CN109355328A - The enzymatic preparation method of Lamivudine - Google Patents
The enzymatic preparation method of Lamivudine Download PDFInfo
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Abstract
The invention discloses a kind of enzymatic preparation methods of Lamivudine.Cis/trans formula-(±) -4- acetylaminohydroxyphenylarsonic acid l- of midbody compound (2- benzoyloxymethy -1,3- oxathiolane -5- base) -2 (1H)-pyrimidones and lipase are dissolved in organic solvent, are reacted；It is filtered, washed, solvent removed by evaporation at reduced pressure, purifies to obtain crude product through chromatographed on silica gel, again with methanol sodium after purification, obtains final product Lamivudine.Cost of material of the present invention is lower, and lipase raw material is easy to get, and preparation process step is brief, and ultimate yield is high, and the experiment condition of no harshness is environmentally friendly.The enantio-selectivity of final product is high, and chemical purity is applicable to the large-scale production of Lamivudine up to 99% or more.
Description
Technical field
The invention belongs to technical field of medicine synthesis, and in particular to the enzymatic preparation method of Lamivudine.
Background technique
The uncleosides as antiviral agents that Lamivudine (Lamivudine) is developed by Canadian BiochemPharma company,
U.S. FDA approval listing is obtained in nineteen ninety-five.Its chemical name is: (2R, 5S) -4- amino -1- (2- methylol -1,3- oxygen thia
Pentamethylene -5- base) -2 (1H)-pyrimidones.Its mechanism of action be after turning to 5'- triphosphate by cellular enzymes phosphoric acid with deoxidation
5'- triphosphate substrate competition inhibits the activity of HIV-l reverse transcriptase and leads to chain termination in conjunction with viral DNA, to reach
Inhibit the effect of virus.
Lamivudine generally passes through the preparation of non-natural glycosyl intermediate reduction, at present it has been reported that many Lamivudines
Improvement in synthesis, synthetic method include: (1) using L- peppermint acid glyoxylic ester as chiral source, are obtained through asymmetric syntheses
Lamivudine (WO9529174)；(2) it is with (2R, 5S) -5- hydroxyl -1,3- oxathiolane -2- carboxylic acid-l-menthol ester
Raw material, after obtaining corresponding chloro thing by chlorination, with N, O- bis- (trimethylsilyl) cytimidine is condensed, is hydrolyzed, obtained
To Lamivudine (CN 10136752B)；(3) with 5- hydroxyl -1,3- oxathiolane -2- carboxylic acid [(1'R, 2'S, 5'R) -
5'- methyl -2- (1- Methylethyl) cyclohexyl] ester reacts to obtain acylate with esterifying agent, under Lewis acid catalysis acylate with
The acyl group cytimidine of single silane or the cytimidine schiff bases of single silane occur glycosylation and obtain lamivudine intermediate,
It restores, deacylation base or hydrolysis, reduction obtain Lamivudine (CN 102796089A)；(4) using L- gulose as raw material, through sulphur
1,6- sulphur-L- gulose is made in acylation, acetylation, bromo, condensation and hydrolysis, then a series of anti-by condensation, Deprotection
Should after obtain target compound (JeongLS, etal.Journal ofMedicinal Chemistry, 1993,36 (2):
181.)。
But above method has the following problems: 1. reaction steps are longer, and process is cumbersome, and final yield is lower；2. hand
Property auxiliary reagent is difficult to recycle, expensive；3. having used thionyl chloride in multinomial document report carries out acetylation, reaction
It is also easy to produce form waste gas of sulfur dioxide in the process, be easy to cause environmental pollution and unnecessary injury.It then becomes necessary to find a kind of life
Produce cost is relatively low, it is environmentally friendly, small preparation route is endangered to correlation synthesis personnel health, to meet for Lamivudine
Large-scale industrial production.
Summary of the invention
It is an object of that present invention to provide a kind of enzymatic preparation method of anti-AIDS drug Lamivudine, this method raw materials
Cheap and easy to get, reaction step is simple.It is urged using a kind of key intermediate and environment amenable lipase-catalyzed dose of progress chirality
Change, whole preparation process step is brief, and ultimate yield is high, and the experiment condition of no harshness is environmentally friendly.
In order to achieve the above objectives, as follows using technical solution:
The enzymatic preparation method of Lamivudine, comprising the following steps:
By cis/trans formula-(±) -4- acetylaminohydroxyphenylarsonic acid l- of midbody compound (2- benzoyloxymethy -1,3- oxygen thia ring
Pentane -5- base) -2 (1H)-pyrimidones and lipase is dissolved in organic solvent, reacted；
It is filtered, washed, solvent removed by evaporation at reduced pressure, purifies to obtain crude product through chromatographed on silica gel, again with methanol sodium is pure
After change, final product Lamivudine is obtained.
According to the above scheme, the midbody compound is prepared as follows:
1) compounds benzoic acid sodium and 2- chloroethene methylal are dissolved in organic solvent, and potassium iodide is added, heated up
Return stirring.After fully reacting, extracting and washing is carried out with methylene chloride and water, obtains compound benzene first through acidification after vacuum distillation
Acyloxy acetaldehyde；
2) compound, 2, the 5- dihydroxy-Isosorbide-5-Nitrae-dithiane obtained step 1 is dissolved in organic solvent, is added to toluene
Sulfonic acid sulfuric monohydrate is catalyzed, and temperature rising reflux stirring obtains 2- benzoyloxymethy -5- hydroxyl-l, 3- oxygen sulphur Polymorphs
Alkane；
3) compound for obtaining step 2 is dissolved in methylene chloride, and chloroacetic chloride is added under cryogenic.Fully reacting
Afterwards, organic layer is separated with saturated sodium bicarbonate, then is dried with anhydrous sodium sulfate, obtain compound 2- benzoyloxymethy-
5- acyl group-l, 3- oxathiolane；
4) cytimidine of the compound and silanization that obtain step 3 carries out coupling reaction, obtains the intermediate compound
Object.
According to the above scheme, the lipase is antarctic candidia lipase A (CAL-A), candida antarctica lipase B
(CAL-B), one of Pseudomonas cepacia lipase (PCL), fold lipase from candida sp (CRL) or any mixing.
According to the above scheme, the mass ratio of the midbody compound and lipase is 0.85~0.95, reaction temperature 15
~45 DEG C, the reaction time be 5~for 24 hours.
According to the above scheme, the molar ratio of the midbody compound and organic solvent is 0.002~0.0025.
According to the above scheme, hexane in chromatographed on silica gel purifying: ethyl acetate=1:1.
According to the above scheme, the organic solvent be one of toluene, the tert-butyl alcohol, tetrahydrofuran, hexane, acetone or
Any mixing.
The present invention prepares emtricitabine and the enzymatic preparation method of Lamivudine is as follows:
Compared with existing synthesis technology, beneficial effects of the present invention are as follows:
Cost of material is lower, and lipase raw material is easy to get, and preparation process step is brief, and ultimate yield is high, the experiment of no harshness
Condition, it is environmentally friendly.
The enantio-selectivity of final product is high, and chemical purity is applicable to the extensive of Lamivudine up to 99% or more
Metaplasia produces.
Specific embodiment
Following embodiment further illustrates technical solution of the present invention, but not as limiting the scope of the invention.
Embodiment 1
(1) preparation of benzoyl oxy-aldehyde
21.6 grams of sodium benzoate are weighed in 1000 milliliters of three-necked flask, is added 400 milliliters of DMF solution, mechanical stirring
Lower 11.4 milliliters of addition chloroethene methylal, 16.6 grams of KI, temperature rising reflux is to 110 DEG C.It is cooled to room temperature, uses after fully reacting
Methylene chloride extracts liquid separation, evaporating solvent under reduced pressure.It is then dissolved in THF solution, addition formic acid, under nitrogen protection, heating
Reflux, stirring, is cooled to room temperature after fully reacting, solvent is evaporated off, extracted with ethyl acetate to product, organic phase is successively used
Saturated sodium bicarbonate solution, saturated sodium-chloride water solution washing, then after being dried over anhydrous sodium sulfate, evaporating solvent under reduced pressure is obtained
Yellow viscous liquid.
(2) preparation of 2- benzoyloxymethy -5- acyl group-l, 3- oxathiolane
Under nitrogen protection, 16.4 grams of benzoyl oxy-aldehydes are dissolved in 120 milliliters of toluene, and added into the solution
Enter 2,5- dihydroxy -7.62 grams of Isosorbide-5-Nitrae-dithiane, stir evenly, is added 0.57 gram of p-methyl benzenesulfonic acid sulfuric monohydrate, heats up back
Stream reacts 1 hour at 60~65 DEG C.After reaction, perfect solution is obtained.
60 milliliters of methylene chloride are added into reaction mixture, and are cooled to 0 DEG C, with ice-salt bath by 21.4 milliliters
Chloroacetic chloride is added drop-wise in solution, and after being added dropwise, temperature is controlled at 10~15 DEG C, reacted 1.5~2 hours by heating.It will reaction
Liquid pours into 40 milliliters of saturated sodium bicarbonate solutions, separates organic layer.Water layer is extracted with dichloromethane, and combined organic layer is used full
It is washed with sodium bicarbonate solution and saturated brine, with the dry solution of anhydrous sodium sulfate, is filtered under diminished pressure, removes solvent.It obtains pale yellow
The grease of color.It need not purify, be directly used in and react in next step.
(3) cis/trans formula-(±) -4- acetylaminohydroxyphenylarsonic acid l- (2- benzoyloxymethy -1,3- oxathiolane -5- base) -2
The preparation of (1H)-pyrimidone
At room temperature, by 12.9 grams of cytimidines, 0.11 milliliter of methanesulfonic acid is added in flask, after mixing evenly, 23 millis is added
Hexamethyldisilazane is risen, washs charging hopper and graduated cylinder with 23 milliliters of methylene chloride.It is heated to outer 60 DEG C of bath, reflux is stirred
It mixes to solid and all dissolves.16 milliliters of triethylamines are added after becoming clarification in solution, and acquired solution is spare.
By the born of the same parents of 2- benzoyloxymethy -5- acyl group-l, 3- oxathiolane and silanization obtained in the reaction of upper step
Pyrimidine is added dropwise in 150 milliliters of dichloromethane solutions, return stirring reaction.Reaction is finished, and is cooled to room temperature, is poured into 50 milliliters of saturations
Sodium sulfite aqueous solution separates organic layer and is washed with saturated brine (2 × 40 milliliters), through anhydrous sodium sulfate after stirring 10min
Dry, evaporating solvent under reduced pressure obtains brown oil, uses ethyl alcohol recrystallization.Mother liquor silica gel chromatograph column separating purification, eluant, eluent are
Acetate-methanol (50:1) is collected.
(4) preparation of Lamivudine
It takes 0.12 g of compound 5 to be dissolved in 15 milliliters of toluene solutions, the fat of 10 equivalent water and 0.12 gram of immobilization is added
Enzyme A (CALA).It fills this blend into triangular flask, reaction is reacted 8 hours in 15 DEG C of water bath with thermostatic control shaking table.Pass through
TLC monitors reaction process (methanol: ethyl acetate=1:50).After fully reacting, it is filtered to remove enzyme, is washed with ethyl acetate
It washs, solvent removed by evaporation at reduced pressure, crude product purifies (methanol: ethyl acetate=1:50) through chromatographed on silica gel, obtains crude product.
Sodium methoxide solution is added dropwise into the absolute methanol solution of crude product, reaction is stirred at room temperature 2~5 hours, is evaporated off
Solvent, residue ethyl alcohol recrystallization obtain 0.061 gram of (yield 88%) white crystals 6, as Lamivudine.
1H NMR: δ 7.3 (d, 1H, J=7.4Hz, C'6-H),5.22(t,1H,C5-H),3.97(t,1H,C2-H),3.89
(m,2H,C2-CH2 ), OH 2.98 (dd, 1H, J=5.6,11.8Hz, C4- H), 2.68 (dd, 1H, J=5.0,11.7Hz, C4-H)。
Embodiment 2
(1) preparation of benzoyl oxy-aldehyde
2.16 grams of sodium benzoate are weighed in three-necked flask, 50 milliliters of DMF solution is added, chloroethene is added under stirring thereto
1.14 milliliters of methylal, 1.7 grams of KI, temperature rising reflux is to 125 DEG C.It is cooled to room temperature after fully reacting, is extracted with methylene chloride
It takes, evaporating solvent under reduced pressure.Obtained product is dissolved in THF solution, addition formic acid, under nitrogen protection, is heated to reflux, stirs,
It is cooled to room temperature after fully reacting, solvent is evaporated off, product extracted with ethyl acetate, organic phase successively uses unsaturated carbonate hydrogen
Sodium solution, saturated sodium-chloride water solution washing, then after being dried over anhydrous sodium sulfate, decompression boils off solvent, obtains clear yellow viscous liquid
Body.
(2) preparation of 2- benzoyloxymethy -5- acyl group-l, 3- oxathiolane
8.2 grams of benzoyl oxy-aldehydes are dissolved in 60 milliliters of toluene, and dihydroxy -1 2,5- is added into the solution,
3.8 grams of 4- dithiane, after mixing evenly, be added 0.28 gram of p-methyl benzenesulfonic acid sulfuric monohydrate, temperature rising reflux to 50~60 DEG C,
Under nitrogen protection, react 1.5 hours.After reaction, perfect solution is obtained.
30 milliliters of methylene chloride are added into reaction mixture, and are cooled to 0 DEG C, with ice-salt bath by 10.7 milliliters
Chloroacetic chloride is added drop-wise in solution, and after being added dropwise, temperature is controlled at 10~15 DEG C, reacted 1.5~2 hours by heating.It will reaction
Liquid is poured slowly into 20 milliliters of saturated sodium bicarbonate solutions, separates organic layer.Water layer is extracted with dichloromethane, combined organic layer
It is washed with saturated sodium bicarbonate solution and saturated brine, with the dry solution of anhydrous sodium sulfate, is filtered under diminished pressure, removes solvent.It obtains
Lurid grease.It need not purify, be directly used in and react in next step.
(3) cis/trans formula-(±) -4- acetylaminohydroxyphenylarsonic acid l- (2- benzoyloxymethy -1,3- oxathiolane -5- base) -2
The preparation of (1H)-pyrimidone
At room temperature, by 6.45 grams of cytimidines, 0.055 milliliter of methanesulfonic acid is added in flask, after mixing evenly, is added 11.5
Milliliter hexamethyldisilazane, is heated to outer 60 DEG C of bath, and return stirring to solid all dissolves.Solution is added after becoming clarification
16 milliliters of triethylamines, acquired solution are spare.
By the born of the same parents of 2- benzoyloxymethy -5- acyl group-l, 3- oxathiolane and silanization obtained in the reaction of upper step
Pyrimidine is successively added dropwise in 75 milliliters of dichloromethane solutions, return stirring reaction.Reaction is finished, and is cooled to room temperature, is poured into 25 milliliters
Saturated aqueous sodium sulfite separates organic layer and is washed with saturated brine (2 × 40 milliliters), through anhydrous sulphur after stirring 10min
Sour sodium is dry, and evaporating solvent under reduced pressure obtains brown oil, uses ethyl alcohol recrystallization.Mother liquor silica gel chromatograph column separating purification, elution
Agent is acetate-methanol (50:1), is collected.
(4) preparation of Lamivudine
It takes 0.12 g of compound 5 to be dissolved in 20 milliliters of toluene solutions, 10 equivalent water and 0.125 gram is added without pretreated
Lipase B (CALB).It fills this blend into triangular flask, reaction is reacted 6 hours in 30 DEG C of water bath with thermostatic control.Pass through
TLC monitors reaction process (methanol: ethyl acetate=1:50).After fully reacting, it is filtered to remove lipase, is carried out with ethyl acetate
Washing, solvent removed by evaporation at reduced pressure, crude product purify (methanol: ethyl acetate=1:50) through chromatographed on silica gel, are slightly produced
Object.
Sodium methoxide solution is added dropwise into the absolute methanol solution of crude product, reaction is stirred at room temperature 2~5 hours, is evaporated off
Solvent, residue ethyl alcohol recrystallization obtain 0.057 gram of (yield 77%) white crystals 6, as Lamivudine.
It is visible to sum up to state experimental result: enantio-selectivity height can be made by the method for the invention, purity is up to 99%, and
Lamivudine of the molar yield up to 85% or more, the method for the present invention for the large-scale industrial production of Lamivudine have it is great into
Exhibition, and there is significant value.
The foregoing is merely presently preferred embodiments of the present invention, is not intended to limit the invention, it is all in spirit of the invention and
Within principle, any modification, equivalent replacement, improvement and so on be should all be included in the protection scope of the present invention.
Claims (7)
1. the enzymatic preparation method of Lamivudine, it is characterised in that the following steps are included:
By cis/trans formula-(±) -4- acetylaminohydroxyphenylarsonic acid l- of midbody compound (2- benzoyloxymethy -1,3- oxathiolane -
5- yl) -2 (1H)-pyrimidones and lipase is dissolved in organic solvent, reacted；
Be filtered, washed, solvent removed by evaporation at reduced pressure, purify to obtain crude product through chromatographed on silica gel, again with methanol sodium after purification,
Obtain final product Lamivudine.
2. the enzymatic preparation method of Lamivudine as described in claim 1, it is characterised in that the midbody compound press with
Lower section method is prepared:
1) compounds benzoic acid sodium and 2- chloroethene methylal are dissolved in organic solvent, and potassium iodide is added, temperature rising reflux
Stirring.After fully reacting, extracting and washing is carried out with methylene chloride and water, obtains compound benzoxy through acidification after vacuum distillation
Ethylhexanal；
2) compound, 2, the 5- dihydroxy-Isosorbide-5-Nitrae-dithiane obtained step 1 is dissolved in organic solvent, and p-methyl benzenesulfonic acid is added
Sulfuric monohydrate is catalyzed, and temperature rising reflux stirring obtains 2- benzoyloxymethy -5- hydroxyl-l, 3- oxathiolane；
3) compound for obtaining step 2 is dissolved in methylene chloride, and chloroacetic chloride is added under cryogenic.After fully reacting, use
Saturated sodium bicarbonate separates organic layer, then is dried with anhydrous sodium sulfate, obtains compound 2- benzoyloxymethy -5- acyl
Base-l, 3- oxathiolane；
4) cytimidine of the compound and silanization that obtain step 3 carries out coupling reaction, obtains the midbody compound.
3. the enzymatic preparation method of Lamivudine as described in claim 1, it is characterised in that the lipase is South Pole vacation silk
One of Yeast-lipase, antarctic candidia lipase, Pseudomonas cepacia lipase, fold lipase from candida sp or
Any mixing.
4. the enzymatic preparation method of Lamivudine as described in claim 1, it is characterised in that the midbody compound and rouge
The mass ratio of fat enzyme be 0.85~0.95, reaction temperature be 15~45 DEG C, the reaction time be 5~for 24 hours.
5. the enzymatic preparation method of Lamivudine as described in claim 1, it is characterised in that the midbody compound with have
The molar ratio of solvent is 0.002~0.0025.
6. the enzymatic preparation method of Lamivudine as described in claim 1, it is characterised in that chromatographed on silica gel purifying in oneself
Alkane: ethyl acetate=1:1.
7. the enzymatic preparation method of Lamivudine as described in claim 1, it is characterised in that the organic solvent is first
One of benzene, the tert-butyl alcohol, tetrahydrofuran, hexane, acetone or any mixing.
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Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1329671A (en) * | 1998-10-09 | 2002-01-02 | 爱尔特斯生物学公司 | Non-homogeneous systems for resolution of enantiomeric mixtures |
| US20050187267A1 (en) * | 2004-02-04 | 2005-08-25 | Hamann Lawrence G. | Sulfonylpyrrolidine modulators of androgen receptor function and method |
| 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 |
| CN101362752A (en) * | 2008-09-18 | 2009-02-11 | 浙江教育学院 | Synthesis method of lamivudine intermediate |
| 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 |
| CN102010404A (en) * | 2010-12-29 | 2011-04-13 | 刘建红 | Method for purifying and refining lamivudine and emtricitabine |
| CN102153545A (en) * | 2011-03-04 | 2011-08-17 | 杭州科本药业有限公司 | Preparation method for lamivudine |
| CN102234269A (en) * | 2010-04-29 | 2011-11-09 | 重庆医药工业研究院有限责任公司 | Industrial preparation method for lamivudine |
-
2018
- 2018-12-07 CN CN201811493553.XA patent/CN109355328A/en active Pending
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1329671A (en) * | 1998-10-09 | 2002-01-02 | 爱尔特斯生物学公司 | Non-homogeneous systems for resolution of enantiomeric mixtures |
| US20050187267A1 (en) * | 2004-02-04 | 2005-08-25 | Hamann Lawrence G. | Sulfonylpyrrolidine modulators of androgen receptor function and method |
| 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 |
| CN101362752A (en) * | 2008-09-18 | 2009-02-11 | 浙江教育学院 | Synthesis method of lamivudine intermediate |
| 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 |
| CN102234269A (en) * | 2010-04-29 | 2011-11-09 | 重庆医药工业研究院有限责任公司 | Industrial preparation method for lamivudine |
| CN102010404A (en) * | 2010-12-29 | 2011-04-13 | 刘建红 | Method for purifying and refining lamivudine and emtricitabine |
| CN102153545A (en) * | 2011-03-04 | 2011-08-17 | 杭州科本药业有限公司 | Preparation method for lamivudine |
Non-Patent Citations (7)
| Title |
|---|
| LEI HU等: "Efficient asymmetric synthesis of lamivudine via enzymatic dynamic kinetic resolution", 《CHEMCOMM》 * |
| 冯婧劼等: "抗 HIV －1 药物及其复方制剂研究新进展", 《药学进展》 * |
| 周鸣强等: "恩曲他滨顺式和反式消旋体的简便合成", 《华西药学杂志》 * |
| 国家食品药品监督管理总局执业药师资格认证中心编写: "《药学专业知识》", 31 January 2016 * |
| 张利刚: "1,3-二芳基-4-醛基吡唑衍生物及杂环类药物吉非替尼、拉米夫定的合成研究", 《中国优秀博硕士学位论文全文数据库 (硕士)工程科技Ⅰ辑》 * |
| 王华等: "拉米夫定的合成工艺优化", 《制药工艺》 * |
| 顾继山等: "恩曲他滨的合成新工艺研究", 《化学试剂》 * |
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