CN108003193B - A kind of preparation method of tenofovir dipivoxil - Google Patents
A kind of preparation method of tenofovir dipivoxil Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
Abstract
The present invention relates to a kind of preparation methods of tenofovir dipivoxil.Specifically, this method improves reaction yield, reduces impurity, simple easily manipulation, is conducive to industrial expanding production the present invention relates to a kind of method for preparing tenofovir dipivoxil of industrial production rank.
Description
Technical field
The present invention relates to a kind of other methods for preparing and purifying tenofovir dipivoxil of technical grade.
Background technique
Tenofovir disoproxil fumarate (tenofovirdisoproxilfumarate, TDF) presses down for nucleotide reverse transcriptase
Preparation, which is approved for individually or with other antiretroviral drugs combining in the U.S. infects for treating HIV-1,
Europe approval is approved to list in the U.S. in October, 2001 for treating HIV infection, is approved within 2 months 2002 to list in Europe,
In March, 2004 lists in Japan, ratifies for treating HIV infection.Meanwhile the medicine is effectively applied to used rummy
The HIV and HBV infection patient that husband treats surely, and can be applied to generate drug resistant patient to Lamivudine.In addition, tenofovir disoproxil
, Zidovudine class reverse transcriptase inhibitor such as Zha Xitading more general than most of cores for being used to treat HIV infection, stavudine etc. produce
Raw cytotoxicity is small, has good tolerance to patient.
In the synthetic route of tenofovir disoproxil fumaric acid reported in the literature, most widely used be with adenine and (R) -1,
After the condensation of 2- propylene carbonate, it is alkylated instead under lithium reagent effect with tolysulfonyl oxygroup methyl phosphinylidyne diethylester
It answers, finally hydrolyzes de- ethyl, Phosphation with bromotrimethylsilane or trim,ethylchlorosilane, fumaric acid complex forming salt is made.But
Intermediate is respectively walked in reaction process without sufficiently purifying, so that the impurity that reaction in next step is added is too many, final product low yield；
Each step synthetic reaction condition is complicated, and not enough, the selection of catalyst and usage amount are not analyzed sufficiently, and a degree of wave is caused for optimization
Take.There are many documents to disclose the synthetic method of tenofovir disoproxil fumarate in the prior art, as CN101531680A,
CN101778855A discloses the synthetic method of tenofovir disoproxil fumarate.
There is small, the post-processing approach products therefrom purity of batch in 80% or so, yield in 60-80% or so in this method,
Purity and yield be not high, also, genotoxicity impurity p-methyl benzenesulfonic acid isopropyl ester content is not disclosed in the method for the prior art；
Art methods are unfavorable for industrial expanding production, it is necessary to improve preparation method, improve purity reduction impurity.
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of synthesis (R) -9- [2- (diethyl phosphonyl methoxyl base) third
Base]-adenine method, simply easily purchase, reaction condition be simple controllable for the reactants such as this method starting material, post-reaction treatment
The approach such as method is simple optimize preparation method, improve yield, are conducive to industrial expanding production.
Technical scheme is as follows:
The present invention provides a kind of method for preparing compound or its stereoisomer shown in formula (I), the method includes,
Step 1, starting material TN01, n,N-Dimethylformamide, tert-butyl alcohol magnesium, tolysulfonyl oxygen methylphosphonic acid two
Ethyl ester reacts to obtain intermediate TN02；
Step 2, intermediate TN02, bromotrimethylsilane react to obtain intermediate TN03；
Step 3, intermediate TN03, N-Methyl pyrrolidone, triethylamine, chloromethyl propylene carbonate react to obtain centre
Body TN04；
Step 4, intermediate TN04, fumaric acid react in isopropanol solvent obtains compound shown in product formula (I)；
It is characterized in that, the post-processing approach of the step 1 are as follows: acetic acid is added after reaction, dichloro is added after concentration
Methane extraction, organic phase dry, filter, acetonitrile stirring are added after filtrate concentration, and intermediate TN02 is obtained after concentration.
In above scheme, the post-processing approach of the step 3 are as follows: water is added after reaction, hexamethylene is extracted step by step
It takes, collects lower layer's water phase；Water and ethyl acetate are added in water phase, repeatedly extracted again, upper organic phase is collected, is done
Intermediate TN04 is obtained after dry, filtering, concentration；The multiple extraction is preferably twice.
Preferably, the post-processing approach of the step 4 are as follows: product crude product is obtained by filtration after reaction, by methyl tertiary butyl ether(MTBE)
It is added in crude product, stirs with ethyl acetate, filter, obtain compound shown in midbody product formula (I) after dry.
It is further preferred that the post-processing approach of the step 2 are as follows: it is concentrated after reaction, water is added dropwise under cryogenic conditions, when
System collects lower layer's water phase, with certain density sodium hydroxide without water and ethyl acetate extraction is directly added into after obvious heat release
It is 3-5 that aqueous solution, which adjusts pH, obtains crude product after continuing stirring, filtering；Obtained crude product is recrystallized with water, filtering, solid are dry
Intermediate TN03 is obtained after dry；
Preferred 0-20 DEG C of the cryogenic conditions, the concentration of the sodium hydrate aqueous solution preferably 50%.
In above scheme, the temperature of the stirring is room temperature, preferably 10-30 DEG C.
In a preferred scheme of the invention, the method is
In step 1 the inventory of starting material TN01 be 20kg, the inventory of N,N-dimethylformamide be 42.5kg,
Tert-butyl alcohol magnesium 19.4kg, tolysulfonyl oxygen methylphosphonic acid diethylester inventory be 40kg；
Step 2, the inventory of bromotrimethylsilane are 48kg；
Step 3, the inventory of N-Methyl pyrrolidone is 60kg, the inventory of triethylamine is 12kg, chloromethyl isobutyl carbonate
The inventory of propyl ester is 33kg；
Step 4, the inventory of fumaric acid are 4.3kg, isopropanol solvent 75.6kg.
Preferably, the post-processing approach of the method is respectively
The post-processing approach of step 1 are as follows: acetic acid 14.9kg is added after reaction, methylene chloride is first added after concentration
200kg extraction, organic phase dry, filter, the stirring of 24kg acetonitrile are added after filtrate concentration, and intermediate TN02 is obtained after concentration；
The post-processing approach of step 2 are as follows: be concentrated after reaction, 20kg water is added dropwise under the conditions of 0-20 DEG C, when system is without obviously putting
It is directly added into water 100kg and ethyl acetate 80kg after heat, is extracted, lower layer's water phase is collected, it is water-soluble with 50% sodium hydroxide
It is 3-5 that liquid, which adjusts pH, obtains crude product after continuing stirring, filtering；By obtained crude product 300kg water, heat temperature raising reflux is carried out
Recrystallization obtains intermediate TN03 after filtering, solid are dry；
The post-processing approach of step 3 are as follows: 24kg water and 55.3kg hexamethylene are added after reaction, stirring, carries out first time extraction
It takes, collects lower layer's water phase；It adds 36kg hexamethylene and carries out second of extraction, collect lower layer's water phase；Solvent is converted, with 30kg water
It is added in water phase with 96kg ethyl acetate, carries out third time extraction, collect upper organic phase；30kg ethyl acetate is added,
Collect upper organic phase；Merge organic phase, with anhydrous sodium sulfate is dry, filtering, obtains intermediate TN04 after concentration；
The post-processing approach of step 4 are as follows: product crude product is obtained by filtration after reaction, by 40kg methyl tertiary butyl ether(MTBE) and 15kg
Ethyl acetate is added in crude product, stirs, and filtering obtains compound shown in midbody product formula (I) after dry.
It is highly preferred that further include the steps that in filtration step in the post-processing approach with eluent solvent filter cake, it is described
Solvent used in rinsing step in step 1 is selected from methylene chloride, and solvent used in the rinsing step in step 3 is selected from
Ethyl acetate, solvent used in the rinsing step in step 4 are selected from methyl tertiary butyl ether(MTBE).
It is further preferred that reaction temperature is 60-80 DEG C in the step 1；The dropwise addition of bromotrimethylsilane in step 2
Temperature is 0 DEG C, reaction temperature is 60-80 DEG C；Reaction temperature is 50-70 DEG C in the step 3；Temperature is reacted in the step 4
Degree is 40-60 DEG C.
Advantageous effect of the invention
Compared with prior art, the technical solution that the present invention prepares compound shown in formula (I) has the advantage that
Compared with the prior art, inventory of the invention is kilogram rank, post-processing approach is conventional extraction, recrystallization
Method, genotoxicity impurity p-methyl benzenesulfonic acid isopropyl ester content is almost nil in the product that the method for the present invention is prepared, HPLC
Under the conditions of the toxic impurities are not detected, the post-processing of reaction is simple, which is easy to industrial expanding production.
Detailed description of the invention
Fig. 1 is that (retention time is for the HPLC map of the tenofovir disoproxil fumarate that the method for the present invention is prepared
23.180min)。
Specific embodiment
With reference to embodiments for further describing the present invention, but these embodiments are not intended to limit the scope of the invention.
Test method without specific conditions in the embodiment of the present invention, usually according to normal condition, or according to raw material or
Condition proposed by commodity manufacturer.The reagent in specific source is not specified, for the conventional reagent of market purchase.
Embodiment
The structure of compound is by nuclear magnetic resonance (NMR) or/and mass spectrum (MS) come what is determined.NMR is displaced (δ) with 10-6
(ppm) unit provides.The measurement of NMR is to use BrukerAVANCE-400 nuclear magnetic resonance spectrometer, and measurement solvent is deuterated reagent.
The preparation (compound shown in formula (I)) of tenofovir disoproxil fumarate
Step 1, the preparation of intermediate TN02
N,N-Dimethylformamide 42.5kg, (R) -9- (2- hydroxypropyl) adenine (TN01) 20kg are sequentially added
In 200L glass-lined reactor, it is added with stirring tert-butyl alcohol magnesium 19.4kg, finishes stirring, is heated to 60~80 DEG C, slowly
Tolysulfonyl oxygen methylphosphonic acid diethylester 40kg, 2~4h of insulated and stirred, sampling HPLC monitoring is added.
30~50 DEG C are cooled to, 14.9kg acetic acid is added, nothing is concentrated under reduced pressure into and obviously distillates.25~35 DEG C are cooled to, is added
Enter 200kg methylene chloride, agitation and dilution is transferred in 300L glass-lined reactor, and 18kg saturated sodium chloride solution, stirring is added
3h is cooled to 0 DEG C of insulated and stirred 2h.It filters, filter cake 50kg eluent methylene chloride.50kg anhydrous sodium sulfate is added, sufficiently stirs
It mixes, dry 12h or more.
It filters, filtrate decompression is concentrated into be gone out without obvious fraction.24kg acetonitrile is added, opens stirring, is concentrated under reduced pressure into without bright
Aobvious fraction, which goes out, obtains TN02.
HPLC purity is 85.5%.
Step 2, the preparation of intermediate TN03
200L glass-lined reactor equipped with TN02 is cooled to 0 DEG C, connects device for absorbing tail gas, starts that 48kg front three is added dropwise
Bromide silane, heat release is violent during dropwise addition, controls interior temperature and is no more than 60 DEG C, and drop finishes, heat temperature raising, temperature 60~80 in control
DEG C, stir 10h, sampling HPLC monitoring.
It is concentrated under reduced pressure into after fully reacting and goes out without obvious fraction, continue to be cooled to 0~20 DEG C of interior temperature, it is pure to start dropwise addition 20kg
Change water；When system is pumped into 100kg purified water without obvious heat release and then directly.Reaction solution is transferred in 300L reactor tank, is added
Enter 80kg ethyl acetate, stir 30min, stratification collects water layer, and water layer is first transferred to clean 300L enamel and is reacted
In tank, stirring is opened, 0~20 DEG C of interior temperature is cooled to, started that prepared 50% sodium hydrate aqueous solution is slowly added dropwise, adjust pH
To 3~5, adjusting is finished, and stirs 2h.TN03 crude product can be obtained in rejection filter.
In 500L glass-lined reactor, the purified water of 300kg is added, opens stirring, TN03 crude product, heat temperature raising is added
Flow back 1h.Then it is cooled to 0 DEG C, 3~6h of insulated and stirred again, rejection filter.Filter cake grinds even paving disk, is put into heated-air circulation oven dry
After 24~36h, rewinding weighing, calculated yield；TN03 can be obtained.
HPLC purity is 99.5%, and two step yields are 64%.
Step 3, the preparation of intermediate TN04
N-Methyl pyrrolidone 60kg and 12kg intermediate TN03 is added in 200L glass-lined reactor.Stirring is opened,
Triethylamine 12kg is added.50~70 DEG C of temperature in heat temperature raising control, is added chloromethyl propylene carbonate 33kg.It finishes, is warming up to
50~70 DEG C of 6~10h of insulated and stirred of interior temperature, sampling HPLC monitoring.
It is cooled to 10~30 DEG C after fully reacting, 24kg purified water is added.55.3kg hexamethylene is added in 500L reactor tank
Alkane opens stirring, reaction solution is transferred in 500L reactor tank from 200L reactor tank, stirs 15min, and stratification is collected
Lower layer；36kg n-hexane is added in 500L reactor tank, opens stirring, then lower aqueous layer is transferred in reactor tank and is stirred
15min, stratification collect lower aqueous layer.
The water layer of collection is transferred in 500L reactor tank, 30kg purified water is added, 96kg ethyl acetate, stirring is added
15min, stratification collect upper layer；30kg ethyl acetate is added into 500L reactor tank, opens stirring, then by lower aqueous layer
It is transferred in the reactor tank, stirs 15min, stratification collects upper layer, and combined ethyl acetate organic layer is in 500L reactor tank
In, the stirring of 500L reactor tank is opened, sodium-chloride water solution will have been prepared and be added into the reactor tank, stirs 15min, stands and divides
Layer, discards lower aqueous layer, obtains ethyl acetate layer.Ethyl acetate layer is transferred in clean 300L glass-lined reactor, is added
It is dry to enter 12kg anhydrous sodium sulfate.
It filters, filter cake is eluted with 9kg~27kg ethyl acetate.Filtrate is pumped into reactor tank, is concentrated under reduced pressure into no fraction and goes out,
TN04 can be obtained.
HPLC purity is 80.2%.
Step 4, the preparation of compound shown in formula (I)
It is pumped into 75.6kg isopropanol, opens stirring, 4.3kg fumaric acid is added, is warming up to 40~60 DEG C, then by step 3 institute
Isopropanol (29.3kg) solution for obtaining intermediate TN04 is pumped into the fumaric acid system.0.5~1h of insulated and stirred is finished, is down to interior
5~15 DEG C of temperature, tenofovir disoproxil fumarate crude product can be obtained in 3~8h of insulated and stirred, rejection filter.
40kg methyl tertiary butyl ether(MTBE) is added in 300L reactor tank, 15kg ethyl acetate opens stirring.Fumaric acid is added to replace
Nuo Fuwei dipivoxil crude product, 10~30 DEG C of 2~4h of stirring, rejection filter.Filter cake is washed with 50~80kg methyl tertiary butyl ether(MTBE), is depressurized
Dry that tenofovir disoproxil fumarate highly finished product can be obtained, HPLC purity is 99.2%, yield 45.8%；Through examining
It surveys, product chirality reaches 100%, more importantly genotoxicity impurity p-methyl benzenesulfonic acid isopropyl ester is not detected, HPLC map
See Fig. 1, retention time 23.180min, peak area relative scale are 100%.
1H-NMR(400MHz,DMSO-d6)δ:8.15(s,1H),8.03(s,1H),7.24(s,2H),6.63(s,2H),
5.56-5.49(m,4H),4.86-4.76(m,4H),4.29-4.14(m,2H),4.02-3.94(m,3H),1.22(d,12H),
1.06(d,3H).
Claims (4)
1. the method for controlling gene poison impurity during compound shown in a kind of industrially prepared formula (I) or its stereoisomer, institute
The method of stating includes,
Step 1, starting material TN01, n,N-Dimethylformamide, tert-butyl alcohol magnesium, tolysulfonyl oxygen methylphosphonic acid diethylester
Reaction obtains intermediate TN02；
Step 2, intermediate TN02, bromotrimethylsilane react to obtain intermediate TN03；
Step 3, intermediate TN03, N-Methyl pyrrolidone, triethylamine, chloromethyl propylene carbonate react to obtain intermediate
TN04；
Step 4, intermediate TN04, fumaric acid react in isopropanol solvent obtains compound shown in product formula (I)；Wherein, it walks
The inventory of starting material TN01 is 20kg in rapid one, the inventory of N,N-dimethylformamide is 42.5kg, tert-butyl alcohol magnesium
19.4kg, tolysulfonyl oxygen methylphosphonic acid diethylester inventory be 40kg；
Step 2, the inventory of bromotrimethylsilane are 48kg；
Step 3, the inventory of N-Methyl pyrrolidone be the inventory of 60kg, TN03 be 12kg, the inventory of triethylamine is
12kg, chloromethyl propylene carbonate inventory be 33kg；
Step 4, the inventory of fumaric acid are 4.3kg, isopropanol solvent 75.6kg；
It is characterized in that,
The post-processing approach of step 1 are as follows: acetic acid 14.9kg is added after reaction, methylene chloride 200kg extraction is first added after concentration
It takes, organic phase dries, filters, the stirring of 24kg acetonitrile is added after filtrate concentration, and intermediate TN02 is obtained after concentration；
The post-processing approach of step 2 are as follows: be concentrated after reaction, under the conditions of 0-20 DEG C be added dropwise 20kg water, when system without obvious heat release it
After be directly added into water 100kg and ethyl acetate 80kg, extracted, collect lower layer's water phase, with 50% sodium hydrate aqueous solution tune
Section pH is 3-5, obtains crude product after continuing stirring, filtering；By obtained crude product 300kg water, heat temperature raising reflux is tied again
Crystalline substance obtains intermediate TN03 after filtering, solid are dry；
The post-processing approach of step 3 are as follows: 24kg water and 55.3kg hexamethylene are added after reaction, stirring, carries out first time extraction,
Collect lower layer's water phase；It adds 36kg hexamethylene and carries out second of extraction, collect lower layer's water phase；Convert solvent, with 30kg water and
96kg ethyl acetate is added in water phase, carries out third time extraction, collects upper organic phase；30kg ethyl acetate is added, is received
Collect upper organic phase；Merge organic phase, with anhydrous sodium sulfate is dry, filtering, obtains intermediate TN04 after concentration；
The post-processing approach of step 4 are as follows: product crude product is obtained by filtration after reaction, by 40kg methyl tertiary butyl ether(MTBE) and 15kg acetic acid
Ethyl ester is added in crude product, stirs, and filtering obtains compound shown in midbody product formula (I) after dry；
The genotoxicity impurity is p-methyl benzenesulfonic acid isopropyl ester.
2. the method as described in claim 1, which is characterized in that the temperature of the stirring is selected from 10-30 DEG C.
3. method according to claim 2, which is characterized in that further include with molten in the filtration step in the post-processing approach
Agent elutes the step of filter cake, and solvent used in the rinsing step in the step 1 is selected from methylene chloride, the leaching in step 3
It washes solvent used in step and is selected from ethyl acetate, solvent used in the rinsing step in step 4 is selected from methyl tertbutyl
Ether.
4. method as claimed in claim 3, which is characterized in that reaction temperature is 60-80 DEG C in the step 1；In step 2
The dropping temperature of bromotrimethylsilane is 0 DEG C, reaction temperature is 60-80 DEG C；Reaction temperature is 50-70 DEG C in the step 3；
Reaction temperature is 40-60 DEG C in the step 4.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103374038A (en) * | 2012-04-11 | 2013-10-30 | 广州白云山制药股份有限公司广州白云山制药总厂 | Preparation method of antiviral medicine |
| CN104672281A (en) * | 2015-02-13 | 2015-06-03 | 安徽安科恒益药业有限公司 | Method for preparing high-purity tenofovir dipivoxil fumarate |
| CN104725423A (en) * | 2013-12-18 | 2015-06-24 | 山东新时代药业有限公司 | Tenofovir disoproxil fumarate synthesis method |
| CN106554371A (en) * | 2016-09-09 | 2017-04-05 | 苏州二叶制药有限公司 | A kind of Tenofovir disoproxil fumarate（TNF）Preparation method |
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2018
- 2018-01-10 CN CN201810024014.5A patent/CN108003193B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103374038A (en) * | 2012-04-11 | 2013-10-30 | 广州白云山制药股份有限公司广州白云山制药总厂 | Preparation method of antiviral medicine |
| CN104725423A (en) * | 2013-12-18 | 2015-06-24 | 山东新时代药业有限公司 | Tenofovir disoproxil fumarate synthesis method |
| CN104672281A (en) * | 2015-02-13 | 2015-06-03 | 安徽安科恒益药业有限公司 | Method for preparing high-purity tenofovir dipivoxil fumarate |
| CN106554371A (en) * | 2016-09-09 | 2017-04-05 | 苏州二叶制药有限公司 | A kind of Tenofovir disoproxil fumarate（TNF）Preparation method |
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| 富马酸替诺福韦二吡呋酯的合成;李银;《中国优秀硕士学位论文全文数据库工程科技I辑》;20170615(第6期);第3章 |
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