CN102627643A

CN102627643A - Refining method for ganciclovir

Info

Publication number: CN102627643A
Application number: CN2012101041870A
Authority: CN
Inventors: 陈敖; 俞军; 陈争一; 李鸣海
Original assignee: CHANGZHOU KANGLI PHARMACEUTICAL Co Ltd
Current assignee: Kang Li (Changzhou) Medicine Pharmaceutical Co. Ltd.
Priority date: 2012-04-10
Filing date: 2012-04-10
Publication date: 2012-08-08
Anticipated expiration: 2032-04-10
Also published as: CN102627643B

Abstract

The invention relates to the technical field of chemical refining, in particular to a refining method for ganciclovir. The refining method specifically comprises the following steps of: heating to dissolve the ganciclovir by using lower fatty acid aqueous solution; filtering off insoluble substances therein; cooling, crystallizing and suction-filtering filtrate; treating through inorganic alkali solution and then adjusting to be neutral, wherein the content of guanine impurity in the ganciclovir is reduced by a method of obtaining solid through crystallization. According to the method of reducing the content of the guanine impurity in the ganciclovir adopted in the refining method, the content of the guanine impurity can be reduced to be below 0.50 percent; and the method has the advantages of no need of repeating crystallization operation, short refining period, low energy consumption and high yield and is suitable for large-scale industrial production.

Description

The process for purification of ganciclovir

Technical field

The present invention relates to the chemical refining technical field, especially the process for purification of ganciclovir.

Background technology

Ganciclovir chemistry 9-(1,3-dihydroxyl-2-third oxygen methyl) by name-guanine is the ucleosides antiviral drug, but competitive inhibition DNA polymerase, and mix among the DNA of virus and host cell, it is synthetic to suppress DNA.Ganciclovir is the verivate of acyclovir, and is more effective than acyclovir, and antiviral spectrum is wider; Cytomegalovirus there is the high degree of specificity effect; The effect that suppresses human cytomegalic inclusion disease virus is better than acyclovir, has certain effect, these article to be released by U.S. Syntex company to herpes simplex virus I-type and II type, varicella zoster virus, Epstein-Barr virus etc.; In approval listing in 1988, be the choice drug of treatment cytomegalovirus infection.

The compound method of ganciclovir mainly contains following two kinds: 1. diacetyl guanine (or single acetyl guanine; The perhaps mixture of single acetyl guanine and diacetyl guanine) with 1; 3-dihalo-2-(acetoxyl group methoxyl group) propane carries out condensation reaction; Carry out replacement(metathesis)reaction with acetate then and obtain the triacetyl ganciclovir, obtain ganciclovir through hydrolysis reaction again; 2. acetyl guanine (or single acetyl guanine; The perhaps mixture of single acetyl guanine and diacetyl guanine) with 1; 3-diacetoxy-2-(acetoxyl group methoxyl group) propane) carrying out condensation reaction prepares the triacetyl ganciclovir, obtains ganciclovir through hydrolysis reaction then, 1. and 2. prepares ganciclovir as stated above; Contain guanine impurity in the product, its structural formula is following.

The guanine foreign matter content is higher relatively in the ganciclovir that 1. method prepares; Generally reach more than 5%, the method for guanine foreign matter content is in the reduction ganciclovir of bibliographical information: under heating condition, with water dissolution bullion ganciclovir; Add big carbon content active then and carry out adsorption treatment; The crystallization of heat filtering postcooling is filtered, and repeats that described hot water is broad to be separated-charcoal absorption-crystallisation by cooling-filtration procedure again; Until obtaining qualified ganciclovir, need the repetition aforesaid operations more than 8 times approximately; The guanine foreign matter content can obtain qualified ganciclovir generally below 1% through 3～5 above-mentioned purification operations in the ganciclovir that 2. method prepares; There is the refining problem that the cycle is long, energy consumption is high and yield is low in process for purification of the prior art.

Summary of the invention

The technical problem that the present invention will solve is: the process for purification that guanine foreign matter content in the reduction ganciclovir that a kind of refining cycle is short, energy consumption is low and yield is high is provided.

The technical solution adopted for the present invention to solve the technical problems is: a kind of process for purification of ganciclovir specifically may further comprise the steps:

(1) in 1g: the ratio of 10～20ml adds the dissolving of lower fatty acid heated in water solution with the ganciclovir bullion, and the ratio that adds 0.05～0.10g in per 1 gram ganciclovir bullion adds gac, refluxes 30 minutes, filters insolubles, gets the filtrating crystallisation by cooling;

(2) suction filtration gained filtrating and crystalline mixture; Getting crystallized product, to use mass concentration be 2～10% inorganic alkali solution stir process 0.5～2.0 hour at room temperature; With hydrochloric acid system is transferred to neutrality then, stirred crystallization is after 2～6 hours, suction filtration; Get the crystallized product oven dry, get the qualified ganciclovir of guanine foreign matter content.

Lower fatty acid in the said step (1) is formic acid or acetate, and mass concentration is 5～30%, ganciclovir bullion and the preferred 1g of lower aliphatic aqueous acid ratio: 15ml; Mineral alkali in the step (2) is sodium hydroxide or Pottasium Hydroxide, mass concentration preferred 5%.

Lower fatty acid preferable formic acid in the said step (1); The preferred sodium hydroxide of mineral alkali in the step (2).

The guanine foreign matter content was greater than 4% o'clock in the ganciclovir bullion; If the guanine foreign matter content is smaller or equal to 0.5% in the ganciclovir that from the lower aliphatic aqueous acid, filters out; Then carry out subsequent operationss such as inorganic alkali solution processing; If guanine content is greater than 0.5%, then needs again once, and then carry out subsequent operations such as inorganic alkali solution processing with the processing of lower aliphatic aqueous acid.

The present invention utilizes inorganic alkali solution to handle the solid of in the lower aliphatic aqueous acid, separating out, and is to be hydrolyzed to ganciclovir again for a small amount of ganciclovir acylate that ganciclovir and lower fatty acid are generated.

The present invention utilizes guanine relatively big character of solubleness in aqueous solutions of organic acids; Adopt lower aliphatic aqueous acid heating for dissolving ganciclovir, filter out insolubles wherein, the filtrating crystallisation by cooling; Suction filtration; Handle through inorganic alkali solution, be transferred to neutrality then, obtain the content that the solid mode reduces guanine impurity in the ganciclovir with crystallization.

Beneficial effect: the method for guanine foreign matter content can be reduced to the guanine foreign matter content below 0.50% in the reduction ganciclovir of the present invention; This method need not repeatedly the recrystallization operation; Have the advantage that the refining cycle is short, energy consumption is low, yield is high, be suitable for large-scale industrial production.

Embodiment

Below in conjunction with specific embodiment the present invention is elaborated, but the present invention is not limited to following specific embodiment.

Embodiment 1

A kind of guanine content is the process for purification of 3.68% 20g ganciclovir bullion, may further comprise the steps:

(1) drop into reaction flask with 20% formic acid solution 300ml, be warmed up to backflow, keep refluxing 0.5 hour, solid does not dissolve entirely, adds the 1g gac, refluxes 30 minutes, filters, and filter cake is used hot water wash, drains, and the refrigerator cold-storage crystallization is put in the washing filtrate merging;

(2) suction filtration gained filtrating and crystalline mixture; Get crystallized product and at room temperature dissolved stir process 1 hour, add the dilution of 100ml water, with Hydrogen chloride system is transferred to neutrality then with 5% NaOH solution 100ml; After the stirred crystallization 2 hours; Suction filtration, get dry after the crystallized product washing ganciclovir 15.7g, impurity guanine content reduces to 0.46%.

Embodiment 2

A kind of guanine content is the process for purification of 1.19% 20g ganciclovir bullion, may further comprise the steps:

(1) drop into reaction flask with 15% formic acid solution 300ml, be warmed up to backflow, solid dissolves the back entirely and adds the 1g gac, refluxes 30 minutes, filters, and filter cake is used hot water wash, drains, and the refrigerator cold-storage crystallization is put in the washing filtrate merging;

(2) suction filtration gained filtrating and crystalline mixture; Get crystallized product and at room temperature dissolved stir process 1 hour, add the dilution of 100ml water, with Hydrogen chloride system is transferred to neutrality then with 5% NaOH solution 100ml; After the stirred crystallization 2 hours; Suction filtration, get dry after the crystallized product washing ganciclovir 16.1g, impurity guanine content reduces to 0.22%.

Embodiment 3

(1) drop into reaction flask with 15% glacial acetic acid solution 300ml, be warmed up to backflow, solid dissolves the back entirely and adds the 1g gac, refluxes 30 minutes, filters, and filter cake is used hot water wash, drains, and the refrigerator cold-storage crystallization is put in the washing filtrate merging;

(2) suction filtration gained filtrating and crystalline mixture; Get crystallized product and at room temperature dissolved stir process 1 hour, add the dilution of 100ml water, with Hydrogen chloride system is transferred to neutrality then with 5% NaOH solution 100ml; After the stirred crystallization 2 hours; Suction filtration, get dry after the crystallized product washing ganciclovir 16.3g, impurity guanine content reduces to 0.42%.

Embodiment 4

(1) drop into reaction flask with 10% formic acid solution 300ml, be warmed up to backflow, solid dissolves the back entirely and adds the 1g gac, refluxes 30 minutes, filters, and filter cake is used hot water wash, drains, and the refrigerator cold-storage crystallization is put in the washing filtrate merging;

(2) suction filtration gained filtrating and crystalline mixture; Get crystallized product and at room temperature dissolved stir process 1 hour, add the dilution of 100ml water, with Hydrogen chloride system is transferred to neutrality then with 5% NaOH solution 100ml; After the stirred crystallization 2 hours; Suction filtration, get dry after the crystallized product washing ganciclovir 16.2g, impurity guanine content reduces to 0.34%.

Embodiment 5

A kind of guanine content is the process for purification of 0.94% 20g ganciclovir bullion, may further comprise the steps:

(2) suction filtration gained filtrating and crystalline mixture; Get crystallized product and at room temperature dissolved stir process 1 hour, add the dilution of 100ml water, with Hydrogen chloride system is transferred to neutrality then with 5% NaOH solution 100ml; After the stirred crystallization 2 hours; Suction filtration, get dry after the crystallized product washing ganciclovir 16.7g, impurity guanine content reduces to 0.24%.

Claims

1. the process for purification of a ganciclovir is characterized in that: may further comprise the steps:

2. the process for purification of ganciclovir as claimed in claim 1, it is characterized in that: the lower fatty acid in the said step (1) is formic acid or acetate, mass concentration is 5～30%, ganciclovir bullion and the preferred 1g of lower aliphatic aqueous acid ratio: 15ml; Mineral alkali in the step (2) is sodium hydroxide or Pottasium Hydroxide, mass concentration preferred 5%.

3. the process for purification of ganciclovir as claimed in claim 2 is characterized in that: the lower fatty acid preferable formic acid in the said step (1); The preferred sodium hydroxide of mineral alkali in the step (2).