CN108997171B

CN108997171B - Synthetic method of 3+2 closed ring

Info

Publication number: CN108997171B
Application number: CN201810647362.8A
Authority: CN
Inventors: 葛敏; 李亮; 胡春晨; 王怀秋; 付明伟; 李令超
Original assignee: Suzhou Zhengji Pharmaceutical Research Co Ltd
Current assignee: Suzhou Zhengji Pharmaceutical Research Co., Ltd
Priority date: 2018-06-21
Filing date: 2018-06-21
Publication date: 2020-11-27
Anticipated expiration: 2038-06-21
Also published as: CN108997171A

Abstract

The invention discloses a synthesis method of a 3+2 ring closure, which strengthens chiral induction through the spatial stereo effect of bridge ring molecules, so that the ring closure reaction has specific and high-efficiency spatial selectivity. The method is applied to synthesis of peramivir and has the characteristics of short synthetic route, high stereoselectivity and simple and convenient operation process.

Description

Synthetic method of 3+2 closed ring

Technical Field

The invention relates to the technical field of drug synthesis, in particular to a synthesis method of 3+2 ring closure.

Background

The antiviral drug Peramivir (Peramivir) is developed by American biological crystal drug product GmbH, is a new Neuraminidase (NA) inhibitor anti-influenza virus drug which is successfully developed and marketed in 1999 after zanamivir and oseltamivir, and is used for treating and preventing influenza A and B of adults and children.

The chemical name of peramivir is (1S, 2S, 3R, 4R, 1 ' S) - (-) -3- [ (1 ' -acetamido-2 ' -ethyl) butyl ] -4- [ [ (aminoimino) methyl ] amino ] -2-hydroxycyclopentane-1-carboxylic acid trihydrate, and the chemical structural formula is as follows:

the prior patents related to the synthesis method of peramivir are CN1282316, CN1358170, CN1367776, J.Med.Chem.2001, 44, 4379-containing 4392 and the like, racemic Venolactam is used as a raw material, and the peramivir is finally prepared by amide alcoholysis resolution, amino protection, 1, 3-dipolar cycloaddition, reduction ring opening, acetylation, deprotection, hydrolysis and formamidization, wherein the chemical reaction formula is summarized as follows:

the method comprises the steps of hydrolyzing and splitting Venus lactam and protecting amino to obtain (1S, 4R) -4-Boc-amino-cyclopentyl-2-alkenyl-1-methyl formate with optical activity, and closing the ring with a chlorooxime intermediate 3+2 to obtain a key intermediate as follows:

this reaction attacks the ring-closing reaction mainly from the back due to steric hindrance, thus producing mainly compound a, but still 1.3% of compound D reacting from the front, and in addition two isomers B and C, the proportion of which is up to 15%. The selectivity of the reaction is not high, so that the yield is low, the industrial cost is increased, and the purification is difficult. Repeated experiments by the inventor also find that in the reaction process, under the condition that basic triethylamine is used for reaction, racemization can occur at the reaction temperature at the carboxylic acid position, and the yield is further reduced.

Disclosure of Invention

In order to overcome the defects and shortcomings of the prior art, the invention provides a novel 3+2 ring-closing synthesis method which can avoid the problems of poor stereoselectivity and the like in the ring-closing reaction.

The specific scheme route of the invention is as follows:

the method comprises the following steps of (1) carrying out a ring closure reaction on (-) -wensilactone serving as a starting material and a chlorooxime intermediate to prepare a compound I; the compound I is subjected to reduction reaction to obtain a compound II, the compound II is subjected to acetyl protection to obtain a compound III, and the compound III is subjected to hydrolysis and formamidization to obtain a compound V.

This route has a total of 5 steps, greatly shortens the reaction steps, and improves the overall yield. Through the research on the ring closure reaction, the direct use of (-) -wenskolide ring closure, due to the existence of bridge ring, enhances the space selectivity, almost does not produce isomerism, and unexpectedly, the generation of isomeric impurities is also greatly reduced, as shown in the following table data:

as can be seen from the above table, the selectivity of the crude reaction product reaches 93%, and the purity of the crude reaction product enables the crude product of the compound I to be directly reduced in a toluene solution without purification and then to be recrystallized for one time to obtain a refined product II meeting the requirements, and the compound II is acetylated and hydrolyzed to obtain a compound IV, and finally formamidinized to obtain a compound V.

As further optimization of the invention, (-) -wensilactone is used as a starting material to perform a ring closing reaction with a chlorooxime intermediate to prepare the compound I, toluene is used as a solvent in the ring closing reaction, the molar ratio of triethylamine to the chlorooxime intermediate is 3:2, and the adding sequence comprises adding triethylamine firstly and then adding the chlorooxime intermediate.

Further, the compound I is reduced to prepare a compound II, the reducing agent is sodium borohydride, and the catalyst is nickel chloride hexahydrate.

Has the advantages that: (1) the invention uses (-) -wensi lactone as raw material, does not need racemate resolution, improves atom utilization efficiency and reduces the discharge of three wastes; (2) the bridge ring structure is used for closing the ring, so that the space guiding effect is enhanced, and the reaction is converted into a target product as much as possible; (3) compared with the prior art, the method adopts the self-bridged ring to replace the protection of amino and carboxyl, shortens the reaction steps, improves the total yield and simplifies the production process.

Detailed Description

The invention is further described below by means of specific examples.

Example 1

Adding (-) -wensitone (1mmol) and triethylamine (3 mmol) into a 250ml three-neck flask, stirring fully, adding a toluene solution (2mmol) of a newly prepared chlorooxime intermediate, stirring and reacting at a reaction liquid temperature, adding water after the reaction is finished, layering, taking a toluene phase, washing the toluene phase twice with water, and standing for later use.

The toluene solution containing compound I from the previous step was added to a 250ml three-necked flask, nickel chloride hexahydrate (0.5mmol) was added, dissolved in methanol, and cooled to 0-5 ℃. And adding sodium hydroxide (0.02mmol) and sodium borohydride (1.5mmol) into another beaker, dissolving with methanol, slowly dropping into a three-necked bottle, and stirring at room temperature for reaction for 12 hours after dropping. Samples were taken and analyzed by HPLC for results. Adding ammonia water for quenching reaction in the post-treatment, heating to 40-50 ℃ for layering, discarding the water phase, washing the organic phase with water once, placing the organic phase in a 500ml three-necked bottle, stirring, cooling and crystallizing, separating out crystals, filtering, washing with toluene, and drying to obtain a refined product of the compound II, wherein the total yield of the two steps is 89%.

Adding a compound II (1.0mmol) into a 250ml three-necked bottle, adding toluene, heating to 50 ℃, dropwise adding glacial acetic acid (1.0mmol) under stirring, stirring for 1-2 hours after adding, cooling, adding water, adjusting the pH value to 2-3 with concentrated hydrochloric acid, stirring for 1-2 hours, layering, washing the toluene phase once with water, combining two water phases, transferring into a 250ml three-necked bottle, cooling in an ice water bath, magnetically stirring, adding sodium hydroxide, adjusting the pH value to 8-9, 1H-1, 2, 4-triazole-1-formamidine monohydrochloride (1.0mmol), stirring for reaction at room temperature, cooling the reaction solution to 0-5 ℃ after the reaction is finished, adding seed crystals, stirring for crystallization, filtering, washing with cold methanol to obtain a crude product of a compound V, and recrystallizing the crude product with water to obtain a refined product.

The above description is only of the preferred embodiments of the present invention, and it should be noted that: it will be apparent to those skilled in the art that various modifications and adaptations can be made without departing from the principles of the invention and these are intended to be within the scope of the invention.

Claims

1. The synthesis method of peramivir is characterized by comprising the following synthesis route:

2. The method of synthesis according to claim 1, characterized in that: the method comprises the following steps of carrying out a ring closing reaction on (-) -wensilactone serving as a starting material and a chlorooxime intermediate to prepare a compound I, wherein toluene is used as a solvent in the ring closing reaction, the molar ratio of triethylamine to the chlorooxime intermediate is 3:2, and the triethylamine and the chlorooxime intermediate are added in sequence.

3. The method of synthesis according to claim 1, characterized in that: the compound I is reduced to prepare a compound II, the reducing agent is sodium borohydride, and the catalyst is nickel chloride hexahydrate.