CN102746284A - Preparation method for lamivudine - Google Patents
Preparation method for lamivudine Download PDFInfo
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- CN102746284A CN102746284A CN2012102319455A CN201210231945A CN102746284A CN 102746284 A CN102746284 A CN 102746284A CN 2012102319455 A CN2012102319455 A CN 2012102319455A CN 201210231945 A CN201210231945 A CN 201210231945A CN 102746284 A CN102746284 A CN 102746284A
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Abstract
The invention provides a preparation method for lamivudine. The method is as follows: the intermediate of lamivudine 5S-cytosine-1'-yl-1,3-oxathiacyclopentane-2-carboxylic acid-(1'R,2'S,5'R) menthyl ester (abbreviated as CME) is subjected to hydrolysis and refining for oriented synthesis of lamivudine impurity A; the structure of the lamivudine impurity A is verified by using 1H NMR and MS, and relative retention time of the impurity and lamivudine is verified by using high performance liquid chromatography (HPLC); and quality control is carried out on the synthetic route of lamivudine, i.e., conditions for hydrolysis of CME are controlled so as to obtain a finished product of lamivudine containing less than 0.3% of the impurity A.
Description
Technical field
(promptly the method for (2R, 5S)-4-amino-1-(2-methylol-1,3-oxygen thia ring penta-5-yl)-1H-pyrimid-2-one) more particularly, relates to the preparation method of the low lamivudine of the sour foreign matter content of lamivudine to the present invention relates to synthetic lamivudine.This method is prepared the high-quality lamivudine product that meets the British Pharmacopoeia requirement through the control to lamivudine synthesis technique and raw materials quality.
Background technology
The structural formula of lamivudine (lamivudine) is:
Chemical being called (2R, 5S)-4-amino-1-(2-methylol-1,3-oxygen thia ring penta-5-yl)-1H-pyrimid-2-one, be a kind of new ucleosides antiviral drug, be applicable to chronic hepatitis B.Lamivudine can suppress hbv replication rapidly, and its restraining effect continues in whole therapeutic process.
Document about lamivudine is a lot, mainly concentrates on synthetic route and isomer fractionation aspect.For example, the patented claim that relates to the lamivudine synthetic route has CN201010141026.X, CN201010158830.9, CN20101018710524; Relate to the patented claim that the lamivudine chirality prepares the aspect and CN200810212154.1 is arranged, CN200810212154.1, CN200910043203.8; The Control of Impurities aspect that relates to lamivudine; Being defined as in the USP34 lamivudine quality standard of latest edition: relative retention time is that 0.4 loi is 0.3%; Relative retention time is that 0.9 loi is 0.2%, and other single loi are 0.1%.Impurity to relative retention time 0.9 is explained, and the impurity of relative retention time 0.4 is not had special argumentation and prescribed limit; Though 2012 editions lamivudines of British Pharmacopoeia are illustrated the impurity that possibly contain in the lamivudine; But in standard, be that 0.36 and 0.91 impurity has carried out limit handling to relative retention time only, be respectively 0.3% and 0.2% of principal constituent contrast solution with Self-control method.
The quality standard of BP2012 lamivudine (British Pharmacopoeia Volume I&II, Lamivudine (Ph. Eur.monograph 2217;
Liquid chromatography (2.2.29)In point out to contain in the lamivudine product impurity A promptly (2R, 5S)-5-(4-amino-2-ketone pyrimidine-1 (2H)-yl)-1,3-oxygen thia penta ring-2-carboxylic acid (be called for short: lamivudine is sour).
In the prior art, through with hexamethyldisilazane, cytosine(Cyt) and (2R, 5S)-((1R; 2S, 5R)-2-sec.-propyl-5-methylcyclohexyl) 5-acetoxyl group-1,3-oxygen thia penta ring-2-manthanoate reacts in solvent; Obtain 5S-cytosine(Cyt)-1 '-Ji-1,3-oxathiolane-2-carboxylic acid-(1 ' R, 2 ' S; 5 ' R) menthyl ester with phosphoric acid salt, Peng Qinghuana reaction, obtains said lamivudine crude product then.
Usually contain impurity A [i.e. (2R in the prior art in the synthetic lamivudine crude product; 5S)-5-(4-amino-2-ketone pyrimidine-1 (2H)-yl)-1; 3-oxygen thia penta ring-2-carboxylic acid (be called for short: lamivudine acid)], this impurity is difficult to remove from product through separation or method of purification (for example passing through recrystallization method).Therefore the content of controlling impurity A in the lamivudine crude product becomes a present difficult problem.
Summary of the invention
The present invention provides a kind of impurity A [i.e. (2R that in the building-up process of lamivudine product, monitors fast, simply, exactly; 5S)-5-(4-amino-2-ketone pyrimidine-1 (2H)-yl)-1; 3-oxygen thia penta ring-2-carboxylic acid (be called for short: lamivudine acid)] the external standard method of content, this method can be utilized the HPLC stratographic analysis to come accurate location and calculate the content of impurity A in the lamivudine product.The present invention also utilize this methods analyst in each step of the whole process of synthetic lamivudine Selection of technological conditions for the influence of impurity A content; And find that the lamivudine impurity A is mainly derived from lamivudine midbody 5S-cytosine(Cyt)-1 '-Ji-1; 3-oxathiolane-2-carboxylic acid-(1 ' R; 2 ' S, 5 ' R) reduction step of menthyl ester (being called for short CME), the reaction conditions of therefore controlling this step becomes the key of control impurity A content.Sodium hydroxide in this reduction step (or potassium) is the crucial controlling factor that in this step reaction, influences the lamivudine quality with ratio, temperature of reaction, the reaction solution pH value of Peng Qinghuana (or potassium).Specifically, preferably, Peng Qinghuana (or potassium): sodium hydroxide (or potassium)=30:1～60:1; Temperature of reaction is controlled at 5～15 ℃; Reaction solution pH value 8～10; Further preferred, the reaction times should be less than 20 hours, more preferably at 10-20 hour, further preferably at 12-16 hour.
The present invention has synthesized the lamivudine impurity A through lamivudine midbody one step orientation first, and through recrystallization, purity reaches more than 98%, and finishes the structure conclusive evidence and confirm to have obtained impurity A; Use the HPLC stratographic analysis to locate impurity A and the content that calculates impurity A then, solved and used relative retention time that impurity is located inaccurate problem in the existing method separately; And through committed step in the synthetic lamivudine technology is controlled, the amount of lamivudine impurity A is less than 0.3% in the control lamivudine finished product.
According to the first embodiment of the present invention; The present invention provides with 5S-cytosine(Cyt)-1 '-Ji-1,3-oxathiolane-2-carboxylic acid-(1 ' R, 2 ' S; 5 ' R) menthyl ester (being called for short CME) is the method for the synthetic lamivudine product of raw material, and this method may further comprise the steps:
A) the cooling under (for example using ice-water bath) at 5S-cytosine(Cyt)-1 '-Ji-1 by 100 weight parts; 3-oxathiolane-2-carboxylic acid-(1 ' R; 2 ' S; 5 ' R) drips Peng Qinghuana (or potassium)-sodium hydroxide (or potassium) aqueous solution lentamente in the aqueous solution that menthyl ester (being called for short CME) forms as reductive agent in water; Keep after being added dropwise to complete temperature of reaction under 5 ℃～15 ℃ conditions, under agitation to carry out reduction reaction 10-20 hour and obtain to contain lamivudine mixture of products, wherein Peng Qinghuana (or potassium) in Peng Qinghuana (or potassium)-sodium hydroxide (or potassium) aqueous solution: sodium hydroxide (or potassium) mol ratio=30:1～60:1;
B) for steps A) in the lamivudine mixture of products that contains that obtains separate and purify acquisition lamivudine product.
Randomly, aforesaid method is further comprising the steps of:
C) analyze impurity A in the gained lamivudine product [promptly (and 2R, 5S)-5-(4-amino-2-ketone pyrimidine-1 (2H)-yl)-1,3-oxygen thia penta ring-2-carboxylic acid (abbreviation: lamivudine is sour)] content.This analyzes the preferred HPLC that adopts.According to the purity (or impurity A content) of products therefrom determine whether further to purify (for example recrystallization).
Preferably, at step B) in separation comprise that extraction removes organic phase, remaining water carries out underpressure distillation and obtains oily matter, at step B) in purification comprise that gained oily matter obtains white crystalline solid lamivudine product with the Virahol recrystallization.
Preferably, above-described Peng Qinghuana (or potassium): sodium hydroxide (or potassium) mol ratio=35:1～55, more preferably 37:1-50:1, further preferred 38:1-48:1, more preferably=40:1～46:1, most preferably 42:1-46:1.Preferably 12-18 hour above-described reduction reaction time, more preferably 14-16 hour, most preferably 15 hours.
Preferably, with respect to the CME of 100 weight parts, the consumption of Peng Qinghuana (or potassium) (calculating by Peng Qinghuana or POTASSIUM BOROHYDRIDE 97MIN solid) is the 10-30 weight part, is more preferably the 15-25 weight part, further preferred 18-22 weight part, preferred especially 20 weight parts.
Preferably, the pH value remains between the pH 8-pH 10 in the process of carrying out reduction reaction, preferably remains between the pH8.5-9.5, particularly preferably in about pH9.To 5S-cytosine(Cyt)-1 '-Ji-1; 3-oxathiolane-2-carboxylic acid-(1 ' R; 2 ' S, 5 ' R) drips in the aqueous solution of menthyl ester (being called for short CME) before the reductive agent through in this CME aqueous solution, adding buffer reagent (for example phosphoric acid salt, like potassium hydrogenphosphate) and form the buffered CME aqueous solution; To guarantee that reduction reaction carries out in above-described pH value scope, promptly the consumption sufficient to guarantee of buffer reagent in reduction reaction the pH value in above-mentioned scope.Certainly; If be not pre-formed the buffered CME aqueous solution; But in the process that drips reductive agent or after being added dropwise to complete, carrying out in the reduction reaction process, interpolation buffer reagent or interpolation acid or alkali are regulated pH and in the above scope, are also fallen within the invention which is intended to be protected.
Second embodiment according to the present invention; The present invention provides and analyzes [i.e. (the 2R of impurity A in the gained lamivudine product; 5S)-5-(4-amino-2-ketone pyrimidine-1 (2H)-yl)-1,3-oxygen thia penta ring-2-carboxylic acid (be called for short: lamivudine acid)] the method for content, this method may further comprise the steps:
S1, with 5S-cytosine(Cyt)-1 '-Ji-1; 3-oxathiolane-2-carboxylic acid-(1 ' R, 2 ' S, 5 ' R) menthyl ester (being called for short CME) is a raw material; The synthetic impurity A that obtains of one one-step hydrolysis; Said impurity A be (2R, 5S)-5-(4-amino-2-ketone pyrimidine-1 (2H)-yl)-1,3-oxygen thia penta ring-2-carboxylic acid (be called for short: lamivudine acid);
Randomly, the lamivudine impurity A that step S1 is obtained carries out
1HNMR and MS structural identification, purity reaches more than 98%;
S2, the lamivudine impurity A that step S1 is obtained position through HPLC (HPLC), and this impurity A is 0.36～0.45 with lamivudine main peak relative retention time under the chromatographic condition (5:95) at methyl alcohol-0.025mol/L Spirit of Mindererus (PH3.9 ± 0.1);
S3, with 5S-cytosine(Cyt)-1 '-Ji-1,3-oxathiolane-2-carboxylic acid-(1 ' R, 2 ' S, 5 ' R) menthyl ester (be called for short CME) be a raw material, synthesizes to obtain the lamivudine product;
S4, the lamivudine acid that obtains with step S1 then are reference substance; Carry out the performance liquid chromatography test for the lamivudine product that obtains among the above S3 or according to the lamivudine crude product that aforesaid method obtained of first embodiment, calculate the content of impurity A in the lamivudine product according to external standard method.
Preferably, step S1 carries out as follows: CME, sodium hydroxide are reacted in solvent, and obtaining the lamivudine impurity A through extracting and separating acquisition water, acid precipitation, suction filtration, recrystallization is white crystalline powder.
Preferably, above step S3 is or comprises the aforesaid method according to first embodiment.
External standard method described here is meant that the ratio according to the peak area sum at the peak area at the peak of impurity A and this impurity peaks and product peak calculates the content of impurity A.
In this application " optional () " represent to be with or without.
Here; Peng Qinghuana (or potassium): sodium hydroxide (or potassium) and Peng Qinghuana or potassium: sodium hydroxide or potassium have identical meaning, promptly comprise following several kinds of situation: Peng Qinghuana: sodium hydroxide, Peng Qinghuana: Pottasium Hydroxide; POTASSIUM BOROHYDRIDE 97MIN: sodium hydroxide, and POTASSIUM BOROHYDRIDE 97MIN: Pottasium Hydroxide.
The method of synthetic lamivudine product is carried out according to following reaction process:
This method belongs to prior art; But the present inventor is in order to control the quality of lamivudine better; Critical process point in this reaction is controlled in step, the relatively variation of impurity A amount in the finished product under the different condition, thereby for the lamivudine raw material quality control standard foundation is provided.
According to USP34 lamivudine bulk drug standard with methyl alcohol-0.025mol/L Spirit of Mindererus (PH3.9 ± 0.1) (5:95) under the chromatographic condition relative retention time of lamivudine impurity A be 0.40, and according to BP2012 lamivudine bulk drug standard with methyl alcohol-0.025mol/L Spirit of Mindererus (PH3.9 ± 0.1) (10:90) under the chromatographic condition relative retention time of lamivudine impurity A be 0.36; Therefore the variation of factors such as moving phase, chromatographic column is very big to the relative retention time influence of lamivudine impurity A.
Our orientation has been synthesized the lamivudine impurity A; Carried out structural identification; The lamivudine impurity A has been carried out positioning analysis (shown in reference implementation example 2); And, adopt external standard method (be the peak area contrast: the peak area at the peak of impurity A and impurity and product be the ratio of the peak area sum at peak separately) to calculate the amount (shown in reference implementation example 2) of lamivudine impurity A to the lamivudine impurity A, thereby effectively the lamivudine final product quality is controlled according to USP34 standard-required chromatographic condition.In above-described method generally with product in impurity A content control to and be lower than 0.3wt%, preferably be lower than 0.25wt%, more preferably less than 0.20wt%, further preferably be lower than 0.15wt%, further preferably be lower than 0.10wt% again, especially preferably be lower than 0.05wt%.
Through above argumentation, can confirm that the lamivudine impurity A is mainly derived from lamivudine midbody 5S-cytosine(Cyt)-1 '-Ji-1,3-oxathiolane-2-carboxylic acid-(1 ' R, 2 ' S, 5 ' R) menthyl ester (being called for short CME) reduction step.The ratio of sodium hydroxide and Peng Qinghuana, temperature of reaction, reaction solution pH value are the CCPs that influences the lamivudine quality in this step reaction.Specifically, Peng Qinghuana: sodium hydroxide=30:1～60:1; Temperature of reaction is controlled at 5～15 ℃; Reaction solution pH value 8～10, the reaction times optimum was less than 20 hours.
Above lamivudine impurity A content assaying method adopts existing routine techniques HPLC method.
Description of drawings
Fig. 1 is an impurity A
1H NMR collection of illustrative plates (solvent: d6-DMSO, detected temperatures: room temperature, interior mark: TMS (TMS)).
Fig. 2 is the LC-MS collection of illustrative plates (liquid chromatographmass spectrometer of impurity A; Solvent: water, ionizer: electron spray(ES) (ESI)).
Fig. 3 is the chromatographic condition with reference to BP2012, advances the collection of illustrative plates that the lamivudine sample+lamivudine acid is obtained.
Fig. 4 is the chromatographic condition with reference to USP34, advances the collection of illustrative plates that the lamivudine sample+lamivudine acid is obtained.
Embodiment
Clearer for technical problem, technical scheme and beneficial effect that the present invention is solved, below in conjunction with embodiment, the present invention is further elaborated.Specific embodiment described herein is only in order to explaining the present invention, and is not used in qualification the present invention.
Reference implementation example 1:
The preparation of lamivudine impurity A
In the 250ml round-bottomed flask, add methanol-water solution (1:1) 100ml, add 25% aqueous sodium hydroxide solution 50ml, 5S-cytosine(Cyt)-1 '-Ji-1,3-oxathiolane-2-carboxylic acid-(1 ' R; 2 ' S, 5 ' R) menthyl ester (CME) 20g, stirring reaction 5h under 25 ℃ of conditions treats the solution clarification; Stopped reaction is used dichloromethane extraction, removes organic phase, collects water; Under 0～5 ℃ of agitation condition, regulate PH to 3～4 with dilute hydrochloric acid solution, stir about was separated out the pale solid, suction filtration after 20 minutes; Use water washing, dry back recrystallization obtains white crystalline powder lamivudine impurity A, that is: 4-amino-1-(2R; 5S)-and 2-(methylol-1,3-oxygen thia ring-5-yl) pyrimidine-2 (1H)-ketone (be called for short: lamivudine acid), HPLC purity>98%.Impurity A
1TMS (TMS)) and LC-MS collection of illustrative plates (liquid chromatographmass spectrometer H NMR collection of illustrative plates (solvent: d6-DMSO, detected temperatures: room temperature, interior mark:; Solvent: water, ionizer: electron spray(ES) (ESI)) respectively referring to Fig. 1 and Fig. 2.
Reference implementation example 2:
The study of pharmacy of lamivudine impurity A:
It is an amount of to take from system lamivudine impurity A and lamivudine sample; With reference to BP2012 and USP34 lamivudine related substance chromatographic condition, respectively with methyl alcohol-0.025mol/L Spirit of Mindererus (PH3.9 ± 0.1) (10:90), methyl alcohol-0.025mol/L Spirit of Mindererus (PH3.9 ± 0.1) (5:95) carries out the impurity positioning analysis under two kinds of chromatographic conditions.Chromatographic condition at BP2012; Practical measurement lamivudine impurity A relative retention time is 0.37; Practical measurement lamivudine impurity A relative retention time is 0.47 under the chromatographic condition of USP34; Lamivudine acid peak and lamivudine main peak separating size>2.0, lamivudine acid theoretical plate number>1000 (tables 1).
The positioning analysis of table 1 lamivudine impurity A
★: practical measurement lamivudine impurity A relative retention time
*: British Pharmacopoeia record lamivudine impurity A relative retention time
▲: USP record lamivudine impurity A relative retention time
Chromatographic condition 1: methyl alcohol-0.025mol/L Spirit of Mindererus (PH3.9 ± 0.1) (10:90)
Chromatographic condition 2: methyl alcohol-0.025mol/L Spirit of Mindererus (PH3.9 ± 0.1) (5:95)
Fig. 3 is the chromatographic condition with reference to BP2012, advances the collection of illustrative plates that the lamivudine sample+lamivudine acid is obtained, and Fig. 4 is the chromatographic condition with reference to USP34, advances the collection of illustrative plates that the lamivudine sample+lamivudine acid is obtained.
Embodiment 1:
The preparation of lamivudine:
In the 500mL flask, add potassium hydrogenphosphate 69g, water 70ml, be stirred to potassium hydrogenphosphate and dissolve entirely.Add ethanol 200ml, drop into CME50g while stirring.Take by weighing the 10g Peng Qinghuana, add 25% sodium hydroxide 1ml solution (Peng Qinghuana: sodium hydroxide mol ratio=42.27:1), add water and be stirred to complete dissolving.Slowly drip Peng Qinghuana-sodium hydroxide solution in the condition of ice bath downhill reaction bottle, about 30min of dropping time.
After dripping off, under pH value 8-10, keep continuing stirring reaction 20 hours under 15 ℃ of conditions of temperature.Standing demix discards the buck layer, and organic layer is cooled to about 15 ℃, drips dilute hydrochloric acid solution and transfers PH to 6.8～7.2.Remove etoh solvent under reduced pressure.Organic phase is removed in extraction, and it is oily matter that the water underpressure distillation obtains crude product, and impurity A content is 0.28wt% in the thick product, obtains white crystalline solid lamivudine (primary purification article) with the Virahol recrystallization, and impurity A content is 0.25wt%; Use the Virahol recrystallization once more, impurity A content reduces to 0.21wt% (highly finished product) (foreign matter content described here is measured with the method for following test example, but also can measure with other method).
Test example:
The mensuration of impurity A in the lamivudine:
(chromatographic column is Dimonsil C18 (5 μ, 200 * 4.6mm)) as weighting agent to use octadecylsilane chemically bonded silica; With methyl alcohol--0.025mol/L Spirit of Mindererus (pH 3.9 ± 0.1) is a moving phase (5:95), and the detection wavelength is 277nm.
It is an amount of to get the lamivudine highly finished product that obtain among the embodiment (for example embodiment 1), adds moving phase and processes the solution that contains lamivudine 250 μ g among every 1ml approximately, as need testing solution; It is an amount of that in addition precision takes by weighing the lamivudine impurity A, with moving phase process contain lamivudine acid 0.0.765 μ g among every 1ml approximately solution as the impurity contrast solution.
Precision is measured each 20 μ l of need testing solution and reference substance solution, injects liquid chromatograph respectively, 3 times of record color atlas to main peak RT, and in the need testing solution as show impurity peaks, lamivudine acid is measured the content of impurity A by external standard method.The product that impurity A content is lower than 0.18wt% is preferred product.
Comparative Examples 1-3 and embodiment 2 and 3
Impurity A distribution situation in the table 2 lamivudine product (percentage composition, wt%)
Data by table 1 can find out, the lamivudine impurity A is difficult to remove through the Virahol recrystallization, and through the optimization to this step process condition, can be in the lamivudine bullion amount of better controlled lamivudine impurity A.
Embodiment 4-6
Self-control lamivudine and the lamivudine standard substance got among the various embodiments of the present invention 4-6 are an amount of; With reference to USP34 lamivudine related substance chromatographic condition, (5:95) carrying out the related substance check under the chromatographic condition with methyl alcohol-0.025mol/L Spirit of Mindererus (PH3.9 ± 0.1).Measure the content of lamivudine impurity A in the self-control lamivudine product, wherein lamivudine acid peak and lamivudine main peak separating size>2.0, lamivudine acid theoretical plate number>1000.
Impurity A distribution situation in the table 3 lamivudine product (percentage composition, wt%)
Claims (10)
1. synthesize the method for lamivudine, this method may further comprise the steps:
A) the cooling under at 5S-cytosine(Cyt)-1 '-Ji-1 by 100 weight parts; 3-oxathiolane-2-carboxylic acid-(1 ' R; 2 ' S; 5 ' R) drips Peng Qinghuana or potassium-sodium hydroxide or aqueous solutions of potassium in the aqueous solution that menthyl ester forms lentamente as reductive agent in water; Keep after being added dropwise to complete temperature of reaction under 5 ℃～15 ℃ conditions, under agitation to carry out reduction reaction 10-20 hour and obtain to contain lamivudine mixture of products, wherein Peng Qinghuana (or potassium) in Peng Qinghuana (or potassium)-sodium hydroxide (or potassium) aqueous solution: sodium hydroxide (or potassium) mol ratio=30:1 ~ 60:1;
B) for steps A) in the lamivudine mixture of products that contains that obtains separate and purify acquisition lamivudine product: (2R, 5S)-4-amino-1-(2-methylol-1,3-oxygen thia ring penta-5-yl)-1H-pyrimid-2-one.
2. further may further comprise the steps according to the process of claim 1 wherein:
C) analyze in the gained lamivudine product impurity A promptly (2R, 5S)-5-(4-amino-2-ketone pyrimidine-1 (2H)-yl)-1, the content of 3-oxygen thia penta ring-2-carboxylic acid.
3. according to the method for claim 1 or 2; Wherein at step B) in separation comprise that extraction removes organic phase; Remaining water carries out underpressure distillation and obtains oily matter, at step B) in purification comprise that gained oily matter obtains white crystalline solid lamivudine product with the Virahol recrystallization.
4. according to the method for claim 3, wherein above-described Peng Qinghuana (or potassium): sodium hydroxide (or potassium) mol ratio=35:1 ~ 55:1.
5. according to the method for claim 3 or 4, the wherein above-described reduction reaction time is 12-18 hour.
6. according to any one method among the claim 1-5; Wherein with respect to 5S-cytosine(Cyt)-the 1 '-Ji-1 of 100 weight parts; 3-oxathiolane-2-carboxylic acid-(1 ' R; 2 ' S, 5 ' R) menthyl ester, the consumption of Peng Qinghuana (or potassium) (calculating by Peng Qinghuana or POTASSIUM BOROHYDRIDE 97MIN solid) is the 10-30 weight part.
7. according to any one method among the claim 1-6, wherein the pH value remains between the pH8-pH10 in the process of carrying out reduction reaction.
8. according to any one method among the claim 2-7, wherein analyze in the lamivudine product impurity A promptly (2R, 5S)-5-(4-amino-2-ketone pyrimidine-1 (2H)-yl)-1, the step C of the content of 3-oxygen thia penta ring-2-carboxylic acid) comprises following substep:
S1, with 5S-cytosine(Cyt)-1 '-Ji-1,3-oxathiolane-2-carboxylic acid-(1 ' R, 2 ' S; 5 ' R) menthyl ester is a raw material, and an one-step hydrolysis is synthetic to obtain impurity A, and said impurity A is (2R; 5S)-5-(4-amino-2-ketone pyrimidine-1 (2H)-yl)-1,3-oxygen thia penta ring-2-carboxylic acid;
S2, the lamivudine impurity A that step S1 is obtained position through HPLC (HPLC), and this impurity A is 0.36 ~ 0.45 with lamivudine main peak relative retention time under the chromatographic condition (5:95) at methyl alcohol-0.025mol/L Spirit of Mindererus (PH3.9 ± 0.1);
S4, the lamivudine acid that obtains with step S1 then are reference substance, carry out the performance liquid chromatography test for the lamivudine product that obtains among the above-described step B, calculate the content of impurity A in the lamivudine product according to external standard method.
9. according to Claim 8 method; Wherein step S1 carries out as follows: with 5S-cytosine(Cyt)-1 '-Ji-1; 3-oxathiolane-2-carboxylic acid-(1 ' R, 2 ' S, 5 ' R) menthyl ester, sodium hydroxide react in solvent; Obtain the lamivudine impurity A through extracting and separating acquisition water, acid precipitation, suction filtration, recrystallization, be white crystalline powder.
10. analyze in the lamivudine product impurity A promptly (2R, 5S)-5-(it comprises following step for 4-amino-2-ketone pyrimidine-1 (2H)-yl)-1, the method for the content of 3-oxygen thia penta ring-2-carboxylic acid:
S1, with 5S-cytosine(Cyt)-1 '-Ji-1,3-oxathiolane-2-carboxylic acid-(1 ' R, 2 ' S; 5 ' R) menthyl ester is a raw material, and an one-step hydrolysis is synthetic to obtain impurity A, and said impurity A is (2R; 5S)-5-(4-amino-2-ketone pyrimidine-1 (2H)-yl)-1,3-oxygen thia penta ring-2-carboxylic acid;
S2, the lamivudine impurity A that step S1 is obtained position through HPLC (HPLC), and this impurity A is 0.36 ~ 0.45 with lamivudine main peak relative retention time under the chromatographic condition (5:95) at methyl alcohol-0.025mol/L Spirit of Mindererus (PH3.9 ± 0.1);
S3, with 5S-cytosine(Cyt)-1 '-Ji-1,3-oxathiolane-2-carboxylic acid-(1 ' R, 2 ' S, 5 ' R) menthyl ester (be called for short CME) be a raw material, synthesizes the lamivudine product;
S4, the lamivudine acid that obtains with step S1 then are reference substance, carry out the performance liquid chromatography test for the lamivudine product that obtains among the above S3, calculate the content of impurity A in the lamivudine product according to external standard method.
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