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Preparation method for chlorbipram PDE4-inhibitor

A PDE4 and inhibitor technology, applied in the field of preparation of PDE4 inhibitors, can solve the problems of many side reactions, unstable bromide, low docking reaction yield, etc., and achieves mild reaction conditions, low equipment requirements, and easily available raw materials. cheap effect

Active Publication Date: 2017-05-10
苏州兰晟医药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to the many side reactions of NBS bromination, the bromide is unstable, and the yield of the docking reaction is low, its synthesis has certain limitations, and it is not suitable for the subsequent research and development of this compound.

Method used

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  • Preparation method for chlorbipram PDE4-inhibitor
  • Preparation method for chlorbipram PDE4-inhibitor
  • Preparation method for chlorbipram PDE4-inhibitor

Examples

Experimental program
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Effect test

Embodiment 1

[0025] (1) Take 30g of raw material A, 3-bromo-4-methoxybenzaldehyde, slowly add NaBH in batches 4 8-10g, react in ethanol. The reaction was monitored by TLC. After the reaction was complete, ethanol was removed, extracted, and the organic phases were combined, dried over anhydrous sodium sulfate, and spin-dried to obtain 30.0 g of 3-bromo-4-methoxybenzyl alcohol as a white solid. The product could be subjected to the next reaction without purification. rate>98%.

[0026] (2) Take 10 g of 3-bromo-4-methoxybenzyl alcohol, add 8.6 g of m-chlorophenylboronic acid, 18.8 g of potassium carbonate, 1.0 g of tetrakistriphenylphosphine palladium, and 100 mL of isopropanol / water solvent, and stir at room temperature. After the solid is completely dissolved, remove the oxygen in the reaction system, react without oxygen, heat, after the reaction, spin off the isopropanol and part of the water under reduced pressure, then extract with ethyl acetate, combine the organic layers, and dry ...

Embodiment 2

[0031] On the basis of Example 1, other steps remain unchanged, and the method of step (2) in Example 1 becomes the following scheme: take 10g of compound B, 3-bromo-4-methoxybenzyl alcohol, add m-chlorophenylboronic acid 8.6 g, potassium carbonate 18.8g, urea 82.8mg, palladium acetate 210mg, isopropanol / water solvent 100mL, stirred at room temperature. After the solid is completely dissolved, remove the oxygen in the reaction system, react without oxygen, heat, after the reaction, spin off the isopropanol and part of the water under reduced pressure, then extract with ethyl acetate, combine the organic layers, and dry with anhydrous sodium sulfate The palladium salt was removed by suction filtration and spin-dried to obtain Compound C, 11.46 g of light yellow viscous liquid, with a yield of >95%. The total yield of this embodiment is 65.5%.

Embodiment 3

[0033] On the basis of Example 1, other steps remain unchanged, and the method of step (3) in Example 1 becomes the following scheme: 8.13g cyanuric chloride, add DMF with slow stirring, stir at room temperature for about half an hour, add dry dichloro Methane, stir evenly, add 11.5 g of raw material C, and stir at room temperature for 4-8 hours. After the reaction, the organic layer was washed with saturated NaCl, dried and spin-dried under reduced pressure. The crude product was purified by column separation to obtain a colorless oily chlorinated product, namely compound D, 11.6 g (95% yield). The calculated total yield was 71%.

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Abstract

The invention discloses a preparation method for a chlorbipram PDE4-inhibitor. The method is capable of using 3-bromine-4-methoxybenzaldehyde as a starting raw material, and synthesizing a target product of E chlorbipram by steps, such as reduction reaction, Suzuki reaction and chlorination. Compared with the prior art, the yield is greatly improved, and the yield is up to 71% proved by experiment. The raw material is easily obtained and cheap, the reaction condition is moderate, the equipment request is low, and the industrial production can be realized. The preparation method is a new efficient and easy way for the synthetic method of the chlorbipram.

Description

technical field [0001] The invention relates to a preparation method of a PDE4 inhibitor, in particular to a preparation method of the compound clobipram. Background technique [0002] Phosphodiesterase 4 (PDE4) is closely related to the functions of the central nervous system and the immune system, and its inhibitors are considered to be new anti-inflammatory drugs acting on intracellular targets and candidate drugs for the central nervous system. [0003] The first-generation PDE4 inhibitors such as rolipram have good antidepressant effects, but the reason why they cannot be marketed is the side effects such as nausea and vomiting caused by the inhibition of PDE4. Compared with the first-generation PDE4 inhibitors, the second-generation PDE4 inhibitors have better therapeutic effects, but so far no PDE4 inhibitors that can prevent vomiting have been marketed. [0004] The development of new PDE4 inhibitors that can avoid nausea and vomiting reactions has a good applicatio...

Claims

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Application Information

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IPC IPC(8): C07D237/22
CPCC07D237/22
Inventor 徐江平
Owner 苏州兰晟医药有限公司
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