CN106632483A - Tenofovir disoproxil preparation method - Google Patents
Tenofovir disoproxil preparation method Download PDFInfo
- Publication number
- CN106632483A CN106632483A CN201611184011.5A CN201611184011A CN106632483A CN 106632483 A CN106632483 A CN 106632483A CN 201611184011 A CN201611184011 A CN 201611184011A CN 106632483 A CN106632483 A CN 106632483A
- Authority
- CN
- China
- Prior art keywords
- preparation
- tenofovir
- reaction
- ionic liquid
- butylperoxyisopropyl carbonate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 30
- 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 title abstract 5
- 229960001355 tenofovir disoproxil Drugs 0.000 title abstract 5
- 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 claims abstract description 48
- 229960004556 tenofovir Drugs 0.000 claims abstract description 43
- 239000002608 ionic liquid Substances 0.000 claims abstract description 14
- 230000035484 reaction time Effects 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 34
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 24
- -1 1- butyl-pyridinium tetrafluoroborates Chemical class 0.000 claims description 17
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 16
- 239000002253 acid Substances 0.000 claims description 15
- 239000011230 binding agent Substances 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 9
- 239000012141 concentrate Substances 0.000 claims description 8
- 239000003208 petroleum Substances 0.000 claims description 8
- 239000000376 reactant Substances 0.000 claims description 8
- 238000003810 ethyl acetate extraction Methods 0.000 claims description 7
- 239000012074 organic phase Substances 0.000 claims description 7
- ZWIYUVLGMPNEOV-UHFFFAOYSA-N CCCCOOC(C)(C)OC(=O)OC Chemical class CCCCOOC(C)(C)OC(=O)OC ZWIYUVLGMPNEOV-UHFFFAOYSA-N 0.000 claims description 5
- 150000002148 esters Chemical class 0.000 claims description 3
- LLDBOMNUMJVCBX-UHFFFAOYSA-N 2-butylperoxypropan-2-yl hydrogen carbonate Chemical compound CCCCOOC(C)(C)OC(O)=O LLDBOMNUMJVCBX-UHFFFAOYSA-N 0.000 claims description 2
- DLYAOBADVUJCDM-UHFFFAOYSA-N C[C]C(C)C Chemical class C[C]C(C)C DLYAOBADVUJCDM-UHFFFAOYSA-N 0.000 claims description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 2
- 238000007867 post-reaction treatment Methods 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- UILVJNNINVCMEX-UHFFFAOYSA-N C(OCBr)(OC(C)(C)OOCCCC)=O Chemical compound C(OCBr)(OC(C)(C)OOCCCC)=O UILVJNNINVCMEX-UHFFFAOYSA-N 0.000 claims 1
- NEHMKBQYUWJMIP-UHFFFAOYSA-N anhydrous methyl chloride Natural products ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 claims 1
- NEHMKBQYUWJMIP-OUBTZVSYSA-N chloromethane Chemical group Cl[13CH3] NEHMKBQYUWJMIP-OUBTZVSYSA-N 0.000 claims 1
- XCVNDBIXFPGMIW-UHFFFAOYSA-N n-ethylpropan-1-amine Chemical compound CCCNCC XCVNDBIXFPGMIW-UHFFFAOYSA-N 0.000 claims 1
- 239000003444 phase transfer catalyst Substances 0.000 abstract description 7
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 abstract description 4
- JHYNXXBAHWPABC-UHFFFAOYSA-N chloromethyl propan-2-yl carbonate Chemical class CC(C)OC(=O)OCCl JHYNXXBAHWPABC-UHFFFAOYSA-N 0.000 abstract 1
- 239000002085 irritant Substances 0.000 abstract 1
- 231100000021 irritant Toxicity 0.000 abstract 1
- 238000000034 method Methods 0.000 description 10
- 238000003756 stirring Methods 0.000 description 7
- YFLBCDPISIYMHR-UHFFFAOYSA-N C(OCCl)(OC(C)(C)OOCCCC)=O Chemical compound C(OCCl)(OC(C)(C)OOCCCC)=O YFLBCDPISIYMHR-UHFFFAOYSA-N 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 238000010792 warming Methods 0.000 description 6
- 238000001035 drying Methods 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 229960004693 tenofovir disoproxil fumarate Drugs 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000012805 post-processing Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 3
- 241000725303 Human immunodeficiency virus Species 0.000 description 3
- 230000031709 bromination Effects 0.000 description 3
- 238000005893 bromination reaction Methods 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 2
- XHIHMDHAPXMAQK-UHFFFAOYSA-N bis(trifluoromethylsulfonyl)azanide;1-butylpyridin-1-ium Chemical compound CCCC[N+]1=CC=CC=C1.FC(F)(F)S(=O)(=O)[N-]S(=O)(=O)C(F)(F)F XHIHMDHAPXMAQK-UHFFFAOYSA-N 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- DFZIVBSSQCEWNU-UHFFFAOYSA-N (1-bromo-2-methylpropan-2-yl) hydrogen carbonate Chemical compound BrCC(C)(C)OC(O)=O DFZIVBSSQCEWNU-UHFFFAOYSA-N 0.000 description 1
- KRFCDKQQGFITOH-UHFFFAOYSA-N (1-chloro-2-methylpropan-2-yl) hydrogen carbonate Chemical compound ClCC(C)(C)OC(O)=O KRFCDKQQGFITOH-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- TVZRAEYQIKYCPH-UHFFFAOYSA-N 3-(trimethylsilyl)propane-1-sulfonic acid Chemical compound C[Si](C)(C)CCCS(O)(=O)=O TVZRAEYQIKYCPH-UHFFFAOYSA-N 0.000 description 1
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 208000033962 Fontaine progeroid syndrome Diseases 0.000 description 1
- 229940126656 GS-4224 Drugs 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 125000005708 carbonyloxy group Chemical group [*:2]OC([*:1])=O 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 229940125532 enzyme inhibitor Drugs 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 150000003009 phosphonic acids Chemical class 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- RKHXQBLJXBGEKF-UHFFFAOYSA-M tetrabutylphosphanium;bromide Chemical compound [Br-].CCCC[P+](CCCC)(CCCC)CCCC RKHXQBLJXBGEKF-UHFFFAOYSA-M 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000001291 vacuum drying Methods 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)
Abstract
The invention discloses a tenofovir disoproxil preparation method. The tenofovir disoproxil preparation method includes enabling tenofovir to react with halogenated chloromethyl isopropyl carbonate in ionic liquid in the presence of acid-capturers so as to obtain tenofovir disoproxil. The tenofovir disoproxil preparation method has the advantages that a great quantity of irritant N-methyl pyrrolidone and phase transfer catalysts are avoided, cost and post-treatment workload are both reduced, reaction time is shortened effectively and high yield is achieved.
Description
Technical field
The invention belongs to technical field of medicine synthesis, is related to a kind of preparation method of tenofovir dipivoxil.
Background technology
Tenofovir disoproxil fumarate (Tenofovir Disoproxil Fumarate), is a kind of novel nucleoside
Acids transcripting enzyme inhibitor, the medicine is researched and developed by the lucky Deco in the U.S. (Gilead Sciences) company, main by suppressing
HIV1-RT activity and suppress inhibition of HIV duplication.Before tenofovir disoproxil fumarate tenofovir
Medicine, active with good AntiHIV1 RT activity and HBV, calendar year 2001 Jing U.S. FDA ratifies the infection for treating human immunodeficiency virus.
At present in multiple countries and regions listings such as Canada, Europe, it is answered as the first-line drug for the treatment of HIV with good
Use prospect.The chemical name of tenofovir disoproxil fumarate is (R)-[[2- (6- amino -9H- purine -9- bases) -1- methyl
Ethyoxyl] methyl] phosphonic acids diisopropyl oxygen carbonyloxy group methyl ester fumarate, particular chemical is as follows：
Tenofovir disoproxil fumarate is then sour in fumaric acid generally by tenofovir dipivoxil is first prepared
Change is obtained.
CN101239989B discloses a kind of nucleic acid acid anhydride analog, specifically discloses the preparation side of tenofovir dipivoxil
Method, with tenofovir and chloromethyl isopropyl carbonic acid as raw material, 1-METHYLPYRROLIDONE is solvent to the method, and triethylamine is to tie up
Sour agent prepares tenofovir dipivoxil.Practice finds that the reaction side reaction is more, effective conversion of tenofovir dipivoxil
Rate is less than 60%.And it is larger to post-process purifying difficulty.
CN102453055B discloses a kind of preparation method of tenofovir dipivoxil, and the method uses tetrabutyl phosphonium bromide
, used as phase transfer catalyst, catalytic effect is good, and yield is greatly improved for ammonium, but phase transfer catalyst TBAB consumption
It is excessive, need that using 1～3 equivalent of substrate good result, the use of a large amount of phase transfer catalysts could be obtained so that reaction
Liquid post processing can in a large number separate out solid, wrap up product, and workload is big, and purifying products are difficult, and TBAB have it is right
Skin, respiratory system etc. stimulate toxicity, are unfavorable for the safety of operator.
Therefore, in view of the problem in the preparation process of above-mentioned tenofovir dipivoxil, needs exploitation a kind of more
Safety, yield are higher, post-process simpler method.
The content of the invention
Present invention aim to overcome that being urged using excitant in a large number in the preparation method of existing tenofovir dipivoxil
Not a kind of the problems such as agent, yield be not high and post-processes difficult, there is provided preparation method of tenofovir dipivoxil.
In order to realize the purpose of the present invention, the present invention provides a kind of preparation method of tenofovir dipivoxil, the preparation
Method includes：In the presence of acid binding agent, tenofovir is reacted with halogenated methyl butylperoxyisopropyl carbonate in ionic liquid and is obtained
Tenofovir dipivoxil.
In the present invention, inventor uses ionic liquid as solvent and is applied to tenofovir and halogenated methyl isopropyl carbon
The reaction of acid esters, ionic liquid both also serves as the catalyst for reacting simultaneously as solvent, solves and use in a large number excitant
The problem of solvent N-methyl pyrilidone and a large amount of excitant phase transfer catalyst such as TBABs etc., in production technology
Workload greatly reduces, and is adapted to industrialized production.
In the present invention, in order that reaction more fully, under preferable case, tenofovir and acid binding agent, halogenated methyl
The consumption mol ratio of butylperoxyisopropyl carbonate is 1：3～5：2～4.
Preferably, relative to every gram of tenofovir, the consumption of ionic liquid is 3～5ml.In the present invention, invention human hair
Existing, different ionic liquid has very big otherness for the result of the present invention, it is preferable that ionic liquid is 1- butyl-pyridiniums four
Borofluoride.
In the present invention, the acid binding agent can be conventional organic base or inorganic base, preferably organic base, further
One or more preferably in diethylamine, triethylamine and diisopropylethylamine.
In the present invention, the condition of reaction includes：Reaction temperature is 30～40 DEG C.The condition provided using the present invention, instead
Reaction can be completed between seasonable for 1～3 hour.
Halo refers to halogen substiuted, such as chloro, bromo, iodo in heretofore described halogenated methyl butylperoxyisopropyl carbonate
Light, such as described halogenated methyl butylperoxyisopropyl carbonate can be chloromethyl butylperoxyisopropyl carbonate or bromomethyl isopropyl carbonic acid
Ester.
In the method that the present invention is provided, course of reaction can be monitored according to conventional means, for example LCMS, GCMS, TLC
Deng.
The method that the present invention is provided can adopt after completion of the reaction general post processing mode, obtain corresponding as needed
The compound of purity requirement, for example, post-reaction treatment can be：After reaction terminates, room temperature is cooled to, reactant liquor is poured in water,
Ethyl acetate is extracted, and organic phase washing, anhydrous sodium sulfate drying, reduced pressure concentration, concentrate petroleum ether is recrystallized to give for promise good fortune
Wei dipivoxil.
The preparation method of the tenofovir dipivoxil that the present invention is provided, it is to avoid using a large amount of excitant N- crassitudes
Ketone and phase transfer catalyst, reduce cost, reduce the workload of post processing, and the reaction time effectively shortens and achieves
Good yield.
Specific embodiment
With reference to specific embodiment, the present invention is described in detail.Following examples will be helpful to the technology of this area
Personnel further understand the present invention, but the invention is not limited in any way.It should be pointed out that the ordinary skill to this area
For personnel, without departing from the inventive concept of the premise, some deformations and improvement can also be made.These belong to the present invention
Protection domain.
Preparation example
[BuPy]BF4The synthesis of (1- butyl-pyridinium tetrafluoroborates)
In there-necked flask is dried, 31.6g pyridines, the bromination of n-butane of 68.5g and 100ml acetonitriles is added to be added to
250ml, reaction system is heated to 75 DEG C, and insulated and stirred is reacted 8 hours, and monitoring reaction is finished, and is concentrated under reduced pressure to give pale yellow colored solid
Body, then by solids washed with acetone three times, 40 DEG C of vacuum drying obtain white bromination N- butyl-pyridinium solid for 12 hours
79.6g, yield 92.2%.
Be dried in there-necked flask another, add 0.2mol brominations N- butyl-pyridinium and 0.25mol sodium fluoborates and
50ml acetone is warming up to 40 DEG C, and keeping temperature stirring reaction 24 hours, monitoring reaction is finished, and suction filtration, filtrate reduced in volume is obtained
N- butyl-pyridinium tetrafluoroborate crude products, by crude product dichloromethane is dissolved in, and is filtered, and filtrate reduced in volume obtains weak yellow liquid N-
Butyl-pyridinium tetrafluoroborate 44.2g, yield 94.3%.
1HNMR(400MHz,D2O, DSS external standard), δ 8.75 (d, J=6.8Hz, 2H)；8.46 (t, J=7.6Hz, 1H)；
8.01 (t, J=6.8Hz, 2H)；4.52 (t, J=7.2Hz.2H)；1.97～1.87 (m, 2H) 1.92；1.34(m,2H)；1.32
～1.25 (m, 2H)；0.90(t,3H).
Embodiment 1
The preparation of tenofovir dipivoxil
By tenofovir 28.7g (0.1mol), acid binding agent 40.5g (triethylamine, 0.4mol), chloromethyl butylperoxyisopropyl carbonate
30.5g (0.2mol) and ionic liquid (1- butyl-pyridinium tetrafluoroborates) 100ml are added in reaction flask, are warming up to 40
DEG C stirring reaction 1.5 hours, after reaction terminates, is cooled to room temperature, and reactant liquor is poured in water, ethyl acetate extraction, organic phase water
Wash three times, anhydrous sodium sulfate drying, reduced pressure concentration, concentrate petroleum ether is recrystallized to give tenofovir dipivoxil 46.6g, receive
Rate 89.7%, HPLC purity 99.65%.
Embodiment 2
The preparation of tenofovir dipivoxil
By tenofovir 28.7g (0.1mol), acid binding agent 50.6g (triethylamine, 0.5mol), chloromethyl butylperoxyisopropyl carbonate
45.8g (0.3mol) and ionic liquid (1- butyl-pyridinium tetrafluoroborates) 120ml are added in reaction flask, are warming up to 40
DEG C stirring reaction 1.5 hours, after reaction terminates, is cooled to room temperature, and reactant liquor is poured in water, ethyl acetate extraction, organic phase water
Wash, anhydrous sodium sulfate drying, reduced pressure concentration, concentrate petroleum ether is recrystallized to give tenofovir dipivoxil 47.1g, yield
90.6%, HPLC purity 99.47%.
Embodiment 3
The preparation of tenofovir dipivoxil
By tenofovir 28.7g (0.1mol), acid binding agent 38.8g (diisopropylethylamine, 0.3mol), chloromethyl isopropyl
Carbonic ester 45.8g (0.3mol) and ionic liquid (1- butyl-pyridinium tetrafluoroborates) 120ml are added in reaction flask, are risen
Temperature after reaction terminates, was cooled to room temperature to 40 DEG C of stirring reactions 1.5 hours, and reactant liquor is poured in water, ethyl acetate extraction, is had
Machine is mutually washed, anhydrous sodium sulfate drying, reduced pressure concentration, and concentrate petroleum ether is recrystallized to give tenofovir dipivoxil 46.8g,
Yield 90.1%, HPLC purity 99.83%.
Embodiment 4
The preparation of tenofovir dipivoxil
By tenofovir 28.7g (0.1mol), acid binding agent 40.5g (triethylamine, 0.4mol), chloromethyl butylperoxyisopropyl carbonate
30.5g (0.2mol) and ionic liquid (1- butyl-pyridinium tetrafluoroborates) 100ml are added in reaction flask, are warming up to 50
DEG C stirring reaction 1.5 hours, after reaction terminates, is cooled to room temperature, and reactant liquor is poured in water, ethyl acetate extraction, organic phase water
Wash three times, anhydrous sodium sulfate drying, reduced pressure concentration, concentrate petroleum ether is recrystallized to give tenofovir dipivoxil 37g, yield
71.3%, HPLC purity 99.65%.
Comparative example 1
By tenofovir 28.7g (0.1mol), acid binding agent 40.5g (triethylamine, 0.4mol), chloromethyl butylperoxyisopropyl carbonate
30.5g (0.2mol) and DMF 100ml are added in reaction flask, are warming up to 40 DEG C and are monitored and stir instead
Answer 15 hours, be cooled to room temperature, reactant liquor is poured in water, ethyl acetate extraction, organic phase is washed three times, and anhydrous sodium sulfate is done
Dry, reduced pressure concentration, concentrate petroleum ether is recrystallized to give tenofovir dipivoxil 9.5g, yield 18.3%, HPLC purity
99.65%.
Comparative example 2
By tenofovir 28.7g (0.1mol), acid binding agent 40.5g (triethylamine, 0.4mol), chloromethyl butylperoxyisopropyl carbonate
30.5g (0.2mol) and 1-METHYLPYRROLIDONE 100ml are added in reaction flask, are warming up to 40 DEG C of monitorings and stirring reaction
10 hours, after reaction terminates, room temperature is cooled to, reactant liquor is poured in water, ethyl acetate extraction, organic phase is washed three times, anhydrous
Sodium sulphate is dried, reduced pressure concentration, and concentrate petroleum ether is recrystallized to give tenofovir dipivoxil 10.4g, yield 20.1%,
HPLC purity 99.65%.
To sum up, the invention provides a kind of preparation method of tenofovir dipivoxil, the method is avoided using a large amount of thorns
Sharp property 1-METHYLPYRROLIDONE solvent and phase transfer catalyst, reduce cost, the workload of post processing are reduced, during reaction
Between effectively shorten and achieve good yield.
Claims (8)
1. a kind of preparation method of tenofovir dipivoxil, the preparation method includes：In the presence of acid binding agent, by tenofovir
React in ionic liquid with halogenated methyl butylperoxyisopropyl carbonate and obtain tenofovir dipivoxil.
2. preparation method as claimed in claim 1, it is characterised in that tenofovir and acid binding agent, halogenated methyl isopropyl carbon
The consumption mol ratio of acid esters is 1：3～5：2～4.
3. preparation method as claimed in claim 1, it is characterised in that relative to every gram of tenofovir, the consumption of ionic liquid
For 3～5ml.
4. such as what preparation method as described in 3 of claim 1, it is characterised in that ionic liquid is 1- butyl-pyridinium tetrafluoroborates.
5. the preparation method as described in claim 1 and 2, it is characterised in that the acid binding agent is that diethylamine, triethylamine and two are different
One or more in propylethylamine.
6. the preparation method as described in claim 1-5, it is characterised in that the condition of reaction includes：Reaction temperature is 30～40
DEG C, the reaction time is 1～3 hour.
7. preparation method as claimed in claim 1 or 2, it is characterised in that the halogenated methyl butylperoxyisopropyl carbonate is chloromethane
Base butylperoxyisopropyl carbonate or bromomethyl butylperoxyisopropyl carbonate.
8. preparation method as claimed in claim 1, it is characterised in that the preparation method also includes post-reaction treatment step, tool
Body ground：After reaction terminates, room temperature is cooled to, reactant liquor is poured in water, ethyl acetate extraction, organic phase washing, anhydrous sodium sulfate
It is dried, reduced pressure concentration, concentrate petroleum ether is recrystallized to give tenofovir dipivoxil.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611184011.5A CN106632483B (en) | 2016-12-20 | 2016-12-20 | A kind of preparation method of tenofovir dipivoxil |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611184011.5A CN106632483B (en) | 2016-12-20 | 2016-12-20 | A kind of preparation method of tenofovir dipivoxil |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106632483A true CN106632483A (en) | 2017-05-10 |
| CN106632483B CN106632483B (en) | 2018-11-16 |
Family
ID=58835171
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201611184011.5A Active CN106632483B (en) | 2016-12-20 | 2016-12-20 | A kind of preparation method of tenofovir dipivoxil |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106632483B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108503550A (en) * | 2018-05-09 | 2018-09-07 | 烟台新特路新材料科技有限公司 | A kind of ionic liquid type antistatic agent and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003093282A1 (en) * | 2002-04-29 | 2003-11-13 | Chemi S.P.A. | Preparation of biphosphonic acids and salts thereof |
| KR20110008559A (en) * | 2009-07-20 | 2011-01-27 | 경희대학교 산학협력단 | Anhydrate form of adefovir dipivoxil and its method using inoic liquid |
| CN105440078A (en) * | 2015-12-31 | 2016-03-30 | 苏州弘森药业有限公司 | Method for synthesizing tenofovir disoproxil fumarate conveniently |
-
2016
- 2016-12-20 CN CN201611184011.5A patent/CN106632483B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003093282A1 (en) * | 2002-04-29 | 2003-11-13 | Chemi S.P.A. | Preparation of biphosphonic acids and salts thereof |
| KR20110008559A (en) * | 2009-07-20 | 2011-01-27 | 경희대학교 산학협력단 | Anhydrate form of adefovir dipivoxil and its method using inoic liquid |
| CN105440078A (en) * | 2015-12-31 | 2016-03-30 | 苏州弘森药业有限公司 | Method for synthesizing tenofovir disoproxil fumarate conveniently |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108503550A (en) * | 2018-05-09 | 2018-09-07 | 烟台新特路新材料科技有限公司 | A kind of ionic liquid type antistatic agent and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106632483B (en) | 2018-11-16 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105541844B (en) | Simple preparation method of high-purity linagliptin | |
| CN105330609B (en) | A kind of method for preparing LCZ696 | |
| CN103570667B (en) | Method for continuously preparing epsilon-lactone | |
| CN104829599B (en) | The preparation method and the midbody compound for preparing Lei Dipawei of Lei Dipawei and its derivative | |
| CN102020663A (en) | Tazobactam synthesis method | |
| CN103724261A (en) | Novel industrial production method for hydroxychloroquine sulfate | |
| CN104844602B (en) | A kind of preparation method of Li Gelieting | |
| CN111635434A (en) | Synthesis method of 1-propylphosphoric cyclic anhydride | |
| CN104262397A (en) | Preparation method of high-purity tenofovir | |
| CN106632483A (en) | Tenofovir disoproxil preparation method | |
| CN102584693B (en) | Preparation method for high purity 2-chlorine-3-aminopyridine hydrochloride | |
| WO2010023679A2 (en) | Preparation of triclopyr, its intermediate and butoxyethyl ester | |
| CN107987021A (en) | A kind of preparation method of 3- difluoromethyls -1- methyl isophthalic acids H- pyrazoles -4- carboxylic acids | |
| CN101531634B (en) | High-purity blonanserin and preparation method thereof | |
| CN102875397B (en) | Meclofenoxatum preparation method | |
| CN102010397A (en) | Method for preparing cyclic carbonic ester in presence of difunctional catalyst | |
| CN108794479A (en) | A kind of synthetic method of 4- chloropyrrolo [2,3-ds | |
| CN104987325B (en) | A kind of preparation method of voriconazole | |
| CN101506141A (en) | 2-(4-methoxycarbonylmethylphenoxymethyl)benzoic acid methyl ester and method for producing the same | |
| CN104478799B (en) | The preparation method of 1,4-diallyl isoquinolin | |
| CN103553932A (en) | Method suitable for industrially preparing memanitine hydrochloride | |
| CN104402813B (en) | Novel method for synthesizing sorafenib | |
| CN106380455A (en) | Synthetic method and application of vortioxetine hydrobromide | |
| CN112624921A (en) | Synthesis method and application of 1-hydroxymethyl cyclopropyl acetic acid | |
| CN101397238B (en) | Method for producing dichloropropanol |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| CB03 | Change of inventor or designer information |
Inventor after: Yan Lei Xu Inventor after: Guo Qizhen Inventor after: Wang Lihua Inventor after: Lv Yanhua Inventor before: Lv Yanhua |
|
| CB03 | Change of inventor or designer information | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20181009 Address after: 261500 77 Town Street, Gaomi City, Shandong Applicant after: Yan Lei Xu Address before: 266520 1 residential 1708, Changjiang East Road, Huangdao District, Qingdao, Shandong, 1708 Applicant before: QINGDAO CHENDA BIOLOGICAL SCIENCE & TECHNOLOGY Co.,Ltd. |
|
| TA01 | Transfer of patent application right | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20230427 Address after: No. 69 Qifeng Road, Gaoqiao Town, Haishu District, Ningbo City, Zhejiang Province, 315173 Patentee after: Zhejiang Yonghe Pharmaceutical Technology Co.,Ltd. Address before: 261500 77 Town Street, Gaomi City, Shandong Patentee before: Sui Yanlei |
|
| TR01 | Transfer of patent right |