CN102153545A - Preparation method for lamivudine - Google Patents
Preparation method for lamivudine Download PDFInfo
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- CN102153545A CN102153545A CN 201110052195 CN201110052195A CN102153545A CN 102153545 A CN102153545 A CN 102153545A CN 201110052195 CN201110052195 CN 201110052195 CN 201110052195 A CN201110052195 A CN 201110052195A CN 102153545 A CN102153545 A CN 102153545A
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Abstract
The invention discloses a preparation method of lamivudine shown as a formula II. The preparation method comprises the following step of: reducing a compound shown as a formula I with a reducing agent to obtain lamivudine, wherein the reducing agent is zinc borohydride or magnesium borohydride. The preparation method disclosed by the invention has the advantages of mild reaction condition, simple process, high operability, high safety, high product purity, high yield and stable quality, and is fully consistent with the using requirement on a raw material medicament.
Description
Technical field
The present invention relates to a kind of preparation method of lamivudine, be specifically related to cis-cytosine(Cyt)-1 '-1 by reduction key intermediate 2R-, 3-oxathiolane-2-carboxylic acid-L-menthyl ester prepares the method for lamivudine.
Background technology
The lamivudine listing has had 10 years, and its English name is Lamivudine, and chemistry is by name: (2R-cis)-4-amino-1-(2-methylol-1,3-oxygen thia ring penta-5-yl)-1H-pyrimid-2-one claims 3-TC again.It is main medicine Epivir, the Combivir of treatment acquired immune deficiency syndrome (AIDS) and the raw material of Trizivir, also is the main medication raw material for the treatment of hepatitis B.In recent years, lamivudine was extensively accepted by doctors and patients as a kind of new nucleoside analog, was best, the most representative nucleoside analog of curative effect in the present clinical application.Its mechanism of action is for suppressing viral DNA polymerase and reverse transcriptase activity, and to the synthetic of viral DNA chain with prolong competitive restraining effect.Along with acquired immune deficiency syndrome (AIDS) rapid spread and hepatitis B patient number worldwide increases, the synthetic technology of R and D lamivudine has caused the extensive interest of whole world pharmaceutical industries.The synthetic method of lamivudine is also constantly weeded out the old and bring forth the new.Comparatively advanced and that be widely adopted at present synthetic route has following several:
Route one (CN200410023744.1):
Route two (CN200910043203.8):
Route three (CN200510015609.7):
All relate to the reduction that intermediate is a Compound I in these several the routes, several routes have been used different reductive agents respectively, and red aluminium, POTASSIUM BOROHYDRIDE, lithium aluminum hydride are arranged.These several reductive agents all exist shortcoming separately, and for example, red aluminium market value is too high, and reactive behavior is strong, the industrial production inconvenient operation, and domestic do not have a manufacturer yet, mainly by import; In aftertreatment, also comparatively bother, reacted posthydrolysis, can generate 2 parts ethylene glycol monomethyl ether, produce sodium metaaluminate simultaneously and be difficult to filter.The potassium borohydride reduction ability relatively a little less than, product yield is not high.The lithium aluminum hydride price is more expensive equally, and severe reaction conditions, easily catches fire poor stability.
Summary of the invention
The objective of the invention is to overcome the defective of prior art, a kind of preparation method of lamivudine is provided, (be 2R-cis-cytosine(Cyt)-1 '-1 promptly to midbody compound I, 3-oxathiolane-2-carboxylic acid-L-menthyl ester) reduction improves, abandon more weak sodium borohydride and the POTASSIUM BOROHYDRIDE of price more expensive red aluminium, lithium aluminum hydride and reducing power, adopt zinc borohydride and magnesium borohydride cheap and easy to get, that reducing power is moderate to reduce, thereby obtain lamivudine efficiently.
For realizing goal of the invention of the present invention, adopt following technical scheme:
The preparation method of the lamivudine shown in a kind of formula II, described preparation method is: the compound shown in the formula I makes lamivudine through the reductive agent reduction, and described reductive agent is zinc borohydride or magnesium borohydride;
Further, the preferred zinc borohydride of described reductive agent.
Zinc borohydride used in the present invention and magnesium borohydride all can be prepared by existing method, as pass through ZnCl
2Or MgCl
2Make with the sodium borohydride reaction, generally prepare the THF solution of zinc borohydride or magnesium borohydride.
Among the present invention, the molar ratio of described reductive agent and Compound I is 0.5～3: 1, is preferably 0.7～1.5: 1, more preferably 0.8～1.2: 1.
Among the present invention, described reduction reaction is carried out in reaction solvent, the preferred tetrahydrofuran (THF) of described reaction solvent.
Among the present invention, the feeding sequence of Compound I and reductive agent influence is not very big, general preferred reductive agent is added drop-wise in the reaction solvent that is dissolved with Compound I.
Among the present invention, described reduction reaction temperature is 0～65 ℃, is preferably 0～45 ℃, more preferably 10～25 ℃.
In the reaction process of the present invention, available ordinary method is such as the carrying out of TLC monitoring reaction.
The present invention is after reduction reaction finishes, obtain highly purified lamivudine by conventional aftertreatment, for example can adopt following post-treating method: after reaction finishes, the saturated aqueous ammonium chloride that adds ice, tell organic layer, it is the lamivudine crude product that dry back concentrating under reduced pressure obtains the off-white color solid, and crude product obtains white crystalline lamivudine after adding activated carbon decolorizing, ethyl alcohol recrystallization.
Beneficial effect of the present invention is: of the present invention with zinc borohydride or magnesium borohydride reductase 12 R-cis-cytosine(Cyt)-1 '-1,3-oxathiolane-2-carboxylic acid-L-menthyl ester obtains the method for lamivudine, the reaction conditions gentleness, technology is simple, and is workable, safe, good product purity, the yield height, steady quality meets the service requirements as bulk drug fully.
Embodiment
Following type reaction is used for illustrating the present invention.Within the technical scheme that those skilled in that art all belong to the present invention to the simple replacement done of invention or improvement etc. and protected.
Embodiment 1:
1. the preparation of zinc borohydride
Under nitrogen protection, add the anhydrous ZnCl of 20.8g (165mmol) in the exsiccant 500mL flask
2And 12.9g (330mmol) NaBH
4, add exsiccant tetrahydrofuran (THF) 250mL then, stir 24h under the room temperature, leave standstill.The clear liquid on upper strata is Zn (BH
4)
2THF solution, concentration is about 0.33M.
2. the preparation of lamivudine
In the four-hole reaction flask of 500mL, add 38.1 gram (0.1mol) 2R-cis-cytosine(Cyt)s-1 '-1,3-oxathiolane-2-carboxylic acid-L-menthyl ester, the 150mL tetrahydrofuran (THF), stir down, drip the above-mentioned zinc borohydride solution 212mL (0.07mol) that makes, 25 ℃ of insulation reaction, TLC follows the tracks of reaction process, to the raw material completely dissolve, add the saturated aqueous ammonium chloride 200mL of ice, tell organic layer, dry back concentrating under reduced pressure obtains off-white color solid lamivudine crude product, crude product adds 1 gram activated carbon decolorizing, behind the 180 gram ethyl alcohol recrystallizations, obtain white crystalline lamivudine 20.7 grams, yield 90.4%.HPLC purity: 99.8% (pressing American Pharmacopeia USP32 method), [α]
22 D-144.5 ° of (c1.01, CH
3OH), M.p.176.2～177.1 ℃.
Data analysis:
1H-NMR(DMSO-d6)δ：7.81(d，1H)，7.25(brs，1H)，7.21(brs，1H)，6.20(m，1H)，5.74(d，1H)，5.31(m，1H)，5.17(m，1H)，3.74(m，2H)，3.40(dd，1H)，3.05(dd，1H)。
Embodiment 2:
1. the preparation of magnesium borohydride
Under nitrogen protection, add the anhydrous MgCl of 15.7g (165mmol) that fully grinds in the exsiccant 500mL flask
2Powder and 12.9g (330mmol) NaBH
4, add exsiccant tetrahydrofuran (THF) 250mL then, stir 24h under the room temperature, leave standstill.The clear liquid on upper strata is Mg (BH
4)
2THF solution, effective concentration is about 0.27M.
2. the preparation of lamivudine
Press embodiment 1, replace zinc borohydride solution, obtain lamivudine 20.2 grams, yield 88.2% with 259mL (0.07mol) magnesium borohydride solution.HPLC purity: 99.6% (pressing American Pharmacopeia USP32 method), [α]
22 D-144.2 ° of (c1.01, CH
3OH), M.p.176.1～177.5 ℃.
Embodiment 3:
Press embodiment 1, the consumption of zinc borohydride solution is 151.5mL (0.05mol), obtains lamivudine 18.4 grams, HPLC purity: 99.3% (pressing American Pharmacopeia USP32 method), yield 80.5%.
Embodiment 4:
Press embodiment 1, the consumption of zinc borohydride solution is 303mL (0.1mol), obtains lamivudine 20.7 grams, HPLC purity: 99.5% (pressing American Pharmacopeia USP32 method), yield 90.5%.
Embodiment 5:
Press embodiment 1, temperature of reaction is controlled at 0 ℃, obtains lamivudine 18.8 grams, HPLC purity: 98.5% (pressing American Pharmacopeia USP32 method), yield 82.1%.
Embodiment 6
Press embodiment 1, temperature of reaction is controlled at 10 ℃, obtains lamivudine 18.9 grams, HPLC purity: 98.9% (pressing American Pharmacopeia USP32 method), yield 82.5%.
Embodiment 7:
Press embodiment 1, temperature of reaction is controlled at 65 ℃, obtains lamivudine 18.2 grams, HPLC purity: 98.7% (pressing American Pharmacopeia USP32 method), yield 79.5%.
Embodiment 8:
Press embodiment 1, temperature of reaction is controlled at 35 ℃, obtains lamivudine 19.1 grams, HPLC purity: 99.3% (pressing American Pharmacopeia USP32 method), yield 83.4%.
Embodiment 9:
Press embodiment 1, temperature of reaction is controlled at 45 ℃, obtains lamivudine 18.9 grams, HPLC purity: 99.0% (pressing American Pharmacopeia USP32 method), yield 82.5%.
Embodiment 10:
Press embodiment 1, temperature of reaction is controlled at 55 ℃, obtains lamivudine 18.4 grams, HPLC purity: 98.7% (pressing American Pharmacopeia USP32 method), yield 80.3%.
Embodiment 11:
In the 500mL reaction flask, add the above-mentioned zinc borohydride solution 212mL (0.07mol) that makes, stir down, drip 38.1 gram (0.1mol) 2R-cis-cytosine(Cyt)s-1 '-1,3-oxathiolane-2-carboxylic acid-L-menthyl ester is dissolved in the solution of 150mL tetrahydrofuran (THF), controlled temperature is about 25 ℃, after dropwising, continue reaction, TLC follows the tracks of reaction and all disappears until raw material, adds the 200mL saturated ammonium chloride solution, crosses and filters out insolubles, tell organic layer, after the drying, concentrate to remove and desolvate, obtaining the off-white color solid is the lamivudine crude product.Crude product obtains white products lamivudine 20.3 grams, HPLC purity: 99.8% (pressing American Pharmacopeia USP32 method), yield 88.8% with activated carbon decolorizing, ethyl alcohol recrystallization.
Claims (7)
1. the preparation method of the lamivudine shown in the formula II, described preparation method is: the compound shown in the formula I makes lamivudine through the reductive agent reduction, it is characterized in that described reductive agent is zinc borohydride or magnesium borohydride;
2. the preparation method of lamivudine as claimed in claim 1, the molar ratio that it is characterized in that described reductive agent and Compound I is 0.5～3: 1.
3. the preparation method of lamivudine as claimed in claim 1, the molar ratio that it is characterized in that described reductive agent and Compound I is 0.7～1.5: 1.
4. the preparation method of lamivudine as claimed in claim 1 is characterized in that described reduction reaction temperature is 0～65 ℃.
5. the preparation method of lamivudine as claimed in claim 1 is characterized in that temperature of reaction is 0～45 ℃.
6. the preparation method of lamivudine as claimed in claim 1 is characterized in that temperature of reaction is 10～25 ℃.
7. the preparation method of lamivudine as claimed in claim 1 is characterized in that described reduction reaction carries out in reaction solvent, described reaction solvent is a tetrahydrofuran (THF).
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109355328A (en) * | 2018-12-07 | 2019-02-19 | 武汉工程大学 | The enzymatic preparation method of Lamivudine |
Citations (7)
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| CN1955177A (en) * | 2005-10-25 | 2007-05-02 | 天津迪爱盟生物技术有限公司 | LAM nucleoside derivate, its preparation method and application |
| CN101407513A (en) * | 2008-11-14 | 2009-04-15 | 江苏科本医药化学有限公司 | Method for synthesizing nucleoside analogue |
| WO2009069012A1 (en) * | 2007-11-29 | 2009-06-04 | Ranbaxy Laboratories Limited | Process and intermediates for the preparation of substituted 1, 3-oxathiolanes, especially lamivudine |
| WO2009069011A1 (en) * | 2007-11-29 | 2009-06-04 | Ranbaxy Laboratories Limited | Process for the preparation of substituted 1,3-oxathiolanes |
| CN101544632A (en) * | 2009-04-24 | 2009-09-30 | 湖南千金湘江药业股份有限公司 | Lamivudine diastereoselective synthesis method |
| CN101597281A (en) * | 2009-07-01 | 2009-12-09 | 济南久创化学有限责任公司 | Lamivudine and intermediates preparation thereof |
| WO2010082128A1 (en) * | 2009-01-19 | 2010-07-22 | Aurobindo Pharma Limited | Process for the preparation of cis-nucleoside derivative |
-
2011
- 2011-03-04 CN CN2011100521950A patent/CN102153545B/en active Active
Patent Citations (7)
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|---|---|---|---|---|
| CN1955177A (en) * | 2005-10-25 | 2007-05-02 | 天津迪爱盟生物技术有限公司 | LAM nucleoside derivate, its preparation method and application |
| WO2009069012A1 (en) * | 2007-11-29 | 2009-06-04 | Ranbaxy Laboratories Limited | Process and intermediates for the preparation of substituted 1, 3-oxathiolanes, especially lamivudine |
| WO2009069011A1 (en) * | 2007-11-29 | 2009-06-04 | Ranbaxy Laboratories Limited | Process for the preparation of substituted 1,3-oxathiolanes |
| CN101407513A (en) * | 2008-11-14 | 2009-04-15 | 江苏科本医药化学有限公司 | Method for synthesizing nucleoside analogue |
| WO2010082128A1 (en) * | 2009-01-19 | 2010-07-22 | Aurobindo Pharma Limited | Process for the preparation of cis-nucleoside derivative |
| CN101544632A (en) * | 2009-04-24 | 2009-09-30 | 湖南千金湘江药业股份有限公司 | Lamivudine diastereoselective synthesis method |
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| 《Tetrahedron Lett.》 20051019 Michael D.Goodyear,et al. Practical enantioselective synthesis of lamivudine(3TCTM) via a dynamic kinetic resolution 8535-8538 1-7 第46卷, 第49期 * |
| 《湘潭大学自然科学学报》 20101231 陈朗秋，等 拉米夫定的合成工艺探讨 78-83 1-7 第32卷, 第4期 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109355328A (en) * | 2018-12-07 | 2019-02-19 | 武汉工程大学 | The enzymatic preparation method of Lamivudine |
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