CN102911167B - Method for preparing nucleoside intermediate with high optical purity - Google Patents
Method for preparing nucleoside intermediate with high optical purity Download PDFInfo
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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, by becoming after phosphorylation after nucleoside triphosphate class medicine, can suppress the activity of the reversed transcriptive enzyme of viral DNA, nucleoside triphosphate class medicine also connects by infiltrating viral DNA simultaneously, hinder synthetic that viral DNA connects, effectively suppress copying of virus and bring into play effective antiviral activity.
Lamivudine and emtricitabine have efficient disease-resistance toxic action to immunodeficient disease (HIV) virus and hepatitis B (HBV) virus, are widely used as one antiviral medicine.The chemical structural formula of lamivudine and emtricitabine is as follows:
In 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, is mainly the method for synthetic compound I a kind of 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
Wherein R
1for formyl radical, ethanoyl, propionyl, butyryl radicals, pentanoyl, isopropyl acyl group, isobutyryl, hydrocinnamoyl or phenylacetyl, wherein optimum is ethanoyl and propionyl.In the time of preparation Compound I I; 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 DEG C of conditions.The cytosine(Cyt) of Compound I I and silylation protection or 5-flurocytosine, by glycosylation, obtain Compound I after deprotection.Because the preparation of Compound I I need to be in catalysis under cold condition, ensure that chiral carbon chiral inversion does not occur and racemization, condition harshness, is unfavorable for batch production production, increases acylations step simultaneously, causes whole production technique distance long, ultimate yield reduces.Prepared by Compound I I in the reaction of Compound I, with cytosine(Cyt) or the 5-flurocytosine of silylation protection.Due to organosilicon reagent costliness, 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, insulation air distillation obtains chlorizate peppermint alcohol radical-5-chloro-1 for 3 hours, 3-thiazole-2-carboxylicesters, in this process, add thionyl chloride to meet water and easily resolve into unpleasant sulfurous gas and hydrochloric acid gas, the also etching apparatus of acid generating, the productive rate of chlorination own is not high, then the product after chlorination is put into bottom reaction, has reduced the productive rate of whole piece reaction by this two-step reaction.To in reaction vessel, add toluene again, hexamethyldisilazane, cytosine(Cyt) and the chloro-1,3-thiazoles-2-of peppermint alcohol radical-5-carboxylicesters, be back to clarification, and crystallization is filtered and is obtained product HDMS.The hexamethyldisilazane ingress of air using 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.Wherein key intermediate 5S-(5'-flucytosine)-1,3-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 dinethylformamide solution, drip gradually thionyl chloride chlorination and obtain trans-5-hydroxyl-1, after 3-oxathiolane-2-carboxylic acid-L menthol ester, it is slowly added to 5-flurocytosine, ammonium sulfate, methylene dichloride, hexamethyldisilazane, refluxes in the mixing solutions of triethylamine 14 hours.Use hexamethyldisilazane is expensive, and consumption is large, and hexamethyldisilazane is perishable simultaneously.
Generally speaking; in prior art, Compound I is mainly by trans-5-hydroxyl-1; 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 the acylations process high requirement that maintains to chiral structure; extend technical process simultaneously, increased process costs, reduced the yield of final product.Be all cytosine(Cyt) or the 5-flurocytosine of protecting by silylation for the introducing of lamivudine or emtricitabine pyrimidine group, due to silylation costliness, 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 the 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, under the existence of azo agents and triple substitution phosphine, in solvent, 0-50 DEG C of reaction obtains intermediate compound I [(2R for 8-24 hour, 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 formyl two piperidines or Cellmic C 121s, the molar weight of azo agents and (2R, the ratio of 5R)-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 base phosphines, the molar weight of triple substitution phosphine and (2R, the ratio of 5R)-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, tetrahydrofuran (THF);
Described deprotection reaction is described intermediate compound I to be placed in to alkali alcosol under argon shield, under room temperature, stir and within 0.5-4 hour, obtain 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];
The reaction of described formation triazole is in solvent, to add intermediate II, 1,2, and 4-triazole and phosphorus oxychloride obtain triazole compound in 14-24 hour in 0-60 DEG C of reaction and be intermediate III under the existence 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 of 0.1mol is dissolved in solvent, adding mass concentration is the ammonia soln 20-50ml of 25-30% again, within 14-25 hour, obtain target product Compound I in 0-80 DEG C 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 reaction, the molar weight of azo agents and (2R, the ratio of 5R)-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 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 reaction, and temperature of reaction is 30 DEG C, and the reaction times is 10h.
Alkali alcosol described in 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.
Described in the reaction of formation triazole, solvent is anhydrous acetonitrile, and described organic bases is trolamine, and temperature of reaction is 30 DEG C, and the reaction times is 16h.
In aminating reaction, temperature of reaction is 30 DEG C, 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 the 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, under the existence of azo agents and triple substitution phosphine, in solvent, 0-50 DEG C of reaction obtains intermediate compound I [(2R for 8-24 hour, 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-are fluoro-2, and 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 formyl two piperidines or Cellmic C 121s, the molar weight of azo agents and (2R, the ratio of 5R)-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 base phosphines, the molar weight of triple substitution phosphine and (2R, the ratio of 5R)-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, tetrahydrofuran (THF);
Described deprotection reaction is described intermediate compound I to be placed in to alkali alcosol under argon shield, under room temperature, stir and within 0.5-4 hour, obtain intermediate II [(2R, 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 in solvent, to add intermediate II, 1,2, and 4-triazole and phosphorus oxychloride obtain triazole compound in 14-24 hour in 0-60 DEG C of reaction and be intermediate III under the existence 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 of 0.1mol is dissolved in solvent, adding mass concentration is the ammonia soln 20-50ml of 25-30% again, within 14-25 hour, obtain target product Compound I in 0-80 DEG C of reaction, chemical name (2R, 5R)-5-hydroxyl-(the fluoro-cytosine(Cyt)-1-of 5-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 reaction, the molar weight of azo agents and (2R, the ratio of 5R)-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 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 reaction, and temperature of reaction is 30 DEG C, and the reaction times is 10h.
Alkali alcosol described in 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.
Described in the reaction of formation triazole, solvent is anhydrous acetonitrile, and described organic bases is trolamine, and temperature of reaction is 30 DEG C, and the reaction times is 16h.
In aminating reaction, temperature of reaction is 30 DEG C, 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:
As R in Compound I
0during for H, be the intermediate of lamivudine, as R in Compound I
0during for F, be the intermediate of emtricitabine.
The present invention is without complicated acylations or chlorination process; Avoid using the organosilicon reagent expensive, 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 obtain 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 product optical purity is high, pollutes littlely, is applicable to industrial production.
Four, embodiment
Embodiment 1: the intermediate of lamivudine synthetic
(1) synthesizing of 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
By (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 tetrahydrofuran (THF), to dissolve diisopropyl azodiformate 20.02g(0.1mol again) 250mL tetrahydrofuran solution slowly add, under 0 DEG C of condition, stir half an hour, react at ambient temperature again 10h, by thin-layer chromatography detection reaction process, after having reacted, in reaction system, add 50ml saturated nacl aqueous solution to stir, use again ethyl acetate (100mlx3) extractive reaction mixing solutions, the separatory phase of anhydrating, organic phase washes with water and is dried after mixing, concentrated organic phase, slough partial solvent, then freezing and crystallizing at-5 ~ 0 DEG C, filter and be dried and obtain intermediate compound I solid 39.62g, yield is 89%, gained solid is directly used in next step reaction.
(2) synthesizing of 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
Under argon shield by 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, by thin-layer chromatography detection reaction process, after reaction finishes, add 20ml water and 50ml ethyl acetate, after stirring, leave standstill separatory; It is once neutral to organic phase 2 times with 50ml distilled water wash that organic phase is used dilute hydrochloric acid (mass concentration is 5%) washing successively, after dry organic phase, partial solvent is removed in distillation, then freezing and crystallizing at-5 ~ 0 DEG C, filter and be dried and to obtain intermediate II solid 33.3g, yield is 80%, and gained solid is directly used in to next step reaction.
(3) intermediate III-triazole compound is synthetic
intermediate III
In the time of 0 DEG C by 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), then stir 2h; The acetonitrile solution that has dissolved intermediate II (38.22g, 0.1mol) is slowly added dropwise in reaction solution to 30 DEG C of reaction 16h; After finishing, reaction adds 100mL saturated nacl aqueous solution, after stirring, leave standstill separatory, it is once neutral to organic phase 2 times with distilled water wash that organic phase is used dilute hydrochloric acid (mass concentration is 5%) washing successively, after dry organic phase, slough partial solvent, then freezing and crystallizing at-5 ~ 0 DEG C, after filtering and being dried, obtain intermediate III solid 37.25g, yield is 86%, and gained solid is directly used in to next reaction.
(4) intermediate of the synthesize-lamivudine 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
By intermediate III (43.32g, 0.1mol) being dissolved in volume ratio is 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 DEG C of conditions, after finishing, reaction adds 100mL saturated nacl aqueous solution, after stirring, leave standstill separatory, it is neutral using successively dilute hydrochloric acid (mass concentration is 5%) washing organic phase solution and distilled water wash to organic phase solution.After dry organic phase, slough partial solvent, residue is freezing and crystallizing at-5 ~ 0 DEG C, and last filtration drying obtains solid 33.92g and is 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 DEG C.
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 synthetic
By (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 tetrahydrofuran (THF), again the 250mL tetrahydrofuran solution that has dissolved 20.02g diisopropyl azodiformate (0.1mol) is slowly added, at 0 DEG C, stir half an hour, react at ambient temperature again 10h, by thin-layer chromatography detection reaction process, after having reacted, in reaction system, add 50ml saturated nacl aqueous solution to stir, use again ethyl acetate (100mlx3) extractive reaction mixing solutions, the separatory phase of anhydrating, organic phase washes with water and is dried after mixing, concentrated organic phase, slough partial solvent, freezing and crystallizing under-5～0 DEG C of condition, after filtration drying, obtain solid 43.89g and be intermediate compound I, yield is 87%, gained solid is directly used in to 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 synthetic
In ar gas environment by 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, by thin-layer chromatography detection reaction process, after finishing, reaction adds 20ml water and 50ml ethyl acetate, after stirring, leave standstill separatory; It is once neutral to organic phase 2 times with 50ml distilled water wash that organic phase is used dilute hydrochloric acid (mass concentration is 5%) washing successively, after dry organic phase, partial solvent is removed in distillation, then freezing and crystallizing under-5 ~ 0 DEG C of condition, filtration drying obtains solid 33.20g and is intermediate II, yield is 83%, directly gained solid is used for to next step reaction.
(3) intermediate III-triazole compound is synthetic
In the time of 0 DEG C by 1,2,4-triazole 17.3g(0.25mol) join 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 acetonitrile (in intermediate II 40.2g, 0.1mol) acetonitrile solution is slowly added dropwise in reaction solution, 30 DEG C of reaction 16h; Reaction adds 100mL saturated nacl aqueous solution after finishing, and after stirring, leaves standstill separatory, organic phase use successively dilute hydrochloric acid (mass concentration is 5%) washing once with distilled water wash 2 times to organic phase for neutral.After dry organic phase, slough partial solvent, then freezing and crystallizing under-5 ~ 0 DEG C of condition, filtration drying obtains solid 37.25g and is intermediate III, and yield is 86%., after being dried, obtaining solid 40.5g and be intermediate III, yield is 90%, and gained solid is directly used in to next step reaction.
(4) target product-Compound I (2R, the intermediate of the synthesize-emtricitabine of 5R)-5-hydroxyl-(the fluoro-cytosine(Cyt)-1-of 5-yl)-[1,3] oxathiolane-2-carboxylic acid (2S-sec.-propyl-5R-methyl isophthalic acid R-cyclohexyl) ester
By intermediate III (45.1g, 0.1mol) being dissolved in volume ratio is 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 DEG C of conditions, after finishing, reaction adds 100mL saturated nacl aqueous solution, after stirring, leave standstill separatory, using successively dilute hydrochloric acid (mass concentration is 5%) washing organic phase solution and distilled water wash to organic phase solution is neutrality, after dry organic phase, slough partial solvent, then freezing and crystallizing under condition at-5 ~ 0 DEG C, last filtration drying obtains solid 36.34g and is target product Compound I, yield is 91.0%.The purity of its HPLC is 98.4%, and chiral purity is 97.5%.Fusing point is 151-153 DEG C.
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. a preparation method for the ucleosides intermediate of high-optical-purity, comprises that light prolongs the 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)-pyrimidine dione is raw material, and under the existence of azo agents and triple substitution phosphine, in solvent, 0-50 DEG C of reaction obtains intermediate compound I for 8-24 hour; (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 formyl two piperidines or Cellmic C 121s, the molar weight of azo agents and (2R, the ratio of 5R)-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 base phosphines, the molar weight of triple substitution phosphine and (2R, the ratio of 5R)-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, tetrahydrofuran (THF); The structural formula of described intermediate compound I is:
Described deprotection reaction is described intermediate compound I to be placed in to alkali alcosol under argon shield, under room temperature, stir and within 0.5-4 hour, obtain intermediate II; The structural formula of described intermediate II is:
The reaction of described formation triazole is in solvent, to add intermediate II, 1,2, and 4-triazole and phosphorus oxychloride obtain triazole compound in 14-24 hour in 0-60 DEG C of reaction and be intermediate III under the existence 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; The structural formula of described intermediate III is:
Described aminating reaction is that the intermediate III of 0.1mol is dissolved in solvent, then to add mass concentration be the ammonia soln 20-50ml of 25-30%, within 14-25 hour, obtains target product Compound I in 0-80 DEG C 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; The structural formula of described target product Compound I is:
2. preparation method according to claim 1, is characterized in that:
It is diisopropyl azodiformate that light prolongs azo agents described in reaction, the molar weight of azo agents and (2R, the ratio of 5R)-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 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 reaction, and temperature of reaction is 30 DEG C, and the reaction times is 10h.
3. preparation method according to claim 1, is characterized in that:
Alkali alcosol described in 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:
Described in the reaction of formation triazole, solvent is anhydrous acetonitrile, and described organic bases is trolamine, and temperature of reaction is 30 DEG C, and the reaction times is 16h.
5. preparation method according to claim 1, is characterized in that:
In aminating reaction, temperature of reaction is 30 DEG C, 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. a preparation method for the ucleosides intermediate of high-optical-purity, comprises that light prolongs the 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)-pyrimidine dione is raw material, and under the existence of azo agents and triple substitution phosphine, in solvent, 0-50 DEG C of reaction obtains intermediate compound I for 8-24 hour; (2R, 5R)-5-hydroxyl-[1,3] oxathiolane-2-carboxylic acid (2S-sec.-propyl-5R-methyl isophthalic acid R-cyclohexyl) ester and 3-benzyl-5-are fluoro-2, and 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 formyl two piperidines or Cellmic C 121s, the molar weight of azo agents and (2R, the ratio of 5R)-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 base phosphines, the molar weight of triple substitution phosphine and (2R, the ratio of 5R)-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, tetrahydrofuran (THF); The structural formula of described intermediate compound I is:
Described deprotection reaction is described intermediate compound I to be placed in to alkali alcosol under argon shield, under room temperature, stir and within 0.5-4 hour, obtain intermediate II; The structural formula of described intermediate II is:
The reaction of described formation triazole is in solvent, to add intermediate II, 1,2, and 4-triazole and phosphorus oxychloride obtain triazole compound in 14-24 hour in 0-60 DEG C of reaction and be intermediate III under the existence 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; The structural formula of described intermediate III is:
Described aminating reaction is that the intermediate III of 0.1mol is dissolved in solvent, then to add mass concentration be the ammonia soln 20-50ml of 25-30%, within 14-25 hour, obtains target product Compound I in 0-80 DEG C 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; The structural formula of described target product Compound I is:
7. preparation method according to claim 6, is characterized in that:
It is diisopropyl azodiformate that light prolongs azo agents described in reaction, the molar weight of azo agents and (2R, the ratio of 5R)-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 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 reaction, and temperature of reaction is 30 DEG C, and the reaction times is 10h.
8. preparation method according to claim 6, is characterized in that:
Alkali alcosol described in 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:
Described in the reaction of formation triazole, solvent is anhydrous acetonitrile, and described organic bases is trolamine, and temperature of reaction is 30 DEG C, and the reaction times is 16h.
10. preparation method according to claim 6, is characterized in that:
In aminating reaction, temperature of reaction is 30 DEG C, and described solvent is selected from Isosorbide-5-Nitrae-dioxane, and the volume ratio of described solvent and described ammonia soln is 2:1.
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