CN103408593B - The preparation method of tynofovir - Google Patents
The preparation method of tynofovir Download PDFInfo
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- CN103408593B CN103408593B CN201310291883.1A CN201310291883A CN103408593B CN 103408593 B CN103408593 B CN 103408593B CN 201310291883 A CN201310291883 A CN 201310291883A CN 103408593 B CN103408593 B CN 103408593B
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Abstract
Present invention is disclosed a kind of tynofovir (Tenofovir, I) preparation method, its preparation process comprises with 4-amino-5-nitro-6-chloropyrimide (II) for raw material, (R)-4-[N-(2-hydroxypropyl) amido]-5-nitro-6-chloropyrimide (III) is generated with (R)-propylene carbonate open loop condensation, intermediate (III) generates (R)-1-(6-chloropurine-9-base)-2-propyl alcohol (IV) through reductive cyclization, intermediate (IV) generates (R)-1-(adenine-9-base)-2-propyl alcohol (V) through ammonia solution, intermediate (V) obtains tynofovir (I) through etherificate and hydrolysis reaction.This preparation method's raw material is easy to get, concise in technology, and side reaction is few, is applicable to suitability for industrialized production.
Description
Technical field
The invention belongs to organic synthetic route design and bulk drug thereof and Intermediate Preparation technical field, particularly a kind of preparation method of tynofovir.
Background technology
Tenofovir disoproxil fumarate (Tenofovir disoproxil fumarate, Tenofovir, TDF) be researched and developed by U.S.'s gill moral (Gilead Sciences) company be used for the treatment of the new drug that human immunodeficiency virus (HIV) and hepatitis B virus (HBV) infect.Get permission in U.S.'s listing in calendar year 2001, commodity are called Wei Ruide (Viread).The whole world is existing comprise China more than the treatment of 100 state approval tynofovirs for acquired immune deficiency syndrome (AIDS).In addition, 2008 FDA (Food and Drug Adminstration) (FDA) have approved the new indication that tenofovir disoproxil is used for the treatment of chronic hepatitis B.At present, more than 30 countries and regions have been had to obtain the approval of this novel indication.2011 Chinese food Drug Administration (SFDA) ratify the Clinical Trials of tenofovir disoproxil Treatment chronic Hepatitis B, this medicine, in the registration of China and approval, brings new therapeutic choice by giving the Chronic Hepatitis B of China.
Tenofovir disoproxil is the acyclic nucleotide phosphodiester analogue of AMP, belongs to nucleotide reverse transcriptase inhibitor.Tynofovir is prodrug, and chemical name is: (R)-9-(2-phosphate methoxy propyl group) VITAMIN B4.
No. US5935946th, the former United States Patent (USP) ground of gill moral company to report with VITAMIN B4 and S-Racemic glycidol through catalytic hydrogenation with No. US5922695, becomes the obtained tenofovir disoproxil of the reactions such as ring coupling and esterification catalysis.For the introducing of chiral hydroxyl group, No. CN102899367th, Chinese patent, No. CN102863445, No. CN102295660, No. CN101906119 and No. CN101648974 etc. report with chirality propylene chlorohydrin, (R)-propylene oxide, (R)-lactate and (R)-1,2-propylene glycol is raw material, generates the method for (R)-1-(adenine-9-base)-2-propyl alcohol (V) respectively with VITAMIN B4 generation condensation reaction.It is the method that raw material and VITAMIN B4 condensation generate intermediate (V) that No. CN102060876th, Chinese patent and No. CN101870713 report with (R)-propylene carbonate.In addition, condensation, esterification and the sequencing of hydrolysis reaction and the guard method of the functional group such as amino, hydroxyl also have more research report.
In sum, although the method preparing tynofovir and ester is varied, its parent nucleus raw material is VITAMIN B4.Thus when there is condensation reaction, or need amido protecting, or need the selectivity being strengthened its reaction by different catalyzer.So existing technique general steps is more, and difficult quality controls." Organic Process Research & Development " 2010,14th phase, the research of 1194-1201 page reports multiple existing its preparation process, point out that existing is in the synthesis process of starting raw material with VITAMIN B4, while generation intermediate (R)-1-(adenine-9-base)-2-propyl alcohol (V), also can produce process contaminants (VI) and (VII) to some extent.
Summary of the invention
In order to overcome defect of the prior art, the present invention is according to the synthesis theory of Green Chemistry, a kind of preparation method of novel tynofovir (I) is provided, this preparation method has the features such as raw material is easy to get, concise in technology, cost are lower and quality controllable, so be beneficial to the suitability for industrialized production of this bulk drug, promote the development of its economic technology.
To achieve these goals, main technical schemes provided by the present invention is as follows: the preparation method of a kind of tynofovir (I),
Described preparation method, its preparation process comprises: with 4-amino-5-nitro-6-chloropyrimide (II) for raw material, open loop condensation reaction generation (R)-4-[N-(2-hydroxypropyl) amido]-5-nitro-6-chloropyrimide (III) is carried out with (R)-propylene carbonate, intermediate (III) generates (R)-1-(6-chloropurine-9-base)-2-propyl alcohol (IV) through reductive ring closure reaction, intermediate (IV) generates (R)-1-(adenine-9-base)-2-propyl alcohol (V) through ammonolysis reaction, intermediate (V) obtains tynofovir (I) through etherificate and hydrolysis reaction.
In addition, the present invention also comprises following attached technical scheme:
The molar ratio that described 4-amino-5-nitro-6-chloropyrimide (II) and (R)-propylene carbonate carry out open loop condensation reaction is 1: 0.85-2.0, preferably 1: 1.1-1.5.
The promotor of the open loop condensation reaction of described 4-amino-5-nitro-6-chloropyrimide (II) and (R)-propylene carbonate is the hydride of metal on the oxyhydroxide of metal on basic metal or alkali, basic metal or alkali, alkali-metal carbonate, alkali-metal supercarbonate or alkali alcoholate, preferred sodium hydride, potassium tert.-butoxide or tert-butyl alcohol magnesium.
The reductive agent of described reduction reaction is zinc powder, iron powder, vat powder, hydrazine hydrate or shortening, preferred zinc powder or vat powder.
The cyclizing agent of described ring-closure reaction is formic acid, methyl-formiate, ethyl formate or methane amide, preferable formic acid.
The ammoniation agent of described ammonolysis reaction is ammoniacal liquor or liquefied ammonia.
Compared to prior art, the preparation method of tynofovir involved in the present invention, has the features such as raw material is easy to get, concise in technology, cost are lower and quality controllable, so be beneficial to the suitability for industrialized production of this bulk drug, promotes the development of its economic technology.
Embodiment
Be further non-limitingly described in detail technical solution of the present invention below in conjunction with several preferred embodiment, wherein obtaining the process of tynofovir (I) by (R)-1-(adenine-9-base)-2-propyl alcohol (V) through etherificate and hydrolysis reaction can with reference to the method for " Drugs ofthe Future " 1998, the 23rd volume 12 phase 1279-1286 page.
Embodiment one:
In reaction flask, add 4-amino-5-nitro-6-chloropyrimide (II) (1.73g, 10mmol) and DMF 20mL, stirring at room temperature is to dissolving.Be cooled to 0-5 DEG C, add potassium tert.-butoxide (2.8g, 2.5eq) in batches, drip (R)-propylene carbonate (1.33g, 13mmol) simultaneously.Slowly rise to room temperature, stir 5 ~ 7 hours.Add toluene, decrease temperature crystalline, filter.Filter cake ethyl alcohol recrystallization obtains off-white color solid (R)-4-[N-(2-hydroxypropyl) amido]-5-nitro-6-chloropyrimide (III) 2.0g, and yield is 85.8%.
Embodiment two:
(R)-4-[N-(2-hydroxypropyl) amido]-5-nitro-6-chloropyrimide (III) (2.32g is added in reaction flask, 10mmol), vat powder (4.35g, 2.5eq), methyl alcohol 25mL and distilled water 25mL, be warming up to 50-60 DEG C, stirring reaction 6 hours.Be evaporated to volume half, with dichloromethane extraction 3 times.Merge organic phase, washing, is concentrated into dry, adds formic acid 25mL, be warming up to 150-170 DEG C, insulation reaction 3 hours.Add activated carbon decolorizing, concentrated, separate out with solid, with water and methyl alcohol making beating rinsing, filter, obtain faint yellow solid (R)-1-(6-chloropurine-9-base)-2-propyl alcohol (IV) 1.7g, yield is 80.2%.
Embodiment three:
(R)-1-(6-chloropurine-9-base)-2-propyl alcohol (IV) (1.1g, 5mmol) and saturated ammonia methanol solution 50mL is added, sealing stirring reaction 16 hours in reaction flask.Be evaporated to dry.To decolour recrystallization with distilled water, take advantage of heat filtering, crystallisation by cooling 5 hours, obtain off-white color solid (R)-1-(adenine-9-base)-2-propyl alcohol (V) 0.8g, yield is 83.1%.
It is pointed out that above-described embodiment is only and technical conceive of the present invention and feature are described, its object is to person skilled in the art can be understood content of the present invention and implement according to this, can not limit the scope of the invention with this.All equivalences done according to spirit of the present invention change or modify, and all should be encompassed within protection scope of the present invention.
Claims (6)
1. a preparation method for tynofovir (I),
It is characterized in that described preparation method, its preparation process comprises: with 4-amino-5-nitro-6-chloropyrimide (II) for raw material, open loop condensation reaction generation (R)-4-[N-(2-hydroxypropyl) amido]-5-nitro-6-chloropyrimide (III) is carried out with (R)-propylene carbonate, described (R)-4-[N-(2-hydroxypropyl) amido]-5-nitro-6-chloropyrimide (III) generates (R)-1-(6-chloropurine-9-base)-2-propyl alcohol (IV) through reductive ring closure reaction, described (R)-1-(6-chloropurine-9-base)-2-propyl alcohol (IV) generates (R)-1-(adenine-9-base)-2-propyl alcohol (V) through ammonolysis reaction, described (R)-1-(adenine-9-base)-2-propyl alcohol (V) obtains tynofovir (I) through etherificate and hydrolysis reaction.
2. the preparation method of tynofovir (I) as claimed in claim 1, is characterized in that: the molar ratio that described 4-amino-5-nitro-6-chloropyrimide (II) and (R)-propylene carbonate carry out open loop condensation reaction is 1:0.85-2.0.
3. the preparation method of tynofovir (I) as claimed in claim 1, is characterized in that: the promotor that described 4-amino-5-nitro-6-chloropyrimide (II) and (R)-propylene carbonate carry out open loop condensation reaction is basic metal, alkali-metal carbonate, alkali-metal supercarbonate or alkali alcoholate.
4. the preparation method of tynofovir (I) as claimed in claim 1, is characterized in that: the reductive agent of described reductive ring closure reaction is zinc powder, iron powder, vat powder or hydrazine hydrate.
5. the preparation method of tynofovir (I) as claimed in claim 1, is characterized in that: the cyclizing agent of described reductive ring closure reaction is formic acid, methyl-formiate, ethyl formate or methane amide.
6. the preparation method of tynofovir (I) as claimed in claim 1, is characterized in that: the ammoniation agent of described ammonolysis reaction is ammoniacal liquor or liquefied ammonia.
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| CN104710424B (en) * | 2013-12-11 | 2017-03-01 | 河南师范大学 | (R) (+) preparation method of 9 (2 hydroxypropyl) adenine |
| CN104530050A (en) * | 2014-12-23 | 2015-04-22 | 江西富祥药业股份有限公司 | Synthesis method of tenofovir disoproxil fumarate intermediate impurity 1-amino adenine-2-propyl alcohol |
| CN105503875B (en) * | 2015-12-23 | 2017-06-20 | 江西富祥药业股份有限公司 | A kind of synthetic method of TDF intermediate impurities |
| CN108285471A (en) * | 2018-03-16 | 2018-07-17 | 安徽华昌高科药业有限公司 | A kind of preparation method of tenofovir |
| CN111961081B (en) * | 2020-10-20 | 2021-03-09 | 北京鑫开元医药科技有限公司 | Preparation method of (R) -2- (2-methoxypropyl phosphate) -adenine |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5935946A (en) * | 1997-07-25 | 1999-08-10 | Gilead Sciences, Inc. | Nucleotide analog composition and synthesis method |
| CN101870713A (en) * | 2010-05-28 | 2010-10-27 | 杭州和素化学技术有限公司 | Industrial production process for tenofovir disoproxil fumarate |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5935946A (en) * | 1997-07-25 | 1999-08-10 | Gilead Sciences, Inc. | Nucleotide analog composition and synthesis method |
| CN101870713A (en) * | 2010-05-28 | 2010-10-27 | 杭州和素化学技术有限公司 | Industrial production process for tenofovir disoproxil fumarate |
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