CN106317115A - Preparation method of adefovir - Google Patents
Preparation method of adefovir Download PDFInfo
- Publication number
- CN106317115A CN106317115A CN201510369297.3A CN201510369297A CN106317115A CN 106317115 A CN106317115 A CN 106317115A CN 201510369297 A CN201510369297 A CN 201510369297A CN 106317115 A CN106317115 A CN 106317115A
- Authority
- CN
- China
- Prior art keywords
- preparation
- adenine
- ethyl
- aqueous solution
- diethoxy
- 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.)
- Pending
Links
- 0 CCOP(CC***C1C=CN=C(*)[C@]1N=CC)(O*)=O Chemical compound CCOP(CC***C1C=CN=C(*)[C@]1N=CC)(O*)=O 0.000 description 3
- ZVDZWGOQIYDFTN-UHFFFAOYSA-N C/C(/OCC[IH]OCN)=[O]/C Chemical compound C/C(/OCC[IH]OCN)=[O]/C ZVDZWGOQIYDFTN-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention discloses a preparation method of adefovir. The preparation method comprises the following steps: adding 9-[2-(diethoxylphosphorylmethoxyl)ethyl]adenine into a water solution of HBr, heating to carry out reactions, cooling, and adjusting the pH to 2-3.5 to precipitate white solids namely white adefovir. The preparation method has the advantages that during the hydrolysis of 9-[2-(diethoxylphosphorylmethoxyl)ethyl]adenine, the step of evaporating organic solvents is eliminated, the reaction time is reduced, thus the preparation time is shortened; trimethyl iodo-silane, trimethyl bromo-silane, or trimethyl chloro-silane is replaced by a water solution of HBr, and the cost is reduced by nearly 100 to 400 yuan. Secondary solvent acetonitrile is not used, influence of pollution and solvent residue on drug quality is reduced; trimethyl bromo-silane is easy to decompose and is harmful to human body, and after HBr substitution, the harm to workers is largely reduced.
Description
Technical field
The present invention relates to the preparation method of a kind of adefovirdipivoxil, belong to medicinal chemistry art.
Background technology
Adefovirdipivoxil (PMEA, 2) is a kind of uncleosides as antiviral agents, chemical entitled 9-(2 phosphorus-acid methoxyl group) ethyl adenine,
Clinical research shows that it has significant inhibitory action to hepatitis B virus (HBV).
The method preparing adefovirdipivoxil (PMEA) at present:
1, utilizing 9-(2-ethoxy) adenine or its N6-benzoyl derivatives, with DMF as solvent, sodium hydride is for urging
Agent after condensation reaction, after be hydrolyzed with Iodotrimethylsilane, obtain product adefovirdipivoxil through ion-exchange chromatography.
2, Arbuzov reaction is carried out, through ion chromatographic separation with 2-acetoxyethoxy chloromethanes and NSC 5284
Purify and after halo, then be condensed with adenine, isolated product adefovirdipivoxil under silica gel chromatographic column separation condition.
Consulting literatures, other synthetic route and both above route there is no big difference.It is all to use different method synthesis
9-(2-diethoxy phosphonium mesitoyl methoxyethyl) adenine, then with Iodotrimethylsilane, bromotrimethylsilane or trimethylchloro-silicane
Alkane in Water in Organic Solvents solutions such as acetonitrile, n-Butyronitrile, chlorobenzenes to adefovirdipivoxil.
And Iodotrimethylsilane, bromotrimethylsilane or trim,ethylchlorosilane are expensive, corrosivity is big, operation need into
Solvent C H used in the strict protection of row and reaction3CN is two kind solvents.When additionally reacting with trim,ethylchlorosilane
Between longer, 20h in butyronitrile, in chlorobenzene 10 hours.Time is oversize is not suitable for industrialized production.
Summary of the invention
The technical problem to be solved in the present invention is to overcome existing defect, it is provided that the preparation method of a kind of adefovirdipivoxil.The party
Method use reagent cheap, toxicity is little, easily operated.
In order to solve above-mentioned technical problem, the invention provides following technical scheme:
A kind of preparation method of adefovirdipivoxil, with 9-[2-(diethoxy phosphatidyl methoxy) ethyl] adenine as raw material, will
9-[2-(diethoxy phosphatidyl methoxy) ethyl] adenine joins in HBr aqueous solution, and heating carries out following anti-of reaction equation
Should, adding water after cooling, regulation pH is 2～3.5, has white solid to separate out i.e. and obtains white adefovirdipivoxil
In order to the productivity making adefovirdipivoxil is higher, in such scheme preferably, 9-[2-(diethoxy phosphatidyl methoxy) second
Base] mass ratio of adenine and HBr aqueous solution is 1:2～5.When ratio is more than 1:2, raw material hydrolysis is incomplete, and not
Being beneficial to solid dissolve, during less than 1:5, yield can substantially reduce.
Preferably, 9-[2-(diethoxy phosphatidyl methoxy) ethyl] adenine is 1:3 with the mass ratio of HBr aqueous solution.
In any of the above-described scheme preferably, the mass concentration of described HBr aqueous solution is 40～48%.
In any of the above-described scheme preferably, the mass concentration of described HBr aqueous solution is 48%.
In order to enable raw material thoroughly to react, provide productivity, heating-up temperature is 80～100 DEG C in such scheme preferably.
Preferably, heating-up temperature is 90 DEG C.When temperature is less than 80 DEG C, sluggish；And solution is difficult to be heated beyond 100 DEG C；
Being 90 DEG C, productivity is the highest.
In order to enable raw material thoroughly to react, improve productivity, in any of the above-described scheme preferably, the reacting by heating time be 4～
8 hours.It is beneficial to improve productivity and the yield of product.Preferably, the reacting by heating time is 5 hours.
In any of the above-described scheme preferably, being cooled to 25～45 DEG C and add water, keeping temperature during regulation pH is less than 45 DEG C.
Why limiting temperature, is owing in N-process, pH constantly raises, and under the conditions of higher pH, temperature rising can make PMEA
Decompose.
In any of the above-described scheme preferably, regulation pH is 2.5.Now, the purity of product is the highest.Regulation pH be in order to
PMEA is allowed to separate out from solution.
In any of the above-described scheme preferably, acid-base reagent can be selected according to common knowledge during regulation pH value.It is preferably with 50%
Sodium hydroxide regulation pH, more conducively product precipitation, improve productivity.
In order to make adefovirdipivoxil more separate out, in any of the above-described scheme preferably, white solid is had to continue stirring after separating out
3～6 hours, preferably 4 hours.
Beneficial effects of the present invention:
1, the hydrolytic process of 9-[2-(diethoxy phosphatidyl methoxy) ethyl] adenine eliminates the operation of organic solvent distillation,
And reduce the response time, shorten man-hour.
2, by Iodotrimethylsilane, bromotrimethylsilane or trim,ethylchlorosilane HBr aqueous solution replace, and per kilogram becomes
This reduction nearly 100-400 unit.
3, eliminate two kind solvent acetonitriles, reduce and pollute and the dissolvent residual impact on drug quality.
4, bromotrimethylsilane is extremely easy in decomposition, and easily damages human body.Reduce workman's hazardness after replacing with HBr.
Accompanying drawing explanation
Fig. 1 is that the HPLC of the embodiment of the present invention 4 product measures the sectional drawing of result after purity；
Fig. 2 is the nuclear magnetic spectrogram of the embodiment of the present invention 4 product.
Detailed description of the invention
Hereinafter the preferred embodiments of the present invention are illustrated, it will be appreciated that preferred embodiment described herein is only used for
Bright and explain the present invention, be not intended to limit the present invention.
9-[2-(diethoxy phosphatidyl methoxy) ethyl] adenine that the present invention uses is limited purchased from Tianjin Inst. of Materia Medica Pharmaceutical
Responsible company.HBr aqueous solution is purchased from Qilu Petrochemical, and NaOH is purchased from Tianjin BoHai Chemical Engineering group company.
Embodiment 1: the preparation method of a kind of adefovirdipivoxil
20g 9-[2-(diethoxy phosphatidyl methoxy) ethyl] adenine is joined in the HBr aqueous solution that 100g concentration is 48%, stirs
Mix and be warmed up to 90 DEG C, react 5h.TLC detection reaction is complete, stopped reaction.Solution is cooled to room temperature and adds water, maintains the temperature at 45 DEG C
Hereinafter, it is neutralized to pH ≈ 2.5 with the sodium hydroxide of 50%.Have a large amount of white solid to separate out, continue stirring 4h, sucking filtration, be dried white
PMEA.HPLC measures purity: 99.0% yield: 83%.The nuclear magnetic data of product is as follows: 1HNMR (D2O)δ:8.37(s,1H,2-H),
(8.35 s, 1H, 8-H), 4.49 (t, 2H, J=6.0Hz, 1 '-H), 3.86 (t, 2H, J=6.0Hz, 2 ' H), 3.51 (d, 2H, J=
9.0Hz,OCH2P)。
Embodiment 2: the preparation method of a kind of adefovirdipivoxil
20g 9-[2-(diethoxy phosphatidyl methoxy) ethyl] adenine is joined in the HBr aqueous solution that 100g concentration is 48%, stirs
Mix and be warmed up to 80 DEG C, react 8h.TLC detection reaction is complete, stopped reaction.Solution is cooled to room temperature and adds water, maintains the temperature at 45 DEG C
Hereinafter, it is neutralized to pH ≈ 2.5 with the sodium hydroxide of 50%.Have a large amount of white solid to separate out, continue stirring 4h, sucking filtration, be dried white
PMEA.HPLC measures purity: 98.7% yield: 81%.
Embodiment 3: the preparation method of a kind of adefovirdipivoxil
20g 9-[2-(diethoxy phosphatidyl methoxy) ethyl] adenine is joined in the HBr aqueous solution that 80g concentration is 48%, stirs
Mix and be warmed up to 90 DEG C, react 5h.TLC detection reaction is complete, stopped reaction.Solution is cooled to room temperature and adds water, maintains the temperature at 45 DEG C
Hereinafter, it is neutralized to pH ≈ 2.5 with the sodium hydroxide of 50%.Have a large amount of white solid to separate out, continue stirring 4h, sucking filtration, be dried white
PMEA.HPLC measures purity: 99.4% yield: 85%.
Embodiment 4: the preparation method of a kind of adefovirdipivoxil
20g 9-[2-(diethoxy phosphatidyl methoxy) ethyl] adenine is joined in the HBr aqueous solution that 60g concentration is 48%, stirs
Mix and be warmed up to 90 DEG C, react 5h.TLC detection reaction is complete, stopped reaction.Solution is cooled to room temperature and adds water, maintains the temperature at 45 DEG C
Hereinafter, it is neutralized to pH ≈ 2.5 with the sodium hydroxide of 50%.Have a large amount of white solid to separate out, continue stirring 4h, sucking filtration, be dried white
PMEA.HPLC measures purity: 99.6% yield: 86%.
Embodiment 5: the preparation method of a kind of adefovirdipivoxil
20g 9-[2-(diethoxy phosphatidyl methoxy) ethyl] adenine is joined in the HBr aqueous solution that 40g concentration is 48%, stirs
Mix and be warmed up to 90 DEG C, react 5h.TLC detection reaction is complete, stopped reaction.Solution is cooled to room temperature and adds water, maintains the temperature at 45 DEG C
Hereinafter, it is neutralized to pH ≈ 2.5 with the sodium hydroxide of 50%.Have a large amount of white solid to separate out, continue stirring 4h, sucking filtration, be dried white
PMEA.HPLC measures purity: 99.1% yield: 83%.
Embodiment 6: the preparation method of a kind of adefovirdipivoxil
20g 9-[2-(diethoxy phosphatidyl methoxy) ethyl] adenine is joined in the HBr aqueous solution that 40g concentration is 48%, stirs
Mix and be warmed up to 90 DEG C, react 5h.TLC detection reaction is complete, stopped reaction.Solution is cooled to room temperature and adds water, maintains the temperature at 45 DEG C
Hereinafter, it is neutralized to pH ≈ 3.5 with the sodium hydroxide of 50%.Have a large amount of white solid to separate out, continue stirring 4h, sucking filtration, be dried white
PMEA.HPLC measures purity: 98.5% yield 80%.
Embodiment 7: the preparation method of a kind of adefovirdipivoxil
20g 9-[2-(diethoxy phosphatidyl methoxy) ethyl] adenine is joined in the HBr aqueous solution that 40g concentration is 40%, stirs
Mix and be warmed up to 90 DEG C, react 4h.TLC detection reaction is complete, stopped reaction.Solution is cooled to room temperature and adds water, maintains the temperature at 45 DEG C
Hereinafter, it is neutralized to pH ≈ 2 with the sodium hydroxide of 50%.Have a large amount of white solid to separate out, continue stirring 3h, sucking filtration, be dried white
PMEA.HPLC measures purity: 98.3% yield 78%.
Embodiment 8: the preparation method of a kind of adefovirdipivoxil
20g 9-[2-(diethoxy phosphatidyl methoxy) ethyl] adenine is joined in the HBr aqueous solution that 100g concentration is 48%, stirs
Mix and be warmed up to 100 DEG C, react 5h.TLC detection reaction is complete, stopped reaction.Solution is cooled to room temperature and adds water, maintains the temperature at
Less than 45 DEG C, it is neutralized to pH ≈ 2.5 with the sodium hydroxide of 50%.Have a large amount of white solid to separate out, continue stirring 6h, sucking filtration, be dried
White PMEA.HPLC measures purity: 98.3% yield 78%.
Finally it is noted that the foregoing is only the preferred embodiments of the present invention, it is not limited to the present invention, to the greatest extent
The present invention has been described in detail by pipe with reference to previous embodiment, and for a person skilled in the art, it is the most permissible
Technical scheme described in foregoing embodiments is modified, or wherein portion of techniques feature is carried out equivalent.All
Within the spirit and principles in the present invention, any modification, equivalent substitution and improvement etc. made, should be included in the present invention's
Within protection domain.
Claims (10)
1. a preparation method for adefovirdipivoxil, with 9-[2-(diethoxy phosphatidyl methoxy) ethyl] adenine as raw material,
It is characterized in that: 9-[2-(diethoxy phosphatidyl methoxy) ethyl] adenine is joined in HBr aqueous solution, heat into
The reaction that row reaction equation is following, adds water after cooling, regulation pH is 2～3.5, has white solid to separate out i.e. and obtains white A De
Fu Wei,
Preparation method the most according to claim 1, it is characterised in that: 9-[2-(diethoxy phosphatidyl methoxy) ethyl]
Adenine is 1:2～5 with the mass ratio of HBr aqueous solution.
Preparation method the most according to claim 2, it is characterised in that: 9-[2-(diethoxy phosphatidyl methoxy) ethyl]
Adenine is 1:3 with the mass ratio of HBr aqueous solution.
Preparation method the most according to any one of claim 1 to 3, it is characterised in that: described HBr aqueous solution
Mass concentration is 40～48%.
Preparation method the most according to claim 4, it is characterised in that: the mass concentration of described HBr aqueous solution is 48%.
Preparation method the most according to any one of claim 1 to 3, it is characterised in that: heating-up temperature is 80～100 DEG C.
Preparation method the most according to claim 6, it is characterised in that: heating-up temperature is 90 DEG C.
Preparation method the most according to claim 6, it is characterised in that: the reacting by heating time is 4～8 hours.
Preparation method the most according to claim 6, it is characterised in that: it is cooled to 25～35 DEG C and adds water.
Preparation method the most according to claim 8, it is characterised in that: keeping temperature during regulation pH is less than 45 DEG C.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510369297.3A CN106317115A (en) | 2015-06-29 | 2015-06-29 | Preparation method of adefovir |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510369297.3A CN106317115A (en) | 2015-06-29 | 2015-06-29 | Preparation method of adefovir |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN106317115A true CN106317115A (en) | 2017-01-11 |
Family
ID=57722539
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510369297.3A Pending CN106317115A (en) | 2015-06-29 | 2015-06-29 | Preparation method of adefovir |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106317115A (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1560059A (en) * | 2004-03-05 | 2005-01-05 | 胡小侠 | Synthesis process for Adefovir ester of anti hepatitis type B virus medicine |
| CN102250146A (en) * | 2011-05-27 | 2011-11-23 | 扬州三友合成化工有限公司 | Method for synthesizing adefovir serving as anti-hepatitis B virus medicine |
| US20120238753A1 (en) * | 2011-03-14 | 2012-09-20 | Vellenki Siva Rama Prasad | Process for the preparation of adefovir dipivoxil |
-
2015
- 2015-06-29 CN CN201510369297.3A patent/CN106317115A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1560059A (en) * | 2004-03-05 | 2005-01-05 | 胡小侠 | Synthesis process for Adefovir ester of anti hepatitis type B virus medicine |
| US20120238753A1 (en) * | 2011-03-14 | 2012-09-20 | Vellenki Siva Rama Prasad | Process for the preparation of adefovir dipivoxil |
| CN102250146A (en) * | 2011-05-27 | 2011-11-23 | 扬州三友合成化工有限公司 | Method for synthesizing adefovir serving as anti-hepatitis B virus medicine |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP0402152A2 (en) | Crystalline 4-amino-1-hydroxybutylidene-1, 1-bisphosphonic acid monosodium trihydrate, process therefor and compositions and use thereof | |
| CN104447739A (en) | Deuterated palbociclib derivative, and preparation method and application thereof | |
| CN107021984B (en) | A kind of Preparation Method And Their Intermediate of TAF nucleoside derivates | |
| Duke et al. | The structure and synthesis of cytokinin metabolites. II. Lupinic acid and O-β-D-glucopyranosylzeatin from Lupinus angustifolius | |
| CA2046755C (en) | /2r/-2-[di/2-propyl/phosphonylmethoxy]-3-p-toluenesulfonyloxy-1-trimethylacetoxypropane, its preparation and use | |
| CN109651371A (en) | A kind of preparation method of valaciclovir hydrochlordide | |
| CN106317115A (en) | Preparation method of adefovir | |
| CN105622671A (en) | Preparing method for realizing industrial mass production of tenofovir disoproxil fumarate | |
| CN104327067A (en) | Preparation method of amorphous dasatinib | |
| CN106008316A (en) | New method for synthesizing Ledipasvir chiral intermediate | |
| CN108794448B (en) | Preparation method of trelagliptin and salt thereof | |
| Xu et al. | Facile Approaches to 2-Deoxy-d-Glucose and 2-Deoxy-α-d-Glucopyranonucleosides from d-Glucal | |
| CN107098936A (en) | A kind of preparation method of TAF nucleoside derivates | |
| CN108623455A (en) | A kind of intermediate of cardiotonic agents | |
| CN105367524A (en) | Preparation method of 3-O-alkyl ascorbic acid | |
| CN103483409A (en) | Synthetic method for preparing nelarabine | |
| CN113637003B (en) | Method for preparing 2-amino-6- (piperidine-4-acyl) pyridine derivative | |
| CN104341452A (en) | Preparation method of tenofovir disoproxil fumarate impurities | |
| CN103980229A (en) | Preparation method of N-phenyl piperazine | |
| US2691023A (en) | Dihydropyrrolo-(3.2-c) quinoline derivatives | |
| CN105439978A (en) | Preparation method of acotiamide intermediate | |
| CN105294828A (en) | Preparation method of Ombitasvir | |
| CN105085595A (en) | Method for synthesizing 2,6-hologenated purine nucleoside by deacylation protection | |
| CN107459534B (en) | Synthetic method of 3- [2- (phosphonomethoxy) ethyl ] adenine | |
| CN113582947B (en) | Method for removing sulfonyl protection of amine |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20170111 |