CN102911167A - Method for preparing nucleoside intermediate with high optical purity - Google Patents
Method for preparing nucleoside intermediate with high optical purity Download PDFInfo
- Publication number
- CN102911167A CN102911167A CN2012104472765A CN201210447276A CN102911167A CN 102911167 A CN102911167 A CN 102911167A CN 2012104472765 A CN2012104472765 A CN 2012104472765A CN 201210447276 A CN201210447276 A CN 201210447276A CN 102911167 A CN102911167 A CN 102911167A
- Authority
- CN
- China
- Prior art keywords
- reaction
- solvent
- oxathiolane
- phosphine
- molar weight
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a method for preparing a nucleoside intermediate with high optical purity. The method includes unit processes of mitsunobu reaction, off-protecting group reaction, reaction for forming triazole, ammonolysis reaction and post-processing. According to the method, complicated acidylation or chlorination process is absent, an organosilicon reagent which is expensive and large in usage amount is not required to serve as a protecting group, the process cost is lowered, the production technology process is short, the production cost is low, and the intermediate with high yield and high optical purity can be obtained.
Description
One, technical field
The present invention relates to a kind of preparation method of Internmediate of anti viral medicine, specifically a kind of preparation method of ucleosides intermediate of high-optical-purity.
Two, background technology
Nucleoside medicine is the important antiviral class medicine of a class.This class medicine is in human body, after becoming nucleoside triphosphate class medicine after the phosphorylation, the activity of reversed transcriptive enzyme that can suppress the DNA of virus, nucleoside triphosphate class medicine also connects by the DNA that infiltrates virus simultaneously, hinder synthetic that the DNA of virus connects, copying of establishment virus and bring into play effective antiviral activity.
Lamivudine and emtricitabine have the efficient disease-resistance toxic action to immunodeficient disease (HIV) virus and hepatitis B (HBV) virus, are widely used as the one antiviral medicine.The chemical structural formula of lamivudine and emtricitabine is as follows:
Among the preparation method of these two kinds of nucleoside medicines, all relate to the preparation of key intermediate compound I at present.The chemical structural formula of compound I is as follows:
Compound I
CN102101856A discloses a kind of high optical purity nucleoside intermediates and preparation method thereof, mainly is the method for a kind of synthetic compound I and the method for synthetic compound I precursor compound II, and its chemical structural formula of compound I I is as follows:
Compound I I
R wherein
1Be formyl radical, ethanoyl, propionyl, butyryl radicals, pentanoyl, isopropyl acyl group, isobutyryl, hydrocinnamoyl or phenylacetyl, wherein optimum is ethanoyl and propionyl.When preparation compound I I, at first by (2R, 5R)-5-hydroxyl-[1; 3] oxathiolane-2-carboxylic acid-[(1'R; 2 ' S, 5'R)-5'-methyl-2'-(1-methylethyl) cyclohexyl] ester and acylting agent through catalyst, obtain compound I I under-30 ~-5 ℃ of conditions.The cytosine(Cyt) of compound I I and silylation protection or 5-flurocytosine obtain compound I by glycosylation behind the deprotection.Because the preparation of compound I I need to guarantee that chiral carbon chiral inversion does not occur and racemization in catalysis under the cold condition, condition is harsh, is unfavorable for batch production production, increases simultaneously the acylations step, causes whole production technique distance long, and ultimate yield reduces.Prepared by compound I I in the reaction of compound I, with cytosine(Cyt) or the 5-flurocytosine of silylation protection.Because organosilicon reagent is expensive, consumption is large, causes whole production technique cost high.
CN101830893A discloses the synthesis and preparation process of a kind of lamivudine intermediate HDMS, at preparation (2R, 5R)-5-(4-amino-2-oxygen-2H-pyrimidine-1-yl)-[1,3]-Evil thiophene alkane-2-carboxylic acid-2s-sec.-propyl)-5R-methyl isophthalic acid R-cyclohexanol is by peppermint alcohol radical-5-hydroxyl-1,3-thiazole-2-carboxylicesters passes through slowly to drip thionyl chloride in the mixed solvent of methylene dichloride and DMF, the insulation air distillation obtained chlorizate peppermint alcohol radical-5-chloro-1 in 3 hours, 3-thiazole-2-carboxylicesters, add thionyl chloride chance water in this process and easily resolve into unpleasant sulfurous gas and hydrochloric acid gas, the acid of generation is etching apparatus also; The productive rate of chlorination own is not high, the product after the chlorination is put into the bottom reaction again, has reduced the productive rate of whole piece reaction by this two-step reaction.To add toluene in the reaction vessel again, hexamethyldisilazane, cytosine(Cyt) and peppermint alcohol radical-5-chloro-1,3-thiazoles-2-carboxylicesters is back to clarification, and crystallization is filtered and is obtained product HDMS.The hexamethyldisilazane ingress of air that uses in this process very easily decomposes, and organosilicon reagent is expensive simultaneously, and usage quantity is large, and process costs is high.The productive rate of two-step reaction is 80%, and productive rate is not high.
CN1010669971A discloses the non-corresponding selection preparation method of emtricitabine, and the synthetic route of a complete emtricitabine is provided.Key intermediate 5S-(5'-flucytosine)-1 wherein, 3-oxathiolane-2R-carboxylic acid-MENTHOL ester is by trans-5-hydroxyl-1,3-oxathiolane-2-carboxylic acid-L menthol ester is at anhydrous methylene chloride and anhydrous N, in the dinethylformamide solution, drip gradually the thionyl chloride chlorination and obtain trans-5-hydroxyl-1, behind 3-oxathiolane-2-carboxylic acid-L menthol ester, it is slowly added 5-flurocytosine, ammonium sulfate, methylene dichloride, hexamethyldisilazane refluxed 14 hours in the mixing solutions of triethylamine.The use hexamethyldisilazane is expensive, and consumption is large, and hexamethyldisilazane is perishable simultaneously.
Generally speaking; compound I mainly is by to trans-5-hydroxyl-1 in the prior art; chlorination or the acylations of 3-oxathiolane-2-carboxylic acid-L menthol ester; pass through linked reaction with cytosine(Cyt) and 5-flurocytosine or with cytosine(Cyt) and the 5-flurocytosine of organosilicon protection again; and chlorination or acylations process are to the high requirement that maintains of chiral structure; prolong simultaneously technical process, increased process costs, reduced the yield of final product.Introducing for lamivudine or emtricitabine pyrimidine group all is cytosine(Cyt) or the 5-flurocytosine of protecting by silylation, because silylation is expensive, consumption is large, and organosilicon reagent is unstable simultaneously, causes the cost of whole production technique larger.
Three, summary of the invention
The present invention aims to provide a kind of preparation method of ucleosides intermediate of high-optical-purity, and technical problem to be solved is to simplify the production technique of prior art, reduces production costs, and improves productive rate.
The present invention is achieved by the following technical solutions:
The preparation method of the ucleosides intermediate of high-optical-purity of the present invention comprises that light prolongs each unit process of reaction, aminating reaction and aftertreatment of reaction, deprotection reaction, formation triazole:
It is with (2R that described light prolongs reaction, 5R)-5-hydroxyl-[1,3] oxathiolane-2-carboxylic acid (2S-sec.-propyl-5R-methyl isophthalic acid R-cyclohexyl) ester and 3-benzyl-2,4-(1H, 3H)-pyrimidine dione is raw material, 0-50 ℃ of reaction obtained intermediate compound I [(2R in 8-24 hour in solvent in the presence of azo agents and triple substitution phosphine, 5R)-5-hydroxyl-(3-benzyl-2,4-(1H, 3H)-pyrimidine dione-1-yl)-[1,3] oxathiolane-2-carboxylic acid (2S-sec.-propyl-5R-methyl isophthalic acid R-cyclohexyl) ester]; (2R, 5R)-5-hydroxyl-[1,3] oxathiolane-2-carboxylic acid (2S-sec.-propyl-5R-methyl isophthalic acid R-cyclohexyl) ester and 3-benzyl-2, the mol ratio of 4-(1H, 3H)-pyrimidine dione is 1:1-10; Described azo agents is selected from diisopropyl azodiformate, diethyl azodiformate, azo two formyls, two piperidines or Cellmic C 121, the molar weight of azo agents and (2R, 5R)-ratio of 5-hydroxyl-[1,3] oxathiolane-2-carboxylic acid (2S-sec.-propyl-5R-methyl isophthalic acid R-cyclohexyl) ester molar weight is 1:1-20; Described triple substitution phosphine is selected from triphenylphosphine, tri-n-butyl phosphine, trimethyl-phosphine, tricyclohexyl phosphine or three sad basic phosphines, the molar weight of triple substitution phosphine and (2R, 5R)-ratio of 5-hydroxyl-[1,3] oxathiolane-2-carboxylic acid (2S-sec.-propyl-5R-methyl isophthalic acid R-cyclohexyl) ester molar weight is 1:1-10; Described solvent is selected from 1,2-monochloroethane, 1, one or more in 1-ethylene dichloride, trichloromethane, tetracol phenixin, the tetrahydrofuran (THF);
Described deprotection reaction is to place alkali alcosol to obtain intermediate II [(2R in 0.5-4 hour stirring under the argon shield under room temperature described intermediate compound I, 5R)-5-hydroxyl-(uridylic-1-yl)-[1,3] oxathiolane-2-carboxylic acid (2S-sec.-propyl-5R-methyl isophthalic acid R-cyclohexyl) ester];
The reaction of described formation triazole is to add intermediate II, 1,2 in solvent, and 4-triazole and phosphorus oxychloride obtained triazole compound in 14-24 hour in 0-60 ℃ of reaction and be intermediate III in the presence of organic bases; The mol ratio of intermediate II and 1,2,4-triazole is 1:1-10, and the mol ratio of intermediate II and phosphorus oxychloride is 1:0.5-5, and the mol ratio of phosphorus oxychloride and organic bases is 1:1-10; Described solvent is selected from anhydrous acetonitrile, propionitrile, N, N '-dimethyl formamide, Isosorbide-5-Nitrae-dioxane, 1,2-ethylene dichloride, trichloroethane or tetracol phenixin; Described organic bases is selected from trolamine, triethylamine, quadrol or Diisopropylamine;
Described aminating reaction is that the intermediate III with 0.1mol is dissolved in the solvent, adding mass concentration is the ammonia soln 20-50ml of 25-30% again, obtained the target product compound I in 14-25 hour in 0-80 ℃ of reaction, chemical name (2R, 5R)-5-hydroxyl-(cytosine(Cyt)-1-yl)-[1,3] oxathiolane-2-carboxylic acid (2S-sec.-propyl-5R-methyl isophthalic acid R-cyclohexyl) ester is the intermediate of lamivudine; Described solvent is selected from Isosorbide-5-Nitrae-dioxane, N, N '-dimethyl formamide or tetrahydrofuran (THF); The volume ratio of described solvent and described ammonia soln is 2:0.5-4.
It is diisopropyl azodiformate that light prolongs azo agents described in the reaction, the molar weight of azo agents and (2R, 5R)-ratio of 5-hydroxyl-[1,3] oxathiolane-2-carboxylic acid (2S-sec.-propyl-5R-methyl isophthalic acid R-cyclohexyl) ester molar weight is 1:1-10;
It is triphenylphosphine that light prolongs the phosphine of triple substitution described in the reaction, and the molar weight of triple substitution phosphine is 1:1-3 with the ratio of (2R, 5R)-5-hydroxyl-[1,3] oxathiolane-2-carboxylic acid (2S-sec.-propyl-5R-methyl isophthalic acid R-cyclohexyl) ester molar weight;
It is tetrahydrofuran (THF) that light prolongs solvent described in the reaction, and temperature of reaction is 30 ℃, and the reaction times is 10h.
Alkali alcosol described in the deprotection reaction be mass concentration be 1-50% sodium methylate, magnesium methylate, sodium tert-butoxide, potassium tert.-butoxide, calcium methylate, lithium hydroxide, potassium hydroxide or sodium hydroxide methanol solution or be the methanol solution of saturated ammonia.
Solvent is anhydrous acetonitrile described in the reaction of formation triazole, and described organic bases is trolamine, and temperature of reaction is 30 ℃, and the reaction times is 16h.
Temperature of reaction is 30 ℃ in the aminating reaction, and described solvent is selected from Isosorbide-5-Nitrae-dioxane, and the volume ratio of described solvent and described ammonia soln is 2:1.
The preparation method of the ucleosides intermediate of high-optical-purity of the present invention comprises that light prolongs each unit process of reaction, aminating reaction and aftertreatment of reaction, deprotection reaction, formation triazole:
It is with (2R that described light prolongs reaction, 5R)-5-hydroxyl-[1,3] oxathiolane-2-carboxylic acid (2S-sec.-propyl-5R-methyl isophthalic acid R-cyclohexyl) ester and 3-benzyl-5-fluoro-2,4-(1H, 3H)-pyrimidine dione is raw material, 0-50 ℃ of reaction obtained intermediate compound I [(2R in 8-24 hour in solvent in the presence of azo agents and triple substitution phosphine, 5R)-5-hydroxyl-(3-benzyl-5-fluoro-2,4-(1H, 3H)-pyrimidine dione-1-yl)-[1,3] oxathiolane-2-carboxylic acid (2S-sec.-propyl-5R-methyl isophthalic acid R-cyclohexyl) ester]; (2R, 5R)-5-hydroxyl-[1,3] oxathiolane-2-carboxylic acid (2S-sec.-propyl-5R-methyl isophthalic acid R-cyclohexyl) ester and 3-benzyl-5-fluoro-2, the mol ratio of 4-(1H, 3H)-pyrimidine dione is 1:1-10; Described azo agents is selected from diisopropyl azodiformate, diethyl azodiformate, azo two formyls, two piperidines or Cellmic C 121, the molar weight of azo agents and (2R, 5R)-ratio of 5-hydroxyl-[1,3] oxathiolane-2-carboxylic acid (2S-sec.-propyl-5R-methyl isophthalic acid R-cyclohexyl) ester molar weight is 1:1-20; Described triple substitution phosphine is selected from triphenylphosphine, tri-n-butyl phosphine, trimethyl-phosphine, tricyclohexyl phosphine or three sad basic phosphines, the molar weight of triple substitution phosphine and (2R, 5R)-ratio of 5-hydroxyl-[1,3] oxathiolane-2-carboxylic acid (2S-sec.-propyl-5R-methyl isophthalic acid R-cyclohexyl) ester molar weight is 1:1-10; Described solvent is selected from 1,2-monochloroethane, 1, one or more in 1-ethylene dichloride, trichloromethane, tetracol phenixin, the tetrahydrofuran (THF);
Described deprotection reaction is to place alkali alcosol to obtain intermediate II [(2R in 0.5-4 hour stirring under the argon shield under room temperature described intermediate compound I, 5R)-5-hydroxyl-(5-FU-1-yl)-[1,3] oxathiolane-2-carboxylic acid (2S-sec.-propyl-5R-methyl isophthalic acid R-cyclohexyl) ester];
The reaction of described formation triazole is to add intermediate II, 1,2 in solvent, and 4-triazole and phosphorus oxychloride obtained triazole compound in 14-24 hour in 0-60 ℃ of reaction and be intermediate III in the presence of organic bases; The mol ratio of intermediate II and 1,2,4-triazole is 1:1-10, and the mol ratio of intermediate II and phosphorus oxychloride is 1:0.5-5, and the mol ratio of phosphorus oxychloride and organic bases is 1:1-10; Described solvent is selected from anhydrous acetonitrile, propionitrile, N, N '-methylformamide, Isosorbide-5-Nitrae-dioxane, 1,2-ethylene dichloride, trichloroethane or tetracol phenixin; Described organic bases is selected from trolamine, triethylamine, quadrol or Diisopropylamine;
Described aminating reaction is that the intermediate III with 0.1mol is dissolved in the solvent, adding mass concentration is the ammonia soln 20-50ml of 25-30% again, obtained the target product compound I in 14-25 hour in 0-80 ℃ of reaction, chemical name (2R, 5R)-5-hydroxyl-(5-fluoro-cytosine(Cyt)-1-yl)-[1,3] oxathiolane-2-carboxylic acid (2S-sec.-propyl-5R-methyl isophthalic acid R-cyclohexyl) ester is the intermediate of emtricitabine; Described solvent is selected from Isosorbide-5-Nitrae-dioxane, N, N '-dimethyl formamide or tetrahydrofuran (THF); The volume ratio of described solvent and described ammonia soln is 2:0.5-4.
It is diisopropyl azodiformate that light prolongs azo agents described in the reaction, the molar weight of azo agents and (2R, 5R)-ratio of 5-hydroxyl-[1,3] oxathiolane-2-carboxylic acid (2S-sec.-propyl-5R-methyl isophthalic acid R-cyclohexyl) ester molar weight is 1:1-10;
It is triphenylphosphine that light prolongs the phosphine of triple substitution described in the reaction, and the molar weight of triple substitution phosphine is 1:1-3 with the ratio of (2R, 5R)-5-hydroxyl-[1,3] oxathiolane-2-carboxylic acid (2S-sec.-propyl-5R-methyl isophthalic acid R-cyclohexyl) ester molar weight;
It is tetrahydrofuran (THF) that light prolongs solvent described in the reaction, and temperature of reaction is 30 ℃, and the reaction times is 10h.
Alkali alcosol described in the deprotection reaction be mass concentration be 1-50% sodium methylate, magnesium methylate, sodium tert-butoxide, potassium tert.-butoxide, calcium methylate, lithium hydroxide, potassium hydroxide or sodium hydroxide methanol solution or be the methanol solution of saturated ammonia.
Solvent is anhydrous acetonitrile described in the reaction of formation triazole, and described organic bases is trolamine, and temperature of reaction is 30 ℃, and the reaction times is 16h.
Temperature of reaction is 30 ℃ in the aminating reaction, and described solvent is selected from Isosorbide-5-Nitrae-dioxane, and the volume ratio of described solvent and described ammonia soln is 2:1.
Reaction scheme of the present invention is as follows:
R in compound I
0Be the intermediate of lamivudine during for H, R in compound I
0Be the intermediate of emtricitabine during for F.
The present invention is without acylations or the chlorination process of complexity; Avoid using the organosilicon reagent expensive, that consumption is large as blocking group, reduced process costs.The technological process of production of the present invention is brief, and production cost is low, can access the intermediate-compound I of the high-optical-purity of high yield.
Technique of the present invention is simple, and cost is low, and yield is high, and the product optical purity is high, pollutes littlely, is applicable to industrial production.
Four, embodiment
Embodiment 1: the intermediate of lamivudine synthetic
(1) intermediate compound I one (2R, 5R)-5-hydroxyl-(3-benzyl-2,4-(1H, 3H)-pyrimidine dione-1-yl)-[1,3] oxathiolane-2-carboxylic acid (2S-sec.-propyl-5R-methyl isophthalic acid R-cyclohexyl) ester synthesis
Intermediate compound I
With (2R, 5R)-5-hydroxyl-[1,3] oxathiolane-2-carboxylic acid (2S-sec.-propyl-5R-methyl isophthalic acid R-cyclohexyl) ester 28.814g(0.1mol), 3-benzyl-2,4-(1H, 3H)-pyrimidine dione 21.90g(0.1mol) and triphenylphosphine 26.229g(0.1mol) add in the tetrahydrofuran (THF), to dissolve again diisopropyl azodiformate 20.02g(0.1mol) the 250mL tetrahydrofuran solution slowly add, stir half an hour under 0 ℃ of condition, react at ambient temperature again 10h, with thin-layer chromatography detection reaction process, after reaction is finished, in reaction system, add the stirring of 50ml saturated nacl aqueous solution, use again ethyl acetate (100mlx3) extractive reaction mixing solutions, the separatory phase of anhydrating, wash with water after organic phase is mixed and drying, concentrated organic phase is sloughed partial solvent again, then at-5 ~ 0 ℃ of lower freezing and crystallizing, filtration and drying obtain intermediate compound I solid 39.62g, and yield is 89%, and the gained solid is directly used in next step reaction.
(2) intermediate II-(2R, 5R)-5-hydroxyl-(uridylic-1-yl)-[1,3] oxathiolane-2-carboxylic acid (2S-sec.-propyl-5R-methyl isophthalic acid R-cyclohexyl) ester synthesis
Under argon shield with intermediate compound I 48.2g(0.1mol) be added in the methanol solution (mass concentration is 3.5%) of the magnesium methylate of 85ml, room temperature condition reacts half an hour, with thin-layer chromatography detection reaction process, add 20ml water and 50ml ethyl acetate after reaction finishes, leave standstill separatory after stirring; It is neutral to organic phase 2 times with the 50ml distilled water wash once that organic phase is used dilute hydrochloric acid (mass concentration is 5%) washing successively, after the dry organic phase, partial solvent is removed in distillation, then at-5 ~ 0 ℃ of lower freezing and crystallizing, filter and the dry intermediate II solid 33.3g of getting, yield is 80%, and the gained solid is directly used in next step reaction.
(3) intermediate III-triazole compound is synthetic
Intermediate III
In the time of 0 ℃ with 1,2,4-triazole 17.3g(0.25mol) join in the acetonitrile of drying dehydration of 100ml, stirring and dissolving adds phosphorus oxychloride 9.16ml(0.1mol subsequently successively) and trolamine 83.5ml(0.6mol), restir 2h; The acetonitrile solution that will dissolve intermediate II (38.22g, 0.1mol) slowly is added dropwise in the reaction solution, 30 ℃ of reaction 16h; After finishing, reaction adds the 100mL saturated nacl aqueous solution, leave standstill separatory after stirring, it is neutral to organic phase 2 times with distilled water wash once that organic phase is used dilute hydrochloric acid (mass concentration is 5%) washing successively, slough partial solvent after the dry organic phase, then at-5 ~ 0 ℃ of lower freezing and crystallizing, filter also and obtain intermediate III solid 37.25g after the drying, yield is 86%, and the gained solid is directly used in next reaction.
(4) intermediate of target product-compound I (2R, 5R)-5-hydroxyl-(cytosine(Cyt)-1-yl)-[1,3] oxathiolane-2-carboxylic acid (2S-sec.-propyl-5R-methyl isophthalic acid R-cyclohexyl) ester synthesis-lamivudine
With intermediate III (43.32g, 0.1mol) to be dissolved in volume ratio be 1 of 2:1, in the 200ml mixing solutions of the ammonia soln of 4-dioxane and mass concentration 28%, stirring reaction 16h under 30 ℃ of conditions, after finishing, reaction adds the 100mL saturated nacl aqueous solution, leave standstill separatory after the stirring, use successively dilute hydrochloric acid (mass concentration is 5%) washing organic phase solution and distilled water wash to organic phase solution to be neutrality.Slough partial solvent after the dry organic phase, residue is at-5 ~ 0 ℃ of lower freezing and crystallizing, and last filtration drying obtains solid 33.92g and is the target product compound I, and yield is 89%.HPLC purity is 98.5%, and chiral purity is 98.2%, and fusing point is 216.8-217.8 ℃.
1H-NMR(CDCl
3)δ:
Embodiment 2: the intermediate of emtricitabine synthetic
(1) intermediate compound I-(2R, 5R)-5-hydroxyl-(3-benzyl-5-fluoro-2,4-(1H, 3H)-pyrimidine dione-1-yl)-[1,3] oxathiolane-2-carboxylic acid (2S-sec.-propyl-5R-methyl isophthalic acid R-cyclohexyl) ester synthesis
With (2R, 5R)-5-hydroxyl-[1,3] oxathiolane-2-carboxylic acid (2S-sec.-propyl-5R-methyl isophthalic acid R-cyclohexyl) ester 28.814g(0.1mol), 3-benzyl-5-fluoro-2,4-(1H, 3H)-pyrimidine dione 23.40g(0.1mol) and triphenylphosphine 26.229g(0.1mol) be dissolved in the tetrahydrofuran (THF), the 250mL tetrahydrofuran solution that will dissolve again 20.02g diisopropyl azodiformate (0.1mol) slowly adds, 0 ℃ of lower stirring half an hour, react at ambient temperature again 10h, with thin-layer chromatography detection reaction process, after reaction is finished, add the 50ml saturated nacl aqueous solution in the reaction system and stir, use again ethyl acetate (100mlx3) extractive reaction mixing solutions, the separatory phase of anhydrating, wash with water after organic phase is mixed and drying, concentrated organic phase is sloughed partial solvent again, freezing and crystallizing under-5～0 ℃ of condition, obtain solid 43.89g behind the filtration drying and be intermediate compound I, yield is 87%, and the gained solid is directly used in next step reaction.
(2) intermediate II-(2R, 5R)-5-hydroxyl-(3-benzyl-5-fluoro-2,4-(1H, 3H)-pyrimidine dione-1-yl)-[1,3] oxathiolane-2-carboxylic acid (2S-sec.-propyl-5R-methyl isophthalic acid R-cyclohexyl) ester synthesis
In ar gas environment with intermediate compound I 50.42g(0.1mol) be added in the methanol solution (mass concentration is 3.5%) of the magnesium methylate of 85ml, room temperature condition reacts half an hour, with thin-layer chromatography detection reaction process, after finishing, reaction adds 20ml water and 50ml ethyl acetate, leave standstill separatory after the stirring; It is neutral to organic phase 2 times with the 50ml distilled water wash once that organic phase is used dilute hydrochloric acid (mass concentration is 5%) washing successively, after the dry organic phase, partial solvent is removed in distillation, then freezing and crystallizing under-5 ~ 0 ℃ of condition, filtration drying gets solid 33.20g and is intermediate II, yield is 83%, directly the gained solid is used for next step reaction.
(3) intermediate III-triazole compound is synthetic
In the time of 0 ℃ with 1,2,4-triazole 17.3g(0.25mol) joins in the acetonitrile of drying dehydration of 100mL, stir, add successively subsequently phosphorus oxychloride 9.16ml(0.1mol) and trolamine 83.5ml(0.6mol), stir 2h, will be dissolved in intermediate II in the acetonitrile (in intermediate II 40.2g, 0.1mol) acetonitrile solution slowly is added dropwise in the reaction solution, 30 ℃ of reaction 16h; React and finish the rear 100mL of adding saturated nacl aqueous solution, leave standstill separatory after the stirring, it is neutral to organic phase 2 times with distilled water wash once that organic phase is used dilute hydrochloric acid (mass concentration is 5%) washing successively.Slough partial solvent after the dry organic phase, freezing and crystallizing under-5 ~ 0 ℃ of condition then, filtration drying obtains solid 37.25g and is intermediate III, and yield is 86%., obtaining solid 40.5g after the drying and be intermediate III, yield is 90%, and the gained solid is directly used in next step reaction.
(4) intermediate of target product-compound I (2R, 5R)-5-hydroxyl-(5-fluoro-cytosine(Cyt)-1-yl)-[1,3] oxathiolane-2-carboxylic acid (2S-sec.-propyl-5R-methyl isophthalic acid R-cyclohexyl) ester synthesis-emtricitabine
With intermediate III (45.1g, 0.1mol) to be dissolved in volume ratio be 1 of 2:1, in the 200ml mixing solutions of the ammonia soln of 4-dioxane and mass concentration 28%, stirring reaction 16h under 30 ℃ of conditions, after finishing, reaction adds the 100mL saturated nacl aqueous solution, leave standstill separatory after the stirring, use successively dilute hydrochloric acid (mass concentration is 5%) washing organic phase solution and distilled water wash to organic phase solution to be neutrality, slough partial solvent after the dry organic phase, then freezing and crystallizing under-5 ~ 0 ℃ of lower condition, last filtration drying obtains solid 36.34g and is the target product compound I, and yield is 91.0%.The purity of its HPLC is 98.4%, and chiral purity is 97.5%.Fusing point is 151-153 ℃.
1H-NMR(CDCl
3)δ:0.80(d,3H,5’-CH
3),0.90(t,6H,2’-CH
3),1,03~2.04(m,9H,2’~6’-H,2’-CH-),3.12(dd,1H,4-H),3.52(dd,1H,4-H),4.78(dt,1H,1’-H),5.46(s,1H,2-H),5.55(brs,1H,NH),6.42(t,1H,5-H),7.47(brs,1H,NH),8.51(d,1H,Ar-H)。
Claims (10)
1. the preparation method of the ucleosides intermediate of a high-optical-purity comprises that light prolongs each unit process of reaction, aminating reaction and aftertreatment of reaction, deprotection reaction, formation triazole, is characterized in that:
It is with (2R that described light prolongs reaction, 5R)-5-hydroxyl-[1,3] oxathiolane-2-carboxylic acid (2S-sec.-propyl-5R-methyl isophthalic acid R-cyclohexyl) ester and 3-benzyl-2,4-(1H, 3H)-and pyrimidine dione is raw material, 0-50 ℃ of reaction obtained intermediate compound I in 8-24 hour in solvent in the presence of azo agents and triple substitution phosphine; (2R, 5R)-5-hydroxyl-[1,3] oxathiolane-2-carboxylic acid (2S-sec.-propyl-5R-methyl isophthalic acid R-cyclohexyl) ester and 3-benzyl-2, the mol ratio of 4-(1H, 3H)-pyrimidine dione is 1:1-10; Described azo agents is selected from diisopropyl azodiformate, diethyl azodiformate, azo two formyls, two piperidines or Cellmic C 121, the molar weight of azo agents and (2R, 5R)-ratio of 5-hydroxyl-[1,3] oxathiolane-2-carboxylic acid (2S-sec.-propyl-5R-methyl isophthalic acid R-cyclohexyl) ester molar weight is 1:1-20; Described triple substitution phosphine is selected from triphenylphosphine, tri-n-butyl phosphine, trimethyl-phosphine, tricyclohexyl phosphine or three sad basic phosphines, the molar weight of triple substitution phosphine and (2R, 5R)-ratio of 5-hydroxyl-[1,3] oxathiolane-2-carboxylic acid (2S-sec.-propyl-5R-methyl isophthalic acid R-cyclohexyl) ester molar weight is 1:1-10; Described solvent is selected from 1,2-monochloroethane, 1, one or more in 1-ethylene dichloride, trichloromethane, tetracol phenixin, the tetrahydrofuran (THF);
Described deprotection reaction is to place alkali alcosol to obtain intermediate II in 0.5-4 hour stirring under the argon shield under room temperature described intermediate compound I;
The reaction of described formation triazole is to add intermediate II, 1,2 in solvent, and 4-triazole and phosphorus oxychloride obtained triazole compound in 14-24 hour in 0-60 ℃ of reaction and be intermediate III in the presence of organic bases; The mol ratio of intermediate II and 1,2,4-triazole is 1:1-10, and the mol ratio of intermediate II and phosphorus oxychloride is 1:0.5-5, and the mol ratio of phosphorus oxychloride and organic bases is 1:1-10; Described solvent is selected from anhydrous acetonitrile, propionitrile, N, N '-dimethyl formamide, Isosorbide-5-Nitrae-dioxane, 1,2-ethylene dichloride, trichloroethane or tetracol phenixin; Described organic bases is selected from trolamine, triethylamine, quadrol or Diisopropylamine;
Described aminating reaction is that the intermediate III with 0.1mol is dissolved in the solvent, and adding mass concentration is the ammonia soln 20-50ml of 25-30% again, obtains the target product compound I in 14-25 hour in 0-80 ℃ of reaction, is the intermediate of lamivudine; Described solvent is selected from Isosorbide-5-Nitrae-dioxane, N, N '-dimethyl formamide or tetrahydrofuran (THF); The volume ratio of described solvent and described ammonia soln is 2:0.5-4.
2. preparation method according to claim 1 is characterized in that:
It is diisopropyl azodiformate that light prolongs azo agents described in the reaction, the molar weight of azo agents and (2R, 5R)-ratio of 5-hydroxyl-[1,3] oxathiolane-2-carboxylic acid (2S-sec.-propyl-5R-methyl isophthalic acid R-cyclohexyl) ester molar weight is 1:1-10;
It is triphenylphosphine that light prolongs the phosphine of triple substitution described in the reaction, and the molar weight of triple substitution phosphine is 1:1-3 with the ratio of (2R, 5R)-5-hydroxyl-[1,3] oxathiolane-2-carboxylic acid (2S-sec.-propyl-5R-methyl isophthalic acid R-cyclohexyl) ester molar weight;
It is tetrahydrofuran (THF) that light prolongs solvent described in the reaction, and temperature of reaction is 30 ℃, and the reaction times is 10h.
3. preparation method according to claim 1 is characterized in that:
Alkali alcosol described in the deprotection reaction be mass concentration be 1-50% sodium methylate, magnesium methylate, sodium tert-butoxide, potassium tert.-butoxide, calcium methylate, lithium hydroxide, potassium hydroxide or sodium hydroxide methanol solution or be the methanol solution of saturated ammonia.
4. preparation method according to claim 1 is characterized in that:
Solvent is anhydrous acetonitrile described in the reaction of formation triazole, and described organic bases is trolamine, and temperature of reaction is 30 ℃, and the reaction times is 16h.
5. preparation method according to claim 1 is characterized in that:
Temperature of reaction is 30 ℃ in the aminating reaction, and described solvent is selected from Isosorbide-5-Nitrae-dioxane, and the volume ratio of described solvent and described ammonia soln is 2:1.
6. the preparation method of the ucleosides intermediate of a high-optical-purity comprises that light prolongs each unit process of reaction, aminating reaction and aftertreatment of reaction, deprotection reaction, formation triazole, is characterized in that:
It is with (2R that described light prolongs reaction, 5R)-5-hydroxyl-[1,3] oxathiolane-2-carboxylic acid (2S-sec.-propyl-5R-methyl isophthalic acid R-cyclohexyl) ester and 3-benzyl-5-fluoro-2,4-(1H, 3H)-and pyrimidine dione is raw material, 0-50 ℃ of reaction obtained intermediate compound I in 8-24 hour in solvent in the presence of azo agents and triple substitution phosphine; (2R, 5R)-5-hydroxyl-[1,3] oxathiolane-2-carboxylic acid (2S-sec.-propyl-5R-methyl isophthalic acid R-cyclohexyl) ester and 3-benzyl-5-fluoro-2, the mol ratio of 4-(1H, 3H)-pyrimidine dione is 1:1-10; Described azo agents is selected from diisopropyl azodiformate, diethyl azodiformate, azo two formyls, two piperidines or Cellmic C 121, the molar weight of azo agents and (2R, 5R)-ratio of 5-hydroxyl-[1,3] oxathiolane-2-carboxylic acid (2S-sec.-propyl-5R-methyl isophthalic acid R-cyclohexyl) ester molar weight is 1:1-20; Described triple substitution phosphine is selected from triphenylphosphine, tri-n-butyl phosphine, trimethyl-phosphine, tricyclohexyl phosphine or three sad basic phosphines, the molar weight of triple substitution phosphine and (2R, 5R)-ratio of 5-hydroxyl-[1,3] oxathiolane-2-carboxylic acid (2S-sec.-propyl-5R-methyl isophthalic acid R-cyclohexyl) ester molar weight is 1:1-10; Described solvent is selected from 1,2-monochloroethane, 1, one or more in 1-ethylene dichloride, trichloromethane, tetracol phenixin, the tetrahydrofuran (THF);
Described deprotection reaction is to place alkali alcosol to obtain intermediate II in 0.5-4 hour stirring under the argon shield under room temperature described intermediate compound I;
The reaction of described formation triazole is to add intermediate II, 1,2 in solvent, and 4-triazole and phosphorus oxychloride obtained triazole compound in 14-24 hour in 0-60 ℃ of reaction and be intermediate III in the presence of organic bases; The mol ratio of intermediate II and 1,2,4-triazole is 1:1-10, and the mol ratio of intermediate II and phosphorus oxychloride is 1:0.5-5, and the mol ratio of phosphorus oxychloride and organic bases is 1:1-10; Described solvent is selected from anhydrous acetonitrile, propionitrile, N, N '-dimethyl formamide, Isosorbide-5-Nitrae-dioxane, 1,2-ethylene dichloride, trichloroethane or tetracol phenixin; Described organic bases is selected from trolamine, triethylamine, quadrol or Diisopropylamine;
Described aminating reaction is that the intermediate III with 0.1mol is dissolved in the solvent, and adding mass concentration is the ammonia soln 20-50ml of 25-30% again, obtains the target product compound I in 14-25 hour in 0-80 ℃ of reaction, is the intermediate of emtricitabine; Described solvent is selected from Isosorbide-5-Nitrae-dioxane, N, N '-dimethyl formamide or tetrahydrofuran (THF); The volume ratio of described solvent and described ammonia soln is 2:0.5-4.
7. preparation method according to claim 6 is characterized in that:
It is diisopropyl azodiformate that light prolongs azo agents described in the reaction, the molar weight of azo agents and (2R, 5R)-ratio of 5-hydroxyl-[1,3] oxathiolane-2-carboxylic acid (2S-sec.-propyl-5R-methyl isophthalic acid R-cyclohexyl) ester molar weight is 1:1-10;
It is triphenylphosphine that light prolongs the phosphine of triple substitution described in the reaction, and the molar weight of triple substitution phosphine is 1:1-3 with the ratio of (2R, 5R)-5-hydroxyl-[1,3] oxathiolane-2-carboxylic acid (2S-sec.-propyl-5R-methyl isophthalic acid R-cyclohexyl) ester molar weight;
It is tetrahydrofuran (THF) that light prolongs solvent described in the reaction, and temperature of reaction is 30 ℃, and the reaction times is 10h.
8. preparation method according to claim 6 is characterized in that:
Alkali alcosol described in the deprotection reaction be mass concentration be 1-50% sodium methylate, magnesium methylate, sodium tert-butoxide, potassium tert.-butoxide, calcium methylate, lithium hydroxide, potassium hydroxide or sodium hydroxide methanol solution or be the methanol solution of saturated ammonia.
9. preparation method according to claim 6 is characterized in that:
Solvent is anhydrous acetonitrile described in the reaction of formation triazole, and described organic bases is trolamine, and temperature of reaction is 30 ℃, and the reaction times is 16h.
10. preparation method according to claim 6 is characterized in that:
Temperature of reaction is 30 ℃ in the aminating reaction, and described solvent is selected from Isosorbide-5-Nitrae-dioxane, and the volume ratio of described solvent and described ammonia soln is 2:1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210447276.5A CN102911167B (en) | 2012-11-09 | 2012-11-09 | Method for preparing nucleoside intermediate with high optical purity |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210447276.5A CN102911167B (en) | 2012-11-09 | 2012-11-09 | Method for preparing nucleoside intermediate with high optical purity |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102911167A true CN102911167A (en) | 2013-02-06 |
| CN102911167B CN102911167B (en) | 2014-06-25 |
Family
ID=47609769
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210447276.5A Active CN102911167B (en) | 2012-11-09 | 2012-11-09 | Method for preparing nucleoside intermediate with high optical purity |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102911167B (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1439177A1 (en) * | 1991-02-22 | 2004-07-21 | Emory University | Antiviral activity and resolution of 2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane |
| 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 |
-
2012
- 2012-11-09 CN CN201210447276.5A patent/CN102911167B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1439177A1 (en) * | 1991-02-22 | 2004-07-21 | Emory University | Antiviral activity and resolution of 2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane |
| 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 |
Non-Patent Citations (2)
| Title |
|---|
| DAVID C. HUMBER等: "EXPEDITIOUS PREPARATION OF (-)-2’-DEOXY-3’.THIACYTIDINE (3TC)", 《TETRAHEDRON LETTERS》 * |
| 马红梅等: "抗病毒药拉米夫定及其类似物合成研究概况", 《沈阳药科大学学报》 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102911167B (en) | 2014-06-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN111205294B (en) | Preparation method of Reidesciclovir intermediate | |
| CN101541818B (en) | Process for preparation of 4'-azido cytidine derivatives | |
| CN102617678B (en) | Method for preparing gemcitabine hydrochloride | |
| CN103987712A (en) | 2',3'-dideoxy-2'-alpha-fluoro-2'-beta-C-methylnucleosides and prodrugs thereof | |
| JP2010505954A5 (en) | ||
| CN101177430A (en) | Hydrogenated pyridine derivative and method for preparing salt thereof | |
| KR20170073649A (en) | Methods of preparing substituted nucleoside analogs | |
| CN102584795B (en) | Preparing method of crizotinib | |
| CN106478747B (en) | The industrial manufacturing process of gemcitabine key intermediate sulfonation sugar | |
| CN102153601A (en) | Method for preparing gemcitabine hydrochloride and intermediate thereof with high selectivity | |
| CN106366146A (en) | 2-dialkyl substituted nucleoside analogue and uses thereof | |
| CN101555267A (en) | Synthesis method of clofarabine of nucleoside analogues | |
| CN105153257B (en) | The preparation method of Suo Feibuwei | |
| CN102911167B (en) | Method for preparing nucleoside intermediate with high optical purity | |
| CN115785181B (en) | Method for preparing Mo Pila-wei intermediate by one-pot method | |
| CN106008459A (en) | Trelagliptin preparation method | |
| JP2019522003A (en) | Improved manufacturing process for the preparation of sofosbuvir | |
| EP3924359A1 (en) | Process for preparing 3'-o-amino-ribonucleotide | |
| CN102532199A (en) | Structure and synthesis of novel benzyl amido phosphate prodrug of nucleoside compound | |
| CN112961198B (en) | Preparation method of purine nucleotide intermediate | |
| CN1821220A (en) | Diethyl 4[(4-oxo-3-bromo) butyl] benzoyl-L-glutamate and preparation and use | |
| CN103664951B (en) | A kind of preparation method treating chronic myelocytic leukemia medicine | |
| CN100427454C (en) | Method for producing difluoro-acetyl-acetic acid alkylesters | |
| CN103788160B (en) | (2R, 5R)-5-phosphatidyl methoxy-2-(2-substituted adenines-9-base)-2,5-dihydrofuran nucleoside analog and its production and use | |
| CN102531985B (en) | Method for preparing ezetimibe key intermediate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |