CN103450166A - Preparation method of nucleotide compound - Google Patents
Preparation method of nucleotide compound Download PDFInfo
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- CN103450166A CN103450166A CN2012101774335A CN201210177433A CN103450166A CN 103450166 A CN103450166 A CN 103450166A CN 2012101774335 A CN2012101774335 A CN 2012101774335A CN 201210177433 A CN201210177433 A CN 201210177433A CN 103450166 A CN103450166 A CN 103450166A
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- C07D411/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms
- C07D411/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings
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Abstract
The invention relates to a preparation method of a nucleotide analog. Specifically, the invention discloses a preparation method of a nucleotide compound shown as a formula I. The preparation method comprises the steps of: reducing in methanol a compound as represented by a formula II in the presence of a reducing agent, thus yielding a reaction mixture containing the compound as represented by the formula I; and separating or purifying the compound as represented by the formula I from the reaction mixture, wherein R in formula I and II is hydrogen or fluorine. The method has high selectivity of reduction reaction, and the prepared product has high yield and good purity. In addition, the method has the advantages of simple posttreatment process, convenience for operation, small usage amount of solvents, low production cost and greatly reduced discharge of '' three wastes ''; therefore, the preparation method satisfies requirements of modern manufacture of EHS and is suitable for industrialized mass production.
Description
Technical field
The invention belongs to the pharmaceutical chemistry technical field, particularly, relate to the method for preparing nucleoside analog, more specifically, relate to the preparation method of lamivudine or emtricitabine.
Background technology
Lamivudine (Lamivudine, 3TC) trade(brand)name: Hepuding, chemical name: (2R-cis)-4-amino-1-(2-methylol-1,3-oxygen sulphur Polymorphs-5-yl)-1H-pyrimid-2-one, structural formula is as follows:
Lamivudine is the ucleosides antiviral drug of Ge Lansu company exploitation, hepatitis B virus (HBV) in external and experimental infection animal body is had to stronger restraining effect, make serum transaminase be down to normally simultaneously, life-time service can significantly improve the struvite change of hepatic necrosis, and alleviates or stop the progress of hepatic fibrosis.
Emtricitabine is that its structural formula is as follows by the ucleosides antiviral drug of Triangle company development:
The method that bibliographical information prepares lamivudine or emtricitabine has a variety of.
That in industrial production, extensively uses at present has a disclosed synthetic route one of WO9529174.
Route one
The 4th step reduction reaction in route one, reaction system is moisture more, and reaction preference is very poor, produce impurity in process more, the purity of target product is not high, can't from water, directly separate out, and buffer system has been introduced a large amount of inorganic salt, product need generate corresponding water-insoluble salt with salicylism reaction, separates the lamivudine salicylate that obtains high-optical-purity, and then use the triethylamine alkaline hydrolysis, just can obtain the lamivudine of higher degree.
The reduction reaction of CN101597281A report is not added catalyzer and buffered soln, shown in the following route two of synthetic route:
Route two
In route two, the glycosylation of synthetic CME need first be used into salt precipitation method and carry out purifying after finishing, and then after obtaining purer CME with the sodium bicarbonate alkaline hydrolysis, carry out again next step reduction reaction, could obtain purer lamivudine by aftertreatment simply.Route two is compared with route one, and step is equally long, and route two has just been used salify-precipitator method in the aftertreatment of glycosylation, and the salify-precipitator method of route one are to be used in the aftertreatment of reduction reaction.The lamivudine highly finished product that reaction obtains by aftertreatment, yield only has 70.3%, and does not report product purity.
Therefore, be badly in need of developing a kind of preparation method easy, the simple and effective nucleoside analog of aftertreatment that synthesizes.
Summary of the invention
One of purpose of the present invention is to provide a kind of preparation method of nucleoside analog easily, and the selectivity of described method reduction reaction is very high, thereby significantly reduces the complicacy of purifying products step.
In first aspect present invention, a kind of preparation method of formula I compound is provided, comprise step:
(a), in methyl alcohol, while having reductive agent, formula II compound is carried out to reduction reaction, thereby obtain the reaction mixture containing formula I compound;
Wherein, in described reaction mixture, ratio≤1/60 of impurity as shown in Equation 2 and the content of formula I compound, preferably≤1/90, more preferably≤1/95;
Above-mentioned various in, R is hydrogen or fluorine; And
(b) isolated or purified formula I compound from described reaction mixture.
In another preference, in described reaction system, can also there is water to exist.
In another preference, described reductive agent comprises: NaBH
4and/or KBH
4.
In another preference, the formula I compound that described method makes, its purity >=99.0%; Preferably >=99.5%.
In another preference, described step (a) also comprises following reductive agent treatment step:
1) with acid, the reaction mixture after the reduction reaction end is regulated to the pH value to 4-6; With
2) mixture with alkali, previous step obtained is regulated the pH value to 7-8.
In another preference, described acid comprises: sulfuric acid, hydrochloric acid, Hydrogen bromide, nitric acid, phosphoric acid, acetic acid or its combination; Preferably, described acid comprises: sulfuric acid or hydrochloric acid; The sulfuric acid or the aqueous hydrochloric acid that for concentration, are more preferably 5-20wt%.
In another preference, described alkali comprises: sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, sodium-acetate, sodium tert-butoxide, potassium tert.-butoxide, sodium methylate, potassium methylate, sodium ethylate, potassium ethylate, Sodium phosphate dibasic, SODIUM PHOSPHATE, MONOBASIC, dipotassium hydrogen phosphate, potassium primary phosphate or its combination; Preferably described mineral alkali comprises: sodium hydroxide, potassium hydroxide, SODIUM PHOSPHATE, MONOBASIC or its combination; More preferably described alkali comprises: the sodium hydroxide that concentration is 5-15wt% or potassium hydroxide aqueous solution.
In another preference, after described reductive agent treatment step, also comprise following inorganic salt removal step:
3) filter the mixture that previous step obtains, concentrated filtrate, thus obtain the enriched material containing formula I compound.
In another preference, after described inorganic salt are removed step, also comprise following menthol removal step:
A) water that the enriched material containing formula I compound previous step obtained is doubly measured (volume/enriched material weight ratio) with 2-5 carries out recrystallization, removes the menthol of separating out; Or
What B) previous step is obtained is dissolved in the water that 6-10 doubly measures (volume/enriched material weight ratio) containing the enriched material of formula I compound, with organic solvent, is extracted, and removes menthol.
In another preference, described organic solvent comprises: toluene, sherwood oil, normal heptane, normal hexane, isopropyl ether or ether.
In another preference, described steps A) recrystallization in is: what in previous step, obtain contains in the enriched material of formula I compound, add 2-5 doubly to measure the water of (volume/enriched material weight ratio), after heating for dissolving (as to 40-60 ℃), cooling (as being cooled to room temperature), crystallization, filter, collect filtrate, remove menthol; Optionally comprise filtrate is removed to remaining menthol with organic solvent extraction.
In another preference, described isolated or purified comprises following separating step:
I) with acid, the reaction mixture after the reduction reaction end is regulated to the pH value to 4-6;
The mixture adjust pH ii) with alkali, previous step obtained is to 7-8;
Iii) filter the mixture that previous step obtains, concentrated filtrate, thus obtain the enriched material containing formula I compound; With
The enriched material containing formula I compound iv) previous step obtained is soluble in water, after removing menthol, and concentrated water, thus obtain formula I compound crude product.
In another preference, described acid comprises: sulfuric acid, hydrochloric acid, Hydrogen bromide, nitric acid, phosphoric acid, acetic acid or its combination; Preferably, described acid comprises: sulfuric acid or hydrochloric acid; The sulfuric acid or the aqueous hydrochloric acid that for concentration, are more preferably 5-20wt%.
In another preference, described alkali comprises: sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, sodium-acetate, sodium tert-butoxide, potassium tert.-butoxide, sodium methylate, potassium methylate, sodium ethylate, potassium ethylate, Sodium phosphate dibasic, SODIUM PHOSPHATE, MONOBASIC, dipotassium hydrogen phosphate, potassium primary phosphate or its combination; Preferably described mineral alkali comprises: sodium hydroxide, potassium hydroxide, SODIUM PHOSPHATE, MONOBASIC or its combination; More preferably described alkali comprises: the sodium hydroxide that concentration is 5-15wt% or potassium hydroxide aqueous solution.
In another preference, step I is v):
A) enriched material containing formula I compound previous step obtained is doubly measured the water recrystallization of (volume/enriched material weight ratio) at 2-5, remove the menthol of separating out; Or
What B) previous step is obtained is dissolved in the water that 6-10 doubly measures (volume/enriched material weight ratio) containing the enriched material of formula I compound, with organic solvent, is extracted, and removes menthol.
In another preference, described organic solvent comprises: toluene, sherwood oil, normal heptane, normal hexane, isopropyl ether or ether.
In another preference, described steps A) recrystallization in comprises step: what in previous step, obtain contains in the enriched material of formula I compound, add 2-5 doubly to measure the water of (volume/enriched material weight ratio), after heating for dissolving (as to 40-60 ℃), cooling (as being cooled to room temperature), crystallization, filter, collect filtrate, remove menthol; Optionally comprise filtrate is removed to remaining menthol with organic solvent extraction.
In another preference, after described separating step, also comprise purification step: the formula I compound crude product that previous step is obtained is at C
1~ C
4recrystallization in alkyl alcohol, thus obtain through refining formula I compound.
In another preference, described re-crystallization step is:
A. formula I compound crude product heating previous step obtained is dissolved in the C that 3-30 doubly measures (volume/crude product weight ratio)
1~ C
4in alkyl alcohol, be cooled to 0-10 ℃ of crystallization, thereby obtain through refining formula I compound;
B. formula I compound crude product heating previous step obtained is dissolved in the C that 3-30 doubly measures (volume/crude product weight ratio)
1～C
4in alkyl alcohol, be concentrated into the 1/3-1/10 that residual volume is original volume, be cooled to 0-10 ℃ of crystallization, thereby obtain through refining formula I compound; Or
C. formula I compound crude product heating previous step obtained is dissolved in the C that 3-30 doubly measures (volume/crude product weight ratio)
1~ C
4in alkyl alcohol, be cooled to 20-25 ℃ of crystallization, collect crystal, be cooled to 0-10 ℃ of crystallization after the 1/5-1/20 that concentrated filtrate to residual volume is original volume, merge crystal, thereby obtain through refining formula I compound.
In another preference, described C
1~ C
4alkyl alcohol is selected from lower group: methyl alcohol, ethanol or its mixing.
In another preference, described formula I compound, its purity >=99.0%.
In another preference, the purity of described formula I compound >=99.5%.
In another preference, the mol ratio of described reductive agent and formula II compound is 1:1-5:1, preferably 2:1-4:1.
In another preference, described reduction reaction is carried out under 0-40 ℃, is preferably 15-25 ℃.
In should be understood that within the scope of the present invention, above-mentioned each technical characterictic of the present invention and can combining mutually between specifically described each technical characterictic in below (eg embodiment), thus form new or preferred technical scheme.As space is limited, tire out and state no longer one by one at this.
Embodiment
The inventor is by long-term and deep research, be surprised to find that, in the reduction reaction for preparing lamivudine or emtricitabine, the methyl alcohol of take can significantly improve the selectivity of this reduction reaction as solvent, greatly simplified product separation and purification step, to improving product yield and purity, there is vital effect.On this basis, the contriver has completed the present invention.
As used herein, term " C
1~ C
4alkyl alcohol " refer to the alcohol containing 1～4 carbon atom, such as methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, the trimethyl carbinol etc.
The preparation method of formula I compound
Raw material for the preparation of the nucleoside analog shown in formula I used herein or reagent is commercially available obtaining all, can be maybe that this area ordinary method makes, and preferably, raw material (CME or 5-F CME) can make by the method for WO9529174.
The invention provides the preparation method of the nucleoside analog shown in a kind of formula I, comprise step:
(a), in methyl alcohol, exist reductive agent (as NaBH
4or KBH
4) time, formula II compound is carried out to reduction reaction, thereby obtain the reaction mixture containing formula I compound;
Wherein, in described reaction mixture, ratio≤1/60 of impurity as shown in Equation 2 and formula I compounds content, preferably≤1/90, more preferably≤1/95;
Above-mentioned various in, R is hydrogen or fluorine; And
(b) isolated or purified formula I compound from described reaction mixture.
In another preference, the formula I compound that described method makes, its purity >=99.0%, preferably >=99.5%.
In another preference, the mol ratio of described reductive agent and formula II compound is 1:1-5:1, preferably 2:1-4:1.
In another preference, described reduction reaction is carried out under 0-40 ℃, is preferably 15-25 ℃.
In method of the present invention, when the reduction reaction of step (a) finishes, if also contain the complete NaBH of unreacted in system
4or KBH
4while existing, because of NaBH
4or KBH
4very active, if directly reaction mixture is concentrated, can cause producing too much impurity.Thereby make follow-up purification process very difficult, therefore, after described reduction reaction, preferably unreacted reductive agent cancellation is processed.
The present invention preferably carries out following reductive agent treatment step:
1) with acid, the reaction mixture after the reduction reaction end is regulated to the pH value to 4-6;
2) the mixture adjust pH with alkali, previous step obtained is to 7-8.
Wherein, described acid or alkali can be this area acid commonly used or alkali, comprise mineral acid commonly used or mineral alkali.When being applied to the conditioned reaction mixture, described acid or alkali can be configured in solvent (as water) with any concentration.
In another preference, described acid comprises: sulfuric acid, hydrochloric acid, Hydrogen bromide, nitric acid, phosphoric acid, acetic acid or its combination; Preferably, described acid comprises: sulfuric acid or hydrochloric acid; The sulfuric acid or the aqueous hydrochloric acid that for concentration, are more preferably 5-20wt%.
In another preference, described alkali comprises: sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, sodium-acetate, sodium tert-butoxide, potassium tert.-butoxide, sodium methylate, potassium methylate, sodium ethylate, potassium ethylate, Sodium phosphate dibasic, SODIUM PHOSPHATE, MONOBASIC, dipotassium hydrogen phosphate, potassium primary phosphate or its combination; Preferably described mineral alkali comprises: sodium hydroxide, potassium hydroxide, SODIUM PHOSPHATE, MONOBASIC or its combination; More preferably described alkali comprises: the sodium hydroxide that concentration is 5-15wt% or potassium hydroxide aqueous solution.
After described reductive agent treatment step, also can comprise inorganic salt removal step:
3) filter the mixture that previous step obtains, concentrated filtrate, thus obtain the enriched material containing formula I compound.
After described inorganic salt are removed step, also preferably include menthol and remove step (as recrystallization or extraction etc.), the present invention preferably carries out following menthol and removes step:
A) enriched material containing formula I compound previous step obtained is doubly measured the water recrystallization of (volume/enriched material weight ratio) at 2-5, remove the menthol of separating out; Or
What B) previous step is obtained is dissolved in the water that 6-10 doubly measures (volume/enriched material weight ratio) containing the enriched material of formula I compound, with organic solvent, is extracted, and removes menthol.
In another preference, described organic solvent comprises: toluene, sherwood oil, normal heptane, normal hexane, isopropyl ether or ether.
In another preference, described A) recrystallization in comprises step: what in previous step, obtain contains in the enriched material of formula I compound, add 2-5 doubly to measure the water of (volume/enriched material weight ratio), after heating for dissolving (as to 40-60 ℃), cooling (as being cooled to room temperature), crystallization, filter, collect filtrate, remove menthol; Optionally comprise filtrate is removed to remaining menthol with organic solvent extraction.
Should understand, the reaction mixture that step (a) obtains, can be described reduction reaction undressed reaction mixture while finishing, can be also reaction mixture or the crude product after reductive agent treatment step as above, inorganic salt are removed step or menthol to remove step process.
In method of the present invention, isolated or purified step in described step (b), can be this area post-processing operation commonly used, the invention provides a kind of following separating step that preferably comprises:
I) with acid, the reaction mixture after the reduction reaction end is regulated to the pH value to 4-6;
The mixture adjust pH ii) with alkali, previous step obtained is to 7-8;
Iii) filter the mixture that previous step obtains, concentrated filtrate, thus obtain the enriched material containing formula I compound;
The enriched material containing formula I compound iv) previous step obtained is soluble in water, after removing menthol, and concentrated water, thus obtain formula I compound crude product.
Wherein, described acid or alkali are as described above.
In another preference, step I is v):
A) enriched material containing formula I compound previous step obtained is doubly measured the water recrystallization of (volume/enriched material weight ratio) at 2-5, remove the menthol of separating out; Or
What B) previous step is obtained is dissolved in the water that 6-10 doubly measures (volume/enriched material weight ratio) containing the enriched material of formula I compound, with organic solvent, is extracted, and removes menthol.
In another preference, described organic solvent comprises: toluene, sherwood oil, normal heptane, normal hexane, isopropyl ether or ether.
In another preference, described A) recrystallization in comprises step: what in previous step, obtain contains in the enriched material of formula I compound, add 2-5 doubly to measure the water of (volume/enriched material weight ratio), after heating for dissolving (as to 40-60 ℃), cooling (as being cooled to room temperature), crystallization, filter, collect filtrate, remove menthol; Optionally comprise filtrate is removed to remaining menthol with organic solvent extraction.
After described separating step, also can comprise purification step: the formula I compound crude product that previous step is obtained is at C
1~ C
4recrystallization in alkyl alcohol (as methyl alcohol, ethanol etc.), thus obtain through refining formula I compound.
In another preference, described purification step comprises:
A. the heating of the formula I compound crude product that previous step obtained is dissolved in the methyl alcohol or ethanol or its combination that 3-30 doubly measures (volume/crude product weight ratio), is cooled to 0-10 ℃ of crystallization, thereby obtains through refining formula I compound; Or
B. the heating of the formula I compound crude product that previous step obtained is dissolved in the methyl alcohol or ethanol or its combination that 3-30 doubly measures (volume/crude product weight ratio), be concentrated into the 1/3-1/10 that residual volume is original volume, be cooled to 0-10 ℃ of crystallization, thereby obtain through refining formula I compound; Or
C. the heating of the formula I compound crude product that previous step obtained is dissolved in the methyl alcohol or ethanol or its combination that 3-30 doubly measures (volume/crude product weight ratio), be cooled to 20-25 ℃ of crystallization, collect crystal, be cooled to 0-10 ℃ of crystallization after the 1/5-1/20 that concentrated filtrate to residual volume is original volume, merge crystal, thereby obtain through refining formula I compound.
Compared with prior art, the present invention mainly has the following advantages:
1, the invention provides the preparation method of a kind of lamivudine or emtricitabine, described method comprises step: take methyl alcohol as solvent, formula II compound is carried out to reduction reaction, thereby obtain formula I compound (being lamivudine or emtricitabine).In described method, the selectivity of reduction reaction is very high, and subsequent disposal is purified without the salify-precipitator method, just can obtain purity and reach 95% crude product, and, in crude product, impurity 1(is as shown in Equation 1) or impurity 2(as shown in Equation 2) content very low, wherein, R is H or F.The method three waste discharge significantly reduces, and meets the requirement of the modern EHS of manufacture, is applicable to industrialized production.
2, in the method for the invention reaction process without adding buffer reagent or catalyzer, also without reaction raw materials is carried out to purifying, the formula II compound prepared according to the disclosed method of WO9529174 (is CME during R=H, during R=F, be 5-F CME) can directly carry out method of the present invention, therefore, raw material sources are more extensive, more economical.
3, method of the present invention makes lamivudine and emtricitabine, purity all can reach more than 99%, even can reach more than 99.5%, and yield all can be up to more than 85%.
Below in conjunction with concrete enforcement, further set forth the present invention.Should be understood that these embodiment only are not used in and limit the scope of the invention for the present invention is described.The experimental technique of unreceipted actual conditions in the following example, usually according to normal condition, or the condition of advising according to manufacturer.Unless otherwise indicated, otherwise per-cent and umber calculate by weight.Raw materials used or the reagent of the present invention, equal commercially available obtaining unless otherwise noted.
The preparation of embodiment 1 lamivudine
In reaction flask, add CME(to make by the method for WO9529174) (38.1g, 0.10mol), methyl alcohol 400ml, stir and make dissolution of solid.Be cooled to 10 ℃, drip NaBH
4(water: 40ml), in the dropping process, temperature control is at 10-15 ℃ for the aqueous solution of (11.7g, 0.31mol).Dropwise, continue insulation reaction 2-3 hour, TLC detects (CH
2cl
2: MeOH=10:1) raw material reaction is complete.
Be cooled to 0-10 ℃, adjust pH=5 with the aqueous sulfuric acid of 10wt%, then adjust pH=7 with the 10wt%NaOH aqueous solution, separate out a large amount of solid salts.Filter, filtrate decompression is concentrated into dry.
Add 150ml water in residue, be heated to 40-50 ℃ of stirring and dissolving, be cooled to room temperature, separate out menthol and reclaim.Filter, filtrate is divided 2 extractions with toluene 50ml, and remaining menthol is removed and reclaimed.Water is evaporated to dry, obtains lamivudine crude product 22.6g, crude product yield 98.6%, and HPLC shows that purity is 95.9%, wherein impurity is respectively: impurity 1H 0.05%, impurity 2H 0.9%.
Add 250ml ethanol in above-mentioned crude product, be heated to reflux, be stirred to dissolve.Add the 1.0g activated carbon decolorizing, filtered while hot, filtrate is cooled to 40 ℃, the decompression steam ethanol most original volume 1/6.Slow cooling to 10 ℃, continue insulated and stirred 2 hours.Filter, with ethyl acetate drip washing filter cake, 50 ℃ of vacuum-dryings obtain lily lamivudine 20.9g, refining yield 92.5%, and HPLC purity 99.6%, MS(ESI) m/z:M+H 230.3.
The preparation of embodiment 2 lamivudines
Add CME(19.0g, 0.05mol in reaction flask), methyl alcohol 200ml, stir and to make dissolution of solid.Be cooled to 10 ℃, drip KBH
4(water: 20ml), in the dropping process, temperature control is at 10-15 ℃ for the aqueous solution of (5.9g, 0.11mol).Dropwise, continue insulation reaction 2-3 hour, TLC detects (CH
2cl
2: MeOH=10:1) raw material reaction is complete.
Be cooled to 0-10 ℃, adjust pH=6 with the aqueous sulfuric acid of 10wt%, then adjust pH=7.5 with the 10wt% KOH aqueous solution, separate out a large amount of solid salts.Filter, filtrate decompression is concentrated into dry.
Add 150ml water in residue, stirring and dissolving, divide 3 extractions with toluene 100ml.Toluene layer reclaims menthol, and water layer adds the 1g activated carbon decolorizing.Filter, filtrate decompression is concentrated into dry, obtains lamivudine crude product 11.2g, crude product yield 98.1%, and HPLC shows that purity is 93.9%, wherein impurity is respectively: impurity 1H0.05%, impurity 2H 1.2%.
Add 70ml ethanol in above-mentioned crude product, be heated to reflux, be stirred to dissolve.Slow cooling to 5 ℃, continue insulated and stirred 3 hours.Filter, with ethanol drip washing filter cake, 50 ℃ of vacuum-dryings obtain lily lamivudine 9.7g, refining yield 86.5%, and HPLC purity 99.3%, MS(ESI) m/z:M+H 230.3.
The preparation of embodiment 3 emtricitabines
In reaction flask, add 5-F CME(to make by the method for WO9529174) (19.9g, 0.05mol), methyl alcohol 200ml, stir and make dissolution of solid.Be cooled to 10 ℃, drip NaBH
4(water: 20ml), in the dropping process, temperature control is at 10-15 ℃ for the aqueous solution of (4.9g, 0.13mol).Dropwise, continue insulation reaction 2-3 hour, TLC detects (CH
2cl
2: MeOH=15:1) raw material reaction is complete.
Add 15ml acetone termination reaction.Be cooled to 0-10 ℃, the hydrochloric acid with 20% is adjusted pH=5, then adjusts pH=7 with the 10%NaOH aqueous solution, separates out a large amount of solid salts.Filter, filtrate decompression is concentrated into dry.
Add 300ml water in residue, be warming up to 35-40 ℃ of stirring and dissolving, with normal heptane 150ml, divide 3 extractions.Organic layer reclaims menthol, and water layer is evaporated to dry, obtains emtricitabine crude product 11.8g, crude product yield 95.4%, and HPLC shows that purity is 95.2%, wherein impurity is respectively: impurity 1F 0.06%, impurity 2F 1.0%.
Add 120ml methyl alcohol in above-mentioned crude product, be heated to 50 ℃, be stirred to dissolve.Slow cooling to 5 ℃, continue insulated and stirred 1 hour.Filter, with ethanol drip washing filter cake.Filtrate decompression is concentrated into volume and is about 30ml, then is cooled to 5 ℃, continues insulated and stirred 2 hours.Filter, with ethanol drip washing filter cake.Merge filter cake, 40 ℃ of vacuum-dryings obtain lily emtricitabine 10.5g, refining yield 89.0%, and HPLC purity 99.5%, MS(ESI) m/z:M+H 248.3.
The preparation (ethanol is made solvent) of Comparative Examples 1 lamivudine
In reaction flask, add CME(to make by the method for WO9529174) (7.6g, 0.020mol), ethanol 120ml, stir, be heated to 40 ℃, make dissolution of solid.Be cooled to 10 ℃, drip NaBH
4(water: 8ml), in the dropping process, temperature control is at 10-15 ℃ for the aqueous solution of (2.3g, 0.062mol).Dropwise, continue insulation reaction 3 hours.
Be cooled to 0-10 ℃, adjust pH=5 with the aqueous sulfuric acid of 10wt%, then adjust pH=7 with the 10wt%NaOH aqueous solution, separate out a large amount of solid salts.Filter, filtrate decompression is concentrated into dry.
Add 50ml water in residue, be heated to 40-50 ℃ of stirring and dissolving, with toluene 50ml, divide 2 extractions, remaining menthol is removed and reclaimed.Water is evaporated to dry, obtains the lamivudine crude product, is yellow oil, and the HPLC purity of described crude product is 88.6%.Wherein, contain two major impurities, structure and content are respectively after testing: impurity 1H has 5.6%, and impurity 2H has 4.3%.And it is more difficult to remove impurity 1H and impurity 2H, especially impurity 2H, be difficult to it is separated with the target product lamivudine.
Above-mentioned experimental results show that: described reduction reaction be take methyl alcohol as solvent, significantly improved the selectivity of this reduction reaction, effectively avoided the impurity separated with the target product difficulty to produce, the purity very high (can reach 95%) of reaction after product crude product, be very beneficial for being further purified.Product purity high (>=99%) after refining, yield good (can reach 90%).Visible, the method for the invention is easy and simple to handle, purifying is simple and easy, more economical, be more suitable for suitability for industrialized production.
All documents of mentioning in the present invention are all quoted as a reference in this application, just as each piece of document quoted separately as a reference.Should be understood that in addition those skilled in the art can make various changes or modifications the present invention after having read above-mentioned teachings of the present invention, these equivalent form of values fall within the application's appended claims limited range equally.
Claims (10)
1. the preparation method of a formula I compound, is characterized in that, comprises step:
(a), in methyl alcohol, while having reductive agent, formula II compound is carried out to reduction reaction, thereby obtain the reaction mixture containing formula I compound;
Wherein, in described reaction mixture, ratio≤1/60 of impurity as shown in Equation 2 and the content of formula I compound;
Above-mentioned various in, R is hydrogen or fluorine; And
(b) isolated or purified formula I compound from described reaction mixture.
2. preparation method as claimed in claim 1, is characterized in that, described reductive agent comprises: NaBH
4and/or KBH
4.
3. preparation method as claimed in claim 1, is characterized in that, the formula I compound that described method makes, its purity >=99.0%.
4. preparation method as claimed in claim 1, is characterized in that, described step (a) also comprises following reductive agent treatment step:
1) with acid, the reaction mixture after the reduction reaction end is regulated to the pH value to 4-6; With
2) mixture with alkali, previous step obtained is regulated the pH value to 7-8.
5. preparation method as claimed in claim 4, is characterized in that, after described reductive agent treatment step, also comprises following inorganic salt removal step:
3) filter the mixture that previous step obtains, concentrated filtrate, thus obtain the enriched material containing formula I compound.
6. preparation method as claimed in claim 5, is characterized in that, after described inorganic salt are removed step, also comprises following menthol removal step:
A) water that the enriched material containing formula I compound previous step obtained is doubly measured (volume/enriched material weight ratio) with 2-5 carries out recrystallization, removes the menthol of separating out; Or
What B) previous step is obtained is dissolved in the water that 6-10 doubly measures (volume/enriched material weight ratio) containing the enriched material of formula I compound, with organic solvent, is extracted, and removes menthol.
7. preparation method as claimed in claim 1, is characterized in that, described isolated or purified comprises following separating step:
I) with acid, the reaction mixture after the reduction reaction end is regulated to the pH value to 4-6;
The mixture adjust pH ii) with alkali, previous step obtained is to 7-8;
Iii) filter the mixture that previous step obtains, concentrated filtrate, thus obtain the enriched material containing formula I compound; With
The enriched material containing formula I compound iv) previous step obtained is soluble in water, after removing menthol, and concentrated water, thus obtain formula I compound crude product.
8. preparation method as claimed in claim 7, is characterized in that, after described separating step, also comprises purification step: the formula I compound crude product that previous step is obtained is at C
1~ C
4recrystallization in alkyl alcohol, thus obtain through refining formula I compound.
9. preparation method as claimed in claim 8, is characterized in that, described formula I compound, its purity >=99.0%.
10. preparation method as claimed in claim 1, is characterized in that, the mol ratio of described reductive agent and formula II compound is 1:1-5:1, preferably 2:1-4:1.
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| CN108409724A (en) * | 2018-06-04 | 2018-08-17 | 安徽帆香料有限公司 | A kind of emtricitabine separation method |
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| EP2377862A1 (en) * | 2010-03-29 | 2011-10-19 | Esteve Química, S.A. | Process for obtaining emtricitabine |
| CN102234269A (en) * | 2010-04-29 | 2011-11-09 | 重庆医药工业研究院有限责任公司 | Industrial preparation method for lamivudine |
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| IL113432A (en) * | 1994-04-23 | 2000-11-21 | Glaxo Group Ltd | Process for the diastereoselective synthesis of nucleoside analogues |
| CN101597281B (en) * | 2009-07-01 | 2012-09-05 | 济南久创化学有限责任公司 | Preparation method of lamivudine and intermediate thereof |
| CN102101856A (en) * | 2009-12-16 | 2011-06-22 | 重庆医药工业研究院有限责任公司 | High optical purity nucleoside intermediates and preparation method thereof |
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| EP2377862A1 (en) * | 2010-03-29 | 2011-10-19 | Esteve Química, S.A. | Process for obtaining emtricitabine |
| CN102234269A (en) * | 2010-04-29 | 2011-11-09 | 重庆医药工业研究院有限责任公司 | Industrial preparation method for lamivudine |
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