CN111157644A - Tenofovir disoproxil related substance, preparation method and detection method thereof - Google Patents
Tenofovir disoproxil related substance, preparation method and detection method thereof Download PDFInfo
- Publication number
- CN111157644A CN111157644A CN202010003152.2A CN202010003152A CN111157644A CN 111157644 A CN111157644 A CN 111157644A CN 202010003152 A CN202010003152 A CN 202010003152A CN 111157644 A CN111157644 A CN 111157644A
- Authority
- CN
- China
- Prior art keywords
- phase
- compound
- formula
- formula iii
- volume ratio
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 238000001514 detection method Methods 0.000 title claims abstract description 12
- 229960001355 tenofovir disoproxil Drugs 0.000 title abstract description 19
- JFVZFKDSXNQEJW-CQSZACIVSA-N tenofovir disoproxil Chemical compound N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N JFVZFKDSXNQEJW-CQSZACIVSA-N 0.000 title abstract description 19
- 239000000126 substance Substances 0.000 title abstract description 15
- 150000001875 compounds Chemical class 0.000 claims description 32
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- 239000000243 solution Substances 0.000 claims description 14
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 14
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 12
- 239000003153 chemical reaction reagent Substances 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 8
- 238000010828 elution Methods 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 239000000010 aprotic solvent Substances 0.000 claims description 7
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- XRBCRPZXSCBRTK-UHFFFAOYSA-N phosphonous acid Chemical compound OPO XRBCRPZXSCBRTK-UHFFFAOYSA-N 0.000 claims description 6
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 6
- YWWDBCBWQNCYNR-UHFFFAOYSA-N trimethylphosphine Chemical compound CP(C)C YWWDBCBWQNCYNR-UHFFFAOYSA-N 0.000 claims description 6
- 239000003643 water by type Substances 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 5
- -1 triphenyl phosphonite Chemical compound 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 4
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims description 4
- 235000019796 monopotassium phosphate Nutrition 0.000 claims description 4
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical group CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 claims description 4
- 239000008363 phosphate buffer Substances 0.000 claims description 4
- 239000000377 silicon dioxide Substances 0.000 claims description 4
- VLSDXINSOMDCBK-BQYQJAHWSA-N (E)-1,1'-azobis(N,N-dimethylformamide) Chemical compound CN(C)C(=O)\N=N\C(=O)N(C)C VLSDXINSOMDCBK-BQYQJAHWSA-N 0.000 claims description 3
- 239000012295 chemical reaction liquid Substances 0.000 claims description 3
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 claims description 3
- NCBFTYFOPLPRBX-UHFFFAOYSA-N dimethyl azodicarboxylate Substances COC(=O)N=NC(=O)OC NCBFTYFOPLPRBX-UHFFFAOYSA-N 0.000 claims description 3
- HASCQPSFPAKVEK-UHFFFAOYSA-N dimethyl(phenyl)phosphine Chemical compound CP(C)C1=CC=CC=C1 HASCQPSFPAKVEK-UHFFFAOYSA-N 0.000 claims description 3
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 claims description 3
- NCBFTYFOPLPRBX-AATRIKPKSA-N methyl (ne)-n-methoxycarbonyliminocarbamate Chemical compound COC(=O)\N=N\C(=O)OC NCBFTYFOPLPRBX-AATRIKPKSA-N 0.000 claims description 3
- UJNZOIKQAUQOCN-UHFFFAOYSA-N methyl(diphenyl)phosphane Chemical compound C=1C=CC=CC=1P(C)C1=CC=CC=C1 UJNZOIKQAUQOCN-UHFFFAOYSA-N 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 claims description 3
- 239000008057 potassium phosphate buffer Substances 0.000 claims description 3
- QKSQWQOAUQFORH-UHFFFAOYSA-N tert-butyl n-[(2-methylpropan-2-yl)oxycarbonylimino]carbamate Chemical compound CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C QKSQWQOAUQFORH-UHFFFAOYSA-N 0.000 claims description 3
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 claims description 3
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 claims description 3
- RXJKFRMDXUJTEX-UHFFFAOYSA-N triethylphosphine Chemical compound CCP(CC)CC RXJKFRMDXUJTEX-UHFFFAOYSA-N 0.000 claims description 3
- 238000004811 liquid chromatography Methods 0.000 claims description 2
- 239000008055 phosphate buffer solution Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 1
- 239000012535 impurity Substances 0.000 abstract description 7
- 238000004458 analytical method Methods 0.000 abstract description 6
- 230000000694 effects Effects 0.000 abstract description 3
- 238000003908 quality control method Methods 0.000 abstract description 2
- 239000003814 drug Substances 0.000 description 9
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical class OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 239000013558 reference substance Substances 0.000 description 3
- 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 description 3
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000003443 antiviral agent Substances 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 229960004693 tenofovir disoproxil fumarate Drugs 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 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
- 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 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 208000000419 Chronic Hepatitis B Diseases 0.000 description 1
- 208000031886 HIV Infections Diseases 0.000 description 1
- 241000725303 Human immunodeficiency virus Species 0.000 description 1
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 1
- 238000006751 Mitsunobu reaction Methods 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 125000000848 adenin-9-yl group Chemical group [H]N([H])C1=C2N=C([H])N(*)C2=NC([H])=N1 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000000798 anti-retroviral effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 208000002672 hepatitis B Diseases 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- RCIJMMSZBQEWKW-UHFFFAOYSA-N methyl propan-2-yl carbonate Chemical compound COC(=O)OC(C)C RCIJMMSZBQEWKW-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 description 1
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
- LWIHDJKSTIGBAC-UHFFFAOYSA-K potassium phosphate Substances [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000012064 sodium phosphate buffer Substances 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000011895 specific detection Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229960004556 tenofovir Drugs 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 229910021642 ultra pure water Inorganic materials 0.000 description 1
- 239000012498 ultrapure water Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
-
- 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
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/50—Conditioning of the sorbent material or stationary liquid
- G01N30/52—Physical parameters
- G01N30/54—Temperature
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/62—Detectors specially adapted therefor
- G01N30/74—Optical detectors
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N2030/022—Column chromatography characterised by the kind of separation mechanism
- G01N2030/027—Liquid chromatography
Landscapes
- Chemical & Material Sciences (AREA)
- Physics & Mathematics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Health & Medical Sciences (AREA)
- Analytical Chemistry (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Organic Chemistry (AREA)
- Spectroscopy & Molecular Physics (AREA)
- Molecular Biology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the field of chemical pharmacy, and relates to a tenofovir disoproxil related substance, a preparation method and a detection method thereof. The invention discloses an impurity of tenofovir disoproxil shown in a formula III and a preparation method thereof, and in addition, the invention also provides a detection method of the impurity, which has important effects on the content analysis and quality control of tenofovir disoproxil.
Description
Technical Field
The invention belongs to the field of chemical pharmacy, and particularly relates to a tenofovir disoproxil related substance, and a preparation method and a detection method thereof.
Background
The Fumarate salt of Tenofovir Disoproxil Fumarate (hereinafter referred to as Tenofovir Disoproxil Fumarate) is a novel oral broad-spectrum antiviral drug developed by giread Sciences, inc, and is currently the first nucleotide analog approved by the FDA for the treatment of HIV-1 infection and recommended as a first-line antiviral drug. The drug was approved by the U.S. Food and Drug Administration (FDA) for use in combination with other antiretroviral drugs in the treatment of HIV-1 infected patients at 10 months 2001; in 11 months 2008, the FDA approved the drug for the treatment of chronic hepatitis b. The drug was introduced into China at 6 months 2008, and the approved indication was HIV, which has the following structural formula:
so far, the prior literatures and literature have disclosed a plurality of related substances of tenofovir disoproxil or fumarate thereof, and the structures of the related substances are mainly as follows:
wherein, the content of the related substance A is not more than 1.0 percent and the content of the related substances B to H is not more than 0.5 percent according to the regulation in the international pharmacopoeia.
The application provides a compound III with a brand-new structure, and the compound is a related substance generated in the synthesis of tenofovir disoproxil through separation, identification and structure confirmation. The compound III is successfully prepared by adopting a specific synthesis method, and the defects that in the prior art, when tenofovir is used for preparing tenofovir disoproxil, a plurality of impurities with very similar properties are generated, and the compound III is difficult to separate by conventional methods such as crystallization, column chromatography purification and the like, so that the quality of a tenofovir disoproxil medicine is not favorably controlled are overcome. The discovery of the compound III in the application can further improve the quality standard of tenofovir disoproxil, remarkably improve the quality of the existing medicine, improve the medication safety of the existing medicine, reduce possible toxic and side effects, and provide an important reference substance or standard substance.
Disclosure of Invention
The invention provides a compound of a formula III or a salt, a hydrate and a stereoisomer thereof, wherein the structural formula of the formula III is as follows:
in some embodiments, the compound of formula iii is 95% pure or greater; in some embodiments, the compound of formula iii is 97% pure or greater; in some embodiments, the compound of formula III is 98% pure
The above; in some embodiments, the compound of formula iii is 99% pure or greater.
The invention also provides a preparation method of the compound shown in the formula III, which comprises the following reaction route:
further, the preparation method comprises the following steps:
a. in the presence of an aprotic solvent, mixing a compound shown in a formula I, a compound shown in a formula II and a phosphine reagent, stirring according to the situation, and cooling to-5-0 ℃;
b. preparing a solution of an azo reagent in the presence of an aprotic solvent;
c. dropwise adding the solution of b into a;
and d, after the dropwise addition is finished, controlling the reaction temperature to obtain the compound shown in the formula III.
Still further, the step d further comprises the steps of:
d1. firstly, controlling the temperature of reaction liquid to be-5-0 ℃ and reacting for about 2 hours;
d2. then the reaction solution is moved to the room temperature and continuously reacted for 3 h-3 d.
Wherein the phosphine reagent comprises any one of trimethyl phosphine, triethyl phosphine, triphenyl phosphine, tributyl phosphine, tricyclohexyl phosphine, dimethyl phenyl phosphine, diphenyl methyl phosphine, trimethyl phosphonite, triethyl phosphonite or triphenyl phosphonite.
Preferably, the phosphine reagent is triphenylphosphine.
Wherein, the azo reagent comprises but is not limited to any one of dimethyl azodicarboxylate, diethyl azodicarboxylate, diisopropyl azodicarboxylate, di-tert-butyl azodicarboxylate and N, N, N ', N' -tetramethyl azodicarboxamide.
Preferably, the azo reagent is diisopropyl azodicarboxylate.
Wherein the aprotic solvent is tetrahydrofuran.
In a particular embodiment, there is provided a process for the preparation of a compound of formula iii, as illustrated in the reaction scheme below:
the preparation method comprises the following steps:
a. mixing a compound shown in a formula I, a compound shown in a formula II and triphenylphosphine in the presence of tetrahydrofuran, stirring according to the situation, and cooling to-5 ℃;
b. preparing a tetrahydrofuran solution of diisopropyl azodicarboxylate;
c. dropwise adding the solution of b into a;
d1. after the dropwise addition, controlling the temperature of the reaction liquid to be-5-0 ℃ and reacting for about 2 hours;
d2. then the reaction solution is moved to the room temperature and continuously reacted for 3 h-3 d.
In addition, the application also provides the application of the compound in the formula III as a standard substance or a reference substance. The present application also provides the use of a compound of formula III as a standard when examining impurities of tenofovir disoproxil or a pharmaceutically acceptable salt thereof.
In addition, the invention also provides an analysis method, which can detect the content and purity of the compound in the formula III in tenofovir disoproxil or pharmaceutically acceptable salt thereof, and can also detect the purity of the compound in the formula III; the method adopts an octadecylsilane chemically bonded silica liquid chromatographic column; the phase A in the mobile phase is a phosphate buffer solution with the pH value of 2-3; phase B is acetonitrile; performing gradient elution on the sample; and detecting by using an ultraviolet detector.
Preferably, the chromatography column is Waters Sunfire C18.
Preferably, the phosphate buffer is potassium phosphate buffer.
Preferably, the volume ratio of the mobile phase A to the mobile phase B is 90: 10-20: 80.
Further, the temperature of the chromatographic column is 30-40 ℃; the flow rate of the mobile phase is 0.5-1.5 mL/min; the ultraviolet detector detects the wavelength of 250 nm-260 nm.
Further, the gradient elution procedure was:
an embodiment of the present invention provides a specific detection method, which includes:
a chromatographic column: waters Sunfire C18, 4.6X 150mm, 3.5 μm;
a detector: a UV detector with the detection wavelength of 260 nm;
flow rate: 1.0 mL/min;
column temperature: 35 ℃;
mobile phase:
phase A: 25mmol/L potassium dihydrogen phosphate water solution, pH 2.5;
phase B: acetonitrile;
the gradient elution procedure was as follows:
| time, min | Phase A,%, volume ratio | Phase B,%, volume ratio |
| 0 | 90 | 10 |
| 2 | 90 | 10 |
| 6.5 | 60 | 40 |
| 11 | 55 | 45 |
| 16 | 46 | 54 |
| 22 | 30 | 70 |
| 26 | 26 | 74 |
| 27 | 90 | 10 |
| 35 | 90 | 10 |
。
In the present invention, the "aprotic solvent" is a solvent which does not give a proton in the reaction system, and includes, but is not limited to, benzene, toluene, diethyl ether, carbon tetrachloride, acetone, tetrahydrofuran, dimethylformamide, dimethylsulfoxide and the like.
In the present invention, the "phosphine reagent" is a phosphorus-containing compound commonly used in the mitsunobu reaction, and includes, but is not limited to, trimethylphosphine, triethylphosphine, triphenylphosphine, tributylphosphine, tricyclohexylphosphine, dimethylphenylphosphine, diphenylmethylphosphine, trimethyl phosphonite, triethyl phosphonite, triphenyl phosphonite, and the like.
In the present invention, the "azo reagent" is an aliphatic azo compound, including, but not limited to, dimethyl azodicarboxylate, diethyl azodicarboxylate, diisopropyl azodicarboxylate, di-tert-butyl azodicarboxylate, N, N, N ', N' -tetramethyl azodicarboxamide, and the like.
In the present invention, "salt" is a pharmaceutically acceptable salt, including but not limited to fumarate and the like.
In the present invention, the "octadecylsilane chemically bonded silica liquid chromatography column" is a chromatography column using octadecylsilane chemically bonded silica as a filler, and includes Waters Sunfire C18, and other chromatography columns having equivalent performance.
In the present invention, the "phosphate buffer" is a phosphate buffer, and includes a sodium phosphate buffer, a potassium phosphate buffer, and the like.
In the present invention, "%" means mass% unless otherwise specified.
In the present invention, unless otherwise specified, the water or aqueous solution used refers to the water for analysis generally used in the field of analysis, including but not limited to purified water, ultrapure water, deionized water, and the like.
In the present invention, whether or not "about" precedes a specific numerical value means that the specific numerical value may fluctuate within a range recognized in the art, and specifically may fluctuate within, for example, an absolute value of the specific numerical value ± 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%.
The invention provides a novel impurity of tenofovir disoproxil, a preparation method and a detection method thereof, wherein the preparation method is simple to operate and high in yield, and a compound with high purity as shown in a formula III can be quickly obtained by the method, so that the compound can be used as a standard reference substance of tenofovir disoproxil impurity; the analysis method can effectively separate the impurities with extremely close properties and the tenofovir disoproxil, and has important effects on the content analysis and quality control of the tenofovir disoproxil. In addition, when the content of the compound III in the tenofovir disoproxil or the salt thereof is less than 0.01%, the content of the compound III does not exceed 0.01% during subsequent storage (e.g., storage at room temperature for 3 or 6 months), thereby ensuring the quality of the product.
Detailed Description
The benefits of the present invention will now be further illustrated by the following examples, which are to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.
Example 1: preparation of ((R) -1- (6-amino-9H-purin-9-yl) propan-2-yl) oxy) (((((R) -1- (6-amino-9H-purin-9-yl)) propan-2-yl) oxy) methyl) phosphoryl) oxy) methyl isopropyl carbonate
Adding a compound I (1.00g, 2.48mmol), a compound II (1.20g, 6.21mmol) and triphenylphosphine (3.25g, 12.39mmol) into tetrahydrofuran (30mL) in a 100mL reaction bottle, stirring and dispersing, cooling to-5 ℃, dropwise adding a tetrahydrofuran (30mL) solution of diisopropyl azodicarboxylate (2.50g, 12.36mmol), controlling the temperature to be-5-0 ℃, continuing stirring for 2 hours, then moving the reaction bottle to room temperature, continuing to react for 3d, controlling the temperature to be slightly lower than 40 ℃, concentrating under reduced pressure to obtain a crude product of the compound III, separating and purifying the crude product by silica gel column chromatography, wherein an eluent is Dichloromethane (DCM) and methanol (MeOH) 100/0-85/15 (V/V), and carrying out gradient elution. Then collecting the purified liquid, concentrating under reduced pressure to obtain white solid product 0.43g with purity of 99.0%, and freezing for storage.
1H-NMR(500MHz,DMSO-d6):8.15(1H,s),8.14(1H,s)，8.03(1H,s),8.01(1H,s)，7.18(2H,s),7.21(2H,s,NH2)，5.44-5.47(2H,m,O-CH2-O),4.80(1H,m),4.21-4.27(2H,m),4.29-4.34(2H,m),3.82-3.84(2H,m),3.67(1H,m),3.68(1H,m),1.20-1.23(6H,d),1.00-1.07(6H,d)。
HRMS(+ESI):m/z 579.2195[M+H]+。
Example 2:
chromatographic conditions are as follows:
a chromatographic column: waters Sunfire C18, 4.6X 150mm, 3.5 μm;
a detector: a UV detector with the detection wavelength of 260 nm;
flow rate: 1.0 mL/min;
column temperature: 35 ℃;
sample introduction volume: 10 mu L of the solution;
mobile phase:
phase A: 25mmol/L potassium dihydrogen phosphate water solution;
phase B: acetonitrile;
the gradient elution procedure was as follows:
| time, min | Phase A,%, volume ratio | Phase B,%, volume ratio |
| 0 | 90 | 10 |
| 2 | 90 | 10 |
| 6.5 | 60 | 40 |
| 11 | 55 | 45 |
| 16 | 46 | 54 |
| 22 | 30 | 70 |
| 26 | 26 | 74 |
| 27 | 90 | 10 |
| 35 | 90 | 10 |
Preparation of a mobile phase:
mobile phase A: 3.4g of monopotassium phosphate is weighed, 1000mL of water is added, the pH is adjusted to 2.5 by phosphoric acid, the mixture is shaken well, filtered by a 0.22 mu m filter membrane and degassed.
Test solution: precisely weighing about 10mg of the compound shown in the formula III, placing the compound in a 10ml measuring flask, adding a proper amount of mobile phase A for ultrasonic dissolution, then adding the mobile phase A for dilution to scale, and shaking up to obtain the compound.
Under the detection conditions, the related substance shown in the formula III can be effectively separated from chromatographic peaks of tenofovir disoproxil and other related substances.
Claims (9)
1. A compound of formula III or a salt or hydrate thereof, having the formula:
2. a process for the preparation of a compound of formula iii according to claim 1, characterized in that: reacting the compound of formula I with the compound of formula II to obtain a compound of formula III,
3. the method of claim 2, comprising the steps of:
a. mixing a compound shown in a formula I, a compound shown in a formula II and a phosphine reagent in the presence of an aprotic solvent, stirring according to needs, and cooling to-5-0 ℃;
b. preparing a solution of an azo reagent in the presence of an aprotic solvent;
c. dropwise adding the solution in the step b into the step a;
and d, after the dropwise addition is finished, controlling the reaction temperature to obtain the compound shown in the formula III.
4. The method of claim 3, wherein the step d further comprises the steps of:
d1. firstly, controlling the temperature of reaction liquid to be-5-0 ℃ and reacting for about 2 hours;
d2. then the reaction solution is moved to the room temperature and continuously reacted for 3 h-3 d.
5. The production method according to any one of claims 3 to 4, wherein the phosphine reagent is selected from any one or more of trimethylphosphine, triethylphosphine, triphenylphosphine, tributylphosphine, tricyclohexylphosphine, dimethylphenylphosphine, diphenylmethylphosphine, trimethyl phosphonite, triethyl phosphonite, or triphenyl phosphonite; triphenylphosphine is preferred.
6. The process according to any one of claims 3 to 5, wherein the azo reagent is selected from any one or more of dimethyl azodicarboxylate, diethyl azodicarboxylate, diisopropyl azodicarboxylate, di-tert-butyl azodicarboxylate, N, N, N ', N' -tetramethyl azodicarboxamide; diisopropyl azodicarboxylate is preferred.
7. The process according to any one of claims 3 to 6, wherein the aprotic solvent is tetrahydrofuran.
8. A method of detecting a compound of formula iii according to claim 1, using an octadecylsilane bonded silica liquid chromatography column; the mobile phase A is a phosphate buffer solution with the pH value of 2-3; phase B is acetonitrile; performing gradient elution on the sample; detecting by adopting an ultraviolet detector; preferably, the chromatographic column is Waters Sunfire C18, and/or the phosphate buffer is potassium phosphate buffer, and/or the volume ratio of the phase A to the phase B is 90: 10-20: 80; further preferably, the temperature of the chromatographic column is 30-40 ℃, the flow rate of the mobile phase is 0.5-1.5 mL/min, and the detection wavelength of the ultraviolet detector is 250-260 nm; more preferably, the gradient elution procedure is:
。
9. The detection method according to claim 8, characterized in that:
a chromatographic column: waters Sunfire C18, 4.6X 150mm, 3.5 μm;
a detector: a UV detector with the detection wavelength of 260 nm;
flow rate: 1.0 mL/min;
column temperature: 35 ℃;
mobile phase:
phase A: 25mmol/L potassium dihydrogen phosphate water solution, pH 2.5;
phase B: acetonitrile;
the gradient elution procedure was as follows:
。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010003152.2A CN111157644A (en) | 2020-01-02 | 2020-01-02 | Tenofovir disoproxil related substance, preparation method and detection method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010003152.2A CN111157644A (en) | 2020-01-02 | 2020-01-02 | Tenofovir disoproxil related substance, preparation method and detection method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN111157644A true CN111157644A (en) | 2020-05-15 |
Family
ID=70561392
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010003152.2A Pending CN111157644A (en) | 2020-01-02 | 2020-01-02 | Tenofovir disoproxil related substance, preparation method and detection method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111157644A (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103641858A (en) * | 2013-12-31 | 2014-03-19 | 湖南千金湘江药业股份有限公司 | Tenofovir disoproxil fumarate and preparation method thereof |
| CN109867696A (en) * | 2017-12-04 | 2019-06-11 | 国药集团国瑞药业有限公司 | A kind of tenofovir dipivoxil tripolymer compound, preparation method and application |
-
2020
- 2020-01-02 CN CN202010003152.2A patent/CN111157644A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103641858A (en) * | 2013-12-31 | 2014-03-19 | 湖南千金湘江药业股份有限公司 | Tenofovir disoproxil fumarate and preparation method thereof |
| CN109867696A (en) * | 2017-12-04 | 2019-06-11 | 国药集团国瑞药业有限公司 | A kind of tenofovir dipivoxil tripolymer compound, preparation method and application |
Non-Patent Citations (4)
| Title |
|---|
| DUNGE ASHENAFI 等: "Development of a validated liquid chromatographic method for the determination of related substances and assay of tenofovir disoproxil fumarate", JOURNAL OF SEPARATION SCIENCE, vol. 33, no. 12, 30 June 2010 (2010-06-30), pages 1708 - 1716 * |
| J.KALPANA 等: "Rapid stability indicating RP-HPLC method for simultaneous quantification of related impurities of antiretroviral drugs", ASIAN JOURNAL OF CHEMISTRY, vol. 27, no. 7, 30 March 2015 (2015-03-30), pages 2393 - 2395 * |
| 万红艳 等: "HPLC法测定富马酸替诺福韦二吡呋酯原料药和胶囊中的有关物质", 中国药房, vol. 26, no. 6, 30 June 2015 (2015-06-30), pages 848 - 850 * |
| 李俊 等: "HPLC法测定富马酸替诺福韦二吡呋酯原料药的有关物质", 广东化工, vol. 43, no. 1, 31 January 2016 (2016-01-31), pages 129 - 130 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR20070088485A (en) | Purification of cinacalcet | |
| CN112047893B (en) | Gefitinib and salicylic acid co-crystal | |
| CN108047265A (en) | A kind of everolimus intermediate prepares purification process | |
| CN111410658B (en) | Impurity A and impurity B of midazolam or pharmaceutical composition thereof and application thereof | |
| CN111620908A (en) | Diastereoisomer of tenofovir alafenamide, preparation method and application thereof | |
| US11440934B2 (en) | Method for preparing cangrelor tetrasodium salt | |
| EP2669293B1 (en) | Preparation method of rocuronium | |
| CN115286521A (en) | Synthesis method of levosalbutamol hydrochloride | |
| US20190135859A1 (en) | Method of manufacturing a pharmaceutical composition | |
| RU2485121C1 (en) | Novel crystalline forms of adefovir dipivoxil and methods for production thereof | |
| CN111157644A (en) | Tenofovir disoproxil related substance, preparation method and detection method thereof | |
| CN116925169A (en) | Steroid compound, preparation method thereof and application thereof in research of impurities of canrenone and spironolactone | |
| CN105440082B (en) | A kind of lobaplatin crystal, preparation method and medicinal application | |
| CN108484624B (en) | Irinotecan hydrochloride impurity and synthesis method and application thereof | |
| CN111285876A (en) | Linagliptin intermediate isomer impurity, preparation method and application thereof | |
| CN104844604B (en) | A kind of preparation method of allopurinol sodium | |
| CN105440083B (en) | A kind of lobaplatin crystal, preparation method and medicinal application | |
| CN103483354B (en) | One class chromone compounds and preparation method thereof and antitumor with the application in enzyme inhibitor medicine in preparation | |
| JP2002080408A (en) | Method for separating organic compound | |
| CN105218587B (en) | A kind of lobaplatin crystal, preparation method and medicinal application | |
| CN109574919B (en) | Etoricoxib purification and preparation method | |
| CN113501846B (en) | Eimerosamine tenofovir hemi-fumaric acid compound, crystal form, preparation method and application thereof | |
| CN108373465B (en) | Dabigatran etexilate impurity and preparation and detection methods thereof | |
| CN114436925B (en) | M-diphenol ether compound, preparation method and application thereof | |
| WO2023236199A1 (en) | Crystal of n-(benzoyl)-phenylalanine compound, and pharmaceutical composition thereof, and preparation method therefor and use thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |