Method for preparing biphenyl-4-formyl corey lactone by using one-pot method

A technology of collidone diol and formyl family, which is applied in the field of chemical drug preparation, can solve the problems of low purity of intermediate products, unfavorable industrialized production, long reaction period and the like, and achieves improved product purity, less impurities and higher yield improved effect

Pending Publication Date: 2018-05-15
JINLIN MEDICAL COLLEGE
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The main disadvantages of this method are: each step requires repeated feeding and post-treatment, and there are many steps and cumbersome operations; there are many side reactions in each step, the intermediate product has low purity, difficult purification, and low yield; a large amount of material is consumed, and the cost is high ; The reaction cycle is long, which is not conducive to industrial production

Method used

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  • Method for preparing biphenyl-4-formyl corey lactone by using one-pot method
  • Method for preparing biphenyl-4-formyl corey lactone by using one-pot method
  • Method for preparing biphenyl-4-formyl corey lactone by using one-pot method

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preparation example Construction

[0048] (A) Preparation of Corylidene Diol Primary Hydroxyl Derivatives: Add Solvent S to a Reactor with Filter Element at the Bottom 1 , add corylactone diol, stir until dissolved, then add triphenylchloromethane to carry out the alkylation reaction of the primary hydroxyl position, and stir the reaction for 6-12h under the condition of temperature control at 10-30°C until the reaction is complete. Solvent S for Lilactone Diol Primary Hydroxyl Derivatives 1 reaction system;

[0049] (B) preparation of the diol derivatives of corylidene diol: the solvent S obtained in the step (A) 1 Under the temperature control of the reaction system at 0-30°C, add biphenyl-4-formyl chloride dropwise to carry out the acylation reaction at the secondary hydroxyl position, and stir for 1-6 hours until the reaction is complete; add pure water and stir for 1-3 hours, and inject nitrogen , press filter, add solvent S 2 , refluxed for 1-4 hours, cooled to room temperature, and press-filtered to o...

Embodiment 1

[0110] Embodiment 1: (+) one-pot method prepares biphenyl-4-formyl corilide

[0111] Add 5L of pyridine to the reactor with a filter element at the bottom, add (+) corylactone diol 1.0kg (1eq) under stirring, add 1.62kg (1eq) triphenylchloromethane, and control the temperature at 10°C for 12h until complete To react, add 1.26kg (1eq) of biphenyl-4-formyl chloride, control the temperature at 0°C and react for 6h until complete reaction; add 10L pure water to the reaction kettle and stir for 3h to obtain a suspension. The filter element at the bottom will be suspended and hydraulically filtered, then add 5L of methanol to the reactor, heat and reflux for 2h, press filter the liquid to obtain solid powder; add 10L of acetonitrile to the reactor, add 7L (6mol / L) hydrochloric acid aqueous solution, and control the temperature React at 30°C for 12 hours until complete reaction, lower the temperature of the reaction system to 0°C, add saturated aqueous sodium bicarbonate solution to ...

Embodiment 2

[0112] Embodiment 2: One-pot method prepares (-) biphenyl-4-formyl corilide

[0113] Add 8.8L of pyridine to the reactor with a filter element at the bottom, add (-) corylactone diol 0.8kg (1eq) under stirring, add 1.56Kg (1.2eq) triphenylchloromethane, and react at a temperature of 30°C for 6h To complete the reaction, add 1.11Kg (1.1eq) biphenyl-4-formyl chloride, and react at a temperature of 30°C for 2 hours until the reaction is complete; add 8.8L of pure water to the reaction kettle and stir for 2 hours to obtain a suspension, which is passed into the reaction kettle Nitrogen, through the filter element at the bottom of the kettle to hydraulically filter the suspension, then add 5L of ethanol to the reaction kettle, heat and reflux for 2h, press filter the liquid to obtain a solid powder; add 8L tetrahydrofuran to the reaction kettle, and drop 7L (4mol / L) Aqueous hydrochloric acid, temperature controlled at 60°C for 3 hours until complete reaction, cooling the reaction s...

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Abstract

The invention discloses a method for preparing biphenyl-4-formyl corey lactone by using a one-pot method. The method comprises the following steps: in a same reaction container, with corey lactone glycol as a raw material, adding a solvent S1 and triphenyl chlorometha to carry out an alkylation reaction in a primary hydroxyl position so as to obtain a solvent S1 reaction system with a corey lactone glycol primary hydroxyl derivative, further adding benzoyl chloride to carry out an acylation reaction in a secondary hydroxyl position, adding a solvent S2, and performing recrystallization so as to obtain a corey lactone glycol double-hydroxyl derivative; adding a solvent S3 and an acid solution to carry out a hydrolysis reaction in a primary hydroxyl position so as to obtain a crude product of biphenyl-4-formyl corey lactone; adding a solvent S4 or/and a solvent S5, and performing recrystallization, thereby obtaining the biphenyl-4-formyl corey lactone with corresponding optical activityat one time. The method is capable of avoiding the situation that materials are repeatedly fed in different steps of tedious reactions, is sufficient in reaction, small in side reaction, high in purity, simple in aftertreatment, high in yield, simple in operation, short in time, high in efficiency, low in material quantity, low in cost and applicable to industrial production.

Description

technical field [0001] The invention relates to a preparation method of biphenyl-4-formylcorylide, in particular to a one-pot method for preparing biphenyl-4-formylcorilelide, which belongs to the technical field of chemical drug preparation. technical background [0002] Prostaglandins are an important class of endogenous physiologically active substances, which are important mediators of various physiological processes and have high pharmacological activity. Biphenyl-4-formyl coli lactone (Corey lactonephenylbenzoate) is a synthetic PGF 2α The chiral intermediate of prostaglandin drugs, the molecular formula is C 21 h 20 o 5 , whose chemical name is hexahydro-4-(hydroxymethyl)-2-oxo-2H-cyclopenta[b]furan-5-yl 1,1'-biphenyl-4-carboxylate, usually includes ( ±) biphenyl-4-formyl corylide (-) biphenyl-4-formyl corylide and (+) biphenyl-4-formyl corylide, whose structural formula is shown in formula 1 : [0003] [0004] In formula 1, A: (±) biphenyl-4-formyl corylide...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/935
CPCC07B2200/07C07D307/935
Inventor 修志明李黎王淑红李志波赵春影彭悦
Owner JINLIN MEDICAL COLLEGE
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