CN113185552A - Preparation method of propane fumarate tenofovir disoproxil degradation impurity - Google Patents
Preparation method of propane fumarate tenofovir disoproxil degradation impurity Download PDFInfo
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- CN113185552A CN113185552A CN202110482040.4A CN202110482040A CN113185552A CN 113185552 A CN113185552 A CN 113185552A CN 202110482040 A CN202110482040 A CN 202110482040A CN 113185552 A CN113185552 A CN 113185552A
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- tenofovir
- fumarate
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- propofol
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- 239000012535 impurity Substances 0.000 title claims abstract description 48
- 230000015556 catabolic process Effects 0.000 title claims abstract description 36
- 238000006731 degradation reaction Methods 0.000 title claims abstract description 36
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- 229960001355 tenofovir disoproxil Drugs 0.000 title claims abstract description 7
- 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 claims abstract description 7
- YYHPFNLBMMEMQU-TYYBGVCCSA-N (e)-but-2-enedioic acid;propane Chemical compound CCC.OC(=O)\C=C\C(O)=O YYHPFNLBMMEMQU-TYYBGVCCSA-N 0.000 title claims description 13
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims abstract description 58
- 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 38
- 238000006243 chemical reaction Methods 0.000 claims abstract description 36
- 239000007864 aqueous solution Substances 0.000 claims abstract description 21
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims abstract description 19
- 229960004134 propofol Drugs 0.000 claims abstract description 19
- OLBCVFGFOZPWHH-UHFFFAOYSA-N propofol Chemical compound CC(C)C1=CC=CC(C(C)C)=C1O OLBCVFGFOZPWHH-UHFFFAOYSA-N 0.000 claims abstract description 19
- 239000000243 solution Substances 0.000 claims abstract description 18
- 239000012071 phase Substances 0.000 claims abstract description 16
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000003513 alkali Substances 0.000 claims abstract description 13
- 239000003960 organic solvent Substances 0.000 claims abstract description 10
- 229960004693 tenofovir disoproxil fumarate Drugs 0.000 claims abstract description 10
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000000460 chlorine Substances 0.000 claims abstract description 8
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 8
- 239000012295 chemical reaction liquid Substances 0.000 claims abstract description 7
- 239000007791 liquid phase Substances 0.000 claims abstract description 7
- -1 malonic acid propylphenol Chemical compound 0.000 claims abstract description 4
- 238000002156 mixing Methods 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 36
- 238000000034 method Methods 0.000 claims description 17
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- 238000004237 preparative chromatography Methods 0.000 claims description 10
- 238000005406 washing Methods 0.000 claims description 8
- 239000012458 free base Substances 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 238000000605 extraction Methods 0.000 claims 2
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 20
- 239000000126 substance Substances 0.000 abstract description 14
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- 239000000047 product Substances 0.000 description 15
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 11
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 11
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 11
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 239000000463 material Substances 0.000 description 9
- 239000002994 raw material Substances 0.000 description 7
- 238000004108 freeze drying Methods 0.000 description 6
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- 238000004321 preservation Methods 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- SVUJNSGGPUCLQZ-FQQAACOVSA-N tenofovir alafenamide fumarate Chemical compound OC(=O)\C=C\C(O)=O.O([P@@](=O)(CO[C@H](C)CN1C2=NC=NC(N)=C2N=C1)N[C@@H](C)C(=O)OC(C)C)C1=CC=CC=C1.O([P@@](=O)(CO[C@H](C)CN1C2=NC=NC(N)=C2N=C1)N[C@@H](C)C(=O)OC(C)C)C1=CC=CC=C1 SVUJNSGGPUCLQZ-FQQAACOVSA-N 0.000 description 5
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000002253 acid Substances 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
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- 238000003786 synthesis reaction Methods 0.000 description 3
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 125000000848 adenin-9-yl group Chemical group [H]N([H])C1=C2N=C([H])N(*)C2=NC([H])=N1 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000001530 fumaric acid Substances 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 238000004811 liquid chromatography Methods 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 208000000419 Chronic Hepatitis B Diseases 0.000 description 1
- 229940126656 GS-4224 Drugs 0.000 description 1
- 241000700721 Hepatitis B virus Species 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 229940123527 Nucleotide reverse transcriptase inhibitor Drugs 0.000 description 1
- 229960003767 alanine Drugs 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
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- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
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- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 238000007867 post-reaction treatment Methods 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
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Images
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 System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
Abstract
The invention discloses a preparation method of a tenofovir disoproxil fumarate degradation impurity, which comprises the following steps: s1, mixing the free alkali of the tenofovir disoproxil, the lithium hydroxide aqueous solution and the chlorine-containing organic solvent to perform two-phase reaction to obtain reaction liquid; s2, extracting a target product in the reaction solution through a liquid-phase preparation column to obtain the degradation impurity of the malonic acid propylphenol tenofovir fumarate. The scheme of the invention utilizes the Propofol tenofovir free alkali to carry out selective hydrolysis reaction in a two-phase system containing aqueous solution of specific alkaline substances and organic solvent to obtain the target compound, and the purity of the target compound can reach more than 98%.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of a fumaric acid, namely a preparation method of a tenofovir disoproxil fumarate degradation impurity.
Background
Tenofovir fumarate (TAF) is a targeted prodrug of the nucleotide reverse transcriptase inhibitor Tenofovir (Tenofovir), developed by Gilidard (Gilead Sciences) Inc., under the trade name Vemlidy, approved in the United states at 2016 at 11 months, for the treatment of chronic Hepatitis B Virus (HBV) infection in adult patients with compensated liver disease, approved in the United states at 2018 at 11 months. The chemical name of TAF is N- [ (S) - [ [ [ (R) -1- (6-amino-9H-purin-9-yl) propan-2-yl ] oxy ] methyl ] (phenoxy) phosphoryl ] -L-alanine isopropyl ester, (2E) -2-butenedioate (2: 1) which has the following chemical structure:
the synthesis of TAF is usually accompanied by the formation of some by-products, as found in the degradation experiments of propofol fumarate tenofovir: the degradation impurity N- [ (S) - [ [ [ (R) -1- (6-amino-9H-purin-9-yl) propan-2-yl ] oxy ] methyl ] (hydroxy) phosphoryl ] -L-alanine (hereinafter referred to as "compound I") is easy to generate, which affects the medicine quality of TAF. Therefore, in order to better carry out quality research on the propane fumarate tenofovir, the method has important significance for obtaining the standard substance of the impurity. If the standard substance of the impurity can be obtained, the impurity can be further used for qualitative and quantitative analysis of the impurity in the production of the propane fumarate tenofovir, so that the quality standard of the propane fumarate tenofovir is improved, and an important guiding significance is provided for safe medication.
Currently, there is less relevant prior art on synthesizing impurity compound I standards, and part of the relevant art discloses the following preparation routes:
the synthesis route adopts another impurity (hereinafter referred to as compound II) to react with trifluoroacetic acid to prepare the compound I. However, the target product compound I of the method can be hydrolyzed continuously under acidic conditions, and forms salts with excessive trifluoroacetic acid, so that the impurity content is high, and the post-treatment is very complicated; secondly, the raw material compound II used by the method is not a common intermediate, and has the defect that raw materials are not easy to obtain.
Therefore, it is very important to provide a method for preparing the standard substance of the impurity compound I degraded by the propane fumarate tenofovir, wherein the post-treatment operation is simple and convenient.
Statements in this background are not admitted to be prior art to the present disclosure.
Disclosure of Invention
The present invention is directed to solving at least one of the problems of the prior art described above. Therefore, the invention provides a preparation method of the degradation impurity of the malonic acid propylphenol tenofovir fumarate, and the product prepared by the method is simple and convenient to operate in post-treatment.
According to one aspect of the invention, the preparation method of the degradation impurity of the malonic acid propylphenol tenofovir fumarate is provided, and comprises the following steps:
s1, mixing the free alkali of the tenofovir disoproxil, the lithium hydroxide aqueous solution and the chlorine-containing organic solvent to perform two-phase reaction to obtain reaction liquid;
s2, extracting a target product in the reaction solution through a liquid-phase preparation column to obtain a fumaric acid, namely, a propofol, tenofovir disoproxil degradation impurity;
wherein the structural formula of the degradation impurity of the propane fumarate tenofovir is as follows:
according to a preferred embodiment of the present invention, at least the following advantages are provided:
1. the scheme of the invention utilizes the Propofol tenofovir free alkali to carry out selective hydrolysis reaction in a two-phase system of lithium hydroxide aqueous solution and organic solvent to obtain a target compound, wherein the purity of the compound can reach more than 98%;
2. the raw materials are simple and easy to obtain, the reaction conditions are easy to control, the product purity is high, the post-treatment is simple, the method is suitable for industrial production of the propane fumarate tenofovir and degradation impurity compound I, and the detection and monitoring of the impurity in the process of synthesizing the propane fumarate tenofovir are facilitated;
3. the sensitivity of the raw material, namely the free alkali of the tenofovir disoproxil to the reaction environment such as the polarity of acid and alkali and a solvent is high, the excessive or too low strength of the acid and alkali can cause hydrolysis of a plurality of sites of the raw material (an active site 1, an active site 2 and an active site 3 shown in the following structural formula), if the selected alkaline substances are improper, the selectivity of the hydrolysis is not high, and by adopting the alkaline substance and the two-phase solvent system of the scheme of the invention, the selectivity is high, a product with high purity can be obtained, and the post-treatment operation is greatly reduced.
The active site 1, the active site 2 and the active site 3 shown in the structural formula of the free base of the propofol tenofovir are as follows:
in some embodiments of the invention, the synthetic route to the preparation method is as follows:
in some embodiments of the invention, the molar ratio of the Propofovir free base to the lithium hydroxide is 1:3.2 to 5. When the ratio of the raw materials in the reaction solution is too high or too low, the yield of the objective product is significantly reduced.
In some preferred embodiments of the invention, the molar ratio of the propofol tenofovir free base to lithium hydroxide is 1: 4. When the molar ratio of the two is 1:4, the yield can be more than or equal to 93 percent.
In some preferred embodiments of the present invention, the reaction temperature in step S1 is 10 to 40 ℃;
more preferably, the reaction temperature in step S1 is 10 to 15 ℃.
In some preferred embodiments of the present invention, the reaction time in step S1 is 10.1-20 h.
In some embodiments of the invention, the volume ratio of the lithium hydroxide aqueous solution to the chlorine-containing organic solvent is 1.5-3: 5;
more preferably, the volume ratio of the lithium hydroxide aqueous solution to the chlorine-containing organic solvent is 2-2.5: 5.
In some embodiments of the invention, the concentration of lithium hydroxide in the aqueous lithium hydroxide solution is from 2.0mol/L to 5.0 mol/L;
more preferably, the concentration of lithium hydroxide in the lithium hydroxide aqueous solution is 2.7-4.5 mol/L.
In some preferred embodiments of the invention, the chlorine-containing organic solvent is selected from one or more of dichloromethane, 1, 2-dichloroethane or chloroform.
In some embodiments of the present invention, the method of extracting through the liquid phase preparative column in step S2 is:
and (4) after the reaction liquid is layered in the step (S1), adjusting the pH value of a water layer to 3.5-6.5, purifying and extracting a target product in the reaction liquid through medium-pressure preparative chromatography, and drying to obtain the degradation impurity of the propane fumarate tenofovir. After layering, carrying out acid adjustment treatment on the water phase, purifying the water layer by using a medium-pressure preparative chromatography, and freeze-drying to obtain an impurity compound I, wherein the purity of the obtained compound I is up to more than 98%, and the compound I can be used as an impurity reference substance; the post-reaction treatment operation is simple, and only the salt in the water phase needs to be removed.
In some preferred embodiments of the present invention, the pH value in the method of extracting through a liquid phase preparative column in step S2 is 4.5 to 5.5.
More preferably, the pH value in step S2 is adjusted by an aqueous solution containing an acidic substance;
more preferably, the acidic substance is one or more of hydrochloric acid, sulfuric acid, phosphoric acid, citric acid and acetic acid.
In some embodiments of the invention, medium pressure preparative chromatography employs isocratic wash mode to isolate the desired product.
In some preferred embodiments of the present invention, the mobile phase used in the isocratic washing mode is an aqueous acetonitrile solution with a volume fraction of 2.0-5.0%.
In some preferred embodiments of the present invention, the isocratic flushing mode uses a flow rate of 10 to 18 mL/min.
In some preferred embodiments of the present invention, the isocratic washing mode uses 80-130 mg per sample.
It will be understood by those skilled in the art that, in accordance with the convention used in the art, the structural formulae used in the radicals described herein
Means that the corresponding bond can be broken hydrolytically, through which point it is linked to other fragments, groups.
Drawings
The invention is further described with reference to the following figures and examples, in which:
FIG. 1 shows the product obtained in example 1 of the present invention1H NMR chart;
FIG. 2 shows the product obtained in example 1 of the present invention13C NMR chart;
FIG. 3 is a liquid chromatogram of the product obtained in example 1 of the present invention;
FIG. 4 is a mass spectrum of the product obtained in example 1 of the present invention.
The letters in fig. 1 and 2 represent coupling constant components, the order of which has no special meaning, only for distinction.
Detailed Description
The concept and technical effects of the present invention will be clearly and completely described below in conjunction with the embodiments to fully understand the objects, features and effects of the present invention. It is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments, and those skilled in the art can obtain other embodiments without inventive effort based on the embodiments of the present invention, and all embodiments are within the protection scope of the present invention. The test methods used in the examples are all conventional methods unless otherwise specified; the materials, reagents and the like used are commercially available reagents and materials unless otherwise specified.
Example 1(LiOH, 3.2eq)
The preparation method of the degradation impurity of the malonic acid propofol tenofovir comprises the following specific steps:
s1, adding 4.76g of prophenoltenofovir free alkali and 50mL of dichloromethane into a reaction bottle, and stirring for dissolving; stirring and dissolving 1.34g of lithium hydroxide monohydrate by using 20mL of water, adding the obtained lithium hydroxide monohydrate aqueous solution into a reaction bottle, carrying out heat preservation reaction at 15 ℃ for 15 hours, standing and layering after the reaction is finished, and removing a dichloromethane layer;
s2, dropwise adding 2% citric acid aqueous solution into the aqueous phase layer to adjust the pH value to 4.5, purifying by a medium-pressure preparative chromatograph, collecting component solution containing materials, and freeze-drying to obtain 0.28g of a white solid tenofovir disoproxil fumarate degradation impurity compound I. HPLC purity 98.4%; wherein the medium-pressure preparative chromatography is separated by isocratic washing, the mobile phase is 4% acetonitrile pure water solution, the flow rate is 18mL/min, and the sample amount is 120 mg/needle.
Example 2(LiOH, 3.5eq)
The preparation method of the degradation impurity of the malonic acid propofol tenofovir comprises the following specific steps:
s1, adding 4.76g of prophenoltenofovir free alkali and 50mL of dichloromethane into a reaction bottle, and stirring for dissolving; stirring and dissolving 1.47g of lithium hydroxide monohydrate by using 20mL of water, adding the obtained lithium hydroxide monohydrate aqueous solution into a reaction bottle, carrying out heat preservation reaction at 15 ℃ for 15 hours, standing and layering after the reaction is finished, and removing a dichloromethane layer;
s2, dropwise adding a 2% acetic acid aqueous solution into the aqueous phase layer to adjust the pH value to 4.5, purifying by a medium-pressure preparative chromatograph, collecting a component solution containing the material, and freeze-drying to obtain 0.88g of a white solid tenofovir disoproxil fumarate degradation impurity compound I. HPLC purity 99.1%; wherein the medium-pressure preparative chromatography is separated by isocratic washing, the mobile phase is 4% acetonitrile pure water solution, the flow rate is 16mL/min, and the sample amount is 120 mg/needle.
Example 3(LiOH, 4.0eq)
The preparation method of the degradation impurity of the malonic acid propofol tenofovir comprises the following specific steps:
s1, adding 4.76g of prophenoltenofovir free alkali and 50mL of dichloromethane into a reaction bottle, and stirring for dissolving; stirring and dissolving 1.68g of lithium hydroxide monohydrate by using 20mL of water, adding the obtained lithium hydroxide monohydrate aqueous solution into a reaction bottle, carrying out heat preservation reaction at 15 ℃ for 15 hours, standing and layering after the reaction is finished, and removing a dichloromethane layer;
s2, dropwise adding 2% citric acid aqueous solution into the aqueous phase layer to adjust the pH value to 4.5, purifying by a medium-pressure preparative chromatograph, collecting component solution containing materials, and freeze-drying to obtain 2.66g of a white solid tenofovir disoproxil fumarate degradation impurity compound I. HPLC purity 99.4%; wherein the medium-pressure preparative chromatography is separated by isocratic washing, the mobile phase is 4% acetonitrile pure water solution, the flow rate is 13mL/min, and the sample amount is 90 mg/needle.
Example 4(LiOH, 4.5eq)
The preparation method of the degradation impurity of the malonic acid propofol tenofovir comprises the following specific steps:
s1, adding 4.76g of prophenoltenofovir free alkali and 50mL of dichloromethane into a reaction bottle, and stirring for dissolving; stirring and dissolving 1.89g of lithium hydroxide monohydrate by using 20mL of water, adding the obtained lithium hydroxide monohydrate aqueous solution into a reaction bottle, carrying out heat preservation reaction at 15 ℃ for 15 hours, standing and layering after the reaction is finished, and removing a dichloromethane layer;
s2, dropwise adding 2% citric acid aqueous solution into the aqueous phase layer to adjust the pH value to 4.5, purifying by a medium-pressure preparative chromatograph, collecting component solution containing materials, and freeze-drying to obtain 0.72g of a white solid tenofovir disoproxil fumarate degradation impurity compound I. HPLC purity 98.9%; wherein the medium-pressure preparative chromatography is separated by isocratic washing, the mobile phase is 4% acetonitrile pure water solution, the flow rate is 16mL/min, and the sample amount is 110 mg/needle.
Example 5(LiOH, 5.0eq)
The preparation method of the degradation impurity of the malonic acid propofol tenofovir comprises the following specific steps:
s1, adding 4.76g of prophenoltenofovir free alkali and 50mL of dichloromethane into a reaction bottle, and stirring for dissolving; stirring and dissolving another 2.10g of lithium hydroxide monohydrate by 25mL of water, adding the obtained lithium hydroxide monohydrate aqueous solution into a reaction bottle, carrying out heat preservation reaction at 10 ℃ for 20 hours, standing and layering the obtained product after the reaction is finished, removing a dichloromethane layer, and controlling the internal temperature of a water phase layer to be 20 ℃;
s2, dropwise adding a 2% acetic acid aqueous solution into the aqueous phase layer to adjust the pH value to 5.0, purifying by a medium-pressure preparative chromatograph, collecting a component solution containing the material, and freeze-drying to obtain 0.27g of a white solid propofol fumarate tenofovir degradation impurity compound I with the HPLC purity of 98.8%; wherein the medium-pressure preparative chromatography is separated by isocratic washing, the mobile phase is 4% acetonitrile pure water solution, the flow rate is 15mL/min, and the sample amount is 110 mg/needle.
Examples 6 to 9
This example prepared a tenofovir fumarate degrading impurity, substantially the same as in example 1, except that the ratio of the amounts of the materials of the tenofovir fumarate free base to lithium hydroxide (indicated as a in table 1) was different, as shown in table 1.
TABLE 1
Comparative examples 1 to 4
This comparative example prepared a tenofovir disoproxil fumarate degradation impurity substantially the same as example 1 except that the basic material was different, as shown in table 2.
TABLE 2
Test examples
The experimental example tests the structures of the impurity compound I degraded by the propane fumarate tenofovir prepared in examples 1-9.
Wherein:
the characterization results of the hydrogen nuclear magnetic resonance spectrum, the carbon spectrum, the Liquid Chromatography (LC) and the Mass Spectrometry (MS) of the impurity-degrading compound I prepared in example 1 are shown in fig. 1 to 4 respectively. The characterization results of other embodiments 2 to 9 are similar to those in fig. 1 to 4, and are not repeated for avoiding redundancy.
1H NMR(400MHz,Deuterium Oxide)δ8.02(s,1H),7.94(s,1H),4.15(dd,J＝14.7,3.8Hz,1H),4.05(dd,J＝14.6,6.2Hz,1H),3.79(td,J＝6.3,3.9Hz,1H),3.49–3.42(m,2H),3.33(dd,J＝12.8,8.9Hz,1H),1.06(d,J＝7.0Hz,3H),0.97(d,J＝6.3Hz,3H).；
13C NMR(101MHz,Deuterium Oxide)δ183.00(d,J＝5.3Hz),155.17,152.07,148.81,143.16,117.77,75.62,75.50,66.54,65.11,52.17,47.73,22.04,15.93.
[M+H+]：359。
The yields in the reaction solutions in examples 1 to 9 and comparative examples 1 to 4 are shown in Table 3:
TABLE 3
It can be seen from table 3 that the alkalinity of the selected alkaline substance has a significant effect on the formation of the product, thereby indicating that when the alkalinity is too strong, the raw material is easily hydrolyzed excessively; when the alkalinity is weak, no target product is generated. In addition, different amounts of the same basic substance also have a certain effect on the conversion rate, and too much or too little addition of the basic substance can reduce the conversion rate. Therefore, lithium hydroxide monohydrate has high reaction selectivity, and the amount of the substance has a large influence on the yield.
The embodiments of the present invention have been described in detail with reference to the accompanying drawings, but the present invention is not limited to the above embodiments, and various changes can be made within the knowledge of those skilled in the art without departing from the gist of the present invention. Furthermore, the embodiments of the present invention and the features of the embodiments may be combined with each other without conflict.
Claims (10)
1. A preparation method of a tenofovir disoproxil fumarate degradation impurity is characterized by comprising the following steps:
s1, mixing the free alkali of the tenofovir disoproxil, the lithium hydroxide aqueous solution and the chlorine-containing organic solvent to perform two-phase reaction to obtain reaction liquid;
s2, extracting a target product in the reaction solution through a liquid-phase preparation column to obtain a tenofovir disoproxil fumarate degradation impurity;
wherein the structural formula of the degradation impurity of the propane fumarate tenofovir is as follows:
2. the method for preparing degradation impurities of propofol fumarate and tenofovir according to claim 1, wherein the molar ratio of the free base of propofol and tenofovir hydroxide is 1: 3.2-5.
3. The method for preparing a degradation impurity of propofol fumarate and tenofovir as claimed in claim 1, wherein the reaction temperature in step S1 is 10-40 ℃.
4. The method for preparing a degradation impurity of propofol fumarate and tenofovir according to claim 1, wherein the reaction time in step S1 is 10.1-20 h.
5. The preparation method of a degradation impurity of propofol fumarate and tenofovir according to claim 1, wherein the volume ratio of the lithium hydroxide aqueous solution to the chlorine-containing organic solvent is 1.5-3: 5; the concentration of the lithium hydroxide in the lithium hydroxide aqueous solution is 2.0 mol/L-5.0 mol/L.
6. The method for preparing degradation impurity of propofol fumarate and tenofovir according to claim 5, wherein the chlorine-containing organic solvent is selected from one or more of dichloromethane, 1, 2-dichloroethane or chloroform.
7. The method for preparing degradation impurity of malonic acid propylphenol fumarate tenofovir according to any one of claims 1 to 4, wherein the method of extraction through the liquid phase preparation column in the step S2 is as follows:
and (S1) after the reaction liquid is layered, adjusting the pH value of a water layer to 3.5-6.5, purifying and extracting a target product in the reaction liquid through medium-pressure preparative chromatography, and drying to obtain the degradation impurity of the propane fumarate tenofovir.
8. The method for preparing a tenofovir disoproxil fumarate degradation impurity according to claim 7, wherein the pH value in the liquid phase preparative column extraction method in step S2 is 4.5-5.5.
9. The process of claim 7, wherein the medium pressure preparative chromatography uses an isocratic wash mode to isolate the desired product.
10. The method for preparing a degradation impurity of propofol fumarate and tenofovir according to claim 8, wherein the mobile phase used in the isocratic washing mode is an acetonitrile water solution with a volume fraction of 2.0-5.0%.
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