CN1910184A - The preparation method of Wiracerovo hydrochloride - Google Patents

Abstract

The present invention provides HPLC methods for analysis of BOC-L-alanine in BOC-L-valine and for analysis of alanine analogues in williamivo hydrochloride, as well as uses thereof and methods for selecting williamivo compositions.

Description

The preparation method of Wiracerovo hydrochloride

Cross-references to related applications

This application claims the benefit of US Provisional Application No. 60/538,362, filed January 21, 2004, and US Provisional Application No. 60/591,707, filed July 27, 2004, the disclosures of which are hereby incorporated as Whole citation.

field of invention

The present invention relates to a process for the synthesis of valacyclovir hydrochloride compositions containing low concentrations of alanine analogues from the starting material BOC-L-valine, which starting material It contains low concentration of BOC-alanine detected by liquid-solid chromatography method.

background of the invention

Valacyclovir (formula I) is a valyl ester prodrug of acyclovir (a natural nucleoside acyclic analog, formula II). Acerovo is reported to have high antiviral activity and is widely used in the treatment and prevention of human viral infections, especially those caused by herpes viruses. See Goodman and Gilman, "The Pharmacological Basis of Therapeutics" (Goodman and Gilman: The Pharmacological Basis of Therapeutics. 1193-1198, 9th ed., 1996).

Formula I

Formula II

Veraserovo hydrochloride can be synthesized from valine bearing an amine protecting group such as t-butoxycarbonyl (t-BOC). For example, US Patent Application No. 20030153757 discloses a method for synthesizing Veraserovo hydrochloride using an amine-protected valine as a starting material. As a useful starting material for the synthesis of Veraserovo, BOC-L-valine may contain impurities such as BOC-alanine. The presence of such impurities in starting materials is undesirable since the final synthetic product obtained from such starting materials would be contaminated with the alanine analogue of Villaserovo.

These impurities can be detected and quantified by high performance liquid chromatography (HPLC).

Overview of the invention

In one aspect, the present invention provides a method to use BOC-L-valine containing less than 0.2area-% BOC-L-alanine as a starting material to synthesize analogs containing less than 0.2area-% alanine A method for the composition of vilacerovo hydrochloride. Preferably, the starting material used contains less than 1 area-% of BOC-L-alanine and the synthesized composition of veracerovo hydrochloride contains less than 1 area-% of alanine. More preferably, the starting material used contains less than 0.05 area-% of BOC-L-alanine, while the synthesized vilacerovo hydrochloride composition contains only undetectable amounts of alanine derivatives.

On the other hand, the present invention also provides a liquid-solid chromatographic method to detect the BOC-alanine concentration in BOC-L-valine, and the alanine in the crude product and final product of vilaserovo hydrochloride is similar concentration of the substance, as well as crystalline wiracerovo hydrochloride.

Detailed description of the invention

As used herein, "gradient elution" means that the composition of the gradient eluent is gradually changed within a fixed period of time, or at a constant rate of change, such as the percentage concentration of the first eluent decreases, The concentration of the second eluent increases.

As used herein, "gradient eluent" refers to an eluent consisting of various concentrations of the first and second eluents.

"Sample" as used herein refers to a small or aliquoted sample taken from a large amount, or from a batch of BOC-L-valine or vilacerovo hydrochloride, for which analysis to assess the characteristics of large samples or a batch of samples.

"Batch" as used herein refers to the number of samples taken in relation to a certain amount of BOC-L-valine or vilacerovo hydrochloride. A batch is a quantity resulting from a process or from an operation. The size of this number depends on the equipment used like everything else.

The term "solid oral dosage form" as used herein refers to capsules and tablets.

The term "dry ingredient" as used herein refers to a mixture of vilacerovo hydrochloride and at least one excipient.

The term "detectable" as used herein refers to the amount that can be detected by the HPLC method with a detection accuracy of 0.01 area-%.

In connection with the amount of alanine analogues in vilacerovo hydrochloride, the word "undetectable" used here means that it cannot be detected by the HPLC method with a detection accuracy of 0.01area-%. amount.

As used herein, the term "alanine analogs" includes Velaserovo-like molecules wherein the moiety bound to the hydroxyethoxymethyl group is alanine instead of valine.

As used herein, the term "about" in relation to the quantity measured refers to the variation in the quantity expected by a skilled person performing the test at a level commensurate with the purpose of the test and with the precision of the instrument used. magnitude.

The term "area-%" used here is a metaphor for the "area under the peak" (hereinafter referred to as "AUP") obtained by analyzing each test performed by the tester, such as in liquid-solid chromatography analysis A chromatographic method. AUP can be calculated using a suitable integrator. Each peak in the chromatogram corresponds to a different component in the mixture loaded on the liquid-solid chromatographic column, and the proportion of the AUP of each detectable component in the total AUP of all components in the sample is the area percentage . The mathematical expression of the area percentage is as follows:

Area i-%＝100(AUPi)/(∑All AUPs)

The Veraserovo Hydrochloride composition consists essentially of Veraserovo Hydrochloride.

Veraserovo hydrochloride can be prepared using BOC-L-valine as a starting material by the method of US Publication No. 2003/0153757 incorporated herein by reference. BOC-L-Valine can be contaminated with BOC-Alanine. The amount of alanine analogues present in the intermediate crude product and in the crystallized final product can be estimated by starting with a lower level of BOC-alanine, especially a lower level of BOC-L-alanine. control. The level of BOC-alanine can be detected by liquid-solid chromatography.

Liquid-solid chromatography methods, especially high pressure liquid chromatography, also called high performance liquid chromatography (hereinafter "HPLC"), are used to detect and quantify impurities in a chemical compound. In HPLC, the components to be separated and measured, usually called analytes, are dissolved in a diluent (solvent), which can be the eluent, or the mobile liquid phase that flows through the column. This mobile liquid phase interacts with dissolved analytes in the packing (often denoted solid phase) in the column. Because different analytes interact differently with the solid phase, each analyte passes through the column at a different rate. See 13 James D. Winefordner, Treatise on Analytical Chemistry, pt. I (2d ed. 1993).

Reverse-phase HPLC utilizes a non-polar solid phase and a polar eluent. Gradient elution improves the separation of sample components by changing the composition of the mobile phase or the composition of the gradient eluent throughout. An indicator is used to monitor the separation by measuring a specific physical property of the eluent. For example, a spectrophotometer to measure the radioactive absorbance of the mobile phase can be used as an indicator.

Applicants have found that, like other things, the concentration of alanine analogs in the final product of vilacerovo or vilacerovo hydrochloride can be controlled by controlling the amount of BOC-alanine in the starting material BOC-L-valine. Amino acid concentration is controlled. There is a need for methods to detect alanine analogues in starting materials, intermediates and final veraserovo hydrochloride synthesis products. It is also necessary to make the final product of vilacerovo hydrochloride contain only alanine analogues as little as possible.

As a specific embodiment, the present invention provides a liquid-solid chromatographic method to detect the concentration of BOC-alanine in BOC-L-valine. The concentration of BOC-alanine contamination in BOC-L-valine can be detected by liquid-solid chromatography, especially by HPLC, especially by the HPLC method described herein below. The HPLC method uses a suitable chromatographic column, such as a reversed-phase chromatographic column Inertsil ODS-3V 5 μm 150×4.6 mm (GL Sciences, Cat. No. 5020-01731).

The first step of the HPLC method for determining the amount of BOC-L-alanine in BOC-L-valine in the present invention comprises loading BOC-L-valine on a liquid-solid chromatographic column. It is more efficient to inject the sample solution into the column by injection. A suitable volume to inject onto the column is 50 µL. The diluent used to make the solution of the sample injectable can be, for example, an eluent. The column can be placed at room temperature, preferably about 25°C. The solid phase in the chromatographic column can be modified, preferably 5 μm silica gel, spherical octadecyl silica gel, capped with 15% carbon filler, preferably InertsilODS-3V. After loading the sample onto the chromatographic column, the chromatographic column is eluted isocratically with the eluent. Preferred eluents are acetonitrile (27%) and water (73%) containing 0.05% phosphoric acid (0.5 g, 85% H ₃ PO ₄ /1 L H ₂ O), with a constant flow rate not greater than 1 mL/min. Monitor the response of the UV detector to the effluent in the chromatographic column, where the UV detector can be a spectrophotometer with a control range of 200-600nm, preferably 210nm. The amount of BOC-alanine in BOC-L-valine was calculated from the detector response to the eluted components and expressed as "area-%".

The suitability of the HPLC system was tested with a system suitability solution consisting of a mixture of BOC-alanine (0.15 mg/mL) and BOC-L-valine (15 mg/mL) diluents.

In another embodiment, the invention provides a liquid-solid chromatographic method for detecting the amount of alanine analogues present in a sample of wiracerovo hydrochloride. The concentration of the alanine analog can be determined by liquid-solid chromatography methods, especially by HPLC. A suitable chromatographic column for this determination is the reversed-phase column Inertsil ODS-3V 5 μm, or a chromatographic column with the same function. Preferably, the method uses gradient elution. This approach allows for more efficient separation of sample components.

The first step of the HPLC method for determining the amount of alanine analogues in the vilacerovo hydrochloride sample in the present invention is to load the vilacerovo hydrochloride sample onto a liquid-solid chromatographic column. It is more efficient to inject the sample solution into the column by injection. When using the injection method to pack the column, the injected volume is about 20 μL. In addition, the diluent used to prepare the sample solution for injection can be, for example, the same first eluent. The column temperature can be higher than room temperature. The preferred column temperature is about 30°C. The solid phase in the chromatographic column can be modified, preferably 5 μm silica gel, spherical octadecyl silica gel, end-capped with 15% carbon filler, preferably Inertsil ODS-3V 1. Then perform gradient elution on the chromatographic column, and the flow rate of the gradient eluent should not exceed 1.5mL/min, so that the gradient elution contains the first and second eluents.

Suitable first eluents are 0.01 M potassium dihydrogen phosphate in water (98%) and acetonitrile (2%). The pH of the first eluent is acidic, preferably about 3.5. The pH can be adjusted with 10% phosphoric acid. A suitable second eluent is acetonitrile. A generally suitable equilibration time is about 7 minutes. The reaction of the UV detector to the effluent from the chromatographic column is monitored, where the UV detector can be a spectrophotometer with a manipulation range of 200-600 nm, preferably 245 nm. Based on the response of the detector, the amount of alanine analogues in wiracerovo hydrochloride was calculated and expressed as "area-%".

A systemic suitability solution can be prepared by dissolving Veraserovo in a guanine solution and a solution of Acerovo. The concentration of the sample solution can be 0.8 mg/mL Vilaserovo diluted with diluent. The sample solution can be injected onto the chromatographic column and the concentration of any impurities can then be determined by measuring the area-% of the various components in the mixture with a suitable integrator.

Another embodiment of the present invention is to provide a method for synthesizing a composition of wiracerovo hydrochloride, which contains a certain amount of alanine analogues, the content of which is less than 0.2area-% but more than less than or equal to 0.1area-%, this method includes the following steps:

a) Obtain one or more BOC-L-valine samples of one or more batches;

b) determining the BOC-L-alanine level in each sample in step (a);

c) Select one or more batches of BOC-L-valine samples, the amount of BOC-L-alanine contained in these samples will be less than 0.2area-% through the detection of step (b) ;as well as

d) Synthesizing said Veraserovo hydrochloride composition with the samples of the batch selected in step (c).

Preferably, the BOC-L-valine sample and the resulting vilacerovo hydrochloride contain less than about 0.1 area-% of both BOC-L-alanine and alanine analogues, respectively. Most preferably, when the BOC-L-valine sample contains less than 0.05 area-% of BOC-L-alanine, there is no detectable amount of alanine in the wiracerovo hydrochloride composition acid.

The amount of BOC-L-alanine in the BOC-L-valine sample is detected by the above-mentioned liquid-solid chromatography method or an equivalent method.

In particular, the present invention provides a method for synthesizing a composition of vilacerovo hydrochloride containing alanine analogues in an amount of less than 0.2 area-%. The first step in this synthetic method is to analyze a BOC-L-valine sample from a batch or batches containing alanine analogues present only as impurities, and pick a batch The second sample, it contains the amount of alanine analogues is less than 0.2area-%. Selected samples of BOC-L-valine are reacted with Acerovo in an organic solvent to obtain a mixture, preferably dicyclohexylcarbonyldiimide (hereinafter referred to as "DCC ") in dimethylformamide (hereinafter referred to as "DMF") solution. This mixture was then combined with 4-dimethylaminopyridine (hereinafter referred to as "DMAP"), followed by the addition of water to obtain a suspension. Precipitated dicyclohexylurea was removed by filtration, and the resulting filtrate was concentrated. The filtrate is then regenerated, or dissolved, in refluxing lower alcohols, especially isopropanol, to obtain protected wilaserovo. This product can be deprotected and recrystallized from water and isopropanol to give crystalline wiracerovo hydrochloride. The synthesis of wiraserovo hydrochloride can be done in different scales and the weight to volume ratios provided are applicable to all reactants.

The wiraserovo hydrochloride obtained by the method of the present invention can be formulated into pharmaceutical components. In addition to the active ingredient, the pharmaceutical formulations of the invention can, and typically do, contain one or more excipients. Typical pharmaceutical compositions are batch formulated and made into solid oral dosage forms such as tablets and capsules. The solid oral dosage form offered for commercial sale may be a dry ingredient or a solid oral dosage form depending on the content of the alanine analogue in vilacerovo hydrochloride.

Excipients are added to the formulation for various purposes. The diluent increases the total amount of the solid pharmaceutical component, which can make the pharmaceutical dosage form containing this component easy to be taken by the patient, and convenient to transport and handle. Diluents for solid components include microcrystalline cellulose (such as Avicel(R), microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sucrose, dextran, dextrin, dextrose , dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g. Eudragit®), potassium chloride, fibers Vegetarian powder, sodium chloride, sorbitol and talc, to name just a few.

Solid pharmaceutical compositions that are formulated into dosage forms, such as tablets, may include excipients whose functions include helping to bind the active ingredient and other excipients together during the compression process. Binders for solid pharmaceutical compositions include gum arabic, alginic acid, methyl esters (such as carbopol), sodium carboxymethylcellulose, dextrin, ethylcellulose, gelatin, gums, hydrogenated rapeseed oil, hydroxyethylcellulose Hydroxypropylcellulose (eg Klucel®), hydroxypropylmethylcellulose (eg Methocel®), liquid dextrose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylate, povidone (eg Kollidon(R), Plasdone(R), pregelatinized starch, sodium alginate and starch.

In order to control the quality, it is better to prepare the pharmaceutical composition with vilacerovo hydrochloride containing a small amount of alanine. Typically pharmaceutical compositions are prepared in batches, or mass-produced. Production batches shall be checked to ensure that the content of alanine analogues does not exceed the range specified for quality control testing. A sample (eg 10-100 capsules or tablets) of the mass-produced product is analyzed for the presence of the alanine analog and, preferably, for the same. In general, all bulk products, excluding reserved samples, will be sold, or shipped by the manufacturer, unless excessive levels of alanine analogues are found. In this case, batch products cannot be sold or distributed, that is, they cannot be used for commercial purposes or for clinical research. The same strategy can also be applied to the mass-produced vilacerovo hydrochloride substrate.

The following non-limiting examples illustrate some examples of the invention.

Example 1

This example illustrates a liquid-solid chromatographic method for the detection of BOC-alanine concentration in BOC-L-valine.

A solution for testing system suitability was prepared with dilutions of 0.15 mg/mL BOC-alanine and 15 mg/mL BOC-L-valine. The diluent used was the same as the eluent, consisting of 73% of 0.05% phosphoric acid in water and 27% of acetonitrile. A 50 μL sample was loaded onto an Inertsil ODS-3V 5 μm 150×4.6mm chromatographic column at 25°C. The detector was set at 210 nm, and the sample was eluted at a flow rate of 1 mL/min. The retention times of BOC-alanine and BOC-L-valine were 6 minutes and 14.5 minutes, respectively. AUPs are then compared using a suitable integrator to determine the BOC-alanine area-% concentration in BOC-L-valine.

Example 2

This example illustrates a liquid-solid chromatographic method for the detection of BOC-alanine concentration in BOC-L-valine.

Prepare a system suitability test solution by dissolving 5 mg of guanine in 10 mL of 0.2N NaOH. This solution was then further diluted to 100 mL with 98% aqueous 0.01 M potassium dihydrogen phosphate (adjusted to pH 3.5 with 10% phosphoric acid and 2% acetonitrile). Then dilute 5mg of Acerovo with diluent to a total of 100mL to make the second solution. 2 mL of each of these two solutions was added to 20 mg of Wiracerovo hydrochloride. Bring the total volume of the wiracerovo hydrochloride solution to 25 mL with the diluent. This dilution also served as the first eluent for the HPLC analysis. The second eluent is acetonitrile. Inject 20 μL of the mixture of veraserovo hydrochloride, guanine and acerovo onto an Inertsil ODS-3V 5 μm 250 × 4.6 mm chromatographic column. The chromatographic column was eluted with a gradient of 0-20% of the second eluent for 32 minutes at a flow rate of 1.5 mL/min and a temperature of 30°C. The integrator was set at 254nm. The retention time of Wiracerovo hydrochloride is 13 minutes. The transformation between guanine and acerovo can be obtained not less than 15.0, and the tail factor is not more than 4.0.

Example 3a

This example describes a method for the synthesis of protected vilacerovo hydrochloride containing no less than about 1.4 area-% alanine analogs.

BOC-L-valine (870 g) containing less than 1 area-% BOC-alanine was fully dissolved in 5874 mL of dimethylformamide (DMF) under nitrogen while stirring. The mixture was then cooled to -5°C. A solution of dicyclohexylcarbodiimide (DCC) (360 g) in DMF (600 g) was added to this mixture over 20 minutes, and the resulting mixture was stirred at -5°C for 20 minutes. 600 g of Acerovo were added to this mixture and after stirring for 5 minutes 98 g of DMAP were added. The mixture was stirred at -5°C for 3 hours. A solution of DCC (330 g) in DMF (600 g) was added over 20 minutes. The mixture was stirred at -5°C for 3 hours. A solution of DCC (438 g) in DMF (780 g) was added over 20 minutes and the resulting mixture was stirred at -5°C for 3 hours. The mixture was heated to 25°C over 2.5 hours and stirred for 4 hours. 204 g of water were added, and the mixture was stirred at 25°C for 4 hours. The resulting precipitate, dicyclohexylurea, was recovered by filtration and washed with 1800 g of DMF. The filtrate was then concentrated under reduced pressure (10 mmHg) to obtain a residue. This residue was dissolved in 6120 g of isopropanol (hereinafter referred to as IPA) under reflux. The mixture was allowed to cool to 25°C and the resulting precipitate - protected Wilaserovo - was recovered by filtration.

Example 3b

This example describes a method for the deprotection of vilaserovo hydrochloride that was protected during the synthesis of vilaserovo hydrochloride containing less than 1.4 area-% of alanine analogues.

578 g dry weight of protected Wiraserovo was dissolved in 1440 mL formic acid at 25°C. 186 mL of water was added, followed by 311 g of 32% hydrochloric acid within 1 hour. The mixture was stirred at 25°C for 1-5 hours until the concentration of protected wilaserovo decreased below 0.5%. To this mixture was added 9200 mL of isopropanol over 30 minutes, and the mixture was cooled to -5°C. The resulting precipitate was recovered by filtration to obtain a crude product of wiracerovo hydrochloride containing less than 1.4 area-% of alanine analogs.

Example 3c

This example describes the formation of crystals of wiracerovo hydrochloride containing less than 1.4 area-% of alanine analogues.

380 g of crude product of vilacerovo hydrochloride was dissolved in 1520 mL of water at 40°C. The mixture was filtered and cooled to 35°C. To this mixture was added 5700 mL of isopropanol over 3 hours. The mixture was cooled to -5°C. The resulting precipitate, crystalline veraserovo hydrochloride, was recovered by filtration. The wet precipitate was vacuum dried, and the dried precipitate was milled. Crystalline vilacerovo hydrochloride contains less than 1.4 area-% of alanine analogues.

Example 4a

This example describes the generation of protected vilacerovo in the synthesis of vilaserovo hydrochloride containing less than 0.03 area-% alanine analogs.

Dissolve 870g of BOC-L-valine containing less than 0.05% BOC-alanine in 5874mL of DMF under nitrogen, and stir at 20-25°C until fully dissolved. The mixture was then cooled to -5°C. To this mixture was added a solution of DCC (330 g) in DMF (600 g) over 20 minutes, and the resulting mixture was stirred at -5°C for 20 minutes. Add 600g of Acerovo to this mixture, stir for 5 minutes before adding 98g of DMAP. The mixture was stirred at -5°C for 3 hours. To this mixture was added a solution of DCC (330 g) in DMF (600 g) over 20 minutes, and the resulting mixture was stirred at -5°C for 3 hours. To this mixture was added a solution of DCC (438 g) in DMF (780 g) over 20 minutes, and the resulting mixture was stirred at -5°C for 3 hours. The mixture was heated to 25°C over 2.5 hours and stirred for 4 hours. 240 g of water were added, and the mixture was stirred at 25°C for 4 hours. The precipitate generated, i.e. dicyclohexyl urea, is recovered by filtration and washed with 1800g DMF. Then the filtrate was concentrated under reduced pressure (10 mmHg) to obtain silkworm dregs. These residues were dissolved in 6120 g of isopropanol at reflux. The mixture was cooled to 25° C., and the resulting precipitate, protected Wilaserovo, was recovered by filtration.

Example 4b

This example describes the production of crude vilaserovo hydrochloride in the synthesis of vilaserovo hydrochloride containing less than 0.03 area-% alanine analogs.

578 g of protected Wiracerovo obtained by the method described in Example 4a on a dry basis was dissolved in 1440 mL of formic acid at 25°C. To this mixture was added 186 mL of water, followed by the addition of 311 g of 32% hydrochloric acid solution within 1 hour. The mixture was stirred at 25°C for 1-5 hours until the concentration of the protected wilaserovo decreased below 0.5%. To this mixture was added 9200 mL of isopropanol over 30 minutes, and then the mixture was cooled to -5°C. The resulting precipitate was recovered by filtration, that is, the crude product of Veraserovo hydrochloride containing less than about 0.03 area-% alanine analogs.

Example 4c

This example describes the formation of crystals of wiracerovo hydrochloride containing less than about 0.03 area-% alanine analogs.

Dissolve 380 g of crude vilacerovo hydrochloride in 1520 mL of water at 40°C. The mixture was filtered and cooled to 35 °C. To this mixture was added 5700 mL of isopropanol over 3 hours. The mixture was then cooled to -5°C. The resulting precipitate is recovered by filtration, which is crystalline Wiracerovo hydrochloride. The wet precipitate was dried in vacuo and the dried precipitate was milled to produce crystalline vilacerovo hydrochloride free of detectable alanine analogues.

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.