CN104910209B - A kind of method for preparing tenofovir - Google Patents
A kind of method for preparing tenofovir Download PDFInfo
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- CN104910209B CN104910209B CN201410088446.4A CN201410088446A CN104910209B CN 104910209 B CN104910209 B CN 104910209B CN 201410088446 A CN201410088446 A CN 201410088446A CN 104910209 B CN104910209 B CN 104910209B
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- tenofovir
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Abstract
The invention discloses a kind of method for preparing tenofovir, and it includes following reaction：
Description
Technical field
The present invention relates to a kind of method for preparing tenofovir, belong to field of pharmaceutical chemistry technology.
Background technology
Tenofovir is as first nucleotide analog for ratifying to infect for treating HIV-1 by FDA, and its importance is
Recognized by the World Health Organization, and be proposed as a line antiviral medication.Due to the material impact of the medicine, India was in 2009 9
The moon receives Indian generic drug manufacturer Cipla request, refuses to carry out patent protection to tenofovir, to ensure that the medicine can be more
Easily received by low income country.Its chemical structural formula is as follows：
Simultaneously as tenofovir also has prominent effect in antiviral therapy field, except being applied to anti-AIDS
Treatment is outer, and good therapeutic effect is also shown on anti-hepatitis virus.
In the periodical literature that 2010 deliver：Organic Process Research＆Development, 2010,14,
1194~1201 by summarizing the existing production technology of tenofovir, and carries out careful comparison and optimization to corresponding links
A synthesis technique for being applied to industrialized production is proposed afterwards：
The technique has very strong production safety and yield stability, but still suffers from following open defect：
1st, in the reaction of generation intermediate 2, when magnesium salts mixture converts to tenofovir, it is necessary to by magnesium salts mixture
Force via ethyl acetate and separated after analysing from system, due to the easy moisture absorption of magnesium salts mixture and adsorption production, at actual place
Operation requires high and very cumbersome in reason；
2nd, intermediate 2 is due to that will dissociate two ethyls, it is necessary to use harsh dissociation condition；
3rd, for from cost, due to using large excess of trimethyl silane and sodium bromide, either production cost also
It is the defects of serious in environmental protection all be present.
A kind of following improvement route is disclosed in Chinese patent CN102219805：
Although the technique overcomes some defects of above-mentioned paper route, using strong when preparing intermediate 1 due to it
For alkali such as sodium hydroxide in 120 DEG C of back flow reactions 22 hours, the reaction condition was violent, took longer, was difficult to control in big production.
One kind is disclosed in Chinese patent CN201210552918.8 and prepares tenofovir by raw material one kettle way of adenine
Method, reaction equation is as follows：
Although this process simplify technological operation, cost is reduced, is advantageous to industrialized production, this method and existing skill
Preparation technology in art on tenofovir is the same：It is and adenine and R- propene carbonates using adenine as initiation material
Reaction can produce the accessory substance of 7- positions substitution：(R) -7- (2- hydroxypropyls) adenine, generally this accessory substance is 7%
More than；And change catalyst, solvent or temperature and all have no idea to reduce the content of the accessory substance, and this isomers
Subsequent reactions can be participated in, so as to cause the raising of the problem of subsequent treatment and cost, so that still can not ideally meet industry
Change the demand for preparing high-purity tenofovir.
The content of the invention
The purpose of the present invention is overcome the deficiencies in the prior art, there is provided a kind of method for preparing tenofovir, with ideally
Meets the needs of preparation of industrialization high-purity tenofovir.
For achieving the above object, the technical solution adopted by the present invention is as follows：
A kind of method for preparing tenofovir, including following reaction：
Wherein：
A is C1~C4 alkyl-carbonyls or the C1~C4 alkyl-carbonyls substituted by aryl；B be H, C1~C4 alkyl-carbonyls or by
C1~C4 alkyl-carbonyls of aryl substitution；R is C1~C3 alkyl；R ' is C1~C3 alkyl；
Reaction a is formula III compound is reacted with R- propene carbonates and tolysulfonyl oxygen dialkyl methyl phosphonate
Intermediate II is generated, specifically includes following operation：Formula III compound, inorganic weak bases, R- propene carbonates are dissolved in organic solvent
In, room temperature is down to after being reacted 2~10 hours at 90~130 DEG C, highly basic is added, is reacted 0.5~2 hour at 20~50 DEG C,
Then tolysulfonyl oxygen dialkyl methyl phosphonate is added, continues reaction at 20~50 DEG C 4~10 hours, is down to room temperature,
Be concentrated under reduced pressure reaction system, obtains intermediate II；
Reaction b is intermediate II is hydrolyzed deprotection base under inorganic acid effect, obtains compound I (tenofovir).
Preferably, formula III compound is prepared by adenine and acylating reagent generation acylation reaction.
Preferably, described inorganic weak bases are potassium carbonate, sodium carbonate, saleratus or sodium acid carbonate；Described
Highly basic is selected from magnesium isopropoxide, tert-butyl alcohol magnesium or potassium tert-butoxide；Described organic solvent is selected from formamide, N, N- dimethyl formyls
Amine, acetamide, N- methylacetamides, N, in N- diisopropyls acetamide, 1-METHYLPYRROLIDONE, N- methylpiperidones at least
It is a kind of.
Preferably, the mol ratio of described inorganic weak bases and formula III compound is 1:1~10:1；Described is strong
The mol ratio of alkali and formula III compound is 1:1~10:1；Described tolysulfonyl oxygen dialkyl methyl phosphonate and formula III
The mol ratio of compound is 1:1~10:1.
Preferably, reacting b includes following operation：Inorganic acid is added into intermediate II, it is anti-at 90~110 DEG C
Room temperature is cooled to after answering 3~6 hours, continues reaction 1~2 hour, then by post processing, obtains tenofovir.
As further preferred scheme, described post processing includes following operation：Filtering reacting liquid, collect filtrate, regulation
Make crystallization in 0~20 DEG C of standing behind pH=2~3 of filtrate；Filter, collect crystal, washed and be dried in vacuo.
As further preferred scheme, described inorganic acid is hydrochloric acid, hydrobromic acid, hydroiodic acid or sulfuric acid.
As further preferred scheme, the mol ratio of described inorganic acid and intermediate II is 1:1~15:1.
Involved tolysulfonyl oxygen dialkyl methyl phosphonate is commercially available in the present invention obtains.
The present invention compared with prior art, has following remarkable result：
1) present invention uses adenine cheap and easy to get as raw material, not only greatly reduces cost, and by 7- positions
The protection of amino, so as to effectively prevent the accessory substance of 7- positions substitution of the prior art：(R) -7- (2- hydroxypropyls) gland is fast
The generation of purine, be advantageous to the raising of follow-up yield and product purity.
2) present invention is reacted in formula III compound is reacted with propylene carbonate ester using weak base, not only has reaction
Mild condition, simple operation and other advantages, it is important to ensure that the protection group of 7- bit aminos is not easy to remove, further avoid 7- positions
Substituted accessory substance：(R) generation of -7- (2- hydroxypropyls) adenine；And subsequently with tolysulfonyl oxygen methylphosphonic acid two
Highly basic is used in Arrcostab reaction so that one pot of removing of protection group of 7- bit aminos, it is more suitable so as to substantially reduce the reaction time
Close industrialized production.
In a word, using the inventive method can realize using raw material cheap and easy to get, simple operations, gentle reaction condition,
Low cost, the purpose for synthesizing high-purity (HPLC purity reaches more than 98%) tenofovir in high yield, energy-conserving and environment-protective, are adapted to scale
Metaplasia is produced, and the industrialized production to realizing tenofovir has conspicuousness value.
Embodiment
With reference to embodiment, the present invention is described in further detail and completely.
Embodiment 1：
As shown in Scheme 1, by compound III (17.4g, 0.13mol), potassium carbonate (21.5g, 0.15mol), R- carbonic acid third
Alkene ester (15.8g, 0.15mol) is dissolved in 50mL DMFs, and it is small to be heated to 90~125 DEG C of insulation reactions 3~6
When；Then room temperature is down to, magnesium isopropoxide (15.7g, 0.14mol) is added under argon gas protection, it is anti-to be warming up to 30~45 DEG C of insulations
Answer 0.5~1 hour；Tolysulfonyl oxygen methylphosphonic acid diethylester (45.9g, 0.15mol) is added dropwise again, continues to protect at 30~45 DEG C
Temperature reaction 4~6 hours；System is finally down to room temperature, be concentrated under reduced pressure reaction system, obtains intermediate II (for sticky oily
Thing).
124g concentrated hydrochloric acids are added into intermediate II, are warming up to 90~110 DEG C of insulation reactions 3~6 hours；Then it is down to room
Temperature, continue reaction at room temperature 1~2 hour, filter, filter cake washs 2 times with 150mL 5wt% diluted hydrochloric acid aqueous solution, filtrate
PH=2~3 are adjusted with sodium hydroxide solution, crystallization is stood at room temperature and stays overnight, be then cooled to 0~3 DEG C, make continuation crystallization 3
Hour；Filter, filter cake successively with 30mL water washings once, the mixed solvent (V/V=1 of 50mL water and acetone:1) wash 2 times,
50mL acetone washs 1 time；In 45 DEG C of vacuum drying, compound I is produced：Tenofovir 40.3g, total moles yield are 74.0%,
HPLC purity is 98.2%.
Embodiment 2：
As shown in Scheme 2, by compound III (17.4g, 0.13mol), potassium carbonate (21.5g, 0.15mol), R- carbonic acid third
Alkene ester (15.8g, 0.15mol) is dissolved in 50mL DMFs, and it is small to be heated to 90~125 DEG C of insulation reactions 3~6
When；Then room temperature is down to, magnesium isopropoxide (15.7g, 0.14mol) is added under argon gas protection, it is anti-to be warming up to 30~45 DEG C of insulations
Answer 0.5~1 hour；Tolysulfonyl oxygen dimethyl methyl phosphonate (44.1g, 0.15mol) is added dropwise again, continues to protect at 30~45 DEG C
Temperature reaction 4~6 hours；System is finally down to room temperature, be concentrated under reduced pressure reaction system, obtains intermediate II (for sticky oily
Thing).
96g concentrated hydrochloric acids are added into intermediate II, are warming up to 90~110 DEG C, insulation reaction 3~6 hours；Then it is down to room
Temperature, continue reaction at room temperature 1~2 hour, filter, filter cake washs 2 times with 150mL 5wt% diluted hydrochloric acid aqueous solution, filtrate
PH=2~3 are adjusted with sodium hydroxide solution, crystallization is stood at room temperature and stays overnight, be then cooled to 0~3 DEG C, make continuation crystallization 3
Hour；Filter, filter cake successively with 30mL water washings once, the mixed solvent (V/V=1 of 50mL water and acetone:1) wash 2 times,
50mL acetone washs 1 time；In 45 DEG C of vacuum drying, compound I is produced：Tenofovir 21.9g, total moles yield are 76.5%,
HPLC purity is 98.2%.
Embodiment 3：
As shown in Scheme 3, by compound III (17.4g, 0.13mol), potassium carbonate (21.5g, 0.15mol), R- carbonic acid third
Alkene ester (15.8g, 0.15mol) is dissolved in 50mL DMFs, and it is small to be heated to 90~125 DEG C of insulation reactions 3~6
When；Then room temperature is down to, magnesium isopropoxide (15.7g, 0.14mol) is added under argon gas protection, it is anti-to be warming up to 30~45 DEG C of insulations
Answer 0.5~1 hour；Tolysulfonyl oxygen methylphosphonic acid diethylester (45.9g, 0.15mol) is added dropwise again, continues to protect at 30~45 DEG C
Temperature reaction 4~6 hours；System is finally down to room temperature, watery hydrochloric acid 50mL is added and stirs 3 hours, be concentrated under reduced pressure reaction system, obtains
Intermediate II (for sticky grease).
96g concentrated hydrochloric acids are added into intermediate II, are warming up to 90~110 DEG C of insulation reactions 3~6 hours；Then it is down to room
Temperature, continue reaction at room temperature 1~2 hour, filter, filter cake washs 2 times with 150mL 5wt% diluted hydrochloric acid aqueous solution, filtrate
PH=2~3 are adjusted with sodium hydroxide solution, crystallization is stood at room temperature and stays overnight, be then cooled to 0~3 DEG C, make continuation crystallization 3
Hour；Filter, filter cake successively with 30mL water washings once, the mixed solvent (V/V=1 of 50mL water and acetone:1) wash 2 times,
50mL acetone washs 1 time；In 45 DEG C of vacuum drying, compound I is produced：Tenofovir 22.3g, total moles yield are 78.1%,
HPLC purity is 98.6%.
Embodiment 4
As shown in Scheme 4, by compound III (17.4g, 0.13mol), potassium carbonate (21.5g, 0.15mol), R- carbonic acid third
Alkene ester (15.8g, 0.15mol) is dissolved in 50mL DMFs, and it is small to be heated to 90~125 DEG C of insulation reactions 3~6
When；Then room temperature is down to, magnesium isopropoxide (15.7g, 0.14mol) is added under argon gas protection, it is anti-to be warming up to 30~45 DEG C of insulations
Answer 0.5~1 hour；Tolysulfonyl oxygen methylphosphonic acid diethylester (45.9g, 0.15mol) is added dropwise again, continues to protect at 30~45 DEG C
Temperature reaction 4~6 hours；System is finally down to room temperature, it is 3~4 to add watery hydrochloric acid regulation pH, and be concentrated under reduced pressure reaction system, obtains
Intermediate compound I (for sticky grease).
96g concentrated hydrochloric acids are added into intermediate II, are warming up to 90~110 DEG C of insulation reactions 3~6 hours；Then it is down to room
Temperature, continue reaction at room temperature 1~2 hour, filter, filter cake washs 2 times with 150mL 5wt% diluted hydrochloric acid aqueous solution, filtrate
PH=2~3 are adjusted with sodium hydroxide solution, crystallization is stood at room temperature and stays overnight, be then cooled to 0~3 DEG C, make continuation crystallization 3
Hour；Filter, filter cake successively with 30mL water washings once, the mixed solvent (V/V=1 of 50mL water and acetone:1) wash 2 times,
50mL acetone washs 1 time；In 45 DEG C of vacuum drying, compound I is produced：Tenofovir 21.9g, total moles yield are 76.8%,
HPLC purity is 98.7%.
Embodiment 5
As shown in Scheme 5, by compound III (17.4g, 0.13mol), potassium carbonate (21.5g, 0.15mol), R- carbonic acid third
Alkene ester (15.8g, 0.15mol) is dissolved in 50mL DMFs, and it is small to be heated to 90~125 DEG C of insulation reactions 3~6
When；Then room temperature is down to, magnesium isopropoxide (15.7g, 0.14mol) is added under argon gas protection, it is anti-to be warming up to 30~45 DEG C of insulations
Answer 0.5~1 hour；Tolysulfonyl oxygen methylphosphonic acid diethylester (45.9g, 0.15mol) is added dropwise again, continues to protect at 30~45 DEG C
Temperature reaction 4~6 hours；System is finally down to room temperature, sodium hydroxide (8g, 0.2mol) is added and stirs 3 hours, is concentrated under reduced pressure anti-
Answer system, obtain intermediate II (for sticky grease).
96g concentrated hydrochloric acids are added into intermediate II, are warming up to 90~110 DEG C of insulation reactions 3~6 hours；Then it is down to room
Temperature, continue reaction at room temperature 1~2 hour, filter, filter cake washs 2 times with 150mL 5wt% diluted hydrochloric acid aqueous solution, filtrate
PH=2~3 are adjusted with sodium hydroxide solution, crystallization is stood at room temperature and stays overnight, be then cooled to 0~3 DEG C, make continuation crystallization 3
Hour；Filter, filter cake successively with 30mL water washings once, the mixed solvent (V/V=1 of 50mL water and acetone:1) wash 2 times,
50mL acetone washs 1 time；In 45 DEG C of vacuum drying, compound I is produced：Tenofovir 21.8g, total moles yield are 76.2%,
HPLC purity is 98.6%.
Finally be necessary described herein be：Above example is served only for further detailed to technical scheme work
Ground explanation, it is impossible to be interpreted as limiting the scope of the invention, those skilled in the art is according to the above of the invention
Some the nonessential modifications and adaptations made belong to protection scope of the present invention.
Claims (8)
- A kind of 1. method for preparing tenofovir, it is characterised in that including following reaction：Wherein：A is C1~C4 alkyl-carbonyls or the C1~C4 alkyl-carbonyls substituted by aryl；B is for H, C1~C4 alkyl-carbonyls or by aryl Substituted C1~C4 alkyl-carbonyls；R is C1~C3 alkyl；R ' is C1~C3 alkyl；Reaction a is formula III compound is generated with R- propene carbonates and the reaction of tolysulfonyl oxygen dialkyl methyl phosphonate Intermediate II, specifically include following operation：Formula III compound, inorganic weak bases, R- propene carbonates are dissolved in organic solvent, It is down to room temperature after being reacted 2~10 hours at 90~130 DEG C, adds highly basic, react 0.5~2 hour at 20~50 DEG C, then Tolysulfonyl oxygen dialkyl methyl phosphonate is added, continues reaction at 20~50 DEG C 4~10 hours, is down to room temperature, is depressurized Reaction system is concentrated, obtains intermediate II；Reaction b is intermediate II is hydrolyzed deprotection base under inorganic acid effect, obtains compound I (tenofovir).
- 2. the method as claimed in claim 1 for preparing tenofovir, it is characterised in that：Formula III compound is by adenine and acyl Change reagent generation acylation reaction to be prepared.
- 3. the method as claimed in claim 1 for preparing tenofovir, it is characterised in that：Described inorganic weak bases be potassium carbonate, Sodium carbonate, saleratus or sodium acid carbonate；Described highly basic is selected from magnesium isopropoxide, tert-butyl alcohol magnesium or potassium tert-butoxide；Described has Solvent is selected from formamide, N,N-dimethylformamide, acetamide, N- methylacetamides, N, N- diisopropyls acetamide, N- first At least one of base pyrrolidones, N- methylpiperidones.
- 4. the method as claimed in claim 1 for preparing tenofovir, it is characterised in that：Described inorganic weak bases and formula III The mol ratio of compound is 1:1~10:1；The mol ratio of described highly basic and formula III compound is 1:1~10:1；It is described to first The mol ratio of benzene sulfonyl oxygen dialkyl methyl phosphonate and formula III compound is 1:1~10:1.
- 5. the method as claimed in claim 1 for preparing tenofovir, it is characterised in that：Reacting b includes following operation：To centre Inorganic acid is added in body II, room temperature is cooled to after being reacted 3~6 hours at 90~110 DEG C, continues reaction 1~2 hour, then By post processing, tenofovir is obtained.
- 6. the method as claimed in claim 5 for preparing tenofovir, it is characterised in that described post processing includes following behaviour Make：Filtering reacting liquid, filtrate is collected, adjust makes crystallization behind pH=2~3 of filtrate in 0~20 DEG C of standing；Filter, collect crystal, Washed and be dried in vacuo.
- 7. the method as claimed in claim 5 for preparing tenofovir, it is characterised in that：Described inorganic acid is hydrochloric acid, hydrogen bromine Acid, hydroiodic acid or sulfuric acid.
- 8. the method as claimed in claim 5 for preparing tenofovir, it is characterised in that：Described inorganic acid and intermediate II Mol ratio is 1:1~15:1.
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| CN107021984B (en) * | 2017-04-28 | 2019-05-10 | 福建广生堂药业股份有限公司 | A kind of Preparation Method And Their Intermediate of TAF nucleoside derivates |
| CN111205326B (en) * | 2020-02-13 | 2020-09-22 | 南京道尔医药科技有限公司 | Green and environment-friendly preparation method of tenofovir |
Citations (3)
| 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 |
| CN101617971A (en) * | 2008-07-03 | 2010-01-06 | 莫松军 | Disposable urine-collecting pocket used for men |
| CN102219805A (en) * | 2011-03-10 | 2011-10-19 | 苏州腾龙生物医药技术有限公司 | Novel production process of tenofovir |
-
2014
- 2014-03-11 CN CN201410088446.4A patent/CN104910209B/en active Active
Patent Citations (3)
| 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 |
| CN101617971A (en) * | 2008-07-03 | 2010-01-06 | 莫松军 | Disposable urine-collecting pocket used for men |
| CN102219805A (en) * | 2011-03-10 | 2011-10-19 | 苏州腾龙生物医药技术有限公司 | Novel production process of tenofovir |
Non-Patent Citations (1)
| Title |
|---|
| "替诺福韦的合成工艺改进";刘嘉等;《药学实践杂志》;20091231;第27卷(第1期);第31-32页 * |
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Effective date of registration: 20221110 Address after: Room 338, Building 2, 456 Liangxin Road, Laogang Town, Pudong New Area, Shanghai, 2013 Patentee after: SHANGHAI DESANO CHEMICAL PHARMACEUTICAL Co.,Ltd. Patentee after: JIANGSU PUXIN PHARMACEUTICAL Co.,Ltd. Address before: 201203 room 687-21, 2 building, No. 351, Guo Shou Jing Road, Zhangjiang hi tech park, Pudong New Area, Shanghai. Patentee before: SHANGHAI ACEBRIGHT PHARMACEUTICALS GROUP Co.,Ltd. Patentee before: SHANGHAI DESANO CHEMICAL PHARMACEUTICAL Co.,Ltd. Patentee before: JIANGSU PUXIN PHARMACEUTICAL Co.,Ltd. |
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