CN105801644A - Method for preparing telbivudine - Google Patents
Method for preparing telbivudine Download PDFInfo
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- CN105801644A CN105801644A CN201610306199.XA CN201610306199A CN105801644A CN 105801644 A CN105801644 A CN 105801644A CN 201610306199 A CN201610306199 A CN 201610306199A CN 105801644 A CN105801644 A CN 105801644A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
- C07H19/073—Pyrimidine radicals with 2-deoxyribosyl as the saccharide radical
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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Abstract
The invention relates to a method for preparing telbivudine. The reaction mechanism is as shown in the specification specifically. Compared with a method of the prior art, the method provided by the invention has the advantages that firstly, all raw materials are low in cost and can be easily obtained from the market; secondly, reaction of different steps is normal reaction, and the reaction steps are simple and easy to implement; and thirdly, production requirements can be met by using normal preparation equipment, the production is easy to control, and industrial production can be achieved.
Description
Technical field
The present invention relates to technical field of organic synthesis, the preparation method particularly relating to a kind of Sebivo.
Background technology
Sebivo, chemistry 1-[(2S by name, 4R, 5S)-4-hydroxyl-5-hydroxymethyl tetrahydrofuran-2-base]-5-methyl isophthalic acid H-pyrimidine-2,4-diketone, being the ucleosides antiviral agents of Idenix and Novartis company cooperative research and development, in JIUYUE, 2006 lists with trade name Sebivo in Switzerland first, and clinic is mainly used in treatment Adult chronic's hepatitis B, decompensated cirrhosis.This product can be generated active triphosphate by cell kinase phosphorylation in vivo, by competing with natural substrate deoxythymidine-5'-triphosphoric acid, mix in viral DNA chain, cause that DNA extends to terminate, thus suppressing the duplication of virus, curative effect is better than lamivudine, and toleration is high, safety is good.
At present, the common production process route of Sebivo has following four kinds:
1, with raw material 2 for initiation material, first reacting generation intermediate 3 with HMDS, then react with raw material 1, generate intermediate 4, finally hydrolysis obtains target product TM (see route one).Raw materials used 1 price comparison of this route is expensive, and actual cost increases, and obtains Sebivo through three-step reaction, and step is cumbersome, and industrialization is relatively costly.
Route one
2, with 2 '-deoxidation-D-thymidine for initiation material, anhydrous pyridine utilizes Methyl benzenesulfonyl is protected 3 ', the hydroxyl of 5 ' obtains 3 ', 5 '-two-O-are to methylbenzene acyl group 2 '-deoxidation-D-thymidine, 3 ', methylbenzene acyl group 2 '-deoxidation-D-thymidine is reacted with Potassium Benzoate by 5 '-two-O-in DMF, make furanose ring 3 ', the upset of the hydroxyl generation configuration of 5 ', thus obtaining 3 ', 5 '-two-O-benzoyl-L-thymidines, and 3 ', the methanol solution hydrolysis of 5 '-two-O-benzoyl-L-thymidine ammonia obtains 2 '-deoxidation-L-thymus pyrimidine and Sebivo (see route two).This route is comparatively laborious, is unfavorable for industrialization.
Route two
3, it is initial with L-arabinose, at K2CO3/NC-NH2Effect under, through adding annellated generation 2-amino-L-arabinofuranosyl adenin [1,2,3,4]-2-azoles quinoline, then reacts obtain 1-(2-carbethoxyl group acrylic)-2-amino-L-arabinofuranosyl adenin [1 with 2-chloromethyl propylene acetoacetic ester under the existence of NaI, 2,3,4]-2-azoles quinoline hydrochlorate, then in anhydrous Na2CO3React overnight with under the effect of hydroquinone, subsequently with Pd-Al2O3Carrying out catalytic hydrogenation for catalyst and obtain O22-dehydration-L-thymidine, obtained product obtains 3 ', 5 '-two-O-acetyl group-2 again with AcBr effect '-bromo-2 '-deoxidation-L-thymidine.Obtained product de-Br under the effect of tri-n-butyl tin and azodiisobutyronitrile obtains 3 ', 5 '-two-O-acetyl group-2 '-deoxidation-2 '-L-thymidine, then at MeOH/NH3Effect under hydrolysis obtain Sebivo (see route three), this route is more complicated, and reagent is partially expensive, is unfavorable for industrialization.
Route three
4, with L-ribose for initiation material, at NC-NH2nullEffect under，Through adding annellated generation 2-amino-L-arabinofuranosyl adenin [1,2,3,4]-2-azoles quinoline，It is obtained by reacting O2 in ethanol with ethyl propiolate,2-dehydration-L-uridnine，Then with the hydroxyl of benzoyl chlorine protection 3 ' and 5 ' positions in pyridine，3 ' are obtained with hcl reaction subsequently at DMF,5 '-two-O-benzoyls-2 '-chloro-2 '-deoxidation-L-uridnine，Then at iodine、In dry pyridine, 3-N-is obtained to chlorobenzene formacyl-5-iodo-3 ' with P-Toluoyl chloride protection after reaction under the catalysis of ammonium ceric nitrate,5 '-two-O-benzoyls-2 '-deoxidation-L-uridnine，Then again with triphenyl phosphorus，Acid chloride，Tetramethyl tin is obtained by reacting 3-N-to chlorobenzene formacyl-3 ',5 '-two-O-benzoyls-2 '-deoxidation-L-uridnine，With methanol-ammonia hydrolysis，Obtain final product Sebivo (see route four)，This route is complicated equally，Reagent price，It is unfavorable for industrialization.
Route four
To sum up, existing Sebivo synthetic route has the disadvantage that: (1) part material high expensive, commercially not easily obtains；(2) reactions steps is complicated, not easily implements；(3) equipment requirements is high, anhydrous and oxygen-free need to be done and process, bad control.Therefore it provides a kind of cheaper starting materials is easy to get, reactions steps is simple, and the preparation method of the Sebivo of production suitable for industrialized is highly significant.
Summary of the invention
It is an object of the invention to the defect for the existence of existing Sebivo preparation method and deficiency, it is provided that the preparation method of a kind of Sebivo, it the specific scheme is that
A kind of preparation method of Sebivo, its reaction mechanism mechanism of reaction is:
(1) compound 1 reacts with TMSCl, obtains compound 3；
(2) under HMDS effect, compound 2 and compound 3 are obtained by reacting Sebivo.
Wherein, TMSCl is trim,ethylchlorosilane, and HMDS is hexamethyldisilane amine.
Step (1) is particularly as follows: compound 1, TMSCl, acid binding agent press 1:(1.1-10): the mol ratio of (1.1-10) is 20-30 DEG C of reaction.
Preferably, described mol ratio is 1:5.9:8.1.
Preferably, the reaction of step (1) carries out in a solvent, and described solvent is selected from one or more in ether solvent, sulfone kind solvent, amide solvent.
It is further preferred that described ether solvent is selected from ether, oxolane, methyl tertiary butyl ether(MTBE), Isosorbide-5-Nitrae-dioxane；Described sulfone kind solvent is selected from dimethyl sulfoxide；Described amide solvent is selected from DMF, N,N-dimethylacetamide.
Most preferably, the solvent adopted in step (1) is oxolane.
Preferably, described acid binding agent is selected from N, N-thebaine (NMM), N, N-diisopropylethylamine (DIPEA), DMAP (DMAP), potassium carbonate or one or more in sodium carbonate, it is preferably N, N-thebaine.
Preferably, also including the step that the reactant liquor of step (1) carries out post processing, described post processing is particularly as follows: adopt toluene that reactant liquor is extracted.More specifically, after reaction terminates, add toluene make temperature be reduced to about 0 DEG C (such as-2 DEG C-2 DEG C) in reactant liquor, be subsequently adding water, keep temperature less than 20 DEG C, take toluene layer after layering, after washing, dry, concentration, namely obtain compound 3.
The all commercially available acquisition of raw material that step (1) relates to, and with low cost；Reaction is popular response, and step is simple, it is easy to industrial operation；The method adopting the present invention, the yield of compound 3 is up to 95%, and purity is up to more than 94%.
Step (2) particularly as follows:
1. according to compound 2:HMDS: compound 3=1:(1-3): the mol ratio of (1-3), first make compound 2 and HDMS in 80-150 DEG C of reaction；
2. step reactant liquor 1. is cooled to room temperature, adds compound 3, react under room temperature；
Preferably, described mol ratio is 1:2:1.1.
Preferably, step raw material 1. also includes ammonium sulfate, and its addition is the 1-5% of compound 2 mole, it is preferred to 3%.
Preferably, step reaction temperature 1. is 120-150 DEG C.
Preferably, 2. step carries out in a solvent, described solvent one in dichloromethane, chloroform, ether solvent, sulfone kind solvent；
It is further preferred that described ether solvent is selected from ether, oxolane, methyl tertiary butyl ether(MTBE), Isosorbide-5-Nitrae-dioxane；Described sulfone kind solvent is selected from dimethyl sulfoxide；
Most preferably, described solvent is chloroform.
Preferably, also including the step that the reactant liquor of step (2) carries out post processing, described post processing is particularly as follows: the pH value regulating reactant liquor is neutral, washed reaction liquid, collect organic facies and be also concentrated into dry, add ketones solvent (preferred acetone) stirring, sucking filtration and get final product；
Similarly, all commercially available acquisition of raw material that step (2) relates to, and with low cost；The reaction related to is popular response, and step is simple, it is easy to industrial operation；The method adopting the present invention, the yield of target product Sebivo is up to 90%, and purity is up to more than 98%.It is essential that step (2) is one pot reaction, it is not necessary to increase hydrolysing step and directly obtain target product, be an innovation of the present invention, and this operation simplify post processing, save workload, save human cost simultaneously.
As the most preferred scheme of the present invention, the preparation method of Sebivo of the present invention comprises the steps:
(1) compound 1, TMSCl, acid binding agent press 1:(1.1-10): the mol ratio of (1.1-10), with oxolane for solvent, 20-30 DEG C of reaction, after reacting completely, add water and toluene, collect toluene and mutually and concentrate and obtain the grease containing compound 3；
(2) by compound 2:HMDS: compound 3=1:(1-3): the mol ratio of (1-3), under 1-5% ammonium sulfate existence condition, first make compound 2 and HDMS in 80-150 DEG C of reaction；After reacting completely, making reactant liquor be cooled to room temperature, add chloroform and compound 3, react under room temperature, after reacting completely, the pH regulating reactant liquor be neutral, and washed reaction liquid is collected organic facies and is also concentrated into dry, adds acetone and stirs, sucking filtration and get final product.
The all commercially available acquisition of the raw material that the present invention relates to and reagent.
Meeting on the basis of this area general knowledge, above-mentioned each optimum condition can be mutually combined, and obtains each preferred embodiment of the present invention.
Detailed description of the invention
Following example are used for illustrating the present invention, but are not limited to the scope of the present invention.
Embodiment 1
(1) preparation of intermediate 3
Compound 1 (61.4g, 0.403mol), oxolane (720mL), NMM (360mL, 3.274mol) are joined 2L reaction system, at room temperature drip TMSCl (300mL, 2.365mol), finish, react 14h；After reaction terminates, in reactant liquor, add 300mL toluene, system is cooled to about 0 DEG C, it is slowly added to 500mL water, keeps temperature less than 20 DEG C, layering, water layer 200mL toluene washing layering, combining methylbenzene layer, use 150mL tap water respectively, 150mL saturated common salt water washing, dries with anhydrous magnesium sulfate, sucking filtration, obtaining organic layer, then at 65 DEG C, vacuum rotary steam removes solvent, finally obtains light yellow oil 112.6g, yield 95.4%, purity 94.5%.
(2) preparation of TM
Compound 2 (46.03g, 0.365mol) is joined in reaction bulb, is subsequently adding HMDS (117.8g, 0.73mol) and ammonium sulfate (1.4g, 0.011mol), it is heated to 145 DEG C, stop heating after reaction 10h, be cooled to room temperature；In reaction system, add the dry chloroform of 500mL, add intermediate 3 (107.1g, 0.402mol), at room temperature react 6h；After reaction terminates, adjusting pH value to neutral with 10% sodium hydroxide solution, washing, layering, organic layer is concentrated into dry, adds the stirring of 150mL acetone, sucking filtration, obtains white solid 79.6g, yield 90%, purity 98%.Fusing point: 187.5-188.0 DEG C (literature value: 188-190 DEG C)
Embodiment 2
(1) preparation of intermediate 3
Compound 1 (61.4g, 0.403mol), oxolane (720mL), NMM (244mL, 2.216mol) are joined 2L reaction system, at room temperature drip TMSCl (280mL, 1.612mol), finish, react 14h；After reaction terminates, in reactant liquor, add 300mL toluene, system is cooled to about 0 DEG C, it is slowly added to 500mL water, keeps temperature less than 20 DEG C, layering, water layer 200mL toluene washing layering, combining methylbenzene layer, use 150mL tap water respectively, 150mL saturated common salt water washing, dries with anhydrous magnesium sulfate, sucking filtration, obtaining organic layer, then at 65 DEG C, vacuum rotary steam removes solvent, finally obtains light yellow oil 107.5g, yield 90.1%, purity 94.0%.
(3) preparation of TM
Compound 2 (46.03g, 0.365mol) is joined in reaction bulb, is subsequently adding HMDS (93.2g, 0.578mol) and ammonium sulfate (1.4g, 0.011mol), it is heated to 145 DEG C, stop heating after reaction 10h, be cooled to room temperature；In reaction system, add the dry chloroform of 500mL, add intermediate 3 (107.1g, 0.402mol), at room temperature react 6h；After reaction terminates, adjusting pH value to neutral with 10% sodium hydroxide solution, washing, layering, organic layer is concentrated into dry, adds the stirring of 150mL acetone, sucking filtration, obtains white solid 75.1g, yield 85%, purity 98%.Fusing point: 187.6-188.0 DEG C (literature value: 188-190 DEG C)
Although, above use generality explanation, detailed description of the invention and test, the present invention is described in detail, but on basis of the present invention, it is possible to it is made some modifications or improvements, and this will be apparent to those skilled in the art.Therefore, these modifications or improvements without departing from theon the basis of the spirit of the present invention, belong to the scope of protection of present invention.
Claims (10)
1. the preparation method of a Sebivo, it is characterised in that its reaction mechanism mechanism of reaction is:
(1) compound 1 reacts with TMSCl, obtains compound 3；
(2) under HMDS effect, compound 2 and compound 3 are obtained by reacting Sebivo.
2. preparation method according to claim 1, it is characterised in that: step (1) is particularly as follows: compound 1, TMSCl, acid binding agent press 1:(1.1-10): the mol ratio of (1.1-10) is 20-30 DEG C of reaction；Preferably, described mol ratio is 1:5.9:8.1.
3. preparation method according to claim 1 and 2, it is characterised in that: the reaction of step (1) carries out in a solvent, and described solvent is selected from one or more in ether solvent, sulfone kind solvent, amide solvent；
Preferably, described ether solvent is selected from ether, oxolane, methyl tertiary butyl ether(MTBE), Isosorbide-5-Nitrae-dioxane；Described sulfone kind solvent is selected from dimethyl sulfoxide；Described amide solvent is selected from DMF, N,N-dimethylacetamide；
It is further preferred that described solvent is oxolane.
4. the preparation method according to any one of claim 1-3, it is characterised in that: described acid binding agent is selected from N, N-thebaine, N, N-diisopropylethylamine, DMAP, potassium carbonate or one or more in sodium carbonate, it is preferably N, N-thebaine.
5. the preparation method according to any one of claim 1-4, it is characterised in that: also including the step that the reactant liquor of step (1) carries out post processing, described post processing is particularly as follows: adopt toluene that reactant liquor is extracted.
6. the preparation method according to any one of claim 1-5, it is characterised in that: step (2) particularly as follows:
1. according to compound 2:HMDS: compound 3=1:(1-3): the mol ratio of (1-3), first make compound 2 and HDMS in 80-150 DEG C of reaction；
2. step reactant liquor 1. is cooled to room temperature, adds compound 3, react under room temperature；
Preferably, described mol ratio is 1:2:1.1.
7. preparation method according to claim 6, it is characterised in that: step raw material 1. also includes ammonium sulfate, and its addition is the 1-5% of compound 2 mole, it is preferred to 3%.
8. the preparation method according to claim 6 or 7, it is characterised in that: 2. step carries out in a solvent, described solvent one in dichloromethane, chloroform, ether solvent, sulfone kind solvent；
Preferably, described ether solvent is selected from ether, oxolane, methyl tertiary butyl ether(MTBE), Isosorbide-5-Nitrae-dioxane；Described sulfone kind solvent is selected from dimethyl sulfoxide；
It is further preferred that described solvent is chloroform.
9. preparation method according to claim 8, it is characterized in that: also include the reactant liquor of step (2) is carried out the step of post processing, described post processing is particularly as follows: the pH value regulating reactant liquor is neutral, washed reaction liquid, collect organic facies and be concentrated into dry, add ketones solvent stirring, sucking filtration and get final product；
Preferably, described ketones solvent is acetone.
10. preparation method according to claim 1, it is characterised in that comprise the steps:
(1) compound 1, TMSCl, acid binding agent press 1:(1.1-10): the mol ratio of (1.1-10), with oxolane for solvent, 20-30 DEG C of reaction, after reacting completely, add water and toluene, collect toluene and mutually and concentrate and obtain the grease containing compound 3；
(2) by compound 2:HMDS: compound 3=1:(1-3): the mol ratio of (1-3), under 1-5% ammonium sulfate existence condition, first make compound 2 and HDMS in 80-150 DEG C of reaction；After reacting completely, making reactant liquor be cooled to room temperature, add chloroform and compound 3, react under room temperature, after reacting completely, the pH regulating reactant liquor be neutral, and washed reaction liquid is collected organic facies and is also concentrated into dry, adds acetone and stirs, sucking filtration and get final product.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201610306199.XA CN105801644A (en) | 2016-05-10 | 2016-05-10 | Method for preparing telbivudine |
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| CN201610306199.XA CN105801644A (en) | 2016-05-10 | 2016-05-10 | Method for preparing telbivudine |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1842535A (en) * | 2003-06-30 | 2006-10-04 | 艾登尼科斯（开曼）有限公司 | Synthesis of beta-l-2'-deoxy nucleosides |
| CN101302239A (en) * | 2007-05-11 | 2008-11-12 | 上海医药工业研究院 | Synthetic method of telbivudine and intermediate thereof |
| WO2015081297A1 (en) * | 2013-11-27 | 2015-06-04 | Idenix Pharmaceuticals, Inc. | 2'-dichloro and 2'-fluoro-2'-chloro nucleoside analogues for hcv infection |
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2016
- 2016-05-10 CN CN201610306199.XA patent/CN105801644A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1842535A (en) * | 2003-06-30 | 2006-10-04 | 艾登尼科斯（开曼）有限公司 | Synthesis of beta-l-2'-deoxy nucleosides |
| CN101302239A (en) * | 2007-05-11 | 2008-11-12 | 上海医药工业研究院 | Synthetic method of telbivudine and intermediate thereof |
| WO2015081297A1 (en) * | 2013-11-27 | 2015-06-04 | Idenix Pharmaceuticals, Inc. | 2'-dichloro and 2'-fluoro-2'-chloro nucleoside analogues for hcv infection |
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