CN108794531A - A kind of preparation method of high-purity tenofovir disoproxil fumarate - Google Patents
A kind of preparation method of high-purity tenofovir disoproxil fumarate Download PDFInfo
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- CN108794531A CN108794531A CN201810302066.4A CN201810302066A CN108794531A CN 108794531 A CN108794531 A CN 108794531A CN 201810302066 A CN201810302066 A CN 201810302066A CN 108794531 A CN108794531 A CN 108794531A
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- tenofovir disoproxil
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- disoproxil fumarate
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- tenofovir
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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 56
- 229960004693 tenofovir disoproxil fumarate Drugs 0.000 title claims abstract description 42
- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- 238000005886 esterification reaction Methods 0.000 claims abstract description 35
- 229960001355 tenofovir disoproxil Drugs 0.000 claims abstract description 27
- 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 claims abstract description 27
- 230000032050 esterification Effects 0.000 claims abstract description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 19
- 229960004556 tenofovir Drugs 0.000 claims abstract description 15
- 238000002425 crystallisation Methods 0.000 claims abstract description 13
- 230000008025 crystallization Effects 0.000 claims abstract description 13
- 239000002904 solvent Substances 0.000 claims abstract description 13
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- 239000003799 water insoluble solvent Substances 0.000 claims abstract description 10
- 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 abstract description 8
- 238000001914 filtration Methods 0.000 claims abstract description 8
- 239000007788 liquid Substances 0.000 claims abstract description 8
- 238000003756 stirring Methods 0.000 claims abstract description 8
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000005457 ice water Substances 0.000 claims abstract description 6
- 238000002156 mixing Methods 0.000 claims abstract description 6
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims abstract description 5
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 13
- 150000002148 esters Chemical class 0.000 claims description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 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
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 4
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 3
- 229940011051 isopropyl acetate Drugs 0.000 claims description 3
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 3
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 230000008859 change Effects 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 abstract description 18
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- 238000000034 method Methods 0.000 abstract description 6
- 238000012805 post-processing Methods 0.000 abstract description 5
- 239000006227 byproduct Substances 0.000 abstract description 3
- 238000006555 catalytic reaction Methods 0.000 abstract 1
- 239000012535 impurity Substances 0.000 description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 238000004128 high performance liquid chromatography Methods 0.000 description 12
- 238000006471 dimerization reaction Methods 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 238000001514 detection method Methods 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- -1 ester fumarate Chemical class 0.000 description 6
- 239000001530 fumaric acid Substances 0.000 description 6
- 238000000605 extraction Methods 0.000 description 4
- DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 241001269238 Data Species 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- 229930024421 Adenine Natural products 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 206010054949 Metaplasia Diseases 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 229960000643 adenine Drugs 0.000 description 2
- 239000012024 dehydrating agents Substances 0.000 description 2
- 239000004519 grease Substances 0.000 description 2
- 208000002672 hepatitis B Diseases 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 230000015689 metaplastic ossification Effects 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 238000005457 optimization Methods 0.000 description 2
- 239000003444 phase transfer catalyst Substances 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- OXHNLMTVIGZXSG-UHFFFAOYSA-N 1-Methylpyrrole Chemical class CN1C=CC=C1 OXHNLMTVIGZXSG-UHFFFAOYSA-N 0.000 description 1
- REACWASHYHDPSQ-UHFFFAOYSA-N 1-butylpyridin-1-ium Chemical compound CCCC[N+]1=CC=CC=C1 REACWASHYHDPSQ-UHFFFAOYSA-N 0.000 description 1
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000002155 anti-virotic effect Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000005352 clarification Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 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 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 239000005416 organic matter Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 238000003672 processing method Methods 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000003021 water soluble solvent Substances 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
-
- 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
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)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a kind of preparation methods of high-purity tenofovir disoproxil fumarate, including are：（1）Tenofovir and chloromethyl butylperoxyisopropyl carbonate are carried out esterification in N-Methyl pyrrolidone solvent, obtain esterification reaction solution with certain molar ratio under triethylamine and tetrabutylammonium bromide catalysis；（2）Esterification reaction solution is added in a certain proportion of mixing crystallization liquid, mixing crystallization liquid is water-insoluble solvent and ice water mixed liquor, and low temperature stirring and crystallizing filters, and filtration cakes torrefaction obtains the tenofovir disoproxil of high-purity；（3）High-purity tenofovir disoproxil is dissolved, at salt, obtains tenofovir disoproxil fumarate；This method esterification high conversion rate of the present invention, by-product is few, post-processing operation is simple, is extracted without multiple, direct crystallization obtains the high tenofovir disoproxil of purity, the tenofovir disoproxil fumarate of purity >=99.5%, at low cost, high income are finally prepared at salt, economically feasible is suitble to industrialized production.
Description
Technical field
The present invention relates to a kind of preparation methods of high-purity tenofovir disoproxil fumarate, belong to pharmaceutical technology field.
Background technology
Tenofovir disoproxil fumarate, chemistry are entitled：(R) two (butyloxycarbonyl of -9- (2- phosphate methoxies propyl) adenine
Oxygen methyl) ester fumarate, structure is shown below：
Tenofovir disoproxil fumarate is researched and developed by Ji Leadd B.V of the U.S., and in October, 2001 lists in the U.S. for the first time, it has anti-
The acyclic nucleoside phosphate compounds of HIV and Anti-HBV effect are tenofovir ((R) -9- (2- phosphate methoxies propyl) -
Adenine) prodrug, into human body after quickly hydrolysis release tenofovir, generate antivirus action, since therapeutic effect is definite,
Adaptability is good, and dosage is suitable, is the line inverase that multiple treatment guidelines recommend, in April, 2008 and August, European Union and
U.S. FDA ratifies it and is used to treat hepatitis B (hepatitis B) according to a large amount of clinical test results, becomes best Anti-HBV activity
One of drug；
Compound United States Patent (USP) US5922695 makes public for the first time the preparation method of tenofovir disoproxil fumarate, is with tenofovir
For raw material, triethylamine is catalyst, carries out condensation reaction with chloromethyl butylperoxyisopropyl carbonate, reaction terminates, and uses isopropyl acetate
It dilutes and cools down, filter, washing layering obtains tenofovir disoproxil grease, grease isopropanol dissolved clarification after organic layer concentration
With fumaric acid tenofovir disoproxil fumarate is obtained at salt；
Esterification is the committed step of tenofovir disoproxil fumarate synthesis, and the product for directly affecting tenofovir disoproxil fumarate is pure
Degree and yield；The conversion ratio of esterification is relatively low in existing synthetic technology, generates a large amount of monoesters impurity（Ⅰ）, N- methylols substitution
Impurity（Ⅱ）With dimerization impurity（Ⅲ）Deng, be mainly reflected in two aspect：First, since tenofovir first generates list in esterification
Ester then proceedes to reaction into tenofovir disoproxil（That is dibasic acid esters）, but monoesters, because steric hindrance increases, reactivity reduces, double esterification
Difficulty increases, and monoesters reaction is not thorough and influences reaction yield, and the reaction time grows the conversion that can promote monoesters, but will produce simultaneously
Dimerization impurity；Second is that the moisture in reaction can slow down monoesters and be converted to the efficiency of dibasic acid esters, while it will produce 5% ~ 10% N- hydroxyl first
Base replaces impurity；
The synthetic route of document patent report is also to be solved in terms of above-mentioned two at present, mainly solvent azeotropic water removing
After carry out esterification, better phase transfer catalyst or substitute, addition deicer and last handling process in esterification
The routes such as process optimization.
The route that esterification is carried out after solvent azeotropic water removing increases water removal phase, significantly reduces the substitution of N- methylols
Impurity, but the problem of unresolved monoesters impurity, while using the azeotropic agents such as n-hexane, hexamethylene, toluene, acetonitrile, cost
Height, environmental pollution is serious, is not suitable for industrialized production.
Better phase transfer catalyst or the esterification route of substitute are mainly reflected in and have used polyethylene glycol and 1-
Butyl-pyridinium tetrafluoroborate, polyethylene glycol belong to two-phase solvent, and soluble easily in water and esters solvent, post-processing operation is cumbersome, and
The separation and purifying of product relatively difficult to achieve；1- butyl-pyridinium tetrafluoroborates needs are prepared, of high cost, it is difficult to realize business
Metaplasia is produced.
The route that deicer is added in esterification has mainly used inorganic metal salt dehydrating agent（Including sodium salt, sylvite, magnesium
Salt, calcium salt etc.）And phosphorus pentoxide, inorganic metal salt dehydrating agent are physics water removal, the influence for water in esterification has
Limit, substantially to no effect；Phosphorus pentoxide belongs to chemical water removal, but the product belong to high-risk chemical product, toxic, is corrosive,
Highly acid contacts with organic matter and easily leads to explosion, and simultaneous reactions monoesters is high, of high cost, dangerous high, is not suitable for industry metaplasia
Production.
The process optimization route of last handling process mainly adds water acidic materials tune pH to acidity by organic layer, will replace
The extraction of Nuo Fuwei ester free alkalis enters water layer, and water layer will replace promise good fortune added with solvent alkaline matter tune pH to neutrality or alkalinity
The extraction of Wei ester free alkali enters organic layer, and vacuum concentration obtains the tenofovir disoproxil of high-purity；The processing method is merely able to remove
A small amount of unknown impuritie, can not remove tenofovir ester analogs impurity, including monoesters impurity, N- methyl impurity and dimerization are miscellaneous
Matter is unable to reach the effect of purifying.
In conclusion currently, conventional method prepares tenofovir disoproxil fumarate, esterification conversion ratio is low, and reaction is endless
Entirely, always there are the impurity such as larger monoesters impurity, N- methyl impurity and dimerization impurity, post-processing is complicated, isolates and purifies effect
Difference causes final total recovery relatively low（50%~65%）, it is of poor quality, it is of high cost the problems such as, be not suitable for industrialized production；Therefore, it develops
A kind of preparation method of high-purity tenofovir disoproxil fumarate is those skilled in the art's technical problem anxious to be resolved.
Invention content
The technical problem to be solved by the present invention is to the shortcomings that overcoming the prior art, provide a kind of high-purity tenofovir
The preparation method of ester fumarate, this method esterification high conversion rate, by-product is few, and post-processing operation is simple, without more
Secondary extraction, direct crystallization obtain the high tenofovir disoproxil of purity, and the fumaric acid that purity >=99.5% is finally prepared at salt replaces promise
Good fortune Wei ester, at low cost, high income, economically feasible are suitble to industrialized production.
The technical solution that the present invention solves the above technical problem is：
A kind of preparation method of high-purity tenofovir disoproxil fumarate, specifically includes following steps：
（1）Tenofovir is urged with certain molar ratio in triethylamine and tetrabutylammonium bromide with chloromethyl butylperoxyisopropyl carbonate
Under change, esterification is carried out in N-Methyl pyrrolidone solvent, obtains esterification reaction solution；
（2）Esterification reaction solution obtained by step 1 is added in a certain proportion of mixing crystallization liquid, mixing crystallization liquid is non-aqueous
Property solvent and ice water mixed liquor, low temperature stirring and crystallizing, filtering, filtration cakes torrefaction obtains the tenofovir disoproxil of high-purity；
（3）By the high-purity tenofovir disoproxil dissolving obtained by step 2, at salt, tenofovir disoproxil fumarate is obtained.
The technical solution that the present invention further limits is：
In the preparation method of aforementioned high-purity tenofovir disoproxil fumarate, step（1）Middle tenofovir and chloromethyl isopropyl
The molar ratio of carbonic ester is 1:2~1:10.
Technique effect, the present invention use excessive chloromethyl butylperoxyisopropyl carbonate so that and esterification can be quickly completed,
Conversion rate of products is high in reaction solution, and monoesters converts completely substantially, monoesters≤2% in reaction solution.
In the preparation method of aforementioned high-purity tenofovir disoproxil fumarate, step（1）The time of middle esterification is
0.5-4h。
In the preparation method of aforementioned high-purity tenofovir disoproxil fumarate, by quality：Volume：Stereometer tenofovir：
N-Methyl pyrrolidone：Mix crystallization liquid=1:（1~10）:（5~50）.
In the preparation method of aforementioned high-purity tenofovir disoproxil fumarate, step（2）Middle water-insoluble solvent and ice water
Volume ratio be 1:5~1:100.
In the preparation method of aforementioned high-purity tenofovir disoproxil fumarate, step（2）Middle water-insoluble solvent is rudimentary
Esters solvent, aromatic hydrocarbon, halogenated aromatic, the halogenated alkane amber of C1 to C6 or the alkane solvent of C1 to C6.
In the preparation method of aforementioned high-purity tenofovir disoproxil fumarate, step（2）Described in water-insoluble solvent be
Ethyl acetate or isopropyl acetate.
In the preparation method of aforementioned high-purity tenofovir disoproxil fumarate, step（2）The temperature of middle low temperature stirring and crystallizing
It is 0 ~ 20 DEG C.
In the preparation method of aforementioned high-purity tenofovir disoproxil fumarate, step（3）In obtained fumaric acid replace promise good fortune
Wei ester purity >=99.5%
The beneficial effects of the invention are as follows：
Reaction solution, is then added to non-by tenofovir disoproxil purity purity 90.0% or so in esterification reaction solution produced by the present invention
The in the mixed solvent crystallization of water-soluble solvent and water, excessive chloromethyl butylperoxyisopropyl carbonate, a small amount of tenofovir disoproxil product and
A large amount of impurity enter water-insoluble solvent, triethylamine, triethylamine salt, tetrabutylammonium bromide and other water soluble salts, N- methyl pyrroles
Pyrrolidone and a small amount of product and impurity enter in water, and a large amount of tenofovir disoproxils are precipitated at solid, realize water-insoluble solvent, water
With the three phase separation of tenofovir disoproxil, filtering, filtration cakes torrefaction obtains high-purity tenofovir disoproxil, purity >=97.0%, monoesters list
Ester≤0.2%；High-purity tenofovir disoproxil, at salt, obtains the tenofovir disoproxil fumarate of purity >=99.5%, total recovery through dissolving
80% or more.
Description of the drawings
Fig. 1 is the HPLC collection of illustrative plates of esterification reaction solution in the embodiment of the present invention；
Fig. 2 is the HPLC collection of illustrative plates of tenofovir disoproxil in the embodiment of the present invention；
Fig. 3 is the HPLC collection of illustrative plates of tenofovir disoproxil fumarate in the embodiment of the present invention.
Specific implementation mode
Embodiment 1
The present embodiment provides a kind of preparation methods of high-purity tenofovir disoproxil fumarate, specifically include following steps：
（1）Under nitrogen protection, by tenofovir 50g（0.174mol）, chloromethyl butylperoxyisopropyl carbonate 132.8g（0.87mol）,
Tetrabutylammonium bromide 56.1g（0.174mol）It puts into N-Methyl pyrrolidone 150ml, is warming up to 45 DEG C, control temperature 45 ~ 55
DEG C, start that triethylamine 44.0g is added dropwise（0.435mol）Esterification is carried out, is added dropwise, insulation reaction 1h is cooled to 10 ~ 20
DEG C, obtain esterification reaction solution；
HPLC detections are carried out to esterification reaction solution, the HPLC collection of illustrative plates of esterification reaction solution is as shown in Figure 1, data are as shown in table 1；
1 esterification reaction solution HPLC detection datas of table
| Retention time（Minute） | Area | % areas | Integral type | |
| 1 | 6.099 | 223916 | 1.924 | BB |
| 2 | 7.154 | 5753 | 0.049 | BB |
| 3 | 13.216 | 9894 | 0.085 | BB |
| 4 | 17.302 | 10572921 | 90.860 | BB |
| 5 | 20.309 | 291982 | 2.509 | BB |
| 6 | 23.107 | 13375 | 0.115 | BB |
| 7 | 35.688 | 2204 | 0.019 | BB |
| 8 | 45.803 | 408125 | 3.507 | BB |
| 9 | 46.602 | 1268 | 0.011 | BB |
| 10 | 47.041 | 2143 | 0.018 | BB |
| 11 | 48.239 | 1411 | 0.012 | BB |
| 12 | 48.820 | 1551 | 0.013 | BB |
| 13 | 49.095 | 98432 | 0.846 | BB |
| 14 | 49.486 | 960 | 0.008 | BB |
| 15 | 49.907 | 3617 | 0.022 | BB |
By Fig. 1 combinations table 1 as it can be seen that tenofovir disoproxil purity=90.86% wherein in esterification reaction solution（RT=17.302min）, monoesters
Impurity=1.924%（RT=6.099min）, N- methyl impurity=2.509%（RT=20.309min）, dimerization impurity=3.507%（RT=
45.803min）；
（2）By step（1）The esterification reaction solution of gained is slowly dropped in the mixed liquor of 90ml ethyl acetate and 910ml ice water and stirs
Crystallization to be mixed, is added dropwise, 0 ~ 10 DEG C of stirring and crystallizing 2h is kept, is filtered, is filtered, filtration cakes torrefaction obtains tenofovir disoproxil 77.2g,
Yield 85.4%, purity >=97.0%；
HPLC detections are carried out to tenofovir disoproxil, the HPLC collection of illustrative plates of tenofovir disoproxil is as shown in Fig. 2, data are as shown in table 2；
2 tenofovir disoproxil HPLC detection datas of table
| Retention time（Minute） | Area | % areas | Integral type | |
| 1 | 7.062 | 96686 | 0.1506 | BB |
| 2 | 18.888 | 62897730 | 97.9403 | BB |
| 3 | 22.705 | 478384 | 0.7449 | BB |
| 4 | 47.35 | 633529 | 0.9865 | BB |
| 5 | 49.42 | 7247 | 0.0113 | BB |
| 6 | 50.084 | 106914 | 0.1665 | BB |
By Fig. 2 combinations table 2 as it can be seen that wherein tenofovir disoproxil purity=97.94%（RT=18.888min）, monoesters impurity=0.151%
（RT=7.062min）, N- methyl impurity=0.745%（RT=22.705min）, dimerization impurity=0.987%（RT=47.350min）；
（3）By step（2）The tenofovir disoproxil 77.2g of gained（0.149mol）It is added in 1000ml isopropanols, it is warming up to 50 ~
55 DEG C of dissolvings, are added fumaric acid 24.3g while hot（0.209mol）, -5 ~ 5 DEG C of stirring and crystallizing 2h are cooled to, are filtered, it is dry, it obtains
Tenofovir disoproxil fumarate 89.2g, yield 94.4%, purity >=99.5%, total recovery 80.62%；
HPLC detections are carried out to tenofovir disoproxil fumarate, the HPLC collection of illustrative plates of tenofovir disoproxil fumarate as shown in figure 3, data such as
Shown in table 3；
3 tenofovir disoproxil fumarate HPLC detection datas of table
| Retention time（Minute） | Area | % areas | Separating degree | Integral type | |
| 1 | 2.346 | 1169589 | 5.405 | BB | |
| 2 | 10.467 | 38929 | 0.180 | 32.62 | BB |
| 3 | 15.189 | 6367 | 0.029 | 19.36 | BB |
| 4 | 18.228 | 20422516 | 94.385 | 8.74 | BB |
By Fig. 3 combinations table 3 as it can be seen that wherein tenofovir disoproxil fumarate purity=99.79%（RT=2.346min is fumaric acid, purity
5.405%, RT=18.228min is tenofovir disoproxil, purity 94.385%）, monoesters impurity=0.180%（RT=10.467min）,
N- methyl impurity is not detected, and dimerization impurity is not detected, other unknown impuritie=0.029%（RT=15.189min）.
Using this method esterification high conversion rate of the present invention, by-product is few, and post-processing operation is simple, without multiple
Extraction, direct crystallization obtain the high tenofovir disoproxil of purity, and the fumaric acid that purity >=99.5% is finally prepared at salt replaces promise good fortune
Wei ester, at low cost, high income, economically feasible are suitble to industrialized production.
In addition to the implementation, the present invention can also have other embodiment.It is all to use equivalent substitution or equivalent transformation shape
At technical solution, fall within the scope of protection required by the present invention.
Claims (9)
1. a kind of preparation method of high-purity tenofovir disoproxil fumarate, which is characterized in that specifically include following steps：
（1）Tenofovir is urged with certain molar ratio in triethylamine and tetrabutylammonium bromide with chloromethyl butylperoxyisopropyl carbonate
Under change, esterification is carried out in N-Methyl pyrrolidone solvent, obtains esterification reaction solution；
（2）Esterification reaction solution obtained by step 1 is added in a certain proportion of mixing crystallization liquid, the mixing crystallization liquid is
Water-insoluble solvent and ice water mixed liquor, low temperature stirring and crystallizing, filtering, filtration cakes torrefaction obtain the tenofovir disoproxil of high-purity；
（3）By the high-purity tenofovir disoproxil dissolving obtained by step 2, at salt, tenofovir disoproxil fumarate is obtained.
2. the preparation method of high-purity tenofovir disoproxil fumarate according to claim 1, it is characterised in that：Step
（1）Described in the molar ratio of tenofovir and chloromethyl butylperoxyisopropyl carbonate be 1:2~1:10.
3. the preparation method of high-purity tenofovir disoproxil according to claim 1 and its fumarate, it is characterised in that：Institute
State step（1）The time of middle esterification is 0.5-4h.
4. the preparation method of high-purity tenofovir disoproxil fumarate according to claim 1, it is characterised in that：By matter
Amount：Volume：Tenofovir described in stereometer：N-Methyl pyrrolidone：Mix crystallization liquid=1:（1~10）:（5~50）.
5. the preparation method of high-purity tenofovir disoproxil fumarate according to claim 1, it is characterised in that：Step
（2）Described in water-insoluble solvent and the volume ratio of ice water be 1:5~1:100.
6. the preparation method of high-purity tenofovir disoproxil fumarate according to claim 1, it is characterised in that：Step
（2）Described in water-insoluble solvent be rudimentary esters solvent, aromatic hydrocarbon, halogenated aromatic, C1 to C6 halogenated alkane amber or C1
To the alkane solvent of C6.
7. the preparation method of high-purity tenofovir disoproxil fumarate according to claim 6, it is characterised in that：Step
（2）Described in water-insoluble solvent be ethyl acetate or isopropyl acetate.
8. the preparation method of high-purity tenofovir disoproxil fumarate according to claim 1, it is characterised in that：Step
（2）Described in low temperature stirring and crystallizing temperature be 0 ~ 20 DEG C.
9. the preparation method of high-purity tenofovir disoproxil fumarate according to claim 1, it is characterised in that：Step
（3）In obtained tenofovir disoproxil fumarate purity >=99.5%.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109942634A (en) * | 2019-01-24 | 2019-06-28 | 深圳科兴药业有限公司 | A kind of the crystal form I and preparation method and application of tenofovir disoproxil fumarate |
| CN110590843A (en) * | 2019-09-19 | 2019-12-20 | 奥锐特药业股份有限公司 | Preparation method of tenofovir disoproxil fumarate |
Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103360425A (en) * | 2012-04-01 | 2013-10-23 | 安徽贝克联合制药有限公司 | Synthesis method of tenofovir disoproxil and fumarate thereof |
| CN103524561A (en) * | 2013-10-11 | 2014-01-22 | 福建广生堂药业股份有限公司 | Preparation method for tenofovir monoester fumarate |
| WO2014033688A1 (en) * | 2012-09-03 | 2014-03-06 | Ithemba Pharmaceuticals (Proprietary) Limited | A process for the preparation of (r)-9-[2-(phosphonometh-oxy)propyl]adenine (pmpa) |
| CN104130288A (en) * | 2014-06-27 | 2014-11-05 | 宁波美诺华药业股份有限公司 | Tenofovir disoproxil salt preparation method |
| CN104974188A (en) * | 2014-04-11 | 2015-10-14 | 浙江九洲药业股份有限公司 | Tenofovir disoproxil crystal form and preparation method thereof |
| CN105418684A (en) * | 2015-12-31 | 2016-03-23 | 苏州弘森药业有限公司 | New method for synthesizing tenofovir disoproxil fumarate |
| CN105418683A (en) * | 2015-12-31 | 2016-03-23 | 苏州弘森药业有限公司 | Preparation method for tenofovir disoproxil fumarate |
| CN105440076A (en) * | 2015-12-31 | 2016-03-30 | 苏州弘森药业有限公司 | Method for preparing tenofovir disoproxil fumarate |
| CN105566394A (en) * | 2016-03-16 | 2016-05-11 | 荆门市帅邦化学科技有限公司 | Production technique of tenofovir disoproxil fumarate |
| CN106008603A (en) * | 2016-06-03 | 2016-10-12 | 东北制药集团股份有限公司 | Preparation methods of tenofovir disoproxil and fumarate thereof |
-
2018
- 2018-04-04 CN CN201810302066.4A patent/CN108794531A/en active Pending
Patent Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103360425A (en) * | 2012-04-01 | 2013-10-23 | 安徽贝克联合制药有限公司 | Synthesis method of tenofovir disoproxil and fumarate thereof |
| WO2014033688A1 (en) * | 2012-09-03 | 2014-03-06 | Ithemba Pharmaceuticals (Proprietary) Limited | A process for the preparation of (r)-9-[2-(phosphonometh-oxy)propyl]adenine (pmpa) |
| CN103524561A (en) * | 2013-10-11 | 2014-01-22 | 福建广生堂药业股份有限公司 | Preparation method for tenofovir monoester fumarate |
| CN104974188A (en) * | 2014-04-11 | 2015-10-14 | 浙江九洲药业股份有限公司 | Tenofovir disoproxil crystal form and preparation method thereof |
| CN104130288A (en) * | 2014-06-27 | 2014-11-05 | 宁波美诺华药业股份有限公司 | Tenofovir disoproxil salt preparation method |
| CN105418684A (en) * | 2015-12-31 | 2016-03-23 | 苏州弘森药业有限公司 | New method for synthesizing tenofovir disoproxil fumarate |
| CN105418683A (en) * | 2015-12-31 | 2016-03-23 | 苏州弘森药业有限公司 | Preparation method for tenofovir disoproxil fumarate |
| CN105440076A (en) * | 2015-12-31 | 2016-03-30 | 苏州弘森药业有限公司 | Method for preparing tenofovir disoproxil fumarate |
| CN105566394A (en) * | 2016-03-16 | 2016-05-11 | 荆门市帅邦化学科技有限公司 | Production technique of tenofovir disoproxil fumarate |
| CN106008603A (en) * | 2016-06-03 | 2016-10-12 | 东北制药集团股份有限公司 | Preparation methods of tenofovir disoproxil and fumarate thereof |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109942634A (en) * | 2019-01-24 | 2019-06-28 | 深圳科兴药业有限公司 | A kind of the crystal form I and preparation method and application of tenofovir disoproxil fumarate |
| CN110590843A (en) * | 2019-09-19 | 2019-12-20 | 奥锐特药业股份有限公司 | Preparation method of tenofovir disoproxil fumarate |
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