CN111303209A - Preparation method of degradation impurity of prophenoltenofovir - Google Patents
Preparation method of degradation impurity of prophenoltenofovir Download PDFInfo
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- CN111303209A CN111303209A CN202010204391.4A CN202010204391A CN111303209A CN 111303209 A CN111303209 A CN 111303209A CN 202010204391 A CN202010204391 A CN 202010204391A CN 111303209 A CN111303209 A CN 111303209A
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- 239000012535 impurity Substances 0.000 title claims abstract description 26
- 230000015556 catabolic process Effects 0.000 title claims abstract description 22
- 238000006731 degradation reaction Methods 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 claims abstract description 48
- 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 47
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 30
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 24
- 229960004556 tenofovir Drugs 0.000 claims abstract description 19
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims abstract description 16
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims abstract description 14
- HVLLSGMXQDNUAL-UHFFFAOYSA-N triphenyl phosphite Chemical group C=1C=CC=CC=1OP(OC=1C=CC=CC=1)OC1=CC=CC=C1 HVLLSGMXQDNUAL-UHFFFAOYSA-N 0.000 claims abstract description 14
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000003960 organic solvent Substances 0.000 claims abstract description 12
- 239000003054 catalyst Substances 0.000 claims abstract description 9
- 150000007530 organic bases Chemical class 0.000 claims abstract description 8
- 238000006482 condensation reaction Methods 0.000 claims abstract description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims abstract description 7
- RGUKYNXWOWSRET-UHFFFAOYSA-N 4-pyrrolidin-1-ylpyridine Chemical group C1CCCN1C1=CC=NC=C1 RGUKYNXWOWSRET-UHFFFAOYSA-N 0.000 claims abstract description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 4
- 230000018044 dehydration Effects 0.000 claims abstract description 4
- 238000006297 dehydration reaction Methods 0.000 claims abstract description 4
- 239000000376 reactant Substances 0.000 claims abstract description 4
- QJWQYVJVCXMTJP-UHFFFAOYSA-N 4-pyridin-4-ylmorpholine Chemical compound C1COCCN1C1=CC=NC=C1 QJWQYVJVCXMTJP-UHFFFAOYSA-N 0.000 claims abstract description 3
- 239000012024 dehydrating agents Substances 0.000 claims abstract description 3
- OLBCVFGFOZPWHH-UHFFFAOYSA-N propofol Chemical compound CC(C)C1=CC=CC(C(C)C)=C1O OLBCVFGFOZPWHH-UHFFFAOYSA-N 0.000 claims abstract 5
- 229960004134 propofol Drugs 0.000 claims abstract 5
- 238000000034 method Methods 0.000 claims description 9
- 230000035484 reaction time Effects 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 abstract description 10
- 239000000126 substance Substances 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 238000001914 filtration Methods 0.000 description 12
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 8
- 239000012065 filter cake Substances 0.000 description 8
- 238000004537 pulping Methods 0.000 description 8
- 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 7
- 229960003560 tenofovir alafenamide fumarate Drugs 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 238000012512 characterization method Methods 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 229940098779 methanesulfonic acid Drugs 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000001291 vacuum drying Methods 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 229960004693 tenofovir disoproxil fumarate Drugs 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 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
- MEJAFWXKUKMUIR-FHPNUNMMSA-N (e)-but-2-enedioic acid;propan-2-yl (2s)-2-[[[(2r)-1-(6-aminopurin-9-yl)propan-2-yl]oxymethyl-phenoxyphosphoryl]amino]propanoate 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 MEJAFWXKUKMUIR-FHPNUNMMSA-N 0.000 description 1
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 208000031886 HIV Infections Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010029155 Nephropathy toxic Diseases 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- -1 alkyl amides Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 208000016350 chronic hepatitis B virus infection Diseases 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 208000002672 hepatitis B Diseases 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000007694 nephrotoxicity Effects 0.000 description 1
- 231100000417 nephrotoxicity Toxicity 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000003017 phosphorus Chemical class 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011403 purification operation Methods 0.000 description 1
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
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- 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
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- 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)
Abstract
The invention belongs to the technical field of chemical pharmacy, and provides a preparation method of degradation impurities of propiophenol tenofovir, wherein tenofovir is used as a reactant, and the reaction is carried out with a dehydration reagent, a catalyst and an organic base in an organic solvent to obtain PMPA phosphoric anhydride through condensation reaction at 70-100 ℃ for 24-48 hours, the organic solvent is one or more of acetonitrile, toluene, N-methylpyrrolidone and N, N-dimethylformamide, the catalyst is 4-pyrrolidinylpyridine, 4-morpholinylpyridine or 4-dimethylaminopyridine, the organic base is pyridine, and the dehydrating agent is triphenyl phosphite. Through the technical scheme, the problems of high cost, low yield and low purity of the preparation method of the impurity PMPA phosphoric anhydride degraded by the propofol tenofovir in the prior art are solved.
Description
Technical Field
The invention belongs to the technical field of chemical pharmacy, and relates to a preparation method of degradation impurities of prophenoltenofovir.
Background
Propofovir Fumarate, the english name Tenofovir Alafenamide Fumarate (TAF), is chemically 9- { (R) -2- [ ((S) - { [ (S) -1- (isopropoxycarbonyl) ethyl ] amino } -phenoxyphosphinyl) methoxy ] propyl } adenine Fumarate (2:1), and is a nucleic acid reverse transcriptase inhibitor. Tenofovir fumarate, developed by Jilided scientific, USA, under the trade name Vemlidy, was approved by the FDA in the United states in 2016 and is currently used clinically for the treatment of chronic hepatitis B and HIV infection.
TAF and the most commonly used hepatitis B drug, namely Tenofovir Disoproxil Fumarate (TDF), are prodrugs of Tenofovir (TFV), and TAF can generate an antiviral effect equivalent to TDF only by one tenth of dosage, so that the risk of nephrotoxicity and osteoporosis is greatly reduced, and the safety and the tolerance are higher.
The molecular structure of TAF is shown below:
in the synthesis process of TAF, some byproducts are generated, wherein PMPA phosphoric anhydride as an impurity is a specific impurity, and the molecular structure of the PMPA phosphoric anhydride is shown as follows:
PMPA phosphoric anhydride was first disclosed in the report of Vi ja ya Mad hy na pu Golla et al, 2016, Stabilt biology of anti virology drivers and the hair combinations.4, Characterization of degradation products of not less than two alkyl amides e f uma te and com pa of not less than two rad and Sta biology of not less than two phosphorus derivatives, journal of Pharmaceutical and biological analysis.
Nanjing Zhengda Nintenbian pharmaceutical Co., Ltd discloses a synthesis method of PMPA phosphoric anhydride in patent CN109081853A for the first time, taking tenofovir as a raw material, and synthesizing PMPA phosphoric anhydride through condensation reaction in the presence of dehydrating agents (such as N, N' -dicyclohexylcarbodiimide, diisopropylcarbodiimide) and organic bases (triethylamine, 1, 8-diazabicycloundecen-7-ene), wherein the synthesis route is as follows:
in the preparation method, a preparation liquid phase with high cost is used for purification, the purity of the prepared PMPA phosphoric anhydride is lower than 95%, the highest yield is only 45.5%, the defects of high cost, low yield and low purity exist, and the obtained product is not suitable for serving as an impurity standard product. Therefore, it is very important to design a method for preparing PMPA phosphoric anhydride standard substance with simple operation, low cost and high purity.
Disclosure of Invention
The invention provides a preparation method of a prophenoltenofovir degradation impurity, which solves the problems of high cost, low yield and low purity of the preparation method of the prophenoltenofovir degradation impurity PMPA phosphoric anhydride in the prior art.
The technical scheme of the invention is realized as follows:
a preparation method of degradation impurities of propiophenol tenofovir is characterized in that tenofovir is used as a reactant, and the reaction is subjected to condensation reaction with a dehydration reagent, a catalyst and an organic base in an organic solvent to obtain PMPA phosphoric anhydride, wherein the reaction formula is as follows:
as a further technical scheme, the condensation reaction temperature is 70-100 ℃, and the reaction time is 24-48 hours.
As a further technical scheme, the organic solvent is one or more of acetonitrile, toluene, N-methyl pyrrolidone and N, N-dimethylformamide.
As a further technical scheme, the organic solvent is acetonitrile.
As a further technical scheme, the catalyst is 4-pyrrolidinylpyridine, 4-morpholinylpyridine or 4-dimethylaminopyridine.
As a further technical scheme, the catalyst is 4-dimethylamino pyridine.
As a further technical scheme, the organic base is pyridine.
As a further technical scheme, the dehydrating agent is triphenyl phosphite.
The working principle and the beneficial effects of the invention are as follows:
1. in the invention, the tenofovir is used as a raw material, and the raw material is subjected to condensation reaction with a dehydration reagent, a catalyst and organic base in an organic solvent to obtain PMPA phosphoric anhydride, so that the raw material is cheap and easy to obtain, the purification operation is simple and convenient, the production cost is greatly reduced, and the method is suitable for popularization and use.
2. The purity of PMPA phosphoric anhydride prepared by the preparation method in the prior art is lower than 95%, and the highest yield is only 45.5%, but the purity of PMPA phosphoric anhydride prepared by the preparation method is as high as 98.7%, and the yield is as high as 92.9%.
Drawings
FIG. 1 is an HPLC chromatogram of the degradation impurity PMPA phosphoric anhydride of Propofovir prepared in example 1 of the present invention;
FIG. 2 is a high resolution mass spectrum of the degradation impurity PMPA phosphoric anhydride of Propofovir prepared in example 1 of the present invention;
FIG. 3 is a nuclear magnetic resonance hydrogen spectrum of PMPA phosphoric anhydride as a degradation impurity of the Propofovir prepared in example 1 of the present invention;
FIG. 4 is a nuclear magnetic resonance carbon spectrum of PMPA phosphoric anhydride as a degradation impurity of Propofovir prepared in example 1 of the present invention.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
A preparation method of degradation impurities of prophenoltenofovir comprises the following steps:
s1, adding 90mL of acetonitrile, 30g of tenofovir, 24.8g of pyridine, 2.5g of 4-dimethylaminopyridine and 48.6g of triphenyl phosphite into a 500mL round-bottom flask, and stirring and heating until reflux reaction is carried out for 24 hours;
s2, after the reaction is finished, distilling under reduced pressure to remove the organic solvent, adding 300mL of N, N-dimethylformamide, adding methanesulfonic acid to adjust the pH value to 2-3, filtering, adding 300mL of N, N-dimethylformamide into a filter cake, pulping, quickly filtering, and repeating for 4 times; adding 300mL of ethyl acetate into the filter cake, pulping, quickly filtering, and repeating for 4 times; and (4) vacuum drying at 40 ℃ to obtain 26g of PMPA phosphoric anhydride, wherein the yield is 89.5%, and the HPLC purity is 98.7%.
Example 2
A preparation method of degradation impurities of prophenoltenofovir comprises the following steps:
s1, adding 60mL of acetonitrile, 60mL of toluene, 30g of tenofovir, 24.8g of pyridine, 2.5g of 4-dimethylaminopyridine and 48.6g of triphenyl phosphite into a 500mL round-bottom flask, and stirring and heating until reflux reaction is carried out for 24 hours;
s2, after the reaction is finished, carrying out reduced pressure distillation to remove the organic solvent, adding 300mL of N, N-dimethylformamide, adding methanesulfonic acid to adjust the pH value to 2-3, and quickly filtering; adding 300mL of N, N-dimethyl formamide into the filter cake, pulping, quickly filtering, and repeating for 4 times; adding 300mL of ethyl acetate into the filter cake, pulping, quickly filtering, and repeating for 4 times; and (4) performing vacuum drying at 40 ℃ to obtain 27g of PMPA phosphoric anhydride, wherein the yield is 92.9%, and the HPLC purity is 98.2%.
Example 3
A preparation method of degradation impurities of prophenoltenofovir comprises the following steps:
s1, adding 90mL of N-methylpyrrolidone, 30g of tenofovir and 24.8g of pyridine, 2.5g of 4-dimethylaminopyridine and 48.6g of triphenyl phosphite into a 500mL round-bottom flask, stirring and heating to 80 ℃ to react for 24 hours;
s2, after the reaction is finished, cooling to room temperature, adding methanesulfonic acid to adjust the pH value to 2-3, and quickly filtering; adding 300mL of N, N-dimethyl formamide into the filter cake, pulping, quickly filtering, and repeating for 4 times; adding 300mL of ethyl acetate into the filter cake, pulping, quickly filtering, and repeating for 4 times; and (4) performing vacuum drying at 40 ℃ to obtain 25.8g of PMPA phosphoric anhydride, wherein the yield is 89.0%, and the HPLC purity is 98.5%.
Example 4
A preparation method of degradation impurities of prophenoltenofovir comprises the following steps:
s1, adding 90mL of acetonitrile, 30g of tenofovir, 24.8g of pyridine, 3.1g of 4-pyrrolidinylpyridine and 48.6g of triphenyl phosphite into a 500mL round-bottom flask, and stirring and heating until reflux reaction is carried out for 24 hours;
s2, after the reaction is finished, carrying out reduced pressure distillation to remove the organic solvent, adding 300mL of N, N-dimethylformamide, adding methanesulfonic acid to adjust the pH value to 2-3, and quickly filtering; adding 300mL of N, N-dimethyl formamide into the filter cake, pulping, quickly filtering, and repeating for 4 times; adding 300mL of ethyl acetate into the filter cake, pulping, quickly filtering, and repeating for 4 times; and (3) carrying out vacuum drying at 40 ℃ to obtain 26.1g of PMPA phosphoric anhydride, wherein the yield is 90%, and the HPLC purity is 98.5%.
The characterization results of PMPA phosphoric anhydride prepared in example 1 are shown in FIGS. 1-4:
HRMS(m/e)：[M-H]-＝555.1393；
1H-NMR(400MHz，D2o) δ (ppm): 8.383(s, 2H), 8.316(s, 2H), 4.474(dd, 2H, J ═ 14.8Hz,6.1Hz), 4.275(dd, 2H, J ═ 14.8Hz,6.1Hz), 4.050(m, 2H), 3.851(m,2H), 3.766(m, 2H), 1.092(D, 6H, J ═ 6.1Hz), the active hydrogens of O-H and N-H are replaced by D2O is exchanged in1No signal peak is shown on the H-NMR spectrum.
13C-NMR(150MHz，D2O)δ(ppm)：18.97，50.88，67.29/68.40，78.56，120.35，147.84，148.50，151.50，152.99。
The above structural characterization test was performed on the monophenyl PMPA prepared in examples 2 to 4, and the characterization results were almost the same as those in FIGS. 1 to 4, and thus were omitted.
The present invention is not limited to the above preferred embodiments, and any modifications, equivalent substitutions, improvements, etc. within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (8)
1. A preparation method of prophenoltenofovir degradation impurities is characterized in that tenofovir is used as a reactant, and the reactant is subjected to condensation reaction with a dehydration reagent, a catalyst and organic base in an organic solvent to obtain PMPA phosphoric anhydride.
2. The method for preparing degradation impurities of propofol, tenofovir according to claim 1, wherein the condensation reaction temperature is 70-100 ℃ and the reaction time is 24-48 hours.
3. The method for preparing the degradation impurity of the propofol tenofovir according to claim 1, wherein the organic solvent is one or more of acetonitrile, toluene, N-methylpyrrolidone and N, N-dimethylformamide.
4. The method for preparing a degradation impurity of propofol, tenofovir according to claim 3, wherein, said organic solvent is acetonitrile.
5. The method for preparing a prophenoltenofovir degradation impurity according to claim 1, wherein the catalyst is 4-pyrrolidinylpyridine, 4-morpholinylpyridine or 4-dimethylaminopyridine.
6. The method for preparing a degradation impurity of propofol, tenofovir, according to claim 5, wherein, said catalyst is 4-dimethylaminopyridine.
7. The method of claim 1, wherein the organic base is pyridine.
8. The preparation method of prophenoltenofovir degradation impurity according to claim 1, wherein the dehydrating agent is triphenyl phosphite.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114195834A (en) * | 2021-12-29 | 2022-03-18 | 石家庄龙泽制药股份有限公司 | Preparation method of impurity of prophenoltenofovir lactose |
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| CN104105484A (en) * | 2012-02-03 | 2014-10-15 | 吉联亚科学公司 | Combination therapy comprising tenofovir alafenamide hemifumarate and cobicistat for use in the treatment of viral infections |
| CN109081853A (en) * | 2018-09-03 | 2018-12-25 | 南京正大天晴制药有限公司 | A kind of preparation method of the third tenofovir of phosphorus in relation to substance |
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Patent Citations (2)
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|---|---|---|---|---|
| CN104105484A (en) * | 2012-02-03 | 2014-10-15 | 吉联亚科学公司 | Combination therapy comprising tenofovir alafenamide hemifumarate and cobicistat for use in the treatment of viral infections |
| CN109081853A (en) * | 2018-09-03 | 2018-12-25 | 南京正大天晴制药有限公司 | A kind of preparation method of the third tenofovir of phosphorus in relation to substance |
Non-Patent Citations (2)
| Title |
|---|
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| CN114195834A (en) * | 2021-12-29 | 2022-03-18 | 石家庄龙泽制药股份有限公司 | Preparation method of impurity of prophenoltenofovir lactose |
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Application publication date: 20200619 |