A method for synthesizing 1H-pyrazolo[3,4-b]pyridine derivatives
Through a multi-step reaction method, the problems of reaction conditions control and product purification in the synthesis of existing 1H-pyrazolo[3,4-b]pyridine derivatives were solved, and a series of novel structure derivatives were successfully synthesized, providing a new functional molecular framework for pharmaceutical research and development.
Patent Information
- Application Number
- CN202411933487.9
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-26
- Publication Date
- 2025-04-04
AI Technical Summary
The existing synthesis method of 1H-pyrazolo[3,4-b]pyridine derivatives has difficulties in controlling reaction conditions, product purification and yield improvement, and it is difficult to synthesize derivatives with different structures.
Compound 1 was gradually obtained by nucleophilic substitution reaction, halogenation reaction, intercalation carbonyl reaction and hydrolysis reaction.
The synthesis of a series of novel structures of 1H-pyrazolo[3,4-b]pyridine derivatives was achieved, which simplified the synthesis route, improved the simplicity of operation and difficulty of synthesis, and provided a new functional molecular framework for pharmaceutical research and development.
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Figure CN119751450A_ABST
Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a method for synthesizing a 1H-pyrazolo[3,4-b]pyridine derivative. Background Art
[0002] 1H-pyrazolo[3,4-b]pyridine compounds are a very important class of fused heterocyclic compounds with a wide range of pharmacological and biological activities. They are widely used as the skeleton for the synthesis of small molecules with therapeutic properties for the treatment of various diseases. This class of compounds has shown great potential in anti-tumor, anti-inflammatory and treatment of specific diseases. For example, some 1H-pyrazolo[3,4-b]pyridine compounds are potent inhibitors of hGSK-3α and have significant anti-tumor activity. GZD82440 is an orally bioavailable inhibitor containing a 1H-pyrazolo[3,4-b]pyridine structure, which has inhibitory effects on a wide range of Bcr-Abl mutants and shows potential in the treatment of chronic myeloid leukemia (CML). Pimitespib is an oral HSP90 inhibitor under development that can specifically bind to and inhibit the activity of HSP90, degrade oncogene downstream proteins, inhibit the signal transduction of downstream proteins, and induce apoptosis of tumor cells. It is a potential drug for the treatment of gastrointestinal stromal tumors (GIST).
[0003] Since compounds such as 1H-pyrazolo[3,4-b]pyridine have up to five diversity centers, they allow for a variety of possible substituent combinations, which means that there are many different methods for synthesizing 1H-pyrazolo[3,4-b]pyridine derivatives, and it is necessary to select a suitable synthetic route according to specific needs. However, in the actual synthesis process, it is also necessary to pay attention to the control of reaction conditions, purification of products, and improvement of yields, in order to synthesize 1H-pyrazolo[3,4-b]pyridine derivatives with different structures. Summary of the invention
[0004] In view of the defects of the prior art, the first purpose of the present invention is to provide a method for synthesizing 1H-pyrazolo[3,4-b]pyridine derivatives. Based on compounds with known structures, further functional group modification and transformation are performed to synthesize 1H-pyrazolo[3,4-b]pyridine derivatives with novel structures, thereby providing new functional molecular skeletons for medical research and development.
[0005] The purpose of the present invention is achieved through the following technical solutions:
[0006] A method for synthesizing a 1H-pyrazolo[3,4-b]pyridine derivative: Compound 1 is sequentially subjected to one or more of the following reactions: nucleophilic substitution reaction, halogenation reaction, carbonyl insertion reaction, and hydrolysis reaction to obtain a 1H-pyrazolo[3,4-b]pyridine derivative of formula I:
[0007]
[0008] Among them, R1 represents C1-C3 alkyl, monosubstituted or polysubstituted phenyl, aromatic ring, aromatic heterocycle; R2 represents hydrogen, halogen, ester group, carboxylic acid; R3 represents hydroxyl group, methoxy group.
[0009] Furthermore, the synthesis method is to obtain compound 2 by subjecting compound 1 to a nucleophilic substitution reaction:
[0010]
[0011] Furthermore, the synthesis method includes subjecting compound 2 to a halogenation reaction to obtain compound 3, wherein the halogenation reaction is a bromination reaction:
[0012]
[0013] Furthermore, the synthesis method includes subjecting compound 3 to carbonyl insertion reaction to obtain compound 4:
[0014]
[0015] Furthermore, the synthesis method includes hydrolyzing compound 4 to obtain compound 5:
[0016]
[0017] Furthermore, the synthesis method also includes a two-step hydrolysis reaction of compound 4 to obtain compound 6:
[0018]
[0019] Furthermore, the nucleophilic reagent in the nucleophilic reaction is one or more of sodium methoxide, sodium ethoxide, sodium hydroxide, and potassium hydroxide; the solvent used in the nucleophilic reaction is one or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, toluene, tetrahydrofuran, benzene, xylene, 1,4-dioxane, ethylene glycol dimethyl ether, ethanol, acetonitrile, and water; and the reaction temperature of the nucleophilic reaction is between 60-120°C.
[0020] Furthermore, the reagent used in the halogenation reaction is one or more of NBS, bromine, elemental iodine, chlorine, NCS, and NIS, and the solvent used in the halogenation reaction is one or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, toluene, tetrahydrofuran, benzene, xylene, 1,4-dioxane, ethylene glycol dimethyl ether, ethanol, acetonitrile, and water.
[0021] Furthermore, compound 3 is subjected to an intercalation reaction under a carbon source atmosphere and catalyzed by a palladium catalyst to obtain compound 4, wherein the palladium catalyst is one or more of Pd(OAc)2, Pd(PPh3)2Cl2, PdCl2, Pd(dppf)Cl2, Pd(MeCN)Cl2, Pd(PPh3)4, Pd2(dba)3, and Pd(dba)2, the carbon source is one or more of carbon monoxide or carbon dioxide, and the base used in the intercalation reaction is one or more of triethylamine, potassium phosphate, potassium carbonate, sodium carbonate, potassium acetate, and sodium acetate.
[0022] Furthermore, the reagent for hydrolyzing the methoxy group in the hydrolysis reaction is one or more of boron tribromide, hydrobromic acid, boron trichloride, aluminum trichloride, sodium ethanethiolate, and TMSI.
[0023] Beneficial effects of the present invention:
[0024] The present invention provides a novel method for synthesizing a series of 1H-pyrazolo[3,4-b]pyridine derivatives. Except for compound 1, the synthesis of other compounds has not been reported in the literature. The method has a reasonable route, simple operation, and relatively easy synthesis. It can be expanded and transformed by functional groups to synthesize more 1H-pyrazolo[3,4-b]pyridine derivatives with novel structures, and can provide a new functional molecular skeleton for medical research and development. BRIEF DESCRIPTION OF THE DRAWINGS
[0025] Figure 1 1H NMR diagram of compound 2 in the example;
[0026] Figure 2 1H NMR diagram of compound 3 in the examples;
[0027] Figure 3 1H NMR diagram of compound 4 in the examples;
[0028] Figure 4 1H NMR chart of compound 6 in the examples. DETAILED DESCRIPTION
[0029] To make the purpose, technical scheme and advantages of the present invention clearer, each embodiment of the present invention will be described in detail below. However, it will be appreciated by those skilled in the art that in each embodiment of the present invention, many technical details are proposed in order to enable the reader to better understand the present invention. However, even without these technical details and various changes and modifications based on the following embodiments, the technical scheme claimed in each claim of the present invention can also be implemented. The raw materials used in the following embodiments of the present invention are conventionally commercially available unless otherwise specified, and the experimental operations used are conventional operations in the art unless otherwise specified.
[0030] Unless otherwise specified, the raw materials used in the following examples are all commercially available in the art.
[0031] Example
[0032] This embodiment provides a synthetic method for preparing a 1H-pyrazolo[3,4-b]pyridine derivative, which comprises the following steps:
[0033]
[0034] Step 1: Under nitrogen protection, compound 1: 6-chloro-3-methyl-1H-pyrazolo[3,4-b]pyridine (600 mg, 1 mmol) was dissolved in methanol (3 mL), and a methanol solution of sodium methoxide (30% wt, 3 mL) was added to the reaction solution. The reaction solution was reacted at 100°C for 16 hours in a sealed pressure reaction bottle. After the reaction was completed, the reaction solution was concentrated. The crude product was separated and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 3:1) to obtain a white solid compound 2: 6-methoxy-3-methyl-1H-pyrazolo[3,4-b]pyridine (300 mg, 51.5%).
[0035] LCMS: m / z = 164.00 [M+H] +
[0036] 1H NMR (400MHz, DMSO-d6) δ12.89(s,1H),8.01(d,J=8.6Hz,1H),6.56(d,J=8.6Hz,1H),3.89(s,3H),2.41(s,3H).
[0037] Step 2: Under nitrogen protection, compound 2, 6-methoxy-3-methyl-1H-pyrazolo[3,4-b]pyridine (300 mg, 1.84 mmol) was dissolved in acetonitrile (10 mL), and NBS (393 mg, 2.21 mmol) was added to the reaction solution in batches. The reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated. The crude product was separated and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 3:1) to obtain a yellow solid compound 3: 5-bromo-6-methoxy-3-methyl-1H-pyrazolo[3,4-b]pyridine (260 mg, 58.6%).
[0038] LCMS: m / z=241.90; 243.90[M+H]+
[0039] 1H NMR (400MHz, DMSO-d6) δ8.43(s,1H),3.97(s,3H),2.41(s,3H).
[0040] Step 3: Dissolve compound 3, 5-bromo-6-methoxy-3-methyl-1H-pyrazolo[3,4-b]pyridine (241 mg, 1.0 mmol) in ethanol (5 mL), and add triethylamine (303 mg, 3.0 mmol) and Pd(dppf)Cl2 (146 mg, 0.2 mmol) to the reaction solution in sequence. The reaction solution was replaced with carbon monoxide gas three times, and reacted at 80°C for 16 hours under a carbon monoxide atmosphere. After the reaction was completed, the reaction solution was filtered and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 3:1) to obtain compound 4 as a white solid: 6-methoxy-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester (180 mg, 76.6%).
[0041] LCMS: m / z = 236.05 [M+H] +
[0042] 1H NMR (400MHz, DMSO-d6) δ13.20 (s, 1H), 8.56 (s, 1H), 4.28 (q, J = 7.1Hz, 2H), 3.96 (s, 3H), 2.46 (s, 3H), 1.31 (t, J = 7.1Hz, 3H).
[0043] Step 4: Under nitrogen protection, compound 4, 6-methoxy-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester (180 mg, 0.77 mmol) was dissolved in DCM (2 mL), and the temperature was lowered to 0°C, and boron tribromide (0.2 mL) was slowly added dropwise to the reaction solution. The reaction solution was stirred at 0°C for 0.5 hours. After the reaction was completed, ethanol (5 mL) was slowly added dropwise to quench the reaction. The resulting mixed solution was concentrated under reduced pressure to obtain compound 5 as a yellow solid: 6-hydroxy-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester (150 mg, 88.6%).
[0044] LCMS: m / z = 222.00 [M+H] +
[0045] Step 5: Under nitrogen protection, compound 5: 6-hydroxy-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester (150 mg, 0.68 mmol) was dissolved in THF (3 mL), methanol (3 mL) and H2O (2 mL), and lithium hydroxide monohydrate (86 mg, 2.03 mmol) was slowly added to the reaction solution. The reaction solution was stirred at room temperature for 1 hour. After the reaction was completed, the pH value of the reaction solution was adjusted to 3-4 with 1N hydrochloric acid aqueous solution, and extracted with DCM (20 mL×3). The organic phases were combined and washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a white solid compound 6: 3-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid (100 mg, 76.4%).
[0046] LCMS: m / z=194.00[M+H]+
[0047] 1H NMR (400MHz, DMSO-d6) δ14.86(s,1H),13.70(s,1H),13.07(s,1H),8.90(s,1H),2.55(s,3H).
[0048] Finally, it should be noted that those skilled in the art can understand that the above-mentioned embodiments are specific examples for realizing the present invention, and in actual applications, various changes can be made in form and details without departing from the spirit and scope of the present invention.
Claims
1. A method for synthesizing a 1H-pyrazolo[3,4-b]pyridine derivative, characterized in that: The method comprises sequentially subjecting compound 1 to one or more of nucleophilic substitution reaction, halogenation reaction, carbonyl insertion reaction, and hydrolysis reaction to obtain a compound of formula I: Among them, R1 represents C1-C3 alkyl, monosubstituted or polysubstituted phenyl, aromatic ring, aromatic heterocycle; R2 represents hydrogen, halogen, ester group, carboxylic acid; R3 represents hydroxyl group, methoxy group.
2. The synthesis method according to claim 1, characterized in that The synthesis method is to obtain compound 2 by subjecting compound 1 to a nucleophilic substitution reaction:
3. The synthesis method according to claim 2, characterized in that The synthesis method comprises the following steps: performing a halogenation reaction on compound 2 to obtain compound 3, wherein the halogenation reaction is a bromination reaction:
4. The synthesis method according to claim 3, characterized in that The synthesis method comprises the following steps: performing carbonyl insertion reaction on compound 3 to obtain compound 4:
5. The synthesis method according to claim 4, characterized in that The synthesis method comprises the following steps: performing a hydrolysis reaction on compound 4 to obtain compound 5:
6. The synthesis method according to claim 4, characterized in that The synthesis method further comprises subjecting compound 4 to a two-step hydrolysis reaction to obtain compound 6:
7. The synthesis method according to claim 2, characterized in that The nucleophilic reagent in the nucleophilic reaction is one or more of sodium methoxide, sodium ethoxide, sodium hydroxide, and potassium hydroxide; the solvent used in the nucleophilic reaction is one or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, toluene, tetrahydrofuran, benzene, xylene, 1,4-dioxane, ethylene glycol dimethyl ether, ethanol, acetonitrile, methanol, and water; and the reaction temperature of the nucleophilic reaction is between 60-120°C.
8. The synthesis method according to claim 3, characterized in that The reagents used in the halogenation reaction are one or more of NBS, bromine, elemental iodine, chlorine, NCS, and NIS, and the solvents used in the halogenation reaction are one or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, toluene, tetrahydrofuran, benzene, xylene, 1,4-dioxane, ethylene glycol dimethyl ether, ethanol, acetonitrile, and water.
9. The synthesis method according to claim 4, characterized in that The compound 3 is subjected to a carbonylation reaction in a carbon source atmosphere under the catalysis of a palladium catalyst to obtain compound 4, wherein the palladium catalyst is one or more of Pd(OAc)2, Pd(PPh3)2Cl2, PdCl2, Pd(dppf)Cl2, Pd(MeCN)Cl2, Pd(PPh3)4, Pd2(dba)3, and Pd(dba)2, the carbon source is one or more of carbon monoxide or carbon dioxide, and the base used in the carbonylation reaction is one or more of triethylamine, potassium phosphate, potassium carbonate, sodium carbonate, potassium acetate, and sodium acetate.
10. The synthesis method according to claim 5, characterized in that: The reagent for hydrolyzing the methoxy group in the hydrolysis reaction is one or more of boron tribromide, hydrobromic acid, boron trichloride, aluminum trichloride, sodium ethanethiolate, and TMSI.