CN111560037A - Phosphate compound and preparation method and application thereof - Google Patents
Phosphate compound and preparation method and application thereof Download PDFInfo
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- CN111560037A CN111560037A CN202010464314.2A CN202010464314A CN111560037A CN 111560037 A CN111560037 A CN 111560037A CN 202010464314 A CN202010464314 A CN 202010464314A CN 111560037 A CN111560037 A CN 111560037A
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- compound
- phenyl
- phosphine oxide
- fluorophenyl
- substituted phenyl
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- -1 Phosphate compound Chemical class 0.000 title claims abstract description 121
- 229910019142 PO4 Inorganic materials 0.000 title claims abstract description 47
- 239000010452 phosphate Substances 0.000 title claims abstract description 47
- 238000002360 preparation method Methods 0.000 title abstract description 18
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 42
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 25
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims abstract description 24
- 125000001891 dimethoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract description 21
- 239000003814 drug Substances 0.000 claims abstract description 15
- 125000001207 fluorophenyl group Chemical group 0.000 claims abstract description 14
- 125000001624 naphthyl group Chemical group 0.000 claims abstract description 14
- 235000010290 biphenyl Nutrition 0.000 claims abstract description 13
- 239000004305 biphenyl Chemical group 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 8
- 239000005416 organic matter Substances 0.000 claims abstract description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 7
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 4
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 32
- 150000001875 compounds Chemical class 0.000 claims description 30
- 150000004820 halides Chemical class 0.000 claims description 12
- 239000002585 base Substances 0.000 claims description 7
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 6
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 claims description 4
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 4
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- FJBFPHVGVWTDIP-UHFFFAOYSA-N dibromomethane Chemical compound BrCBr FJBFPHVGVWTDIP-UHFFFAOYSA-N 0.000 claims description 4
- NZZFYRREKKOMAT-UHFFFAOYSA-N diiodomethane Chemical compound ICI NZZFYRREKKOMAT-UHFFFAOYSA-N 0.000 claims description 4
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 3
- 150000002894 organic compounds Chemical class 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 4
- AUONHKJOIZSQGR-UHFFFAOYSA-N oxophosphane Chemical compound P=O AUONHKJOIZSQGR-UHFFFAOYSA-N 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 13
- 229940079593 drug Drugs 0.000 abstract description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 43
- 238000001228 spectrum Methods 0.000 description 42
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- SMFFZOQLHYIRDA-UHFFFAOYSA-N 3,4-dimethoxyphenol Chemical compound COC1=CC=C(O)C=C1OC SMFFZOQLHYIRDA-UHFFFAOYSA-N 0.000 description 24
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
- YFPJFKYCVYXDJK-UHFFFAOYSA-N Diphenylphosphine oxide Chemical compound C=1C=CC=CC=1[P+](=O)C1=CC=CC=C1 YFPJFKYCVYXDJK-UHFFFAOYSA-N 0.000 description 21
- 238000001819 mass spectrum Methods 0.000 description 14
- 238000006243 chemical reaction Methods 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 239000000126 substance Substances 0.000 description 11
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- 238000004679 31P NMR spectroscopy Methods 0.000 description 7
- 239000011734 sodium Substances 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- 230000005311 nuclear magnetism Effects 0.000 description 6
- 239000002202 Polyethylene glycol Substances 0.000 description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 5
- 229910052760 oxygen Inorganic materials 0.000 description 5
- 239000001301 oxygen Substances 0.000 description 5
- 229910052698 phosphorus Inorganic materials 0.000 description 5
- 239000011574 phosphorus Substances 0.000 description 5
- 229920001223 polyethylene glycol Polymers 0.000 description 5
- JNNKFUNOEOWVSD-UHFFFAOYSA-N 1-fluoro-3-(3-fluorophenyl)phosphonoylbenzene Chemical compound FC1=CC=CC(P(=O)C=2C=C(F)C=CC=2)=C1 JNNKFUNOEOWVSD-UHFFFAOYSA-N 0.000 description 4
- HEPZFFPKWCVANH-UHFFFAOYSA-N 3-diphenylphosphoryloxypropane-1,2-diol Chemical compound OCC(O)COP(=O)(c1ccccc1)c1ccccc1 HEPZFFPKWCVANH-UHFFFAOYSA-N 0.000 description 4
- KKBXIQVJXZVRHH-UHFFFAOYSA-N C1=CC=C2C(P(C=3C4=CC=CC=C4C=CC=3)=O)=CC=CC2=C1 Chemical compound C1=CC=C2C(P(C=3C4=CC=CC=C4C=CC=3)=O)=CC=CC2=C1 KKBXIQVJXZVRHH-UHFFFAOYSA-N 0.000 description 4
- BURLUCWESWRNKW-UHFFFAOYSA-N C=1C=C(C=2C=CC=CC=2)C=CC=1P(=O)C(C=C1)=CC=C1C1=CC=CC=C1 Chemical compound C=1C=C(C=2C=CC=CC=2)C=CC=1P(=O)C(C=C1)=CC=C1C1=CC=CC=C1 BURLUCWESWRNKW-UHFFFAOYSA-N 0.000 description 4
- RULHCULEISLQMT-UHFFFAOYSA-N COC1=CC(OC)=CC(P(=O)C=2C=C(OC)C=C(OC)C=2)=C1 Chemical group COC1=CC(OC)=CC(P(=O)C=2C=C(OC)C=C(OC)C=2)=C1 RULHCULEISLQMT-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- CLERWYLNXGOODS-UHFFFAOYSA-N [PH2](OC1=CC(=CC=C1)F)=O Chemical compound [PH2](OC1=CC(=CC=C1)F)=O CLERWYLNXGOODS-UHFFFAOYSA-N 0.000 description 4
- BHIIGRBMZRSDRI-UHFFFAOYSA-N [chloro(phenoxy)phosphoryl]oxybenzene Chemical compound C=1C=CC=CC=1OP(=O)(Cl)OC1=CC=CC=C1 BHIIGRBMZRSDRI-UHFFFAOYSA-N 0.000 description 4
- MIYITCTXDGORJJ-UHFFFAOYSA-N bis(4-fluorophenyl)-oxophosphanium Chemical group C1=CC(F)=CC=C1[P+](=O)C1=CC=C(F)C=C1 MIYITCTXDGORJJ-UHFFFAOYSA-N 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 231100000331 toxic Toxicity 0.000 description 4
- 230000002588 toxic effect Effects 0.000 description 4
- QYIXCDOBOSTCEI-QCYZZNICSA-N (5alpha)-cholestan-3beta-ol Chemical compound C([C@@H]1CC2)[C@@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@H](C)CCCC(C)C)[C@@]2(C)CC1 QYIXCDOBOSTCEI-QCYZZNICSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- FEOVBLSXJYRJOY-UHFFFAOYSA-N O=[PH2]Oc1cccc2ccccc12 Chemical compound O=[PH2]Oc1cccc2ccccc12 FEOVBLSXJYRJOY-UHFFFAOYSA-N 0.000 description 3
- QYIXCDOBOSTCEI-UHFFFAOYSA-N alpha-cholestanol Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(C)CCCC(C)C)C1(C)CC2 QYIXCDOBOSTCEI-UHFFFAOYSA-N 0.000 description 3
- 239000002259 anti human immunodeficiency virus agent Substances 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 239000003426 co-catalyst Substances 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000007800 oxidant agent Substances 0.000 description 3
- 230000001590 oxidative effect Effects 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- VSTXCZGEEVFJES-UHFFFAOYSA-N 1-cycloundecyl-1,5-diazacycloundec-5-ene Chemical compound C1CCCCCC(CCCC1)N1CCCCCC=NCCC1 VSTXCZGEEVFJES-UHFFFAOYSA-N 0.000 description 2
- MJISHEUWOLGNHK-UHFFFAOYSA-N 1-fluoro-3-[(3-fluorophenyl)-methoxyphosphoryl]benzene Chemical compound C=1C=CC(F)=CC=1P(=O)(OC)C1=CC=CC(F)=C1 MJISHEUWOLGNHK-UHFFFAOYSA-N 0.000 description 2
- 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 description 2
- 208000030507 AIDS Diseases 0.000 description 2
- 229940124321 AIDS medicine Drugs 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 241000238631 Hexapoda Species 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- 241000607479 Yersinia pestis Species 0.000 description 2
- 230000000843 anti-fungal effect Effects 0.000 description 2
- 229940121375 antifungal agent Drugs 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- 150000001868 cobalt Chemical class 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000005265 energy consumption Methods 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- YNPNZTXNASCQKK-UHFFFAOYSA-N phenanthrene Chemical compound C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- 238000004293 19F NMR spectroscopy Methods 0.000 description 1
- CFMZSMGAMPBRBE-UHFFFAOYSA-N 2-hydroxyisoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(O)C(=O)C2=C1 CFMZSMGAMPBRBE-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- RYFWKKPOIPDSBC-UHFFFAOYSA-N O=[PH2]C1=CC=CC=C1C1=CC=CC=C1 Chemical group O=[PH2]C1=CC=CC=C1C1=CC=CC=C1 RYFWKKPOIPDSBC-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000004134 energy conservation Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000002917 insecticide Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- BCDIWLCKOCHCIH-UHFFFAOYSA-M methylphosphinate Chemical compound CP([O-])=O BCDIWLCKOCHCIH-UHFFFAOYSA-M 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 239000012434 nucleophilic reagent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 229940113115 polyethylene glycol 200 Drugs 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000027756 respiratory electron transport chain Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
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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
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/30—Phosphinic acids R2P(=O)(OH); Thiophosphinic acids, i.e. R2P(=X)(XH) (X = S, Se)
- C07F9/32—Esters thereof
- C07F9/3205—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/3229—Esters of aromatic acids (P-C aromatic linkage)
-
- 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
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/30—Phosphinic acids R2P(=O)(OH); Thiophosphinic acids, i.e. R2P(=X)(XH) (X = S, Se)
- C07F9/32—Esters thereof
- C07F9/3258—Esters thereof the ester moiety containing a substituent or a structure which is considered as characteristic
- C07F9/3264—Esters with hydroxyalkyl compounds
-
- 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
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/30—Phosphinic acids R2P(=O)(OH); Thiophosphinic acids, i.e. R2P(=X)(XH) (X = S, Se)
- C07F9/32—Esters thereof
- C07F9/3258—Esters thereof the ester moiety containing a substituent or a structure which is considered as characteristic
- C07F9/3282—Esters with hydroxyaryl compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J51/00—Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00
Abstract
The invention discloses a phosphate compound and a preparation method and application thereof, wherein the phosphate compound has a molecular structure shown in a formula (I):
wherein R is1Is one of phenyl, biphenyl, fluorophenyl, dimethoxy substituted phenyl and naphthyl; r2Is one of phenyl, biphenyl, fluorophenyl, dimethoxy substituted phenyl and naphthyl; r3Is (3S, 5S, 8R, 9S, 10S, 13R, 14S, 17R) -10, 13-dimethyl-17- ((R) -6-methylheptan-2-yl) hexadecahydro-1H-cyclopentane [ a ]]One of phenanthrene-3-yl, dimethoxy substituted phenyl, 2, 3-dihydroxypropyl and methyl, wherein when R is3When it is methyl, R1And R2Is not phenyl. The invention uses certain proportion of phosphine oxide compound and hydroxyl group to substituteThe organic matter is used as the raw material, the phosphate compound is prepared under mild conditions, the yield is high, and the method can be applied to the field of drug synthesis.
Description
Technical Field
The invention relates to the technical field of organic synthesis, and particularly relates to a phosphate compound and a preparation method and application thereof.
Background
The phosphate ester compound has certain medicinal activity, is widely applied in the aspect of medicine, and can also be used for preventing and treating various plant diseases and insect pests in agriculture. Chinese patent CN107522741A proposes a phosphate ester compound, which is synthesized by taking alcohol and H-phosphite ester compounds as raw materials, taking oxygen as an oxidant, taking divalent cobalt salt and N-hydroxyphthalimide as a co-catalyst, and reacting at 80-110 ℃ for 12-18H to obtain the phosphate ester compound, but the preparation method uses toxic cobalt salt as a catalyst, needs to react at high temperature for a long time, has large energy consumption and low yield, is not beneficial to energy conservation and environmental protection, and is not beneficial to industrial production. Therefore, there is a need for a new phosphate compound and a new preparation method thereof, which has milder reaction conditions and higher yield, and does not require toxic salts as a catalyst.
Disclosure of Invention
The invention aims to solve the technical problems of the preparation of the existing phosphate compound that toxic salts are used as catalysts, high-temperature conditions are needed, energy consumption is high, and the yield is low, and provides the phosphate compound.
The invention also aims to provide a preparation method of the phosphate compound.
The invention also aims to provide application of the phosphate compound.
The above purpose of the invention is realized by the following technical scheme:
a phosphate ester compound has a molecular structure shown in a formula (I):
wherein R is1Is one of phenyl, biphenyl, fluorophenyl, dimethoxy substituted phenyl and naphthyl; r2Is one of phenyl, biphenyl, fluorophenyl, dimethoxy substituted phenyl and naphthyl; r3Is (3S, 5S, 8R, 9S, 10S, 13R, 14S, 17R) -10, 13-dimethyl-17- ((R) -6-methylheptan-2-yl) hexadecahydro-1H-cyclopentane [ a ]]One of phenanthrene-3-yl, dimethoxy substituted phenyl, 2, 3-dihydroxypropyl and methyl, wherein when R is3When it is methyl, R1And R2Is not phenyl.
Preferably, said R is1Is one of fluorophenyl, dimethoxy substituted phenyl and naphthyl; r2Is one of fluorophenyl, dimethoxy substituted phenyl and naphthyl; r3Is (3S, 5S, 8R, 9S, 10S, 13R, 14S, 17R) -10, 13-dimethyl-17- ((R) -6-methylheptan-2-yl) hexadecahydro-1H-cyclopentane [ a ]]Phenanthrene-3-yl, dimethoxy substituted phenyl and 2, 3-dihydroxypropyl.
More preferably, said R1Is one of 3-fluorophenyl, 3, 5-dimethoxy substituted phenyl and 1-naphthyl; r2Is one of 3-fluorophenyl, 3, 5-dimethoxy substituted phenyl and 1-naphthyl; r3Is (3S, 5S, 8R, 9S, 10S, 13R, 14S, 17R) -10, 13-dimethyl-17- ((R) -6-methylheptan-2-yl) hexadecahydro-1H-cyclopentane [ a ]]Phenanthrene-3-yl, 3, 4-dimethoxy substituted phenyl and 2, 3-dihydroxypropyl.
Further preferably, the molecular structure has a molecular structure represented by the formulae (II) to (VIII):
the invention protects the preparation method of the phosphate compound, which comprises the following steps:
in a molar ratio of1: 1-10 phosphine oxide compound and hydroxyl substituted organic matter are dissolved by organic solvent, and then halide and alkali are added to react for 2-5 h at 10-40 ℃, and nucleophilic substitution is carried out to generate phosphate compound; the molar ratio of phosphine oxide compound to halide is 1: 0.1 to 1.5; the molar ratio of phosphine oxide compound to base is 1: 0.5 to 3; the molecular structure of the phosphine oxide compound is
The molecular structure of the hydroxyl-substituted organic matter is R3-OH, wherein R1Is one of phenyl, biphenyl, fluorophenyl, dimethoxy substituted phenyl and naphthyl; r2Is one of phenyl, biphenyl, fluorophenyl, dimethoxy substituted phenyl and naphthyl; r3Is (3S, 5S, 8R, 9S, 10S, 13R, 14S, 17R) -10, 13-dimethyl-17- ((R) -6-methylheptan-2-yl) hexadecahydro-1H-cyclopentane [ a ]]One of phenanthrene-3-yl, dimethoxy substituted phenyl, 2, 3-dihydroxypropyl and methyl, wherein when R is3When it is methyl, R1And R2Is not phenyl.
The invention designs and synthesizes a phosphate compound, the preparation method takes phosphine oxide compound and hydroxyl substituted organic matter with a certain proportion as raw materials, oxygen as oxidant, trace halide and alkali as co-catalyst, phosphorus free radical with higher activity is generated by reaction, and finally the phosphate compound is prepared by nucleophilic substitution reaction, the reaction condition is mild, and the phosphate compound has wide substrate adaptability and high yield.
Preferably, the molar ratio of the phosphine oxide compound to the hydroxyl-substituted organic substance is 1: 1-5.
Preferably, the molar ratio of phosphine oxide compound to halide is 1:1 to 1.5.
Preferably, the molar ratio of phosphine oxide compound to base is 1: 1.5 to 2.
Preferably, the halide is one of carbon tetrachloride, chloroform, methylene bromide, diiodomethane and 1, 2-dibromoethane.
More preferably, the halide is one of carbon tetrachloride, chloroform and methylene bromide.
Further preferably, the halide is chloroform.
Preferably, the base is one of sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, potassium phosphate, triethylamine, 1, 8-diazabicycloundecen-7-ene.
More preferably, the base is one of sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, 1, 8-diazabicycloundec-7-ene.
Further preferably, the base is 1, 8-diazabicycloundecen-7-ene.
Preferably, the organic solvent is one of N, N-dimethylformamide, acetonitrile, polyethylene glycol 200, polyethylene glycol 40, dichloromethane, water, nitromethane, 1, 2-dichloroethane, tetrahydrofuran, and dimethylsulfoxide.
Preferably, the reaction temperature is 25 ℃ and the reaction time is 3 h.
Preferably, the preparation method further comprises the following steps of post-treatment:
after the reaction is finished, ethyl acetate is added to quench the reaction, saturated sodium sulfate solution is used for washing, an organic phase is separated, a water phase is extracted for 3 times by ethyl acetate, the organic phase is combined, and column chromatography separation is carried out to obtain the phosphate compound.
The invention also protects the application of the phosphate compound in synthesizing medicaments.
Furthermore, the medicine is anti-AIDS medicine, antifungal medicine, anticancer medicine, and pesticide.
The phosphate ester compound has pharmaceutical activity, is mostly used as a skeleton of a drug molecule, not only can be used for treating various diseases such as viruses and cancers, but also can be used for preventing and treating various plant diseases and insect pests in agriculture.
Compared with the prior art, the invention has the beneficial effects that:
the invention synthesizes a new phosphate compound, the preparation method is more efficient and environment-friendly, specifically, phosphine oxide compound and hydroxyl substituted organic matter with a certain proportion are used as raw materials, halide and alkali are used as co-catalysts, the reaction is carried out in the air atmosphere, oxygen is used as an oxidant, the phosphine oxide compound and the hydroxyl substituted organic matter are subjected to nucleophilic substitution reaction at normal pressure and low temperature to generate the phosphate compound, and the selection of substrates is wide; compared with the traditional method, the method has the advantages of mild conditions, less waste discharge, simple reaction equipment, easy industrial production and the like; the method does not need toxic salts as a catalyst, utilizes oxygen in the air for oxidation, has mild reaction conditions and high yield which can reach 100 percent at most, and is environment-friendly; and the method can be applied to the field of drug synthesis, and provides more phosphate compounds as choices for the research of synthetic drugs.
Drawings
FIG. 1 shows the nuclear magnetic H spectrum of 3, 4-dimethoxyphenyldiphenylphosphinate prepared in example 1.
FIG. 2 shows the nuclear magnetic C spectrum of 3, 4-dimethoxyphenyl diphenylphosphinate prepared in example 1.
FIG. 3 is a nuclear magnetic P spectrum of 3, 4-dimethoxyphenyldiphenylphosphinate prepared in example 1.
FIG. 4 is a nuclear magnetic H spectrum of 2, 3-dihydroxypropyldiphenylphosphinate prepared in example 2.
FIG. 5 is a nuclear magnetic C spectrum of 2, 3-dihydroxypropyldiphenylphosphinate prepared in example 2.
FIG. 6 is a nuclear magnetic P spectrum of 2, 3-dihydroxypropyldiphenylphosphinate prepared in example 2.
FIG. 7 is a nuclear magnetic H spectrum of methyl bis [ [1,1' -biphenyl ] -4-yl ] phosphinate obtained in example 3.
FIG. 8 is a nuclear magnetic C spectrum of methyl bis [ [1,1' -biphenyl ] -4-yl ] phosphinate obtained in example 3.
FIG. 9 is a nuclear magnetic P spectrum of methyl bis [ [1,1' -biphenyl ] -4-yl ] phosphinate obtained in example 3.
FIG. 10 is a nuclear magnetic H spectrum of methyl bis (3-fluorophenyl) phosphinate obtained in example 4.
FIG. 11 is a nuclear magnetic C spectrum of methyl bis (3-fluorophenyl) phosphinate obtained in example 4.
FIG. 12 is a nuclear magnetic P spectrum of methyl bis (3-fluorophenyl) phosphinate obtained in example 4.
FIG. 13 is a nuclear magnetic H spectrum of methyl bis (3, 5-dimethoxyphenyl) phosphinate prepared in example 5.
FIG. 14 is a nuclear magnetic C spectrum of methyl bis (3, 5-dimethoxyphenyl) phosphinate prepared in example 5.
FIG. 15 is a nuclear magnetic P spectrum of methyl bis (3, 5-dimethoxyphenyl) phosphinate prepared in example 5.
FIG. 16 is a nuclear magnetic H spectrum of methyl bis (naphthalen-1-yl) phosphinate prepared in example 6.
FIG. 17 is a nuclear magnetic C spectrum of methyl bis (naphthalen-1-yl) phosphinate prepared in example 6.
FIG. 18 is a nuclear magnetic P spectrum of methyl bis (naphthalen-1-yl) phosphinate prepared in example 6.
FIG. 19 is a nuclear magnetic H spectrum of (3S, 5S, 8R, 9S, 10S, 13R, 14S, 17R) -10, 13-dimethyl-17- ((R) -6-methylheptan-2-yl) hexadecahydro-1H-cyclopenta [ a ] phenanthreneanthracene-3-diphenylphosphinate prepared in example 7.
FIG. 20 is a nuclear magnetic C spectrum of (3S, 5S, 8R, 9S, 10S, 13R, 14S, 17R) -10, 13-dimethyl-17- ((R) -6-methylheptan-2-yl) hexadecahydro-1H-cyclopenta [ a ] phenanthreneanthracene-3-diphenylphosphinate prepared in example 7.
FIG. 21 is a nuclear magnetic P spectrum of (3S, 5S, 8R, 9S, 10S, 13R, 14S, 17R) -10, 13-dimethyl-17- ((R) -6-methylheptan-2-yl) hexadecahydro-1H-cyclopenta [ a ] phenanthreneanthracene-3-diphenylphosphinate prepared in example 7.
Detailed Description
The present invention will be further described with reference to specific embodiments, but the present invention is not limited to the examples in any way. The starting reagents employed in the examples of the present invention are, unless otherwise specified, those that are conventionally purchased.
Example 1
A phosphate compound is 3, 4-dimethoxy phenyl diphenyl phosphinate, and has a molecular structure shown as a formula (II):
a process for the preparation of a compound of formula (ii) as described above comprising the steps of:
a15 mL pressure-resistant reaction tube was charged with 61mg of diphenylphosphineoxide, 231mg of 3, 4-dimethoxyphenol, 36mg of chloroform, 69mg of 1, 8-diazabicycloundec-7-ene (DBU), and 2mL of acetonitrile, and the mixture was left to react with the mixture under an open atmosphere and stirred at room temperature for 3 hours. After the reaction is finished, 10mL of ethyl acetate is added to quench the reaction, 10mL of saturated sodium sulfate solution is used for washing, an organic phase is separated, a water phase is extracted for 3 times by ethyl acetate, the organic phase is combined, and the 3, 4-dimethoxy phenyl diphenyl phosphinate pure product (colorless oily substance) is obtained by column chromatography separation, wherein the yield is 95%; wherein the molar ratio of the diphenyl phosphine oxide to the 3, 4-dimethoxyphenol is 1: 5, the molar ratio of diphenyl phosphine oxide to chloroform is 1:1, the molar ratio of diphenyl phosphine oxide to DBU is 1: 1.5.
the nuclear magnetic results of the compound of formula (II) are shown in FIG. 1,1H NMR(400MHz,CDCl3)7.88(dd,J＝12.5,8.0Hz,4H),7.58–7.40(m,6H),6.75(s,1H),6.68(s,2H),3.78(s,3H),3.75(s,3H).
as can be seen from the figure 2 of the drawings,13C NMR(101MHz,CDCl3)149.39,146.03,144.51(d,J＝8.4Hz),132.43(d,J＝2.9Hz),131.84(d,J＝10.3Hz),130.95(d,J＝138.0Hz),128.56(d,J＝13.4Hz),111.98(d,J＝4.7Hz),111.35,105.40(d,J＝4.5Hz),56.12,55.93.
as can be seen from the figure 3 of the drawings,31P NMR(162MHz,CDCl3)30.57.
the mass spectrum results for the compound of formula (ii) above are: HRMS (ESI-Orbitrap) M/z: [ M + Na]+calcdforC20H19O4PNa 377.09132,found 377.09082.
The obtained substance is proved to be 3, 4-dimethoxyphenyl diphenyl phosphinate by combining the nuclear magnetism H spectrum, the nuclear magnetism C spectrum, the nuclear magnetism P spectrum and the mass spectrum.
The reaction mechanism is as follows: firstly, removing a proton from diphenyl phosphine oxide (1) under the action of oxygen through single electron transfer to generate a phosphorus free radical (2), then capturing a chlorine in chloroform by the phosphorus free radical (2) to generate diphenyl phosphoryl chloride (3) and a dichloromethyl free radical (4), wherein the dichloromethyl free radical (4) can initiate the diphenyl phosphine oxide (1) to generate the phosphorus free radical (2) and dichloromethane, and finally, 3, 4-dimethoxyphenol (5) serving as a nucleophilic reagent attacks the phosphorus in the diphenyl phosphoryl chloride (3) to generate 3, 4-dimethoxyphenyl diphenyl phosphinate (6) and hydrogen chloride.
The 3, 4-dimethoxyphenyl diphenyl phosphinate can be used as a raw material of anti-AIDS drugs.
Example 2
A phosphate ester compound is 2, 3-dihydroxypropyl diphenyl phosphinate, and has a molecular structure shown as a formula (III):
the compound of the formula (III) was prepared in the same manner as in example 1 except that 231mg of 3, 4-dimethoxyphenol was replaced with 138mg of glycerol to give 85mg of pure 2, 3-dihydroxypropyldiphenylphosphinate in 96% yield; wherein the molar ratio of diphenyl phosphine oxide to glycerol is 1: 5, the molar ratio of diphenyl phosphine oxide to chloroform is 1:1, the molar ratio of diphenyl phosphine oxide to DBU is 1: 1.5.
the nuclear magnetic results of the compound of formula (III) are shown in FIG. 4,1H NMR(400MHz,CDCl3)7.85–7.75(m,4H),7.60–7.51(m,2H),7.50–7.41(m,4H),4.11(dd,J＝11.0,5.0Hz,2H),3.95(p,J＝4.8Hz,1H),3.71(d,J＝4.7Hz,2H).
as can be seen from the figure 5 of the drawings,13C NMR(101MHz,CDCl3)132.95–132.27(m),131.67(dd,J＝10.3,6.2Hz),130.99–129.28(m),128.78(dd,J＝13.3,2.3Hz),70.76(d,J＝3.4Hz),67.17(d,J＝6.3Hz),62.69.
as can be seen from the figure 6 of the drawings,31P NMR(162MHz,CDCl3)36.24.
the mass spectrum results for the compound of formula (iii) above are: HRMS (ESI-Orbitrap) M/z: [ M + Na]+calcdforC15H17O4PNa 315.07567,found 315.0755.
The obtained substance is proved to be 2, 3-dihydroxypropyl diphenyl phosphinate by combining the nuclear magnetism H spectrum, the nuclear magnetism C spectrum, the nuclear magnetism P spectrum and the mass spectrum.
The 2, 3-dihydroxypropyl diphenyl phosphinate can be used as a raw material of an insecticide.
Example 3
A phosphate compound is bis (1, 1' -biphenyl)]-4-yl]The phosphate ester compound has a molecular structure shown in a formula (IV):
the preparation process of the compound of the above formula (IV) was the same as in example 1 except that 106mg of bis ([1,1 '-biphenyl ] -4-yl) phosphine oxide was substituted for diphenylphosphine oxide, 48mg of 3, 4-dimethoxyphenol was substituted for methanol, and 2002mL of acetonitrile was substituted for polyethylene glycol to give 98mg of methyl bis [ [1,1' -biphenyl ] -4-yl ] phosphinate as a pure product (white solid) in a yield of 85%; wherein the molar ratio of bis ([1,1' -biphenyl ] -4-yl) phosphine oxide to methanol is 1: 5, bis ([1,1' -biphenyl ] -4-yl) phosphine oxide to chloroform molar ratio of 1:1, bis ([1,1' -biphenyl ] -4-yl) phosphine oxide to DBU molar ratio of 1: 1.5.
the nuclear magnetic results of the above compound of formula (VII) are shown in FIG. 7,1H NMR(400MHz,CDCl3)7.94(dd,J＝11.9,8.3Hz,4H),7.70(dd,J＝8.3,3.2Hz,4H),7.63–7.56(m,4H),7.48–7.42(m,4H),7.41–7.35(m,2H),3.83(d,J＝11.2Hz,3H).
as can be seen from the graph of figure 8,13C NMR(101MHz,CDCl3)144.93(d,J＝2.9Hz),139.77,132.07(d,J＝10.5Hz),130.24,128.81,128.05,127.27,127.13,51.50(d,J＝6.0Hz).
as can be seen from the view in figure 9,31P NMR(162MHz,CDCl3)33.31.
the mass spectrum results for the compound of formula (VII) above are: HRMS (ESI-Orbitrap) M/z: [ M + Na]+calcdforC25H21O2PNa 407.11714,found 407.11691.
The results of the above-mentioned nuclear magnetic H spectrum, nuclear magnetic C spectrum, nuclear magnetic P spectrum and mass spectrum were combined to confirm that the obtained substance was bis [ [1,1' -biphenyl ] -4-yl ] phosphinic acid methyl ester.
The bis [ [1,1' -biphenyl ] -4-yl ] phosphinic acid methyl ester can be used as a raw material of anti-AIDS drugs.
Example 4
A phosphate ester compound is bis (3-fluorophenyl) methyl phosphinate, and the phosphate ester compound has a molecular structure shown in a formula (V):
the preparation of the compound of the formula (V) was carried out in the same manner as in example 1 except that 71mg of diphenylphosphine oxide was replaced with 71mg of bis (3-fluorophenyl) phosphine oxide, 48mg of 3, 4-dimethoxyphenol was replaced with 48mg of methanol, and 2002mL of acetonitrile was replaced with polyethylene glycol to give 73mg of methyl bis (3-fluorophenyl) phosphinate as a pure product (colorless oily substance) in 91% yield; wherein the molar ratio of the bis (3-fluorophenyl) phosphine oxide to the methanol is 1: 5, the molar ratio of the bis (3-fluorophenyl) phosphine oxide to the chloroform is 1:1, bis (3-fluorophenyl) phosphine oxide to DBU molar ratio of 1: 1.5.
the nuclear magnetic results of the above compound of formula (VIII) are shown in FIG. 10,1H NMR(400MHz,CDCl3)7.65–7.53(m,2H),7.53–7.38(m,4H),7.22(t,J＝8.3Hz,2H),3.78(d,J＝9.8Hz,3H)。
as can be seen from the view in figure 11,13C NMR(101MHz,CDCl3)162.55(dd,J＝250.3,18.7Hz),133.17(dd,J＝138.2,5.6Hz),130.76(dd,J＝15.4,7.4Hz),127.40(dd,J＝9.5,3.2Hz),119.71(dd,J＝21.2,2.3Hz),118.50(dd,J＝22.3,10.8Hz),51.92(d,J＝5.9Hz).
as can be seen from the graph of figure 12,31P NMR(162MHz,CDCl3)29.86；19F NMR(376MHz,CDCl3)-110.88(d,J＝5.6Hz)。
the mass spectrum results for the compound of formula (VIII) above are: HRMS (ESI-Orbitrap) M/z: [ M + Na]+calcdforC13H11F2O2PNa 291.03569,found 291.03531.
The results of the nuclear magnetic H spectrum, the nuclear magnetic C spectrum, the nuclear magnetic P spectrum and the mass spectrum are combined, and the obtained substance is confirmed to be bis (3-fluorophenyl) phosphinic acid methyl ester.
The bis (3-fluorophenyl) phosphinic acid methyl ester can be used as a raw material of an antitumor medicament.
Example 5
The phosphate compound is bis (3)5-dimethoxyphenyl) methyl phosphinate, wherein the phosphate compound has a molecular structure shown as a formula (VI):
the preparation process of the compound of the formula (VI) was the same as in example 1, except that 96mg of diphenylphosphine oxide was replaced with bis (3, 5-dimethoxyphenyl) phosphine oxide, 48mg of 3, 4-dimethoxyphenol was replaced with methanol, and 2002mL of polyethylene glycol was replaced with acetonitrile to give 101mg of methyl bis (3, 5-dimethoxyphenyl) phosphinate as a pure product (colorless oily substance) in 96% yield; wherein the molar ratio of the bis (3, 5-dimethoxyphenyl) phosphine oxide to the methanol is 1: 5, the molar ratio of the bis (3, 5-dimethoxyphenyl) phosphine oxide to the chloroform is 1:1, bis (3, 5-dimethoxyphenyl) phosphine oxide to DBU molar ratio of 1: 1.5.
the nuclear magnetic results of the above compound of formula (IX) are shown in FIG. 13,1H NMR(400MHz,CDCl3)6.89(dd,J＝13.6,2.3Hz,4H),6.54(t,J＝2.3Hz,2H),3.75(s,12H),3.73(d,J＝11.2Hz,3H)；
as can be seen from the graph in figure 14,13C NMR(101MHz,CDCl3)160.79(d,J＝19.6Hz),132.52(d,J＝137.2Hz),109.00(d,J＝11.2Hz),104.49(d,J＝2.5Hz),55.43,51.60(d,J＝6.0Hz).
as can be seen from the view in figure 15,31P NMR(162MHz,CDCl3)33.46。
the mass spectrum of the compound of formula (IX) above gives: HRMS (ESI-Orbitrap) M/z: [ M + Na]+calcdforC17H21O6PNa 375.0968,found 375.09631.
The above-mentioned nuclear magnetic H spectrum, nuclear magnetic C spectrum, nuclear magnetic P spectrum and mass spectrum were combined to confirm that the obtained substance was bis (3, 5-dimethoxyphenyl) phosphinic acid methyl ester.
The bis (3, 5-dimethoxyphenyl) phosphinic acid methyl ester can be used as a raw material of antifungal medicines.
Example 6
A phosphate compound is di (naphthalene-1-yl) methyl phosphinate, and the phosphate compound has a molecular structure shown in a formula (VII):
the preparation process of the compound of the above formula (VII) was the same as in example 1 except that 91mg of bis (naphthalen-1-yl) phosphine oxide was substituted for diphenylphosphine oxide, 48mg of methanol was substituted for 3, 4-dimethoxyphenol, and 2002mL of polyethylene glycol was substituted for acetonitrile to give 90mg of pure bis (naphthalen-1-yl) phosphinic acid methyl ester (white solid) in 90mg of yield; wherein the molar ratio of bis (naphthalen-1-yl) phosphine oxide to methanol is 1: 5, bis (naphthalen-1-yl) phosphine oxide to chloroform molar ratio of 1:1, bis (naphthalen-1-yl) phosphine oxide to DBU molar ratio of 1: 1.5.
the nuclear magnetic results of the above compound of formula (VII) are shown in FIG. 16,1H NMR(400MHz,CDCl3)8.59(dd,J＝6.2,3.4Hz,2H),8.13(dd,J＝15.8,7.1Hz,2H),8.03(d,J＝8.2Hz,2H),7.88(dt,J＝5.4,2.3Hz,2H),7.57–7.44(m,6H),3.85(d,J＝11.3Hz,3H)。
as can be seen from the graph of figure 17,13C NMR(101MHz,CDCl3)134.12(d,J＝10.4Hz),133.70,133.58(d,J＝3.1Hz),132.97(d,J＝10.3Hz),128.86(d,J＝1.4Hz),127.47,127.36(d,J＝133.7Hz),126.46(d,J＝4.8Hz),126.34,124.63(d,J＝15.0Hz),51.69(d,J＝6.0Hz).
as can be seen from the graph in figure 18,31P NMR(162MHz,CDCl3)36.22。
the mass spectrum results for the compound of formula (VII) above are: HRMS (ESI-Orbitrap) M/z: [ M + Na]+calcdforC21H17O2PNa 355.08584,found 355.08545.
The above-mentioned nuclear magnetic H spectrum, nuclear magnetic C spectrum, nuclear magnetic P spectrum and mass spectrum were combined to confirm that the obtained substance was bis (naphthalen-1-yl) phosphinic acid methyl ester.
The bis (3, 5-dimethoxyphenyl) phosphinic acid methyl ester can be used as a raw material of anti-AIDS medicaments.
Example 7
A phosphate ester compound is (3S, 5S, 8R, 9S, 10S, 13R, 14S, 17R) -10, 13-dimethyl-17- ((R) -6-methylheptan-2-yl) hexadecane-1H-cyclopentyl [ a]Phenanthrene anthracene-3-diphenyl phosphinate ester has a molecular structure as shown in formula (VIII):
the preparation method of the compound of the formula (VIII) is the same as that in example 1, except that 583mg of dihydrocholesterol is replaced by 3, 4-dimethoxyphenol, and 2mL of tetrahydrofuran is replaced by acetonitrile to obtain 71mg of (3S, 5S, 8R, 9S, 10S, 13R, 14S, 17R) -10, 13-dimethyl-17- ((R) -6-methylheptan-2-yl) hexadecahydro-1H-cyclopenta [ a ] phenanthreneanthracene-3-diphenylphosphinate pure product (white solid), wherein the yield is 40%, and the yield of the prepared phosphate compound is generally low (about 30%) due to the fact that the solubility of dihydrocholesterol is much lower than that of other hydroxyl substituted organic compounds, and the yield of the invention is improved to a certain extent; wherein the molar ratio of diphenyl phosphine oxide to dihydrocholesterol is 1: 5, the molar ratio of diphenyl phosphine oxide to chloroform is 1: 1.5, the molar ratio of diphenyl phosphine oxide to DBU is 1: 2.
FIG. 19 shows the NMR results for compounds of formula (VIII):1H NMR(400MHz,CDCl3)7.86–7.75(m,4H),7.53–7.39(m,6H),4.32(ddt,J＝10.9,8.4,5.6Hz,1H),1.98–1.85(m,3H),1.84–1.39(m,10H),1.37–0.91(m,20H),0.91–0.83(m,11H),0.82(s,3H).
the results of FIG. 21 are:31P NMR(162MHz,CDCl3)29.87.
the results in FIG. 20 are:13C NMR(101MHz,CDCl3)133.25(d,J＝2.4Hz),131.90(d,J＝2.6Hz),131.62(dd,J＝10.1,6.0Hz),128.39(d,J＝13.0Hz),76.16(d,J＝6.3Hz),56.31(d,J＝13.9Hz),54.15,44.71,42.57,39.96,39.52,36.85,36.61(d,J＝3.5Hz),36.16,35.79,35.44,35.28,31.95,30.09(d,J＝3.8Hz),28.50,28.23,28.01,24.19,23.83,22.82,22.57,21.19,18.67,12.27,12.06.
the mass spectrum results for the compound of formula (VIII) above are: HRMS (ESI-Orbitrap) M/z: [ M + Na]+calcdforC39H57O2PNa 611.39814,found 611.39886.
The results of the nuclear magnetic H spectrum, the nuclear magnetic C spectrum, the nuclear magnetic P spectrum and the mass spectrum prove that the obtained substance is (3S, 5S, 8R, 9S, 10S, 13R, 14S, 17R) -10, 13-dimethyl-17- ((R) -6-methylheptan-2-yl) hexadecyl-1H-cyclopenta [ a ] phenanthrene anthracene-3-diphenyl phosphinic acid ester.
The (3S, 5S, 8R, 9S, 10S, 13R, 14S, 17R) -10, 13-dimethyl-17- ((R) -6-methylheptan-2-yl) hexadecane-1H-cyclopenta [ a ] phenanthrene anthracene-3-diphenyl phosphinate ester can be used as a raw material of anti-AIDS medicaments.
Example 8
A phosphate ester compound has a molecular structure shown as a formula (IX):
the compound of the formula (IX) described above was prepared in the same manner as in example 2 except that diphenylphosphine oxide was replaced with biphenylylphosphine oxide; chloroform was replaced with dibromomethane and DBU was replaced with sodium carbonate.
The compound of the formula (IX) described above can be used as a starting material for hormone drugs.
Example 9
A phosphate ester compound has a molecular structure shown in formula (X):
the compound of the above formula (X) can be prepared by the same procedure as in example 1 except that diphenylphosphine oxide is replaced with bis (4-fluorophenyl) phosphine oxide; chloroform is replaced by diiodomethane, DBU is replaced by triethylamine, and the molar ratio of bis (4-fluorophenyl) phosphine oxide to 3, 4-dimethoxyphenol is 1: 10, the molar ratio of bis (4-fluorophenyl) phosphine oxide to diiodomethane is 1: 1.5, the molar ratio of bis (4-fluorophenyl) phosphine oxide to triethylamine is 1: 3.
the compound of formula (X) can be used as a raw material for anti-AIDS drugs.
Example 10
A phosphate compound has a molecular structure represented by formula (XI):
the compound of the formula (XI) described above was prepared in the same manner as in example 1 except that diphenylphosphine oxide was replaced with [1,1' -biphenyl ] -4-yl (3, 5-dimethoxyphenyl) phosphine oxide; replacing 3, 4-dimethoxyphenol with methanol, chloroform with 1, 2-dibromoethane, DBU with potassium carbonate, and a molar ratio of [1,1' -biphenyl ] -4-yl (3, 5-dimethoxyphenyl) phosphine oxide to methanol of 1:1, [1,1' -biphenyl ] -4-yl (3, 5-dimethoxyphenyl) phosphine oxide to 1, 2-dibromoethane in a molar ratio of 1: 0.1, [1,1' -Biphenyl ] -4-yl (3, 5-dimethoxyphenyl) phosphine oxide to potassium carbonate molar ratio of 1: 0.5.
the compound of formula (XI) can be used as raw material of anti-AIDS medicine.
It should be understood that the above-described embodiments of the present invention are merely examples for clearly illustrating the present invention, and are not intended to limit the embodiments of the present invention. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. And are neither required nor exhaustive of all embodiments. Any modification, equivalent replacement, and improvement made within the spirit and principle of the present invention should be included in the protection scope of the claims of the present invention.
Claims (10)
1. A phosphate ester compound is characterized by having a molecular structure shown as a formula (I):
formula (I) wherein R1Is one of phenyl, biphenyl, fluorophenyl, dimethoxy substituted phenyl and naphthyl; r2Is one of phenyl, biphenyl, fluorophenyl, dimethoxy substituted phenyl and naphthyl; r3Is (3S, 5S, 8R, 9S, 10S, 13R, 14S, 17R) -10, 13-dimethyl-17- ((R) -6-methylheptan-2-yl) hexadecahydro-1H-cyclopentane [ a ]]One of phenanthrene-3-yl, dimethoxy substituted phenyl, 2, 3-dihydroxypropyl and methyl, wherein when R is3When it is methyl, R1And R2Is not phenyl.
2. The phosphate ester based compound according to claim 1, wherein R is1Is one of fluorophenyl, dimethoxy substituted phenyl and naphthyl; r2Is one of fluorophenyl, dimethoxy substituted phenyl and naphthyl; r3Is (3S, 5S, 8R, 9S, 10S, 13R, 14S, 17R) -10, 13-dimethyl-17- ((R) -6-methylheptan-2-yl) hexadecahydro-1H-cyclopentane [ a ]]Phenanthrene-3-yl, dimethoxy substituted phenyl and 2, 3-dihydroxypropyl.
3. The phosphate ester-based compound according to claim 1 or 2, wherein R is1Is one of 3-fluorophenyl, 3, 5-dimethoxy substituted phenyl and 1-naphthyl; r2Is one of 3-fluorophenyl, 3, 5-dimethoxy substituted phenyl and 1-naphthyl; r3Is (3S, 5S, 8R, 9S, 10S, 13R, 14S, 17R) -10, 13-dimethyl-17- ((R) -6-methylheptan-2-yl) hexadecahydro-1H-cyclopentane [ a ]]Phenanthrene-3-yl, 3, 4-dimethoxy substituted phenyl and 2, 3-dihydroxypropyl.
4. The phosphate ester compound according to claim 3, having a molecular structure represented by formula (II) to formula (VIII):
5. the method for producing a phosphate ester compound according to any one of claims 1 to 4, comprising the steps of:
dissolving a phosphine oxide compound and a hydroxyl substituted organic matter in a molar ratio of 1: 1-10 in an organic solvent, adding a halide and an alkali, reacting at 10-40 ℃ for 2-5 h, and performing nucleophilic substitution to generate a phosphate compound; the phosphine oxide compoundThe molar ratio of the compound to the halide is 1: 0.1 to 1.5; the molar ratio of phosphine oxide compound to base is 1: 0.5 to 3; the molecular structure of the phosphine oxide compound is
The molecular structure of the hydroxyl-substituted organic matter is R3-OH, wherein R1Is one of phenyl, biphenyl, fluorophenyl, dimethoxy substituted phenyl and naphthyl; r2Is one of phenyl, biphenyl, fluorophenyl, dimethoxy substituted phenyl and naphthyl; r3Is (3S, 5S, 8R, 9S, 10S, 13R, 14S, 17R) -10, 13-dimethyl-17- ((R) -6-methylheptan-2-yl) hexadecahydro-1H-cyclopentane [ a ]]One of phenanthrene-3-yl, dimethoxy substituted phenyl, 2, 3-dihydroxypropyl and methyl, wherein when R is3When it is methyl, R1And R2Is not phenyl.
6. The production method according to claim 5, wherein the molar ratio of the phosphine oxide compound to the hydroxyl-substituted organic compound is 1:1 to 5.
7. The production method according to claim 5, wherein the molar ratio of the phosphine oxide compound to the halide is 1:1 to 1.5.
8. The production method according to claim 5, wherein the molar ratio of the phosphine oxide compound to the base is 1: 1.5 to 2.
9. The method of claim 5, wherein the halide is one of carbon tetrachloride, chloroform, methylene bromide, methylene iodide, and 1, 2-dibromoethane.
10. The use of the phosphate compound of any one of claims 1 to 4 in the synthesis of a medicament.
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| CN112010896A (en) * | 2020-08-28 | 2020-12-01 | 湖南理工学院 | Novel method for preparing phosphonate by oxidative dehydrogenation coupling of copper-catalyzed diaryl phosphorus oxide and alcohol |
| WO2024046794A1 (en) * | 2022-09-02 | 2024-03-07 | Clariant International Ltd | Phosphinate flame retardant and process for manufacture thereof |
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| CN103980306A (en) * | 2014-04-28 | 2014-08-13 | 湖南大学 | Preparation method for hypophosphorous acid / phosphorous acid/ phosphate compounds by adopting P(O)-OH-contained compounds |
| CN110903316A (en) * | 2019-12-05 | 2020-03-24 | 中南大学 | Phosphonate compound and preparation method and application thereof |
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| CN103980306A (en) * | 2014-04-28 | 2014-08-13 | 湖南大学 | Preparation method for hypophosphorous acid / phosphorous acid/ phosphate compounds by adopting P(O)-OH-contained compounds |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN112010896A (en) * | 2020-08-28 | 2020-12-01 | 湖南理工学院 | Novel method for preparing phosphonate by oxidative dehydrogenation coupling of copper-catalyzed diaryl phosphorus oxide and alcohol |
| CN112010896B (en) * | 2020-08-28 | 2022-08-19 | 湖南理工学院 | Novel method for preparing phosphonate by oxidative dehydrogenation coupling of copper-catalyzed diaryl phosphorus oxide and alcohol |
| WO2024046794A1 (en) * | 2022-09-02 | 2024-03-07 | Clariant International Ltd | Phosphinate flame retardant and process for manufacture thereof |
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