Synthesis method of novel 5-aryl-3-alkyl pyrazolo [1, 5-a] pyridine

Abstract

The invention discloses a novel synthesis method of 5-aryl-3-alkyl pyrazolo [1, 5-a] pyridine, which comprises the following specific synthesis steps: adding an X2 donor compound into a solvent containing a compound SM at 0-5 DEG C, stirring at 0-5 DEG C for complete reaction, and performing post-treatment to obtain a compound 1; adding the compound 1 into a solvent, adding an organic metal reagent at 0-5 DEG C in a protective atmosphere, stirring at room temperature for complete reaction, and performing post-treatment to obtain a compound 2; dissolving the compound 2 and triethyl silane in a solvent, adding trifluoroacetic acid, stirring to react completely, and performing post-treatment to obtain a compound 3; under a protective atmosphere, dissolving the compound 3, Pd (dppf) Cl2, B2Pin2 and alkali in an organic solvent, and carrying out reflux stirring reaction completely to obtain a compound 4; and under a protective atmosphere, adding water, Pd (dppf) Cl2 and ArX into the reaction liquid containing the compound 4, carrying out reflux stirring to completely react, and carrying out post-treatment on the reaction liquid to obtain a target compound 5. The method is short in step, easy to operate in each step, high in yield and suitable for large-scale amplification.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, specifically relating to a novel method for synthesizing 5-aryl-3-alkylpyrazolo[1,5-a]pyridine. Background Technology

[0002] 5-Aryl-3-alkylpyrazolo[1,5-a]pyridine belongs to the fused heterocyclic pyrazolo[1,5-a]pyridine family, in which the aryl group (including heteroaryl groups) is located at C-5 and the alkyl group is located at C-3. This planar skeleton is rich in heteroatoms and is commonly used as a hinge-binding motif or preferred core in small molecule medicinal chemistry projects. ACS Omega. 2019, 4 , 15289–1530). This compound is primarily used for the following biological / pharmacological applications: 1. Kinase Inhibitors. Numerous substituted pyrazolo[1,5-a]pyridines (including 5-aryl variants) appear in patents and literature relating to kinase programs (RET, TRK, JAK, Pim family, and other tyrosine / serine kinases). The 5-aryl group typically extends into the selectivity pocket, while the fused core is hydrogen-bonded to the hinge region. Several family patents and academic structural compound (SAR) papers explicitly list 5-arylpyrazolo[1,5-a]pyridine compounds as ret kinase inhibitors (WO2018071447A1).

[0003] 2. Antibacterial / Anti-tuberculosis lead compounds. Related pyrazolo[1,5-a]pyridine derivatives (various 3-position substitution modes) have been reported in medicinal chemistry reports to have activity against Mycobacterium tuberculosis and other microbial targets. This is a common starting point for exploring lipophilic heteroaromatic inhibitors (ACSMed. Chem. Lett. 2015, 6, 814–818. Design, Synthesis, and Biological Evaluation of Pyrazolo[1,5-a]pyridine-3-carboxamides as Novel Antitubercular Agents).

[0004] Anti-inflammatory / Other Indications. Pyrazolopyridine compounds have been tested in inflammation, central nervous system, and other therapeutic areas through patent and academic screening; their activity depends largely on the nature of the 5-aryl group and other substituents. This scaffold is expected to have broad application prospects rather than a single typical indication (Arab. J. Chem. 2022,15, 04015).

[0005] Below is a brief summary of the main published synthetic routes for this class of compounds and an explanation of their applicability. Literature and patents employ several reliable strategies for synthesizing 5-aryl-3-alkylpyrazolo[1,5-a]pyridine. The following are some typical synthetic methods.

[0006] 1. First, a fused pyrazolo[1,5-a]pyridine core is constructed, and then a 5-aryl group is introduced through a cross-coupling reaction.

[0007] Workflow: Preparation of 5-halopyrazolo[1,5-a]pyridine (bromine or iodine) with the desired 3-isopropyl group → Suzuki / Negishi / Buchwald is cross-coupled with arylboronic esters / organometallic reagents (or 5-bromophenyl and aryl halides are used).

[0008] Reasons for use: High degree of modularity (5-aryl group can be changed later), reliable at the milligram to gram scale, and widely described in patents and scale-up literature.

[0009] Typical conditions: Pd catalyst (Pd2(dba)3, Pd(PPh3)4, Pd-PEPPSI), ligand (XPhos / SPhos / BrettPhos), base (K3PO4, Cs2CO3), solvent (dioxane / H2O or DMAc), temperature 80–110 °C o C.

[0010] Tetrahedron 2012, 68 , 5434-5444. Optimized scale up of 3-pyrimidinylpyrazolo[1,5-a]pyridine via Suzuki coupling; a general method of accessing a range of 3-(hetero) arylpyrazolo[1,5-a]pyridine. 2. Using an alkyne with an isopropyl equivalent, a core is constructed via a [3+2] cycloaddition reaction (N-iminopyridine ylide / methyliminoimine), followed by derivatization at the C-5 position.

[0011] Workflow: N-iminopyridine ylide + alkyne → controllable C-3 substituted pyrazolo[1,5-a]pyridine; then halogenated or directly coupled if conditions permit.

[0012] Reasons for use: It is ideal for the direct mounting of 3-isopropyl groups and allows for rapid core construction from simple precursors. Many academic groups and reviews list this method as the preferred approach for core synthesis. ACS Omega. 2019, 4 , 15289–15303.Synthetic Strategy for Pyrazolo[1,5- a ]pyridineand Pyrido[1,2- b ]indazoleDerivatives through AcOH and O2-Promoted Cross-dehydrogenative CouplingReactions between 1,3-Dicarbonyl Compoundsand N -Amino-2-iminopyridines) 3. Direct heteroaryl-heteraryl cross-coupling (pre-formed 5-halogenated core with arylboronic ester) Direct, standard Suzuki coupling of 5-halopyrazole nuclei with various arylboronic esters is common in patents (rapid structure-activity relationships). This is used when both ligands are readily available (EP17787843NWB1).

[0013] 4. CH arylation / C-5 direct arylation (an emerging, step-economical method) Workflow: Palladium-catalyzed pyrazolopyridine is directly activated by C–H, allowing the installation of an aryl group at the C-5 position without pre-halogenation.

[0014] Reasons for application: Reduces steps and waste; promotes rapid and green chemistry, but requires careful screening of catalysts / ligands / solvents and may have regioselectivity issues for heterocyclic compounds. The number of reports on this type of method has been increasing in the literature from 2020 to 2024. Org. Lett. 2022, 24, 1454-1459. Regioselective Synthesis of Pyrazolo[1,5-a]pyridine via TEMPO-Mediated [3 + 2]Annulation–Aromatization of N-Aminopyridines and α,β-Unsaturated Compounds).

[0015] 5. Cycloning / Multi-component / One-pot process There are also cyclization and tandem sequences, which can be used to construct fusion systems while introducing aryl chaperones (less common for 5-aryl compounds, but useful in library generation). Org. Biomol. Chem 2022, 20 , 4331-4337.Base-mediated [3 + 2]-cycloannulation strategy for thesynthesis of pyrazolo[1,5-a]pyridine derivatives using (E)-β-iodovinyl sulfones).

[0016] The practical considerations, advantages, and disadvantages of existing synthetic routes are as follows: 1. Cross-coupling (5-halogen → aryl): Very flexible and stable for SAR, but requires preparation / processing of the 5-halogenated compound (an additional step) or arylboronic ester (which can undergo ortho-deboronization). Suitable for both working and large-scale compound library construction.

[0017] 2. [3+2] Cycloaddition to the core, followed by halogenation / coupling: This allows for efficient one-step installation of the C-3 substituent; however, attention should be paid to the C-5 regioisomer and halogenation selectivity.

[0018] 3. Direct CH arylation: Reduces steps and waste, but requires careful optimization to avoid over-arylation or low regioselectivity. It is best suited for experienced teams that want to reduce steps.

[0019] This application summarizes the advantages and disadvantages of various existing synthetic methods, adjusts and optimizes the synthetic steps, and proposes a new synthetic method for synthesizing compounds such as 5-aryl-3-alkylpyrazolo[1,5-a]pyridine through continuous exploration and verification. Summary of the Invention

[0020] In view of this, the object of the present invention is to provide a method for synthesizing 5-aryl-3-alkylpyrazolo[1,5-a]pyridine.

[0021] To achieve the above objectives, the present invention provides the following technical solution: A novel method for synthesizing 5-aryl-3-alkylpyrazolo[1,5-a]pyridine, characterized by the following synthetic route: R1 and R2 are each independently selected from one of C1 to C6 alkyl, aryl, and substituted aryl groups; X, X1, and X2 are each independently selected from one of halogen, pseudohalogen, sulfoxide, and sulfone; Ar is aryl or heterocyclic aryl. The specific synthesis steps are as follows: (1) Add X2 donor compound to solvent containing compound SM at 0~5℃, keep stirring at 0~5℃ until the reaction is complete, and then process to obtain compound 1, wherein the molar ratio of SM to X2 donor compound is (1~2):(1~2). (2) Compound 1, Add to solvent, under a protective atmosphere, add organometallic reagent at 0-5°C, stir at room temperature until complete, and then post-process to obtain compound 2. Compound 1, ... The molar ratio of the organometallic reagent is 1:(5~10):(1~2); (3) Compound 2 and triethylsilane were dissolved in a solvent, and trifluoroacetic acid was added. The reaction was stirred until complete, and compound 3 was obtained after post-treatment. The molar ratio of compound 2, triethylsilane and trifluoroacetic acid was 1:(2.5~3.5):(4~6). (4) Under a protective atmosphere, compound 3, Pd(dppf)Cl2, B2Pin2 and the base were dissolved in an organic solvent and heated and stirred until the reaction was complete to obtain compound 4. The molar ratio of compound 3, Pd(dppf)Cl2, B2Pin2 and the base was 1:(0.03~0.05):(1~1.5):(2~3). (5) Under a protective atmosphere, water, Pd(dppf)Cl2, ArX and base are added to the reaction solution containing compound 4 in step (4), and the reaction is heated and stirred until complete. The reaction solution is then post-treated to obtain target compound 5. The molar ratio of compound 4, Pd(dppf)Cl2, base and ArX is 1: (0.03~0.05): (2~3): (1~2).

[0022] Furthermore, R1 and R2 are each independently selected from one of C1-C6 alkyl, phenyl, and benzyl groups; X, X1, and X2 are each independently selected from one of F, Cl, Br, and I; Ar is... G and W are each independently selected from C and N, and R3 is one of F, Cl, Br and I. More preferably, X2 is Br or I, in which case the X2 donor compound is NBS (N-bromosuccinimide) or NIS (N-iodosuccinimide).

[0023] Further, in step (1), the solvent is methanol, ethanol, tetrahydrofuran, or dichloromethane, and the concentration of compound SM in the solvent is 0.5~1 mol / L. Post-treatment refers to vacuum concentrating the reaction solution, dissolving the residue in dichloromethane, washing the organic matter with a saturated Na2S2O3 aqueous solution, and then vacuum concentrating to obtain the final product.

[0024] Further, in step (2), the solvent is methanol, ethanol, tetrahydrofuran, or dichloromethane, and the concentration of compound 1 in the solvent is 0.2~1 mol / L. The organometallic reagent is one or a mixture of two or more of the following reagents in any proportion: isopropyl magnesium chloride-lithium chloride reagent, diisopropyl magnesium chloride-lithium chloride reagent, n-butyl magnesium chloride-lithium chloride reagent, and sec-butyl magnesium chloride-lithium chloride reagent.

[0025] Further, in step (2), the post-treatment refers to adding ethyl acetate and saturated ammonium chloride aqueous solution to the reaction system, drying the organic phase, filtering, evaporating the solvent to obtain the crude product, and purifying the crude product by silica gel column chromatography. The volume ratio of ethyl acetate to saturated ammonium chloride aqueous solution is (1.5~2.5):1.

[0026] Further, in step (3), the solvent is methanol, ethanol, tetrahydrofuran, or dichloromethane, and the concentration of compound 2 in the solvent is 0.2~1 mol / L. The post-treatment refers to concentrating the reaction solution, dissolving it in ethyl acetate, washing it successively with saturated sodium bicarbonate solution and saturated brine, drying the organic phase, filtering, concentrating it to obtain a crude product, and purifying it by column chromatography to obtain compound 3.

[0027] Furthermore, in steps (4) and (5), the alkali is any one of KOAc, NaHCO3, NaOAc, Na2CO3, K2CO3, KOH and NaOH. Specifically, KOAc is used in step (4) and K2CO3 is used in step (5).

[0028] Further, in step (4), the solvent is 1,4-dioxane, and the concentration of compound 3 in the solvent is 0.2~1 mol / L. In steps (4) and (5), the heating temperature is 90~110℃. The volume ratio of the solvent in step (4) to the water in step (5) is (9~11):1.

[0029] Further, in step (5), the post-treatment refers to adding ethyl acetate and water to the reaction system, drying the organic phase, filtering, evaporating the solvent to obtain the crude product, and purifying the crude product by silica gel column chromatography to obtain compound 5.

[0030] This method avoids metal-catalyzed coupling reactions as much as possible, replacing them with a convenient, easy-to-operate, and cost-effective approach. It features short steps, simple operation at each step, high yield, and suitability for large-scale production. It is currently the optimal choice among all available methods. Attached Figure Description

[0031] Figure 1 The 1H NMR spectrum of compound 2; Figure 2 The 1H NMR spectrum of compound 3; Figure 3 The 1H NMR spectrum of compound 5 is shown. Detailed Implementation

[0032] The technical solution of the present invention will be further described in detail below with reference to the accompanying drawings, but the scope of protection of the present invention is not limited thereto.

[0033] In Example 1 below, DCM represents dichloromethane, PE represents petroleum ether, EA represents ethyl acetate, and the proportions of eluents refer to volume ratios.

[0034] Example 1 A novel synthetic method for 5-aryl-3-alkylpyrazolo[1,5-a]pyridine is described below: Step 1: At 0°C, 1-iodopyrrolidine-2,5-dione (142.7 g, 0.635 mol) was slowly added to a methanol (750 mL) solution of 5-bromopyrazolo[1,5-a]pyridine (SM) (125 g, 0.635 mol). The mixture was stirred at 0°C for 30 minutes, then heated to room temperature and stirred for 5 hours. The mixture was concentrated under vacuum, and the residue was dissolved in DCM (dichloromethane). The organic matter was washed with a saturated aqueous solution of Na2S2O3. The organic matter was then concentrated under vacuum to give 5-bromo-3-iodopyrazolo[1,5-a]pyridine (compound 1) (190 g, 0.589 mol, yield 92.6%) as a grayish-white solid.

[0035] Step 2: 5-Bromo-3-iodopyrazolo[1,5-a]pyridine (compound 1) (70 g, 217 mmol) and acetone (100 g, 1.74 mol) were dissolved in tetrahydrofuran (500 mL). Under nitrogen protection, isopropyl magnesium chloride-lithium chloride complex (250 mL, 325 mmol) was added at 0 °C, and the mixture was heated to room temperature and stirred for 16 h (O / N indicates overnight). After the reaction was complete, 800 mL of ethyl acetate and 400 mL of saturated ammonium chloride aqueous solution were added to the reaction system. The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation under reduced pressure. The crude product was purified by silica gel column chromatography (PE / EA = 1 / 0 to PE / EA = 1 / 1) to give 2-(5-bromopyrazolo[1,5-a]pyridin-3-yl)prop-2-ol (compound 2) (30 g, 54%), whose 1H NMR spectrum is shown below. Figure 1 As shown, 1 H NMR (400MHz, DMSO- d 6 ): δ 8.60-8.50 (m, 1H), 8.10 (s, 1H), 7.85 (s, 1H), 6.90-6.80 (m,1H), 5.20 (s, 1H), 1.49 (s, 6H). Step 3: Dissolve 2-(5-bromopyrazolo[1,5-a]pyridin-3-yl)prop-2-ol (compound 2) (30 g, 117 mmol) and triethylsilane (40 g, 350 mmol) in DCM (300 mL), and slowly add trifluoroacetic acid (66.5 g, 583 mmol). Stir the reaction mixture at room temperature for 3 h. Concentrate the reaction solution and dissolve it in 500 mL of ethyl acetate. Wash the solution successively with saturated sodium bicarbonate solution and saturated brine. Dry the organic phase with anhydrous magnesium sulfate, filter, and concentrate to obtain the crude product. Purify the crude product by column chromatography (PE:EA = 10:1) to obtain 5-bromo-3-isopropylpyrazolo[1,5-a]pyridine (compound 3) (20 g, 71%), which is a yellow oil. Its 1H NMR spectrum is shown below. Figure 2 As shown, 1 H NMR (400 MHz, CDCl3): δ 8.25 (d, J = 10.5 Hz, 1H), 7.78 (s,1H), 7.64 (s, 1H), 6.75 (d, J = 9.4 Hz, 1H), 3.10 (q, J = 7.3, 6.8 Hz, 1H), 1.34-1.30 (m, 6H).

[0036] Step 4: Under argon protection, 5-bromo-3-isopropylpyrazolo[1,5-a]pyridine (compound 3) (33 g, 138 mmol, 1 eq.), Pd(dppf)Cl2 (4.0 g, 5.47 mmol, 0.04 eq.), B2Pin2 (pinacol diboronate, 46.2 g, 182 mmol, 1.3 eq.), and KOAc (34 g, 346 mmol, 2.5 eq.) were dissolved in 1,4-dioxane (330 mL). The reaction mixture was heated and stirred at 90 °C for 2 hours. After cooling to room temperature, water (33 mL), Pd(dppf)Cl2 (4.0 g, 5.47 mmol, 0.04 eq.), K2CO3 (47.6 g, 344 mol, 2.5 eq.), and 2,4-dichloropyrimidine (29.7 g, 199 mmol, 1.44 eq.) were added to the crude product (compound 4) reaction mixture. The mixture was heated and stirred at 90 °C for 2 hours. After the reaction was complete, 800 mL of ethyl acetate and 400 mL of water were added to the reaction system. The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation under reduced pressure. The crude product was purified by silica gel column chromatography (PE / EA=1 / 0 to PE / EA=1 / 2) to obtain 5-(2-chloropyrimidin-4-yl)-3-isopropylpyrazolo[1,5-a]pyridine (compound 5) (32 g, 84.8%), a yellow solid, whose 1H NMR spectrum is shown below. Figure 3 As shown, 1 H NMR (400 MHz, Chloroform- d ) δ 8.68 (s, 1H), 8.61- 8.44 (m, 1H), 8.34 (s, 1H), 7.88 (s, 1H), 7.67 (s, 1H), 7.51-7.30 (m, 1H), 3.28 (d, J = 10.5 Hz, 1H),1.38 (d, J =5.7 Hz, 6H).

[0037] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the specific implementation of the present invention and not to limit it. Those skilled in the art should understand that any equivalent substitutions or obvious modifications made to the implementation of the present invention without changing its performance or use, without departing from the spirit of the present invention, should be covered within the scope of protection claimed by the present invention.

Claims

1. A novel method for synthesizing 5-aryl-3-alkylpyrazolo[1,5-a]pyridine, characterized in that, The synthesis route is as follows: R1 and R2 are each independently selected from one of C1 to C6 alkyl, aryl, and substituted aryl groups; X, X1, and X2 are each independently selected from one of halogen, pseudohalogen, sulfoxide, and sulfone; Ar is aryl or heterocyclic aryl. The specific synthesis steps are as follows: (1) Add X2 donor compound to solvent containing compound SM at 0~5℃, keep stirring at 0~5℃ until the reaction is complete, and then process to obtain compound 1, wherein the molar ratio of SM to X2 donor compound is (1~2):(1~2). (2) Compound 1, Add to solvent, under a protective atmosphere, add organometallic reagent at 0-5°C, stir at room temperature until complete, and then post-process to obtain compound 2. Compound 1, ... The molar ratio of the organometallic reagent is 1:(5~10):(1~2); (3) Compound 2 and triethylsilane were dissolved in a solvent, and trifluoroacetic acid was added. The reaction was stirred until complete, and compound 3 was obtained after post-treatment. The molar ratio of compound 2, triethylsilane and trifluoroacetic acid was 1:(2.5~3.5):(4~6). (4) Under a protective atmosphere, compound 3, Pd(dppf)Cl2, B2Pin2 and the base were dissolved in an organic solvent and heated and stirred until the reaction was complete to obtain compound 4. The molar ratio of compound 3, Pd(dppf)Cl2, B2Pin2 and the base was 1:(0.03~0.05):(1~1.5):(2~3). (5) Under a protective atmosphere, water, Pd(dppf)Cl2, ArX and base are added to the reaction solution containing compound 4 in step (4), and the reaction is heated and stirred until complete. The reaction solution is then post-treated to obtain target compound 5. The molar ratio of compound 4, Pd(dppf)Cl2, base and ArX is 1: (0.03~0.05): (2~3): (1~2).

2. The synthesis method according to claim 1, characterized in that, R1 and R2 are each independently selected from one of C1-C6 alkyl, phenyl, and benzyl groups; X, X1, and X2 are each independently selected from one of F, Cl, Br, and I; Ar is... G and W are each independently selected from C and N, and R3 is one of F, Cl, Br and I.

3. The synthesis method according to claim 1, characterized in that, In step (1), the solvent is methanol, ethanol, tetrahydrofuran or dichloromethane. The post-treatment refers to the vacuum concentration and mixing of the reaction solution, dissolving the residue in dichloromethane, washing the organic matter with a saturated Na2S2O3 aqueous solution, and then vacuum concentration to obtain the final product.

4. The synthesis method according to claim 1, characterized in that, In step (2), the solvent is methanol, ethanol, tetrahydrofuran or dichloromethane, and the organometallic reagent is one or more of the following reagents in any proportion: isopropyl magnesium chloride-lithium chloride reagent, diisopropyl magnesium chloride-lithium chloride reagent, n-butyl magnesium chloride-lithium chloride reagent and sec-butyl magnesium chloride-lithium chloride reagent.

5. The synthesis method according to claim 1, characterized in that, In step (2), the post-treatment refers to adding ethyl acetate and ammonium chloride aqueous solution to the reaction system, drying the organic phase, filtering, and evaporating the solvent to obtain the crude product, which is then purified by silica gel column chromatography to obtain the final product.

6. The synthesis method according to claim 1, characterized in that, In step (3), the solvent is methanol, ethanol, tetrahydrofuran or dichloromethane. The post-treatment refers to concentrating the reaction solution, dissolving it in ethyl acetate, washing it successively with saturated sodium bicarbonate solution and saturated brine, drying the organic phase, filtering, concentrating it to obtain the crude product, and purifying it by column chromatography to obtain compound 3.

7. The synthesis method according to claim 1, characterized in that, In steps (4) and (5), the base is any one of KOAc, NaHCO3, NaOAc, Na2CO3, K2CO3, KOH and NaOH.

8. The synthesis method according to claim 1, characterized in that, In step (4), the solvent is 1,4-dioxane.

9. The synthesis method according to claim 1, characterized in that, In step (5), the post-treatment refers to adding ethyl acetate and water to the reaction system, drying the organic phase, filtering, evaporating the solvent to obtain the crude product, and purifying the crude product by silica gel column chromatography to obtain compound 5.

10. The synthesis method according to claim 1, characterized in that, In steps (4) and (5), the heating temperature is 90~110℃.

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