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A kind of preparation method of 5-fluoro-1h-pyrrole-[2,3-b]pyridine-4-carbaldehyde

A technology of 3-b and pyridine, which is applied in the field of preparation of 5-fluoro-1H-pyrrole-[2,3-b]pyridine-4-carbaldehyde, can solve the problem that raw materials are not easily available, product separation and purification are difficult, heavy metal hazardous wastes, etc. problems, to achieve the effect of easy availability of raw materials, high purity and lower production costs

Active Publication Date: 2021-02-09
南京合巨药业有限公司
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Problems solved by technology

[0007] The technical problem to be solved by this invention is to overcome the defects of the prior art and provide a preparation method of 5-fluoro-1H-pyrrole-[2,3-b]pyridine-4-carbaldehyde, which effectively reduces the cost, and solve the problems that the raw materials in the existing method are not easy to obtain, the separation and purification of the product are difficult, and a large amount of heavy metal hazardous waste is generated

Method used

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  • A kind of preparation method of 5-fluoro-1h-pyrrole-[2,3-b]pyridine-4-carbaldehyde
  • A kind of preparation method of 5-fluoro-1h-pyrrole-[2,3-b]pyridine-4-carbaldehyde
  • A kind of preparation method of 5-fluoro-1h-pyrrole-[2,3-b]pyridine-4-carbaldehyde

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preparation example Construction

[0034] A preparation method of 5-fluoro-1H-pyrrole-[2,3-b]pyridine-4-carbaldehyde, comprising the following steps:

[0035] (1) Dissolve 5-fluoro-1H-pyrrolo[2,3-b]pyridine in a solvent, and add triisopropylchlorosilane under alkaline conditions to obtain 5-fluoro-1-triisopropyl Silyl-pyrrolo[2,3-b]pyridine;

[0036] (2) Dissolve 5-fluoro-1-isopropylsilyl-pyrrolo[2,3-b]pyridine in a solvent, add formylating reagent under alkaline conditions, and then add desiliconizing reagent Position deprotection gives 5-fluoro-1H-pyrrole-[2,3-b]pyridine-4-carbaldehyde;

[0037] The reaction process is:

[0038] .

[0039] 5-fluoro-1H-pyrrole-[2,3-b]pyridine-4-carbaldehyde of the present invention 1 HNMR picture as shown figure 1 shown.

Embodiment 1

[0041] (1) Synthesis of 5-fluoro-1-isopropylsilyl-pyrrolo[2,3-b]pyridine:

[0042]

[0043] Dissolve 5-fluoro-1H-pyrrole-[2,3-b]pyridine (35.00 g, 257.1 mmol, 1.0 equiv.) in 200 ml DMF, cool down to 0 °C, add NaH (60 Wt% in mineral oil , 10.80 g, 270.0 mmol, 1.05 equiv.), reacted for 30 min, added triisopropylchlorosilane (54.53 g, 282.8 mmol, 1.1 equiv.), reacted at 0°C for 2 hours, TLC showed that the reaction was complete. Add 50 ml of water dropwise to quench, pour the system into 1L of water, add 1L of petroleum ether, separate the liquid, filter with a pad of silica gel, and concentrate the mother liquor to obtain 82.10 g of crude yellow oil, which is directly injected into the next step.

[0044] LC-MS (ESI+): m / z 293.29 (M+H).

[0045] (2) Synthesis of 5-fluoro-1H-pyrrole-[2,3-b]pyridine-4-carbaldehyde:

[0046]

[0047] Dissolve 5-fluoro-1-isopropylsilyl-pyrrolo[2,3-b]pyridine (82.10 g, 257.1 mmol, 1.0 equiv., theoretical content) in 400 ml THF, cool to -70°C,...

Embodiment 2

[0052] (1) Synthesis of 5-fluoro-1-isopropylsilyl-pyrrolo[2,3-b]pyridine:

[0053]

[0054] Dissolve 5-fluoro-1H-pyrrole-[2,3-b]pyridine (IV) (13.61 g, 100 mmol, 1.0 equiv.) in 200ml THF, cool down to 0°C, add n-butyllithium (2.5 M, 50 ml, 120 mmol, 1.2 equiv.), reacted at 0°C for 30 min, added triisopropylchlorosilane (21.21 g, 110 mmol, 1.1 equiv.), naturally rose to room temperature for 2 hours, TLC showed that the reaction was complete . Carefully add 300 ml of water and 500 ml of petroleum ether, separate the layers, dry over anhydrous sodium sulfate, and concentrate the organic phase under reduced pressure to obtain 32.17 g of yellow oil, which is directly used for the next step.

[0055] LC-MS (ESI+): m / z 293.29 (M+H).

[0056] (2) Synthesis of 5-fluoro-1H-pyrrole-[2,3-b]pyridine-4-carbaldehyde:

[0057]

[0058] Dissolve 5-fluoro-1-isopropylsilyl-pyrrolo[2,3-b]pyridine (32.17 g, 100 mmol, 1.0 equiv., theoretical content) in 150 ml of ether, cool to -70°C, drop...

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Abstract

The invention discloses a preparation method of 5-fluoro-1H-pyrrole-[2,3-b]pyridine-4-formaldehyde, which is characterized in that it comprises the following steps: 5-fluoro-1H-pyrrolo[2, 3-b]pyridine is dissolved in a solvent, and under alkaline conditions, triisopropylchlorosilane is added to react to obtain 5-fluoro-1-triisopropylsilyl-pyrrolo[2,3-b]pyridine; 5‑fluoro‑1‑isopropylsilyl‑pyrrolo[2,3‑b]pyridine is dissolved in a solvent, under alkaline conditions, after adding a formylating reagent for reaction, adding a desiliconizing reagent for in-situ deprotection to obtain 5-fluoro-1H-pyrrole-[2,3-b]pyridine-4-carbaldehyde. The preparation method of 5-fluoro-1H-pyrrole-[2,3-b]pyridine-4-formaldehyde of the present invention is prepared by a two-step method, the preparation line is short, the raw materials are easy to obtain, the operation is simple, and the production cost is significantly reduced , and no heavy metal solid waste is generated, and is suitable for large-scale production of 5-fluoro-1H-pyrrole-[2,3-b]pyridine-4-formaldehyde.

Description

technical field [0001] The invention relates to a preparation method of 5-fluoro-1H-pyrrole-[2,3-b]pyridine-4-carbaldehyde, which belongs to the technical field of preparation of pharmaceutical intermediates. Background technique [0002] 5-Fluoro-1H-pyrrole-[2,3-b]pyridine-4-carbaldehyde (I) is an important intermediate in the synthesis of a class of dihydropyrrolidine JAK kinase inhibitors. At present, JAK kinase inhibitors have important applications in the treatment of hematological diseases, tumors, rheumatoid arthritis and other diseases. In addition, the synthesis of fluorine-containing compounds has always been one of the hot research directions in the field of chemistry and medicine. Due to the stability of C-F bond energy, fluorine-containing drugs usually have better metabolic stability in vivo. At the same time, due to the higher lipophilicity of fluoride, fluorine-substituted drugs are usually better absorbed by the body and thus have better bioavailability. ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 潘国骏
Owner 南京合巨药业有限公司
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