CN102234269A - Industrial preparation method for lamivudine - Google Patents
Industrial preparation method for lamivudine Download PDFInfo
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- CN102234269A CN102234269A CN201010159550XA CN201010159550A CN102234269A CN 102234269 A CN102234269 A CN 102234269A CN 201010159550X A CN201010159550X A CN 201010159550XA CN 201010159550 A CN201010159550 A CN 201010159550A CN 102234269 A CN102234269 A CN 102234269A
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Abstract
The invention discloses an industrial preparation method for lamivudine (3TC). The method is characterized in that: 5-hydroxyl-1,3-oxathiolane-2-carboxylic acid [(1<,>R, 2<,>S, 5<,>R)-5<,>-methyl-2<,>-(1-methylethyl) cyclohexyl] ester reacts with a acylating agent to obtain a acylate; the acylate and monosilylated acyl cytosine or monosilylated cytosine schiff's base are subjected to a glycosylation through a catalysis of lewis acid to obtain a 3TC intermediate, followed by reducing and deacylating or hydrolyzing and reducing to obtain the 3TC. The method provided by the present invention has advantages of simple, available and cheap raw materials, simple operation, safe production, high yield, less waste pollution, and is applicable for industrial production.
Description
Technical field
The invention belongs to chemistry or pharmaceutical chemistry field, be specifically related to the industrialized process for preparing of anti-hepatic-B virus medicine lamivudine.
Background technology
(Lamivudine, 3TC) suc as formula shown in (I), its chemistry (2R-cis)-4-amino-1-(2-methylol-1,3-oxygen thia ring penta-5-yl) by name-1H-pyrimid-2-one is the nucleoside analog antiviral drug to lamivudine.Nucleotide is the raw material of synthesized human hereditary material DNA and RNA, lamivudine is structurally simulated the structure of Nucleotide, but the function that does not have Nucleotide, 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.Therefore in the DNA building-up process, nucleoside analog can mix into, but can not synthesize the nucleic acid chains that normal function is arranged, thereby makes the termination of duplicating of virus.Lamivudine has become the main medicine of treatment virus of AIDS and hepatitis B virus at present.
Lamivudine is an optical isomer, and 2 chiral centres are arranged in the molecular structure, and the asymmetric synthesis complex process is so industrialized process for preparing is very crucial.
CN1563003 discloses a kind of lamivudine and has been fit to industrialized preparation method, intermediate product (the 5R)-acetoxyl group-1 of this method preparation, the 3-oxathiolane-(2R)-carboxylic acid-[(1 ' R, 2 ' S, 5 ' R)-5 '-methyl-2 '-(1-methylethyl) cyclohexyl] yield of ester only is 40%; At (5R)-acetoxyl group-1; the 3-oxathiolane-(2R)-carboxylic acid-[(1 ' R; 2 ' S; 5 ' R)-5 '-methyl-2 '-(1-methylethyl) cyclohexyl] forms the cytosine(Cyt) of pair protected silanes in the actual procedure of ester and cytosine(Cyt) reaction earlier with the cytosine(Cyt) reaction by silane reagent; again with (5R)-acetoxyl group-1; the 3-oxathiolane-(2R)-carboxylic acid-[(1 ' R, 2 ' S, 5 ' R)-5 '-methyl-2 '-(1-methylethyl) cyclohexyl] ester condensation reaction.Used inflammable and explosive ether in this method aftertreatment; but also adopted after the silica gel adsorption again the purification process of recrystallization after the column chromatography for separation; process is numerous and diverse; the production operation difficulty is not suitable for suitability for industrialized production, in addition; this method is owing to adopt silane reagent to form the cytosine(Cyt) of two protected silanes earlier with the cytosine(Cyt) reaction; hexamethyl nitrogen silane is not only as solvent but also as reaction reagent, and it is too many to consume hexamethyl nitrogen silane, causes the cost of lamivudine to increase.
CN1566112 discloses a kind of cis-selectivity preparation method of lamivudine; at preparation (2R; 5S)-5-(4-acetoxyl group-2 oxos-pyrimidine-1-yl)-1; in 3-oxathiolane-2-carboxylic acid-(-)-norbornene ester process; actual procedure is to adopt N-acetylcytosine and the reaction of first silylating reagent to form the N-acetylcytosine of single protected silane; the N-acetylcytosine of single protected silane again with 5-chloro-1,3-oxathiolane-2-carboxylic acid-(-)-norbornene ester condensation.This method prepares 5-chloro-1, and the chlorination process of 3-oxathiolane-2-carboxylic acid-(-)-norbornene ester has been used the great sulfur oxychloride of equipment corrosion; Reaction process produces form waste gas of sulfur dioxide, serious environment pollution; Chloro thing and N-acetylcytosine reaction yield are not high only to be 66%, the neither suitability for industrialized production that is beneficial to of above factor.
CN101597281A discloses a kind of lamivudine and intermediates preparation thereof, this method is at preparation (2R, 5R)-5-ethanoyl-[1,3] use diacetyl oxide, Acetyl Chloride 98Min. in the process of oxathiolane-2-carboxylic acid (2S-sec.-propyl-5R-methyl isophthalic acid R-cyclohexyl) ester, though yield reaches 90% or 88.5%, but the product purity that obtains is low; At preparation (2R; 5R)-5-propionyl-[1; 3] use propionic anhydride in the process of oxathiolane-2-carboxylic acid (2S-sec.-propyl-5R-methyl isophthalic acid R-cyclohexyl) ester; yield 86%; at preparation (2R; 5S)-5-(4-amino-2-oxo pyridine-1-yl)-[1; 3] adopt silane reagent to form the cytosine(Cyt) of the two protections of silane earlier with the cytosine(Cyt) reaction in the process of oxathiolane-2-carboxylic acid (2S-sec.-propyl-5R-methyl isophthalic acid R-cyclohexyl) ester; the cytosine(Cyt) of two protected silanes participates in condensation reaction again; though improved yield; but the purity of the product that obtains is lower; purity with this lamivudine for preparing is also lower; must just can reach medicinal requirements through recrystallization purifying repeatedly, operating process is loaded down with trivial details, realizes the suitability for industrialized production difficulty.
More than the preparation method of disclosed lamivudine, still deposit some deficiency, it is all high to seek a kind of simple to operate, safety and environmental protection, yield and purity, the method that is fit to suitability for industrialized production is necessary.The present invention finishes for this reason.
Summary of the invention
Purpose of the present invention provides a kind of industrialized process for preparing of lamivudine, and this method has overcome the deficiencies in the prior art, and its advantage is: raw material be simple and easy to, low price, easy and simple to handle, the product purity height can fulfilling medicinal requirements, the yield height, three-waste pollution is few, is fit to suitability for industrialized production.
For realizing purpose of the present invention, provide following embodiment.
In one embodiment, the industrialized process for preparing of lamivudine of the present invention (I), its process comprises:
A) 5-hydroxyl-1,3-oxathiolane-2-carboxylic acid [(1 ' R, 2 ' S, 5 ' R)-5 '-methyl-2 '-(1-methylethyl) cyclohexyl] ester (II) and acylation reaction obtain acylate (III), wherein,
R in formula (III) acylate is alkyl acyl group, aromatic base carboxyl groups or alkylsulfonyl group;
B) glycosylation takes place and obtains formula (VA) compound or formula (VB) compound in the cytosine(Cyt) schiff bases (IVB) of the acyl group cytosine(Cyt) (IVA) of the acylate that step a) is obtained (III) and single silanization or single silanization under Louis acid catalysis,
Wherein, formula (IVA) and (VA) X in the compound be formyl radical, ethanoyl, propionyl, different propionyl, butyryl radicals, formula (IVB) and (VB) Y in the compound be phenyl, m-nitro base, p-nitrophenyl, a chloro-phenyl-, rubigan, p-methoxyphenyl, p-methylphenyl, o-methyl-phenyl-, a hydroxy phenyl, o-hydroxy-phenyl, benzyl;
C) formula that step b) is obtained (VA) compound obtains compound (VIA) through reduction, or formula (VB) compound obtains compound (VIB) through hydrolysis;
(VIA) (VIB)
Wherein, the X in formula (VIA) compound is formyl radical, ethanoyl, propionyl, different propionyl, butyryl radicals;
D) compound that step c) is obtained (VIA) is sloughed acyl group or compound compound (VIB) reduction that step c) obtains is obtained lamivudine (I).
In above-mentioned embodiment, the formula of step a) (III) acylate, wherein, said alkyl acyl group comprises formyl radical, ethanoyl, propionyl, different propionyl, butyryl radicals, isobutyryl, pentanoyl, phenylacetyl, hydrocinnamoyl, preferred ethanoyl, propionyl, different propionyl or butyryl radicals, more preferably ethanoyl, propionyl; Said aromatic base carboxyl groups comprises benzoyl, to toluyl, p-nitrophenyl formyl radical; Said alkylsulfonyl group comprises methane sulfonyl, ethane alkylsulfonyl, benzenesulfonyl, p-toluenesulfonyl or acetparaminosalol benzenesulfonyl.
In above-mentioned embodiment, in step b) or the step c), said X is ethanoyl or propionyl, and said Y is phenyl or p-methylphenyl.
In above-mentioned embodiment, the acylating agent in the step a) comprises diacetyl oxide, Acetyl Chloride 98Min., acetyl bromide, acetyliodide, acetic ester, acetate, propionic anhydride, propionyl chloride, propionyl bromide, propionyl iodide, propionic ester or propionic acid, preferred diacetyl oxide or propionic anhydride.
In above-mentioned embodiment, the acylation reaction of step a) is by formula (II) compound and solvent, catalyst mix, carries out at a certain temperature, wherein, said solvent is tetrahydrofuran (THF), trichloromethane, methylene dichloride or their mixture, preferred tetrahydrofuran (THF); Described catalyzer is 4-Dimethylamino pyridine (DMAP), N, N-dicyclohexylcarbodiimide (DCC) or their mixture, preferred 4-Dimethylamino pyridine; Said temperature of reaction is that said temperature of reaction is-60～-5 ℃, preferred-30～-15 ℃, more preferably-25～-20 ℃.
In above-mentioned embodiment, the acyl group cytosine(Cyt) (IVA) of the single silanization in the step b) is to be made by acyl group cytosine(Cyt), catalyzer, silylating reagent and solvent afterreaction.Wherein, said acyl group cytosine(Cyt) comprises N-formyl cytosine(Cyt), N-acetylcytosine, N-propionyl cytosine(Cyt), the different propionyl cytosine(Cyt) of N-, N-butyryl cytosine(Cyt), preferred N-acetylcytosine, N-propionyl cytosine(Cyt), more preferably N-acetylcytosine; Said catalyzer comprises ammonium sulfate, ammonium chloride, methylsulfonic acid, tosic acid, the preferably sulfuric acid ammonium; Said silylating reagent comprises trimethylchlorosilane, Iodotrimethylsilane, hexamethyldisilazane, preferred hexamethyldisilazane; Said solvent comprises methylene dichloride, trichloromethane, benzene, toluene, preferred trichloromethane.
In above-mentioned all embodiments, the Lewis acid in the said step b) comprises the mixture that Iodotrimethylsilane, trimethylchlorosilane or trimethylchlorosilane and potassiumiodide or sodium iodide are formed, preferred Iodotrimethylsilane.
In above-mentioned embodiment, said reduction is to carry out in the presence of a kind of reductive agent in the step c), wherein, described reductive agent comprises POTASSIUM BOROHYDRIDE, sodium borohydride, lithium borohydride, zinc borohydride, hydroboration calcium, sodium cyanoborohydride, sodium triacetoxy borohydride, lithium triethylborohydride, 3-sec-butyl lithium borohydride, tetrahydrochysene lithium aluminium or three tert.-butoxy lithium aluminum hydrides, preferred POTASSIUM BOROHYDRIDE, sodium borohydride or lithium borohydride, more preferably POTASSIUM BOROHYDRIDE.
In above-mentioned embodiment, in the step c), said hydrolysis is to carry out in the presence of diluted acid, and wherein, said diluted acid comprises dilute hydrochloric acid, acetic acid,diluted, dilute sulphuric acid or rare nitric acid, preferred dilute hydrochloric acid.
In above-mentioned embodiment, in the step d), formula (VIA) compound is sloughed acyl group and is obtained lamivudine and carry out under alkaline condition, and wherein, said alkaline condition comprises the aqueous solution, alkali alcosol or their mixture of alkali.The aqueous solution of said alkali, alkali alcosol, wherein said alkali comprises sodium hydroxide, potassium hydroxide, lithium hydroxide, strontium hydroxide, salt of wormwood, saleratus, yellow soda ash, sodium bicarbonate or ammonia, preferred ammonia; Described alcohol is methyl alcohol, ethanol or Virahol, particular methanol.Preferred alkaline condition is the methanol solution of ammonia or the methanol solution of sodium hydroxide.
In above-mentioned embodiment, in step d), it is to carry out in the presence of reductive agent that the reduction of formula (VIB) compound obtains lamivudine, wherein, said reductive agent comprises POTASSIUM BOROHYDRIDE, sodium borohydride, lithium borohydride, zinc borohydride, hydroboration calcium, sodium cyanoborohydride, sodium triacetoxy borohydride, lithium triethylborohydride, 3-sec-butyl lithium borohydride, tetrahydrochysene lithium aluminium or three tert.-butoxy lithium aluminum hydrides, preferred POTASSIUM BOROHYDRIDE, sodium borohydride or lithium borohydride, more preferably POTASSIUM BOROHYDRIDE.
In above-mentioned embodiment, the cytosine(Cyt) schiff bases (IVB) in the step b) is to be made by the reaction of the phenyl aldehyde of cytosine(Cyt) and phenyl aldehyde or replacement.Wherein, the phenyl aldehyde of said replacement comprises m-nitrobenzaldehyde, paranitrobenzaldehyde, m chlorobenzaldehyde, 4-chloro-benzaldehyde, p-tolyl aldehyde, o-methyl-benzene formaldehyde, m-hydroxybenzaldehyde, salicylaldhyde, phenylacetic aldehyde or aubepine, preferred phenyl aldehyde or p-tolyl aldehyde.
The industrialized process for preparing of lamivudine of the present invention specifically describes:
Method of the present invention is with 5-hydroxyl-1; 3-oxathiolane-2-carboxylic acid [(1 ' R; 2 ' S; 5 ' R)-5 '-methyl-2 '-(1-methylethyl) cyclohexyl] ester (II) and acylation reaction obtain acylate; glycosylation takes place and obtains lamivudine intermediate formula (VA) and formula (VB) in the acyl group cytosine(Cyt) (IVA) of acylate and single silanization or the cytosine(Cyt) schiff bases (IVB) of single silanization under Louis acid catalysis; formula (VA) restores, the deacylated tRNA base obtains lamivudine, and formula (VB) hydrolysis, reduction obtain lamivudine.
Method of the present invention; reagent and operations such as inflammable and explosive ether, loaded down with trivial details column chromatography, corrodibility sulfur oxychloride big and big for environment pollution and acyl chlorides have been cut off; the acyl group cytosine(Cyt) is the industrialization raw material, and the preparation of cytosine(Cyt) schiff bases is simple, and industrialization is easy to implement.
Preparation of industrialization lamivudine method of the present invention, its synthetic route is as follows:
Synthetic route 1:
Synthetic line 2:
Wherein, in the formula (III), R is alkyl acyl group, aromatic base carboxyl groups and alkylsulfonyl group, wherein the alkyl acyl group comprises formyl radical, ethanoyl, propionyl, different propionyl, butyryl radicals, isobutyryl, pentanoyl, phenylacetyl, hydrocinnamoyl etc., the aromatic base carboxyl groups comprises benzoyl, to toluyl, p-nitrophenyl formyl radical etc., the alkylsulfonyl group comprises methane sulfonyl, ethane alkylsulfonyl, benzenesulfonyl, p-toluenesulfonyl, acetparaminosalol benzenesulfonyl, is preferably ethanoyl, propionyl; X is formyl radical, ethanoyl, propionyl, different propionyl, butyryl radicals in formula (IVA), formula (VA) and the formula (VIA), is preferably ethanoyl, propionyl, more preferably ethanoyl; Y is phenyl, m-nitro base, p-nitrophenyl, a chloro-phenyl-, rubigan, p-methoxyphenyl, p-methylphenyl, o-methyl-phenyl-, a hydroxy phenyl, o-hydroxy-phenyl, benzyl in formula (IVB), formula (VB) and the formula (VIB), is preferably phenyl or p-methylphenyl.
Method of the present invention, its concrete steps are:
A) with 5-hydroxyl-1,3-oxathiolane-2-carboxylic acid [(1 ' R, 2 ' S, 5 ' R)-5 '-methyl-2 '-(1-methylethyl) cyclohexyl] ester (II) and acylation reaction obtain acylate (III);
B) glycosylation takes place and obtains lamivudine midbody compound (VA) or (VB) in the cytosine(Cyt) schiff bases (IVB) of the acyl group cytosine(Cyt) (IVA) of the acylate that is obtained by step a) (III) and single silanization or single silanization under Louis acid catalysis;
C) the lamivudine midbody compound (VA) that is obtained by step b) obtains compound (VIA) through the reductive agent reduction, and the lamivudine midbody compound (VB) that is obtained by step b) obtains compound (VIB) through dilute acid hydrolysis;
D) the lamivudine midbody compound (VIA) that is obtained by step c) is sloughed acyl group and is obtained lamivudine (I) under alkaline condition, and lamivudine midbody compound (VIB) obtains lamivudine (I) through the reductive agent reduction.
The method of the invention described above, each reactions steps specifically describes as follows:
Step a): 5-hydroxyl-1,3-oxathiolane-2-carboxylic acid [(1 ' R, 2 ' S, 5 ' R)-5 '-methyl-2 '-(1-methylethyl) cyclohexyl] ester (II) and solvent, catalyst mix, carry out acylation reaction at a certain temperature, reaction finishes back dropping alkali aqueous solution and is transferred to neutrality, standing demix, water layer solvent extraction, collected organic layer, dry filter, filtrate decompression concentrates, and obtains acylate (III) with the aqueous ethanol recrystallization; Wherein, suitable solvent is tetrahydrofuran (THF), trichloromethane, methylene dichloride or their mixture, and preferred solvent is a tetrahydrofuran (THF); Appropriate catalyst is 4-Dimethylamino pyridine (DMAP) or N, N-dicyclohexylcarbodiimide (DCC) or 4-Dimethylamino pyridine and N, and the mixture that the N-dicyclohexylcarbodiimide is formed, preferred catalyst is the 4-Dimethylamino pyridine; Suitable reaction temperature is-60～-5 ℃, preferred-30～-15 ℃, more preferably-25～-20 ℃; R in formula (III) acylate is alkyl acyl group, aromatic base carboxyl groups and alkylsulfonyl group, wherein the alkyl acyl group comprises formyl radical, ethanoyl, propionyl, different propionyl, butyryl radicals, isobutyryl, pentanoyl, phenylacetyl, hydrocinnamoyl etc., the aromatic base carboxyl groups comprises benzoyl, to toluyl, p-nitrophenyl formyl radical etc., the alkylsulfonyl group comprises methane sulfonyl, ethane alkylsulfonyl, benzenesulfonyl, p-toluenesulfonyl, acetparaminosalol benzenesulfonyl, is preferably ethanoyl, propionyl; When the R in formula (III) acylate was ethanoyl, suitable acylating agent was diacetyl oxide, Acetyl Chloride 98Min., acetyl bromide, acetyliodide, acetic ester, acetate, preferred diacetyl oxide; When the R in (III) acylate was propionyl, suitable acylating agent was propionic anhydride, propionyl chloride, propionyl bromide, propionyl iodide, propionic ester, propionic acid, preferred propionic anhydride.
Step b): acyl group cytosine(Cyt), catalyzer, silylating reagent, solvent, heat up until reaction solution dissolving clarification, obtain the acyl group cytosine(Cyt) (IVA) of single silanization; Wherein suitable acyl group cytosine(Cyt) comprises N-formyl cytosine(Cyt), N-acetylcytosine, N-propionyl cytosine(Cyt), the different propionyl cytosine(Cyt) of N-, N-butyryl cytosine(Cyt), preferred N-acetylcytosine, N-propionyl cytosine(Cyt), more preferably N-acetylcytosine; Appropriate catalyst comprises ammonium sulfate, ammonium chloride, methylsulfonic acid, tosic acid, the preferably sulfuric acid ammonium; Suitable silylating reagent comprises trimethylchlorosilane, Iodotrimethylsilane, hexamethyldisilazane, preferred hexamethyldisilazane; Suitable solvent comprises methylene dichloride, trichloromethane, benzene, toluene, preferred trichloromethane.
Glycosylation takes place with the acyl group cytosine(Cyt) (IVA) of single silanization and obtains lamivudine midbody compound (VA) in the acylate (III) that is obtained by step a) under Louis acid catalysis; Wherein suitable Lewis acid comprises the mixture that four Iodotrimethylsilanes, trimethylchlorosilane or trimethylchlorosilane and potassiumiodide or sodium iodide are formed, preferred Iodotrimethylsilane.
The phenyl aldehyde of cytosine(Cyt) and phenyl aldehyde or replacement reacts under suitable solvent and makes the cytosine(Cyt) schiff bases.Cytosine(Cyt) schiff bases, catalyzer, silylating reagent, solvent heat up until reaction solution dissolving clarification, obtain the cytosine(Cyt) schiff bases (IVB) of single silanization; Wherein, the phenyl aldehyde that replaces comprises m-nitrobenzaldehyde, paranitrobenzaldehyde, m chlorobenzaldehyde, 4-chloro-benzaldehyde, p-tolyl aldehyde, o-methyl-benzene formaldehyde, m-hydroxybenzaldehyde, salicylaldhyde, phenylacetic aldehyde, aubepine, preferred phenyl aldehyde or p-tolyl aldehyde; Appropriate catalyst comprises ammonium sulfate, ammonium chloride, methylsulfonic acid, tosic acid, the preferably sulfuric acid ammonium; Suitable silylating reagent comprises trimethylchlorosilane, Iodotrimethylsilane, hexamethyldisilazane, preferred hexamethyldisilazane; Suitable solvent comprises methylene dichloride, trichloromethane, benzene, toluene, preferred trichloromethane.
Glycosylation takes place with the cytosine(Cyt) schiff bases (IVB) of single silanization and obtains lamivudine midbody compound (VB) in the acylate (III) that is obtained by step a) under Louis acid catalysis; Wherein suitable Lewis acid comprises the mixture that Iodotrimethylsilane, trimethylchlorosilane, trimethylchlorosilane and potassiumiodide or sodium iodide are formed, preferred Iodotrimethylsilane.
Step c): the compound (VA) that is obtained by step b) obtains compound (VIA) with the reductive agent reduction in solvent; Wherein appropriate reductant comprises POTASSIUM BOROHYDRIDE, sodium borohydride, lithium borohydride, zinc borohydride, hydroboration calcium, sodium cyanoborohydride, sodium triacetoxy borohydride, lithium triethylborohydride, 3-sec-butyl lithium borohydride, tetrahydrochysene lithium aluminium, three tert.-butoxy lithium aluminum hydrides, preferred POTASSIUM BOROHYDRIDE, sodium borohydride, lithium borohydride, more preferably POTASSIUM BOROHYDRIDE.
The compound (VB) that is obtained by step b) obtains compound (VIB) in hydrolysis, and hydrolysising condition comprises dilute hydrochloric acid, dilute sulphuric acid, acetic acid,diluted, rare nitric acid, preferred dilute hydrochloric acid.
Step d): the compound (VIA) that is obtained by step c) is sloughed acyl group and is obtained lamivudine (I) crude product under alkaline condition, the gained crude product gets lamivudine through recrystallization.Wherein alkaline condition comprises the aqueous solution, alkali alcosol or their mixture of alkali, and the aqueous solution of alkali comprises the aqueous solution of sodium hydroxide, potassium hydroxide, lithium hydroxide, strontium hydroxide, salt of wormwood, saleratus, yellow soda ash, sodium bicarbonate, ammonia; Alkali alcosol comprises methyl alcohol or the ethanol or the aqueous isopropanol of sodium hydroxide, potassium hydroxide, lithium hydroxide, strontium hydroxide, salt of wormwood, saleratus, yellow soda ash, sodium bicarbonate, ammonia; Their mixture is methyl alcohol or the ethanol or the isopropanol water solution of sodium hydroxide, potassium hydroxide, lithium hydroxide, strontium hydroxide, salt of wormwood, saleratus, yellow soda ash, sodium bicarbonate, ammonia, the methanol solution of preferred ammonia and the methanol solution of sodium hydroxide.
The compound (VIB) that is obtained by step c) obtains lamivudine (I) crude product with the reductive agent reduction, and the gained crude product gets lamivudine through recrystallization; Wherein appropriate reductant comprises POTASSIUM BOROHYDRIDE, sodium borohydride, lithium borohydride, zinc borohydride, hydroboration calcium, sodium cyanoborohydride, sodium triacetoxy borohydride, lithium triethylborohydride, 3-sec-butyl lithium borohydride, tetrahydrochysene lithium aluminium, three tert.-butoxy lithium aluminum hydrides, preferred POTASSIUM BOROHYDRIDE, sodium borohydride, lithium borohydride, more preferably POTASSIUM BOROHYDRIDE.
The advantage of method of the present invention: method of the present invention, in step a), do not use the big sulfur oxychloride of corrodibility, acyl chlorides, adopted non-corrosive diacetyl oxide, propionic anhydride.In step b), acyl group cytosine(Cyt) source is easy to get, and it is few, with low cost to prepare the silylating reagent that the acyl group cytosine(Cyt) (IVA) of single silanization consumes, and yield is higher; In described step b), preparation cytosine(Cyt) schiff bases is simple and convenient, and it is few, with low cost to prepare the silylating reagent that the cytosine(Cyt) schiff bases (IVB) of single silanization consumes, and yield is higher.In step c), the compound (VA) that is obtained by step b) obtains the inexpensive POTASSIUM BOROHYDRIDE of compound (VIA) use with the reductive agent reduction in solvent, product chiral purity height, and yield is higher; In step c), the compound (VB) that is obtained by step b) obtains compound (VIB) in hydrolysis, uses the dilute hydrochloric acid hydrolysis, and is convenient and easy.In described step d), compound (VIA) is sloughed acyl group and is obtained lamivudine (I) crude product under alkaline condition, uses the methanol solution of the ammonia that cheaply is easy to get and the methanol solution of sodium hydroxide; Compound (VIB) obtains lamivudine (I) crude product with the reductive agent reduction, uses inexpensive POTASSIUM BOROHYDRIDE, product chiral purity height, and yield is higher.Reaction process does not have loaded down with trivial details column chromatography, repeatedly operation such as recrystallization, and industrialization is implemented easily.
In a word, raw material of the present invention is simple and easy to, and is easy and simple to handle, production safety, and the yield height, three-waste pollution is few, is fit to suitability for industrialized production.
Compound (II) 5-hydroxyl-1,3-oxathiolane-2-carboxylic acid [(1 ' R, 2 ' S, 5 ' R)-5 '-methyl-2 '-(1-methylethyl) cyclohexyl] ester can be according to the method preparation of introducing among the US6051709, and US6051709 introduces the present invention in full.
Embodiment
Following examples are used for further explaining the present invention, but do not limit the scope of the invention.
In following examples, the per-cent that relates to is weight percentage, and temperature is a centigradetemperature; And having used the abbreviation of following form, DMAP represents the 4-Dimethylamino pyridine.
Embodiment 1:
(5R)-and acetoxyl group-1,3-oxathiolane-(2R)-carboxylic acid-[(1 ' R, 2 ' S, 5 ' R)-5 '-methyl-2 '-(1-methylethyl) cyclohexyl] preparation of ester (IIIA)
With compound (II) 5-hydroxyl-1,3-oxathiolane-2-carboxylic acid [(1 ' R, 2 ' S, 5 ' R)-5 '-methyl-2 '-(1-methylethyl) cyclohexyl] ester (200g) drops in the 2L there-necked flask, adds DMAP (10.16g) and tetrahydrofuran (THF) 600ml, stirring and dissolving, be cooled to-25～-20 ℃, dripped diacetyl oxide 99ml in 2～3 hours, dropwise the back and continue reaction 45～60min, slowly dripping 10% aqueous sodium carbonate accent pH then is 7, change in the separating funnel, standing demix, water layer extracts 2 times with the 100ml tetrahydrofuran (THF), collected organic layer, anhydrous magnesium sulfate drying spends the night, filter, filter cake washs with a small amount of tetrahydrofuran (THF), 60 ℃ of concentrating under reduced pressure of filtrate, with 90% ethanol (600ml) recrystallization, filter, filter cake washs with a small amount of frozen ethanol, and 40 ℃ of drying under reduced pressure spend the night, get compound (IIIA) needle crystal 103.1g, yield 45%, content 99.5%, mp104-105 ℃.
Embodiment 2:
(5R)-and propionyloxy-1,3-oxathiolane-(2R)-carboxylic acid-[(1 ' R, 2 ' S, 5 ' R)-5 '-methyl-2 '-(1-methylethyl) cyclohexyl] preparation of ester (IIIB)
With compound (II) 5-hydroxyl-1,3-oxathiolane-2-carboxylic acid [(1 ' R, 2 ' S, 5 ' R)-5 '-methyl-2 '-(1-methylethyl) cyclohexyl] ester (200g) drops in the 2L there-necked flask, adds DMAP (10.16g) and tetrahydrofuran (THF) 600ml, stirring and dissolving, be cooled to-25～-20 ℃, dripped propionic anhydride 134ml in 2～3 hours, dropwise the back and continue reaction 45～60min, slowly dripping 10% aqueous sodium carbonate accent pH then is 7, change in the separating funnel, standing demix, water layer extracts 2 times with the 110ml tetrahydrofuran (THF), collected organic layer, anhydrous magnesium sulfate drying spends the night, filter, filter cake washs with a small amount of tetrahydrofuran (THF), 60 ℃ of concentrating under reduced pressure of filtrate, with 90% ethanol 600ml recrystallization, filter, filter cake washs with a small amount of frozen ethanol, and 40 ℃ of drying under reduced pressure spend the night, get compound (IIIB) needle crystal 155.3g, yield 65%, content 99.5%, mp78.2-78.6 ℃.
1H-NMR(CDCl
3)6.73-6.74(d，1H)，5.54(s，1H)，4.64-4.69(t，1H)，3.08-3.39(m，2H)，2.28-2.33(q，2H)，1.93-1.95(m，1H)，1.84-1.90(m，1H)，1.61-1.63(m，2H)，1.42-1.44(br，1H)，1.32-1.36(m，1H)，1.09-1.1(t，3H)，0.76-1.02(m，9H)，0.69-0.7(d，3H)。
13C-NMR(CDCl
3)173.25，168.73，99.79，79.97，76.19，47.16，40.71，37.37，34.23，31.47，27.68，26.17，23.38，22.07，20.83，16.26，8.84ppm。
(+)ESI-MS：358(M+NH
4)。
Embodiment 3:
5S-[5-(4-acetylaminohydroxyphenylarsonic acid 2-oxo-1 (2H)-pyrimidine bases)]-1,3-oxathiolane-2R-carboxylic acid-[(1 ' R, 2 ' S, 5 ' R)-5 '-methyl-2 '-(1-methylethyl) cyclohexyl] preparation of ester (VA)
N-acetylcytosine 25.5g, ammonium sulfate 0.77g, hexamethyldisilazane 22.0ml and trichloromethane 500ml are dropped in the 1L three-necked bottle, stir temperature rising reflux 2 hours until reaction solution dissolving clarification, temperature is 0 ℃ in being cooled to, and obtains the chloroform soln of compound (IVA); Nitrogen protection; chloroform soln to compound (IVA) under 0 ℃ of stirring of the interior temperature of maintenance drips Iodotrimethylsilane 44.0ml; 1.5 dropwise in～2 hours; dripped compound (IIIA) chloroform soln 100ml (48.0g) again in 2 hours, be warming up to 30～35 ℃ of reaction 15h, reaction solution is evaporated to dried; add methyl tertiary butyl ether 100ml and stir 3h; filter, filter cake washs with a small amount of methyl tertiary butyl ether, 45 ℃ of drying under reduced pressure 4h.Above-mentioned gained solid is dropped in the 500ml three-necked bottle, add purified water 200ml and triethylamine 30ml and stirred the ice-water bath cold filtration 3 hours, filter cake is with a small amount of refrigerated water washing, 50 ℃ of drying under reduced pressure, compound (VA) white solid 47.8g, yield 75%, content 99.0%.
Embodiment 4:
5S-[5-(4-acetylaminohydroxyphenylarsonic acid 2-oxo-1 (2H)-pyrimidine bases)]-1,3-oxathiolane-2R-carboxylic acid-[(1 ' R, 2 ' S, 5 ' R)-5 '-methyl-2 '-(1-methylethyl) cyclohexyl] preparation of ester (VA)
N-acetylcytosine 25.5g, ammonium sulfate 0.77g, hexamethyldisilazane 22.0ml and trichloromethane 500ml are dropped in the 1L three-necked bottle, stir temperature rising reflux 2 hours until reaction solution dissolving clarification, temperature is 0 ℃ in being cooled to, and obtains the chloroform soln of compound (IVA); Nitrogen protection; chloroform soln to compound (IVA) under 0 ℃ of stirring of the interior temperature of maintenance drips Iodotrimethylsilane 44.0ml; 1.5 dropwise in～2 hours; dripped compound (IIIB) trichloromethane 100ml solution (50.0g) again in 2 hours, be warming up to 30～35 ℃ of reaction 15h, reaction solution is evaporated to dried; add methyl tertiary butyl ether 100ml and stir 3h; filter, filter cake washs with a small amount of methyl tertiary butyl ether, 45 ℃ of drying under reduced pressure 4h.Above-mentioned gained solid is dropped in the 500ml three-necked bottle, add 200ml purified water and 30ml triethylamine, stirred 3 hours, the ice-water bath cold filtration, filter cake is with a small amount of refrigerated water washing, 50 ℃ of drying under reduced pressure, get compound (VA) white solid 54.1g, yield 85%, content 99.0%.
Embodiment 5:
(2R, 5S)-4-acetylaminohydroxyphenylarsonic acid 2-oxo-1 (2H)-pyrimidine bases)-1, the preparation of 3-oxathiolane (VIA)
Three hypophosphite monohydrate hydrogen dipotassium 27.0g are dissolved among the purified water 30ml, 20 ℃ of stirrings, getting compound (VA) (23.0g) drops in the reaction flask, add dehydrated alcohol 160ml, this suspension stirs 15min, 2 hours inherent purification of aqueous solutions 40ml that drip the POTASSIUM BOROHYDRIDE 8g that contains 25% sodium hydroxide (0.4ml) below 25 ℃, stirring at room 1 hour again after dropwising, leave standstill separatory, discard lower floor's solution, upper solution changes in the three-necked bottle, transfers pH to 4 with concentrated hydrochloric acid under the ice-water bath cooling and stirring, transfer pH to 7 with 20% sodium hydroxide solution again, with toluene wash water layer 3 times, water layer evaporated under reduced pressure, resistates adds dehydrated alcohol 200ml, be heated to 60-70 ℃, filtered while hot is removed inorganic salt, and filtrate decompression concentrates and finishes, and gets white solid compound (VIA) 13.0g with dehydrated alcohol 50ml crystallization, content 99.7%, yield 87%.
Embodiment 6:
The preparation of lamivudine (I)
10.0g is dissolved in methyl alcohol 210ml with compound (VIA), adds the saturated methanol solution 40ml of ammonia, 30～50 ℃ of airtight stirrings 8-10 hour.Reaction finishes, and reducing pressure 70 ℃ reduces pressure down steams solvent, and resistates adds dehydrated alcohol 150ml, be heated to 60-70 ℃, filtered while hot is removed inorganic salt, and filtrate changes in the reaction flask, drip the 400ml isopropyl acetate in 2 hours, naturally cool to room temperature, stirring and crystallizing, filter, filter cake washs with a small amount of refrigerated isopropyl acetate, drains, 50 ℃ of drying under reduced pressure get lamivudine (I) white powder solid 7.7g, mp176.9-177.5 ℃, purity 99.7%, yield 96%.
Embodiment 7:
The preparation of lamivudine (I)
Add sodium hydroxide 6g stirring and dissolving to methyl alcohol 200ml, with compound (VIA) 10.0g in 20～40 ℃ of airtight stirrings 10-12 hour.Reaction finishes, ice bath is reconciled pH to 7 with 18% hydrochloric acid down, decompression steams solvent under 90 ℃, resistates adds dehydrated alcohol 160ml, is heated to 60-70 ℃, and filtered while hot is removed inorganic salt, filtrate changes in the reaction flask, drip the 400ml isopropyl acetate in 2 hours, naturally cool to room temperature, stirring and crystallizing, filter, filter cake washs with a small amount of refrigerated isopropyl acetate, drains 50 ℃ of drying under reduced pressure, get lamivudine (I) white powder solid 6.9g, mp176.9-177.5 ℃, purity 99.7%, yield 91%.
Embodiment 8:
5S-[5-(4-benzimide-2-oxo-1 (2H)-pyrimidine bases)]-1,3-oxathiolane-2R-carboxylic acid-[(1 ' R, 2 ' S, 5 ' R)-5 '-methyl-2 '-(1-methylethyl) cyclohexyl] preparation of ester (VB1)
Add methyl-sulphoxide 100ml, cytosine(Cyt) 24.2g, distilled phenyl aldehyde 38.6g again at the flask of 300ml, be heated to backflow under stirring, the solid solvent soln is orange-yellow, waits the solid dissolving to finish and continues the 2～3h that refluxes, and adds toluene 40ml, distilling off solvent, cool to room temperature stirs the downhill reaction drop and adds the about 100ml of ethyl acetate, separates out behind the solid stirring 2 hours, 40 ℃ of drying under reduced pressure obtain 4-benzimide cytosine(Cyt) 34.8g (cytosine(Cyt) schiff bases), transformation efficiency 80% behind the suction filtration.
4-benzimide cytosine(Cyt) 33.4g, ammonium sulfate 0.77g, hexamethyldisilazane 22.0ml and trichloromethane 500ml are dropped in the 1L three-necked bottle, stir temperature rising reflux 2 hours until reaction solution dissolving clarification, temperature is 0 ℃ in being cooled to, and obtains the chloroform soln of compound (IVB); Nitrogen protection; chloroform soln to compound (IVB) under 0 ℃ of stirring of the interior temperature of maintenance drips Iodotrimethylsilane 44.0ml; 1.5 dropwise in hour; dripped compound (IIIA) trichloromethane 100ml solution (48.0g) again in 2 hours, be warming up to 30～35 ℃ of reaction 15h, reaction solution is evaporated to dried; add methyl tertiary butyl ether 100ml and stir 4h; filter, filter cake washs with a small amount of methyl tertiary butyl ether, 45 ℃ of drying under reduced pressure 4h.Above-mentioned gained solid is dropped in the 500ml three-necked bottle, add 200ml purified water and 30ml triethylamine, stirred 3 hours, the ice-water bath cold filtration, filter cake is with a small amount of refrigerated water washing, 50 ℃ of drying under reduced pressure, get compound (VB1) white solid 53.1g, yield 78%, content 99.0%.
Embodiment 9:
5S-[5-(4-benzimide-2-oxo-1 (2H)-pyrimidine bases)]-1,3-oxathiolane-2R-carboxylic acid-[(1 ' R, 2 ' S, 5 ' R)-5 '-methyl-2 '-(1-methylethyl) cyclohexyl] preparation of ester (VB1)
Add methyl-sulphoxide 100ml, cytosine(Cyt) 24.2g, distilled phenyl aldehyde 38.6g again at the flask of 300ml, be heated to backflow under stirring, the solid solvent soln is orange-yellow, waits the solid dissolving to finish and continues the 2～3h that refluxes, and adds toluene 40ml, distilling off solvent, cool to room temperature stirs the downhill reaction drop and adds the about 100ml of ethyl acetate, separates out behind the solid stirring 2 hours, 40 ℃ of drying under reduced pressure obtain 4-benzimide cytosine(Cyt) 34.8g, transformation efficiency 80% behind the suction filtration.
4-benzimide cytosine(Cyt) 33.4g, ammonium sulfate 0.77g, hexamethyldisilazane 22.0ml and trichloromethane 500ml are dropped in the 1L three-necked bottle, stir temperature rising reflux 2 hours until reaction solution dissolving clarification, temperature is 0 ℃ in being cooled to, and obtains the chloroform soln of compound (IVB); Nitrogen protection; chloroform soln to compound (IVB) under 0 ℃ of stirring of the interior temperature of maintenance drips Iodotrimethylsilane 44.0ml; 1.5 dropwise in hour; dripped compound (IIIB) trichloromethane 100ml solution (50.0g) again in 2 hours, be warming up to 30～35 ℃ of reaction 15h, reaction solution is evaporated to dried; add methyl tertiary butyl ether 100ml and stir 4h; filter, filter cake washs with a small amount of methyl tertiary butyl ether, 45 ℃ of drying under reduced pressure 4h.Above-mentioned gained solid is dropped in the 500ml three-necked bottle, add 200ml purified water and 30ml triethylamine, stirred 3 hours, the ice-water bath cold filtration, filter cake is with a small amount of refrigerated water washing, 50 ℃ of drying under reduced pressure, get compound (VB1) white solid 58.5g, yield 86%, content 99.0%.
Embodiment 10:
5S-[5-(4-amino-2-oxo-1 (2H)-pyrimidine bases)]-1,3-oxathiolane-2R-carboxylic acid-[(1 ' R, 2 ' S, 5 ' R)-5 '-methyl-2 '-(1-methylethyl) cyclohexyl] preparation of ester (VIB)
The dilute hydrochloric acid 500ml that compound (VB1) white solid 50.0g adds mol/L stirred 12 hours in 20-30 ℃, suction filtration is to doing, and to doing, 40 ℃ of decompression oven dry obtain compound (VIB) white solid 38.6g to neutral back suction filtration in water washing, mp210.7-212.7 ℃, [α]
25 D=-143.0 ° (c=1, chloroform), yield 95%.
Embodiment 11:
5S-[5-(4-is to methylbenzene azomethine-2-oxo-1 (2H)-pyrimidine bases)]-1,3-oxathiolane-2R-carboxylic acid-[(1 ' R, 2 ' S, 5 ' R)-5 '-methyl-2 '-(1-methylethyl) cyclohexyl] preparation of ester (VB2)
Add methyl-sulphoxide 100ml, cytosine(Cyt) 24.2g, distilled p-tolyl aldehyde 43.7g again at the flask of 300ml, be heated to backflow under stirring, the solid solvent soln is orange-yellow, waits the solid dissolving to finish and continues the 2～3h that refluxes, and adds toluene 40ml, distilling off solvent, cool to room temperature stirs the downhill reaction drop and adds the about 100ml of ethyl acetate, separates out behind the solid stirring 2 hours, 40 ℃ of drying under reduced pressure obtain 4-to methylbenzene azomethine cytosine(Cyt) 36.2g, transformation efficiency 78% behind the suction filtration.
4-is dropped in the 1L three-necked bottle methylbenzene azomethine cytosine(Cyt) 35.7g, ammonium sulfate 0.77g, hexamethyldisilazane 22.0ml and trichloromethane 500ml, stir temperature rising reflux 2 hours until reaction solution dissolving clarification, temperature is 0 ℃ in being cooled to, and obtains the chloroform soln of compound (IVB2); Nitrogen protection; chloroform soln to compound (IVB2) under 0 ℃ of stirring of the interior temperature of maintenance drips Iodotrimethylsilane 44.0ml; 1.5 dropwise in hour; dripped compound (IIIB) trichloromethane 100ml solution (50.0g) again in 2 hours, be warming up to 30～35 ℃ of reaction 15h, reaction solution is evaporated to dried; add methyl tertiary butyl ether 100ml and stir 4h; filter, filter cake washs with a small amount of methyl tertiary butyl ether, 45 ℃ of drying under reduced pressure 4h.Above-mentioned gained solid is dropped in the 500ml three-necked bottle, add 200ml purified water and 30ml triethylamine, stirred 3 hours, the ice-water bath cold filtration, filter cake is with a small amount of refrigerated water washing, 50 ℃ of drying under reduced pressure, get compound (VB2) white solid 58.1g, yield 83%, content 99.0%.
Similar operation, compound (IIIA) (48.0g) feed intake compound (VB2) white solid 52.6g, yield 75%, content 99.0%.
Embodiment 12:
5S-[5-(4-amino-2-oxo-1 (2H)-pyrimidine bases)]-1,3-oxathiolane-2R-carboxylic acid-[(1 ' R, 2 ' S, 5 ' R)-5 '-methyl-2 '-(1-methylethyl) cyclohexyl] preparation of ester (VIB)
The dilute hydrochloric acid 500ml that compound (VB2) white solid 50.0g adds mol/L stirred 12 hours in 20-30 ℃, suction filtration is to doing, and to doing, 40 ℃ of decompression oven dry obtain compound (VIB) white solid 36.7g to neutral back suction filtration in water washing, mp210.7-212.7 ℃, [α]
25 D=-143.0 ° (c=1, chloroform), yield 93%.
Embodiment 13:
The preparation of lamivudine (I)
Three hypophosphite monohydrate hydrogen dipotassium 27.0g are dissolved among the purified water 30ml, 20 ℃ of stirrings, getting compound (VIB) (23.0g) drops in the reaction flask, add dehydrated alcohol 160ml, this suspension stirs 15min, 2 hours inherent purification of aqueous solutions 40ml that drip the POTASSIUM BOROHYDRIDE 8g that contains 25% sodium hydroxide (0.4ml) below 25 ℃, stirring at room 1 hour again after dropwising, leave standstill separatory, discard lower floor's solution, upper solution changes in the three-necked bottle, transfers pH to 4 with concentrated hydrochloric acid under the ice-water bath cooling and stirring, transfer pH to 7 with 20% sodium hydroxide solution again, with toluene wash water layer 3 times, water layer evaporated under reduced pressure, resistates adds dehydrated alcohol 200ml, be heated to 60-70 ℃, filtered while hot is removed inorganic salt, and filtrate decompression concentrates and finishes, and gets lamivudine (I) white solid compound 12.0g with dehydrated alcohol 50ml crystallization, content 99.7%, yield 87%.
The invention is not restricted to the foregoing description, any simple modification, equivalent variations or modification that all foundations technical spirit of the present invention is done the foregoing description all belong in the technology of the present invention scope.
Claims (15)
1. the industrialized process for preparing of a lamivudine (I), its process comprises:
A) 5-hydroxyl-1,3-oxathiolane-2-carboxylic acid [(1 ' R, 2 ' S, 5 ' R)-5 '-methyl-2 '-(1-methylethyl) cyclohexyl] ester (II) and acylation reaction obtain acylate (III), wherein,
R in formula (III) acylate is alkyl acyl group, aromatic base carboxyl groups or alkylsulfonyl group;
B) glycosylation takes place and obtains compound (VA) or (VB) in the cytosine(Cyt) schiff bases (IVB) of the acyl group cytosine(Cyt) (IVA) of the acylate that is obtained by step a) (III) and single silanization or single silanization under Louis acid catalysis,
Wherein, formula (IVA) and (VA) X in the compound be formyl radical, ethanoyl, propionyl, different propionyl, butyryl radicals, formula (IVB) and (VB) Y in the compound be phenyl, m-nitro base, p-nitrophenyl, a chloro-phenyl-, rubigan, p-methoxyphenyl, p-methylphenyl, o-methyl-phenyl-, a hydroxy phenyl, o-hydroxy-phenyl, benzyl;
C) compound that is obtained by step b) (VA) obtains compound (VIA) through reduction, and compound (VB) obtains compound (VIB) through hydrolysis;
Wherein, the X in formula (VIA) compound is formyl radical, ethanoyl, propionyl, different propionyl, butyryl radicals;
D) compound that is obtained by step c) (VIA) is sloughed acyl group or is obtained lamivudine (I) by compound compound (VIB) reduction that step c) obtains.
2. method according to claim 1, it is characterized in that: the formula of step a) (III) acylate, wherein, said alkyl acyl group comprises formyl radical, ethanoyl, propionyl, different propionyl, butyryl radicals, isobutyryl, pentanoyl, phenylacetyl, hydrocinnamoyl; Said aromatic base carboxyl groups comprises benzoyl, to toluyl, p-nitrophenyl formyl radical; Said alkylsulfonyl group comprises methane sulfonyl, ethane alkylsulfonyl, benzenesulfonyl, p-toluenesulfonyl, acetparaminosalol benzenesulfonyl.
3. method according to claim 2 is characterized in that: the formula of step a) (III) acylate, wherein, said alkyl acyl group is ethanoyl, propionyl, different propionyl or butyryl radicals.
4. method according to claim 1 is characterized in that: in step b) or the step c), said X is ethanoyl or propionyl, and said Y is phenyl or p-methylphenyl.
5. according to claim 1 or 2 or 3 described methods, said acylating agent comprises diacetyl oxide, Acetyl Chloride 98Min., acetyl bromide, acetyliodide, acetic ester, acetate, propionic anhydride, propionyl chloride, propionyl bromide, propionyl iodide, propionic ester or propionic acid, preferred diacetyl oxide or propionic anhydride.
6. method according to claim 1 is characterized in that: the acylation reaction of said step a) is by formula (II) compound and solvent, catalyst mix, carries out at a certain temperature.
7. method according to claim 6, said solvent are tetrahydrofuran (THF), trichloromethane, methylene dichloride or their mixture, preferred tetrahydrofuran (THF); Described catalyzer is 4-Dimethylamino pyridine (DMAP), N, N-dicyclohexylcarbodiimide (DCC) or their mixture, preferred 4-Dimethylamino pyridine; Said temperature of reaction is-60～-5 ℃, preferred-30～-15 ℃, more preferably-25 ℃～-20 ℃.
8. method according to claim 1, wherein, in step b), X is that single silanization cytosine(Cyt) (IV) of alkyl acyl is to be made by acyl group cytosine(Cyt), catalyzer, silylating reagent and solvent afterreaction.
9. method according to claim 8, said acyl group cytosine(Cyt) comprise N-formyl cytosine(Cyt), N-acetylcytosine, N-propionyl cytosine(Cyt), the different propionyl cytosine(Cyt) of N-, N-butyryl cytosine(Cyt), preferred N-acetylcytosine; Said catalyzer comprises ammonium sulfate, ammonium chloride, methylsulfonic acid, tosic acid, the preferably sulfuric acid ammonium; Said silylating reagent comprises trimethylchlorosilane, Iodotrimethylsilane, hexamethyldisilazane, preferred hexamethyldisilazane; Said solvent comprises methylene dichloride, trichloromethane, benzene, toluene, preferred trichloromethane.
10. method according to claim 1 is characterized in that: the Lewis acid in the said step b) comprises the mixture that Iodotrimethylsilane, trimethylchlorosilane or trimethylchlorosilane and potassiumiodide or sodium iodide are formed, preferred Iodotrimethylsilane.
11. method according to claim 1, it is characterized in that: said reduction is to carry out under a kind of existence of reductive agent in the step c), wherein, described reductive agent comprises POTASSIUM BOROHYDRIDE, sodium borohydride, lithium borohydride, zinc borohydride, hydroboration calcium, sodium cyanoborohydride, sodium triacetoxy borohydride, lithium triethylborohydride, 3-sec-butyl lithium borohydride, tetrahydrochysene lithium aluminium or three tert.-butoxy lithium aluminum hydrides, preferred POTASSIUM BOROHYDRIDE, sodium borohydride or lithium borohydride.
12. method according to claim 1 is characterized in that: said hydrolysis is to carry out in the presence of diluted acid in the step c), and wherein, said diluted acid comprises dilute hydrochloric acid, acetic acid,diluted, dilute sulphuric acid or rare nitric acid, preferred dilute hydrochloric acid.
13. method according to claim 1; it is characterized in that: step d) Chinese style (VIA) compound is sloughed acyl group and is obtained lamivudine and carry out under alkaline condition, and wherein said alkaline condition comprises the aqueous solution, alkali alcosol or their mixture of alkali.
14. method according to claim 15, the aqueous solution of said alkali, alkali alcosol, wherein, described alkali comprises sodium hydroxide, potassium hydroxide, lithium hydroxide, strontium hydroxide, salt of wormwood, saleratus, yellow soda ash, sodium bicarbonate or ammonia, preferred ammonia; Described alcohol is methyl alcohol, ethanol or Virahol, particular methanol.
15. method according to claim 1, it is characterized in that: it is to carry out in the presence of reductive agent that compound in the step d) (VIB) reduction obtains lamivudine, wherein, reductive agent comprises POTASSIUM BOROHYDRIDE, sodium borohydride, lithium borohydride, zinc borohydride, hydroboration calcium, sodium cyanoborohydride, sodium triacetoxy borohydride, lithium triethylborohydride, 3-sec-butyl lithium borohydride, tetrahydrochysene lithium aluminium or three tert.-butoxy lithium aluminum hydrides, preferred POTASSIUM BOROHYDRIDE, sodium borohydride or lithium borohydride.
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| CN102746284A (en) * | 2012-07-05 | 2012-10-24 | 湖南千金湘江药业股份有限公司 | Preparation method for lamivudine |
| CN109311862A (en) * | 2016-06-14 | 2019-02-05 | 纳尔逊曼德拉城市大学 | The manufacturing method of Lamivudine and emtricitabine |
| CN108409724A (en) * | 2018-06-04 | 2018-08-17 | 安徽帆香料有限公司 | A kind of emtricitabine separation method |
| CN109355328A (en) * | 2018-12-07 | 2019-02-19 | 武汉工程大学 | The enzymatic preparation method of Lamivudine |
| CN116199679A (en) * | 2022-12-23 | 2023-06-02 | 吉斯凯(苏州)制药有限公司 | Industrial preparation method of lamivudine |
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