CN105622671A - Preparing method for realizing industrial mass production of tenofovir disoproxil fumarate - Google Patents
Preparing method for realizing industrial mass production of tenofovir disoproxil fumarate Download PDFInfo
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- CN105622671A CN105622671A CN201610106069.1A CN201610106069A CN105622671A CN 105622671 A CN105622671 A CN 105622671A CN 201610106069 A CN201610106069 A CN 201610106069A CN 105622671 A CN105622671 A CN 105622671A
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- tenofovir
- disoproxil fumarate
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- acid
- adenine
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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 claims abstract description 49
- 229960004693 tenofovir disoproxil fumarate Drugs 0.000 title claims abstract description 19
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 8
- 238000000034 method Methods 0.000 title abstract description 7
- 229960004556 tenofovir Drugs 0.000 claims abstract description 29
- 229930024421 Adenine Natural products 0.000 claims abstract description 13
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 claims abstract description 13
- 229960000643 adenine Drugs 0.000 claims abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 11
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims abstract description 9
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 15
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 230000006837 decompression Effects 0.000 claims description 9
- 238000004821 distillation Methods 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 7
- 238000003756 stirring Methods 0.000 claims description 7
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 238000001514 detection method Methods 0.000 claims description 6
- 238000000605 extraction Methods 0.000 claims description 6
- 239000000706 filtrate Substances 0.000 claims description 6
- 239000004519 grease Substances 0.000 claims description 6
- 238000000926 separation method Methods 0.000 claims description 6
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 5
- 239000003054 catalyst Substances 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 5
- 239000011777 magnesium Substances 0.000 claims description 5
- 229910052749 magnesium Inorganic materials 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
- YFLBCDPISIYMHR-UHFFFAOYSA-N C(OCCl)(OC(C)(C)OOCCCC)=O Chemical compound C(OCCl)(OC(C)(C)OOCCCC)=O YFLBCDPISIYMHR-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 239000011230 binding agent Substances 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- 239000012065 filter cake Substances 0.000 claims description 4
- 239000001530 fumaric acid Substances 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 3
- 239000012043 crude product Substances 0.000 claims description 3
- 230000018044 dehydration Effects 0.000 claims description 3
- 238000006297 dehydration reaction Methods 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims description 2
- 238000005903 acid hydrolysis reaction Methods 0.000 claims description 2
- 239000012445 acidic reagent Substances 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 claims description 2
- 239000000347 magnesium hydroxide Substances 0.000 claims description 2
- 229910001862 magnesium hydroxide Inorganic materials 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 abstract 3
- 230000009286 beneficial effect Effects 0.000 abstract 1
- 238000007670 refining Methods 0.000 abstract 1
- 238000007086 side reaction Methods 0.000 abstract 1
- 229960001355 tenofovir disoproxil Drugs 0.000 abstract 1
- 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 abstract 1
- 230000015572 biosynthetic process Effects 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- 208000030507 AIDS Diseases 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- 108020005202 Viral DNA Proteins 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- MJZYTEBKXLVLMY-RXMQYKEDSA-N (2r)-1-(6-aminopurin-9-yl)propan-2-ol Chemical compound N1=CN=C2N(C[C@H](O)C)C=NC2=C1N MJZYTEBKXLVLMY-RXMQYKEDSA-N 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- BDJRBEYXGGNYIS-UHFFFAOYSA-N Nonanedioid acid Natural products OC(=O)CCCCCCCC(O)=O BDJRBEYXGGNYIS-UHFFFAOYSA-N 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 238000011225 antiretroviral therapy Methods 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 238000010668 complexation reaction Methods 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 208000012839 conversion disease Diseases 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000011026 diafiltration Methods 0.000 description 1
- XQRLCLUYWUNEEH-UHFFFAOYSA-N diphosphonic acid Chemical compound OP(=O)OP(O)=O XQRLCLUYWUNEEH-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical class [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 208000002672 hepatitis B Diseases 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 239000012567 medical material Substances 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- -1 nucleoside acids Chemical class 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 229940048102 triphosphoric acid Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
- C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
-
- 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)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
Abstract
The invention relates to a preparing method for realizing industrial mass production of tenofovir disoproxil fumarate.The preparing method includes the following steps of preparing (R)-9-[2-(diethoxyphosphonylmethoxy) propyl] adenine, synthesizing tenofovir, refining tenofovir, dewatering tenofovir, synthesizing tenofovir disoproxil and synthesizing tenofovir disoproxil fumarate.The technical scheme is easy to operate, selected reagents are low in price, the number of side reactions is small, the yield is high, few three wastes are generated in the reaction process, and the preparing method is beneficial for environment protection and suitable for industrial mass production.
Description
Technical field
The invention belongs to pharmaceutical technology field, the preparation method relating to a kind of medical material tenofovir disoproxil fumarate for acquired immune deficiency syndrome (AIDS) and treating hepatitis B field.
Background technology
Tenofovir disoproxil fumarate is a kind of new oral broad-spectrum antiviral drug, it it is the ester prodrug thereof of tenofovir, belong to novel nucleoside acids reverse transcriptase inhibitors, chemical name is 5-(((1R)-2 (6-amino-9H-purine-9-base)-1-methyl ethoxy) methyl)-2,4,6,8-tetra-oxygen-5-phospha Azelaic Acid diisopropyl ester-5-oxide fumarates, English name tenofovirdisoproxilfumarate. It is hydrolyzed to tenofovir after this product oral administration, then by cell kinase phosphorylation, generate the metabolite tenofovir diphosphonic acid with pharmacologically active, the latter's acid competition sweet with 5 '-triphosphoric acid deoxidation gland, participate in the synthesis of viral DNA, after entering viral DNA, owing to lacking 3 '-OH groups, thus result in DNA prolongation to be obstructed, and then the duplication of blocking virus. SFDA ratifies tenofovir disoproxil fumarate sheet in China's import registration on June 18th, 2008. It is listed in the free AIDS antiretroviral therapy Second line Drug of country at present at home.
Existing having applied for or in disclosed tenofovir disoproxil fumarate patent, synthesis technique is complex, and yield is relatively low, environmental pollution is big, improper industrialized great production.
Summary of the invention
In order to overcome deficiency of the prior art, the invention provides a kind of can the preparation method of industrialized great production tenofovir disoproxil fumarate, improve purity and the yield of tenofovir disoproxil fumarate, the needs of industrialized great production can be met.
Present inventor is by substantial amounts of experiment, constantly grope, the preparation and purification of tenofovir disoproxil fumarate are realized by four steps, the technical scheme adopted is: first with (R)-9-(2-hydroxypropyl) adenine for raw material, (R)-9-[2-(diethoxy phosphonylmethoxy base) propyl group] adenine is generated with tolysulfonyl oxygen methylphosphonic acid diethylester alkylation, adding hydrobromic acid makes the de-ethyl of (R)-9-[2-bis-(ethyl phosphonylmethoxy base) propyl group] adenine prepare tenofovir, react with chloromethyl butylperoxyisopropyl carbonate again, so as to obtain tenofovir disoproxil fumarate with fumaric acid complexation after post processing.
Synthesis route is as follows:
Synthesis step is as follows:
The first step: by N, dinethylformamide, (R)-9-2-(hydroxypropyl) adenine and base catalyst, stirring, drip tolysulfonyl oxygen methylphosphonic acid diethylester, thin layer TLC detection reacts completely, add acid reagent, regulate pH value to 6.5��7.5, add methylene chloride reflux, separation and Extraction, filter, decompression distillation, obtain (R)-9-[2-(diethoxy phosphonylmethoxy base) propyl group] adenine. Base catalyst can be: tert-butyl alcohol magnesium.
Second step: (R)-9-[2-(diethoxy phosphonylmethoxy base) propyl group] adenine is added in reaction vessel, add hydrobromic acid hydrolysis, backflow, thin layer TLC detection reacts completely, decompression distillation, add dichloromethane and water, separation and Extraction, alkaline reagent regulates pH value to 2.0 ~ 3.5, crystallize of lowering the temperature, filter, obtain tenofovir crude product. Add water, dissolve, crystallize of lowering the temperature, filters, obtains tenofovir fine work. Drying under reduced pressure, obtains tenofovir. Alkaline reagent can be magnesium hydroxide, potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide.
3rd step: tenofovir is added N-Methyl pyrrolidone and acid binding agent reaction, stirring, heating, drip chloromethyl butylperoxyisopropyl carbonate, insulated and stirred is reacted, TLC detection reacts completely, and adds ethyl acetate, filters, wash by ethyl acetate, filtrate adds suitable quantity of water washing, adds anhydrous sodium sulfate dehydration, filters. Filtrate, through decompression distillation, obtains tenofovir dipivoxil grease. Acid binding agent can be triethylamine, ethylenediamine.
4th step: tenofovir dipivoxil grease adds isopropanol and fumaric acid, heats up and makes it dissolve, and cooling crystallization filters, the appropriate washed with isopropyl alcohol of filter cake, obtains tenofovir disoproxil fumarate.
Present invention advantage compared with prior art is in that: the preparation method of key intermediate PMPA (tenofovir) has been reformed, has both decreased pollution, reduced again cost. Use hydrobromic acid as de-ethyl phosphonic acid ester raw material through our process route of research. Hydrobromic acid is prone to buy convenient transport, and practical effect is desirable, and product yield is high. Catalyst employs that character is soft and industrialized tert-butyl alcohol magnesium, and reaction conversion ratio is high, improves yield. New technology only synthesizes through four steps so that operation simplifies, and decreases pollution, and yield improves, and cost reduces; Synthesis technique is innovated, and obtains new crystal form, patent applied for.
Detailed description of the invention
Embodiment 1:(1) preparation of (R)-9-[2-(diethoxy phosphonylmethoxy base) propyl group] adenine
DMF 100g, (R)-9-2-(hydroxypropyl is added in reaction vessel) adenine 30g, tert-butyl alcohol magnesium 8g and tolysulfonyl oxygen methylphosphonic acid diethylester 90g, stirring, heating is to 90 ~ 95 DEG C, insulated and stirred 8 hours, terminates reaction, obtains reactant. It is cooled to room temperature, adds glacial acetic acid, regulate pH value to pH6.5��7.5. Add methylene chloride q, reflux 5 hours, separation and Extraction dichloromethane layer, filters, washed with dichloromethane, merges diafiltration liquid, decompression distillation, obtain thick liquid. (R)-9-2-(hydroxypropyl) mol ratio of adenine and tert-butyl alcohol magnesium is: 1:0.6.
Embodiment 2:(2) tenofovir synthesis
Being added by (R)-9-[2-(diethoxy phosphonylmethoxy base) propyl group] adenine in reaction vessel, add hydrobromic acid 450g, stirring, temperature rising reflux 10 hours, reaction terminates. Decompression distillation, is cooled to room temperature, adds dichloromethane and water is appropriate, separation and Extraction dichloromethane layer, and the sodium hydroxide solution with 20% regulates pH3.0, is cooled to 10 DEG C, crystallize 12 hours, filters, obtains tenofovir crude product. Adding suitable quantity of water, heating, to making solid dissolve, is cooled to 10 DEG C, crystallize 12 hours, filters, obtains tenofovir fine work. 55 DEG C of drying under reduced pressure, obtain tenofovir dry product.
Embodiment 3:(3) synthesis of tenofovir dipivoxil
Adding N-Methyl pyrrolidone 300g, triethylamine 90g and tenofovir 25g, stirring in reaction vessel, heating, to 70 DEG C, drips chloromethyl butylperoxyisopropyl carbonate 40g, and insulated and stirred is reacted 10 hours, stopped reaction. Add appropriate ethyl acetate, filter, with appropriate ethyl acetate washing filtering residue, merge washing filtrate, add suitable quantity of water and wash 3 times, add anhydrous sodium sulfate dehydration, filter. Filtrate, through 55 DEG C of decompression distillations, is evaporated, obtains tenofovir dipivoxil grease. The mol ratio of tenofovir and triethylamine is: 1:10.
Embodiment 4:(4) synthesis of tenofovir disoproxil fumarate
Tenofovir dipivoxil grease is added appropriate isopropanol and 105g fumaric acid, heats up and make it dissolve, be cooled to 10 DEG C, crystallize 12 hours, filters, the appropriate washed with isopropyl alcohol of filter cake, obtains tenofovir disoproxil fumarate solid. Filter cake, through 50 DEG C of drying under reduced pressure, obtains tenofovir disoproxil fumarate.
Claims (1)
1. one kind can the preparation method of industrialized great production tenofovir disoproxil fumarate, it is characterised in that realized by following steps:
The first step: by N, dinethylformamide, (R)-9-2-(hydroxypropyl) adenine and base catalyst, stirring, drip tolysulfonyl oxygen methylphosphonic acid diethylester, thin layer TLC detection reacts completely, add acid reagent, regulate pH value to 6.5��7.5, add methylene chloride reflux, separation and Extraction, filter, decompression distillation, obtain (R)-9-[2-(diethoxy phosphonylmethoxy base) propyl group] adenine; Base catalyst can be: tert-butyl alcohol magnesium;
Second step: added by (R)-9-[2-(diethoxy phosphonylmethoxy base) propyl group] adenine in reaction vessel, adds hydrobromic acid hydrolysis, backflow, thin layer TLC detection reacts completely, decompression distillation, adds dichloromethane and water, separation and Extraction, alkaline reagent regulates pH value to 2.0 ~ 3.5, crystallize of lowering the temperature, filter, obtain tenofovir crude product, add water, dissolve, crystallize of lowering the temperature, filter, obtain tenofovir fine work, drying under reduced pressure, obtain tenofovir; Alkaline reagent can be magnesium hydroxide, potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide;
3rd step: tenofovir is added N-Methyl pyrrolidone and acid binding agent reaction, stirring, heating, dropping chloromethyl butylperoxyisopropyl carbonate, insulated and stirred is reacted, and TLC detection reacts completely, add ethyl acetate, filtering, wash by ethyl acetate, filtrate adds suitable quantity of water washing, add anhydrous sodium sulfate dehydration, filtering, filtrate, through decompression distillation, obtains tenofovir dipivoxil grease; Acid binding agent can be triethylamine, ethylenediamine;
4th step: tenofovir dipivoxil grease adds isopropanol and fumaric acid, heats up and makes it dissolve, and cooling crystallization filters, the appropriate washed with isopropyl alcohol of filter cake, obtains tenofovir disoproxil fumarate.
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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 |
CN108586532A (en) * | 2018-04-03 | 2018-09-28 | 山东科兴生物制品有限公司 | A kind of preparation method of tenofovir disoproxil fumarate |
CN111943982A (en) * | 2020-08-14 | 2020-11-17 | 山东罗欣药业集团股份有限公司 | Synthesis process of antiviral drug |
CN113214322A (en) * | 2021-04-30 | 2021-08-06 | 山东立新制药有限公司 | Green and environment-friendly preparation method of tenofovir |
-
2016
- 2016-02-26 CN CN201610106069.1A patent/CN105622671A/en active Pending
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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 |
CN108586532A (en) * | 2018-04-03 | 2018-09-28 | 山东科兴生物制品有限公司 | A kind of preparation method of tenofovir disoproxil fumarate |
CN108586532B (en) * | 2018-04-03 | 2020-05-08 | 科兴生物制药股份有限公司 | Preparation method of tenofovir disoproxil fumarate |
CN111943982A (en) * | 2020-08-14 | 2020-11-17 | 山东罗欣药业集团股份有限公司 | Synthesis process of antiviral drug |
CN111943982B (en) * | 2020-08-14 | 2023-10-10 | 山东罗欣药业集团股份有限公司 | Synthesis process of antiviral drug |
CN113214322A (en) * | 2021-04-30 | 2021-08-06 | 山东立新制药有限公司 | Green and environment-friendly preparation method of tenofovir |
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