CN108003193A - A kind of preparation method of tenofovir dipivoxil - Google Patents
A kind of preparation method of tenofovir dipivoxil Download PDFInfo
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- CN108003193A CN108003193A CN201810024014.5A CN201810024014A CN108003193A CN 108003193 A CN108003193 A CN 108003193A CN 201810024014 A CN201810024014 A CN 201810024014A CN 108003193 A CN108003193 A CN 108003193A
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- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 title abstract description 14
- 238000002360 preparation method Methods 0.000 title abstract description 12
- 229960004556 tenofovir Drugs 0.000 title abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims abstract description 34
- 238000000034 method Methods 0.000 claims abstract description 28
- 238000004519 manufacturing process Methods 0.000 claims abstract description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 65
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 40
- 238000003756 stirring Methods 0.000 claims description 35
- 239000000543 intermediate Substances 0.000 claims description 30
- 238000013459 approach Methods 0.000 claims description 23
- 238000012805 post-processing Methods 0.000 claims description 23
- 239000012043 crude product Substances 0.000 claims description 20
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 19
- 238000001914 filtration Methods 0.000 claims description 19
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 18
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- 239000012071 phase Substances 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 14
- 239000000047 product Substances 0.000 claims description 13
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 12
- 239000012074 organic phase Substances 0.000 claims description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 11
- 238000000605 extraction Methods 0.000 claims description 11
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 10
- 239000001530 fumaric acid Substances 0.000 claims description 9
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 9
- 238000001035 drying Methods 0.000 claims description 8
- 239000007864 aqueous solution Substances 0.000 claims description 7
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 claims description 7
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 claims description 7
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- 239000012065 filter cake Substances 0.000 claims description 6
- 239000000706 filtrate Substances 0.000 claims description 6
- 239000011777 magnesium Substances 0.000 claims description 5
- 229910052749 magnesium Inorganic materials 0.000 claims description 5
- 239000007858 starting material Substances 0.000 claims description 5
- KVSBJABNUGATFM-UHFFFAOYSA-N C(C)OP(OCC)(=O)C.[O] Chemical compound C(C)OP(OCC)(=O)C.[O] KVSBJABNUGATFM-UHFFFAOYSA-N 0.000 claims description 4
- GKFPQXSITDCUDW-UHFFFAOYSA-N C(O)(O)=O.ClCC=CC Chemical compound C(O)(O)=O.ClCC=CC GKFPQXSITDCUDW-UHFFFAOYSA-N 0.000 claims description 4
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 4
- 239000007787 solid Substances 0.000 claims description 4
- -1 Magnesium alkoxide Chemical class 0.000 claims description 2
- 238000003810 ethyl acetate extraction Methods 0.000 claims description 2
- 238000010992 reflux Methods 0.000 claims description 2
- 238000003809 water extraction Methods 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 238000002425 crystallisation Methods 0.000 claims 1
- 230000008025 crystallization Effects 0.000 claims 1
- 238000002386 leaching Methods 0.000 claims 1
- 239000000126 substance Substances 0.000 claims 1
- 239000012535 impurity Substances 0.000 abstract description 7
- 230000009286 beneficial effect Effects 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 10
- 239000010410 layer Substances 0.000 description 10
- 229960004693 tenofovir disoproxil fumarate Drugs 0.000 description 8
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 238000013517 stratification Methods 0.000 description 5
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 4
- 208000031886 HIV Infections Diseases 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 208000037357 HIV infectious disease Diseases 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 229960000643 adenine Drugs 0.000 description 3
- 231100000025 genetic toxicology Toxicity 0.000 description 3
- 230000001738 genotoxic effect Effects 0.000 description 3
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- SDQCGKJCBWXRMK-UHFFFAOYSA-N propan-2-yl 4-methylbenzenesulfonate Chemical compound CC(C)OS(=O)(=O)C1=CC=C(C)C=C1 SDQCGKJCBWXRMK-UHFFFAOYSA-N 0.000 description 3
- 238000005070 sampling Methods 0.000 description 3
- 239000003643 water by type Substances 0.000 description 3
- 229930024421 Adenine Natural products 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 238000004140 cleaning Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 238000005457 optimization Methods 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 235000002639 sodium chloride Nutrition 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 229960001355 tenofovir disoproxil Drugs 0.000 description 2
- JFVZFKDSXNQEJW-CQSZACIVSA-N tenofovir disoproxil Chemical compound N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N JFVZFKDSXNQEJW-CQSZACIVSA-N 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- HAKFWHINKUNSIR-UHFFFAOYSA-N CP(O)(O)=O.[O] Chemical compound CP(O)(O)=O.[O] HAKFWHINKUNSIR-UHFFFAOYSA-N 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 241000725303 Human immunodeficiency virus Species 0.000 description 1
- 102100034343 Integrase Human genes 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- QOSMNYMQXIVWKY-UHFFFAOYSA-N Propyl levulinate Chemical compound CCCOC(=O)CCC(C)=O QOSMNYMQXIVWKY-UHFFFAOYSA-N 0.000 description 1
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 1
- XNKLLVCARDGLGL-JGVFFNPUSA-N Stavudine Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1C=C[C@@H](CO)O1 XNKLLVCARDGLGL-JGVFFNPUSA-N 0.000 description 1
- OATWCNSODQAOQC-UHFFFAOYSA-N [SiH4].Br Chemical compound [SiH4].Br OATWCNSODQAOQC-UHFFFAOYSA-N 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 230000000798 anti-retroviral effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- NLTCPNKKJDMJQD-UHFFFAOYSA-N chloromethyl 2-methylpropyl carbonate Chemical compound CC(C)COC(=O)OCCl NLTCPNKKJDMJQD-UHFFFAOYSA-N 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 210000003298 dental enamel Anatomy 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 229960001627 lamivudine Drugs 0.000 description 1
- JTEGQNOMFQHVDC-NKWVEPMBSA-N lamivudine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 238000007867 post-reaction treatment Methods 0.000 description 1
- RUOJZAUFBMNUDX-UHFFFAOYSA-N propylene carbonate Chemical class CC1COC(=O)O1 RUOJZAUFBMNUDX-UHFFFAOYSA-N 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229960002668 sodium chloride Drugs 0.000 description 1
- 229960001203 stavudine Drugs 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 229960002555 zidovudine Drugs 0.000 description 1
- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 description 1
Classifications
-
- 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 Table
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a kind of preparation method of tenofovir dipivoxil.Specifically, the present invention relates to a kind of method for preparing tenofovir dipivoxil of industrial production rank, this method improves reaction yield, reduces impurity, simple easily manipulation, beneficial to industrial expanding production.
Description
Technical field
The present invention relates to a kind of other method for preparing and purifying tenofovir dipivoxil of technical grade.
Background technology
Tenofovir disoproxil fumarate (tenofovirdisoproxilfumarate, TDF), presses down for nucleotide reverse transcriptase
Preparation, the medicine are approved for individually in the U.S. or are combined with other antiretroviral drugs for treating HIV-1 infection,
Europe approval is used to treat HIV infection, is approved to list in the U.S. in October, 2001, is approved within 2 months 2002 to list in Europe,
In March, 2004 lists in Japan, and approval is used to treat 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 produce drug resistant patient to Lamivudine.In addition, tenofovir disoproxil
The productions such as, Zidovudine more general class reverse transcriptase inhibitor such as Zha Xitading than most of cores for being used for treating HIV infection, stavudine
Raw cytotoxicity is small, has good tolerance to patient.
In the synthetic route of the tenofovir disoproxil fumaric acid of document report, most widely used be with adenine and (R) -1,
After the condensation of 2- propylene carbonates, it is alkylated instead with tolysulfonyl epoxide methyl phosphinylidyne diethylester under lithium reagent effect
Should, finally it is made with bromotrimethylsilane or the de- ethyl of trim,ethylchlorosilane hydrolysis, Phosphation, fumaric acid complex forming salt.But
Respectively step intermediate is purified without abundant in reaction process, so that the impurity for adding reaction in next step is too many, final product low yield；
Each step synthetic reaction condition is complicated, and optimization is inadequate, and the selection of catalyst and usage amount are not analyzed fully, cause a degree of wave
Take.Have the synthetic method that many documents disclose 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 its preparation method, improve purity reduction impurity.
The content of the invention
The technical problem to be solved in the present invention is to provide one kind synthesis (R) -9- [2- (diethyl phosphonyl methoxyl base) third
Base]-adenine method, the reactant such as this method starting material simply easily purchase, the simple controllable, post-reaction treatment of reaction condition
The approach optimization preparation methods such as method is simple, improve yield, beneficial to industrial expanding production.
Technical scheme is as follows：
Present invention offer is a kind of to prepare compound shown in formula (I) or the method for its stereoisomer, the described 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 TN03,1-methyl-2-pyrrolidinone, 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 is：Acetic acid is added after reaction, and dichloro is added after concentration
Methane extracts, organic phase drying, adds acetonitrile stirring after filtering, filtrate concentration, intermediate TN02 is obtained after concentration.
In such scheme, the post-processing approach of the step 3 is：Water is added after reaction, hexamethylene is extracted step by step
Take, collect lower water phase；Water and ethyl acetate are added in water phase, repeatedly extracted again, collects upper organic phase, is done
Intermediate TN04 is obtained after dry, filtering, concentration；The repeatedly extraction is preferably twice.
Preferably, the post-processing approach of the step 4 is：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, compound shown in midbody product formula (I) is obtained after dry.
It is further preferred that the post-processing approach of the step 2 is：Concentrated after reaction, water is added dropwise under cryogenic conditions, when
System collects lower 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, continue to stir, filter after obtain crude product；Obtained crude product is recrystallized with water, filtering, solid are done
Intermediate TN03 is obtained after dry；
Preferred 0-20 DEG C of the cryogenic conditions, the concentration preferably 50% of the sodium hydrate aqueous solution.
In such scheme, the temperature of the stirring is room temperature, preferably 10-30 DEG C.
In a preferable 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, the inventory of tolysulfonyl oxygen methylphosphonic acid diethylester are 40kg；
Step 2, the inventory of bromotrimethylsilane is 48kg；
Step 3, the inventory of 1-methyl-2-pyrrolidinone 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 is 4.3kg, isopropanol solvent 75.6kg.
Preferably, the post-processing approach of the method is respectively
The post-processing approach of step 1 is：Acetic acid 14.9kg is added after reaction, and dichloromethane is first added after concentration
200kg is extracted, organic phase drying, adds the stirring of 24kg acetonitriles after filtering, filtrate concentration, intermediate TN02 is obtained after concentration；
The post-processing approach of step 2 is：Concentrated after reaction, 20kg water is added dropwise under the conditions of 0-20 DEG C, when system is without substantially putting
Water 100kg and ethyl acetate 80kg are directly added into after heat, is extracted, collects lower water phase, it is water-soluble with 50% sodium hydroxide
It is 3-5 that liquid, which adjusts pH, continue to stir, filter after obtain crude product；By obtained crude product 300kg water, heat temperature raising reflux, carry out
Recrystallization, intermediate TN03 is obtained after filtering, solid drying；
The post-processing approach of step 3 is：24kg water and 55.3kg hexamethylenes, stirring are added after reaction, carries out first time extraction
Take, collect lower water phase；Add 36kg hexamethylenes and carry out second of extraction, collect lower water phase；Solvent is converted, with 30kg water
It is added to 96kg ethyl acetate in water phase, carries out third time extraction, collects 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 is：Product crude product is obtained by filtration after reaction, by 40kg methyl tertiary butyl ether(MTBE)s and 15kg
Ethyl acetate is added in crude product, stirs, and filtering, compound shown in midbody product formula (I) is obtained after dry.
It is highly preferred that the step of further including in filtration step in the post-processing approach with eluent solvent filter cake, described
Solvent used in rinsing step in step 1 is selected from dichloromethane, 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
Spend for 40-60 DEG C.
Advantageous effect of the invention
Compared with prior art, the technical solution of compound has the following advantages shown in present invention preparation formula (I)：
Compared with the prior art, inventory of the invention is conventional extraction, recrystallization for kilogram rank, post-processing approach
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 be not detected by the toxic impurities, the post processing of reaction is simple, which is easy to industrial expanding production.
Brief description of the drawings
Fig. 1 is that (retention time is for the HPLC collection of illustrative plates of the tenofovir disoproxil fumarate that the method for the present invention is prepared
23.180min)。
Embodiment
It is used to further describe the present invention with reference to embodiments, but these embodiments are not intended to limit the scope of the invention.
The experimental method of actual conditions is not specified 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 determined by nuclear magnetic resonance (NMR) or/and mass spectrum (MS).NMR displacements (δ) are with 10-6
(ppm) unit provides.The measure of NMR is to use BrukerAVANCE-400 nuclear magnetic resonance spectrometers, and measure 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- hydroxypropyls) adenine (TN01) 20kg are sequentially added
In 200L glass-lined reactors, lower addition tert-butyl alcohol magnesium 19.4kg is stirred, stirring is finished, is heated to 60~80 DEG C, slowly
Add tolysulfonyl oxygen methylphosphonic acid diethylester 40kg, 2~4h of insulated and stirred, sampling HPLC monitorings.
30~50 DEG C are cooled to, adds 14.9kg acetic acid, nothing is concentrated under reduced pressure into and substantially distillates.25~35 DEG C are cooled to, is added
Enter 200kg dichloromethane, agitation and dilution is transferred in 300L glass-lined reactors, adds 18kg saturated nacl aqueous solutions, stirring
3h, is cooled to 0 DEG C of insulated and stirred 2h.Filter, filter cake 50kg eluent methylene chlorides.50kg anhydrous sodium sulfates are added, are fully stirred
Mix, dry more than 12h.
Filter, filtrate decompression is concentrated into be gone out without obvious cut.24kg acetonitriles are added, stirring is opened, is concentrated under reduced pressure into without bright
Aobvious cut, which goes out, obtains TN02.
HPLC purity is 85.5%.
Step 2, the preparation of intermediate TN03
200L glass-lined reactors equipped with TN02 are cooled to 0 DEG C, connect device for absorbing tail gas, start that 48kg front threes are added dropwise
Bromide silane, heat release is violent during dropwise addition, and temperature is no more than 60 DEG C in control, and drop finishes, heat temperature raising, temperature 60~80 in control
DEG C, stir 10h, sampling HPLC monitorings.
It is concentrated under reduced pressure into after the reaction was complete and goes out without obvious cut, continue to be cooled to interior 0~20 DEG C of temperature, it is pure starts dropwise addition 20kg
Change water；When system is pumped into 100kg purified waters without obvious heat release and then directly.Reaction solution is transferred in 300L retort, is added
Enter 80kg ethyl acetate, stir 30min, stratification, collects water layer, and the 300L enamels that water layer is first transferred to cleaning react
In tank, stirring is opened, is cooled to interior 0~20 DEG C of temperature, started that prepared 50% sodium hydrate aqueous solution is slowly added dropwise, adjust pH
To 3~5, adjusting finishes, and stirs 2h.Rejection filter can obtain TN03 crude products.
In 500L glass-lined reactors, the purified water of 300kg is added, opens stirring, adds TN03 crude products, heat temperature raising
Flow back 1h.Then 0 DEG C, 3~6h of insulated and stirred is cooled to again, rejection filter.Filter cake grinds even paving disk, is put into heated-air circulation oven dry
After 24~36h, rewinding is weighed, calculated yield；It can obtain TN03.
HPLC purity is 99.5%, and two step yields are 64%.
Step 3, the preparation of intermediate TN04
1-methyl-2-pyrrolidinone 60kg and 12kg intermediates TN03 is added in 200L glass-lined reactors.Open stirring,
Add triethylamine 12kg.50~70 DEG C of temperature in heat temperature raising control, adds chloromethyl propylene carbonate 33kg.Finish, be warming up to
Interior 50~70 DEG C of 6~10h of insulated and stirred of temperature, sampling HPLC monitorings.
10~30 DEG C are cooled to after the reaction was complete, adds 24kg purified waters.55.3kg hexamethylenes are added in 500L retort
Alkane, opens stirring, reaction solution is transferred in 500L retort from 200L retort, stirs 15min, stratification, is collected
Lower floor；36kg n-hexanes are added in 500L retort, open stirring, then lower aqueous layer is transferred in retort and is stirred
15min, stratification, collects lower aqueous layer.
The water layer of collection is transferred in 500L retort, adds 30kg purified waters, adds 96kg ethyl acetate, stirring
15min, stratification, collects upper strata；30kg ethyl acetate is added into 500L retort, opens stirring, then by lower aqueous layer
It is transferred in the retort, stirs 15min, stratification, collects upper strata, combined ethyl acetate organic layer is in 500L retort
In, the stirring of 500L retort is opened, sodium-chloride water solution will have been prepared and added into the retort, stirs 15min, stands and divides
Layer, discards lower aqueous layer, obtains ethyl acetate layer.Ethyl acetate layer is transferred in the 300L glass-lined reactors of cleaning, added
Enter the drying of 12kg anhydrous sodium sulfates.
Filter, filter cake is eluted with 9kg~27kg ethyl acetate.Filtrate is pumped into retort, is concentrated under reduced pressure into no cut and is gone out,
It can obtain TN04.
HPLC purity is 80.2%.
Step 4, the preparation of compound shown in formula (I)
75.6kg isopropanols are pumped into, open 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, 3~8h of insulated and stirred of temperature, rejection filter can obtain tenofovir disoproxil fumarate crude product.
40kg methyl tertiary butyl ether(MTBE)s are added in 300L retort, 15kg ethyl acetate, opens stirring.Fumaric acid is added to replace
Nuo Fuwei dipivoxil crude products, 10~30 DEG C of 2~4h of stirring, rejection filter.Filter cake is washed with 50~80kg methyl tertiary butyl ether(MTBE)s, is depressurized
Dry to can obtain tenofovir disoproxil fumarate highly finished product, HPLC purity is 99.2%, yield 45.8%；Through inspection
Survey, product chirality reaches 100%, and what is more important genotoxicity impurity p-methyl benzenesulfonic acid isopropyl ester does not detect, HPLC collection of illustrative plates
See Fig. 1, its retention time is 23.180min, peak area relative scale is 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 (9)
1. a kind of prepare compound shown in formula (I) or the method for its stereoisomer, the described method 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 TN03,1-methyl-2-pyrrolidinone, 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)；
It is characterized in that, the post-processing approach of the step 1 is：Acetic acid is added after reaction, and dichloromethane is added after concentration
Extraction, organic phase drying, adds acetonitrile stirring after filtering, filtrate concentration, intermediate TN02 is obtained after concentration.
2. the method as described in claim 1, it is characterised in that the post-processing approach of the step 3 is：After reaction add water,
Hexamethylene is extracted step by step, collects lower water phase；Water and ethyl acetate are added in water phase, repeatedly extracted again
Take, collect upper organic phase, intermediate TN04 is obtained after dry, filtering, concentration；The repeatedly extraction is preferably twice.
3. method as claimed in claim 2, it is characterised in that the post-processing approach of the step 4 is：Filtered after reaction
To product crude product, methyl tertiary butyl ether(MTBE) and ethyl acetate are added in crude product, stirred, filtered, intermediate production is obtained after dry
Compound shown in thing formula (I).
4. method as claimed in claim 3, it is characterised in that the post-processing approach of the step 2 is：Concentrated after reaction, it is low
Water is added dropwise under the conditions of temperature, water and ethyl acetate extraction are directly added into after system is without obvious heat release, lower water phase is collected, with one
Determining the sodium hydrate aqueous solution of concentration, to adjust pH be 3-5, continue to stir, filter after obtain crude product；By obtained crude product water weight
Crystallization, intermediate TN03 is obtained after filtering, solid drying；
Preferred 0-20 DEG C of the cryogenic conditions, the concentration preferably 50% of the sodium hydrate aqueous solution.
5. such as the method any one of claim 1-4, it is characterised in that the temperature of the stirring is room temperature, preferably 10-
30℃。
6. the method as described in claim 1, it is characterised in that the method is
The inventory of starting material TN01 is 20kg in step 1, the inventory of N,N-dimethylformamide is 42.5kg, tertiary fourth
Magnesium alkoxide 19.4kg, the inventory of tolysulfonyl oxygen methylphosphonic acid diethylester are 40kg；
Step 2, the inventory of bromotrimethylsilane is 48kg；
Step 3, the inventory of 1-methyl-2-pyrrolidinone is 60kg, the inventory of triethylamine is 12kg, chloromethyl propylene carbonate
Inventory be 33kg；
Step 4, the inventory of fumaric acid is 4.3kg, isopropanol solvent 75.6kg.
7. method as claimed in claim 6, it is characterised in that the post-processing approach of the method is respectively
The post-processing approach of step 1 is：Acetic acid 14.9kg is added after reaction, and dichloromethane 200kg extractions are first added after concentration
Take, organic phase drying, add the stirring of 24kg acetonitriles after filtering, filtrate concentration, intermediate TN02 is obtained after concentration；
The post-processing approach of step 2 is：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 water phase, with 50% sodium hydrate aqueous solution tune
Section pH is 3-5, continue to stir, filter after crude product；By obtained crude product 300kg water, heat temperature raising reflux, tied again
Crystalline substance, intermediate TN03 is obtained after filtering, solid drying；
The post-processing approach of step 3 is：24kg water and 55.3kg hexamethylenes, stirring are added after reaction, carries out first time extraction,
Collect lower water phase；Add 36kg hexamethylenes and carry out second of extraction, collect lower 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 is：Product crude product is obtained by filtration after reaction, by 40kg methyl tertiary butyl ether(MTBE)s and 15kg acetic acid
Ethyl ester is added in crude product, stirs, and filtering, compound shown in midbody product formula (I) is obtained after dry.
8. the method for claim 7, it is characterised in that further included in the filtration step in the post-processing approach with molten
Agent elutes the step of filter cake, and solvent used in the rinsing step in the step 1 is selected from dichloromethane, the leaching in step 3
Wash solvent used in step and be selected from ethyl acetate, solvent used in the rinsing step in step 4 is selected from methyl tertbutyl
Ether.
9. method as claimed in claim 8, it is characterised 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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| 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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| 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 |
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| 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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