Method for synthesizing intermediates and improved method for synthesizing melatonin receptor antagonist

A technology of receptor antagonist and melatonin, which is applied in the field of antagonist synthesis, can solve the problems of difficult purchase of synthetic raw materials and high cost, and achieve the effect of high product yield and simple operation

Inactive Publication Date: 2015-11-04
CHENGDU ZHIPULAI BIOMEDICINE TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The object of the present invention is to solve the problem that the synthetic raw materials for synthesizing the target compound cis-1 in the prior ar

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] An improved method for synthesizing a melatonin receptor antagonist, the specific steps are as follows:

[0033] (1) Use 2-naphthol, Lewis acid and benzene as the reaction raw materials, stir until the reaction is completed, the reaction solution is extracted, dried and separated to obtain the intermediate shown in formula I, formula I: .

[0034] (2) Obtain the target compound cis-1 through the intermediate shown in formula I; the specific process is as follows:

[0035] (21) Weigh the intermediate shown in formula I, add propionamide, p-toluenesulfonic acid and toluene, and reflux reaction under the protection of nitrogen. After the reaction is completed, carry out cooling, suction filtration and washing, and the organic phase is dried and separated to obtain crude Product, the crude product is purified to obtain the light yellow solid product shown in formula II; formula II: ;

[0036] (22) Weigh the solid product shown in formula II and dissolve it in trifluoro...

Embodiment 2

[0048] The difference between this example and Example 1 is that the anhydrous aluminum trichloride in the step of preparing the intermediate shown in formula I is replaced with anhydrous aluminum tribromide, and the specific preparation process is as follows:

[0049] Weigh 4 g (27.8 mmol) of 2-naphthol and 22.0 g (83.4 mmol) of anhydrous aluminum tribromide, place them in a 100 ml single-necked flask, add 50 ml of benzene, stir overnight at room temperature, and monitor the progress of the reaction by TLC. -After the naphthol is consumed, add ice water to quench the reaction, then extract with dichloromethane, remove the solvent after the organic phase is dried over anhydrous sodium sulfate, and the residue is separated and purified with ethyl acetate:petroleum ether=1:50~100 Obtained 5.2 g of oily matter, and calculated that the yield of the intermediate represented by formula I was 84%.

[0050] The intermediate shown in formula I was detected by proton nuclear magnetic re...

Embodiment 3

[0053] This embodiment is a comparative example of Embodiment 1 and Embodiment 2. The intermediate shown in Formula I in this embodiment is synthesized by phenylacetyl chloride and styrene in the prior art. The specific synthesis process is as follows:

[0054] Aluminum trichloride 3.9g (29 mmol) is placed in 130ml dry dichloromethane, and this suspension is cooled to 0 o C. Under the protection of nitrogen, add dropwise a solution of 1.0 g (9.7 mmol) of freshly distilled styrene in dry dichloromethane (120 ml), and the addition is completed in about 15 minutes. Continue to stir at this temperature for 15 minutes, add saturated potassium sodium tartrate solution to quench the reaction, drop the organic phase three times with saturated sodium bicarbonate solution, separate the organic phase, dry over anhydrous sodium sulfate, remove the solvent under reduced pressure, and leave The product was quickly separated by column with cyclohexane / ethyl acetate=7:3, and the obtained yell...

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PUM

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Abstract

The invention discloses a method for synthesizing intermediates and an improved method for synthesizing melatonin receptor antagonist. The problems that in the prior art, synthesis raw materials for synthesizing target compounds cis-1 can not be bought easily and are high in cost are solved. The method includes the steps that 2-naphthol, lewis acid and benzene serve as reaction raw materials and are stirred till a reaction is completed, and the intermediates shown in the formula (I) (please see the specification for the formula (I)) are obtained after the reaction liquid is extracted, dried and separated. The target compounds cis-1 (please see the specification for the chemical general formula of the cis-1) are obtained through the intermediates shown in the formula (I). The method and the improved method have the advantages that the raw materials can be more easily obtained, the price is lower, operation is easier and more convenient, and the yield of the target product is higher.

Description

technical field [0001] The invention relates to a synthetic method of an antagonist, in particular to an improved method for synthesizing a melatonin receptor antagonist. Background technique [0002] The target compound cis-1 is a melatonin receptor antagonist, which has a selective antagonistic effect on MT2 receptors. The general name of the target antagonist is 4-P-PDOT. [0003] In the prior art, the synthesis process of the target compound cis-1 all adopts phenylacetyl chloride and styrene as synthetic raw materials, and the specific synthesis process is as follows: [0004] ; [0005] Among them, a is AlCl 3 , dichloromethane (CH 2 Cl 2 ), 0°C, 30min; b is propylamide, p-toluenesulfonic acid (PTSA), catalyst (cat.), toluene, reflux, 4h; c is triethylsilane (TES), trifluoro Acetic acid (TFA), -10°C, 10min. [0006] The synthetic raw material phenylacetyl chloride used for the synthesis of the intermediate shown in formula I in the above-mentioned synthetic proc...

Claims

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Application Information

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IPC IPC(8): C07C49/67C07C45/51C07C233/06C07C231/12
CPCC07C45/512C07C231/12C07C49/67C07C233/06
Inventor 陈伟赵刚蒲林刘继峰
Owner CHENGDU ZHIPULAI BIOMEDICINE TECH CO LTD
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