CN1910184A - Process for the preparation of valacyclovir hydrochloride - Google Patents

Process for the preparation of valacyclovir hydrochloride Download PDF

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Publication number
CN1910184A
CN1910184A CN 200580002698 CN200580002698A CN1910184A CN 1910184 A CN1910184 A CN 1910184A CN 200580002698 CN200580002698 CN 200580002698 CN 200580002698 A CN200580002698 A CN 200580002698A CN 1910184 A CN1910184 A CN 1910184A
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China
Prior art keywords
valacyclovir
prestige
boc
hydrochloric acid
ala
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CN 200580002698
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Chinese (zh)
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Z·哈雷尔
M·佩萨乔维奇
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Teva Pharmaceutical Industries Ltd
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Teva Pharmaceutical Industries Ltd
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Abstract

Provided are HPLC methods for analyzing BOC-L-alanine in BOC-L-valine and alanine analogues in valacyclovir hydrochloride and a use and method of selecting valacyclovir compositions.

Description

The preparation method of hydrochloric acid prestige valacyclovir
Quoting alternately of related application
This application requires to enjoy 60/538, No. 362 of putting on record on January 21st, 2004 and the rights and interests of 60/591, No. 707 US provisional application case of putting on record on July 27th, 2004, and the disclosed content of this two routine provisional application is used as integral body at this and quotes.
FIELD OF THE INVENTION
The present invention relates to the synthetic method of hydrochloric acid prestige valacyclovir (valacyclovir hydrochloride) composition, said composition contains the L-Ala analogue from the lower concentration of initiator BOC-L-Xie Ansuan, and this initiator detects the BOC-L-Ala that contains lower concentration through the liquid-solid chromatography method.
The background of invention
Prestige valacyclovir (valacyclovir, formula I) is a kind of valyl ester prodrug of A Sailuowo (acyclovir, a kind of no ring analogues of natural nucleus glycoside, formula II).It is reported that A Sailuowo has high antiviral active, be widely used in the human viral infection, particularly by in treatment of infecting due to the simplexvirus and the prevention.See Goodman and Gilman work " therapeutic pharmacological basis " (Goodman and Gilman:The Pharmacological Basis ofTherapeutics.1193-1198,9th ed., 1996).
Formula I
Formula II
The available Xie Ansuan synthetic hydrochloric acid prestige valacyclovir that has an amine protecting group group (for example uncle-butoxy carbonyl group (t-BOC)).For example the Xie Ansuan of a kind of amine protection of No. 20030153757 disclosed usefulness of U.S. Patent application is as the method for initiator synthetic hydrochloric acid prestige valacyclovir.As a kind of initiator of useful synthetic prestige valacyclovir, the BOC-L-Xie Ansuan can contain the impurity of BOC-L-Ala and so on.Do not wish to contain in the initiator this class impurity, because the final synthetic product that obtains can be polluted by the L-Ala analogue of prestige valacyclovir from such initiator.
Usable highly effective liquid phase chromatography (HPLC) detects and quantitative these impurity.
The general introduction of invention
On the one hand, the invention provides a kind of usefulness and contain the BOC-L-Xie Ansuan that is less than the 0.2area-%BOC-L-L-Ala as the synthetic hydrochloric acid prestige valacyclovir method for compositions that is less than 0.2area-% L-Ala analogue that contains of initiator.Preferably, used initiator contains the BOC-L-L-Ala that is less than 1area-%, and synthetic hydrochloric acid prestige valacyclovir composition contains the L-Ala that is less than 1area-%.More preferably, used initiator contains the BOC-L-L-Ala that is less than 0.05area-%, and only contains the alanine derivatives that is difficult to detected level in the synthetic hydrochloric acid prestige valacyclovir composition.
On the other hand, the present invention also provides a kind of liquid-solid chromatography method to detect BOC-L-Ala concentration in the BOC-L-Xie Ansuan, the concentration of L-Ala analogue in hydrochloric acid prestige valacyclovir crude product and the final product, and crystalline hydrochloric acid prestige valacyclovir.
The detailed description of invention
The component that " gradient elution " used herein refers to gradient eluent a fixed in the period step by step, perhaps change with a kind of fixed velocity of variation, reduce as the percentage concentration of first elutriant, the concentration of second elutriant increases.
" gradient eluent " used herein refers to the elutriant of being made up of first and second elutriants of various concentration.
" sample " used herein refers to from a large amount of, or a small amount of of taking out from one batch BOC-L-Xie Ansuan or hydrochloric acid prestige valacyclovir or the sample of five equilibrium, to the analysis of this sample characteristics with an assessment large sample or a batch of sample.
Relate to the BOC-L-Xie Ansuan or the hydrochloric acid prestige valacyclovir of some amount, used herein " batch " refer to the quantity of taking out sample.One batch is from primary treatment or from the resulting quantity of single job.The size of this quantity depends on used equipment as other things.
" solid oral agent type " speech used herein refers to capsule and tablet.
" doing batching " speech used herein refers to the mixture of hydrochloric acid prestige valacyclovir and at least a vehicle.
It is the amount that the HPLC method of 0.01area-% can detect that " can detect " speech used herein refers to accuracy of detection.
Relate to the amount of the L-Ala analogue in the hydrochloric acid prestige valacyclovir, " can not detect " vocabulary used herein shows that with said accuracy of detection here be the amount that the HPLC method of 0.01area-% can not detect.
" L-Ala analogue " speech used herein comprises the molecule of prestige valacyclovir sample, and the part that wherein is combined in the hydroxyl-oxethyl methyl group is L-Ala rather than Xie Ansuan.
Relate to the amount that is detected, " approximately " speech used herein refers to utilization and the purpose that detects and is engaged in the rangeability of the desired detection limit of the those skilled in the art of this detection with the level that the precision of used instrument adapts.
To be metaphor to the tester did detect " area-% " speech used herein each time analyzes " area under the peak value " that draw (below be called " AUP "), for example a kind of chromatographic process in liquid-solid chromatography is analyzed.Can calculate AUP with a kind of suitable totalizing instrument.Each peak correspondence in the chromatogram a kind of different composition in the mixture that is loaded on the liquid-solid chromatography post, and every kind of its AUP of the composition that can detect shared ratio in total AUP of sample all the components is the area percentage.The percentile mathematical expression of area as shown in the formula:
Area i-%=100 (AUPi)/(AUPs that ∑ is all)
Hydrochloric acid prestige valacyclovir composition is made up of hydrochloric acid prestige valacyclovir basically.
Hydrochloric acid prestige valacyclovir can use the method for the US number of delivering 2003/0153757 of quoting as a reference to prepare herein with the BOC-L-Xie Ansuan as initiator.The BOC-L-Xie Ansuan can be polluted by the BOC-L-Ala.The amount of the L-Ala analogue in the middle of being present in crude product and the crystalline end product can be controlled as initiator with the BOC-L-L-Ala of BOC-L-Ala, particularly lower level with lower level.The available liquid-solid chromatography method of the level of BOC-L-Ala detects.
Liquid-solid chromatography method, particularly high pressure lipuid chromatography (HPLC), also cry high performance liquid chromatography (to call " HPLC " in the following text) be used to detect with quantitative a kind of chemical compound in impurity.Among the HPLC, the to be separated of so-called assay and the composition of measuring are dissolved in a kind of thinner (solvent), this thinner can be exactly an elutriant, or flows through the mobile liquid phase of chromatographic column.This mobile liquid phase and dissolved assay filler (the being typically expressed as solid phase) lining in chromatographic column reacts to each other.Because different assays is different with reacting to each other of solid phase, every kind of assay passes through the speed difference of chromatographic column.See 13 James D.Winefordner, Treatiseon Analytical Chemistry, pt.I (2d ed.1993).
Reversed-phase HPLC utilizes a kind of nonpolar solid phase and a kind of polar elutriant.The component that gradient elution changes the component of moving phase or gradient elution agent by whole process has been improved the separation of sample composition.Monitor separation with a kind of indicator by the specific physical properties of measuring elutriant.For example, measuring the radiation absorption value of moving phase with a spectrophotometer just can be as an index.
The applicant finds that as other things, the L-Ala analogue concentration in prestige valacyclovir or the hydrochloric acid prestige valacyclovir end product can be controlled by the BOC-L-Ala concentration in the control initiator BOC-L-Xie Ansuan.Need certain methods and detect L-Ala analogue in initiator, intermediate product and the final hydrochloric acid prestige valacyclovir synthetic product.Also need to make in the hydrochloric acid prestige valacyclovir end product and only contain the L-Ala analogue of trying one's best few.
As a particular embodiment, the invention provides a kind of liquid-solid chromatography method and detect BOC-L-Ala concentration in the BOC-L-Xie Ansuan.The concentration of the BOC-L-Ala pollutent in the BOC-L-Xie Ansuan can detect with the liquid-solid chromatography method, particularly uses the HPLC method, especially particularly detects with HPLC method described below herein.The HPLC method is used a suitable chromatography column, for example reverse-phase chromatographic column Inertsil ODS-3V 5 μ m 150 * 4.6mm (GLSciences, Cat.No.5020-01731).
The first step of measuring the HPLC method of the BOC-L-L-Ala amount in the BOC-L-Xie Ansuan among the present invention comprises BOC-L-Xie Ansuan dress sample to the liquid-solid chromatography post.With injection the solution of sample being injected chromatographic column can be more effective.The appropriate vol of injecting on the chromatographic column is 50 μ L.The diluent that is used for making the solution of sample to inject can be, for example, and elutriant.Chromatographic column can be placed room temperature, preferably about 25 ℃.Solid phase in the chromatographic column can be the silica gel of the preferred 5 μ m of modification, and spherical 18 alkyl silica gel is with 15% carbon filler end-blocking, preferably InertsilODS-3V.After sample loaded onto chromatographic column, with elutriant with chromatographic column constant speed ground (isocratically) wash-out.Preferred elutriant is acetonitrile (27%) and contains 0.05% phosphoric acid (0.5g, 85%H 3PO 4/ 1L H 2O) water (73%), the flow velocity perseverance is not more than 1mL/min.Monitoring UV detector is to the reaction of effluent in the chromatographic column, and the UV detector here can be to control scope 200-600nm, preferably the spectrophotometer of 210nm.According to the amount of detector, be expressed as " area-% " to BOC-L-Ala in the reaction calculating BOC-L-Xie Ansuan of wash-out composition.
The suitability of HPLC system can detect with a kind of system suitability solution, and this solution comprises the mixture of BOC-L-Ala (0.15mg/mL) and BOC-L-Xie Ansuan (15mg/mL) thinner.
Another particular embodiment the invention provides the liquid-solid chromatography method that a kind of detection is present in the amount of the L-Ala analogue in the hydrochloric acid prestige valacyclovir sample.By the liquid-solid chromatography method,, can measure the concentration of L-Ala analogue particularly by HPLC.The suitable chromatographic column of doing this mensuration is reversed-phase column Inertsil ODS-3V 5 μ m, or the chromatographic column of tool identical function.Preferably, present method is used gradient elution.This method can make sample composition more effectively separate.
The first step of measuring the HPLC method of the amount of L-Ala analogue in the hydrochloric acid prestige valacyclovir sample among the present invention is that hydrochloric acid prestige valacyclovir sample is installed on the liquid-solid chromatography post.With injection the solution of sample being injected chromatographic column can be more effective.During with injection method dress post, the amount of injection is about 20 μ L.In addition, the diluent that is used for preparing injected sample solution can be, for example, and the first identical elutriant.Column temperature can be than room temperature height.Preferred column temperature is about 30 ℃.Solid phase in the chromatographic column can be the silica gel of the preferred 5 μ m of modification, spherical 18 alkyl silica gel, and with 15% carbon filler end-blocking, preferably Inertsil ODS-3V 1.With the chromatographic column gradient elution, the flow velocity of gradient eluent does not surpass 1.5mL/min, makes gradient elution contain first and second elutriants then.
The first suitable elutriant is the aqueous solution (98%) and the acetonitrile (2%) of 0.01M potassium primary phosphate.The pH of first elutriant is acid, and preferably the pH value is about 3.5.Available 10% phosphorus acid for adjusting pH value.The second suitable elutriant is an acetonitrile.Normally suitable starting time is about 7 minutes.The UV detector is monitored the reaction of chromatogram effluent, and the UV detector here can be to control scope 200-600nm, preferably the spectrophotometer of 245nm.According to the reaction of detector, calculate the amount of L-Ala analogue in the hydrochloric acid prestige valacyclovir, be expressed as " area-% ".
The prestige valacyclovir can be dissolved in the suitability solution that comes preparation system in a kind of guanine solution and a kind of A Sailuowo solution.The concentration of sample solution can be the 0.8mg/mL prestige valacyclovir with the thinner dilution.Sample solution can be injected on the chromatographic column, can measure the concentration that the area-% of various compositions in the mixture measures any impurity with a kind of suitable totalizing instrument then.
Another particular embodiment of the present invention has provided synthetic a kind of hydrochloric acid prestige valacyclovir method for compositions, contain a certain amount of L-Ala analogue in this composition, its content be less than 0.2area-% but more than or equal 0.1area-%, this method comprises the steps:
A) obtain the BOC-L-Xie Ansuan sample of one or more batch or a plurality of batches;
B) measure the BOC-L-L-Ala level in each sample in (a) step;
C) select the BOC-L-Xie Ansuan sample of batch or a plurality of batches, the amount of contained BOC-L-L-Ala will be less than 0.2area-% through the detection of (b) step in these samples; And
D) with the synthetic said hydrochloric acid prestige valacyclovir composition of the sample of selected batch of (c) step.
Preferably, BOC-L-Xie Ansuan sample and the resulting hydrochloric acid prestige valacyclovir amount that contains BOC-L-L-Ala and L-Ala analogue respectively all is less than about 0.1area-%.Most preferably, when the amount of the BOC-L-L-Ala that contains when BOC-L-Xie Ansuan sample is less than 0.05area-%, but do not contain the L-Ala of detected level in the hydrochloric acid prestige valacyclovir composition.
Detect the amount of BOC-L-L-Ala in the BOC-L-Xie Ansuan sample with the method for above-mentioned liquid-solid chromatography method or equivalence with it.
Especially, the invention provides a kind of synthetic hydrochloric acid prestige valacyclovir method for compositions, the amount of contained L-Ala analogue is less than 0.2area-% in this composition.The first step of this synthetic method is a BOC-L-Xie Ansuan sample of analyzing in batch or a plurality of batches of samples, wherein contained L-Ala analogue only exists with the impurity meaning, and select one batch sample, the amount of the L-Ala analogue that it is contained is less than 0.2area-%.Selected BOC-L-Xie Ansuan sample reacts to obtain a kind of mixture with the A Sailuowo in a kind of organic solvent, and this organic solvent is dimethyl formamide (being hereinafter referred to as " the DMF ") solution of dicyclohexyl carbonyl diurethane imines (being hereinafter referred to as " DCC ") preferably.Then this mixture and 4-dimethylaminopyridine (being hereinafter referred to as " DMAP ") are merged, add water then and obtain a suspension.Remove by filter sedimentary dicyclohexylurea (DCU), then the filtrate that generates is concentrated.Then filtrate is regenerated in, or be dissolved in the lower alcohol, particularly Virahol of backflow, to obtain protected prestige valacyclovir.This product can go the protection, and from water and Virahol recrystallize, to provide crystalline hydrochloric acid prestige valacyclovir.The synthetic of hydrochloric acid prestige valacyclovir can be accomplished different scales, and the weightmeasurement ratio that is provided is applicable to all reactants.
The hydrochloric acid prestige valacyclovir that obtains by method of the present invention can be mixed with drug component.Except effective constituent, can, typically also contain one or more vehicle really under the situation in the formula of medicine of the present invention.Typical drug component is prepared in batch, and makes the solid oral agent type, for example tablet and capsule.The solid oral agent type that offers commercial distribution can be the batching of doing according to the content of L-Ala analogue in the hydrochloric acid prestige valacyclovir, perhaps is exactly solid-state oral dosage form.
Be that various purposes add vehicle in the prescription.Thinner has increased the total amount of solid-state drug component, and the pharmaceutical dosage form that contains this component is taken by the patient easily, transports processing and also makes things convenient for.The thinner of solids fraction comprises microcrystal-state cellulose (for example Avicel ), fine cellulose, lactose, starch, preceding gelling starches, lime carbonate, calcium sulfate, sucrose, dextran, dextrin, D-glucose, bibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesiumcarbonate, magnesium oxide, Star Dri 5, mannitol, polymethacrylate (for example Eudragit ), Repone K, cellulose powder, sodium-chlor, Sorbitol Powder and talcum powder, the just sub-fraction of mentioning here.
Be made into the solid pharmaceutical composition of formulation, for example tablet can comprise vehicle, and its function is included in and helps in the pressing process effective constituent and other vehicle are bonded together.The tackiness agent of solid pharmaceutical composition comprises Sudan Gum-arabic, alginic acid, methyl esters class (for example carbopol), carbonyl methyl cellulose sodium, dextrin, ethyl cellulose, gel, natural gum, hydrogenation rape oil, Natvosol, hydroxypropylcellulose (for example Klucel ), Vltra tears (for example Methocel ), liquid glucose, magnesium aluminum silicate, Star Dri 5, methylcellulose gum, polymethacrylate, povidone (for example Kollidon , Plasdone ), preceding gelling starches, sodiun alginate and starch.
Be controlling quality, preferably with the hydrochloric acid prestige valacyclovir manufacture of pharmaceutical components that contains a small amount of L-Ala.Typical drug component is preparation in quantity, or produce on a large scale.Must check that the batch of producing is no more than the scope that quality control detects regulation with the content that guarantees the L-Ala analogue.Sampling from the product of producing in batches (for example 10～100 capsule or tablet) analyze the L-Ala analogue that exists and, preferably, analyze identical content.In general, whole bulk articles is removed the sample of reservation, all will sell, or be sent out by manufacturer, unless find L-Ala analogue content overproof.Bulk article can not be sold or provide in this case, promptly can not do commercial use and can not do clinical study usefulness.Same strategy also can be applicable to the hydrochloric acid prestige valacyclovir substrate produced in batches.
Following indefiniteness embodiment will describe examples more of the present invention.
Embodiment 1
The present embodiment explanation is used for detecting a kind of liquid-solid chromatography method of BOC-L-Xie Ansuan BOC-L-Ala concentration.
The solution for preparing a kind of detection system suitability with the diluent of the BOC-L-Xie Ansuan of the BOC-L-Ala of 0.15mg/mL and 15mg/mL.Used diluent is identical with elutriant, and 0.05% phosphate aqueous solution by 73% and 27% acetonitrile constitute.With the sample of 50 μ L on the chromatographic column that installs to an Inertsil ODS-3V 5 μ m 150 * 4.6mm under 25 ℃.Detector is set in 210nm, with the flow velocity of 1mL/min with the sample wash-out.The retention time of BOC-L-Ala and BOC-L-Xie Ansuan was respectively 6 minutes and 14.5 minutes.Come comparison AUPs to determine the BOC-L-Ala area-% concentration in the BOC-L-Xie Ansuan with a suitable totalizing instrument then.
Embodiment 2
The present embodiment explanation is used for detecting a kind of liquid-solid chromatography method of BOC-L-Xie Ansuan BOC-L-Ala concentration.
The 5mg guanine is dissolved in the solution for preparing a kind of detection system suitability among the NaOH of 10mL 0.2N.Use 98% 0.01M potassium dihydrogen phosphate aqueous solution (transferring pH to 3.5) that this solution further is diluted to 100mL then with 10% phosphoric acid and 2% acetonitrile.Again 5mg A Sailuowo is made second solution with diluted to total amount 100mL.These two kinds of solution are got 2mL for every kind and are added in the 20mg hydrochloric acid prestige valacyclovir.With diluent the total amount of hydrochloric acid prestige valacyclovir solution is added to 25mL.First elutriant that this diluent is also analyzed as HPLC.Second elutriant is an acetonitrile.The mixture of 20 μ L hydrochloric acid prestige valacyclovirs, guanine and A Sailuowo is expelled on the chromatographic column of an Inertsil ODS-3V 5 μ m 250 * 4.6mm.This chromatographic column is done gradient elution with 0-20% second elutriant, and 32 minutes, flow velocity 1.5mL/min, 30 ℃ of temperature.Totalizing instrument is set in 254nm.The retention time of hydrochloric acid prestige valacyclovir is 13 minutes.The transformation that can obtain between guanine and the A Sailuowo is no less than 15.0, the hydrochloric acid prestige valacyclovir of the tail factor no more than 4.0.
Embodiment 3a
Present embodiment is described in the synthetic method that contains the hydrochloric acid prestige valacyclovir of the protection that is no less than about 1.4area-% L-Ala analogue.
To contain the BOC-L-Xie Ansuan (870g) that is less than the 1area-%BOC-L-Ala and under logical nitrogen condition, fully be dissolved in the dimethyl formamide (DMF) of 5874mL, stir simultaneously.Then mixture is cooled to-5 ℃.In 20 minutes, a kind of dicyclohexylcarbodiimide (DCC) DMF (600g) solution (360g) is added in this mixture and goes, the mixture that obtains was stirred 20 minutes down at-5 ℃.600g A Sailuowo is added in this mixture, stirs adding 98g DMAP after 5 minutes.Mixture was stirred 3 hours down at-5 ℃.In 20 minutes, DMF (600g) solution of DCC (330g) is added.Mixture was stirred 3 hours down at-5 ℃.In 20 minutes, DMF (780g) solution of DCC (438g) is added, the mixture that obtains was stirred 3 hours down at-5 ℃.Mixture at 2.5 hours internal heating to 25 ℃, was stirred 4 hours.Add 204g water, mixture was stirred 4 hours down at 25 ℃.The precipitation that generates, dicyclohexyl urine is used reclaiming by filtration, with 1800g DMF washing.Then filtrate decompression (10mmHg) is concentrated and obtain resistates.This resistates backflow is dissolved in the 6120g Virahol (to call IPA in the following text).Make mixture be cooled to 25 ℃, by precipitation---the protected prestige valacyclovir of filtered and recycled generation.
Embodiment 3b
Present embodiment is described will be in the synthetic de-protected method of protected hydrochloric acid prestige valacyclovir when containing the hydrochloric acid prestige valacyclovir of the L-Ala analogue that is less than 1.4area-%.
The protected prestige valacyclovir of dry basis 578g is dissolved in the 1440mL formic acid under 25 ℃.Add 186mL water, in 1 hour, add the hydrochloric acid of 311g 32% then.Under 25 ℃, this mixture was stirred 1～5 hour, reduce to below 0.5% up to the concentration of protected prestige valacyclovir.In 30 minutes, in this mixture, add the 9200mL Virahol, this mixture is cooled to-5 ℃.The precipitation that filtered and recycled generates obtains containing the crude product of the hydrochloric acid prestige valacyclovir of the L-Ala analogue that is less than 1.4area-%.
Embodiment 3c
Present embodiment is described the hydrochloric acid prestige valacyclovir crystalline that contains the L-Ala analogue that is less than 1.4area-% and is generated.
The crude product of 380g hydrochloric acid prestige valacyclovir is dissolved in the 1520mL water under 40 ℃.This mixture is cooled to 35 ℃ after filtering.In 3 hours, in this mixture, add the 5700mL Virahol.This mixture is cooled to-5 ℃.The precipitation that generates is a crystalline hydrochloric acid prestige valacyclovir, passes through filtered and recycled.With this moist precipitate vacuum-drying, again the throw out of doing is milled.Crystalline hydrochloric acid prestige valacyclovir contains the L-Ala analogue that is less than 1.4area-%.
Embodiment 4a
Present embodiment is described in the generation of synthesizing protected prestige valacyclovir when containing the hydrochloric acid prestige valacyclovir that is less than 0.03area-% L-Ala analogue.
Under logical nitrogen condition, 870g is contained the BOC-L-Xie Ansuan that is less than the 0.05%BOC-L-Ala and be dissolved among the 5874mL DMF, stir down at 20～25 ℃, up to abundant dissolving.Then mixture is cooled to-5 ℃.DMF (600g) solution that added DCC (330g) in 20 minutes in this mixture stirs resulting mixture 20 minutes down at-5 ℃.600g A Sailuowo is added in this mixture, stir and add 98g DMAP again after 5 minutes.This mixture was stirred 3 hours down at-5 ℃.DMF (600g) solution that added DCC (330g) in 20 minutes in this mixture stirs resulting mixture 3 hours down at-5 ℃.DMF (780g) solution that added DCC (438g) in 20 minutes in this mixture stirs resulting mixture 3 hours down at-5 ℃.This mixture at 2.5 hours internal heating to 25 ℃, was stirred 4 hours.Add 240g water, mixture was stirred 4 hours down at 25 ℃.With the precipitation that generates, i.e. dicyclohexylurea (DCU), filtered and recycled is with 1800g DMF washing.Then filtrate decompression (10mmHg) is concentrated and obtain the silkworm slag.These residues backflows are dissolved in the 6120g Virahol.Mixture is cooled to 25 ℃, and with the precipitation that generates, promptly protected prestige valacyclovir passes through filtered and recycled.
Embodiment 4b
Present embodiment is described in the generation of synthesizing hydrochloric acid prestige valacyclovir crude product when containing the hydrochloric acid prestige valacyclovir that is less than 0.03area-% L-Ala analogue.
The protected prestige valacyclovir that obtains by the described method of embodiment 4a of dry basis 578g is dissolved in the 1440mL formic acid under 25 ℃.In this mixture, add 186mL water, in 1 hour, add the hydrochloric acid soln of 311g 32% then again.This mixture was stirred 1～5 hour down at 25 ℃, reduce to below 0.5% up to the concentration of protected prestige valacyclovir.In 30 minutes, in this mixture, add the 9200mL Virahol, this mixture is cooled to-5 ℃ then.The precipitation that filtered and recycled generates is containing of generation and is less than the hydrochloric acid prestige valacyclovir crude product of about 0.03area-% L-Ala analogue.
Embodiment 4c
Present embodiment is described and is contained the hydrochloric acid prestige valacyclovir crystalline generation that is less than about 0.03area-% L-Ala analogue.
40 ℃ with 380g hydrochloric acid prestige valacyclovir dissolving crude product in 1520mL water.Mixture is filtered and be cooled to 35 ℃.In 3 hours, in this mixture, add the 5700mL Virahol.Again mixture is cooled to-5 ℃.The precipitation that filtered and recycled generates is crystalline hydrochloric acid prestige valacyclovir.With wet precipitation vacuum-drying, the throw out of doing to be milled, the crystalline hydrochloric acid prestige valacyclovir of generation does not contain the L-Ala analogue that can detect.

Claims (18)

1. one kind prepares and contains the hydrochloric acid prestige valacyclovir method for compositions that is less than about 0.2area-% L-Ala analogue, comprising:
A) obtain a collection of or many batches of one or more samples that BOC-L-figured silk fabrics ammonia is calculated;
B) content of BOC-L-L-Ala in each sample of mensuration (a) step;
C) selected a collection of BOC-L-Xie Ansuan, its contained BOC-L-L-Ala level is lower than 0.2area-% through the detection of (b) step; And
D) with this batch BOC-L-Xie Ansuan synthetic hydrochloric acid prestige valacyclovir composition of selecting through (c) step.
2. one kind prepares and contains the hydrochloric acid prestige valacyclovir method for compositions that is less than about 0.2area-% L-Ala analogue, comprising:
A) the BOC-L-L-Ala in the mensuration BOC-L-Xie Ansuan sample, the BOC-L-Xie Ansuan sample is here selected from a collection of or many batches of BOC-L-Xie Ansuans;
B) selected a collection of BOC-L-Xie Ansuan sample, its contained BOC-L-L-Ala is less than about 0.2area-%;
C) selected BOC-L-Xie Ansuan is reacted to obtain a kind of mixture in a kind of organic solvent with A Sailuowo;
D) in the mixture of (c) step, add 4-dimethylaminopyridine, add water again to obtain a kind of precipitation;
E) remove the precipitation of (d) step, and the filtrate that is generated is concentrated;
F) in the thickening filtration thing of (e) step, reflux a kind of lower alcohol of adding to obtain protected prestige valacyclovir;
G) make the protected prestige valacyclovir in (f) step in formic acid, water and HCl, go protection to obtain hydrochloric acid prestige valacyclovir crude product; And
H) make hydrochloric acid prestige valacyclovir in (g) step by water and Virahol recrystallize to obtain containing the composition that is less than about 0.2area-% L-Ala analogue.
3. claim 1 and any one method of 2, wherein selected that batch BOC-L-Xie Ansuan contains the BOC-L-L-Ala that is less than about 0.1area-%, and contains the BOC-L-L-Ala analogue that is less than about 0.1area-% in the resulting hydrochloric acid prestige valacyclovir composition.
4. the method for claim 3, wherein selected that batch BOC-L-Xie Ansuan contains the BOC-L-L-Ala of the 0.05area-% that has an appointment, but and does not contain the L-Ala analogue of detected level in the resulting hydrochloric acid prestige valacyclovir composition.
5. the method for claim 2, wherein the organic solvent of (c) step is the mixture of a kind of dicyclohexyl carbonyl diurethane imide and dimethyl formamide.
6. the method for claim 2, wherein the lower alcohol of (f) step is a Virahol.
7. claim 1 and 2 each method, the sample that wherein detects the BOC-L-Xie Ansuan is the amount that detects BOC-L-L-Ala in the BOC-L-Xie Ansuan sample with the liquid-solid chromatography method, comprises the steps:
A) sample is installed on the liquid-solid chromatography post;
B) with about 1mL/min or lower fixed flow rate usefulness elutriant elution chromatography post, the elutriant here is made up of about 27% acetonitrile and about 73% 0.05% phosphate aqueous solution;
C) UV detector of monitoring is to the reaction of eluate in the chromatographic column, and wherein the operating restraint of UV detector is set in 200～600nm; And
D) press the amount that area percentage calculates the BOC-L-L-Ala in the BOC-L-Xie Ansuan according to the reaction of detector.
8. the method for claim 2, wherein the area percentage of the alanine derivatives in the hydrochloric acid prestige valacyclovir sample is measured with a kind of liquid-solid chromatography method, comprises the steps:
A) sample is installed on the liquid-solid chromatography post;
B) with the fixed flow rate of a kind of about 1.5mL/min chromatographic column is done gradient elution with a kind of gradient eluent, the gradient eluent here comprises first and second elutriants, wherein first elutriant is 98% 0.01M potassium dihydrogen phosphate aqueous solution and 2% acetonitrile, and second elutriant is an acetonitrile;
C) UV detector of monitoring is to the reaction of eluate in the chromatographic column, and wherein the operating restraint of UV detector is set in 200～600nm; And
D) press the amount that area percentage calculates L-Ala analogue in the hydrochloric acid prestige valacyclovir according to the reaction of detector.
9. each method in the claim 7 and 8, chromatographic column wherein is a silica gel chromatographic column
10. the method for claim 8, wherein the pH value of first elutriant is about 3.5.
11. the method for claim 8, wherein the column temperature of chromatographic column is about 30 ℃.
12. a liquid-solid chromatography method of measuring L-Ala content in the hydrochloric acid prestige valacyclovir comprises the steps:
A) sample is installed on the liquid-solid chromatography post;
B) with the fixed flow rate of a kind of about 1.5mL/min chromatographic column is done gradient elution with a kind of gradient eluent, the gradient eluent here comprises first and second elutriants, wherein first elutriant is 98% 0.01M potassium dihydrogen phosphate aqueous solution and 2% acetonitrile, and second elutriant is an acetonitrile;
C) UV detector of monitoring is to the reaction of eluate in the chromatographic column, and wherein the operating restraint of UV detector is set in 200～600nm; And
D) press the amount that area percentage calculates L-Ala analogue in the hydrochloric acid prestige valacyclovir according to the reaction of detector.
13. the quality control apportioning method of a hydrochloric acid prestige valacyclovir solid oral agent type comprises the steps:
A) produce a collection of dried hydrochloric acid prestige valacyclovir and at least a vehicle;
B) that batch product of step a) is processed into the solid oral agent type of a collection of hydrochloric acid prestige valacyclovir;
C) from that batch of step b) product, take a sample, detect the wherein amount of L-Ala analogue according to the method for claim 12; And
D), then that batch of step b) product is put to the merchant and sells if the amount of the L-Ala analogue that step c) detects is less than about 0.2area-%.
14. the quality control apportioning method of a hydrochloric acid prestige valacyclovir solid oral agent type comprises the steps:
A) measure the amount of the L-Ala analogue in the hydrochloric acid prestige valacyclovir sample according to the method for claim 12;
B), produce the hydrochloric acid prestige valacyclovir and at least a vehicle done of a collection of step a) if the amount of the L-Ala analogue that step a) records is less than about 0.2area-%;
C) that batch product of step b) is processed into the solid oral agent type of a collection of hydrochloric acid prestige valacyclovir; And
D) that batch of step c) product being put to the merchant sells.
15. a method for preparing hydrochloric acid prestige valacyclovir pharmaceutical preparation comprises the steps:
A) from a collection of hydrochloric acid prestige valacyclovir, take a sample;
B) amount of L-Ala analogue in the usefulness method calculation sample of claim 12; And
C) amount that detects contained L-Ala analogue with that batch sampling is less than the pharmaceutical preparation of the product preparation hydrochloric acid prestige valacyclovir of about 0.2area-%.
16. the method for claim 15, wherein that batch product is less than about 0.1area-% through the amount that step c) detects contained L-Ala analogue in its sample.
17. the method for claim 15, wherein that batch product is less than about 0.05area-% through the amount that step c) detects contained L-Ala analogue in its sample.
18. a method for preparing hydrochloric acid prestige valacyclovir comprises that the BOC-L-Xie Ansuan that is less than about 0.2area-% with contained BOC-L-L-Ala does the step that initiator prepares hydrochloric acid prestige valacyclovir.
CN 200580002698 2004-01-21 2005-01-21 Process for the preparation of valacyclovir hydrochloride Pending CN1910184A (en)

Applications Claiming Priority (3)

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US53836204P 2004-01-21 2004-01-21
US60/538,362 2004-01-21
US60/591,707 2004-07-27

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CN1910184A true CN1910184A (en) 2007-02-07

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