, the reaction temperature is 70 ℃~120 ℃, preferably 100 ℃; the reaction time is 12~36 hours, preferably 24 hours. When step (3) is carried out under hydrogenation conditions, the reaction temperature is 25~60 ℃, preferably 25~40 ℃; the reaction time is 2~24 hours, preferably 2~16 hours. Step (3) involves a reaction in water, an organic solvent, or a mixture of water and an organic solvent, preferably water; the organic solvent is selected from alcohols, aromatic hydrocarbons, and halogenated hydrocarbon solvents; the alcohol solvent is selected from methanol, ethanol, n-propanol, n-butanol, or benzyl alcohol, or any combination thereof, preferably methanol; the aromatic hydrocarbon solvent is selected from toluene, xylene, or ethylbenzene, or any combination thereof, preferably toluene; the halogenated hydrocarbon solvent is selected from dichloromethane, chloroform, carbon tetrachloride, dichloroethane, or trichloroethane, or any combination thereof, preferably dichloromethane; In step (3), the volume of solvent used (mL) is 3 to 10 times the mass of compound 3 (g), preferably 6 times.
8. A compound having the structure shown in compound 2 or compound 3: 、 ； in, R1 and R2 are independently selected from H and C. 1~3 Alkyl groups, preferably H- or methyl groups; R3 is selected from C 1~6 Primary or secondary alkyl groups, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, n-pentyl, isopentyl, or neopentyl; R4 is selected from acetyl Ac, benzoyl Bz, trifluoroacetyl Tfa, 9-fluorenylmethoxycarbonyl Fmoc, p-toluenesulfonyl Ts or methanesulfonyl Ms, preferably acetyl Ac, benzoyl Bz, or trifluoroacetyl Tfa; X is selected from Cl, Br, I, p-toluenesulfonyloxy OTs, methanesulfonyloxy OMs or trifluoromethanesulfonyloxy OTf, preferably Cl, Br or I; More preferably, compounds with the structure shown in formula (2-1) or formula (3-1): 、 。 9. Use of the compound of claim 8 in the preparation of 4-amino-6-chloropyridine-2-carboxylic acid ester derivatives.
10. A method for preparing 4-amino-6-chloropyridine-2-carboxylic acid ester derivatives, characterized in that, The method includes the preparation method according to any one of claims 1 to 7.