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Synthesis method of key intermediate of immunomodulator

An immunomodulator and synthesis method technology, applied in chemical instruments and methods, preparation of organic compounds, preparation of carboxylates, etc., can solve the problems of application impact, residual metal substances, insufficient purity of the final product, etc., and reduce metal residues. Effect

Pending Publication Date: 2021-10-12
SUZHOU IBIO TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The existing synthesis method has cumbersome steps, and multiple metal catalysis is used in the reaction, resulting in the possibility of metal residues in the final product, resulting in insufficient purity of the final product, which has an impact on the subsequent preparation of pharmaceuticals

Method used

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  • Synthesis method of key intermediate of immunomodulator
  • Synthesis method of key intermediate of immunomodulator
  • Synthesis method of key intermediate of immunomodulator

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] The preparation of compound 4, its reaction formula is as follows:

[0030]

[0031] 1.2eq of compound 2 and 340mg of compound 4 were dissolved in 100mL of ethanol, 5 equivalents of potassium carbonate was added, nitrogen was replaced 3 times, 2mol% S-Phos was added under the protection of nitrogen, and the temperature was raised to 40°C for 12 hours. After the reaction, cool down to room temperature, filter, concentrate, add water and dichloromethane, wash the organic phase with dilute hydrochloric acid, and dry over anhydrous sodium sulfate. The crude product was purified by column chromatography to obtain 355 mg with a yield of 84%.

Embodiment 2

[0033] The preparation of compound 5, its reaction formula is as follows,

[0034]

[0035] 400mg of compound 4 was dissolved in tetrahydrofuran, added 1.5eq N, O-dimethylhydroxylamine hydrochloride and 2eq triethylamine, 1.8eq EDCI. After stirring at room temperature for 12 hours. Water was added to quench the reaction, then dichloromethane was added and washed with aqueous ammonium chloride. The organic phase was dried over anhydrous sodium sulfate and concentrated three times with dry tetrahydrofuran. To the resulting tetrahydrofuran solution was added DIBAL (diisobutylaluminum hydride) at -78°C. After the reaction was completed, an aqueous solution of potassium bisulfate was added below 0°C. After the resulting mixture was filtered, dichloromethane and 1N hydrochloric acid were added to wash. The obtained organic phase was concentrated to dryness and directly sent to the next step without purification.

Embodiment 3

[0037] The preparation of compound 1, its reaction formula is as follows:

[0038]

[0039] 1.5eq of compound 5 and 167mg of compound 6 were mixed in dry dichloromethane, and after 30 minutes of reaction, 2eq of Dess-Martin oxidation reagent (1,1,1-Triacetoxy-1,1-dihydro-1,2-benzodoxol-3 (1H)-one). After the detection reaction was completed, compound 1 was obtained only through silica gel column purification with a yield of 80%.

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Abstract

The invention provides a synthesis method of a key intermediate of an immunomodulator, which comprises the following steps: dissolving a compound 2 and a compound 3, adding potassium carbonate, replacing nitrogen, and adding S-Phos to react; cooling, filtering, concentrating, and washing and drying an organic phase to obtain a compound 4; dissolving in tetrahydrofuran, and adding N, O-dimethyl hydroxylamine hydrochloride and triethylamine; stirring at room temperature, adding dichloromethane after quenching, and washing with an ammonium chloride aqueous solution; drying an organic phase, concentrating by using tetrahydrofuran, adding diisobutylaluminium hydride into a tetrahydrofuran solution for reaction, adding a potassium hydrogen sulfate aqueous solution, filtering an obtained mixture, and adding dichloromethane and hydrochloric acid for washing; concentrating an organic phase to be dry to obtain a compound 5; mixing with a compound 6 to react in dichloromethane, adding a Dess-Martin oxidation reagent, and purifying to obtain a compound 1; according to the route, only one step of metal catalysis is used, and the step is far away from a final compound, so that metal residues in medicine molecules are greatly reduced.

Description

technical field [0001] The invention belongs to the technical field of chemical synthesis, and in particular relates to a method for synthesizing a key intermediate of an immunomodulator. Background technique [0002] The immune system plays an important role in controlling and eradicating diseases such as cancer. However, cancer cells can develop new ways to evade or suppress the immune system in order to benefit their growth. One such mechanism is to alter the expression of co-stimulatory and co-inhibitory molecules on immune cells. Blocking the signaling of inhibitory immune checkpoints, such as PD-I, has proven to be a promising and effective therapeutic modality. [0003] Programmed death receptor 1 (PD-I), also known as CD279, is a cell surface receptor expressed on activated T cells, natural killer T cells, B cells and macrophages. It acts as an intrinsic negative feedback system, preventing the activation of T cells, which in turn reduces autoimmunity and promotes...

Claims

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Application Information

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IPC IPC(8): C07D263/57C07C51/353C07C63/331C07C45/41C07C47/546
CPCC07D263/57C07C51/353C07C45/41C07C63/331C07C47/546
Inventor 黄保华刘小栋马良鑫胡新礼戴建
Owner SUZHOU IBIO TECH CO LTD
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