CN101362752B - Synthesis method of lamivudine intermediate - Google Patents
Synthesis method of lamivudine intermediate Download PDFInfo
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- CN101362752B CN101362752B CN2008101208317A CN200810120831A CN101362752B CN 101362752 B CN101362752 B CN 101362752B CN 2008101208317 A CN2008101208317 A CN 2008101208317A CN 200810120831 A CN200810120831 A CN 200810120831A CN 101362752 B CN101362752 B CN 101362752B
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- cytosine
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- oxathiolane
- carboxylic acid
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- 0 CC[C@@](C)C[C@@](*C(CC1SC[C@](O)O1)=O)[C@@](C)C(C)C Chemical compound CC[C@@](C)C[C@@](*C(CC1SC[C@](O)O1)=O)[C@@](C)C(C)C 0.000 description 3
- UCPYLLCMEDAXFR-UHFFFAOYSA-N O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl Chemical compound O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 2
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Abstract
The invention discloses a synthetic method of lamivudine intermediate, namely (2R, 5S)-5-(5-cytosine-1-base)-1, 3-oxathiolane-2- carboxylic acid-L-menthyl ester with the structural formula shown as the formula (VI). (2R, 5S)-5- hydroxyl-1, 3- oxathiolane -2- carboxylic acid-L-menthyl ester with the structural formula shown as the formula (III) is taken as raw material and a chlorine substitute with the structural formula shown as the formula (IV) is obtained by chloro-substituted reaction; the chlorine substitute (IV) and N, O-bi (tri-silicon-base) 5-cytosine with the structural formula shownas the formula (V) are condensed and hydrolyzed to obtain the intermediate. The method takes bi (trichloromethyl) carbonate to replace thionyl chloride applied in the prior art as a chloro-substituted reagent and has the advantages of safe and reliable operation and environmental protection.
Description
(1) technical field
The present invention relates to a kind of synthetic method of lamivudine intermediate, be specifically related to (2R, 5S)-5-(cytosine(Cyt)-1-yl)-1, the synthetic method of 3-oxathiolane-2-carboxylic acid-L-menthyl ester.
(2) background technology
Lamivudine (Compound I) is a kind of medicine material with good resistance virus activity, is mainly used in hepatitis B and AIDS virus resisting, is the main active ingredient for the treatment of at present in hepatitis B and the AIDS drug cocktail therapy (treatment).
Lamivudine has two chiral carbon, relates to three-dimensional the selection in its building-up process and synthesizes, and relevant its synthetic bibliographical information is a lot, and main route has:
(1) with the L-gulose is synthetic route (Beach, J.et al, J.Org.Chem., 57 (8), the 2217-19 (1992) of raw material; Humber, David C.et al TetrahedronLett., 33 (32), 4625-28 (1992)); (2) with (+)-2-hydroxyl-3-thiohydracrylic acid be the synthetic route (David C., et al, Tetrahedron Lett., 33 (32), 4625-28 (1992)) of raw material; (3) with oxoethanoic acid, 1,4-dithiane-2,5-glycol are the synthetic route (Haolun J.et al, J.Org.Chem., 60,2621-23 (1992)) of raw material; (4) be chiral source with L-peppermint acid glyoxylic ester, get lamivudine (Goodyear, M.et al, WO9529174 (1995)) through asymmetric synthesis.
Wherein, be chiral source with L-peppermint acid glyoxylic ester monohydrate (Compound I I), through asymmetric synthesis and route that must lamivudine is the most economical and the most practical at present, also be a method of normal use in the existing industrial production, process is as follows:
In the method, (2R, 5S)-5-(cytosine(Cyt)-1-yl)-1,3-oxathiolane-2-carboxylic acid-L-menthyl ester (compound VI) is the key intermediate of synthetic lamivudine.Gained (2R, 5S)-5-(cytosine(Cyt)-1-yl)-1,3-oxathiolane-2-carboxylic acid-L-menthyl ester through the Whitfield's ointment salify, with behind the free purifying of triethylamine alkalization, just obtains the lamivudine of pharmaceutical use through sodium borohydride reduction then.
Bibliographical information, (2R, 5S)-5-(cytosine(Cyt)-1-yl)-1, synthesizing of 3-oxathiolane-2-carboxylic acid-L-menthyl ester mainly by (2R, 5S)-and 5-hydroxyl-1,3-oxathiolane-2-carboxylic acid-L-menthyl ester (compound III) gets ((Goodyear with silicon etherate (compound V) reaction of cytosine(Cyt) behind the sulfur oxychloride chloro, M.et al, WO9529174 (1995); Goodyear, M.et al, Tetrahedron Lett, 46 (49), 8535-38 (2005)).This method also is a classical way in big at present the production.In this reaction, owing to use sulfur oxychloride to be chlorinating agent, material toxicity is big, simultaneously, produces a large amount of form waste gas of sulfur dioxide in the reaction process, and is serious to equipment corrosion, and produces serious pollution ring environment, influences operator's health and safety.
Two (trichloromethyl) carbonic ether (compound VI I) is white or off-white color xln, and fusing point 79-81 ℃, normal temperature is stable down, is a kind of chlorinating agent of environmental protection, is usually used in substituting of Poisons such as phosgene, phosphorus oxychloride, sulfur oxychloride.Because two (trichloromethyl) carbonic ethers are a kind of solids, its transportation, storage and use are all as safe as a house, and metering is convenient, and the by product that produces behind the chlorination is a carbonic acid gas, use in process of production, have characteristics such as easy-to-operate, environmental protection.
(3) summary of the invention
The technical problem to be solved in the present invention be to provide a kind of alternative sulfur oxychloride synthesize the lamivudine key intermediate (2R, 5S)-5-(cytosine(Cyt)-1-yl)-1, the preparation method of 3-oxathiolane-2-carboxylic acid-L-menthyl ester.
For solving the problems of the technologies described above, the present invention adopts following technical scheme: structure is suc as formula (the 2R shown in (VI), 5S)-5-(cytosine(Cyt)-1-yl)-1, the synthetic method of 3-oxathiolane-2-carboxylic acid-L-menthyl ester, with structure suc as formula (2R shown in (III), 5S)-5-hydroxyl-1,3-oxathiolane-2-carboxylic acid-L-menthyl ester is a raw material, obtain structure suc as formula the chloro thing shown in (IV) by chlorination, chloro thing (IV) and the N of structure shown in formula V, the condensation of O-two (front three is silica-based) cytosine(Cyt), hydrolysis make;
Described chlorination is as follows: (2R, 5S)-5-hydroxyl-1,3-oxathiolane-2-carboxylic acid-L-menthyl ester (III) is at N, under the dinethylformamide catalysis, in reaction solvent, at 0～50 ℃ chlorination takes place suc as formula two (trichloromethyl) carbonic ethers shown in (VII) with structure and obtain chloro thing (IV).
In chlorination, described (2R, 5S)-5-hydroxyl-1,3-oxathiolane-2-carboxylic acid-L-menthyl ester (III), two (trichloromethyl) carbonic ether (VII) and N, the amount of substance ratio that feeds intake of dinethylformamide is recommended as 1:0.35～1.0:1～3, preferred 1:0.35～0.5:1～1.5.
Concrete, described chlorination carries out according to following steps: add (2R in reaction vessel, 5S)-5-hydroxyl-1,3-oxathiolane-2-carboxylic acid-L-menthyl ester (III), N, dinethylformamide and organic solvent A, fully stir and make (2R, 5S)-5-hydroxyl-1,3-oxathiolane-2-carboxylic acid-L-menthyl ester (III) dissolving, drip the solution with two (trichloromethyl) carbonic ethers of same organic solvent A dissolved then, the control dropping temperature slowly is warming up to 30～35 ℃ at 0～10 ℃ after dropwising, insulation reaction 1～6 hour, gained reaction solution A is the solution of chloro thing (IV).Described organic solvent A is methylene dichloride, ethylene dichloride, chloroform or toluene; The consumption of described organic solvent A is so that (2R, 5S)-5-hydroxyl-1, the quality of 3-oxathiolane-2-carboxylic acid-L-menthyl ester (III) is counted 2～20mL/g, preferred 3～5mL/g.
(2R of the present invention, 5S)-5-(cytosine(Cyt)-1-yl)-1, the synthetic method of 3-oxathiolane-2-carboxylic acid-L-menthyl ester can be carried out according to following steps: controlled temperature is between 30～80 ℃, the solution of above-mentioned prepared chloro thing (IV) slowly splashed into use the organic solvent B dissolved, the N that adds acid binding agent in advance, in the solution of O-two (front three is silica-based) cytosine(Cyt), in the dropping process, keep that reaction system is little boils, drip off the back 40～50 ℃ of insulation reaction 2～8 hours, gained reaction solution B obtains (2R through aftertreatment, 5S)-5-(cytosine(Cyt)-1-yl)-1,3-oxathiolane-2-carboxylic acid-L-menthyl ester (VI), described organic solvent B is a toluene, methylene dichloride, ethylene dichloride or trichloroethane, described acid binding agent are triethylamine, Tri-n-Propylamine, tri-isopropyl amine, tri-n-butylamine or pyridine.Employed acid binding agent and N, the amount of substance ratio of O-two (front three is silica-based) cytosine(Cyt) is 1～2:1.
Preferably, described (2R, 5S)-5-(cytosine(Cyt)-1-yl)-1,3-oxathiolane-2-carboxylic acid-L-menthyl ester with structure suc as formula the (2R shown in (III), 5S)-5-hydroxyl-1,3-oxathiolane-2-carboxylic acid-L-menthyl ester is a raw material, the employing one kettle way is synthetic, described one kettle way is synthetic to carry out according to following steps: using organic solvent B dissolved N, add N in the solution of O-two (front three is silica-based) cytosine(Cyt), dinethylformamide and acid binding agent, be about 2～25 ℃ in temperature then, slowly drip with organic solvent A dissolved (2R, 5S)-5-hydroxyl-1, the mixing solutions of 3-oxathiolane-2-carboxylic acid-L-menthyl ester (III) and two (trichloromethyl) carbonic ethers, after dripping off, be incubated 2～4 hours, slowly be warming up to 40～45 ℃ again, reacted 6～10 hours, the gained reaction liquid C obtains (2R through aftertreatment, 5S)-5-(cytosine(Cyt)-1-yl)-1,3-oxathiolane-2-carboxylic acid-L-menthyl ester (VI), described organic solvent B is a toluene, methylene dichloride, ethylene dichloride or trichloroethane, described acid binding agent is a triethylamine, Tri-n-Propylamine, tri-isopropyl amine, tri-n-butylamine or pyridine, described organic solvent A is a methylene dichloride, ethylene dichloride, chloroform or toluene.
Described N, O-two (front three is silica-based) cytosine(Cyt) can be prepared as follows: at consumption is in 3～8 times the organic solvent B of cytosine(Cyt) quality, 1～3% the methylsulfonic acid that with the consumption is the cytosine(Cyt) quality is a catalyzer, cytosine(Cyt) and hexamethyldisilazane reflux to solution are clarified, cold slightly, promptly get N, the solution of the organic solvent B of O-two (front three is silica-based) cytosine(Cyt), the amount of substance ratio that feeds intake of described cytosine(Cyt) and hexamethyldisilazane is 1:0.5～2.
The present invention is in above-mentioned reaction process, and described (2R, 5S)-5-hydroxyl-1, the amount of substance of 3-oxathiolane-2-carboxylic acid-L-menthyl ester (III) and cytosine(Cyt) is than being 1:0.5～2.
Described aftertreatment can be carried out according to following steps: reaction solution B or reaction liquid C are poured in the mixing solutions of the normal hexane that contains triethylamine and water, stirred 2～12 hours, filter, the gained filter residue is water and vinyl acetic monomer drip washing successively, vacuum drying below 60 ℃, get white solid product and be (2R, 5S)-5-(cytosine(Cyt)-1-yl)-1,3-oxathiolane-2-carboxylic acid-L-menthyl ester (VI), employed triethylamine and (2R, 5S)-and 5-hydroxyl-1, the amount of substance ratio of 3-oxathiolane-2-carboxylic acid-L-menthyl ester (III) is 1～2:1.
Compared with prior art, beneficial effect of the present invention is:
1) the present invention substitutes sulfur oxychloride as chlorinating agent with two (trichloromethyl) carbonic ethers in chlorination, has that operational safety is reliable, the advantage of environmental protection.
2) the present invention can adopt one kettle way to react, and makes reactions steps simplify, save production cost under the situation of not losing yield, and is significant for industrial production.
To sum up, (2R of the present invention, 5S)-and 5-(cytosine(Cyt)-1-yl)-1, the synthetic method of 3-oxathiolane-2-carboxylic acid-L-menthyl ester has that operational safety is reliable, environmental protection, processing step is simplified, production cost is low characteristics, is suitable for suitability for industrialized production.
(4) embodiment
The invention will be further described below in conjunction with specific embodiment, but protection scope of the present invention is not limited to this.
Embodiment 1
The preparation of chloro thing: at the there-necked flask of 250m L, add (2R, 5R)-5-hydroxyl-1,3-oxathiolane-2-carboxylic acid-L-menthyl ester (compound III) 28.8 grams (0.1mol), N, dinethylformamide 7.3g, 100m L methylene dichloride, and constantly be stirred to the compound III dissolving.Be cooled to about 0 ℃, controlled temperature is 5-10 ℃, drips by two (trichloromethyl) carbonic ether 11.9 and restrains (0.04mol) in the mixing solutions of 50m L methylene dichloride, slowly is warming up to 30-35 ℃ after all dripping off, and is incubated 2 hours.The gained reaction solution is chloro thing (compound IV) solution, and is stand-by.
N, the preparation of O-two (front three is silica-based) cytosine(Cyt): the there-necked flask of 500m L, add 11.1 gram (0.1mol) cytosine(Cyt)s, hexamethyldisilazane 24.5 grams, 100mL toluene, 3 methylsulfonic acids, reflux 3 hours, to the solution clarification, cold slightly, this is N, the toluene solution of O-two (front three is silica-based) cytosine(Cyt).
(2R, 5S)-5-(cytosine(Cyt)-1-yl)-1, the preparation of 3-oxathiolane-2-carboxylic acid-L-menthyl ester: in temperature is about 80 ℃, and chloro thing (compound IV) solution is slowly splashed into the N that has added 12 gram triethylamines, the toluene solution of O-two (front three is silica-based) cytosine(Cyt), in the dropping process, temperature can slowly reduce, and keeps little the boiling of reaction this moment, to dripping off, the reaction insulation is 6 hours then, stopped reaction.
Aftertreatment: reaction solution is poured one into and is contained in 100g water, 12 gram triethylamines, 60 mixing solutionss that are made into of gram normal hexanes, stirred 6 hours, filter, the gained solids is with 100mL water and the drip washing of 100mL Iso Butyl Acetate, vacuum drying below 60 ℃, get white solid product: 26.5 grams, HPLC purity: 99.12%, chiral purity: 99.03%, fusing point: 217.1-218.3 ℃, yield: 69.5%.
Embodiment 2
The preparation of chloro thing: at the there-necked flask of 250m L, add (2R, 5R)-5-hydroxyl-1,3-oxathiolane-2-carboxylic acid-L-menthyl ester (compound III) 28.8 grams (0.1mol), N, dinethylformamide 7.3g, 100m L methylene dichloride, and constantly be stirred to the compound III dissolving.Be cooled to about 0 ℃, controlled temperature is 5-10 ℃, drips by two (trichloromethyl) carbonic ether 14.9 and restrains (0.05mol) in the mixing solutions of 50m L methylene dichloride, slowly is warming up to 30-35 ℃ after all dripping off, and is incubated 2 hours.The gained reaction solution is chloro thing (compound IV) solution, and is stand-by.
N, the preparation of O-two (front three is silica-based) cytosine(Cyt): with embodiment 1.
(2R, 5S)-5-(cytosine(Cyt)-1-yl)-1, the preparation of 3-oxathiolane-2-carboxylic acid-L-menthyl ester: with embodiment 1
Aftertreatment:, get white solid product with embodiment 1: 26.8 grams, HPLC purity: 99.02%, chiral purity: 99.15%, fusing point: 218.0-218.9 ℃, yield: 70.34%.
Embodiment 3 one kettle ways
The there-necked flask of 500m L adds 11.1 gram (0.1mol) cytosine(Cyt)s, hexamethyldisilazane 24.5 grams, and 100mL toluene, 3 methylsulfonic acids, reflux 3 hours, to the solution clarification, this is N, the toluene solution of O-two (front three is silica-based) cytosine(Cyt).Cold slightly, add N, dinethylformamide 7.3g (0.1mol), the triethylamine of 12 grams, in temperature is about 15～20 ℃, slowly drip by (2R, 5R)-5-hydroxyl-1,3-oxathiolane-2-carboxylic acid-L-menthyl ester (compound III) 28.8 grams (0.1mol) and two (trichloromethyl) carbonic ether 11.9 restrain the mixing solutions that (0.04mol) is dissolved in 150m L methylene dichloride, after dripping off, be incubated 3 hours, slowly be warming up to 40～45 ℃ again, reacted 8 hours.Stopped reaction.
Aftertreatment: reaction solution is poured one into and is contained in 100g water, 12 gram triethylamines, 60 mixing solutionss that are made into of gram normal hexanes, stirred 8 hours, filter, the gained solids is with 100mL water and the drip washing of 100mL Iso Butyl Acetate, vacuum drying below 60 ℃, get white solid product: 27.3 grams, HPLC purity: 99.15%, chiral purity: 99.09%, fusing point: 217.5-218.6 ℃, yield: 71.7%.
Embodiment 4 one kettle ways
The there-necked flask of 500m L adds 11.1 gram (0.1mol) cytosine(Cyt)s, hexamethyldisilazane 24.5 grams, and 150mL toluene, 3 methylsulfonic acids, reflux 4 hours, to the solution clarification, this is N, the toluene solution of O-two (front three is silica-based) cytosine(Cyt).Cold slightly, add N, dinethylformamide 7.3g (0.1mol), the triethylamine of 12 grams, in temperature is about 30～35 ℃, slowly drip by (2R, 5R)-5-hydroxyl-1,3-oxathiolane-2-carboxylic acid-L-menthyl ester (compound III) 28.8 grams (0.1mol) and two (trichloromethyl) carbonic ether 11.9 restrain the mixing solutions that (0.04mol) is dissolved in 150m L methylene dichloride, after dripping off, be incubated 2 hours, slowly be warming up to 40～45 ℃ again, reacted 6 hours.Stopped reaction.
Aftertreatment:, get white solid product with embodiment 3: 27.8 grams, HPLC purity: 99.11%, chiral purity: 99.16%, fusing point: 217.1-218.6 ℃, yield: 73.0%.
Embodiment 5 one kettle ways
The there-necked flask of 500m L adds 11.1 gram (0.1mol) cytosine(Cyt)s, hexamethyldisilazane 24.5 grams, and 100mL toluene, 3 methylsulfonic acids, reflux 2 hours, to the solution clarification, this is N, the toluene solution of O-two (front three is silica-based) cytosine(Cyt).Cold slightly, add N, dinethylformamide 7.3g (0.1mol), the triethylamine of 12 grams, in temperature is about 20～25 ℃, slowly drip by (2R, 5R)-5-hydroxyl-1,3-oxathiolane-2-carboxylic acid-L-menthyl ester (compound III) 28.8 grams (0.1mol) and two (trichloromethyl) carbonic ether 14.9 restrain the mixing solutions that (0.05mol) is dissolved in 150m L methylene dichloride, after dripping off, be incubated 2 hours, slowly be warming up to 40～45 ℃ again, reacted 8 hours.Stopped reaction.
Aftertreatment:, get white solid product with embodiment 3: 27.4 grams, HPLC purity: 99.09%, chiral purity: 99.16%, fusing point: 217.1-218.6 ℃, yield: 71.9%.Embodiment 6 one kettle ways
The there-necked flask of 500m L adds 11.1 gram (0.1mol) cytosine(Cyt)s, hexamethyldisilazane 24.5 grams, and 100mL toluene, 3 methylsulfonic acids, reflux 2 hours, to the solution clarification, this is N, the toluene solution of O-two (front three is silica-based) cytosine(Cyt).Cold slightly, add N, dinethylformamide 7.3g (0.1mol), the triethylamine of 12 grams, in temperature is about 20～25 ℃, slowly drip by (2R, 5R)-5-hydroxyl-1,3-oxathiolane-2-carboxylic acid-L-menthyl ester (compound III) 28.8 grams (0.1mol) and two (trichloromethyl) carbonic ether 17.8 restrain the mixing solutions that (0.06mol) is dissolved in 150m L methylene dichloride, after dripping off, be incubated 2 hours, slowly be warming up to 40～45 ℃ again, reacted 8 hours.Stopped reaction.
Aftertreatment:, get white solid product with embodiment 3: 26.9 grams, HPLC purity: 99.18%, chiral purity: 99.21%, fusing point: 217.1-218.8 ℃, yield: 70.6%.
Claims (10)
1. structure is suc as formula (the 2R shown in (VI), 5S)-5-(cytosine(Cyt)-1-yl)-1, the synthetic method of 3-oxathiolane-2-carboxylic acid-L-menthyl ester, with structure suc as formula (2R shown in (III), 5S)-and 5-hydroxyl-1,3-oxathiolane-2-carboxylic acid-L-menthyl ester is a raw material, obtains structure suc as formula the chloro thing shown in (IV) by chlorination, chloro thing (IV) and the N of structure shown in formula V, the condensation of O-two (front three is silica-based) cytosine(Cyt), hydrolysis make;
It is characterized in that described synthetic method carries out according to following steps: controlled temperature is between 30～80 ℃, the solution of chloro thing (IV) slowly splashed into use the organic solvent B dissolved, the N that adds acid binding agent in advance, in the solution of O-two (front three is silica-based) cytosine(Cyt) (V), in the dropping process, keep that reaction system is little boils, drip off the back 40～50 ℃ of insulation reaction 2～8 hours, gained reaction solution B obtains (2R through aftertreatment, 5S)-5-(cytosine(Cyt)-1-yl)-1,3-oxathiolane-2-carboxylic acid-L-menthyl ester (VI), described organic solvent B is a toluene, methylene dichloride, ethylene dichloride or trichloroethane, described acid binding agent are triethylamine, Tri-n-Propylamine, tri-isopropyl amine, tri-n-butylamine or pyridine;
The solution of described muriate (IV) makes by chlorination, described chlorination specifically carries out according to following steps: add (2R in reaction vessel, 5S)-5-hydroxyl-1,3-oxathiolane-2-carboxylic acid-L-menthyl ester (III), N, dinethylformamide and organic solvent A, fully stir and make (2R, 5S)-5-hydroxyl-1,3-oxathiolane-2-carboxylic acid-L-menthyl ester (III) dissolving, drip solution then with two (trichloromethyl) carbonic ethers (VII) of same organic solvent A dissolved, the control dropping temperature is at 0～10 ℃, slowly be warming up to 30～35 ℃ after dropwising, insulation reaction 1～6 hour, gained reaction solution A is the solution of chloro thing (IV); Described organic solvent A is methylene dichloride, ethylene dichloride, chloroform or toluene;
2. synthetic method as claimed in claim 1, it is characterized in that described (2R, 5S)-5-hydroxyl-1,3-oxathiolane-2-carboxylic acid-L-menthyl ester (III), two (trichloromethyl) carbonic ether (VII) and N, the amount of substance ratio that feeds intake of dinethylformamide is 1: 0.35～0.5: 1～1.5.
3. synthetic method as claimed in claim 1, the consumption that it is characterized in that described organic solvent A is so that (2R, 5S)-5-hydroxyl-1, the quality of 3-oxathiolane-2-carboxylic acid-L-menthyl ester (III) is counted 2～20mL/g.
4. synthetic method as claimed in claim 1, it is characterized in that described N, O-two (front three is silica-based) cytosine(Cyt) can be prepared as follows: at consumption is in 3～8 times the organic solvent B of cytosine(Cyt) quality, 1～3% the methylsulfonic acid that with the consumption is the cytosine(Cyt) quality is a catalyzer, cytosine(Cyt) and hexamethyldisilazane reflux to solution are clarified, cold slightly, promptly get N, the solution of the organic solvent B of O-two (front three is silica-based) cytosine(Cyt), the amount of substance ratio that feeds intake of described cytosine(Cyt) and hexamethyldisilazane is 1: 0.5～2.
5. synthetic method as claimed in claim 4 is characterized in that described (2R, 5S)-5-hydroxyl-1, the amount of substance ratio of 3-oxathiolane-2-carboxylic acid-L-menthyl ester (III) and cytosine(Cyt) is 1: 0.5～2.
6. synthetic method as claimed in claim 1, it is characterized in that described post-processing step is: reaction solution B is poured in the mixing solutions of the normal hexane that contains triethylamine and water, stirred 2～12 hours, filter, the gained filter residue is water and vinyl acetic monomer drip washing successively, vacuum drying below 60 ℃, get white solid product and be (2R, 5S)-5-(cytosine(Cyt)-1-yl)-1,3-oxathiolane-2-carboxylic acid-L-menthyl ester (VI), employed triethylamine is with (2R, 5S)-5-hydroxyl-1, the amount of substance ratio of 3-oxathiolane-2-carboxylic acid-L-menthyl ester (III) is 1～2: 1.
7. structure is suc as formula (the 2R shown in (VI), 5S)-5-(cytosine(Cyt)-1-yl)-1, the synthetic method of 3-oxathiolane-2-carboxylic acid-L-menthyl ester, it is characterized in that described (2R, 5S)-5-(cytosine(Cyt)-1-yl)-1,3-oxathiolane-2-carboxylic acid-L-menthyl ester with structure suc as formula (2R shown in (III), 5S)-5-hydroxyl-1,3-oxathiolane-2-carboxylic acid-L-menthyl ester is that raw material adopts one kettle way synthetic, described one kettle way is synthetic to carry out according to following steps: using organic solvent B dissolved N, add N in the solution of O-two (front three is silica-based) cytosine(Cyt) (V), dinethylformamide and acid binding agent, it is 2～25 ℃ in temperature then, slowly drip with organic solvent A dissolved (2R, 5S)-5-hydroxyl-1, the mixing solutions of 3-oxathiolane-2-carboxylic acid-L-menthyl ester (III) and two (trichloromethyl) carbonic ethers (VII), after dripping off, be incubated 2～4 hours, slowly be warming up to 40～45 ℃ again, reacted 6～10 hours, the gained reaction liquid C obtains (2R through aftertreatment, 5S)-5-(cytosine(Cyt)-1-yl)-1,3-oxathiolane-2-carboxylic acid-L-menthyl ester (VI), described organic solvent B is a toluene, methylene dichloride, ethylene dichloride or trichloroethane, described acid binding agent is a triethylamine, Tri-n-Propylamine, tri-isopropyl amine, tri-n-butylamine or pyridine, described organic solvent A is a methylene dichloride, ethylene dichloride, chloroform or toluene;
8. synthetic method as claimed in claim 7, it is characterized in that described N, O-two (front three is silica-based) cytosine(Cyt) can be made each as follows: at consumption is in 3～8 times the organic solvent B of cytosine(Cyt) quality, 1～3% the methylsulfonic acid that with the consumption is the cytosine(Cyt) quality is a catalyzer, cytosine(Cyt) and hexamethyldisilazane reflux to solution are clarified, cold slightly, promptly get N, the solution of the organic solvent B of O-two (front three is silica-based) cytosine(Cyt), the amount of substance ratio that feeds intake of described cytosine(Cyt) and hexamethyldisilazane is 1: 0.5～2.
9. synthetic method as claimed in claim 8 is characterized in that described (2R, 5S)-5-hydroxyl-1, the amount of substance ratio of 3-oxathiolane-2-carboxylic acid-L-menthyl ester (III) and cytosine(Cyt) is 1: 0.5～2.
10. synthetic method as claimed in claim 7, it is characterized in that described post-processing step is: reaction liquid C is poured in the mixing solutions of the normal hexane that contains triethylamine and water, stirred 2～12 hours, filter, the gained filter residue is water and vinyl acetic monomer drip washing successively, vacuum drying below 60 ℃, get white solid product and be (2R, 5S)-5-(cytosine(Cyt)-1-yl)-1,3-oxathiolane-2-carboxylic acid-L-menthyl ester (VI), employed triethylamine is with (2R, 5S)-5-hydroxyl-1, the amount of substance ratio of 3-oxathiolane-2-carboxylic acid-L-menthyl ester (III) is 1～2: 1.
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| CN101830893A (en) * | 2010-05-31 | 2010-09-15 | 安徽一帆香料有限公司 | Synthesis and preparation process of lamivudine intermediate HDMS |
| CN103864835A (en) * | 2013-03-26 | 2014-06-18 | 安徽贝克联合制药有限公司 | Preparation method for improving stereoselectivity of lamivudine intermediate |
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| Title |
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| Michael D. Goodyear ET-AL.Practical enantioselective synthesis of lamivudine (3TCTM) via a dynamic kinetic resolution.《tetrahedron letters》.2005,第46卷(第49期), * |
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