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Novel synthetic method of beta-tetrahydrocarboline compound by using pentamethyleneamine as raw material

A technology of tetrahydrocarboline and piperonyl ring, applied in the new synthesis field of beta-tetrahydrocarboline compounds, can solve the problems of high cost of derivatives, low product content, low yield, etc., avoiding social problems and cheap raw materials The effect of easy availability and lower production costs

Inactive Publication Date: 2013-03-06
SHANDONG UNIV OF SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] Simultaneously, the most important problem that exists in the existing method for synthesizing piperonal is that a reaction cannot be carried out completely to the end, the productive rate is not high, and the product content is low, and needs to be separated and recycled, which not only causes the output of piperonal to be low, but also leads to Purchasing piperonal for synthetic production of its derivatives becomes costly

Method used

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  • Novel synthetic method of beta-tetrahydrocarboline compound by using pentamethyleneamine as raw material

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach 1

[0017] 1) Add N,N-dimethylformamide (7.5g, 0.1025mol) into a 250mL three-necked flask, and add phosphorus oxychloride (16.3g, 0.1063mol) dropwise at no more than 10°C. , add piperonylcycline (6.1g, 0.049mol), slowly heat up under stirring, after heating for 8 hours, wash and separate the mixed solution of piperonylcycline and piperonal;

[0018] 2) In a 500mL three-necked flask, add D-tryptophan methyl ester hydrochloride (12.5g, 0.049mol) into the mixture in the previous step, then add 150mL of nitroethane, reflux for 4 hours, cool, pump 15.6g of yellow-white solid was obtained by filtration, which was β-tetrahydrocarboline compound, and the yield was 82.5%;

[0019] 3) The filtrate is distilled under reduced pressure, and the obtained pepper ring is applied mechanically, and added into the first step.

Embodiment approach 2

[0021] 1) Add N-methylaniline (10.8g, 0.1025mol) into a 250mL three-necked flask, add phosphorus oxychloride (16.3g, 0.1063mol) dropwise at room temperature, after the addition is complete, add piperonylcycline (6.1g, 0.049mol), heating after stirring, separates the mixed solution of piperonylcycline and piperonal;

[0022] 2) In a 500mL three-neck flask, add D-tryptophan methyl ester hydrochloride (12.5g, 0.049mol) to the mixture in the previous step, then add 100mL of nitroethane, reflux for 8 hours, cool, and filter with suction Obtained 13.6g yellow-white solid, yield rate is 78.5%;

[0023] 3) The mother liquor is recovered by distillation to recover the pepper ring, which is applied mechanically and added to the first step.

Embodiment approach 3

[0025] 1) Add N-methylaniline (15g, 0.205mol) into a 500mL three-necked flask, add phosphorus oxychloride (32.6g, 0.213mol) dropwise at room temperature, after the addition is complete, add piperonylcycline (6.1g, 0.049 mol), heated after stirring, separated to obtain the mixed solution of piperonylcycline and piperonal;

[0026] 2) In a 500mL three-necked flask, add D-tryptophan methyl ester hydrochloride (25g, 0.1mol) to the mixed solution in the previous step, then add 200mL of nitroethane, reflux for 10 hours, cool, and filter with suction to obtain 28g yellow-white solid, the yield is 79.5%;

[0027] 3) The mother liquor is recovered by distillation to recover the pepper ring, which is applied mechanically and added to the first step.

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Abstract

The invention discloses a novel synthetic method of a beta-tetrahydrocarboline compound by using pentamethyleneamine as a raw material, belonging to the synthesis field of medical intermediates. The invention aims to provide a novel method for preparing the beta-tetrahydrocarboline compound by using pentamethyleneamine as the raw material through formylation reaction in a two-steps cascade reaction manner, wherein the first step of reaction is used for preparing a mixture containing heliotropin and pentamethyleneamine, and the mixture is simply treated but not separated and then directly carries out second step of P-S reaction with D-tryptophan methyl ester or a salt of D-tryptophan methyl ester for cascade-preparing the beta-tetrahydrocarboline compound. Compared with the traditional synthetic method, the synthetic method is a cascade reaction, thereby avoiding purchasing and storing heliotropin which is a precursor chemical product and omitting a complex purification step. The novel synthetic method has the advantages of reducing the cost, saving expenses, having low requirements on production equipment and environment conditions, and achieving high yield and is suitable for industrial production.

Description

Technical field: [0001] The invention belongs to the field of pharmaceutical intermediates and relates to a new synthesis method of β-tetrahydrocarboline compounds. technical background: [0002] β-Tetrahydrocarboline compound is an important structural compound, it can have a wide range of substitution types, and its structural modification can produce a variety of ikeline alkaloids with good antiviral, antibacterial and antitumor activities. Therefore, it has received widespread attention. Among them, tadalafil, the most famous drug for treating impotence, is prepared from β-tetrahydrocarboline compound as a synthetic intermediate, and the intermediate is then subjected to chloroacetylation reaction and ring closure reaction to obtain the final product. Because the synthesis of this intermediate is the most critical synthetic step, improving the synthesis efficiency of this compound and reducing its synthesis cost are of great significance for the synthesis of tadalafil. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04
Inventor 王鹏杨文斌王浩李莹
Owner SHANDONG UNIV OF SCI & TECH
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