CN102234269B - The industrialized process for preparing of lamivudine - Google Patents
The industrialized process for preparing of lamivudine Download PDFInfo
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- XHXUANMFYXWVNG-ADEWGFFLSA-N CC(C)[C@H](CC[C@@H](C)C1)[C@@H]1OC(C)=O Chemical compound CC(C)[C@H](CC[C@@H](C)C1)[C@@H]1OC(C)=O XHXUANMFYXWVNG-ADEWGFFLSA-N 0.000 description 1
- QMYKWNYBSBURDT-JINKPPJBSA-N CC(C)[C@H](CC[C@@H](C)C1)[C@@H]1OC([C@H]1SC[C@@H](N(C=CC(N)=N2)C2=O)O1)=O Chemical compound CC(C)[C@H](CC[C@@H](C)C1)[C@@H]1OC([C@H]1SC[C@@H](N(C=CC(N)=N2)C2=O)O1)=O QMYKWNYBSBURDT-JINKPPJBSA-N 0.000 description 1
- FVMQSDLIZRHKHK-UHFFFAOYSA-N C[Si+](C)(C)Oc1nccc(N)n1 Chemical compound C[Si+](C)(C)Oc1nccc(N)n1 FVMQSDLIZRHKHK-UHFFFAOYSA-N 0.000 description 1
- JTEGQNOMFQHVDC-NKWVEPMBSA-N NC(C=CN1[C@H]2O[C@@H](CO)SC2)=NC1=O Chemical compound NC(C=CN1[C@H]2O[C@@H](CO)SC2)=NC1=O JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 description 1
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Abstract
The invention discloses the industrialized process for preparing of lamivudine; the method is with 5-hydroxyl-1; 3-oxathiolane-2-carboxylic acid [(1 ' R; 2 ' S; 5 ' R)-5 '-methyl-2 '-(1-methylethyl) cyclohexyl] ester and acylation reaction obtain acylate; under Louis acid catalysis, the acyl group cytosine(Cyt) of acylate and single silanization or the cytosine(Cyt) schiff bases generation glycosylation of single silanization obtain lamivudine intermediate, restore, deacylated tRNA base or hydrolysis, reduction obtain lamivudine.Raw material of the present invention low price simple and easy to get, easy and simple to handle, production safety, yield is high, and three-waste pollution is few, is applicable to suitability for industrialized production.
Description
Technical field
The invention belongs to chemistry or medicinal chemistry art, be specifically related to the industrialized process for preparing of anti-hepatic-B virus medicine lamivudine.
Background technology
Lamivudine (Lamivudine, 3TC) such as formula shown in (I), its chemistry (2R-cis)-4-amino-1-(2-methylol-1,3-oxygen sulphur Polymorphs-5-base)-1H-pyrimid-2-one by name is nucleoside analog antiviral medicine.Nucleotide is the raw material of synthesized human hereditary material DNA and RNA, lamivudine structurally simulates the structure of Nucleotide, but not there is the function of Nucleotide, its mechanism of action for suppressing viral DNA polymerase and reverse transcriptase activity, and to the synthesis of viral DNA chain with extend competitive restraining effect.Therefore in DNA building-up process, nucleoside analog can mix into, but can not synthesize the nucleic acid chains having normal function, thus make virus copy termination.Current lamivudine has become the key agents for the treatment of virus of AIDS and hepatitis B virus.
Lamivudine is an optical isomer, has 2 chiral centres, asymmetric synthesis complex process, so industrialized process for preparing is very crucial in molecular structure.
CN1563003 discloses a kind of lamivudine and is applicable to industrialized preparation method, intermediate product (5R)-acetoxyl group-1 prepared by the method, 3-oxathiolane-(2R)-carboxylic acid-[(1 ' R, 2 ' S, 5 ' R)-5 '-methyl-2 '-(1-methylethyl) cyclohexyl] yield of ester is only 40%; At (5R)-acetoxyl group-1; 3-oxathiolane-(2R)-carboxylic acid-[(1 ' R; 2 ' S; 5 ' R)-5 '-methyl-2 '-(1-methylethyl) cyclohexyl] first react by silane reagent the cytosine(Cyt) forming pair protected silanes with cytosine(Cyt) in ester and the cytosine(Cyt) actual procedure of reacting; again with (5R)-acetoxyl group-1; 3-oxathiolane-(2R)-carboxylic acid-[(1 ' R; 2 ' S, 5 ' R)-5 '-methyl-2 '-(1-methylethyl) cyclohexyl] ester condensation reaction.Inflammable and explosive ether is employed in the method aftertreatment; but also the purification process of recrystallization after column chromatography for separation again after have employed silica gel adsorption; process is numerous and diverse; production operation difficulty, is not suitable for suitability for industrialized production, in addition; the method first reacts owing to adopting silane reagent the cytosine(Cyt) forming two protected silanes with cytosine(Cyt); hexamethyl nitrogen silane, not only as solvent but also as reaction reagent, consumes hexamethyl nitrogen silane too many, 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 oxo-pyrimidine-1-base)-1; in 3-oxathiolane-2-carboxylic acid-(-)-norbornene ester process; actual procedure adopts N-acetylcytosine and first silylating reagent to react the N-acetylcytosine forming single protected silane; N-acetylcytosine chloro-1,3-oxathiolane-2-carboxylic acid-(-)-norbornene ester condensation with 5-again of single protected silane.The chlorination process that the method prepares chloro-1,3-oxathiolane-2-carboxylic acid-(-)-norbornene ester of 5-employs 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 is not high is only 66%, above factor is neither beneficial to suitability for industrialized production.
CN101597281A discloses the preparation method of a kind of lamivudine and intermediate thereof, the method is at preparation (2R, 5R)-5-ethanoyl-[1, diacetyl oxide, Acetyl Chloride 98Min. is used in the process of 3] oxathiolane-2-carboxylic acid (2S-sec.-propyl-5R-methyl isophthalic acid R-cyclohexyl) ester, although yield reaches 90% or 88.5%, but the product purity obtained is low, at preparation (2R, 5R)-5-propionyl-[1, propionic anhydride is used in the process of 3] 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-base)-[1, silane reagent is adopted first react the cytosine(Cyt) forming silane pair and protect with cytosine(Cyt) in the process of 3] oxathiolane-2-carboxylic acid (2S-sec.-propyl-5R-methyl isophthalic acid R-cyclohexyl) ester, the cytosine(Cyt) of two protected silane participates in condensation reaction again, although improve yield, but the purity of the product obtained is lower, the purity of the lamivudine prepared with this is also lower, have to pass through repeatedly recrystallization purifying and just can reach medicinal requirements, operating process is loaded down with trivial details, realize suitability for industrialized production difficulty.
The preparation method of disclosed lamivudine above, still deposit some deficiency, searching one is simple to operate, safety and environmental protection, yield and purity are all high, and the method being applicable to suitability for industrialized production is necessary.The present invention completes for this reason.
Summary of the invention
Object of the present invention provides a kind of industrialized process for preparing of lamivudine, the method overcomes the deficiencies in the prior art, and its advantage is: raw material is simple and easy to get, low price, easy and simple to handle, product purity is high can fulfilling medicinal requirements, and yield is high, three-waste pollution is few, is applicable to suitability for industrialized production.
For realizing object 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 sulphonyl groups;
Under Louis acid catalysis, glycosylation is there is and obtains formula (VA) compound or formula (VB) compound in the acylate (III) b) step a) obtained with the acyl group cytosine(Cyt) (IVA) of single silanization or the cytosine(Cyt) schiff bases (IVB) of single silanization
Wherein, X in formula (IVA) and (VA) compound is formyl radical, ethanoyl, propionyl, iso-propionyl, butyryl radicals, and the Y in formula (IVB) and (VB) compound 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;
C) by step b) formula (VA) compound that obtains 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, iso-propionyl, butyryl radicals;
D) by step c) compound (VIA) that obtains slough acyl group or by step c) Compound Compound (VIB) reduction that obtains obtains lamivudine (I).
In above-mentioned embodiment, step formula a) (III) acylate, wherein, said alkyl acyl group comprises formyl radical, ethanoyl, propionyl, iso-propionyl, butyryl radicals, isobutyryl, pentanoyl, phenylacetyl, hydrocinnamoyl, preferred ethanoyl, propionyl, iso-propionyl or butyryl radicals, more preferably ethanoyl, propionyl; Said aromatic base carboxyl groups comprises benzoyl, to toluyl, p-nitrophenyl formyl radical; Said sulphonyl groups comprises methane sulfonyl, ethanesulfonyl, benzenesulfonyl, p-toluenesulfonyl or acetparaminosalol benzenesulfonyl.
In above-mentioned embodiment, step b) or step c) in, said X is ethanoyl or propionyl, and said Y is phenyl or p-methylphenyl.
In above-mentioned embodiment, step a) in acylating agent comprise diacetyl oxide, Acetyl Chloride 98Min., acetyl bromide, acetyliodide, acetic ester, acetic acid, propionic anhydride, propionyl chloride, propionyl bromide, propionyl iodide, propionic ester or propionic acid, preferred diacetyl oxide or propionic anhydride.
In above-mentioned embodiment, step acylation reaction 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 DMAP (DMAP), N, N-dicyclohexylcarbodiimide (DCC) or their mixture, preferred DMAP; Said temperature of reaction is said temperature of reaction is-60 ~-5 DEG C, preferably-30 ~-15 DEG C, more preferably-25 ~-20 DEG C.
In above-mentioned embodiment, step b) in the acyl group cytosine(Cyt) (IVA) of single silanization be obtained by reaction after acyl group cytosine(Cyt), catalyzer, silylating reagent and solvent.Wherein, said acyl group cytosine(Cyt) comprises N-formyl cytosine(Cyt), N-acetylcytosine, N-propionyl cytosine(Cyt), N-isopropyl acyl cytosine(Cyt), 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, 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, said step b) in Lewis acid comprise the mixture that Iodotrimethylsilane, trimethylchlorosilane or trimethylchlorosilane and potassiumiodide or sodium iodide form, preferred Iodotrimethylsilane.
In above-mentioned embodiment, step c) in said reduction be carry out under a kind of existence of reductive agent, wherein, described reductive agent comprises POTASSIUM BOROHYDRIDE, sodium borohydride, lithium borohydride, zinc borohydride, calcium borohydride, sodium cyanoborohydride, sodium triacetoxy borohydride, lithium triethylborohydride, 3-sec-butyl lithium borohydride, tetrahydrochysene lithium aluminium or three tertiary butyoxy aluminium lithiums, preferred POTASSIUM BOROHYDRIDE, sodium borohydride or lithium borohydride, more preferably POTASSIUM BOROHYDRIDE.
In above-mentioned embodiment, step c) in, said hydrolysis carries out under the existence of diluted acid, and wherein, said diluted acid comprises dilute hydrochloric acid, acetic acid,diluted, dilute sulphuric acid or dust technology, preferred dilute hydrochloric acid.
In above-mentioned embodiment, steps d) in, formula (VIA) compound is sloughed acyl group and is obtained lamivudine and carry out in the basic conditions, and wherein, said alkaline condition comprises the aqueous solution of alkali, alkali alcosol or their mixture.The aqueous solution of said alkali, alkali alcosol, wherein said alkali comprises sodium hydroxide, potassium hydroxide, lithium hydroxide, strontium hydroxide, salt of wormwood, saleratus, sodium carbonate, 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 steps d) in, the reduction of formula (VIB) compound obtains lamivudine and carries out in the presence of a reducing agent, wherein, said reductive agent comprises POTASSIUM BOROHYDRIDE, sodium borohydride, lithium borohydride, zinc borohydride, calcium borohydride, sodium cyanoborohydride, sodium triacetoxy borohydride, lithium triethylborohydride, 3-sec-butyl lithium borohydride, tetrahydrochysene lithium aluminium or three tertiary butyoxy aluminium lithiums, preferred POTASSIUM BOROHYDRIDE, sodium borohydride or lithium borohydride, more preferably POTASSIUM BOROHYDRIDE.
In above-mentioned embodiment, step b) in cytosine(Cyt) schiff bases (IVB) be react obtained by 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-tolualdehyde, 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 is there is 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, deacylated tRNA base obtains lamivudine, formula (VB) is hydrolyzed, reduction obtains lamivudine.
Method of the present invention; reagent and the operation such as sulfur oxychloride and acyl chlorides that inflammable and explosive ether, loaded down with trivial details column chromatography, corrodibility are large and big for environment pollution are cut off; acyl group cytosine(Cyt) is Industrial 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 formula (III), R is alkyl acyl group, aromatic base carboxyl groups and sulphonyl groups, wherein alkyl acyl group comprises formyl radical, ethanoyl, propionyl, iso-propionyl, butyryl radicals, isobutyryl, pentanoyl, phenylacetyl, hydrocinnamoyl etc., aromatic base carboxyl groups comprises benzoyl, to toluyl, p-nitrophenyl formyl radical etc., sulphonyl groups comprises methane sulfonyl, ethanesulfonyl, benzenesulfonyl, p-toluenesulfonyl, acetparaminosalol benzenesulfonyl, is preferably ethanoyl, propionyl; In formula (IVA), formula (VA) and formula (VIA), X is formyl radical, ethanoyl, propionyl, iso-propionyl, butyryl radicals, is preferably ethanoyl, propionyl, is more preferably ethanoyl; In formula (IVB), formula (VB) and formula (VIB), 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, 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);
Under Louis acid catalysis, glycosylation is there is and obtains lamivudine intermediate compound (VA) or (VB) in the acylate (III) b) a) obtained by step with the acyl group cytosine(Cyt) (IVA) of single silanization or the cytosine(Cyt) schiff bases (IVB) of single silanization;
C) by step b) the lamivudine intermediate compound (VA) that obtains obtains compound (VIA), by step b through reductive agent reduction) the lamivudine intermediate compound (VB) that obtains obtains compound (VIB) through dilute acid hydrolysis;
D) by step c) the lamivudine intermediate compound (VIA) that obtains sloughs acyl group in the basic conditions and obtains lamivudine (I), and lamivudine intermediate compound (VIB) obtains lamivudine (I) through reductive agent reduction.
The method of the invention described above, each reactions steps specifically describes as follows:
Step is 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 terminates rear dropping alkali aqueous solution and is transferred to neutrality, stratification, water layer solvent extraction, collected organic layer, dry filter, filtrate reduced in volume, obtains acylate (III) with aqueous ethanol recrystallization; Wherein, suitable solvent is tetrahydrofuran (THF), trichloromethane, methylene dichloride or their mixture, and preferred solvent is tetrahydrofuran (THF); Suitable catalyzer is the mixture that DMAP (DMAP) or N, N-dicyclohexylcarbodiimide (DCC) or DMAP and N, N-dicyclohexylcarbodiimide form, and preferred catalyst is DMAP; Suitable temperature of reaction is-60 ~-5 DEG C, preferably-30 ~-15 DEG C, more preferably-25 ~-20 DEG C; R in formula (III) acylate is alkyl acyl group, aromatic base carboxyl groups and sulphonyl groups, wherein alkyl acyl group comprises formyl radical, ethanoyl, propionyl, iso-propionyl, butyryl radicals, isobutyryl, pentanoyl, phenylacetyl, hydrocinnamoyl etc., aromatic base carboxyl groups comprises benzoyl, to toluyl, p-nitrophenyl formyl radical etc., sulphonyl groups comprises methane sulfonyl, ethanesulfonyl, benzenesulfonyl, p-toluenesulfonyl, acetparaminosalol benzenesulfonyl, is preferably ethanoyl, propionyl; When the R in formula (III) acylate is ethanoyl, suitable acylating agent is diacetyl oxide, Acetyl Chloride 98Min., acetyl bromide, acetyliodide, acetic ester, acetic acid, preferred diacetyl oxide; When the R in (III) acylate is propionyl, suitable acylating agent is 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, heating direct dissolves clarification to reaction solution, obtains 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), N-isopropyl acyl cytosine(Cyt), N-butyryl cytosine(Cyt), preferred N-acetylcytosine, N-propionyl cytosine(Cyt), more preferably N-acetylcytosine; Suitable catalyzer comprises ammonium sulfate, ammonium chloride, methylsulfonic acid, tosic acid, preferably sulfuric acid ammonium; Suitable silylating reagent comprises trimethylchlorosilane, Iodotrimethylsilane, hexamethyldisilazane, preferred hexamethyldisilazane; Suitable solvent comprises methylene dichloride, trichloromethane, benzene, toluene, preferred trichloromethane.
Under Louis acid catalysis, glycosylation is there is and obtains lamivudine intermediate compound (VA) in the acylate (III) a) obtained by step with the acyl group cytosine(Cyt) (IVA) of single silanization; Wherein suitable Lewis acid comprises the mixture that four Iodotrimethylsilanes, trimethylchlorosilane or trimethylchlorosilane and potassiumiodide or sodium iodide form, preferred Iodotrimethylsilane.
The phenyl aldehyde of cytosine(Cyt) and phenyl aldehyde or replacement reacts obtained cytosine(Cyt) schiff bases under suitable solvent.Cytosine(Cyt) schiff bases, catalyzer, silylating reagent, solvent, heating direct dissolves clarification to reaction solution, obtains the cytosine(Cyt) schiff bases (IVB) of single silanization; Wherein, the phenyl aldehyde replaced comprises m-nitrobenzaldehyde, paranitrobenzaldehyde, m chlorobenzaldehyde, 4-chloro-benzaldehyde, p-tolyl aldehyde, o-tolualdehyde, m-hydroxybenzaldehyde, salicylaldhyde, phenylacetic aldehyde, aubepine, preferred phenyl aldehyde or p-tolyl aldehyde; Suitable catalyzer comprises ammonium sulfate, ammonium chloride, methylsulfonic acid, tosic acid, preferably sulfuric acid ammonium; Suitable silylating reagent comprises trimethylchlorosilane, Iodotrimethylsilane, hexamethyldisilazane, preferred hexamethyldisilazane; Suitable solvent comprises methylene dichloride, trichloromethane, benzene, toluene, preferred trichloromethane.
Under Louis acid catalysis, glycosylation is there is and obtains lamivudine intermediate compound (VB) in the acylate (III) a) obtained by step with the cytosine(Cyt) schiff bases (IVB) of single silanization; Wherein suitable Lewis acid comprises the mixture that Iodotrimethylsilane, trimethylchlorosilane, trimethylchlorosilane and potassiumiodide or sodium iodide form, preferred Iodotrimethylsilane.
Step c): by step b) compound (VA) that obtains obtains compound (VIA) with reductive agent reduction in a solvent; Wherein suitable reductive agent comprises POTASSIUM BOROHYDRIDE, sodium borohydride, lithium borohydride, zinc borohydride, calcium borohydride, sodium cyanoborohydride, sodium triacetoxy borohydride, lithium triethylborohydride, 3-sec-butyl lithium borohydride, tetrahydrochysene lithium aluminium, three tertiary butyoxy aluminium lithiums, preferred POTASSIUM BOROHYDRIDE, sodium borohydride, lithium borohydride, more preferably POTASSIUM BOROHYDRIDE.
By step b) compound (VB) that obtains obtains compound (VIB) in hydrolysis, and hydrolysising condition comprises dilute hydrochloric acid, dilute sulphuric acid, acetic acid,diluted, dust technology, preferred dilute hydrochloric acid.
Steps d): by step c) compound (VIA) that obtains sloughs acyl group in the basic conditions and obtains lamivudine (I) crude product, gained crude product obtains lamivudine through recrystallization.Wherein alkaline condition comprises the aqueous solution of alkali, alkali alcosol or their mixture, and the aqueous solution of alkali comprises the aqueous solution of sodium hydroxide, potassium hydroxide, lithium hydroxide, strontium hydroxide, salt of wormwood, saleratus, sodium carbonate, sodium bicarbonate, ammonia; Alkali alcosol comprises sodium hydroxide, potassium hydroxide, lithium hydroxide, strontium hydroxide, salt of wormwood, saleratus, sodium carbonate, sodium bicarbonate, the methyl alcohol of ammonia or ethanol or aqueous isopropanol; Their mixture is sodium hydroxide, potassium hydroxide, lithium hydroxide, strontium hydroxide, salt of wormwood, saleratus, sodium carbonate, sodium bicarbonate, the methyl alcohol of ammonia or ethanol or isopropanol water solution, the methanol solution of preferred ammonia and the methanol solution of sodium hydroxide.
By step c) reduction of compound (VIB) reductive agent that obtains obtains lamivudine (I) crude product, and gained crude product obtains lamivudine through recrystallization; Wherein suitable reductive agent comprises POTASSIUM BOROHYDRIDE, sodium borohydride, lithium borohydride, zinc borohydride, calcium borohydride, sodium cyanoborohydride, sodium triacetoxy borohydride, lithium triethylborohydride, 3-sec-butyl lithium borohydride, tetrahydrochysene lithium aluminium, three tertiary butyoxy aluminium lithiums, preferred POTASSIUM BOROHYDRIDE, sodium borohydride, lithium borohydride, more preferably POTASSIUM BOROHYDRIDE.
The advantage of method of the present invention: method of the present invention, step a) in, do not use sulfur oxychloride, acyl chlorides that corrodibility is large, have employed non-corrosive diacetyl oxide, propionic anhydride.In step b) in, acyl group cytosine(Cyt) source is easy to get, and the silylating reagent that the acyl group cytosine(Cyt) (IVA) preparing single silanization consumes is few, with low cost, and yield is higher; At described step b) in, prepare cytosine(Cyt) schiff bases simple and convenient, the silylating reagent that the cytosine(Cyt) schiff bases (IVB) preparing single silanization consumes is few, with low cost, and yield is higher.In step c) in, by step b) compound (VA) that obtains obtains compound (VIA) with reductive agent reduction in a solvent and uses inexpensive POTASSIUM BOROHYDRIDE, and product chiral purity is high, and yield is higher; In step c) in, by step b) compound (VB) that obtains obtains compound (VIB) in hydrolysis, with dilute hydrochloric acid hydrolysis, convenient and easy.In described steps d) in, compound (VIA) is sloughed acyl group in the basic conditions and is obtained lamivudine (I) crude product, uses the methanol solution of the ammonia be cheaply easy to get and the methanol solution of sodium hydroxide; Compound (VIB) reductive agent reduction obtains lamivudine (I) crude product, and use inexpensive POTASSIUM BOROHYDRIDE, product chiral purity is high, and yield is higher.Reaction process does not have the operations such as loaded down with trivial details column chromatography, repeatedly recrystallization, and industrialization is easily implemented.
In a word, raw material of the present invention is simple and easy to get, easy and simple to handle, production safety, and yield is high, and three-waste pollution is few, is applicable 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 according to the method preparation introduced in US6051709, and US6051709 introduces the present invention in full.
Embodiment
Following examples are used for explaining the present invention further, but do not limit the scope of the invention.
In the examples below, the per-cent related to is weight percentage, and temperature is centigradetemperature; And employing the abbreviation of following form, DMAP represents DMAP.
Embodiment 1:
(5R) preparation of-acetoxyl group-1,3-oxathiolane-(2R)-carboxylic acid-[(1 ' R, 2 ' S, 5 ' R)-5 '-methyl-2 '-(1-methylethyl) cyclohexyl] ester (IIIA)
By 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 2L there-necked flask, add DMAP (10.16g) and tetrahydrofuran (THF) 600ml, stirring and dissolving, be cooled to-25 ~-20 DEG C, diacetyl oxide 99ml is dripped in 2 ~ 3 hours, dropwise rear continuation reaction 45 ~ 60min, then slowly dripping 10% aqueous sodium carbonate adjusts pH to be 7, proceed in separating funnel, stratification, water layer 100ml tetrahydrofuran (THF) extracts 2 times, collected organic layer, anhydrous magnesium sulfate drying spends the night, filter, the a small amount of tetrahydrofuran (THF) of filter cake washs, filtrate 60 DEG C of concentrating under reduced pressure, with 90% ethanol (600ml) recrystallization, filter, the a small amount of frozen ethanol of filter cake washs, 40 DEG C of drying under reduced pressure spend the night, obtain compound (IIIA) needle crystal 103.1g, yield 45%, content 99.5%, mp104-105 DEG C.
Embodiment 2:
(5R) preparation of-propionyloxy-1,3-oxathiolane-(2R)-carboxylic acid-[(1 ' R, 2 ' S, 5 ' R)-5 '-methyl-2 '-(1-methylethyl) cyclohexyl] ester (IIIB)
By 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 2L there-necked flask, add DMAP (10.16g) and tetrahydrofuran (THF) 600ml, stirring and dissolving, be cooled to-25 ~-20 DEG C, propionic anhydride 134ml is dripped in 2 ~ 3 hours, dropwise rear continuation reaction 45 ~ 60min, then slowly dripping 10% aqueous sodium carbonate adjusts pH to be 7, proceed in separating funnel, stratification, water layer 110ml tetrahydrofuran (THF) extracts 2 times, collected organic layer, anhydrous magnesium sulfate drying spends the night, filter, the a small amount of tetrahydrofuran (THF) of filter cake washs, filtrate 60 DEG C of concentrating under reduced pressure, with 90% ethanol 600ml recrystallization, filter, the a small amount of frozen ethanol of filter cake washs, 40 DEG C of drying under reduced pressure spend the night, obtain compound (IIIB) needle crystal 155.3g, yield 65%, content 99.5%, mp78.2-78.6 DEG C.
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 1L three-necked bottle, stir temperature rising reflux 2 hours until reaction solution dissolves clarification, be cooled to interior temperature 0 DEG C, obtain the chloroform soln of compound (IVA); Nitrogen protection; chloroform soln to compound (IVA) under temperature 0 DEG C stirring in keeping drips Iodotrimethylsilane 44.0ml; dropwise in 1.5 ~ 2 hours; in 2 hours, drip the chloroform soln 100ml of compound (IIIA) (48.0g) again, be warming up to 30 ~ 35 DEG C of reaction 15h, reaction solution is evaporated to dry; add methyl tertiary butyl ether 100ml and stir 3h; filter, a small amount of methyl tertiary butyl ether of filter cake washs, 45 DEG C of drying under reduced pressure 4h.Above-mentioned gained solid is dropped in 500ml three-necked bottle, adds purified water 200ml and triethylamine 30ml stirs 3 hours, ice-water bath cold filtration, filter cake water washing freezing on a small quantity, 50 DEG C of drying under reduced pressure, obtain 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 1L three-necked bottle, stir temperature rising reflux 2 hours until reaction solution dissolves clarification, be cooled to interior temperature 0 DEG C, obtain the chloroform soln of compound (IVA); Nitrogen protection; chloroform soln to compound (IVA) under temperature 0 DEG C stirring in keeping drips Iodotrimethylsilane 44.0ml; dropwise in 1.5 ~ 2 hours; in 2 hours, drip the trichloromethane 100ml solution of compound (IIIB) (50.0g) again, be warming up to 30 ~ 35 DEG C of reaction 15h, reaction solution is evaporated to dry; add methyl tertiary butyl ether 100ml and stir 3h; filter, a small amount of methyl tertiary butyl ether of filter cake washs, 45 DEG C of drying under reduced pressure 4h.Above-mentioned gained solid is dropped in 500ml three-necked bottle, adds 200ml purified water and 30ml triethylamine, stir 3 hours, ice-water bath cold filtration, filter cake water washing freezing on a small quantity, 50 DEG C of drying under reduced pressure, obtain compound (VA) white solid 54.1g, yield 85%, content 99.0%.
Embodiment 5:
(2R, 5S)-4-acetylaminohydroxyphenylarsonic acid 2-oxo-1 (2H)-pyrimidine bases) preparation of-1,3-oxathiolane (VIA)
Three hypophosphite monohydrate hydrogen dipotassium 27.0g are dissolved in purified water 30ml, 20 DEG C of stirrings, getting compound (VA) (23.0g) drops in reaction flask, add dehydrated alcohol 160ml, this suspension agitation 15min, the purification of aqueous solutions 40ml of 2 hours inherent less than the 25 DEG C POTASSIUM BOROHYDRIDE 8gs of dropping containing 25% sodium hydroxide (0.4ml), stirring at room temperature 1 hour again after dropwising, leave standstill separatory, discard lower floor's solution, upper solution proceeds in three-necked bottle, pH to 4 is adjusted with concentrated hydrochloric acid under ice-water bath cooling and stirring, pH to 7 is adjusted again with 20% sodium hydroxide solution, with toluene wash water layer 3 times, water layer evaporated under reduced pressure, resistates adds dehydrated alcohol 200ml, be heated to 60-70 DEG C, filtered while hot removing inorganic salt, filtrate reduced in volume is complete, compound as white solid (VIA) 13.0g is obtained with dehydrated alcohol 50ml crystallization, content 99.7%, yield 87%.
Embodiment 6:
The preparation of lamivudine (I)
Compound (VIA) 10.0g is dissolved in methyl alcohol 210ml, adds the saturated methanol solution 40ml of ammonia, 30 ~ 50 DEG C of airtight stirring 8-10 hour.React complete, decompression at 70 DEG C of reducing pressure steams solvent, and resistates adds dehydrated alcohol 150ml, be heated to 60-70 DEG C, filtered while hot removing inorganic salt, filtrate proceeds in reaction flask, drip 400ml isopropyl acetate in 2 hours, naturally cool to room temperature, stirring and crystallizing, filter, filter cake isopropyl acetate freezing on a small quantity washing, drains, 50 DEG C of drying under reduced pressure, obtain lamivudine (I) white powder solid 7.7g, mp176.9-177.5 DEG C, purity 99.7%, yield 96%.
Embodiment 7:
The preparation of lamivudine (I)
Sodium hydroxide 6g stirring and dissolving is added, by compound (VIA) 10.0g in 20 ~ 40 DEG C of airtight stirring 10-12 hour to methyl alcohol 200ml.React complete, pH is reconciled to 7 with 18% hydrochloric acid under ice bath, at 90 DEG C, decompression steams solvent, resistates adds dehydrated alcohol 160ml, is heated to 60-70 DEG C, filtered while hot removing inorganic salt, filtrate proceeds in reaction flask, drip 400ml isopropyl acetate in 2 hours, naturally cool to room temperature, stirring and crystallizing, filter, filter cake isopropyl acetate freezing on a small quantity washing, drains, 50 DEG C of drying under reduced pressure, obtain lamivudine (I) white powder solid 6.9g, mp176.9-177.5 DEG C, 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 at the flask of 300ml, phenyl aldehyde 38.6g that re-distillation is crossed, backflow is heated under stirring, dissolution of solid solution is orange-yellow, Deng the complete continuation backflow of dissolution of solid 2 ~ 3h, add toluene 40ml, distilling off solvent, cool to room temperature, stirring downhill reaction drop adds ethyl acetate and is about 100ml, stir 2 hours after separating out solid, after suction filtration, 40 DEG C of drying under reduced pressure obtain 4-benzimide cytosine(Cyt) 34.8g (cytosine(Cyt) schiff bases), transformation efficiency 80%.
4-benzimide cytosine(Cyt) 33.4g, ammonium sulfate 0.77g, hexamethyldisilazane 22.0ml and trichloromethane 500ml are dropped in 1L three-necked bottle, stir temperature rising reflux 2 hours until reaction solution dissolves clarification, be cooled to interior temperature 0 DEG C, obtain the chloroform soln of compound (IVB); Nitrogen protection; chloroform soln to compound (IVB) under temperature 0 DEG C stirring in keeping drips Iodotrimethylsilane 44.0ml; dropwise in 1.5 hours; in 2 hours, drip the trichloromethane 100ml solution of compound (IIIA) (48.0g) again, be warming up to 30 ~ 35 DEG C of reaction 15h, reaction solution is evaporated to dry; add methyl tertiary butyl ether 100ml and stir 4h; filter, a small amount of methyl tertiary butyl ether of filter cake washs, 45 DEG C of drying under reduced pressure 4h.Above-mentioned gained solid is dropped in 500ml three-necked bottle, adds 200ml purified water and 30ml triethylamine, stir 3 hours, ice-water bath cold filtration, filter cake water washing freezing on a small quantity, 50 DEG C of drying under reduced pressure, obtain 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 at the flask of 300ml, phenyl aldehyde 38.6g that re-distillation is crossed, backflow is heated under stirring, dissolution of solid solution is orange-yellow, waits the complete continuation backflow of dissolution of solid 2 ~ 3h, adds toluene 40ml, distilling off solvent, cool to room temperature, stirring downhill reaction drop adds ethyl acetate and is about 100ml, stirs 2 hours after separating out solid, after suction filtration, 40 DEG C of drying under reduced pressure obtain 4-benzimide cytosine(Cyt) 34.8g, transformation efficiency 80%.
4-benzimide cytosine(Cyt) 33.4g, ammonium sulfate 0.77g, hexamethyldisilazane 22.0ml and trichloromethane 500ml are dropped in 1L three-necked bottle, stir temperature rising reflux 2 hours until reaction solution dissolves clarification, be cooled to interior temperature 0 DEG C, obtain the chloroform soln of compound (IVB); Nitrogen protection; chloroform soln to compound (IVB) under temperature 0 DEG C stirring in keeping drips Iodotrimethylsilane 44.0ml; dropwise in 1.5 hours; in 2 hours, drip the trichloromethane 100ml solution of compound (IIIB) (50.0g) again, be warming up to 30 ~ 35 DEG C of reaction 15h, reaction solution is evaporated to dry; add methyl tertiary butyl ether 100ml and stir 4h; filter, a small amount of methyl tertiary butyl ether of filter cake washs, 45 DEG C of drying under reduced pressure 4h.Above-mentioned gained solid is dropped in 500ml three-necked bottle, adds 200ml purified water and 30ml triethylamine, stir 3 hours, ice-water bath cold filtration, filter cake water washing freezing on a small quantity, 50 DEG C of drying under reduced pressure, obtain 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 stirs 12 hours in 20-30 DEG C, suction filtration is to dry, water washing is to neutral rear suction filtration to dry, 40 DEG C of decompression dryings obtain compound (VIB) white solid 38.6g, mp210.7-212.7 DEG C, [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 at the flask of 300ml, p-tolyl aldehyde 43.7g that re-distillation is crossed, backflow is heated under stirring, dissolution of solid solution is orange-yellow, waits the complete continuation backflow of dissolution of solid 2 ~ 3h, adds toluene 40ml, distilling off solvent, cool to room temperature, stirring downhill reaction drop adds ethyl acetate and is about 100ml, stirs 2 hours after separating out solid, after suction filtration, 40 DEG C of drying under reduced pressure obtain 4-to methylbenzene azomethine cytosine(Cyt) 36.2g, transformation efficiency 78%.
4-is dropped in 1L three-necked bottle to 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 dissolves clarification, be cooled to interior temperature 0 DEG C, obtain the chloroform soln of compound (IVB2); Nitrogen protection; chloroform soln to compound (IVB2) under temperature 0 DEG C stirring in keeping drips Iodotrimethylsilane 44.0ml; dropwise in 1.5 hours; in 2 hours, drip the trichloromethane 100ml solution of compound (IIIB) (50.0g) again, be warming up to 30 ~ 35 DEG C of reaction 15h, reaction solution is evaporated to dry; add methyl tertiary butyl ether 100ml and stir 4h; filter, a small amount of methyl tertiary butyl ether of filter cake washs, 45 DEG C of drying under reduced pressure 4h.Above-mentioned gained solid is dropped in 500ml three-necked bottle, adds 200ml purified water and 30ml triethylamine, stir 3 hours, ice-water bath cold filtration, filter cake water washing freezing on a small quantity, 50 DEG C of drying under reduced pressure, obtain compound (VB2) white solid 58.1g, yield 83%, content 99.0%.
Similar operation, compound (IIIA) (48.0g) feeds intake to obtain 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 stirs 12 hours in 20-30 DEG C, suction filtration is to dry, water washing is to neutral rear suction filtration to dry, 40 DEG C of decompression dryings obtain compound (VIB) white solid 36.7g, mp210.7-212.7 DEG C, [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 in purified water 30ml, 20 DEG C of stirrings, getting compound (VIB) (23.0g) drops in reaction flask, add dehydrated alcohol 160ml, this suspension agitation 15min, the purification of aqueous solutions 40ml of 2 hours inherent less than the 25 DEG C POTASSIUM BOROHYDRIDE 8gs of dropping containing 25% sodium hydroxide (0.4ml), stirring at room temperature 1 hour again after dropwising, leave standstill separatory, discard lower floor's solution, upper solution proceeds in three-necked bottle, pH to 4 is adjusted with concentrated hydrochloric acid under ice-water bath cooling and stirring, pH to 7 is adjusted again with 20% sodium hydroxide solution, with toluene wash water layer 3 times, water layer evaporated under reduced pressure, resistates adds dehydrated alcohol 200ml, be heated to 60-70 DEG C, filtered while hot removing inorganic salt, filtrate reduced in volume is complete, lamivudine (I) compound as white solid 12.0g is obtained with dehydrated alcohol 50ml crystallization, content 99.7%, yield 87%.
The invention is not restricted to above-described embodiment, all above-described embodiment is done according to technical spirit of the present invention any simple modification, equivalent variations or modification, all belong within the scope of the technology of the present invention.
Claims (1)
1. an industrialized process for preparing for 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) is obtained by reacting acylate (III) with acylating agent diacetyl oxide or propionic anhydride under solvents tetrahydrofurane and catalyzer DMAP exist; temperature of reaction is-25 DEG C ~-20 DEG C
Wherein, the R in formula (III) acylate is ethanoyl or propionyl;
Glycosylation is there is and obtains compound (VB) in the cytosine(Cyt) schiff bases (IVB) of the acylate (III) b) a) obtained by step and single silanization under the catalysis of Lewis acid Iodotrimethylsilane or trimethylchlorosilane
Wherein, the Y in formula (IVB) and (VB) compound is phenyl or p-methylphenyl;
C) by step b) compound (VB) that obtains obtains compound (VIB) through hydrolysis under the diluted acid being selected from dilute hydrochloric acid, acetic acid,diluted, dilute sulphuric acid and dust technology exists;
D) by step c) compound (VIB) that obtains obtains lamivudine (I) through potassium borohydride reduction under dipotassium hydrogen phosphate exists.
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| CN102746284B (en) * | 2012-07-05 | 2014-10-29 | 湖南千金湘江药业股份有限公司 | Preparation method for lamivudine |
| GB201610327D0 (en) * | 2016-06-14 | 2016-07-27 | Univ Nelson Mandela Metropolitan | Process for producing Lamivudine and Entricitabine |
| 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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